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Enf. Por Ricketsias
Enf. Por Ricketsias
Enf. Por Ricketsias
Rickettsial Diseases
David H Walker
76
agents were described or discovered in the last two decades. A rickettsial
Chapter Contents agent was first identified in 1906 in the Bitterroot Valley of western
Spotted fever and typhus group rickettsial infections . . . . . . . . . . 1243 Montana by Howard Ricketts, who also recognized its transmission by
Scrub typhus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1248 feeding ticks. In 1916, S. Burt Wolbach visualized this agent, subse-
quently named Rickettsia rickettsii, within endothelial cells. Charles
Human ehrlichioses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1249 Nicolle discovered in 1909 that lice transmitted epidemic typhus, and
Human granulocytotropic anaplasmosis . . . . . . . . . . . . . . . . . . . . . . . 1250 over the next few years this disease was found to be caused by another
Q fever. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1250 rickettsial organism, Rickettsia prowazekii. Epidemic louse-borne
typhus influenced the outcome of most European wars after 1500,
including Napoleons failed Russian invasion in 1812 and World War I,
during and after which typhus affected 25 million persons and caused
3 million deaths in Russia. In 1934, recrudescent typhus (BrillZinsser
disease) was determined to be caused by reactivation of latent R. prowa-
zekii infection. Endemic or murine typhus was shown during the 1930s
Key features to have a rat reservoir and flea vector.
! Rickettsiae are small, obligately intracellular, Gram-negative
bacteria Epidemiology
! Rickettsiae reside in an arthropod host (tick, flea, louse or mite) Spotted fever group rickettsiae are maintained in nature principally via
during part of their life cycle transmission of the bacteria in infected ova from one generation of tick,
! The arthropod vector transmits the rickettsiae in its saliva or feces mite or flea to the next (see Table 76.1). During feeding, infected ticks
during feeding instill saliva containing rickettsiae into their hosts skin. Thus, the
! The major vertebrate target cells of Rickettsia (endothelium), seasonal and geographic distribution of particular diseases (Fig. 76.2)
Orientia (endothelium), Ehrlichia (monocytes or neutrophils), depends upon the range and the host-seeking activity of the particular
Anaplasma (neutrophils) and Coxiella (macrophages) determine to vector tick, mite or flea. For example, RMSF usually occurs during tick
a large degree the pathogenesis of the disease season (from late spring until the end of summer).
Typhus group rickettsiae are deposited on the hosts skin in the feces
! In most spotted fever rickettsioses and scrub typhus, an eschar at of feeding human body lice (R. prowazekii) or fleas (R. typhi). The
the site of the vectors inoculation of organisms is an important organisms are subsequently scratched into the skin, rubbed into mucous
physical sign membranes, or inhaled. Humans who recover from louse-borne typhus
! A rash is the diagnostically critical clinical manifestation of Rocky remain latently infected and years later may develop recrudescent
Mountain spotted fever, other spotted fevers, murine typhus and illness (BrillZinsser disease) and associated rickettsemia. Such indi-
louse-borne typhus viduals can infect feeding lice, which may then spread the disease to
! One of the most common rickettsial diseases in travelers is African another person and ignite an epidemic. In addition, a zoonotic cycle of
tick bite fever, which is seen in those who have been on safari or R. prowazekii is maintained in flying squirrels and their fleas and lice2.
bush walking in southern Africa R. typhi is maintained in natural cycles, classically in rats and oriental
rat fleas as well as in opossums and cat fleas.
Pathogenesis
After entry into the dermis, rickettsiae spread throughout the body via
INTRODUCTION the bloodstream. They attach to vascular endothelial cells by outer
Members of the order Rickettsiales are small, obligately intracellular, membrane protein B and, in the case of spotted fever group rickettsiae,
Gram-negative bacteria that reside in an arthropod host for at least part outer membrane protein A as well3. The organisms enter the cells by
of their life cycle1. At least 19 bacterial species belonging to four genera induced phagocytosis and then escape from the phagosome into the
(Rickettsia, Orientia, Ehrlichia and Anaplasma) in this order and the cytosol, where they obtain amino acids, nucleotides and other building
related Coxiella genus in the order Legionellales are known agents of blocks for growth from the host cell and divide by binary fission3.
human diseases (Table 76.1). Cutaneous manifestations vary from Spotted fever group rickettsiae move intracellularly and from cell to cell
nearly always present in some spotted fevers and typhus to rare in by stimulating propulsion via the host cells actin, resulting in a contigu-
others, such as human granulocytotropic anaplasmosis and Q fever ous network of infected endothelial cells that represent the source of
(Table 76.2). Clinical recognition of a rash is frequently the event that the vascular-based disease manifestations (including skin lesions). The
leads to appropriate antimicrobial treatment for life-threatening Rocky spotted fever rickettsiae injure the host endothelium by stimulating
Mountain spotted fever (RMSF) and other rickettsioses. these cells to produce toxic reactive oxygen species, and typhus group
rickettsiae replicate within the infected endothelial cell until it bursts.
The major pathophysiologic effect of rickettsial infection is increased
SPOTTED FEVER AND TYPHUS GROUP vascular permeability, which can result in edema, hypovolemia and
hypotension4. Although endothelial cells of the microcirculation are
RICKETTSIAL INFECTIONS infected in every organ, the critical target organs in life-threatening
infections are the lung and brain. A fatal outcome can result if increased
History vascular permeability leads to non-cardiogenic pulmonary edema, acute
Epidemic typhus was described by Fracastorius in Italy in 1546; RMSF, respiratory distress syndrome and meningoencephalitis.
by Maxey in Idaho in 1899; and boutonneuse fever, by Conor in Tunisia As the infection progresses, macrophages and lymphocytes infiltrate 1243
in 1910. At least ten of the diseases in this group and/or their etiologic the walls of affected vessels and act as effector cells, secreting cytokines
SECTION
Table 76.1 Epidemiology of rickettsial infections. Additional potentially emerging rickettsial infections for which a small number of cases have been described
1244 include: Rickettsia massiliae (Rhipicephalus spp.; Europe, South America); Rickettsia species 364D (Dermacentor occidentalis; California); and Rickettsia heilongjiangensis
(Haemaphysalis spp.; Eastern Asia Far East spotted fever). A new Ehrlichia species transmitted by Ixodes scapularis was recently found to cause a febrile illness in the
upper midwestern US.
CHAPTER
Rickettsial Diseases
Blacklegged tick (Ixodes scapularis)
DC
adult adult
female male nymph larva
NN
0
0.21.5
1.519
19-77
American dog tick (Dermacentor variabilis)
*Per 1,000,000 persons per year
anemia and abnormal liver and renal function tests. As the clinical
course progresses, hypotension, acute renal failure, respiratory failure
and coma may develop7.
1cm Severe rickettsioses continue to have fatalities owing to misdiagnosis
and/or initiation of delayed antirickettsial treatment, with mortality
rates as follows: ~4% for RMSF and louse-borne typhus; ~3% for bou-
tonneuse fever; and ~1% for murine typhus8,9. If not treated with an
appropriate antimicrobial agent, approximately 25% and 15% of patients
Fig. 76.1 Comparison of Ixodes scapularis (blacklegged tick), Amblyomma with RMSF and louse-borne typhus, respectively, will die10. The case
americanum (lone star tick) and Dermacentor variabilis (American dog tick), fatality rate is higher with older age, male gender, and underlying
by life stage. From Chapman AS, et al. MMWR Recomm Rep. 2006;55:127. diseases.
Fig. 76.3 Rocky Mountain spotted fever. The cutaneous lesions often appear Fig. 76.4 Rocky Mountain spotted fever. Petechiae on the palms and soles
first on the wrists and ankles. Courtesy, Philippe Berbis, MD. often develop relatively late in the disease course. Courtesy, Ronald P Rapini, MD.
(which 40% of patients do not recall), affected individuals present with R. parkeri and R. africae, closely related strains of spotted fever group
fever, myalgias, headache and, in >50% of patients, gastrointestinal rickettsiae transmitted by Amblyomma ticks, cause two similar emerg-
symptoms. The rash typically appears 35 days after onset of the illness ing infections, Maculatum disease (American tick bite fever) and
as subtle erythematous macules on the wrists and ankles, which is African tick bite fever, respectively. The former is endemic in the south
followed by centripetal spread to the trunk, formation of papular central and southeastern US (the range of A. maculatum, the Gulf
lesions, and eventual development of petechiae (~50% of patients). Coast tick; see Fig. 76.10) and in South America, while the latter is
1246 However, cutaneous findings are absent in 1015% patients and may endemic in sub-Saharan Africa and represents the rickettsial disease
be difficult to recognize in darkly pigmented skin. with the highest incidence among travelers returning to the US13,14.
CHAPTER
76
Rickettsial Diseases
A
the face (Fig. 76.7B) as well as the trunk and extremities, in no particu-
lar sequence. Approximately 20 to 40 skin lesions typically develop,
evolving from erythematous macules and papules to papulovesicles to
hemorrhagic crusts. The palms and soles are occasionally affected, and
an enanthem characterized by small erosions on the tongue, palate and
Patients with these conditions typically present with mild constitu- pharynx may occur.
tional symptoms (e.g. fever, headache, myalgias), one or more eschars,
and tender lymphadenopathy in the region draining the eschar(s). In Pathology
5080% of affected individuals, usually 24 days after disease onset, a Rickettsial infection is multifocal, which is reflected in the scattered
rash develops on the trunk and extremities (sometimes involving the distribution of cutaneous lesions. However, randomly obtained tissue
palms and soles). The eruption may be relatively sparse and often samples are unlikely to contain the classic finding of a lymphohistio-
features small central vesicles or pustules within erythematous macules cytic vasculitis, which is present in the center of a petechial macule
and papules. No deaths have been reported for either type of infection. or papule. The early finding of perivascular edema is difficult to
Despite the substantial difference in severity, it is likely that many R. identify histopathologically because of formalin-associated tissue
parkeri infections are misdiagnosed as RMSF owing to serologic cross- shrinkage. In more developed lesions, extravasated erythrocytes (cor-
reactivity with R. rickettsii15. responding to petechiae) are observed. Thrombosis occurs in a minus-
Rickettsialpox occurs primarily in urban areas, especially cities in cule portion of infected blood vessels, and, when present, is usually a
the northeastern US. A papulovesicle arises within 48 hours at the site non-occlusive hemostatic plug in a focus of denuded endothelium.
of the bite of a mite that parasitizes house mice and eventuates in an Later in the disease course, vasculitis can be detected histopathologi-
eschar with surrounding erythema and induration (Fig. 76.7A). Con- cally in the skin and other organs. The inflammatory infiltrate around
stitutional symptoms (e.g. fever, headache, myalgias) begin 1 to 2 weeks and within vessel walls is composed of macrophages and lymphocytes 1247
later, followed in 2 to 3 days by a cutaneous eruption that often involves (Fig. 76.8).
SECTION
litis, while jaundice and elevated hepatic enzymes may prompt the
consideration of viral hepatitis or leptospirosis.
When the cutaneous eruption initially develops, the differential diag-
nosis may include a viral exanthem, a drug eruption, ehrlichiosis,
Kawasaki disease and early secondary syphilis. Exanthems due to
enteroviruses, EpsteinBarr virus, parvovirus B19, adenovirus, dengue
fever and measles can have a petechial component (see Fig. 81.2). When
petechial and/or purpuric lesions become more prominent, meningo-
coccemia, small vessel vasculitis, disseminated gonococcal infection,
dengue hemorrhagic fever and other viral hemorrhagic fevers (see Table
81.7) may also be considered. In patients with thrombocytopenia,
immune thrombocytopenic purpura or thrombotic thrombocytopenic
purpura represent additional possibilities. The differential diagnosis for
rickettsialpox and other rickettsial eruptions with a vesicular compo-
nent may include vesicular viral exanthems (e.g. due to coxsackievi-
ruses), varicella, disseminated HSV infection, pityriasis lichenoides et
varioliformis acuta (PLEVA), drug eruptions, bullous insect bite reac-
tions, and scabies. Cutaneous necrosis resembling an eschar can be
Fig. 76.8 Histologic findings in Rocky Mountain spotted fever. Typical seen in spider bites, ecthyma, ecthyma gangrenosum (typically in
lymphohistiocytic vasculitis involving a dermal blood vessel. Courtesy, James W immunocompromised hosts), cutaneous anthrax, Bacillus cereus infec-
Patterson, MD.
tion, cutaneous diptheria, tularemia, scrub typhus (see below), and
primary syphilis.
Treatment
The drug of choice for rickettsial infections in nearly all patients,
including young children, is doxycycline (Table 76.3)9,16. Chloramphen-
icol is a less effective alternative, having a higher rate of fatal outcomes.
However, chloramphenicol is generally recommended for treatment of
RMSF during pregnancy.
Mild cases of boutonneuse fever in children have been treated
with azithromycin or clarithromycin with an outcome equivalent to
treatment with chloramphenicol, and these macrolide antibiotics (as
well as josamycin, a related agent not available in the US) may repre-
sent therapeutic options for mild rickettsioses during pregnancy. Fluoro-
quinolones have also been used successfully to treat patients with
boutonneuse fever and murine typhus. Of note, treatment of severe
rickettsial infection with macrolides or fluoroquinolones is not
recommended.
SCRUB TYPHUS
Scrub typhus was described in association with red mites in China in
313 AD. Orientia tsutsugamushi was discovered in Japan by Nagayo
and Ogata in the 1920s and early 1930s. This organism differs from
Rickettsia spp. in its cell wall composition, having entirely unrelated
proteins and a distinct ultrastructure as well as lacking lipopolysaccha-
Fig. 76.9 Immunohistochemical detection of spotted fever rickettsiae. ride. Orientia tsutsugamushi is maintained in nature via transovarial
Organisms within the endothelium of a dermal blood vessel are highlighted by transmission by its vector, trombiculid mites (see Table 76.1). Eggs laid
brown staining.
by infected mites hatch with the emergence of infected larvae (chiggers)
that feed on the rat population. Both humans and rats are dead-end
hosts.
It is estimated that one million cases of scrub typhus occur annually,
Diagnosis and Differential Diagnosis affecting rural populations in a large portion of Asia (from Afghanistan
The diagnosis of rickettsiosis is based on clinical and epidemiologic to Japan) and northern Australia. Infection of more than 3% of the
criteria such as the signs, symptoms and potential tick exposure16. It population per month has been documented in endemic regions of
is essential to begin empiric treatment with effective antirickettsial southeast Asia. Immunity is strain-specific and transient, resulting in
agents based on clinical suspicion rather than awaiting laboratory con- reinfections. The severity of the illness is age-dependent and varies
firmation. Indeed, serologic diagnosis is usually retrospective, because geographically.
antibodies do not develop until day 7 of the illness or later17. Circulating A cutaneous eschar forms at the site of chigger feeding in 6090% of
rickettsiae are generally too few early in the illness to be detected by primary infections. This is followed by regional lymphadenopathy, fever
PCR-based assays, but rickettsiae can be identified by immunofluores- and headache; generalized lymphadenopathy, conjunctival hyperemia
cence or immunohistochemistry in a biopsy specimen of an eschar or and hearing loss may also develop18. A rash occurs in approximately
a maculopapular lesion (Fig. 76.9), especially if the latter is petechial. half of patients, usually appearing as erythematous macules on the
Prior to the onset of the rash, the differential diagnosis may include trunk 4 to 6 days after disease onset. Lesions then become papular,
a wide variety of viral infections (which often present with similar with subsequent centrifugal spread. Interstitial pneumonia frequently
symptoms), ehrlichiosis and typhoid fever. Patients with prominent occurs, presenting with cough, tachypnea and radiographic infiltrates;
nausea and vomiting are often suspected to have viral or bacterial meningoencephalitis is a less common manifestation19. In severe cases,
1248 enterocolitis. The abdominal pain and tenderness can suggest an acute acute respiratory distress syndrome, acute renal failure and hypotensive
surgical abdomen, and this has led to exploratory laparotomies. Cough shock may develop.
CHAPTER
Rickettsial Diseases
First choice for virtually all rickettsial Doxycycline 100 mg po or iv twice daily 2.2 mg/kg (max. 100 mg) Until 3 days after defervescence, for a
infections in children and adults* po or iv twice daily minimum total course of 57 days
First choice for non-life-threatening RMSF Chloramphenicol 500 mg iv every 6 hours Not recommended Until 3 days after defervescence, for a
in pregnant women minimum total course of 57 days
First choice for non-life-threatening HME or Rifampin 300 mg po twice daily 10 mg/kg (max. 300 mg) Until 3 days after defervescence, for a
HGA in pregnant women twice daily minimum total course of 710 days
Alternative for resistant scrub typhus
First choice for scrub typhus in pregnant Azithromycin 500 mg po daily 10 mg/kg po daily 3 days
women and potentially in children
Alternative for mild rickettsioses (e.g. early
boutonneuse fever) during pregnancy or in
children
*With the exception of infections in pregnant women, although doxycycline administration during pregnancy can be considered in life-threatening situations when the suspicion of RMSF or
other severe rickettsioses is high; other tetracyclines are also effective for rickettsial infections.
Recommended by the CDC; others recommend a 10-day course.
May be associated with gray baby syndrome when administered late in the third trimester of pregnancy.
Clarithromycin may also be considered.
Table 76.3 Treatment of rickettsial diseases. Empiric treatment with an appropriate agent should be initiated immediately when a diagnosis of Rocky Mountain
spotted fever (RMSF), human monocytotropic ehrlichiosis (HME), human granulocytotropic anaplasmosis (HGA) or another potentially severe rickettsiosis is
suspected clinically.
HUMAN EHRLICHIOSES
Ehrlichial infections have been well known to veterinarians for >75
years, but human infection was not recognized until 1986, when Ehrli-
chia chaffeensis was implicated as the etiologic agent of human mono-
cytotropic ehrlichiosis (HME)21. In 1999, E. ewingii was found to cause
human infections (most often in immunosuppressed patients) with
Ixodes scapularis distribution
clinical manifestations similar to HME22. Ehrlichia spp. are obligately
intracellular, Gram-negative bacteria that target monocytes/macrophages Ixodes pacificus distribution
(E. chaffeensis) or neutrophils (E. ewingii), in which they reside as a Amblyomma americanum distribution
cytoplasmic microcolony that is occasionally visible in a peripheral blood Overlapping distribution (I. scapularis and A. americanum)
smear. Both agents are maintained in a zoonotic cycle involving persist-
ently infected white-tailed deer as the major reservoir and lone star ticks Fig. 76.10 Approximate distribution in the US of vector tick species for
(Amblyomma americanum), which are found primarily in the south human monocytotropic ehrlichiosis, human granulocytotropic anaplasmosis,
central and southeastern US (with extension as far north as Illinois and Maculatum disease and Lyme borreliosis. It has been postulated that
Connecticut), as the primary vector (Fig. 76.10; see Table 76.1)21. In Amblyomma maculatum, which is classically found primarily along the Atlantic
addition, a new Ehrlichia species transmitted by Ixodes scapularis was and Gulf coasts, has a range as broad as that of Amblyomma americanum. From
Chapman AS, et al. MMWR Recomm Rep. 2006;55:127.
recently found to cause human infections clinically similar to HME in
the upper midwestern US22a.
HME is a serious infectious disease with a ~3% case fatality rate. Its
incidence is likely underestimated due to the lack of specific clinical
findings, and one study found that ehrlichial infection was twice as
likely as RMSF among febrile patients living in North Carolina with a
history of a recent tick bite16. Patients with HME and Ehrlichia ewingii petechial eruptions involving the trunk and extremities are most often
infection typically present with fever, headache and myalgias; common observed, but the morphology and distribution of skin lesions can vary
laboratory abnormalities include thrombocytopenia, leukopenia and considerably25,26 (Table 76.4). Ehrlichia ewingii infection has not been
elevated transaminases. Progression to acute respiratory distress syn- reported to have cutaneous manifestations22. The differential diagnosis
drome, meningoencephalitis and toxic shock syndrome-like manifesta- of ehrlichioses is similar to that of rickettsioses (see above).
tions can occur, even in immunocompetent individuals with HME. In PCR-based assays can identify Ehrlichia spp. and Anaplasma phago-
addition, overwhelming ehrlichial infection may develop in immuno- cytophilum (see below) in blood samples and assist in the rapid diag-
compromised hosts, such as those with HIV infection and organ trans- nosis of these infections; however, empiric treatment should be initiated
plant recipients23,24. based on clinical suspicion rather than awaiting laboratory confirma-
Approximately 3040% of patients with HME have cutaneous mani- tion. Doxycycline is the drug of choice for both HME and Ehrlichia
festations, which develop a median of 5 days after the onset of the illness ewingii infection. In vitro evidence suggests that chloramphenicol is 1249
and may be more common in children25. Macular, maculopapular and not an effective therapy for these infections.
SECTION
Macular or maculopapular exanthematous eruptions association with HGA28. As for HME, the first-line treatment is
Mottled or diffuse macular erythema (transient or persistent)
doxycycline.
Petechiae (favor the palms, soles, trunk and palate)
Vesicles
Edema (especially of hands, feet and scrotum)
Purpuric papules (with histologic evidence of vasculitis)
Q FEVER
Nodules secondary to polyarteritis nodosa Coxiella burnetii differs substantially from organisms in the order Rick-
Ulceration (reported on the penis)
ettsiales, being more closely related to bacteria of the genus Legionella.
Table 76.4 Cutaneous manifestations of human monocytotropic Although C. burnetii are obligately intracellular bacteria found in many
ehrlichiosis. Several types of lesions may be present simultaneously or species of ticks, they are transmitted to humans primarily by inhalation
sequentially in an individual patient. of aerosols generated from the placenta and birth fluids of infected
animals such as sheep, cattle and cats (see Table 76.1). The bacteria
target macrophages, where they thrive in the acidic environment of
phagolysosomes. The presence of a stable extracellular form accounts
HUMAN GRANULOCYTOTROPIC ANAPLASMOSIS for their persistence in the environment.
The acute disease typically presents as a nonspecific febrile illness;
Anaplasma phagocytophilum, previously referred to as the human atypical pneumonia or granulomatous hepatitis occasionally occur.
granulocytotropic ehrlichiosis (HGE) agent, is an obligately intra- Chronic Q fever most often manifests as culture-negative endocardi-
cellular bacterium (closely related to Ehrlichia spp.) that causes human tis affecting a previously damaged heart valve.
granulocytotropic anaplasmosis (HGA; formerly known as HGE). HGA Cutaneous manifestations of Q fever are rare (see Table 76.2). A
occurs in the same geographic distribution as Lyme borreliosis (and truncal maculopapular rash, an urticarial eruption, erythema nodosum,
babesiosis) owing to their transmission by the same Ixodes spp. tick palpable purpura, palatal petechiae, and vasculitis (reported in associa-
vectors (see Table 76.1 and Fig. 76.10). The clinical features of HGA tion with mixed cryoglobulinemia) have all been described in patients
are similar to those of HME, but HGA has a lower case fatality rate with Q fever.
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