What are the causes and treatment options for pneumonitis?

Pneumonitis: Etiology and Treatment

Etiologies of Pneumonitis

Pneumonitis encompasses a broad spectrum of lung inflammation with diverse causes, ranging from drug-induced immune reactions to infectious agents, hypersensitivity reactions, and radiation exposure.

Drug-Induced Pneumonitis (Immune Checkpoint Inhibitors)

• Anti-PD-1/PD-L1 monoclonal antibodies cause pneumonitis in 2-4% of patients, with grade 3-4 events in 1-2% and fatal pneumonitis in 0.2%. 1
• Anti-CTLA4 monotherapy causes acute interstitial pneumonitis/diffuse alveolar damage syndrome (DADS), organizing inflammatory pneumonia, and sarcoidosis-like pulmonary granulomatosis. 1
• Combination immunotherapy (anti-PD-1/PD-L1 plus anti-CTLA4) increases pneumonitis risk 3-fold compared to monotherapy, with incidence reaching 10% versus 3% for monotherapy. 1
• Median time to onset is 2.8 months (range 9 days to 19.2 months), occurring earlier with combination therapy (2.7 versus 4.6 months). 1
• Patients with NSCLC have more treatment-related deaths from pneumonitis compared to other tumor types. 1

Infectious Pneumonitis

• Diplococcus pneumoniae (Streptococcus pneumoniae) remains the most frequent cause of community-acquired bacterial pneumonia. 2
• Other common bacterial pathogens include Hemophilus influenzae, Klebsiella organisms, and Staphylococcus aureus in community settings. 2
• Hospital-acquired pneumonias are predominantly caused by gram-negative bacilli: E. coli, Proteus, Klebsiella-Enterobacter, Pseudomonas, and Serratia species. 2
• Mycoplasma pneumoniae is common in older children and young adults. 2
• Viral causes include respiratory syncytial virus, adenoviruses, varicella-zoster virus, herpes simplex virus, influenza A and B, and cytomegalovirus. 3
• Fungal pneumonitis occurs in endemic areas (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) or in immunocompromised hosts (Candida, Aspergillus, Phycomycetes, Nocardia asteroides). 2

Hypersensitivity Pneumonitis

• Caused by repeated inhalation of organic antigens, resulting in immunologically mediated lung disease with mononuclear cell infiltration, granulomas, and potential progression to fibrosis. 4
• Characterized by suppressor cytotoxic lymphocytosis in BAL fluid and serum precipitating antibodies (IgG). 4

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Treatment Algorithm Based on Severity

Grade 1 Pneumonitis (Asymptomatic Radiologic Changes)

• Continue causative therapy with close monitoring; corticosteroids are not required at this stage. 5
• Monitor symptoms and oxygen saturation every 2-3 days using pulse oximetry, with weekly clinical visits. 5, 6
• Perform CT chest imaging to identify ground-glass opacities, patchy nodular infiltrates, or interstitial patterns. 5
• If radiologic abnormalities resolve, continue treatment with close follow-up. 6

Red flags for escalation: Development of respiratory symptoms (cough, dyspnea, chest pain), decreased oxygen saturation, or radiographic progression. 6

Grade 1-2 Pneumonitis (Mild Symptoms)

• Discontinue the suspected causative agent immediately. 5
• Initiate oral corticosteroids: prednisone 1 mg/kg daily or equivalent. 5
• Taper steroids over 4-6 weeks after recovery. 5
• Perform bronchoscopy with BAL to exclude infections, especially in grade 2 or higher pneumonitis. 5

Grade 3-4 Pneumonitis (Severe/Life-Threatening)

• Hospitalize immediately and permanently discontinue the offending agent. 5
• Administer high-dose intravenous corticosteroids: methylprednisolone 2-4 mg/kg/day or equivalent. 5
• Administer broad-spectrum antibiotics in parallel if infectious status cannot be reliably assessed. 5
• If no improvement after 48 hours, add additional immunosuppressive agents: infliximab, mycophenolate mofetil (MMF), or cyclophosphamide. 5
• Consider transbronchial or surgical lung biopsy (VATS) when etiology remains unclear, though not routinely required. 1, 5
• Bronchoscopy with BAL is recommended to identify infections, including opportunistic or atypical agents. 1

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Critical Management Principles

Diagnostic Confirmation

• Improvement following drug cessation without glucocorticoid therapy strongly supports drug-related pneumonitis. 5
• Clinical improvement with glucocorticoid therapy supports but does not definitively confirm drug-related pneumonitis. 5
• Radiological features are not pathognomonic and can mimic cryptogenic organizing pneumonia, interstitial pneumonia, or hypersensitivity pneumonitis patterns. 1

Special Considerations for ICI-Related Pneumonitis

• Steroid tapering must be very slow (6+ weeks minimum) as relapses during tapering are well-documented. 5
• 86% of patients improve or resolve with drug withholding and immunosuppression. 1
• Approximately 2% of NSCLC or melanoma patients develop chronic pneumonitis persisting despite ICI discontinuation. 6

Common Pitfalls to Avoid

• Do not delay CT imaging for any new respiratory symptom—disease progression, infection, and pneumonitis must be formally excluded. 1
• Do not change initial antibiotic therapy in infectious pneumonitis within the first 72 hours unless marked clinical deterioration occurs. 1
• Do not proceed with lung biopsy routinely; reserve for cases where etiology remains unclear after less invasive testing. 1
• Fatal cases have been reported, making vigilant monitoring of all respiratory symptoms mandatory. 1