Bleomycin-Induced Lung Injury

Bleomycin induced lung injury is dose related lung toxicity from bleomycin, which is used in germ cell tumours, Hodgkin lymphoma and some squamous cancers. It causes interstitial pneumonitis, organising pneumonia and fibrosis, and occurs in about 10% of patients and fatally in 1 to 3%.

The risks rise with a cumulative dose above 400 units (lower in the elderly), age over 70 years, renal impairment (since the drug is renally cleared), prior or concurrent thoracic radiotherapy, high inspired oxygen concentrations, smoking and use of colony stimulating factors with cisplatin.

Pathophysiology. Bleomycin generates free radicals and causes DNA strand breaks in alveolar epithelium and endothelium, with weak inactivation by the lung (low bleomycin hydrolase activity). Injury leads to inflammatory cell recruitment, then fibroblast proliferation and collagen deposition. Oxygen exposure potentiates toxicity.

Dry cough, progressive dyspnoea, pleuritic chest pain and low grade fever during treatment or in the weeks to months after. Examination may show fine basal crackles. Presentation can be acute with a hypersensitivity picture, or in the postoperative period after oxygen exposure.

Rapid hypoxaemia, a fall in oxygen saturation or new infiltrates during chemotherapy need urgent assessment, since infection, tumour and heart failure also cause these.

• Clinical diagnosis after exclusion of other causes, in a patient who has received bleomycin.
• Lung function: baseline spirometry and DLCO before treatment and before each cycle in those at risk. A fall in DLCO of over 20% from baseline, or a fall in FVC of over 10%, prompts review and a stop of the drug.
• High resolution CT: bibasal subpleural reticulation and ground glass opacity, multifocal nodules or consolidation (organising pneumonia pattern), with traction bronchiectasis in fibrosis.
• Bronchoalveolar lavage and microbiological testing to exclude infection including Pneumocystis and viruses, since patients are immunosuppressed.
• Echocardiography and natriuretic peptide for heart failure, and CT pulmonary angiography when pulmonary embolism is possible.
• Renal function, since reduced clearance raises toxicity.

Differential diagnosis.

• Opportunistic and bacterial pneumonia
• Tumour progression or lymphangitic spread
• Pulmonary embolism
• Heart failure or fluid overload
• Radiation pneumonitis
• Other drug induced pneumonitis (cyclophosphamide, gemcitabine)

• Stop bleomycin at the first sign of toxicity, and do not restart. Alternative non-bleomycin regimens are chosen by the oncology team.
• Corticosteroid: prednisolone 1 mg/kg daily (usually 40 to 60 mg) for 4 to 6 weeks, then tapered over 3 to 6 months. In acute severe disease, methylprednisolone 500 to 1000 mg intravenously daily for 3 days.
• Oxygen policy: give the lowest oxygen concentration that maintains a saturation of 88 to 92% (or the minimum needed), and warn all staff, including anaesthetists, that high inspired oxygen can trigger severe lung injury in previously treated patients, for many years afterwards.
• Empirical antimicrobials while infection is excluded: ceftriaxone 2 g intravenously daily with azithromycin 500 mg daily, and co-trimoxazole for Pneumocystis if prednisolone is used long term (960 mg three times weekly).
• Prevention: limit the cumulative dose to 400 units where possible (270 units in older patients), reduce or avoid in renal impairment (adjust for creatinine clearance), avoid concurrent thoracic radiotherapy, monitor DLCO, and avoid unnecessary oxygen.
• Supportive: pulmonary rehabilitation, vaccination against influenza, pneumococcus and COVID-19, and smoking cessation.

Complications and prognosis. Some recover with steroids, others progress to fibrosis and respiratory failure. Mortality is 1 to 3% overall and higher in acute disease.

Monitoring. Spirometry and DLCO before each cycle, review at 4 and 12 weeks after stopping, and CT if function falls. Long term follow up for restrictive disease.

Referral and escalation. Refer to the oncology team the same day when a fall in DLCO or new symptoms occur, and to a respiratory physician for severe disease.