Pneumonitis

Types and Causes

1. Hypersensitivity Pneumonitis (HP)

• Robbins Basic Pathology (Robbins Pathology), p. 463

2. Drug-Induced Pneumonitis

• Bleomycin - direct cytotoxicity + inflammatory cell recruitment causing pneumonitis and fibrosis
• Amiodarone - associated with pneumonitis and fibrosis
• Methotrexate - can produce lung infiltrates similar to RA-related lung disease
• Checkpoint inhibitors (immunotherapy) - increasingly recognized cause

3. Radiation Pneumonitis

4. HIV-Related Pneumonitis

• Lymphocytic interstitial pneumonitis - classically affects HIV-infected infants; may occur in adults at CD4 >350 cells/μL
• Nonspecific interstitial pneumonitis - often asymptomatic; can mimic Pneumocystis pneumonia at CD4 <200 cells/μL
• Goldman-Cecil Medicine

Immunopathogenesis of HP

• BAL shows increased CD4+ and CD8+ T lymphocytes and elevated proinflammatory chemokines (MIP-1α / CCL3, IL-8)
• Most patients have specific antibodies (precipitins) against the causative antigen
• Complement and immunoglobulins deposited within pulmonary vessel walls
• Nonnecrotizing granulomas in two-thirds of cases, implying Type IV (T cell-mediated) hypersensitivity - Robbins Pathologic Basis of Disease, p. 715

Histopathology

Hypersensitivity pneumonitis: loosely formed (noncohesive), nonnecrotizing interstitial granulomas in a peribronchiolar location with a dense mononuclear infiltrate. - Robbins & Kumar Pathologic Basis of Disease

• Acute (hours-days): Alveolar damage; patchy interstitial infiltrate of lymphocytes, plasma cells, macrophages; variable neutrophils
• Subacute: Poorly formed peribronchiolar granulomas; interstitial pneumonitis centered on bronchioles; features overlapping NSIP and organizing pneumonia
• Chronic/fibrotic: Interstitial fibrosis, fibroblastic foci, honeycombing, obliterative bronchiolitis - bilateral, often upper-lobe dominant; may show UIP or NSIP pattern

Classification (Current)

Clinical Features

• Acute flu-like syndrome: malaise, fever, chills arising 4-8 hours after antigen exposure
• Respiratory: nonproductive cough, dyspnea
• Symptoms resolve within 24-48 hours but recur with re-exposure
• Temporal relation to exposure usually recognized

• Insidious onset: progressive exertional dyspnea, cough, malaise, weight loss
• Temporal relation to exposure often not recognized
• May present as a progressive ILD indistinguishable from IPF
• Velcro-type crackles on auscultation
• Clubbing in some

Diagnosis

• Nonfibrotic: Diffuse bilateral ground-glass opacities, centrilobular nodules, air trapping on expiration
• Fibrotic: Reticulation, traction bronchiectasis, honeycombing, architectural distortion - often upper/mid-lobe predominant
• "Headcheese" sign: Multifocal ground-glass opacity with areas of mosaic perfusion (lobular low attenuation) on the same inspiratory scan, reflecting simultaneous infiltrative and obstructive abnormalities - moderately sensitive (49%) and highly specific (93%) for fibrotic HP

Fig. 91.5: The "headcheese" sign. (A) Axial HRCT shows multifocal ground-glass opacity (infiltrative) with lobular low-attenuation areas/mosaic perfusion (obstructive) - arrowheads. This variegated pattern is likened to headcheese (B). - Murray & Nadel's Textbook of Respiratory Medicine

• Lymphocytosis (≥25% lymphocytes) on BAL differential - most common cellular profile in HP and drug-induced ILD
• CD8+ (T suppressor) lymphocyte predominance is common in drug-induced HP; CD4+ predominance in other HP types
• Also used to exclude infection

Pulmonary Function Tests

• Decreased FVC, TLC, lung compliance
• Decreased DLCO (diffusing capacity for CO)
• In fibrotic HP with coexisting emphysema: DLCO markedly low but lung volumes may be relatively preserved

Prognostic Indicators (Baseline)

• Male sex, older age
• Auscultatory crackles
• Low FVC%, low DLCO%
• Honeycombing, traction bronchiectasis, increased fibrosis on HRCT
• Fibroblast foci on biopsy
• MUC5B variant; short telomere length
• Unknown inciting antigen
• Smoking; acute exacerbation; pulmonary hypertension

Management

1. Antigen Avoidance (cornerstone)

• Identify and remove (or remove patient from) the antigen source
• Nonfibrotic HP: complete resolution expected if antigen is eliminated promptly
• Fibrotic HP: antigen removal alone does not reverse established fibrosis but may slow progression

2. Pharmacologic Therapy

• Corticosteroids (prednisone): First-line; accelerate symptom resolution in acute/subacute forms. Tapering regimen required
• Steroid-sparing agents: Azathioprine (AZA), mycophenolate mofetil (MMF) for chronic fibrotic disease or if steroids cannot be tapered

3. Supportive Measures

• Supplemental oxygen for hypoxemia
• Pulmonary rehabilitation
• Smoking cessation
• Vaccinations (influenza, pneumococcal)
• Management of comorbidities (pulmonary hypertension)

4. Lung Transplantation

• For end-stage fibrotic HP refractory to medical management
• Referral for evaluation if indicated

Drug-Induced Pneumonitis: Diagnostic Approach

1. Establish that a recognized drug with known pulmonary toxicity is being used
2. Clinical history, exam, labs, and HRCT compatible with known patterns of lung injury
3. Exclude infection via BAL culture
4. Multidisciplinary approach: pulmonology, radiology, rheumatology, pathology
5. Rechallenge is generally not advised; improvement after drug withdrawal supports the diagnosis

Key Differentials

• Infectious pneumonia (bacterial, viral, fungal, Pneumocystis)
• Idiopathic interstitial pneumonias (IPF, NSIP, COP)
• Sarcoidosis
• Eosinophilic pneumonia
• Connective tissue disease-associated ILD
• Drug-induced ILD

• Murray & Nadel's Textbook of Respiratory Medicine (Ch. 91 - Hypersensitivity Pneumonitis)
• Robbins & Kumar Pathologic Basis of Disease (Ch. 15)
• Robbins Basic Pathology (Ch. 11)
• Fishman's Pulmonary Diseases and Disorders (Drug-Induced Respiratory Disease)
• Goldman-Cecil Medicine (HIV-related pneumonitis)