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Tuberculosis - Comprehensive Review

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1. Etiology and Organism

• Slow-growing (generation time ~15-20 hours); grows on Lowenstein-Jensen (LJ) medium in 3-6 weeks
• Cell wall contains cord factor (trehalose dimycolate) - inhibits phagosome-lysosome fusion, key virulence factor
• Sulfolipids in the cell envelope promote coughing - enhancing transmission
• Related pathogens: M. bovis (cattle, rare), M. africanum, and M. microti comprise the M. tuberculosis complex (MTBC)

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2. Epidemiology

• Park's Textbook of Preventive and Social Medicine

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3. Mode of Transmission

• 60-71% of aerosolized MTB survive for 3 hours indoors; 28-32% for 9 hours under standard conditions
• Close (household) contacts: ~50% become infected; ~15 per 1,000 develop active TB
• Non-close contacts: ~15% infected; ~3 per 1,000 develop active TB
• Patients with cavitary lesions (10^7-10^9 bacilli per cavity) are the most infectious; smear-negative patients can still transmit
• Environmental factors promoting transmission: poor ventilation, recirculating air systems, overcrowding, darkness (UV light kills bacilli)
• UV light irradiation is used in hospital waiting rooms and clinics to reduce transmission

• Murray & Nadel's Textbook of Respiratory Medicine; Goldman-Cecil Medicine

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4. Etiopathogenesis

Step 1: Initial Infection and Innate Response

• Blocking phagosome-lysosome fusion (cord factor, lipoarabinomannan)
• Inhibiting autophagy
• Inducing the Warburg effect
• Activating ESX-1 secretion system to escape the phagosome

Step 2: Adaptive Immunity and Granuloma Formation

• Dendritic cells carry antigen to regional lymph nodes and present to T cells
• CD4+ T cells (Th1) produce IFN-γ, activating macrophages to kill intracellular bacilli
• CD8+ T cells have cytotoxic activity
• IL-12 from macrophages drives Th1 differentiation - patients with IL-12 receptor deficiency have severe mycobacterial infections
• A granuloma forms: a structured collection of activated macrophages (epithelioid cells), Langhans giant cells, lymphocytes, and fibroblasts walling off the bacilli
• Central caseous necrosis (cheese-like, acidic, hypoxic, nutrient-poor) develops, creating a hostile environment that limits bacterial replication but does not eliminate all bacilli

Step 3: Primary TB Complex (Ghon Complex)

• The initial lung parenchymal lesion = Ghon focus (subpleural, typically mid-lung zone)
• Ghon focus + caseating hilar/regional lymph nodes = Ghon (Primary) Complex
• In ~95% of immunocompetent individuals: granulomas calcify, infection is controlled, bacilli remain dormant (latent TB)
• In <5%: primary disease progresses without control

Step 4: Latent TB Infection (LTBI)

• ~1.7 billion people worldwide have LTBI
• Bacilli remain dormant within granulomas, held in check by immune surveillance
• Lifetime risk of reactivation: ~5-10% (without HIV); ~10% per year (with HIV)
• Reactivation triggers: HIV infection, immunosuppressive drugs (TNF-alpha inhibitors, corticosteroids), diabetes mellitus, malnutrition, silicosis, end-stage renal disease, head/neck cancer, lymphoma, advanced age, gastrectomy

Step 5: Post-Primary (Secondary/Reactivation) TB

• Bacilli reactivate, typically in the apices of upper lobes (high O₂ tension favors aerobic MTB growth)
• Rapid tissue destruction due to Type IV (delayed-type) hypersensitivity - the sensitized immune system mounts a vigorous but tissue-destructive response
• Cavitation occurs readily; cavities may erode into airways, releasing infectious bacilli into sputum
• Robbins, Cotran & Kumar Pathologic Basis of Disease; Goldman-Cecil Medicine; Murray & Nadel's

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5. Types / Classification of Tuberculosis

A. By Site

• Involves the lung parenchyma
• Miliary TB is classified as PTB (lesions present in lungs)
• Most common form; source of community transmission

• Lymph nodes (most common EPTB site globally): cervical lymphadenopathy ("scrofula"), non-tender, matted
• Pleura: Pleural effusion (exudative, lymphocyte-predominant, high ADA)
• CNS: Tuberculous meningitis (TBM), tuberculoma - mortality 18-40%
• Spine (Pott's disease): Vertebral body destruction, paravertebral abscess, gibbus deformity, cord compression
• Genitourinary: "Sterile pyuria," ureteric strictures, renal calcification ("putty kidney")
• Peritoneum: Ascites, abdominal pain, peritoneal thickening
• Pericardium: Constrictive pericarditis
• Miliary TB: Hematogenous dissemination producing 1-2 mm millet-seed-like granulomas in multiple organs; can affect lungs, liver, spleen, bone marrow, meninges

B. By Treatment History (WHO Classification)

• New: Never treated or treated <1 month
• Relapse: Previously cured/completed, now recurrent
• Treatment after failure: Treatment failed at end of last course
• Treatment after loss to follow-up: (previously "treatment after default")
• Other previously treated: Unknown/undocumented outcome

C. By Drug Resistance

• Monoresistance: Resistance to one first-line drug
• Polydrug resistance: Resistance to >1 first-line drug (but not both INH and RIF)
• MDR-TB: Resistance to at least isoniazid (INH) and rifampicin (RIF)
• XDR-TB (new 2021 WHO definition): MDR/RR-TB + resistance to any fluoroquinolone AND at least one of bedaquiline or linezolid
• Pre-XDR-TB: MDR/RR-TB + resistance to a fluoroquinolone
• RR-TB: Rifampicin-resistant TB (any resistance to rifampicin)
• Park's Textbook of Preventive and Social Medicine; Murray & Nadel's Respiratory Medicine

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6. Clinical Features

Primary TB

• Usually asymptomatic or subclinical
• May present with: low-grade fever, malaise, nonproductive cough, shortness of breath
• Rare: erythema nodosum (immune-mediated), phlyctenular conjunctivitis
• CXR: mid-lung field patchy opacity (Ghon focus) + hilar lymphadenopathy

Post-Primary (Secondary/Reactivation) TB

• Low-grade fever (typically remittent, highest in the afternoon)
• Night sweats
• Anorexia and significant weight loss (cachexia)
• Fatigue, malaise

• Chronic productive cough (>2-3 weeks) - initially mucoid, then mucopurulent
• Hemoptysis - present in ~50% of pulmonary TB cases; ranges from blood-streaked sputum to massive hemorrhage (Rasmussen aneurysm erosion)
• Dyspnea (with extensive disease, pneumothorax, pleural effusion)
• Pleuritic chest pain (when infection extends to pleural surfaces)
• Rales/crepitations over the apices

Miliary TB

• Fever, weight loss, hepatosplenomegaly
• Diffuse miliary nodules on CXR (1-2 mm "millet seed" pattern)
• Can present with meningism if CNS involved
• May be missed early due to non-specific presentation; bone marrow biopsy may confirm

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7. Systemic / Local Effects (Complications)

Pulmonary Complications

• Cavitation → secondary bacterial infection, aspergilloma (fungus ball in old cavity)
• Bronchiectasis
• Pneumothorax (from pleural disease or bronchopleural fistula)
• Massive hemoptysis
• Respiratory failure (extensive bilateral disease)
• Destroyed lung / fibrosis

Extrapulmonary Complications

Immune-mediated Effects

• Erythema nodosum
• Phlyctenular keratoconjunctivitis
• Reactive arthritis (Poncet's disease)

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8. Laboratory Diagnosis

Bacteriological Tests (Gold Standard)

• ZN staining (standard) or Fluorescent staining (auramine-rhodamine, more sensitive)
• At least 2-3 sputum samples collected (early morning specimens preferred)
• Sensitivity ~40-60%; Specificity ~99% (smear cannot distinguish MTB from NTM)
• A positive smear means the patient is highly infectious (smear-positive TB)

• Solid media: Lowenstein-Jensen (LJ) medium - growth in 3-6 weeks
• Liquid media (automated): BACTEC MGIT 960, BacT/Alert, VersaTrek - results in 1-2 weeks
• Allows drug susceptibility testing (DST)

• Modified proportionate sensitivity testing (MGIT 960 system)
• Economic variant proportion method (1%) on LJ medium
• Essential for diagnosing drug resistance

• GeneXpert MTB/RIF (CBNAAT): PCR-based; simultaneously detects MTB AND rifampicin resistance; results in <2 hours; WHO-recommended first-line test; sensitivity ~89% overall, ~98% in smear-positive
• Truenat MTB: Point-of-care molecular test
• Line Probe Assay (LPA):
  • First-line LPA (FL-LPA): Detects MTB complex + INH and RIF resistance (rpoB, katG, inhA mutations)
  • Second-line LPA (SL-LPA): Detects fluoroquinolone and second-line injectable resistance
• Whole-genome sequencing (WGS): Predicts susceptibility to first-line drugs with >90% accuracy; not yet widely available

Immunological Tests

• Intradermal injection of 0.1 mL (2 TU) PPD (purified protein derivative) into the forearm
• Read at 48-72 hours; measure induration (not erythema) in mm
• Interpretation (induration thresholds):
  • ≥5 mm: HIV positive, recent TB contact, immunosuppressed, old fibrotic lesion on CXR
  • ≥10 mm: High-risk groups (healthcare workers, immigrants from endemic areas, prisoners, diabetics, silicosis, renal failure, children <5 years)
  • ≥15 mm: General population with no risk factors
• False negatives: Active severe TB, HIV/immunosuppression, malnutrition, viral infections (measles, chickenpox), recent live-virus vaccination, incorrect injection, very old infection (waning immunity)
• False positives: BCG vaccination, NTM infection
• Two-step testing: Used for periodic retesting (e.g., healthcare workers) to detect boosting phenomenon
• Does NOT differentiate latent from active TB

• Blood tests: T-cells are stimulated with MTB-specific antigens (ESAT-6, CFP-10 - absent in BCG strains)
• Two commercial assays: QuantiFERON-TB Gold Plus (whole blood ELISA) and T-SPOT.TB (ELISPOT)
• Advantages over TST: Not affected by BCG vaccination, requires only one visit, more specific
• Also cannot differentiate active from latent TB; similar sensitivity to TST
• Preferred in BCG-vaccinated populations and healthcare workers

Radiological Diagnosis

• Primary TB: Mid-lung opacity + hilar lymphadenopathy (Ghon complex)
• Post-primary TB: Upper lobe infiltrates, cavitation, fibrosis, calcification, pleural effusion
• Miliary TB: Diffuse bilateral 1-2 mm nodules throughout both lung fields

• More sensitive than CXR; detects small cavities, tree-in-bud pattern (bronchogenic spread), miliary nodules
• MRI: Better for pleural involvement and characterizing caseous necrosis; preferred in pregnant women and children (no radiation)
• FDG-PET/CT: Useful for monitoring treatment response and differentiating active from inactive disease

Other Diagnostic Tests

• ADA (Adenosine Deaminase): Elevated in pleural, pericardial, peritoneal, and CSF TB
• Histopathology: Caseating granuloma with Langhans giant cells on biopsy (lymph node, pleura, bone)
• CSF analysis (TBM): Lymphocytic pleocytosis, elevated protein, low glucose, low chloride; India ink (exclude cryptococcal meningitis)
• Nucleic Acid Amplification Tests (NAAT): As sensitive as culture in smear-positive samples; less sensitive in smear-negative or pediatric TB
• Murray & Nadel's Respiratory Medicine; Park's Preventive Medicine; Robbins & Cotran Pathology; Sherris & Ryan's Medical Microbiology

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9. Treatment of TB

Principles of Anti-TB Therapy

1. Kill rapidly dividing bacilli (bactericidal activity - early)
2. Kill persisting bacilli in acidic/hypoxic environments (sterilizing activity)
3. Prevent emergence of drug resistance

• Intensive phase: 3-4 drugs for 2 months - rapid kill, reducing bacterial load
• Continuation phase: 2 drugs for 4 months - sterilize residual "persisters," prevent relapse

First-Line Anti-TB Drugs (HRZE)

Standard Treatment Regimens

• 2HRZE / 4HR (2 months intensive phase HRZE + 4 months continuation phase HR)
• Daily regimen is preferred; intermittent (thrice-weekly) also used under DOTS supervision

• Drug susceptibility testing (DST) before starting treatment
• 2HRZES / 1HRZE / 5HRE (older regimen) OR individualized based on DST

• TB meningitis: 2HRZE / 7-10HR (total 9-12 months) + adjuvant dexamethasone
  • Adults: dexamethasone 0.4 mg/kg/24hr with reducing course over 6 weeks
  • Children: prednisolone 4 mg/kg/24hr for 4 weeks, then taper
• Bone/joint TB: 2HRZE / 4-7HR (6-9 months total)
• Spinal TB (Pott's disease): Medical management preferred; surgery for cord compression, poor response to treatment

• 3HP: 3 months of weekly isoniazid + rifapentine (preferred regimen; 12 doses)
• 1HP: 1 month of daily isoniazid + rifapentine
• 3HR: 3 months of daily isoniazid + rifampicin
• 4R: 4 months of daily rifampicin
• 6H: 6 months of daily isoniazid (alternative)
• 9H: 9 months of daily isoniazid (conditionally recommended)
• Isoniazid 5 mg/kg/day (adults), 10-20 mg/kg/day (children), max 300 mg/day
• Murray & Nadel's Respiratory Medicine; Park's Preventive Medicine

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10. MDR-TB (Multidrug-Resistant Tuberculosis)

• ~3.3% of newly diagnosed patients worldwide
• ~20% of previously treated patients
• India: ~2.8% new cases, ~14% previously treated cases

1. Inadequate/irregular treatment (poor adherence)
2. Incorrect prescription (wrong drugs, doses, or duration)
3. Poor drug quality or supply
4. Incomplete treatment courses (patient defaulting)
5. Drug malabsorption
6. Transmission of already-resistant strains

WHO Grouping for MDR-TB Treatment (Longer Regimen)

• Park's Preventive Medicine; Murray & Nadel's; Schwartz's Surgery

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11. XDR-TB (Extensively Drug-Resistant Tuberculosis)

• Rifampicin (part of MDR/RR-TB definition) AND
• Any fluoroquinolone (levofloxacin, moxifloxacin) AND
• At least one of bedaquiline or linezolid

• Remaining susceptible second and third-line agents
• Newer drugs: bedaquiline, linezolid, delamanid, pretomanid
• BPaL/BPaLC regimen: Bedaquiline + Pretomanid + Linezolid ± Clofazimine (TB-PRACTECAL, ZeNix trials)
• Surgery in selected cases (resection of localized disease)

• Complete, adequate, and regular treatment is the most important preventive measure
• DOTS (Directly Observed Treatment, Short-course) - a key WHO strategy
• Rapid DST to guide treatment
• Infection control measures in health facilities

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12. Prophylaxis

A. Chemoprophylaxis (Preventive Therapy for LTBI)

• HIV-positive individuals (regardless of TST/IGRA result in high-burden countries)
• Household contacts of sputum-positive TB (especially children <5 years, immunocompromised)
• Healthcare workers with LTBI
• Patients on anti-TNF therapy
• Patients with fibrotic lesions consistent with old TB (TST/IGRA positive)

B. BCG Vaccination (Primary Prevention)

• Vaccine: BCG (Bacille Calmette-Guérin) - live attenuated strain of M. bovis developed by Calmette and Guérin (1921)
• Efficacy: 70-80% protection against severe forms of childhood TB: tuberculous meningitis, miliary TB. Protection against pulmonary TB in adults is variable (0-80% in different trials)
• Dose: 0.1 mg in 0.1 mL (standard); newborns <4 weeks: 0.05 mL (thinner skin, risk of abscess with full dose)
• Route: Intradermal, into the deltoid (left arm, just above deltoid insertion); using tuberculin syringe with 26-gauge needle; produces a 5 mm wheal if correctly administered
• Age (India policy): At birth (institutional deliveries) or 6 weeks of age (simultaneously with DPT and polio)
• Site: Left deltoid (if injected too high/forward/backward, regional lymph nodes may become involved)

1. 2-3 weeks: papule develops
2. ~5 weeks: papule reaches 4-8 mm, then may ulcerate (shallow, usually crusted)
3. 6-12 weeks: heals, leaves permanent scar (4-8 mm round scar = evidence of successful vaccination)
4. 8-14 weeks: Mantoux test becomes positive

• Local ulceration and lymphadenitis: 1-10% of vaccinations
• Disseminated BCG infection: <1 per million vaccinations (associated with severe cellular immunodeficiency, e.g., SCID)
• Osteomyelitis (rare)

• Park's Preventive Medicine

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13. Prevention and Control (RNTCP/NTP Strategies)

DOTS (Directly Observed Treatment, Short-Course)

1. Government commitment to sustained TB control
2. Case detection by bacteriological examination (sputum microscopy)
3. Standardized short-course chemotherapy under direct observation
4. Regular, uninterrupted supply of all essential anti-TB drugs
5. Recording and reporting system for monitoring and evaluation

End TB Strategy (WHO)

1. Integrated, patient-centered care and prevention
2. Bold policies and supportive systems
3. Intensified research and innovation

Key Prevention Measures

1. BCG vaccination (primary prevention - especially for children)
2. Early case detection and prompt treatment (breaking transmission chain)
3. Contact tracing and LTBI treatment (especially household contacts)
4. Infection control in healthcare facilities: N95 respirators, negative-pressure rooms, UV irradiation of room air, HEPA filtration, adequate ventilation
5. Addressing risk factors: Control of HIV (antiretrovirals reduce TB risk), diabetes management, improved nutrition, reduced overcrowding and poverty
6. Active screening of vulnerable groups: prisoners, homeless, healthcare workers, immunocompromised, TB contacts
7. Notification: TB is a notifiable disease; mandatory reporting under national programs
8. Prevention of drug resistance: Ensuring treatment completion, use of fixed-dose combinations (FDCs), DST-guided therapy

Notification and Recording

• All TB cases must be notified to the National Tuberculosis Elimination Programme (NTEP, formerly RNTCP) in India
• Treatment outcomes recorded: Cured, Treatment completed, Treatment failed, Died, Lost to follow-up, Not evaluated

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Summary Table

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Recent WHO Guidelines on TB Diagnosis and Drug-Resistant TB Management (2024-2026)

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WHO Consolidated Guidelines - Module Structure (Updated 2025)

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PART 1: Updated WHO Guidance on TB Diagnosis (Module 3, August 2025)

1. Rapid Molecular Tests - Now the First-Line Standard

• A 2023 UN High-Level Meeting target requires that 100% of people diagnosed with TB should initially be tested with a WHO-recommended rapid diagnostic test by 2027
• 2024 WHO benchmarks: 12 standards defined for universal access to rapid TB diagnostics

• Low-complexity automated NAATs (e.g., GeneXpert MTB/RIF Ultra, Cobas MTB)
• Manual NAATs (e.g., Truenat MTB, MTB Plus)
• Biomarker-based point-of-care tests (e.g., LF-LAM for HIV-positive patients)

2. Xpert MTB/RIF Ultra - Updated Evidence (Cochrane 2025)

3. New Near-Point-of-Care Tests (March 2026)

• Portable battery-powered molecular tests delivering results in <1 hour, at less than half the cost of existing molecular diagnostics
• Recommended for tongue swab samples - a new, easy-to-collect sample type for adults and adolescents who cannot produce sputum (previously untestable population)
• Sputum pooling strategy - combining samples from multiple individuals reduces commodity costs and machine time (recommended when resources are exceptionally constrained)
• These devices have potential future use for HIV, mpox, and HPV testing

4. Targeted Next-Generation Sequencing (tNGS)

• Updated tNGS solutions for detection of drug-resistant TB (resistance to more drug classes than GeneXpert)
• Revised pooled diagnostic accuracy estimates for NAATs
• New figure guiding use of DST results for treatment regimen selection

5. New and Updated IGRAs

• New policy statements on use of newer-generation IGRA platforms for detection of TB infection
• Updated diagnostic algorithms for:
  • Adults and adolescents with HIV (concurrent respiratory + non-respiratory sample testing)
  • Children with HIV
  • Children without HIV or with unknown HIV status

6. Isoniazid-Resistant TB - New Emphasis

• WHO 2025 data: Isoniazid-resistant, rifampicin-susceptible TB is now the most prevalent form of drug resistance globally (aside from streptomycin resistance)
  • ~7% of newly diagnosed cases
  • ~8-11% of previously treated cases
• INH-resistant TB carries a higher risk of acquiring further resistance and evolving toward MDR-TB if treated with standard 2HRZE/4HR
• Dedicated guidance for this category: add levofloxacin to cover INH resistance

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PART 2: Updated WHO Guidance on Drug-Resistant TB Treatment (Module 4, 2025)

Key Paradigm Shift: All-Oral Shorter Regimens

A. 6-Month BPaLM Regimen - New Standard for MDR/RR-TB

B. Pre-XDR-TB: New Trial Evidence - endTB-Q (Lancet Respir Med, September 2025)

• 6-month BDLC for limited disease, 9-month BDLC for extensive disease
• Favourable outcome at week 73: 87% (BDLC) vs. 89% (control) in mITT population
• Adjusted risk difference: +0.2% (95% CI -9.1 to +9.5; p-noninferiority = 0.0051) - non-inferiority demonstrated in mITT
• Per-protocol analysis did not show non-inferiority (borderline result)
• This trial provides important evidence supporting all-oral regimens even for fluoroquinolone-resistant TB

C. Bedaquiline + Linezolid - Meta-Analysis

D. STREAM Stage 2 - Long-Term Data (Lancet Respir Med, December 2024)

E. Indian RCT on BPaL Linezolid Dosing (Clin Infect Dis, December 2024)

F. QTc Monitoring - TB-PRACTECAL Data

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PART 3: DS-TB - Shorter Regimen Research (Clo-Fast Trial, Lancet Infect Dis, January 2026)

• The trial was stopped early for lack of clinical efficacy - the 3-month clofazimine-containing regimen did not meet non-inferiority criteria
• Important negative result: this particular shortening strategy did not work
• However, ATS/CDC/ERS/IDSA 2025 updates conditionally recommend 4-month regimens (rifapentine + moxifloxacin-based) for selected DS-TB patients ≥12 years old

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PART 4: TB and Undernutrition (WHO Module 6, October 2025)

• Nutritional assessment and counselling for ALL people with TB and household contacts - now a core TB strategy
• Addressing food insecurity is integrated into people-centered care under the End TB Strategy
• Undernutrition is one of the most significant drivers of the TB epidemic globally

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Summary of What Changed vs. Prior Guidelines

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• WHO Global TB Report 2025 - Section 2.2 Diagnostic Testing (data as of July 30, 2025)
• WHO Operational Handbook Module 3: Diagnosis, updated August 2025
• WHO new near-POC diagnostic tools, March 24, 2026
• BPaLM systematic review: Silva et al., J Bras Pneumol 2025 (PMID 39813501)
• endTB-Q pre-XDR trial: Guglielmetti et al., Lancet Respir Med 2025 (PMID 40683298)
• Xpert Ultra in children (Cochrane 2025): Kay et al., Cochrane Database 2025 (PMID 41128098)
• WHO Module 6 - TB and undernutrition, October 2025

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HIV / AIDS - Comprehensive Review

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1. Introduction and Epidemiology

• ~39 million people living with HIV worldwide (2022)
• ~630,000 deaths annually
• ~67% of all cases in Sub-Saharan Africa
• ART transformed HIV from a fatal disease to a manageable chronic illness (after 1995-96 in high-income countries)
• UNAIDS 95-95-95 targets (by 2030): 95% know status, 95% on ART, 95% virally suppressed - already achieved by 5 countries (Botswana, Eswatini, Rwanda, Tanzania, Zimbabwe)
• First-line ART now costs <$45/year in low- and middle-income countries (vs. >$10,000/year in 2000)
• Harrison's Principles of Internal Medicine 22E (2025); Robbins & Kumar Basic Pathology

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2. The Virus - Virology

• HIV-1: Responsible for the global pandemic; more virulent
• HIV-2: Predominantly West Africa; less transmissible, slower progression; NNRTIs, enfuvirtide, and fostemsavir are NOT active against HIV-2

• Enveloped RNA virus; genome is single-stranded positive-sense RNA (two copies)
• Outer envelope: gp120 (surface glycoprotein, binds CD4) + gp41 (transmembrane; mediates fusion)
• Capsid protein: p24 (marker of acute infection)
• Matrix protein: p17
• Enzymes within the virion: Reverse transcriptase (RNA → DNA), Integrase (integrates viral DNA into host genome), Protease (cleaves polyproteins into functional proteins)

• Structural: gag (core proteins), pol (enzymes), env (envelope proteins)
• Regulatory: tat (transactivator - key for viral replication), rev (RNA export), nef, vif, vpr, vpu

• T-tropic (X4) strains: Infect CD4+ T cells using CXCR4 as co-receptor (dominant in late disease)
• M-tropic (R5) strains: Infect macrophages/monocytes using CCR5 as co-receptor (dominant in early infection, sexually transmitted)
• Dual-tropic strains: Use both co-receptors

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3. Mode of Transmission

A. Sexual Transmission (Most Common)

• Vaginal, anal (highest risk for receptive partner), or oral sex
• Risk factors: high viral load in source, lack of condom use, concurrent STIs (especially ulcerative: syphilis, herpes, chancroid), uncircumcised male
• USA: ~70% of new infections in MSM (men who have sex with men), ~20% heterosexual
• Africa/Asia: heterosexual transmission dominant, equal sex distribution; accounts for >80% of new infections worldwide

B. Parenteral Transmission

• Sharing of contaminated needles/syringes (IV drug users) - 6% of US cases
• Blood/blood product transfusion (largely eliminated by screening)
• Needlestick injuries in healthcare workers (risk ~0.3% per needlestick from HIV+ source)
• Occupational exposure: corneal/mucous membrane splash (risk ~0.09%)

C. Mother-to-Child Transmission (MTCT / Vertical)

• During delivery (birth canal) - most common
• Transplacental (in utero, less common)
• Breastfeeding
• Overall rate WITHOUT intervention: ~25-40%; WITH ART: <1% in US
• Major cause of pediatric AIDS

• Robbins & Kumar Basic Pathology; Sherris & Ryan's Medical Microbiology

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4. Pathogenesis

Step 1: Entry and Initial Infection

• gp120 binds CD4 on T helper cells and macrophages
• Co-receptor binding: CCR5 (early, M-tropic) or CXCR4 (later, T-tropic)
• gp41 mediates membrane fusion → viral core enters cytoplasm
• Memory CD4+ T cells in mucosal-associated lymphoid tissue (MALT/GALT) are the first major target - massive depletion occurs here early
• Dendritic cells in the epithelium capture virus and transport it to lymph nodes via direct cell-to-cell contact with CD4+ T cells

Step 2: Viremia and Dissemination

• Within days of exposure: viral replication in lymph nodes detectable
• High-level viremia: Virus disseminates throughout the body; infects CD4+ T cells, macrophages, and dendritic cells in peripheral lymphoid tissues
• Blood: >10^6 viral copies/mL during acute phase

Step 3: Immune Response and Acute HIV Syndrome

• 3-6 weeks post-infection: 40-90% of individuals develop acute HIV syndrome (acute retroviral syndrome / primary HIV infection)
• Host mounts humoral (anti-HIV antibodies) and cell-mediated (HIV-specific CD8+ cytotoxic T lymphocytes) responses
• Seroconversion occurs 3-7 weeks after exposure (window period)
• Viremia falls; patient enters clinical latency

Step 4: Chronic/Latent Phase

• Virus concentrates in lymphoid tissues; low-level ongoing replication continues
• CD4+ T cell count slowly declines (~50-100 cells/µL per year without ART)
• Lymph nodes: early reactive hyperplasia of B cell follicles → later follicular dissolution and lymphoid depletion (morphologic reflection of immunosuppression)
• Patient clinically asymptomatic; may have persistent generalized lymphadenopathy (PGL)
• Duration: typically 8-10 years without treatment (range 1-20 years)

Step 5: Progressive Immunodeficiency and AIDS

• HIV infects and kills CD4+ T cells through:
  • Direct cytopathic effect (viral budding, pore formation)
  • Immune-mediated killing of infected cells by CD8+ CTLs
  • Syncytia formation (fusion of infected and uninfected cells)
  • Chronic immune activation and bystander apoptosis
• Macrophages: infected but more resistant to cytopathic effects → serve as reservoirs
• CNS: HIV carried into brain by infected monocytes ("Trojan horse"); neurologic effects mostly indirect via viral products and cytokines from infected macrophages (neurons not directly infected)

HIV Reservoirs (Key barrier to cure)

1. Cellular reservoirs: Resting CD4+ T cells (central memory TCM, transitional memory TTM, effector memory TEM) with integrated HIV provirus; CD34+ bone marrow stem cells
2. Anatomical reservoirs: GALT (gut-associated lymphoid tissue), lymph nodes (low ART penetration); CNS

• Robbins & Kumar Basic Pathology; Sherris & Ryan's Medical Microbiology 8e

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5. Clinical Stages / Natural History

Phase 1: Acute HIV Syndrome (Primary HIV Infection)

• Fever, myalgias, arthralgias
• Sore throat, pharyngitis
• Maculopapular rash (trunk and arms)
• Lymphadenopathy
• Headache, retroorbital pain
• Diarrhea, nausea, vomiting
• Oral ulcers (aphthous)
• Aseptic meningitis (in some)

Phase 2: Clinical Latency / Asymptomatic Phase

• Duration: ~8-10 years average without ART
• Patient asymptomatic or has only Persistent Generalized Lymphadenopathy (PGL): bilateral, non-tender, >1 cm, in ≥2 extrainguinal sites for >3 months
• Ongoing viral replication, gradual CD4+ decline
• Viral set point determines prognosis

Phase 3: Early Symptomatic HIV (WHO Stage 2-3)

• CD4 count ~200-500 cells/µL
• Recurrent bacterial infections, mucosal candidiasis, oral hairy leukoplakia, herpes zoster, seborrhoeic dermatitis, unexplained weight loss (<10%), chronic diarrhea, recurrent sinusitis, recurrent upper respiratory infections

Phase 4: AIDS (CDC Stage 3 / WHO Stage 3-4)

1. CD4+ count <200 cells/µL, OR
2. CD4+ percentage <14%, OR
3. Presence of an AIDS-defining condition (regardless of CD4 count)

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6. WHO Clinical Staging System

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7. AIDS-Defining Conditions (CDC/WHO Stage 4)

Opportunistic Infections

• Pneumocystis jirovecii pneumonia (PCP) - CD4 <200
• Cryptococcal meningitis - CD4 <100
• Disseminated histoplasmosis, coccidioidomycosis
• Esophageal candidiasis - CD4 <100
• Penicilliosis (Talaromyces marneffei) - Southeast Asia

• Disseminated Mycobacterium avium complex (MAC/MAI) - CD4 <50
• TB (both pulmonary and extrapulmonary) - any CD4 count
• Recurrent Salmonella septicemia
• Recurrent pneumonia (>2 episodes in 12 months)

• CMV retinitis/colitis/esophagitis - CD4 <50
• HSV chronic ulcers >1 month; bronchitis, pneumonitis, esophagitis
• Progressive multifocal leukoencephalopathy (PML) - JC virus - CD4 <50

• Disseminated toxoplasmosis (cerebral toxoplasmosis) - CD4 <100
• Cryptosporidiosis with diarrhea >1 month
• Microsporidiosis
• Isosporiasis

AIDS-Defining Malignancies

• Kaposi's sarcoma (HHV-8) - vascular skin lesions, violaceous plaques; visceral involvement
• Non-Hodgkin lymphoma (particularly Burkitt's and diffuse large B-cell)
• Primary CNS lymphoma (EBV-associated) - CD4 <50
• Invasive cervical carcinoma (HPV-related)

Neurologic AIDS-Defining Conditions

• HIV-associated neurocognitive disorder (HAND) / HIV encephalopathy - most common cause of dementia under 50 in pre-ART era
• Vacuolar myelopathy
• Progressive encephalopathy

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8. Systemic Effects by Organ System

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9. Laboratory Diagnosis

A. Tests for HIV Infection

• Gold standard for initial screening
• Detects: HIV-1/2 antibodies + p24 antigen simultaneously
• Positive from 18-45 days post-infection (shorter window period than 3rd-generation Ab-only tests)
• If reactive: confirm with HIV-1/HIV-2 antibody differentiation immunoassay
• If confirmatory test negative/indeterminate: order HIV RNA NAAT (to detect acute infection)

• Detects HIV antibodies; sensitivity ~99.5%, specificity ~99.5%
• Reactive ELISA must be confirmed with Western blot or differentiation assay
• Window period: 3-12 weeks (average 6 weeks) for 3rd-generation; shorter for 4th-generation

• Detects antibodies to specific HIV proteins
• Positive: Bands to p24, gp41, gp120/160
• Indeterminate: Insufficient bands - repeat in 1 month or do RNA test
• Being replaced by HIV-1/HIV-2 differentiation immunoassay in many settings

• Detects viral RNA as early as 10-14 days post-infection
• Used for: diagnosing acute HIV (seronegative window period), confirming diagnosis in indeterminate serology, pediatric diagnosis in infants born to HIV+ mothers
• Essential for viral load monitoring (see below)

• Point-of-care; results in 20-30 minutes; detect HIV antibodies
• Used for urgent situations, resource-limited settings
• All reactive rapid tests require confirmatory testing

• Detects viral core protein; positive from ~2 weeks post-infection
• Now usually part of 4th-generation combination test

B. Monitoring Tests (for HIV+ Patients)

• Absolute number (cells/µL) and percentage
• Normal: 500-1500 cells/µL
• Indicates degree of immunosuppression and risk of OIs:

• Measured in copies/mL; ideally expressed as log10
• Goals of ART: achieve viral suppression <50 copies/mL (undetectable)
• "Undetectable = Untransmittable" (U=U): virally suppressed patients do not sexually transmit HIV
• Monitored: baseline, 2-4 weeks after starting/changing ART, then every 3-6 months
• Virologic failure: Detectable viral load (>200 copies/mL) after 6 months of ART

• Performed at: HIV diagnosis (before starting ART), virologic failure, any change due to failure
• Identifies resistance mutations in reverse transcriptase, protease, and integrase genes
• Guides selection of active ART drugs

• Cryptococcal antigen (serum, CSF)
• CMV PCR (serum, vitreous)
• Toxoplasma serology (IgG)
• TB testing (IGRA, sputum AFB)
• Hepatitis B and C serology
• Sherris & Ryan's Medical Microbiology; Robbins & Kumar Basic Pathology; Harrison's Principles 22E

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10. Antiretroviral Therapy (ART)

When to Start

Classes of Antiretroviral Drugs

Preferred First-Line Regimens (Current US DHHS Guidelines)

• Biktarvy (Bictegravir/TAF/FTC) - single pill, once daily; most commonly prescribed
• Dolutegravir + TAF or TDF + FTC/3TC
• Dolutegravir + ABC + 3TC (Triumeq) - if HLA-B*5701 negative

• Dolutegravir + 3TC (Dovato) - for hepatitis B-negative patients with baseline viral load <500,000 copies/mL

• Cabotegravir (CAB) + Rilpivirine (RPV) long-acting - given as IM injections every 1 or 2 months; improves adherence; equivalent efficacy to daily oral ART
• Represents a major shift in how ART is delivered

Principles of ART Use

• Never use monotherapy - rapid resistance develops
• Minimum of 3 active agents from ≥2 classes (or 2-drug INSTI-based regimens in selected patients)
• Goal: HIV RNA <50 copies/mL (undetectable) on all monitoring tests
• Adherence is critical - even brief gaps lead to resistance
• Drug resistance testing before starting therapy and at virologic failure
• Fixed-dose combinations (FDCs) greatly improve adherence

Key Side Effects of ART

Immune Reconstitution Inflammatory Syndrome (IRIS)

• Paradoxical worsening of a pre-existing OI after starting ART, despite rising CD4 and falling viral load
• Due to restored immune response attacking residual antigens
• Common with: TB, cryptococcal meningitis, MAC, CMV, Kaposi's sarcoma
• Management: Continue ART; NSAIDs or corticosteroids for severe cases
• Prevention: Delay ART for 2-4 weeks after starting TB or cryptococcal treatment

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11. Prophylaxis for Opportunistic Infections

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12. Prevention of HIV

A. Pre-Exposure Prophylaxis (PrEP)

• MSM or bisexual men not using condoms
• Transgender individuals
• Multiple sexual partners
• History of STIs
• Individuals from high-prevalence areas (≥3%)
• Injection drug users sharing equipment
• Sex workers

• Daily oral TDF/FTC (Truvada) - highly effective (~99% when adherent)
• On-demand/pericoital TDF/FTC (2-1-1 regimen) - for planned sex in MSM
• Long-acting injectable Cabotegravir (CAB-LA) - every 2 months IM injection; now recommended as first-line PrEP for all sexual risk populations; superior to oral TDF/FTC in trials (HPTN 083, HPTN 084)

B. Post-Exposure Prophylaxis (PEP)

• TDF 300 mg + FTC 200 mg (once daily) + Dolutegravir 50 mg (once daily) OR Raltegravir 400 mg twice daily
• Darunavir/ritonavir is an alternative third drug

C. Prevention of Mother-to-Child Transmission (PMTCT)

• ART for all HIV+ pregnant women (regardless of CD4) - reduces MTCT from ~25-40% to <1%
• Elective cesarean section in women with detectable viral load near delivery
• Infant prophylaxis: Zidovudine or nevirapine syrup for 4-6 weeks after birth
• Avoidance of breastfeeding in resource-rich settings (where safe alternatives available)

D. Behavioral and Structural Prevention

• Condom use - consistent and correct use reduces transmission by ~70-80%
• Male circumcision - reduces risk in heterosexual men by ~60%
• Harm reduction for IDU: Needle/syringe exchange programs, opioid substitution therapy
• HIV testing and counseling - CDC recommends routine testing for all ages 13-64 at least once
• Treatment as Prevention (TasP): Undetectable = Untransmittable (U=U) - virally suppressed HIV+ individuals cannot transmit HIV sexually
• Education and behavior modification - cornerstone of any strategy
• Blood safety: Mandatory screening of blood donations; donor deferral criteria
• Healthcare worker precautions: Universal precautions; avoid recapping needles; immediate wound wash after exposure; prompt PEP initiation; HBV vaccination (important because HBV is 50x more transmissible than HIV from needlestick)

E. Vaccine Development

• Harrison's Principles of Internal Medicine 22E (2025); Goldman-Cecil Medicine; Robbins & Kumar Basic Pathology; Sherris & Ryan's Medical Microbiology 8e

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Summary Table

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Rabies - Comprehensive Review

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1. Introduction

• ~55,000-59,000 deaths per year globally (WHO estimate)
• Nearly 100% mortality once clinical symptoms develop
• >95% of human deaths occur in Asia and Africa; dog bites cause >90% of deaths in developing countries
• First successful post-exposure prophylaxis: Louis Pasteur, July 1885 (9-year-old Joseph Meister after a dog bite)

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2. Etiology / The Virus

• Family: Rhabdoviridae
• Genus: Lyssavirus (currently 14 species in 3 phylogroups)
• Type: Negative-sense, single-stranded RNA virus

• Bullet-shaped (unique - diagnostic shape), enveloped
• 70 nm × 180 nm
• Helical nucleocapsid (N protein) wrapped around the RNA genome
• Surface: knob-like glycoprotein (G) spikes embedded in the lipid envelope
• Matrix protein (M) lies between the nucleocapsid and envelope

• The glycoprotein (G) elicits virus-neutralizing and hemagglutination-inhibiting antibodies - the basis for vaccine immunity
• G protein binds to host cell receptors (nicotinic acetylcholine receptors at neuromuscular junctions, neural cell adhesion molecules, p75 neurotrophin receptor)
• Strains from different animals (bats, dogs, skunks, foxes, raccoons) show antigenic heterogeneity - this may explain occasional vaccine failures
• An RNA-dependent RNA polymerase is enclosed within the nucleocapsid

• Worldwide: Dogs (primary reservoir, cause >90% human deaths globally)
• North America: Bats (primary source of human rabies in USA), raccoons (eastern USA), skunks (central USA), foxes, coyotes
• Europe: Foxes, bats
• Small rodents (squirrels, rats, mice, hamsters) and lagomorphs (rabbits): rabies is rare in these animals
• Hawaii: Rabies-free
• Sherris & Ryan's Medical Microbiology 8e; Red Book 2021

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3. Epidemiology and Transmission

Transmission Routes

• Animal bite - virus transmitted via infected saliva
• Scratch with contaminated saliva on broken skin
• Lick on broken skin or mucous membranes

• Aerosol transmission - documented in bat-inhabited caves (Frio cave, Texas) and laboratory accidents
• Organ/corneal transplantation from donors dying of unrecognized rabies (documented clusters - 2004: 4 recipients died; corneal transplants)
• No documented person-to-person bite transmission in the USA

• Small rodents (squirrels, rats, mice, hamsters, gerbils, chipmunks), rabbits, hares - rabies is extremely rare in these species
• Animals with intact vaccination status that remain healthy for 10 days after bite

Animal observation rule:

• A dog, cat, or ferret that remains healthy for 10 days of confinement after biting a person has NOT transmitted rabies - no PEP needed
• Unimmunized biting animals should be euthanized and brain tested

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4. Pathogenesis

Step 1: Inoculation

• Virus inoculated through epidermis (animal bite)
• Also possible via inhalation of heavily contaminated aerosol

Step 2: Replication in Muscle

• Virus first replicates in striated muscle tissue at the site of inoculation
• This "peripheral replication phase" provides the window of opportunity for vaccination to prevent neural invasion
• Immunization given during this phase can prevent migration into neural tissues

Step 3: Entry into Peripheral Nervous System

• Virus binds to receptors at neuromuscular junctions and enters peripheral nerve endings
• Travels centrally by retrograde axonal transport (not via bloodstream)
• Rate of spread: ~3 mm/hour along axons

Steps 4-5: Passive Ascent via Sensory Fibers, Replication in Dorsal Ganglion

• Travels up sensory fibers to dorsal root ganglia
• Replicates in dorsal ganglion (explains paresthesias at bite site as an early symptom)

Step 6-7: Rapid Ascent to CNS

• Rapid ascent in the spinal cord → brainstem, cerebellum, cerebral cortex
• Replicates exclusively within the gray matter of the CNS
• Neuropathology: lymphocytic infiltration, neuronal destruction, most severe in brainstem, limbic system, hippocampus

Step 8: Centrifugal Spread (Descending)

• After CNS infection established, virus spreads centrifugally along autonomic nerves to:
  • Salivary glands → facilitates transmission to next host
  • Adrenal medulla
  • Kidneys
  • Lungs
  • Eyes, skin (corneal epithelium - explains diagnostic utility of nuchal skin biopsy)

Key Neuropathological Feature: Negri Bodies

• Negri bodies = eosinophilic, oval or round intracytoplasmic inclusions in neurons
• Pathognomonic for rabies
• Located in: hippocampus (Ammon's horn - most common site), cerebral cortex, cerebellum (Purkinje cells), dorsal spinal ganglia
• Represent accumulations of viral nucleocapsid proteins
• Found in 75-90% of rabies cases in dogs by microscopy
• Size: 2-10 µm; may contain a central darkly staining granule

Why rabies has a variable incubation period:

• Incubation depends on distance from bite to CNS (leg bite longer than face/neck bite), viral inoculum, and site-specific nerve density
• Face/neck bites → short incubation; lower limb bites → longer incubation
• Sherris & Ryan's Medical Microbiology 8e; Bradley and Daroff's Neurology; Park's Preventive Medicine

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5. Incubation Period

• Usual: 1-3 months (average 20-90 days)
• Range: 10 days to several years (documented up to 6+ years)
• Factors determining incubation:
  • Shorter: Head/neck/face bites, multiple deep wounds, high viral inoculum, bites near nerve-rich areas
  • Longer: Lower extremity bites, distal wounds, low inoculum
• Incubation in dogs: 3-8 weeks (range: 10 days to >1 year)

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6. Clinical Features

Phase 1: Prodromal Phase (2-10 days)

• Fever, malaise, headache, fatigue
• Anorexia, nausea, vomiting
• Paresthesias, pain, or pruritus at the bite site - highly characteristic (reflects viral replication in dorsal root ganglia)
• Anxiety, agitation, depression
• Sore throat, cough

Phase 2: Acute Neurological Phase

A. Furious (Encephalitic) Rabies (~80% of cases)

• Hydrophobia (fear of water) - present in up to 80% of patients
  • Severe, painful spasms of pharyngeal and nuchal muscles on swallowing or seeing water
  • Triggered by: swallowing attempts, tactile, auditory, visual, olfactory stimuli
  • Spasms last 1-5 minutes
  • Mechanism: exaggerated respiratory tract protective reflex
• Aerophobia - spasms triggered by air blown on the face
• Hyperactivity, agitation, confusion, hallucinations
• Autonomic hyperactivity: hypersalivation ("foaming at the mouth"), excessive sweating, piloerection, hyperthermia (up to 105-107°F), tachycardia, hypertension
• Seizures
• Cranial nerve palsies
• Bat-acquired rabies more commonly shows: tremor, myoclonus, local sensory symptoms at the exposure site, abnormal cranial nerve and motor examinations

B. Paralytic (Dumb) Rabies (~20% of cases)

• Characterized by ascending flaccid paralysis resembling Guillain-Barré syndrome
• Paresthesias and weakness in the bitten extremity → progressive quadriplegia
• Hydrophobia less prominent or absent
• More commonly seen with bat-acquired rabies
• Consciousness preserved longer than in furious form
• Often misdiagnosed as GBS - rabies should be in the differential of any unexplained ascending paralysis

Phase 3: Coma and Death

• Both forms progress to coma
• Death from: respiratory paralysis (major cause), cardiac arrhythmias, autonomic failure
• Survival after symptom onset: typically 2-7 days (furious); slightly longer in paralytic form
• Outcome: nearly universally fatal - only a handful of documented survivors (most following some pre-exposure vaccination history)

Clinical features in animals:

• Furious rabies in dogs: Change in behavior (cardinal sign), aggression, biting without provocation, running amuck, hoarse voice/inability to bark, excessive salivation and foaming, then paralysis
• Dumb rabies in dogs: Predominantly paralytic; withdrawal, sleepiness, death in ~3 days
• Infected animals rarely survive more than a week after symptom onset

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7. Differential Diagnosis

• Tetanus (shorter incubation <2 weeks; trismus; normal CSF; no hydrophobia)
• Viral encephalitis (herpes, arboviral, EV-71)
• Guillain-Barré syndrome (for paralytic rabies)
• Intoxications (strychnine, atropine)
• Psychiatric illness, hysteria, rabies phobia (hysterical response to animal bite)
• Postvaccinal encephalitis (rare, with older nerve-tissue vaccines)

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8. Laboratory Diagnosis

In Humans (Antemortem)

In Animals (Postmortem)

CSF findings:

• Mononuclear pleocytosis (present in >50% in first week, >87% beyond first week)
• Slightly elevated protein

MRI findings (when available):

• T2/FLAIR signal abnormalities in gray matter: basal ganglia, thalamus, midbrain, pontine nuclei, brainstem, cortex
• Park's Preventive Medicine; Bradley and Daroff's Neurology; Red Book 2021; Sherris & Ryan's Medical Microbiology

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9. WHO Wound Category Classification and Post-Exposure Prophylaxis (PEP)

WHO Categories of Exposure

• Biting animal is a known reservoir/vector species (bats, foxes, raccoons, skunks, dogs in endemic areas)
• Animal appears sick or behaves abnormally
• Wound or mucous membrane contaminated with saliva
• Bite was unprovoked
• Animal is unvaccinated or vaccination status unknown
• Biting animal cannot be traced

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10. Post-Exposure Prophylaxis (PEP) - Detailed Steps

Step 1: Immediate Local Wound Treatment (Most Important First Step)

• Flush and wash wound thoroughly with plenty of soap and water, preferably under running tap, for at least 15 minutes
• If no soap available: flush with large volumes of water alone
• For puncture wounds: use catheters/syringes to irrigate deeply
• Should not be neglected even if hours or days have elapsed

• After cleansing, apply virucidal agent: 70% alcohol, tincture of iodine, or 0.01% aqueous povidone-iodine
• Inactivates residual virus

• Do NOT immediately suture bite wounds - avoids spreading virus into deeper tissues
• If suturing is necessary: delay 24-48 hours, apply minimum stitches, under cover of RIG locally

• Give antibiotics if wound infection risk
• Anti-tetanus prophylaxis as indicated

Step 2: Rabies Immunoglobulin (RIG) - Passive Immunization (Category III only)

• Human Rabies Immunoglobulin (HRIG): 20 IU/kg body weight
• Equine Rabies Immunoglobulin (ERIG) / F(ab')₂ products: 40 IU/kg body weight (purified equine products now safe and effective)

• Administer once only, preferably at the time of first vaccine dose (can be given up to day 7 after first vaccine dose; after day 7, active antibody response is presumed to have occurred, so RIG is NOT indicated)
• As much as anatomically feasible should be infiltrated directly into and around the wound(s)
• Remaining volume: inject intramuscularly at a site distant from vaccine injection site
• Do NOT exceed the recommended dose - may partially suppress active antibody production
• RIG can be diluted to sufficient volume to infiltrate all wounds without causing compartment syndrome

Step 3: Active Immunization - Rabies Vaccines

• HDCV - Human Diploid Cell Vaccine (gold standard; embryonic fibroblast cells)
• PCECV - Purified Chick Embryo Cell Vaccine
• PVRV - Purified Vero Cell Rabies Vaccine (Vero cells - African green monkey kidney)
• PDEV - Purified Duck Embryo Vaccine
• Primary hamster kidney cell vaccine

• No RIG required (already have protective antibodies)
• Vaccine only: Days 0 and 3 (2 doses IM or ID) OR single-visit 4-site ID regimen
• Condition: documented complete prior PrEP or PEP with CCEEV OR neutralizing antibody titre ≥0.5 IU/mL

• 5 full IM doses required
• Comprehensive wound management + RIG infiltration
• Check neutralizing antibody titre 2-4 weeks after vaccination

Important notes on vaccine administration:

• Inject in the deltoid (adults) or anterolateral thigh (young children) - never in the gluteal area (poor absorption)
• Vaccine and RIG must be given at separate anatomical sites
• People taking chloroquine (malaria prophylaxis/treatment) should receive rabies vaccine IM, not ID (reduced response with intradermal route)

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11. Pre-Exposure Prophylaxis (PrEP)

• Veterinarians, animal handlers, wildlife workers
• Laboratory workers handling rabies virus
• Travelers to endemic areas with limited healthcare access (especially long-term travelers >1 month)
• Cave explorers (spelunkers - bat exposure risk)
• Children in endemic areas (due to higher risk of unrecognized bites)

• 3 doses IM or ID: Days 0, 7, 21 or 28

• Still require post-exposure wound treatment + 2 booster doses (days 0 and 3)
• No RIG required in previously vaccinated individuals

• Healthcare workers and lab personnel: every 2 years (or based on serological monitoring; maintain titre ≥0.5 IU/mL)

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12. Treatment of Clinical Rabies

• Sedation (benzodiazepines, barbiturates) for agitation, seizures, spasms
• Analgesia for pain
• Airway management, mechanical ventilation
• Management of autonomic instability
• Isolation precautions (universal precautions; staff vaccination)

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13. Prevention and Control

Primary Prevention (Avoiding Infection)

1. Animal vaccination campaigns - mass vaccination of dogs is the most cost-effective intervention; WHO target: vaccinate ≥70% of dog population in endemic areas
2. Wildlife rabies control - oral rabies vaccine (ORV) baits distributed in wildlife habitats (especially effective in Europe for fox rabies elimination)
3. Elimination of stray dogs in endemic areas
4. Public education - avoid contact with wild/unknown animals; do not feed stray animals; teach children to report all animal bites

Secondary Prevention (After Exposure)

Healthcare Worker/Laboratory Protection

• Universal precautions for all contacts with suspected rabies patients
• Rabies virus isolated from saliva of infected patients - saliva should be treated as infectious
• All healthcare workers caring for rabies patients should be vaccinated
• Notify public health authorities after any potential exposure

Key facts for control:

• Over 90% of human deaths in developing countries are caused by dog bites
• Eliminating dog rabies would prevent the vast majority of human rabies deaths
• Hawaii is the only US state that is rabies-free (due to strict quarantine measures)
• Rabies is a notifiable disease in most countries

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Summary Table

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Hepatitis - Comprehensive Review

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Overview Comparison Table

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1. Hepatitis A (HAV)

Virology

• 27 nm RNA picornavirus (non-enveloped)
• 4 capsid proteins (VP1-4); single serotype worldwide
• NOT cytopathic to hepatocytes - liver injury is immune-mediated (both cellular and humoral)
• Stable in environment; resistant to drying, heating to 60°C

Epidemiology and Transmission

• Fecal-oral route - primarily via contaminated food or water
• Ingestion of raw shellfish from contaminated waters (classic)
• Person-to-person spread in households, day-care centers
• High-risk groups: people who inject drugs, MSM, travelers to endemic areas, persons exposed to sewage, raw seafood consumers
• Historically accounts for ~1/4 to 1/3 of acute hepatitis cases in USA
• Epidemics linked to waterborne and foodborne contamination
• Most virulent in middle-aged and older people; children often have subclinical infection

Clinical Features

• Incubation period: 15-50 days (average ~28 days)
• Acute illness: fever, malaise, anorexia, nausea, vomiting, right upper quadrant discomfort
• Jaundice develops in 50-70% of infected adults (but rarely in children)
• Most recover fully within 2-4 weeks
• No chronic form - always self-limiting
• Special situations:
  • Cholestatic hepatitis A: Weeks of jaundice + pruritus in some adults
  • Relapsing hepatitis A: In up to 5% of patients, 1-3 months after initial illness; associated with viremia but recovery always ensues
  • Mortality ~2% in those over 60 years
  • Can precipitate severe hepatitis or liver failure in patients with pre-existing chronic HBV or HCV

Diagnosis

Treatment

• Supportive only: Rest, adequate nutrition, avoid alcohol and hepatotoxic drugs
• No specific antiviral therapy

Prevention

• Vaccine: Three types: monovalent HAV, combined HAV+HBV (Twinrix), combined HAV+typhoid
• Schedule: 2 doses (day 0 and booster at 12 months) → immunity up to 20 years
• All children should be immunized; adults at high risk; international travelers
• Passive immunization: Normal immune globulin (IG) can be given for post-exposure prophylaxis within 2 weeks of exposure in unvaccinated individuals

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2. Hepatitis B (HBV)

Virology

• 42 nm DNA virus = Dane particle (complete, infectious virion)
• Family: Hepadnaviridae
• Genome: Partially double-stranded circular DNA, ~3200 nucleotides
• Overlapping reading frames (one of the most compact genomes)
• Uses reverse transcriptase activity (like retroviruses) - error-prone, high mutation rate

• Genotype A: North America, Northern Europe
• Genotype C: Asia (higher risk of cirrhosis, HCC, poor IFN response)
• Genotypes A, B: Better response to interferon
• Clinical importance: predictor of natural course and treatment response

Epidemiology and Transmission

• Most common chronic viral infection worldwide: ~350 million chronically infected
• Highest prevalence: Southeast Asia, sub-Saharan Africa (>8% population)
• Routes:
  1. Parenteral: Blood/blood products, sharing needles (IDU), needlestick injuries in HCW
  2. Sexual transmission: Especially MSM, heterosexual with multiple partners
  3. Vertical (mother-to-child): Most important route in endemic areas; occurs mainly perinatally (during delivery); transplacental rare (~2%)
• Without intervention: 90% of perinatally infected infants develop chronic HBV
• In adults: 5-10% develop chronic HBV after acute infection

Pathogenesis

• HBV is NOT directly cytopathic - liver damage is immune-mediated
• Hepatocytes express HBcAg + HLA class I proteins on surface → primed CD8+ T lymphocytes attack infected hepatocytes
• Chronic hepatitis results from incomplete immune clearance
• Many chronic HBV patients have deficient interferon response → cannot express adequate HLA antigens for lymphocyte targeting

Clinical Features

• Incubation: 45-180 days (average 60-90 days)
• Prodrome: malaise, anorexia, nausea, RUQ discomfort, arthralgias, fever
• Icteric phase: jaundice, dark urine (bilirubinuria), pale stools, hepatomegaly, splenomegaly
• Serum sickness-like syndrome: urticaria, arthralgias (immune complex-mediated) - characteristic of HBV
• Resolution: most immunocompetent adults recover within 3-6 months
• Fulminant hepatitis: ~1% of cases; acute liver failure, encephalopathy, coagulopathy

• Most patients asymptomatic initially; detected by abnormal LFTs or screening
• Symptoms: fatigue, right upper quadrant discomfort
• Progressive: cirrhosis → portal hypertension → hepatocellular carcinoma (HCC)
• Extrahepatic manifestations (1-10% of patients, immune complex-mediated):
  • Polyarteritis nodosa (most classic association)
  • Glomerulonephritis (membranous)
  • Cryoglobulinemia
  • Polymyalgia rheumatica
  • Myocarditis, Guillain-Barré syndrome

HBV Serology - Interpretation

• HBsAg: First marker to appear in infection; active infection marker; persists >6 months = chronic
• Anti-HBs (≥10 IU/mL): Protective immunity; vaccine response or past resolved infection
• Anti-HBc IgM: Acute/recent infection (high titer); also positive in flares of chronic HBV (lower titer)
• Anti-HBc Total (IgG): Past or present infection; NOT induced by vaccine; marker of prior exposure
• HBeAg: Active viral replication, high infectivity
• Anti-HBe: Seroconversion = viral control, declining infectivity (but check HBV DNA - some precore mutants remain replicative)
• HBV DNA: Quantifies viral load; monitors treatment; definitive marker of active replication
• HBsAg quantification: Predicts treatment response; declining levels = treatment response

Laboratory Tests (LFTs)

• ALT > AST (in uncomplicated viral hepatitis)
• AST/ALT ratio >1 suggests alcohol-related liver disease or cirrhosis
• Elevated bilirubin, alkaline phosphatase, GGT
• Prolonged prothrombin time (PT) in severe/fulminant disease

HBV Treatment

• Finite duration (48 weeks); no resistance; stimulates host immune response
• Higher rate of HBeAg seroconversion and durable off-treatment response
• Side effects: flu-like symptoms, depression, cytopenia, autoimmune thyroiditis, teratogenic
• Contraindicated: decompensated cirrhosis, psychiatric disease, cytopenias, autoimmune disease, pregnancy
• Better response: Genotypes A and B; high ALT; low HBV DNA; low HBsAg

HBV Vaccination

• Recombinant HBsAg vaccine (Engerix-B, Recombivax HB)
• 3-dose schedule: 0, 1, 6 months (IM deltoid)
• Protective antibody level: anti-HBs ≥10 IU/mL

• 90% seroconversion in healthy adults; >95% in children

• Universal infant vaccination is global standard
• Perinatal prophylaxis for infants of HBsAg+ mothers:
  • HBIG (0.06 mL/kg IM) + first dose HBV vaccine within 24 hours of birth

  • 95% effective in preventing perinatal transmission

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3. Hepatitis C (HCV)

Virology

• 50-60 nm enveloped flavivirus (+ss RNA)
• Family: Flaviviridae
• Genome encodes a single polyprotein cleaved into structural (Core, E1, E2) and non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B)
• NS5B = RNA-dependent RNA polymerase (target of sofosbuvir)
• NS5A = regulatory protein (target of ledipasvir, velpatasvir, pibrentasvir)
• NS3/4A = protease (target of glecaprevir, grazoprevir, voxilaprevir)
• 6 major genotypes (1-6) with subtypes; global distribution varies
• High mutation rate → quasispecies → major obstacle to vaccine development

Epidemiology and Transmission

• ~58-71 million people chronically infected worldwide
• Primarily parenteral transmission:
  • IDU (sharing needles) - most common in developed countries
  • Blood transfusions (before 1992 screening)
  • Needlestick injuries in HCW
  • Tattooing, piercing with contaminated equipment
• Sexual transmission: Low risk (0.07% per sexual encounter); higher in HIV+ MSM
• Vertical (mother-to-child): Low risk (~3-5%)
• Not transmitted by casual contact, sharing food, hugging

Clinical Features

• Incubation: 14-180 days (average 6-8 weeks)
• Mostly asymptomatic (70-80%) - "silent epidemic"
• 10-30% develop jaundice when clinical disease occurs
• ALT elevation typically ~6-8 weeks after infection
• HCV RNA detectable 1-2 weeks after exposure
• 15-25% clear infection spontaneously (especially younger women with IL28B CC genotype)
• 75-85% develop chronic infection (much higher than HBV in adults)

• Often asymptomatic for 20-30 years
• Fatigue is the most common symptom
• Progressive fibrosis → cirrhosis (20-30% of patients over 20-30 years)
• Cirrhosis → HCC (~1-4% per year)
• HCV is the leading indication for liver transplantation in many countries

• Mixed cryoglobulinemia (most characteristic) - purpura, arthralgia, neuropathy, glomerulonephritis
• Membranoproliferative glomerulonephritis (MPGN)
• Porphyria cutanea tarda (PCT)
• Lichen planus
• Non-Hodgkin lymphoma (B-cell)
• Insulin resistance/type 2 diabetes
• Sicca syndrome (Sjögren-like)
• Thyroid disorders

HCV Diagnosis

• 3rd generation ELISA: sensitivity >99%
• Window period: 2-3 weeks after infection (3rd gen); positive in ~50% at time of clinical acute presentation
• Positive anti-HCV requires confirmation with HCV RNA (as anti-HCV persists lifelong even after clearance)
• Does NOT distinguish active from past resolved infection

• Detectable 1-2 weeks after exposure (before antibodies)
• Gold standard for active infection
• Qualitative: confirms infection; detects acute infection when antibody negative
• Quantitative (viral load): monitors treatment response

• Determines duration and regimen selection
• Reference method: direct sequencing

• Rapid Virologic Response (RVR): Undetectable HCV RNA at week 4
• Early Virologic Response (EVR): ≥2 log10 decline by week 12
• Sustained Virologic Response (SVR): Undetectable HCV RNA 12-24 weeks after treatment completion = functional cure

HCV Treatment - Direct-Acting Antivirals (DAAs)

• Treatment goal: SVR12 (undetectable HCV RNA ≥12 weeks post-treatment) = cure
• SVR reduces risk of HCC, liver failure, all-cause mortality
• Even cirrhotic patients can be treated (adjust regimen if decompensated)
• Ledipasvir/sofosbuvir: 99% SVR in treatment-naïve GT1 patients
• Drug interaction alert: Avoid rifampin (P-glycoprotein inducer) and St. John's wort with SOF-based regimens; avoid amiodarone with sofosbuvir (risk of fatal bradycardia)
• No vaccine available; prevention relies on harm reduction (needle exchange, safe sex)

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4. Hepatitis D (HDV) - Delta Hepatitis

Virology

• 36 nm incomplete RNA virus (obligate satellite virus)
• Family: Deltaviridae
• Genome: Single-stranded, circular, antisense (negative-sense) RNA - the smallest mammalian viral genome
• Cannot replicate independently - requires HBsAg as its envelope protein
• Encodes only one protein: Delta antigen (HDAg)

Key Clinical Features

• Worldwide prevalence: ~4.5% among HBsAg-positive individuals
• High-risk regions: China, Russia, Eastern Europe, Africa, South America
• Risk factors: IDU, HCV/HIV coinfection, travel to endemic areas
• Extremely infectious; strongly associated with IV drug use
• ~10 million infected worldwide (declining with reduced HBV incidence)

• Typically self-limiting acute hepatitis
• Only 2-8% progress to chronic (same as HBV alone)
• Higher risk of fulminant hepatitis than HBV alone
• Higher mortality

• HDV superimposed on existing chronic HBV infection
• ~90-100% develop chronic HDV infection
• ~80% progress to cirrhosis within 5-10 years
• Estimated: cirrhosis 4%/year; HCC 3%/year
• Dramatic worsening of liver disease

HDV Diagnosis

Treatment

• Pegylated interferon-alpha was the only available therapy for decades (high relapse rates)
• Bulevirtide (Hepcludex): New entry inhibitor; prevents HDV entry by blocking sodium taurocholate cotransporting polypeptide (NTCP receptor); conditionally approved in Europe (2020)
• Prevention: HBV vaccination prevents HDV (cannot have HDV without HBV)

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5. Hepatitis E (HEV)

Virology

• 32-34 nm non-enveloped RNA virus (+ss RNA)
• Family: Hepeviridae
• 4 major genotypes (GT1 and GT2: humans only; GT3 and GT4: zoonotic - pigs, deer, wild boar)

Epidemiology and Transmission

• Fecal-oral transmission (like HAV)
• GT1/2: Epidemic form in developing countries (South Asia, Central Asia, Africa, Mexico); contaminated water supplies; large outbreaks
• GT3/4: Sporadic zoonotic infection in developed countries (via undercooked pork, deer, game)
• High mortality in pregnant women: 15-25% mortality in third trimester (unique feature)
• Usually self-limiting; no chronic form in immunocompetent individuals
• Chronic hepatitis E occurs in immunocompromised patients (transplant recipients, HIV+, hematologic malignancy patients) with GT3/4

Clinical Features

• Incubation: 15-60 days (average ~40 days)
• Similar to HAV: fever, jaundice, nausea, RUQ pain
• Cholestasis often prominent
• Self-limiting; no chronic form in immunocompetent
• Extrahepatic: Neurological manifestations (Guillain-Barré, neuralgic amyotrophy) associated with GT3
• Pregnancy: Disproportionate severity, risk of fulminant hepatic failure, preterm labor, fetal loss; 15-25% mortality in third trimester

Diagnosis

Treatment

• Immunocompetent: Supportive only (self-limiting)
• Chronic HEV (immunocompromised):
  • Reduce immunosuppression (first step)
  • Ribavirin for 3-6 months (off-label; first choice)
  • Pegylated interferon (second line; cannot use in transplant recipients)

Prevention

• Vaccine: HEV 239 (Hecolin) - licensed and available in China since 2012; not globally licensed
• Boil drinking water in endemic areas; avoid uncooked pork/game in developed countries
• Safe water supply and good sanitation

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6. Hepatitis G (HGV/GBV-C)

• Flavivirus; bloodborne; co-infects with HIV
• Not clearly pathogenic - does not cause clinically significant hepatitis
• May actually be beneficial in HIV-infected individuals (slower HIV progression)
• No treatment indicated

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7. General Clinical Features of Acute Viral Hepatitis

Phases

• Flu-like: fever, malaise, fatigue, headache, myalgia
• GI: nausea, vomiting, anorexia, RUQ discomfort
• Aversion to cigarettes and alcohol (characteristic)
• Arthralgia, urticaria (especially HBV - serum sickness-like)
• Pale/clay-colored stools; dark urine (bilirubinuria) appears before jaundice

• Jaundice (icteric sclera first), dark urine, pale stools
• Hepatomegaly, splenomegaly
• Tenderness in right hypochondrium
• Pruritus (especially if cholestatic)
• Systemic symptoms often improve when jaundice appears (unlike in fever-related jaundice)

• Jaundice resolves, appetite returns, fatigue improves

Complications

• Fulminant hepatic failure: Acute liver failure, encephalopathy, coagulopathy; highest risk with HBV+HDV coinfection, HEV in pregnancy
• Cholestatic hepatitis (prolonged jaundice, mainly HAV)
• Relapse (HAV - 5% of cases)
• Chronic hepatitis → cirrhosis → HCC (HBV, HCV, HDV)

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8. Laboratory Investigations

Liver Function Tests (LFTs)

Causes of Chronic Hepatitis (Diagnostic workup)

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9. Histopathology of Viral Hepatitis

• Hepatocyte swelling (ballooning degeneration)
• Acidophil (Councilman) bodies - apoptotic hepatocytes
• Lobular disarray
• Mononuclear portal and lobular inflammatory infiltrate
• Cholestasis

• Interface hepatitis (periportal hepatocyte necrosis - "piecemeal necrosis")
• Portal inflammatory infiltrate
• Bridging necrosis (connecting portal tracts or central veins) = severe disease
• Fibrosis (staging: F0-F4)
• Grading (activity): degree of inflammation
• Staging (fibrosis): F0=none → F4=cirrhosis

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10. Prevention Summary

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