As the treatment of malignancy evolves, the number patients who are receiving active chemotherapy presenting to the Emergency Department is increasing.  Many of these patients present with respiratory chief complaints ranging from mild dyspnea to acute respiratory distress. While the differential diagnosis of these patients commonly includes thromboembolism, primary infection, and worsening tumor burden, a particular focus on pulmonary toxicity secondary to the patient's chemotherauptic agents should also be included. This post aims to introduce chemotherapy-induced pulmonary toxicity and review those chemotherapuetic agents that commonly affect the lungs.

Mechanism of Injury from Chemotherapeutic Agents:

• Direct damage to pneumocytes or alveolar capillary endothelium
• Immunologic-mediated toxicity
• Capillary leak
• *Secondary effects of chemotherapy can affect the lungs (i.e. pancytopenia causing alveolar hemorrhage or infection)
• *Particularly seen in patients being treated for hematologic malignancy

What this Does to the Lungs:

• Interstitial/Hypersensitivity pneumonitis
• Non-cardiogenic pulmonary edema (NCPE)
• Alveolar hemorrhage
• BOOP (Bronchiolitis olbiterans organizing pneumonia)
• Pleural effusions
• Bronchospasm
• Pulmonary venoocclusive disease
• Acute Lung Injury/ARDS

Cytarabine:

• Chemotherapy for the treatment of leukeumia
• Causes non-cardiogenic pulmonary edema (NCPE)
• Onset 2 to 21 days follow treatment
• Causes respiratory failure in 11-28% of patients with a mortality of 13-69%
• Treatment: Remove offending agent, corticosteroids (0.75-4 mg/kg/day), diuretics, supportive care

Gemcitabine:

• Causes non-cardiogenic pulmonary edema (NCPE) at rate of 0.1% although mortality is high without treatment
• Pulmonary toxicity will increase with each successive dose
• Gemcitabine causes separate self-limiting dyspnea in 5-8% of patients that is not related to pulmonary toxicity
• Treatment: Remove offending agent, corticosteroids, diuretics, supportive care

Interleukin-2 (IL-2):

• Causes non-cardiogenic pulmonary edema (NCPE) in 3-20% of patients
• Mechanism secondary to enothelial leak
• Excessive volume resusication can exacerbate toxicity
• Treatment: Remove offending agent, corticosteroids, diuretics, supportive care

Retinoic Acid:

• Can cause Retinoic Acid Syndrome (ATRA): Constellation of fever, weight gain, leukocytosis, respiratory distress, pleural/pericardial effusions, interstitial infiltrates, hypotension, and acute renal failure after initiation of therapy for leukemia.
• Incidence of 2-11% with mortality of 2%

Bleomycin:

• Causes pulmonary fibrosis after 1-6 months of therapy in up to 10% of patients
• Mechanism of toxicity is through generation of reactive oxygen species (ROS) which are toxic to pneumocytes
• Pulmonary toxicity can be exacerbated by giving supplemental oxygen
• Inhaled nitric oxide can be used as an oxygen-sparing strategy

Bevacizumab:

• Used in the treatment of non-small cell lung cancer
• Can cause alveolar hemorrhage in 2% of patients
• Mechanism of toxicity is secondary through tumor response to therapy

References:
1. Hale KE. Toxicities of Chemotherapy. In: Hall JB, Schmidt GA, Kress JP. eds. Principles of Critical Care, 4e. New York, NY: McGraw-Hill; 2015.