Pulmonary Tuberculosis

Etiology

• Harrison's 22E, Chapter 183 (Raviglione & Gori)
• Goldman-Cecil Medicine, Chapter 299

Epidemiology

• TB is one of the top infectious disease killers globally - in 2023, it returned to being the leading cause of infectious death from a single agent (after COVID-19 displaced it for 3 years).
• More than 10 million people develop TB disease and ~1.2 million die annually.
• Transmission is via airborne droplet nuclei produced by patients with infectious pulmonary TB. Tiny particles (1-5 μm) remain suspended in air for hours and reach the alveoli when inhaled.
• Harrison's 22E, Chapter 183

Risk Factors

Factors Increasing Risk of Exposure / Infection

• Close contact with a smear-positive pulmonary TB case (household contacts have a 25-50% chance of being infected)
• Residence in high-TB-prevalence country or community
• Overcrowded, poorly ventilated settings (prisons, shelters, hospitals)
• Healthcare workers (nosocomial exposure)
• Foreign-born individuals from endemic regions

Host Factors Increasing Risk of Progression from Infection to Disease

• Harrison's 22E, Chapter 183

Precipitating Factors

1. HIV infection - the single most powerful precipitating factor; HIV destroys CD4+ T cells critical for granuloma maintenance
2. Immunosuppressive drugs - corticosteroids, anti-TNF agents (infliximab, adalimumab), JAK inhibitors, cancer chemotherapy
3. Malnutrition and significant weight loss - particularly protein-energy malnutrition
4. Diabetes mellitus - poorly controlled DM significantly increases risk of reactivation
5. Silicosis - causes progressive damage to alveolar macrophages
6. Gastrectomy or intestinal bypass - nutritional deficiency, malabsorption
7. End-stage renal disease - uremic immunosuppression
8. Haematological malignancies (lymphoma, leukemia) - cell-mediated immunity impairment
9. Physiological stress - pregnancy (postpartum period), psychosocial stress
10. Old age - immunosenescence
11. Heavy alcohol use - impairs macrophage function and cell-mediated immunity

Pathogenesis

1. Initial infection: Bacilli reach the alveoli and are phagocytosed by alveolar macrophages. Most cases are eliminated or lead to a subclinical primary infection forming the Ghon focus (lower lobe or mid-zone subpleural focus) with hilar lymphadenopathy = Ghon complex (primary complex).
2. Haematogenous dissemination occurs early during primary infection to seed many organs.
3. Cell-mediated immunity (CMI) develops over 2-8 weeks: CD4+ T helper cells release IFN-γ and activate macrophages. This leads to granuloma formation - the hallmark of TB pathology. Granulomas contain Langerhans giant cells, epithelioid cells, lymphocytes, and fibrous tissue, often with central caseation necrosis (cheese-like material).
4. Latent TB (LTBI): Bacilli are contained but not eradicated in most (90-95%) infected people. They remain dormant, held in check by intact CMI.
5. Reactivation: If CMI fails (see precipitating factors above), dormant bacilli multiply, granulomas break down, and active disease ensues - typically in the apical-posterior upper lobes where oxygen tension is highest, favoring M. tuberculosis growth.

• Harrison's 22E, Chapter 183

Pathology

• Primary TB: Ghon focus + ipsilateral hilar lymphadenopathy = primary complex. Pleural effusion may occur. Usually heals with calcification.
• Post-primary (reactivation) TB: Upper lobe consolidation progressing to caseation, then liquefaction and cavitation when caseous material is discharged into a bronchus. Cavities have thick walls and contain large numbers of bacilli - this is the most infectious form.
• Caseating granulomas with Langerhans giant cells on histology are the defining pathological feature.
• Fibrocaseous TB: Extensive fibrosis around cavities in chronic disease.
• Harrison's 22E, Chapter 183

Clinical Features

Symptoms

• Fever - typically low-grade, afternoon rise (afternoon fever)
• Night sweats - drenching, characteristic feature
• Weight loss and anorexia - often marked ("consumption")
• Fatigue and malaise

• Persistent cough - the most common symptom; initially dry, becomes productive with mucupurulent sputum; present in >75% of culture-confirmed cases. Up to 25% have no cough.
• Haemoptysis - occurs in advanced disease; ranges from blood-streaking of sputum to massive haemoptysis
• Pleuritic chest pain - especially when pleura is involved
• Dyspnoea - in extensive disease or with complications (pneumothorax, effusion)

• Goldman-Cecil Medicine, Chapter 299
• Murray & Nadel's Respiratory Medicine

Physical Signs

• Post-tussive crepitations (rales) over the upper zones - a classic sign
• Amphoric (cavernous) breath sounds - indicates an underlying cavity
• Dullness to percussion over areas of consolidation or pleural effusion
• Reduced breath sounds over effusion
• Tracheal deviation (towards the lesion in fibrosis, away in effusion)
• Wasting and cachexia in advanced disease
• Lymphadenopathy - uncommon in immunocompetent adults with pulmonary TB; more common in HIV-positive patients
• Clubbing - may occur in chronic, cavitary disease

Investigation / Diagnosis

Chest X-Ray (CXR)

• Hilar/paratracheal lymphadenopathy (most characteristic in children)
• Homogeneous consolidation in any lobe
• Pleural effusion

• Apical and posterior segment consolidation of upper lobes (right > left), and/or superior segment of lower lobes
• Cavitation - thick-walled cavities, often in upper zones
• Patchy heterogeneous shadows
• Fibrosis, volume loss, calcification (old disease)
• Miliary pattern - fine 1-2 mm nodules throughout both lung fields (disseminated TB)
• Pneumothorax or hydropneumothorax (rare)

Sputum Smear Microscopy

• Ziehl-Neelsen (ZN) staining of sputum for acid-fast bacilli (AFB)
• 3 sputum samples collected (spot, early morning, spot) on 2 consecutive days
• Sensitivity: ~50-80% in smear-positive pulmonary TB; lower in HIV
• Positive if >10,000 organisms/mL
• Auramine-rhodamine fluorescent stain is more sensitive than ZN, used where available

Culture

• Gold standard for diagnosis
• Lowenstein-Jensen (LJ) medium (egg-based): colonies in 3-8 weeks
• BACTEC MGIT (liquid medium): positive in 9-16 days - faster
• Allows drug susceptibility testing (DST)

Molecular Tests

• GeneXpert MTB/RIF (Xpert): WHO-recommended first-line test where available. Simultaneously detects M. tuberculosis DNA and rifampin resistance mutations within 2 hours. High sensitivity (~89%) and specificity (~99%).
• Line Probe Assay (LPA): Detects resistance to isoniazid and rifampin (MDR-TB)
• Whole Genome Sequencing: Increasingly used for full DST and strain typing

Tuberculin Skin Test (TST / Mantoux)

• 5 TU PPD injected intradermally; read at 48-72 hours
• Induration (not erythema) ≥10 mm = positive (≥5 mm in HIV-positive or immunocompromised)
• Indicates infection, not necessarily active disease; positive in LTBI too
• False negatives: severe TB, HIV, malnutrition, steroid use, elderly

Interferon-Gamma Release Assays (IGRA)

• QuantiFERON-TB Gold and T-SPOT.TB
• Measure IFN-γ released by sensitized T-cells in response to M. tuberculosis-specific antigens (ESAT-6, CFP-10)
• More specific than TST (not affected by BCG vaccination or most NTM)
• Preferred in BCG-vaccinated populations and healthcare workers
• Harrison's 22E, Chapter 183

Bronchoscopy

• Bronchoalveolar lavage (BAL) for smear-negative cases with high suspicion
• Transbronchial biopsy if endobronchial involvement

Other Tests

• CBC: Mild normocytic anaemia, leukocytosis, lymphopenia; elevated ESR
• LFTs: Baseline before anti-TB drugs (hepatotoxic drugs)
• Serum sodium: Hyponatraemia (SIADH in TB meningitis, but can occur in pulmonary TB)
• ADA (Adenosine Deaminase) in pleural fluid: elevated in TB pleuritis
• Histopathology: Caseating granulomas with Langerhans giant cells

Management

Aims

1. Cure the patient (sterilize all bacilli)
2. Prevent transmission to others
3. Prevent emergence of drug resistance
4. Prevent relapse

General Measures

• Notification to public health authorities (legally required in most countries)
• Isolation for the first 2 weeks of treatment (until sputum smear negative on 3 consecutive specimens)
• Nutritional support
• Contact tracing and testing
• Screen for HIV, diabetes, and other comorbidities

Drug Treatment: Drug-Susceptible Pulmonary TB

First-Line Drugs (mnemonic: RIPES or HRZE)

Standard Regimen (WHO / ATS / CDC)

• Intensive phase: HRZE × 2 months (2HRZE)
• Continuation phase: HR × 4 months (4HR)
• Total duration: 6 months (2HRZE / 4HR)

• Cavitary disease with positive sputum culture at 2 months
• Incomplete pyrazinamide course
• Delayed culture conversion (sputum positive at 3 months)

4-Month Regimen (new, 2020)

• Harrison's 22E, Chapter 186

Latent TB Infection (LTBI) Treatment

• Harrison's 22E, Chapter 186

Drug-Resistant TB

• MDR-TB: Resistant to at least INH + Rifampicin
  • Treatment: Bedaquiline + Pretomanid + Linezolid (BPaL) for 6 months - WHO recommended 2022
  • Older regimens: 18-24 months using fluoroquinolones, injectable agents, and other second-line drugs
• XDR-TB (Extensively Drug Resistant): MDR-TB + resistance to fluoroquinolone + one injectable; now redefined (2021) as MDR/RR-TB + resistance to any fluoroquinolone
• A single drug must never be added to a failing regimen (promotes further resistance)

Directly Observed Therapy (DOT)

• WHO-recommended strategy for ensuring adherence
• A healthcare worker or designated person watches the patient swallow every dose
• DOTS (DOT + Short-course) strategy remains the backbone of national TB programs

Monitoring During Treatment

• Monthly clinical assessment
• Sputum smear and culture monthly until negative on 2 consecutive specimens
• By 2 months: ~75-80% should be sputum culture negative
• By 3 months: ~95% negative
• Sputum positive at 4 months = treatment failure
• LFTs - baseline and if symptoms of hepatitis develop
• Visual acuity and colour vision tests for ethambutol
• Audiometry for streptomycin/aminoglycosides
• Uric acid for pyrazinamide
• Goldman-Cecil Medicine, Chapter 299

Complications

Pulmonary Complications

1. Haemoptysis
   • Minor (blood-streaked sputum) to massive (>600 mL/24 h)
   • Massive haemoptysis can be life-threatening; due to Rasmussen's aneurysm (erosion of pulmonary artery by a cavity)
   • Management: bed rest, antitussives, bronchial artery embolization, surgery
2. Pneumothorax / Pyopneumothorax
   • Rupture of a subpleural cavity or bleb into the pleural space
   • Can be spontaneous; requires chest drain
3. Pleural Effusion (TB Pleuritis)
   • Exudative effusion, often unilateral; may be the sole manifestation
   • ADA elevated, lymphocyte predominant
4. Aspergilloma (Mycetoma)
   • Aspergillus fumigatus colonizes old healed TB cavities
   • Presents with haemoptysis; "air crescent sign" on CT
   • Management: antifungal therapy; surgery if haemoptysis massive
5. Empyema Thoracis
   • Spread of infection into the pleural space
   • Requires drainage + anti-TB therapy
6. Bronchiectasis
   • Permanent dilatation of bronchi following repeated infection and destruction
   • Leads to chronic productive cough and recurrent infections
7. Bronchopleural Fistula
   • Communication between a bronchus and the pleural cavity; complication of cavitary disease or surgery
8. Respiratory Failure
   • Progressive destruction of lung parenchyma in untreated or MDR-TB
9. Pulmonary Fibrosis
   • End-stage sequela; leads to restrictive lung disease
10. Obstructive Lung Disease
    • Airway obstruction from endobronchial TB, lymph node compression, or fibrotic distortion

Extrapulmonary Complications (Dissemination)

1. Miliary TB
   • Haematogenous dissemination of bacilli throughout the body
   • Small (1-2 mm) granulomas in lungs, liver, spleen, bone marrow, meninges
   • CXR: "millet seed" pattern
   • Life-threatening; requires immediate treatment
2. TB Meningitis
   • Most serious extrapulmonary form; 20-50% mortality even with treatment
   • Raised ICP, cranial nerve palsies, hydrocephalus, cognitive impairment
   • Add corticosteroids (dexamethasone) to anti-TB therapy
3. TB Pericarditis
   • Constrictive pericarditis is a chronic sequela
   • Add corticosteroids to reduce risk of constriction
4. Hyponatraemia (SIADH) - occurs in severe pulmonary TB
5. Cor Pulmonale
   • Chronic pulmonary hypertension from extensive fibrosis/destruction

Drug-Related Complications

1. Hepatotoxicity - all three of INH, Rifampicin, Pyrazinamide are hepatotoxic; monitor LFTs; stop drugs if LFTs >3-5x ULN with symptoms
2. Peripheral Neuropathy - INH (prevented by B6)
3. Optic Neuritis - Ethambutol (dose-dependent, reversible if caught early)
4. Hyperuricaemia / Gout - Pyrazinamide
5. Orange discoloration of urine/tears - Rifampicin (harmless; warn patients)
6. Drug Interactions - Rifampicin is a potent hepatic enzyme inducer (CYP450); reduces levels of oral contraceptives, antiretrovirals, anticoagulants

Social Complications

1. Loss of employment, stigma, mental health impact, family disruption

Prevention

• BCG vaccination: Given at birth or shortly after in high-prevalence countries; highly effective against miliary TB and TB meningitis in children; variable efficacy against pulmonary TB in adults (~0-80% depending on latitude)
• LTBI treatment (see above)
• Infection control in healthcare settings: negative-pressure rooms, N95 respirators, UV light, adequate ventilation
• Contact tracing of all close contacts of smear-positive cases
• Screening of high-risk populations (HIV, prisoners, healthcare workers, migrants from endemic areas)

Summary Table: First-Line Anti-TB Drugs

• Harrison's Principles of Internal Medicine 22E (2025), Chapters 183 (Raviglione & Gori - TB pathogenesis, epidemiology, clinical features, diagnosis) and 186 (treatment of mycobacterial infections)
• Goldman-Cecil Medicine International Edition, Chapter 299 (Bailey & Phillips - Tuberculosis: active disease management, clinical features)
• Murray & Nadel's Textbook of Respiratory Medicine, Block 12 (Diagnosis of Pulmonary Tuberculosis)

Note on SN Chugh and Davidson: Neither SN Chugh's Bedside Clinics in Medicine nor Davidson's Principles and Practice of Medicine are available in the digital library. The content above is drawn from the three most authoritative standard references available - Harrison's, Goldman-Cecil (equivalent scope to Davidson's for internal medicine), and Murray & Nadel's (dedicated respiratory medicine text). The clinical content covers all major topics taught from Chugh and Davidson as well.The above is the comprehensive answer. Here is a quick summary of what was covered and a transparency note:

• Harrison's Principles of Internal Medicine 22E (2025) - Chapters 183 and 186
• Goldman-Cecil Medicine - Chapter 299
• Murray & Nadel's Textbook of Respiratory Medicine - Diagnosis chapter

1. Etiology - M. tuberculosis, acid-fast bacillus, cell wall structure
2. Epidemiology - 10 million cases/year, #1 infectious killer globally (2023)
3. Risk Factors - HIV (100x risk), silicosis, DM, ESRD, immunosuppressants, malnutrition, age extremes, smoking, alcohol
4. Precipitating Factors - HIV, steroids, anti-TNF agents, malnutrition, DM, haematologic malignancy, renal failure, alcohol, old age
5. Pathogenesis - Ghon focus, primary complex, granuloma formation, caseation, reactivation in apical zones
6. Pathology - Caseating granulomas, Langerhans giant cells, cavitation, fibrocaseous disease
7. Clinical Features - Constitutional (fever, night sweats, weight loss) + respiratory (cough, haemoptysis, chest pain, dyspnoea) + physical signs (post-tussive crepitations, amphoric breath sounds, cavitation signs)
8. Investigation - CXR (apical cavitation), ZN smear, culture (gold standard), GeneXpert, IGRA, TST, bronchoscopy, ADA
9. Management - Standard 2HRZE/4HR regimen; new 4-month regimen; LTBI treatment options; DOT; MDR-TB (BPaL); drug side effects and monitoring
10. Complications - Haemoptysis (Rasmussen's aneurysm), pneumothorax, pleural effusion, aspergilloma, empyema, bronchiectasis, miliary TB, TB meningitis, cor pulmonale, drug toxicity (hepatitis, optic neuritis, neuropathy)
11. Prevention - BCG, LTBI treatment, infection control, contact tracing

AIDS (Acquired Immunodeficiency Syndrome)

1. Definition

• AIDS = Acquired Immunodeficiency Syndrome
• End-stage of HIV (Human Immunodeficiency Virus) infection
• Diagnosed when CD4+ T cell count falls below 200 cells/μL OR an AIDS-defining illness occurs, in the presence of HIV infection
• Caused by HIV-1 (most common worldwide) or HIV-2 (mainly West Africa)

2. Etiology / Causative Agent

• Virus: HIV - a retrovirus belonging to the genus Lentivirus, family Retroviridae
• Two types: HIV-1 (global) and HIV-2 (West Africa, less virulent)
• Structure: Enveloped RNA virus with:
  • Core proteins: p24 (capsid antigen - used in diagnosis), p17 (matrix)
  • Envelope glycoproteins: gp120 (binds CD4 receptor) and gp41 (fusion)
  • Enzymes: Reverse transcriptase, Integrase, Protease - all drug targets
• Genome: Two copies of single-stranded RNA with 9 genes (gag, pol, env + regulatory genes)

3. Epidemiology

• As of 2023: 39.9 million people living with HIV globally
• 1.3 million new infections in 2023
• ~95% in low- and middle-income countries
• Eastern and Southern Africa most severely affected (>1 in 20 adults)
• Global new infections down 60% from peak in 1995
• India: One of the highest burden countries in Asia

4. Transmission (Modes)

• Unprotected heterosexual intercourse (HIV-1 most commonly transmitted via heterosexual route globally)
• Men who have sex with men (MSM) - higher risk due to rectal mucosal vulnerability
• Risk per act: receptive anal intercourse ~1.4%, vaginal ~0.08-0.1%

• Sharing contaminated needles/syringes (IV drug users)
• Blood transfusion (screened blood dramatically reduces this)
• Needlestick injuries in healthcare workers (~0.3% risk per exposure)

• During pregnancy (transplacental), delivery, or breastfeeding
• Risk: 15-45% without intervention; reduced to <1% with ART + formula feeding

5. Pathogenesis

• HIV gp120 binds to CD4 receptor on CD4+ T cells, macrophages, dendritic cells
• Co-receptor binding: CCR5 (R5 viruses - early disease) or CXCR4 (X4 viruses - late disease)
• gp41 mediates fusion; viral core enters cell

• Reverse transcriptase converts viral RNA → double-stranded DNA (prone to errors = mutation/resistance)
• Integrase inserts viral DNA into host genome → provirus (latent reservoir; cannot be eradicated)
• Viral proteins produced; new virions bud off, destroying the cell

• Direct: viral budding, accumulation of viral DNA, syncytia formation
• Indirect: apoptosis, pyroptosis (caspase-1), activation-induced cell death, autoimmunity, innocent bystander killing
• Progressive loss of CD4+ T cells → collapse of cell-mediated immunity

• CD4 <500: mild immune compromise
• CD4 <200: AIDS-defining threshold; susceptibility to opportunistic infections (OIs) and malignancies
• CD4 <50: life-threatening OIs (MAC, CMV retinitis)

6. Clinical Stages / Natural History

Stage 1 - Acute HIV Syndrome (2-4 weeks after infection)

• Occurs in 50-70% of newly infected individuals
• Resembles infectious mononucleosis (hence "mono-like illness")
• Symptoms (Table - Acute HIV Syndrome):
  • General: Fever, pharyngitis, lymphadenopathy, headache, arthralgia/myalgia, fatigue, anorexia, weight loss, nausea/vomiting/diarrhoea
  • Neurological: Aseptic meningitis, encephalitis, peripheral neuropathy, myelopathy
  • Dermatological: Erythematous maculopapular rash, mucocutaneous ulceration
• High plasma viral load; CD4 temporarily drops, then recovers
• Lasts 1-several weeks; subsides as immune response develops
• Window period (before antibodies detectable): 3-12 weeks

Stage 2 - Chronic Asymptomatic (Clinical Latency)

• Lasts average 10 years without ART (some progress faster, some slower)
• Virus continues replicating in lymphoid tissue
• CD4 count slowly declines (~50-80 cells/μL/year)
• Patient may be asymptomatic but infectious
• Only sign may be persistent generalized lymphadenopathy (PGL)

Stage 3 - Symptomatic HIV / AIDS-Related Complex (ARC)

• CD4 typically 200-500 cells/μL
• Minor OIs and constitutional symptoms appear

Stage 4 - AIDS

• CD4 <200 cells/μL OR AIDS-defining illness

7. WHO Clinical Staging System

8. AIDS-Defining Conditions (CDC Category C)

• Pneumocystis jirovecii pneumonia (PCP) - most common OI
• Toxoplasmosis of brain
• Cryptococcal meningitis (extrapulmonary)
• CMV retinitis / CMV disease
• Herpes simplex: chronic ulcers >1 month
• Mycobacterium avium complex (MAC) - disseminated
• Extrapulmonary tuberculosis
• Recurrent bacterial pneumonia (≥2 episodes/year)
• Cryptosporidiosis (chronic intestinal)
• Histoplasmosis / Coccidioidomycosis (disseminated)
• Progressive multifocal leukoencephalopathy (PML) - JC virus
• Isosporiasis (chronic)
• Candidiasis of oesophagus/trachea/bronchi

• Kaposi's sarcoma (HHV-8)
• Non-Hodgkin's lymphoma (Burkitt's, immunoblastic)
• Invasive cervical carcinoma

• HIV encephalopathy (AIDS dementia complex)
• HIV wasting syndrome (>10% weight loss + diarrhoea/fever >30 days)
• HIV-associated nephropathy
• HIV-associated cardiomyopathy

9. Diagnosis

Serological Tests

• ELISA (4th generation): Detects HIV antibodies + p24 antigen; sensitivity >99.5%; used for screening
• Western Blot: Confirmatory test (now replaced by HIV-1/HIV-2 differentiation immunoassay in CDC guidelines)
• Rapid HIV tests: Point-of-care; oral fluid or finger-prick blood
• Window period: 3-12 weeks (ELISA); shorter with 4th gen tests (p24 detectable at ~2 weeks)

Virological Tests

• HIV RNA (Viral Load): Quantifies plasma virus copies; used for monitoring (undetectable <50 copies/mL = treatment goal)
• HIV DNA PCR: Used in infants (maternal antibodies confound ELISA in first 18 months)
• Nucleic Acid Testing (NAT): Used in blood banks; window period ~12 days

Immunological Tests

• CD4+ T cell count: Determines stage, when to start ART, and OI prophylaxis thresholds
• CD4/CD8 ratio: Normal ~2:1; inverted in HIV (<1:1 is characteristic)

Resistance Testing

• Genotypic assay: Sequence analysis of HIV genome for resistance mutations
• Phenotypic assay: In vitro growth in presence of drugs
• Done at diagnosis and at virologic failure

10. Management

General Principles

• Antiretroviral Therapy (ART) is the mainstay - cannot cure but suppresses viral replication
• Goal: Undetectable viral load (<50 copies/mL) → immune restoration → normal life expectancy
• ALL HIV-positive individuals should be offered ART regardless of CD4 count (WHO 2015/2021)
• "Treatment as Prevention" (TasP): Undetectable = Untransmittable (U=U)

ART Drug Classes and Mechanism

First-Line Regimen (WHO Preferred, 2023)

• Dolutegravir + Tenofovir + Lamivudine (or Emtricitabine)
  • DTG/3TC/TDF - highly effective, well tolerated, high barrier to resistance
• Combination of ≥3 drugs from ≥2 classes always required (to prevent resistance)

Monitoring on ART

• Viral load at 6 months, then every 6-12 months
• CD4 count at baseline, then when clinically indicated
• LFTs, renal function, CBC, lipids
• Virologic failure: Viral load >1000 copies/mL on 2 consecutive measures → switch regimen

OI Prophylaxis (Primary)

PEP (Post-Exposure Prophylaxis)

• Started within 72 hours of exposure (sooner = better)
• Duration: 28 days
• Regimen: TDF + FTC + DTG (or Raltegravir)

PrEP (Pre-Exposure Prophylaxis)

• TDF + FTC daily for high-risk individuals
• Reduces transmission by >90%

11. Complications

Infectious Complications

• Respiratory: PCP (fever, non-productive cough, SOB, bilateral infiltrates), TB (most common OI globally), bacterial pneumonia
• CNS: Toxoplasmosis (ring-enhancing lesions on CT), cryptococcal meningitis, CMV encephalitis, PML (JC virus), HIV dementia
• GI: Oesophageal candidiasis (dysphagia), CMV colitis, cryptosporidiosis (chronic diarrhoea), MAC (diarrhoea, wasting)
• Eye: CMV retinitis (CD4 <50) - "pizza pie" appearance; can cause blindness
• Skin: Herpes zoster, molluscum contagiosum, seborrhoeic dermatitis

Malignancies

• Kaposi's Sarcoma: Violaceous skin/mucosal lesions; caused by HHV-8; commonest AIDS malignancy
• Non-Hodgkin's Lymphoma: Often cerebral or systemic; EBV-related
• Cervical carcinoma: HPV-related

HIV-Direct Organ Complications

• AIDS Dementia Complex (HIV Encephalopathy): Cognitive decline, motor slowing, behavioral changes
• HIV Wasting Syndrome: >10% weight loss + diarrhoea or fever >30 days
• HIV Nephropathy (HIVAN): Focal segmental glomerulosclerosis; can lead to ESRD
• HIV Cardiomyopathy: Dilated cardiomyopathy
• Peripheral Neuropathy: Direct viral effect

ART-Related Complications

• Lipodystrophy: Fat redistribution (peripheral wasting + central obesity) - mainly with older NRTIs
• Metabolic Syndrome: Dyslipidaemia, insulin resistance
• Hepatotoxicity: Nevirapine, PIs
• Nephrotoxicity: Tenofovir (TDF)
• Osteopenia/Osteoporosis: Long-term ART
• Immune Reconstitution Inflammatory Syndrome (IRIS): Paradoxical worsening of OI symptoms 2-12 weeks after starting ART as immune system recovers; TB-IRIS most common

12. Physiotherapy Relevance in HIV/AIDS

• Pulmonary rehabilitation: For PCP, TB, HIV-associated pulmonary disease - chest PT, breathing exercises, nebulisation
• Exercise therapy: Aerobic and resistance training improves CD4 count, reduces fatigue, improves quality of life; shown to be safe at all stages
• Peripheral neuropathy management: TENS, balance training, splinting, footwear advice
• Wasting syndrome: Resistance training for muscle mass restoration; nutritional counselling co-ordination
• Pain management: Musculoskeletal pain, neuropathic pain - TENS, heat, massage, exercise
• HIV encephalopathy: Cognitive rehabilitation, gait training, falls prevention
• Fatigue management: Graded exercise, energy conservation techniques
• Kaposi's sarcoma limb lymphoedema: Manual lymphatic drainage, compression garments
• Postural correction and joint mobility: For long-term survivors on ART with lipodystrophy
• Psychosocial support: Group exercise programs reduce depression and improve adherence to ART

13. Prevention

• Safe sex practices: Condom use (reduces transmission by ~85%)
• PrEP for high-risk individuals
• PEP within 72 hours of exposure
• PMTCT (Prevention of Mother to Child Transmission): ART during pregnancy + labour + infant NVP + safe infant feeding
• Harm reduction for IDUs: Needle exchange programs, opioid substitution therapy
• Blood safety: Universal screening of donated blood
• Universal precautions in healthcare settings
• Voluntary counselling and testing (VCT)
• Male circumcision: Reduces female-to-male HIV transmission by ~60%
• No vaccine currently available (multiple trials failed; broadly neutralizing antibody research ongoing)

1. Risk factors for AIDS (factors that increase risk of getting HIV/developing AIDS)
2. Precipitating factors (factors that trigger progression from HIV+ to AIDS)
3. Clinical features of AIDS (stage by stage, organ-system by organ-system)

AIDS - Risk Factors, Precipitating Factors & Clinical Features

A. RISK FACTORS FOR HIV/AIDS

1. Sexual Risk Factors

• Unprotected receptive anal intercourse - highest sexual risk (138 per 10,000 exposures)
• Unprotected insertive anal intercourse - 11 per 10,000 exposures
• Unprotected receptive vaginal intercourse - 8 per 10,000 exposures
• Unprotected insertive vaginal intercourse - 4 per 10,000 exposures
• Multiple sexual partners - increases cumulative exposure
• High viral load in partner - directly proportional to transmission risk
• Presence of other STIs especially ulcerative genital diseases (herpes, syphilis, chancroid) - disrupt mucosal barrier, increase transmission 3-5 fold
• Lack of male circumcision - foreskin is rich in Langerhans cells (target cells)
• Sex work and clients of sex workers

2. Parenteral / Blood-Borne Risk Factors

• Blood transfusion with unscreened blood - highest risk (9,250 per 10,000 exposures)
• Sharing contaminated needles/syringes (IDUs) - 63 per 10,000 exposures
• Needlestick injury (healthcare workers) - 23 per 10,000 exposures
• Use of non-sterile medical/dental instruments
• Tattooing/piercing with unsterilized equipment

3. Vertical (Mother-to-Child) Risk Factors

• Untreated HIV-positive mother during pregnancy, delivery, or breastfeeding
• High maternal viral load - directly correlates with MTCT risk
• Prolonged breastfeeding in developing countries without ART
• Preterm delivery - immature immune system in infant
• Vaginal delivery (vs. elective caesarean section) - higher exposure

4. Host / Immunological Risk Factors

• Absence of CCR5-Δ32 mutation - individuals homozygous for this mutation are resistant to R5-tropic HIV
• Certain HLA types - some HLA haplotypes (e.g., HLA-B57, HLA-B27) are protective; others are permissive
• Absence of natural immunity - some exposed but uninfected individuals have strong HIV-specific CTL responses and high CCR5 ligand levels
• Malnutrition - impairs mucosal integrity and immune response
• Young age and elderly - less robust immune defenses

5. Socio-Behavioral Risk Factors

• Injection drug use (IDU)
• Men who have sex with men (MSM)
• Transgender individuals
• Prisoners (overcrowding, lack of harm reduction)
• Living in high-prevalence region (Sub-Saharan Africa, South/Southeast Asia)
• Low socioeconomic status - reduced access to prevention and healthcare
• Alcohol and substance use - impairs judgment, increases unprotected sex

B. PRECIPITATING FACTORS (Factors That Trigger Progression from HIV+ to AIDS)

1. Immunosuppressive Conditions

• HIV co-infection with other viruses: CMV, EBV, HSV, HHV-6, HTLV-1 - all activate HIV replication by increasing cellular activation
• Other infections: Malaria, TB, other STIs - systemic immune activation drives HIV replication
• Malignancy (lymphoma, leukaemia) - destroys immune cells; chemotherapy further immunosuppresses

2. Medications / Iatrogenic

• Corticosteroids (long-term use) - suppress CD4 T cell function
• Chemotherapy - destroys proliferating immune cells
• Immunosuppressive drugs (post-transplant: cyclosporine, tacrolimus, mycophenolate)
• Anti-TNF-α agents (infliximab, adalimumab) - reduce macrophage function
• Radiation therapy

3. Nutritional Factors

• Severe protein-energy malnutrition - reduces CD4 count, lymphocyte function, and mucosal immunity
• Micronutrient deficiencies: Vitamin A, zinc, selenium deficiencies impair immune reconstitution
• Wasting - accelerates disease progression; weight loss >10% is itself an AIDS-defining condition

4. Behavioural / Lifestyle Factors

• Non-adherence to ART - most important modifiable cause of progression; allows viral rebound and drug resistance
• Heavy alcohol use - toxic to lymphocytes; impairs macrophage function; hepatotoxic (liver is key immune organ)
• Tobacco smoking - increases oxidative stress, promotes pulmonary infections
• Injection drug use (continued) - repeated exposure to infections; adulterated drugs are immunotoxic

5. Viral Factors

• High baseline viral load (set-point viral load) - higher set-point = faster progression
• Co-receptor switch: Transition from R5 (CCR5-using) to X4 (CXCR4-using) viruses - X4 viruses are more cytopathic and associated with rapid CD4 decline
• Drug-resistant HIV strains - resist ART, viral replication continues unchecked
• Superinfection with a different HIV strain - can accelerate progression

6. Host Genetic Factors

• Absence of protective HLA types (HLA-B57, HLA-B27)
• HLA-B35 homozygosity - associated with rapid progression
• CCR5 wild-type (no protective Δ32 mutation)
• SDF-1 3'A polymorphism - associated with faster progression to AIDS

7. Physiological States

• Pregnancy - relative immunosuppression; CD4 counts may fall; viral load may rise in 3rd trimester and postpartum
• Old age - immunosenescence reduces ability to mount CD8 CTL responses
• Psychological stress / chronic stress - elevates cortisol, suppresses cell-mediated immunity
• Sleep deprivation - impairs lymphocyte proliferation

8. Co-morbidities

• Diabetes mellitus - impairs leukocyte function
• Renal failure - uraemic immunosuppression
• Liver disease / Hepatitis C co-infection - immune dysregulation; liver is key for immune protein synthesis
• Hepatitis B co-infection - both viruses target CD4+ cells and hepatocytes

C. CLINICAL FEATURES OF AIDS

Stage 1 - Acute HIV Syndrome (2-6 weeks after infection)

• Fever (most common)
• Pharyngitis (sore throat)
• Lymphadenopathy (generalised)
• Headache and retroorbital pain
• Arthralgia / Myalgia
• Lethargy / Malaise
• Anorexia and weight loss
• Nausea, vomiting, diarrhoea

• Erythematous maculopapular rash (trunk and face)
• Mucocutaneous ulceration

• Aseptic meningitis
• Encephalitis (rare)
• Peripheral neuropathy
• Myelopathy
• Note: Resembles infectious mononucleosis; lasts 1-4 weeks; self-limiting

Stage 2 - Chronic Asymptomatic / Clinical Latency (average 10 years)

• Often completely asymptomatic
• Persistent Generalized Lymphadenopathy (PGL) - enlarged lymph nodes in ≥2 extra-inguinal sites >3 months; no other cause
• Patient remains infectious throughout this period
• CD4 slowly declines (~50-80 cells/μL/year)

Stage 3 - Symptomatic HIV (CD4 200-500 cells/μL)

• Low-grade fever, night sweats
• Weight loss (>10% body weight)
• Chronic diarrhoea (>1 month)
• Fatigue and malaise

• Oral candidiasis (thrush) - white curd-like plaques on buccal mucosa; painful
• Oral hairy leukoplakia - white corrugated lesions on lateral tongue (EBV); not painful, cannot be scraped off
• Herpes zoster (shingles) - dermatomal vesicular rash; may be multi-dermatomal or disseminated
• Seborrheic dermatitis - florid, difficult to control
• Papular pruritic eruption
• Angular cheilitis
• Recurrent oral ulcers
• Fungal nail infections

• Recurrent bacterial pneumonia
• Pulmonary TB (current)
• Recurrent upper respiratory tract infections

• Cervical dysplasia / CIN
• Unexplained anaemia, thrombocytopenia, or neutropenia

Stage 4 - AIDS (CD4 <200 cells/μL)

Respiratory Features

• PCP (Pneumocystis jirovecii Pneumonia) - most common OI
  • Dry non-productive cough, progressive dyspnoea, fever
  • CXR: bilateral perihilar interstitial infiltrates ("butterfly" pattern)
  • PaO2 reduced; KL-6 elevated; LDH elevated
• Pulmonary TB (severe or extrapulmonary)
• Bacterial pneumonia (recurrent ≥2/year)
• Cryptococcal pneumonia
• CMV pneumonitis
• Aspergillosis (in severely immunocompromised)

Neurological Features

• AIDS Dementia Complex (HIV Encephalopathy):
  • Cognitive decline, memory loss, poor concentration
  • Motor slowing, ataxia, leg weakness
  • Behavioural changes (apathy, depression, psychosis)
  • In advanced cases: incontinence, mutism, paraplegia
• Cryptococcal Meningitis (CD4 <100):
  • Subacute meningoencephalitis: fever, headache, nausea/vomiting, altered consciousness, meningeal signs
  • India ink positive in CSF; raised opening pressure; cryptococcal antigen positive
• CNS Toxoplasmosis (CD4 <100):
  • Headache, focal neurological deficits, seizures, fever
  • CT/MRI: multiple ring-enhancing lesions, especially basal ganglia
• Progressive Multifocal Leukoencephalopathy (PML) - JC virus:
  • Progressive focal neurological deficits, cognitive decline
  • MRI: white matter lesions (non-enhancing)
• CMV Encephalitis (CD4 <50):
  • Confusion, personality change, lethargy
• Peripheral Neuropathy:
  • Distal symmetric sensory neuropathy (most common) - burning, tingling feet/legs
  • Also from drugs (ddI, ddC, d4T)

Gastrointestinal Features

• Oesophageal Candidiasis:
  • Dysphagia, odynophagia (painful swallowing), retrosternal chest pain
  • Oral thrush usually present concurrently
• CMV Colitis: Bloody diarrhoea, abdominal pain, fever; may perforate
• Cryptosporidiosis: Profuse watery diarrhoea (>10 L/day in severe cases), cramping, weight loss; chronic (>1 month)
• Microsporidiosis: Chronic watery diarrhoea
• MAC (Mycobacterium avium Complex) (CD4 <50):
  • Fever, night sweats, profound weight loss, diarrhoea, abdominal pain
  • Massive hepatosplenomegaly, markedly elevated ALP
• Isosporiasis: Chronic diarrhoea, malabsorption

Eye Features

• CMV Retinitis (CD4 <50) - most important:
  • Initially asymptomatic; progressing to floaters, visual field defects, decreased visual acuity
  • Fundoscopy: "pizza-pie" or "crumbled cheese and ketchup" appearance - perivascular haemorrhages and exudates
  • Can cause blindness if untreated
• HIV microvasculopathy: Cotton-wool spots (most common finding)
• Herpes zoster ophthalmicus
• Toxoplasmosis chorioretinitis

Skin Features

• Kaposi's Sarcoma (KS) - caused by HHV-8:
  • Violaceous (purple-red), non-blanching, painless plaques/nodules on skin, mucosa, viscera
  • Common sites: legs, face, oral cavity, genitalia
  • May involve lungs (haemoptysis), GI tract (bleeding), lymph nodes
• Disseminated herpes simplex: Chronic ulcers >1 month; perianal/oral
• Molluscum contagiosum: Multiple, giant, facial lesions
• Extensive wart virus (HPV) infection
• Norwegian (crusted) scabies: Thick crusted, hyperkeratotic plaques; highly infectious

Wasting Syndrome

• Weight loss >10% of body weight PLUS
• Chronic diarrhoea >30 days OR unexplained fever >30 days
• Profound muscle wasting (sarcopenia)

Haematological Features

• Anaemia - normochromic normocytic; due to HIV itself, OIs, or drugs (AZT)
• Thrombocytopenia - immune-mediated (HIV-related ITP); petechiae, easy bruising
• Neutropenia - risk of bacterial infections
• Non-Hodgkin's Lymphoma:
  • Systemic (B symptoms + rapidly enlarging mass) or CNS (headache, focal deficits)
  • Often EBV-related; aggressive histology (Burkitt's, diffuse large B-cell)
• Cervical carcinoma (HPV-related, invasive)

Renal Features

• HIV-Associated Nephropathy (HIVAN):
  • Nephrotic syndrome (heavy proteinuria, hypoalbuminaemia, oedema)
  • Rapidly progressive to ESRD in untreated patients
  • Ultrasound: enlarged echogenic kidneys
  • Histology: focal segmental glomerulosclerosis (FSGS)

Cardiac Features

• HIV Cardiomyopathy: Dilated cardiomyopathy; heart failure
• Pericardial effusion (often due to TB or Kaposi's)
• Non-bacterial thrombotic endocarditis (marantic endocarditis)

Endocrine / Metabolic Features

• Adrenal insufficiency (CMV adrenalitis; TB adrenalitis): fatigue, hypotension, hyponatraemia, hyperkalaemia
• Hypogonadism: Testosterone deficiency; loss of libido, erectile dysfunction, muscle wasting
• Metabolic syndrome on ART: dyslipidaemia, insulin resistance, central obesity

Summary Table: CD4 Count and Clinical Events

AIDS - Risk Factors, Precipitating Factors & Clinical Features

A. RISK FACTORS

• Unprotected anal/vaginal intercourse
• Multiple sexual partners
• Other STIs (especially ulcerative - syphilis, herpes)
• Absence of male circumcision
• Sex workers / MSM

• Unscreened blood transfusion (highest risk)
• Sharing needles (IV drug users)
• Needlestick injury (HCW)

• HIV+ mother during pregnancy, delivery, or breastfeeding
• High maternal viral load

• Living in high-prevalence area
• Low socioeconomic status
• Alcohol/substance use → risky behaviour

B. PRECIPITATING FACTORS

• Non-adherence to ART - most important
• HIV co-infections - TB, CMV, EBV, Hepatitis B/C → activate HIV replication
• Immunosuppressive drugs - corticosteroids, chemotherapy, anti-TNF agents
• Malnutrition / wasting - reduces CD4 count and immunity
• Heavy alcohol use - toxic to lymphocytes
• Continued IV drug use
• Malignancies (lymphoma, leukaemia)
• Diabetes mellitus - impairs immune function
• Renal/liver failure - uraemic/hepatic immunosuppression
• Pregnancy / postpartum - relative immunosuppression
• Old age - immunosenescence
• Viral factors - high viral load set-point; switch to X4-tropic virus (more cytopathic); drug-resistant strains
• Chronic psychological stress - raises cortisol, suppresses CMI

C. CLINICAL FEATURES

Stage 1 - Acute HIV Syndrome (2-6 weeks)

• Fever, sore throat, lymphadenopathy
• Headache, myalgia, arthralgia, fatigue
• Maculopapular rash on trunk
• Nausea, vomiting, diarrhoea
• Aseptic meningitis (rare)
• Resembles infectious mononucleosis; resolves in 2-4 weeks

Stage 2 - Asymptomatic (up to 10 years)

• No symptoms
• Persistent Generalized Lymphadenopathy (PGL) only

Stage 3 - Symptomatic HIV (CD4 200-500)

• Fever, night sweats, weight loss (>10%), chronic diarrhoea
• Oral candidiasis (thrush)
• Oral hairy leukoplakia (lateral tongue)
• Herpes zoster (shingles)
• Seborrhoeic dermatitis
• Recurrent bacterial RTIs
• Pulmonary TB

Stage 4 - AIDS (CD4 <200)

• PCP - dry cough, breathlessness, fever (most common OI)
• TB (pulmonary/extrapulmonary)

• AIDS Dementia Complex - memory loss, motor slowing, behavioural change
• Cryptococcal meningitis - fever, headache, raised ICP
• CNS Toxoplasmosis - ring-enhancing lesions, seizures, focal deficits
• Peripheral neuropathy - burning/tingling feet

• Oesophageal candidiasis - dysphagia, odynophagia
• Cryptosporidiosis - profuse watery diarrhoea
• CMV colitis - bloody diarrhoea

• CMV retinitis (CD4 <50) - floaters, field defects → blindness; "pizza-pie" fundus

• Kaposi's Sarcoma - violaceous nodules/plaques (HHV-8)
• Disseminated herpes, molluscum contagiosum

• Wasting syndrome (>10% weight loss + chronic diarrhoea/fever)
• MAC (CD4 <50) - fever, sweats, diarrhoea, hepatosplenomegaly

• Anaemia, thrombocytopenia, neutropenia
• Non-Hodgkin's lymphoma

• HIVAN - nephrotic syndrome → ESRD

Quick CD4 Reference