Patients with DILD may be observed in several different clinical settings, the most common being rheumatology and gastroenterology, cardiology, and general practice. 

Cardiology

Concerning cardiovascular agents, amiodarone is the main cause of lung toxicity, followed by other antiarrhythmics, anticoagulants and antihypertensives.

• Amiodarone (Fig.2 and 3)

The main pattern of pulmonary toxicity from amiodarone is OP, but other possible manifestations may include eosinophilic pneumonia, hypersensitivity pneumonia or fibrotic patterns. Amiodarone toxicity has been linked to risk factors such as increasing age, dose and presence of underlying lung disease [6]. Patients receiving amiodarone may also present with hyperattenuating lung parenchyma on non-contrast CT, due to accumulation of iodine. This finding, however, does not indicate a drug reaction. Disease progression and recurrence has been described even after drug withdrawal owing to a long half-life and accumulation in fatty tissues.

Fig 2: Fig.2 70-year-old female patient on treatment with amiodarone, presenting with weight loss, low energy levels, and recent onset of cough and shortness of breath. CT (A-D) shows upper-lobe predominant airspace and ground glass opacity, with a perilobular distribution. Imaging and transbronchial biopsy was in keeping with organising pneumonia, secondary to amiodarone.

Fig 3: Fig.3 77-year-old female patient, under treatment with amiodarone for two years, presenting with 3 weeks of shortness of breath. CT imaging (A-F) showed features of organising pneumonia with perilobular and arc-like bands with a peribronchovascular predominance. Transbronchial biopsy confirmed these findings.

Rheumatology and Gastroenterology

Patients are treated with disease modifying antirheumatic drugs (DMARDS) which include conventional agents (such as methotrexate, leflunomide or sulfasalazine) or biological DMARDs (Rituximab, etanercept, infliximab).  

• Methotrexate (Fig.4 and 5)

Lung toxicity from methotrexate usually presents with cough and shortness of breath, sometimes also with fever. It is not correlated to cumulative dose or duration of treatment, and symptom usually present within the first few months of treatment. The main CT manifestations of methotrexate DILD are interstitial pneumonitis, most often NSIP, which may be present in up to 1% of patients. The higher incidence reported in older studies may be due to under recognised rheumatoid arthritis related interstitial lung disease misdiagnosed as methotrexate induced.

Fig 4: Fig.4 Axial (A-E) and coronal (F) views from CT scan of an 80-year-old female patient who was being treated with methotrexate for rheumatoid arthritis. The CT scan shows diffuse bilateral ground glass opacities with lobular areas of air trapping, more prominent in the upper lobes, in keeping with hypersensitivity pneumonitis which was attributed to methotrexate. Treatment was discontinued, with improvement of clinical symptoms and CT features.

Fig 5: Fig.5 Axial (A-D) images from a HRCT scan of an 80-year-old female patient who was being treated with methotrexate for rheumatoid arthritis, who presented with widespread ground glass opacity, most in keeping with diffuse alveolar damage pattern. The patient improved on discontinuation of the drug.

• Rituximab (Fig. 6, 7)

Rituximab is an anti-CD20 monoclonal antibody which can be used to treat rheumatoid arthritis and vasculitis. DILD from rituximab usually presents within 3 months from the beginning of treatment. At CT, the predominant pattern of rituximab induced DILD is represented by organising pneumonia, followed by interstitial pneumonitis with a NSIP pattern. Drug induced sarcoid like reactions is also recognised from biological DMARDs.

Fig 6: Fig.6 34-year-old patient with systemic lupus erythematosus, presenting with shortness of breath after rituximab infusion. CT imaging (A-B) shows diffuse ground glass opacity, with PET imaging (C-D) displaying diffuse lung tracer uptake. This was most suggestive of a drug related hypersensitivity pneumonitis.

Fig 7: Fig.7 60-year-old female patient presenting with rheumatoid arthritis and known nonspecific interstitial pneumonia, shown at the first CT scan (A-C), acquired while she was not under immunosuppressant treatment. Three years later, after starting rituximab, she presented with a 6-week history of breathlessness, and a subsequent CT scan (D-F) showed signs of peribronchovascular interstitial and air space changes. Mediastinal windows (G-I) show enlarged mediastinal and hilar nodes. EBUS and transbronchial biopsy confirmed graunlomatous inflammation. This was most likely related to sarcoid like reaction from Rituximab. Interval resolution of both nodes and parenchymal changes six months later (J).

Gastroenterology and renal clinics

Patients in these clinics include those on treatment for hepatitis and can be on multiagent antiviral drug regimens, as well as those who undergo immunosuppression with drugs such as cyclosporine or rituximab for a previous solid organ transplant and may present with DILD [4, 5].

Patients with autoimmune bowel and cholestatic liver disease can be taking conventional and biologic DMARDs. These underlying diseases themselves are also associated with thoracic manifestations which cause the same pathological and CT pattern as a drug reaction. For example, patients can develop an OP pattern related to inflammatory bowel disease and from the DMARDs therapy.  A thorough review of medications and temporal correlation of initiation of drug with onset of lung disease is required in these situations.

• Leflunomide (Fig. 8)

Leflunomide may also cause DILD. Usually, patients present with DILD within three months of starting treatment, with a rapid onset of symptoms. A prior history of ILD is a significant risk factor for leflunomide-related DILD. CT features are variable, with interstitial pneumonitis being the most common presentation.

Fig 8: Fig.8 68-year-old female patient on treatment with leflunomide for Crohn’s disease, presenting with shortness of breath, with CT imaging (A-D) showing peripheral arcade like areas of ground glass opacity, suggestive of organising pneumonia.

• Sulfasalazine (Fig. 9)

Sulfasalazine, which is often used to treat patients with immune conditions such as inflammatory bowel disease, usually presents between 1 week and 8 months after starting treatment. The main CT appearance of sulfasalazine DILD is eosinophilic pneumonia. However, it may also manifest as interstitial or organising pneumonia.

Fig 9: Fig.9 79-year-old female patient treated with sulfasalazine for rheumatoid arthritis. Presented with acute worsening of respiratory symptoms, with normal blood natriuretic peptide and no sign of heart failure. Subsequent CT showed new bibasal curvilinear opacities, in keeping with interstitial lung disease, which was attributed to drug reaction.

• Antivirals: Interferon and ribavirin (Fig. 10 and 11)

Even though rarely, patients treated with antivirals for hepatitis may sometimes present with DILD. Most patients with DILD from antiviral treatments present with interstitial pneumonitis, However, sarcoid-like reactions and bronchiolitis may also be manifestations of DILD in this setting.

Fig 10: Fig.10 71-year-old male patient being treated for hepatitis with interferon and ribavirin, who presented with increasing shortness of breath and hypoxia. CT scan showed perilobular ground glass and airspace opacity with reticulation in the mid and lower zones, along with multiple tiny centrilobular nodules in the upper and mid zones. Imaging features were in keeping with drug reaction with hypersensitivity and organising pneumonia components. Treatment was subsequently discontinued. See interval imaging (Fig. 11).

Fig 11: Fig.11 71-year-old male patient being treated for hepatitis with interferon and ribavirin. 6-week follow-up CT, showing resolution of the previous findings.

• Sirolimus (Fig. 12)

Sirolimus therapy may be associated with pulmonary toxicity, usually presenting with dry cough, dyspnoea, fatigue, and fever. Sirolimus-related DILD is more common in those patients switching to sirolimus, rather than de novo users. CT imaging usually shows peripheral infiltrates or ground glass opacities.

Fig 12: Fig.12 Axial (A-E) and coronal (F) views of a CT scan from a 59-year-old female patient who switched from ciclosporin to sirolimus due to side effects. After two months, she developed dyspnoea and dry cough. She was initially treated with antibiotics, with no clinical benefit. The CT scan revealed multifocal areas of ground glass opacity and consolidation, in a subpleural and peribronchovascular distribution. A transbronchial biopsy showed evidence of interstitial pneumonitis and organising intra-alveolar fibrinous exudates. The cell differential from the bronchoalveolar lavage revealed a lymphocytosis. The radiological and histopathological findings are compatible with Sirolimus related organising pneumonia.

Family medicine

Family medicine physicians may often deal with patients who are being treated for infectious diseases or chronic conditions such as epilepsy or osteoporosis. Among antibiotics, nitrofurantoin is the most common cause of DILD; followed by amphotericin B, sulphonamides, and sulfasalazine. Among antiepileptic drugs, levetiracetam may lead to DILD, along with carbamazepine [7].

• Nitrofurantoin (Fig. 13, 14)

Nitrofurantoin is typically used for the treatment and prophylaxis of urinary tract infections, often in women. This can cause either acute hypersensitivity reactions, usually 1-2 weeks after treatment, or chronic pulmonary changes after longer exposure [8]. Acute reactions may present with fever, dyspnoea, and cough, whereas chronic reactions present with dyspnoea and cough, usually at least one month after treatment. The CT patterns of nitrofurantoin DILD include organising pneumonia, hypersensitivity pneumonitis and interstitial pneumonitis, usually with NSIP pattern.

Fig 13: Fig.13 84-year-old female patient with recurrent UTIs on long term treatment with nitrofurantoin, who presented with a 8-week history of shortness of breath and reduced exercise tolerance., who underwent chest X-ray as first exam (E). The CT scan (A-D) showed peripheral ground glass opacity with mild reticulation and perilobular bands. Appearances were most in keeping with organising pneumonia due to nitrofurantoin. Symptoms and imaging improved after discontinuation of treatment and steroids.

Fig 14: Fig.14 86-year-old female patient on long term treatment with nitrofurantoin, who presented with a 6-month history of cough and increasing shortness of breath, which did not improve with antibiotic treatment. The CT scan (A-D) shows reticulation with distal traction bronchiectasis within all zone of both lungs associated with mild ground glass opacity and generalised thickening of the bronchovascular interstitium. Appearances were most in keeping with fibrotic phase of organising pneumonia due to nitrofurantoin.

• Levitiracetam (Fig. 15)

Levitiracetam, a drug used to treat partial epilepsy, may rarely cause DILD, especially in those patients presenting with prior lung disease. Levitiracetam DILD mainly presents as eosinophilic or organising pneumonia or, less commonly, interstitial pneumonitis with an NSIP pattern.

Fig 15: Fig.15 59-year-old female patient under treatment with levitiracetam for epilepsy, presenting with increased shortness of breath. CT findings include extensive peribronchovascular and peripheral consolidation with ground glass opacity, more prominent in the mid and upper zones, associated with reticulation and interlobular septal thickening.  The diagnosis of eosinophilic pneumonia was made given the concurrent peripheral eosinophilia. Symptoms and imaging findings improved  after prednisolone and cessation of drug.