What is Pneumonitis?
Pneumonitis is focal or diffuse inflammation of the lung parenchyma caused by non-infectious agents including drugs, environmental exposures, radiation, and immune checkpoint inhibitors. 1
Core Definition and Distinction from Pneumonia
Pneumonitis differs fundamentally from pneumonia in that it represents an inflammatory process rather than an infectious one. 1 The inflammation can affect the lung tissue through various mechanisms:
- Immune-mediated responses to inhaled antigens (as in hypersensitivity pneumonitis) 2, 3
- Direct toxic injury from drugs or radiation 1, 4
- Aberrant immune activation from checkpoint inhibitor therapy 1
Major Categories of Pneumonitis
Drug-Related Pneumonitis
- Cancer drugs, immunosuppressants for autoimmune diseases, amiodarone, and antibiotics are the most frequent culprits 1
- Can present with varying severity from asymptomatic radiographic findings to life-threatening respiratory compromise 1
Hypersensitivity Pneumonitis (HP)
- Results from repeated inhalation of organic antigens (fungal, bacterial, avian) or less commonly non-organic antigens 2
- Characterized by bronchiolocentric granulomatous lymphocytic alveolitis that can progress to fibrosis 2, 3
- Affects genetically susceptible individuals who develop an exaggerated immune response mediated by CD4+ T cells differentiating into Th1 cells 1
- The causative antigen often goes unrecognized or has ceased prior to diagnosis 2
Radiation Pneumonitis
- Occurs typically 3-12 weeks after radiation exposure 4
- Presents with dyspnea, dry cough, chest pain, and sometimes low-grade fever 4
- Key diagnostic feature: radiographic opacities correspond to the radiation portal 4
Immune Checkpoint Inhibitor-Related Pneumonitis
- Overall incidence <5% for monotherapy, up to 10% with combination therapies 1
- PD-1 inhibitors carry higher risk (3.6%) compared to PD-L1 inhibitors (1.3%) 1
- Higher incidence in non-small cell lung cancer patients versus melanoma patients 1
Clinical Presentation
Symptoms
- Dyspnea and dry cough are the most common presenting symptoms 4, 3
- Fatigue with activities of daily living 1
- Fever, malaise, and weight loss may occur, particularly in hypersensitivity pneumonitis 2, 3
- Chest pain and hypoxia in more severe cases 4
Temporal Relationship
The temporal relationship between exposure to the causative agent and symptom onset is crucial for diagnosis. 1 This distinguishes pneumonitis from other pulmonary conditions and guides diagnostic evaluation.
Diagnostic Features
Radiographic Patterns
Chest CT should be performed as early as possible when pneumonitis is suspected 1:
- Ground-glass opacities are common across multiple types 2, 4
- Consolidation in more advanced cases 1, 4
- Mosaic attenuation is characteristic of hypersensitivity pneumonitis 1
- Centrilobular nodules in HP 2
- Traction bronchiectasis and honeycombing in fibrotic cases 2, 5
Histopathologic Patterns
Pneumonitis can manifest several histologic patterns 1:
- Cryptogenic organizing pneumonia (COP) pattern
- Nonspecific interstitial pneumonitis (NSIP) pattern
- Hypersensitivity pneumonitis pattern with poorly formed non-necrotizing granulomas
- Usual interstitial pneumonitis (UIP)/pulmonary fibrosis pattern
Laboratory Findings
- BAL lymphocytosis >15% supports the diagnosis, particularly in HP 1
- Serum precipitating antibodies (IgG) to suspected antigens in HP 6, 5
- Elevated IL-1α and IL-6 levels correlate with radiation pneumonitis 7
Critical Differential Diagnoses
Pneumonitis must be distinguished from 1, 4:
- Infectious pneumonia
- Diffuse alveolar hemorrhage
- Pulmonary edema
- Pulmonary embolism
- Tumor progression
- Cardiac events
Management Principles
Primary Approach
Identify and remove the causative agent immediately. 1 This is the cornerstone of treatment for all forms of pneumonitis.
Pharmacologic Treatment
- Discontinue the offending drug in drug-related pneumonitis 1
- Corticosteroids for moderate to severe cases are recommended 1
- For immune checkpoint inhibitor-related pneumonitis, treatment is based on severity grading with drug withdrawal for all grades 1
- Additional immunosuppression (infliximab, cyclophosphamide) for recalcitrant disease 1
- Nintedanib for progressive fibrotic HP with declining lung function 8
Antigen Avoidance
In hypersensitivity pneumonitis, avoidance of further exposure is key to management 3, 8
Prognosis and Complications
Risk of Progression
If unchecked, pneumonitis can lead to pulmonary fibrosis. 1 Early recognition and treatment are essential to prevent progression to chronic, irreversible disease 1.
Fibrotic Disease
- Patients with fibrotic HP have worse outcomes 8
- A proportion develop a progressive phenotype with worsening fibrosis, declining lung function, and early mortality 8
- Patients with pre-existing interstitial lung disease have markedly elevated risk of severe and potentially lethal radiation pneumonitis 4