Drug-induced interstitial lung disease

Overview

Drug-induced ILD (DI-ILD) is one of the few reversible causes of ILD - early drug withdrawal is critical. Presentation is often indistinguishable from other ILD subtypes; diagnosis is one of exclusion.

Presentation

•Progressive dyspnoea - initially on exertion, later at rest

•Dry cough - non-productive

•Fine bibasal end-inspiratory (Velcro) crackles - do not clear on coughing

•Fever - more common in immune-mediated reactions (methotrexate, nitrofurantoin)

•Digital clubbing - sign of established fibrosis

🎯
DI-ILD is lower zone-predominant (like IPF, asbestosis, RA-ILD). Always consider drugs - especially amiodarone, methotrexate, or prior chemotherapy - in any patient with bibasal changes.

Investigations

🥇 First-line

•Chest X-ray - bilateral reticular/ground-glass shadowing, lower zones; may be normal early

•Spirometry - restrictive pattern (FEV1/FVC >0.7, reduced FVC); reduced DLCO is earliest and most sensitive abnormality

•FBC - eosinophilia (nitrofurantoin, methotrexate); lymphopenia with cytotoxics

•Autoimmune screen (ANA, ANCA, RF, anti-CCP, ENA, Scl-70) - to exclude CTD-associated ILD

🏆 Gold standard

•HRCT thorax - ground-glass opacity, reticulation, traction bronchiectasis, honeycombing; amiodarone causes characteristic high-attenuation opacities

🥈 Second-line

•BAL - lymphocytosis (drug hypersensitivity), eosinophilia (eosinophilic pneumonia), foamy macrophages (amiodarone); also excludes infection

•Lung biopsy - reserved for diagnostically uncertain cases

Management

•Withdraw the causative drug promptly - even before histological confirmation; continued exposure risks irreversible fibrosis

•Stopping amiodarone requires cardiology input (risk of refractory arrhythmia); note long half-life means toxicity may persist after withdrawal

•Prednisolone - used for immune-mediated reactions (e.g. methotrexate hypersensitivity, amiodarone toxicity) to accelerate recovery

Prognosis

Prognosis by mechanism
PatternExample drugsPrognosis
Immune-mediatedMethotrexate, nitrofurantoinGood - most recover full/near-full lung function after withdrawal ± steroids
Direct cytotoxicBleomycin, cyclophosphamideHigher risk of permanent fibrosis, especially if delayed diagnosis
Combined toxic/inflammatoryAmiodaroneIntermediate - recovery slow/incomplete in established fibrosis; toxicity may worsen briefly after stopping due to long half-life

Pattern	Example drugs	Prognosis
Immune-mediated	Methotrexate, nitrofurantoin	Good - most recover full/near-full lung function after withdrawal ± steroids
Direct cytotoxic	Bleomycin, cyclophosphamide	Higher risk of permanent fibrosis, especially if delayed diagnosis
Combined toxic/inflammatory	Amiodarone	Intermediate - recovery slow/incomplete in established fibrosis; toxicity may worsen briefly after stopping due to long half-life

Key culprit drugs and mechanisms

High-yield drug causes of ILD
DrugMechanismDistinguishing feature
AmiodaroneToxic + inflammatory (phospholipidosis)High-attenuation opacities on HRCT (iodine); foamy macrophages on BAL; very long half-life - toxicity may persist/worsen after stopping
MethotrexateImmune-mediated (granulomatous hypersensitivity)Fever common; lymphocytosis on BAL; good prognosis with withdrawal ± steroids
NitrofurantoinImmune-mediated (eosinophilic pneumonitis)Acute onset (days); eosinophilia on FBC/BAL; good prognosis
BleomycinDirect cytotoxic (reactive oxygen species)Sensitises lung to O2 toxicity - even years later; higher risk of permanent fibrosis
CyclophosphamideDirect cytotoxicHigher risk of irreversible fibrosis, especially if diagnosis delayed

Drug	Mechanism	Distinguishing feature
Amiodarone	Toxic + inflammatory (phospholipidosis)	High-attenuation opacities on HRCT (iodine); foamy macrophages on BAL; very long half-life - toxicity may persist/worsen after stopping
Methotrexate	Immune-mediated (granulomatous hypersensitivity)	Fever common; lymphocytosis on BAL; good prognosis with withdrawal ± steroids
Nitrofurantoin	Immune-mediated (eosinophilic pneumonitis)	Acute onset (days); eosinophilia on FBC/BAL; good prognosis
Bleomycin	Direct cytotoxic (reactive oxygen species)	Sensitises lung to O2 toxicity - even years later; higher risk of permanent fibrosis
Cyclophosphamide	Direct cytotoxic	Higher risk of irreversible fibrosis, especially if diagnosis delayed

🚨
Bleomycin sensitises the lung to oxygen toxicity permanently - anaesthetic teams must always be informed of prior bleomycin exposure.

Monitoring and prevention

•Baseline HRCT and PFTs (including DLCO) before starting bleomycin or cyclophosphamide

•Annual CXR and PFTs for patients on long-term amiodarone

•DLCO decline >15-20% from baseline on methotrexate - prompt drug cessation and specialist review

•Avoid high-dose oxygen in patients who have received bleomycin