What are the initial steps in diagnosing and treating pneumonitis, including differentials and empiric therapy?

Differential Diagnosis of Pneumonitis

When evaluating pneumonitis, the differential diagnosis must systematically distinguish between infectious pneumonia, hypersensitivity pneumonitis, drug-induced pneumonitis, and other inflammatory lung diseases through targeted exposure history, imaging patterns, and bronchoalveolar lavage findings.

Primary Differential Categories

Infectious vs. Non-Infectious Pneumonitis

Infectious pneumonia remains the most critical differential to exclude first, as it requires immediate antimicrobial therapy and carries significant mortality risk if untreated 1. Key distinguishing features include:

• Acute bacterial pneumonia: Fever, productive cough, lobar consolidation on imaging, elevated white blood cell count with left shift 1
• Atypical pneumonia: Gradual onset, dry cough, patchy infiltrates, caused by Mycoplasma, Chlamydophila, or Legionella 2
• Viral pneumonitis: Influenza, RSV, adenovirus, CMV (especially in immunocompromised), HSV, or varicella-zoster virus 3
• Fungal pneumonia: Endemic fungi (histoplasmosis, coccidioidomycosis, blastomycosis) or opportunistic infections in immunocompromised patients 1

Hypersensitivity Pneumonitis (HP)

HP must be considered in any patient with newly identified interstitial lung disease 1. This immune-mediated reaction to inhaled organic antigens presents in two phenotypes:

Nonfibrotic HP 1:

• Acute/subacute presentation with fever, chills, dyspnea occurring 4-8 hours after antigen exposure 4
• Ground-glass opacities, poorly defined centrilobular nodules, mosaic attenuation on HRCT 4
• Lymphocytosis (>40% lymphocytes) on BAL with CD8+ predominance 1, 5

Fibrotic HP 1:

• Insidious onset with progressive dyspnea and cough over months to years 4
• Reticular opacities, traction bronchiectasis, volume loss, honeycombing on HRCT 4
• May mimic usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP) patterns 4

Common exposures to identify 1:

• Bird exposure (pigeons, parakeets) - most common residential cause 6, 4
• Contaminated humidifiers or hot tubs 6
• Indoor molds (especially water-damaged buildings) 6
• Occupational organic dusts (farmer's lung from moldy hay, mushroom worker's lung) 7, 5

Drug-Induced Pneumonitis

Immune checkpoint inhibitor (ICI) pneumonitis is increasingly common and requires specific management 1, 8:

Grading and presentation 1, 8:

• Grade 1: Asymptomatic, <25% lung involvement, radiographic finding only
• Grade 2: Symptomatic, 25-50% lung involvement, limiting instrumental activities
• Grade 3: Severe symptoms, >50% lung involvement, oxygen required
• Grade 4: Life-threatening, intubation required

Other drug causes 1:

• Chemotherapy agents (bleomycin, methotrexate, cyclophosphamide)
• Amiodarone
• Nitrofurantoin
• Biologics and targeted therapies

Other Inflammatory Lung Diseases

Additional differentials that can mimic pneumonitis 1:

• Organizing pneumonia (cryptogenic or secondary): Patchy consolidation, peripheral distribution, responds to corticosteroids
• Eosinophilic pneumonia: Peripheral blood eosinophilia, "photographic negative of pulmonary edema" pattern
• Sarcoidosis: Bilateral hilar lymphadenopathy, perilymphatic nodules, upper lobe predominance
• Wegener's granulomatosis: Cavitary nodules, upper airway involvement, positive c-ANCA
• Acute interstitial pneumonitis: Rapidly progressive, diffuse alveolar damage on biopsy

Non-Pulmonary Mimics

Critical non-infectious conditions that present similarly 1:

• Pulmonary embolism with infarction: Sudden onset, pleuritic chest pain, wedge-shaped peripheral opacity
• Congestive heart failure: Cardiomegaly, pulmonary vascular redistribution, pleural effusions
• Intrapulmonary hemorrhage: Hemoptysis, diffuse alveolar infiltrates, anemia
• Obstructing bronchogenic carcinoma: Focal consolidation, post-obstructive pneumonitis

Initial Diagnostic Approach

Essential History Elements

Exposure assessment is paramount 1:

• Detailed occupational history including specific tasks and materials
• Home environment assessment (pets, humidifiers, water damage, hobbies)
• Temporal relationship between symptoms and exposures (improvement away from exposure strongly suggests HP) 1
• Medication history including recent additions or dose changes 1, 8
• Immunosuppression status (HIV, transplant, chemotherapy) 1

Imaging Strategy

High-resolution CT chest (preferably with contrast) is the preferred initial imaging modality 1, 8:

• Ground-glass opacities suggest acute/subacute process (HP, drug-induced, viral, PCP) 8, 4
• Patchy nodular infiltrates with mosaic attenuation suggest HP 8, 4
• Lobar consolidation suggests bacterial pneumonia 1
• Interstitial patterns with fibrosis suggest chronic HP or other ILD 1, 4

Laboratory and Invasive Testing

For suspected HP 1:

• Serum IgG antibodies against suspected antigens (avian proteins, thermophilic actinomycetes, fungal antigens) - positive in 90% but not specific 1, 6
• BAL with lymphocyte differential: >40% lymphocytes with CD4/CD8 ratio <1 strongly supports HP 1, 5
• Transbronchial biopsy showing granulomas and lymphocytic infiltration 1
• Surgical lung biopsy reserved for unclear cases after other testing 1

For suspected infection 1, 8:

• Nasal swab, sputum culture and sensitivity, blood cultures, urine antigens (Legionella, pneumococcus) 1
• BAL with bacterial, fungal, viral, and mycobacterial cultures 1, 8
• COVID-19 testing per institutional protocols 1

For drug-induced pneumonitis 8:

• Bronchoscopy with BAL to exclude infection, especially for grade ≥2 8
• Transbronchial or surgical biopsy if etiology unclear, though not routinely required 8

Critical Pitfalls to Avoid

Do not rely solely on clinical improvement with therapy to confirm diagnosis 1:

• HP may improve with corticosteroids, but so do other ILDs like NSIP 1
• Lack of improvement with antigen avoidance does not rule out HP, especially in fibrotic cases 1
• Bacterial pneumonia improves with antibiotics, but drug-induced pneumonitis may also improve with drug cessation alone 8

Do not miss dual pathology 1:

• Infection can coexist with drug-induced pneumonitis, particularly in immunosuppressed patients 1
• Consider empiric antibiotics for grade 3 ICI pneumonitis if infection cannot be reliably excluded 8

Do not overlook chronic HP mimicking IPF 4:

• Up to 15% of cases diagnosed as IPF may actually be chronic fibrotic HP 4
• Always reassess for occult exposures in patients with "idiopathic" pulmonary fibrosis 1, 4