HIV AND THE LUNG - Structured MD Exam Answer (10 Marks)

INTRODUCTION

I. IMMUNOPATHOGENESIS OF HIV IN THE LUNG

• HIV causes immune dysregulation, dysfunction, and deficiency with progressive decline in CD4+ T lymphocytes
• HIV impairs multiple lines of pulmonary host defense:
  • Reduces mucociliary clearance
  • Impairs innate (macrophage) and adaptive (lymphocyte) immunity
  • Decreases secretory IgA and alveolar macrophage function
  • Increases susceptibility to respiratory pathogens (influenza, M. tuberculosis)
• HIV causes chronic stimulation and activation of inflammatory cells within the alveolar space
• Lung cells infected by HIV: alveolar macrophages, T cells, and fibroblasts - these serve as reservoirs
• Unlike the GI tract, the lung does NOT show mucosal CD4+ T-cell depletion; BAL fluid paradoxically has MORE CD4+ cells than terminal ileum
• Persistent inflammation and immune activation - linked to non-infectious chronic lung complications (COPD, lung cancer, PAH)

II. SPECTRUM OF PULMONARY COMPLICATIONS

A. Infections

B. Malignancies

• Kaposi sarcoma (KS)
• Non-Hodgkin lymphoma (NHL)
• Bronchogenic carcinoma

C. Interstitial Pneumonitides

• Lymphocytic interstitial pneumonitis (LIP)
• Nonspecific interstitial pneumonitis (NSIP)

D. Other Non-infectious Conditions

• COPD / emphysema
• Asthma
• Pulmonary arterial hypertension (PAH)
• Sarcoidosis
• Immune reconstitution inflammatory syndrome (IRIS)

III. CD4+ COUNT AND RISK STRATIFICATION

IV. KEY INFECTIOUS PULMONARY COMPLICATIONS

1. Pneumocystis jirovecii Pneumonia (PCP)

• Most common AIDS-defining fungal pneumonia; formerly called PCP (Pneumocystis carinii)
• Occurs at CD4+ < 200 cells/µL
• Clinical: Subacute onset, progressive exertional dyspnea, dry non-productive cough, low-grade fever
• CXR: Bilateral interstitial/perihilar infiltrates ("butterfly" pattern); may be normal early
• HRCT: Ground-glass opacification
• Diagnosis: Induced sputum (40-90% sensitivity), BAL (> 90% sensitivity), GMS/DIF staining
• LDH elevated - marker of disease severity
• Treatment: TMP-SMX (first line) x 21 days; Add prednisone if PaO2 < 70 mmHg or A-a gradient > 35 mmHg
• Prophylaxis: TMP-SMX when CD4+ < 200 cells/µL
• Complications: Pneumothorax (especially with pentamidine prophylaxis), ARDS, respiratory failure

2. Tuberculosis (TB)

• Worldwide, TB is the most common infectious lung complication and a major cause of HIV-associated morbidity and mortality
• HIV is the strongest known risk factor for reactivation of latent TB
• Atypical presentations at low CD4+ counts:
  • Lower lobe or diffuse infiltrates (rather than classic upper lobe)
  • Absence of cavitation
  • Mediastinal adenopathy prominent
  • Disseminated/miliary TB more common
  • Extrapulmonary involvement (lymph nodes, CNS, bone marrow, pericardium)
• TST/IGRA may be falsely negative due to anergy
• Diagnosis: Sputum AFB, culture (gold standard), GeneXpert MTB/RIF (rapid, also detects rifampicin resistance)
• Treatment: Standard RHEZ regimen; rifabutin replaces rifampicin in patients on PIs
• HIV-TB co-management: ART should be started within 2-8 weeks of TB treatment initiation (except TB meningitis - delay 4-8 weeks)

3. Bacterial Pneumonia

• Most common acute pulmonary infection at ANY CD4+ count
• Incidence ~5-10x higher than in HIV-negative persons
• Common pathogens: S. pneumoniae (most common), H. influenzae, S. aureus, P. aeruginosa
• At CD4+ < 200: bacteremia is frequent; gram-negative rods more common
• CXR: Lobar consolidation (typical); multilobar or atypical patterns at low CD4+
• Management: As per standard community-acquired pneumonia guidelines + ART optimization

4. Cryptococcal Pneumonia

• Usually at CD4+ < 100-200 cells/µL
• Often disseminated - associated with meningitis
• CXR: Nodules, interstitial infiltrates, lobar consolidation
• Diagnosis: Serum/BAL cryptococcal antigen (CRAG), India ink stain, culture
• Treatment: Liposomal amphotericin B + flucytosine (induction) → fluconazole (consolidation + maintenance)

5. MAC (Mycobacterium avium Complex)

• Occurs at CD4+ < 50 cells/µL; usually disseminated disease
• Pulmonary: Cough, fever, weight loss; adenopathy on CT
• Diagnosis: Blood/respiratory cultures
• Treatment: Azithromycin + ethambutol (± rifabutin)

V. NON-INFECTIOUS PULMONARY COMPLICATIONS

1. Kaposi Sarcoma (KS) of the Lung

• Caused by HHV-8 (Human Herpesvirus-8)
• Occurs in HIV with immune suppression; less common since HAART
• Pulmonary KS: affects larynx, trachea, bronchi, parenchyma, and pleura
• Symptoms: Hoarseness, airway obstruction, cough, hemoptysis, dyspnea
• CXR/CT: Multiple small nodules, peribronchovascular distribution, pleural effusions (bloody, rare)
• Bronchoscopy: Bluish-red endobronchial nodules - pathognomonic
• Treatment: ART (cornerstone); systemic chemotherapy (liposomal doxorubicin) for advanced disease

2. COPD / Emphysema

• HIV-infected persons have higher rates of COPD and emphysema independent of smoking
• Mechanisms: Recurrent infections, systemic inflammation, oxidative stress, direct HIV effects on lung tissue
• Accelerated lung aging; emphysema detected on CT even in non-smokers with HIV
• Treatment: Standard COPD management + ART

3. Pulmonary Arterial Hypertension (HIV-PAH)

• Prevalence ~0.5% in HIV-infected persons (much higher than general population)
• Occurs at any CD4+ count, including in patients with undetectable viral load
• Mechanism: HIV-related endothelial dysfunction, cytokine-mediated vasoconstriction (Tat, gp120)
• Clinical and hemodynamic features similar to idiopathic PAH
• Diagnosis: Echo, right heart catheterization
• Treatment: ART (may improve PAH); PAH-specific therapy (prostanoids, ERA, PDE5-inhibitors) - drug interactions with ART must be considered

4. Lymphocytic Interstitial Pneumonitis (LIP)

• More common in HIV-infected children; also seen in adults
• CD8+ lymphocytic infiltration of alveolar walls
• CXR: Bilateral reticulonodular infiltrates
• Diagnosis: Lung biopsy; CD8+ predominance on BAL
• Treatment: Steroids; ART

5. Lung Cancer

• Significantly increased risk in HIV-infected persons (2-4x), partly from smoking but also independently
• Adenocarcinoma most common histological type
• Often presents at advanced stage; aggressive course
• ART does not fully eliminate the excess risk

VI. DIAGNOSTIC APPROACH

• Severity warrants prompt diagnosis
• Suspected pulmonary KS (visual diagnosis)
• Diagnosis unknown after non-invasive studies
• Empirical therapy is failing

Key principle: Multiple pathologies may coexist. Definitive diagnosis is required given substantial treatment toxicities and drug interactions.

VII. IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)

• Occurs after initiating ART in HIV-infected patients
• Results from restored immune system causing exuberant inflammatory response to previously recognized or subclinical infections
• Types:
  • Paradoxical IRIS: Worsening of a previously recognized/treated infection (e.g., TB-IRIS)
  • Unmasking IRIS: Unveils a subclinical, undiagnosed infection
• More likely when: ART started with CD4+ < 100 cells/µL, rapid virologic response, ART started close to opportunistic infection treatment
• TB-IRIS: Fever, worsening lymphadenopathy, new/enlarging infiltrates
• Management:
  • Continue ART in most cases
  • NSAIDs for mild cases
  • Prednisone for severe/life-threatening cases (1.5 mg/kg/day x 2 weeks then taper)
  • For high-risk TB-HIV patients: prophylactic prednisone (PredART trial) - 40 mg/day x 14d → 20 mg/day x 14d reduces IRIS risk
  • Despite IRIS risk, early ART initiation improves survival

VIII. KEY POINTS SUMMARY

1. HIV infection progressively depletes CD4+ T lymphocytes and impairs lung host defense
2. CD4+ count is the most important predictor of which pulmonary complication will develop
3. TB is the most common infectious lung complication worldwide
4. Bacterial pneumonia and PCP are also common infectious complications
5. Non-infectious conditions - COPD, lung cancer, PAH - occur with increased frequency
6. IRIS must be anticipated when starting ART in patients with active opportunistic infections
7. Differential diagnosis is broad; clinical and radiographic features overlap significantly
8. Definitive diagnosis should always be sought given drug toxicities and interaction profiles
9. ART is the cornerstone of management - it reduces all pulmonary complications
10. Prophylaxis: TMP-SMX for PCP (CD4+ < 200), azithromycin for MAC (CD4+ < 50), INH for latent TB

• Murray & Nadel's Textbook of Respiratory Medicine, 7th ed., Chapter 123 (pp. 2841-2866)
• Fishman's Pulmonary Diseases and Disorders, 5th ed., Chapter 27 (Kaposi Sarcoma), Chapter 119 (HIV Infection)