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PART I: MYCOBACTERIAL DISEASES

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CHAPTER 183 - TUBERCULOSIS

1. The Organism

• M. tuberculosis (sensu stricto) - the dominant human pathogen
• M. africanum - West/Central/East Africa
• M. bovis - bovine TB, pyrazinamide-resistant; ~140,000 human cases/year via unpasteurized milk
• M. caprae, M. pinnipedii, M. canetti - rare zoonotic agents

• Rod-shaped, non-spore-forming, thin aerobic bacterium: 0.5 μm × 3 μm
• Neutral on Gram stain (not Gram-positive or negative)
• Acid-fast bacilli (AFB): Once stained, cannot be decolorized by acid-alcohol - due to high mycolic acid content in the cell wall
• Cell wall structure: mycolic acids → arabinogalactan → peptidoglycan - this makes the wall nearly impermeable, conferring drug resistance and immune evasion
• Other acid-fast organisms (differential): Nocardia, Rhodococcus, Legionella micdadei, Isospora, Cryptosporidium

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2. Epidemiology

• TB is the #1 cause of death from a single infectious agent (returned to top after COVID-19 temporarily displaced it in 2020-2022)
• Population genomic studies: M. tuberculosis emerged ~70,000 years ago in Africa
• Highest burden: Sub-Saharan Africa, South/Southeast Asia
• WHO estimates ~10 million new TB cases/year
• Untreated TB is fatal in >70% of cases; properly treated drug-susceptible TB is curable in vast majority

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3. Pathogenesis - The Sequence You Must Know

• First cells infected: myeloid dendritic cells (earliest phase)
• Then: alveolar macrophages (alternatively activated, non-activated) phagocytose the bacilli
• Adhesion via: complement receptors, mannose receptor, IgG Fcγ receptors, type A scavenger receptors
• Surfactant protein D can prevent phagocytosis

• M. tuberculosis blocks phagosome-lysosome fusion by:
  • Reducing acidification (incomplete proton-ATPase assembly)
  • Lipoarabinomannan (LAM) inhibits Ca²+/calmodulin pathway
  • Inhibiting phosphatidylinositol 3-phosphate production (which earmarks phagosomes for maturation)
  • Bacterial factors block autophagy (the cell's backup system)
• The ESX-1 secretion system (encoded in the RD1 region) mediates macrophage rupture and spread
• Bacterial replication begins → macrophage ruptures → cycle continues

• TNF-α and other cytokines drive granuloma formation - a hallmark of TB
• The granuloma walls off infection. In immunocompetent hosts, 90% of infections are controlled here = latent TB infection (LTBI)
• In 10%: primary disease progresses, or reactivation occurs later in life

• katG gene: encodes catalase/peroxidase - protects against oxidative stress AND is required for isoniazid activation (loss = INH resistance)
• RD1 locus: encodes ESAT-6 and CFP-10 antigens; absent in BCG (key attenuating mutation)
• Genes encoding lipid metabolism enzymes (isocitrate lyase) aid survival in macrophages

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4. Clinical Manifestations

Primary TB

• Often asymptomatic in immunocompetent hosts
• Ghon complex: peripheral parenchymal lesion + ipsilateral hilar lymph node enlargement
• In children and immunocompromised: may progress to miliary TB or tuberculous meningitis

Latent TB Infection (LTBI)

• Positive TST or IGRA without symptoms, normal CXR
• Lifetime reactivation risk: ~10% overall (5% in first 2 years)
• Risk factors for reactivation: HIV (highest risk - 5-10% per year), TNF inhibitors, silicosis, DM, renal failure, malnutrition, recent infection

Pulmonary TB (Post-primary/Reactivation)

• Constitutional: fever, night sweats, weight loss, fatigue (insidious onset)
• Pulmonary: cough >2-3 weeks, hemoptysis, dyspnea, chest pain
• "Consumption" - the classic wasting appearance

• Upper lobe predominance (posterior segments of upper lobes, superior segments of lower lobes)
• Fibronodular infiltrates, cavitation (pathognomonic when present)
• Cavities = high organism load, high transmissibility

Extrapulmonary TB (up to 1/3 of cases)

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5. Diagnosis

Bacteriological Methods

Immunological Methods (for LTBI)

Clinical Pearl: IGRA is preferred in BCG-vaccinated individuals and healthcare workers. TST is preferred in children <5 years.

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6. Treatment

First-Line Drug-Susceptible TB (Standard Regimen)

• 2 months: INH (H) + Rifampicin (R) + Pyrazinamide (Z) + Ethambutol (E) - intensive phase
• 4 months: INH + Rifampicin - continuation phase

CRITICAL PEARL: Pyrazinamide is the key drug that shortened treatment from 9 to 6 months - it sterilizes the "persistent" population of semi-dormant bacilli inside macrophages.

Drug-Resistant TB

• Bedaquiline: ATP synthase inhibitor - first new TB drug in 40 years
• Pretomanid: Nitroimidazole; requires metabolic activation
• Delamanid: Nitroimidazole; inhibits mycolic acid synthesis

LTBI Treatment

• 6H: 6 months INH (standard)
• 9H: 9 months INH (higher efficacy, especially HIV+)
• 3HP: 3 months INH + Rifapentine weekly (preferred, better adherence)
• 4R: 4 months Rifampicin alone
• 1HP: 1 month INH + Rifapentine daily (approved for certain patients)

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7. TB in Special Situations

• HIV is the strongest risk factor for developing active TB from LTBI
• Risk: 5-10% per year in HIV+ (vs 10% lifetime in HIV-)
• Clinical features in HIV+: atypical presentations - lower lobe involvement, no cavitation, negative sputum smear, extrapulmonary disease more common
• Treatment: ART + anti-TB therapy (start ART within 2-8 weeks of TB treatment; if CD4 <50 start within 2 weeks)
• Drug interactions: Rifampicin induces CYP450 → reduces levels of most antiretrovirals; prefer rifabutin as substitute or use dolutegravir-based ART
• Immune reconstitution inflammatory syndrome (IRIS): paradoxical worsening 2-8 weeks after starting ART - treat with NSAIDs or corticosteroids

• Predominantly primary progressive disease
• High risk of meningitis and miliary disease
• Diagnosis challenging (sputum difficult to obtain)
• Gastric aspirate or induced sputum used

• INH, RIF, EMB are safe
• Pyrazinamide: WHO now recommends; some guidelines still restrict
• Streptomycin: contraindicated (ototoxicity to fetus)

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8. Prevention

• Live attenuated M. bovis
• Highly effective against miliary TB and TB meningitis in children (~80%)
• Variable efficacy against pulmonary TB (0-80%)
• Given at birth in endemic countries
• Does not prevent infection, only severe/disseminated disease
• RD1 locus is absent in BCG - this is the key attenuating mutation

• Airborne precautions (N95 respirator)
• Negative pressure rooms
• HEPA filtration
• UV irradiation

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CHAPTER 184 - LEPROSY (HANSEN'S DISEASE)

1. The Organism

• Obligate intracellular, AFB-staining, rod-shaped bacterium: 1-8 μm × 0.3 μm
• Has never been cultured in artificial media (only in armadillo footpads and mouse footpads)
• Doubling time: 12-14 days (extremely slow - among the slowest of all bacteria)
• Optimal temperature for growth: 27-30°C (explains predilection for skin, peripheral nerves, testes, upper airways - all cooler body areas)
• Predominantly found in macrophages and Schwann cells
• Infects 9-banded armadillos (animal reservoir)
• Bacteriologic Index (BI): 0 to 6+ (logarithmic scale measuring density of bacilli in slit-skin smear)
• Morphologic Index (MI): % of solid (viable) bacilli among all bacilli counted

• 174,087 new cases reported in 2022 from 182 countries
• Neglected tropical disease - often misdiagnosed or missed
• Early diagnosis prevents irreversible nerve damage

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2. The Spectrum of Leprosy (Ridley-Jopling Classification)

Tuberculoid (TT) ←→ Borderline (BB) ←→ Lepromatous (LL)
[Strong CMI, few bacilli]          [Weak CMI, many bacilli]

• Paucibacillary (PB): 1-5 skin patches (includes TT, BT)
• Multibacillary (MB): >5 skin patches (includes BB, BL, LL)

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3. Clinical Features

• Hypopigmented or erythematous macules/plaques
• ALWAYS check sensation - loss of sensation within the lesion is pathognomonic
• Lepromatous: diffuse nodules, plaques, "leonine facies" (diffuse facial infiltration)
• Madarosis (loss of lateral eyebrows)

• Superficial peripheral nerves at anatomical "cooling" points:
  • Ulnar nerve - at elbow (claw hand - 4th, 5th fingers)
  • Median nerve - carpal tunnel (claw thumb, thenar wasting)
  • Common peroneal nerve - fibular head (foot drop)
  • Radial nerve - spiral groove (wrist drop)
  • Facial nerve - zygomatic arch (lagophthalmos - inability to close eye → corneal damage)
  • Greater auricular nerve - neck (palpable thickening)
  • Posterior tibial nerve - plantar anesthesia → neuropathic ulcers

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4. Leprosy Reactions (Major Clinical Emergency)

• Occurs in borderline (BT, BB, BL) - the immune "upgrade"
• Sudden increase in cell-mediated immunity
• Existing lesions become inflamed, edematous, tender
• New nerve function loss (NFI) - THE EMERGENCY
• No systemic features
• Treatment: Prednisolone 40-60 mg/day, taper over 6 months

• Occurs in BL/LL only (multibacillary)
• Immune complex-mediated (Type III hypersensitivity)
• Tender nodules on skin + systemic features: fever, arthritis, iritis, orchitis, dactylitis, glomerulonephritis
• Recurrent and chronic
• Treatment: Thalidomide (most effective for ENL; teratogenic), or prednisolone
• Clofazimine has anti-inflammatory effect in ENL

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5. Diagnosis

Classic picture: Hypopigmented anaesthetic skin patch + thickened peripheral nerve + AFB on slit skin smear = leprosy until proven otherwise.

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6. Treatment

Clinical Pearl: Clofazimine skin pigmentation is a major reason for non-adherence (cosmetically disfiguring) - counsel patients upfront.

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CHAPTER 185 - NONTUBERCULOUS MYCOBACTERIAL (NTM) INFECTIONS

1. Overview

• >199 identified species (growing, due to DNA sequence typing)
• Ubiquitous in soil, water, and environment
• No human-to-human transmission (with rare exception in cystic fibrosis)
• Cause disease only when host defenses are impaired or breached

2. Key Species and Clinical Syndromes

3. Disseminated MAC in AIDS

• Occurs when CD4 <50 cells/μL (marker of advanced immunosuppression)
• Presents with: fever, night sweats, weight loss, diarrhea, hepatosplenomegaly, elevated ALP
• Blood cultures (BACTEC/lysis-centrifugation) - most sensitive
• Treatment: Azithromycin/Clarithromycin + Ethambutol ± Rifabutin (macrolide-based combination)
• Prophylaxis: Azithromycin 1200 mg weekly when CD4 <50 (can stop once CD4 >100 on ART)

4. Pulmonary NTM Disease (Lady Windermere Syndrome)

• Typically in: post-menopausal women, tall/slender (scoliosis, pectus excavatum, mitral valve prolapse)
• Organisms: MAC most common
• Radiology: bronchiectasis with nodules in middle lobe / lingula
• Criteria for treatment (ATS/IDSA):
  1. Positive culture from ≥2 sputum samples, OR
  2. Positive culture from bronchoalveolar lavage, OR
  3. Positive culture from biopsy + compatible histology/radiology
• Treatment: Azithromycin/Clarithromycin + Rifampicin + Ethambutol (3-drug regimen) for ≥12 months after sputum conversion

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PART II: HIV DISEASE AND AIDS

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CHAPTER 208 - HIV DISEASE: AIDS AND RELATED DISORDERS

1. The Virus

• Retrovirus (family Retroviridae, genus Lentivirus)
• Enveloped; 100 nm diameter
• Genome: 2 identical copies of (+)ssRNA, ~9.7 kb
• Enzymes: Reverse transcriptase (RNA→DNA), Integrase (inserts into host genome), Protease (cleaves polyprotein)

• gp120: Surface glycoprotein; binds CD4 receptor
• gp41: Transmembrane glycoprotein; mediates membrane fusion
• CD4 receptor + CCR5 or CXCR4 co-receptor = both required for viral entry

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2. Epidemiology (2023 Data from Harrison's)

• 39.9 million people living with HIV worldwide (2023)
• 1.3 million new infections in 2023 (down 60% from peak ~3.3 million in 1995)
• ~630,000 AIDS-related deaths in 2023
• 95% of cases in low- and middle-income countries
• 53% are female globally; 1.4 million are children <15 years
• WHO Eastern and Southern Africa: Most severely affected - >1 in 20 adults (5.7%) living with HIV; accounts for >50% of global burden
• Key high-risk populations: sex workers, PWID, transgender people, MSM, prisoners, and their partners = 55% of all new infections in 2022

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3. Transmission

• Heterosexual: dominant in sub-Saharan Africa
• MSM (men who have sex with men): dominant in high-income countries
• Risk per act: receptive anal intercourse has highest risk (~1.4%), receptive vaginal ~0.08%
• Factors increasing transmission: STIs (esp. ulcerative), high viral load, uncircumcised male partner, genital trauma

• IV drug use - sharing needles
• Needlestick injuries (healthcare workers): ~0.3% risk per exposure
• Blood products (now rare with screening)

• In utero, intrapartum (most common), breastfeeding
• Without intervention: ~25-40% transmission
• With PMTCT (prevention of mother-to-child transmission): <1-2% (ART for mother + infant prophylaxis)

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4. Replication Cycle (Step by Step)

1. Attachment: gp120 binds CD4 on T cells/macrophages
2. Co-receptor binding: gp120 conformational change → binds CCR5 (R5-tropic, macrophage-tropic) or CXCR4 (X4-tropic, T-cell tropic)
3. Fusion: gp41 inserts into cell membrane → membrane fusion
4. Uncoating: Viral core enters cytoplasm
5. Reverse transcription: ssRNA → dsDNA (by reverse transcriptase; error-prone → high mutation rate)
6. Nuclear import: pre-integration complex enters nucleus
7. Integration: Viral integrase integrates proviral dsDNA into host chromosome → provirus (permanent; HIV reservoir)
8. Transcription: Host RNA polymerase transcribes proviral DNA (Tat enhances this enormously)
9. Translation: Viral mRNA translated → polyproteins
10. Assembly + budding: New virions bud from cell surface
11. Maturation: Protease cleaves polyproteins → infectious virion

High mutation rate: RT lacks 3'→5' proofreading exonuclease → ~1 error per cycle → genetic diversity, drug resistance, immune escape

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5. Viral Dynamics (Quantitative Understanding)

• ~10¹⁰-10¹¹ virions produced and cleared daily
• Half-life of circulating virion: ~30-60 minutes
• Half-life of productively infected cells: ~1 day
• Minimum HIV-1 replication cycle in vivo: ~2 days
• Main site of HIV replication: lymphoid tissue (lymph nodes, GALT - gut-associated lymphoid tissue)
• GALT: massive depletion of CD4+ T cells occurs very early (within days to weeks of infection) - this is one of the earliest and most devastating events

• High set point → rapid progression to AIDS
• Low set point → slow progression
• Elite controllers: <50 HIV RNA copies/mL without ART (<1% of infected individuals)

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6. Immunopathogenesis

• Direct viral cytopathic effects
• Immune-mediated killing of infected cells
• Apoptosis (both infected and bystander cells)
• Chronic immune activation → "activation-induced cell death"
• Pyroptosis: caspase-1-mediated death of abortively infected CD4+ cells

• Microbial translocation from damaged gut (LPS, bacterial products enter systemic circulation)
• Persistent viremia even at low levels
• Leads to: T cell exhaustion, monocyte activation (elevated sCD14), dysfunctional B cells, cardiovascular and end-organ damage

• Polyclonal hypergammaglobulinemia (despite poor specific responses)
• Poor response to vaccination
• Increased susceptibility to polysaccharide-encapsulated bacteria (pneumococcus, H. influenzae)

• Tissue macrophages serve as persistent HIV reservoir
• Brain microglial cells and pulmonary alveolar macrophages infected
• sCD14 remains elevated even with ART suppression

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7. Clinical Stages of HIV Infection

Stage 1: Acute HIV Syndrome (Primary HIV Infection)

• Occurs 2-4 weeks after infection
• Mononucleosis-like illness: fever, lymphadenopathy, pharyngitis, myalgia, headache, rash (maculopapular), oral ulcers
• Corresponds to: massive viremia (viral load >10⁶ copies/mL), sharp drop in CD4 cells
• Immune response → viremia falls → CD4 partially recovers
• This phase is often missed/undiagnosed (resembles infectious mono or flu)
• Highly infectious - viral set point is being established

Stage 2: Clinical Latency (Asymptomatic Phase)

• Duration: weeks to years (average ~10 years without ART)
• Clinically silent, but not microbiologically latent (virus actively replicates)
• CD4 count gradually declines (~50-100 cells/μL/year untreated)
• Persistent Generalized Lymphadenopathy (PGL): ≥2 extralinguinal sites >3 months; common during this phase
• Term "clinical latency" is misleading - progression is relentless even if asymptomatic

Stage 3: Symptomatic HIV (Early AIDS)

• CD4 typically 200-500 cells/μL
• Minor opportunistic conditions: thrush (oral candidiasis), hairy leukoplakia, recurrent herpes, seborrheic dermatitis, molluscum contagiosum, HSV

Stage 4: AIDS (Advanced HIV Disease)

• CD4 <200 cells/μL (US CDC definition: AIDS-defining condition OR CD4 <200)
• Highly susceptible to opportunistic infections and AIDS-defining cancers

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8. AIDS-Defining Conditions (Major OIs by CD4 Count)

Key Opportunistic Infections (High Yield):

• Most common AIDS-defining OI in developed countries
• CD4 <200; gradual onset: dry cough, progressive dyspnea, low-grade fever
• CXR: bilateral perihilar/diffuse interstitial infiltrates ("ground glass" on CT)
• BAL with Gomori methenamine silver (GMS), Giemsa stain, or direct fluorescent antibody
• β-D-glucan elevated (non-specific but sensitive)
• Treatment: TMP-SMX (Bactrim) × 21 days (+ prednisone if PaO₂ <70 mmHg or A-a gradient >35)
• Prophylaxis: TMP-SMX when CD4 <200 (stop when CD4 >200 on ART for >3 months)

• CD4 typically <100
• Subacute meningitis: headache, fever, altered mental status; meningismus may be absent
• CSF: India ink positive; cryptococcal antigen (CrAg) positive in CSF and serum; mildly elevated protein, low glucose, mild lymphocytosis
• Treatment: Induction: Amphotericin B liposomal + Flucytosine × 2 weeks → Consolidation: Fluconazole 400 mg/day × 8 weeks → Maintenance: Fluconazole 200 mg/day indefinitely (until CD4 >200)
• Raised ICP: serial lumbar punctures; may need lumbar drain or VP shunt
• Start ART 4-6 weeks after starting antifungals (to avoid IRIS)

• CD4 <100; reactivation of latent Toxoplasma gondii
• Multiple ring-enhancing lesions on MRI (T1+gadolinium), often at basal ganglia
• Clinically: headache, focal neurological deficits, fever, altered sensorium
• Serum Toxoplasma IgG positive (primary infection vs reactivation)
• Treatment: Pyrimethamine + Sulfadiazine + Folinic acid × 6 weeks → maintenance
• Prophylaxis: TMP-SMX (double strength) when CD4 <100 + Toxo IgG positive

• CD4 <50; most common cause of blindness in AIDS
• "Pizza pie" or "brush fire" appearance on fundoscopy: yellow-white areas with hemorrhages along vessels
• Painless visual loss, "floaters," visual field defects
• Treatment: Ganciclovir (IV or intravitreal) or Valganciclovir (oral)

• CD4 <50; fever, night sweats, weight loss, diarrhea, hepatosplenomegaly, elevated ALP
• Blood cultures most sensitive (BACTEC)
• Treatment: Clarithromycin + Ethambutol ± Rifabutin
• Prophylaxis: Azithromycin 1200 mg/week when CD4 <50

• 10% involuntary weight loss + chronic diarrhea OR fever >30 days

• JC virus reactivation; CD4 <100-200
• MRI: multifocal white matter lesions without mass effect or enhancement
• Treatment: No specific therapy; ART (immune reconstitution is the treatment)

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9. Diagnosis of HIV

U=U (Undetectable = Untransmittable): People with HIV who maintain undetectable viral load on ART cannot sexually transmit HIV. This is now scientifically established.

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10. Antiretroviral Therapy (ART)

When to Start

• ALL people with HIV should start ART regardless of CD4 count (current WHO and US guidelines)
• Urgent initiation (within hours-days): symptomatic disease, pregnancy, TB, OIs (with some exceptions like cryptococcal meningitis)

Classes of Antiretroviral Drugs

Preferred First-Line Regimens (Current Guidelines 2025)

• DTG/TDF/FTC or DTG/TAF/FTC (dolutegravir-based) - WHO and US preferred
• BIC/TAF/FTC (bictegravir-based, single tablet regimen) - US preferred
• CAB+RPV LA (long-acting injectable) - maintenance in virologically suppressed

Goals of ART

1. Viral suppression: HIV RNA <50 copies/mL within 24 weeks
2. Immune reconstitution: CD4 rise typically 100-150 cells/μL/year
3. Prevention of OIs
4. Prevention of transmission (U=U)
5. Reduction of non-AIDS morbidity (cardiovascular, renal, neurological)

Monitoring on ART

• HIV RNA: at 4 weeks, 12 weeks, every 3-6 months once suppressed
• CD4: every 6-12 months until stable >500
• Renal function, LFTs, CBC, lipids, glucose: routine

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11. Immune Reconstitution Inflammatory Syndrome (IRIS)

• Occurs weeks to months after starting ART in patients with pre-existing OIs
• Immune system "wakes up" and mounts exaggerated response to residual antigens
• Two types:
  • Unmasking IRIS: New OI becomes apparent after ART start
  • Paradoxical IRIS: Pre-treated OI worsens after ART start
• Common IRIS presentations: worsening TB (most common), CMV retinitis, cryptococcal meningitis, herpes zoster
• Treatment: Continue ART; NSAIDs; corticosteroids for severe cases
• Prevention: For cryptococcal meningitis, delay ART 4-6 weeks; for TB with CD4 >50, delay 8 weeks

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12. Prevention of HIV

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13. HIV and Nervous System

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14. HIV and Other Systems

• Collapsing focal segmental glomerulosclerosis (FSGS)
• Almost exclusively in Black patients
• Rapid progression to ESRD without ART
• ART is the primary treatment

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15. Genetic Factors in HIV Pathogenesis

Berlin Patient / London Patient: CCR5 Δ32 homozygous bone marrow transplant → apparent HIV cure. Proof of concept that CCR5 is a valid cure target.

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SUMMARY TABLE: Quick Review

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What You Just Learned - Structure

PART I: Mycobacterial Diseases

• Organism (M. tuberculosis complex, acid-fastness, cell wall)
• Epidemiology (global burden, mortality)
• Full pathogenesis sequence (inhalation → macrophage invasion → phagosome subversion → granuloma)
• Clinical manifestations (primary, LTBI, pulmonary, every extrapulmonary site)
• Diagnosis (smear, culture, GeneXpert, TST vs IGRA)
• Treatment (2HRZE/4HR, all drug mechanisms and toxicities, MDR-TB regimens, LTBI treatment)
• Special situations (TB/HIV, IRIS, pediatric, pregnancy)
• Prevention (BCG, infection control)

• Organism (M. leprae, cannot be cultured, temperature preference)
• Ridley-Jopling spectrum (TT to LL) with immune basis
• WHO classification (PB vs MB)
• Clinical features (skin, nerve involvement, specific nerves and deficits)
• Leprosy reactions (Type 1 reversal vs Type 2 ENL - emergency management)
• Treatment (MDT regimens, drug toxicities including clofazimine pigmentation)

• Key species and their syndromes
• Disseminated MAC in AIDS
• Lady Windermere syndrome
• ATS diagnostic criteria
• Treatment principles

PART II: HIV/AIDS

• Virus structure, genome, all regulatory genes
• 2023 global epidemiology
• Transmission routes and risks
• Full replication cycle (step by step)
• Viral dynamics (set point, virion half-life, daily production)
• Immunopathogenesis (CD4 destruction, chronic immune activation, B/NK/monocyte dysfunction)
• Clinical stages (acute → latency → AIDS)
• AIDS-defining OIs by CD4 threshold with treatments
• Diagnosis (4th-gen testing, viral load, CD4)
• All ART drug classes with mechanisms and toxicities
• Preferred first-line regimens
• IRIS
• Prevention (PrEP, PEP, PMTCT, U=U)
• Neurological complications
• Other organ involvement (cardiovascular, renal HIVAN)
• Host genetic factors (CCR5Δ32, HLA, restriction factors)

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MCQ ONE-LINERS: MYCOBACTERIAL DISEASES & HIV/AIDS

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🦠 TUBERCULOSIS

1. M. tuberculosis is acid-fast due to high mycolic acid content in cell wall
2. M. tuberculosis is neutral on Gram stain (neither Gram+ nor Gram-)
3. M. tuberculosis size: 0.5 × 3 μm
4. M. bovis is characteristically resistant to pyrazinamide
5. M. tuberculosis emerged ~70,000 years ago in Africa
6. Untreated TB is fatal in >70% of cases
7. TB returned as #1 infectious killer after COVID-19 displaced it in 2020-22
8. First cells affected after inhalation: myeloid dendritic cells (before alveolar macrophages)
9. M. tuberculosis survives in macrophage by blocking phagosome-lysosome fusion
10. Phagosome-lysosome fusion is blocked via Ca²+/calmodulin pathway inhibition by LAM (lipoarabinomannan)
11. ESX-1 secretion system (encoded in RD1 locus) mediates macrophage rupture
12. RD1 locus is absent in BCG - this is the key attenuating mutation
13. katG gene encodes catalase/peroxidase - required for INH activation; loss = INH resistance
14. ESAT-6 and CFP-10 are the two key antigens encoded by RD1 (used in IGRA)
15. Surfactant protein D prevents phagocytosis of M. tuberculosis
16. Only <10% of inhaled bacilli reach the alveoli
17. Lifetime risk of reactivation from LTBI: ~10% overall
18. HIV increases TB reactivation risk to 5-10% per year
19. BCG is highly effective against miliary TB and TB meningitis in children (~80%)
20. BCG has variable efficacy (0-80%) against pulmonary TB
21. Upper lobe predominance in post-primary TB: posterior segments of upper lobes + superior segments of lower lobes
22. Most common extrapulmonary TB site: lymph nodes (scrofula)
23. Spinal TB (Pott's disease): lower thoracic > lumbar spine most affected
24. Ileocecal TB can mimic Crohn's disease
25. Genitourinary TB: classic "sterile pyuria" (pyuria with negative routine cultures)
26. Miliary TB: "millet seed" pattern on CXR; choroid tubercles on fundoscopy
27. ADA (adenosine deaminase) is elevated in tuberculous pleural effusion
28. Xpert MTB/RIF gives results in 2 hours and simultaneously detects rifampicin resistance
29. IGRA is preferred over TST in BCG-vaccinated individuals
30. TST is preferred over IGRA in children <5 years
31. TST false positive causes: BCG vaccination, NTM infection
32. Standard TB regimen: 2HRZE / 4HR (2 months intensive + 4 months continuation)
33. Pyrazinamide is the drug responsible for shortening treatment from 9 to 6 months
34. Pyrazinamide kills semi-dormant bacilli in acidic macrophage environment
35. Isoniazid mechanism: inhibits mycolic acid synthesis (InhA enzyme, enoyl-ACP reductase)
36. Isoniazid toxicity: peripheral neuropathy (prevent with pyridoxine/B6), hepatotoxicity
37. Rifampicin mechanism: inhibits bacterial RNA polymerase (rpoB)
38. Rifampicin is a CYP450 inducer - major drug interactions (reduces levels of ARVs, warfarin, OCP)
39. Rifampicin causes orange discoloration of urine, tears, sweat
40. Ethambutol mechanism: inhibits arabinosyl transferase (arabinogalactan synthesis)
41. Ethambutol toxicity: optic neuritis (dose-dependent; check visual acuity monthly)
42. Pyrazinamide toxicity: hepatotoxicity, hyperuricemia/gout
43. Streptomycin is contraindicated in pregnancy (fetal ototoxicity)
44. MDR-TB = resistance to INH + Rifampicin
45. XDR-TB = MDR + fluoroquinolone + one injectable resistance
46. Bedaquiline = first new TB drug in 40 years; mechanism: ATP synthase inhibitor
47. WHO MDR-TB regimen: BPaL(M) = Bedaquiline + Pretomanid + Linezolid ± Moxifloxacin for 6 months
48. LTBI shortest regimen: 1HP (1 month INH + Rifapentine daily)
49. LTBI best-adherence regimen: 3HP (3 months weekly INH + Rifapentine)
50. In TB/HIV: start ART within 2 weeks if CD4 <50; 8 weeks if CD4 >50
51. In TB/HIV: prefer rifabutin over rifampicin to avoid ART drug interactions
52. IRIS = paradoxical worsening 2-8 weeks after starting ART in TB/HIV; treat with NSAIDs/corticosteroids

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🟤 LEPROSY (HANSEN'S DISEASE)

1. Leprosy caused by M. leprae - an obligate intracellular AFB
2. M. leprae cannot be cultured on artificial media (only in armadillo footpads/mouse footpads)
3. M. leprae doubling time: 12-14 days (one of the slowest-growing bacteria)
4. M. leprae optimal temperature: 27-30°C - explains predilection for skin, peripheral nerves, testes, upper airways
5. M. leprae predominantly infects macrophages and Schwann cells
6. Global leprosy cases in 2022: 174,087 from 182 countries
7. Tuberculoid leprosy: strong CMI, few bacilli (1-3 well-defined skin lesions)
8. Lepromatous leprosy: absent CMI, many bacilli (BI 5-6+), numerous symmetric lesions
9. Lepromin test: positive in tuberculoid, negative in lepromatous
10. WHO Paucibacillary = 1-5 skin patches (TT, BT)
11. WHO Multibacillary = >5 skin patches (BB, BL, LL)
12. Hallmark of leprosy diagnosis: anaesthetic skin patch (loss of sensation within lesion)
13. Leonine facies = diffuse lepromatous infiltration of face
14. Madarosis = loss of lateral eyebrows in lepromatous leprosy
15. Lagophthalmos (inability to close eye) = facial nerve involvement → corneal damage → blindness
16. Ulnar nerve at elbow → claw hand (4th, 5th fingers)
17. Common peroneal nerve at fibular head → foot drop
18. Posterior tibial nerve → plantar anesthesia → neuropathic ulcers
19. Type 1 (Reversal) Reaction: occurs in borderline leprosy, sudden increase in CMI, existing lesions inflame, nerve function loss is the emergency
20. Type 1 reaction treatment: Prednisolone 40-60 mg/day for 6 months
21. Type 2 (ENL) Reaction: immune complex-mediated (Type III hypersensitivity), only in BL/LL, systemic features
22. ENL treatment: Thalidomide (most effective; teratogenic) or prednisolone
23. Clofazimine has anti-inflammatory effect in ENL
24. PB leprosy treatment: Rifampicin + Dapsone × 6 months
25. MB leprosy treatment: Rifampicin + Clofazimine + Dapsone × 12 months
26. Dapsone toxicity: hemolytic anemia (especially in G6PD deficiency), methemoglobinemia
27. Clofazimine toxicity: gray-brown skin pigmentation (major cause of non-adherence) + ichthyosis
28. Bacteriologic Index (BI): 0 to 6+, logarithmic scale, falls 1 log unit/year with MDT
29. Morphologic Index (MI): % of viable (solid, uniformly stained) bacilli

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🌿 NONTUBERCULOUS MYCOBACTERIA (NTM)

1. NTM = >199 identified species; ubiquitous in soil and water
2. NTM: no human-to-human transmission except in cystic fibrosis
3. Disseminated NTM = significant immune dysfunction (CD4 <50 in HIV)
4. Pulmonary NTM = associated with pulmonary structural disease (bronchiectasis), NOT systemic immunodeficiency
5. M. avium complex (MAC): most common NTM in disseminated AIDS disease and pulmonary NTM
6. M. marinum = "fish tank granuloma" - ascending nodular lymphangitis; aquarium/pool exposure
7. M. ulcerans = Buruli ulcer - painless necrotizing ulcer; West Africa
8. M. fortuitum = wound infections; pedicure-associated furunculosis
9. M. kansasii = pulmonary disease resembling TB; COPD/HIV patients
10. Lady Windermere syndrome = pulmonary MAC in post-menopausal, tall/slender women; middle lobe/lingula bronchiectasis
11. Disseminated MAC treatment: Clarithromycin + Ethambutol ± Rifabutin
12. MAC prophylaxis: Azithromycin 1200 mg/week when CD4 <50; stop when CD4 >100 on ART

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🔴 HIV / AIDS

1. HIV is a retrovirus (family Retroviridae, genus Lentivirus)
2. HIV genome: 2 identical copies of (+)ssRNA, ~9.7 kb
3. HIV surface proteins: gp120 (binds CD4) + gp41 (membrane fusion)
4. HIV requires CD4 + CCR5 or CXCR4 co-receptor for entry
5. R5-tropic (CCR5) = macrophage-tropic; X4-tropic (CXCR4) = T-cell tropic
6. Nef = downregulates CD4 and MHC-I; increases infectivity
7. Tat = transcriptional transactivator (essential for viral replication)
8. Vif = counteracts host restriction factor APOBEC3G
9. Vpu = counteracts tetherin; degrades CD4
10. High HIV mutation rate: RT lacks 3'→5' proofreading exonuclease
11. HIV virions produced daily: 10¹⁰ - 10¹¹
12. Half-life of circulating HIV virion: ~30-60 minutes
13. Half-life of productively infected cell: ~1 day
14. Minimum HIV replication cycle in vivo: ~2 days
15. Main site of HIV replication: lymphoid tissue (lymph nodes + GALT)
16. GALT (gut-associated lymphoid tissue): massive CD4 depletion within days to weeks of infection
17. Viral set point established at 6-12 months post-infection - key prognostic marker
18. Elite controllers: <50 HIV RNA copies/mL without ART (<1% of infected individuals)
19. Global HIV prevalence 2023: 39.9 million
20. New HIV infections 2023: 1.3 million (down 60% from peak of 3.3 million in 1995)
21. HIV peak incidence year: 1995
22. Most affected region: WHO Eastern and Southern Africa (>1 in 20 adults = 5.7%)
23. HIV highest risk sexual exposure: receptive anal intercourse (~1.4% per act)
24. Needlestick injury HIV risk: ~0.3% per exposure
25. Without PMTCT, mother-to-child transmission: 25-40%; with PMTCT: <1-2%
26. Acute HIV syndrome occurs 2-4 weeks after infection
27. Acute HIV: viral load >10⁶ copies/mL + sharp CD4 drop → then partial recovery
28. Acute HIV resembles infectious mononucleosis (fever, pharyngitis, lymphadenopathy, rash)
29. PGL (Persistent Generalized Lymphadenopathy): ≥2 extralinguinal sites >3 months; during clinical latency
30. Clinical latency average duration without ART: ~10 years
31. CD4 decline rate without ART: ~50-100 cells/μL/year
32. AIDS definition (CDC): CD4 <200 cells/μL OR presence of AIDS-defining condition
33. HIV B cell defect: polyclonal hypergammaglobulinemia + poor response to vaccination
34. Microbial translocation from gut: LPS enters circulation → chronic immune activation (even on ART)
35. sCD14 remains elevated even with suppressive ART = marker of residual monocyte activation
36. Tissue macrophages serve as persistent HIV reservoir - obstacle to eradication
37. 4th-generation HIV Ag/Ab combo test: detects HIV-1/2 Ab + HIV-1 p24 antigen; window period ~18-45 days
38. U=U: Undetectable = Untransmittable (virologically suppressed cannot sexually transmit HIV)

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💊 OIs BY CD4 THRESHOLD

1. CD4 <500: TB, Kaposi's sarcoma, recurrent herpes zoster, oral hairy leukoplakia
2. CD4 <200: PCP (start TMP-SMX prophylaxis), Toxoplasma, Cryptococcus, Histoplasma, Coccidioides, PML, Cryptosporidium
3. CD4 <100: Cryptococcus, Toxoplasma, Bartonella
4. CD4 <50: Disseminated MAC, CMV retinitis, CNS lymphoma, Aspergillosis

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🫁 OI TREATMENT ONE-LINERS

1. PCP treatment: TMP-SMX × 21 days; add prednisone if PaO₂ <70 mmHg or A-a gradient >35
2. PCP prophylaxis: TMP-SMX when CD4 <200; stop when CD4 >200 on ART for >3 months
3. PCP diagnosis: BAL with GMS (Gomori methenamine silver) or direct fluorescent antibody
4. PCP CXR: bilateral perihilar ground-glass infiltrates
5. Cryptococcal meningitis CSF: India ink positive; CrAg positive; low glucose, mild lymphocytosis
6. Cryptococcal meningitis induction: Amphotericin B liposomal + Flucytosine × 2 weeks
7. Cryptococcal meningitis consolidation: Fluconazole 400 mg/day × 8 weeks
8. Cryptococcal meningitis maintenance: Fluconazole 200 mg/day until CD4 >200
9. In cryptococcal meningitis - delay ART 4-6 weeks to avoid IRIS
10. Toxoplasma encephalitis: multiple ring-enhancing lesions at basal ganglia on MRI
11. Toxoplasma treatment: Pyrimethamine + Sulfadiazine + Folinic acid
12. Toxoplasma prophylaxis: TMP-SMX DS when CD4 <100 + Toxo IgG positive
13. CMV retinitis: "pizza pie" or "brush fire" appearance; most common cause of blindness in AIDS
14. CMV retinitis treatment: Ganciclovir / Valganciclovir
15. PML (progressive multifocal leukoencephalopathy): JC virus; no mass effect/enhancement on MRI; treat with ART only
16. HIV Wasting Syndrome: >10% involuntary weight loss + chronic diarrhea OR fever >30 days
17. Kaposi's sarcoma: caused by HHV-8; violaceous lesions; most common AIDS cancer in MSM

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💉 ART ONE-LINERS

1. ALL people with HIV should start ART regardless of CD4 count
2. Goal of ART: HIV RNA <50 copies/mL within 24 weeks
3. NRTIs mechanism: incorporated into viral DNA → chain termination
4. TDF (tenofovir) toxicity: nephrotoxicity, bone demineralization
5. AZT (zidovudine) toxicity: anemia, myopathy, macrocytosis
6. Abacavir hypersensitivity: screen for HLA-B*5701 before prescribing
7. NNRTIs mechanism: bind allosteric site on reverse transcriptase
8. Efavirenz toxicity: CNS effects (vivid dreams, dizziness), teratogenicity (neural tube defects)
9. Nevirapine toxicity: hepatotoxicity, Stevens-Johnson syndrome
10. Rilpivirine: requires food + acidic pH for adequate absorption
11. Protease inhibitors require boosting with ritonavir or cobicistat (pharmacokinetic enhancers)
12. PIs cause: dyslipidemia, lipodystrophy, insulin resistance
13. INSTIs (Dolutegravir, Bictegravir) mechanism: block integration of proviral DNA
14. Dolutegravir concern in early pregnancy: neural tube defects (now considered low risk but counsel)
15. Dolutegravir is WHO preferred first-line ART drug globally
16. Maraviroc (CCR5 antagonist): requires tropism testing before use (must confirm R5-tropic virus)
17. Enfuvirtide (T-20): first fusion inhibitor; gp41; injectable; expensive
18. Cabotegravir + Rilpivirine LA: long-acting injectable every 1-2 months (best adherence option)
19. PrEP: TDF/FTC daily reduces HIV acquisition by >99% when adherent
20. PEP: must start within 72 hours; 28-day course; reduces transmission ~80-85%
21. IRIS occurs weeks to months after starting ART; continue ART; treat severe cases with corticosteroids
22. In TB/HIV IRIS: NSAIDs first; corticosteroids if severe

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🧬 GENETIC FACTORS

1. CCR5 Δ32 homozygous = complete resistance to R5-tropic HIV
2. HLA-B*57 and B*27 = associated with elite controllers and slow progression
3. APOBEC3G = host restriction factor that mutates HIV DNA (C→U); counteracted by Vif
4. TRIM5α = binds HIV capsid; blocks infection (especially in non-human primates)
5. Tetherin (BST-2) = tethers budding virions; counteracted by Vpu
6. SAMHD1 = depletes dNTPs; blocks reverse transcription in non-dividing cells; counteracted by Vpx (HIV-2/SIV)
7. Berlin/London patient: CCR5 Δ32 homozygous bone marrow transplant → apparent HIV cure (proof of concept)

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🧠 NEURO-HIV

1. HAND (HIV-Associated Neurocognitive Disorder): subcortical pattern - attention, processing speed, motor
2. HIV encephalopathy = subcortical dementia (AIDS Dementia Complex); MRI: white matter changes + atrophy
3. Vacuolar myelopathy: thoracic cord; progressive spastic paraparesis
4. CNS lymphoma in AIDS: EBV-associated; ring-enhancing lesion; CD4 <50; treat with ART + radiation

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🫀 HIV AND OTHER ORGANS

1. HIVAN (HIV-Associated Nephropathy): collapsing FSGS; almost exclusively in Black patients; ART is primary treatment
2. HIV increases risk of myocardial infarction × 2 (chronic inflammation → accelerated atherosclerosis)
3. LIP (Lymphocytic Interstitial Pneumonitis): especially in HIV-positive children

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All one-liners sourced from Harrison's Principles of Internal Medicine, 22nd Edition (2025) - Chapters 183, 184, 185, 208.