ADULT IMMUNIZATION o Two live parenteral vaccines can be given

together, with the 2nd dose of the same

General Principles
KEY DIFFERENCES BETWEEN LIVE ATTENUATED AND
INACTIVATED VACCINES
- Live Attenuated Vaccines
o derived from wild viruses or bacteria which are
modified or weakened in laboratories.
o Immunity is elicited by replication of the
attenuated organism in the vaccinated person.
o The immune response to a live attenuated
vaccine is identical to that induced by natural
infection.
- Inactivated Vaccines
o produced by growing the bacteria or virus in
culture media which are then subjected to heat
or chemical agents.
o In fractional or subunit form of these vaccines,
organisms are treated to be able to derive those
components needed to produce the vaccines.
o Both the inactivated or sub-unit preparations
must contain sufficient antigenic mass to
stimulate the desired response.
o It is incapable of replicating inside the host.
vaccines usually administered after 4 weeks.
§ Example: MMR and JE can be given
together.
o It is not necessary to restart the series of any
vaccine due to extended interval between
doses.
o Vaccine doses should not be administered at
less than the recommended minimum
intervals or earlier than the indicated
minimum age.
VALID AND INVALID CONTRAINDICATIONS TO
VACCINATIONS
o Contraindication is a condition that increases the risk
of a serious adverse reaction to vaccination. A vaccine
should not be administered when a contraindication
is documented.
o Precaution is a condition that may increase the risk of
an adverse event or that may compromise the ability
of the vaccine to evoke immunity.

TYPES OF VACCINES AND EXAMPLES

GUIDELINES ON TIMING AND SPACING OF VACCINES

- Multiple vaccines can be administered at the
recommended schedule and time using different
injection sites.
- Two to three inactivated injectable vaccines can be
given in the same visit.
o Simultaneous administration of 2 live
vaccines can be given in same visit.
§ Example: Oral Polio and MMR

1
 RECOMMENDED VACCINATION IN
SPECIAL POPULATIONS
- Haemophilus influenzae type b vaccine
o Anatomical or functional asplenia
(including sickle cell disease): 1 dose if
previously did not receive Hib; if elective
splenectomy, 1 dose, preferably at least 14
days before splenectomy
o Hematopoietic stem cell transplant (HSCT):
3-dose series 4 weeks apart starting 6–12
months after successful transplant,
regardless of Hib vaccination history
- Hepatitis A vaccine
o At risk for hepatitis A virus infection: 2-dose
series HepAb or 3-dose series
§ Chronic liver disease
§ HIV infection
Adult Immunization Schedules
§ Men who have sex with men
RECOMMENDED VACCINATION BY AGE GROUP IN THE
§ Injection or noninjection drug use
ABSENCE OF DOCUMENTED VACCINATION OR EVIDENCE OF
§ Persons experiencing homelessness
PAST INFECTION;
§ Work with hepatitis A virus
CONTRAINDICATED VACCINES IN SPECIAL POPULATIONS;
§ Travel in countries with high or
intermediate endemic
§ hepatitis A
§ Close, personal contact with
international adoptee
§ Pregnancy if at risk for infection or
severe outcome from infection
during pregnancy
§ Settings for exposure
- Hepatitis B vaccine
o Age 60 years or older* and at risk for
hepatitis B virus infection: 2-dose (Heplisav-
B) or 3-dose (Engerix-B, Recombivax HB)
series or 3-dose series HepA-HepB (Twinrix)
§ Chronic liver disease
§ HIV infection
INDICATED VACCINATION IN SPECIAL POPULATIONS IF
§ Sexual exposure risk
BENEFIT OF PROTECTION OUTWEIGHS RISK
§ Current or recent injection drug use
§ Percutaneous or mucosal risk for
exposure to blood
§ Incarcerated persons
§ Travel in countries with high or
intermediate endemic hepatitis B
- Human papillomavirus vaccine
o Age ranges recommended above for routine
and catch-up vaccination or shared clinical
decision-making also apply in special
situations
§ Immunocompromising conditions,
including HIV infection: 3-dose
series, even for those who initiate
vaccination at age 9 through 14
years.
§ Pregnancy: Pregnancy testing is not
needed before vaccination; HPV
vaccination is not recommended

2
 until after pregnancy; no mononuclear cells through TLR4 -> endothelial
intervention needed if hyperpermeability and vascular and complement
inadvertently vaccinated while activation -> plasma leakage and accumulation of
pregnant fluid in third space -> dengue shock syndrome
- Influenza vaccine WHO CASE DEFINITIONS OF DENGUE INFECTION/SPECTRUM
o Egg allergy, hives only: any influenza vaccine - PROBABLE DENGUE
appropriate for age and health status - DENGUE FEVER
annually - SEVERE DENGUE
o Egg allergy–any symptom other than hives
(e.g., angioedema, respiratory distress) or
required epinephrine or another emergency
medical intervention
o Severe allergic reaction (e.g., anaphylaxis) to
a vaccine component or a previous dose of
any influenza vaccine
o History of Guillain-Barré syndrome within 6
weeks after previous dose of influenza
vaccine: Generally, should not be vaccinated
unless vaccination benefits outweigh risks
for those at higher risk for severe
complications from influenza
- MMRV vaccine

DENGUE

Etiology, pathogenesis, case definitions, clinical

CLINICAL MANIFESTATIONS OF DENGUE BASED ON LEVEL OF
manifestations
SEVERITY OR PHASES OF DISEASE
ETIOLOGIC AGENTS AND DISEASE - FEBRILE PHASE
VECTORS o Lasts 2-7 days
- It is caused by Dengue virus, a positive stranded RNA o High fever
virus from the family Flaviviridae o Facial flushing, skin erythema, generalized
- Its vectors are mosquitoes (predominantly Aedes body ache, myalgia, arthralgia
aegypti and Aedes albopictus). o Retroorbital eye pain, photophobia
- It has four serotypes- DENV 1, 2, 3, and 4 o Rubeliform exanthema
EPIDEMIOLOGY OF DENGUE o Headache
- It is the most prevalent arthropod-borne viral disease o Sore throat, infected pharynx conjunctival
worldwide, with ~400 million infections occurring per injection
year. o Anorexia, vomiting, nausea
- It is endemic in >100 countries including Africa, o Decrease in total white cel count
Americas, eastern Mediterranean, South-Eastern - CRITICAL PHASE
Asia, and the western Pacific. o Around time of defervescence (day 3-8) (T:
- There were approximately >400,000 cases in 2019 in 37.5 to 38 C or less)
the Philippines alone. o Warning signs
TRANSMISSION AND PATHOGENESIS OF DENGUE § Persistent vomiting and severe
- It is transmitted through a bite of an infected vector § Abdominal pain
- Primary infection is the initial or first infection with a § Lethargic
certain serotype. § Spontaneous mucosal bleeding
- Most are asymptomatic or manifest as mild febrile § Increasing liver size and a tender
illness. liver
o Re-infection with the same serotype is given § Fluid accumulation
immunity o Progressive leukopenia
o However, this immunity is short-lived (1 or 2 o Rapid decrease in platelet count
years) o Increase in hematocrit
- NS1 antigen causes disruption of endothelial - RECOVERY PHASE
monolayer integrity by eliciting inflammatory o 48-72 hours after critical phase
cytokine production due to activation of o General wellbeing improves
macrophages and human peripheral blood o Appetite returns

3
 o Gastrointestinal symptoms abates o Upper respiratory tract
o Haemodynamic status stabilizes - HACEK organisms:
o Diuresis ensues o Haemophilus species
o Erythematous or petechial rash (isles of o Aggregatibacter species
white in the sea of red” o Cardiobacterium hominis
o Bradycardia o Eikenella corrodens
o ECG changes o Kingella kingae
o WBC starts to rice - Community-acquired NVE → Caused by organisms that
o Respiratory distress (if excessive IVF has cause PVE >12 months post-op
been administered) - Cardiovascular implantable electronic devices (CIED-IE)
§ From massive pleural effusion and → Majority of cases are caused by S. aureus and
ascites, pulmonary edema, Coagulase-negative Staph
congestive heart failure - Persons who inject drugs (PWID) → commonly caused by
S. aureus (involving the tricuspid valve)
- IE with negative blood cultures → Caused by prior
antibiotic use in 1/3 to ½ of cases
o The remainder causes are:
§ Granulicatella and Abiotrophia species
§ HACEK organisms
§ Coxiella burnetii
§ Bartonella species

PATHOGENESIS
- Endothelial injury → direct infection by virulent
organisms or the development of a platelet–fibrin
thrombus—a condition called nonbacterial thrombotic
endocarditis (NBTE) → serves as a site of bacterial
attachment during transient bacteremia

CLINICAL MANIFESTATIONS
- Cardiac:
INFECTIVE ENDOCARDITIS (LE)
o Murmurs → Absent initially but ultimately are
detected in 85% of cases of Acute IE
Etiology, Pathogenesis, Clinical Manifestations
o Congestive heart failure (CHF) → 30–40% of patients
- Infection most commonly involves heart valves o Paravalvular abscesses → May cause intracardiac
- May also occur on the low-pressure side of a ventricular fistulae with new murmurs
septal defect, on mural endocardium damaged by o Heart block on ECG → Caused by Aortic paravalvular
aberrant jets of blood or foreign bodies, or on infection interfering with conduction
intracardiac devices o Coronary artery emboli → 2% of patients
o Infective endarteritis → Infection involving AV shunts, - Noncardiac:
arterio-arterial shunts (patent ductus arteriosus), or a o Janeway lesions → In Subacute IE
coarctation of the aorta o Subungual hemorrhage, Osler’s nodes → In Acute IE
- Classification: o Neurologic complications:
o Acute IE § Aseptic or purulent meningitis
§ Febrile illness that rapidly damages cardiac § Intracranial hemorrhage
structures § Ruptured mycotic aneurysms
§ Seeds extracardiac sites § Seizures
§ Progresses to death within weeks if untreated - Specific predisposing conditions:
o Subacute IE o PWID → 35–60% of IE is limited to the tricuspid valve
§ Indolent course § Presents with fever
§ Causes structural cardiac damage only slowly § Faint or no murmur
§ Rarely metastasizes § No peripheral manifestations
§ Gradually progressive o CIED-IE → May be associated with obvious or cryptic
- Incidence of IE → increased among the elderly generator pocket infection
o Congenital heart diseases → constant predisposition § May also arise through bacteremic seeding
- Portals of entry: without pocket infection
o Oral cavity
o Skin

4
 Diagnosis

o Enterococci:

o Staphylococci:

o Other organisms:

- Definite IE:
o 2 major criteria, or - Empirical therapy:
o 1 major and 3 minor criteria, or o For acute IE → should cover MRSA
o 5 minor criteria o PWID or for health care–associated NVE →
- Possible IE: potentially antibiotic-resistant gram-negative
o 1 major and one minor, or bacilli
o 3 minor criteria - May complete therapy as outpatients:
- Serologic tests → Used to implicate organisms that are o Fully compliant
difficult to recover by blood culture o Clinically stable patients
o Brucella o No clinical or echocardiographic findings that
o Bartonella suggest an impending complication
o T. whipplei - Monitoring of antibiotic therapy:
o C. burnetiid o Blood tests to detect renal, hepatic, and
- Echocardiography → anatomically confirms and hematologic toxicity should be performed
measures vegetations, detects intracardiac periodically
complications, and assesses cardiac function

Treatment
- Therapy must be bactericidal and prolonged
- Organism-specific Therapies:
o Streptococci:

5
- Indications for surgical management in IE RECOMMENDED MANAGEMENT APPROACH

INDICATIONS FOR C-CSF OR GM-SCF

- Recommendations for IE prophylaxis

FEBRILE NEUTROPENIA

DEFINITION
- Clinical presentation of fever and <1500 granulocytes/Μl

RISK FACTORS
- Older age
- Comorbidities
- Specific type of cancer
- Type and number of myelosuppressive chemotherapy
agents in use

6
 FEVER OF UNKNOWN ORIGIN (FUO) o Most frequently giant cell arteritis and polymyalgia
rheumatica
Definition, Etiology And Epidemiology o TB is the most common infectious disease associated
Definition of FUO with FUO in elderly patients
- Febrile illness without an initially obvious etiology - Full table at Harrison’s 21st Ed, pg. 146, Table 20-2
- Prolonged febrile illnesses without an established
etiology despite intensive evaluation and diagnostic Infections Neoplasms
testing Bacterial, nonspecific Hematologic malignancy
- Petersdorf and Beeson (1961): illness of > 3 weeks’ Bacterial, specific Solid tumors
duration with fever > 38.3*C (> 101*F) on two occasions Fungal Benign tumors
and an uncertain diagnosis despite 1 week of inpatient Parasitic Miscellaneous causes
evaluation Viral Thermoregulatory
- Excludes immunocompromised patients NIID Disorders
- Criteria: Systemic rheumatic and Central
1. Fever > 38.3*C (> 101*F) on at least 2 occasions autoimmune diseases Peripheral
2. Illness duration of > 3 weeks Vasculitis
3. No known immunocompromised state Granulomatous disease
4. Diagnosis that remains uncertain after a thorough Autoinflammatory
history-taking, PE, and the following obligatory syndromes
investigations:
a. ESR and CRP level Common Noninfectious Inflammatory Diseases (NIIDs)
b. Platelet count presenting as FUO
c. Leukocyte and differential - Common – adult-onset:
d. Measurement of hemoglobin, electrolytes, o Still’s disease
creatinine, total protein, alkaline phosphatase, o Large-vessel vasculitis
ALT, AST, LDH, creatinine kinase, ferritin, o Polymyalgia rheumatica
antinuclear antibodies, and rheumatoid factor o Systemic lupus erythematosus (SLE)
e. Protein electrophoresis o Sarcoidosis
f. Urinalysis - Very rare – young patients: Hereditary autoimmune
g. Blood cultures (n = 3) inflammatory syndromes (except familial Mediterranean
h. Urine culture fever)
i. Chest x-ray - Schnitzler syndrome
j. Abdominal ultrasonography o Uncommon and presents at any age
k. TST or interferon y release assay (IGRA) o Often diagnosed in a patient with FUO who presents
- Inflammation of unknown origin (IUO) with urticaria, bone pain, and monoclonal
o Same definition as FUO, except for the body gammopathy
temperature criteria - Full table at Harrison’s 21st Ed, pg. 146, Table 20-2
o Defined as the presence of elevated inflammatory
parameters (CRP or ESR) on multiple occasions for a Most common cancer causes of FUO
period of atleast 3 weeks in an immunocompetent - Malignant lymphoma is the most common cause
patient with normal body temperature, for which a - Most tumors can present with fever
final explanation is lacking despite history-taking, PE, - Fever precedes LAD detectable by PE
and the obligatory tests listed above - Full table at Harrison’s 21st Ed, pg. 146, Table 20-2
- Causes and workup for IUO are the same as FUO
Most common miscellaneous causes of FUO
Etiologies of FUO and Epidemiology - Drug-induced fever
- Non-Western cohorts: infection is the most common o Includes DRESS (drug reaction with eosinophilia and
cause of FUO systemic symptoms)
- Western cohorts: noninfectious inflammatory diseases o Often accompanied by eosinophilia & LAD
(NIIDs) are the most common cause o More common causes of drug-induced fever:
o Autoimmune, autoinflammatory, and granulomatous § Allopurinol, carbamazepine, lamotrigine
diseases, vasculitides § Phenytoin, sulfasalazine, furosemide
o Can be diagnosed only after prolonged observation § Antimicrobials (sulfonamides, minocycline,
and exclusion of other diseases vancomycin, B-lactam antibiotics, isoniazid)
- A cause is more likely to be found in elderly patients § Cardiovascular drugs
o FUO results from an atypical manifestation of a § Antiretroviral drugs
common disease - Exercise-induced hyperthermia

7
 o Defined as elevated body temperature that is
associated with moderate to strenuous exercise
lasting from half an hour up to several hours without
an increase in CRP level or ESR
o Patients sweat during the temperature elevation
- Factitious fever
o Fever artificially induced by the patient (e.g., IV
injection of contaminated water)
o Considered in all patients but most common in young
women in health-care professions
- Fraudulent fever
o Normothermic patient but manipulates the
thermometer
o Dissociation between pulse rate & temperature
o Simultaneous measurements at different body sites
(rectum, ear, mouth) should be done
- Full table at Harrison’s 21st Ed, pg. 146, Table 20-2
Diagnostic Approach
First-stage Diagnostic Tests and Interventions in the Work-
up of FUO
- Search for potentially diagnostic clues (PDC’s)
o Defined as all localizing signs, symptoms, and
abnormalities potentially pointing toward a diagnosis
- History
o Fever pattern (continuous or remittent) and duration
o Previous medical history
o Present and recent drug use
o Family history
o Sexual history
o Country of origin
o Recent and remote travel
o Unusual environmental exposures associated with
travel or hobbies
o Animal contacts
- Complete physical examination
o Special attention to the eyes, LN, temporal arteries,
liver, spleen, sites of previous surgery, entire skin
surface, and mucous membranes
- Antibiotics and glucocorticoid treatment may mask
diseases and should be stopped
- Rule out factitious or fraudulent fever
- All medications should be discontinued early in the
evaluation to exclude drug fever
Guided Diagnostic Steps in the Work-up of FUO
- Multiple blood samples should be cultured
- Performing > 3 blood cultures or > 1 urine culture is
useless in patients with FUO in the absence of PDC’s
- Repeating blood or urine cultures is useful only when
previously cultured samples were collected during
antibiotic treatment or within 1 week after its
discontinuation
- Microbiologic examination of CSF
o For FUO with headache
o For organisms HSV, Cryptococcus neoformans, M.
tuberculosis
- Microbiologic serology should not be included in the
workup of patients without PDCs for specific infections
- Tuberculin skin test (TST) and Interferon y release assay
(IGRA)
o A negative TST or IGRA does not exclude TB
o IGRA is influenced by prior vaccination with BCG or by
infection with non-TB mycobacteria
- Miliary TB
o Liver biopsy for acid-fast smear, culture, and PCR has
the highest yield
o Biopsy of bone marrow, LN, or other involved organs
can be considered
Role of Imaging and Functional Imaging Studies
- Obligatory simple, low-cost diagnostic tests
o Ultrasound
§ Abdominal ultrasound is preferred to abdominal
CT as an obligatory test due to low cost, lack of
radiation burden, and absence of side effects
o Chest x-rays
- Not used as screening procedures d/t diagnostic yield in
absence of PDC
o Echocardiography, sinus radiography, radiologic or
endoscopic evaluation of the GIT, and bronchoscopy
- Fluorodeoxyglucose Positron Emission Tomography
(18F-FDG PET/CT)
o FDG
§ Accumulate in tissues with a high rate of
glycolysis, not only in malignant cells but also in
activated leukocytes, thus permits imaging of
acute and chronic inflammatory processes
§ Vascular uptake is increased in vasculitis
o Advantages
§ Higher resolution
§ Greater sensitivity in chronic low-grade infections
§ High degree of accuracy in the central skeleton
o Guides additional diagnostic tests
o Physiologic uptake of FPG may obscure pathologic
foci in the brain, heart, bowel, kidneys, and bladder
§ Bone marrow uptake is increased d/t cytokine
activation which upregulates glucose transporters
in bone marrow cells
o Correct timing of PET/CT increases its diagnostic
value
o Pathologic FDG uptake is quickly eradicated by
treatment with glucocorticoids in many diseases and
should be stopped or postponed until after FDG-
PET/CT is performed
- Radiolabeled leukocyte scintigraphy
o Diagnostic value: 8-31%
o Alternative when PET/CT is not available
Second-stage Diagnostic Tests in the Work-up of FUO
- Chest and abdominal CT
o Diagnostic yield: 20%
8
 o May be used as screening procedures at a later stage
of the diagnostic protocol d/t their noninvasive
nature or high sensitivity
- Bone marrow aspiration
o Seldom useful in the absence of PDC for bone marrow
disorders
- Temporal artery biopsy
o Recommended for patients > 55 years of age in a later
stage of the diagnostic protocol
- Liver biopsy
o Abnormal liver tests are not predictive of a diagnostic
liver biopsy in FUO
o An invasive procedure that carries the possibility of
complications and even death
o Should not be used for screening purposes in patients
with FUO except in those with PDC for liver disease or
miliary TB
Role of Late-stage Diagnostic Tests in the Work-up of FUO
- Abnormalities found with imaging often need to be
confirmed by pathology and/or culture of biopsy
specimens
- Repetition of a thorough history-taking and PE and
review of lab tests and imaging studies are
recommended
- Waiting for new PDCs to appear is better than ordering
more screening investigations
Management And Prognosis
Treatment Principles and Approach to Treatment of FUO
- Empiric therapeutic trials with antibiotics,
glucocorticoids, or anti TB agents should be avoided in
FUO except when a patient’s condition is rapidly
deteriorating after the aforementioned diagnostic tests
have failed to provide a definite diagnosis
Contraindications and Indications for Therapeutic Trials
of Antibiotics, NSAIDs, Glucocorticoids, or Anti-TB drugs
- Antibiotics and anti-TB therapy
o Antibiotics or anti-TB therapy may irrevocably
diminish the ability to culture fastidious bacteria or
mycobacteria
o Indications
§ Hemodynamic instability or neutropenia
§ TST or IGRA positive
§ Granulomatous disease is present with anergy or
sarcoidosis
o If the fever does not respond after 6 weeks of
empirical anti-TB treatment, another diagnosis
should be considered
- Colchicine
o Prevents attacks of familial Mediterranean fever
(FMF) but is not always effective once an attack is well
under way
o Treatment show remarkable improvement in the
frequency and severity of subsequent febrile
episodes within weeks to months
o Indications
§ Patients with features compatible with FMF,
especially when these patients originate from a
high-prevalence region
- NSAIDs
o Indications: adult-onset Still’s disease
o Contraindications: avoided unless infectious diseases
and malignant lymphoma have been largely ruled out
and inflammatory disease is probable, debilitating, or
threatening
- Glucocorticoids
o Early empirical trials decrease the chances of
reaching a diagnosis for which more specific and
sometimes life-saving treatment might be
appropriate
o Indications
§ Giant cell arteritis
§ Polymyalgia rheumatica
o Contraindications: avoided unless infectious diseases
and malignant lymphoma have been largely ruled out
and inflammatory disease is probable, debilitating, or
threatening
Role of Other Anti-inflammatory Agents
- Interleukin 1 inhibition
o Interleukin 1 (IL) is a key cytokine in local and
systemic inflammation and the febrile response
9
 o Anakinra AIDS-defining Opportunistic Illnesses in HIV Infection
§ Recombinant form of IL-1 receptor antagonist (IL-
1Ra), blocks the activity of both IL-1a and IL-1B
§ Effective in treatment of autoinflammatory
syndromes and other chronic inflammatory
disorders
§ Considered in patients whose FUO has not been
diagnosed after later-stage diagnostic tests
o Monotherapy with IL-1 blockade can provide
improved control without the metabolic,
immunologic, and GI side effects of glucocorticoid
administration

Prognosis of FUO
- Prognosis is favorable
- FUO-related mortality rates have continuously declined
over the recent decades
- Majority of fevers are caused by treatable diseases
- Risk of death related to FUO is dependent on the
underlying disease

HIV/AIDS

Definition, Etiology, Pathogenesis, Transmission,

Epidemiology
Classification based on HIV infection stages
- Stage 0:
o Negative HIV test within 6 months of the first HIV
infection diagnosis
o Remains 0 until 6 months after diagnosis
- Stage 1
- Stage 2
- Stage 3 (Advanced HIV disease or AIDS)
o If one or more opportunistic illness has been
diagnosed (see table 202-1) Characteristics of the Etiologic Agent HIV and its Antigenic
- Stage U (Unknown) Determinants Crucial for Infection
o If none of the criteria apply - HIV virion is an icosahedral structure with numerous
external spikes formed by 2 major envelope proteins
o External gp120
o Transmembrane gp41
- Envelope exists as a trimeric heterodimer
- Virion buds from the surface of the infected cell and
incorporates a variety of host cellular proteins into its
lipid bilayer

10
Replication Cycle of HIV o Predominant in US, Canada, South America, western
Europe, Australia
- Asia: CRF01_AE and subtypes B and C predominate

Predominant CRF in Southeast Asia

- Southeast Asia: CRF01_AE
- West and Central Africa: CRF02_AG

Mechanisms of Viral Transmission in Different Settings

- Sexual contact (heterosexual and male-to-male)
- Blood and blood products
o Injection drug use (IDU)
o Transfused blood and blood products
- Infected mothers to infants
o Intrapartum, perinatally, or via breast milk
- Occupational transmission
o Healthcare workers
o Laboratory workers
o Health care setting
- Other body fluids
o Saliva (low titers; no convincing evidence)
o Human bite (rare)
o Tears, sweat, urine (no evidence)
Molecular Heterogeneity of HIV-1 and the Four Groups of
HIV-1
- HIV sequence diversity arises directly from the limited
fidelity of the reverse transcriptase
- The four groups (M, N, O, P) are the result of 4 separate
chimpanzee-to-human transfers
GROUP Natural Reservoir
HIV-M Chimpanzee subspecies Pan
HIV-N troglodytes troglodytes

HIV-O
Cameroonian gorillas
HIV-P
- M (Major) Group
o Responsible for most of the infections in the world
o Comprises 10 subtypes or clades (A, B, C, D, E, F, G, H,
J, K, and L) and > 100 known circulating recombinant
forms (CRFs) and unique recombinant forms
o Subtypes and CRFs create the major lineages of the M
group of HIV-1
- Nine strains account for the vast majority of HIV
Epidemiology of HIV Infection and AIDS in Asia and SEA
infections globally:
- Asia and the Pacific
o HIV-1 subtypes: A, B, C, D, F, G
o 5.8 million people with HIV at the end of 2020
o CRFs: CRF01_AE, CRF02_AG, CRF07_BC
o Reduced in Thailand and Vietnam
- Subtype C
o Increased in Pakistan and the Philippines
o Dominates the global pandemic
o HIV prevalence is highest in SEA countries
o More transmissible than other subtypes
o Only Thailand has an adult seroprevalence rate that
o Most common form worldwide
reaches 1%
o Cause most of the infections in sub-Saharan Africa
o China, India, and Indonesia account for three
(home to 2/3 of all individuals with HIV/AIDs)
quarters of all people living with HIV in the region
o Seen in > 95% of infections in India
o Rising numbers of new infections among gay men and
- Subtype B
other men who have sex with men are a major
concern

11

Pathophysiology, Pathogenesis
General Hallmark of HIV Disease
- Profound immunodeficiency resulting from a progressive
quantitative and qualitative deficiency of the subset of T
lymphocytes (helper T cells) occurring in a setting of
aberrant immune activation
Mechanisms of CD4+ T-cell Depletion or Dysfunction
- Direct infection and destruction of cells by HIV
- Indirect effects
o Immune clearance of infected cells
o Cell death associated with aberrant immune
activation and inflammation
§ Caspase 1-mediated pyroptosis prompted by
tissue CD4+ T cells undergoing abortive
/nonproductive HIV infection
o Immune exhaustion d/t persistent cellular activation
with resulting cellular dysfunction
Course of Primary HIV Infection, Initial Viremia, and Viral
Dissemination
- Efficiency of initial infection of susceptible cells may vary
with the route of infection
o By infected blood or blood products
§ Virus enters directly into bloodstream is cleared
first from circulation to the spleen and other
lymphoid organs where primary organ infection
begins
§ Followed by wider dissemination throughout
other lymphoid tissues
o Sexual transmission
§ Transmitting viruses (Founder Viruses) diverges
and accumulates in glycosylation sites, becoming
progressively more resistant to neutralization
- Acute HIV Syndrome
o Acute burst of viremia and wide dissemination of
virus in primary HIV infection
o Occur in 50% of individuals within 2-4 weeks of initial
infection
o Associated with millions of copies of HIV RNA per mm
of plasma that last for several weeks
o Acute mononucleosis-like symptoms are well
correlated with the presence of high levels of plasma
viremia
o High levels of viremia is associated with higher
likelihood of transmission of virus to others by other
routes
Role of Co-receptors in HIV Pathogenesis
- A co-receptor must be present together with CD4 for
efficient binding, fusion, and entry of HIV-1 into target
cells
- HIV-1 uses 2 major co-receptors for fusion & entry:
o CCR5
o CXCR4
- These are the primary receptors for chemokines and
belong to the 7-transmembrane-domain GPC family of
receptors
Mechanisms of Establishing Chronic and Persistent Infection
- The establishment of chronic persistent infection is the
hallmark of HIV disease
- Chronic infection develops and persists with varying
degrees of continual virus replication in the untreated
patient for a median of 10 years before the patient
becomes clinically ill
12
 - There is continual low level of virion production
- Once infection is established, virus escapes complete
immune-mediated clearance and paradoxically thrives
on immune activation and is never eliminated from the
body completely
Immune Evasion, Immune Activation and Inflammation in
HIV Pathogenesis
- Establishment of a sustained level of replication
associated with regeneration of viral diversity via
mutation and recombination
o Viral escape from CTLs through high rates of mutation
o The high rate of virus replication associated with
inevitable mutations also contributes to the inability
of the antibody to neutralize and/or clear the
autologous virus
o Humoral immune system does not readily produce
classic neutralizing antibodies against the HIV
envelope and does so only after years of persistent
virus replication and after the infection is firmly
established
- Strong immune response becomes qualitatively
dysfunctional owing to the overwhelming immune
activation associated with persistent viral replication,
leading to immune “exhaustion” that affects both arms
of adaptive immunity
- Downregulation of HLA class I molecules on the surface
of HIV-infected cells by viral proteins Nef, Tat, and Vpu,
resulting in the lack of ability of CD8+ CTLs to recognize
and kill infected target cells
- Sequestration of infected cells in immunologically
privileged sites (CNS) & the low frequency of virus-
specific CD8+ CTLs in areas of lymphoid tissues (germinal
centers) where HIV actively replicates
- Three mechanisms to evade neutralizing antibody
response:
o Hypervariability in the primary sequence of the
envelope
o Extensive glycosylation of the envelope
o Conformational masking of neutralizing epitopes
- The escape of HIV from immune-mediated elimination
allows formation of a pool of latently infected CD4+ T
cells (Viral Reservoir)
Reservoirs of HIV-infected Cells
- Resting CD4+ T cells
o Serve as one component of the persistent reservoir of
virus
o Carry an integrated form of HIV DNA in the genome
of the host and can remain in this stat until an
activation signal drives the expression of HIV
transcripts
o Only a small fraction of latently infected cells contain
replication-competent virus
o Majority of cells contain defective proviruses
incapable of a full replication cycle
- Preintegration latency
o HIV enters a resting CD4+ T cell and in absence of
activation signal, reverse transcription of the HIV
genome occurs to a certain extent but the resulting
proviral DNA fails to integrate into the host genome
o Lasts hours to days
o If no activation is delivered to the cell, the proviral
DNA loses its capacity to initiate a productive
infection
o If activation occurs prior to decay, reverse
transcription proceeds to completion and the virus
continues along its replication cycle
- Reservoirs of HIV-infected cells (latent or active)
o Lymphoid tissue
o Peripheral blood
o CNS (cells of monocyte/macrophage lineage)
Features of Advanced HIV Disease
- CDC case definition of stage 3 (AIDS)
o HIV-infected individuals > 5 years with CD4+ T cell
counts < 200/uL
- May develop constitutional signs and symptoms
- May develop an opportunistic disease abruptly without
any prior symptoms
- Depletion of CD4+ T cells continues to be progressive and
unrelenting in this phase
Definition of Long-term Survivors, Long-term Non-
progressors, and Elite Controllers
- Long-term survivors
o HIV-infected individuals treated with ART
- Long-term non-progressors
o Defined as long-term survivors (but the reverse is not
always true)
o Individuals were considered to be long-term
nonprogressors if they had been infected with HIV for
a long period (> 10 years), their CD4+ T cells counts
were in the normal range, their plasma viremia
remained relatively low, and they remained clinically
stable over years without receiving ART
- Elite controllers
o Constituted a fraction of 1% of HIV-infected
individuals
13
 o Individuals have extremely low levels of plasma Guidelines on Serologic Testing in HIV-1 Diagnosis
viremia that is often undetectable by standard assays
and normal CD4+ T cell counts

Diagnosis, Clinical Manifestations

Diagnostic Approach in HIV Infection
- CDC recommends that screening for HIV infection be
performed as a matter of routine health care
- Diagnosis depends on demonstration of antibodies to
HIV and/or the direct detection of HIV or one of its
components
o Antibodies to HIV generally appear in the circulation
3-12 weeks following infection
- Standard blood screening tests for HIV are based on the
detection of antibodies to HIV and/or the p2 4 antigen of
HIV
- Enzyme immunoassay (EIA)
o Sensitivity > 99.5%
o Commercial kit that contains antigens from both HIV-
1 and HIV-2 and can detect antibodies to either
o Uses both natural and recombinant antigens
- 4th generation EIA tests
o Detection of antibodies to HIV-1 or HIV-2 with
detection of the p24 antigen of HIV
o Scoring:
§ Positive – highly reactive
§ Negative – nonreactive
§ Indeterminate – partially reactive
o False-positives
§ Antibodies to class II antigens (following Laboratory Monitoring in HIV Infection
pregnancy, blood transfusion, or transplant) - Determinations of peripheral blood CD4+ T cell counts
§ Autoantibodies and measurements of plasma levels of HIV RNA provide
§ Hepatic disease a powerful set of tools for determining prognosis and
§ Recent influenza vaccination monitoring response to therapy
§ Acute viral infections - CD4+ T cell count
§ Administration of HIV vaccine o Measured directly or calculated as the product of the
- Anyone suspected of having HIV infection based on a percent of CD4+ T cells and the total lymphocyte
positive EIA test should have results confirmed with a count
more specific assay o Best indicator of and correlates with the level of
o HIV-1 or HIV-2-specific antibody immunoassay immunologic competence; important factor to
o Western blot determine if there is a need to initiate prophylaxis
o Plasma HIV RNA level § CD4+ T cell counts < 200/uL: high risk of disease
- HIV-infected individual treated early in the course of from P. jiroveci
infection may revert to a negative EIA § CD4+ T cell counts < 50/uL: high risk of disease
o Does not indicate clearing od infection from CMV
o Signifies levels of ongoing exposure to virus or viral o Measured at the time of diagnosis and every 3-6
proteins insufficient to maintain a measurable months thereafter during the first 2 years of ART, and
antibody response for those who were not started on ART
- CDC recommendations indicate that a positive 4th - HIV RNA determination
generation assay confirmed by a second HIV-1 or HIV-2 o Number of copies of HIV RNA per mm of serum or
specific immunoassay or a plasma HIV RNA level is plasma
adequate for diagnosis o HIV RNA can be detected in virtually every patient
o Western blot is no longer used for this purpose with HIV infection
o Used to monitor ART effectiveness (can have viral
suppression 8-24 weeks after ART initiation)

14
 o CDC recommends monitoring of HIV viral load before
initiation of ART, and 2-4 weeks (not later than 8
weeks) after initiation or modification
o Monitoring of viral load is done at 4-8 weeks until
viral suppression is achieved, then monitoring can be
decreased to 3-4 months, or 6 months if stable for 2
years or more
- HIV resistance testing
o Drug resistance testing in the setting of virologic
failure should be performed while the patient is still
on the failing regiment
Clinical Manifestations of Acute HIV Infection
- Occurs 3-6 weeks after primary infection along with a
burst of plasma viremia
- Symptoms: fever, skin rash, pharyngitis, myalgia
- Most patients recover spontaneously from this
syndrome
- Many have only a mildly depressed CD4+ T cell count that
remains stable for a variable period before beginning its
decline
Definition of Clinical Latency in HIV Infection
- Median time: 10 years (for untreated patients)
- Ongoing and progressive HIV disease with active viral
replication
- Rate of disease progression is directly correlated with HIV
RNA levels
o Patients with high levels of HIV RNA in plasma
progress to symptomatic disease faster than do
patients with low levels of HIV RNA
- The average rate of CD4+ T-cell decline is 50/uL per year
in an untreated patient
- When CD4+ T-cell count falls < 200/uL, the resulting state
of immunodeficiency is severe enough to place the
patient at high risk for opportunistic infections,
neoplasms, and clinically apparent disease
Clinical Manifestations of Opportunistic Infections in AIDS
- Check Harrison’s 21st Ed, Pg 1564, Table 202-11
- Respiratory system
o Pulmonary disease is one of the most frequent
complications of HIV infection
§ Pneumonia is the most common manifestation
o Acute bronchitis and sinusitis are prevalent during all
stages of HIV infection
- Cardiovascular system
o Heart disease is a common postmortem finding
o Coronary heart disease is the most common form of
heart disease
o HIV-associated cardiomyopathy is a late complication
of HIV infection
- Oropharynx and GI system
o Most frequently dur to secondary infections
o Oral lesions:
§ Thrush
§ Hairy leukoplakia
§ Aphthous ulcers
o Infections with enteric pathogens as Salmonella,
Shigella, and Campylobacter are more common in
men who have sex with men and are often more
severe and more apt to relapse in patients with HIV
infection
o Nonspecific symptoms: fever, anorexia, fatigue, and
malaise of several week’s duration
o Diarrhea is common but may be absent
- Hepatobiliary diseases
o With evidence of infection with HBV, HCV, and co-
infections with hepatitis D, E, and/or G viruses
- Kidney and GUT
o May be a direct consequence of HIV infection, due to
an opportunistic infection or neoplasm, or related to
drug toxicity
o Microalbuminuria (20%)
o Proteinuria (2%)
o HIV-associated nephropathy (HIVAN)
§ A true direct complication of HIV infection
§ Patients have CD4+ T cell counts < 200/uL
o GUT infections present with skin lesions, dysuria,
hematuria and/or pyuria
o Vulvovaginal candidiasis is common in women with
HIV infection
§ Pruritus, discomfort, dyspareunia, dysuria
15
 § Vulvar infection as morbilliform rash that may
extent to the thighs
§ Vaginal infection with white discharge and
plaques along an erythematous vaginal wall
- Endocrine and Metabolic disorders
o May be a direct consequence of HIV infection, due to
an opportunistic infection or neoplasm, or related to
drug toxicity
o Lipodystrophy
§ Elevated plasma TG, total cholesterol, and
apolipoprotein B
o Hyperinsulinemia
o Hyperglycemia
o Truncal obesity
o Peripheral wasting or lipoatrophy on the face and
buttocks and prominence of veins in legs
o Metabolic syndrome
o SIADH Management
o Altered thyroid function
Principles of Therapy in HIV Infection
o Hypogonadism in men
- CDC guidelines call for the testing for HIV infection to be
- Immunologic and rheumatologic diseases
part of routine medical care
o Drug allergies
o It is recommended that the patient be informed of
o Reactive arthritis
the intention to test and be given the opportunity to
o HIV or AIDS-associated arthropathy
“opt out”
o Painful articular syndrome
- Hematopoietic system
o Lymphadenopathy (persisten, generalized)
o Anemia
o Leukopenia
o Thrombocytopenia
- Dermatologic diseases
o Seborrheic dermatitis
o Folliculitis
o Pruritic popular eruption
o Eosinophilic pustular folliculitis
o Prurigo nodularis
o Norwegian scabies
o Psoriasis and ichthyosis
o Reactivation herpes zoster (shingles)
o HSV infection with recurrent orolabial, genital, and
perianal lesions
o Diffuse skin eruptions d/t Molluscum contagiosum
o Stevens-Johnson syndrome and toxic epidermal
necrolysis as a reaction to drugs
- Neurologic diseases

16
 IRIS and its Management
- Paradoxical IRIS: IRIS related to a preexisting infection or
neoplasm
- Unmasking IRIS: IRIS associated with a previously
undiagnosed condition
- Immune reconstitution disease (IRD): used to
distinguish IRIS manifestations related to opportunistic
diseases from IRIS manifestations related to
autoimmune diseases
- Common in patients with underlying untreated
mycobacterial or fungal infections
- Severe cases: immunosuppressive drugs
o To blunt the inflammatory component of the
reactions while specific antimicrobials takes effect

Recommended Therapy of HIV Infection, Including

Pregnant Women
- Check Harrison’s 21st Ed, Pg 1587, Table 202-21
Recommended Prophylaxis Against Opportunistic
Drug Categories used in HAART and their Adverse Effects Infections in Patients with HIV Infection
- Check Harrison’s 21st Ed, Pg 1587, Table 202-21

Recommended Management of Common Opportunistic

Diseases in HIV Infection
- For patients diagnosed with an opportunistic infection
and HIV infection at the same time and a CD4+ count >50
cells/μL, one may consider a 2- to 4-week delay in the
initiation of antiretroviral therapy during which time
treatment is focused on the opportunistic infection

LEPROSY

Etiology, Pathogenesis, Diagnosis

Characteristics and Epidemiology of Mycobacterium leprae
- M. leprae
o Size: 1-8 um in length
o Diameter: 0.3 um

17
 o Obligate, intracellular, acid-fast staining, rods
o Dead organism: irregularly stained and fragmented or
granular
o Solid, viable bacilli: brightly & uniformly stained
o Mainly affects macrophages and Schwann cells
o Growth & reproduction
§ Never been grown in artificial media
§ Reproduce by binary fission
§ Grows slowly over 12-14 days in footpads of mice
§ Temperature required for survival and
proliferation is between 27-30*C
• Explains preference in skin, peripheral nerves,
testicles, and upper airways
o Remains viable for 9 days in the environment
- Ultrastructural Characteristics
o Cytoplasm: with structures common in gram-positive
microorganisms
o Plasma membrane: with permeable lipid bilayer
containing proteins (protein surface antigens)
o Cell wall:
§ Attached to the plasma membrane
§ Composed of peptidoglycans bound to branched-
chain polysaccharides
§ Peptidoglycans: arabinogalactans (support
mycolic acids) and lipoarabinomannan (LAM)
o Capsule
§ Outermost structure
§ With lipids (PGL-1) containing trisaccharides that
are antigenically specific for M. leprae and are
helpful for diagnosis of leprosy
- Genome of M. leprae
o 4 distinct strains originated in East Africa or Central
Asia
o Circular genome
o Molecular mass of 2.2 x 109 Da with 3,268,203 base
pairs, and a guanine-plus-cytosine content of 57.8%
- Culture difficulties
o Underwent reductive evolution, gene decay, and
genomewide downsizing
§ Smaller genome rich in inactive or entirely dead
genes
§ Longer generation time
§ Inability to culture leprosy bacillus in artificial
media
o Thus, propagation of M. leprae has been restricted to
animal models
o Growth in mouse footpads allows assessment of the
viability of the bacteria and testing the drug
susceptibility in clinical isolates
- Immunologic Properties
o Induces both humoral and cell-mediated immune
responses
o Immunogenic components
§ Polysaccharides
• Induce mainly humoral immune response
§ Proteins
• Induce both humoral and cell-mediated
immune responses
o Immunogens form 2 distinct groups
§ Cytoplasmic antigens
§ Antigens from the mycobacterial cell
- Sex: women > men
o Poor access to health services
o Illiteracy
o Low status
o Cultural factors
- Age: bimodal – teenage years & adulthood
o 8% in children < 15 years old
§ Indicates continued/recent transmission
o Rare in children < 5 years old
o 5% of all patients have a grade 2 disability
- Geographic distribution
o 80% in India, Brazil, and Indonesia
- Reservoirs
o Humans – reservoir of infection for M. leprae
o Armadillo – reservoir for human infection
- Incubation period
o Leprosy: 2 to > 10 years
o Multibacillary leprosy: 5 to > 10 years
o Paucibacillary leprosy: ~ 2-5 years
- Risk factors for leprosy
o Low level of education
o Poor hygiene
o Food shortages
- Most important risk factors
o Intimacy and duration of contact with leprosy patient
o In particular with an index case with multibacillary
leprosy
o Intensity of contact with and physical distance from
the index patient
- Genetic susceptibility
o Twins
Indices of Infection in Leprosy
- Morphologic index
o A measure of uniformly stained solid bacilli on slit-
skin smear examination
o Calculated as percentage of viable bacilli among the
total number of bacilli counted under oil-immersion
microscopy
o Slit-skin smear examination
§ Found in clumps or globi within macrophages
(lepra cells)
§ Inside lepra cells, M. leprae
• Multiplies in unrestricted fashion
• Arranged in parallel arrays placed side by side as
a result of the presence of surface lipids (glial
substances)
- Bacteriologic index
o A logarithmic-scaled measure of the density of
bacilli of all forms found in the dermis upon slit-skin
smear examination
18
 o Vary from 0 to 6+ (with or without globi) from the • Stained with Ziehl-Neelsen reagent and examined with a
light microscope
tuberculoid to the lepromatous end of the disease
• Bacteriologic index: determined with a standard
spectrum logarithmic scale and graded from 0-6
o Average of 1 log unit per year with multidrug • Microbiologic index: determined as the percentage of
solid, stained AFB
therapy
• To confirm diagnosis of leprosy, to classify the disease, to
Skin Biopsy support the diagnosis of reactions, and to determine cure
Approach to Diagnosis of Leprosy after the completion of multidrug therapy
- Clinical diagnosis – three cardinal signs: diagnosis can be • PGL-1 ELISA
o Used for serologic diagnosis of leprosy
established when 2/3 signs are present o Positive in 90-95% of multibacillary cases and in 25-
o Hypopigmented or erythematous skin lesion/s with PGL-1 60% of paucibacillary cases
definite loss or impairment of sensation Antibody Test • ML flow test
o For detection of AB to PGL-1
§ Skin patches or plaques with definite loss or o Positive in 92-97% of multibacillary cases and in 32-
impairment of sensation (light touch, pain, and/or 40% of paucibacillary cases
temperature) • Measures cellular immunity against lepromin
o Involvement of peripheral nerves demonstrated by • Provides information about the ability of an individual’s T
cells to respond to M. leprae and the likelihood of
definite thickening with sensory impairment granuloma formation in them
Lepromin
§ Thickening of peripheral nerve assessed by (MItsuda) Skin • Reaction to lepromin is measured as induration in mm 3-
palpation of the affected nerve and comparison Test 4 weeks after intradermal inoculation
• Negative test is seen in patients with LL or BL leprosy
with the corresponding contralateral nerve (lack of protective cellular response
• Multibacillary leprosy: bilateral
§ Nerve tenderness is established by application of
• Gene amplification enhances the detection of M. leprae
mild pressure on the nerve during palpation with PCR in bacteriologic index-negative leprosy and cases that do
the fingertips Technique not fulfill the criteria for the cardinal signs of leprosy
§ Peripheral nerves commonly palpated: DIAGNOSTIC TOOLS FOR NERVE FUNCTION IMPAIRMENT
• Great auricular, ulnar, radial, radial cutaneous,
median, lateral popliteal, posterior tibial, • Uses ulnar and median nerves and the posterior tibial
nerve
sural, and superficial peroneal nerves • Semmes-Weinstein monofilament test
o Positive AFB Touch
o Ballpoint pen can be used instead
§ Positive AFB in slit-skin smears o Stimulus is delivered by touching the test sites with
Sensation
the tip of ballpoint pen held at an angle of 45
§ Presence of AFB in a skin smear or biopsy sample Testing
degrees relative to the skin
§ Positive result in biopsy PCR • Impairment of < 6 months duration and/or new nerve
function impairment should be treated glucocorticoid
treatment
WHO Classification
PAUCIBACILLARY MULTIBACILLARY
(all of the following) (any one of the following) • Evaluates the motor function of hands and feet
• Muscle functions most affected in leprosy:
• 1-5 skin lesions • > 5 skin lesions
o Eye closure (facial nerve)
• Only 1 nerve trunk involved • > 1 nerve trunk involved Voluntary
o Finger abduction (ulnar nerve)
• (-) AFB in skin smears • (+) AFB in skin smears Muscle
o Thumb opposition (median nerve)
Testing
o Wrist extension (radial nerve)
WHO Disability Grading 1998 o Ankle extension (common peroneal nerve)
GRADE HANDS, FEET EYES • Strength is assed as strong, weak, or paralyzed
• No anesthesia, • No eye problems or evidence of Nerve • Can detect early signs of peripheral neuropathy
0
deformity or damage visual impairment Conduction • Sensory nerve conduction parameters are affected
• With anesthesia • With eye problems Test months ahead fo clinical tests
1 • No deformity or • Vision 6/60 or better, can count 6
• Palpable enlargement of peripheral nerves is one of the
damage fingers at 6 meters UTZ Testing of
cardinal signs of leprosy
• Severe visual impairment Nerves
• Can detect nerve enlargement accurately
• With visible • Iridocyclitis
2 • Doppler measurement of autonomic vasomotor reflexes
deformity or damage • Lagophthalmos
• Corneal opacities Doppler is a sensitive method for detection of peripheral
autonomic nerve damage

DIAGNOSTIC TOOLS
• Light touch: cotton wool or a feather Modes of Transmission
• Pain: ability to distinguish between sharp and blunt ends - Shed in large numbers from the mouth and nose of
Test of skin
of a wooden or bamboo toothpick
sensation
• Thermal sensation thresholds are assessed with patients with untreated multibacillary leprosy (droplet
computer-assisted sensory testing equipment infection)
• Taken from 4 sites: - From damaged skin
o Right earlobe
Slit-skin
o Forehead above the eyebrows
- Human-to-human transmission
Smear
o Chin - Zoonotic transmission through wild armadillos
o Left buttock (men) or left upper thigh (women - Enters the body through the respiratory tract or through
skin (wounds or tattoos)

19
 o Fever, malaise, edema of hands & feet
Clinical Features, Disease Spectrum - Type 2 Leprosy Reaction (T2R)
The Various Spectrum of Leprosy based on Clinical, o Aka ENL (erythema nodosum leprosum)
Bacteriologic, Pathologic and Immunologic Parameters o Pathogenesis
Tuberculoid Leprosy Borderline Leprosy Lepromatous Leprosy § Immune complex-mediated syndrome
TT BT BB BL LL
§ Causes inflammation of skin, nerves, and other
organs & general malaise
Clinical Stable Unstable Stable
§ An example of type III hypersensitivity reaction
Immunologic
resistance
Strongest <-> Weakest
(Coombs and Gell classification) or Arthus
• Symmetric, poorly
marginated infiltrated phenomenon
• Sharply defined annular
asymmetric • Ill-defined plaques with
nodules/plaques or
diffuse infiltration
§ Occur mostly during multidrug therapy but also in
Skin lesions macules/plaques with
central clearing •
occasional sharp margins
Few or many in numbers
• Xanthoma-like or
dermatofibroma
untreated patients
• Elevated borders papules o Skin lesions
• Leonine facies
• Eyebrow alopecia § Evanescent, pink-to-red maculopapular, popular,
Nerve lesions
•
•
Sometimes enlarged
Abscesses most common
• Nerve trunk palsies
•
•
Nerve palsies variable
Acral, distal, symmetric
nodular, or plaque lesions
• At times symmetric
in BT anesthesia common § On the outer aspects of thighs, legs, face
Single or
# of lesions Single
few
Several Many Very many
§ Painful/tender and warm
Hypoesthesia
Sensation Anesthetic (absent) early Hypoesthetic or anesthetic
(late sign) § Blanch with light finger pressure
AFB 0-1 + 3-5 + 4-6 (plus globi) § Lasts for a few days
Lymphocytes 2 1 0-1
§ Lesions change in color from pink/red to bluish
Macrophage Undiff or and brownish after 24-48h and turn dark in a
Epithelioid Foamy changes
differentiation
Langerhans
foamy
week
1-3 0
giant cells § Erythema nodosum necroticans
Strong Weak
Lepromin test
(+++) (++)
Negative • Vesicular, pustular, bullous, and necrotic
Lymphocyte
transformation
Positive 1-10% 1-2% • Breaks down to produce ulceration
o Constitutional symptoms
• TT (tuberculoid): strong cell-mediated immunity, stable but does not downgrade, may undergo spontaneous cure in 3 years
§ Malaise and fever
•
•
BT (borderline tuberculoid): immunity strong enough to contain infection, unstable
BB (borderline): immunologic midzone
§ With/without painful joint swelling
•
•
BL (borderline lepromatous): low immunity to contain infection resulting in destructive inflammation
LL (lepromatous): lack of cell-mediated immunity permits bacillary dissemination resulting in multiorgan involvement
o Other associated signs
§ LN enlargement, myositis, arthritis, synovitis
§ Rhinitis, epistaxis, laryngitis, iridocyclitis
§ Glaucoma, painful dactylitis
§ Acute epididymoorchitis
Clinical and Pathologic Features of Various Reactional States § Nephritis and renal failure
in Leprosy § Splenomegaly, anemia, amyloidosis (late)
- Type 1 Leprosy Reaction (T1R) o Nerves
o Aka reversal reaction d/t upgrading of CM1 status § Severe T2R: swollen, painful, tender nerve trunks
o Pathogenesis with sensory and motor deficits
§ Delayed hypersensitivity reaction with sudden
alteration of CM1 status Characteristics of Specific Tissue/Organ Involvement
§ Leads to left shift in patient’s position on the - Lucio’s Phenomenon
leprosy spectrum o Seen in diffuse leprosy of Lucio and Latapi
§ Marked infiltration of lesions by activated CD4+ T o A variant of erythema nodosum necroticans
lymphocytes (T helper cells) o Marked vasculitis and thrombosis of the superficial
o Observed in the borderline portion of spectrum and deep vessels result in hemorrhage and infarction
o Skin lesions of the skin
§ Acute swelling and redness o Skin reaction
o Nerves § Begins as slightly indurated, bluish-red, ill-
§ Painful and tender d/t neuritis defined, painful
§ With nerve damage and disfigurement - Nerve function impairment, neuritis, disfigurement
§ Nerve abscess in severe T1R o These terms are used interchangeably for the
§ Silent neuritis sensory, motor, and/or autonomic nerve deficits that
• Loss of nerve function is less obvious when it occur because of the pathologic process resulting
occurs without other signs of inflammation from M. leprae infection of the nerve
• Leads to sensory and motor impairment in o Neuritis
hands, feet, and face § Nerve inflammation
o Arthralgia or arthritis; tenosynovitis

20
 § Subacute, demyelinating, and unremitting event • Acts by blocking folic acid • Mild hemolysis (anemia)
synthesis and is only weakly • Psychosis
involving cutaneous nerves and larger peripheral bactericidal • G6PD
nerves • DDS syndrome (dapsone
§ Silent neuritis or quite nerve paralysis hypersensitivity syndrome)
o Fever, skin rash, LAD,
• A progressive sensory or motor impairment in
eosinophilia, hepatitis,
the absence of symptoms (paresthesia, pain, encephalopathy
or tenderness of the nerves and larger o Erythema multiforme, SJS, toxic
epidermal necrolysis, exfoliative
peripheral nerves)
dermatitis
§ Can occur any time during leprosy but is more • Rare: agranulocytosis, hepatitis,
common and severe during leprosy reactions cholestatic jaundice
(mainly in T1R)
o Sensory and motor neuropathy
§ Leads to secondary impairments in UE & LE
• Muscle atrophy CLOFAZIMINE
• Mobile and fixed joint contractures • Weak bactericidal action • Skin discoloration (red to purple or
black; dose-dependent)
• Bone absorption of digits
• Pink urine, sputum, sweat
• Cracks and wounds • Ichthyosis on shins & forearm
• Mild cramps, diarrhea
Treatment • Weight loss

WHO Treatment Recommendation Based on the

Form/Spectrum of Leprosy LEPTOSPIROSIS

Mechanisms and Adverse Effects of Various Drugs Used
for Leprosy
MECHANISM OF ACTION
RIFAMPIN
• Act by inhibiting DNA-dependent
RNA polymerase, thereby
interfering with bacterial RNA
synthesis
DAPSONE
Epidemiology, Pathogenesis
Characteristics and Sources of Transmission of Etiologic
Agent
- Leptospira species (Spirochetes)
o Order Spirochaetales
o Family Leptospiraceae
o Genus Leptospira comprised 2 species
§ Pathogenic L. interrogans (L. interrogans sensu
lato)
§ Free-living L. biflexa (L. biflexa sensu lato)
o 64 Leptospira species
§ Pathogenic (17 species)
§ Intermediate (21 species)
§ Nonpathogenic (26 species)
o Size: 6-20 yum long
o Diameter: ~0.1 um
o Coiled, thin, highly motile organism
o With hooked ends and 2 periplasmic flagella
o With polar extrusions from the cytoplasmic
membrane (responsible for motility)
o Stain poorly but seen microscopically by dark-field
examination and after silver impregnation staining of
tissues
o Requires special media and conditions for growth
o May take weeks-months for cultures to become
positive
- Transmission
ADVERSE EFFECT
o Exposure to environmental contamination (more
• Hepatotoxicity common)
• Mild transient elevation of hepatic o Direct contact with urine, blood or tissue from an
aminotransferases
• Urine discoloration
infected animal
o Human-to-human transmission is rare
o Through cuts, abraded skin, or mucus membranes
(conjunctival and oral mucosa)
o Water is an important vehicle for transmission

21
 - Thrombocytopenia
Pathogenesis of Leptospirosis o Platelet consumption
- Consumptive coagulopathy
o Elevated markers of coagulation activation
(thrombin-antithrombin complexes, prothrombin
fragments 1 and 2, C)
o Diminished anticoagulant markers (antithrombin,
protein C)
o Deregulated fibrinolytic activity
o Overt DIC
- Elevated plasma levels of soluble E-selectin and von
Willebrand factor
o Reflects endothelial cell activation
- Pathogenic leptospires or leptospiral proteins
o Activates endothelial cells in vitro
o Disrupts endothelial-cell barrier function and
promote dissemination
- Platelets aggregate on activated endothelium
o Histology: swelling of activated endothelial cells; no
evident vasculitis or necrosis
- Immunoglobulin and complement deposition in lung
tissue involved in pulmonary hemorrhage

- Renal pathology
o Acute tubular damage and interstitial nephritis
o Acute tubular lesions progress to interstitial edema
and acute tubular necrosis
o Severe nephritis
§ In patients who survive long enough to develop it
§ A secondary response to acute epithelial damage
o Impaired Na absorption, tubular K wasting, and
polyuria
§ Due to deregulation of the expression of
transporters along the nephron
- Liver pathology
o Focal necrosis
§ Widespread hepatocellular necrosis is usually not
found
o Foci of inflammation
o Plugging of bile canaliculi
o Hepatocyte apoptosis
o Infiltration of Disse space (perisinusoidal space) and Temporal Pattern of Detection of Leptospires in Blood, CSF,
migration between hepatocytes with detachment of and Urine
intercellular junctions and disruption of bile canaliculi - Incubation period: 1-2 weeks (2-30 days)
à bile leakage - Biphasic
- Petechiae and hemorrhages o Acute leptospiremic phase
o Heart § Fever of 3-10 days duration
o Lungs § Organisms can be cultured from blood and
o Kidneys and adrenals detected by PCR
o Pancreas o Immune phase
o Liver § Resolution of symptoms coincide with
o GIT (retroperitoneal fat, mesentery, omentum) appearance of antibodies
o Muscles § Leptospires can be cultures from urine
o Prostate - Leptospira can be cultured from the CSF in the early
o Testes phase
o Brain (subarachnoid bleeding)

22
 - Milder cases do not always include the second phase - Case-fatality rate: 1-50%
- Severe disease may be monophasic and fulminant - Higher mortality rates:
o Age > 40 years
Clinical Manifestations, Diagnosis o Altered mental status
Clinical Features of Mild Leptospirosis o Acute renal failure
- Most are asymptomatic or only mildly ill and do not seek o Respiratory insufficiency
medical attention o Hypotension
o Serologic evidence of past inapparent infection is o Arrhythmias
frequently found in persons who have been exposed - Weil’s syndrome – classic triad:
but have not become ill o Hemorrhage
- Symptomatic o Jaundice
o Flu-like illness with sudden onset o Acute kidney injury
o Fever - Hemorrhage: death is due to septic shock with
o Chills multiorgan failure and/or severe bleeding complications
o Headache o Lungs: Pulmonary Hemorrhage
§ Intense § A widespread public health problem
§ Localized to the frontal or retroorbital region § With or without jaundice
(resembles that occurring in dengue) § Cough
§ Sometimes with photophobia § Chest pain
o Nausea § Respiratory distress
o Vomiting § Hemoptysis (may not be apparent until patients
o Abdominal pain are intubated)
o Conjunctival suffusion (redness without exudate) o GIT: melena, hemoptysis
o Myalgia o Urogenital tract: hematuria
§ Intense muscle pain o Skin: petechiae, ecchymosis, bleeding from
§ Affects calves, back, and abdomen venipuncture sites
o CNS - Jaundice (5-10%)
§ Aseptic meningitis o Can be profound and give an orange cast to skin
• More common in children than adults o Not usually associated with fulminant hepatic
§ Majority of cases follow a benign course necrosis
§ CNS symptoms disappear within a few days but o PE: enlarged and tender liver
may persist for weeks - Acute kidney injury
- Physical examination o Common in severe disease
o Fever o Presents after several days of illness
o Conjunctival suffusion o Can be either nonoliguric or oliguric
o Pharyngeal injection o Electrolyte abnormalities
o Muscle tenderness § Hypokalemia
o Lymphadenopathy § Hyponatremia
o Rash § Low magnesium in urine is associated with
§ Often transient leptospiral nephropathy
§ Macular, maculopapular, erythematous, or o Hypotension is associated with:
hemorrhagic (petechial or ecchymotic) § Acute tubular necrosis
§ May be misdiagnosed as d/t scrub typhus or viral § Oliguria
infection § Anuria
o Meningismus o Hemodialysis is lifesaving
o Hepatomegaly § Renal function return to normal in survivors
o Splenomegaly - Leptospiral meningitis
o Crackles on lung auscultation o Altered mental status
o Mild jaundice o Diagnosis is challenging
- Spontaneous resolution within 7-10 days § Patients may be anicteric or lack other diagnostic
o But symptoms may persist hallmarks of severe leptospirosis
- Mortality: low o Neurologic sequelae are described months after
o In absence of a clinical diagnosis and antimicrobial acute illness
therapy o Without antibiotics à mortality rate: 13%
o With antibiotics à mortality rate: 2%
Clinical Features of Severe Leptospirosis/Weil’s Syndrome - Other syndromes
- Often rapidly progressive o Pancreatitis (necrotizing)

23
 o Cholecystitis
o Skeletal muscle involvement
o Rhabdomyolysis with moderately elevated serum
creatinine kinase levels
- Cardiac involvement
o ECG: nonspecific ST and T wave changes
o Poor prognosis: repolarization abnormalities and
arrhythmias
o Myocarditis
- Rare hematologic complications
o Hemolysis
o Thrombotic thrombocytopenic purpura
o Hemolytic-uremic syndrome
- Long-term symptoms after severe leptospirosis
o Fatigue, myalgia, malaise, and headache
o May persist for years
o Autoimmune-associated uveitis (chronic condition)
Approach to the Diagnosis of Leptospirosis
- Clinical diagnosis: exposure history + any protean
manifestations of the disease
o Returning travelers from endemic areas
§ History of recreational freshwater activities or
other mucosal or percutaneous contact with
contaminated surface waters or soil
o Nontravelers
§ Recreational or accidental water/soil contact
§ Occupational hazards that involve direct or
indirect animal contact
- Nonspecific biochemical, hematologic, and urinalysis
findings in acute leptospirosis
- CBC
o Signs of bacterial infection
§ Leukocytosis with left shift
§ Elevated CRP, procalcitonin, ESR
o Thrombocytopenia (platelet < 100 x109/L)
§ Common and associated with bleeding and renal
failure
o Severe: signs of coagulation activation
- Kidneys
o Mild
§ Urinary sediment changes: leukocytes,
erythrocytes, and hyaline/granular cells
§ Mild proteinuria
o Severe
§ Renal failure and azotemia
o Nonoliguric hypokalemic renal insufficiency
o High serum bilirubin levels
o Moderate AST, ALT, and alkaline phosphatase
- Pancreas
o Elevated amylase levels
o Symptoms of pancreatitis are not common
- Meningitis
o CSF
§ Pleocytosis: few cells to > 1000 cells/uL with
lymphocytic predominance
§ Predominant PMN pleocytosis
• Related to the timing of LP: PMN cells are
found in early disease and are later replaced
by lymphocytes
§ Normal glucose levels
§ Normal/slightly elevated protein levels
- Pulmonary radiographic abnormalities
o Most common: patchy bilateral alveolar pattern
§ Corresponds to scattered alveolar hemorrhage
§ Affects the lower lobes
o Pleura-based densities (areas of hemorrhage)
o Diffuse ground-glass attenuation typical of ARDS
- Definitive diagnosis
o Isolation of organism from the patient
o A positive result in the PCR
o Seroconversion or a rise in antibody titer
- Standard serologic procedures
o MAT
o ELISA
- MAT
o Single antibody titer of 1:200-1:800 is required
§ Depending on whether the case occurs in a low or
high endemic area
o Uses a battery of live leptospiral strains
o Used for determination of antibody titer and for
tentative identification of the involved leptospiral
group and the putative serovar
o Cross-reactions occur frequently
o Lacks sensitivity in the early acute phase of disease
(up to day 5) and thus cannot be used as basis for a
timely decision about whether to start treatment
- ELISA: uses a broadly reacting antigen
- PCR: confirms the diagnosis of leptospirosis with a high
degree of accuracy during the first 5 days of illness
Management
Treatment Recommendations in Mild and Moderate/Severe
Leptospirosis
24
 • Single exposure*
• With wounds, cuts, or • 200 mg OD for 3-5 days
open skin lesions • Given within 24-72 h
• Accidental ingestion of from exposure
contaminated water
HIGH-RISK EXPOSURE
• Continuous exposure**
• With or without wounds,
cuts, or open skin lesions
• Swimming in flooded • 200 mg once weekly until
waters, especially if the end of exposure
infested with sewer rats
and ingestion of
contaminated water

* Single exposure: history of wading in flood or

contaminated water
** Continuous exposure: > 1 exposure or several days (e.g.,
Source: Leptospirosis CPG, 2010 residing in flooded areas, rescuers, relief workers)

- In regions where rickettsia diseases are coendemic

o Doxycycline
o Azithromycin
- Jarisch-Herxheimer reaction
o Develops within hours after initiation of
antimicrobial therapy in rare instances
Supportive Therapy in Severe Leptospirosis
- Nonoliguric renal dysfunction
o Aggressive fluid and electrolyte resuscitation
o To prevent dehydration and precipitation of oliguric
renal failure
- Oliguric renal failure
o Peritoneal dialysis or hemodialysis
o Rapid initiation of HD reduces mortality risk and is
necessary only for short periods
- Pulmonary hemorrhage
o Mechanical ventilation with low TV to avoid high
ventilation pressures
Role/indication of Chemoprophylaxis
- Most effective measure is avoidance of high-risk
exposure and use of protective equipment
- There is no current recommended pre-exposure
prophylaxis for pregnant/lactating women
- Doxycycline
o Recommended post-exposure prophylactic agent,
but is not 100% effective
o Contraindicated in pregnancy
Prognosis of Leptospirosis
- Most patients with leptospirosis recover
- Post-leptospirosis symptoms may occur and persist for
years after acute disease
- Mortality rates are highest:
o Elderly
o Severe disease (pulmonary hemorrhage, Weil’s
syndrome)
- Leptospirosis during pregnancy is associated with high
fetal mortality rates
- Long-term follow up of patients with renal failure and
hepatic dysfunction has documented good recovery of
renal and hepatic function
MALARIA
Etiology, Pathogenesis, Epidemiology
Various Species Associated with Malarial Infection in Humans
and Their Characteristics

DEFINITION DOXYCYCLINE DOSE

LOW-RISK EXPOSURE
• Single exposure* • 200 mg single dose
• No wounds, cuts, or open • Given within 24-72 h
skin lesions from exposure
MODERATE-RISK EXPOSURE

25
Pathogenesis of Malarial Infection
- Pre-erythrocytic
o Human infection begins when a female anopheline
mosquito inoculates plasmodial sporozoites from its
salivary glands during a blood meal → motile forms of
the malaria parasite are carried rapidly via the
bloodstream to the liver → invade hepatic
parenchymal → begin a period of asexual
reproduction → intrahepatic or preerythrocytic
schizogony → single sporozoite may produce from
10,000 to >30,000 daughter merozoites
- Asexual Erythrocytic
o few swollen infected liver cells eventually burst →
discharging motile merozoites into the bloodstream
→ invade red blood cells (RBCs) to become
trophozoites → multiply six- to twentyfold every 48 h
(P. knowlesi, 24 h; P. malariae, 72 h) → parasites
reach densities of ~50/μL of blood → symptomatic
stage of the infection begins → attachment of
merozoites to erythrocytes → trophozoites enlarge,
species-specific characteristics become evident,
malaria pigment (hemozoin) becomes visible →
parasite assumes an irregular or ameboid shape →
consumed two-thirds of the RBC’s hemoglobin and
occupies most of the cell and is called a schizont →
infected RBC then ruptures to release 6–30 daughter
merozoites → invading a new RBC and repeating the
cycle
▪ in P. vivax and P. ovale, a proportion remain
dormant or called or hypnozoites (cause of the
relapses)
- Transmission and Sporogony
o Some of the blood-stage parasites develop into
morphologically distinct, longer-lived sexual forms
called gametocytes → ingested in the blood meal of a
biting female anopheline mosquito → male
gametocyte exflagellates and divides rapidly into
eight motile male gametes → fuse with female
gametocytes → undergoing meiosis to form a zygote
in the insect’s midgut → matures into an ookinete →
penetrates and encysts in the mosquito’s gut wall →
oocyst expands by asexual division until it bursts to
liberate myriad motile sporozoites → migrate in the
hemolymph to the salivary gland of the mosquito to
await inoculation into another human
Definition of Endemicity
- Endemicity traditionally has been defined in terms of
rates of microscopy-detected parasitemia or palpable
spleens in children 2–9 years of age and has been
classified as hypoendemic (<10%), mesoendemic (11–
50%), hyperendemic (51–75%), and holoendemic
(>75%).
- In holo- and hyperendemic areas where there is intense
P. falciparum transmission, people may sustain one or
more infectious mosquito bites per week and are
infected repeatedly throughout their lives.
o malaria morbidity and mortality are substantial
during early childhood
o Immunity is hard following repeated symptomatic
infections in childhood, but, if the child survives,
infections become increasingly likely to be
asymptomatic.
Determinants of Epidemiology of Malaria
- The principal determinants of the epidemiology of
malaria are the number (density), the human-biting
habits, and the longevity of the anopheline mosquito
vectors. More than 100 of the >400 anopheline species
can transmit malaria, but the ~40 species that do so
commonly vary considerably in their efficiency as malaria
vectors
- The transmission of malaria is directly proportional to the
density of the vector, the square of the number of human
bites per day per mosquito, and the tenth power of the
probability of the mosquito surviving for 1 day.
- In order to transmit malaria, the mosquito must
therefore survive for >7 days.
- Sporogony is not completed at cooler temperatures—
i.e., <16°C (<60.8°F) for P. vivax and <21°C (<69.8°F) for
P. falciparum
Pathology, Host Response
Erythrocytic Change in Malaria
- After invading an erythrocyte, the growing malarial
parasite progressively consumes and degrades
intracellular proteins, principally hemoglobin.
o toxic heme is detoxified by lipid-mediated
crystallization to biologically inert hemozoin (malaria
pigment).
- The parasite also alters the RBC membrane and becomes
more irregular in shape, more antigenic, and less
deformable.
- In P. falciparum infections, membrane protuberances
appear on the erythrocyte’s surface 12–15 h after cell
invasion.
o extrude a high-molecular-weight, antigenically
variant, strain-specific erythrocyte membrane
adhesive protein (PfEMP1) that mediates attachment
26
 to receptors on venular and capillary endothelium
(cytoadherence).
o Erythrocytes containing more mature parasites stick
inside and eventually block capillaries and venules.
o These infected RBCs may also adhere to uninfected
RBCs (to form rosettes) and to other parasitized
erythrocytes (agglutination).
o They result in the sequestration of infected RBCs in
vital organs (particularly the brain), where they
interfere with microcirculatory flow and metabolism.
o In severe malaria, uninfected erythrocytes also
become less deformable, which compromises their
passage through the partially obstructed capillaries
and venules and shortens their survival. In the other
human malarias, significant sequestration does not
occur, and all stages of the parasite’s development
are evident on peripheral-blood smears.
- P. vivax and P. ovale show a marked predilection for
young RBCs and P. malariae for old cells
- P. falciparum can invade erythrocytes of all ages and may
be associated with very high parasite densities.
- Dangerously high parasite densities may also occur in P.
knowlesi infections, with rapid increases as a result of the
shorter (24-h) asexual life cycle.
Nonspecific Host Defense to Malaria
- Host responds to malaria infection by activating
nonspecific defense mechanisms.
- The spleen removes damaged ring-form parasites (a
process known as “pitting”) from within the red cell and
returns the once-infected cells back to the circulation,
where their survival is shortened.
o The parasitized cells escaping splenic removal are
destroyed when the schizont ruptures.
▪ material released induces monocyte/macrophage
activation and the release of proinflammatory
cytokines, which cause fever and other pathologic
effects.
o Temperatures of ≥40°C (≥104°F) damage mature
parasites;
▪ In untreated infections, the effect of such
temperatures is to further synchronize the
parasitic cycle, with eventual production of the
regular fever spikes and rigors that originally
characterized the different malarias.
▪ These regular fever patterns (quotidian, daily;
tertian, every 2 days; quartan, every 3 days) are
seldom seen today as patients receive prompt and
effective antimalarial treatment.
Genetic Disorders That Confer Protection Against Severe
Malaria
- Thalassemias, Sickle cell disease, Hemoglobins C and E,
Hereditary ovalocytosis, and Glucose-6 phosphate
Dehydrogenase (G6PD) deficiency
Immune Response to Malaria
- Nonspecific host defense mechanisms stop the
infection’s expansion, and the subsequent strain-specific
immune response then controls the infection.
- Exposure to sufficient strains confers protection from
high-level parasitemia and disease but not from
infection.
- As a result, premunition or asymptomatic parasitemia is
very common among adults and older children living in
regions with stable and intense transmission (i.e., holo-
or hyperendemic areas)
o Parasitemia in asymptomatic fluctuates in density but
often averages ~5000/mL—just below the level of
microscopy detection but sufficient to generate
transmissible densities of gametocytes.
- Immunity is mainly specific for both the species and the
strain of infecting malarial parasite.
- Immune individuals have a polyclonal increase in serum
levels of IgM, IgG, and IgA, although much of this
antibody is unrelated to protection.
- Passive transfer of maternal antibody contributes to the
partial protection of infants from severe malaria in the
first months of life. This complex immunity to disease
declines when a person lives outside an endemic area for
several months or longer.
Clinical Features, Diagnosis
Clinical features of malarial infection
- Initial constitutional symptoms
o The first symptoms of malaria are nonspecific; the
lack of a sense of well-being, headache, fatigue,
abdominal discomfort, and muscle aches followed by
fever are all similar to the symptoms of a minor viral
illness.
o Nausea, vomiting, and orthostatic hypotension are
common.
o The classic malarial paroxysms, in which fever spikes,
chills, and rigors occur at regular intervals, are
unusual and at presentation suggest infection (often
relapse) with P. vivax or P. ovale. The fever is usually
irregular at first (that of falciparum malaria may never
become regular). The temperature of nonimmune
individuals and children often rises above 40°C
(104°F), with accompanying tachycardia and
sometimes delirium.
- Manifestations of severe falciparum malaria
o Cerebral Malaria
▪ manifests as a diffuse symmetric encephalopathy;
focal neurologic signs are unusual; some passive
resistance to head flexion may be detected, signs
of meningeal irritation are absent; corneal
reflexes are preserved, except in deep coma;
tendon reflexes are variable, and the plantar
reflexes may be flexor or extensor; the abdominal
and cremasteric reflexes are absent; ~15% of
patients have retinal hemorrhages; with pupillary
27
 dilation and indirect ophthalmoscopy, this figure ● results from both shortened survival of
increases to 30–40% uninfected RBCs and marked
▪ Convulsions, which are usually generalized and dyserythropoiesis.
often repeated, occur in ~10% of adults and up to ▪ Slight coagulation abnormalities are common in
50% of children with cerebral malaria falciparum malaria, and mild thrombocytopenia is
▪ The majority of these deficits improve markedly usual (a normal platelet count should question
or resolve completely within 6 months the diagnosis of malaria).
o Hypoglycemia o Liver Dysfunction
▪ associated with a poor prognosis; results from ▪ Mild hemolytic jaundice is common in malaria.
both a failure of hepatic gluconeogenesis and an ▪ Severe jaundice is associated with P. falciparum
increase in the consumption of glucose by the infections
host and, to a much lesser extent, the malaria ● more common among adults than among
parasites children
o Acidosis ● results from hemolysis, hepatocyte injury, and
▪ from accumulation of organic acids, is an cholestasis.
important cause of death from severe malaria ▪ When accompanied by other vital-organ
compounded by coexisting renal impairment dysfunction (often renal impairment), liver
▪ Acidotic breathing, sometimes called “respiratory dysfunction carries a poor prognosis.
distress,” is a sign of poor prognosis.
▪ Lactic acidosis is caused by the combination of
anaerobic glycolysis in tissues where sequestered
parasites interfere with microcirculatory flow,
lactate production by the parasites, and a failure
of hepatic and renal lactate clearance.
o Renal Impairment
▪ Acute kidney injury is common in severe
falciparum malaria.
▪ The pathogenesis may be related to erythrocyte
sequestration and agglutination interfering with
renal microcirculatory flow and metabolism.
▪ Syndrome manifests as acute tubular necrosis.
▪ In survivors, urine flow resumes in a median of 4
days, and serum creatinine levels return to normal
in a mean of 17 days
▪ Early dialysis or hemofiltration considerably
improves the chances of survival, particularly in
acute hypercatabolic renal failure. Oliguric renal
failure is rare among children.
o Hematologic Abnormalities
▪ Anemia results from accelerated RBC removal by
the spleen, obligatory RBC destruction at parasite
schizogony, and ineffective erythropoiesis.
▪ A hemoglobin of ≤3g/dL on presentation is
associated with increased mortality.
▪ Acute hemolytic anemia with massive
hemoglobinuria (“blackwater fever”) may occur.
▪ Hemoglobinuria may contribute to renal injury.
▪ In non-immune patients sudden hemolysis may
follow many days after artesunate treatment of
hyperparasitemia, usually as a result of relatively
synchronous loss of once-parasitized “pitted”
RBCs.
▪ As a consequence of repeated malarial infections,
children in high-transmission areas are usually
anemic and often develop severe anemia.

28
- Features associated with poor prognosis in severe parasitemias complicated by anemia, hypoglycemia,
falciparum malaria and acute pulmonary edema.
o Fetal distress, premature labor, and stillbirth or low
birth weight are common results.
o Congenital malaria occurs in <5% of newborns of
infected mothers; its frequency and the level of
parasitemia are related directly to the timing of
maternal infection and the parasite density in
maternal blood and in the placenta.

- Transfusion malaria
o Malaria can be transmitted by blood transfusion,
needlestick injury, or organ transplantation.
o The incubation period in these settings is often short
because there is no preerythrocytic stage of
development, and thus there are no relapses of P.
vivax and P. ovale infections.
o Primaquine is not needed for vivax or ovale malaria
as there are no liver stages.

Chronic complications of malaria

- Hyperreactive Malarial Splenomegaly
o Chronic or repeated malarial infections produce
hypergammaglobulinemia; normochromic,
normocytic anemia and splenomegaly
o This syndrome has been associated with the
production of cytotoxic IgM antibodies to CD8+ T
lymphocytes, antibodies to CD5+ T lymphocytes, and
an increase in the ratio of CD4+ to CD8+ T cells.
o These events may lead to uninhibited B cell
production of IgM and the formation of cryoglobulins
(IgM aggregates and immune complexes).
▪ stimulates lymphoid hyperplasia and clearance
activity and eventually produces splenomegaly.
o Patients present with an abdominal mass or a
dragging sensation in the abdomen and occasional
sharp abdominal pains suggesting perisplenitis. There
is usually anemia and some degree of pancytopenia
(hypersplenism).
- Malaria in pregnancy
o In some cases, malaria parasites cannot be found in
o Malaria in early pregnancy causes fetal loss.
peripheral-blood smears by microscopy.
o In areas of high malaria transmission, falciparum
o Respiratory and skin infections are common and
malaria in primi- and secundi gravid women is
many patients die of overwhelming sepsis.
associated with low birth weight (average reduction,
o Persons with hyperreactive malarial splenomegaly
~170 g) and consequently increased infant mortality
living in endemic areas should receive antimalarial
rates.
chemoprophylaxis; the results are usually good.
o Infected mothers in areas of stable transmission
o In nonendemic areas, antimalarial treatment is
remain asymptomatic despite intense accumulation
advised. Some cases have been mistaken for
of parasitized erythrocytes in the placental
hematologic malignancy.
microcirculation.
- Quartan Malarial Nephropathy
o Maternal HIV infection predisposes pregnant women
o Chronic or repeated infections with P. malariae (and
to more frequent and higher-density malaria
possibly with other malarial species) may cause
infections, predisposes their newborns to congenital
soluble immune complex injury to the renal
malarial infection, and exacerbates the reduction in
glomeruli, resulting in the nephrotic syndrome.
birth weight associated with malaria.
▪ The histologic appearance is that of focal or
o In areas with unstable transmission of malaria,
segmental glomerulonephritis with splitting of the
pregnant women are prone to severe infections and
capillary basement membrane.
are particularly likely to develop high P. falciparum

29
 ▪ Subendothelial dense deposits are seen on
electron microscopy, and immunofluorescence
reveals deposits of complement and
immunoglobulins and P. malariae antigens are
often visible.
▪ A coarse-granular pattern of basement
membrane immunofluorescent deposits
(predominantly IgG3) with selective proteinuria
carries a better prognosis than a fine-granular,
predominantly IgG2 pattern with nonselective
proteinuria.
▪ It usually responds poorly to treatment with
either antimalarial agents or glucocorticoids and
cytotoxic drugs.
- Burkitt’s Lymphoma and Epstein-Barr Virus Infection
o It is possible that malaria-related immune
dysregulation provokes infection with lymphoma
viruses.
o Childhood Burkitt’s lymphoma is strongly associated
with Epstein-Barr virus (EBV) and with high
transmission of P. falciparum.
Approach to diagnosis of malaria
- Demonstration of parasite
o definitive diagnosis of malaria rests on the
demonstration of asexual forms of the parasite in
stained peripheral-blood smears
o Of the Romanowsky stains, Giemsa at pH 7.2 is
preferred; Field’s, Wright’s, or Leishman’s stain can
also be used. Staining of parasites with the
fluorescent dye acridine orange allows more rapid
diagnosis of malaria (but not speciation of the
infection) in patients with low-level parasitemia.
o Both parasites and white blood cells (WBCs) are
counted, and the number of parasites per unit
volume is calculated from the total leukocyte count.
o Before a thick smear is judged to be negative, 100–
200 fields should be examined.
o In high-transmission areas, the presence of up to
10,000 parasites/μL of blood may be tolerated
without symptoms or signs in partially immune
individuals.
o Rapid, simple, sensitive, and specific antibody-based
diagnostic stick or card tests that detect P.
falciparum–specific, histidine-rich protein 2 (PfHRP2),
lactate dehydrogenase, or aldolase antigens in finger-
prick blood samples are now being used widely in
control programs
o In severe malaria, a poor prognosis is indicated by a
predominance of more mature P. falciparum
parasites (i.e., >20% of parasites with visible pigment)
in the peripheral-blood film or by the presence of
phagocytosed malarial pigment in >5% of neutrophils
(an indicator of recent schizogony).
o Molecular diagnosis by polymerase chain reaction
(PCR) amplification of parasite nucleic acid is more
sensitive than microscopy or rapid diagnostic tests for
detecting malaria parasites and defining malarial
species.
o Serologic diagnosis with either indirect fluorescent
antibody or enzyme-linked immunosorbent assays is
useful for screening of prospective blood donors and
may prove useful as a measure of transmission
intensity in future epidemiologic studies. Serology
has no place in the diagnosis of acute illness.
30
 - Laboratory Findings in Malaria Adverse effects of commonly used anti-malarial drugs
o Normochromic, normocytic anemia is usual. The
leukocyte count is generally normal, although it may
be raised in very severe infections.
o There is slight monocytosis, lymphopenia, and
eosinopenia, with reactive lymphocytosis and
eosinophilia in the weeks after acute infection.
o The platelet count is usually reduced to ~105/μL.
o The erythrocyte sedimentation rate, plasma viscosity,
and levels of C-reactive protein and other acute-
phase proteins are elevated.
o Antithrombin III levels are reduced even in mild
infection.
o Findings in severe malaria may include metabolic
acidosis, with low plasma concentrations of glucose,
sodium, bicarbonate, phosphate, and albumin,
together with elevations in lactate, BUN, creatinine,
urate, muscle and liver enzymes, and conjugated and
unconjugated bilirubin
o In adults and children with cerebral malaria, the
mean cerebrospinal fluid (CSF) opening pressure at
lumbar puncture is ~160 mm H2O; usually the CSF
content is normal or there is a slight elevation of total
protein level (<1.0 g/L [<100 mg/dL]) and cell count
(<20/μL).

Management, Prognosis
Recommended treatment based on the type of malarial
disease

Complications of severe malaria

- Acute Renal Failure
o Fluid administration should be restricted to prevent
volume overload.
o As in other forms of hypercatabolic acute renal
failure, renal replacement therapy is best performed
early
o Hemofiltration and hemodialysis are more effective
than peritoneal dialysis and are associated with lower
mortality risk. Renal function usually improves within
days, but full recovery may take weeks.
- Acute Respiratory Distress Syndrome
o Caused by increased pulmonary capillary
permeability.

31
 o Patients should be positioned with the head of the
bed at a 45° elevation and should be given oxygen
and IV diuretics.
o Positive-pressure ventilation should be started early
if the immediate measures fail
o Rarely, may require extracorporeal membrane
oxygenation.
- Hypoglycemia
o An initial slow injection of 20% dextrose (2 mL/kg
over 10 min) should be followed by an infusion of 10%
dextrose (0.10 g/kg per hour).
o The blood glucose level should be checked regularly
as recurrent hypoglycemia is common, particularly
among patients receiving quinine
- Sepsis
o Hypoglycemia or gram-negative septicemia should be
suspected when the condition of any patient
suddenly deteriorates for no obvious reason during
antimalarial treatment.
o In malaria-endemic areas, it is usually impossible to
distinguish severe malaria from bacterial sepsis with
confidence.
▪ should be treated with both antimalarials and
broad-spectrum antibiotics with activity against
nontyphoidal Salmonella species from the outset.
o Empirical antibiotics should also be given to adults
with >20% parasitemia.
o Antibiotics should be considered for severely ill
patients of any age who are not responding to
antimalarial treatment or deteriorate unexpectedly.
- Other complications
o Patients who develop spontaneous bleeding should
be given fresh blood and IV vitamin K.
o Convulsions should be treated with IV or rectal
benzodiazepines and, if necessary, respiratory
support.
o Aspiration pneumonia should be suspected in any
unconscious patient with convulsions, particularly
with persistent hyperventilation; IV antimicrobial
agents and oxygen should be administered, and
pulmonary toilet should be undertaken
Indications for chemoprophylaxis and choice drugs
- Pregnant women planning to visit malarious areas should
be warned about the potential risks
o Mefloquine is the only drug advised for pregnant
women traveling to areas with drug-resistant malaria;
this drug is generally considered safe in the second
and third trimesters of pregnancy
- Antimalarial prophylaxis has been shown to reduce
mortality rates among children between the ages of 3
months and 4 years in malaria-endemic areas; however,
it is not a logistically or economically feasible option in
many countries.
- The alternative—to give intermittent preventive
treatment (IPT) to pregnant women, and in some areas
to infants as well, or seasonal malaria chemoprevention
(SMC) to young children—is being implemented. Other
strategies are being evaluated, such as intermittent
screening and treatment
o IPT in pregnancy (IPTp)
▪ giving treatment doses of sulfadoxine-
pyrimethamine at each antenatal visit (maximum,
once monthly) in the second and third trimesters
of pregnancy.
▪ Women with HIV infection who are taking
trimethoprim-sulfamethoxazole as prophylaxis
should not be given concomitant
sulfadoxinepyrimethamine.
▪ Dihydroartemisinin-piperaquine is being
evaluated as an alternative.
o IPT in infancy (IPTi)
▪ giving treatment doses of sulfadoxine-
pyrimethamine along with the immunizations
included in the WHO’s Expanded Program on
Immunization at 2, 3, and 9 months of life.
o Seasonal malaria chemoprevention involves giving
monthly treatment doses of amodiaquine and
sulfadoxine-pyrimethamine to children aged
between 3 and 59 months during the 3- to 4-month
rainy season across the Sahel region of Africa.
Children born to nonimmune mothers in malaria-
endemic areas (usually expatriates moving to these
areas) should receive prophylaxis from birth.
o Travelers to a malaria endemic region should start
taking antimalarial drugs 2 days to 2 weeks before
departure and should continue for 4 weeks after the
traveler has left the endemic area, except if
atovaquone proguanil or primaquine has been taken
(have significant activities against the liver stage of
the infection) and can be discontinued 1 week after
departure from the endemic area.
o Presumptive self-treatment for malaria with
atovaquone-proguanil (for 3 consecutive days) or one
of the artemisinin-based combinations can be
considered under special circumstances
32

RABIES
Etiology, Epidemiology, Pathogenesis
Etiologic agent and epidemiology of rabies
- Rabies virus is a member of the family Rhabdoviridae.
Two genera in this family, Lyssavirus and Vesiculovirus,
contain species that cause human disease.
o Rabies virus is a lyssavirus;
▪ single-strand RNA virus has a nonsegmented,
negative sense (antisense) genome
- Rabies virus is usually transmitted to humans by the bite
of an infected animal
- Transmission from non-bite exposures is relatively
uncommon.
Pathogenesis of rabies
- Incubation period: is usually 20–90 days, but in rare cases
is either as short as a few days or >1 year
- In muscles, the virus is known to bind to nicotinic
acetylcholine receptors on postsynaptic membranes at
-
neuromuscular junctions, but the exact details is
unknown
- Rabies virus spreads centripetally along peripheral
nerves toward the spinal cord or brainstem via
retrograde fast axonal transport with delays at intervals
of ~12 h at each synapse
- Neurons are prominently infected in rabies; infection of
astrocytes is unusual → established CNS infection →
centrifugal spread along sensory and autonomic nerves
to other tissues, including the salivary glands, heart,
adrenal glands, and skin → virus replicates in acinar cells
of the salivary glands → secreted in the saliva of rabid
animals that serve as vectors of the disease
Neuropathologic changes in rabies
- Mononuclear inflammatory infiltration in the
leptomeninges, perivascular regions, and parenchyma,
including microglial nodules called Babes nodules
- The most characteristic pathologic finding in rabies is the
Negri body
o eosinophilic cytoplasmic inclusions in brain neurons
33
 o commonly observed in Purkinje cells of the
cerebellum and in pyramidal neurons of the
hippocampus
Clinical Manifestations, Diagnosis
Clinical presentations of rabies:
- Prodrome
o begin with nonspecific prodromal manifestations,
including fever, malaise, headache, nausea, and
vomiting
o earliest specific neurologic symptoms of rabies
include paresthesias, pain, or pruritus near the site of
the exposure, one or more of which occur in 50–80%
- Encephalitic
o Two acute neurologic forms
▪ Encephalitic (furious) form in 80%
● manifestations of encephalitic rabies,
including fever, confusion, hallucinations,
combativeness, and seizures
● Autonomic dysfunction is common in rabies
and may result in hypersalivation, gooseflesh,
cardiac arrhythmia, and priapism
● Rabies encephalitis is distinguished by early
brainstem involvement, which results in the
classic features of hydrophobia (involuntary,
painful contraction of the diaphragm and
accessory respiratory, laryngeal, and
pharyngeal muscles in response to swallowing
liquids) and aerophobia
o probably due to dysfunction of infected
brainstem neurons that normally inhibit
inspiratory neurons near the nucleus
ambiguus, resulting in exaggerated
defense reflexes that protect the
respiratory tract
▪ Paralytic form in 20%
● muscle weakness predominates and cardinal
features of encephalitic rabies
(hyperexcitability, hydrophobia, and
aerophobia) are lacking. There is early and
prominent flaccid muscle weakness, often
beginning in the bitten extremity and
spreading to produce quadriparesis and facial
weakness. Sphincter involvement is common,
sensory involvement is usually mild, and these
cases are commonly misdiagnosed as Guillain-
Barré syndrome. Patients with paralytic rabies
generally survive a few days longer than those
with encephalitic rabies, but multiple-organ
failure nevertheless ensues.
Approach to diagnosis and laboratory evaluation
- Most routine laboratory tests in rabies show nonspecific
abnormalities.
- Complete blood counts are usually normal.
- CSF examination often reveals mild mononuclear-cell
pleocytosis with a mildly elevated protein level.
o Severe pleocytosis (>1000 white cells/μL) is should
prompt a search for an alternative diagnosis.
- Imaging is usually performed to exclude other diagnostic
possibilities.
o CT head scans are usually normal
o MRI brain scans may show signal abnormalities in the
brainstem or other gray-matter areas, but
nonspecific.
- Electroencephalograms typically show only nonspecific
abnormalities.
- Once rabies is suspected, rabies-specific laboratory tests
should be performed to confirm the diagnosis.
- Diagnostically useful specimens include serum, CSF, fresh
saliva, skin biopsy samples from the neck, and brain
tissue (rarely obtained before death).
o samples are usually taken from hairy skin at the nape
of the neck.
- Corneal impression smears are of low diagnostic yield
and are generally not performed.
- Rabies Virus - Specific Antibodies - may be detected
within a few days after the onset of symptoms; presence
suggests rabies encephalitis
- RT-PCR Amplification - highly sensitive and specific;
detect virus in fresh saliva samples, skin biopsy
specimens, CSF (less sensitive), and brain tissues.
- Direct Fluorescent Antibody Testing Direct fluorescent
antibody (DFA) - highly sensitive and specific for the
detection of rabies virus antigen in tissues; the test can
be performed quickly and applied to skin biopsy and
brain tissue samples
Differential diagnosis in rabies
- Anti-NMDA encephalitis occurs in young patients
(especially females) and is characterized by behavioral
changes, autonomic instability, hypoventilation, and
seizures.
- Postinfectious (immune-mediated) encephalomyelitis
may follow influenza, measles, mumps, and other
infections; it may also occur as a sequela of immunization
with rabies vaccines derived from neural tissues, which
are now infrequently used and only in resource-limited
and resource-poor countries
- Paralytic rabies may mimic Guillain-Barré syndrome;
fever, bladder dysfunction, a normal sensory
34
 examination, and CSF pleocytosis favor a diagnosis of o Rabies vaccine and RIG should never be administered
rabies at the same site or with the same syringe.
o Two purified inactivated rabies vaccines are available
Management for rabies PEP in the United States.
Supportive management of rabies ▪ Four 1-mL doses of rabies vaccine should be given
- There is no established treatment for rabies. A palliative IM in the deltoid area or anterolateral aspect of
approach may be appropriate for many patients who are the thigh
not considered candidates for aggressive management ▪ Ideally, the first dose should be given as soon as
possible after exposure; failing that, it should be
Role and indications of postexposure prophylaxis given without further delay.
- Since there is no effective therapy for rabies, it is ▪ The three additional doses should be given on
extremely important to prevent the disease after an days 3, 7, and 14; a fifth dose on day 28 is no
animal exposure. longer recommended.
- Healthy dogs, cats, or ferrets may be confined and ▪ Pregnancy is not a contraindication for
observed for 10 days. PEP is not necessary if the animal immunization.
remains healthy. If the animal develops signs of rabies ▪ Titers should be measured 2–4 weeks after
during the observation period, it should be euthanized immunization in immunocompromised persons.
immediately; the head should be transported to the Local reactions (pain, erythema, edema, and
laboratory under refrigeration, rabies virus should be pruritus) and mild systemic reactions (fever,
sought by DFA testing, and viral isolation should be myalgias, headache, and nausea) are common;
attempted by cell culture and/or mouse inoculation. anti-inflammatory and antipyretic medications
- In high-risk exposures and in areas where canine rabies may be used, but immunization should not be
is endemic, rabies prophylaxis should be initiated discontinued.
without waiting for laboratory results. If the laboratory ▪ If human RIG is unavailable, purified equine RIG
results prove to be negative, it may safely be concluded can be used in the same manner at a dose of 40
that the animal’s saliva did not contain rabies virus, and IU/kg. The incidence of anaphylactic reactions and
immunization should be discontinued. serum sickness has been low with recent equine
- If an animal escapes after an exposure, it must be RIG products.
considered rabid, and PEP must be initiated unless
information from public health officials indicates
otherwise.
- Wound care should not be delayed, even if the initiation
of immunization is postponed pending the results of the
10-day observation period. All bite wounds and scratches
should be washed thoroughly with soap and water.
- Devitalized tissues should be debrided, tetanus
prophylaxis given, and antibiotic treatment initiated
whenever indicated. Previously unvaccinated persons
(but not those who have previously been immunized)
should be passively immunized with rabies immune
globulin (RIG).
- If RIG is not immediately available, it should be
administered no later than 7 days after the first vaccine
dose.
o After day 7, endogenous antibodies are being
produced, and passive immunization may actually be
counterproductive.
o entire dose of RIG (20 IU/kg) should be infiltrated at
the site of the bite, and any RIG remaining after
infiltration of the bite site should be administered IM
at a distant site.
o With multiple or large wounds, the RIG preparation
may need to be diluted in order to obtain a sufficient
volume for adequate infiltration of all wound sites.
o If the exposure involves a mucous membrane, the
entire dose should be administered IM.

35
SARS/SARS-COV
Etiology, Pathogenesis
Etiologic agents of SARS, MERS and COVID
- Members of the genus Coronavirus also contribute to
respiratory illness, including severe disease.
- An outbreak of infection with SARS-associated
coronavirus (SARS-CoV) first showed that animal
coronaviruses have the potential to cross from other
species to humans, with devastating effects.
- SARS-CoV causes a systemic illness with a respiratory
route of entry
o SARS lacks upper respiratory symptoms, although
cough and dyspnea occur in most patients.
o patients present with a nonspecific illness
manifesting as fever, myalgia, malaise, and chills or
rigors; watery diarrhea may occur as well.
Investigators have reported the identification of a
fourth human coronavirus, HCoV-NL63.
o HCoV-HKU1 was first described in January 2005 after
its detection in a patient with pneumonia.
- The Middle East respiratory syndrome coronavirus
(MERS-CoV), first isolated in 2012, causes severe disease
in humans, with ~35% mortality and >2500 cases
reported to date
o zoonotic virus; likely emerged from bats in the Middle
East, although studies have shown that humans are
infected through direct or indirect contact with an
intermediate host—infected dromedary camels.
- SARS-CoV-2 is the cause of a respiratory disease called
COVID-19; emerged in an outbreak in Wuhan, China, that
spread worldwide causing a severe pandemic.
o The virus is a member of lineage B of the
Betacoronavirus genus that not only includes the
highly pathogenic viruses SARS-CoV-1 (which caused
a smaller epidemic in 2002−2003) and MERS-CoV (a
lineage C virus that caused small epidemics in 2012,
2015, and 2018), but also contains the lineage A
common cold viruses CoV-OC43 and CoV-HKU1 and
MERS-CoV.
o enveloped, positive-sense RNA viruses encoded by a
viral RNA genome that is quite large, a single linear
RNA segment of nearly 30,000 nucleotides that
encodes four structural proteins, designated the S
(spike), E (envelope), M (membrane), and N
(nucleocapsid) proteins, and a large polyprotein that
is cleaved into 16 nonstructural proteins in infected
cells.
o The trimeric S protein is primed by the
transmembrane protease serine 2 (TMPRSS2) to
facilitate entry of SARS-CoV-2. SARS-CoV-2 S protein
is a type 1 fusion machine that also mediates
attachment using a receptor binding domain (RBD)
that binds to the human angiotensin-converting
enzyme 2 (hACE2) protein receptor.
Clinical Manifestations, Diagnosis
Clinical manifestations of SARS, MERS, and COVID
- In COVID-19
o The disease course varies widely, including
asymptomatic infection, mild disease, moderate
disease, or severe disease requiring hospitalization,
oxygen therapy intensive care, and mechanical
ventilation.
o A third of those infected are asymptomatic, but those
individuals can transmit the virus to others.
o Most with symptomatic infection have mild disease
(no pneumonia).
o Severe disease, typically requiring hospitalization and
involving pneumonia and associated manifestations
(dyspnea, radiographic involvement of more than
half of the lung, and/or hypoxia with oxygen
saturation ≤94%), is common.
o Critical disease with manifestations of respiratory
failure requiring mechanical ventilation, multiorgan
failure, or shock occurs and requires intensive care.
Approach to diagnosis of SARS, MERS, and COVID
- The specific diagnosis of infection typically is made using
NAAT of respiratory tract secretions.
- Nasopharyngeal swabs are used mostly commonly, while
saliva testing also has been implemented,
- Other more general laboratory testing during severe or
critical illness reveals widespread abnormalities
consistent with systemic disease
o including lymphopenia and thrombocytopenia;
elevated inflammatory markers, such as interleukin 6
(IL-6), tumor necrosis factor α, ferritin, and C-reactive
protein; elevated liver enzymes and lactate
dehydrogenase; elevated markers of acute kidney
injury; elevated D-dimer and prothrombin time; and
elevated troponin and creatine phosphokinase.
- Research-grade tests show that antibodies and T cells
also arise during the first 1−2 weeks after exposure.
- Chest radiographs may exhibit abnormal findings such as
consolidation and ground-glass opacities that are
distributed bilaterally, especially in the lower lung
regions, but also may be normal despite respiratory
compromise.
- Chest computed tomography (CT) has features (ground
glass opacifications with or without mixed consolidation,
pleural thickening, interlobular septal thickening, and air
bronchograms) that can be systematically interpreted as
typical, indeterminate, or atypical for COVID-19.
o may be more sensitive than radiographs, but CT
should be used principally for medical management
of respiratory disease, not as a primary diagnostic
tool for COVID-19.
Management, Prognosis
Supportive management of SARS, MERS, COVID
36
 - As bacterial infection is an uncommon complication of
COVID-19, antibiotics are not generally indicated, but
when the diagnosis is uncertain, empiric antibiotic
regimens for community acquired or healthcare–
associated pneumonia should be considered.
- Since there is such a substantial risk of thromboembolic
complications, many experts recommend pharmacologic
prophylaxis of venous thromboembolism for all
hospitalized patients with COVID-19
- Systemic treatment with glucocorticoids including
dexamethasone, prednisone, methylprednisolone, and
hydrocortisone reduces inflammation during severe
COVID-19 of clinical benefit, especially in reducing
mortality or the need for mechanical ventilation
Role of antiviral therapy in SARS, MERS, COVID
- Remdesivir is an enzyme inhibitor that was known prior
to the pandemic to exhibit in vitro inhibitory activity
against the coronavirus RNA–dependent, RNA
polymerases of SARS-CoV-1 and MERS-CoV.
o is now approved for hospitalized children ≥12 years
and adults with COVID-19 with any level of severity.
o The efficacy is difficult to assess because of the many
covariates in trials including differences in disease
severity, concomitant therapies, comorbidities, and
other factors.
o Its efficacy may be highest in those with mild to
moderate disease,
- The FDA issued an EUA for the Janus kinase inhibitor
baricitinib to be used only in combination with
remdesivir in COVID-19 patients requiring oxygen or
mechanical ventilation.
o typically are used for treatment of rheumatoid
arthritis because of their known immunomodulatory
effects, which probably also improve inflammation
during COVID-19, but baricitinib also may mediate
some direct antiviral effects by interfering with viral
entry into cells.
SCHISTOSOMIASIS
Etiology, Epidemiology, Pathogenesis, Immunity
Sequence of infection and transmission
- Contracted through contact with freshwater bodies
harboring infected intermediate-host snails
o Cercariae (larval stage) penetrate intact human skin
→ transform to schistosomula → enter a small vein or
lymphatic vessel → circulate in the bloodstream
through the lung capillaries → pumped via the heart
to all parts of the body to reach the portal vein →
worms mature into adult males or females, pair, and
migrate to their final location in the mesenteric or
pelvic venous plexus.
- Prepatent period - interval from cercarial penetration to
sexual maturation and egg production
o lasts 5–7 weeks (up to 12 weeks for S. haematobium).
- The female worm begins to produce eggs, which are
excreted via feces or, for S. haematobium, urine.
o 50% of eggs are retained in tissue, where they are
responsible for organ-specific morbidity
o when eggs reach water, they hatch and release a free-
swimming larval stage (miracidium), which, after
penetrating a host snail, undergoes several rounds of
asexual multiplication.
- After ~4–6 weeks, infective cercariae are shed from the
infected snails into the water. One snail, infected by one
miracidium, can shed thousands of cercariae per day for
several months; thus, the transmission potential of
schistosomes is enormous.
- The schistosome egg is the only stage of the parasites’
life cycle that can be detected in humans
o S. haematobium eggs are ~140 mm long, with a
terminal spine;
o S. mansoni eggs are ~150 mm long, with a lateral
spine;
o S. japonicum eggs are smaller, rounder, and ~90 mm
long, with a small lateral spine or knob.
- Adult schistosomes
o male worm is flat, and the body forms a groove or
gynecophoric canal in which the mature adult female
is held like a sausage in a hotdog roll.
o females are longer, thinner, and rounded.
o The lifespan of an adult schistosome averages 3–5
years but can be as long as 30 years.
o Schistosome worms feed on red blood cells; the
debris is regurgitated in the host’s blood, where it can
be detected as circulating antigens
Pathogenesis of chronic schistosomiasis and its complications
- Schistosome eggs, and not adult worms, induce the
organ-specific morbidity caused by schistosome
infections.
o half of the eggs are trapped in intestinal or hepatic
tissue (S. mansoni, S. japonicum, and S. mekongi) or
in the bladder and urogenital system (S.
haematobium).
o induce a granulomatous host immune response
composed primarily of lymphocytes, eosinophils, and
alternatively activated macrophages.
- In the chronic phase of infection, regulatory cytokines
are responsible for immunomodulation or
downregulation of host responses to schistosome eggs
and play an important role in reducing the size of
granulomas.
- When S. mansoni or S. japonicum eggs are swept into the
small portal branches of the liver via the portal vein →
lodge in the presinusoidal periportal tissues →
granuloma formation around the eggs → enlargement of
the spleen and liver
o In some infected individuals, egg-induced
granulomatous responses lead to severe periportal
fibrosis (Symmers clay pipestem fibrosis), with
deposition of collagen around the portal vein,
37
 occlusion of the smaller portal branches, and severe,
often irreversible, pathology. Occlusion of the portal
branches may result in marked portal hypertension.
- The signs and symptoms of S. haematobium infection
relate to the worms’ predilection for the veins of the
urogenital plexus
o result from deposition of eggs in the bladder, ureters,
and genital organs → followed by sloughing off of the
epithelial surface, ulceration, and bleeding → egg-
induced tissue inflammation → bladder wall
thickening and development of masses and
pseudopolyps.
o Inflammation and granuloma formation around the
ureteral ostia can lead to hydronephrosis.
- Generally, late chronic-stage infections are characterized
by accumulation of dead calcified eggs in tissue.
Clinical Features, Diagnosis
Disease manifestations of intestinal schistosomiasis
- S. mansoni, S. japonicum
- Adult worms are located in the mesenteric veins, and
disease manifestations are associated with parasite eggs
passing through or becoming trapped in intestinal tissue.
- The symptoms tend to be more pronounced with a high
intensity of infection and include intermittent abdominal
pain, loss of appetite, and sometimes bloody diarrhea.
Disease manifestations of S. haematobium
- Urogenital Schistosomiasis
- The signs and symptoms of S. haematobium infection
relate to the worms’ predilection for the veins of the
urogenital tract.
- Two stages of infection
o An active stage
▪ occurring mainly in children, adolescents, and
younger adults
▪ characterized by egg excretion in the urine, with
proteinuria and macroscopic or microscopic
hematuria and deposition of eggs in the urinary
tract.
▪ A chronic stage in older individuals is
characterized by sparse or no urinary egg
excretion despite urogenital tract pathology.
▪ A characteristic sign in the active stage is painless,
terminal hematuria.
o Fibrotic stage
▪ the inflammatory component decreases and
fibrosis becomes more prominent.
▪ The symptoms at this stage are nocturia, urine
retention, dribbling, and incontinence.
▪ Cystoscopy reveals “sandy patches” composed of
large numbers of calcified eggs surrounded by
fibrous tissue and an atrophic mucosal surface.
o Egg deposition may cause granulomas and lesions in
the genital organs, most commonly in the cervix and
vagina in women and the seminal vessels in men.
▪ The results may include dyspareunia, abnormal
vaginal discharge, contact bleeding, and lower
back pain in women and perineal pain, painful
ejaculation, and hematospermia in men.
▪ Genital symptoms like bloody discharge and
genital itch are associated with S. haematobium
infection in school-aged girls living in
schistosomiasis-endemic areas.
▪ Symptoms such as hematospermia and perineal
discomfort have been described in travelers, and
eggs have been demonstrated in seminal fluid.
- Chronic S. haematobium infection is associated with
squamous cell carcinoma of the urinary bladder.
Features of other organ involvement in schistosomiasis
- Worms and eggs can sometimes be located in ectopic
sites, causing site-specific manifestations and symptoms.
- Neuroschistosomiasis - most severe clinical forms of
schistosomiasis and is caused by the inflammatory
response around eggs in the cerebral or spinal venous
plexus.
- Transverse myelitis - S. mansoni and S. haematobium
worms end up in the spinal venous plexus, sometimes
seen in travelers returning home with schistosomiasis.
- Granulomatous lesions in the brain - S. japonicum causes
epileptic seizures, encephalopathy with headache, visual
impairment, motor deficit, and ataxia.
- Pulmonary schistosomiasis - caused by portacaval
shunting of eggs into the lung capillaries, where they
induce granulomas in the perialveolar area. The
consequences may be fibrosis, pulmonary hypertension,
and cor pulmonale.
Approach to diagnosis of schistosomiasis
- Recent travels to endemic areas and exposure to
freshwater bodies through recreational or other
activities is important in the diagnosis of schistosomiasis
in travelers.
- Information about exact geographic locations can
facilitate identification of the relevant species of
Schistosoma
- Eosinophilia - common finding and is often associated
with helminthic infections such as schistosomiasis
- Detection of schistosome eggs in stool or urine is
indicative of active infection and is the standard
diagnostic method.
o diagnosis is often based on the detection of eggs in a
fixed small amount of excreta—e.g., 50 mg of stool or
filtration of 10 mL of urine. However, levels of egg
excretion in people from nonendemic areas may be
very low
o Eggs can also be detected in rectal biopsies (both S.
mansoni and S. haematobium) and occasionally in
Pap smears and semen samples (S. haematobium).
o PCR–based detection of parasite DNA in stool or urine
is more sensitive than parasitologic methods and is
increasingly used.
38
 - Serology, with detection of specific antibodies to
schistosomes, is useful in travelers but less so in people
from endemic areas
- Schistosome proteoglycans—circulating anodic and
cathodic antigens (CAAs and CCAs)—regurgitated into
the bloodstream by the feeding worms can be detected
in serum and urine by ELISA or monoclonal antibody–
based lateral flow assays.
o positivity is an indication of active infection, and
levels of these antigens correlate well with the
intensity of infection
Treatment
Recommended treatment of schistosomiasis based on stage
and clinical presentation
- The drug of choice for treatment of schistosomiasis is
praziquantel
o does not affect the young migrating stages of
schistosomes - necessary to repeat the dose 6-12
weeks later
- In patients who are not cured by initial treatment, the
same dose can be repeated at weekly intervals for 2
weeks.
- Glucocorticoids can be added in Katayama fever to
suppress the hypersensitivity reaction.
Infections associated with vesicles, bullae, and crusted
lesions
SKIN AND SOFT TISSUE INFECTIONS
Dermatologic Manifestations Of Infections
Dermal anatomy and the risk of specific infections
- Protection against infection of the epidermis depends on
the mechanical barrier afforded by the stratum corneum
since the epidermis itself is devoid of blood vessels
o Disruption of the stratum corneum allows
penetration of bacteria to the deeper structures.
- Hair follicles can serve as a portal either for components
of the normal flora (e.g., Staphylococcus) or for extrinsic
bacteria (e.g., Pseudomonas in hot-tub folliculitis).
- Intracellular infection of the squamous epithelium with
vesicle formation may arise from cutaneous inoculation
o infection with herpes simplex virus (HSV) type 1
o from the dermal capillary plexus (varicella) and
infections due to other viruses associated with
viremia
o from cutaneous nerve roots (HZV).
- The rich plexus of capillaries beneath the dermal papillae
provides nutrition to the stratum germinativum, and
physiologic responses of this plexus produce important
clinical signs and symptoms.
o Infective vasculitis of the plexus results in petechiae,
Osler’s nodes, Janeway lesions, and palpable
purpura, which, if present, are important clues to the
existence of endocarditis
o Metastatic infection within this plexus can result in
cutaneous manifestations of disseminated fungal
infection, gonococcal infection, Salmonella infection,
Pseudomonas infection, meningococcemia, and
staphylococcal infection.
o The postcapillary venules of this plexus are a
prominent site of polymorphonuclear leukocyte
sequestration, diapedesis, and chemotaxis to the site
of cutaneous infection.
- Vesicles
o Varicella and variola
▪ viremia precedes the onset of a diffuse
centripetal rash that progresses from macules to
vesicles, then to pustules, and finally to scabs over
the course of 1–2 weeks
▪ Vesicles of varicella have a “dewdrop”
appearance and develop in crops randomly about
the trunk, extremities, and face over 3–4 days
▪ In Smallpox, viremia begins after an incubation
period of 12 days is followed by a diffuse
maculopapular rash, with rapid evolution to
vesicles, pustules, and then scabs
o Herpes zoster
39
 ▪ occurs in a single dermatome; vesicle appearance
is preceded by pain
▪ most common among immunosuppressed and
elderly
o Herpes Simplex Virus
▪ found on or around the lips (HSV-1) or genitals
(HSV-2) but also may appear on the head and neck
of young wrestlers (herpes gladiatorum) or on the
digits of health care workers (herpetic whitlow)
▪ Recurrent herpes labialis (HSV-1) and herpes
genitalis (HSV-2) commonly follow primary
infection
o Rickettsialpox
▪ papule with a central vesicle evolves to form a 1-
to 2.5-cm painless crusted black eschar with an
erythematous halo and proximal adenopathy
- Bullae
o SSSS is caused by a toxin (exfoliatin) from phage
group II S. aureus
▪ must be distinguished from TEN, occurs primarily
in adults, is drug-induced, and is associated with a
higher mortality rate
▪ Punch biopsy with frozen section
● SSSS - cleavage plane is stratum corneum
● TEN - cleavage plane is stratum germinatum
- Crusted lesions
o Impetigo contagiosa (S. pyogenes) and bullous
impetigo (S. aureus)
▪ have an early bullous stage but then appear as
thick crusts with a golden-brown color
▪ Streptococcal lesions are most common among
children 2–5 years of age
● important to recognize impetigo contagiosa
because of its relationship to
poststreptococcal glomerulonephritis.
Rheumatic fever is not a complication of skin
infection caused by S. pyogenes.
o Primary infections with dimorphic fungi such as
Blastomyces dermatitidis and Sporothrix schenckii
can initially present as crusted skin lesions resembling
ringworm.
o Disseminated infection with Coccidioides immitis can
also involve the skin, and biopsy and culture should
be performed on crusted lesions when the patient is
from an endemic area.
o Crusted nodular lesions caused by Mycobacterium
chelonee have been described in HIV-seropositive
patients. Treatment with clarithromycin looks
promising.
Etiologies of folliculitis
- S. aureus is the most common cause of localized
folliculitis.
- Sebaceous glands empty into hair follicles and ducts and,
if blocked, form sebaceous cysts that may resemble
staphylococcal abscesses or may become secondarily
infected.
- Inflammation of sweat glands (hidradenitis suppurativa)
also can mimic infection of hair follicles, particularly in
the axillae, but new treatments with potent anti-
inflammatory agents hold promise.
- Chronic folliculitis is uncommon except in acne vulgaris,
where constituents of the normal flora (e.g.,
Propionibacterium acnes) may play a role. Diffuse
folliculitis occurs in two settings.
- Hot-tub folliculitis is caused by Pseudomonas aeruginosa
in waters that are insufficiently chlorinated and
maintained at temperatures of 37–40°C, disease is
usually self-limited
- Swimmer’s itch occurs when a skin surface is exposed to
water infested with freshwater avian schistosomes.
o Free-swimming schistosomal cercariae readily
penetrate human hair follicles or pores but quickly die
and elicit a brisk allergic reaction, causing intense
itching and erythema.
Infections associated with popular and nodular lesions
- Mycobacterium marinum infections of the skin may
present as cellulitis or as raised erythematous nodules.
- Mycobacterium abscessus and M. chelonei have been
described among patients undergoing cosmetic laser
surgery and tattooing, respectively.
- Bartonella henselae causes erythematous papules
- Cutaneous larva migrans - Raised serpiginous or linear
eruptions caused by burrowing larvae of dog or cat
hookworms (Ancylostoma braziliense) and which
humans acquire through contact with soil that has been
contaminated with dog or cat feces.
- Dracunculiasis - similar burrowing raised lesions caused
by migration of the adult female nematode Dracunculus
medinensis.
- Onchocerca volvulus - nodules measuring 1–10 cm in
diameter and occur mostly in persons bitten by Simulium
flies in Africa.
o contain the adult worm encased in fibrous tissue.
o Migration of microfilariae into the eyes may result in
blindness.
- Verruga peruana - caused by Bartonella bacilliformis
o transmitted to humans by the sandfly Phlebotomus.
o single gigantic lesions (several centimeters in
diameter) or multiple small lesions (several
millimeters in diameter).
- Cysticercosis - larvae of Taenia solium; numerous
subcutaneous nodules
- Schistosomiasis - multiple erythematous papules
o represents a cercarial invasion site.
- Leprosy - skin nodules as well as thickened subcutaneous
tissue
- Tertiary Syphilis - Large nodules or gummas
- Secondary Syphilis - flat papulosquamous lesions
- Human papillomavirus may cause singular warts (verruca
vulgaris) or multiple warts in the anogenital area
40
 (condylomata acuminata). The latter are major problems
in HIV-infected individuals.
Infections associated with ulcerations
- Cutaneous anthrax begins as a pruritic papule, which
develops within days into an ulcer with surrounding
vesicles and edema and then into an enlarging ulcer with
a black eschar.
o may cause chronic nonhealing ulcers with an
overlying dirty gray membrane, although lesions may
also mimic psoriasis, eczema, or impetigo.
- Ulceroglandular tularemia may have associated
ulcerated skin lesions with painful regional adenopathy.
- Plague - buboes are the major cutaneous manifestations,
but in 25% ulcers with eschars, papules, or pustules are
also present
- Mycobacterium ulcerans typically cause chronic skin
ulcers on the extremities of individuals living in the
tropics.
- Mycobacterium leprae - associated with cutaneous
ulcerations in patients with lepromatous leprosy related
to Lucio’s phenomenon (immune-mediated destruction
of tissue bearing high concentrations of M. leprae bacilli
occurs)
- Decubitus ulcers - tissue hypoxemia secondary to
pressure-induced vascular insufficiency
o may become secondarily infected with components
of the skin and gastrointestinal flora, including
anaerobes.
- Ulcerative lesions on the anterior shins may be due to
pyoderma gangrenosum
- Ulcerated lesions on the genitals may be either painful
(chancroid) or painless (primary syphilis).
Erysipelas
Etiologic agents
- S. pyogenes
- Classic cases of erysipelas, with typical features, are
almost always due to β-hemolytic streptococci, usually
GAS and occasionally group C or G.
- Infants and elderly adults are most commonly afflicted
Clinical manifestation and Diagnosis
- Abrupt onset of fiery-red swelling of the face or
extremities.
- The distinctive features
o are well-defined indurated margins, particularly
along the nasolabial fold;
o rapid progression; and intense pain
o flaccid bullae may develop during the second or third
day of illness, but extension to deeper soft tissues is
rare.
o desquamation of the involved skin occurs 5–10 days
into the illness.
Management of erysipelas
- Treatment with penicillin is effective; and swelling may
progress despite appropriate treatment, although fever,
pain, and the intense red color diminish.
Cellulitis
Etiologic agents
- It may be caused by indigenous flora colonizing the skin
and appendages (e.g., S. aureus and S. pyogenes) or by a
wide variety of exogenous bacteria.
- S. aureus spreads from a central localized infection, such
as an abscess, folliculitis, or an infected foreign body
(e.g., a splinter, a prosthetic device, an IV catheter).
- MRSA is rapidly replacing MSSA as a cause of cellulitis in
both inpatient and outpatient settings.
- MSSA or MRSA is usually associated with a focal
infection, such as a furuncle, a carbuncle, a surgical
wound, or an abscess
- S. pyogenes is a more rapidly spreading, diffuse process
that is frequently associated with lymphangitis and fever
and should be referred to as nonpurulent cellulitis.
- Recurrent streptococcal cellulitis of the lower extremities
may be caused by organisms of group A, C, or G in
association with chronic venous stasis or with saphenous
venectomy for coronary artery bypass surgery.
- Streptococci also cause recurrent cellulitis among
patients with chronic lymphedema resulting from
elephantiasis, lymph node dissection, or Milroy disease.
o more common among individuals who have
eosinophilia and elevated serum levels of IgE (Job
syndrome) and among nasal carriers of staphylococci.
- Streptococcus agalactiae (group B Streptococcus) occurs
primarily in elderly patients and those with diabetes
mellitus or peripheral vascular disease.
- Haemophilus influenzae - causes periorbital cellulitis in
children in association with sinusitis, otitis media, or
epiglottitis.
- Cellulitis associated with cat bites and, to a lesser degree,
with dog bites is commonly caused by Pasteurella
multocida, although in the latter case Staphylococcus
intermedius and Capnocytophaga canimorsus also must
be considered.
41
 - Aeromonas hydrophila causes aggressive cellulitis and
occasionally necrotizing fasciitis in tissues surrounding
lacerations sustained in freshwater (lakes, rivers, and
streams).
- P. aeruginosa causes three types of soft tissue infection:
ecthyma gangrenosum in neutropenic patients, hot-tub
folliculitis, and cellulitis following penetrating injury.
Most commonly, P. aeruginosa is introduced into the
deep tissues when a person steps on a nail.
- The gram-positive aerobic rod Erysipelothrix
rhusiopathiae is most often associated with fish and
domestic swine and causes cellulitis primarily in bone
renderers and fishmongers
- M. marinum, which can cause cellulitis or granulomas on
skin surfaces exposed to the water in aquariums or
injured in swimming pools which is on fish food
containing the water flea Daphnia
Clinical manifestation and Diagnosis
- Cellulitis is an acute inflammatory condition of the skin
that is characterized by localized pain, erythema,
swelling, and heat.
- When there is drainage, an open wound, or an obvious
portal of entry,
o Gram’s stain and culture provide a definitive
diagnosis.
o In the absence of these findings, establishing an
etiology will be difficult
Management
- Pasteurella - resistant to dicloxacillin and nafcillin but is
sensitive to all other β-lactam antimicrobial agents as
well as to quinolones, tetracycline, and erythromycin.
- Amoxicillin-clavulanate, ampicillin sulbactam, and
cefoxitin are good choices for the treatment of animal or
human bite infections.
- Aeromonas hydrophila - sensitive to aminoglycosides,
fluoroquinolones, chloramphenicol, trimethoprim-
sulfamethoxazole, and third-generation cephalosporins;
it is resistant to ampicillin
- P. aeruginosa
o Treatment includes surgical inspection and drainage,
particularly if the injury also involves bone or joint
capsule.
o Choices for empirical treatment include an
aminoglycoside, a third-generation cephalosporin
(ceftazidime, cefoperazone, or cefotaxime), a
semisynthetic penicillin (ticarcillin, mezlocillin, or
piperacillin), or a fluoroquinolone (although drugs of
the last class are not indicated for the treatment of
children <13 years old).
- E. rhusiopathiae - susceptible to most β-lactam
antibiotics (including penicillin), erythromycin,
clindamycin, tetracycline, and cephalosporins but is
resistant to sulfonamides, chloramphenicol, and
vancomycin.
- M. marinum - rifampin plus ethambutol has been an
effective therapeutic combination in some cases; some
strains of M. marinum are susceptible to tetracycline or
trimethoprim-sulfamethoxazole.
Necrotizing Fasciitis
Etiologic agents
- Formerly called streptococcal gangrene, may be
associated with group A Streptococcus or mixed aerobic–
anaerobic bacteria or may occur as a component of gas
gangrene caused by Clostridium perfringens.
- Strains of MRSA that produce the Panton-Valentine
leukocidin (PVL) toxin have been reported to cause
necrotizing fasciitis.
Clinical manifestation and Diagnosis
- Early diagnosis may be difficult when pain or unexplained
fever is the only presenting manifestation.
- Swelling then develops and is followed by brawny edema
and tenderness.
o progresses to a dark-red induration of the epidermis
along with bullae filled with blue or purple fluid.
o later, skin becomes friable and takes on a bluish,
maroon, or black color - thrombosis of blood vessels
in the dermal papillae is extensive.
o Extension to the deep fascia causes this tissue to take
on a brownish-gray appearance.
o Rapid spread occurs along fascial planes, through
venous channels and lymphatics.
- Necrotizing fasciitis caused by mixed aerobic–anaerobic
bacteria begins with a breach in the integrity of a mucous
membrane barrier, such as the mucosa of the
gastrointestinal or genitourinary tract.
o The portal can be a malignancy, a diverticulum, a
hemorrhoid, an anal fissure, or a urethral tear.
o Other predisposing factors include peripheral
vascular disease, diabetes mellitus, surgery, and
penetrating injury to the abdomen.
o Leakage into the perineal area results in a syndrome
called Fournier’s gangrene (massive swelling of the
scrotum and penis with extension into the perineum
or the abdominal wall and the legs)
- Necrotizing fasciitis caused by S. pyogenes has increased
in frequency with two distinct clinical presentations
o No portal of entry
▪ Often begin deep at the site of a nonpenetrating
minor trauma, such as a bruise or a muscle strain.
▪ Affected patients present with only severe pain
and fever.
▪ Late in the course, the classic signs of necrotizing
fasciitis, such as purple (violaceous) bullae, skin
sloughing, and progressive toxicity, develop.
o Defined portal of entry.
▪ S. pyogenes may reach the deep fascia from a site
of cutaneous infection or penetrating trauma.
▪ Have early signs of superficial skin infection with
progression to necrotizing fasciitis.
42
 ▪ Toxicity is severe, and renal impairment may
precede the development of shock. In 20–40% of
cases, myositis occurs concomitantly, and, as in
gas gangrene (see below), serum creatine
phosphokinase levels may be markedly elevated.
▪ Prompt surgical exploration down to the deep
fascia and muscle is essential. Necrotic tissue
must be surgically removed, and Gram’s staining
and culture of excised tissue are useful in
establishing whether group A streptococci, mixed
aerobic–anaerobic bacteria, MRSA, or Clostridium
species are present
Management
- Necrotizing fasciitis (group A streptococcal)
o Firstline Treatment
▪ Clindamycin (600–900 mg IV q6–8h) plus penicillin
G (4 million units IV q4h)
o Alternative Treatment
▪ Clindamycin (600–900 mg IV q6–8h) plus a
cephalosporin (first- or second-generation)
- Necrotizing fasciitis (mixed aerobes and anaerobes)
o Firstline Treatment
▪ Ampicillin (2 g IV q4h) plus clindamycin (600–900
mg IV q6–8h) plus ciprofloxacin (400 mg IV q6–8h)
o Alternative
▪ Vancomycin (1 g IV q6h) plus metronidazole (500
mg IV q6h) plus ciprofloxacin (400 mg IV q6–8h)
Myositis/Myonecrosis
Infectious agents with muscle involvement
- Muscle involvement can occur with viral infection (e.g.,
influenza, dengue, or coxsackievirus B infection) or
parasitic invasion (e.g., trichinellosis, cysticercosis, or
toxoplasmosis).
- Severe muscle pain is the hallmark of pleurodynia
(coxsackievirus B), trichinellosis, and bacterial infection.
- Acute rhabdomyolysis predictably occurs with clostridial
and streptococcal myositis but may also be associated
with influenza virus, echovirus, coxsackievirus, Epstein-
Barr virus, and Legionella infections.
Clinical features and etiologic causes of pyomyositis and
primary myositis
- Pyomyositis is usually due to S. aureus, is common in
tropical areas
o Muscle infection begins at the exact site of blunt
trauma or muscle strain
o Infection remains localized, and shock does not
develop unless organisms produce toxic shock
syndrome toxin 1 or certain enterotoxins and the
patient lacks antibodies to the toxin produced by the
infecting organisms
- Myonecrosis occurs concomitantly with necrotizing
fasciitis in ~50% of cases
Clinical features and etiologic causes of gas gangrene and
spontaneous nontraumatic gangrene
- Gas gangrene usually follows severe penetrating injuries
that result in interruption of the blood supply and
introduction of soil into wounds.
o usually caused by the clostridial species C.
perfringens, C. septicum, and C. histolyticum.
o nontraumatic gangrene among patients with
neutropenia, gastrointestinal malignancy,
diverticulosis, or recent radiation therapy to the
abdomen where C. septicum is the most commonly
involved
- C. sordellii has also been implicated in medically induced
abortion
o present as a unique clinical picture: little or no fever,
lack of a purulent discharge, refractory hypotension,
extensive peripheral edema and effusions,
hemoconcentration, and a markedly elevated white
blood cell count
o C. sordellii and C. novyi have also been associated
with cutaneous injection of black tar heroin; mortality
rates are lower among the affected individuals,
probably because their aggressive injection-site
infections are readily apparent and diagnosis is
therefore prompt.
- Synergistic non-clostridial anaerobic myonecrosis, also
known as necrotizing cutaneous myositis and synergistic
necrotizing cellulitis, is a variant of necrotizing fasciitis
caused by mixed aerobic and anaerobic bacteria with the
exclusion of clostridial organisms
Principles and approach to treatment of myositis and
myonecrosis
- Gas Gangrene
o Firstline
▪ Clindamycin (600–900 mg IV q6–8h) plus penicillin
G (4 million units IV q4–6h)
o Alternative
▪ Clindamycin (600–900 mg IV q6–8h) plus cefoxitin
(2 g IV q6h)
INFECTIOUS ARTHRITIS
Diagnosis
Diagnostic approach to suspected case of infectious arthritis
- Staphylococcus aureus, streptococci, and Neisseria
gonorrhoeae are the most common causes of infectious
arthritis
- Acute bacterial infection - involves a single joint or a few
joints.
- Mycobacterial or fungal infection - subacute or chronic
monarthritis or oligoarthritis suggests
- Syphilis, Lyme disease, and the reactive arthritis -
episodic inflammation that follows enteric infections and
chlamydial urethritis.
43

Criteria for definitive diagnosis of infection in infectious
arthritis
- Definitive diagnosis relies on stained smears of synovial
fluid, cultures of synovial fluid and blood, or NAATs and
immunologic techniques
o Aspiration of synovial fluid
▪ Normal - <180 cells (predominantly mononuclear
cells)
▪ Acute bacterial infection - cell counts of
100,000/μL (range, 25,000–250,000/μL) with
>90% neutrophils
▪ Noninfectious inflammatory arthritides -
<30,000–50,000 cells/μL
▪ Mycobacterial and fungal infections - cell counts
of 10,000–30,000/μL, with 50–70% neutrophils
o Gram stain is positive in 30-50%; Synovial fluid
culture is positive in >60% of nongonococcal bacterial
arthritis
o Matrix-assisted laser desorption/ ionization–time of
flight (MALDI-TOF) mass spectrometry - useful in
negative culture and high suspicion of infectious
arthritis.
o Sonication of explanted prosthetic joints increases
yield of organism (esp in antibiotic use within 14 days)
Acute Bacterial Arthritis
Pathogenesis of acute bacterial arthritis
- Bacteria enter the joint from
o bloodstream (most common route)
▪ bacteria lodges into synovial capillaries (no
basement membrane) → neutrophilic infiltration
of synovium → bacterial adherence to articular
cartilage → increased intraarticular pressure,
release of proteases and cytokines, invasion of
bacteria and neutrophils to the cartilage →
cartilage degradation within 48 hrs
o contiguous site of infection in bone or soft tissue
o direct inoculation during surgery, injection, bite,
trauma
Etiologic agents based on route of entry
- Hematogenous Route
o Infants - group B streptococci, gram-negative enteric
bacilli, and S. aureus are
o Children < 5 years old - S. aureus, Streptococcus
pyogenes, and Kingella kingae
o Young adults and adolescents - N. gonorrhoeae
o Adults - S. aureus, gram-negative bacilli,
pneumococci, and β-hemolytic streptococci
- Direct inoculation
o Surgical procedures or penetrating injuries - most
often S. aureus
o Prosthetic joints or arthroscopy - coagulase-negative
staphylococci
o Bites or scratches from animals - Pasteurella
multocida or Bartonella henselae
o Bites from humans - Eikenella corrodens
o Penetration of sharp object through a shoe -
Pseudomonas aeruginosa
Predisposing risk factors for septic arthritis
- Rheumatoid arthritis - highest incidence for infective
arthritis (often due to S. areus)
- Diabetes mellitus, glucocorticoid therapy, hemodialysis,
and malignancy - increased risk for S. aureus and gram-
negative bacilli
- TNF inhibitors - predispose to mycobacterial infections
- HIV - Pneumococci, Salmonella species, and H. influenza
- Primary immunoglobulin deficiency - mycoplasmal
arthritis
- IV drug users - staphylococcal and streptococcal
infections (from own flora) and pseudomonal and other
gram-negative infections (from drugs and injection
paraphernalia)
Clinical manifestations of acute bacterial arthritis
- Usually present with joint pain aggravated by movement,
joint swelling, and/or erythema.
o 90% of patients present with monoarthralgia — most
commonly the knee; less frequently the hip; and still
less often the shoulder, wrist, or elbow.
o Small joints of the hands and feet - affected after
direct inoculation or a bite.
44
 o Spine, sacroiliac joints, and sternoclavicular joints
among IV drug users
- Polyarticular infection is most common among patients
with rheumatoid arthritis and may resemble a flare of the
underlying disease.
- Usual presentation
o moderate to severe, uniform pain around the joint,
effusion, muscle spasm, and decreased range of
motion.
o Fever in the range of 38.3–38.9°C
o Cellulitis, bursitis, and acute osteomyelitis is
distinguished from septic arthritis by preservation of
passive range of motion and less-than-
circumferential swelling.
- Plain radiographs show evidence of soft tissue swelling,
joint space widening, and displacement of tissue planes
by the distended capsule.
- Narrowing of the joint space and bony erosions indicate
advanced infection and a poor prognosis.
- Imaging
o Ultrasound is useful for detecting effusions in the hip
o CT or MRI can demonstrate infections of the sacroiliac
joint, the sternoclavicular joint, and the spine very
well.
Laboratory findings in acute bacterial arthritis
- Specimens of peripheral blood and synovial fluid should
be obtained before antibiotics are administered.
- Blood cultures are positive in up to 50–70% of S. aureus
infections
- Synovial fluid
o Turbid, serosanguineous, or frankly purulent.
o Total protein and LDH are elevated with decrease
glucose levels - not specific for infection, and not
necessary for diagnosis
o Should be examined for crystals because gout and
pseudogout can resemble septic arthritis
o Organisms on smears are three-quarters infection
with S. aureus and streptococci and in 30–50% of
infections due to gram-negative and other bacteria
o Cultures are positive in >90% of cases
- Gram-stained smears confirm the presence of large
numbers of neutrophils.
- Nucleic acid amplification (NAA)-based assays for
bacterial DNA or MALDI-TOF - useful for the diagnosis of
partially treated or culture-negative bacterial arthritis.
- Inflammatory markers (ESR and CRP) are elevated in
septic arthritis but are nonspecific.
- Serum procalcitonin elevation is only ~50% sensitive and
should not be used to rule out infectious arthritis.
Approach to treatment of acute bacterial arthritis
- Initial therapy should consist of IV-administered
bactericidal agents; direct instillation of antibiotics into
the joint is not necessary to achieve adequate levels in
synovial fluid and tissue.
- Gram-positive cocci on the smear, IV vancomycin (15−20
mg/kg/dose) every 8–12 h should be started empirically.
- If MRSA is an unlikely pathogen, cefazolin (2 g every 8 h),
oxacillin (2 g every 4 h), or nafcillin (2 g every 4 h) should
be given.
- Gram-negative bacilli, an IV third generation
cephalosporin such as cefotaxime (1 g every 8 h) or
ceftriaxone (1–2 g every 24 h)
- IV drug users and other patients in whom P. aeruginosa
is likely, cefepime (2 g every 8−12 h) or ceftazidime (2 g
every 8 h) should be given
- Duration of therapy
o Staphylococci are treated with cefazolin, oxacillin,
nafcillin, or vancomycin for 4 weeks.
o Patients without evidence of endocarditis, IV
antibiotics can be used for at least 14 days of
treatment followed by oral antibiotics to complete
the treatment course.
o Pneumococcal and streptococcal infections
▪ penicillin-susceptible organisms - 2 weeks of
therapy with penicillin G (2 million units IV every
4 h);
▪ penicillin-resistant - cefotaxime or ceftriaxone for
2 weeks.
o Gram-negative infections - 3–4 weeks second- or
third-generation cephalosporin given IV or by a
fluoroquinolone such as levofloxacin (500 mg IV or PO
every 24 h).
o P. aeruginosa - at least 2 weeks with a combination
regimen composed of an aminoglycoside plus either
an extended spectrum penicillin such as piperacillin
(3−4 g IV every 4 h) or an antipseudomonal
cephalosporin such as ceftazidime (1−2 g IV every 8
h).
▪ If tolerated, this regimen is continued for an
additional 2 weeks;
▪ Alternatively, a fluoroquinolone such as
ciprofloxacin (750 mg PO twice daily) is given by
itself or with the penicillin or cephalosporin in
place of the aminoglycoside.
- Timely drainage of pus and necrotic debris from the
infected joint is required for a favorable outcome
- Arthroscopic drainage and lavage may be employed
initially or within several days if repeated needle
aspiration fails to relieve symptoms, decrease the
volume of the effusion and the synovial white cell count,
and clear bacteria from smears and cultures.
- Septic arthritis of the hip is best managed with
arthrotomy, particularly in young children, in whom
infection threatens the viability of the femoral head.
- Weight bearing should be avoided until signs of
inflammation have subsided, but frequent passive
motion of the joint is indicated to maintain full mobility.
- Although addition of glucocorticoids to antibiotic
treatment improves the outcome of S. aureus arthritis in
experimental animals, no clinical trials have evaluated
this approach in humans.
45

Gonococcal Arthritis
Clinical features and diagnosis of diffuse gonococcal infection
- The most common manifestation of DGI is a syndrome of
fever, chills, rash, and articular symptoms.
o Papules that progress to hemorrhagic pustules
develop on the trunk and the extensor surfaces of the
distal extremities.
o Migratory arthritis and tenosynovitis of the knees,
hands, wrists, feet, and ankles are prominent.
o These are believed to be the consequence of an
immune reaction to circulating gonococci and
immune-complex deposition in tissues.
- Cultures of synovial fluid are consistently negative, and
blood cultures are positive in <45% of patients.
- Synovial fluid may be difficult to obtain from inflamed
joints and usually contains only 10,000–20,000
leukocytes/μL.
Clinical features and diagnosis of true gonococcal septic
arthritis
- True gonococcal septic arthritis is less common than the
DGI syndrome and always follows DGI
- A single joint such as the hip, knee, ankle, or wrist is
usually involved.
- Synovial fluid, which contains >50,000 leukocytes/μL, can
be obtained with ease;
- Occasionally seen in Gram-stained smears
- Cultures of synovial fluid are positive in <40% of cases.
- Blood cultures are almost always negative.
Approach to diagnosis of gonococcal arthritis
- Specimens for culture should be obtained from
potentially infected mucosal sites.
- NAA-based urine tests also may be positive.
- Culture requires endocervical (in female patients) or
urethral (in male patients) swab specimens.
o Plated onto Thayer-Martin agar directly or in special
transport media at the bedside and transferred
promptly to the microbiology laboratory in an
atmosphere of 5% CO2
- NAA-based assays are extremely sensitive in detecting
gonococcal DNA in synovial fluid.
o A dramatic alleviation of symptoms within 12–24 h
after the initiation of appropriate antibiotic therapy
supports a clinical diagnosis of the DGI syndrome if
cultures are negative.
Treatment of gonococcal arthritis
- Initial treatment consists of ceftriaxone (1 g IV or IM
every 24 h) to cover possible penicillin-resistant
organisms.
o Once local and systemic signs are clearly resolving, a
7-day course of antibiotics may be completed with
daily IM ceftriaxone given at 250 mg daily.
o An oral fluoroquinolone such as ciprofloxacin (500 mg
twice daily) may be used if the organism is known to
be susceptible.
o If penicillin-susceptible organisms are isolated,
amoxicillin (500 mg three times daily) may be used.
- Suppurative arthritis usually responds to needle
aspiration of involved joints and 7–14 days of antibiotic
treatment.
- Patients with DGI should be treated for Chlamydia
trachomatis infection unless ruled out by appropriate
testing.
o Addition of azithromycin (1 g orally as a single dose)
is recommended to treat chlamydial co-infection,
which is common.
o Sexual partners should be offered testing and
presumptive treatment for gonorrhea and chlamydial
infection
TETANUS
Definition, Etiology, Pathogenesis
Tetanus
- acute disease manifested by skeletal muscle spasm and
autonomic nervous system disturbance
- caused by a powerful neurotoxin produced by the
bacterium Clostridium tetani
- completely preventable by vaccination
Probable Tetanus
- “an acute illness with muscle spasms or hypertonia in the
absence of a more likely diagnosis”
Neonatal Tetanus
- “an illness occurring in a child who has the normal ability
to suck and cry in the first 2 days of life but who loses this
ability between days 3 and 28 of life and becomes rigid
and has spasms.”
Maternal Tetanus
- tetanus occurring during pregnancy or within 6 weeks
after the conclusion of pregnancy (whether with birth,
miscarriage, or abortion).
C. Tetani
▪ anaerobic, gram-positive, spore-forming rod
▪ spores are highly resilient and can survive readily
in the environment
▪ resist boiling and many disinfectants
o C. tetani spores survive in intestinal
systems of animals, fecal carriage is
common
- Spores enter the body through abrasions, wounds,
umbilical stump (neonates) → organisms grow,
multiply, and release tetanus toxin in anaerobic
environment
- Highly potent exotoxin- minimal lethal human dose,
2.5 ng/kg
- 20–30% of cases of tetanus- no puncture wound
- In adults, superficial abrasions of limbs- most
common infection site
46
 - Deeper infections- attributable to open fracture, ● muscles of the face and jaw are often affected
abortion, or drug injection, severe disease & worse first
prognosis ● d/t shorter distance the toxin must travel up
- Neonates- inadequate umbilical-cord care → motor nerves to reach presynaptic terminals
umbilical stump infection ● neonates present with an inability to suck
- Circumcision/ ear piercing- Neonatal tetanus ▪ Local
● mild form
Pathogenesis ● only isolated areas of the body are affected &
Bacteria producing tetanus toxin (tetanospasmin) → only small areas of local muscle spasm may be
tetanus apparent
- Closely related to botulinum toxin in structure and ● If the cranial nerves are involved in localized
mode of action cephalic tetanus, pharyngeal or laryngeal
- Undergoes retrograde transport into the CNS muscles may spasm → aspiration or airway
- Tetanus toxin → intra axonally transported to motor obstruction
nuclei of the cranial nerves or ventral horns of the ● the prognosis may be poor
spinal cord
- Single 150-kDa protein → heavy (100-kDa) and light
(50-kDa) chains linked by a disulfide bond and
noncovalent forces
- Carboxy terminal of heavy chain binds to specific
membrane components in presynaptic α-motor nerve
terminals
- Binding to both polysialogangliosides and membrane
proteins → toxin internalization & nerve uptake
- Inside the neuron, toxin enters a retrograde transport
pathway → carried proximally to motor neuron body
- Several different pH-dependent conformations = can
interact with different receptors
- Can evade degradation
- Undergoes translocation across the synapse to the
▪ In assessing prognosis- speed at which tetanus
GABA-ergic presynaptic inhibitory interneuron
develops is important
terminals
▪ Shorter incubation period = worst outcome
- Zinc-dependent endopeptidase light chain cleaves
▪ In neonatal tetanus, younger infant is when sx
vesicle associated membrane protein 2
occur = worse prognosis
(VAMP2/synaptobrevin)
▪ Common initial symptoms:
- VAMP2- necessary for presynaptic binding and
● trismus (lockjaw)
release of neurotransmitter
● muscle pain and stiffness
- Tetanus toxin prevents transmitter release &
● back pain
effectively blocks inhibitory interneuron discharge
● difficulty swallowing
- Results in unregulated activity in the motor nervous
▪ In neonates- difficulty in feeding
system (skeletal muscle spasm & autonomic system
▪ As the disease progresses → muscle spasm
disturbance)
develops
- ↑ circulating catecholamine levels in severe cases =
▪ Generalized muscle spasm can be very painful.
cardiovascular complications
▪ Commonly, the laryngeal muscles are involved
- Recovery can take weeks
early or even in isolation → complete airway
- Peripheral nerve sprouting may occur
obstruction
- Toxin degradation can be a mechanism of recovery
▪ Spasm of the respiratory muscles → respiratory
failure
Clinical Features, Diagnosis
▪ Without ventilatory support, respiratory failure is
Clinical Manifestations
the most common cause of death in tetanus.
- occur only after tetanus toxin has reached presynaptic
▪ Spasms can be strong enough to cause tendon
inhibitory nerves
avulsions and crush fractures (rare).
- once effects are apparent, little that can be done to
▪ During the 2nd week of severe tetanus,
affect disease progression
autonomic disturbance is maximal and death due
- treatment should not be delayed
to cardiovascular events becomes the major risk
- wide spectrum of clinical features divided into:
▪ BP is usually labile, with rapid fluctuations from
▪ Generalized (includes neonatal)
high to low along with tachycardia

47
 ▪ Episodes of bradycardia and heart block can occur
▪ Autonomic involvement:
● gastrointestinal stasis
● sweating
● increased tracheal secretions
● acute (often high-output) renal failure
Diagnosis
▪ Is based on clinical findings
▪ Treatment should not be delayed while laboratory
tests are conducted
▪ Wound culture of C. tetani as supportive evidence
▪ Serum anti-tetanus immunoglobulin G may be
measured in a sample taken before the
administration of antitoxin or immunoglobulin
● Levels >0.1 IU/mL (measured by standard
enzyme- linked immunosorbent assay) are
deemed protective
● Do not support the diagnosis of tetanus
● If levels are below this threshold, a bioassay
for serum tetanus toxin may be helpful
● negative results do not exclude the diagnosis,
not generally performed.
● PCR can be performed but sensitivity is
unknown, and a negative result does not
exclude the diagnosis.
▪ Conditions that mimic generalized tetanus:
● Strychnine poisoning
● Dystonic reactions to antidopaminergic drugs
▪ Abdominal rigidity is continuous in tetanus
▪ Cephalic tetanus- can be confused with trismus of
other etiologies, such as oropharyngeal infection
▪ Hypocalcemia and meningoencephalitis- ddx of
neonatal tetanus.
Management, Prognosis
Management strategies aim to:
- neutralize remaining unbound toxin
- support vital functions until the effects of the toxin have
worn off
- recent studies done on Intrathecal methods of antitoxin
administration to neutralize toxin in the CNS and limit
disease progression
- entry wound should be identified, cleaned, and debrided
of necrotic material in order to remove anaerobic foci of
infection and prevent further toxin production
- Metronidazole- 400 mg rectally or 500 mg IV every 6 h
for 7 days is preferred for antibiotic therapy
- Penicillin (100,000–200,000 IU/kg per day)- alternative
therapy
o theoretically may exacerbate spasms
- Antitoxin- should be given early in an attempt to
deactivate any circulating tetanus toxin and prevent its
uptake into the nervous system
o 2 preparations:
▪ Human tetanus immune globulin (TIG)-
preparation of choice, less associated with
anaphylactoid reactions
● Single IM dose (500–5000 IU) is given, with a
portion injected around the wound.
● Intrathecal administration of TIG inhibits
disease progression and leads to a better
outcome.
▪ Equine antitoxin
● available widely and is used in low-income
countries
● after hypersensitivity testing, 10,000–20,000
U is administered IM as a single dose or as
divided doses.
- Spasms- controlled by heavy sedation with
benzodiazepines
● Chlorpromazine and phenobarbital
● IV magnesium sulfate- muscle relaxant
▪ Problem encountered with doses needed to
control spasms can cause respiratory depression.
▪ Respiratory failure is a common cause of death-
resource limited settings without mechanical
ventilators
▪ In places with ventilation equipment- severe
spasms are best controlled with a combination of
sedatives or magnesium and relatively short-
acting, cardiovascularly inert, nondepolarizing
neuromuscular blocking agents that allow
titration against spasm intensity
▪ Propofol infusion- control spasms and provide
sedation
▪ Early establishment of a secure airway is
important in tetanus
▪ Px should be nursed in a calm, quiet environments
because light and noise can trigger spasms
▪ ↑ Tracheal secretions in tetanus, and dysphagia
due to pharyngeal involvement combined with
hyperactivity of laryngeal muscles makes
endotracheal intubation difficult
▪ Ventilator support for several weeks
▪ Tracheostomy is the usual method of securing the
airway in severe tetanus
▪ Cardiovascular instability in severe tetanus is
difficult to treat
● Rapid fluctuations in HR and BP can occur
● CVS stability improved by ↑ sedation with IV
magnesium sulfate (plasma concentration, 2–
4 mmol/L or titrated against disappearance of
the patellar reflex), morphine, fentanyl, or
other sedatives
o Esmolol, calcium antagonists, and
inotropes may be required
o Short acting drugs- preferred, allow rapid
titration
o Long acting drugs- associated with
hypotensive cardiac arrest
● Complications from treatment:
48
 ○ thrombophlebitis associated with diazepam
injection
○ ventilator-associated pneumonia
○ central-line infections
○ septicemia
● Some centers do prophylaxis against deep-vein
thrombosis
● Recovery- may take 4–6 weeks
○ px must be given a full primary course of
immunization as tetanus toxin is poorly
immunogenic
○ the immune response following natural
infection is inadequate
● Prognosis:
○ Rapid development of disease = more severe
disease → poorer outcome
○ Note time of onset and length of incubation
period
● Predictors of prognosis:
○ Elderly- surviving tetanus is associated with
reduced long-term functional outcome
measures
○ Children and neonates- higher incidence of
neurologic sequelae
○ Neonates- ↑risk for learning disabilities,
behavioral problems, cerebral palsy,
deafness
Prevention
● Good wound care and immunization
● Neonates
○ use of safe, clean delivery and cord
care practices
○ maternal vaccinatin
○ WHO guidelines for tetanus
vaccination:
■ primary course of three
doses in infancy
■ boosters at 4–7, 12–15
years of age
■ 1 booster in adulthood
● Standard WHO recommendations for
prevention of maternal and neonatal tetanu:
○ 2 doses Tetanus toxoid- at least 4
weeks apart to previously
unimmunized pregnant women
○ 3rd dose- given at least 6 months
later
○ 1 dose in subsequent pregnancies
(or intervals of at least 1 year)
○ total of five doses= long-term
immunity
● High risk areas- all women of childbearing
age receiving a primary course along with
education on safe delivery and postnatal
practices
● Individuals sustaining tetanus-prone wounds
○ immunized if their vaccination
status is incomplete or unknown or
if their last booster was given >10
years earlier
● Px with inadequate vaccine status who
sustain wounds not classified as clean or
minor
○ passive immunization with TIG
● Tetanus toxoid be given in conjunction with
diphtheria toxoid in a preparation with or
without acellular pertussis:
○ DTaP for children <7 years old, Td
for 7- to 9-year-olds, and Tdap for
children >9 years old and adults
.
TYPHOID FEVER
Etiology, Pathogenesis, Epidemiology
Enteric (typhoid) fever
- is a systemic disease characterized by fever and
abdominal pain
- caused by dissemination of S. Typhi or S. Paratyphi
- enlarged Peyer’s patches and mesenteric lymph nodes
Epidemiology
- S. Typhi and S. Paratyphi serotypes A, B, and C
▪ No known hosts other than humans
- Food-borne or waterborne transmission- fecal
contamination by ill or asymptomatic chronic carriers
- Sexual transimission between male partners has been
described
- HCWs- may acquire through exposure to infected
patients or during processing of clinical specimens
and cultures
- Due to improved food handling and water/sewage
treatment- enteric fever has lessened
o Highest annual incidence- (>100
cases/100,000 population) in South
Central and Southeast Asia
o Medium (10–100 cases/100,000)- rest of
Asia, Africa, Latin America, and Oceania
(excluding Australia and New Zealand)
o Low in other parts of the world
- High incidence correlated with mixing of drinking water
with human sewage
49
 - Endemic regions o Salmonella can be cultured from punch
o enteric fever is more common in poor neighborhoods biopsies of these lesions
in large cities than rural areas o Hard to detect in highly pigmented px
o young children and adolescents
- Risk factors:
o fecally contaminated drinking water or ice
o flooding, food and drinks purchased from street
vendor
o raw fruits and vegetables grown in fields fertilized
with sewage
o ill household contacts
o lack of hand washing and toilet access
o evidence of prior H. pylori infection (related to
chronically reduced gastric acidity)
- Estimated 1 case of paratyphoid fever for every four
cases of typhoid fever
- Multidrug-resistant (MDR) strains of S. Typhi emerged in
the 1980s in China and Southeast Asia and is
disseminated widely. .
o Contain plasmids ● hepatosplenomegaly (3–6%)
o Encode resistance to chloramphenicol, ampicillin, ● epistaxis
and trimethoprim ● relative bradycardia at the peak of high fever
o ↑ use of fluoroquinolones = ↓ susceptibility to (<50%)
ciprofloxacin (DSC; minimal inhibitory concentration Complications
[MIC], ≥0.125 μg/mL) or ciprofloxacin resistance - estimated to occur in ∼27% of hospitalized patients
(MIC, ≥1 μg/mL) - correlate with a longer duration of symptoms before
o Spread to India, Southern Asia, Eastern and Southern hospitalization
Africa - host factors: host genetics,
o Strains represent clone H58- clinical treatment failure immunosuppression, acid suppression
of fluoroquinolones therapy previous exposure, and vaccination
status
Clinical Manifestations And Diagnosis - strain virulence and inoculum
Clinical Course - choice of antibiotic therapy
- Fever and abdominal pain are variable - GI (6%) & intestinal perforation (1%)- most commonly
o Fever is documented at >75% of cases occur in the 3rd and 4th weeks of illness
o Abdominal pain is reported in only 30–40% - hyperplasia, ulceration, and necrosis of the
o High index of suspicion for this potentially fatal ileocecal Peyer’s patches at the initial site of
systemic illness is necessary Salmonella infiltration
▪ Fever + history of travel to a developing country - Both are life threatening complications
o Mean incubation period for S. Typhi requiring immediate fluid resuscitation &
▪ 10–14 days but ranges from 5 to 21 days surgical intervention
▪ depends on the inoculum size - broadened antibiotic coverage for
▪ host’s health and vaccination status polymicrobial peritonitis
o Most prominent symptom: - treatment of GI hemorrhages (bowel
▪ prolonged fever (38.8°–40.5°C [101.8°–104.9°F]), resection)
which can continue for up to 4 weeks if untreated. - Neurologic manifestations- in 2–40% of patients
▪ S. Paratyphi A- milder disease than S. Typhi, with - meningitis
GI symptoms - Guillain-Barré syndrome
▪ Early PE findings: - neuritis
● rash (“rose spots”; 30%) - neuropsychiatric symptoms ( “muttering
o faint, salmon colored, blanching, delirium” or “coma vigil”) with picking at
maculopapular rash bedclothes or imaginary objects
o located on the trunk and chest
o rash is evident in ∼30% of patients at the
end of the first week
o resolves without a trace after 2–5 days
o Px can have 2 or 3 crops of lesion

50

Uncommon Complications
- disseminated intravascular coagulation,
hematophagocytic syndrome, pancreatitis, hepatic
and splenic abscesses and granulomas, endocarditis,
pericarditis, myocarditis, orchitis, hepatitis,
glomerulonephritis, pyelonephritis and hemolytic-
uremic syndrome, severe pneumonia, arthritis,
osteomyelitis, endophthalmitis, and parotitis
- reduced by prompt antibiotic treatment
- 10% of untreated patients with typhoid fever excrete
S. Typhi in the feces for up to 3 mont
- 2–5% develop chronic asymptomatic carriage,
shedding S. Typhi in either urine or stool for >1 year
- Chronic carriage- common among women, infants, &
persons who have biliary abnormalities or concurrent
bladder infection with Schistosoma haematobium
- S. Typhi, & other salmonellae- adapted to survive in
the gallbladder environment by forming biofilms on
gallstones and invading gallbladder epithelial cells
- Chronic carriage- ↑risk of gallbladder cancer
Diagnosis
- clinical presentation is non-specific
- dx is considered in any febrile traveler returning from
a developing region (Philippines, or Latin America)
- Other ddx: malaria, hepatitis, bacterial enteritis,
dengue fever, rickettsial infections, leptospirosis,
amebic liver abscesses, and acute HIV infection
- no specific laboratory test is diagnostic for enteric
fever
- positive culture for diagnosis
- in 15-25%, leukopenia and neutropenia are
detectable
- leukocytosis is more common among children
- first 10 days
- in cases complicated by intestinal
perforation or secondary infection
- nonspecific laboratory findings
- moderately elevated values in liver function
tests and muscle enzyme levels
- definitive diagnosis:
- isolation of S. Typhi or S. Paratyphi from
blood, bone marrow, other sterile sites, rose
spots, stool, or intestinal secretions
- diagnostic sensitivity of blood culture is only ∼60%
and is lower with low blood sample volume and
among patients with prior antimicrobial use or in the
first week of illness, reflecting the small number of S.
Typhi organisms (i.e., <15/mL) typically present in the
blood
- almost all S. Typhi organisms in blood- associated with
mononuclear cell/platelet fraction, centrifugation of
blood and culture of the buffy coat ↓ time to isolation
of the organism but do not increase sensitivity.
- bone marrow culture- >80% sensitive, its yield is not
reduced by up to 5 days of prior antibiotic therapy
- culture of intestinal secretions
- can be positive despite a negative bone
marrow culture
- blood, bone marrow, and intestinal secretions are all
cultured, the yield is >90%
- stool cultures- can become positive during the third
week of infection in untreated patients
- classic Widal serologic test for “febrile agglutinins”
- simple and rapid
- limited sensitivity and specificity
- inability to differentiate active from prior
infection or vaccination
- other rapid serologic tests: IDL Tubex and Typhidot
- greater accuracy
- cost has limited its use
Treatment
- overall case–fatality rate of 2.5%, and it rises to 4.5% in
hospitalized px
- prompt administration of appropriate antibiotic therapy
prevents severe complications of enteric fever and
reduces mortality to <1%
- initial choice of antibiotics- susceptibility of the S. Typhi
and S. Paratyphi strains in the area of residence or travel
- for drug susceptible typhoid fever
o fluoroquinolones- most effective class of agents
o cure rates of ∼98%
o relapse and fecal carriage rates of <2%
- extensive experience with ciprofloxacin
- short-course ofloxacin therapy- similarly successful
against infection caused by quinolone-susceptible strains
- Px infected with DSC strains of S. Typhi or S. Paratyphi-
treated with ceftriaxone or azithromycin
- Px with ceftriaxone-resistant S. Typhi infection
o Empirical treatment with carbapenem
51
 URINARY TRACT INFECTION

Definitions, Epidemiology, Risk Factors, Etiology,

Pathogenesis
UTI is a common and painful human illness that is rapidly
responsive to modern antibiotic therapy, if the correct
antibiotic is chosen for the particular urinary pathogen.
- Nitrofurantoin
o was available in the 1950s
o was the first tolerable and effective agent for the
treatment of UTI
- common manifestation of UTI: acute cystitis which is
more prevalent among women than among men, most
clinical research on UTI has involved women
UTI may be:
- asymptomatic (subclinical infection)
- symptomatic (disease)
Both UTI and ASB connote the presence of bacteria in the
urinary tract, usually accompanied by white blood cells and
inflammatory cytokines in the urine.

Asymptomatic bacteriuria (ASB)

- ASB occurs in the absence of symptoms attributable
to the bacteria in the urinary tract and usually does
not require treatment
Urinary Tract Infection
- assumed to imply symptomatic disease that warrants
antimicrobial therapy
- catheter- associated infection, does not differentiate
between UTI and ASB
Cystitis
- symptomatic infection of the bladder
Prevention and Control
Prostatitis
- travelers to developing countries should be advised to
-
monitor their food and water intake carefully
Pyelonephritis
- strongly consider immunization against S. Typhi.
- symptomatic infection of the kidneys
- Two typhoid vaccines are commercially available in
- occurs when the infection involves the renal
the United States:
parenchyma
- (1) Ty21a, an oral live attenuated S. Typhi
Uncomplicated Urinary Tract Infection
vaccine (given on days 1, 3, 5, and 7, with
- to an infection confined to the bladder, or acute
revaccination with a full four-dose series
cystitis
every 5 years); in January 2021, manufacture
Complicated Urinary Tract Infection
of Ty21a was suspended due to COVID-19-
- accompanied by symptoms that suggest the infection
related reductions in international travel;
extends beyond the bladder, such as a fever or signs
- (2) Vi CPS, a parenteral vaccine consisting of
or symptoms of systemic illness
purified Vi polysaccharide from the bacterial
Recurrent Urinary Tract Infection
capsule (given in a single dose, with a
- not necessarily complicated; individual episodes can
booster every 2 years).
be uncomplicated and treated as such
- The minimum age for vaccination is 6 years
Catheter-associated Bacteriuria
for Ty21a and 2 years for Vi CPS.
- can be either symptomatic (CAUTI) or asymptomatic.
- Typhoid vaccine should be considered even for
persons planning <2 weeks of travel to high- risk
New approach to UTI categorization differs from the classical
areas.
approach, in which men with UTI are automatically considered
- Clinical microbiology or research laboratory staff at
complicated.
risk of occupational exposure to S. Typhi and
household contacts of known S. Typhi carriers should
Key points in work up and therapy
be vaccinated.

52
 - whether the patient is stable for outpatient
management and whether the antimicrobial agents
need to achieve adequate levels in blood and tissue
Epidemiology and Risk Factors
- UTI occurs far more commonly in females than in
males
- Neonatal period- incidence of UTI is slightly higher
among males than among females because male
infants more commonly have congenital urinary tract
anomalies
- >50 years old- obstruction from prostatic hypertrophy
becomes common in men, and the incidence of UTI is
almost as high among men as among women
- between 1-50 years- UTI and recurrent UTI are
predominantly diseases of females
- ASB is ∼5% among women between ages 20- 40
- as high as 40–50% among elderly women and men
- 50–80% of women- acquire at least one UTI during
their lifetime (uncomplicated cystitis)
- Independent risk factors for acute cystitis:
- Recent use of a diaphragm with spermicide
- frequent sexual intercourse
- history of UTI
- Cystitis- related to recent sexual intercourse in a
dose–response manner
- ↑ relative risk ranging from 1.4 with one
episode of intercourse in the preceding week
to 4.8 with five episodes
- for post-menopausal women
- risk factors: sexual activity, diabetes
mellitus, and incontinence
- Pyelonephritis/Cystitis risk factors:
- frequent sexual intercourse, a new sexual
partner, a UTI in the previous 12 months, a
maternal history of UTI, diabetes, and
incontinence
- shared risk factors since pyelonephritis
typically arises through the ascent of
bacteria from the bladder to the upper
urinary tract
- pyelonephritis can occur without
symptomatic antecedent cystitis
- 20–30% of women who have had one episode of UTI
will have recurrent episodes
- Early recurrence (within 2 weeks)- regarded as
relapse, may indicate the need to evaluate the patient
for a sequestered focus
- In pregnant women
- ASB has clinical consequences, and both
screening for and treatment of this condition
are indicated.
- ASB during pregnancy is associated with
maternal pyelonephritis, which in turn is
associated with preterm delivery.
- majority of men with UTI- have functional or
anatomic abnormality of the urinary tract, most
commonly urinary obstruction secondary to prostatic
hypertrophy
- not all men with UTI have detectable urinary
abnormalities; this point is particularly relevant for
men ≤45 years of age
- no circumcision- ↑ risk of UTI because Escherichia
coli is more likely to colonize the glans and prepuce -
migrate into the urinary tract
- women with diabetes- 2- to 3fold higher rate of ASB
and UTI than women without diabetes
- ↑ duration of diabetes, use of insulin associated with
an inc risk of UTI among women with diabetes
- poor bladder function, obstruction in urinary
flow, incomplete voiding
- Impaired cytokine secretion may contribute to ASB in
diabetic women
- sodium–glucose co-transporter 2 (SGLT2) inhibitors
result in glycosuria
Etiology
- uropathogens causing UTI vary by clinical syndrome
- enteric gram-negative rods that have
migrated to the urinary tract
- acute uncomplicated cystitis
- E. coli accounts for 75–90% of isolates;
Staphylococcus saprophyticus for 5–15%
(with particularly frequent isolation from
younger women); and Klebsiella, Proteus,
Enterococcus, and Citrobacter species
- complicated UTI
- E. coli- predominant organism,
- aerobic gram-negative rods- Pseudomonas
aeruginosa, Klebsiella, Proteus, Citrobacter,
Acinetobacter, and Morganella species
- Gram-positive bacteria (enterococci and
Staphylococcus aureus) and yeasts
- Available data demonstrate a worldwide increase in
the resistance of E. coli to specific antibiotics
commonly used to treat UTI
- In community- acquired infections, the increased
prevalence of multidrug-resistant uropathogens has
left few oral options for therapy in some cases
Pathogenesis
- urinary tract is as an anatomic unit linked by a
continuous column of urine extending from the
urethra to the kidneys
- majority of UTIs, bacteria establish infection by
ascending from the urethra → bladder → ascent up
the ureter to the kidney is the pathway for most renal
parenchymal infections
- interplay of host, pathogen, and environmental
factors determines whether tissue invasion and
symptomatic infection will ensue
- Abnormal micturition and/or significant residual
urine volume promotes infection
53
 - anything that increases the likelihood of bacteria
entering the bladder and staying there increases the
risk of UTI
urinary diversion surgery create an environment
favorable to UTI
- distance of the urethra from the anus-e primary
reason why UTI is predominantly an illness of young
women rather than of young men

Host Factors
- familial disposition to UTI and to pyelonephritis is well
documented
- women with recurrent UTI are more likely to have had
their first UTI before the age of 15 years and to have
a maternal history of UTI
- component of the underlying pathogenesis of this
familial predisposition to recurrent UTI may be
persistent vaginal colonization with E. coli, even
during asymptomatic periods
- vaginal and periurethral mucosal cells from women
with recurrent UTI bind 3-fold more uropathogenic
bacteria than do mucosal cells from women without
recurrent infection
- Epithelial cells from women who are non-secretors of
certain blood group antigens- possess receptors to
Hematogenous spread of bacteria
which E. coli can bind facilitating colonization and
- accounts for <2% of documented UTIs
invasion
- usually results from bacteremia from virulent organisms
- Mutations in host innate immune response genes-
(Salmonella and S. aureus)
linked to recurrent UTI and pyelonephritis
- isolation of either of these pathogens from a patient without
a catheter or other instrumentation warrants a search for a
Microbial Factors
bloodstream source
- an anatomically normal urinary tract presents a
- may produce focal abscesses or areas of pyelonephritis within
stronger barrier to infection
a kidney and result in positive urine cultures
- strains of E. coli that cause invasive symptomatic
- Candida in the urine of a non-instrumented
infection of the urinary tract in otherwise normal
immunocompetent patient implies either genital
hosts often possess and express genetic virulence
contamination or potentially widespread visceral
factors
dissemination
- surface adhesins that mediate binding to
specific receptors on the surface of
Environmental Factors
uroepithelial cells
- Vaginal Ecology- Colonization of the vaginal introitus
- P fimbriae- hair-like protein structures that
and periurethral area with organisms from the
interact with a specific receptor on renal
intestinal flora (usually E. coli) is the critical initial step
epithelial cells
in the pathogenesis of UTI
- adhesin is the type 1 pilus (fimbria)- which all
- Nonoxynol-9 in spermicide is toxic to the normal
E. coli strains possess but not all E. coli
vaginal lactobacilli and thus is likewise associated
strains express, they mediate binding to
with an increased risk of E. coli vaginal colonization
mannose on the luminal surface of bladder
and bacteriuria
uroepithelial cells.
- given the side effects of systemic hormone
- metal (iron) acquisition systems, biofilm formation, and
replacement, oral estrogens should not be used to
capsules- contribute to the ability of pathogenic E. coli to thrive
prevent UTI
in the bladder
Anatomic and Functional Abnormalities
Clinical Manifestations, Diagnosis
- Anything that permits urinary stasis or obstruction
Characterization of the clinical syndrome as ASB,
predisposes the individual to UTI
uncomplicated cystitis, pyelonephritis, prostatitis, or
- Foreign bodies (stones or urinary catheters)- inert
complicated UTI is the first issue to be addressed
surface for bacterial colonization and formation of a
persistent biofilm.
Asymptomatic Bacteriuria
- vesicoureteral reflux, ureteral obstruction secondary
- considered only when the patient does not have local
to prostatic hypertrophy, neurogenic bladder, and
or systemic symptoms referable to the urinary tract

54
 ▪ bacteriuria detected incidentally when a patient
undergoes a screening urine culture for a reason
unrelated to the genitourinary tract
▪ systemic signs are nonspecific and do not merit a
diagnosis of symptomatic UTI
Cystitis
- present with dysuria, urinary frequency, and urgency
- Nocturia, hesitancy, suprapubic discomfort, and gross
hematuria
- Unilateral back or flank pain- upper urinary tract is
involved, and are thus inconsistent with
uncomplicated cystitis
- Fever- invasive infection beyond the bladder,
involving kidney, prostate, or bloodstream

Pyelonephritis
- Mild pyelonephritis
- low-grade fever with or without lower-back
or costovertebral-angle pain, whereas
- Severe pyelonephritis
- can manifest as high fever, rigors, nausea, vomiting,
and flank and/or loin pain

- Fever is the main feature distinguishing cystitis from

pyelonephritis.
- Pyelonephritis typically exhibits a high spiking “picket-fence”
pattern and resolves over 72 h of therapy

Emphysematous pyelonephritis
- severe form of the disease that is associated with the
production of gas in renal and perinephric tissues and
occurs almost exclusively in diabetic patients

Xanthogranulomatous pyelonephritis
- chronic urinary obstruction (often by staghorn
calculi), together with chronic infection, leads to
suppurative destruction of renal tissue

Prostatitis
- both infectious and noninfectious abnormalities of
the prostate gland

55
 - infections can be acute or chronic
- almost always bacterial in nature
- acute bacterial prostatitis- dysuria, frequency, and
pain in the prostatic pelvic or perineal area
- fever, chills, symptoms of bladder outlet obstruction
- Chronic bacterial prostatitis- recurrent episodes of
cystitis, with associated pelvic and perineal pain
Complicated UTI
- systematic illness with an infectious focus in the
urinary tract and frequently occurs in patients with an
anatomic predisposition to infection, such as a foreign
body in the urinary tract
Management
Diagnostic Tools
- Dx of any of the UTI syndromes or ASB begins with a
detailed history
- Women presenting with at least 1 symptom of UTI
(dysuria, frequency, hematuria, or back pain) and
without complicating factors, the probability of acute
cystitis or pyelonephritis is 50%
- vaginal discharge and complicating factors are absent
and risk factors are present- probability of UTI is close to
90%, no need for laboratory evaluation
- dysuria + urinary frequency in the absence of vaginal
discharge increases the probability of UTI to 96%
▪ dipstick testing or urine culture is not necessary
▪ unless with concern for resistant pathogens
Urine Dipstick Test, Urinalysis, and Urine Culture
- both of which provide point-of-care information
- urine culture
- can retrospectively confirm a prior diagnosis
and provide organism susceptibility data for
the patient’s next UTI
- Urine Microscopy
- reveals pyuria in nearly all cases of cystitis
and hematuria in ∼30% of cases
- patient’s symptoms and presentation should
outweigh an incongruent result on
automated urinalysis
- detection of bacteria in a urine culture from
a patient with symptoms of cystitis can
confirm the diagnosis of UTI
Treatment
- antimicrobial therapy is warranted for any UTI that is
truly symptomatic
- responsible use of antibiotics for this common
infection has broad implications for preserving
antibiotic effectiveness into the future
- choice of antimicrobial agent, the dose, and the
duration of therapy depend on the site of infection
and the presence or absence of complicating
conditions
- fosfomycin and pivmecillinam are not available in all
countries but are considered first-line options where
they are available because
- retain activity against uropathogens that
produce extended-spectrum β-lactamases
INTRAABDOMINAL INFECTIONS AND ABSCESSES
Intraperitoneal infections generally arise because a normal
anatomic barrier is disrupted
- appendix, a diverticulum, or an ulcer ruptures
- bowel wall is weakened by ischemia, tumor, or
inflammation (IBD)
- with adjacent inflammatory processes (pancreatitis
or pelvic inflammatory disease)
enzyme leakage into the peritoneal cavity
- Intraabdominal infections occur in two stages:
Peritonitis
Abscess formation
Peritonitis
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 - a life-threatening event that is often accompanied by
bacteremia and sepsis syndrome
- peritoneal cavity is large but is divided into
compartments
o upper and lower peritoneal cavities- divided by the
transverse mesocolon
o greater omentum extends from the transverse
mesocolon and from the lower pole of the stomach
to line the lower peritoneal cavity
o pancreas, duodenum, and ascending and descending
colon are located in the anterior retroperitoneal
space
o kidneys, ureters, and adrenals are found in the
posterior retroperitoneal space
o liver, stomach, gallbladder, spleen, jejunum, ileum,
transverse and sigmoid colon, cecum, and appendix-
within the peritoneal cavity
- serous membrane- exploited in peritoneal dialysis
- serous fluid- protein content (consisting
mainly of albumin) of <30 g/L and <300 white
blood cells (WBCs, generally mononuclear
cells) per microliter
- in bacterial infxs
- leukocyte recruitment- influx of PMN) and a
prolonged subsequent phase of
mononuclear cell migration
Primary Bacterial Peritonitis
- without an apparent source of contamination
- adults- primary bacterial peritonitis (PBP) occurs most
commonly in conjunction with cirrhosis of the liver
(frequently the result of alcoholism
- although PBP virtually always develops in patients
with preexisting ascites in general, an uncommon
event
- ≤10% of cirrhotic patients
- Treatment:
- directed at the isolate from blood or
peritoneal fluid
- until culture is available, therapy should
cover gram-negative aerobic bacilli and
gram-positive cocci
- cefotaxime- 2 g q8h, administered IV
- piperacillin/tazobactam, 3.375 g q6h IV for
adults with normal renal function
- ceftriaxone- 2 g q24h IV
- for nosocomially acquired PBP- ceftolozane-
tazobactam or ceftazidime-avibactam
Secondary Bacterial Peritonitis
- develops when bacteria contaminate the peritoneum
as a result of spillage from an intra abdominal viscus
- organisms found almost always constitute a mixed
flora in which facultative gram-negative bacilli and
anaerobes predominate, especially when the
contaminating source is colonic
- Early death in this setting is attributable to gram-
negative bacillary sepsis and to potent endotoxins
circulating in the bloodstream
- Treatment:
- early administration of antibiotics aimed
particularly at aerobic gram-negative bacilli
and anaerobes
- most appropriate regimen depends on the
anticipated flora and the degree of illness
- Community-acquired infections associated
with mild to moderate disease
- broad- spectrum β-lactam/β-
lactamase inhibitor combinations-,
ticarcillin/clavulanate, 3.1 g q4–6h
IV; or piperacillin/tazobactam,
3.375 g q6h IV
- levofloxacin, 750 mg q24h IV
- third-generation cephalosporin
ceftriaxone, 2 g q24h IV +
metronidazole 500 mg q8h IV
- ICU patients and those with health care–
associated infections
- target gram negative organisms
(Pseudomonas aeruginosa)
- Imipenem (500 mg q6h IV),
meropenem (1 g q8h IV), higher-
dose piperacillin/tazobactam (4.5 g
IV q6h)
- cefepime (2 g IV q8h) or ceftazidime
(2 g IV q8h) plus metronidazole
Intraperitoneal And Retroperitoneal Abscesses
Abscess formation is common in untreated peritonitis if overt
gram- negative sepsis either does not develop or develops but
is not fatal.
- mixed aerobic and anaerobic organisms have been
implanted intraperitoneally
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 - of all intra abdominal abscesses, 74% are intraperitoneal
or retroperitoneal and are not visceral.
▪ Most result from fecal spillage from a colonic
source ( inflamed appendix)
▪ Diagnosis:
● Abdominal CT- highest yield
● Ultrasonography- useful for the right upper
quadrant, kidneys, and pelvis
● Indium-labeled WBCs & gallium -localize
abscesses, useful in finding a collection
- Treatment:
o determination of the initial focus of infection
o administration of broad-spectrum antibiotics
targeting the organisms involved
o performance of a drainage procedure if one or more
definitive abscesses have formed

Visceral Abscesses
Liver Abscesses
- the organ most subject to the development of
abscesses
- may be solitary or multiple
- arise from hematogenous spread of bacteria
or from local spread from contiguous sites of
infection within the peritoneal cavity
- appendicitis with rupture and subsequent
spread of infection- most common source
before
- associated disease of the biliary tract- most
common currently
- Pylephlebitis (suppurative thrombosis of the
portal vein)- common cause of seeding
- Fever- most common presenting sign
- Fever of unknown origin may be the only
manifestation of liver abscess, especially in
the elderly.
- Imaging studies- most reliable methods for
diagnosing liver abscesses
- ultrasonography, CT
- indium-labeled WBC or Gallium scan
- MRI
Treatment:
- Drainage is the mainstay of therapy for
intraabdominal abscesses including liver abscesses
- either percutaneous with a pigtail catheter
kept in place
- a device that can perform pulse lavage to
fragment and evacuate the semisolid
contents of a liver abscess
- transluminal (with endoscopic ultrasound
guidance)
- surgical
- blood cultures & diagnostic aspirate of abscess
contents should be obtained before the initiation of
empirical therapy with antibiotic choices adjusted to
results of Gram stain and culture
Periphrenic Abscess
- Perinephric and renal abscesses are not common
- hematogenous in origin
- complicating prolonged bacteremia, with S. aureus
most commonly recovered
- organisms involved E. coli, Proteus species, and
Klebsiella species
Treatment:
- drainage of pus and antibiotic therapy directed at the
organism recovered
- for perinephric abscesses, percutaneous drainage is
usually successful.
Psoas Abscess
• surgical drainage and the administration of an
antibiotic regimen directed at the inciting organism

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