Professional Documents
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Tropics - Infectious Diseases
Tropics - Infectious Diseases
PA R T
CLINICAL PRACTICE IN
THE TROPICS
A
SECTION
ORGAN-BASED CHAPTERS
1 Tropical Lung Diseases
Ilias C Papanikolaou, Om P Sharma
FIGURE 1.1 (A) World Health Organization algorithm for diagnosing pneumonia
in children (modified with permission from World Health Organization, Family and A Is tachypnoea present?
Community Health Cluster, Department of Child and Adolescent Health and
Development. Consultative meeting to review evidence and research priorities in
the management of acute respiratory infections (ARI). Meeting report. Geneva: Yes No
WHO; 2003:1–30.). (B) IMCI (Integrated Management of Childhood Illness)
guidelines for treating pneumonia (modified with permission from WHO/UNICEF. Yes
Integrated Management of Childhood Illness (IMCI) for high HIV settings. Geneva: Is wheeze present Is indrawing present?
WHO; 2009;11:2.) and does child have
history of wheeze?
No No
CLASSIFY
THEN ASK ABOUT MAIN SYMPTOMS:
Does the child have a cough or difficult breathing?
• No signs of Cough or cold • If wheezing (even if it disappeared after rapidly acting bronchodilator) give an inhaled
pneumonia bronchodilator for 5 days*
or very severe • Soothe the throat and relieve the cough with a safe remedy
disease • If coughing for more than 3 weeks or if having recurrent wheezing, refer for assessment
for TB or asthma
• Advise the mother when to return immediately
• Follow-up in 5 days if not improving
*in settings where inhaled bronchodilator is not available, oral salbutamol may be the second choice
6 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
TABLE 1-1 Incidence of Pneumonia Cases and Pneumonia Deaths Among Children Under 5 Years of Age, by UNICEF
Region, 2004*
A B
106 108
104 106
102 104
102
100
ºF ºF 100
98
98
96 96
94 94
92 92
1 2 3 4 5 6 7 8 9 2 3 4 5 6 7
Days Days
C D
106 108
104 106
102 104
102
100
ºF ºF 100
FIGURE 1.2 Various patterns of fever. 98
98
(A) In lobar pneumonia, fever subsides 96 96
by crisis within a week. (B) In
94 94
bronchopneumonia, fever comes down
slowly by lysis and takes longer. (C) In 92 92
tuberculosis, fever is remittent. (D) In 1 3 5 7 9 11 13 15 17 19 21 23 1 1 1 2 1 2 1 2 3 1 2 3 1 2
malaria, fever is typically intermittent. Days Days Quotidian Tertian Quartan
lung abscess and necrotizing pneumonia. The presence of Gram- When available, chest x-ray is extremely helpful (Table 1-2). Tubercu-
positive diplococci indicates pneumococcal pneumonia; small Gram- losis is omnipresent in the tropics; upper lobe lesions with or without
negative coccobacillary forms are typical of H. influenzae, and cavities strongly suggest tuberculosis.
staphylococcal organisms appear in tetrads and grapelike clusters. In
mycoplasma, viral and legionella pneumonia, typical bacterial organ- In children, the Integrated Management of Childhood Illness (IMCI)
isms are not seen. If sputum is not available, a specimen can be guidelines for treating pneumonia are recommended (see Fig. 1.1)
obtained by tracheobronchial suction. [8]. Nevertheless, a patient’s illness has to be assessed based on
geography, prevalence of potential etiologies, virulence of the organ-
A blood count usually reveals leukocytosis in bacterial pneumonia, ism, and the drug sensitivity pattern (Box 1.1). In some areas, particu-
leukopenia in viral infection, and eosinophilia in parasitic infestation. larly Papua New Guinea, South Africa and Spain, resistance of the
Tro p i c a l Lu ng Diseases 7
TABLE 1-2 Clinical Features of Typical and Atypical Common Community-Acquired Pneumonias
TABLE 1-3 Serum IgE Levels in Syndromes with Pulmonary Involvement and Eosinophilia
it is mild and occurs only on heavy exertion. With progression of and the glucose ≥60 mg/dL. A bloody effusion is caused by hemotho-
airway obstruction, patients become more short of breath and eventu- rax, trauma, malignancy and pulmonary embolism.
ally cannot breathe at rest. Physical examination in the early stage is
Exudative effusions typically have cell counts, protein and biochemi-
normal, but in advanced disease, prolonged expiration and expiratory
cal markers opposite to those of transudates. Exudates can be further
wheezes are audible. In severe cases, the thoracic cage becomes barrel-
classified into neutrophilic, lymphocytic and eosinophilic. Neu-
shaped with increased anterior–posterior diameter; percussion note is
trophilic exudates may be due to bacterial infection, gastrointestinal
hyperresonant. When chest x-ray and pulmonary function testing are
diseases, pulmonary embolism, collagen-vascular diseases (CVD) and
not available, a peak-flow meter is an inexpensive device to assess
asbestos-related benign effusion. Pleural effusion occurs in about
severity of airway obstruction and monitor the response to treatment.
50% cases of pneumonia, and can progress to a complicated effusion
Cessation of smoking is essential. Oral theophylline and beta-agonist (pleural fluid pH<7.2, positive Gram stain) or to an empyema, both
drugs control symptoms. Antibiotics (ampicillin, tetracycline and necessitating pleural fluid drainage with a chest tube thoracostomy in
sulfa drugs) are available to treat COPD exacerbations in the tropics. addition to antibiotic treatment. Empyema can occur in pneumococ-
cal, staphylococcal (most often) and Klebsiella infections. A right-sided
pleural effusion may be associated with amebic liver abscess.
PLEURAL EFFUSION The disease presenting with the highest pleural fluid lymphocytosis
Pleural effusion is a frequent condition with variable clinical signs is tuberculous pleuritis; however, early in the course, there can be a
and symptoms. Small effusions can remain silent and are often neutrophilic exudate. A large volume of pleural fluid should be
detected only on chest radiography. Large effusions are associated obtained for examination for acid-fast bacilli. In about one-third of
with dyspnea and diminished chest movements on the affected side. cases, the tuberculin skin test is negative initially and converts to posi-
Vocal fremitus is reduced; percussion note is stony dull; and ausculta- tive after 2–4 weeks. Knowledge of the HIV status of a patient with
tion reveals diminished breath sounds and decreased vocal resonance. pleural effusion, if positive, significantly inclines to a tuberculosis.
Sometimes, bronchial breathing is heard at the upper level of dull-
An eosinophilic exudate is more common in the tropics. Endemic
ness. In addition there may be a pleural friction sound.
parasitic and fungal infections are major causes of such an effusion.
If possible, all but the smallest effusions should be tapped. It should Ascariasis, echinococcosis and paragonimiasis are some of the causa-
be established whether the fluid is serous, bloody, pus or chylous. The tive parasitic infections. Paragonimiasis is associated with low pleural
effusion can be further divided into transudative and exudative, fluid glucose and low pH. Fungal diseases responsible for such an
according to pleural fluid characterization (Table 1-5). Laboratory effusion are histoplasmosis, cryptococcosis and coccidioidomycosis.
tests that can guide the management of a pleural effusion are macro-
scopic appearance (Table 1-6), pleural fluid cell counts, biochemistry, NONTUBERCULOUS
pH and Gram stain. A simple test is centrifugation of the fluid. If an
originally “milky” fluid clears with that process, it is presumably an GRANULOMATOUS LUNG DISEASE
empyema. If not, it is either a chylothorax (pleural fluid triglycerides In the absence of chest x-ray or biopsy evidence, it is not possible to
>110 mg/dL, e.g. lymphoma, post thoracic surgery) or a cholesterol diagnose pulmonary involvement due to sarcoidosis and other granu-
effusion (pleural fluid cholesterol >200 mg/dL). lomatous diseases. Consequently, in the tropics, these disorders
Transudative pleural effusions occur in heart failure, liver remain undiagnosed. The possibility of sarcoidosis should be consid-
disease, endomyocardial fibrosis, hypoproteinemia/malnutrition and ered in a patient with dyspnea, uveitis, hepatosplenomegaly, periph-
hypothyroidism. The pleural fluid white blood cell count is typically eral lymphadenopathy, chronic skin lesions, and a chest x-ray film
<10,000 cells/mm3, the pH >7.2, protein <3.0 g/L, the LDH <200 IU/L showing bilateral hilar adenopathy [18].
Podoconiosis is an endemic nonfilarial elephantiasis occurring in 9. Catchup Study Group. Clinical efficacy of co-trimoxazole versus amoxicillin
individuals exposed to red clay soil derived from alkaline rock. A twice daily for treatment of pneumonia: a randomised controlled clinical trial
chronic and debilitating disease, it exerts a large economic burden. in Pakistan. Arch Dis Child 2002;86:113–18.
The silica particles are found in the skin, lymph nodes and lymphatics 10. Shann F, Barker J, Poore P. Chloramphenicol alone versus chloramphenicol
of affected and unaffected individuals. These individuals have reduced plus penicillin for severe pneumonia in children. Lancet 1985;2:684–6.
11. Duke T, Poka H, Dale F, et al. Chloramphenicol versus benzylpenicillin and
lung function as compared with adults living in areas of low silica
gentamicin for the treatment of severe pneumonia in children in Papua New
concentration [19].
Guinea: a randomised trial. Lancet 2002;359:474–80.
12. Martin G. Approach to the patient with tropical pulmonary disease. In: Guer-
REFERENCES rant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases: Principles,
Pathogens and Practice. Philadelphia: Churchill Livingstone Elsevier; 2006:
1. Zumla A, James D. Immunological aspects of tropical lung disease. Clin Chest 1544–53.
Med 2002;23:283–308. 13. Carvalho CRR, Bethlem EP. Pulmonary complications of leptospirosis. Clin
2. UNICEF/WHO. Pneumonia: the forgotten killer of children. Geneva: UNICEF/ Chest Med 2002;23:469–78.
WHO; 2006. 14. Currie BJ, Fisher DA, Howard DM, et al. The epidemiology of melioidosis in
3. Vijayan V. Parasitic lung infections. Curr Opin Pulm Med 2009;15:274–82. Australia and Papua New Guinea. Acta Trop 2000;74:121–7.
4. Charoenratanakul S. Tropical infections and the lung. Arch Chest Dis 15. Kronman K, Truett A, Hale B, Crum-Cianfione N. Melioidosis after brief
1977;52:376–9. exposure: a serological survey in US Marines. Am J Trop Med Hyg 2009;
5. Steinoff M. Pulmonary disease. In: Strickland GT, ed. Hunter’s Tropical Medi- 80:182–4.
cine, 7th edn. Philadelphia: WB Saunders; 1991:1–7. 16. Magalhaes C, Vasconcelos P, Pereira M, et al. Kawasaki disease: a clinical
6. World Health Organization, Family and Community Health Cluster, Depart- and epidemiological study of 70 children in Brazil. Trop Doct 2009;39:
ment of Child and Adolescent Health and Development. Consultative 99–101.
meeting to review evidence and research priorities in the management 17. Luna C, Faure C. Common tropical pneumonias. In: Sharma OP, ed. Lung
of acute respiratory infections (ARI). Meeting report. Geneva: WHO; Biology in Health and Disease: Tropical Lung Disease, 2nd edn. New York:
2003:1–30. Taylor & Francis; 2006:211:117–42.
7. Metlay J, Schults R, Li Y, et al. Influence of age on symptoms and presentation 18. Mihailovic-Vucinic V, Sharma O. Tropical granulomas: diagnosis. In: Sharma
in patients with community acquired pneumonia. Arch Intern Med 1997;157: OP, ed. Lung Biology in Health and Disease: Tropical Lung Disease, 2nd edn.
112–24 New York: Taylor & Francis; 2006:211:173–93.
8. WHO/UNICEF. Integrated Management of Childhood Illness (IMCI) for high 19. Morrison C, Davey G. Assessment of respiratory function in patients with
HIV settings. Geneva: WHO; 2009;11:2. podoconiosis. Trans R Soc Trop Med Hyg 2009;103:315–17.
2 Cardiovascular Diseases
Bongani M Mayosi, John Lawrenson
HEART FAILURE
Key features Heart failure is a clinical syndrome of effort intolerance secondary to
a cardiac abnormality with altered neurohumoral adaptation, leading
● The pattern of cardiovascular disease is changing in tropical to salt and water retention. Heart failure is the dominant form of
cardiovascular disease in many tropical and subtropical regions of the
countries. Although infectious diseases still dominate,
world. The epidemiology of heart failure in the tropics differs from
increasing urbanization is producing a new pattern of that in industrialized countries in several respects [1]. First, heart
disease that includes hypertension, stroke, diabetes mellitus failure in the tropics is due largely to nonischemic causes. Second, the
and ischemic heart disease common causes of heart failure in the tropics (Table 2-1) present for
● While ischemic heart disease is increasing, it remains rare in the most part in children and young adults before middle-age. Finally,
rural areas of Africa, India and South America infections remain a significant cause of heart failure. Pulmonary
hypertension due to lung disease and schistosomiasis, together with
● Rheumatic heart disease, tuberculous pericarditis, Chagas tuberculous pericarditis, accounts for at least 10% of cases of heart
disease and cardiomyopathies are major contributors to failure. The burden of tuberculous pericarditis and cardiomyopathy
cardiovascular disease in many lower-income countries has increased in regions where HIV/AIDS has reached epidemic pro-
● Rheumatic heart disease still disables young patients and is portions. Chagasic heart disease due to Trypanosoma cruzi infection
the largest contributor to the cases of heart failure in continues to exact a heavy toll on people living in Latin America [2].
children and young adults In contrast to industrialized nations, where degenerative valvular
● Peripartum cardiomyopathy is highly prevalent in parts of heart disease predominates, valvular disease in the tropics is almost
Africa; endomyocardial fibrosis is confined to the peri- always the result of infection. Valvular disease in developed nations
is an insidious disease of the elderly, who frequently have comorbidi-
equatorial tropical regions of Africa, America and Asia
ties. In developing countries, valvular disease (with a rapid course) is
● Chagas disease is a major cause of disability secondary to encountered in the young.
tropical diseases in young adults in Latin American
The epidemiology of nonrheumatic valvular disease in the tropics is
countries
poorly defined. Myxomatous mitral valve disease associated with
● HIV infection is associated with a shortening in life mitral valve prolapse is an uncommon indication for mitral valve
expectancy, a reduction in body mass index, and a fall in surgery compared with rheumatic valve disease. Congenital subvalvu-
systolic blood pressure. There is also an increased incidence lar aneurysms below the mitral and aortic valves are rare forms of
of inflammatory cardiovascular disorders, resulting in valvular heart disease that were first described in Africa. These con-
cardiomyopathy, tuberculous pericarditis, pulmonary genital subvalvular aneurysms can be associated with varying degrees
of valve regurgitation, can rupture or compress the coronary arteries,
hypertension, stroke and vasculopathy, in HIV-infected or can predispose to infective endocarditis or thrombus with systemic
people. Antiretroviral treatments can be associated with embolization.
insulin resistance, dyslipidemia and lipodystrophy
The major clinical aspects of infective endocarditis in the tropics are
● Lack of access to resources leads to an excess of early reminiscent of the experience in industrialized countries before the
deaths from congenital heart disease and the late antibiotic era. Infective endocarditis is a disease of the young with
presentation of survivors high morbidity and mortality. Underlying rheumatic heart disease is
the major predisposing factor [3].
STROKE
The World Health Organization (WHO) defines stroke as rapidly
developing clinical signs of focal (or global) disturbance of cerebral
COMMON SYNDROMES OF function, with symptoms lasting 24 hours or longer or leading to
CARDIOVASCULAR DISEASE death, with no apparent cause other than vascular origin. The age-
standardized mortality, case fatality and prevalence of disabling stroke
IN THE TROPICS in the tropics are similar to or higher than those measured in most
The principal syndromes of acquired cardiovascular disease are heart industrialized countries. In the tropics, stroke incidence is higher in
failure, stroke and vascular disorders. The causes of these clinical people less than 65 years of age, and there is a greater proportion of
syndromes are summarized in Tables 2-1 to 2-3. hemorrhagic (30% vs 15%) compared to ischemic stroke than in
industrialized countries. In the tropics, more than 90% of patients
Congenital heart disease is discussed at the end of the chapter. with hemorrhagic stroke and more than half with ischemic stroke are
12
Ca rd i ova s c u l ar Diseases 13
Intracardiac causes
Endocardial diseases Valvular endocardium or annular defect ● Acute rheumatic fever
● Rheumatic heart disease, infective endocarditis
● Congenital submitral or subaortic aneurysm
Mural endocardium ● Endomyocardial fibrosis
Myocardial diseases Acute ● Acute rheumatic fever
● Septic myocarditis
● Diphtheria
● Coxsackie B infection
● Acute Chagas disease
Chronic ● Dilated cardiomyopathy
● Peripartum cardiomyopathy
● HIV-associated cardiomyopathy
● Chronic Chagas disease
● Ischemic heart disease
Nutritional ● Thiamine deficiency (beri-beri)
● Selenium deficiency (Keshan disease)
Pericardial diseases Acute ● Acute bacterial pericarditis with or without HIV infection
● Acute rheumatic fever
Chronic ● Tuberculous pericardial effusion or effusive constrictive
pericarditis
● Constrictive pericarditis
Extracardiac causes
Increased peripheral ● Hypertension ● Essential hypertension
resistance ● Secondary to Takayasu arteritis, chronic
glomerulonephritis
Increased pulmonary ● Cor pulmonale ● Destructive hypoxic lung disease
vascular resistance ● HIV-associated pulmonary hypertension
● Schistosomal pulmonary arteriolitis
Conditions causing ● Anemia
high cardiac output ● Thiamine deficiency (beri-beri)
● Thyrotoxicosis
● Post-traumatic arteriovenous fistula
hypertensive. While hypertension is the single most important factor disease may present with angina, cerebral ischemic symptoms, absent
for stroke, non-hypertensive causes explain nearly half of cases of pulses, and hypertension – a common presentation in children [6].
ischemic stroke. These factors include structural heart disease, cardiac
arrhythmia, HIV/AIDS and other infections (Table 2-2) [4]. Atherosclerotic disease of the medium-sized vessels presents with a
number of clinical syndromes including cardiac pain and coronary
Infection with HIV is associated with an increased risk of stroke. HIV- thrombosis, intermittent claudication and gangrene of the legs, and
associated stroke occurs in younger patients and is due to an ischemic mesenteric artery occlusion. These ischemic syndromes are particu-
mechanism in the majority of cases. In tropical countries, treatable larly common in people of Asian, Melanesian and Polynesian origin
infections account for the majority of causes, with extracranial and (who also have a high incidence of diabetes mellitus). Angina in the
intracranial vasculopathy contributing to 20% of cases [5]. tropical environment may also be due to valvular heart disease, hyper-
trophic cardiomyopathy, dysrhythmias, syphilitic arteritis or anemia.
VASCULAR DISORDERS Hemoglobin disorders (such as sickle cell disease) contribute to the
The range of arterial and venous syndromes includes diseases of the cardiovascular disease burden either by exacerbating existing cardiac
aorta, atherosclerotic diseases of medium-sized arteries, and unusual disease with anemia, or by causing peripheral vascular occlusion or
vascular disorders of the tropics (Table 2-3). pulmonary hypertension.
Atheroma and dissection of the aorta is present in communities with Idiopathic gangrene of the extremities, gangrene associated with trop-
an accumulation of risk factors, including hypertension. Similarly, ical phlebitis, and gangrene associated with acquired hemolytic
atheroma and aortic aneurysm is becoming more common in people anemia are unusual vascular disorders encountered in Africa. Idio-
living in tropical environments as their cardiovascular risk profile pathic gangrene of the extremities presents mainly in infants and
worsens. By contrast, aortitis resulting from syphilis is less common children with bilateral symmetrical gangrene. No cause is found,
due to the early use of penicillin. Idiopathic tropical aortitis or although infection with Salmonella typhi, S. paratyphi and Neisseria
Takayasu’s disease is found in sub-Saharan Africa and Asia. The clinical meningitidis has been incriminated. Predisposing factors are dehydra-
manifestations depend on the stage and anatomy of the disease. The tion and malnutrition. The onset of the illness is acute, with fever,
14 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
TABLE 2-3 Vascular Disorders that are Encountered DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
in the Tropics
Heart Failure
Pathology Clinical syndrome The differential diagnosis of heart failure is listed in Table 2-1. The
diagnosis of cardiomyopathy is made by clinically excluding other
Diseases of the aorta ● Aortic dissection causes of heart failure such as hypertension and valvular disease.
● Aortic aneurysm Patients with hypertensive heart disease and severe systolic dysfunc-
● Syphilitic aortitis
tion may present initially with blood pressure in the normal range,
● Idiopathic tropical aortitis/
with hypertension declaring itself after a period of treatment; their
Takayasu aortitis
presenting blood pressure is low because of markedly reduced cardiac
Atherosclerosis of ● Cardiac pain and coronary output. It may be difficult to distinguish hypertensive heart failure
medium-sized arteries thrombosis from idiopathic dilated cardiomyopathy, because the latter is accom-
(other than vertebrobasilar ● Intermittent claudication panied by blood pressure readings in the hypertensive range in up to
insufficiency and cerebral and gangrene of the leg 8% of cases. This difficulty is compounded by the fact that the end-
thrombosis resulting in ● Mesenteric artery occlusion organ effects of hypertension, such as renal involvement and aortic
stroke) causing intestinal angina dilatation, may not be apparent clinically.
and infarction of the gut
It is essential to exclude reversible forms of nutritional heart muscle
Unusual vascular disorders ● Idiopathic gangrene of the disease such as beriberi (thiamine deficiency). The diagnosis of beri
of the tropics extremities beri should be considered when heart failure occurs in an alcoholic
● Gangrene associated with or in an impoverished person or child living in an area where pol-
tropical phlebitis ished rice forms the major part of the diet. In beriberi, neurologic
● Gangrene associated with symptoms such as paresthesiae and weakness of peripheral neuropa-
acquired hemolytic anemia thy and Wernicke’s encephalopathy are occasionally present. The
definitive diagnosis is made by demonstrating diminished erythrocyte
transketolase activity, which increases after the addition of thiamine
malaise and petechial rash associated with symmetrical gangrene pyrophosphate. In areas where this testing is not available, a short
affecting the digits. course of thiamine supplementation in all patients with heart failure
may be beneficial. A rapid response to therapy, with a decrease in
Gangrene of the limbs, associated with tropical phlebitis, is thought cardiac size clinically and on x-ray seen within 2 weeks, will occur in
to be part of the same spectrum of disease as the peripheral gangrene the patient who is thiamine-deficient.
syndrome. The veins are inflamed and later thrombosed and occluded.
An adjoining artery may be affected. The cavernous sinus, internal The forms of cardiomyopathy that are unique to people living
jugular vein or limb veins may be affected [7]. in tropical environments include peripartum cardiomyopathy,
Ca rd i ova s c u l ar Diseases 15
LV
LA
screen in young patients with unexplained stroke. Lumbar puncture There are few studies comparing the outcome of patients with heart
is indicated in suspected subarachnoid hemorrhage or meningitis failure and vascular disorders in the tropics versus nontropical regions.
as well as in those patients with an ischemic stroke who are By contrast, a systematic analysis of stroke studies has shown several
HIV-positive. differences in relation to outcome in the tropics compared to the rest
of the world. The available case fatality data from hospital-based
Vascular Disorders prospective studies reveal a rate of about 30% at 1 month – a value
much higher than the 20% reported for older populations in the rest
The clinical diagnosis of aortic and medium-sized vessel arterial of the world. The prevalence of disabling stroke in sub-Saharan Africa
disease should be confirmed using angiography if possible. In athero- is at least as high as in high-income areas.
sclerotic disease of the aorta and medium-sized arteries, the etiology
is related to cardiovascular risk factors which require specific testing
and control. In aortitis, the etiologic diagnosis is between syphilis and PEDIATRIC CONSIDERATION:
idiopathic aortitis. When there is doubt about the diagnosis, a biopsy
of the artery may be necessary.
CONGENITAL HEART DISEASE
Congenital heart disease refers to malformations of heart structure
MANAGEMENT AND OUTCOMES existing at birth (WHO). It is the most common congenital abnormal-
ity occurring in isolation or in combination with other genetic abnor-
The principles of management of patients with heart failure, stroke malities. Whereas, as a result of access to surgery, survival into
and vascular disease are the same in the tropics as elsewhere in the adulthood is the norm for more than 90% of patients born with
world. There is, however, a need for empiric treatment in certain congenital heart disease in industrialized nations, opportunities for
instances before a definitive diagnosis is reached. For example, in surgical correction of defects are rare in developing nations. In many
patients presenting with a large pericardial effusion from a commu- developing countries, the commencement and sustainability of surgi-
nity where tuberculosis is endemic, it is appropriate to commence cal programs must be balanced against the need to control infectious
antituberculosis treatment if pericardiocentesis is not possible or disease and diseases related to poverty.
before microbiology results become available.
In patients with valvular disease and heart failure due to rheumatic CLINICAL PRESENTATION
heart disease (Fig. 2.3), ongoing penicillin prophylaxis (past the The cause of a congenital heart lesion in most cases is unknown.
age of 35 years) is recommended even if surgery is not undertaken Exposure to teratogens and genetic syndromes account for a relatively
[10]. small proportion of the total number of defects.
An approach to classification is shown in Figure 2.4.
Approximately 40% of all patients born with congenital heart disease
will need surgery in the first years of life to survive. The introduction
of a surgical program needs to coincide with major improvements in
the under-5-year mortality in a country – a level of less than 30/1000
would appear to be the threshold value. Relatively few developing
countries have established surgical programs which meet or partly
meet the needs of the population in this regard.
The attrition of complex patients in early life therefore will mean that
the practitioner is likely to encounter adults with moderate left-to-
right shunts, uncomplicated valvular heart disease, and obstructive
pulmonary vascular disease. In areas with a high prevalence of rheu-
matic heart disease, congenital heart disease is likely to be confused
with valvular heart disease.
A heart lesion should be suspected in any patient with a recognizable
genetic abnormality. The practitioner caring for the patient with
A
Down syndrome or Marfan syndrome should be aware that cardiac
disease is an integral part of the disorder.
As would be expected, the adult population with congenital heart
disease is dominated by atrial septal defect, small ventricular septal
defects, and mild to moderate aortic and pulmonary stenosis. The
majority of patients seen are symptomatic, with dyspnea and palpita-
tions being the commonest presenting complaints.
Table 2-4 compares the physical signs, ECG and chest x-ray findings
in patients presenting in adulthood with the more common congeni-
tal heart lesions.
The final diagnosis will be confirmed by echocardiography; fortu-
nately, the cost of quality echocardiographic machines has declined
with time.
In patients with underlying congenital heart disease, comorbid
conditions common in tropical climates can be present. For example,
sickle cell disease is associated with significant risk of pulmonary
B
hypertension.
FIGURE 2.3 An echocardiogram of rheumatic mitral regurgitation showing Diuretics and digoxin are used to obtain symptomatic relief in
a dilated left atrium, thickening and deformation of the anterior and patients with large left-to-right shunts. This practice is not based on
posterior mitral valve leaflets (A), and the mosaic pattern of severe mitral evidence from controlled trials but is an extension from the practice
regurgitation extending to the back of the left atrium (B). in patients with heart failure.
Ca rd i ova s c u l ar Diseases 17
TABLE 2-4 Comparison of Physical Signs and Investigative Findings in Patients Presenting in Adulthood with the More
Common Congenital Heart Lesions
The relief of symptoms, however, will only be achieved with surgical 3. Nkomo VT. Epidemiology and prevention of valvular heart diseases and infec-
repair. Access to surgery varies markedly. Many countries rely on tive endocarditis in Africa. Heart 2007;93:1510–19.
charity; well-organized humanitarian missions (such as those 4. Mensah GA. Epidemiology of stroke and high blood pressure in Africa. Heart
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tive than movement of patients to high-income countries. Some
1320–4.
countries, such as Guatemala, have growing programs which aim to
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serve as training hubs for a region. Other countries, such as Brazil,
ogy. New York: Springer-Verlag; 1992.
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surgery. In: Principles of Medicine in Africa, 3rd edn. Cambridge, UK: Cambridge
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3 Gastrointestinal Diseases
Ramnik J Xavier, Harry J Thomas
Complications
elicited concern the assessment of hydration (Box 3.2); the patient The leading cause of death in patients with acute diarrhea is dehydra-
should be weighed at first presentation, as weight gain or loss can be tion, which requires prompt fluid and electrolyte replacement. The
a valuable guide to the effectiveness of rehydration. nutritional state of children often deteriorates because of anorexia,
nutrient malabsorption, and the practice of not feeding children who
The rapid onset of nausea, vomiting and diarrhea after food consump- have diarrhea. Hypolactasia is a sequela of many gut infections and
tion is most often due to the ingestion of a preformed toxin produced may cause persistent diarrhea. Dysentery can be associated with severe
by Staphylococcus aureus, Bacillus cereus or Clostridium perfringens. local complications such as hemorrhage, toxic megacolon and bowel
20 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
potential adverse effects of antibiotics and the risk of antibiotic is underlying portal hypertension (indicated by a serum–ascites
resistance. albumin gradient of 1.1 g/dL or greater). Cirrhosis and tuberculous
peritonitis are among the most common causes. Chronic hepatic
In people who develop traveler’s diarrhea, antibiotic therapy reduces schistosomiasis is a common cause of ascites in endemic areas. Malig-
the duration of symptoms, even in those in whom a pathogen cannot nancy can cause ascites through a number of mechanisms; while
be identified. As the prevalence of fluoroquinolone-resistant Campy- ascitic fluid cytology may be positive in peritoneal carcinomatosis, it
lobacter spp. is increasing, azithromycin is emerging as an effective will be negative if the ascites is due to portal hypertension from
alternative in the treatment of traveler’s diarrhea. Rifaximin is another massive liver metastases. In chylous ascites, the ascitic fluid appears
option, though it is not recommended in patients with invasive cloudy due to the high levels of triglycerides; the most common
disease. In addition to a short course of antibiotic therapy, patients causes in developing countries are infections leading to lymphatic
should be advised regarding hydration and diet, and those without obstruction, such as tuberculosis and filariasis. Cardiac ascites may
evidence of invasive disease may benefit from an antimotility agent. result from tricuspid regurgitation, constrictive pericarditis, or any
cause of right-sided heart failure. Spontaneous bacterial peritonitis
ABDOMINAL PAIN may complicate ascites due to cirrhosis; however, it is very rare in
non-cirrhotic ascites, as these patients have a higher concentration of
Upper abdominal pain is commonly due to peptic ulcer disease, and
ascitic fluid opsonins. The classic presentation is with fever and
worsening of the symptoms may herald a complication such as per-
abdominal pain and tenderness, but it may be asymptomatic or
foration or penetration. The differential diagnosis of upper abdomi-
present with encephalopathy or renal failure.
nal symptoms with ulceration in the stomach or duodenum includes
infections (e.g. tuberculosis, Mycobacterium avium intracellulare, A massive ovarian cyst can present with abdominal distension, but
cytomegalovirus, herpes simplex virus), neoplasms (either primary the central location of the swelling, presence of a fluid thrill, and
tumor or metastatic disease) and infiltrative diseases. Acute pancrea- absence of shifting dullness help to distinguish this from ascites.
titis is another cause of acute upper abdominal pain; gallstones and
alcohol are the most common causes worldwide, though infectious Abdominal distension may be due to gas, either within or outside
etiologies are important in the immunocompromised. Chronic pan- the bowel lumen. Extraluminal gas is seen in bowel perforation,
creatitis is characterized by abdominal pain, steatorrhea and diabetes which is a surgical emergency. Gaseous distension of the bowel may
mellitus. Alcohol abuse accounts for the majority of cases worldwide; be due to mechanical obstruction or motility disorder. Bloating is a
however, in several parts of the tropics, the most common cause of common symptom in lactose malabsorption, which is commonplace
chronic pancreatitis is tropical calcific pancreatitis, a condition of among Africans and Asians after childhood, and in irritable bowel
unknown etiology that commonly affects children. Pancreatic calcifi- syndrome.
cations may be seen on plain film of the abdomen, and ductal dilata-
tion may be evident on ultrasonography or computed tomography. INTESTINAL OBSTRUCTION
Right upper quadrant pain may be seen in biliary colic, acute chole- The cardinal features are colicky abdominal pain, vomiting, constipa-
cystitis, acute cholangitis, acute hepatitis, and liver abscess (see hepa- tion and abdominal distension. A bolus of worms can cause intra
tobiliary chapter). Left upper quadrant pain may be caused by luminal obstruction in children with heavy Ascaris lumbricoides
disorders of the spleen such as splenomegaly or splenic abscess or infestation; it may also serve as a lead point for intussusception and
infarction. In evaluating the patient with upper abdominal pain, it is volvulus. Colorectal carcinoma is increasingly recognized in the
important to consider supradiaphragmatic causes such as pneumonia tropics, but may not be evident until presentation with obstruction
and myocardial infarction. of the large bowel. The differential diagnosis includes inflammatory
masses that can lead to intramural obstruction, such as: ileocecal
A number of parasitic worms may cause nonspecific gastrointestinal tuberculosis, histoplasmosis, actinomycosis, amebiasis, schistosomia-
symptoms including epigastric pain. In addition, parasitic infections sis and angiostrongyliasis. Extramural obstruction is most commonly
of the biliary tract may lead to acute pancreatitis, as exemplified by due to incarcerated hernia. Umbilical hernias are more common in
adult Ascaris lumbricoides worms, which can migrate from the jejunum African children, but usually the defects close spontaneously. Symp-
and invade the papilla, obstructing the pancreatic and bile ducts. toms and signs of small bowel obstruction may also be seen in para-
lytic ileus, in which there is bowel dilatation without mechanical
Right lower quadrant pain is commonly due to acute appendicitis;
obstruction. This is a common complication of abdominal surgery,
not uncommonly, however, infection with Yersinia or Campylobacter
but may also occur in peritonitis or after trauma. Plain film or com-
can cause severe pain that is misdiagnosed as appendicitis. In females
puted tomography of the abdomen in paralytic ileus shows gas in the
with acute lower abdominal pain, it is important to consider ectopic
colon and rectum, helping to differentiate it from small bowel
pregnancy, pelvic inflammatory disease, and adnexal pathologies.
obstruction in which the colon is decompressed. Treatment is sup-
Colicky abdominal pain is one of the cardinal features of bowel portive, consisting of fluid resuscitation, correction of electrolyte
obstruction. It may also be seen in intussusception in children. Gen- abnormalities (especially hypokalemia) and discontinuation of anti
eralized abdominal pain and tenderness may be caused by peritonitis, kinetic drugs. Another motility disorder that may be misdiagnosed as
which can occur as a result of perforated peptic ulcer, ileal perforation mechanical obstruction is chronic intestinal pseudo-obstruction,
in typhoid fever, colonic perforation in amebic colitis, or rupture of which may occur in Chagas disease [10]. Here, gross dilation of the
a hydatid cyst. Severe abdominal pain with minimal or no tenderness colon (megacolon), most commonly involving the sigmoid colon,
is seen in acute mesenteric ischemia. In addition to considering such causes constipation; it may be complicated by toxic megacolon or
surgical emergencies, it is important to consider “medical” causes of volvulus.
abdominal pain. Patients with sickle cell disease may have acute
painful episodes due to vaso-occlusion that is difficult to distinguish
from other causes of an acute abdomen. Abdominal pain is a common
GASTROINTESTINAL BLEEDING
symptom in several infectious diseases, most notably malaria. Upper gastrointestinal bleeding, defined as bleeding emanating from
a source proximal to the ligament of Treitz, presents with hematem-
esis and/or melena. It is most commonly due to bleeding peptic ulcer.
ABDOMINAL DISTENSION In areas with a high prevalence of cirrhosis, bleeding from esophageal
Patients with ascites may complain of abdominal pain, early satiety and gastric varices is common. Mallory–Weiss tears are mucosal lac-
or dyspnea due to splinting of the diaphragm. Analysis of ascitic fluid erations at the gastroesophageal junction that are most commonly
is helpful in determining the cause of ascites: (1) to determine associated with repeated retching. Gastric and duodenal neoplasms
whether the fluid is infected (spontaneous bacterial peritonitis is can present with overt gastrointestinal bleeding, though occult blood
defined as a polymorphonuclear leukocyte count over 250 cells/mL loss is more common. Unusual causes of upper gastrointestinal bleed-
with a positive bacterial culture); and (2) to determine whether there ing include vascular abnormalities.
22 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Hematochezia is most often due to colorectal sources but may be the deformity. It is thought to occur after fecal–oral transmission in young
first sign of a brisk upper gastrointestinal hemorrhage. Patients with children who are at risk due to a complex interplay between infection,
infectious colitis present with bleeding in association with diarrhea, malnutrition and immunocompromise – a combination that is
abdominal pain and systemic upset. Gastrointestinal bleeding is a common in impoverished areas of Africa, Asia and Latin America. The
common complication of typhoid fever. Many causes of lower gas- acute stage may present with unilateral facial pain and swelling, hali-
trointestinal bleeding that are common in the West – colonic diver- tosis, oral discharge and systemic upset; management consists of
ticular bleeding, ischemic colitis, colorectal cancer and hemorrhoids broad-spectrum antibiotics and local wound care together with treat-
– are unusual in the tropics due to epidemiologic differences. Lym- ment of associated diseases and nutritional deficiencies. However,
phoma and Kaposi sarcoma may affect any part of the gastrointestinal most patients are not brought to medical attention until the infection
tract and are common causes of gastrointestinal bleeding in patients is well established – characterized by a necrotic center with a well-
with AIDS. demarcated perimeter – at which time reconstructive surgery is
required.
The initial management of patients with acute gastrointestinal bleed-
ing consists of fluid resuscitation and, if coagulopathy or thrombocy-
topenia is present, transfusion of blood products. Once patients are ESOPHAGUS
stabilized, endoscopy should be performed in order to diagnose and
treat the source of bleeding. Cirrhotic patients with upper gastroin- Esophagitis
testinal bleeding are at risk for bacterial infections including sponta- The main presenting features are odynophagia, dysphagia and retro
neous bacterial peritonitis; broad-spectrum antibiotics may reduce sternal chest pain. While noninfectious conditions such as gastro-
this risk. esophageal reflux disease and pill esophagitis are the most common
causes in immunocompetent hosts, infections of the esophagus are
common in the immunocompromised. In patients with HIV infec-
ANATOMIC DIFFERENTIALS tion, the most common cause is esophageal candidiasis. While the
presence of oropharyngeal candidiasis can be a clue to esophageal
MOUTH infection, its absence does not rule it out. Diagnosis can be made by
endoscopy, which reveals white plaques on the esophageal mucosa;
Dental Caries biopsy reveals the presence of budding yeasts. An alternative strategy
Dental caries is a chronic disease in which the composition of the is to undertake a therapeutic trial of a systemic antifungal agent; if the
oral flora is altered as a result of chronic consumption of high-sugar symptoms do not resolve within days, then further investigation is
substances. This leads to demineralization of the enamel, eventually warranted. Cytomegalovirus esophagitis causes similar symptoms, but
causing a dental cavity. Dental caries is a major oral health problem endoscopy reveals ulcerative lesions. Ulcers are also seen in herpes
worldwide, and the incidence is increasing in developing countries as simplex virus esophagitis, but they tend to have heaped-up borders as
people engage in Western dietary practices [11]. Three factors are opposed to the more shallow lesions of cytomegalovirus; there may or
important in the prevention of caries: dietary counseling, oral hygiene, may not be associated oropharyngeal lesions. It is important to note
and fluoride supplementation. that a number of patients with HIV infection presenting with esophag-
itis may have simultaneous infection with more than one agent,
whereas others will have no infection identified. The latter condition,
Oral Cancer named idiopathic esophageal ulcer, may respond to steroids.
Oral cancer should be suspected in any patient with a nonhealing
ulcer or mass in the mouth. As with all squamous cell carcinomas of
the head and neck, the major risk factors are tobacco and alcohol use.
Caustic Esophageal Injury
Additional risk factors include viral infection (Epstein-Barr virus, Caustic injuries to the esophagus may result from ingestion of acid
which is strongly associated with nasopharyngeal carcinoma, human or alkali. The main complaint is pain, and there may be signs of
papillomavirus and HIV) and betel-nut chewing, which is widespread complications such as perforation, mediastinitis or peritonitis.
in South and Southeast Asia. Attempts at inducing emesis or neutralizing the ingested substance
must be avoided, lest the injury be aggravated. Endoscopy may be
helpful for risk stratification and guiding further management. Late
Candidiasis complications include esophageal strictures, which cause dysphagia
Oral infection with Candida (“thrush”) is usually characterized by and necessitate dilation, and squamous cell carcinoma.
white plaques on the oral mucosa, though there is also an atrophic
form that presents as erythema without plaques. It is a common
finding in patients with HIV infection; other risk factors include treat-
Esophageal Varices
ment with antibiotics or steroids (both oral and inhaled). Treatment Esophageal varices are relatively common in the tropics. The causes
consists of a topical antifungal agent or, in patients with more severe of portal hypertension can be classified as pre-hepatic, hepatic and
disease, systemic therapy. post-hepatic. Pre-hepatic causes include the tropical splenomegaly
syndrome and portal or splenic vein thrombosis. Hepatic causes
may be classified as pre-sinusoidal, sinusoidal and post-sinusoidal,
Herpes Simplex Virus Infection exemplified by schistosomiasis, cirrhosis and veno-occlusive disease,
Primary infection of the oral cavity with herpes simplex virus causes respectively. Budd–Chiari syndrome and cardiac causes (restrictive
gingivostomatitis and pharyngitis. The lesions can be vesicular or cardiomyopathy, congestive heart failure) are post-hepatic causes.
ulcerative and may be associated with fever and cervical lymphaden- Variceal bleeding carries a high mortality rate worldwide. Initial man-
opathy. Reactivation of the virus leads to vesicular lesions of the oral agement consists of restoration of the circulating volume, with caution
mucosa (“cold sores”). Treatment should be directed toward provid- to avoid over-transfusion, the use of agents to reduce portal pressure
ing symptomatic relief; antiviral therapy may be helpful if primary (e.g. terlipressin or octreotide), and antibiotic prophylaxis. After sta-
infection is detected early or for patients with recurrent infection who bilization, endoscopic variceal ligation is the ideal approach. For
can identify a characteristic precipitating factor or prodrome. patients with refractory bleeding, balloon tamponade can be a tem-
porizing measure while awaiting portosystemic shunting.
Cancrum Oris (Noma)
This is a gangrenous, polymicrobial infection affecting the orofacial Megaesophagus
tissues [12]. It starts as a gingival ulceration, which, if left untreated, Marked dilation of the esophagus is the most common gastrointesti-
spreads rapidly through the soft and hard tissues of the mouth and nal manifestation of chronic Chagas disease and occurs due to a loss
face, breaching normal anatomic barriers and resulting in gross of neurons in the enteric nervous system. Dysphagia is the most
G a s t ro i nte s t i n al Diseases 23
prominent symptom, but patients may also complain of odynophagia Gastric Neoplasms
and regurgitation; aspiration is a common complication. The condi-
tion cannot be reversed by antitrypanosomal agents, but symptomatic Gastric cancer is the second most common cause of death from cancer
relief can be achieved through balloon dilations of the lower esopha- worldwide. Uncommon in developed countries, the incidence is
geal sphincter or through surgery. highest in East Asia and parts of South America. Part of the geographic
variation may be due to dietary factors and prevalence of H. pylori.
The most common presenting symptoms are weight loss and abdomi-
Esophageal Cancer nal pain; other features include dysphagia, early satiety, and iron
deficiency anemia due to chronic blood loss. The majority of patients
Squamous cell carcinoma usually arises in the mid portion of the have metastatic disease at the time of presentation, precluding cura-
esophagus in patients with a history of tobacco and alcohol use or tive resection.
preexisting esophageal diseases. In contrast, adenocarcinoma affects
the lower third of the esophagus in patients with Barrett’s esophagus. Over 90% of gastric cancers are adenocarcinomas; gastric MALT lym-
Both types of cancer have a similar clinical presentation, with dys- phomas make up a minority, but are important, as early lesions are
phagia and weight loss being the most common symptoms. Diagno- curable with H. pylori eradication therapy alone. Nonresponsive or
sis is made at endoscopy with biopsy. Over half of patients present recurrent disease requires chemotherapy.
with incurable disease.
SMALL BOWEL
STOMACH A wide variety of disease processes give rise to similar histologic
abnormalities in the mucosa of the small intestine, resulting in pre-
A variety of gastroduodenal pathologies are related to infection with
dictable clinical manifestations. The first event is infiltration of
Helicobacter pylori. This Gram-negative, spiral-shaped bacterium
lymphocytes into the epithelium, resulting in an intraepithelial lym-
adheres to the gastric epithelium and is able to survive in the acidic
phocytosis. Next, there is increased crypt cell proliferation, resulting
environment of the stomach due to a urease that converts urea into
in crypt hyperplasia. Then, loss of villous cells leads to increasing
ammonia, which increases the pH of the immediate vicinity. It is
degrees of villous atrophy, eventually leading to a flat mucosa. As a
spread by person-to-person (likely fecal–oral) transmission and is
consequence of mucosal malabsorption, patients present with
usually acquired at an earlier age in developing countries than in
diarrhea, steatorrhea and weight loss. Laboratory studies may be
developed countries. It is found worldwide, though the prevalence is
helpful in defining the extent of the malabsorption syndrome. Anemia
decreasing with improved sanitation and hygiene. Infection causes
may result from deficiencies of iron, folate and/or vitamin B12 – the
acute gastritis, which leads to chronic gastritis. Peptic ulcer disease is
latter implying that the mucosal damage extends to involve the ter-
a common complication, while a small minority of patients with H.
minal ileum. Prolongation of the prothrombin time may be due to a
pylori infection go on to develop gastric adenocarcinoma or MALT
deficiency of vitamin K (one of the fat-soluble vitamins, along with
(mucosa-associated lymphoid tissue) lymphoma.
A, D and E), which occurs in fat malabsorption. Hypophosphatemia,
hypocalcemia and an elevated alkaline phosphatase are seen in
Gastritis vitamin D deficiency, which may cause osteomalacia or osteoporosis.
Conditions that cause these histologic abnormalities and present with
Both inflammation of the stomach (gastritis) and damage to the these clinical and laboratory features include parasitic infections,
gastric epithelium with minimal or no inflammation (gastropathy) celiac disease, tropical sprue, bacterial overgrowth and Crohn’s disease
may cause epigastric pain and nausea and vomiting, but they may (Box 3.4). Similar clinical manifestations may be seen in other disor-
be asymptomatic. The most common infectious cause of gastritis is ders with specific pathologic findings, such as intestinal lymphoma
H. pylori infection. A number of agents cause gastropathy, the most and amyloidosis. The general principles of treating disorders of the
common being nonsteroidal anti-inflammatory drugs (NSAIDs), small intestinal mucosa include treating the underlying disease and
alcohol, and bile reflux. correcting any nutrient deficiencies that may be present. In addition,
a lactose-free, low-fat diet may be beneficial.
Peptic Ulcer Disease
Population-based endoscopy studies have shown that the preva- Tropical Sprue
lence of peptic ulcer disease is almost 10% in the East, twice as high Abnormalities of the small intestinal mucosa, resulting in increased
as in Western countries [13]. Historically, duodenal ulcers were intestinal permeability and decreased absorption, have been described
more common than gastric ulcers in the tropics – due to the higher in both residents of and visitors to certain tropical and subtropical
prevalence of H. pylori and lower usage of NSAIDs – but this ratio is
changing with time. While patients with peptic ulcer may be
asymptomatic, the usual symptom is epigastric discomfort or pain,
which may radiate to the back. The four major complications are
hemorrhage, penetration, perforation, and gastric outlet obstruc-
tion. Bleeding peptic ulcer is a common cause of acute upper gas- BOX 3.4 Causes of Malabsorption
trointestinal hemorrhage; management consists of hemodynamic
resuscitation, endoscopic therapy, and, for refractory cases, surgery. l Infections
Treatment with a proton pump inhibitor reduces the risk of l Celiac disease
rebleeding after endoscopic hemostasis. Penetration of the ulcer l Tropical sprue
through the bowel wall causes intense pain; further erosion results l Bacterial overgrowth
in bowel perforation, causing peritonitis and necessitating emer-
l Crohn’s disease
gency laparotomy. Gastric outlet obstruction is usually a complica-
tion of a longstanding ulcer, due to chronic inflammation and l Malignancies
fibrosis. A test for H. pylori should be performed in all patients with l Immunoproliferative small intestinal disease
peptic ulceration; this may be performed either at endoscopy or l Intestinal lymphoma
noninvasively. If positive, eradication of H. pylori should be under- l Hypolactasia
taken; this should consist of a proton pump inhibitor and two anti- l Pancreatitis
biotics, taking into account local resistance patterns. Unlike
l Alcoholic pancreatitis
duodenal ulcers, which are very rarely neoplastic, gastric ulcers may
be malignant in etiology, so follow-up endoscopy is necessary to l Chronic calcific pancreatitis
ensure resolution.
24 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
countries. Variously referred to as tropical sprue or tropical enteropa- it is important to continue the investigation, as approximately 10%
thy, the disorder is characterized by a chronic malabsorption syn- of IgA-competent celiac disease patients are seronegative. Although
drome, either following an episode of acute infectious diarrhea or the diagnosis was previously restricted to those individuals with
developing more insidiously; it has even been reported to develop villous atrophy on biopsy, it is now recognized that patients with
years after leaving an endemic area. Its incidence appears to be lesser degrees of mucosal damage – that is, crypt hyperplasia or
decreasing, mainly as a result of the increasing recognition of non- intraepithelial lymphocytosis alone – have a mortality rate that is at
tropical sprue, or celiac disease, and perhaps also due to the increasing least as high as those with frank villous atrophy [15]. Thus, current
use of antibiotics for patients with acute diarrheal diseases. It occurs diagnosis of celiac disease is based on a positive small bowel biopsy
in the Indian subcontinent, Southeast Asia and some parts of the (defined as intraepithelial lymphocytosis with or without crypt hyper-
Caribbean; however, it is not endemic in all tropical areas, being plasia and villous atrophy) with clinical and/or histologic improve-
notably rare or absent in Africa and other parts of the Caribbean such ment upon removal of gluten from the diet. Serologic tests, though
as Jamaica. There is considerable heterogeneity in disease presenta- not necessary for the diagnosis, are also helpful in the management
tion among these areas, suggesting that tropical sprue may represent of celiac disease – as a positive test will turn negative once the patient
a spectrum of related disorders. The etiology is unknown, but infec- is on a strict gluten-free diet. Nonresponsive celiac disease is usually
tious etiologies are considered likely given the epidemiology of the due to intentional or inadvertent ingestion of gluten; if these are ruled
disease and its response to antibiotics; although a number of infec- out, it may be due to coexistent diseases such as microscopic colitis
tious agents have been implicated, there has been little consistency (which is associated with celiac disease), refractory celiac disease, or
between studies. In addition, folate deficiency has been implicated in enteropathy-associated T-cell lymphoma. Epidemiologic studies have
the etiology of tropical sprue, given the prevalence of folate deficiency shown that patients with celiac disease have an increased risk of both
in these patients and the histologic improvement observed upon folic gastrointestinal and non-gastrointestinal malignancies.
acid repletion; this and other theories – for example, implicating
malnutrition or excess T-cell activity – are flawed due to the inability Protein-Losing Enteropathy
to separate cause from effect. The clinical, laboratory and endoscopic
features of tropical sprue are largely similar to those of celiac disease. Loss of protein into the gastrointestinal tract may occur as a result of:
While the mucosal lesion can be patchy in both conditions, the (1) erosive mucosal disease, in which protein leaks across damaged
villous atrophy in tropical sprue tends to be less severe – with a flat membranes; (2) non-erosive mucosal disease, in which protein loss
mucosa being uncommon – but more diffuse throughout the small is due to altered epithelial permeability; and/or (3) lymphatic disease,
intestine. The key factors distinguishing tropical sprue from celiac in which lymph leaks into the lumen. The most common cause of
disease are the absence of celiac disease-specific autoantibodies and non-erosive mucosal disease is intestinal infection. Lymphatic dys-
the absence of clinical and histologic improvement on a gluten-free function may be due to obstruction, as in mesenteric tuberculosis, or
diet. Thus, tropical sprue is a diagnosis of exclusion, suggested by impaired drainage, as occurs in portal hypertension or right-sided
villous atrophy in a patient with malabsorption who is living or has heart failure. The diagnosis is suggested by the presence of hypoalbu-
lived in an endemic area. The disease can be cured with antibiotics, minemia without protein malnutrition, proteinuria or liver disease.
usually tetracycline for up to 6 months, in combination with In addition to correcting the underlying disorder, treatment consists
folic acid. of providing medium-chain triglycerides for nutritional support.
advanced disease. Laboratory findings are notable for hypoalbumine- features. Laboratory findings are nonspecific, though a leukocytosis is
mia and hypogammaglobulinemia (from protein-losing enteropa- usually present. In areas with access to radiographic studies, ultra-
thy). The finding of alpha heavy chains in the serum is diagnostic, sonography or computed tomography may establish the diagnosis,
but this may be absent in a minority of patients; in the remainder, though imaging should not delay surgical exploration in cases where
immunohistochemical staining of biopsy specimens is positive. the diagnosis of acute appendicitis is very likely based on the clinical
assessment. For patients presenting soon after the onset of symptoms,
Treatment and Prognosis the treatment of choice is immediate appendectomy, with the addi-
tion of broad-spectrum antibiotics in those with frank perforation;
Early-stage IPSID can be cured with antibiotic therapy, which histori- patients with a longer duration of symptoms may be managed non-
cally has involved tetracycline with or without metronidazole (for operatively with antibiotics. The differential diagnosis of acute appen-
associated parasitic infections) although newer agents may also be dicitis includes acute gastroenteritis, in which diarrhea is usually a
effective. In advanced disease, chemotherapy may be required. In prominent symptom and abdominal pain is more diffuse. In contrast,
unresponsive cases, surgery may be required for bulky abdominal gastroenteritis due to Yersinia infection may present with little diarrhea
disease causing obstruction. and right lower quadrant abdominal pain, causing it to be misdiag-
nosed as appendicitis.
Enteritis Necroticans (Pigbel)
This is a necrotizing infection affecting either the small or large intes- Intestinal Tuberculosis
tine that occurs after ingestion of food containing the beta toxin of
Clostridium perfringens type C. It classically affects chronically mal- This can affect any part of the gastrointestinal tract, but the ileocecal
nourished people who ingest a high-protein meal; it was first recog- region is an area of predilection. In addition to the classic constitu-
nized in children and adults in Papua New Guinea after eating a pork tional symptoms of fever, night sweats and weight loss, abdominal
feast, but has since been described in people from other parts of Asia involvement may be manifested by distension due to ascites, diarrhea
and Africa. A cofactor for the infection is decreased trypsin activity, due to malabsorption, obstruction due to stenosing disease, or the
which is seen in protein malnutrition and in people ingesting foods presence of an abdominal mass. Less than half of patients with intes-
with antitrypsin properties, such as sweet potatoes. The toxin causes tinal tuberculosis have open pulmonary disease. Laboratory tests
tissue necrosis, usually affecting the small intestine but occasionally usually reveal anemia and raised inflammatory markers, though these
extending to involve the colon. Histologic examination reveals exten- are nonspecific. Tuberculin tests are usually strongly positive in
sive inflammation and necrosis of the mucosa together with large patients who are adequately nourished but are frequently negative in
numbers of bacteria on the affected surface. Patients present with those with malnutrition or HIV infection. Sputum and gastric wash-
abdominal pain and distension, bloody diarrhea, and shock. Surgical ings should be examined for tubercle bacilli. Radiographic contrast
resection of the affected section of bowel may be curative, but the studies of the gut show a range of changes, including mucosal ulcera-
disease is often fatal. tion, stricture formation, segmental narrowing, and fistula formation.
Colonoscopy may establish the diagnosis when acid-fast bacilli or
caseating granulomas are found on biopsy; however, these findings
Intussusception are not always present, and other endoscopic findings can be difficult
Intussusception is defined as the telescoping of one part of the to distinguish from other diseases of the colon, most notably Crohn’s
bowel into another. Ninety-five percent of cases occur in children, in disease. Laparoscopy or laparotomy with microscopic examination
whom the classic features are sudden onset of colicky abdominal pain and culture of biopsies may be the only means of establishing the
and vomiting, a right-sided abdominal mass (as the ileocecal junction diagnosis in some patients. If facilities for investigation are inade-
is the most common site), and currant-jelly stool (due to the mixture quate, it may be necessary to treat the patient with antituberculous
of blood and mucus). Most cases can be treated non-operatively drugs on the basis of a clinical diagnosis.
using air, saline, or barium enemas. The majority of cases are idio-
pathic; in the remainder, a variety of lesions in the intestine can act
as a lead point for intussusception – for example, Meckel’s diverticu- Inflammatory Bowel Disease
lum, polyp or vascular malformation. The opposite is true in adults The inflammatory bowel diseases, Crohn’s disease and ulcerative
with intussusception, in whom an underlying disorder is almost colitis, are chronic inflammatory disorders of the bowel that are
always found; in addition to benign and malignant neoplasms, ame- thought to occur as a result of the interplay between genetic factors,
bomas and schistosomal granulomas have been found to act as the environmental factors and the host immune response. Classically
lead point. Owing to the risk of underlying malignancies in adults considered diseases of the West, it is now appreciated that the inci-
with intussusception, surgical resection is favored over non-operative dence is increasing in many developing countries. Although the
reduction. hygiene hypothesis is almost certainly an oversimplification of the
etiology of these diseases, the altered Th1/Th2 balance as a result of
decreased exposure to helminths in childhood may be partly respon-
COLON sible for the increasing incidence in tropical countries that are under-
Appendicitis going demographic transition [18]. In addition, it is likely that a
substantial proportion of true cases were misdiagnosed in the past as
Acute appendicitis is one of the most common causes of the acute infectious colitis.
abdomen, occurring at all ages. Inflammation of the appendiceal wall
leads to ischemia, necrosis, and eventually perforation, which may Crohn’s disease can involve any part of the gastrointestinal tract, but
result in a localized abscess or generalized peritonitis. The inciting has a predilection for the terminal ileum and cecum. Inflammatory
event is obstruction of the appendix, which is commonly due to feca- lesions cause right lower quadrant abdominal pain, diarrhea and
liths or calculi. However, the cause of the appendiceal obstruction weight loss. The differential diagnosis of ileocecal inflammatory
varies by age, with lymphoid hyperplasia being common in children lesions includes: bacterial infections such as yersiniosis or actinomy-
and tumors occasionally found in adults. In areas where schisto- cosis; tuberculosis; histoplasmosis; parasitic infections such as ame-
somiasis is endemic, schistosome ova have been found in the appen- biasis; and helminthic infections such as strongyloidiasis. Microscopic
diceal wall in patients undergoing appendectomy, suggesting a examination of biopsy specimens is notable for transmural inflam-
potential causative role for certain parasitic infestations in the patho- mation, lymphoid aggregates, and noncaseating granulomas. It can
genesis of acute appendicitis. Regardless of the etiology, the clinical be challenging to differentiate Crohn’s disease from intestinal tuber-
features of acute appendicitis are similar: the classic symptoms include culosis on the basis of clinical, endoscopic and histologic features; in
pain that migrates from the periumbilical area to the right iliac fossa, areas where tuberculosis is endemic, an empiric trial of antitubercu-
fever, anorexia and vomiting, though the diagnosis may be more lous drugs is undertaken [19]. Management of Crohn’s disease
challenging in children and the elderly who present with less specific involves both medical and surgical approaches: medical therapies
26 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
include broad-spectrum antibiotics and immunosuppressive agents; testing. STI testing should be performed prior to rectal examination,
surgical management is necessary if the disease is complicated by as some lubricants are bacteriostatic. Anoscopy may not be possible
strictures, fistulizing disease or abscesses. due to pain; if performed, the mucosa is seen to be edematous, ery-
thematous and friable with exudates or ulceration. If the proctitis is
In ulcerative colitis, the inflammation starts at the rectum and spreads likely due to an STI but the causative agent is unknown, empiric
proximally; the mucosa appears red and raw on proctosigmoidos- antimicrobial therapy should be started; the combination of ceftriax-
copy. Histologic examination reveals that the inflammation is limited one, doxycycline and valacyclovir is effective against the four main
to the submucosa. In addition, there is an inflammatory cell infiltrate causes. Sexual partners should be identified and treated; counseling
in the lamina propria, neutrophil accumulation in crypt abscesses, regarding barrier protection is important, as proctitis increases the risk
and depletion of goblet cells from the epithelium; granulomas are of HIV transmission.
absent. Unlike Crohn’s disease, in which lesions may occur through-
out the bowel, ulcerative colitis is limited to the colon and rectum;
thus, if the disease is not responsive to medical therapy, total colec- Rectal Prolapse
tomy is curative.
Either the mucosa or all layers of the rectal wall may prolapse
through the anus. This is almost always secondary to an underlying
Megacolon disorder. Common causes in children in the tropics are diarrheal
diseases, especially shigellosis, parasitic infestations (e.g. with Tri-
Patients with large bowel dilatation may be ill-appearing with abdom- churis trichiura), and malnutrition. Among adults, rectal prolapse is
inal pain, distension and tenderness. Toxic megacolon can complicate more common in elderly women due to pelvic floor weakness as a
any of the infectious colitides, e.g. it is a relatively common complica- result of vaginal delivery. Treatment is focused on correcting the
tion of C. difficile infection; it is also seen in fulminant colitis from underlying disorder and, if repeated manual reductions are neces-
the inflammatory bowel diseases; rarely, it is due to drug-induced sary, surgical repair.
intestinal hypomotility. Abdominal examination is remarkable for a
distended abdomen with absence of bowel sounds. Plain film of the
abdomen shows a markedly distended colon. Stool should be sent Anal Lesions
for bacterial culture, C. difficile toxin, and examination for ova and
parasites. However, regardless of the etiology, the treatment is colec- Common benign lesions that occur around the anus include ulcers
tomy; without surgical treatment, the risk of bowel perforation and and warts. Both may cause pruritus, bleeding and pain. Ulcers are
peritonitis is unacceptably high. usually caused by herpes simplex virus, syphilis or chancroid; in addi-
tion, patients with HIV are susceptible to ulcers caused by cytomega-
In contrast, some patients may have large bowel dilatation without lovirus, tuberculosis and fungal infection. A proportion of patients
systemic toxicity. This results in constipation due to chronic intestinal with HIV have ulcers without evidence of any of these infectious
pseudo-obstruction. It may be due to acquired absence of the gangli- agents, so-called idiopathic anal ulcers. Condylomata acuminata
ons in the enteric nervous plexus, as in Chagas disease. (anal warts) are caused by human papillomavirus infection, which is
related to sexual activity. These exophytic, flesh-colored lesions should
be distinguished from the flat lesions of condyloma lata, seen in
Stenosing Lesions of the Colon and Rectum secondary syphilis.
Stenosing lesions of the bowel can be caused by amebiasis, schis
tosomiasis, tuberculosis and lymphogranuloma venereum, which
involves the rectum. Strictures can also be inflammatory, occurring in Anal Cancer
Crohn’s disease or after an episode of diverticulitis, or neoplastic. Cancer of the anal canal, usually squamous cell carcinoma, makes up
only a small proportion of gastrointestinal malignancies. However,
The cecum is the most common site for ameboma formation, but any the incidence is increasing worldwide, likely due to the widespread
part of the colon may be affected. Occasionally, multiple amebomas prevalence of human papillomavirus infection. The risk may be
occur in the same patient. Persisting diarrhea with blood in the stools increased further in patients co-infected with HIV. Patients present
and localized abdominal pain are the usual features, and one or more with rectal bleeding or a mass at the anal verge. The treatment options
tender masses may be palpable in the abdomen. The lesion itself are chemoradiotherapy or surgery.
consists of granulation tissue with areas of necrosis and fibroblast
proliferation. Amebas are often difficult to find, but serologic tests are
positive in over 90% of cases. Rapid resolution follows specific treat-
ment, and surgical excision is not required. GASTROINTESTINAL DISEASES IN
Granulomatous lesions of the colon due to schistosomiasis can cause PATIENTS WITH HIV/AIDS
narrowing of the bowel. Early lesions are reversible with antischisto- Acute HIV-1 infection presents with a mononucleosis-like illness in
somal treatment. The rare fibrotic strictures that form may require which gastrointestinal symptoms are not usually prominent but may
surgical removal. include nausea and vomiting and diarrhea. Rarely, patients may have
pancreatitis or hepatitis. In contrast, advanced HIV infection com-
monly involves the gastrointestinal tract, with the main syndromes
RECTUM AND ANUS being esophageal disease and chronic diarrhea (Box 3.5). The causes
Proctitis of organ-specific disease in HIV-infected patients can usually be attrib-
uted to one of three causes: due to HIV infection itself; due to oppor-
Inflammation of the rectum causes rectal pain, tenesmus and a tunistic infection; or due to the medications used to treat HIV or
mucopurulent rectal discharge. While any of the infectious causes of prevent its complications [21]. The etiologies vary depending on the
colitis may involve the rectum, isolated proctitis is more commonly degree of immunosuppression.
a sexually transmitted infection (STI), usually seen in men who have
sex with men who engage in unprotected anal intercourse [20]. Chronic diarrhea is a common problem in patients with AIDS,
Common causes are gonorrhea, herpes simplex, lymphogranuloma causing significant morbidity and mortality. While the CD4 cell count
venereum secondary to chlamydia (which is endemic in Africa, South is preserved, the causes are similar to those in patients without HIV.
and Southeast Asia, and Central and South America), and syphilis. As the infection becomes more advanced, parasitic, fungal and viral
Noninfectious causes of proctitis include the inflammatory bowel infections become more prevalent. Many of these pathogens can also
diseases, radiation, ischemia and neoplasia. Infectious workup should be identified in AIDS patients without diarrhea, showing that asymp-
include rectal swab cultures for gonorrhea, lymphogranuloma tomatic infection is common. Workup should include stool speci-
venereum and herpes simplex virus, and blood for syphilis serologic mens for bacterial culture and ova and parasite examinations. If these
G a s t ro i nte s t i n al Diseases 27
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BOX 3.5 Gastrointestinal Involvement 1. Kosek M, Bern C, Guerrant RL. The global burden of diarrhoeal disease, as
in AIDS estimated from studies published between 1992 and 2000. Bull World Health
Organ 2003;81:197–204.
l Dysphagia 2. Hogenauer C, Langner C, Beubler E, et al. Klebsiella oxytoca as a causative
l
Candida esophagitis organism of antibiotic-associated hemorrhagic colitis. N Engl J Med 2006;
355:2418–26.
l CMV esophagitis
3. Pawlowski SW, Warren CA, Guerrant R. Diagnosis and treatment of acute or
l HSV esophagitis
persistent diarrhea. Gastroenterology 2009;136:1874–86.
l Idiopathic esophageal ulcer 4. Ramakrishna BS, Venkataraman S, Mukhopadhya A. Tropical malabsorption.
l Diarrhea Postgrad Med J 2006;82:779–87.
l Opportunistic infections 5. Roy SK, Hossain MJ, Khatun W, et al. Zinc supplementation in children with
cholera in Bangladesh: randomised controlled trial. BMJ 2008;336:266–8.
– CMV 6. Lucas MES, Deen JL, von Seidlein L, et al. Effectiveness of mass oral cholera
– Salmonellosis, campylobacteriosis vaccination in Beira, Mozambique. N Engl J Med 2005;352:757–67.
– Tuberculosis, Mycobacterium avium-intracellulare 7. Hill DR, Ryan ET. Management of travellers’ diarrhoea. BMJ 2008;337:a1746.
infection 8. Steffen R. Epidemiology of traveler’s diarrhea. Clin Infect Dis 2005;41(Suppl
8):S536–40.
– Cryptosporidium hominis/parvum, Cyclospora cayetan-
9. Shah N, DuPont HL, Ramsey DJ. Global etiology of travelers’ diarrhea: system-
ensis, Isospora belli, Entamoeba histolytica, Giardia atic review from 1973 to the present. Am J Trop Med Hyg 2009;80:609–14.
lamblia, Strongyloides stercoralis 10. Teixeira AR, Nitz N, Guimaro MC, et al. Chagas disease. Postgrad Med J
– Microsporidiosis, cryptococcosis, coccidioidomycosis, 2006;82:788–98.
histoplasmosis 11. Section on Pediatric Dentistry and Oral Health. Preventive oral health inter-
vention for pediatricians. Pediatrics 2008;122:1387–94.
l AIDS enteropathy
12. Enwonwu CO, Falkler WA Jr, Phillips RS. Noma (cancrum oris). Lancet
l Medications 2006;368:147–56.
l Lymphoma 13. Leong RW. Differences in peptic ulcer between the East and the West. Gastro-
l Malignancy – any location, due to enterol Clin North Am 2009;38:363–79.
14. Bhatnagar S, Gupta SD, Mathur M, et al. Celiac disease with mild to moderate
l Kaposi sarcoma
histologic changes is a common cause of chronic diarrhea in Indian children.
l Non-Hodgkin lymphoma
J Pediatr Gastroenterol Nutr 2005;41:204–9.
15. Ludvigsson JF, Montgomery SM, Ekbom A, et al. Small-intestinal histopathol-
ogy and mortality risk in celiac disease. JAMA 2009;302:1171–8.
16. Al-Saleem T, Al-Mondhiry H. Immunoproliferative small intestinal disease
(IPSID): a model for mature B-cell neoplasms. Blood 2005;105:2274–80.
are unrevealing, flexible sigmoidoscopy with biopsy may be helpful 17. Lecuit M, Abachin E, Martin A, et al. Immunoproliferative small intestinal
in the diagnosis, especially in the identification of cytomegalovirus disease associated with Campylobacter jejuni. N Engl J Med 2004;350:
infection. Treatment should be directed at the specific enteric patho- 239–48.
gen identified and antiretroviral therapy, which is the only treatment 18. de Silva HJ, de Silva NR, de Silva AP, et al. Emergence of inflammatory bowel
for some infections such as cryptosporidiosis and microsporidiosis, disease “beyond the West”: do prosperity and improved hygiene have a role?
should be initiated. Trans R Soc Trop Med Hyg 2008;102:857–60.
19. Almadi MA, Ghosh S, Aljebreen AM. Differentiating intestinal tuberculosis
In a substantial proportion of AIDS patients with diarrhea, no enteric from Crohn’s disease: a diagnostic challenge. Am J Gastroenterol 2009;104:
pathogens are isolated. Small intestinal biopsy specimens from these 1003–12.
patients are notable for villous atrophy and lymphocytic infiltration 20. Davis TW, Goldstone SE. Sexually transmitted infections as a cause of proctitis
into the lamina propria. This idiopathic condition is named AIDS in men who have sex with men. Dis Colon Rectum 2009;52:507–12.
enteropathy, and may represent the mucosal response to atypical 21. Cello JP, Day LW. Idiopathic AIDS enteropathy and treatment of gastrointes-
pathogens, including HIV. tinal opportunistic pathogens. Gastroenterology 2009;136:1952–65.
4 Hepatobiliary Diseases
Mark Danta, Arthur Y Kim
ALT/AST ALP/GGT
Hepatitis screen Unconjugated Conjugated Imaging
bilirubin bilirubin
Normal
ALT/AST
hemoglobin which is conjugated by the liver. Elevation can result and imaging. A hepatitis screen usually includes viral serologies (hep-
from an increased load (pre-hepatic), reduced hepatic conjugation or atitis A, B and C), immune serologies (including antinuclear antibody
transport, or post-hepatic biliary obstruction. Elevation of hepatic [ANA], antimitochondrial antibody [AMA] and anti-smooth muscle
cytosolic alanine aminotransferase (ALT) and mitochondrial aspar- antibody), and metabolic markers such as iron or copper studies.
tate aminotransferase (AST) indicates parenchymal inflammation and Applicability of tests will depend on local resources and prevalence
hepatocyte injury. In contrast, alkaline phosphatase (ALP), lining the of specific conditions. An ultrasound is a useful, usually accessible
hepatic canalicular membrane, and gamma-glutamyl transpeptidase investigation that can identify parenchymal and biliary disease and
(GGT), expressed on the epithelium of the bile ducts, are cholestatic cirrhosis. It may also detect evidence of portal hypertension, including
enzymes that increase in biliary disease. However, alkaline phos- reversal of portal vein flow and splenomegaly. More detailed investi-
phatase also increases in some parenchymal and granulomatous gations include computed tomography (CT) and magnetic resonance
disease, while GGT can also be elevated following injury mediated by imaging (MRI) for parenchymal and vascular disease, and magnetic
alcohol and drugs, such as phenytoin. Using these biochemical resonance cholangiopancreatography (MRCP) and endoscopic retro-
markers, however, patterns of liver injury can be characterized as grade cholangiopancreatography (ERCP) for biliary disease. Finally,
hepatocellular (ALT/AST), cholestatic (ALP/GGT), or mixed. The true liver biopsy may be required for definitive diagnosis and staging of
functional tests of hepatic function include assessing blood levels of disease [4].
albumin, bilirubin and coagulation factors. Thrombocytopenia in
chronic liver disease is often secondary to portal hypertension. In the
tropics, peripheral blood eosinophilia can be useful in suggesting
certain parasitic infections. Based on clinical and blood parameters,
HEPATITIS AND JAUNDICE (Table 4-2
two scoring systems exist that relate the severity of chronic liver AND Fig. 4.1)
disease and prognosis: the Childs Pugh classification and the Model
for End-stage Liver Disease (MELD) score [3] (Table 4-1). ACUTE HEPATITIS
The primary approach to the differential diagnosis depends on the Acute hepatitis can be defined as any syndrome that causes elevation
results of the initial examination and laboratory testing as outlined of liver function tests (LFTs) for less than 6 months. This can be
in Figure 4.1. Further investigations may include a hepatitis screen caused by a variety of infections, toxin/drug exposures, or metabolic
30 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Other causes of chronic liver disease leading to hepatic failure include: Cystic Abscess Simple cyst
granulomatous diseases, metabolic diseases and alcoholic liver Pyogenic Polycystic liver disease
disease. Systemic infections can be associated with granulomas in the Amebic
liver. In addition to schistosomiasis, these include: mycobacteriosis, Hydatid
leishmaniasis, histoplasmosis, brucellosis and syphilis. Noninfectious Solid Tuberculosis Hepatocellular
causes include sarcoidosis, lymphoma, primary biliary cirrhosis, and Syphilitic gumma carcinoma (HCC)
drug reactions. High environmental copper ingestion in children can Liver fluke: Adenoma
also lead to cirrhosis (copper-associated childhood cirrhosis or Indian Fasciola Fibronodular
childhood cirrhosis); recognition of how to prevent and treat this Clonorchis hyperplasia (FNH)
entity has decreased the incidence of this disease. African Bantu Opisthorchis Hemangioma
hemosiderosis is a disease of iron overload similar in manifestations Regenerative nodule
to hemochromatosis; the presumed genetic basis of this disease is
currently unknown. It is important to counsel those with chronic liver Metastatic disease
disease to avoid additional hepatic insults via prevention of exposures Lymphoma
to infectious agents and toxins, as well as provision of vaccination Biliary Liver fluke: Cholangiocarcinoma
against hepatitis A and hepatitis B viruses. obstruction Fasciola Gallbladder cancer
Clonorchis Pancreas: pancreatic
JAUNDICE AND BILIARY OBSTRUCTION Opisthorchis
Microsporidiosis
tumor or
pancreatitis
Many tropical diseases may result in cholestasis and jaundice, through Cryptosporidiosis Gallstone
varied mechanisms. Overload of unconjugated bilirubin can occur
during acute hemolysis due to malaria, babesiosis, Oroya fever
(caused by Bartonella bacilliformis), and hemolytic uremic syndrome
caused by E. coli O157:H7 or Shigella dysenteriae, and sepsis related to
Clostridium perfringens. Hemolytic crises can also complicate hemo-
globinopathies and may be precipitated by infections. Jaundice may in 221 of the 225 cases (98.2%), suggesting that fine needle aspiration
also be caused by processes that result in impaired conjugation and/ for diagnosis is not necessary in the majority of cases [11]. Determin-
or excretion of bilirubin by the liver. Some tropical diseases may be ing the size and whether the lesion is solid or cystic are useful in
associated with both hemolysis and impaired excretion (i.e. lepto stratifying the diagnostic approach (Table 4-4). As a rule, small lesions
spirosis). Non-obstructive causes include any causes of generalized (<1 cm) are often benign, while larger lesions and those occurring in
liver dysfunction (i.e. during fulminant acute hepatitis or subsequent the context of chronic liver disease have higher potential for
to chronic liver disease/cirrhosis). Obstructive causes include nonin- malignancy.
fectious causes (gallstones and tumors), helminthic infection (such
as those caused by Ascaris lumbricoides. or Clonorchis sinensis and other In an individual presenting with a cystic liver lesion associated with
liver flukes) and certain protozoa (such as Cryptosporidium hominis/ right upper quadrant pain and fever, consideration should be given
parvum, particularly in those with HIV or other states of immunosup- to differentiating amebic from pyogenic abscesses. While both are
pression). Any biliary obstruction can be complicated by bacterial associated with a significant mortality, treatment differs. The typical
cholangitis. Some of these entities often cause obstruction by mass imaging appearance of a pyogenic abscess is a fluid-filled lesion with
lesions (see below section) that may also involve blockage of the surrounding parenchymal edema. However, imaging could not satis-
pancreatic duct; serum pancreatic enzymes and ultrasound and/or factorily differentiate pyogenic from amebic abscesses in a large series
other imaging may be useful tests to help identify specific [12]. In this series, multivariate analysis identified pyogenic abscesses
etiologies. to be associated with older age (>50 years), pulmonary findings on
examination, multiple lesions and negative amebic serology
(<1:256 IU). The major route of seeding in both is the portal circula-
VASCULAR LIVER DISEASE tion. Pyogenic liver abscesses are commonly polymicrobial, usually
(see Table 4-2) caused by mixed enteric facultative and anaerobic species. Klebsiella
pneumoniae and Streptococcus milleri are common pathogens [13].
Vascular diseases of the liver are uncommon and include: Budd– Focal liver abscesses can also complicate melioidosis (caused by the
Chiari syndrome, which is obstruction of the intrahepatic portion of Gram-negative bacillus Burkholderia pseudomallei). Melioidosis occurs
the inferior vena cava or hepatic veins; portal vein thrombosis; sinu- in Southeast Asia, China and northern Australia populations, particu-
soidal obstruction syndrome (previously termed veno-occlusive larly in patients with diabetes, alcoholism or renal failure [14].
disease); nodular regenerative hyperplasia and peliosis [10]. Other Pyogenic abscesses require early percutaneous drainage and broad-
causes include ischemic hepatitis and congestive hepatopathy as a spectrum antibiotics. Studies do not support a difference between
result of cardiac failure, for example right heart failure related to intermittent versus continuous drainage of these abscesses [15]. In
mycobacterial constrictive pericarditis. Usually, these vascular lesions contrast, amebic abscesses are usually treated medically. Liver abscess
are associated with portal hypertension which precedes hepatic syn- is the most common extraintestinal manifestation of Entamoeba his-
thetic failure. Doppler ultrasound or contrast CT are useful imaging tolytica infection (see Chapter 89), occurring in endemic areas such as
techniques for delineating the vessels of the liver. Central and South America, West and South Africa, and India [16].
Amebic abscesses may be solitary or multiple, and often occur in the
FOCAL LIVER LESIONS (Table 4-4) right hepatic lobe (75%). Diagnosis is usually based on detection of
antibody in blood, or antigen in stool or hepatic aspirates, as well as
The evaluation of a focal liver lesion may include noninvasive tests, response to empiric treatment [17] with metronidazole or its analogs,
including serology, blood parameters, tumor markers and microbio- followed by a luminal amebicide such as paromomycin, iodoquinol
logic assessment, as well as further imaging with ultrasound, CT or or diloxanide furoate to eliminate infection [16]. Drainage, however,
MRI. Biopsy may be required to differentiate lesions; however, in a should be considered if there is impending rupture or involvement
large study of focal liver lesions, preoperative assessment was correct of the pleura or pericardium.
H e p ato b i l i a r y Diseases 33
Other cystic lesions of the liver include simple hepatic cysts and cystic
hydatid disease caused by Echinococcus granulosus (see Chapter 128) TABLE 4-5 HIV Infection and the Liver
[18]. Hydatid cysts have a typical radiologic appearance which has led
to a staging classification based on imaging appearance [19]. Gener-
ally, hydatid cysts have thick pericystic walls which may be calcified. Infection Tumor Other
The cysts usually have septa and may contain “daughter” cysts [20].
CD4 Mycobacterium Non-Hodgkin
Unlike abscesses, surrounding liver tissue is normal. Anti- E. granulo- <100 avium infection lymphoma
sus antibodies are positive in a majority of cases [19]. Current treat- cells/µL Cryptococcosis (NHL)
ment usually involves albendazole with or without mechanical Cytomegalovirus Kaposi sarcoma
drainage or removal. (KS)
Primary malignant hepatobiliary tumors in the developing world CD4 Tuberculosis Non-Hodgkin
often relate to underlying infectious etiologies. Hepatocellular carci- >200 lymphoma
noma (HCC) leads to over 600,000 deaths annually worldwide, cells/µL Kaposi sarcoma
usually occurring in the context of chronic liver disease [21]. An esti-
mated 85% of cases are associated with chronic viral hepatitis (HBV CD4 Viral hepatitis Hepatocellular Drug-induced
and HCV), which currently infects over 500 million people worldwide >500 (hepatitis B virus, carcinoma liver injury (DILI)
[22,23]. Levels of HBV viremia correlate with the risk of developing cells/µL hepatitis C virus) Lipodystrophy
HCC [24], and successful anti-HBV vaccination programs lead to a Immune
significant reduction in the incidence of HCC [25]. Other risk factors reconstitution
for HCC include alcohol and aflatoxins, which may in part explain
the higher incidence of HCC in West African and Chinese populations
without underlying HBV-related cirrhosis [23]. Diagnosis usually
involves a combination of consistent findings on imaging studies, and and Kaposi sarcoma (KS) can occur at moderate levels (CD4 >200
elevated alpha-fetoprotein (AFP) levels in the setting of chronic liver cells/µL) of immunodeficiency [32,33]. Of the OIs infecting the liver,
disease. Typically, HCCs appear as hypervascular lesions on imaging, Mycobacterium avium complex is the most common. Other infections
a result of neovascularization from the hepatic artery. Approximately include Cryptococcus neoformans, Pneumocystis jiroveci, cytomegalovirus
70% of cases are associated with an elevated AFP. In the largest rand- and tuberculosis. In particular geographic areas, visceral or dissemi-
omized study of ultrasound and AFP screening in over 18,000 Chinese nated leishmaniasis is also prevalent. AIDS cholangiopathy is associ-
patients, biannual screening reduced HCC mortality by 37% [26]. ated with cryptosporidial and microsporidial infection in patients
However, the benefit of screening in resource-limited settings is con- with CD4 counts <100 cells/µL, and can lead to biliary obstruction
troversial [27]. [34]. While the presentation is variable, it is usually a variation of
cholangitis with diarrhea, which is the result of the intestinal infection
To date, HCC treatment involves either locoregional therapies, includ- with these pathogens.
ing alcohol injection, radiofrequency ablation, or transarterial chemo
embolization (TACE), or surgical resection in those with small tumors Following the initiation of ART in individuals with low CD4 T-cell
and sufficient hepatic reserve without portal hypertension. However, counts (<100 cells/µL), approximately 10–30% of individuals present
overall prognosis of HCC is usually poor. Newer targeted chemothera- with a new opportunistic infection or worsening clinical symptoms
pies such as sorafenib are emerging, but their current cost precludes of an already established infection, termed immune reconstitution
use in the resource-limited settings [28]. Benign parenchymal liver syndrome [35]. This is of particular relevance for those co-infected
tumors include adenomas, fibronodular hyperplasia, and hemangi- with viral hepatitis with advanced hepatic fibrosis, as fatal hepatic
omas. Chronic biliary inflammation associated with persistent Salmo- flares have been reported [36]. Finally, drug-induced liver injury
nella infection of the biliary tract and Clonorchis/Opisthorchis liver (DILI) is commonly associated with ART, and this entity is more likely
flukes has also been associated with gallbladder cancer and cholan- when there is co-infection with viral hepatitis [37].
giocarcinoma, respectively [29]. Individuals with these entities may
usually eventually present with biliary obstruction, with elevation of
alkaline phosphatase and GGT with or without jaundice, and biliary
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19. McManus DP, Zhang W, Li J, Bartley PB. Echinococcosis. Lancet 2003, 2007,356:1445–54.
362:1295–304. 32. Spano JP, Costagliola D, Katlama C, et al. AIDS-related malignancies: state of
20. Doyle DJ, Hanbidge AE, O’Malley ME. Imaging of hepatic infections. Clin the art and therapeutic challenges. J Clin Oncol 2008,26:4834–42.
Radiol 2006,61:737–48. 33. Engels EA, Pfeiffer RM, Goedert JJ, et al. Trends in cancer risk among people
21. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer with AIDS in the United States 1980–2002. AIDS 2006,20:1645–54.
J Clin 2005,55:74–108. 34. Margulis SJ, Honig CL, Soave R, et al. Biliary tract obstruction in the acquired
22. Wands JR. Prevention of hepatocellular carcinoma. N Engl J Med 2004, immunodeficiency syndrome. Ann Intern Med 1986,105:207–10.
351:1567–70. 35. Crane M, Matthews G, Lewin SR. Hepatitis virus immune restoration disease
23. Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver of the liver. Curr Opin HIV AIDS 2008,3:446–52.
Dis 1999,19:271–85. 36. Crane M, Oliver B, Matthews G, et al. Immunopathogenesis of hepatic flare
24. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a bio- in HIV/hepatitis B virus (HBV)-coinfected individuals after the initiation of
logical gradient of serum hepatitis B virus DNA level. JAMA 2006,295: HBV-active antiretroviral therapy. J Infect Dis 2009,199:974–81.
65–73. 37. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associ-
25. Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan ated with antiretroviral therapy in adults infected with human immunodefi-
and the incidence of hepatocellular carcinoma in children. Taiwan Childhood ciency virus and the role of hepatitis C or B virus infection. JAMA 2000,
Hepatoma Study Group. N Engl J Med 1997,336:1855–9. 283:74–80.
Hematologic Diseases 5
Stephen McKew, Jamilla Rajab, Imelda Bates
TABLE 5-1 Normal Red Cell Indices Expressed as Mean ±2SD (95% Range)15
Hb (g/dl) RBC (x1012) PCV (l/l) MCV (fl) MCH (pg) MCHC (g/dl)
Birth 18 ± 4 6.0 ± 1.0 0.6 ± 0.15 110 ± 10 34 ± 3 33 ± 3
1 month 14.0 ± 2.5 4.2 ± 2.5 0.43 ± 0.1 104 ± 12 33 ± 3 33 ± 4
1 year old 12.6 ± 1.5 4.5 ± 0.6 0.34 ± 0.04 78 ± 6 27 ± 2 34 ± 2
2–6 years 12.5 ± 1.5 4.6 ± 0.6 0.37 ± 0.03 81 ± 6 27 ± 3 34 ± 3
6–12 years 13.5 ± 2.0 4.6 ± 0.6 0.4 ± 0.05 86 ± 9 29 ± 4 34 ± 3
Men 15.0 ± 2.0 5.0 ± 0.5 0.45 ± 0.05 92 ± 9 29.5 ± 2.5 33 ± 1.5
Women 13.5 ± 1.5 4.3 ± 0.5 0.41 ± 0.05 92 ± 9 29.5 ± 2.5 33 ± 1.5
From Lewis SM, Bain BJ, Bates I. Dacie and Lewis. Practical Haematology, 10th edn. Philadelphia, PA: Churchill Livingstone; 2006.
35
36 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
cardiac output, and, eventually, heart failure (“decompensated bone marrow activity and is characterized by anemia with an inap-
anemia”). There may be severe breathlessness, angina and claudica- propriately low reticulocyte count. Hematinic deficiencies are usually
tion with pulmonary edema, peripheral edema, and ascites and hypo- caused by poor nutrition and, because the deficiency develops gradu-
tension. Mortality is high once heart failure occurs. ally, quite severe degrees of anemia can be tolerated. Some of these
deficiencies are associated with specific features described below.
MANAGEMENT PRINCIPLES
The cause of the anemia should be identified and treated. Blood Iron Deficiency (Table 5-4)
transfusion rapidly corrects the anemia but may exacerbate cardiac This may present with angular stomatitis, koilonychia, glossitis
failure and carries significant infection risks, especially in low-income (Figs 5.1–5.2) and loss of melanin skin pigmentation.
countries, so it should only be used as a last resort. In low-resource
settings, anemia is often caused by several factors acting simultane- The mean corpuscular volume (MCV) and mean corpuscular Hb
ously, for example malnutrition, hemoglobinopathies and infections (MCH) are reduced, the platelet count is often raised, and hypochro-
[3, 4]. Some of these factors have a degree of interdependency, such mia, microcytosis and characteristic “pencil cells” are evident on the
as iron deficiency and infection, which may explain why the tradi- blood film (Fig. 5.2). Serum ferritin may be low but, as it is an acute
tional single-treatment approaches have failed to make a significant phase protein, it has been suggested that the lower cut-off level
impact on the huge public health burden of anemia. More than one
of the factors causing anemia described in this section may, therefore,
be present in an individual and anemia will not completely resolve
unless all contributory causes are addressed.
TABLE 5-4 Common Causes of Iron Deficiency Anemia TABLE 5-5 Summary of the Relationship between
Infections Causing Blood Loss and Anemia17
Decreased iron intake Inadequate diet
Impaired absorption Infection Relationship to anemia
Coeliac disease
Tannins, phytates (e.g. in grains Hookworm (heavy infections) Very strong
and beans)
Hookworm (light infections) Strong
Increased loss Gastrointestinal bleeding
Hookworm Trichuris (heavy infections) Strong
Schistosomiasis
Trichuriasis Trichuris (light infections) Moderate
Gastroesophageal ulceration Schistosomiasis Strong/moderate
Malignancy
NSAIDs use Ascaris Weak/absent
Menstrual loss
Bladder neoplasm Poly-infections
WHO region Demography 2003 % of the population carrying Affected conceptions (per 1000) Affected
+ b e births (%
Population Crude Annual Under-5 Significant α Thalassemia Any Sickle-cell Thalassemias Total of under-5
(millions) birthrate births mortality varianta variantc disordersd mortality)
(1000s) rate
African 586 39.0 22 895 168 18.2 41.2 44.4 10.68 0.07 10.74 6.4
American 853 19.5 16 609 27 3.0 4.8 7.5 0.49 0.06 0.54 2.0
Eastern 573 29.3 16 798 108 4.4 19.0 21.7 0.84 0.70 1.54 1.4
Mediterranean
European 879 11.9 10 459 25 1.1 2.3 3.3 0.07 0.13 0.20 0.8
South-east 1 564 24.4 38 139 83 6.6 44.6 45.5 0.68 0.66 1.34 1.6
Asian
Western 1 761 13.6 23 914 38 3.2 10.3 13.2 0.00 0.76 0.76 2.0
Pacific
World 6 217 20.7 128 814 81 5.2 20.7 24.0 2.28 0.46 2.73 3.4
a 0 b + + c
Significant variants include Hb S, Hb C, Hb E, Hb D etc. β thalassemia, α thalassemia. α thalassemia includes heterozygous and homozygous α thalassemia. Allows for (1) coincidence of α and β variants, and (2) harmless
combinations of β variants. dSickle-cell disorders include SS, SC, S/β thalassemia. eThalassemias include homozygous β thalassemia, hemoglobin E/β thalassemia, homozygous α0thalassemia, α0/ α+thalassemia (hemoglobin H
disease).
From Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ 2008;86:480–7.
H e m ato l o gic Diseases
39
40 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
FIGURE 5.5 Global distribution of (A) α and β thalassemia and (B) haemoglobins S and E. (Reproduced with permission from Weatherall DJ, Clegg JB. Inherited
haemoglobin disorders: an increasing global health problems. Bulletin of the WHO 2001;79:704–11, Fig 2 and 3 p77).
Southeast Asia, but is less common in the Mediterranean region and (HbAS) have 10-fold protection against severe malaria compared with
rare in infants of African descent. individuals with normal Hb. The mechanism of protection probably
involves both innate and immune-mediated mechanisms.
SICKLE CELL HEMOGLOBINOPATHIES
Sickle hemoglobin (HbS) is caused by a mutation in the β globin SICKLE CELL DISEASE (HBSS) [11]
gene which affects the stability and solubility of the β chain. When
HbS is deoxygenated (e.g. during inflammation, infection, dehydra- The high prevalence of HbS in sub-Saharan Africa leads to approxi-
tion or hypoxia) it polymerizes and distorts the red cell, eventually mately 230,000 infants being born with sickle cell disease (HbSS)
resulting in the characteristic sickle shape. The red cell damage leads each year. These are mostly HbSS, but also Hb sickle cell (HbSC) and
to hemolysis and vascular occlusion which is the basis for the clinical HbS/β+ thalassemia. In these infants, symptoms such as hemolytic
symptoms. anemia, splenomegaly and vaso-occlusive episodes become apparent
after the first 6 months of life as the protective effect of HbF is lost.
HbS is found in high frequency in Africa and also areas of the Middle The age of onset of symptoms is variable, but most children will
East, where the prevalence can reach >30%. HbS occurs in parts of experience problems by the age of 6 years. Children with HbSS are
the world where P. falciparum malaria is endemic and it now has a stunted, with bossing of the bones of the skull similar to that seen in
global distribution contributed to initially by the transAtlantic slave β-thalassemia (Fig. 5.7). Both conditions cause expansion of the bone
trade and now by modern travel. Individuals with sickle cell trait marrow, which is the cause of the bossing and other abnormalities of
42 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Dactylitis. Typically the bones of the hands and feet are affected
with fever and leukocytosis. It is often the first event in
young children and can occur multiple times until the age
of 3 years
Painful crises. Typically occurs after the first few years in bones
or occasionally abdominal viscera. Pain is due to ischemia and
can be very severe. Crises are associated with low-grade fever
and mild leukocytosis in comparison to osteomyelitis where
fever and leukocytosis are more pronounced. Pain relief with
paracetamol, non-steroidal anti-inflammatory drugs or
opoids, as appropriate, should be instigated immediately.
Supportive measures such as hydration, intravenously if
necessary, and oxygen also help to reduce the duration of the
pain crisis. Any precipitating cause such as infection, should
be treated
FIGURE 5.8 Photomicrograph of a blood film. Sickle cell anemia Central nervous system events. Strokes occur in up to 17%
(homozygosity for hemoglobin S). Shows elliptical sickle cells, target cells of children and young adults. The pathogenesis is unclear
and Pappenheimer bodies (reproduced with permission from Elsevier, Dacie but angiography often shows occlusions or stenosis.
and Lewis: Practical Haematology, 11th edition, 2011, pp84, fig 5.55). Recurrence is likely unless a long-term transfusion
programme is initiated
Acute chest syndrome. This is a common cause of death
development of the facial bones. HbS can be co-inherited with other presenting with fever, tachypnea chest pain, leukocytosis and
Hb abnormalities (e.g. sickle cell/Hb C disease, sickle cell/β- chest pain often with a sudden drop in hemoglobin. It can be
thalassemia) when it produces a similar clinical picture to sickle cell difficult to differentiate from infection, infarction and
disease. Cells containing HbSS form sickle-shaped cells in tissues embolism. Common precipitating causes are pulmonary fat
where there is low oxygen tension. This triggers a complex process embolism and infections. Treatment is with transfusion
involving activation of adhesion, inflammation and coagulation (simple or exchange), antibiotics and aggressive treatment of
which ultimately results in microthrombi and the pain crises so typical hypoxia
of sickle cell disease. Splenic sequestration. This occurs in children between 6 months
and 2 years. It is caused by sudden trapping of red cells
within the spleen producing a sudden drop in hemoglobin
Investigations and rapidly enlarging spleen eventually leading to
The blood count is normal at birth but Hb falls during the first year hypovolemic shock and death. Management includes early
of life. The adult Hb is 6–10 g/dl, but can drop to less than 2 g/dl detection of the rapidly enlarging spleen and blood
transfusion
during a crisis. Blood films (Fig. 5.8) show the typical sickle cells,
Priapism. Engorgement of the penis can be short-lived and
as well as target cells, polychromasia and nucleated red cells. After self-terminating or can last in excess of 24 hours and may
the age of 3 years, features of hyposplenism (e.g. Howell-Jolly bodies) lead to impotence. Initial management is with fluids and
become apparent. Reticulocytes and the white cell count are often analgesia but persistent priapism (>12 hours) may need
raised. Diagnosis can be confirmed by Hb electrophoresis or HPLC. partial exchange transfusion and corporal aspiration
A useful screening test for the presence of HbS is the sickle solubility Infections. Overwhelming infection with Streptococcus
test. pneumonia is the most common cause of death in children.
Other common causes of infections in sickle cell disease
The sickle solubility test is based on the principle that HbS has
include H. influenzae and Salmonella.19 A significant reduction
reduced solubility at low oxygen tensions. A positive test indicates the in the number of deaths from sepsis has resulted from the
presence of Hb S but does not differentiate between homozygotes (i.e. routine use of vaccinations against these organisms and
patients with sickle cell disease) and heterozygotes (i.e. sickle cell antibiotic prophylaxis. Malaria prophylaxis should be
trait). A blood film is not a reliable way to differentiate sickle cell considered in endemic areas
disease from sickle cell trait as in HbSS in steady state there may be
very few sickled cells. False-negative sickle screening tests can occur if
the patient is very anemic (ideally use packed cells to avoid this), if
the reagents are out of date, if the infant is less than 6 months old or
if the patient has had a recent transfusion. False-positives are associ- 1000 mg per day after 8 weeks. The dose can be increased further
ated with very high white cell counts and high protein results; this (2000 mg or 20–30 mg/kg) but the neutrophil count should be mon-
can also be minimized by the use of packed cells. itored regularly and the dose reduced if the neutrophil count falls. As
in β-thalassemia major, a well-matched bone marrow transplant, even
from a sibling with HbAS, may be the most cost-effective manage-
Management and Outcome ment strategy.
Sickle cell disease is a chronic condition requiring a multidisciplinary, Life expectancy depends largely on the availability of healthcare. With
long-term approach to the education and management of the patient high-quality health care, survival into middle age is common but,
and family. Early diagnosis is facilitated by antenatal screening; where health systems are weak, less than 2% of children born with
routine folic acid, penicillin prophylaxis and vaccinations to prevent HbSS will survive beyond 4 years.
infections are important. Sickle cell disease is characterized by both
acute (Table 5-8) and chronic (Table 5-9) problems.
SICKLE CELL TRAIT
HbF has a protective effect in HbSS. Drugs such as hydroxycarbamide/
hydroxyurea, which increase HbF levels, have been shown to reduce Individuals with sickle cell trait (HbAS) are generally asymptomatic
some of the complications of sickle cell disease, such as painful crises, with a normal Hb and normal life expectancy. Complications are
acute chest syndrome and anemia. extremely uncommon but can include poor perfusion of the renal
papillae and increased bacteruria [12]. The blood film is either normal
Hydroxycarbamide is generally well-tolerated. It should be started at or shows a slight microcytosis. Diagnosis can be confirmed by Hb
500 mg per day (or 10–15 mg/kg in children) and increased to electrophoresis or HPLC. The sickle solubility test is positive.
H e m ato l o gic Diseases 43
LEUKEMIA
TABLE 5-10 Common Causes of Increased White Cells The acute and chronic leukemias are a heterogeneous group of malig-
nancies that arise from immature hematopoietic stem cells. They are
Neutrophilia Infection (bacterial, viral, fungal, parasitic) classified as myeloid or lymphoid and further subclassified on the
Inflammation (trauma, burns, infarction, basis of morphology, cytochemistry, immunophenotype and genetics.
autoimmune disease) Management varies with the subtype of leukemia but often the tech-
Chemicals (e.g. drugs, steroids, hormones, nology required to provide an accurate classification, and the full
venoms) range of therapies, are not available in most hospitals in low-income
Hematological malignancy (e.g. countries. For this reason, and because the prognosis for patients with
myeloproliferative disease, chronic myeloid leukemia is better if they are managed in a specialist center, the sec-
leukemia)
tions below focus predominantly on features that may prompt referral
Other malignancies
to a specialist.
Hemorrhage
Pregnancy and delivery
Miscellaneous (e.g. cigarette smoking, Acute Leukemias
post-splenectomy)
Acute lymphoblastic leukemia (ALL) and acute myeloblastic leuke-
Lymphocytosis Viral infections (e.g. measles, hepatitis, mia (AML) have different epidemiologic patterns in low-income and
varicella, rubella) industrialized countries. ALL occurs most commonly in childhood,
Protozoal infections (e.g malaria, Toxoplasma with a peak at 2–4 years in industrialized countries and 5–14 years
gondii) in less wealthy countries. This age difference is thought to be caused
Childhood infection by delayed exposure to infection and possibly less breastfeeding in
Leukemias and lymphomas industrialized countries. The incidence of ALL in children in industri-
Miscellaneous (e.g. stress, trauma, vigorous alized countries is fourfold higher than that of AML, whereas in low-
exercise, post-splenectomy) income tropical countries, the incidence of childhood ALL and AML
Eosinophilia Helminthic infections
is similar. Risk factors for AML include smoking and exposure to
Allergic syndromes (e.g. asthma, eczema, chemicals and alkylating agents.
urticaria) The clinical presentation of ALL and AML are similar because in both
Many drugs conditions the leukemic blast cells infiltrate the bone marrow causing
Malignancy (e.g. Hodgkin’s lymphoma, pancytopenia. Patients therefore present with symptoms caused by
leukaemia) bone marrow failure, such as anemia, fever, infection, bleeding and
Miscellaneous (e.g. post-splenectomy, skin
bony pains. Hepatosplenomegaly is commonly seen and some have
rashes, rheumatoid arthritis, sarcoidosis)
infiltration of the skin and gums by leukemic cells. Chloromas, a solid
Monocytosis Infection (e.g. malaria, trypanosomiasis, mass of leukemic blasts, are more common in AML where they may
typhoid) occur in 10–20% of all patients and up to 30% of young boys.
Chronic infections (e.g. TB, brucellosis)
Malignancy (e.g. myelodysplasia, Hodgkin’s
lymphoma) Investigations
In both types of acute leukemia, the white cell count is usually raised
because of the presence of blast cells, but occasionally it can be
reduced, and the Hb and platelet count are often reduced. A blood
film will usually show blast cells, but occasionally they may be absent
or very infrequent. In children, the clinical features and blood film of
TABLE 5-11 Common Causes of Reduced White Cells acute viral infection may mimic those of ALL, and a leukemoid reac-
tion mimicking AML may occur in severe tuberculosis. Suspicious
Neutropenia Viral infection (e.g. HIV, influenza) blood films should therefore always be interpreted by a specialist.
Overwhelming bacterial infection Cytochemical stains of peripheral blood with Sudan black, myeloper-
Parasitic infections oxidase and nonspecific esterase can help to differentiate between ALL
Many drugs and myelomonocytic and monocytic AML. Flow cytometry and
Hypersplenism cytogenetic analysis undertaken at a specialist center can provide
Autoimmune disease information to guide treatment strategies and to indicate prognosis.
Felty’s syndrome
Bone marrow failure (e.g. leukemia,
lymphoma, aplastic anemia, malnutrition) Management and Outcome
Miscellaneous (e.g. familial, cyclical, idiopathic) Supportive care should be commenced while the diagnosis is being
confirmed. Survival without definitive treatment is usually only a few
Lymphopenia Infections (e.g. HIV, other viral infections) months. Anemia, thrombocytopenia and any bleeding diathesis can
Autoimmune disease (e.g. SLE, rheumatoid) be treated with appropriate blood products. Infections should be
Bone marrow failure
treated aggressively and allopurinol started for hyperuricemia. The
treatment of ALL is complex, involving chemotherapy and radio-
therapy, but can be extremely effective when delivered in specialist
centers. In AML, blood transfusions and oral cytoreductive therapy,
decreased counts encountered in low-income countries are listed in such as hydroxycarbamide/hydroxyurea, may achieve survival rates of
Tables 5-10 and 5-11. Mild neutropenia is a normal finding in indi- 6–12 months. Curative treatment involves intensive regimens of cyto-
viduals of African descent. toxic drugs or bone marrow transplantation.
The combination of depleted clotting factors (i.e. prolonged PT and the type of thrombophilia. Interpretation of the results, understand-
aPTT) and a falling platelet count with red cell fragments on the blood ing the limitations of the tests and explaining the implications
film is strong evidence of DIC. Raised D-dimers or fibrin degradation to patients requires considerable expertise and should be done by
products, and reduced fibrinogen levels are characteristic. Manage- specialists.
ment involves treating or removing the underlying cause, correction
of blood pressure and correcting the hemostatic abnormalities with
combinations of platelets, cryoprecipitate and FFP. REFERENCES
1. Critchley J, Bates I. Haemoglobin colour scale for anaemia diagnosis
Immune Thrombocytopenic Purpura (ITP) where there is no laboratory: a systematic review. Int J Epidemiol 2005;
34:1425–34.
Immune thrombocytopenic purpura (ITP) is caused by immune 2. Medina Lara A, Mundy C, Kandulu J, et al. Evaluation and costs of different
destruction of platelets. Although it is usually primary, it can be asso- haemoglobin methods for use in district hospitals in Malawi. J Clin Pathol
ciated with underlying conditions, such as lymphomas and infections 2005;58:56–60.
including HIV. It may present incidentally or with bruising. Bleeding 3. Boele van Hensbroek M, Calis JC, Phiri KS, et al. Pathophysiological mecha-
from the nose or gums, or petichiae are more likely if the platelet nisms of severe anaemia in Malawian children. PLoS ONE 2010;5:e12589.
count is <30 × 109/l. Spontaneous recovery occurs more often in 4. Calis JC, Phiri KS, Vet RJ, et al. Erythropoiesis in HIV-infected and uninfected
children than in adults. Malawian children with severe anemia. AIDS 2010;24:2883–7.
5. Phiri KS, Calis JC, Siyasiya A, et al. New cut-off values for ferritin and soluble
Increased numbers of platelet precursors in the bone marrow support transferrin receptor for the assessment of iron deficiency in children in a high
a diagnosis of ITP. It is important to exclude other causes of throm- infection pressure area. J Clin Pathol 2009;62:1103–6.
bocytopenia, such as drugs, disseminated intravascular coagulation or 6. Deicher R, Horl WH. New insights into the regulation of iron homeostasis.
sepsis. Treatment is usually only necessary if the platelet count is <30 Eur J Clin Invest 2006;36:301–9.
× 109/l or if there is bleeding. Treatment is initially with prednisolone 7. Volberding PA, Levine AM, Dieterich D, et al. Anemia in HIV infection: clini-
at doses of 0.25–0.5 mg/kg which should be tapered off over several cal impact and evidence-based management strategies. Clin Infect Dis 2004;
weeks once the platelet count has improved. Second-line treatments 38:1454–63.
include immunosuppressive agents and danazol. Splenectomy may 8. Calis JC, van Hensbroek MB, de Haan RJ, et al. HIV-associated anemia in chil-
result in a long-term improvement in platelet count but the benefits dren: a systematic review from a global perspective. AIDS 2008;22:1099–112.
need to be balanced against the risks of splenectomy, particularly in 9. Casals-Pascual C, Roberts DJ. Severe malarial anaemia. Curr Mol Med 2006;
low-income settings where infections are common. Platelet transfu- 6:155–68.
sions or intravenous gammaglobulin can be used to increase the 10. Bedu-Addo G, Bates I. Causes of massive tropical splenomegaly in Ghana.
Lancet 2002;360:449–54.
platelet count in an emergency or prior to surgical procedures.
11. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 2010;376:
2018–31.
Congenital Bleeding Disorders 12. Tsaras G, Owusu-Ansah A, Boateng FO, Amoateng-Adjepong Y. Complica-
The congential bleeding disorders occur with the same frequency tions associated with sickle cell trait: a brief narrative review. Am J Med 2009;
throughout the world. Hemophilia A has a prevalence of about 122:507–12.
13. Nkhoma ET, Poole C, Vannappagari V, et al. The global prevalence of glucose-
10/10,000, von Willebrand’s deficiency is >10/10,000 and hemophilia
6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis.
B is <0.1/10,000. Although the diagnosis may be suspected from the
Blood Cells Mol Dis 2009;42:267–78.
patient’s personal and family history, diagnosis should be confirmed 14. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency.
by a specialist center. Treatment options include replacement of the Lancet 2008;371:64–74.
missing coagulation factors and cryoprecipitate. Von Willebrand’s 15. Lewis SM, Bain BJ, Bates I. Dacie and Lewis. Practical Haematology, 10th edn.
disease may respond to desmopressin. Philadelphia, PA: Churchill Livingstone; 2006.
16. World Health Organization. Worldwide prevalence of anaemia 1993–2005.
THROMBOPHILIA Geneva: World Health Organization; 2008.
17. Bates I, McKew S, Sarkinfada F. Anaemia: A useful indicator of neglected
Thrombophilia (hypercoagulability) may be inherited (e.g. deficien- disease burden and control. PLoS Medicine 2007;4:e231.
cies of thrombin, protein S or protein C) or acquired (e.g. anti- 18. Modell B, Darlison M. Global epidemiology of haemoglobin disorders and
phospholipids) and results in venous or arterial thromboembolism. derived service indicators. Bull World Health Organ 2008;86:480–7.
The patient’s personal and family history and the results of clinical 19. Williams TN, Uyoga S, Macharia A, et al. Bacteraemia in Kenyan children with
and imagining examinations may suggest the diagnosis. Several sickle-cell anaemia: a retrospective cohort and case-control study. Lancet
laboratory tests are required to determine the cause and classify 2009;374:1364–70.
Urinary Tract Diseases 6
Chris F Heyns
This chapter focuses on renal and urinary tract diseases that are more IMAGING
common in tropical countries; a wide spectrum of disease associated Ultrasonography is relatively inexpensive and avoids the risks associ-
with renal and urinary tract pathology occurs in tropical regions ated with radiologic contrast and ionizing radiation (Fig. 6.3). It is
(Table 6-1) [1]. especially valuable in the evaluation of patients with renal failure
(Box 6.3).
INVESTIGATIONS Intravenous pyelography (IVP), or excretory urography (EUG),
In addition to a complete history and physical examination, urinaly- remains an excellent imaging study. The contraindications are
sis, both dipstick (Fig. 6.1) and microscopy (Fig. 6.2), provides the iodine allergy, renal failure, pregnancy, hemorrhagic shock and
most important clues to urinary tract disease. A midstream urine dehydration.
(MSU) specimen should be collected in a sterile container. In non- Computed tomography (CT) is more accurate than ultrasonography
toilet-trained children, bag specimens can be used for obtaining a or IVP for imaging all abdominal organs, but it is expensive and not
urine sample. readily available. Non-contrast-enhanced CT is becoming the modal-
ity of choice for imaging urinary tract stones.
URINE DIPSTICK In patients with renal failure, when ultrasound shows hydronephro-
Hematuria sis, bladder catheterization may solve the problem if there is infravesi-
cal obstruction; if not, uni- or bilateral percutaneous nephrostomy
Hematuria (blood in the urine) (Box 6.1) can be macroscopic (visibly can be life-saving.
red urine) or microscopic. A positive dipstick test for blood can be
caused by either free hemoglobin or myoglobin, therefore microscopy
is indicated to confirm the presence of red cells [2]. KEY SYNDROMES
Leukocytes and Nitrites URINARY TRACT INFECTION (UTI)
Dipstick urinalysis that is positive for leukocytes as well as nitrites has UTI is most often caused by Gram-negative organisms. In women,
a high specificity for UTI.[3]. Microscopy is more time-consuming further investigations are indicated only for recurrent, persistent or
and expensive than a dipstick, but is faster and less expensive than complicated UTI. However, in children and adult men, imaging is
urine culture. If microscopy shows pyuria (white cells in the urine) indicated to rule out underlying urinary tract abnormalities. UTI is
47
48 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
TABLE 6-1 Conditions Associated with Renal and BOX 6.2 Causes of Sterile Pyuria
Urinary Tract Disease
l Gram-negative UTI on antibiotic treatment
More common in Common in all regions l Tuberculosis of the urinary tract
tropical regions of the world l Schistosomiasis
l Urolithiasis
Malaria Congenital anomalies
Schistosomiasis Hypertension l Papillary necrosis
AIDS Diabetes mellitus l Chlamydia trachomatis infection
Tuberculosis Urinary tract infection l Chemical or radiation cystitis
Sickle cell disease Urolithiasis l Bladder cancer
Filariasis Renal failure
Hydatid disease Benign prostatic hyperplasia
Vesicovaginal fistula (females) Cancer of the kidney,
Urethral stricture (males) bladder and prostate
FIGURE 6.1 Urine dipstick – essential for the clinical evaluation of any
patient.
the cause of fever of unknown origin (FUO) in almost 10% of chil-
dren <3 years of age in tropical countries, and UTI often coexists with
gastroenteritis, protein energy malnutrition and acute respiratory
infection [4]. Treatment of UTI is indicated in Box 6.4.
B
A
C
D
E F
FIGURE 6.2 Urine sediment. Light microscopy of (A) normal red blood cells, (B) white blood cells, and (C) dysmorphic red cells; phase contrast microscopy
of (D) red cells, (E) white cells, (F) bacteria (cocci);
Continued
50 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
H
G
FIGURE 6.2, cont’d (G) red cell cast, (H) white cell
cast, (I) granular cast, (J) ovum of Schistosoma J
haematobium.
However, recent reviews found little evidence for steroid-resistant Chronic renal failure (CRF) in tropical countries is commonly caused
“tropical glomerulopathies” in children with NS and suggested that by infection-related glomerulonephritis (possibly related to the high
the term “tropical nephrotic syndrome” should be discarded. prevalence of soft tissue infections), diabetic nephropathy, hyperten-
sive nephrosclerosis, malaria, schistosomiasis, tuberculosis, HIV infec-
In Africa, focal segmental glomerulosclerosis (FSGS) is now becoming tion and sickle cell nephropathy.
the most common cause of NS in renal biopsies instead of minimal
change glomerulonephritis and amyloid, which were the most Facilities for hemodialysis are not readily available in many tropical
common causes prior to the AIDS pandemic. countries. However, chronic ambulatory peritoneal dialysis (CAPD)
is an effective and less expensive option, with the advantage that
patients are less hospital-dependent. The risk of infective peritonitis
RENAL FAILURE is increased.
Acute renal failure (ARF) in tropical regions may be caused by condi-
tions not commonly seen in nontropical areas: infectious diarrheal
disease, malaria, leptospirosis, snakebite, insect stings, herbal medi- MALARIA
cines and pregnancy-related conditions (septic abortion, eclampsia, Malarial acute kidney injury (MAKI) predominantly affects adults and
peripartum hemorrhage and puerperal sepsis). older children from areas of low intensity of malaria transmission,
U r i n a r y Tra c t Diseases 51
HIV-ASSOCIATED NEPHROPATHY (HIVAN) On urinalysis, acid sterile pyuria should raise the suspicion of TB, but
in up to one-third of patients a Gram-negative organism is cultured.
HIV/AIDS has a high prevalence in several tropical regions (especially Micro- or macroscopic hematuria is often present. Ziehl–Neelsen
sub-Saharan Africa) and HIVAN occurs in up to 10% of AIDS patients. (ZN) staining of urine has a high false-negative rate. At least three
It presents with proteinuria and renal failure, usually in patients with early morning urine specimens should be sent for TB culture.
an AIDS-defining condition, CD4 counts <200 cells/µL, and normal
to enlarged echogenic kidneys on ultrasonography. ESRD invariably IVP is the best imaging modality for suspected UGTB. Biopsy of the
develops, usually within 4–6 months. Some studies have demon- bladder wall, epididymis or prostate may confirm the diagnosis
strated dramatic responses to ART. histologically.
Treatment of UGTB requires combination therapy to prevent bacterial
HEMOLYTIC UREMIC SYNDROME (HUS) resistance – usually four drugs for 2 months (isoniazid, rifampicin,
HUS is a thrombotic microangiopathy that may present in (1) a clas- pyrazinamide and ethambutol) and two drugs for the remaining 4
sical form, associated with gastroenteritis, and (2) an idiopathic form, months (rifampicin and isoniazid). Drug-resistant TB can be treated
not associated with diarrhea. Classical HUS results from gastrointes- with addition of streptomycin or ciprofloxacin.
tinal infections with shiga toxin-producing Escherichia coli and Shigella
spp. Most cases are in children 6 months to 4 years of age, but infants SICKLE CELL DISEASE (SCD)
and adults can be affected. The mortality of HUS was reduced from
nearly 50% to 2–4% with the use of peritoneal dialysis. SCD is an autosomal recessive inherited disorder with a genetic preva-
lence of 25–50% in some West African areas. Relative hypoxia in the
renal medulla leads to sickling, with obliteration of the vasa recta,
SCHISTOSOMIASIS (BILHARZIA) papillary necrosis and macroscopic hematuria. Patients with SCD
The ova of Schistosoma haematobium are deposited in the wall of the have an increased susceptibility to bacterial infections. Renal failure
bladder and ureters, where they evoke a granulomatous inflammatory is the cause of death in about 14% of cases. A common problem in
reaction with eventual calcification of the bladder wall (Fig. 6.4) [9]. men with SCD is priapism (prolonged painful erection).
The typical presentation is painful terminal hematuria. Secondary Microscopic examination of a blood smear may show sickle cells.
bacterial infection may occur, particularly with Pseudomonas, Proteus Hemoglobin electrophoresis is required to establish the diagnosis.
or Salmonella, especially following instrumentation of the bladder. Treatment includes bed rest, IV fluids, diuretics, urine alkalinization
Dipstick hematuria is valuable for screening children at risk of urinary with sodium bicarbonate, blood transfusion, bladder washout for
schistosomiasis. Microscopic examination of a fresh urine sample removal of blood clots, and irrigation of the pelvicaliceal system with
usually shows S. haematobium ova (see Fig. 6.2). Serologic tests are silver nitrate.
useful in confirming the diagnosis in the absence of ova. Ultrasonog-
raphy can assess bladder abnormalities and urinary tract obstruction. CHYLURIA
Cystoscopy and bladder biopsy should only be performed if the diag-
nosis can not be established noninvasively. Chyluria is caused by microfilariae of a mosquito-borne nematode
(Wuchereria bancrofti) causing rupture of lymphatic varices into the
Treatment is usually with praziquantel. Praziquantel lacks efficacy urinary tract [10]. It occurs in about 2% of filarial afflicted patients,
against juvenile schistosomes, leading to lower cure rates in hyperen- mainly in South Asian countries. Chyluria may result in severe protein
demic areas. loss leading to hypoalbuminemia and anasarca. The urine is usually
milky white, but may be pink if there is also hematuria. Spontaneous
UROGENITAL TUBERCULOSIS (UGTB) resolution occurs in >50% of cases. A low-fat diet and high fluid
intake reduce the risk of urinary stasis and clot formation. Diethylcar-
Most patients with UGTB are <50 years of age. The symptoms include bamazine (DEC) may result in long-term remission.
LUTS, recurrent UTI, abdominal pain, epididymitis, macroscopic
hematuria, hemospermia or infertility. On examination there may be
hypertension, an abdominal mass secondary to hydronephrosis, or HYDATID DISEASE
scrotal swelling. The urinary tract is involved in 2–4% of cases of cystic hydatid
disease caused by the tapeworm Echinococcus granulosus. Flank pain
occurs in about 60% of cases. Hydaturia (scoleces in the urine) is
rare (5%). Ultrasonography typically shows a complex cyst. The
Casoni test or indirect hemagglutination test can be used to confirm
the diagnosis. Percutaneous aspiration of the cyst carries the risk of
anaphylaxis and hydatid seeding. Albendazole is the first-line treat-
ment, because surgery carries the risk of dissemination if spillage
occurs.
UROLITHIASIS
Risk factors for urolithiasis in the tropics include low urine volumes
due to sweating or chronic diarrhea [11]. The incidence of upper
urinary tract stones in adults is increasing in more affluent, urban-
ized populations. In children, bladder stones are more common
in tropical countries, probably due to dietary factors or chronic
diarrhea.
URETHRAL STRICTURES Authoritative review of the etiology, histology, prevention, and management of
glomerular diseases in the tropics.
In men, urethral strictures due to previous gonorrheal or chlamydial 6. Mishra SK, Das BS. Malaria and acute kidney injury. Semin Nephrol
urethritis are relatively common in some tropical countries. It may 2008;28:395–408.
present with UTI or urinary retention. Transurethral catheterization is Clinically useful review of the management of acute renal dysfunction associated
impossible; therefore, a suprapubic catheter is required until dilata- with malaria.
tion, internal urethrotomy or urethroplasty can be performed. 7. Bruneel F, Gachot B, Wolff M, et al. Corresponding Group. Resurgence of
blackwater fever in long-term European expatriates in Africa: report of 21 cases
REFERENCES
and review. Clin Infect Dis 2001;32:1133–40.
8. Jha V, Chugh KS. Nephropathy associated with animal, plant, and chemical
toxins in the tropics. Semin Nephrol 2003;23:49–65.
1. Hotez PJ, Kamath A. Neglected tropical diseases in sub-Saharan Africa: review
Interesting review of the recently recognized entity of toxic nephropathy as an impor-
of their prevalence, distribution, and disease burden. PLoS Negl Trop Dis
tant segment of renal disease in tropical countries.
2009;3:e412.
9. Jyding Vennervald B, Kahama AI, Reimert CM. Assessment of morbidity in
2. Rodgers M, Nixon J, Hempel S, et al. Diagnostic tests and algorithms used in
Schistosoma haematobium infection: current methods and future tools. Acta
the investigation of haematuria: systematic reviews and economic evaluation.
Trop 2000;77:81–9.
Health Technol Assess 2006;10:iii–iv, xi–259.
10. Gulati S, Gupta N, Singh NP, et al. Chyluria with proteinuria or filarial neph-
3. Whiting P, Westwood M, Bojke L, et al. Clinical effectiveness and cost-
ropathy? An enigma. Parasitol Int 2007;56:251–4.
effectiveness of tests for the diagnosis and investigation of urinary tract infec-
11. Robertson WG. Renal stones in the tropics. Semin Nephrol 2003;23:77–87.
tion in children: a systematic review and economic model. Health Technol
12. Gutman RE, Dodson JL, Mostwin JL. Complications of treatment of obstetric
Assess 2006;10:iii–iv, xi–xiii, 1–154.
fistula in the developing world: gynatresia, urinary incontinence, and urinary
4. Jeena PM, Coovadia HM, Adhikari M. Probable association between urinary
diversion. Int J Gynaecol Obstet 2007;99(Suppl 1):S57–64.
tract infections (UTI) and common diseases of infancy and childhood: a
Comprehensive review of existing literature and expert recommendations of the Gates
hospital-based study of UTI in Durban, South Africa. J Trop Pediatr
Fistula Institute meeting on surgical repair of obstetric fistula, including its complica-
1996;42:112–14.
tions such as gynatresia and urinary incontinence.
5. Seedat YK. Glomerular disease in the tropics. Semin Nephrol 2003;23:
12–20.
7 Sexually Transmitted Infections
David Mabey, Philippe Mayaud
improved services for the management of STIs, using the syndromic l not contraindicated for pregnant or lactating women
approach in rural health facilities, reduced the incidence of HIV infec-
tion by 40% over a 2-year period [3]. Trials of STI case management Appropriate drugs should be included in the national essential
using either the syndromic approach or periodic mass treatment in drugs list, and, in choosing drugs, consideration should be
Uganda failed to show any impact on HIV incidence [4,5]. Review of given to the capabilities and experience of health personnel.
the data from these trials suggested that improved STI case manage-
ment is more likely to reduce HIV incidence in the early stages of an Reproduced with permission from World Health Organization. Guidelines for the
HIV epidemic, when most HIV infections are concentrated in groups Management of Sexually Transmitted Infections; Revised version. Geneva: WHO;
with high numbers of concurrent sexual partnerships who also have 2003.
a high prevalence of other curable STIs [9].
HIV and HSV-2 each appears to facilitate the transmission of the
management of STI patients. The history should include details of the
other virus. Suppressive treatment for HSV-2 has been shown to
present complaint, including treatment already received, details of
reduce HIV shedding and plasma viral load in co-infected individuals
sexual partners since the onset of symptoms and in the preceding
but, disappointingly, two recent trials found no evidence that suppres-
month; and past history of STIs.
sive herpes treatment reduced the risk of HIV acquisition among
high-risk groups, and one large trial found no impact of HSV sup Examination should include inspection of the mucous membranes,
pressive therapy on HIV transmission among serodiscordant couples palms and anogenital region; palpation of the inguinal glands, penis
[10–13]. and scrotum in men, with retraction of the foreskin, if present. In
women, a speculum examination to visualize the cervix and a biman-
STIs represent important cofactors of HIV transmission, and STI
ual examination are required to assess possible lower abdominal
control could significantly reduce the incidence of HIV infection
tenderness (sign of pelvic inflammatory disease, PID, or for differen-
worldwide, although the impact of interventions may vary according
tial diagnosis with surgical conditions). The examination should be
to the local epidemiologic context.
performed in private in a good light, and gloves should be worn.
TREAT FOR
GONOCOCCAL INFECTION AND CHLAMYDIA TRACHOMATIS
FIGURE 7.1 Urethral discharge. Reproduced with permission from World Health Organization. Guidelines for the Management of Sexually Transmitted Infections;
Revised version. Geneva: WHO; 2003.
countries establish and use national standardized treatment protocols SCROTAL SWELLING (EPIDIDYMO-ORCHITIS)
for STIs. These can help to ensure that all patients receive adequate
treatment at all levels of healthcare services. The protocols can also
(see Fig. 7.5)
facilitate the training and supervision of healthcare providers and can Epididymitis is an important complication of gonococcal or chlamy-
help to reduce the risk of development of resistance to antimicrobials. dial urethritis. It presents as a painful swelling of the scrotum, usually
Finally, having a standardized list of antimicrobial agents can also unilateral; the onset is usually more acute in gonococcal than in
facilitate drug procurement (see Table 7-1 for WHO-recommended chlamydial disease. Torsion of the testis is an important differential
drug regimens for the main STI pathogens and syndromes). diagnosis, requiring urgent surgical repair. Other differential diag-
noses include trauma and tumor or other infectious causes such as
mumps, tuberculosis or brucellosis. In men over 50 years of age,
URETHRAL DISCHARGE (see Figs 7.1 & 7.2) epididymo-orchitis is more likely to be secondary to a bacterial
Most male patients presenting with urethral discharge or dysuria urinary tract infection than to urethritis, at least in developed
(when young) will have urethritis, defined as the presence of ≥5 poly- countries.
morphonuclear leukocytes per high-power field on a Gram stain of a
urethral swab, caused by one of four pathogens (see Table 7-1). In the
syndromic management, treatment of a patient with urethral dis- GENITAL ULCER (see Fig. 7.3)
charge (see Fig. 7.1) should adequately cover these most frequent There are five common causes of genital ulceration (see Table 7-1).
organisms causing gonorrhea (N. gonorrhoeae) and non-gonococcal In most developing countries, in the 1980s and 1990s, the majority
urethritis (Chlamydia trachomatis) which cannot always be distin- of genital ulcers were due to either syphilis or chancroid, and in some
guished by clinical presentation (presence of profuse purulent versus settings (e.g. Papua New Guinea, the Caribbean, South Africa), dono-
mucoid discharge) or incubation period (shorter usually for gonor- vanosis (caused by Klebsiella granulomatis) or lymphogranuloma
rhea, 3 to 7 days, versus 5 to 21 days). Although variable by setting, venereum (caused by L1–L3 strains of C. trachomatis). However, the
dual infections are not uncommon, accounting for up to 10% of pattern of genital ulcer disease (GUD) changes from locale to locale
cases. If a microscope is available, the diagnosis of gonorrhea can be and over time. Since the advent of HIV/AIDS, genital herpes caused
confirmed by the presence of intracellular diplococci on a Gram stain. by HSV-2 has become the dominant etiology of GUD worldwide.
Persistent or recurrent symptoms of urethritis may result from drug Clinical differential diagnosis of genital ulcers is inaccurate, particu-
resistance, poor compliance or re-infection. Given the high prevalence larly in settings where several etiologies are common. Clinical mani-
of these once-neglected infections in some settings, Trichomonas vagi- festations and patterns of GUD may be further altered in the presence
nalis and Mycoplasma genitalium should be suspected in cases of per- of HIV infection. Patients with ulcers should therefore be treated for
sistent urethral discharge [15] (see Fig. 7.2). syphilis and chancroid and all locally relevant bacterial etiologies.
S ex u a l l y Tra n s m i t te d I nfec tions 57
TABLE 7-1 Major Curable and Incurable STIs and STI Syndromes and Their Treatment
TABLE 7-1 Major Curable and Incurable STIs and STI Syndromes and Their Treatment—cont’d
Patient complains of
persistent/recurrent urethral
discharge or dysuria
NO
TREAT FOR
TRICHOMONAS VAGINALIS
Refer
FIGURE 7.2 Persistent/recurrent urethral discharge in men. Reproduced with permission from World Health Organization. Guidelines for the Management of
Sexually Transmitted Infections; Revised version. Geneva: WHO; 2003.
However, treatment of genital herpes with antivirals (e.g. acyclovir), may be only a reflection of a previous infection, and a negative test
even though it simply helps healing but does not cure the infection, does not necessarily exclude primary syphilis as seroreactivity may
is now recommended by WHO (see Fig. 7.3) in high HIV prevalence take 2–3 weeks to show.
settings.
Laboratory-assisted differential diagnosis is rarely helpful for GUD, INGUINAL BUBO (see Fig. 7.4)
and mixed infections are common. Herpes simplex infection can be Inguinal lymphadenopathy is a common feature of chancroid, lym-
diagnosed by culture, antigen detection or PCR, but these are rarely phogranuloma venereum (LGV) and syphilis. Syphilitic adenopathy
available in resource-poor settings. Chancroid can be diagnosed by is usually painless and does not suppurate, in contrast to the buboes
culture, but Haemophilus ducreyi is difficult to grow. PCR has been used of chancroid and LGV. In males, a genital ulcer is usually visible when
in research settings, but there is no commercially available test. Dark- a bubo results from one of these conditions, although the primary
field microscopy for syphilis requires specialist expertise and lacks lesion of LGV is often small, painless and transient. In women, the
sensitivity. In areas of high syphilis prevalence, a reactive serologic test ulcer may be overlooked unless a careful speculum examination is
60 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
NO NO
Ulcer(s) healed? Ulcer(s) improving? Refer
YES YES
FIGURE 7.3 Genital ulcers. Reproduced with permission from World Health Organization. Guidelines for the Management of Sexually Transmitted Infections; Revised
version. Geneva: WHO; 2003.
performed. The differential diagnosis includes inguinal hernia, septic women presenting with vaginal discharge syndrome have cervical
lesion of the lower limb, HIV infection with generalized lymphaden- infections. To improve algorithm accuracy and to save costs linked to
opathy, filariasis, tuberculosis and plague. Laboratory investigation is overtreatment, WHO has suggested the use of individual risk assess-
rarely helpful, though elementary bodies of C. trachomatis may be ment scores, which are combinations of sociodemographic and
detected by immunofluorescent staining in lymph node aspirates behavioral risk factors and clinical signs found to be locally associated
from cases of LGV. with cervical infections and/or the results of simple laboratory or
bedside tests. Past evaluations of risk assessment scores have yielded
mixed results, with sensitivities and specificities not usually exceeding
VAGINAL DISCHARGE (see Figs 7.6–7.8) 70%, and with higher positive predictive values and better cost-
The syndromic approach for the management of vaginal discharge effectiveness profiles found in settings with higher N. gonorrhoeae or
syndrome aims to include treatment of cervicitis caused by N. C. trachomatis prevalence [16]. Such findings imply that effectiveness
gonorrhoeae and C. trachomatis alongside treatment of vaginitis caused may vary not just between countries, but also between settings within
by T. vaginalis, bacterial vaginosis (BV) and Candida spp. (see Fig. 7.6). a country. The WHO STI guidelines have recommended that risk
The syndromic approach lacks both sensitivity and specificity, as assessment scores incorporate background cervical infection preva-
most cervical infections are asymptomatic and only a minority of lence levels in the target population.
61
Patient complains of
inguinal swelling
NO TREAT FOR
Ulcer(s) present?
LYMPHOGRANULOM VENEREUM AND CHANCROID
FIGURE 7.4 Inguinal bubo. Reproduced with permission from World Health Organization. Guidelines for the Management of Sexually Transmitted Infections; Revised
version. Geneva: WHO; 2003.
Patient complains of
scrotal swelling/pain
YES
TREAT FOR
GONOCOCCAL INFECTION AND CHLAMYDIA TRACHOMATIS
FIGURE 7.5 Scrotal swelling. Reproduced with permission from World Health Organization. Guidelines for the Management of Sexually Transmitted Infections; Revised
version. Geneva: WHO; 2003.
62 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
YES
Lower abdominal tenderness? Use flowchart for lower abdominal pain
NO
TREAT FOR
High GC/CT prevalence GONOCOCCAL INFECTION,
YES
setting¹ or risk CHLAMYDIA TRACHOMATIS,
assessment posituive? BACTERIAL VAGINOSIS AND
TRICHOMONAS VAGINALIS
NO
NO
FIGURE 7.6 Vaginal discharge. Reproduced with permission from World Health Organization. Guidelines for the Management of Sexually Transmitted Infections; Revised
version. Geneva: WHO; 2003.
NO
TREAT FOR
Cervical mucopus/erosions or GONOCOCCAL INFECTION,
YES
High GC/CT prevalence setting¹ CHLAMYDIA TRACHOMATIS,
or risk assessment positive? BACTERIAL VAGINOSIS AND
TRICHOMONAS VAGINALIS
NO
NO
¹ The determination of high prevalance levels • Manage and treat partner if cervical mucopus present
needs to be made locally • Manage and treat partner if microscopy demonstrates TV
FIGURE 7.7 Vaginal discharge: bimanual and speculum, with or without microscope. Reproduced with permission from World Health Organization. Guidelines
for the Management of Sexually Transmitted Infections; Revised version. Geneva: WHO; 2003.
leading to infertility or ectopic pregnancy. In developing countries, and in female sex-workers, yet no approach for case management was
the diagnosis of PID is usually clinical (lower abdominal and cervical included in the WHO guidelines. It is likely that a substantial number
motion tenderness) (see Fig. 7.9). Laparoscopy is helpful when it is of anorectal infections go unrecognized and untreated, especially
available. Important differential diagnoses include ectopic pregnancy, when low levels of clinical suspicion are combined with stigmatiza-
appendicitis and endometriosis. Treatment should cover N. gonor- tion of anal intercourse. Thus, there have been calls to introduce a
rhoeae, C. trachomatis and anaerobic bacteria. new algorithm for management of the anorectal syndrome, which
will soon be published by WHO, but which will require further
ANORECTAL SYNDROME validation.
In recent years, outbreaks of lymphogranuloma venereum (LGV) have The likely infectious causes of anorectal syndrome in both men and
been reported in Europe and North America, usually among HIV- women are N. gonorrhoeae and C. trachomatis, both non-LGV and LGV
positive men who have sex with men (MSM). Most patients presented (L1–L3) strains, but can also include syphilis, HSV and HPV (involv-
with proctitis, and symptoms included severe rectal pain, mucoid ing the stratified squamous epithelium) as well as infections of the
and/or hemorrhagic rectal discharge, tenesmus, constipation and rectum and colon, e.g. shigella, campylobacter, cytomegalovirus, ame-
other signs of lower gastrointestinal inflammation, sometimes severe, biasis. Differential diagnosis includes neoplastic lesions, perineal
whilst genital ulcers and inguinal adenopathy were rare. The resur- abscesses, and chronic conditions such as ulcerative colitis or Crohn’s
gence of LGV in settings where only a few imported cases had been disease. Investigations sometimes performed in resource-rich settings
seen each year, with its unusual clinical presentation, highlighted the include DNA amplification tests for N. gonorrhoeae and C. trachomatis,
need to have more accurate diagnostic, management and control though these have not been approved by the Food and Drug Admin-
tools. Studies conducted among men and women in Asia and Latin istration (FDA) for rectal specimens. Serology for syphilis and HIV are
America have shown a high prevalence of anorectal infections in MSM recommended.
64 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
NO
TREAT FOR
GONOCOCCAL INFECTION AND CHLAMYDIA TRACHOMATIS
Cervical mucopus/erosions or YES
High GC/CT prevalence setting¹ PLUS
or risk assessment positive? vaginal infection according to speculum and microscope
examination findings
NO
Perform wet mount microscopy of vaginal specimen for TV and yeast cells (optiional)
Risk factors need adaption to local social, ¹ The determination of high prevalance levels
behavioral and epidemiological situation needs to be made locally
FIGURE 7.8 Vaginal discharge: bimanual, speculum and microscope. Reproduced with permission from World Health Organization. Guidelines for the Management
of Sexually Transmitted Infections; Revised version. Geneva: WHO; 2003.
Partner Notification
CONTROL OF STIs Even in the case of easily treatable STIs, control is difficult because of
Given sufficient resources, it is possible to control curable STIs the high prevalence of asymptomatic infection in both men and
through the provision of accessible, acceptable and affordable clinical women. Partner identification and treatment is an important approach
services, combined with partner notification and screening programs to a frequently asymptomatic, high-risk population. In developing
in high-risk groups. In most developing countries, case management countries, resources are not usually available for the notification of
of STIs must be syndromic, because facilities for laboratory diagnosis partners by the healthcare provider. Patients must be relied on to refer
are unavailable outside a few specialist centers. their contacts(s). It is important that the clinician spend time
S ex u a l l y Tra n s m i t te d I nfec tions 65
Patient complains of
lower abdominal pain
YES
FIGURE 7.9 Lower abdominal pain. Reproduced with permission from World Health Organization. Guidelines for the Management of Sexually Transmitted Infections;
Revised version. Geneva: WHO; 2003.
explaining the importance of treating partners, both to avoid deaths per year [6]. This is one of the cheapest and most cost-effective
re-infection and to prevent sequelae in the partner and any future health interventions available. New simple, rapid, cheap point-of-care
children. Many clinics give contact notes to index cases to pass on to serologic tests for syphilis, which can be performed on whole blood
their sexual partners. Unfortunately, partner notification rarely results obtained from a finger prick, are now available [19]. Since they can
in the treatment of more than a small number of individuals. Alterna- be stored at room temperature, and require no laboratory equipment,
tive strategies, e.g. providing treatment to the index partner to provide they could greatly increase the coverage of prenatal syphilis screening
to his or her partner(s), have been piloted in trials in developing at the primary healthcare level in developing countries.
countries, but it is difficult to ascertain their impact. Moreover, there
are risks associated with partner notification in the context of syndro-
mic management, since women with vaginal discharge syndrome Male circumcision
frequently do not have an STI but an endogenous infection (VVC, This has been shown to reduce HIV incidence by about 60% in three
BV). Requesting them to refer their partner(s) for STI treatment may randomized controlled trials in African men, and also reduces the risk
be a waste of resources and may expose them to domestic violence. of acquiring some other STIs such as herpes and HPV [20,21].
Screening Vaccination
In view of the serious consequences of syphilis in pregnancy, serologic There are no vaccines against bacterial STIs. However, safe and effec-
screening for active syphilis is recommended for all women attending tive vaccination can be provided to prevent the sexual acquisition of
antenatal clinics [17,18]. Universal screening of pregnant women for hepatitis B virus (HBV), particularly in high-risk populations (e.g.
syphilis, and treatment with single-dose benzathine penicillin before homosexual men, injecting drug users, or prisoners). In addition, two
28 weeks’ gestation, could prevent more than 500,000 perinatal effective vaccines against oncogenic HPV strains 16 and 18, which
66 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
YES
TREAT FOR
GONORRHOEA AND CHLAMYDIA
TREAT MOTHER AND PARTNER(S) FOR GONORRHOEA AND CHLAMYDIA
• Educate mother
• Counsel mother
• Advise to return in 3 days
NO
Improved? Refer
YES
FIGURE 7.10 Neonatal conjunctivitis. Reproduced with permission from World Health Organization. Guidelines for the Management of Sexually Transmitted Infections;
Revised version. Geneva: WHO; 2003.
cause around 70% of cervical cancers worldwide, are now available in improving living conditions for the poor, particularly women, in
and are being given to young women in industrialized countries, but both the developed and the developing world.
they are expensive and are not yet available in most developing coun-
tries [22]. WHO has produced useful guidelines for the introduction
of HPV vaccines [23].
REFERENCES
Ocular Prophylaxis 1. Joint United Nations Programme on AIDS (UNAIDS). http://data.unaids.org/
pub/Report/2009/2009_epidemic_update_en.pdf
The prevention of neonatal conjunctivitis (also called ophthalmia
2. WHO. Global estimates of the prevalence and incidence of selected sexually
neonatorum) due to N. gonorrhoeae or C. trachomatis should be a transmitted infections: overview and estimates, 1999. Geneva: WHO; 2001.
simple matter. More than 100 years ago, Crede prevented the disease http://www.who.int/hiv/pub/sti/who_hiv_aids_2001.02.pdf
by the instillation of 1% silver nitrate drops into the eyes of infants 3. Grosskurth H, Mosha F, Todd J, et al. Impact of improved treatment of sexu-
at delivery. More recently, 1% tetracycline ointment, which is cheap, ally transmitted diseases on HIV infection in rural Tanzania: randomised
widely available and easy to store, was shown to be equally effective controlled trial. Lancet 1995;346:530–6.
[24]. Due to the spread of tetracycline-resistant gonococcal strains, This community randomized trial showed that improved syndromic management of
erythromycin 0.5% eye ointment may be more effective. Given the STIs in rural health centers in Tanzania reduced the incidence of HIV infection by
high incidence of neonatal conjunctivitis and its devastating conse- 38%.
quences (Fig. 7.10), this simple measure is one of the most cost- 4. Wawer MJ, Sewankambo NK, Serwadda D, et al. Control of sexually transmit-
effective health interventions available. Yet there are very few ted diseases for AIDS prevention in Uganda: a randomised community trial.
developing countries in which prophylaxis of neonatal conjunctivitis Rakai Project Study Group. Lancet 1999;353:525–35.
is systematically carried out. Moreover, a quadrivalent vaccine has 5. Kamali A, Quigley M, Nakiyingi J, et al. Syndromic management of sexually-
additional high effectiveness in preventing anogenital warts caused by transmitted infections and behaviour change interventions on transmission
HPV genotypes 6 and 11. of HIV-1 in rural Uganda: a community randomised trial. Lancet 2003;361:
645–52.
Ultimately, control of STIs depends on tackling social, cultural, gender 6. Schmid G. Economic and programmatic aspects of congenital syphilis preven-
and economic disparities in health and in accessing healthcare, and tion. Bull World Health Organ 2004;82:402–9.
S ex u a l l y Tra n s m i t te d I nfec tions 67
7. Weiss HA, Buvé A, Robinson NJ, et al. The epidemiology of HSV-2 infection 15. Pépin J, Sobéla F, Deslandes S, et al. Etiology of urethral discharge in West
and its association with HIV infection in four urban African populations AIDS Africa: the role of Mycoplasma genitalium and Trichomonas vaginalis. Bull World
2001;15(Suppl 4):S97–108. Health Organ 2001;79:118–26.
8. Fleming DT, Wasserheit JN. From epidemiological synergy to public 16. Mayaud P, Ka-Gina G, Cornelissen J, et al. Validation of a WHO algorithm
health policy and practice: the contribution of other sexually transmitted with risk assessment for the clinical management of vaginal discharge in
diseases to sexual transmission of HIV infection. Sex Transm Infect 1999; Mwanza, Tanzania. Sex Transm Infect 1998;74(suppl 1):77–84.
75:3–17. 17. Watson-Jones D, Changalucha J, Gumodoka B, et al. Syphilis and pregnancy
This excellent review assesses the evidence that other STIs enhance the sexual trans- outcomes in Tanzania. 1. Impact of maternal syphilis on outcome of preg-
mission of HIV, and considers the public health implications of interactions between nancy in Mwanza Region, Tanzania. J Infect Dis 2002;186:940–7.
HIV and other STIs. 18. Watson-Jones D, Gumodoka B, Changalucha J, et al. Syphilis in pregnancy in
9. Korenromp EL, White RG, Orroth KK, et al. Determinants of the impact of Tanzania II. The effectiveness of antenatal syphilis screening and single dose
sexually transmitted infection treatment on prevention of HIV infection: a benzathine penicillin treatment for the prevention of adverse pregnancy out-
synthesis of evidence from the Mwanza, Rakai, and Masaka intervention trials. comes. J Infect Dis 2002;186:948–57.
J Infect Dis 2005;191(Suppl 1):S168–78. This study, conducted in antenatal clinics in Tanzania, showed that a single dose of
10. Nagot N, Ouedraogo A, Foulongne V, et al. Reduction of HIV-1 RNA levels benzathine penicillin, given before 28 weeks’ gestation, prevents adverse pregnancy
with therapy to suppress herpes simplex virus. N Engl J Med 2007;356: outcomes due to syphilis.
790–9. 19. Mabey D, Peeling RW, Ballard R, et al. Prospective, multi-centre clinic-based
11. Watson-Jones D, Weiss HA, Rusizoka M, et al. Effect of herpes simplex sup- evaluation of four rapid diagnostic tests for syphilis. Sex Transm Infect
pression on incidence of HIV among women in Tanzania. N Engl J Med 2008; 2006;82(suppl v):v13–16.
358:1560–71. 20. Siegfried N, Muller M, Deeks JJ, Volmink J. Male circumcision for prevention
12. Celum C, Wald A, Lingappa JR, et al. Acyclovir and transmission of HIV-1 of heterosexual acquisition of HIV in men. Cochrane Database Syst Rev
from persons infected with HIV-1 and HSV-2. N Engl J Med 2010;362: 2009;(2):CD003362.
427–39. 21. Tobian AA, Serwadda D, Quinn TC, et al. Male circumcision for the preven-
This study among HIV-discordant couples in whom the HIV-positive partner was tion of HSV-2 and HPV infections and syphilis. N Engl J Med 2009;
HSV-2 seropositive showed that suppressive treatment of the HIV-positive partner 360:1298–309.
with acyclovir did not reduce transmission to the HIV-seronegative partner 22. Louie KS, de Sanjose S, Mayaud P. Epidemiology and prevention of human
13. Celum C, Wald A, Hughes J, et al. Effect of aciclovir on HIV-1 acquisition in papillomavirus and cervical cancer in sub-Saharan Africa: a comprehensive
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a randomised, double-blind, placebo-controlled trial. Lancet 2008;371: 23. World Health Organization. Preparing for the introduction of HPV vaccines.
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This study, and reference 11, showed that suppressive treatment with acyclovir did www.who.int/reproductivehealth/publications/cancers/RHR_06.11/en/index.
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14. World Health Organization. Guidelines for the Management of Sexually ophthalmia neonatorum. A comparison of silver nitrate and tetracycline.
Transmitted Infections; Revised version. Geneva: WHO; 2003. N Engl J Med 1988;318:653–7.
8 Tropical Dermatology
Arturo Saavedra, David Rosmarin
accompanying sign. There are five different types, with the AIDS-
associated type commonly being the presenting manifestation that
leads to a diagnosis of HIV. Gastrointestinal and pulmonary involve-
ment by Kaposi sarcoma can lead to death from hemorrhage, hemo-
ptysis or bowel obstruction.
Tuberculosis verrucosa cutis occurs by direct contact. A papule forming Cutaneous anthrax, caused by Bacillus anthracis, is usually due to
a verrucous plaque with centrifugal progression and central scarring contact with livestock, animal products or soil. Initially, there is pru-
is typical. ritus at the site of inoculation, followed by the development of a
papule. Vesicles may surround the papule and coalesce until there is
Scrofula and scrofuloderma result when there is contiguous spread rupture and formation of a 4–6-cm ulcer. There is significant perile-
from underlying necrotic tuberculoid lymph nodes. The neck is the sional edema. The ulcer develops a thick black, depressed, painless
most common site of involvement. A firm, deep, adherent, purple-red eschar that is characteristic of the disease. Cutaneous infection can
nodule may become fluctuant, suppurate or ulcerate, and form a cause systemic illness. The differential diagnosis includes orf, bullous
fistula. Less commonly, self-inoculation near natural orifices can lead impetigo, plague, a burn, rickettsial eschar, ecthyma gangrenosum
to tuberculosis cutis orificialis that appears as yellow-red nodules in and cutaneous diphtheria, although perilesional edema surrounding
or near the mucosa. These lesions frequently ulcerate and are tender. an eschar strongly suggests cutaneous anthrax. In addition to the
Lupus vulgaris is a destructive process that usually involves the face, cutaneous form of anthrax, which represents 95% of cases, there are
leaving central atrophy. Lupus vulgaris needs to be differentiated from also gastrointestinal and pulmonary anthrax that follow ingestion
leishmaniasis, sarcoidosis, discoid lupus erythematosus, cutaneous and inhalation of spores, respectively.
T-cell lymphoma, tuberculoid leprosy, pyodermatitis vegetans and Plague is caused by Yersinia pestis carried by fleas and is maintained
paracoccidioidomycosis. Dermatologic manifestations of dissemi- in a number of rodent reservoirs. At the site of a flea bite, a papule,
nated miliary tuberculosis include papules and pustules that are dif- pustule, vesicle, ulcer or eschar may develop, and patients have high
fusely distributed throughout the body. Papulonecrotic tuberculids fever and appear systemically ill. Regional lymph nodes may become
are firm, pustulonecrotic, symmetric papules on the extensor surfaces swollen, warm and very tender (buboes). If the bacteria enter into the
that resolve over several weeks. Lichen scrofulosorum consists of tiny, blood, disseminated intravascular coagulopathy, sepsis, petechiae,
flat-topped, keratotic papules on the trunk which grow in groups. purpura fulminans and acral gangrene can occur.
Erythema induratum appears as symmetric, erythematous subcutane-
ous nodules on the posterior calves with overlying atrophy and slight Cutaneous diphtheria, caused by Corynebacterium diphtheriae, presents
scale, commonly in middle-aged women. It is thought to be a hyper- in a variety of ways, including an anesthetic ulcer called ecthyma
sensitivity reaction during tuberculosis. Erythema nodosum may diphthericum which begins as a vesicle. A membrane may be adher-
appear similar, but is more often on the shins, is more painful, and ent. Infection of the respiratory tract causes a low-grade fever, sore
does not ulcerate. throat, and purulent nasal discharge which may become erosive. An
adherent grayish pseudomembrane may develop on the tonsils, with
Skin lesions can also be due to nontuberculous mycobacteria. Rapidly
significant “bull neck” cervical edema and lymphadenopathy.
growing M. fortuitum and M. chelonae/abscessus can cause subcutane-
ous abscesses or cellulitides. M. marinum can lead to erosions, ver- Cancrum oris or noma pudenda is a progressive polymicrobial infec-
rucous papules or plaques, and is commonly acquired from aquariums tion of the face that leads to destruction and ulceration, most com-
or lakes. M. marinum, M. kansasii and other nontuberculous myco- monly in severely malnourished children.
bacteria can cause lesions in a sporotrichoid (lymphangitic) pattern
(Fig. 8.3). M. ulcerans is the cause of Buruli ulcer, a chronic process In Old World cutaneous leishmaniasis, a papule first forms at the site
that first manifests as a solitary, indurated, painless nodule that ulcer- of a sandfly bite. Next, a well-defined ulcer with surrounding ery-
ates and develops undermined borders. Buruli ulcers most often affect thema, crusting and variable pyoderma is usually noted. The “oriental
children living in Australia and Africa, and less frequently in Latin sore” may also exhibit undermined ulcer edges that have been con-
America. fused for smaller lesions of pyoderma gangrenosum. Most lesions
heal with minimal scarring, atrophy or depigmentation in a self-
Rickettsialpox is caused by Rickettsia akari and transmitted by the bite limited fashion over 6–24 months. The lesions may vary wildly in
of rodent-associated mites. At the site of inoculation, an erythematous size and depth, as smaller satellite lesions may coalesce with the
papule first occurs, which then develops into a vesicle that then rup- primary ulcer. Ulcers may be “wet” or “dry.” Leishmanial lesions are
tures and ulcerates. An eschar can occur. There is often an accompany- not painful. Hyperkeratotic variants occur. In diffuse cutaneous leish-
ing papulovesicular eruption, as well as regional lymphadenopathy, maniasis (DCL), the initial papule rarely ulcerates, but rather, several
and patients are febrile and report headache and myalgia. other papules appear with minimal erythema or pigmentation out-
wardly spreading from the initial site. As lesions evolve, they may
become deeper and nodular. A chronic form of cutaneous disease
called leishmania recidivans causes sarcoidal-appearing lesions, with
outwardly enlarging dermal induration and central clearance. If
pressed against a glass slide, the erythematous to violaceous colora-
tion and dusky nature of the lesion may blanche into an “apple-
green” appearance, reflecting the presence of histiocytes and other
chronic inflammatory cells in tissue. Post-kala-azar dermal leishma-
niasis (PKDL) refers to diffuse nodular involvement that occurs fol-
lowing resolution of visceral leishmaniasis (kala-azar). Multiple
primary morphologies may be noted, including diffuse macules,
papules and nodules.
Cutaneous New World leishmaniasis appears similar to the Old
World variant. A specific New World mucocutaneous manifestation
of L. braziliensis is termed espundia. Following resolution of a pri-
mary skin lesion, leishmania infection can relapse, specifically
involving oro-naso-mucosal membranes, including the nasal septum,
pharynx, larynx and buccal mucosa. Untreated, mucocutaneous
leishmaniasis can be disfiguring and can lead to central destruction
of the face.
Rhinosporidiosis may rarely be confused with mucosal leishmania.
FIGURE 8.3 Atypical mycobacteria. These papulonodular lesions assemble The physical examination is notable for pedunculated polyps,
almost in a linear distribution, suggestive of lymphangitic spread. Note the often arising from nasal mucosa and conjunctiva, but also may be
lack of scale or ulceration that could otherwise resemble papulonecrotic found in the genitals. Rarely, cutaneous, non-mucosal disease is
tuberculid. documented.
Tro p i c a l D er matology 71
SUBCUTANEOUS MYCOSES cutaneous lesions may present with verrucous papules or ulcers
similar to subcutaneous mycoses.
Direct inoculation of a fungus into the skin, often by a splinter or
other trauma, may result in a subcutaneous mycosis. Clinically, sub-
cutaneous mycoses result in an ulcer or verrucous plaque. The most PAINLESS PAPULES
common types are sporotrichosis, mycetoma, chromoblastomycosis,
Molluscum contagiosum manifests as umbilicated papules that can
phaeohyphomycosis and lobomycosis. Treatment can be difficult and
coalesce into plaques. Clinicians may confuse the diagnosis with
may require long courses of oral antifungals, cryotherapy or surgical
herpetic disease, but relatively simple bedside maneuvers can assist in
excision, alone or in combination.
diagnosis. Lancing lesions of molluscum leads to extravasation of a
Sporotrichosis is caused by Sporothrix schenckii and follows direct “white cheesy material” which can be stained with hematoxylin and
inoculation, classically involving thorns or cats’ claws. Lymphangitic eosin, revealing eosinophilic globules. In the patient with unknown
spread is common. This type of sporotrichoid spread is also seen in HIV status, confluent facial molluscum contagiosum is a reason to
atypical mycobacteriosis, leishmaniasis and nocardiosis, and differs test for HIV. Therapy is often via destruction with curettage or cryo-
from regional lymphadenopathy. therapy, or with reconstitution of the immune system in those with
deficiencies.
Chromoblastomycosis usually manifests as a classic verrucous plaque.
Central atrophy with scarring may also be seen. Chromoblastomyco-
sis is due to dematiaceous (melanin-producing) fungi, often Fonsecaea
pedrosoi, and most commonly involves the lower extremities of indi-
PAINFUL PAPULES/URTICARIA
viduals involved in soil-related occupations. Infestation of skin with fly larvae is called myiasis. A large, tender,
cyst-like structure or papule may be noted with surrounding ery-
Phaeohyphomycosis can manifest in a number of ways, most com- thema, a central punctum and occasional suppuration. Patients
monly as black eschars with scalloped, erythematous borders. Subcu- usually report movement within the lesions. Lesions may be multiple.
taneous abscesses should be excised. New World myiasis is caused by the botfly; Old World disease is most
Lobomycosis due to Lacazia loboi is reported in areas of Latin America, commonly caused by the tumbu fly. Treatment involves asphyxiating
and manifests as asymptomatic, smooth-surfaced, keloidal lesions, the larvae, usually via application of an occlusive dressing or sub-
often on the ear. stance, followed by larval extrusion. Surgical excision may sometimes
be required. Bacterial suprainfection can occur.
Mycetoma, or Madura foot, is caused by bacteria (actinomycetoma)
or fungi (eumycetoma). The clinical presentation is one of an asymp- Tungiasis (also called jiggers) is caused by Tunga penetrans, the sand
tomatic, subcutaneous swelling with sinus tracts that discharge “gran- flea. The female flea burrows into skin, usually on the feet, but can
ules” or “grains.” Granules from bacteria tend to be lighter in color, involve any exposed skin area, creating a callus-like papule, often with
whereas granules from fungi tend to be dark. Radiologic imaging some hyperpigmentation. The terminus of the flea is often visible in
should be performed as bone involvement is common. the center of the lesion. Pain is usually present. Treatment involves
mechanical removal.
Zygomycoses are divided into two types – the opportunistic type typi-
fied by mucormycosis that affects hosts immunosuppressed by dis- Many insect bites and plant dermatitides occur in the tropics. The
eases other than AIDS, such as diabetes, and entomophthoromycosis physical examination is often helpful at suggesting the diagnosis.
that affects immunocompetent hosts living in the tropics. Mucormy- Insect bites may result in erythematous papules of variable size and
cosis commonly presents around the nose, forming black necrotic distribution. Urticarial-like erythema is seen around lesions, at times
tissue and involving the orbit and brain, while entomophthoromy- enlarging far over 10 cm in diameter. A number of beetles, millipedes
cosis forms a solitary, painless nodule or slowly expansile mass, most and centipedes can cause a severe contact dermatitis. Plant der-
commonly on an extremity. matitides may manifest in both acute and chronic forms, depending
on the repetitive nature of contact. Whereas contact dermatitis is the
most common presentation, characterized by vesicles on an ery-
DEEP MYCOSES thematous base in a linear or geographic distribution, chronic disease
Aside from subcutaneous mycoses, deep cutaneous fungal infections may present as eczematous dermatitis. Occupational disease, as seen
often result from systemic infection. The cutaneous presentations are in florists or gardeners, can present as atopic dermatitis of the hands,
protean. Sometimes, cutaneous infection causes erythema nodosum, with severe dryness, scaling, cracking, erythema, and even fibrotic-like
sterile, tender erythematous nodules on the shin which have a favo- constriction in palmar function.
rable prognosis. Other times, there is a nonspecific presentation such
as a morbilliform eruption. Accompanying signs and symptoms of
fever, gastrointestinal upset and emaciation aid in the diagnosis of a PRURITUS AND PAPULES
systemic infection. Schistosomal cercarial dermatitis can occur at the site of skin penetra-
Histoplasmosis may present with mucocutaneous ulcerations and tion with the infectious form of Schistosoma spp. following water
granulomas. Care must be taken not to misdiagnose as sarcoidosis. exposure. Nonhuman Schistosome spp., especially avian species, can
Children sometimes present with purpura, fever, fatigue and gastroin- cause prominent dermatitis that may manifest as multiple, highly
testinal symptoms. Blastomycosis is endemic in North America and pruritic, erythematous papules. Distribution is of skin exposed to
often affects the bone, particularly ribs and vertebrae along with the infectious water. Seabather’s eruption can cause similar lesions but is
skin. The cutaneous lesions are multiple, growing slowly, forming caused by larval forms of coelenterates (jelly fish), but distribution
verrucous and granulomatous lesions with thick crust overlying gran- usually reflects a “bathing suit” distribution, since the larvae become
ulation tissue and sometimes central white scars. Paracoccidioidomy- entrapped by clothing. Pediculosis (or lice) is caused by louse infesta-
cosis is endemic in Latin America. It may present with mucocutaneous tion. Different lice are responsible for each form of human involve-
disease, most commonly of the gingiva, with small papules and ulcer- ment: corporis (body), capitis (head) and pubis (genitals). Louse
ations. The disease is fifteen times more common in men than in infestation can result in pruritus and excoriations. The body louse
women. Penicilliosis is endemic in Southeast Asia, sometimes causing (Pediculus humanus corporis) takes a daily blood meal, but lives in
umbilicated papules or oral lesions. Cryptococcus has a particular clothing. It is transmitted from person to person, usually in over-
affinity for the central nervous system and skin. crowded and impoverished conditions, and during periods of war and
social unrest. The head louse (Pediculus humanus capitis) is also trans-
In patients with AIDS, coccidioidomycosis, histoplasmosis, penicil- mitted from person to person. It is particularly common in school-
liosis and molluscum contagiosum may all appear as umbilicated aged children. Pubic lice (Phthirus pubis) are spread by sexual contact,
vesicles, and be indistinguishable on clinical examination. Primary creating intense pruritus in the groin, commonly known as “crabs”.
72 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Lice can be seen adherent to pubic hair. Symptoms are regional, pathology of these lesions may mimic insect bites. Interestingly,
although lice and nits may occasionally be seen on eyelashes. symptoms as well as response to therapy may correspond with the
CD4 count in HIV-infected individuals. Finally, when these papules
Scabies is an important infestation caused by Sarcoptes scabei mites; it show a necrotic center, the patient is less pruritic, and the diagnosis
is often misdiagnosed. The organism burrows superficially, just under- of papulonecrotic tuberculosis needs to be considered. Acne-like
neath the stratum corneum. It does not penetrate the skin, and as nodules and papules in a sun-exposed distribution should raise sus-
such it is not a true infection. Contrary to common belief, dermatitis picion for eosinophilic folliculitis which may manifest during the
does not occur immediately following infestation. Dermatitis occurs immune reconstitution syndrome, but may also suggest viral resist-
as a hypersensitivity reaction created by the mite, its eggs or its excre- ance, worsening CD4 counts, or untreated infection altogether.
ment, termed scybala. Clinical findings vary according to the immune
status of the host. Immunocompetent patients suffer from extreme
pruritus. Close inspection reveals erythematous papules or nodules,
with superficial crusting and excoriation, and there is a particular
PRURITUS WITHOUT PRIMARY
predilection for involvement of genital, intertriginous and acral skin SKIN LESIONS
(Fig. 8.4). In immunosuppressed hosts, the infirm, or institutional-
In patients who have severe pruritus and minimal primary skin mani-
ized patients, a functionally debilitating pruritic dermatosis can occur.
festations, it is important to evaluate for underlying causes. The dif-
There is a specific association of severe scabies and infection with
ferential diagnosis includes obstructive liver disease, chronic hepatitis,
HTLV-1. In these severe cases, patients present with disseminated
uremia, hypo- and hyperthyroidism, hematopoietic diseases, poly-
eczematous dermatitis, nodules and, occasionally, generalized urti-
cythemia vera, lymphoma, leukemia, myeloma, internal malig
caria. Late findings include hyperpigmentation, lichenification and
nancies, intestinal parasites, carcinoid, multiple sclerosis, AIDS,
psoriatic-like lesions. Also denoted Norwegian or crusted scabies, this
medications and neuropsychiatric diseases, especially anorexia
diffuse involvement may progress to wart-like lesions. In the elderly,
nervosa. In a patient presenting with idiopathic pruritus, a thorough
lesions may appear bullous, often mimicking bullous pemphigoid.
physical examination is warranted, along with the following labora-
In the newborn, lesions may be vesicular, and the disease may present
tory tests: complete blood count with differential, thyroid-stimulating
as failure to thrive. Pustular diseases of the newborn, including acro-
hormone, liver function tests, renal panel, hepatitis serologies, HIV
pustulosis and neonatal acne, may be considered, but the dissemi-
antibody, urinalysis, stool guaiac, chest x-ray, stool for ova and para-
nated nature of the disease, examination of the vesicular fluid, as well
sites, and possibly serum protein electrophoresis. While topical ster-
as a diagnostic examination of a scraping following application of
oids can often provide relief for patients who itch due to pruritic skin
mineral oil to identify mites or their products, can quickly aid in
disorders, if there is an internal cause, the pruritus is often recalcitrant
making the correct diagnosis. Topical treatments for limited disease
to topical treatments, and a search for correcting the underlying cause
include permethrin 5% cream, lindane, crotamiton 10% cream,
becomes even more essential.
sulfur, malathion and ivermectin lotion. Crusted or nodular scabies
and disease in the immunosuppressed often require systemic ivermec-
tin at 200 mcg/kg. The entire family, including pets, should be treated,
and clothes, bedding, and frequently used fomites should be imme-
HYPOPIGMENTATION/
diately washed in warm water. A second treatment a week after is DEPIGMENTATION
usually recommended. Oral antipruritics may be needed.
Vitiligo is a common autoimmune disease in the tropics. Caused by
Prurigo nodularis manifests as hyperkeratotic nodules, linear excoria- selective melanocyte destruction, patients present with depigmented
tions and lichenification, particularly over areas that the patient can patches that can involve all cutaneous surfaces and hair. Wood’s light
reach. In this condition, patients may experience diffuse or focal examination may be useful in distinguishing complete depigmenta-
pruritus. Rather than scratching, patients tend to “pick”, creating tion from hypopigmented skin, particularly if post-inflammatory
“picker nodules”. Therapy is with topical or injectable steroids or hypopigmentation resulting from prior dermatologic disease is sus-
phototherapy. Nodules may also raise concern for scabies, particularly pected. Seborrheic dermatitis, pityriasis alba, early tinea infections
in the patient with severe pruritus. It is important to consider the and secondary syphilis may cause such hypopigmentation in skin. It
diagnosis of papular eruption of HIV, where patients develop ery- is important to highlight that hypopigmentation may also be seen in
thematous papules with urticarial-type erythema. Chronic cases may so-called “trichrome” vitiligo, where a transition from normal skin to
resemble prurigo nodularis. Recent reports have shown that the hypopigmented and then depigmented skin is noted. Unfortunately,
the disease is often colloquially confused for leprosy, particularly in
Southeast Asia, and affected patients can be subject to discrimination.
Attention must also be paid to other systemic autoimmune diseases
that may include anemia and thyroid disease.
MORBILLIFORM EXANTHEMS
Individuals with measles develop a morbilliform exanthem, usually
in the setting of fever and coryza. For the purpose of this discussion,
such an exanthem describes erythematous, blanchable macules,
patches, papules, and occasionally even plaques, on a hyperemic
background. Koplik spots are almost pathognomonic, and manifest
in the mouth as white papules with surrounding erythema of sand-
grain-like texture. They often precede the rash by 1–2 days. The exan-
them starts in the forehead and neck, and then generalizes to the
trunk and extremities. Clinical symptoms such as fever, malaise and
coryza are often present. Cases may be difficult to correctly diagnose
in those who have previously been vaccinated and present with atypi-
cal measles. Unlike its common form, patients with atypical measles
lack coryza and Koplik spots, but may present with high fever, pneu-
monia, hepatitis, edema and paresthesias. In this case, skin lesions
FIGURE 8.4 Scabies. Scabies incognito in which an elderly patient with a may be vesicular, hemorrhagic and urticarial. Clinical prodromes in
neuropathy had a nonspecific, asymptomatic hand “rash” that proved to addition to a morbilliform exanthem may indicate the presence of
be due to crusted scabies. other viral infections.
Tro p i c a l D er matology 73
Human monocytotropic ehrlichiosis (HME), caused by Ehrlichia chaf- body. This can sometimes be confused with erythema gyratum repens
feensis, human granulocytotropic anaplasmosis (HGA), caused by which is associated with an underlying malignancy. However, a KOH
Anaplasma phagocytophilium, and Ehrlichiosis ewingii infection lead to stain will help differentiate these two diseases.
nonspecific symptoms such as fever, chills, headaches and leukope-
nia. A macular and papular skin eruption on the trunk and extremities Nondermatophyte superficial mycosis includes tinea versicolor, a
is more common in pediatric patients with these infections than in chronic mildly pruritic scaly discoloration of the upper trunk, arms
adults. The cutaneous manifestations often occur after other systemic and neck caused by Malassezia spp. On KOH scraping, a characteristic
symptoms arise. “spaghetti and meatball” pattern is seen, corresponding to the short
thick hyphae and spores. Even after treatment and cure, the hypopig-
Trench fever, caused by Bartonella quintana, gives rise to a nonspecific mentation may persist for months.
morbilliform eruption of the trunk, along with systemic symptoms.
Tinea nigra, caused by Hortaea werneckii or Stenella araguat, is found
primarily in Africa, Asia, the Caribbean and Latin America. Clinically,
PAPULOSQUAMOUS AND it causes a solitary, asymptomatic, light brown macule, often on the
ECZEMATOID LESIONS palm, that darkens and grows. Though confused with melanoma, this
lesion will scrape off, and can be confirmed with KOH staining.
Papulosquamous lesions are rashes that are both raised and have Topical azoles or keratolytics can be used for treatment.
scale, such as psoriasis and tinea corporis (Table 8-1). In tineasis, the
Black piedra, caused by the astromycete Piedraia hortae, is found pri-
dermatophytes Microsporum, Trichophyton and Epidermophyton infect
marily in Africa, Asia and Latin America. It causes black, hard, fixed
keratinized tissue. Characteristically, they appear as erythematous,
nodules attached to the hair. White piedra is most commonly caused
annular plaques, with serpiginous borders, with scale at the leading
by Trichosporon beigelii, and manifests as yellow or beige soft sheaths
edge, and are named based on the location of involvement: tinea
coating hair shafts. Treatment for black and white piedra consists of
capitis – scalp; tinea corporis – body; tinea faciei – face; tinea cruris
a short haircut, although antifungals can also be used.
– groin; tinea pedis – feet; tinea manuum – hand; tinea barbae –
beard; tinea unguium – nails. Diagnosis can be confirmed by per- Candida is a commensal inhabitant of the gastrointestinal and geni-
forming a scraping of the scale and applying one or two drops of tourinary tracts, but is also a pathogen which grows during conditions
potassium hydroxide (KOH) and visualizing the hyphal structures of warmth, moisture and increased pH. Thrush, or oral candidiasis,
under 10× magnification. The differential diagnosis includes other manifests as grayish-white plaques in the mouth that scrape off. Per-
papulosquamous or scaly raised lesions (see Table 8-1). For limited lèche is candida-associated erythematous scaling at the angles of the
disease, topical antifungals are usually effective, except for tinea capitis oral commissure that can mimic some nutritional deficiencies. Can-
and onychomycosis, which often require oral antifungal medications. didiasis often affects the perianal region, inguinal folds and inframam-
As recurrence is common, multiple courses of therapy are often mary areas, and manifests as beefy red erythema with satellite lesions
required. and occasional pustules. Antibiotics and immunosuppression predis-
pose to candidiasis.
Tinea capitis causes circular, scaly patches on the scalp with alopecia
and black dots caused by breakage of the hair shaft. Some causative M. leprae usually affects skin on the extremities, which is cooler in
species such as Microsporum audouinii fluoresce on Wood’s lamp exam- temperature, while sparing warmer areas of the body, including the
ination. Favus is a particular type of tinea capitis which causes yellow, axilla and scalp. There is a wide range of disease, from the limited
concave cup-shaped crusts on the scalp around loose hairs and is tuberculoid type to the diffuse lepromatous type of leprosy (Hansen’s
caused by T. schoenleinii. There is a characteristic mousy odor which disease). In tuberculoid leprosy, there are well-demarcated solitary,
aids in the diagnosis. KOH staining of an affected hair shows air hypopigmented plaques with raised borders and slight scale. The
bubbles in the shaft. hypoesthesia, absence of hair and lack of sweating within the lesions
is very characteristic. In lepromatous leprosy, owing to an absence of
Tinea imbricata is a rare form of tinea corporis due to Trichophyton
cell-mediated immunity, there are numerous small hypopigmented
concentricum that causes concentric, polycyclic, scaly rings over the
or erythematous macules that are ill-defined. Loss of the lateral
eyebrow, leonine facies, madarosis, glove-and-stocking neuropathy,
claw-finger and toe deformities are late manifestations. Borderline
lesions exist between the continuum of tuberculoid and lepromatous
TABLE 8-1 Differential Diagnosis leprosy.
of Papulosquamous Lesions Other diseases that cause hypopigmentation include pityriasis
alba, post-inflammatory hypopigmentation and tinea versicolor.
Uniform scale Annular scale Tinea versicolor also causes a hypopigmented scaly thin plaque
Psoriasis Tinea types (Fig. 8.5). A Wood’s lamp can be helpful in demonstrating that the
lesions in leprosy and tinea are hypopigmented and not depig-
Pityriasis rubra pilaris Pityriasis rosea mented as in vitiligo. The differential diagnosis also includes papu-
losquamous disorders such as cutaneous T-cell lymphoma, pityriasis
Mycosis fungoides Porokeratosis rosea, para-psoriasis, lupus erythematosus, sarcoidosis and second-
Subacute lupus Secondary syphilis ary syphilis.
FIGURE 8.5 Tinea versicolor. This chronic disease is characterized by FIGURE 8.6 Ichthyosis. Note the fine white scales in the lower extremities.
macules and thin patches and plaques with subtle scale. The term versicolor
refers to the changing coloration of lesions, often appearing lighter than fail to indicate a superficial cutaneous infection, though ectopic infec-
surrounding tan skin in the summer, but darker than sun-protected skin tion such as streptococcal pharyngitis may precipitate an attack.
during colder months. Though oral steroids may improve symptoms, upon withdrawal,
disease can re-flare.
Pityriasis rubra pilaris, a close relative of psoriasis, may also be the
Tertiary, late-stage syphilis may manifest as noduloulcerative lesions cause of erythroderma. Patients often have conspicuous “islands of
consisting of reddish-brown firm nodules. sparing”, where seemingly normal skin is noted among erythroder-
HTLV-1 infection may be associated with a number of dermatologic mic skin. Hyperlinearity may be seen in palms and soles, in addition
conditions. HTLV-1 infection is most frequently recognized in the to a salmon-colored, sand-papered type of scale with sharp demarca-
Caribbean, and areas of Asia and Latin America, and in the latter is tion along transgrediens lines (the line boundary between cutaneous
most frequently reported among Amerindian populations. Patients skin and the sole of the foot, for instance).
may present with recalcitrant eczematoid dermatitis, seborrheic der- Other important diagnoses to consider include atopic dermatitis, viral
matitis and blepharitis. The diagnosis is usually made after several exanthems, cutaneous T-cell lymphoma, which in the leukemic phase
attempts at controlling the eruption with topical steroids or immu- is termed Sézary syndrome, the staphylococcal skin scalded syndrome,
nomodulators. In adults, dermatologic disease may be a presenting as well as toxic shock syndrome. In HIV-positive individuals or those
manifestation of adult T-cell leukemia. Affected patients present with with other immunosuppressing disorders, seborrheic dermatitis may
disseminated papules that coalesce into plaques and nodules, with lead to erythroderma. Uncommonly, systemic malignancies such as
striking infiltrative morphology. Patients also have systemic symp- colon and lung carcinoma, as well as lymphoma and leukemia, can
toms and the systemic evidence of acute T-cell leukemia, including also be culprits. In those who have had a bone marrow transplant,
hepatosplenomegaly, systemic lymphadenopathy and central nervous erythroderma may be a result of graft-versus-host disease. Red man
system involvement. Affected patients will exhibit circulating leuke- syndrome indicates a state of erythroderma where no clear culprit can
mic cells, termed “flower cells” or “ATL cells”. The disease is often fatal, be ascertained.
but smoldering forms, chronic disease and lymphoma-type disease
have also been reported.
ICTHYOSIS
ERYTHRODERMA Fish-like scaling on cutaneous surfaces (ichthyosis) may be seen in a
variety of conditions, both congenital and acquired. Disease may
Correctly diagnosing the cause of diffuse erythroderma or whole- range from limited and asymptomatic, to disseminated and life-
body erythema presents a unique challenge to the physician. These threatening. Most commonly, ichthyosis vulgaris is inherited in an
patients may present with marked systemic symptoms, and can suffer autosomal dominant fashion, and develops as scaling over relatively
severe morbidity from lack of epidermal barrier function, including uninflamed skin. Usually, antecubital fossae are spared. Scales may
dehydration, infection and severe pain. Ectropion may be seen. become hyperpigmented and feel tightly adherent to underlying skin
Diffuse erythema can lead to severe imbalances of electrolytes and (Fig. 8.6). It may be coincident with atopic dermatitis or its associated
minerals, and hypocalcemic tetany can occur. As the eruption findings, such as the follicularly based, spiny, hyperkeratotic papules
improves, generalized exfoliation is the norm. The evaluation of of keratosis pilaris over the upper extremities and thighs. Though
patients with erythroderma often requires histopathologic evaluation, ichthyosis may be the presenting sign of a lymphoma, it is found most
to exclude full-thickness epidermal necrosis, including toxic epider- commonly in the general population and may go unnoticed. Con-
mal necrolysis (TEN). TEN is commonly caused by a drug, but infec- genital ichthyoses include lamellar disease, which is inherited in an
tious etiologies have also been implicated, particularly mycoplasma autosomal recessive pattern. Ectropion and alopecia may be a distin-
and herpetic infections. guishing feature. The scale is often likened to “reptile skin”. Though
Erythroderma may be caused by severe drug reactions. The presence it can be seen in adults, patients readily exhibit disease in their early
of small, superficial pustules may indicate exanthematous generalized years, even at birth. X-linked ichthyosis presents as adherent fish-like
pustular dermatosis (AGEP), most commonly caused by β-lactam and scaling, usually hyperpigmented and giving an impression of “dirty
cephalosporin antibiotics. Patients present with fever and can have skin”.
peripheral blood leukocytosis, commonly prompting evaluation for
an infectious disease. A similar finding may be noted in pustular
psoriasis, which may occur in patients with no prior history of pso-
SERPIGINOUS LESIONS
riasis. Though nail findings may be helpful in those with prior history, Cutaneous larva migrans is caused by zoonotic hookworms. Also
such findings may not be seen in those with an acute, first episode. referred to as “creeping eruption”, the primary lesion is a serpiginous,
Patients appear ill and are often hospitalized. Cultures of the pustules slightly swollen, erythematous lesion that may induce local urticaria
Tro p i c a l D er matology 75
EDEMA
Lymphatic filariasis is associated with lymphangitis, and recurrent
and worsening episodes of lymphedema. Lymphedema is due to web spaces, genital involvement, and evidence of the causative mite
impedance in lymphatic flow, or outright lymphatic channel destruc- on a mineral oil preparation can usually readily diagnose the latter
tion. Lichenification, fissuring and scaling can be seen in longstanding condition. Of note, hyperpigmentation is not a distinguishing feature
infections. End-stage disease can be mistaken for elephantiasis ver- in differentiating among these diseases, as chronic infection in both
rucosa nostra from chronic stasis dermatitis, as well as podoconiosis, may lead to atopic dermatitis-like disease and patchy hypo/
the latter caused by lymphatic obstruction secondary to silica-laden hyperpigmentation. Plate-like ichthyosis over leathery skin with
volcanic ash. Unilateral chronic extremity edema should prompt con- hypo/hyperpigmentation, commonly referred to as leopard skin,
sideration of filariasis or a unilateral obstructing mass in the draining would point to the diagnosis of chronic onchocerciasis. Loss of elas-
lymph nodes. Other important clues to the diagnosis of lymphatic ticity of skin can lead to “hanging groin”.
filariasis include testicular hydrocele and lymphadenopathy.
Trichinosis can also be the cause of edema, though in this case, peri-
Loiasis is a filarial infection in which the adult Loa loa worm migrates orbital, nondependent edema is most commonly noted. Other der-
in subcutaneous tissue and across the conjunctiva (“eye worm”). matologic findings may include a hypersensitivity-like petechial rash,
Localized edema from a hypersensitivity reaction can occur over xerosis and subconjunctival hemorrhage.
joints and bony prominences as the worm passes, so-called Calabar
swellings. Peripheral eosinophilia is prominent. Compared to American trypanosomiasis can be difficult to diagnose acutely given
lymphatic filariasis, loaiasis-associated edema is transient and its nonspecific systemic and dermatologic manifestations. Distin-
migratory. guishing features of acute disease include the so-called “chagoma”,
where the protozoal inoculum causes subcutaneous swelling, indura-
Onchocerca volvulus, the causative organism of onchocerciasis (river tion and erythema accompanied by local lymphadenopathy. When
blindness), is another filarial infection that often first manifests in the the eye is the portal of entry, Romaña’s sign may develop, comprised
skin. Microfilariae are produced by adult worms that reside in subcu- of unilateral, painless, periorbital edema and conjunctival swelling.
taneous nodules, so-called onchocermata. Microfilariae migrate freely African trypanosomiasis also includes skin manifestations. A chancre
through subcutaneous and ocular structures. Dying microfilariae can develop at the site of a bite from an infecting tsetse fly. The lesion
provoke an intense inflammatory response, leading to pruritus and can rapidly enlarge and ulcerate, and can be associated with local
excoriations, and a diffuse papular dermatitis. Papules and plaques lymphadenopathy. In East African trypanosomiasis, caused by T.
can be seen with overlying lichenified streaks indicating chronic rhodesiense, high fever and toxemia are common, and patients often
scratching and rubbing by afflicted patients. Scabetic infection may present for clinical attention. A diffuse macular rash may also be
enter the differential diagnosis, but linear burrows along interdigital present. In West African trypanosomiasis, caused by T. gambiense,
76 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
initial skin involvement may be mild, and patients often only come Cestari TF, Pessato S, Ramos-e-Silva M. Tungiasis and myiasis. Clin Dermatol 2007
to clinical attention in the late stages of the disease when the central Mar–Apr;25(2):158–64.
nervous system is involved. Dracunculiasis can also be associated with Haddad V Jr, Lupi O, Lonza JP, Tyring SK. Tropical dermatology: marine and
swelling and pain in an extremity, often the legs. An acral nodule will aquatic dermatology. J Am Acad Dermatol 2009 Nov;61(5):733–50.
progress to a blister on the affected limb, and upon immersion in Handog EB, Gabriel TG, Pineda RT. Management of cutaneous tuberculosis. Der-
matol Ther 2008 May–Jun;21(3):154–61.
water, part of the female worm will extrude through the ruptured
Lupi O, Tyring SK. Tropical dermatology: viral tropical diseases. J Am Acad Der-
blister.
matol 2003 Dec;49(6):979–1000.
Lupi O, Tyring SK, McGinnis MR. Tropical dermatology: fungal tropical diseases.
CACHEXIA – NUTRITIONAL J Am Acad Dermatol 2005 Dec;53(6):931–51.
DEFICIENCIES
Lupi O, Madkan V, Tyring SK. Tropical dermatology: bacterial tropical diseases.
J Am Acad Dermatol 2006 Apr;54(4):559–78.
Naafs B, Padovese V. Rural dermatology in the tropics. Clin Dermatol 2009
Signs to alert the physician that a patient may have a nutritional
May–Jun;27(3):252–70.
disorder include: cachexia, abnormal fat distribution, edema, glossitis
Ramos-e-Silva M, Rebello PF. Leprosy. Recognition and treatment. Am J Clin
of the tongue, seborrheic dermatitis, abnormalities in hair/nails, Dermatol 2001;2(4):203–11.
cheilitis and periorificial dermatitis. For specific clinical manifesta- Sampaio SA, Rivitti EA, Aoki V, Diaz LA. Brazilian pemphigus foliaceus, endemic
tions of nutritional deficiencies, see Table 8-2 and corresponding pemphigus foliaceus, or fogo selvagem (wild fire). Dermatol Clin 1994
chapters. Oct;12(4):765–76.
Welsh O, Vera-Cabrera L, Salinas-Carmona MC. Mycetoma. Clin Dermatol 2007
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Zeegelaar JE, Faber WR. Imported tropical infectious ulcers in travelers. Am J Clin
Ameen M. Chromoblastomycosis: clinical presentation and management. Clin Dermatol 2008;9(4):219–32.
Exp Dermatol 2009 Dec;34(8):849–54. Epub 2009 Jul 2.
Bonifaz A, Gómez-Daza F, Paredes V, Ponce RM. Tinea versicolor, tinea nigra,
white piedra, and black piedra. Clin Dermatol 2010 Mar 4;28(2):140–5.
Ophthalmological Diseases 9
Hugh R Taylor, Angus W Turner
be sought, and questions about ocular discharge, pain and discomfort
should be asked.
Key features
A basic part of the ophthalmic examination is the assessment of visual
l Disease burden: acuity, which is traditionally measured with a letter test chart, placed
6 meters away from the patient. The acuity of small children can be
l Worldwide, 161 million people are blind or visually
assessed by determining their ability to fixate upon and follow a
impaired target, such as a light, evaluating one eye at a time while the other eye
l An additional 153 million have uncorrected refractive is covered. Children will also often object to covering of the normal
error eye but not a poorly seeing eye. Picture charts are sometimes used for
l Unique features in tropics – increased prevalence of: pre-literate children. An E chart is also used for illiterate adults, where
the direction of the “tumbling E” of diminishing sizes is identified.
l Blinding infections, e.g. filariasis and corneal ulcers
secondary to fungal infections Simple observation of the eye will often give much information,
l Ocular trauma especially in terms of the presence and site of infection or trauma (Fig.
l Acute glaucoma (Asian countries) 9.2 – demonstrates ocular anatomy), the alignment and movement
of the eyes, or their possible displacement. Careful examination of
l Resource-poor countries:
the front of the eye with a hand light will reveal gross corneal or
l Ocular sequelae of malnutrition, e.g. vitamin deficiency conjunctival disease, including xerophthalmia, trachoma, foreign
l Late presentation of disease, e.g. diabetic eye disease bodies and corneal ulcers. It also reveals much about the anterior
and glaucoma chamber and lens, the presence of blood or pus in the eye, acute
l Industrialized countries: glaucoma and significant lens opacities (cataract). Whenever possible,
the front of the eye should be examined with some magnification,
l Baseline of unavoidable blindness
e.g. 2.5× magnification loupe, or a direct ophthalmoscope using a +10
l Chronic conditions affecting elderly diopter lens.
l Screening programs to detect asymptomatic disease
l Expensive treatments for glaucoma and macular
The diagnosis of mild trachoma requires examination of the conjunc-
tiva on the undersurface of the upper lid, which is accomplished by
degeneration everting the eyelid (Fig. 9.3). The pupils can also be examined with a
hand light, taking note of their size, shape and response to light. It is
usually easier to examine the pupils in a somewhat darkened room.
A direct ophthalmoscope is essential for examining the back of the
interior eye, to search for abnormalities of the optic disc, macular
region, blood vessels and other areas.
Trachoma
4%
Refractive error Macular
18% degeneration
7%
Glaucoma
10%
Corneal opacities
4%
Childhood
blindness
4%
Other
11%
Onchocerciasis
1%
Diabetic retinopathy
4% Cataract
FIGURE 9.1 Global blindness causes. 37%
drops (four times per day) and as 1.0% ointment at night. Alterna-
tively, and especially in children, antibiotic ointment, such as 1.0%
TABLE 9-1 Global Loss of Vision Table with Blind and tetracycline (four times per day) may be used for 1 week. Other oph-
Low Vision thalmic solutions may also be used, such as those containing fluoro-
quinolone antibiotics, although expense may be prohibitive in many
Presenting Eye disease Refractive Total regions of the world. Patients should be cautioned to keep their eyes
vision error clean by washing away accumulated discharge. They should wash
their hands carefully and not share towels or clothes with others, to
Blindness 37 million 8 million 45 million avoid spreading infection.
Low vision 124 million 145 million 269 million Neonatal gonococcal conjunctivitis is a medical emergency. The
Total 161 million 153 million 314 million infant should be hospitalized to confirm response to therapy and a
single dose of either ceftriaxone 25–50 mg/kg (not to exceed 125 mg)
Presbyopia: Difficulty 410 million; uncorrected 517 million or cefotaxime 50 mg/kg should be administered intravenously or
– Total: 1.04 billion. intramuscularly. The neonate should also receive treatment for pre-
From Resnikoff S, Pascolini D, Mariotti SP, Pokharel GP. Global magnitude of visual sumptive chlamydial conjunctivitis with a 1–3-day course of oral
impairment caused by uncorrected refractive errors in 2004. Bull World Health azithromycin 20 mg/kg/day to maximal dose of 1 g or erythromycin
Organ 2008;86:63–70. syrup (50 mg/kg/day divided into four doses per day for 14 days).
Saline irrigation of the eyes should be performed immediately and
then at hourly intervals for as long as necessary to eliminate the
is mucopurulent or purulent. A frankly purulent discharge is espe- purulent discharge [3].
cially common in gonococcal infections. Mucopurulent and purulent Chlamydial conjunctivitis and trachoma in adults and non-neonatal
discharges frequently accumulate on the eyelashes and lid margins, children should be treated with systemic azithromycin with a 1 g
causing the lids to stick together. single oral dose. In children, a dose of 20 mg/kg is given [4].
The most consistent sign of conjunctivitis is conjunctival injection. Viral conjunctivitis does not respond to antibiotics. Significant symp-
The superficial and tortuous vessels of the conjunctiva appear dilated tomatic relief can be obtained with the use of cold compresses and
and bright red or pink, giving rise to the common term “pink eye”. local vasoconstrictors, which also can be used for patients with aller-
In severe inflammation, pseudomembranes, or even true membranes, gic conjunctivitis. Topical steroids should never be used without the
may be present. These are seen as dirty gray sloughs on the tarsal direct supervision of an ophthalmologist.
conjunctiva. In viral and chlamydial conjunctivitis, follicles are fre-
quently present. Giant, fleshy papillae may occur in allergic conjunc-
tivitis. A detailed description of trachoma and inclusion conjunctivitis KERATITIS AND CORNEAL ULCERATION
is provided in Chapter 35. Keratitis and corneal ulceration are common causes of painful, red
Visual acuity is usually not affected in conjunctivitis. The cornea is eyes and are usually uni-ocular. Severe photophobia is often the main
clear and bright; the pupil is circular and reacts normally; and the symptom, and the vision is usually blurred. Secondary uveitis may
anterior chamber is clear and of normal depth. develop and cause ciliary injection. Ciliary injection shows a ring of
redness, which is most intense around the limbus, and is a sign of
Bacterial conjunctivitis usually requires specific antibiotic treatment. inflammation of the ciliary body and iris. A history of trauma can
Antibiotics such as chloramphenicol may be given topically as 0.5% often be elicited. At other times, a corneal ulcer and, more especially,
O p ht h a l m o l o gi c al Diseases 79
Tarsal conjunctiva
Optic nerve
Eyelash
Clear cornea
Optic disc
Pupil Lens
Iris Vitreous body
Anterior chamber Macula
Posterior chamber
Retina
Choroid
Sclera
FIGURE 9.2 A diagram of the front of
eye and a cross-sectional diagram of
the eye. Bulbar conjunctiva
Do you have redness, irritation Yes Do you have purulent (pus) Yes Bacterial conjunctivitis
or itching IN the eyes? discharge from your eye? Trachoma – chronic conjunctivitis
No
Viral conjunctivitis – associated with cold or ARI
No Allergic conjunctivitis
Do you have blood in the Yes Subconjunctival
white part of the eye? hemorrhage
No
Warning signs
Are the eye lids rolled out Yes Ectropion – eye lids turned out – Refer •Pain with unilateral red eye
or rolled in? Entropion – eye lids turned into eye – Refer •Any loss of vision
•Pupils that don't react to light
•A corneal ulcer
No
•Chemical burns of eyes
•Pus or blood in the anterior
Refer for further evaluation chamber of the eye
FIGURE 9.4 Algorithm for diagnosis and referral of common eye pathology. Courtesy of the Nick Simons Institute, Nepal, 2009.
FIGURE 9.5 A dendritic ulcer due to herpetic keratitis in a patient with From Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis
previous corneal graft. nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for
reporting clinical data. Results of the First International Workshop. Am J
Ophthalmol 2005;140:509–16.
For both fungal and acanthamoeba corneal infections, a microbio- Chemical burns to the eyes are best treated with immediate, thorough
logic diagnosis should be obtained before treatment is commenced. and copious irrigation. Ideally, sterile saline solution should be used,
As with conjunctivitis, steroids should not be used in patients with but rather than delay irrigation, tap water should be used if saline is
corneal ulcers and keratitis unless under close supervision by an not available. The damage caused by an acid burn can usually be
ophthalmologist. determined immediately. Because alkali continues to penetrate
the eye, alkaline burns are frequently much more severe than
initially realized. All chemical burns should be assessed by an
CORNEAL NECROSIS ophthalmologist.
A number of systemic conditions are associated with corneal ulcera-
tion and necrosis, including collagen vascular diseases, leukemia and Conjunctival hemorrhages, which may be traumatic or spontaneous,
granulomatoses. In developing countries, nutritional keratopathy require no treatment and will resolve in 1 to 2 weeks. Minor conjunc-
relating to vitamin A deficiency (xerophthalmia, keratomalacia) is a tival lacerations do not require suturing and will heal in a few days.
common cause of childhood blindness (Chapter 139). In many Topical antibiotics are usually given until the eye has healed.
poorer Asian countries, measles is an important precipitating event All cases of penetrating trauma to the eye and laceration to the globe,
for xerophthalmia (Chapter 28.1). Even in well-nourished Western including corneal lacerations and intraocular foreign bodies, are
children, measles may cause a mild, superficial, self-limiting keratitis medical emergencies that require prompt referral to and careful
that does not require therapy. In much of Africa, however, measles assessment by an ophthalmologist.
itself is considered an important blinding condition. The mechanism
is not entirely clear. In many instances, it represents precipitation of
acute xerophthalmia, as in Asia. In others, it appears to represent UVEITIS
secondary herpetic infection, which also accounts for the accompany-
The classification of uveitis may be anatomical, clinical, pathological
ing stomatitis and skin ulcers. In still others, corneal damage is a
or etiological. All systems may be useful for management purposes.
chemical keratitis or bacterial infection secondary to the common
practice of placing herbal and other traditional medicines in the eyes Anterior uveitis is a relatively uncommon cause of a sore, red eye. The
of measles patients. term is used to describe inflammation of the anterior uveal structures
– the iris and the ciliary body. The less common posterior uveitis refers
CORNEAL TRAUMA to inflammation of the retina and choroid.
With trauma, ocular signs and symptoms are usually unilateral and Uveitis may occur as a primary event, either in isolation or in associa-
the onset is sudden. A history of trauma or foreign bodies is usually tion with some underlying systemic disease. Causes are considered to
present. Conjunctival foreign bodies cause pain and a feeling of be infective, noninfective or masquerades (Table 9-3) [6]. Secondary
having “something in the eye”. Conjunctival vascular injection and anterior uveitis is commonly seen with corneal trauma and
some watering of the eye are usually present. A foreign body may be ulceration.
seen with a simple external examination. At other times, however,
Primary anterior uveitis has a gradual onset, with moderate to severe
conjunctival foreign bodies lodge behind the upper eyelid and are not
pain and some blurring of vision. It may be unilateral or bilateral,
seen until the lid is everted, at which time they can be easily removed.
and the patient may have a history of similar episodes. Ciliary injec-
A corneal foreign body usually produces more severe pain and pho- tion is the most important feature. This injection decreases with dis-
tophobia. After some time, it will often cause a secondary inflamma- tance from the limbus, and the conjunctiva of the fornices and lids is
tion with ciliary-limbal injection. Most corneal foreign bodies can be not inflamed. There is usually no discharge.
removed fairly easily with a cotton-tipped swab, but if this is not pos-
The other important sign in anterior uveitis is a pupillary change.
sible, the case should be referred to an ophthalmologist. A single
The pupil is usually small and reacts poorly to light. Frequently, the
application of antibiotic ointment may be used prophylactically, if
pupil is irregular because of adhesions, called posterior synechiae,
available.
between the pupillary margin and the lens. On examination with a
In tropical environments in particular, corneal abrasions from plant slit lamp, keratic precipitates or inflammatory cells may be seen on
matter, whether or not they leave a foreign body behind, carry a high the back of the cornea and also inflammatory cells and an aqueous
risk of subsequent fungal infection. These can be notoriously difficult “flare” in the anterior chamber. In severe cases, these changes may be
to treat and should be watched for closely. recognized during the examination of the front of the eye with an
82 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
ophthalmoscope, using the +10 diopter lens. Posterior uveitis may be ophthalmologist. An iridectomy or laser iridotomy is generally indi-
asymptomatic or involve severe vision loss if inflammation involves cated to prevent further episodes. Pilocarpine 1–2% should be initi-
the macula. ated twice daily in the fellow eye to reduce the risk of an acute attack
until definitive surgical prophylaxis [7].
Due to possible secondary causes, patients with recurrent episodes of
anterior uveitis or other systemic symptoms should be examined in
detail to exclude the possibility of such an underlying condition. All CHRONIC DISEASES
patients with posterior uveitis warrant further investigation.
Refractive error, cataracts, glaucoma and macular degeneration are
Treatment for anterior uveitis involves cycloplegia and mydriasis major causes of blindness in aged populations of both developed and
obtained with topical drops, such as atropine 1% (three times per developing countries.
day). A systemic analgesic, such as aspirin, will often give sympto-
matic relief. Topical steroids are frequently indicated, but they should
be given only at the direction of an ophthalmologist. If an underlying REFRACTIVE ERROR
disease such as syphilis, tuberculosis or brucellosis is present, targeted Refractive errors include short-sightedness (myopia) and long-
systemic treatment should also be initiated. In severe uveitis and in sightedness (hyperopia) with or without astigmatism (when an eye
chronic uveitis, secondary cataracts and secondary glaucoma may can only sharply focus a line in one meridian). These conditions can
develop. These conditions require specific treatment. be rectified with appropriate optical correction. This is a cost-effective
intervention and has an important impact on development and
Posterior uveitis is difficult to manage and requires referral to an
quality of life. Presbyopia is the progressive loss of near-vision ability
ophthalmologist to manage the ocular inflammation and to investi-
that occurs in everyone over about 40 years of age. This may be easily
gate further. Treatment may involve topical, intraocular and systemic
corrected with ready-made magnifiers. Cost and access barriers to
steroids or antimicrobials.
appropriate refractive correction are a problem in many developing
areas, but much work is being carried out to rectify this situation.
Endophthalmitis
Endophthalmitis refers to diffuse inflammation of the eye including CATARACT
uveitis and vitritis. Patients usually present with loss of vision. Involve- Opacification of the lens interferes with transmission of clear images
ment of the eye can be “exogenous” following eye surgery or trauma, to the retina by both decreasing and scattering the light rays as they
or “endogenous” representing hematogenous seeding of the eye pass through. To the examiner, the pupillary area may look opaque
during bacteremia or fungemia. Patients often do not have fever and whitish or dark brown on hand-light illumination, and fundus
unless there is an ongoing systemic infection. Examination of the eye details will be obscured when viewed with the direct ophthalmo-
may disclose a hypopyon and haziness of the vitreous. Treatment scope. Aside from cataracts of rare congenital origin and those that
involves intraocular antibiotics, and all patients with endophthalmitis result from chronic inflammation, most cataracts are lumped together
should be referred to an ophthalmologist. Endogenous infections under the heading “senile”. These are undoubtedly of multifactorial
should also be systemically treated. origin. Because the precise causes of such cataracts are as yet unknown,
preventive measures do not currently exist. Cataracts can be surgically
removed with a high degree of technical success and likelihood of
ACUTE ANGLE-CLOSURE GLAUCOMA return of useful vision.
Acute angle-closure glaucoma is a relatively uncommon cause of a
painful, red eye, although its diagnosis is of great importance because In general, cataracts are the leading cause of blindness in developing
irreversible blindness can result without prompt treatment. Acute countries. Visually disabling cataracts appear to occur earlier in life in
angle-closure glaucoma is characterized by a sudden increase in some cultures than in others. More importantly, surgical therapy is
intraocular pressure when the drainage channels for the intraocular commonly unavailable to large segments of the population. Some
fluid (aqueous humor) are obstructed. The persistence of elevated countries are overcoming the paucity and maldistribution of ophthal-
intraocular pressure can cause permanent and total loss of vision mologists by conducting intensive rural “cataract camps”; others are
within 1 to 2 days. The condition is most frequent in Asian popula- doing so by training properly supervised paramedical personnel to
tions due to the anatomically short eye. A mature cataractous lens remove cataracts. Because the potential for intraoperative complica-
causes further crowding of the anterior segment and predisposes to tions and postoperative infections is high under these circumstances,
angle-closure. these approaches require careful consideration and detailed organiza-
tion. However, as no other recourse often exists, these methods
Acute angle-closure glaucoma usually starts with sudden and severe require further development and extension.
ocular pain, often severe enough to cause nausea and vomiting.
Vision is markedly reduced, and the patient often complains of seeing Merely removing an advanced cataract can improve vision, but
halos or colored rings around lights. On examination, there may be removal alone will not restore reading acuity. Some form of aphakic
ciliary injection, but the most striking features are the “steamy” or correction, most commonly intraocular lenses or spectacles, is also
hazy cornea and the greatly increased intraocular pressure. The required.
corneal changes are due to corneal edema. Intraocular pressure can
be assessed by gently palpating the globe through the closed upper GLAUCOMA
lid and comparing the degree of resilience of the affected eye with
that of the other eye, or with that of the eye of a person with normal There are two major forms of glaucoma – acute and chronic. As
vision. Increased intraocular pressure causes the eye to feel firmer or already discussed, the acute form, with its red, injected, painful
hard. eyes, is the more dramatic. Chronic open-angle glaucoma, however,
is much more common and is the more important cause of
The anterior chamber is usually very shallow in angle-closure glau- blindness.
coma, and the iris appears to be almost touching the cornea. The
pupil is frequently found to be semi-dilated and unreactive, and it Chronic elevation of intraocular pressure, at levels below those
may have an irregular or vertically oval shape. reached in acute angle-closure glaucoma, results in progressive
destruction of the optic nerve. After many years (usually 10 to 20),
Medical attempts to reduce intraocular pressure in such patients this painless, asymptomatic destruction of the optic nerve results in
should be started without delay. Diuretics such as acetazolamide, loss of visual field, detectable by careful visual field examination.
500 mg orally or intravenously, should be given up to four times Antiglaucoma therapy may delay or prevent further damage, but it
daily. Any available anti-glaucoma pressure-lowering topical drops cannot replace the vision that has already been lost. Unfortunately,
should also be given frequently. These patients require referral to an patients are usually unaware of the problem until late in the course
O p ht h a l m o l o gi c al Diseases 83
of the disease, when central acuity is finally involved and little vision AMD has a strong genetic basis and is also associated with cigarette
or optic nerve remains to be saved. smoking [8]. Early in the disease, scattered, white, deep-retinal dots,
known as drusen, can be seen concentrated in the macular area. Some,
Glaucoma is the classic disease in which screening methods have but not all, people with these signs eventually develop progressive
played an important role. Unfortunately, the simplest technique, that degeneration of their retinal pigment epithelium and the underlying
of demonstrating by tonometry that the intraocular pressure is greater choroid. Loss of vision is gradual, unpredictable, and is usually con-
than 21 mmHg, is far from infallible. Half of those with established fined to loss of fine reading acuity. Patients rarely develop “black
glaucomatous field loss will have a normal pressure on a single casual blindness” (total loss of vision) and can usually care for themselves.
screening test, and only 1 in 20 or 30 people with an elevated pressure In some, a net of new blood vessels grows from the choroid, and these
will already have field loss. The higher the pressure, however, the vessels may leak or bleed. Such vascular networks may be treated with
greater the likelihood of having, or soon developing, field loss. Screen- injections in the eye of anti-VEGF agents. However, these are very
ing is improved by combining tonometry with examination of the expensive, seldom available, and require repeated administration.
optic disc (by direct ophthalmoscopy or, preferably, with a slit lamp Laser treatment may also be effective for certain subtypes.
and contact lens). Deep, large, asymmetric optic disc cupping, equal
to or greater than 0.6 disc diameter, suggests glaucomatous damage.
DIABETIC RETINOPATHY
Ultimately, diagnosis requires demonstration of classic changes in the
visual fields. Diabetic retinopathy includes a wide, complex spectrum of changes.
Because few long-time diabetics survive in the poor, rural communi-
Treatment consists of lowering the intraocular pressure below ties of developing countries, diabetic retinopathy is less common than
21 mmHg or to whatever level prevents further damage. A variety of in developed countries and in increasingly affluent urban communi-
topical medications may accomplish this: prostaglandin analogues ties elsewhere. The major treatable component of the disease is the
are generally used first-line in developed countries. Beta-blockers such growth of neovascular membranes which extend into the vitreous
as timolol are less expensive and equally effective at lowering intraoc- from the surface of the optic nerve or retina. Timely laser therapy
ular pressure. Alpha-agonists, e.g. brimonidine, and topical carbonic provides substantial benefit and dramatically reduces the risk of
anhydrase inhibitors are also used. If one agent proves inadequate, blindness. Laser treatment also benefits patients with fluid accumula-
others may be added to the regimen. tion in the macula (macular edema) if they are treated early. Diabetics
should have their eyes examined annually if possible to ensure that
Glaucoma management requires careful monitoring of pressure and suitable laser treatment is applied prior to the development of sight-
visual field and frequent adjustment of dosage and regimen, while threatening complications.
compliance of patients with the treatment plan is generally poor.
Laser trabeculoplasty is effective at lowering intraocular pressure for PROPTOSIS
5–10 years and has far less complications than surgery. Improved
compliance is a significant advantage over the topical medications. Abnormal protrusion of the eye is uncommon but usually signifies
The treatment is also cost-effective as initial treatment. serious orbital pathology. Although included in this chronic section,
there are a number of acute causes. Causes include: inflammatory
When visual field loss continues, even on “maximum” medical disease, e.g. thyroid eye disease; infection, e.g. orbital cellulitis (bacte-
therapy, the patient requires filtering surgery. A small channel is pro- rial, parasitic, fungal); tumors; and vascular anomalies, e.g. carotid–
duced through the tough outer coats of the eye, so that some of the cavernous fistula (perhaps after trauma).
aqueous may percolate out of the eye into the subconjunctival space,
where it is absorbed. Such artificial channels are at least temporarily
successful, after one or more operations, in 85% of Caucasian patients. REFERENCES
African patients do not fare so well because of their greater tendency 1. Resnikoff S, Pascolini D, Etya’ale D, et al. Global data on visual impairment
for scarring, which closes the new channel. Concomitant local use of in the year 2002. Bull World Health Organ 2004;82:844–51.
antimetabolites increases success. 2. Resnikoff S, Pascolini D, Mariotti SP, Pokharel GP. Global magnitude of visual
impairment caused by uncorrected refractive errors in 2004. Bull World
Despite the potential for preventative measures, glaucoma is an espe- Health Organ 2008;86:63–70.
cially difficult clinical problem in tropical countries; screening and 3. O’Hara MA. Ophthalmia neonatorum. Pediatr Clin North Am 1993;40:
diagnostic procedures are time-consuming and complex, and medical 715–25.
therapy is expensive, requires careful monitoring, and usually is 4. Taylor HR. Trachoma. Melbourne, Australia: Haddington Press; 2008:204.
attended by poor compliance. 5. Wilhelmus KR. Therapeutic interventions for herpes simplex virus epithelial
keratitis. Cochrane Database Syst Rev 2008;(1):CD002898.
6. Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomen-
AGE-RELATED MACULAR DEGENERATION clature (SUN) Working Group. Standardization of uveitis nomenclature for
reporting clinical data. Results of the First International Workshop. Am J
In temperate climates, age-related macular degeneration (AMD) is the Ophthalmol 2005;140:509–16.
first or second leading cause of blindness. AMD has received little 7. Salmon JF, Kanski JJ. Glaucoma, 3rd edn. Oxford, UK: Butterworth Heine-
attention in the tropics because it is difficult to diagnose without a mann; 2004:69.
dilated pupil fundus examination, occurs mainly in the elderly, and 8. Kanski JJ. Clinical Ophthalmology, 6th edn. Edinburgh, UK: Butterworth
does not have easily available treatment options. Heinemann; 2003:629.
10 Neurologic Diseases
Tom Solomon, Hadi Manji
Vascular
Ischemia/infarct
Subarachnoid/subdural/extradural/intracerebral hemorrhage
Hypertension/hypotension
Infectious
Bacteria
Direct effect Meningococcus, Streptococcus, Haemophylus influenzae, tuberculous
on CNS
Viruses
Arboviruses, herpes viruses, enteroviruses, rabies
84
N e u ro l o gic Diseases 85
Parasites
Protozoans
Malaria (Plasmodium falcipaurm) African trypanosomiasis (Trypanosoma brucei
gambiense and rhodesiense)
Toxoplasmosis (Toxoplasma gondii) Amoebiasis (Entaboema histolytica)
Trematodes (Flukes)
Paragonimiasis, schistosomiasis (esp. Schistosoma japonicum)
Cestodes (tapeworms)
Cysticercosis (Taenia solium), hydatidosis (Echinococcus granulosa)
Nemotodes (round worms)
Ascariasis (Ascaris lumbricoides) Parastronglyliasis (Parastrongylus cantonensis)
Gnathostomiasis Trichinosis (Trichonella spiralis)
Spirochetes
Neurosyphilis (Treponema pallidum) Lyme disease (Borrelia burgdorferi)
Leptospirosis (Leptospira species) Louse-borne/epidemic relapsing fever (B.
recurrentis)
Tick-borne/endemic- relapsing fever (B. duttoni)
Rickettsiae
Epidemic/louse-borne typhus Endemic/murine/flea-borne typhus (R. typhi/
(Rickettsia prowazekii) mooseri)
Scrub typhus (R. tsutsugamushi) Rocky Mountain spotted fever (R. rickettsii)
Fungi
Cryptococcosis Histoplasmosis
Aspergillosis Coccidiomycosis
Candidiasis Paracoccidiomycosis
Blastomycosis Nocardia*
Indirect effect Toxin-mediated infectious diseases (tetanus, diphtheria, shigella)
of infection Immune-mediated, post-infectious inflammatory (GBS, acute disseminated encephalomyelitis)
Metabolic
Hypoglycemia, diabetic ketoacidosis, hepatic encephalopathy, uremia, hyponatremia, hypo-/hyperthyroidism,
Addison’s disease
Tumors/trauma/ toxins
Alcohol, drugs (medical, recreational, traditional), pesticides, poisons
Other Hydrocephalus
Epilepsy
Psychiatric disease—hysteria
*Nocardia is an actinomycetes bacteria that is grouped with fungi because of its morphology and behavior.
CNS, central nervous system; GBS, Guillain-Barré syndrome.
BOX 10.1 Pointers to HIV Infection BOX 10.2 Lumbar Puncture Guidelines
History All patients with a suspected CNS infection should have a
Risk factors for HIV—multiple sexual partners, male sex lumbar puncture (LP) as soon as possible, unless there are con-
with males, sex workers, intravenous drug abuse, blood traindications. In Western industrialized settings, LP use
products declined somewhat in the 1990s, following concerns that it
might precipitate brain shift and herniation syndromes in
For children, death of mother and father patients with incipient herniation. In the West, a CT scan is
Weight loss; unexplained pyrexi therefore recommended before LP in patients with clinical fea-
tures suggestive of incipient herniation; whilst this is per-
Persistent diarrhea formed, appropriate antimicrobial therapy is started and a LP is
Clinical Signs performed as soon as it is deemed safe.
Wasting In the tropics, where CT is less readily available and infections
Lymphadenopathy are more common, the benefits of accurate diagnosis and
appropriate treatment are often felt to outweigh the theoretical
Hairy leukoplaqia, oral candida on oral examination risk of herniation, and even patients with a relative contraindi-
Seborrhoebic dermatitis, Kaposi’s sarcoma, molluscan conta- cation often undergo a LP with no apparent harm.
geosum, zoster, herpes simplex
Imaging preferred before lumbar puncture, if possible to
Intravenous drug injection sites exclude brain shift, swelling, or space-occupying lesion.
Retinitis (cytomegalovirus, toxoplasma, syphilis), papilloedema, Antimicrobial treatment should be started whilst awaiting
uveitis, iritis on ocular examination imaging.
After LP, most patients will be classified as having normal cerebrospi Notes
nal fluid (CSF), consistent with viral meningitis, bacterial meningitis l In settings where CT is not readily available, the benefits of
or tuberculous meningitis (Box 10.4); in some patients a microorgan
rapid accurate diagnosis from LP and appropriate treat-
ism will have been seen on CSF microscopy, thus guiding treatment.
If CSF is consistent with acute bacterial meningitis, empirical anti ment are often felt to outweigh the theoretical risk of her-
biotics (usually a third-generation cephalosporin) are started. If the niation, and even patients with a relative contraindication
initial CSF findings suggest tuberculosis meningitis (TBM), microbio often undergo a lumbar puncture with no apparent harm.
logic confirmation requires large volumes of CSF (e.g. 6–10 ml). l There is no agreement on the depth of coma that necessi-
Therefore, unless the patient is very unwell, it is worth waiting 24 tates imaging before LP; some argue Glasgow Coma Score
hours to repeat LP removing large CSF volumes. It is important to <12, others say <10 or <8.
remember that the differential diagnosis of aseptic meningitis is
l Imaging is preferable in patients with known severe immu-
broad (see Table 10-2).
nocompromise (e.g. advanced AIDS).
There has, for many years, been controversy over the role of corticos
teroids in treating acute bacterial meningitis. A recent meta-analysis Modified from Solomon T. Meningitis. Brain’s Diseases of the Nervous System.
of data from five studies, including two from Malawi and one from Oxford: Oxford University Press; 2009:1327–54.
Vietnam, showed that dexamethasone did not reduce deaths or neu
rologic sequelae; a sub-group analysis showed it did reduce death and
the composite analysis of death, neurologic sequelae and severe
hearing loss in patients over 55 years old [2]. This is in contrast to
TBM, where corticosteroids are thought to be of benefit [3].
The investigation and management of the common diagnoses are
ENCEPHALOPATHY
covered in individual chapters: AND ENCEPHALITIS
Bacterial Meningitis (Chapter 54).
Tuberculous Meningitis (Chapter 39). KEY SYNDROMES AND CLINICAL APPROACH
Angiostrongyloides (Chapter 118). Encephalopathy is the syndrome of reduced or altered level of con
Cryptococcus (Chapter 84). sciousness, ranging from the obvious (coma), to the subtle (changed
N e u ro l o gic Diseases 87
BOX 10.4 Cerebrospinal Fluid (CSF) Interpretation—Typical CSF Findings in Central Nervous
System Infections (CNS)
Viral meningitis Acute bacterial Tuberculous Fungal Normal*
or encephalitis meningitis meningitis meningitis
Opening pressure Normal/high High High High–very high 10–20 cm
Color ‘Gin’ clear Cloudy Cloudy/yellow Clear/cloudy Clear
Cells/mm3 Normal–high High–very high Sl. increased Normal–high
0–1000 1000–50,000 25–500 0–1000 <5
Differential Lymphocytes Neutrophils Lymphocytes Lymphocytes Lymphocytes
CSF/plasma Normal Low Low–very low Normal–low 66%
Glucose ratio (e.g.<30%)
Protein (g/L) Normal–high High High–very high Normal–high <0.5
0.5–1 >1 1–5 0.2–5.0
*Normal values:
Normal CSF opening pressure is <20 cm for adults, <10 cm for children below the age of eight years old.
Although 66% is quoted as the normal glucose ratio, only values below 50% are taken as being significant in many settings.
A bloody tap will falsely elevate the CSF white cell count and protein. To correct for a bloody tap, subtract 1 white cell for every 700 red blood cells/mm3 in the CSF
and 0.1 g/dL of protein for every 1000 red blood cells.
Some important exceptions:
In viral CNS infections, an early lumbar puncture (LP) may give predominantly neutrophils, or there may be no cells in early or late LPs.
In patients with acute bacterial meningitis that has been partially pretreated with antibiotics (or patients younger than one year old), the CSF cell count may not
be very high and may be mostly lymphocytes.
Tuberculous meningitis (TBM) may have predominant CSF polymorphs early on.
Listeria can give a similar CSF picture to TBM, but the history is shorter.
CSF findings in bacterial abscesses range from near normal to purulent, depending on location of the abscess and whether there is associated meningitis or rupture.
A cryptococcal antigen test (CRAG) and India ink stain should be performed on the CSF of all patients in whom Cryptococcus is possible.
For assessing depth of coma in adults and children over the age of l Exposure to contaminated water (leptospirosis, schistosomiasis).
five, the Glasgow Coma score is used (Box 10.6); in children under l Illness in the community (measles, mumps).
the age of five, a range of scores are used, including the Alert, Voice, l Generalized illness (infectious mononucleosis).
Pain, Unresponsive (AVPU) score (see Box 10.5) and the Blantyre l Time of year.
Coma score (Box 10.7). l Geographical location in the tropics.
A careful history and examination greatly assist the classification of The general medical examination can provide essential clues:
patients presenting with altered consciousness. Consider evidence for
HIV infection or other immunocompromise (Box 10.1). l Examine for signs of trauma (check ears and nose for blood or
CSF leak).
In the history pay attention to: l Smell breath for alcohol and ketoacidosis.
l Duration of onset of coma: l Examine skin for:
l rapid (minutes–hours) suggests vascular cause, especially l rash (meningococcal rash, dengue or other hemorrhagic fever,
brainstem cerebrovascular accidents or subarachnoid hemor typhus, relapsing fever);
rhage; if preceded by hemispheric signs, then intracerebral l needle marks of drug abuse;
hemorrhage; l recent tick-bite or eschar (tick-borne encephalitis, tick paraly
l coma caused by some infections (e.g. malaria, encephalitis) sis, tick-borne typhus or relapsing fever);
can also develop rapidly, especially when precipitated by l chancre, with or without circinate rash (trypanosomiasis,
convulsions; especially rhodesiense);
l intermediate (hours–days) suggests diffuse encephalopathy l healed dog-bite (rabies);
(metabolic or, if febrile, infectious); l snake bite.
l prolonged (days–weeks) suggests tumors, abscess, chronic l Check the fundi for papilloedema (longstanding raised intracra
subdural hematoma. nial pressure) or signs of hypertension.
l Any drugs? l Lymphadenopathy (HIV, tuberculosis), hepatosplenomegaly.
l Any trauma?
A focused neurologic examination includes assessment of level of
l Important past medical history (e.g. hypertension)?
consciousness (Boxes 10.6 and 10.7), then examination of pupils, eye
l Family history (e.g. tuberculosis)?
movements, breathing patterns and response to pain to help deter
l Known epidemic area (e.g. viral encephalitis)?
mine whether a patient has:
l Exposure to insects—mosquitoes (malaria, flaviviruses), ticks (fla
viviruses, borrelia). l a diffuse encephalopathy (usually metabolic or infectious);
l Exposure to sick animals—dogs, cats (rabies). l supratentorial focal damage (i.e. above the cerebellar tentorium),
l Ingestion of contaminated food—snails (Angiostrongylus), which usually manifests as hemispheric signs;
unpasteurized milk/dairy products (brucella, listeria), fresh l damage in the diencephalon or brainstem (midbrain, pons or
produce/water (cysticercosis, typhoid). medulla), which may indicate a syndrome of cerebral herniation
N e u ro l o gic Diseases 89
BOX 10.5 Rapid Assessment of Patient with BOX 10.7 Blantyre Coma Scale for Children
Coma in the Tropics <5 Years Old
l Airways Best motor response
l Breathing—give oxygen; intubate if breathing is inade- 2 Localizes painful stimulus
quate or gag reflex impaired 1 Withdraws limb from pain
l Circulation—establish venous access 0 Nonspecific or absent response
l obtain blood for immediate bedside blood glucose test
Best verbal response
(hypoglycemia)
2 Appropriate cry
l malaria film (look for parasites and pigment of partially
1 Moan or inappropriate cry
treated malaria)
0 None
l full blood count, electrolytes, blood cultures, arterial
blood gases Eye movements
l Disability 1 Directed (e.g. follows mother’s face)
l Start IV: 10% dextrose (50 ml in adults, 5 ml/kg in chil- 0 Not directed
dren) irrespective of blood glucose
Total score ranges from 5 to 0; the term “unrousable coma” is
l Give adults 100 mg thiamine intravenously (especially if
sometimes used to reflect a score <2
alcohol abuse suspected)
l Immobilize cervical spinal cord if neck trauma
suspected
l Determine whether Alert, responds to Voice, to Pain, or
Unresponsive (the AVPU scale)
l If responds to pain or is unresponsive, examine the
pupils, eye movements, respiratory pattern, tone and
posture for signs of brain shift (herniation—see below) through the tentorial hiatus or the foramen magnum (Box 10.8,
l If herniation suspected, start treatment for this
Fig. 10.1).
l If purpuric rash present, give cefotaxime for presumed Determining whether there are brainstem signs can be helpful
meningococcal meningitis (after blood cultures) prognostically.
l Look for, and treat, generalized seizures, focal seizures and Based on the history, general examination and neurological examina
subtle motor seizures (mouth or finger twitching, or tonic tion, patients will usually fall into one of the following categories,
eye deviation) with differentials as shown.
Posterior horn
BOX 10.8 Examination for Brainstem Signs
(Figure 10.1) Dorsal root ganglion
Sensory neuron
Examine pupil size, and reaction to light cell body
l Normal reaction (i.e. constriction)—diffuse encephalo
pathy.
l Unilateral large pupil—herniation of the temporal lobe Dorsal root
uncus.
l Small or mid-sized but reactive pupil—diencephalic
syndrome. Anterior horn
l Unreactive midsized pupils—midbrain or pontine lesions. Peripheral nerve
Motor neuron cell body
l Unreactive large pupils in medullary lesions. Axon
Ventral root
Note: pinpoint pupils occur following opiate or organophos-
Myelin sheath
phate overdose, or in isolated pontine lesion; other drugs can
cause large unreactive pupils.
Assess eye movements (holding eyelids open
if necessary) Motor neuron Sensory neuron
l Spontaneous eye movements (brainstem is intact).
l Oculocephalic (doll’s eye) reflex (rotate the head, the eyes
normally deviate away from the direction of rotation): Neuromuscular
l Normal indicates brainstem is intact (i.e. diffuse junction
encephalopathy);
l Reduced or absent responses occur in uncal hernia-
tion and in brainstem damage (or, rarely, in deep
metabolic coma).
Assess breathing pattern
A normal pattern occurs in a diffuse encephalopathy. Muscle Skin
Cheyne-Stokes breathing and hyperventilation occur in revers- FIGURE 10.1 Peripheral nervous system (PNS). The PNS consists of all of
ible herniation syndromes. the neural elements outside of the central nervous system (CNS; brain and
Shallow, ataxic or apneic respiration occurs in more severe spinal cord) and provides the connections between the CNS and all other
body organ systems. The PNS consists of somatic and autonomic
brainstem syndromes (Figure 10.1). components. The somatic component innervates skeletal muscle and skin
Other causes of hyperventilation include: and is shown here (see Figure 2.15 for the autonomic nervous system). The
somatic component of the peripheral nerves contains both motor and
l acidosis; sensory axons. Cell bodies of the motor neurons are found in the anterior
l aspiration pneumonia; horn gray matter, whereas the cell bodies of sensory neurons are located
l flaccid paralysis of respiratory musculature. in the dorsal root ganglia.
BOX 10.9 Recognition and Management of Acute Symptomatic Seizures in Patients with Central
Nervous System (CNS) Infection
l In some severe brain infections (cerebral malaria, viral encepha- l A World Health Organization (WHO) algorithm for manage-
litis), children in status epilepticus may have subtle motor sei- ment of status epilepticus in children is shown below (taken
zures, rather than generalized tonic clonic seizures. Usually, this from [6]). In many settings, facilities for intubation and ventila-
is in children who had multiple tonic clonic seizures before tion are very limited and difficult decisions have to be made
hospitalization. Clinical manifestations include twitching of about which patients are likely to benefit. Bag and mask ven-
digit, mouth or eyelid, tonic deviation of the eyes, excess saliva- tilation by family members is often employed for hours, and
tion and an abnormal respiratory pattern. even days, through lack of facilities.
Status epilepticus
(convulsion lasting > 30 minutes)
Vascular access?
Yes No
IV access necessary
Convulsion persists
Reproduced with permission from Solomon (Chair), T. and Japanese Encephalitis Working Group. World Health Organization: Japanese
encephalitis Clinical Care Guidelines. Geneva: World Health Organization; 2005.
N e u ro l o gic Diseases 93
Uncus Uncal
•Unilateral dilated pupil, with ptosis
•Reduced response on testing OCR/OVR
•Hemiparesis (ipsilateral)
Diencephalon Diencephalon
•Small or midsized pupils reactive to light Transtentorial
•Full deviation on testing OVR
•Cheyne-Stokes respiration
herniation-
•Flexor response to pain and/or decorticate posturing intact survival
•Hypertonia and/or hypereflexia with extensor plantars possible
Midbrain Midbrain/upper pontine
•Midsized pupils, fixed to light
•Reduced response on testing OCR/OVR
•Hyperventilation
Brainstem
•Extensor response to pain and/or decerebrate posturing
Pons Lower pontine
•Midsized pupils, fixed to light
•No response on testing OCR/OVR
•Shallow or ataxic respiration
•No response to pain, or leg flexion only
Foramen
•Flaccid tone with extensor plantars magnum
Medulla Medullary herniation-
•Pupils dilated and fixed to light intact survival
•No response on testing OCR/OVR not possible
•Slow irregular, gasping or absent repiration
•No response to pain
•Flaccid tone with no reflexes
FIGURE 10.2 Sagittal section of brain showing anatomy and key abnormal findings of midline herniation syndromes, and (above) coronal section showing
herniation of the uncus of the temporal lobe—this compresses the ipsilateral third nerve (to cause a palsy of CNIII) and the contralateral cerebral peduncle
(to cause an ipsilateral hemiparesis). OCR, occulocephalic (doll’s eye reflex); OVR, oculovestibular (caloric) reflex.
Common motor symptoms include tripping because of weakness of neuropathies, e.g. diabetes, HIV, and sometimes leprosy in the early
ankle dorsiflexors (foot drop), unable to turn keys or open jars stages, reflexes may remain present.
because of weakness of small hand muscles. Note: in GBS, bulbar and
respiratory muscle weakness may be life-threatening. In order to reach a diagnosis for peripheral nerve syndromes, the
following questions need to answered after the history and
Examination of patients with peripheral nerve disorders or radicu examination:
lopathies may reveal evidence of a “lower motor neuron syndrome”
with wasting ± fasciculation ± weakness in the distribution of a 1. Temporal evolution?
root(s), peripheral nerve(s) or plexus(i) ± depressed or absent reflexes l acute (days up to 4 weeks), e.g. GBS, vasculitis, toxic
± sensory loss in the appropriate dermatomes. Note: in small fiber (drugs such as anti-retrovirals), nutritional deficiency;
N e u ro l o gic Diseases 95
MYOPATHIC SYNDROMES
There are a more limited number of myopathic syndromes. The
important ones to consider in the tropics include HIV and drugs used
to treat it, such as azidothymidine (AZT) (Box 10.14).
Symptoms: muscle pain (myalgia) and tenderness, dysphagia, dark and respiratory muscles (maybe life-threatening), as well as limb
urine (myoglobinuria). Weakness suggestive of proximal weakness muscles.
(difficulty rising from the floor or chair, climbing stairs, reaching
above the head). Exercise-induced muscle pains and cramps. Examination: in MG, fatiguability (increasing weakness with exertion,
e.g. test shoulder abduction before and after 20 repetitive abduction,
Examination: weakness of neck flexion (sternomastoid muscles), adduction movements at the shoulders) is pathognomonic, but in
muscles around the shoulder girdle [shoulder abductors (deltoid Lambert-Eaton syndrome (LEMS), the opposite occurs. In botulism,
muscle)], pelvic girdle [hip flexors and extensors (iliopsoas and glutei there is progressive weakness, starting with ocular muscles with
muscles)]. Reflexes are usually intact except in profoundly weak and pupillary involvement (fixed pupils), followed by bulbar and limb
wasted muscles, such as quadriceps (knee jerk, L3, L4). muscle weakness with autonomic dysfunction as the toxin binds
Note: in inclusion body myositis (IBM, the commonest cause of irreversibly with post-synaptic receptors at the cholinergic neuromus
inflammatory myopathy in patients over the age of 50 years), the cular junction.
forearm flexors and quadriceps muscles are selectively affected. Drugs such as penicillamine can rarely cause a myasthenic syndrome.
Rare congenital syndromes are also described. Organophosphates,
used as pesticides and in chemical warfare, may also be ingested with
MYASTHENIC SYNDROMES suicidal intent. This causes an acute cholinergic crisis as a result of
Symptoms: Painless, fluctuating weakness may affect ocular muscles acetylcholinesterase inhibition with ocular, bulbar, limb and respira
[with drooping eyelids (ptosis) and double vision (diploplia)], bulbar tory weakness.
APPROACHES TO INVESTIGATION, DIAGNOSIS 2. van de Beek D, Farrar JJ, de Gans J, et al. Adjunctive dexamethasone in bacte
rial meningitis: a meta-analysis of individual patient data. Lancet Neurol
AND MANAGEMENT 2010;9:254–63.
The approach to investigation and diagnosis of peripheral nerve, 3. Thwaites GE, Nguyen DB, Dung NH, et al. Dexamethasone for the treatment
muscle and myasthenic disorders depends on whether only basic or of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;
more advanced facilities are available (Box 10.15). 351:1741–51.
4. Newton CRJC, Crawley J, Sowumni A, et al. Intracranial hypertension in
The management of peripheral nerve syndromes depends on the Africans with cerebral malaria. Arch Dis Child 1997;76:219–26.
diagnosis. Approaches to managing GBS, CIDP, vasculitis and neuro 5. Maitland K, Kiguli S, Opoka RO, et al. for the FEAST Trial Group. Mortality
pathic pain are shown in Box 10.16. The approach to managing after fluid bolus in African children with severe infection. N Engl J Med
myopathic syndromes is given in Box 10.17, whilst in Box 10.18 an 2011;364:2483–95.
overview of the approach to MG is shown. Some clinical pearls in 6. Solomon (Chair), T. and Japanese Encephalitis Working Group. World Health
approaching patients with peripheral nerve and muscle syndromes Organization: Japanese encephalitis Clinical Care Guidelines. Geneva: World
are given in Box 10.19. Health Organization; 2005.
7. Solomon T. Meningitis. Brain’s Diseases of the Nervous System. Oxford:
Oxford University Press; 2009:1327–54.
REFERENCES 8. Molyneux EM, Walsh AL, Phiri D, et al. Does the use of urinary reagent strip
tests improve the bedside diagnosis of meningitis? Trans R Soc Trop Med Hyg
1. van de Beek D, de Gans, J, Spanjaard L, et al. Clinical features and prognostic 1999;93:409–10.
factors in adults with bacterial meningitis. N Engl J Med 2004;351:
1849–59.
11 Psychiatric Diseases
Robert C Stewart, Kinke M Lommerse, Atif Rahman
l Try to establish basic primary care for mental health using simple
Key features protocols for nonpsychiatric healthcare staff and community
personnel.
ASSESSMENT
BOX 11.1 Common Syndromes
Basic Principles
l Ensure safety (see management of aggression below). l The acutely disturbed or stuporose patient
l Attempt to ensure confidentiality and explain the purpose of the l The patient who is sad, worried or has unexplained somatic
interview. complaints
l If using an interpreter:
l The patient who is misusing alcohol or other substances
● Speak directly to the patient, with the interpreter repeating
l Common psychiatric emergencies (see Boxes 11.2 & 11.3):
your questions.
● Ask the interpreter to translate exactly what the patient says l The aggressive patient
and not to tell you what he/she thinks was meant. l The suicidal patient
● The interpreter may be a useful source of information on l The chronically confused patient (see Box 11.5).
cultural issues. l The disturbed child (see Box 11.6)
History
l Personal details.
l Who referred and why?
l HIV (and CD4) testing with counseling and consent procedures,
l History of presenting complaint: Establishing accurate timelines
but can be done without if patient lacks capacity and outcome of
for events may prove difficult. Refer to significant dates to help
test would change management.
with this.
l Past psychiatric history including self-harm: Be wary of previous
diagnoses as these may not be accurate. ASSESSMENT AND DIFFERENTIAL
l
l
Past medical history: e.g. epilepsy, HIV status, pregnancy.
Medication history: Note any medications known to have neu- DIAGNOSIS OF COMMON
ropsychiatric side effects (e.g. mefloquine (antimalarial), Efa- SYNDROMES (Box 11.1)
virenz (antiretroviral)).
l Drugs and alcohol.
l Family psychiatric history.
THE ACUTELY DISTURBED OR STUPOROSE
l Personal history and current social circumstances. PATIENT
l Forensic history. Patients may present with a mixture of symptoms and often an
l Premorbid personality: Is this new behavior or has the person unclear history. Precise diagnosis may be difficult.
always acted like this?
Delirium
Mental State Examination Altered level of consciousness, impaired attention, disorientation
and visual hallucinations. Cause indicated by history and exa
l Appearance and behavior: Note general physical condition.
mination, e.g. infective, traumatic, intoxication/poisoning, alcohol
l Speech.
withdrawal (delirium tremens).
l Mood: Subjective and objective.
l Thought: Delusions, e.g. persecutory, grandiose; cognitions typical
of depression (guilt, worthlessness, hopelessness); suicidal ideas, Acute Psychosis
thoughts of harm to others. Delusions, hallucinations, muddled thinking and loss of insight.
l Perception: Hallucinations: visual, auditory, other. Hostile and suspicious, restless and disinhibited, or withdrawn and
l Cognition: Level of consciousness, attention and concentration, stuporose. Many conditions can cause acute psychosis. Characteristic
orientation, memory. features will guide diagnosis:
l Insight.
l Recent substance misuse (e.g. cannabis, stimulants), some
“organic” features (confusion, visual hallucinations) and short
Informant History and Previous Case Notes duration indicate drug-induced psychosis or withdrawal.
l Subtle confusion, physical signs or a history suggestive of a tem-
l Informant history is particularly important in psychiatric illness
(loss of insight) and high-risk situations. poral relationship between psychiatric and physical symptoms,
l Take care not to breach confidentiality.
indicate organic psychosis.
l Epilepsy-associated psychiatric syndromes, e.g. postictal confu-
sion (minutes/hours), postictal psychosis (days/weeks), and
Physical Examination interictal psychosis (months/years).
l Acute onset in response to a clear stressor (e.g. bereavement, job
l Any suspicion of delirium or organic cause should prompt inves-
loss) with no previous episodes suggests a brief reactive psycho-
tigation for infective and metabolic causes, head injury, substance
sis (likely to resolve quickly with good prognosis).
misuse, poisoning, etc.
l Delusions that one’s thoughts or actions are being controlled,
l People with chronic mental illness are at high risk for physical
auditory hallucinations in the third person, disjointed and “off-
disorders (e.g. tuberculosis) but tend to be neglected by medical
the-point” speech (formal thought disorder) and a history of
services.
gradual decline in work and social functioning (negative symp-
l Improving general health by treating comorbid conditions (e.g.
toms) suggest schizophrenia.
anemia, parasitic infections) can promote recovery.
l Onset of psychosis soon after childbirth (mood symptoms or
confusion may be prominent) indicates puerperal psychosis. Be
Investigations sure to exclude delirium.
l Conduct focused and appropriate investigations as resources
allow. Mood Disorder
l If suspicion of delirium or organic cause: blood glucose, full l Elated or irritable mood, disinhibition and recklessness (social,
blood count, urea and electrolytes, urinalysis, blood film for sexual, financial), pressured speech, flight of ideas (rapidly
malaria, syphilis test, chest x-ray, lumbar puncture, brain CT scan. jumping between tenuously related topics), grandiose delusions
100 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
5. Using the problem-solving approach or other psychologic 5. Patel V, Pereira J, Mann AH. Somatic and psychological models of common
intervention, help the person avoid relapse by identifying mental disorder in primary care in India. Psychol Med 1998;28:135–43.
and avoiding triggers (e.g. stress, particular social groups). 6. Taylor D, Paton C. The Maudsley Prescribing Guidelines, 10th edn. London:
If available, refer to a community support organization. Informa Healthcare; 2009.
6. If someone is alcohol- or drug-dependent, he/she should 7. Patel V, Simon G, Chowdhary N, et al. (2009) Packages of care for depression
in low- and middle-income countries. PLoS Med 2009;6:e1000159.
not abruptly stop use, but taper down gradually to avoid
8. Prince MJ, Acosta D, Castro-Costa E, et al. (2009) Packages of care for dementia
withdrawal symptoms.
in low- and middle-income countries. PLoS Med 2009;6:e1000176.
7. Treat alcohol withdrawal/delirium tremens with a reduc-
ing regimen of benzodiazepine, e.g. diazepam 10–20 mg
three to four times a day, reducing to stop over 5 days. Give
parenteral B vitamins if available, otherwise oral thiamine FURTHER READING
100 mg three times a day for 4 weeks. Patel V. Where There Is No Psychiatrist – A Mental Health Care Manual. London:
RCPsych Publications; 2003.
REFERENCES Patel V, Thornicroft G. Packages of care for mental, neurological, and substance
use disorders in low- and middle-income countries: PLoS Medicine Series.
1. World Health Organisation. ICD-10: The ICD-10 Classification of Mental and PLoS Med 2009;6:e1000160.
Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Semple D, Smyth R. Oxford Handbook of Psychiatry, 2nd edn. Oxford, UK:
Geneva: WHO; 1992. Oxford University Press; 2009.
2. Prince M, Patel V, Saxena S, et al. No health without mental health. Lancet Ungvari G, Kau LS, Wai-Kwong T, Shing NF. The pharmacological treatment of
2007;370:859–77. catatonia: an overview. Eur Arch Psychiatry Clin Neurosci 2001;251(Suppl
3. Lancet Series on Global Mental Health, 2007. 1);I31–4.
4. Jilek WG. Culturally related syndromes. In: Gelder MG, Lopez-Ibor JJ, World Health Organisation. mhGAP intervention guide for mental, neurological
Andreasen N, eds. New Oxford Textbook of Psychiatry, Vol. 1. Oxford, UK: and substance use disorders in non-specialised health settings: mental health
Oxford University Press; 2000:1061–6. Gap Action Programme (mhGAP), 2010.
12 ENT
Charlotte M Chiong, Jose M Acuin
Basic ear evaluation includes first the inspection of the pinna and
postauricular areas to look for swelling or fistulae, followed by exami-
Key features nation with adequate illumination through a head mirror, head light,
otoscope or otomicroscope. A 512-Hz tuning fork can detect the pres-
l Hearing impairment is the most common cause of ear, nose ence of either a conductive hearing loss (Weber’s test lateralizes to
and throat (ENT) disability worldwide worse ear with Rinne test negative or air conduction [AC] < bone
l Chronic otitis media is the most common cause of conduction [BC]) or a sensorineural hearing loss (Weber’s lateralizes
to the good ear and Rinne test is positive or AC>BC).
preventable hearing loss in the world
l Cancers of the head and neck also account for significant Audiologic evaluation is performed when equipment is available and
global morbidity and mortality will usually include:
l Cleft lip and palate often go unrepaired in many resource- l OAE (otoacoustic emissions) – A pass or refer result is detected
limited areas by clicks from an ear probe causing outer hair cell vibration-
l Over 70% of patients with acute rhinosinusitis improve after induced “echoes” to be detected by a sensitive microphone and
mostly used for newborn hearing screening.
7 days, with or without antimicrobial therapy
l PTA (pure tone audiometry) – From age 3 years, sound stimula-
l The deep fascial spaces of the head and neck are potential tion given through a headphone or an earphone is used to detect
cavities and can be involved in infections that extend from the threshold (minimum level at which sound is detected) in the
adjacent structures such as the teeth, tonsils, lymph nodes, frequencies 1 kHz, 2 kHz, 4 kHz, 8 kHz, 500 Hz and 250 Hz for
salivary glands and soft tissues both bone-conducted and air-conducted sounds.
l Speech audiometry – monosyllables and two-syllable words in a
standardized word list are used to check for ability to understand
speech.
l Tympanometry – measures pressure in the middle ear and checks
GLOBAL BURDEN OF ENT DISEASES the compliance of the tympanic membrane. Maximal compliance
The burden of ear, nose and throat (ENT) disorders is high in resource- at atmospheric pressure is type A and found in normal ears;
limited countries due to the scarcity of otolaryngologists (ENT special- decreased compliance at atmospheric pressure from ossicular
ists), a high prevalence and severity of many infections of the head chain fixation is type As; increased compliance at atmospheric
and neck, and the impact of immunocompromising disorders (HIV, pressure in ossicular chain dislocation is type Ad; flat type B is
malnutrition) and regional behavioral influences (betel nut chewing, when there is middle ear fluid or when there is a tympanic mem-
cigarette smoking). Hearing impairment is the most common cause brane perforation and type C is produced by peak compliance at
of ENT disability worldwide. Approximately 80% of the almost 300 negative pressure with Eustachian tube dysfunction.
million with disabling hearing impairment live in low- and middle- l Auditory brainstem response (ABR) testing shows tiny brainstem
income countries [1]. According to Alberti [2], 50% of all disabling waves (I–V) from more central auditory centers produced in
hearing losses are preventable by vaccination programs or better response to sounds like tone bursts or clicks, allowing detection
hearing protection from noise exposure. Cancers of the head and neck of hearing loss in both adults and children. It is also valuable as
also account for significant morbidity and mortality. In Southeast a screening tool for retrocochlear lesions or tumors in the cerebel-
Asia, 13% of all cancers involve the mouth or oropharynx [3]. lopontine angle.
Oropharyngeal cancer is more common in developing than devel- l Auditory steady state response (ASSR) testing – see Box 12.2.
oped countries, and the prevalence of oral cancer is particularly high l Genetic testing for hearing loss is now offered in more developed
among men. Cleft lip and palate often go unrepaired in many countries, followed by genetic counseling. This testing is not
resource-limited areas. readily available in most developing countries.
l Radiologic imaging may include mastoid x-rays (Towne’s view,
Law’s and Stenger’s views) that can detect mastoiditis and the
DEAFNESS AND HEARING presence of cholesteatoma (Fig. 12.1) which is still common in
IMPAIRMENT the tropics. Complicated chronic suppurative otitis media is
ideally investigated with computed tomography (CT) of the tem-
Disabling hearing impairment is defined by the World Health Organi- poral bone to assess for labyrinthine fistula or facial canal ero-
zation (WHO) as hearing thresholds that fall above 30 db in the sions in cases of facial paralysis and tegmental erosion that might
better ear in children, and thresholds that fall above 40 db in the suggest intracranial involvement (Fig. 12.2); gadolinium-
better-hearing ear in adults. Hearing loss can be either congenital or enhanced magnetic resonance imaging (MRI) gives soft tissue
acquired. The most common acquired conditions include chronic details in the internal auditory canals and cerebellopontine
otitis media, ototoxicity, noise-induced hearing loss, presbycusis, and angles, and in cases of asymmetric hearing loss can rule out a
sudden hearing loss from trauma or specific infections such as scrub vestibular schwannoma or other rare lesions such as hydatid cyst
typhus (Box 12.1). (Fig. 12.3). A three-dimensional CISS MRI of the inner ear may
104
ENT 105
demonstrate cochlear obliteration (following meningitis) or those with scrub typhus. Severe otalgia, initially paroxysmal and inter-
inner ear malformations such as cochlear absence or cochlear mittent, becomes persistent for several hours. Hearing loss and tin-
nerve aplasia in cases of congenital hearing loss. nitus tend to appear 2 weeks after the onset of scrub typhus. Otalgia
appears during the first week. Hearing loss can be permanent.
Chronic otitis media is the most common cause of preventable
hearing loss in the world [4]. Extracranial complications include sub-
periosteal abscess and labyrinthine fistula, facial weakness, foul ear AUDITORY REHABILITATION
discharge, postauricular swelling and abscess formation. Sequelae Aural rehabilitation requires identification of the presence, type and
may include facial paralysis, profound deafness, and intracranial com- degree of hearing loss. For hearing loss between 40 db and 85 db,
plications, including meningitis. conventional hearing aids provide the greatest benefit. However, the
Patients with chronic suppurative otitis media should be treated with cost of hearing aids is prohibitive in most resource-limited settings,
antibiotics. Topical antibiotics can have some benefit in the setting of although low-cost solar battery options are being developed. For severe
an open communication to the middle ear, but ototoxic drugs to profound sensorineural hearing loss, vibrotactile devices or cochlear
(for example, topical aminoglycosides) should be avoided in this implants may be helpful, but are usually not feasible or available.
setting. A topical fluoroquinolone such as ciprofloxacin, or oral
amoxicillin–clavulanic acid are commonly administered agents [4–
7]. If intractable to medical treatment or when there is evidence of
CLEFT LIP AND PALATE
cholesteatoma, surgery is indicated. For non-cholesteatomatous ears, The global incidence of oral clefts has been variably reported as 1 per
a Cochrane review revealed low-quality and scanty literature compar- 500 to 1000 live births, making it one of the most common congenital
ing tympanoplasty versus tympanoplasty with mastoidectomy in dis- anomalies [19]. Gender and race differences have been reported, and
charging ears [8]. In the setting of a cholesteatoma, a canal-wall-down Asians in particular are at high risk. A 1997 study showed the inci-
mastoidectomy or open cavity technique may be indicated. There is dence of oral clefts in the Philippines to be about 2 per 1000 live births
level 3 evidence of improved or equivalent hearing outcomes with [20]. Etiologic risk factors include micronutrient deficiency, maternal
unstaged rather than staged tympanoplasty [9,10]. exposure to tobacco smoke, alcohol, corticosteroids, exogenous estro-
gen, organic pollutants and occupational chemicals. History and
Given the tremendous surgical backlog in resource-limited countries physical examination include a search for other possible abnormali-
because of the lack of ear surgeons, some countries hold “surgical ear ties, as 300 syndromes (Stickler syndrome: Pierre Robin sequence plus
camps” like the BRINOS (British Nepal Otological Surgery) and Rural myopia or retinal problems, velocardiofacial, Treacher–Collins, fetal
Ear Foundation in Thailand. alcohol, oro-facial-digital type) have been associated with cleft lip and
palate. Evaluation and treatment is best done by a multidisciplinary
Other Causes of Deafness team composed of an oral surgeon, otologist, speech pathologist,
Ototoxicity: Many ototoxic drugs are routinely used in resource- psychologist and education specialist. Genetic counseling of high-risk
limited settings, including streptomycin (used for tuberculosis treat- families is important. The timing of surgical repair should be empha-
ment), neomycin, kanamycin and gentamicin. sized: repair cleft lips at 3 months (with myringotomy and ventilation
tube placement), palatoplasty at 18 months, speech intervention at
Platinum-containing chemotherapy with cisplatin or carboplatin and 3–4 years, velopharyngeal surgery at 4–6 years, alveolar bone grafting
radiotherapy for neck tumors may also cause hearing loss [11,12]. at 9–11 years, nasal reconstruction at 12–18 years, and orthognathic
surgery, when needed, after 16 years of age.
Noise-induced hearing loss can be caused by exposure to intense
sounds, and if caused by a broadband noise such as in industrial set-
tings, a characteristic 4-kHz notch or dip is noted on audiometric NOSE AND THROAT INFECTIONS
testing. Prevention by hearing conservation programs should include
education on the risks of hearing loss with noise exposure, the effec-
tive use of hearing protection devices, monitoring hearing and noise ACUTE AND CHRONIC RHINOSINUSITIS
levels at the workplace, and minimizing the duration of exposure. Infections of the paranasal sinuses (ethmoid, maxillary, frontal and
sphenoid sinuses) may occur as a result of contiguous infections (e.g.
Presbycusis is characterized as decreased high-frequency hearing sen- rhinitis, dental abscesses). Acute sinusitis is produced by inflamma-
sitivity usually beyond the age of 50 years, typically involving both tory thickening of the mucoperiosteal lining of the sinus cavities and
ears. Central auditory deficits also increase with age [13]. increased mucus secretions. Mucosal congestion and edema, occur-
Sudden hearing loss should be considered an emergency since early ring in the areas surrounding the sinus openings, result in blocked
treatment may reverse the loss. Sudden hearing loss is defined as a sinus drainage and accumulation and stasis of sinus secretions. Pres-
hearing loss of >30 db over 72 hours and affected patients may sure on the nerve endings in the sinus mucosa produces facial pain
present with aural fullness although otoscopic findings are normal. and fullness. Suppurative complications, including meningitis and
Ideally, an MRI with gadolinium should be performed to evaluate for orbital cellulitis, can occur. Acute sinusitis may evolve into chronic
a retrocochlear lesion. An empiric trial of prednisone at 1 mg/kg/day sinusitis. In the latter condition, mechanical obstruction of sinus
for 2 weeks followed by a taper, or its methylprednisolone equivalent, drainage occurs from persistently swollen mucosa, polyp formation,
has shown benefit in some patients. A study showed the group given bony protuberances, nasal septal deviations or spurs. Longstanding
steroids improved significantly, with 5 : 1 relative odds of >50% recov- infection can lead to squamous metaplasia of the normally cuboidal
ery [14]. A steroid-effective zone of 40–90 db (moderate to severe) and columnar epithelia of the paranasal sinuses, leading to loss of
loss was defined, with best results if treated within 10–14 days of functional mucociliary transport and thickening of sinus mucus.
onset. Empiric addition of acyclovir or valacyclovir did not improve Fungal sinusitis may manifest along a spectrum ranging from local-
results [15,16] Intratympanic steroids are now being tried in some ized, largely asymptomatic colonization of the nasal and paranasal
centers, and initial results report this to be promising as a salvage sinus mucosa, to chronic invasive rhinosinusitis with granuloma for-
treatment for patients who fail to respond to initial systemic steroids mation. Severe acute invasive rhinosinusitis is usually seen among
administration [17]. There are reports of acute hearing loss and immunocompromised patients, and is characterized by a fulminant,
otalgia following scrub typhus infection [18]. Scrub typhus is an acute necrotizing process.
febrile disease secondary to infection by an obligate intracellular bac-
terium, Orientia tsutsugamushi, transmitted via Leptotrombidium chigger It is difficult to distinguish bacterial from viral rhinosinusitis. Anterior
mite bites. Symptoms include myalgia, diffuse lymphadenopathy, rhinoscopy, using a nasal speculum and sufficiently bright and
fever, eschars, and erythematous maculopapular rashes. Complica- focused illumination, may demonstrate purulent discharge from the
tions include pneumonia, myocarditis, meningitis, hepatitis, acute middle meatus (next to the middle turbinate) in either condition.
renal failure and hearing loss. Hearing loss can affect up to a third of Transillumination in a darkened room, using a penlight held against
ENT 107
the skin overlying the frontal or maxillary sinuses, may suggest acute precipitated by loud sounds can be caused by syphilitic fixation of the
sinusitis if there is unequal transillumination due to fluid accumula- stapes footplate to the oval window.
tion. Sinus x-rays, CT and nasal endoscopy are recommended when
the condition fails to respond to therapy, when the diagnosis or the
extent of disease is in question, or when surgery is being planned. SALIVARY GLAND INFECTIONS
Paranasal sinus x-rays (Waters’, Caldwell’s and lateral views) or ultra- Bacterial infections of the parotid, submandibular and sublingual
sound may demonstrate fluid accumulation inside the maxillary sinus salivary glands may result from oral or dental infections. Acute
(x-rays must be taken with the patient upright) or varying degrees of enlargement of intraparotid nodes may be due to many viruses and
sinus opacification or thickening of the sinus mucoperiosteum. In can lead to swelling and secondary suppuration of the parotid gland.
patients with chronic rhinosinusitis, nasal endoscopy using a 0 degree (Primary viral infections of the parotid gland are discussed else-
Hopkins rod telescope may be performed to more closely inspect the where.) Intraductal and parenchymal edema and congestion can lead
mucosa of the middle turbinate and middle meatus and visualize to stasis and accumulation of secretions and blockade of salivary
small polyps. This is an office procedure that requires minimal-to-no drainage. The resulting swelling, pain and tenderness can produce
topical anesthesia. CT of the sinuses can better demonstrate the extent trismus and dysphagia. Infections of the salivary glands are usually
of sinus disease, bony and soft tissue abnormalities that obstruct criti- treated empirically. For fluctuant, painful swellings or for patients
cal nasal and sinus passageways, and soft tissue masses, such as sinus who do not respond to empiric antimicrobial therapy, aspiration or
mucoceles, polyps and cysts. Bacterial culture, taken either by an open drainage with culture and sensitivity testing of the purulent
endoscopically guided swab of the middle meatus or by a puncture discharge may be required. The most common organisms involving
of the maxillary sinus antrum, is considered the reference standard in salivary glands include Staphylococcus aureus and Streptococcus pyogenes.
diagnosing acute bacterial rhinosinusitis, but is only used when Treatment should include antibiotic therapy directed against these
medical treatment fails. Streptococcus pneumoniae and Haemophilus bacteria, anti-inflammatory agents and adequate hydration.
influenza are the most commonly isolated organisms, although anaer-
obes may also be present [21].
DEEP FASCIAL SPACE INFECTIONS
Over 70% of patients with acute rhinosinusitis improve after 7 days, The deep fascial spaces of the head and neck are potential cavities
with or without antimicrobial therapy. Thus, patients with mild fever and can be involved in infections that extend from adjacent structures
and facial pain should be given analgesics and observed regularly. such as the teeth, tonsils, lymph nodes, salivary glands and soft
About seven patients must be treated with antibiotics to achieve one tissues. Involvement and abscess formation and edema can result in
more clinical cure beyond spontaneous resolution [22]. Ampicillin, obstruction (swallowing and breathing), pain, tenderness, trismus
amoxicillin, trimethoprim–sulfamethoxazole, macrolides and and neck stiffness. Visible soft tissue swelling can result from infec-
cefaclor, given for 7 to 14 days, have all been shown to be effective tions of the peritonsillar, parapharyngeal, parotid, submandibular,
treatment for most cases of acute bacterial rhinosinusitis [23]. The suprahyoid, periauricular and masseteric spaces. Peritonsillar abscess
final choice should be guided by local bacterial prevalence and anti- formation, also known as Quinsy, presents with unilateral swelling
biotic resistance patterns. Diarrhea and adverse events are 80% more of the soft palate above the tonsil. Abscess formation beneath the
common in patients who receive antimicrobials. If symptoms fail to floor of the mouth, called Ludwig’s angina, produces tense and tender
resolve with antibiotics, the diagnosis should be reconfirmed, other swelling behind the chin and between the angles of the jaw. Vincent’s
illnesses should be excluded, risk factors should be addressed, and angina, or trench mouth, presents with localized or multiple necrotic
antibiotic treatment extended. For patients with chronic rhinosinusi- mucosal ulcerations and foul breath. Retropharyngeal and retro-
tis, antibiotics are often given for 4 weeks or more. If inhalant allergies esophageal abscesses produce dysphagia and neck rigidity. Mediasti-
are known or suspected, intranasal steroids may be prescribed to nal spread is a potential complication that can lead to sepsis; rupture
decrease mucosal inflammation associated with acute and chronic may lead to respiratory obstruction. Erosion of the great vessels of
rhinosinusitis [24]. Surgery is indicated for extranasal spread of infec- the neck can lead to catastrophic hemorrhage. Soft tissue lateral views
tion, evidence of mucocele or pyocele, fungal sinusitis or obstructive of the head and neck may aid in diagnosing retropharyngeal and
nasal polyposis, and is often performed in patients with recurrent or retroesophageal abscesses. Purulent material that is drained or aspi-
persistent infection not improved by drug therapy [25]. Surgical treat- rated from deep neck abscesses should be submitted for culture and
ment of chronic rhinosinusitis is performed with fine surgical instru- sensitivity studies and the results used to adjust the selection of anti-
ments under endoscopic control and is aimed at removing abnormal biotics. Treatment should include aggressive antibiotic therapy
bone and mucosa in the natural sinus ostia and other critical sinus against both Gram-positive and Gram-negative organisms (including
passageways to improve ventilation and preserve mucociliary func- anaerobes), prompt incision and drainage of abscesses, and adequate
tion. The success of this procedure in resolving sinusitis is supported nutrition and fluid therapy. Respiratory obstruction should be proac-
by evidence of variable quality [25] and depends on specific sinus tively addressed with consideration of artificial airways.
conditions, the surgeon’s expertise, and the patient’s compliance with
postoperative care.
CYSTICERCOSIS
Granulomatous Involvement of the Head Cysticercosis can present as nontender, solitary or multiple subcutane-
ous or submucosal nodules in the face, eyes, neck, nose, mouth,
and Neck tongue and pharynx [26,27].
Granulomas of the head and neck can occur as single or multiple
lesions in virtually any area. Mycobacterial pathogens are the leading
cause. Although becoming increasingly rare, leprosy produces charac- ORAL ULCERS
teristic nodules and/or leonine deformities of the soft tissues of the Lesions of the mucosa of the lips, gums, tongue, floor of mouth,
face. Tuberculosis of the head and neck can result in granulomas of buccal cavity, palate and pharynx can be secondary to inflammatory,
the face, salivary glands, oral, pharyngeal and laryngeal cavities, ear traumatic, neoplastic, metabolic, immunologic, hematologic and idi-
and temporal bone, nose and paranasal sinuses. Tuberculous infec- opathic causes. Different etiologies can be expressed in similar ways.
tion of the lymph nodes of the neck (scrofula) can present as a slow- For instance, infections, malignancies, autoimmune disorders and
growing mass that then can rapidly enlarge, leading to tenderness blood dyscrasias can all produce painful mouth ulcers. Oral disease
and suppuration. Chronic recurrent breakdown of the overlying skin caused by fungal, bacterial or viral infections can also be commonly
can results in multiple draining sinuses and scarring. Syphilitic found in immunocompromised hosts. For instance, oral lesions are
involvement of the head and neck can be expressed as necrotizing strongly associated with HIV infection such as pseudomembranous
chancres of the mouth, nose and paranasal sinuses, granulomas of oral candidiasis, oral hairy leukoplakia, HIV gingivitis and periodon-
the oropharynx, nose and nasopharynx, draining buboes of the neck, titis, Kaposi sarcoma and non-Hodgkin lymphoma. All mucosal
intracranial gummas, and cranial and peripheral neuropathies. Vertigo ulcers of the oral cavity that do not heal or do not show signs of
108 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Benign Malignant
CANCRUM ORIS
Noma (cancrum oris, stomatitis gangrenosa) is a serious and often Nose and Nasal polyp, hemangioma, Squamous cell
fatal condition characterized by a quickly spreading orofacial gan- paranasal inverting papilloma, carcinoma;
grene in children, caused by a combination of malnutrition, debilita- sinuses mucocele, dermoid, esthesioneuroblastoma;
tion because of concomitant diseases (measles), and intraoral meningioma sarcomas
infections. Cancrum starts as a stomatitis followed by ulceration,
Face Nevus, epidermal inclusion Squamous cell
spreads rapidly through orofacial tissues, and often has a blackened
cyst; sebaceous cyst carcinoma; basal cell
necrotic center. Management entails antisepsis, wound debridement, carcinoma; malignant
antibiotics (intravenous penicillin and metronidazole) and nutrition. melanoma
Reconstructive plastic surgery is often required in survivors.
Oral cavity Squamous papilloma; Squamous cell
LEISHMANIASIS mucocele; torus
mandibularis/palatinus;
carcinoma; sarcoma
HEAD AND NECK NEOPLASMS Nasopharyngeal angiofibromas are highly vascular tumors that arise
from the superolateral wall of the nasopharynx. They are found exclu-
Neoplasms of the head and neck may arise from skin, mucosa, soft sively in adolescent males and present with recurrent, at times massive,
tissues and salivary glands. Table 12-1 lists the most commonly epistaxis. They can spread to the adjacent nasal vault, ethmoid sinuses,
encountered benign and malignant tumors in the different regions of pterygomaxillary fossa and infratemporal fossa, sphenoid and base of
the head and neck. the skull. Branches of the internal maxillary artery may give rise to
feeding vessels.
BENIGN NEOPLASMS Benign neoplasms of the larynx include nodules, polyps and cysts that
By far the most common nasal neoplasm is a mucosal polyp that arise from the true vocal folds or adjacent tissues. These are single,
develops in a patient with chronic rhinosinusitis. Polyps are edema- circumscribed masses that may lead to hoarseness and subtle voice
tous outpouchings of nasal mucosa covered by squamous epithelium changes. They are associated with longstanding voice misuse or abuse.
and originate from the ethmoids and other sinuses. Untreated, they Laryngeal papilloma, either juvenile or the adult type, are usually
can fill the nasal vault up to the vestibule, widen the nasal dorsum, multiple pedunculated masses arising from any area of the larynx,
and result in severe obstruction to breathing and smelling. By with a propensity to spread to the tracheobronchial tree. They are
obstructing the natural ostia of the sinuses and destroying bone, they associated with human papillomavirus infection acquired either
often perpetuate the infectious process. Hemangiomatous polyps and while passing through the birth canal of an infected mother or
hemangiomas often present with epistaxis or nosebleed. An inverting through intimate contact later in life.
papilloma may present like a nasal polyp but aggressively proliferates,
invades bony partitions, and may harbor carcinoma. Cervical lymph node enlargement associated with infections of the
upper respiratory tract, oral cavity, scalp and face occurs frequently in
Benign neoplasms of the face and oral cavity are usually slow growing, children. Cystic hygroma and lymphangioma are both malformations
well circumscribed, and produce few symptoms. An ameloblastoma of the lymphatic channels of the neck that present as solitary, soft,
ENT 109
painless, poorly demarcated masses in young children. The malignant Papillary carcinoma is by far the most common thyroid malignancy,
counterpart is lymphoma, either Hodgkin or non-Hodgkin, character- followed by follicular cancer. Other rarer varieties include medullary
ized by massive multiple enlargement of lymph nodes on the poste- cancer and undifferentiated (anaplastic) cancer.
rior triangle of the neck.
Benign neoplasms constitute 75% of salivary gland tumors, of which INVESTIGATIONS
pleomorphic adenoma of the parotid gland is the most common. Neoplasms should usually be biopsied to establish a diagnosis. Fine
Other benign salivary gland tumors include Warthin’s tumor, which needle (gauge 22) aspiration biopsy of soft tissue masses with intact
occurs mostly in males at the fourth to fifth decade of life. surfaces is often the most feasible procedure to perform. Once the
needle has penetrated the substance of the mass, the plunger of the
syringe is pulled to maintain negative pressure while the needle is
MALIGNANT NEOPLASMS carefully and repeatedly plunged to sample several areas. The plunger
is then released and the needle momentarily disconnected from the
Squamous cell carcinoma is the most common malignancy of the syringe to release any negative pressure and preserve the aspirated
head and neck. Depending on the stage at diagnosis, degree of dif- specimen within the bore of the needle. A bloody aspirate must be
ferentiation, and the site of origin, it can present early or late, destroy avoided as this obscures cellular detail. The specimen must be
overlying bone, invade adjacent soft tissues, extend intracranially or expressed from the needle on to several glass slides, smeared and
spread to the submandibular and deep jugular chain of neck nodes. soaked in 95% ethyl alcohol for 2 minutes. Training and experience
The mass is usually fungating and bleeds easily to touch. Tobacco are necessary to ensure correct diagnosis (86% and 96% for malignant
smoking and chewing, alcohol intake, infection by Epstein-Barr virus and benign head and neck tumors, respectively [30]) and to minimize
or human papillomavirus types 16, 18 and 31, and exposure to betel missed diagnoses to as low as 2% [31]. An accuracy level of 89% has
quid, heavy metals, leather tanning and woodworking products are been reported for solitary thyroid nodules [32]. Polyps, papillomas
risk factors. Symptoms include local pain, ulceration, bleeding and and similar pedunculated masses may be gently avulsed so that a
swallowing difficulty. Laryngeal cancer presents with hoarseness, representative portion can be submitted for histopathologic examina-
hemoptysis, throat pain, cough and breathing difficulty. In the oral tion after immersing the entire specimen in 10% formaldehyde. Cysts
cavity, submucosal spread of the tumor should be determined by of the soft tissues and bones of the face may be excised both for
palpation. A second primary cancer should always be considered. diagnosis and for definitive management. Tonsillectomy may be done
Squamous cell carcinoma of the ear presents with ear mass, bleeding when tonsillar lymphoma is suspected. Neck nodes are usually not
and pain, and may arise on a background of a chronic otitis media. biopsied unless the primary lesion has been identified by histopathol-
Late symptoms include facial paralysis, sensorineural hearing loss, ogy. This may require rigid or flexible endoscopic examination of the
vertigo and severe ear pain. nose, pharynx, oral cavity, pharynx, larynx and esophagus. If endo-
Malignancies of the head and neck spread to the draining submental, scopic results are negative or equivocal for malignancy, a fine needle
submandibular, and deep jugular chain of lymph nodes in one or aspiration biopsy of the neck nodes may be performed. An open
both sides of the neck. Distant metastasis to the lungs, liver and brain biopsy should be considered as the last resort. Biopsy should not be
occur in late stages. done for vascular tumors such as hemangiomas and nasopharyngeal
angiofibromas. These often present with massive bleeding, so they are
Verrucous carcinoma is a special type of well-differentiated squamous usually diagnosed on clinical grounds and appearance. Angiography
cell carcinoma which is wart-like, indolent and frequently recurs after may be required to visualize feeding blood vessels and to plan for
excision. It arises from the skin of the lips and gums. arterial ligation or embolization prior to definitive excision.
Nasopharyngeal carcinoma occurs as an undifferentiated lymphoepi-
thelioma, or a poorly differentiated or a well-differentiated squamous DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
cell carcinoma. It arises from the posterolateral nasopharyngeal walls Benign and malignant neoplasms of the face, salivary glands, neck
and may initially present with hearing loss (from blockade of the and external parts of the ears, mouth and nose present with lumps or
Eustachian tube), diplopia (from impingement of the abducens nerve masses. These may be present at birth, such as dermoid and cystic
and consequent lateral rectus palsy) or epistaxis. It is not uncommon hygroma, at early childhood, such as branchial cleft cyst and thy-
for patients to present with an enlarged lymph node just behind the roglossal duct cyst, at adolescence, such as nasopharyngeal angiofi-
angle of the jaw. It is common among people of Chinese descent and broma, at adulthood. Their location may be determined by their
is associated with eating spicy preserved fish. This malignancy has a embryologic origin; thus, dermoids occur in the midline and other
great potential for early spread to the deep jugular lymph nodes of fusion lines, and branchial cleft cysts are found along the paths of the
the neck and the base of the skull. Lymphoma, either Hodgkin or branchial clefts present in early fetal life. Benign masses are usually
non-Hodgkin type, can arise from the chain of lymphoid tissues circumscribed, mobile masses that exhibit little or slow change in size,
encircling the oropharyngeal opening (i.e. the Waldeyer’s ring consist- consistency or number over time. Malignant masses exhibit more
ing of the pharyngeal, palatine, tubal and lingual tonsils). dynamic and rapid changes, and tend to involve adjacent tissues.
The malignant neoplasms of the skin include squamous cell carci- Neoplasms that occur in cavities, such as the nose, paranasal sinuses,
noma, basal cell carcinoma and malignant melanoma, the latter two mouth, pharynx, larynx and ears, are less clinically apparent, and may
being associated with sunlight exposure. While squamous cell carci- initially present with subtle signs such as nosebleeds, mucosal discol-
nomas are expansile, aggressive and spreading, basal cell carcinomas orations, voice changes, and mild hearing impairment. As the tumor
are ulcerative, more indolent and localized. The areas around the lips, enlarges, it can obstruct preformed cavities, such as the larynx and the
nose and cheeks are especially prone to this cancer. Malignant nasal cavity, or press on bony walls, such as the paranasal sinuses.
melanoma is a locally destructive superficial malignancy with a high Owing to the proximity of the base of the skull, neoplasms of the
tendency to postoperative and systemic spread. nose, paranasal sinuses, nasopharynx and ear can present with neu-
rologic signs and symptoms such as facial paralysis, headache, sei-
Sarcomas, such as rhabdomyosarcoma, leiomyosarcoma, osteosar- zures and diplopia. Destruction of bony walls and invasion of
coma, hemangiosarcoma and neurosarcoma, are solid and rapidly adjacent soft tissues suggest aggressive behavior, although they do not
enlarging masses seen in younger patients. They quickly spread via necessarily mean malignancy. Destruction of anatomic boundaries,
the bloodstream into distant organs. marked enlargement of draining lymph nodes of the neck, and spread
to distant sites are more typical of carcinomas and sarcomas.
In the salivary glands, the malignant variants are adenoid cystic
carcinoma and mucoepidermoid carcinoma. These are also com-
monly seen in the parotid gland. As a rule, however, minor salivary MANAGEMENT AND OUTCOMES
gland tumors tend to be malignant more often than parotid gland Benign neoplasms that are small, circumscribed and solitary can be
tumors. managed with simple excision. However, if they occur in the face or
110 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
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Diseases of the Musculoskeletal
13 System
Richard A Gosselin, Jonathan J Phillips, R Richard Coughlin
Violence
10.8%
War
3.4%
Other intentional
injuries
0.2%
Poisoning
6.7%
Other unintentional
injuries
18.1% Falls
7.5%
Fires
Drowning 6.2%
7.3%
FIGURE 13.1 Distribution of global injury mortality by cause. Redrawn from WHO Global Burden of Disease Project 2002, Version 1.
within the bone and patients are less likely to have acute symptoms
of pain and fever, but these longstanding fistulas are at increased risk
TABLE 13-1 The 20 Leading Non-fatal Injuries*
of sarcomatous degeneration. Joints where the metaphyses are intra-
Sustained as a Result of Road Traffic Collisions, World, articular (shoulder, elbow, hip and ankle) very often also have septic
2002 arthritis.
Type of injury Rate per 100,000 Proportion of all Acute OSM should always be suspected in a sick child complaining
sustained population traffic injuries of limb pain, even if x-rays are normal. Fever, local swelling and ten-
derness, and guarding are common physical findings. Leukocytosis
Intracranial injury† 85.3 24.6 with a left shift, a very elevated erythrocyte sedimentation rate (ESR)
(short-term‡) and a negative malaria test are usual laboratory findings. Because
malaria is a common cause of fever, patients with acute OSM often
Open wound 35.6 10.3 present late. Another reason for late presentation, as demonstrated in
Fractured patella, tibia 26.9 7.8 a study from Uganda, is that more than half of patients have first seen
or fibula a traditional healer [7]. Thus, abnormal x-ray findings are common
even at initial assessment.
Fractured femur 26.1 7.5
(short-term‡) Treatment involves antibiotics and often surgery. If culture results are
available, appropriate antibiotics should be given according to sensi-
Internal injuries 21.9 6.3 tivity. However, this is rarely the case. Staphylococcus aureus is the most
common pathogen globally and should always be covered when treat-
Fractured ulna or 19.2 5.5
ing empirically [8]. As in developed countries, methicillin-resistant
radius
S. aureus (MRSA) is now seen in LMIC. The antibiotic regimen should
Fractured clavicle, 16.7 4.8 also cover pathogens that are locally endemic. There is agreement that
scapula or humerus 6 weeks of total antibiotics is sufficient, at least 7 to 10 days of which
should be given intravenously [8,9]. Surgery is indicated when clinical
Fractured facial bones 11.4 3.3 and radiographic findings are both found, where multiple drill holes
Fractured rib or 11.1 3.2
in the metaphysis will help decompress the intraosseous pus, and
sternum hopefully before irreversible vascular damage has occurred. It is essen-
tial to disturb the periosteum as little as possible.
Fractured ankle 10.8 3.1
In chronic OSM, the clinical diagnosis is easier. Treatment will depend
Fractured vertebral 9.4 2.7 on the severity of the symptoms. The occasional painful flare-up can
column often be successfully managed by palliative antibiotics. Curative treat-
ment is surgical, but recurrences are common.
Fractured pelvis 8.8 2.6
Sprains 8.3 2.4 SEPTIC ARTHRITIS
Fractured skull 7.9 2.3 Bacterial septic arthritis can affect any joint, but hip, knee and shoul-
(short-term‡) der are the most common, either as an isolated pathology or in
conjunction with an intra-articular metaphyseal osteomyelitis. Late
Fractured foot bones 7.2 2.1 presentation is common. Parents often give a history of trauma: the
patient fell a few days ago and has refused to bear weight ever since
Fractured hand bones 6.8 2.0
on the involved extremity. Examination usually reveals a septic child,
Spinal cord injury 4.9 1.4 with localized swelling over the involved joint, which is painful on
(long-term§) palpation or passive mobilization. Basic laboratory findings are non-
specific: elevated white blood cell count (WBC) and ESR. Plain x-rays
Fractured femur 4.3 1.3 can appear normal early on, or show only soft tissue swelling, but
(long-term§) there will eventually be a widening of the joint space when compared
Intracranial injury† 4.3 1.2 to the contralateral side, which can lead to complete dislocation.
(long-term§) The differential diagnosis should include tuberculosis, inflammatory
Other dislocation 3.4 1.0 arthropathies, transient synovitis, post-traumatic hemarthrosis, and
avascular necrosis. Joint aspiration can be very useful. S. aureus is the
*Requiring admission to a health facility. most common pathogen, but other bacteria can be involved, such as
†Traumatic brain injury. gonococcus in adolescents, Haemophilus influenzae in newborns and
‡Short-term = lasts only a matter of weeks. very young infants, and Salmonella enterica in patients with sickle cell
§Long-term = lasts until death, with some complications resulting in reduced disease. Surgical drainage should be considered whenever there is a
life expectancy. clinical suspicion, and performed as early as possible. The downsides
Source: WHO Global Burden of Disease Project, 2002, Version 1. of a negative arthrotomy are far outweighed by the dire consequences
of a neglected septic arthritis, particularly in a weight-bearing joint.
Other nonbacterial pathogens can involve the musculoskeletal
system: fungi (histoplasmosis, actinomycosis, blastomycosis, aspergil-
the host response will attempt to reabsorb all the necrotic material, losis), treponema (yaws, syphilis) or parasites (dracunculiasis or
including the dead cortical bone, or sequestrum. The periosteum will guinea worm, onchocerciasis). Their diagnosis and treatment are dis-
lay down new living bone, called involucrum (Fig. 13.3). If the resorp- cussed in other sections of this text.
tion process is incomplete, some of the sequestrum may be incorpo-
rated within the involucrum. This piece of dead bone acts as a foreign
body that harbors bacteria, and cannot be sterilized by antibiotics SOFT TISSUE INFECTIONS
alone. This is the stage of chronic OSM, with recurrent intermittent Lacerations and penetrating injuries are seen in manual laborers,
episodes of acute OSM-like symptoms that are relieved by antibiotics often with foreign bodies such as splinters, thorns, pieces of rock or
and/or spontaneous drainage from a re-opened fistula. Chronic metal, and shards of glass. They can lead to cellulitis, or superficial
drainage from permanently patent sinuses prevent pressure build-up and deep abscesses. Some deep infections, such as hand flexor tendon
D i s e a s e s o f t h e M u s c u l o s k e l etal System 115
Destruction of
Microcirculation
Generation of sequestra:
When both the medullary and
Ischemic necrosis periosteal blood supplies are
compromised, large areas
of dead bone may be formed
The host response attempts
to reabsorb all necrotic Migration of infectious
material including the material from 1º focus If pus finds It way through
sequestrum. the cortical bone, the
The viable periosteum will periosteum is separated
also lay down new bone, from the cortex which then
the involucrum. becomes avascular
Resorption & new bone
If the process of resorption
growth, resolution
is incomplete some of the
sequestrum may be
incorporated into the
involucrum
The periosteum attempts Perforation through the
to wall off the infectious, periosteum may
process. This becomes vislble produce soft tissue abscesses
on plain x-rays as a periosteal as pus tracks along paths
reaction within 10–20 days of least resistance or
The piece of dead may break through the skin
bone acts as a foreign body to form a sinus or fistula
that harbors bacteria and Chronic OSM
cannot be sterillzed with
antibiotics alone
sheaths, require early surgical debridement, or significant functional purulent material, and should be done when the diagnosis is sus-
impairment can result. pected. Orthopedic management is incision and drainage of abscesses
or debridement of necrotic tissue if involvement is extensive. Antibiot-
Other soft tissue infections that can be seen in tropical environments ics are necessary.
are: atypical bacteria (tularemia, brucellosis), fungi (aspergillosis,
cryptococcosis), and parasites (echinococosis, trichinosis).
TUBERCULOSIS
Tropical pyomyositis was first described in Uganda in 1968 and
Approximately 5% of HIV-negative tuberculosis (TB) patients have
presents with single to multiple suppurative lesions within skeletal
involvement of their musculoskeletal system. This increases in HIV-
muscle. It is more common in HIV-positive patients. Large muscles
positive TB patients. Thus, there could be at least one million people
of the lower extremities and pelvic girdle are common sites of infec-
worldwide with TB of their bones and joints. Around half of skeletal
tion. Studies suggest up to 50% of patients report a previous injury.
TB involves the spine, 40% have articular disease, mostly hip and
Examination usually reveals fever, diffuse fusiform swelling, and sig-
knee, and the remaining 10% have either isolated soft tissue or extra-
nificant tenderness on palpation or passive stretching of the involved
articular osseous involvement (Figs 13.4 & 13.5).
muscle, but usually no palpable fluid collection or fluctuation. The
abscess is subfascial, within the muscle tissue itself, and poorly con- Routine laboratory testing is nonspecific, with usually a mild to mod-
tained. S. aureus accounts for near 90% of cases. Multiple attempts at erately elevated ESR and a normal to slightly elevated WBC. Aspira-
aspiration with a large-bore needle are often necessary to retrieve tion can be nonspecific, with fluid ranging from mildly inflammatory
116 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
LEPROSY
The incidence of leprosy saw a 4% decrease in global cases in the
period of 2007–2008; new cases detected in 2008 across 121 countries
totaled 249,000. Leprosy is now largely limited to high prevalence
pockets, including areas of India, Nepal, central Africa, and Brazil.
Leprosy results in disabling limb deformities that have social implica-
tions and disrupt the ability of those afflicted to seek employment,
or contribute to subsistence farming. Secondary changes to bone
account for the majority of cases seen for orthopedic management.
Motor denervation and fixed contractures result in clawing of the toes
and fingers, while loss of afferent sensory nerve conduction predis-
poses to the development of trophic ulceration and secondary infec-
tions. Treatment with multidrug therapy (MDT) consisting of
rifampicin, clofazimine and dapsone, is efficacious in interrupting
transmission and treating infection.
POLIOMYELITIS
Four countries remain endemic for polio: India, Pakistan, Afghanistan
and Nigeria. Several other countries in Africa, South Asia, and central
Europe have reintroduced polio. New-onset disease is usually seen in
the under-5 age group, however, much of what is encountered today
may be residual disease. The seminal work of Huckstep remains the
classic reference on the topic [10].
FIGURE 13.4 Characteristic spinal involvement of tuberculosis with
contiguous disc involvement and kyphotic deformity.
PEDIATRIC CONDITIONS
to bloody to frankly caseous in appearance. Plain x-rays can be useful Early identification of pediatric conditions is important, as timely
in identifying a primary pulmonary focus. The diagnosis rests on a intervention can dramatically alter the course of a child’s life. Pediatric
high level of clinical suspicion, and chemotherapy is most often initi- orthopedic conditions include scoliosis, congenital hip dysplasia,
ated on the basis of a combination of nonspecific findings. limb length discrepancies, Legg–Calve–Perthes disease, genus varum,
and osteogenesis imperfecta. This chapter describes congenital talipes
The cornerstone of TB treatment is combination chemotherapy. equinovarus and cerebral palsy.
Surgery may be indicated for diagnostic purposes if appropriate labo-
ratory facilities are available. For spinal TB, surgery is indicated to
decompress an epidural abscess compressing the cord and causing CONGENITAL TALIPES EQUINOVARUS
paraparesis, particularly with no improvement or continuous deterio- In the tropics, an important condition presenting at birth is that of
ration after initiation of the chemotherapeutic regimen (MRC). For congenital talipes equinovarus (CTE) or “clubfoot”. Childbearing at
osteoarticular TB, surgery is indicated as palliation in late-stage disease home, in rural areas, outside the reach of an equipped medical facility,
[6]. Some destroyed stiff and painful joints can be treated by resection translates into higher rates of late-presentation clubfoot, requiring
D i s e a s e s o f t h e M u s c u l o s k e l etal System 117
surgical correction. The late Dr Ignacio Ponseti revolutionized club arthropathies are also increasingly recognized. Symptomatic treat-
foot management in the 1950s. He introduced a conservative non- ment is with aspirin, analgesics, early generations of nonsteroidal
operative technique to treat the deformity when it is recognized in anti-inflammatory drugs (NSAIDs), and corticosteroids.
infants and this is the gold standard across much of the world [11].
Back pain is common worldwide. With greater than 80–90% of the
Management following the Ponseti technique involves gradual workforce in the developing world undertaking strenuous physical
manipulation utilizing serial casting methods, with or without a labor, one might suspect that the prevalence of low back pain would
simple percutaneous tenotomy, and has a near 95% success rate. be increased over that seen in industrialized nations. Osteoarthritis,
Given the serial nature of the casting intervention, gradual reduction spinal stenosis, disc degeneration, and osteoporosis all increase in
of the deformity takes place over a period of about 6 weeks, with aging populations.
subsequent bracing for an extended time.
The morbidity associated with osteoporosis is secondary to fractures
that occur in fragile low-density bone. Common fracture sites are the
CEREBRAL PALSY spine, hip and upper extremity. Spine and hip fractures are particu-
Poor maternal–fetal and neonatal health services during the prenatal larly debilitating. Vertebral compression fractures lead to deforming
and postpartum periods are commonly cited as reasons for an scoliosis and painful nerve root compressions, while hip fractures
increased incidence of cerebral palsy (CP). The neuromuscular disor- necessitate long periods of hospitalization and may be fatal in up to
der affects mobility, postural stability, and the ability to maintain 20% of cases. Where there is dependence upon subsistence farming,
balance, through variable effects on muscle tone. Orthopedic surgery a debilitating spine or hip fracture can be of severe detriment.
is often required when deformities or contractures limit performance Increasing age is a risk factor for the development of prostate, breast
of daily activities, or decrease function. and lung cancers, each of which has a high propensity to metastasize
to bone. It is likely that there will be an increase in the burden of
AGE-RELATED CONDITIONS secondary bone cancer. Slow development of many primary cancers,
combined with lack of education and lack of access to chemothera-
Age-related musculoskeletal disease accounts for an increasing share peutics and radiotherapy, result in the neglect of many primary
of the musculoskeletal burden. Degenerative conditions can occur cancers. Disruption of the structural integrity of bone by cancerous
everywhere, but disability is greatest when weight-bearing joints are lesions reduces the load-bearing capacity. Pathologic fractures may
involved. Degenerative disease of joints can be primary (idiopathic) result, and should be suspected in patients with nonspecific symp-
or secondary to a vast array of conditions: congenital (developmental tomatology who develop a fracture with a mechanism of injury
dysplasia of the hip, talipes equinovarus), hereditary (osteogenesis inconsistent with fracture severity.
imperfecta, achondroplasia), infectious (sequelae of septic arthritis),
angular deformities (Blount’s disease) or avascular necrosis (sickle cell
disease, Legg–Perthes disease). They can also be the result of trauma, REFERENCES
particularly of intra-articular fractures that have been unrecognized or 1. Mock C, Cherian MN. The global burden of musculoskeletal injuries. Clin
neglected. Orthop Relat Res 2008;466:2306–16.
The rise of adult diabetes is associated with an increased incidence of 2. Lopez AD, Mathers CD, Ezzati M, et al, eds. Global Burden of Disease and
Risk Factors. Washington, DC: Oxford University Press; 2006.
neuropathic joints, particularly around the foot and ankle. Chronic
3. Atijosan O, Rischewski D, Simms V, et al. A national survey of musculoskeletal
low back pain (LBP) and significant osteoporosis are becoming more
impairment in Rwanda: prevalence, causes and service implications. PLoS
widespread (Fig. 13.6). Metastases to the bone secondary to neo-
One 2008;3:e2851.
plasms are also likely to increase. Clinical, radiographic, and basic 4. Woolf A, Brooks P, Mody GM. Prevention of musculoskeletal conditions in
laboratory parameters can be used for diagnosis. Inflammatory the developing world. Best Pract Res Clin Rheumatol 2008;22:759–72.
5. Kingham TP, Kamara TB, Cherian MN, et al. Quantifying surgical capacity in
Sierra Leone: a guide for improving surgical care. Arch Surg 2009;144:
122–7.
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SKILLS-BASED CHAPTERS
14 General Surgery in the Tropics
Donald E Meier, John L Tarpley, Robert Riviello
surgeon must decide which supplies and drugs are essential and then
obtain them locally when possible, import them, or improvise from
local materials. Nylon fishing line can substitute for monofilament
BOX 14.1 The Eleven Golden Rules of
suture, and carpet/sewing thread for multifilament suture. If dispos- Anesthesia
able dressing gloves are not available, plastic bread bags can serve as
inexpensive barrier-protection gloves when handling dressings, exam- 1. Perform an adequate history and physical examination
ining wounds, and performing digital rectal examinations. Worn 2. Perform operations on fasting patients. For abdominal
sheets can be converted into rolled bandages, and towels cut to serve emergencies, empty the stomach with a nasogastric tube
as laparotomy sponges. Non-chemically treated mosquito netting can and use a crash induction
substitute for medical-grade mesh for tension-free hernia repairs [8]. 3. Place the patient on a tilt-top table
4. Check the anesthetic equipment BEFORE you begin
5. Always have suction capability available
Sterilization 6. Keep the airway clear and open
Reaching Western sterilization standards may not be possible. Sterili- 7. Be prepared to control the patient’s ventilation (have an
zation techniques used in RPAs include steam autoclaving, soaking ambu-type bag available)
in antiseptic solution, boiling and gassing. Steam autoclaving can use 8. Have a good IV line (optional in some instances of local
electricity, gas, wood, coal or kerosene as an energy source and is anesthesia or IM ketamine)
preferred for instrument sets and cloth packs. Soaking solutions such 9. Monitor the patient frequently
as methyl alcohol (readily available in RPAs) is helpful in sterilizing 10. Have someone around to help
scissors and blades that tend to dull or rust when steam-autoclaved. 11. Be ready with equipment and agents to manage resuscita-
Boiling does not kill spores, but it can serve as a “flash” technique for tion from a cardiopulmonary arrest
dropped instruments. Gas sterilization is helpful in re-sterilizing
rubber and plastic tubes, catheters, drains, electrical cords, and instru- After King M, ed. Primary Anesthesia. Oxford, UK: Oxford University Press;
ments such as diathermy pencils and power drills. Ethylene oxide 1986.
ampoule systems are ideal, but relatively expensive for RPAs and
cannot be transported by air or even on many container ships. An
improvised gas sterilization system utilizes formaldehyde inside a
discarded refrigerator with intact rubber seals. Inexpensive solar auto-
claves made from locally available materials are currently being tested.
Wound infections in RPAs can be decreased by providing patients a
place to bathe with water and soap before entering the operating
room. For elective operations, on-the-table skin preparation with
commercially available soap and methyl alcohol has been shown to
be as effective as the more expensive Betadine technique [9].
Anesthesia
Safe anesthesia is the key component to successful operations in RPAs.
Few formally trained physician anesthesia providers exist in RPAs
outside of university hospitals. In most RPA hospitals, the anesthesia
“department” usually consists of the surgeon and a personally trained
nurse or technician. The surgeon must pay close attention to all activi-
ties on both sides of the ether screen. A functioning pulse oximeter
is arguably the most important piece of equipment in an RPA operat-
ing room. Anesthetic options include vocal and hypnotic techniques,
acupuncture, local and regional techniques, and dissociative and
general techniques. The choice of technique depends on the patient,
the procedure, the availability of drugs and trained personnel, and the
preference of the patient and surgeon. Airway management is of
prime importance in all techniques. The Eleven Golden Rules of
Anesthesia [10] should be followed regardless of the level of medical
sophistication (Box 14.1). General anesthesia capability necessitates
additional equipment and personnel. Inhalational anesthetic systems
that are technologically appropriate for RPAs have been developed.
Drawover units, exemplified by the EMO (Epstein Macintosh Oxford)
ether vaporizer, do not require compressed gases or electricity and FIGURE 14.1 Drawover vaporizer and oxygen concentrator: inhalational
have been modified for use with halothane. Because halothane has a general anesthesia without commercial gas cylinders.
cardiodepressant action, it should be given with oxygen enrichment.
Portable oxygen concentrators can supply up to 6 L oxygen/minute
to supplement these drawover systems (Fig. 14.1). Air compressors abscess drainage, wound dressings, cast changes, burn debridement,
employed in combination with Boyle’s type units can provide freshly herniorrhaphy, and, with repeated injections, for long procedures
compressed air as the carrier gas, thus eliminating the need for expen- such as orthopedic and plastic procedures of the extremities. In adults,
sive and hard-to-find nitrous oxide. intravenous ketamine is especially useful as a short-duration anes-
thetic for dressing or cast changes and abscess drainage. Concomitant
Ketamine, a neuroleptic agent providing dissociative anesthesia, is
glycopyrrolate or atropine administration helps reduce hypersaliva-
used extensively in RPAs because of its effectiveness, availability, rela-
tion. Benzodiazepine co-medication decreases emergence phenom-
tively low cost, and safety [11]. It rarely causes hypotension or respira-
ena in adults but is not routinely needed in children since the
tory depression, but airway monitoring, as with all anesthetic
incidence of emergence phenomena is quite low in children [11].
techniques, is mandatory. It may serve as the sole anesthetic agent
(particularly in children), as an induction agent, or as one part of a Emergency intra-abdominal procedures present an anesthetic chal-
balanced technique. It does not provide muscle relaxation, but intra- lenge. Gastric decompression to minimize the risk of aspiration is
muscular or intravenous ketamine safely anesthetizes children for obligatory before delivery of any anesthetic. Spinal anesthesia can be
122 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
used for emergency procedures below the diaphragm, but hypovo- GENERAL SURGERY
lemia must be corrected before anesthesia delivery, because the
spinal technique abolishes the sympathetic tone of the lower extremi- Trauma, infections, neoplasms, and abdominal problems including
ties, increases the capacitance, and produces hypotension. General groin hernias constitute the four major areas of general surgery. Endo-
anesthesia with a controlled airway is safer in emergency situations if crine procedures are generally limited to the thyroid.
appropriate equipment, agents and personnel are available.
Trauma
Laboratory Half of tropical surgery beds are filled by trauma victims. Mortality is
high, and survivor morbidity and disability pose great socioeconomic
The only consistently available tests in most RPA hospitals are: hema-
costs for families and society. Some of the world’s highest traffic fatal-
tocrit, leukocyte count and urinalysis. Other tests, in order of decreas-
ity rates are reported from tropical countries. Crash scene and trans-
ing availability, are: Gram stain, blood urea nitrogen, creatinine, liver
port care is generally rendered by untrained “good Samaritans”
enzymes, electrolytes, coagulation studies and blood cultures. Arterial
without regard for spinal injuries. Emergency rooms are seldom
blood gases are rarely available. HIV testing is available in most loca-
equipped or staffed adequately for normal activities, much less for 50
tions, but reagents and test kits may be in short supply.
mass casualty victims in various stages of dying, being delivered
simultaneously. The RPA trauma surgeon must be a “general” surgeon
Imaging and Endoscopy with a functional knowledge of orthopedics, neurosurgery, urology,
Outside of teaching hospitals and certain urban medical centers, the and plastic surgery in addition to general and thoracic surgery (Fig.
tropical surgeon rarely encounters radiologists, functioning fluoro- 14.3). In the face of economic adversity, the proliferation of well-
scopic units, or interventional technique capability. Ultrasound (US) made, inexpensive motorcycles has led over the past decade to a
is relatively inexpensive, noninvasive and portable, but is operator- threefold increase in motorcycle crashes with subsequent head and/
dependent. US, especially useful in assessing the pelvis for obstetrics, or spine injuries and long-bone fractures. Motorcycle “taxis” are a
can also provide the surgeon with important anatomic information ubiquitous scourge in many RPAs.
about the biliary tract, liver, pancreas and kidneys. US can detect
ascites, distinguish solid from cystic masses, and localize intra- Infections, Bites and Stings
abdominal abscesses. It is having an increasing role in the diagnosis Stings from scorpions and bites from humans, dogs, cats, wild
and follow-up of parasitic diseases, e.g., schistosomiasis, hydatid cysts, animals, snakes, spiders and insects cause local and systemic prob-
amebic liver abscess and lymphatic filariasis. lems. A bite near a hand joint must be examined closely, opened if
Endoscopy has become more widespread, and flexible fiberoptic there is suspicion of violation, irrigated, and left unsutured with the
esophagogastroduodenoscopy is sometimes found even in peripheral patient admitted for antibiotic administration and extremity eleva-
areas. Initial cost and equipment maintenance, however, limit the tion. Rabies is a major concern, primarily from dog bites. Poisonous
availability of this valuable diagnostic tool. snakebites vary in incidence and type by topography and locale. Sys-
temic antivenom may be indicated, and local care with wound exci-
sion and fasciotomy may be required to treat local and vascular
Histopathology compartment problems. Procaine infiltration, ice and analgesics can
Frozen-section capability is usually unavailable. The turnaround time relieve the pain of scorpion envenomation. Black widow spider bites
for histopathologic reports can be months, and decisions relating to produce generalized muscle spasms while brown recluse spider bites
diagnosis, adequacy of margins, and institution of chemotherapy produce a local ulcer with ischemic necrosis.
(e.g., antitubercular or antineoplastic) must often be made on clinical
Abscesses of the skin, subcutaneous tissue, muscles (pyomyositis),
grounds alone or deferred for unacceptably long periods.
bones (osteomyelitis), joints (pyarthrosis), thorax (empyema), and
pericardial sac occur frequently and require drainage. Staphylococcus
Transfusion Service aureus is the most frequent etiologic agent. Multiple abscesses are
The transfusion service is largely a blood typing and collecting station common and may occur synchronously or metachronously. Early and
and not a blood storage facility. Transfusions usually involve on-the- wide drainage with antibiotic administration minimizes hematoge-
spot donor recruitment and immediate transfusion. Local customs nous spread of infection. Hand infections pose a special difficulty
and beliefs can inhibit blood donation, and consequently, establish- because most patients delay seeking medical care; and even after
ing and maintaining a blood bank is difficult. “Walking” blood banks, drainage, antibiotics, elevation and physiotherapy, residual hand
whereby volunteers in an institution, organization or community are deformity is frequently the outcome.
typed, can provide a measure of emergency supply. Clinically important mycoses include mycetoma, aspergillus granu-
loma, phycomycosis, histoplasmosis and chromoblastomycosis. Myc-
AN OVERVIEW OF SURGICAL etoma (Madura foot) is a clinically defined lesion with swelling
(chronic inflammation), multiple sinuses, and discharge of granules.
PRACTICE IN THE TROPICS Surgical treatment options include observation, local excision to
The tropical surgeon encounters few disease processes that the temper- healthy tissue, and amputation.
ate surgeon does not encounter, but those common to both surgeons
are usually far advanced on presentation in the tropics (Fig. 14.2). Cancer
RPA surgeons therefore must treat patients with advanced problems The mortality rate from cancer in RPAs is higher than the rate in high-
often using minimal equipment and supplies. Patients in RPAs tend income areas [12]. Accurate statistics are not widely available, but
to be younger and more undernourished and to have less comorbid cancers of the cervix, esophagus, stomach, liver, breast and prostate
disease (atherosclerotic vascular disease and smoking-related pulmo- predominate. Primary hepatocellular carcinoma is more frequent in
nary disease). Elective operating schedules are frequently difficult to high hepatitis B and C virus areas. Most malignancies present at an
achieve, since trauma, infection, and obstetric emergencies crowd out advanced stage (see Fig. 14.2), and operations are usually palliative.
elective cases and consume most of the surgeon’s time. Operating Increased tobacco production and use in RPAs has been accompanied
rooms in RPAs can have poor illumination and climate control, with by an increase in tobacco-related illnesses, including lung cancer.
dust and flying insects part of the operating room environment.
Operative cases should be made as simple as possible. Distance, incon-
venience, expense, and lack of perceived need limit patient follow-up, Abdominal Surgery
and the physician’s knowledge of treatment outcomes is severely Tropical gastrointestinal surgeons have noted changing disease
limited. Information sharing by surgeons is usually anecdotal. patterns. Appendicitis is increasing in incidence, and intestinal
G e n e ra l S u rg e r y i n the Tropics 123
FIGURE 14.2 Typical stage at presentation: A 18-year-old male with ameloblastoma of the right mandible; B 55-year-old female with locally advanced and
metastatic malignant melanoma; C 62-year-old male with thyroid carcinoma; D 43-year-old female with locally advanced and metastatic breast cancer.
obstruction is assuming a more Western pattern, with adhesions and acceptance. It is also difficult to perform therapeutic laparoscopic
neoplasms joining hernias as common causes. Appendiceal perfora- procedures in RPA hospitals with a sporadic electrical supply. An
tion, strangulated bowel (intestinal obstruction, hernia, volvulus), ethical consideration in laparoscopy is the training of RPA surgeons.
ileal typhoid perforations, and perforated duodenal ulcers are leading The teaching of open procedures should not be neglected when lapar-
causes of secondary bacterial peritonitis and carry a high mortality oscopy is added to a training curriculum, since surgical trainees who
rate because of advanced sepsis due to delays in seeking medical care. primarily learn laparoscopic procedures in teaching hospitals will find
Since people rarely present until after a hernia is complicated (Fig. it difficult to function in situations where the only option is an open
14.4), obstruction, strangulation and peritonitis occur and sometimes procedure.
cause fatalities.
Volvulus
Laparoscopy Sigmoid volvulus is a leading cause of intestinal obstruction. Previ-
The role of laparoscopy in RPAs is yet to be defined. To compensate ously healthy patients will present with marked abdominal distention
for the lack of computed tomography (CT) and magnetic resonance and tympany to percussion but without peritonitis unless strangula-
imaging (MRI), diagnostic laparoscopy using non-disposable equip- tion or perforation has occurred. Although sigmoidoscopic deflation
ment and locally crafted dissectors can reduce the need for diagnostic can be attempted, operation is the usual treatment since the colon is
laparotomy, especially in sexually active females when pelvic pathol- often strangulated. If at laparotomy the bowel is viable, a rectal tube
ogy is difficult to differentiate from appendicitis. Surgeons in India can be passed under guidance, the loop deflated, and the volvulus
have decreased costs to $1.20 per patient [13]. However, initial equip- manually reduced. After bowel preparation, an interval sigmoid resec-
ment cost and subsequent maintenance remain obstacles to broader tion can be performed to avoid the recurrence that is likely after
124 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
A B
FIGURE 14.3 A 5-year-old boy’s right foot traumatized by a taxi. A Preoperative view with exposed ankle joint, tarsal joints and soft tissue defect.
B Fasciocutaneous flap elevated from the left calf. C Cross-leg flap placed to cover right foot defect. D Postoperative result: full coverage and function.
B
FIGURE 14.4 A Femoral and inguinal hernias. B Inguinoscrotal hernias
G e n e ra l S u rg e r y i n the Tropics 125
NEUROSURGERY
Imaging techniques, equipment and personnel to detect and treat
tumors, arteriovenous malformations and various congenital abnor-
malities are rarely available. CT scanners are available at a few teaching
hospitals and private clinics in the tropics, but scanner maintenance
and expense limit availability and access.
Tropical neurosurgery focuses on trauma. Without benefit of sophis-
ticated diagnostic equipment, head injury victims who have deteriora-
tion in their level of consciousness or who develop lateralizing
neurologic signs should undergo exploration through burr holes with
drainage if an epidural or subdural hematoma is found. Patients with
open, depressed skull fractures require operation for debridement,
hemostasis, elevation, and closure and coverage of the dura. Pond
fractures (circular depressed fractures) in children can be observed or
elevated using an obstetric vacuum extractor.
Spinal injuries from vehicular crashes or falls from trees are a major
FIGURE 14.7 Cancrum oris (noma). Gangrenous stomatitis with soft tissue cause of morbidity and mortality. Spinal cord injury rehabilitation
and bone defect producing an orocutaneous fistula in a 5-year-old programs are rarely existent in RPAs; and if the para- or quadriplegic
malnourished boy. patient survives the in-hospital period of stabilization by traction, he
or she often succumbs to urinary or decubitus ulcer-related sepsis after
discharge. Spinal tuberculosis also causes paralysis. If deterioration of
neurologic function in a patient with Pott’s disease is recent or if it
dental abscesses, and otitis media with or without mastoiditis are continues while the patient is receiving adequate antituberculous
common infections of the head and neck. Croup and laryngotracheo- chemotherapy, drainage of the paraspinal abscess with spine stabiliza-
bronchitis, especially as a complication of measles, may so compro- tion should be considered.
mise a child’s airway that tracheostomy is mandatory. If nursing care,
suctioning and humidification are deficient, serious complications PEDIATRIC SURGERY
may accompany tracheostomy. Cancrum oris (noma), usually seen in Special concerns in tropical pediatric surgery include congenital
malnourished children, is a destructive, necrotic process (Fig. 14.7) anomalies of imperforate anus, bowel atresia, esophageal atresia,
that can produce oro-naso-cutaneous fistulas and ankylosis of the abdominal wall defects, and neural tube defects. These anomalies are
temporomandibular joint. Once infarction, infection and inflamma- apparent at birth before the child has been named and officially
tion respond to debridement, penicillin and diet, the resultant fibrosis recognized as a family member, and parents may not seek treatment
and tissue defects present a formidable reconstructive challenge. Myo- for such neonates and may refuse operative intervention if it is offered.
cutaneous flaps such as the pectoralis major island flap can be used Hirschsprung’s disease, urinary tract abnormalities, and pediatric
to repair these complex problems. Dental care in RPAs is often extrac- tumors, on the other hand, are usually detected after familial accept-
tive rather than preventative and preservative in nature and is not ance, and surgical help is sought, although stomas are often refused.
available in many rural areas. Intussusception is a leading cause of intestinal obstruction in children
3 months to 2 years of age. Hydrostatic reduction is not routinely
PLASTIC SURGERY employed because of the uncertainty of adequate reduction as well as
the scarcity of barium, film and fluoroscopy units. Operative reduc-
Caring for large, infected, neglected wounds using a minimum of
tion is the usual management for intussusception, and a nonviable
equipment and supplies occupies a large percent of the tropical sur-
intussusceptum is common. The mortality rate can be high [16].
geon’s time. Simplified negative pressure wound therapy (“wound
vacuuming”) can often speed the rate of wound closure.
CARDIOTHORACIC SURGERY
Thermal burns may receive inadequate initial treatment with resultant
Pump oxygenators and the technological and financial support they
high mortality from renal failure and burn wound sepsis. In acute
require are rarely found in RPAs. Rheumatic fever with resultant val-
burn survivors, residual contractures and hypertrophic scarring are
vular problems, congestive failure, congenital heart diseases, endomy-
crippling. Skin-grafting capability for burn wound care is essential,
ocardial fibrosis and other cardiomyopathies, e.g., Chagas heart
with grafts taken freehand or with a drum or electric dermatome. The
disease, and the pericardial problems of constriction (tuberculosis)
Tanner meshing technique allows expansion of the graft and improves
and effusion (pyopericardium) are the major problems facing cardi-
graft “take”. Early tangential excision and skin grafting should be
ologists and cardiac surgeons. Non-cardiac thoracic surgeons deal
considered except for extensive burns.
primarily with tuberculosis, thoracic empyema (commonly after
Burns of the hands are especially debilitating, but improved func- measles), hemoptysis from destroyed lung, bronchiectasis, hydatid
tional results can be obtained with early tangential excision and graft- cyst, lung abscess, and trauma. Lung cancer is not widespread in RPAs
ing, proper splinting, and conscientious physiotherapy. Infections and but is increasing as tobacco use increases.
non-thermal hand injuries are very common and require prompt
treatment to avoid fibrosis and contractures. Techniques of groin- and OPHTHALMOLOGY
abdominal-flap coverage are particularly helpful in treating hand
injuries. Eighty percent of the world’s preventable blindness occurs in patients
living in the developing world. Causes of blindness include trauma,
A common congenital abnormality is cleft lip with or without a trachoma, onchocerciasis, corneal scarring, xerophthalmia (dryness
palatal defect. Access to corrective procedures and rehabilitation is and vitamin A deficiency) and cataracts. Cataracts blind 18 million
often poor. Parents, disturbed by the neonate’s deformity, want imme- people in the developing world, with the number doubling every
diate repair. Counseling is indicated because lip repairs traditionally 20–25 years. A nation may have major eye treatment centers, but only
should not be undertaken until “10 weeks of age, 10 pounds of a select population has access to such care. Most people with treatable
weight, and a hemoglobin level of at least 10 g/dL”. Palatal repair is eye diseases never see an ophthalmic surgeon.
G e n e ra l S u rg e r y i n the Tropics 127
REFERENCES 9. Meier DE, Nkor SK, Aasa D, et al. Prospective randomized comparison of two
preoperative skin preparation techniques in a developing world country.
1. Farmer P, Kim J. Surgery and global health: a view from beyond the OR. World World J Surg 2001;25:441–3.
J Surg 2008;32:533–6. 10. King M, ed. Primary Anesthesia. Oxford, UK: Oxford University Press; 1986.
2. MacGowan WAL. Surgical manpower worldwide. ACS Bulletin 1987;72:5–7. 11. Meier DE, OlaOlorun DA, Nkor SK, et al. Ketamine – a safe and effective
3. Ozgediz D, Riviello R. The “other” neglected diseases in global public health: anesthetic agent for children in the developing world. Pediatr Surg Int
surgical conditions in sub-Saharan Africa. PLoS Med 2008;5:e121. 1996;11:370–3.
4. Gosselin RA, Thind A, Bellardinelli A. Cost/DALY averted in a small hospital 12. Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin
in Sierra Leone: what is the relative contribution of different services? World 1999;49:33–64.
J Surg 2006;30:505–11. 13. Udwadia TE, Udwadia RT, Menon K, et al. Laparoscopic surgery in the devel-
5. WHO Western Pacific Region – Fact sheets – Health, poverty and MDG. http:// oping world. An overview of the Indian scene. Int Surg 1995;80:371–5.
www.wpro.who.int/media_centre/fact_sheets/fs_20050621.htm. 14. Halcombe C, Tsimiri S, Eldridge J, et al. Prevalence of antibody to helicobacter
6. Haynes AB, Wiser TG, Berry WR, et al. A surgical safety list to reduce morbidity pylori in children in northern Nigeria. Trans R Soc Trop Med Hyg 1993;87:
and mortality in a global population. N Engl J Med 2009;360:491–9. 19–21.
7. Meier DE. Opportunities and improvisations: a pediatric surgeon’s sugges- 15. Tamini TM, Wosornu L, Abdul-Ghani A, et al. Increased cholecystectomy rates
tions for successful short-term surgical volunteer work in resource-poor areas. in Saudi Arabia. Lancet 1990;336:1235–7.
World J Surg 2010;34:941–6. 16. Meier DE, Coln CD, Rescorla FJ, et al. Intussusception in children – an inter-
8. Freudenberg S, Sano D, Ouangré E, et al. Commercial mesh versus nylon national perspective. World J Surg 1996;20:1035–40.
mosquito net for hernia repair. A randomized double-blind study in Burkina
Faso. World J Surg 2006;30:1784–90.
Oral Health and
Disease in the Tropics 15
Martin H Hobdell, Tepirou Chher
INTRODUCTION Next, pull back the lips and examine their lining mucosa; then the
cheeks, as far back as is possible, for ulceration or localized changes
The most prevalent oral diseases in poor tropical communities are the in color and/or texture. Ask the patient to open their mouth so that
result of poverty and institutional neglect combined with a lack of you can examine the hard and soft palate. Take a soft gauze and get
education. Dental caries (= dental decay) particularly of the primary the patient to protrude their tongue; grasp it gently with the gauze
(or baby) teeth is the most common childhood disease and the most and examine the dorsal and ventral surfaces – again looking for
frequent non-communicable disease worldwide. Most of the decay ulceration or localized changes in color (be careful not to cut the soft
remains untreated and leads to infection of dental origin (= odon- ventral surface of the tongue on the incisal edges of the lower anterior
togenic) with serious impacts on child health and development [1]. teeth). Then examine the teeth for cavities (see section on dental
caries) and how the teeth meet together. Check how the patient opens
The oral conditions with the most serious consequences are: oral their mouth; is it smooth, without clicking, do the midlines of the
cancer, the oral manifestations of HIV/AIDS, noma (or cancrum oris; jaws move parallel with each other?
= gangrene of the facial tissues), and trauma to the face and oral
tissues (Boxes 15.1 & 15.2).
Providing dental care for patients in resource-poor communities
DENTAL CARIES
poses the same problems as for other medical disciplines – limited
equipment, materials and adequately trained personnel. This chapter DESCRIPTION
presents simple frontline emergency care that can be provided using Dental caries most commonly presents as pain on eating or drinking,
simple, but effective methods. particularly of hot or cold foods. In its later stages, when pulpal infec-
tion has passed to the periapical tissues surrounding the root tip(s),
It is not exhaustive either in the provision of extensive clinical man-
there may be swelling, redness and heat of the infected area, and, if
agement details or in its presentation of detailed pathologic informa-
the infection has spread to the deeper tissues, trismus (= in ability to
tion on all oral diseases. It provides the basics necessary for a field
open the mouth). Other systemic symptoms are those of an acute
officer to deal with the most commonly presenting oral conditions.
infection: fever, malaise.
Details of technical procedures can be found online at: http://
www.hesperian.org/publications_download.php: look for “Where
there is no dentist” by Murray Dickson. ETIOLOGY
The resting saliva of the mouth normally has a neutral or alkaline pH.
BACKGROUND INFORMATION This changes when the microorganisms attached to the surfaces of the
teeth (or dental plaque) metabolize dietary sugars to produce acids.
The World Health Organization, since the 1960s, has been gather- These acids, through chemical action, release calcium and phosphate
ing data on the prevalence and severity of oral diseases, which are ions from the hydroxyapatite crystallites that form the enamel
129
130 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Continued
132 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
SIGNS/SYMPTOMS AND DIFFERENTIAL tissue damage and may have life-threatening implications if not dealt
with appropriately. It can lead to permanent disfigurement and
DIAGNOSIS (Table 15-2) impaired function. Cut lips and bruised skin are frequent. Fractured
Differential Diagnosis (Table 15-3) teeth, alveolar bone fractures, maxillary and mandibular fractures are
common. Oro-maxillo-facial trauma often occurs with other trauma
to the patient’s body.
ORO-MAXILLO-FACIAL TRAUMA
AETIOLOGY
DESCRIPTION In many communities located in peri-urban, low-income, self-built,
Oro-maxillo-facial trauma is particularly common in resource-poor poor-housing areas, intentional violence is common. It involves beat-
tropical countries. It ranges from superficial flesh wounds to hard ings, knife and gun shot wounds. Industrial accidents are common in
situations where health and safety issues are not strong components All serious trauma cases must receive emergency care promptly to
of industrial regulations/laws. To these have to be added motor maintain the airway, stop hemorrhage and maintain the heart rate
vehicle accidents that occur in poor countries, caused by poor vehicle and then be referred to those capable of making a full assessment and
maintenance, poor driving and poor road conditions. providing treatment.
Less often seen are physical and chemical burns both to the face and
inside the mouth. The flammable nature of housing and the use of
kerosene lamps, heaters and cooking stoves make fire a frequent event
in poor areas. Burns to the face and upper body occur often.
SYMPTOMS/SIGNS AND DIFFERENTIAL
DIAGNOSIS AND EMERGENCY ACTIONS
Chemical burns may occur because patients with untreated dental (Table 15-4)
caries and toothache often resort to using aspirin or other substances.
Believing their pain is associated with a particular tooth, they may
place an aspirin in the buccal sulcus next to the painful tooth, not
realizing of course that aspirin works systemically and not locally. If
the aspirin remains in place for long, it will cause ulceration of the
REFERENCE
oral mucosa; a chemical burn. This ulcer is then painful itself and will 1. Petersen PE, Bourgeois D, Ogawa H, et al. The global burden of oral diseases
take time to heal. and risks to oral health. Bull World Health Organ 2005;83:661–9.
Maternal and Newborn Health 16
Nynke R van den Broek
GENERAL INTRODUCTION
Each year, at least 358,000 women worldwide die from complications TABLE 16-2 Indicators for Progress Millennium
of pregnancy and childbirth [1]. Many more survive but suffer ill Development Goal 5
health and disability as a result of these complications. Ninety-nine
percent of all maternal deaths occur in South Asia and sub-Saharan
Africa. In addition, an estimated 4 million neonatal deaths occur each Target 5a
year, accounting for almost 40% of all deaths under the age of 5 years
[2]. The health of the neonate is closely related to that of the mother To reduce maternal mortality by three quarters between 1990
and the majority of deaths in the first month of life could be pre- and 2015:
l reduce the maternal mortality ratio
vented if interventions were in place to ensure good maternal health.
l increase the number of births attended by skilled health
There have been significant global efforts to reduce maternal and personnel
newborn mortality and morbidity in the last few decades. The “Safe
Motherhood Initiative” was launched in Nairobi in 1987. One of Target 5b
its stated aims was to reduce maternal mortality by 50% by the To achieve universal access to reproductive health by 2015:
year 2000. However, figures at the turn of the millennium remained l increase the contraceptive prevalence rate
disappointingly unchanged from the start of the initiative. This was l reduce adolescent birth rate
partly because of better data collection and documentation of the l increase antenatal care coverage
problems, and also because reducing maternal and newborn health l reduce unmet need for family planning
requires a coordinated and multifaceted approach. In 2000, nearly
135
136 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
TABLE 16-3 Estimates of maternal mortality ratio and number of maternal deaths by United Nations Regions for 2005
and 2008
MATERNAL MORTALITY
The number of maternal deaths in a population is related both to the
BOX 16.1 The 3-Delay Model
risk of mortality associated with each pregnancy or birth (reflected in
the maternal mortality ratio, which is the number of maternal deaths Delay 1: Are women aware of the need for care and the danger
per number live births, ×100,000) and the number of pregnancies signs of pregnancy?
experienced by women of reproductive age [reflected in the maternal
Delay 2: Are services inaccessible because they are not availa-
mortality rate, which is the number of maternal deaths per number
of women of reproductive age (taken as 15–49), ×100,000]. ble, because of distance and/or cost of services, or do socio-
cultural barriers prevent women from accessing services?
There is still a lack of accurate data, especially from developing coun-
tries where maternal mortality is high. In the absence of complete and Delay 3: Is the care received at the facility, timely and
accurate civil registration systems, which are almost non-existent in effective?
resource-poor settings, maternal mortality ratios and rates are esti-
mated based on a variety of methods, including household surveys,
“sisterhood” methods, reproductive age mortality studies, censuses
and modeling. Since 1990, using all available data and/or statistical examined and reached a consensus on a new classification system for
modeling, estimates have been developed by the United Nations cause of maternal death in 2009. This new classification is aligned
(UN) agencies which allow for international comparison and analysis with International Classification of Diseases (ICD) 10 and will feed
of progress. The latest estimates from 2008 show that of the 358,000 into the new ICD 11 system of classification [9].
maternal deaths that are estimated to occur annually, the vast majority
occur in developing countries. Almost two-thirds are in sub-Saharan
Africa (207,000) followed by South Asia (139,000) (Table 16-3). HEMORRHAGE
Obstetric haemorrhage is the most commonly documented cause of
Analysis of trend shows that at the global level, the decrease in mater-
maternal death. This can take the form of antepartum bleeding (e.g.
nal mortality between 1990 and 2008 was estimated to be 2.3%
as a result of placenta praevia or placental abruption), intrapartum
overall, which is well below the estimated 5.5% decrease needed
bleeding (e.g. as a result of rupture of the uterus) or post-partum
annually to achieve MDG 5 by 2015 [6].
hemorrhage (e.g. as a result of atony of the uterus, associated with
disseminated vascular coagulopathy, or trauma to the genital tract).
CAUSES OF MATERNAL MORTALITY— Any bleeding during pregnancy and delivery should be considered a
WHY DO WOMEN DIE? “danger” or warning sign and requires urgent attention.
Placental abruption can occur suddenly and unexpectedly. In many
A seminal review by Thaddeus and Maine in 1994 introduced the resource-poor settings, in the absence of ultrasonography, the warning
“Three Delay Model” [7]. They acknowledged that there are numerous signs of bleeding, coupled with the clinical sign of a “uterus en bois”
factors that contribute to maternal mortality and that when obstetric (woody hard uterus which feels contracted), will alert the healthcare
complications occur, with prompt adequate treatment, the outcome provider to this emergency. In the case of placenta previa, a cesarean
is usually satisfactory. They therefore examined the factors that affect section is needed.
the interval between the onset of an obstetric complication and its
outcome. The three delays described and examined are: (i) delay in Post-partum hemorrhage is commonly defined as blood loss of more
deciding to seek care; (ii) delay in reaching the healthcare facility; and, than 500 ml and severe post-partum hemorrhage as a loss of more
(iii) delay in receiving care after getting to the healthcare facility. This than 1000 ml. Most cases are unpredictable and it is vital that there
framework is now widely used to examine and address factors con- is early recognition of excess blood loss and immediate action. The
tributing to maternal deaths in many countries (Box 16.1). majority of cases are the result of uterine atony post-delivery, either
after vaginal delivery or cesarean section. The recommended treat-
Medically, the main direct causes of maternal deaths are obstetric ment is uterotonics (drugs to stimulate uterine contraction) and
hemorrhage, hypertensive disorders (eclampsia and pre-eclampsia), prompt replacement of volume lost to avoid hypovolemic shock.
sepsis or infection, and complications of obstructed labour and abor-
tion. There is some variation both across and within geographical There are a number of uterotonics available, including oxytocin and
regions (Figs 16.1 and 16.2) [8]. Based on the need for much better ergometrine (the traditional and well-proven first-line approach), as
identification and understanding of the causes of maternal deaths, a well as more recent prostaglandins, such as carboprost and misop
World Health Organization (WHO) Technical Working Group rostol. Blood transfusion is frequently needed and many women in
M ate r n a l a n d N e w bor n Health 137
Unclassified deaths
5.4%
Embolism
2.0%
Anemia
3.7%
HIV/AIDS
6.2%
Ectopic pregnancy
0.5%
Other direct
4.9%
Hypertensive disorders
Obstructed labor 9.1%
4.1%
Abortion
3.9% Sepsis/infections
9.7%
FIGURE 16.1 Causes of maternal deaths in Africa.
Unclassified deaths
6.1%
Embolism 0.4%
Anemia
12.8%
HIV/AIDS 0.0%
Ectopic pregnancy
Other direct 1.6% 0.1%
Hypertensive
disorders
Obstructed labor
9.1%
9.4%
Abortion Sepsis/infections
5.7% 11.6%
FIGURE 16.2 Causes of maternal deaths in Asia.
138 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
resource-poor areas do not survive hemorrhage because blood trans- disease) may be associated with kidney failure with reduced urine
fusion services are not available at all or insufficient blood is given. output.
In addition, in cases of hemorrhage as a result of coagulopathy, such
as is associated with abruption placenta and eclampsia, the availabil-
ity of blood is crucial. SEPSIS
Most maternal deaths from infection occur in the postnatal period as
It may be necessary to explore the uterus for retained placental tissue. a result of puerperal sepsis defined as “a temperature rise above 38.5
Retained placenta is a common problem leading to post-partum hem- degrees Celsius maintained over 24 hours or recurring during the
orrhage and all skilled birth attendants need to be able to carry out a period from the end of the first to the end of the tenth day after
manual removal of placenta under suitable analgesia (or anesthesia) childbirth or after abortion”. Clinical signs and symptoms include
and/or refer a woman with this condition to a higher level facility in fever, lower abdominal pain and uterine tenderness, subinvolution of
good time. Retained placental tissue and/or membranes can lead to the uterus with foul smelling, sometimes purulent, discharge with or
prolonged bleeding and high risk of infection. This requires careful without vaginal bleeding. Failure to recognize and manage puerperal
exploration of the uterus under anesthesia and curettage. For hemor- sepsis early on will lead to septic shock and coagulopathy.
rhage occurring after a cesarean section, re-laparotomy may be neces-
sary to check that this is not the result of unrecognized tears in the The clinical diagnosis of sepsis is relatively simple and does not
uterus and/or faulty surgical technique. In some cases with unstop- require laboratory tests. In practice, fever in the post-partum period
pable hemorrhage, the only solution may be to perform a (subtotal) is often attributed solely to malaria, especially in malaria-endemic
hysterectomy. areas. Full clinical examination and a thick film slide will help with
the differential diagnosis, as will the realization that, in many post-
Post-partum hemorrhage can be prevented—it is recommended that partum women, such fever is more likely to be associated with puer-
all women have active management of the third stage of labor. This peral sepsis than malaria. Parenteral antibiotics are needed and
consists of administering a uterotonic (preferably oxytocin intramus- generally given for 24–48 hours. There are various recommended
cularly) at the time of delivery, together with clamping and cutting regimens but in the absence of availability of blood-culture testing (as
the cord and controlled cord traction (gentle cord traction with in most resource-poor areas), the best combination is ampicillin,
manual support of the uterus) to deliver the placenta. The oxytocin gentamycin and metronidazol. The presence of retained placental
is given at the time of birth of the anterior shoulder; if it is not known fragments and/or fetal tissue in the case of abortion must be consid-
whether this could be a multiple pregnancy, it should be given at the ered. Poor hygiene during delivery, during obstetric surgery, such as
time of the birth of the baby, after checking there is no second baby. cesarean section or evacuation of the uterus (for termination of preg-
In some cases, this is combined with uterine massage or fundal pres- nancy or removal of retained products after an incomplete abortion),
sure after delivery of the placenta. The routine administration of can all lead to puerperal sepsis. Good hand-washing practice and
oxytocin reduces the risk of hemorrhage by more than half when adequate sterilization of equipment used during surgical procedures
compared with “physiologic” or expectant management (i.e. no oxy- are crucial preventive measures. Prophylactic antibiotics should be
tocic, no controlled cord traction, with the cord being clamped and given in all cases of cesarean section. Infection with HIV is associated
cut after the placenta has been delivered by maternal effort only). with reduced immunity, an increased risk of opportunistic infections
and reported increased difficulty in treating post-partum sepsis, either
PRE-ECLAMPSIA AND ECLAMPSIA after delivery or cesarean section.
Pre-eclampsia (hypertension with proteinuria) is specific to preg-
nancy and will progress to eclampsia (convulsions) if unrecognized.
There is some evidence that eclampsia may be more common in COMPLICATIONS OF OBSTRUCTED LABOR
certain developing countries, but good epidemiologic data are scarce. Obstructed labor is a condition contributing to maternal death in a
Pre-eclampsia is a multi-organ disease with unknown etiology. Early number of ways, for example via haemorrhage as a result of rupture
detection of hypertension and proteinuria is important and measure- of the uterus or via sepsis. Morbidity associated with obstructed labor
ment of blood pressure with examination of urine must be done includes obstetric fistulae (vesico-vaginal and/or rectal). Obstructed
regularly during pregnancy, delivery and the postnatal period. Severe labor is said to occur when there are good uterine contractions but
pre-eclampsia is associated with clinical signs and symptoms such as there is no descent of the fetus through the pelvis. This may be
headache, visual disturbances, upper epigastric pain and hyper- because the fetus is too large for the pelvis (fetopelvic disproportion)
reflexia. An eclamptic convulsion is essentially the same as an epilep- and/or there are pelvic abnormalities (e.g. associated with rickets).
tic fit with tonic and clonic seizures. Recurrent seizures can lead to Malposition of the fetus or congenital fetal abnormalities (e.g. hydro-
maternal death but, most commonly, death is probably the result of cephalus) can also be associated with obstructed labor. Clinical signs
intracerebral hemorrhage following untreated hypertension. of rupture of the uterus include vaginal bleeding, hypovolemic shock,
tender abdomen, an abnormal uterine contour, absent fetal heart and
Delivery of the fetus and placenta is the “cure” for pre eclampsia and
easily palpable fetal parts. A “Bandl’s” ring can often be seen prior to
eclampsia, and, in many instances, a careful balance of risks needs to
rupture of the uterus and is a visible horizontal depression in the
be made, especially if the fetus is premature. In addition to planning
lower abdominal contour near the umbilicus which indicates the
a timely delivery, magnesium sulfate has been consistently shown to
marcation between the thick muscular upper uterine segment and a
be the drug of choice for pre-eclampsia in a number of important
very thin, stretched out lower uterine segment.
trials that included developing country populations. Magnesium
sulfate can be given either intramuscularly or intravenously in cases In cases of obstructed labor, in order to save both the mother and
of severe pre-eclampsia (to prevent eclampsia) and in eclampsia (to baby’s lives, a timely cesarean section is needed. For this, the woman
prevent seizures). Dosage can be monitored by checking the deep will need to be delivered in a health facility providing all the nine
tendon reflexes and monitoring respiratory rate; absence of reflexes signal functions of Comprehensive Essential Obstetric Care (see Box
and respiratory depression indicate over-dosage. 16.2) and referral may be needed if she is laboring at a lower-level
facility. Such referral must be well organized and requires transport
Anti-hypertensive treatment must be given in pre-eclampsia and
and communication systems to be in place.
eclampsia. There are a variety of drugs available—all with proven
benefit—including hydralazine (commonly preferred first-line drug), Obstructed labor can be detected by using a partograph. This is a
nifedipine and labetalol. Drugs often need to be given intravenously simple structured graphical one-page representation of the progress
and may be combined with oxytocin, for example, to induce labor. of a woman’s labor and is recommended as a tool to monitor progress
Fluid input and output must be carefully monitored in the patient in all women during labor, as well as a documentation of the fetal
with pre-eclampsia and eclampsia. Cardiopulmonary overload is a condition. It consists of a graph depicting cervical dilatation in rela-
frequent complication, especially when oxytocin (antidiuretic effect) tion to time—in most cases also the degree of descent of the fetal
is needed to induce labor. In addition, pre-eclampsia (a multi-organ presenting part—the strength and frequency of contractions and the
M ate r n a l a n d N e w bor n Health 139
At least 80% of all maternal deaths result from five complications that (or criterion-) based audit. These tools have been successfully used in
are well understood and can be readily treated: hemorrhage, sepsis, a variety of settings and such audit is recommended as part of every-
eclampsia, ruptured uterus as a result of obstructed labor and com- day good clinical practice. All types of audit essentially ask the ques-
plications of abortion; there are existing effective medical and surgical tions: what was done well, what was not done well and how can care
interventions that are relatively inexpensive. In 1997, the key interven- be improved in future [17, 18]?
tions needed were bundled into a package now known as “Essential
(or Emergency) Obstetric Care” (Box 16.2). There is unified agree- An absolutely fundamental principle is the importance of a non-
ment and criteria for what constitutes Essential Obstetric Care, as well threatening environment and a “no shame, no blame” approach.
as on what constitutes the minimum coverage levels needed at popu- Wherever possible, confidentiality and anonymity must be main-
lation level and on what constitutes good-quality evidence based tained. Death reviews—conducted in this way—should result in rec-
practice [13–15]. ommendations for change. Such recommendations need to be (and
in practice usually are) simple, affordable, effective and in line with
Two levels of Essential (Emergency) Obstetric Care can be distin- evidence-based care.
guished: Basic Essential Obstetric Care and Comprehensive Essential
Obstetric Care. In addition to agreement on the components (signal Confidential enquiries are a systematic, usually multidisciplinary,
functions), there are agreed specifications for levels of coverage anonymous review of all or a representative sample of maternal
needed. Thus, the UN agencies recommend that, for a population of deaths occurring in an area, for example national or sub-national.
500,000, there should be at least one health facility that is able to Through aggregation of data, a confidential enquiry can make recom-
provide the nine signal functions of comprehensive care and at least mendations of a more general nature, inform wider health policy and
four that provide the seven signal functions of basic care. It is impor- practice, and can be used for advocacy to improve maternal and
tant that these facilities are equitably distributed geographically with newborn health.
regard to distance and time needed to travel to the health facility. In
addition, the signal functions must be available 24 hours a day and REFERENCES
7 days a week for the facility to be considered fully functional.
1. Hogan MC, Foreman KJ, Naghavi M, et al. Maternal mortality for 181 coun-
A number of surveys have assessed the availability, accessibility and tries, 1980–2008: a systematic analysis of progress towards Millennium Devel-
quality of essential obstetric care in countries with high maternal opment Goal 5. Lancet 2010;375:1609–23.
mortality. These surveys consistently find that coverage with facilities 2. World Health Organization. Neonatal and Perinatal mortality–Country,
able to provide care is inadequate and minimum UN agreed stand- regional and global estimates 2004. Geneva: World Health Organization; 2007.
ards are not yet in place. In many settings, there are relatively large 3. Enkin M, Keirse MJNC, Neilson J, et al. A guide to Effective Care in Pregnancy
numbers of health facilities but these are often not providing the full and Childbirth, 3rd edn. Oxford, UK: Oxford University Press; 2000 (reprinted
complement of signal functions for either basic or comprehensive 2004). Available at: www.childbirthconnection.org (last accessed 30/7/2012).
essential obstetric care. In addition, the geographical distribution of 4. Kerber KJ, de Graft-Johnson JE, Bhutta ZE, et al. Continuum of care for mater-
facilities is such that these tend to be clustered in urban areas with nal, newborn and child health: from slogan to service delivery. Lancet 2007;
370:1358–69.
poor coverage particularly in more rural areas [16].
5. World Health Organization. Making Pregnancy Safer: the critical role of the
skilled attendant. A joint statement by WHO, ICM and FIGO. Making Preg-
QUALITY OF CARE nancy Safer, Department of Reproductive Health and Research. Geneva: World
There is accumulating evidence that poor-quality care (or the third Health Organization; 2004.
6. World Health Organization. Trends in Maternal Mortality:1990–2008.
delay, as defined by the “three delay model”) contributes significantly
Geneva: World Health Organization; 2010.
to adverse maternal and newborn outcomes in resource poor areas.
7. Thaddeus S, Maine D. Too far to walk: maternal mortality in context. Soc Sci
Quality of Care should include the concept of effective care and
Med 1994;38:1091–110.
timely access, and of reproductive health rights. 8. Khan KS, Wojdyla D, Say L, et al. WHO analysis of causes of maternal death:
The quality of the provision of care and the quality of care as experi- a systematic review. Lancet 2006;367:1066–74.
enced by users are both essential components (Box 16.3). The use of 9. Pattinson R, Say L, Souza JP, et al. on behalf of the WHO Working Group on
services and outcomes are the result not only of the provision of care Maternal Mortality and Morbidity Classifications. WHO maternal death and
near-miss classifications. Bull World Health Organ 2009;87:734.
but also of women’s experience of that care. Provision of care may be
10. World Health Organization. Unsafe Abortion—global and regional estimates
deemed of high quality against recognized standards of care but unac-
of the incidence of unsafe abortion and associated mortality in 2000, 4th ed.
ceptable to the woman and her family (the community). Conversely,
Geneva: World Health Organization; 2004.
some aspects of care may be popular with women but may be inef- 11. Lawn JE, Cousens S, Bhutta ZA, et al. Why are 4 million newborn babies dying
fective or harmful to health. each year? Lancet 2004;364:399–401.
For maternal and newborn health in particular, there are well estab- 12. Adegoke A, van den Broek N. Skilled Birth Attendance—lessons learnt. BJOG
lished tools for assessing and improving quality of care. These include 2009;116:33–40.
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maternal and perinatal death audit, “near miss” audit and standards
nal Death and Disability. Monitoring emergency obstetric care: a handbook.
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BOX 16.3 Quality of Care 15. van den Broek N. Life Saving Skills Manual—Essential Obstetric and Newborn
Care, revised edn. London: RCOG Press; 2007.
“Quality of care is the degree to which maternal health serv- 16. van den Broek NR, Hofman JJ, Increasing the capacity for essential obstetric
and newborn care. In: Kehoe S, Neilson JP, Norman JE, eds. Maternal and
ices for individuals and populations increase the likelihood
Infant Deaths—Chasing Millennium Development Goals 4 and 5. London:
of timely and appropriate treatment for the purpose of RCOG Press; 2010.
achieving desired outcomes that are both consistent with 17. Kongnyuy E, van den Broek N. Audit for maternal and newborn health serv-
current professional knowledge and uphold basic reproduc- ices in resource poor countries. BJOG 2009;116:7–10.
18. Pattinson RC, Say L, Makin JD, Bastos MH. Critical Incident audit and feed-
tive rights.” (Hulton, 2010)
back to improve perinatal and maternal mortality and morbidity. Cochrane
“The question should not be why do women not accept the Database Syst Rev 2005;CD002961.
19. Hulton L, Murray S, Thomas D. The evidence towards MDG5: a working
service that we offer, but why do we not offer a service that
paper. London: Options Consulting Services; 2010.
women will accept.” (Fathalla, 1998). 20. Fathalla M. Preface. Paediatric and Perinatal Epideiology 1988;12(suppl. 2):
vii–viii.
Pediatrics in a Resource-
constrained Setting 17
Elizabeth M Molyneux
Pediatrics in the tropics is challenging. It is not only the management implementation. The need for support from national health policy,
of children with tropical diseases; it is caring for children in a health financial commitment and health system strengthening is empha-
system that may be under-resourced, under-staffed and frequently sized [4].
overwhelmed by numbers. It is adapting to do the best with limited
resources and few staff. It is the sharing of ideas and practice with a Additional challenges have included the need to adapt it to take
team that may have very different levels of medical education, but a account of diseases that are important in particular settings, for
common goal. It is to use clinical acumen for diagnosis and to be example dengue is a much more important cause of illness in Asia
creative in finding solutions for what may seem, on first encounter, than Africa. Because of its WHO endorsement, there may be a ten-
to be insuperable. It can be demanding, sometimes overwhelming, dency for its implementation in inappropriate settings, for example
always interesting and very rewarding. in countries where healthcare workers are already trained to a high
standard.
Most children in the world have their medical care provided by health
workers with little access to diagnostic aids and with limited therapies. A seven-country audit of inpatient pediatric care was undertaken by
The first-line health worker may have received only minimal training. the WHO in 1997. It showed that there were many gaps in health
The World Health Organization (WHO) has provided guidelines for care delivery and there was a universal need for triage, emergency care
the diagnosis and management of common clinical problems based and patient monitoring [5]. In response to these findings, the WHO
on pattern recognition of a collection of signs and symptoms, and produced the “Pocket Book of Hospital Care for Children: Guidelines
syndromic treatment designed to treat the common causes of identi- for the Management of Common Illness with Limited Resources”,
fied clinical problems. In the past, the management of individual also known as the The Hospital Pocket Book or Blue Book [6]. The
illnesses was taught separately but these have been drawn together in book of guidelines is for use by doctors, senior nurses and other
the Integrated Management of Childhood Illnesses (IMCI) [1]. In this senior healthcare workers responsible for the inpatient and outpatient
scheme, a child is assessed for danger signs, treated appropriately, care of young children at the first referral level in developing countries
referred when necessary and the family is counseled about immuniza- (Fig. 17.2). The guidelines cover the most common diagnoses and
tions, nutrition and follow-up (Fig. 17.1). problems in resource-constrained countries and assume that only
basic laboratory support, essential drugs and inexpensive medicines
Syndromic management leads to over-treatment but simplifies are available, with no specialist care on site. It focuses on the major
looking after large numbers of patients with few staff. National causes of childhood mortality, such as pneumonia, diarrhea, severe
policy should make appropriate drugs available for every level of malnutrition, malaria, meningitis, measles, HIV infection and related
healthcare. conditions. It also covers neonatal problems and surgical conditions
of children which can be managed in small hospitals. The Pocket
IMCI strategy has three main components: Book can be purchased in a hardcopy or downloaded free from the
WHO website [6]. A three-and-a-half-day course on Emergency Triage
l To improve the case-management skills of health carers using Assessment and Treatment (ETAT) is available on the WHO Child and
locally adapted clinical guidelines that do not focus on a single Adolescent Health Division website [7].
diagnosis, but rather on selected signs and symptoms to guide
rational treatment.
l This needs support through the provision of appropriate therapies PREVENTIVE SCHEMES
and referral chains.
l The child is seen in the context of the family and the clinic visit
It is important to provide protection to vulnerable children in the
because of an acute event which is used to provide, not only form of immunizations, supplementary food, intermittent prophylac-
immediate curative treatment, but also attention to nutrition, tic drug therapy against malaria, bed nets, etc. All these tasks of testing
immunization, counseling and other holistic health needs. and treating mothers and children, giving advice, giving medications
or immunizations fall to the health assistant or the nurse. These
In Tanzania, this led to a 13% reduction in the cost of care and better community workers have gradually acquired a multitude of duties
outcomes [2]. A re-analysis of these data to include the quality of towards the child and their family. Each duty is small and important,
care given showed that the cost of using IMCI was $4.02/person per but together they make for a heavy workload. Extended Programmes
annum compared with $25.70 without IMCI [3]. To reach these for Immunizations (EPI) days and antenatal visits are times when
improvements requires all the ingredients of IMCI to be available— mothers and babies encounter the health service and these visits have
training, drugs, staff, immunizations and time; training alone will not acquired a lot of “add on” activities; all good but a lot for a worker
suffice. to convey or a mother to recall (Table 17-1).
Although the ICMI works well in many settings, local and national
constraints include low healthcare worker compliance, the perceived
EXPANDED PROGRAMME FOR
length and expense of training, inadequate counseling of child care- IMMUNISATION (EPI)
givers, the weakness of health systems to support ICMI policy The EPI was established in 1974 through a World Health Assembly
and lack of institutional or governmental budget allocations for resolution to build on the success of the global smallpox eradication
141
142 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
CLASSIFY
THEN ASK ABOUT MAIN SYMPTOMS:
Does the child have a cough or difficult breathing?
• No signs of Cough or cold • If wheezing (even if it disappeared after rapidly acting bronchodilator) give an inhaled
pneumonia bronchodilator for 5 days
or very severe • Soothe the throat and relieve the cough with a safe remedy
disease • If coughing for more than 3 weeks or if having recurrent wheezing, refer for assessment
for TB or asthma
• Advise the mother when to return immediately
• Follow-up in 5 days if not improving
FIGURE 17.1 The first page of the Integrated Management of Childhood Illness Chart Booklet, showing initial assessment for danger signs (http://
whqlibdoc.who.int/publications/2008/9789241597289_eng.pdf ).
programme and to ensure that all children in all countries benefited original six recommended in 1974. Most countries, including the
from life-saving vaccines. The first diseases targeted by the EPI were majority of low-income countries, have added hepatitis B and Hae-
diphtheria, whooping cough, tetanus, measles, poliomyelitis and mophilus influenzae type b (Hib) to their routine infant immunization
tuberculosis. In 2009, an estimated 82% of children globally had schedules and an increasing number are in the process of adding
received at least three doses of diphtheria, pertussis, tetanus (DPT) pneumococcal conjugate vaccine and rotavirus vaccines to their
vaccine (DPT3). Additional vaccines have now been added to the schedules.
Pe d i at r i c s i n a R e s o u rce - co n s t ra i ned S etting 143
Use jaw thrust without head tilt. Place the 4th and 5th finger behind Bed net Bed net Bed net Bed net
the angle of the jaw and move it upwards so that the bottom of the HIV test HIV tests/PCR HIV test / PCR1
jaw is thrust forwards, at 90o to the body
BP Measles
immunisation
Weight Weight Weight/height/
MUAC2
Urine protein iPDT*
Threats to MALNUTRITION AND HIV INFECTION
good health
and growth POVERTY, INACCESSIBILITY TO HEALTH CARE,
PARENTAL SICKNESS, SOCIAL UNREST,
If the child is still not breathing after ORPHANHOOD, WOODSMOKE
carrying out the above, ventilate with
BCG, Bacillus-Calmette-Guérin; BP, blood pressure; Hb, hemoglobin; IPDT,
bag and mask intermittent preventive drug therapy for malaria; KMC, Kangaroo Mother Care;
MUAC, mid upper arm circumference; PMTCT, preventing mother to child
FIGURE 17.2 Page from the WHO Pocket Book showing how to manage
transmission of HIV; RPR, rapid plasma reagin; VDRL, Venereal Disease Research
the airway.
Laboratory test.
*Intermittent preventive drug therapy for malaria.
1
Polymerase chain reaction.
2
Mid Upper Arm Circumference.
The overall coverage for childhood immunizations varies from
country to country. In some countries (e.g. Malawi), the uptake is
good, with 82% coverage for all three doses of the pentavalent vaccine
[diphtheria, tetanus, whooping cough, hepatitis B and H. influenza
type b (DPTHibHepB)] and 64% for measles. In other countries, the five-year protection measured by antibody levels to the nine serotypes
uptake is poor and the difference in urban/rural uptake is great [8]. of the study conjugate vaccine of 77% [confidence interval (CI) 95%
EPI programs include the periodic distribution of vitamin A supple- 51.90] [11, 12].
ments to children. Not all countries have the pentavalent vaccine—
many are still using DPT. The pentavalent vaccine raises the cost of The Pneumococcal Accelerated Development and Introduction Plan
vaccination 10-fold and can only be sustained with external funding, (pneumoADIP) is striving to make the seven-valent pneumococcal
such as from the Global Alliance for Vaccines and Immunisation conjugate vaccine (PCV-7) available for young infants in resource-
(GAVI). poor countries and Rwanda was the first country in Africa to introduce
it into its infant EPI program. In 2010, the Rwandan Ministry of
Measles remains a cause of significant morbidity and mortality despite Health, with the help of international partners, made pneumococcal
the availability of an effective vaccine (see Chapter 28.1). The WHO conjugate vaccine available through the EPI program to all infants.
estimates that there are about 350,000 measles deaths a year [9]. Through GAVI, it is anticipated that the cost of funded PCV-7 will be
Many of the deaths are not from acute measles, but from post-measles brought down to about US $1 for a three-dose course [13].
diarrhea and pneumonia. In countries where measles is common, it
tends to occur in young children (<12 months of age). Therefore,
children need to be immunized earlier than their counterparts in HIV/AIDS
well-resourced countries. The measles vaccine is given at 9 months Countries with a high HIV/AIDS burden are struggling to care for all
of age and is not repeated. Given at this age, it provides 80–90% the people who are living with AIDS (PLWA).
protection [10].
Prophylactic cotrimoxazole, recommended for all children (and
Pneumococcal conjugate vaccine is not widely available in resource- adults) with HIV infection and HIV-exposed infants [14], and fixed
constrained countries because of cost, but its introduction into the combination drugs (FDC) are available and provided through the
EPI service would be enormously beneficial. In HIV-infected infants, global fund. Local national programs provide registration procedures,
immunization is not as effective or as long-lasting compared with protocols, training, stock control, prescribing controls and monitor-
uninfected children, but a study from the Gambia showed an overall ing; the human resources required and logistical implications are
144 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
huge. Children are expected to form about 10% of the total number
Dry the baby Birth
of people on antiretroviral therapies (ARTs), but their access to
therapy has been slower than that of adults. Reasons for this include Remove any wet towels and cover AT
difficulty in deciding how to provide suitable doses for children with Start the clock or note the time
a limited variety of FDC tablets available (and none of them child-
friendly tablets), although pediatric combination tablets are now
available. The need to confirm a diagnosis below the age of 15 months
with PCR testing is a challenge. Studies have shown that infants Assess (tone), breathing 30s
started on ARTs before they develop opportunistic infections have a and heart rate ALL
much better survival [15]. It is not easy to advise about infant feeding.
What is best for babies whose chances of acquiring HIV infection
from breast feeding are about 14–42% but whose chance of dying of
gastroenteritis or malnutrition in a poor family if bottle fed is much If gasping or not breathing:
greater? Recent studies from Zambia and Malawi both showed Open the airway
increased mortality with abrupt cessation of breast feeding of all Give 5 inflation breaths STAGES
infants and, in Malawi, there was no reduction in HIV transmission Consider SpO2 monitoring 60s
[16, 17]. The WHO recommends considering the ability of the mother
to maintain artificial feeding under the headings Acceptability, Feasi-
bility, Affordability, Sustainability and Safety (AFASS) before giving
any advice [18], i.e. will replacement feeding be acceptable, feasible, Re-assess
affordable, sustainable and safe? Considerations include analyzing If no increase in heart rate look
the family’s access to clean water, electricity, hygienic latrines or ASK:
for chest movement
toilets, their financial situation, and other social and economic factors
necessary to support replacement feeding. A breast-feeding mother on
ART that reduces her viral load to negligible amounts could breast
feed her baby without fear of HIV transmission: this would seem the
If chest not moving: Acceptable
way forward in preventing vertical transmission of the disease, but not
Recheck head position pre-ductal SpO2
at the cost of infections and malnutrition that could be prevented by
breast feeding. Consider 2-person airway control 2 min 60%
and other airway maneuvers 3 min 70%
Repeat inflation breaths 4 min 80%
NEWBORNS Consider SpO2 monitoring 5 min 85%
Infant mortality has decreased in several countries, but this fall in the Look for a response 10 min 90%
case fatality rate has been mainly in children over 2 months of age
(Fig. 17.3). The United Nations Millennium Eight Development
Goals were established following the Millennium Summit in 2000
[19]; they comprise eight international development goals that all If no increase in heart rate look
DO
192 United Nations member states, and at least 23 international for chest movement
organizations, have agreed to achieve by the year 2015. To achieve the
fourth Millennium Development Goal of halving child mortality by
2015, neonatal mortality must be tackled [20]. About 40% of all child
deaths (4 million per year) occur in the neonatal period. Almost 75% When the chest is moving: YOU
of neonatal deaths occur in the first week of life, of which 85% are If heart rate is not detectable
caused by prematurity, infection and birth asphyxia (Fig. 17.4). or slow (<60 min)
Skilled attendance at delivery, simple care of the premature—such as Start chest compressions
Kangaroo Mother Care (KMC)—and good hygiene would prevent 3 compressions to each breath
many of these deaths. Tetanus can be prevented by maternal immu- NEED
nization. In Kenya, Opiyo et al. showed that a one-day training
course in neonatal resuscitation led to a significant improvement in
resuscitation steps and techniques (66% v 27% p=0.001) [21].The Reassess heart rate every 30 s
training was based on the one-day UK Resuscitation Council training If heart rate is not detectable HELP?
[22] (Fig. 17.5) adapted to the Kenyan setting and included an A or slow, (<60 min) consider
(Airway), B (Breathing) and C (Circulation) approach to resuscita- venous access and drugs
tion, laying down a clear, step-by-step strategy for the first minutes of
resuscitation at birth with practical scenarios using infant manikins.
FIGURE 17.3 Steps to infant resuscitation from the UK Resuscitation
KMC is when a mother gives warmth, nutrition and love to her baby Council Training Manual [http://www.resus.org.uk/pages/nls.pdf (p. 121)].
who is placed, skin-to-skin, between her breasts, and nursed there.
The baby is kept in this position most of the day and night, providing
a constant, even body temperature. KMC babies grow more quickly reduce mortality and decrease the use of antibiotics [24]. The recom-
than those nursed in incubators. It is ideal care for premature and mendations include assessment of the following:
small-for-dates infants, and mothers can continue KMC at home until
l clinical signs in children presenting with a cough or difficult
the baby’s body weight is 2.5 kg. In hospital, this releases nurses to
breathing;
care for the very sick infants, as mothers provide most of the KMC for
l fast breathing;
their infants [23].
l in-drawing of the lower chest wall;
l other specified danger signs.
PNEUMONIA Antibiotics are recommended for treatment of pneumonia, acute
Pneumonia causes most deaths in childhood and the majority streptococcal pharyngitis, acute otitis media and mastoiditis, but not
of these deaths occur in resource-constrained parts of the world. for treatment of acute upper respiratory infections, such as coughs
Qazi et al. showed that simple, standardized training in acute respira- and colds. Commercial cough remedies containing ineffective or
tory infection management, based on WHO recommendations, will harmful ingredients are discouraged.
Pe d i at r i c s i n a R e s o u rce - co n s t ra i ned S etting 145
150
50
Target for
FIGURE 17.4 Neonatal deaths and the Millennium 0 MDG-4
Development Goals (Reproduced with permission from
Lawn J, Cousens S, Bhutta Z, et al. Why are 4 million newborn 1960 1980 2000 2020
babies dying each year? Lancet 2004;364:399–401). Year
Other 7%
Congenital 7%
Sepsis/
pneumonia 26%
Infections 36%
Asphyxia 23%
Tetanus 7%
Diarrhea 3%
Despite the size of the problem, in Kenya and Papua New Guinea helpful. Sputum samples cannot be easily obtained and chest x-ray is
oxygen was unavailable in several health facilities and even fewer had seldom diagnostic. Gastric aspirates must be collected from an empty
oxygen saturation monitors [25]. In HIV-endemic areas, both the stomach and immediately placed in a buffered solution. In our hands,
diagnosis and management of pneumonia have become increasingly the results have been unrewarding. The mortality in HIV-infected
difficult. HIV-infected children are prone to bacterial pneumonia children is higher than in HIV-negative children and is related to the
(often caused by Streptococcus pneumoniae) but after repeated infec- CD4 count [26]. LIP has a characteristic lacy radiologic appearance
tions that cause structural damage and radiologic changes, it can be and, clinically, there is generalized lymphadenopathy; fever is uncom-
difficult to decide what is new, what is old and what is the best treat- mon. LIP may be complicated by the presence of bronchiectasis and
ment for the present problem. Staphylococcal infections and carriage TB, making the diagnosis more complicated.
are more common in HIV-infected children. Bacterial pneumonia
may occur on a background of lymphocytic interstitial pneumonitis MALARIA
(LIP) and/or tuberculosis (TB).
One million children die of malaria every year. Deaths are almost all
Pneumocystis jiroveccii pneumonitis (PCP) may be the presenting caused by Plasmodium falciparum infections. Malaria comes in several
illness of HIV-infected infants aged 3–8 months. Despite treatment forms and is most commonly asymptomatic or causes mild fever.
with high-dose cotrimoxazole and steroids, the prognosis is poor and Complicated malaria—accompanied by anemia or altered conscious-
it is hoped that by giving all HIV PCR-positive infants ART, the ness (cerebral malaria) and respiratory distress—carries a significant
number and severity of all infections will be reduced. PCP has a mortality [27]; urgent treatment is needed. Most countries with
distinctive clinical presentation—air hunger with hyperinflation of endemic P. falciparum malaria are using an artemisinin-based first-line
the lungs which are clear on auscultation. Body temperature is only combination therapy to overcome resistance to drugs such as chloro-
minimally raised and even high flow oxygen often only marginally quine and sulfamethoxazole (SP). Combination drugs are used to
improves oxygenation. slow down the development of resistance to artemisinins, which
should not be prescribed on their own.
On the other hand, TB can be difficult to diagnose. A contact history
of TB is one of the most helpful findings in making the diagnosis. Several studies have identified malaria, particularly associated with
The purified protein derivative (PPD) skin tests are usually negative convulsions, as a major cause of long-term neurologic sequelae,
in HIV-infected children, but when strongly positive it can be very including epilepsy and behavioral disorders. It was always known that
146 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
about 15–20% of children with severe or cerebral malaria developed 3. Bryce J, Cesar V, Habicht J-P, et al. The multicountry evaluation of the IMCI
gross neurologic sequelae, such as hemiplegia, blindness or cerebral strategy: lessons for the evaluation of public health interventions. Am J Public
palsy, but, more recently, subtle forms of sequelae have been studied Health 2004;94:406–15.
and identified [28]. 4. Ahmed HM, Mitchell M, Hedt B. National implementation of Integrated
Management of Childhood Illness (IMCI): policy constraints and strategies.
Bed nets, intermittent prophylactic therapeutic medication (iPTpd) Health Policy 2010;96:128–33.
and indoor residual spraying will help reduce the prevalence and 5. Nolan T, Angos P, Cunha AJ, et al. Quality of hospital care for seriously ill
severity of malaria; some malaria vaccines also look promising [29]. children in developing countries. Lancet 2001;357:86–7, 106–10.
6. WHO Pocket book for hospital care for children. Guidelines for the manage-
Malaria and malnutrition both lead to anemia and there is a known ment of common illnesses with limited resources. Geneva: World Health
association between this anemia and non-typhoidal salmonellosis Organization; 2005. Available at: http://www.who.int/child_adolescent_
(NTS). NTS is the most common cause of bacteremia in malarial areas health/documents/9241546700/en/index.html.
[30]. It is important to know the resistance pattern to antibiotics of 7. WHO Emergency Triage Assessment and Treatment (ETAT). Manual for par-
the common pathogens in the region so that antibiotic guidelines can ticipants. Geneva: World Health Organization. Available at: http://www.
reflect the local findings. who.int/child_adolescent_health/documents/.
8. Otten M, Kezaala R, Fall A, et al. Public-health impact of accelerated measles
31. http://www.who.int/cholera/technical/en/. 34. Rotavirus vaccine: an update WHO. Weekly epidemiological record. No 51-52.
32. Fischer Walker CL, Friberg IK, Binkin N, et al. Scaling up diarrhea prevention 2009;84:533–40 http://www.who.int/wer/.
and treatment interventions: a Lives Saved Tool analysis. Plos Med 2001; 35. Zinc supplementation in the management of diarrhoea. http:/www.who.int/
8(3):e10000428. entity/elena/titles/zinc_diarrhoea/en/.
33. Maitland K, Kiguli S, Opoka RO, et al; FEAST Trial group. Mortality after fluid
bolus in African children with severe infection. NEJM 2011;364(26):
2483–95.
Disasters, Complex Emergencies,
18 and Population Displacement
Trueman W Sharp, Charles W Beadling
resource-poor regions. In 2009, there were an estimated 42 million respiratory infections and malnutrition [11] (Fig. 18.2). One of the
refugees and displaced people, more than 80% of whom were in the most important principles for the health responder to keep in mind,
developing world [8] (Box 18.2). though, is that while there are certainly common diseases, every dis-
aster has a unique epidemiology and must be dealt with somewhat
THE HEALTH EFFECTS OF differently [12]. Whereas an earthquake often causes many immediate
trauma deaths and usually does not result in food shortages, a flood
COMPLEX EMERGENCIES typically causes few immediate deaths and disrupts food production
and distribution networks. An earthquake in Haiti has a markedly
Over the last two decades there has been an explosion in our under- different impact than an earthquake in southern California, because
standing of the health effects of disasters and displaced populations the extent of the development, the local building codes, population
and how to respond effectively to them. It is fair to say that disaster density, and local response capabilities are very different. One refugee
relief overall has become an important niche of medicine with a population may be devastated by measles, while in another, in which
substantial body of scientific literature, standards of care, proven vaccination coverage has been high, diarrhea may be the most impor-
approaches, and ever more formal training programs [10]. While the tant cause of morbidity and mortality. In the CEs of the 1970s, which
reader is cautioned that all disasters are different, it is clear that most were mainly in sub-Saharan Africa and Southeast Asia, infectious
of the morbidity and mortality in disasters of all types results from diseases in displaced populations were the predominant issue. This
population displacement. Displaced populations almost always have led to the recognition of the importance of interventions such as
significantly higher morbidity and mortality than when they are in measles vaccine programs and diarrheal disease control programs
their baseline state. [13]. In some of the CEs of the 1990s, in places such as the former
Consistently, in resource-poor environments, while the relative order
of importance may change, the five leading causes of death in the
emergency phase of a crisis involving displaced people have been
remarkably similar. The main causes of serious morbidity and mortal- BOX 18.2 Refugees and Internally Displaced
ity are almost invariably diarrheal illnesses, measles, malaria, acute
People
A refugee is a person outside of his or her country of nationality
BOX 18.1 Definitions who is unable or unwilling to return because of persecution or
a well-founded fear of persecution on account of race, religion,
Disaster – an event of environmental disruption or des nationality, membership in a particular social group, or political
truction that is severe enough to overwhelm the resources opinions.
of the affected community and necessitates outside
An internally displaced person (IDP) is a person who has been
assistance.
forced or obliged to flee or to leave their homes or places of
Natural disaster – a humanitarian crisis caused by either
habitual residence, in particular as a result of or in order to avoid
climatologic or geologic events.
the effects of armed conflict, situations of generalized violence,
Man-made disaster (also called Technological) – a humani
violations of human rights or natural or human-made disasters,
tarian crisis caused by either accidental (e.g. nuclear, chemi
and who has not crossed an internationally recognized State
cal release) or intentional (e.g. terrorism, war) factors.
border.
Complex emergency (also complex humanitarian emer
gency) – a humanitarian crisis in a country, region or society Comment: Both refugees and IDPs have similar health needs;
where there is a breakdown of authority resulting from however, they have very different status and rights under inter
internal or external conflict, usually characterized by national law. This distinction may seem artificial but can have
extreme violence, and requires an international response major consequences with respect to their rights, protections,
that goes beyond the mandate of a single agency or the and access to relief. The region with the largest IDP population
existing United Nations country program. is Africa with some 11.8 million IDPs in 21 countries [9].
Other
ARI Measles
1.0%
9.0% Other 10.0%
22.0%
Diarrhea
Measles Malaria
30.0%
53.0% 25.0%
Malnutrition
23.0%
Diarrhea
Malaria
11.0%
7.0% ARI
9.0%
FIGURE 18.2 Leading causes of death in emergency phase of displaced people crisis in Sudan, 1985 (left) and Malawi, 1990 (right). Adapted with
permission from Toole MJ. Communicable diseases and disease control. In: Noji EK, ed. The Public Health Consequences of Disasters. New York: Oxford University Press;
1997:80–100.
Time
BOX 18.3 Displaced and Vulnerable
Populations
Disaster Recovery Development
Transition Displaced populations in general are at increased risk of
Emergency disease and injury due to degradation of sanitation and limited
response safe water, food, shelter and security. This is evidenced by a
consistent, marked increase in crude mortality rates. However,
FIGURE 18.3 Hypothetical timeline of disaster response. Adapted with
permission from Burkholder BT, Toole MJ. Evolution of complex disasters. Lancet some subgroups of the displaced population are at greater
1995;346:1012–15. increased risks and considered especially vulnerable.
Yugoslavia, trauma and chronic health conditions were more impor- Vulnerable populations include, but are not limited to,
tant causes of morbidity and mortality, requiring different types of women, especially pregnant or breastfeeding mothers, young
interventions [14]. children, the elderly, and anyone with a physical or mental dis
ability. However, in some circumstances, certain ethnic groups
Furthermore, it is important to consider that within any given disaster,
relief needs can evolve considerably over time. Some authors have and even young healthy males can be vulnerable as well.
described the phases of natural disasters, such as an impact phase,
post-impact phase, and recovery phase, to discuss the importance of
understanding how relief needs change markedly over time [15]. In agriculturally based clans who were not participants in the fighting
the impact phase after earthquakes, for example, there may be an urgent were particularly devastated by the civil conflict and had extremely
need for trauma services in the first few days but then health needs shift limited access to emergency relief services. Even adults and adoles-
to other conditions. Thus, deploying trauma hospitals that will arrive cents, who are the most capable segments of the population, require
4 or 5 days after the earthquake can be fruitless and wasteful. special attention in some circumstances.
caused thousands of deaths in just a few weeks. Studies among refugees Deficiency of this vitamin has been shown to be an important cause
show that large measles outbreaks can occur even if vaccine coverage of mortality particularly in measles cases but also in mortality from
rates exceed 80%. Therefore, measles immunization campaigns must all causes. Vitamin A supplementation is cheap and easy. Thus, mass
be given the highest priority. They should not be delayed until measles administration of vitamin A at the same time as measles vaccination
cases are reported or until other vaccines become available. Measles can be an important adjunct intervention to reduce the consequences
deaths occur primarily in young children, but children as old as 14 of measles infection, particularly in malnourished populations (Boxes
to 15 years have been affected. The most common nutritional defi- 18.5 & 18.6). In selected situations, vaccination against diphtheria,
ciency in refugee and displaced populations is lack of vitamin A. pertussis, tetanus, polio, tuberculosis, meningococcal meningitis, or
cholera may be appropriate. But rarely, if ever, will these interventions critical in its access and use. Cultural considerations can also be
be as important as immunization against measles. These other immu- important factors in how water is accessed and used by the local
nizations usually become considerations after the emergency phase population. The technical skills and other considerations in waste
has passed. disposal, vector control, and personal hygiene can be equally complex.
Some relief organizations attempt to focus on environmental health
Institute Diarrhea Control Programs issues but most do not. The technical challenges and lack of donor
appeal of environmental issues remain major problems.
Diarrheal diseases are often a principal cause of morbidity and mor-
tality in complex emergencies [21]. Common pathogens such as rota-
virus and E. coli are often important causes of diarrhea outbreaks, but Provide Adequate Shelter, Clothes
Vibrio cholera and drug-resistant Shigella spp. have also caused devas- and Blankets
tating outbreaks. Prevention of all types of diarrhea involves provid-
ing good sanitation, clean water, and adequate personal hygiene. Shelter is a basic human need. The provision of the basic means to
Simple emergency measures to prevent diarrhea include organizing be protected from the elements – sun, rain and cold – is a high prior-
chlorination brigades, isolating defecation fields, and providing soap. ity. In populations with nutritional deficits, substantial energy can be
Simple measures such as providing soap are inexpensive and can expended simply in trying to keep warm. Consequently, some have
substantially reduce person-to-person disease transmission. In some argued that, in certain situations, distributing shelter, clothes and
situations, though, and particularly in the emergency phases of a relief blankets may be more effective in preventing morbidity and mortality
effort, preventive measures may not be feasible or effective. The critical than is distributing food. As with environmental interventions, there
intervention in coping with diarrheal disease then becomes prevent- is a substantial body of knowledge that deals with the technical con-
ing mortality through effective case management. Sound case man- siderations of emergency housing [24]. The selection of the specific
agement of diarrheal disease, even in cholera epidemics, can reduce sites for shelter, the layout of camps, and the type of materials used
case fatality rates to less than 1%. Effective case management of in construction are all important issues. Camps constructed in poor
diarrhea is based primarily on providing fluid replacement through locations and with inadequate design can accelerate communicable
aggressive oral rehydration therapy (Box 18.7). Intravenous fluid disease transmission. Other factors to consider are the local availabil-
replacement and antibiotics are used selectively and according to ity of materials, the economic level of development of the population,
protocols relevant to the situation. While these concepts are easy to the social habits, the local customs, and the political context. The
understand, experience has shown that effective diarrhea treatment decision to provide shelter can have significant long-term conse-
programs require substantial organization and numerous personnel quences. Simple shelters provided on an emergency basis may unin-
with experience and training. In northern Iraq in 1991, for example, tentionally evolve into a permanent camp and end up attracting more
the abundance of rehydration salts and enthusiastic medical providers refugees to the site. Many of these issues may become a fait accompli
was not enough in the absence of effectively run rehydration centers before reasoned decisions can be made by relief officials. Refugees are
[22]. An important component of diarrhea control programs is devel- often forced by circumstances into poor locations that would never
oping community outreach programs to seek out cases that may not have been chosen by relief workers who had been given the oppor-
present to treatment facilities. Education of the community, particu- tunity to make decisions based on health and safety.
larly mothers, on the use of oral rehydration therapy, the importance
of continuing breastfeeding, and the importance of personal hygiene
is also a priority. Active case finding, surveillance, and outbreak inves-
Ensure Food Supplies are Adequate and
tigation are essential in determining the causes of the outbreak. Care Reach Intended Recipients
providers must appreciate that the approach to diarrhea management One of the hallmarks of complex emergencies is a shortage of food.
in a CE is different from the approach that would be followed in the Thus, providing at least 2000 kcal per day per person is an essential
developed world. priority in emergency situations [25]. While it is often uncertain how
many people actually die of starvation during complex emergencies,
acute malnutrition has been shown to be a critical underlying cause
Provide Elementary Sanitation and of much morbidity and mortality [26]. There are many ways of pro-
viding emergency food relief. General food rations can be distributed
Clean Water widely to the population, perhaps in exchange for work or school
Many of the diseases that occur in disasters, particularly in the setting attendance. General food rations consist of nutritionally balanced
of a CE, are to a great extent the consequence of poor environmental basic commodities that are appropriate to the situation and culture.
conditions [23]. Water is often in short supply and of poor quality. Selective or supplemental feeding programs target food for certain
There are limited means to dispose of waste. Vectors of communicable high-risk people, such as malnourished children, tuberculosis patients,
diseases may be prevalent. The means for basic personal hygiene may or lactating mothers. This food may be distributed as rations to take
be lacking. Addressing these environmental health issues, particularly home or can be provided at feeding centers, such as “soup kitchens”.
providing potable water, usually is a very high priority. Water needs Therapeutic or rehabilitative feeding can be provided for significantly
are frequently underestimated. Only 3 to 5 liters of potable water per malnourished people as a medical intervention and is usually given
day must be consumed for short-term survival, but adults need at least on an inpatient basis through assisted eating, nasogastric tube, or
15 to 20 liters per day for cooking, cleaning, medical care, and, some- intravenous line. The mechanics of managing food distribution and
times, important ritual purposes. In some situations, such as when feeding programs are often complex. For example, an intensive reha-
people are active in a hot environment, water needs are even greater. bilitative program for severely malnourished children must have
Medical facilities require much more water, usually at least 100 liters mechanisms to identify patients in the affected population. To some
per patient per day. Environmental issues are often very difficult to extent, patients may be self-referred, but often they must be proac-
resolve because they require considerable resources and technical tively sought through clinic referrals and community outreach
expertise. Providing potable water to a group of refugees, for example, workers. Protocols and procedures must be developed to screen
may require experienced engineers who can locate the best sources of patients and determine who is eligible. Refeeding is labor-intensive
water, whether from the ground, the surface, or a spring. Expertise, and requires care providers with training and experience. Patients
such as how to construct a proper well and select the appropriate typically have other aggravating illnesses and infections, such as
pump, is needed to access the source. The characteristics of a water malaria, that can complicate refeeding efforts. After discharge,
distribution system are important because they can greatly influence follow-up programs must exist to prevent relapse. Sometimes family
the way water is accessed and therefore used; if people have a difficult interventions are needed to counteract the social context that was a
time obtaining water, they will use it sparingly. Assessing and main- factor in the malnutrition. For example, in some cultures one child
taining water quality is a critical aspect of a water program. Local water may be singled out to be deprived so that the other children may
may be a limited resource and local political considerations may be survive. The management of other food distribution programs can be
154 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Supplemental references:
l WHO position paper on oral rehydration salts to reduce mortality from cholera, www.who.int/cholera/technical/en
l First steps for managing an outbreak of acute diarrhea, www.searo.who.int/en/Section 1257/Section2263/info-kit/WHO-Managing_
Diarrhea_outbreak.pdf
l WHO/UNICEF Joint Statement clinical management of acute diarrhea, www.whqlibdoc.who.int/hq/2004/WHO_FCH_CAH_04.7.pdf
l Oral rehydration salts production of the new ORS, www.whqlibdoc.who.int/hq/2006/WHO_FCH_CAH_06.1.pdf
complicated also and requires technical skills and experience. Food Care, Catholic Relief Services, World Vision, and Feed the Children.
programs have not always been successful, due in part to formidable On the scene of an emergency, other agencies, such as the ICRC and
problems of logistics, security, and distribution. Food aid can be private volunteer organizations, often assume responsibility for
highly politicized and food relief misused. Food supplies must be actually distributing food and for administering feeding programs.
nutritionally balanced and culturally appropriate, and there has been
much debate about the appropriate number of calories and the best
content of food rations. Remarkably, micronutrient deficiencies have Establish Appropriate Curative Services
occurred in populations relying on donated food [27]. The causes of Probably most importantly for direct care providers, establishing cura-
food shortages are complex and may involve disruption of harvests, tive medical services that follow standard treatment protocols, are
collapse of markets, lack of distribution systems, manipulation of based on essential drug lists, and provide basic coverage to the com-
food supplies by warring factions, and many other factors. Thus, an munity as a whole are a high priority in CEs. Providing acute medical
emergency feeding campaign must not only provide food urgently care is one of the most visible and understandable aspects of a relief
and effectively, but also begin to address the root problems of the operation, and experience has shown that many external medical
crisis. Supplying seeds and agricultural implements may, in the long providers are willing to volunteer in an emergency. One of the hall-
run, be as important as supplying emergency food. There are a marks of emergency relief is the dispatch of medical teams from
number of agencies that specialize in managing the “food pipeline” developed countries to treat sick victims. However, what medical care
to emergency situations: the procurement, processing, shipping, and is actually needed should be carefully considered before providing
storing of bulk food. The World Food Program is the principal inter- curative services; noble intentions may not necessarily translate into
national agency. In the US, some of the principal agencies include effective patient management. As indicated above, much of effective
D i s a s te r s, Co m p l ex E m e rg e n c i e s, a n d Po p u l at i o n D i splacement 155
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C
SECTION
SERVICE-BASED CHAPTERS
19 Diagnostic Imaging in the Tropics
Elizabeth Joekes, Sam Kampondeni
hemoglobinopathies, and nutritional diseases such as rickets and clinical setting. Ultrasound should be the first modality in investiga-
scurvy. The widespread use of skull x-rays in head trauma should be tion of the renal tract, where it will identify hydronephrosis, tumors,
strongly discouraged even in the absence of CT. Management will TB, and schistosomiasis-related abnormalities, in addition to simple
depend on the neurologic symptoms rather than on the presence or calculi. This applies to all levels of care, including those with access
absence of a skull fracture on x-ray. Similarly, the use of lumbar spine to intravenous urography (IVU). If ultrasound is available, IVU should
x-rays in chronic back pain, in the absence of trauma or a suspicion no longer be used as the primary investigation for hydronephrosis
of malignancy or TB, is not indicated as it will not significantly alter or hematuria. Ascites, effusions and soft tissue abscesses can be
management. diagnosed with relative ease. In more experienced hands, ultrasound
can pick up intra-abdominal adenopathy, TB peritonitis, psoas
As the imaging appearances of many tropical infections overlap, it is abscesses and bowel masses. It can guide biopsies and percutaneous
important to correlate all findings with the clinical presentation and treatment of abscesses and hydronephrosis. Pediatric applications
laboratory test results. Even then it may be difficult to make a defini- include many of the above, as well as the diagnosis and treatment of
tive diagnosis with the available imaging results. In addition, asymp- intussusception and subperiosteal abscess [30]. In neonates and
tomatic or previous infection with a wide variety of organisms is very young infants, the large fontanelle can be used as a window to assess
common. They are often not the cause of the presenting symptoms, the brain for hydrocephalus, congenital malformations, hemorrhage
but may show abnormalities on imaging. For example, a fibrotic lung and infections.
following successful TB treatment in the past may be mistaken for
active infection. Assuming all these findings are active disease will Although not specifically related to tropical diseases, assessment of
lead to multiple diagnoses and overburdening of medical services. the acute abdomen with ultrasound can reduce the need for explora-
Similarly, differences in endemic background and comorbidities may tory laparotomy and thus avoid unnecessary morbidity and cost to
change the way diseases present: HIV co-infection alters the present- the patient.
ing appearances of TB on chest x-rays [25], and primary infection
patterns that are classically seen in children in endemic areas can be Overall, ultrasound is a very powerful diagnostic tool which is cur-
present in adults in non-endemic areas. Knowledge of local disease rently greatly underutilized in low-resource settings. However, as
patterns is essential for accurate interpretation of imaging studies. stated previously, to benefit from its full potential and to avoid unnec-
Other pitfalls in the interpretation of imaging studies are the geo- essary harm, further development of high-quality training programs
graphic variation in the appearances of both infectious and noninfec- and regulation of misuse are essential.
tious diseases, as well as the variation in baseline standards between
different populations. For example, Asian fetal biometric tables on ADVANCED IMAGING TECHNIQUES
low-cost Chinese ultrasound equipment cannot be applied in African Fluoroscopy, CT, MRI and nuclear medicine are complex imaging
countries, as the average birth weight of the Asian population is lower, techniques which fall outside the scope of this chapter. The main
leading to overestimation of fetal size in African countries. indications for fluoroscopy are related to the gastrointestinal tract and
include esophageal strictures, stomach ulcers and ileocolitis.
ULTRASOUND In the current setting of soaring numbers of road traffic accidents, the
As in the industrialized world, antenatal care and emergency obstet- greatest benefit of CT scanning probably lies in the assessment of head
rics are the most common indications for ultrasound in the tropics. injuries rather than tropical diseases. Detection of neuro-infections
Its application is now recognized as a valuable tool in low-resource such as TB, toxoplasmosis and cysticercosis is possible, but unlikely
settings [26]. Increasingly, ultrasound has also been implemented in to be cost-effective in low-resource settings.
general medical, surgical and tropical diseases. It is currently used
extensively in the diagnosis of liver diseases, including abscesses,
hydatid disease, and schistosomiasis-related peri-portal fibrosis [27–
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Blood Transfusion in
20 Resource-limited Settings
Oliver Hassall, Imelda Bates, Kathryn Maitland
severe anemia, infectious diseases, and bleeding in pregnancy. Based donation as uninfected, either because of imperfect test sensitivity or
on the limited supply of data and using the lowest WHO estimate of human error. The higher the incidence of new infection in the donor
demand (10 donations per 1000 population), the shortfall in blood population, the greater the likelihood that blood will be donated
donations for those countries responding to the survey and excluding during the window period before a serologic screening test is capable
South Africa is about 2.6 million units. of detecting the infection.
Although the magnitude of the shortage of blood for transfusion in Reducing the risk of TTI, therefore, has three main components: the
sub-Saharan Africa is not certain, the patient groups who suffer the identification of population groups with a low prevalence and inci-
greatest impact are easier to identify. Young children have a high dence of TTI from which to recruit blood donors; health screening of
demand for blood, with the prevalence of severe anemia (defined as potential donors to allow exclusion/self-exclusion of those with risk
hemoglobin <5 g/dL) in hospitalized children ranging from 8% to factors for TTI; and the screening of all blood donations for TTIs with
29% [5]. In malaria-endemic areas, Plasmodium falciparum malaria as sensitive and quality-assured tests in good laboratories.
well as other infections and nutritional deficiencies have also been
HIV is readily transmitted by whole blood transfusion with a sero-
associated with severe anemia in children [6–8]. In some hospitals,
conversion rate of 96% [14] and, historically, blood transfusion was
50% of all children admitted are transfused, and children may
thought to account for 10% of all new HIV infections in sub-Saharan
account for up to 70% of all transfusions prescribed in malaria-
Africa [15]. In the mid-1990s, the risk of HIV infection from a blood
endemic Africa [9–11].
transfusion in Kenya was 2% [16]. In a recent analysis, Jayaraman and
Women of reproductive age are also major users of blood transfusions colleagues constructed a mathematical model to quantify the transfu-
in resource-limited countries. Of the 20 countries worldwide with the sion risks of three viruses (HIV, hepatitis B and hepatitis C) in 45
highest maternal death rates, 19 are in sub-Saharan Africa, where the sub-Saharan African countries [17]. Although the authors recognized
risk of maternal death is 1 in 16, compared with 1 in 2800 in indus- methodologic bias in the epidemiologic sample base, they estimated
trialized countries. The most common cause of maternal death is that if projected annual transfusion requirements were met, transfu-
severe bleeding, contributing to over 40% of maternal deaths, and it sions alone would be responsible for 28,595 HBV infections, 16,625
has been estimated that a quarter of these women die because of HCV infections and 6650 HIV infections every year [17].
blood shortages [12]. Another infectious risk of blood transfusion, for which laboratory
screening is not routinely performed, is bacterial contamination. In
BLOOD SAFETY wealthy countries, the risk of bacterial contamination of red cell prod-
ucts is low. In the Netherlands, a study of whole blood units cultured
Infectious Risk of Blood Transfusions within 24 hours of donation reported a contamination rate of 0.34%
Blood is a biologic tissue and when transferred from one individual [18], and the frequency of bacterial contamination of red blood cell
to another it can transmit infection with potentially devastating con- concentrates is thought to be approximately 1 in 30,000 [19]. Clini-
sequences for the recipient. Viruses (e.g. HIV, hepatitis), bacteria (e.g. cally significant episodes resulting from bacterial contamination of
Treponema pallidum), parasites (e.g. malaria, trypanosomes) and blood products in wealthy countries are even rarer, with reported rates
prions (e.g. vCJD) may all be transmitted by blood transfusion. of 5.8 per million units (France) and 0.21 per million units (USA)
Reducing the risk of such an event is an important responsibility of [20,21].
providers of blood for transfusion.
Recent data from sub-Saharan Africa suggest that the risk of bacterial
The transfusion-transmissible infections (TTI) for which all blood for contamination in whole blood units may be much higher than in
transfusion should be screened are HIV, hepatitis B, hepatitis C, and wealthy countries. Bacterial contamination, with predominantly envi-
syphilis [13]. For any TTI, the risk of an infectious unit entering the ronmental organisms, was found in 9% of pediatric transfusions
donor pool is related to the prevalence and incidence of the infection issued in a Kenyan hospital [22]. Pediatric transfusions are particu-
within the donor population. The higher the prevalence, the more larly vulnerable to contamination in resource-limited countries, since,
often a laboratory screening test will incorrectly identify an infected in the absence of pediatric transfusion packs, small volumes have to
164 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
be drawn from adult (500 mL) packs. A recent study from northern Blood Donor Selection
Ghana on whole blood packs identified a contamination rate of
17.5%; the majority of contaminants in this case were thought to One of the key goals of the WHO strategy is to ensure all donors are
originate from the skin of the donor [23]. Another recent study from voluntary and non-remunerated, but many of the world’s poorest
southern Ghana demonstrated a 13% bacterial contamination rate of countries are still struggling to achieve this goal (Fig. 20.2). For
whole blood [24]. example, in 15 countries in Africa, accounting for 45% of the regions’
population, only 25–50% of blood was collected from voluntary
donors. Overall, 1.2 million units, nearly half of the 2.8 million units
Other Risks of Transfusion of blood collected in sub-Saharan Africa, were from family or paid
Systems for the routine detection of adverse consequences of blood donors [4]. Recent data indicate that the difference in HIV prevalence
transfusions (hemovigilance) only exist where transfusion safety has between voluntary and replacement donors may be related to their
been identified as a health priority by the government [25]. In low- different age structures rather than whether they are voluntary or
income countries, the frequency of noninfectious adverse events replacement donors [34]. Furthermore, the voluntary donors may
related to blood transfusion is largely unknown as hemovigilance have higher incidence rates of HIV infection because of their younger
activities are very limited. The transfusion of the incorrect unit with age profile [35]. In fact, the safest type of donor is one who is unpaid
the possibility of ABO incompatibility and a life-threatening hemo- and donates regularly, irrespective of whether they were originally a
lytic transfusion reaction remains the most common hazard of trans- voluntary or replacement donor.
fusion in the developed world [26,27]. Clerical and other human
errors are frequently to blame, even in health systems that are sophis- PROGRESS IN IMPROVING BLOOD SUPPLY
ticated and well resourced. AND SAFETY IN SUB-SAHARAN AFRICA
In low-income countries, most blood is transfused as whole blood. Over the past decade, several countries in sub-Saharan Africa have
Febrile nonhemolytic transfusion reactions (FNHTR) are therefore made progress in achieving the goals defined by the WHO to improve
likely to be common because they are caused by biologically active blood safety, financed largely by international donors. For example,
substances associated with donor leukocytes, such as cytokines, com- the US President’s Emergency Plan For AIDS Relief (PEPFAR) provides
plement fragments, antibodies and adhesion molecules [26,27]. direct support to 14 countries to strengthen blood transfusion serv-
Detection of these reactions in low-income countries is difficult ices. Between 2003 and 2007, this resulted in an increase in the
because many transfusion recipients may already be febrile as a result number of total blood donations and the proportion from voluntary
of their underlying condition. In the only published study of its type, donors, and a decrease in the percentage of donations reactive for HIV
40% of transfusions (26,973 units) in Yaounde, Cameroon were asso- [36]. These improvements have been achieved by establishing regional
ciated with fever [28]. In most resource-rich countries, leukocyte centers, which make up a national blood transfusion service, to
reduction of transfusion products has decreased the risk of immuno- replace hospital-based systems. Although the increase in voluntary
genicity and cytokine release, and significantly reduced the number donors has reduced the number of replacement blood donors, many
of FNHTR [29,30], post-transfusion purpura, and transfusion- of the voluntary donors are secondary school students, so there is a
associated graft-versus-host disease [31]. risk of blood shortages during the school holidays, which may also
coincide with periods of peak demand.
The transfusion of whole blood may have other adverse consequences,
such as activation of adhesion molecules that are thought to be National blood transfusion services are more expensive than hospital-
important in the generation of transfusion-related acute lung injury based facilities because they need to establish efficient donor
resulting in noncardiogenic pulmonary edema [27,32]. Transfusion- recruitment and selection programs, maintain distribution and com-
associated immunomodulation is associated with accelerated disease munication networks, and support quality-assured laboratory serv-
progression and mortality in patients with HIV infection, due to ices. Most of the donors attending hospital-based facilities are
transfusion-related immunosuppression [33]. recruited by families of patients (i.e. replacement donors), so the
hospitals do not bear the cost of donor recruitment [37]. There are, TRANSFUSION GUIDELINES
therefore, concerns about the sustainability of systems requiring a
high level of financial support in low-income countries where cost The decision whether or not to prescribe a blood transfusion should
recovery is unlikely. be based on an assessment of the clinical condition of the patient,
taking into account their hemoglobin level. Trials based in wealthy
countries have found that 30-day mortality was the same in two
CLINICAL USE OF BLOOD groups of critically ill patients irrespective of whether hemoglobin
TRANSFUSION levels of 7 g/dL or 9 g/dL were used to trigger the transfusion [38]. In
less acutely ill or younger patients, 30-day mortality was lower in the
group with the trigger of 7g/dL [38]. One of the largest pediatric trials
WHO NEEDS BLOOD? ever conducted also concluded that a hemoglobin transfusion thresh-
In wealthy countries, the use of blood is strictly monitored through old of 7 g/dL decreased transfusion requirements without increasing
specialist transfusion practitioners, hospital transfusion committees, adverse outcomes [39]. Similar trials are needed in Africa, where, due
and national reporting systems. In resource-limited countries, appro- to a shortage of blood, transfusion triggers tend to be much lower
priate use of blood and blood products and monitoring of transfu- (4 g/dL or under 5 g/dL in symptomatic patients) [40].
sions are poorly taught and rarely monitored. Evidence underpinning Pediatric guidelines in low-income countries where malaria is preva-
guidelines for the clinical use of blood in low-income countries is lent often indicate that profound anemia (hemoglobin < 4 g/dL)
often weak or inappropriate for settings with few resources. The should be treated with a transfusion [40]. Most transfusions received
pattern of usage of blood in low-income countries, with most transfu- are whole blood and not packed red cells. This is supported by evi-
sions given predominantly as an emergency treatment to children and dence suggesting that children with hemoglobin concentration less
pregnant women, is very different from that in more wealthy coun- than 3.9 g/dL who were transfused had a lower mortality than those
tries (see Fig. 20.3A,B). The high percentage of blood used for pedi- with similar hemoglobin concentrations who were not transfused [7].
atric transfusions (19–67%) and pregnancy-related complications in Transfusions may be needed at higher hemoglobin levels if dehydra-
women (15–40%) contrasts markedly with equivalent figures of 1% tion, shock, impaired consciousness, heart failure, or labored breath-
and 4% from a district hospital in the UK. The majority of pediatric ing are present.
transfusions are for young children; in the studies for which data are
available, children under the age of 5 years receive 43% to 62% of all
blood transfusions. MISUSE OF BLOOD TRANSFUSIONS
Even in wealthy countries with good supplies of blood, there can be
significant overuse of blood transfusions [37]. In resource-limited
countries, there is also often poor adherence to transfusion guidelines,
and despite the lack of blood, 50–75% of blood transfusions may be
given inappropriately [41,42]. This has led some to observe that “no
other pharmaceutical preparation of comparable cost and toxicity is
Pregnancy-related prescribed with [such] a cavalier attitude towards risk” [43]. Other
Hematology studies have shown that over a third of transfused children did not
Children
have their hemoglobin measured prior to transfusion, and of those
in whom the pre-transfusion hemoglobin was checked, 18% had
levels above the recommended transfusion trigger of 6 g/dL without
Trauma any additional indications for transfusion [42].
The decision to transfuse in resource-limited settings is often based
on a clinical diagnosis of anemia using signs of severe pallor of the
palms and/or the conjunctiva [44]. However, clinical assessment of
pallor may over-diagnose anemia [41,42] or miss a large proportion
Surgery of patients with severe anemia [45]. Clinical assessment of anemia is
therefore not precise enough to inform the decision to prescribe a
scarce and potentially dangerous therapy such as a blood transfusion.
Medical An accurate hemoglobin measurement is essential to avoid putting
A transfusion recipients at unnecessary risk, and to prevent inappropri-
ate use and wastage of blood.
Hematology Manual measurement of hemoglobin requiring dilution techniques,
Trauma as performed in laboratories in many resource-limited countries, is
Pregnancy-related often inaccurate. Reasons include poorly maintained equipment, lack
of supplies and quality standards, and inadequate training and super-
Medical vision [46,47]. A photometric method (HemoCue® AB–Hb Photom-
eter, Quest Diagnostics Ltd) does provide a direct hemoglobin reading
on a small volume of blood, but uses disposable cuvettes which may
Surgery
be too expensive for resource-constrained laboratories with heavy
workloads [48]. The packed cell volume is often used as a substitute
for hemoglobin in pediatric practice [49], but this too does not give
an accurate estimation of anemia [50,51]. The Hemoglobin Colour
Scale (HCS) [52] is a simple, rapid and cheap method for assessing
anemia, but its usefulness for guiding decisions about blood transfu-
sions has not been evaluated in appropriate field trials in low-income
countries [53].
B
OUTCOMES OF BLOOD TRANSFUSIONS
Children
In-hospital case-fatality rates following blood transfusions in low-
FIGURE 20.3 Estimates for the proportionate use of blood in the United income African countries range from 6% to 20% [7,54–56]. In chil-
Kingdom (A) and resource-limited countries in Africa (B). dren, prostration, respiratory distress and profound anemia
166 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
(hemoglobin <4 g/dL) are all associated with an increased risk of 6. Newton CR, Marsh K, Peshu N, Mwangi I. Blood transfusions for severe
death. Around a third of these deaths occur within 6 hours of admis- anaemia in African children. Lancet 1992;340:917–18.
sion to hospital, so appropriate emergency management is crucial [9]. 7. Lackritz EM, Campbell CC, Ruebush TK 2nd, et al. Effect of blood transfusion
Recent studies have indicated that the respiratory distress and cardio- on survival among children in a Kenyan hospital. Lancet 1992;340:524–8.
vascular changes associated with acute severe anemia in children are 8. Calis JC, Phiri KS, Faragher EB, et al. Severe anemia in Malawian children.
N Engl J Med 2008;358:888–99.
due to hypovolemia rather than heart failure [57–59], and studies are
9. English M, Ahmed M, Ngando C, et al. Blood transfusion for severe anaemia
underway to determine the optimal emergency management proce-
in children in a Kenyan hospital. Lancet 2002;359:494–5.
dures for these children. In some children in malaria-endemic regions, 10. Greenberg AE, Nguyen-Dinh P, Mann JM, et al. The association between
anemia may fail to resolve or severe anemia may recur within a few malaria, blood transfusions, and HIV seropositivity in a pediatric population
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21 Infection Control in the Tropics
Haider J Warraich, Syed Faisal Mahmood, Anita KM Zaidi
BURDEN OF HEALTHCARE-ASSOCIATED
Key features INFECTIONS IN DEVELOPING COUNTRIES
HAIs are a serious problem in industrialized countries, with 1.7
l Patients in developing countries suffer high rates of million cases, and an estimated 100,000 deaths, per annum reported
healthcare-associated infections in the US alone [1]. However, with scant attention to infection control
and poor quality of hospital care in most developing countries, HAIs
l Unique challenges of infection control in the tropics are now recognized as a huge health burden in developing countries,
include: too, responsible for both increased morbidity and mortality, and
l Lack of resources and trained personnel waste of precious resources. In addition, HAIs subvert patient expecta-
l Low accessibility to clean water tions of quality medical care and increase negativity towards the
l Inappropriate use of invasive devices formal health system in favor of other options, especially since the
costs of HAIs are borne by the patients themselves in many develop-
l Easy availability of over-the-counter antibiotics
ing countries. The World Health Organization (WHO) estimates that
l Overcrowding and understaffing 1.4 million people suffer from HAIs worldwide. Furthermore, the risk
l Poor vector control of acquiring HAIs in developing countries is 2 to 20 times higher than
l Standard Infection Control Precautions (hand hygiene, in developed countries. Reducing the risk of HAIs faced by popula-
patient isolation, aseptic technique, use of personal tions in developing countries is a major priority of the WHO [2].
protective barriers, appropriate sterilization and disinfection
of reused equipment, and safe injection practices) form the RISK FACTORS FOR HEALTHCARE-ASSOCIATED
cornerstone of infection control in hospitals INFECTIONS IN DEVELOPING COUNTRIES
l Adequate attention to hand hygiene compliance is the Risk factors universally associated with an increased risk of HAIs are
most important component of basic infection control severity of underlying disease, length of hospital stay, inter-hospital
l Effective, low-cost, practical solutions addressing behavior transfers, use of invasive medical devices (intravascular devices,
modification to improve adherence to infection control urinary catheters, intubation and mechanical ventilation), surgery,
and prolonged and/or broad-spectrum antimicrobial therapy. An
practices, coupled with surveillance, and provision of interplay of multiple complex factors lies at the heart of HAIs in
essential resources can decrease the rate of healthcare- developing countries (Table 21-1). These include lack of robust sur-
associated infections in developing countries veillance systems to control infections and outbreaks, indiscriminate
l Establishment of an effective infection control program in a antibiotic use, nonadherence to basic infection control practices such
health facility requires an infection control committee and as hand washing, inadequate sterilization of medical equipment,
reuse of single-use devices, and presence of reservoirs of infection such
strong institutional commitment to the program
as contaminated food and water inside the hospital. Some of these
are easier to address – for example, by staff training, adequate steriliza-
tion of equipment, and improving compliance with hand hygiene –
than are others, such as overcrowding and understaffing.
Infection control policies and procedures are designed to prevent MODES OF TRANSMISSION
acquisition of healthcare-associated infections (HAIs) among patients
as well as healthcare workers and visitors. The complexities of infec- In healthcare settings, most infections are transmitted through direct
tion control in hospital environments have challenged medical or indirect contact. In developing countries, lack of hand hygiene
systems throughout the world, and are constantly evolving with results in transmission of infectious agents from one infected patient
advances in medical technology and care of increasingly vulnerable to another. Table 21-2 provides a summary of different modes of
patients. In this chapter, we have considered the tropics to be synony- transmission of infectious organisms, all of which necessitate specific
mous with developing countries, since most developing countries are transmission-based precautions.
located in tropical regions of the world. The term nosocomial infec-
tion has traditionally been used to refer to hospital-acquired infec-
tions among patients presenting 72 hours after hospitalization. We
SPECIAL PROBLEMS OF THE TROPICS
prefer the term healthcare-associated infections (HAIs) because many
infections associated with the delivery of healthcare occur in outpa- ANTIMICROBIAL RESISTANCE
tient settings and hospital-acquired infections may present sooner Antimicrobial resistance is a major challenge [3]. HAIs in develo
than 72 hours after admission. This chapter includes a review of the ping countries are dominated by Gram-negative organisms [4].
burden of HAIs in developing countries, selected problems unique to The proportion of resistant organisms, such as methicillin-resistant
the tropics that have a great impact on the people and the health Staphylococcus aureus, extended-spectrum β-lactamase-producing
system, and a discussion of basic infection control measures. Enterobacteriaceae, multidrug-resistant Pseudomonas aeruginosa and
168
I n fe c t i o n Co nt ro l i n the Tropics 169
Mode Features
Programmatic Lack of resources (financial, programmatic,
factors institutional) Contact transmission Most common route. Divided into
Low priority of infection control two sub-groups:
Lack of integration of infection control
practices in routine medical care Direct contact Organisms are transferred from one
Over-the-counter availability and infected person to another without
indiscriminate use of antibiotics a contaminated intermediate, e.g.
Lack of infection surveillance systems body fluid of patient directly enters
Lack of microbiological laboratory facilities for healthcare worker’s body through
reliable identification of infecting mucous membrane or cut in skin
pathogens and antimicrobial susceptibility
Indirect contact Transfer of organism through a
Healthcare Lack of infection control training contaminated intermediate object
staff factors Poor compliance with standard infection or person. Important intermediates
control practices, especially hand washing include hands of healthcare workers,
Carriage of organisms (hands, clothing, linen) patient care devices and
Understaffing instruments, and clothing
Inadequate sterilization and disinfection of
equipment Droplet transmission Respiratory droplets (>5 µm) carry
Use of devices (ventilators, central lines, organisms directly from the
urinary catheters) without aseptic respiratory tract of the patient, over
precautions short distances (usually ≤3 feet),
necessitating facial protection such
Facility-related Inadequate vector control (pests, rodents, as with masks: e.g. Bordetella
factors arthropods) pertussis, Mycoplasma pneumoniae,
Overcrowding respiratory syncytial virus and
Lack of ventilation, climate control and influenza virus
effective isolation areas
Lack of sinks and running water, soap, alcohol Airborne Transmission of droplet nuclei
rubs, gloves, and other supplies transmission (≤5 µm) or small particles containing
Reservoirs of community infections in infectious agents that remain
hospitals infective over time and distance,
Re-use of single-use invasive devices (syringes, e.g., Mycobacterium tuberculosis,
catheters, tubings) because of supply measles virus, varicella-zoster virus.
shortages These necessitate use of special air
Inadequate facilities for sterilization and handling and ventilation systems
disinfection
Host factors Severity of underlying disease
Length of hospital stay
High burden of infectious diseases in the
patient population essential drug policies provide greater access to essential drugs for
vulnerable populations with less indiscriminate prescription of anti-
Pathogen High prevalence of multidrug-resistant microbials and injections [6].
factors organisms
Access to reliable microbiologic data with information on etiology
and antimicrobial susceptibility patterns of pathogens is also essen-
tial. Microbiology facilities are usually inadequate in resource-poor
settings, contributing to high rates of empiric antimicrobial use,
Acinetobacter spp., is also substantially higher in developing coun- impeding surveillance, epidemiologic study of resistance patterns,
tries. Factors that predispose to infections with resistant organisms and infection control.
are poor hospital hygiene, high, and often irrational broad-spectrum
antimicrobial use, overcrowding, lack of resources for infection DEVICE-ASSOCIATED INFECTIONS
control, unavailability of reliable microbiologic culture and antimi-
crobial susceptibility results, and a lack of personnel trained in con- Device-associated infections (DAIs) include central-line-associated
trolling infections. bloodstream infections, catheter-associated urinary tract infections,
and ventilator-associated pneumonia. The use of invasive devices in
Control of antibiotic resistance requires strict adherence to infection hospitals in developing countries has rapidly increased without equal
control measures and restricted use of antibiotics. Hospitals can attention given to instituting infection control, resulting in rates of
rationalize antibiotic use through antibiotic stewardship programs. device-associated infections that are much higher than in industrial-
However, antibiotic policies only have limited impact in countries ized countries. Surveillance by the International Nosocomial Infec-
where antimicrobials such as third-generation cephalosporin and tion Control Consortium (INICC) in 98 ICUs in resource-poor
fluoroquinolones are freely available over-the-counter and are widely settings in Latin America, Asia, Africa and Europe, using Centers for
and inappropriately used [5]. Misuse of antibiotics (inappropriate Disease Control and Prevention (CDC) definitions for HAIs, showed
prescription, suboptimal dosing and duration) as well as low-potency that among 43,114 patients over an aggregate of 272,279 days from
formulations are widespread and a major factor associated with the 2002 through 2007, the pooled mean rates of DAIs were much higher
emergence of resistant organisms. Although antibiotic stewardship compared to industrialized countries [7]. Catheter-associated blood-
programs can reduce and rationalize use of antibiotics, such programs stream infection rates were 8.9 per 1000 central line (CL)-days com-
are seldom implemented in developing countries. A review of anti- pared to 2.4 per 1000 CL-days in comparable medical-surgical ICUs
microbial use has shown that countries that adhere to WHO’s in the US, ventilator-associated pneumonia was 19.8 versus 3.6
170 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
per 1000 ventilator-days, and catheter-associated urinary tract infec- with inadequate vector control procedures serve as amplifiers of
tions rates were 6.6 versus 3.4 per 1000 catheter-days. Implementation vector-borne illnesses because of the presence of infected patients in
of guidelines designed by the consortium for decreasing rates of infec- an overcrowded environment. Rodents such as mice and rats have
tions from ventilators, catheters and central lines by using positive been implicated in spread of infectious diseases. Attention to waste
feedback programs for hand hygiene and central line, ventilator and disposal, screened doors and windows, and traps are of use in vector
urinary catheter care [8]. control. New and more cost-effective LED insect traps have been
shown to be effective in tropical climates, with minimal trap
failures.
SURGICAL SITE INFECTIONS
Surgical procedures are associated with higher postoperative wound
infection rates in developing countries due to inadequate attention to TUBERCULOSIS
aseptic precautions. While most data are anecdotal, surgical wound Individuals co-infected with HIV and TB have rapidly progressive
infections are reported to be as high as 12.5% in Vietnam and 19.6% disease, and those with pulmonary disease are highly infectious, via
in Kenya. A surgical checklist developed by WHO has reduced surgical aerosolized droplets, posing great challenges for infection control in
mortality and morbidity by encouraging use of simple measures by resource-limited settings.
surgery, anesthesia and nursing staff. Ensuring delivery of antibiotic
Healthcare workers, including laboratory workers, are at risk of
prophylaxis in the operating room using verbal confirmation alone
acquiring TB. US CDC guidelines recommend rapid diagnosis and
improved antibiotic prophylaxis compliance from 56% to 83%.
treatment, isolation in negative pressure rooms and special masks to
Chlorhexidine-alcohol is the antiseptic of choice for preoperative sur-
prevent nosocomial transmission, which are rarely feasible in
gical site skin cleansing, and is superior to povidone-iodine in pre-
resource-poor settings. However, simple measures such as early diag-
venting postoperative wound infections [9]. Evidence also suggests
nosis and treatment of patients with short-course chemotherapy, out-
that chlorhexidine-gluconate-based scrubs are more effective than
patient evaluation of suspected TB patients, a separate TB ward with
povidone-iodine-based aqueous scrubs in reducing bacterial contami-
adequate ventilation using exhaust fans and large open windows
nation on staff hands prior to operative procedures. A recent study
allowing UV rays from sunlight, early collection of samples, disinfect-
showed that S. aureus-associated postoperative wound infections can
ing sputum containers and treating the sputum with household
be decreased by treating nasal carriers of S. aureus with preoperative
bleach can be applied in resource-poor settings [14]. WHO has
mupirocin nasal-ointment and chlorhexidine soap. However, applica-
published guidelines to control transmission of TB in healthcare
tion in developing countries may be limited by the need to identify
settings [15]. However, there is little evidence regarding efficacy and
S. aureus carriers using rapid DNA detection methods such as real-
cost-effectiveness.
time PCR.
BOX 21.1 Basic Infection Control Measures TABLE 21-3 Components of Standard Infection
for Health Facilities Control Precautions
positive feedback programs and appropriate attention to device care, strong institutional commitment exists. Despite the enormity of the
have resulted in substantially lowering infection rates in ICUs challenge, studies reviewing cost-effectiveness of infection control
in developing countries. Efforts to increase motivation and awareness measures are universally optimistic. Even minimally effective hospital
of staff are crucial since lapses in hygiene practices are frequent infection control programs are cost-effective, lowering the costs
unless continuously reinforced. Alcohol-based hand rubs are useful incurred from HAIs due to longer hospital stays, greater disease mor-
where access to running water is limited. They have better acceptabil- bidity and mortality, and antimicrobial agents. Measures of the effec-
ity, less skin irritation compared to soap and water, and quicker tiveness of infection control can be used as an indicator of the quality
application, resulting in improved compliance. Commercially pre- of hospital care [22,23]. Any intervention program should comprise
pared products are available, but an effective low-cost gel can be a holistic approach that includes basic infection control measures.
prepared by hospital pharmacies using 20 mL of glycerin, propylene WHO and CDC have issued guidelines to control spread of infections.
glycol or sorbitol, mixed with 980 mL of >70% isopropanol. Gels However, the most effective solutions will be those that are indige-
combining chlorhexidine and alcohol may be more effective than nously developed and implemented, and improved through active
alcohol alone because of chlorhexidine’s prolonged bactericidal learning cycles and feedback. Local research will be necessary to iden-
effect, but are expensive for routine hand hygiene. Their use is best tify critical points in infection transmission and solutions to address
limited to situations when a high degree of hand antisepsis is neces- these.
sary, such as before surgical procedures and placement of invasive
devices.
For optimal effectiveness, alcohol-based hand rubs should be com-
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the reservoir of asymptomatic, colonized patients. Active surveillance, through close person-to-person contact. Lancet 1984;2:82–4.
on the other hand, involves screening asymptomatic patients for 12. Nyarango RM, Aloo PA, Kabiru EW, Nyanchongi BO. The risk of pathogenic
resistant organisms and can be more effective in rapidly isolating intestinal parasite infections in Kisii Municipality, Kenya. BMC Public Health
colonized patients. However, cost considerations are major limiting 2008;8:237.
factors. Which patient populations should be targeted for screening, 13. Schierhorn C. Bug out! Using an integrated management approach to pest
what the optimal method of screening is, and under what circum- problems. Health Facil Manage 2002;15:40–2, 44.
stances is screening most effective remain unresolved. Hospitals 14. Harries AD, Maher D, Nunn P. Practical and affordable measures for the
should assess what can be done well in their setting and implement protection of health care workers from tuberculosis in low-income countries.
what is feasible. To overcome surveillance shortcomings, WHO has Bull World Health Organ 1997;75:477–89.
developed a low-cost computer-based antimicrobial resistance sur- 15. WHO. Guidelines for the prevention of tuberculosis in health care facilities
veillance program (WHONET), which has been used successfully to in resource-limited settings. http://www.who.int/entity/tb/publications/who_
monitor trends and generate locally applicable guidelines on antimi- tb_99_269/en/index.html
crobial use [21]. An additional impediment to surveillance of resistant 16. Centers for Disease Control and Prevention and World Health Organization.
organisms is the lack of reliable antimicrobial culture and susceptibil- Infection Control for Viral Haemorrhagic Fevers in the African Health Care
Setting. Atlanta, GA: Centers for Disease Control and Prevention; 1998:
ity data. Standardization and quality assurance of clinical microbiol-
1e198.
ogy laboratories is not enforced in most developing countries and
17. Siegel JD, Rhinehart E, Jackson M, et al. Healthcare Infection Control Practices
therefore assessing the true burden of antimicrobial resistance is
Advisory Committee 2007 Guideline for Isolation Precautions: Preventing
challenging. Transmission of Infectious Agents in Healthcare Settings, June 2007. http://
www.cdc.gov/ncidod/dhqp/gl_isolation.html (accessed 4 November 2009).
STRENGTHENING HEALTH SYSTEMS 18. Boyce JM, Pittet D. Guideline for Hand Hygiene in Health-Care Settings.
IN THE TROPICS Recommendations of the Healthcare Infection Control Practices Advisory
Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force.
One of the major limitations that hospitals face is the lack of resources Society for Healthcare Epidemiology of America/Association for Professionals
directed towards infection control. However, while many problems in Infection Control/Infectious Diseases Society of America. MMWR Recomm
are attributed to this, there are means to achieve infection control if Rep 2002;51:1–45.
I n fe c t i o n Co nt ro l i n the Tropics 173
19. Muto CA, Jernigan JA, Ostrowsky BE, et al. SHEA guideline for preventing 21. Stelling JM, O’Brien TF. Surveillance of antimicrobial resistance: the WHONET
nosocomial transmission of multidrug-resistant strains of Staphylococcus program. Clin Infect Dis 1997;24 Suppl 1:S157–68.
aureus and enterococcus. Infect Control Hosp Epidemiol 2003;24:362–86. 22. Damani N. Simple measures save lives: an approach to infection control in
20. Webster J, Pritchard MA. Gowning by attendants and visitors in newborn countries with limited resources. J Hosp Infect 2007;65 Suppl 2:151–4.
nurseries for prevention of neonatal morbidity and mortality. Cochrane Data- 23. Travis P, Bennett S, Haines A, et al. Overcoming health-systems constraints to
base Syst Rev 2003;(3):CD003670. achieve the Millennium Development Goals. Lancet 2004;364:900–6.
D
SECTION
TOPIC-BASED CHAPTERS
23 Cancer in the Tropics
Katie Wakeham, Robert Newton, Freddy Sitas
80+ Male
75-79 Female
70-74
65-69
60-64
55-59
Age Ranges
50-54
45-49
40-44
35-39
30-34
25-29
20-24
15-19
10-14
5-9
0-4
50000 40000 30000 20000 10000 0 10000 20000 30000 40000 50000 60000
Population 1000's
80+ Male
75-79 Female
70-74
65-69
60-64
55-59
Age Ranges
50-54
45-49
40-44
35-39
30-34
25-29
20-24
15-19
10-14
5-9
0-4
340000
320000
300000
280000
260000
240000
220000
200000
180000
160000
140000
120000
100000
80000
60000
40000
20000
0
20000
40000
60000
80000
100000
120000
140000
160000
180000
200000
220000
240000
260000
280000
300000
320000
Population 1000's
FIGURE 23.1 Age structure of developing (bottom) and developed (top) country populations.
importance of tobacco control programs. For example, in some Asian account for up to 80% of cancers of the anus and approximately one-
countries, lung cancer mortality rates have more than doubled in the third of cancers of the penis, vagina and vulva. HPV infection may
last 30 years. Indeed, it has been estimated that if smoking rates could also cause some cancers of the head and neck (particularly cancers of
be halved, between 20 and 30 million premature deaths from all the oral cavity) [6]. In developed countries, cervical cancer screening
causes would be avoided by 2025 and about 150 million deaths by programs that rely on the detection, by exfoliative cervical cytology,
2050 [4]. Efforts to reduce tobacco consumption are therefore central of treatable precancerous lesions, are established and are effective at
to preventing deaths from cancer and other diseases. reducing both the incidence and mortality of invasive cervical cancer.
However, in many developing countries, screening procedures do not
yet exist and incidence and mortality rates are still very high. Vaccina-
INFECTIONS tion against the main HPV subtypes at an early age holds the most
Collectively, infectious agents are the most important established promise to substantially reduce the incidence of this cancer, although
cause of cancer after tobacco. Approximately 18% of cancers world- the cost remains prohibitively high. However, cheaper HPV DNA
wide (about 1.6 million cases per year) are attributable to viral (13%), screening technology has emerged and this is proving to be much
bacterial (5%), and helminth (0.1%) infections, the majority of more cost-effective than vaccination at current costs [7].
which occur in the developing world [4]. In theory, if these infectious
diseases were controlled, up to one in four cancers in developing Chronic infection with the hepatitis B virus is responsible for causing
countries, and one in ten cancers in developed countries, could be more than 300,000 liver cancers (specifically hepatocellular carci-
prevented. noma) each year, which corresponds to about 60% of all primary liver
cancers across the world [6]. Approximately 10% of the population
More cancer cases are attributable to human papillomavirus (HPV) in parts of sub-Saharan Africa, China, and Southeast Asia are infected
infection than to any other transmissible agent. It is well established with the hepatitis B virus. Transmission can occur from a mother to
that certain HPVs are the major causative agent for invasive cervical her child, from person to person during childhood, and via sexual or
cancer. The most common HPV subtypes identified in tumors are parenteral transmission during adulthood. About two-thirds of these
HPV16, 18, 31, 33 and 45, although in some Asian countries the people will develop chronic hepatitis, and a quarter of these will
subtypes HPV52 and 58 are more common. The same subtypes also eventually die from primary liver cancer or cirrhosis, making liver
188 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
cancer one of the most common cancers in these areas. Prospects for About half of the world’s population is chronically infected with the
the prevention of hepatitis B virus-associated liver cancer are good. In bacterium Helicobacter pylori. This bacterium colonizes the stomach
developed countries, screening of blood and organ donors has lining, and, although many people remain asymptomatic, some go
reduced the spread of infection among adults. In areas where infec- on to develop gastric or duodenal ulcers. In a very small proportion
tion is most prevalent, however, the best hope for prevention lies with of infected individuals, gastric adenocarcinoma and, to a lesser extent,
mass vaccination against the hepatitis B virus. Although it will be gastric non-Hodgkin lymphoma may develop [6]. Although it is clear
many years before an effect on the incidence of liver cancer is dem- that H. pylori infection plays a role in the development of stomach
onstrated in adults, the introduction of mass vaccination in Taiwan cancer, other factors, such as diet, are also involved. The prevalence
has already been associated with a sharp decline in the incidence of of infection is highest in developing countries and increases rapidly
liver cancer in children and young adults [4]. during the first two decades of life, such that 80–90% of the popula-
tion may be infected by early adulthood; in most developed countries,
The unrelated hepatitis C virus is also involved in the etiology of the prevalence of infection is now substantially lower. Rates of infec-
hepatocellular carcinoma and may cause about 25% of all liver tion with H. pylori have fallen over the last few decades, and this could
cancers, with particularly high proportions in Africa (41%), Japan explain much of the parallel decline in stomach cancer rates seen in
(36%) and Oceania (33%). The prevalence of hepatitis C virus infec- most countries. This may be due to improvements in living condi-
tion is estimated to be about 1–1.5% in Europe and North America, tions and trends towards a smaller family size, both of which are risk
about 3% in Japan and Oceania (excluding Australia and New factors for H. pylori infection. Although antibiotics are effective in
Zealand), and up to 3.6% in Africa. Transmission is commonly via eradicating H. pylori in about 80% of cases, this has proved to be dif-
the parenteral route, although sexual and perinatal transmission can ficult to implement on a large scale and re-infection is common.
also occur. However, almost half of all hepatitis C-infected individuals
have no identifiable risk factors [8]. Although a vaccine is not cur- Infestation with the water-borne trematode Schistosoma haematobium,
rently available, screening programs have greatly reduced transmis- which causes schistosomiasis (bilharzia), is associated with an
sion of hepatitis C via blood transfusions. increased risk of squamous cell carcinoma of the bladder, and is the
predominant cause of this cancer in tropical and subtropical areas.
Infection with the Epstein-Barr virus (EBV) is involved in the etiology Schistosomiasis affects approximately 200 million people worldwide
of several types of lymphoma (including Burkitt’s lymphoma, and is endemic in Northern Africa and the Middle East; in these areas,
Hodgkin disease, and immunosuppression-related lymphomas) and over half of the population is at risk of infection from contaminated
nasopharyngeal carcinoma, and may contribute up to 100,000 cancers water supplies (lakes, rivers, swamps) that contain the larvae. There is
per year worldwide [6]. Indeed, Burkitt lymphoma (associated with also some evidence that S. japonicum and, to a lesser extent, S. mansoni
both EBV and malaria) is the commonest childhood cancer in many are related to the development of cancers of the liver and colorectum
tropical areas. EBV infects more than 90% of the world’s population in China. Although treatable, preventative measures focusing on
and is usually acquired during childhood. It is transmitted orally in reducing contact with contaminated water supplies are currently the
saliva and establishes a latent infection with lifelong persistence in best method of reducing infection. Food-borne trematodes (liver
the infected host. The overgrowth of virally transformed B cells is flukes), such as Opisthorchis viverrini, Opisthorchis felineus and Clonor-
controlled by specific cytotoxic T-cell responses, the absence of which chis sinensis, are an established cause of cancer of the bile ducts
(in HIV-infected people for example) can result in lymphoma. (cholangiocarcinoma) in parts of Southeast Asia, due to consumption
of raw or undercooked freshwater fish that contain the infective stage
Kaposi’s sarcoma-associated herpesvirus (KSHV) is related to the of the fluke. Control of infection has been achieved in some areas by
Epstein-Barr virus and is the principal cause of Kaposi’s sarcoma [6]. a combination of chemotherapy, health education, and improved
It also causes a rare type of lymphoma (primary effusion lymphoma) sanitation. However, eradication programs have, as yet, had little
and a lymphoproliferative B-cell disorder (Castleman’s disease). effect on the incidence of cholangiocarcinoma in these areas and a
KSHV is most prevalent in populations at highest risk of developing vaccine is not yet available.
Kaposi sarcoma, such as homosexual men infected with HIV in
Western countries and in African populations where the tumor has
long been endemic. OTHER FACTORS
Hormonal and reproductive factors play an important role in the
Human T-cell leukemia virus type 1 (HTLV-1) is a causal agent of etiology of a number of cancers in women, especially breast cancer.
adult T-cell leukemia/lymphoma. It is estimated that there are about Established risk factors include early age at menarche, older age at first
15–20 million individuals infected with HTLV-1 worldwide, predomi- birth, low parity, and late age at menopause. The combination of
nantly in Japan, the Caribbean, South America, and Central Africa. these factors may explain much of the geographic variation in the
Adult T-cell leukemia/lymphoma develops in about 2–5% of HTLV- incidence of breast cancer. Many of these reproductive factors suggest
1-infected individuals and is especially frequent among those infected that cumulative exposure to estrogens during a woman’s lifetime
early in life. Perinatal transmission has been greatly reduced in Japan increases the risk of breast cancer. It is now known that high circulat-
by avoidance of prolonged breastfeeding (i.e. more than 6 months), ing levels of estrogens are directly associated with breast cancer risk,
although this is not an option for many developing countries, where at least in postmenopausal women [10]. Further evidence for a role
the risk of death from diarrheal disease rises markedly if breastfeeding of hormones comes from consistent observations that current users
is curtailed. Several countries have introduced universal screening of of exogenous hormones, either in the form of oral and injectable
blood donors [6,8]. contraceptives or hormone replacement therapy (HRT), have a 25–
35% higher risk of developing breast cancer than never-users [10].
There is little evidence that the human immunodeficiency virus (HIV)
However, this risk appears to be transient and has largely disappeared
has a direct oncogenic effect. Instead, its immunosuppressive effect
after 10 years since stopping. Reproductive factors are also strongly
appears to facilitate the development of Kaposi sarcoma, non-
related to ovarian cancer and, as for endometrial cancer, the most
Hodgkin and Hodgkin lymphoma, and cancers of the cervix, anus
established protective factors are parity and use of hormonal contra-
and conjunctiva [6]. In areas of sub-Saharan Africa where HIV infec-
ceptives. In general, a first-term pregnancy is associated with about a
tion is highly prevalent, the incidence of Kaposi sarcoma has increased
40% reduction in risk, with a smaller reduction in risk with each term
about 20-fold with the spread of HIV, such that in Uganda and Zim-
pregnancy thereafter.
babwe it is now the most common cancer in males and among the
most common in females. There is evidence of a reduction in the Several dietary factors, such as fat and meat, have been suggested to
increase in risk of both Kaposi’s sarcoma and non-Hodgkin lym- increase cancer risk, while other factors, such as fruit, vegetables and
phoma among those on antiretroviral therapy for HIV [9]. However, fibre, have been hypothesized to decrease risk. However, despite
in the developing world, the incidence of HIV-associated cancers is extensive research over the last two decades, few specific dietary deter-
increasing as the epidemic spreads. minants of cancer risk have been established, even for cancers such
Ca n ce r i n the Tropics 189
as colorectal cancer where dietary factors are the most obvious can- benign to aggressive]) and patient comorbidities or performance
didate risk factors. This is due to various reasons, the most important status.
being the difficulty in accurately measuring dietary intake in epide-
Cure or long-term survival from cancer is largely dependent on cancer
miologic studies. Other problems with epidemiologic studies of diet
stage. All treatment modalities work best on small localized tumors
and cancer include the relatively narrow range of dietary exposures
with nonaggressive histologic features. In low-income settings, pres-
within one population, and the changes in dietary patterns over time,
entation with cancer (like other illnesses) is very often late with wide-
so that it is very difficult to determine whether dietary habits at a
spread neoplastic disease and a high burden of symptoms. Factors
young age may affect cancer risk later in life. A high intake of alcoholic
impacting on access to medical care are multifactorial, involving
beverages increases the risk of cancers of the upper respiratory and
patient awareness of cancer and symptoms, fear of stigmatization,
digestive tracts (oral cavity, tongue, pharynx, larynx, esophagus).
preference for traditional healers [13], cultural barriers that cancer is
These cancers are also caused by smoking, and the increase in risk is
induced by supernatural forces and /or incurable [14], health worker
particularly great for people who both smoke and drink heavily [5].
knowledge, health infrastructure, and cost to patients. Once accessed,
Heavy and prolonged alcohol consumption is also associated with
the availability of diagnostic and treatment modalities is often limited,
liver cancer via the development of cirrhosis and alcoholic hepatitis.
resulting in generally poor survival in these settings. Adherence to
Cancers of the upper gastrointestinal tract are particularly associated
treatment regimens is often low [15]. For countries already over-
with excessive alcohol consumption, although a moderate intake of
stretched and grappling with infectious disease including HIV, TB and
10 g of alcohol per day (approximately one drink) has been shown
malaria, cancer is not a priority for healthcare. Cancer survival in
to increase the risk of breast cancer by around 7%.
resource-poor settings is currently very poor, particularly in sub-
Aflatoxins are mycotoxins produced by many species of the fungus Saharan Africa [16,17], and is directly associated with per capita
Aspergillus and are among the most carcinogenic substances known. annual government healthcare expenditure and number of physicians
The fungi live in soil, particularly in warm and damp conditions, such [16]. Government expenditure on health in 2006 (US$), was $8 for
as in the tropics, and are a common contaminant of cereals, oilseeds, low-income countries compared to $3076 in the USA, with only four
nuts and spices. The toxin can also be found in milk from humans physicians per 10,000 population in low-income countries compared
and livestock if the food supply is contaminated [11]. Consequences to 27 per 10,000 in high-income countries [18].
of exposure can include growth retardation and hepatic necrosis
Surgery is an essential part of treatment for solid neoplastic disease
leading to cirrhosis and carcinoma of the liver. Concurrent infection
and the modality most likely to cure. Again, the probability of cure
with hepatitis B virus increases the risk of cancer further, since it
is increased when the cancer is small and localized, but surgery also
interferes with the metabolism of aflatoxins.
plays a role in the management of metastasis and in palliation, for
Overweight and obesity are usually measured in terms of an indi- example of bowel obstruction, fistulas and gastrointestinal bleeds.
vidual’s body mass index (BMI) (weight in kilograms divided by There is a paucity of data from resource-poor settings on surgical
height in meters squared), where a BMI of greater than 25 kg/m2 is oncology provision, but unmet surgical need it likely to be very high
considered overweight and a BMI of greater than 30 kg/m2 is consid- [19].
ered obese. Overweight and obesity increase the risk of colon cancer
Cancer chemotherapies kill cancer cells by preventing cell division,
by about a third and increase the risk of breast cancer in postmeno-
disrupting DNA or RNA or nucleic acids. It is effective against systemic
pausal (but not premenopausal) women by about a half. Over-
disease and can be used with both palliative and curative intent before
weight and obesity are associated with an approximate threefold
and after surgery and/or radiotherapy. Other forms of drug treatments
increased risk of endometrial cancer in both pre- and postmenopau-
include hormones (for example, the anti-estrogen tamoxifen for estro-
sal women, and may account for up to 40% of endometrial cancer
gen receptor-positive breast cancer, and LHRH antagonists for pros-
worldwide. Overweight and obesity also increase the risk of cancers
tate cancer) and immunotherapy (for example, interferon-alpha, used
of the kidney and gallbladder and of adenocarcinoma (but not
for some hematologic malignancies, and monoclonal antibodies,
squamous cell carcinoma) of the esophagus. It has been estimated
including trastuzumab and rituximab). Drugs with different mecha-
that overweight and obesity account for about 5% of all cancers in
nisms of action are often given in combination to increase efficacy.
Europe, most of which are cancers of the colon, endometrium and
In resource-limited settings, low availability of cancer drugs – together
breast. Thus, up to 36,000 cases of cancer could be prevented each
with the drugs required to control side effects, including antiemetics
year if the prevalence of overweight and obesity in Europe was
and antibiotics is problematic. Cytotoxic agents, tamoxifen and ster-
halved [12]. In countries such as the US, where the prevalence of
oids are listed in the WHO essential medicines complementary list,
obesity is higher than in Europe, an even higher proportion of
which presents essential medicines for priority diseases which need
cancers may be attributable to being overweight. Furthermore, the
specialist care and/or high costs [20]. Chemotherapies ideally require
prevalence of obesity is increasing in both developed and develop-
specialist pharmacy rooms for preparation, a high degree of sterility,
ing countries, and is therefore expected to lead to a greater burden
dedicated and highly trained staff and high levels of support to
of cancers in the future.
manage iatrogenic toxicities.
Radiotherapy is a common component of cancer treatment for cure
MANAGEMENT OF CANCER or palliation and can be used alone or as an adjuvant to surgery to
destroy cancer cells remaining in the tumor bed or with chemother-
Cancer management requires multidisciplinary services and is often
apy. Radiation acts by damaging cellular DNA by forming free radi-
a complex and expensive process. In Western countries, the pathway
cals. Cancer cells have less ability to repair DNA damage than healthy
starts with access to cancer services, often through screening or a
cells and lose reproductive capacity or die by apoptosis. Radiotherapy
primary care physician. Decisions surrounding the most appropriate
can be broadly divided into external beam or local, where the radia-
treatment for an individual with cancer require: 1) an accurate patho-
tion source is placed in the body, within or close to the cancer. Exter-
logic diagnosis which may involve sophisticated immunohistologic
nal beam megavoltage radiation can be derived from a radioactive
and genetic profiling; 2) imaging, for stage, planning treatment, and
source such as cobalt-60 or by accelerating electrons at high energy
monitoring; 3) biochemical markers, for example prostate-specific
to produce photons (linear accelerator). Resource-limited settings are
antigen (PSA), for monitoring, diagnosis, prognosis, response and
more likely to use a radioactive source over a linear accelerator as it
relapse; and 4) laboratory work-up including hematology and renal
is comparatively cheaper, robust, requires only limited electricity and
and liver function tests. There are four general modalities of treatment
is much easier to maintain. Safe provision requires specifically
for cancer: 1) surgery; 2) drugs, including hormones and chemothera-
designed buildings, monitoring, and an extensive team of trained
pies; 3) radiotherapy; and 4) symptom control or palliative care.
medical, engineering and scientific staff.
Outcome for treatment of malignant disease, in general, depends on
the clinical and pathologic stage (tumor, size, nodal involvement, Programme of Action for Cancer Therapy (PACT) is part of the
metastasis [local or distant], histologic features [spectrum from International Atomic Energy Authority (IAEA). It was established
190 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
in 2004 to support and monitor radiotherapy in developing formulations are easy to administer, and it appears on the WHO
countries. A survey of Africa in 2002 reported that the provision three-step analgesic ladder and list of essential medicines. But few of
of megavoltage radiotherapy machines was only 18% of the those in need in a resource-limited setting have access to it or indeed
estimated need [21] (Fig. 23.2). Most low-income countries have less to any opioid. Barriers to opioid access include: 1) cost, 2) lack of
than one machine per million population and many have no machine trained medical workforce to administer, 3) international regulations
at all. on manufacture and distribution of opioids, and 4) health worker
and public attitude and knowledge due to concerns over addiction
The WHO state that “inadequate management of pain due to cancer (Fig. 23.3). Advocacy groups, including Hospice Africa, have made
is a serious public health problem in the world” [22]. Opioid anal- great progress in improving access to symptom control by lobbying
gesics are essential for pain relief. Morphine is highly effective for governments, training, increasing awareness and developing feasible
moderate and severe cancer pain. It is relatively cheap, the oral models of care for resource-limited settings.
Ca n ce r i n the Tropics 191
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24 Heat-associated Illness
Michael V Callahan
TABLE 24-1 Clinical Spectrum of Heat Illness TABLE 24-2 Physical Heat Loss
for invasive monitoring by covering the probe with a prophylactic Heat exhaustion is an imprecise clinical syndrome characterized by
condom or glove and inserting the lead immediately beyond the anal nonspecific findings unified under a history of heat exposure. Core
verge. Continuous core temperature monitoring offers advantages in body temperature for heat exhaustion is <40°C. Common symptoms
austere environments as monitoring will dictate triage priority and include nausea and vomiting, headache and weakness. Respiratory
can be maintained during all phases of prehospital and hospital rate may be elevated. The cardiac and pulmonary exam may be
management. Mental status and the presence of focal neurologic normal; however, tachycardia may be present from concomitant dehy-
problems should be assessed next. The cerebellum is highly sensitive dration. The presence of sweating in heat exhaustion patients is an
to heat stroke and therefore finger–nose–finger or other exam to important finding as it is frequently absent in heat stroke patients.
assess dysdiadochokinesia and cerebellar function should be per- The patient’s mental status may suggest mild confusion and com-
formed. The oral cavity should be examined for evidence of gingival plaints may include dizziness. Symptoms of heat exhaustion tend to
bleeding and the stool assessed for hemoglobin-positive results which resolve with any modest interventions that lower body temperature.
may herald early coagulopathy. Pulmonary exam should assess for
rales. Skin exam will help determine the patient’s hydration status and Heat stroke is a life-threatening condition defined by a core body
the presence of miliaria. Muscle exams should include active and temperature >40°C and mental status or neurologic symptoms that
passive flexion of shoulders, thighs and calves; the presence of local- do not respond to initial therapy (rest, cold treatment and hydration)
ized pain may indicate muscle breakdown. Urine should be collected [13]. Patients may be combative, with delirium, seizure, obtundation
by a Foley if necessary and inspected for evidence of myoglobin, or coma. Clues to differentiate early heat stroke from heat exhaustion
hemoglobin and sediment. Disposable urine analysis “dip-sticks” are include significant mental status changes, diarrhea and dry skin in
useful in the field as results guide rehydration and may aid detection heat stroke. A minority of heat stroke casualties may present with
of hemoglobinuria or myoglobinuria. In recent years, the prolifera- sweating; however, this usually stops as thermoregulation continues
tion of cartridge-based handheld blood chemistry units in field clinics to fail. Complications of heat stroke include acute renal failure from
increases the probability that basic blood chemistry may be obtained. rhabdomyolysis, liver failure, disseminated intravascular coagulation
The current-generation cartridges for these hand-held units require (DIC), acute respiratory distress syndrome (ARDS), seizure, coma and
refrigeration; if test results are inconsistent with the clinical picture, death [1]. Select differential diagnostic features of heat stroke and heat
the provider should suspect that the cartridges are outdated. If con- exhaustion are listed in Table 24-4A, below. The differential diagnosis
ventional coagulation studies are not possible, a whole-blood clotting of hyperthermia is listed in Table 24-4B.
assay can be used to assess for coagulopathy and a Weintraub sedi-
mentation tube can be used to assess for hemoconcentration. The
improvised coagulopathy and hemoconcentration tests discussed are
most accurate when conducted with “controls” provided by a healthy TABLE 24-4A Differential Diagnosis of Heat Exhaustion
bystander. Table 24-3 summarizes laboratory tests that are helpful in and Heat Stroke
assessing heat illness casualties.
Factor Heat exhaustion Heat stroke
DIAGNOSIS Patient age All ages Often young/healthy
The differential diagnosis of heat illness requires a history of heat
exposure, a detailed physical exam and bedside studies. Infectious Symptoms Nausea +/− vomiting Nausea +/− diarrhea
etiologies and rare causes of hyperthermia need to be ruled out. The Body <40C >40C
differential diagnosis should include malignant hyperthermia, neu- temperature
roleptic malignant syndrome, endocrine and hypothalamic disorders,
and fictitious hyperthermia. Heat edema and heat syncope are sug- CNS status Normal: mild Delirium, ataxia,
gested by advanced patient age, deconditioning, low cardiac reserve confusion dysarthria, seizures, coma
and recent arrival in the tropics from cooler regions. Miliaria, a dis-
tinct heat dermatosis, is differentiated from other tropical skin mala- Vital signs +/− tachypneic Tachypneic, tachycardia,
hypotensive
dies by the timing, distribution and physical appearance of skin
vesicles. Miliaria responds promptly to antihistamines or dilute Dermatologic Sweating; Little or no sweat
topical chlorhexidine. Heat cramps are a second common malady in findings +/− miliaria
unacclimatized individuals; diagnosis is suggested by resolution of
cramps with rest and cool treatment, stretching and fluids, and elec- Laboratory Normal Elevated transaminases
trolyte repletion. The two most dangerous heat illnesses – heat results (AST > ALT); DIC, urine:
exhaustion and heat stroke – have overlapping clinical features and muddy brown casts; Cr
are discussed in greater detail below. elevated; CBC: WBC
elevated
EFFECTIVENESS FIGURE 25.1 The traditional healer Thiemoko Bengaly and the plant
Argemone mexicana used in his decoction against malaria (South Mali).
Traditional medicines do not escape the plague of counterfeit prod- spiritual practices, and initial work on the development of networks
ucts. Irregularities have been detected in traditional preparations, of herbalists in the Thai–Burma border region [26, 28]. Training
including adulteration, substitution, contamination (e.g. with heavy programs were found to have contributed to stimulating several grass-
metals or fungi), misidentification and incorrect preparation [23]. roots initiatives and to the development of herbal clinics along the
border region.
Attempts are being made to control products, with identification of
constituents and assessment of product quality problems, be it inten- These examples of integrating and supporting traditional health
tional or not, and to trace back the source of inadequate products. resources within refugee interventions highlight the need for increased
Activities of drug quality control involve the International Criminal international awareness regarding existing health resources within
Police Organization (INTERPOL), the WHO, national authorities and refugee populations.
non-governmental organizations (NGOs).
Improving the control of traditional preparations may, in turn, In a Health District
increase the level of public confidence in these products. Patients typically undertake their own self-referral, with few errors.
They choose when they need to go to the modern medical system and
TRADITIONAL AND MODERN when to turn to their traditional health practices. In the modern
health center, the most frequent diagnoses (i.e. the ‘case-mix’) are
HEALTH SYSTEMS—THE NEED typically infant and childhood diarrhea, pneumonia and malaria. In
FOR COOPERATION the traditional practitioner clinic, patients present with chronic and
congenital disorders, mental problems, and functional and terminal
It is important for physicians, whether in private practice, working in diseases. These diagnoses represent a challenge for modern medicine
a hospital, a research institute or in health administration to keep a which often has little to offer in resource-poor settings. Patients can
close and lively relationship with the population that they are sup- be counselled and supported in making their choices in order to
posed to serve. Traditional medicine is one of the many community minimize mistakes.
health factors that physicians need to know about and take into
account. If a professional perspective is maintained along with a well-
informed, constructive and non-judgemental attitude towards all DEVELOPMENT OF NEW DRUGS AND
health practices, community members will acknowledge this as a sign
of respect and the outcome can be very rewarding in terms of relation-
TREATMENTS; INTELLECTUAL
ship with the population. PROPERTY RIGHTS
In the classical research process, many substances are selected through
EXAMPLES field studies (ethnobotany or ethnopharmacology), but very few are
eventually found safe and effective in human studies. The selection
In a Refugee Population process itself is questionable [29], as it is hard to find any treatment
In a number of studies among refugees, it was found that Western that has been found through this process in history. Conventional
physicians and treatments were not able to address cultural disease drug development is slow and expensive. The finished products are
constructs or traditional practices, in some cases resulting in false often unavailable and unaffordable to the poorest patients in remote
diagnoses and inappropriate, or ineffective, care [24–26]. These lapses areas, unless they are part of a heavily subsidized scheme.
in understanding and care can (and have) compromise refugee
health. Such oversight of cultural perceptions and practices has also In contrast, phytomedicines consisting of locally available products
deterred refugees from seeking timely, and often vital, Western health can, if proven safe and effective, become useful complements to
services for fear of misunderstandings or stigma attached to tradi- imported drugs if they are cheaper and more readily available. The
tional practices. development of local phytomedicines of proven safety and effective-
ness can be conducted through a relatively cheap and fast process
When working in a refugee camp, it can be helpful to seek out those called “reverse pharmacology” [30].
refugees interested in helping to set up and maintain the best possible
interim health system, given the difficult situation that this popula- Exploitation of traditional medical knowledge for drug development
tion faces. There may be physicians and nurses who can readily work without the consent of customary knowledge holders is not accept-
with the expatriate teams; there may be paramedics who will be ready able under international law {[United Nations (UN) Convention on
to help in preventive interventions; and there may be traditional Biological Diversity (CBD), [31]}. Under the CBD, state parties are
practitioners, who should be contacted for, at very the least, safety required to “respect, preserve and maintain knowledge, innovations
reasons. Because of their displacement, they may well be unfamiliar and practices of indigenous and local communities embodying tradi-
with local flora and could be at risk of providing unsafe preparations. tional lifestyles …and promote involvement of the holders of such
Meetings between displaced and local traditional healers can be knowledge and practices encourage the equitable sharing of the ben-
organized, if possible with a botanical outing, for refugees to learn to efits arising from the utilisation of such knowledge, innovations and
recognize local plants and avoid dangerous ones. practices”.
Many studies on psychosocial and primary health practices among The International Society of Ethnobiology [32] has developed a com-
refugees validate the effects of integrating traditional practices into prehensive set of ethical guidelines for researchers working on tradi-
refugee care. One of the first examples of such integration efforts was tional medicine, which can be accessed at: http://ethnobiology.net/
seen in the 1980s, when Dr J.P. Hiegel of the International Committee code-of-ethics/.
for the Red Cross (ICRC) helped Cambodian refugees in Thailand set The WHO’s Global Strategy and Plan of Action on Public Health,
up traditional medicine centers. Western clinicians and traditional Innovation and Intellectual Property [33] gives priority to research in
practitioners cooperated to build a dual treatment system with effec- this field and supports drug research and development in traditional
tive, mutual referral procedures [27]. medicine systems in developing countries (http://apps.who.int/gb/
Another leading example is seen in Cambodia, where the Harvard ebwha/pdf_files/A61/A61_R21-en.pdf).
Center for Refugee Trauma has shown that refugee trauma can be
reduced by re-introducing traditional healing systems to dislocated
communities [24]. Work with Karen refugees and internally displaced
CLINICAL SCENARIOS
persons at the Thai–Burma border has included the training of refugee The following anecdotal cases are not meant to recommend the par-
community health workers clinic staff in herbal medicine, research ticular intervention or strategy, but rather to illustrate that traditional
on refugee patients’ use of, and belief in, traditional medicine and medicine and practices are deeply established in many cultures and
Tra d i t i o n al M edicine 201
FIGURE 25.3 A traditional bone-setter in Mali taking care of a patient FIGURE 25.4 Traditional healers in the Sahara, practicing Greco-Arabic
with acute low back pain. medicine (Mauritania).
Antimalarial Methods (RITAM) (www.gifts-ritam.org); The Swiss Coop- 16. Phan TT, Hughes MA, Cherry GW, et al. An aqueous extract of the leaves of
eration and the Organisation Antenna Technologies (Geneva) for their Chromolaena odorata (formerly Eupatorium odoratum) inhibits hydrated colla-
gen lattice contraction by normal human dermal fibroblasts. J Altern and
support; Merlin Willcox, Jacques Falquet and Jean-Claude François for
Complement Med 1996;2:335–44.
their pictures; populations and authorities in the many tropical coun- 17. Phan TT, Wang L, See P, et al. Phenolic compounds of Chromolaena odorata
tries where the authors have gained experience: India, China, Vietnam, protect cultured skin cells from oxidative damage: implication for cutaneous
Thailand, Laos, Malaysia; Erytrea and Ethiopia; countries in East and wound healing. Biol Pharm Bull 2001;24:1373–9.
18. Burford G, Bodeker G, Ryan TJ. Skin disease. In: Bodeker G, Burford G, eds.
Southern Africa, particularly Kenya, Tanzania, Uganda and South Africa;
Public Health and Policy Perspectives on Traditional, Complementary and
Madagascar; Mauritania, Mali, Oman, etc. Alternative Medicine. London: Imperial College Press; 2007.
19. Courtright P, Lewallen S, Kanjaloti S. Changing patterns of corneal disease
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Environmental Health Hazards
in the Tropics 26
Ema G Rodrigues, David C Christiani
cumulative effects leading to disease, whereas the effects of short-term forest fires and dust storms). Air pollution is comprised of various
or periodic exposures may be naturally repaired. For example, expo- contaminants, including particulate matter (PM), sulfur dioxide
sure to heavy metals may induce DNA damage, but DNA repair (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3)
mechanisms may prevent the development of disease if exposures are and polycyclic aromatic hydrocarbons (PAHs), among others. Rapid
short-term. Timing of exposure is also important since individuals are industrialization in several tropical countries has led to significantly
more susceptible to the health effects of environmental exposures higher concentrations of air pollutants compared to those in devel-
during certain periods of life, such as during fetal development, child- oped countries. Increase in some air pollutants, such as NO2 and O3,
hood, and advanced age. is often due to an increase in the use of motor vehicles, coupled with
lack of environmental regulations to enforce controls [2].
MAJOR ENVIRONMENTAL AND Increased air pollution levels have been associated with cardiovascular
OCCUPATIONAL HAZARDS disease, upper and lower respiratory tract infections, and lung cancer
[3–5]. Additionally, individuals with chronic health conditions such
as asthma, emphysema and cardiovascular disorders are more suscep-
AMBIENT AIR POLLUTION tible to the health effects associated with air pollution. Particulate
Air pollution is a widespread environmental health hazard with matter, typically characterized by particle size defined by the aerody-
sources ranging from anthropogenic sources (e.g. combustion of namic diameter in microns (e.g. PM10, PM2.5, PM1.0), has been shown
fossil fuels in power plants or motor vehicles) to natural sources (e.g. to be especially harmful. While larger particles are typically trapped
in the nose and throat, smaller particles are more likely to be inhaled
into the deeper regions of the lung (i.e. alveoli), making smaller
particles more likely to contribute to pulmonary and heart disease.
TABLE 26-1 Child Labor, 5–14 Years (%), 1999–2007
Weather conditions in many tropical zones may exacerbate the level
of pollution. For instance, high temperatures in combination with
Bangladesh 13 high humidity and lack of rain lead to faster rates of the formation
of smog, a term used to describe the interaction of nitrogen oxides,
Belize 40 volatile organic compounds, and other pollutants, and there is some
evidence that ambient PM10 concentrations have a greater effect on
Brazil 6 mortality and hospitalizations due to cardiovascular and respiratory
Cambodia 45 causes during the warm periods and summer [6].
Ghana 34
INDOOR AIR POLLUTION
India 12 The health effects associated with indoor air pollution (IAP) are of
great concern in developing countries, where it has been estimated
Mexico 16
that more than 2.4 billion people use biomass fuels (BMF) such
Nicaragua 15 as wood, dung and coal for cooking and heating [7]. Figure 26.1
indicates that developing countries in tropical zones account for
Data from: The State of the World’s Children 2009, UNICEF. © 2009 the United the majority of deaths attributed to exposure to indoor smoke
Nations Children’s Fund. from burning of solid fuels. BMF smoke is also associated with
chronic obstructive pulmonary disease (COPD), tuberculosis, lung
IAP deaths/million
0–10
10–50
50–100
100–200
200–300
300–400
FIGURE 26.1 Deaths from indoor smoke from solid 400–610
fuels. Redrawn from WHO World Health Report, 2002.©
WHO 2005. All rights reserved. Data not available
E nv i ro n m e nt a l H e a l t h H a z a rd s i n the Tropics 205
ARSENIC
Arsenic (As), a naturally occurring metal embedded in the earth’s
crust, is characterized as a known human carcinogen by the Interna-
tional Agency for Research on Cancer [10]. Exposure to arsenic occurs
mainly through ingestion of contaminated water from deep wells
(30–180 feet), but can also occur through food or inhalation of
arsenic fumes from coal burning or smelting. Arsenic is leached into
drinking water supplies from the bedrock surrounding the aquifers,
and elevated arsenic levels in drinking water have been documented
in several tropical countries such as India, Chile, Mexico, Bangladesh,
A
Peru, Taiwan, Mongolia and Thailand, as well as in parts of the US.
While inorganic arsenic occurs in several forms, the trivalent (AsIII)
and pentavalent (AsV) species are most toxic, whereas organic forms
such as arsenobetaine occur in shellfish such as shrimp and are not
toxic to humans.
In an effort to provide clean water free of microbial contamination,
the United Nations Children’s Fund (UNICEF) began to install tube
wells in Bangladesh in the 1970s. While this effort was aimed at
reducing the morbidity and mortality due to gastrointestinal disease,
it also caused one of the largest arsenic poisonings in history. It has
been estimated that more that 35–77 million people may be exposed
to arsenic-contaminated drinking water across Bangladesh [11]. Also,
large numbers of people in nearby West Bengal in India have been
similarly affected. The clinical manifestations of chronic arsenic expo-
sure are numerous, and include hyperpigmentation, keratoses, and
skin, bladder and lung cancers (Fig. 26.2) [12–14]. There is no ideal
treatment for chronic arsenic-related health effects, but affected indi-
viduals are usually told to avoid drinking additional arsenic-
contaminated water and to consume a protein-rich diet. Additionally,
higher selenium blood levels may reduce the risk of arsenic-related
skin lesions [15]. In severe cases of arsenic poisoning, chelation with B
2,3-dimercapto-1-propanesulfonate (DMPS) can increase the urinary
excretion of arsenic and improve symptoms. Additionally, for arsenic- FIGURE 26.2 Hyperkeratotic rash of arsenic intoxication. Photos courtesy
related cancers, surgical methods can be used to remove the cancer if of Dr Molly Kile, Harvard School of Public Health
it is detected early [16].
LEAD POISONING
Lead is a durable, malleable metal that is highly resistant to corrosion BOX 26.1 Pediatric Considerations – Lead
and is used worldwide for many applications. It has been used for the
manufacture of water pipes, as an anti-knock agent in gasoline, as an l Children absorb lead more efficiently than adults
anti-corrosive pigment in paint, additive in cosmetics, and in tradi- l Children who are malnourished are particularly susceptible
tional medicines. Among the many uses, leaded gasoline is one of the to lead due to lower intakes of iron and calcium which can
major sources of airborne lead pollution and personal exposure. The
reduce the absorption of lead
phase-out of lead from gasoline has significantly reduced the air lead
l Blood lead levels ≥10 µg/dL among children are considered
concentrations and blood lead levels in humans in many countries,
including Austria, Brazil, Canada, Colombia, India [17], Japan, Paki- elevated, but no level is considered safe
stan [18], Slovakia, Sweden, Thailand and the US. Another source of
lead, especially in developing countries, is lead glazes used in ceram-
ics. When ceramic pottery is used for cooking or storing food, the lead
contained in the glaze may leach into food [19]. Another source of
stored in bone and soft tissues until remobilized into the blood-
lead exposure and poisonings in developing countries is the recycling
stream. Because lead has a relatively long half-life for excretion (T1/2
of electronics containing lead and lead-acid batteries [20]. While lead
~28 days), health effects associated with lead are chronic and long-
exposures are very high in these workplaces, children and adults can
lasting. Health effects related to increased blood lead levels in chil-
also be exposed to dangerous levels of lead in air or soil while living
dren include encephalopathy, and decreases in IQ, hemoglobin
near one of these facilities or living with an individual working with
synthesis, growth, nerve conduction velocity and cognitive function
lead [21]. Cosmetics and traditional remedies containing lead are also
(Box 26.1). Abdominal symptoms (called “lead colic”) include
commonly used in tropical countries.
abdominal pain, intermittent vomiting and constipation. High-level
Given its many uses, lead is a very common contaminant and is a exposure can lead to interstitial nephritis. Research has shown that
leading cause of environmental-related illness among both children children in India under 3 years of age with blood lead levels ≥10 µg/
and adults worldwide. Lead is mainly absorbed into the bloodstream dL are more likely to have moderate or severe anemia, but no lead
through ingestion and inhalation. Absorbed lead is redistributed and level is considered safe [22]. Health effects in adults include anemia,
206 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
TABLE 26-2 Health Effects Associated with Fibrogenic and Metal Dusts
Metals
Lead Battery recycling Anemia Fatigue
Construction/painting Reproductive effects (male and female) Nausea
Electronics Cardiovascular disease Headaches
Encephalopathy Hypertension
Nephropathy Constipation
Death Increased blood lead levels
Increased erythrocyte protoporphyrin
Manganese Manganese processing Manganism Neurological effects
Battery manufacturing Anemia Slowed hand movements
Welding Behavioral changes
Steel production Tremors
Mining Hypertension
Glass manufacturing
Fungicides
Chromium Steel production Eczema Skin rashes/dermatitis
Chrome plating Asthmatic bronchitis Ulcers
Leather industry Kidney damage
Cement
Beryllium Ceramics Beryllium sensitization Shortness of breath
Nuclear weapons Chronic beryllium disease (CBD)
Mercury Battery manufacturing Minamata disease Dermatitis
(inorganic) Mercury recycling Mood changes
Auto manufacturing Memory loss
Thermometers Muscle weakness
Lighting Tremors
Kidney effects
Respiratory failure
Slurring of speech
E nv i ro n m e nt a l H e a l t h H a z a rd s i n the Tropics 207
Continued
208 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
developed countries (e.g. arsenic oxide, DDT, parathion), but these electrolyte levels, hydration (orally or intravenously), alkalization, or
regulations are not normally extant or are not enforced in developing surgical removal of the stones [33].
countries. In fact, DDT was banned in several African countries for
several years before it was reintroduced for indoor use due to an
increase in malaria deaths. Currently, a Global Environment Facility RECOGNITION OF ENVIRONMENTAL
(GEF) initiative aims to phase-out the use of DDT by the early 2020s, AND OCCUPATIONAL HAZARDS
while assuring that malaria infection rate reductions are met.
Several methods can be used by physicians and public health profes-
sionals to identify diseases related to environmental conditions. Sen-
MOLD/FOOD IMPURITIES tinel cases or unexpected cases of disease may give clues to causative
The high heat, humidity, and long rainy seasons in tropical countries agents. For example, in 1775, Percivall Pott was one of the first sur-
make infestation of mold a likely environmental problem, especially geons to observe a high incidence of scrotal cancers in young boys
in agricultural communities. Aflatoxins, highly toxic metabolites pro- who worked as chimney sweeps. Pott suspected that this unexpected
duced by the fungi Aspergillus flavus and Aspergillus parasiticus, are high incidence of cancer was a result of dermal contact with coal soot
contaminants found in animal feed and some crops such as corn, (that is now known to contain various polycyclic aromatic hydrocar-
peanuts and cotton. Ingestion of aflatoxins can lead to liver necrosis, bons and now known to be carcinogenic), and he noted that regular
failure and cirrhosis. A recent outbreak of aflatoxin poisoning in washing prevented the disease. Continuous surveillance and the
eastern and central provinces in Kenya (2004) due to contaminated maintenance of disease registries can also be valuable in the identifi-
maize that had been stored in damp conditions lead to 317 cases of cation of an environmental or occupational health outcome. Regis-
acute poisoning and 125 deaths. Levels of aflatoxin measured in tries allow for the methodical collection of demographic and
maize from the households that were affected ranged from 20 ppb to occupational information from individuals who have developed spe-
8000 ppb, up to 400 times the WHO recommended maximum limit cific illnesses (e.g. cancer, asthma, diabetes). Additionally, targeted
[26]. Aflatoxin is also a major contributor to liver cancer [27,28] and registries can collect biological measurements on healthy people who
is classified as a Group 1 human carcinogen by the International may be at high risk for specific exposures (e.g. blood lead levels
Agency for Research on Cancer (IARC) [29]. Diagnosis usually among construction workers).
involves clinical recognition, especially of outbreaks from common Physicians play a crucial role in detecting and the critical role in treat-
ingestion, and measuring toxin or metabolites in blood or urine. ing individuals with disease relating to environmental exposure or
Treatment is usually supportive. poisoning. In many cases, the best treatment for an environmental
Ergotism (also called St. Anthony’s Fire), a disease caused by the disease is removal from exposure. Information about the patient’s
ingestion of ergot alkaloids produced by ergot, is manifested in two work environment as well as the home environment is crucial in the
forms: the gangrenous form and the convulsive form. The causative identification of disease. It is also important for physicians to consider
agent, alkaloid ergotamine, and derivatives affect vascular constriction previous jobs as well as current jobs. Some diseases have a long
and neurotransmission. The gangrenous form of ergotism is charac- latency period and may have clinical impact years after the patient
terized by symptoms including edema of the legs, severe pain, and was exposed. Thorough exposure histories may identify a causative
gangrene at the tendons, while the convulsive form is characterized agent responsible for the patient’s symptoms, and medical screening
by nausea and vomiting followed by drowsiness, twitching, uterine tests (e.g. beryllium sensitization test, pulmonary function) can be
contractions and abortion, convulsions, blindness, hallucinations used to monitor exposed patients
and paralysis. Chronic complications include cardiac valvular fibrosis.
The main source of exposure to ergot alkaloids is contaminated grains
(especially rye) that are stored in humid environments susceptible to CONTROL AND REDUCTION
contamination of fungi of the genus Claviceps. The clinical symptoms OF ENVIRONMENTAL AND
experienced by individuals who have ingested ergot alkaloids depend
on the type of alkaloids produced by the various fungi. Ergotism can OCCUPATIONAL HAZARDS
be prevented by thorough cleaning practices and by destroying the While several methods can be used to reduce the levels of personal
alkaloids by cooking and baking the flour products [30]. exposure to environmental hazards, each method differs in terms of
Farmer’s lung disease (FLD) is a type of hypersensitivity pneumonitis feasibility, expense and efficacy. The most efficient way to reduce the
resulting from an allergic reaction to inhaled microbial agents, includ- health effects associated with a hazard is to eliminate it from use or
ing mold spores. Farmers may inhale fungal microorganisms typically substitute it with a less hazardous substance. A common successful
found in hay stored in damp conditions with poor ventilation. The implementation of this is the elimination and substitution of lead in
symptoms of this disease include shortness of breath, productive gasoline in several countries. Elimination of a hazard is the most
cough, bronchospasm, fever, and malaise. The chest x-ray shows bilat- desirable option, but it may not always be feasible. It is necessary to
eral, fleeting infiltrates. Additionally, patients with FLD have been have a suitable less hazardous substitute that can be used for the
shown to have higher precipitating immunoglobulin G (IgG) levels purpose. When substitution is not an option, engineering controls,
associated with various microbes, compared with farmers without the such as ventilation, or a redesigning of equipment can be used to
disease [31]. Chronic farmer’s lung can lead to obliterating bronchi- minimize personal exposures to the hazard. While engineering con-
olitis and fibrosis. Treatment usually involves minimizing additional trols are usually effective, they can be expensive to implement and
exposure and treatment with steroids (inhaled and systemic) and maintain over time. The implementation of cooking stoves with
bronchodilators. enclosed wood-burning chambers with chimneys as opposed to open
fires is an example of a redesign that reduced personal exposure to
Melamine is another example of a toxic food impurity. Unlike mold indoor air pollution and respiratory symptoms, specifically among
contamination, food products containing melamine have been inten- women [34,35]. In the absence of feasible engineering controls, the
tionally contaminated. Foods contaminated with melamine will use of administrative controls can reduce workplace exposures (not
appear to have higher protein content because melamine is rich in necessarily environmental exposures) to individuals by rotating jobs
nitrogen, which is measured to determine protein levels. In an attempt among workers or limiting the time a worker performs a specific task,
to make some food items more marketable, a variety of products, such such as spraying pesticides. Finally, workers can use personal protec-
as infant formula and wheat flour used in pet food, originating in tive equipment (PPE), such as respirators, and protective clothing (e.g.
China have been contaminated with melamine. Tens of thousands of gloves, overalls, boots) to minimize the absorption of environmental
infants and young children in China have been hospitalized with hazards that cannot be controlled by any other means. The use of PPE
kidney stones and obstructive renal failure after the consumption may be effective, but it also poses additional challenges to workers.
of melamine-contaminated formula. Some cases resulted in death PPE requires routine cleaning and maintenance for efficacy and can
[32]. Successful treatment of cases included dialysis to correct their be very cumbersome to wear, especially in hot and humid climates.
E nv i ro n m e nt a l H e a l t h H a z a rd s i n the Tropics 211
Other common control measures include regular hand washing to 17. Nichani V, Li WI, Smith MA, et al. Blood lead levels in children after phase-out
avoid exposure through hand-to-mouth contact while eating, drink- of leaded gasoline in Bombay, India. Sci Total Environ 2006;363:95–106.
ing or smoking, and changing clothes after being exposed to dusts or 18. Kadir MM, Janjua NZ, Kristensen S, et al. Status of children’s blood lead levels
chemicals to minimize further absorption and exposure to others. in Pakistan: implications for research and policy. Public Health 2008;
122:708–15.
19. Romieu I, Palazuelos E, Hernandez Avila M, et al. Sources of lead exposure
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Human Immunodeficiency
Virus Infection 27
Philip J Peters, Barbara J Marston, Paul J Weidle, John T Brooks
INTRODUCTION poverty [5]. Globally, AIDS is the leading cause of death among
people aged 15–59 years old in low-income countries (especially sub-
As of the end of 2009, the World Health Organization (WHO) esti- Saharan Africa) [6]. Despite the remarkably rapid scientific advances
mated that 33.3 million (31.4–35.3 million) persons were living with that have been made in epidemiology, basic science and treatment,
HIV infection [1]. During 2009, an estimated 2.6 million (2.3–2.8 in 2011, the HIV pandemic continues to represent one of the world’s
million) new infections occurred worldwide. Sub-Saharan Africa has most urgent public health challenges.
been most heavily affected by the HIV pandemic and bears the great-
est burden of both prevalent (22.5 million or 68%) and new (1.8 HIV has also changed the practice of tropical medicine [7]. In
million or 69%) infections. The majority (52%) of persons living with many countries in eastern and southern Africa, 50–75% of adult
HIV worldwide are women. Since the late 1990s, the global annual medical inpatients at urban hospitals are HIV-infected [8–10]. As a
number of new infections has steadily declined (Fig. 27.1). Likewise, result of the immunosuppression caused by HIV infection, suscepti-
with the significant scale up of antiretroviral therapy (ART), AIDS- bility to, and severity of, other infectious diseases, especially oppor-
related deaths have also decreased globally by 14% since 2004, when tunistic infections (e.g. tuberculosis, cryptococcal meningitis) is
the availability of ART in the developing world dramatically expanded. increased. HIV-infected patients can exhibit atypical clinical presen-
As a result, prevalence has continued to increase (Fig. 27.2), although tations of infections (e.g. fever as the only presenting symptom of
at a slower pace during the past decade. cryptococcal meningitis) [11] and immunosuppressed HIV-infected
patients can have multiple pathologic processes occurring simulta-
The first cases of AIDS were recognized in the USA in 1981 [2]. Phylo- neously. The differential diagnoses for infectious diseases in HIV-
genetic analysis of HIV sequences suggests that HIV originated in infected persons can be broad, making empiric therapy difficult.
Central Africa and may have been transmitted to humans around Thus, rapid and accurate diagnostic testing—when available—is
1930 [3]. By 1985, human HIV infection had been identified in every important.
region of the world [4].
The HIV pandemic has also heightened our global consciousness to
In some African countries, HIV has reduced life expectancy by more health disparities, social justice and human rights, and mobilized
than 20 years, slowed economic growth and deepened household unprecedented political, financial and human resources to scale-up
4.0
3.5
Number of persons
3.0
(millions)
2.5
2.0
1.5
1.0
0.5
0.0
`90 `91 `92 `93 `94 `95 `96 `97 `98 `99 `00 `01 `02 `03 `04 `05 `06 `07 `08 `09
Year
FIGURE 27.1 Annual number of people newly infected with HIV, worldwide 1990–2009. Source: Joint United Nations Programmed on HIV/AIDS (UNAIDS). Global
report: UNAIDS report on the global AIDS epidemic 2010. Available at: http://www.unaids.org/globalreport/Global_report.htm (accessed 5 May 2011).
40
Number of persons
35
30
(millions)
25
20
15
10
5
0
`90 `91 `92 `93 `94 `95 `96 `97 `98 `99 `00 `01 `02 `03 `04 `05 `06 `07 `08 `09
Year
FIGURE 27.2 Number of people living with HIV, worldwide 1990–2009. Source: Joint United Nations Programmed on HIV/AIDS (UNAIDS). Global report: UNAIDS
report on the global AIDS epidemic 2010. Available at: http://www.unaids.org/globalreport/Global_report.htm (accessed 5 May 2011).
217
218 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
A F,G,H,J,K
B CRF01_AE
C CRF02_AG
D Other CRFs
URFs
FIGURE 27.3 Global distribution of HIV-1 subtypes and recombinants, 2004–2007. (Source: Hemelaar J, Gouws E, Ghys PD, Osmanov S. Global trends in molecular
epidemiology of HIV-1 during 2000–2007. AIDS 2011;25:679–89).
HIV prevention, care and treatment programs in the most affected 49 circulating recombinant forms (CRFs) [30]. The number of
countries [12–15]. described CRFs is cataloged at the Los Alamos HIV sequence database
[30]. There are also a variety of unique recombinant forms (URFs)
EPIDEMIOLOGY that have only been identified in a single person or in an epidemio-
logically linked pair of persons. The effects of variation between HIV-1
subtypes on pathogenesis, transmission, drug resistance, and immune
MOLECULAR EPIDEMIOLOGY control are not well understood.
There are two main types of HIV (a lentivirus): HIV-1 and HIV-2. The initial genetic diversification of HIV-1 group M viruses likely
HIV-1 comprises three phylogenetically distinct groups, termed occurred in Central Africa, where the greatest diversity and earliest
group M (main), group O (outlier), and group N (non-M, non-O) cases of HIV-1 have been identified [31]. Subsequently, HIV-1 sub-
[16]. A fourth group (group P) has been proposed based on a single types have spread with a geographically heterogeneous distribution
infection with a genetically unique HIV strain [17]. Each group has (Fig. 27.3) [21]. Subtype C, the dominant subtype in Southern Africa,
likely evolved from independent cross-species transmissions of Ethiopia, and India, causes nearly half (48%) of HIV infections world-
chimpanzee simian immunodeficiency virus (SIVcpz) to humans wide [21]. The predominance of subtype C, especially in countries
[18–20]. HIV-1 group M has spread to every region of the world and with high-prevalence epidemics driven by heterosexual sexual contact,
is the virus responsible for the current global pandemic [21]. Group has led to speculation that subtype C might have an increased fitness
O infections are uncommon and limited to people living in, or epi- for transmission [32, 33]. Subtype A accounts for 12% of infections
demiologically linked to, Central Africa (especially Cameroon) [22]. worldwide and has a broad geographic distribution. CRF01_AE and
Group N infections have been described rarely and only in Cam- CRF02_AG are two additional recombinant viruses involving subtype
eroon [23]. A that are epidemiologically important in Southeast Asia and West
HIV-2 is a primate lentivirus related to HIV-1 that is less pathogenic Africa respectively [21]. The emergence of these CRFs has raised
and transmissible (see HIV-2 section) [24, 25]. HIV-2 evolved from concern that recombination may contribute to the selection of viruses
the cross-species transmission of sooty mangabey SIV (SIVsm) to with increased fitness, immune escape or transmissibility [34].
humans [19, 26]. Although HIV-2 infections have been reported Subtype B predominates in the Americas, western and central Europe,
throughout the world, they are most prevalent in Guinea-Bissau [27, and Australia. Finally, URFs are important components of the epi-
28] and in surrounding West African countries, as well as other demics in East Africa, Central Africa, West Africa, and South America,
nations with economic or cultural links to the region (e.g. Portugal, and it is expected that some of these URFs will emerge as important
India, Angola, Mozambique, Cote d’Ivoire, Senegal, France) [24]. CRFs in the future [21, 35–37].
Recent data suggest the prevalence of HIV-2 in Guinea-Bissau has
declined to less than 5% [27, 28]. Dual infection with HIV-1 and Modes of Transmission
HIV-2 has been described but the viruses do not appear to recombine
with each other [29]. HIV can be transmitted by sexual contact; through contact with
infected blood, blood products, or human tissues; and from mother
High rates of viral replication coupled with continuous mutation and to child (Table 27-1) [38, 39]. Although HIV has been isolated from
recombination events have resulted in the rapid genetic diversification a variety of body fluids, only blood, semen, genital fluids, and breast
of HIV-1 group M viruses into 9 distinct subtypes (or clades) and over milk have been proven as sources of infection. HIV is not transmitted
H u m a n I m m u n o d e f i c i e n c y Vi r us I nfec tion 219
TABLE 27.1 Estimated Per-Act Risk for Acquisition of TABLE 27.2 Select Host Factors Affecting Susceptibility
HIV by Exposure Route* to HIV Infection and Disease Progression
1
“Universal precautions”, as defined by the Centers for Disease Control and Sub-Saharan Africa
Prevention (CDC), are a set of precautions designed to prevent transmission of HIV is a generalized epidemic in many parts of sub-Saharan Africa,
bloodborne pathogens, such as HIV, when providing first aid or health care. which contains 68% of all infections worldwide, but only 12.5% of
Information can be found at the Joint United Nations Programmed on HIV/AIDS
(UNAIDS) website: http://www.unaids.org/en/KnowledgeCentre/Resources/
2
PolicyGuidance/Techpolicies/Univ_pre_technical_policies.asp and the CDC Adult prevalence—prevalence among the proportion of the population 15–49
website: http://www.cdc.gov/ncidod/dhqp/bp_universal_precautions.html. years old (adults of reproductive age).
220 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
the world’s total population [1, 55]. Although considerable efforts risk of acquiring infection [61]. In a 2007 Kenyan survey of adult
have improved access to antiretrovirals, 1.3 million Africans died of men and women who reported not testing for HIV because they
AIDS in 2009 (72% of the AIDS deaths worldwide) [1]. Southern were low risk, the HIV prevalence was 4.9% and 5.9% respectively
Africa now has the highest adult HIV prevalence in the world, fol- [56]. Only recently has the burden of HIV infections among
lowed by East Africa. Most countries in West and Central Africa have MSM [62–66] and IDUs [67] in sub-Saharan Africa begun to be
maintained a relatively low HIV prevalence (12 countries in West and appreciated. The contribution of infections by MSM is estimated to
Central Africa had an HIV prevalence of ≤2% in 2009). Geographic be greater than that by IDU because many MSM also have sex
prevalence varies within countries. In Kenya, for example, HIV preva- with women, whereas injection drug use is a new, and smaller, phe-
lence estimated in 2007 varied from 0.8% in the northeast to 14.9% nomenon that provides fewer opportunities for bridging transmis-
in the western province of Nyanza [56]. sions [67, 68].
HIV arrived late in southern Africa (South Africa had a HIV prevalence
of less than 1% in 1988) but has spread rapidly (Fig. 27.5). Swaziland Asia
now has the most intense HIV epidemic in the world with an esti- Although the adult HIV prevalence is lower in Asia (Fig. 27.7) than
mated one in four (26%) adults living with HIV infection in 2009 sub-Saharan Africa, there were still an estimated 4.5–5.5 million
[1]. The nine countries with the highest adult HIV prevalence world- people living with HIV in 2009, with over 360,000 new infections
wide (with an HIV prevalence greater than 10%) are all located in and more than 300,000 deaths in 2009 [1]. Prevalence is highest in
southern Africa. Various social and biologic factors have played a role Southeast Asia, where commercial sex work, sex between men and
in the high prevalence rates. These include high rates of men migrat- injection drug use are the primary modes of transmission. HIV in the
ing for work, concurrent sexual partnerships, genital herpes, low rates region is concentrated in high-risk groups (there are no generalized
of male circumcision and gender-based inequalities [57]. epidemics) and in many countries there are significant regional vari-
Before the mid-2000s, new HIV infections in sub-Saharan Africa ations in their HIV prevalence. In China, for example, five provinces
combined with AIDS-related deaths led to substantial decreases in account for over 50% of people living with HIV [69]. In India, unpro-
life expectancy (Fig. 27.6) [58]. In Botswana, life expectancy fell from tected sex accounts for the majority of new infections (90%); however,
65 years in 1985 to 34 years in 2006; however, with antiretroviral sharing contaminated injection equipment is the main mode of trans-
scale-up covering approximately 90% of eligible persons, AIDS- mission in India’s north-eastern states [70].
related deaths have been cut in half from an estimated 18,000 in In Thailand and Cambodia, HIV spread rapidly in the late 1980s and
2002 to 9100 in 2009 [59]. In Malawi, provision of ART has been early 1990s. Initial cases were reported among MSM and IDUs, and,
linked to a 10% drop in the adult death rate between 2004 and later, among female sex workers. Extensive public education and pre-
2008 [60]. vention campaigns have had some success. In Thailand, increased
Efforts at preventing new infections are gaining traction. In Zambia, knowledge of HIV and changes in sexual behavior (e.g. increased
there is delayed sexual debut and increased condom usage among condom usage, fewer visits to sex workers) have correlated with reduc-
young adults age 15–19 years with coincident reductions in multiple tions in HIV prevalence among new military conscripts [71].
sexual partnerships [1]. Throughout southern Africa, declining HIV Thailand’s “100% Condom” campaign, which educated sex workers
prevalence among young adults, increased testing and counseling and promoted condom use, has also decreased HIV transmission
services, and provision of perinatal ART for prevention of mother-to- from female commercial sex workers [72].
child transmission (PMTCT) have reduced new infections among
children by 32% [1]. Latin America
Denial of risk remains a barrier. In a 2005 South African survey, Brazil, the most populous country in Latin America, had an esti-
half of people who tested HIV-positive believed they were not at mated 460,000–810,000 people living with HIV in 2009 [1]. In the
H u m a n I m m u n o d e f i c i e n c y Vi r us I nfec tion 221
1990 1996
FIGURE 27.5 HIV prevalence among adults aged 15–49 2002 2009
years in sub-Saharan Africa, 1990–2009. Source: Joint
United Nations Programmed on HIV/AIDS (UNAIDS). Global
No data 5%–< 10%
report: UNAIDS report on the global AIDS epidemic 2010.
Available at: http://www.unaids.org/globalreport/Global_ <1% 10%–<20%
report.htm (accessed 5 May 2011). 1%–<5% 20%–28%
70
65
60
Life expectancy at birth (years)
55
50
45
40
35
30
25
20
1970–1975 1975–1980 1980–1985 1985–1990 1990–1995 1995–2000 2000–2005 2005–2010
1990s, many experts predicted that Brazil’s epidemic would rapidly reported having sex with at least one female partner in the previous
accelerate. However, the country’s sustained campaign to promote sex 6 months, underscoring the potential for HIV to bridge to women in
education, condom use, harm reduction and HIV testing, and to this region [75].
provide universal ART has held adult prevalence below 1% [1]. The
majority of HIV infections in South America occur among MSM [73] More detailed global and regional information is published annually
and IDU [67]. Incarcerated men are at particularly high risk [74]. In by the WHO and UNAIDS (http://www.unaids.org; http://www.who.
addition, in Central America, a high proportion of MSM (22%) have int/hiv/en/).
222 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
1990 1996
FIGURE 27.7 HIV prevalence among adults aged 15–49 2002 2009
years in Asia, 1990–2009. Source: Joint United Nations
Programmed on HIV/AIDS (UNAIDS). Global report: UNAIDS
No data 0.5%–<1%
report on the global AIDS epidemic 2010. Available at: http://
www.unaids.org/globalreport/Global_report.htm (accessed 5 <0.1% 1%–<1.5%
May 2011). 0.1%–<.5% 1.5%–2.5%
0 1000 2000 3000 4000 5000 6000 7000 8000 9000 9719
FIGURE 27.8 HIV-1 gene map. Source: Los Alamos National Laboratory. The circulating recombinant forms(CRFs), HIV sequence database. Available at: http://www.
hiv.lanl.gov/content/sequence/HIV/CRFs/CRFs.html (accessed 5 May 2011).
NATURAL HISTORY, PATHOGENESIS HIV is able to avoid intracellular antiviral defenses (e.g. APOBEC3G/3F
AND PATHOLOGY and TRIM5α), while activating and exploiting cellular machinery to
replicate (Fig. 27.10). HIV infects and replicates in cells that express
The HIV-1 genome is organized into three major regions: gag, encod- the CD4 receptor, in particular CD4+ T lymphocytes. HIV’s envelope
ing structural proteins, pol, encoding enzymes (e.g. reverse tran- protein (gp120) binds to the CD4 receptor and to additional
scriptase, protease and integrase) necessary for viral replication, and co-receptors (i.e. CCR5 or CXCR4), leading to viral fusion with the
env, encoding envelope proteins (Fig. 27.8) [76]. In addition, the cell and entry of HIV’s inner viral core (steps 1 and 2 in Fig. 27.10)
HIV genome contains six regulatory genes (tat, rev, nef, vpr, vpu, and [77]. HIV’s reverse transcriptase then converts the single-stranded HIV
vif) that facilitate viral replication and host immune evasion. HIV is RNA genome into double-stranded DNA (step 3). Reverse tran-
spherical with a diameter of 1/10,000 of a millimeter (Fig. 27.9) scriptase is error prone and it is at this step that mutations and strand
[77]. The outer coat, known as the viral envelope, is composed of recombinations generate genetically distinct viral variants. The viral
two lipid layers taken from the membrane of a human cell when a DNA then complexes with HIV integrase, is transported into the host
newly formed virus particle buds. Within the inner viral protein cell’s nucleus and is integrated with the help of host DNA repair
core are two copies of positive, single-stranded RNA that are tightly enzymes into a transcriptionally active location in the host’s chromo-
bound to nucleocapsid proteins and viral enzymes necessary for somal DNA (step 4). This step irreversibly transforms the cell into a
replication. producer of virus. A certain proportion of cells infected by HIV are
H u m a n I m m u n o d e f i c i e n c y Vi r us I nfec tion 223
gp120 - Docking
Lipid membrane glycoprotein TABLE 27.3 Signs and Symptoms of Acute HIV Infection
gp41 - Transmembrane
glycoprotein Sign and Symptoms Percent of patients with
Viral RNA
acute HIV infection
Any sign or symtom 84%
1
Fusion of HIV
2
to the host cell HIV RNA, reverse
surface transcriptase, intergrase,
and other viral proteins
enter the host cell
HIV
gp120
CD4
Preintegration
Co-receptor
complex
(CCR5 or CXCR4)
Host cell 3
Viral DNA is
formed by reverse
transcription Viral RNA
Reverse
4 transcriptase
Viral DNA is
transported across the
nucleus and integrates
into the host DNA
Integrase
Viral DNA
Host DNA
Mature virion
New viral RNA
5
New viral RNA is
used as genomic RNA
7 and to make viral
The virus matures proteins
by protease
releasing individual
HIV proteins
6
New viral RNA and
proteins move to the
cell surface and a new,
immature, HIV forms
FIGURE 27.10 HIV life cycle. Source: National Institute of Allergy and Infectious Diseases. HIV Replication Cycle. Available at: http://www.niaid.nih.gov/topics/HIVAIDS/
Understanding/Biology/Pages/hivReplicationCycle.aspx (accessed 26 April 2011).
H u m a n I m m u n o d e f i c i e n c y Vi r us I nfec tion 225
107
106
105
104
103 Risk of
transmission
102
Viral diversity
FIGURE 27.11 The course of HIV-1 infection.
Plasma viremia (top) and dynamic changes in T 10
lymphocyte compartments and HIV-specific anti
bodies (bottom). Primary infection characterized
by high plasma viremia (solid dark blue line, top),
low CD4 cells (solid light blue line, bottom) and 700 HIV antibodies
absence of HIV-1 specific antibodies (light gray
600
dashed line, bottom). Viremia drops as cytotoxic
CD8+ T lymphocytes (CTL) develop (black dashed
Cell number/titre
500
line, bottom) and an individual viral-load set point Cytotoxic CD8+
is reached during chronic infection. Viral set 400 T cells (CTL)
points differ greatly among individuals (e.g. top)
and predict disease progression. Viral diversity 300
increases throughout the disease (closed circles, CD4+T cells
top). The risk of transmission is highest in the first 200
weeks when viremia peaks (closed circles, top). 100
GALT, gut-associated lymphoid tissues. Source:
Simon V, Ho DD, Abdool Karim Q. HIV/AIDS epi CD4+depletion in GALT
0
demiology, pathogenesis, prevention, and treatment.
Lancet 2006;368:489–504. Weeks Years
myalgia, malaise, lymphadenopathy, oral ulcers, pharyngitis, and STAGING OF HIV DISEASE
weight loss [92]. The presence of fever and rash has the best positive
predictive value [93]. Unfortunately, acute symptomatic HIV infection The two commonly used systems for the clinical staging of HIV
is rarely diagnosed by healthcare providers as its symptoms are often disease are those developed by the WHO [103] and the USA Centers
attributed to other viral infections or secondary syphilis [94]. for Disease Control and Prevention (CDC) [104]. While these staging
systems were defined primarily for surveillance purposes, they provide
Acute HIV infection is defined as having detectable HIV RNA3 or HIV important prognostic and management information. The WHO clini-
p24 antigen (a major core protein of HIV) in the presence of a nega- cal staging system classifies patients from Stage 1 (asymptomatic) to
tive or indeterminate serologic HIV antibody test [97]. Although a Stage 4 (life-threatening opportunistic infections or HIV-associated
positive HIV RNA or HIV p24 antigen in the setting of a negative or conditions) based on clinical and laboratory findings (Table 27-4).
indeterminate serologic HIV antibody test is diagnostically consistent In resource-limited settings, inadequate laboratory capacity can limit
with acute HIV infection, the diagnosis should be confirmed with an the ability to measure CD4 cell counts or diagnose HIV-associated
HIV antibody test performed over the next 3 months to document illnesses and accurately stage disease. The CDC surveillance case defi-
seroconversion [98, 99]. New advances in HIV testing technology [i.e. nitions are: Stage 1 (CD4+ T-lymphocyte count ≥500 cells/µl); Stage
the increased use of fourth-generation enzyme immunoassay (EIA) 2 (CD4+ T-lymphocyte count = 200–499 cells/µl); Stage 3 (CD4+
tests that can detect both p24 antigen and anti-HIV antibodies] may T-lymphocyte count of <200 cells/µL or an AIDS-defining condition);
improve its diagnosis [100, 101]. Identifying individuals during acute or Stage unknown (Table 27-5).
HIV is an important public health goal. During acute infection, HIV In the absence of effective ART, HIV infection induces progressive
replicates extensively and can achieve a very high viral load, which immune suppression. Opportunistic illnesses closely relate to the
increases the risk of further transmission (Fig. 27.11) [41, 46]. Preg- degree of immune suppression. The risk for specific opportunistic
nant women in high HIV prevalence settings may be particularly illness can be anticipated based on the patient’s CD4+ count. Con-
vulnerable to acute HIV infection and subsequent mother-to-child versely, the occurrence of certain opportunistic illnesses can be a
transmission of HIV [102]. Diagnosis should prompt preventive marker for the degree of HIV disease progression. Figure 27.12 illus-
counseling to inform patients that they are highly infectious and to trates the CD4+ T lymphocyte counts at which opportunistic illnesses
help reduce their risk of transmitting HIV. If testing for HIV RNA is typically occur.
not available but acute HIV is suspected, the patient should receive
preventive counseling and repeat HIV antibody testing in 3–6 months.
OPPORTUNISTIC ILLNESSES
Variation in risk by gender for some opportunistic illnesses has been
3
reported (i.e. higher rates of tuberculosis among HIV-infected men
HIV RNA can be detected by qualitative and quantitative nucleic acid amplifica- [105]); however, observed differences have not been great enough to
tion tests (NAAT). The level of HIV viremia usually peaks with the onset of clinical
symptoms of acute HIV infection [46]. Clinicians should suspect a false positive
alter screening and prophylaxis recommendations for women com-
NAAT result if the HIV RNA level is less than 10,000 copies/ml in a patient with pared with men. Disease in children mirrors that in adults with
symptoms suggestive of acute HIV infection [95, 96]. In this setting, a repeat NAAT several important differences [106]. Cytomegalovirus (CMV) and dis-
test should be performed as a rising HIV RNA level would suggest a true positive seminated herpes simplex (HSV) infections are more common in
result. adults, whereas lymphoid interstitial pneumonia (also known as
226 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
TABLE 27.4 WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological Classification
of HIV-Related Disease in Adults and Children
Chronic herpes simplex infection (orolabial, genital, or anorectal of > 1 month’s duration)
Esophageal candidiasis
Extrapulmonary tuberculosis
Kaposi’s sarcoma
Central nervous system toxoplasmosis
HIV encephalopathy
H u m a n I m m u n o d e f i c i e n c y Vi r us I nfec tion 227
TABLE 27.4 WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification
of HIV-related disease in adults and children—cont’d
TABLE 27.5 CDC Staging of HIV Infection* for Adults and Adolescents
pulmonary lymphoid hyperplasia) causes substantial illness among with the fungus Penicillium marneffei occurs with advanced immuno-
HIV-infected children [107]. For unclear reasons, the prevalence of suppression (CD4 cell count <50 cells/µl) [109]. Histoplasma capsula-
Pneumocystis jirovecii pneumonia (PCP) among adults in most of sub- tum occurs throughout central and southern USA, the tropics and
Saharan Africa is low compared with other parts of the world, but subtropics, but is rare in Europe and Asia [110, 111]. Finally, there is
PCP is a substantial cause of morbidity and mortality among African substantial overlap between geographic areas affected by HIV, tuber-
children [108]. culosis, and malaria (Fig. 27.13 and 27.14) [112].
Visceral leishmaniasis occurs in parts of sub-Saharan Africa, around Management of opportunistic illnesses is complex and must be
the Mediterranean Sea, on the Indian subcontinent and in South tailored to the local spectrum of disease [108, 113]. The WHO and
America. In Southeast Asia, most notably Thailand, systemic infection others have developed and updated international guidelines for the
228 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
0 50 100
A HIV prevalence among adults B Estimated new tuberculosis C Spatial distribution of P. falciparum
aged 15–49 years, 2009 cases per 100,000 population, 2009 annual parasite incidence per
1,000 people per year displayed as a
No data 5%–<10% No estimate 50–99
continuum of blue from 0%–100%
<1% 10%–<20% 0–24 100–299
1%–<5% 20%–28% 25–49 >300
FIGURE 27.13 Prevalences of HIV infections, tuberculosis and P. falciparum malaria in sub-Saharan Africa, 2009. (A) Joint United Nations Programmed on HIV/
AIDS (UNAIDS). Global report: UNAIDS report on the global AIDS epidemic 2010. Available at: http://www.unaids.org/globalreport/Global_report.htm (accessed 5 May
2011). (B) World Health Organization. Global Control of Tuberculosis 2010. Geneva: World Health Organization; 2010. (C) Reprinted with permission from Hay SI, Guerra
CA, Gething PW, et al. A world malaria map: Plasmodium falciparum endemicity in 2007. PLos Med 2009;6:1000048.
Approximately 50% of HIV-infected patients with cryptococcal men- “Prevention: Special Considerations for Antimicrobial Prophylaxis in
ingitis have elevated baseline intracranial pressures [i.e. >25 cm of Resource-Limited Settings” below). PCP is most common in patients
cerebrospinal fluid (CSF)] and patients with a higher intracranial with CD4 cell counts <200 cells/µl. PCP typically presents with fever,
pressure tend to have a higher fungal burden [117]. The organism can a dry cough and progressive dyspnea. Hypoxia is common, serum
be cultured from CSF in the majority of patients and from the blood lactate dehydrogenase is typically elevated and chest x-ray usually
in up to 75% of patients [115]. Testing for cryptococcal antigen (CrAg) reveals diffuse interstitial infiltrates that are often perihilar.
in CSF or in serum is sensitive and specific [118–120]. Serum CrAg
testing can be useful for screening or when lumbar puncture cannot
be performed. BACTERIAL INFECTIONS
While identification of bacterial illness is unusual in resource-
The most effective treatment for cryptococcal meningitis (see Chapter
limited settings, epidemiologic studies have confirmed the impor-
84) is a combination of amphotericin B and flucytosine with manage-
tance of Streptococcus pneumoniae and non–typhoid Salmonella in
ment of increased intracranial pressure, such as by repeated lumbar
adults and children with HIV [131, 132], and Haemophilus influenzae
punctures [121]. Fluconazole is an alternative when amphotericin
in children [133, 134]. Clinical manifestations of S. pneumoniae
cannot be given and should be combined with flucytosine if flucyto-
vary; pneumococcal infection presents most commonly as pneumo-
sine and laboratory monitoring are available [122, 123]. Mono-
nia or sinusitis, but meningitis also occurs and any presentation can
therapy with fluconazole is likely inferior [124] but, in some situations,
be accompanied by pneumococcal bacteremia. WHO guidelines on
may be the only option.
the treatment of diarrhea and pneumonia in HIV-infected children
In persons with acute cryptococcal meningitis, there are conflicting and infants should be consulted for up-to-date recommendations:
data regarding the optimal timing of ART (e.g. concurrent with initia- (http://whqlibdoc.who.int/publications/2010/9789241548083_
tion of antifungal therapy or delayed) [125–128]. A randomized clini- eng.pdf) [135].
cal trial in Zimbabwe evaluated the timing of ART in HIV-infected
patients who were newly diagnosed with cryptococcal meningitis and
treated with fluconazole monotherapy. In this trial, early initiation of SEXUALLY TRANSMITTED INFECTIONS (STIs)
ART (within 72 hours of the cryptococcal meningitis diagnosis) was Many HIV-infected persons are at risk for STIs; these can also increase
associated with increased mortality [presumably as a result of immune the risk of HIV transmission and acquisition [136]. Diagnosis and
reconstitution inflammatory syndrome (IRIS)] compared with delay- management of STIs in persons with HIV is similar to persons without
ing ART for 10 weeks [126]. Thus, it may be prudent to delay initiation HIV. However, clinical presentations of some STIs can be more severe
for at least 2 weeks—possibly longer if fluconazole monotherapy is with HIV, for example ulcerative lesions may be more extensive. Algo-
used. For persons who recover from an initial episode, secondary rithms for syndromic management of STIs have not performed as well
prophylaxis is recommended. While there are few data from resource- in persons with HIV and specific diagnoses should be confirmed
limited settings, it is assumed that discontinuation following immune where possible [137].
recovery on ART is safe. Primary prophylaxis with fluconazole pre-
vents cryptococcal disease, and may be cost effective in settings with
high disease prevalence [129]. Alternate approaches to reducing VIRAL HEPATITIS
the burden of cryptococcal disease are early initiation of ART or pre- Prevalence of hepatitis B (HBV) and hepatitis C (HCV) in HIV-infected
emptive antifungal therapy to persons with asymptomatic cryptococ- persons can be higher than in HIV-uninfected persons because of
cal infection [130]. shared routes of transmission [138]. Co-infection of HIV with HBV
or HCV increases the mortality risk, but may have modest impact on
Pneumocystis Pneumonia the progression of HIV disease. However, co-infected patients are
PCP disease progression can be rapid, particularly in children, thus at increased risk of cirrhosis, liver failure, and hepatocellular
prevention by primary antimicrobial prophylaxis is a priority (see carcinoma.
230 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
All persons with HIV and viral hepatitis should avoid alcohol con-
sumption and use precautions to prevent transmission of viral hepa-
titis. A number of antiretroviral agents are active against both HIV and
HBV. Therefore, guidelines now recommend that ART be started in
any person diagnosed with active HBV or HCV [98, 139–141] (see
“Antiretroviral Therapy: What to Start—Special Considerations in Patients
with Chronic Hepatitis B Infection” below).
Baseline testing of HIV-infected persons for active hepatitis B infection
can identify persons who should be prioritized to receive dually active
antiretroviral regimens [142]. In settings where HBV prevalence is
high, it may be cost-effective to consider empiric ART with dually
active (i.e. active against both HIV and HBV) regimens. The objectives
of treating HBV are normalization of alanine aminotransferase, hepa-
titis B e antigen seroconversion, suppression of hepatitis B viral load
and improvement in liver histology. Withdrawal of dually active
therapy in HBV-co-infected patients can lead to HBV reactivation
[143, 144]. Therefore, HBV-infected patients on dually active regi-
mens should be advised against self-discontinuation and closely
monitored for hepatic injury if the regimen must be stopped.
Cure of HCV infection, defined as the sustained elimination of HCV
RNA from the serum and liver, is possible. The existing standard of
care—HCV protease inhibitors, pegylated interferon and ribavirin—is
complex to manage because of the usual occurrence of adverse events FIGURE 27.15 Pruritic papular eruption of HIV disease. Pruritic papular
that require clinical and laboratory monitoring. Directly-acting agents eruption occurring in individuals with human immunodeficiency virus
against HCV infection (e.g. HCV protease inhibitors) are in develop- infection. Detail from dorsal surface of hand showing excoriated papules.
ment [145–150]. (Reprinted with permission from Amerson EH, Maurer TA. Dermatologic
manifestations of HIV in Africa. Top HIV Med 2010;18:16–22)
SELECT MAJOR CLINICAL pruritic and occur more commonly on the upper trunk and buttocks.
SYNDROMES Staphylococcal folliculitis can be treated with topical or oral anti-
staphylococcal antibiotics. Eosinophilic folliculitis presents with pru-
FEVER ritic papules on the face, neck, and upper trunk, and can mimic acne.
It responds best to ART, but may paradoxically worsen. Topical ster-
Prolonged fever is common, especially among patients with low CD4 oids or oral itraconazole can improve symptoms.
cell counts (e.g. <200 cells/ml) who are not receiving ART [151], and
differential diagnosis is broad and varies geographically. Infectious Scabies can present with pruritic papular lesions similar to those seen
etiologies are responsible for the majority of fevers. with PPE; however, scabies lesions tend to be clustered in the finger
webs, waist, ankles, axillae, breasts, and genital areas, and burrows can
Tuberculosis should be considered in all patients with fever especially sometimes be seen. Severe scabies (‘Norwegian’ scabies) can present
if cough, shortness of breath, weight loss, night sweats, or lymphaden- with a crusted thick grayish scale teeming with mites. Scratching of
opathy are present (see Chapter 39, “Tuberculosis”) [131]. Other causes scabies lesions can lead to bacterial superinfection. Oral ivermectin
of fever are cryptococcal disease (e.g. C. neoformans bloodstream infec- or topical agents are effective. Prurigo nodularis—a condition that
tion), bacteremia (e.g. Salmonella, Rhodococcus), pneumonia, both results from intense scratching—presents with larger (>1 cm) pruritic
bacterial (e.g. S. pneumoniae) and fungal (e.g. PCP), malaria, CMV, nodules that often start on the extremities with a symmetric distribu-
and lymphoma. Multiple concurrent etiologies occur. tion; management should identify the underlying cause of pruritis.
The diagnostic work-up for fever should be driven by the clinical Topical steroids, topical capsaicin, and oral antihistamines can amel-
presentation and availability of diagnostic tests. Blood cultures, blood iorate symptoms.
smear for malaria, mycobacterial blood cultures and serum cryptococ- Seborrheic dermatitis presents with dandruff and indistinct plaques
cal antigen testing can be helpful. Chest radiography, urine culture, of yellowish scale involving the scalp, face, chest, back, and groin.
bone marrow aspirate and biopsy, and other radiologic studies (e.g. Although it can typically be seen on the hair-bearing area of the head
brain imaging, abdominal imaging) may be necessary. Certain etiolo- (e.g. eyebrows, outer ear canal), in the context of HIV infection, and
gies such as mycobacterial disease, Pneumocystis, Bartonella, lymphoma especially in Africa, it occurs at skin folds (e.g. axillae, inner thighs).
and certain fungal infections can be particularly difficult to diagnose Mild cases respond to dandruff shampoo (e.g. selenium sulfide or
and should be considered when fever persists despite a diagnostic zinc pyrithione). More severe cases require topical antifungals (e.g.
work-up. ketoconazole) directed against Pityrosporum yeasts such as Malassezia
furfur and steroids. Refractory cases may require oral ketoconazole.
DERMATOLOGIC DISEASE Photodermatitis frequently occurs in Africa and presents with an
Dermatologic disease can have a broad differential diagnosis, espe- itchy, scaly rash. It is differentiated from seborrheic dermatitis by its
cially in patients with advanced immunosuppression [152]. The Inter- distribution on sun-exposed areas of skin. Although sulfonamides
national AIDS Society-USA (www.iasusa.org) has useful reference can be photosensitizing, their use in treating HIV infection is impor-
materials [152]. tant and they should not be stopped, if possible, because of
photodermatitis.
Pruritic papular eruption (PPE) is common in tropical environments.
PPE may be caused by a hypersensitivity to insect bites and presents Human herpesvirus 8 infection (HHV-8), the cause of Kaposi’s
with extremely pruritic papules (<1 cm) predominately on the sarcoma (KS), is endemic to much of Africa. KS commonly occurs in
extremities that can be hyperpigmented and excoriated from scratch- patients with advanced HIV disease (see “HIV-associated Malignancies”
ing [153] (Fig. 27.15). PPE is diagnosed clinically and improves with below) [154]. It presents with reddish, violaceous or brown non-
ART; topical steroids and capsaicin can help. Bacterial folliculitis (e.g. tender macules and papules that progress to nodules. KS often
staphylococcal folliculitis) can present with lesions similar to involves the head and neck but can involve several anatomical sites;
PPE. However, the lesions are follicular, fewer in number, variably oral lesions on the tongue, palate, and buccal mucosa may precede
H u m a n I m m u n o d e f i c i e n c y Vi r us I nfec tion 231
skin disease. Advanced KS causes widely disseminated skin disease PULMONARY DISEASE
with lymphatic obstruction and involvement of the lungs and gas-
trointestinal tract. KS can regress with ART, especially if detected at an In most clinical and autopsy case series of lung disease in HIV-infected
early stage. Bacillary angiomatosis caused by infection with Bartonella patients, tuberculosis is among the most frequently identified patho-
henselae or quintana can cause similar lesions as KS but is treated gens and should be considered with any pulmonary infection (see
effectively with antibiotics. Likewise, dermal non-Hodgkin lym- Chapter 39, “Tuberculosis”). Community-acquired pneumonia, fre-
phoma can have a similar presentation but occurs rarely. quently caused by S. pneumoniae, is the next most common cause of
lung disease [161, 162]. Tuberculosis and community-acquired pneu-
Molluscum contagiosum is caused by a poxvirus and is common in monia can occur at any time during HIV infection, but risk increases
HIV-infected children. It presents with dome-shaped umbilicated as the CD4 cell count declines. Cotrimoxazole prophylaxis and pneu-
papules. Disseminated cryptococcosis can present with similar lesions mococcal conjugate vaccination may be effective prevention strategies
that precede the development of systemic disease but the onset is [163, 164]. PCP presents as a subacute process. KS, histoplasmosis,
usually abrupt. cryptococcosis, nocardiosis and, in children, lymphoid interstitial
pneumonititis, are less common causes.
Genital and non-genital warts caused by human papillomavirus are
common in tropical environments and HIV-infected children may Pleural effusions are most often secondary to infection or malignancy
develop hundreds of flat warts. Syphilis should be considered in [165]. Pleural tuberculosis can occur with or without parenchymal
patients presenting with disseminated maculopapular skin disease or disease. Tuberculous pleural effusions are exudative, lymphocytic and
condylomata lata. not acidic or hypoglycemic. They typically demonstrate concentra-
tions of adenosine deaminase (ADA) greater than 50 U/l [166]. A
The possibility of drug eruptions should always be considered. Muco- pleural fluid acid-fast smear is positive in less than 15% of cases, but
cutaneous eruptions, blisters or other erosive dermal lesions should a sputum smear may be positive. Pleural biopsies with examination
prompt consideration of Stevens-Johnson syndrome or toxic epider- for acid-fast bacilli and granulomas have the highest likelihood of
mal necrolysis [155, 156]. Decisions on whether to stop treatment confirming pleural infection. Bacterial pneumonia often causes para-
with the suspect agent or to “treat through” need to be made on a pneumonic effusions. KS, multicentric Castleman’s disease, primary
case-by-case basis. effusion lymphoma, B-cell non-Hodgkin lymphoma, and lung cancer
are malignant causes of effusion.
OPHTHALMOLOGIC DISEASE
Eye disease is an important complication [157–159]. CMV retinitis is ESOPHAGEAL DISEASE
the most common cause of retinal disease and vision loss with Dysphagia (i.e. difficulty swallowing with a sensation of food
advanced immunosuppression (i.e. CD4 cell count < 50 cells/µl) sticking) and odynophagia (i.e. pain on swallowing) occur with
[158]. CMV retinitis can be diagnosed by retinal examination that advanced HIV infection and suggest esophagitis. Candidiasis is
demonstrates large white or creamy lesions with granular borders and the most common cause [115, 167] and is usually associated with
associated hemorrhage (Fig. 27.16). Lesions often begin in the periph- oropharyngeal candidiasis (thrush) (Fig. 27.17). Empiric treatment
ery and progress centrally; patients complain of unilateral floaters for candidal esophagitis with fluconazole is usually indicated, espe-
followed by progressively decreased visual acuity and eventual blind- cially in patients with a CD4 count <200 cells/µL or if oral thrush is
ness. CMV retinitis should be treated with ART and CMV antiviral present. Patients who do not respond to fluconazole can be treated
therapy (e.g. oral valganciclovir, intravenous ganciclovir, or intraocular with a higher dose, and patients who still do not respond should be
ganciclovir). It can be confused with HIV retinopathy, which has considered for upper endoscopy with biopsy. Other etiologies are
characteristic “cotton-wool” spots on retinal examination. These CMV, herpes simplex virus, and aphthous ulcers, each of which tends
lesions are not sight threatening and often resolve spontaneously to be associated with more prominent odynophagia (often without
[160]. Other causes of rapid vision loss are progressive outer retinal dysphagia).
necrosis caused by varicella-zoster virus and, less commonly, by herpes
simplex. Squamous cell carcinoma of the conjunctiva, corneal micro-
sporidiosis, ocular tuberculosis, and syphilitic chorioretinitis and GASTROENTERITIS/DIARRHEAL DISEASE
uveitis can cause ophthalmologic disease in low-income settings. Acute diarrhea suggests a viral or bacterial pathogen although certain
parasitic infections (Isospora belli, Entamoeba histolytica) can present
acutely. Diarrhea and fever suggest Salmonella, Shigella, or Campylo- IMMUNE RECONSTITUTION INFLAMMATORY
bacter, especially if mucus or blood are in the stool [168]. Bacterial
diarrhea should be treated with antibiotics [115] guided by culture
SYNDROME (IRIS)
and antimicrobial sensitivity testing. Enteric viruses (e.g. norovirus, Occasionally, and especially in persons with low CD4 cell counts,
rotavirus, adenovirus) and pathogenic Escherichia coli (e.g. enteroag- immune reconstitution following initiation of ART can unmask a
gregative, enterotoxigenic and enterohemorrhagic E. coli) can also clinically quiescent co-infection or lead to paradoxical worsening of
cause acute diarrhea [169, 170]. Clostridium difficile occurs among an active previously diagnosed co-infection; in both cases the patient’s
HIV-infected patients in developed nations exposed to antibiotics or clinical condition can worsen [185]. This ART-mediated IRIS occurs
who have been hospitalized [171]. Non-infectious etiologies of acute with mycobacterial infections, usually tuberculosis, as well as CMV
diarrhea can be secondary to drugs, food poisoning (e.g. bacterial or retinitis, cryptococcal meningitis, and PML [185]. However, it has
marine toxins), lactose intolerance, inflammatory bowel disease, or occurred with almost every AIDS-associated opportunistic infection
infiltrative diseases (i.e. lymphoma or Kaposi’s sarcoma). ART, espe- and a variety of non-AIDS-associated infections and illnesses [186,
cially protease inhibitors (e.g. nelfinavir), can also be associated with 187]. In general, the benefits of early initiation of ART outweigh the
diarrhea and should be considered if other etiologies can be ruled out risk of IRIS. IRIS can usually be managed without interrupting ART
[172]. ART-associated diarrhea can often be managed symptomati- by treating the associated co-infection and providing supportive care,
cally but in severe cases may require a single drug substitution to an which can include non-steroidal anti-inflammatory drugs (NSAIDs)
alternative medication. or corticosteroids. ART should be stopped with IRIS that is either life-
threatening or that cannot be managed with supportive care.
In patients with a low CD4 count (<200 cells/µl), cryptosporidiosis
owing to infection with Cryptosporidium parvum, C. hominis, or C.
maleagridis is a cause of chronic diarrhea [173–176]. Other causes are HIV-ASSOCIATED MALIGNANCIES
isosporiasis, microsporidiosis, Mycobacterium avium complex, cyclo Persons with HIV infection are at increased risk for three malignan-
sporiasis, and CMV. Giardiasis, amoebiasis, and strongyloidiasis can cies: KS, non-Hodgkin lymphomas, and cervical cancer [104, 188].
occur at any stage of HIV infection. Even with access to diagnostic The incidence of KS and non-Hodgkin lymphomas has declined dra-
testing (e.g. stool leukocyte evaluation, stool culture, stool examina- matically in high-income countries among persons receiving ART
tion for ova and parasites with a modified acid-fast stain for Crypto [189–191]. In regions where life expectancies of persons living with
sporidium) and endoscopy with biopsy, a significant proportion of HIV infection have increased, the incidence of non-AIDS-associated
chronic diarrhea has no pathogen identified and is attributed to HIV malignancies has increased at rates in excess of rates for the same
enteropathy [177]. While some causes of chronic diarrhea can be cancers in HIV-uninfected persons [192]. Whether similar trends are
treated (i.e. trimethoprim-sulfamethoxazole for isosporiasis and occurring in resource-limited settings is difficult to determine [193].
cyclosporiasis), cryptosporidiosis and microsporidiosis are often Many non-AIDS malignancies are associated with chronic oncogenic
refractory to antimicrobial therapy alone. For these patients, immune viral infections: human papillomavirus (HPV; anal and oropharyn-
reconstitution with ART is necessary [178]. geal cancer), Epstein-Barr virus (non-Hodgkin lymphoma), and viral
hepatitis B and C (hepatoma) [194, 195]. Others are associated with
FOCAL CENTRAL NERVOUS SYSTEM lifestyle factors that are more prevalent among certain populations
(e.g. tobacco use). Some data suggest that HIV infection independ-
(CNS) LESIONS ently increases risk for non-AIDS malignancies; however, it is not
HIV-infected patients with advanced immunosuppression who evident whether ART affects this risk [196–198].
present with focal neurologic symptoms or seizures often have a
central nervous system (CNS) mass lesion caused by an opportun-
istic infection or HIV-associated malignancy. The evaluation and
Kaposi’s Sarcoma (KS)
management of these lesions can be challenging if access to radio KS is caused by HHV-8 and the endemic prevalence (i.e. HIV-unasso-
graphy [e.g. computed tomography (CT), magnetic resonance ciated) generally correlates with regional HHV-8 seroprevalence;
imaging (MRI)] and neurosurgery are limited [179, 180]. The most however, immunosuppression from HIV can increase the incidence
common etiology of focal CNS lesions in low-income settings and prevalence of KS [199–202]. KS is common in African countries
has been tuberculosis (tuberculomas) [179], but neurocysticercosis, of Zambia, Democratic Republic of Congo, Zimbabwe, Uganda,
toxoplasma encephalitis, primary CNS lymphoma, non-Hodgkin Rwanda, and Burundi [203–205]. Although endemic KS is uncom-
lymphoma, bacterial brain abscess, cryptococcosis and, in South mon in the Americas, Europe, and Asia, persons with HIV infection,
America, brain chagoma caused by Trypanosoma cruzi, are con and especially MSM, experience greater incidence of disease [206].
siderations. Tuberculosis should be strongly suspected if there is With ART, KS may regress [207] and protease inhibitors appear to
evidence of non-neurologic tuberculosis (e.g. lung disease), basal have specific activity against HHV-8 [208]. Extensive visceral or rapidly
meningeal enhancement on CT scan or a CSF pleocytosis with a progressive disease often requires cytotoxic chemotherapy and radia-
high protein. tion therapy, which are generally palliative and not curative [201].
Toxoplasma encephalitis presents with fever, headache, weakness,
altered mental status or confusion, and possibly seizures; physical Non-Hodgkin Lymphoma
exam usually demonstrates focal neurologic abnormalities [181]. Non-Hodgkin lymphomas are the second most common malignancy
Most patients have a CD4 cell count <100 cells/µl and positive associated with HIV infection and comprise a heterogeneous group
toxoplasma serology [182]. Empiric therapy with pyrimethamine, of tumors that are almost all of B-cell origin [209]. Many of these
sulfadiazine, and leucovorin is indicated; clinical improvement tumors appear causally related to either Epstein-Barr virus or HHV-8
should be seen within 1–2 weeks if the diagnosis is correct. In [210]. Incidence is increased substantially among patients with low
resource-limited settings, use of trimethoprim-sulfamethoxazole CD4 cell counts. Diagnosis is based on clinical presentation (e.g.
may be considered if the first-line drugs are not available [183, lymphadenopathy, fevers, night sweats, weight loss) and biopsy. Treat-
184]. ment and prognosis vary according to the type of tumor and available
therapy.
Progressive multifocal leukoencephalopathy (PML) is an insidious
and progressive disorder caused by John Cunningham (JC) virus that
usually presents with one or more rapidly progressive focal neuro- Cervical Cancer
logic deficits without fever in advanced HIV infection [115]. The Cervical cancer is a leading cause of death among women worldwide
diagnosis can be made by identification of JC virus in CSF or dem- and a common AIDS-related malignancy [211]. The vast majority of
onstration of characteristic lesions by CNS imaging. No specific cervical cancers, including among HIV-infected women, are caused by
therapy exists; treatment is ART to restore immunity against the infection with oncogenic types of HPV [212, 213]. HPV infections are
JC virus. more common and persistent in women with HIV. Risk for cervical
H u m a n I m m u n o d e f i c i e n c y Vi r us I nfec tion 233
cancer is not correlated with CD4 cell count. Incidence of cervical populations with a high HIV prevalence, testing is feasible in rural
cancer has not declined significantly in high-income settings where settings and can be effectively offered by teams going door-to-door
ART use is widespread [193], although women who are adherent to [236]. HIV testing results should be presented with counseling about
ART demonstrate lower incidence and prevalence of oncogenic HPV HIV prevention and risk reduction. For persons who test positive, it
types [214]. is critical to provide psychosocial support and clinical services, and to
ensure patients are referred to, and linked into, medical care [237]
Screening and earlier intervention are key aspects of preventing cervi- (see “HIV counseling” below).
cal cancer. Traditional population-based cervical cancer prevention
programs that rely upon examination of cervical cells face substantial
barriers to sustainability in resource-limited settings. These include a HIV DIAGNOSIS
lack of resources (e.g. cytopathology services, surgery and chemo- HIV infection should be diagnosed with a rapid or conventional
therapy, infrastructure to support screening, and treatment) and serologic assay for antibodies against HIV (e.g. an EIA). Rapid HIV
trained healthcare workers (e.g. persons that collect specimens, cyto- testing is faster (tests results are often available in less than 30
technologists, clinicians for medical and surgical management of cer- minutes), less costly and increases the number of clients who receive
vical disease), and the requirement that patients attend multiple their results [238]. Most rapid tests do not require access to running
medical visits [215]. Innovative “see-and-treat” programs, where water or electricity and some can be performed on oral fluids.
women with cervical pathology during direct visual examination of
the cervix after application of acetic acid are treated at the same visit Results that are reactive by a serologic assay should be confirmed with
with cryotherapy, show great promise [215]. National programs to another assay. Clinicians should follow local guidelines for confirma-
vaccinate young women and men against HPV prior to sexual debut tory testing, which may involve repeat HIV testing with a different
could substantially reduce the burden of cervical cancer and other rapid EIA test, performing a Western blot for antibodies against spe-
HPV-associated malignancies (e.g. anal cancer, head and neck cancer). cific HIV proteins or an assay that directly detects HIV RNA.
Studies of the effectiveness of HPV vaccination in HIV–infected In low-income settings with a high HIV prevalence, there are algo-
women are ongoing (www.clinicaltrials.gov). rithms using a series of rapid tests to confirm HIV infection (Fig.
27.18). Although HIV serology has sensitivities and specificities that
PATIENT EVALUATION, DIAGNOSIS approach 99.9%, false-positive and false-negative results occur. False-
positive serology is more frequent among persons with autoimmune
AND DIFFERENTIAL DIAGNOSIS disease, multiple myeloma, chronic renal failure, in persons recently
vaccinated, in women who have experienced multiple pregnancies
HIV TESTING and in persons who have been vaccinated with a candidate HIV
vaccine in clinical trials. Importantly, in low-prevalence situations
Many persons with HIV infection do not get tested until late in their
(e.g. <0.1% HIV prevalence), even tests with high specificity may yield
disease [216]. Not only is their access to ART delayed, but they remain
a relatively high proportion of falsely positive results. False-negative
unaware that they need to protect their sex or needle-sharing partners
results can occur during acute HIV infection when the person has not
from becoming infected. Many HIV-infected persons will decrease risk
yet developed detectable anti-HIV antibodies (i.e. seroconversion),
behaviors when they are aware of their positive HIV status [217, 218].
termed the “window period”. Certain tests can detect HIV RNA and
Medical treatment that lowers plasma HIV viral load also reduces risk
other HIV antigens (e.g. p24) early in infection during this “window
for transmission to others [219–221]. An international randomized
period”; however, there still remains a period of time between infec-
clinical trial demonstrated that treating an HIV-infected individual
tion and the ability to detect the virus, termed the “eclipse phase”.
with antiretrovirals can reduce the risk of sexual transmission of HIV
During both the window period and eclipse phase, HIV-infected
to their HIV-uninfected partner by 96% [222].
persons can transmit infection.
In countries with generalized epidemics, the WHO recommends HIV
HIV infection in infants and children younger than 18 months cannot
testing all persons accessing health care. Testing should be considered
be reliably diagnosed with serology because of the persistence of
a part of the standard of routine clinical care, and patients should be
transplacentally acquired maternal antibody [239]. Prompt diagnosis
informed that they will be tested for HIV infection and that they can
of HIV-infected infants with molecular testing is essential because a
“opt-out”. The highest priority for testing should be given to persons
high proportion (15–20%) experience rapid disease progression
with syndromes that suggest HIV infection (Table 27-4) and to
within the first year of life [240]; HIV-infected infants require early
persons whose behaviors or exposures substantially increase their
initiation of ART and opportunistic infection prophylaxis to survive.
risk of acquiring HIV, such as persons with other STIs, commercial
Molecular HIV testing of newborns and infants can be performed by
sex workers, IDUs, MSM, and children whose mothers have HIV
either quantifying HIV RNA or HIV proviral DNA (preferred if the
infection.
mother is taking ART). The availability of these tests is limited in low-
All pregnant women should be tested at their initial antenatal visit. income settings.
HIV testing can identify women who need their own treatment and
HIV testing algorithms should use HIV diagnostic tests that have a
who need to receive prenatal prophylaxis to PMTCT of HIV. In the
high sensitivity for locally circulating HIV subtypes (clades). Most
absence of perinatal prophylaxis or interventions to prevent transmis-
HIV EIA tests can detect the vast majority of emerging HIV-1 subtypes
sion at birth [223–226] and through breastfeeding [227, 228],
and CRFs; certain assays can also detect HIV-1 Group O and N [241–
approximately 15–40% of infants born to HIV-infected mothers will
245]. Most current EIA tests also detect both HIV-1 and HIV-2, but
become infected. Timely perinatal prophylaxis for the mother and
only a few tests will distinguish between them. Patients whose
infant, and administration of ART to the mother or infant while
EIA suggests dual infection should be confirmed with HIV-1 and
breastfeeding, can reduce the rate to <1% [39, 52, 229–233].
HIV-2 specific RNA testing or other confirmatory tests. Many com-
Clinicians should also consider testing all women during their third mercial molecular tests can detect and quantify most HIV subtypes;
trimester or at delivery, especially in regions where the HIV epidemic certain assays can quantify group O and N viruses [246, 247]. False-
is generalized among women of reproductive age. Among women negative molecular tests, however, have been reported with URFs
whose previous testing was negative, re-testing can identify women [248, 249].
who have become HIV infected or who were seroconverting. A second
HIV test during the third trimester is cost-effective [234, 235]. HIV COUNSELING
HIV-testing should be available and offered to persons in the general Post-test counseling is necessary for all patients who test positive
population. Effective models have used rapid test kits that allow [237]. Emotional support should be provided to address issues of
for immediate delivery of test results and have employed trained stigma and fear of disclosing one’s HIV status. Risk reduction informa-
lay counselors in settings with healthcare worker shortages. In tion and the value of male and female condoms should be provided
234 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
FIGURE 27.18 Example of a rapid HIV testing algorithm. Reproduced with permission from Bennett BB, Delaney K, Owen M, et al. HIV Testing Algorithms: A Status
Report. A publication of the Association of Public Health Laboratories and CDC. 2009, updated March 2010. Available at: http://www.aphl.org/aphlprograms/infectious/
hiv/Pages/HIVStatusReport.aspx (accessed 24 June 2011).
in non-judgmental language. Ideally, these devices should be made (CD4+ T lymphocyte count = 200–499 cells/µl), or Stage 3 (CD4+ T
available to the client. Counseling should emphasize that HIV infec- lymphocyte count of <200 cells/µl or an AIDS-defining condition),
tion can be treated. Patients should be encouraged to disclose their or Stage unknown (Table 27-5) [255]. HIV RNA viral load measure-
status to trusted family members and friends. Any known sexual or ment and HIV genotypic resistance testing provide information useful
needle-sharing contacts should seek HIV testing. Providers should for assessing prognosis and optimizing ART regimens. These tests are
also provide referrals to appropriate follow-up services. not widely available in resource-limited settings. In areas with a high
burden of tuberculosis, active disease can be present in up to 20–30%
INITIAL EVALUATION OF THE NEWLY of HIV-infected persons receiving clinical care [250].
moved the CD4 cell count threshold for ART initiation to 350–500
cells/µl and some recommend ART at any CD4 cell count as soon as
TABLE 27.6 Sources of Authoritative Information
HIV infection is diagnosed considering the harmful impact of on-
on HIV/AIDS going HIV replication [98, 139, 140, 266]. The initiation of ART at
CD4 cell count >350 cells/µL in resource-limited settings will be
Source Website problematic until there is the availability of more options for second-
line regimens when resistance to first-line ART develops.
World Health http://www.who.int/hiv/
Organization
ART: Initiating Therapy for Women of
U.S. Department of http://aidsinfo.nih.gov/
Health and Human
Reproductive Age
Services Most HIV-infected women and men remain sexually active, and many
continue to have children or to not use any form of contraception
European AIDS http://europeanaidsclinicalsociety.org/ [267–269]. Women of reproductive age presenting for care must be
Clinical Society assessed for pregnancy before starting therapy and referred for con-
British HIV Association http://www.bhiva.org/ traceptive counseling if not pregnant (see “Initial evaluation of newly
diagnosed women of reproductive age” above). ART should be offered to
International AIDS http://www.iasusa.org/ pregnant women with HIV infection who need it for their own health
Society – USA and started as early as possible in pregnancy for PMTCT.
NAM – aidsmap http://www.aidsmap.com/
ART: WHAT TO START
HIV InSite http://www.hivinsite.com/
More than 20 antiretroviral drugs are commercially available. Antiret-
rovirals are characterized within five drug classes according to their
mechanism of action (Table 27-7). The oldest, and most widely
used, drugs against HIV are nucleoside/nucleotide analogues that
infrastructure necessary to deliver ART and HIV care. By the end of inhibit HIV reverse transcriptase (NRTIs). Non-nucleoside reverse-
2009, more than 5.2 million of the estimated 15 million treatment- transcriptase inhibitors (NNRTIs) target reverse-transcriptase but
eligible people residing in low- and middle-income countries were are structurally dissimilar to endogenous nucleosides, and to each
receiving ART [1]. other. Protease inhibitors inhibit the HIV protease and interrupt
assembly of the mature virion. Protease inhibitors are typically co-
GOALS OF ART administered with a low dose (e.g. 100 mg) of the protease inhibitor
ritonavir that “boosts” the serum concentration of the other protease
The goal of ART is to maximally suppress HIV replication and improve inhibitors by inhibiting their hepatic metabolism. Integrase inhibitors
the health of the individual. Improving the survival of young and target HIV’s integrase enzyme and block integration of HIV DNA into
middle-aged adults reduces the number of orphaned children and is the host genome. Entry inhibitors block entry of HIV into the cell
associated with improved economic outcomes [258]. At the individ- and include fusion inhibitors and agents that block the CCR5
ual level, ART is associated with a reduction in sexual transmission of co-receptor. As of 2011, this class is not available in most resource-
HIV from an HIV-infected individual to their HIV-uninfected partner limited settings.
[222]. At the population level, reduction of the viral load of the com-
munity of HIV-infected persons leads to decreases in new HIV infec- Since 2002, the WHO has recommended use of standardized treat-
tions [259, 260]. ment regimens in resource-limited settings with reduced frequency of
monitoring compared with high-income countries [141, 270]. Table
27-8 lists combinations of first-line antiretrovirals recommended by
ART: WHEN TO START the WHO [141]. Standardization of treatment simplifies training of
ART should be initiated in persons who have developed an AIDS- clinicians, medication dispensers (e.g. pharmacists, pharmacy techni-
related opportunistic infection or illness (WHO Stage 4 or CDC Stage cians, and technologists), counselors, and community workers. There
3 illness), who have symptoms of advanced HIV disease (WHO Stage are also standards for treatment during pregnancy and co-infection
3 illness) or who have a CD4 cell count <200 cells/µl (CDC Stage 3 with tuberculosis (for special considerations in patients with tubercu-
illness) (Tables 27-4 and 27-5). HIV-infected persons with CD4 cell losis see Chapter 39, “Tuberculosis”) or hepatitis B.
counts <200 cells/µl can be asymptomatic for prolonged periods
before developing a WHO clinical indication for treatment, thus, it is
important to assess the CD4 cell count. The introduction of simplified
ART: What to Start—Special Considerations
formulations (e.g. once or twice daily combination pills), more toler- for Women Previously Given Antiretroviral
able and durable medications, and antiretrovirals that target new Drugs as Prevention of Mother-to-Child
steps in HIV’s lifecycle (e.g. integrase inhibitors, CCR5 inhibitors) Transmission (PMTCT) of HIV
have improved treatment options during earlier stages of disease
(i.e. at higher CD4 cell counts). Observational cohort studies have Women who require PMTCT should be given highly active triple
also demonstrated that initiation of continuous ART at higher CD4 combination ART; this strategy reduces the risk of perinatal HIV trans-
cell counts improves survival, increases AIDS-free survival, reduces mission and minimizes development of resistance. In resource-
non-AIDS associated outcomes (e.g. end-organ disease) [261–263] limited settings, many programs have used only one or two drugs.
and may help control inflammatory responses related to chronic Antiretroviral resistance can emerge under these circumstances [271],
HIV infection [262–264]. A randomized trial in Haiti confirmed that particularly resistance to lamivudine [272] and nevirapine [273, 274].
initiation of ART and CD4 cell counts ≤350 cells/µL was associated The resistance mutation to lamivudine confers increased susceptibil-
with lower mortality and lower rates of tuberculosis than initiation ity of HIV to other NRTIs. Thus, if this is the sole mutation present,
at a CD4 cell count of 200 cells/µl [265]. Definitive randomized then lamivudine can be used in combination with other NRTIs to
controlled trials of starting ART at even higher CD4 cell counts are treat mothers and their HIV-infected infants. Women who can wait at
underway [details can be found at: www.clinicaltrials.gov (Identifier: least one year after having received nevirapine prophylaxis for PMTCT
NCT00867048) or at http://insight.ccbr.umn.edu/start/]. respond as well to NNRTI-containing highly active antiretroviral
therapy (HAART), as women who had not been exposed to nevirap-
As of 2011, the WHO recommends treating all patients with CD4 ine [275–282]. However, if less than a year has passed, a protease
counts of ≤350 cells/µl, irrespective of their WHO clinical stage of inhibitor-based regimen is preferred [283]. Antiretroviral resistance
disease [141]. Multiple guidelines from developed countries have testing should be conducted for all women and HIV-infected infants
236 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
identify barriers to adherence and options to overcome them, and recognizing that access to laboratory capacity can be limited. Where
provide resources for assistance [292, 293]. laboratory testing is available, guidelines recommend measuring the
CD4 cell count at initiation of ART and at least twice a year thereafter.
Training healthcare personnel and community workers as treatment Monitoring CD4 cell counts provides prognostic information and
supporters can be facilitated if there is a set of essential messages. For informs the use of opportunistic illness prophylaxis. Although adding
advanced disease, improved health with ART (e.g. weight gain, CD4 cell counts to clinical monitoring improves outcomes [300, 301],
increased strength, improved social functioning) can provide positive discordant responses (e.g. viral load suppression without an accom-
reinforcement. For those with less symptomatic disease, side effects panying increase in the CD4 cell count) can occur in 20% or more
are a challenge, especially if the patient experiences minimal improve- of patients [302].
ments in their perceived wellbeing. Adherence can be improved if the
health workers, and patient, understand what to expect after initiating Monitoring plasma HIV RNA viral load is controversial. Most authori-
ART and how to differentiate minor side effects from more severe ties recommend HIV RNA viral load testing, although in resource-
events that require clinical evaluation. limited settings, adding this to routine patient monitoring does not
improve outcomes [300, 303]. HIV RNA viral load provides the most
Initiatives to maximize retention in care should identify persons who direct measure of antiretroviral effectiveness and can indirectly assess
have lapsed (e.g. missed clinic visits, missed pharmacy refills) and adherence. Confirming virologic failure rather than poor adherence
reach out to those patients in the community [294]. Successful inter- generally requires a repeat test. In developed countries, genotypic or
ventions have ranged from community workers making home visits phenotypic antiretroviral resistance testing is recommended prior to
to the use of cell phones and text messaging that enable staff at a starting treatment and as needed during treatment to optimize ART
central clinic to contact patients and community workers. Refilling in patients who are virologically failing [98, 304]. The WHO’s stand-
antiretroviral medications more regularly (a proxy for adherence to ardized approach to second-line ART for resource-limited settings
medications and retention in care) has been associated with improved limits the need for HIV-resistance testing by making treatment recom-
virologic response and survival [295–297]. It is important to retain mendations based on the assumption that prior treatment could have
persons who do not yet qualify for ART, but who need regular visits induced resistance.
for CD4 count testing and other benefits such as cotrimoxazole
prophylaxis [298].
ART: MONITORING FOR TOLERABILITY
ART: MONITORING THE EFFECTIVENESS Antiretroviral drugs have early and late-onset side effects that
OF ART can affect tolerance. Some side effects, such as headache and nausea,
The WHO recommends a minimum standard for monitoring clinical are common at treatment initiation but are usually transient and
response to ART [141, 299]. Immunologic (i.e. CD4 cell count) and manageable. Table 27-9 lists some of the most common severe
virologic (i.e. HIV RNA viral load) monitoring are not emphasized, antiretroviral side effects.
Directed assessments for adverse events (e.g. questionnaires that ART: HOW TO CHANGE (SWITCH) ART
review specific signs and symptoms, monofilament testing for periph-
eral neuropathy) can help ensure that early side effects are identified If genotypic or phenotypic antiretroviral resistance testing is available,
when it is possible to change therapy to prevent their progression. As clinicians should optimize regimens according to those results [312].
ART continues, the frequency of assessment can be decreased. It is not Resistance testing should be obtained while the patient is taking the
currently possible to identify which patients will develop side effects; failing antiretroviral regimen or shortly after treatment discontinua-
however, the risk for ART-related events may be greater in patients tion. If the first-line regimen consisted of two NRTIs combined with
with more advanced disease [305–307]. an NNRTI, a reasonable second-line regimen would consist of a riton-
avir-boosted protease inhibitor combined with two new NRTIs.
If available, routine laboratory monitoring is an important adjunct to Importantly, for HIV-infected patients who have chronic active hepa-
care and can be used to monitor for ART-associated toxicities (e.g. titis B infection, the second-line and subsequent regimens should
liver enzymes to assess for nevirapine-associated hepatotoxicity, maintain two antiretrovirals with activity against hepatitis B.
hemoglobin to assess for zidovudine-associated anemia). Laboratory
monitoring, however, is not a prerequisite for the initiation of ART
[141]. In high-income settings, guidelines typically recommend quar- ART FOR CHILDREN
terly or semi-annual testing of complete blood counts, serum chem- For perinatally infected children, ART should be started within the
istries and urinalyses, as well as CD4 cell count and plasma HIV RNA first few months of life as, without treatment, opportunistic illnesses
viral load [98]. If resources are limited, laboratory testing should be and death can occur very early. ART may need to be initiated in infants
directed by clinical signs and symptoms (see Table 27-9) [141]. The with a presumptive diagnosis of severe HIV disease (criteria are pub-
WHO also recommends testing that is tailored to the ART (e.g. creati- lished by the WHO at: http://www.who.int/hiv/pub/guidelines/art/
nine clearance for tenofovir) [141]. en/), as access to infant diagnosis (i.e. HIV proviral DNA testing) may
Most patients with advanced HIV disease starting ART experience a not be available (see “HIV Diagnosis” above) [239, 315]. These infants
return to health with improvements in functional status and labora- must be closely monitored and must have their HIV diagnosis con-
tory parameters. However, high early mortality during the first 3–6 firmed as soon as possible (at the latest, with HIV antibody testing at
months of treatment has been observed among persons with advanced 18 months of age) [316]. In all settings, pediatric ART has been com-
disease in resource-limited settings [308, 309]. Contributors to early plicated by the lack of approved drugs in child-friendly formulations
mortality include undiagnosed or untreated opportunistic infection, (e.g. liquid products). As children grow, dosages must be adjusted.
IRIS, and severe malnutrition [310]. Some manufacturers have produced child-friendly tablets at pediatric
dosages in fixed-dose combination tablets that are scored for easy
splitting and are dispersible in water [317–320].
ART: METABOLIC COMPLICATIONS Perinatally infected children can be at greater risk of infection with
DURING TREATMENT strains of HIV that have primary resistance to antiretrovirals that the
ART has been associated with the development of metabolic com mother has taken for PMTCT. Treating all HIV-infected mothers with
plications: abnormal changes in body fat distribution (lipoatrophy triple antiretroviral prophylaxis for PMTCT creates a barrier to trans-
and lipoaccumulation), serum dyslipidemias, insulin resistance and mitting drug-resistant infection [256]. Drug resistance can also emerge
glucose intolerance, and osteopenia [311]. Many metabolic complica- in HIV-infected children administered extended-prophylaxis with
tions increase the risk for chronic medical conditions (e.g. myocardial nevirapine (with or without concomitant zidovudine) during breast-
infarction, stroke, hepatic and renal failure, fragility bone fracture), feeding [321, 322] or if exposed to antiretroviral drugs through breast-
and some, particularly lipodystrophy, can impair the quality of life. feeding when their mothers are taking ART [323]. Lamivudine,
In industrialized nations, the care of HIV-infected persons is increas- nevirapine, efavirenz, but not zidovudine, are transmitted in biologi-
ingly dominated by management of these complications. cally significant concentrations via breast milk [257].
selection pressure leading to cotrimoxazole-resistant infections patients should be screened for mood and thought disorders, and
among a small number of individuals [336]; however, its use has been drug and alcohol dependency. Where feasible, supportive counseling,
associated with decreases in overall rates of sulfa-resistant malaria medication, and referral to specialists or specialized treatment pro-
[337]. Cotrimoxazole prophylaxis against Pneumocystis pneumonia grams should be provided [355].
can be safely discontinued in individuals who maintain CD4 cell
counts >200 cells/µl for >3 months [115]. It is less clear whether Vaccinations
cotrimoxazole in resource-limited settings should be discontinued; a
marked increase in the risk of malaria and diarrheal disease following Vaccination guidelines for international travel and primary prophy-
its discontinuation has been demonstrated [338]. laxis are available [342, 356–358]. Safety is a concern with some live
virus vaccines and their use should be avoided when possible, espe-
cially in persons with CD4 cell counts <200 cells/µl. Generally, vac-
Fluconazole and Itraconazole cinations are more immunogenic in persons with higher CD4 cell
Randomized clinical trials conducted in the USA, Uganda, and Thai- counts. For persons in whom immune reconstitution is anticipated
land demonstrated that primary prophylaxis with fluconazole or and vaccine resources are limited, vaccination can be deferred until
itraconazole reduces the incidence of cryptococcal disease in adults the CD4 cell count has improved (e.g. ≥200 cells/µl). Persons with
with advanced HIV disease, particularly those with CD4 counts low CD4 cell counts can be vaccinated at entry to care, and then reas-
<50–100 cells/µl [129, 339–343], and, in one trial, improved survival sessed once their CD4 cell count has improved and be revaccinated
[340]. Primary prophylaxis is not recommended in high-income if warranted.
countries with a low prevalence of cryptococcosis [115] but may be
beneficial in countries with a high prevalence of azole-susceptible Nutrition
fungal opportunistic illness (e.g. cryptococcosis, penicilliosis) [250].
Food insecurity, inadequate energy intake, malnutrition, and specific
Fluconazole can also reduce the risk of recurrent candidal infections
micronutrient deficiencies are endemic in many areas with high HIV
but the benefits are felt to be outweighed by cost and concerns about
prevalence [359–362]. The diet and nutritional status of people living
induction of fluconazole resistance [250]. Because of possible tera-
with HIV should be routinely assessed. In developed nations where
togenicity, women prescribed azoles should take effective birth
patients have had long-standing access to ART, “return to health” has
control [344].
been associated with increased rates of obesity [363]. For patients
whose expected lifespan has increased significantly, dietary coun-
Non-Tuberculosis Anti-Mycobacterials seling and exercise promotion are indicated.
[Mycobacterium Avium Complex (MAC)]
Prophylaxis against Mycobacterium avium complex (MAC) is recom- PRIMARY HIV PREVENTION
mended in developed countries for HIV-infected adults with CD4 cell Comprehensive, sustained prevention programs can reduce HIV
counts <50 cell/µl [115]. The organism is ubiquitous in the environ- transmission [364]; however, interventions do not reach most people
ment worldwide [345–347]. However, MAC infections have not at risk. Successful behavioral interventions engage high-risk popula-
emerged as a substantial cause of disease in HIV-infected persons tions and offer educational messages coupled with prevention skills,
outside of North and South America and Europe. Primary prophylaxis such as how to negotiate condom use and how to refuse sex.
against MAC is not addressed in WHO guidelines [141].
HIV testing is an important component of primary HIV prevention
as half of all persons living with HIV worldwide are unaware of their
NON-PHARMACOLOGIC INTERVENTIONS status [365]. Offering opt-out HIV testing in most clinical settings (e.g.
Insecticide-treated bed nets or indoor residual spraying for mosqui- antenatal clinics, pediatric and adult general medicine clinics, inpa-
toes can prevent malaria, especially the associated risk for placental tients settings) has been widely recommended. Couples testing and
infection and its complications. Interventions to improve point-of-use counseling is acceptable in high-risk populations where transmission
water safety and hand hygiene (e.g. latrines, soap-and-water hand- is predominately heterosexual [216]. Couples testing can be linked to
washing) can decrease the risk of diarrheal disease at both the family, ART of an HIV-infected partner, which can reduce transmission to the
clinic and community levels. Reducing the burden of tuberculosis in HIV-negative partner by as much as 96% through suppression of viral
persons with HIV should also include infection control measures, load [221, 222, 366].
such as early triage and separation of persons with suspected tuber-
culosis and efforts to optimize ventilation [348]. A safe and effective HIV vaccine would be a major advance and is the
subject of intense research efforts [367]. Male circumcision reduces a
man’s risk of acquiring HIV heterosexually by 50–60% [43–45]. In
CHRONIC PRIMARY CARE CONSIDERATIONS high prevalence areas where a large fraction of the regional popula-
tion is uncircumcised, large-scale implementation of male circumci-
Smoking Cessation sion has the potential to prevent many new infections.
Adult male prevalence estimates for daily cigarette smoking in 2006
ranged from 4–27% for countries in Africa, 18–57% for countries in Interventions that women can control, such as vaginal microbicides
Asia, and 2–39% for countries in the Americas [348]. In many coun- containing antiretrovirals, have shown early promise (39% reduction
tries, rates of tobacco smoking in HIV-infected adults are substantially in HIV incidence) [368], and are the subject of intense investigation.
higher than rates in the general population [196, 349–351]. HIV- Daily oral administration of antiretroviral drugs to high-risk, HIV-
infected adults are at increased risk of many diseases for which the negative individuals, termed “pre-exposure prophylaxis”, has been
burden is greater in tobacco smokers: cardiovascular disease (e.g. demonstrated in one trial to prevent HIV infection among MSM (44%
myocardial infarction), pulmonary disease (e.g. bacterial pneumonia, reduction in HIV incidence) [369]. Trials among heterosexual men
chronic obstructive pulmonary disease (COPD), tuberculosis [352]), and women have also demonstrated an HIV prevention benefit from
and cancer (e.g. lung cancer) [348]. Smoking cessation is among the pre-exposure prophylaxis in Botswana (62% reduction in HIV inci-
most cost-effective interventions for reducing long-term morbidity dence) and in Kenya and Uganda (67–75% reduction in HIV inci-
and mortality for HIV-infected persons [353]. dence) [370, 371]. Higher levels of protection were observed with
more consistent use of pre-exposure prophylaxis in these trials.
However, another trial conducted in Kenya, South Africa, and Tanza-
Mental Health nia among high-risk, HIV-negative women failed to demonstrate
Mental health conditions, such as depression and substance abuse, benefit; it is likely that low overall adherence contributed to the lack
are common among people with HIV, reduce quality of life and of efficacy, though other contributing factors may have made pre-
present challenges to adherence and retention in care [354]. All exposure prophylaxis less effective [372].
240 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
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Viral Respiratory Infections 29
H Rogier van Doorn, Hongjie Yu
TABLE 29-1 Results of Recent Etiological Studies on Respiratory Viral Infections in Tropical and Subtropical Regions
Country Years Setting Patients Method Disease Number RSV hMPV FluA FluB PIV1 PIV2 PIV3 PIV4 Adeno Entero Corona Rhino Boca KI-WU
NL63 HKU1 229E OC43
Adeno, Adenovirus; ARI, Acute Respiratory Infection; CAP, Community Acquired Pneumonia; Entero, Enterovirus; FluA, influenza virus A; FluB, influenza virus B; H, Hospitalized; hMPV, human metapneumovirus; HO, Hospitalized and Outpatients; LRTI, Lower
Respiratory Tract Infection; O, Outpatients, PIV, parainfluenza virus; RSV, respiratory syncytial virus; RT-PCR, Reverse Transcription-Polymerase Chain Reaction; Corona, Coronavirus; Rhino, Rhinovirus; Boca, Bocavirus, KI-WU, KI and WU polyomaviruses.
Vi ra l R e s p i rato r y I nfec tions 271
FIGURE 29.1 The reservoir of influenza A viruses. The working hypothesis is that wild aquatic birds are the primordial reservoir of all influenza viruses for
avian and mammalian species. Transmission of influenza has been demonstrated between pigs and humans (solid lines). There is extensive evidence for
transmission between aquatic birds and other species including pigs and horses and indirect transmission to humans through pigs and evidence for direct
transmission to humans from chickens (with permission from Elsevier Ltd, Encyclopedia of Virology 2nd edition; 1999; pp 824-829).
such an introduction, the new virus becomes the dominant circulat- passed and around 18,000 people died from infection during the
ing lineage of influenza A. One exception was the re-introduction pandemic phase. The virus has now become established as a seasonal
of H1N1 in the human population in 1977, which was possibly virus, has largely replaced the former H1N1 virus and is co-circulating
caused by an escape from a research laboratory. Since 1977, two line- with H3N2.
ages of H1N1 and H3N2 influenza A viruses have been co-circulating
among humans, causing yearly seasonal epidemics worldwide Sporadic, dead-end human infections of animal viruses are known to
(Fig. 29.2). Influenza B viruses co-circulate with influenza A viruses occur and have caused concern about the pandemic potential of these
and also cause yearly epidemics but have not been associated with viruses. H7N7, H7N3 and H9N2 viruses have caused conjunctivitis
pandemics. and mild, flu-like illness in patients who were in close contact with
infected birds or seals. In contrast, H5N1 avian influenza viruses have
In 2009, a novel lineage of H1N1 influenza A virus emerged, most caused severe human respiratory illness in Asia and North Africa, with
likely from pigs, in North America and caused a worldwide pandemic a mortality of over 50%. Highly pathogenic H5N1 viruses were first
of relatively mild influenza. At the time of writing, the pandemic has detected in birds in 1996 in China. Transmission to 18 humans
272 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
2009 H1N1 epidemic of SARS, with 8096 cases and 744 deaths in 29 countries
across 5 continents, started in November 2002 and came to an end
H1N1
in July 2003. Few sporadic community- and laboratory-acquired
H3N2 infections, including limited person-to-person transmission, have
H2N2 been recorded since. SARS was characterized by fever and myalgia,
rapidly progressing to a respiratory syndrome of cough and dyspnea
H1N1 followed by acute respiratory distress syndrome. Mortality was signifi-
1918 1957 1968 1977 2009 cantly lower in children.
FIGURE 29.2 Timeline of circulating subtypes of influenza virus A from SARS is primarily spread by the respiratory route, but oral–fecal trans-
1918 onwards. In 1977, H1N1 was reintroduced and has since then mission has also been implicated. Why the SARS epidemic did not
co-circulated with H3N2. In 2009 a new H1N1 lineage (pdm09) was continue to spread is subject to much speculation. Explanations may
introduced which has replaced the former H1N1 subtype. include the fact that SARS is most infectious in a later stage of infec-
tion, allowing for timely containment, and an extraordinary world-
wide public health effort to control spread [16].
occurred in Hong Kong, six of which were fatal. During the next 6 PICORNAVIRUSES: RHINOVIRUSES,
years, no human or animal cases were recorded. In 2003, the virus ENTEROVIRUSES AND PARECHOVIRUSES
re-emerged in China. Since then, it has become panzootic among Rhinoviruses are the most important cause of the common cold and
poultry and wild birds and, at the time of writing, has caused 584 may be associated with exacerbations of asthma and chronic bron-
sporadic infections (345 fatal) in humans, most of whom reported chitis. Enterovirus and parechoviruses typically present with aseptic
close contact with wild birds or domestic poultry. Despite their world- meningitis but are also associated with (mild) respiratory illness.
wide presence for many years, and the huge human–animal interface
in Asia, no efficient human-to-human transmission episodes have
been recorded. The possibility of mutations or re-assortment in these ADENOVIRUSES
viruses remains a cause for concern and warrants continuous moni- Adenoviruses are a frequent cause of epidemic infective conjunctivitis
toring and surveillance of H5N1 viruses [15]. in developing countries and of respiratory tract infections in children
and young adults worldwide. Outbreaks can occur in closed com-
PARAMYXOVIRIDAE: RESPIRATORY munities such as day care centers and boarding schools, and among
military recruits. Most adenoviral infections remain subclinical.
SYNCYTIAL VIRUS (RSV), PARAINFLUENZA
VIRUS 1–4 AND HUMAN METAPNEUMOVIRUS
(HMPV) NATURAL HISTORY
These six human viruses are the most important causes of lower res- AND PATHOGENESIS
piratory tract infections in children worldwide. RSV is the single most
important cause of bronchiolitis and the leading cause of respiratory Acute respiratory viral infections usually start in the upper respiratory
tract infections requiring hospitalization. Human metapneumovirus tract as the port of entry is the nose, mouth or eyes. Spread to the
(hMPV) causes similar, but less frequent, disease, whereas the parain- lower parts of the airways occurs within two to four days. Syndromes
fluenza viruses are associated with croup. overlap considerably, are usually accompanied by symptoms such as
fever, cough and malaise, and can be caused by any of the pathogens
Infections with these viruses are very common and virtually all described above.
children will have been infected with RSV by 2 years of age and by
hMPV at 5 years of age. Immunity against all viruses is incomplete, In developing countries in particular, crowding of large families in
although re-infections tend to be milder. Severe disease is common small houses, low levels of sanitation and personal hygiene, indoor
from RSV and hMPV in the first year of life. Re-infection with RSV or and outdoor smoke pollution, malnutrition, vitamin and mineral
parainfluenza viruses is also a common cause of pneumonia in deficiencies, and a high frequency of respiratory infections may have
elderly and immunocompromised patients [6]. Other paramyxoviri- detrimental effects on the integrity of the respiratory mucosa, respira-
dae, such as rubeola virus (measles) or the zoonotic nipah virus may tory function and the immune status, making the patient more prone
also be associated with respiratory disease as part of disseminated to repeated, and more severe, viral infection and to secondary bacte-
infection. These are discussed in separate chapters. rial infection. Old and very young age, including prematurity are
additional risk factors for a more severe course.
CORONAVIRUSES AND SEVERE ACUTE
RESPIRATORY SYNDROME CLINICAL FEATURES
(SARS)-CORONAVIRUS Common Cold
The four main human respiratory coronaviruses (229E, OC43, NL63
The common cold, or coryza, is the most frequent disease worldwide.
and HKU1) are associated with relatively mild upper respiratory infec-
Specific symptoms include a runny or stuffed nose, sneezing and sore
tions and may cause 10–25% of episodes of common colds, but are less
throat. Picorna- and coronaviruses are often involved. Symptoms are
frequently implicated in severe infections requiring hospitalization.
caused by local infection of the ciliated nasal mucosal epithelium cells
In 2002–2003, a novel, severe form of pneumonia of unknown etiol- and surrounding increased vascular permeability. Disease is usually
ogy emerged in Guangdong, China and was named Severe Acute self-limiting.
Respiratory Syndrome (SARS). After smoldering for several months,
the disease then spread rapidly across the world, facilitated by inter-
national air travel and a few so-called “super-spreaders”, with the Pharyngitis
most notable outbreaks in Hong Kong and Toronto. Twenty-one Sore throat often accompanies the common cold but is typically
percent of affected cases were healthcare workers. The rapidly identi- not the result of inflammation of the throat, rather it is caused by
fied culprit, SARS coronavirus, is thought to have jumped to humans excretion of chemical inflammation mediators that stimulate pain
from Civet cats (considered a delicacy in Asia) in live animal markets nerve endings. Bacteria are a common cause of true pharyngitis, as
in Guangdong. Wild civet cats, however, do not carry these viruses but are coxsackieviruses, Epstein-Barr virus (EBV) and cytomegalovirus
certain bat species have been implicated as the natural reservoir. The (CMV).
Vi ra l R e s p i rato r y I nfec tions 273
Acute Laryngotracheobronchitis (Croup) The identification of one viral agent does not rule out a double infec-
tion or mixed bacterial–viral infection. Recently, several novel viruses
Croup affects children under the age of 3 years; the hallmark symp- have been identified in the human respiratory tract (Bocavirus, WU
toms are a barking cough and acute inspiratory stridor. Symptoms are and KI polyomaviruses, amongst several others). The exact signifi-
caused by localized subglottic inflammation and edema leading to cance of the role of these viruses as pathogens has yet to be
airflow impediment. established.
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9. Bharaj P, Sullender WM, Kabra SK, et al. Respiratory viral infections detected 19. Smith GJ, Bahl J, Vijaykrishnaa D, et al. Dating the emergence of pandemic
by multiplex PCR among pediatric patients with lower respiratory tract influenza viruses. PNAS 2009;106:11709–12.
infections seen at an urban hospital in Delhi from 2005 to 2007. Virol J
2009;6:89.
Viral Gastroenteritis 30
Osamu Nakagomi, Nigel A Cunliffe
3.5
Key features Over age five
3.0 Under age five
l Viruses are the major etiologic agents of acute
2.5
gastroenteritis, both in developing and developed
Deaths in millions
countries, particularly in children younger than 5 years of
2.0
age; in this age group diarrhea is the second most common
cause of death 1.5
l All gastroenteritis viruses, also referred to as diarrhea viruses,
cause acute-onset, watery, non-bloody diarrhea 1.0
l There are currently four genera and one species of viruses
recognized as established causes of gastroenteritis in 0.5
humans: Rotavirus, Norovirus, Sapovirus, Astrovirus and
Human adenovirus F (also referred to as enteric 0
adenoviruses)
es
io y
is
ia
as al
S
ct or
ID
os
ar
se he
sl
ns
es
fe at
/A
al
ea
ul
di iarr
l Diarrhea caused by these gastroenteritis viruses is
in pir
M
rc
IV
M
D
s
be
H
indistinguishable by clinical features alone; etiologic
re
Tu
e
ut
INTRODUCTION
Acute diarrhea is the cardinal symptom of viral gastrointestinal infec-
tion and is defined as the passage of three or more watery or looser-
than-usual stools within the preceding 24 hours for less than 2 weeks’
duration. Globally, diarrhea is the second most common cause of
death (18%, 10.8 million) in children younger than 5 years of age
and it causes more deaths in this age group than HIV/AIDS, tubercu-
losis and malaria put altogether (Fig. 30.1). Viruses account for the
major proportion of causative agents responsible for acute gastroen-
teritis both in developing and developed countries.
Viral gastroenteritis generally presents a similar clinical picture—
whatever the virus—requiring laboratory investigation for establish-
ing its etiology. Signs and symptoms of typical acute viral gastroenteritis
include acute onset of diarrhea, often with preceding vomiting, and
sometimes with fever and abdominal pain. The most important com-
plication is dehydration and this requires oral or intravenous fluid
replacement therapy depending on the degree of dehydration. The
disease typically lasts 3–5 days and is self-limiting. The viruses are
transmitted feco–orally and infect the epithelial cells of the small
intestine. Damage to the villous epithelium of the small intestine
affects the absorption of fluid and causes watery diarrhea. No inflam-
mation occurs as the viruses only multiply within the enterocytes in FIGURE 30.2 Negative-stain electron micrograph of rotavirus particles.
the intestinal epithelium and do not spread into the submucosa. The bar represents 100 nm (courtesy of Brian Getty, University of Liverpool).
275
TABLE 30-1 Characteristics of the Major Gastroenteritis Viruses
There are currently four genera and one species of viruses recognized sapovirus is to be made at the level of nucleotide sequence. The use
as established causes of gastroenteritis in humans: Rotavirus, Norovirus, of the term “human calicivirus” is discouraged because it is some-
Sapovirus, Astrovirus and Human adenovirus F (to which serotypes 40 times confusing whether human calicivirus refers to both norovirus
and 41 belong and which are also referred to as enteric adenoviruses). and sapovirus (they are calicivirses causing disease in humans) or
As these viruses are often shed in large numbers into stool, they can only morphologically identified human caliciviruses, in which case
be identified by direct, negative-stain electron microscopy based on noroviruses are excluded.
their characteristic morphology (Fig. 30.2). What were previously
called small-round structured viruses (SRSV) roughly correspond to The major features of these gastroenteritis viruses are summarized in
norovirus and morphologically identified human caliciviruses corre- Table 30-1.
spond to sapovirus; however, the distinction of both norovirus and
31 Viral Hepatitis
G Thomas Strickland, Samer S El-Kamary
CLINICAL FEATURES this complication is less common in other areas. It has been reported
in less than 1 in 200 cases of HAV, is very rare in acute HCV infections,
The particular virus causing hepatitis can rarely be clinically ascer- but is more common in acute HBV, particularly when there is a con-
tained. However, hepatitis viruses have some tendency to manifest comitant HDV infection.
differently.
Cirrhosis
ACUTE HEPATITIS Chronic hepatitis B and C are the most common cause of cirrhosis
Characteristically, there are four phases of viral hepatitis. After expo- of the liver. Several factors are associated with the fibrosis progression
sure, the virus incubates for from 2–6 weeks for HAV and HEV, and rate: duration of infection, age, male gender, alcohol consumption,
from 4–10 weeks for HBV and HCV [4, 22]. Then there may be a HBV, HCV and HIV co-infections, and low CD4 count. Steatosis,
prodromal illness, characterized by fever, chills, headache, fatigue, being overweight and diabetes are cofactors of fibrogenesis. The viral
malaise, rash, arthritis, right upper quadrant pain and a tender liver. genotype and viral load have no relationship with the development
Several days later and often coincident with an improvement in sys- of cirrhosis.
temic symptoms, the patient will have more pronounced anorexia,
nausea, vomiting, weight loss and right upper quadrant abdominal
pain. Jaundice is usual and may persist for several weeks in associa- PATIENT EVALUATION
tion with dark urine, light (clay-colored) stools, and pruritus [2, 25, The classical finding in acute viral hepatitis is jaundice, although
26]. Often, the patient feels better following the onset of jaundice. patients with milder infections may have bilirubin levels below the
Most symptoms of viral hepatitis abate within 1–3 weeks. Acute 2.0–2.5 mg/dL in which jaundice is not detectable. Patients with
HCV infections are usually anicteric and are often not diagnosed. chronic hepatitis usually do not have jaundice. In both conditions,
During outbreaks of HAV, and particularly HEV, there are many the patient has other symptoms and signs listed in other sections. The
asymptomatic, mild and anicteric cases. As the acute hepatitis con- classic laboratory abnormalities of acute hepatitis are elevated serum
tinues to convalesce, the patient may, or may not, remain icteric, but ALT and aspartate aminotransferase (AST) 10–20 times higher than
they almost always have anorexia, nausea, weight loss, and, if they normal. The serum bilirubin is usually elevated, often peaking 10–15-
smoke cigarettes, lose their taste for smoking. Patients infected with times normal. Clinical jaundice is noted when it exceeds 2.5–3.0 mg/
HAV or HEV are more likely to have intestinal symptoms, dL. There may be elevations in alkaline phosphatase, and atypical
while those with HBV infections may have rash, arthralgias and lymphocytes can be noted in the peripheral blood film in the pres-
arthritis [2]. ence of a normal leukocyte count. Bilirubin is often also present in
the urine. These laboratory abnormalities can help detect mild and
CHRONIC HEPATITIS asymptomatic cases [2, 25].
While acute infections with hepatitis A and E resolve, HBV, HCV and Diagnosis of anicteric cases of hepatitis are often based upon obtain-
HDV infections may persist. The frequency of persistence varies with ing a history of potential exposures to patients with hepatitis or risk
the virus and the host and inversely correlates with the severity of factors of infection. The severity of acute viral hepatitis is best meas-
acute infection suggesting that cell mediated immunity (CMI) is ured by the clinical symptoms and serum levels of bilirubin, ALT or
involved in resolving the infection. HBV infection persists in less than AST. The severity of chronic hepatitis is best measured by these same
5% of those infected as adults, but in greater than 80% of those findings and may be supplemented by liver biopsy, ultrasonography
infected as infants. Acute HCV infection is symptomatic less fre- and other noninvasive tests of hepatic fibrosis.
quently than hepatitis B and is less likely to become chronic in chil-
dren than in adults and in women than in men. Published prevalence Each virus elicits a characteristic antibody response. Detection of
of persistence of HCV infections range from 60–85%. virus-specific IgM class immunoglobulins generally represents acute
infection, while IgG antibodies may be present years after resolution
Patients with persistent hepatitis B and C often develop a smoldering of disease. Recognition of viral antigens or nucleic acid represents
chronic hepatitis that usually remains asymptomatic for 15–35 years ongoing infection and correlates with transmissibility.
before complications of cirrhosis and hepatocellular carcinoma occur.
Bouts of mild acute hepatitis can occur intermittently in patients with
occult chronic HCV infections [25]. They usually have mild flu-like TREATMENT AND PREVENTION
symptoms and mild jaundice with alanine transaminase (ALT) levels There is no specific treatment for acute HAV and HEV hepatitis. Sup-
100–200 mg/dL. These abnormalities and symptoms often clear in of portive care, including rest, is important [26, 27]. Silymarin, a milk
2–3 weeks. There have been recent reports of persistent HEV infec- thistle extract, was reported to slightly accelerate recovery of some
tions which led to chronic hepatitis, but these are very rare. symptoms of acute clinical hepatitis; however, the most effective dose
schedule has not been ascertained [28]. Secondary transmission
COMPLICATIONS should be prevented through active and passive immunization and
Usually, the symptoms of acute hepatitis abate after 2–3 weeks, but careful sanitation and behavior modification.
malaise, fatigue, anorexia and weight loss may persist for up to 6–8 See subchapters on HBV, HCV and HDV below on treatment of acute
weeks. and chronic infection with these viruses.
Highly effective vaccines are available for preventing HAV and HBV
Fulminating Hepatitis infections [3, 17, 23, 30]. Phase III clinical trials for HEV vaccines were
Rarely, acute viral hepatitis may be fulminant, associated with altered 95% effective, but they are not commercially available [111, 112].
mental status, coagulopathy and severe jaundice, leading to death. Several preventive and/or therapeutic HCV vaccines are currently
Fulminating hepatitis occurs more frequently during acute HEV infec- undergoing Phase II clinical trials [29]. HDV infections requiring HBV
tions, particularly in pregnant women in the Indian subcontinent, but replication can be prevented by immunization for HBV.
292 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
31.1 Hepatitis A
ROUTES OF TRANSMISSION
HAV-caused acute viral hepatitis is principally transmitted person-to-
person by a fecal-oral route 2–6 weeks following exposure. It usually
requires levels of exposures that occur within a family or between
playmates. Asymptomatic transmission between children and then to
a parent is especially characteristic, illustrating why daycare centers
may be implicated in the spread of infection. Food- and water-borne
HAV infection often involves a food handler with hepatitis A who
failed to observe hand-washing protocol after defecation. Contamina-
tion of inadequately chlorinated water sources has led to both epi-
demic and sporadic HAV infections. Shellfish are particularly
associated with HAV transmission, as they concentrate the virus by
filtering large volumes of contaminated water. A massive epidemic of
HAV occurred in Shanghai in 1988 following ingestion of under-
cooked shellfish. The short period of viremia before the onset of
symptoms makes parenteral transmission possible, but this is rare.
Specific risk factors for HAV infection in developed countries include
contact with another person with hepatitis or jaundice, homosexual-
ity, travel to a less developed country, contact with children attending
daycare centers and intravenous drug abuse. HAV infection is still
endemic among Native Americans in the western states of the USA
and Alaska.
CLINICAL FEATURES
After a susceptible person ingests HAV, viral replication occurs prin-
FIGURE 31.2 Hepatitis A virus particles in a fecal extract obtained from a cipally in the liver. Virions can be detected in stool and blood before
patient during the late incubation period of the infection. The particles the onset of symptoms. Serum transaminases increase several days
measure 25–27 nm in diameter and possess cubic symmetry (× 300,000). after viral replication begins, indicating that hepatocellular damage
Vi ral Hepatitis 293
31.2 Hepatitis B
EPIDEMIOLOGY
It is estimated there are 400 million people living with chronic HBV
infection (the majority in Asia, sub-Saharan Africa and other develop-
ing countries). Half a million deaths occur annually because of HBV-
associated cirrhosis and hepatocellular carcinoma; an additional
40,000 die of acute HBV infection [24].
GEOGRAPHIC DISTRIBUTION
There are marked geographic differences in the prevalence of HBV
infection (Fig. 31.5) and principal routes of transmission. The inci-
dence of infection has been markedly reduced by wide-spread use of
the HBV vaccines, serologic tests to screen blood transfusions and
blood products, and by the availability and use of disposable syringes FIGURE 31.4 Electron micrograph showing the complex morphology of
and needles. Despite a marked reduction in transmission in devel- hepatitis B virus in serum: (1) small spherical particles of HBsAg; (2) tubular
oped countries over the past 30–35 years, HBV remains a major structures of the surface antigen; (3) large spheroidal particles and the
cause of chronic liver disease. This is mostly because of the delay complete virus particle, which may be solid or double-shelled (× 252,000).
Vi ral Hepatitis 295
concentrations of virus or a break in mucosal barriers, for example as of persistence can generally be detected histologically (immune active
might occur with anal receptive intercourse, in someone with a genital phase). In one study, the five-year survival was 86% in patients with
ulcer, and between children with ulcerative skin lesions. chronic active hepatitis and 55% once cirrhosis was evident.
+ + – + + – Acute hepatitis B
– – + +/– + + Convalescence
– – – – + + Recovery
surface (anti-HBs) and e (anti-HBe) antigens then appear, with anti- for patients with hepatic decompensation, immunosuppression, or
HBe indicating low infectivity and resolving infection [37]. medical or psychiatric contraindications. The advantage of interferon
is that it is administered for a finite duration and is associated with a
DETECTION OF HBV-DNA higher rate of HBsAg and HBeAg clearance and sustained suppression
of viral replication. The main disadvantages of interferon are the need
The presence of HBV-DNA represents viral replication and infectivity for parenteral administration and its frequent side effects. Nucleos(t)
and is present early in acute cases of HBV and persistently in chronic ide analogs are administered orally and are well tolerated; however,
infections. In addition, the loss of HBV-DNA has been used as a viral relapse is common once treatment is discontinued, necessitating
marker of successful therapy. long durations of treatment with associated risks of antiviral drug
resistance.
TREATMENT [39, 41] The nucleos(t)ide analogs in use for treating hepatitis B fall into three
HBV therapy is complicated and it is recommended that more detailed groups: L-nucleosides, including lamivudine and telbivudine; acyclic
instructions be used for its management. Clearance of HBsAg natu- nucleoside phosphonates, including tenofovir and adefovir; and ente-
rally occurs in about 2% of chronic carriers each year. Seroclearance cavir, a deoxyguanosine analog. Mutations associated with drugs in
is greater in older individuals and those with lower viral loads; one group confer some resistance to other drugs within the same
HBV-DNA levels almost always become undetectable before HBsAg group and may reduce the sensitivity to drugs in other groups. The
clears [42]. Treatment is given for chronic hepatitis B to prevent the selection of the initial treatment should be based on antiviral activity
development of cirrhosis and hepatocellular carcinoma. Treatment and risk of antiviral resistance. Entecavir, telbivudine and tenofovir
criteria are based on HBV replication status and stage of liver disease, have more potent antiviral activity, while entecavir and tenofovir have
modulated by the patient’s age and HBeAg status. Therapeutic end a lower rate of resistance. Nucleos(t)ide analogs are most appropriate
points are viral suppression, ALT normalization, HBeAg and HBsAg for patients with decompensated liver disease, or contraindications to
loss, and improvement in liver histology [41]. interferon, and who will tolerate long durations of treatment. Ente-
cavir and tenofovir have the best profile regarding efficacy, safety and
Two formulations of interferon and five orally-administered nucleos(t) drug resistance. Entecavir is preferred in patients with other medical
ide analogs are approved for use in the USA. These therapies are effec- conditions that are associated with increased risks of renal insuffi-
tive in suppressing HBV replication and prevent disease progression. ciency, whereas tenofovir is preferred in young female patients con-
They have reduced the number of patients requiring liver transplants templating pregnancy and patients who may have been exposed to
and age -elated HBV deaths. However, there is still uncertainty about lamivudine in the past. Lamivudine and telbivudine should not be
when to start treatment: which medication should be used first, when used as first-line therapy because of high rates of drug resistance,
can treatment be stopped? whereas adefovir is largely superseded by tenofovir because of its weak
Treatment is clearly indicated for patients with acute liver failure, antiviral activity.
decompensated cirrhosis, advanced fibrosis with high serum HBV
DNA levels, and those who are HBsAg positive who will be receiving Peginterferon-alpha-2a (40 kD; PEG INF) is used to treat adults with
cancer or immunosuppressive chemotherapy. Therapy is also often HBeAg-positive or HBeAg-negative chronic hepatitis B with compen-
recommended for patients with compensated cirrhosis who have high sated liver disease having viral replication and hepatic inflammation.
levels of HBV replication, i.e. HBeAg positive and/or high levels of It is given subcutaneously once a week; 48 weeks of therapy with PEG
serum HBV DNA. As chemotherapy reduces the incidence of hepato- INF with, or without, lamivudine was more effective than lamivudine
cellular carcinoma, these criteria may be broadened to treat all alone in achieving a sustained response in patients with HBeAg-
patients with compensated cirrhosis. positive or -negative chronic hepatitis B. A long-term follow-up study
in patients with HBeAg-positive disease who received PEG INF mono-
The decision to use nucleos(t)ide or interferon therapy is based on therapy revealed an HBeAg seroconversion rate of 42% one year after
patient characteristics and preference. Interferon is not recommended the end of treatment. A five-year follow-up after the end of treatment
Vi ral Hepatitis 297
of HBeAg-negative patients who received PEG INF with, or without, also available, as are recombinant vaccines that include pre-S and
lamivudine reported HBsAg clearance in 12% of patients and inactive S antigens.
chronic hepatitis B in 17%.
Hepatitis B vaccines are among the safest and most immunogenetic
A meta-analysis of 15 studies reported that 33% and 37% of interferon- products available. Mild injection-site reactions occur in about
treated patients had undetectable levels of HBeAg and HBV-DNA 20% of people, but fever and other systemic symptoms are uncom-
compared with 12% and 17% among those given placebo. The mon. Protection occurs in more than 95% of healthy infants, children
nucleos(t)ide analogues can reduce HBV replication and increase the and adults. Although the recommended schedule includes three
rate of HBeAg clearance and decrease hepatic inflammation. However, doses at 0, 1 and 6 months, minor alterations in the timing of
in most patients the effect is not sustained when the drug is discon- vaccine administration does not reduce the immunogenicity. Protec-
tinued, which has lead to the recommendation that treatment be given tion is evident within a couple of weeks of the second dose correlates
for years. Clearance of HBeAg following treatment has been associated with anti-HBs titers above 10 mIU/mL. Generally, immunization
with improved biochemical, virologic and histologic outcomes in schedules include a booster dose 4–6 months after primary immuni-
both HBeAg-positive and -negative patients. For a few patients this is zation in order to obtain higher antibody titers and more durable
associated with resolution of infection. For others it leads to remission protection.
and a reduced risk of progressing to cirrhosis, hepatocellular carci-
noma, liver transplant and death. For others who do not respond, or A nationwide HBV vaccination program in Taiwan has markedly
who relapse, re-treatment with another agent can be considered. reduced the prevalence of HBsAg carriage [43]. This program, which
was started in 1984, had already markedly reduced the incidence of
hepatocellular carcinoma in Taiwanese children by 1994 [44]. Even
PREVENTION AND CONTROL [6] in North America, Europe and other areas with low HBV incidence,
the high risk of chronic disease resulting from HBV infection occur-
HBV infection can be prevented by reducing exposures, by passive ring in childhood, the difficulty reaching persons at risk later in life
immunoprophylaxis and by immunization. Dramatic reductions in and other factors make universal vaccination of infants a rational
post-transfusion HBV infection have been achieved by screening strategy [45].
blood and blood products for HBsAg. Infection control policies to
prevent transmission in hemodialysis units and healthcare centers
also have reduced nosocomial transmission. Reductions in high-risk
POST-EXPOSURE PROPHYLAXIS
sexual and drug-related practices led to declining rates of HBV infec- HBV infection can also be prevented after exposure has occurred
tion in some homosexual and drug-using populations. [46]. Common examples include perinatal or sexual exposures, and
needle-stick accidents. Anti-HBsAg should be assessed in individuals
who have been vaccinated or who are at high risk of infection. Those
HBV VACCINATION with anti-HBs titers greater than10 mIU/mL can be reassured. Previ-
Vaccination is the most important means of reducing HBV transmis- ously vaccinated persons with anti-HBs titers less than10 mIU/mL
sion. The heat-inactivated or chemically-inactivated subviral particles should receive HBV-enriched immunoglobulin (HBIG) and a dose of
derived from chronic HBsAg carriers (plasma-derived vaccine) vaccine. Individuals without prior HBV vaccination or infection
has largely been replaced by HBsAg particles expressed from recom- should receive HBIG and three doses of vaccine. This regimen can
binant DNA in the yeast Saccharomyces cerevisiae (recombinant vaccine). markedly reduce the incidence of HBV infection in infants born to
Combination vaccines that contain recombinant HBsAg coupled HBeAg-positive mothers and to those having occupational or sexual
with HAV, Haemophilus influenzae and other childhood vaccines are exposures [47, 48].
in the upper Amazon River basin along the Purus and Juruá Rivers in
Brazil [49, 50].
Key features
HDV is an unclassified RNA virus that is dependent on HBV envelope
l Hepatitis delta virus (HDV) infection occurs either with proteins for replication [51]. HDV is distinct from antigenic deter
acute HBV (co-infection) or in a patient chronically infected minants of HBV and is localized in the nuclei of liver cells of
patients with HBV infection. HDV-RNA encodes for two forms of the
with HBV (superinfection) nucleocapsid protein, the delta antigen (HDAg). The two HDAg prod-
l Transmission by parenteral, sexual and household exposures ucts function differently, the short form being necessary for viral
l Superinfection in person with chronic HBV is associated with replication while the longer is required for packaging the genome and
more severe hepatitis and increased progression to cirrhosis suppressing replication.
l Can be prevented by HBV immunization
EPIDEMIOLOGY
The distribution and transmission of HDV infection has three pat-
INTRODUCTION terns: (1) endemic and associated with non-parenteral spread in Italy,
other Mediterranean countries and the Middle East; (2) endemic-
In 1981 an outbreak of severe hepatitis was investigated among Amer- epidemic in the Amazon area and other remote areas of South
indians in Venezuela. The disease, having a high mortality, especially America; and, (3) sporadic and associated with parenteral transmis-
among young children and adolescents, was caused by the delta sion in almost all other geographic areas. Like HBV and HCV, HDV
agent. The clinical and epidemiologic features of the outbreak were is parenterally transmitted [9]. HDV in developed countries is most
similar to those in previous reports of Labrea hepatitis (black fever) prevalent in certain high-risk groups, for example illicit intravenous
298 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
drug users. It can be transmitted both sexually and through non- decompensation occurred in 33% and hepatocellular carcinoma in
sexual household contacts; the latter is the most common route of 13%. The 5- and 10-year survival free of events were 96.8% and
transmission in indigenous populations in South America, Africa and 81.9%, respectively, for patients with chronic hepatitis, and 83.9%
parts of Central and Southeast Asia. and 59.4% for cirrhotics. Lack of antiviral therapy, cirrhosis at pres-
entation and male sex independently predicted a worse outcome. Half
of HDV-infected patients who develop cirrhosis advanced to liver
CLINICAL FEATURES AND NATURAL failure and interferon therapy was recommended to slow, or alter, the
HISTORY [9] natural course of liver disease [52].
HDV infection can occur with acute HBV (co-infection) or in a patient
chronically infected with HBV (superinfection). After an incubation of DIAGNOSIS
4–8 weeks, there is a viral hepatitis syndrome that is generally more Acute HDV and HBV co-infection is recognized by transient detection
severe than with other hepatitis viruses and which may be fulminant. of HDAg or, more often, antibody to HDAg (anti-HD) with the
When HDV and HBV co-infection occurs, recovery is the rule. In con- typical serologic profile for acute HBV infection. Within months of
trast, HDV superinfection of chronic hepatitis B persists in more than infection, there may be no serologic evidence of HDV co-infection.
60% of patients and is associated with a threefold increased rate of HDV superinfection occurs in a HBsAg-positive patient and is recog-
progression to cirrhosis [9]. nized by anti-HD (IgG or IgM) and/or HDV RNA or HDAg. Per
A retrospective study of 188 Italian patients studied the impact of viral sistent detection of these HDV markers generally signifies chronic
and patient features on survival [52]. Eighty-two patients (43%) had infection.
chronic hepatitis at histology; the remaining 106 individuals had a
clinical/histologic diagnosis of cirrhosis. Ninety-six patients received
interferon or lamivudine therapy; 27 (30%) attained a sustained viral
PREVENTION
cure. During follow up, 21 of the treated patients with chronic hepa- There is no antiviral treatment for HDV. HDV infection is deterred by
titis progressed to cirrhosis. Of the 127 cirrhotic patients, hepatic prevention of HBV infection using its vaccine.
31.4 Hepatitis C
TRANSMISSION
Sharing of needles by injecting illicit drugs account for most hepatitis
PATHOGENESIS AND PATHOLOGY
C cases in developed countries [14, 68]. Inhabitants of developing Individuals with chronic hepatitis C generally have lymphocytic
countries are usually infected from parenteral exposures from injec- inflammation with lymphoid aggregation in portal tracts (Fig. 31.1).
tions and other activities that penetrate the skin, inadequate screening There may also be microvesicular fatty changes and damage to bile
of blood and blood products before transfusion, during renal dialysis, ducts and acidophilic changes in hepatocytes—histologic findings
as well as from “interfamilial exposures” [10, 71–74]. that may also occur with HBV infection, but are more characteristic
of hepatitis C. Cirrhosis may also be present, being associated with a
In developed countries such as the USA, Europe and Japan, HCV
long duration of infection [80].
infection as a result of blood transfusions has become rare. However,
in some developing countries with high rates of HCV infections, HCV infections usually persist, owing, at least in part, to the rapid
transfusions remain risky because there is inadequate screening of replication of the virus and its tendency to mutate, hence forming
blood or blood products for HCV. Two to six percent of infants born variants not contained by the immune response [81]. Some of the
to HCV-infected mothers have persistent infections [11, 12]. In chil- resulting population of viral strains, the HCV quasi-species, may be
dren, perinatal transmission, albeit rare, is the commonest route of neutralized. However, other quasi-species may still transmit HCV
transmission in developed countries and is more likely when the infection. Chimpanzees can be experimentally re-infected with inocu-
mother is dually infected with HIV-1 and when there are high quanti- lates of HCV and natural re-infections have been reported in children
ties of maternal virus [75, 76]. Breastfeeding is not an important with thalassemia who received multiple blood transfusions and in
transmission route [12, 77]. Assessment of infant HCV infection adult intravenous drug users [82].
300 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
CLINICAL FEATURES thyroiditis, lichen planus and porphyria cutanea tarda. This occurs in
several types of chronic liver disease, often in association with iron
overload.
ACUTE INFECTIONS [22]
The onset of HCV infection is usually unrecognized. Within 1–3 Essential Mixed Cryoglobulinemia [86]
weeks of exposure, HCV RNA can be detected in blood. Transami-
Hepatitis C appears to be the most common cause of this syndrome,
nases may become elevated 3–9 weeks (average 50 days) later, but
which is marked by varying combinations of fatigue, myalgia, arthral-
only 20–25% are jaundiced or are symptomatic. HCV is the cause of
gia and arthritis, hives, purpura or vasculitis, neuropathy and glomer-
20% of the cases of acute viral hepatitis in the USA and the Middle
ulonephritis. Cryoglobulins, composed of immune complexes of
East [22]. When symptoms are experienced, there is a prodrome that
HCV and anti-HCV, immunoglobulins, rheumatoid factor and com-
tends to have a gradual onset and to be mild. The mean incubation
plement, are present in the serum. Cryoglobulins are detectable in up
period until the onset of symptoms is 7 weeks and clinical illness
to a third of patients with chronic hepatitis C, but the clinical syn-
usually lasts from 2–12 weeks. ALT and AST return to normal and
drome of essential mixed cryoglobulinemia occurs in less than 2%; it
HCV RNA becomes undetectable within that time. Fulminating hepa-
sometimes improves with treatment of the HCV infection.
titis from HCV infection is rare.
and/or hepatocellular carcinoma among those who are infected. Other antiviral therapies are being evaluated [93]. To date, two pro-
People with HCV-related cirrhosis are at 30% risk over 10 years of tease products have completed Phase III clinical trials and have been
developing hepatic decompensation, as well as hepatocellular carci- approved by the Food and Drugs Adminstration (FDA). Telaprevir
noma (1–3% per year). A liver biopsy and/or noninvasive fibrosis and bocepravir are both protease inhibitors that significantly increased
marker can assist in selection of individuals who might benefit from the sustained virologic response when used in combination with
antiviral therapy, as the level of fibrosis is a predictor for the develop- PEGINF and ribavirin [96–98].
ment of cirrhosis.
31.5 Hepatitis E
Key features
l Enteric transmitted virus causing 20–30% of acute viral l Water-borne outbreaks occur, primarily in the Indian
hepatitis in many developing countries and rarely in the USA subcontinent; it is also transmitted feco–orally and by viremic
and Europe blood exposure and by eating undercooked pork
l It has a single serotype and six genotypes l Prevention is primarily related to improving sanitation; two
l Some genotypes, for example genotype-1, cause acute viral effective vaccines have been developed but have not yet been
hepatitis in humans while others, for example genotype-3, marketed
are zoonotic and primarily cause infection in animals—
primarily pigs
302 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
INTRODUCTION exposed to pigs, or who ate rare pig or boar in Japan [104]. Genotype-3
HEV has been isolated from pigs in Egypt (which are rare in the
In 1983, hepatitis E virus (HEV) was visualized by immune electron country) and genotype-1 has been isolated from a few cases of HEV-
microscopy (IEM) in stool from infected patients. It was then trans- caused acute viral hepatitis in humans. HEV causes 20–25% of the
mitted to a human volunteer and cynomolgus monkeys, thereby cases of acute viral hepatitis in Egypt [31], but it is uncertain whether
establishing its role in enterically transmitted non-A, non-B (NANB) zoonotic transmission of genotype-3 is the cause of the 70–80% rate
hepatitis [99]. Development of specific diagnostic tests followed of HEV-antibodies in the country [105, 106].
cloning of the HEV genome in 1990 and by recombinant DNA tech-
nology expressing viral antigens [100]. HEV was retrospectively recog-
nized as a major cause of fecal-oral transmitted NANB hepatitis when CLINICAL FEATURES
clinical samples collected during epidemics of water-borne hepatitis The course of HEV infection is similar to that of hepatitis A. The
in India in the 1950s and 1960s were serologically tested [101, 102]. incubation period averages 40 days (range 15–60 days). After oral
HEV is a single-stranded, positive-sense RNA virus that has been inoculation, the virus principally replicates in the liver and produces
placed in the genus, Hepevirus, but has not been assigned to a viral cytopathic changes. HEV can be detected in stool and blood 3–4
family. Although genomic and virulence variability occurs among weeks after ingestion, prior to the onset of symptoms, and for 1–2
geographically distinct isolates, HEV has at least one major cross- weeks afterwards. Like hepatitis A, there are many more asymptomatic
reactive epitope. and anicteric infections with HEV than diagnosed cases of acute viral
hepatitis. Children often have asymptomatic, anicteric infections,
EPIDEMIOLOGY while the clinical attack rate is higher in the 15–40 year age group,
and severity of illness increases with age.
HEV infections, transmitted by a fecal-oral route, are rarely detected Symptoms and signs are similar to those caused by other types of viral
in the USA or other developed countries. However, sporadic cases of hepatitis: malaise, fatigue, anorexia, nausea and vomiting, jaundice
HEV have been recognized in most developing countries, and major and dark urine, abdominal pain, fever and hepatomegaly. The most
water-borne epidemics have been reported in India, Pakistan, Nepal common laboratory findings include elevated bilirubin, ALT, AST,
and Africa [100]. HEV is also endemic to the remainder of Central and alkaline phosphatase. Histopathologic findings in biopsies from
and Southeast Asia, the Middle East, Africa and Central America patients with HEV hepatitis have included both cholestatic hepatitis
(Fig. 31.7). In these areas, HEV is the etiologic cause of 20–30% of and classic acute viral hepatitis changes.
cases of acute viral hepatitis and, even more so, in the Indian subcon-
tinent and during outbreaks. HEV is a risk to travelers to endemic Clinical symptoms, hyperbilirubinemia and elevated aminotrans-
areas, albeit less so than HAV [103]. ferase levels generally resolve 1–6 weeks after onset of illness. Jaundice
may be prolonged with HEV infection, which may also cause fulmi-
Although sharing the same basic route of transmission as HAV, HEV nant hepatitis; 10–20% of pregnant women in the third trimester who
infection in endemic countries occurs more often in the second and are hospitalized with acute HEV infection during outbreaks in India
third decades of life, while HAV infection more commonly occurs in were reported to have fatal fulminant hepatitis [107, 108]. HEV
the first and second decades. Also, the secondary attack rate is lower very rarely causes chronic infection in immunosuppressed patients
for HEV than for HAV. Although not completely explaining the dif- [109, 110].
ferences in transmission rates, lower quantities of HEV are excreted in
the stool for shorter periods of time. Links to a common source of
contaminated water are the rule during large outbreaks, and these DIAGNOSIS
often follow heavy rains. As with HAV, HEV infection can occur after
exposure to contaminated blood products, owing to viremia that Acute HEV infection can be diagnosed by detecting IgM HEV
occurs during acute infection. antibody, high titers of IgG anti-HEV or increasing titers of total
HEV antibody by commercial enzyme immunoassays (EIAs) using
HEV is a zoonosis, having been isolated from pigs, rats, and other recombinant-expressed proteins or synthetic peptides in patients with
animals. The rare cases of HEV reported in North America, Europe or acute viral hepatitis [4]. The titer of IgM anti-HEV declines rapidly but
Japan are caused by human genotype-1 infections in travelers to can be detected in some patients for 5–6 months. IgG HEV-antibodies
endemic areas or because of porcine genotype-3 infections in people persist and have often been detected in persons from regions without
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3
PA R T
BACTERIAL INFECTIONS
A
SECTION
35.1 Trachoma
EPIDEMIOLOGY
Key features Trachoma is endemic in 57 countries, with an estimated 40.6 million
people suffering from active disease and 8.2 million people afflicted
l Trachoma is the leading infectious cause of blindness with trachomatous trichiasis (in-turning of eyelashes that abrade the
l Caused by Chlamydia trachomatis serotypes A–C, a surface of the globe) [2]. Africa bears the highest load of active tra-
Gram-negative, intracellular bacterium choma, but countries in the Middle East, Asia, Latin America and the
Western Pacific also have areas of endemic trachoma (Fig. 35.1) [3,4].
l Repeated episodes of infection result in scarring of the
However, half the global burden of trichiasis is concentrated in China,
tarsal conjunctiva which leads to in-turning of the eyelashes Ethiopia and Sudan (Fig. 35.2) [4].
that rub against the surface of the globe. The constant
abrasion subsequently leads to corneal scarring and Trachoma perpetuates the cycle of poverty and blindness. Trachoma-
tous blindness and low vision not only lead to poverty from loss of
blindness productivity (US$3.5 billion annually—year of costing: 2003) [5], but
l Diagnosis requires a 2.5 × magnifying glass and a flashlight impoverished communities are where risk factors for trachoma, such
for illumination. The surface of the globe should be as overcrowding and poor sanitation facilities, exist.
examined, followed by eversion of the upper eyelid Poor access to, or inappropriate use of, water for hygiene purposes
l The major risk factor is poor facial hygiene. Other factors leads to dirty faces with bacteria-loaded secretions. Infected facial
associated with poor hygiene and trachoma include secretions are spread through close contact secondary to overcrowd-
overcrowding, inadequate water supply, lack of latrines and ing or by flies that thrive on poor sanitation conditions. The relative
flies importance of different risk factors may vary from one community to
another, although the lack of clean faces in children appears to be the
l Trachoma is clustered among the most impoverished final, common pathway.
communities of the world and in those with the most
disadvantaged families Young children, especially preschool children, are the reservoir for
C. trachomatis which causes episodes of chronic conjunctivitis. With
l The trachoma control strategy recommended by the World increasing age, children appear to be re-infected less often, leading to
Health Organization is the SAFE strategy: Surgery, a reduction in both the duration and cumulative incidence of active
Antibiotics, Facial cleanliness and Environmental disease. Repeated episodes of infection eventually cause blinding
improvement. Without a coordinated public health sequelae in older age groups (Fig. 35.3) [6]. Females are usually at
approach incorporating all these components, the higher risk of blinding trachoma as a result of their roles as child
treatment of individuals with trachoma is futile caregivers that increases their exposure to active infection. It is esti-
mated that the global disability adjusted life years (DALYs) lost by
females are at least 25% more than those lost by males. This gender
bias is not universal and is less pronounced or nonexistent in some
populations where the division of labor is not as distinct, such as in
INTRODUCTION Australian Aboriginal populations.
Trachoma is the leading cause of infectious blindness in the world. It
is caused by Chlamydia trachomatis, an obligate, intracellular bacte- NATURAL HISTORY, PATHOGENESIS
rium that has existed since the Jurassic period [1]. Trachoma began
to manifest when humans congregated into the first settlements,
AND PATHOLOGY
spreading rapidly until populations in North America and Europe Trachoma is caused by infection with C. trachomatis, almost exclu-
were widely affected. Trachoma slowly disappeared from the devel- sively with serotypes A, B, Ba and C. A single episode of infection
oped world and is even continuing to disappear from the developing results in a self-limiting episode of chlamydial conjunctivitis (inclu-
world with socioeconomic development and improvements in sanita- sion conjunctivitis). Infection with C. trachomatis occurs in the con-
tion and hygiene. Though the estimated proportion of blindness junctival epithelium and active inflammation involves all layers of the
worldwide owing to trachoma has decreased from 15.5% in 1996 to conjunctiva. It has been recognized that chlamydia itself is not intrin-
4% in 2004, trachoma still causes significant economic losses in sically toxic, but trachoma is a result of the immune response to
affected countries. chlamydial antigens [7]. This immune response is characterized by a
384
Tra c h o m a a n d I n c l u s i o n Co njunc tivitis 385
Infection
Scarring delayed-type hypersensitivity reaction. The typical clinical feature of
the disease is the lymphoid follicle in the stroma surrounded by an
Prevalence
FIGURE 35.4 Trachoma grading card. Reproduced with permission from Negrel AD, Taylor HR, West S. Guidelines for Rapid Assessment for Blinding Trachoma. Report
No.: WHO/PBD/GET/00.8. Geneva: World Health Organization; 2001. © 2009, World Health Organization. All right reserved.
CLINICAL FEATURES document the effects of trichiasis and corneal opacity. A grading of
corneal opacity is usually associated with vision of less than 6/12
Most cases of active disease are asymptomatic and only a minority or 20/40.
present with mucopurulent discharge. Therefore, trachoma is often
only diagnosed on routine screening. The clinical signs of the
disease are illustrated by the World Health Organization’s (WHO)
PATIENT EVALUATION, DIAGNOSIS
simplified trachoma grading classification system (Fig. 35.4) AND DIFFERENTIAL DIAGNOSIS
[12,13]. The five signs of the disease are independently assessed,
but are not mutually exclusive, and two or more features can coexist Trachoma is usually diagnosed using clinical grading based on the
in the same eye. WHO’s simplified grading classification system. Clinical diagnosis is
easily learnt by health workers and has been shown to be highly
Active inflammation is characterized by follicles on the upper tarsal reproducible [12]. There are a number of laboratory tests that have
conjunctiva (trachomatous inflammation follicular). If the inflamma- been used to detect C. trachomatis (Table 35-1) [14] and the tests of
tion is severe, the conjunctiva becomes thickened and intensely red, highest sensitivity and specificity for the detection of trachoma at
obscuring the underlying vessels (trachoma inflammation intense). present are nucleic acid amplification tests, such as PCR. However,
Scarring appears as fine, white fibrous bands across the upper tarsal the correlation between clinical and laboratory methods is quite
conjunctiva (trachomatous conjunctival scarring). The late stages of variable, ranging from 10–70%. Clinically active trachoma has been
the disease appears as in-turning of the eyelashes with at least one shown to resolve more slowly than laboratory evidence of infection
eyelash rubbing against the surface of the eyeball (trachomatous with follicles persisting for 3–6 months after the infection has
trichiasis) and an eventual white corneal opacity obscuring view of resolved. Also, more severe inflammation is associated with a high
the pupil margin (corneal opacity). rate of detectable infection as a result of higher levels of organism
being shed. The use of laboratory methods is often limited by high
Examination for trachoma should be performed with a 2.5 × loupe cost and accessibility issues in trachoma-endemic areas. Until an
(magnifying lens) for magnification and a pocket flashlight/pen- inexpensive, reliable, rapid, field-based assay is developed, clinical
torch for illumination. In children, the upper eyelid needs to be grading appears to be the best method of trachoma diagnosis in
gently everted to expose the upper tarsal conjunctiva using your operational conditions.
thumb or another small object, such as a cotton bud. The tarsal
surface should then be examined for signs of active inflammation There are differential diagnoses to consider in the diagnosis of both
and scarring. In adults, the lid margin of the upper lid should be active trachoma and trachomatous scarring (Table 35-2). However,
gently lifted from the eye to identify any corneal opacity prior to in the absence of laboratory tests, cases of follicular conjunctivitis
eversion of the upper lid. Visual acuity should be measured to and/or conjunctival scarring in an area of known trachoma
Tra c h o m a a n d I n c l u s i o n Co njunc tivitis 387
TABLE 35-1 Methods Used for Laboratory Diagnosis TABLE 35-2 Differential Diagnosis and Distinguishing
of Trachoma Features of Follicular Conjunctivitis and Conjunctival
Scarring
Method Description Comments
Follicular conjunctivitis*
Microscopy Identifies typical Requires conjunctival
intracytoplasmic scrapings that can Trachoma Likely diagnosis in an area of known
inclusions using be traumatic endemicity or high-risk factors. Can
Giemsa staining May be the least be confirmed by laboratory
sensitive test evidence of C. trachomatis
Inexpensive
Viral conjunctivitis Self-limiting resolving in
Direct Detects cellular Requires conjunctival approximately two weeks. Often
fluorescent proteins using scrapings associated with mucopurulent
antibody fluorescent- Specificity discharge
(DFA) labeled antibodies dependent on user
expertise Hypersensitive History will often reveal chronic
conjunctivitis exposure to ocular drugs or
Culture Uses egg yolk or Requires conjunctival cosmetics
other suitable scrapings
cell-culture High specificity and Vernal conjunctivitis Usually associated with history of
systems to grow moderate atopy and seasonal recurrences
the bacteria sensitivity
Time-consuming and Toxic conjunctivitis Associated with multiple nodules
expensive secondary to on eyelid or eyelid margin
Dependent on user molluscum
expertise contagiosum
Nucleic acid Identifies unique Requires conjunctival Inclusion conjunctivitis Sexually transmitted and may be
amplication chlamydial DNA scrapings associated with a history of vaginits,
techniques or RNA via High sensitivity and cervicitis or urethritis. Can be
(NAAT) probing or specificity confirmed by laboratory evidence
amplification Expensive of C. trachomatis
techniques
Conjunctival scarring
Serology Measure Poor reproducibility
antichlamydial Limited diagnostic Repeated episodes of Likely diagnosis in an area of known
antibodies in host value trachomatous endemicity or high-risk factors
serum or inflammation
secretions Previous severe Associated with history of
Reproduced from Wright HR, Taylor HR. Clinical examination and laboratory tests bacterial conjunctivitis conjunctivitis with purulent
for estimation of trachoma prevalence in a remote setting: what are they really discharge
telling us? Lancet Infect Dis 2005;5:313–20.
Previous chalazion Associated with history of lump on
lid
endemicity or that has risk factors for trachoma should be regarded Trauma Associated with history of trauma
as trachoma.
*Follicles found in the fornices without associated inflammation and not
involving the superior tarsus, especially in young children, may occur
TREATMENT independently of any other pathology—a condition known as folliculosis.
TABLE 35-3 The Evidence-Based Role of Azithromycin in the Eradication of Blinding Trachoma
How often to treat? Annual treatment in endemic Single mass-treatment will 2 [23–25]
and biannual treatment in not eliminate trachoma
hyperendemic areas
When to stop treatment? When the prevalence is Complete community-wide 2 [23,26]
reduced to 5% elimination is achievable
*Category 1, double masked study; 2, clinical trial >20 subjects; 3, clinical trial <20 subjects; 4, case series; 5, anecdotal case reports.
CLINICAL FEATURES
Key features In adults, inclusion conjunctivitis usually presents as acute follicular
conjunctivitis with mucopurulent discharge. The infection is often
l Caused by Chlamydia trachomatis, serotypes D–K, a initially unilateral and frequently associated with pre-auricular lym-
phadenopathy. Superficial punctuate keratitis or peripheral subepi-
Gram-negative, intracellular bacterium
thelial infiltrates may occur.
l Infection is by inoculation of infected genital secretion into
the eye: in adults, this occurs during sexual contact; in Signs of neonatal chlamydial conjunctivitis include a mucopurulent
disharge, conjunctival injection, diffuse papillary reaction of the tarsal
neonates, this occurs during vaginal delivery
conjunctiva and lid swelling. If severe, pseudomembranes may
l If untreated, serious complications of conjunctivitis are develop and, rarely, untreated cases may develop conjunctival scarring
uncommon; however, systemic considerations require oral and corneal pannus.
treatment: in adults to minimize the risk of infertility from
concomitant genital chlamydial infection and in neonates
to treat possible chlamydial pneumonia
PATIENT EVALUATION, DIAGNOSIS
l Treatment of adult inclusion conjunctivitis is with a single
AND DIFFERENTIAL DIAGNOSIS
dose of oral azithromycin. Examination and treatment of Inclusion conjunctivitis is usually diagnosed clinically and confirmed
sexual contacts is important. Treatment of neonatal by laboratory testing (Table 35-1). Culture from a swab containing
chlamydial conjunctivitis is with a 14-day course of oral conjunctival epithelial cells was the “gold standard” for diagnosis,
with high specificity and moderate sensitivity, dependent on user
erythromycin, although one study has shown oral expertise. Enzyme immunoassay (EIA) and direct fluorescent anti-
azithromycin to be safe and effective body assays (DFA) have high specificity, but sensitivity may be limited
by the type of kit used. Nucleic acid amplification techniques (e.g.
PCR) have higher sensitivity than culture methods while retaining
INTRODUCTION high specificity and thus have replaced the other techniques [40]. If
resources are limited, Giemsa-stained conjunctival scrapings can be
Inclusion conjunctivitis is an acute conjunctivitis usually caused by examined for the presence of blue-stained intracytoplasmic inclusions
“genital” serotypes of Chlamydia trachomatis. It is typically found in within epithelial cells.
young adults and is usually associated with urogenital infection.
The differential diagnosis of adult inclusion conjunctivitis is similar
Neonates may be exposed to the infection during the birth process
to the differential of active trachoma (Table 35-2). The most impor-
and subsequently develop a severe, purulent conjunctivitis, pneumo-
tant differential diagnosis in neonates is conjunctivitis caused by Neis-
nia, or both.
seria gonorrhoea. However, gonococcal ophthalmia usually occurs
earlier (2–5 days after birth) and is more rapidly progressive. Gono-
EPIDEMIOLOGY coccal ophthalmia and other pyogenic conjunctivitis, such as staphy-
lococcal conjunctivitis, can be differentiated on Gram stain and
Similar to the distribution of genital chlamydial infection, inclusion subsequent culture.
conjunctivitis is prevalent worldwide [37]. Adolescents or young
adults are at highest risk of chlamydial inclusion conjunctivitis. Infec-
tion usually results from inoculation of infected genital secretions TREATMENT
into the eye; the incubation period is 7–14 days. Chlamydia trachomatis
In adults with inclusion conjunctivitis, 1g of oral azithromycin as a
is the most common sexually transmitted bacterium. Symptoms of
single dose is now standard treatment [41]. Alternatives include doxy-
urogenital infection are often absent or minimal; thus, a large reser-
cycline 100 mg twice daily for seven days, or erythromycin 500 mg
voir of the pathogen goes undetected in the community. Chronic,
four times a day for seven days. Topical erythromycin, tetracycline or
silent urogenital infection is a leading cause of infertility.
sulfacetamide ointment can be given as an adjunct if there is marked
The risk of transmission of C. trachomatis to an infant born through ocular discharge. Most importantly, sexual partners need to be exam-
an infected birth canal is reported to be as high as 70%, with the risk ined and treated because of the risk of silent infection and subsequent
of chlamydial conjunctivitis being 20–50% [38,39]. However, the infertility.
prevalence of neonatal chlamydial conjunctivits is lower in areas
Chlamydial infection in neonates is potentially serious and should
where routine screening and treatment of chlamydial infection in
be treated with a systemic antibiotic. Oral erythromycin base or ethy-
pregnant women occurs. Neonatal chlamydial conjunctivitis usually
succinate, 50 mg/kg/d in four divided doses for 14 days is standard
develops 5–21 days after birth. Pneumonia may develop later, between
therapy; however, there are compliance and tolerance issues with this
4 and 12 weeks after birth.
regimen [41]. Oral azithromycin, 50 mg/kg/d as one daily dose for
three days has been shown to be safe and effective in the treatment
NATURAL HISTORY, PATHOGENESIS of neonatal chlamydial conjunctivitis in one small study [42].
AND PATHOLOGY
The “genital” serotypes of C. trachomatis causing inclusion conjuncti-
PREVENTION AND CONTROL
vitis are serotypes D–K. However, there may be some overlap between Screening and treatment for C. trachomatis is recommended for all
“genital” and “ocular” serotypes. The pathogenesis of the conjuncti- pregnant women as early as possible before delivery [43]. Erythromy-
vitis is similar for both “genital” and “ocular” serotypes. If untreated, cin (500 mg four times a day for seven days) or amoxicillin (500 mg
cases of both neonatal and adult inclusion conjunctivitis usually three times a day for seven days) is the WHO recommended first-line
resolve spontaneously with few complications. However, scarring, antimicrobial for the treatment of genital Chlamydia infection in preg-
similar to that seen in trachoma, has been noted, but the clinical nancy [41,44]. However, azithromycin (1 g as a single dose) has been
changes tend to be more marked in the lower eyelid. shown to be safe and effective in a small number of studies, and is
390 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
recommended as first-line treatment by the CDC [30]. Silver nitrate 22. Burton M, Holland MJ, Faal N, et al. Which members of a community need
drops given topically to prevent gonococcal ophthalmia at birth do antibiotics to control trachoma? Conjunctival Chlamydia trachomatis infection
not prevent Chlamydia. Betadine eye drops (2.5%) have been shown load in Gambian villages. Invest Ophthalmol Vis Sci 2003;44:4215.
to be cheaper and more effective than silver nitrate in preventing 23. Melese M, Alemayehu W, Lakew T, et al. Comparison of annual and biannual
both chlamydial and gonococcal ophthalmia, and is associated with mass antibiotic administration for elimination of infectious trachoma. JAMA
2008;299:778–84.
appreciably less chemical conjunctivitis [45]. There is no evidence
24. Lietman T, Porco T, Dawson C, Blower S. Global elimination of trachoma:
that prophylactic treatment should be given to infants born to
how frequently should we administer mass chemotherapy? Nat Med 1999;5:
mothers with untreated chlamydial infection and there is also no
572–6.
evidence that infants with chlamydial infections should be isolated 25. Biebesheimer JB, House J, Hong KC, et al. Complete local elimination of
(standard hygiene precautions are recommended). infectious trachoma from severely affected communities after six biannual
mass azithromycin distributions. Ophthalmology 2009;116:2047–50.
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choma. Bull World Health Organ 2005;83:913–19. Vis Sci 2000;41:4074–9.
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9. West SK, Munoz B, Mkocha H, et al. Progression of active trachoma to scarring Tarsal Rotation Procedure. Report No.: WHO/PBL/93.29. Geneva: World
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Group A Streptococcus 36
Thomas L Snelling, Jonathan R Carapetis
settings, while only 1 episode every 7–8 child years has been observed
in developed urban settings. Limited data on the incidence of Group
Key features A Streptococcus pharyngitis in tropical areas suggest significant variabil-
ity, with rates comparable to temperate climates in some settings but,
l Group A Streptococcus or Streptococcus pyogenes is the in others, the documented rate is considerably lower. Transmission is
predominant global cause of bacterial pharyngitis and skin higher in winter months. Impetigo is common in childhood; trans-
infection mission occurs readily in school and preschool care settings, espe-
cially in the summer months. In tropical settings where the burden
l Group A Streptococcus is also a cause of severe invasive,
is particularly high, the majority of children in some communities
necrotizing and toxin-mediated syndromes and debilitating have impetigo at any one time.
non-suppurative sequelae, including rheumatic fever and
acute post-streptococcal glomerulonephritis Cellulitis and erysipelas are the most frequent manifestations of inva-
sive Group A Streptococcus infection and, in contrast to pharyngitis and
l Group A Streptococcus is estimated to result in over 500,000 impetigo, incidence increases with age. In the mid-1980s, reports
deaths annually, mostly in developing countries and mostly emerged from industrialized countries of both increasing numbers of
because of invasive infection or from rheumatic heart severe necrotizing Group A Streptococcus infections and of streptococ-
disease and its complications cal toxic shock syndrome [4]. Group A Streptococcus strains belonging
l Group A Streptococcus remains universally sensitive to to emm types 1 and 3, in particular, have been implicated in this
rise. Most cases of severe invasive Group A Streptococcus disease are
penicillin which remains the mainstay of treatment of
sporadic, but secondary cases and case clusters have been reported.
Group A Streptococcus infections and the prevention of Limited data suggest that both the incidence and case-fatality of inva-
rheumatic heart disease sive Group A Streptococcus disease in resource-limited countries is
several-fold higher than in industrialized countries.
Acute rheumatic fever and rheumatic heart disease continue to result
in a substantial component of Group A Streptococcus-related morbid-
INTRODUCTION ity and mortality in resource-limited settings. Of the 517,000 Group
A Streptococcus-related deaths each year, it is estimated that two thirds
Group A Streptococcus causes a diverse spectrum of disease, ranging
are caused by rheumatic heart disease or its complications [3]. The
from benign and self-limited infection of the throat or skin, to lethal
true prevalence of rheumatic heart disease remains uncertain, with
soft tissue infections accompanied by multi-organ failure. Until the
estimates of at least 1.3 per 1000 school-aged children in developing
advent of the antibiotic era, Group A Streptococcus was a major cause
countries based on auscultatory screening, while estimates based on
of death in industrialized countries as a result of sepsis, rheumatic
echocardiography suggest the true prevalence may be more than 10
heart disease and fatal epidemics of scarlet fever [1, 2]. The 1980s saw
times higher [5]. Acute rheumatic fever has become uncommon in
an increase in rheumatic fever cases in the Rocky Mountain states of
industrialized settings, although the incidence remains high among
the USA, along with an apparent resurgence in severe Group A Strep-
indigenous populations in Australia and New Zealand.
tococcus disease in industrialized countries. The resultant increased
attention paid to Group A Streptococcus disease in recent years has The incidence of acute post-streptococcal glomerulonephritis appears
also brought to focus the continuing high burden of Group A Strep- to be declining in industrialized settings, but sporadic cases still occur.
tococcus disease in developing countries, particularly those in tropical Acute post-streptococcal glomerulonephritis continues to occur both
regions [3]. sporadically and in epidemics in tropical climates (where Group A
Streptococcus pyoderma is also common); limited data suggest that
EPIDEMIOLOGY acute mortality and chronic morbidity from acute post-streptococcal
glomerulonephritis may be higher in developing settings.
The burden of all Group A Streptococcus infections is highest in
resource-limited settings, most of which are in tropical regions. It is
assumed that the major reasons for this relate to poverty, overcrowded
NATURAL HISTORY, PATHOGENESIS
living conditions and limited access to medical care, although geog- AND PATHOLOGY
raphy and climate may also play a role. The estimated number of cases
and deaths of Group A Streptococcus diseases is shown in Table 36-1. The oropharynx and the skin of humans are the only recognized
Of the more severe diseases, 79% of rheumatic heart disease cases, ecologic niches for Group A Streptococcus and they represent the major
95% of acute rheumatic fever cases, 97% of acute post-streptococcal entry sites for both local and invasive infection [6] (see Fig. 36.1).
glomerulonephritis cases and 97% of invasive Group A Streptococcus Up to 20% of school-aged children may be colonized in the orophar-
cases come from less developed countries [3]. ynx in temperate and some tropical regions, although in many tropi-
cal settings, less than 5% of children carry Group A Streptococcus
Pharyngitis is the most common manifestation of Group A Streptococ- (with groups C and G streptococci being more common). Surface
cus disease—its incidence is highest in school-aged children. One proteins facilitate specific adhesion of Group A Streptococcus to either
episode occurs every 1–2 child years in some resource-limited the mucosal epithelium of the throat or to the skin (or both).
391
392 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Asymptomatic
colonization GI/Genital tract Throat Skin
Benign local
Pharyngitis Impetigo/pyoderma
infection
APSGN
Immune-mediated
disease ?
ARF/RHD
Scarlet fever
Toxin-mediated
disease
STSS
Pneumonia
Invasive infection Meningitis
(hematogenous) Osteomyelitis
Bacteremia
FIGURE 36.1 The inter-related manifestations of Group A Streptococcus colonization and local and invasive infection, including immune-mediated and
toxin-mediated syndromes. ARF, acute rheumatic fever; RHD, rheumatic heart disease.
or days of onset. Initially, the overlying skin is relatively spared and a pre-existing focus of Group A Streptococcus infection (e.g. pharyngi-
severe escalating pain may be disproportionate to clinical findings. tis, otitis media) or with other risk factors (e.g. skull defect or post-
The skin subsequently becomes violaceous and bullae may form and cranial surgery) [10]. Puerperal sepsis caused by Group A Streptococcus
then slough. STSS is characteristically associated with Group A Strep- was a frequent cause of death in the pre-antibiotic era with outbreaks
tococcus necrotizing fasciitis, although it may arise in the setting of resulting from nosocomial transmission. A study in four tropical
other invasive Group A Streptococcus infections. The case definition of developing countries (Papua New Guinea, Ethiopia, The Gambia and
STSS requires the confirmation of Group A Streptococcus infection, The Philippines) during the 1990s found that Group A Streptococcus
along with hypotension and two or more features of multi-organ was one of the three leading causes of bacteremia in children aged
involvement: rash, coagulopathy, respiratory distress syndrome, renal <90 days, suggesting that Group A Streptococcus puerperal sepsis and
failure or hepatic impairment [8]. septic abortion remain common in less developed, tropical countries
[11]. Unlike Group B Streptococcus, Group A Streptococcus more com-
Otitis media, retropharyngeal and peritonsillar abscess, sinusitis, monly affects the mother than the infant, manifesting as post-partum
meningitis, pneumonia, bacteremia and endocarditis may arise either endometritis, peritonitis, septic thrombophlebitis or bacteremia
as a complication of tonsillopharyngitis, following surgery or trauma without focus [12]. However, chorioamnionitis and neonatal sepsis
(including burns), following varicella infection, or without apparent are also reported.
antecedent. Historically, outbreaks of Group A Streptococcus pneumo-
nia were reported among previously healthy adults, although more Acute rheumatic fever is characterized by various combinations of
recent reports have described the highest risk amongst the elderly and fever, polyarthritis or arthralgias, carditis, characteristic rash (erythema
those with underlying medical conditions; infection in these indi- marginatum), chorea and subcutaneous nodules [13] (Table 36-3).
viduals is often associated with high case fatality [9]. A viral prodrome Chorea and insidious carditis can occur as a manifestation of acute
is often reported, although the onset of fever, chest pain and dyspnea rheumatic fever in the absence of other features. Severe or recurrent
is characteristically rapid. Group A Streptococcus pneumonia may be episodes of acute rheumatic fever may result in progressive damage
necrotizing with pleural effusions frequently present early and early to the mitral valve (and sometimes the aortic valve) resulting in
complications include lung abscess formation, mediastinitis and peri- incompetence and progressive heart failure (rheumatic heart disease).
carditis. Group A Streptococcus is an uncommon cause of meningitis Over several years, the valve may eventually become stenotic. Acute
in children and adults, with most reports arising in individuals with post-streptococcal glomerulonephritis can occur 1–2 weeks after
394 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
throat infection or a few weeks after Group A Streptococcus skin infec- Group A Streptococcus infection, especially for skin and osteoarticular
tion. The features are hematuria (microscopic or gross), edema infections and necrotizing pneumonia. The features which may help
(which may be most evident peri-orbitally) and hypertension. Severe to distinguish Group A Streptococcus from S. aureus and other skin
cases can also be complicated by encephalopathy. The illness is gener- infections are listed in Table 36-2. In addition, a form of toxic shock
ally benign in childhood, but there may be an appreciable mortality syndrome (TSS) may complicate S. aureus infection, and shares many
among adults as a result of renal and congestive cardiac failure. Pedi- features with STSS with the exception that it is more frequently associ-
atric autoimmune neuropsychiatric disorders associated with strepto- ated with colonization rather than bacteremia or severe underlying
coccal infections (PANDAS) is a term used to describe some children infection.
with tic or obsessive compulsive disorders in whom symptoms appear
to develop or worsen following Group A Streptococcus infection. The Invasive infections resulting from trauma or bites, exposure to water
existence of PANDAS is controversial [14]. Post-streptococcal reactive or soil, or involving immunocompromised hosts (including diabetic
arthritis describes a syndrome of polyarthritis that differs from acute foot infections) may be caused by a more expanded array of patho-
rheumatic fever by affecting a range of smaller joints, being relatively gens and therefore require broader empirical therapy and heightened
resistant to anti-inflammatory treatment and not being associated efforts to obtain a microbiologic diagnosis [17].
with carditis, although cases of acute rheumatic fever have been mis- The arthritis of acute rheumatic fever may be mistaken for septic
diagnosed as post-streptococcal reactive arthritis [15, 16]. arthritis (e.g. the polyarthritis of disseminated gonococcosis or multi-
focal S. aureus infection), rheumatologic causes of polyarthritis,
including juvenile rheumatoid arthritis, and post-streptococcal reac-
PATIENT EVALUATION, DIAGNOSIS tive arthritis (see Table 36-2). Acute rheumatic fever is the most
AND DIFFERENTIAL DIAGNOSIS common cause of chorea in most populations with a high incidence
of acute rheumatic fever—particularly those in tropical, less-
Viruses account for most episodes of acute pharyngitis in all age developed countries—and can occur in the absence of other features
groups. Group A Streptococcus is isolated in only 20–40% of cases of of acute rheumatic fever or serologic evidence of Group A Streptococ-
exudative pharyngitis in school-aged children and an even lower pro- cus infection. However, chorea may also be a manifestation of
portion of cases in younger children and adults. Recovery of the systemic lupus erythematosus, neurovascular disease, drugs, thyro-
organism may not represent infection, but colonization. The distin- toxicosis, Wilson’s disease and a number of genetic neurodegenera-
guishing features of Group A Streptococcus pharyngitis and scarlet tive diseases that must be considered, especially where acute
fever, and differential diagnoses, are detailed in Table 36-2. rheumatic fever is uncommon.
Staphylococcus aureus is a major cause of community-acquired pyo- Group A Streptococcus pharyngitis may be diagnosed presumptively by
genic infection and an important differential diagnosis for invasive culturing colonies of Gram-positive cocci displaying surrounding
TABLE 36-2 Differential Diagnosis for Selected Group A Streptococcus Infections and Group A Streptococcus-Related
Syndromes
TABLE 36-2 Differential Diagnosis for Selected Group A Streptococcus Infections and Group A Streptococcus-Related
Syndromes—cont’d
Scarlet fever
Primary Measles l Measles and rubella should be considered, especially if unvaccinated or
Rubella history of recent contact
Roseola l Measles is associated with prodromal conjunctivitis and coryzal
EBV symptoms and Koplik spots. Rubella is associated with post-auricular
Parvovirus B19 lymphadenopathy
l Parvovirus “fifth disease or erythema infectiosum” associated with
Secondary Kawasaki disease distinctive “slapped cheek” rash of face and reticular rash of limbs
Still’s disease appearing after fever resolution
Enteroviruses l Roseola rash associated with defervescence and affects younger
Drug eruption children (infants) more than scarlet fever
Anticonvulsant hypersensitivity syndrome l Kawasaki disease (KD) and Still’s disease (SD; systemic-onset juvenile
rheumatoid arthritis) associated with multiple symptoms and prolonged
fever (>5 days). KD is also associated with conjunctivitis, edema of the
hands and feet, and stomatitis. SD is associated with transient or
“evanescent” rash, lymphadenopathy, hepatosplenomegaly, uveitis,
+/− arthritis
Impetigo
Primary Staphylococcus aureus l Staphylococcus aureus impetigo is more commonly (but not always)
Group C and G beta-hemolytic streptococci bullous and may co-infect with Group A Streptococcus in pyodermatous
Scabies impetigo
Tinea l Non-group A beta-hemolytic streptococci may cause clinically
indistinguishable lesions to Group A Streptococci, but are not
associated with acute rheumatic fever or acute post-streptococcal
glomerulonephritis
l Scabies may result in crusted lesions and burrows that are itchy and
involve the interdigital spaces or diffusely involving the trunk.
Infestation may predispose to pyoderma
l Tinea causes superficial scaly non-exudative lesions frequently with
central sparing
Necrotizing fasciitis
Primary Polymicrobial l Unlike other forms of necrotizing fasciitis, Group A Streptococcus
Clostridium perfringens necrotizing fasciitis is rarely associated with gas formation
l Polymicrobial infection may be associated with abdominal surgery or an
Secondary Vibrio vulnificus occult colonic source, typically involving the perineum and abdominal
wall (Fournier’s gangrene) and in patients with diabetes or peripheral
Other Clostridium septicum
vascular disease
l Clostridial “gas gangrene”: usually secondary to traumatic interruption
of vascular supply to affected limb or a colonic pathology in case of
C. septicum
l Vibrio vulnificus associated with underlying illnesses and water
exposure
Continued
396 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
TABLE 36-2 Differential Diagnosis for Selected Group A Streptococcus Infections and Group A Streptococcus-Related
Syndromes—cont’d
zones of beta-hemolysis on blood agar. Other beta-hemolytic strep- operative specimens, if not from blood in patients with necrotizing
tococci may colonize the oropharynx (e.g. Group C and G strepto- fasciitis.
cocci), and differentiation requires the demonstration of growth
inhibition by bacitracin or the use of commercially available, group- The diagnosis of a primary episode of acute rheumatic fever is based
specific antigen detection kits. Rapid diagnostic tests have been devel- on the most recent version of the Jones’ criteria—currently the 1992
oped to allow clinicians to reliably distinguish Group A Streptococcus version (Table 36-3). These clinical and investigational criteria have
from viral pharyngitis at the point of care. Evaluations of these tests been repeatedly revised since the original 1944 version to maintain
suggested variable sensitivity of earlier generation kits (~85%), but their positive predictive value in settings where incidence is decreas-
improved sensitivity of later-generation optical immunoassay-based ing. As a result, some high-burden settings have chosen to modify the
kits and good specificity. revised criteria to retain their sensitivity and negative predictive value
[18].
Group A Streptococcus cellulitis and erysipelas are clinical diagnoses In acute post-streptococcal glomerulonephritis, activation of the alter-
that are only occasionally confirmed by positive blood cultures. native complement pathway results in a depressed C3 level (usually
Culture of percutaneous aspirates is helpful if positive, but is usually with a normal C4) that resolves after several weeks. Diagnosis gener-
negative. The clinical suspicion of necrotizing fasciitis or myonecro- ally rests on the presence of signs and symptoms, together with sero-
sis must be confirmed promptly by the demonstration of nonviable logic evidence of recent Group A Streptococcus infection and a
tissue at surgery. Imaging results are frequently nondefinitive and compatible complement profile. Biopsy is reserved for atypical fea-
may inadvertently delay the diagnosis and institution of appropriate tures, such as anuria or failure of renal function, hypertension or
treatment. Group A Streptococcus can usually be cultured from depressed complement that does not improve after several weeks.
G ro u p A S t repto co ccus 397
TABLE 36-4 Antibiotic Treatment Guidelines for Selected Group A Streptococcus Infections
Impetigo
l Alleviate symptoms Topical mupirocin 2% 1 8-hourly for 7 days Preferred for mild disease, but
l Prevent secondary cases ointment not proven in high-endemic
l Possibly prevent invasive settings. Use saline, soap water
complications or 0.1% potassium
permanganate to remove
crusts prior to applying. Strains
of Staphylococcus aureus may
be resistant or may acquire
resistance to topical antibiotics
Oral di/flucloxacillin 1 12.5 mg/kg up to 500 mg q First-line treatment if multiple
6-hourly for 10 days lesions and S. aureus is likely
IM benzathine penicillin 1 3–6kg: 225 mg Preferred in endemic settings
G 6–10kg: 337.5 mg where risk of acute post-
10–15kg: 450 mg streptococcal
15–20kg: 675 mg glomerulonephritis is high
20+ kg: 900 mg as a single and/or adherence to oral
dose therapy not assured. Exclude
S. aureus infection if refractory
to treatment
Oral erythromycin 1 12.5 mg/kg up to 500 mg TDS If hypersensitive to penicillin
for 10 days
TABLE 36-4 Antibiotic Treatment Guidelines for Selected Group A Streptococcus Infections—cont’d
Necrotizing fasciitis§
Prevent death IV meropenem 5 25 mg/kg up to 1 g q 8-hourly Broad-spectrum cover is
Prevent complications recommended in addition to
Alleviate symptoms surgical debridement until
Minimize disfigurement Group A Streptococcus
infection is confirmed,
thereafter penicillin +
clindamycin is
recommended
IV benzylpenicillin 2 45 mg/kg up to 1.8 g If Group A Streptococcus
q 4-hourly infection is confirmed. Use in
addition to surgical
debridement
IV cephalothin 5 50 mg/kg up to 2 g q 6-hourly If GAS confirmed and
non-immediate type
hypersensitivity to penicillin. If
there is a history of
immediate-type
hypersensitivity to ß-lactams,
seek expert advice
Continued
400 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
TABLE 36-4 Antibiotic Treatment Guidelines for Selected Group A Streptococcus Infections—cont’d
Management of acute rheumatic fever is primarily symptomatic. Peni- adjunct. Dialysis is occasionally required to manage severe hyperka-
cillin is generally given to eradicate colonization, although acute lemia or symptomatic uremia.
infection has usually passed by the time symptoms of acute rheumatic
fever develop. Salicylates are used to relieve fever and the pain from Contacts of patients with Group A Streptococcus infection may be
arthritis that is often severe. Where necessary, cardiac failure is colonized with the same Group A Streptococcus strain, but primary
managed with diuretics and angiotensin-converting enzyme (ACE) prophylaxis of contacts is rarely indicated for simple Group A
inhibitors. Steroids are sometimes used in cases of severe carditis, Streptococcus pharyngitis. Even for contacts of severe invasive infec-
although there is no evidence that they improve the long-term tions, it is estimated that around 2000 contacts would need to
outcome in RHD. Mitral valve repair, balloon valvuloplasty, or valve receive prophylaxis in order to avoid a single, severe infection—
replacement may be required to manage patients with severe valve opinion on the value of treating contacts is divided [24]. If pro-
disease in rheumatic heart disease. phylactic treatment of contacts is attempted, regimens combining
rifampin with penicillin, or using alternative antibiotics such as
Management of acute post-streptococcal glomerulonephritis is based cephalosporins or azithromycin, are usually recommended as a
on control of hypertension with fluid restriction and use of a loop result of the increasing failures of penicillin alone in eradicating
diuretic such as furosemide. ACE inhibitors may also be needed as an carriage.
G ro u p A S t repto co ccus 401
However, regular secondary prophylaxis is recommended for all chil- 10. Mathur P, Arora NK, Kapil A, Das BK. Streptococcus pyogenes meningitis. Ind
dren and adults with previous acute rheumatic fever or established J Pediatr 2004;71:423–6.
rheumatic heart disease. Monthly intramuscular benzathine penicillin 11. Bacterial etiology of serious infections in young infants in developing coun-
G is central to the management of children and adults with acute tries: results of a multicenter study. The WHO Young Infants Study Group.
rheumatic fever and rheumatic heart disease (see Table 36-4). Pediatr Infect Dis J 1999;18(suppl. 10):S17–S22.
12. Chuang I, Van Beneden C, Beall B, Schuchat A. Population-based surveillance
During outbreaks of acute post-streptococcal glomerulonephritis sec- for postpartum invasive group a streptococcus infections, 1995–2000. Clin
ondary to Group A Streptococcus pyoderma, community-based treat- Infect Dis 2002;35:665–70.
ment of infected individuals and their contacts with benzathine 13. Special Writing Group of the Committee on Rheumatic Fever E, and Kawasaki
penicillin G appears to decrease the transmission of acute post- Disease of the Council on Cardiovascular Disease in the Young of the Ameri-
streptococcal glomerulonephritis-producing Group A Streptococcus can Heart Association. Guidelines for the diagnosis of rheumatic fever. Jones
strains. In addition to treating infected individuals, reducing the trans- Criteria, 1992 update. JAMA 1992;268:2069–73.
mission of Group A Streptococcus pyoderma in resource-limited set- 14. Kurlan R, Johnson D, Kaplan EL. Streptococcal infection and exacerbations
of childhood tics and obsessive-compulsive symptoms: a prospective blinded
tings is likely to require skin hygiene measures, including the control
cohort study. Pediatrics 2008;121:1188–97.
of scabies.
15. De Cunto CL, Giannini EH, Fink CW, et al. Prognosis of children with post-
After a century of research, the development of a vaccine against streptococcal reactive arthritis. Pediatr Infect Dis J 1988;7:683–6.
Group A Streptococcus disease is at last showing promise. The most 16. Shulman ST, Ayoub EM. Poststreptococcal reactive arthritis. Curr Opin Rheu-
advanced of the current candidates is a multivalent vaccine including matol 2002;14:562–5.
26 of the most common Group A Streptococcus emm types encoun- 17. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis
tered in North America and Europe. Unfortunately, there is a limited and management of skin and soft-tissue infections. Clin Infect Dis 2005;
41:1373–406.
match of these strains with prevalent emm types in Africa and the
18. National Heart Foundation of Australia (RF/RHD guideline development
Pacific, where emm types are more variable [25]. Other candidate
working group) and the Cardiac Society of Australia and New Zealand. Diag-
vaccines, containing antigens conserved among most, or all, Group A
nosis and management of acute rheumatic fever and rheumatic heart disease
Streptococcus strains, are approaching clinical trials. in Australia—an evidence-based review; 2006.
19. Stevens DL, Gibbons AE, Bergstrom R, Winn V. The Eagle effect revisited:
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A streptococcal diseases. Lancet Infect Dis 2005;5:685–94. 22. Norrby-Teglund A, Muller MP, McGeer A, et al. Successful management of
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37 Diphtheria
Tejpratap SP Tiwari
120,000 100
90
100,000
Immunization coverage (%)
80
70
Number of cases
80,000
60
Number of cases
60,000 Official coverage 50
WHO/UNICEF estimates 40
40,000
30
20
20,000
10
0 0
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
FIGURE 37.1 Diphtheria global reported incidence and DTP3 coverage, 1980–2008.
404 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
CLINICAL FEATURES involving the larynx, or trachea and bronchi may narrow the lumen
of the airways, particularly in infants and young children, and progress
Infection usually results from exposure to respiratory secretions from to dyspnea, exhaustion and death.
cases or carriers, or exudates from cutaneous lesions. The incubation
period is usually from 1–5 days, but occasionally can be longer. The Nasal diphtheria is more frequent among infants and young children
frequency and severity of clinical symptoms and signs depend on the who usually present with a profuse mucoid, serosanguineous, or
site of infection, size of the pseudomembrane and the patient’s mucopurulent nasal discharge that can cause an erosive reaction on
immunization history. However, regardless of the site of infection, the external nares and upper lip. A dirty-white membrane is usually
systemic manifestations are similar and consequent to absorption of present on the nasal septum. The symptoms are generally mild and
diphtheria toxin from these sites. The disease is usually localized to manifestations of systemic toxicity are rare.
mucous membrane in the upper respiratory tract, the skin, or both. Cutaneous diphtheria is usually more common in warm, tropical
Symptoms and signs can develop at multiple sites in the upper respi- climates and is normally associated with colonization of pre-existing
ratory tract, including the nose, pharynx, tonsils and larynx [5]. The skin lesions, such as surgical wounds, pyoderma, eczema, burns,
characteristic feature of diphtheria is the formation of a tough, dirty- impetigo, psoriasis and insect bites. Co-infection with Staphylococcus
gray, leather-like pseudomembrane at the site of infection. aureus and group A Streptococcus pyogenes is typical. Outbreaks of
The most common site for respiratory diphtheria is the faucial area cutaneous diphtheria have occurred among impoverished or indigent
including the posterior pharynx, soft palate, periglottal area, uvula populations, homeless individuals and alcoholics, and in environ-
and tonsillar mucosa (Fig. 37.2). The onset is usually insidious and ments with overcrowding and unhygienic living arrangements. The
patients usually present with a low-grade fever (<103°F), sore throat, disease classically presents as single or multiple punched-out ulcers
pain on swallowing, hoarseness of voice, pharyngeal injection, nasal with rolled-out margins and a dirty-gray or black adherent pseu-
discharge, cough, malaise and prostration [5, 6]. The pulse is usually domembrane over the base. Common sites for cutaneous lesions
more rapid than the fever would justify. On initial examination, the include the lower legs (Fig. 37.3), feet and hands. Lesions from which
pharynx is injected, but patches of exudates may appear a day after C. diphtheriae are isolated are indolent, nonprogressive, superficial
illness onset. These patches may expand and coalesce to form a white- and indistinguishable from those caused by other bacteria. Although
to-dirty-gray, tenacious membrane over one or both tonsils, the systemic complications rarely occur from local absorption of toxin in
nasopharynx, uvula and soft palate, and can extend downward into cutaneous diphtheria, sufficient toxin may be absorbed to act as a
the larynx and trachea. The edge of the membrane is surrounded by natural immunizing event to induce production of high antitoxin
a narrow zone of erythema and a broader zone of mucosal edema. levels and protective immunity. If untreated, cutaneous diphtheria
Cervical lymph nodes are usually tender and enlarged and, along with may persist for months. Shedding of C. diphtheria from skin lesions
cervical soft tissue edema, gives rise to the so-called bull-neck appear- occurs over a longer time period than from respiratory tract coloniza-
ance and may cause respiratory stridor. Extension of the pseudomem- tion, and exudates from cutaneous diphtheria can contaminate the
brane from the pharynx to the larynx can result in life-threatening environment and may be an important and efficient means of person-
airway obstruction. to-person spread in tropical countries [7].
The laryngeal or tracheobronchial mucosa may be the primary site of Rarely, the primary site of infection may be the mucous membranes
infection in 5% of patients. However, tonsillopharyngeal membrane at other localized sites, such as the conjunctiva, external auditory
may extend downward into the larynx in about 10% of patients. canal and vulva [5]. A local ulcer with exudate or pseudomembrane
Laryngeal diphtheria typically presents with hoarseness and stridor, may be present and, in the ear, diphtheria may manifest as a chronic
dyspnea and a brassy cough. Edema and membrane formation purulent discharge. However, lesions are self-limiting and rarely asso-
ciated with systemic toxicity.
Complications frequently result from systemic absorption of diph
theria toxin, particularly in the heart, nerves and kidneys. Cardiac
manifestations generally occur during the second week, but may occa-
sionally be present from the first week or manifest as late as the sixth
week of illness. The risk of myocarditis directly correlates with the
duration, extent and severity of disease, and delay in initiating treat-
ment with diphtheria antitoxin [5]. Diphtheritic myocarditis can
FIGURE 37.2 Faucial diphtheria showing gray pseudomembrane over FIGURE 37.3 A diphtheria skin lesion on the leg (photo courtesy of the
tonsils and pharynx (photo courtesy of the Public Health Image Library, Centers Public Health Image Library, Centers for Disease Control and Prevention, Atlanta,
for Disease Control and Prevention, Atlanta, GA, USA). GA, USA).
Diphther ia 405
present as a wide variety of abnormalities that includes dyspnea, from biochemical tests. Toxigenicity of C. diphtheriae can be deter-
angina, syncope, diminished heart sounds, new or altered murmurs, mined by in vivo (guinea pig) or in vitro (Elek) testing. PCR tests for
conductive disturbance arrhythmias, ectopic beats, a gallop rhythm, gene coding for the A and B fragments of the exotoxin can confirm
cardiac enlargement, low cardiac output or hypotension. Although up the presence of toxigenic organisms, but not toxin. PCR testing is
to 65% of patients have electrocardiographic (ECG) evidence of myo- sensitive and rapid and is most useful in specimens taken from
carditis after 1–2 weeks from onset, most are asymptomatic. Clinically patients who received antibiotics. However, it is currently only avail-
significant myocarditis develops in 7–20% of patients with respiratory able at some reference laboratories. Molecular subtyping of C. diph-
diphtheria compared with 0–5% with cutaneous diphtheria. Abnor- theriae strains shows considerable promise in aiding epidemiologic
malities in ECG pattern, particularly ST-T wave changes and first- investigations and is available at some reference laboratories [13].
degree heart block, can progress to more severe forms of block,
atrioventricular dissociation and other arrhythmias that carry a poor The differential diagnosis includes streptococcal or viral tonsillophar-
prognosis. Patients with ECG findings that do not exceed ectopic yngitis, infectious mononucleosis, Vincent’s angina, herpetic tonsil-
supraventricular beat, sinus bradycardia, prolonged P-R interval and litis, thrush and acute epiglottitis.
minor T-wave changes generally do well and are associated with little,
if any, increased risk of death. Patients with single bundle branch
blocks, QRS widening, ST-T segment shifts, T wave inversions, pro-
TREATMENT
longed QT wave intervals or supraventricular tachycardias are associ- The hallmark of treatment of respiratory diphtheria is prompt admin-
ated with a 10–50% mortality. The fatality rate exceeds 90% in istration of diphtheria antitoxin to neutralize free circulating diphthe-
patients with third-degree block, more than two ventricular prema- ria toxin; diphtheria antitoxin cannot neutralize cell-bound toxin. The
ture contractions, ventricular tachycardia and congestive cardiac antitoxin, an equine antiserum, is critical in the management of res-
failure. Cardiac pacing appears to be of little value in patients with piratory diphtheria and is effective in reducing the extent and severity
third-degree block. These patients have severe cardiac injury and die of local disease, as well as the risk of systemic complications, such
from congestive cardiac failure or ventricular tachycardia. Death from as myocarditis and polyneuropathy. As the patient’s condition may
myocarditis occurs within two weeks of illness onset. Abatement deteriorate rapidly, a single dose of diphtheria antitoxin should be
of ECG abnormalities reflects improving cardiac function and favors promptly administered if diphtheria is strongly suspected, without
survival. Elevations of serum creatine kinase and serum aspartate awaiting laboratory confirmation of the clinical diagnosis [12]. Early
aminotransaminase/serum glutamic oxaloacetic transaminase (AST/ institution of antitoxin therapy is associated with a significant reduc-
SGOT) concentration closely parallel the intensity of myocarditis tion in mortality risk. As diphtheria antitoxin is an equine product,
and so may be used to monitor its course. Detectable cardiac injury skin testing should be performed prior to administration to rule out
may completely resolve over months, or even years, but some survi- immediate-type hypersensitivity. Patients who exhibit hypersensitivity
vors are left with persistent conduction defects requiring long-term require desensitization before a full therapeutic dose of antitoxin is
follow-up [8]. administered. Irrespective of the patient’s age, the Centers for Disease
Control and Prevention (CDC) recommend intravenous administra-
Approximately two-thirds of individuals with severe diphtheria
tion of 20,000–40,000 units of diphtheria antitoxin for pharyngeal
develop neuropathy. Affected patients develop palatine and posterior
or laryngeal disease of less than 2 days’ duration, 40,000–60,000 units
pharyngeal wall paralysis and cranial neuropathies involving muscles
for cases with nasopharyngeal pseudomembrane formation, and
of the eye, face, pharynx and larynx, causing dysphagia and predispos-
80,000–100,000 units for disease with duration of 3 days or more or
ing these patients to nasal regurgitation and aspiration. The ocular
extensive disease with neck swelling. A repeat dose is of no benefit
manifestations of diphtheria include blurred vision and failure of
and may increase the risk of anaphylaxis to horse serum protein. In
accommodation. Later, several weeks after the sore throat, a periph-
the USA, diphtheria antitoxin is no longer manufactured or licensed
eral motor demyelinating neuritis can occur, beginning in the proxi-
for use. However, it is available from CDC under a Food and Drug
mal muscle groups in the extremities and progressing distally. In the
Administration (FDA)-approved investigational new drug protocol.
lower extremity, the dorsiflexors of the feet may be particularly
Physicians in the USA may obtain diphtheria antitoxin by calling
affected. Occasionally, motor nerves of the trunk, neck and upper
the Emergency Operations Center of the Centers for Disease Control
extremity are involved (as are sensory nerves) resulting in a glove-and-
and Prevention at 770-488-7100; additional information may be
stocking neuropathy. Generally, there is slow but total resolution of
obtained from the CDC website http://www.cdc.gov/vaccines/vpd-
the limb weakness [9, 10].
vac/diphtheria/dat/dat-main.htm. Diphtheria antitoxin may be pro-
Less commonly, renal failure and pneumonia may occur in severe duced and available locally outside the USA.
cases. Rare instances of encephalitis and cerebral infarction have been
The administration of recommended antibiotic therapy serves to
documented. Case fatality rates have remained stable at ~10% in
eliminate the organism, thereby stopping toxin production, improv-
developed countries over the past five decades and are highest in the
ing local symptoms and signs of infection, and preventing spread of
very young and very old; fatal outcomes are rare in fully vaccinated
the organisms to susceptible contacts. Patients should be maintained
persons [11].
in strict droplet isolation throughout therapy. Respiratory diphtheria
should be treated with penicillin or erythromycin – the antibiotics of
choice [12, 14, 15]. Both drugs are equally effective in resolving local
PATIENT EVALUATION, DIAGNOSIS symptoms and disappearance of the pseudomembrane. Procaine
AND DIFFERENTIAL DIAGNOSIS penicillin G is given at a dosage of 600,000 units (for children,
12,500–25,000 IU/kg) intramuscularly (IM) every 12 h until the
Respiratory diphtheria should be suspected in the presence of a gray patient can swallow comfortably, after which oral penicillin V is given
pseudomembrane in a patient with sore throat, mild fever, cervical at 125–250 mg four times daily to complete a 14-day course. Alter-
lymphadenopathy, neck swelling, hoarseness of voice and signs of natively, erythromycin is given at a dosage of 500 mg IV every 6 h (for
systemic toxicity. The diagnosis is confirmed by culturing toxigenic C. children, 40–50 mg/kg per day IV in two or four divided doses) until
diphtheriae from swabs taken from the throat, respiratory tract or the patient can swallow comfortably, after which 500 mg is given PO
membrane [12, 13]. Throat swab specimens should be taken before four times daily to complete a 14-day course. A single, IM dose of
administration of antibiotics to increase the chance of a positive benzathine penicillin G (600,000–1,200,000 units) may be consid-
culture and immediately transported to the laboratory. If clinical ered when compliance with oral therapy is uncertain. Erythromycin
specimens cannot be immediately transported, they should be sent is marginally superior to penicillin in eradicating the carrier state and
in a transport medium or, if a long delay is anticipated, in silica gel. may be preferred for initial treatment; however, there is increased
Specimen culture optimally requires the use of a tellurite-containing risk of gastrointestinal irritation and intolerance when given orally
medium. Identification of C. diphtheriae and its biotypes is made from and thrombophlebitis when administered intravenously. Alternative
colony morphology (black colonies with a surrounding halo) and agents for patients who are allergic to penicillin or cannot take
406 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
erythromycin include rifampin and clindamycin. Cutaneous diphthe- Tdap if they have not previously received a Tdap dose. For persons in
ria should be treated with antibiotics as described for respiratory whom pertussis vaccine is contraindicated, DT and Td should be used
disease, but patients seldom require antitoxin. It is important to treat instead of DTaP/DTwP and Tdap respectively. Unvaccinated individu-
the underlying cause of the dermatoses in addition to the co-infection als who are ≥7 years of age should receive a three-dose primary series
with C. diphtheriae. with Td with the first two doses given at 4–8-week intervals and the
third dose 6–12 months later. Booster doses are recommended at
Following therapy, eradication of C. diphtheriae should be docu- 10-year intervals [15, 16].
mented by two consecutive negative cultures at 24-hour intervals and
taken at least 1 day after antimicrobial therapy is complete. A repeat The childhood vaccination schedule varies in developing countries.
throat culture two weeks later is recommended. For patients in whom The WHO’s Expanded Program on Immunization recommends a
the organism is not eradicated after a 14-day course of erythromycin three-dose primary immunization series with combined diphtheria
or penicillin, an additional 10-day course followed by repeat culture and tetanus toxoids and pertussis vaccines (DTwP) starting at six
is recommended. Treatment of acute diphtheria with prednisone is weeks of age and administered at least four weeks apart. Some coun-
of limited, or no, value and does not reduce the incidence of myocar- tries recommend one or two additional booster doses to be given at
ditis or polyneuropathy [12]. 12 months of age and at school entry. The vaccination strategy for
decennial booster doses varies by country and depends on vaccine
Supportive care is very important. Patients in whom diphtheria is resources, the capacity of immunization services and the epidemio-
confirmed should be hospitalized in respiratory-droplet isolation logic pattern of diphtheria. While some developed countries routinely
rooms. Bed rest is recommended during the acute phase of illness offer an adolescent dose, most countries do not recommend an adult
(the first 2–3 weeks from onset of illness), but proof of its benefit booster dose [17].
once the patient feels able to ambulate is lacking. Early in the disease,
cardiac and respiratory complications can occur. ECG abnormalities
secondary to myocarditis can occur within three days from onset of REFERENCES
disease and progress to cardiogenic shock within a week. As signifi-
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cant ECG abnormalities may develop in patients without clinical
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evidence of myocarditis, it is important to routinely monitor their
2. World Health Organization. WHO vaccine preventable diseases monitoring
cardiograms. Cardiac complications can be detected and minimized system: 2009 global summary. Geneva: World Health Organization; 2009.
by close ECG monitoring and initiation of indicated supportive care, Available at: http://www.who.int/immunization/documents/WHO_IVB_
including inotropy, after-load reduction and pacing. From a prog 2009/en/index.html.
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Airway obstruction can result from aspiration of dislodged pharyn- 4. Hadfield TL, McEvoy P, Polotsky Y, et al. The pathology of diphtheria. J Infect
geal membrane, its direct extension into the larynx or from external Dis 2000;181(suppl. 1):S116–20.
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anesthesiologist or an ear, nose and throat specialist is recommended a ten-year period at the Los Angeles County Hospital. Am J Med 1954;17:
because of the possibility that tracheostomy or intubation will be 229–45.
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eliminate the risk of sudden asphyxia. Patients should also be moni- JAMA 1979;242:2197–201.
tored for development of primary or secondary pneumonia. While 7. Belsey MA, Sinclair M, Roder MR, LeBlanc DR. Corynebacterium diphtheriae
awaiting return of neurologic function in patients with neuropathies, skin infections in Alabama and Louisiana. A factor in the epidemiology of
physical therapy is indicated to maintain range of motion in paretic diphtheria. N Engl J Med 1969;280:135–41.
8. Celik T, Selimov N, Vekilova A, et al. Prognostic significance of electrocardio-
extremities. In addition, nasogastric tube-feeding may be required in
graphic abnormalities in diphtheritic myocarditis after hospital discharge: A
patients who have palatine or pharyngeal paralysis to prevent aspira-
long-term follow-up study. Ann Noninvasive Electrocardiol 2006;11:28–33.
tion. Protective or long-term immunity may not occur in cases of
9. Logina I, Donaghy M. Diphtheritic polyneuropathy: a clinical study and
diphtheria – diphtheria toxoid is administered during the convales- comparison with Guillain-Barre syndrome. J Neurol Neurosurg Psychiatry
cent phase to boost immunity and prevent recurrence [11, 12, 14, 15]. 1999;67:433–8.
10. Piradov MA, Pirogov VN, et al. Diphtheritic polyneuropathy – Clinical analy-
PREVENTION sis of severe forms. Arch Neurol 2001;58:1438–42.
11. Wharton M, Vitek CR. Diphtheria Toxoid. In: Plotkin SA, Orenstein WA, eds.
Immunization with diphtheria toxoid is the most effective means of Vaccines, 4th edn. Philadelphia: W.B. Saunders; 2004:211–28.
primary prevention. Diphtheria toxoid is available in combination 12. Farizo KM, Strebel PM, Chen RT, et al. Fatal respiratory disease due to Coryne-
with tetanus toxoid (DT) and whole-cell pertussis (DTwP) or acellular bacterium diphtheriae: case report and review of guidelines for management,
pertussis antigens (DTaP) for use in children <7 years of age; the investigation, and control. Clin Infect Dis 1993;16:59–68.
antigenic content of diphtheria toxoid in these preparations ranges 13. Efstratiou A, Engler KH, Mazurova IK, et al. Current approaches to the labora-
from 6.7–15 limit of flocculation (Lf) units. Because the frequency tory diagnosis of diphtheria. J Infect Dis 2000;181(suppl. 1):S138–45.
14. Begg N. Diphtheria: manual for the management and control of diphtheria
and severity of local reactions from diphtheria toxoid increases with
in the European Region. Copenhagen: World Health Organization; 1994:
age, a combination vaccine (Td or Tdap) with lower antigenic content
WHO ICP/EPI 038 (B).
(≤2 Lf units) is used in children ≥7 years or older and adults. In the
15. American Academy of Pediatrics. Diphtheria. In: Pickering LK, Baker CJ, Long
USA, the Advisory Committee on Immunization Practices recom- SS, McMillan JA, eds. Red Book: 2009 Report of the Committee on Infectious
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beginning at 2 months of age, a fourth dose at 15–18 months, and a 16. Centers for Disease Control. Preventing tetanus, diphtheria, and pertussis
preschool booster dose at 4–6 years of age. An adolescent booster among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and
with tetanus toxoid and a reduced diphtheria toxoid and acellular acellular pertussis vaccines: recommendations of the Advisory Committee on
pertussis antigens (Tdap) is recommended at 11–12 years of age, fol- Immunization Practices (ACIP). MMWR 2006;55(RR-3):1–50.
lowed thereafter by a decennial Td booster dose. For added protection 17. World Health Organization. Diphtheria vaccine: WHO position paper. Wkly
against pertussis in adults, a Td booster dose may be substituted with Epidemiol Rec 2006;81:24–32.
B
SECTION
,<9TPSS
12% 0%
13% 44%
0% 7%
1% 23%
=<0.10
FIGURE 38.2 Incidence of pneumonia at the 0.11–0.20
country level (courtesy of Igor Rudan; redrawn with
0.21–0.30
permission from Rudan I, Boschi-Pinto C, Biloglav Z, et al.
Epidemiology and etiology of childhood pneumonia. 0.31–0.40
Bull World Health Organ 2008;86:408–16.) 0.41–0.50
(sub-Saharan Africa), and Salmonella Typhi (South Asia) have been adenoviruses and others (discussed elsewhere), and bacterial supra-
isolated from the blood of children with pneumonia in Africa and infection of lung tissue following viral infection is common, with S.
Asia, this may represent co-infection, rather than imply causation. pneumoniae, S. aureus, Streptococcus spp., and H. influenzae being the
Mycobacterium tuberculosis, Mycoplasma pneumoniae and Chlamydia spp. most commonly associated supra-infecting agents. The causes of acute
have also been reported as causes of acute childhood pneumonia; bacterial pneumonia in children infected with HIV mirror those seen
however, there is little consensus regarding their relative importance in HIV non-infected children, with S. pneumoniae and H. influenzae
to acute childhood pneumonia [3]. Viral etiologies are also common being the most commonly reported. Children co-infected with HIV
causes of acute childhood pneumonia and include influenza virus, are more likely to develop acute bacterial pneumonia than HIV non-
respiratory syncytial virus, parainfluenza virus, metapneumonia virus, infected children.
410 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
NATURAL HISTORY, PATHOGENESIS age-specific cut-offs as follows (breaths/minute): age <2 months ≥60/
minute; age 2–11 months ≥50/min; children 12–59 months ≥40/min
AND PATHOLOGY [10]. In addition to tachypnea, a history and presentation of cough is
nearly universal. These two signs, fast breathing and cough should
Pathogen invasion and entry into the respiratory tract is poorly under-
place pneumonia at the top of a differential diagnosis until proven
stood, although animal studies suggest that, at least in the case of
otherwise by systematic exclusion. Other clinical features are dis-
pneumococcus, it is receptor mediated [6]. The syndrome of pneu-
cussed below in patient evaluation.
monia, however, is one in which the alveoli and interstitium become
inflamed, and fluid and cells fill the alveolar air sacs. Because liquids
have surface tension, the fluid in the alveolar sacs draws the walls of
the alveoli together, collapsing the alveoli. During inspiration, these PATIENT EVALUATION, DIAGNOSIS
alveolar air sacs are forcibly re-opened against this surface tension,
giving rise to the crackling sound heard during inspiration by auscul-
AND DIFFERENTIAL DIAGNOSIS
tation with a stethoscope. In turn, this surface tension creates lower
airway obstruction. Normally, the alveolar air sac is only one cell layer CLINICAL EXAMINATION FINDINGS
thick, allowing for easy gas exchange. Transudate fluid and debris in A thorough history should precede the examination, with emphasis
the alveolar air sac compromises oxygenation (air entry into the lung) on the initial symptom onset, progression of other symptoms and
and respiration (gas exchange or the transfer of CO2 in exchange for their duration prior to seeking medical care. During the history, the
oxygen). The body’s initial compensatory reaction is increased respi- clinician should observe the patient, specifically looking for rate and
ratory rate (tachypnea). This is, perhaps, the most sensitive indicator effort of breathing, cyanosis, level of alertness and responsiveness to
of lower airway obstruction [7]. As more alveoli become fluid the caretaker. These should be evaluated in the context of the patient’s
filled, lower air obstruction becomes more severe and effort shifts to age (the younger the patient is, the more vulnerable they are to
keeping the alveoli open. This is appreciated clinically by the use of respiratory failure) and nutritional status (if severe malnutrition is
accessory muscles – initially the intercostal muscles (intercostal present, hospitalize – even if pneumonia signs are not severe). The
retractions) – and, as obstruction progresses, the diaphragm contracts interview should solicit any history of convulsions, feeding behavior,
with greater force to overcome inertia, producing lower chest wall and responsiveness to the caregiver.
in-drawing (primarily noted in children less than three years old
whose chest walls are relatively soft because of a greater cartilage/bone A systematic clinical examination is necessary, with emphasis on key
ratio). Other compensatory mechanisms at this stage include grunt- organ systems that may be compromised by the underlying patho-
ing, which is a sound produced by exhaling against a partially closed physiology. These include: (i) the respiratory tract, with emphasis
glottis or “laryngeal braking” [8]. This maintains positive pressure in on the effort of breathing, the quality of breath sounds and investiga-
the airway by retaining inspired air in the alveolar sac longer in order tion for hypoxia; (ii) neurologic status, with emphasis on level of
to prevent alveolar collapse [9]. This increases lung volume and func- alertness and responsiveness to external stimuli; and (iii) supportive
tional residual capacity, the effect of which is to increase alveolar findings suggestive of severe bacterial infection, including tempera-
ventilation (the amount of air that reaches the alveoli such that ture, perfusion, the presence of skin lesions and an ability to drink
oxygen can be exchanged for CO2 per unit time), which results in a or feed.
measurable increase in arterial oxygen tension (PaO2) and a decrease Pneumonia is graded according to three levels of severity: non-severe,
in arterial carbon dioxide (PaCO2). The respiratory muscles in a severe and very severe (Table 38-1 – online only). It is important to
young child, particularly the diaphragm, have little reserve and are note that even non-severe pneumonia is a severe illness, as anything
prone to fatigue and respiratory failure. Laryngeal braking (grunting) that compromises breathing in a small child is potentially life-
decreases diaphragmatic work by keeping more alveoli open at the threatening and should prompt intervention. Non-severe pneumonia is
end of expiration and improving gas exchange. Additional accessory characterized by age-specific tachypnea and history of cough. The
muscles of the upper and lower thorax may be recruited in more child may be irritable or less active than normal, but should otherwise
advanced stages of lower airway obstruction, resulting in the clinical be alert and responsive. On auscultation, crepitations (short, fine
signs of “head-bobbing” and chest–abdomen “see-sawing”. Clinically, crackles on inspiration) or reduced breath sounds should be appreci-
these changes are seen as “respiratory distress”. Maladaptive compen- ated. This requires that the health provider time the breath sound
satory responses to obstruction include cessation of feeding, resulting with the breathing cycle in order to minimize confusion with other
in the WHO danger sign of “inability to feed or drink” [10]. As the adventitious breath sounds, such as wheezing (long, high-pitched
child is fighting to prevent alveolar collapse and maintain positive whistling sounds primarily on expiration that originate in the bron-
pressure at the end of the respiratory cycle, as well as maximize alveo- chioles). Chest-wall percussion is less diagnostic in young children
lar ventilation, it opts against breath holding, which is necessary for than in adults. Severe pneumonia is characterized by tachypnea, with
swallowing during feeding. The effect is to deprive the child’s respira- cough and at least one of the following signs: lower chest wall
tory muscles of needed fuel, which will hasten respiratory fatigue and in-drawing (not to be confused with intercostal retractions), nasal
failure, and is thus a danger sign. As lower airway obstruction contin- flaring or grunting (primarily in young infants <24 months old). Of
ues without intervention, diaphragmatic and accessory muscle fatigue these, lower chest wall in-drawing is the most obvious. This is the
set in and respiratory rate and effort fall. This can be misinterpreted collapse of the lower chest wall during inspiration and is caused by a
as evidence that lower airway obstruction is not severe, rather than as sharp decrease in intrathoracic pressure as the child forcibly contracts
decompensation and impending respiratory failure. As PaCO2 rises, the diaphragm to overcome lower airway obstruction. The external
the child may become initially agitated; as it rises further, the child atmospheric pressure subsequently collapses the chest wall, much like
may convulse. As PaO2 falls and the child’s brain is progressively the effect on a paper straw when one forcibly sucks against resistance.
deprived of oxygen, the child may, at first, become less active, then The chest wall of a young child, particularly less than three years old,
lethargic or obtunded. These are terminal phases before complete is composed of more cartilage than that of an older child and is thus
respiratory failure and death. softer and more collapsible. Chest wall in-drawing may not be con-
sistently appreciated in children older than three years of age [11].
CLINICAL FEATURES Very severe pneumonia is characterized by tachypnea and cough plus at
least one of the classic WHO danger signs: central cyanosis; inability
The clinical features of pneumonia follow from the underlying patho- to drink or feed (or vomiting anything ingested); lethargy or obtunda-
physiology of infection followed by inflammation and congestion in tion; convulsions; and other signs of severe respiratory distress such
the lower airway. There is a range of symptoms that may vary some- as head nodding and chest–abdominal see-sawing. As noted above,
what with age [7]. The most consistent feature is tachypnea, or rapid tachypnea may not be present in the later stages of very severe pneu-
breathing, the underlying pathophysiology of which is described monia as the patient begins to decompensate; however, the other
above. This is age-dependent and the WHO have established danger signs will be present, particularly a decline in mental status
B a c te r i a l Pneumonia 410.e1
TABLE 38.1
(lethargy, obtundation). This combination should prompt immediate Reactive Airways Disease (RAD or Asthma)
intervention (Table 38-1 – online only).
This is reversible lower airway obstruction, associated with history of
cough (particularly at night), with or without wheezing on ausculta-
SUPPORTIVE CLINICAL FINDINGS tion (long, musical, high-pitched whistling sound on expiration origi-
Hypoxia is an under-appreciated feature of pneumonia with prognos- nating in the bronchioles) and can be differentiated from crepitations
tic significance. Up to 59% of children admitted to hospital with (short crackling sounds on inspiration associated with pneumonia)
pneumonia have oxygen saturation <90% (moderate hypoxia) or in the alveoli by both the quality of the sound and particularly by the
even less (severe hypoxia; SPO2 at elevation can be lower than 50%) timing in the respiratory cycle. RAD may follow, or accompany, a viral
[1]. The risk of mortality is substantially increased (by up to four times infection, but often persists after the viral infection has resolved, and
in certain settings) among hypoxic children. Clinical signs for identi- may be triggered by other causes (e.g. indoor air pollution). Fever is
fying hypoxia have proven less reliable than pulse oxymetry. The use often not present. Cough, particularly night-time coughing may be
of pulse oxymetry has been shown to reduce mortality by up to 35% the primary sign. This may be diagnosed by a beta-agonist challenge,
compared with clinical criteria [1]. Continuous oxygen therapy by such as with an albuterol nebulizer and is appreciated by a decrease
nasal prongs or nasal cannula is recommended for all children with in respiratory rate (by ≥5 breaths/minute) and effort, and improved
moderate or greater hypoxia, as well as those with cyanosis, inability oxygen saturation.
to drink or feed, or a respiratory rate >60/minute.
Bronchiolitis
LABORATORY INVESTIGATIONS This is usually, but not always, viral in origin and is commonly caused
by respiratory syncytial virus (RSV), but is associated with many res-
Blood cultures are insensitive at establishing an etiologic agent [1].
piratory viruses. It is characterized by cough and wheezing on expira-
Nasopharyngeal swabs are indicative of carriage, but do not establish
tion, along with signs of viral infection – notably fever and often
invasiveness. A number of rapid antigen assays to detect respiratory
rhinorrhea. Children tend to be <2 years of age and may present with
viruses in nasopharyngeal washes or swabs are available in industrial-
wheezing for the first time. Children may or may not respond to beta-
ized countries, but these are not readily available in resource-limited
agonist challenge, but young age and febrile wheezing are strongly
settings. Outside of intensive care settings, lung aspirates are consid-
suggestive.
ered too invasive as a general diagnostic approach. As such, there is
currently no gold standard for etiologic diagnosis of acute pneumo-
nia, although a positive blood culture with a potentially causative Tuberculosis
agent is, in most cases, considered conclusive of invasive disease. Tuberculosis has been discussed above, but should also be considered
Newer technologies to identify invasive pathogens include assays in children who have been successfully treated for pneumonia who
resting on antigen detection and/or amplification, but none of these then return with subsequent pneumonia re-diagnoses. These may
have, as yet, become a standard. occur within days or weeks of prior successful treatment. Tuberculosis
should also be considered in children who do not respond com-
CHEST ROENTGENOGRAMS (CHEST X-RAYS) pletely to conventional antibiotic therapy and/or have weight loss or
failure-to-thrive (failure to appropriately gain weight), and/or have a
Abnormal chest roentgenograms (CXRs) show reasonable sensitivity known exposure or other suggestive history. Sputum for acid fast
but poor specificity for bacterial pneumonia [12]; however, many bacilli (AFB) is difficult to obtain in children, but gastric lavage, tuber-
children with pneumonia initially have normal chest radiographs. culous skin testing (e.g. Mantoux) and CXR may all be considered.
One reason is that CXR findings can lag behind clinical presentation
[13], and CXRs are often not repeated. Current emphasis is on empiri-
cal therapy, rather than radiographic diagnosis [7]. Malaria
Malaria has been shown to present with many of the same signs and
symptoms as severe pneumonia in high malaria endemic areas. Pallor
MISCELLANEOUS CLINICAL FINDINGS (signs of anemia) and hemorrhagic skin lesions favor malaria [10].
Staphylococcal pneumonia may be associated with rapid illness Blood smears will identify malaria parasites, but may not always be
progression in the presence of treatment, and can result in lung diagnostic. Intervention in these cases should follow local or national
cavitation, pneumatocele, pneumothorax, pleural effusions and guidelines.
empyema.
Tuberculosis is often a diagnosis of exclusion in the absence of avail- Foreign Body Aspiration
able laboratory support. If children have fever for >14 days and clini- This can mimic infectious pneumonia and can be identified by
cal pneumonia, health providers should consider tuberculosis. If patient history if ingestion was observed or suspected by a missing
other causes of fever cannot be identified, then anti-tuberculosis object. Auscultation findings can include either crepitations and/or
therapy should also be considered based on national epidemiology wheezing depending on the location of the foreign body. A CXR can
and guidelines. be diagnostic and treatment often requires bronchoscopy, where
Pneumocystis (carinii) jiroveci infection should be considered in HIV- available.
infected children, especially in the setting of hypoxia, respiratory dis-
tress and interstitial infiltrates on CXR. Therapy should be tailored Pertussis
accordingly. Pertussis is a vaccine-preventable infection that may present with a
paroxysmal cough followed by a “whoop” on inhalation. The infec-
DIFFERENTIAL DIAGNOSIS tion is primarily in the bronchi. Fever may or may not be present.
Other indicators suggestive of pertussis include: subconjunctival hem-
The signs and symptoms of clinical pneumonia are designed to be orrhages (from extreme Valsalva-straining during paroxysms); apnea
maximally sensitive (include the largest possible fraction of true following cough; and an absence of diphtheria-pertussis-tetanus
pneumonia-positive cases), while sacrificing specificity (inclusion of immunization.
false-positives – children without pneumonia) in order to ensure
that the largest possible fraction of true pneumonia patients receive
antimicrobial treatment. Although there are regional differences in Diphtheria
the prevalence of other diagnoses and comorbidities, some of the Diphtheria is a vaccine-preventable infection that is characterized by
more important syndromes to consider include the following, listed fever, a gray membrane in the posterior pharynx and enlarged cervical
below. lymph nodes often resulting in a “bull neck”.
412 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Category 5: reviews
Review [17] To review Best first-line agent for
recommendations for non-severe childhood
first-line treatment of pneumonia is amoxicillin
non-severe pneumonia, twice daily for 3–5 days
targeting S. pneumoniae with antibiotic change
and Haemophilus (e.g. high-dose
influenzae type b amoxicillin/clavulanate or
macrolide) for failure to
improve after 48–72 hours
Review [33] Determine the efficacy of ß-lactams good for
ß-lactams for CAP sensitive and intermediate
resistant pneumococci. For
hospitalized patients with
CAP, recommend
combination therapy
(ß-lactam plus macrolide)
Review [34] Evaluate amoxicillin/ Amoxicillin/clavulanate ER
clavulanate extended effective in outpatient
release against CAP against these
ß-lactamase-producing pathogens
pathogens (H. influenzae,
Moraxella catarrhalis,
Haemophilus
parainfluenzae,
Staphylococcus aureus)
and S. pneumoniae with
reduced susceptibility
(MIC 2.0 µg/ml)
Review [35] To evaluate the efficacy Gemifloxacin given twice
of new respiratory daily for 5–7 days is
fluoroquinolones against non-inferior and even
resistant organisms superior to other standard
agents
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or severe malnutrition: guidelines for care at the first-referral level in develop- severe pneumonia, without associated co-morbidities such as severe malnutri-
ing countries. Geneva: World Health Organization and UNICEF; 2000:162. tion, in an urban health clinic in Dhaka, Bangladesh. Arch Dis Child 2008;
11. Harari M, Shann F, Spooner V, et al. Clinical signs of pneumonia in children. 93:490–4.
Lancet 1991;338:928–30. 24. Subhi R, Adamson M, Campbell H, et al. The prevalence of hypoxaemia
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for chest radiographs interpretation in children with pneumonia. Arch Argent Dis 2009;9:219–27.
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39 Tuberculosis
Sonya S Shin, Kwonjune J Seung
EPIDEMIOLOGY
Key features About two billion people – one-third of the world’s population – have
Mycobacterium tuberculosis infection. Among the 22 countries identi-
l Tuberculosis (TB) is the second leading infectious cause of fied by the World Health Organization (WHO) as high TB burden
death and the leading killer of people with HIV countries, 19 are low- or lower middle-income countries defined by
l TB is a disease of poverty, with the vast majority of cases the World Bank. Of the 9.27 million new TB cases reported in 2007,
2.98 million (32%) occurred in sub-Saharan Africa and 13 of the 15
occurring in low- or lower middle- income countries
countries with the highest TB incidence are in Africa (Table 39-1, Fig.
l HIV infection greatly increases the risk of developing active 39.1) [2].
TB for people infected with latent TB
High rates of TB incidence in African countries are attributed to the
l Multidrug-resistant TB (MDR-TB) is on the rise and is heavy burden of TB/HIV co-infection. Approximately 80% of HIV
associated with lower cure rates compared with co-infected TB patients live in sub-Saharan Africa. In 2007, an esti-
susceptible TB mated 14.8% of incident TB cases were HIV-positive. TB is the leading
l Most TB involves the lung, but extra-pulmonary cause of death among HIV-positive people – 23% of all TB deaths
involvement is more common among occurred in HIV-positive people. Although TB typically affects men
more than women over the age of 14, in countries with an HIV preva-
immunocompromised individuals and children
lence of greater than 1%, this ratio is reversed as a result of biologic
l Pulmonary TB radiographic findings can be subtle, mimic and social factors that contribute to increased vulnerability to HIV
community-acquired pneumonia or show severe infection and more rapid disease progression among women [2].
disseminated or cavitary disease
Another concerning trend is the increase in multidrug-resistant TB
l Extra-pulmonary TB commonly involves the lymph nodes, (MDR-TB, resistant to at least isoniazid and rifampin), which is asso-
pleural space, central nervous system (CNS), bones or ciated with lower cure rates than cases of pan-susceptible TB. In 2007,
gastrointestinal tract MDR-TB incidence was estimated at 500,000 cases, comprising
l TB diagnosis is particularly difficult in immunocompromised approximately 3% of new TB cases and 19% of previously-treated TB
cases (Table 39-1) [3]. China and India account for about half of new
individuals or children, and a clinical diagnosis of active TB
MDR-TB cases. The Russian Federation and countries of the former
and MDR-TB with empiric treatment is often necessary Soviet Union have the highest proportion of MDR-TB among TB
l Combination therapy is necessary to avoid selection of cases, estimated at 18–22.2% [4]. Recently, the term “extensively drug-
drug-resistant pathogens resistant TB” (XDR-TB) was established to refer to MDR-TB strains
that are also resistant to fluoroquinolones and at least one second-line
injectable agent. Outbreaks of XDR-TB have been associated with
lethal clinical outcomes, particularly among HIV co-infected cases. To
date, 55 countries have reported XDR-TB cases, with the highest
reported rates of XDR-TB – 13.6% of all MDR-TB cases – in the region
INTRODUCTION of Eastern Europe and Russia. However, the epidemiology of XDR-TB
is greatly underestimated because drug susceptibility testing (DST) is
Tuberculosis (TB) is an ancient infection of humanity. DNA- not available in many countries [5].
confirmed cases date to 9000 years ago and suspected TB lesions
have been described in Homo erectus bones from 500,000 years ago.
Ironically, TB remains a global public health threat as the second
NATURAL HISTORY, PATHOGENESIS,
leading single pathogen infectious cause of death after HIV. Since AND PATHOLOGY
the advent of effective anti-tuberculosis agents in the 1950s, TB has TB is an airborne pathogen. A cough or sneeze from an infectious
come to epitomize diseases of poverty: a curable disease that con- host emits thousands of aerosolized droplet nuclei that are much
tinues to kill 2 million people per year. As TB predominantly affects smaller than respiratory droplets (approximately 1–5 µm). Bacilli-
working-age populations, the macro-economic impact of TB in containing droplets remain airborne for hours to days and are small
developing countries is also immense, with a 0.2–0.4% decrease in enough to be inhaled into the terminal alveoli.
annual economic growth for every 10% increase in TB incidence [1].
Despite global efforts to eliminate TB, prevalence continues to rise Following inhalation, bacilli may extend via lung lymphatics to other
and, in Eastern Europe and Africa, incidence is also on the rise. This areas of the lungs and to other organs throughout the body. Cellular
reversal of trends is due, in large part, to “deadly synergies” with immunity develops after approximately 6–12 weeks, resulting in
other chronic diseases, the emergence of strains resistant to anti-TB either eradication of bacilli or the formation of granulomas around
agents and deepening social inequality in both developed and devel- the sites of infection. This cellular immunity is the basis for the
oping countries. tuberculin skin test (TST; described below). Cell-mediated immunity
416
Tuberculosis 417
PULMONARY TUBERCULOSIS
Primary pulmonary TB is often characterized by lower lobe infiltrates LNTB
B 35%
(Fig. 39.3) and/or hilar adenopathy, reflecting the site of inoculation
and early spread via lymphatics. Symptoms and radiographic findings
FIGURE 39.2 Distribution of TB presentation, by HIV status. (A) Distribution
can be subtle or mimic community-acquired pneumonia. Inquiry
of TB cases by anatomical site in HIV-negative patients. (B) Distribution of
into recent TB contacts is important to increase the index of suspicion.
TB cases by anatomical site in HIV-positive patients PTB pulmonary TB;
Immunosuppressed individuals, such as infants and HIV-positive EPTB extrapulmonary TB; GUTB genitourinary TB, MTB miliary TB; TBM
individuals are less able to contain the infection and therefore more tuberculosis meningitis; ABD abdominal TB; LNTB lymph node tuberculosis
likely to present with primary TB. Cavitary lesions are frequently (redrawn from Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med
associated with hemoptysis. Physical findings may include the use of Res 2004; 120:316–53.)
accessory muscles, tachycardia with a widely split S2, as well as club-
bing, pale conjunctiva and slow capillary refill. Lung auscultation can
Bilateral involvement is not uncommon. Chronic progression can lead
vary widely, ranging from a normal exam to focal râles, generalized
to suppuration and formation of sinus tracts. Up to half of TB adenitis
wheezing or focally absent breath sounds. A cavitary lesion may emit
cases may present without systemic symptoms.
a hollow, tubular low-pitched sound, sometimes producing a “water-
fall” sound if fluid is present in the cavity.
PLEURAL TUBERCULOSIS
TUBERCULOUS ADENITIS TB pleurisy is commonly a manifestation of primary disease, although
Lymphadenitis is the most common extra-pulmonary manifestation it can also be seen in the context of re-activation. In many developing
of TB. As with all forms of extra-pulmonary TB, adenitis has classically countries, TB is the most common cause of pleural effusions. Symp-
been a pediatric presentation, but is increasingly observed in adults toms may be acute or subacute, and include pleuritic chest pain,
co-infected with HIV. Cervical lymphadenopathy (scrofula) is the most nonproductive cough and progressive dyspnea. Effusions are exuda-
common (Fig. 39.4), while generalized lymphadenopathy may reflect tive and more than 90% are unilateral. Approximately 20–40% of
disseminated infection. When computerized tomography (CT) or cases are associated with ipsilateral parenchymal involvement. Effu-
magnetic resonance imaging (MRI) is available, other sites of involve- sions are usually small-to-moderate in size – up to 30% may be locu-
ment, such as intra-abdominal and retroperitoneal lymph nodes may lated. Less commonly, active infection within the pleural space results
be identified. Single or multiple lymph nodes may be enlarged; the in TB empyema, which can be associated with a bronchopleural
lympadenopathy is usually painless, unless super-infection occurs. fistula or empyema necessitatis, extending into the extra-pleural space.
Tuberculosis 419
FIGURE 39.3 Chest radiograph of primary TB. Primary TB with right lower
lobe infiltrate and right hilar adenopathy in a HIV-positive patient.
TB may result in delayed diagnosis. Advanced disseminated disease SPUTUM SMEAR MICROSCOPY
may be associated with polyserositis or acute respiratory distress syn-
drome. TB is also associated with rheumatologic manifestations, such Sputum smear microscopy is often the only diagnostic test available
as erythema nodosum and aseptic reactive polyarthritis (known as in resource-limited settings. Smear microscopy should be performed
Poncet’s disease). for all suspected cases of TB, including individuals with cough lasting
more than two weeks and cases of suspected extrapulmonary TB.
Ideally, two or three sputum samples should be collected on consecu-
PATIENT EVALUATION, DIAGNOSIS tive mornings. The sensitivity of a single smear microscopy is 22–
AND DIFFERENTIAL DIAGNOSIS 43%, with a mean incremental yield in sensitivity of 9% with a
second sample and 4% with a third sample. Unfortunately, 20–60%
That the mainstay of TB diagnosis is an insensitive assay developed of HIV-negative patients with pulmonary TB are sputum smear-
more than a century ago is testament to the urgent need for accurate negative. HIV-positive patients and children are more likely to have
diagnostics. In particular, smear-negative pulmonary TB and extrapul- clinically significant disease at early stages, when the bacillary burden
monary TB remain predominantly clinical diagnoses. Among immu- is still low, and therefore present with smear-negative or pauci-
nosuppressed individuals who present with attenuated manifestations bacillary microscopy [8]. For individuals with minimal pulmonary
of disease, under-diagnosis is still the norm, as evidenced by undiag- involvement and/or scant sputum production, induced sputum,
nosed TB identified post-mortem in 14–54% of HIV-positive indi- gastric lavage or broncoscopy can increase test sensitivity. Sputum
viduals and in 20% of children (Box 39.1). Diagnostic delays or processing, such as liquefaction or concentration by centrifugation,
failure to obtain diagnostic confirmation should not preclude initia- and the use of fluorescence microscopy can also increase the sensitiv-
tion of appropriate therapy. ity of smear microscopy.
RADIOGRAPHY
Chest radiograph and fluorography are commonly used to diagnose
pulmonary TB. Because there are numerous other pulmonary diseases
BOX 39.1 Diagnosis of Pediatric Tuberculosis that look similar to active TB (Table 39-2), clinical findings must
complement radiographic findings to make the clinical diagnosis of
l History: cough, fever, night sweats, failure to thrive, weight TB. Re-activation TB – more frequently observed among HIV-negative
loss, age (TB presentation is similar to adults among chil- cases – classically presents with apical involvement because of the
high oxygen tension in the upper lung zones. Chronic findings
dren over 4 years old).
include cavities, fibrosis, collapse of upper lobes and retraction of the
l Physical examination: weight for age, mid-upper arm cir- mediastinal structures (Fig. 39.6). Atypical presentations, such as
cumference, lymphadenopathy. miliary features, intrathoracic adenopathy, pleural effusions and
l Diagnostics: lower lobe infiltrates are common in HIV-positive patients. Chest
l evidence of TB infection [tuberculin skin test (TST) or radiographs are particularly useful for “ruling out” pulmonary TB
interferon-gamma release assays (IGRA)] helpful; before starting treatment for latent TB infection. However, chest radio-
graphs may be normal in up to 14% of HIV-positive individuals with
l radiology: atypical presentations (i.e. lymphadenopathy,
culture-confirmed pulmonary TB. CT and ultrasound are useful for
miliary) more common; evaluating patients with suspected extrapulmonary TB, although find-
l sputum smear microscopy and culture: often negative ings are often nonspecific and can include organomegaly, lymphad-
because of difficulty producing sample and low bacillary enopathy, ascites and abscesses. Plain radiographs may reveal bony
load – gastric lavage or bronchoscopy can improve yield; destruction or compression fractures at sites of bony involvement. CT
l extra-pulmonary sites: aggressive efforts to aspirate or or MRI in suspected cases of CNS TB may reveal basilar meningeal
biopsy suspected sites helpful. enhancement and hydrocephalus, and can be helpful in ruling out
alternative diagnoses in HIV-positive individuals, such as lymphoma
l Response to empiric therapy may provide diagnostic
and toxoplasmosis. In Pott’s disease, compression fractures, disciitis
confirmation. and adjacent soft tissue involvement with cold abscesses may be
revealed on imaging.
TABLE 39-4 Characteristics of Novel Methods to BOX 39.2 Criteria for Positive Tuberculin
Diagnose Tuberculosis (TB) and Drug-resistant TB Skin Test (TST) by Risk Group
Method Characteristics Response with ≥5 mm induration
Nitrate reductase Low-cost, simple assay in which HIV positive persons
method Mycobacterium tuberculosis reduces nitrate Recent contacts of TB case patients
to nitrate, resulting in color change when Fibrotic changes on chest X-ray consistent with TB
detection reagent added to tube. Pooled
sensitivity/specificity for direct drug Patients with organ transplants and other immunosuppressed
susceptibility testing (DST) 99%/100% for patients receiving the equivalent of 15 mg/dl of prednisone
Rifampin (R) and 94%/100% for Isoniazid for 1 month or more*
(H). Pooled sensitivity/specificity for
indirect DST 97%/100% for R and Response with ≥10 mm induration
96%/99% for H. Turn-around time 14–21 Recent immigrants (i.e., within the last 5 years) from high preva-
days. lence countries
Microscopic Low-cost, simple assay in which liquid Injection drug users
observation drug culture allows early visualization of Residents or employees† of the following high-risk congregate
susceptibility assay cord-like structures using inverted settings: prisons and jails, nursing homes and other long-
(MODS) microscope. Performs well on smear- term facilities for the elderly, hospital and other health care
negative samples. Pooled sensitivity/
specificity for direct DST for detecting facilities, residential facilities for patients with AIDS, and
resistance to R and H: 96%/96% and homeless shelters
92%/96% respectively. Turn-around time Mycobacteriology laboratory personnel
approximately 21 days. Persons with the following clinical conditions that place them
Genotype Molecular test similar to Genotype MTBDR, at high risk: silicosis, diabetes mellitus, chronic renal failure,
MTBDRplus (Hain but detects a wider array of rpoB and katG/ some hematologic disorders (e.g., leukemias and lympho-
Life Sciences, inhA mutations associated with resistance mas), other specific malignancies (e.g., carcinoma of the
Nehren, Germany) to R and H. Specialized equipment
head, neck and lung), weight loss ≥ 10% of ideal body
required. Risk of DNA contamination in
laboratory. Pooled sensitivity/specificity for weight, gastrectomy, and jejunoileal bypass
direct DST for detecting resistance to R Child younger than 4-years of age or infants, children, and ado-
and H: 99%/99% and 96%/100% lescents exposed to adults at high risk
respectively; turnaround time 1–2 days.
Response with ≥15 mm induration
INNO-LiPA Rif TB Line probe assay to detect most common Persons with no risk factors for TB
assay rpoB mutations associated with R
(Immunogenetics, resistance. Specialized equipment
Source: American Thoracic Society. Targeted tuberculin testing and treat-
Ghent, Belgium) required. Risk of DNA contamination in
ment of latent tuberculosis infection. American Thoracic Society. MMWR
laboratory. Pooled sensitivity/specificity of Recomm Rep. 2000 Jun 9;49(RR-6):1–51.
both direct and indirect assays were *Risk of TB in patients treated with corticosteroids increases with a higher
97%/99% for detecting R resistance. dose and longer duration.
Turnaround time 1–2 days. †
For persons who are otherwise at low risk and are tested at the start of
employment, a 15 mm induration response or higher is considered positive.
with TB, and alternative diagnoses are not obvious. For individuals soon after the start of therapy may be observed. This is more common
with chronic cough, a trial of antibiotic therapy may be attempted among HIV-positive individuals, in particular shortly after initiation
prior to empiric TB treatment. In such cases, agents with anti- of anti-retroviral therapy (i.e. immune reconstitution syndrome [15,
mycobacterial activity, such as fluoroquinolones, should be avoided. 16]). However, paradoxical responses can be observed in immuno-
In high-burden TB settings, there should be a low threshold for competent individuals, including up to 10% of individuals with CNS
empiric TB treatment, especially if the patient is ill or HIV-positive. TB. HIV-positive patients may also have other AIDS-related complica-
tions that confuse the clinical picture. More than one issue can con-
MONITORING TREATMENT RESPONSE tribute to failure to clinically respond to TB treatment in a single
patient. Furthermore, in smear-negative disease, confirming a defini-
With effective treatment, patients experience rapid improvement in tive diagnosis can be challenging. It is often necessary to provide
constitutional symptoms followed by a gradual decrease in cough and empiric treatment for several likely diagnoses. In patients who are
sputum production. Smear microscopy is a simple way to monitor clinically unstable, hospitalization may be necessary to assess the
treatment for cases with initially smear-positive disease. Sputum is patient carefully and quickly.
generally smear-negative by the end of the first month of treatment;
over 90% will be smear-negative after two months of regular
treatment. TREATMENT
Any suggestion that the patient is not responding to treatment by the TB treatment has been extensively studied in controlled clinical trials,
second month of treatment should trigger immediate re-evaluation which support the use of multidrug regimens along with measures to
(Table 39-5). Adherence to treatment can be assessed by careful, non- ensure optimal treatment adherence [17–19]. Therapy generally con-
judgemental inquiry of the patient, family and providers. Drug- sists of an “intensive phase” with daily administration of at least four
resistant TB should be considered, especially in settings with significant anti-tuberculous drugs, followed by “continuation phase” involving
rates of primary TB and/or individuals with suboptimal treatment daily or intermittent therapy with a reduced number of drugs. A
adherence. Patients with drug-resistant TB, even MDR-TB, may ini- summary of anti-tuberculosis drugs and drug interactions is provided
tially respond favorably to first-line TB drugs. Paradoxical worsening in Tables 39-6–39-12, which appear online [20, 21].
Tuberculosis 423
Drug name Description and adult dose Side effects Monitoring requirements
(abbreviation) and comments
Isoniazid (H) Description: bactericidal; inhibits Common: hepatitis (10–20% have Monitoring: consider baseline
mycolic acid synthesis most elevated of transaminases), peripheral and monthly aspartate
effectively in dividing cells; neuropathy (dose-related; increased aminotransferase (SGOT),
hepatically metabolized risk with malnutrition, alcoholism, especially if age greater than 50
diabetes, concurrent use of years
Dose: 300 mg/day or 900 mg/day
aminoglycoside (AG) or ethionamide
twice or thrice weekly Comments: give with pyridoxine
(ETO)
50 mg/day if using large dose or
Less common: gynecomastia, rash, if patient is at risk for peripheral
psychosis, seizure neuropathy (diabetes, alcoholism,
HIV, etc.)
Rifamycins Description: bactericidal; inhibits Common: orange-colored bodily Monitoring: baseline SGOT and
Rifampicin (R) protein synthesis by blocking secretions, transient transaminitis, bilirubin, repeat if symptoms
(Rifampin) Rifabutin mRNA transcription and synthesis; hepatitis, gastrointestinal (GIT) (jaundice, fatigue, anorexia,
(Rfb) hepatically metabolized distress weakness, or nausea and
vomiting for more than three
Dose: R: 600 mg/ Less common: cholestatic jaundice
days)
day; Rfb 300 mg/day
Pyrazinamide (Z) Description: bactericidal; Common: arthritis/arthralgias, Monitoring: Baseline and monthly
mechanism unclear; effective in hepatotoxicity, hyperuricemia, SGOT; uric acid can be measured
acidic milieu (e.g. cavitary disease, adominal distress if arthalgias, arthritis, or
intracellular organisms); hepatically symptoms of gout are present
Less common: impaired diabetic
metabolized, renally excreted
control, rash Comments: usually given once
Dose: 15–30 mg/kg/day daily, but can split dose initially
to improve tolerance
Ethambutol (E) Description: bacteriostatic at Common: generally well-tolerated Monitoring: baseline and monthly
conventional dosing (15 mg/kg); visual acuity and red/green color
Less common: optic neuritis, GI
inhibits lipid and cell wall vision test when dosed at greater
distress, arthritis/arthralgia
metabolism; renally excreted than 15 mg/kg/day (more than
10% loss is considered
Dose: 15–25 mg/kg, consider
significant); regularly question
decreasing to 15 mg/kg once
patient about visual symptoms
patient is culture-negative
424 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Drug name Description and adult dose Side effects Monitoring requirements
(abbreviation) and comments
Aminoglycosides Description: bactericidal; Common: pain at injection site, Monitoring: baseline and then
(AG) aminogycosides inhibit protein proteinuria, serum electrolyte bi-weekly creatinine, urea, and
Amikacin (AMK) synthesis through disruption of disturbances serum potassium; more
Kanamycin (K) ribosomal function; less effective frequently in high risk patients. If
Less common: cochlear otoxocity
Streptomycin (S) in acidic, intracellular potassium is low, check
(hearing loss, dose-related to
environments; polypeptides magnesium and calcium. Baseline
cumulative and peak concentrations,
Polypeptides: appear to inhibit translocation of audiometry and monthly
increased risk with renal insufficiency,
the peptidyl-tRNA and the monitoring in high risk patients
may be irreversible), nephrotoxicity
Capreomycin (CM) initiation of protein synthesis; (high risk patients = elderly,
(dose-related to cumulative and peak
Viomycin (VM) renally excreted diabetic or HIV-positive patients,
concentrations, increased risk with
or patients with renal
Dose: 15–20 mg/kg/day renal insufficiency, often irreversible),
insufficiency)
peripheral neuropathy, rash,
vestibular toxicity (nausea, vomiting, Comments: observe for problems
vertigo, ataxia, nystagmus), with balance; increase dosing
eosinophilia interval or reduce dose and
monitor serum drug
Otoxocity potentiated by certain
concentrations as needed to
diuretics, especially loop diuretics
control side effects
Electrolyte disturbances are more
common in patients receiving CM
Fluoroquinolones Description: bactericidal; Common: generally well-tolerated, Monitoring: no laboratory
DNA-gyrase inhibitor; renally well-absorbed monitoring requirements
Ciprofloxacin (CPX) excreted
Less common: diarrhea, dizziness, GI Comments: do not administer
Ofloxacin (OFX)
Dose: distress, headache, insomnia, with antacids, sucralfate, iron,
Levofloxacin (LFX)
Ciprofloxacin 1500 mg/day photosensitivity, rash, vaginitis, zinc, calcium, or oral potassium
Moxifloxacin (MFX)
Ofloxacin 800 mg/day psychosis, seizure [central nervous and magnesium replacements;
Levofloxacin 750 mg/day system (CNS) effects seen almost LFX, MFX have the most activity
Moxifloxacin 400 mg/day exclusively in elderly]; synotenovitis against Mycobacterium
tuberculosis
Cycloserine (CS) Description: bacteriostatic; alanine Common: neurologic and psychiatric Monitoring: consider serum drug
analogue; interferes with cell-wall disturbances, including headaches, monitoring to establish optimal
proteoglycan synthesis; renally irritability, sleep disturbances, dosing
excreted aggression, and tremors
Comments: give 50 mg for every
Dose: 500–1000 mg/day (initiate at Less common: psychosis, peripheral 250 mg of CS (to lessen
500 mg/day for 2–3 days then neuropathy, seizures (increased risk of neurologic adverse effects)
gradually increase to full dose) CNS effects with concurrent use of
ethanol, H, ETO, or other centrally-
acting medications), hypersensitivity
Thiamides Description: may be bactericidal or Common: GI distress (nausea, Monitoring: consider baseline
bacteriostatic depending on vomiting, diarrhea, abdominal pain, and monthly SGOT
Ethionamide (ETO) susceptibility and concentrations loss of appetite), dysgeusia (metallic
Comments: may split dose or
Prothionamide (PTO) attained at the infection site; the taste), hypothyroidism (especially
give at bedtime to improve
carbotionamide group, also found when taken with PAS)
tolerability; ETO and PTO
on thiacetazone, and the pyridine
Less common: arthralgias, dermatitis, efficacies are considered similar;
ring, also found on H, appear
gynecomastia, hepatitis, impotence, PTO may cause fewer GI side
essential for activity; hepatically
peripheral neuropathy, effects
metabolized, renally excreted
photosensitivity
Dose: 500–1000 mg/day (initiate at
500 mg/day for 2–3 days then
gradually increase to full dose)
Para-aminosalicylic Description: bacteriostatic; disrupts Common: GI distress (nausea, Monitoring: no laboratory
acid (PAS) folic acid metabolism (thought to vomiting, diarrhea), hypersensitivity, monitoring requirements
inhibit the biosynthesis of hypothyroidism (especially when
Comments: some formulas of
co-enzyme F in the folic acid taken with ETO)
enteric coated granules need to
pathway); hepatic acetylation,
Less common: hepatitis, electrolyte be administered with an acidic
renally excreted.
abnormalities food or beverage (i.e. yogurt or
Dose: 150 mg/day divided into 3 acidic juice)
Drug interactions: decreased H
doses
acetylation, decreased R absorption
in non-granular preparation,
decreased B12 uptake
Adapted from PIH Guide to the Medical Management of Multidrug-Resistant Tuberculosis. Boston: Partners In Health; 2004. Available at: http://ftp.pih.org/inforesources/
pihguide-mdrtb.html
TABLE 39-7 Pediatric Dosing of Tuberculosis Drugs TABLE 39-8 World Health Organization(WHO)
Recommended Use of Fixed-dose Combinations for
Medication Dose Maximum First-line Treatment for Adults
(abbreviation) daily dose
Isoniazid (H) 4–6 mg/kg daily or 300 mg Weight Initial phase (two Continuation phase
8–12 mg 3 × wk months) (four months)
Ethambutol (E) 25 mg/kg daily 1200 mg Daily 56 total doses Daily 112 total doses
TABLE 39-9 Recommendations for Concomitant Treatment of Tuberculosis (TB) and HIV Infection
Combined regimen PK effect of the Tolerability/ toxicity Antiviral activity when Recommendation
for treatment of HIV rifamycin used with rifampin (comments)
and tuberculosis
Efavirenz-based ART* Well-characterized, Low rates of Excellent Preferred (efavirenz should
with rifampin-based TB modest effect discontinuation not be used during the first
treatment trimester of pregnancy)
PI-based ART* with Little effect of rifabutin Low rates of Favorable, though Preferred for patients
rifabutin-based TB on PI concentrations, but discontinuation (if published clinical unable to take efavirenz†
treatment marked increases in rifabutin is appropriately experience is not extensive
rifabutin concentrations dose-reduced)
Nevirapine-based ART Moderate effect Concern about Favorable Alternative for patients who
with rifampin-based TB hepatotoxicity when used cannot take efavirenz and if
treatment with isoniazid, rifampin rifabutin not available
and pyrazinamide
Zidovudine/ lamivudine/ 50% decrease in Anemia No published clinical Alternative for patients who
abacavir/ tenofovir with zidovudine, possible experience cannot take efavirenz and if
rifampin-based TB effect on abacavir not rifabutin not available
treatment evaluated
Zidovudine/ lamivudine / 50% decrease in Anemia Favorable, but not Alternative for patients who
tenofovir with rifampin- zidovudine, no other evaluated in a randomized cannot take efavirenz and if
based TB treatment effects predicted trial rifabutin not available
Zidovudine/ lamivudine/ 50% decrease in Anemia Early favorable experience, Alternative for patients who
abacavir with rifampin- zidovudine, possible but this combination is less cannot take efavirenz and if
based TB treatment effect on abacavir not effective that efavirenz- rifabutin not available
evaluated based regimens in persons
not taking rifampin
Super-boosted lopinavir- Little effect Hepatitis among healthy Good among young Alternative if rifabutin not
based ART with adults, but favorable children (<3 years) available; preferred for
rifampin-based TB experience among young young children when
treatment children (<3 years) rifabutin not available
*with two nucleoside analogues.
†
includes patients with non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV, those unable to tolerate efavirenz, women during the first 1–2 trimesters of
pregnancy.
ART, antiretroviral therapy.
Managing Drug Interactions in the Treatment of HIV-related Tuberculosis. Centers for Disease Control and Prevention; 2007. Available at: www.cdc.gov/tb/publications/
guidelines/TB_HIV_Drugs/default.htm
426 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Integrase inhibitors
Recommended change in dose Recommended change Comments
of antiretroviral drug in dose of rifampin
Raltegravir No change No change (600 mg/day) No clinical experience; raltegravir concentrations ↓ by
40–61%
Managing Drug Interactions in the Treatment of HIV-related Tuberculosis. Centers for Disease Control and Prevention; 2007. Available at: www.cdc.gov/tb/publications/
guidelines/TB_HIV_Drugs/default.htm
Tuberculosis 427
Atazanavir No change ↓ to 150 mg every other day or 3x/ No published clinical experience. Rifabutin AUC ↑ by
week 250%
Indinavir 1000 mg every 8 ↓ to 150 mg/day or 300 mg 3x/week Rifabutin AUC ↑ by 170%; indinavir concentrations ↓ by
hours 34%
Nalfinavir No change ↓ to 150 mg/day or 300 mg 3x/week Rifabutin AUC ↑ by 207%; insignificant change in
nelfinavir concentration
Integrase inhibitors
Raltegravir No change No change No clinical experience; a significant interaction is
unlikely, but this has not yet been studied
Managing Drug Interactions in the Treatment of HIV-related Tuberculosis. Centers for Disease Control and Prevention; 2007. Available at: www.cdc.gov/tb/publications/
guidelines/TB_HIV_Drugs/default.htm
428 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Continued
Tuberculosis 429
Patient adherence is the most important factor associated with success months from time of culture-conversion but can be pro-
of TB treatment. Adherence is difficult because of the heavy pill longed if the patient has a highly resistant strain or slow
burden and prolonged treatment. Patients should be educated before clinical response. The continuation phase should last >12
starting treatment about the importance of adherence and the danger months from time of culture-conversion;
of treatment failure and drug resistance. International consensus l pyridoxine should be co-administered.
endorses the use of directly observed treatment (DOT), although
l Consider adjunctive surgery if there is localized disease.
efficacy data from controlled trials are equivocal [28]. DOT varies
l Provide comprehensive monitoring and adherence
widely by program [29]. Patients may travel to a health facility for
DOT; community health workers or outreach teams may visit patients support.
to observe treatment; or community volunteers or family members
may be trained to observe and record doses. Enhanced-DOT includes
additional adherence strategies and has been shown to be more
effective than DOT alone or self-administration [30]. Incentives and
enablers include transportation reimbursement, cash transfers, case- HIV-positive individuals, repeated or prolonged LTBI treatment may
management and outreach support. Nutritional supplementation can be useful in preventing re-infection. Furthermore, consensus on treat-
also increase adherence and may have an independent effect on treat- ment of individuals at risk of latent MDR-TB infection is lacking.
ment success, particularly in resource-limited settings where chronic Some experts recommend the use of at least two drugs to which the
malnutrition is rampant. infecting isolate is likely to be susceptible (based on contact or
regional resistance data).
TREATMENT OF LATENT TUBERCULOSIS
INFECTION REFERENCES
A number of regimens for treatment of patients with latent TB infec-
1. Skolnik R. Essentials of Global Health. Sudbury: Jones & Bartlett Publishers;
tion (LTBI) help prevent the development of active TB disease [31,
2008.
32]. The standard of care for treatment of latent TB infection – isoniazid 2. World Health Organization. WHO Report 2009: Global Tuberculosis Control.
300 mg daily for 6–9 months – has been shown to be effective in Geneva: World Health Organization; 2009.
preventing progression to active TB and has not been associated with 3. World Health Organization. Anti-Tuberculosis Drug Resistance in the World.
the development of isoniazid resistance. Latent TB infection treatment Geneva: The WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resist-
policies vary widely. In settings with low TB prevalence, latent TB ance Surveillance; 2008.
infection treatment is often recommended for all individuals with a 4. World Health Organization. Anti-tuberculosis Drug Resistance in the World:
positive tuberculin skin test (TST). In most high TB-prevalence set- Report No. 4. Geneva: World Health Organization; 2008.
tings, latent TB infection treatment is often limited to HIV-positive 5. Senior K. Relentless spread of extensively drug-resistant tuberculosis. Lancet
patients and pediatric household contacts of active TB cases. For Infect Dis 2009;9:403.
432 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
6. Grzybowski S. Natural history of tuberculosis. Epidemiology. Bull Int Union 21. PIH Guide to the Medical Management of Multidrug-Resistant Tuberculosis.
Tuberc Lung Dis 1991;66:193–4. Boston: Partners In Health; 2004. Available at: http://ftp.pih.org/inforesources/
7. Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004; pihguide-mdrtb.html
120:316–53. 22. El-Sadr WM, Tsiouris SJ. HIV-associated tuberculosis: diagnostic and treat-
8. Colebunders R, Bastian I. A review of the diagnosis and treatment of smear- ment challenges. Semin Respir Crit Care Med 2008;29:525–31.
negative pulmonary tuberculosis. Int J Tuberc Lung Dis 2000;4:97–107. 23. Marais BJ. Tuberculosis in children. Pediatr Pulmonol 2008;43:322–9.
9. Goto M, Noguchi Y, Koyama H, et al. Diagnostic value of adenosine deami- 24. Marais BJ, Gie RP, Schaaf HS, et al. Childhood pulmonary tuberculosis: old
nase in tuberculous pleural effusion: a meta-analysis. Ann Clin Biochem wisdom and new challenges. Am J Respir Crit Care Med 2006;173:1078–90.
2003;40:374–81. 25. Centers for Disease Control and Prevention. Prevention and treatment of
10. Bwanga F, Hoffner S, Haile M, Joloba ML. Direct susceptibility testing for tuberculosis among patients infected with human immunodeficiency virus:
multi drug resistant tuberculosis: a meta-analysis. BMC Infect Dis 2009;9:67. principles of therapy and revised recommendations. MMWR Recomm Rep
11. Nyendak MR, Lewinsohn DA, Lewinsohn DM. New diagnostic methods for 1998;47:1–58.
tuberculosis. Curr Opin Infect Dis 2009;22:174–82. 26. Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis.
12. Ling DI, Zwerling AA, Pai M. GenoType MTBDR assays for the diagnosis of Cochrane Database Syst Rev 2008:CD002244.
multidrug-resistant tuberculosis: a meta-analysis. Eur Respir J 2008;32: 27. Engel ME, Matchaba PT, Volmink J. Corticosteroids for tuberculous pleurisy.
1165–74. Cochrane Database Syst Rev 2007:CD001876.
13. Targeted tuberculin testing and treatment of latent tuberculosis infection. 28. Volmink J, Garner P. Directly observed therapy for treating tuberculosis.
American Thoracic Society. MMWR Recomm Rep 2000;49:1–51. Cochrane Database Syst Rev 2007:CD003343.
14. Mazurek GH, Jereb J, Lobue P, et al. Guidelines for using the QuantiFERON-TB 29. Kangovi S, Mukherjee J, Bohmer R, Fitzmaurice G. A classification and meta-
Gold test for detecting Mycobacterium tuberculosis infection, United States. analysis of community-based Directly observed therapy programs for tuber-
MMWR Recomm Rep 2005;54:49–55. culosis treatment in developing countries. J Community Health 2009;34:
15. Meintjes G, Rabie H, Wilkinson RJ, Cotton MF. Tuberculosis-associated 506–13.
immune reconstitution inflammatory syndrome and unmasking of tubercu- 30. Chaulk CP, Kazandjian VA. Directly observed therapy for treatment comple-
losis by antiretroviral therapy. Clin Chest Med 2009;30:797–810. tion of pulmonary tuberculosis: Consensus Statement of the Public Health
16. Leone S, Nicastri E, Giglio S, et al. Immune reconstitution inflammatory Tuberculosis Guidelines Panel. JAMA 1998;279:943–8.
syndrome associated with Mycobacterium tuberculosis infection: a systematic 31. Prevention, C.f.D.C.a. Latent TB Infection (LTBI) Guideline Updates. 2009.
review. Int J Infect Dis 2010;14:e283–91. Available at: http://www.cdc.gov/tb/publications/reportsarticles/mmwr/
17. Blumberg HM, Leonard Jr MK, Jasmer RM. Update on the treatment of tuber- mmwr_updates.htm.
culosis and latent tuberculosis infection. JAMA 2005;293:2776–84. 32. Marais BJ, Ayles H, Graham SM, Godfrey-Faussett P. Screening and preventive
18. World Health Organization. Treatment of Tuberculosis: guidelines for therapy for tuberculosis. Clin Chest Med 2009;30:827–46.
national programmes. Geneva: World Health Organization; 2003. 33. World Health Organization. Multidrug and extensively drug-resistant TB (M/
19. American Thoracic Society, Center for Disease Control and Prevention, XDR-TB): 2010 Global Report on Surveillance and Response. Geneva: World
Infectious Diseases Society of America. Treatment of Tuberculosis. MMWR Health Organization; 2010.
Recomm Rep 2003;20;52:1–77.
20. Managing Drug Interactions in the Treatment of HIV-related Tuberculosis.
Centers for Disease Control and Prevention; 2007. Available at:
www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs/default.htm
Pertussis 40
Kevin Forsyth
2,500,000 100
90
2,000,000 80
1,500,000 60
50
500,000 20
10
0 0
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
FIGURE 40.1 Pertussis global annual reported cases and DTP3 coverage (1980–2009).
TABLE 40-1 World Health Organization Regional and Global Summaries of Pertussis Incidence, 1980, 1990 and 1996–2005
Year
Location 1980 1990 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Africa 367,961 89,515 35,682 12,101 38,961 11,066 52,008 50,386 19,452 16,418 26,335 22,139
Americas 123,763 38,009 17,901 16,496 28,375 22,089 18,144 12,811 15,162 12,756 26,194 8747
Eastern 171,631 27,437 2823 3210 4367 2840 2112 4257 2650 1161 81,987 5164
Mediterranean
Europe 90,546 129,735 54,745 67,307 56,317 48,897 53,675 31,084 25,176 25,530 42,220 26,425
Southeast Asia 399,310 156,028 22,479 41,940 46,666 127,76 34,930 37,813 43,250 39,371 39,002 37,764
Western Pacific 829,173 35,653 8009 25,953 15,875 17947 25,282 32,182 30,682 11,348 21,106 21,560
Global 1,982,384 476,377 141,339 167,007 185,561 115,615 186,151 168,533 13,6372 106,584 236,844 121,799
Noumber of 151 164 155 163 151 156 159 162 162 150 165 156
countries
(CDC) noted a 19-fold increase in the number of cases reported in is the pertussis toxin. It is possible that the pertussis toxin acts within
individuals aged 10–19 years and a 16-fold increase in persons over the central nervous system to exacerbate coughing fits. Hence, there
20 years of age. Data such as these are what has prompted the recom- are both central and local factors inducing cough.
mendation that anti-pertussis immunization not stop in young child-
hood (which was the previous recommendation).
CLINICAL MANIFESTATIONS
Pertussis is essentially a disease of the respiratory system. Initial symp-
NATURAL HISTORY, PATHOGENESIS toms consist of a runny nose and perhaps mild fever, but are quite
AND PATHOLOGY nonspecific. This is considered the early phase of the disease, generally
up to one week, followed by persistent coughing, which is the key
Following a usual incubation period of 5–10 days, individuals with feature of pertussis. The cough has a characteristic repetitive nature to
clinical pertussis may manifest with a prodromal period lasting a few it, with bursts of coughing triggered by a number of external factors,
days to one week with upper respiratory symptoms (rhinorrhea, including cold air, exercise and inhaled irritants, or it can just occur
fever), followed by a hacking, paroxysmal cough. The second phase— spontaneously. One of the traps for the unwary clinician is that a
the characteristic phase of pertussis with its coughing paroxysms— parent can give a history typical of pertussis, describing particularly
lasts 2–6 weeks, while the third phase—convalescence —may last up in a young infant a terrible repetitive cough. When examined by the
to 4 months: this phase is characterized by gradual reduction in doctor the child may appear to have no respiratory signs whatsoever
coughing. The organisms of pertussis, B. pertussis and B. parapertussis and can be dismissed from the doctor’s room only to have a spasm
(and, less commonly, Bordetella bronchiseptica) infect respiratory of coughing on going outside after receiving a blast of cold air as an
mucosa, leading to mucus hypersecretion and cilial paresis. The irritant. Hence, history is critical in this condition—a history charac-
organisms release a number of toxins, the most important of which terized by repetitive spasmodic coughing.
Per tussis 435
The cough will, at times, lead to vomiting in a younger child, typically There may need to be different clinical criteria used for episodic cases
at the end of a period of coughing. At the end of a coughing bout in contrast to epidemic cases.
there may be a sharp inspiration of air with the characteristic “whoop”
sound. Any history of prolonged paroxysmal coughing followed by Given the elasticity in clinical case definition, where there are
vomiting or whooping is highly characteristic of pertussis disease. The available laboratory diagnostics, a more substantive approach to
pertussis cough is sometimes colloquially termed “the 100 day cough”. diagnosis can be made through appropriate use of laboratory
Interestingly, this cough may appear to disappear and then reoccur investigations.
within six months or so of the primary infection when the patient
is exposed to certain irritants or another unrelated respiratory LABORATORY DIAGNOSIS
infection.
The classical way to provide laboratory confirmation of B. pertussis is
It is important to emphasize that pertussis disease is particularly through the collection of a nasopharyngeal swab plated onto appro-
problematic in infants. Mortality rates for infants are high; they can priate media. Although this approach gives high specificity, it has low
present with atypical forms of the disease, such as apnea, encepha- sensitivity and is not practical for rapid diagnoses.
lopathy or even multisystem organ failure unrelated to respiratory
disease. Hence, early immunization of infants is critical. It is con
sidered that three doses of vaccine are required to provide signifi-
SEROLOGY
cant immunity to younger children. Three doses are not normally Serological diagnosis of pertussis by ELISA (using specific B. pertussis
achieved until 5 or 6 months of age. Hence, infants in their first six proteins as antigens) using paired sera with demonstration of a rise
months of life have little protection. In addition, they have small in antibodies of fourfold from the first sample to the second sample
airways and appear highly vulnerable to the effects of pertussis is the classical way to confirm infection by serology. However, this
toxin. requires two blood tests and a delay in time which is not helpful for
the acute diagnosis of pertussis. Hence, there have recently been
In addition to the clear respiratory manifestations of pertussis disease, moves to look at single serology estimates for the diagnosis of pertus-
there are also multiple side effects from this disease, for example sis. Although different laboratories achieve different results, in general
subconjunctival hemorrhages caused by the force of the coughing, is a single measurement of IgG ≥27 IU/ml can be considered appropri-
characteristic of pertussis. There can also be pneumonia, encepha- ate for laboratory confirmation of clinical pertussis in adults in the
lopathy and seizures. first three weeks of an outbreak [9].
A more recent study [10] comparing high-sensitivity real time PCR
PATIENT EVALUATION assays and single serum pertussis serology showed that single serology
was the most efficient diagnostic test with relatively high sensitivity
CLINICAL DIAGNOSIS (greater than 64%) and high specificity (greater than 90%). Using
PCR, it was found that this was the second most efficient tool. An
There have been a number of different criteria used for the clinical advantage of PCR is utilizing nasopharyngeal aspirates compared
definition of pertussis. The WHO definition of pertussis illness with blood.
requires a paroxysmal cough lasting for at least 21 days and laboratory
confirmation or contact with a culture-positive case. Unfortunately, The precision (sensitivity and specificity) in the diagnosis of pertussis
this rather strict definition requires a fairly severe form of illness is, however, laboratory dependent. It is recommended that practition-
given the 21-day cough requirement and availability of laboratory ers become familiar with the laboratory diagnostic test offered by their
diagnostics. Another definition that is in common use is of 14 days local laboratory service. All of these tests are ancillary and helpful in
of cough, which can have a sensitivity of 84–92% and a specificity of the diagnosis but need to be interpreted with some degree of caution.
63–90% [8]. Clinicians need to be respectful of the overall clinical and laboratory
436 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
setting in which the patient presents and the stability of the source were unlikely to get pertussis and the high adverse event profile of
material as it is transferred to the laboratory. the whole-cell pertussis-based vaccines in older children and adults.
As mentioned above, however, cases of pertussis among older chil-
TREATMENT dren and adults has been increasing. This fact, and the development
of safe, effective and well-tolerated acellular pertussis vaccine products
Bordetella pertussis and B. parapertussis are susceptible to a range of has subsequently led to the endorsement of broader pertussis immu-
antibiotics in vitro. Antibiotics to which these organisms are sensitive nization programs for older children and adults with Tdap. Unfortu-
include the penicillins, the macrolides, tetracyclines, chloramphenicol nately, most older children and adults in resource-limited settings do
and trimethoprim-sulfamethoxazole. not have access to, or the ability to receive, such vaccines. As a starting
point, the Global Pertussis Initiative has recommended that a number
Unfortunately, the antibiotics make no difference to the course or of strategies that may be adopted at a country level in resource-limited
outcomes of pertussis disease. What they are effective at is eliminating settings to supplement the Expanded Program in Immunization
the organism from the nasopharynx. This is an important considera- program. In addition to adherence to standard immunization sched-
tion. Efforts to reduce transmission to other people, particularly ules, the Global Pertussis Initiative recommends that there be univer-
infants, require prioritization. Hence, if a case is confirmed, it is sal adolescent immunization of an anti-pertussis vaccine, that there
advised that elimination of the organism may reduce spread of this be selective immunization of new mothers, family and close contacts
disease. of newborns (the cocoon strategy), that a preschool booster at 4 years
The most commonly recommended antimicrobial to use is erythro- of age be administered, that there be selective immunization of
mycin estolate because of its higher levels of active antibiotic in the healthcare workers and childcare workers, and, possibly, a move
secretions of the respiratory tract. However, other forms of erythro- towards a universal adult immunization strategy [12].
mycin are also considered to be acceptable. For public health benefits against pertussis to be realized, there needs
Short-term antibiotics (azithromycin for 3 to 5e days, or clarithromy- to be a clear public health strategy at a country level. Such a public
cin or erythromycin for 7 days) are as effective as long-term (erythro- health strategy should include an effective vaccine delivery mecha-
mycin for 10 to 14 days) in eradicating B. pertussis from the nism. This may be through regional child health clinics, family medi-
nasopharynx but has fewer side effects. Trimethoprim/sulfamethoxa- cine clinics and local hospitals. Utility can only be measured through
zole for seven days is also effective. Contact prophylaxis of contacts adequate surveillance processes.
older than 6 months of age with antibiotics does not significantly
improve clinical symptoms or the number of cases developing cul-
ture-positive B. pertussis [11]. REFERENCES
If there is an outbreak of pertussis, then immunization is the first step 1. World Health Organisation. World Health Report 2011. Available at: http://
in management. Close contacts of an infected case can be treated with www.who.int/immunization_monitoring/diseases/pertussis/en/index.html
erythromycin or azithromycin, as recommended. However, most (accessed March 3, 2012).
countries only recommend the use of antimicrobial prophylaxis for 2. Centres for Disease Control and Prevention. Pertussis—United States. 2011.
those at greatest risk from pertussis disease, i.e. young infants. Eryth- Available at: http://www.cdc.gov/pertussis/about/index.html (accessed March
3, 2012).
romycin treatment is not recommended for infants younger than 2
3. NNDSS Reports. Annual Reports. CDI 1999;23:11.
weeks of age.
4. Kakar RM, Mojadidi MK, Mofleh J. Pertussis in Afghanistan 2007–2008.
Emerg Infect Dis 2009;15:501.
IMMUNIZATION STRATEGIES 5. Harnden A, Grant C, Harrison T, et al. Whooping cough in school age children
with persistent cough: prospective cohort study in primary care. BMJ 2006;
Given that antimicrobial treatment can eliminate the organism and, 333:174–7.
hence, transmission to others, but has no impact on the course of 6. Wang J, Yang Y, Li J, et al. Infantile pertussis re-discovered in China. Emerg
disease in an individual patient, primary prevention through the use Infect Dis 2002;8:859–61.
of immunization becomes paramount. The mainstay of immuniza- 7. Arevshatian L, Clements CJ, Lwanga SK, et al. An evaluation of infant immu-
tion for pertussis over the years has been the whole cell pertussis nization in Africa: is a transformation in progress? Bull WHO 2007;85:
vaccine. Three immunizations with the vaccine afford approximately 449–57.
90% protective efficacy that lasts throughout infancy, but whole cell 8. Patriarca P, Biellik R, Sanden G, et al. Sensitivity and specificity of clinical case
vaccines are associated with common moderate and severe local reac- definitions of pertussis. Am J Public Health 1998;78:833–6.
tions and fever. 9. Mertens P, Stals F, Steyerbeg E, Richardus J. Sensitivity and specificity of single
IGA and IGG antibody concentrations for early diagnosis of pertussis in
“Acellular” vaccines contain subsets of immunogenic antigens from adults: an evaluation for outbreak management in public health practice.
Bordetella and are much better tolerated, although they are more DMC Infect Dis 2007;7:53.
expensive. In resource-limited settings, childen often receive DTwP. In 10. Andre P, Caro V, Njamkepo E, et al. Comparison of serological and real-time
resource-rich settings, children usually receive DTaP. For children, as PCR assays to diagnose Bordetella pertussis infection in 2007. J Clin Micro
part of the Expanded Program in Immunization, most countries use 2008;45:1672–7.
a 2, 3, 4-, or 2, 4, 6-month immunization regimen of DTwP or DTaP. 11. Altunaiji S, Kukuruzovic R, Curtis N, Massie J. Antibiotics for whooping cough
(pertussis). Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004404.
Historically, adults and older children did not receive booster immu- 12. Forsyth K, Tan T, Wirsing Von Konig C-H, et al. Potential strategies to reduce
nizations. This was owing, in part, to the assumption that adults the burden of pertussis paediatric. Infect Dis J 2005;24:S69–S74.
C
SECTION
GASTROINTESTINAL TRACT
INFECTIONS
41 Helicobacter pylori Infection
Caroline M den Hoed, Ernst J Kuipers
70%
30% 30%
80%
40% 50%
50%
70%
90%
70% 70%
70%
90% 70%
80%
80% 20%
FIGURE 41.1 World map with Helicobacter pylori
infection prevalence [2, 3, 8]. Percentages on the
map are the H. pylori infection rates in the specific
regions.
CLINICAL FEATURES to 100% of patients with low-grade gastric MALT lymphoma have
evidence of H. pylori infection. H. pylori eradication is the primary
H. pylori infection is associated with chronic gastritis, peptic ulcer treatment for these patients, as it leads to partial, or complete, regres-
disease, distal gastric adenocarcinoma, gastric MALT lymphoma and sion in more than 70% of patients [5, 8].
Ménétrier’s disease.
MÉNÉTRIER’S DISEASE
GASTRITIS Ménétrier’s disease, also called hypertrophic gastropathy, is a rare
Colonization with H. pylori is in the first weeks can be associated with condition of unknown etiology. However, a majority has evidence
acute gastritis, which can be accompanied by transient, nonspecific of H. pylori infection; successful eradication can lead to major im
dyspepsia symptoms, such as fullness, nausea and vomiting. The provement of symptoms and should therefore always be considered
majority of subjects do not clear the infection, despite the humoral [5, 8].
and cellular response, and continue to develop chronic colonization
with chronic active gastritis [1].
GASTROESOPHAGEAL REFLUX
DISEASE (GERD)
PEPTIC ULCER DISEASE Although H. pylori has been clearly demonstrated as a cause of the
It is estimated that approximately 20% of H. pylori-positive subjects above-mentioned diseases, discussion remains as to whether it also
develop peptic ulcer disease during their lifetime, and those with an carries potential beneficial effects. This discussion, in particular,
ulcer have a more than 50% risk for recurrent ulcer disease in the years focuses on the negative association between H. pylori colonization
thereafter. Ulcers may be associated with intestinal bleeding and per- and the development of gastroesophageal reflux disease (GERD) and
foration and, in some cases, stricture formation. Eradication of H. its sequelae, including esophageal cancer [5, 8].
pylori prevents recurrence of ulcers and their complications in most
patients, unless they have a second risk factor for ulceration, in par-
ticular use of nonsteroidal anti-inflammatory drugs (NSAIDs) or H. PYLORI INFECTION IN CHILDREN
aspirin. This strong association exists for both duodenal ulcers and H. pylori infection in children may be associated with recurrent
gastric ulcers [1, 5]. abdominal pain, iron deficiency and, during conditions of nutritional
limitation, with growth retardation; however, the incidence of peptic
GASTRIC CANCER ulcer disease is lower than in adults. In contrast, there are reports
which suggest that H. pylori protects children from developing asthma
H. pylori infection is the starting point in a cancer-associated cascade and atopy [2, 5, 8].
that passes through the stages of chronic gastritis, atrophic gastritis,
intestinal metaplasia and dysplasia, and cancer. H. pylori may initiate
this process by causing chronic cellular proliferation, increasing the PATIENT EVALUATION, DIAGNOSIS
likelihood of mutagenic processes in the presence of carcinogenic
substances. Although development of the initial stages of this progres-
AND DIFFERENTIAL DIAGNOSIS
sive cascade (in particular atrophic gastritis and intestinal metaplasia) H. pylori can be diagnosed by various methods, each with advantages
are common in H. pylori-positive individuals, only 1–2% of H. pylori- and disadvantages. Noninvasive testing is recommended for primary
infected patients eventually develop gastric carcinoma as a result of screening of young individuals and children who present with upper
lifelong infection [4–8]. abdominal complaints. These tests are based on the detection of H.
pylori enzyme activity, antigen or antibodies. Invasive testing is usually
MUCOSA-ASSOCIATED LYMPHOID TISSUE reserved for patients undergoing diagnostic or therapeutic upper
intestinal endoscopy as part of a broader evaluation, and involves
(MALT) LYMPHOMA sampling of mucosal tissue for evaluation of presence of H. pylori
Healthy gastric mucosa normally does not contain lymphoid follicles, through direct detection of measuring enzyme activity. As H. pylori
but lymphocytes are inevitably present in the gastric mucosa in all H. may not be evenly spread throughout the stomach in infected indi-
pylori-positive individuals. In rare cases, this eventually leads to the viduals, multiple biopsy samples from various locations are required
development of MALT B-cell lymphomas (usually low-grade). Close for optimal sensitivity [8, 9].
440 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
TABLE 41-2 Overview of Antibiotics Used for Helicobacter pylori Eradication (Adapted from [8] and [11])
in developing countries [2, 8, 11]. EHEC can be transmitted by low and conversion of the cell from a net absorptive state to a net secretory
inocula (101–102 organisms) and is primarily transmitted by ingestion state [1, 2, 16].
of contaminated food vehicles, although it can also be transmitted
directly by contact spread [2, 12, 13]. The modes of transmission of
EAEC and DAEC are not yet clearly defined.
ENTEROINVASIVE ESCHERICHIA COLI (EIEC)
EIEC closely resembles Shigella in its pathogenesis, involving an early
step of enterotoxin production leading to intestinal secretion and
NATURAL HISTORY, PATHOGENESIS invasion of intestinal epithelium. EIEC possesses virtually the identi-
AND PATHOLOGY cal 140 MDa virulence plasmid as Shigella flexneri. Many of the patho-
genic effects of EIEC are mediated through a T3SS which injects a
Different categories of diarrheagenic E. coli have certain pathogenesis distinct set of toxins that mediate invasion. The bacteria disseminate
motifs in common. A brief summary of these properties for each in the epithelial layer, are taken up into enterocytes, spread intracel-
category of diarrheagenic E. coli is shown in Table 42-1. lularly and intercellularly, and cause death of the enterocytes. EIEC
infection is characterized by an influx of polymorphonuclear leuko-
ENTEROTOXIGENIC ESCHERICHIA COLI (ETEC) cytes into the lamina propria of affected intestinal mucosa [1, 2, 17].
ETEC carry one or two plasmids circa 60 MDa in size that encode
heat-labile (LT) or heat-stable (ST) enterotoxins (or both). These also ENTEROHEMORRHAGIC ESCHERICHIA
encode one or more fimbrial colonization factor antigens (CFAs) and COLI (EHEC)
genes encoding the regulatory protein necessary for the high-level EHEC carries an ~60 MDa plasmid that appears to be involved in the
expression of CFAs. LT closely resembles cholera enterotoxin and has expression of adherence fimbriae. Phages carried by EHEC encode the
a similar mode of activity (ADP ribosylation of Gs protein). ST, which powerful cytotoxins, Shiga toxin 1 or 2. EHEC express the 94-kd
consists of peptides of 18 or 19 amino acids in length, activates gua- intimin protein and harbor a T3SS homologous to that expressed by
nylate cyclase, which results in an intracellular accumulation of cyclic EPEC. EHEC expressing these proteins can cause attaching and effac-
GMP that leads to secretion [1, 5]. Genomic studies suggest that ETEC ing lesions of the colon, whereas EPEC induces these lesions in the
strains share a very small number of genes in addition to these small intestine [1, 2].
primary virulence factors [14].
ENTEROAGGREGATIVE ESCHERICHIA
ENTEROPATHOGENIC ESCHERICHIA COLI (EAEC)
COLI (EPEC) EAEC harbors a plasmid of ~60 MDa in size that encodes fimbrial
In contrast to ETEC, EPEC strains harbor a large array of virulence- colonization factors that mediate the pathognomonic aggregative
associated genes, which execute a complex and finely orchestrated adherence to HEp-2 cells. EAEC expresses at least two enterotoxins
pathogenetic strategy (reviewed in [15]). All classic EPEC strains carry that may contribute to pathogenesis, including the Pet cytotoxin and
a circa 60 MDa plasmid which encodes the bundle-forming pilus the plasmid-encoded EAEC heat-stable enterotoxin (EAST) [1, 9].
(BFP); BFP mediates initial attachment and microcolony formation
on the small intestinal mucosa. The plasmid also encodes PerC, a
transcriptional activator for the BFP and for a large number of chro- DIFFUSE-ADHERENT ESCHERICHIA
mosomal genes. One such gene encodes intimin, a 94 kd protein that COLI (DAEC)
mediates intimate attachment to enterocytes. The receptor for intimin The characteristic diffuse adherence to epithelial cells is mediated by
is the translocated intimin receptor (Tir), which is injected directly fimbriae. Some DAEC strains produce a protease called Sat which may
into the target cell cytoplasm via an extraordinarily complex organelle disrupt tight junctions and induce cytoskeletal alterations [1, 18, 19].
called a type III secretion system (T3SS). In addition to Tir, the EPEC
T3SS additionally injects more than 20 additional protein toxins into
the enterocyte. In aggregate, this panoply of toxins leads to cytoskel-
etal changes in the target enterocyte, the consequence of which is a
CLINICAL FEATURES
pathognomonic “attaching and effacing” intestinal lesion observed by The different categories of diarrheagenic E. coli cause distinct clinical
electron microscopy Other phenotypes induced by the T3SS include syndromes, closely related to their virulence mechanisms, which are
loss of tight junction integrity, release of pro-inflammatory cytokines summarized in Table 42-2.
444 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Category Characteristic Predominant geographic Peak age incidence of Molecular diagnostic targets
clinical syndrome* distribution disease
ETEC Watery diarrhea Developing world Infants, adult travelers ST, LT genes
EPEC Watery diarrhea Developing world Very young infants EAF plasmid, BFP and intimin genes
†
EIEC Dysentery Worldwide Toddlers, preschool children Inv plasmid
EHEC Hemorrhagic colitis, HUS Developed world, Latin America Children 2–7 years of age EHEC plasmid; intimin and Shiga
toxin genes
EAggEC Persistent diarrhea Worldwide Mainly infants AA plasmid
DAEC Watery diarrhea Unknown Preschool children F1845 fimbrial genes
*In mild cases, the clinical illness caused by any of the categories of diarrheagenic E. coli consists of watery diarrhea, low-grade fever, nausea and mild abdominal
cramps and is indistinguishable.
†
Dysentery occurs in only 10% of patients; the other 90% exhibit watery diarrhea without blood.
AA, aggregative adherence; BFP, bundle forming pili; DAEC, diffusely adherent E. coli; EAF, EPEC adherence factor; EAggEC, enteroaggregative E. coli; EHEC,
enterohemorrhagic E. coli; EIEC, enteroinvasive E. coli; EPEC, enteropathogenic E. coli; ETEC, enterotoxigenic E. coli; LT, heat-labile enterotoxin; ST, heat-stable
enterotoxin.
EIEC
With the absence of overt dysentery, clinical EIEC infection exhibits
no characteristic clues. On the other hand, among patients with overt
dysentery, EIEC must be one of the agents considered in the differen-
tial diagnosis [1, 20]. If mucus from a diarrheal stool with or without
gross blood is stained and microscopic examination reveals large
numbers of fecal leukocytes, EIEC should be considered in the dif-
ferential diagnosis along with Shigella, Salmonella and Campylobacter
jejuni; Yersinia enterocolitica, which also results in many fecal leuko-
cytes, is rarely diagnosed in the tropics.
EHEC
The occurrence of hemorrhagic colitis is indicative of EHEC infection.
In the tropics, HUS is more likely to be caused by Shigella dysenteriae
serotype 1; nevertheless, EHEC must be considered in the differential
diagnosis [20].
DAEC
There are no characteristic clinical features of DAEC-associated
diarrhea.
LABORATORY TESTS
Stool Culture
Some EIEC are late lactose fermenters (or even fail to ferment lactose)
[27], and some EHEC, particularly of serotype O157:H7, do not
ferment sorbitol [28]. All other diarrheagenic E. coli are visually indis-
tinguishable on the usual enteric media from normal flora strains of
E. coli.
Immunoassays
ELISAs have been described to identify ETEC, EPEC, EIEC and EHEC
using colony blots or culture supernatants [2, 5, 28]. ELISAs that can FIGURE 42.2 The aggregative pattern of adherence to HEp-2 cells
be used directly on stool extracts are available to identify heat-labile diagnostic of enteroaggregative E. coli (EAggEC). Note the stacked brick
(LT), heat-stable (ST) and Shiga toxins [5, 28]. appearance of bacteria attaching both to the tissue culture cells and to the
glass slide in between the cells.
TREATMENT
4. Neter E, Korns RF, Trussel RE. Association of Escherichia coli serogroup 0111
with two hospital outbreaks of epidemic diarrhea of the newborn infant in
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Assessment of hydration status and appropriate rehydration should
5. Qadri F, Svennerholm AM, Faruque AS, Sack RB. Enterotoxigenic
be the critical first step in management of diarrheagenic E. coli. In Escherichia coli in developing countries: epidemiology, microbiology,
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diarrhea in infants was significantly ameliorated by treatment with tematic review from 1973 to the present. Am J Trop Med Hyg 2009;
appropriate antibiotics [2, 29], although rigorous comparative effec- 80:609–14.
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Importantly, EPEC is not associated with adult diarrhea. ETEC type 1-induced haemolytic uraemic syndrome. Pediatr Nephrol 2008;23:
diarrhea in infants in developing countries responds adequately to 1425–31.
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ETEC can be treated with antibiotics (fluoroquinolones, azithromy- tainties and necessities. J Infect Dev Ctries 2009;3:817–42.
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cantly diminishes the severity and duration of illness [5, 30]. Without Gastroenterol 2009;25:8–11.
treatment, however, traveler’s diarrhea is usually self-limited. Antibiot- 10. Spano LC, Sadovsky AD, Segui PN, et al. Age-specific prevalence of diffusely
ics are indicated in the treatment of persistent diarrhea in children adherent Escherichia coli in Brazilian children with acute diarrhoea. J Med
caused by EAEC, although the optimal regimen is not known and can Microbiol 2008;57:359–63.
11. Ochoa TJ, Barletta F, Contreras C, Mercado E. New insights into the epidemi-
be appropriately guided by results of susceptibility testing. It is likely
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that the same antibiotics effective for ETEC will also be effective for
Hyg 2008;102:852–6.
EAEC infections. Although there are no controlled trials of EIEC anti- 12. Grif K, Orth D, Lederer I, et al. Importance of environmental transmission in
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Shigella infections, including oral azithromycin, or cefixime, or 13. Orth D, Grif K, Zimmerhackl LB, Wurzner R. Prevention and treatment of
parenteral ceftriaxone in young children, and oral fluoroquinolones, enterohemorrhagic Escherichia coli infections in humans. Expert Rev Anti
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istration of most antibiotics to individuals with EHEC can markedly conservation. Infect Immun 2011;79:950–60.
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low or absent fever who may have EHEC-associated diarrhea [21, 31, 16. Lapointe TK, O’Connor PM, Buret AG. The role of epithelial malfunction in
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17. Kosek M, Yori PP, Olortegui MP. Shigellosis update: advancing antibiotic
resistance, investment empowered vaccine development, and green bananas.
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18. Guignot J, Chaplais C, Coconnier-Polter MH, Servin AL. The secreted
Adequate sanitation and proper personal and food hygiene practices autotransporter toxin, Sat, functions as a virulence factor in Afa/Dr diffusely
minimize the chance of acquiring E. coli diarrheal infection. To adhering Escherichia coli by promoting lesions in tight junction of polarized
prevent ETEC-associated diarrhea, travelers must be assiduous about epithelial cells. Cell Microbiol 2007;9:204–21.
what they eat and drink. There is limited evidence for non-absorbable 19. Servin AL. Pathogenesis of Afa/Dr diffusely adhering Escherichia coli. Clin
antimicrobial prophylaxis (rifaximin) for adults in situations where Microbiol Rev 2005;18:264–92.
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responses of both an antitoxin and an anticolonizing nature. The 22. Harrington SM, Dudley EG, Nataro JP. Pathogenesis of enteroaggregative
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43 Cholera and Other Vibrios
Debasish Saha, Regina C LaRocque
In severe cholera (cholera gravis), the characteristic symptom is the developed for rapid testing in field settings without access to labora-
frequent passage of profuse “rice-water” stool (Fig. 43.3)—a watery tory facilities.
stool with flecks of mucus and a typical fishy odor. Stool output can
reach as high as 1 liter per hour in the most severe cases. Abdominal
discomfort, borborygmi and vomiting are other common symptoms, TREATMENT
particularly in the early phases of disease. Fever is rare.
Treatment of cholera is simple and inexpensive. Most importantly, the
Dehydration and electrolyte abnormalities are the most important fluid deficit and ongoing fluid loss must be corrected. Antibiotics,
complications of cholera. Examination may reveal sunken eyes although not necessary, can be administered to stop multiplication
(Fig. 43.4), dry mouth, cold clammy skin, decreased skin turgor, or of the organism and to decrease the duration of illness. Complica-
wrinkled hands and feet (“washer woman’s hands”). Patients are tions need to be recognized and addressed in a timely manner.
frequently apathetic and lethargic. Kussmaul breathing may occur as
a result of acidosis. The peripheral pulse is rapid and initially thready; CORRECTION OF FLUID LOSS
it may become difficult to palpate as blood pressure drops. Urine
output decreases with time and renal failure with acute tubular necro- Correction of dehydration through fluid replacement and mainte-
sis may occur. Muscle cramping and weakness caused by the loss of nance remains the cornerstone of cholera treatment. A cholera patient
potassium and calcium are common. In children, depletion of glyco- can lose between 5 and 10 percent of their body weight in fluid during
gen stores and inadequate gluconeogenesis can lead to severe hypogly- the course of the illness. Fluid therapy rests upon assessing the level
cemia or even coma. Aspiration pneumonia is a common comorbidity of dehydration (Fig. 43.5). Fluid replacement occurs in two phases.
in children. There are no long-term complications of cholera when it In the rescue phase, aggressive fluid replacement, usually adminis-
is appropriately treated. Blood stream invasion by the organism is tered intravenously, is given in a short period of time to replace the
rare. Laboratory testing of cholera patients, when performed, may fluid deficit. In the maintenance phase, intravenous fluid or ORS is
reveal hypokalemia, hyponatremia, hypocalcemia and acidosis. given to replenish ongoing fluid losses. Frequent assessment of
ongoing fluid loss is necessary. Stool output should be measured
“Cholera sicca” is an unusual form of the disease whereby fluid accu- every 4–6 hours during the maintenance phase. Such measurement
mulates in the intestinal lumen. Circulatory collapse and even death can be facilitated by the use of a cholera cot: a simple plastic cot with
can occur in the absence of diarrhea. a central hole to facilitate collection of stool in a bucket. Intravenous
and oral rehydration fluids are designed to correct the water and
PATIENT EVALUATION, DIAGNOSIS electrolyte loss in cholera stool (Table 43-1). The most commonly
used intravenous solution is commercially available Ringer’s lactate.
AND DIFFERENTIAL DIAGNOSIS Locally prepared “Dhaka fluid”, which contains more potassium than
Ringer’s lactate, is used in endemic countries like Bangladesh.
Cholera often occurs in outbreaks and hence the diagnosis should be
quickly suspected in the appropriate epidemiologic setting. Mild-to- The use of ORS, a readily prepared sugar and salt solution, has revo-
moderate cases of V. cholerae may be indistinguishable from infection lutionized the treatment of cholera, as well as dehydration caused by
with other pathogens, such as enterotoxigenic Escherichia coli, Campy- other organisms [7]. ORS takes advantage of the fact that glucose-
lobacter spp. or Salmonella spp. mediated cotransport of sodium and water across the mucosal surface
of the small intestine remains intact during cholera. Rice-based ORS
Vibrio cholerae O1 or O139 infection is confirmed by the isolation of involves the use of rice powder instead of glucose and has been shown
the organism in stool culture, followed by biochemical tests and to be equally effective as standard ORS in adults. Recently, a reduced
serogrouping with specific antisera. Thiosulfate citrate bile salts osmolar ORS that is better tolerated has been developed and is associ-
sucrose (TCBS) agar or tellurite taurocholate gelatin agar (TTGA) are ated with lower rates of associated hypernatremia. Hypo-osmolar
used for the selective isolation of V. cholerae. Cholera can be more ORS (Box 43.1) is currently recommended by the WHO.
rapidly diagnosed using direct dark field microscopy of stool where
motile Vibrio organisms appear like “shooting stars”. An immuno- Packets for the easy preparation of ORS are widely available in devel-
chromatographic dipstick test specific for V. cholerae has also been oping countries. If ORS packets are not available, dehydration can
450 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Upon ingestion,
toxigenic strains
colonize the
small intestine
Treatment and prevention
• Oral and intravenous rehydration
• Antibiotics
• Hygiene measures including
safe water and waste sanitation
ORS composition
Six level teaspoons of sugar
and one-half level teaspoon
of salt in a liter of water
be treated with a solution made with six level teaspoons of sugar administration of zinc (10 mg/day x 2 weeks in children < 6 months;
and one-half level teaspoon of salt dissolved in one liter of clean 20 mg/day x 2 weeks in children 6 months–5 years) has proven effec-
water. tive in reducing the duration of diarrhea, as well as reducing successive
diarrhea episodes [8].
Multiple intravenous lines may be required to infuse an adequate
amount of fluid to a cholera patient during the rescue phase of rehy-
dration. If an intravenous line cannot be established, fluid should be ANTIBIOTICS
introduced through a nasogastric tube. In children, an interosseous
line in the medial aspect of the tibia can be considered. Antimicrobial therapy is an adjunct to fluid therapy in cholera and
has been shown to reduce the duration and volume of diarrheal stool
Apart from fluid replacement, the intake of freshly prepared food is by half. The WHO advocates the use of antibiotics for individuals with
encouraged when tolerated and breastfeeding should be continued severe dehydration, basing choice on local availability and susceptibil-
where appropriate. For children up to 5 years of age, supplementary ity pattern [2]. A wide range of antibiotics, both in single- and
C h o l e ra a n d O t her Vibr ios 451
TABLE 43-1 Electrolyte content of cholera stool and fluids used in the treatment
of cholera
PREVENTION
A clean water supply and appropriate sanitation are essential to the
prevention of cholera. Breastfeeding is protective for young infants in
endemic settings. Filtering water through a sari cloth before drinking
has been demonstrated to be effective in lessening the likelihood of BOX 43.1 Recipe for Making one Liter of
V. cholerae infection acquired from surface water sources, probably Hypo-osmolar ORS [10]
through removal of V. cholerae adherent to particulates. Two oral,
killed cholera vaccines are currently available in various countries. Sodium chloride (NaCl) 2.6 g
These vaccines are usually administered in 1–3 doses 10–15 days
Sodium citrate 2.9 g
apart and are given in 150 milliliters of safe water. The WHO recom-
mends use of cholera vaccines in select situations in conjunction Potassium chloride (KCl) 1.5 g
with improved water supplies, adequate sanitation and health educa- Glucose 13.5 g
tion [9].
452 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
YES
• Nasogastric tube can be used for ORS administration if patient cannot drink
• Reassess the patient regularly
YES
Severe dehydration:
• Place IV
• Rehydrate with Ringer’s lactate or normal saline
• 100 ml/kg in 3 hour period
• 100 ml/kg in 6 hour period for children < 1 year
• Start rapidly: 30 ml/kg in 30 minutes, then slow down
• Goal: 200ml/kg in the first 24 hours
• Reassess the patient regularly
EPIDEMIOLOGY
Key features Shigellosis remains an important cause of morbidity and mortality
worldwide. Although estimates of disease burden are hampered by
l Shigellosis is caused by an invasive Gram-negative bacteria, limited surveillance and reporting [2], it is estimated that more than
Shigella, which destroys ilieal and colonic epithelium and 150 million clinical infections with Shigella, and more than 200,000
elicits a local and systemic inflammatory response deaths, occur annually. Approximately two-thirds of these infections
and deaths occur in children less than 5 years of age [3]. However,
l Four distinct Shigella species cause infection, with clinical
mortality, if not incidence, may currently be less given a recent decline
presentations varying by species and serotype. Of these, in the number of S. dysenteriae type 1 epidemics.
Shigella dysenteriae type 1 is associated with epidemic
disease and the highest risk of mortality Although shigellosis can occur in all ages, infection predominantly
occurs in young children. This may be a result of both the less fastidi-
l Humans are the only reservoir for Shigella and infection ous hygiene habits of the young and the lack of protective immunity
occurs by fecal–oral or human-to-human transmission in infants and young children, which may result from previous expo-
where hygiene and sanitation are problematic, such as in sure. Although many areas with high rates of endemic shigellosis also
developing countries or in daycare centers have a high prevalence of HIV, there is little evidence that those with
l Patients with severe shigellosis have tenesmus, cramps, HIV are disproportionally at risk of Shigella infection in developing
countries [4].
passage of bloody-mucoid stools, and high fever
l Patients with dysentery or systemic symptoms require The geographic distribution of Shigella infections varies by species
antimicrobial therapy, while those with less severe (Fig. 44.1). In wealthy, industrialized countries S. sonnei is the pre-
dominant cause of infection; the more virulent S. flexneri is less
symptoms may be managed symptomatically
common. The reverse is true in relatively poor countries in the tropics,
l Because of lack of microbiology facilities in most where S. flexneri predominates (Fig. 44.1) [2, 5]. Indeed, the switch
developing country settings, the decision to initiate from a preponderance of S. flexneri infections to S. sonnei infections
treatment with an antimicrobial agent should be empiric, (as has recently occurred in Thailand) [5] may be a marker of a coun-
based upon a presumptive clinical diagnosis try’s social and economic development.
l A number of complications may occur in patients with Epidemics of dysentery, especially those with high mortality rates, are
shigellosis, including hemolytic uremic syndrome (with usually the result of S. dysenteriae type 1 infections. In recent decades,
S. dysenteriae type 1), reactive arthritis and seizures endemic and epidemic S. dysenteriae type 1 infections have most com-
monly occurred in South Asia and central and east Africa. Since 2000,
l Synonyms: bacillary dysentery
S. dysenteriae type 1 infections have become uncommon in these
regions. Infections with S. boydii have, historically, been most common
in South Asia and have also been reported from Africa, but never
account for a majority of infections [2]. Infections with S. dysenteriae
other than type 1 are even less common.
INTRODUCTION Humans are the only natural reservoir of Shigella and infections
usually result from either fecal–oral or direct person-to-person trans-
Epidemic dysentery has been known since antiquity. The causative mission. Transmission by water or by commercial food products is
organism, Shigella dysenteriae type 1, a Gram-negative bacillus, was less common but does occur. Transmission of Shigella can occur with
identified by the pioneering Japanese microbiologist Kiyoshi Shiga in a low inoculum—less than 10 organisms have been shown to be able
1897 [1]. Subsequently, other species of Shigella causing endemic to transmit infection.
dysentery or diarrhea were identified and received eponymous species
names (Shigella flexneri, Shigella boydii and Shigella sonnei). These
species vary in their virulence, with S. dysenteriae type 1, the only
NATURAL HISTORY, PATHOGENESIS
species that produces Shiga toxin, being the most virulent, and AND PATHOLOGY
S. sonnei generally the least virulent.
Shigellosis is an infection of the distal ileum and colon. Shigellae are
Shigellosis is associated with poor hygiene and under-development, enteroinvasive, i.e. they invade, multiply within and destroy colonic
and continues to be an important health problem in developing epithelial cells resulting in tissue destruction, mucosal ulceration,
countries. Although efforts to develop an effective vaccine are ongoing, disruption of small vessels and hemorrhage, and microabscesses in
none have yet been marketed. Thus, control of shigellosis continues the colon (Fig. 44.2). Infection and inflammation is most severe in
to require improvement in hygienic conditions and appropriate iden- the rectosigmoid and less severe proximally [6]. There may also be
tification and treatment of those who are infected. involvement of the distal ileum.
454
Shigellosis 455
S. sonnei
S. flexneri
FIGURE 44.1 Geographic distribution of Shigella S. flexneri with intermittent
by species and serotype. S. dysenteriae type 1 epidemics
FIGURE 44.2 Microscopic view of colonic epithelium obtained from FIGURE 44.3 Characteristic dysenteric stool of a patient with shigellosis
descending colon of patient with shigellosis showing extensive ulceration containing blood, mucus, and small amounts of fecal matter.
to the level of the lamina propria (arrow).
Fever is a characteristic of most Shigella infections and can often be Shigella may also cause infection of epithelial surfaces outside the gut,
high (40oC) and sustained. The rapid rise of fever with shigellosis including the cornea and the vagina [12, 13], and may also be sys-
leads to a relatively high incidence of seizures in young children temically invasive, causing bacteremia and sepsis [14]. Bacteremia
who are infected (≈ 5% in one study of hospitalized patients) and with other bacterial pathogens may also occur during Shigella infec-
can occur with infection of any of the species of Shigella [9]. The tion, presumably from the translocation of gut bacteria across a
metabolic complications described below can also produce seizures damaged epithelium or from iatrogenic causes, including contami-
(Fig. 44.6). nated intravenous fluids and catheter-related infections [15].
Patients, especially children, may also develop encephalopathy. Leth- Perhaps the most serious complication of Shigella infection is the
argy and confusion are common in severe shigellosis; obtundation development of HUS [16]. This complication occurs with S. dysente-
and coma may also occur. These mental status changes may result riae type 1 infection, which, like enterohemorrhagic E. coli (EHEC),
from the metabolic complications described below or because shigel- produces an exotoxin—Shiga toxin (Shiga-like toxin in EHEC)—that
losis, especially S. dysenteriae type I, induces more generalized, but is thought to be related to the development of HUS. In addition to
poorly understood, neurologic complications. the microangiopathic anemia and renal failure, leukemoid reaction
(peripheral blood polymorphonuclear cell count > 50,000 mm3) and
Metabolic complications (Table 44-1) include hypoglycemia from thrombocytopenia may occur in association with HUS, or separately
inadequate gluconeogenesis [10] and hyponatremia, presumably from as a “forme fruste” of HUS.
inappropriate antidiuretic hormone (ADH) secretion. Though the
blood loss from the intestinal microhemorrhages is usually not severe
enough to cause anemia, it may exacerbate pre-existing anemia, or PATIENT EVALUATION, DIAGNOSIS,
cause anemia in those with underlying hepatic or clotting abnormali-
ties. Hypoproteinemia can occur, presumably resulting from a combi-
AND DIFFERENTIAL DIAGNOSIS
nation of protein loss in the gut, diminished nutrition during illness The diagnosis of shigellosis is important because, unlike watery
and systemic inflammation causing diminished protein synthesis [11]. diarrhea caused by noninvasive enteric pathogens (rotavirus, other
enteric diarrheogenic viruses, enterotoxigenic E. coli), patients with
dysentery caused by Shigella require antimicrobial therapy, rather than
simply fluid therapy to prevent, or treat, dehydration. Antimicrobial
therapy is important both to relieve the suffering that occurs from the
primary disease—tenesmus is an agonizing condition —and to
prevent complications from occurring [17].
Although isolation of Shigella from stool is required for the definitive
diagnosis of shigellosis, the time required for isolation—48 hours—
the lack of diagnostic microbiologic facilities at most health facilities
in developing countries and the insensitivity of current culture
methods [6], make such an approach not particularly useful in the
management of individual patients. The initiation of treatment must
be empiric, based upon a presumptive clinical diagnosis.
The distinguishing feature of shigellosis is dysentery. In developing
countries where shigellosis is endemic, children with dysentery
FIGURE 44.4 Child with complete rectal prolapse. (bloody-mucoid stools and tenesmus) have a high probability of
A B
FIGURE 44.5 (A, B) Child with toxic megacolon showing dilated loops of bowel; obstruction and air fluid levels on abdominal radiograph.
Shigellosis 457
Extraintestinal complications
Metabolic complications
Dehydration Shigella sonnei, Watery diarrhea, with or without Severe dehydration Rarely lethal alone, no
other species dysentery, can be a feature of all uncommon. Oral or long-term sequelae if
Shigella infections. Watery diarrhea intravenous fluid as managed appropriately
maybe caused by Shigella appropriate
enterotoxins 1 and 2. Also increased
fluid loss because of fever. Decreased
fluid intake because of anorexia
Hyponatremia S. dysenteriae type 1, Probable inappropriate secretion of If severe (Na <120 mmol/L) If treated, no long-term
less commonly S. antidiuretic hormone with altered consciousness complications. If not
flexneri infusion of 3% NaCl (12 ml/kg recognized, can cause
over a 4-hour period); less seizures, unconsciousness
severe episode (Na; 120–
130 mmol/L), infusion of 0.9%
NaCl; restriction of water
intake
Hypoglycemia S. dysenteriae type 1 Depleted glycogen stores; impaired Intravenous infusion of No long-lasting
gluconeogenesis dextrose (2.0 ml/kg of 25% complications if
glucose) recognized early
Hypoproteinemia S. dysenteriae type 1, Protein loss in stool; decreased High-protein diet; Pulmonary edema, ascites.
S. flexneri protein synthesis because of management of edema Complications will resolve
inflammation if hypoproteinemia is
corrected
the diagnosis of shigellosis primarily remains a clinical one based on l are effective when given orally because of the difficulties of
the patient having the classic signs of dysentery. providing parenteral therapy where the majority of Shigella
infections occur;
If microbiologic laboratory facilities are available, definitive diagnosis
l are preferably available in a liquid formulation suitable for use in
is done by isolation of Shigella from the stool. Shigellae are not hardy, children;
thus cultures are best done by plating a stool sample at the bedside
l are inexpensive.
or immediately transporting a sample to the laboratory. If stools
samples cannot be immediately processed, they should be trans- A wide variety of drugs have proven effective in the treatment of
ported in a buffered-glycerol saline media, which has a higher yield shigellosis. Previous mainstays of therapy included ampicillin,
than the more commonly available Cary-Blair transport media. Stool trimethoprim-sulfamethoxazole, and nalidixic acid. However, wide-
samples are plated upon media selective for Gram-negative organ- spread resistance to all three drugs limits their current usefulness for
isms. Shigella does not ferment lactose and thus appear white or treating shigellosis. Despite good serum concentrations and in vitro
colorless on selective media containing acid-sensitive indicator dyes. activity, amoxicillin [22] and oral cephalosporins have not been
Non-lactose-fermenting colonies are then further analyzed using bio- effective in the treatment of shigellosis [23, 24].
chemical tests for definitive confirmation that they are Shigella.
Optimally, the choice of antibiotic is based upon knowledge of local
Another important cause of dysentery in developing countries— resistance patterns—information that is all too often lacking. Because
intestinal amebiasis caused by Entamoeba histolytica infection—is a of current widespread resistance to the previous mainstays of therapy,
much less frequent cause of the dysentery syndrome, especially in fluoroquinolones and azithromycin are the current drugs of choice
children. When compared with patients with shigellosis, patients with for treating shigellosis. Both fluoroquinolones and azithromycin have
amebiasis are less likely to have fever, have fewer white cells in their been demonstrated to be effective in well-conducted, randomized,
stool and are generally less toxic [19]. If direct microscopy is available, controlled trials. However, resistance to these newer agents is now
the finding of enterophagocytic trophozoites of E. histolytica on exam- starting to appear—particularly with S. dysenteriae type 1, but also
ination of stool is characteristic of amebiasis—the presence of E. with other Shigella species. Treatment doses and recommendations
histolytica cysts is not. Campylobacter jejuni infections, though common are shown in Table 44-2.
in children, are less often symptomatic; cramping is more common
than tenesmus and stools are less bloody than in shigellosis. Ulcera- Patients with Shigella infection but without dysentery or systemic
tive colitis is exceedingly rare in comparison with shigellosis. The signs of illness do not require antimicrobial therapy. However, such
chronicity of ulcerative colitis will, in time, distinguish it from mild cases of Shigella infection are unlikely to be identified as stool
shigellosis. cultures are not usually obtained from such patients [25].
Drugs that are effective, and useful, in the treatment of shigellosis have Rectal prolapse is best treated with warm magnesium sulfate com-
the following characteristics [21]: presses to reduce edema and definitive treatment of the infection to
lessen the tenesmus that causes the prolapse. Convulsions that occur
l are effective in vitro against Shigella; in the absence of any metabolic derangements, such as hypernatremia
l achieve concentrations in the blood stream in excess of the or hypoglycemia are usually not complex or sustained and are best
minimum inhibitory concentration (MIC) of the infecting strain managed using local protocols for the management of febrile convul-
of Shigella; sions in children, including the provision of antipyretics.
460 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
REFERENCES 15. Struelens MJ, Patte D, Kabir I, et al. Shigella septicemia: prevalence, presenta-
tion, risk factors, and outcome. J Infect Dis 1985;152:784–90.
1. Trofa AF, Ueno-Olsen H, Oiwa R, Yoshikawa M. Dr. Kiyoshi Shiga: discoverer 16. Rahaman MM, Jamiul Alam AK, Islam MR, Greenough WB III. Shiga bacillus
of the dysentery bacillus. Clin Infect Dis 1999;29:1303–6. dysentery associated with marked leukocytosis and erythrocyte fragmenta-
2. Ram PK, Crump JA, Gupta SK, et al. Part II. Analysis of data gaps pertaining tion. Johns Hopkins Med J 1975;136:65–70.
to Shigella infections in low and medium human development index coun- 17. Bennish ML, Khan WA, Begum M, et al. Low risk of hemolytic uremic syn-
tries, 1984–2005. Epidemiol Infect 2008;136:577–603. drome after early effective antimicrobial therapy for Shigella dysenteriae type
3. Kotloff KL, Winickoff JP, Ivanoff B, et al. Global burden of Shigella infections: 1 infection in Bangladesh. Clin Infect Dis 2006;42:356–62.
implications for vaccine development and implementation of control strate- 18. Nato F, Phalipon A, Nguyen TL, et al. Dipstick for rapid diagnosis of Shigella
gies. Bull World Health Organ 1999;77:651–66. flexneri 2a in stool. PLoS One 2007;2:e361.
4. van Eijk AM, Brooks JT, Adcock PM, et al. Diarrhea in children less than two 19. Speelman P, McGlaughlin R, Kabir I, Butler T. Differential clinical features and
years of age with known HIV status in Kisumu, Kenya. Int J Infect Dis stool findings in shigellosis and amoebic dysentery. Trans R Soc Trop Med
2010;14:e220–5. Hyg 1987;81:549–51.
5. von Seidlein L, Kim DR, Ali M, et al. A multicentre study of Shigella diarrhoea 20. Haltalin KC, Nelson JD, Ring R III, et al. Double-blind treatment study of
in six Asian countries: disease burden, clinical manifestations, and microbiol- shigellosis comparing ampicillin, sulfadiazine, and placebo. J Pediatr
ogy. PLoS Med 2006;3:e353. 1967;70:970–81.
6. Speelman P, Kabir I, Islam M. Distribution and spread of colonic lesions in 21. Salam MA, Bennish ML. Antimicrobial therapy for shigellosis. Rev Infect Dis
shigellosis: a colonoscopic study. J Infect Dis 1984;150:899–903. 1991;13:S332–S341.
7. Parsot C. Shigella spp. and enteroinvasive Escherichia coli pathogenicity 22. Nelson JA, Haltalin KC. Amoxicillin less effective than ampicillin against
factors. FEMS Microbiol Lett 2005;252:11–8. Shigella in vitro and in vivo: relationship of efficacy to activity in serum.
8. Bennish ML, Azad AK, Yousefzadeh D. Intestinal obstruction during shigel- J Infect Dis 1974;129(suppl.):S222–7.
losis: incidence, clinical features, risk factors, and outcome. Gastroenterology 23. Salam MA, Seas C, Khan WA, Bennish ML. Treatment of shigellosis: IV. Cefix-
1991;101:626–34. ime is ineffective in shigellosis in adults. Ann Intern Med 1995;123:505–8.
9. Khan WA, Dhar U, Salam MA, et al. Central nervous system manifestations 24. Nelson JD, Haltalin KC. Comparative efficacy of cephalexin and ampicillin
of childhood shigellosis: prevalence, risk factors, and outcome. Pediatrics for shigellosis and other types of acute diarrhea in infants and children.
1999;103:E18. Antimicrob Agents Chemother 1975;7:415–20.
10. Bennish ML, Azad AK, Rahman O, Phillips RE. Hypoglycemia during diarrhea 25. World Health Organization. Guidelines for the control of shigellosis,
in childhood. Prevalence, pathophysiology, and outcome. N Engl J Med incuding epidemics due to Shigella dysenteriae 1. Geneva: World Health
1990;322:1357–63. Organization; 2005. Available at: http://whqlibdoc.who.int/publications/2005/
11. Bennish ML, Salam MA, Wahed MA. Enteric protein loss during shigellosis. 9241592330.pdf.
Am J Gastroenterol 1993;88:53–7. 26. Bennish ML, Harris JR, Wojtyniak BJ, Struelens M. Death in shigellosis: inci-
12. Murphy TV, Nelson JD. Shigella vaginitis: report of 38 patients and review of dence and risk factors in hospitalized patients. J Infect Dis 1990;161:500–6.
the literature. Pediatrics 1979;63:511–6. 27. Kabir I, Malek MA, Mazumder RN, et al. Rapid catch-up growth of children
13. Macdonald R Jr, Edwards WC. Shigella corneal ulcer. Am J Ophthalmol fed a high-protein diet during convalescence from shigellosis. Am J Clin Nutr
1965;60:136–9. 1993;57:441–5.
14. Duncan B, Fulginiti VA, Sieber OF Jr, Ryan KJ. Shigella sepsis. Am J Dis Child
1981;135:151–4.
45 Nontyphoid Salmonella Disease
Melita A Gordon, Nicholas A Feasey, Stephen M Graham
INTRODUCTION
The importance of nontyphoid Salmonellae (NTS) as a cause of inva-
sive disease in Africa has overtaken their importance as a cause of
diarrheal illness and enterocolitis. NTS have been a significant cause
of invasive bacterial disease among children in the tropics, particularly
in sub-Saharan Africa, for many decades, pre-dating the HIV epi-
demic. In 1983, the first six cases of AIDS presenting among African
adults were described, three of whom had Salmonella Typhimurium Acinetobacter spp Non-typhoid salmonellae
bacteremia [1, 2]. Invasive NTS (iNTS), associated with AIDS in Africa,
was first described as being predominantly caused by S. typhimurium, Citrobacter spp Salmonella Typhi
with an absence of diarrhea and a high recurrence rate [3] now all Cryptococcus neoformans Staphylococcus aureus
well-recognized features of this illness. Recurrent NTS bacteremia was
added to the CDC case definition of AIDS in 1987. As the HIV epi- Escherichia coli Serratia spp
demic has evolved, iNTS disease has become one of the commonest Enterobacter spp Streptococcus pneumoniae
causes of febrile adult admission in sub-Saharan Africa. iNTS in chil-
dren and HIV-infected adults carries a high mortality and, even with Haemophilus influenzae Streptococci - beta haemolytic
appropriate antibiotic treatment, there is a 30–50% rate of recurrence. Klebsiella spp Streptococci - other
Empiric diagnosis and management remain challenging, and multi-
drug antimicrobial resistance is a rapidly developing problem. Neisseria meningitis A Vibrio cholerae
Proteus spp Other pathogens
EPIDEMIOLOGY Pseudomonas spp
Blood culture series of febrile adults and children in HIV- FIGURE 45.1 Pathogens isolated from blood cultures among febrile adults
endemic Africa have consistently shown that NTS are one of the and paediatric admissions in Blantyre, Malawi, 1998–2004 (listed from the
commonest causes of invasive bacterial infection together with 12 o’clock position on the pie-chart).
462
N o nt y p h o i d S a l m o n ella Disease 463
ana (mm)
400
60
200 250
50
0 200
40
0 10 20 30 40 50 60 150 30
Age in NTS in years 100 20
50 10
FIGURE 45.2 The distribution of cases of invasive NTS disease by age in
Blantyre, Malawi. 0 0
00
01
02
03
04
-
-
Jan
Jan
Jan
Jan
Jan
6/100,000 over the age of 5 years [10–12]. There is a lower incidence
among infants in the first 4 months of life, consistent with protection 450 100
from maternal IgG or from secretory IgA in breastmilk [8], but NTS 400 90
ana (mm)
60
In children, severe malaria and malnutrition are associated with an 250
50
increased risk of invasive bacterial disease, including iNTS. Compared 200
40
with other bacterial pathogens in children, iNTS is associated with 150 30
severe anemia, often in the context of malaria [14–18]. Sickle cell 100
anemia is strongly associated with iNTS in African children, but this 20
50 10
is not a common risk factor. HIV infection also confers an increased
risk of iNTS in African children but, in contrast to adults, most cases 0 0
-00
-01
-02
-03
-04
of iNTS in African children are not HIV-related.
Jan
Jan
Jan
Jan
Jan
In adults, there is a close association between iNTS and advanced HIV
disease in sub-Saharan Africa, with over 95% of cases occurring in FIGURE 45.3 The relationship between rainy season and incidence of
HIV-infected individuals [6, 19]. The incidence of iNTS in HIV- invasive NTS in adults and children, by month, in Malawi, 2000–2004.
infected adults ranges from 2000–8500/100,000 person years of
observation. Events are rare at high CD4 counts, but rise up to
9000/100,000 when CD4 <200 cells/µl [20]. The impact of widely
available anti-retroviral treatment (ART) in Africa is not yet clear. idiopathic inflammatory bowel disease on biopsy. Asymptomatic car-
Other conditions predisposing adults to invasive NTS disease include riage in the stool may continue for several months. Antibiotic treat-
diabetes, long-term steroid use, hematologic or solid cancers, autoim- ment is known to increase the rate and duration of carriage in the
mune disease, advanced liver disease (particularly alcoholic liver stool after an episode of Salmonella diarrhea.
disease), renal or other transplantation, and the use of other immu-
nosuppressive drugs, including anti-tumor necrosis factor (TNF) anti- INVASIVE DISEASE
body treatment. Invasive NTS disease is also seen in children with
NTS causing invasive disease likely invade through the small bowel
specific primary immunodeficiencies, including chronic granuloma-
mucosa causing a primary bacteremia. As many patients do not report
tous disease and rare genetic deficiencies of cytokine subunits or
gastrointestinal symptoms, such as pain or diarrhea, this may occur
receptors in the interleukin (IL)12/IL23 pathway [20].
without overt inflammation. The lack of inflammation and diarrhea
iNTS incidence in both adults and children is associated with seasonal in HIV-infected patients may be because of a loss of mucosal Th17 T
rainfall (see Fig. 45.3), although it is uncertain whether this results cells, leading to a lack of recruitment of neutrophils [22]. By the time
from increased waterborne transmission, or whether it is because it patients present with fever, they usually already have an established
coincides with the peak period for malaria and malnutrition, which disseminated intracellular infection with replication in the bone
are also risk factors. The relationship between invasive disease, marrow and reticuloendothelial system, as well as bacteremia (see
diarrheal disease, and stool carriage of NTS is poorly understood and Fig. 45.4) [23, 24]. This may be the explanation for the high rate of
transmission routes are not well-defined. In contrast to the well- recrudescence, even after antibiotic treatment. Although the patho-
known role of infected food-animals or contaminated food items in genesis of iNTS is reminiscent of that of enteric fever, classic complica-
diarrheal Salmonella disease in industrialized countries, studies have tions of enteric fever such as small bowel perforation and hemorrhage
failed to identify a major animal, food, or environmental reservoir of are not usually seen in iNTS disease.
iNTS in Africa, and person-to-person spread may play a relatively
greater role in transmission [21]. The conditions in many hospitals in
tropical Africa may also support nosocomial transmission, especially
MICROBIOLOGY
in the emergence of drug-resistant NTS. Salmonella is a genus of motile, facultative anerobic Gram-negative
bacilli closely related to Escherichia coli. Definitive diagnosis of iNTS
disease is by aerobic blood culture, and of diarrheal NTS disease by
NATURAL HISTORY, PATHOGENESIS, stool culture in appropriate selective broth and plates. There are two
AND PATHOLOGY species, S. enterica and S. bongori; all Salmonellae causing human
disease fall within the species S. enterica, which has six subspecies.
Human isolates usually fall within the subspecies enterica. A serologic
DIARRHEAL DISEASE method of typing devised by Kaufman and White, based on lipopoly-
Diarrheal disease caused by NTS in immunocompetent individuals is saccharide (LPS) somatic cell wall O antigens, envelope antigens
characterized by inflammatory mucosal disease, with inflammatory (eg Vi antigen) and phase 1 and phase 2 flagellar H antigens enables
infiltrates in the lamina propria of the ileum and colon, and crypt differentiation of Salmonella into serovars, designated with names
abscess formation (enterocolitis). A lack of colonic crypt architectural describing clinical syndromes (e.g. Choleraesuis, Typhimurium,
disturbance may be helpful in distinguishing infective colitis from Enteritidis), or the place where the organism was described (e.g.
464 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Reticulo-endothelial
Replication and persistence Bone
(bone marrow, spleen, liver) Joints
Renal
Biliary
Spleen
Gall bladder / bile Liver
infection? Chest
Secondary gut CNS
infection Soft tissue
Dublin, Newport). To distinguish serovars from species and sub INVASIVE DISEASE (iNTS)
species, they are notated in non-italicized text with a capital letter
(e.g. Salmonella enterica subsp. enterica serovar Typhimurium, usually The usual presentation of iNTS is a nonspecific febrile illness and the
shortened to S. Typhimurium). frequency of common presenting clinical features is shown in Table
45-1. As these data show, the clinical picture is heterogeneous and
Among human isolates, Salmonella Typhi and Paratyphi are consid- there may be no obvious clinical focus. Diarrhea is often absent. The
ered “typhoidal” and cause a human-restricted illness called enteric clinical picture may be complicated by co-infections—especially in
fever. All other serovars, which have a wider vertebrate host range, are HIV-infected patients—including respiratory, such as tuberculosis
considered “non-typhoid Salmonellae”, or NTS. (TB), S. pneumoniae or Klebsiella spp. A concurrent respiratory infec-
tion may cause a simultaneous intravascular Gram-negative sepsis to
The vast majority of diarrheal illness is caused by only a few serovars,
be overlooked [19]. In young children especially, there is clinical
with S. Enteritidis, S. Typhimurium, S. Virchow, S. Newport, S. Hadar,
overlap with the presentation of pneumonia, severe malaria, and
S. Heidelberg, S. Agona, and S. Indiana being the most common
anemia [26]. This means that clinical diagnosis is especially difficult
globally, although data from the tropics are scanty.
in the resource-limited setting and that empiric antibiotic treatment
Invasive Salmonella disease in the industrialized world is typically, but must have broad coverage (see below). Mortality associated with an
not exclusively, associated with serotypes S. Cholerasuis, S. Virchow, index event of iNTS is very high (25–50%), even in microbiologically
and S. Dublin. Invasive disease in tropical settings is most commonly confirmed cases with appropriate antibiotic treatment [19, 25, 27].
caused by S. Typhimurium and S. Enteritidis. A novel sub-Saharan
In adults, iNTS generally presents during stage 4 HIV disease and
African variant of S. Typhimurium, designated ST313 has emerged,
80% of patients at index presentation have a CD4 count of below 200
which has loss of genes required for an enteric lifestyle, similar to that
cells/µl. Features of advanced HIV disease may be present. Other
seen in S. Typhi, suggesting recent evolution of S. Typhimurium
causes of immunosuppression should be sought in the absence of
towards a more human-adapted invasive lifestyle [24].
HIV in adults.
Antibiotic resistance is an emerging problem among Salmonellae
worldwide including among iNTS. Plasmid-borne multidrug resist-
ance to chloramphenicol, cotrimoxazole and ampicillin is now docu-
RECURRENT iNTS DISEASE
mented from many sites in Africa. Resistance to fluoroquinolones or Recurrence of NTS bacteremia occurs in 30–40% of survivors, even
cephalosporins is not yet widespread in Africa, but is emerging and after 2 weeks of antibiotic treatment. Relapse is typically seen after
likely to continue and spread, given the increasing empiric use of 2–6 weeks and represents a recrudescence with the same index isolate.
these agents for bacterial infections during HIV infection [25]. The number of viable bacteria is higher in bone marrow at relapse
compared with the first presentation, suggesting an established intra-
cellular niche. Re-treatment with antibiotics is not always successful,
CLINICAL FEATURES and 25% of patients with one recurrence go on to have multiple
recurrences [19]. If ART is available, successful immune reconstitution
appears to greatly reduce the risk of iNTS recurrence.
DIARRHEAL NTS DISEASE
NTS enterocolitis presents with abdominal cramps, nausea and vom-
iting, and watery diarrhea, which may also be bloody in severe cases. FOCAL AND SUPPURATIVE NTS DISEASE
Patients may be febrile, and 1–4% of adults have a transient bacter- Salmonellae have a capacity to cause focal suppurative disease [28].
emia, which may lead to focal or metastatic infection, particularly in This is a problem in the elderly, in young children with diarrheal
elderly patients. In severe cases, enterocolitis may be accompanied by disease and transient bacteremia, in immunosuppressed patients, and
shock related to dehydration or to associated sepsis. Diarrheal illness in children with invasive NTS infection. There is a particular predelic-
usually lasts 2–5 days, resolving spontaneously. Complications tion to cause osteomyelitis and pyogenic arthritis, particularly in sickle
including toxic colonic dilatation and perforation may be heralded cell disease [29]. Intravascular infections at structurally damaged sites,
by a prolonged disease course, severe pain, abdominal tenderness, such as atheroma, aneurysms, or damaged heart valves cause persist-
signs of peritonitis or shock. Diarrheal disease may be followed by ent bacteremia, usually require combined surgical and medical
seronegative reactive arthritis or Reiter’s syndrome. therapy, and have a poor outcome. Focal infections during HIV are
N o nt y p h o i d S a l m o n ella Disease 465
also described in the chest (empyema and, rarely, primary pneumo- TREATMENT
nia), renal tract, genital tract, and hepatobiliary tract [20].
NTS meningitis in adults and children in Africa has a very poor DIARRHEAL DISEASE
outcome (60% mortality among children, 80% mortality among Management of enterocolitis caused by NTS should be supportive;
adults) [13, 30], and subdural or epidural empyema are also described. antibiotic treatment is not indicated except in severe, or compli-
Of particular note in the tropics is a phenomenon where active schis- cated, cases. In cases of dysentery (grossly bloody diarrhea), where
tosomiasis is associated with persistent or recurrent NTS bacteremia an etiologic agent is not sought or identified, empiric antibiotic
among children, despite antibiotic treatment. This occurs because the therapy should be directed against Shigella species, which are more
bacterium is able to adhere to the adult helminth’s tegument using common causes of dysentery and also derive a clear benefit from
a bacterial pilus, providing it with a sanctuary where it can evade treatment. In contrast, antibiotics do not reduce the duration of
antimicrobial treatment. Treatment with praziquantel kills the diarrheal illness caused by NTS, and they prolong stool shedding
adult helminth, and allows effective antibiotic eradication of the and increase the risk of side effects from treatment itself (evidence
Salmonella with prompt resolution of fever [31]. grade 1).
466 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
INVASIVE DISEASE susceptible African children [8]. Among some HIV-infected adults,
however, the observation has been made that there is an excess of
The choice of empiric therapy for febrile patients requiring hospital inhibitory anti-Salmonella antibodies directed again LPS, that compete
admission in an HIV-endemic area is difficult. Reliance on narrow- with killing antibodies. This raises the possibility that a vaccine
spectrum penicillin, even if respiratory features are prominent, may directed against LPS might do harm, so a vaccine directed against
miss cases of iNTS. There is also widespread resistance of iNTS to Salmonella membrane proteins or other targets would be more appro-
chloramphenicol, ampicillin and co-trimoxazole. Broader-spectrum priate [33].
cover (see below) may be considered necessary and judged according
to known local antimicrobial resistance patterns and local availability
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However, as recrudescence is often early, resistance to cotrimoxazole
22. Milledge J, Calis JC, Graham SM, et al. Aetiology of neonatal sepsis in
and logistical difficulties in early initiation of ARVs may reduce the
Blantyre, Malawi: 1996-2001. Ann Trop Paediatr 2005;25:101–10.
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effective agent as it recurs remains the best option (evidence grade 5). Salmonella Typhimurium causing invasive disease in sub-Saharan Africa have
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VACCINATION 25. Gordon MA, Graham SM, Walsh AL, et al. Epidemics of invasive Salmonella
enterica serovar Enteritidis and Salmonella enterica serovar Typhimurium infec-
There is currently no vaccine for NTS. Antibody is likely to be protec- tion associated with multidrug resistance among adults and children in
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2001;42:44–9. stream infections as a cause of fever in Malawi - clinical predictors and
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a review. Int Orthop 2007;31:137–44. 2010;328:508–12.
46 Campylobacter Infections
Paola J Maurtua-Neumann, Richard A Oberhelman
EPIDEMIOLOGY
Key features Campylobacter infection is a zoonotic disease, observed in most parts
of the world. Animals (fowl, swine, cattle, sheep, dogs, cats and
l Campylobacter species are microaerophilic, small, curved rodents) are the major reservoir for the bacteria and are usually
Gram-negative rods associated with diarrhea in both asymptomatic. Campylobacter enteritis has no seasonal preference in
developed and developing countries developing countries in contrast with developed countries, where
epidemics occur in summer and early autumn.
l Commonly colonizes gastrointestinal tract of chickens and
other animals, which serve as reservoirs In higher-income countries, acquisition of organisms results from the
l Major cause of pediatric diarrhea and traveler’s diarrhea in handling or consumption of poultry in about 50% of cases. Other
causes include the consumption of beef, pork, raw milk and contami-
resource-poor countries, presenting as dysentery or as
nated water, and contact with pets and farm animals. In the USA,
watery diarrhea surveillance studies showed a 30% decrease in incidence of culture-
l Usually presents as bloody diarrhea and dysentery in confirmed Campylobacter infections from 1996 to 2006, with an
higher-income country populations average of 13.9 cases per 100,000 in 2006. In New Zealand, incidence
l Associated with post-infectious inflammatory conditions, has been increasing since the 1980s, with almost 400 cases per
100,000 persons in 2003. Europe reported 45 per 100,000 persons in
including post-infectious arthropathy, Reiter’s sundrome
2005 and in Canada the rate in 2004 was 30 cases per 100,000. The
and Guillain-Barré syndrome (GBS) variations in incidence between countries may be caused, in part, by
l Diagnosed by stool culture, using special techniques differences in surveillance systems [1, 4].
developed specifically for this organism
In studies from resource-poor countries in Latin America and Africa,
l Macrolide antibiotics or fluoroquinolones are usually used Campylobacter is the most commonly isolated bacterial pathogen
for cases requiring antibiotic therapy among children with diarrhea. The incidence of Campylobacter enteri-
tis among children younger than 5 years old in these areas is as high
as 40,000/100,000. Although these rates seem extraordinarily high,
they are substantiated by Campylobacter diarrhea rates in travelers to
INTRODUCTION these countries of 27,000–38,000/100,000 per year. In developing
parts of Asia, Africa and Latin America, Campylobacter isolation rates
Campylobacter jejuni is currently the leading identified cause of bacte- have ranged from 5–20% in surveys performed in children with
rial gastroenteritis in the developed world and of significant preva- diarrhea. Older children and adults are infected less frequently
lence in developing countries. Young children are the most susceptible because acquired immunity increases with age. Healthy children
group, in both the developing and the developed world [1]. Most living in tropical countries frequently have asymptomatic infection.
Campylobacter infections are caused by C. jejuni or Campylobacter coli. Infections caused by C. coli are more likely to be asymptomatic than
These organisms are motile, comma-shaped, microaerophilic, Gram- ones caused by C. jejuni [1, 4].
negative rods with a corkscrew-like motion produced by a polar,
unsheathed flagellum. They commonly occur as commensals in Well-documented risk factors for Campylobacter infections include
warm-blooded animals, especially poultry [2]. Campylobacter jejuni drinking well-water, visiting or living on a farm, and having exposure
strains can be differentiated by using two different serotyping schemes, to pets with diarrhea and exposure to chickens living in the house-
one based on heat-labile flagellar protein, referred to as Lior serotypes hold. Studies of fecal output of household chickens of peri-urban
(there are over 100 Lior serotypes), the other based on heat-stable shantytowns in Lima, Peru, demonstrated that up to 61% of chickens
flagellar proteins referred to as Penner serotypes (there are over 60 were colonized with Campylobacter. Viable bacteria can survive in
Penner serotypes). chicken droppings for about 4 days. Contact with cats and dogs is
also significant. Secondary spread of infection from person to person
Campylobacter was first identified in 1916 when two British veterinary has not been documented, although household contacts have higher
surgeons reported a peculiar organism in the uterine mucus of preg- rates of infection than persons living in houses without cases of infec-
nant sheep. In 1947, Vincent et al. isolated the organism from the tion. This increased rate of infection is attributable to common
blood of three pregnant women with sepsis and spontaneous abor- sources of exposure [1, 5, 6].
tion. The organism was most probably Campylobacter fetus, a common
cause of veterinary disease but uncommon in humans. Later,
Campylobacter-like organisms were associated with other infections, TRAVELER’S DIARRHEA
including endocarditis, meningitis and gastroenteritis. The associa- Campylobacter species are important causes of diarrhea in travelers to
tion between Campylobacter and diarrhea was not made until the the developing world. Isolation rates vary by geographic location but
1970s; this link was challenging to prove because of the fastidious tend to be highest in travelers returning from South America, North
nature of the organism and because of the stringent culture condi- and East Africa, the Middle East, and South and Southeast Asia. In a
tions required to isolate the organism from stool [3]. study in Sweden, researchers found that the highest risk was seen in
468
Ca m py l o b a c te r I nfec tions 469
Jun
Jun Nov
Jun Jun
Sept Mar
Apr Dec
Feb Sept
Mar
returning travelers from the Indian subcontinent (1253 cases/100,000 Guillain-Barré syndrome (GBS). Post-infectious inflammatory com-
travelers) and the lowest in travelers from the other Nordic countries plications usually present within 1–6 weeks after ingestion [3].
(3/100,000 travelers). In Africa, there are large differences in risk
between regions (502/100,000 in travelers from East Africa compared In the developed world, Campylobacter jejuni enteritis can be quite
with 76/100,000 from West Africa and 50/100,000 from Central severe in children and adults. The most prominent features among
Africa) (Fig. 46.1) [6, 7]. patients who seek medical attention are bloody diarrhea, abdominal
pain and fever. Abdominal pain is the most characteristic manifesta-
tion of illness. In hospital surveys, bloody diarrhea occurs in about
NATURAL HISTORY, PATHOGENESIS half of the patients [3, 6].
AND PATHOLOGY In developing countries, Campylobacter jejuni enteritis is milder than
in patients in developed countries. In Thailand, about one-third of
Campylobacter infection causes local acute inflammatory changes in symptomatic infections are bloody, one-third are watery and one-
both the small and large bowel. The organism is able to invade and third are mucoid. In the developing world, bloody diarrhea is most
replicate in gut epithelia, causing interleukin-8 (IL 8) production, often seen with Shigella infections. In one study in Thailand, Shigella
activation of the innate immune system via Toll-like receptors (TLR)-2 organisms were associated with grossly bloody diarrhea in 37% of
and TLR-4, and disruption of the integrity of the epithelial barrier. cases, whereas Campylobacter and Salmonella organisms were associ-
The induction of IL-8 causes the recruitment of dendritic cells, mac- ated with bloody stools in 14% and 26%, respectively. More than 10
rophages and neutrophils that interact with C. jejuni. These interac- fecal leukocytes per high-power microscopic field (an indicator of
tions result in a massive pro-inflammatory response and increases in invasive diarrheal disease) were present in 24–36% of patients
corresponding cytokines [8]. infected with Campylobacter species. The incidence of bloody diarrhea
After 6 months of age, baseline levels of serum antibody increase. and the duration of illness decrease with age among children from
Higher antibody responses in older children correlate with excretion most developing countries [6].
of few organisms and with the presence of milder, non-bloody
diarrhea—findings consistent with the development of immunity TRAVELER’S DIARRHEA
[9]. Campylobacter species is an important cause of traveler’s diarrhea.
Most Campylobacter infections in travelers cause symptoms, although
BREASTFEEDING AND INFECTION frank dysentery is rare. In a study of Spanish travelers with Campylo-
bacter enteritis acquired in developing countries, only 4% had dysen-
The protection in breast-fed infants against Campylobacter appears to
tery. Abdominal cramps were present in 83% of cases, fever in 46%,
occur through acquired and innate defense factors found in human
nausea and vomiting in 42%, and grossly bloody diarrhea in only 3%
milk, including antibodies, oligosaccharides and their glycol-
of cases [6, 7].
conjugates. Milk glycans prevent Campylobacter infections and decrease
its disease severity [10].
POST-INFECTIOUS INFLAMMATORY
COMPLICATIONS
CLINICAL FEATURES
Guillain-Barré Syndrome
In humans, the infective dose for Campylobacter jejuni is between 500
and 10,000 organisms. Symptoms occur 1–7 days following inges- GBS is an acute, immune-mediated flaccid paralysis frequently associ-
tion. Disease usually manifests as self-limited gastroenteritis lasting ated with Campylobacter infection. GBS is the most serious complica-
up to 7 days. Excretion of Campylobacter organisms typically lasts 2–3 tion of Campylobacter infection and C. jejuni is the most frequently
weeks without treatment [2]. observed antecedent infection in cases of GBS. Its incidence is about
1/1000 infections, and 1 in 3 GBS cases is associated with a preceding
The clinical spectrum ranges from watery diarrhea to dysentery C. jejuni infection. Symptoms of GBS usually occur 1–3 weeks after
and may include mesenteric adenitis—giving a clinical picture that the onset of Campylobacter enteritis. GBS cases associated with Campy-
mimics appendicitis. Post-infectious complications include irritable lobacter infection are usually more severe than non-Campylobacter-
bowel syndrome, post-infectious arthropathy, Reiter’s syndrome and associated cases. The association of GBS and Campylobacter infection
470 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
relates to immune responses that target surface antigens of certain For confirmed C. jejuni infection, macrolide antibiotics such as eryth-
C. jejuni strains and cross-reactive human antigens on the surface of romycin, azithromycin or clarithromycin are the antibiotics of choice.
neuronal sheath cells [3, 11]. Treatment courses are usually for 3–7 days [16, 17]. Unfortunately,
resistance of C. jejuni to fluoroquinolones is now common, especially
in Southeast Asia, markedly limiting the utility of these agents in
Irritable Bowel Syndrome treating individuals with campylobacteriosis. Owing to widespread
Post-infectious irritable bowel syndrome can occur following Campy- resistance, tetracyclines should also not be used.
lobacter enteritis and usually manifests as persistent abdominal dis-
comfort, bloating and diarrhea, alternating with constipation, that In patients with bacteremia, treatment should be based on the iden-
continue even with clearance of the inciting pathogen [12]. tity of the infecting species and susceptibilities when available. Campy-
lobacter fetus is the most common species associated with bacteremia
and it is generally susceptible to aminoglycosides, extended-spectrum
Reactive Arthritis cephalosporins, meropenem and imipenem [16, 17].
Reactive arthritis is a spondyloarthropathy—a group of diseases with
a strong association with HLA-B27, absence of rheumatoid factor,
family aggregation and frequent extra-articular symptoms. Acute reac-
PREVENTION AND CONTROL
tive arthritis is characterized by sterile joint inflammation. It typically Appropriate precautions in the handling and preparation of foods of
develops within 4 weeks following an intestinal or urogenital infec- animal origin reduce cross-contamination. Raw meat and poultry
tion with obligate or facultative intracellular bacteria, such as Salmo- should be cooked adequately. Hands should be washed thoroughly
nella, Shigella, Yersinia and Campylobacter. The joint symptoms vary with soap after handling raw foods of animal origin and before touch-
from mild mono- or oligo-arthralgia, to severely disabling polyarthri- ing anything else. Chopping boards used for raw meats should not
tis. The arthritis has a predilection for joints of the lower extremity, be used for preparing other foods and should be cleaned well with
particularly knees and ankles [13]. soap and hot water. No vaccine is commercially available to prevent
disease in humans.
Campylobacter infection can lead to reactive arthritis with conjunctivi-
tis and urethritis (Reiter’s syndrome).
REFERENCES
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trends. Clin Infect Dis 2001;32:1201–6.
Transport of stool samples from patients with diarrhea looking for 2. Snelling WJ, Matsuda M, Moore JE, Dooley JS. Campylobacter jejuni. Lett
Campylobacter can be done in conventional containers but if delay is Appl Microbiol 2005;41:297–302.
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bacter enteritis can be diagnosed by direct microscopic examination Campylobacter infections, FoodNet 1996–2006. Foodborne Pathogen Dis
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Epidemiol 1989;129:785–99.
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agar, Butzler agar, Campy-cefex) and charcoal-containing media (e.g. 8. Young KT, Davis LM, DiRita VJ. Campylobacter jejuni: molecular biology and
modified charcoal cefoperazone deoxycholate agar, Karmali agar or pathogenesis. Nat Rev Microbiol 2007;5:665–79.
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[14]. J Clin Microbiol 1989;57:2542–6.
10. Morrow AL, Ruiz-Palacios GM, Jiang X, Newburg DS. Human-milk glycans
Passive filtration is another isolation method—it takes advantage that inhibit pathogen binding protect breast-feeding infants against infectious
of Campylobacter’s high motility, obviates the need for selective diarrhea. J Nutr 2005;135:1304–7.
media and can be used in resource-limited settings. Use of both selec- 11. Chowdhury D, Arora A. Axonal Guillain Barre syndrome: a critical review.
tive media and a filter method is associated with maximal sensitivity Acta Neurol Scand 2001;103:267–77.
[15]. 12. Thabane M, Kottachchi DT, Marshall JK. Systematic review and meta-analysis:
The incidence and prognosis of postinfectious irritable bowel syndrome.
Campylobacter species can also be detected directly in stool specimens Aliment Pharmacol Ther 2007;26:535–44.
by commercially available enzyme immunoassay or in research labo- 13. Pope JE, Krizova A, Garg AX, et al. Campylobacter reactive arthritis: a system-
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[15]. membrane filter method for isolation of Campylobacter species from Spanish
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Campylobacter enteritis is often a self-limited infection not requiring lobacter coli. J Antimicrob Chemother 2006;58:243–55.
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individuals, including those with HIV infection [3]. campylobacteriosis. BMC Infect Dis 2004;4:54.
D
SECTION
SEXUALLY TRANSMITTED
DISEASES
48 Chlamydial Infections
David Mabey, Rosanna Peeling
1000 organisms. These are released by lysis of the host cell 30–48 h
after the start of the cycle. Chlamydia trachomatis contains two biovars:
Key features the more invasive lymphogranuloma venereum (LGV) biovar and the
more common trachoma biovar, which is largely confined to squamo-
l The most common bacterial sexually transmitted infection columnar epithelial cells of the eye and genital tract. Both contain
l Most prevalent in younger, sexually active age groups several serovars defined by the presence of serovar-specific epitopes
l Often asymptomatic on the major outer membrane protein (MOMP). Serovars D–K cause
genital and oculo-genital infections.
l A cause of reproductive sequelae, such as infertility and
ectopic pregnancy
l Controlled by case finding, screening and prompt treatment
PATHOGENESIS AND IMMUNITY
of patients and their sexual partners After an incubation period of 5–10 days, C. trachomatis elicits an acute
l Usually diagnosed by sensitive nucleic acid amplification inflammatory response with a purulent exudate. A period of chronic
inflammation ensues, with the development of sub-epithelial folli-
tests which can be performed on urine samples or
cles; this eventually leads, in some cases, to fibrosis and scarring,
self-administered vaginal swabs which is responsible for much of the morbidity associated with
C. trachomatis. It is particularly likely to be seen after repeated
infections.
The Chlamydiae are pathogenic bacteria that can only replicate inside Genital C. trachomatis infection is most prevalent in the youngest
eukaryotic host cells. Their unique developmental cycle involves alter- sexually active age groups, suggesting that infection elicits a degree of
nation between a metabolically inert, infectious, spore-like elemen- protective immunity—the chlamydial isolation rate for men with
tary body that can survive in the extracellular environment, and a non-gonococcal urethritis is lower in those who have had previous
metabolically active, replicating reticulate body that cannot. The episodes. In animal models and human ocular infection, cell-
Chlamydiae have their own order (Chlamydiales) and family mediated immune responses mediated by CD4+ lymphocytes are
(Chlamydiaceae). important for the clearance of infection. Trachoma vaccine trials
showed that killed, whole organism vaccines provided some degree
CLASSIFICATION of protection against ocular C. trachomatis infection in humans and
non-human primates [3], but also suggested that vaccination could
The Chlamydiae have been classified as four species belonging to a provoke more severe, immunopathologic disease on subsequent chal-
single genus, Chlamydia: C. trachomatis, a human pathogen causing lenge [4]. This would be in keeping with the histopathology of C.
ocular and genital infections; C. pneumoniae causing mainly human trachomatis infection, in which the lymphoid follicle is the hallmark.
respiratory disease; C. psittaci which infects birds and other animals; A chlamydial heat-shock protein (hsp 60), homologous with the
and C. pecorum, a pathogen of cattle and sheep. The latter two occa- GroEL protein of Escherichia coli, elicits antibody responses that are
sionally affect humans. A recent taxonomic re-classification based on associated with the damaging sequelae of C. trachomatis infections. In
ribosomal DNA sequence data has not been widely adopted. Chlamy- recent years, research has focused on the development of a subunit
diae have one of the smallest bacterial genomes, containing around 1 vaccine against C. trachomatis. Purified preparations of MOMP were
million base pairs [1]. Virtually all strains of C. trachomatis also protective in murine models, provided the native trimeric structure of
contain a 4.4 MDa plasmid of unknown function. Genomes of C. the protein was maintained. In non-human primates, a similar prepa-
trachomatis serovars D, A, B and L2 have been sequenced, and show ration reduced peak shedding from the ocular surface, but had no
a high level of conservation of gene order and content (>99%) [2]. A effect on the duration of infection or on ocular disease [5, 6].
high degree of genetic conservation is also seen across Chlamydia
species. EPIDEMIOLOGY
BIOLOGY Chlamydia trachomatis is the most common bacterial sexually trans-
mitted infection (STI) [7]. It is common in all sexually active popula-
The elementary body is approximately 300 nm in diameter, binds to tions; prevalence is usually highest in the young. The World Health
the host cell and enters by “parasite-specified” endocytosis. Fusion of Organization estimates that 101 million new cases of genital chlamy-
the chlamydia-containing endocytic vesicle with lysosomes is inhib- dial infection occur annually worldwide.
ited, and the elementary body differentiates into the larger,
metabolically active reticulate body which divides by binary fission.
By 20 hours post-infection, a proportion of reticulate bodies has
CLINICAL MANIFESTATIONS
begun to re-organize into a new generation of elementary bodies. The clinical manifestations of genital C. trachomatis infection are
These reach maturity up to 30 h after entry into the cell and accumu- similar to those of gonorrhea, but are usually less severe (Table 48-1).
late within the endocytic vacuole, which typically contains more than Many chlamydial infections are asymptomatic. Long-term sequelae,
478
C h l a myd i a l I nfec tions 479
cough, but usually no fever. Radiographs show hyperinflation of the trachomatis IgM antibody is the gold standard for the diagnosis of
lungs with bilateral diffuse, symmetrical, interstitial infiltration and chlamydial pneumonia in babies.
scattered areas of atelectasis.
TREATMENT OF CHLAMYDIA
DIAGNOSIS TRACHOMATIS INFECTION
An endocervical swab is needed for the diagnosis of C. trachomatis
Tetracyclines and macrolides are the mainstay of treatment for C.
infection by culture or antigen detection assay. However, the greater
trachomatis infections. Treatment is often started before a microbio-
sensitivity of nucleic acid amplification tests (NAATs) for C. trachoma-
logic diagnosis can be established, so additional broad-spectrum anti-
tis means that vaginal swabs (which may be self-administered) and
biotics are needed to cover gonococcal and, in the case of PID,
“first-catch” urine specimens give equivalent results to endocervical
anaerobic infections. Treatment of patients’ partners is essential to
swabs when using these assays [10].
prevent re-infection.
NUCLEIC ACID AMPLIFICATION 4. Brunham RC, Rey-Ladino J. Immunology of Chlamydia infection: implica-
tions for a Chlamydia trachomatis vaccine. Nature Reviews Immunology 2005;
TESTS (NAATs) 5:149–61.
The PCR assay, the strand displacement assay (SDA) and the 5. Kari L, Whitmire WM, Carlson JH, et al. Pathogenic diversity among Chlamy-
dia trachomatis ocular strains in non-human primates is affected by subtle
transcription-mediated amplification (TMA) technique are extremely
genomic variations. J Infect Dis 2008;197:449–56.
sensitive, detecting 10–100 organisms. Commercial assays based on
6. Kari L, Whitmire WM, Crane DD, et al. Chlamydia trachomatis native major
each of these three amplification methods are widely used. The first
outer membrane protein induces partial protection in nonhuman primates:
two assays amplify nucleotide sequences of the cryptic plasmid implication for a trachoma transmission blocking vaccine. J Immunol
present in multiple copies in each chlamydial elementary body. A 2009;182:8063–70.
recently described Swedish variant of C. trachomatis harbors a deletion 7. www.who.int/topics/sexually_transmitted_infections/en/
in the plasmid, which gives rise to false-negative results with these 8. Silveira MF, Ghanem KG, Erbelding EJ, et al. Chlamydia trachomatis infection
assays [11, 12]. The TMA reaction is directed against rRNA, which during pregnancy and the risk of preterm birth: a case-control study. Int J STD
is also present in multiple copies. These assays are now the “gold AIDS 2009;20:465–9.
standard” for the diagnosis of C. trachomatis infection. 9. Beem MO, Saxon EM. Respiratory tract colonisation and a distinctive pneu-
monia syndrome in infants infected with Chlamydia trachomatis. N Engl J Med
POINT-OF-CARE TESTS 1977;296:306–10.
10. Cook RL, Hutchison SL, Østergaard L, et al. Systematic review: noninvasive
Several point-of-care antigen detection tests are available for the diag- testing for Chlamydia trachomatis and Neisseria gonorrhoeae. Ann Intern Med
nosis of C. trachomatis infection, but they are less sensitive than NAATs 2005;142:914–25.
and cannot be used on vaginal swabs or urine samples. 11. Seth-Smith HMB, Harris SR, Persson K, et al. Co-evolution of genomes and
plasmids within Chlamydia trachomatis and the emergence in Sweden of a new
SEROLOGIC TESTS variant strain. BMC genomics 2009;10:239.
12. Watson EJ, Templeton A, Russell I, et al. The accuracy and efficacy of screening
Serologic tests may be helpful in the diagnosis of PID, LGV and in tests for Chlamydia trachomatis: a systematic review. J. Med. Micro 2002;
Curtis Fitz-Hugh syndrome, as antibody titers tend to be higher in 51:1021–31.
these conditions than in uncomplicated cervical infections. Chlamydia 13. www.cdc.gov/std/treatment/2010/default.htm
Lymphogranuloma Venereum 49
August Stich
other ulcerative STIs became possible. The first full description of LGV
was given in 1913 by Durand, Nicolas and Favré. The introduction of
Key features an intradermal skin test by Frei in 1925 allowed a distinct diagnosis
of lesions, formerly called “climatic” or “tropical bubo” and con-
l Lymphogranuloma venereum (LGV) is a sexually transmitted nected the late complications of elephantiasis and rectal stricture with
disease caused by the invasive intracellular bacteria LGV. With the isolation and culture of chlamydiae in the 1930s and
Chlamydia trachomatis serotypes L1–L3 the introduction of specific serologic tests in the 1960s, the natural
history of LGV could be fully described. Advances in immunology
l LGV is a systemic disease with an aggressive nature and
and molecular biology in the last decades of the 20th century led to
initially presents as a painless genital papule or ulcer a new understanding of the disease. DNA amplification tests began
leading to excessive regional lymphadenopathy, sometimes to replace cell culture as the gold standard of diagnosis.
even resulting in lymphedema or elephantiasis
Chlamydiae are highly specialized, obligate, intracellular Gram-
l Diagnosis is best done by PCR negative bacteria, with a unique reproductive cycle (see Chapter 48,
l Doxycycline is the treatment of choice, and is highly “Chlamydial infections”). Whereas the other serotypes of C. trachoma-
effective when given early in the course of the disease tis all produce superficial epithelial infections of mucous membranes
in the eyes, genitalia or respiratory system, serotypes L1–L3 (the “LGV
strains”) display a distinct invasive behavior in lymphatic tissue. They
grow rapidly in cell culture, show enhanced resistance to phagocytosis
and kill mice after intracerebral inoculation.
INTRODUCTION LGV is primarily a lymphatic disease. Chlamydia gain access to lym-
Lymphogranuloma venereum (LGV), along with gonorrhea, syphilis, phatic vessels through microtrauma of the skin or mucous membranes.
chancroid and donovanosis, is one of the five classic venereal diseases. Being partly the result of an excessive T-cell mediated immune response,
There is considerable confusion about terminology, especially the leading pathologic feature of LGV is a progressive thrombolym-
between the latter and LGV (Table 49-1). phangitis. Endothelial cells along the lymphatic vessel walls proliferate,
finally causing stenosis and obstruction, and the inflammatory reac-
EPIDEMIOLOGY tion spreads to the surrounding tissue. Regional lymph nodes are
invaded by neutrophils and mononuclear macrophages, leading to
granuloma formation and the characteristic three- or four-cornered
GEOGRAPHICAL DISTRIBUTION “stellate” microabscesses, finally resolving in progressive fibrosis and
LGV has a worldwide distribution but is more prevalent in tropical scarring. Although the immune system is capable of suppressing
and subtropical areas. LGV is sporadic in North America and Europe, chlamydial replication, it usually cannot completely eradicate the
where recent outbreaks have been reported among men who have sex organism that can persist for decades in local lesions [3].
with men [1, 2]. LGV remains endemic in parts of Africa, India,
Southeast Asia, the Caribbean and Brazil. Prevalence depends on the
quality of diagnostic facilities and the training of health personnel.
CLINICAL FEATURES
LGV is a systemic disease with three distinct stages. The clinical fea-
tures vary according to gender and sexual practices of the patient.
TRANSMISSION Immunosuppression, for example underlying HIV disease, seems to
LGV is a sexually transmitted infection (STI). Major sources are result in more severe and prolonged symptoms.
asymptomatic carriers, especially women with LGV endocervicitis.
The frequency of infection following exposure seems to be relatively
low, although the actual risk of infection is unknown. Extragenital PRIMARY LYMPHOGRANULOMA
transmission, mostly in laboratory infections, occasionally occurs. VENEREUM (LGV)
Autoinfection (conjunctivitis) is possible. A small papule, erosion or ulcer develops at the site of infection
LGV is six times more frequently observed in men. However, delayed (usually penis, labia, vulva or cervix) after an incubation period
complications, such as lymphedema or rectal strictures, are more varying from 3 to 30 days. The initial lesion is inconspicuous and may
commonly reported among women. resemble herpes simplex infection, but is usually painless. It is more
often seen in men, with a ratio of four men to every woman, and
heals spontaneously after a few days.
ETIOLOGY AND PATHOLOGY Other locations of primary LGV are the anus, rectum or urethra.
A relationship between inguinal bubos and granulomas was first Extragenital manifestations are rare—the best known being a con-
observed in the 18th century. The first description of LGV was by junctivitis with pre-auricular lymphadenopathy and lymphedema of
Wallace in 1833. With the introduction of the first serologic tests for the eyelid (“Parinaud’s oculoglandular syndrome”), usually following
venereal diseases by Wassermann in 1906, separation of syphilis from autoinfection.
481
482 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Anorectal Syndrome
An LGV-associated anorectal syndrome is most commonly reported
in men who have anally receptive sex with men. Patients present with
a hemorrhagic proctitis or proctocolitis resembling histologically
chronic ulcerative bowel disease. Extensive lymphadenopathy may
develop in the pelvic, obturator or iliac area, leading to complaints
of lower abdominal or back pains. When left untreated, the condition
may result in rectal fistulae, perirectal abscess formation, adhesion of
the rectum to the pelvic wall and rectal strictures, usually with a long
and tubular appearance.
TERTIARY LYMPHOGRANULOMA
VENEREUM (LGV)
Late complications of untreated LGV may appear months or years
after the initial infection in about 25% of inappropriately treated
patients. Obstruction of lymphatic vessels results in lymphedema and
elephantiasis of the external genitalia and sometimes the lower limbs.
Patients with these presentations are rare except in areas with very
limited health facilities.
FIGURE 49.1 Lymphogranuloma venereum. Bilateral inguinal buboes
with separation of the matted left inguinal and femoral lymph nodes by
the inguinal ligament, creating the pathognomonic sign of the “groove”. DIAGNOSIS
MICROSCOPIC DIAGNOSIS
LGV cannot be diagnosed exclusively on clinical grounds; specialized
SECONDARY LYMPHOGRANULOMA laboratory examinations are required. Smears, scrapings, aspirated
VENEREUM (LGV) material or biopsies can be Giemsa-stained and examined for inclu-
From the site of the primary lesion, the infection reaches the neigh- sion bodies in the cytoplasm of macrophages or stellate abscesses in
boring lymph nodes, resulting in an extensive inflammation of the tissue sections. Microscopic examination has a low sensitivity and
regional lymphatic tissue. This feature is often the first noted presenta- specificity that can be enhanced by using fluorescein-conjugated
tion of the disease and seen at a time when the primary lesion has monoclonal antibodies and immunofluorescence.
already healed.
MOLECULAR DIAGNOSIS
Inguinal Syndrome Isolation and strain differentiation in cell culture is an expensive and
Most commonly, patients present with an “inguinal syndrome”, a technically demanding method that was formerly the gold standard
painful inguinal lymphadenopathy that usually develops 2–6 weeks for the diagnosis of LGV. This method has now been largely replaced
after the initial infection. The inflammation starts unilaterally but by nucleic acid amplification techniques (NAAT) that enable direct
tends to spread to the other side in about a third of cases. Progressive pathogen detection in smears and affected tissues. The diagnosis of a
periadenitis involves the overlying skin. Small abscesses coalesce, C. trachomatis infection can be established by sequencing the outer
forming bubos that may rupture spontaneously. Multiple fistulae and membrane protein A (ompA) gene. However, NAAT have not been
sinuses break open and discharge purulent fluid. The enlargement of approved by the United States Food and Drug Administration (FDA)
lymph nodes above and below the inguinal ligament results in a for the diagnosis of rectal chlamydial infection.
characteristic “groove sign” (Fig. 49.1).
After several months, spontaneous healing occurs leaving extensive ANTIBODY DETECTION TESTS
scars and masses of fibrotic granulomatous tissue. Relapse occurs in Antibody detection tests are of limited value for diagnosing LGV.
about 20% of untreated cases. Normally, a fourfold or greater increase in a specific titer is considered
Ly m p h o gra n u l o m a Venereum 483
to be diagnostic. Several test assays are available based on ELISA, SURGICAL TREATMENT
complement fixation or indirect immunofluorescence techniques.
Pus from bubos should be aspirated and drained and fistulas should
The intradermal skin test (Frei test) is historical and no longer in use. receive clean dressings. The severe deformities of tertiary LGV can only
be treated with plastic surgery, which should only be performed after
TREATMENT a prolonged course of antibiotics. Patients with extensive scarring
should be monitored at least annually and, if necessary, suspicious
lesions should be biopsied to assess for presence of malignancy.
ANTIBIOTIC TREATMENT
Antibiotics can stop progressive inflammation, but cannot prevent
tissue destruction and scarring. The treatment of choice for LGV is
doxycycline 100 mg b.i.d. for 21 days. Alternatively, tetracycline
REFERENCES
500 mg q.i.d. can be used. Resistance to these antibiotics is not 1. Kapor S. Re-emergence of lymphogranuloma venereum. JEADV 2008;
known. Treatment failure is usually a result of misdiagnosis, poor 22:409–16.
compliance or re-infection. 2. Stary G, Stary A. Lymphogranuloma venereum outbreak in Europe. JDDG
2008;6:935–9.
Should tetracyclines be contraindicated, erythromycin (500 mg q.i.d. 3. Perine PL, Stamm WE. Lymphogranuloma venereum. In: Holmes KK, ed. Sexu-
for 21 days), azithromycin (1 g daily for 21 days), rifampicin or chlo- ally Transmitted Diseases, 3rd edn. New York: McGraw-Hill; 1999:
ramphenicol can be used. Comparative studies have not been done. 423–32.
The activity of fluoroquinolones is uncertain. Penicillins, cepha- 4. Mabey D, Peeling RW. Lymphogranuloma venereum. Sex Transm Infect
losporines and aminoglycosides are not effective [4]. 2002;78:90–2.
50 Gonorrhea
Ronald C Ballard
gonococci may be resistant to many antibiotics as a result of chromo- The severity of the condition may vary from being virtually asympto-
somal mutations. Strains showing chromosomal resistance to matic to life-threatening. A profuse vaginal discharge, often with an
penicillin/ampicillin/amoxicillin may also show decreased suscepti- offensive odor, is commonly noted and is often associated with
bility to cephalosporins, tetracycline and macrolide antibiotics. dysuria. Abnormal uterine bleeding occurs in 35–40% of patients,
Decreased susceptibility and high-level chromosomal resistance of probably as a result of endometritis. Patients with gonococcal pelvic
gonococcal strains to the fluoroquinolone antibiotics emerged more inflammatory disease (PID) may have associated chlamydial infec-
recently in many countries. Such resistance is thought to be the result tion, while anaerobic super-infection may contribute to disease etiol-
of the acquisition of point mutations in genes encoding gonococcal ogy, particularly in severe cases [3].
DNA gyrase (gyrA) and topoisomerase IV (parC) enzymes, and
changes in bacterial cell membrane permeability. These mechanisms Clinical findings include pyrexia, tachycardia, lower abdominal ten-
of resistance can occur in combination, rendering most treatment derness and pelvic, or even generalized, peritonitis. Vaginal examina-
options ineffective. Where fluoroquinolone resistance is common, the tion reveals cervical excitation tenderness and, frequently, adnexal
only class of antibiotic that can be used with confidence is the cepha- tenderness. Adnexal masses may be formed from tubo-ovarian
losporins. Even here, problems have emerged with oral cephalosporin abscesses or from omentum and bowel adherent to the inflamed
treatment failures being recorded in the Far East. It is clear that, tubes and ovaries. Occasionally, a patient may present in extremis, with
barring the development of a new class of antibiotic active against N. features of generalized peritonitis, septicemic shock and disseminated
gonorrhoeae, the era of single-dose, single-agent treatment for gonor- intravascular coagulopathy. In some severe cases, the liver capsule can
rhea may be coming to an end, and that combination therapy may become inflamed and attached to the peritoneum by fine “violin-
become routine in the near future. string” adhesions. This perihepatitis is also known as Fitz-Hugh-Cur-
tis syndrome. Resolution of tubal infections may result in formation
of fine scars that are associated with increased risk of ectopic preg-
CLINICAL MANIFESTATIONS nancy and tubal infertility.
DISSEMINATED GONOCOCCAL INFECTION the basis of a Gram stain, oxidase test and sugar fermentation reac-
tions. Neisseria gonorrhoeae produces oxidase and ferments glucose,
Disseminated gonococcal infection (DGI) occurs as a result of gono- but not sucrose, lactose or maltose. Alternatively, isolated organisms
coccal bacteremia. The source of infection tends to be asymptomatic can be identified by using monoclonal antibodies in commercial
endocervical, pharyngeal, rectal or urethral disease. The most common co-agglutination tests.
form of DGI is the dermatitis-arthritis syndrome, in which patients,
usually women, develop arthralgias and macular, pustular, hemor- While culture is largely being replaced by nonculture methods for the
rhagic or necrotic skin lesions on the distal extremities. A minority of diagnosis of gonorrhea in many industrialized countries, it is essential
patients develops septic joints with a purulent effusion and associated to maintain culture capability for N. gonorrhoeae in order to perform
fever. The disease normally affects isolated joints. Other manifesta- antimicrobial susceptibility testing where necessary.
tions of gonococcal bacteremia include endocarditis and meningitis.
Fortunately, these complications are extremely rare.
NONCULTURE TESTS
Commercially available nonculture tests for the diagnosis of gonor-
LABORATORY DIAGNOSIS rhea include antigen detection tests, for example ELISA assays, non-
amplified nucleic add probes and nucleic acid amplification tests
THE GRAM STAIN (NAATs), such as PCR, strand displacement amplification (SDA),
transcription-mediated amplification (TMA) and real-time PCR tests.
The finding of intracellular Gram-negative diplococci in Gram-stained These amplified tests, although relatively expensive, are more sensitive
smears of urethral or conjunctival material is generally regarded as than culture and have the advantage that they can be applied to
sufficient evidence for a presumptive diagnosis of gonococcal infec- “noninvasive” specimens, such as self-administered vaginal swabs in
tion in symptomatic men with acute urethritis and in patients with women and first-catch urine in men—making them ideal for screen-
conjunctivitis (Fig. 50.3). However, whenever possible, the exudate ing applications. Despite the emergence of NAATs as the diagnostic
should be cultured on a selective medium to confirm the diagnosis. tests of choice for gonorrhea, false-positive results are known to occur,
Owing to the presence of large numbers of bacteria that can be mis- particularly when testing specimens obtained from nongenital sites.
taken for (or mask) N. gonorrhoeae in the female genital tract and It is therefore recommended that positive gonococcal NAAT results
rectum, or the presence of other Neisseria spp., especially in the should be confirmed with another NAAT which uses an alternative
oropharynx, Gram-stained smears of genital secretions from women target sequence in order to reduce the possibility of false-positive
and from the rectum or pharynx of patients with suspected gonococ- results that are known to occur with related Neisseria spp. Unfortu-
cal infection are of questionable diagnostic value. nately, all nonculture tests share the disadvantage that they can detect
nonviable N. gonorrhoeae. Therefore, they cannot be recommended
CULTURE for evaluation of tests of cure following treatment.
Urethral swabs should be taken from men and endocervical, urethral
and rectal swabs from women to optimize isolation rates. Pharyngeal TREATMENT
swabs should be taken from patients with a history of recent orogeni-
tal contact.
UNCOMPLICATED GONOCOCCAL INFECTIONS
Specimens for culture of N. gonorrhoeae should be plated directly onto Single-dose therapy is preferred to overcome problems associated
a selective medium such as Thayer-Martin or New York City medium, with patient compliance. However, in many countries where gonor-
each of which is composed of a gonococcal, or equivalent, agar base, rhea is common, the choice of treatment is limited by financial con-
with additional growth supplements and antibacterial and antifungal straints and the availability of antibiotics. The likelihood of concurrent
agents. If the specimen is obtained from a site that is usually sterile infection justifies the use of combination therapies active against all
(e.g. blood or synovial fluid), it can be inoculated directly onto plates possible causes of the presenting disease “syndrome”. This “syndro-
of nonselective chocolate agar. Inoculated plates can be stored at mic approach” to the management of sexually transmitted infections
room temperature in a candle extinction jar for up to 6 hours without has been advocated by the World Health Organization (WHO) [4].
significant loss of viability. Alternatively, specimens may be sent to Since 1985, the treatment guidelines for gonorrhea published by the
the laboratory in Stuart’s or Amies’ transport medium. After incuba- Centers for Disease Control (CDC) have recommended that single-
tion for 24–48 hours at 35–36.5°C in an atmosphere of 10% carbon dose treatments effective for eradication of N. gonorrhoeae be auto-
monoxide, in air, isolated colonies can provisionally be identified on matically followed by a 7-day course of a tetracycline or a macrolide
antibiotic, which would be expected to eradicate concomitant Chlamy-
dia trachomatis infection and other causes of nongonococcal urethritis.
In many countries with few laboratory facilities, routine treatment of
acute urethritis in men is achieved with such dual therapy, while
routine therapy of sexually acquired vaginal discharge and PID is
achieved by addition of multidose metronidazole to this regimen to
eradicate trichomoniasis, bacterial vaginosis and anaerobes associated
with pelvic infection.
In the few regions of the world where antimicrobial resistance of N.
gonorrhoeae is not a problem, single-dose treatment with either cipro-
floxacin 500 mg or ofloxacin 400 mg, by mouth, remains acceptable,
followed by a 7-day course of doxycycline 100 mg twice daily or tet-
racycline 500 mg four times daily, both by mouth. In areas where
fluoroquinolone resistance is common, cefixime 400 mg as a single
oral dose or ceftriaxone 250 mg or spectinomycin 2 g as a single,
intramuscular injection (IM) may precede the 7-day treatment for
other infections. Less expensive, and possibly less effective, alterna-
tives used in some developing countries include combining anti-
chlamydial therapy with either kanamycin 2 g or gentamicin 240 mg
as a single, intramuscular injection. Sexual partners of patients with
FIGURE 50.3 Gram-stained smear of urethral exudate showing Gram- gonorrhea should be treated simultaneously, regardless of the results
negative intracellular diplococci. of laboratory investigations.
G onor r hea 487
Africa and many areas of Asia where it once accounted for 50% or
more of genital ulcerating disease (GUD). In 2007, H. ducreyi still
Key features caused about 15% of GUD in Malawi, but less than 1% in South
Africa and Botswana [3–6]. Studies in the 1980s demonstrated that
l A painful ulcerative sexually transmitted infection (STI) chancroid flourishes in societies in which men are uncircumcised,
caused by Haemophilus ducreyi where many men have sex with a few women (most of whom are
l A disease of core groups, especially sex workers and their commercial sex workers) and where sexually transmitted disease
(STD) control programs are ineffective [7, 8]. The disappearance of
clients
chancroid has not been carefully studied, but it may be occurring
l Diagnosed by PCR or by culture, but culture is difficult because of improved STD control during the HIV era and the wide-
owing to the fastidious growth requirements of H. ducreyi spread use of quinolones for the treatment of STIs. Although accurate
l Was the leading cause of genital ulceration in Africa in the incidence figures are not available, in 2010 chancroid occurs in only
1980s, but its incidence has fallen in recent years and a few countries, and even in these countries the incidence is falling
[3, 4, 6].
Herpes simplex now causes a much greater proportion of
genital ulcers
RESERVOIR
The reservoir for H. ducreyi is presumed to be sexually active persons
with genital ulcers [7]. The attack rate following unprotected inter-
course is high, with at least 50% of men acquiring genital ulcers [7].
DEFINITION Secondary attack rates are also substantial, with at least half of subse-
In 1889, Ducrey described the etiologic agent, Haemophilus ducreyi, quent partners infected.
responsible for the genital ulcerating disease, chancroid. Classic chan-
croid is an acutely painful, irregular genital ulcer with associated INTERACTION WITH HIV
inguinal lymphadenitis that may proceed to bubo formation. Numerous studies have demonstrated that H. ducreyi and HIV infec-
tion interact to increase heterosexual transmission of HIV, while con-
ETIOLOGY comitantly altering chancroid [9–11]. HIV sero-negative men with
chancroid have a fivefold greater risk of HIV seroconversion than men
Haemophilus ducreyi is a small, Gram-negative, bipolar staining organ- with urethritis following exposure to HIV-infected women [9].
ism that often has a “school of fish” arrangement on stained micro- Women with genital ulcers who sell sex are at greater risk of acquiring
scopy. The organism requires hemin and the amino acids glutamine HIV. The immune response to H. ducreyi recruits and activates mac-
and cystine. Its taxonomic placement is controversial, but it is more rophages and T-helper lymphocytes, which may predispose individu-
closely related to the Actinobacillus than to the Haemophilus genus. als with ulcers to susceptibility of HIV infection. Excretion of HIV in
Haemophilus ducreyi replaces nitrate and produces alkaline phos- genital discharge is increased; as a result, genital ulcers become both
phatase. It possesses several characteristics that appear important for the portal of HIV entry and exit. Patients with chancroid who are
virulence including pili, a hemolysin, several toxins and a hemo- HIV-infected more commonly fail treatment or relapse. As a result of
globin receptor [1]. these interactions, a cycle of amplification between H. ducreyi and HIV
occurs that markedly increases the risk of transmission of HIV [8,10].
PATHOGENESIS
As few as 30 H. ducreyi organisms can produce ulceration following CLINICAL FEATURES
inoculation on the forearms of healthy human volunteers [1]. Immu- After an incubation period of 3–7 days, a rapidly eroding genital ulcer
nohistochemical analysis of the ulcerating lesions has shown that a develops. About 50% of chancroid ulcers are classic and present as
cell-mediated Th1 response consisting predominantly of T lym- irregular, non-indurated, very painful lesions of variable depth with
phocytes and macrophages is present interstitially and perivascularly an undermined edge and yellow-gray purulent exudative base that
[2]. Presumably, cytotoxins and hemolysins produced by H. ducreyi bleeds readily. The skin surrounding the ulcer is usually not inflamed.
cause tissue destruction [1]. The pathogenesis of the lymphadenitis Other presentations include: giant ulcers formed when several smaller
and bubo formation is not understood. ones merge (Fig. 51.1); dwarf ulcers, which are tiny, shallow, round
ulcers that mimic genital herpes; transient superficial ulcers that
EPIDEMIOLOGY resemble lymphogranuloma venereum; single, painless ulcers that
can be confused with syphilis; and beefy, raised indurated lesions
Chancroid was endemic in many developing countries with frequent that clinically appear to be granuloma inguinale. The sensitivity and
introductions, often at seaports, in the developed world. However, specificity of the clinical diagnosis depends on the relative proportion
since the year 2000, chancroid has largely disappeared from East of genital ulcers caused by H. ducreyi in the population [12].
488
Chancroid 489
LABORATORY DIAGNOSIS
Specimens should be either plated directly or swabs transported at 4°
and plated within 24 hours [15]. The culture should be plated on
gonococcal agar with added vancomycin (3 mg/L) to inhibit the
growth of Gram-positive bacteria, 2% hemoglobin, 1% vitamin
enrichment and 0.25% charcoal [15]. Incubation should be carried
out at 32° in a 100% humidity, CO2-enriched environment. A candle
extinction jar with a moist paper towel is adequate. After 2–5 days,
small, yellow-gray colonies of varying size appear on the culture plate.
The colonies can be moved intact with a straight wire [15].
Nucleic acid technologies are sensitive and specific for the diagnosis
of H. ducreyi infection [16]. Serologic studies have been used for the
diagnosis of H. ducreyi, but these are insensitive and best reserved for
seroimmunologic investigation of populations.
TREATMENT
Haemophilus ducreyi acquires plasmids readily and antimicrobial
resistance develops and spreads quickly. In most of the world, H.
FIGURE 51.1 Chancroid. Large penile ulceration with a suppurative left ducreyi is resistant to tetracycline, ampicillin, sulfonamides and tri-
inguinal bubo. methoprim. In addition, plasmids that mediate resistance to kanamy-
cin, streptomycin and chloramphenicol have been described.
Erythromycin 500 mg three times daily for 7 days or azithromycin as
a single, 1-g dose are equally effective treatment regimens. Ceftriaxone
as a single 250-mg dose administered intramuscularly is effective but
treatment failures occur in patients concomitantly infected with HIV.
Ciprofloxacin and other fluoroquinolones are very effective, with cure
rates of 95% following a 3-day regimen.
Fluctuant buboes should be incised or aspirated.
PREVENTION
With the evidence that links chancroid to explosive heterosexual
transmission of HIV, control and elimination of chancroid from
populations should be a priority [17]. Enhanced STD control strate-
gies to include effective treatment regimens based on syndromic diag-
nosis at the point of first contact with the health care system, the
increased use of condoms (particularly by female sex workers), pro-
grams to provide care and treatment for prostitutes, and partner refer-
ral can all successfully control and regionally eliminate chancroid
[17]. A rapid response to outbreaks should be included in all national
STD control programs to ensure that chancroid, once eliminated from
a country or region, is not re-introduced and allowed to become
endemic again. Strategies for surveillance and expedited control with
a goal of maintaining societies free of chancroid should be part of all
national and international STD programs. Chancroid is the one STD
that is susceptible to rapid control strategies with the goal of elimina-
tion. Its proven role in facilitating HIV transmission requires contin-
ued efforts to ensure its control [17].
FIGURE 51.2 Chancroid. Labial lesion. (Courtesy of the Armed Forces Institute
of Pathology, Photograph Neg. No. 82-9102)
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volunteers with Haemophilus ducreyi: Fifteen years of clinical data and experi-
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lesions occurring on the prepuce in uncircumcised men. Kissing 2. King R, Gough J, Ronald A, et al. An immunohistochemical analysis of natu-
lesions are common on adjacent cutaneous surfaces. In women, the rally ccurring chancroid. J Infect Dis 1996;174:427–30.
majority of lesions are on the fourchette, labia and perineal area (Fig. 3. Freeman EE, Orroth KK, White RG, et al. Proportion of new HIV infections
51.2). About 40% of patients develop painful inguinal adenitis that attributable to herpes simplex 2 increases over time: simulations of the chang-
can progress to bubo formation with overlying erythema; buboes may ing role of sexually transmitted infections in sub-Saharan African HIV epi-
demics. Sex Trans Infect 2007;83(suppl.1):i17.
rupture and produce an inguinal abscess.
4. Hoffman I, Kamanga G, Mapanj E, et al. The etiology of GUD in Malawi
Careful, definitive laboratory studies suggest that about 10–15% of 1992–2007. Abstract P-318. International Society for Sexually Transmitted
patients with chancroid also have a second ulcerating pathogen, Diseases Research, June 2009.
usually either herpes simplex or Treponema pallidum. 5. Jaiswal AK, Banerjee S, Matety AR, Grover S. Changing trends in sexually
transmitted diseases in North Eastern India. Indian J Dermatol Venereol
Two recent reports, both from the South Pacific Islands, have identi- Leprol 2002;68:65–6.
fied H. ducreyi in children presenting with chronic cutaneous infec- 6. Paz-Bailey G, Rahman M, Chen C, et al. Changes in the etiology of sexually
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Haemophilus ducreyi in Nairobi. Lancet 1983;322:1293–5. diagnosis of genital ulcer disease (GUD) in a primary health care setting in
8. Weiss HA, Thomas SL, Munabi SK, Hayes RJ. Male circumcision and risk of Nairobi. Int J STD AIDS 1996;7:201–5.
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Sex Transm Infect 2006;82:101–10. a visitor from Vanuatu. Australas J Dermatol 2008;49:98–9.
9. Cameron DW, Simonsen JBN, D’Costa IJ, et al. Female to male transmission 14. Ussher JE, Wilson E, Campanella S, et al. Haemophilus ducreyi causing chronic
of human immunodeficiency virus type 1: risk factors for seroconversion in skin ulcerations in children visiting Samoa. Clin Infect Dis 2007;4:e85–7.
men. Lancet 1989; 334:403–7. 15. Alfa M. The laboratory diagnosis of Haemophilus ducreyi. Can J Infect Dis Med
10. Jessamine P, Ronald AR. Chancroid and the role of genital ulcer disease in Microbiol 2005;16:31–4.
the spread of human retroviruses. Med Clin N Amer 1990;74:1417–32. 16. Orle KA, Gates CA, Martin DH, et al. Simultaneous PCR detection of Haemo-
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Granuloma Inguinale 52
John Richens
EPIDEMIOLOGY
Key features Syphilis is found throughout the world (Fig. 53.2), but prevalence
studies indicate marked distinctions between high- and low-income
l Syphilis is an ulcerative treponematosis transmitted through settings. In developing countries, a prevalence of 2–5% is often
sexual contact caused by Treponema pallidum subsp. reported in pregnant women (Fig. 53.3) and even higher levels are
pallidum often observed among female sex workers. Prevalence peaks at the age
of greatest sexual activity, i.e. young adults. In high-income countries,
l Characterized at microscopic level by obliterative
syphilis rates are notably higher in white Caucasian males, largely
endarteritis linked to homosexual behavior. Within individual countries, syphilis
l A triphasic natural history passing from primary ulcer has shown marked fluctuations over time, with notable peaks occur-
(chancre) to a secondary stage dominated by florid skin ring at times of war, in the period following the introduction of the
symptoms and a tertiary stage involving the cardiovascular oral contraceptive pill until the emergence of HIV and, most recently,
and nervous systems following the fall in AIDS mortality that followed improvements in
HIV treatment. There have been suggestions that syphilis fluctuates
l A major cause of abortion, stillbirth, and low birth weight in within populations over an 8–11-year cycle, correlating with the rises
developing countries and falls of herd immunity.
l Diagnosis is usually based on clinical recognition and
Among adults, syphilis usually presents with either a primary chancre,
serology skin lesions of secondary syphilis or as a latent infection detected
l Treatment involves the use of penicillin serologically [2]. Presentations with neurologic or cardiovascular
l There is no commercially available vaccine manifestations of tertiary syphilis (common prior to the introduction
l Non-venereal treponematoses respond to penicillin of penicillin treatment) are now rarely encountered, although an
exception could be made for the early development of neurologic
treatment and include yaws, pinta, and endemic syphilis involvement among HIV co-infected patients.
Congenital syphilis remains a significant public health problem in
settings where effective screening and treatment for syphilis in preg-
INTRODUCTION nancy are not implemented. This results in significant levels of fetal
wastage, low birth weight, stillbirth, and congenital syphilis.
The treponematoses form an interesting group of infections caused
by a group of closely related spirochetes found in humans and pri- Transmission of syphilis via blood transfusion is prevented by screen-
mates. At present, the bacteria responsible for the treponematoses are ing donated blood and storage at low temperature.
all classified as subspecies of Treponema pallidum; commercially
available serologic tests remain incapable of differentiating between
venereal and non-venereal infections. Some authorities believe that
venereal syphilis and the endemic treponematoses are essentially the
NATURAL HISTORY, PATHOGENESIS,
same disease, with the route of transmission explaining the differ- AND PATHOLOGY
ences in epidemiology and clinical features. Nonetheless, the trepone- Treponema pallidum is remarkable for its ability to survive for extended
matoses show distinct differences in clinical features and the periods in humans. Recent research suggests that the evasion of an
propensity for visceral involvement and vertical transmission. Recent effective immune response is attributable to a well-developed mecha-
research points to small, but important, genetic differences and tissue nism for antigenic variation in the face of immunologic attack. These
tropisms in strains associated with different clinical variants. The events are believed to underlie the emergence of secondary syphilis
Columbian hypothesis posits that syphilis was a new disease intro- shortly after the clearance of bacteria from the primary lesion and
duced to Europe from North America in 1493. A recent phylogenetic similarly in the transition from secondary to late syphilis. The key
study has provided support for both hypotheses by showing a close pathologic feature of syphilis, observable at all stages, is an oblitera-
similarity between sexually transmitted strains of T. pallidum world- tive endarteritis and periarteritis. Depending on the location, the
wide and two strains obtained from cases of yaws in Guyana [1]. The endarteritis can engender the formation of ulcers, gummata, aneu-
findings of this study suggest the Old World treponematoses represent rysms, and lesions of the nervous system.
the earliest of the treponematoses, and that venereal syphilis evolved
from American strains of yaws before being exported back to Europe Syphilis is usually initiated when a susceptible individual is exposed
(Fig. 53.1). In affluent countries, syphilis is predominantly found to the spirochetes of a sexual partner. After 9–90 days of incubation,
among men who have sex with men and migrants from the tropics. primary lesions develop—most commonly genital—but lesions of
In the tropics, it remains highly endemic in many countries, contrib- the mouth, breast, and anus are also well known. A clean, indurated,
uting significantly to fetal and neonatal morbidity and mortality, and painless ulcer (termed the primary chancre), accompanied by local
challenging physicians with a notoriously diverse array of clinical adenopathy constitutes the primary stage of infection. Cerebrospinal
presentations in adults. fluid (CSF) studies at this stage show the presence of spirochetes in
494
Sy p h i l i s a n d t h e E n d e m i c Tre p onematoses 495
T. pallidum subsp.
endemicum
GGTG
1
unknown
GGTA
1
2
1
New World pallidum
subsp. pertenue
Endemic syphilis
Yaws
n = number of nucleotide substitutions
FIGURE 53.1 A network path for four informative substitutions shows that New World subsp. pertenue, or yaws-causing strains, are the closest relatives of
modern subsp. pallidum strains. The geographical distribution of the endemic treponemal diseases c.1900 is shown based on a map created by Hackett.
Each polymorphism pattern is linked to the sites where the strains that contain it were gathered. Arrows convey the directionality of change, determined
from phylogenetic trees. The four substitutions were located in two genes located on separate sides of the genome, tprI and gpd. (Reproduced with permission
from Harper KN, Ocampo PS, Steiner BM, et al. On the origin of the treponematoses: a phylogenetic approach. PLoS Negl Trop Dis 2008;2:e148.)
Sub-Saharan Africa:
Latin America and the 4,000,000
Australia and
Caribbean: 3,000,000 New Zealand: 10,000
FIGURE 53.2 Estimated new cases of syphilis among adults by region for 1999. Data from the World Health Organization.
about 25% of patients, indicating rapid, early dissemination of infec- tertiary syphilis is characterized by gumma formation affecting skin,
tion. In the absence of treatment, the primary chancre usually heals bone, or viscera. Cardiovascular syphilis shows a predilection for the
spontaneously by 6 weeks. As a new generation of spirochetes evolves, ascending aorta, resulting in aneurysm formation and aortic incom-
syphilis moves into the secondary stage, during which skin manifesta- petence. The attack of syphilis on the nervous system can take many
tions predominate, including widespread rashes, mucosal lesions, forms. The classic forms affect the spinal cord (tabes dorsalis) and
and condylomata lata. Untreated, this phase can last up to 2 years, brain (general paresis), with psychosis, seizures, and dementia as
with alternating periods of activity and latency. prominent components, and the eye (optic neuritis and Argyll-
Robertson pupils).
The final, tertiary stage of syphilis is seldom encountered nowadays.
Data from the famous Oslo natural history study suggest that late- Untreated, syphilis in pregnancy can lead to a combined fetal and
stage disease may take 10–30 years to emerge. The so-called “benign” perinatal mortality of around 40%. The risk of vertical transmission
496 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
7.0 7.0
6.0 6.0
Prevalence (%)
4.0 4.0
3.0 3.0
2.0 2.0
1.0 1.0
0.0 0.0
FIGURE 53.3 Prevalence of syphilis among pregnant BOL** COL** PER* CHI*** PAR* BRA**** ELS* HON* PAN* CUB*
women and incidence of congenital syphilis per
1000 live births (lb) in countries of South America. Prevalence of syphilis in pregnant women **** 2004
BOL, Bolivia; COL, Colombia; PER, Peru; CHI, Chile; Congenital syphilis incidence *** 2000–01
PAR, Paraguay; BRA, Brazil; ELS, El Salvador; HON, ** 2002
Honduras; PAN, Panama; CUB, Cuba. * 2003
is highest during secondary syphilis, but can linger on into late syphi-
lis. The natural history of congenital syphilis varies from a fulminating
early infection leading to rapid death, to an indolent late presenting
form, including keratitis, deafness, dental and nasal anomalies, and
arthritis.
It is important to stress that the natural history of syphilis shows much
variation from person to person. Infection may terminate at any stage,
and a significant number of persons acquire latent infection without
manifesting any outward signs. Onward progression, particularly to
late syphilis, occurs in a minority (about 30%) of untreated persons.
Since the advent of HIV, is has become apparent that immunosup-
pression can alter clinical presentation, for instance in delaying reso-
lution of chancres, overlap of primary and secondary stages, and
higher frequency and earlier presentation of neurosyphilis and
gumma formation.
PRIMARY SYPHILIS
The most characteristic lesion (Fig. 53.4) is a painless, solitary, genital
ulcer of up to 3 centimeters in diameter with an indurated base
accompanied by non-tender rubbery inguinal adenopathy. The classic
locations are the distal penis or vulva, but lesions of the mouth, lips,
fingers, anus, and cervix also occur. Occasionally, more than one
primary lesion is seen (notably in the presence of HIV) [3]. Extrageni-
tal chancres are more likely to be painful.
recommended in order to determine whether an intensive neurosyph- sometimes used to ameliorate the reaction in patients with advanced
ilis treatment regimen is indicated. Patients diagnosed as having late, pregnancy and those with eye or aortic involvement; however, steroid
latent syphilis are advised to have electrocardiography (ECG) and use in the first trimester carries risks of teratogenicity. Benzathine
chest x-ray performed to exclude evidence of syphilitic aortitis, which penicillin is a painful injection and some clinicians co-administer the
carries potential hazards during treatment. It is recommended that all dose with 8 ml of 1% lidocaine. In patients with penicillin allergy,
patients diagnosed with syphilis are also screened for co-infection desensitization according to careful protocols is the preferred option
with gonorrhea, chlamydia, and HIV. in some centers. Doxycycline is the most favored alternative except
for in pregnant women. Pregnant women with an allergy to penicillin
A definitive diagnosis of congenital syphilis requires demonstration can be desensitized to penicillin or receive treatment with erythromy-
of spirochetes within lesions or a positive test for treponemal IgM cin. There is now considerable treatment experience with erythromy-
antibodies. Treponemal IgG antibodies may come from the mother cin and azithromycin, but an important point mutation that causes
and can only be considered significant if the titer is four or more times full resistance to these drugs has recently emerged on such a signifi-
higher than in the mother. Infants testing positive should undergo cant scale that these drugs can no longer be recommended as a first-
further assessment, including CSF studies and x-rays of the long line treatment [5]. Patients with late syphilis are given more extended
bones. To minimize the risk of congenital syphilis, repeat testing or forms of treatment as spirochetes are believed to replicate more
presumptive treatment should be considered. slowly. Some experts argue in favor of adopting a similar approach
for any patients co-infected with HIV. For further details of recom-
DIFFERENTIAL DIAGNOSIS mended treatments see Tables 53-2 and 53-3. Post-treatment sero-
Primary syphilis needs to be distinguished from the other ulcerative logic follow-up should start at one month and continue until reagin
STIs, namely herpes, chancroid, donovanosis, and lymphogranuloma titers have reverted to a negative or stable, low level. CSF examination
venereum. Pointers to diagnosis are summarized in Table 53-1. is advised in patients failing to respond to treatment.
TABLE 53-3 Treatment of Congenital Syphilis and Infants Born to Mothers with Syphilis
Africa, Indonesia, Papua New Guinea, and Timor L’Este, with smaller before the primary lesion has resolved, or up to 2 years later. They
foci in Central and South America. consist of papules and papillomas that exude highly infectious serum,
a variety of squamous macular lesions and hyperkeratotic lesions on
the palms and soles. The clinical appearance varies by season, with
CLINICAL FEATURES lesions being less profuse during the dry season and more likely to
be restricted to moist areas such as the axillae or perineum. Early bone
Clinical features of endemic treponematoses can be divided into
lesions, such as painful osteo-periostitis affecting the arms, legs, or
primary, secondary, and tertiary stages, as with venereal syphilis, but
fingers may occur at this stage. Secondary lesions resolve spontane-
congenital infection rarely, if ever, occurs.
ously over a period of weeks or months, but relapses may occur.
Tertiary lesions (gummas) appear in about 10% of cases after a period
Yaws of latency, involving the skin, subcutaneous tissues (e.g. palmoplantar
The primary lesion starts as a papule at the site of inoculation, usually hyperkeratosis), bones, and joints. Involvement of the facial bones
on the foot, leg, or buttocks. This enlarges to form a papilloma, which may lead to swelling and destruction of the nose and palate, and
is typically painless, may ulcerate and persists for 3–6 months; there chronic osteitis of the tibia may lead to characteristic curvature (sabre
may be regional lymphadenopathy. Secondary lesions may appear tibia). De-pigmentation of the skin, especially affecting the hands, is
500 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
INFECTIONS CAUSING
NEUROLOGIC MANISFESTATIONS
54 Acute Bacterial Meningitis
Rathi Guhadasan, Enitan D Carrol
Senegal
Mauritania Eritrea
Mali
Niger
Gambia Chad
Sudan
Guinea-Bissau
Ethiopia
Guinea
Burkina Faso
Cote d'Ivoire Northern Kenya
Democratic
Ghana Nigeria
Republic
Southern of Congo
Togo Nigeria
Benin Cameroon Uganda
Meningitis belt
Central African
Republic
13%
5%
40% Pneumococcus
Hib
11% Meningococcus
Salmonella spp.
Negative cultures
28%
22%
S. pneumoniae
N. meningitidis
Other Gram negatives
2% S. aureus
2%
FIGURE 54.2 The proportion of acute bacterial meningitis Alph-Haemolytic strep.
attributed to each pathogen in children and adults in Malawi 4% Cryptococcus
Reproduced with permission from Lin AL, Safdieh JE. The evaluation 1% TB
1% 59%
and management of bacterial meningitis: Current practice and Not meningitis
emerging developments. Neurologist 2010;16:143–51. (A) Cause of 5%
Probable bacterial meningitis
childhood bacterial meningitis 2002. (B) Causes of meningitis 4%
in adults in Malawi, 2007.
protein A (CbpA) [4]. Young children mount inadequate immune avoiding host defence mechanisms, particularly complement-
responses to bacterial capsular polysaccharides, rendering them par- dependent killing. Neisseria meningitidis and S. pneumoniae both
ticularly vulnerable to these infections [5]. Bacteria invade the mucosal recruit complement factor H, the main regulator of the alternative
epithelium via a number of processes that include transcytosis, complement pathway that controls early activation of the comple-
through phagocytes in a “Trojan horse” manner, or directly following ment cascade. Neisseria meningitidis produces Factor H binding protein
damage to the integrity of the mucosa, such as occurs with a viral and the S. pneumoniae proteins CbpA and pneumococcal surface
infection. Survival within the bloodstream depends on the bacteria protein C (PspC) bind complement factor H.
504 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
1 2
Mucosa
3
Bloodstream
4 5
Blood
brain
barrier
7 6
CSF
Autolysis
IL-1b
TNF-α FIGURE 54.4 Opisthotonus in a Malawian child with bacterial meningitis.
8 9 MMP
IL-6
NO
Bacterial
products A rash may be present in 10–15% of cases of acute bacterial
meningitis—most commonly this is the purpuric rash of meningo-
FIGURE 54.3 Pathogenesis of bacterial meningitis. 1. Adherence and coccal meningitis with septicemia, but a purpuric rash may also be
colonization of mucosa; 2. Invasion of blood stream; 3. Multiplication in caused by other pathogens. Shock and disseminated intravascular
bloodstream; 4. Increased permeability of blood brain barrier and bacteria coagulation occur in meningococcemia. Cushing’s triad of systemic
cross blood-brain barrier; 5. Infiltration of CSF by white cells; 6. Release of hypertension, bradycardia and respiratory depression occurs late and
pro- inflammatory cytokines; 7. Uncontrolled replication of bacteria in indicates raised intracranial pressure and shift of brain compartments
sanctuary site, CSF; 8. Bacterial products stimulate inflammatory cascade; [8]. HIV-positive children with acute bacterial meningitis are more
9. Activated leukocytes lead to production of matrix metalloproteinase likely to present in extremis and have pneumococcal meningitis, sei-
(MMP) and oxidants. zures or a focus of infection, such as otitis media. They take longer to
defervesce and are more likely to die or experience recurrence.
Patients should be monitored closely for dehydration, shock, seizures,
altered conscious level or rising intracranial pressure. Cerebrovascular
Bacterial translocation of the blood brain barrier is a result of specific
events, such as infarction and/or edema, obstructive or communicat-
bacteria-host interactions involving cell signal transduction pathways
ing hydrocephalus, epidural abscess and subdural empyema are
with effects on actin cytoskeleton rearrangements [6]. Bacteria cross
uncommon complications. Immune complex-mediated arthritis
the blood brain barrier by a number of processes that include: (i)
occurs late in Hib or meningococcal illness. Neurologic sequelae, such
disruption of the tight junctions; (ii) transcellular migration by tran-
as deafness, cognitive impairment and developmental delay, occur in
scytosis; and, (iii) surviving within phagocytes using a “Trojan horse”
5–40% of survivors [8].
mechanism.
Once within the CSF, bacteria enter a sanctuary site with relatively low
concentrations of complement and antibody. Bacteria and bacterial PATIENT EVALUATION, DIAGNOSIS,
products (resulting from autolysis) stimulate an inflammatory AND DIFFERENTIAL DIAGNOSIS
response of pro-and anti-inflammatory cytokines. In turn, the pro-
inflammatory cells stimulate the release of chemokines. Neuronal cell PATIENT EVALUATION
death occurs mainly in the hippocampus, through apoptosis, and in Initial evaluation should include a thorough history to elicit informa-
the cortex, through necrosis. White matter injury also occurs, second- tion on duration of illness, history of seizures, anti-retroviral or anti-
ary to small-vessel vasculitis, focal ischemia or venous thrombosis. tuberculous treatment, HIV status and previous antibiotics or
The process is summarized in Figure 54.3. anti-malarials. Examination should include assessment of nutritional
status, presence of a rash, examination of the fontanelle and eliciting
CLINICAL FEATURES neck stiffness. In the tropics, features of acute bacterial meningitis
often overlap with those of severe malaria or cerebral malaria, leading
In infants and young children, clinical features are very non-specific to difficulties in the early recognition of acute bacterial meningitis in
and include fever, lethargy, irritability, poor feeding, seizures, respira- children. Several predictor algorithms to assist in establishing the
tory distress, vomiting and diarrhea, and a bulging fontanelle [7, 8], diagnosis of acute bacterial meningitis have been derived, most of
while older children and adults have headache (80–95%), photopho- which include laboratory data. Only two of these have been evaluated
bia (30–50%), neck stiffness (50–90%), lethargy, confusion, and in resource-poor settings. In children, Berkley et al. reported that the
positive Kernig’s sign (resistance to knee extension upon passive hip presence of one or more of the following is an indication for lumbar
flexion; 5%) and Brudzinski’s sign (hip flexion upon passive neck puncture [10]: bulging fontanelle, neck stiffness, cyanosis, impaired
flexion; 5%) [1, 8]. Adults with acute bacterial meningitis usually consciousness, partial seizures and seizures outside the febrile convul-
present with features of fever, neck stiffness and altered mental status. sions age range. Thwaites et al. described a weighted diagnostic score
However, it has recently been proposed that this triad should now to distinguish acute bacterial meningitis from tuberculous meningitis
become a quartet to include fever, neck stiffness, headache and altered in adults, which included age, white blood cell count, duration of
mental status, which are present in 95% of adults with acute bacterial history of illness, CSF white cell count and CSF percentage neu-
meningitis [9]. More advanced disease may include opisthotonus, trophils [11]. In areas with a high incidence of HIV infection, S.
focal neurologic deficit (20–30%), seizures (15–30%) and a reduced pneumoniae is the commonest cause of acute bacterial meningitis;
level of consciousness (Fig. 54.4). however, tuberculous meningitis and cryptococcal meningitis are also
Ac u te B a c te r i a l M eningitis 505
TABLE 54-1 WHO Recommended Empirical Antibiotic Treatment in Non-epidemic Situations in Resource-poor Settings
without Laboratory Support
Source from World Health Organization. Standardised treatment of bacterial meningitis in Africa in epidemic and non-epidemic situations; 2007. Available at: http://www.who.
int/csr/resources/publications/meningitis/WHO_CDS_EPR_2007_3/en/index.html.
506 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
High rates of Hib and pneumococcal chloramphenicol resistance high-income countries, and of Hib and pneumococcal meningitis in
occur in Africa (10–13%) and Southeast Asia [3, 16]. Pneumococcal the African countries where these have been introduced [1]. Conju-
resistance to cephalosporins is a growing global concern; as many as gate vaccines are the most effective form of immunization for those
41% of isolates worldwide (5% in Africa) demonstrate cephalosporin under two years of age who are particularly vulnerable to bacterial
and penicillin resistance [1, 3, 17], necessitating the addition of van- meningitis. High-income countries have reported an increase in inva-
comycin or rifampin [16]. sive pneumococcal disease from non-vaccine serotypes with the intro-
duction of conjugate vaccines. Therefore, enhanced surveillance will
In non-resource-limited settings, ampicillin should also be adminis- be necessary for resource-poor countries when pneumococcal conju-
tered to individuals at risk of listeriosis; neonates in non-resource- gate vaccines are introduced. Single (Group A) and quadrivalent cap-
limited settings are usually treated with ampicillin and gentamycin, sular polysaccharide meningococcal vaccines have been used in the
cetriaxone or cefotaxime. African meningitis belt; a conjugate meningococcus group A vaccine
Epidemics are usually caused by meningococci; empiric treatment (MenAfriVacTM) has been rolled out in several African countries in the
usually involves ceftriaxone in any age group and irrelevant of pre- meningitis belt (www.meningvax.org) [1, 7].
gancy status, or oily chloramphenical in children over 2 years of age
and non-pregnant adults [3]. REFERENCES
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pneumococcal meningitis. Lancet Infect Dis 2002;2:721–36.
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[15]. A Cochrane review of three trials comparing unrestricted and 17. Deghmane AE, Alonso JM, Taha MK. Emerging drugs for acute bacterial
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Conjugate vaccines have substantially reduced the incidence of 23. Peltola H, Roine I, Fernandez J, et al. Adjuvant glycerol and/or dexamethasone
Hib, pneumococcus and Group C meningococcus meningitis in to improve the outcomes of childhood bacterial meningitis: a prospective,
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25. Ajdukiewicz KM, Cartwright KE, Scarborough M, et al. Glycerol adjuvant
therapy in adults with bacterial meningitis in a high HIV seroprevalence
55 Tetanus
Guy E Thwaites, C Louise Thwaites
groups include injection drug users and those aged over 60 years of
age with decreased antibody concentrations [1].
Key features
Vaccination against tetanus is highly effective. The vaccine consists
l Tetanus is a neurologic syndrome characterized by acute of an inactivated tetanus toxin, or toxoid, which induces antibody-
mediated protective immunity against the toxin. The WHO guidelines
skeletal muscle spasm and autonomic nervous system
for tetanus vaccination recommend a primary course of three vaccina-
disturbance, caused by a neurotoxin released from tions in infancy, then boosters at 4–7 and 12–15 years, and one in
Clostridium tetani, a ubiquitous environmental bacterium adult life. Centers for Disease Control and Prevention (CDC) recom-
that can contaminate wounds mendations in the USA suggest an additional dose at 14–16 months
l Tetanus can be completely prevented by vaccination, yet and boosters every 10 years. ‘Catch-up’ schedules recommend a three-
more than 100,000 people develop tetanus each year, dose primary course for non-immunized adolescents followed by
two further doses. For those with a complete childhood primary
primarily in regions with inadequate vaccination programs
course but no further boosters, two doses at least 4 weeks apart are
l Tetanus is a clinical diagnosis. The cardinal clinical features recommended.
are muscle spasms, airway obstruction, and (in severe cases)
Standard WHO recommendations for the prevention of maternal and
autonomic dysfunction
neonatal tetanus are of two doses of tetanus toxoid at least 4 weeks
l At diagnosis, the management priorities are to secure the apart. However, in high-risk areas success has been achieved with a
airway, administer antitoxin immune globulins and debride more intensive approach aiming to provide all women of childbear-
potentially infected wounds ing age with a primary course of vaccination plus additional educa-
l Spasms can be controlled with high-dose benzodiazepines; tion on safe delivery and postnatal practices [2].
magnesium sulfate infusions may help control spasms and Individuals sustaining tetanus-prone wounds should also be immu-
autonomic dysfunction nized if they have incomplete or unknown vaccination status, or if a
l Disease does not confer immunity: vaccinate all survivors booster was given >10 years previously. In the USA, the CDC also
recommends that unvaccinated individuals sustaining high risk, dirty
wounds should also receive passive immunization with tetanus
immune globulin (human; TIG).
CLINICAL FEATURES
Tetanus can produce a spectrum of clinical features depending on the
site of infection and the amount of toxin produced. In its mildest
form, isolated areas of the body are affected and only local muscle
spasm may be apparent. In such cases, outcome is usually good, with
the important exception of cephalic tetanus. In this condition, the
cranial nerves are involved and phargyngeal or laryngeal muscles may
spasm, leading to sudden aspiration or airway obstruction. These
patients require careful observation.
Generalized muscle spasm is the most typical feature of tetanus. The
muscles of the face and jaw are often affected first, producing the
characteristic “risus sardonicus” and trismus (lockjaw) [3]. Many
patients also experience difficulty swallowing, back pain, and general-
ized muscle pain and stiffness. Neonates typically present with diffi-
culty in feeding. As the disease progresses, generalized muscle spasms
develop, which can be very painful. Commonly, the laryngeal muscles FIGURE 55.1 Opisthotonus in neonatal tetanus.
are involved early, which can be life-threatening as it may lead to
sudden and complete airway obstruction. Spasm of the respiratory
muscles results in respiratory failure and, without mechanical ventila-
tion, is the commonest cause of death. Spasms strong enough to
TREATMENT
produce tendon avulsions and crush fractures have been reported, but Once the tetanus toxin has reached the inhibitory interneurons in the
are rare. CNS and symptoms have begun, there is limited opportunity to affect
disease progression. Wound debridement may stop the production of
Autonomic disturbance is maximal during the second week of the
further toxin and neutralizing immunoglobulins (antitoxin) may
illness and can be fatal. Blood pressure, heart rate and temperature
limit disease severity but, in general, management strategies aim to
can fluctuate wildly, and can be associated with gastrointestinal stasis,
support vital functions until the effects of the toxin have worn off.
sweating and increased secretions.
It is important to establish a secure airway early in severe tetanus;
Rapid development of tetanus is associated with more severe disease
hyperactivity and spasm of laryngeal muscles can make endotracheal
and poor outcome. The incubation period (time from wound to first
intubation difficult once the disease has progressed and many advo-
symptom) and period of onset (time from first symptom to the first
cate early tracheostomy. In addition, patients should be cared for in
generalized spasm) are of particular significance, with shorter times
a quiet environment, as light and noise can trigger spasms.
associated with worse outcome. Likewise, in neonatal tetanus, the
younger the infant when symptoms occur, the worse the prognosis If possible, the entry wound should be identified, cleaned and debri-
(Fig. 55.1). ded of any necrotic material in order to remove any anaerobic focus
of infection and prevent further tetanus toxin production. Failure to
PATIENT EVALUATION, DIAGNOSIS identify or remove the focus can be associated with prolonged or
recurrent tetanus. Antibiotics may be helpful; metronidazole (400 mg
AND DIFFERENTIAL DIAGNOSIS rectally, or 500 mg intravenously every 6 hours for 7 days) is preferred,
despite a lack of comparative studies with other antibiotics [6]. Ben-
The diagnosis of tetanus depends upon typical clinical features rather zylpenicillin is an alternative, although there are theoretical concerns
than the results of laboratory tests. Therefore, disease definitions exist that penicillins may exacerbate spasms.
to assist diagnosis and to enable comparative clinical and epidemio-
logic surveys. Tetanus is defined by “the acute onset of hypertonia, or Antitoxin should be given early in an attempt to neutralize any circu-
by painful muscular contractions (usually of the muscles of the jaw lating tetanus toxin and prevent its uptake into the nervous system.
and neck) and generalized muscle spasms without other apparent Antitoxin can be given by intramuscular or intrathecal injection. A
medical cause” [5]. Neonatal tetanus is defined by the WHO as “an recent meta-analysis of controlled trials suggested a single 50–1500 IU
illness occurring in a child who has the normal ability to suck and intrathecal dose of human antitoxin was associated with reduced
cry in the first 2 days of life but who loses this ability between days disease progression and improved outcomes in neonates and adults
3 and 28 days of life and becomes rigid and has spasms” [2]. Maternal compared with the intramuscular route [7]. There are two antitoxin
tetanus is defined as occurring during pregnancy or within 6 weeks preparations available – human tetanus immune globulin and equine
of the end of pregnancy (whether pregnancy ended with birth, miscar- antitoxin. Human tetanus immune globulin is preferred because it is
riage, or abortion) [2]. less likely to be associated with anaphylactic reactions. Standard intra-
muscular therapy is 3000–6000 IU as a single dose (or 10,000–
Few conditions mimic generalized tetanus, but strychnine poisoning 20,000 U/kg equine preparation).
and dystonic reactions to antidopaminergic drugs (e.g. metaclopra-
mide) can produce similar clinical features. Continuous abdominal The best way to control the severe muscle spasms of tetanus has not
muscle rigidity is characteristic of tetanus, whereas it is episodic in been defined by controlled trials. Most authorities, however, use high-
the other two conditions. Cephalic tetanus can be confused with dose benzodiazepines (up to 100 mg/hour diazepam has been
other causes of trismus, such as oropharyngeal infection. Hypocal- reported) in combination with other drugs, such as chlorpromazine
cemia or meningoencephalitis can be confused with tetanus in or phenobarbitone [8]. More recently, intravenous magnesium sulfate
neonates. has been used as a muscle relaxant [9].
510 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
The problem with all these treatments is that the doses necessary to
control spasms also cause respiratory depression, thus controlling
REFERENCES
spasms, while maintaining adequate ventilation is a particular issue 1. McQuillan GM, Kruszon-Moran D, Deforest A, et al. Serologic immunity to
in settings without facilities for mechanical ventilation. Respiratory diphtheria and tetanus in the United States. Ann Intern Med 2002;136:
failure is a common cause of death in these circumstances. If mechan- 660–6.
ical ventilation is available, severe spasms are best dealt with using a 2. Roper MH, Vandelaer JH, Gasse FL. Maternal and neonatal tetanus. Lancet
combination of benzodiazepines, magnesium, and relatively short- 2007;370:1947–59.
acting, cardiovascularly inert, nondepolarizing neuromuscular block- 3. Thwaites CL, Yen LM, Nga NTN, et al. Impact of improved vaccination
ing agents, as they allow titration against spasm intensity. Infusions programme and intensive care facilities on incidence and outcome of tetanus
in southern Vietnam, 1993–2002. Trans R Soc Trop Med Hyg 2004;98:
of propofol have also been used successfully to control spasms and
671–7.
provide sedation.
4. Caleo M, Schiavo G. Central effects of tetanus and botulinum neurotoxins.
The autonomic disturbance of severe tetanus is notoriously difficult Toxicon 2009;54:593–9.
to treat. A recent, double-blind, placebo-controlled trial of intrave- 5. Bardenheier B, Prevots DR, Khetsuriani N, Wharton M. Tetanus surveillance
nous magnesium sulfate (plasma concentrations 2–4 mmol/l) for – United States, 1995–1997. Mor Mortal Wkly Rep CDC Surveill Summ
severe tetanus found treatment with magnesium was associated with 1998;47:1–13.
reduced requirements for benzodiazepines, nondepolarizing muscle 6. Farrar JJ, Yen LM, Cook TF, et al. Tetanus. J Neurol Neurosurg Psychiatry
2000;69:292–301.
relaxants (pipecuronium), and verapamil (used for the control of
7. Kabura L, Ilibagiz D, Menten J, Van den Ende J. Intrathecal vs. intramuscular
tachycardia) [10]. In addition to magnesium, morphine and drugs
administration of human antitetanus immunoglobulin or equine tetanus
acting specifically on the cardiovascular system (e.g. esmolol, calcium antitoxin in the treatment of tetanus: a meta-analysis. Trop Med Int Health
antagonists, and inotropes) may be required. 2006;11:1075–81.
Complications arising from the treatment of tetanus are common. 8. Okoromah CNLF. Diazepam for treating tetanus (Cochrane Review). The
Ventilator-associated pneumonia, central venous catheter infections, Cochrane Library. Chichester: John Wiley & Sons; 2004.
and septicemia are particularly important. In some centers, prophy- 9. Attygalle D, Rodrigo N. Magnesium as first line therapy in the management
of tetanus: a prospective study of 40 patients. Anaesthesia 2002;57:
laxis against deep vein thrombosis and thromboembolism is routine.
811–17.
Recovery from tetanus may take 4–6 weeks with prolonged immobil- 10. Thwaites CL, Yen LM, Loan HT, et al. Magnesium sulphate for treatment of
ity secondary to muscle stiffness. In addition, patients must be given severe tetanus: a randomised controlled trial. Lancet 2006;368:1436–43.
a full primary course of immunization, as tetanus toxin is poorly
immunogenic and does not provoke a protective immune response.
Botulism 56
Stephen J Aston, Nicholas J Beeching
uncooked food products as heating food to >85°C for more than five
minutes inactivates toxin. Although botulinum spores may poten-
Key features tially contaminate many foodstuffs, germination and toxin produc-
tion only occur when spores are incubated in an anaerobic, low-salt
● Botulism is a rare paralytic illness caused by potent milieu at greater than 4°C. The processes of canning and fermenta-
neurotoxins produced by Clostridium botulinum tion of foods are particularly conducive to producing such conditions.
● Botulism typically presents with bilateral cranial nerve Effective methods of inactivating spores introduced in the early 20th
palsies followed by symmetrical descending flaccid paralysis century mean that outbreaks of food-borne botulism attributable to
commercially canned foods are now rare. However, home-canned
and occasional progression to respiratory muscle weakness. foods continue to be a major source of intoxication, especially in
The four “Ds” are the key clues—dysphonia, dysphagia, Eastern Europe and the southern USA [5]. There is an exceptionally
dysarthria and descending paralysis high incidence of food-borne botulism in Alaska attributable to the
● Clostridial spores are ubiquitous in the environment and widespread consumption of fermented aquatic mammal meat [6].
botulism is presumed to occur worldwide, but under-
reporting is significant Wound Botulism
● Several naturally occurring forms are recognized: food- Wound botulism follows the absorption of toxin produced by organ-
isms contaminating a wound site, so clinical incubation periods are
borne botulism, wound botulism, infant botulism and adult
longer than for botulism caused by food which contains preformed
intestinal toxemia botulism toxin. Cases have increased in developed countries in recent years,
● Food-borne disease remains a significant problem in driven by an epidemic among injecting drug-users and strongly asso-
countries where home-preservation of food is popular ciated with the practice of injecting into the subcutaneous tissues or
● Wound botulism has increased in recent years as a result of muscle, known as “skin-” or “muscle-popping”. The majority of cases
occur in the USA [7]. Sporadic cases of botulism associated with
an epidemic among injecting drug users
contaminated compound fractures are occasionally reported.
Infant Botulism
INTRODUCTION Infant botulism is caused by the endogenous production of toxin by
Botulism is a rare, naturally-occurring paralytic illness caused by C. botulinum that has colonized the infant gastrointestinal tract fol-
potent neurotoxins produced by Clostridium botulinum and, rarely, lowing the germination of ingested spores [8]. In 2008, 83 cases, rep-
other Clostridium species. It manifests as a characteristic syndrome of resenting 70% of total botulism cases, were reported in the USA.
symmetrical cranial nerve palsies followed, to a varying extent, by Ingestion of honey, which is often contaminated by C. botulinum
symmetrical descending paralysis of voluntary muscle that can spores, was implicated in the majority of early cases. More recently,
progress to respiratory compromise and death. Botulinum spores are concerns have been raised over the potential for contamination of
ubiquitous in the natural environment and cases occur worldwide, commercial powdered infant formula and corn-syrup. A few cases of a
although they are probably greatly under-reported. similar syndrome have been described in adults and has been termed
“adult intestinal toxemia botulism”, and is associated with gastrointesti-
The first complete clinical description of botulism was published by nal surgery, inflammatory bowel disease and/or antimicrobial use.
Kerner in 1822 who termed the disease “sausage poisoning”, having
observed outbreaks associated with the consumption of spoiled meat. Iatrogenic botulism following the direct inoculation of concentrated
The early 20th century saw a massive rise in cases of botulism owing botulinum toxin preparations for cosmetic purposes has been
to the increasing popularity of food canning. Following the elucida- reported. Intoxication following absorption of toxin across the respi-
tion of its mechanism of action in the mid-20th century, the potential ratory mucosa, termed inhalational botulism, has also been rarely
therapeutic use of botulinum toxin has been exploited [1–3]. reported.
(GBS), myasthenia gravis, stroke syndromes, Eaton-Lambert syn- monitored carefully during administration and medication for the
drome and tick paralysis. Table 56-1 includes other differential diag- management of acute allergic reactions should be readily available.
noses with important distinguishing features. Some national guidelines recommend repeat treatment within 24
hours if the patient continues to deteriorate.
GBS typically presents as an ascending paralysis and there is often a
history of antecedent infection. Distinguishing botulism from the All patients with botulism should be managed in a high-dependency
triad of ophthalmoplegia, ataxia and areflexia that characterize the setting to facilitate close monitoring. Ventilatory support should be
Miller Fisher variant, is often more difficult. However, in contrast to promptly instituted upon development of respiratory compromisa-
botulism, areflexia typically precedes the onset of significant muscle tion, indicated by diminishing vital capacity; up to 50% of patients
weakness in GBS. Fatiguable muscle weakness is the hallmark of with food-borne botulism require ventilatory support. Meticulous
myasthenia gravis. A marked improvement with administration of attention should be paid to the prevention and early treatment of
edrophonium is highly suggestive of myasthenia gravis, although nosocomial infection and to the maintenance of adequate nutritional
about 25% of patients with botulism show some response. Patients status. Attendants should remember that, unlike many patients on
with Eaton-Lambert syndrome usually have clinically apparent lung ventilatory support, patients with botulism are fully awake and have
cancer, although electromyographic findings are indistinguishable no sensory deficits, unless they have specifically received sedation.
from botulism. The asymmetrical weakness and upper motor neurone
signs caused by most stroke syndromes should be readily distinguish- In wound botulism, appropriate management of the wound is also
able from botulism on clinical examination. Tick paralysis causes essential in order to prevent relapse caused by ongoing toxin produc-
paresthesiae and ascending paralysis; the diagnosis is particularly tion by persisting vegetative organisms after antitoxin has been cleared
apparent if the tick is still attached. from the body. All wounds should be surgically debrided and treated
with antibiotics until completely healed. Relevant wounds may
Cerebrospinal fluid analysis may be useful; protein levels are normal appear trivial or innocuous, and the presence of deep-seated abscesses
in botulism compared with GBS, where they are typically raised, should be always considered.
although this may not be apparent until several days after symptom
onset. Electromyography (EMG) may also be helpful. In particular, Upon suspicion of a diagnosis of botulism, the local public health
repetitive stimulation at high frequencies shows facilitation of muscle authorities should be contacted immediately. Investigations should
action potentials in botulism that is not evident in either GBS or be undertaken to rapidly identify other possible cases and suspected
myasthenia gravis. EMG is best performed and interpreted by an expe- food exposures, as rapid control measures such as impounding
rienced operator, as results may vary between muscle groups. To avoid home-canned foods or emergency products recalls may need to be
false-negative results, it is essential that clinically affected muscle instigated.
groups are tested. Brain imaging by computed tomography (CT) or
magnetic resonance imaging (MRI) should be used to uncover the rare PEDIATRIC CONSIDERATIONS
brain stem stroke syndromes that produce symmetrical bulbar palsies. CLINICAL FEATURES
Definitive laboratory confirmation of botulism requires the demon- Constipation is usually the first manifestation of infant botulism.
stration of toxin in specimens of patient serum, gastric secretions or Over 1–2 weeks, neurologic features develop leading to presentations
stool or, in the case of food-borne botulism, a food sample. The with a weakened cry, diminished feeding and an increasingly “floppy”
standard method for the demonstration of botulinum toxin is the infant as descending paresis occurs. Examination reveals hypotonia,
mouse lethality bioassay in which mice are observed for the presence loss of facial expression, extraocular muscle weakness and dilated
of botulism-specific symptoms following intraperitoneal injection of pupils. The extent and severity of clinical features is highly variable,
extracts of clinical specimens. It is performed in only a limited number ranging from mild hypotonia to severe flaccid paralysis. Up to 70%
of laboratories and there is a significant false-positivity rate. Moreover, of patients require intubation and ventilation, although mortality
it cannot be used as a basis for clinical management decisions as rates are <1%.
results may not be available for up to four days. Several rapid in vitro
assays are currently in development, but none are yet widely standard- TREATMENT
ized as adequate replacements for mouse bioassays to confirm botu-
lism diagnosis. Historically, equine-derived antitoxin has not been used to treat infant
botulism because of concerns regarding serious hypersensitivity reac-
tions and an inadequate duration of therapeutic effect. A human-
TREATMENT derived antitoxin product, known as BabyBIG, has been recently
developed. A randomized, controlled trial demonstrated that when
The core principles of botulism management are the early administra- administered early in the disease course it significantly reduces the
tion of antitoxin and the prompt recognition of respiratory compro- duration of mechanical ventilation and length of hospital stay [3].
misation, allowing the timely implementation of ventilatory support.
Having been as high as 70%, the current mortality rate from botulism REFERENCES
is less than 5% where adequate intensive care is available.
1. Sobel J. Botulism. Clin Infect Dis 2005;41:1167–73.
Most antitoxin preparations contain combinations of equine-derived 2. Centers for Disease Control and Prevention: Botulism in the United States,
antibodies directed against specific botulinum toxin serotypes [9]. 1899–1996. Handbook for Epidemiologists, Clinicians, and Laboratory
The only preparation for which there is prospective comparative trial- Workers. Atlanta: Centers for Disease Control and Prevention; 1998.
based evidence of effectiveness is the use of human-derived botuli- 3. Chalk C, Benstead TJ, Keezer M. Medical treatment for botulism. Cochrane
num immune globulin for the treatment of infant botulism [3]. Database Syst Rev 2011;3:CD008123.
Systemic administration of antitoxin neutralizes botulinum toxin that 4. Reller ME, Douce RW, Maslanka SE, et al. Wound botulism acquired in the
is not yet bound to nerve terminals and thus arrests further disease Amazonian rain forest of Ecuador. Am J Trop Med Hyg 2006;74:628–31.
progression. In retrospective series of food-borne botulism, its early 5. Sobel J, Tucker N, Sulka A, et al. Food-borne botulism in the United States,
use is associated with a reduction in mortality and shortening of the 1990–2000. Emerg Infect Dis 2004;10:1606–11.
duration of respiratory failure requiring ventilatory support. Hyper- 6. Fagan RP, McLaughlin JB, Castrodale LJ, et al. Endemic foodborne botulism
sensitivity reactions, including anaphylaxis, have previously been a among Alaska Native persons—Alaska, 1947–2007. Clin Infect Dis 2011;
significant concern, although using currently recommended dosing 52:585–92.
7. Werner SB, Passaro D, McGee J, et al. Wound botulism in California, 1951–
schedules serious reactions are seen in <1% patients.
1998: Recent epidemic in heroin injectors. Clin Infect Dis 2000;31:1018.
The use of antitoxin is indicated on the basis of clinical suspicion 8. Brook I. Infant botulism. J Perinatol 2007;27:175–80.
of botulism and treatment should not be delayed while waiting 9. Tacket CO, Shandera WX, Mann JM, et al. Equine antitoxin use and other
for the results of laboratory investigations. Botulinum antitoxins are factors that predict outcome in type A food-borne botulism. Am J Med
generally given by slow intravenous infusion. Vital signs should be 1984;76:794–8.
Leprosy 57
Diana NJ Lockwood, Saba Lambert
Indeterminate leprosy,
hypo-pigmented patch,
can heal or progress to
established disease:
TT BT BB
BL LL
FIGURE 57.3 Young patient with extensive leprosy patches (BT) that
are hypo-pigmented, dry, hairless and anesthetic. There are several
facial palsy, acute foot drop, or a painless burn or ulcer in an anes- lesions with a well-defined, but irregular, edge; a few satellite lesions
thetic hand or foot. Patients may also present with painful eyes as a are visible.
first indication of lepromatous leprosy. The diagnosis of leprosy
should be considered in anyone from an endemic area who presents
with typical skin lesions, neuropathic ulcers, or a peripheral neuropa-
thy (sensory loss and/or weakness). Recent advances have been made in serologic diagnostic test. Anti
bodies to the M. leprae-specific antiphenolic glycolipid (PGL-1)
are present in 90% of patients with untreated lepromatous disease,
LABORATORY TESTS but only 40–50% of patients with paucibacillary disease and 1–5 %
The presence of AFB in skin smear examination or biopsy material of healthy controls [7]. An easy to use immunohistochromatographic
examination can provide supporting evidence for the diagnosis. The assay, the ML flow test, based on PGL-1 detection, is being assessed
Bacterial Index gives a measure of bacterial density in the skin sample by a Brazilian team [8]. PCR for detection of M. leprae-encoding
under examination on a logarithmic scale ranging from 0 to 6. His- specific genes or repeat sequences is potentially highly sensitive and
topathologic evaluation is essential for accurate classification of specific, as it detects M. leprae DNA in 95% of multibacillary and
leprosy lesions and is the best diagnostic test in a well-resourced 55% of paucibacillary patients. PCR is currently not used in clinical
setting, both for confirming and excluding the diagnosis of leprosy. practice [7].
Leprosy 521
TT BT BB BL LL
Cell- Antibody
mediated response
immunity
M leprae in tissues
Leprosy reactions
Reversal reaction
ENL
CLASSIFICATION OF LEPROSY
Leprosy may be considered an immunologic disease. Immunity FIGURE 57.5 A 25-year-old man with lepromatous leprosy. The skin is
defines susceptibility to leprosy, type of clinical leprosy, pathology heavily infiltrated and multiple nodules are present, giving a leonine
and major clinical complications of leprosy. Classification of the appearance. Partial madurosis and nodules on the ears are present.
disease is important to determine prognosis, patients at higher risk of
reactions and nerve damage, as well as select appropriate treatment.
Leprosy patients can be classified using two systems: the Ridley- Antibiotic chemotherapy is based on the WHO multidrug therapy
Jopling system and the WHO system. regimens (MDT) (Table 57-2).
The Ridley-Jopling system [9] (Fig. 57.4) uses clinical and histopatho- Over the past 20 years, more than 14 million people have received
logic features and the Bacterial Index. Leprosy manifests in a spectrum MDT and have been cured of M. leprae infection. Relapse rates follow-
of disease forms, ranging from the tuberculoid to the lepromatous. ing treatment with MDT vary from 0–2.5% in paucibacillary disease.
The clinical manifestations of leprosy are determined by the host’s In multi-bacillary disease, the published rates of relapse are between
response to the leprosy bacillus: tuberculoid (TT) patients have a 0 and 7.7% (www.clinical evidence.com). The study with the highest
strong cell-mediated immune response manifesting as limited clinical relapse rate in multi-bacillary patients demonstrated that 90% of
disease, granuloma formation and no detectable mycobacteria; lepro- relapses occurred in patients who had an initial Bacterial Index of >4
matous (LL) patients have no cell-mediated immunity to M. leprae [10]. Leprosy can occur in children and the doses of medication will
and have widespread disease and a high bacterial load. Between these be lower. Consultation with a specialist is recommended.
two extremes there is a range of variations in host response; these
In the USA, treatment regimens vary from the WHO-MDT (Table
comprise borderline cases (BT, borderline tuberculoid; BB, borderline
57-3). The more common side effects of the WHO MDT drugs are
borderline; BL, borderline lepromatous). Immunologically, border-
summarized in Table 57.4.
line cases are unstable and polar tuberculoid and lepromatous cases
are stable. Patients can move along the spectrum in the absence or
presence of treatment. ALTERNATIVE ANTI-MICROBIAL AGENTS
The WHO classification is a simplified version that can be used in the Minocycline 100 mg daily can be used as a substitute for Dapsone in
field when slit skin smears are not available. Patients with fewer than individuals who do not tolerate this drug. It can also be used instead
six lesions are classified as paucibacillary and those with six or more of clofazimine, although currently there is no evidence that minocy-
lesions (Fig. 57.5) are classified as multi-bacillary. This is a quick and cline protects patients against developing erythema nodosum lepro-
useful tool that can be employed by a wide variety of healthcare sum (ENL).
workers as it provides a low-cost strategy for leprosy diagnosis, Clarithromycin 500 mg daily is also effective against M. leprae, and
without the need for skilled neurologic assessment and slit skin smear can be used as a substitute for any of the other drugs in a multi-drug
examination. regimen.
CLINICAL FEATURES Ofloxacin 400 mg daily may also be used in place of clofazimine for
adults.
The cardinal signs of leprosy are anesthetic skin lesions, numbness or
weakness as a result of damage to sensory and motor nerves and
ulcers or burns in an anesthetic hand or foot. However, the clinical
REACTIONS
presentation ultimately depends on the host’s immunity to M. leprae Leprosy is complicated by immunologic phenomena called “reac-
and clinical features can be divided into the disease spectrum classi- tions”. These sudden episodes of acute inflammation are a medical
fied according to Ridley-Jopling (Table 57-1). emergency and occur in approximately 30% of leprosy patients. The
inflammation is caused by immune reactions against M. leprae anti-
TREATMENT gens. Patients can present in reaction before MDT treatment, and a
significant proportion of patients develop reactions within the first six
The management of leprosy consists of treating the M. leprae infection months of treatment. There is also an increase in the incidence of
with antibiotic chemotherapy, managing the immune-mediated reac- reactions in post-partum patients. However, reactions can also occur
tions (discussed separately), preventing nerve damage and educating after successful MDT treatment and are probably caused by the
the patient. persistence of M. leprae antigens. Patients may experience repeated
522 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
patients and health providers. Patients should be taught self- The stigma associated with the diagnosis of leprosy is still a very real
examination of the hands and feet with early medical review if signs problem and the management of someone with the disease should
of inflammation or trauma occur. Adequate footwear or other protec- include discussion of their psychosocial status and education for the
tive devices should be made available to those with insensitive or patient and their family.
deformed feet. Ulcers in anesthetic feet are the most common cause
of hospitalization. Ulcers are treated by rest and cleaning, although
any signs of osteomyelitis need to be referred for surgical debride- REFERENCES
ment. Appropriate early physiotherapy must be instituted and patients 1. Walker SL, Lockwood DN. Leprosy. Clin Dermatol 2007;25:165–72.
must be referred to the appropriate specialist for evaluation and cor- 2. World Health Organization. Leprosy Update 2011. Weekly Epidemiological
rection of deformity. Leprosy still elicits stigma in many communities Record No. 36 2011;86:389–400.
and the patient will benefit from social and psychological support. 3. Cole ST, Eiglmeier K, Parkhill J, et al. Massive gene decay in the leprosy bacil-
lus. Nature 2001; 409:1007–11.
4. Davey TF, Rees RJW. The nasal discharge in leprosy: clinical and bacteriological
Chemoprophylaxis and Immunotherapy aspects. Lepr Rev 1974;45:135–44.
To date, no specific vaccine has been developed to prevent infection 5. Brandsma JW, Yoder Land Macdonald M. Leprosy acquired by inoculation
by M. leprae, although there is good evidence that Bacillus Calmette- from a knee injury. Lepr Rev 2005;76:175–9.
6. Desikan KV, Sreevatsa. Extended studies on the viability of M. leprae outside
Guérin (BCG) has protective efficacy. A meta-analysis of 26 studies
the human body. Lepr Rev 1995;66:287–95.
demonstrated an overall protective effect between 26% and 61%. The
7. Britton WJ, Lockwood DNJ. Leprosy. Lancet 2004;363:1209–19.
age at vaccination did not predict the protective effect of BCG [15].
8. Lyon S, Lyon AC, Castorina Da Silva R, et al. A comparison of ML Flow serol-
A Bangladeshi study showed that the overall reduction in incidence ogy and slit skin test smears to assess the bacterial load in newly diagnosed
of leprosy using a single dose of rifampin in the first 2 years was 57% leprosy patients in Brazil. Leprosy Review 2008;79:162–70.
[16]. However, the difference was no longer significant in the third 9. Ridley DS, Jopling WH. Classification of leprosy according to immunity.
and fourth years. A five-group system. Int J Lepr Other Mycobact Dis 1966;34:255–73.
10. Deshpande J, Chougule SG, Thakar UH, Revankar CR. Rate of relapse and
reactions in MB leprosy patients after 24 and 12 months of MDT in Mahar-
Leprosy and HIV ashtra. Indian J Lepr 2004;76:229–30.
11. Van Brakel WH, Khawas IB. Nerve damage in leprosy: an epidemiological and
There were concerns that an interaction between HIV and M. leprae clinical study of 396 patients in west Nepal—Part 1. Definitions, methods
infection would result in an increased incidence of leprosy cases. and frequencies. Lepr Rev 1994;65:204–21.
However, studies in Uganda, Mali, Ethiopia, and South India have 12. Sandor Rao PSS, Sugamaran DST, Richard J, Smith WCS. Multi-centre, double
not shown an increased prevalence of leprosy cases associated with blind, randomized trial of three steroid regimens in the treatment of type-1
HIV infection [17–19]. reactions in leprosy. Lepr Rev 2006;77:25–33.
13. Pocaterra L, Jain S, Reddy R, et al. Clinical course of erythema nodosum
An association has been found between HIV infection and complica-
leprosum: an 11-year cohort study in Hyderabad, India. Am J Trop Med Hyg
tions of leprosy. In a case-controlled study in Uganda, HIV seroposi- 2006;74:868–79.
tivity was found to be a significant risk factor for developing reactions 14. Richardus JH, Withington SG, Anderson AM, et al. Adverse events of standard-
and neuritis; an unusual finding because reversal reactions are associ- ized regimens of corticosteroids for prophylaxis and treatment of nerve func-
ated with an increase in CD4 cells. Similarly, Sampaio et al. found tion impairment in leprosy: results from the ‘TRIPOD’ trials. Lepr Rev 2003;
that HIV-infected patients with low CD4 counts had normal granu- 74:319–27.
loma formation with numerous CD4 cells [20]. 15. Setia MS, Steinmaus C, Ho CS, et al. The role of BCG in prevention of leprosy:
a meta-analysis. Lancet Infect Dis 2006;6:162–70.
Treatment of a leprosy patient with concurrent HIV infection does not
16. Moet FJ, Pahan D, Oskam L, Richardus JH. Effectiveness of single dose
differ from that of a seronegative leprosy patient and reactions should rifampicin in preventing leprosy in close contacts of patients with newly
be managed with corticosteroids or thalidomide as appropriate. diagnosed leprosy: cluster randomised controlled trial. BMJ 2008;336:
Since the introduction of highly active anti-retroviral therapy (HAART) 761–4.
in the management of HIV, leprosy is being increasingly reported as 17. Kawuma HJS, Bwire R, Adatu-Engwau F. Leprosy and infection with the
part of the immune reconstitution inflammatory syndrome (IRIS) human immunodeficency virus in Uganda.; a case-control study. Int J Lepr
[21]. It is possible that the immune response to M. leprae in an HIV- 1994;62:521–6.
infected person is suppressed before starting HAART and that leprosy 18. Lienhardt C, Kamate B, Jamet P et al. Effect of HIV infection on leprosy: a
manifests as IRIS with the sudden reversal of this suppression and the three year survey in Bamako, Mali. Int J Lepr Other Mycobact Dis 1996;
rise of CD4 [22]. Further studies are needed to understand the clinical 64:383–91.
and pathologic features in HIV and leprosy co-infection. 19. Sekar B, Jayasheela M, Chattopadhya D, et al. Prevalence of HIV Infection and
high-risk characteristics among leprosy patients of South India; a case-control
study. Int J Lepr 1994;62:527–31.
CONCLUSION 20. Sampaio EP, Caneshi JRT, Nery JAC, et al. Cellular immune response to
Mycobacterium leprae infection in human immunodeficiency virus infected
Since the implementation of MDT in 1982 in endemic areas, more individuals. Infect Immun 1995;63:18848–54.
than 90% of registered cases have received treatment, 14 million 21. Deps PD, Lockwood DNJ. Leprosy occurring as immune reconstitution syn-
patients have been cured and global prevalence has declined. The drome. Trans R Soc Trop Med Hyg 2008;102:966–8.
continuation of surveillance and leprosy control programs are 22. Ustianowski AP, Lawn SD, Lockwood DNJ. Interactions between HIV infec-
essential. tion and leprosy: a paradox. Lancet Infect Dis 2006;6:350–60.
23. Marlowe SN, Hawksworth RA, Butlin CR, et al. Clinical outcomes in a rand-
The current treatment for leprosy reactions is still not optimal, with omized controlled study comparing azathioprine and prednisolone versus
a significant number of patients not responding to prednisolone and prednisolone alone in the treatment of severe leprosy type 1 reactions in
some ENL patients requiring chronic thalidomide therapy. Research- Nepal. Trans R Soc Trop Med Hyg 2004;98:602–9.
ers are still looking for different immunosuppressant drugs with 24. Marlowe SN, Leekassa R, Bizuneh E, et al. Response to ciclosporin treatment
efficacy in the treatment of reactions (e.g. azathioprine [23] and in Ethiopian and Nepali patients with severe leprosy Type 1 reactions. Trans
cyclosporine [24]). R Soc Trop Med Hyg 2007;101:1004–12.
Buruli Ulcer 58
Mark H Wansbrough-Jones, Richard O Phillips
l Mycobacterium ulcerans causes chronic skin ulcers, referred Buruli ulcer can affect people of all ages but, in West Africa, it pre-
dominantly affects children aged 5 to 15 years, and in Southeast
to as Buruli ulcers
Australia, it affects elderly residents in retirement towns.
l Common in parts of rural West Africa, but the mode of
transmission is unknown
l Subcutaneous necrosis is caused by secretion of
CLINICAL PRESENTATION
mycolactone toxin, a plasmid-encoded polyketide molecule Most patients with Buruli ulcer present with a chronic ulcer, often of
l Treatment includes 8 weeks of rifampin and streptomycin a few months’ duration. Patients fail to present early because the
lesions are painless and affected individuals often live in remote rural
l Early recognition and treatment including physiotherapy areas lacking easy access to affordable health care [3]. The disease
can prevent disabilities manifests as a 1–5 cm painless subcutaneous nodule attached to the
overlying skin (Fig. 58.3A). In Australia, early lesions are often
papular. More extensive indurated plaques may also occur, the
margins of which are difficult to define. Nodules, plaques, and ulcers
may be associated with edema in surrounding tissue (10–15% in
INTRODUCTION Ghana) which spreads outwards (Fig. 58.3B). Ulceration spreads
from the initial lesion into edematous areas. The patient remains well
Buruli ulcer is the accepted name for a disease caused by skin infection and there is no fever or pain unless secondary bacterial infection
with Mycobacterium ulcerans, an unusual mycobacterium that secretes occurs. Occasionally, osteomyelitis occurs in bone adjacent to a skin
a toxin that causes disease. Infections can be successfully treated with lesion, but involvement of other organs is rare.
rifampin and streptomycin. Current challenges include educating
individuals in endemic zones to recognize infection early and deliver- The distinguishing features of Buruli ulcers are that they are painless
ing treatment to affected individuals in rural tropical areas. and that the edges are undermined so that a swab can be pushed a
few millimeters (or sometimes centimeters) under the surrounding
EPIDEMIOLOGY AND TRANSMISSION skin (Fig. 58.3C). The ulcer border is not raised. Tissue destruction is
caused by cytotoxic mycolactone toxin that also prevents the develop-
Buruli ulcer is a disease of high focal prevalence mainly within coun- ment of an inflammatory response [4]. The process is chronic and
tries in West Africa (Fig. 58.1), but sporadic cases have been reported histologic examination of affected tissue often shows a mixture of scar
in many countries with high humidity in tropical wetlands. Buruli formation, featureless necrosis around clumps of proliferating acid-
ulcer has been seen among people living in more than 30 countries fast mycobacteria, and acute, chronic and granulomatous inflamma-
around the world (Fig. 58.2), including French Guiana, Peru, Mexico, tion. Organisms are rarely seen within macrophages in untreated
Papua New Guinea, Japan, and Southern China. Outbreaks are also lesions but careful immunohistologic studies have demonstrated that
observed in temperate South Eastern Australia, where the association intracellular organisms can be observed during antibiotic treatment
of M. ulcerans with Buruli (Bairnsdale) ulcer was first recognized in when the effect of mycolactone is lost [5].
1948. Disturbance of water systems by mining, deforestation or flood- In 90% of cases, ulcers involve the limbs but they can also involve
ing has been associated with increased incidence of disease. Newly the head, neck, or trunk. When scarring occurs close to a joint, there
arrived migrants in endemic zones are susceptible to infection, as is often limitation of joint movement; large lesions on the trunk may
demonstrated by the occurrence of Buruli ulcer among displaced inhibit spinal movement. Buruli ulcers recognize no anatomic
Rwandans in the Kinyara refugee camps in Uganda in the 1960s. boundaries and may involve critical sites, such as the face, breast, and
These refugees were displaced from a non-endemic zone and devel- genital area.
oped ulcers within 4–10 weeks of arrival, suggesting the disease’s
incubation period.
Mycobacterium ulcerans has been identified in wild koalas and ringtail
DIAGNOSIS
possums. It is difficult to culture, although it has been isolated from Diagnosis is usually based on clinical recognition. Buruli ulcers on
fresh water bugs in endemic zones following serial passage in mice the lower extremities may be difficult to distinguish from diabetic or
[1]. Mycobacterium ulcerans probably exists in an ecologic niche related venous stasis ulcers. Acid-fast bacilli can be detected in about 40% of
to slow-flowing or stagnant water in West Africa, but how it is trans- ulcers when a swab is taken from the base, close to undermined areas.
mitted to humans remains unknown. Experimental evidence shows Cultures (on Löwenstein Jensen medium at 32°C) are more sensitive
that it can be transmitted from infected water bugs to mice by biting (up to 60% positive), yielding mycobacterial growth when performed
[2]. In Australia, DNA from M. ulcerans was detected in mosquitoes in a laboratory near the endemic area, but it can take 6 weeks or more
from an affected area, but not in mosquitoes from a non-infected for mycobacterial growth to be detectable. Histologic examination
525
526 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
can be 85% sensitive but is not available in many endemic areas. The
most sensitive diagnostic test (98%) is PCR for the IS2404 repeat
Upper East sequence of M. ulcerans. PCR can be applied to swabs, punch biopsies
(3–4mm diameter) and fine needle aspirates. The latter approaches
Upper West may be helpful in diagnosing individual nodules, plaques, and ede-
N
matous lesions that have not yet ulcerated [6].
Number of cases
FIGURE 58.2 New cases of Buruli ulcer reported to Non-endemic countries >=100 and <500
the WHO in 2008. Provided by Dr Kingsley Asiedu, Endemic countries, no data available >=500 and <1000
WHO. Less than 100 1000 and above
Buruli Ulcer 527
A B C
FIGURE 58.3 Clinical forms of Buruli ulcer disease. (A) Subcutaneous firm, painless nodule attached to the skin. (B) Extensive edema of the left arm and
leg and genitalia with ulceration on the left arm and knee. (C) Partially debrided ulcer on the right knee with further ulceration on the leg and foot. All
the ulcers were probably connected subcutaneously.
When a Buruli ulcer is close to a joint there may be limitation of joint 2. Marsollier L, Robert R, Aubry J, et al. Aquatic insects as a vector for Mycobacte-
movement, and an increased risk of scarring. Functional limitation rium ulcerans. Appl Environ Microbiol 2002;68:4623–8.
can be prevented by simple physiotherapy that can be taught to the 3. Asiedu K, Etuaful S. Socioeconomic implications of Buruli ulcer in Ghana:
patient and family when treatment is started. a three-year review. Am J Trop Med Hyg 1998;59:1015–22.
4. Demangel C, Stinear TP, Cole ST. Buruli ulcer: reductive evolution
enhances pathogenicity of Mycobacterium ulcerans. Nat Rev Microbiol 2009;7:
PREVENTION 50–60.
5. Schutte D, Um-Boock A, Mensah-Quainoo E, et al. Development of highly
Understanding how M. ulcerans infection is transmitted to humans is organized lymphoid structures in buruli ulcer lesions after treatment with
a priority as this information could lead to preventative strategies. rifampicin and streptomycin. PLoS Negl Trop Dis 2007;1:e2.
Epidemiologic studies have shown that exposure to water sources 6. Phillips R. O, Sarfo FS, Osei-Sarpong F, et al. Sensitivity of PCR targeting
near endemic villages is a risk factor for developing Buruli ulcer but Mycobacterium ulcerans by use of fine needle aspirates for diagnosis of Buruli
reducing exposure, particularly of children, to such sources is imprac- ulcer. 2009. J Clin Microbiol 2009;47:924–26.
tical in rural West Africa. 7 Chauty A, Ardant MF, Adeye A, et al. Promising clinical efficacy of streptomycin-
rifampin combination for treatment of buruli ulcer (Mycobacterium ulcerans
No effective vaccine is currently available, although Bacillus Calmette- disease). Antimicrob Agents Chemother 2007;51:4029–35.
Guérin (BCG) vaccine has been associated with short-lived protection 8. Etuaful S, Carbonnelle B, Grosset J, et al. Efficacy of the combination rifampin-
in small trials. streptomycin in preventing growth of Mycobacterium ulcerans in early lesions
of Buruli ulcer in humans. Antimicrob Agents Chemother 2005;49:3182–6.
REFERENCES 9. Nienhuis WA, Stienstra Y, Thompson WA, et al. Antimicrobial treatment for
early, limited Mycobacterium ulcerans infection: a randomised controlled trial.
1. Portaels F, Meyers WM, Ablordey A, et al. First Cultivation and Characterization Lancet 2010;375:664–72.
of Mycobacterium ulcerans from the Environment. PLoS Negl Trop Dis
2008;2:e178.
59 Mycobacterium marinum Infection
Francisco Vega-López
FIGURE 59.1 Sporotrichoid dissemination in fish tank granuloma following FIGURE 59.2 Erythematous and flesh-colored nodules on the right upper
dog bite. limb in a fish tank owner.
A B
C D
FIGURE 59.3 Fish tank granuloma erythemato-violaceous nodules before and after treatment.
60 Anthrax
Arthur M Friedlander, Nicholas J Vietri
ZOONOTIC ANTHRAX
Key features Anthrax is chiefly a disease of herbivores. Animals are infected via the
gastrointestinal tract by grazing on contaminated pasture and rarely by
l Anthrax is an acute bacterial zoonosis predominantly of contact with other infected animals. Before death, animals often con-
taminate the soil with infected saliva, blood, urine, or feces. Soil, forage
herbivorous animals
and, to a lesser extent, groundwater are major reservoirs of anthrax.
l It is caused by Bacillus anthracis that persists in the
environment as dormant spores and may be transmitted to
humans by inoculation, inhalation, or ingestion
GEOGRAPHIC OCCURRENCE
Outbreaks are sporadic in developed nations, while disease remains
l The majority of naturally occurring human cases involve the endemic in parts of Africa, India, Southeast Asia, the Middle East,
skin; only very rarely are the respiratory and gastrointestinal Greece, Albania, southern Italy, Romania, the former Soviet Union,
tracts affected and Central and South America (Fig. 60.1). Bacillus anthracis spores
l Cutaneous anthrax is characterized by the development of germinate in soil at 20–44°C in areas with >85% humidity. Germi-
a papule followed by a black eschar, often surrounded by nated bacilli are destroyed by other soil microbes. Therefore, in many
tropical regions, animal anthrax occurs predominantly in the dry
significant edema. It may be complicated by septicemia
season, with some persistence into the wet season. It is likely that
and death in 5–20% of untreated cases persistence in soil results from amplification caused by growth in
l Inhalational anthrax and gastrointestinal anthrax, both infected animals and sporulation in animal carcasses with subsequent
characterized by regional lymphadenitis and septicemia, contamination of the soil. Vultures and non-biting flies may be
have a mortality rate approaching 100% if untreated and responsible for dissemination of anthrax.
~50% even with antimicrobial therapy and supportive care
l Vaccines are available HUMAN ANTHRAX
Human anthrax is traced to agricultural, industrial or, rarely, labora-
tory acquisition. Only two cases of human-to-human transmission
have been reported involving contact with a cutaneous case.
INTRODUCTION
Anthrax is an acute bacterial zoonosis, predominantly of herbivores, INDUSTRIALLY ACQUIRED ANTHRAX
caused by Bacillus anthracis. Animal anthrax is rare in developed In economically developed countries, industrial acquisition accounts
nations as a result of intensive surveillance and control. However, the for ~80% of cutaneous anthrax and almost all inhalational anthrax,
disease remains endemic in animals and not uncommon in humans and occurs predominantly among tanners or leather, hair, wool, or
in many developing countries. Humans become infected after contact bone-meal fertilizer workers. Subclinical infection and seroconver-
with infected animals or contaminated animal products by inocula- sion among workers in these industries may be more common than
tion, ingestion, or inhalation. A major concern is the use of anthrax overt illness. Infections in developed countries are acquired from
to intentionally cause disease, as occurred in 2001 with the mailing contaminated animal hides, hair, or bones imported from developing
of letters containing anthrax spores. countries with zoonotic anthrax. Leather goods and drums from Haiti
and West Africa have been vehicles of anthrax transmission. Recently,
cutaneous cases have been seen in heroin addicts in the UK and
EPIDEMIOLOGY Germany.
singly or in short chains. Bacillus anthracis also develops spores in indicate that inhaled spores are ingested by alveolar phagocytes and
culture or soil, but not in vivo unless exposed to ambient air. Spores carried to tracheobronchial and mediastinal lymph nodes. There, the
are resistant to heat and many disinfectants. They are destroyed by spores germinate into bacilli with the production of capsule and
boiling for 10 min, dry heat (140°C) for 3 h or autoclaving (121°C) toxins. Hemorrhagic edema and necrosis of mediastinal lymph nodes
for 15 min, but remain viable for years in dry soil. Cattle have become ensue. Alveoli show a hemorrhagic exudate and only rarely bacilli;
infected by grazing in fields where animals died of anthrax decades neutrophils are usually absent. Alveolar capillaries contain fibrin
before [1]. thrombi and bacilli [3]. Hemorrhagic pleural effusions commonly
occur. Hematogenous dissemination to the meninges, spleen, and
intestine can occur.
BACILLUS ANTHRACIS VIRULENCE FACTORS
Bacillus anthracis possesses three major virulence factors: a poly-γ-D-
glutamic acid capsule and two protein exotoxins. The capsule is
GASTROINTESTINAL ANTHRAX
antiphagocytic, enabling the bacillus to resist killing by leukocytes. Oropharyngeal and intestinal anthrax follow ingestion of poorly
The anthrax toxins are composed of a eukaryotic cell receptor-binding cooked, contaminated meat [4]. An ulcer in the stomach, terminal
protein and a second protein possessing cytotoxic activity. The cell ileum, or cecum may be present, and hemorrhage and edema of
receptor-binding protein protective antigen combines with edema regional lymphatics occurs.
factor, a calmodulin-dependent adenylate cyclase, to produce edema
toxin or with lethal factor, a zinc metalloprotease, to produce a lethal SEPTICEMIC ANTHRAX
toxin. Protective antigen is necessary for binding and translocation of
Generalized sepsis may follow cutaneous anthrax and, almost invari-
the cytotoxic proteins. Edema toxin raises intracelluar levels of cyclic
ably, accompanies inhalational and gastrointestinal anthrax. Vascular
adenosine monophosphate (cAMP), interfering with cell function,
injury may result from the proliferation of bacteria in the blood and
while lethal factor inactivates mitogen-activated protein (MAP)
effects of the exotoxins acting directly on the endothelium or indirectly
kinases, interfering with signal transduction [2]. The toxins interfere
through other mediators. Widespread capillary thrombosis, circulatory
with innate immunity, having been shown in vitro to impair the func-
failure, and shock occur prior to death. Adrenocortical hemorrhage
tion of neutrophils, macrophages, lymphocytes, and dendritic cells.
can occur. In addition, anthrax bacteremia may lead to hemorrhagic
Additional effects of the toxins occur in vivo because of the fact that
meningitis. The leptomeninges reveal scant inflammation but wide-
the toxin receptors are expressed on a wide variety of cells.
spread hemorrhages. The brain has hemorrhages and generalized
cerebral edema. Subarachnoid hemorrhage may also occur.
CUTANEOUS ANTHRAX
Cutaneous anthrax follows inoculation of spores into skin. Spores CLINICAL FEATURES
then germinate and the bacilli multiply and elaborate their virulence
factors. Hematogenous dissemination follows in 5–20% of untreated
cases. Cutaneous lesions may demonstrate satellite bullous lesions in CUTANEOUS ANTHRAX
which Gram-positive bacilli can be observed; pus is not present. Cutaneous anthrax accounts for >95% of human infections and com-
monly involves areas of the face, neck, hands, and arms [5]. The
incubation period is 12 hours to 7 (mean 3) days. The initial lesion
INHALATIONAL ANTHRAX is a small, erythematous macule or papule. It turns brown and deve
Inhalational anthrax follows the inhalation of spores of 1–5 µm in lops a ring of erythema and a vesicle. Vesicular satellite lesions may
diameter. Larger particles are cleared by the mucociliary mechanism appear (Fig. 60.2) and, after a few days, the clear, vesicular fluid
of the lungs. Spore aerosols may be encountered by workers handling becomes blue-black from hemorrhage. The papule ulcerates, develop-
contaminated batches of hair, wool, or bone-meal fertilizer. The ing a black eschar by the fifth to seventh day. Non-pitting, gelatinous
aerosol infective dose for human infection is high – in wool mills, edema may be prominent, occasionally extending to the iliac crest
non-immune workers inhaled as many as 510 spores of 5 µm or less from lesions of the head and neck. This so-called “malignant edema”,
in diameter per 8-hour shift without becoming ill. Animal studies together with a black eschar, is pathognomonic for anthrax. Patients
532 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
course of antibiotics is based on the possible germination of retained potential infectious nature of an untreated cutaneous anthrax lesion
dormant spores late after infection. While the prolonged course of or gastrointestinal anthrax, contact and secretion precautions should
antibiotics is necessary for post-exposure prophylaxis (PEP) as be used.
described below, recent studies in nonhuman primates demonstrated
that a 10-day course of antibiotics is sufficient to treat established
inhalational anthrax. Although historically viewed as invariably fatal,
POST-EXPOSURE PROPHYLAXIS (PEP)
data from the 2001 inhalational anthrax cases showed that a multid- PEP requires a different therapeutic approach compared with treat-
rug antibiotic regimen combined with supportive therapy reduced ment of established disease (Table 60-2). Most spores deposited into
mortality to 45% [9]. the alveolar spaces germinate within a few days. However, germina-
tion is not synchronous. Studies have demonstrated viable spores in
the lungs of rhesus macaques 100 days after exposure and anthrax has
SUPPORTIVE THERAPY occurred several months after exposure in animals given antibiotics
The evolution of the anthrax skin lesion is not modified by antimi- for short periods. As spores can remain dormant for long periods and
crobial treatment. Pleural fluid drainage was likely associated with antibiotics act only after spores have germinated, PEP to prevent
decreased mortality in the 2001 anthrax cases. disease from dormant spores that may subsequently germinate
requires either a prolonged course of antibiotics or antibiotics plus
vaccination. The current CDC recommendation for PEP for exposure
ISOLATION OF PATIENTS to aerosolized B. anthracis spores is 60 days of oral antibiotics com-
Human-to-human transmission has not been observed in inhala- bined with anthrax vaccine (BioThrax) 0.5 ml given subcutaneously
tional or gastrointestinal anthrax. Therefore, standard infection at 0, 2 and 4 weeks [10]. Antibiotics recommended for PEP include
control precautions should suffice. However, if bloody sputum is ciprofloxacin or doxycycline. Levofloxacin is recommended as a
present, respiratory isolation should be instituted. Because of the second-line antibiotic owing to limited long-term safety data. Penicil-
lin should not be used presumptively for PEP of anthrax. Although
not US Food and Drug Administration (FDA)-approved, amoxicillin
can be used to complete the 60-day course of therapy once the strain
is proven to be penicillin-susceptible. Other antibiotics to be consid-
ered for off-label use in patients unable to tolerate first-line antibiotics
TABLE 60-2 Post-exposure Prophylaxis after Bacillus
include other fluoroquinolones, clindamycin, rifampin, and chloram-
anthracis Exposure in Adults and Children* phenicol [8].
Adults
REFERENCES
Ciprofloxacin, 500 mg PO twice daily
or 1. Turnbull PCB. Anthrax in Humans and Animals, 4th edn. Geneva: World
Doxycycline, 100 mg PO twice daily Health Organization; 2008.
or 2. Montecucco C, Mock M. Anthrax. Mol Aspects Med 2009;30:345–6.
If intolerant to ciprofloxacin or doxycycline, use levofloxacin, 3. Grinberg LM, Abramova FA, Yampolskaya OV, et al. Quantitative pathology
500 mg PO once daily of inhalational anthrax I: quantitative microscopic findings. Mod Pathol
2001;14:482–95.
Children 4. Kunanusont C, Limpakarnjanarat K, Foy HM. Outbreak of anthrax in
Thailand. Ann Trop Med Parasitol 1990;84:507–12.
Ciprofloxacin: 15 mg/kg PO twice daily (max. 1 g/day) 5. Friedlander AM. Anthrax – Clinical features, pathogenesis, and potential bio-
or logical warfare threat. In: Remington JS, Swartz MN, eds. Current Clinical
Doxycycline, >8 yrs and >45 kg: 100 mg PO twice daily; >8 yrs Topics in Infectious Diseases. Malden: Blackwell Science; 2000:335.
and <45 kg: 2.2 mg/kg PO twice daily; <8 yrs: 2.2 mg/kg PO 6. Jernigan JA, Stephens DS, Ashford DA, et al. Bioterrorism-related inhalational
twice daily (max. 200 mg/day) anthrax: the first 10 cases reported in the United States. Emerg Infect Dis
or 2001;7:933–44.
If intolerant to ciprofloxacin or doxycycline, use levofloxacin, 7. Kuehnert MJ, Dolye TJ, Hill HA. Clinical features that discriminate inhala-
>6 months and <50 kg: 8 mg/kg PO twice daily (max. tional anthrax from other acute respiratory illnesses. Clin Infect Dis
500 mg/day); >50 kg: 500 mg PO once daily 2003;36:328–36.
8. Stern EJ, Uhde KB, Shadomy SV, et al. Conference report on public health
Once the organism is shown to be susceptible to penicillin,
and clinical guidelines for anthrax. Emerg Infect Dis 2008;14:e1.
amoxicillin 15 mg/kg PO three times daily (max. 1500 mg/
9. Holty JE, Bravata DM, Lui H, et al. Systematic review: a century of inhalational
day) can be used
anthrax cases from 1900 to 2005. Ann Intern Med 2006;144:270–80.
*The PEP antimicrobial regimen should continue for 60 days, combined with 10. Centers for Disease Control and Prevention. Use of anthrax vaccine in the
three doses of anthrax vaccine (BioThrax). United States. Recommendations on the Advisory Committee on Immuniza-
tion Practices (ACIP), 2009. MMWR 2010;59(No. RR-6):1–29.
G
SECTION
FEBRILE SYSTEMIC
SYNDROMES WITH
OR WITHOUT
LYMPHADENOPATHY
61 Epidemic Louse-borne Typhus
Aurélié Renvoise, Didier Raoult
EPIDEMIOLOGY
Key features Epidemic typhus has been traditionally associated with wars and
other catastrophic conditions that lead to poor sanitary conditions
l The etiological agent of epidemic louse-borne typhus is with lice infestation. It has been described as a disease of the high-
Rickettsia prowazekii lands, cold areas, poverty, imprisonment and civil unrest, when
l Epidemic typhus is transmitted by body lice and largely people are forced to repetitively wear the same clothing, often in
crowded and unhygienic conditions; however, epidemic typhus has a
affects impoverished or displaced people
potentially worldwide repartition. Incidence of epidemic typhus is
l Epidemic typhus manifests as an acute febrile illness with highest in colder months (it mainly occurs during the winter and
headache and myalgia. Neurologic manifestations, rash, spring). Men and women are equally affected [3]. Brill-Zinsser disease
vasculitis, and gangrene of extremities can occur. In (the relapsing form of the disease) can occur up to 40 years after
untreated cases, mortality is high primary infection under stress conditions or in immunocompro-
mised hosts. Sylvatic forms associated with flying squirrels and the
l Diagnosis is usually based on clinical suspicion, especially in
presence of R. prowazekii in ticks suggest that reservoirs and transmis-
the right epidemiologic situation. Serology is available sion dynamics of R. prowazekii are more complex than previously
l Treatment is simple, safe and inexpensive, and usually described [4].
involves a single 200-mg dose or short course of
In 1997, a large outbreak of typhus was reported in Burundi during
doxycycline the civil war; 100,000 people were estimated to be infected and the
l Relapses years after initial infection are termed Brill-Zinsser case fatality rate was 15% [1]. Small outbreaks and sporadic cases
disease have also been reported in different regions of the world since 1997,
l Synonyms: epidemic typhus, louse-borne typhus, including Russia, Peru, Northern Africa, the USA, and France (Fig.
61.1). This highlights the persistent threat of epidemic typhus. Eradi-
exanthematic typhus, jail fever
cation of epidemic typhus appears to be difficult because of possible
l Control efforts should focus on de-lousing both individuals recrudescence of R. prowazekii in infested people which is associated
and populations and providing hygienic conditions with Brill-Zinsser disease, and the unknown contribution of nonhu-
man reservoirs.
interest is the reservoir formed by flying squirrels (Glaucomys volans). Prior to the development of antimicrobial treatment, mortality could
Reported cases of epidemic typhus in the USA have been associated reach 60%. With appropriate antibiotics, mortality of approximately
with contact with flying squirrels [4]. The role of animal reservoirs in 4% is now common. Severity is associated with malnutrition and
the global burden of typhus is currently not well-defined. After enter- advanced age.
ing the body of an infected human, the bacteria spread through blood
and lymph, then they infect endothelial cells of the small capillaries. Brill-Zinsser disease usually occurs with advancing age and waning
Rickettsial infection leads to endothelial damage, which is associated immunity. Cases are sporadic and unrelated to recent louse infesta-
with widespread vasculitis; the clinical signs and symptoms relate to tion. Compared with acute infection, Brill-Zinsser disease is shorter
the affected organs. Endothelial injury can also lead to micro- and and its clinical features are usually mild, although fatal cases can
macroscopic foci of hemorrhages. Vasculitis can also be associated occur. Rashes are reported to be less frequent.
with thrombi in small vessels and surrounding inflammatory infil- Cases of typhus related to flying squirrels are sporadic. These cases
trates. These correspond to typhus nodules and may occur focally may clinically present as meningitis. This form of typhus is poorly
throughout the central nervous system (CNS); these lesions explain understood.
the neurologic features commonly associated with epidemic typhus
[3]. The vasculitis of R. prowazekii infection is generalized and, thus,
any organ may be involved.
PATIENT EVALUATION, DIAGNOSIS,
CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
Clinical diagnosis of sporadic cases is difficult, although clinically
Clinical features of epidemic typhus are nonspecific and consequently diagnosing a compatible case during a known epidemic is less uncer-
not easy to differentiate from other infectious processes. The incuba- tain. Taken in isolation, differentiating the clinical signs of typhus
tion period is usually 10–14 days, but may be as short as 6 days. A from those of other infections is not easy. This underscores the impor-
prodromal malaise may pre-date the onset of fever by 1–3 days. Onset tance of obtaining a thorough history of animal and lice or arthropod
of typhus is usually abrupt and manifested by fever (which continues contact in patients with acute febrile illness. However, a cluster of
until death or recovery), severe headaches, severe myalgias, abdomi- sudden onset of severe pyrexia among louse-infested people living in
nal pain, arthralgias, malaise, anorexia, chills, photophobia, and non- cold, crowded and unhygienic conditions should immediately alert
productive cough. Facial flushing and conjunctival suffusion can the clinician to possible typhus. Any severe outbreak of unexplained
occur, as can nausea, vomiting, diarrhea, or constipation. During a fever in unhygienic environments should also evoke consideration of
1997 outbreak in Burundi [1], a crouching attitude named “sutama” epidemic typhus.
was reported, caused by myalgia and severe fatigue.
The main differential diagnoses that should be considered when con-
In untreated cases, as the illness progresses, neurologic manifestations sidering louse-borne typhus are typhoid (these diagnoses have been
become more common. In up to 80% of untreated cases, CNS mani- clinically confused for centuries), murine typhus, other riskettsioses,
festations, such as delirium that interrupts stupor, coma, seizures, and malaria, and hemorrhagic fevers. Finally, lice transmit three diseases
hearing loss, can occur. Rash is often present, although difficult to which must be suspected in case of fever in louse-infested patients as
discern in individuals with dark skin. The rash is initially non- they can occur simultaneously [1]: relapsing fever, trench fever, and
confluent, with erythematous and blanching areas; macules, petechiae, epidemic typhus. The fever pattern in epidemic typhus is daily or
and purpura can occur. It begins on the trunk and the axilla and may continuous, while in the other two entities it is often more cyclical.
spread centrifugally. It is not found on the face, palms, or soles, except
in severely ill patients. In mild cases, it may fade in 1 or 2 days. Cough Laboratory findings during epidemic typhus include thrombocytope-
is reported in 38–70% of patients. Primary pulmonary involvement, nia (40% of cases), increased hepatic transaminase activity (up to
as well as secondary bacterial pneumonia, can occur during epidemic 60%; although jaundice is rare), hyperbilirubinemia (20%) and
typhus. In severe cases, symptoms secondary to vasculitis can provoke increased blood urea nitrogen concentrations (31%). Oliguria and
cerebral thrombosis, gangrene (that can require amputation), and proteinuria are common. In the early phase, leukopenia can be
multiple organ dysfunction, shock, and death [3]. observed.
538 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
9. Walker DH, Parks FM, Betz TG, et al. Histopathology and immunohistologic 17. Whiteford SF, Taylor JP, Dumler JS. Clinical, laboratory, and epidemiologic
demonstration of the distribution of Rickettsia typhi in fatal murine typhus. features of murine typhus in 97 Texas children. Arch Pediatr Adolesc Med
Am J Clin Pathol 1989;91:720. 2001;155:396.
10. Binford CH, Ecker HD. Endemic (murine) typhus: report of autopsy findings 18. Gikas A, Kokkini S, Tsioutis C, et al. Murine typhus in children: Clinical and
in three cases. Am J Clin Pathol 1947;17:797–806. laboratory features from 41 cases in Crete, Greece. Clin Microbiol Infect
11. Betz TG, Rawlings JA, Taylor JP, Davis BL. Endemic typhus in Texas. Tex Med 2009;15(suppl. 2):211–12.
1983;79:48–53. 19. Gikas A, Doukakis S, Pediaditis J, et al. Comparison of the effectiveness of
12. Tselentis Y, Babalis U, Chrysanthis D, et al. Clinicoepidemiological study of five different antibiotic regimens on infection with Rickettsia typhi: therapeutic
murine typhus on the Greek island of Evia. Eur J Epidemiol 1992;8:268–72. data from 87 cases. Am J Trop Med Hyg 2004;70:576–9.
13. Whelton A, Donadio JV Jr, Elisberg BL. Acute renal failure complicating rick- 20. Laferl H, Fournier PE, Seiberl G, et al. Murine typhus poorly responsive to
ettsial infections in glucose-6-phosphate dehydrogenase-deficient individuals. ciprofloxacin: a case report. J Travel Med 2002;9:103–4.
Ann Intern Med 1968;69:323. 21. Strand O, Stromberg A. Ciprofloxacin treatment of murine typhus. Scand J
14. Stuart BM, Pullen RL. Endemic (murine) typhus fever: clinical observations Infect Dis 1990;22:503–4.
of 180 cases. Ann Intern Med 1945;23: 520–36. 22. Committee on Infectious Diseases of the American Academy of Pediatrics.
15. La Scola B, Raoult D. Laboratory diagnosis of rickettsiosis: current approaches Report of the Committee on Infectious Diseases. American Academy of Pedi-
to diagnosis of old and new rickettsial diseases. J Clin Microbiol 1997;35: atrics, 22nd edn. Elk Grove Village; 1991:407.
2715–27. 23. Raoult D, Drancourt M. Antimicrobial therapy of rickettsial diseases. Antimi-
16. Brouqui P, Bacellar F, Baranton G, et al. ESCMID Study Group on Coxiella, crob Agents Chemother 1991;35:2457–62.
Anaplasma, Rickettsia and Bartonella; European Network for Surveillance of 24. Rolain JM, Stuhl L, Maurin M, Raoult D. Evaluation of antibiotic susceptibili-
Tick-Borne Diseases. Guidelines for the diagnosis of tick-borne bacterial dis- ties of three rickettsial species including Rickettsia felis by a quantitative PCR
eases in Europe. Clin Microbiol Infect 2004;12:1108–32. DNA assay. Antimicrob Agents Chemother 2002;46(9):2747–2751.
63 Scrub Typhus
Paul N Newton, Nicholas PJ Day
Maintaining Incidental
hosts hosts
Established colony
(mite island)
PATIENT EVALUATION, DIAGNOSIS,
Nonparasitic postlarval
stages in soil
AND DIFFERENTIAL DIAGNOSIS
The majority of scrub typhus patients are not diagnosed or treated. A
FIGURE 63.2 The life cycle of O. tsutsugamushi. Reproduced with permission
patient with fever, headache, and myalgia with an eschar in an
from Audy JR, Red Mites and Typhus. Published by The Athlone Press, University of
endemic area is likely to have scrub typhus. The differential diagnosis
London, 1968.
would include spotted fever group rickettsiosis, which would also be
expected to respond to tetracyclines. Scrub typhus eschars could be
disease can manifest as pneumonitis, acute respiratory distress confused with the lesions of anthrax, tularemia, chancroid, lym-
syndrome, jaundice with mildly raised transaminases, meningoen- phogranuloma venereum, and injury. In the absence of an eschar, few
cephalitis, coagulopathy, multi-organ failure, acute renal failure, acute clinical features are helpful. Murine typhus, leptospirosis, Q fever,
transverse myelitis, myocarditis, and Guillain-Barré syndrome. Why dengue, hemorrhagic fever with renal syndrome (HFRS), infectious
some, and not others, develop severe disease is not understood. Mor- mononucleosis, HIV seroconversion, septicemia (especially typhoid),
tality is positively correlated with blood bacterial load [5]. Orientia and malaria are important differential diagnoses. In comparison with
tsutsugamushi DNA has been demonstrated in cerebrospinal fluid those with Q fever, Taiwanese patients with scrub typhus had a higher
(CSF), with normal glucose, a mild increase in white cell density frequency of residence or travel in a mountainous region or offshore
(ranging from 11–88% lymphocytes) and raised protein [7]. Scrub island, and skin rash. In comparison to HFRS in China, eschar,
typhus appears to be less severe in children, but there have been no regional lymphadenopathy and maculopapular rash were more
544 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
TABLE 63-1 Clinical Trial and Clinical Case Series Evidence for Antibiotic Therapy for Scrub Typhus
commonly found in patients with scrub typhus. In Laos, the presence Interpretation of data informing treatment decisions is difficult, as
of peripheral lymphadenopathy, chest signs and eschars are clinically studies are few, often of small sample size and “relapses” were usually
useful signs that suggest scrub, rather than murine, typhus [2]. not proven to be relapses of scrub typhus, rather than another cause
of fever (Table 63-1). Current data suggest that fluoroquinolones are
Laboratory diagnosis of scrub typhus is difficult. Culture (requiring inferior to doxycycline as therapy for scrub typhus. For uncomplicated
BSL3 facilities) is 100% specific, but has low sensitivity. Immunofluo- disease, the data available do not allow generalizable conclusions of
rescence (IFA) and immunoperoxidase IgM and IgG antibody tests the duration of doxycycline therapy or whether a loading dose is
have been commonly used, but these are expensive, rarely accessible required. In Laos and Thailand, a 7-day treatment course of 2 mg/kg
and are bedevilled by subjectivity of interpretation and uncertainty as twice daily after a loading dose of 4 mg/kg is administered. There is
to the most appropriate cut-off titers in different communities [10]. evidence from Malaysia that shorter courses may be efficacious [14].
Ideally, they should be interpreted by comparing titers between paired Upper gastrointestinal side effects are common; patients should be
acute and convalescent samples. Karp, Gilliam, and Kato prototypic counseled to take doxycycline with plenty of fluid, during meals, and
antigens are usually used in IFAs and therefore may not detect anti- while sitting or standing. Chloramphenicol, telithromycin, rifampicin,
bodies to other strains. The Weil-Felix OXK test is still commonly used and azithromycin are potential alternatives [15–20].
in Asia, but has low sensitivity. Conventional and quantitative real-
time PCR assays for the detection of O. tsutsugamushi in blood, eschar There are few data to guide the antibiotic treatment of severe disease
tissue, and CSF have been developed [11, 12]. However, there remain – parenteral or nasogastric doxycycline or chloramphenicol are poten-
great difficulties in the accessibility of the diagnosis of scrub typhus tial options. Appropriate supportive care is essential. The treatment
in rural endemic areas. Mixed infections may occur with, for example, of scrub typhus in pregnancy is problematic – chloramphenicol
leptospirosis but, given the persistence of antibodies, distinguishing (although contraindicated in the last trimester), azithromycin, and
these from serial infections without culture or PCR techniques is rifampicin have been used. In children, the risks of short-course doxy-
difficult. cycline are almost certainly exceeded by the benefit of effective cure.
In a retrospective analysis of children with scrub typhus, no significant
differences in fever clearance times were found between doxycycline,
TREATMENT chloramphenicol, or roxithromycin therapy [21].
Given the difficulties of making a timely laboratory diagnosis and the Mortality is very variable, ranging from 0–60% in untreated patients,
significant minority who develop severe disease, empirical treatment for reasons that are unclear. Delayed administration of doxycycline
should be considered for all cases with scrub typhus in the differential has been associated with major organ dysfunction and prolonged
diagnosis. The diversity of O. tsutsugamushi suggests it is unlikely that hospitalization, emphasizing the importance of early empirical doxy-
one treatment regimen will be appropriate across the wide distribu- cycline therapy. Relapse was described during volunteer experiments
tion of this organism. Chloramphenicol- and doxycycline-resistant in Malaysia, but whether this is an important phenomenon in clinical
scrub typhus have been described in northern Thailand [13], but there practice is uncertain. Insecticides have been used to control chiggers,
are no subsequent published data on this clinical problem. both in high-risk habitats and on blankets and clothes, but neither
S c rub Typhus 545
are currently practical in rural Asia for farmers (who are at most risk 10. Blacksell SD, Bryant NJ, Paris DH, et al. Scrub typhus serologic testing with
of scrub typhus). For short-term adult visitors, weekly 200 mg doxy- the indirect immunofluorescence method as a diagnostic gold standard: a lack
cycline reduces the risk of contracting scrub typhus. There is currently of consensus leads to a lot of confusion. Clin Infect Dis 2007;44:391–401.
no safe and effective vaccine available. 11. Paris DH, Aukkanit N, Jenjaroen K, et al. A highly sensitive quantitative real-
time PCR assay based on the groEL gene of contemporary Thai strains of
Orientia tsutsugamushi. Clin Microbiol Infect 2009;15:488–95.
REFERENCES 12. Paris DH, Blacksell SD, Newton PN, Day NP. Simple, rapid and sensitive
detection of Orientia tsutsugamushi by loop-isothermal DNA amplification.
1. Kelly DJ, Fuerst PA, Ching WM, Richards AL. Scrub typhus: the geographic Trans R Soc Trop Med Hyg 2008;102:1239–46.
distribution of phenotypic and genotypic variants of Orientia tsutsugamushi. 13. Watt G, Chouriyagune C, Ruangweerayud R, et al. Scrub typhus infections
Clin Infect Dis 2009;48(suppl. 3):S203–30. poorly responsive to antibiotics in northern Thailand. Lancet 1996;348:
2. Phongmany S, Rolain JM, Phetsouvanh R, et al. Rickettsial infections and 86–9.
fever, Vientiane, Laos. Emerg Infect Dis 2006;12:256–62. 14. Brown GW, Saunders JP, Singh SL, et al Single dose doxycycline therapy for
3. Phimda K, Hoontrakul S, Suttinont C, et al. Doxycycline versus azithro scrub typhus. Trans R Soc Trop Med Hyg 1978;72:413–6.
mycin for treatment of leptospirosis and scrub typhus. Antimicrob Agents 15. Kim YS, Yun HJ, Shim SK, et al. A comparative trial of a single dose of
Chemother 2007;51:3259–63. azithromycin versus doxycycline for the treatment of mild scrub typhus.
4. Kweon SS, Choi JS, Lim HS, et al. A community-based case-control study of Clin Infect Dis 2004;39:1329–35.
behavioral factors associated with scrub typhus during the autumn epidemic 16. Kim DM, Yu KD, Lee JH, et al. Controlled trial of a 5-day course of telithro-
season in South Korea. Am J Trop Med Hyg 2009;80:442–6. mycin versus doxycycline for treatment of mild to moderate scrub typhus.
5. Sonthayanon P, Chierakul W, Wuthiekanun V, et al. Association of high Ori- Antimicrob Agents Chemother 2007;51:2011–5.
entia tsutsugamushi DNA loads with disease of greater severity in adults with 17. Panpanich R, Garner P. Antibiotics for treating scrub typhus. Cochrane Data-
scrub typhus. J Clin Microbiol 2009;47:430–4. base Syst Rev 2002;CD002150.
6. Paris DH, Jenjaroen K, Blacksell SD, et al. Differential patterns of endothelial 18. Sheehy TW, Hazlett AD, Turk RE. Scrub typhus: A comparison of chloram-
and leucocyte activation in ‘typhus-like’ illnesses in Laos and Thailand. Clin phenical and tetracycline in its treatment. Arch Int Med 1973;132:77–80.
Exp Immunol 2008;153:63–7. 19. Song JH, Lee C, Chang LW, et al. Short course doxycycline treatment versus
7. Pai H, Sohn S, Seong Y, et al. Central nervous system involvement in patients conventional tetracycline therapy for scrub typhus: A multiple randomized
with scrub typhus. Clin Infect Dis 1997;24:436–40. trial. Clin Infect Dis 1995;21:506–10.
8. Mathai E, Rolain JM, Verghese L, et al. Case reports: scrub typhus during 20. Watt G, Kantipong P, Jongsakul K, et al. Doxycycline and rifampicin for mild
pregnancy in India. Trans R Soc Trop Med Hyg 2003;97:570–2. scrub-typhus infections in northern Thailand: a randomised trial. Lancet
9. Saunders JP, Brown GW, Shirai A, Huxsoll DL. The longevity of antibody to 2000;356:1057–61.
Rickettsia tsutsugamushi in patients with confirmed scrub typhus. Trans R Soc 21. Lee KY, Lee HS, Hong JH, et al. Roxithromycin treatment of scrub typhus
Trop Med Hyg 1980;74:253–7. (tsutsugamushi disease) in children. Pediatr Infect Dis J 2003;22:130–3.
Tick-borne Spotted Fever
64 Rickettsioses
Cristina Socolovschi, Philippe Parola, Didier Raoult
continent and Torres Strait Island to the southeastern corner (Wilson’s pink, blanching macules (typically on the wrists, ankles and fore-
promontory in Victoria) [8]. Most cases (78%) occur between June arms) that evolve maculopapules. Within 24 hours, it spreads cen-
and November. The disease is characterized by sudden onset of fever, trally to involve the legs, buttocks, arms, axillae, trunk, neck and face.
headache and myalgia. Within 10 days, a maculopapular or vesicular The entire body may be involved, including the mucous membranes
rash appears. An inoculation eschar is identified in 65% of cases and of the palate and pharynx [11]. Characteristic of the rash are petechial
lymphadenopathy in 71% of cases. lesions, in a distribution that includes the palms and soles, which
occur in 36% to 82% of patients. In some severe cases, petechiae may
coalesce to form large ecchymoses. No eschar at the inoculation site
FLINDERS ISLANDS SPOTTED FEVER is visible. Severe manifestations may include pulmonary edema and
Flinders Islands spotted fever, caused by Rickettsia honei, occurs pri- hemorrhage, cerebral edema, myocarditis, renal failure, disseminated
marily in Australia (Tasmania, South Australia, Queensland, Torres intravascular coagulopathy and gangrene. Three factors are independ-
Strait Islands) and may be worldwide (Thailand, Sri Lanka, Italy) ent predictors of failure by the physician to initiate therapy the first
[1, 8]. Aponomma hydrosauri, the reptile tick, is suspected to be a vector time a patient is seen: absence of a rash, presentation between August
of this disease. It is a relatively mild disease—no deaths have yet been 1 and April 30, and presentation within the first three days of illness.
recorded. The incidence of Flinders Islands spotted fever was esti- In untreated patients who survive their illness, the natural course of
mated at 150 per 100,000 persons. It causes a summer febrile illness fever terminates after two to three weeks.
associated with a rash, being erythematous in the majority of cases,
while it was purpuric in two severe cases associated with thrombocy-
topenia. An eschar typical for spotted fever group rickettsiosis (25%) SCALP ESCHAR AND NECK
and enlarged local nodes (55%) was observed. Recently, a genetic
variant of R. honei, the “marmionii” strain transmitted by Haema-
LYMPHADENOPATHY (SENLAT)
physalis novaeguineae and Ixodes holocyclus, was reported to cause acute The tick-borne rickettsial etiological agents of scalp eschar and
disease in several patients in eastern Australia. neck lymphadenopathy (SENLAT) are Rickettsia slovaca and Rickettsia
raoultii, which are transmitted by the ticks Dermacentor marginatus
Spotted fever related to Rickettsia parkeri has been described in the and Dermacentor reticulatus. The old name of this disease is tick-borne
USA and South America. The first recognized case of infection in a lymphadenitis (TIBOLA) or Dermacentor-borne necrosis erythema
human was reported in 2004, 65 years after the initial isolation of lymphadenopathy (DEBONEL). Recently, the spectrum of the causa-
this rickettsia from ticks. This disease was previously confused with tive agents of SENLAT was extended, and several reports demonstrated
Rocky Mountain spotted fever or with Rickettsialpox. Recently, six that this syndrome can be caused by Borrelia burgdorferi, Bartonella
new confirmed cases were reported. This disease is characterized by: henselae, Coxiella burnetii, R. rioja, and Francisella tularensis, all trans-
fever; myalgia; malaise; headache; maculopapular, vesicular or pustu- mitted by the above ticks. SENLAT occurs in Europe, more frequently
lar eruption; and inoculation eschar (sometimes multiple eschars). in women and children during the colder months. The clinical
No deaths were reported [9]. description is similar for R. slovaca and R. raoultii infection, including
fever, headache, asthenia, rash, painful eschar, painful adenopathies
ROCKY MOUNTAIN SPOTTED FEVER and face edema. The difference between these two infections is that
alopecia lasting for several months has been recorded in 59% or more
The severity of symptoms of Rocky Mountain spotted fever caused by of the cases with R. slovaca, but not with R. roultii [12, 13].
R. rickettsii separates this disease from other tick-borne rickettsioses.
Rocky Mountain spotted fever is endemic to regions of North, Central
and South America, in both rural and urban zones. The peak of LYMPHANGITIS-ASSOCIATED
disease occurs during the months of April to September. Since its
initial description in the late 19th century, Rocky Mountain spotted
RICKETTSIOSIS
fever has been considered a lethal infection. For example, from 1904 Rickettsia sibirica mongolitimonae causes lymphangitis-associated rick-
to 1913 in Montana, 96 (63%) of 153 patients diagnosed with Rocky ettsiosis. It appears that the distribution of this disease corresponds
Mountain spotted fever died from this disease. The fatality rate of to the distribution of Hyalomma spp. ticks. Recently, R. sibirica mon-
Rocky Mountain spotted fever was reduced to approximately 23% by golitimonae was detected in Rh. pusillus ticks in Portugal and in France.
advances in supportive care and the discovery of antimicrobial Sixteen cases were confirmed in the literature: 13 from Europe (France,
therapy. In the recently published “Summary of Notifiable Diseases— Portugal, Greece and Spain) and 3 from Africa (Algeria, South Africa
United States, 2006”, a total of 3908 cases of Rocky Mountain spotted and Egypt). The available clinical features for the 16 reported cases
fever were reported in 2002–2004, including 22 deaths, making the (ten men and six women) include fever in all patients (range 38–
case-fatality rate 0.7%. There are a few reasons to believe that the fatal 39.5°C), chills (three patients), headache (13 patients), myalgia (13
cases are more often unreported than benign cases: (i) some cases are patients), arthralgia (three patients), cutaneous rash (11 patients),
confounded with spotted fever caused by R. parkeri, R. massiliae, Rick- enlarged lymph nodes (ten patients), lymphangitis expanding from
ettsia amblyommi, Rickettsia akari, and Rickettsia felis; (ii) some imported an inoculation eschar to the draining node (six patients) and retinal
cases of rickettsioses, for example African tick-bite fever in travelers vasculitis in a pregnant woman [3, 14]. Lymphangitis-associated rick-
are incorrectly reported as Rocky Mountain spotted fever; and (iii) in ettsiosis occurred primarily between March and September; a single
some R. rickettsii strains, there are variations in virulence (for example, case was reported in December in Greece.
in an early description of Rocky Mountain spotted fever in the Idaho
region, a 5% case-fatality rate was reported compared with 70–80%
in Montana) [10]. In Brazil, where Rocky Mountain spotted fever is AFRICAN TICK-BITE FEVER
endemic to at least five states, mortality was 40% in Minas Gerais
State between 1981 and 1989. The risk factors for severity are: old age; African tick-bite fever is caused by R. africae and transmitted by Ambly-
a delay between disease onset and diagnosis; wrong antibiotic choice; omma ticks in rural sub-Saharan Africa and the West Indies (Fig. 64.3)
and no known documentation of tick bite. [1, 15]. Some reports indicate that African tick-bite fever poses a
significant problem to local populations. In Zimbabwe, the annual
Around one week after being bitten by an infected tick, the disease incidence rate of African tick-bite fever is 60–80 cases per 100,000 in
begins with fever, chills, myalgia and headache. During the next few areas where Amblyomma is endemic. Whereas reports on African tick-
days, these symptoms continue and may be accompanied by ano- bite fever in indigenous populations are scarce, the number of
rexia, nausea, vomiting, abdominal pain, diarrhea, photophobia and reported cases has recently increased in travelers from Europe and
cough. The fever is typically high (39–41°C) and associated with a elsewhere. Usually, grouped cases of African tick-bite fever are
severe frontal headache. Rash, considered the hallmark feature of described, for example several cases in the same family or in the same
Rocky Mountain spotted fever, appears on day three of fever as small, travel group.
Ti c k- b o r n e S p o t te d Fe ve r R i ckettsioses 551
FIGURE 64.4 Amblyomma variegatum adult ticks (male right, female left),
The clinical course typically comprises an abrupt onset of fever a vector of African tick-bite fever, the etiological agent of Rickettsia africae.
(59–10%), nausea, headache (62–83%), and neck myalgia (81%)
beginning 5–10 days after a tick bite. Most patients develop an inocula- inoculation eschars. The strain of R. monacensis isolated from human
tion eschar (53–100%) at the site of the tick bite and up to 54% of samples was not analyzed by another laboratory; its epidemiology
patients have multiple eschars—a rather specific clinical sign. A painful remains unknown.
regional lymphangitis (43–100%) is common and may be seen in the
absence of an inoculation eschar. A generalized cutaneous rash, some- Candidatus Rickettsia kellyi was detected in human samples from a
times vesicular and usually most visible close to the eschar, is present one-year-old boy from India. He presented with fever and maculopa-
in 15–46% of patients (Fig. 64.4). Less frequent clinical signs of pular rash. To date, the rickettsial strain has not been isolated from
African tick-bite fever include aphtous stomatitis (11%) and arthralgia. human samples or arthropod vector. Further investigations are
Complications are rarely seen, but long-lasting fever, reactive arthritis, required for characterization of its role in human pathology [7].
subacute cranial or peripheral neuropathy, chronic fatigue, neuropsy-
chiatric symptoms and myocarditis have been reported. There are no
known fatal cases [15]. African tick-bite fever should be considered
DIAGNOSIS
along with malaria and other tropical fevers in the differential diag-
nosis of all febrile patients returning from the tropics. STANDARD LABORATORY FEATURES
Hematological anomalies include anemia with thrombocytopenia,
INFREQUENTLY REPORTED TICK- with neutropenia in the acute phase of disease and leukocytosis in
the later stages. Non-specific biochemical changes include decreased
BORNE RICKETTSIAL DISEASES levels of protein (particularly albumin), sodium, potassium and chlo-
ride, and elevated hepatic enzyme levels during the first 10 days of
Rickettsia aeschlimannii was detected in Hyalomma ticks from several disease. Creatinine phosphokinase and lactic dehydrogenase are also
African countries, southern Europe and Kazakhstan (Table 64-1) [7]. often raised.
Four clinical cases were described in the literature: one patient return-
ing from Morocco to France, one patient returning from a hunting
and fishing trip in South Africa, and two cases in Algeria. All of these DIAGNOSTIC TOOLS
patients presented with typical signs of spotted fever: an inoculation The diagnosis of tick-borne rickettsioses is based on clinical and epi-
eschar (in one case two inoculation eschars), fever, headache and a demiologic findings. The diagnosis should be suspected in a febrile
generalized maculopapular rash [1]. patient with a history of tick bite, headache, a rash and/or a skin lesion
Rickettsia massiliae has been detected in several species of Rhipicephalus consisting of a black necrotic area surrounded by erythema or a pseu-
ticks in tropical African countries—the Central African Republic, dofurunculus or crust. The classic features of tick-borne rickettsioses
Senegal, Ivory Coast and Mali—and also in southern Europe and the may only occur in 50–75% of patients. Confirmation of the diagnosis
USA [1]. It is an emergent pathogen with only three cases of human may be assessed by specific serology or by isolation or molecular
infection described in Italy, in France, and in Argentina. These three identification of the causative organism. For serologic diagnosis, one
patients presented the same clinical signs as Mediterranean spotted serum sample should be collected early in the course of the disease;
fever. The French patient presented acute visual loss and bilateral a second sample should be obtained two to three weeks later. If anti-
chorioretinitis [5]. body titers remain negative in these two samples, a later sample must
be tested (4 to 6 weeks). Usually, antibodies are absent in the early
Rickettsia helvetica has been detected in Ixodes ricinus in many phase of the disease. The presence of specific IgM antibodies or a
European countries, northern Africa and Asia. Among 4604 clinical fourfold increase in titer of IgG antibodies from acute-phase illness
rickettsial cases reported in Italy from 1998 to 2002, three cases of a to the convalescent phase is considered diagnostic. The interpretation
mild form of rickettsiosis were serologically attributed to R. helvetica. of serologic data can be confounded by the cross-reactivity that occurs
The R. helvetica infection presented as a mild disease in the warm among spotted fever group rickettsiae. Western blot analysis will yield
season and was associated with fever, headache and myalgia, and false-positive results because of cross-reacting antibodies that are
sometimes with a cutaneous rash. Additional evaluation and isolation directed mainly against lipopolysaccharides. Western blots, particu-
of the bacterium from clinical samples are needed to confirm the larly in conjunction with sera that have been cross-adsorbed, can also
pathogenicity of this bacterium. be used to identify the infecting rickettsial species, but the technique
is only appropriate for reference laboratories (Fig. 64.5).
Rickettsia monacensis has been detected in Europe, northern Africa and
the USA [7]. Recently, two cases were described in Spain. The clinical To isolate rickettsiae organisms from skin biopsy and heparin, blood
picture is the same as with Mediterranean spotted fever, without specimens collected before antimicrobial therapy (preferably from
552 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
A B C
FIGURE 64.5 Western blot before and after cross-adsorption with Rickettsia sibirica mongolitimonae (A), R. helvetica (B), or R. massiliae (C). When cross-
adsorption is performed with R. helvetica, the specific antigen-corresponding line disappears—this implicates R. helvetica as the causative microorganism.
A C
FIGURE 65.2 (A) Ventral aspect of an adult female L. sanguineus (Acari: Dermanyssidae), the mite vector of rickettsialpox. Cleared specimen stained with
acid fuchsin. (B) The house mouse (M. musculus), an important vertebrate host involved in the epidemiology of rickettsialpox. (C) Giménez-stained R. akari
bacteria in mouse peritoneal macrophages. We gratefully acknowledge Larry Masters for image B.
periadnexal inflammatory cell infiltrates of the cutaneous lesions and developed papulovesicles show subepidermal vesicle formation that
only rarely in vascular endothelial cells. The histopathology of the is a characteristic histopathologic feature of rickettsialpox. Inflamed
inoculation eschar demonstrates extensive necrosis of the epidermis blood vessels demonstrate varying degrees of endothelial swelling,
and dermis, with subjacent perivascular and periadnexal inflamma- blurring or obliteration of the vessel wall by inflammatory cell infil-
tory cell infiltrates and occasional panniculitis. The histopathology of trates, mural necrosis, extravasation of red cells, or fibrin thrombi.
the rash is typically more variable and age-dependent; however, fully Lymphocytes and macrophages comprise the predominant
R i c kettsialpox 555
inflammatory cell types, although neutrophils are occasionally of the inoculation eschar. In patients who do not receive specific
present in, and around, necrotic foci [3, 20, 21]. antibiotic therapy, these symptoms persist for approximately 7–10
days. The peak temperature is 38–40°C, although it may rise to 41°C.
CLINICAL FEATURES A headache, usually frontal and occasionally severe, is described in
approximately 90–100% of patients. Myalgias are frequently reported
Estimated limits of the incubation period range from 6 to 15 days and are most commonly described as backache. Less frequently
following the bite of an infected mite. The primary lesion, or inocula- described findings include conjunctivitis, splenomegaly, pharyngitis,
tion eschar, is described for 83–100% of patients in several large series nausea and vomiting. Rickettsialpox is recognized as a relatively
(Table 65-1). In its early stages, it is a painless, non-pruritic, erythema- benign, self-limited illness and, in most case series, patients are hos-
tous papule that soon enlarges and develops a central vesicle contain- pitalized infrequently. Moderate-to-severe manifestations are reported
ing clear, or opaque, fluid (Fig. 65.3A). Eventually, the vesicle ruptures rarely and include hepatitis, disseminated intravascular coagulopathy
and a dark brown or black crust develops over the lesion, forming the with hemorrhagic diatheses, photophobia and nuchal rigidity. No
characteristic eschar (Figs 65.3B, C). The eschar is often surrounded deaths have been attributed to infection with R. akari [2, 11, 23].
by a larger zone of erythema. Primary lesions range in size from 0.5
to 2.5 cm and are most frequently observed on the extremities, but
may be found anywhere on the body. Two eschars are occasionally PATIENT EVALUATION, DIAGNOSIS,
identified on separate anatomic sites. The eschar generally persists for
3–4 weeks and may heal to form a small, depressed scar. A cutaneous
AND DIFFERENTIAL DIAGNOSIS
eruption develops in most patients 1–4 days following the onset of The differential diagnosis of a patient with an eschar and fever
fever. This eruption is characterized by small (2–10 mm), discrete, includes ecthyma gangrenosum, herpetic dermatitis, aspergillosis,
erythematous maculopapules distributed on the extremities, cutaneous leishmaniasis, tularemia, melioidiosis and cutaneous
abdomen, back, chest, and face, and only rarely on the palms and anthrax; however, several other rickettsial diseases, including African
soles. After 2–3 days, some lesions become indurated and develop a tick-bite fever, Rickettsia parkeri rickettsiosis, boutonneuse fever,
small vesicle containing cloudy fluid at the apex. The number of Queensland tick typhus, scrub typhus, (Table 65-1) are, perhaps, the
papules varies from 5 to more than 100, although most patients most likely to clinically resemble rickettsialpox [24–27]. Among these
develop approximately 20–30 of these lesions. The rash is neither diseases, rickettsialpox is notable for the frequent occurrence of a
painful nor pruritic and generally resolves within 7 days to leave vesicular rash and the relative infrequency of regional adenopathy. A
small, hyperpigmented spots. An enanthem occurs in approximately carefully collected patient history that includes questions about area
20–25% of patients and is characterized by small (2–4 mm) vesicles, of residence, recent travel and potential exposures to rodents (particu-
maculopapules or erosions on the oral mucosae [2, 4–8, 22]. larly house mice) can provide additional diagnostic clues [3, 6, 7, 21].
Patients with rickettsialpox typically develop fever, diaphoresis, las- Laboratory diagnosis of rickettsialpox is ascertained most often by
situde, myalgias, and headache within 2–7 days after the appearance serologic methods. Most patients with rickettsialpox, in contrast with
TABLE 65-1 Clinical and Epidemiologic Characteristics of Rickettsialpox and Other Selected Eschar-Associated
Rickettsioses
A B C
FIGURE 65.3 (A) Vesicular lesion on the ankle of a patient with rickettsialpox. (B) Inoculation eschar on the arm of a patient with rickettsialpox. Rickettsia
akari was subsequently isolated in cell culture from this lesion. (C) Inoculation eschar on the chest of a patient approximately 2 days prior to onset of fever
and headache and 6 days prior to the onset of a papulovesicular rash. We gratefully acknowledge the following individuals for their assistance: David E.
Geist, M.D (University of Massachusetts Medical School) for image A, Tamara Koss, M.D. (Columbia University College of Physicians and Surgeons) for image
B and Benjamin Gewurz, M.D. (Brigham and Women’s Hospital) for image C.
6. Koss T, Carter EL, Grossman ME, et al. Increased detection of rickettsialpox 19. Choi YJ, Lee EM, Park JM, et al. Molecular detection of various rickettsiae in
in a New York City hospital following the anthrax outbreak of 2001: use of mites (Acari: Trombiculidae) in southern Jeolla province, Korea. Microbiol
immunohistochemistry for the rapid confirmation of cases in an era of bioter- Immunol 2007;51:307–12.
rorism. Arch Dermatol 2003;139:1545–52. 20. Walker DH, Hudnall SD, Szaniawski WK, Feng HM. Monoclonal antibody-
7. Paddock CD, Zaki SR, Koss T, et al. Rickettsialpox in New York City: a persist- based immunohistochemical diagnosis of rickettsialpox: the macrophage is
ent urban zoonosis. Ann N Y Acad Sci 2003;990:36–44. the principal target. Mod Pathol 1999;12:529–33.
8. Saini R, Pui JC, Burgin, S. Rickettsialpox: report of three cases and a review. 21. Paddock CD, Koss T, Eremeeva ME, et al. Isolation of Rickettsia akari from
J Am Acad Dermatol 2004;51:S65–70. eschars of patients with rickettsialpox. Am J Trop Med Hyg 2006;75:732–8.
9. Radulovic S, Feng HM, Morovic M, et al. Isolation of Rickettsia akari from a 22. Rose HM. The clinical manifestations and laboratory diagnosis of rickettsial-
patient in a region where Mediterranean spotted fever is endemic. Clin Infect pox. Ann Intern Med 1949:31:871–83.
Dis 1996;22:216–20. 23. Madison G, Kim-Schulger L, Braverman S, et al. Hepatitis in association with
10. Choi YJ, Jang WJ, Ryu JS, et al. Spotted fever group and typhus group rick- rickettsialpox. Vector-Borne Zoonotic Dis 2008;8:1–5.
ettsioses in humans, South Korea. Emerg Infect Dis 2005;11:237–44. 24. Raoult D, Fournier PE, Fenollar F, et al. Rickettsia africae, a tick-borne pathogen
11. Zavala-Castro JE, Zavala-Velázquez JE, Peniche-Lara GF, Sulú Uicab JE. in travelers to sub-Saharan Africa. N Engl J Med 2001;344:1504–10.
Human rickettsialpox, southeastern Mexico. Emerg Infect Dis 2009;15: 25. Paddock CD, Finley RW, Wright CS, et al. Rickettsia parkeri rickettsiosis and
1665–7. its clinical distinction from Rocky Mountain spotted fever. Clin Infect Dis
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Infect Dis 2003;9:1498–9. 26. Hudson BJ, Hofmeyr A, Williams E, et al. Prospective study of Australian
13. Le Gac P, Giroud P. Rickettsiose vésiculeuse en Oubangui-Chari (A.E.F.). Bull spotted fever—clinical and epidemiological features. In: Abstracts of the 4th
Soc Pathol Exot 1951;44:413–15. International Conference on Rickettsiae and Rickettsial Diseases, Logrono, La
14. Eustis EB, Fuller HS. Rickettsialpox. II. Recovery of Rickettsia akari from mites, Rioja, Spain 2005 June 18–21. Abstract P-201.
Allodermanyssus sanguineus, from West Hartford, Conn. Proc Soc Exp Biol Med 27. Berman SJ, Kundin WD. Scrub typhus in South Vietnam, a study of 87 cases.
1952;80:546–9. Ann Intern Med 1973;79:26–30.
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the causative agent from house mice in Boston, Massachusetts. Am J Hyg and African tick bite fever by PCR of lesion swabs. Emerg Infect Dis
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16. Jackson EB, Danauskas JX, Coale MC, Smadel JE. Recovery of Rickettsia 29. Rolain JM, Maurin M, Vestris G, Raoult D. In vitro susceptibilities of 27 rick-
akari from the Korean reed vole Microtus fortis pelliceus. Am J Hyg 1957;66: ettsiae to 13 antimicrobials. Antimicrob Agents Chemother 1998;
301–8. 42;1537–41.
17. Bennett SG, Comer JA, Smith H, Webb JP. Serologic evidence of Rickettsia 30. Ives TJ, Manzewitsch P, Regnery RL, et al. In vitro susceptibilities of Bartonella
akari-like infection among wild-caught rodents in Orange County and in henselae, B. quintana, B. elizabethae, Rickettsia rickettsii, R. conorii, R. akari, and
humans in Los Angeles County, California. J Vector Ecol 2007;32:198–201. R. prowazekii to macrolide antibiotics as determined by immunofluorescent
18. Philip CB, Hughes LE. The tropical rat mite, Liponyssus bacoti, as an experi- antibody analysis of infected Vero cell monolayers. Antimicrob Agents Chem-
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66 Q Fever
Matthieu Million, Didier Raoult
or purpuric rash, pericarditis, myocarditis, aseptic meningitis, and/or infection, while an anti-phase I IgG titer >800 suggests chronic infec-
encephalitis and gastroenteritis. Acute acalculous cholecystitis has tion [19]. As the persistence of high levels of anti-phase I antibodies
been reported [13], as has uveitis [14] and other rare, organ-specific 6 months after completion of treatment, and the reappearance of
immunologic manifestations [15]. previously decreasing antibody titers may signal the development of
chronic infection, serologic monitoring should be performed for at
CHRONIC INFECTION least 6 months after acute Q fever, especially for immunocompro-
mised or pregnant patients, and those with valvular or vascular
Chronic Q fever may develop insidiously months or years after acute abnormalities.
disease, especially in immunocompromised patients and in those
with significant comorbidities. Chronic Q fever may include endocar-
ditis, vascular mycotic aneurysm or infection of prosthetic devices, all IMMUNOHISTOCHEMISTRY
with an accompanying poor prognosis [16, 17]. Other manifestations Coxiella burnetii can be identified by immunohistochemical analysis
of chronic Q fever include osteoarthritis, osteomyelitis, and isolated of resected valve or liver biopsy specimens using a monoclonal anti-
hepatitis, possibly complicated by hepatic fibrosis and cirrhosis. body and hematoxylin counter-stain (Figs 66.1 and 66.2).
Q FEVER IN PREGNANCY
During pregnancy, Q fever is most often asymptomatic, but may result
in obstetrical complications, such as spontaneous abortion, intrauter-
ine growth retardation, intrauterine fetal death, oligoamnios, and
premature delivery [12, 20–22]. Although intrauterine transmission
of C. burnetii has been documented, the consequences of congenital
Q fever are uncertain.
CHILDREN
In children, acute Q fever is mostly asymptomatic. Endocarditis may
occur in children with congenital heart disease or in those with a
history or rheumatic fever.
PCR
PCR has been successfully employed to detect DNA in both cell cul-
tures and clinical samples [19]. In addition, PCR testing is helpful in
confirming the serologic diagnosis of chronic infection in patients
who have persistent elevations of IgG anti-phase I titers (see below).
CULTURE
If microbiologic culturing for C. burnetii is to be performed, isolation
must be undertaken using Biosafety Level (BSL) 3 containment
because of the risk of laboratory-associated infection [19]. Shell vial
culture is the best, and simplest, technique, allowing isolation of C.
burnetii from blood or tissues, including cardiac valves.
SEROLOGY
An immunofluorescence assay (IFA) assessing IgG, IgM, and IgA levels FIGURE 66.2 Immunohistochemical detection of Coxiella burnetii in a
against C. burnetii phase I versus phase II antigens is currently the resected valve from a patient with Q fever endocarditis using a monoclonal
reference method used to serodiagnose patients with Q fever. Anti- antibody and hematoxylin counterstain. Note the intracellular location of
phase II IgG titers ≥200 and IgM ≥50 are indicative of recent Q fever the bacteria in the macrophage cytoplasm (original magnification ×400).
560 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Tropheryma whipplei, Abiotrophia elegans, Mycoplasma hominis, and 4. Pantanowitz L, Telford SR, Cannon ME. Tick-borne diseases in transfusion
Legionella pneumophila [23]. medicine. Transfus Med 2002;12:85–106.
5. Raoult D, Levy PY, Dupont HT, et al. Q fever and HIV infection. AIDS
1993;7:81–6.
TREATMENT 6. Milazzo A, Hall R, Storm PA, et al. Sexually transmitted Q fever. Clin Infect
Dis 2001;33:399–402.
MEDICAL THERAPY 7. Gardon J, Heraud JM, Laventure S, et al. Suburban transmission of Q fever in
In acute disease, treatment of patients infected with C. burnetii should French Guiana: evidence of a wild reservoir. J Infect Dis 2001;184:278–84.
target only those who are symptomatic. Doxycycline therapy (100 mg 8. Tissot DH, Raoult D, Brouqui P, et al. Epidemiologic features and clinical
presentation of acute Q fever in hospitalized patients: 323 French cases. Am
PO twice daily for 14 days) is the recommended regimen for
J Med 1992;93:427–34.
symptomatic acute Q fever [24]. Fluoroquinolones and newer mac-
9. Stein A, Saunders NA, Taylor AG, Raoult D. Phylogenic homogeneity of Cox-
rolides may be of clinical use and can be considered as second-line
iella burnetii strains as determinated by 16S ribosomal RNA sequencing. FEMS
agents [25]. Microbiol Lett 1993;113:339–44.
10. Hackstadt T, Williams JC. Biochemical stratagem for obligate parasitism of
ACUTE Q FEVER IN PATIENTS WITH eukaryotic cells by Coxiella burnetii. Proc Natl Acad Sci USA 1981;78:
UNDERLYING VALVULAR DISEASE 3240–4.
11. Dupuis G, Petite J, Peter O, Vouilloz M. An important outbreak of human Q
In patients with underlying valvular disease and acute Q fever, experts fever in a Swiss Alpine valley. Int J Epidemiol 1987;16:282–7.
suggest that hydroxycholoroquine should be used in combination 12. Tissot-Dupont H, Vaillant V, Rey S, Raoult D. Role of sex, age, previous valve
with doxycycline for 12 months [18]. This regimen may prevent lesion, and pregnancy in the clinical expression and outcome of Q fever after
endocarditis. a large outbreak. Clin Infect Dis 2007;44:232–7.
13. Rolain JM, Lepidi H, Harle JR, et al. Acute acalculous cholecystitis associated
PREGNANCY with Q fever: report of seven cases and review of the literature. Eur J Clin
Microbiol Infect Dis 2003;22:222–7.
Treatment of pregnant women with Q fever infection is difficult. 14. Matonti F, Conrath J, Bodaghi B, et al. Uveitis in the course of Q-fever. Clin
Many of the drugs used to treat Q fever are contraindicated during Microbiol Infect 2009;15:176–7.
pregnancy (e.g. doxycycline, fluoroquinolones). The use of long-term 15. Million M, Lepidi H, Raoult D. Q fever: current diagnosis and treatment
cotrimoxazole therapy has been shown to decrease the risk of placen- options. Med Mal Infect 2009;39:82–94.
titis, obstetrical complications, and maternal chronic Q fever infection 16. Brouqui P, Dupont HT, Drancourt M, et al. Chronic Q fever. Ninety-two cases
[26]. Newer macrolides may also be of clinical use. from France, including 27 cases without endocarditis. Arch Intern Med
1993;153:642–8.
17. Botelho-Nevers E, Fournier PE, Richet H, et al. Coxiella burnetii infection of
Q FEVER ENDOCARDITIS aortic aneurysms or vascular grafts: report of 30 new cases and evaluation of
Patients with Q fever endocarditis should be treated with a prolonged outcome. Eur J Clin Microbiol Infect Dis 2007;26:635–40.
course of combination therapy of hydroxychloroquine and doxycy- 18. Fenollar F, Thuny F, Xeridat B, et al. Endocarditis after acute Q fever in patients
cline [27]. The optimum duration of treatment is 18 months for with previously undiagnosed valvulopathies. Clin Infect Dis 2006;42:
native valves and 24 months for prosthetic valves [28]. This duration 818–21.
19. Fournier PE, Marrie TJ, Raoult D. Diagnosis of Q fever. J Clin Microbiol
should be extended only in the absence of favorable serological out-
1998;36:1823–34.
comes. Patients should be serologically monitored for at least 5 years
20. Carcopino X, Raoult D, Bretelle F, et al. Q Fever during pregnancy: a cause of
because of the risk of relapse.
poor fetal and maternal outcome. Ann NY Acad Sci 2009;1166:79–89.
21. Raoult D, Fenollar F, Stein A. Q fever during pregnancy: diagnosis, treatment,
CHILDREN and follow-up. Arch Intern Med 2002;162:701–4.
No reliable antibiotic regimen can be recommended for children. 22. Stein A, Raoult D. Q fever during pregnancy: a public health problem in
southern France. Clin Infect Dis 1998;27:592–6.
Doxycycline should be prescribed when the disease is
23. Houpikian P, Raoult D. Blood culture-negative endocarditis in a reference
life-threatening.
center: etiologic diagnosis of 348 cases. Medicine (Baltimore) 2005;84:
162–73.
PREVENTION 24. Raoult D. Treatment of Q fever. Antimicrob Agents Chemother 1993;37:
A human vaccine is commercially available in Australia (Q-VAX). 1733–6.
Prevention usually involves limiting exposure to infected animals and 25. Gikas A, Kofteridis DP, Manios A, et al. Newer macrolides as empiric treat-
ment for acute Q fever infection. Antimicrob Agents Chemother 2001;45:
their products, especially placental materials.
3644–6.
26. Carcopino X, Raoult D, Bretelle F, et al. Managing Q fever during pregnancy:
REFERENCES the benefits of long-term cotrimoxazole therapy. Clin Infect Dis 2007;45:
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1. Raoult D, Marrie T. Q fever. Clin Infect Dis 1995;20:489–95. 27. Raoult D, Houpikian P, Tissot DH, et al. Treatment of Q fever endocarditis:
2. Raoult D, Marrie T, Mege J. Natural history and pathophysiology of Q fever. comparison of 2 regimens containing doxycycline and ofloxacin or hydroxy-
Lancet Infect Dis 2005;5:219–26. chloroquine. Arch Intern Med 1999;159:167–73.
3. Wade AJ, Cheng AC, Athan E, et al. Q fever outbreak at a cosmetics supply 28. Million M, Thuny F, Richet H, Raoult D. Long-term outcome of Q fever
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Trench Fever 67
Barbara Doudier, Philippe Brouqui
Trench fever is caused by Bartonella quintana, a facultative intracellular Bartonella quintana is also a cause of bacillary angiomatosis and pelio-
bacterium transmitted by the human body louse. An estimated 1 sis hepatis. These are disorders of vascular hyperproliferation linked
million people were affected by trench fever during World War I [1]. with endothelial cell proliferation and pseudo-tumor formation in
It is characterized by attacks of fever that last 2–4 days and is associ- immunocompromised persons, especially those with advanced HIV
ated with headache, pain in the shin and dizziness, which recur every infection [11]. Variable outer membrane proteins (“VOMPS”) of B.
4–6 days, although each succeeding attack is usually less severe. quintana are involved in vascular endothelial growth factor (VEGF)
Trench fever is now most commonly associated with conditions that secretion and inducing vascular proliferation.
predispose to louse infestation, including civil conflict, poverty, over-
crowding, and displacement [2], as well as homelessness in industrial-
ized areas, including Europe and the USA [3].
CLINICAL FEATURES
TRENCH FEVER
EPIDEMIOLOGY Trench fever is an acute disease characterized by sudden onset of
Bartonella quintana is a cosmopolitan bacterium transmitted by the high-grade fever, headaches, dizziness, and a characteristic pain in the
human body louse, Pediculus humanus corporis, which lives in clothes shins. Dizziness and headaches are sometime so sudden that soldiers
and is associated with poverty, lack of hygiene, and cold weather (Fig. have been known to fall over in the trenches. Other symptoms include
67.1). Pediculosis (lice infestation) is transmitted by contact with post-orbital pain (typically exacerbated by movement), pain in the
clothes or bedding and is prevalent in impoverished, as well as home- lower limbs and back, constipation, a rash on the face, and a loss of
less, populations (Fig. 67.2). In San Francisco, 33.3% of body lice- appetite [12]. The first episode of fever may last 2–4 days and may be
infested persons and 25% of head lice-infested persons had lice pools followed by relapses every 4–6 days, giving rise to trench fever’s
561
562 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
IMMUNOHISTOCHEMISTRY
Immunohistochemistry may also be used to detect B. quintana in
tissue samples, such as resected cardiac valvular tissue or bacillary
angiomatosis tissue.
TROPICAL AREAS
The burden of B. quintana infection and trench fever in resource-
limited settings is uncertain. Bartonella quintana has a worldwide dis-
tribution: trench fever has occurred among refugees in Burundi [2];
B. quintana-associated endocarditis has been reported in Ethiopia,
Algeria, Tunisia [13], and Senegal; and bacillary angiomatosis has
been reported in HIV patients in South Africa.
TREATMENT
Adults with trench fever or B. quintana chronic bacteremia should be
treated with doxycycline 200 mg orally daily for 4 weeks and gen-
tamycin 3 mg/kg IV once a day for 2 weeks [15]. Optimal treatment
FIGURE 67.2 Pediculosis and super infection in a homeless man seeking for children younger than 8 years of age is unknown, but erythromy-
care during a snapshot intervention in shelters. (Reproduced with permission
cin may be an alternative. Individuals with bacillary angiomatosis or
from Brouqui P, Stein A, Dupont HT, et al. Ectoparasitism and vector-borne diseases
hepatic peliosis should be treated with erythromycin 500 mg orally
in 930 homeless people from Marseilles. Medicine (Baltimore) 2005;84:61–8.)
4 times a day for 3 and 4 months, respectively [15]. Children can be
similarly treated with oral erythromycin ethylsuccinate 40 mg/kg
total/day in four divided doses (maximum total daily dose, 2 g/day)
appellation of “quintane” fever (reflected in its scientific name, B.
for 3–4 months, respectively [15].
quintana).
The incubation period is typically 15–25 days but may be reduced to
6 days in experimental infections. Although trench fever often results REFERENCES
in prolonged disability, it is rarely fatal. 1. Raoult D, Roux V. The body louse as a vector of reemerging human diseases.
Clin Infect Dis 1999;29:888–911.
CHRONIC INFECTION AND COMPLICATIONS 2. Raoult D, Ndihokubwayo JB, Tissot-Dupont H, et al. Outbreak of epidemic
typhus associated with trench fever in Burundi. Lancet 1998;352:353–8.
CAUSED BY B. QUINTANA 3. Badiaga S, Raoult D, Brouqui P. Preventing and controlling emerging and
Persistent bacteremia has long been associated with B. quintana infec- reemerging transmissible diseases in the homeless. Emerg Infect Dis 2008;
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20–30% of patients; B. quintana has been detected in the blood of 4. Bonilla DL, Kabeya H, Henn J, et al. Bartonella quintana in body lice and head
trench fever patients up to 8 years after initial infection. lice from homeless persons, San Francisco, California, USA. Emerg Infect Dis
2009;15:912–15.
Bartonella species are associated with culture-negative endocarditis. 5. Brouqui P, Stein A, Dupont HT, et al. Ectoparasitism and vector-borne diseases
Clinical features include fever. Bartonella endocarditis is typically in 930 homeless people from Marseilles. Medicine (Baltimore) 2005;84:
diagnosed in individuals without previous valvular abnormalities, 61–8.
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6. Raoult D, Birtles RJ, Montoya M, et al. Survey of three bacterial louse-associated 11. Schulte B, Linke D, Klumpp, S, et al. Bartonella quintana variably expressed
diseases among rural Andean communities in Peru: prevalence of epidemic outer membrane proteins mediate vascular endothelial growth factor secre-
typhus, trench fever, and relapsing fever. Clin Infect Dis 1999;29:434–6. tion but not host cell adherence. Infect Immun 2006;74:5003–13.
7. Seki N, Kasai S, Saito N, et al. Quantitative analysis of proliferation and excre- 12. Kostrzewski J. Epidemiology of trench fever. Med Dosw Mikrobiol 1950;2:19–
tion of Bartonella quintana in body lice, Pediculus humanus L. Am J Trop Med 51 [in Polish].
Hyg 2007;77:562–6. 13. Znazen A, Rolain JM, Hammami N, et al. High prevalence of Bartonella quin-
8. Drancourt M, Tran-Hung L, Courtin J, et al. Bartonella quintana in a 4000-year- tana endocarditis in Sfax, Tunisia. Am J Trop Med Hyg 2005;72:503–7.
old human tooth. J Infect Dis 2005;191:607–11. 14. Badiaga S, Foucault C, Rogier C, et al. The effect of a single dose of oral
9. Raoult D, Dutour O, Houhamdi L, et al. Evidence for louse-transmitted ivermectin on pruritus in the homeless. J Antimicrob Chemother 2008;62:
diseases in soldiers of Napoleon’s Grand Army in Vilnius. J Infect Dis 404–9.
2006;193:112–20. 15. Rolain JM, Brouqui P, Koehler JE, et al. Recommendations for treatment of
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Bartonellosis: Carrion’s Disease and
68 other Bartonella Infections
Ciro Maguiña, Eloy E Ordaya
FIGURE 68.2 Peruvian wart, miliary form (small) final. FIGURE 68.3 Peruvian wart, mular form.
demonstrating proliferation of endothelial cells, monocytes, and resistant to vancomycin, aminoglycosides, clindamycin, and
macrophages, and neovascularization. Mitoses may be evident. Analy- carbapenems.
sis of tissue using the Warthin-Starry stain can reveal bacteria dis-
persed in the tissue. Immunohistochemistry may also be used to Because of the high rate of co-infection with Salmonella during the
indentify B. bacilliformis [7, 8]. acute Oroya fever phase, many experts use a fluoroquinolone, such as
ciprofloxacin, or chloramphenicol as front-line therapy (Table 68-2).
Serologic methods like western blot or PCR are also available to Amoxicillin plus clavulanic acid may be used in pregnant women;
diagnose individuals with Carrion’s disease, but are not used widely there are also anecdotal reports of clinical effectiveness with amoxicil-
because of their high cost and lack of standardization. lin alone.
Dexamethasone is sometimes administered for 3–4 days in patients
TREATMENT with severe neurologic complications in an attempt to reduce cerebral
edema, but this approach has not been well studied. Blood transfu-
In vitro, B. bacilliformis is susceptible to ß-lactams, tetracyclines, fluoro- sions are indicated for patients with severe anemia; pericardial effu-
quinolones, macrolides, rifampin, and chloramphenicol. They are sions may require drainage.
During the chronic verruga peruana phase, chloramphenicol and
ß-lactam penicillins are ineffective. Azithromycin is now the drug of
choice, although ciprofloxacin or rifampin are alternatives [9, 10].
TABLE 68-1 Differential Diagnosis of Bartonellosis or
Carrion’s Disease
OTHER BARTONELLA INFECTIONS
Oroya fever Over a dozen Bartonella spp. have been identified to cause disease in
humans. Beyond B. bacilliformis, perhaps the other two Bartonella of
Typhoid fever most clinical significance are Bartonella quintana, the agent of trench
Malaria fever, and Bartonella henselae, a cause of cat scratch disease.
Brucellosis
Viral hepatitis Trench fever was described in soldiers during World War I who deve
Leptospirosis loped a relapsing febrile illness associated with 5 days of fever. It is
Sepsis caused by B. quintana and the vector is the human body louse, Pedicu-
Systemic tuberculosis lus humanus humanus. Homelessness, poor sanitation, and lack of
Hematological malignancies personal hygiene are factors associated with this condition. The clini-
Parvovirus B19 infection cal course varies from a mild, afebrile state, to a relapsing fever with
Hemolytic anemias rash, bone pain, myalgias, headaches, and marked conjunctival injec-
Aplastic anemia tion. The organism can be cultured using special media, but most
Peruvian wart cases are diagnosed on clinical grounds or serology tests including
ELISA or immunofluorescent antibody (IFA) assay. Trench fever is a
Angioma self-limiting disease, but chloramphenicol or tetracycline show rapid
Bacillary angiomatosis disappearance of symptoms [1, 10].
Granuloma Pyogenicum
Kaposi’s sarcoma Cat scratch disease is cosmopolitan in distribution and is more
Leprosy common in children than adults. It is considered to be the most
Lymphomatoid papillomatosis common Bartonella infection worldwide. Bartonella henselae is now
Fibrosarcoma regarded as the main etiologic agent of cat scratch disease. It is trans-
Cutaneous lymphoma mitted to cats through fleas. Human infection occurs after scratches,
Reticuloendotheliosis bites, or licks from infected cats or from the bite of an arthropod
Molluscum contagiosum vector. Cat scratch disease classically presents as a chronic papular,
Chickenpox pustular or ulcerative skin lesion and regional lymphadenopathy after
Yaws a cat scratch, but, not infrequently, B. henselae can cause systemic
Spitz nevus manifestations including encephalitis, retinitis, non-specific fever, and
Parinaud’s oculoglandular syndrome. Diagnosis is usually based on
clinical presentation, serology, or histopathology. Cat scratch disease practice, 2nd edn. Philadelphia: Elsevier Churchill Livingstone; 2006:
is often self-limited, but patients are often treated with azithromycin 454–62.
or doxycycline [1, 11]. 4. Maguiña C, Garcia PJ, Gotuzzo E, et al. Bartonellosis (Carrion’s Disease) in
the modern era. Clin Inf Dis 2001;33:772–9.
Bartonella henselae and B. quintana can also cause bacillary angioma- 5. Kosek M, Lavarello R, Gilman RH, et al. Natural history of infection with
tosis, a disorder of vascular hyperproliferation. The typical lesion is a Bartonella bacilliformis in a nonendemic population. J Infect Dis
reddish-purple papule, but may be a hyperkeratotic plaque, or an 2000;182:865–72.
infiltrative or hypervascular nodule. Bacillary angiomatosis is most 6. Maguiña Vargas C, Ordaya Espinoza E, Ugarte-Gil C, et al. Cardiovascular
commonly seen in severe immunocompromised patients, especially involvement during the acute phase of Carrion’s disease or human Bartonel-
those with advanced HIV infection. Involvement can be confined to losis: A 20-year experience in Cayetano Heredia National Hospital. Acta Med
the skin, or can involve deep organs and structures. Involvement of Peruana 2008;25:30–8.
the liver is referred to as peliosis hepatis. Diagnosis is confirmed by 7. Birtles RJ, Fry NK, Ventosilla P, et al. Identification of Bartonella bacilliformis
histopathology using Warthin-Starry or Giemsa stain. Treatment genotypes and their relevance to epidemiological investigations of human
bartonellosis. J Clin Microbiol 2002;40:3606–12.
usually involves prolonged use of erythromycin alone or combined
8. Henriquez C, Infante B, Merello J, et al. Identificación de Bartonella
with doxycycline in AIDS patients [1, 10, 12].
bacilliformis por métodos moleculares. Rev Med Hered 2002;13:58–63
A number of Bartonella species can also cause “culture-negative” [in Portuguese].
chronic endocarditis, which is most frequently caused by B. quintana 9. Tarazona A, Maguiña C, Lopez de Guimaraes D, et al. Terapia antibiótica para
or B. henselae, or both. el manejo de la bartonelosis o enfermedad de Carrión en el Perú. Rev Perú
Med Exp Salud Publica 2006;23:188–200. [in Portuguese].
10. Rolain JM, Brouqui P, Koehler JE, et al. Recommendations for treatment of
REFERENCES human infections caused by Bartonella species. Antimicrob Agents Chemother
2004;48:1921–33.
1. Maguiña C, Guerra H, Ventosilla P. Bartonellosis. Clin Dermatol 11. Piérard-Franchimont C, Quatresooz P, Piérard GE. Skin diseases associated
2009;27:271–80. with Bartonella infection: Facts and controversies. Clin Dermatol
2. Maguiña Vargas C, Ugarte-Gil C, Breña Chavez P, et al. Update of Carrion’s 2010;28:483–8.
disease. Rev Med Hered 2008;19:36–41. 12. Maguiña C, Gotuzzo E. Bartonelose. In: Focaccia R, ed. Tratado de Infecto
3. Walker D, Maguiña C, Minnick M. Bartonelloses. In: Guerrant R, logia, 3rd edn. Sao Paulo: Atheneu; 2006: 759–62 [in Portuguese].
Walker D, Weller P, eds. Tropical infectious diseases: principles, pathogens, &
Typhoid and Paratyphoid
69 (Enteric) Fever
Jason B Harris, W Abdullah Brooks
regions with the highest incidence are South central Asia (~1000
cases/100,000 person-years) and Southeast Asia (~100 cases/100,000
Key features person-years). Sub-Saharan Africa reports more non-typhoidal Sal-
monella bacteremia than S. Typhi, yet major epidemics of typhoid
l Salmonella enterica serotypes Typhi and Paratyphi A, B, and fever occur.
C are the causative agents of typhoid and paratyphoid
Paratyphoid fever. Salmonella Paratyphi A causes approximately 5
fever, respectively. Enteric fever refers to either typhoid or million cases of enteric fever annually [2]. The proportion of cases of
paratyphoid fever enteric fever caused by S. Paratyphi A has increased over the past two
l Enteric fever is a nonspecific illness characterized by decades, and now exceeds 50% in parts of southern Asia [3]. This is
prolonged fevers and persistent bacteremia significant as current typhoid fever vaccines do not protect against S.
Paratyphi A. Serotypes Paratyphi B and C are rare causes of enteric
l Life-threatening complications of enteric fever include
fever.
intestinal hemorrhage, perforation, and encephalopathy
l The diagnosis of enteric fever should be considered in any
TRANSMISSION AND PATTERNS OF INFECTION
patient with prolonged fever and exposure in an endemic
area Source of Infection
l Because of the limitations of diagnostic tests, the initiation Salmonella Typhi and S. Paratyphi A, B, and C are human-restricted
of antibiotic treatment for enteric fever is often based on a pathogens; no known animal reservoirs exist. Enteric fever patients
shed organisms in the stool during acute illness and often for months
presumptive diagnosis
after convalescence. In the pre-antibiotic era, up to 3% of typhoid
l The choice of empiric antibiotic therapy depends on local fever survivors developed chronic asymptomatic bacterial shedding in
patterns of antibiotic resistance the stool. Chronic carriage can persist for life; gallbladder disease is a
l Vaccines to prevent typhoid are available major risk factor for carriage. A recent study in Nepal found that 5%
of individuals undergoing elective cholecystectomy for gallstones
grew S. Typhi of S. Paratyphi A from biliary cultures [4]. While chronic
carriers are a source of transmission where disease is sporadic, it is
unclear whether carriers are an important reservoir in endemic areas.
INTRODUCTION
Typhoid and paratyphoid fever are systemic febrile illnesses caused Mode of Transmission
by Salmonella enterica serotype Typhi and serotypes Paratyphi A, B, or In endemic areas, most infections are acquired via contaminated food
C, respectively. Enteric fever refers to either typhoid or paratyphoid or water – with water playing the greater role in endemic urban set-
fever. Collectively, S. Typhi and S. Paratyphi A cause approximately tings. The inoculum required to produce disease in 50% of adult
27 million cases of enteric fever and over 200,000 deaths annually volunteers (ID50) is 107 organisms, although as few as 103 organisms
(Box 69.1). may produce disease. Risk factors include drinking non-boiled water
and eating food prepared outside the home. While direct contact with
Both typhoid and paratyphoid fever are characterized by prolonged a typhoid fever patient is an infection risk factor, more than 80% of
fever and sustained bacteremia. The name typhoid, meaning “typhus- cases occur in individuals with no known contact [5]. In South central
like”, was coined in 1829 by A. Louis and reflects the difficulty physi- Asia and Southeast Asia, peak transmission occurs during the
cians had in differentiating the illness from epidemic typhus. Among monsoon season, although disease is present year-round. Large water-
19th-century American physicians, “typho-malaria” was a common borne epidemics may be superimposed on endemic seasonality.
diagnosis, indicative of the difficulty differentiating typhoid from
other causes of persistent fever. This proved fortuitous in 1948, when
two patients were referred for a study of the efficacy of chlorampheni- Antimicrobial Resistance
col in scrub typhus, but were subsequently found to have S. Typhi Chloramphenicol-resistant S. Typhi was described in 1950 – 2 years
bacteremia. Both patients improved rapidly after antibiotic therapy after the antibiotic was first used to treat patients with typhoid fever.
– a finding that ushered in the post-antibiotic era in typhoid fever [1]. Multidrug-resistant S. Typhi, carrying plasmid-mediated resistance
to chloramphenicol, ampicillin, trimethoprim, and sulfonamides,
EPIDEMIOLOGY became common in the 1980s, and nalidixic-acid-resistant S. Typhi
and S. Paratyphi A in the 1990s. Nalidixic-acid-resistant strains are
INCIDENCE AND DISTRIBUTION OF ENTERIC associated with decreased susceptibility to fluoroquinolones (an
increased risk of treatment failure) and increased mortality [6]. In
FEVER (Fig. 69.1) Asia, most S. Typhi and Paratyphi A strains are now nalidixic-acid-
Typhoid fever. Salmonella Typhi causes approximately 22 million cases resistant. In the past decade, complete resistance to ciprofloxacin and
of typhoid fever annually with an estimated mortality of 1% [2]. The extended spectrum cephalosporins has emerged [7]. While resistance
568
Ty p h o i d a n d Pa rat y p h o i d ( E nter ic) Fever 569
to these newer agents is increasing, susceptibility to original first-line range by location (0–15%), with a median mortality rate of 2% [8].
agents may be re-emerging, at least in some locations. Thus, antimi- In the USA, where disease is sporadic, the fatality rate of reported cases
crobial resistance in S. Typhi and Paratyphi A varies significantly by is 0.2% [9].
region and patterns of antibiotic use.
Age and Immunity
Severity In the most highly endemic communities, the incidence of enteric
The majority of cases are not severe enough to require hospitalization. fever is highest in children between the age 1 and 5 years old. In such
Case fatality prevalence for typhoid fever patients in the pre-antibiotic areas, S. Typhi is the leading cause of bacteremia in children and may
era was approximately 15%. Current hospital-based mortality rates be responsible for over 75% of cases of occult bacteremia [10]. In less
endemic areas, the median age of patients with typhoid fever increases.
Relapse and recurrent infections among patients who have recovered
from typhoid fever demonstrate that immunity is neither lifelong nor
universally acquired after a single illness.
BOX 69.1 Nomenclature of Salmonella
Infections Sporadic Disease and Travelers
In countries where typhoid fever is sporadic (<1/100,000 person-
The multiple microbiologic, serologic and clinical designations years), most cases are imported through travel. In the USA, over 75%
applied to Salmonella infections are confusing [36]. Most patho- of cases are travel-related. The typhoid fever incidence is estimated at
genic Salmonella belong to a single subspecies designated Sal- 10 per 1 million travelers arriving from Asia, but increases to 89 per
monella enterica subspecies enterica. In addition to this species 1 million travelers arriving from India. Many remaining cases can be
traced to small, foodborne outbreaks and/or a chronic carrier [9]. The
designation, Salmonella are classified serologically. The sero- risk of travel-related enteric fever is higher among travelers visiting
group is assigned based on the O antigen alone, while the friends and relatives [11].
serotype designation, from which the name is derived, is based
on both the O and H antigens.
NATURAL HISTORY, PATHOGENESIS
Salmonella enterica subsp. enterica includes over 1400 sero- AND PATHOLOGY
types. Although the full name of the cause of typhoid fever is
Salmonella enterica subsp. enterica serotype Typhi, it is nor- INVASION AND LATENCY
mally just shortened to: S. Typhi. While serogroup designation Salmonella Typhi and S. Paratyphi A, B, and C are rod-shaped, Gram-
is performed routinely in many laboratories, the test lacks clini- negative bacteria that have adapted to survive and replicate in human
cal utility. Complete serotype identification is often performed macrophages. Salmonella Typhi and Paratyphi breach the intestinal
barrier though specialized microfold cells (M cells) that transport the
in a reference laboratory; however, S. Typhi and Paratyphi A can
bacteria across the basolateral membrane where they are phagocy-
also be identified by biochemical tests in a routine microbiol- tosed by macrophages in the intestinal lymphoid tissue. This invasion
ogy laboratory. Identification of S. Typhi and Paratyphi A are phase of infection is usually asymptomatic, but may be accompanied
reviewed in detail in the World Health Organization’s “The diag- by transient diarrhea in 10–20% of patients. Latent infection typically
nosis, treatment and prevention of typhoid fever” [22]. lasts one to two weeks (range 3–60 days), depending on the number
of organisms ingested.
Clinically, Salmonella are classified as typhoidal or non-
typhoidal. The typhoidal serotypes are S. Typhi and Paratyphi A, DISSEMINATED INFECTION
B and C. All others are classified as non-typhoidal. However, this
Typhoidal Salmonella deploy an array of virulence factors that enable
is also misleading as many non-typhoidal strains also cause them to persist and replicate in an intracellular compartment [12].
invasive infection that may mimic typhoid fever. Intracellular organisms disseminate throughout the reticuloendothe-
lial tissues via the blood and lymphatic system. Infection is
CLINICAL FEATURES fever varies depending on the time, region and the type of clinical population
(hospitalized or ambulatory) assessed. Estimates are drawn from recent case
The clinical features of enteric fever are nonspecific. The major clinical series in an endemic area presenting for ambulatory or inpatient care [16, 37].
findings in enteric fever are listed in Table 69-1. Fever, without local-
izing signs or symptoms, may be the sole manifestation of enteric
fever.
Most enteric fever cases are diagnosed in the ambulatory setting, are
mild and up to 90% are treated as outpatients [15]. In contrast, classic In contrast to other causes of bacteremia, patients with enteric fever
descriptions of typhoid fever are based on hospitalized patients with rarely demonstrate leukocytosis, neutrophilia, or increased immature
more severe disease. Although life-threatening complications of neutrophils. A typical leukocyte count is 5–8 × 106 cells per mL, with
enteric fever usually occur more than a week after fever onset, both 60–75% neutrophils [16]. However, neither leukocytosis nor leuko-
intestinal perforation and encephalopathy may occur within days of penia excludes enteric fever. Hematocrit and platelet counts are
initial fever. usually normal or slightly low. Modest elevations, typically double
the upper end of the normal range, in aspartate transaminase and
Historically, paratyphoid fever was considered less severe than typhoid alanine transaminase are common. Excessive levels of blood transam-
fever. Current evidence suggests that infections caused by S. Typhi and inases should prompt concern for other etiologies, including viral
S. Paratyphi A are clinically indistinguishable and equally severe [16]. hepatitis.
NEUROLOGIC COMPLICATIONS
Severe enteric fever may present with encephalopathy. A history of
confusion is common and patients often demonstrate an apathetic
affect. Severe encephalopathy manifested by delirium and stupor;
coma occurs in a smaller number of hospitalized patients and is
associated with a high risk of mortality [18, 20, 21]. Seizures are most
common in young children and are associated with increased mortal-
ity risk [18]. Even in severe encephalopathy or seizure cases, cerebro-
spinal fluid (CSF) cultures are usually negative and pleocytosis, if
FIGURE 69.2 Intraoperative photograph of intestinal perforation caused present, reveals fewer than 35 cells per uL [20, 21]. Meningitis is
by S. Typhi. A single perforation is seen on the anti-mesenteric border of uncommon and is primarily seen in infants. Focal neurologic findings
the inflamed small bowel along with patchy exudates on the serosal have been reported but should prompt consideration of an alternative
surface (photo courtesy of Dr Pukar Maskey, Patan Hospital, Katmandu, Nepal). diagnosis.
572 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
OTHER COMPLICATIONS include the culture medium, prior antibiotic exposure, blood volume
and the duration of illness prior to sample collection. The overall
Pneumonia is a serious comorbidity associated with severe enteric sensitivity of blood culture ranges from 40–80%, reflecting the low
fever [18]. Although enteric fever is a disseminated bacterial infection, number of organisms present in the blood and prior antibiotic use.
distal pyogenic complications are not common. This contrasts with High blood volumes optimize the yield of blood culture; the World
invasive non-typhoidal Salmonella in which osteomyelitis and Health Organization (WHO) recommends that 10–15 ml of blood
endovascular infection occur more frequently. Numerous other be obtained from school-aged children and 2–4 ml of blood be used
enteric fever complications have been reported, affecting all major for culture in toddlers and pre-school-aged children [22]. Although
organ systems [15]. alternatives to standard blood culture (e.g. direct plating of the buffy
coats or the use of selective ox bile media) have been recommended,
the use of routine blood cultures with standard broth media is prefer-
PATIENT EVALUATION, DIAGNOSIS able because such methods may detect other potential bacterial path-
AND DIFFERENTIAL DIAGNOSIS ogens as well.
Enteric fever can be a life-threatening infection if not treated with Bone marrow cultures have an 80–95% sensitivity for isolating S.
appropriate antimicrobial therapy and should be suspected in any Typhi. Bone marrow cultures may remain positive for several days
patient with prolonged fever and exposure to an endemic area. There after initiating antibiotics. However, the invasiveness of bone marrow
are no reliable clinical criteria to establish the diagnosis of enteric culture limits its practical utility in uncomplicated cases. Under
fever, and no sensitive or specific diagnostic laboratory tests. There- optimal conditions, a single high volume (>15 ml) blood culture in
fore, the diagnosis of enteric fever is usually presumptive. an adult has a sensitivity nearly equivalent to a 1 ml bone marrow
culture [13, 23].
CLINICAL EVALUATION Stool cultures are positive in over 50% and 30% of infected children
The first requirement for diagnosis is clinical suspicion. In a highly and adults, respectively. Rectal swabs are not recommended, and the
endemic area, three or more days of nonfocal fever should prompt yield of stool cultures is optimized by the use of >1 g of stool and a
consideration of enteric fever. Patients should undergo a routine clini- selective enrichment broth [22]. Cultures obtained from intestinal
cal history and physical examination. Although most of the findings biopsies of patients with perforation are rarely positive [19].
associated with enteric fever are nonspecific, many other causes of
febrile illness will become apparent after a careful history and exami- SEROLOGIC AND MOLECULAR DIAGNOSIS
nation. Routine laboratory studies are also of limited value in estab-
lishing a diagnosis of enteric fever, but may be more useful in The most commonly utilized diagnostic test for enteric fever is Widal’s
eliminating other potential causes of nonfocal fever. test, which was developed in 1896 and detects agglutinating antibod-
ies against the O and H antigens of S. Typhi. Widal’s test is not suf-
In a highly endemic area, factors that should increase the clinical ficiently sensitive, specific or reliable enough to be an optimal
suspicion for enteric fever early in the course of the illness include: diagnostic assay for typhoid fever and it does not aid in the diagnosis
young age; a temperature above 39°C; ill appearance; and any of paratyphoid fever, as these antibodies are not cross-reactive against
abdominal complaints, including diarrhea, constipation or abdomi- S. Paratyphi A, B and C antigens. A false-negative Widal’s test may
nal pain [10]. In the most highly endemic settings, three of more days result from the assay being performed early in the course of illness
of fever without localizing signs and a combination of any of these and a false-positive Widal’s test is more likely in an area of high
features, in the absence of another obvious cause, may be sufficient endemnicity where antibodies may represent past infection.
to prompt a diagnostic evaluation for enteric fever along with the
initiation of empiric therapy. Rapid serologic tests, including the IDL Tubex® and Typhidot® assays
are available. In principle, tests such as Tubex, which detects IgM
As fever duration increases, the likelihood of enteric fever increases. antibodies to the O9 antigen – a T-cell independent response to
Any patient with seven or more days of unexplained fever from an Salmonella infection which is, therefore, rapid – and Typhidot, which
area where enteric fever is endemic should undergo a diagnostic detects both IgM and IgG to the 50kD antigen of S. Typhi, should be
evaluation and empiric treatment should be considered, given the useful in identifying early acute infection [22]. However, in practice,
potential complications of untreated enteric fever [15]. these tests have met with mixed success in high endemic settings
because they have not consistently demonstrated an ability to distin-
DIFFERENTIAL DIAGNOSIS guish between current and past infection and, in some cases, have not
consistently been as sensitive as the Widal test [24, 25]. While diag-
The differential diagnosis should reflect local febrile disease preva- nostic approaches based on nucleic acid detection appear promising,
lence. Malaria, dengue fever, influenza, leptospirosis, rickettsial infec- these tests are not widely available.
tions, urinary tract infection, and other causes of childhood occult
bacteremia (e.g. Streptococcus pneumoniae, Haemophilus influenzae, and
Neisseria meningitiditis) should all be considered in the differential
diagnosis of fever without localizing signs. In patients with prolonged
TREATMENT AND PREVENTION OF
fever (>7 days) with or without localizing signs, the infectious dif- ENTERIC FEVER
ferential diagnosis includes malaria, Epstein–Barr virus infection, Appropriate antibiotics and supportive care reduce the mortality of
tuberculosis, brucellosis, tularemia, plague, occult abscesses (includ- enteric fever from 10–15% to less than 1%. Fevers resolve after an
ing amebic liver abscess), and typhus. average of 3–5 days of appropriate antibiotics, compared with 3–4
weeks in untreated infections. The widespread emergence of antibi-
MICROBIOLOGIC DIAGNOSIS otic resistant S. Typhi and Paratyphi A complicates the choice of
Although presumptive diagnosis of enteric fever is sufficient justifica- antibiotics. Most patients can be managed in an ambulatory setting.
tion to initiate treatment in an ill-appearing patient, a definitive diag-
nosis of enteric fever can only be made by detection or isolation of ANTIBIOTICS FOR ENTERIC FEVER
S. Typhi or S. Paratyphi A, B, or C from blood, bone marrow, or
other normally sterile clinical specimen. The isolation of a causative Uncomplicated enteric fever is usually treated with a single antibacte-
organism also provides the opportunity to optimize antimicrobial rial drug. Antimicrobial choice depends on patient age, their ability
therapy. to take oral medications, and drug availability and cost. Knowledge
of antibiotic resistance patterns is essential because, in most cases,
Isolation of S. Typhi or Paratyphi A is most commonly achieved by empiric antibiotics are initiated before an isolate is obtained. Table
blood culture. Factors that affect the sensitivity of blood isolation 69-3 summarizes antibiotic therapy for enteric fever.
Ty p h o i d a n d Pa rat y p h o i d ( E nter ic) Fever 573
TABLE 69-3 Antibiotics Commonly Used to Treat Individuals with Enteric Fever
CHLORAMPHENICOL, AMPICILLIN, the risk of relapse and chronic carriage. Ampicillin, and its oral for-
mulation amoxicillin, and trimethoprim-sulfamethoxazole are also
AND TRIMETHOPRIM- inexpensive, broad-spectrum antibiotics that are effective against sus-
SULFAMETHOXAZOLE ceptible strains of S. Typhi and Paratyphi A.
possibility of a poor clinical response to ciprofloxacin, even if the NaR MANAGEMENT OF INTESTINAL
strain meets the Clinical Laboratory and Standards Institute’s cut-off
for susceptibility to ciprofloxacin [6].
COMPLICATIONS
Prompt surgical intervention in suspected cases of perforation is the
In the absence of NaR, ciprofloxacin, levofloxacin and ofloxacin are mainstay of therapy. The majority of cases involve single perforation
highly efficacious in the treatment of enteric fever. These agents have along the anti-mesenteric border of the terminal ileum. However,
excellent oral bioavailability, result in rapid defervescence (an average careful inspection of the bowel is required, as multiple perforations
of ~3–4 days) and decreased rates of relapse and carriage compared are present in approximately 25% of patients and perforation can
with chloramphenicol and ß-lactam antibiotics. Concern about occur along the proximal or distal bowel. Surrounding tissues are
fluoroquinolone-induced cartilage toxicity in children is based on usually inflamed and friable. While simple closure may be performed
animal models; however, several studies support their safety in chil- in some cases, wedge excision with debridement of the necrotic bowel
dren [27]. or segmental resection is more often necessary. In cases of multiple
Gatifloxacin is a newer generation fluoroquinolone available in many perforations, more extensive resections and temporary ileostomy may
countries where enteric fever is endemic, has good in vitro activity be required. Drainage of fluid collections and peritoneal lavage
against NaR S. Typhi, and has demonstrated efficacy in the treatment should be performed prior to wound closure. Antibiotic coverage
of uncomplicated enteric fever caused by NaR Salmonella [28]. should be broadened to include other intestinal flora, including
Unfortunately, gatifloxacin was associated with increased frequency anaerobes. Perforation-associated mortality rates are variable; early
of hypoglycemia and hyperglycemia compared to other fluoroqui- recognition, surgical intervention and supportive care enhance sur-
nolones and, for this reason, was withdrawn from the US market and vival [19].
should be used, if ever, with caution. Alternative fluoroquinolones Intestinal hemorrhage can usually be managed through supportive
with improved safety profiles are available. care. Blood products, including packed red cells and plasma may
be needed to correct resulting anemia and optimize coagulation
THIRD-GENERATION CEPHALOSPORINS parameters in severe cases. Refractory bleeding and severe bleeding
The emergence of NaR stains with decreased fluoroquinolone suscep- leading to shock suggest the need for surgical resection of the involved
tibility (and associated treatment failures) have caused a shift toward bowel.
the use of third generation cephalosporins as first-line therapy in
more severe cases, although this approach may result in a longer TREATMENT OF RELAPSE
period until defervescence and has a higher relapse rate compared Relapse usually occurs within two weeks of the discontinuation of
with the use of effective fluoroquinolones [27]. Ceftriaxone is an antibiotics. Isolates obtained following a relapsed infection typically
effective antibiotic for treating enteric fever, including cases caused by have the same antibiotic susceptibility as the isolate from the primary
NaR isolates. However, ceftriaxone must be given parenterally and episode. Relapsed illness is usually milder compared with the primary
short courses (≤7 days) are associated with high rates of relapse [29]. episode. The approach to treating a relapsed infection is the same as
Furthermore, clinical defervescence may be delayed and longer treating a primary episode.
courses of ceftriaxone may be required, depending on the clinical
response [30]. Cefixime is an oral, third-generation cephalosporin
that may be used to treat enteric fever, although short courses of TREATMENT OF CHRONIC CARRIERS
cefixime also result in high rates of relapse. Resistance to ceftriaxone Chronic carriage is asymptomatic and not associated with recurrence
and other extended spectrum ß-lactam antibiotics is rare, but of illness. Although chronic carriage is associated with an increased
increasing [7]. risk of gallbladder carcinoma, no clear, causal relationship is estab-
lished and it is unknown whether the eradication of carriage reduces
AZITHROMYCIN this risk of carcinoma. The decision to attempt to eradicate carriage
is based on public health considerations and it is more difficult to
Azithromycin is an effective oral treatment for uncomplicated enteric
eliminate carriage in patients with cholelithiasis. However, in some
fever, including enteric fever caused by NaR and multidrug-resistant
case-series, ciprofloxacin has demonstrated over 90% efficacy in the
isolates [31]. A 7-day course of azithromycin appears to be as effective
eradication of carriage [34]. Cholecystectomy may be necessary to
as gatifloxacin in the treatment of enteric fever caused by NaR isolates
eradicate carriage in persons with cholelithiasis that fail medical
and results in lower rates of clinical failure and relapse compared with
therapy but for whom eradication is essential for public health
cefixime or ceftriaxone. Azithromycin is safe in children, has excellent
reasons (e.g. food-handlers).
bioavailability and pharmacokinetics with once-daily dosing and
reaches high intracellular concentrations that may contribute to the
high rates of cure seen after seven days of therapy. PREVENTION
There are two licensed commercially-available vaccines for typhoid
SUPPORTIVE AND ADJUNCTIVE THERAPY fever: the Vi (capsular) polysaccharide parenteral vaccine and a live
Adjunctive therapy is aimed at managing the inflammatory complica- attenuated Ty21a oral vaccine (Table 69-4). Both vaccines are prima-
tions of infection. In a double-blind trial in Indonesia in the 1980s, rily used by travelers; neither vaccine protects against paratyphoid
a short course of high-dose intravenous dexamethasone initiated con- fever A. Although the WHO’s Strategic Advisory Group of Experts
currently with the first dose of antibiotics significantly reduced mor- (SAGE) has recommended that typhoid vaccination programs be con-
tality in critically ill patients with typhoid fever with shock and/or sidered in highly endemic settings [35], these vaccines are not yet
profound encephalopathy manifested as delirium or obtundation widely utilized in most endemic regions. A Vi-conjugate vaccine
[32]. In suspected cases of severe typhoid fever with shock or encepha- has also been shown to be both safe and immunogenic, including
lopathy in adults and children, dexamethasone should be adminis- in young children in areas of the world endemic for typhoid. A previ-
tered along with intravenous antibiotics as soon as possible, usually ous whole-cell, killed parenteral vaccine required multiple injections,
before the results of blood cultures are obtained, and may be admin- was associated with a high adverse event profile and should not
istered at an initial dose of 3 mg/kg IV, followed by 1 mg/kg IV every be used.
6 hours for eight additional doses.
Other strategies to prevent S. Typhi and Paratyphi A include interven-
Supportive care, including rehydration and nutritional management, tions to reduce exposure to food- and waterborne bacteria. At a house-
are important in patients with enteric fever. Rehydration and nutri- hold level, strategies include boiling and storing water in
tional supplementation can be managed according to WHO stand- narrow-mouthed, covered containers. Food safety involves hand-
ards. Despite historical concerns regarding their use, debilitating washing with soap before preparing or consuming foods, and the
fevers and malaise can be managed safely with antipyretics [33]. avoidance of certain food types in endemic areas, such as raw foods
Ty p h o i d a n d Pa rat y p h o i d ( E nter ic) Fever 575
TABLE 69-4 Commercially Available Vaccines for Typhoid Fever [11, 22]
Vaccine Type Route Dose and interval Minimum Protection Boosting Licensed in
age against interval in # countries
S. Typhi travelers
Ty21a Live-attenuated Oral Four doses 5* 50–80% Every five years 56**
Administer one dose every
other day until complete
Vi capsule Polysaccharide Intramuscular 1 2 50–80% Every two years >90**
antigen
*Five years and older per WHO [22], 6 years and older per Advisory Committee on Immunization Practices [11]. **As of March 2010.
and shellfish, and consuming only foods that are thoroughly cooked
and hot at the time of consumption [22]. At a community level,
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Brucellosis 70
Georgios Pappas
TABLE 70-1 Clinical Manifestations of Brucellosis (Focal TABLE 70-2 Differential Diagnosis of Brucellosis
Complications in Descending Order of Frequency)
Clinical Differential diagnosis
System involved Manifestations syndrome (in descending order of frequency)
General Fever, malaise, anorexia Fever with Lymphoma; malaria in endemic areas;
nonspecific Q fever; typhoid fever; tularemia;
Reticuloendothelial Lymphadenopathy, hepatosplenomegaly constitutional rheumatic/autoimmune syndromes; viral
system symptoms infections including mononucleosis
Osteoarticular Spondylitis Osteoarticular Septic arthritis/spondylitis; tuberculous
disease spondylitis; rheumatic/autoimmune
Peripheral arthritis syndromes
Sacroiliitis Chronic complaints Psychiatric disorders; chronic fatigue
Genitourinary Epididymo-orchitis in males with nonspecific syndrome; hypothyroidism
findings
Possible increased risk of abortion in
pregnant females
Liver Moderate and rarely severe hepatitis, considered positive, even in endemic areas. ELISAs are available, but
granuloma formation, chronic suppurative analysis has not been standardized. PCR assays for brucellosis are also
disease, decompensation of pre-existing available and real-time PCR, in particular, has been shown to be
liver pathology extremely sensitive and specific in numerous settings [8, 13, 14].
Hematologic Lymphocytosis, pancytopenia, rarely Table 70-2 summarizes important differential diagnostic considera-
hemophagocytosis tions for the commonest clinical patterns of human brucellosis.
Skin Various rashes, vasculitis
Respiratory Pneumonia/bronchitis TREATMENT
Antibiotic regimens to treat individuals with brucellosis usually
Gastrointestinal Vomiting and diarrhea, rarely peritonitis,
cholecystitis, colitis
contain at least two agents and treatment should be continued for
weeks. Consensus recommendations for uncomplicated disease are
Central nervous Meningitis/meningoencephalitis, myelitis, summarized in Table 70-3 [15]. Doxycycline and streptomycin may
system radiculopathy, rarely peripheral be microbiologically optimal but, because of convenience, doxycy-
neuropathy cline and rifampin are usually the drugs of choice for treating indi-
viduals with non-spondylitic brucellosis. Doxycycline and gentamycin
Cardiovascular Endocarditis, mycotic aneurysms are also being used.
Ocular Uveitis There is evidence to suggest that doxycycline-streptomycin is the
combination of choice for patients with brucellosis complicated by
Brucellosis 579
TABLE 70-3 Consensus “Ioannina Recommendations” for the Treatment of Human Brucellosis
spondylitis (but not other osteoarticular complications) and that 5. De BK, Stauffer L, Koylass MS, et al. Novel Brucella strain (BO1) associated
treatment in such patients should be extended possibly to 12 weeks with a prosthetic breast implant infection. J Clin Microbiol 2008;46:43–9.
[16]. Many clinicians use at least three drugs to treat individuals with 6. Almuneef MA, Memish ZA, Balkhy HH, et al. Importance of screening house-
brucellosis involving the central nervous system and individuals with hold members of acute brucellosis cases in endemic areas. Epidemiol Infect
brucella-associated endocarditis usually require surgical intervention. 2004;132:533–40.
7. Pappas G, Panagopoulou P, Christou L, Akritidis N. Brucella as a biological
Young children with brucellosis are usually treated with rifampin and
weapon. Cell Mol Life Sci 2006;63:2229–36.
trimethoprim-sulfamethoxazole.
8. Bouza E, Sánchez-Carrillo C, Hernangómez S, et al. Laboratory-acquired bru-
Even with effective drug treatment, relapses occur in 5–10% of cellosis: a Spanish national survey. J Hosp Infect 2005;61:80–3.
patients, usually in the early post-treatment period. Relapses tend to 9. Vrioni G, Pappas G, Priavali E, et al. An eternal microbe: Brucella DNA load
be mild and can be re-treated with the same, or another, first-line persists for years after clinical cure. Clin Infect Dis 2008;46:e131–6.
regimen. 10. Pappas G, Akritidis N, Bosilkovski M, Tsianos E. Brucellosis. N Engl J Med
2005;352:2325–36.
A minority of patients complain of malaise and nonspecific depres- 11. Mavridis AK, Drosos AA, Tsolas O, Moutsopoulos HM. Lactate levels in Bru-
sive symptoms following completion of effective drug regimens. Bru- cella arthritis. Rheumatol Int 1984;4:169–71.
cella have occasionally been isolated from such patients years after 12. Colmenero JD, Jiménez-Mejías ME, Sánchez-Lora FJ, et al. Pyogenic, tubercu-
treatment, underscoring the potential chronicity of brucellosis [9, 17]. lous, and brucellar vertebral osteomyelitis: a descriptive and comparative
Currently, there is no vaccine commercially available for use in study of 219 cases. Ann Rheum Dis 1997;56:709–15.
humans. Prevention is usually targeted to risk factor reduction and 13. Navarro E, Segura JC, Castaño MJ, Solera J. Use of real-time quantitative
behavioral modifications, for example avoidance of the consumption polymerase chain reaction to monitor the evolution of Brucella melitensis DNA
of unpasteurized dairy products. load during therapy and post-therapy follow-up in patients with brucellosis.
Clin Infect Dis 2006;42:1266–73.
14. Queipo-Ortuño MI, Colmenero JD, Reguera JM, et al. Rapid diagnosis of
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71 Melioidosis and Glanders
Nicholas J White
Endemicity
FIGURE 71.1 Global distribution of B. pseudomallei.
Reproduced with permission from Cheng AC, Currie BJ. Not recorded Sporadic
Melioidosis: epidemiology, pathophysiology, and Endemic Environmental isolates
management. Clin Microbiol Rev 2005;18:383–416. Possibly endemic Unconfirmed reports
NATURAL HISTORY, PATHOGENESIS, interferon-gamma is essential for host defense, but other components
are also important.
AND PATHOLOGY Human infection with B. mallei has occurred rarely among laboratory
Burkholderia pseudomallei is a soil saprophyte and can be readily recov- workers and those in direct contact with infected animals. Person-to-
ered from water and wet soil (often rice paddy fields) in endemic person spread of B. mallei is extremely rare. The bacteria usually enter
areas [5]. The bacterium is a motile, aerobic, non-spore-forming, the body through the eyes, nose, mouth, cracked skin, or cuts. Direct
Gram-negative bacillus. In contrast, B. mallei is an obligate pathogen. contact with the skin can lead to a localized cutaneous infection.
The genome of B. pseudomallei is one of the largest and most complex Inhalation leads to pneumonia, septicemia, or disseminated abscesses
bacterial genomes yet sequenced. It comprises 7.24 Mb, divided in muscle, liver, and spleen – a pattern similar to that of melioidosis.
unequally between two circular chromosomes (4.07 Mb and 3.17 Burkholderia mallei is a dangerous organism in the laboratory and
Mb) encoding ~5800 genes with an overall G + C content of 68%. should be investigated only in Biosafety Level (BSL) 3 facilities. It is
The molecular and epidemiologic evidence suggests that mammalian highly infectious as an aerosol and, as infection requires only a few
pathogenicity is unimportant in B. pseudomallei ecology, whereas organisms, it has been used as a biological warfare agent. Use during
B. mallei appears to have undergone reductive evolution from a B. the American Civil War, World Wars I and II, and the Russian invasion
pseudomallei ancestor (they have 99% homology in conserved genes) of Afghanistan has all been reported.
and in adapting to its equine host has shed approximately 1.41 Mb
of DNA containing the genes necessary for soil survival. Burkholderia
pseudomallei, like many soil bacteria, is a difficult organism to kill: it CLINICAL FEATURES
can survive in triple-distilled water for years; it is resistant to comple-
ment and lysosomal defensins and cationic peptides; it survives inside Melioidosis presents as a febrile illness, ranging from a chronic, debil-
several cell lines; and it produces proteases, lipase, lecithinase, cata- itating, localized infection to an acute, fulminant septicemia charac-
lase, peroxidase, superoxide dismutase, hemolysins, and siderophores. terized by local or metastatic abscess formation [5]. Usually, there is
The genome encodes many classical virulence genes, such as adhesins, no obvious infected wound or trauma. The majority of cases are
fimbriae, exopolysaccharides, and Type III secretion systems [6]. The septicemic. Nearly all clinical studies have come from Thailand,
cell wall lipopolysaccharide, which is the immunodominant antigen, Malaysia, Singapore, and Northern Australia. The overall mortality in
is highly conserved and contains two distinct O-polysaccharides. Bur- adults in Thailand is approximately 50%, with many deaths occurring
kholderia pseudomallei produces a highly hydrated glycocalyx “capsule” rapidly before microbiologic confirmation. In Northern Australia, the
– an important virulence determinant – that forms a slime. This mortality of severe melioidosis has been falling in recent years with
facilitates the formation of microcolonies in which the organism earlier recognition and intensive care treatment [4]. The lung is the
is both protected from antibiotic penetration and phenotypically most commonly affected organ, presenting either with a lung abscess
altered. Organisms that cause invasive disease are indistinguishable or pneumonia, or secondary multifocal “blood-borne pneumonia”.
from those found in the environment. Large or peripherally sited lung abscesses commonly rupture into the
pleural space to cause empyema. Seeding and abscess formation may
Melioidosis in humans is usually acquired by inoculation or inhala- occur in any organ, although the liver, spleen, skeletal muscle, and
tion. There is no evidence it can be acquired by ingestion. Occasional prostate are relatively common sites. Renal abscesses are often associ-
nosocomial infections have occurred and sexual transmission has ated with calculi and urinary infection. In nearly 3000 patients pro-
been reported twice. Rice farmers suffer repeated minor cuts and abra- spectively studied in Thailand, a wide variety of clinical presentations
sions whilst immersed for much of the day in water containing have been seen, but primary meningitis or endocarditis have not
B. pseudomallei, but they do not develop active infection unless an (although secondary meningitis from cerebral abscesses and mycotic
underlying predisposing condition develops. The risk of disease is aneurysms does occur). Melioidosis may present as an uncompli-
proportional to the concentration of organisms in the soil. Neu- cated, localized infection of the skin, subcutaneous tissues, or eye.
trophils play a central role in innate host defense, which is initiated Corneal ulcers secondary to trauma and then exposure to contami-
by Toll-like receptors (TLRs; principally TLR-2) [6]. In animal models, nated water are rapidly destructive. Metastatic pyomyositis is relatively
582 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
common. Melioidosis causes acute suppurative parotitis. This unique susceptibility profile (i.e. gentamicin and colistin resistance but
syndrome occurs mainly in children (29% of pediatric cases, 1% of co-amoxiclav susceptibility) in an oxidase-positive, Gram-negative
adult cases,) with no other evidence of an underlying predisposing rod is also useful for rapid identification. Burkholderia mallei generally
condition. In approximately 10% of cases, the parotitis is bilateral. shows a similar pattern of antimicrobial susceptibility, except that it
The patient presents with fever, pain, and swelling over the parotid is gentamicin-sensitive.
gland. In advanced cases, there may be rupture either to the skin or
through to the external ear. Incision and drainage are often required; Cultures should be plated on routine blood agar and Ashdown’s
great care must be taken to avoid damaging the facial nerve. Delay in selective medium. Swabs from open, contaminated sites should also
drainage may also result in a permanent Bell’s palsy. be placed in a selective pre-incubation broth. Small colonies are often
evident on agar plates in 24 hours. The median time to blood culture
In approximately 4% of cases from Australia and, less commonly, positivity is 48 hours but is shorter with automated systems. Direct
elsewhere (<0.2% of cases in Thailand), melioidosis presents as a immunofluorescence on sputum, urine, or pus is 98% specific and
brainstem encephalitis with peripheral motor weakness or flaccid approximately 70% sensitive compared with culture but allows a
paraparesis. Prominent features of the brain stem syndrome on pres- diagnosis to be made in less than 30 minutes. Burkholderia pseudomal-
entation are unilateral limb weakness, cerebellar signs, and cranial lei has a characteristic biochemical profile and can be rapidly identi-
nerve palsies. Focal, multiple, small microabscesses in the brainstem fied by specific latex agglutination tests. The definitive diagnosis of
and spinal cord are thought to be the cause. The clinical experience melioidosis is made by isolation of B. pseudomallei from any site; the
from Northern Australia is generally similar to that in Southeast Asia, organism is not carried asymptomatically. In the past, serologic tests,
but with two other notable differences; parotid abscess is uncommon such as the indirect hemagglutination (IHA) assay were used widely.
(although children comprise only 4% of cases compared with 15% The IHA predominantly detects antibodies directed against the
in Thailand) and genitourinary infections (commonly prostatic remarkably conserved lipopolysaccharide – the immunodominant
abscess) comprise 15% of cases compared with <2% elsewhere. antigen. Serologic tests may be of value in excluding melioidosis or
supporting the diagnosis in areas where prevalence is low; however,
Glanders is characterized by initial onset of fever, rigors, and malaise they are of less value in endemic areas where a significant proportion
culminating in a rapid onset of pneumonia, bacteremia, skin pus- of the population is seropositive.
tules, and disseminated abscesses. Death occurs in 7–10 days without
antibiotic treatment. Even with antibiotic treatment, septicemic glan-
ders has a mortality of 50%. The course of infection depends on the TREATMENT
route of acquisition.
Initial intensive care management of severe melioidosis is similar to
that of any severe Gram-negative septicemia. Patients should be resus-
PATIENT EVALUATION, DIAGNOSIS, citated with adequate intravenous fluids as hypovolemia is common
in the acute phase. There have been eight randomized trials of
AND DIFFERENTIAL DIAGNOSIS parenteral antibiotic treatment and four of oral eradication therapy,
Melioidosis should be suspected in any severely ill febrile patient with all conducted in northeast Thailand. Carbapenems kill B. pseudomallei
an underlying predisposing condition who lives in, or has traveled more rapidly than cephalosporins. Imipenem proved equivalent to
from, an endemic area. The differential diagnosis includes any other ceftazidime in a large, randomized trial. Meropenem is currently
bacterial cause of septicemia, cavitating pneumonia, or abscess forma- being evaluated, but the most evaluated drug has been ceftazidime.
tion. In northeast Thailand, B. pseudomallei is the most common cause Thus, the antibiotics of choice are ceftazidime or a carbapenem
of septicemic illness during the rainy season in adult diabetics. There (meropenem or imipenem; see Table 71-1). Other third-generation
is often abscess formation, either in the lungs (seen on the chest cephalosporins are less effective. Parenteral co-amoxiclav was associ-
radiograph) or in the liver and spleen (seen on ultrasound examina- ated with a similar mortality to ceftazidime, but had a higher rate of
tion). Splenic abscess is a pointer to melioidosis in endemic areas (in treatment failure. Cefoperazone-sulbactam has also proved effective.
northeast Thailand, 95% of splenic abscesses are caused by B. pseu- Thus, co-amoxiclav is an appropriate empirical treatment for septi-
domallei). In up to 13% of cases with septicemia, subcutaneous cemia in areas where melioidosis is endemic, but treatment should
abscesses are present in which Gram-negative rods can be demon- be changed to ceftazidime or a carbapenem once the diagnosis of
strated. Burkholderia pseudomallei is readily cultured from infected sites melioidosis has been confirmed. Large and accessible abscesses
or the blood. Throat swab culture is 90% sensitive compared with should be drained. Melioidosis is difficult to treat. Systemic infections
sputum culture and is more easily obtained in children or debilitated respond very slowly to specific treatment. The median time to fever
patients.
In the laboratory, B. pseudomallei grows aerobically on most agar
media producing clearly visible colonies within 48 hours at 37°C. TABLE 71-1 Parenteral Treatment of Melioidosis
Ashdown’s selective medium (a simple agar containing crystal violet,
glycerol, and gentamicin) is commonly used to culture the organism. Parenteral drug Dose
The colonies develop a characteristic appearance (becoming rugose,
or cornflower head-like, with a silvery sheen) and they take up the Ceftazidime 40 mg/kg: 8-hourly*
crystal violet dye [7]. Gram-stain reveals Gram-negative rods that are Imipenem 20 mg/kg: 8-hourly
often described as bipolar staining or like safety pins – although in
clinical specimens morphology and staining is extremely variable. The Meropenem 20 mg/kg: 8-hourly
organism is oxidase-positive, utilizes glucose by an oxidative pathway
and can be reliably identified from its biochemical profile using Amoxicillin-clavulanate 20 mg/5mg/kg: 4-hourly
kit-based systems. Burkholderia pseudomallei is intrinsically resistant *or 19 mg/kg IV stat followed by a continuous infusion of 3.5 mg/kg/h.
to many antibiotics. In general, it is susceptible to chloramphenicol, Parenteral treatment should continue until there is clear improvement and
the tetracyclines, trimethoprim-sulfamethoxazole, ureidopenicillins, the patient can take oral medications. Parenteral treatment should be given
third-generation cephalosporins, carbapenems and, unusually for a for at least 10 days. The therapeutic response is very slow (median fever
“pseudomonad”, amoxicillin-clavulanate. Burkholderia pseudomallei is clearance: 9 days). Physicians often switch antibiotics prematurely, fearing
intrinsically resistant to other penicillins, first- and second-generation the emergence of resistance (which occurs in <3% of patients). Dosages
cephalosporins, macrolides, rifamycins, colistin, and the aminoglyco- often require adjustment for renal failure. Other third-generation
sides. Rare, naturally occurring mutants have been reported that cephalosporins (e.g. cefotaxime, ceftriaxone) should not be used, as these
lack the efflux pump and are susceptible to both macrolides and have been associated with an increased mortality despite apparent in vitro
aminoglycosides. The fluoroquinolones have weak activity and have susceptibility.
proved very disappointing in clinical trials. This unusual antibiotic,
M e l i o i d o s i s a nd Glanders 583
Dead rodent
Soil contamination
Contamination of burrowing
rodent by inhalation/ingestion
of contaminated soil
role during historical epidemics [9]. Transmission by the anthro- World Health Organization (WHO) 2009 update indicated that, in
pophilic flea Pulex irritans and by the human body-louse Pediculus 2007, 966 cases were reported in the Congo, 700 in Zambia, 591 in
humanus has been suggested during familial cases of plague [10], the Madagascar, 257 in Uganda, 59 in Tanzania, 7 in the USA, and one
latter being supported by experimental evidence [11]. in Mongolia [12] (Fig. 72.3). Plague can therefore be considered a
re-emerging disease, mainly contracted during outdoor professional
GEOGRAPHIC DISTRIBUTION and recreational activities, contrary to what had been observed during
the large historic urban outbreaks of the preceding centuries. In the
OF HUMAN PLAGUE USA, it has been shown that activities with close extended contacts
A soil reservoir and the relative resistance of various rodent species with pet dogs (such as sleeping in the same bed as a pet dog) were
may explain why plague regularly re-emerges in long-lasting plague significantly associated with plague [13]. In Europe, no human cases
foci in all continents except Antartica and Oceania (Fig. 72.3). During have been recently reported, but animal plague is still present along
the last 15 years, at least 8 geographic areas have experienced out- the western banks of the Caspian Sea. In all geographic areas, a sea-
breaks of human plague after silent periods of 30–50 years: India in sonal pattern of human plague is observed, although the seasonal
1994, Zambia in 1996, Indonesia in 1997, Algeria in 2003 and 2009, pattern is different from one geographic area to another, even within
Congo in 2005, Uganda in 2006, and Lybia and China in 2009. The the same country [6].
586 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Contaminated meat
• Avoid contacts <1.5m
• Wear mask
• Standard isolation
Cook meat >71°C
• Antibiotics
- tetracycline
- doxyxycline
- cotrimoxazole
Dead animals
Cases
0–100
100–500
500–1000
1000–5000
5000–15000
B 6000 Africa
America
5000 Asia
Number of plague cases
4000
3000
2000
1000
0
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
FIGURE 72.3 (A) The global distribution of plague 1994–2009, featuring the countries with known presence of plague in animal reservoirs and the countries
where human plague has been either published or declared to the WHO (*, sporadic cases). Countries with human plague cases prior to 1994 are not
listed. Compiled from the WHO and MedLine databases. (B) Annual regional incidence of human plague 1987–2008.
TABLE 72-1 Antibiotic Treatment of Plague (Evidence Category: 1 = double blind study; 2 = clinical trial >20 subjects;
3 = clinical trial <20 subjects; 4 = series; 5 = anecdotal case reports)
Typing of Y. pestis is done by testing nitrate reduction, glycerol assimi- for the manipulation of dead animals and carcasses, and cooking
lation and rhamnose assimilation to determine biotype [15]; molecu- meat on an open-flame grill or on a clam-shell type electric
lar typing can be done by single nucleotide polymorphism analysis, grill [28].
regions of deletion analysis, clustered regularly interspaced short pal-
indromic repeats analysis, multiple loci variable number of tandem Vaccines (live attenuated Y. pestis EV76 strain; formalin-inactivated,
repeats (VNTR) analysis [15], multilocus sequence typing, restriction whole-cell plague; heat-killed whole-cell plague; F1 fraction) can be
fragment length polymorphism (RFLP) analysis and multispacer administrated by aerosol (EV76), subcutaneously (EV76; heat-killed
sequence typing analysis [3]. VNTR analysis has proved useful in CSL vaccine; CSL Ltd, Victoria, Australia) or intramuscularly (formalin-
identifying sources of human exposure [24]. inactivated Greer vaccine; Greer Laboratories Inc., NC, USA) [29]. The
F1 fraction vaccine appears to have low efficacy (<60%) and side
Serology using modern techniques is useful to measure seropreva- effects in 35% of vaccines. There is not enough evidence to evaluate
lence in sentinel animals and could be used for the rapid diagnosis the effectiveness of any plague vaccine or the relative effectiveness
of patients for whom serum is the only available specimen, during between vaccines and their tolerability. Circumstantial data
outbreaks [25]. from observational studies suggest that killed vaccines may be more
effective against bubonic plague and have fewer adverse effects than
attenuated vaccines. No evidence is available regarding the long-term
TREATMENT effects of any plague vaccine and their role in controlling plague
outbreaks [29].
Rapid administration of an effective antibiotic to patients with
suspected plague is mandatory. Streptomycin, the historical reference In the case of potential exposure to Y. pestis, secondary prevention
antibiotic still used in Madagascar, is no longer available in relies on the administration of tetracycline or trimethoprim-
most countries. Gentamicin alone, or in combination with a tetracy- sulfamethoxazole to people who are bitten by fleas during a local
cline, is an acceptable substitute [26] (Table 72.1). Gentamicin outbreak or who are exposed to tissues or fluids from a plague-
and doxycycline were shown to be equivalent in curing patients, infected animal, people living in a household with a bubonic plague
except in terminal stage disease [27]. Fluoroquinolones, as well patient (as they may also be exposed to infected fleas), and people in
as cephalosporins, are effective in animal models, yet they are not close contact with a person or pet with suspected pneumonic plague
recommended as, with the exception of a single reported case of [26]. Recent evaluation indicates that doxycycline should be consid-
plague successfully treated with ciprofloxacin [6], there are no clinical ered as a first-line antibiotic in the management of bioterrorism
data addressing their efficacy. Antibiotic treatment should be contin- agents, including Y. pestis [30]. For a mass casualty situation, oral
ued for 10 days. Improvement is clinically evident 2–3 days therapy with doxycycline, tetracycline or ciprofloxacin has been rec-
after initiation of antibiotics, although fever may persist for a few ommended [2], the latter option being supported by animal models.
more days. Prevention of human-to-human transmission from patients with
pneumonic plague can be achieved by implementing standard isola-
Supportive therapy should be undertaken in case of septic shock and tion procedures until at least four days after the initiation of antibiotic
septicemic plague. treatment.
Control of plague is based on active surveillance of sentinel animals.
PREVENTION AND CONTROL In areas with epizootic outbreaks, it is mandatory to eliminate food
and shelter for rodents around homes, work places, and certain rec-
Before exposure to Y. pestis, primary prevention relies on: avoiding reational areas, such as picnic sites or campgrounds where people
areas with known epizootic plague; avoiding apparently sick and dead congregate. Remove brush, rock piles, junk and food sources, includ-
animals; reporting such animals to the health department and avoid- ing pet food. Treat pets (cats and dogs) for flea control regularly.
ing exposure to rats and fleas from diseased rats or other rodents, Likewise, the control of a human plague outbreak mainly relies on
including use of protective clothes and repellents to avoid exposure the rapid confirmation of the diagnosis and treatment of confirmed
to ectoparasites when outdoors; applying insect repellent containing and suspected cases. Killing any human ectoparasite is mandatory
N,N-Diethyl-meta-toluamide (DEET) to legs and ankles; applying during plague outbreak, as well as killing animal fleas using appropri-
repellents and insecticides to clothes and outer bedding; using gloves ate and licensed insecticides.
590 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
animals and humans (Table 73-1). Ixodidae ticks are the primary Human contamination may occur directly after contact with an
vectors and a major reservoir of F. tularensis worldwide. Other poten- infected animal or animal carcass, by ingestion of contaminated
tial vectors include mosquitoes (mainly in Scandinavia [10]) and water or food, by arthropod inoculation, or after contact with a
tabanids (deer flies, i.e. Chrysops sp.) in the USA (particularly in contaminated environment (Table 73-1) [3]. Human-to-human
Wyoming, Utah, Nevada, and California) [11]. Francisella tularensis transmission is considered unlikely. Farmers, hunters, trappers,
can survive for months in humid and cold environments (e.g. water, meat handlers, veterinarians, animal care professionals, pet owners,
mud), possibly in association with amebae. and persons walking in tick-infested lands (prairies, forest, etc.) in
Tularemia 593
endemic areas are considered most at risk of contracting tularemia. observed. The use of specific monoclonal or polyclonal antibodies
Arthropod-borne tularemia cases usually occur in spring, summer allows visualization of F. tularensis within infected tissues.
and early autumn during the main activity of these vectors and when
persons are most exposed to their bites by wearing short clothes.
In contrast, tularemia caused by direct contact with game animals CLINICAL FEATURES
usually occurs during the winter hunting season. Laboratory workers The incubation period of tularemia is typically 3–5 days, but may vary
handling F. tularensis cultures are also at high risk of developing from a few hours to up to 2 weeks [1, 10]. Many patients have few
tularemia; laboratory staff should be notified when handling samples symptoms and remain undiagnosed. More symptomatic patients
potentially containing F. tularensis. Such samples and subcultures usually seek medical attention several days or weeks after symptom
should be handled in biosafety cabinets-hoods to minimize aerosol- onset. A minority of patients experience acute, severe, and even ful-
based exposure. minant, disease (e.g. pneumonic or typhoidal form). Infected patients
usually experience a sudden onset of flu-like symptoms including
fever, chills, headaches, myalgias, and arthralgias. Coughing is fre-
NATURAL HISTORY, PATHOGENESIS, quent, and mild diarrhea is found in about 10% of patients. Relative
AND PATHOLOGY bradycardia is a classically described but uncommon finding. About
20–40% of patients develop a generalized papular or maculopapular
Human inoculation with F. tularensis can occur through the skin, the rash that may become vesicular or pustular. Erythema nodosum has
conjunctiva, and the digestive or respiratory mucosa [12]. Local infec- also been reported, especially in women.
tion may lead to a cutaneous ulcer, conjunctivitis, pharyngitis, enteri-
tis, or pneumonia. Bacteria rapidly invade the regional lymph nodes, The spectrum of the clinical manifestations of tularemia is wide, but
draining the territory of the skin or mucosa lesions. Enlarged lymph six clinical syndromes are classically recognized and may occasionally
nodes may develop at various sites: epitrochlear, subclavicular, axil- be combined [1, 10]: the ulceroglandular form; the glandular form;
lary, cervical, pretragal, mesenteric, inguinal, mediastinal, etc. A tran- the oculoglandular form; the oropharyngeal and digestive form; the
sient bacteremia often allows F. tularensis to spread throughout the pneumonic form; and the typhoidal form. Another classification only
body, infecting reticuloendothelial cells. In most patients, the immune differentiates ulceroglandular tularemia (the three former syndromes)
response will control the disease. In about 20–30% of cases, the from typhoidal tularemia (patients without skin or lymph-node
lymphadenopathy will evolve to chronic suppuration and necrosis. involvement and with systemic symptoms) [16].
Less frequently, secondary localizations may supervene (e.g. menin- Approximately 75–90% of patients present with an ulceroglandular
gitis, encephalitis, pneumonia, endocarditis, osteomyelitis), possibly form, which combines a cutaneous lesion at the site of F. tularensis
leading to death. Whatever the portal of entry, a fulminant course of skin inoculation and a regional lymphadenopathy (Figs 73.2 and
tularemia with persistent F. tularensis bacteremia, delirium and septic 73.3). The skin lesion first corresponds to a small papule that devel-
shock is referred to as the typhoidal form of tularemia. ops within a few days into a pustule and then a cutaneous eschar that
Francisella tularensis virulence factors have been partially characterized, is typically erythematous, indurated and nonhealing. In the much
but the higher virulence of type A compared with type B strains rarer glandular form (about 2% of cases), a cutaneous lesion has not
remains unexplained [13]. Francisella tularensis is an intracellular developed or it has healed at the time of the first medical visit. In
pathogen that predominantly grows in macrophages, but probably both forms, the patient usually consults when the lymph nodes
also in neutrophils, dendritic cells, and non-professional phagocytic become severely enlarged and tender. The lymphadenopathy may be
cells, such as alveolar epithelial cells, endothelial cells and hepato- epitrochlear, subclavicular, axillary, cervical or inguinal, and typically
cytes. This bacterium harbors a pathogenicity island (FPI) that lasts for several weeks, and even months. It evolves to suppuration in
includes genes necessary for intramacrophage growth and virulence, about 20–30% of cases, sometimes with skin fistulization, especially
such as the intracellular growth locus operon iglABCD and pdp genes when adapted antibiotic therapy has been delayed for more than 2
(especially pdpA). Bacteria phagocytized by macrophages escape the weeks. The progression of the lymphadenopathy is poorly influenced
phagocytic vacuole to the cell cytosol where they multiply. Francisella by antibiotic therapy and surgical treatment is often needed for cure
tularensis does not trigger a high pro-inflammatory host response after several weeks or months of progression. However, lymph node
because of a relatively inert lipopolysaccharide (LPS) and a probable incision should not be performed in the early stage of the disease
direct inhibition of pro-inflammatory cytokine signaling pathways. because of the frequent spread of infection to surrounding tissues.
Type IV pili appear essential for tissue adhesion and invasion, and a Although rarely fatal, the glandular and ulceroglandular forms may
surface exopolysaccharide capsule protects bacteria from the killing evolve to disseminated disease and secondary localizations (e.g.
action of serum complement during bacteremia. spleen, liver, lung or brain).
A humoral response develops within 2 weeks following infection with The oropharyngeal and digestive form of tularemia (the second
F. tularensis, with antibodies primarily directed against the bacterial most frequent form) usually occurs a few days after ingestion of
LPS, but also against outer membrane proteins (OmpA, FopA) and
intracellular proteins (GroEL, KatG) [14]. These antibodies probably
control F. tularensis bacteremia and extracellular multiplication.
Mucosal antibody response (mainly of IgA type) may also partially
protect vaccinated or previously infected persons from re-infection.
Cell-mediated immunity (i.e. CD4+ and CD8+ T cells) is assumed
to play a major role in controlling intracellular multiplication of
F. tularensis.
Pathologic aspects of tularemia are not specific [15]. In chronically
enlarged lymph nodes, histologic lesions may range from well-
defined zones of acute inflammation and necrosis located within the
outer cortex of lymph nodes, to generalized necrosis that can obliter-
ate the node. Granulomatous inflammation may also be present.
Caseous necrosis is usually absent. Post-mortem examination of
tissues from patients dying of tularemia may reveal lesions resembling
those of tuberculosis, particularly the presence of well-developed
granulomas in lungs, liver, spleen, and lymph nodes. Necrotizing
pneumonia with abundant fibrin, cellular debris, edema, and neu- FIGURE 73.2 A tularemia skin eschar of the left hand after manipulation
trophils within alveolar walls and alveolar spaces may also be of a hare (courtesy of Dr B. Castan).
594 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
undercooked food or water contaminated with F. tularensis. The Other rare clinical manifestations of tularemia may include meningi-
disease often manifests as clustered cases, either in a family (food- tis, encephalitis, pericarditis, endocarditis, peritonitis, hepatitis, splen-
borne infections) or in a localized population (water-borne infec- itis, osteoarticular infections, septic shock with rhabdomyolysis, and
tions). Large outbreaks have recently been reported in Turkey, acute renal failure.
Kosovo, and Bulgaria, with most patients presenting with oropha-
ryngeal tularemia [17–19]. Patients with oropharyngeal involvement
present with fever and acute exudative or membranous pharyngitis PATIENT EVALUATION, DIAGNOSIS,
and rapid development of swollen cervical lymph nodes. Enlarged
tonsils with yellow-white pseudomembranes may suggest diphthe-
AND DIFFERENTIAL DIAGNOSIS
ria. Pharyngitis is usually severe, of prolonged duration (several Mild-to-moderate tularemia cases are usually managed on an out
weeks to months) and resists ß-lactam therapy. Complications may patient basis. Patients with severe clinical manifestations (pneumo-
include cervical lymph node suppuration with skin fistulization and nia, typhoidal tularemia, severe digestive involvement, brain or
tonsillar phlegmon. Gastrointestinal tularemia probably develops in cardiac involvement) should be hospitalized and possibly admitted
patients after ingestion of a high dose of bacteria and may manifest to an intensive care unit, especially if septic shock is present.
by mild diarrhea, abdominal pain, nausea, vomiting and gastroin-
testinal bleeding. Enlarged mesenteric lymph nodes may be found. Nonspecific biologic abnormalities may include moderate leukocyto-
Extensive ulceration of the bowel may lead to severe symptoms and sis with granulocytosis, a relative increase in mononuclear cells, an
even death. inflammatory syndrome with mild elevation of C-reactive protein
and, rarely, a mild elevation of liver enzymes.
The oculoglandular form (2–3% of cases) usually corresponds to
conjunctival inoculation of F. tularensis by touch with a contaminated Tularemia diagnosis is usually confirmed by serologic methods, espe-
finger, for example following manipulation of an infected animal or cially the microagglutination test and, less frequently, the indirect
after crushing a tick. Symptoms usually manifest early and correspond immunofluorescence and ELISA techniques [21, 22]. These tests are
to Parinaud’s oculoglandular syndrome, combining a granulomatous both sensitive and specific, although serology may be negative in the
unilateral conjunctivitis with homolateral regional lymphadenopathy early course of the disease. Antibody titers are usually only detected
(Fig. 73.4). The inflamed conjunctiva is painful, with numerous yel- at significant levels 2–3 weeks following symptom onset, peak after
lowish nodules and pinpoint ulcers. Enlarged lymph nodes may be 6–8 weeks progression of the disease and then decline slowly over
found in the pretragal, retroauricular or cervical regions. ß-lactams are months or years. Serologic titers of 1 : 160 or more are usually con-
not effective and the conjunctivitis may last for several weeks or sidered significant for the microagglutination test, but cut-off titters
months without appropriate antibiotic treatment. The most frequent may vary between laboratories using different techniques and anti-
complications include keratitis, sometimes with corneal perforation, gens. A seroconversion or a fourfold rise in antibody titers between
lymph node suppuration and cellulitis in nearby skin tissue. acute-phase and convalescent-phase sera is considered diagnostic.
Cross-reacting antibodies have been reported between Francisella sp.,
The pneumonic form may develop after inhalation of an infectious Brucella sp., Proteus OX19, Yersinia enterocolitica O:3 and Yersinia pestis
aerosol, for example during lawn mowing or brush cutting [20], fol- antigens, but titers are usually low and not confounding. The Western
lowing aerosolized laboratory exposure, or, alternatively, as a second- blot technique may be used. Importantly, serologic tests cannot deter-
ary localization of F. tularensis bacteremia. Symptoms are those of mine the Francisella subspecies and clade involved.
atypical pneumonia, including fever, a nonproductive cough, dyspnea,
and pleuritic chest pain. Bilateral patchy infiltrates are found on chest Francisella tularensis culture remains tedious and hazardous for labora-
radiography. Pleural effusions and empyema may develop. Mediasti- tory personnel [21, 22]. Type A strains are class 3 pathogens, and
nal lymph nodes may develop and persist for several months after should be grown in a Biosafety Level (BSL) 3 laboratory. Ideally, clini-
resolution of pneumonia. Pneumonia is often fulminant with lung cal samples should be transported frozen at −80°C or directly inocu-
tissue necrosis when caused by a type A strain. lated to antibiotic-containing medium to prevent overgrowth by
commensal species. Isolation of F. tularensis requires enriched medium
The typhoidal form corresponds to a rapid systemic progression of containing cysteine (e.g. Thayer-Martin medium, chocolate agar sup-
tularemia with fever, a typhoid state and shock in the absence of plemented with Polyvitex™ or Isovitalex™) and incubation at 37°C
apparent portal of entry (e.g. skin lesion) or lymphadenopathy. This for a minimum of 3–5 days. Automated blood culture systems are
form is often fatal. useful in the rare patients with bacteremia. Francisella tularensis may
Tularemia 595
be grown from blood, skin eschar discharges, lymph node samples, Typhoidal tularemia may be observed in many other severe infectious
conjunctival or throat swabs, cerebrospinal fluid (CSF), sputum, and diseases, including typhoid fever.
other suppurations or organ biopsies. Culture sensitivity is considered
low (about 25% for cutaneous and lymph node samples) and
decreases significantly after administration of effective antibiotics. TREATMENT
Suspected colonies may be rapidly identified as F. tularensis by using Human tularemia cases are usually more severe in North America
a specific antiserum or by PCR amplification of specific genes (e.g. than in Eurasia. Respective global mortality rates for type A and type
fopA or tul4). B infections changed from 5–10% and 0.5–1% before the antibiotic
PCR-based techniques now provide a rapid, sensitive and specific era, to 2–3% and close to 0% when appropriate antibiotic therapy
diagnosis of tularemia and carry a much lower infection risk for labo- became available [21]. Higher mortality rates have been reported in
ratory personnel than culture [21, 22]. Sensitivities of 73–78% have patients with the pneumonic or typhoidal forms (30–60%) and in
been reported for skin samples from patients with ulceroglandular immunocompromised patients. Recently, mortality rates of 4%, 24%,
tularemia. PCR may remain positive despite previous administration 0% and 7% have been associated in the USA with the A1a, A1b, A2
of antibiotics or when testing formalin-fixed tissue specimens. PCR and B genotypes, respectively [7].
targets include the insertion sequence ISFtu2, the 16SrRNA-encoding In vitro, most strains of F. tularensis are resistant to penicillin G and
gene, the succinate dehydrogenase gene SdhA and genes encoding aminopenicillins because of the action of a ß-lactamase [21]. Suscep-
outer membrane-associated proteins (Tul4, a 17-kDa lipoprotein tibility to third-generation cephalosporins (e.g. cefotaxime, ceftriax-
encoded by the tul4 gene; OmpA, a 43-kDa protein encoded by the one) varies according to the strains studied, but these antibiotics are
fopA gene; and an unnamed 23-kDa protein). Francisella tularensis not effective against intracellular F. tularensis and they are clinically
DNA has been amplified from blood, lymph nodes, skin ulcer dis- unreliable [23].
charge and skin biopsies, conjunctival discharge, pharynx and CSF.
These PCRs are genus- or species-specific. The F. tularensis subspecies Chloramphenicol, cotrimoxazole, and macrolides are poorly effec-
and clade involved may be identified by several molecular methods, tive. The aminoglycosides, the fluoroquinolones, the tetracyclines,
including analysis of whole-genome restriction digests by pulse-field rifampin and the ketolide telithromycin display a bactericidal activity
gel electrophoresis (PFGE), amplified fragment length polymorphism against F. tularensis, both in axenic medium and in cell systems.
(AFLP), regional difference analysis (RD1 or pdpD locus) and multiple- The optimum treatment of tularemia cannot be based on rand-
locus variable number tandem repeat analysis (MLVA). omized, controlled clinical trials because the disease is so rare. Accord-
Tularemia should be systematically evoked in patients living in (or ing to clinical experience, the aminoglycosides are considered
visiting) an endemic area, with compatible clinical manifestations the most effective antibiotics (Table 73-2) [21, 24]. Streptomycin
and a potential exposure. When suggestive epidemiologic conditions has been used for decades with success rates of over 97%. This anti-
are lacking, however, the differential diagnosis of tularemia may be biotic is now difficult to obtain in many countries. Gentamicin is
wide because symptoms are poorly specific [21]. Ulceroglandular currently used as an alternative, whereas other aminoglycosides are
tularemia is the most easily diagnosed form, but atypical skin lesions less effective. Administration of an aminoglycoside is still recom-
associated with enlarged lymph nodes may suggest infections caused mended in severe tularemia cases, with the monitoring of antibiotic
by Staphylococcus aureus, Streptococcus pyogenes or Mycobacterium serum levels. However, aminoglycosides have many side effects
marinum, as well as cat-scratch disease, pasteurellosis, syphilis, anthrax, (including ototoxicity and nephrotoxicity) and are only administra-
rat-bite fever, rickettsiosis and sporotrichosis. The chronically-evolving ble parenterally.
lymphadenopathy of the glandular form is more challenging and may The fluoroquinolones are now proposed as first-line drugs in the vast
suggest other infectious diseases [tuberculosis, non-tuberculous majority of patients with mild-to-moderate clinical manifestations,
mycobacterial diseases, cat-scratch disease, plague, lymphogranuloma including in children, as the risk of skeletal toxicity appears low. Their
venereum, Ebstein Barr virus (EBV), cytomegalovirus (CMV) or HIV clinical efficacy is better documented in type B than in type A
infections, toxoplasmosis or histoplasmosis] and non-infectious tularemia. These antibiotics are less toxic than aminoglycosides and
diseases (immunologic diseases, malignant diseases including administrable orally. Ciprofloxacin has been used in most cases
lymphoma, etc.). Oropharyngeal tularemia may suggest S. pyogenes reported in the literature with success rates over 95%. Ofloxacin
(group A) infection or diphtheria in the case of pseudomembranous (200 mg twice daily) or levofloxacin (500 mg once daily) may also
pharyngitis. Failure of ß-lactam therapy may prompt the clinician to be effective, but clinical data are scarce.
make further investigations, but diagnosis is often delayed. Parinaud’s
oculoglandular syndrome is not specific and Mycobacterium tuberculo- Tetracyclines, especially doxycycline, represent a possible alternative,
sis, Bartonella henselae and herpes virus are more frequent etiologies although more frequent relapses are observed upon antibiotic
of this syndrome, among others. Francisella tularensis pneumonia withdrawal. Gastrointestinal side effects are frequent, but may be
should be considered, together with other causes of atypical pneumo- reduced by taking the drug with food. Tetracyclines are classically
nia, including plague and anthrax in the context of bioterrorism. contraindicated in children less than eight years old because of the
risk of tooth discoloration, and in pregnant women because of fetal 4. Pérez-Castrillón JL, Bachiller-Luque P, Martín-Luquero M, et al. Tularemia
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19. Kantardjiev T, Ivanov I, Velinov T, et al. Tularemia outbreak, Bulgaria, 1997–
tularemia [25, 26]. Live attenuated vaccines were first developed in
2005. Emerg Infect Dis 2006;12:678–80.
the former Soviet Union where millions of people were vaccinated
20. Feldman KA, Enscore RE, Lathrop SL, et al. An outbreak of primary
with the attenuated strains 15 and 155 until 1960. The live vaccine
pneumonic tularemia on Martha’s Vineyard. N Engl J Med 2001;345:
strain developed in the USA was derived from these Russian strains. 1601–6.
The live vaccine strain mainly protects from the occurrence of severe 21. Tärnvik A, Chu MC. New approaches to diagnosis and therapy of tularemia.
tularemia disease (e.g. the pneumonic and typhoidal forms), but it is Ann NY Acad Sci 2007;1105:378–404.
less effective in preventing ulceroglandular tularemia. It has not been 22. Hepburn MJ, Simpson AJ. Tularemia: current diagnosis and treatment
licensed by the Food and Drug Administration (FDA) in the USA, nor options. Expert Rev Anti Infect Ther 2008;6:231–40.
in any other country because of significant side effects and because 23. Cross JT, Jacobs RF. Tularemia: treatment failures with outpatient use of
the basis of attenuation of this strain has not been fully characterized. ceftriaxone. Clin Infect Dis 1993;17:976–80.
Construction of defined attenuated strains of F. tularensis is under way. 24. Enderlin G, Morales L, Jacobs RF, Cross JT. Streptomycin and alternative
agents for the treatment of tularemia: review of the literature. Clin Infect Dis
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25. Wayne Conlan J, Oyston PC. Vaccines against Francisella tularensis. Ann NY
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ence with 88 cases. Medicine 1985;64:251–69. 26. Isherwood KE, Titball RW, Davies DH, et al. Vaccination strategies for
2. Dennis DT, Inglesby TV, Henderson DA, et al; Working Group on Civilian Francisella tularensis. Adv Drug Deliv Rev 2005;57:1403–14.
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cal manifestations. Ann N Y Acad Sci 2007;1105:1–29. pediatric patients. Pediatr Infect Dis J 1995;14:151–2.
Leptospirosis 74
George Watt
tissue, but their role in mediating kidney damage is unknown. Inter- abandoned. The median incubation period is 10 days, with a range
stitial nephritis is primarily found in individuals who have survived of 2–26 days. The duration of the incubation period has no prognos-
until inflammation has had an opportunity to develop, but is fre- tic significance. Once symptoms develop, they may follow a biphasic
quently absent in patients with fulminant disease. Impaired renal course: after an initial febrile illness there is defervescence of fever and
perfusion constitutes the fundamental nephropathic change. In some symptomatic improvement followed by a second period of disease.
geographic areas, pulmonary hemorrhage is the principal cause of However, a clear demarcation between the first and second stages is
death and is associated with the linear deposition of immunoglobu- atypical of icteric leptospirosis and, in mild cases, the distinction can
lins and complement on the alveolar surface [6]. It is unclear why be unclear or the second stage may never occur. The diagnostic useful-
renal failure predominates as the principal cause of death in some ness of a history of a biphasic illness has been overemphasized. HIV
places, while pulmonary hemorrhage is the major cause in others, co-infection does not seem to affect the clinical presentation of lept-
even where the most common infecting serovars are the same. There ospirosis in the few co-infected patients described thus far.
are only minor histopathologic changes in the kidneys and livers of
patients with marked functional impairment of these organs. Patients
who survive severe leptospirosis have complete recovery of hepatic ANICTERIC LEPTOSPIROSIS
and renal function – consistent with the lack of structural damage to Symptoms and Signs
these organs.
Typically, the disease begins with the abrupt onset of intense head-
ache, fever, chills, and myalgia. Fever often exceeds 40°C (103°F) and
CLINICAL FEATURES is preceded by rigors. Muscle pain can be excruciating and occurs most
commonly in the thighs, calves, lumbosacral region, and abdomen.
The most common clinical features of leptospirosis are summarized Abdominal wall pain accompanied by palpation tenderness can
in Table 74-1. mimic an acute surgical abdomen. Nausea, vomiting, diarrhea, and
Subclinical infection is common and less than 10% of symptomatic sore throat are other frequent symptoms. Cough and chest pain figure
infections result in severe, icteric illness. Even relatively virulent sero- prominently in reports of patients from Korea and China.
vars, such as icterohaemorrhagiae lead more often to anicteric than Conjunctival suffusion is a helpful diagnostic clue that usually appears
to icteric disease. Old terms such as peapicker’s disease, swineherd’s two or three days after the onset of fever and involves the bulbar
disease and canicola fever, which linked specific serotypes with conjunctiva. Pus and serous secretions are absent and there is no
distinct disease manifestations, are misleading and should be matting of the eyelashes and eyelids. Mild suffusion can easily be
overlooked. Less common and less distinctive signs include pharyn-
geal injection, splenomegaly, hepatomegaly, lymphadenopathy, and
TABLE 74-1 The Most Common Clinical skin lesions. Within a week, most patients become asymptomatic.
Manifestations of 208 Leptospirosis Patients in Puerto After several days of apparent recovery, the illness resumes in some
Rico individuals. Manifestations of the second stage are more variable and
mild than those of the initial illness and usually last 2–4 days. Lepto-
Symptoms Anicteric Icteric spires disappear from the blood, cerebrospinal fluid (CSF), and
tissues, but appear in the urine. Serum antibody titers rise – hence the
(% of cases) (106 cases) (102 cases)
term “immune” phase. Meningitis is the hallmark of this stage of
Fever 100 99 leptospirosis. Pleocytosis of the CSF can be demonstrated in 80–90%
of all patients during the second week of illness, although only about
Myalgia 97 97 50% will have clinical signs and symptoms of meningitis. Meningeal
signs can last several weeks, but usually resolve within a day or two.
Headache 82 95
Uveitis is a late manifestation of leptospirosis, generally seen 4–8
Chills 84 90 months after the illness has begun. The anterior uveal tract is most
frequently affected and pain, photophobia, and blurring of vision are
Sore throat 72 87 the usual symptoms.
Nausea 71 81
Laboratory Findings
Vomiting 65 75
White blood cell count varies, but neutrophilia is usually present.
Eye pain 54 38 Urinalysis may show proteinuria, pyuria, and microscopic hematuria.
Enzyme markers of skeletal muscle damage, such as creatinine kinase
Diarrhea 23 30 and aldolase are elevated in the sera of 50% of patients during the
Oliguria 20 30 first week of illness. Chest radiographs from patients with pulmonary
manifestations show a variety of abnormalities, but none is patho
Cough 15 32 gnomonic of leptospirosis. The most common finding is small,
patchy, snowflake-like lesions in the periphery of the lung fields.
Hemoptysis 5 14
DIAGNOSIS
Most cases go undiagnosed because symptoms and signs are often
Bleeding is occasionally seen in anicteric cases but is most prevalent nonspecific and serologic confirmation is rarely available where most
in severe disease. Purpura, petechiae, epistaxis, bleeding of the gums, disease transmission occurs. Failure to diagnose leptospirosis is par-
and minor hemoptysis are the most common hemorrhagic manifesta- ticularly unfortunate: severely ill patients often recover completely
tions; however, deaths occur from subarachnoid hemorrhage and with prompt treatment but delayed therapy is likely to result in a
exsanguination from gastrointestinal bleeding. Conjunctival hemor- poor clinical outcome. Late disease can often be recognized by its
rhage is an extremely useful diagnostic finding and, when combined typical clinical manifestations, but the presentation of early lept-
with scleral icterus and conjunctival suffusion, produces eye findings ospirosis is usually nonspecific and is therefore difficult to identify
strongly suggestive of leptospirosis (see Fig. 74.1). The frequency with clinically. Leptospirosis has long been acknowledged to be a frequent
which severe pulmonary hemorrhage complicates leptospirosis is cause of undifferentiated febrile illness in developing countries.
variable but is a cardinal feature of some outbreaks. Co-infection with diseases such as malaria and scrub typhus has
Life-threatening renal failure is a complication of icteric disease, been reported and adds to the diagnostic confusion of tropical
although all forms of leptospirosis may be associated with mild fevers.
kidney dysfunction. Oliguria or anuria usually develop during the Laboratory diagnosis of leptospirosis remains problematic. The
second week of illness, but may appear earlier. Complete anuria is a microscopic agglutination test is considered the serodiagnostic
grave prognostic sign often seen in patients who present late in the method of choice for leptospirosis, but its complexity limits its use to
course of illness with frank uremia and irreversible disease. Because reference laboratories. Dilutions of patient sera are applied to a panel
renal failure develops very quickly in leptospirosis, symptoms and of live, pathogenic leptospires. The results are viewed under dark-field
signs of uremia are frequently encountered. Anorexia, vomiting, microscopy and expressed as the percentage of organisms cleared
drowsiness, disorientation, and confusion are seen early and rapidly from the field by agglutination. Inadequate quality controls of the live
progress to convulsions, stupor, and coma in severe cases. Distur- reference strain panels can lead to frequent false-negative results [7].
bances of consciousness in a patient with severe leptospirosis are A new generation of commercially available, rapid serodiagnostic kits
usually caused by uremic encephalopathy, whereas in anicteric cases that rely on whole Leptospira antigen preparations have been devel-
aseptic encephalitis is the usual cause. Renal function eventually oped. Unfortunately, these assays seem to have unacceptably low
returns to normal in survivors of Weil’s disease, although detectable sensitivities during acute-phase illness and persistent antibody pro-
abnormalities may persist for several months. duces low specificity in regions of high endemic transmission. The
Leptospirosis-associated severe pulmonary hemorrhage syndrome need for practical, affordable diagnostic kits to be available in areas
(SPHS) is now recognized as a widespread public health problem where leptospirosis is common cannot be overemphasized. PCR and
with a case fatality rate of about 50%. This lethal complication of urine antigen detection are research tools that would be of the greatest
leptospirosis can occur either with or without jaundice and renal potential diagnostic value in patients who present early, before anti-
failure. Hemoptysis is the cardinal sign but may not be apparent bodies have reached detectable levels.
until patients are intubated. Real-time PCR has shown that lepto- Isolation of leptospires from blood or CSF is possible during the first
spiremia is 10,000 or more bacteria per milliliter of blood in SPHS 10 days of clinical illness, but specialized media are necessary. Serially
– the apparent critical threshold for severe outcomes such as SPHS diluted urine provides the highest yield. Unfortunately, culture results
and death [6]. are only known 4–6 weeks later – too late to benefit severely ill,
hospitalized patients.
Laboratory Features of Weil’s Disease Several attempts have been made to formulate diagnostic algorithms
Hyperbilirubinemia results from increases in both conjugated (direct) by assigning points to various clinical, epidemiologic and laboratory
and unconjugated (indirect) bilirubin, but elevations of the direct parameters. The points are totaled and the score is then used to rep-
fraction predominate. Prolongations of the prothrombin time com- resent the likelihood that the patient in question has leptospirosis.
monly occur but are easily corrected by the administration of vitamin An example is shown in Table 74-2. The usefulness of these scoring
K; modest elevations of serum alkaline phosphatase are typical. There systems is limited by their complexity, by marked regional variability
is mild hepatocellular necrosis; greater than fivefold increases of in the quality of available diagnostic tests and by regional differences
transaminase (aminotransferase) levels are exceptional. Jaundiced in the prevalent differential diagnoses that must be considered.
patients usually have leukocytosis in the range of 15,000 to 30,000 However, these scoring systems are useful teaching tools, and empha-
per mm3 and neutrophilia is constant. Anemia is common and mul- size the important epidemiologic and clinical characteristics of
tifactorial; blood loss and renal dysfunction contribute frequently, leptospirosis.
600 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
TABLE 74-2 Modified World Health Organization BOX 74.1 Clinical Pearl
(WHO) Criteria for Diagnosis of Leptospirosis
Muscles of patients with leptospirosis can be exquisitely tender
Part A Clinical signs and symptoms (score) and painful to the touch
• Fever >39.0°C (2 points) but………
• Conjunctival suffusion (4 points) palpation of painful muscles in patients with scrub typhus
• Myalgias (4 points) sometimes provides pain relief.
practical consideration is that antibiotics should not be withheld serovar-specific vaccine and the wearing of protective clothing (e.g.
because of the fear of a possible Jarisch–Herxheimer reaction. rubber boots in rice fields) is both prohibitively expensive and
impractical. Providing proper sanitation in urban slum communities
The management of pulmonary hemorrhage often requires prompt would be the most effective control measure in this setting.
intubation and mechanical ventilation. SPHS patients have physio-
logic and pathologic evidence for acute respiratory distress syndrome
so ventilation using low tidal volumes and high post-expiratory REFERENCES
end-pressures should be provided. Respiratory support to maintain 1. Ko AI, Goarant C, Picardeau M. Leptospira: the dawn of the molecular genet-
adequate tissue oxygenation is essential because in nonfatal cases ics era for an emerging zoonotic pathogen. Nature 2009;7:736–47.
complete recovery of pulmonary function can be achieved. Ensuring 2. Ko AI, Galvao Reis M, Ribiero Dourado CM, et al. Urban epidemic of severe
adequate renal perfusion prevents renal failure in the vast majority leptospirosis in Brazil. Lancet 1999; 354:820–5.
of oliguric individuals. Continuous hemofiltration has been shown to 3. Thaipadungpanit J, Wuthiekanun V, Chierakul W, et al. Leptospira interrogans
be more effective than peritoneal dialysis in treating infection- associated with an outbreak of human leptospirosis in Thailand. PLoS Negl
associated hypercatabolic renal failure. Peritoneal dialysis, however, Trop Dis 2007;1:e56.
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2005,18:376–85.
PREVENTION
6. Nicodemo AC, Duarte MI, Alves VA, et al. Lung lesions in human leptospiro-
sis: microscopic, immunohistochemical, and ultrastructural features related
to thrombocytopenia. Am J Trop Med Hyg 1997;56:181–7.
Doxycycline 200 mg taken once a week prevents infection by patho-
7. Smythe LD, Wuthiekanun V, Chierakul W, et al. The microscopic agglutina-
genic leptospires. Widespread use of doxycycline prophylaxis is not tion test (MAT) is an unreliable predictor of infecting Leptospira in Thailand.
indicated, but it can benefit those who are at high risk for a short Am J Trop Med Hyg 2009;81:695–7.
time, such as military personnel and certain agricultural workers. 8. Zaki SR, Shieh WJ, the Epidemic Working Group. Leptospirosis associated
Infection by leptospires confers only serovar-specific immunity; with outbreak of acute febrile illness and pulmonary haemorrhage, Nicara-
second attacks caused by different serovars can occur. The efficacy and gua. Lancet 1996;347:535–6.
safety of human leptospiral vaccines have yet to be conclusively dem- 9. Watt G, Padre LP, Tuazon ML, et al. Placebo-controlled trial of intravenous
onstrated. Prevention of leptospirosis in the tropics is particularly penicillin for severe and late leptospirosis. Lancet 1988;1:433–5.
difficult. The large animal reservoir of infection is impossible to elimi- 10. Alexander AD, Benenson AS, Byrne RJ, et al. Leptospirosis in Puerto Rico.
nate, the occurrence of numerous serovars limits the usefulness of Zoonoses Res 1963;2:152–227.
75 Relapsing Fever and Borrelioses
Michel Drancourt
EPIDEMIOLOGY
Key features
RESERVOIRS AND TRANSMISSION OF
l Relapsing fevers (RF) are ectoparasite-borne, tropical RELAPSING FEVER (RF) BORRELIAE (FIG. 75.1)
diseases caused by a group of related species of Borrelia, Borrelia recurrentis is unique among RF borreliae, being a human-
different from the Borrelia species responsible for the Lyme restricted pathogen transmitted by the body louse Pediculus humanus;
disease crushing the infected louse introduces B. recurrentis organisms into
l RF is a common and often unappreciated cause of fever in scratched skin; prolonged excretion of B. recurrentis in lice feces may
many areas of Africa and Asia enhance transmission [4, 7]. Other RF borreliae are responsible for
TBRF transmitted from various reservoirs without any apparent
l RF can be louse-borne (LBRF) or tick-borne (TBRF) adverse effects upon their vectors [4]. TBRF borreliae are transmitted
l LBRF is a human-restricted infection caused by Borrelia by soft ticks belonging to the genus Ornithodoros, family Argasidae.
recurrentis associated with human body lice They have nocturnal feeding habits involving painless bites. TBRF
l TBRF is associated with a number of borreliae, including borreliae invade all tick organs, including salivary glands and excre-
tory organs; infectious saliva and coxal fluid may contaminate the
Borrelia duttoni, transmitted by soft ticks often associated
feeding site [3]. Borrelia duttonii was believed to predominately affect
with animal reservoirs humans, but it may have other significant reservoirs, as suggested by
l RFs are characterized by recurrent/relapsing episodes of the detection of B. duttonii DNA in chickens and pigs [4]. Other TBRF
fever and spirochetemia Borrelia species primarily infect rodents and insectivorous animals
l RF can be severe. Mortality can exceed 30% in untreated and are largely zoonotic [8]. Bats have been implicated as reservoirs
for Borrelia persica in Central Asia [2], and a new, unnamed TBRF
cases of LBRF
species related to B. recurrentis was recently identified in a bat in the
l Rapid diagnosis usually relies on microscopic observation of UK [9]. The new TBRF, Borrelia johnsonii, was found in a Carios bat
borreliae on thick blood smear, but PCR-based diagnosis tick in the USA [10]. Competence of birds as reservoir has not been
tests are also available determined, but the same Borrelia hermsii genotype has been docu-
l Treatment usually involves administration of doxycycline or mented in an owl and a pine squirrel in Montana [11], and seabirds
infested with Carios ticks in Japan were found to be infected by a
penicillin
new TBRF [12]. TBRF borreliae can survive in ticks for up to 7 years
l The Jarisch-Herxheimer reaction is frequent within the first after feeding, and some ticks demonstrate transovarial transmission
2 hours of treatment [2, 4].
l Prevention involves de-lousing and minimizing exposure to
soft ticks; no vaccine is available GEOGRAPHIC DISTRIBUTION (FIG. 75.2)
Each RF Borrelia species is considered to be vector-specific [3]. In
Europe, a few cases have been related to an unnamed TBRF Borrelia
most closely related to Borrelia hispanica in Spain [13]. In Africa,
Ornithodoros erraticus transmits B. hispanica in coastal areas of Morocco,
INTRODUCTION Algeria, and Tunisia, Ornithodoros sonrai (formerly Alectorobius sonrai)
Relapsing fevers (RF) are a group of bacterial diseases characterized transmits Borrelia crocidurae in West Africa and several arid areas of
by recurrent episodes of fever and spirochetemia. The true global Northern Africa, Ornithodoros moubata/Ornithodoros porcinus transmit
burden of RF is uncertain, but a number of studies suggest that RF is B. duttonii in Central, Eastern and Southern Africa, whereas B. recur-
a very common cause of fever in areas of Africa, especially among rentis persists only in Ethiopia [3, 4, 14]. In Tanzania, molecular
populations where louse infestation is common, or where humans studies have identified a non-cultured Borrelia species most closely
are exposed to competent tick vectors. The term RF was first used to related to North America TBRF borreliae; its role in human infection
describe an illness that broke out in Edinburgh from 1843 to 1846. is unknown [4]. In Central Asia, B. persica is transmitted by O. tholo-
A causative Borellia agent was first observed in the blood of German zani [15, 16]. In North America, B. hermsii is the main cause of TBRF
patients by Otto Obermeier in the Berlin Charité Hospital in 1873 in western areas, extending from southern British Columbia down to
[1]. Tholozan then described RF in Eurasia in 1882 [2]. Tick transmis- Los Angeles county [17]; Borrelia turicatae is transmitted by O. turicatae
sion was demonstrated in 1905 in Western Africa by Dutton and Todd in Texas and Borrelia lonestari has been isolated only from Amblyomma
[3] after tick-borne relapsing fever (TBRF) plagued the David Living- americanum ticks in the south-eastern and south-central USA, where
stone expedition in Africa [4]. American cases were first documented it is a putative agent of the “Southern tick-associated rash illness”
in 1915 in Colorado [5]. (STARI) [18, 19]. Among TBRF borreliae of unknown pathogenicity
in humans, Borrelia anserina is recognized as the agent of fowl spiro-
RF remains a major cause of morbidity and mortality in large areas chetosis [20] and Borrelia coriaceae is a putative agent of epizootic
of Africa and Asia [4, 6]. bovine abortion [21].
602
R e l a p s i n g Fe ve r a n d B or relioses 603
Pigs Chickens
??
?
O. moubata P. humanus
B. hermsii
(O. hermsii) B. hispanica
B. turicatae (O. erraticus)
(O. turicata) B. miyamotoi
(I. persulcatus)
B. lonestari
(A. americanum)
B. duttonil
B. venezuelensis (O. moubata)
(O. rudis) B. recurrentis
(P. humanus)
B. crocidurae
B. crocidurae
(O. sonrai)
B.duttonii
(O. moubata)
FIGURE 75.2 Geographic distribution of RF borrelioses.
B. recurrentis*
91
B. duttonii*
98 B. crocidurae*
Eurasia/Africa
50 (Old World)
B. hispanica*
borreliae
B. perscia*
B. anserina (?)
B. hermsii*
B. parkeri (?)
America
50
B. turicatae* (New World)
borreliae
Candidatus B. texasensis (?)
B. coriaceae (?)
83 B. miyamotoi (?)
B. lonestari (?)
B. burgdorferi*
0.005
FIGURE 75.3 The various RF borreliae as depicted by analysis of the 16S rDNA gene. Number at node indicates the bootstrap value. Borrelia burgdorferi,
the Lyme disease Borrelia, was put as an outgroup to root the tree. Pathogenicity for human is either certain (*) or unknown (?) when the TBRF has been
characterized only in ticks.
R e l a p s i n g Fe ve r a n d B or relioses 605
PREVENTION AND CONTROL 18. Varela AS, Luttrell MP, Howerth EW, et al. First culture isolation of Borrelia
lonestari, putative agent of southern tick-associated rash illness. J Clin Micro-
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visiting caves and similar sites [25]. Advice should be given on mini- by an Amblyomma americanum tick. J Infect Dis 2001;183:1810–14.
20. Lisboa RS, Teixeira RC, Rangel CP, et al. Avian spirochetosis in chickens fol-
mizing exposed skin and pretreating bed nets and clothes with an
lowing experimental transmission of Borrelia anserina by Argas (Persicargas)
insecticide such as permethrine or dimethyltoluamide to prevent the
miniatus. Avian Dis 2009;53:166–8.
attachment of all stages of Argasidae ticks to humans [41]. Pre-exposure 21. LeFebvre RB, Perng GC. Genetic and antigenic characterization of Borrelia
prophylaxis with amoxicillin has been successfully used [2]. coriaceae, putative agent of epizootic bovine abortion. J Clin Microbiol
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4
PA R T
THE MYCOSES
76 General Principles
Roderick J Hay
rigid carbohydrate cell wall. They may have septa along their length.
Hyphae increase in length only at their tips. Because they regularly
Key features send out side branches, new growing tips are constantly formed and
the rate of colonization of host substrate can increase rapidly.
l Mycoses are diseases caused by fungi and are among the
For many fungi, growth of the vegetative phase in artificial media and
most common microorganisms. Fungi are highly successful
in the natural environment is followed by development of a reproduc-
organisms that have spread widely; they affect humans tive phase. Fungi produce an enormous range of spore types that are
both indirectly and directly useful in distinguishing different species. Spores are also the means
l As agents of spoilage and destruction they cause serious by which the pathogen can gain access to its host. Many spores
losses to crops and stored foodstuffs (conidia) are dispersed in the air and infection is acquired by the
respiratory route. Some fungi, for example yeasts, are unicellular and
l Several fungi can cause disease by invasion of external or
reproduce via production of daughter cells by budding.
internal body surfaces. The type of infection varies from
localized superficial colonization of hair shafts to invasive In several of the more important pathogenic species, fungi may
disease with a high mortality assume one form when growing in their natural habitat (e.g. soil,
decaying vegetation) or in culture media, and a different form in
l Fungi may also produce toxins that can be highly potent. parasitized tissue (dimorphism). The saprophytic and pathogenic
Outbreaks of mycotoxicoses have been reported in the phases in several species, for example Histoplasma capsulatum and
tropics where individuals or communities consume grain or Blastomyces dermatidis, correspond to filamentous (hyphal) and yeast-
other produce that has become moldy like (budding) growth respectively.
l Fungi may produce airborne spores, sometimes in very
large numbers, that can sensitize atopic subjects, causing DIAGNOSIS
symptoms of respiratory allergy after inhalation
Isolation and identification of the causal agent are valuable laboratory
l Fungal infections are diagnosed by staining and microscopic procedures. Serologic tests can be helpful, although they may yield
examination of scrapings, exudates or biopsies, or by culture equivocal results. Direct microscopy of skin fragments or scrapings,
on specialized media; serology may also be useful sputum or examination of tissue sections stained with special fungal
l Management may be the simple application of topical stains [e.g. methenamine silver, Grocott modification or periodic acid-
Schiff (PAS)] can provide unequivocal evidence of fungal etiology and
therapies or requires prolonged, complex, and often toxic,
identity. A feature of most mycoses is the development of a host
systemic treatment immune response, including the appearance of specific antibodies.
Immunologic tests may therefore be of value in epidemiologic studies
(using skin tests to assess previous infection) and in diagnosis (using
serologic procedures to detect and quantitate specific antibodies).
Increasingly, genetic methods are used in diagnosis, epidemiology
DISTRIBUTION AND MEDICAL and for the investigation of pathogenesis, although there are few com-
IMPORTANCE mercial diagnostic tests.
Some mycoses are restricted to certain geographic areas; others are
worldwide. Their recognition may be comparatively simple but, in DISEASE CLASSIFICATION
many instances, the full spectrum of diagnostic aids, including micro-
Traditionally, mycoses have been classified according to their route of
scopy, culture, gene analysis and serology are necessary before an
infection and body site [1-4].
etiology can be established. Mycoses do not rank with parasites or
bacteria as causes of mortality in the tropics, but they are common
causes of morbidity, and individual patients can develop progressively SUPERFICIAL MYCOSES (see Chapter 77)
disabling or disseminated disease. Although most fungal infections These mycoses, for example pityriasis versicolor, affect only the outer
are acquired exogenously, some mycoses, for example candidosis, are layers of the epidermis. Living tissues are seldom invaded. Some of
initiated by fungi that are a part of the normal human microflora. these mycoses, for example tinea, although confined to keratinized
parts of the body, can elicit acute or chronic inflammatory changes
MORPHOLOGY in the skin. These changes can be painful, unsightly or disfiguring.
Invasion of nails can result in dystrophy. Superficial mycoses can
The basic vegetative organization of most pathogenic fungi is filamen- be acute or chronic, inflammatory or non-inflammatory, and –
tous. In substrates supporting growth, the cells and hyphae are cylin- unusually among fungal infections – acquired via person-to-person
drical or branching, usually about 3–5 µm in diameter, bound by a transmission.
608
G e n e ra l Pr inciples 609
SUBCUTANEOUS MYCOSES OR MYCOSES OF zygomycosis, are able to infect because of the susceptibility of the
host, rather than an inherent pathogenicity of the fungus. They occur
IMPLANTATION (see Chapter 78) in patients whose normal defenses have been compromised by AIDS,
These diseases, for example mycetoma, are introduced through the leukemia, diabetes, and malnutrition, for example, or by defects in
skin surface by a penetrating wound, such as a thorn prick or splinter the immune system, by cancer or transplantation chemotherapy, or
wound. The agents are usually environmental saprophytes. Once by treatment with broad-spectrum antibiotics.
established they provoke an intense and destructive host response.
The lesions tend to be localized and progressive, usually without a
tendency to heal spontaneously. REFERENCES
1. Chandler F, Kaplan W, Ajello L. A Color Atlas and Textbook of the histopathol-
SYSTEMIC MYCOSES (see Chapters 79, 80) ogy of mycotic diseases. London: Wolfe Medical Publications; 1980.
2. Merz WG, Hay RJ, eds. Medical Mycology. In: Topley and Wilson’s Microbiol-
Some of the respiratory mycoses, for example histoplasmosis, are ogy and Microbial Infections. London: Hodder Arnold; 2005.
acquired by inhalation of airborne spores, with the initial site of 3. Kibbler CC, McKenzie DWR, Odds FC. Principles and Practice of Clinical
multiplication in the lung. While most infections are self-limiting, Mycology. Chichester: Wiley; 1996.
serious progressive or disseminated disease occurs in a small propor- 4. Dismukes WE, Pappas PG, Sobel JD. Clinical Mycology. New York: Oxford
tion of patients, particularly those who are immunocompromised. University Press; 2003.
Opportunistic mycotic infections (see Chapter 79), for example
77 Superficial Mycoses
Roderick J Hay
TINEA IMBRICATA
Key features Trichophyton concentricum is the cause of the tropical infection known
as tinea imbricata or tokelau. It is characterized by the appearance of
l Filamentous fungal infections of skin, hair, and nails homogeneous sheets or concentric rings of scaling that may cover
large areas of the body (Fig. 77.1). Tinea imbricata is best known in
l Acquired from animals, other humans, or soil the Pacific Islands and Melanesia, but reports of the disease in isolated
l Cause tinea or ringworm infections populations, often living in primitive conditions, have been reported
l Scalp, groin, and body infections common in tropics from Malaysia, India, Brazil, and Mexico.
l Respond to topical azoles or oral antifungal drugs such as
terbinafine, griseofulvin, or itraconazole NATURAL HISTORY, PATHOLOGY, AND
PATHOGENESIS
Infection follows transfer from an individual or animal source by
contact. Host resistance to dermatophytosis depends on several innate
INTRODUCTION and acquired immunologic factors. These include increased epider-
mal turnover, locally produced peptides and fatty acids, and transfer-
The dermatophytes cause infections (ringworm or tinea) that are rin. In addition, acquired immunity mediated through T lymphocyte
confined to the superficial stratum corneum, as well as keratinized (Th1) cytokines is critical, although its effectiveness is reduced in
structures, for example hair or nail arising from skin [1]. In temperate non-inflammatory infections, for example the soles of the feet and
climates, tinea pedis affects the interdigital spaces on the feet and is tinea imbricata.
the most common symptomatic form of ringworm in the tropics,
however, groin, body, and scalp infections are more prevalent. Infec-
tions are derived from three main sources – humans (anthropophilic), CLINICAL MANIFESTATIONS
animals (zoophilic), and soil (geophilic). Zoophilic infections tend The clinical features of dermatophytosis depend on the site of infec-
to produce lesions of the scalp or body and are often highly inflam- tion. In temperate areas, occluded surfaces, such as the groin, toe
matory. The anthropophilic organisms can cause lesions in any site webs, and axillae are most often infected, but in the tropics any site
and, depending on the species involved, the inflammatory response can be involved.
is often minimal. Organisms originating from soil are uncommon.
The fungi that cause dermatophyte infections in humans are confined
to three genera, defined by culture or genetic characteristics: Trichophy- FOOT INFECTIONS
ton, Microsporum, and Epidermophyton.
Athlete’s foot or tinea pedis is a term used to describe scaling and
maceration accompanied by itching between the toes, particularly the
EPIDEMIOLOGY fourth interdigital space. It is a syndrome that may be caused by
Candida species, erythrasma or Gram-negative bacteria, as well as by
The most common cause of ringworm worldwide is Trichophyton dermatophytes. In dermatophyte infections, the area between the toes
rubrum (Table 77-1). Trichophyton violaceum has been isolated may be wet or dry and, in some infections, particularly those caused
predominantly from patients in India and the Far and Middle by Trichophyton interdigitale, vesicular. Involvement of the dorsum of
East. the foot or the sole may occur. The commonest cause is T. rubrum.
Distribution of agents of scalp ringworm throughout the tropical Symptoms may be minimal. It is more common in people who wear
world is complex [2]. In sub-Saharan Africa, there is considerable shoes and socks and is therefore associated with urban areas in the
variation in the types of scalp ringworm. Frequently, small pockets of tropics.
infection with distinct organisms occur, for example Microsporum
audouinii in West Africa and T. violaceum in North Africa, India, Tinea pedis in tropical areas must be distinguished from eczema and,
East Africa, and the Middle East. The factors underlying this pattern less commonly, plantar psoriasis [4]. The interplay between bacteria
include the stability of the population, absence of control measures and fungi is poorly understood but, in the tropics, secondary Gram-
and, on occasion, spread via external agents, such as hairdressers’ negative bacterial infection on top of interdigital dermatophytosis can
equipment [3]. occur.
610
S u p e r f i c ial M ycoses 611
Two non-dermatophyte fungi (Scytalidium dimidiatum and Scytalidium FIGURE 77.3 Tinea corporis caused by T. rubrum (image courtesy of the St
hyalinum) cause infections that closely resemble the dry type of John’s Institute of Dermatology, London).
palmar, plantar, interdigital and nail infections caused by T. rubrum
[5].
margin [6]; however, appearance varies with the organism and host.
Particularly in the tropics, T. rubrum can be associated with persistent
TINEA CRURIS (RINGWORM OF THE GROIN) and minimally inflammatory tinea corporis. Discoid eczema,
Dermatophyte infections of the groin are frequently seen in the impetigo, psoriasis, and discoid lupus erythematosus can be mistaken
tropics. A ring of itchy erythema with a scaling margin radiates from for ringworm.
the groin down the inner border of the thigh (Fig. 77.2). Tinea cruris
is more common in males and may extend posteriorly to include the
intergluteal cleft. In women in tropical areas, an extensive form of
TINEA CAPITIS (RINGWORM OF THE SCALP)
ringworm may be found in the waist area that involves a large part of Invasion of scalp hairs is seen with certain dermatophytes. In some,
the skin surface around the hip girdle. Candida intertrigo may closely particularly those spread from animals, scalp hairs often break several
resemble tinea cruris. millimeters above the skin surface. There can be considerable
exudation and erythema. In other infections, including many of
those spread from child to child, the onset is insidious. Hairs break
TINEA CORPORIS (RINGWORM OF THE BODY) at scalp level and inflammation can be minimal. Most cases present
The characteristic lesion of dermatophyte infection on trunk or limbs with hair loss, usually in patches, and a varying degree of scaling (Fig.
is an annular plaque with a varying degree of erythema and a promi- 77.4). However, kerions (very inflammatory pustular lesions) can
nent edge (kerion) (Fig. 77.3). Scaling is most prominent at this develop.
612 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
commonly with T. rubrum. Often, only one hand is involved and the
fingernails on that side may be invaded. The palm shows mild scaling
similar to the dry type of sole infection.
DIAGNOSIS
Although not essential, laboratory diagnosis is helpful as the clinical
diagnosis is not always reliable – particularly in scalp ringworm.
Scrapings or a hair sample can be taken from the lesion with a scalpel,
mounted in 10% potassium hydroxide and examined with a
microscope.
CULTURE
Scrapings or hairs can be plated onto Sabouraud’s agar. Their gross
and microscopic appearance, as well as nutritional requirements, are
used in identification. Molecular probes can identify and type
organisms.
FIGURE 77.4 Tinea capitis, caused by Microsporum audouinii, presents with TREATMENT
multiple patches of alopecia with scaling in this boy (image courtesy of the
Armed Forces Institute of Pathology, Photograph Neg. 7–6860). TOPICAL THERAPY
Dermatophytoses can be treated topically. Topically applied dyes are
Favus, a scalp infection seen in some parts of Africa, for example known to have weak antifungal properties and may be sufficient to
Ethiopia, presents with hair loss accompanied by the formation of treat some dermatophytes, for example tinea cruris. Gentian violet
crusts or scutula. These tend to coalesce to form a dense mat in and magenta paint are examples. Whitfield’s ointment (BPC), which
patches or large areas of the scalp. The diagnosis of tinea capitis is contains 3% salicylic acid and 3% benzoic acid, is a weak antifungal
facilitated by filtered ultraviolet light examination (Wood’s light), agent but is inexpensive and effective in treating all dermatophyte
although only Microsporum species fluoresce under these conditions. infections apart from scalp or nail disease, or kerion.
Ringworm of the scalp must be distinguished from seborrheic derma-
titis, psoriasis, or cicatricial alopecia. The last may be produced in
end-stage favus.
TOPICAL ANTIFUNGALS
Antifungal compounds include imidazole creams or ointments
(miconazole, clotrimazole, econazole, and bifonazole) and terbin-
ONYCHOMYCOSIS afine [8]. All are available for topical therapy in 1–2% concentration.
Dermatophyte invasion of the nails is uncommon in the tropics. The Many are also effective against candidiasis and pityriasis versicolor.
nail plate is invaded from the distal border and lateral surfaces, Topical antifungals have no place in the management of tinea capitis.
usually from the underside. The affected nail becomes thickened and
opaque with a varying degree of onycholysis. Patients often have
infection of other sites, such as the soles or toe webs. In addition to
SYSTEMIC THERAPY
psoriasis, other fungal infections, for example candida or Scytalidium, For nail and scalp disease, or extensive or severe infections, including
must be differentiated from onychomycosis caused by dermatophytes kerion, systemic treatment is necessary. Griseofulvin is given in a daily
[7]. dose of 500–1000 mg in adults or 10 mg/kg in children. For scalp
infections, 6–8 weeks of treatment are usually necessary. More rapid
treatment for these indications is provided by terbinafine (250 mg
DERMATOPHYTOSIS OF OTHER SITES daily) and itraconazole (100–400 mg daily) [9]. These agents shorten
Dermatophytosis of the beard area (tinea barbae) may be highly the treatment period and provide effective therapy; however, they are
inflammatory and persistent. Involvement of the palms is most more expensive than griseofulvin.
l
usually have a predisposing reason for candidiasis
Oral infection can be an early sign of AIDS
EPIDEMIOLOGY
l Avoid long-term treatment (more than 1 month) with Candidiasis occurs throughout the world. Candida albicans is the
organism most commonly associated with superficial candidiasis;
fluconazole if the infection is not responding as drug however, other species, such as Candida tropicalis or Candida guillier-
resistance can develop mondii, can be involved. Candida albicans is a common saprophyte on
mucosal surfaces, particularly in the mouth, gastrointestinal tract, and
S u p e r f i c ial M ycoses 613
VAGINAL CANDIDIASIS
TABLE 77-2 Predisposing Factors in Superficial Vaginal infection with Candida is common and although it can be
Candidiasis associated with diabetes and the third trimester of pregnancy, the
majority of those affected have no obvious underlying abnormality.
Infancy, pregnancy, old age The symptoms of vaginal candidiasis are irritation and discomfort
Occlusion of epithelial surfaces, for example by dentures, associated with a creamy discharge. Similar to oral infection, the
occlusive dressings vaginal mucosa can be covered with small white plaques or become
Disorders of immune function red and friable. Infection must be distinguished from Trichomonas and
Primary, for example chronic granulomatous disease gonorrhea. Candidiasis of the groin is erythematous with a promi-
Secondary, for example HIV/AIDS, leukemia, corticosteroid nent border. Small “satellite” pustules or crusts are often seen outside
therapy this border.
Chemotherapy
Immunosuppressive
Antibiotic PARONYCHIA AND CANDIDA
Endocrine disease, for example diabetes mellitus ONYCHOMYCOSIS
Carcinoma
Infection of the nail folds by Candida species is a cause of paronychia.
Miscellaneous, for example damaged nail folds
The periungual skin is raised and painful, and a prominent gap devel-
ops between the fold and the nail plate. Rarely, invasion of the nail
plate with onycholysis occurs. The condition is caused by a number
of factors, including bacterial infection, although women with heavy
domestic responsibilities (e.g. washing, cooking) seem to be predis-
posed. Superficial erosion on the web space between the fingers can
also be caused by Candida infection in the tropics.
vagina. Oral colonization may begin in infancy, although its inci-
dence is increased by a number of factors, including hospitalization
and bottle-feeding. Candida albicans can be isolated from the environ- CANDIDA INTERTRIGO
ment, often where contact with humans is frequent, such as wash Candida intertrigo is the name given to a painful or irritative inflam-
basins and drinking bowls. matory dermatosis confined to body folds; secondary bacterial infec-
tions can contribute to the process. Infection is most common in
NATURAL HISTORY AND overweight or diabetic subjects.
PATHOGENESIS DIAGNOSIS
When C. albicans causes infection as opposed to colonization, it is
usually in individuals with predisposing factors (Table 77-2). Some Laboratory diagnosis is made by demonstration of Candida in potas-
of these factors are systemic and others relate to local conditions on sium hydroxide wet mounts. Yeast and hyphal forms are both seen.
the skin or mucosa. The effect of climate on infection is unknown, Candida can be cultured on Sabouraud’s agar.
although in the tropics there is a high incidence of saprophytic car-
riage of Candida species. TREATMENT
Topical treatment with gentian violet is effective in some patients.
CLINICAL MANIFESTATIONS However, locally applied amphotericin, nystatin, or an imidazole
preparation is preferable, and powders, lotions, and/or pessaries
ORAL CANDIDIASIS (THRUSH) (vaginal tablets) are available. Oral treatments for superficial candi-
This is common, particularly in the elderly, infants, and denture diasis are fluconazole, itraconazole, voriconazole, posaconazole, and
wearers [11]. It can follow immunosuppression or antibiotic therapy ketoconazole. These are best reserved for severe oral or chronic forms
and is an important marker of AIDS. Infection presents with solitary of candidiasis. AIDS patients with oral candidiasis should usually be
or confluent white plaques on the oral mucosa (pseudomembranous treated with fluconazole, but may respond to topical therapy [13].
candidiasis). Alternatively, the mucosa may appear glazed and ery- Resistance to fluconazole can develop if the drug is continuously
thematous (erythematous candidiasis). Oral candidiasis in AIDS employed in clinically unresponsive infection. Vaginal infections
patients in the tropics is often accompanied by esophageal infection respond to intensive topical therapy given for 3–5 days using a com-
[12]. One of the earliest features of oral candidiasis is the appearance bination of cream and pessaries; however, a single dose of fluconazole
of cracking at the angles of the mouth, or angular cheilitis. is more effective and convenient.
EPIDEMIOLOGY
Infection occurs throughout the world and is extremely common in
the tropics where, in some areas, 60% of the population may be
infected.
CLINICAL MANIFESTATIONS
FIGURE 77.5 Pityriasis (tinea) versicolor on the chest (image courtesy of
The lesions of pityriasis versicolor are small, scaling macules that are the St John’s Institute of Dermatology, London).
hypopigmented or hyperpigmented (Fig. 77.5) [15]. Scaling is usually
not prominent but can be elicited by scratching affected areas. This
feature is helpful in distinguishing this infection from other types of
macular pigmentary disorders, for example vitiligo. Under Wood’s
light, the patches can fluoresce pale yellow. The areas most commonly
infected are the upper trunk, neck, and upper arms. In the tropics,
infection can extend beyond these areas to involve the face, abdomen, the fungi is facilitated by the addition of equal quantities of blue-
lower arms, and penis. The rash is rarely symptomatic but may cause black ink to the potassium hydroxide.
concern because of its superficial resemblance to certain types of
leprosy.
TREATMENT
DIAGNOSIS Application of 2.5% selenium sulfide twice daily for 7–10 days is
usually effective. The response to a topical imidazole may be more
The diagnosis can be confirmed by demonstration of clusters of yeast rapid, and 5 days of 200 mg itraconazole is also reported to be
and pseudo-hyphae in potassium hydroxide mounts. Recognition of effective.
12. Khongkunthian P, Grote M, Isaratanan W. Oral manifestations in 45 HIV- 14. Ashbee HR. Recent developments in the immunology and biology of Malas-
positive children from Northern Thailand. J Oral Pathol Med 2001; sezia species. FEMS Immunol Med Microbiol 2006;47:14–23.
30:549–52. 15. Crespo Erchiga V, Delgado Florencio V. Malassezia species in skin diseases.
13. Mofenson LM, Brady MT, Danner SP, et al. Guidelines for the Prevention and Curr Opin Infect Dis 2002;15:133–42.
Treatment of Opportunistic Infections among HIV-exposed and HIV-infected 16. Therizol-Ferly M, Kombila M, Gomez de Diaz M, et al. White piedra and
children: recommendations from CDC, the National Institutes of Health, the Trichosporon species in equatorial Africa: 1. History and clinical aspects: an
HIV Medicine Association of the Infectious Diseases Society of America, the analysis of 449 superficial inguinal specimens. Mycoses 1994;37:249–53.
Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. 17. Perez C, Colella MT, Olaizola C, et al. Tinea nigra: report of twelve cases in
MMWR Recomm Rep 2009;58:1–166. Venezuela. Mycopathologia 2005;160:235–8.
Subcutaneous Mycoses:
78 General Principles
Roderick J Hay
FIGURE 78.1 Mycetoma (eumycetoma) affecting the palm (image courtesy FIGURE 78.2 Grain of Streptomyces somaliensis surrounded by acute
of the St John’s Institute of Dermatology, London). inflammatory cells (hematoxylin and eosin stain, magnification ×360;
image courtesy of the St John’s Institute of Dermatology, London).
DIAGNOSIS finely textured – the filaments are 1 µm or less in diameter – and are
not individually distinguishable.
Grains produced by different agents may be distinctive enough for the
diagnosis to be made by examination of hematoxylin and eosin-
stained tissue sections (Fig. 78.2). Fungal grains have a coarser texture DIRECT EXAMINATION
and may be pigmented, consisting of a dense mass of interwoven fila- Exudates should be examined for the presence of grains. Opening a
ments (hyphae) 2–5 µm in diameter. Actinomycete grains are more surface pustule over a sinus tract with a sterile needle may reveal them.
618 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
DIFFERENTIAL DIAGNOSIS
Chronic osteomyelitis of bacterial etiology, for example syphilitic, ACTINOMYCETOMA
actinomycotic or tuberculous may resemble mycetoma, particularly Medical treatment with trimethoprim/sulfamethoxazole (co-
in the early stages. Botryomycosis, in which persistent bacterial infec- trimoxazole) and streptomycin or rifampin is often effective. Good
tion is associated with granule and sinus formation, must also be results have been claimed with a combination of dapsone and strep-
distinguished. tomycin. Alternatives include amikacin and fusidic acid.
78.2 Sporotrichosis
CLINICAL FEATURES
Key features The route of entry is via minor traumatic subcutaneous inoculation.
The incubation period varies from 1–4 weeks and, rarely, up to 6
l Tropics and subtropics months. About 75% of infections affect an upper extremity. There is
evidence to suggest that some patients have self-limited infections [7].
l Occasionally can appear in small epidemics
l Diagnosis can be confirmed by culture
CUTANEOUS SPOROTRICHOSIS
l Common differentials – Mycobacterium marinum and
The most common form of sporotrichosis is lymphangitic, in which a
leishmaniasis
small, firm, movable subcutaneous nodule develops at the site of
l Responds to potassium iodide, itraconazole, and terbinafine inoculation. The nodule later becomes soft and breaks down to form a
persistent friable ulcer or chancre. Subsequently, additional nodules
develop along the draining lymphatics that progress to ulceration. The
presence of a persistent ulcer on a finger or hand and a chain of swollen
lymph nodes extending up the arm is suspicious for sporotrichosis. In
about a quarter of cutaneous infections, the lesion remains “fixed”,
without lymphatic spread. Fixed infections are more common in chil-
INTRODUCTION dren and in Latin America. Less commonly, lesions may present as
Sporotrichosis is a chronic fungal infection principally affecting the chronic ulcers, mycetoma-like lesions, or well-defined granulomas. Dis-
skin, lymphatics, and subcutaneous tissues. Pulmonary and dissemi- seminated cutaneous lesions have been reported in patients with AIDS.
nated forms, with involvement of the lungs, osteoarticular and mus-
culoskeletal tissues, viscera, mucous membranes, and central nervous PULMONARY SPOROTRICHOSIS
system (CNS), are uncommon. Sporotrichosis is caused by a single Primary pulmonary infection is rare. It can be asymptomatic but, in
species, Sporothrix schenckii, which is widely distributed as a soil sapro- individuals with a low level of immunity, it can progress to dissemi-
phyte. It is dimorphic, existing as a mold in nature and a yeast in nated disease.
infected tissue.
sporotrichosis can occur in Mycobacterium marinum and some South a cure within 3 months. An adult can be given 1 ml of KI three times
American forms of cutaneous leishmaniasis. daily, with drops in incremental increases to a maximum of 4–6 ml
3 times daily after 1 month. To increase palatability, the drug may be
TREATMENT administered with milk. Treatment should be continued for 3–4
weeks after clinical cure. Alternatives include itraconazole 100–200 mg
The usual treatment for cutaneous infection is orally administered daily or terbinafine 250 mg daily.
potassium iodide (KI) in saturated solution, which usually produces
78.3 Chromoblastomycosis
hyperplasia with microabscess formation. On microscopy of scrap-
ings, distinctive brown fungal cells can be identified in 20% potas-
Key features sium hydroxide (Fig. 78.4). In tissue sections, fungal cells, i.e.
muriform cells or sclerotic bodies, are 5–12 µm in diameter, common
l Seen in humid tropical regions in some sections and rare in others. Culture and identification of the
l Presents with verrucous (warty) or flat plaques
l Diagnosis depends on histopathology with demonstration
of pigmented fungal cells
l Responds to itraconazole or terbinafine
INTRODUCTION
Chromoblastomycosis (chromomycosis) is a chronic mycosis affect-
ing skin and subcutaneous tissues characterized by slow-growing ver-
rucous nodules that coalesce and form hyperkeratotic plaques [9]. It
is caused by several species of related fungi; the most common are:
Fonsecaea pedrosoi, Fonsecaea compactum, Phialophora verrucosa, and
Cladophialophora carriomi. Irrespective of the species, each has an iden-
tical appearance in infected tissues, i.e. single or clustered, rounded
or angular, thick-walled and dark-brown bodies (“sclerotic or muri-
form cells”). Like saprophytes, the organisms are commonly found
in soil and wood.
EPIDEMIOLOGY
Chromoblastomycosis is a tropical mycosis diagnosed more fre-
quenlty in males than in females and is more prevalent in rural than
urban areas. The disease has a worldwide distribution with a high
prevalence in Costa Rica (1/21,000 population) and Madagascar
(1/30,000 population). FIGURE 78.3 Chromoblastomycosis – an early lesion on the ankle (image
courtesy of the St John’s Institute of Dermatology, London).
CLINICAL MANIFESTATIONS
The initial lesion is a warty papule on an exposed site, for example
leg or arm, that enlarges slowly to form a verrucous plaque. In some
instances, the primary lesion is a pustule, a flat plaque, or an ulcer
[10]. As infection progresses, ulceration and serous exudation occur
(Fig. 78.3). Non-painful, large hyperkeratotic plaques up to 3 cm
thick with central scar formation occur. Super-infection may be
responsible for lymphostasis and resultant elephantiasis, and
secondary-infected lesions have an unpleasant smell.
78.4 Rhinosporidiosis
INTRODUCTION DIAGNOSIS AND DIFFERENTIAL
Rhinosporidiosis is a chronic, localized granulomatous condition DIAGNOSIS
that presents with polyp-like lesions. The causative organism has been
Examination of hematoxylin and eosin-stained sections reveals spor-
identified by genetic techniques as a member of the aquatic Protista
angia of varying sizes and stages of development. Culture serologic
[11]. There are no experimental models and the organism cannot be
tests are not helpful. Nasal lesions must be distinguished from polyps
cultured. Disease has been reported from many tropical countries, but
and lesions in other sites, particularly in the perianal region, must be
90% of reported cases are from India and Sri Lanka.
distinguished from warts, condylomata and hemorrhoids
Rhinosporidiosis is most commonly seen in children and young
adults, and in males more than females (three to one). TREATMENT
The most common site of rhinosporidiosis is the nose (70% of cases), Chemotherapy is of little proven value. The treatment of choice is
with sessile or pedunculated polyps affecting the nostrils. Lesions can surgical excision.
affect the conjunctiva and, rarely, the larynx, genitals, and skin. Dis-
semination has been reported, but is exceptional.
Males are more commonly affected than females. Most infections are
reported from West Africa, particularly Nigeria, but cases have been
recognized in India and South America.
The mode of infection is unknown, but is probably inoculation of
contaminated soil or vegetable matter through minor trauma or
insect bites.
CLINICAL MANIFESTATIONS
Infection apparently originates in the nasal mucosa, leading to nasal
obstruction, which may be unilateral. Tissue swelling becomes pro-
nounced affecting the nose and nasolabial folds, cheeks, and upper
lip, eventually producing gross facial distortion (Fig. 78.5). The
infected areas have distinct margins but the mass is not movable over
the underlying tissues. There are few symptoms.
TREATMENT
FIGURE 78.5 Nigerian patient with subcutaneous zygomycosis caused
Treatment is the same as for Basidiobolus (Chapter 78.5).
by Conidiobolus (image courtesy of the Armed Forces Institute of Pathology,
Photograph Neg. No. 76-6165).
10. Minotto R, Bernardi CD, Mallmann LF, et al. Chromoblastomycosis: a review 13. Prabhu RM, Patel R. Mucormycosis and entomophthoramycosis: a review of
of 100 cases in the state of Rio Grande do Sul, Brazil. J Am Acad Dermatol the clinical manifestations, diagnosis and treatment. Clin Microbiol Infect
2001;44:585–92. 2004;10(suppl. 1):31–47.
11. Arseculeratne SN. Rhinosporidiosis: what is the cause? Curr Opin Infect Dis 14. Rinaldi MR. Phaeohyphomycosis. Dermatol Clin 1996;14:147–53.
2005;18:113–8. 15. Paniz-Mondolfi AE, Reyes Jaimes O, Dávila Jones L. Lobomycosis in Vene-
12. Gugnani HC. A review of zygomycosis due to Basidiobolus ranarum. Eur J zuela. Int J Dermatol 2007;46:180–5.
Epidemiol 1999;15:923–9.
Protothecosis 79
Ann M Nelson, Ronald C Neafie
TREATMENT
Simple bursectomy cures protothecosis of the olecranon bursa. The
cutaneous lesions in immunosuppressed patients resist treatment
and may persist for several years, eventually spreading to other
sites [2]. Topical treatments, including Castellani’s paint, saturated
copper sulfate, potassium permanganate and amphotericin B, as
well as systemic griseofulvin, penicillin, emetine hydrochloride,
5-fluorouricil, and pentamidine isothionate, have not been effective.
In vitro studies have demonstrated sensitivity to amphotericin B, tet-
racycline, gentamicin, and ketoconazole [2]. Combined therapy with
tetracycline and amphotericin B may be effective. Isolated cutaneous,
bursal and soft tissue lesions are best treated with local excision and
ketoconazole. Infections that are multifocal, visceral or occur in
FIGURE 79.1 Protothecosis of the foot of a rice farmer from Sierra Leone.
The lesion began as a papule on the instep 9 years earlier. It now encircles immunocompromised hosts require amphotericin-B or combined
the foot and there is a satellite lesion (Armed Forces Institute of Pathology, Neg. therapy.
No. 75-12872-2. Photograph courtesy of Dr P.O. Wakelin).
REFERENCES
1. Chandler FW, Watts JC. Protothecosis and infections caused by green algae. In:
Pathologic Diagnosis of Fungal Infections, 2nd edn. Chicago: American Society
of Clinical Pathologists; 1987:43–53.
2. Lass-Flörl C, Mayr A. Human protothecosis. Clin Microbiol Rev 2007;20:
230–42.
3. Connor DH, Gibson DW, Zeifer AM. Diagnostic features of three unusual
infections: Micronemiasis, pheomycotic cyst, and protothecosis. In: Manjo G,
Cotran RS, eds. Current Topics in Inflammation and Infection. Baltimore:
William and Wilkins; 1982:205–39.
4. Nelson AM, Neafie RC, Connor DH. Cutaneous protothecosis and chlorellosis,
extraordinary :aquatic-borne” algal infections. In Mandojano RM, ed. Clinic
in Dermatology (Aquatic Dermatology). Philadelphia: J. B. Lippincott; 1987:
76–8.
5. Kuo TT, Hsueh S, Wu JL, et al. Cutaneous protothecosis: a clinicopathologic
study. Arch Pathol Lab Med 1987;111:737–40.
6. Lanotte P, Baty G, Senecal D, et al. Fatal algaemia in patient with chronic
lymphocytic leukemia. Emerg Infect Dis 2009;15:1129–30.
7. Luong-Player AT, Romansky SG. Human protothecosis: Lethal, disseminated
infection by Prototheca zopfii in a pediatric patient with leukemia. Arch Pathol
Lab Med 2009;133:1709.
8. Woolrich A, Koestenblatt E, Don P, et al. Cutaneous protothecosis and AIDS.
J Am Acad Dermatol 1994;31:920–4.
EPIDEMIOLOGY
Key features In the USA, the Mississippi and Ohio river valleys are endemic. Infec-
tions are associated with outdoor activities and exposure to starling
l Histoplasmosis is a widely distributed infection caused by roost or soil upheaval.
Histoplasma capsulatum, a dimorphic fungus
The tropical presence of H. capsulatum was established from a
l Individuals from endemic areas are often infected description of the post-mortem pathology of construction workers
subclinically, whereas symptomatic disease depends upon building the Panama canal. Skin testing [3] indicates high prevalence
interplay between the intensity of infection and the host’s throughout Latin America; however, few population-based studies
immune status are available from other tropical areas. In the tropics, conditions
that support the growth of H. capsulatum occur in bat roosting sites,
l Clinical syndromes include acute pulmonary infection
including caves, where exposure in the confined space has resulted in
following heavy exposure, chronic cavitary pulmonary epidemics.
infection in persons with underlying chronic obstructive
pulmonary disease and disseminated infection usually in With the environmental isolation of H. capsulatum in Southeast Asia,
the Indian continent, and the Middle East, the increase in immuno-
immunosuppressed individuals. In Central and West Africa, a
compromising therapies in the developing world and the AIDS pan-
variety of histoplasmosis due to Histoplasma duboisii causes demic, there has been a rise in symptomatic histoplasmosis in all
skin and bone infection areas in the tropics including sub-Saharan Africa [4, 5]. Imported
l Diagnosis is through demonstration of typical budding infections have also been acquired by travellers.
yeast in sputum or biopsy, culture, DNA probes, or antigen
detection NATURAL HISTORY, PATHOGENESIS,
l Although an immunocompetent person with mild-to-
moderate pulmonary infection can be managed
AND PATHOLOGY
symptomatically, those with severe pulmonary infection or Histoplasma capsulatum grows in its mycelial form at lower tempera-
tures (25–30°C) [1]. This phase, characterized by hyphae with slender
disseminated disease should be treated with amphotericin
conidiophores and characteristic tuberculate macroconidia, is the
flowed by itraconazole saprobic state found in the environment. When incubated at 37°C
on an enriched medium, the conidia germinate into yeast – the phase
also found in host tissue.
Histoplasmosis is acquired by the respiratory route; conidia are aero-
solized from soil containing bat or bird guano and inhaled into
alveoli. Alveolar macrophages, modulated by T lymphocytes, contain
this initial infection, resulting in localized granulomatous inflamma-
INTRODUCTION tion. This self-limiting process is evidenced by the development of
delayed-type skin reactions and the production of specific antibodies,
Histoplasmosis is a widely distributed infection caused by Histoplasma as well as asymptomatic calcification in the lung, spleen, and medi-
capsulatum, a dimorphic fungus. Darling, who first described the astinal lymph nodes. A small percentage of these episodes advance to
pathology of histoplasmosis in 1905, named the organism Histo- progressive pulmonary or disseminated infection, often in the immu-
plasma capsulatum because the small yeasts within the cytoplasm of nocompromised [6].
macrophages resembled encapsulated parasites.
Histoplasma capsulatum var. capsulatum generally causes subclinical
infection in persons from endemic areas [1]. However, following high
CLINICAL FEATURES
exposure, symptomatic pulmonary infection can occur and debili- Histoplasmosis can be classified by site (pulmonary, extrapulmonary,
tated or immunocompromised persons can present with dissemi- or disseminated), by duration (acute, subacute, and chronic) and by
nated disease. Infections caused by H. capsulatum var. duboisii are pattern (primary versus reactivation). Most infections in normal hosts
restricted to West and Central Africa [2]. African histoplasmosis clas- are asymptomatic; even symptomatic primary infection can be under-
sically presents with cutaneous and skeletal involvement. diagnosed given its brief, mild nature [7].
625
626 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Asymptomatic fungemia occurs with the primary infection, as evi- Histopathology of valvular lesions reveals extracellular yeast and myc-
denced by splenic and pulmonary calcifications. Unrecognized dis- elial elements. Adrenal involvement is common [8].
semination permits subsequent reactivation at pulmonary and
extrapulmonary sites if the host becomes immunocompromised [8].
Acute disseminated disease is often reported in young children and PATIENT EVALUATION, DIAGNOSIS,
infants, or in patients with cellular immune deficiency, and can be a AND DIFFERENTIAL DIAGNOSIS
fulminant, fatal disease.
COLLECTION AND TRANSPORT OF
PULMONARY HISTOPLASMOSIS SPECIMENS [1]
Acute primary pulmonary histoplasmosis (APPH) develops in immu- Most diagnostic specimens will be sputum, bronchoalveolar lavage,
nocompetent hosts exposed to a heavy inoculum. A history of envi- transtracheal aspirates, or lung biopsy. Specimens should be trans-
ronmental exposure should be sought and public health authorities ported and processed promptly to avoid overgrowth by bacteria or
notified if a source is identified. Symptoms of APPH often resemble saprophytic fungi. Mycelial conidia are highly infectious and easily
those of an influenza-like illness [7]. The sudden onset of fever, ery- transmissible by aerosolization. When cultures are handled for iden-
thema nodosum or multiforme, and a brassy cough secondary to tification or sent to reference laboratories, they must be sealed.
airway compression from lymphadenopathy can be accompanied, in
severe cases, by pericarditis, nights sweats, cyanosis, hemoptysis, or
disseminated disease. Chest x-ray demonstrates a diffuse alveolar- DIRECT EXAMINATION
interstitial infiltrative or reticulonodular pattern. Radiographic Histoplasma capsulatum should be examined with special stains. The
changes resolve slowly or leave a miliary pattern. Features that can budding yeast of H. capsulatum (2–4 µm) in a calcofluor white
differentiate this from tuberculosis are the pattern of grouped calcifi- or potassium hydroxide preparation of sputum can be too small
cation in paratracheal nodes and larger calcifications (>4 mm in the for reliable detection and can be confused with Candida glabrata
parenchyma and >1 cm in the mediastinum). In patients with active (Fig. 80.1).
pulmonary histoplasmosis, yeast can be observed on direct examina-
tion of sputum, often within pulmonary alveolar macrophages. Bone marrow aspirates, buffy coat smears and peripheral blood
smears are valuable in disseminated disease. Touch preparations of
bone marrow biopsies, lymph nodes, and other tissues can also detect
CHRONIC CAVITARY PULMONARY fungi. Giemsa or Wright stain reveals yeast within circulating mono-
HISTOPLASMOSIS (CCPH) cytes or tissue macrophages. Staining of a paraffin-embedded clot
This is an indolent, progressive respiratory infection of patients with section of bone marrow aspirate by periodic acid-Schiff (PAS),
underlying chronic obstructive pulmonary disease that is rarely Gomori methenamine stain (GMS), Giemsa and Wright stains allows
described in the tropics. These patients are usually elderly, cigarette- visualization in granulomas.
smoking males who suffer progressive deterioration of pulmonary
function, most likely caused by a combination of chronic lung disease CULTURE [10]
and histoplasmosis [7]. Plating and study of cultures should be performed within a biosafety
cabinet. Isolation media for sputum samples should contain
DISSEMINATED HISTOPLASMOSIS
Acute Disseminated Histoplasmosis
This can occur with primary infection, often in young children or
infants, or in the immunosuppressed host. The disease varies in sever-
ity, clinical manifestations and course from a fulminant, fatal disease
marked by shock, to a subacute disease with little systemic inflamma-
tion and focal, organ-specific signs and symptoms [1].
The most severely compromised hosts present with hectic fever,
cough, dyspnea, and pulmonary infiltrates and adenopathy. Weight
loss, infiltration of the reticuloendothelial system and bone marrow,
diffuse cutaneous lesions and central nervous system (CNS) involve-
ment reflect systemic spread. Rapidly fatal overwhelming infections
marked by disseminated intravascular coagulation (DIC), adult respi-
ratory distress syndrome (ARDS), bone marrow suppression and
multi-organ failure occur in a minority. Children often have marked
hepatosplenomegaly, gastrointestinal bleeding, and anemia. AIDS
patients present with lymphadenopathy, CNS manifestations, and
skin lesions that vary from erythematous macules, purpura and ulcers,
to papules resembling molluscum contagiosum [6, 9].
A B
FIGURE 80.2 (A) Small, intracellular yeasts packed in tissue macrophages from a patient with classic histoplasmosis (Histoplasma capsulatum var. capsulatum;
hematoxylin and eosin, X 400). (B) Histoplasma capsulatum var. duboisii infection revealing aggregates of giant cells with large ovoid yeast cells (hematoxylin
and eosin, x310) (images courtesy of the Armed Forces Institute of Pathology Photograph Neg. Nos. 54-17185 and 54-19426, respectively).
disseminated histoplasmosis have been successfully treated with itra- walls, and located within giant cells (Fig. 80.2B). The place of serology
conazole alone; ketoconazole has been associated with failure and in African histoplasmosis is not established.
relapse. Therapeutic response, particularly in HIV-infected patients
who have a high H. capsulatum antigen burden, can be monitored by Solitary cutaneous lesions can be surgically removed and, in many
serial urine and serum samples. cases, do not recur. Oral itraconazole (200–600 mg daily) is effective
in most cases [13], either on its own or in addition to surgery. In
Histoplasma meningitis can be refractory to treatment with frequent widespread infection, amphotericin B may be necessary (Chapter 87).
relapses, even with intrathecal amphotericin B. Surgical resection of Reasonable responses have also been seen with ketoconazole. Relapse
valves in endocarditis with systemic amphotericin B affords the best after therapy is common.
chance for cure.
REFERENCES
PREVENTION 1. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Micro-
There is no practical environmental control, although it is useful to biol Rev 2007;20:115–32.
post warning notices in caves known to contain the organism. Spray- 2. Cockshott WP, Lucas AO. Histoplasma duboisii. Q J Med 1964;33:223–38.
ing contaminated soil with 3% cresol or formalin may eliminate 3. Edwards PQ, Billings EL. Worldwide pattern of skin sensitivity to histoplas-
viable organisms mosis. Am J Trop Med Hyg 1971;20:288–319.
4. Ajello L, Manson-Bahr PEC, Moore JC. Amboni caves, Tanganyika, a new epi-
demic area for Histoplasma capsulatum. Am J Trop Med Hyg 1960;9:633–8.
AFRICAN HISTOPLASMOSIS 5. Suzuki A, Kimura M, Kimura S, et al. An outbreak of acute pulmonary histo-
plasmosis among travellers to a bat inhabited cave in Brazil. J Jpn Assoc Infect
African histoplasmosis is an uncommon illness restricted to the Dis 1995;69:444–6.
African continent. It is most prevalent in West Africa and has not been 6. Wheat JD, Connolly-Springfield PA, Baker RL, et al. Disseminated histoplas-
recognized north of the Sahara Desert or in countries south of the mosis in the acquired immune deficiency syndrome; Clinical findings, diagno-
Zambesi River [2]. Although the portal of entry is presumed to be sis, and treatment, and review of the literature. Medicine 1990;69:361–74.
respiratory, cases with pulmonary involvement are rare. Histoplasmin 7. Goodwin RA, Lloyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medi-
surveys cannot estimate the risk of subclinical exposure because cine 1981;60:231–66.
classic histoplasmosis can be endemic in the same areas and both 8. Wang TL, Cheah JS, Holmberg K. Case report and review of disseminated
organisms are antigenically related. histoplasmosis in South East Asia: Clinical and epidemiological implications.
Trop Med Internal Health 1996;1:35–42.
The most common clinical sites for African histoplasmosis are skin 9. Barton EN, Roberts L, Ince WE, et al. Cutaneous histoplasmosis in the
and bone [2, 13]. Skin lesions present as small papules that can acquired immunodeficiency syndrome: a report of three cases from Trinidad.
develop an umbilicated center, nodules, abscesses, or ulcers. With Trop Geogr Med 1988;40:153–7.
larger lesions, underlying bone deposits are common. Bone deposits 10. Wheat JD, Kohler R, Tewari L. Diagnosis of disseminated histoplasmosis
are well circumscribed and lytic, and typically found in the long detection of Histoplasma capsulatum antigen in serum and urine specimens. N
bones and skull. Patients presenting with African histoplasmosis Engl J Med 1986;314:83–8.
should be investigated radiologically for occult bone foci. Involve- 11. Wheat JD, Hafrier R, Korzun AH, et al. Itraconazole treatment of disseminated
ment of lung, lymph nodes, and gastrointestinal tract is less common. histoplasmosis in patients with the acquired immunodeficiency syndrome.
Multi-organ invasion rarely occurs and is associated with a poor Am J Med 1995;98:336–42.
prognosis. 12. Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the
management of patients with histoplasmosis: 2007 update by the Infectious
The diagnosis is made by biopsy, smears, and cultures taken from skin Diseases Society of America. Clin Infect Dis 2007;45:807–25.
or bone lesions. Histoplasma duboisii are larger than H. capsulatum 13. Velho GC, Cabral JM, Massa A. African histoplasmosis: therapeutic efficacy of
measuring 8–15 µm in diameter, round or oval in shape with thick itraconazole. J Eur Acad Dermatol Venereol 1998;10:77–80.
Coccidioidomycosis 81
Gregory M Anstead, John R Graybill
Fever” after the San Joaquin Valley of California, a focus of coccidioid- accompanied by hilar or paratracheal lymphadenopathy [2]. In
omycosis [2]. These may be the only manifestations of primary coc- studies of community-acquired pneumonia in Arizona, serologic
cidioidomycosis, or may blend into invasive forms of disease. studies demonstrated that coccidioidomycosis is the etiology in 15%
of patients [5].
PULMONARY INFECTION Typically, the symptoms of acute pulmonary coccidioidomycosis
Most symptomatic patients have a transient pulmonary infection resolve spontaneously in less than a month. Alternatively, the
occurring 1–3 weeks after exposure, which manifests as fever, dry pulmonary infiltrates may condense into nodules that may resolve
cough, and pleuritic chest pain. Although this is usually indistin or persist asymptomatically. While primary pneumonia usually
guishable from community-acquired pneumonia, it is commonly resolves, in 5–19% of patients, the disease may linger for months,
with chronic pulmonary infiltrates, cough and pleuritic chest pain.
Pulmonary infiltrates can also undergo cavitation. Cavitary disease
can be asymptomatic or cause chronic productive cough and occa-
sional hemoptysis, or rupture into the pleura [2]. Cavities may also
develop secondary bacterial or Aspergillus (fungus ball) infection.
Small cavities (<5 cm diameter) are more likely to resolve spontane-
ously than large ones. Chronic pulmonary coccidioidomycosis may
San Francisco follow an intermittent waxing and waning course or be slowly pro-
San Joaquin Valley gressive over years [6].
Uncommonly, patients have fulminating pneumonia, with diffuse
Los Angeles reticulonodular infiltrates, fever, and hypoxia (Fig. 81.3). Aggressive
pulmonary disease can occur in pregnancy, especially the last trimes-
Phoenix ter, and in other immunosuppressive conditions, such as AIDS, or
San Diego
Tucson treatment with corticosteroids or tumor necrosis factor-alpha antago-
nists [6].
EXTRAPULMONARY DISEASE
Extrapulmonary coccidioidomycosis usually presents as skin lesions
(papules, nodules, abscesses, verrucous plaques, ulcers), lymphadeni-
tis, deep abscesses, osteoarticular disease (manifested by lytic bone
lesions and thickened synovium), or CNS disease [2, 6]. Nearly any
organ can be involved in coccidioidomycosis [6].
MENINGITIS
Coccidioidal meningitis manifests as progressive headache, cranial
neuropathies, and altered mental status [2]. Granuloma formation
MEXICO causes a variety of focal neurologic signs. The cerebrospinal fluid
(CSF) is characteristic of granulomatous meningitis, with lymphocy-
tosis and hypoglycorrachia. CSF eosinophilia, if present, is a helpful
diagnostic characteristic and the CSF is usually positive for IgG anti-
body. CSF cultures are positive in <50% of cases. Untreated, coccidi-
FIGURE 81.1 Endemic range of coccidioidomycosis in North America. oidal meningitis is lethal within 2 years [6].
A B
FIGURE 81.2 (A) Lesion with Coccidioides immitis spherule within a collection of neutrophils in an abscess (poor immune response; Courtesy of the Armed
Forces Institute of Pathology, Photograph Neg. No. 59-5706). (B) Giant cell with intracellular spherule and endospores. The spherule has a poorly defined cell
wall (better immune response).
Co cc i d i o idomycosis 631
TREATMENT drug interactions are extensive and problematic [9]. Tacrolimus and
cyclosporine (among other drugs) doses must be reduced and
Treatment guidelines were published in 2005 [1]. In vitro susceptibil- rifampin can induce metabolism to the degree that itraconazole is
ity testing is not helpful; Coccidioides isolates are generally susceptible unmeasurable in the serum. There is much less experience with itra-
to amphotericin B and multiple triazoles in vitro, but treatment conazole in the treatment of coccidioidal meningitis [6].
responses are highly dependent on host factors, such as immunocom-
petence and race/ethnicity [1, 2, 6]. Mycelia of Coccidioides are suscep- For life-threatening coccidioidomycosis, amphotericin B desoxycho-
tible to echinocandins but the spherules can be less vulnerable and late or a lipid formulation of amphotericin B should be used [1]. The
clinical experience is limited [6]. Treatment courses are prolonged and latter is generally preferred because of the need for prolonged therapy
should continue many months after clinical improvement. Because and its decreased risk of nephrotoxicity. There is no evidence that high
some lesions can progress while others wane, a scoring system has doses of the lipid formulations (e.g. 10 mg/kg) are more effective than
been developed. This initially included scoring for symptoms and doses of 3–6 mg/kg. Responses to amphotericin therapy on the order
signs, cultures, radiographically apparent lesions and serologic titers, of 50–70% are seen [6]. When the patient has improved or when
with a reduction of a cumulative score to less than 50% of baseline nephrotoxicity occurs, treatment is shifted to triazoles for the remain-
considered to be the criterion of response to therapy [6]. As cultures der of the therapy.
are often not repeated (especially if invasive methods are required) Because the triazoles may be teratogenic, another indication for
and serologic titers change very slowly, the burden of disease has amphotericin B is coccidioidomycosis during pregnancy [1]. If a preg-
recently been measured using clinical signs and symptoms and radio- nant patient develops severe nephrotoxicity, one may be forced to use
graphic evaluation of lesion size. In coccidioidal meningitis, normali- a triazole for at least a limited time, preferably later in pregnancy [6].
zation of CSF findings can be used as an indicator of treatment
response. A challenge in the management of coccidioidomycosis is treatment
when initial therapy fails, or when the patient relapses (which may
Selection of the antifungal agent depends, in part, on the involved be years later). At present, there are two options for salvage. The first
site and the severity of disease [1]. No treatment is recommended for is voriconazole at 400–600 mg/day, which has proven successful in
asymptomatic coccidiomas, which have been resected during a search six of seven patients with refractory disease [10]. However, we have
for presumptive lung cancer. The nephrotoxicity of amphotericin B seen one patient respond well to voriconazole given as a “last ditch”
initially discouraged physicians from treating primary coccidioidal effort, only to have her relapse more than a year after treatment was
pneumonia, which usually resolves spontaneously in most patients. stopped. Another salvage option is posaconazole, 200 mg four times
However, all patients require observation for at least 2 years to docu- per day with a fatty meal. More than half of patients who have failed
ment resolution of infection and to promptly identify complications. other treatments respond to posaconazole [11, 12]. Posaconazole has
With the efficacy of triazoles demonstrated in a variety of the mani- also been used as primary therapy with responses in 85% of 20
festations of coccidioidomycosis, fluconazole has been increasingly patients [13]. Unfortunately, the trial was terminated at 6 months of
deployed to treat primary coccididioidal pneumonia. Nevertheless, therapy, with relapses later appearing in a third of 15 patients who
there are no clear data to indicate the efficacy of fluconazole in the initially responded.
treatment of primary coccidioidal pneumonia or the prevention of
later dissemination [1]. For coccidioidal meningitis, there is the additional option of intrathe-
cal amphotericin B. However, intrathecal amphotericin B can cause
For patients at risk for disseminated disease (the immunosuppressive arachnoiditis and vasculitis and should be administered with corti-
conditions and ethnic/racial groups listed above), antifungal treat- costeroids to suppress these inflammatory adverse events; it is seldom
ment of primary coccidioida pneumonia is appropriate. Other indica- used in the post-fluconazole era [6]. Voriconazole has also been used
tions for treatment are severe disease: infiltrates involving both lungs successfully in salvage treatment of coccidoidal meningitis [10].
or more than half of one lung, or significant hilar or mediastinal Hydrocephalus may require ventriculoperitoneal shunting. Occasion-
lymphadenopathy; IgG titers >1 : 16; highly symptomatic disease ally, hydrocephalus may recur with granuloma formation at the distal
(weight loss >10%; night sweats >3 weeks; symptoms >2 months) [1]. shunt orifice causing obstruction. Reduction of immunosuppression
Signs of chronic infection, such as weight loss, night sweats, persistent is an important adjunct to antifungal therapy, including the initiation
multi-lobar infiltrates and symptoms of more than 2 months dura- of antiretroviral therapy if the patient has AIDS. It is unclear when to
tion suggest progression to the chronic pulmonary form. These terminate antifungal treatment of patients with AIDS, though some
patients should also be treated. have considered this when the CD4 count is above 250 cells/mm3 [1].
Based on excellent tolerability, linear renal clearance, limited drug It has been increasingly appreciated that patients with coccidioidal
interactions and good efficacy, fluconazole has become the drug of meningitis require lifelong antifungal therapy [1, 2, 6]. This may also
choice for less severely ill patients. In a clinical trial, the response rate apply to patients with relapsing non-meningeal disease.
in chronic pulmonary and disseminated disease was 50% for fluco- There are other measures which have been used in the treatment of
nazole versus 63% for itraconazole (p = 0.08) [8]. Fluconazole doses coccidioidomycosis, such as surgical debulking of large abscesses or
of 400 mg/day are used initially, but slow responses and clinical granulomatous lesions, but these have no proven efficacy. Treatment
failures in meningitis have led physicians to use initial doses as high for vertebral osteomyelitis may require surgical stabilization [2].
as 1000 mg per day for meningitis [1]. A course of treatment for 6
months has been suggested for primary pneumonia and treatments During recent decades, there have been multiple efforts to develop a
of greater than 12 months after response of chronic, or severe pulmo- vaccine against coccidioidomycosis. Although there are many vaccine
nary or disseminated, disease [1]. candidates, there is no clearly efficacious vaccine.
6. Anstead GM, Graybill JR. Coccidioidomycosis. Infect Dis Clin N Amer 10. Freifeld A, Proia L, Andes D, et al. Voriconazole use for endemic fungal infec-
2006;20:621–43. tions. Antimicrob Agents Chemother 2009;53:1648–51.
7. Durkin M, Connolly P, Kuberski T, et al. Diagnosis of coccidioidomycosis 11. Stevens DA, Rendon A, Gaona-Flores V, et al. Posaconazole therapy for
with use of the Coccidioides antigen enzyme immunoassay. Clin Infect Dis chronic refractory coccidioidomycosis. Chest 2007;132:952–8.
2008;47:e69–73. 12. Anstead GM, Corcoran G, Lewis J, et al. Refractory coccidioidomycosis treated
8. Galgiani JN, Catanzaro A, Cloud GA, et al. Comparison of oral fluconazole with posaconazole. Clin Infect Dis 2005;40:1770–6.
and itraconazole for progressive, nonmeningeal coccidioidomycosis – a ran- 13. Catanzaro A, Cloud GA, Stevens DA, et al. Safety, tolerance, and efficacy of
domized, double-blind trial. Ann Intern Med 2000;133:676–86. posaconazole therapy in patients with nonmeningeal disseminated or chronic
9. Graybill JR, Galgiana JN, Stevens DA, et al. Itraconazole treatment of coccidi- pulmonary coccidioidomycosis. Clin Infect Dis 2007;45:562–8.
odomycosis. Am J Med 1990;89:292–300.
82 Blastomycosis
Keyur S Vyas, Robert W Bradsher Jr
CLINICAL FEATURES
LUNG LESIONS
Acute pulmonary blastomycosis can present as an asymptomatic FIGURE 82.2 Blastomycosis of left lower lobe.
radiographic infiltrate or as a pneumonia that is indistinguishable
from acute bacterial pneumonia with fever, chills, and productive
cough with or without hemoptysis. Another presentation is several
months of fever, nightsweats, productive cough, and chest pain; this
is typical for patients with chronic pulmonary blastomycosis. Adult
respiratory distress syndrome can manifest in patients with miliary or
endobronchial spread of infection and is associated with a high mor-
tality. Pulmonary findings are present radiologically in half of patients.
The radiologic appearance can resemble bacterial pneumonia in
patients who present more acutely (Fig. 82.2) or as a mass lesion in
patients with a more indolent course [11]. Chronic pulmonary lesions
may show fibrosis and cavitation. Calcification, pleural effusion or
hilar adenopathy are rarely encountered.
SKIN LESIONS
The skin is the most common extrapulmonary site of infection, with
40–80% of patients having skin involvement [12]. Lesions are often
multiple and tend to be located on the face and extremities (Fig.
82.3). They are typically erythematous, well-circumscribed, hyper
keratotic, crusted nodules or plaques that enlarge over weeks. These
lesions may ulcerate to leave an undermined edge (Fig. 82.4). Some
central healing can occur in chronic cases forming a hypopigmented,
atrophic, fibrotic area. Lesions may also occur in the mucous mem-
branes of the nose, lips, larynx, and vagina.
BONE LESIONS
Osteomyelitis occurs in up to 25% of patients, affecting essentially
any bone [2]. Osteolytic lesions and an adjacent cold abscess are FIGURE 82.3 Cutaneous blastomycosis in a 50-year-old patient in the
typical features. In the majority, concomitant skin or lung infection USPHS Hospital, New Orleans, LA, USA. No pulmonary lesions were visible
allows the diagnosis to be made. The treatment course is usually of radiographically (courtesy of the Armed Forces Institute of Pathology, Photograph
longer duration for bone infection [10]. Neg. No. 75-9748).
SYSTEMIC INFECTIONS
Almost every organ has been reported to be infected with B. dermati- PATIENT EVALUATION, DIAGNOSIS,
tidis. Systemic signs of fever and weight loss are mild early in the
course, but become progressively more severe with disease extension.
AND DIFFERENTIAL DIAGNOSIS
After a period of time ranging from weeks to years, chronic infection Microscopic examination of stained histopathology or cytology speci-
may disseminate to multiple organs and cause death if unrecognized. mens and culture of secretions or tissues remains the cornerstone of
Spontaneous remission is rarely observed once infection has pro- diagnosis for blastomycosis. When clinical suspicion is high, direct
gressed beyond the lung. microscopic examination of sputum, skin, aspirates of abscess fluid,
636 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
200–400 mg daily is now the recommended drug for all but the most
severe cases. Amphotericin B was the drug of choice for all patients
in the past and continues to be initial therapy for those with life-
threatening blastomycosis or central nervous system (CNS) infection
[10]. The deoxycholate formulation is given intravenously at a dose
of 0.7–1mg/kg daily. Alternatively, the liposomal formulation, which
is preferred for CNS disease, can be given at 3–5 mg/kg daily with
fewer side effects, but at greater cost. Amphotericin formulations are
typically given for 1–2 weeks (4–6 weeks for CNS disease), until
improvement occurs, after which therapy can be completed with oral
itraconazole. Non-life-threatening infections can be treated for the
entire course with itraconazole alone. Itraconazole achieves cure rates
of approximately 95% in those completing therapy [15]. It also has
fewer adverse effects than amphotericin B. Fluconazole has lower
success rates in treatment and requires much higher doses than itra-
conazole. A few cases have been treated with voriconazole or
posaconazole.
REFERENCES
FIGURE 82.4 Small hyperkeratotic skin lesion of blastomycosis. 1. Bradsher RW. Blastomycosis. Infect Dis Clin North Am 1988;2:4.
2. Bradsher RW, Chapman SW, Pappas PG. Blastomycosis. Infect Dis Clin North
Am 2003;17:21–40.
3. Bradsher RW. Water and blastomycosis: Don’t blame beaver. Am Rev Respir
or body fluid following either digestion of human cells with 10% Dis 1987;136:1324–6.
potassium hydroxide or staining with calcafluor white or Papanico- 4. Klein BS, Vergeront JM, Weeks RJ, et al. Isolation of B. dermatitidis in soil
laou’s stain is the most rapid and effective means for diagnosis. The associated with a large outbreak of blastomycosis in Wisconsin. N Engl J Med
organism can be visualized in tissue specimens stained with methen- 1986;314:529–34.
amine silver or periodic acid-Schiff stains [12]. 5. Furcolow ML, Chick EW, Busey JD, Menges RW. Prevalence and incidence
studies of human and canine blastomycosis cases in the United States 1885-
Culture should be done and is positive in almost all cases. At room 1968. Am Rev Respir Dis 1970;102:60–7.
temperature, the organism will grow as a mold in 2–4 weeks on a 6. Schutze GE, Hickerson SL, Fortin EM, et al. Blastomycosis in children. Clin
wide range of culture media, including Sabouraud agar. Skin tests are Infect Dis 1996;22:496–502.
not helpful and are not available. Serologic studies using a variety of 7. Craig MW, Davey WN, Green RA. Conjugal blastomycosis. Am Rev Respir Dis
antigens and methods have likewise been unreliable for diagnosis 1970;102:86–90.
[13]. An assay to detect B. dermatitidis antigens in urine is available 8. Maxson S, Miller SF, Tryka AF, Schutze GE. Perinatal blastomycosis: a review.
commercially and may be helpful, although significant cross-reactivity Pediatr Infect Dis J 1992;11:760–3.
has been noted with histoplasmosis, paracoccidioidomycosis, and 9. Pappas PG, Pottage JC, Powderly WG, et al. Blastomycosis in patients with
penicilliosis [14]. the acquired immunodeficiency syndrome. Ann Intern Med 1994;116:
847–53.
10. Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice guidelines for
DIFFERENTIAL DIAGNOSIS the management of blastomycosis: 2008 update by the Infectious Diseases
Skin lesions may be mistaken for basal or squamous cell carcinoma. Society of America. Clin Infect Dis 2008;46:1801–12.
Nasal lesions may resemble leishmaniasis and paracoccidioidomyco- 11. Halvorsen RA, Duncan JD, Merten DF, et al. Pulmonary blastomycosis: Radio-
sis. Laryngeal lesions mimic epidermoid carcinoma both clinically logic manifestations. Radiology 1984;150:1–5.
and pathologically. Pulmonary blastomycosis may resemble tubercu- 12. Saccente M, Woods GL. Clinical and laboratory update on blastomycosis. Clin
Micro Rev 2010;23:367–81.
losis and other granulomatous infections, or bronchogenic carcinoma
13. Bradsher RW, Pappas PG. Detection of specific antibodies in human blasto-
both symptomatically and radiographically.
mycosis by enzyme immunoassay. South Med J 1995;88:1256–9.
14. Durkin M, Witt J, Lemonte A, Wheat B, Connolly P. Antigen assay with the
TREATMENT potential to aid in diagnosis of blastomycosis. J Clin Microbiol 2004;42:
4873–5.
The vast majority of patients coming to medical attention will 15. Dismukes WE, Bradsher RW, Cloud GC, et al. Itraconazole therapy of blasto-
need antifungal chemotherapy [2]. Oral itraconazole at a dose of mycosis and histoplasmosis. Am J Med 1992;93:489–97.
Paracoccidioidomycosis 83
Ricardo Negroni
l Chronic progressive form: oropharyngeal ulcers, The incidence and prevalence of paracoccidioidomycosis are not
known because there is no compulsory reporting.
granulomatous laryngitis, chronic respiratory disease, skin
ulcers, and adrenal insufficiency
l Acute form of juvenile type: patient of less than 30 years of NATURAL HISTORY, PATHOGENESIS,
age, fever, adenomegalies, hepatosplenomegaly, diarrhea, AND PATHOLOGY
and loss of body weight
In infected tissue and culture at 37°C, P. brasiliensis appears as spheri-
l Rural population of tropical regions in South America cal cells of 10–40 µm in diameter with a thick bi-refringent cell wall
l Mixed granuloma, epithelioid and suppurative, showing and several peripheral buds, like a pilot wheel. Mother cells with a
multibudding yeast-like cells single blastoconidium and short chains of three to four budding cells
l Synonyms: South American blastomicosis and Lutz’s are often found (Fig. 83.2). In Sabouraud dextrose agar and in yeast
extract agar at 25°C, P. brasiliensis grows very slowly and yields cotton-
mycosis
like, whitish colonies that exhibit microscopically branched, septated
and hyaline hyphae with chlamidospores and aleurioconidiae. This
fungal species is genetically heterogeneous and a new species, with
the same morphologic characteristics, named Paracoccidiodes lutzi, has
INTRODUCTION been proposed [1, 3, 6]. This strain was isolated from southwest Brazil.
Paracoccidioidomycosis is a systemic mycosis endemic in South and Infection occurs following inhalation of aleurioconidiae that turn
Central America caused by a dimorphic fungus, Paracoccidioides into yeast-like elements inside alveolar macrophages. A nonspecific
brasiliensis. inflammatory reaction is initially observed. In a few days these inflam-
matory changes progress to epithelioid cell granuloma with giant
This mycosis was discovered by Adolfo Lutz in Brazil in 1908. Alfonso cells, plasmacytes, and lymphocytes. Microabscesses are common and
Splendore (1912) published several cases in São Paulo (Brazil) and caseous necrosis is observed in lymph nodes. Tissue repair involves
described the etiologic agent. Floriano P. de Almeida (1930) clearly fibrosis. Cell-mediated immunity, with a predominant Th1 cytokine
separated this mycosis from coccidioidomycosis [1–3]. response (INF-γ, IL12, IL2, TNF-α), is the most important defense
mechanism, this type of reaction is genetically controlled. Antibodies
EPIDEMIOLOGY are also produced during progressive disease but their significance in
the control of the infection is not well understood [7].
Paracoccidioidomycosis is endemic in humid tropical and subtropical
areas of Latin America, from Southern Mexico to 34° South in Argen- Progressive paracoccidioidomycosis may be the result of reactivation
tina and Uruguay (Fig. 83.1). It is frequent in Brazil, where 80% of of a latent focus of infection (in chronic forms) or the lack of control
all patients are detected, and where it is the eighth leading cause of of the primary infection (in the acute juvenile type) [5].
death. This mycosis also occurs in Argentina, Colombia, Ecuador,
Paraguay, and Venezuela [4].
CLINICAL FEATURES
The endemic zones have acid soils, rich in organic material, with
many streams and rivers, and exuberant vegetation. The habitat of P. NONPROGRESSIVE INFECTIONS
brasiliensis is not well known; it probably lives in soil near water. It
has been isolated from different natural sources, but these isolations Primary infections are often asymptomatic or subclinical and self-
have not been replicated. Beside humans, infection has been observed limited. Symptomatic primary infections are rare, calcifications of
in armadillos and squirrel monkeys. Animal-to-human and human- lung or lymph node foci are infrequent and 6–50% of inhabitants of
to-human transmission have not been confirmed [2–4]. endemic regions have positive paracoccidioidin skin tests as evidence
of a prior subclinical infection [5].
Infection is most likely acquired by airborne inhalation of conid-
iae; primary infections of skin or mucosa are rare. Primary pulmo-
nary infection is often asymptomatic or mild and self-limited PROGRESSIVE FORMS
(paracoccidioidomycosis-infection) [5].
Reactivation of latent pulmonary or extrapulmonary foci leads to Acute form of Juvenile Type
progressive clinical forms that are severe (paracoccidioidomycosis This clinical form in children and adolescents has an acute course
disease). This presentation is frequently observed in adult males marked by toxemia, fever, asthenia, anorexia, weight loss, subcu
above 35 years of age, the majority of whom are rural workers; taneous abscesses, diffuse lymphadenopathy, hepatosplenomegaly,
637
638 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
20°
0°
Low
Moderate
High
35°
FIGURE 83.4 Granulomatous ulcerated lesion of the oral mucosa in a FIGURE 83.7 Bronchoalveolar lavage smear stained by Grocott
patient with a chronic progressive paracoccidiodomycosis. methenamine silver. Typical yeast-like elements of P. brasiliensis are
observed (400×).
frequently detected. All these alterations may revert with clinical Other drugs that have been successfully used are voriconazole, posa-
improvement [2, 3, 5, 7]. conazole, and terbinafine, but clinical experience with them remains
limited.
The differential diagnosis depends upon the clinical manifestation.
Chronic disseminated disease can be confused with tuberculosis, his- Paracoccidiodomycosis is always a severe infection that requires pro-
toplasmosis, leishmaniasis, carcinoma, and sarcoidosis; acute dis- longed treatment. Relapses are common and cure often leaves inca-
seminated disease presents with clinical characteristics similar to pacitating sequelae, for example laryngeal and tracheal stenosis,
tuberculosis, malaria, leukemia, and lymphomas. buccal atresia, and pulmonary fibrosis.
Although several antigens have been studied as inmunogens to
TREATMENT prevent paracoccidiodomycosis in laboratory animals, none of them
have been used in human beings and there is no measure to avoid
Sulfonamides, ketoconazole, itraconazole, and amphotericin B have the risk of infection [3, 7, 8].
been successfully used in the treatment of paracoccidioidomycosis.
Accepted treatment schedules are: ketoconazole 200–400 mg/day for
12 months; itraconazole 100–200 mg/day for 6 months; and ampho- REFERENCES
tericin B given intravenously at daily dose of 0.7–0.8/kg, up to a 1. Brummer E, Castañeda E, Restrepo A. Paracoccidioidomycosis; an update.
maximum total dose of 35 mg/kg. The azoles are administered by Clin Microbiol Rev 1993;6:89–117.
oral route after a meal. Amphotericin B is indicated in severe cases 2. Negroni R. Paracoccidioidomycosis (South American blastomicosis, Lutz’s
where there is malabsorption. Itraconazole is the treatment of choice Mycosis). Intern J Dermatol 1993;32:847–59.
and is effective in more than 95% of cases. However, its absorption 3. Restrepo Moreno A. Paracoccidioidomycosis. In: Dismukes W, Pappas P, Sobel
requires gastric acid and its effect can be reduced by involvement of JD, eds. Medical Mycology. Oxford: Oxford University Press; 2003:328–45.
mesenteric lymph nodes, especially in acute disseminated form. It 4. Wanke B, Londero AT. Paracoccidioides brasiliensis. In: Ajello L, Hay R eds.
should not be used for patients with tuberculosis under treatment Medical Mycology. Topley and Wilson’s Microbiology and Microbial Infec-
with rifampin. tions, 9th edn, Vol. 4. London, Sydney, Auckland: Arnold; 1998:395–407.
5. de Franco MF, Lacaz C da S, Restrepo-Moreno A, Del Negro G, eds. Paracoc-
Co-trimoxazole is still frequently used in Brazil, especially in recently cidioidomycosis. Boca Raton. Ann. Arbor, London, Tokyo: C.R.C. Press; 1994.
diagnosed patients with no previous therapy, in chronic unifocal 6. Felipe MS, Teixeira MM. Is Paracoccidioides brasiliensis an unique species?
progressive disease, and as maintenance after a course of amphoter- Biomédica 2008;28:136.
icin B. It is given to adults every 12 hours, at a dosage of 160 mg of 7. Calich VLG, da Costa TA, Felonato M, et al. Innate immunity to Paracoccidi-
trimethoprim and 800 mg of sulfamethoxazole, for 2–3 years [3, 7]. oides brasiliensis infection. Mycopathologia 2008;165:223–36.
8. Negroni R. Paracoccidioides brasiliensis. In: Yu V, Weber R, Raoult D, eds. Anti-
Children suffering paracoccidiodomycosis are usually treated with microbial Therapy and Vaccines, 2nd edn. New York: Apple Trees Production
amphotericin B intravenously at daily dose of 0.7 mg/kg of body LLC; 2002:1097–105.
weight or sulfadiazine 200 mg/kg/day by oral route, often because of 9. Camargo ZP de, Franco MF de. Current knowledge on pathogenesis and
the difficulty they have in taking oral medication and the frequent immunodiagnosis of paracoccidioidomycosis. Rev Iberoamer Micol 2000;
involvement of mesenteric lymph nodes [3, 7]. 17:41–8.
Cryptococcosis 84
Françoise Dromer, Olivier Lortholary
l
AIDS
Severity of disease (central nervous system involvement,
NATURAL HISTORY, PATHOGENESIS,
dissemination, high antigen titers, acute respiratory AND PATHOLOGY
symptoms) needs to be assessed for optimization of Infection by C. neoformans usually represents reactivation of a latent
treatment infection acquired early in life by inhalation [8]. However, acute
l The most severe patients should be treated with a pneumonia following massive inhalation of contaminated dust or
primary skin infection following injury occurs. Disease with C. gattii
combination of an amphotericin B formulation and is estimated to begin anywhere from 2–11 months after exposure [9].
flucytosine for at least 2 weeks when possible and switched
to fluconazole for a total of 10–12 weeks and then Cryptococcus spp. are encapsulated yeasts. The capsule is composed of
polysaccharides of which the main component, glucuronxyloman-
maintenance therapy with low-dose fluconazole
nan, is a major virulence factor. It is secreted during growth in vitro
l Control of elevated intracranial pressure is crucial for and during the infection. Its detection in body fluids is used for the
treatment efficacy diagnosis of cryptococcosis with commercially available and reliable
kits. Other virulence factors have been uncovered, such as the ability
to grow at 37°C, melanin production and production of other
enzymes [8].
INTRODUCTION Invasion of the central nervous system (CNS) following fungemia is
a key feature. The term meningoencephalitis rather than meningitis
Cryptococcosis is a major cause of global mortality (fourth, before is used because of frequent involvement of the brain parenchyma.
tuberculosis), particularly with the AIDS epidemic and the lack of The presence of polysaccharide around the pseudocysts/masses
availability of anti-retroviral therapy in many countries. Outbreaks formed by dilatations of the Virchow-Robin spaces is responsible for
caused by Cryptococcus gattii have recently been reported in both brain edema and increased intracranial pressure (Fig. 84.1). Infection
apparently immunocompetent and immunodeficient hosts in the by C. neoformans is usually characterized by a low inflammatory
Pacific Northwest of North America. response of the host, especially HIV-infected patients, in contrast to
those caused by C. gattii where brain and lung granulomas can be
EPIDEMIOLOGY observed. The immune reconstitution inflammatory syndrome (IRIS)
which corresponds to a granulomatous tissue reaction induced by
Cryptococcus neoformans [cosmopolitan, including variety grubii (sero-
the restoration of a Th1 response following initiation of HAART
type A) and var. neoformans (serotype D) and C. gattii (serotypes B
can provoke severe symptoms requiring intensive care hospitalization
and C)] are basidiomycetous yeasts found in the environment (espe-
[10, 11]. It has to be differentiated from cryptococcosis relapse.
cially bird droppings, dust). Cryptococcus gattii is mostly found in
tropical and subtropical areas but a highly virulent lineage has recently
spread to Vancouver Island, the Canadian mainland, and Pacific
Northwest.
CLINICAL FEATURES
HIV infection is a major risk factor for cryptococcosis: ~ 1 million CRYPTOCOCCUS NEOFORMANS INFECTIONS
cases/year, particularly in sub-Saharan Africa and Southeast Asia with
>600,000 deaths/year [1]. The incidence rate was 95/100,000 among Central Nervous System (CNS) Involvement
HIV-infected persons and 1400/100,000 among persons living with Meningoencephalitis is diagnosed in ≥75% of cases and more fre-
AIDS in a population-based surveillance program in South Africa [2]. quently in HIV-infected patients [12]. Symptoms are rarely acute.
The prevalence of infection was 18% among HIV-infected Cambo- More often, patients complain of dizziness, headache, and nausea.
dian patients with <200 CD4+/mm3 [3]. When available, highly active Changes in behavior can be noted. Fever is rarely high and is usually
anti-retroviral therapy (HAART) decreases the incidence of cryptococ- intermittent. As infection progresses, impaired vision or hearing,
cosis [4] and the associated long-term mortality and relapse rate [5]. coma, seizures, and other palsies can occur. Signs of meningeal irrita-
Patients with AIDS are only rarely infected with C. gattii. tion are often lacking. Neurologic abnormalities are present in up to
641
642 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
malignancies, to many opportunistic bacterial, fungal, viral, or para- In contrast, low-dosage fluconazole has been shown to be effective
sitic infections. for the primary prophylaxis of cryptococcal meningitis in HIV-infected
patients in Thailand and is recommended in the field by several
TREATMENT public health authorities.
Guangxi
Taiwan
Manipur
Hong Kong
Myanmar
Laos
Thailand Vietnam
Cambodia Malaysia
FIGURE 85.2 Typical papulonecrotic skin lesions on the arm of an HIV- FIGURE 85.4 A photomicrograph of a Wright-stained sputum smear from
infected patient with penicilliosis marneffei. an HIV-infected patient, showing numerous intracellular yeast-like
organisms, some of which have the typical septate yeast forms.
where systemic fungal infections are common, primary prophylaxis with advanced human immunodeficiency virus infection in Thailand. Clin
of AIDS-associated opportunistic infections can be considered [12]. Infect Dis 2002;34:277–84.
The first double-blind, randomized, controlled trial to demonstrate the efficacy and
In advanced HIV disease and P. marneffei infection, antiretroviral safety of using oral itraconazole for primary prophylaxis in HIV-infected patients
therapy (ART) should be administered after 2 to 8 weeks of antifungal with CD4+ cell counts of <200 cells/mm3, in an area where Penicillium marneffei
therapy in all patients who are clinically stable. Primary and second- is endemic.
ary prophylaxis of penicilliosis marneffei can be discontinued in 13. Chaiwun B, Khunamornpong S, Sirivanichai C, et al. Lymphadenopathy due
patients receiving ART and with CD4+ cell counts of >100 cells/mm3 to Penicillium marneffei infection: diagnosis by fine needle aspiration cytology.
for at least 6 months [22]. However, antifungal prophylaxis should Mod Pathol 2002;15:939–42.
be reintroduced if the CD4+ count decreases to <100 cells/mm3. 14. Supparatpinyo K, Sirisanthana T. Disseminated Penicillium marneffei infection
diagnosed on examination of a peripheral blood smear of a patient with
human immunodeficiency virus infection. Clin Infect Dis 1994;18:246–7.
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21. Supparatpinyo K, Perriens J, Nelson KE, et al. A controlled trial of itraconazole
8. Duong TA. Infection due to Penicillium marneffei, an emerging pathogen:
to prevent relapse of Penicillium marneffei infection in patients infected with
review of 155 reported cases. Clin Infect Dis 1996;23:125–30.
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A literature review of all patients with penicilliosis marneffei, including both HIV
The first double-blind, randomized, controlled trial to demonstrate the efficacy and
and non-HIV cases, reported before 1996 from many countries. This emphasizes the
safety of using oral itraconazole for the secondary prophylaxis of penicilliosis marnef-
emerging nature of this fungal pathogen.
fei in HIV-infected patients after successful primary treatment. This resulted in the
9. Ranjana KH, Priyokumar K, Singh TJ, et al. Disseminated Penicillium marneffei
recommendation of secondary prophylaxis as a standard of care in endemic areas.
infection among HIV-infected patients in Manipur state, India. J Infect Dis
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11. Hilmarsdottir I, Coutellier A, Elbaz J, et al. A French case of laboratory-
infected patients after having received antiretroviral therapy and with CD4+ cell
acquired disseminated Penicillium marneffei infection in a patient with AIDS.
counts >100 cells/mm3 for at least 6 months.
Clin Infect Dis 1994;2:357–8.
12. Chariyalertsak S, Supparatpinyo K, Sirisanthana T, et al. A controlled trial of
itraconazole as primary prophylaxis for systemic fungal infections in patients
Pneumocystis Pneumonia 86
Powel Kazanjian
efficacy to TMP-SMX. For those unable to tolerate TMP-dapsone, 4. Hughes WT. Pneumocystosis. In: Strickland GT, ed. Tropical Medicine and
either atovaquone (750 mg twice daily, with food), or primaquine Emerging Infectious Diseases. Philadelphia: WB Saunders; 2000:701–4.
(30 mg/day) plus clindamycin (300–450 mg three times a day) can 5. Beard CB, Carter JL, Keely SP, et al. Genetic variation in Pneumocystis carinii
be used. isolates from different geographic regions: implications for transmission.
Emerg Infect Dis 2000;6:265–72.
In general, intravenous regimens should be given in severe disease This study examined the geographic variation of Pneumocystis genotypes from patients
(pO2 <70; A-a gradient >35 mmO2) [14]. The agent of choice is TMP- in differing locales, and showed that the genotypes at the time of diagnosis matched
SMX; the intravenous dose is identical to the oral regimen. For the person’s place of diagnosis, not the place of birth. This supports the theory that
patients intolerant to or not responding to TMP-SMX after 7 days of disease results from new acquisition of Pneumocystis rather than latent reactivation.
treatment, pentamidine isethionate (3 mg/kg/day) can be used. Pen- 6. Walzer P. Pneumocystosis. In: Guerrant RL, Walker DH, Weller PF, eds. Tropi-
tamadine is almost as effective as TMP-SMX, but it has a higher rate cal Infectious Diseases: Principles, Pathogens, and Practice. Philadelphia:
of serious side effects, including renal insufficiency, arrhythmias and Churchill Livingstone; 1999:673–84.
pancreatitis. For patients with severe disease, adjunctive corticoster- 7. Kovacs JA, Hiemenz JW, Macher AM, et al. Pneumocystis carinii pneumonia: a
comparison between patients with the acquired immunodeficiency syndrome
oids initiated within 24 to 72 hours of anti-pneumocystis therapy
and patients with other immunodeficiencies. Ann Intern Med 1984;
prevents early deterioration of oxygenation by reducing inflammation
100:663–71.
associated with lysis of P. jiroveci organisms. The dose is prednisone
8. DeLorenzo LJ, Huang CT, Maguire GP, et al. Roentgenographic patterns of
40 mg twice daily days 1–5, 40 mg daily days 6–10, then 20 mg daily Pneumocystis carinii pneumonia in 104 patients with AIDS. Chest 1987;
days 11–21 [15]. 91:323–7.
There are several points about treatment outcomes in developing 9. Marty FM, Koo S, Bryar J, et al. Beta-D-Glucan assay positivity in patients with
countries. First, in adult patients, the mortality rates range from 10% Pneumocystis jiroveci pneumonia. Ann Intern Med 2007;147:70–2.
10. Metersky ML, Aslenzadeh J, Stelmach P. A comparison of induced and expec-
to 27%, similar to those reported in the US. However, PCP mortality
torated sputum for the diagnosis of Pneumocystis carinii pneumonia. Chest
rates in children are higher than in industrialized countries, ranging
1998;113:1555–9.
from 10% to 80% [16]. A more rapid progression of HIV infection
Sputum induction when done properly can be a simple and relatively well-tolerated
may be a factor contributing to mortality, since ART was not available procedure with a sensitivity of 55%. This method of diagnosis is important in regions
in developing countries at the time the treatment studies were con- in the developing world where bronchoscopic techniques are not available.
ducted. Based on the degree of oxygen exchange impairment, it is also 11. Wakefield AE, Miller RF, Guiver LA, et al. Oropharyngeal samples for detection
possible that lower response rates may have been due to late initiation of Pneumocystis carinii by DNA amplification. Q J Med 1993;86:401–6.
of anti-pneumocystis treatment. This underscores the importance of PCR technology has allowed for the use of specimens obtained from oropharyngeal
early recognition and prompt treatment for improving outcomes. gargling to diagnose PCP. This study reported a sensitivity of 84%, equivalent to
Second, a full array of anti-pneumocystis regimens used in industrial- that of induced sputum.
ized nations may not be available in developing countries. Thus, 12. Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention and treat-
treatment options for those not responding to or intolerant to ment of opportunistic infections in HIV-infected adults and adolescents:
TMP-SMX may be limited. recommendations from CDC, the National Institutes of Health, and the HIV
Medicine Association of the Infectious Diseases Society of America. MMWR
For prophylaxis in people with AIDS and a CD4 cell count <200 cells/ Recomm Rep 2009;58:1–207.
mm3, TMP-SMX reduces the incidence of PCP. AIDS patients who 13. Safrin S, Finkelstein DM, Feinberg J, et al. Comparison of three regimens for
respond to ART by increasing CD4 cell counts to >200 for more than treatment of mild to moderate Pneumocystis carinii pneumonia in patients
3 months may discontinue PCP prophylaxis. with AIDS. Ann Intern Med 1996;124:792–802.
14. Sattler FR, Cowan R, Nielsen DM, et al. Trimethoprim-sulfamethoxazole or
be decreased by 50% and 75% when the CrCl is less than 50 and CASPOFUNGIN
20 mL/min, respectively. For patients on hemodialysis, a full dose is
given after each dialysis. Caspofungin (Cancidas, Merck) is highly protein bound and slowly
cleared from plasma by distribution into tissues [12]. Metabolism is
by slow peptide hydrolysis. There is no interaction with the P450
VORICONAZOLE system. Tacrolimus levels are decreased by 25%. The usual loading
Voriconazole is an advance for treatment of invasive Aspergillus infec- dose is 70 mg followed by 50 mg daily. No adjustment is needed with
tions and Fusarium and Scedosporium apiospermum [9]. The drug is renal insufficiency or dialysis. With moderate hepatic insufficiency,
structurally related to fluconazole and is available as an intravenous the maintenance dose is decreased to 35 mg daily. Efavirenz, nevirap-
formulation, as tablets (50 and 200 mg) and an oral suspension ine, dexamethasone, rifampin, phenytoin and carbamazepine all
(40 mg/mL). The oral formulations have a 96% oral bioavailability. reduce serum levels by about 20%. When these drugs are used, a daily
Voriconazole is extensively metabolized by cytochrome P450 enzymes, dose of 70 mg should be maintained. Caspofungin is well tolerated;
especially CYP2C19 and to a lesser extent by CYPC2C9 and CYP3A4. reported adverse events include fever, headache, nausea, vomiting,
Large inter-patient variability in serum levels has been reported owing phlebitis and abnormal liver function tests. Histamine-related symp-
to genetic polymorphisms. Low levels are associated with clinical toms have been noted (rash, pruritus, facial flushing).
failure, while increased levels are associated with neurologic toxicity,
including encephalopathy. Monitoring of trough drug levels is recom- MICAFUNGIN
mended after 1 week of therapy, with a target of >1 to 5.5 mg/L [10].
Micafungin (Mycamine, Astellas) is metabolized in the liver and
The most frequent adverse event has been visual disturbances, occurring excreted in an inactive form in the bile and urine [13]. Drug interac-
in 20–30% of patients. These usually start within 30 minutes of the tions are limited as the drug is not metabolized by the P450 system.
dose, last about 30 minutes, and are described as increased brightness, Sirolimus and nifedipine levels are increased by 20%. Micafungin is
blurred vision, altered color perception, and photopsia. Nausea and well tolerated, with a side-effect profile similar to that of caspofungin.
vomiting (6%), and diarrhea and headache can occur. Hallucinations, The recommended dose is 50 mg/day for prophylaxis and 100 mg/
elevated transaminases (3%) and rare hepatic failure have been day when used for treatment. There is no dose adjustment for renal
reported. Mild to moderate rashes (7%) and photosensitivity can be insufficiency or mild–moderate liver disease.
seen.
The intravenous dose of voriconazole is a loading dose of 6 mg/kg ANIDULAFUNGIN
every 12 hours for 24 hours, followed by a maintenance dose of 4 mg/ Anidulafungin (Eraxis, Pfizer) is biotransformed by biochemical deg-
kg every 12 hours. The oral dose is 200 mg every 12 hours (1 hour radation and excreted in the feces [14]. It is not metabolized, so there
before or after eating) for those weighing >40 kg and 100 mg every are few drug interactions, and there is no dose adjustment with renal
12 hours for those who weigh <40 kg. For patients with a CrCl or hepatic insufficiency. Anidulafungin is well tolerated, with only
<50 mL/min, the intravenous formulation should be avoided, as the rare adverse events. The recommended dose for esophageal candidia-
cyclodextrin used to solubilize the voriconazole will accumulate. With sis is 100 mg loading dose followed by 50 mg daily. For invasive
mild to moderate cirrhosis, patients can receive the normal loading candidiasis, the loading dose is 200 mg followed by 100 mg daily.
dose, but the maintenance dose should be reduced by 50%.
POSACONAZOLE REFERENCES
1. Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formulations of amphoter-
Posaconazole is a broad-spectrum azole and the first antifungal with
icin B: clinical efficacy and toxicities. Clin Infect Dis 1998;27:603–18.
significant activity against the agents of mucormycosis, chromoblasto-
2. Bowler WA, Oldfield EC. New approaches to amphotericin B administration.
mycosis, phaeohyphomycosis, mycetoma, and Scedosporium apiosper- Infections in Medicine 1992;9:17–23.
mum [11]. The drug is available only as an oral suspension (Noxafil, Practical review of how to administer AMB, including management of infusion-
Schering). It must be administered with a full meal or a liquid nutri- related toxicity, premedication and nephrotoxicity.
tional supplement for absorption (bioavailability increases 2.5–4.0- 3. Burke LC, Aisner J, Fortner CL, et al. Meperidine for the treatment of shaking
fold). Posaconazole is metabolized by glucuronidation, with the chills and fever. Arch Intern Med 1980;140:483–4.
majority of the drug excreted unchanged in the feces. There is no dose 4. Lomaestro BM. Azole drug interaction update. J Invasive Fungal Infect
adjustment for renal or hepatic insufficiency. 2007;1:122–32.
5. [Anonymous]. Itraconazole. Med Lett Drugs Ther 1993;35:7–9.
Posaconazole is well tolerated, with elevated liver function tests (3%), 6. Chin TWF, Loeb M, Fong IW. Effects of an acidic beverage (Coca-Cola) on
nausea (8%) and vomiting (6%), similar to fluconazole. The dose for absorption of ketoconazole. Antimicrob Agents Chemother 39:1671–5,
invasive infections is 400 mg twice daily with a meal or nutritional 1995.
supplement. If food or supplement is not tolerated, the dose should 7. Ahmad SR, Singer SJ, Leissa BG. Congestive heart failure associated with
be 200 mg four times daily to optimize absorption. Proton pump itraconazole. Lancet 2001;357:1766–7.
inhibitors should be avoided. 8. Kowalsky SF, Dixon DM. Fluconazole: a new antifungal agent. Clin Pharm
1991;10:179–94.
ECHINOCANDINS 9. Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin
Infect Dis 2003;36:630–7.
Echinocandins inhibit fungal cell wall glucan by inhibiting beta-1,3 10. Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitor-
glucan synthesis. The three available echinocandins, caspofungin, ing in patients with invasive mycoses improves efficacy and safety outcomes.
micafungin and anidulafungin, are therapeutically equivalent. The Clin Infect Dis 2008;46:201–11.
11. Nagappan V, Deresinski S. Posaconazole: a broad spectrum triazole antifungal
drugs are available only as intravenous formulations; choices between
agent. Clin Infect Dis 2007;45:1610–17.
them are based upon cost or drug interactions. The major use of
12. Deresinski SC, Stevens DA. Capofungin. Clin Infect Dis 2003;36:1445–57.
echinocandins is in the treatment of systemic candidal infections, 13. Chandrasekar PH, Sobel JD. Micafungin: a new echinocandin. Clin Infect Dis
especially the empiric treatment of candidemia prior to species iden- 2006;42:1171–8.
tification. They are also used for empiric therapy in febrile neutrope- 14. Vazquez JA, Sobel JD. Anidulafungin: a novel echinocandin. Clin Infect Dis
nia. The echinocandins are highly active against Aspergillus spp. 2006;43:215–22.
5
PA R T
PROTOZOAL INFECTIONS
88 General Principles
Alan J Magill
PARASITISM vector carries a parasite from one host to another but is not essential
for the parasite’s life cycle (e.g. houseflies for Entamoeba histolytica).
DEFINITIONS
Parasite comes from the Greek word parasitos and is defined as “a PROTOZOA
plant or an animal which lives upon or within another living organ-
ism at whose expense it obtains some advantage”. Parasitism is a type DEFINITIONS
of symbiosis in which an intimate and obligatory relationship exists Protozoa, derived from the Greek words, protos, meaning first or
between two heterospecific organisms. The parasite, generally the primary, and zoon, meaning animal, is a phylum comprising some of
smaller of the two, is usually metabolically dependent on its host. the morphologically simplest organisms of the animal kingdom.
This association may be beneficial to both (mutualism), beneficial Most species are unicellular, eukaryotic and microscopic in size; most
to one with little effect on the other (commensalism), or beneficial to are free-living and motile, but some have commensalistic, mutualistic
one and detrimental to the other (parasitism). The term parasite is or parasitic relationships. Approximately 10,000 of the described
generally reserved for animal species of protozoa, helminths, and living species are parasitic. Protozoa infect most vertebrate and inver-
arthropods. tebrate species and have developed the capacity to adapt to living in
most host organs.
NATURAL HISTORY The parasitic protozoa, unlike almost all helminths, can replicate
(sexually, asexually or both ways) within the host’s body—a phenom-
HOST enon that largely explains their survival, as well as the overwhelming
infections that develop from single exposures.
The organism on, or within, which the parasite lives is called the host.
The lifecycle of the parasite may take place in a single host species
(e.g. Entamoeba histolytica—human), in two host species (e.g. Plasmo-
dium vivax—human and mosquito) or in more than two host species
CLASSIFICATION
(e.g. Clonorchis sinensis—human, snail, and cyprinoid fish). It remains convenient to divide protozoa pathogenic to man into four
phyla or subphyla (or superclasses in the case of the sporozoa) accord-
A definitive host (e.g. humans for Taenia saginata) is one in which a
ing to their type of locomotion: (1) Sarcodina (amebae); (2) Mas-
parasite undergoes sexual reproduction. Humans may be the only
tigophora (flagellates); (3) Ciliophora (ciliates); and (4) Sporozoa.
definitive host for some parasites (e.g. Trichomonas vaginalis), whereas
others may have several definitive hosts (e.g. bushbuck, other game
animals, and humans for Trypanosoma brucei rhodesiense). Animals that SARCODINA
harbor a parasite that is pathogenic for other animals are called res- Ameboid movements produce pseudopods in the Sarcodina. Repro-
ervoir hosts (e.g. dogs for Leishmania infantum). Parasites that have duction is almost exclusively asexual, usually by binary fission.
reservoir hosts (e.g. Brugia malayi) are more difficult to eradicate than Amebae that infect man include E. histolytica (Chapter 89). Other
those that do not (e.g. Wuchereria bancrofti); the reservoir host serves species of Sarcodina that can be either parasitic (e.g. Naegleria fowleri,
as an alternate in the lifecycle, thus increasing the chance of transmis- normally a free-living organism), mutualistic or commensalistic (e.g.,
sion and survival. Entamoeba hartmanni and Entamoeba coli) are covered in Chapters 102
The animal in which the larval or asexual stage habitates (e.g. fresh- and 94. Most are parasites or commensals of the gastrointestinal tract.
water snail for Schistosoma species) is known as the intermediate host.
A transfer or paratenic host (e.g. large predator fish for Diphyllobothrium
latum) is not necessary for the completion of the lifecycle of the para-
MASTIGOPHORA
site but is utilized as a temporary refuge and vehicle for reaching the Flagella produce a whip-like motion. Most species, like those of the
obligatory or definitive host. An incidental host is one that is acciden- Sarcodina, have both cysts (transmission stage) and trophozoites (pro-
tally infected and is not required for the parasite’s survival or develop- liferative stage). Flagellates that infect man include Giardia lamblia
ment (e.g. humans for Toxoplasma gondii and Leshmania). (Chapter 90), T. vaginalis (Chapter 95), Trypanosoma brucei gambiense,
T. b. rhodesiense and Trypanosoma cruzi (Chapters 97 and 98), and
Leishmania species (Chapter 99). Species in this group are capable of
VECTOR infecting many different tissues and cells.
A vector (from the Latin vehere, to carry), usually an arthropod, trans-
fers an infectious agent from one host to another. The parasite may
develop or multiply within the body of the vector before becoming CILIOPHORA
infective, in which case the vector is called a biologic vector. Biologic Cilia supply the motion in this subphylum. They have two kinds of
vectors are actually hosts—definitive hosts in the case of anopheline nuclei: a macronucleus and a micronucleus. Reproduction is by
mosquitoes for human Plasmodium species or intermediate hosts in asexual transverse binary fission and sexual conjugation. Balantidium
the case of Cyclops species for Dracunculus medinensis. A mechanical coli, the largest intestinal parasite of man, is a ciliate (Chapter 94).
656
G e n e ra l Pr inciples 657
REPRODUCTION
Asexual or binary fission-type reproduction is characteristic of the
AFRICAN TRYPANOSOMIASIS
Sarcodina, Mastigophora and Ciliophora. In some species, asexual Infection with either T. b. gambiense or T. b. rhodesiense almost always
reproduction is more complex. Sexual reproduction in the Sporozoa causes severe human illness. If untreated, it is fatal; fortunately,
always takes place in the definitive host (e.g. mosquito for malarial however, relatively few people are infected. Trypanosoma brucei brucei,
parasites, cat for T. gondii); it results in the formation of a zygote. which is morphologically identical to the subspecies causing human
Asexual reproduction occurs in the intermediate host (e.g. humans sleeping sickness (Chapter 97), causes infection in cattle (nagana)
for malarial parasites and for T. gondii). across much of Central and East Africa. Thus, cattle-raising is limited,
greatly interfering with economic development and with the nutri-
tional status of the entire area but probably protecting the environ-
TRANSMISSION ment from overgrazing, which has occurred in much of Africa. An
increase in fatal cases of African trypanosomiasis was reported in the
INTESTINAL PROTOZOA late 1990s and early 2000s, particularly in Angola, the Democratic
Republic of Congo, and southern Sudan owing to a collapse in health-
These are usually transmitted from host to host by the fecal–oral route care infrastructure and delivery associated with conflicts. In 2009, after
via food and water. Many species have a cystic stage that is capable of intensive control efforts, the number of cases reported has dropped
resisting adverse environmental conditions (e.g. drying, heat, and below 10,000 (9878) for the first time in 50 years.
cold). Toxoplasma gondii is also transmitted by ingestion of under-
cooked meat (contaminated with cysts) or soil, food or other vehicles
contaminated with cat feces (contaminated with oocysts). AMERICAN TRYPANOSOMIASIS
Trypanosoma cruzi affects as many as 15 million people living in
BLOOD AND TISSUE PROTOZOA South and Central America. Although acute infections may be fatal,
most infections are not detected (Chapter 98). Unfortunately,
Most of these have two hosts—vertebrate (man) and an invertebrate
chronic complications years later often lead to severe disability and
vector (arthropod). The parasite is usually transmitted by the vector’s
death from Chagas’ cardiopathy and the “mega” syndromes. The
bite (e.g. in infections with Plasmodium species, T. b. gambiense and
poor ,who live in crudely built huts infested with the vector, “the
T. b. rhodesiense, Leishmania species, or Babesia species) or by exposure
kissing bug,” contract Chagas’ disease. Infection can be transmitted
to contaminated vector feces (e.g. in infections with T. cruzi).
transplacentally from mother to fetus and by blood transfusion.
Increasing immigration from Central and South America to the
MAGNITUDE OF THE HEALTH USA, led to concern regarding the safety of blood transfusions and
PROBLEM Food and Drugs Administration (FDA) approval of the first blood
screening tests in the USA for Chagas disease on 2006. There are still
Protozoal infections cause man more disease and misery than any no FDA-approved efficacious and safe drugs for treating the infec-
other group of infectious agents. tion, particularly the chronic form. Over 1500 confirmed positive
cases of Chagas have been detected via the new blood donor screen-
ing policies as of 2011.
MALARIA
Infections with Plasmodium species remain one of the greatest
causes of mortality and morbidity in the world today, particularly in LEISHMANIASIS
children under 5 years of age and in pregnant women. The World Leishmania species infect millions worldwide and cause clinical
Health Organization (WHO) has set a long-term goal of control of syndromes varying from a minimal, single, self-healing chronic
transmission with drugs, insecticide-treated bed nets and indoor ulceration (urban oriental sore) to a severe, and often fatal,
658 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
generalized febrile illness (kala-azar [Chapter 99]). Leishmania species improved treatments met with some success in heroic clinical trials
causing these different syndromes appear morphologically identical. conducted by MSF and Drugs for Neglected Diseases Initiative
Polymorphisms can be detected, however, by using biochemical, (DNDi). The combination of 10 days of oral nifurtimox combined
immunologic and genetic techniques that correlate with epidemio- with a shorter 7-day course of intravenous eflornithine was shown to
logic and clinical differences. Improved diagnosis to include molecu- be as effective as the standard 14-day course of intravenous eflorni-
lar techniques has demonstrated more cases of subclinical and mild thine. The Nifurtimox-Eflornithine Combination Therapy (NECT)
infections than of the characteristic diseases. Patients with silent significantly decreases the number of intravenous injections needed
chronic infections with species causing visceral disease, i.e. Leishmania and thus is easier for field administration in endemic areas. With the
donovani, L. infantum, or Leishmania chagasi, sometimes develop vis- inclusion in April 2009 of NECT in the WHO Essential List of Medi-
ceral leishmaniasis when they become immunocompromised. Asso- cines, disease-endemic countries now have a new opportunity and a
ciated with the conflict in Afghanistan, tens of thousands of people less complex option to treat the second stage of the Gambiense form
have been infected with epidemic anthroponotic Leishmania tropica of HAT.
during the past 10 years.
AMERICAN TRYPANOSOMIASIS
NEW DEVELOPMENTS There has been renewed interest in developing new efficacious and
safe drugs for treating the infection, particularly the chronic form. The
There have been several developments in protozoology since the last Benznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT)
edition of this book was published. project, is a large, multicenter (most sites are in Brazil and Argentina),
randomized, double-blind, placebo-controlled phase III clinical trial
MALARIA investigating the role of benznidazole in patients with chronic Chagas
The introduction and increasing worldwide use of oral artemisinin heart disease began in 2004 with initial results anticipated in 2013.
combination treatments (ACTs) for the treatment of uncomplicated This project investigates whether etiologic treatment significantly
P. falciparum malaria has led to a decrease in the morbidity and reduces parasite burden, as assessed by PCR-based techniques and
mortality caused by malaria in many countries. In addition, two also will determine the safety and tolerability profile of the trypano-
large, randomized, controlled, clinical trials—one in adults in South- cidal drug in this type of chagasic population.
east Asia and in one children in sub-Saharan Africa—comparing intra- The non-profit drug research and development organization, DNDi,
venous artesunate with intravenous quinine for the treatment of is teaming up with Eisai, a Japanese pharmaceutical company, to test
severe and complicated malaria demonstrated the superiority of the safety and effectiveness of a prodrug of the antifungal ravucona-
artesunate in decreasing all-cause mortality. The possible emergence zole in patients with Chagas disease. The trial, the first in 40 years of
of artemisinin-resistant falciparum malaria along the Thailand– a new drug for this disease, began in June of 2011 in South America.
Cambodian border will increase the difficulty and the cost of treating In addition, Schering-Plough also began a study of oral posaconazole
and controlling that disease. The introduction of RDTs for the diag- in the treatment of asymptomatic chronic chagas disease in Argentina
nosis of malaria has proven to be a valuable tool for the optimal use in July of 2011 as well.
of anti-malarial drugs. Providing useful alternative diagnostic testing
for those who test negative for malaria parasites remains challenging.
In general when available control interventions, such as drugs, diag- LEISHMANIASIS
nostic testing, bed nets, and vector control measures, are introduced The decade between 2000 and 2010 saw a significant expansion in
in a malaria endemic area, especially in a coordinated and integrated available drug treatments for visceral leishmaniasis, especially in the
manner, the reductions in disease incidence and prevalence have been Indian subcontinent. At the beginning of the decade we faced pen-
striking. tavalent antimony-resistant visceral leishmaniasis in India, and had
few other options. A significant expansion in the use of amphotericin
B out of necessity was accompanied by a series of clinical trials dem-
AFRICAN TRYPANOSOMIASIS onstrating the remarkable efficacy and relative safety of liposomal
The significant decline in reported cases of human African trypano- amphotericin B (LAMB) when given as a single 10-mg/kg infusion.
somiasis (HAT) over the last 5 years is as a result of improved case Current WHO recommendations also include intramuscular paromo-
detection and management. Thanks to a partnership between Sanofi mycin and oral miltefosine. Optimal regimens for East Africa remain
Aventis (the manufacturer of the world’s supply of pentamidine, to be determined. Unfortunately there have not been significant
melarsoprol, and intravenous eflornithine) and the WHO, these life- advances for the treatment of cutaneous leishmaniasis or mucosal
saving drugs have been distributed to countries where the disease is leishmanaisis except to show the efficacy of LAMB for both syn-
endemic, thanks to the logistics of the association Doctors Without dromes. The cost of LAMB is prohibitive in resource poor countries
Borders (known as MSF—Médecins sans Frontières). Efforts to develop with endemic disease.
A
SECTION
FIGURE 89.2 Amebic liver abscess. Chest x-ray shows reactive right lower
lobe atelectasis and pleural effusion.
red blood cells (Fig. 89.3), which is more compatible with E. histo-
lytica than E. dispar or E. moshkovskii. Amebic cysts and trophozoites
Pleuropulmonary amebiasis is the most common complication of are passed intermittently in the stool and, therefore, three stools
amebic liver abscess and can take the form of pneumonitis, lung should ideally be submitted, as this has increased the sensitivity of
abscess or bronchohepatic fistula [19]. It generally occurs as a result detection by 23% [22]. In some series, 18% of stools with E. histolytica
of the rupture of a superior right lobe abscess with erosion through diarrhea will be hemoccult-positive. Fecal leukocytes are variable and
the diaphragm to involve the pleural space, lung parenchyma or Charcot-Leyden crystals have been reported. In general, microscopy
bronchus. In contrast, serous pleural effusion and atelectasis are is neither sensitive nor specific.
common findings and do not indicate extension of disease (Fig.
89.2). Intraperitoneal rupture occurs rarely but is associated with a ANTIGEN DETECTION
high mortality. Left lobe abscesses are more likely to progress to
Current antigen detection tests are a great advance over microscopy;
rupture because of late clinical presentation. Pericardial amebiasis, a
however, they are expensive and poorly available in resource-limited
rare complication, usually presents with fever and abdominal pain
settings. Presently, there are several commercially-available antigen
with progression to chest pain. Signs are typical of pericarditis, includ-
kits for detecting Entamoeba (TechLab E. histolytica II, Blacksburg, VA,
ing a friction rub.
USA; Ridascreen Entamoeba, R-Biopharm, Darmstadt, Germany; Triage
Cerebral amebiasis has an abrupt onset, and progresses rapidly Micro Parasite Panel, Biosite Diagnostics, Inc., San Diego, CA, USA;
to death over 12–72 hours without adequate therapy [20]. Thus, ProSpecT E. histolytica, Remel Inc., Lenexa, KS; CELISA Path, Cellabs,
when patients with known amebiasis have alteration of mental states Brookvale, Australia). Unfortunately, these tests require fresh, not
or focal signs, amebic brain abscess or encephalitis should be consid- fixative-preserved, stool for analysis. The TechLab and Cellabs kits
ered and CT or MRI of the brain should be performed if available. report being specific for E. histolytica and thus offer the benefit of
Genitourinary amebiasis is rare and includes rectovaginal fistulas and excluding E. dispar and E. moshkovskii.
vulvar lesions in women and penile amebiasis, in homosexual men
in particular [21]. PCR
Research laboratories can perform PCR on stool or liver abscess pus,
PATIENT EVALUATION, DIAGNOSIS, as well as isoenzyme analysis on cultured trophozoites to confirm
AND DIFFERENTIAL DIAGNOSIS E. histolytica.
FIGURE 89.4 Colonoscopy of a 54-year-old male who presented with lower FIGURE 89.6 MRI of amebic liver abscess.
gastrointestinal bleeding caused by E. histolytica colitis.
for diagnosis. Upon aspiration, amebic abscesses are described as is as potent as the nitroimidazoles in vitro. The drug is cardiotoxic and
“anchovy paste”, chocolate-colored fluid consisting predominantly of congestive failure and deaths have been reported. Electrocardiogram
necrotic hepatocytes. Gram stain is negative, unlike most cases of monitoring is recommended. The drug is given intramuscularly.
pyogenic liver abscess. Trophozoites are rarely seen from aspirates, as The synthetic derivative dehydroemetine is less cardiotoxic and is
these are usually found at the junction of the abscess and viable liver, recommended over emetine if available. Procurement is difficult. In
which usually requires an open drainage procedure [24, 25]. the USA, it is available from the Centers for Disease Control and
Prevention (CDC) Drug Service for metronidazole-refractory amebia-
The differential diagnosis of amebic dysentery includes any other sis (1600 Clifton Road, MS/D09 Atlanta, GA 30333; Tel: (404) 639-
dysenteric infection, thus bacterial stool culture should be per- 3670; Fax: (404) 639-3717).
formed to identify Shigella, Campylobacter, Salmonella, enteroinvasive
Escherichia coli, and enterohemorrhagic E. coli. Non-infectious causes When patients fail medical treatment and undergo open surgery for
of abdominal pain and bloody diarrhea include IBD, ischemic acute abdomen, gastrointestinal bleeding or toxic megacolon [39],
colitis, diverticulitis, and arterio-venous malformation. Occasionally, mortality is extremely high and broad-spectrum antibiotics should be
patients with ongoing intestinal symptoms undergo colonoscopy added for bacterial spillage into the peritoneum.
with biopsy and the diagnosis is made by the pathologist, where
clues include patchy areas of ulceration and periodic acid-Schiff Chloroquine has also been used for amebic liver abscess and has
staining trophozoites (not to be confused with macrophages). IBD shown similar cure rates to metronidazole, although improvement
has been confused pathologically with amebic colitis; thus, in a was slower [40]. It is reported to have little effect on intestinal disease
patient with possible exposure to E. histolytica, the diagnosis of IBD and little in vitro activity [41]. Extended courses have been recom-
should be confirmed with the pathologist, as steroids can worsen mended for liver abscess because relapses have historically been
amebiasis. common, but these probably reflect the drug’s ineffectiveness against
intestinal parasites; 20 days should be adequate if followed by a
course of a luminal agent. For severe liver abscess progressing on
TREATMENT metronidazole/tinidazole beyond 72 hours, switching to chloroquine
and dehydroemetine can be considered [42]; however, procurement
of the dehydroemetine is difficult and should not delay consideration
AMEBIC COLITIS of drainage.
Since the 1960s, the mainstay of therapy for amebic colitis has been
the nitroimidazoles, in particular metronidazole and tinidazole.
Powell and coworkers performed the first clinical trial of metronida-
DRAINAGE
zole in patients with acute amebic dysentery which demonstrated the The role for liver abscess drainage is when antibiotics are failing in
superiority of 800 mg tid given for 10 days [26]. Lower doses were order to prevent impending rupture. Any liver abscess rupture is a
less effective, but subsequent studies have demonstrated that the high-mortality event (6–30%), particularly if into the pericardium
800 mg po tid regimen can be shortened to 5 days [27, 28]. Newer [43], and requires open surgery. Given the high mortality, the ques-
studies have successfully used nitroimidazoles with longer half-lives tion of when to prophylactically drain an abscess arises. Criteria that
including tinidazole [29], secnidazole [30] and ornidazole for even would prompt consideration of drainage include an abscess >10 cm
shorter durations. Tinidazole has had the most experience, is better in diameter, a left lobe abscess to prevent rupture into the peri
tolerated than metronidazole and can be administered for only 3 days cardium or any abscess close to a serosal surface (Fig. 89.8). Aspira-
[31, 32]. The common side effects of metronidazole include nausea, tion is also indicated for abscesses that are not promptly responding
headache, anorexia and a metallic taste; less common ones include a to drugs alone and for abscesses of uncertain cause. The majority of
disulfuram-like reaction to alcohol, vomiting and peripheral neu- amebic liver abscesses that are relatively small (<10 cm) usually
ropathy. The nitroimidazoles are rapidly absorbed after oral admin- respond to drug therapy alone. Many studies indicate that routine
istration and are not effective against luminal trophozoites and drainage of amebic liver abscess confers no clinical benefit over anti-
exhibit a 40–60% rate of parasite persistence in the intestine after biotics alone [44] and a meta-analysis concluded therapeutic aspira-
therapy with these agents [12, 33]. Therefore, a course of treatment tion could not be supported or refuted because of lack of evidence
should be followed with a course of a luminal agent. A potential new [45]. One study showed that failure to respond by 72 hours in terms
agent for intestinal amebiasis is nitazoxanide. This drug, administered of prolonged fever, leukocytosis and hepatomegaly identified a group
at 500 mg po bid for three days, was associated with resolution of at high risk for abscess rupture [46]. We therefore feel that ongoing
E. histolytica/E. dispar-associated diarrhea in 80–90% of patients (vs. pain while on appropriate therapy for 72 h is a reasonable criteria for
40–50% in patients receiving placebo) along with microscopic drainage, especially with large left lobe abscesses, as these are associ-
improvement [34]. The tetracyclines have also been used but they are ated with a greater frequency of complications [25]. Percutaneous
not as effective as metronidazole [35]. aspiration under ultrasound guidance has shown good results com-
pared with open drainage or needle aspiration [47]. Serial liver scans
and sonograms have shown that most liver abscesses completely heal
AMEBIC LIVER ABSCESS 4–8 months after chemotherapy. The resolution time may be longer
The initial amebic colitis trials with metronidazole also included for large abscesses; however, patients usually remain asymptomatic in
groups of “not severely ill patients” with amebic liver abscess. Liver these cases.
abscess was found to be, in general, more responsive than colitis. We
recommend the standard high dose of metronidazole for 10 days or ASYMPTOMATIC INTESTINAL COLONIZATION
tinidazole for 5 days [36] as the lower-dose or single-dose groups had
The WHO recommends against treatment of asymptomatic patients
slower recoveries or more failures [37].
when only a microscopic diagnosis by stool examination is available
(i.e. E. histolytica/E. dispar/E. moshkovskii) [1]. If E. histolytica is con-
SEVERE DISEASE firmed by specific testing (fecal antigen test, serology) or is suspected
The metronidazole trials to date have been in “not severely ill patients”. (e.g. close contact with a case of invasive amebiasis or during an
In a severely ill patient who cannot take oral medications, such as outbreak of amebiasis) then treatment is appropriate. There are at
those with fulminant amebic colitis, it is logical to assume that intra- least three classes of luminal agents that have shown efficacy in clini-
venous metronidazole would be effective in these patients; however, cal trials for asymptomatic intestinal colonization: dichloracetanilide
data is limited to a case series from Japan that showed promise [38]. derivatives, oral aminoglycosides and 5-hydroxyquinolines. The spe-
cific agents include diloxanide furoate, paromomycin and iodoquinol/
In patients with either colitis or liver abscess failing or progressing diiodohydroxyquin. All have a large, worldwide experience and poor
on metronidazole, a potential alternative or additional therapy is gastrointestinal absorption, which allows high luminal concentra-
emetine. It is derived from ipecac, has been used since the 1920s and tions but renders them less effective in invasive disease. One of these
E n t a m o e b a h i s to l y t i ca (Amebiasis) 665
Start metronidazole
or tinidazole BOX 89.1 Anti-amebic drugs for children
and pregnant women
Children
Rupture or peritonitis
Most anti-amebic drugs mentioned have pediatric dosing regi-
mens (Table 89-1). Tinidazole is only approved in the USA in
children over 3 years old and nitazoxanide in children over 1
No Yes year old.
Pregnancy
Of the drugs mentioned for asymptomatic infection, paromo-
High risk features to consider Open surgical drainage
mycin has been used safely in pregnancy [54] and would be the
early percutaneous drainage:
• Absess ≥10 cm drug of choice. For invasive intestinal disease, there is contin-
• Abscess in the left lobe ued controversy over the use of metronidazole in pregnancy
• Thin-wall abscess at the with reports of facial defects and central nervous system tumors
periphery or adjacent to in children born to mothers taking metronidazole in the first
diaphragm trimester [55] but large analyses have simultaneously found no
increased risk above controls [56]. A caveat is that the dose used
for E. histolytica infection is higher than that used in most analy-
Progressive pain after ses. Some would recommend a trial of paromomycin for mild
3 days of imidazole therapy? invasive intestinal disease [57]. For severe colitis or liver abscess,
we feel that the risk of metronidazole to the fetus is less than
that of the disease to the mother, particularly in second or third
trimester. One could consider trying chloroquine for liver
No Yes
abscess, as this drug has been used safely (at lower doses) in
pregnant women for malaria prophylaxis.
Complete treatment • Percutaneous catheter
course drainage
• Add chloroquine and/or
dehydroemetine if available
Clinical syndrome Drugs of choice Adult dose (pediatric dose) Reference Evidence
base
Asymptomatic or Paromomycin 25–35 mg/kg/d po ÷ tid × 7 d [48] 3
post-treatment
intestinal cure Diloxanide 500 mg po tid (20 mg/kg/d ÷ tid) × 10 d [51] 4
Iodoquinol 650 mg po tid (30–40 mg/kg/d ÷ tid) × 20 d
Intestinal amebiasis Metronidazole 750 mg po tid (35–50 mg/kg/d ÷ tid) × 5–10 d [26] 3
courses should always be given after a treatment course for invasive 19. Ibarra-Pérez C. Thoracic complications of amebic abscess of the liver: report
intestinal or extra-intestinal disease to reduce the rate of relapse. of 501 cases. Chest 1981;79:672–7.
20. Viriyavejakul P, Riganti M. Undiagnosed amebic brain abscess. Southeast
Paromomycin has also been effective in a number of trials. We con- Asian J Trop Med Public Health 2009;40:1183–7.
sider it our drug of choice for luminal infection because it is widely 21. Hejase MJ, Bihrle R, Castillo G, Coogan CL. Amebiasis of the penis. Urology
available and demonstrated better efficacy than diloxanide [48]. Many 1996;48:151–4.
of these have also shown cure rates for mild invasive disease [49, 50]. 22. Hiatt RA, Markell EK, Ng E. How many stool examinations are necessary to
Side effects with oral therapy are generally mild, but include diarrhea detect pathogenic intestinal protozoa? Am J Trop Med Hyg 1995;53:36–9.
and other gastrointestinal disturbances and less commonly, headache 23. Lodhi S, Sarwari AR, Muzammil M, et al. Features distinguishing amoebic
and dizziness. Therapy should be given with meals and for a full seven from pyogenic liver abscess: a review of 577 adult cases. Trop Med Int Health
days, as failures have occurred with shorter courses. 2004;9:718–23.
24. Nordestgaard AG, Stapleford L, Worthen N, et al. Contemporary management
Diloxanide furoate is a relative of chloramphenicol used since the of amebic liver abscess. Am Surg 1992;58:315–20.
1950s. The CDC experience with the drug from 1977 to 1990 docu- 25. vanSonnenberg E, Mueller PR, Schiffman HR, et al. Intrahepatic amebic
mented a parasitologic cure rate in 86% of patients with asympto- abscesses: indications for and results of percutaneous catheter drainage. Radi-
matic E. histolytica/E. dispar infection [51]. The drug is well-tolerated, ology 1985;156:631–5.
with only 14% of patients reporting mild side effects—mainly flatu- 26. Powell SJ, MacLeod I, Wilmot AJ, Elsdon-Dew R. Metronidazole in amoebic
lence or other gastrointestinal symptoms. In the USA, the drug is only dysentery and amoebic liver abscess. Lancet 1966;2:1329–31.
available through compounding pharmacies. Iodoquinol (diiodohy- 27. Powell SJ, Wilmot AJ, Elsdon-Dew R. Further trials of metronidazole in
droxyquionoline) has been widely used for asymptomatic intestinal amoebic dysentery and amoebic liver abscess. Ann Trop Med Parasitol 1967;
colonization because it is effective and inexpensive. A large study in 61:511–4.
28. Powell SJ, Wilmot AJ, Elsdon-Dew R. Single and low dosage regimens of
India found it to be 85% effective in non-dysenteric E. histolytica/E.
metronidazole in amoebic dysentery and amoebic liver abscess. Ann Trop
dispar patients [52]. However, it requires a 20-day course and there
Med Parasitol 1969;63:139–42.
have been case reports of loss of vision [53], we would thus consider
29. Garcia EG. Treatment of symptomatic intestinal amoebiasis with tinidazole.
it a second-line agent. Common side effects include constipation and Drugs 1978;1:16–8.
enlargement of the thyroid gland (the drug contains 64% iodine) (see 30. Soedin K, Syukran OK, Fadillah A, Sidabutar P. Comparison between the
Box 89.1). efficacy of a single dose of secnidazole with a 5-day course of tetracycline and
clioquinol in the treatment of acute intestinal amoebiasis. Pharmatherapeu-
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90 Giardiasis
Rodney D Adam
but does not cause weight loss and resolves with elimination of
lactose from the diet. Irritable bowel syndrome frequently presents
TREATMENT
with chronic diarrhea, but does not cause weight loss. As noted below, Drugs from several different classes have excellent efficacy for treat-
it is particularly common after an episode of giardiasis. Chronic ment of giardiasis (Table 90-3) [17,18]. The nitroimidazoles are the
diarrhea is commonly found in advanced HIV infection with or most commonly used drugs in the US, and perhaps worldwide, pri-
without an identifiable pathogen. Conversely, HIV-infected patients marily metronidazole and tinidazole. These two drugs are essentially
are at increased risk for a variety of enteric pathogens, but there is not 100% absorbed by the oral route. Initial concerns regarding metroni-
a notable increase in frequency or severity of giardiasis in these dazole in pregnancy have been allayed, at least for the second and
patients. Campylobacter or Salmonella spp. can occasionally cause pro- third trimesters, by extensive experience with treating bacterial vagi-
longed diarrhea, so these pathogens should be considered. nosis. Nausea and a metallic taste are common and potentially
treatment-limiting side effects. These drugs also have a disulfiram-like
The initial diagnostic test when giardiasis is considered is a micro- activity after ethanol ingestion, so alcohol use during treatment is
scopic examination of a concentrated fecal specimen for cysts or prohibited. Single-dose and short courses of therapy with metronida-
trophozoites. Cysts are much more commonly found than tropho- zole have had high failure rates, so treatment should be continued
zoites, and can be identified equally well from fresh or preserved for 5 to 10 days, while tinidazole demonstrates excellent efficacy with
specimens. In contrast, freshly collected specimens are required for single-dose therapy, which may make it the preferred agent in many
the identification of trophozoites. When trophozoites are found, they settings. Secnidazole and ornidazole are other nitroimidazoles that
correlate highly with symptomatic infection. Three separate speci- have excellent efficacy with single-dose treatment courses, but are not
mens should be evaluated for optimal sensitivity. Alternatively, there available in the US.
are several commercial Giardia cyst antigen tests available, all of which
detect cyst antigens in fecal samples, either by immunoassay or by Albendazole is an antihelminthic agent that inhibits tubulin and has
immunofluorescence or chromatographic detection (Table 90-2). activity against giardiasis. In addition, its broad antihelminthic activ-
These are more sensitive than conventional microscopy, such that a ity may be an advantage in settings with a high prevalence of intestinal
single test can suffice. The sensitivity of the immunoassay tests is in helminth infections. However, single-dose therapy has demonstrated
the 93–100% range and the fluorescent antibody test near 100%, but poor efficacy for the treatment of giardiasis, so treatment courses of
with the caveat that there is not an adequate gold standard for a vali- 5 days are used. Some studies have shown reduced efficacy in com-
dation of the diagnosis, so these numbers should be taken with parison with nitroimidazoles. Albendazole has been associated with
caution. The specificity of the tests is in the 98–99% range, so there embryopathy, so it should be avoided at least during the first trimester
should be few false-positive results in populations with a high preva- of pregnancy.
lence. One limitation of these antigen-based tests is that they detect
Quinacrine has excellent efficacy and at one time was the drug of
cysts, but not trophozoites. However, the enzyme imunoassay is less
choice in the US, but has been largely replaced by the nitroimidazoles,
labor-intensive and does not require the availability of a fluorescent
partly because of nausea and vomiting and occasional reports of
microscope. The use of PCR testing has been reported, but is not yet
psychosis.
commercially available.
Nitazoxanide has activity for Giardia and Cryptosporidium as well as
For some patients with giardiasis, fecal examinations are repeatedly
other microbes and has been approved for use in the US. Nitazoxa-
negative but Giardia trophozoites can be detected in the duodenum
nide has been studied in children using 3-day courses, yielding
by endoscopy or by the string test. The string test involves the patient
response rates of about 70–80%, and has been well tolerated.
swallowing a capsule on the end of a string, pulling it out after 4 hours
to overnight, and then examining the end microscopically for the Furazolidone became popular for treating giardiasis in children
presence of trophozoites. An alternative approach is to perform an because it is tolerated better than quinacrine and is available in liquid
upper endoscopy with a biopsy and sampling of duodenal contents suspension. In clinical studies, it has yielded cure rates of 80–94%.
(see Fig. 90.2 for a histologic specimen of the small intestine showing However, compliance is more difficult than with some drugs, since it
a flattened villous and a mononuclear inflammatory response), is administered four times daily for 7 to 10 days.
which adds the potential of identifying other entities such as tropical
or celiac sprue. Paromomycin has been evaluated in a few earlier studies, demonstrat-
ing an efficacy of about 55–90% [17]. It is commonly recommended
There are no serologic tests that are useful for the diagnosis of for treatment of giardiasis during pregnancy, at least during the first
giardiasis. trimester, because of its perceived safety in that setting.
In clinical practice, it is very common to empirically treat for giardiasis Persistent symptoms after treatment of giardiasis are common and
in patients who have a clinical presentation consistent with giardiasis, usually do not represent continued infection. After a large outbreak
especially in resource-poor areas. of giardiasis in Norway, as many as 40% of patients had prolonged
A B
FIGURE 90.2 A jejunal biopsy specimen from a patient with giardiasis. A. A trophozoite is demonstrated in the lumen. B. A diffuse mononuclear
inflammatory response is demonstrated. C. A flattened villous and a normal villous are shown in the same biopsy specimen.
Drug FDA approved/ FDA approved Oral Half-life Dose (adult and Duration of Treatment
Commerically indication for bioavailability maximum treatment efficacy
available the treatment (%) pediatric dose) (%)
of giardiasis
Metronidazole Yes/Yes No 100 6–10 h 5 mg/kg tid (250 mg) 5 to 10 days 90–100
Tinidazole Yes/Yes Yes 100 12 h Adults: 50 mg/kg (2 g) Single dose 90–100
Pediatric patients older
than 3 years of age:
50 mg/kg (up to 2 g)
with food
Albendazole Yes/Yes No 1–5 8–12 h 15 mg/kg qid (400 mg) 5 days 90–100
Paromomycin Yes/Yes No 0 NA 10 mg/kg tid (500 mg) 5 to 10 days 55–90
Furazolidone No/No No 10 min 2 mg/kg qid (100 mg) 7 to 10 days 80–94
Nitazoxanide Yes/Yes Yes Parent drug not 1.3–1.8 h Adults: 500 mg bid 3 days 70–80
detected Ages 1–3: 100 mg bid
Ages 4–11: 200 mg bid
Quinacrine No No Good 5–14 days 2 mg/kg tid (100 mg) 5 to 7 days 80–100
*These agents have all been studied in controlled (and usually randomized) studies [17,18]. The treatment efficacy reflects the success found with the majority of studies.
Quinacrine is no longer generally available in the US, but can be obtained from a compounding pharmacy. NA, not applicable.
672 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
fatigue and abdominal symptoms without evidence of ongoing infec- 3. Oksenhendler E, Gerard L, Fieschi C, et al. Infections in 252 patients with
tion [19] or benefit from Giardia-specific treatment. Persistent gas- common variable immunodeficiency. Clin Infect Dis 2008;46:1547–54.
trointestinal symptoms are common after treatment of several other 4. Yoder JS, Beach MJ; Centers for Disase Control and Prevention (CDC). Giar-
intestinal pathogens as well [20]. Therefore, if someone has persistent diasis surveillance – United States, 2003–2005. MMWR Surveill Summ
or recurrent symptoms after treatment for giardiasis, the presence or 2007;56:11–18.
5. Gilman RH, Marquis GS, Miranda E, et al. Rapid reinfection by Giardia
absence of giardiasis should be confirmed by fecal examination. A
lamblia after treatment in a hyperendemic Third World community. Lancet
negative test in someone with persistent diarrhea but no weight loss
1988;1:343–5.
suggests post-infectious irritable bowel or perhaps lactose intolerance.
6. Carranza PG, Lujan HD. New insights regarding the biology of Giardia
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9. Nash TE. Surface antigenic variation in Giardia lamblia. Mol Microbiol
few susceptibility studies have been performed. In addition, relapses
2002;45:585–90.
may be more common in the setting of immunoglobulin deficiency, 10. Brodsky RE, Spencer HC Jr, Schultz MG. Giardiasis in American travelers to
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re-treatment with a standard course of a nitroimidazole usually 11. Kent GP, Greenspan JR, Herndon JL, et al. Epidemic giardiasis caused by a
respond to subsequent treatment with metronidazole in addition to contaminated public water supply. Am J Public Health 1988;78:139–43.
either albendazole or quinacrine. 12. Moore GT, Cross WM, McGuire D, et al. Epidemic giardiasis at a ski resort.
N Engl J Med 1969;281:402–7.
PREVENTION 13. Osterholm MT, Forfang JC, Ristinen TL, et al. An outbreak of foodborne
giardiasis. N Engl J Med 1981;304:24–8.
The majority of cases of giardiasis occur through the ingestion of 14. Shaw PK, Brodsky RE, Lyman DO, et al. A communitywide outbreak of giar-
contaminated water, so backpackers and travelers to regions with diasis with evidence of transmission by a municipal water supply. Ann Intern
inadequately purified water should purify the water by filtration with Med 1977;87:426–32.
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a 1–2-µm (or smaller) pore size or by heating the water to 70°C for
1971;124:235–7.
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16. Pawlowski SW, Warren CA, Guerrant R. Diagnosis and treatment of acute or
must be prolonged. Contaminated hands are the source of Giardia in
persistent diarrhea.Gastroenterology 2009;136:1874–86.
the setting of daycare or food, therefore hand washing should be 17. Gardner TB, Hill DR. Treatment of giardiasis. Clin Microbiol Rev
employed. 2001;14:114–28.
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Cryptosporidiosis 91
Lihua Xiao, Jeffrey K Griffiths
Thick-walled oocyst
ingested by host
Contamination of water
and food with oocysts
Thick-walled oocyst
(sporulated) exits host
3
Thick-walled oocyst
ingested by host
Contamination of
environment
with oocysts
2
Thick-walled oocyst
(sporulated) exits host
FIGURE 91.1 Life cycle of Cryptosporidium hominis (upper panel) and Cryptosporidium parvum (lower panel). Sporulated oocysts are excreted by the
infected host through feces (1). Transmission of C. parvum and C. hominis occurs mainly through contact with contaminated water (e.g. drinking or
recreational water), food and infected persons (for C. hominis and C. parvum) or animals (for C. parvum only). Zoonotic and anthroponotic transmission of
C. parvum and anthroponotic transmission of C. hominis occur through exposure to infected individuals or water, food, and fomites contaminated by feces
of infected animals/persons (2). Humans (for C. hominis and C. parvum) and animals (for C. parvum) become infected after ingestion (and possibly inhalation)
of oocysts (3). Sporozoites released by oocysts go through several rounds of multiplications in the small intestine and colon and sporulated oocysts are
generated and excreted by infected persons or animals. Oocysts are infective upon excretion, thus permitting direct and immediate fecal-oral transmission
[reproduced with permission from Laboratory Identification of Parasites of Public Health Concern (DPDx): http://www.dpd.cdc.gov/dpdx/].
Cr y p tospor idiosis 675
severe in young children. Asymptomatic infections are seen after prior Toxoplasma or Babesia) which are intracellular but intracytoplasmic. It
symptomatic infections. Disease resolution depends upon intact cell- has been theorized that drugs that enter the host cell cytoplasm may
mediated immunity and the antibody response appears to be nearly not be able to cross the membrane between the cytoplasm and the
irrelevant [15]. Persistent infection can also be relatively asympto- parasite.
matic or quite severe with malabsorption and weight loss. A cholera-
like, severely dehydrating, rapidly fatal syndrome in persons with Immune competence is an important determinant in the severity and
AIDS has been described. While persistent infection occurs in persons duration of intestinal disease in humans. Cryptosporidiosis is a self-
with inflammatory bowel disease, immunosuppression, or renal limiting illness of 7–14 days duration in immunocompetent indi-
disease, the greatest burden is in pediatric persistent diarrhea and in viduals but it can be a life threatening illness in the severely
persons with HIV/AIDS. immunocompromised (such as people with AIDS), hypogamma-
globulinemia or those receiving immunosuppressive drugs for cancer
Cryptosporidium parasites infect the colonic mucosa and, less com- or to prevent rejection in transplantation.
monly, the small intestine and stomach. Replicating parasites may,
however, infect the entire gut from oropharynx to anus. Histologically,
mononuclear cell infiltration in the lamina propia, mucosal cell CLINICAL FEATURES
apoptosis and mucosal inflammation with villus blunting, and cryp-
titis are seen which can lead to a loss of barrier function and malab- Enteric cryptosporidiosis has no unique clinical signs or symptoms
sorption (Fig. 91.2). Illness severity correlates with the extent of and it resembles many other forms of diarrheal disease. First infec-
infection and host immunity. In persons with HIV, infection of the tions are usually symptomatic with watery diarrhea, vomiting, nausea,
crypts suggests more severe disease, as does infection of the proximal abdominal cramps and fatigue. Blood or leukocytes are rarely seen in
small bowel with villus flattening [2, 16–18]. Diarrhea with chloride stool specimens. Low grade fever and cough also occur. In developing
secretion and impaired glucose absorption is mediated by Substance countries where repeated exposure is common, most infected chil-
P, a gastrointestinal tract neuropeptide [19]. dren are asymptomatic. Those with symptoms are generally sick for
less than seven days (median of two days). Weight loss and dehydra-
This parasite (Fig. 91.3) uniquely occupies an intracellular but extra- tion are common. Cryptosporidiosis is more common in malnour-
cytoplasmic site. This may account for its resistance to therapeutic ished children and those with persistent diarrhea. Both asymptomatic
drugs which are effective against similar parasites (such as malaria, and symptomatic cryptosporidiosis appear to cause malnutrition,
676 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
standard microscope and simultaneous detection of other pathogens DFA are increasingly prevalent. Oocysts are intermittently shed in
relevant to persons with HIV/AIDS, such as Isospora, Cyclospora and stools. If Cryptosporidium infection is suspected and initial stool speci-
Mycobacteria species. In experienced hands, modified acid-fast stain- men is negative, multiple specimens at intervals of 2–3 days should
ing and microscopy will detect ~85% of the cases of cryptosporidiosis be examined [23]. Yeasts are morphologically similar to Cryptosporid-
detected via PCR. In industrialized nations, antigen detection and ium spp. but do not stain or stain the same color as the counterstain.
Many commercial or hospital laboratories do not routinely provide
acid fast staining when physicians request ova and parasite examina-
tions, Cryptosporidium testing is only done with a specific request.
BOX 91.1 AIDS patients with Cryptosporidium sclerosing cholangitis usually
have elevated serum alkaline phosphatase levels and right upper
Diarrhea ± vomiting quadrant pain if there is also biliary involvement [16]. Diagnosis is
by endoscopic retrograde cholangiopancreatography (ERCP) and
Increased Suspicion: biopsy. Ultrasonography or computed tomography may reveal
Persistent or chronic diarrhea biliary involvement but do not provide an etiological diagnosis. Res-
piratory involvement is characterized by hypoxia and the presence
Immunosuppression, HIV/AIDS
of diffuse infiltrates on chest radiography. It can be diagnosed by
Malnutrition detecting oocysts via acid-fast staining, DFA or PCR in sputa, or via
Travel biopsy. Bronchoscopy may be necessary to differentiate it from
Pneumocystis pneumonia.
Residence in Developing Country
Zoonotic Exposure TREATMENT AND PREVENTION
Ongoing epidemic outbreak Oral or intravenous rehydration, antimotility agents and nutritional
support are used for the symptomatic treatment of diarrhea (see Box
No bacterial pathogen found with 91.2) [24]. Almost no drugs have been shown to be even modestly
prior culture effective in controlled clinical trials [10, 24–26]. Nitazoxanide (NTZ)
is the only Food and Drugs Administration (FDA)-approved drug for
Negative ‘Ova and Parasites’ exam cryptosporidiosis. NTZ can shorten clinical disease by a day or so on
average and reduce parasite loads in immunocompetent patients [25].
Failure to respond to empiric Unfortunately, NTZ is not consistently effective for immunodeficient
treatment persons [16] (Table 91-2). An open-label study did find that a sus-
Diagnose with: tained positive clinical response was observed in 59% of 365 patients
with HIV/AIDS who received high doses (500–1500 mg of NTZ twice
1. Acid-fast staining (inexpensive, high sensitivity for most daily) for prolonged periods (median of 62 days) [27], although it
clinical cases, especially with experienced microscopists) was unclear whether study patients were on anti-retroviral therapy.
However, a recent controlled trial of high-dose, prolonged (28 days)
2. PCR (expensive research tool, but detects cased with NTZ therapy in HIV infected children found no significant benefit.
low levels of parasite excretion and allows genetic Mortality did not differ between control and NTZ treatment arms and
characterization) was 28% at 28 days. Our personal advice is that NTZ can be consid-
ered for mildly immunocompromised HIV/AIDS patients, for persons
3. Anitgen-detection ELISA/ICT kit (used in some industrial- in whom cancer chemotherapy is being temporarily deferred because
ized country hospitals) of cryptosporidiosis, or when trying to limit infection during HAART
initiation [26]. Paromomycin and macrolides, such as azithromycin,
4. Immunofluorescent antibody (highly sensitive research have led to anecdotal success, though not in controlled trials [24, 26],
technique) and, when no other options exist, they could be tried in combination
with NTZ as a salvage attempt. No studies of NTZ in combination
FIGURE 91.4 Cryptosporidium oocysts as seen in direct wet-mount microscopy (left) and as stained with the modified acid-fast method. The Cryptosporidium
oocysts are marked with pink arrows in the image on the left and a budding yeast is marked with the brown arrow. In the image on the right, sporozoites
can be seen within the two stained oocysts on the right (courtesy of the Centers for Diseases Control Public Health Image Library).
678 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
with other agents have been published, and thus we emphasize that
HAART is the critical therapy for persons with HIV/AIDS.
BOX 91.2
The most effective Cryptosporidium treatment and prophylaxis for
Confirmed AIDS patients is HAART to restore cell-mediated immunity [24, 25,
Evaluate for HIV/AIDS 28]. It is believed that this is related to CD4+ cell replenishment in
Cryptosporidiosis
Evaluate nutritional status treated persons and perhaps the anti-parasitic activities of HAART
protease inhibitors [25, 28]. Some protease inhibitors (indinavir,
and hydration nelfinavir and ritonavir) demonstrate anti-cryptosporidial activity
[24]. Relapse of cryptosporidiosis is common in AIDS patients who
have stopped taking HAART [10]. Because malnutrition may occur
because of cryptosporidiosis, or contribute to its persistence, most
Reverse dehydration and keep If the person has HIV/
experienced clinicians aggressively treat malnutrition. Nutritional
hydrated during evaluation AIDS , focus on hy- support may help restore cellular immunity in the severely malnour-
process dration and aggressive ished and, in persons with HIV/AIDS, allow survival when HAART is
nutritional support. being initiated.
If malnourished (e.g. from
persistent diarrhea), begin Treat any co-infections. Cholecystectomy may be used in the treatment of cryptosporidial
aggressive nutritional rehabil- acalculous cholecystitis and ERCP with sphincterotomy and/or stent
Begin anti-retroviral placement can ameliorate sclerosing cholangitis [24]. The therapy of
itation which improves cell-
therapy which will, if respiratory cryptosporidiosis has not been systematically explored. In
mediated immunity. Treat any our opinion, both biliary and respiratory disease in the immunocom-
successful, reverse the
co-infections promised is best treated by HAART or temporarily stopping the use
underlying immuno-
of chemotherapy if the person has cancer.
Consider anti-Cryptosporidium suppression and may
therapy with drugs such as allow the person to
nitazoxanide, paromomycin, resolve the infection. PREVENTION
azithromycin if symptoms are This may take weeks. To prevent fecal-oral transmission, strict attention to personal hygiene,
severe or not improving with especially hand-washing, is emphasized. Cooking kills Cryptosporid-
ium in food. Oocysts are killed by pasteurization (72°C for 5 seconds),
supportive therapy. No clinical heating to 60°C for 30 minutes, or freezing at -7°C for 1 hour. No
studies have shown any con- safe and effective disinfectant has been identified for decontaminating
sistent benefits with these produce.
drugs for persons with HIV/
Preventing Cryptosporidum contamination of drinking water requires
AIDS but there are anecdotal modern water filtration and purification systems that are not available
reports of success. in lower income countries. Concentrations of chlorine (1–2 mg/l)
used to disinfect drinking water are not effective against
HIV– persons
Malnourished Zambia 100 mg twice daily for 3 days 3/22 13/25 (52%) 5/22 (23%) 14/25 (56%) [38]
children (14%)
Adults and Egypt 100 (1–3-year-old), 200 (4–11- 11/50 39/49 (67%) 20/49 39/49 (80%) [40]
children year-old) or 500 mg (>11–year- (22%) (41%)
old) twice daily for 3 days
Adults and Egypt 500 mg twice daily for 3 days 10/27 26/28 (93%) for 11/27 27/28 (96%) for [41]
children (37%) tablets; 28/31 (90%) (41%) tablets; 27/31 (87%)
for suspension for suspension
*Based on partial data presented in Pantenburg B, Cabada MM, White AC, Jr. Treatment of cryptosporidiosis. Expert Rev Anti Infect Ther 2009;7:385–91.
Cr y p tospor idiosis 679
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92 Cyclosporiasis
David R Shlim, Bradley A Connor
from endemic foci and ingestion of contaminated imported foods. Reliable, commercially available serologic assays to determine human
Fatigue and anorexia should be specifically inquired about. A history exposure to Cyclospora are not available.
of sudden onset of moderately severe diarrhea that becomes less
severe and more chronic after several days should increase the suspi
cion of cyclosporiasis. Many patients with Cyclospora have already
taken an antibiotic, such as ciprofloxacin. Because the initial phase of TREATMENT
cyclosporiasis closely resembles a bacterial infection, and gets better Trimethoprim–sulfamethoxazole (TMP-SMX) is the only proven
spontaneously within a few days, it often appears as if the initial effective treatment of cyclosporiasis. In a randomized placebo con
course of empiric antibiotics was beneficial, although the patient fails trolled trial, a dose of sulfamethoxazole 800 mg and trimethoprim
to return to his or her usual state of health. Tests for malabsorption, 160 mg given twice daily for 7 days was 94% curative [9]. The few
such as the d-xylose absorption test, although rarely necessary, are patients who were not cured with 7 days of therapy were cured by a
abnormal in cyclosporiasis. total of 10 days of treatment. In patients who are diagnosed early
during the acute phase when diarrhea is prominent, the response to
The differential diagnosis, at the beginning of the illness, would TMP-SMX is fairly rapid, within 1–2 days. In later-stage illness, people
include pathogenic enteric bacteria or viruses. However, as the illness start to feel better quite rapidly, but since they have usually been ill
progresses, the differential would include other intestinal protozoa, for a while before treatment, they do not feel better all at once. The
including Giardia lamblia. A rare cause of illness in travelers, Cysto recommended adult dose and regimen is sulfamethoxazole 800 mg
isospora belli, can produce a prolonged diarrhea after travel, and is and trimethoprim 160 mg given twice daily for 7 days. The treatment
sensitive to trimethoprim–sulfamethoxazole. Fatigue and weight loss dose for children is sulfamethoxazole 20 mg/kg and trimethoprim
can be caused by Entamoeba histolytica, but anorexia is not as promi 4 mg/kg every 12 hours for 7 days.
nent. Dientamoeba fragilis can cause prolonged, low-grade intestinal
symptoms, but without anorexia or weight loss. Fatigue and weight Cyclosporiasis has been described among HIV-positive patients in
loss can be due to tropical sprue, which is a rare cause of prolonged Haiti. The symptoms were not more severe than in immunocompe
diarrhea in travelers. Celiac sprue occasionally manifests during tent patients. Infection was easily treated with TMP-SMX, but relapse
foreign travel. or re-infection was common. A dose of TMP-SMX three times per
week prevented subsequent Cyclospora infection in HIV-positive
The diagnosis is confirmed by stool examination. Although organ patients during 7 months of surveillance [10].
isms can be detected in unstained stool by an experienced micro
scopist (Fig. 92.1), the organism is most easily detected using a In an evaluation of alternate regimens for patients who cannot toler
concentration technique such as formalin–ethyl acetate centrifuga ate sulfa-based treatments, 10 of 11 (90%) HIV-positive patients in
tion, and then staining with a modified acid-fast stain (Fig. 92.2). Haiti given ciprofloxacin 500 mg twice daily for 7 days were asymp
Individuals with acute and severe disease can shed few organisms, so tomatic on day 8 and 64% (7 of 11) had negative stool specimens.
concentration techniques are essential. Concentration of the stool has The standard regimen of TMP-SMX usually eliminates parasites by
been shown to increase the diagnostic yield by over 40% [8]. Once day 8, even in HIV-infected patients. Anecdotal use of ciprofloxacin
identified on acid-fast staining, C. cayetanensis, which measures 8 to in immunocompetent patients with Cyclospora in other settings,
10 µm, must be distinguished form Cryptosporidium spp., which however, has not been effective. In a case report, nitazoxanide, 500 mg
measure only 4 to 5 µm. Ultraviolet fluorescence microscopy can be twice daily for 7 days, resulted in improved symptoms and clearing
useful as C. cayetanensis is autofluorescent while Cryptosporidium spp. of Cyclospora oocysts from the stool in a patient with severe sulfa
are not. Cyclospora oocysts stain variably with modified Ziehl-Neelsen allergies [11]. Nitazoxanide was tried in an informal study at the
acid-fast stain. Some oocysts stain dark red, others stain pale pink and CIWEC Clinic in Kathmandu, and did not appear efficacious. A wide
some do not take up stain at all. Safranin stains oocysts uniformly variety of antimicrobials have been tried against Cyclospora without
when the fecal smear and stain are heated by microwave treatment. success, including albendazole, trimethoprim (used alone), azithro
Other stains used in parasite detection, such as Giemsa and trichrome, mycin, nalidixic acid, tinidazole, metronidazole, quinacrine, tetracy
do not stain Cyclospora oocysts. The organism is consistently shed in cline, doxycycline, and diloxanide furoate. Thus, currently, only
the stools of infected patients until the illness ends. C. cayetanensis ciprofloxacin and nitazoxanide have any published evidence that they
does not cause an inflammatory diarrhea and fecal leukocytes are not might be effective against Cyclospora in individuals who cannot take
usually seen. TMP-SMX.
682 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
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chlorinated drinking water. Lancet 1994;344:1360–1. 11. Zimmer SM, Schuetz AN, Franco-Paredes C. Efficacy of nitazoxanide for
5. Herwaldt BL. Cyclospora cayetanensis: a review, focusing on the outbreaks of cyclosporiasis in patients with sulfa allergy. Clin Infect Dis 2007;44:466–7.
cyclosporiasis in the 1990s. Clin Infect Dis 2000;31:1040–57.
6. Ortega YR, Sanchez R. Update on Cyclospora cayetanensis, a food-borne and
waterborne parasite. Clin Microbiol Rev 2010;23:218–34.
Cystoisospora belli
(syn. Isospora belli) 93
Rebecca Dillingham, Eric R Houpt
CLINICAL FEATURES
Cystoisospora belli generally produces an asymptomatic or self-limited
diarrheal illness in otherwise healthy persons. Symptoms are nonspe- FIGURE 93.1 Cystoisospora belli in iodine-stained stool specimen from
cific, with watery diarrhea and abdominal pain, cramps, nausea and patient with diarrhea (image courtesy of Herman Zaiman collection).
683
684 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
dose may be needed for immunocompromised patients). In Haiti, 5. Dwivedi KK, Prasad G, Saini S, et al. Enteric opportunistic parasites among
this treatment resulted in complete symptomatic relief for most HIV infected individuals: associated risk factors and immune status. Jpn J
patients within 2–3 days and for all patients within 7 days [4, 11]. In Infect Dis 2007;60:76–81.
Haiti, 47% of HIV-infected individuals who did not receive prophy- 6. Dillingham RA, Pinkerton R, Leger P, et al. High early mortality in patients
laxis after treatment for cystoisosporiasis relapsed [4]; therefore, with chronic acquired immunodeficiency syndrome diarrhea initiating
antiretroviral therapy in Haiti: a case-control study. Am J Trop Med Hyg
maintenance therapy is recommended for immunocompromised
2009;80:1060–4.
individuals with one of two regimens—one double-strength TMP-SMX
7. Lindsay DS, Dubey JP, Blagburn BL. Biology of Isospora spp. from humans,
tablet three times a week or one Fansidar tablet (pyrimethamine
nonhuman primates, and domestic animals. Clin Microbiol Rev 1997;10:
25 mg plus sulfadoxine 500 mg) once a week [12]. For treatment of 19–34.
patients who are intolerant of sulfonamide-containing medications, 8. Benator DA, French AL, Beaudet LM,et al. Isospora belli infection associated
alternative regimens include: ciprofloxacin 500 mg twice daily for 7 with acalculous cholecystitis in a patient with AIDS. Ann Intern Med
days or oral pyrimethamine 50–75 mg/day in individual doses (plus 1994;121:663–4.
leucovorin 10–25 mg/day) [11, 13]. In cases of severe extraintestinal 9. Valentiner-Branth P, Steinsland H, Fischer TK, et al. Cohort study of Guinean
disease or during intestinal malabsorption, treatment with intrave- children: incidence, pathogenicity, conferred protection, and attributable risk
nous TMP/SMX has been used [14]. The presence of cystoisosporiasis for enteropathogens during the first 2 years of life. J Clin Microbiol 2003;
should not delay the initiation of anti-retroviral therapy in HIV- 41:4238–45.
infected patients requiring therapy [6] (Table 93-1). 10. ten Hove RJ, van Lieshout L, Brienen EA, et al. Real-time polymerase chain
reaction for detection of Isospora belli in stool samples. Diagn Microbiol Infect
Dis 2008;61:280–3.
REFERENCES 11. Verdier RI, Fitzgerald DW, Johnson WD, Jr, Pape JW. Trimethoprim-
sulfamethoxazole compared with ciprofloxacin for treatment and prophylaxis
1. Brandborg LL, Goldberg SB, Breidenbach WC. Human coccidiosis–a possible of Isospora belli and Cyclospora cayetanensis infection in HIV-infected patients.
cause of malabsorption. N Engl J Med 1970;283:1306–13. A randomized, controlled trial. Ann Intern Med 2000;132:885–8.
2. Restrepo C, Macher AM, Radany EH. Disseminated extraintestinal isosporiasis 12. Pape JW, Verdier RI, Johnson WD, Jr. Treatment and prophylaxis of Isospora
in a patient with acquired immune deficiency syndrome. Am J Clin Pathol belli infection in patients with the acquired immunodeficiency syndrome.
1987;87:536–42. N Engl J Med 1989;320:1044–7.
3. Assefa S, Erko B, Medhin G, et al. Intestinal parasitic infections in relation to 13. Weiss LM, Perlman DC, Sherman J, et al. Isospora belli infection: treatment
HIV/AIDS status, diarrhea and CD4 T-cell count. BMC Infect Dis 2009;9:155. with pyrimethamine. Ann Intern Med 1988;109:474–5.
4. DeHovitz JA, Pape JW, Boncy M, Johnson WD, Jr. Clinical manifestations and 14. Bialek R, Overkamp D, Rettig I, Knobloch J. Case report: Nitazoxanide treat-
therapy of Isospora belli infection in patients with the acquired immunodefi- ment failure in chronic isosporiasis. Am J Trop Med Hyg 2001;65:94–5.
ciency syndrome. N Engl J Med 1986;315:87–90.
Miscellaneous Intestinal Protozoa 94
Lynne S Garcia
94.1 Balantidiasis
FIGURE 94.2 Balantidium coli. (A) trophozoite from a fecal specimen (note
the large macronucleus); (B) cyst from a fecal specimen (note the large
macronucleus). Organisms in wet preparations may be easier to
see; occasionally in stained preparations that are stained too dark, the
organisms may resemble large debris.
DIAGNOSIS
Wet preparation examinations of fresh and concentrated fecal mate-
rial (O&P examination) will demonstrate the organisms (Fig. 94.2).
FIGURE 94.1 Balantidium coli. Tissue section of a colon biopsy specimen Organism recognition and identification on a permanent stained
showing necrosis and organisms within an ulcerated area. smear is difficult; these ciliates are so large that they tend to stain
very darkly, thus obscuring any internal morphology.
EPIDEMIOLOGY DIAGNOSIS
Dientamoeba fragilis is found worldwide and past surveys provide Diagnosis of D. fragilis infections depends on proper stool collec-
incidence rates of 1.4–19%. Much higher incidence figures have tion (a minimum of three fecal specimens, one collected every other
been reported for mental institution inmates, missionaries and day) and processing techniques. Although the survival time for this
Native Americans in Arizona. In some laboratories in countries parasite has been reported as 24–48 h, the survival time in terms
such as Canada and the Netherlands, D. fragilis is the most common of morphology is limited, and stool specimens must be examined
protozoa found on stool ova and parasite examination. The life immediately or preserved in a suitable fixative soon after defeca-
cycle and mode of transmission of D. fragilis have not been con- tion. It is very important that permanently-stained smears of stool
firmed, although transmission via helminth eggs such as those of material be examined with the oil immersion objective (100 ×, total
Ascaris and Enterobius spp. has been postulated. The cyst stage has magnification 1000×). These organisms have been recovered in
not been confirmed to date. formed stool; therefore, a permanent stained smear must be pre-
pared for every stool sample submitted for a parasite examination
(O&P). Organisms seen in direct wet mounts may appear as refrac-
NATURAL HISTORY, PATHOGENESIS, tile, round forms; the nuclear structure cannot be seen without
AND PATHOLOGY examination of the permanent stained smear. Although the organ-
isms can be isolated in culture, this approach is not a routine
Dientamoeba fragilis is assumed to be noninvasive and thus elicit procedure in most clinical laboratories.
symptoms by epithelial irritation. The significance of two geneti-
cally distinct forms of D. fragilis may, ultimately, serve to clarify the
issues of virulence and clinical perceptions regarding pathogenicity. TREATMENT
In some cases, the organism has been found in the biliary tree. We recommend treatment in individuals with persistent symptoms
and D. fragilis infection, particularly if D. fragilis is the only patho-
CLINICAL FEATURES gen found. No clinical trials have been performed to evaluate thera-
pies against D. fragilis. Clinical improvement has been observed in
Although its pathogenic status is still not well defined, D. fragilis adults receiving tetracycline, diiodohydroxyquin, metronidazole
has been associated with diarrhea and a number of other symp- and paromomycin. We favor paromomycin at a dosage of 500 mg
toms, including intermittent diarrhea, abdominal pain, nausea, three times a day for 7 days because this is the shortest course and
anorexia, malaise, fatigue, poor weight gain, and unexplained appears effective.
A B C
FIGURE 94.3 Dientamoeba fragilis. (A) trophozoite from stool (one nucleus, note the nuclear chromatin is getting ready to fragment); (B) trophozoite (one
nucleus, nuclear chromatin has already fragmented); (C) trophozoite (two nuclei with fragmented chromatin). No known cyst form.
688 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
CLINICAL FEATURES
Although the majority of cases diagnosed with E. polecki infection
have been asymptomatic, several cases have been documented
in which the patients were symptomatic. Symptoms included ano-
rexia, diarrhea, mucoid stools, abdominal pain, malaise and
eosinophilia.
DIAGNOSIS
Differentiation of this organism from either E. histolytica/E. dispar/
E. moshkovskii or E. coli is rarely accomplished on the basis of a wet
preparation examination and is difficult even with the permanent
stained smear (Fig. 94.4). The nuclear morphology of the tropho-
zoite is almost a composite of those of E. histolytica/E. dispar,
E. moshkovskii and E. coli. Without some of the cyst stages for com-
parison, it would be very difficult to identify this organism to the
species level on the basis of the trophozoite alone. The cyst nor-
mally has only a single nucleus, chromatoidal material like that FIGURE 94.4 Entamoeba polecki. Uninucleate cyst in stool. Note the
seen in E. histolytica and, frequently, an inclusion body. This mass prominent inclusion, chromatoidal bars and single nucleus (morphology
tends to be round or oval and is not sharply defined on the edges. of the nucleus is a composite of all the Entamoeba species nuclei).
A B
FIGURE 94.5 Blastocystis hominis. Central body forms from stool. Note the small nuclei around the periphery; also note the organism on the left (A) is
dividing.
A number of non-pathogenic amebae and flagellates are often has come in contact with something contaminated with fecal mate-
found during the routine O&P stool examination, including E. coli, rial containing infective cysts. If the patient is symptomatic, it is
Endolimax nana, Iodamoeba bütschlii, Chilomastix mesnili and Pentatri- important to perform additional testing to detect possible patho-
chomonas (formerly trichomonsa) hominis (Tables 94-2 and 94-3). gens that might also be present.
Although these are non-pathogens, this finding indicates the patient
REFERENCES 8. Salaki JS, Shirey JL, Strickland GT. Successful treatment of symptomatic Enta-
moeba polecki infection. Am J Trop Med Hyg 1979;28:190.
1. Beaver PC, Jung RC, Cupp EW. Clinical Parasitology, 9th edn. Philadelphia: 9. Verweij JJ, Polderman AM, Clark CG. Genetic variation among human isolates
Lea & Febiger; 1984. of uninucleated cyst-producing Entamoeba species. J Clin Microbiol 2001;
2. Garcia LS. Diagnostic Medical Parasitology, 5th edn. Washington: ASM Press; 39:1644–6.
2007. 10. Sohail MR, Fischer PR. Blastocystis hominis and travelers. Travel Med Infect Dis
3. Schuster FL, Ramirez-Avila L. Current world status of Balantidium coli. Clin 2005;3:33–8.
Microbiol Rev 2008;21:626–38. 11. Tan TC, Suresh KG, Smith HV. Phenotypic and genotypic characterization of
4. Garcia-Laverde A, de Bonilla L.Clinical trials with metronidazole in human Blastocystis hominis isolates implicates subtype 3 as a subtype with pathogenic
balantidiasis. Am J Trop Med Hyg 1975;24:781–3. potential. Parasitol Res 2008;104:85–93.
5. Johnson EH, Windsor JJ, Clark CG. Emerging from obscurity: biological, 12. Cox FEG. Taxonomy and classification of human parasitic protozoa
clinical and diagnostic aspects of Dientamoeba fragilis. Clin Microbiol Rev and helminths. In: Versalovic J, Carroll KC, Funke G, et al. (eds). Manual of
2004;17:563–70. Clinical Microbiology, 10th ed, Section VIII Parasitology. ASM Press,
6. Stark DJ, Beebe N, Marriott D, et al. Dientamoebiasis: clinical importance and Washington, DC, 2011:2041–6.
recent advances. Trends Parasitol 2006;22:92–6.
7. Gay JD, Abell TL, Thompson JH, et al. Entamoeba polecki infection in Southeast
Asian refugees: Multiple cases of a rarely reported parasite. Mayo Clin Proc
1985;60:523.
Trichomoniasis 95
Michael F Rein
Most infected men come to treatment as sexual contacts of infected by the infection, but its presence should raise concerns for coincident
women. T. vaginalis causes a minority of cases of nongonococcal salpingitis.
urethritis, presenting as some combination of dysuria and urethral
discharge, and resembling NGU of more common etiologies.
Trichomonal urethritis is usually recognized when the condition fails
to respond to standard antibacterial therapies [6,8]. Rarely, epidi-
COMPLICATIONS
dymitis is encountered, and the organism has been identified in the Trichomoniasis is generally a benign disease. Gestational trichomo-
prostate [6]. niasis has been associated with premature rupture of the fetal mem-
branes and preterm delivery [10]. Unfortunately, two studies suggest
that treating trichomoniasis in pregnancy is actually associated with
PHYSICAL EXAMINATION an increased frequency of these complications [11,12]. Symptomatic
The vulva is erythematous in less than one-third of patients. On infections require treatment, but some specialists recommend post-
speculum examination, excessive discharge is noted in 50% to 75% poning treatment of asymptomatic trichomoniasis in pregnancy until
of infected women. A yellow vaginal discharge suggests trichomonia- after the 37th week of gestation [13].
sis, but the classically yellow or green, frothy discharge is seen in only
a minority of patients. Indeed, bubbles are present in only 8% to 50% Trichomoniasis, with its brisk inflammatory response and micro
of infected women in various series, and since bubbles are also ulcerations of the genital epithelium, may increase the risk of acquir-
observed in bacterial vaginosis, their presence is nonspecific [9]. ing HIV [2]. In addition, treatment of trichomoniasis reduces the
concentration of HIV in vaginal secretions about fourfold, theoreti-
Vaginal wall erythema, occasionally with edema, is observed in 20% cally reducing the risk of transmitting the HIV [14].
to 75% of cases, and punctate hemorrhages are observed on the
vaginal walls or the exocervix (strawberry cervix) in about 2% of A possible association of trichomoniasis with pelvic inflammatory
women during routine physical examination, but the characteristic disease and cervical cancer is sometimes hypothesized, but observa-
hemorrhages are visualized in 45% by colposcopy. tions may be confounded by frequent past or present co-infection
with other sexually transmitted agents, such as chlamydia or human
In my experience, mild adnexal tenderness is occasionally elicited on papillomavirus, more strongly associated with upper tract disease and
bimanual examination. This may be due to pelvic adenitis induced genital malignancy.
Signs
Labial erythema 1+–4+ 1–4+ 0
Discharge
Consistency Frothy (25%) Minimal to curdy Homogeneous, often frothy
Color Yellow-green (25%) White Gray, white
Adherence to vaginal walls 0 Often Usually
Whiff test 60–90% 0 70–90%
Alkalinity ≥4.7 (70–90%) ≤4.5 ≥4.7 (90%)
Bimanual examination
Adnexal tenderness Occasional 0 0
Vaginal wall tenderness 0–2+ 0–2+ 0
Wet mount
Epithelial cells Normal Normal Clue cells (90%)
PMN/ epithelial cell ≥1 Variable ≤1
Bacteria Rods or coccobacilli Rods Coccobacilli and motile rods
Pathogens Trichomonads (70%) Yeasts and pseudohyphae (50%) Nonspecific
PMN, polymorphonuclear neutrophils.
Tr i c homoniasis 693
TREATMENT
Decades of experience and old studies confirm the value of oral
5′-nitroimidazoles for treating men and women. Metronidazole or
tinidazole are preferred in the US, but in other parts of the world,
ornidazole and nimorazole are used as well. High-dose vaginal sup-
positories are available in some areas, but low-dose metronidazole
vaginal preparations designed for bacterial vaginosis are inadequate
for trichomoniasis. Male partners should be treated simultaneously
even if asymptomatic. Treatment of trichomoniasis can be effectively
accomplished with metronidazole 2 g orally in a single dose, tinida-
zole 2 g orally in a single dose, or metronidazole 500 mg orally twice
daily for 7 days. Metronidazole can be used in pregnancy (Category
B), but tinidazole (Category C) should not [13,17]. The optimal
management of patient allergy or trichomonal resistance to the imi-
dazoles remains incompletely defined.
REFERENCES
1. Van der Pol B. Trichomonas vaginalis infection: the most prevalent nonviral
FIGURE 95.1 Trichomoniasis. Wet mount of vaginal discharge showing sexually transmitted infection received the least public health attention. Clin
several round polymorphonuclear neutrophils and two ovoid trichomonads. Infect Dis 2007;44:13–22.
Anterior flagella are visible. (Phase contrast, ×1000.) 2. McClelland RS, Sangare L, Hassan WM, et al. Infection with Trichomonas vagi-
nalis increases the risk of HIV-1 acquisition. J Infect Dis 2007;195:698–702.
3. Sutton M, Sternberg M, Koumans EH, et al. The prevalence of Trichomonas
vaginalis infections among reproductive-age women in the United States. Clin
Infect Dis 2007;45:1139–26.
PATIENT EVALUATION, DIAGNOSIS, 4. Sena AC, Miller WC, Hobbs MM, et al. Trichomonas vaginalis infection in male
sexual partners: implications for diagnosis, treatment, and prevention. Clin
AND DIFFERENTIAL DIAGNOSIS Infect Dis 2007;44:13–22.
5. Van der Pol B, Williams JA, Orr DP, et al. Prevalence, incidence, natural
Clinicians often manage symptomatic women who present with history, and response to treatment of Trichomonas vaginalis infection among
some combination of vaginal discharge, vulvar irritation, and odor. adolescent women. J Infect Dis 2005;192:2039–44.
The clinical and laboratory features that assist in differentiating tri- 6. Krieger JN: Trichomoniasis in men: old issues and new data. Sex Transm Dis
chomoniasis from bacterial vaginosis and candidiasis are presented 1995;22:83–96.
in Table 95-1. A history of contact with a new partner supports the 7. Gray RH, Kigozi G, Serwadda D, et al. The effects of male circumcision on
diagnosis of sexually transmitted vaginitis. Odor without much irrita- female partners’ genital tract symptoms and vaginal infections in a rand-
tion is more consistent with bacterial vaginosis than with trichomo- omized trial in Rakai, Uganda. Am J Obstet Gynecol 2009;200:42.e1–e7.
niasis, in which irritation is more prominent. After completing the 8. Centers for Disease Control and Prevention. Sexually transmitted diseases
physical examination, it is useful to determine the pH of vaginal treatment guidelines, 2006. MMWR Recomm Rep 2006;55:36–7.
secretions. This is conveniently accomplished by inserting a strip of 9. Wolner-Hanssen P, Krieger JN, Stevens CE, et al. Clinical manifestations of
indicator paper into the vaginal discharge pooled in the lower lip of vaginal trichomoniasis. JAMA 1989;264:571–6.
the speculum. Normal vaginal pH of 4.7 or less is maintained in most 10. Cotch MF, Pastorek JG 2nd, Nugent RP, et al. Trichomonas vaginalis associated
with low birth weight and preterm delivery. The Vaginal Infections and Pre-
patients with vulvovaginal candidiasis. Vaginal pH is elevated above
maturity Study Group. Sex Transm Dis 1997;24:353–60.
4.7 in most women with trichomoniasis, but an elevated pH is also
11. Rigg MA, Klebanoff MA. Treatment of vaginal infections to prevent preterm
found in most women with bacterial vaginosis and is not specific. The birth: a meta-analysis. Clin Obstet Gynecol 2004;47:796–807.
pH of vaginal material may be artifactually elevated if contaminated 12. Hay P, Czeizel AE. Asymptomatic trichomonas and candida colonization in
with cervical discharge or semen. After the pH has been determined, pregnancy outcome. Best Pract Clin Obstet Gynecol 2007;21:403–9.
several drops of 10% to 20% potassium hydroxide should be added 13. Centers for Disease Control and Prevention. Sexually transmitted disease
to the discharge in the speculum. The clinician then seeks the elabora- treatment guidelines, 2010. MMWR 2010;59(RR-12):58–61.
tion of a pungent, fishy, amine-like odor. This positive result of the 14. Wang CC, McClelland RS, Reilly M, et al. The effect of treatment of vaginal
whiff test is manifested by 75% of women with trichomoniasis but infections on shedding of human immunodeficiency virus type 1. J Infect Dis
also by most women with bacterial vaginosis. The whiff test is not 2001;183:1017–22.
positive in vulvovaginal candidiasis. Such point-of-care testing is par- 15. Madhivanan P, Krupp K, Hardin J, et al. Simple and inexpensive point-of-care
ticularly useful in resource-poor venues [15]. tests improve diagnosis of vaginal infections in resource-constrained settings.
Trop Med Int Health 2009;14:703–8.
Definitive diagnosis is based on demonstrating the parasite (Fig. 16. Hobbs MM, Lapple DM, Lawing LF, et al. Methods for detection of Tri-
95.1). A swab of vaginal material can be agitated in about 1 mL of chomonas vaginalis in the male partners of infected women: implications for
saline and a drop transferred to a microscope slide to which a cover- control of trichomoniasis. J Clin Microbiol 2006;44:3994–9.
slip is then applied. This wet mount is observed at 400× with the 17. Okun N, Gronau KA, Hannah ME. Antibiotics for bacterial vaginosis or
substage condenser racked down and the substage diaphragm closed. Trichomonas vaginalis in pregnancy: a systematic review. Obstet Gynecol
Its sensitivity for trichomoniasis is only about 60%. T. vaginalis culture 2005;105:857–68.
B
SECTION
Stable, PfAPI > 0.1 per thousand pa Unstable, PfAPI < 0.1 per thousand pa
B
Stable, PfAPI > 0.1 per thousand pa Unstable, PfAPI < 0.1 per thousand pa
FIGURE 96.1 P. falciparum malaria risk defined by annual parasite incidence (top) and temperature and aridity (bottom). Areas were defined as stable (dark
blue areas, where PfAPI ≥0.1 per thousand pa), unstable (light blue, where PfAPI <0.1 per thousand pa), or no risk (no color). The few areas for which no
PfAPI data could be obtained, mainly found in India, are not colored. The borders of the 87 countries defined as P. falciparum endemic are shown. The
aridity mask excluded risk in a step-wise fashion, reflected mainly in the larger areas of unstable (light blue) areas compared to the top panel, particularly
in the Sahel and southwest Asia (southern Iran and Pakistan). Reproduced from Guerra CA, Gikandi PW, Tatem AJ, et al. The limits and intensity of Plasmodium
falciparum transmission: implications for malaria control and elimination worldwide. PLoS Med 2008;5(2):e38.
> 50/year “high transmission”. For clinicians working in settings Irrigation schemes, dams and other man-made changes affecting land
where data on EIRs are not readily available, surrogate measures use can radically alter stable patterns of malaria transmission.
include the spleen rate and parasite prevalence rates in children (Box
96.1). Transmission dynamics are regarded as stable when transmis-
sion is constant throughout the year, or predictably seasonal. Unsta-
ACQUIRED IMMUNITY
ble transmission (characteristic of epidemics) occurs when there are The incidence and prevalence of malaria illness is determined largely
changes in the environment (e.g. sudden, heavy rains) or in the popu- by acquired immunity. The burden of disease and death is borne by
lation (e.g. migration). non-immune individuals. In areas of stable transmission (e.g. most
of sub-Saharan Africa), young children are the non-immune individu-
Malaria transmission is also influenced by climate. The optimal con- als at risk of life-threatening malaria. Older children and adults are
ditions occur when the temperature is between 20°C and 30°C and “semi-immune”; their malaria infections may be asymptomatic or
the mean relative humidity is at least 60%. Sporogony does not occur they may develop uncomplicated malaria illnesses.
at temperatures below 16°C or higher than 33°C. Water temperatures
regulate the duration of the aquatic cycle of the mosquito vector. A Attributing a cause-and-effect relationship between parasites and the
high relative humidity increases mosquito longevity and therefore often nonspecific symptoms of an uncomplicated malaria illness in
increases the probability that an infected mosquito will survive long semi-immune patients is difficult and bedevils the diagnosis of a
enough to become infective. “malaria illness” in this group (see “Interpreting the results of malaria
diagnostic tests” below).
The proximity of human habitation to breeding sites directly influ-
ences vector-human contact and, therefore, transmission. The stability Where transmission is unstable, there is little acquired immunity and
of breeding sites is influenced by water supply, soil and vegetation. individuals from all age groups can develop severe disease. Whether
698 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
acquired immunity can wax and wane with transmission intensity The duration of the asexual replication phase inside the hepatocytes
remains to be seen [6], but this will become increasingly important varies from 11–12 days in P. falciparum, P. vivax and P. ovale, to 35
as malaria control efforts increase and expand. days in P. malariae (Table 96-1). The nucleus undergoes repeated divi-
sion, resulting in the formation of thousands of uninucleate mero-
INNATE IMMUNITY zoites, each measuring 0.7–1.8 μm in diameter. The nucleus of the
liver cell is displaced, but there is no inflammatory reaction in the
On a population level, several genetic polymorphisms and mutations surrounding liver tissue, and the host is asymptomatic.
conferring risk or protection have been identified; most involve muta-
tions in the alpha or beta chain of hemoglobin (hemoglobinopa- In P. falciparum and P. malariae infections, the liver tissue schizonts/
thies), such as sickle cell anemia and trait, the thalassemias, meronts rupture at about the same time and none persists in the liver.
hemoglobin C, red blood cell enzyme deficiencies, such as glucose 6 In contrast, P. vivax and P. ovale have two types of exoerythrocytic
phosphate deficiency (G6PD), or mutations affecting the red cell forms: a primary type develops and ruptures within 6–9 days; the
exoskeleton, such as ovalocytosis. Individuals with sickle cell trait secondary type – the hypnozoite – may remain dormant in the liver
(HbAS) are less likely to develop severe malaria once infected than for weeks, months, or up to 5 years before developing, and causing
are individuals who are homozygous (HbAA). Practically speaking, relapses of erythrocytic infection unless the patient is treated with
information on genetic polymorphisms is rarely available quickly primaquine – a drug that targets this lifecycle stage. The pre-patent
enough to be useful during an acute illness; it may be potentially period for P. knowlesi in humans has not yet been determined. Most
useful when considering risks associated with travel to malaria- infected hepatocytes rupture when the schizont forms mature and the
endemic areas and it provides some insight into mechanisms of merozoites that are released into the circulation quickly attach to, and
disease pathogenesis, susceptibility and protection. invade, red blood cells.
Plasmodium falciparum and P. knowlesi are capable of invading erythro
NATURAL HISTORY, PATHOGENESIS, cytes of any age, but P. vivax and P. ovale selectively invade reticulo-
AND PATHOLOGY cytes. Serial cycles of asexual replication take place in erythrocytes
and, again, the duration varies with the species, ranging from 24
Malaria is usually transmitted during the bite of an infected female hours in P. knowlesi to 48 hours in P. falciparum, P. vivax and P. ovale,
Anopheles mosquito or, more rarely, through the direct inoculation of and 72 hours in P. malariae (Table 96-1).
infected red blood cells (i.e. congenital malaria, transfusion malaria
and malaria from contaminated needles). The youngest stages in the blood are small, rounded trophozoites,
known as ring forms. As they grow, they become more irregular and
ameboid. During development, the parasites consume hemoglobin
LIFECYCLE leaving an iron-containing compound known as hematin or hemo-
Infection begins when sporozoites in mosquito saliva enter the blood- zoin as the product of digestion; it is visible in the cytoplasm of the
stream and, within 30 minutes, have invaded hepatocytes (Fig 96.2). parasite as dark granules. The schizont/meront stage begins when the
M alar ia 699
Malaria
Hepatic schizogony
(some P. vivax or ovale, RBC release merozoites
not falciparum or malariae, to cause:
can remain dormant hypnozoites • Anemia
for several months up to 5 years) • Splenomegaly
• Fever
Only sporozoites • Nausea
enter liver cells • Vomiting
• Rigors
• Headache
• Coma
Ookinete
parasite undergoes nuclear division and culminates in segmentation These late-stage parasites are very active metabolically, consuming up
to form merozoites. to 75 times more glucose than earlier ring stages and generating
lactate as an end product. At this stage, the red cell surface is studded
In response to a variety of stimuli, some parasites undergo gameto- with “knobs” (proteins of parasite origin) and these mediate the
cytogenesis. When male and female gametes are ingested by a female cytoadherence of parasitized red cells to receptors on the luminal
anopheline taking a blood meal from a human host, the sexual rep- surface of endothelial cells. This leads to sequestration of the parasit-
lication phase of the malaria parasite ensues, starting in the mosquito ized red cells in various organs (brain, gut, subcutaneous fat, cardiac
mid-gut and ending in the salivary glands. The erythrocytic lifecycle muscle), particularly in capillaries and post-capillary venules, in such
continues until it is abrogated by effective chemotherapy or reined in large numbers that blood flow is impaired [7] (Fig. 96.3).
by the host’s acquired immunity.
The life cycle of P. falciparum differs from the other four human The “natural history” of malaria infection and illness is difficult to
malaria parasites in one important respect: during the latter half of capture. In its early stages, a malaria illness is indistinguishable from
the intra-erythrocytic cycle, mature falciparum-infected red blood other common causes of fever. In endemic areas, and for returning
cells (schizonts) effectively disappear from the peripheral blood. travelers, if malaria infections are identified as such and treated
700 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
promptly with effective drugs, clinical progression is rare. If the initial fevers are rarely as periodic as the erythrocytic cycles themselves, prob-
symptoms are not attributed to malaria, “tertiary care” may not be ably because parasite population dynamics within a host are not
sought until complications (commonly coma and convulsions) synchronous.
develop. Volunteers who are “challenged” with the bites of infected
mosquitoes for research studies are provided with effective therapy at Anemia
the first sign of infection and their natural history is truncated at that Malarial anemia results largely from the hemolysis of infected red
point. The mean incubation period (Box 96.1) is 8.9 days (range blood cells at the time of schizont rupture, accelerated immune-
7–14); the most commonly reported symptoms are fatigue, myalgias, mediated destruction of uninfected red blood cells, bone marrow
arthralgias, headache, chills and nausea. The mean pre-patent period suppression and dyserythropoiesis, despite appropriate concentra-
(Box 96.1) is slightly longer (10.5 days, range 9–14) and the appear- tions of erythropoietin. Severe intravascular hemolysis, also known as
ance of peripheral parasitemia is associated with a mild, transient blackwater fever and manifesting as hemoglobinuria, can precipitate
pancytopenia in most patients. acute renal failure.
PATHOGENESIS Hypoglycemia
Pathophysiologic changes in malaria are caused by a number of dif- Because of its deleterious effects on the central nervous system (CNS),
ferent parasite-derived stimuli involving many different organ systems. and because of the necessity for treatment with exogenous glucose,
Blood-stage parasites are the main source of these various stimuli; this is the most important of the biochemical aberrations described
exoerythrocytic stages, gametocytes and sporozoites do not induce to date [8]. Hypoglycemia (usually defined as blood glucose concen-
pathophysiologic changes. Malaria pathogenesis and pathology are trations <40 mg/dL or 2.2 mmol/L) can develop, prior to any anti-
linked inextricably to stages in the lifecycle (Fig. 96.2). malarial treatment, in up to 20% of children with severe P. falciparum
malaria. Plasma insulin levels are low and gluconeogenic precursors
and adrenal hormones are present in high concentrations in the
Fever blood, so parasite consumption of glucose and/or inadequate hepatic
Schizont rupture is the likely source of the fevers associated with gluconeogenesis are the most likely etiologies for pretreatment of
malaria, although the specific pyrogens have yet to be identified. The hypoglycemia. It is not possible to detect hypoglycemia on clinical
M alar ia 701
A B
C D
FIGURE 96.3 Four human tissue autopsy samples demonstrating sequestration and other pathologies in cerebral malaria. (A) The brain: several of the
classic features can be seen including a ring hemorrhage surrounding a blood vessel which contains a fibrin plug; distended congested blood vessels
throughout the section; and sequestered parasites (hematoxylin and eosin [H&E], 200×). (B) The colon has many parasites sequestered in tissues, similar
to the entire glandular gastrointestinal tract, which are most prominent in the small capillaries of the lamina propria. In this section, the presence of later
stage trophozoites and schizonts can be readily appreciated (H&E, 400×). (C) The adipose tissue of the skin can variably contain sequestered parasites
within the rich vessel network (H&E, 1000×). Many other organs, including the heart (D), show variable amounts of sequestered parasites (H&E, 400×).
(Courtesy of Dr Danny A Milner).
grounds in these patients, so in situations where the blood glucose examined both pH and lactate, so although they are likely to be highly
cannot be measured in comatose parasitemic patients, immediate correlated, the precise relationship is not known. Acidosis and
treatment with 50% dextrose is recommended. Unconscious patients hypoglycemia are strongly associated, suggesting parasite and/or host
who present with pretreatment hypoglycemia have a worse prognosis metabolism may be contributing to both. Full-blown circulatory
than those who do not, and the risk of a poor outcome is inversely shock is rarely a feature of severe and complicated malaria, so grossly
associated with blood glucose concentrations, even those above the impaired perfusion is unlikely to be a cause of the metabolic acidosis
traditional cutoff of 2.2 mmol/L (40 mg/dL) [8]. Anti-malarial treat- of malaria. This acidosis generally improves rapidly once intravenous
ment can precipitate hypoglycemia. Rapid infusions of quinine (IV) treatment with an effective anti-malarial drug and maintenance
(>10 mg/kg/hr) can stimulate pancreatic insulin secretion; pregnant fluids is started. The transient nature of the acidosis is consistent with
women appear to be especially susceptible to this complication of the possibility that seizures are a contributing factor. Convulsions are
treatment. common in malaria, and seizures alone can cause an acute lactic
acidosis. Acidosis persists longer in those patients who die and is also
Metabolic acidosis associated with a slower respiratory rate; this suggests that the usual
centrally-mediated respiratory response to metabolic acidosis may be
Acidosis is now recognized as an important marker of severity in compromised in these patients.
falciparum malaria infections. “Acidotic breathing” alone was associ-
ated with a 19% mortality rate in Kenyan children. In this population,
the mortality rate in children with impaired consciousness uncompli- Acute respiratory distress (ARDS)
cated by acidotic breathing was 12%; in children with acidotic breath- Non-cardiogenic pulmonary edema is a common feature of compli-
ing and impaired consciousness, the mortality rate was 32% [8] cated malaria in adults, but only rarely develops in children.
(Fig. 96.4). Elevated plasma and cerebrospinal fluid (CSF) lactate The specific cause of this syndrome in malaria patients has yet to be
levels are also associated with a poor outcome but few studies have identified [9].
702 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
by geography (Fig. 96.1), by parasite density (parasitemias >2% are Non-immune individuals with P. falciparum infections may deterio-
more commonly seen in P. falciparum and P. knowlesi) and by parasite rate very rapidly; prompt and effective treatment in this high-risk
morphology – best appreciated on thin blood films (Table 96.1). group is important and should be provided on an emergent basis.
Low-grade infections of P. malariae can persist for years and individu- When feasible, patients should be monitored closely to detect early
als with P. vivax and P. ovale may have pre-patent periods of a year signs of clinical deterioration. A high index of suspicion is warranted
or more. for travelers and others who have been in malaria-endemic areas.
704 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Serial examination of the peripheral blood (every 12 hours) may aid relatively rapid; most children who survive an episode of cerebral
in the identification of low density parasitemias; thrombocytopenia malaria have regained full consciousness within 48 hours. The rapid
is another helpful clue in oligo-parasitemic or initially aparasitemic evolution and reversibility of the dramatic neurologic features of cere
patients. bral malaria are among the most intriguing aspects of the disease.
The clinical history is generally notable for a sudden deterioration in
COMPLICATED MALARIA the patient’s clinical status – the transition from uncomplicated to
complicated malaria can be as brief as a single seizure.
Long considered to be unique to falciparum malaria, several of the
features of complicated malaria (Table 96-2) have now been described With point-of-care bedside tests for malaria parasitemia, blood
in patients with P. vivax and P. knowlesi infections. In addition to the glucose, hemoglobin or hematocrit and lactate combined with a
complications described in Table 96-2, splenic rupture is a rare com- careful physical examination, nearly all patients with complicated
plication of P. vivax infections, and nephrotic syndrome is occasion- malaria can be identified quickly and without sophisticated labora-
ally seen in patients after a P. malariae illness. tory support.
In a parasitemic patient, the presence of any of the clinical or labo- Important elements of the physical examination include inspection
ratory features of complicated malaria represents a medical emer- for prostration (the inability to sit unaided or, in infants who cannot
gency; these patients should be provided with the best available yet sit, to look for the mother’s breast and feed) and deep breathing,
medical care. assessing the Blantyre [14] or Glasgow Coma Score (Box 96.3),
inspecting nail beds and conjunctivae for pallor (Fig. 96.6), cardiac
The clinical presentation of complicated malaria is different in adults and pulmonary auscultation for signs of high output cardiac failure
than it is in children (Table 96-2). Cerebral malaria alone is more (i.e. a systolic murmur, a gallop rhythm, widened pulse pressure,
characteristic of pediatric severe malaria, whereas multi-organ system enlarging liver), measuring blood pressure and checking capillary
involvement is seen frequently in adults with complicated malaria refill (Box 96.4) (to identify patients in shock), and palpating the
illnesses. abdomen to identify hepato- and splenomegaly and urinary reten-
Cerebral malaria is a highly variable clinical syndrome consisting of tion. Acute renal failure will become evident over time on the basis
P. falciparum parasitemia of any density and coma (Blantyre Coma of urinary output and can be confirmed by measures of serum creati-
Score <2 in children/Glasgow Coma Score <9 in adults, unrelated to nine. In order to identify hyperparasitemia, the capacity to stain blood
hypoglycemia, meningitis or a postictal state). Children with cerebral films and count parasites is required.
malaria frequently demonstrate symptoms suggesting widespread Among patients meeting the standard clinical case definition of cere
involvement of the CNS, including generalized tonic-clonic convul- bral malaria [15], a careful ocular funduscopic exam is very useful for
sions, focal seizures, posturing (opisthotonos, decerebrate rigidity, distinguishing patients with “true” cerebral malaria from patients
decorticate rigidity), conjugate gaze deviations and respiratory rhythm with incidental parasitemias and a non-malarial cause of coma (see
abnormalities (including Cheyne-Stokes respirations). Convulsions “Complicated Malaria” below).
(focal and generalized) are very common, particularly in children.
Intracranial pressure is often elevated in children with cerebral malaria
and deaths consistent with various herniation syndromes have been METABOLIC ACIDOSIS
described. An unusual feature of pediatric malarial comas is that the Capillary blood pH <7.3, plasma bicarbonate <15 mmol/L or plasma
eyes are frequently wide open (Fig. 96.5) – this can be confusing for lactate concentrations >5 mmol/L are all associated with severe
parents and caregivers. Among patients who survive, the recovery is disease and with poor outcomes. Acidosis, manifested clinically as
M alar ia 705
depends on its intended use. For example, does it need to distinguish A second dilemma is the febrile individual with a negative malaria
between a recent malaria infection and a current infection? Should test. Withholding anti-malarial drugs in situations where malaria
it be able to distinguish between falciparum and non-falciparum infection is a real possibility is difficult for clinicians. The dangers of
species? Will treatment decisions be based on the results, or is it being missing a malaria diagnosis and thus delaying treatment are well
employed for epidemiologic purposes? known. This apprehension, accompanied by a degree of skepticism
regarding the reliability of the parasitologic diagnosis (especially via
The choice of which malaria RDT to use in a given situation is complex microscopy), is used to justify a “better safe than sorry” approach to
and depends on availability, cost, quality of the test and performance the use of anti-malarial drugs. In malaria-endemic areas, patients
characteristics. The WHO sponsors independent RDT product testing themselves, along with parents and other caregivers, have come to
in collaboration with the Foundation for Innovative New Diagnostics expect malaria chemotherapy for many febrile illnesses. Clinical evi-
(FIND), the Special Program for Research and Training in Tropical dence for other non-malaria diagnoses should be sought (Box 96.2)
Diseases (TDR) and the WHO Global Malaria Program (GMP). to support the decision to withhold anti-malarials in patients who are
Testing is performed at the US Centers for Disease Control and Pre- not infected with plasmodia.
vention (CDC). Summary results of the most recent round are avail-
able online [21]. These comparisons help to inform procurement The absence of parasites in the peripheral blood should prompt the
decisions for national malaria control programs and to guide United clinician to consider other etiologies of the patient’s symptoms. In
Nations (UN) procurement policies. non-immune patients at risk for malaria infection, several parasito-
logic assessments carried out at 12-hour intervals during a 36–48
In resource-constrained endemic areas, parasitologic diagnosis is not hour period are recommended before concluding that the individual
always available – even when it is available, quality and accuracy are is free of infection. Intra-erythrocytic falciparum parasites are typically
a continuing challenge. When parasitologic diagnoses are not avail- in circulation for the first 24–36 hours of the 48-hour lifecycle, and
able, algorithms devised on the basis of the prevalence of parasitemia the intra-erythrocytic parasites for the other four infecting species are
in various age groups [22] help to balance the risk of under-treating always present in the peripheral blood, so it is not necessary to “time”
those at risk of progressing to severe disease against the risks of unnec- blood collections to any particular symptoms (e.g. fever, rigor,
essary drug use in the semi-immune population, excessive costs and diaphoresis). The WHO recommends withholding anti-malarial treat-
drug pressure, which could accelerate the development of drug resist- ment in the face of negative (often repeatedly negative) tests; in prac-
ant parasites. tice, as noted above, this can be difficult, given the well-known
Serial parasitologic assessments after the start of treatment are helpful dangers of untreated malaria and the challenges of obtaining a reli-
for documenting response to treatment; if these are paired with an able parasitologic diagnosis.
assessment of anemia (either hemoglobin concentration or hemato
crit), it may be possible to anticipate the need for blood transfusion COMPLICATED MALARIA
(see below for guidelines).
Parasitemic individuals with any of the clinical or laboratory features
described in Table 96-2 are likely to have complicated malaria, but
BLOOD FILMS the possibility of a “false-positive” assessment should be considered,
The gold standard of malaria diagnosis remains the blood film. For particularly (but not exclusively) in the semi-immune population.
detecting parasites, a thick blood film is superior as it concentrates The mortality rate of untreated severe malaria is probably over 75%;
the red cells by a factor of 20–40. Identifying species on thick films with good management, the mortality rate of cerebral malaria is
may be difficult because the red cells have lysed and the morphologic roughly 15–20%.
features of the parasites have been altered. Species identifications are
Concomitant meningitis should be excluded via lumbar puncture; if
made more easily using thin blood films. Thick and thin films can be
a lumbar puncture is contraindicated on clinical grounds, the patient
prepared on the same slide, although they are processed differently
should be provided with the appropriate antibiotic coverage (penicil-
(thin films must be fixed in methanol before they are stained). Quan-
lin + gentamicin, or ceftriaxone).
titating parasitemias, even semiquantitatively (0, + - ++++) is useful
for predicting whether the illness is likely to be caused by malaria, for Co-infections with blood-borne bacteria are common and should be
anticipating the need for blood transfusion and for following response sought when the capacity exists [23, 24]. Septic shock should be
to anti-malarial treatment. considered in the differential diagnosis and empiric antibiotic therapy
administered if there are signs of acidosis or impaired perfusion.
Parasites can be counted as a percentage of red cells on a thin film,
or against white blood cells on a thick film, and if the total red cell An autopsy-based study of pediatric cerebral malaria demonstrated
or white cell counts are known, the parasite densities can be calculated. that the standard clinical case definition of cerebral malaria was incor-
Blood can be stained with Giemsa, Leishman, Field or Wright’s stains. rect in approximately 25% of cases – non-malarial causes of death
were identified and those patients had no evidence of parasite seques-
The most important initial distinction is to determine whether
tration in the cerebral microcirculation. In contrast, 75% of cases in
malaria parasites are present: for this, a thick film is most efficient.
this series did have cerebral sequestration of parasitized erythrocytes
Species identification is best done on thin films (Table 96-1). The
and no other causes of death were identified at autopsy [25]. The best
golden brown malaria pigment (hemozoin) in monocytes or leuko-
clinical indicator of “true” cerebral malaria was the presence of at least
cytes suggests a current or recent malaria infection, even in the absence
one of the three features of a recently described malaria retinopathy:
of a patent parasitemia.
vessel color changes, macular or extra-macular whitening, and white-
centered hemorrhages [26] (Fig 96.7). With autopsy findings as the
INTERPRETING THE RESULTS OF MALARIA gold standard, the specificity of retinal findings is 93%, the sensitivity
DIAGNOSTIC TESTS is 97% and the positive and negative predictive values are 97% and
93% respectively.
In practice, clinicians in malaria-endemic areas with little diagnostic
capacity prescribe anti-malarial drugs to symptomatic individuals Malarial retinopathy is best appreciated in eyes that have been fully
whenever parasites are detected; however, the clinical challenge is to dilated with mydriatics (a combination of tropicamide and phenyl
decide if additional treatment (e.g. antibiotics) is needed. In semi- ephrine eye drops will dilate the eyes within 15–20 minutes) and
immune individuals, asymptomatic or “incidental” parasitemia is examined with a hand-held direct ophthalmoscope (which provides
common, and the presence of peripheral parasitemia can be mislead- magnification) and an indirect ophthalmoscope (which provides a
ing. In these individuals, it would be prudent to consider other etiolo- three-dimensional perspective, as well as a wider field of view). These
gies for the symptoms, particularly in patients with lower density examinations are routine for trained ophthalmologists, but non-
parasitemias (Box 96.2). Anti-malarial treatment is warranted if para- ophthalmologist clinicians can learn to recognize these features, too.
sites are detected, but additional treatment may also be required. Ninety percent of retinopathy-positive patients can be identified on
708 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
FIGURE 96.7 Malaria retinopathy. Examples of clinical ocular fundus findings in African children with P. falciparum malaria. 1, Retinal hemorrhages, some
with white centers. 2. Grade 2 macular whitening, less than 1/3 of the disc area of whitening. 3. Grade 2 macular whitening, between 1/3 and 1 disc area
of whitening. 4. Grade 3 macular whitening, greater than 1 disc area of whitening. 5. Grade 1 extramacular whitening, note 2 foci of whitening. 6. Grade
2 extramacular whitening; scattered white spots in the upper half of the photograph represent the density of whitening for the 2+ grade. 7. Grade 3
extramacular whitening; this definite mosaic represents the minimum whitening for the 3+ grade. 8. Grade 3 extramacular whitening; confluence of
whitening. 9. Abnormal vessels; orange delineation of vessels. 10. Abnormal vessels; segmental whitening. 11. Abnormal vessels, extensive delineation of
capillaries with some irregular delineation of terminal portion of larger vessels. (From Lewallen S, Harding SP, Ajewole J, et al. A review of the spectrum of clinical
ocular fundus findings in P. falciparum malaria in African children with a proposed classification and grading system. Trans Roy Soc Trop Med Hyg 1999;93:619–22.).
M alar ia 709
the basis of observations of the optic disc, the macula and the area in Irrespective of the alkaloid selected, a loading dose is required in order
between [27]. to achieve a therapeutic drug concentration quickly. More care is
required to administer quinine and quinidine than the artemisinins.
Severe pneumonia was a common cause of death in parasitemic Quinine and quinidine, when infused too rapidly, stimulate the pan-
children who satisfied the clinical case definition of cerebral malaria creatic secretion of insulin and hypoglycemia may ensue.
in the autopsy study described above. Pneumonia may be suspected
on the basis of the history and physical examination, and should Intravenous quinine was enshrined as the treatment for severe malaria
definitely be considered when oxygen saturations are <90%. Given well before pharmacokinetic studies were possible; current regimens
the frequency of this particular co-morbidity, empiric antibiotic have evolved on the basis of experience and some computer model
therapy based on the clinical assessment is reasonable [28]. ing. Regimens for intramuscular quinine and the intravascular/
intramuscular formulations of the artemisinin derivatives are based
If pediatric patients have a history of aspirin intake, or if there is
on sound pharmacokinetics (Table 96-4).
hepatomegaly in the face of recurrent hypoglycemia, Reyes Syndrome
should be included in the differential diagnosis. Randomized clinical trials comparing IV quinine with IV artesunate
have established the superiority of IV artesunate in adults and chil-
TREATMENT dren [29, 30].
Patients with complicated malaria should receive parenteral anti-
CLEARING THE PARASITE malarials for at least 24 hours; after that, a full course of an effective
oral drug can be administered, beginning as soon as the patient can
For patients who are able to swallow, oral medications (Table 96-3) swallow (Table 96-4).
are recommended [20]. Prior treatment is common, and should be
taken into consideration when deciding how to treat individual
patients; quinine use following mefloquine may be arrhythmogenic, PREGNANT PATIENTS
for instance. For pregnant women living in malaria-endemic areas, the WHO
recommends Intermittent Preventive Treatment during pregnancy
Although chloroquine is no longer recommended by the WHO as the (IPTp) [20] with two doses of sulfadoxine-pyrimethamine (SP)
primary treatment of P. falciparum infections, it remains the most administered at monthly intervals after the onset of fetal movements.
commonly used drug in a few parts of the world including Haiti, IPTp should be extended into the third trimester for HIV-infected
the Dominican Republic, most regions of the Middle East, and pregnant women who are not taking cotrimoxazole prophylaxis.
Central America, west of the Panama Canal. Even in settings where
chloroquine-resistance is widespread, the drug, an effective analgesic Chemotherapy for pregnant women who develop malaria illnesses
and antipyretic, has considerable popularity. during pregnancy is similar to that recommended for non-pregnant
patients with the following caveats:
Chloroquine is recommended for the blood-stage infections of P.
malariae, P. ovale and most P. vivax infections. Chloroquine-resistant l few pharmacokinetic studies have been carried out in pregnant
vivax malaria has been reported from Indonesia and Papua New women;
Guinea, and those infections should be treated with artemisinin com- l chloroquine is well tolerated;
bination therapies, atovaquone-proguanil, mefloquine or quinine l the recommended doses of quinine and quinidine are safe;
followed by doxycyline or tetracycline. l mefloquine may be associated with an increased risk of stillbirth
[31], but can be used when no other treatment options are
Primaquine is required for radical cures of the liver stage parasites in available;
P. vivax and P. ovale. In most situations, a daily dose (0.25–0.5 mg/ l tetracycline, doxycycline, primaquine and halofantrine are con-
kg) of primaquine for two weeks is sufficient. Patients should be traindicated in pregnancy, and neither primaquine or the tetracy-
screened for G6PD-deficiency prior to administration of primaquine. clines should be used while breastfeeding;
In settings where laboratory testing is not available, a test dose of l primaquine is contraindicated during pregnancy, given the uncer-
primaquine followed by careful observation and repeated measures tain G6PD status of the fetus.
of hemoglobin or hematocrit may be necessary.
There are very few data on the safety of the artemisinin drugs during
In general, though, monotherapy for falciparum malaria has been pregnancy; in general, they are not recommended during the first
supplanted by drug combinations (co-formulated or co-packaged) of trimester and amodiaquine use during pregnancy is eschewed because
artemisinin-based compounds (rapidly parasiticidal, but with short of the risk of agranulocytosis.
half-lives) and partner drugs (more slowly acting, but with longer
half-lives). The artemisinins typically clear 90% of the parasites within
24–36 hours and the partner drug clears the rest. Most regimens TREATING THE PATIENT
(Table 96-3) require twice daily administration of the drug combina- Supportive care
tion over three days. The WHO currently recommends five different
Dedicated nursing care is important in the management of these
combinations; specific choices depend on prevailing parasite drug
patients. Vital signs, urine output and an appropriate coma score
sensitivities, procurement opportunities and cost [20].
should be monitored as frequently as possible. The most common
For patients who are unable to swallow, parenteral drug treatment causes of a drop in coma score following the initiation of therapy are
is required; both options are contemporary formulations of tradi- convulsions, hypoglycemia and anemia. Blood glucose, lactate, para-
tional, plant-based remedies. Quinine (and its stereoisomer, quini- sitemia and hemoglobin/hematocrit can be monitored every 4–6
dine) come from the bark of the cinchona tree and the artemisinins hours on fingerprick samples of blood. Patients not on ventilatory
are derived from Artemesia annua, known colloquially as “sweet support should be nursed in the lateral decubitus position to mini-
wormwood”. mize the chance of aspiration. IV fluids containing 5% dextrose are
important initially, but nasogastric tube feeding can be started within
The cinchona alkaloids have been the mainstay of treatment for com-
18–24 hours of admission if the patient is unable to eat.
plicated malaria since they were introduced to Europe from Peru in
the 17th century. Quinine is used more commonly, but quinidine is
as effective, albeit more likely to engender cardiac dysrhythmias. Fever
Although the IV route is preferred, intramuscular administration is There is no consensus on how best to treat malarial fevers. Aggressive
effective – the drug, as formulated (at 300 mg base/ml) is fairly acidic, fever management may decrease the risk of convulsions and subse-
though and should be diluted 4–6-fold prior to intramuscular injec- quent neurologic damage but parasite sequestration is less effective at
tion. Large-volume injections should be divided between two large higher temperatures. Acetaminophen/paracetamol and ibuprofen are
muscle masses (preferably the anterior thighs). all effective antipyretics in malaria patients.
710 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
l Quinine sulfate: 542 mg base (= 650 mg salt) p.o. Rapid IV or IM administration can precipitate hypoglycemia
three times a day for 3 days (7 days for infections Doxycycline and tetracycline are not recommended during
acquired in Southeast Asia) pregnancy or in children under the age of 8 years.
l Doxycycline: 100 mg p.o. twice a day for 7 days Clindamycin is recommended for these two groups
l Tetracycline: 250 mg p.o. four times a day for 7 days Doxycycline should be taken with food to minimize the
l Clindamycin: 20 mg base/kg/day, p.o., divided three risk of esophageal erosions
times a day for 7 days Both drugs may cause photosensitivity and disrupt normal
flora enough to precipitate vaginal yeast infections
l Atovaquone-proguanil Atovaquone targets an element of the parasite electron
Adult tablet: 250 mg atovaquone, 100 mg proguanil transport chain and is thus well-tolerated by the host
Pediatric tablet: 62.5 mg atovaquone, 25 mg proguanil Proguanil interferes with folate metabolism and has been
5–8 kg: two 25-mg pediatric tablets daily for 3 days associated with aphthous oral ulcers
9–10 kg: three 25-mg pediatric tablets daily for 3 days Side effects include vomiting, dizziness, and exacerbation
11–20 kg: one adult 100-mg tablet daily for 3 days of cardiac conduction abnormalities
21–30 kg: two adult 100-mg tablets daily for 3 days Not recommended for individuals with a history of
31–40 kg: three adult 100-mg tablets daily for 3 days psychiatric disorders
>40 kg: four adult 100-mg tablets daily for 3 days May disrupt sleep or cause vivid dreams
l Mefloquine
Adults: 684 mg base (= 750 mg salt) p.o., followed by
456 mg base (= 500 mg salt) p.o., 6–12 hours later
Children: 13.7 mg base/kg (= 15 mg salt/kg) p.o., followed
by 9.1 mg base/kg (= 10 mg salt/kg) p.o., 6–12 hours
later
Treatment failure within 14 days
Second-line treatment:
l a different ACT, known to be effective in the region
l AS + tetracycline, doxycycline or clindamycin, for 7
days
l quinine + tetracycline, doxycycline or clindamycin, for
7 days
See above for details re dosage regimens
Treatment failure after 14 days
Repeat the original ACT unless it contained MQ; in that
case, use a different ACT
M alar ia 711
hyperbilirubinemia are seen in about 50% of patients. The hemo- standard light microscopy detection of parasites on thick films. In
globin count tends to be normal. The undifferentiated febrile clini- the endemic communities, P. malariae is a common cause of mor-
cal presentation cannot be distinguished from other malarias. bidity with the highest incidence of febrile episodes among chil-
dren less then 10 years old. As febrile episodes are often treated
Plasmodium ovale is considered a relapsing malaria [42]. However, empirically and the confirmation of low-density P. malariae infec-
the relapse frequency and relapse interval of P. ovale is poorly tions by microscopy is difficult, the true incidence of P. malariae
described. Recently, the existence of a true hypnozoite in P. ovale malaria is underestimated.
malaria has been questioned [43]. The existence of P. ovale hypno-
zoites has never been proven by biologic experiments. On one Plasmodium malariae is unique in that without treatment, blood
hand, indirect evidence of the existence of hypnozoites, i.e. reports stage parasites persist for extremely long periods of time – likely
on the occurrence of true relapses undoubtedly caused by this the lifetime of the host. The persistent, low-density parasitemia in
parasite is rare; true P. ovale relapses have been reported only occa- otherwise healthy individuals may produce distinctive clinical fea-
sionally. On the other hand, P. ovale cases reported without any tures, or individuals may be so asymptomatic that they qualify as
preventive medication where relapses did not occur outnumber blood donors. This is why P. malariae causes about 25% [53] of
reported relapses caused by this parasite. If true hypnozoites exist transfusion related cases of malaria although it accounts for only
then the relapse frequency must be very low. 1–2% of imported cases of malaria [54].
Likewise, asymptomatic persons can re-introduce P. malariae into
DIAGNOSIS previously malaria-free areas [55]. Years later, when carriers are
immunosuppressed with drugs [56] or stressed by surgery [57], the
There tends to be lower initial parasitemias (<500 parasites per μl) parasites can recrudesce and they become symptomatic with typical
with P. ovale malaria, making the diagnosis by routine microscopy symptoms of malaria.
insensitive. Plasmodium ovale and P. vivax can be difficult to distin-
guish morphologically by oil immersion microscopy. Mixed infec- The most important and unique feature of prolonged P. malariae
tions, especially in endemic areas, are common. In endemic regions parasitemia is an irreversible, immune-mediated, nephrotic sym-
where P. falciparum and/or P. vivax predominate, P. ovale is fre- drome first noted in West Africa in the 1960s [58, 59]. Nephrotic
quently overlooked. For more accurate diagnosis and estimates of syndrome caused by P. malariae can also present outside of malaria
the burden of P. ovale infections, more sensitive diagnostic methods endemic areas years after the last exposure [60].
are needed [44].
Plasmodium ovale malaria is currently problematic to diagnose CLINICAL PRESENTATION
in travelers, with early attempts complicated by the lack of
specific clinical features, the rarity of biologic changes and the poor Plasmodium malariae is a relatively mild form of malaria, although
sensitivity of diagnostic tools to detect low parasitaemia. Thus, the the initial paroxysms can be similar to those seen with P. falciparum
diagnosis is commonly delayed or missed. and P. vivax. The undifferentiated febrile presentation is indistin-
guishable from other malarias. Deaths associated with P. malariae
Molecular diagnosis and differentiation of the two subspecies can are not from acute infection but rather caused by end-stage renal
be accomplished with PCR protocols in reference laboratories [45], disease [61].
but the genetic polymorphisms of the two subspecies require
appropriate protocols [46]. The nephrotic syndrome associated with chronic P. malariae is caused
by an immune complex, basement membrane nephropathy and
Rapid diagnostic tests (RDTs) have not been developed to detect P. presents no differently from nephrotic syndrome associated with
ovale, and the performance of currently-available RDTs varies greatly other causes. Usually, there is a several-month history of progres-
in their capability to detect P. ovale parasites. Sensitivity varies sively worsening lower extremity edema, frothy urine, hypertension
between 0% and 80%, with parasite density a key factor [47–50]. and multiple abnormal laboratory findings including proteinuria,
A negative RDT test result cannot exclude the diagnosis of P. ovale hypoalbuminemia, hyperlipidemia, high serum creatinine and
malaria. anemia. Renal biopsy is usually required to confirm the diagnosis
and properly guide management [61]. Plasmodium malariae as the
TREATMENT true cause of the nephrotic syndrome may be very difficult to diag-
nose because the patients may have exceedingly low parasitemias
Chloroquine at 25 mg/kg divided over three days is the treatment and negative rapid diagnostic test (RDT) results. Parasitologic con-
of choice if a mono-infection with P. ovale is confirmed. Artemisinin firmation in this syndrome requires exhaustive, expert, microscopic
combination treatments (ACTs) are effective and could be used in review of smears and carefully directed molecular methods [60].
settings of diagnostic uncertainty. Currently, a radical cure dose of
30 mg primaqine base (0.5 mg/kg) by mouth daily for 14 days is
recommended to eliminate hypnozoites; however, note the contro- DIAGNOSIS
versy in this regard above. Use of lower dose primaquine has been The preferred diagnostic method to confirm P. malariae remains
associated with therapeutic failures and recurrent P. ovale malaria traditional Giemsa-stained thick and thin peripheral blood smears.
[51]. In the growing parasite, pigment increases rapidly with many jet-
black granules. The trophozoite assumes variable shapes but
often stretches across the width of the red blood cell to appear as
PLASMODIUM MALARIAE a “band form” (see Fig. 96.3), which is often considered diagnostic,
although this band form can be seen with other species, especially
Plasmodium malariae was first described by Golgi in 1886 when he P. knowlesi and P. inui. Red blood cells infected with trophozoites
noted the relationship between the 72-hour lifecycle of the parasite of P. malariae parasites are not enlarged and do not contain promi-
in the blood of patients and the corresponding appearance of fever nent stippling, which distinguishes them from P. vivax and P. ovale
and chills (the paroxysm) [52]. Fever caused by P. malariae was [62].
historically known as “quartan malaria” because of the appearance When considering the microscopic diagnosis of P. malariae, three
of fever every fourth day (assuming the first day of fever is day 1). considerations should be kept in mind:
Plasmodium malariae has been reported from all continents but is
only relatively common in tropical Africa and the Southwest Pacific. l there tends to be lower initial and maximal parasitemias with P.
The prevalence of P. malariae varies from less than 1% to as high as malariae than with other species because the number of mero-
30–40% in focal areas of West Africa and Indonesia based on zoites per red blood cell replication cycle is lower (6–14), the
M alar ia 715
three-day versus two-day developmental cycle produces slower common cause of malaria on the Malaysian Peninsula in particular,
growth, and P. malariae’s preference for older red blood cells limits and in Southeast Asia in general, especially in populations living
the number of cells that can be infected [62]; in close proximity to the simian reservoir [81].
l in endemic regions where P. falciparum and/or P. vivax predomi-
nate, mixed infections are the rule and P. malariae is frequently The most common clinical syndrome is a febrile illness, indistin-
overlooked unless more sensitive diagnostic methods, such as guishable from uncomplicated falciparum malaria, but a small
molecular diagnostic tests, are used [63]; proportion of patients (<10%) progress to severe and complicated
disease, in which respiratory distress (ARDS) and renal failure
l even careful microscopic examination may not be sufficient
to morphologically distinguish P. knowlesi – an emerging cause feature more prominently than in severe falciparum malaria
of severe and potentially fatal malaria in Southeast Asia – from [68, 71–74]. In contrast to falciparum malaria, coma is a relatively
P. malariae on the peripheral smear [64]. Molecular methods may rare complication of infection with P. knowlesi. Surprisingly, the
be needed to confirm the diagnosis of P. malariae where the two salient findings in the one case of fatal P. knowlesi malaria that
parasite distributions overlap. was autopsied are similar to fatal falciparum malaria: there was
selective accumulation of parasitized red cells in the brain, heart
RDTs for malaria are not developed to specifically diagnose P. malar- and kidneys, the brain was slate gray in color and there were
iae, and the detection of parasites relies on various pan-Plasmodium petechial hemorrhages scattered through the cerebrum and cerebel-
capture reagents not specifically optimized for P. malariae. The per- lum [75]. Plasmodium knowlesi is a quotidian parasite, undergoing
formance of currently available RDTs varies greatly (0–100%) in asexual replication every 24 hours, which may explain the relatively
their capability to detect P. malariae parasites. Clinical studies are high incidence of severe anemia [73]. Thrombocytopenia, often
usually designed to evaluate the sensitivity and specificity of RDTs profound, is nearly a constant feature in P. knowlesi infections, but
for P. falciparum and P. vivax, and small numbers of P. malariae are no clinically evident coagulopathies have been reported [71–74].
encountered and reported. Whether the poor sensitivity is because The disease in children is fairly similar to that in adults, but there
of the very low parasitemias (and presumably low antigen levels) is one striking contrast in pediatric infections with P. knowlesi
in patients or because of the lack of cross-reaction with the capture compared with P. falciparum: pediatric P. knowlesi infection is
reagents is not known. A negative RDT test result cannot exclude restricted to school-age children, whereas falciparum malaria affects
the diagnosis of P. malariae malaria. all ages [72].
Molecular testing is not commercially available or standardized, Microscopically, P. knowlesi resembles P. falciparum young ring
and results may vary based on regional differences in target gene stages and P. malariae in the mature trophozoite blood stages, there-
sequences; caution should be used when relying solely on molecu- fore a high index of suspicion and judicious use of molecular
lar results to make clinical decisions. As also seen in P. ovale, the methods are required to establish the diagnosis definitively [76].
targets of P. malariae molecular probes may exhibit geographic Median parasitemias are typically approximately 1400 parasites per
variation suggesting subspecies of P. malariae [65] and an addi- microliter (interquartile range 6–250,000) [71]. To date, there is no
tional reason why PCR reactions could yield a false-negative result. evidence that P. knowlesi is a relapsing malaria and, thus far, treat-
ment with a wide variety of anti-malarial drugs (quinine, artesu-
nate, various artemisinin combination therapies [ACTs], mefloquine,
TREATMENT with and without primaquine) have been successful [71–74].
The treatment of choice for the typical, uncomplicated febrile Plasmodium knowlesi malaria has been called the “fifth human
illness associated with P. malariae mono-infection is chloroquine at malaria”, but there is, as yet, no definitive evidence for cyclical
25 mg/kg total dose divided over three days. Artemisinin combina- transmission by mosquitoes from human to human. Without this
tion treatments (ACTs), as well as other anti-malarial drugs, are evidence, it remains a simian malaria with occasional zoonotic
effective and could be used in settings of diagnostic uncertainty. human infections [77]. Analysis of archival blood films suggests
Clinicians should be aware of the possibility of occasional recurrent that P. knowlesi has infected humans for many years in Malaysian
parasitemias with clinical symptoms following treatment with a Borneo [78] and recent epidemiologic studies suggest that macaque
standard course of chloroquine [66]. These cases likely represent monkeys are the reservoir host [79]. The recent upsurge in clinical
delayed parasite clearance rather than true resistance. There is a episodes may be related to changes in human exposure to monkeys,
16–59 day range in the length of the pre-patent period in experi- deforestation and a decline in P. vivax infections [80].
mental mosquito transmitted P. malariae [62] and it is thought that
some parasites could emerge from the liver days or weeks after
treatment is initiated when drug levels are inadequate to prevent DIAGNOSIS
parasitemia [67]. On such occasions, either re-treatment with a full Plasmodium knowlesi infections are limited to areas where humans
treatment course of chloroquine or another standard anti-malarial (local residents or travelers) are near the reservoir hosts: long-tailed
treatment regimen would be satisfactory. (Macaca fasciularis) and pig-tailed macaques (Macaca nemestrina).
Treating the underlying P. malariae in fully established nephrotic Microscopic identification of a malaria infection is the first step, but
syndrome does not improve renal function, as segmental sclerosis because of the morphologic similarities between P. falciparum, P.
and hyalinization of the nephron are irreversible. These patients malariae and P. knowlesi, the definitive diagnosis of P. knowlesi rests
often become hemodialysis dependent. To prevent end-stage renal on molecular detection using a nested PCR technique [14]. Com-
disease, P. malariae must be considered, diagnosed and effectively binations of rapid diagnostic tests (RDTs) can be used to increase
treated as soon as renal symptoms develop [61]. diagnostic certainty, but there is no RDT specifically for P. knowlesi
at this time.
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97 African Trypanosomiasis
Sanjeev Krishna, August Stich
1 1
2–10 2–10
11–50 11–50
51–100 51–100
101–500 101–500
501–1000
0 1000 2000
kilometers
FIGURE 97.2 Map of distribution of human African
trypanosomiasis Lambert azimuthal equal area projection
BLOOD FILMS
Thick blood films, stained with Field’s or Giemsa’s stains identical to
the ones used for malaria diagnosis, can sometimes show trypano-
somes, although concentration techniques are required routinely to
identify parasites in a T. b. gambiense infection. Morphology may be
poor in thick films, but the longer time required to examine thin films
that preserve morphology may outweigh their value in screening for
this infection. In contrast, blood film examinations are much more
useful in T. b. rhodesiense infections.
CONCENTRATION METHODS
Many approaches to concentrate parasites before visualization have
been successfully developed. Probably the most robust one relies on
a mini anion exchange column that allows trypanosomes through its
cellulose matrix when 300 µL of blood is added to it (compared to
FIGURE 97.9 Morular cell of Mott (H&E stain) in cerebrospinal fluid of
patient with stage II disease.
~10 µL of blood volume examined on a thick film). The kit is not
commercially available and is used only by specialized laboratories.
Another method has been adapted from malaria diagnosis, the quan-
titative buffy coat (QBC) method. A similar approach uses capillary
state. Other evidence of CNS involvement includes inability to execute
tube centrifugation (CTC). These approaches can be combined with
relatively simple tasks (Fig. 97.8). In some cases, morular cells of
better visualization techniques such as fluorescence labeling to
Mott, activated plasma cells with eosinophilic inclusions containing
improve parasite recognition and together with field-adapted, rela-
IgM antibodies, can be seen in the CSF (Fig. 97.9). Progressive wasting
tively cheap fluorescence microscopes with light-emitting diodes as
and dehydration follows the inability to eat and drink.
source illumination are being developed by the Foundation for Inno-
In children, HAT seems to progress even more rapidly. Parents often vative New Diagnostics (FIND), which aims to improve diagnostic
notice insomnia and behavioral changes, and stage II is usually approaches for African trypanosomiasis.
already reached when the diagnosis is established.
NUCLEIC ACID AMPLIFICATION TECHNIQUES
PATIENT EVALUATION, DIAGNOSIS, Genus, species and subspecies specific primers are well described and
AND DIFFERENTIAL DIAGNOSIS available for use in epidemiologic studies of African trypanosomiasis,
but conventional PCR currently lacks sensitivity to detect parasites in
Few infections demand a confirmed diagnosis as much as African low abundance in the clinic. Newer approaches including the use of
trypanosomiasis, because the treatments available can be fatally toxic. isothermal PCR techniques that demand much less in the way of
Clinical suspicion is triggered when a patient returns from an area equipment are being investigated by FIND, but until now molecular
endemic for trypanosomiasis. A distinction should be made between diagnostic tests are still inferior to conventional parasite detection.
the two forms: For T. b. rhodesiense infections, the appearance of a
chancre and the presence of high fever should raise suspicion and
trigger a vigorous search for parasites in the blood film. T. b. gambiense SEROLOGIC ASSAYS
infections can present, sometimes months or years after exposure, A card agglutination test (CATT) has been used for many years to
with symptoms that may be relatively nonspecific, even sometimes screen for antibodies against T. b. gambiense using a mixture of abun-
mimicking psychoses. Again, detection of parasites is critical to man- dant parasite antigens. This is a rapid, field-adapted test that detects
agement, and these can be sought in aspirate from a chancre, in antibodies by their ability to agglutinate antigen, but does not confirm
Af r i c a n Tr y p a nosomiasis 723
the infection. Rather, a positive result should stimulate the search for related to the route of administration or its dose and are usually
parasites. The CATT can be obtained from the Department of Parasi- reversible.
tology, Prince Leopold Institute of Tropical Medicine, Nationalestraat
155 B – 2000 Antwerp, Belgium (www.itg.be). In clinical medicine, pentamidine is also used as second-line therapy
for visceral leishmaniasis and especially in the prophylaxis and treat-
ment of opportunistic Pneumocystis jiroveci pneumonia in AIDS. Since
TREATMENT the start of the HIV pandemic, the cost of pentamidine was increased
more than tenfold by producers, making it unaffordable for health
Treatment of HAT is difficult and dangerous for the patient in all institutions in low-income countries. After an intervention led by the
stages. Hospitalization is usually necessary. Patient management World Health organization (WHO), a limited amount of pentami-
requires not only the availability and correct administration of drugs dine is now made available for use in HAT through a public–private
with numerous side effects, but also good general medical skills and partnership..
nursing care to deal with treatment reactions and concomitant
pathologies, as most patients with late stage trypanosomiasis are
severely ill and malnourished [9]. However, sleeping sickness is a Suramin
disease of rural, remote places where the healthcare system is rudi- In the early twentieth century, the development of the complex sul-
mentary. The active foci of sleeping sickness are usually in far-away phated naphthylamine suramin (“Bayer 205”), resulting from German
and insecure places, which are difficult to access. Many treatment research on the trypanosomicidal activity of various dyes and heavy
centers work under emergency conditions with extremely restricted metals, was a major breakthrough in the field of tropical medicine.
resources. For the first time, African trypanosomiasis, at least in its early stages,
became treatable without causing major harm. Suramin, under the
However, if managed properly, HAT can be cured, especially when the
trade name of Germanin® soon became a figurehead of German
diagnosis is made at an early stage of the disease.
research in tropical medicine. That German politicians tried to use
Still, HAT treatment is not standardized. Trypanosomiasis treatment suramin to regain access to Africa to reverse the loss of the German
regimens vary considerably between countries and treatment centers, colonies after World War I is another sad chapter on how tropical
as many country programs have traditionally developed their own medicine was instrumentalized for political ambitions.
treatment protocols. Results from different centers are comparable to
Suramin is still the drug of choice to treat stage I HAT caused by T. b.
only a very limited extent. Few properly conducted and sufficiently
rhodesiense. Like pentamidine, it does not reach therapeutic levels in
powered clinical trials are available to evaluate duration, dosage, pos-
CSF. Suramin is injected intravenously after dilution in distilled water.
sible combinations of drugs, and co-administration of auxiliary treat-
ments. Sufficient infrastructure for carrying out clinical research exists Adverse effects, especially pyrexia and nephrotoxicity, depend on
in only a handful of places. nutritional status, concomitant illnesses (especially onchocerciasis)
and the patient’s clinical condition. Although life-threatening reac-
MANAGEMENT OF HAT STAGE I tions like anaphylactic shock have been described, serious adverse
effects are rare.
The treatment of HAT depends on the trypanosome subspecies and
the stage of the disease (Tables 97-2 & 97-3).
MANAGEMENT OF HAT STAGE II
Pentamidine Melarsoprol
Since its introduction in 1937, pentamidine has become the drug of Until the systematic introduction of the arsenical compound melar-
choice for gambiense HAT stage I, achieving cure rates as high as 98%. soprol in 1949, late stage trypanosomiasis was virtually untreatable.
But in T. rhodesiense HAT there are frequent failures. Lower rates of Since then, it has remained the most widely used stage II antitrypano-
cellular pentamidine uptake in T. b. rhodesiense may explain these somal drug for both T. b. gambiense and rhodesiense infections and has
differences. Some cures of stage II infections have also been reported, thus saved many lives. However, melarsoprol displays a high rate of
but CSF drug levels are usually not sufficiently high to guarantee a dangerous adverse effects [10]. In addition, there is increasing evi-
reliable trypanosomicidal effect in the CNS. dence of frequent relapses and resistance in some parts of Congo,
Angola, Sudan and Uganda.
Pentamidine is usually given by deep intramuscular injection, which
sometimes can be managed on an outpatient basis. If hospital care
and reasonable monitoring conditions are available, an intravenous
infusion, given in normal saline over 2 hours, might be used instead.
The main advantage of pentamidine over other drugs is the short
treatment course and ease of administration. Adverse effects are
TABLE 97-3 Treatment Protocols for Antitrypanosomal
Drugs
Key features
l Caused by Trypanosoma cruzi, a flagellate protozoan parasite l The natural history includes the acute phase lasting 2–3
of the order Kinetoplastida, family Trypanosomatidae months and the chronic phase, which lasts the lifetime of the
l Endemic in the Americas from Mexico to northern Argentina host. An estimated 20–30% of people who initially have the
and Chile. Twenty-eight million people are at risk; it is indeterminate (asymptomatic) form progress over a period
estimated that 8–10 million people are currently infected. of years to clinically-evident cardiac and/or gastrointestinal
Forty-one thousand and two hundred new infections and disease
12,500 deaths are estimated to occur annually l Severe and fatal cases of T. cruzi infection following organ,
l The southern half of the USA has enzootic vector-borne tissue, or cell transplantation, and HIV co-infection can occur
transmission and rare autochthonous human cases l Diagnosis of acute and early congenital T. cruzi infection
l Owing to migration now seen in North America, Europe requires demonstration of the parasite in blood by microscopy,
(particularly Spain), Australia and Japan, acute Chagas disease PCR or hemoculture. Diagnosis of chronic infection relies on
has rarely been reported in travelers returning from endemic serologic tests (e.g. ELISA) to detect IgG antibodies to T. cruzi
countries l Indication for anti-parasitic therapy depends on the phase of
l Transmitted by hematophagous triatomine vectors (Hemiptera, the disease and the clinical status and age of the patient.
Reduviidae, Triatominae), more than 100 species of mammal There are currently only two available drugs: benznidazole
act as reservoirs and nifurtimox
l Trypanosoma cruzi can also be transmitted congenitally, by l Prevention and control relies on residual application of
blood transfusion or organ donation, and via contaminated long-lasting insecticides in human dwellings and peridomestic
food or drink structures, and serologic screening of blood donors, pregnant
l Factors that may affect pathogenesis include parasite burden, women and the newborns of women found to be infected
the severity of the initial infection, host immune response and l Chagas disease has now emerged in North America and
human genetic factors. Tissue inflammation may be caused Europe. Physicians in non-endemic countries should therefore
directly by the parasite and secondary to the host’s immune be aware of the existence, or even the potential transmission,
response of this parasitic disease during their routine clinical practice
eggs. Thus, nymphs and adults of either sex may be infected with rural communities have adult infection prevalences >20%, followed
T. cruzi, but infection rates increase with increasing vector stage and by Argentina, El Salvador and Honduras. However, vector-borne
age. There are at least 130 triatomine species in the Americas, many transmission occurred historically throughout the Americas from the
of which have been documented to carry T. cruzi. However, a handful southern USA to Chile and Argentina in the south [2]. Because cardiac
of highly domiciliated vector species are of disproportionate impor- and gastrointestinal manifestations usually begin in early adulthood
tance in the human epidemiology of disease [3]. These include: and progress over a period of years (to decades), the prevalence of
Triatoma infestans in the Southern Cone (Argentina, Bolivia, Chile, symptomatic clinical disease increases with increasing age.
Paraguay, southern Peru, Uruguay and southern Brazil); Rhodnius pro-
lixus and Triatoma dimidiata in northern South America and Central Several Chagas disease control initiatives have made major advances
America; and Panstrongylus megistus and Triatoma brasiliensis in Brazil. in decreasing house infestation and ensuring T. cruzi screening of
Most domestic species feed nocturnally and are able to complete their blood supplies [9, 10]. As a consequence, the estimated global preva-
blood meal without waking the host. The major Latin American lence of Chagas disease has fallen from 18 million in 1991 to 8–10
vectors defecate during, or immediately after taking, a blood meal, million in 2005. At the same time, migration has brought infected
increasing the likelihood of infecting the host. Some triatomine individuals to cities both within and outside of Latin America. The
species can infest both domestic and sylvatic sites and may play a estimated disease burden outside of Latin America includes as many
bridging role. as 67,000 T. cruzi-infected immigrants in Spain and tens of thousands
in Italy, France and Switzerland [11]. Immigrants with Chagas disease
More than 100 species of mammals have been reported to carry are also known to be living in Japan, Australia and Canada (Fig. 98.1).
natural infections with T. cruzi. Sylvatic transmission cycles are main-
tained by wild mammals and triatomine species; the vectors often The USA is a special case in that the southern half of the USA contains
colonize nests of rodent or marsupial reservoir hosts. Wild triatomine established enzootic cycles of T. cruzi, involving several triatomine
adults may fly into human dwellings, attracted by light, and cause vector species and mammalian hosts, such as rodents, raccoons, opos-
sporadic human infections. Domestic transmission cycles occur sums and domestic dogs. A total of seven vector-borne T. cruzi infec-
where vectors are adapted to living in human houses and nearby tions are documented to have occurred in the USA since the 1950s,
animal enclosures. The peridomestic environment provides abundant but most are presumed to go undetected [12]. Nevertheless, the
hosts that act as blood meal sources and poor quality housing pro- number of autochthonous T. cruzi infections is dwarfed by the esti-
vides crevices and other diurnal hiding places for triatomines. In mated 300,000 infected immigrants from endemic areas of Latin
endemic communities, a high proportion of houses may be infested, America [13].
and a house and its immediate surroundings may support large colo-
nies of bugs. Dogs, cats and guinea pigs act as important domestic
T. cruzi reservoir hosts, while opossums, rodents, armadillos and
CONTROL AND PREVENTION
raccoons are important sylvatic hosts. Application of long-lasting insecticides in human dwellings and peri-
domestic structures is effective against domestic triatomine vectors,
but must be followed by monitoring for re-infestation [9]. Between
NON-VECTORIAL TRYPANOSOMA CRUZI 1991 and 2004, four sub-regional control programs were established.
TRANSMISSION The major aims were to control transmission by domestic vectors
Trypanosoma cruzi can also be transmitted congenitally, by blood trans- through house spraying programs and to prevent blood-borne T. cruzi
fusion or organ donation, and via contaminated food or drink. An transmission by establishing blood donation screening. Programs to
estimated 5–6% (range 1–10%) of infants of infected mothers are address congenital T. cruzi infection were subsequently added in
born with congenital T. cruzi infection [4]. Congenital transmission several countries.
can occur from women who were infected congenitally, perpetuating The Southern Cone Initiative, the first program to be established, has
the disease in the absence of the vector. Factors reported to increase resulted in the certification of elimination of transmission by T.
risk include higher maternal parasitemia level, less robust maternal infestans in Chile (1999), Uruguay (1997) and Brazil (2006), plus
anti-T. cruzi immune responses, HIV and, in an animal model, para- several departments/provinces of Argentina and Paraguay [10]. The
site strain. Transfusional transmission of T. cruzi was first hypothe- success of the Southern Cone Initiative inspired the subsequent estab-
sized in 1936 and the first documented occurrence was published in lishment of initiatives in Central America, the Amazon and Andean
1952. The risk of T. cruzi transmission per infected unit transfused is countries. Trypanosoma cruzi transmission by R. prolixus was certified
estimated to be 10–25% [5]. Platelet transfusions are thought to pose as interrupted throughout Guatemala in 2008.
a higher risk than those of other components, such as packed red cells.
Uninfected recipients who receive an organ from a T. cruzi-infected Serologic screening of blood components for T. cruzi is now compul-
donor may develop acute T. cruzi infection. However, transmission is sory in all but one of the endemic countries in the region, and the
not universal and varies depending on the organ transplanted and prevalence of infection in screened donors has decreased substantially
degree of immunosuppression [6]. In a series of 16 uninfected recipi- [14]. Nevertheless, Chagas disease screening coverage by country was
ents of kidneys from infected donors, only 3 (19%) acquired T. cruzi estimated to vary from 25% to 100% in 2002, and the risk of trans-
infection; cardiac transplantation is thought to pose a much higher mission through blood transfusion, though much decreased, has not
risk. Eighteen instances of transmission by organ transplantation have been eliminated. The residual risk in Latin America where screening
been documented in the literature to date (12 kidney, 1 kidney and has been implemented is estimated to be 1 : 200,000 units.
pancreas, 3 liver, 2 heart transplants) [6]. Recently, increasing atten-
Congenital Chagas disease screening programs usually rely on prena-
tion has focused on the oral route of T. cruzi transmission, with several
tal serologic screening followed by microscopic examination of
outbreaks attributed to contaminated fruit or sugar cane juice reported
concentrated cord blood from infants of seropositive mothers [4].
from Brazil and Venezuela [7, 8].
Conventional IgG serology is recommended after nine months of age
for infants with negative screening tests at birth. These programs have
GEOGRAPHIC DISTRIBUTION been challenged by suboptimal sensitivity of cord blood screening
AND DISEASE BURDEN and high loss to follow-up later in infancy.
Historically, Chagas disease primarily affected rural Latin America [2, Surveys of sentinel populations, usually children younger than five
9]. In settings with endemic vector-borne transmission, T. cruzi infec- years of age or new military recruits, are used to monitor the impact
tion is usually acquired in childhood. Because the infection is life- of control initiatives: steep declines in T. cruzi infection prevalence
long, the seroprevalence in an area with sustained vector-borne have been documented in many Latin American countries. However,
transmission rises with age and may reach high levels in adulthood, focal vector-borne transmission continues in most endemic countries
reflecting cumulative incidence. The country with the highest esti- of Latin America and the success of the Southern Cone Initiative is
mated prevalence of T. cruzi infection is Bolivia, where many endemic now challenged by re-infestation from residual vector colonies and
Am e r i c a n Tr y p a n o s o m i a s i s (C h a gas disease) 727
Intracellular amastigotes
transform into trypomastigotes,
then burst out of the cell and
enter the bloodstream
CLINICAL MANIFESTATIONS
ACUTE TRYPANOSOMA CRUZI INFECTION
Following vector-borne T. cruzi exposure, the incubation period is 1–2 FIGURE 98.3 Acute Chagas disease in a child. The eye sign of Romaña is
weeks, after which the acute phase of infection begins [2]. The acute present. This is frequently seen in acute cases and is presumed to mark the
phase lasts 8–12 weeks and is characterized by circulating trypomas- point of entry of the parasite. (From Special Programme for Reseach & Training
tigotes detectable by microscopy of fresh blood or buffy coat smears. in Tropical Diseases, World Health Organization).
Most patients are asymptomatic or have mild, nonspecific symptoms,
such as fever, lymphadenopathy and/or hepatosplenomegaly, and do pericardial effusion, and/or meningoencephalitis. Acute Chagas
not come to clinical attention during the acute phase. In some disease carries an estimated risk of mortality in the range of 1 in 200
patients, acute infection is associated with inflammation and swelling to 1 in 400 cases [2]. Orally-transmitted T. cruzi infection appears to
at the site of inoculation, known as a chagoma. Chagomas typically be associated with more severe acute morbidity and higher mortality
occur on the face or extremities, and parasites may be demonstrable than vector-borne infection. For example, 75% of 103 infected indi-
in an aspirate of the lesion. Inoculation via the conjunctiva leads to viduals in a 2007 outbreak in a Caracas school linked to contami-
the characteristic unilateral swelling of the upper and lower eyelid nated fruit juice were symptomatic, 59% had electrocardiography
known as the Romaña sign (Fig. 98.3). Severe acute disease occurs in (ECG) abnormalities, 20% were hospitalized and there was one death
less than 1% of patients; manifestations include acute myocarditis, from acute myocarditis [8].
Am e r i c a n Tr y p a n o s o m i a s i s (C h a gas disease) 729
CHAGAS CARDIOMYOPATHY
Chagas cardiomyopathy is characterized by chronic inflammation
affecting all chambers of the heart, conduction system damage and
often an apical aneurysm [22]. The first manifestations usually consist
of right bundle branch block, left anterior fascicular block and/or
segmental left ventricular wall motion abnormalities (Table 98-1) [2,
23]. Later manifestations include: complex ventricular extrasystoles
and non-sustained and sustained ventricular tachycardia; sinus node
dysfunction leading to severe bradycardia; a high degree of atrioven-
tricular block; an apical aneurysm, usually in the left ventricle; emboli
as a result of thrombus formation in the dilated left ventricle or
aneurysm; and progressive dilated cardiomyopathy with congestive
heart failure. Signs of impaired left ventricular function, New York
Heart Association functional class III or IV, cardiomegaly on chest
x-ray and/or non-sustained ventricular tachycardia on 24-hour ambu-
latory ECG monitoring indicate poor prognosis and high risk of
mortality in the short-term [24].
A
TABLE 98-1 Interpretation of Electrocardiogram (ECG)
Findings in a Patient with Chagas disease
*Criteria based on the Minnesota Code Manual of Electrocardiographic FIGURE 98.4 (A) The trypomastigote form of Trypanosoma cruzi in a Giemsa-
Findings with modifications from Maguire JH, Mott KE, Souza JA, et al. stained peripheral blood smear from a patient with acute Chagas disease.
Electrocardiographic classification and abbreviated lead system for population- (B) Several nests of T. cruzi amastigotes in a hematoxylin and eosin stained
based studies of Chagas’ disease. Bull Pan Am Health Organ 1982;16:47–58. slide of heart muscle tissue. The parasites in the nest at the bottom of the
Different criteria may be required for ECGs in children. image are in the process of transformation to trypomastigotes (Fom Division
of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention).
730 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
constipation and may give rise to fecaloma, volvulus and bowel The incubation period can be prolonged over several months to more
ischemia. than one year. A relatively severe clinical spectrum has been reported,
with manifestations that include fever, malaise, anorexia, hepato
splenomegaly, acute myocarditis and decreased cardiac function; 2 of
CONGENITAL TRYPANOSOMA the 18 reported patients presented with fulminant myocarditis and
CRUZI INFECTION congestive heart failure.
Most infected newborns are asymptomatic or have subtle findings,
but a minority presents with severe life-threatening disease [4]. The Reactivation of chronic Trypanosoma cruzi
manifestations of symptomatic congenital Chagas disease can include
low birth weight, prematurity, low Apgar scores, hepatosplenomegaly, infection in organ recipients
anemia and thrombocytopenia. Severely affected neonates may have Patients with chronic T. cruzi infection are considered candidates for
myocarditis, meningoencephalitis, gastrointestinal megasyndromes, organ transplants. Indeed, in a large cohort of heart transplant
anasarca, pneumonitis and/or respiratory distress. In published patients, survival of patients who received the transplant because of
studies from the 1990s and earlier, mortality among infected infants chronic Chagas cardiomyopathy was better than among those with
was significantly higher than in uninfected infants, ranging from <5% idiopathic or ischemic cardiomyopathy, and T. cruzi reactivation
to 20%. However, even severe congenital Chagas disease may not be was a rare cause of death [25]. The cumulative risk of reactivation
recognized, as signs are often non-specific or the diagnosis is not among patients who received a heart transplant for Chagas cardio-
considered. More recent cohort studies have shown lower rates of myopathy ranged from 29% to 50% in published cohort studies.
severe congenital Chagas disease and some investigators hypothesize Reactivation was diagnosed at times varying from 38 days to more
that disease severity has decreased as a result of better vector control than 7 years after transplantation. In addition to fever and acute
and decreasing maternal parasite exposure. Chagas myocarditis in the transplanted heart, common manifesta-
tions of reactivation disease include inflammatory panniculitis and
skin nodules [26]. Central nervous system (CNS) involvement has
TRYPANOSOMA CRUZI INFECTION IN THE been reported, but is a much less frequent manifestation of reacti-
IMMUNOCOMPROMISED HOST vation among transplant recipients than in AIDS patients. Reactiva-
Acute Trypanosoma cruzi infection in organ tion should be considered in the differential diagnosis of febrile
episodes and apparent rejection crises. When reactivation is sus-
transplantation recipients pected, serial monitoring by peripheral blood buffy coat examina-
Acute T. cruzi infection in organ recipients has several features that tion and PCR is recommended (see below “Utility of PCR for
differ from acute T. cruzi infection in immunocompetent hosts [6]. Diagnosis or Monitoring” and Box 98.1).
TABLE 98-5 Specific Antiparasitic Treatment for Trypanosoma cruzi: Dosage, Regimens and Toxicity
Nifurtimox (Lampit®) Gastrointestinal tract complaints in 30–70%. Anorexia, nausea, vomiting, and occasionally
Released in 1967 by Bayer, but suspended abdominal pain and diarrhea
the production in Argentina in 1997. Central nervous system toxicity. Irritability, insomnia, disorientation and, less often, tremors.
In 2000, production was resumed at Less common but more serious are paresthesias, polyneuropathy and peripheral neuritis.
the company’s plant in Ilopango (El The peripheral neuropathy is dose-dependent, appears late in the treatment course and
Salvador). Available in 30-mg and should prompt interruption
120-mg tablets. Additional adverse effects include skin disorders, headache, dizziness or vertigo, nervous
Standard dosage regimen: 8–10 mg/kg/day excitation, myalgias and arthralgias
p.o. in 3–4 doses for 90–120 days in Monitoring: laboratory testing (complete blood cell count and levels of hepatic enzymes,
adults; 12.5–15 mg/kg/day in 3–4 doses bilirubin, serum creatinine and blood urea nitrogen) before beginning treatment and
for 90–120 days in children aged 11–16 repeated at 4–6 weeks and at the end of treatment¶. Patients should be weighed and
years; 15–20 mg/kg/day p.o. in 3–4 doses monitored for symptoms and signs of peripheral neuropathy every 2 weeks, especially
for 90–120 days in children 1–10 years during the second and third months of treatment. Alcohol should be avoided
*Neither drug is commercialized in Western countries but can be obtained under investigational/foreign drug protocols.
†
Children have fewer adverse effects than adults and tolerate higher doses.
§
Contraindicated in pregnancy or severe hepatic or renal dysfunction.
¶
Treatment must be discontinued with the appearance of peripheral neuropathy, leucopoenia (white blood cell count <2.500 cells/µl) or severe rash not responding to
oral steroids. Mild rash may be managed initially with oral antihistamines or steroids and by decreasing the dose or stopping the anti-trypanosomal drugs temporarily. A
threefold increase in aspartate transaminase serum levels is an indication for decreasing or stopping the anti-trypanosomal drugs temporarily (reversible temporary
secondary effect).
serology remain positive for years (to decades) after successful treat- to adults with chronic T. cruzi infection in the absence of advanced
ment and experimental tests of cure have not been rigorously cardiomyopathy. In a systematic review of 696 studies and meta-
validated. In the second half of the 1990s, two double-blinded, analysis of 9 studies on the treatment of chronic Chagas disease with
randomized, placebo-controlled trials of benznidazole treatment in benznidazole compared with placebo or no treatment [47], benzni-
children with chronic T. cruzi infection demonstrated cure rates of dazole increased the probability of response to therapy 18-fold.
60–85%, as measured by conversion to negative serology four years However, up to 18% of patients discontinued treatment because
post-treatment and, in one trial, by xenodiagnoses [44, 45]. Each trial of toxicity. A multicenter, randomized, double-blinded, placebo-
used a different, experimental serologic test to assess cure. Based on controlled trial of benznidazole 5 mg/kg/day for 60 days in patients
these trials, treatment of children up to 12 years of age with chronic with mild-to-moderate Chagas cardiomyopathy is currently under
T. cruzi infection became the standard of care by the late 1990s. way (BENEFIT study). Data from this study are expected in 2012–2013
and should help clarify treatment decisions for this group of patients.
The evidence base for anti-trypanosomal treatment of adults with
longstanding chronic T. cruzi infection remains suboptimal, but, since
2000, there has been an increasing trend to offer treatment to these INDICATIONS FOR ANTI-TRYPANOSOMAL
patients. This trend is based on the growing consensus that persistence THERAPY
of parasites, coupled with an unbalanced immune response in some Recommendations for anti-trypanosomal therapy vary according to
individuals, leads to the sustained inflammatory responses that phase and form of Chagas disease and by patient age (Table 98-6).
underlie the characteristic lesions of chronic Chagas disease. In con-
trast to long-held views, this new paradigm indicates that elimination
of T. cruzi may be a prerequisite to arrest the evolution of Chagas
Treatment of acute and early
disease and avert its irreversible long-term consequences, and implies congenital infection
that Chagas disease must be treated primarily as an infectious and All acute and congenital infections should be treated. The earlier treat-
not an autoimmune condition. In a non-randomized, non-blinded ment is begun, the better the response obtained. There is currently no
trial that included 566 adults followed for a mean of 9.8 years, benz pediatric formulation of benznidazole or nifurtimox, and preparation
nidazole treatment was associated with decreased development and of the drugs for infants and young children should be performed by
progression of Chagas cardiomyopathy [46]. Based on these, and a compounding pharmacy. A dispersible tablet containing a pediatric
other data, most experts now recommend that treatment be offered dose of benznidazole is under development.
Am e r i c a n Tr y p a n o s o m i a s i s (C h a gas disease) 735
Offered
• Adults aged 19–50 years with indeterminate form or mild-moderate cardiomyopathy BII
• Women of reproductive age BIII
Optional
• Adults >50 years old without advanced cardiomyopathy CIII
Contraindicated
• Pregnancy EIII
• Severe renal or hepatic insufficiency EIII
Adapted from Bern C, Montgomery SP, Herwaldt BL, et al. Evaluation and treatment of Chagas disease in the United States: a systematic review. JAMA 2007;298: 2171–81.
Drugs and dosage regimens outlined in Table 98-5.
†
Infectious Diseases Society of America quality of evidence standards. Strength of recommendation graded A–E. A: both strong evidence for efficacy and substantial
clinical benefit support recommendation for use; should always be offered. B: moderate evidence for efficacy or strong evidence for efficacy but only limited benefit,
support recommendation for use. Should generally be offered. C: evidence for efficacy is insufficient to support a recommendation for or against use; or evidence for
efficacy might not outweigh adverse consequences or cost of treatment under consideration. Optional. D: moderate evidence for lack of efficacy or for adverse outcome
supports recommendation against use. Should generally not be offered. E: good evidence for lack of efficacy or for adverse outcome supports recommendation against
use. Should never be offered. Quality of evidence supporting the recommendation graded as I–III. I: evidence from at least one properly designed, randomized clinical
trial. II: evidence from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than one
center), or from multiple time-series studies; or dramatic results from uncontrolled experiments. III: evidence from opinions of respected authorities based on clinical
experience, descriptive studies, or reports of expert committees.
§
Follows standard dosing recommendations but may need to be prolonged to 90 days for benznidazole or 120 days for nifurtimox. Drug toxicity may be increased.
Management of accidental exposures of age with longstanding infection and no cardiac signs or symptoms
may have a low risk of developing significant disease during the rest
Management of accidental exposures remains controversial. Some of their lifetime.
experts advocate presumptive prophylaxis of all moderate-to-high
risk accidental exposures with a short course of benznidazole (7–
10 mg/kg/day for 10 days). However, the efficacy of short-course Treatment of immunocompromised patients
therapy has not been established, and presumptive treatment may
suppress parasitemia and mask indicators of inadequately treated Reactivation carries a high risk of morbidity and mortality even with
infection. Laboratory monitoring, preferably by PCR, as well as serol- adequate anti-parasitic treatment. Treatment consists of the standard
ogy, at regular intervals (e.g. weekly for four weeks, then monthly for daily dosage regimen, but the course may need to be prolonged based
four months) is therefore generally recommended, and treatment is on the clinical and parasitologic response.
usually only offered if infection is documented. In patients with pre-existing T. cruzi infection who undergo organ
transplantation, presumptive anti-trypanosomal treatment is unlikely
Treatment of chronic infection to be curative and is not recommended in the absence of evidence of
reactivation. Monitoring for T. cruzi reactivation is recommended with
Treatment is indicated for all children up to age 18 years with chronic the same schedule used for rejection monitoring, for example 1, 3, 6,
T. cruzi infection. For adults between 19 and 50 years who do not 9 and 12 months after transplantation, plus one month after steroid
have advanced cardiomyopathy, treatment should generally be treatment for rejection and when fever or other symptoms occur.
offered, bearing in mind the less certain efficacy and the higher fre- Laboratory testing should include microscopy and/or PCR of serial
quency of side effects in adults compared with children. For adults peripheral blood or buffy coat specimens, plus PCR and histologic
older than 50 years, treatment is considered optional and should examination of endomyocardial biopsy specimens collected for
reflect a careful assessment of the potential risks and benefits. Char- routine rejection monitoring.
acteristic early signs (e.g. right bundle branch block) may indicate a
higher risk of future cardiac progression and may alter the risk-benefit In HIV-T. cruzi co-infected patients, standard dosing regimens are used
equation toward treatment. On the other hand, a patient over 50 years for treatment of reactivation, but a more prolonged course (90–120
736 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
MANAGEMENT OF DIGESTIVE DISEASE 21. de Oliveira RB, Troncon LE, Dantas RO, Menghelli UG. Gastrointestinal mani-
festations of Chagas’ disease. Am J Gastroenterol 1998;93:884–9.
There are no data to suggest that anti-parasitic treatment affects pro- 22. Marin-Neto JA, Cunha-Neto E, Maciel BC, Simoes MV. Pathogenesis of
gression of gastrointestinal tract disease. Patients with megaesophagus chronic Chagas heart disease. Circulation 2007;115:1109–23.
with significant dysphagia will not be able to take oral drugs. 23. Rassi A Jr, Rassi A, Little WC. Chagas’ heart disease. Clin Cardiol
2000;23:883–9.
Treatment of megaesophagus is similar to that for idiopathic achalasia 24. Rassi A Jr, Rassi A, Rassi SG. Predictors of mortality in chronic Chagas
[21]. Sublingual nitrates and nifedipine induce lower esophageal- disease: a systematic review of observational studies. Circulation 2007;
sphincter relaxation and could be used before meals. Endoscopic 115:1101–8.
botulin toxin injection in the sphincteric region is rarely used because 25. Bocchi EA, Fiorelli A. The paradox of survival results after heart transplanta-
of its transitory efficacy. The same is true for endoscopic pneumatic tion for cardiomyopathy caused by Trypanosoma cruzi. First Guidelines Group
balloon dilatation, which is reserved for selected cases. Non-advanced for Heart Transplantation of the Brazilian Society of Cardiology. Ann Thorac
megaesophagus is best treated by laparoscopic Heller’s myotomy and Surg 2001;71:1833–8.
fundoplication, a more definitive form of treatment. In advanced 26. Riarte A, Luna C, Sabatiello R, et al. Chagas’ disease in patients with kidney
cases, different techniques of esophageal resection have been used transplants: 7 years of experience 1989–1996. Clin Infect Dis 1999;29:
with variable results. 561–7.
27. Diazgranados CA, Saavedra-Trujillo CH, Mantilla M, et al. Chagasic encepha-
The early stage of colonic dysfunction can be treated with a fiber- litis in HIV patients: common presentation of an evolving epidemiological
rich diet and abundant fluid intake, as well as laxatives and intermit- and clinical association. Lancet Infect Dis 2009;9:324–30.
tent enemas. Fecal impaction can occur as the disease progresses, 28. Sartori AM, Ibrahim KY, Nunes Westphalen EV, et al. Manifestations of Chagas
requiring manual emptying under general anesthesia. Patients with disease (American trypanosomiasis) in patients with HIV/AIDS. Ann Trop
megacolon who fail to respond to conservative measures, and those Med Parasitol 2007;101:31–50.
with frequent fecaloma or sigmoid volvulus, need to undergo surgical 29. Duffy T, Bisio M, Altcheh J, et al. Accurate real-time PCR strategy for monitor-
organ resection. ing bloodstream parasitic loads in Chagas disease patients. PLoS Negl Trop
Dis 2009;3:e419.
30. Sosa-Estani S, Gamboa-Leon MR, Del Cid-Lemus J, et al. Use of a rapid test
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by consumption of acai palm fruit, Brazil. Emerg Infect Dis 2009;15:653–5. methods for detection of Trypanosoma cruzi DNA in blood samples from
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2010;201:1308–15. Chagas disease in the United States: a systematic review. JAMA 2007;298:
9. Dias JC, Silveira AC, Schofield CJ. The impact of Chagas disease control in 2171–81.
Latin America: a review. Mem Inst Oswaldo Cruz 2002;97:603–12. 38. Pazin-Filho A, Romano MM, Almeida-Filho OC, et al. Minor segmental wall
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47. Perez-Molina JA, Perez-Ayala A, Moreno S, et al. Use of benznidazole to treat 50. Gorlin J, Rossmann S, Robertson G, et al. Evaluation of a new Trypanosoma cruzi
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crob Chemother 2009;64:1139–47. 51. Ramirez JD, Guhl F, Umezawa ES, et al. Evaluation of adult chronic Chagas’
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Leishmaniasis 99
Alan J Magill
i
3
Promastigotes transform
into amastigotes inside
macrophages d
4
Amastigotes multiply in cells
(including macrophages) of
various tissues d
Ingestion of
6 parasitized cell
5 Sandfly takes a blood meal
(ingests macrophages infected
FIGURE 99.1 Life cycle of Leishma- with amastigotes)
i = Infective Stage
niasis. (Adapted from http://dpd.cdc.
gov/dpdx/HTML/Leishmaniasis.htm) d = Diagnostic Stage
739
740 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Amastigote
Kinetoplast
with reference standards. Molecular methods to characterize nuclear followed months to years later by destructive nasopharyngeal lesions
and kinetoplast DNA from cutaneous lesions, liver and spleen, and (“espundia”). In the Old World, mucosal leishmaniasis-like syn-
bone marrow specimens and cultured isolates are available and dromes associated with Leishmania major have rarely been reported.
widely used.
Another clinically useful classification is to describe clinical syn-
dromes in terms of the parasite burden. For example, polyparasitic
CLINICAL CLASSIFICATION syndromes, such as visceral leishmaniasis and diffuse cutaneous leish-
maniasis, are characterized by very large numbers of parasites in the
A simplified clinical classification separates the leishmaniases into host. Oligoparasitic syndromes, such as mucosal and cutaneous leish-
three major syndromes: (1) visceral leishmaniasis, (2) cutaneous maniasis and leishmaniasis recidivans, have relatively fewer parasites.
leishmaniasis, and (3) mucosal leishmaniasis. (Table 99-2) Visceral This has implications for the clinician in choosing the best technique
leishmaniasis is characterized classically by fever, wasting, pancytope- for diagnosis and determining optimal treatment.
nia, hepatosplenomegaly (especially splenomegaly), and hypergam-
maglobulinemia. “Incomplete”, or atypical, syndromes, in which one
or more of these clinical features are missing, are common. Visceral
leishmaniasis is usually caused by parasites of the Leishmania donovani
TRANSMISSION AND EPIDEMIOLOGY
complex. The typical clinical presentation of cutaneous leishmaniasis The phlebotomine sandflies that transmit Leishmania parasites are
is a localized, nonhealing ulcerative skin lesion. Less common cutane- small (1.5–2.5 mm), hairy flies that are recognized by their charac-
ous leishmaniasis presentations include nodular, psoriaform and ver- teristic hopping movement and the position of their wings, which are
rucous forms. Other, less common, cutaneous syndromes include held in a nearly erect V configuration over the body (Fig. 99.3). Sand-
diffuse cutaneous leishmaniasis, post-Kala-azar dermal leishmaniasis flies are generally inactive in daylight, seeking shelter in dark, moist
(PKDL) and leishmaniasis recidivans. In the New World, mucosal places. They breed in dark, damp places rich in organic matter, for
leishmaniasis is most often associated with Leishmania (Viannia) bra- example leaf litter in tropical rain forests, rubble and loose earth, caves
ziliensis and characterized by a primary cutaneous lesion that may be and rock holes [2]. Female sandflies feed on a variety of warm- and
Le i shmaniasis 741
New World
Leishmania (Leishmania)
L. chagasi/infantum Honduras, Costa Rica
L. mexicana (“chiclero ulcer”) Central America, Mexico, Texas
L. venezuelensis Venezuela
L. amazonensis Amazon basin
Leishmania (Viannia)
L. braziliensis Brazil, Bolivia, Colombia, Ecuador, Paraguay, Peru,
Venezuela
L. guyanensis (“Pian bois”) Brazil, Colombia, French Guiana, Guyana, Surinam
L. panamensis Costa Rica, Colombia, Panama
L. peruviana (“uta”) Peru, Argentina
L. shawi, L. naiffi, L. lainsoni, L. lindenbergi South America
L. amazonensis South America
Disseminated CL L. amazonensis Brazil
Mucosal Leishmaniasis
L. (V.) braziliensis Argentina, Brazil, Bolivia, Ecuador, Paraguay, Peru
“Espundia”
L. panamensis (rare) Colombia, Costa Rica, Panama
L. guyanensis (rare) Guyana, Surinam, northern Amazon Basin
L. major, L. aethiopica (rare) Sudan
Leishmaniasis Recidivans
L. tropica Middle East, North Africa
*Typical CL refers to the classic chronic ulcerative disease. Atypical CL refers to nodular and sporotrichoid presentations and less common atypical forms, e.g., plaques,
verrucous, and psoriaform lesions.
742 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
cold-blooded hosts, including humans, cats, dogs, rodents, cattle, leishmaniasis, delayed hypersensitivity specifically to leishmanial
bats, birds, and lizards. They can acquire Leishmania with their first antigens and nonspecifically to tuberculin and other unrelated anti-
blood meal and are capable of disease transmission 7–10 days later. gens is suppressed; there is proliferation of reticuloendothelial cells
They then remain infective throughout adult life, which is usually and an exaggerated humoral immune response with the production
only a few weeks. Leishmania-infected sandflies have abnormal feeding of polyclonal, nonprotective immunoglobulins.
behavior, with increased probing while attempting to take a blood
meal. This behavior may facilitate transmission to the vertebrate host.
DIAGNOSTIC TESTING
Sandfly saliva contains maxadilan, a potent vasodilatory peptide. The
presence, and relative abundance, of maxadilan has been correlated Parasitologic diagnosis refers to the demonstration of amastigotes in
with the course of human infection. For example, sandflies of the tissues or clinical specimens, visualizing promastigotes in in vitro
Lutzomyia longipalpis complex transmit Leishmania chagasi in the New cultures or the detection of parasite genetic material. Immunologic
World. Visceral leishmaniasis caused by L. chagasi is common in Brazil diagnosis refers to the detection of an antibody or delayed-type hyper-
but rare in Costa Rica, whereas non-ulcerative cutaneous leishmania- sensitivity (DTH) response in the host to Leishmania antigens.
sis caused by L. chagasi is found in Costa Rica but not in Brazil. Costa It is important to note there is not a single diagnostic test that is
Rican sandfly saliva has a negligible content of salivary maxadilan, optimal in all clinical settings. It is always preferable to perform more
induces very little erythema but enhances cutaneous proliferation, than one parasitologic assay when possible. For example, smears,
whereas Brazilian sandfly saliva has more maxadilan, induces cultures, and PCR can be employed in the confirmation of parasites
moderate-to-marked erythema, but does not exacerbate cutaneous from a bone marrow or splenic aspirate.
infections [3]. Substances in sandfly saliva are at least partly respon-
sible for the tropism observed in Leishmania isolates.
IN VITRO CULTURE
Transmission of Leishmania is either zoonotic (mammalian reservoir, Promastigotes can be grown in a variety of media at 22–25°C. A
often canine or rodent reservoirs) or anthroponotic (human reser- biphasic medium, for example Nicolle’s modification of Novy and
voir). Zoonotic transmission can occur in completely wild (sylvatic) MacNeal’s medium (NNN) is often used [12]. Schneider’s Drosophila
or peri-domestic situations. Two important human diseases – Indian medium supplemented with fetal bovine serum is often more effec-
sub-continent visceral leishmaniasis caused by L. donovani and urban tive in primary isolation from New World cutaneous lesions. When
cutaneous leishmaniasis caused by Leishmania tropica – are character- animal or human specimens are being cultured, penicillin and strep-
ized by anthroponotic transmission [4]. The epidemiology of various tomycin should be added with the inoculum to prevent bacterial
forms of leishmaniasis is discussed in Chapters 99.2, 99.3 and 99.4 overgrowth. 5-Fluorocytosine can be used to inhibit fungal contami-
below. nation, but amphotericin B should not be added as it may inhibit
Globally, there are an estimated 1.5–2.0 million new cases and 70,000 growth of Leishmania. Promastigotes are generally found 2–7 days
deaths annually, and about 350 million are at risk of infection. Cuta- after inoculation of amastigotes into Schneider’s medium and after
neous leishmaniasis is endemic in more than 70 countries of the 7–21 days in NNN medium.
tropics and neo-tropics, with 90% of cases reported from Afghanistan,
Algeria, Brazil, Pakistan, Peru, Saudi Arabia, and Syria [5]. Cutaneous THE LEISHMANIN SKIN TEST
leishmaniasis is under-reported in most areas and active surveillance Injection of killed promastigotes (Montenegro test) or preparations
reveals a 5–10-fold higher number of actual cases. made from killed promastigotes will induce a DTH reaction in indi-
Although most parasite transmission is by the bite of infected sand viduals with prior exposure to Leishmania. In most leishmanin skin
flies, several other routes of transmission include blood transfusion test (LST) preparations currently in use, cultured promastigotes are
[6], needle-sharing in drugs users [7], congenital transmission [8], washed in 0.5% phenol saline, diluted to 1 × 106/ml, and 0.1 ml is
sexual contact [9] and laboratory accidents [10]. injected intradermally. Another method is to disrupt a promastigote
pellet via sonication or microfluidization. The resulting material is
filtered to remove particulates and the crude, soluble solution is
IMMUNOLOGY standardized by protein content. The injection site is examined 48
The protective immune response to leishmaniasis is primarily cell- hours later and induration of ≥5 mm is considered a positive test. A
mediated. High titers of antibodies detected in visceral leishmaniasis positive LST denotes present or past infection with Leishmania. The
appear to play no part in defense against the parasite. In contrast, a LST is generally positive when the lesions of cutaneous and mucosal
positive leishmanin skin test correlates with resistance to leishmania- leishmaniasis are present, but negative in active visceral leishmaniasis.
sis. It is negative during active visceral leishmaniasis, becoming posi- Although Leishmania share common antigens with mycobacteria and
tive after recovery. In addition, some patients with subclinical, trypanosomes, the LST is not positive in pulmonary tuberculosis,
self-curing visceral leishmaniasis have had positive leishmanin skin leprosy, African trypanosomiasis, or Chagas’ disease. Occasional false-
tests associated with well-developed tuberculoid granulomas demon- positive reactions have been noted in patients with glandular tuber-
strated in liver biopsies. Cell-mediated immunity (CMI) is not entirely culosis and systemic fungal infections, but rigorous studies have not
beneficial, as it also causes tissue destruction. The onset of ulceration been done.
correlates with the development of a positive leishmanin skin test in Although there are many different LST preparations in use worldwide,
cutaneous leishmaniasis. In mucosal leishmaniasis, the reaction to there are no licensed or available LSTs for use in the USA (as of 2012).
the leishmanin skin test is much larger in individuals with more Sensitivity, specificity and appropriate dose-ranging studies in differ-
severe mucosal damage. ent geographic settings with standardized products have not been
performed. It is not advisable to assume that performance character-
SPECTRUM OF CLINICAL DISEASE istics obtained in one area are applicable to another. For example, a
study in Brazil comparing LSTs made from New World antigens to
In all forms of leishmaniasis, there is a spectrum of clinical disease LSTs made from Old World antigens showed markedly different
[11]. In cutaneous leishmaniasis, the spectrum varies from a progres- results in individuals with confirmed cutaneous and visceral leishma-
sive nonhealing lesions associated with anergy (diffuse cutaneous niasis. The Old World LST, containing L. major, detected only 19% of
leishmaniasis) to the exaggerated hypersensitivity seen in mucosal prior cutaneous leishmaniasis cases, whereas the New World LST,
leishmaniasis and leishmaniasis recidivans, in which severe tissue containing a mixture of New World parasites, detected 100% of the
damage is mediated by the immune response. In visceral leishmania- prior cutaneous leishmaniasis cases [13]. In addition, a soluble
sis, many infections are subclinical and self-healing, although malnu- antigen from New World L. chagasi detected 96% of cases of prior
trition or an immunosuppressive process can reactivate latent visceral leishmaniasis, whereas an Old World LST, made from Leish-
infection. In those who develop the syndrome of visceral mania infantum, detected 71% of cases.
Le i shmaniasis 743
90% of VL in 5 countries:
Bangladesh, India, Nepal,
Sudan, & Brazil
L. infantum
L. donovani
Endemic zones
Hyperendemic zones
Increasing leishmaniasis -
HIV co-infection
Decreasing leishmaniasis -
HIV co-infection
Sporadic cases
L. infantum
Sporadic cases
Endemic zones
Hyperendemic zones
affecting older children and adults. Foxes are also reservoirs in Brazil
and jackals are probably an important source of the sporadic, mainly
rural, cases that occur in the Middle East and central Asia.
PATHOGENESIS
Following inoculation by the sandfly, promastigotes enter reticuloen-
dothelial cells and multiply. Parasites spread to local lymph nodes
and then, hematogenously within macrophages, to the liver, spleen,
and bone marrow, resulting in a spectrum of outcomes from asymp-
tomatic infection to oligosymptomatic disease with spontaneous
resolution or disseminated infection and the clinical syndrome of
visceral leishmaniasis. Patients with progressive disease develop FIGURE 99.6 Overt Kala-azar.
marked splenomegaly as a result of hyperplasia of reticuloendothe-
lial cells filled with parasites. In acute cases, the spleen is smooth and
friable, but in the more usual chronic cases it is firm. Splenic infarcts
are common. The liver is usually enlarged and contains numerous SIGNS
amastigote-laden Kupffer cells with little, or no, surrounding cellular The patient is often weak and emaciated. The abdomen is usually
reaction. In subclinical cases, non-caseating granulomas with few distended by a markedly enlarged spleen and a moderately enlarged
parasites are scattered throughout the liver. Lymph nodes may be liver (Fig. 99.6). In acute visceral leishmaniasis, the spleen may not
enlarged and contain macrophages filled with amastigotes, usually be palpably enlarged. Femoral and inguinal lymphadenopathy is
with few surrounding lymphocytes. Tonsillar lymphoid tissue may often noted, especially in African visceral leishmaniasis, and general-
also contain Leishmania. In subclinical cases or in lymphatic leishma- ized lymphadenopathy is a feature of lymphatic leishmaniasis.
niasis, there is a granulomatous and giant cell reaction closely resem- Trophic changes of the hair (thinning, dryness, hypopigmentation,
bling tuberculosis but without caseation. In the gastrointestinal tract, and loss of curl) and of the skin on the lower legs are common. Heart
there is proliferation of reticuloendothelial cells in the duodenum murmurs are often present and edema of the legs, jaundice, petechiae,
and jejunum, infiltration of the submucosa with parasitized cells and purpura may sometimes be noted. Mucosal lesions are occasion-
and, sometimes, villous atrophy with hyperplasia of crypt cells. ally seen in patients with visceral leishmaniasis in the Sudan and rarely
Small ulcerations may occur in which parasites can be demonstrated. in patients from East Africa and India. Oral lesions appear as nodules
The bone marrow usually contains numerous parasite-laden macro- or ulcers of the gum, palate, tongue, or lip. Lesions of the nasal mucosa
phages. The skin may contain Leishmania and, in fatal cases, all may cause perforation of the septum. Nasopharyngeal and laryngeal
levels beneath the epidermis are often heavily infiltrated, with masses lesions present with mucosal swelling and hoarseness. These lesions
of parasitized cells concentrated around the sweat glands and arteri- may be associated with active visceral infections or with post-Kala-azar
oles. Parasites have also been identified in heart muscle and the dermal leishmaniasis (PKDL). They respond to therapy and may be
adrenal glands. The kidneys may show an interstitial nephritis or a caused by an exaggerated, nonhealing immune response. Uncommon
mild proliferative glomerulonephritis and may contain immune presenting syndromes, which precede the development of overt vis-
complexes. Renal amyloidosis is an uncommon late complication. ceral leishmaniasis, include bacteremia, acute hepatitis and Guillain-
Barré syndrome. Only after the classic signs and symptoms of visceral
CLINICAL MANIFESTATIONS leishmaniasis develop are these unusual (or uncommonly recog-
nized) manifestations of visceral leishmaniasis associated with Leish-
mania infection. In addition, uncommon systemic manifestations
SYMPTOMS associated with overt visceral leishmaniasis include retinal hemor-
The incubation period is generally 2–6 months, although disease rhages, massive hepatic necrosis, pancytopenia without splenomegaly,
occasionally occurs many years after the patient has left an endemic cholecystitis and distal extremity paresthesias. Lymphatic leishmania-
area. The patient usually does not recall a primary skin lesion. The sis also occurs not infrequently. Both generalized and regional aden-
onset of the disease in naïve adults (migrants, soldiers, and visitors opathy with, and without, systemic symptoms may occur. Leishmania
to an endemic area) is frequently acute with high fever, chills, and infection is an uncommon, treatable cause of secondary hemat-
malaise [19]. This syndrome, initially described early in the 20th ophagocytic syndrome, especially in children [20]. This syndrome is
century in India, is often mistaken for malaria; however, early clini- oligoparasitic and parasitologic confirmation can be difficult [21].
cians commented that visceral leishmaniasis patients did not appear
as “toxic” as malaria patients. In endemic areas, the disease progres- LABORATORY ABNORMALITIES
sion is described as more gradual, with intermittent fever, progressive
enlargement of the spleen and liver, and vague abdominal discom- Hematologic
fort. The initial acute illness may not be recognized. Other common Hemoglobin concentrations of 5–9 g/dl, white blood cell (WBC)
symptoms include weight loss, epistaxis, diarrhea, and nonproductive counts of 2000–4000/mm3 and platelet counts of 50,000–200,000/
cough. mm3 are typical, although much lower counts are sometimes seen in
746 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
advanced disease [22]. The anemia is multifactorial. Erthrocyte sur- INFECTIONS IN IMMUNOCOMPROMISED
vival time is shortened owing to hypersplenism and possibly to
autoimmune mechanisms. Bone marrow depression is indicated by
HOSTS
a reticulocytosis lower than expected for the degree of anemia. Coex- Prior to the routine use of modern anti-retroviral therapy for HIV
istent iron deficiency may be present. The Coombs test is usually infection, Leishmania was a significant opportunistic infection in
positive, with both C3 and lgG present on red blood cells, but does patients with AIDS. Co-infection with Leishmania and HIV is a recog-
not correlate with the severity of the anemia. The neutrophil survival nized problem in the Southern Mediterranean and has been reported
time is shortened and the WBC differential demonstrates neutrope- in 20 other countries [27]. As the incidence of HIV infection increases
nia, relative lymphocytosis, and an almost complete absence of eosi- in India, Brazil, and East Africa, the numbers of people at risk of
nophils. Agranulocytosis is rare. co-infection will also increase dramatically.
Clinical signs and symptoms of visceral leishmaniasis usually occur
Other as a late-stage manifestation in patients with AIDS. CD4 T lymphocyte
Liver transaminases (alanine transaminase [ALT] more than aspartate counts, when reported, are usually less than 50 mm3 and are almost
transaminase [AST]) are mildly elevated in the majority of patients, always less than 200 mm3. In general, patients with overt disease
but elevations of serum bilirubin are uncommon. The prothrombin associated with visceral leishmaniasis have very high parasite burdens
time is usually 2–4 seconds longer than that in controls, and serum but seem to tolerate the parasite co-infection reasonably well. Many
albumin is generally less than 3 g/dl. A polyclonal hypergammaglob- clinicians believe that Leishmania does not cause severe symptoms in
ulinemia of 5–10 g/dl, most of which is lgG, is usual. In some reports, these patients but rather is just one more of the many opportunistic
albuminuria is common, but in others the urinalysis is normal, as are infections that plague patients with severely depressed CD4 counts.
tests of renal function. Numerous viscerotropic, dermotropic and novel L. infantum zymo-
demes have been isolated from co-infected patients in Europe.
SEROLOGIC TESTS
High-titer anti-leishmanial antibodies are present in visceral leishma-
niasis and can be detected by ELISA, immunofluorescence, and direct
agglutination. Sensitivity and specificity vary based on the antigens
FIGURE 99.7 Nodular lesions of post-Kala-azar dermal leishmaniasis in a used in the assay and the infecting parasites. Whole promastigotes,
Kenyan woman. crude promastigote lysates and recombinant antigens are in use. In
general, current serologic tests for visceral leishmaniasis have sensitivi-
ties >90% but with lower specificities. False-positive results, especially
with PKDL are serologically and biochemically identical to L. donovani with lower titers, can be seen in malaria, trypanosomiasis, tuber
isolated from patients with visceral leishmaniasis. Because the lesions culosis, enteric fever, and schistosomiasis. In addition, antibodies
of PKDL may persist for up to 20 years, such patients may act as a may persist for many months following treatment for visceral
chronic reservoir of infection. leishmaniasis.
The ELISA test using whole, soluble promastigote or recombinant
DIAGNOSIS antigens appears as sensitive and specific as the indirect fluorescent
antibody test (IFA) and, because of economy and technical practical-
ity, it is especially useful for large-scale epidemiologic studies. Both
CLINICAL DIAGNOSIS the IFA and ELISA can be performed on sera eluted from filter papers
A clinical diagnosis of visceral leishmaniasis can be made with varying impregnated with 50 µl of capillary blood.
degrees of certainty depending on the local epidemiologic factors and
clinical presentation The positive predictive value of a clinical diag- The IFA is positive in more than 95% of patients with visceral leish-
nosis of late-stage visceral leishmaniasis, with classic signs and symp- maniasis, generally with titers above 1:256. Whole, culture-derived
toms, in an endemic area is likely to be very high. Although a promastigotes are fixed in wells of a special glass slide. Serum at dif-
confirmatory parasitologic diagnosis is preferable prior to starting ferent dilutions is applied to the wells. Antibodies in the serum that
treatment, in settings where safely performing an invasive procedure bind to surface antigens on the promastigotes are then detected by an
is difficult, a presumptive diagnosis can be made when clinical antibody to the Ig molecule conjugated to a fluorescent marker. A
improvement in response to appropriate therapy is seen within a microscopist reports a titer (the reciprocal of the dilution) that cor-
week or so. A clinical diagnosis early in the course of infection when responds to a certain percentage of parasites that fluoresce. IFA testing
the classic features of disease are not yet established is much less is somewhat subjective and requires rigorous technique and relatively
certain. expensive equipment.
The direct agglutination test (DAT) is based on direct agglutination of
DEMONSTRATION OF PARASITES L. donovani promastigotes that react specifically with anti-leishmania
antibodies in the serum specimen resulting in agglutination of the
Specimens can be obtained from the bone marrow, liver, spleen, or
promastigotes. Serial, twofold dilutions (starting 1:100) from the
enlarged lymph nodes. Splenic aspiration has the highest sensitivity.
serum samples, are made in a V-shaped microtiter plate. The antigen
In experienced hands, the procedure is safe and well tolerated;
is added and the plates are read the next day. Agglutination is visible
however, deaths have occurred after splenic aspiration, presumably
as a blue/purple mat in the wells of the microtiter plate. The freeze-
owing to splenic laceration – careful observation after the procedure
dried antigen is available from the Royal Tropical Institute (KIT)
is mandatory [34, 35]. Contraindications to splenic aspiration are a
Biomedical Research in Amsterdam, The Netherlands (http://
soft spleen in acute disease, a prothrombin time ≥5 seconds com-
www.kit.nl/-/INS/52859/Royal-Tropical-Institute) and can be stored
pared with the normal control, or a platelet count below 40,000/
at ambient temperature for at least 2 years. After reconstitution of the
mm3. The procedure uses a 21-gauge needle attached to a 5-ml syringe,
antigen in saline and storage at 4°C, the antigen can be used at least
which is inserted just under the skin over the middle of the spleen or
for a week. DAT test sensitivity and specificity estimates were 94.8%
via an intercostal approach if the spleen is minimally enlarged. As
(95% confidence interval 92.7–96.4%) and 85.9% (72.3–93.4%),
suction is applied, the needle is rapidly inserted into the spleen and
respectively, in a meta-analysis [38].
withdrawn, with the needle remaining in the spleen only a fraction
of a second. The small amount of splenic tissue and blood in the The recombinant protein rK39 is used as the capture antigen in ELISA
needle is expressed into culture medium and onto slides for thin tests and in point-of-care, dipstick-type, rapid diagnostic tests to detect
smears. Splenic smears stained with Giemsa or Leishman’s stain antibodies in the serum of patients with visceral leishmaniasis. In the
748 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
same meta-analysis, the rK39 test sensitivity and specificity were very (Glucantime®, Sanofi-Aventis, Suzano, Brazil) commonly used in
similar to the DAT at 93.9% (87.7–97.1%) and 90.6% (66.8–97.9%) Latin America and French-speaking parts of Africa and Europe. There
respectively [38]. Sensitivity is higher and more homogeneous in the are numerous local and regional manufacturers around the world of
studies carried out in South Asia and the specificity varies depending SSG and other SbV formulations. It is not known how these different
on the choice of controls. Quantitative titers to rK39 determined by preparations compare with each other in terms of safety and efficacy,
ELISA also decrease following successful chemotherapy and tend to as no comparative trials have ever been performed. However, it is
rise in cases of relapse, making it useful for the recognition of treat- unwise to assume one preparation will perform the same as another
ment failures. In the rapid assays, the rK39 antigen is striped onto or have the same safety and tolerability profile. Deaths have been
nitrocellulose paper and a drop of whole blood is placed onto a associated with the use of generic SbV and every batch of generic SSG
sample pad with immunolabeled gold. Human lgG binds to the should be subject to rigorous quality control prior to use [39].
labeled gold and migrates up the strip. If antibodies to rK39 are
present in the serum, they bind to the rK389 antigen stripe giving a SbV can be administered intravenously or intramuscularly. There is
visual positive test result. A Food and Drug Administration (FDA)- variation in the total antimony (Sb) content, the proportion of SbV
cleared rK39 assay is commercially available (Kalazar Detect™, Inbios to trivalent Sb (trivalent Sb is much more toxic than SbV), and the
International Inc., Seattle, WA, USA; http://www.inbios.com/rapid- physical and chemical characteristics of different lots of SbV from the
tests/kalazar-detect). The rK39 test is not useful in screening asymp- same manufacturer and between preparations from different manu-
tomatic individuals for infection but should be used in individuals facturers. Many investigators believe these lot variations are responsi-
with a compatible clinical syndrome. ble for the different safety and efficacy profiles observed in treated
patients. Several cardiac deaths in India were associated with use of a
SbV preparation with high osmolarity [40]. In addition, SbV dissoci-
LEISHMANIN SKIN TEST (LST) ates or polymerizes over time, so storage conditions and shelf-life are
The Leishmanin skin test (LST) test is almost uniformly negative in important considerations. Storage at 4°C in the dark is optimal.
active visceral leishmaniasis but becomes positive in 90% of patients In the USA, Pentostam® is available from the Centers for Disease
6 weeks to 1 year after recovery. Tuberculin sensitivity is usually simi- Control and Prevention (CDC) under an investigational new drug
larly depressed during active Kala-azar, indicating a broad defect in (IND) application. The recommended treatment regimen for visceral
cell-mediated immunity (CMI). leishmaniasis is 20 mg of SbV/kg/day given intravenously for 28 days.
Undiluted intravenous injections are not recommended. The daily
DIFFERENTIAL DIAGNOSIS dose can be given as 1:10 dilution with 5% D/W to reduce the inci-
The differential diagnosis of late-stage visceral leishmaniasis is limited. dence of local thrombosis through a steel butterfly needle placed and
Hematologic and lymphatic malignancies, disseminated histoplas- removed daily. In endemic areas, the intramuscular route of admin-
mosis and hepatosplenic schistomiasis have rarely been reported to istration is more common although the large-volume injections are
mimic late-stage visceral leishmaniasis. Early disease has a much moderately painful.
broader differential that includes malaria, African trypanosomiasis, SbV drugs are safe, although with a poorly tolerated side effect profile.
brucellosis, enteric fevers, bacterial endocarditis, generalized histo- Nausea, anorexia, abdominal pain, malaise, headache, arthralgias,
plasmosis, chronic myelocytic leukemia, Hodgkin disease and other myalgias, and lethargy are frequent, beginning about 7–10 days into
lymphomas, sarcoidosis, hepatic cirrhosis, and tuberculosis. Tropical therapy [41]. These side effects are more noticeable in cutaneous
splenomegaly syndrome is especially difficult to differentiate, leishmaniasis and mucosal leishmaniasis patients, as they do not have
although high titers of antimalarial antibodies and a characteristic systemic symptoms associated with their disease. In general, visceral
histologic appearance of the liver suggest this disease. Patients with leishmaniasis patients seem to tolerate SbV better than cutaneous
multiple myeloma and Waldenström’s macroglobulinemia have leishmaniasis or mucosal leishmaniasis patients. In particular, large
monoclonal hypergammaglobulinemia. joint arthralgias can be quite problematic. Fortunately, these symp-
toms resolve shortly after therapy is complete.
TREATMENT Shortly after beginning therapy, patients treated with SbV prepara-
tions develop elevations in serum amylase and serum lipase, lipase
NONSPECIFIC OR SUPPORTIVE CARE greater than amylase, which peak at 7–14 days [42]. Although most
are asymptomatic, many develop some degree of anorexia, nausea
Patients should receive a nutritious diet, as patients are often mal- and mid-epigastric pain consistent with pancreatitis. Lipase and
nourished. Antimicrobial agents are given when concurrent pneumo- amylase levels return to normal despite continuing the drug.
nia, tuberculosis or other bacterial infections are suspected. Patients
with chronic disease generally tolerate anemia well, but blood trans- Deaths attributed to pancreatic necrosis have been reported in patients
fusion may be needed if associated with respiratory distress or the receiving SbV; therefore, monitoring of serum amylase and lipase in
hemoglobin level falls below 6 g/dl. Coexistent iron or vitamin defi- patients is recommended. When patients develop symptoms or signs
ciency my also require specific treatment. of pancreatitis, it is recommended that SSG be temporarily halted
for a few days. Serum amylase and lipase rapidly return to normal
and the regimen can then usually be completed without another
SPECIFIC ANTI-LEISHMANIAL THERAPY interruption. Even in asymptomatic patients, it is reasonable to tem-
Pentavalent antimony compounds (SbV) have historically been the porarily interrupt therapy for significant elevations of serum amylase
drugs of choice for the treatment of visceral leishmaniasis worldwide or lipase.
since their introduction in the mid-1930s. However, reports of
primary treatment failures with SbV in India became more prevalent Anemia, neutropenia, and thrombocytopenia associated with hypo-
in the mid-1990s leading to trials of amphotericin B compounds as plasia of the bone marrow have all been seen during SbV therapy and
initial therapy for both Mediterranean and Indian visceral leishma- are occasionally severe enough to interrupt therapy. Abnormalities
niasis. Currently, many favor the use of liposomal amphotericin B as reverse on discontinuation of the drug. Again, baseline values prior
first-line therapy for visceral leishmaniasis. SbV remains efficacious to treatment and monitoring during therapy are recommended if
when given at appropriate doses in East Africa and the Americas. feasible. Transient increases in serum transaminases are also seen in
the majority of patients during treatment. AST levels rise three- to
fourfold above the upper limit of normal between days 7 and 14 but
PENTAVALENT ANTIMONIALS (SbV) decline despite continued therapy. Renal tubular acidosis and acute
There are two widely available commercial SbV formulations: sodium renal failure associated with SbV have been reported. SSG causes
stibogluconate (SSG; Pentostam®, GlaxoSmithKline, UK) largely lymphopenia that has been associated with occasional cases of herpes
used in English-speaking countries and meglumine antimoniate zoster occurring during the course of treatment.
Le i shmaniasis 749
MILTEFOSINE
AMPHOTERICIN B Miltefosine was originally developed as an oral anticancer drug but
Amphotricin B deoxycholate was successfully introduced to treat cases was later shown to have anti-leishmanial activity. Miltefosine com-
of visceral leishmaniasis that failed to respond to SbV in the 1990s, monly induces gastrointestinal side-effects such as anorexia, nausea,
especially in India. The regimen is 1 mg/kg administered by slow vomiting (38%), and diarrhea (20%). Most episodes are brief and
intravenous infusion over 4–6 hours every 2 days, until a total dose resolve as treatment is continued. Occasionally, the side effects can be
of about 20 mg/kg has been given. Although some initiate treatment severe and require interruption of treatment. Skin allergy, elevated
with an incremental escalation of doses in an attempt to decrease the hepatic transaminase concentrations and, rarely, renal insufficiency
infusion-related side effects of amphotericin B, a clinical trial of 120 may be observed. Miltefosine should be taken after meals and, if
Indian patients with visceral leishmaniasis showed no difference in multiple doses are to be taken, they should be divided. Miltefosine is
infusion-related side effects between those receiving the incremental potentially teratogenic and should not be used by pregnant women
dose and those receiving 1 mg/kg from day 1 [45]. The widespread or women with child-bearing potential for whom adequate contra-
use of amphotericin B deoxycholate has been hindered because of the ception cannot be assured for the duration of treatment and for 3
well-known infusion-related side effects of fever, chills and throm- months afterwards. Miltfosine is given at a dose of 2.5 mg/kg per day
bophlebitis, long-term problems of renal insufficiency, anemia and for 28 days to children aged 2–11 years and for people aged 12 years
hypokalemia, and poor tolerability (anorexia, nausea). Also, ampho- and above at a dose of 50 mg/day for those weighing <25 kg, 100 mg/
tericin B deoxycholate should be used with caution in those previ- day for 25–50 kg body weight and 150 mg/day for >50 kg body
ously receiving SbV. Sudden cardiac death has been reported following weight for 28 days, has shown a 95% cure rate in immunocompetent
the first dose of amphotericin B deoxycholate in these patients. It is patients in India [54, 55] and about 90% in Ethiopia [56].
thought that the ECG abnormalities associated with SbV therapy
predispose to cardiac events [46]. It seems prudent to recommend
that a baseline ECG be obtained and a rest period be observed until COMBINATION TREATMENT
the ECG normalizes, usually within 10 days of the end of SbV therapy, The use of long-duration monotherapy in unsupervised settings is
and any electrolyte abnormalities be corrected before starting ampho- concerning for the risk of developing resistance to established or
tericin B deoxycholate. newly introduced drugs, especially in anthroponotic foci. The current
The desire to develop less toxic and more effective preparations of World Health Organization (WHO) policy is to limit the use of
amphotericin B to treat systemic mycoses led to the introduction of monotherapy to liposomal LAMB [57].
lipid-associated amphotericin B preparations in the mid-1990s. Lipo- Combination treatment has the potential advantages of shortening
somal amphotericin B (LAMB) (AmBisome®, Astellas Pharma US, the duration of treatment, reducing the overall dose of medicines and
Inc., USA) was approved in 1997 by the FDA for the treatment of reducing the probability of selection of drug-resistant parasites which
visceral leishmaniasis [47, 48]. will improve compliance, reduce drug toxicities, lower costs and
LAMB has been shown in a series of trials to be a very effective and prolong the effective life of the available medicines.
safe drug for the treatment of visceral leishmaniasis acquired in Brazil, Several trials of combinations have been conducted, with favorable
India, Kenya, and the Mediterranean [16, 49–51]. The current FDA- results. A combination of paromomycin and antimonials resulted in
approved regimen for immunocompetent patients, based on data a higher cure rate in visceral leishmaniasis patients in Bihar, India
from the Mediterranean and Brazil, is 3 mg/kg daily on days 1–5, a than antimonials alone, to which lack of response was common. In
sixth dose on day 14 and a seventh dose on day 21 (total dose with East Africa, the combination of sodium stibogluconate at 20 mg/kg
this regimen is 21 mg/kg). Overall success rate with this dose regimen SbV + plus paromomycin given at 15 mg/kg (11-mg base) for 17 days
is practically 100%. Lower-dose regimens have been effective in trials showed an efficacy of 93%. The safety and efficacy of the combination
from Brazil, India, and Kenya. A dose of 3–4 mg/kg daily on days 1–5 treatment and sodium stibogluconate alone were similar. Further-
with a sixth dose on day 10 is probably adequate for visceral leish- more, there were no differences in the efficacy of the combination
maniasis acquired in the Mediterranean and Brazil, and a dose of treatment in Ethiopia, Kenya, and the Sudan, suggesting that this
2–3 mg/kg daily on days 1–5 and a sixth dose on day 10 for visceral regimen could be used across the region. In several phase 3 studies
leishmaniasis acquired in East Africa and India. Culminating a series in India, three separate combinations showed 98–99% cure rates. The
of investigations spanning a decade, Indian investigators have shown treatment included two sequential administrations, with either lipo-
that a single 10 mg/kg dose of LAMB was >95% efficacious [51]. somal amphotericin B (5 mg/kg, single infusion) plus 7 days’ milte-
Lower-dose regimens may have a somewhat lower efficacy than the fosine (dosage as above) or liposomal amphotericin B (5 mg/kg,
near 100% reported with the higher-dose regimen, but the cost single infusion) plus 10 days’ paromomycin (11-mg/kg base), and
savings and decreased potential for infusion-related side effects may co-adminstration of 10 days’ miltefosine plus 10 days’ paromomycin
make a lower-dose regimen optimal for some geographic regions. The (dose as above). No safety issues were recorded.
current FDA-approved regimen for immunosuppressed patients is a
higher-dose regimen of 4 mg/kg daily on days 1–5, 10, 17, 24, 31 and
38 (total dose of 40 mg/kg). Even with the higher total dose, relapse
is common in immunocompromised patients. For the rare cases of
TREATMENT OF RELAPSES
visceral leishmaniasis treated in the non-endemic areas, LAMB is the Relapse usually occurs within 6 months of the end of treatment, often
recommended drug and should be used unless contraindicated. within a few months. Persistent splenomegaly and thrombocytopenia
750 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
are useful prognostic indicators. Co-infection with tuberculosis and miltefosine should not be used in pregnancy [57, 61]. Miltefosine is
HIV should be considered in those who fail to respond or relapse. potentially embryotoxic and teratogenic and should not be used
Successful treatment of coexisting tuberculosis usually results in during pregnancy. Women of child-bearing age should be tested for
response of the visceral leishmaniasis. Patients who fail to respond or pregnancy before treatment and use effective contraception for 3
relapse after initial therapy should be treated with a different drug months after treatment.
regimen. For example, if a visceral leishmaniasis patient fails to
respond to liposomal amphotericin B, then a trial of SbV could begin. Amphotericin B deoxycholate and LAMB are the best therapeutic
Additional doses, or higher doses, of the same regimen could be tried, options for visceral leishmaniasis. No abortions or vertical transmis-
but only under close supervision. sion have been reported in mothers treated with liposomal ampho-
tericin B [61, 62].
SPLENECTOMY
Splenectomy is rarely indicated in patients with visceral leishma PROGNOSIS
niasis. The more common dilemma is inadvertent splenectomy Infection with L. donovani comprises a spectrum of diseases, and
because of failure to consider the diagnosis of visceral leishmaniasis spontaneous cure of inapparent infection is more common than was
[58]. Patients with a protracted clinical course and frequent relapses formerly realized. In contrast, the established syndrome of visceral
who are resistant to treatment and develop severe cytopenias with leishmaniasis is almost always fatal in the absence of specific
massive splenomegaly may require splenectomy. The use of elective chemotherapy.
splenectomy is effective for restoring the hematologic parameters
and reduces the need for blood transfusions, but it does not avoid Response to treatment should be monitored by daily assessment of
relapsing visceral leishmaniasis. There is usually a prompt rise in sense of wellbeing, appetite, temperature and weekly assessment of
hemoglobin levels and WBC and platelet counts after splenectomy, hemoglobin, platelet and neutrophil counts, body weight and spleen
but additional chemotherapy is necessary, or cure is unlikely [59]. size. Repeat splenic or bone marrow aspirates to document parasito-
Splenectomized patients are at increased risk of overwhelming logic improvement are not routinely indicated in the face of clinical
sepsis because of penumococci and other encapsulated bacteria and improvement. In most patients, the fever disappears within days,
should receive anti-pneumococcal vaccination before splenectomy. appetite returns and the patient feels better. The hemoglobin level
Because malaria is often fatal in splenectomized individuals, life- rises and the spleen becomes smaller within 2 weeks, although return
long anti-malarial prophylaxis is essential in countries where to baseline size may not occur until months after therapy. When fever
malaria occurs. persists and the general condition does not improve during treatment,
concomitant tuberculosis or HIV infection should be suspected.
Within 6–12 months, the spleen usually becomes non-palpable, and
POST-KALA-AZAR DERMAL elevated immunoglobulin levels and serologic tests become normal.
LEISHMANIASIS (PKDL) Persistent splenomegaly after otherwise successful treatment may be
Treatment of PKDL depends on the severity of the condition in caused by portal hypertension.
individual patients. In Bangladesh, India, and Nepal either an Follow-up examination is important for the early detection and treat-
extended regimen of amphotericin B deoxycholate at 1 mg/kg per ment of relapses. Relapse is suggested by an increase in spleen size, a
day by infusion (20 days on, 20 days off), up to 60–80 doses over 4 fall in hemoglobin levels, and a decrease in eosinophil counts to fewer
months or miltefosine orally at 50 mg three times daily for 60 days than 50/mm3 and should be confirmed by the demonstration of
or twice daily for 90 days for 12 weeks is recommended. Disappear- parasites. Relapses are most common during the first 2–6 months
ance of the lesion is considered clinical cure. In East Africa, PKDL is after finishing treatment but, occasionally, they occur several years
not routinely treated, as the majority of cases (85%) heal spontane- later, particularly in patients who become immunocompromised by
ously within a year. Only patients with severe or disfiguring disease, disease or medication.
those with lesions that have remained for longer than 6 months,
those with concomitant anterior uveitis and young children with
oral lesions that interfere with feeding are treated. Treatment with PREVENTION AND CONTROL
either SSG at 20 mg/kg SbV+ per day for up to 2 months or a 20-day
course of liposomal amphotericin B at 2.5 mg/kg per day is recom-
mended. Clinical cure is defined as flattening of lesions and improve-
TREATMENT OF CASES
ment of dyschromia, although pigmentary changes may persist In epidemics of visceral leishmaniasis in which humans are the res-
indefinitely. ervoir (India and, perhaps, parts of East Africa), aggressive case-
management may help interrupt the epidemic.
HIV CO-INFECTION
Response to initial treatment with pentavalent antimony is only 50%,
POST-KALA-AZAR DERMAL
whereas response to liposomal amphotericin B is near 100%. LEISHMANIASIS (PKDL)
However, relapse is common after both drugs. The optimal induction Patients with PKDL can actively transmit Leishmania parasites and
therapeutic regimen, including choice of drug, dose and duration for may represent a persistent human reservoir responsible for ongoing
different infecting parasites is not known. Optimal intermittent main- transmission as these patients seldom receive treatment [63].
tenance regimens are likewise unknown. Currently, immune system
reconstitution through highly active anti-retrovial therapy (HAART)
is the optimal therapy, where feasible. It is reasonable to recommend
RESERVOIR CONTROL
an initial course of induction therapy using LAMB to decrease the Zoonotic visceral leishmaniasis (ZVL) caused by Leishmania infantum
parasite burden closely followed by HAART to raise the CD4 cell is an important disease of humans and dogs. Transmission among
count. dogs can be maintained by non-sandfly routes, such as congenital and
sexual transmission, as well as between dogs by sandfly transmission.
Dogs are the only confirmed primary reservoir of infection. Review of
PREGNANCY intervention studies examining the effectiveness of current control
Treatment of pregnant women is always a risk–benefit assessment. methods highlights the lack of randomized controlled trials of both
The possibility of a fatal outcome of leishmaniasis for the mother, the dog culling and residual insecticide spraying. Topical insecticides
fetus and the newborn is much greater than the risk for adverse drug (deltamethrin-impregnated collars and pour-ons) have been shown
effects. When untreated, spontaneous abortion, small-for-birth date to provide a high level of individual protection to treated dogs, but
and congenital leishmaniasis have been described [60]. SbV and further community-level studies are needed [64].
Le i shmaniasis 751
L. infantum
L. major
L. donovani
L. tropica
L. aethiopica
L. archibaldi
Increasing leishmaniasis - HIV
co-infection
Decreasing leishmaniasis - HIV
co-infection
Isolated lymphadenopathy
reported
Mucous forms reported
Diffuse cutaneous forms
reported
Post-kala-azar forms reported
LEISHMANIA AETHIOPICA
Leishmania aethiopica is a zoonotic parasite found in stable, low ende-
micity foci in mountain valleys of the Rift Valley of Ethiopia and
Kenya. The mammalian reservoir is the rock hyrax (Procavia habessi-
nica) and the tree hyrax (Heterohyrax brucei), with the high-altitude
sandfly vectors Phlebotomus longipes (Ethiopia) and Phlebotomus pedifer
(Kenya). Human cases are closely associated with proximity to hyrax
colonies and often occur when homesteads encroach on the zoonotic FIGURE 99.9 Cutaneous leishmania caused by Leishmania major.
cycle on deforested mountain slopes [68].
LEISHMANIA INFANTUM
Leishmania infantum, the usual cause of Mediterranean visceral leish-
maniasis, has been isolated from indurated, nodular cutaneous
lesions, as well as in countries throughout the Mediterranan littoral,
Iran, the Caucasus, and foci in the New World [69]. Isoenzyme analy-
sis shows that “dermotropic” L. infantum strains are more commonly
found in cutaneous lesions and have also been isolated from visceral
sites in AIDS patients.
PATHOGENESIS
The development of clinical disease following infection depends on
the parasite strain and inoculum, the genetically determined host
innate and acquired immune responses, prior exposures and sandfly
factors to include components of the saliva [66]. The host inflamma-
tory responses mediate disease expression resulting in asymptomatic
infection to predominantly self-healing ulcerative cutaneous leish
maniasis or chronic, nonhealing diffuse cutaneous leishmaniasis, FIGURE 99.10 Leishmania tropica.
mucosal leishmaniasis or leishmaniasis recidivans. In general, disease
resolution is mediated by cell-mediated immune responses (CMI). In
self-healing cutaneous leishmaniasis, delayed-type hypersensitivity is Different forms of cutaneous leishmaniasis vary in some of their clini-
usually present and tends to correlate to ulcer size and number, as cal features. The lesions of rural disease caused by L. major tend to be
determined by skin test reactivity [70]. In leishmaniasis recidivans, larger, multiple and can be accompanied by marked inflammation
there is healing in the center of the lesion but failure to heal peripher- and crusting. They mature rapidly and heal relatively quickly, lasting
ally, where a granulomatous reaction without caseation is seen. a few months. The lesions of urban disease caused by L. tropica tend
Parasites are scanty and the histologic changes are similar to those to be smaller, single, develop more slowly and persist for a year or
of lupus vulgaris. In diffuse cutaneous leishmaniasis, there is a defect more (Fig. 99.10).
in the CMI response and numerous macrophages filled with amastig-
otes are seen with no cellular reaction or only a few surrounding Cutaneous leishmaniasis lesions caused by L. aethiopica are the least
lymphocytes. inflamed and most chronic; however, most lesions usually eventually
heal spontaneously within 2–5 years. Leishmania aethiopica gives rise
principally to localized cutaneous nodular lesions; less frequently, it
CLINICAL MANIFESTATIONS gives rise to oronasal leishmaniasis, which may distort the nostrils
and lips, and a small percentage of infected individuals develop non-
The incubation period of cutaneous leishmaniasis is generally 2–8 healing diffuse cutaneous leishmaniasis. Most lesions evolve slowly
weeks but, in exceptional cases, the incubation period may be as long and may spread locally. Ulceration is late or absent.
as 3 years. The first sign of cutaneous leishmaniasis is often an unno-
ticed area of erythema at the site of the sandfly bite that slowly The clinical appearance of the lesions reflects the degree of the host’s
becomes an inflammatory papule. It may persist as a flattened plaque immune response and may vary from small papules to non-ulcerated
or may progress to a nodule after a few days or weeks, with the surface plaques to large ulcers with well-defined, raised, indurated margins.
becoming covered with fine, papery scales (Fig. 99.9), which are white When multiple lesions are present, they are usually similar in appear-
and dry at first, but later become moist and adherent, uncovering a ance and enlarge and heal together. After a few months to more than
shallow ulcer as they fall off. As the ulcer enlarges, it oozes serous a year, healing begins with central granulation tissue that spreads
fluid and may become covered with a thick crust. A raised, indurated peripherally. The resultant depressed white or pink scar is often cos-
area with a characteristic dusky discoloration surrounds the edge of metically disfiguring, especially when on the face. Leishmania major
the ulcer. Satellite lesions are common and may ultimately merge infections may be associated with severe scarring, which can cause
with the parent lesion. Over many weeks to months the typical fea- disability if located at critical sites, for example the wrist or elbow,
tures of ulcerative cutaneous leishmaniasis emerge [71]. and substantial stigma for affected individuals.
Le i shmaniasis 753
SEROLOGIC TESTS topicals appears quite promising, the best formulation and optimal
dose regimen are not yet determined. It is likely that the optimal dose
Low titers of anti-leishmanial antibodies are detected in many patients regimens will have to be determined for each major geographic area.
with cutaneous leishmaniasis, but these tests are generally of little
diagnostic help. Intralesional SbV, defined as local infiltration of 0.3–0.8 mL of SbV,
has been used extensively for Old World cutaneous leishmaniasis
with some success and merits consideration, especially for early, non-
DIFFERENTIAL DIAGNOSIS ulcerated lesions. Each lesion is injected individually, dividing the
On clinical grounds, the lesions of cutaneous leishmaniasis must be dose into four quadrants if possible. The reported number of injec-
distinguished from diphtheritic or veldt sores, tropical ulcer, tertiary tions and the daily dose used vary widely, but efficacy is similar to
syphilis, yaws, lupus vulgaris, blastomycosis, basal cell carcinoma, intramuscular administration. Intralesional SbV can be very painful
squamous cell carcinoma and other causes of chronic nodules and depending on the location injected but avoids systemic toxicity and
ulcers. Although the LST is sometimes helpful, definitive diagnosis reduces costs.
depends on demonstration or isolation of the organism.
Combinations of intralesional SbV co-administered with cryotherapy
have been shown to be superior to either one alone [78].
TREATMENT
SYSTEMIC CHEMOTHERAPY
TYPICAL OLD WORLD CUTANEOUS Systemic treatment is indicated for large, or multiple, lesions and to
LEISHMANIASIS patients with lesions in functionally or cosmetically important areas,
The majority of Old World cutaneous leishmaniasis lesions, especially for example the wrist, feet, and ankles, or face when local treatments
rural zoonotic cutaneous leishmaniasis caused by L. major, are self- are not indicated. SbV can be given intramuscularly or intravenously
healing, requiring a few months to heal completely. Urban anthro- at 20 mg Sb/kg/day for 10–20 days. Cutaneous leishmaniasis caused
ponotic cutaneous leishmaniasis caused by L. tropica can take many by L. tropica and L. aethiopica usually requires a longer treatment dura-
months or a few years to heal. In general, systemic treatment is less tion, while cutaneous leishmaniasis caused by L. major may be ade-
commonly employed in Old World disease compared with New quately treated with the shorter 10-day regimen. The true efficacy
World disease. There is a paucity of evidence-based data from high- of SbV in Old World cutaneous leishmaniasis in most locations
quality clinical trials in Old World cutaneous leishmaniasis [74]. has never been established and is thought by many to be minimally
effective [57].
LOCAL THERAPY Oral fluconazole at 200 mg daily for 6 weeks was shown to shorten
Local treatments include thermotherapy, cryotherapy, topical paro- the time to healing in L. major infections in Saudi Arabia compared
momycin ointments, intralesional administration of SbV and combi- with placebo [79]. A more recent randomized controlled trial in
nations of all of the above. patients with L. major in Iran showed that a higher fluconazole dose
of 400 mg was superior to the 200 mg dose in shortening the time
Local heat therapy is useful in treating small lesions. One or two to healing [80]. The optimal dose of fluconazole remains to be
applications of localized heat (50°C for 30 s) with the ThermoMed® determined.
device was as effective as intralesional SbV (70% cure rate) in L. tropica
acquired in Afghanistan [75] and more effective (70% cure rate) than
systemic SbV+ in L. major acquired in Iraq [76]. The device is expen- LEISHMANIASIS RECIDIVANS
sive but works on a battery – a significant advantage for field use. The World Health Organization (WHO)-recommended treatment for
Local anesthesia must be applied to the lesion prior to using the leishmaniasis recidivans is 15–20 mg SbV+/kg per day intramuscu-
device. A blister is seen 1–2 days after thermotherapy, but appears to larly or intravenously for 15 days plus oral allopurinol 20 mg/kg for
be well-tolerated. Application of a topical antibiotic ointment and 30 days, to treat leishmaniasis recidivans caused by L. tropica [57].
wound care decreases the incidence of secondary wound infections.
Cryotherapy is achieved with application of liquid nitrogen every 3–7 DIFFUSE CUTANEOUS LEISHMANIASIS
days for 1–5 sessions. Each weekly administration is usually two Diffuse cutaneous leishmaniasis in Ethiopia and Kenya responds
application cycles of 10–15 seconds of freezing time, with a thawing poorly to treatment with SbV. The WHO currently recommends
interval of 20 seconds. Freezing should reach up to a few millimeters 20 mg SbV+/kg per day intramuscularly or intravenously plus paro-
of healthy skin surrounding the lesion. Liquid nitrogen application momycin, 15 mg (11-mg base)/kg per day intramuscularly for 60 days
requires specific devices and a skilled healthcare provider. Post- or longer to treat diffuse cutaneous leishmaniasis [57]. Whatever the
cryotherapy care includes daily cleansing with an antiseptic solution regimen used, treatment should be prolonged for several weeks
and topical application of antibiotic ointment. beyond clinical cure.
Topical paromomycin creams at various doses, regimens and formula-
tions have been used for decades. A topical formulation of 15%
paromomycin with 12% methylbenzethonium chloride in soft white
PREVENTION AND CONTROL
paraffin (Leshcutan®, Teva, Israel) gives variable responses in L. major
ranging from 30–75%, and little-to-no efficacy in L. tropica. Because VECTOR CONTROL
this preparation causes significant local reactions consisting of pruri- Reducing the vector population can decrease the incidence of cutane-
tus, paresthesias and vesicle formation in about 25% of patients, ous leishmaniasis. Improved general sanitation and removal of refuse
other, better-tolerated preparations have been developed. A 10% and rubble in which sandflies breed reduces the incidence of urban
paromomycin/10% urea formulation used twice daily for 14 days was cutaneous leishmaniasis. Residual spraying with dichlorodiphenyl-
no better than placebo in controlled trials in Iran and Tunisia. A trichloroethane (DDT) for malaria control had eliminated cutaneous
longer regimen (up to 12 weeks) of 12–15% paromomycin/10% urea leishmaniasis in many areas, although it has returned with the cessa-
applied daily cured 23 out of 27 patients at the Hospital for Tropical tion of spraying.
Diseases in London in a mean of 6.7 weeks and was reported as
nontoxic. None of the topical agents are effective against cutaneous
leishmaniasis caused by L. tropica. A third-generation formulation of RESERVOIR CONTROL
15% paromomycin and 0.5% gentamicin was shown to be superior In the central Asian republics of the former Soviet Union, cutaneous
to placebo in L. major acquired in Tunisia and was safe and well- leishmaniasis incidence has been reduced by deep plowing of fields
tolerated [77]. Although the next generation of paromomycin-based to destroy burrows and eliminate gerbils from the area.
Le i shmaniasis 755
LEISHMANIA (VIANNIA) PANAMENSIS L. braziliensis infections [85, 86]. Multiple skin lesions owing to
metastatic spread along lymphatics are common with L. guyanensis
This parasite is found from Guatemala in the north through Central infections, and subcutaneous lymphatic nodules resembling sporo
America and Colombia and Ecuador in the south. The principal reser- trichosis are often seen in L. panamensis infections.
voir is the tree sloth, Choloepus hoffmanni. Other sloths, procyonids, and
forest primates are secondary hosts. The major vector, Lutzomyia trapi- Trauma to uninvolved skin can lead to the formation of lesions
doi, usually lives in the forest canopy in close contact with the known caused by Leishmania (Koebner phenomenon) [87]. Persons living in
reservoirs. However, at certain times of the year, when rainfall is moder- endemic areas note the ulcers of cutaneous leishmania develop along
ate, it can be found close to the ground where it can bite humans. machete cuts or other such blunt and sharp trauma. Postoperative
Human disease is common in rural agricultural workers, especially in granulomas caused by Leishmania have also been reported as postsur-
the first year after settlement before deforestation is complete, and in gical complications.
military personnel participating in jungle warfare training.
MUCOSAL DISEASE
LEISHMANIA (VIANNIA) GUYANENSIS One to five percent of persons infected with L. braziliensis develop
Pian bois or forest yaws, the human disease caused by Leishmania mucosal leishmaniasis. Mucosal leishmaniasis is more commonly
guyanensis occurs in the Guyanas and northern Brazil. Because the seen in Bolivia, Brazil and Peru, and is much less common in north-
principal vector, Lutzomyia umbratilis, has a high infection rate (up to ern South America and Central America [88]. The lesions of ML may
7%) and readily bites humans in the daytime when disturbed from appear concurrently with the primary cutaneous ulcer but more often
its resting sites on tree trunks. Disease is common among forest several months to many years after healing of the initial cutaneous
workers. The major reservoir of L. guyanensis is the two-toed forest lesion. The nasal mucosa is the first site involved. Initially, patients
sloth. may complain of nasal stuffiness, difficulty in breathing through their
nose and occasional bleeding as their first symptoms associated with
erythema and edema of the involved nasal mucosa. This proceeds to
LEISHMANIA (VIANNIA) PERUVIANA septum ulceration covered with a mucopurulent exudate. There is
Leishmania peruviana is found in high Andean valleys between 800 often mutilating destruction of the nasal septum (Fig. 99.14), palate,
and 3000 meters above sea level in Peru. Dogs with unapparent infec- lips, pharynx and larynx in severe mucosal leishmaniasis. The lesions
tion are the principal reservoir hosts for transmission. Human disease are chronic and progressive and death can be caused by aspiration or
(uta) is contracted in, and around, the home and, in some villages, inanition. Mucosal leishmaniasis can also less commonly be seen
90% of people are infected or scarred. with L. panamensis and L. guyanensis infections. Hoarseness should
prompt evaluation of the vocal cords for laryngeal involvement.
Mucosal leishmaniasis does not spontaneously resolve, is more dif-
INFECTIONS CAUSED BY OTHER ficult to treat especially in patients with severe or extensive disease
LEISHMANIA SPECIES and secondary bacterial infections are common.
Parasites have been cultured from lesions of cutaneous leishmaniasis There is currently no way to predict the development of mucosal
in various parts of South America that have isoenzyme patterns and leishmaniasis in a person with primary cutaneous leishmaniasis.
growth characteristics in culture and laboratory animals that are dif- However, risk factors for the development of mucosal leishmaniasis
ferent from those of known species of Leishmania. Leishmania infantum are male gender, older age, severe malnutrition and lesion duration
causes non-ulcerative nodular cutaneous leishmaniasis in Honduras of over four months [89]. In addition, a genetic component for the
and Costa Rica. risk of developing mucosal leishmaniasis has long been suspected to
include association between human leukocyte antigen (HLA) loci and
DIFFUSE CUTANEOUS LEISHMANIASIS
A diffuse form of cutaneous leishmaniasis is rarely seen in Bolivia,
Brazil, Colombia, Costa Rica, Dominican Republic, Ecuador, Guate-
mala, Mexico, Peru, Venezuela, or the USA. Diffuse cutaneous leish-
maniasis in the New World is usually associated with L. mexicana and
L. amazonensis infections.
CLINICAL MANIFESTATIONS
CUTANEOUS DISEASE
The lesions of New World cutaneous leishmaniasis are generally
similar to those of Old World disease. A few weeks to several months
after infection, an erythematous, often pruritic, papule develops at the
site of inoculation. The initial papule may become scaly or gradually
enlarge, developing a raised indurated margin with central ulceration.
Verrucous and acneiform lesions are uncommon, but nodular lesions
are seen in about 10%. Ulcerative lesions are usually painless unless
secondarily infected. The natural history varies depending on the
infecting species, location of the lesion and host immunity. Leishma-
nia mexicana infections generally have one or a few lesions that heal
spontaneously within six months. In Guatemala, 22 out of 25 lesions
caused by L. mexicana (88%) completely re-epithelialized by a median
lesion age of 14 weeks (range: 6–44 weeks) and 17 (68%) were clas-
sified as cured six months later [84]. However, lesions on the ear occur
in 40% of patients and are chronic, lasting many years. Simple cutane-
ous lesions caused by parasites of the L. braziliensis complex generally
require 6–18 months for spontaneous healing but sometimes persist
much longer. In addition, enlargement of the lymph nodes draining
the bite site commonly accompanies, or precedes, the ulcer in FIGURE 99.14 Mucosal leishmaniasis.
Le i shmaniasis 757
leishmaniasis caused by L. mexicana, L. guyanensis and L. panamemsis cutaneous leishmaniasis is characteristically a relapsing or chronically
[57]. Miltefosine is also 75% effective against CL caused by L. bra- progressive disease.
ziliensis acquired in Bahia Brazil [96], 70% effective in Colombia, 70%
in Bolivia [97], but only 53% effective in Guatemala [98]. The
response of L. braziliensis to miltefosine may vary depending on the PREVENTION AND CONTROL
geographic area. Vaccines and chemoprophylactic drugs are not available. Because of
the forest location of vectors and reservoirs, control of American
Local agents cutaneous leishmaniasis and mucosal leishmaniasis is not possible.
The only exception is uta, which, because of its domiciliary nature,
Intralesional injections of SbV, accepted therapy for disease in the Old can be mimimized by spraying houses with insecticides. Insect
World, have not seen wide use in the Americas. There are no large repellents, long-sleeved shirts and fine-mesh bed-netting may
comparative trials on which to base recommendations. reduce the risk of infection for individual travelers. Permethrin-
Topical application of paromomycin formulations has been evaluated impregnated clothing is also effective. In a study of Colombian mili-
in Ecuador and Colombia. In Ecuador, an open, non-randomized tary personnel in an endemic area for 6.6 weeks and followed for an
trial of 15% paromomycin with 12% methylbenzethonium chloride additional 12 weeks, 4 out of 143 (3%) soldiers wearing permethrin-
in white paraffin cured 90% of 52 patients [99]. In Colombia, impregnated uniforms acquired disease, whereas 18 out of 143
another open, non-randomized trial of 15% paromomycin with (18%) soldiers who did not wear impregnated uniforms acquired
5% methylbenzethonium chloride combined with parenteral Glu- disease [104].
cantime at 20 mg/kg daily for 7 days cured 18 out of 20 (90%)
patients [100]. The true efficacy remains to be determined in control-
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Babesiosis 100
Edouard Vannier, Peter J Krause
CLINICAL MANIFESTATIONS
BABESIA MICROTI INFECTION
Symptoms of B. microti infection vary in number and intensity. Three
patterns of infection have been described: i) asymptomatic infection;
ii) mild-to-moderate viral-like illness; and, iii) severe illness that may
be fulminant and culminate in prolonged illness or death.
As many as a quarter of adults and half of children do not have
FIGURE 100.1 Ring forms of Babesia microti on a Giemsa-stained human
symptoms [6]. Asymptomatic infection may persist for weeks to blood film (magnification x1000).
months following resolution of symptoms, even after standard anti-
biotic therapy has been administered [7]. The infection is also asymp-
tomatic during the incubation period that typically lasts from 1 to 4
weeks following tick bite. TABLE 100-1 Diagnosis of Babesiosis
Babesiosis is a viral-like illness that consists of a gradual onset of
malaise and fatigue followed by fever as high as 40.6°C (105°F) and Epidemiology
one or more of the following: chills, sweats, headache, myalgia, ano-
rexia, non-productive cough, arthralgia and nausea [1, 6]. Less com- l Residence in, or travel to, an area endemic for babesiosis
monly noted are emotional lability and depression, hyperesthesia, l Ixodes tick bite within 1 to 4 weeks
sore throat, abdominal pain, conjunctival injection, photophobia l Blood transfusion within 1 to 9 weeks
and weight loss. Fever is the most common finding on physical exami- Symptoms
nation. Rash is seldom noted, although ecchymoses and petechiae
have been described. Mild splenomegaly, hepatomegaly, or both, l Fever, fatigue, chills, sweats, headache, myalgia, anorexia,
occasionally occur. Slight pharyngeal erythema, jaundice, hematuria, non-productive cough, arthralgia and nausea
and retinopathy with splinter hemorrhages and retinal infarcts have l Less common: emotional lability and depression,
been reported. Severe infection requires hospital admission and often hyperesthesia, sore throat, abdominal pain, conjunctival
occurs in people over 50 years of age and in people immunocompro- injection, photophobia and weight loss
mised by asplenia, malignancy, HIV infection or immunosuppressive
drugs [1, 8]. The most common complications consist of pulmonary Signs on physical examination
edema [acute respiratory distress syndrome (ARDS)], disseminated l Fever
intravascular coagulopathy (DIC), congestive heart failure and renal l Splenomegaly, hepatomegaly, pallor
failure [9]. Splenic infarcts and splenic rupture have been noted.
Highly immunocompromised hosts may experience a persistent or Common laboratory diagnostic procedures
relapsing illness [8]. Outcome is fatal in 6–9% of all hospitalized
l Visualization of Babesia parasites on peripheral blood smears
cases and up to 28% of cases in immunocompromised hosts.
l Amplification of Babesia DNA in blood using PCR
l Presence of serum Babesia IgM antibody or a fourfold rise in
OTHER BABESIA INFECTIONS Babesia IgG antibody
Patients infected with B. divergens present with a fulminant illness and
nearly all reported cases have occurred in splenectomized individuals
[2]. Symptoms include high fever, shaking chills, intense sweats, head-
ache, myalgia and lumbar and abdominal pain. Hemoglobinuria and When parasites are too few to be detected on blood smears, as often
jaundice are almost always present. Several decades ago most cases occurs in the early phase of infection and after resolution of symp-
were fatal but, with the advent of exchange transfusion combined with toms, infection is best detected by PCR [1]. Amplification and
effective antibiotic therapy, death is rare. Cases of B. duncani infection sequence analysis of the entire18S rRNA gene allows for molecular
have been few and have ranged in severity from asymptomatic to fatal. classification of Babesia species.
Similarly, B. venatorum infection has ranged from mild to severe. Supportive laboratory findings include moderate-to-severe hemolytic
anemia, thrombocytopenia, an elevated reticulocyte count and an
DIAGNOSIS elevated erythrocyte sedimentation rate. The leukocyte count is
normal-to-slightly decreased, with a “left shift.” In severe cases, ele-
The diagnosis of babesiosis should be considered in any person who vated serum bilirubin and liver enzyme concentrations, elevated
resides in, or has traveled to, an endemic area and who presents with serum blood urea nitrogen and creatinine concentrations, and hema-
symptoms of babesiosis during the summer or early autumn. turia and proteinuria are noted.
The definitive diagnosis of babesiosis is made by microscopic analysis Immunofluorescence assay (IFA) serology is useful in confirming the
of Giemsa-stained thick or thin blood smears, although parasites can diagnosis. IgM antibody titers ≥1 : 64 and IgG antibody titers of
be visualized using Wright’s stain (Fig. 100.1, Table 100-1) [1]. Babesia ≥1 : 1024 signify active, or recent, infection. IgG titers typically decrease
typically appear as ring forms that may be mistakenly identified as to ≤1 : 64 within 12 months. Thin blood smears, PCR and serology
Plasmodium falciparum. Trophozoites divide by binary fission, yielding tests are available at most large commercial laboratories in endemic
two to four merozoites that remain in close proximity. The four areas. Certain university medical center laboratories and the Centers
merozoites are distributed as a “Maltese cross”, but this pattern is for Disease Control and Prevention (CDC) serve as reference
seldom noted. laboratories.
Babesiosis 763
TISSUE INFECTION
101 Toxoplasmosis
Luc Paris
FIGURE 101.1 Life cycle of Toxoplasma gondii. Dashed arrow indicate transmission by tachyzoites; dark blue arrows indicate transmission by cysts
(bradyzoites); and light blue arrows indicate transmission by oocysts.
TRANSMISSION
Humans become infected by ingesting tissue cysts when eating raw
or undercooked meat (lamb, beef or pork) of animals harboring
tissue cysts, and by ingestion of oocysts in soil-contaminated food
(raw vegetables) or drinking water—believed to be the major source
of infection in tropical areas. Transmission can also occur when
changing the litter box of a pet cat, by blood transfusion or organ
transplantation, and transplacentally from mother to fetus, leading to
congenital infections.
A transplanted solid organ from a donor seropositive for toxoplasmo-
sis can transmit T. gondii to a seronegative recipient. Heart transplant
recipients are particularly at risk for this mode of acquisition, and
additional cases have been described with other organs (kidney, lung,
liver). Although T. gondii has been isolated from the peripheral blood
of acutely symptomatic patients, transmission by transfusion is rare.
Transplacental infection occurs in approximately 30% of women if
they are first infected during pregnancy and thus have no pre-existing
immunity. The risk of transmission to the uterus is lowest in the time
just after conception (<1%) and increases to virtually 100% if the
FIGURE 101.2 Numerous intracellular Toxoplasma gondii in bone marrow. mother is infected just before delivery. Additionally, transplacental
Coloration RAL 1555 ×1000. (From personal collection, Luc Paris, Laboratoire de transmission during chronic infection has been observed in immu-
Parasitologie-Mycologie, Groupe Hospitalier Pitié-Salpêtrère, Paris, France). nosuppressed women.
768 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Although uncommon, occupational exposure and transmission via phenomenon has been described in the USA, where the seropreva-
needlestick can occur when working with live Toxoplasma-infected lence declined from 14.1% in the 1988–1994 National Health and
materials in the laboratory. Nutrition Examination Survey (NHANES) to 9% in the 1999–2004
NHANES.
DISTRIBUTION AND PREVALENCE (Fig. 101.4) In developing and tropical countries, prevalence depends on environ-
Toxoplasma is distributed worldwide, but the incidence in humans mental conditions and climate. It is higher in urban than in rural
varies widely [3]. Prevalence depends on local eating habits, environ- areas, and higher in wet compared with dry climates. Foci of high
mental conditions, and the presence of definitive hosts. Prevalence prevalence (>80%) exist in Latin America, parts of Eastern/Central
also increases with age. The overall prevalence in Western Europe is Europe, the Middle East, parts of Southeast Asia and Africa. Regional
30–50%. Since the initial studies of the 1950s and 1960s, a trend seroprevalence variation relates to the dietary practices of individual
towards lower seroprevalence has been observed in many European subpopulations. A trend toward lower seroprevalence has also been
countries. In France, the prevalence declined from more than 80% in observed in Africa: in Gabon, the prevalence in Franceville was 56%
the 1960s to 54.3% in 1995, and to 43.8% in 2003. This has been in 2007 compared with 71% 15 years earlier. Prevalence is generally
attributed to improved hygiene, new habits of food consumption (e.g. higher in South America (e.g. 53% in Southern Brazil) or in Africa
freezing of meat) and better awareness in the general population (e.g. 46% in Tanzania and 40.8% in Lagos, Nigeria) than in India
regarding the risks of consuming undercooked meat. The same (20.3% in Bangalore) or in the Far East (<10% in Korea or China).
Globally, toxoplasmosis seroprevalence is continuingly evolving,
subject to regional socioeconomic parameters and population habits.
PATHOPHYSIOLOGY
The primary route of infection is via oral ingestion into the gastroin-
testinal tract and progression through lymphatics to widespread dis-
FIGURE 101.3 Cysts in the brain. semination. Asexual multiplication of the parasite occurs within the
>60% 10–20%
40–60% <10%
20–40% No data
FIGURE 101.4 Global status of Toxoplasma gondii seroprevalence (adapted from Pappas G, Roussos N, Falagas, ME. Toxoplasmosis snapshots: global status of
Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis. Int J Parasitol 2009;39:1385–94.).
Toxoplasmosis 769
intestinal epithelial cells following ingestion of infective cysts. This TOXOPLASMOSIS IN IMMUNOCOMPROMISED
early infection period is associated with peripheral parasitemia with
T. gondii tachyzoites circulating freely, or within mononuclear phago-
HOSTS
cytic cells, until the development of an effective immune response. In immunocompromised patients, toxoplasmosis is a severe disease.
Differentiation of tachyzoites into bradyzoites correlates with the Most cases are reactivation of chronic infection resulting from
onset of protective immunity and begins after a few days. In the impaired of T cell immunity. High-risk groups include HIV-infected
setting of T cell immune deficiency, bradyzoites can reactivate into patients with a CD4 cells count <100/mm3, patients treated with
tachyzoites. The genetic background of the host may have influence immunosuppressive agents and bone marrow transplant patients.
the risk of reactivation. This is well known in HIV-infected patients Such patients, if seronegative, are also at risk for newly acquired infec-
for whom the risk of reactivated toxoplasmosis is higher or lower tion. Although classically a localized and a disseminated form have
depending on the host’s human leukocyte antigen (HLA) haplotype. been described, in reality the presentation is often less distinct. Initial
The absence of effective T cell immunity in the fetus explains the diagnosis will often focus on a clinically localized finding, whereas
gravity of congenital toxoplasmosis. further evaluation will reveal disseminated infection. The most
common clinical presentation is multifocal necrotizing encephalitis.
CLINICAL MANIFESTATIONS Patients present with headache and a focal deficit with fever in 50%
of cases [11]. Other common neurologic presentations include gener-
Although infection with T. gondii in developed countries is asympto- alized seizures, with or without encephalitis. Compute tomography
matic in 80% of newly infected patients, there are several distinct (CT) and magnetic resonance imaging (MRI) of the head typically
clinical syndromes. show multiple, low-density lesions at corticomedullary junction or in
the basal ganglia that enhance following administration of intrave-
ACUTE POSTNATAL-ACQUIRED nous contrast (Fig. 101.5). Meningeal signs are uncommon. Mono-
nuclear cerebrospinal fluid (CSF) pleocytosis and mildly elevated
TOXOPLASMOSIS IN protein in the CSF are common.
IMMUNOCOMPETENT PATIENTS
Another common clinical presentation is pneumonia (which can
In the 20% of patients with symptoms at presentation, the disease is resemble pneumocystosis) but any organ can be involved because
generally mild. The incubation period is 1–2 weeks. The most fre-
quent symptoms are fever, asthenia and a single, enlarged cervical
lymph node, but regional and generalized lymphadenopathy can
occur. The lymph nodes are nontender and do not suppurate. Macular
or urticarial rash, arthralgia, myalgia and hepatitis are less common
findings. The clinical presentation may resemble a mild influenza-like
episode. Symptoms usually resolve spontaneously within a few weeks
or months. Ocular involvement is also possible—more frequently
reported in South America (particularly Brazil) —but not specifically
associated with recent primary infection or with a wild toxoplasmosis
cycle. In Europe and North America the great majority of these clas-
sical mild cases are supposedly caused by infection with a type II
strain. Clinically, the patient presents with a mononucleosis syn-
drome and the diagnosis is made by serology.
There have been fewer than 100 cases of severe primary toxoplasmosis
caused by an atypical or recombinant strain of T. gondii in immuno-
competent patients reported. The majority of these patients were
infected in French Guiana, but cases have also been reported from
other areas. In some European cases, the source of infection has been
determined to be undercooked horse meat imported from South
America [9]. Clinically, the patient presents with a marked, nonspe-
cific infectious syndrome with visceral involvement. Fever higher than
39°C and prolonged more than 10 days is prominent. In two-thirds
of cases there is weight-loss of >5% body weight, generalized lym-
phadenopathy, elevated liver enzyme levels and pulmonary involve-
ment. Fifty percent of the patients have severe headache and a third
have diarrhea, hepatosplenomegaly or chorioretinitis. Other reported
complications include Guillain-Barré syndrome, pericarditis, myositis
and cutaneous rash. Prognosis is poorer with lung involvement,
which occurs generally 10–15 days after the onset of fever and may
require hospitalization. For a third of the patients there is an acute
respiratory distress syndrome. The main differential diagnosis in
South America is histoplasmosis. Without treatment, this severe pres-
entation can be fatal. The diagnosis can be confirmed by classical
serology, but direct parasitologic diagnosis is also possible in many
cases. An outbreak of severe acute primary toxoplasmosis in a Suri-
namese village was described with 11 cases; all the patients were
infected by the same atypical strain. There were five disseminated
acute toxoplasmosis—all hospitalized—with one death; four less
severe cases (without hospitalization) and two lethal cases of congeni-
tal toxoplasmosis. Different clinical outcomes may be explained by
different genetic background in hosts or by the size or type of parasite
inoculum [10]. It is important to consider the diagnosis of acute toxo-
plasmosis in patients who live in, or have recently travelled to, South
America—especially the Amazon region—and who present with a
severe infectious syndrome with pulmonary involvement. FIGURE 101.5 MRI toxoplasma encepahalitis.
770 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
T. gondii infects all nucleated cell types. Forty percent of AIDS patients
with ocular localization will also have a brain abscess. Disseminated
toxoplasmosis usually presents with high and prolonged fever with
altered mental status, arthralgia, rash and focal clinical (CNS abscess,
pneumonia) or laboratory (elevated liver enzymes, hemophagocyto-
sis) findings. There is a higher rate of cerebral involvement in AIDS
patients than in those whose immunosuppression is not HIV related;
for these patients, pulmonary involvement is more frequent. In tropi-
cal areas, the rate of toxoplasma reactivation is dependent on the local
prevalence of infection in the community.
Although host factors are much more involved than parasite factors
in immunocompromised patients’ susceptibility to toxoplasmosis
[12], the genetic makeup of the particular T. gondii strain involved
may be associated with atypical presentations. Ghosn et al. [13]
reported one case of inguinal lymphadenopathy in a HIV patient with
undetectable viral load and CD4 cell count of >500/mm3. This patient
was likely infected by T. gondii in the West Indies several years before.
An atypical strain was isolated from the lymph node and the patient
required treatment with trimethoprim-sulfamethoxazole followed by
secondary prophylaxis.
Severe generalized toxoplasmosis with high fatality rates occurs when
FIGURE 101.6 Active ocular toxoplasmosis.
recipient negative persons receive donor positive organs. Universal
prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is
effective in preventing post-transplant toxoplasmosis [14]
MANAGEMENT OF ACUTE TOXOPLASMOSIS consequences for the mother, although the few reported cases have
DURING PREGNANCY been associated with severe congenital disease in the newborn [16].
Presence of such atypical strains of T. gondii could explain a reported
Primary infection of the mother with consequent infection of the
case of re-infection with congenital transmission in a mother who
placenta is the mechanism for congenital transmission. The placenta
had been exposed to toxoplasmosis before conception, suggesting
allows transmission to the fetus in 30–50% of infections acquired in
that acquired immunity against archetypal strains may not protect
pregnancy. The rate of transplacental infection and severity of disease
against reinfection by atypical strains [9].
in the fetus vary with the time of infection in relation to gestation.
When maternal infection occurs in the first trimester, the risk of fetal
infection is only about 10% but disease is severe. When maternal OCULAR TOXOPLASMOSIS
infection occurs in the third trimester, the risk of fetal infection rises Ocular toxoplasmosis is the main cause of posterior uveitis world
to 65% and approaches 100% at term; however, neonatal infection wide [17]. Previously considered a late sequelae of congenital toxo
in these cases is usually asymptomatic. plasmosis, it is now believed the majority of ocular disease in
Suspected or confirmed toxoplasmosis during pregnancy leads to immunocompetent patients is postnatally-acquired infection [18,
complex and ongoing management challenges [15]. With appropriate 19]. Ocular involvement is not specifically associated with recent
monitoring and management of seroconversion, the great majority primary infection, but can be delayed several months (or even years)
(70–80%) of congenital infection is asymptomatic. In settings where after primary infection [20]. In all cases, the main clinical presenta-
such prenatal monitoring is unavailable, congenital infection rates are tion of chorioretinitis is a focally necrotic retinal lesion with fuzzy
much higher. outlines (Fig. 101.6). It is accompanied by a whitish vitreous exudate
that sometimes obscures the lesion [21]. A new lesion can occasion-
One strategy is to place pregnant women suspected of having toxo- ally arise from the edge of an old one. This chorioretinitis may be
plasmosis on spiramycin 1 g, three or four times daily to prevent fetal associated with edema of the retina and optic nerve, optic neuritis,
infection, if this has not yet occurred, while waiting for the results of iridocyclitis and, in rare instances, panuveitis. In congenital toxoplas-
serologic testing. If a recent infection with toxoplasmosis is con- mosis, the ocular lesions are more likely bilateral versus unilateral in
firmed, an amniocentesis is performed and PCR testing of amniotic postnatally acquired cases. Ocular toxoplasmosis is characterized by
fluid is done. If positive, one option would be to terminate the preg- recurrent episodes of chorioretinitis that can be associated with severe
nancy, depending on the parent’s wishes. If the PCR is negative, infec- morbidity if the disease extends to structures critical for vision or if
tion did not occur and spiramycin could be continued through there is a retinal detachment. The timing of recurrences is unpredict-
delivery. In resource-limited, lower-income counties, the sophisti- able, but the individual risk is estimated to be as high as 50%. The
cated reference laboratories for serologic testing and antenatal diag- genetic diversity of T. gondii may partially explain this phenomenon.
nostic procedures are not available. A high prevalence of ocular toxoplasmosis has been reported in South
America [22] and Africa [23]. In the UK, the risk of ocular toxoplas-
mosis is 100 times higher in black people born in West Africa than
CONGENITAL TOXOPLASMOSIS in subjects born in Britain [23]. In Brazil, the incidence of ocular
Severe congenital toxoplasmosis presents at birth with intracranial toxoplasmosis is 17.7% compared with 0.6% in Alabama (USA).
calcifications, hydrocephalus and chorioretinitis. The diagnosis is Similarly, in Brazil, the ocular sequelae of congenital toxoplasmosis
more difficult in mild or asymptomatic forms. Sequelae may develop are more frequent, more recurrent and more severe than in Europe
just after delivery, or later. Physicians must consider congenital toxo- [24]. As discussed previously, there is considerable genetic diversity
plasmosis when a newborn exhibits ocular abnormalities (chori- in tropical areas with many atypical strains of T. gondii circulating; in
oretinitis, blindness, strabismus, cataracts or nystagmus), epilepsy, Brazil there is no archetypal strain II that predominates in USA. Type
mental retardation, microcephaly, intracranial calcifications, diarrhea, II strain in France can be responsible for ocular toxoplasmosis in both
hypothermia or anemia. The main determinant of the severity of immunocompetent and immunocompromised patients [25]. Cumu-
congenital toxoplasmosis remains the stage of pregnancy at the time latively, these data suggest that some strains probably have a tropism
of infection. In non-archetypal (i.e. not types I, II or III) strains, for eye tissues but that there are also host factors involved in the
primary infection of the mother does not appear to have any unique occurrence of ocular toxoplasmosis.
Toxoplasmosis 771
DIAGNOSIS IgM antibodies. The historic gold standard is the dye test developed
by Sabin and Feldman in 1948 for the detection of IgG [28]. In 1968,
Remington developed an indirect immunofluorescence (IIF) test for
LABORATORY DIAGNOSIS IgM detection [29]. The dye test is only available in a specialized refer-
The differential diagnosis of the various syndromes of toxoplasmosis ence laboratories and the IIF test requires specific material, therefore,
is broad and laboratory confirmation is recommended in all sus- today, the great majority of laboratories use ELISA or electro-
pected cases, and is essential in the immuncompromised or in those chemiluminescence immunoassay (ECLIA). Agglutination and indi-
with severe syndromes. The diagnosis of toxoplasmosis is confirmed rect hemagglutination tests are easy to perform. Results of IgG studies
by direct detection of parasites in patient specimens or by serology. are generally expressed as international units per milliliter (IU/mL),
whereas IgM levels are reported as an index or as serial dilutions. The
modern gold standard for IgM is the immuno-sorbent agglutination
DIRECT DETECTION AND IDENTIFICATION assay (ISAgA). The interpretation of toxoplasma antibody tests can be
OF THE PARASITE complex (Table 101-1).
Toxoplasma tachyzoites or cysts can be demonstrated on tissue The determination of the avidity of anti-toxoplasma IgG antibodies
imprints, biologic fluids (blood, bronchoalveolar lavage, CSF, amni- by their ability to stay bound to the antigen when exposed to chao-
otic fluid) or biopsies (CNS, lymph node, bone marrow) that are fixed tropic salt solutions, can be useful to distinguish early versus later
and stained appropriately. The diagnosis of acute infection requires infection. Anti-toxoplama antibodies formed in the few months fol-
the visualization of tachyzoites. The tachyzoites of toxoplasmosis lowing infection are less tightly bound (lower avidity) than antibodies
must be distinguished from other intracellular parasites such as His- found much later in the infection (higher avidity). Avidity assays may
toplasma, Leishmania, Sarcocystis and Trypanosoma cruzi. Isolation of be useful in the differential diagnosis of lymphadenopathy and dating
parasites from blood or other body fluids by intraperitoneal inocula- infection in pregnant women [30]. The Food and Drug Administra-
tion in mice is very useful in isolating the strain. The mice should be tion (FDA)-cleared VIDAS TOXO IgG Avidity assay (bioMérieux Inc.,
tested for the presence of Toxoplasma organisms in the peritoneal fluid Hazelwood, MO, USA) helps determine whether a pregnant woman
6–10 days post-inoculation; if no organisms are found, serology can or a person with swollen lymph nodes testing positive for toxoplas-
be performed on the animals 4–6 weeks post-inoculation. There are mosis developed the infection within the past 4 months.
no accepted cell culture techniques for diagnosis because of a lack of
sensitivity. The detection of T. gondii DNA by real-time PCR has super-
seded the classical methods. Several studies confirm that rep529 is the DIAGNOSIS OF ACUTE POSTNATAL-
more sensitive DNA target for the diagnosis [26, 27]. Sensitivity using ACQUIRED TOXOPLASMOSIS IN
this technique is 95% for antenatal diagnosis in amniotic fluid and
for disseminated toxoplasmosis in blood. In localized toxoplasmosis,
IMMUNOCOMPETENT PATIENTS
the sensitivity is similar if PCR is performed on an appropriate sample Acute infection is assessed by seroconversion from a negative to a
(BAL (broncho alveolar lavage), cerebral biopsy) but is less sensitive positive serology. It is the appearance of IgG that defines seroconver-
in blood. In AIDS patients with cerebral abscesses, PCR on CSF is sion; the presence of IgM alone can be nonspecific or related to cross-
positive in only 30–60% of cases. reactions. If no negative baseline sample exists, a fourfold rise in IgG
titers, combined with a positive IgM, drawn at 2–3 week intervals and
run in parallel is highly suggestive of an acute infection. Modern IgM
SEROLOGIC TESTING immunosorbent assays are very sensitive and specific but the persist-
Serologic diagnosis is the routine method of diagnosis for most ence of these IgM antibodies means that their presence is not, by itself,
patients and is based on the detection of T. gondii-specific IgG and sufficient to diagnose an acute infection. In such cases, a high IgG
772 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
avidity index may exclude an acute infection. The lack of standardiza- compared with serum antibody (Goldmann-Witmer coefficient) is
tion between assays may lead to discrepant results; no conclusions calculated as (anti-Toxoplasma IgG in aqueous humor/total IgG in
can be drawn comparing two results obtained from two different aqueous humor)/(anti-Toxoplasma IgG in serum/total IgG in serum).
laboratories using different reagents. Routine serology tests are suffi- A value of 2 is considered evidence of intraocular Ab synthesis. Immu-
cient for diagnosis of “Guyanese toxoplasmosis” strains; serologic noblotting can also be utilized.
response to these strains is generally brisk, with very high IgG titers
and a long persistence of specific IgM and IgA. The differential diagnosis of acute toxoplasmic encephalitis includes
uveitis caused by syphilis, tuberculosis, leprosy and sacrcoidosis.
The differential diagnosis of acute toxoplasmosis is broad and
includes infectious mononucleosis caused by Epstein-Barr and cyto
megalovirs viruses, acute HIV infection, cat-scratch disease, tubercu-
TREATMENT
losis, lymphoma, Hodgkin’s disease and sarcoidosis. Most drugs used for the treatment of toxoplasmosis are active only
against the tachyzoite forms of the parasite and treatment does not
eradicate the infection. Atovaquone has limited in vitro activity against
DIAGNOSIS OF TOXOPLASMOSIS IN the cyst forms.
IMMUNOCOMPROMISED HOSTS Specific treatment is not indicated for a healthy person with mild
Positive serology indicates only that the diagnosis is possible. A nega- symptoms who is not pregnant, as they usually resolve within a few
tive serology excludes the diagnosis, except in case of primary infec- weeks. Treatment is usually recommended for severe illness in the
tion; for these patients, the appearance of an IgM and IgG response immunocompetent, infection acquired infection during pregnancy,
can be delayed. The diagnosis is confirmed by demonstration of the clinical manifestations compatible with toxoplasmosis in immuno-
parasite in biopsies or biologic fluids by PCR. In the case of cerebral suppressed patients, congenital infection (whether the infant is symp-
lesions, a therapeutic trial is frequently initiated, with biopsy per- tomatic or not), or persons with active ocular disease or severe illness.
formed only if there is no clinical improvement after one week of The treatment of toxoplasmosis in immunocompromised patients is
treatment. Brain biopsy without a therapeutic trial is indicated in a medical emergency. Primary prophylaxis is used in severely immu-
immunocompromised patients with a negative specific IgG serologic nosuppressed patients. Current treatment recommendations are
test, non-enhancing single lesions and those on routine prophylaxis found in Table 101-2.
with TMP/SMX because these abnormalities are unlikely to be caused Standard therapy for most indications is a combination of oral
by Toxoplasma. pyrimethamine and a sulfonamide. A 200-mg loading dose of
The most common clinical presentation of T. gondii infection among pyrimethamine given in divided doses is followed by a daily dose of
patients with AIDS is focal encephalitis with headache, confusion, or 1 mg/kg in adults and every 1–3 days for children.
motor weakness and fever [31]. Physical examination might demon- The new gold standard in tropical countries should be TMP/SMX.
strate focal neurologic abnormalities and, in the absence of treatment, Maintenance therapy is given until effective immune reconstitution
disease progression results in seizures, stupor and coma. occurs. Primary prophylaxis is necessary for patients with CD4 T
Retinochoroiditis, pneumonia and evidence of other multifocal organ cell depletion of less than 200 cells/mm3. The regimen is the same
system involvement can be observed after dissemination of infection for primary or secondary prophylaxis, with one tablet (160
but are rare manifestations in this patient population. A CT scan or trimethoprim/800 mg sulfamethozole) daily.
MRI of the brain will typically show multiple contrast-enhancing Treatment recommendations in pregnancy vary; in some countries
lesions, often with associated edema [32]. However, toxoplasmosis treatment by pyrimethamine-sulfonamide is systematically given in
also can manifest as single lesions in the brain. cases of seroconversion after the first trimester of the pregnancy. In
The differential diagnosis of CNS toxoplasmosis in immunocompro- others locations, spiramycin is given until the result of amniocentesis
mised individuals mimics other causes of enhancing mass lesions is known and pyrimethamine-sulfonamide used only if the antenatal
such as lymphoma, metastatic carcinoma, tuberculoma, and brain diagnosis is positive. There is also variability in the duration of the
abscess. pyrimethamine-sulfonamide regimen used (only one month or until
delivery). Changes in antibody titers are not useful for monitoring
responses to therapy.
DIAGNOSIS OF CONGENITAL TOXOPLASMOSIS
Patients with Toxoplasma encephalitis should be monitored routinely
The gold standard for the antenatal diagnosis of congenital toxoplas- for adverse events and clinical and radiologic improvement. Common
mosis is PCR performed on amniotic fluid. If there are no abnormali- pyrimethamine toxicities include rash, nausea and bone marrow sup-
ties on fetal ultrasound, the mother is treated until delivery. If severe pression (neutropenia, anemia and thrombocytopenia) that can
abnormalities are detected on ultrasound, medical interruption of the often be reversed by increasing the dose of leucovorin to 50–100 mg/
pregnancy might be considered based on the parents’ choice and local day administered in divided doses. Common sulfadiazine toxicities
laws. If an antenatal diagnosis is negative or was not performed, include rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea
neonatal diagnosis is done via child/mother comparison via the and crystalluria. Common clindamycin toxicities include fever, rash,
immunoblot method and inoculation of placental tissue into mouse nausea, diarrhea (including pseudomembranous colitis or diarrhea
peritoneum. After one week of life, the presence of IgA or IgM in the related to Clostridium difficile toxin) and hepatotoxicity. Common
child serum confirms the diagnosis. IgG passively transferred from TMP-SMX toxicities include rash, fever, leukopenia, thrombocytope-
mother to child should disappear by 10–12 months. nia and hepatotoxicity. Drug interactions between anticonvulsants
The differential diagnosis of congenital toxoplasmosis includes con- and anti-retroviral agents should be evaluated carefully and doses
gental infections with cytomegalovirus, herpes simplex, rubella, Liste- adjusted according to established guidelines. Several cases of neuro-
ria, syphilis, T. cruzi and erythroblastosis fetalis. logic disease have been attributed to immune reconstitution and
toxoplasmosis, but more data are needed to verify that such cases are
immune reconstitution syndrome related to T. gondii [34].
DIAGNOSIS OF OCULAR TOXOPLASMOSIS
The current gold standard for diagnosis of ocular toxoplasmosis is a
thorough an ophthalmologic examination. In patients with atypical
CONCLUSION
lesions, laboratory methods may confirm the diagnosis [33]. The Since its recognition as a human pathogen in 1939, understanding of
most reliable method is aspiration of aqueous humor that can be Toxoplasma has evolved dramatically. Since the end of the 1990s,
tested for local specific antibody production or for T. gondii DNA by description of T. gondii’s genetic composition has led to a better under-
PCR. The ratio of local specific intraocular antibody production standing of its biological diversity and pathologic variability. We
TABLE 101-2 Current Treatment Recommendations for Toxoplasmosis
Immuncocompromised patients
Encephalitis in HIV Adults: 200 loading mg of Pyrimethamine penetrates the brain parenchyma The preferred alternative Add folinic acid if mental [36, 37]
infected patients with pyrimethamine given for one efficiently, even in the absence of inflammation regimen for patients who status is altered and until
AIDS day followed by 50–75 mg per Adjunctive corticosteroids (e.g. dexamethasone) are unable to tolerate or clinical improvement is
day plus sulfadiazine at should be administered to patients with TE when who fail to respond to seen (generally 3–5 days)
100–150 mg/kg (e.g. 4–6 g/day clinically indicated only for treatment of a mass effect first-line therapy is If the patient is comatose,
for an adult in 1–1.5 g four associated with focal lesions or associated edema pyrimethamine plus treatment is initially given
times per day plus folinic acid Anticonvulsants should be administered to patients clindamycin plus leucovorin intravenously at the same
(leucovorin) 5–10 mg with each with TE who have a history of seizures, but should not TMP/SMX is 10/50 mg/kg/ dose
dose of pyrimethamine) be administered as prophylactics to all patients day given BID, or 15/75 mg/ TMP-SMX was reported in
Children: Anticonvulsants, if administered, should be continued kg/day a small (77 patients)
pyrimethamine 1 mg/kg plus at least through the period of acute therapy. Atovaquone at 750 mg four randomized trial to be
sulfadiazine 100–150 mg/kg Acute therapy for TE should be continued for at least times a day plus effective and better
given in four divided daily six weeks, if there is clinical and radiologic pyrimethomine tolerated than
doses improvement. Longer courses might be appropriate if pyrimethamine-
To avoid the hematologic clinical or radiologic disease is extensive or response is sulfadiazine
toxicity of this regimen, folinic incomplete at six weeks. Great inter-individual
acid is administered in a dose Because of the potential immunosuppressive effects of variability in drug
of 25 mg daily for adults and corticosteroids, they should be discontinued as soon atovaquone absorption
1 mg daily for children as clinically feasible. Patients receiving corticosteroids
should be monitored closely for the development of
other OIs, including CMV retinitis and TB disease
Toxoplasmosis
773
774
know today that the disease, once considered to be benign, is poten- 18. Balasundaram MB, Andavar R, Palaniswamy M, Venkatapathy N. Outbreak
tially severe in immunocompetent patients. Acute toxoplasmosis of acquired ocular toxoplasmosis involving 248 patients. Arch Ophthalmol
must be considered in the differential diagnosis of a patient living in, 2010;128:28–32.
or returning from, tropical areas—particularly the Amazon region of 19. Montoya JG, Remington JS. Toxoplasmic chorioretinitis in the setting of acute
South America—who presents with a severe infectious syndrome with acquired toxoplasmosis. Clin Infect Dis 1996;23:277–82.
20. Silveira, C, Belfort R, Jr, Muccioli C, et al. A follow-up study of Toxoplasma
pulmonary involvement.
gondii infection in southern Brazil. Am J Ophthalmol 2001;131:351–4.
21. Delair E, Latkany P, Noble AG, et al. Clinical manifestations of ocular toxo-
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4. Howe DK, Sibley LD. Toxoplasma gondii comprises three clonal lineages: cor- 25. Fekkar A, Ajzenberg D, Bodaghi B, et al. Direct genotyping of Toxoplasma gondii
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1561–6. nance of type II in France. J Clin Microbiol 2011;49:1543–7.
5. Lehmann T, Graham DH, Dahl ER, et al. Variation in the structure of Toxo- 26. Mesquita RT, Ziegler AP, Hiramoto RM, et al. Real-time quantitative PCR in
plasma gondii and the roles of selfing, drift, and epistatic selection in maintain- cerebral toxoplasmosis diagnosis of Brazilian human immunodeficiency
ing linkage disequilibria. Infect Genet Evol 2004;4:107–14. virus-infected patients. J Med Microbiol 2010;59:641–7.
6. Bossi P, Caumes E, Paris L, et al. Toxoplasma gondii-associated Guillain-Barre 27. Sterkers Y, Varlet-Marie E, Cassaing S, et al. Multicentric comparative analyti-
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Pathogenic and Opportunistic
102 Free-living Ameba Infections
Govinda S Visvesvara
DIAGNOSTIC MICROBIOLOGY
The CSF is characterized by pleocytosis, with predominance of poly-
morphonuclear leukocytes but with an absence of bacteria. The CSF
pressure is elevated (100–600 mmHg). Glucose concentration may
be slightly reduced or normal, but the protein content is elevated,
ranging from 100 mg/100 mL to 1000 mg/100 mL. Differentiation of
PAM from acute pyogenic or bacterial meningoencephalitis is made
by recognizing motile amebae in direct wet mount examination of
the CSF. Smears of CSF should also be stained with Giemsa or tri-
chrome in order to detect the characteristic Naegleria nuclear mor-
phology [1,2]. Neuroimaging can be nonspecific but can include
edema, basilar meningeal enhancement, and obliteration of the cis- FIGURE 102.1 Central nervous system section of a primary amebic
terns around the midbrain and the subarachnoid space [7]. Many meningoencephalitis (PAM) case, demonstrating numerous trophozoites
cases have been diagnosed postmortem based on examination of of Naegleria fowleri (H&E; ×400). Note the absence of cysts. Inset:
hematoxylin and eosin (H&E)-stained sections, immunohistochemi- trophozoites showing large nucleus with densely staining nucleolus
(×1000).
cal tests and PCR assay. Recently, a real-time multiplex PCR has been
developed which identifies N. fowleri DNA in the CSF within 5 hours,
thus greatly facilitating rapid and accurate diagnosis [8].
Little information exists on the antibody response to N. fowleri infec- antibiotics or chemotherapeutic medications [1–3]. B. mandrillaris
tion, probably because most patients die before serum antibodies causes infection in both immunodeficient and immunocompetent
become detectable. However, in one patient who survived PAM, an individuals [2]. GAE is an insidious disease and has a long and pro-
antibody titer of 1 : 4096 to N. fowleri was demonstrated by immuno tracted clinical course. Clinical signs can progress from personality
fluorescence in serum samples obtained at 7, 10 and 42 days of changes, headache, low-grade fever, nausea and vomiting, to lethargy,
hospitalization [2]. Low levels of antibodies to N. fowleri and other diplopia, hemiparesis, seizures, depressed levels of consciousness and
Naegleria species in sera of hospitalized patients and in apparently coma. Third and sixth cranial nerve palsies may be seen in some
healthy people have been reported. Apparently, normal human patients. GAE may mimic bacterial leptomeningitis, tuberculous or
serum, but not heat-inactivated serum, stimulates production of viral meningitis, or single or multiple space-occupying lesions. Pneu-
protein kinases in N. fowleri, which may be effective in destroying monitis may also occur.
complement and protecting amebae from the membrane-attack
complex of the complement cascade [2]. DIAGNOSTIC MICROBIOLOGY
CSF in patients with GAE reveals a lymphocytic pleocytosis with
PATHOLOGIC FEATURES mildly elevated protein and normal levels of glucose. Neuroimaging
At autopsy, the cerebral hemispheres are swollen and edematous. The studies can reveal single or multiple heterogeneous, hypodense, non-
olfactory bulbs and the orbitofrontal cortices are necrotic and hemor- enhancing, space-occupying lesions involving the basal ganglia, cer-
rhagic. The arachnoid membrane is severely congested with scant ebral cortex, subcortical white matter, cerebellum and pons, suggesting
purulent exudate. Amebic trophozoites, but not cysts, are usually seen abscess, tumor or intracerebral hematoma. Brain and skin biopsies
within the Virchow–Robin spaces with minimal or no inflammatory are important diagnostic procedures. Molecular techniques such as
reaction (Fig. 102.1) [1,2]. PCR and real-time PCR have also been used recently to identify Acan-
thamoeba in the CSF, brain and corneal tissue as well as in tear fluid.
Acanthamoeba spp. can be easily cultured from infected tissue on
MANAGEMENT bacterially seeded agar plates [1–3]. B. mandrillaris can be isolated
The few patients who have survived this infection have done so pri- from the CNS by inoculating monkey kidney cell culture with brain
marily because of early diagnosis and aggressive treatment with tissue [2].
intrathecal and/or intravenous amphoterecin B, miconazole and oral
rifampin [2,9]. Amphotericin B and azithromycin were found to be PATHOLOGIC FEATURES
synergistic in vitro and in a mouse model [10].
The cerebral hemispheres are edematous. Encephalomalacia with
multifocal areas of cortical softening and hemorrhagic necrosis may
PREVENTION be seen. Multifocal necrotic lesions often accompanied by Acan-
The trophic and the cyst forms of N. fowleri are susceptible to chlorine thamoeba trophozoites and cysts (Fig. 102.2) may also be seen in
and are killed at 2 mg/L. It is therefore important for swimming pools the posterior fossa structures, midbrain, thalamus, brainstem and
to be maintained properly with adequate chlorination at all times cerebellum. Occasionally, angiitis may be seen with perivascular
[1,2]. Warning signs should be posted in geographic areas with warm, cuffing by inflammatory cells, chiefly lymphocytes, a few plasma cells
freshwater bodies of water, particularly during the summer months. and macrophages. In patients with AIDS, ulcerations of the skin with
acute and chronic inflammation and trophozoites and cysts may
be seen. The kidneys, prostate gland, adrenal glands, lungs and liver
GRANULOMATOUS AMEBIC may also be involved, suggesting hematogenous dissemination.
ENCEPHALITIS (GAE) Recently, two clusters of transmission of B. mandrillaris infection
through solid organ transplantation were reported, further suggesting
GAE caused by Acanthamoeba spp. usually occurs in chronically ill, that the route of invasion to the brain is via the bloodstream [11].
debilitated individuals, in immunosuppressed patients including Histopathologically, Balamuthia can be differentiated from Acan-
those who have AIDS, or in those who have received broad-spectrum thamoeba since the nucleus of Balamuthia sometimes contains
778 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Prevention
Since Acanthamoeba spp. can grow and colonize hot water tanks,
jacuzzis, filters used in HVAC units, and in-line filters used for purify-
ing portable water supplies and eye wash stations, periodic inspection
and cleaning of these systems is recommended.
DIAGNOSTIC MICROBIOLOGY
Accurate diagnosis of AK requires deep corneal scrapings and biopsy.
Unfixed specimens should be cultured on bacterially seeded agar
FIGURE 102.3 Central nervous system section of a granulomatous amebic plates (as above). Smears should also be prepared and stained with
encephalitis (GAE) case due to Balamuthia mandrillaris, showing numerous Giemsa–Wright, Hemacolor, or with Wheatly’s or Masson’s trichrome
trophozoites of B. mandrillaris (H&E; ×100). Inset: more than one nucleolus stain which help differentiate trophozoites of Acanthamoeba spp from
can be seen within the nucleus of the trophozoite (×1000). host corneal cells. Confocal microscopy has also been used recently
to diagnose AK [2,3].
MANAGEMENT
multiple nucleoli (Fig. 102.3). Immunohistochemical analysis using
rabbit anti-Acanthamoeba spp. or anti-B. mandrillaris sera can also dif- Unlike with GAE, successful treatment of AK is feasible, using aggres-
ferentiate the two amebae [1–3]. sive topical application of polyhexamethylene biguanide or chlor
hexidine gluconate in combination with propamidine isethionate
(Brolene) and neomycin. Debridement of the cornea, penetrating
MANAGEMENT keratoplasty and corneal grafting has also been performed with good
There is no effective treatment for GAE and therefore the prognosis is results in some patients. Recurrence of AK has been reported after
poor. Diagnosis of GAE is often made postmortem. A few patients corneal transplantation because of persistence of Acanthamoeba cysts
diagnosed pre-mortem and a few with cutaneous infections without in the corneal stroma [15].
CNS involvement have been successfully treated with a combination
of antimicrobials including pentamidine isethionate, sulfadiazine, Prevention
flucytosine, fluconazole or itraconazole, and miltefosine [12,13].
Eye-care professionals need to educate patients about the proper care
Although the majority of patients with Balamuthia GAE have died, a and use of contact lenses. Contact lenses and contact lens parapher-
few patients have survived the infection. Notably, two transplant nalia, particularly the solutions, should be kept meticulously clean.
recipients have survived after treatment with a combination of penta- Contact lens wearers should follow the directions and recommenda-
midine isethionate, sulfadiazine, a macrolide (azithromycin or clari- tions of the manufacturers and eye-care professionals. Contact lens
thromycin), fluconazole, 5-fluorocytosine and miltefosine [2,8,11,14]. use should be avoided during swimming or other water sports.
Pat h o g e n i c a n d O p p o r t u n i s t i c Fre e - l i v i n g Am e b a I nfec tions 779
DISCLAIMER 9. Seidel JS, Harmatz P, Visvesvara GS, et al. Successful treatment of primary
amebic meningoencephalitis. N Engl J Med 1982;306:346–8.
The findings and conclusions in this report are those of the authors 10. Soltow SM, Brenner GM. Synergistic activities of azithromycin and ampho-
and do not necessarily represent the views of the Centers for Disease tericin B against Naegleria fowleri in vitro and in a mouse model of primary
Control and Prevention. amebic meningoencephalitis. Antimicrob Agents Chemother 2007;51:23–7.
11. Centers for Disease Control 2010. Balamuthia mandrillaris transmitted through
organ transplantation – Mississippi, 2009. MMWR Morb Mortal Wkly Rep
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12. Slater CA, Sickel JZ, Visvesvara GS, et al. Successful treatment of disseminated
1. Martinez AJ, Visvesvara GS. Free-living, amphizoic and opportunistic amebas. Acanthamoeba infection in an immunocompromised patient. N Engl J Med
Brain Pathol 1997;7:583–98. 1994;331:85–7.
2. Visvesvara GS, Moura H, Schuster FL. Pathogenic and opportunistic free-living 13. Aichelberg AC, Walochnik J, Assadian O, et al. Successful treatment of dis-
amoebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and seminated Acanthamoeba infection and granulomatous amoebic encephalitis
Sappinia diploidea. FEMS Immunol Microbiol 2007;50:1–26. in an immunocompromised patient with military tuberculosis and tubercu-
3. Marciano-Cabral F, Cabral G. Acanthamoeba spp. as agents of disease in lous meningitis with miltefosine, an alkylphosphocholine. Emerg Infect Dis
humans. Clin Microbiol 2003;16:273–307. 2008;14:1743–6.
4. Gelman BB, Popov V, Cahlijub G, et al. Neuropathological and ultrastructural 14. Deetz TR, Sawyer MH, Billman G, et al. Successful treatment of Balamuthia
features of amebic encephalitis caused by Sappinia diploidea. J Neuropathol amoebic encephalitis: presentation of two cases. Clin Infect Dis 2003;37:
Exp Neurol 2003;62:990–8. 1304–12.
5. Qvarnstrom Y, da Silva AJ, Schuster FL, et al. Molecular confirmation of Sap- 15. Dart JKG, Saw VPJ, Kilvington S. Acanthamoeba keratitis: diagnosis and treat-
pinia pedata as causative agent of amebic encephalitis. J Infect Dis 2009; ment update. Am J Ophthalmol 2009;148:487–99.
199:1139–42. 16. Verani J, Lorick S, Yoder JS, et al. National outbreak of Acanthamoeba keratitis
6. Fowler M, Carter RF. Acute pyogenic meningitis probably due to Acanthamoeba associated with use of a contact lens solution, United States. Emerg Infect Dis
sp.: a preliminary report. Br Med J 1965;2:740–3. 2009;15:1236–42.
7. Singh P, Kochhar R, Vashishta RK, et al. Amebic meningoencephalitis: spec-
trum of imaging findings. Am J Neuroradiol 2006;27:1217–21.
8. Qvarnstrom Y, Visvesvara GS, Sriram R, Da Silva AJ. A multiplex real-time
PCR assay for simultaneous detection of Acanthamoeba spp., Balamuthia man-
drillaris and Naegleria fowleri. J Clin Microbiol 2006;44:3589–95.
103 Sarcocystosis
Benjamin M Rosenthal
PATHOGENESIS
Key features Sarcocystis parasites are obligatory, two-host, intracellular, intestinal,
coccidian parasites. Sarcocystis hominis and S. suihominis use humans
l Sarcocystis parasites are a rare cause of eosinophilic enteritis, as definitive hosts and are responsible for intestinal sarcocystosis in
subcutaneous nodules, and eosinophilic myositis the human host. Humans may also become dead-end hosts for non-
l Humans are definitive hosts for Sarcocystis hominis and human Sarcocystis spp. after the accidental ingestion of oocysts.
Sarcocysti suihominis, the agents responsible for intestinal Both sporulated oocysts (containing two sporocysts) and individual
sarcocystosis. Ingesting sarcocysts found in uncooked or sporocysts can be passed in stool. Sporocysts contain four sporozoites
undercooked beef or pork may cause mild enteritis, but and a refractile residual body. Sporocysts ingested by the intermediate
most infections are thought to be asymptomatic host (cattle for S. hominis and pigs for S. suihominis) rupture, releasing
sporozoites. Sporozoites enter endothelial cells of blood vessels and
l Humans may also become dead-end (intermediate) hosts undergo schizogony, resulting in first-generation schizonts. Mero-
for nonhuman Sarcocystis spp. after the accidental ingestion zoites derived from the first generation invade small capillaries and
of oocysts. This ingestion leads to muscular sarcocystosis, a blood vessels, becoming second-generation schizonts. The second-
clinical spectrum ranging from asymptomatic muscle cysts generation merozoites invade skeletal and heart myocytes, as well as
to a severe, acute, eosinophilic myositis associated with neurons, and develop into metrocysts and undergo a series of internal
systemic symptoms with peripheral eosinophilia mitotic divisions (endodyogeny). When filled with bradyzoites, the
metrocyst becomes a sarcocyst (Fig. 103.2A) that will be infectious
l Most human cases have been described from Southeast when eventually consumed by the definitive host. There is no evi-
Asia, but Sarcocystis parasites have a worldwide distribution, dence that rupture of sarcocysts in the intermediate host can initiate
especially where livestock is raised, and human infections in new rounds of replication in the intermediate host.
other areas have been described but may be Much of our understanding of the pathogenesis of intestinal infection
under-recognized in humans comes from experiments infecting human volunteers
with sarcocysts (although, arguably, unnaturally large numbers were
ingested). Several days after exposure, and for several days thereafter,
infected persons will excrete oocysts and infective sporocysts in the
stool. Although people can experience lengthy, indeed lifelong infec-
tion with sarcocysts, the identity and natural history of those parasites
TRANSMISSION AND EPIDEMIOLOGY remain unknown. Excellent, illustrated reviews of zoonotic sarcocys-
tosis are available [4–6].
Humans are the definitive hosts when they consume undercooked
pork or beef containing tissue cysts (sarcocysts) (Fig. 103.1) of the two
recognized human species, Sarcocystis hominis and Sarcocystis suihom- CLINICAL MANIFESTATIONS
inis, and they develop intestinal sarcocystosis – a transient infection Human disease can manifest as either an enteric infection or as a
restricted to the gastro-intestinal tract. muscular infection (Table 103-1) Older reviews of sarcocystis infec-
The vast majority of over 100 different parasite species are found in tions in man are available [7, 8].
other mammals. In nature, carnivores acquire infection by consuming
prey whose tissues harbor encysted parasites. The carnivores excrete ENTERIC INFECTION
the parasite oocysts which are then consumed by herbivores ingesting
contaminated vegetation or water. Humans are accidental intermedi- Most individuals with intestinal sarcocystosis remain asymptomatic
ate hosts for several other Sarcocystis species. and naturally occurring gastrointestinal illness is rare, or rarely recog-
nized. Symptoms induced by experimental challenge include nausea,
Sarcocystis parasites have a worldwide distribution. Our understand- abdominal discomfort and self-limited diarrhea, with symptom
ing of the epidemiology of human sarcocystosis relies on sporadic severity dependent on the amount of meat consumed [5]. Onset of
case reports and occasional outbreaks, mostly described from South- diarrhea is generally rapid (in some subjects 3–6 hours post-ingestion),
east Asia, especially Malaysia and Thailand. Limited seroprevalence normally within 48 hours of ingestion. Illness is typically brief and
studies and stool surveys confirm widespread distribution and expo- self-limited, usually resolving within 36 hours of onset. A segmental,
sures, and suggest human infections are likely under-recognized [2]. eosinophilic, necrotizing enteritis attributed to sexual forms of Sarco-
Incidental findings at autopsy suggest widespread infection in cystis has been reported; however, causation in these cases was not
endemic areas. One series of 100 consecutive, routine autopsies from definitely established [9]. The intensity of symptoms may be related
Malaysia documented evidence of sarcocystosis in 21% of muscle to the infectious dose of sarcocysts ingested, rather than the infecting
tissue examinations [3]. species of Sarcocystis.
780
S a rcoc ystosis 781
FINAL HOST
Man
Infected meat
eaten by man
Gametes
INTERMEDIATE HOSTS
Bovine and swine
Sporulated
Unsporulated
oocyst
oocyst
Sporocyst
A B
FIGURE 103.2 Photomicrographs of Sarcocystis muris. (A) Developing sarcocyst in muscle tissue. Immature metrocytes (mc) and mature bradyzoites (bz)
are enclosed by the sarcocyst wall (scw). (B) Two sporulated oocysts. Sporozoites (sz) and residuum bodie (rb) are enclosed by the prominent sporocysts
wall (spw) which, in turn, are paired within the oocyst wall (ow). In many instances, unpaired sporocysts will be recovered owing to rupture of the oocysts
wall. The scale bar denotes 20 microns.
PUBLIC HEALTH BURDEN 6. Dubey JP, Speer CA, Fayer R. Sarcocystosis of animals and man. Boca Raton:
CRC Press; 1989.
The public health burden of human sarcocystosis remains unknown. 7. Jeffrey HC. Sarcosporidiosis in man. Trans R Soc Trop Med Hyg
Although veterinary data implicate immune suppression as a clinical 1974;68:17–29.
risk factor for sarcocystosis, and although pregnancy and AIDS mark- 8. Beaver PC, Gadgil K, Morera P. Sarcocystis in man: a review and report of five
cases. Am J Trop Med Hyg 1979;28:819–44.
edly exacerbate toxoplasmosis (caused by a closely related zoonotic
9. Bunyaratvej S, Unpunyo P, Pongtippan A. The Sarcocystis-cyst containing beef
parasite), less is currently known about how vulnerability to sarcocys-
and pork as the sources of natural intestinal sarcocystosis in Thai people.
tosis may vary among individuals [15]. J Med Assoc Thai 2007;90:2128–35.
Intensive transmission should be limited to those who routinely 10. Arness MK, Brown JD, Dubey JP, et al. An outbreak of acute eosinophilic
consume uncooked meat and live where untreated human wastes myositis attributed to human Sarcocystis parasitism. Am J Trop Med Hyg
routinely expose livestock to renewed exposure [9]. Indeed, epidemics 1999;61:548–53.
have been documented where such circumstances prevail. However, 11. Mehrotra R, Bisht D, Singh PA, et al. Diagnosis of human Sarcocystis infection
from biopsies of the skeletal muscle. Pathology 1996;28:281–2.
the population at risk for such infections has never been defined with
12. Xiang Z, Chen X, Yang L, et al. Non-invasive methods for identifying oocysts
certainty. Prevalent S. hominis in European cattle [16], but not in
of Sarcocystis spp. from definitive hosts. Parasitol Int 2009;58:293–6.
American cattle [17], suggest that geographic variation in risk may 13. Giboda M, Ditrich O, Scholz T, et al. Current status of food-borne parasitic
occur, even among developed countries. zoonoses in Laos. Southeast Asian J Trop Med Public Health 1991;22
(suppl.):56–61.
REFERENCES 14. Dubey JP, Saville WJ, Sreekumar C, et al. Effects of high temperature and
disinfectants on the viability of Sarcocystis neurona sporocysts. J Parasitol
1. Murrell KD, Fayer R, Dubey JP. Parasitic Organisms. Advances in Meat 2002;88:1252–4.
Research. West Port, CT: AVI Publishing Co.; 1986. 15. Velásquez JN, Di Risio C, Etchart CB, et al. Systemic sarcocystosis in a patient
2. Wilairatana P, Radomyos P, Radomyos B, et al. Intestinal sarcocystosis in Thai with acquired immune deficiency syndrome. Hum Pathol 2008;39:1263–7.
laborers. Southeast Asian J Trop Med Public Health 1996;27:43–6. 16. Vangeel L, Houf K, Chiers K, et al. Molecular-based identification of Sarcocystis
3. Wong KT, Pathmanathan R. High prevalence of human skeletal muscle sar- hominis in Belgian minced beef. J Food Prot 2007;70:1523–6.
cocystosis in southeast Asia. Trans R Soc Trop Med Hyg 1992;86:631–2. 17. Pritt B, Trainer T, Simmons-Arnold L, et al. Detection of Sarcocystis parasites
4. Dubey JP, Fayer R. Sarcocystosis. Br Vet J 1983;139:371–7. in retail beef: a regional survey combining histological and genetic detection
5. Fayer R. Sarcocystis spp. in human infections. Clin Microbiol Rev 2004;17: methods. J Food Prot 2008;71:2144–7.
894–902.
104 Microsporidiosis
Louis M Weiss
l Microsporidia are a diverse group of obligate intracellular Microsporidia are obligate intracellular parasites which are classified
in a separate phylum—the Microsporidia—consisting of approxi-
eukaryotic parasites most closely related to fungi
mately 170 genera and more than 1200 species [2, 3]. They are clas-
l Microsporidia form characteristic spores that are diagnostic sified based on their ultrastructural features, including size and
for the phylum. Spores possess a unique organelle—the morphology of the spores, number of coils of the polar tube, devel-
polar tubule or polar filament—which is coiled inside the opmental lifecycle and host–parasite relationship [4]. Molecular data,
spore based primarily on small subunit RNA genes, have also been used to
define taxonomic relationships and for the diagnosis of these patho-
l Spores of species associated with human infection measure
gens. Although traditionally believed to be “primitive” protozoa,
1–4 µm molecular phylogenetic analysis has suggested that the Microsporidia
l While Microsporidia can infect immunocompetent hosts, are instead related to the Fungi [5, 6]. The genome size of the Micro-
they are more commonly seen in the setting of cell- sporidia varies from 2.3 to 19.5 Mb with that of the Encephalitizoo-
mediated immune dysfunction nidae being less than 3.0 Mb, making them among the smallest
eukaryotic nuclear genomes so far identified.
l The most common manifestations of infection are diarrhea
and keratoconjunctivitis; however, Microsporidia can infect
virtually any organ, causing a variety of symptoms, EPIDEMIOLOGY
including disseminated disease, hepatitis, myositis, kidney The Microsporidia infect virtually all animal phyla, including other
and urogenital infection, ascites, cholangitis, and protists. They have a worldwide distribution and are important agri-
asymptomatic carriage cultural parasites in insects, fish, and mammals. They have been
l Examination of stool or urine specimens using special stains found in every tissue and organ, and spores are common in environ-
mental sources [2]. Many human infections are likely zoonotic and/
is a practical method for the diagnosis of microsporidiosis.
or transmitted by water [7]. Domestic and wild animals may be natu-
Definitive species diagnosis requires transmission electron rally infected with E. cuniculi, E. intestinalis, and Enterocytozoon bieneusi.
microscopy visualization of spore ultrastructure or Birds, especially parrots (parakeets, love birds, budgies), are naturally
molecular methods (PCR) infected with E. hellem. Enterocytozoon bieneusi and V. corneae have
l Albendazole is the drug of choice to treat gastroenteritis
caused by Encephalitozoon intestinalis and to treat
disseminated microsporidiosis with or without local
manifestations (Encephalitozoon hellem, Encephalitozoon
cuniculi, E. intestinalis, Pleistophora sp., Trachipleistophora sp.,
Brachiola vesicularum)
l Fumagillin is the drug of choice to treat gastroenteritis and
disseminated infection caused by Enterocytozoon bieneusi,
but is associated with thrombocytopenia
l The treatment of choice for ocular microsporidiosis (E.
hellem, E. cuniculi, Vittaforma corneae) is oral albendazole plus
topical fumagillin. Corneal infections with V. corneae often do
not respond to chemotherapy and may require keratoplasty
INTRODUCTION
First recognized by Nageli in 1857 as the cause of disease in silkworms,
microsporidia were not suspected as being a cause of human disease
until 1959, when they were found in a child with encephalitis. Con-
clusive evidence of Microsporidia as pathogens dates to 1973, when FIGURE 104.1 Anncaliia (Nosema) connori (arrow) in a human infant
a 4-month-old athymic boy died with severe diarrhea and malabsorp- (×1260) (courtesy of Drs Daniel Connor and Ann Cali, and the Armed Forces
tion caused by Nosema (now Anncaliia) connori (Fig. 104.1). Interest Institute of Pathology, Photograph Neg. No. 71–5882).
784
M i c rospor idiosis 785
been identified in surface waters, and spores of Nosema sp. (likely represents an important and emerging opportunistic disease, occur-
Anncaliia algerae) have been identified in ditchwater. Human-to- ring mainly, but not exclusively, in severely immunocompromised
human transmission is likely although not proven. patients with AIDS. Additionally, cases of microsporidiosis in immu-
nocompromised persons not infected with HIV, as well as in immu-
Prevalence of microsporidiosis varies from not detected to over 80% nocompetent persons, also have been reported. Microsporidia is
depending on the geographic region, method of diagnosis and demo- likely a common enteric pathogen causing self-limited disease and
graphic characteristics of the population being studied. Microsporidi- asymptomatic carriage. The clinical manifestations of microsporidi-
osis is increasingly recognized in non-HIV-infected populations, such osis are very diverse, varying according to the causal species, with
as travelers, children, the elderly and organ transplant recipients. Most chronic or persistent diarrhea being the most common presenting
infections in immunocompetant and naïve hosts are likely self- syndrome. Microsporidiosis can also present as keratoconjunctivitis,
limited or asymptomatic. Current understanding suggests that Micro- disseminated disease, hepatitis, myositis, kidney and urogenital infec-
sporidia are as common in humans as they are in other mammals, tion, ascites and/or cholangitis.
and are associated with travel or residence in developing nations [8].
Microsporidal keratitis is increasingly recognized in endemic areas The genus Microsporidium is used to designate Microsporidia of uncer-
and is likely associated with exposure to soil, muddy water and minor tain taxonomic status. No one genus is uniquely associated with a
trauma, with higher incidence during the rainy season [9]. specific clinical syndrome; rather, there is considerable overlap in
clinical disease across species.
Genus Enterocytozoon
Enterocytozoon bieneusi Chronic diarrhea, acalculous cholecystitis, wasting syndrome, sinusitis, rhinitis and can invade
cholangioepithelium leading to sclerosing cholangitis, cholangiopathy and cholecystitis
Genus Trachipleistophora
Trachipleistophora anthropophthera Disseminated infection, keratoconjunctivits, encephalitis
Trachipleistophora hominis Myositis, stromal keratitis, (probably disseminated infection)
Genus Pleisitophora
Pleistophora ronneafiei and Pleistophora sp. Myositis
Genus Nosema/Vittaforma
Nosema ocularum Keratoconjunctivitis
Vittaforma (Nosema) corneae Keratoconjunctivitis, urinary tract infections
Genus Microsporidium
Microsporidium africanus Corneal ulcer
Microsporidium ceylonensis Corneal ulcer
competent patients from Botswana (Microsporidium africanus) and Sri E. intestinalis; however, other microsporida have also been demon-
Lanka (M. ceylonesis). Other cases of keratitis have since been identi- strated in cases of diarrheal disease (e.g. Anncaliia connori, Vittaforma
fied to be caused by Nosema ocularum and N. corneum (now V. cornea). spp., E. hellem, E. cuniculi). In patients undergoing liver and bone
Treatment of these infections has often required surgery (keratoplasty marrow transplantation, clinical manifestations have included watery,
and/or corneal transplant). Encephalitozoon spp. and Trachipleistophora non-bloody diarrhea; nausea; and diffuse abdominal pain. Kotler and
anthropophthera corneal infections have been described in contact Orenstein found that 39% of patients with HIV and diarrhea, present-
lens-wearers. These infections have responded to topical therapy. In a ing to a gastroenterology clinic had microsporidosis and that the
report from India on 40 immune competent patients, epidemic kera- presence of Microsporidia was associated with wasting, a mean CD4
toconjuctivits has been associated with Microsporidia [12]. Many of count of 28 cells/mm3 and an abnormal D-xylose test result, whereas
these resolved without specific treatment. only 2.6% of HIV-infected patients without diarrhea had micro-
sporidiosis [13]. Coyle and colleagues, using PCR employing primers
to the small subunit rRNA gene of E. bieneusi, also found a significant
INFECTIONS IN PATIENTS WITH association between the presence of diarrhea and Microsporidia in
IMMUNE DEFICIENCIES patients with AIDS [11].
While the majority of reported infections have been in patients with Ocular infection in immune compromised hosts has been restricted
AIDS (and CD4 counts less than 100 cells/mm3), infections have been to the superficial epithelium of the cornea and conjunctiva (i.e. super-
seen in organ transplantation patients, patients with various hemato- ficial keratoconjunctivitis) (Fig. 104.3). This keratitis rarely progresses
logic malignancies and those being treated with immunosuppressive to corneal ulceration. Most patients present with bilateral coarse
medications (especially antibodies to tumor necrosis factor [TNF]-α). punctate epithelial keratopathy and conjunctival inflammation result-
Gastrointestinal infection usually involves chronic diarrhea of 3–10 ing in redness, foreign body sensation, photophobia and changes in
bowel movements per day, anorexia, weight loss and bloating without visual acuity [14]. Biopsy specimens examined with transmission
associated fever. It is usually caused by E. bieneusi and, occasionally, electron microscopy (TEM) have revealed numerous microsporidian
M i c rospor idiosis 787
A C D
FIGURE 104.3 Encephalitozoon hellem keratoconjunctivitis. (A) Slit lamp examination demonstrating punctuate keratoconjunctivitis, (B) conjunctival
scraping stained with Giemsa demonstrating organisms with typical morphology of microsporidia, (C) conjunctival scraping stained with calcofluor white
demonstrating fluorescent spores, (D) TEM of Encephalitozoon hellem in conjunctival tissue from a patient with keratoconjunctivitis. The characteristic
coiled polar tube is present in cross section (arrows).
PATIENT EVALUATION, DIAGNOSIS, Examination of stool specimens by light microscopy using modified
AND DIFFERENTIAL DIAGNOSIS trichrome stain (chromotrope 2R) (Fig. 104.5), Uvitex 2B or cal-
cofluor white is the standard method for diagnosing gastrointestinal
A confirmed diagnosis of microspordiosis requires parasitologic con- microsporidiosis. Overall, the sensitivity of Uvitex 2B and calcofluor
firmation of the parasite in a clinical specimen with an appropriate white is slightly higher than that of modified trichrome stain; however,
laboratory test. There are several methods useful for diagnosing sus- the specificity of the chemofluorescent stains is lower. Microscopy
pected microsporidiosis. does not allow identification of microsporidia to the species level.
788 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
As renal involvement with shedding of spores in the urine is common Fumagillin, an antibiotic derived from the fungus Aspergillus fumiga-
in all of the species of Microsporidia that disseminate, urine speci- tus, have in vitro and in vivo activity against E. cuniculi, E. hellem, E.
mens should be obtained whenever the diagnosis of microsporidiosis intestinalis, E. bieneusi, Nucleospora (Ent.) salmonis, and V. corneae. Fum-
is considered. This has therapeutic implications, as the Microsporidia agillin has been demonstrated in a dose-escalation trial, case reports
that disseminate (e.g. Encephalitozoon) are usually sensitive to alben- and a randomized clinical trial to be effective for the treatment of
dazole, whereas those that do not disseminate (e.g. E. bieneusi) are human infection with E. bieneusi at a dose of 60 mg/day (20 mg three
resistant. In tissue sections (Figs 104.2 and 104.5), touch preparations times daily) for 2 weeks [23]. The main limiting toxicity of treatment
or corneal scrapings (Figs 104.3B, C), Microsporidia are discernible was thrombocytopenia beginning about a week after initiation of
with hematoxylin-eosin, Giemsa, tissue Gram or chromotrope 2R treatment and reaching a nadir three days after the end of treatment.
stains. Histologically, microsporidian spores are easily discernible Thrombocytopenia was reversible in 1–2 weeks on stopping fumagil-
with a modified tissue chromotrope 2R or tissue Gram stain (Brown- lin treatment. Complete blood counts should be monitored every
Hopp or Brown-Brenn) in sections prepared from fixed tissue using other day and the drug discontinued if platelet counts fall below
routine procedures. 75,000 per cubic millimeter. Oral fumagillin at 20 mg/kg 3 or 4 times
daily for 7–10 days is also recommended in transplant-associated
microsporidiosis caused by E. bienusi, although the optimal dose
TREATMENT (Table 104-1) regimen has not been defined [24].
Microsporidiosis is primarily an opportunistic infection in the immu- Solutions of the soluble salt, Fumidil B (fumagillin bicylohexylam-
nocompromised host. monium), applied topically have been demonstrated to be nontoxic
to the cornea and treatment of ocular microsporidiosis can be accom-
Studies have demonstrated that immune reconstitution can result plished using a 3-mg/ml solution of Fumidil B in saline (fumagillin
in clinical response in patients with microsporidiosis secondary to 70 µg/ml) [11]. Treatment should probably be continued indefinitely,
immune dysfunction. Immune reconstitution with cART in patients as recurrence has been reported upon stopping the drops.
with AIDS or reversal of iatrogenic immunosuppression, when pos-
sible, is an important management principle [2]. The efficacy of imidazole compounds on microsporidiosis is variable.
Other medications used without success in the treatment of gastroin-
Immune reconstitution syndrome (IRIS) has been reported in testinal microsporidiosis are azithromycin, metronidazole, paromo-
a patient with microsporidiosis treated with anti-retroviral therapy mycin, sulfamethoxazole and quinacrine.
[17]; however, based on clinical experience, IRIS reactions
are not common in this setting. Aspartyl protease inhibitors of HIV Microsporidal keratitis with and without systemic involvement is a
have been shown to inhibit replication of E. intestinalis in tissue specialized clinical manifestation that requires management in con-
culture. junction with an ophthalmologist. Topical flouroquinolones as mon-
otherapy or in combination with topical fumagillin, topical steroids
Albendazole is a benzimidazole effective against many helminths and and systemic albendazole may all be appropriate depending on the
protozoa that inhibits microtubule assembly. Albendazole was ini- extent of infection [25].
tially shown effective in severely immunosuppressed (<50 CD4 cells/
ml) patients with AIDS with systemic disease, disseminated infection For a review of drugs used in microsporidiosis in humans and animals
with E. intestinalis and chronic diarrhea. Treatment with albendazole see Costa and Weiss [26]. Neither oral nor topical fumagillin is an
400 mg twice daily resulted in a dramatic and rapid clinical resolution approved drug by the United States Food and Drug Administration
of diarrhea and transient elimination of the organism from feces and (FDA) and are not easily available in the USA.
urine [18]. In a subsequent small, randomized, double-blind, con-
trolled trial, albendazole at 400 mg twice daily for three weeks led to
rapid clinical improvement and elimination of the pathogen [19]. PREVENTION
Prevention of relapse is best accomplished by immune reconstitution As the Microsporida that infect humans are likely food- or water-
but albendazole at 400mg twice daily was shown to significantly borne pathogens, standard sanitary measures that prevent contamina-
delay relapse [19]. Treatment with albendazole for intestinal disease tion of food and water with the urine and feces of animals should
caused by E. bieneusi in patients with AIDS has not proven effective. decrease the chance for infection. Hand-washing and general hygienic
Albendazole at 400 mg twice daily for one month in patients with habits probably reduce the chance for contamination of the conjunc-
chronic diarrhea, weight loss and malabsorption did not clear infec- tiva and cornea in contact lens-wearers. The presence of infective
tion, although there was a statistically significant decrease in bowel spores in various bodily fluids suggests that universal precautions in
movements from seven per day to four per day [20]. healthcare settings and general attention to hand-washing and other
Albendazole has also been used for the treatment of clinical syn- personal hygiene measures should be useful in preventing primary
dromes caused by microsporidia other than E. intestinalis although infections. Immune compromised patients may wish to consider
clinical trial data is lacking. Clinical and radiographic improvement using bottled or filtered water in some settings. No prophylactic anti-
was seen in a case of chronic sinusitis caused by E. hellem treated with parasitic agents have been identified for these organisms.
albendazole 400 mg bid. Marked clinical improvement with alben-
dazole occurred in a patient with disseminated infection caused by E.
cuniculi involving the conjunctiva, sinuses, kidneys and lungs. Resolu- REFERENCES
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caused by T. hominis treated with albendazole. Albendazole as a sys- patient with AIDS. J Protozool 1985;32:250–4.
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endemic areas and also returning travelers. In a randomized, open Rev Microbiol 1992;18:285.
study in Costa Rica, albendazole at 15 mg/kg/day twice a day for 5. Weiss LM, Vossbrinck CR. Microsporidiosis: molecular and diagnostic aspects.
seven days was effective in improving clinical symptoms and decreas- Adv Parasitol 1998;40:351–95.
ing duration of illness from 10 days to 5 days in children ages 6–36 6. Lee SC, Corradi N, Byrnes EJ, 3rd, et al. Microsporidia evolved from ancestral
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8. Didier ES, Stovall ME, Green LC, et al. Epidemiology of microsporidiosis: 18. Molina JM, Oksenhendler E, Beauvais B, et al. Disseminated microsporidiosis
sources and modes of transmission. Vet Parasitol 2004;126:145–66. due to Septata intestinalis in patients with AIDS: Clinical features and response
9. Sharma S, Das S, Joseph J, et al. Microsporidial keratitis: need for increased to albendazole therapy. J Infect Dis 1995;171:245.
awareness. Surv Ophthalmol 2011;56:1–22. 19. Molina JM, Chastang C, Goguel J, et al. Albendazole for treatment and proph-
10. Khan I, Moretto M, Weiss LM. Immune response against Encephalitozoon ylaxis of microsporidiosis due to Encephalitozoon intestinalis in patients with
cuniculi infection. Microbes Infect 2001;3:401–5. AIDS: a randomized double-blind controlled trial. J Infect Dis 1998;177:
11. Coyle CM, Wittner M, Kotler DP, et al. Prevalence of microsporidiosis (Ente- 1373–7.
rocytozoon bieneusi and Encephalitozoon [Septata] intestinalis) in AIDS related 20. Dieterich DT, Lew EA, Kotler DP, et al. Treatment with albendazole for intes-
diarrhea as determined by the polymerase chain reaction to microsporidian tinal disease due to Enterocytozoon bieneusi in patients with AIDS. J Infect Dis
small subunit ribosomal RNA. Clin Infect Dis 1996;23:1002. 1994;169:178–83.
12. Das S, Sharma S, Sahu SK, et al. New microbial spectrum of epidemic kera- 21. Tremoulet AH, Avila-Aguero ML, París MM, et al. Albendazole therapy for
toconjunctivitis: clinical and laboratory aspects of an outbreak. Br J Ophthal- Microsporidium diarrhea in immunocompetent Costa Rican children. Pediatr
mol 2008;92:861–2. Infect Dis J 2004;23:915–18.
13. Kotler DP, Orenstein JM. Prevalence of intestinal microsporidiosis in HIV 22. Wichro E, Hoelzl D, Krause R, et al. Microsporidiosis in travel-associated
infected individuals referred for gastroenterological evaluation. Am J Gastro- chronic diarrhea in immune-competent patients. Am J Trop Med Hyg 2005;
enterol 1994;89:1998. 73:285–7.
14. Rastrelli PD, Didier ES, Yee RW. Microsporidial keratitis. Ophthalmol Clin 23. Molina JM, Tourneur M, Sarfati C, et al. Fumagillin treatment of intestinal
North Am 1994;7:617. microsporidiosis. N Engl J Med 2002;346:1963–9.
15. Moura H, Schwartz DA, Bornay-Llinares F, et al. A new and improved “quick- 24. Lanternier F, Boutboul D, Menotti J, et al. Microsporidiosis in solid organ
hot Gram-chromotrope” technique that differentially stains microsporidian transplant recipients: two Enterocytozoon bieneusi cases and review. Transpl
spores in clinical samples, including paraffin-embedded tissue sections. Arch Infect Dis 2009;11:83–8.
Pathol Lab Med 1997;121:888–93. 25. Loh RS, Chan CM, Ti SE, et al. Emerging prevalence of microsporidial keratitis
16. Weiss LM, Vossbrinck CR. Microsporidiosis: molecular and diagnostic aspects. in Singapore: epidemiology, clinical features, and management. Ophthalmol-
Adv Parasitol 1998;40:351–95. ogy 2009;116:2348–53.
17. Sriaroon C, Mayer CA, Chen L, et al. Diffuse intra-abdominal granulomatous 26. Costa SF, Weiss LM. Drug treatment of microsporidiosis. Drug Resist Update
seeding as a manifestation of immune reconstitution inflammatory syndrome 2000;3:384–99.
associated with microsporidiosis in a patient with HIV. STDS 2008;22:
611–12.
Miscellaneous Tissue Protozoa 105
Edward T Ryan
Protozoal organisms may be seen during histologic examination of severely immunocompromised, including individuals with AIDS,
tissue samples in a number of infectious processes other than toxo- severe combined immunodeficiency syndrome, severe hypogamma-
plasmosis, Chagas’ disease, sarcocystosis and microsporidiosis. Leish- globulinemia, or lymphoma. Such extension usually involves the
manial organisms infect monocytic and macrophage cell lines, and biliary system and may include bile duct wall thickening, acalculus
leishmaniasis is most commonly categorized as cutaneous, mucocu- cholecystitis, sclerosing cholangitis, and ampullary stenosis [4].
taneous or visceral (see Chapter 99). In immunocompetent individu- There have also been rare reports involving severely immunocom-
als with leishmaniasis, the most commonly involved tissues include promised individuals with cryptosporidial involvement extending
bone marrow, spleen, liver, lymph nodes, skin, and mucous mem- into the respiratory epithelium lining the trachea, bronchi, and
branes of the nasopharyngeal area. In immunocompromised indi- bronchioles [5, 6].
viduals, there may also be involvement of gastrointestinal tissues and
mesenteric lymph nodes [1, 2]. Histologic examination of these
tissues will disclose intra-marcophage protozoal Leishmania species REFERENCES
parasites, often Leishmania donovani. Gastrointestinal involvement is 1. Laguna F, García-Samaniego J, Soriano V, et al. Gastrointestinal leishmaniasis
most commonly encountered in individuals with severe immuno- in human immunodeficiency virus-infected patients: report of five cases and
compromising states, including advanced HIV infection or AIDS review. Clin Infect Dis 1994;19:48–53.
(most commonly in individuals with a CD4 count of <200/mm3). 2. Stenzinger A, Nemeth J, Klauschen F, et al. Visceral leishmaniasis in a patient
Immunocompromised individuals with gastrointestinal leishmania- with AIDS: early pathological diagnosis using conventional histology, PCR
sis may present with diarrhea, dysphagia, abdominal discomfort, and and electron microscopy is the key for adequate treatment. Virchows Arch
weight loss. Endoscopy may disclose normal-appearing superficial 2012;460:357–60.
mucosa in almost half of cases [1]; however, histologic examination 3. Muñoz-Rodríguez FJ, Padró S, Pastor P, et al. Pleural and peritoneal leishma-
will disclose infiltration of the lamina propria and submucosal tissue niasis in an AIDS patient. Eur J Clin Microbiol Infect Dis 1997;16:246–8.
with leishmanial-laden macrophages and monocytes. In rare cases, 4. Seaman DL, Chahal P, Sanderson SO, et al. Biliary cryptosporidiosis in a
involvement of the peritoneum and pleural cavities has also been patient without HIV infection: endosonographic, cholangiographic, and his-
described [3]. tologic features (with video). Gastrointest Endosc 2009;70:590–2.
5. Moore JA, Frenkel JK. Respiratory and enteric cryptosporidiosis in humans.
Similarly, cryptosporidiosis is most commonly considered an intra Arch Pathol Lab Med 1991;115:1160.
cellular protozoal infection of the intestinal mucosal epithelial 6. Travis WD, Schmidt K, MacLowry JD, et al. Respiratory cryptosporidiosis in a
surface (see Chapter 91). However, tissue involvement may extend patient with malignant lymphoma. Report of a case and review of the litera-
beyond the intestinal epithelial surface in individuals who are ture. Arch Pathol Lab Med 1990;114:519.
791
6
PA R T
HELMINTHIC INFECTIONS
106 General Principles
G Thomas Strickland, David R Hill
The important trematodes of humans belong to the following genera: TRANSMISSION BY SKIN PENETRATION
(1) adults that live in the venous system—Schistosoma (Chapter 122);
(2) adults that live in the intestines—Fasciolopsis, Echinostoma, Hetero- Larval stages of hookworm and S. stercoralis in the soil cause infec-
phyes, Gastrodiscoides, and Metagonimus (Chapter 123); (3) adults that tion when they penetrate intact skin. The larvae of dog and cat hook-
live in the biliary system—Clonorchis, Opisthorchis, Fasciola, and Dicro- worms can penetrate unbroken skin, but cannot develop fully in
coelium (Chapter 124); and (4) adults that live in the bronchi—Para- humans, and cause a creeping eruption. Cercariae of Schistosoma
gonimus (Chapter 125). species penetrate the skin of those exposed to contaminated water.
Species not capable of developing in humans cause a rash called
swimmer’s itch.
CESTODA
This comprises the true tapeworms, which have a head (scolex) and TRANSMISSION BY BITE OF A VECTOR
segments (proglottids). Adults are all parasitic and hermaphroditic
and live in the intestinal lumen of vertebrate hosts. Those that can The filarial parasites develop within the biologic vector, which is also
infect humans include Diphyllobothrium latum and Diphyllobothrium an intermediate host. These can be mosquitoes (W. bancrofti or B.
pacificum, Taenia saginata and Taenia solium, Hymenolepis nana and malaya), black flies (O. volvulus), or Chrysops flies (Loa loa).
Hymenolepis diminuta and Dipylidium caninum. Their invasive larval
stages (hydatid, cysticercus, sparganum, coenurus) can be found in
various organs and tissues of humans and other intermediate hosts
MAGNITUDE OF THE HEALTH
(Chapters 127–131). PROBLEM
ANATOMY AND PHYSIOLOGY TROPICS AND SUBTROPICS
Because many people are infected with more than one species of
Helminths are complicated multicellular organisms. Those infecting helminth, there are more different species of helminths infecting
humans range in length from 0.3 mm (e.g. T. canis and A. braziliense people than there are people in the world. The numbers infected
larvae) to 12 m (e.g. adult T. saginata). They are round (nematodes) with hookworms, Ascaris, Trichuris, pinworm, schistosomes,
or flat (flukes and tapeworms). They all have an outer coating—the onchocerca and filariae are each in the many millions, although they
cuticle—which provides protection and is involved in active transport have often been “neglected” in tropical disease control priorities. A
of water, electrolytes, and other substances. common trinity of intestinal helminthiasis, termed the soil-
Almost all helminths are unable to multiply in their host. The repro- transmitted helminths, includes ascariasis, hookworm infection, and
ductive organs make up a large portion of the body cavities. The trichuriasis.
nematodes are sexually distinct, with separate males and females. The The magnitude of disease caused by helminths is related to the inten-
trematodes and cestodescan have separate male and female sexes sity of infection. Individuals with light infections have few, or no,
(schistosomes) or male and female reproductive organs in the same abnormal findings, whereas those with heavy and prolonged infec-
worm or proglottid segment (other flukes and the tapeworms). The tions often have clinical symptoms and signs and can develop com-
trematodes reproduce by self-fertilization or by cross-fertilization, and plications. This is well documented in schistosomiasis, hookworm
sperm can be transferred between adjacent mature proglottids of the disease, onchocerciasis, and filariasis.
tapeworms.
TEMPERATE CLIMATES
TRANSMISSION Prior to the middle of the twentieth century, the helminthiases were
Parasitic worms infect humans in almost all regions of the world, but a significant cause of morbidity in the USA. Infections with the intes-
there is a particular abundance in the tropics of parasite species and tinal nematodes were particularly common in the Southeast. However,
infected individuals. Many parasites require special conditions of tem- improvements in sanitation have decreased the incidence, except cos-
perature and humidity for survival and multiplication. Others require mopolitan parasites such as pinworm.
particular vertebrate or invertebrate hosts, for example fish, snails,
crustaceans, or insects, for the completion of their lifecycles. The MIGRANTS AND TRAVELERS
intermediate hosts, particularly insect vectors, are also more abundant
in warm climates. Helminths can be found in migrants to high-income countries and
in those who have lived for prolonged periods in tropical regions. The
usual intestinal nematodes, as well as the liver flukes (C. sinensis and
ORAL TRANSMISSION Opisthorchis viverrini), the lung fluke (P. westermani) and Schistosoma
The distribution of intestinal nematodes whose eggs are passed in mekongi and Schistosoma japonicum, are sometimes found in migrants
human feces is affected by climatic conditions (e.g. rainfall, tempera- from Southeast Asia. Those from Mexico and Central America may
ture, and humidity), as well as sanitary practices. There can be pollu- have intestinal nematodes. Epilepsy caused by cerebral cysticercosis is
tion of soil, water supplies, and foods (particularly vegetables), seen in migrants from Latin America. Migrants from Africa can have
resulting in a high prevalence of fecally transmitted nematodes. intestinal nematodes, S. mansoni and S. haematobium, T. saginata, W.
bancrofti, and O. volvulus.
Eating habits account for the transmission of other helminths. Inges-
tion of undercooked or raw meat (T. spiralis, Taenia species) or fish
(anisakid larvae, D. latum, and Clonorchis sinensis and Opisthorchis CHEMOTHERAPY
species) infected with larval stages of the parasite transmits some
helminths. Other helminthic infections follow the ingestion of larvae- Treatment of helminths involves mass drug treatment of populations
contaminated water (D. medinensis), raw snails (Angiostrongylus and treatment of individuals. Mass drug treatment can be given to
species), raw or undercooked crabs (Paragonimus westermani), and decrease the burden of infection and disease in a population, for
aquatic plants (Fasciola hepatica and Fasciolopsis buski). example, ivermectin treatment of filiarial infections in Africa or alben-
dazole for soil-transmitted helminths. Treatment of an individual has
People are infected with Toxocara canis and Echinococcus granulosus the aim of decreasing the intensity of worm infection or curing infec-
following the ingestion of substances contaminated with dog feces tion. Therapy of specific helminths will be covered in subsequent
containing the helminth eggs. chapters.
A
SECTION
INTESTINAL NEMATODE
INFECTIONS
Nematodes Limited to the
Intestinal Tract (Enterobius
vermicularis, Trichuris trichiura,
Capillaria philippinensis and
107 Trichostrongylus spp.)
Donald AP Bundy, Edward S Cooper, Simon Brooker
A B
FIGURE 107.1 Enterobius vermicularis in appendix. (A) Cross-section of adult pinworms in lumen shows bilateral crests (narrow arrows); one worm contains
eggs (wide arrow). (B) Longitudinal section of adult worm in lymphatic nodule shows prominent esophageal bulb (arrow). (Courtesy of the Louisiana State
University School of Medicine, New Orleans.)
The most successful diagnostic approach uses a strip of transparent Routine stool examination is positive in only 10–15% of infected
tape, which is held with the adhesive side out, affixed to a tongue persons. Rarely, eggs are found incidentally in Papanicolaou-stained
depressor. Before the person defecates or bathes on arising in the vaginal smears or in urine sediment.
morning, the buttocks are spread and the tape is pressed against the
anal or perianal skin. The strip is transferred to a microscope slide,
adhesive side down. Debris can be cleared by adding a drop of TREATMENT
toluene. Eggs are prominent at low power. Examination of a single E. vermicularis is susceptible to several anthelmintic drugs, with cure
smear detects approximately 50% of infections, and 90% are detected rates of >90%. Mebendazole (100 mg orally) or pyrantel embonate
with three swabs. Six negative swabs on separate days are necessary (10 mg/kg) is given in a single dose and repeated once or twice 2 to
to exclude the diagnosis. 4 weeks later. Albendazole is given as a single dose (400 mg for adults
800 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
and children >2 years; 100 mg for children <2 years), and repeated maps [5]. In many areas where latrines have been installed, the inci-
after 7 days. Piperazine 50 mg/kg is taken on each of seven successive dence of soil-transmitted nematodes is still high because of the prac-
days and repeated after 2 to 4 weeks. Because family members are tice of using untreated feces as fertilizer (night soil). As with other
usually infected, treatment for the entire family is recommended. helminths, the intensity of infection in communities is uneven. In a
Benzimidazoles should not be given during the first trimester of community where the average worm burden is 100 worms, most
pregnancy. individuals will have considerably fewer but some harbor several
thousand [6]. These individuals appear to be predisposed to intense
Hygiene measures, including hand washing, particularly after bowel infection for immunologic or ecologic reasons, and tend to reacquire
movements, are important. Simple laundering of clothes and linen is infections of above average intensity after successful treatment. There
adequate to disinfect them. is now evidence of genetic variation in susceptibility within commu-
nities [7]. Intensity of infection is age-related, with the most intense
TRICHURIASIS infections typically occurring in children of school age [8]. Treatment
of this age group has been advocated as a cost-effective approach to
Trichuris trichiura (whipworm) was thought to be benign; however, it community-wide control because it will reduce transmission to the
is now recognized that intense infection is associated with colitis and rest of the population.
dysentery, and that moderate infection can impair development in
childhood [4]. It is estimated that 800 million people are infected. NATURAL HISTORY, PATHOGENESIS
The name whipworm derives from the morphology of the 3- to 5-cm
adult. AND PATHOLOGY
T. trichiura infects humans as its primary host, but numerous members
of the genus Trichuris infect domestic animals. T. suis is a morphologi-
EPIDEMIOLOGY cally identical parasite that rarely and abortively infects humans, and
Trichuris is distributed worldwide, where fecal contamination of moist T. vulpis of dogs has been reported occasionally in humans. The life
soils allows maturation of eggs. Infection often occurs concurrently cycle of T. trichiura (Fig. 107.3) begins with ingestion of the embryo-
with ascariasis and has similar population dynamics (see Chapter nated egg. Larvae emerge in the cecum, where they penetrate the
108). Recent analyses utilizing geographical information systems, crypts of Lieberkühn and migrate within the mucosal epithelium.
remote sensing and spatial statistics have helped to better define the On molting to the adult, the posterior end is projected out of the
environment limits of transmission, enabling the development of risk epithelium, leaving the threadlike anterior portion embedded in a
Larvae hatch
Adults in cecum
in intestine
Man
Ingested
External environment
A B
FIGURE 107.5 (A) Prolapse of rectum in a heavy infection with Trichuris trichiura. (B) Adult T. trichiura attached to prolapsed bowel. (Courtesy of Drs P C
Beaver and R V Platou, Tulane University School of Medicine, New Orleans.)
syncytium created from epithelial cells. The mature female produces manifest abdominal pain and chronic diarrhea, and rectal prolapse
2000 to 6000 eggs per day. Eggs are passed in feces, where they must (Fig. 107.5).
mature in soil for a period that varies with temperature but is at least
10 to 14 days. About 3 months is necessary for a patent infection to The clinical picture of trichuriasis has been divided into two descrip-
be produced from the ingestion of eggs. Adult worms can persist for tions: the classic dysenteric form (trichuris dysentery syndrome,
years. massive infantile trichuriasis) and the more recently recognized
milder form, chronic Trichuris colitis with growth retardation [4].
Infection results in a well-defined humoral immune response Although the latter is not sharply demarcated from the former,
(Th2-mediated), and IgE-mediated local anaphylaxis; cell-mediated affected children are more likely to be brought to medical attention
inflammatory responses are conspicuously absent [9]. Local eosi- because of short stature rather than because of chronic diarrhea.
nophilic infiltration is present in the submucosa, and in heavy infec- Finger clubbing and rectal prolapse with chronic diarrhea in children
tion the bowel wall may be edematous and friable [10]. Under these are considered pathognomonic of trichuriasis in endemic areas.
circumstances, the mucosa can bleed easily, but worms do not suck Recent studies suggest that infection can impair not only physical
blood. Blood loss from inflamed mucosa can be important in people growth but also cognitive ability [12,13]. This could lead to education
with marginal iron intake [11]. Heavy infection (Fig. 107.4) can compromise.
802 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
TREATMENT
Therapy of trichuriasis is more difficult than that of other soil-
transmitted nematodes [14]. A 3-day course of either mebendazole
100 mg twice daily or albendazole 400 mg once a day is usually cura-
tive in heavy infections [15]. Ivermectin, 200 µg/kg orally for 3 days,
is an alternative therapy. However, compliance with a 3-day course is
lower than with single-dose treatment. A single dose of mebendazole
500 mg or albendazole 400 mg may be effective in mild to moderate
infections and is appropriate for community treatment. Oxantel
pamoate and combination therapy with mebendazole and ivermectin FIGURE 107.6 Capillaria philippinensis. Three transverse sections of larval
show better efficacy against heavy infections, but optimal treatment C. philippinensis embedded in intestinal glands (×100). (Courtesy of Armed
doses have yet to be established. Although high priority should be Forces Institute of Pathology, Photograph Neg. No. 69–1065.)
given to the treatment of pregnant women, these drugs should not be
administered during the first trimester.
INTESTINAL CAPILLARIASIS
Capillaria philippinensis is related to Trichuris trichiura. It is capable of
autoinfection and therefore can cause pathology of the small intestine
after a relatively light exposure.
EPIDEMIOLOGY
Most cases have been recognized in the Philippines, where the infec-
tion was first noted in the 1960s [16]. Endemic areas are recognized
in several provinces where both sporadic cases and outbreaks occur.
A few cases have been reported from Thailand, Japan and Taiwan,
and may be expected in other areas of Asia where freshwater fish are
eaten without cooking [17]. There are case reports from Egypt and
Iran [18].
NATURAL HISTORY, PATHOGENESIS, 4. Bundy DAP, Cooper ES. Trichuris and trichuriasis in humans. Adv Parasitol
1989;28:107–73.
AND PATHOLOGY 5. Brooker S, Clements ACA, Bundy DAP. Global epidemiology, ecology and
Under favorable conditions of humidity and temperature, ova hatch control of soil-transmitted helminth infections. Adv Parasitol 2006;62:
in the environment within 24 to 36 hours. They are resistant to cold 221–61.
6. Bundy DA. Epidemiological aspects of Trichuris and trichuriasis in Caribbean
and desiccation. The hatched larvae pass through three free-living
communities. Trans R Soc Trop Med Hyg 1986;80:706–18.
stages, reaching the infective stage in 60 hours or more. Eggs and
7. Williams-Blangero S, Vandeberg JL, Subedi J, et al. Two quantitative trait loci
larvae flourish in areas with shade, high humidity, and vegetation.
influence whipworm (Trichuris trichiura) infection in a Nepalese population.
Infection usually follows ingestion of larvae in contaminated food or J Infect Dis 2008;197:1198–203.
water, although larvae can enter through unbroken skin. Unlike 8. Bundy DA, Cooper ES, Thompson DE, et al. Age-related prevalence and
Strongyloides stercoralis and the hookworms, Trichostrongylus species do intensity of Trichuris trichiura infection in a St Lucian community. Trans R Soc
not need to migrate through the lungs for completion of the life cycle. Trop Med Hyg 1987;81:85–94.
9. Bradley JE, Jackson JA. Immunity, immunoregulation and the ecology of tri-
Little is known about the pathology of human trichostrongyliasis
churiasis and ascariasis. Parasite Immunol 2004;26:429–41.
[19]. The usual site of infection is the duodenum or the upper
10. Cooper ES, Spencer JM, Whyte-Alleng CAM, et al. Immediate hypersensitivity
jejunum. Adult worms are thought to suck blood at times and to
in the colon of children with Trichuris dysentery. Lancet 1991;338:1104–7.
damage the mucosa of the small intestine at or near their sites of 11. Ramdath DD, Simeon DT, Wong MS, Grantham-McGregor SM. Iron status of
attachment. Most human infections are mild and asymptomatic, but schoolchildren with varying intensities of Trichuris trichiura infection. Parasi-
epigastric pain, diarrhea and flatulence can occur. Rarely, anemia and tology 1995;110:347–51.
emaciation are associated with heavy infections. Eosinophilia is 12. Taylor-Robinson DC, Jones AP, Garner P. Deworming drugs for treating
present in a minority and sometimes exceeds 25%. soil-transmitted intestinal worms in children: effects on growth and school
performance. Cochrane Database Syst Rev 2007;(4):CD000371.
PATIENT EVALUATION, DIAGNOSIS AND 13. Bundy DAP, Kremer M, Bleakley H, et al. Deworming and development:
asking the right questions, asking the questions right. PLoS Negl Trop Dis
DIFFERENTIAL DIAGNOSIS 2009;3:e362.
The diagnosis of trichostrongyliasis depends on the identification of 14. Keiser J, Utzinger J. Efficacy of current drugs against soil-transmitted helminth
ova in the stool. Concentration techniques are necessary. Care should infections: systematic review and meta-analysis. JAMA 2008;299:1937–48.
15. Steinmann P, Utzinger J, Du ZW, et al. Efficacy of single dose and triple-dose
be taken to differentiate Trichostrongylus eggs, which are larger and
albendazole and mebendazole against soil-transmitted helminth infections
more pointed on one or both ends, from those of the hookworms.
and Taenia spp.: single-blind randomized controlled trial. Trop Med Int
The diagnosis is occasionally made by finding Trichostrongylus larvae
Health 2009;14S:194.
in duodenal aspirates. Identification of species requires examination 16. Cross JH, Basaca-Sevilla V. Albendazole in the treatment of intestinal capil-
of adult worms. lariasis. Southeast Asian J Trop Med Public Health 1987;18:507–10.
17. Saichua P, Nithikathkul C, Kaewpitoon N. Human intestinal capillariasis in
TREATMENT Thailand. World J Gastroenterol 2008;14:506–10.
18. Ahmed L, el-Dib NA, el-Boraey Y, Ibrahim M. Capillaria philippinensis: an
Mebendazole 100 mg twice daily for 3 days or a single dose of alben- emerging parasite causing severe diarrhoea in Egypt. J Egypt Soc Parasitol
dazole 400 mg is effective. Pyrantel pamoate 11 mg/kg once (maximal 1999;29:483–93.
dose 1 g) can be used as an alternative. Although thiabendazole 19. Boreham RE, McCowan MJ, Ryan AE, et al. Human trichostrongyliasis in
25 mg/kg twice daily (maximal daily dose of 3 g) for 2 days is Queensland. Pathology 1995;27:182–5.
Intestinal Nematodes:
108 Ascariasis
Donald A P Bundy, Nilanthi de Silva, Simon Brooker
Trachea
Lungs
Pharynx
Swallowed
Circulation
Adults in lumen
of small intestine
Ingested
Egg in feces
(diagnostic stage)
Embryonated egg with
2nd stage larva Fertilized – 1 cell
(infective stage)
Unfertilized
External environment
decreases as the worm burden increases, and thus egg counts may not
linearly reflect intensity of infection. Adults live for approximately
a year.
IMMUNE RESPONSE
The human immune response is associated with elevated immu-
noglobulin (Ig)E, tissue eosinophilia and mastocytosis, and a strong
localized T helper cell type 2 (Th2) response. Although cross-sectional
studies of communities often show features consistent with develop-
ment of immunity to Ascaris, examination of antibody responses to
A. lumbricoides has not shown humoral immunity to have a role in
limiting infection. Antibodies to both adult and larval Ascaris antigens
simply reflect the intensity of infection. It is likely that infection with
Ascaris modulates allergic responses to non-parasite allergens, and
affects allergic sensitization and expression of allergic diseases such
as asthma [8,9]. It is also possible that immunomodulation in chronic
infections could affect HIV-1 disease progression. A recent placebo-
controlled, randomized clinical trial conducted among adult Kenyans
co-infected with HIV-1 and A. lumbricoides found that treatment with
albendazole resulted in significantly increased CD4 counts during 3
FIGURE 108.2 Terminal part of ileum opened, showing obstructing months of follow-up [10].
bolus of ascarids. (Courtesy of Drs D W Aiken and F N Dickman. From JAMA
164:1317, 1957.)
CLINICAL FEATURES
old, is obstruction of the terminal ileum by a bolus of worms
(Fig. 108.2). PULMONARY MIGRATION
It can take from 10 to 12 weeks from ingestion of eggs to the produc- Ascaris larvae usually cause few symptoms along their migratory path,
tion of eggs. The number of adult worms per infected person can vary but in sensitized hosts, pulmonary manifestations can start within 1
widely in an infected population; egg production per female worm week after ingestion of eggs. Symptoms are likely to occur where
806 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
transmission is seasonal or sporadic, e.g., in Saudi Arabia. Other pancreatic duct is obstructed it can lead to pancreatitis. Appendicitis
allergic manifestations to migrating larvae, such as urticaria, are more can be triggered by Ascaris obstructing the appendix (Fig. 108.4).
common at the end of the pulmonary phase. Fever, cough, wheezing
and dyspnea can be accompanied by sputum production, sometimes Heavy worm burdens can cause more serious complications; the most
with small amounts of blood; chest pain and cyanosis are noted in frequently reported, especially in children <10 years old, is obstruc-
the most severe cases. Chest film examination can show unilateral or tion of the terminal ileum by a bolus of worms [5] (Fig. 108.2). Rarely,
bilateral abnormalities, ranging from nodular densities to diffuse the section of intestine containing the bolus of worms may act as a
interstitial patterns. The illness usually is limited to several weeks, but fixed point resulting in a volvulus. Ileocecal intussusception as well
can persist as long as larvae pass through the lungs. Leukocytosis and as solitary intestinal perforation has been attributed to Ascaris, but the
marked eosinophilia can occur, fulfilling the clinical picture of Löf- causative role of Ascaris in these cases is not always clear.
fler’s syndrome. Rarely, severe pulmonary inflammation has pro-
gressed to death. PATIENT EVALUATION, DIAGNOSIS
AND DIFFERENTIAL DIAGNOSIS
INTESTINAL INFECTIONS
The diagnosis of ascariasis is made by stool examination. Character-
The intestinal phase of the infection is generally asymptomatic, but
istic eggs (55 to 75 µm by 35 to 50 µm) can be seen on direct or
even moderately heavy infections can affect the health, growth, and
concentrated stool specimens. Unfertilized eggs can be more difficult
physical fitness of children.
to identify because of their atypical size and appearance. Decorticate
The more serious complications of ascariasis result from migration of eggs lacking the outer mamillated covering are sometimes produced,
adult worms. Migrating worms can reach the upper gastrointestinal and these may be confused with the eggs of other nematodes; the
(GI) tract and be vomited or passed per rectum. Worms can intertwine thick hyaline shell is typical of Ascaris. Infections consisting of only
and form a bolus, which can cause partial or complete intestinal male worms produce no eggs; if such infections are symptomatic, the
obstruction, with abdominal pain, vomiting, and occasionally a pal- worms may sometimes be detected radiologically as linear filling
pable abdominal mass (Fig. 108.2). Rarely, such a mass causes a defects outlined by contrast media (Fig. 108.5). Intestinal worms may
volvulus or leads to perforation of the small intestine. More fre- sometimes ingest barium and be seen as thin, curved linear densities.
quently, the migrating worms enter ducts or diverticula, where they In cases of suspected biliary ascariasis or pancreatitis, duodenoscopy
can perforate or cause obstruction. The common bile duct is the most with retrograde cholangiopancreatography can be useful both in
often obstructed, leading to biliary colic or cholangitis (Fig. 108.3). A establishing a diagnosis and in providing a nonsurgical means of
worm that ascends higher in the biliary tree can result in liver abscess removing the worms. Ultrasonography is also useful in the diagnosis
or can penetrate the bile duct and lead to bile peritonitis. When the of biliary ascariasis but is of less value in pancreatitis.
A B
C D
FIGURE 108.3 Ascaris lumbricoides eggs in saline smears (×400 magnification) showing (A) mammilated outer cortex (B) fertilized decorticated egg
(C) embryonated egg (D) unfertilized egg.
I nte s t i n a l N e m ato d e s : Ascar iasis 807
Swallowed
Pharynx
Attached to
Trachea small intestine
Lungs
Circulation Man
Adults in
small intestine
Penetrates skin
Eggs in feces
(diagnostic stage)
Filariform larva
(infective stage)
External environment
Rhabditiform
larva hatches
Rhabditiform
larva in soil
FIGURE 109.1 Life cycle of hookworm. (Redrawn from Melvin DM, Brooke MM, Sadun EH: Common Intestinal Helminths of Man. Atlanta, Centers for Disease Control,
DHEW Publication No. [CDC] 75–8286, 1964.)
roughly 0.5 mg of iron. This amount is equivalent to the daily iron Iron Deficiency Anemia (IDA)
intake of a child [4].
The hallmark of chronic hookworm disease is IDA, which manifests
as a microcytic and hypochromic anemia. The development of IDA
CLINICAL FEATURES depends on the number and species of infecting hookworm, the iron
The clinical features of hookworm infection correspond to the life reserves and requirements of the host, and the availability of iron in
cycle of the organism and the intensity of infection [1]. the diet. Lassitude, weakness, apathy, and depression are characteristic
of anemia. On physical examination, the mucous membranes, con-
Ground Itch and Cutaneous Larva Migrans junctivae, and skin appear pale. Iron deficiency has also been associ-
ated with koilonychia and angular stomatitis. A yellowish-green hue
Associated with the penetration of the skin by L3 larvae, there is (chlorosis) that results in a sallow complexion can be seen in heavy
intense itching, and, in some instances, erythematous, pruritic papules infections. Anemia is often accompanied by eosinophilia, and, in
at the site of penetration. Cutaneous larva migrans is a related condi- severe cases, protein loss and hypoalbuminemia occur. In children,
tion caused by skin penetration of animal hookworms, classically A. chronic hookworm infection and disease lead to deficits in growth
braziliense, and results in raised, reddened, serpiginous tracks that and physical fitness as well as reductions in intelligence and cogni-
mark the migration of the worm. They are the most frequent on the tion. These changes can lead to reduced school performance and
lower extremities, followed by the buttocks and anogenital area, attendance. IDA from chronic hookworm infection in pregnancy is
although both the trunk and upper extremities may also be affected. associated with increased maternal morbidity as well as low birth-
weight and prematurity. Severe cases of hookworm anemia and
Pulmonary Manifestations hypoalbuminemia are accompanied by cardiovascular changes.
As larvae pass through the lungs, patients may complain of cough and
wheezing. In a small percentage of patients, eosinophilic infiltrates PATIENT EVALUATION, DIAGNOSIS, AND
appear on chest film. DIFFRENTIAL DIAGNOSIS
Hookworm disease should be considered in any patient from an
Gastrointestinal Manifestations endemic area who presents with anemia, eosinophilia, or both. The
Epigastric pain and tenderness occur early in the intestinal phase. diagnosis is confirmed by identifying hookworm ova in the stool
Abdominal pain can be severe enough to suggest peptic ulcer disease. (Fig. 109.1). The eggs of N. americanus and A. duodenale are almost
810 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
A B
C D
FIGURE 109.2 (A) Mouthparts of Necator americanus. Note two pairs of chitinized cutting plates characteristic of this species. (B) Mouthparts of Ancylostoma
duodenale. Note two large pairs of teeth, each of the medial pair bearing a small accessory process. (C) Mouthparts of A. braziliense. Note two pairs of
teeth, a large outer pair and a small inner pair without accessory processes. (D) Mouthparts of A. caninum. Note three well-developed pairs of teeth.
EPIDEMIOLOGY
Strongyloidiasis has a patchy, widespread distribution through warm,
wet tropical and subtropical areas. In temperate regions, it is encoun-
tered in institutions where sanitary facilities are poor or in moist
conditions such as mines or tunnels. Some have conservatively esti-
mated that 30 to 100 million people are infected. The difficulties in
diagnosing strongyloidiasis have contributed to our limited under-
standing of the global prevalence and disease burden [9, 10]. Strongy-
loides infections are endemic in tropical Asia, Africa, and Latin
America, as well as in rural Appalachia in the US and in parts of
southern and eastern Europe. Although infection is widespread, the
prevalence is typically low (<10%). Prevalence is reportedly elevated
in older HTLV-1-affected patients in regions where this virus is
endemic (e.g. Japan, Caribbean).
Immigrants, travelers, or military veterans from endemic areas, e.g.,
southern Asia, can have prolonged infections. The latter are usually
older males, veterans who have lived in endemic tropical areas, and
those with underlying malignant, metabolic, pulmonary or renal
disease. They have mild to moderate chronically relapsing symptoms.
Because infection can be maintained for 40 years or more, and
FIGURE 109.3 Longitudinal section through hookworm attached to because effective therapy has been available only since 1967, many
intestinal mucosa. (Courtesy of Dr Pedro Morera, Facultad de Microbiologia, persons, e.g. military personnel who were in the South Pacific in
Universidad de Costa Rica.) World War II, the Korean War, or the Vietnam War, may remain
infected and at risk for episodic symptoms of chronic infection or
overwhelming hyperinfection, especially if they receive corticosteroid
when used as a single dose in mass drug administration, albendazole therapy.
may be the only acceptable agent. Outside of resource-poor settings,
mebendazole when administered in a dose of 100 mg orally twice
daily for three successive days may be as effective as albendazole, as NATURAL HISTORY, PATHOGENESIS,
well as pyrantel pamoate administered as a dose of 11 mg/kg (max. AND PATHOLOGY
1 g) for 3 days. The life cycle of S. stercoralis is complex (Fig. 109.4). Like other intes-
Because of the teratogenicity and embryotoxicity of albendazole and tinal nematodes, it can involve host and soil stages. However, unlike
other benzimidazoles when used in high doses in laboratory animals, most other helminths, the life cycle can also occur completely in the
two special circumstances warrant caution. In children greater than 1 soil (free-living cycle) or completely in the host (internal or external
year but less than 2 years of age, albendazole should be administered autoinfection). Autoinfection is the basis of both persistence of infec-
at one-half of the recommended dose (200 mg), weighing the effect tion, as well as overwhelming hyperinfection syndrome in patients
of chronic hookworm infection on development and growth, with receiving corticosteroids.
the theoretical risks of treatment. Similarly, in women in their second Human infection begins with exposure of the skin to L3 larvae that
and third trimesters of pregnancy, treatment has had proven benefits reside in fecally contaminated, moist soil (Fig. 109.4). These larvae
in terms of reduced maternal and perinatal morbidity and mortality have slender bodies, and notched tails that distinguish them from
[3]. No anthelminthic treatment should be administered during the hookworm larvae. The L3 migrate through the lungs and ascend the
first trimester, but subsequently the risks of treatment need to be airways to the trachea and epiglottis before being swallowed to com-
weighed against the high risk of hookworm infection on pregnancy plete their life cycle in the small intestine. There, after two molts, adult
outcome. During pregnancy, treating anemia of hookworm disease females (2.2 mm long) emerge, penetrate and reside in the superficial
with both anthelminthic drugs and iron therapy is superior to either mucosa of the duodenum and jejunum. The evidence for the exist-
treatment alone An experimental vaccine to prevent hookworm infec- ence of male worms is controversial. In the intestine, adult female
tion and re-infection is under development [7,8]. worms, eggs, and larvae are found in the superficial submucosa and
in the mucosal crypts, causing mechanical trauma, mucous discharge
STRONGYLOIDES INFECTIONS and microscopic ulceration but usually minimal inflammation. Pro-
gressive involvement may lead to edema, flattened villi, malabsorp-
tion, and even ulceration, enteritis and secondary bacterial invasion.
INTRODUCTION
Nearly 1 month after infection, the adult female lays oval, thin-
Strongyloidiasis, threadworm infection, results from infection by shelled, embryonated eggs that closely resemble hookworm eggs but
Strongyloides stercoralis, the female of which is usually embedded in are usually not seen because they rapidly hatch in the intestinal
the mucosa of the small intestine. S. stercoralis is unusual among mucosa to produce first-stage, noninfectious rhabditiform larvae (Fig.
helminths in its ability to multiply within the host and maintain 109.5). It is this rhabditiform larval stage that is characteristically
persisting infection for years. Recognized since 1876, when Normand found in the stool or the upper small bowel. Under favorable soil
described the larvae in stools of French soldiers in Southeast Asia with conditions, rhabditiform larvae transform into infective L3 within 24
Cochin-China diarrhea, S. stercoralis has a complex life cycle of enter- hours after fecal passage, a process that may also occur in the perianal
ing the skin, migrating through the lungs, and residing in the small region after defecation. L3 larvae can also survive for several weeks
bowel (Fig. 109.4).The capacity of S. stercoralis to overwhelm immu- under moist conditions, and develop into adult male and female
nocompromised hosts with hyperinfection is well recognized. There worms (Fig. 109.4).
is a link between strongyloidiasis and co-infection with human T-cell
lymphotrophic virus type 1 (HTLV-1) [9, 10]. Although almost all Alternatively, autoinfection can occur by rapid transformation of
Strongyloides infections are with S. stercoralis, the primate parasite S. rhabditiform larvae to infectious L3 in the gut lumen, where they
fulleborni is recognized in humans in Africa and in Papua New Guinea, penetrate the intestinal mucosa (internal autoinfection) to proceed via
812 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Trachea Pharynx
Lungs Swallowed
Egg in mucosa
(occasionally in feces)
Filariform larva
Direct development
External environment
Free-living
adults in soil
Indirect development
Rhabditiform
larva in soil
Eggs in soil
FIGURE 109.4 Life cycle of Strongyloides stercoralis. (Redrawn from Melvin DM, Brooke MM, Sadun EH: Common Intestinal Helminths of Man. Atlanta, Centers for
Disease Control, DHEW Publication No. [CDC] 75–8286, 1964.)
the lungs to maintain infection (Fig.109.4). Under selected condi- urticaria called larva currens, which is usually seen on the buttocks
tions, the autoinfective process may become dysregulated, leading to area with external autoinfection, can occur. Cough, shortness of
large number of L3 penetrating the gut, cycling through the lungs and breath, wheezing, fever, transient pulmonary infiltrates, and eosi-
re-entering the intestine. This process can lead to hyperinfection, asso- nophilia are infrequent, but may be encountered with the migration
ciated secondary bacteremias and bacterial meningitis. Among condi- of larvae through the lungs. When adult worms develop and penetrate
tions associated with hyperinfection are immunosuppressive drug the mucosa in the small bowel, nonspecific aching or epigastric
therapies, especially corticosteroids. Other conditions are hemato- abdominal pain and diarrhea can develop. With heavy infections,
logic malignancies, solid organ transplantations, and autoimmune vomiting, malabsorption, steatorrhea, weight loss, edema, or a para-
disorders, although in many of these conditions corticosteroids are lytic ileus with edema in the small bowel wall are recognized.
used during treatment. Infection with HTLV-1 (as well as co-infections
with tuberculosis, leprosy, syphilis) is another risk factor; however, the
basis for this has not been established. In some patients with hyper-
Chronic, Persisting Infection
infection, the migrating larvae can develop to adult worms in ectopic This condition probably occurs as a result of internal autoinfection
sites, e.g. the lung and central nervous system. This condition is and is best described in military veterans or in former prisoners of
known as disseminated strongyloidiasis. In cases of external autoin- war who have returned from endemic tropical areas in Asia or in the
fection, the L3 may also develop in the colorectal area and penetrate South Pacific. The classically recognized triad of symptoms is larva
the perianal skin with resultant pruritic creeping eruption or larva currens, abdominal pain, and diarrhea. An endemic focus also occurs
currens and external autoinfection. in southeastern Kentucky and elsewhere in Appalachia, where most
patients are usually white, male, older than 50 years, and from lower
socioeconomic backgrounds. Viral HTLV-1 infection is an important
CLINICAL FEATURES risk factor for chronic, persisting infection.
The clinical manifestations of S. stercoralis infection are acute infec-
tion, chronic persisting infection, and the hyperinfection syndrome.
The latter two syndromes are the best characterized [9, 10].
Hyperinfection Syndrome
Gastrointestinal signs and symptoms are common but nonspecific
and include crampy abdominal pain, bloating, watery diarrhea and
Acute Infection constipation. Patients can develop an ileus and small bowel obstruc-
Although an estimated one-third or more of individuals are asymp- tion, with diffuse tenderness and hypoactive bowel sounds. Pulmo-
tomatic, a pruritic maculopapular rash or rapidly migrating linear nary manifestations are variable, and larva currens is common. Of
H o o k wo r m a n d S t ro n g y l o i d e s I nfec tions 813
bc and looked for tracks of bacteria from migrating larvae, used the
bc bc Baermann funnel gauze concentration method, or used Harada Mori
bc
cultures on vertical strips of damp filter paper (where the larvae
migrate down). Although previous serologic tests were complicated
es es es es by lack of sensitivity and specificity, an improved immunofluores-
cence antibody assay using Strongyloides antigen has been described.
nr mb Improved ELISA also gives high specificity and sensitivity, particularly
if combined with Western blot. All immunodiagnostic methods are
nr complicated by cross-reactivity with other nematode helminth infec-
nr tions. Sensitivity may decrease in co-infection with HTLV-1. S. stercora-
nr
c c lis antigen is not widely available for routine diagnostic use.
c
TREATMENT
c
Because of the potential for chronic symptomatic infection, autoinfec-
tion over many years, and the hyperinfection syndrome, all individu-
als who are infected with S. stercoralis should be treated. The first-line
treatment for acute or chronic infection is ivermectin, at a recom-
mg mg mg mg
mended dose of 200 µg/kg per day orally, on two successive days. The
safety of ivermectin in young children (<15 kg) and in pregnancy has
gp not been established. Albendazole at 400 mg orally twice a day for 7
gp days is an alternative. Albendazole should be taken with a fatty meal
gp
to promote absorption; ivermectin should be taken on an empty
stomach and with water. Patients with HTLV-1 should be treated until
their stools are negative for larvae or until they become seronegative.
gp
Treatment of immunocompromised patients suspected of having a
life-threatening, hyperinfection syndrome should be continued until
the clinical signs resolve. Because the autoinfective life cycle requires
at least 2 weeks, some investigators recommend that treatment and
screening should continue at least until fecal cultures have been nega-
tive for this period of time. A veterinary parental formulation has been
a used in patients who are unable to take or reliably absorb oral medi-
a a cations. In disseminated strongyloidiasis, combination therapy with
albendazole and ivermectin has been suggested, although there are
no carefully controlled clinical trials to support this. In patients
a with hyperinfection, co-infection with enteric bacteria is common, as
well as bacteremia and bacterial meningitis; patients may require
co-administration of oral or parenteral antibiotics. Patients with
Strongyloides hyperinfection are infectious and may require isolation.
cb Following treatment for hyperinfection, some clinicians choose to
A B C D keep patients on chronic suppressive therapy with anthelminthic
agents.
FiGURE 109.5 Figures of typical rhabditiform larval stages of: (A)
Strongyloides; (B) hookworm; (C) Trichostrongylus; and (D) Rhabditis (ca.
×400). Explanation of labels: a, anus; bc, buccal chamber; c, cardiac bulb of REFERENCES
esophagus; cb, beadlike swelling of caudal tip; es, esophagus; gp, genital
primordia; mb, midesophageal bulb; mg, midgut; nr, nerve ring. (Redrawn 1. Hotez PJ, Brooker S, Bethony JM, et al. Hookworm infection. N Engl J Med
from Beaver PC, Jung RC, Cupp EW: Clinical Parasitology, 9th ed. Philadelphia, Lea 2004;351:799–807.
& Febiger, 1984.) Review of the major features of human hookworm infection.
2. Bethony J, Brooker S, Albonico M, et al. The soil-transmitted helminth infec-
tions. Lancet 2006;367:1521–32.
special concern is the high mortality, often with bacterial infection 3. Brooker S, Hotez PJ, Bundy DAP. Hookworm-related anaemia among preg-
secondary to extensive larval spread from the intestine. Sepsis, men- nant women: a systematic review. PLoS Negl Trop Dis 2008;2:e291.
ingitis, peritonitis and endocarditis are commonly documented, often 4. Crompton DW. The public health importance of hookworm parasitology.
with the microbiological recovery of Gram-negative enteric bacteria Parasitology 2000;121(Suppl):S39–50.
[9, 10]. 5. Hotez PJ. Mass drug administration and the integrated control of the
world’s high prevalence neglected tropical diseases. Clin Pharmacol Ther
2009;85:649–64.
PATIENT EVALUATION, DIAGNOSIS, AND 6. Keiser J, Utzinger J. Efficacy of current drugs against soil-transmitted helminth
DIFFRENTIAL DIAGNOSIS infections: systematic review and meta-analysis. JAMA 2008;299:1937–48.
Up-to-date meta-analysis of the major drugs used to treat intestinal helminthiases.
Any individual from a strongyloidiasis-endemic area who is diag-
7. Diemert D, Bethony J, Hotez PJ. Hookworm vaccines. Clin Infect Dis
nosed with HTLV-1 infection or who is expected to undergo corticos-
2008;46:282–8.
teroid therapy (including doses as low as 1 mg of dexamethasone 8. Hotez PJ, Bethony JM, Diemart DJ, et al. Developing vaccines to combat
daily) should be screened for strongyloidiasis. The important aspects hookworm infection and intestinal schistosomiasis. Nat Rev Microbiol
of diagnosing Strongyloides infections include a high index of suspi- 2010;8(11):814–26.
cion in patients with histories of exposure and characteristic skin and 9. Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised
intestinal symptoms. Second, an experienced person may have to population. Clin Microbiol Rev 2004;17:208–17.
diligently search in fecal specimens to find the characteristic rhabdi- Up-to-date review of hyperinfection and disseminated infection, with treatment and
tiform larvae (Fig. 109.5). Several researchers have made efforts to patient management recommendations.
improve the likelihood of finding Strongyloides larvae by amplifying 10. Ramanathan R, Nutman T. Strongyloides stercoralis infection in the immuno-
the indirect life cycle in vitro. They have placed feces on nutrient agar compromised host. Curr Infect Dis Rep 2008;10:105–10.
B
SECTION
FILARIAL INFECTIONS
110 Lymphatic Filariasis
LeAnne M Fox, Christopher L King
Ongoing interventions
Interventions not started
Stopped interventions
Not required interventions
Non-endemic countries
FIGURE 110.1 Global distribution of lymphatic filariasis and status of mass drug administration as of 2009.
necessary for the parasite survival especially for embryogenesis and CHRONIC MANIFESTATIONS
molting that is critical for transition from one parasite stage to another
[10, 11]. It is estimated that of the 120 million persons infected worldwide,
approximately one-third, or 40 million, have some form of clinically-
overt disease; 25 million with hydrocele and 15 million with lymph-
CLINICAL FEATURES edema or elephantiasis.
The clinical expression of lymphatic filariasis varies from subclinical
infection to pronounced chronic manifestations. The three species of GENITAL MANIFESTATIONS
parasite cause similar signs and symptoms, although urogenital In many endemic areas, the most common chronic manifestation of
disease and chyluria do not occur with Brugia infection. lymphatic filariasis caused by W. bancrofti is hydrocele. Other forms
of genital disease including epididymitis, orchitis, funiculitis, lymph-
SUBCLINICAL INFECTION edema of the scrotum and vulvar lymphedema have also been noted
[18, 19]. (Figs 110.4 and 110.5). The pathogenesis of filarial hydrocele
Most infected persons are asymptomatic, despite circulating micro-
is thought to be as a result of lymphatic damage caused by living adult
filariae or filarial antigen in the peripheral blood [12]. Although they
W. bancrofti. In filariasis-endemic areas, clinically-apparent hydrocele
may be clinically asymptomatic, infected individuals have underlying
may actually be chylocele, resulting from rupture of dilated intrascro-
lymphatic damage [13, 14]. Microscopic hematuria or proteinuria are
tal lymphatic vessels and leakage of lymph into the cavity of the
also found in infected persons [15].
testicular tunica vaginalis [20]. Hydroceles can become quite large
(over 30 cm in diameter) and inguinal lymph nodes may be enlarged.
ACUTE MANIFESTATIONS
Infected persons may exhibit acute manifestations, particularly acute
filarial lymphangitis (AFL) and acute dermatolymphangioadenitis
(ADLA). AFL involves acute inflammation of a lymphatic vessel that
progresses distally along the vessel and is thought to be caused by the
death of the adult worm [16]. Patients usually give a history of pain,
erythema and tenderness in the affected lymph node region for hours
or a day prior to the onset of lymphangitis. Localized inflammatory
nodules in breast, scrotum or subcutaneous tissues have also been
reported.
ADLA is a separate and clinically distinct syndrome that is caused by
bacterial infection of the small collecting lymphatic vessels in areas
of lymphatic dysfunction [16, 17]. Unlike true filarial lymphangitis,
this syndrome develops in a reticular rather than a linear pattern and
is more commonly associated with severe pain, fever and chills. There
is often a history of injury to the skin, such as trauma, insect bites or
interdigital fungal infections. ADLA is often diagnosed as cellulitis
and symptoms can last 3–15 days.
The adenolymphangitis of brugian filariasis (both B. malayi and B.
timori) is more distinct, more dramatic and more destructive. In
brugian filariasis, a single local abscess can form along the lymphatic
tract, most often in the inguinal area, but sometimes in the axillae. FIGURE 110.4 Man from the Democratic Republic of the Congo with
These can suppurate and form sterile abscesses that often leak lymph bilateral filarial hydrocele progressing to “hanging-groin” (courtesy of Dr
before healing with a characteristic scar (Fig. 110.3). Tony Ukety).
CHYLURIA
Chyluria, resulting from rupture of dilated retroperitoneal lymphatic
structures into the renal pelvis, is a rare, but serious, manifestation of
lymphatic filariasis. As a result of loss of chyle, which contains dietary
lipids, proteins and vitamins, weight loss and malnutrition can ensue.
The condition is painless. The frequency of chyluria in filariasis
endemic areas has not been established, but it is lower than lymph-
edema or hydrocele [24].
DIFFERENTIAL DIAGNOSIS
The differential diagnosis varies based on the clinical presentation.
Bacterial infection, thrombophlebitis or trauma can be mistaken for
acute filarial adenolymphangitis. Filarial lymphangitis is retrograde,
which helps differentiate it from bacterial lymphangitis. Tuberculosis,
leprosy, sarcoidosis and other systemic granulomatous diseases
may be confused with filarial disease. Chronic lymphedema can be
caused by malignancy, postoperative changes, congenital malforma-
tions or a hereditary form of lymphostasis (Milroy’s disease), as well
as renal or cardiac failure. Physical examination cannot distinguish a
filarial from a nonfilarial cause of lymphedema or elephantiasis.
A foreign body reaction to silica dust introduced into traumatized
legs, termed podoconiosis, accounts for elephantiasis in some parts
of the world.
Patients with filarial lymphedema are often amicrofilaremic, so that
diagnosis depends on the epidemiologic and clinical history as well
as the physical examination and can be supported by positive serol-
ogy. In cases of orchitis and epididymitis, sexually transmitted infec-
tions must be considered. For tropical pulmonary eosinophilia, a
failure to respond to DEC treatment should suggest an alternative
FIGURE 110.7 Microfilaria of W. bancrofti on a thick blood film stained with diagnosis.
hematoxylin (courtesy of Dr Mark L. Eberhard, Division of Parasitic Diseases and
Malaria, Centers for Disease Control and Prevention, Atlanta, GA, USA).
TREATMENT
Diethylcarbamazine (DEC, 6 mg/kg per day for 12 days for a total
a 3–5-µm nucleopore filter or centrifugation of fluid fixed in dose of 72 mg/kg or single-dose DEC at 6 mg/kg) is the recom-
2% formalin (Knott’s concentration technique) are more sensitive mended treatment for active lymphatic filariasis (antigen and/or
methods [28]. Diagnostic sampling must take into account the microfilaremia positive, adults worms by ultrasound). DEC is active
periodicity of microfilaria. For example, microfilaria of W. bancrofti against both the microfilaria and adult worms, although treatment
circulate at highest concentration at night; therefore, blood specimens may not kill all adult worms. Infected individuals, particularly those
should be collected between 22.00 h and 02.00 h. Microfilaria can be with parasitemia, are at increased risk for adverse reactions from DEC
found in blood, hydrocele fluid and, occasionally, in other fluids, treatment. Reactions are associated with the rapid killing of adult
such as urine. Microfilariae of the three species are distinguished worms, which can lead to scrotal pain in men or acute lymphangioad-
morphologically. enitis with nodules containing dying worms. Rapid killing of micro-
filariae induces systemic inflammation, most likely from release
Other tests may be helpful in individuals who do not have micro- Wolbachia antigens. To reduce this risk of side effects, an escalating
filaremia. Assays that detect circulating W. bancrofti antigen, primarily dose of DEC can be used. Alternatively, individuals can be pretreated
from the adult worm, are available and allow diagnosis of both micro- with 1–3 days of oral steroids, depending on the intensity of infection
filaremic and amicrofilaremic infections, even in the daytime blood as most severe reactions occur within the first 48 hours.
of those with nocturnally-periodic microfilariae. Two assays for circu-
lating antigens exist, an ELISA [29] and a rapid-format immunchro- The mechanism of action of DEC is still not completely understood,
matographic card test [30]. Both assays have high sensitivity and but it results in the sequestration of microfilariae and their eventual
specificity, but are not currently Food and Drugs Administration destruction by the immune system, and is dependent on inducible
(FDA)-approved for diagnosis of filariasis in the USA. There are cur- nitric oxide synthase and cyclooxygenase. It is important to exclude
rently no tests for circulating antigens in brugian filariasis. co-infections with onchocerciasis and loiasis. Co-infections are most
likely to occur in areas of west and central Africa, but not in Asia or
Antibody-based assays have suffered from poor specificity as they the Pacific regions. Treatment with DEC can cause rapid death of
cannot distinguish among the filarial parasites that infect humans. Onchocerciasis volvulus microfilaria in the skin (or eye), resulting in
Improvements have been made with the detection of antifilarial IgG4, severe skin and eye reactions. High levels of circulating microfilaria
which cross-reacts less with other nonfilarial helminthes [31]. Ele- from Loa loa have been associated with severe systemic reactions and
vated antifilarial IgG4 levels indicate active filarial infection. Species- even death with DEC treatment.
specific recombinant antigens have also been developed for brugian
and bancroftian filariasis [32]. In addition, a rapid dipstick has Other drugs are effective against W. bancrofti and Brugia species.
been developed for the detection of B. malayi infection in endemic Albendazole inhibits the polymerization of worm β-tubulin and
areas [33]. microtubule formation. A single dose of 400 mg decreases W. ban-
crofti microfilaraemia for 6–12 months and when it is used in com-
PCR-based assays to detect W. bancrofti and B. malayi in blood may bination with diethylcarbamazine (or ivermectin), the numbers of
be available in research laboratories [34, 35]. microfilaria are reduced for a longer length of time than after a single
dose of DEC. A combined dose of DEC (6 mg/kg daily) plus 400 mg
Adult worms localized in lymphatic vessels or lymph nodes have been daily of albendazole is likely to kill adult worms more rapidly than
found in pathologic specimens [27]. Examination of superficial lym- DEC alone and the combination could shorten the duration of DEC
phatics of the extremities and female breast or the intrascrotal lym- therapy, although this has not been tested.
phatics in men using high-frequency ultrasound in conjunction with
Doppler techniques has demonstrated motile adult worms within Ivermectin is highly active against microfilaria, and contributes to
dilated lymphatics, termed the filaria dance sign [36–39]. Filarial sterilization of adult worms, but does not kill them. It acts by hyper-
worms have been visualized in the intrascrotal lymphatics in up to polarization of glutamate-sensitive channels and was shown to block
85% of infected men [38]. Ultrasonography has also been used to the contractile activity of the excretory/secretory vesicle [41]. As a
visualize the adult worms of children [40, 14]. Radionuclide lympho- result, molecules that may modulate the immune response are not
scintigraphic imaging of the extremities has demonstrated lymphatic released, leaving the microfilaria susceptible to host killing near
Ly m p h at ic Filar iasis 821
release from adult worms rather than in the peripheral circulation or 12. Ottesen EA. Infection and disease in lymphatic filariasis—an immunological
skin in onchocerciasis. There are less adverse reactions in subjects perspective. Parasitology 1992;104:571.
co-infected with onchocerciasis. 13. Shenoy RK, Suma TK, Kumaraswami V, et al. Lymphoscintigraphic evidence
of lymph vessel dilation in the limbs of children with Brugia malayi infection.
As Wolbachia are essential for W. bancrofti and Brugia spp. treatment J Commun Dis 2008;40:91–100.
with a course lasting 4, 6 or 8 weeks of a doxycycline, 200 mg daily, 14. Fox LM, Furness BW, Haser JK, et al. Ultrasonographic examination of
results in long-term sterility and eventual death of >90% of adult Haitian children with lymphatic filariasis: a longitudinal assessment in the
worms [42]. This slow death of worms is an advantage as it leads to context of antifilarial drug treatment. Am J Trop Med Hyg 2005;72:642–8.
fewer side effects compared with more rapidly-acting drugs like DEC. 15. Dreyer G, Ottesen EA, Galdino E, et al. Renal abnormalities in microfilaremic
Shorter courses of doxycycline do not kill most adult worms, except patients with Bancroftian filariasis. Am J Trop Med Hyg 1992;46:745–51.
in a recent study showing that three weeks of doxycycline followed 16. Dreyer G, Medeiros Z, Netto MJ, et al. Acute attacks in the extremities of
by a single dose of DEC (6 mg/kg) had similar efficacy [43] to 4 weeks persons living in an area endemic for bancroftian filariasis: Differentiation
or more of doxycycline. There is evidence that anti-Wolbachia therapy of two syndromes. Trans Roy Soc Trop Med Hyg 1999;93:413–17.
17. Olszewski WL, Jamal S, Manokaran G, et al. Bacteriologic studies of blood,
leads to improvements in lymphatic pathologic features and decreased
tissue fluid, lymph, and lymph nodes in patients with acute dermatolym-
severity of lymphoedema and hydrocele [44]. The disadvantages of
phangioadenitis (DLA) in course of ‘filarial’ lymphedema. Acta Trop 1999;
doxycycline are that it is contraindicated in children <9 years of age
73:217–24.
and in pregnant or breastfeeding women. Therefore, a four-week 18. Aguiar-Santos AM, Leal-Cruz M, Netto MJ, et al. Lymph scrotum: an unusual
course of doxycycline could be considered in the appropriate patient. urological presentation of lymphatic filariasis. A case series study. Rev Inst
More potent drugs are needed to kill adult worms. Flubendazole, Med Trop Sao Paulo 2009;51:179–83.
which is related to albendazole, is highly effective in killing adult 19. Adesiyun AG, Samaila MO. Huge filarial elephantiasis vulvae in a Nigerian
worms; however, in its current formulation, it cannot be absorbed woman with subfertility. Arch gynecol Obstet 2008;278:597–600.
from the gut and is under further development. 20. Dreyer G, Noroes J, Figueredo-Silva J, et al. Pathogenesis of lymphatic disease
in bancroftian filariasis: A clinical perspective. Parasitol Today 2000;16:
40. Dreyer G, Noroes J, Addiss D, et al. Bancroftian filariasis in a paediatric 43. Supali T, Djuardi Y, Pfarr KM, et al. Doxycycline treatment of Brugia
population: An ultrasonographic study. Trans Roy Soc Trop Med Hyg malayi-infected persons reduces microfilaremia and adverse reactions after
1999;93:633–6. diethylcarbamazine and albendazole treatment. Clin Infect Dis 2008;46:
41. Moreno Y, Nabhan JF, Solomon J, et al. Ivermectin disrupts the function of 1385–93.
the excretory–secretory apparatus in microfilariae of Brugia malayi. Proc Natl 44. Debrah AY, Mand S, Specht S, et al. Doxycycline reduces plasma VEGF-C/
Acad Sci USA 2010;107:20120–5. sVEGFR-3 and improves pathology in lymphatic fi lariasis. PLoS Pathog
42. Taylor MJ, Makunde WH, McGarry HF, et al. Macrofilaricidal activity after 2006;2:e92.
doxycycline treatment of Wuchereria bancrofti: a double-blind, randomised
placebo-controlled trial. Lancet 2005;365:2116–21.
Loiasis 111
Amy D Klion
INTRODUCTION
Infection with the filarial nematode Loa loa was first described by
Mongin in 1770, when he extracted an adult worm from the eye of
an African slave [1]. The clinical manifestations were not fully
described, however, until 1781 by Guyot. Adult worms migrate
through the subcutaneous tissues causing intermittent “Calabar swell-
ings” and sometimes migrate beneath the conjunctiva (hence the
popular name eye worm). Although many infected people are asymp-
tomatic despite large numbers of circulating microfilariae in the
blood, administration of microfilaricidal agents, including diethylcar-
bamazine and ivermectin, can cause severe, sometimes fatal,
treatment-associated reactions. This has created challenges for the
Global Programme to Eliminate Lymphatic Filariasis.
EPIDEMIOLOGY
It has been estimated that Loa loa infects 3 to 13 million people in
Central and West Africa with a distribution that mirrors the distribu-
tion of the Chrysops fly vectors, which breed in wet mud on the edge
of shaded streams beneath the high-canopied rain forest. The endemic
areas of Africa are illustrated in Figure 111.1. Isolated cases have also
been reported in Uganda, Malawi, Zambia and Ethiopia, and in the
region from Ghana to Guinea.
Infection rates are usually higher in adults, particularly males, than in
children, probably because of increased exposure to biting flies. Non-
human primates harbor a form of Loa, but there is no evidence that FIGURE 111.1 Geographic distribution of loiasis. Endemic areas are
they act as reservoir hosts for human Loa loa, and infection of humans shaded. Please note that the prevalence of infection within an endemic
by the simian strain has not been demonstrated. area is typically focal.
823
824 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Adults in
subcutaneous tissues Microfilariae
including subconjunctiva
Subcutaneous tissues
Human Blood
Enters through
fly bite wound
Microfilaria in blood
(diagnostic stage)
3rd stage larva
(infective stage)
Migrates to head
and proboscis
Ingested
Fly
(Chrysops)
Penetrates
stomach wall
CLINICAL FEATURES
The clinical spectrum of loiasis is broad, ranging from asymptomatic
infection to life-threatening complications of encephalitis, cardiomy-
opathy and renal failure. With the exception of eye worm and renal
abnormalities (see below), clinical signs and symptoms are more
common in visitors to Loa-endemic areas than in people native to
these areas and reflect a heightened immune response to the parasite.
Conversely, microfilariae are detectable in the peripheral blood
of most endemic individuals with loiasis but are rare in infected
visitors [4].
CALABAR SWELLINGS
Recurrent episodes of localized angioedema, or Calabar swellings
(Fig. 111.3), are one of the characteristic manifestations of loiasis. FIGURE 111.3 Calabar swelling. (Courtesy of Joseph Kamgno.)
Although their precise etiology is unproved, Calabar swellings are
thought to be a hypersensitivity response to antigenic material
released by a migrating, developing or adult worm. They are most the carpal tunnel and may be transiently exacerbated by diethylcar-
common on the face and extremities. Typically, an area of pain or bamazine (DEC) treatment.
itching develops, followed within hours by the development of a 10-
to 20-cm area of nonpitting edema. The edema lasts from a few days
to several weeks and is usually painless, except when the location of EYE WORM
the swelling causes restriction of joint movement or nerve compres- Subconjunctival migration of the adult eye worm (Fig. 111.4), is
sion. Peripheral nerve compression is most common in the region of generally accompanied by transient swelling of the lid and intense
Loiasis 825
swellings can be associated with C1 esterase deficiency, other helminth dwellings, screening houses, and use of protective clothing can effec-
infections such as gnathostomiasis and trichinosis, and allergic tively reduce personal exposure to Chrysops in endemic areas. DEC at
diseases. Subconjunctival migration of an adult worm is highly sug- a dose of 300 mg weekly is effective in preventing loiasis in long-term
gestive of loiasis, although other etiologies, including Dirofilaria repens travelers to endemic areas [13].
and Thelazia californiensis, have been described.
REFERENCES
TREATMENT 1. Mongin. Observation on a worm found under conjunctiva in Maribou, Saint
In patients with few or no circulating microfilariae, DEC at a dose of Domingue Island. J Med Chir Pharm Paris 1770;32:338–9.
8 to 10 mg/kg/day for 21 days is the drug of choice (Table 111-1). The 2. Duke BOL. Behavioural aspects of the life cycle of Loa. In: Canning ED,
drug is not directly toxic to the parasites but works in conjunction Wright CA, eds. Behavioural Aspects of Parasite Transmission. London: Aca-
with the host immune responses to kill microfilariae and adult demic Press; 1972:97–108.
worms. DEC is curative in most cases, although multiple courses of 3. Büttner DW, Wanji S, Bazzocchi C, et al. Obligatory symbiotic Wolbachia
endobacteria are absent from Loa loa. Filaria J 2003;2:10.
therapy are often necessary, and relapses have been documented as
4. Klion AD, Massougbodji A, Sadeler B-C, et al. Loiasis in endemic and non-
late as 8 years after treatment [7].
endemic populations: immunologically mediated differences in clinical pres-
Mild side effects of DEC treatment, including Calabar swellings, urti- entation. J Infect Dis 1881;163:1318–25.
caria, arthralgias, fever and right upper quadrant tenderness, are 5. Nutman TB, Zimmerman PA, Kubofcik J, et al. ELISA-based detection of PCR
common during the first few days of therapy and generally respond products: a universally applicable approach to the diagnosis of filarial and
to antihistamines or a short course of corticosteroids. DEC should not other infections. Parasitol Today 1994;10:239–43.
be used in patients with concomitant onchocerciasis, because of the 6. Burbelo PD, Ramanathan R, Klion AD, et al. Rapid, novel, specific, high-
throughput assay for diagnosis of Loa loa infection. J Clin Microbiol 2008;
risk of severe cutaneous and ocular reactions in these individuals.
46:2298–304.
Serious complications of DEC treatment, including meningoencepha-
Diagnosis of loiasis can be difficult, especially in the absence of microfilariae in the
litis and renal failure, are most common in patients with high
blood. The authors describe a novel antibody assay for specific diagnosis of Loa loa
numbers of circulating microfilariae (>2500/mL) and are thought to infection.
be due to the massive release of antigens from dying microfilariae [8]. 7. Klion AD, Ottesen EA, Nutman TB. Effectiveness of diethylcarbamazine in
Although advocated in the past, neither a gradual increase in DEC treating loiasis acquired by expatriate visitors to endemic regions: long term
dose nor pretreatment with corticosteroids is completely effective in follow-up. J Infect Dis 1994;169:604–10.
preventing encephalitis in such patients. Consequently, if therapy is 8. Carme B, Boulesteix J, Boutes H, et al. Five cases of encephalitis during
indicated in a patient with high numbers of circulating microfilariae, treatment of loiasis with diethylcarbamazine. Am J Trop Med Hyg 1991;
cytapheresis should be used to reduce the microfilarial load prior to 44:684–90.
the initiation of DEC and corticosteroid therapy [9]. 9. Chandenier J, Pillier-Loriette C, Datry A, et al. Value of cytapheresis in the
treatment of loaiasis with high blood microfilaria levels. Results in 7 cases.
Albendazole, at a dose of 200 mg twice daily for 3 weeks, reduced Loa Bull Soc Pathol Exot Filiales 1987;80:624–33.
microfilaremia by approximately 80% over the course of several 10. Klion AD, Massougbodji A, Horton J, et al. Albendazole in human loiasis:
months without adverse effects [10]. Shorter courses of higher-dose results of a double-blind, placebo-controlled trial. J Infect Dis 1993;168:
albendazole appear to be less effective [11]. Albendazole is thought 202–6.
to have an effect on adult parasites by inhibiting microtubular func- 11. Tsague-Dongmo L, Kamgno J, Pion SDS, et al. Effects of a 3-day regimen of
tion and glucose uptake. Albendazole has been used successfully in albendazole (800 mg daily) on Loa loa microfilaremia. Ann Trop Med Para-
DEC-refractory Loa loa infection. sitol 2002;96:707–15.
12. Gardon J, Gardon-Wendel N, Demanga-Ngangue, et al. Serious reaction after
Ivermectin, the treatment of choice for onchocerciasis, has activity mass treatment of onchocerciasis with ivermectin in an area endemic for Loa
against Loa loa microfilariae, but little, if any, effect on adult worms. loa infection. Lancet. 1997;350:18–22.
Consequently, since ivermectin is not curative and causes similar side Severe post-treatment reactions have been recognized as a complication of DEC
effects to those seen with DEC in patients with high microfilarial treatment of loiasis for decades. This study demonstrates similar post-treatment reac-
loads [12], it should not be used for the treatment of loiasis. Doxy- tions during mass administration of ivermectin for onchocerciasis control.
cycline is not effective in loiasis due to the absence of the bacterial 13. Nutman TB, Miller KD, Mulligan M, et al. Diethylcarbamazine prophylaxis
endosymbiont Wolbachia. for human loiasis. Results of a double-blind study. N Engl J Med 1988;319:
752–6.
Elimination of insect vectors using larvicides has been hampered by
the inaccessibility of vector breeding sites. Clearance of forest around
Onchocerciasis 112
Philip J Cooper, Thomas B Nutman
0°
0°
Endemic onchocerciasis
Area covered by the OCP
2
1
3
4
5
6 7
Endemic onchocerciasis 8 9
1. Oaxaca focus
2. Northern Chiapas focus
3. Southern Chiapas focus
12 10
4. Huehuetenango focus 11
5. Solola-Suchitepequez focus
13
6. Escuintia focus
7. Santa Rosa focus 14
8. North-central focus
9. North-eastern focus
10. Souhern focus
11. Amazonas-Roraima focus
12. López de Micay focus
13. Nariño focus
14. Esmeraldas focus
FIGURE 112.1 Maps showing the distribution of onchocerciasis: Africa and Central and South America. (By permission of the World Health Organization.)
characterized by enlarged, soft, regional lymph nodes associated with composed mainly of lymphocytes and eosinophils which starts at the
localized skin changes that histologically show a hyperreactive inflam- level of Bowman’s membrane. Mild, chronic uveitis is common with
matory cell infiltrate with sclerosis and edema but few microfilariae. heavy microfilarial invasion of the anterior chamber. Lesions of the
Scarring in lymph nodes may lead to regional lymphedema, hanging posterior chamber include optic atrophy and chorioretinopathy. The
groin (Fig. 112.6F), or elephantiasis. extent of chorioretinal changes is highly variable and the retinal
pigment epithelium can show migration, clumping, atrophy, or focal
Individuals with higher microfilarial burdens are more likely to hyperplasia. Chronic nongranulomatous chorioretinitis consists of an
develop severe ocular disease. Ocular lesions are caused by the inva- infiltrate of lymphocytes, plasma cells and eosinophils with second-
sion and local death of microfilariae. Microfilariae can enter the eye ary degenerative changes in the overlying retinal pigment epithelium
through the bulbar conjunctiva, along the sheaths of the scleral vessels and neuroretina. Loss of the photoreceptors and outer layers of the
and nerves, or by embolization in the choroidal or ciliary capillaries. retina can be due to inflammatory damage to the retinal pigment
Punctate keratitis (Fig. 112.7A) is observed clinically in the corneal epithelium and choriocapillaris. This is followed by consecutive loss
stroma and clears without scarring. Punctate opacities are focal accu- of the inner neuroretina, ganglion cells, and nerve fibres. Profound
mulations of lymphocytes and eosinophils around degenerating chorioretinal atrophy can develop with loss of almost all the retina
microfilariae with local edema. Sclerosing keratitis (Fig. 112.7B) and choroid. Optic atrophy is common in the more advanced stages
is a progressive fibrovascular pannus and inflammatory infiltrate of ocular onchocerciasis (Fig. 112.7E,F).
O n c hocerciasis 829
FIGURE 112.2 One of the black flies in the Simulium damnosum complex.
The length of the fly is about 3.5 mm (×14.8). (Courtesy of the Armed Forces
Institute of Pathology, Photograph Neg. No. 72-4519E.)
CLINICAL FEATURES
SKIN DISEASE
The earliest and most troublesome symptom of onchocercal skin
involvement is itching [6]. The skin changes have been classified as B
acute papular onchodermatitis (APOD), chronic papular onchoder-
matitis (CPOD), lichenified onchodermatitis (LOD), atrophy, and FIGURE 112.3 Adult worms of O. volvulus. (A) Microscopic section through
depigmentation [6]. More than one skin disease type can coexist in an onchocercal nodule (1.3 × 0.7 cm), showing several coiled adult worms
an individual. APOD consists of small pruritic papules (Fig. 112.6A). (mostly gravid females). The worms are surrounded and incarcerated by
Because of pruritus, there can be excoriations, secondary infection, hyalinized scar (Russell-Movat, ×8.2). (Courtesy of the Armed Forces Institute of
and ulceration. APOD is the typical presentation in individuals with Pathology, Photograph Neg. No. 69-3639). (B) Entangled adult worms, after
short exposure histories, and in such individuals, microfilariae may collagenase digestion of an onchocercal nodule. The cluster measures
not be detectable. about 1.1 × 0.9 cm. The individual worms are up to 0.5 mm across and
50 cm long (×6.9). (Courtesy of the Armed Forces Institute of Pathology,
CPOD consists of flat-topped papules that vary in size and height Photograph Neg. No. 80-12068.)
above the skin surface (Fig. 112.6B). Some lesions can be macular.
Itching can occur, and individuals with CPOD may also have acute
lesions. LOD or “sowda” typically affects young adults and is charac-
terized by pruritic, hyperpigmented and hyperkeratotic plaques (Fig.
112.6C). The distribution is asymmetric, involving one limb, and is LYMPH NODES
associated with regional lymphadenopathy. In later stages, the skin Lymph node changes are commonly seen where they drain areas of
can be grossly lichenified. Itching is intense in the acute stage; this onchodermatitis. Usually the nodes are only slightly enlarged, firm,
condition can coexist with APOD or CPOD. Atrophy of the skin is and nontender. Acute regional lymphadenopathy can accompany
relatively common in areas of high endemicity (Fig. 112.6D). Atrophic acute papular eruptions and lymphedema, but lymph node pathol-
skin adopts many of the characteristics of aging, such as loss of elastic- ogy is usually clinically silent.
ity, and the skin appears excessively wrinkled. Hairs may be lost and
sweating reduced. Onchocercal depigmentation or “leopard skin” is
associated with patches of complete pigment loss and generally affects
EYE DISEASE
the lower leg anteriorly (Fig. 112.6E). A rare manifestation is “hanging Punctate keratitis (fluffy or snowflake opacities) consists of opacities
groin” or “adenolymphocele” that is observed only in heavy and of the superficial corneal stroma (Fig. 112.7A). They can be seen by
longstanding infections, and consists of a pouch of lymphedematous the naked eye or visualized using a slit lamp. Up to 100 or more
tissue in which hang atrophic inguinal or femoral nodes (Fig. 112.6F). opacities measuring 0.5 mm in diameter may be observed, and these
Inflammatory damage to the lymph nodes and lymphatics may, over lesions heal without scarring. Punctate keratitis can be asymptomatic
the long term, lead to elephantiasis of the limbs or genitalia. or accompanied by conjunctival injection, chemosis, limbitis and
epiphora. Longstanding and heavy infections can result in massive
invasion of the cornea, leading to the development of sclerosing
NODULES keratitis, a slowly progressive scarring of the cornea (Fig. 112.7B).
Onchocercomata are subcutaneous fibrous nodules containing adult Severe anterior uveitis (iridocyclitis) can occur with the development
worms, found in the region of the iliac crest, the trochanter, the of posterior synechiae and pear-shaped deformity of the pupil, a loss
sacrum, the upper thorax and head (Fig. 112.8). Nodules are often of the iris pigment frill and a pumice-stone appearance of the iris [7].
absent among patients with short exposure histories but may become Extensive synechiae can cause seclusio- and occlusio-pupillae, second-
detectable later in the course of the infection. ary cataracts, and secondary glaucoma [7].
830 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Adults in
subcutaneous nodule Microfilariae
Subcutaneous tissues
Man Skin
Enters through
fly bite wound
Microfilaria in skin
(diagnostic stage)
3rd stage larva
(infective stage)
Migrates to head
and proboscis
Ingested
Fly
Penetrates
stomach wall
A B C
FIGURE 112.5 Effects of diethylcarbamazine (DEC) on O. volvulus microfilariae. (A) O. volvulus microfilariae are found at the dermo-epidermal junction,
eliciting minimal host inflammatory response. (B) After DEC treatment, intraepidermal microabscesses can form in the epidermis, characterized by dead
and degenerating microfilariae surrounded by eosinophils and neutrophils. (C) Edema and papular dermatitis developing after DEC treatment.
O n c hocerciasis 831
A B
C D
E F
FIGURE 112.7 Ocular changes in onchocerciasis. (A) Punctate opacities in the cornea. (B) Sclerosing keratitis. (Courtesy of Dr I Murdoch.) (C) Early mottling
of retina temporal to the macula (arrow). (D) Mottling of retina temporal to macula (Courtesy of Dr R Proaño.) (E) Post-neuritic optic atrophy with peripapillary
pigmentation and temporal chorioretinal scar. (F) Post-neuritic optic atrophy and geographic atrophy of the retinal pigment epithelium with choriocapillary
atrophy. (Courtesy of Dr. I. Murdoch.)
Chorioretinitis or chorioretinopathy is slowly progressive, taking many choriocapillary atrophy (the choroidal vessels become exposed) and
years before visual loss is evident. It is characterized by retinal pigment subretinal fibrosis. The macula is often preserved until late in the course
epithelial atrophy and chorioretinal scarring [7]. Chorioretinopathy in of disease. Mild forms of RPE atrophy may be detected only by fluores-
onchocerciasis is first seen as a loss of pigment lateral to the macula cein angiography. Fundal changes are usually symmetric. Post-neuritic
(Fig. 112.7C,D) or nasal to the optic disc at the level of the retinal optic atrophy reflects previous episodes of active inflammation of the
pigment epithelium (RPE). Pigment loss appears as a grey-yellow mot- optic nerve [7] (Fig. 112.7E). Onchocercal optic atrophy can also follow
tling. RPE loss progresses in an arc around the macula and extensive destruction of the retina (Fig. 112.7F). Both forms are gener-
eventually may become confluent, producing areas of geographic ally accompanied by inflammatory changes such as peripapillary
atrophy (Fig. 112.7F). Extensive atrophy can be accompanied by hyperpigmentation and sheathing of the central retinal vessels.
O n c hocerciasis 833
A B
OTHER COMPLICATIONS specialized laboratories and are highly sensitive and specific. Although
current serologic assays have limited ability to discriminate past expo-
Chronic infections are associated with low body weight and diffuse
sures from current infections, the detection of O. volvulus DNA in
musculoskeletal pain. A form of dwarfism, Nakalanga dwarfism, has
microscopically negative skin snips is useful in individuals with light
been attributed to pituitary involvement in this disease in the Mabira
infections.
forest of Uganda [8]. An association with epilepsy has also been
reported [8, 9]. Other conditions are reproductive abnormalities with Individuals with no evidence of O. volvulus microfilariae in the skin
secondary amenorrhea, spontaneous abortion, and infertility. or eyes can be challenged using the Mazzotti test. The patient is given
a single oral dose of 25–50 mg of diethylcarbamazine (DEC). Patients
PATIENT EVALUATION, DIAGNOSIS should have a complete ocular examination before considering the
performance of this test because DEC may cause irreversible damage
AND DIFFERENTIAL DIAGNOSIS to the posterior segment of the eye. Infected individuals develop
intense pruritus between 30 minutes and 24 hours after the test,
The chance of acquiring O. volvulus infection increases with greater which can be accompanied by erythema, edema and papular derma-
exposure time in endemic regions (Box 112.1). Some patients may titis (Fig. 112.5C). The presence of M. streptocerca may cause false-
be diagnosed through investigation of eosinophilia. A presumptive positive reactions.
diagnosis can be made based on a history of exposure in an endemic
area, the presence of subcutaneous nodules, or typical skin and/or
ocular signs. Early onchodermatitis is rarely diagnosed correctly and TREATMENT
must be distinguished from atopic dermatitis, food allergies, contact
dermatitis, insect bites and scabies. Chronic skin lesions can be mis- Ivermectin is the most important drug for the treatment of onchocer-
taken for severe chronic eczema, malnutrition and presbydermia. ciasis. It is well tolerated, highly efficacious, and rapidly reduces
“Leopard skin” must be distinguished from other causes of hypochro- microfilarial numbers in the skin [16]. The drug is administered as a
mia, including vitiligo and leprosy. single dose of 150 µg/kg. Because ivermectin has limited effects on
adult worms, treatment must be repeated at annual or semi-annual
Definitive diagnosis depends on the identification of microfilariae in intervals for the duration of the lives of adult worms to suppress
skin snips or of the adult worms from excised or aspirated nodules dermal microfilarial levels [17]. Ivermectin significantly reduces the
[10]. Ocular microfilariae can be detected by slit lamp examination. itching of reactive onchocercal skin disease (APOD, CPOD and
The chances of detection are increased if patients are asked to sit with LOD), but because microfilariae can re-invade the skin within 6
their head between their legs for up to 10 minutes prior to examina- months of treatment, annual treatments may not be sufficient to
tion. Microfilariae in the anterior chamber are seen as small wriggling control pruritus, and treatments every 3 months may be necessary for
worms. Live microfilariae in the cornea are transparent and coiled up. the first 1–2 years. Contraindications for ivermectin treatment are
Skin snips can be obtained using a corneoscleral punch (Fig. 112.9A) conditions associated with an impaired blood–brain barrier because
or by elevating a crease of skin with the point of a needle (Fig. 112.9B) penetration into the CNS can cause lethargy, ataxia, tremors and
and obtaining a small circular disc-shaped slice of epidermis and death. The drug is not approved for use in children weighing less than
superficial dermis using a scalpel blade. The skin snip is then incu- 15 kg (Box 112.2), pregnant women, and mothers nursing infants
bated on a glass slide in saline and examined using a dissecting during the first week of life. Ivermectin has no significant drug
microscope (or magnifying glass) to detect emergent microfilariae interactions.
[10].
Ivermectin has a marked beneficial effect on anterior segment disease
Assays to detect specific antibodies to Onchocerca [11–14] and PCR [7, 18]. A single dose of ivermectin is associated with a reduction
[15] to detect onchocercal DNA in skin snips are now in use in in the prevalence of punctate corneal opacities and microfilariae
834 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
REFERENCES
BOX 112.2 Pediatric Considerations
1. World Health Organization (WHO). Onchocerciasis and its Control. Report
– Treatment of a WHO Expert Committee on Onchocerciasis Control. WHO Technical
Report Series 852. Geneva: WHO; 1995.
l Ivermectin is not approved for use in children weighing less 2. World Health Organization (WHO). Working to Overcome the Global Impact
than 15 kg of Neglected Tropical Diseases. WHO/HTM/NTD/2010.1. Geneva: WHO;
2010.
l Doxycycline is contraindicated in children aged below 9
3. [Anonymous]. Report from the Inter-American Conference on Onchocercia-
years and in pregnant women sis, November 2007. Wkly Epidemiol Rec 2008;83:256–60.
4. [Anonymous]. African Programme for Onchocerciasis Control – report on
task force meeting, July 2008. Wkly Epidemiol Rec 2008;83:307–12.
5. Lipner EM, Law MA, Barnett E, et al. For the GeoSentinel Surveillance. Filaria-
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in the anterior chamber (MfAC). Repeated treatments result in an 6. World Health Organization (WHO). The Importance of Onchocercal Skin
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shown to be beneficial against the development of optic atrophy but Trop Med Hyg 1998;92:236.
not chorioretinal diseases [7, 18]. Control programs using ivermectin 9. Pion SD, Kaiser C, Boutros-Toni F, et al. Epilepsy in onchocerciasis endemic
areas: systematic review and meta-analysis of population-based surveys. PLoS
are expected to have a major impact on the development of the
Negl Trop Dis 2009;3:e461.
lesions of ocular onchocerciasis, and should prevent much of the
10. Eberhard ML, Lammie PJ. Laboratory diagnosis of filariasis. Clin Lab Med
visual loss and blindness associated with this infection [7, 18].
1991;11:977–1010.
There are few side effects and it is generally well tolerated. A mild 11. Burbelo PD, Leahy HP, Iadorola MJ, Nutman TB. A four antigen mixture for
clinical reaction (Mazzotti-like reaction) occurs in 10–20% of patients rapid assessment of Onchocerca volvulus infection. PLoS Negl Trop Dis
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seen. Most reactions occur on the second day after treatment, although 12. Lobos E, Weiss N, Karam M, et al. An immunogenic Onchocerca volvulus
antigen: a specific and early marker of infection. Science 1991;251:1603–5.
severe reactions can commence within 12 hours. During subsequent
13. Ramachandran, CP. Improved immunodiagnostic tests to monitor onchocer-
treatments, the frequency and severity of adverse reactions is reduced.
ciasis control programmes – a multicenter effort. Parasitol Today 1993;9:77–9.
Reactions are characterized by worsening of rash in previously affected
14. Weil GJ, Steel C, Liftis F, et al. A rapid-format antibody card test for diagnosis
areas. Edema can affect one limb or the face and is associated with of onchocerciasis. J Infect Dis 2000;182:1796–9.
enlarged tender regional lymph nodes. A systemic reaction may be 15. Zimmerman PA, Guderian RH, Aruajo E, et al. 1994. Polymerase chain
observed, characterized by fever, arthralgia, musculoskeletal pain, and reaction-based diagnosis of Onchocerca volvulus infection: improved detection
severe postural hypotension. Patients with LOD tend to have more of patients with onchocerciasis. J Infect Dis 1994;169:686–9.
severe reactions following treatment. Mild reactions require only 16. Greene BM, Taylor HR, Cupp EW, et al. Comparison of ivermectin and
symptomatic treatment (e.g. antihistamines and antipyretics). Severe diethylcarbamazine in the treatment of onchocerciasis. N Engl J Med 1985;
reactions may require intramuscular or intravenous steroids. Extreme 313:133–8.
caution should be exercised in those with a possible exposure history 17. Basanez MG, Pion SD, Boakes E, et al. Effect of single-dose ivermectin on
to loiasis – the death of Loa loa microfilariae can cause severe, or Onchocerca volvulus: a systematic review and meta-analysis. Lancet Infect Dis
even fatal, encephalitis [19]. It is recommended that the presence of 2008;8:310–22.
heavy infections with Loa loa should be excluded using thin blood 18. World Health Organization (WHO). The effect of repeated ivermectin treat-
films [19]. ment on ocular onchocerciasis. Report of an informal consultation. TDR/
TDE/ONCHO 1993;4–5.
Because a Wolbachia endosymbiotic bacteria is present in O. volvulus 19. Gardon J, Gardon-Wendel N, Demanga N, et al. Serious reactions after mass
and is required for the survival of Onchocerca, doxycycline at a daily treatment of onchocerciasis with ivermectin in an area endemic for Loa loa
dose of 200 mg for 6 weeks inhibits O. volvulus fertility and kills infection. Lancet 1997;350:18–22.
approximately 50% of adult worms when given with a single standard 20. Hoerauf A, Volkmann L, Hamelmann C, et al. Endosymbiotic bacteria in
dose of ivermectin [20–22]. Such treatment regimens have even been worms as targets for a novel chemotherapy in filariasis. Lancet 2000;355:
used in small community-based treatment programs. This approach 1242–3.
(doxycycline plus ivermectin) provides a macrofilaricidal treatment 21. Hoerauf A, Specht S, Buttner M, et al. Wolbachia endobacteria depletion by
option for individuals who do not live in endemic areas and are thus doxycycline as antifilarial therapy has macrofilaricidal activity in onchocer-
unlikely to get re-infected. ciasis: a randomized placebo-controlled study. Med Microbiol Immunol
2008;197:295–311.
22. Hoerauf A, Specht S, Marfo-Debrekyei Y, et al. Efficacy of 5-week doxycycline
CONTROL treatment on adult Onchocerca volvulus. Parasitol Res 2009;104:437–47.
The initial objective of onchocerciasis control strategies was to reduce Doxycycline is the first effective and well-tolerated macrofilaricidal drug.
community microfilarial burdens to levels that were associated with 23. Thylefors B, Alleman M. Towards the elimination of onchocerciasis. Ann Trop
negligible morbidity. Elimination of onchocerciasis is now considered Med Parasitol 2006;100:733–46.
24. Osei-Atweneboana MY, Eng JK, Boakye DA, et al. Prevalence and intensity of
a realistic objective not only in small foci in parts of Latin America
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(e.g. Ecuador) [3, 23, 24] but also in many regions of Africa [25].
ties in Ghana: a two-phase epidemiological study. Lancet 2007;369:2021–9.
Currently, the focus of control strategies is through semi-annual (in
25. Cupp EW, Sauerbrey M, Richards F. Elimination of human onchocerciasis:
Latin America) [3] or annual distribution (in Africa) [26] of ivermec- history of progress and current feasibility using ivermectin (Mectizan) mono-
tin that has been provided gratis by the manufacturer (Merck & Co) therapy. Acta Trop 2011 (in press).
for as long as it is needed. The highly successful Onchocerciasis Useful review of the use of ivermectin in control programs and potential for elimina-
Control Programme (OCP) in West Africa that relied on vector control tion of infection using ivermectin alone in Latin American and Africa.
measures was phased out in 2002 [26], and control presently relies 26. Vieira JC, Cooper PJ, Lovato R, et al. Impact of long-term treatment with
on ivermectin as the primary control measure [26]. Concerns for both ivermectin for onchocerciasis in Ecuador: potential for elimination of infec-
suboptimal microfilaricidal responses to ivermectin or possible resist- tion. BMC Med 2007;5:9.
ance [27] have surfaced such that measures that would be adjunctive 27. Taylor MJ, Awadzi K, Basanez MG, et al. Onchocerciasis control: vision for
to annual ivermectin distribution are being sought. the future from a Ghanian perspective. Parasit Vectors 2009;2:7.
Miscellaneous Filariae 113
Amy D Klion
The infected larvae penetrate the skin and develop over the course of
9 to 12 months into adult worms (males 35–45 mm × 50–70 µm;
Key features females 60–80 mm × 100–150 µm) that inhabit the pleural, perito-
neal and pericardial cavities, as well as the mesentery, perirenal and
l Mansonella species that infect humans include M. perstans, retroperitoneal tissues [4]. Microfilariae of M. perstans, which are
M.ozzardi, and M. streptocerca small (3.5–4.5 µm × 100–200 µm) and unsheathed with a round
l Mansonella species vary considerably in their geographic terminal nucleus at the tip of the tail (Fig. 113.1), circulate in the
blood without periodicity. Some isolates of M. perstans harbor the
distribution and the location of adult and larval parasites in
bacterial endosymbiont Wolbachia, found in most other filarial patho-
the host gens of humans [5].
l Despite high prevalences of infection in endemic areas,
clinical manifestations of Mansonella infections are
uncommon CLINICAL FEATURES
l Dirofilaria infection is a zoonosis spread by mosquitoes that Although most patients with M. perstans infection are asymptomatic,
is worldwide in distribution clinical manifestations include transient subcutaneous swellings
l The most common presentation of Dirofilaria immitis (dog similar to the Calabar swellings of loiasis, urticaria, pruritus, arthral-
heartworm) infection in humans is an asymptomatic coin gias, abdominal pain, and fatigue. Serositis, including pleuritis and
pericarditis, meningoencephalitis, neuropsychiatric disturbances,
lesion seen on chest radiography
hepatitis, granulomatous nodules in the conjunctiva, retinal lesions
l Responses of Mansonella and Dirofilaria parasites to and periorbital inflammation surrounding dead adult worms (bung-
antifilarial treatment vary by species eye or bulge-eye) have also been described. Eosinophilia and elevated
serum IgE levels are common [6].
TREATMENT
Although diethylcarbamazine (DEC) and albendazole appear
ineffective in the treatment [13], resolution of clinical symptoms
and reduction of microfilarial levels have been reported in a single
patient treated with ivermectin [14]. More recently, a placebo-
controlled, double-blind study of 40 patients in Trinidad demon-
strated an 82% reduction in M. ozzardi microfilarial levels after 4
years of annual ivermectin (6 mg/year) [15]. The efficacy of doxycy-
cline in treating infections with other Wolbachia-containing filarial
FIGURE 113.1 Thin blood film, Mansonella perstans microfilaria (Giemsa parasites has been well documented but has not been explored in
stain, ×890); cephalic space (ces), nucleus (n), nerve ring (nr), anal pore (ap). M. ozzardi infection.
(Courtesy of the Armed Forces Institute of Pathology, Photograph Neg. No. 74.5605.)
STREPTOCERCIASIS
MANSONELLA OZZARDI INFECTION
INTRODUCTION
INTRODUCTION In 1922, Macfie and Corson described microfilariae in the skin
In 1897, Manson first described microfilariae in the blood of Amer- of Ghanaians that were morphologically distinct from Onchocerca
indians in Guyana [9]. He named the species Filaria ozzardi after volvulus [16]. Adult male and female worms were not demonstrated
Ozzard, who obtained the specimens. In 1929, Faust named the new in humans until 1972 and 1975, respectively [17]. The clinical
genus Mansonella. significance of streptocerciasis is likely underestimated due to
overlap in symptomatology and geographic distribution with
onchocerciasis.
EPIDEMIOLOGY
M. ozzardi is restricted to Central America, South America (Colombia,
Venezuela, Guyana, Suriname, Brazil, Argentina, Bolivia) and the Car- EPIDEMIOLOGY
ibbean islands (Puerto Rico, Antigua, Guadeloupe, Nevis, Dominican Although streptocerciasis was believed to be limited to the
Republic, Haiti, Martinique, St Kitts, St Lucia, St Vincent, and Trini- tropical rain forests of western and central Africa, including northern
dad). Although the total number of people infected with M. ozzardi Angola, Cameroon, Central African Republic, People’s Republic of
is unknown, the prevalence of microfilaremia may reach 70% in Congo, Equatorial Guinea, Nigeria, and the Democratic Republic of
highly endemic villages. Infection of travelers is uncommon [3]. Congo, a focus was identified in western Uganda [18]. Prevalence
Humans are the only major reservoir of infection. rates vary widely, but can reach 90% focally. Infection of travelers is
uncommon [3]. Although natural infection of nonhuman primates
NATURAL HISTORY, PATHOGENESIS, occurs, their importance as reservoirs of streptocerciasis remains
AND PATHOLOGY unknown.
M. ozzardi is transmitted by biting midges of the genus Culicoides as
well as by the black fly, Simulium amazonicum. Infective larvae pene-
trate the skin and develop over the course of months to years into NATURAL HISTORY, PATHOGENESIS,
adult worms that are often found in the thoracic and peritoneal cavi- AND PATHOLOGY
ties, and have also been described in the lymphatics. M. ozzardi adult M. streptocerca is transmitted by the biting midge, Culicoides grahamii.
females measure 65–81 mm × 210–250 µm. Only a fragment of a The infective larvae penetrate the skin and develop over the course
male worm (38 mm × 200 µm) from humans has been described. of months to years into adult worms that live in the dermis of
Microfilariae can be found in the skin and blood, where they circulate the upper trunk and shoulder girdle. M. streptocerca adult worms
without periodicity [10]. M. ozzardi microfilariae are small (3–5 µm measure approximately 27 mm × 85 µm (females) and 17 mm ×
× 170–240 µm) and sheathless and are characterized by a cephalic 50 µm (males). Dermal microfilariae are small (2.5–5 µm × 180–
space 2 to 6 µm long with two or three overlapping nuclei and a 240 µm), unsheathed and characterized by a sharp curving of the
caudal space 3 to 8 µm long with oval terminal nuclei (Fig. 113.2). posterior end that frequently gives them a shepherd’s crook configura-
M. ozzardi harbors the bacterial endosymbiont Wolbachia [11]. tion (Fig. 113.3). The cephalic space is 3 to 5 µm long with four oval
nuclei in single file followed by seven to ten smaller rounder nuclei.
CLINICAL FEATURES There are no published data on the presence of Wolbachia in M.
streptocerca.
Although most patients with M. ozzardi infection are asymptomatic
[12], clinical manifestations include urticaria, pruritic skin eruptions,
edema, lymphadenopathy, articular pains, fever, headache, vertigo,
and pulmonary symptoms. Peripheral eosinophilia is common. CLINICAL FEATURES
The clinical manifestations of streptocerciasis appear to be restricted
PATIENT EVALUATION, DIAGNOSIS, AND to the skin and lymph nodes [19]. Although infection is often asymp-
tomatic, the most common complaint is chronic pruritus, most pro-
DIFFERENTIAL DIAGNOSIS nounced over the shoulder girdle and thorax. Characteristic findings
M. ozzardi infection should be considered in individuals with a com- include dermal thickening, non-anesthetic hypopigmented macules,
patible travel history who present with unexplained eosinophilia and/ and axillary or inguinal adenopathy. Occasionally, papules may be
or any of the clinical signs and symptoms described above. Definitive present. Peripheral blood eosinophilia is common.
M i s ce l l a n e ous Filar iae 837
A B C
FIGURE 113.2 Thick blood film, Mansonella ozzardi microfilaria (Giemsa stain). (A) ×820. (Courtesy of the Armed Forces Institute of Pathology, Photograph Neg.
No.74-19692.) (B) Anterior end, cephalic space (ces), nerve ring (nr), ×1620. (C) Posterior end, anal pore (ap), caudal space (cas), ×1620.
A B
FIGURE 113.3 Diagnostic features of microfilariae of Mansonella streptocerca in sections of skin. The microfilariae are extravascular in the dermal collagen.
(A) Anterior end, showing cephalic space and nuclei (×1080). (Courtesy of the Armed Forces Institute of Pathology, Photograph Neg. No.71-10075.) (B) Posterior
end with “shepherd’s crook” configuration and nuclei that reach nearly to the tip (×1080). (Courtesy of the Armed Forces Institute of Pathology, Photograph Neg.
No.71-10074.)
PATIENT EVALUATION, DIAGNOSIS, AND Skin histopathology may be necessary to distinguish M. streptocerca
DIFFERENTIAL DIAGNOSIS macular lesions from those of early leprosy.
M. streptocerca infection should be considered in individuals with a
compatible exposure history who present with pruritus, a macular TREATMENT
hypopigmented rash, or bilateral inguinal or axillary adenopathy. DEC (6 mg/kg/day) for 14 to 21 days is effective in killing both
Diagnosis is made by morphologic identification of microfilariae microfilariae and adult worms, but can be accompanied by an exa
from skin snips or biopsies (see Chapter 112). PCR has been described cerbation of clinical symptoms, including pruritus, papular eruptions
and is more sensitive than standard techniques [20]. As in other (Fig. 113.4), urticaria, arthralgias, myalgias, fever, headache, nausea,
Mansonella infections, serology is not helpful in making a diagnosis. and vomiting. These effects generally subside within 24 to 48 hours
838 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
chamber of the eye). Most worms die without treatment and are
absorbed without clinical sequelae.
REFERENCES
1. Manson P. Parental form of Filaria perstans. Br Med J 1899;1:429.
2. Wanji S, Tendongfor N, Esum M, et al. Epidemiology of concomitant infec-
tions due to Loa loa, Mansonella perstans, and Onchocerca volvulus in rain forest
villages of Cameroon. Med Microbiol Immunol 2003;192:15–21.
3. Lipner EM, Law MA, Barnett E, et al. Filariasis in travelers presenting to the
GeoSentinel Surveillance Network. PLoS Negl Trop Dis 2007;1:e88.
4. Baird JK, Neafie RC, Lanoie L, Connor DH. Adult Mansonella perstans in the
abdominal cavity in nine Africans. Am J Trop Med Hyg 1987;37:578–84.
5. Keiser PB, Coulibaly Y, Kubofcik J, et al. Molecular identification of Wolbachia
from the filarial nematode Mansonella perstans. Mol Biochem Parasitol
2008;160:123–8.
6. Fux CA, Chappuis B, Holzer B, et al. Mansonella perstans causing symptomatic
hypereosinophilia in a missionary family. Travel Med Infect Dis 2006;4:275–
80.
7. Bregnani ER, Rovellini AA, Mbaidoum N, Magnini MG. Comparison of dif-
FIGURE 113.6 Female Dirofilaria tenuis in conjunctiva of left eye. (Courtesy ferent anthelminthic drug regimens against Mansonella perstans filariasis. Trans
of the Armed Forces Institute of Pathology, Photograph Neg. No.74-6351-1.) R Soc Trop Med Hyg 2006;100:458–63.
8. Coulibaly YI, Dembele B, Diallo AA, et al. A randomized trial of doxycycline
for Mansonella perstans infection. N Engl J Med 2009;361:1448–58.
Mansonella perstans infection is refractory to standard antifilarial therapies. Based
on the premise that M. perstans contains the intracellular symbiont Wolbachia,
this study demonstrates that doxycycline is effective in lowering M. perstans micro-
filaremia, providing the first example of effective therapy for this infection.
9. Manson P. On certain new species of nematode haematozoa occurring in
America. Br Med J 1897;1930:1837–8.
10. Nathan MB, Bartholomew CF, Tikasingh ES. The detection of Mansonella
ozzardi microfilariae in the skin and blood with a note on the absence of
periodicity. Trans R Soc Trop Med Hyg 1978;72:420–2.
11. Casiraghi M, Favia G, Cancrini G, et al. Molecular identification of Wolbachia
from the filarial nematode Mansonella ozzardi. Parasitol Res
2001;87:417–20.
12. Bartoloni A, Cancrini G, Bartalesi F, et al. Mansonella ozzardi infection in
Bolivia: prevalence and clinical associations in the Chaco region. Am J Trop
Med Hyg 1999;61:830–3.
13. Bartholomew CF, Nathan MB, Tikasingh ES. The failure of diethylcarbamazine
in the treatment of Mansonella ozzardi infections. Trans R Soc Trop Med Hyg
1978;72:423–4.
14. Nutman TB, Nash TE, Ottesen EA. Ivermectin in the successful treatment of
a patient with Mansonella ozzardi infection. J Infect Dis 1987;156:662–5.
15. Gonzalez AA, Chadee DD, Rawlins SC. Ivermectin treatment of mansonellosis
in Trinidad. West Indian Med J 1999;48:231–4.
16. Macfie JWS, Corson JF. A new species of filarial larva found in the skin of
FIGURE 113.7 Transverse section of immature female Dirofilaria immitis in natives in the Gold Coast. Ann Trop Med Parasitol 1922;16:465–71.
lung (Movat stain, ×275). (Courtesy of the Armed Forces Institute of Pathology, 17. Neafie RC, Connor DH, Meyers WM. Dipetalonema streptocerca (Macfie and
Photograph Neg. No.71-1045.) Corson, 1922): description of the adult female. Am J Trop Med Hyg
1975;24:264–7.
18. Fischer P, Bamuhiiga J, Buttner DW. Occurrence and diagnosis of Mansonella
streptocerca in Uganda. Acta Trop 1997;63:43.
19. Meyers WM, Connor DH, Harman LE, et al. Human streptocerciasis. A clinico-
biopsy or autopsy specimen. Filarial serology may be positive or nega- pathologic study of 40 Africans (Zairians) including identification of the adult
tive, is not species-specific, and is rarely helpful in establishing a filaria. Am J Trop Med Hyg 1972;21:528–45.
diagnosis. 20. Fischer P, Buttner DW, Bamuhiiga J, Williams SA. Detection of the filarial
Histopathology typically reveals a central zone of necrosis surrounded parasite Mansonella streptocerca in skin biopsies by a nested polymerase chain
reaction-based assay. Am J Trop Med Hyg 1998;58:816–20.
by granulomatous inflammation and a fibrous wall. A single, coiled,
21. Fischer P, Tukesiga E, Buttner DW. Long-term suppression of Mansonella strep-
usually necrotic and sometimes calcified, worm is found in the lumen
tocerca microfilariae after treatment with ivermectin. J Infect Dis
of an artery within the area of necrosis (pulmonary dirofilariasis) or 1999;180:1403–5.
in a subcutaneous abscess (Fig. 113.7). Dirofilaria have a number of 22. Simon F, Morchon R, Gonzalez-Miguel J, et al. What is new about animal and
morphologic features that help in their identification in tissue sec- human dirofilariosis? Trends Parasitol 2009;25:404–9.
tions, including their relatively large size (100 to 350 µm in diame- The authors provide an excellent recent review of both human and animal diro-
ter), a thick cuticle, and abundant musculature. Species-specific PCR filariasis, addressing epidemiology, the host–parasite relationship, and the role of the
has also been used to identify and differentiate between Dirofilaria intracellular endosymbiont Wolbachia in pathogenesis and treatment.
species in tissues [25]. 23. Fleck R, Kurz W, Quade B, et al. Human dirofilariasis due to Dirofilaria repens
mimicking a scrotal tumor. Urology 2009;73:209.e1–e3.
TREATMENT 24. Perret-Court A, Coulibaly B, Ranque S, et al. Intradural dirofilariasis mimick-
ing a Langerhans cell histiocytosis tumor. Pediatr Blood Cancer 2009;53:
The only known treatment is surgical removal of the worm, as has 485–7.
often occurred during the diagnostic workup. Removal of the worm 25. Favia G, Lanfrancotti A, Della Torre A, et al. Polymerase chain reaction-
is not essential, however, except in cases where ongoing inflammation identification of Dirofilaria repens and Dirofilaria immitis. Parasitology
is likely to cause permanent damage (ex. a worm inside the anterior 1996;113:567–71.
C
SECTION
INTRODUCTION
Dracunculiasis is caused by the nematode Dracunculus medinensis, and
is a disabling disease of poor rural residents in parts of six countries
in Africa [1, 2]. This infection manifests by 2–3-foot (~1 m)-long
worms that emerge directly through a lesion on the skin; it has an
enormous adverse impact on agricultural production and school
attendance. The infection is close to being eradicated. D. medinensis
has been known since ancient Egyptian times. The life cycle of the
parasite was first fully described by Alexei Fedechenko in 1870 [3].
EPIDEMIOLOGY 2008
During the nineteenth and twentieth centuries, dracunculiasis was
common in much of southern Asia, and in North, West and East FIGURE 114.1 Extent of areas in Africa affected by dracunculiasis in 1986
Africa. When the Dracunculiasis Eradication Program was getting and in 2008.
842
D ra cunculiasis 843
copepods are killed by the digestive juices in the stomach, the larvae countries near the Gulf of Guinea (e.g. Ghana and southern Nigeria),
are released and move to the small intestine, where they penetrate the the disease peaks during the dry season, from October to March,
intestinal wall and migrate to the connective tissues of the thorax [6]. when mostly stagnant sources of drinking water remain, in contrast
Male and female larvae mature and mate 60–90 days after infection. to abundant surface water sources during the rest of the year. The
Over the next 10–14 months, gravid female worms mature, reaching seasonal emergence of the worm often coincides with harvest or
lengths of 70–100 cm (2–3 feet), and slowly migrate to the surface planting seasons, and thus significantly affects agricultural productiv-
of the body (Fig. 114.2), where they become visible through ulcera- ity and also school attendance. Sudan, the country with the highest
tion. On contact with fresh water, powerful contractions cause a loop incidence of dracunculiasis, in 2008 reported 47% of 3618 cases of
of the worm’s uterus to break and discharge a swarm of motile larvae. dracunculiasis among young adults (ages 16–35); 47% of the cases
Contraction of the worm and discharge of larvae may be repeated were male (Makoy SYL, personal communication).
if the lesion is again submerged in water, until the entire brood of
larvae is discharged. Motile free-swimming larvae are ingested whole
by copepods and mature in the body cavity in about 2 weeks. Stag- NATURAL HISTORY, PATHOGENESIS,
nant sources of drinking water such as ponds, cisterns, pools in
dried-up river beds, and shallow unprotected hand-dug wells com-
PATHOLOGY, AND
monly harbor copepods, and are the usual sites where infection is CLINICAL FEATURES
transmitted.
Infected people remain asymptomatic for approximately a year after
Seasonality varies according to location. In the remaining countries infection, until the mature female worm approaches the skin and
with endemic transmission in the Sahel area of Africa (e.g. Mali, Niger, forms a painful papule in the dermis. This papule can become a
northern Nigeria, Southern Sudan, and Ethiopia), transmission blister within 24 hours or may enlarge for several days before blister-
usually peaks during the rainy season at mid-year (May–September). ing (Fig. 114.3). The blister is accompanied by redness and indura-
This is because stagnant surface sources of water are more common tion, and is usually preceded by systemic symptoms of low-grade fever
during the 5–6-month-long rainy season. In currently endemic and allergic symptoms (erythema, urticarial rash, intense pruritus,
Emerging worm
Copepods
First-stage larve
3
FIGURE 114.2 Life cycle of Dracunculus medinensis.
(Courtesy of Encyclopedia Britannica, Inc., © 1996.) Third-stage larve
844 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Pain and other symptoms may lessen with the rupture of the blister,
but, at this time, pyogenic organisms invariably invade the superficial
lesion and worm tract and aggravate the condition (Fig. 114.4). If the
worm breaks during extraction and the remaining part retracts into
the tissue, an intense inflammatory reaction occurs, with pain, swell-
ing, and cellulitis along the worm tract, and usually the formation of
an abscess. The reported period of incapacitation ranges from 2 to 16
weeks (average 8.5 weeks) [7–14] and more than half of a village’s
population may be affected at the same time. In addition to the blis-
ters and skin lesions, the secondary bacterial infections usually exac-
erbate local inflammation and often lead to sepsis, abscesses, septic
arthritis, contracture of muscles near joints, or even tetanus [15].
Chronic manifestations are due to inflammation of the joints, with
signs and symptoms of arthritis, synovitis [16], and muscle and
tendon contractures with resultant ankylosis of the limb [17]. Migra-
tion of the worms to the retroperitoneum and from the retroperito-
neum to the subcutaneous tissue in the leg sometimes results in
aberrant (ectopic) locations such as the pancreas, lung, periorbital
tissues, testis, pericardium [18], and the spinal cord, producing com-
pression [19] as well as focal abscess formation.
FIGURE 114.3 Blisters caused by Dracunculus medinensis and rupture of
blisters resulting in skin lesions with protruding Guinea worms. (Courtesy
of Elizabeth Long, The Carter Center.) PATIENT EVALUATION, DIAGNOSIS,
AND DIFFERENTIAL DIAGNOSIS
There are no serodiagnostic tests available to detect a patient with an
incubating Guinea worm. Diagnosis is based on the clinical history
and findings with an appropriate exposure. The blister fluid is bacte-
riologically sterile and initially contains polymorphonuclear leuko-
cytes and later lymphocytes, eosinophils and macrophages. Larvae are
always present in the fluid and white blood cells adhere to them [6].
With time, the blister and worm track can become secondarily
infected.
Because differentiation between human and zoonotic species of Dra-
cunculus (which rarely affect humans) requires morphologic examina-
tion of adult male worms (which are rarely available), efforts are
underway to map the genome of the Guinea worm’s DNA in order
A to ascertain the infecting parasite’s species more precisely. Although
there are several known zoonotic species of Dracunculus, only medin-
ensis is specific to humans. A molecular tool is now available to dif-
ferentiate between D. medinensis and other tissue-dwelling nematodes,
including other Dracunculus species that may on rare occasions infect
humans [20]. Work on determining the genome of D. medinensis is
ongoing at the Centers for Disease Control and Prevention (Eberhard
ML, personal communication).
TREATMENT
There is no curative drug or vaccine against dracunculiasis. Infected
people do not develop immunity. Applying wet compresses to the
B lesion may relieve pain during the worm’s emergence. Placing an
occlusive bandage on the wound keeps it clean and may help prevent
FIGURE 114.4 Pyogenic organisms invade the superficial lesion and worm the patient from contaminating sources of drinking water. Oral anal-
tract, aggravating the condition. (Courtesy of The Carter Center.) gesics and anti-inflammatory medicines can be administered to allevi-
ate pain and inflammation. Topical antiseptics or antibiotic ointment
may minimize the risk of secondary bacterial infections, reduce
inflammation, and may permit removal of the worm by gentle trac-
dizziness, nausea, vomiting). The lesion produces intense irritation tion over a number of days. Systemic antibiotics may be used in
and burning, inducing the patient to seek relief by immersing the established infections. Patients usually recover completely, but
affected limb in water, where the blister breaks, allowing the adult repeated infections may occur.
worm to discharge larvae into the water (Fig. 114.4).
Eighty to ninety percent of lesions occur on the lower extremities,
including the ankle or foot, but the worms can exit from anywhere
PREVENTION
on the body, including the head, upper extremities, buttocks and Prevention of dracunculiasis includes education of the at-risk popula-
genitalia. More than one worm may emerge from a given patient tion about the disease and avoidance measures, filtration of drinking
either simultaneously or sequentially over a period of weeks or water to remove copepods, and prevention of infected people from
months. As the worm emerges through the skin lesion, the affected entering water intended for drinking. Developing safe sources for
person pulls it out slowly and carefully (because of inflammation and drinking water is also a key feature of control [21]. The global eradica-
pain), usually by winding a few centimeters of the worm each day on tion program has achieved great success towards its goal, with only
a small stick. This very painful process may last many weeks. six remaining endemic countries [1, 2].
D ra cunculiasis 845
REFERENCES 9. Smith GS, Blum D, Huttley SRA. Disability from dracunculiasis: effect on
mobility. Ann Trop Med Parasitol 1989;83:151–8.
1. Hopkins DR, Ruiz-Tiben E, Eberhard ML, Roy S. Progress towards global 10. Watts SJ. Guinea worm: an in depth study of what happens to mothers, fami-
eradication of dracunculiasis, January 2008-June 2009. MMWR Morb Mortal lies, and communities. Soc Sci Med 1989;29:1043–9.
Wkly Rep 2009;58:1123–5. 11. Adeyeba OA, Kale OO. Epidemiology of dracunculiasis and its socio-economic
This paper provides an update on the status of the global campaign to eradicate impact in a village in south-west Nigeria. West Afr J Med 1991;10:208–15.
dracunculiasis as of mid-2009. Annual cases of dracunculiasis have decreased from 12. Ilegbodu VA, Ilegbodu AE, Wise RA, et al. Clinical manifestations, disability,
3.5 million to fewer than 10,000 since the World Health Assembly mandated eradi- and use of folk medicine in dracunculiasis in Nigeria. J Trop Med Hyg
cation in 1986. The number of indigenous dracunculiasis cases continued to decline 1991;94:35–41.
and fell below 5000 for the first time in 2008. In 2009, the continued success of 13. Chippaux JP, Benzou A, Agbede K. Social and economic impact of dracuncu-
the eradication campaign is threatened most by program disruptions from sporadic liasis: a longitudinal study carried out in two villages in Benin. Bull World
insecurity, violence and unrest, particularly in Southern Sudan. Health Organ 1992;70:73–8.
2. World Health Organization. Dracunculiasis eradication: global surveillance 14. Rhode JE, Sharma BL, Patto H, et al. Surgical extraction of Guinea worm:
summary 2008. Wkly Epidemiol Rec 2009;84:162–71. disability reduction and contribution to disease control. Am J Trop Med Hyg
This report summarizes the status of the global campaign to eradicate dracunculiasis 1993;48:71–6.
as of the end of 2008, when only 4619 cases were reported from six countries 15. Adeyeba OA. Secondary infections in dracunculiasis: Bacteria and morbidity.
(Ethiopia, Ghana, Mali, Niger, Nigeria, and Sudan) a reduction of 52% from the Int J Zoonoses 1985;12:147.
9585 cases reported in 2007. The status of national campaigns is discussed country 16. Robineau M, Sereni D. Arthrite aiguë du genou avec presence intra-articulaire
by country. de microfilaires de D. medinensis. Évolutions clinique et immunologique
3. Fedchenko AP. Concerning the structure and reproduction of the guinea compares. A propos d’un cas. Bull Soc Pathol Exot Filiales 1978;71:85–9.
worm (Filaria medinensis L.). Proceedings of the Imperial Society of the 17. el Garf A. Parasitic rheumatism: rheumatic manifestations associated with
Friends of Natural Sciences, Anthropology, and Ethnography. Vol 8 (in calcified guinea worm. J Rheumtol 1985;12:976–9.
Russian), 1870, Reprinted in: Am J Trop Med Hyg 1971:20:511–23. 18. Kinare SG, Parulkar GB, Sen PK. Constrictive pericarditis resulting from dra-
4. Watts SJ. Dracunculiasis in Africa: its geographical extent, incidence, and cunculosis. Br Med J 1962;1:845.
at-risk population. Am J Trop Med Hyg 1987;37:119–25. 19. Odaibo SK, Agowun IA, Oshagbemi K. Paraplegia complicating dracontiasis.
5. World Health Organization. Dracunculiasis: global surveillance summary: J R Coll Surg 1986;31:376–8.
1996. Wkly Epidemiol Rec 1997;72:133–9. 20. Bimi L, Freeman AR, Eberhard ML, et al. Differentiating Dracunculus medin-
6. Muller R. Dracunculus and dracunculiasis. Adv Parasitol 1971;6:73–151. ensis from D. insignis, by the sequence analysis of the 18S rRNA gene. Ann
7. Belcher DW, Wurapa FK, Ward WB, et al. Guinea worm in southern Ghana: Trop Med Parasitol 2005;99:511–17.
its epidemiology and impact on agricultural productivity. Am J Trop Med Hyg 21. Barry M. The tail end of guinea worm – global eradication without a drug or
1975;24:243–9. a vaccine. N Engl J Med 2007;356:2561–4.
8. Khan HD, Aminuddin M, Shah CH. Epidemiology and socio-economic
implications of dracunculiasis in eleven rural communities of District Bannu
(Pakistan). J Pakistani Med Assoc 1986;36:233–9.
115 Trichinellosis
Fabrizio Bruschi, K Darwin Murrell
Trichinella spiralis
Larvae circulate
via blood system
Newborn larvae
pass through
L1 larvae encysted
lymphatic system
in striated muscle
FIGURE 115.1 Life cycle of Trichinella spiralis showing stages and locations of development.
TABLE 115-2 Clinical Phases of Trichinellosis TABLE 115-3 Signs and Symptoms Useful in Assessing
the Probability of Being Infected With Trichinella
Days after Developmental Symptoms and signs
infection phase (heavy infections) Group A Group B Group C Group D
2 to 7 Intestinal Gastrointestinal signs, i.e. Fever Diarrhea Eosinophilia (> Positive
nausea, abdominal pain, 1 G/l and/or serology (with
headache increased IgE a highly
levels) specific test)
9 to 28 Muscle Muscular pain, facial
edema, fever, chills, Eyelid and/or Neurological Increased levels Seroconversion
eosinophilia, tachycardia, facial edema signs of muscular
coma, respiratory enzymes
difficulties
Myalgia Cardiological Positive
14+ Encystment or chronic Mental apathy, signs muscular
neurotoxic symptoms, biopsy
possible myocarditis,
anemia, muscular Conjunctivitis
swelling
Subungual
hemorrhages
is with mebendazole (in adults, usually at a daily dose of 5 mg/kg [in 2. Bruschi F, Murrell KD. Trichinellosis. In: Guerrant RL, Walker DH, Weller PF,
some countries up to 20–25 mg/kg/day] in two doses for a period of eds. Tropical Infectious Diseases: Principles, Pathogens and Practice, 3rd edn.
10 to 15 days) or albendazole (administered at a dose of 15 mg/kg/ Philadelphia: Churchill Livingstone Elsevier; 2011.
day in two doses for 10 to 15 days, in adults). For severe infection, 3. Bruschi F, Murrell KD. New aspects of human trichinellosis: the impact of
treatment may be repeated after 5 days. new Trichinella species. Postgrad Med J 2002;78:15–22.
4. Murrell KD, Bruschi F. Clinical trichinellosis. Prog Clin Parasitol
Factors such as the Trichinella species, intensity of infection (worm 1994;4:116–50.
burden), duration of infection, and the host’s response characteristics, 5. Kennedy ED, Hall RL, Montgomery SP, et al. Trichinellosis surveillance –
especially immunocompetence and/or premunition, should help United States, 2002-2007. MMWR Surveill Summ 2009;58:1–7.
dictate treatment. Unfortunately, only a limited number of prospec- 6. Dupouy-Camet J, Bruschi F. Management and diagnosis of human trichinel-
tive, controlled clinical trials of treatment for trichinellosis have been losis. In: Dupouy-Camet J, Murrell KD, eds. FAO/WHO/OIE Guidelines for
carried out, which has led to uncertainties in the treatment choice [6]. the Surveillance, Management, Prevention and Control of Trichinellosis.
Paris: OIE; 2007:37–69.
This reference is one of the most complete and updated reviews on human
REFERENCES trichinellosis.
7. Gamble HR, Pozio E, Bruschi F, et al. International Commission on Trichinel-
1. Pozio E, Murrell KD. Systematics and epidemiology of Trichinella. Adv Para- losis: recommendations on the use of serological tests for the detection of
sitol 2006;63:367–439. Trichinella infection in animals and man. Parasite 2004;11:3–13.
This reference represents the landmark for people involved in the study of taxonomy
of the genus Trichinella.
116 Toxocariasis
Dana M Woodhall
EPIDEMIOLOGY
CLINICAL FEATURES
The geographic distribution of toxocariasis is worldwide. In the USA, The development of clinical disease depends on the parasite load, the
the overall seroprevalence for antibodies to Toxocara is 14%; in other host’s immune response and migration path of the larvae. In many
countries, studies have demonstrated seroprevalence ranges from cases, infection is asymptomatic; however, two syndromes, visceral
4–86%; however, a positive serologic test does not necessarily indicate toxocariasis and ocular toxocariasis, are well defined. It is uncommon
active clinical disease [2]. Higher seropositivity has been noted in for patients to present with manifestations of both visceral and ocular
non-Hispanic blacks and linked to low socioeconomic status, toxocariasis.
increased blood lead levels and dog or cat ownership. The true preva-
lence of active clinical disease remains unknown. VISCERAL TOXOCARIASIS (VISCERAL
Playgrounds and sandboxes are common sources of Toxocara, as LARVA MIGRANS)
animals frequently defecate there. An older study demonstrated con- Visceral toxocariasis, usually diagnosed in very young children (mean
tamination rates in soil as high as 40% [3]. Children comprise the age 2–4 years), is a marked inflammatory immune response to numer-
majority of patients diagnosed with toxocariasis as they often visit ous larvae migrating to the liver or other tissues. Signs and symptoms
contaminated areas and put their fingers, toys, or other objects into may include fever, abdominal pain, or hepatomegaly. Symptoms
their mouths. A few studies have cited a male predominance for may also include wheezing or coughing; pulmonary infiltration
seropositivity, possibly associated with greater risk activities, such as is evident in a third of patients. A potential association between infec-
an increased likelihood to accidentally ingest dirt. Other associations tion with Toxocara and asthma or neurologic manifestations, such as
850
Toxocar iasis 851
Eggs
An infected dog or cat
sheds Toxocara eggs
Toxocara larvae develop
in their feces
over a 2-4-week time period
Toxocara larvae
in meat
seizures, has been described [5, 6]. Rare fatal cases have resulted from
larval migration to the myocardium or the central nervous system
PATIENT EVALUATION, DIAGNOSIS,
(CNS) [1]. AND DIFFERENTIAL DIAGNOSIS
The diagnosis of visceral toxocariasis should be considered in persons
OCULAR TOXOCARIASIS (OCULAR with a persistently elevated eosinophil count. Identification of larvae
LARVA MIGRANS) in biopsy tissue permits definitive diagnosis of Toxocara infection
(Fig. 116.2); other larval nematodes can be differentiated based on
Ocular involvement is more common in older children and adults characteristic morphologic features. However, biopsy is often unre-
(mean age 7–17 years). Ocular toxocariasis is caused by migration of warding because, unless the infection is massive, specimens may not
Toxocara larvae to the eye resulting in inflammation and scarring yield larvae.
which can lead to permanent vision loss [7]. Ocular disease is usually
unilateral and typically affects the posterior segment of the eye. Pre- A history of geophagia or association with dogs or cats is helpful. The
senting symptoms can include eye redness, eye pain, strabismus, pho- clinical and laboratory findings (other than serologic tests) are non-
tophobia or vision changes. Specific signs, such as subretinal specific and do not help to differentiate visceral toxocariasis from
granulomatous mass, endophthalmitis or posterior pole granuloma other conditions associated with eosinophilia. Because the parasite
can be evident on ophthalmologic exam. does not mature beyond the larval stage in human tissues, adult
worms do not develop in the intestine and diagnosis by egg detection
COVERT OR COMMON TOXOCARIASIS in feces is not possible.
The term “covert” or “common” toxocariasis is used to describe signs Loss of vision in a child may not be recognized immediately. Disuse
and symptoms that are mild and nonspecific but together form a of the affected eye commonly leads to strabismus and the parents may
recognizable symptom complex consistent with toxocariasis. Such note that a squint has developed. In other individuals, routine exami-
symptoms can include abdominal pain, anorexia, sleep and behavior nation may reveal poor or absent sight in one eye; ophthalmologic
disturbances, wheezing, and fever. exam can demonstrate vitritis, retinal scarring, granuloma formation,
852 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
TREATMENT
Asymptomatic toxocariasis does not require anthelmintic therapy.
Although there are isolated reports of ocular disease occurring years
after exposure to Toxocara, available data suggest that asymptomatic
individuals have spontaneous resolution of their eosinophilia and
seroreactivity without adverse sequelae.
Treatment of patients with symptoms of visceral toxocariasis is pri-
marily supportive. Anthelmintics, albendazole (400 mg PO BID), or
mebendazole (100–200mg PO BID), have been used for treatment in
adults and children although the optimum duration of treatment
remains unknown. A 5-day course is considered sufficient, although
some practitioners treat for up to 20 days for severe infections. Severe
pulmonary, myocardial, or CNS involvement may warrant corticos-
teroid therapy.
Treatment of acute ocular toxocariasis is directed toward suppressing
the inflammatory response. Systemic and intraocular corticosteroids
FIGURE 116.2 A portion of a Toxocara canis larva is surrounded by (prednisone 30–60 mg PO each day for 2–4 weeks; triamcinolone
inflammatory cells in a preretinal mass. (× 220; Courtesy of the Armed Forces acetonide 40 mg sub-tenon weekly for 2 weeks; or topical pred-
Institute of Pathology, Photograph Neg. No. 29856329081.) nisolone acetate) are commonly utilized [8]. The benefit of concur-
rent use of anthelminthic drugs in managing ocular toxocariasis
remains unclear. A single study showed improved visual acuity in
persons treated with albendazole and corticosteroids, however, there
or retinal detachment. Toxocara larva is rarely identified on ophthal- was no comparison group [9]. Relapse and progression of ocular
mologic exam. disease are common and often lead to permanent structural damage.
Intraocular fibrous adhesions, retinal traction and detachment, and
chronic vitreal inflammation are most effectively managed by surgical
LABORATORY FINDINGS intervention. Surgical procedures may include pars plana vitrectomy
Eosinophilia is common in active visceral toxocariasis, but its dura- or scleral buckling.
tion is inconsistent and is probably related to the quantity and recent- Implementation of simple prevention strategies can lead to a reduc-
ness of the infecting dose and the frequency of re-infection. In ocular tion in the number of cases of human toxocariasis. Good hygiene
toxocariasis, peripheral eosinophilia is often absent. practices such as hand-washing and teaching children not to eat dirt
will minimize human exposure to infectious eggs. Excluding pets
SEROLOGIC TESTS from play areas and prompt disposal of pet feces will decrease envi-
ELISA, using excretory-secretory antigens from infective-stage larvae, ronmental contamination. Routine veterinarian care for pets, includ-
is the diagnostic test of choice. In patients whose clinical signs ing deworming, will reduce Toxocara infection in dogs and cats.
and history suggest visceral toxocariasis, a positive Toxocara ELISA is Healthcare providers should educate patients about toxocariasis to
strong presumptive evidence of Toxocara infection. A rising or falling increase public awareness of this preventable disease.
titer with a twofold difference in a recently ill patient is consistent
with visceral toxocariasis. Because Toxocara antibody titers can remain
elevated for years after initial infection, a measurable titer is not
REFERENCES
proof of a causative relationship between T. canis or T. cati and the 1. Despommier D. Toxocariasis: clinical aspects, epidemiology, medical ecology,
current illness. Surveys have shown that as many as 1–10% of asymp- and molecular aspects. Clin Microbiol Rev 2003;16:265–72.
tomatic children have ELISA titers of 1 : 32 or more. In patients with 2. Won KY, Kruszon-Moran D, Schantz PM, Jones JL. National seroprevalence and
ocular lesions compatible with toxocariasis, positive ELISA titers risk factors for Zoonotic Toxocara spp. infection. Am J Trop Med Hyg 2008;
79:552–7.
support the diagnosis but do not rule out other eye pathology.
3. Dubin S, Segall S, Martindale J. Contamination of soil in two city parks with
Toxocaral ELISA testing is available at the Centers for Disease Control
canine nematode ova including Toxocara canis: a preliminary study. Am J Public
and Prevention (CDC) and several other clinical laboratories in
Health 1975;65:1242–5.
the USA. 4. Glickman LT, Schantz PM. Epidemiology and pathogenesis of zoonotic toxo-
cariasis. Epidemiol Rev 1981;3:230–50.
DIFFERENTIAL DIAGNOSIS 5. Buijs, J, Borsboom G, van Gemund JJ. Toxocara seroprevalence in 5-year old
elementary schoolchildren: relation with allergic asthma. Am J Epidemiol
Visceral toxocariasis must be differentiated from infections caused by
1994;140:839–47.
other tissue-migrating helminths (other ascarids, hookworm, filiaria, 6. Critchley EM, Vakil SD, Hutchinson, DN. Toxoplasma, Toxocara, and epilepsy.
Strongyloides stercoralis, and Trichinella spiralis) and hypereosinophilic Epilepsia 1982;23:315–23.
syndromes. Hepatic capillariasis can be confused with toxocariasis 7. Stewart JM, Cubillan LD, Cunningham ET. Prevalence, clinical features, and
involving the liver when patients present with hepatomegaly, eosi- causes of vision loss among patients with ocular toxocariasis. Retina 2005;
nophilia, and abnormal liver function test results. Differentiation 25:1005–13.
between the two diseases is through liver biopsy which may demon- 8. Taylor MR. The epidemiology of ocular toxocariasis. J Helminthol 2001;75:
strate eggs of Capillaria species within a hepatic granuloma. Retino- 109–18.
blastoma, ocular tumors, developmental anomalies, exudative 9. Barisani-Asenbauer T, Maca SM, Hauff W, et al. Treatment of ocular toxocariasis
retinitis (Coats disease), tuberculosis, trauma, and other childhood with albendazole. J Ocul Pharmacol Ther 2001;17:287:94.
Gnathostomiasis 117
Paron Dekumyoy, Dorn Watthanakulpanich
EPIDEMIOLOGY
Gnathostomiases, especially G. spinigerum, have become more
CLINICAL FEATURES
common. Since 1889, patients infected with G. spinigerum have been The most common manifestation is intermittent, migratory swelling
reported in Thailand (Fig. 117.1) and G. binucleatum is currently in in the skin and subcutaneous tissues. If the swelling is subcutaneous,
Mexico and other neighboring Latin American countries. Gnathostoma there are usually signs of inflammation, redness, and pain. The swell-
hispidum, G. doleresi, and G. nipponicum have been reported in Japan ing is hard and non-pitting and lasts for 1–4 weeks before it disap-
and China [1]. A few gnathostomiasis cases have been reported from pears. Re-appearance of swelling can occur after an asymptomatic
non-endemic countries, for example G. spinigerum infection in interval of 1 week to several months in a new location not far from
Zambia, South Africa and Brazil, and G. hispidum infection in Spain. the previous one (Figs 117.2 and 117.3).
It is likely that gnathostomiasis is under-reported in many Asian
countries. Patients can initially suffer from epigastric pain, nausea, or vomiting
which are likely caused by penetration of the gastric wall by the
Definitive hosts for gnathostomiasis are dogs, cats, pigs, wild pigs, ingested larvae. Other features can be fever, liver tenderness, and
weasels, and other mammals [1, 2]. Several species of amphibians, pleuro-pulmonary involvement. Frequent coughing, hemoptysis,
reptiles, avians, and mammals act as intermediate hosts of both G. chest pain, dyspnea, pneumothorax, hematuria with or without renal
spinigerum and G. binucleatum. In Thailand, 48 species of vertebrates pain, and granuloma formation in the peritoneal cavity can occur.
(including 20 species of freshwater fish) can serve as second inter With CNS invasion, eosinophilic meningitis or meningoencephalitis,
mediate and/or paratenic hosts. In Mexico, 25 species of fish and subarachnoid, intracerebral or intraventricular hemorrhage, radicu-
seven species of fish-eating birds are recorded as intermediate hosts. lopathy, paralysis, seizures, altered conciousness, coma and death can
853
854 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
A B
FIGURE 117.1 Gnathostoma spinigerum advanced third-stage larvae from livers of freshwater eels. A specific characteristic is the head-bulb and body; its
body length is in a range of 2.5–6 mm.
occur [1, 6]. With ocular invasion, probably by migration of the worm An increased eosinophil count in peripheral blood or CSF can be
along the optic nerves, there can be decreased visual acuity and present; however, the eosinophil count may also not be elevated,
blindness. which may lead to a delay in diagnosis. In one clinical series, 47%
had eosinophilia [7].
With G. binucleatum, clinical features are similar to G. spinigerum with
the additional invasion of peripheral extremities, face, head, and pos- The differential diagnosis for cerebral, visceral and cutaneous gnath-
sibly cardiac tissue [8]. ostomiases includes intracerebral tuberculosis, syphilis, lymphoma,
eosinophilic meningitis, or meningoencephalitis, intracranial haem-
Physical examination findings depend on the area of the body into orrhage, localized angioedema, and helminth infections of loiasis,
which the worms migrate and vary between Gnathostoma species. In spirurina larvae, and baylisascariasis (roundworms of raccoons).
cases of G. spinigerum and G. binucleatum infection, the disease can Computerized tomography (CT), magnetic resonance imaging (MRI),
persist in subcutaneous tissue with relapses over several years, while and ultrasound can assist in the detection of gnathostomiasis, but
in cases of G. hispidum, G. nipponicum, and G. doloresi infection, surface serologic tests should accompany imaging studies. Antibody detec-
skin lesions spontaneously disappear within 3 months even without tion using serum and/or CSF can be used to identify a specific IgG to
treatment. A peripheral blood leukocytosis with hyper-eosinophilia a 24-kDa antigen from G. spinigerum larvae. This test is highly sensitive
occurs in acute cases. The degree of eosinophilia (sometimes as high and specific [10]. Gnathostoma spinigerum cDNA recombinant antigens
as 90%) does not correlate with clinical severity. In cerebral gnathos- have also been developed for antibody detection – two matrix
tomiasis, the cerebrospinal fluid (CSF) is usually bloody or xan- metalloproteinase-like proteins. The sensitivity and specificity of these
thochromic and has a pleocytosis [9]. tests have yet to be established.
90–94% cure rate for cutaneous gnathostomiasis [11, 12]. In alben- tropical diseases, Thailand in 2000-2005. Southeast Asian J Trop Med Pub
dazole- and/or ivermectin-treated patients, gnathostomes may be Health 2010;41:1316–21.
stimulated to move to the skin surface [13, 14]. Patients on a month 5. Miyazaki I. Gnathostoma and gnathostomiasis in Japan. Prog Med Parasitol
of albendazole can experience nausea, headache, and vomiting, and Japan 1966;3:531.
should be monitored for liver toxicity. Ivermectin at 0.2 mg/kg single 6. Daengsvang S. Gnathostoma spinigerum and human gnathostomiasis : a brief
review. The 25th Anniversary of the Faculty of Tropical Medicine, Bangkok,
dose has been shown to be effective in killing third-stage larvae of G.
Thailand 1986;124–47.
spinigerum, with cure rates of 76%, while repeated ivermectin used in
7. Moore DA, McCroddan J, Dekumyoy P, Chiodini PL. Gnathostomiasis: an
relapsed cases demonstrates cure rates of nearly 100% [15]. In one
emerging imported disease. Emerg Infect Dis 2003;9:647–50.
study, ivermectin at 0.2 mg/kg body weight for 2 consecutive days 8. Lazo RF. Gnathostoma and Gnathostomiasis in Ecuador. Southeast Asian J Trop
demonstrated a cure rate of 100% with mild side effects [16]. A com- Med Public Health 2004;35(suppl.1):92–96.
bination of supportive, symptomatic and anti-inflammatory treat- 9. Punyagupta S, Bunnag T, Juttijudata P. Eosinophilic meningitis in Thailand:
ments can also be used. In CNS gnathostomiasis, corticosteroids may clinical and epidemiological characteristics of 162 patients with myeloen-
have an additional role in reducing CNS inflammation and intensive cephalitis probably caused by Gnathostoma spinigerum. J Neurol Sci 1990;
neurologic care is important in critical cases; however, recurrence of 96:241–56.
symptoms is possible. Therefore, post-treatment, long-term follow-up 10. Tapchaisri P, Nopparatana C, Chaicumpa W, Setasuban P. Specific antigen of
of antibody levels and eosinophilia may be helpful to observe Gnathostoma spinigerum for immunodiagnosis of human gnathostomiasis. Int
decreases over time. Following antibody levels for at least 1 year is J Parasitol 1991;21:315–19.
recommended. 11. Kraivichian P, Kulkumthorn M, Yingyoud P, et al. Albendazole for the treat-
ment of human gnathostomiasis. Tran R Soc Trop Med Hyg 1992;86:
418–21.
REFERENCES 12. Suntharasamai P, Riganti M, Chittamas S, Desakorn V. Albendazole stimulates
outward migration of Gnathostoma spinigerum to the dermis in man. Southeast
1. Waikagul J, Diaz Camacho SP. Gnathostomiasis. In: Murrell KD, Fried B, eds. Asian J Trop Med Health 1992; 23:716–22.
Food-Borne Parasitic Zoonoses. New York: Springer; 2007:235–261. 13. Boongird P, Phnapradit P, Siridej N, et al. Neurological manifestation of
2. Rojekittikhun W, Chaiyasith T, Nuamtanong S, Komalamisra C. Gnathostoma gnathostomiasis. J Neurol Sci 1977 31:279–91.
infection in fish caught for local consumption in Nakhon Nayok province, 14. Kraivichian K, Nuchprayoon S, Siriyasatien P, et al. Resolution of eosinophilia
Thailand, I. Prevalence and fish species. Southeast Asian J Trop Med Public after treatment of cutaneous gnathostomiasis. J Med Assoc Thai 2005;88(suppl.
Health 2004;35:523–30. S4):163–66.
3. Xuan LT, Hoa PTL, Dekumyoy P, et al. Gnathostoma infection in South 15. Kraivichian K, Nuchprayoon S, Sitichalernchai P, et al. Treatment of cutaneous
Vietnam. Southeast Asian J Trop Med Public Health 2004;35(suppl. 1): gnathostomiasis with ivermectin. Am J Trop Med Hyg 2004;71:623–28.
97–9. 16. Nontasut P, Claesson BA, Dekumyoy P, et al. Double-dose ivermectin vs
4. Bussaratid V, Dekumyoy P, Desakorn V et al. Predictive factors for Gnathostoma albendazole for the treatment of gnathostomiasis. Southeast Asian J Trop Med
seropositivity in patients visiting gnathostomiasis clinic at hospital for Public Health 2005;36:650–52.
Eosinophilic Meningitis
(Angiostrongylus cantonensis,
118 Parastrongylus cantonensis)
Yupaporn Wattanagoon, John H Cross†
DIFFERENTIAL DIAGNOSIS
Eosinophilic meningitis can be caused by other parasitic infections,
such as gnathostomiasis, paragonimiasis, cysticercosis, schistosomia
sis, toxocariasis, baylisascariasis or trichinellosis (Fig. 118.4). In Thai
land, gnathostomiasis is an important differential and should be
suspected if the patient has a previous history of migratory swellings
and they have hemorrhagic or xanthochromic spinal fluid and eosi
nophilic pleocytosis. Serologic diagnosis can be performed to differ
entiate these two infections.
TREATMENT
FIGURE 118.2 Ocular angiostrongyliasis. An intravitreal Angiostrongylus
nematode killed with laser photocoagulation before surgical removal. Most patients spontaneously recover within a few weeks after receiv
(Courtesy of Dr Suthasinee Sinawat, Department of Ophthalmology, Khon Kaen ing supportive treatment to alleviate headache. Acetaminophen and
University, Khon Kaen, Thailand). repeated lumbar punctures may be clinically indicated.
There have been a few clinical trials of treatment; most of those have
included eosinophilic meningitis, but not always specifically docu
mented Angiostrongylus infection (Box 118-1). Oral prednisolone
(60 mg/day divided into three doses) for two weeks significantly
female is 33 mm long with vulva and anus located near the caudal
end; the male is 20 mm long with a copulatory bursa and two spicules
Key features approximately 300 µm in length [2]. Eggs are released within the
mesenteric arteries and carried by the blood into the intestinal wall,
● Characterized by granulomatous inflammation with where they embryonate (Fig. 119.1). First-stage larvae hatch and
eosinophilic infiltration of the intestinal wall migrate through the intestinal wall. They are excreted in the rat’s feces
● The lifecycle involves rodents (definitive hosts) and mollusks and reach the soil, where they are eaten by the intermediate host—
usually slugs. Two molts take place in the mollusk and, after 18 days,
(intermediate hosts)
the infective third-stage larva matures. The definitive host, usually the
● Human infection mostly occurs in Central and South cotton rat, becomes infected by eating the mollusk. The prepatent
America, from southern Mexico to Argentina period lasts 24 days [3].
● Children are more frequently infected and the male-to- In Costa Rica, the cotton rat, Sigmodon hispidus, is the most important
female ratio for infection is 2:1 host, but at least 12 different species of rat and one coati have been
● Prevention involves avoiding ingesting slugs and raw food found to be naturally infected. Marmosets and two rodents have been
and water that may be contaminated with slugs or slug found infected with A. costaricensis in eastern Peru and southern
secretions Brazil, respectively [4].
● Synonyms include: Angiostrongylus costaricensis, Although several mollusks are naturally infected with A. costaricensis,
Morerastrongylus costaricensis [1], and eosinophilic veronicellid slugs are considered the main intermediate hosts.
granuloma Humans become infected when they ingest slugs or food items con-
taminated with small mollusks or their secretions, for example small
● There is no specific anti-parasitic therapy; surgical treatment slugs hidden in salad greens could be finely chopped and inadvert-
may be necessary ently eaten raw. Several cases have followed ingestion of mollusks by
infants. Most human infections are probably caused by ingestion of
the infective larvae shed in the mollusk’s secretions (Fig. 119.1). Slugs
have been found in ripe fruits that have fallen to the ground. Char-
INTRODUCTION acteristic mucous trails left by the mollusks can be observed through-
out endemic areas. The propensity for small children to put things in
Abdominal angiostrongylosis, caused by Angiostrongylus costaricensis is their mouths could explain why they have the highest infection rates.
characterized by a granulomatous inflammatory reaction with heavy
eosinophilic infiltration of the intestinal wall, especially in the ileoce- At least two species of veronicellid slugs in Costa Rica (Saranisula
cal region. The disease has been observed in Costa Rica since 1952; plebeia and Diplosolenodes occidentalis) and several species in Brazil
since 1971, it has been reported from most countries of the Americas, (Phyllocaulis variegatus and Sarasinula linguaeformis, among other
especially Central and South America. In addition, cotton rats natu- species) are naturally infected with A. costaricensis. Fifty percent of
rally infected with the parasite have been found in the USA. 6025 slugs from 20 Costa Rican localities, from sea level to an altitude
of 2000 meters, were found to be infected and more than 16,000
infected larvae were counted in a single specimen.
EPIDEMIOLOGY In most cases, lesions caused by A. costaricensis are located in the
The disease has been reported from the USA to Argentina, including ileocecal region. They also occur in the hepatic flexure and descending
some Caribbean islands. One human case has been reported from colon, regional lymph nodes, liver, and testicles. Two major patho-
Africa. In Costa Rica, its distribution is universal, from sea level to an genic mechanisms are present: (i) the adult worms living within the
altitude of 2000 meters. With the first recognition of A. costaricensis mesenteric arteries (Fig. 119.2) damage the endothelium, inducing
until the mid-1980s, 20–60 cases were reported annually. Secondary thrombosis and, consequently, necrosis of the tissues perfused by the
to better identification of the disease by medical personnel, the vessels; and (ii) eggs, embryos, and larvae, as well as excretion-
annual incidence increased to 600 cases per year (20 cases per 100,000 secretion products, cause inflammatory reactions. These features, as
inhabitants). Improvements in sanitation and mollusk control since well as the patient’s susceptibility and the number and localization
2000 have decreased the number of cases to about 185 cases/year over of parasites, determine the pathophysiology of the infection.
the last 10 years.
INTESTINAL LESIONS
NATURAL HISTORY, PATHOGENESIS, Gross pathology shows a hardened and thickened intestinal wall
AND PATHOLOGY with yellowish foci in the serosal surface of the intestine. The intes
tinal lumen is reduced, sometimes causing partial or complete
Angiostrongylus costaricensis is a filariform nematode normally living obstruction. Necrotic areas can perforate. In many cases, cecal lesions
within the mesenteric arteries of the definitive host—a rodent. The are detected during an appendectomy. Histopathology demonstrates
859
860 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
Larvae migrate to
ation
cul brain, lung, eye
cir
Man
n
ulatio Larvae migrate to
circ
mesenteric artery
sis
en
sis
on
en
ant
ic
A. c
ar
st
co
A.
Rodents
Infected
hosts 1st stage
ingested larva
A B C
FIGURE 119.3 Angiostrongylus costaricensis ova in tissues. (A) Section of the intestine showing several granulomas and giant cells. Eggs (arrows) are
scattered in the tissue. (B) Eggs in the cecal wall surrounded by inflammatory cells (eosinophils). (C) Embryonated eggs in the liver.
granulomatous inflammatory reactions (Fig. 119.3A) with heavy eosi- (Fig. 119.3C), larvae and even adult worms in the hepatic parenchyma
nophilic infiltration, especially in the intestinal mucosa and submu- establishes the diagnosis. In excised testicles, worms have been
cosa; the serosa and muscular layers are often involved to a lesser observed obstructing the arteries of the spermatic cord and there can
degree. Eggs (Fig. 119.3B), embryos, and larvae are in small cavities be extensive parenchymal hemorrhagic necrosis.
lined by endothelium. Unfertilized eggs usually degenerate and are
difficult to recognize. These structures, as well as the excretion-
secretion antigens, are easily identified by immunochemical tech-
CLINICAL FEATURES
niques. Large areas of necrosis are caused by arterial thrombosis. Abdominal angiostrongylasis predominantly affects children. Among
116 patients studied in a pediatric hospital, 50% were school age, 40%
were preschool age and 10% were infants; two-thirds were male [5].
EXTRAINTESTINAL LESIONS When worms are located in the ileocecal region, most patients com-
Eggs and embryos are present in the mesenteric lymph nodes, which plain of pain in the right iliac fossa and the right flank. Palpation in
show reticuloendothelial hyperplasia and eosinophilic infiltration. this area often causes pain. Rectal examination is also painful in about
Hepatic lesions caused by A. costaricensis are similar to those caused one-half of the patients and most patients present with fever of 38–
by Toxocara canis (Chapter 116). However the finding of eggs 38.5°C, rarely accompanied by chills. In chronic cases, a mild fever
Ab d o m i n a l An gi o s t rongyliasis 861
EXTRAINTESTINAL FINDINGS
Sometimes the patient complaints of pain in the right upper quad-
rant. In these cases, the liver is almost always enlarged and tender
to palpation. At laparoscopy, small yellowish spots (granulomas) are
seen on the surface of the liver. Most patients have hepatic involve-
ment along with intestinal angiostrongyliasis. When the testicle
is involved, the patient experiences acute pain, accompanied by
redness and then purple discoloration. Eosinophilia and leukocytosis
are also conspicuous. All patients with testicular necrosis have been
misdiagnosed as having testicular torsion—the correct diagnosis
being made only following surgery.
TABLE 120-1 Epidemiology and Clinical Characteristics of Parasites Associated With Cutaneous Disease Including
Cutaneous Larva Migrans
first symptom is typically intense pruritus followed by a raised, ery- the larvae migrate randomly in advance of the visible tracks and may
thematous track that starts near the site of penetration. The track, not be in the treated area. Topical therapy with anthelminthics has
typically about 3 mm wide and up to 20 mm long, can move in the been shown to be effective but needs repeated applications over large
skin at a rate of several millimeters per day; the larva itself is usually areas of skin. Oral treatment with albendazole (400 mg/day orally for
migrating somewhere ahead of the track. Usually, only one or a few 3–7 days) or ivermectin (200 µg/kg orally single dose) eliminates the
tracks are present but there may be multiple tracks in more intense symptoms and kills the migrating larvae; in more severe cases of fol-
infections. Vesiculobullous lesions and edema can accompany the liculitis, additional doses may be necessary. Rarely, relapse can occur
track; folliculitis is uncommon and may be related to the infecting but usually is resolved by repeated treatment [6,8,9].
species of hookworm. Eosinophilia is not consistently present and is
likely when larvae have penetrated to deeper tissues or a greater Pediatric treatment: In children over 15 kg, a single dose of ivermectin
inflammatory reaction is present [6,8]. 200 µg/kg orally is effective. Children under the age of 2 years should
receive albendazole 200 mg orally for 3 days. Topical preparations
of either drug have been suggested as alternative treatments in
PATIENT EVALUATION, DIAGNOSIS, children.
AND DIFFERENTIAL DIAGNOSIS
Cutaneous larva migrans is a clinical diagnosis based on the presence REFERENCES
of characteristic pruritus and an erythematous raised track that moves 1. Bowman DD, Montgomery SP, Zajac AM, et al. Hookworms of dogs and cats
randomly in the dermis, as well as a history of skin exposure to as agents of cutaneous larva migrans. Trends Parasitol 2010;26:162–7.
contaminated soil or sand in endemic areas. Serologic testing to 2. Kirby-Smith J, Dove W, White G. Creeping eruption. Arch Dermatol Syphilol
confirm infection is not available; skin biopsy is not useful since the 1926;13:137–73.
location of the migrating larva cannot be predicted by the visible 3. Lederman ER, Weld LH, Elyazar IR, et al. Dermatologic conditions of the ill
track. Clinical features and travel history can also help to define dif- returned traveler: an analysis from the GeoSentinel Surveillance Network. Int
ferential diagnoses, including other parasitic infections such as human J Infect Dis 2008;12:593–602.
hookworm, gnathostomiasis, strongyloidiasis, or noninfectious con- 4. Feldmeier H, Heukelbach J. Epidermal parasitic skin diseases: a neglected
ditions such as cutaneous pili migrans. Myiasis and scabies can mimic category of poverty-associated plagues. Bull World Health Organ
CLM [1,6,8]. 2009;87:152–9.
5. Blackwell V, Vega-Lopez F. Cutaneous larva migrans: clinical features and
management of 44 cases presenting in the returning traveler. Br J Dermatol
TREATMENT 2001;145:434–7.
6. Heukelbach J, Feldmeier H. Epidemiological and clinical characteristics
CLM can be prevented by wearing shoes, sitting or lying on protective of hookworm-related cutaneous larva migrans. Lancet Infect Dis
mats while at the beach, and taking other protective measures to avoid 2008;8:302–9.
contact with contaminated soil or sand. Regular deworming of cats 7. Heukelbach J, Jackson A, Ariza L, Feldmeier H. Prevalence and risk factors of
and dogs and prompt disposal of animal waste in the environment hookworm-related cutaneous larva migrans in a rural community in Brazil.
help to control sources of infective larvae [1]. CLM is self-limiting; Ann Trop Med Parasitol 2008;102:53–61.
larvae migrating in the skin usually will die after 5–6 weeks, although 8. Hochedez P, Caumes E. Hookworm-related cutaneous larva migrans. J Travel
delayed onset and persistent clinical disease have been reported. Med 2007;14:326–33.
Treatment may be necessary to resolve severe symptoms and address 9. Caumes E. Treatment of cutaneous larva migrans and Toxocara infection.
secondary bacterial infections. Cryotherapy is not recommended, as Fundam Clin Pharmacol 2003;17:213–16.
121 Anisakidosis
Davidson H Hamer
EPIDEMIOLOGY
The annual incidence is greatest in Japan, where the consumption of
raw fish is common. Of the approximately 20,000 reported cases
worldwide, more than 90% occur in Japan [3]. Most other cases have
been described in Korea and Europe, especially the Netherlands,
Germany, France, Spain and Italy. During the last two decades, there FIGURE 121.1 Pseudoterranova decipiens larvae embedded in the flesh of
have been increasing reports from the US, Canada, Brazil, Chile, Egypt Atlantic cod.
864
Anisak idosis 865
NATURAL HISTORY, PATHOGENESIS, Primary hosts for Anisakis are dolphins, porpoises, and whales.
Primary hosts for P. decipiens are seals, walruses, and sea lions.
AND PATHOLOGY After ingestion of raw or undercooked saltwater fish by humans, the
The adult worm is found in the stomachs or intestines of marine larvae embed themselves in the gastric or intestinal mucosa and then
mammals such as whales, dolphins, sea lions, and seals [5]. Eggs die. The burrowing or dead larva precipitates an intense hypersensitiv-
hatch in seawater to form free-living larvae (L2) that infect intermedi- ity reaction characterized by a granulomatous, eosinophilic tissue
ate hosts, usually crustaceans, e.g. krills (Fig. 121.2). Within the first infiltrate. A Th2 immune response has been demonstrated in humans,
intermediate host, the parasite matures into L3 larvae which are sub- with mucosal and submucosal inflammatory infiltrate composed of
sequently ingested by marine fish or squid, which serve as transport eosinophils and lymphocytes.
(second intermediate) hosts. The third-stage larvae migrate into the
viscera, peritoneal cavity and musculature of this host. Ingestion of
uncooked fish or squid by a marine mammal (final host) or humans
(accidental hosts) leads to infection. The nematode larvae develop
CLINICAL FEATURES
into fourth-stage larvae and then adults in the marine mammal final There are four major clinical syndromes in humans: gastric, intestinal,
host. ectopic (or extra-gastrointestinal), and allergic [3]. Infection with P.
d
i Infective stage
Diagnosis of gastric anisakiasis can be
made by endoscopy during which the d diagnostic stage
~2 cm larvae can be removed
TREMATODE INFECTIONS
122 Schistosomiasis
Bruno Gryseels, G Thomas Strickland
3
5
Each ovum contains one ciliated larva, called a miracidium, which next 10–15 days, germinal cells in the mother sporocyst differentiate
matures over 6–10 days. The miracidium secretes proteolytic enzymes into motile daughter sporocysts. The daughter sporocysts migrate to,
that help the eggs to penetrate through the vascular wall and into and grow in, the hepatic and gonadal tissue of the snail, where they
surrounding tissues into the lumen of the bladder (S. haematobium) metamorphose within 2–4 weeks into bifurcated, mobile larvae
or the intestine (other species). About 50% of the eggs are eventually called cercariae. The entire non-sexual reproduction stage in the snail
excreted with the urine or the feces, where they may stay viable for takes 4–6 weeks, but cercariae may be shed for up three months at a
seven days (African species) or up to several months (Oriental rate of dozens (S. japonicum) to thousands (S. mansoni, S. haemato-
species), depending on the temperature and humidity in the environ- bium) per day. While snail life expectancy is reduced by schistosome
ment. The other ova are dislodged and partly destroyed in the liver infection because of damage to hepatic and gonadal tissue, one snail
or spleen, but many remain stuck in the tissues of the bladder or infected by one miracidium can shed thousands of cercariae every day
ureters, the intestinal wall, or the liver or spleen (depending on for months and may produce up to 100,000 cercariae in its lifetime.
species) where immune responses lead to most of the host’s
pathology. The cercariae are unisexual, highly mobile larvae measuring 400–
600 µm in length. They feature a pear-shaped head with two embryo
The excreted ova release the miracidium upon contact with water of nic suckers and a long slender tail ending in a typical short fork.
the right temperature (20–30°C), which then swims freely and swiftly Cercarial shedding is stimulated by direct sunlight and temperatures
around in search of its snail intermediate host. They are propelled by between 24–30°C, leading to peak transmission rates between
flagellating cilia and guided by positive phototaxis and chemotaxis 11.00 h and 15.00 h and, in subtropical regions, during summer
(attracted by light and snail substances) and negative geotaxis (moving months. Schistosoma japonicum cercariae may also be shed at night.
away from the bottom mud). In addition to this typical movement
and cilia, the miricidia have pulsating flame and gland cells. They can Cercariae may survive up to 48–72 hours, though infectivity starts
remain infective for 6–12 hours and penetrate the snail intermediate to decrease after 12 hours. Activity in water varies with the species:
host’s soft parts by aid of lytic substances. S. mansoni and S. haematobium cercariae move vertically, alternating
between active movements toward the surface and slow sinking;
After snail penetration, the miracidium loses its cilia and transforms S. japonicum cercariae tend to remain at rest in the water surface
into a non-motile sac-like embryo: the mother sporocyst. Over the film unless disturbed. When cercariae meet a suitable definitive host,
S c h i stosomiasis 871
they attach themselves to its skin by their ventral or oral suckers, built up slowly over many years [21]. The availability of praziquantel
assisted by mucoid secretions. Vertical, vibratory movements and lytic has also allowed testing and confirming of this hypothesis by measur-
secretions lead to penetration of the skin, usually complete within ing re-infection rates after population-based treatment. After con-
3–5 minutes. Only some of the cercariae will develop further after firmed chemotherapeutic cure, egg counts usually rise much quicker
penetration, depending on the physiologic and immunologic reac- to initial levels in children than in adults, with minimal correlation
tions of the host. to exposures to contaminated water. This partial immunity is medi-
ated by IgE against larval and adult worm antigens, which stimulate
The cercariae lose their tail and undergo an intensive outer membrane eosinophils to release cytotoxins targeting schistosomulae [22]. Efforts
modification to become schistosomula which are tolerant to a saline to develop a protective vaccine are ongoing but are unlikely to result
environment and, even more strikingly, to at least part of the hosts’ in a commercially-available product in the near future [3, 22, 23].
immune responses. They remain in subcutaneous tissue for about 48
hours before beginning the 3–6 day migration through the blood-
stream to the heart and then the lungs, where they are able to stretch MORBID IMMUNITY
the capillaries between the arterioles and venules. Within 5–10 days The main pathology in schistosomiasis is actually caused by cellular
they reach the small vessels of the liver where they mature within immune responses against eggs retained in the tissues, rather than the
another 3–4 weeks into adult male or female worms, mate and adult worms [12, 24]. The enzymes and metabolites released by the
migrate against the blood flow to their perivesicular or mesenteric ova that are trapped in the tissues provoke granulomatous reactions
destination where the cycle starts all over again. Egg deposition and by eosinophils, monocytes and lymphocytes orchestrated by CD4+ T
excretion thus starts 6–8 weeks after infection. cells. In the early stages of infection, cytokine responses are predomi-
nantly of the TH1 type featuring interferon-γ. As egg production pro-
THE SNAIL INTERMEDIATE HOSTS AND OTHER ceeds, they shift to a TH2 profile with high levels of IgE, interleukin
(IL)-4 and eosinophilia. In long-standing chronic infection, this TH2
RESERVOIR HOSTS profile modulates to production of IL-10, IL-13 and IgG4, which leads
The snail intermediate hosts of S. mansoni and S. haematobium are to the regression of the granulomas and their replacement by colla-
red-brownish in color and are non-operculate, i.e. they have no cover gen. In most infected persons, however, anti-inflammatory IL-10, and
or lid on the shells. The major intermediate hosts for S. haematobium possibly transforming growth factor (TGF)-β, induced by regulatory
and S. intercalatum are Bulinidae, with conic shells with a left-twisted T cells, prevents excessive TH1 or TH2 polarization and, hence, severe
spiral. The genus Biomphalaria serves as the intermediate host for disease manifestations in the late stages of the disease.
S. mansoni and is characterized by its disk- or lens-shaped shells [1,
5, 6]. The snail intermediate hosts of S. japonicum, members of IMMUNE RESPONSES AND CO-INFECTIONS
Oncomelania hupensis species, are operculate with conical or turriculate
shells. Various bidirectional interactions between immune responses to
schistosomiasis and HIV/AIDS have been described, but their clinical
Other freshwater mollusks serve as intermediate hosts for incomplete significance remains undetermined [3, 25]. Treatment of concomitant
avian schistosome infections (causing cercarial dermatitis) but may schistosomiasis appears to have little effect on HIV viral load or
be difficult to distinguish from the intermediate hosts of human results, at most, in a lower HIV RNA increase in patients with a
schistosomes, requiring the use of rigid determination keys or genetic delayed intervention. Reduced CD4+ T cell counts may increase the
analysis. susceptibility to schistosome infections and serodiagnostic reliabili-
ties may be affected in concomitant infections.
The aquatic snails important to the transmission of S. mansoni and S.
haematobium live in lightly-shaded, slow-flowing shallow waters. There have been experimental animal and human studies reporting
Biomphalaria, and particularly Bulinus, can survive protracted droughts, that chronic schistosomiasis, by downregulating the TH1 and upregu-
hiding in moist mud until the next rains come and rivers swell again. lating the TH2 immune responses, could cause viral infections,
The amphibious Oncomelania intermediate host of S. japonicum notably hepatitis B and C, to become chronic and more severe [26].
spends part of its time out of water, preferring moist soil in marshy The situation is complicated as parenteral treatment of schistosomia-
habitats, at the edge of slow-flowing streams, or irrigation canals. It sis has caused the spread of some blood-borne viral infections [13],
can survive dry periods, as well as long and cold winters. The popula- but the clinical importance of the immunosuppressive effects of schis-
tion dynamics of the snails, and consequently the transmission tosomiasis on hepatitis B and C is less than the pathophysiology
dynamics of the parasite populations, may differ greatly from one caused by having multiple infections.
area, one season or one year to another. The infective dynamics of the
intermediate host are such that usually less than 0.5% is infected with
schistosomes at any one time. As only a very small proportion of the EPIDEMIOLOGY
total snail population can be sampled, it may be difficult to find any
infected snails or cercariae even in highly endemic areas [20]. GEOGRAPHIC DISTRIBUTION (Fig. 122.3)
There is no identified functional reservoir host for S. haematobium. The distribution of the different species depends primarily on the
Schistosoma mansoni infects rodents and baboons living in some ecology of the snail hosts. The introduction and sustained transmis-
endemic areas and they can maintain the transmission cycle. However, sion of Schistosoma infections requires suitable snail hosts, a tropical
humans are by far the main reservoir of infection. In contrast, S. climate for at least 4–6 months a year, human settlement, fecal or
japonicum is a zoonotic parasite that naturally infects dogs, cats, cattle, urinary contamination of the surface waters harboring the snails and
water buffaloes, pigs, horses, sheep, goats and rodents; some of these, human contact with these waters. The geographic distribution of
i.e. cattle and water buffaloes, are as important for transmission as schistosomiasis is, thus, largely confined to an area between 36°
humans [6, 20]. north and 34° south latitude, where freshwater temperatures average
25–30°C and socioeconomic conditions impose regular contact with
snail-infested water [1, 3, 4]. In addition, within populations and age
IMMUNOLOGY groups, schistosomes are not evenly distributed – a small number of
individuals carry most of the parasite burden [27].
PROTECTIVE IMMUNITY The epidemiology of schistosomiasis is highly focal and can vary
Epidemiologic and clinical observations show that people living in strongly from one area, village or hamlet to another [1, 3, 4]. While
endemic areas develop acquired immunity, but only after several years S. haematobium mostly occurs in warm plains, S. mansoni can be
of exposure [21]. Indeed, prevalence and intensities of infection transmitted in a variety of ecotypes, from savannah to rain forest and
decline after the age of 10–15 years. Cross-sectional data are, however, highland areas of up to 2500 m. Transmission of both species takes
difficult to relate with exposure, as the worm burdens in adults were place in the great lakes of Central and East Africa; in many other small
872 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
and large, natural and artificial lakes throughout the continent; in mathematical models or using circulating antigen levels. Other meth-
surface irrigation and drainage systems; and in innumerable natural odologic handicaps include difficulty measuring snail densities and
streams and ponds. Transmission of S. japonicum takes place in hot infection rates, cercarial of miracidial densities, human water contact
southern areas in China, as well as in the mountains of Sichuan and or acquired resistance [20].
the central lakes, where winters are severe but summers are hot and
long enough to allow intense seasonal transmission. The overall prevalence of infection in communities living under
endemic conditions is usually between 30% and 100% [1]. However,
The main foci of S. mansoni are in sub-Saharan Africa, including particularly in areas with low intensities of transmission and infec-
Madagascar; Lower and Middle Egypt; the Arabian peninsula; north- tions, many light infections go undetected on routine screening, and
east Brazil; Surinam; Venezuela; and parts of the Caribbean. Schisto- the true prevalence may be 2–3 times higher than that observed [29].
soma haematobium occurs in large parts of sub-Saharan Africa, In addition, many adults who are microscopically negative for ova
Madagascar, Middle and Upper Egypt, the Maghreb and the Arabian have probably had earlier infections, as demonstrated by the persist-
peninsula. Schistosoma japonicum is found along the central lakes and ence of specific antibodies.
the Yangtze River in China, including the mountain areas of Sichuan
and Yunnan; and Mindanao, Leyte and other small sites in the Philip- Depending on the intensity of transmission and local habits, infec-
pines. It is not clear whether transmission still occurs in some small tions can be detected in toddlers from the age of 6 months onwards
historical pockets in Indonesia. The distribution of S. mekongi is – sometimes even earlier [30]. In almost all foci, prevalence and
limited to the central Mekong basin in Laos and Cambodia, and of intensities of infection, as measured by egg excretion, rise strongly
S. intercalatum to pockets in West and Central Africa. from the age of 5–7 years to a peak in the age group between the age
of 8 and15 years, and then decline substantially in adults [1, 3]. The
Schistosomiasis is typically an infection of traditional rural areas, but peak age usually falls a few years earlier in heavily infected communi-
it has also spread to many human settlements around artificial dams ties. Boys are usually more heavily infected than girls as they play
and irrigated lands [1–3, 28]. Examples are Lake Nasser and several more often and intensively in water. In adults, gender differences
newly reclaimed areas in Egypt; Lake Volta in West Africa; dams on depend on occupational activities.
the Senegal River in Mali, Mauritania and Senegal; hundreds of small
village dams throughout Africa; the irrigated sugar estates in Brazil; While these observations can be partly explained by water contact
canal systems in China, and, possibly in the future, the Three Gorges patterns, many epidemiologic, clinical and immunologic studies indi-
Dam area. Despite mandatory and elaborate risk assessments, food cate that people living in endemic areas develop some form of
production and socioeconomic development take precedence over acquired resistance after years of exposure [1, 22]. However, similar
future health concerns. Urban schistosomiasis is becoming an increas- age-related infection rates are also observed in communities only
ing problem throughout Africa, South America and Asia. In many recently exposed to transmission through migration or newly estab-
shantytowns, snail populations thrive in local canals, drains or small lished transmission. As acquired immunity cannot be invoked in such
irrigated plots. As sanitation and water supply are often poor, migra- cases, it might represent age-related innate resistance, possibly influ-
tory and other exchanges with rural endemic areas easily leads to the enced by hormonal changes [21].
establishment of permanent transmission within city boundaries.
CLINICAL DISEASE AND PATHOLOGIC
COMMUNITY EPIDEMIOLOGY
Our understanding of the epidemiology of schistosomiasis is based
CORRELATES
on indirect measures of worm burdens, i.e. the presence and number The pathogenesis of schistosomiasis is largely based upon the host
of eggs excreted by individuals in a known volume of excreta [1, 3, reaction against the different parasite stages, rather than their pres-
27]. These are useful at the community and group level, but much ence. The adult worms living in the bloodstream are seldom associ-
less accurate in individuals owing to significant day-to-day and indi- ated with clinical illness. They rarely cause vascular obstruction in
vidual variations of egg excretion. Worm burdens have been directly ectopic areas, for example cerebral or spinal arteries. Early clinical
counted in only a few autopsy studies, and further approximated in manifestations associated with migratory schistosomulae include
S c h i stosomiasis 873
A B
FIGURE 122.5 Histopathology in schistosomiasis: early (A) and late (B) egg granulomas in the liver. (Reproduced with permission from Gryseels B, Polman K,
Clerinx J, Kestens L. Human schistosomiasis. Lancet 2006;368:1106–18.)
Lesions can reverse spontaneously with age and usually heal well after
antischistosomal therapy. Chronic infection may lead to obstructive
uropathy, renal failure and bladder cancer.
Bladder Cancer
Chronic urinary schistosomiasis is epidemiologically associated with
high incidences of squamous cell bladder carcinoma in Egypt and,
less clearly, in some other African foci [3, 37]. In Egypt, the incidence
of bladder cancer has decreased over the past 2–3 decades along with
the prevalence of urinary schistosomiasis following praziquantel
MDA. In addition to causing chronic inflammation of the bladder
wall, the schistosomal lesions may enhance the exposure of the A B
bladder epithelium to carcinogenic substrates. Apart from gross
hematuria, bladder cancer often presents with frequency, urgency, FIGURE 122.9 Early (A) and late (B) hepatosplenic schistosomiasis
dysuria, weight loss and metastasis to the inguinal, femoral and ret- mansoni. (Reproduced with permission from Gryseels B, Polman K, Clerinx J,
roperitoneal lymph nodes. Kestens L. Human schistosomiasis. Lancet 2006;368:1106–18.)
INTESTINAL SCHISTOSOMIASIS
The eggs of S. mansoni, S. japonicum and other species migrate through
the intestinal wall where they provoke mucosal granulomatous
inflammation, pseudopolyposis, micro-ulcerations and superficial
bleeding. Most lesions are situated in the large bowel and the rectum;
small bowel pathology is rare [38].
Most common symptoms attributed to intestinal schistosomiasis are
chronic or intermittent abdominal pain and discomfort, loss of appe-
tite and mucous diarrhea with or without blood, although occult
blood in the stool is very common [1–3, 39]. Physical examination
may be normal or show moderate abdominal distention, diffuse mild
abdominal tenderness and hyperactive bowel sounds.
Intestinal polyposis, ulcers, fistula and strictures have been attributed
to S. mansoni. In such cases, diffuse, protein-losing enteropathy may
occur, with chronic mucohemorrhagic diarrhea, weight loss and FIGURE 122.10 Cut surface of the liver showing Symmer’s clay pipe stem
anemia. Physical examination reveals a distended abdomen with fibrosis in a patient infected with Schistosoma mansoni. (Courtesy of U. S.
diffuse tenderness or localized tenderness over the transverse and Naval Medical Research Unit No. 3, Cairo, Egypt).
descending colon. Severe, long-standing granulomatous or polypous
lesions may result in partial or complete bowel obstruction and, in It is the main cause of schistosomal hepatomegaly in children and
rare cases, appendicitis or perforation. Intense dysenteric syndromes adolescents, often associated with hyperplastic splenomegaly and
are exceptional, but in some cases fatal. Schistosoma japonicum and S. strongly correlated with the intensity of infection. Typical features
mansoni have both been associated with colon cancer, but the evi- include sharp-edged enlargement of the left lobe of the liver and
dence for causation is weak. nodular splenomegaly. In most cases, the organomegaly is mild but
The reported frequency of intestinal disease in people living in sometimes the liver and spleen may extend below the umbilicus and
endemic areas infected with S. mansoni or S. japonicum is usually into the pelvis (Fig. 122.9A). Usually, liver cell function is normal and
10–50% [39]. In general, intestinal morbidity is strongly correlated jaundice is absent. In young children, clinical differentiation from
with intensities of infection, both at the population and at the indi- malaria may be difficult. In heavily endemic areas, this type of
vidual level. hepatomegaly, with or without splenomegaly, is present in 30% or
more of infected children and adolescents, but much less in adults.
The frequency and severity correlate with intensities of infection, but
HEPATOSPLENIC SCHISTOSOMIASIS are also subject to methodologic variations, immunogenetic predis-
(Figs 122.9 and 122.10) position and other confounding factors [39].
Hepatic schistosomiasis can be caused by S. mansoni, S. japonicum and
S. mekongi. The pathologic impact of S. intercalatum is restricted to Fibrotic or Chronic Hepatic Schistosomiasis
mild intestinal disease. Hepatic and hepatosplenic schistosomiasis can
This complication develops years later in the course of infection and
be caused by either early inflammatory or late fibrotic hepatic disease,
in a minority of those infected. It is believed to be a consequence of
with quite different underlying pathology and prognoses [1–3].
long-standing intense infection, as well as dysfunctional or over-
polarized immune responses which fail to downregulate granuloma-
Inflammatory Hepatic Schistosomiasis tous and fibrotic reactions [24]. Diffuse collagen deposits in the
This is an early reaction to ova trapped in the hepatic presinusoidal periportal spaces occur (Fig. 122.5B) and confluence of the resulting
periportal spaces where many granulomas are produced (Fig. 122.5A). fibrotic streaks leads to the pathognomic “Symmer’s pipe stem
876 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
fibrosis”, in which the elongated periportal fibrotic lesions resemble a regular finding in travelers. Hypertrophic and ulcerative lesions of
clay pipe stems (Fig. 122.10). Physical occlusion of the portal veins the vulva, vagina and cervix may facilitate the transmission of sexually
leads to portal hypertension, increased splenic vein pressure and tor- transmitted infections, including HIV. Lesions of the ovaries and the
tuosity and splenomegaly. Portal hypertension results in collaterali- fallopian tubes can lead to infertility. In males, the epididymis, testi-
zation of the abdominal venous circulation, which may show cles, spermatic cord and prostate may be affected; hemospermia is a
externally as a “caput medusa”, and leads internally to portocaval common symptom [42].
shunting and gastrointestinal varices. This condition also facilitates
the distribution of Schistosoma eggs into the general circulation and
the occurrence of ectopic lesions in the lungs, spinal cord (Fig.
Neuroschistosomiasis
122.11) or the brain. End-stage hepatosplenic schistosomiasis can be This severe complication is caused by inflammation around ectopic
marked by ascites (Fig. 122.9B). worms or eggs in the cerebral or spinal venous plexus, which can
evolve to irreversible fibrotic scars if left untreated [1–3, 43]. Ectopic
The extent of exposure, immunogenetic predisposition, concomitant S. mansoni and S. haematobium infections mainly cause spinal cord
infections and nutritional deficiencies all contribute to the severity of pathology with transverse myelitis, which is also a potential complica-
the disease. The liver is not necessarily enlarged, but is usually hard tion of acute schistosomiasis in travelers [31, 33]. Symptoms vary with
and nodular on palpation. In contrast to cirrhosis, the parenchyma, the location and the degree of the myelitis, and may include paraple-
hepatocellular functions and its biologic parameters remain largely gia and loss of bladder and/or anal sphincter control. Sometimes, the
unaffected. Fibrotic hepatic schistosomiasis is mainly seen in young patient may have pain or loss of sensation; rarely there will be a rash
and middle-aged adults, although it can occur in heavily infected around the body affecting the dermatome at the level of the spinal
adolescents. In S. mansoni infections, this takes at least 5–15 years to cord lesion.
develop, by which time ova may not be present or detectable. In S.
japonicum, the progression may be more rapid, in some cases with Schistosoma japonicum, possibly because of the larger number and
little, or no, interval between acute and chronic disease. smaller size, or the clustering of the eggs, is associated with cerebral
granulomatous lesions that can be either diffuse or focal, possibly
Bleeding from gastro-esophageal varices is the most serious, and often depending on whether eggs have been randomly embolized from a
fatal, complication of fibrotic hepatic schistosomiasis. In S. mansoni distance or locally-released by ectopic worm pairs. Depending on type
infections, it tends to recur and become more severe over time; in S. and location, the resulting syndrome may have an epileptic, paralytic
japonicum, bleeding is often sudden and massive. Repeated or occult or meningo-encephalitic character. The acute phase, which occurs
bleeding may lead to anemia, hypoalbuminemia, cachexia and months after exposure, may be accompanied by fever, urticaria, eosi-
growth retardation. Ascites can be caused by a combination of nophilia and angioneurotic edema suggesting an allergic encepha-
hypoalbuminemia and portal hypertension, or concomitant infection lopathy. There may be delirium, confusion, personality changes,
with hepatitis B or C. incontinence, coma, nuchal rigidity, pyramidal track signs and cere-
Advanced liver fibrosis caused by schistosomiasis used to be a bellar symptoms. The acute phase may merge into a chronic phase,
frequent and severe health problem in large parts of Egypt, Brazil, which could be asymptomatic or mimic intracranial neoplasm. Epi-
China, the Philippines and other countries. Over the past few decades, leptic syndromes often include Jacksonian or grand mal seizures,
chemotherapy and general socioeconomic development have led to stemming from lesions in the parietal lobe. Other neurologic signs
a dramatic reduction of such morbidity worldwide. Symptomatic liver and symptoms are headaches, speech difficulties, visual disturbances,
fibrosis has always been less frequent in sub-Saharan Africa, except papilledema and cerebellar symptoms [43].
for some East-African foci, for example West Nile in Uganda, Macha-
kos in Kenya and Gezirah in Sudan [39]. These varying continental Other Sites
and regional morbidity patterns may be partially explained by ethnic
Ectopic schistosomal lesions in the skin can present as maculopapules
and genetic factors, in addition to the intensities of exposure to
or wart-like protuberances, the latter particularly in the genital area
infection.
[2]. Schistosomal granulomas in the peritoneum may be mistaken for
endometriosis, miliary tuberculosis or cancer metastasis. Granulomas
OTHER COMPLICATIONS AND ECTOPIC around stray eggs have also been documented in the pancreas, gall-
SCHISTOSOMIASIS bladder, stomach, heart, kidney and adrenal glands, with or without
recognized clinical manifestations.
Pulmonary Schistosomiasis
This syndrome is a complication of portocaval shunting caused by
portal hypertension in chronic S. mansoni infection which allows ova
ASSOCIATION OF SCHISTOSOMIASIS
to pass into the peri-alveolar capillary beds [1, 3, 40]. The ensuing AND OTHER INFECTIONS
granulomas cause obliterative arteritis which leads to fibrosis resulting Chronic Salmonella Co-Infections
in pulmonary hypertension, increased right heart pressure, pulmo-
nary artery and right atrial dilatation, and right ventricular hypertro- Schistosomiasis has been associated with the presence of several
phy. Schistosomal cor pulmonale has been mostly described in Brazil co-infections, especially chronic persistent Salmonella bacteremia [1].
and Egypt, but appears to have become much less frequent over the Possible explanations include immunologic tolerance caused by
last decades. schistosomiasis and the physical attachment and proliferation of Sal-
monella bacteria on, or in, adult worms. The syndrome was seen
mainly in males between the age of 15–30 years, but has become rare.
Schistosomal Glomerulonephritis It is characterized by a long history of indolent febrile disease, bacter-
Immune complexes can be deposited in the renal glomeruli during emia with one or more Salmonella species and chronic active schisto-
S. mansoni infections [41]. Schistosomal glomerulonephritis used to somiasis. It differs from enteric fever caused by S. typhi by negative
be found quite commonly in renal biopsies from patients with S. stool cultures, a petechial rash on the lower extremities rather than
mansoni infection in Brazil, but this finding was usually asymptomatic on the abdomen, and the absence of systemic complications, for
or clinically insignificant. Nephrotic syndrome is seen occasionally in example prostration, delirium or localized infections.
patients with S. mansoni or S. haematobium infections, sometimes
associated with chronic Salmonella bacteremia or bacteriuria. Co-Infections with Hepatitis B and C
Chronic S. mansoni infected patients co-infected with hepatitis B or C
Genital Schistosomiasis are prone to have clinically more severe infections. Prior parenteral
Schistosoma haematobium and S. mansoni ova that are trapped in the treatment for schistosomiasis may also have substantially increased
reproductive organs remain mostly occult in endemic areas, but are the risk for hepatitis infections in some areas, especially Egypt [13,
S c h i stosomiasis 877
26]. Patients with co-infections more often develop jaundice, intrac- or visited, endemic areas must be asked about skin contact with
table ascites and hepatic failure. In fact, patients with chronic schis- freshwater of any kind, even if considered locally as safe or snail-free.
tosomiasis who have elevations in serum alanine transaminase (ALT) Contacts of any type or duration can lead to infection. The patient
or aspartate transaminase (AST) have a high probability of having may, or may not, report itching or rash shortly after the water contact.
concomitant hepatitis B and/or C infections. Proper precautions Visual inspection may help diagnose “swimmers’ itch” after recent
should be taken in the management of the patient and the handling exposure.
of blood samples.
A medical history may reveal intermittent symptoms since the poten-
tial exposure, including flu-like syndromes in the weeks or months
INDIRECT PATHOLOGY AND MORBIDITY thereafter. Malaise, fatigue, muscle pains, appetite loss, intermittent
Before the advent of modern treatment and control, S. japonicum diarrhea, vague abdominal pain and red or dark urine are potential
infection was believed to be related to reduced stature, weight, weight- warning signs – partly depending on the suspected species. A neuro-
for-height, skin-fold thickness, muscle mass and other anthropomet- logic history and examination is performed to exclude early cerebro-
ric measures, especially during childhood and adolescence. These spinal involvement. Abdominal palpation may reveal hepatomegaly
clinical and epidemiologic observations, although historical and not or splenomegaly of varying degrees and abdominal tenderness or
always rigorously documented, indicate an independent effect of the distention, but also may be entirely negative.
infection on nutrition, growth and development. This impact on
physical development was widespread and is thought to have sub- LABORATORY FINDINGS
stantially reduced economic productivity in China at one time, when
schistosomiasis was considered “the plague of gods” and its control Rapid tests can include a visual inspection or a hematuria dip-stick
received high political priority [2]. test of the urine for S. haematobium, or occult blood in the stools for
S. mansoni and S. japonicum; these are very useful tools for rapid
However, early studies to establish an association between general diagnosis and community screening in the endemic areas [1–3, 39].
wellbeing, anthropometric indices, nutritional status and physical or In tourists and migrants, the most important hematologic indicator
cognitive performance, and the presence or intensity of S. mansoni or is eosinophilia, which is usually elevated in acute schistosomiasis but
S. haematobium infection were largely inconclusive or contradictory may be negative in chronic cases. Other hematologic or biochemical
[39]. Possibly, they were obscured by the frequent comorbidities parameters, including liver function tests, are often within normal
from malarial, intestinal helminths, protozoa, bacterial and viral limits but abnormal values can indicate chronic complications, for
infections. As severe disease from Schistosoma infections has waned example anemia or renal failure, or comorbidities, such as hepatitis.
in many areas, subtle or “indirect” morbidity has become the target Mild anemia is not unusual in infected persons living in endemic
of more focused research efforts and is providing a rationale for sus- areas and the serum alkaline phosphatase level may be elevated. If
tained control strategies. Significant associations have now been the ALT or AST levels are elevated, a concomitant hepatitis B and/or
demonstrated for anemia, nutritional status, cognitive and physio- C infection should be suspected. Recently, DNA detection in serum
logic capacities [44]. was shown to be very sensitive and specific for the early diagnosis of
schistosomiasis [48].
GLOBAL BURDEN OF DISEASE (GBD)
SCHISTOSOMA OVA IDENTIFICATION BY
Schistosomiasis is highly prevalent but the associated morbidity is
low and variable. The GBD of schistosomiasis, as expressed in MICROSCOPY (Fig. 122.11)
Disability-Adjusted Life Years (DALY), depends on the number of The microscopic demonstration and identification of eggs in excreta
people infected on one hand, and the mortality and disability attrib- remains the gold standard for the diagnosis of active schistosomiasis,
uted to it on the other [45]. The total number of cases in the world but has low sensitivity in light infections [29]. In rare cases, incidental
is estimated by the WHO at 200 million, a figure that is consistently exposure may lead to infection with only male or female worms, in
quoted in the literature but may need to be revised downward in view which case there is no ova production. If eggs are found, their size
of recent trends [2, 7–9]. The GBD estimates report up to 15,000 lives and shape allows easy detection and identification under low magni-
lost to schistosomiasis annually, and applies a “disability weight” of fication. Direct microscopic examinations of wet-mounted slides are
0.06. The total number of DALYs lost to schistosomiasis is estimated not reliable, as they contain only a few milligrams of feces or millilit-
at 1.75–2.0 million, of which 85% are in sub-Saharan Africa. This is ers of urine. Concentration methods and repeated examinations in
a fraction of the GBD of AIDS, malaria or tuberculosis, and puts it in different urine or stool specimens on different days may be required
the same league as lymphatic filariasis, leishmaniasis and trypano- to confirm the presence of active infections. Stools may be concen-
somiasis. Schistosomiasis would account for 0.1% of the GBD in the trated with general techniques, for example Ritchie’s formol-ether
world and 0.4% of the GBD in sub-Saharan Africa. method, or more specific ones, such as conical flask sedimentation in
glycerine water, sieving or miracidial hatching. Urine may be centri-
These figures have been contested by many schistosomiasis experts fuged, sedimented or passed through paper or nylon filters with a
when advocating for global control efforts [8, 44, 46, 47]. Upgrades variety of devices [1, 49, 50]. Sensitivity increases considerably with
of as much as a 40-fold increase of schistosomiasis mortality in sub- the weight or volume of the sample examined. The excretion of S.
Saharan Africa, and a 4–30-fold upgrade of the disability weight have haematobium eggs in the urine is not uniform over a day, and samples
been proposed. These revised data have not been empirically vali- collected between 10.00 h and 14.00 h are more likely to be positive.
dated, however, and remain inconsistent with total mortality and Also, physical exercise before sampling increases the chance of finding
GBD data. This does not reduce the need, however, to bring treatment eggs in the urine. The microscopic examination of crushed rectal
and control to affected populations. snips, obtained during proctoscopy or sigmoidoscopy, is remarkably
sensitive for S. mansoni and S. japonicum, as well as S. haematobium
DIAGNOSIS infection. Rectal biopsies can be performed during proctoscopy or
sigmoidoscopy by taking 1–3 small mucosal samples from inflamed
or granulomatous lesions, or from random areas of normal-appearing
MEDICAL HISTORY AND EXAMINATION mucosa. The mucosal sample is pressed between a cover slip and a
Within endemic areas, schistosomiasis must be suspected in all glass slide until it becomes transparent. If ova are present, they can
patients presenting any symptom, however vague, that can be related be seen under low power microscopy. Also, bladder biopsies obtained
to the infection. In travelers and migrants, a careful residence or travel during cystoscopy can be directly examined for eggs. The biopsies
history can help establish the diagnosis of schistosomiasis [31, 33]. can be partly fixed in formalin for histologic staining and examina-
In several sub-Saharan areas, both S. mansoni and S. haematobium, and tion, which may reveal eggs, as well as inflammation and typical
even S. intercalatum, can be contracted. The patient who has lived in, granulomas.
878 HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE
A B C
FIGURE 122.11 Schistosome eggs under the microscope. (A) S. mansoni (from lateral spine); (B) S. haematobium (from terminal spine); (C) S. japonicum
(from small lateral spine). (Reproduced with permission from Gryseels B, Polman K, Clerinx J, Kestens L. Human schistosomiasis. Lancet 2006;368:1106–18.)
Egg counts in calibrated samples provide a quantitative assessment of (EIA). Seroconversion takes place usually within 4–8 weeks after
the infection. Quantitative egg counts after standardized urine filtra- infection, but, rarely, antibodies might not be detected for 4–5
tion or in calibrated fecal thick smears (Kato-Katz method) are espe- months after infection. Most assays remain positive for at least two
cially useful for epidemiologic surveys and control, as they correlate years after cure, and often much longer.
reasonably well with worm burdens and morbidity. For the Kato-Katz
method, a 50 mg sample of feces is pressed through a 105-mesh steel
sieve and fitted in the hole of a punched template, which rests on a
Circulating Schistosome Antigens
glass microscope slide. This calibrated sample of filtered feces is then Circulating anodic antigen (CAA) and circulating cathodic antigen
covered with a cellophane cover-slip impregnated with glycerin, (CCA) can be detected and quantified in serum or urine with labeled
inverted and pressed onto a bed of filter paper. The slide is left for monoclonal antibodies in different formats, including reagent strips
24–48 hours while the fecal matter clears. Then, all eggs on the slide [50, 52, 53]. These are Schistosoma gut glycoproteins regurgitated with
are counted under a microscope. Multiplying by 20 gives the number the metabolized blood particles into the circulation of the human
of eggs per gram of feces (EPG). Limitations of the test are that formed host. Antigen detection in serum is not sensitive in light infections,
stools are desirable, light infections tend to be missed when examin- however, and therefore not very useful for clinical applications. These
ing small amounts of feces, and the microscopist must be reliable. assays are primarily used in epidemiologic and therapeutic studies.
The most common quantitative technique for urine is filtrating 10 ml Urine-based assays are more sensitive, but less specific.
with a syringe through a paper, nucleopore or nytrel filter, which is
then examined under a microscope and the number of eggs counted.
This method provides a measure of eggs per 10 ml of urine [49, 50].
CHEMICAL TESTING
Using reagent strips to test for blood in urine and simple question-
In clinical settings and in field surveys requiring accuracy, 3–5 repeated naires for visible hematuria are inexpensive, easy and effective tools
examinations with Kato-Katz or 10 ml urine filtration may be needed. for the screening and rapid assessment of urinary schistosomiasis
It may be important to verify the ova’s viability, particularly to deter- [1–3, 29, 49, 50]. Indirect diagnostic methods for intestinal or hepatic
mine whether drug treatment has been successful. Dead Schistosoma schistosomiasis, for example examining the stool for mucus and
ova in the tissues can be excreted in the urine and stool for months blood, are reasonably sensitive, but less specific.
after adult worms are dead. Eggs passed more than one week after
treatment are usually not viable. Microscopic examination of viable
eggs will reveal clear, transparent structures with moving organelles ENDOSCOPY AND CYSTOSCOPY
(flame cells) of the miracidium. Dead eggs are often deformed, dark Endoscopy can visualize esophageal varices; sigmoidoscopy and
or half-empty, and show no internal movement. Alternatively, ova colonoscopy allow visualizing of typical schistosomiasis lesions and
may be hatched to demonstrate their viability by diluting a small provide access to biopsy specimens for tissue egg identification
amount of urine or stool sediment in distilled water at room tem- [1, 54]. The endoscopist can visualize small petechiae in otherwise
perature and exposing it to light for 15–20 minutes. Ideally, it is put normal rectal mucosa, dull patches with a sandpaper-like appearance,
in a covered, darkened flask with a narrow top, which is left exposed superficial erosions, stellate superficial ulcerations, hyperemic, easy
to the light. Examination with a hand-held lens will reveal swimming bleeding areas, and granulomatous or polyp disease; the latter
miracidia. can be removed during the procedure. Laparoscopy can reveal granu-
lomatous inflammation or periportal fibrosis. Needle biopsies of the
SEROLOGY liver may not sample the hard fibrotic lesions; wedge biopsies may
be needed, for instance, to differentiate periportal fibrosis from post-
Antibody-Based Serum Assays infectious or alcoholic cirrhosis. Cystoscopy may reveal hemorrhagic
Many serologic methods have been developed for the indirect diag- inflammation, granulomatosis, polyposis, fibrosis or calcification of
nosis of schistosomiasis [49–52]. These are quite sensitive but can not the bladder, and allow biopsy sampling.
distinguish a past infection from a present active one. Some tests also
may cross-react with other helminths and they are not easily applica- IMAGING (Figs 122.7, 122.8, 122.12)
ble in the field. Serologic assays are important, however, for diagnosis
in travelers, migrants and other occasionally-exposed people. They X-Rays and Scans
can also provide important circumstantial evidence when complica- Intravenous pyelography and ultrasonography allow visualization of
tions of schistosomiasis are suspected, especially neuroschistosomia- renal, ureteral and bladder pathology quite easily and plain x-rays
sis, even when urine and stools are microscopically negative. Most may show calcified tissues and lesions, including renal or bladder
routine techniques detect IgG, IgM or IgE against soluble worm stones (Figs 122.7 and 122.8) [55]. In hepatic schistosomiasis,
antigen (SWA) or crude egg antigen (CEA) by enzyme immune assays contrast radiology can demonstrate portal vein distension or
S c h i stosomiasis 879
Ultrasound
Over the past three decades, ultrasonography has provided marked
improvement in the diagnosis and study of schistosomiasis pathol-
ogy [56, 57]. Sonography is an excellent noninvasive technique to
demonstrate the pathognomonic periportal fibrosis and can esti-
mate the degree of portal hypertension by measuring the distension
of the portal vein (Fig. 122.12). Standardized protocols have been
developed in order to classify hepatic fibrosis and urinary tract
lesions. These protocols require specific expertise and experience,
and results may be subject to considerable inter- and intra-observer
variation.
TREATMENT
Once active infection is confirmed by detection of ova, or a clinical
diagnosis of schistosomiasis is made, specific chemotherapy is
A
indicated.
CHEMOTHERAPEUTIC AGENTS
Praziquantel, the drug of choice, is effective against all schistosome
species, as well as other flukes (e.g. Clonorchis sinensis and Paragonimus
westermani) and cestodes (e.g. Taenia saginata, Taenia solium, Diphyl-
lobothrium latum and Hymenolepis nana) [2, 3, 54, 58]. Praziquantel is
mostly marketed as scored 600-mg tablets. The drug acts within an
hour after ingestion by provoking tetanic contraction of the adult
worms and damaging their tegument, but the precise molecular
mechanisms remain unknown. The antigens revealed induce humoral
and cellular immune responses, enhancing the direct drug action.
Side effects are mild and include nausea, vomiting, malaise and
abdominal pain. In heavy infections, acute colic with bloody diarrhea
may occur, probably provoked by massive worm shifts and antigen
releases induced by praziquantel.
The original brand of praziquantel, Biltricide® (Bayer), has lost most
market share to about 30 generic brands. Consequently, the price
falling from $2.00–4.00 to less than $0.20 per treatment has made
the drug widely available for control purposes [58]. On the downside
of this development, large pharmaceutical companies have given up
investments to find new schistosomicides [14].
B
The quality of generic praziquantel may vary and counterfeit praziqu-
antel has been reported in Sudan [59]. The toxicity, mutagenicity and
embryotoxicity of praziquantel are very low in animal models and,
after 30 years of widespread application, no significant safety prob-
lems have been documented in humans. It is therefore no longer
recommended to withhold treatment from young children and preg-
nant women [60].
The standard single dose of 40 mg/kg of body weight for treating S.