Is a patient who has received CAR-T (Chimeric Antigen Receptor T-cell) cell therapy more likely to experience pneumonitis or an infection?

Infection Risk After CAR-T Cell Therapy: Pneumonitis vs. Infection

Patients who have received CAR-T cell therapy are more likely to experience infections than pneumonitis as an adverse effect, with infection rates reported in up to 70% of patients compared to pneumonitis being a rare complication. 1

Infection Risk Following CAR-T Cell Therapy

Infection Epidemiology

• Infections are extremely common after CAR-T therapy, occurring in up to 70% of patients in clinical trials 1
• Highest risk period is within the first 30 days after CAR-T infusion 1
• Bacterial infections predominate in the early post-infusion period 2
• Viral and fungal infections can occur later, particularly in patients with prolonged immunosuppression 3

Mechanisms of Infection Risk

1. Pre-existing factors:

   • Prior immunosuppressive therapies
   • Underlying disease burden
   • Previous infections 2

2. CAR-T specific factors:

   • Lymphodepleting chemotherapy before CAR-T infusion
   • On-target/off-tumor effects causing B-cell aplasia
   • Hypogammaglobulinemia (reported in up to 53% of patients) 1
   • Prolonged cytopenias (neutropenia, lymphopenia)
   • CRS management with immunosuppressants (tocilizumab, corticosteroids) 1

Risk Factors for Infection

• Neutropenia before CAR-T therapy
• Prior infections
• Corticosteroid treatment for CRS management 2
• Severity of CRS 1
• Immune effector cell-associated neurotoxicity syndrome (ICANS) 1

Pneumonitis After CAR-T Cell Therapy

Pneumonitis as a direct adverse effect of CAR-T therapy is relatively rare but can occur through several mechanisms:

1. Immune-mediated pneumonitis:

   • Can develop as a late complication (weeks to months after therapy) 4
   • Similar to other immunotherapy-associated pneumonitis
   • Not associated with infection

2. CRS-related pulmonary manifestations:

   • Pulmonary edema and respiratory distress as part of CRS
   • Typically occurs during peak CRS (days 2-7 after infusion) 1

Diagnostic Approach to Pulmonary Infiltrates Post-CAR-T

When pulmonary infiltrates are detected after CAR-T therapy:

1. Timing considerations:

   • Early infiltrates (within 30 days): More likely infectious
   • Late infiltrates (beyond 30 days): Consider both infectious and non-infectious causes

2. Clinical features suggesting infection:

   • Fever
   • Productive cough
   • Positive microbiology
   • Response to antimicrobial therapy
   • Concurrent infections at other sites

3. Features suggesting pneumonitis:

   • Dry cough
   • Negative infectious workup
   • Response to immunosuppressive therapy
   • Radiographic pattern consistent with immune-mediated pneumonitis

Management Recommendations

Infection Prevention

• Prophylaxis against HSV/VSV reactivation and Pneumocystis jirovecii pneumonia is recommended for all patients 1
• Consider monthly IVIG replacement (400-500 mg/kg) for patients with:
  • IgG levels <400-600 mg/dL AND
  • Serious or recurrent infections (particularly bacterial) 1
• Continue IVIG until IgG levels normalize and infections resolve

Management of Pulmonary Infiltrates

1. Initial approach:

   • Comprehensive infectious workup including blood cultures, respiratory viral panel, sputum cultures
   • Chest imaging (CT preferred over X-ray for detail)
   • Consider bronchoscopy with BAL in unclear cases

2. Empiric therapy:

   • Start broad-spectrum antimicrobials while awaiting culture results
   • Consider coverage for opportunistic pathogens in prolonged immunosuppression

3. For confirmed pneumonitis:

   • Consider IVIG without tocilizumab or glucocorticoids for mild cases 4
   • For severe cases, follow institutional protocols for immune-related pneumonitis

Special Considerations

Viral Pneumonia Risk

• CMV pneumonia can occur months after CAR-T therapy and can be fatal 3
• Consider CMV monitoring in high-risk patients
• Prompt antiviral therapy for suspected viral pneumonia

Impact on Survival

• Infections after CAR-T therapy are associated with significantly shorter survival (126 vs 409 days) 2
• Early recognition and management of infections is critical

Conclusion

While both pneumonitis and infections can cause pulmonary infiltrates after CAR-T cell therapy, infections are substantially more common and should be the primary consideration in the differential diagnosis. A thorough infectious workup should be performed before attributing pulmonary infiltrates to immune-mediated pneumonitis.