19th May 2025

Drug-induced interstitial lung disease

Introduction

The lungs have a large contact surface area and act as a site of metabolism for certain drugs; drug-induced lung injury is therefore not uncommon. Of this large collection of diseases, drug-induced interstitial lung disease (DILD) is the most common manifestation of drug-induced lung injury. DILD is caused by a wide range of drugs. Its incidence, severity and underlying mechanisms are variable dependent on the causative drug. Often, the precise mechanism of DILD for a particular drug is unclear. DILD severity can range from relatively innocuous benign infiltrates to respiratory failure and acute respiratory distress syndrome. The pathologic, radiologic and physiologic changes seen in DILD are highly variable and non-specific, which can make it difficult to recognise. The most common causative drugs are anti-neoplastic agents, disease-modifying anti-rheumatic drugs, antibiotics, and anti-arrhythmic agents. The diagnosis of DILD should be made by exclusion. Re-challenge of the suspected causative agent is generally not advised due to the risk of harm. Treatment is cessation of the drug, avoidance of further exposure and in severe cases systemic glucocorticoid therapy should be considered.

Clinical features

Signs and symptoms

Symptoms are typically non-specific e.g. dyspnoea, cough, and pleuritic chest pain. Rash, wheeze and haemoptysis may be seen. Signs may include hypoxaemia, crackles on auscultation, clubbing of the fingers, and signs of pulmonary hypertension causing right ventricular dysfunction such as peripheral oedema and jugular venous distention. 

Pulmonary function tests 

Changes are nonspecific. Most drugs causing DILD cause a restrictive lung disease pattern with decreased total lung capacity. Reduction in diffusing capacity for carbon monoxide (DLCO) is typically seen. Drugs causing bronchiolitis obliterans may cause an obstructive pattern

Histology

In general, if there is exposure to a drug resulting in damage to the pulmonary interstitium, particularly in the case of persistent exposure or dysregulated repair processes, interstitial tissue replaces the capillaries and alveoli. Often nonspecific histopathological changes are seen, and almost all patterns of interstitial lung disease caused by therapeutic agents have been demonstrated, including: diffuse alveolar damage (DAD), hypersensitivity pneumonia (HP), granulomatous pneumonitis (GP), bronchiolitis obliterans organising pneumonia (BOOP), non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), organising pneumonia (OP), eosinophilic pneumonia (EP), and granulomatous lung disease (GLD). Some drugs may be responsible for more than one pattern of DILD. Several drugs demonstrate characteristic histopathologic changes; amiodarone may cause NSIP, and methotrexate causes an acute granulomatous ILD which closely resembles opportunistic infective histological changes.

Radiographic findings

Plain film radiographs commonly show bilateral pulmonary infiltrates but may also be normal. 

Computed tomography (CT) may demonstrate numerous patterns of interstitial change; most commonly ground glass opacification, with or without consolidation which can follow a basal, peripheral and bilateral distribution. Changes in keeping with OP, NSIP and HP are most commonly seen. 

High-resolution CT (HRCT) has been reported to be the best modality to demonstrate changes in DILD, which can correspond to the histological subtype. It can also be useful in identifying findings suggestive of an alternate pathology. As a general rule, pneumonitis induced by anti-neoplastic agents shows a pattern of scattered or diffuse ground glass opacities with intralobular interstitial thickening. Those agents causing hypersensitivity pneumonia, including cyclophosphamide, sulfonamides or sulfasalazine may show bilateral patchy ground-glass opacities and/or centrilobular upper lobe nodules. Antibiotic-induced pneumonitis has been reported as showing scattered ground-glass and centrilobular opacification and interlobular septal lines.

Serological tests

A sensitive marker for interstitial lung disease in general is Krebs von den Lungen-6 (KL-6), however its specificity in DILD is not yet established. SP-A and SP-D are serum biomarkers specific for pulmonary fibrosis; again, at present the diagnostic value in DILD is unclear. 

Bronchoscopy + bronchoalveolar lavage 

When performing bronchoalveolar lavage in DILD the most common finding is a lymphocytic alveolitis. Raised lymphocyte, neutrophil and eosinophil counts are typically seen. The presence of reactive type II pneumocytes has been reported in severe DILD cases. Bronchoscopy is also useful for detecting key differentials such as vasculitis, alveolar haemorrhage, pneumonia, and lymphangitic carcinomatosis. 

Biopsy

Lung biopsy is not typically recommended as part of the diagnostic workup as it is unlikely to aid in providing a definitive diagnosis of DILD, however it can be useful for excluding key differential diagnoses.

Pathophysiological mechanisms

The underlying pathophysiology driving DILD in general is split into two categories: direct cytotoxic effects, and immune-mediated effects. Different drugs follow different aetiological mechanisms within these two classes, and some drugs may produce both patterns of disease.

Direct cytotoxic effects

Some of the key directly cytotoxic mechanisms via which causative mechanisms may result in DILD are listed below: 

• Formation of reactive oxygen species
• Decreased deactivation of metabolites within lungs
• Cytokine release
• Impaired repair mechanisms within alveoli

The above mechanisms result in direct injury to pneumocytes or the alveolar capillary endothelium. This leads to alveolitis and pulmonary oedema. Acute damage to the lung parenchyma may progress to chronic inflammation and eventually fibrosis. Some examples of drugs with direct cytotoxic effects causing DILD and further details on the underlying mechanisms are given below.

Amitriptyline – endothelial damage secondary to disruption of tight junctions as a result of dysregulated intracellular calcium levels.

Methotrexate – stimulates release of free oxygen radicals (e.g. nitric oxide) and cytokines. The effect is not dose-dependent, has variable time and rate of onset; time of onset reportedly ranges from 23 days to 4 years, including after treatment cessation. 

Amiodarone – activates pathways that trigger pulmonary epithelial cell apoptosis. Amiodarone is one of the commonest causes of DILD. Presentation is most commonly subacute, but an acutely fatal form has been reported. High mortality rates (37%) are reported in patients who are admitted to hospital with DILD caused by amiodarone. Cumulative dose is a key risk factor. 

Mitomycin C, nitrofurantoin, bleomycin – trigger release of reactive oxygen species which generate hydrogen peroxide, and oxide ions. 

Nitrofurantoin – can cause an acute pulmonary reaction within days of initiation, and in some cases within hours if there has been previous exposure. Most cases demonstrate rapid resolution on cessation of the drug. It is seen more commonly in patients taking long-term nitrofurantoin for urinary tract infection prophylaxis.

Immune-mediated effects

In general, immune reactions leading to DILD are influenced and ultimately triggered by multiple key factors: 

• antigenic features of drug’s molecular structure  
• genetic factors of individuals including gene polymorphisms encoding metabolic enzymes
• environmental factors including concurrent infection, pollution
• drug factors including dose, frequency of administration, duration of therapy

Immune-mediated DILD reactions are largely T-cell mediated. Specific examples are given below:

• Minocycline – minocycline-induced pneumonia is an example of an immune-mediated DILD– it manifests as an EP. Cytotoxicity develops as a result of lymphocyte-mediated processes. 
• Amiodarone – in addition to having directly cytotoxic effects, amiodarone can also trigger an immune-mediated reaction; this is reported to be influenced by an individual’s balance of Th1/Th2. 
• Bleomycin – demonstrates both direct cytotoxicity and immune-mediate effects. Bleomycin produces variable clinical presentations of DILD including asymptomatic cases. Changes may occur any time during treatment.

Pulmonary fibrosis causative agents 

Anti-TNF-alpha – these drugs cause systemic / pulmonary shifts towards a pro-fibrotic state, eventually causing pulmonary fibrosis. It also potentiates the pulmonary toxicity of methotrexate.

Rituximab – rituximab is an anti-CD20 antibody which causes DILD via release of cytokines. It may also activate complement or cytotoxic T cell lymphocytes. Activated cytotoxic lymphocytes can damage alveoli and pulmonary vasculature causing pulmonary inflammation and eventually fibrosis.

Table 4: list of the most commonly implicated drugs in DILD

Diagnosis

Diagnosis of DILD should be one of exclusion, and is based on: 

• a confirmed history of exposure to a suspected offending medication
• clinical features, imaging and histopathology in keeping with recognised patterns of DILD associated with this medication
• meticulous exclusion of other lung disease
• improvement in symptoms and signs following cessation of the drug
• Re-challenge of offending drug not advised due to the risk of harmful sequelae – lung damage is generally considered irreversible.

Risk factors for DILD

• Increased age (>60 years) – may be in part due to reduced renal excretory function 
• Pre-existing lung disease e.g. pre-existing ILD, COPD, bronchiectasis and asbestosis
• Smoking
• Drug dose – clear dose-dependency exists for DILD caused by amiodarone and bleomycin 
• Poor performance status 
• Pre-existing advanced lung cancer
• Drug interaction – concomitant use of certain drugs can increase an agent’s potential to cause DILD e.g. higher rates of bleomycin-induced interstitial lung disease when given concomitantly with cisplatin or gemcitabine
• Prior or concomitant thoracic radiotherapy – higher rates of pulmonary toxicity with concomitant radiotherapy e.g. for bleomycin
• Pattern of HLA class II allele presentation may be responsible either for resistance or preponderance to DILD e.g. increased risk of gold-induced pneumonitis with HLA-B40 in patients with rheumatoid arthritis
• Cytochrome P450 single nucleotide polymorphisms are believed to be a key genetic factor influencing individual differences in drug absorption, distribution, metabolism and excretion

Management

Withdrawal of the offending drug once DILD is suspected is key. 

The role of glucocorticoid therapy is controversial; evidence with regards to its benefit is limited as many studies employed steroid administration at same time as the suspected offending drug was stopped. Reports on efficacy are highly variable between studies. Current recommendations are to use glucocorticoid therapy in severely affected patients, and in those in whom DILD appears to progress despite cessation of the suspected offending drug. Some sources advise pneumococcal vaccination and annual influenza vaccination in patients with DILD.  

Prognosis 

Prognosis varies between causative agents. In some cases, complete recovery is seen following dose reduction or cessation of the causative agent, with or without glucocorticoid use. Mortality of DILD in patients with underlying malignancy is reported as between 14 and 52.3%, while in the non-cancer population it is from 0 to 41%. Cases of rapid onset, high disease severity and hypoxia on initial diagnosis demonstrate higher mortality.  Possible complications include pulmonary fibrosis and respiratory failure necessitating mechanical ventilation.