What are the clinical signs and symptoms of pneumonitis?

Clinical Signs and Symptoms of Pneumonitis

Pneumonitis presents with dyspnea and cough, with or without fever, ranging from asymptomatic to acutely progressive respiratory failure, and requires a high index of suspicion based on temporal relationship to drug exposure, radiation, or environmental antigens. 1

Core Clinical Presentation

The clinical manifestations of pneumonitis vary by etiology and severity:

Primary Respiratory Symptoms

• Dyspnea is the cardinal symptom, present in the majority of symptomatic patients, ranging from mild exertional breathlessness to severe respiratory distress 1, 2
• Cough is typically dry and non-productive, though this varies by pneumonitis type 1, 2
• Hypoxia may develop in moderate to severe cases 1
• Chest pain can accompany respiratory symptoms, particularly in radiation pneumonitis 1, 2

Constitutional Symptoms

• Fever is variably present—common in acute presentations but may be absent in subacute or chronic forms 1
• Fatigue with activities of daily living is frequently reported 3
• Weight loss, malaise, and anorexia occur in chronic or subacute presentations 1, 4

Physical Examination Findings

• Inspiratory crackles are the most common auscultatory finding, heard in approximately 81% of cases 5
• Tachypnea is frequently present and clinically significant 1, 5
• Physical examination may be surprisingly unremarkable despite significant radiographic abnormalities 1

Context-Specific Presentations

Drug-Related Pneumonitis (Including Immunotherapy)

• Symptoms develop days to months after drug initiation, with median onset at 2.8 months for immune checkpoint inhibitors 1
• Asymptomatic presentations are common—many patients are identified only through routine imaging 1, 3
• Acute presentations can progress rapidly to respiratory failure requiring mechanical ventilation 1
• Any new respiratory symptom in patients on molecular targeted agents or immune checkpoint inhibitors warrants immediate CT evaluation 1

Radiation Pneumonitis

• Symptoms typically occur 3-12 weeks after radiation exposure 1, 2
• The triad of dyspnea, dry cough, and chest pain with low-grade fever is characteristic 1, 2
• Symptoms correspond to the radiation portal—a key distinguishing feature 2

Hypersensitivity Pneumonitis

• Acute episodes present with dyspnea, fever, and prominent constitutional symptoms 4-6 hours after antigen exposure 4, 6, 7
• Chronic presentations show insidious onset of dyspnea, cough, and weight loss over months to years 4, 6
• Symptoms may improve away from the exposure source (e.g., improvement on weekends or vacations) 8, 6

Acute Interstitial Pneumonia (Hamman-Rich Syndrome)

• Fulminant presentation over days to weeks in previously healthy individuals 1
• Fever, cough, and severe dyspnea progressing rapidly to respiratory failure 1
• Moderate to severe hypoxemia requiring mechanical ventilation in most cases 1

Critical Diagnostic Considerations

Temporal Relationships

The temporal association between symptom onset and exposure to a causative agent is the single most important diagnostic clue 1, 3

• Drug-related: onset within days to months of drug initiation 1, 3
• Radiation: 3-12 weeks post-exposure 1, 2
• Hypersensitivity: hours after antigen exposure (acute) or insidious over years (chronic) 4, 6, 7

Essential Differential Diagnosis

Pneumonitis must be distinguished from:

• Infectious pneumonia: fever, chills, productive cough, myalgia, positive cultures 1
• Pulmonary edema: frothy sputum, cardiac or renal failure history 1
• Diffuse alveolar hemorrhage: hemoptysis (in two-thirds), anemia 1
• Disease progression: particularly critical in cancer patients 1
• Pulmonary embolism and cardiac events: must be excluded in dyspneic patients 2

Common Pitfalls and Caveats

Recognition Challenges

• Pneumonitis can be completely asymptomatic, discovered only on routine imaging—maintain high suspicion in at-risk patients 1, 3
• Elderly patients may have atypical or minimal symptoms despite significant disease 5
• Symptoms are non-specific and overlap substantially with other pulmonary conditions 1, 6

Critical Action Points

• Any new respiratory symptom in patients receiving immune checkpoint inhibitors or molecular targeted agents requires immediate CT imaging to exclude pneumonitis 1
• Do not wait for fever—many pneumonitis cases are afebrile 1
• Improvement with drug cessation strongly supports the diagnosis but is not always observed 1

High-Risk Scenarios

• Patients with pre-existing interstitial lung disease have markedly elevated risk of severe and potentially lethal radiation pneumonitis 2
• Non-small cell lung cancer patients have higher pneumonitis rates than melanoma patients on immunotherapy 3
• Combination immunotherapy (anti-PD-1/PD-L1 plus anti-CTLA4) increases pneumonitis risk 3-fold compared to monotherapy 1
• Fatal pneumonitis occurs in approximately 0.2% of patients on immune checkpoint inhibitors, with higher mortality in NSCLC patients 1