19th May 2025

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