What is pneumonitis?

What is Pneumonitis?

Pneumonitis is focal or diffuse inflammation of the lung parenchyma caused by non-infectious agents including drugs, environmental exposures, and immune checkpoint inhibitors, distinguishing it fundamentally from pneumonia which is an infectious process. 1

Core Definition and Pathophysiology

Pneumonitis represents an immunologically mediated inflammatory response in lung tissue that occurs without direct infection. 1 The key distinguishing feature is that pneumonitis results from:

• Drug exposures (cancer drugs, autoimmune medications, amiodarone, antibiotics) 1
• Environmental and occupational antigens (fungal, bacterial, or avian proteins in hypersensitivity pneumonitis) 2
• Immune checkpoint inhibitors used in cancer treatment 1

The inflammatory process involves cytokine release and accumulation of inflammatory cells in the lung parenchyma and interstitium, but without the purulent exudate and pathogen-driven damage seen in pneumonia. 1, 3

Critical Distinction from Pneumonia

Pneumonitis must be differentiated from pneumonia, which is an infectious lower respiratory tract infection characterized by new lung infiltrate with fever, purulent sputum, leukocytosis, and pathogen clearance failure. 1, 4 While pneumonia involves pus accumulation in the parenchyma from infectious organisms, pneumonitis is a sterile inflammatory process. 4, 5

Other conditions to distinguish from pneumonitis include diffuse alveolar hemorrhage, pulmonary edema, radiation pneumonitis, and pulmonary metastases. 1

Clinical Presentation Spectrum

Pneumonitis presents with highly variable severity ranging from asymptomatic radiographic findings to life-threatening respiratory failure. 1 Common manifestations include:

• Fatigue with activities of daily living 1
• Dyspnea and cough (particularly in subacute/chronic forms) 6
• Fever, chills, and myalgias (in acute hypersensitivity pneumonitis) 7

Diagnostic Approach

Essential Diagnostic Elements

The temporal relationship between exposure to a causative agent and symptom onset is crucial for establishing the diagnosis. 1 A thorough environmental and occupational exposure history is fundamental, despite its complexity. 2

Chest CT should be performed as early as possible when pneumonitis is suspected and is more sensitive than plain radiography. 1

Radiologic Patterns

Common imaging findings include:

• Consolidation 1
• Mosaic attenuation (characteristic of hypersensitivity pneumonitis) 1
• Ground-glass opacities and poorly defined nodules with patchy air trapping (acute/subacute hypersensitivity pneumonitis) 6
• Reticular opacities, volume loss, and traction bronchiectasis (chronic forms) 6

Histopathologic Features

When lung biopsy is performed for suspected hypersensitivity pneumonitis, characteristic findings include:

• Bronchiolocentric cellular and/or fibrosing interstitial pneumonia 2
• Poorly formed non-necrotizing granulomas with or without multinucleated giant cells 2
• Peribronchiolar metaplasia and/or organizing pneumonia 2

Bronchoalveolar lavage showing >15% lymphocytes can support the diagnosis, with specific cellular patterns having diagnostic implications. 1

Types of Pneumonitis

Hypersensitivity Pneumonitis (HP)

HP is an immunologically mediated lung disease from repeated inhalation of environmental/occupational antigens in genetically susceptible individuals. 2 The pathogenesis involves:

• Immune complex-mediated reactions in acute forms 3
• Th1 and likely Th17 T cell-mediated hypersensitivity in subacute/chronic cases 6
• CD4+ T cell differentiation into Th1 cells promoting granuloma formation 1

Drug-Related Pneumonitis

One of the most common forms, with cancer drugs, autoimmune disease medications, amiodarone, and antibiotics being frequent culprits. 1

Immune Checkpoint Inhibitor-Related Pneumonitis

• Overall incidence <5% for monotherapy, up to 10% with combination therapies 1
• PD-1 inhibitors have higher incidence (3.6%) compared to PD-L1 inhibitors (1.3%) 1
• Higher risk in non-small cell lung cancer patients versus melanoma patients 1

Management Principles

The primary therapeutic approach is identifying and removing the causative agent. 1 This is the mainstay of treatment across all grades of severity.

For moderate to severe cases:

• Discontinuation of the offending agent plus corticosteroids 1
• Severity grading guides management for immune checkpoint inhibitor-related pneumonitis 1
• Additional immunosuppression (infliximab, cyclophosphamide) for recalcitrant disease 1

Prognosis and Complications

If unchecked, pneumonitis can progress to irreversible pulmonary fibrosis. 1 Early recognition and treatment are essential to prevent chronic, irreversible disease. 1

Advanced chronic cases may develop:

• Respiratory failure 7
• Cor pulmonale 7
• Death in progressive end-stage illness (where lung transplantation should be considered) 6

The histopathologic evolution from acute inflammation to granulomatous changes to fibrosis mirrors the natural history of many interstitial lung diseases. 3, 6