Main points

• Pulmonary adverse events and drug-induced lung disease (DILD) can occur in treating many conditions.

• Although DILD is difficult to distinguish clinically from other causes of diffuse pulmonary opacities, radiological findings play a key role.

• Radiologists should be familiar with DILD because the proper management of DILD is vital.

When treating many diseases, pulmonary adverse events (AEs) and drug-induced lung disease (DILD) may occur due to medications. Although most of these AEs are clinically mild, they can be severe and even life threatening.^1,2 Patients with malignancy, systemic inflammatory diseases, and elderly patients are at high risk for DILD.² The increasing use of novel therapeutic agents, including immune checkpoint inhibitors (ICIs) and molecular targeting agents, have increased the frequency and spectrum of DILD.^3,4,5 It is also crucial to determine whether the clinical and imaging findings in these patients are due to an underlying condition, infection, pulmonary edema, hemorrhage, or medication. Computed tomography (CT) plays a crucial role in diagnosis and can reveal the pattern-based distribution and severity of pulmonary abnormalities.⁶ This article reviews the essential radiological results of DILD and summarizes the critical clinical and imaging findings, emphasizing novel therapeutic agents.

Clinical features of DILD

The reported incidence of DILD varies widely, but a recent systematic analysis reported an incidence of DILD in 0.4–1.24/100,000 cases per year.² Moreover, approximately 3%–5% of all cases of diffuse interstitial lung disease are due to medication.^2,7,8 The temporal relationship between drug intake and the onset of pulmonary symptoms is essential for the clinical suspicion of DILD, but this timescale can vary widely.^2,4,6 Although the clinical condition of patients with DILD can range from asymptomatic to life-threatening, symptoms are usually mild and depend on the severity of the lung disease. Shortness of breath, coughing, and wheezing are the most frequently reported symptoms of DILD.^1,2,7

A simple clinical grading system has been defined for drug-induced organ toxicity. It is used as an indicator, both in the management of DILD and for determining the patient’s prognosis (Supplementary Table S1).⁹

Radiological findings of DILD

Imaging methods, particularly chest CT, play a crucial role in diagnosing DILD in patients receiving medications that potentially cause pulmonary toxicity.⁶ Although chest X-ray is usually the first-choice imaging tool and provides helpful information in evaluating patients with mild-to-moderate symptoms for DILD, it has low sensitivity and specificity in assessing the presence of pulmonary infiltration and disease extent.¹⁰ Thin-slice chest CT is a valuable tool for a pattern-based assessment of DILD in the presence of appropriate medical history and clinical findings. Moreover, chest CT can reveal other causes of respiratory symptoms or pulmonary infiltrations, and the severity of pulmonary infiltrations in patients with DILD can be assessed visually or quantitatively using CT (Supplementary Figure S1).¹¹

As recently stated in a Fleischner Society position paper, five commonly described radiological patterns and rare drug-induced lung abnormalities [such as sarcoid-like granulomatosis (SLG), radiation recall, and pneumonitis flare] may be encountered in chest CT due to novel therapeutic agents (Figure 1).⁶ Pneumonitis flare, SLG, and radiation recall pneumonitis do not have typical radiological findings, and clinical history is of great importance when diagnosing these entities.^5,6,10

Radiologic organizing pneumonia (OP) pattern

The OP pattern is a form of acute lung injury and is the most common form of DILD.^5,9,12 Histopathologically, it is characterized by intra-alveolar, intra-bronchial granulation tissue and interstitial inflammation.³ Bilateral, multifocal, peripheral, and peribronchovascular ground-glass opacities (GGOs) and/or consolidation areas with mid-lower lung zone predominance are common imaging findings.^4,5,6,12 Areas of GGO with a peripheral rim of consolidation (also known as reverse-halo or atoll sign) can be found but are not specific (Figure 2 and Supplementary Figure S2). Airspace opacities can be migratory and change configuration over time.^4,5,6,12 Although eosinophilic pneumonia (EP) can be present in similar imaging findings with an OP pattern, EP is characterized by peripheral band-like opacities and predominance in the upper lobes (Figure 3).^5,6

Radiologic non-specific interstitial pneumonia (NSIP) pattern

The NSIP pattern is the second most common form of DILD and is associated with a median of grade 1 toxic effects.^5,9,12 Histopathologically, it is characterized by the thickening of the pulmonary interstitium due to an inflammatory infiltrate (cellular NSIP) and/or fibrosis (fibrotic NSIP).^3,6 Bilateral, patchy, or diffuse GGOs with or without reticular opacities with peripheral and basilar predominance are the common imaging manifestations of NSIP. Immediate subpleural sparing can also be seen in NSIP cases, and consolidative opacities are unusual. Lung fibrosis shows temporal and spatial homogeneity, and lung abnormalities are usually bilateral and symmetrical (Figures 4, 5).^5,9,12

Radiologic hypersensitivity pneumonitis (HP) pattern

The HP pattern is a rare form of DILD associated with a median of grade 1 toxic effects and mild clinical symptoms.^9,12 Histopathologically, the HP pattern is characterized by cellular bronchiolitis, granulomas, multinucleated giant cells, and interstitial inflammation.³ Areas of GGO with or without air trapping and centrilobular nodules, which may be diffuse or predominantly distributed in the upper lobes, are common CT findings (Figure 6).^5,6,12 Parenchymal abnormalities, such as traction bronchiectasis, a honeycomb appearance, and upper lobe fibrosis consistent with fibrotic HP, are unusual in DILD.^5,6

Radiologic diffuse alveolar damage (DAD) pattern

The DAD pattern, or acute interstitial pneumonia (AIP), is a rare pattern of DILD often associated with acute clinical symptoms and diffuse pulmonary infiltrations on imaging.^6,9,12 Histopathologically, it is characterized by necrosis of type 2 pneumocytes, alveolar edema, and alveolar endothelial cell necrosis.^3,6 The DAD pattern is characterized by GGOs or dependent consolidation areas on imaging that usually affect the majority of, and sometimes, the entirety of the lung area (Figure 7). The “crazy paving” pattern characterized by interlobular septal thickening and intralobular lines can often be seen in the DAD pattern. In addition, other patterns, such as OP, can progress to DAD if not treated early (Figures 8, 9, and Supplementary Figure S3).^5,6,12,13

DAD–AIP findings can also be seen in extra-pulmonary causes, such as acute respiratory distress syndrome, sepsis, and transfusion-related acute lung injury (Supplementary Figure S4).^5,14 Furthermore, diffuse alveolar opacities can be observed on CT in patients with acute promyelocytic leukemia due to differentiation syndrome, which is a rare condition that occurs during all-trans retinoic acid therapy (Supplementary Figure S5).⁵

Radiologic simple pulmonary eosinophilia (SPEo) pattern

Although SPEo is generally reported in therapies with ICIs (especially with osimertinib), its etiopathogenesis is not fully understood.⁶ Patients with an SPEo pattern are usually clinically asymptomatic and indicate a median of grade 1 toxic effects.⁶ SPEo is radiologically characterized by unilateral or bilateral non-segmental, patchy GGOs or areas of consolidation. These lung abnormalities are typically transient and spontaneously resolve within a few weeks (Figure 10).^6,13

Sarcoid-like granulomatosis

Sarcoid-like granulomatosis is an atypical presentation of DILD and is usually associated with ICI therapy. It has been reported in 5%–7% of patients with malignant melanoma treated with ipilimumab.¹² The condition is characterized by histopathological and imaging features identical to sarcoidosis and includes enlarged hilar, mediastinal, and abdominal lymph nodes and perilymphatic (along with interlobular septae and bronchovascular bundles) lung nodules (Figure 11).^4,5,6,10,12 In positron emission tomography CT, lymph nodes and lung nodules can mimic metastatic disease by showing intense ¹⁸F-fluoro-2-deoxy-d-glucose uptake in patients with SLG. Therefore, it is important to be aware of this rare but important drug-induced disorder and consider this diagnosis appropriately to avoid false-positive interpretations of metastatic disease.¹²

Pneumonitis flare

A pneumonitis flare is a rare entity and is defined in patients on ICI therapy. Pneumonitis flares were reported in only 1 case out of 20 patients with ICI-related pneumonitis.¹⁰ The flaring of ICI pneumonitis is characterized as a flare-up (exacerbation) of pneumonitis when tapering, or during, the cessation of corticosteroid intake without the re-treatment of ICIs (Figure 12).^6,10,12

Radiation recall

Radiation recall is an acute inflammatory condition that occurs in a previously irradiated field after exposure to a provocative agent and is observed in many organs or systems, including the lungs.^5,12 In the past, reports of radiation recall pneumonitis were common in treatments with taxane-based chemotherapy agents and gemcitabine, although radiation recall pneumonitis due to ICI therapy has been reported recently with increasing frequency. Shibaki et al.¹⁵ recently reported that the average time between radiotherapy and radiation recall pneumonitis diagnosis due to ICI therapy was approximately two years. The frequency of radiation recall pneumonitis was reported as 4.4% in patients who had previously received radiotherapy and were treated with tyrosine kinase inhibitors.¹⁶ Although its etiopathogenesis is unclear, an awareness of this condition is essential to avoid the misdiagnosis of underlying disease progression.¹²

Diagnosis and management of DILD

Early diagnosis and prompt clinical management are essential for DILD. Although DILD is difficult to distinguish clinically from other causes of diffuse pulmonary opacities, radiological findings play a key role (Table 1).^5,6 Additionally, laboratory findings, along with clinical and medication history, are complementary in the diagnosis of DILD. Bronchoscopy and biopsy may rarely be preferred for diagnosis depending on the clinical situation and benefit–risk analysis. Recently, the Fleischner Society recommended the following diagnostic criteria for DILD: (a) newly identified pulmonary opacities, (b) temporal relationship of presentation with the initiation of medication, and (c) exclusion of other possible causes.⁶

Multidisciplinary discussion is recommended when determining the diagnosis and management of patients with suspected DILD.^5,6,17 The clinical grading and management of drug-induced organ toxicity are shown in Supplementary Table S1, and the drugs that are most likely to cause pulmonary toxicity are shown in Supplementary Table S2.

Conclusion

Radiologists should be familiar with DILD, as the condition requires a prompt diagnosis to initiate the appropriate treatment and prevent further morbidity and mortality.

Conflict of interest disclosure

The authors declared no conflicts of interest.