---

AIDS — Etiology, Routes of Transmission, Natural History & Diagnosis

---

1. Etiology

• HIV-1 — responsible for the global pandemic; more virulent
• HIV-2 — largely confined to West Africa; less pathogenic

Structure of HIV-1

Genome

• Structural genes: gag (core proteins), pol (enzymes), env (envelope glycoproteins)
• Regulatory genes: tat (1000× increase in viral transcription — critical for replication), rev, vif, nef, vpr, vpu
• LTRs (Long Terminal Repeats) — regulate gene expression

— Robbins Cotran & Kumar: Pathologic Basis of Disease

---

2. Routes of Transmission

A. Sexual Transmission

• Most common route worldwide — predominantly heterosexual transmission globally
• In the United States, men who have sex with men (MSM) account for >50% of reported cases (~70% of new cases)
• Heterosexual transmission accounts for ~20% of US cases
• Virus is present in semen and cervical/vaginal secretions
• Receptive anal intercourse carries the highest risk; mucosal disruption amplifies risk

B. Parenteral Transmission (Blood-borne)

• Intravenous drug users sharing contaminated needles — a major risk group
• Transfusion of infected blood or blood products (now rare in countries with blood screening)
• Needle-stick injuries in healthcare workers (risk ~0.3% per exposure)
• Sharing of contaminated needles, syringes

C. Vertical (Mother-to-Child) Transmission

• Transplacental spread during pregnancy
• Intrapartum — exposure to infected maternal blood/secretions during delivery
• Breastfeeding (postpartum)
• ART has dramatically reduced vertical transmission

Notable: HIV is not transmitted by casual contact, insect vectors, saliva, tears, or shared utensils.

— Robbins Cotran & Kumar: Pathologic Basis of Disease

---

3. Natural History — Phases of HIV Infection

---

Phase 1: Acute (Primary) HIV Infection

• Virus enters via mucosal surfaces; initially infects CD4+ T cells, dendritic cells (DCs), and macrophages
• Massive viral replication → viremia → widespread dissemination to lymphoid organs
• CD4+ T cell count drops sharply; then partially recovers as immune response mounts
• Viral load peaks then falls to a "viral set point" — this plateau level predicts future progression rate

• Flu-like/mononucleosis-like illness: fever, lymphadenopathy, pharyngitis, rash, myalgia, headache
• Self-limiting, lasting 2–4 weeks
• Window period: antibodies not yet detectable (hence ELISA may be negative for up to 3–4 weeks)

---

Phase 2: Chronic Infection (Clinical Latency Phase)

• Lymph nodes and spleen are sites of continuous HIV replication
• CD4+ T cells are progressively destroyed (HIV destroys up to 2 × 10⁹ CD4+ cells/day)
• CD4 count steadily declines; >90% of body's T cells reside in lymphoid organs
• Despite apparent clinical silence, viral replication is not truly "latent" — it is ongoing in lymphoid tissue

• Only 8% of patients with viral load <4,350 copies/μL progressed to AIDS in 5 years vs. 62% of those with >36,270 copies

• Patient often asymptomatic for years
• Minor opportunistic infections may appear: oral candidiasis (thrush), vaginal candidiasis, herpes zoster, tuberculosis
• Persistent generalized lymphadenopathy (PGL) — enlarged nodes in ≥2 extra-inguinal sites for >3 months
• Autoimmune thrombocytopenia possible

---

Phase 3: AIDS (Acquired Immunodeficiency Syndrome)

• Complete breakdown of host cellular immunity
• Dramatic rise in viral load (CD4 cell loss overwhelms regenerative capacity)
• Destruction of lymphoid tissue architecture

• Fever (>1 month), fatigue, weight loss ("AIDS wasting"), diarrhea, generalized lymphadenopathy

• Kaposi sarcoma (KS) — caused by HHV-8; most common AIDS-associated tumor
• B-cell lymphomas (EBV-associated) — particularly CNS lymphoma
• Invasive cervical carcinoma (HPV-associated)

• HIV-associated neurocognitive disorder (HAND) / AIDS dementia complex
• Vacuolar myelopathy, peripheral neuropathy
• Aseptic meningitis (at seroconversion)
• CNS toxoplasmosis, cryptococcal meningitis

---

Special Patterns of Progression

— Robbins Cotran & Kumar: Pathologic Basis of Disease

---

4. Diagnosis

A. Serological Tests

1. ELISA (Enzyme-Linked Immunosorbent Assay) — Screening Test

• 4th generation ELISA (currently used): detects both anti-HIV antibodies (IgG/IgM) AND p24 antigen simultaneously
• Detects infection 2–4 weeks after exposure (earlier than antibody-only tests)
• High sensitivity (~99.9%) but lower specificity — positive results must be confirmed
• False positives possible in: autoimmune diseases, multiple pregnancies, recent viral infections, malignancies

2. Western Blot — Confirmatory Test

• Detects antibodies to specific HIV proteins separated by molecular weight
• Positive: bands against ≥2 of: p24, gp41, gp120/160
• Negative: no bands
• Indeterminate: some bands but not meeting criteria → repeat in 4–6 weeks

3. RT-PCR (Real-Time Reverse Transcriptase PCR) — Viral Load / NAT

• Detects HIV RNA directly in plasma
• Used for:
  • Early diagnosis (before seroconversion — detects virus in ~10 days)
  • Measuring viral load (copies/mL) — monitors disease progression and treatment response
  • Neonatal diagnosis (maternal antibodies cross placenta and persist up to 18 months — serology unreliable in infants)
  • Resolving indeterminate Western blot

4. CD4+ T Cell Count — Immunological Assessment

• Measured by flow cytometry
• Normal: 500–1500 cells/μL
• Used to:
  • Stage disease (CDC classification)
  • Determine when to start ART
  • Monitor treatment response
  • Assess risk of specific opportunistic infections
• AIDS diagnosed when CD4 <200 cells/μL

Diagnostic Algorithm (Summary)

Screening: 4th Gen ELISA (p24 Ag + Ab)
      ↓ Reactive
Confirmatory: Western Blot or HIV-1/2 differentiation assay
      ↓ Positive
CD4+ T cell count → Stage disease
Viral load (RT-PCR) → Baseline & monitor therapy

B. AIDS Diagnosis Criteria (CDC)

1. HIV-positive status (ELISA + Western blot) AND
2. CD4+ T cell count <200 cells/μL OR
3. Presence of an AIDS-defining illness (regardless of CD4 count)

C. p24 Antigen Detection

• Useful in the window period before antibody development
• Incorporated into 4th generation combination ELISA assays

— Medical Microbiology 9e; Robbins Cotran & Kumar: Pathologic Basis of Disease

---

Quick Revision Summary

---

Pneumonia — Pathology (Robbins & Kumar)

---

Definition

---

Classification

By Clinical Setting

---

Predisposing Factors / Pathogenesis

• Mucociliary clearance (mucociliary elevator)
• Alveolar macrophages
• Secretory IgA (upper airway)
• Serum IgM/IgG in alveolar lining fluid
• Complement activation
• Recruited neutrophils

---

Morphological Patterns

1. Lobar Pneumonia

• Consolidation of a large portion or entire lobe
• Caused most often by Streptococcus pneumoniae
• Passes through four classical stages:

Pleural fibrinous reaction (pleuritis) is often present in the early stages when consolidation reaches the lung surface — may resolve or organize into fibrous adhesions.

2. Bronchopneumonia (Lobular Pneumonia)

• Patchy consolidation — typically multilobar, bilateral, and basal (secretions gravitate to lower lobes)
• Lesions slightly elevated, dry, granular, gray-red to yellow, poorly delimited
• Histology: neutrophil-rich exudate filling bronchi, bronchioles, and adjacent alveolar spaces
• Pattern of involvement depends on the causative organism AND host susceptibility — the same organism can produce either pattern

---

Causative Organisms — Key Points

Community-Acquired Bacterial (CAP)

• Most common cause of CAP
• Distribution: usually lobar
• Gram stain of sputum: gram-positive, lancet-shaped diplococci in neutrophils
• Capsular polysaccharide vaccines available
• Blood cultures positive in only 20–30% early in illness

Community-Acquired Viral Pneumonia

• Influenza A & B, RSV, metapneumovirus, adenovirus, COVID-19
• Viruses attach to and enter respiratory epithelial cells → cytopathic changes → cell death → secondary inflammation
• Damage to mucociliary clearance predisposes to bacterial superinfection (often more serious than the primary viral illness)
• Histology: interstitial lymphocytic inflammation (vs. intraalveolar neutrophilic inflammation in bacterial pneumonia)

Atypical Pneumonias

• Moderate fever, non-productive cough
• X-ray: patchy interstitial infiltrates disproportionate to clinical findings
• Interstitial inflammation, diffuse alveolar damage

Aspiration Pneumonia

• Debilitated patients with impaired gag/swallowing reflexes (stroke, unconscious, vomiting)
• Chemical + bacterial — gastric acid irritation + oral flora
• Multiple organisms (aerobes > anaerobes)
• Typically necrotizing, fulminant course
• Common complication: lung abscess

Hospital-Acquired (Nosocomial) Pneumonia

• Severely ill, immunosuppressed, prolonged antibiotics, ventilator-dependent patients
• Dominant organisms: gram-negative rods (Klebsiella, Serratia, E. coli, Pseudomonas) + MRSA
• Ventilator-associated pneumonia (VAP): gram-negatives predominate
• High mortality; antibiotic resistance common

Healthcare-Associated Pneumonia

• Risk factors: hospitalization within 90 days, nursing home, IV antibiotics/chemotherapy
• Organisms: MRSA, P. aeruginosa most common
• Higher mortality than CAP; requires broad-spectrum empirical antibiotics

---

Clinical Features

• Abrupt onset of high fever, shaking chills
• Cough with mucopurulent sputum ± haemoptysis
• Pleuritic chest pain + pleural friction rub (if pleuritis present)
• CXR: radiopaque entire lobe (lobar) or focal opacities (bronchopneumonia)
• Appropriately treated patients become afebrile within 48–72 hours of antibiotics
• <10% of hospitalised patients now die (usually from complications or comorbidities)

• Gradual onset, moderate fever, non-productive ("dry") cough, headache, myalgia
• CXR: patchy interstitial bilateral infiltrates

---

Complications

1. Lung abscess — tissue destruction/necrosis; especially with S. aureus, Klebsiella, anaerobes
2. Empyema — spread to pleural cavity → intrapleural fibrinopurulent reaction
3. Bacteraemia/septicaemia → metastatic abscesses, endocarditis, meningitis, suppurative arthritis
4. Pleuritis / fibrous adhesions — organizing fibrinous exudate
5. Respiratory failure in severe cases

---

Viral Pneumonia — Histological Distinction

---

Quick Summary Table

— Robbins, Cotran & Kumar: Pathologic Basis of Disease