Drug-Induced Pulmonary Toxicity in the Era of Immunotherapy and Biologics: A Narrative Review of Mechanism, Diagnosis, and Management.

Key Summary Points

Drug-induced ILD (DI-ILD) remains difficult to diagnose due to its heterogeneous clinical and radiological manifestations and the absence of pathognomonic features, requiring careful exclusion of alternative causes through integrated clinical, imaging, and laboratory assessment. The expanding use of immune checkpoint inhibitors and CAR T-cell therapies is increasing the spectrum and frequency of pulmonary toxicities, underscoring the need for vigilant monitoring, structured evaluation of new respiratory symptoms, and individualized management strategies. Optimal care of DI-ILD depends on a multidisciplinary approach, incorporating timely drug withdrawal, appropriate immunosuppression, and coordinated input from pulmonology, radiology, oncology, and pathology, while future progress hinges on the development of predictive biomarkers, standardized protocols, and robust prospective studies.

Introduction

Drug-induced interstitial lung disease (DI-ILD) is a rare but increasingly recognized complication of various medications, causing significant morbidity and mortality and presenting diagnostic and therapeutic challenges due to its nonspecific respiratory symptoms and imaging findings [ 1 – 3 ].

The expanding use of novel therapeutic agents such as immune checkpoint inhibitors (ICI), chimeric antigen receptor T-cell (CAR-T) therapies, and biologic drugs, alongside conventional agents, has expanded the spectrum of drug-induced interstitial lung disease, which presents diverse mechanisms, risks, and clinical manifestations requiring tailored diagnostic and management approaches [ 1 , 3 – 11 ].

Given the nonspecific nature of many DI-ILD presentations, diagnosis requires a comprehensive clinical evaluation, including a detailed drug exposure history, imaging studies, exclusion of alternative causes such as infection or disease progression, and in selected cases, bronchoalveolar lavage (BAL) or lung biopsy [ 2 , 12 ]. Management generally involves discontinuation of the offending agent and initiation of corticosteroids. In severe cases, additional immunosuppressive therapy or respiratory support may be necessary [ 13 – 16 ].

This narrative review aims to provide an up-to-date, clinically relevant overview of DI-ILD across key therapeutic categories, including ICIs, CAR-T therapies, biologics, and other common drugs, to support early recognition, informed clinical decision-making, and a multidisciplinary management approach.

For this purpose, we performed a PubMed literature search for English-language studies including case reports, trial reports, literature reviews, and guidelines on the epidemiology, pathophysiology, diagnosis, prognosis, and treatment of DI-ILD using the following terms: “pulmonary toxicity,” “interstitial lung disease,” “drug-related pneumonitis,” “amiodarone,” “nitrofurantoin,” “methotrexate,” “biological agents,” “immune checkpoint inhibitors,” “chimeric antigen receptor T-cell,” and “anti-cancer drug.” The authors performed a careful and focused reading of the abstracts of the most cited articles in the search to determine the suitability of inclusion in the review and chose the most significant and recent ones and then made a global synthesis of the information and data of articles. Publications up to August 2025 were included. The reference lists of selected articles were manually inspected for other relevant articles. Additionally, we used data from the Pneumotox website ( https://www.pneumotox.com/drug/index/ ), a free online resource containing information on drug-induced pulmonary injuries reported to date [ 17 ].

Ethical Approval

This narrative review is based on previously published studies and does not include any new studies with human participants or animals performed by the authors. The manuscript includes deidentified radiological images from the authors’ clinical practice. In accordance with the policies of the Hospital Clínic de Barcelona, this activity does not constitute human subjects research and institutional review board/ethics committee approval was not required. Written informed consent for publication of the images was obtained from all patients.

Diagnostic Approach to DI-ILD

The diagnosis of DI-ILD is a process of exclusion, with no standardized criteria. Briefly, the diagnostic evaluation requires establishing a temporal relationship between drug exposure and symptom onset, and it is important to exclude infection and autoimmune disease with different blood test batteries, pulmonary function tests, diagnostic imaging including a high-resolution computed tomography (HRCT), and sometimes a bronchoalveolar lavage (BAL). BAL is mainly useful to rule out infection or malignancy, showing findings such as lymphocytosis, foamy macrophages, or eosinophilia depending on the radiologic patterns. In some cases, a biopsy could be necessary if uncertainty persists (Table 1 ) [ 1 , 18 ]. DI-ILD severity is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), which guides clinical decisions ranging from observation and dose adjustment to permanent drug discontinuation and systemic corticosteroid therapy (Table 2 ). Table 1 Diagnostic workup for drug-induced interstitial lung disease [ 1 , 2 , 12 ] Test/procedure Purpose Comments High-resolution CT scan Identify radiographic patterns and assess extent of lung involvement Higher resolution for subtle interstitial changes Pulse oximetry Monitor oxygen saturation and respiratory function Key for continuous O 2 monitoring Complete blood count Evaluate for inflammation/infection indicators (leukocytosis, eosinophilia) Assesses overall immune-related events Blood chemistry panel Assess organ function and inflammation markers (liver, renal, LDH, CRP) ALT, AST, creatinine, electrolytes, CRP, LDH Infectious workup Rule out infectious etiologies with viral, bacterial, and fungal panels Blood cultures, sputum cultures, respiratory panel Bronchoscopy + BAL Obtain cytology and microbiology samples from airways (Grade ≥ 2) Differentiates drug-related vs infectious causes Pulmonary function test (PFT) Evaluate lung volumes, airflow (spirometry), and DLCO Serial testing to monitor progression Tissue biopsy Confirm diagnosis in unclear cases Usually reserved for severe/unclear cases LDH lactate dehydrogenase, CRP C-reactive protein, ALT alanine aminotransferase, AST aspartate aminotransferase, BAL bronchoalveolar lavage, PFT pulmonary function test, DLCO diffusing capacity of the lung for carbon monoxide Table 2 Grading of drug-induced interstitial lung disease (DI-ILD) Grade 1 (mild) Asymptomatic, radiographic findings only Grade 2 (moderate) Symptomatic, not interfering with activities of daily living Grade 3 (severe) Symptomatic, interfering with activities of daily living or oxygen indicated Grade 4 (life-threatening or disabling) Life-threatening, or ventilator support required Grade 5 (fatal) Death Adapted from the National Cancer Institute Common Terminology Criteria for Adverse Events [ 19 ]

Recently, an up-to-date Classification of Interstitial Pneumonias was published by the European Respiratory Society/American Thoracic Society (ERS/ATS) [ 18 ], in which it is stated that drug toxicity is a secondary cause of multiple morphologic interstitial pneumonia patterns. Associated Interstitial patterns include usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), bronchiolocentric interstitial pneumonia (BIP), diffuse alveolar damage (DAD), and pleuroparenchymal fibroelastosis (PPFE). Alveolar patterns include organizing pneumonia (OP), alveolar macrophage pneumonia (AMP), rare acute fibrinous and organizing pneumonia (AFOP), and eosinophilic pneumonias. It is important to note that the presence of a mixed pattern (e.g., NSIP + OP) often suggests drug toxicity. Table 3 suggests the association of patterns, HRCT features, and drugs involved. Table 3 Morphologic patterns, radiologic features, and associated drugs [ 1 , 18 ] Morphologic pattern Radiologic features Common drugs Usual interstitial pneumonia Subpleural, basal reticulation; honeycombing ± traction bronchiectasis; minimal ground glass Bleomycin, cyclophosphamide, TNF-α inhibitors Nonspecific interstitial pneumonia Bilateral ground glass with fine reticulation; traction bronchiectasis; lower lobe predominance; subpleural sparing Methotrexate, nitrofurantoin, leflunomide, azathioprine, ICIs Bronchiolocentric interstitial pneumonia Centrilobular nodules, mosaic attenuation, air trapping; peribronchovascular fibrosis in chronic cases Methotrexate, amiodarone, TNF-α inhibitors, biologics (rituximab, abatacept) Diffuse alveolar damage Bilateral ground glass, consolidation, crazy paving; later reticulation and traction bronchiectasis Bleomycin, ICIs, mTOR inhibitors (everolimus, sirolimus) Pleuroparenchymal fibroelastosis Biapical pleural thickening, dense subpleural fibrosis, upper lobe volume loss Cyclophosphamide, post-transplant regimens Organizing pneumonia Patchy consolidation (peripheral or peribronchovascular), ground glass, reversed halo sign Amiodarone, ICIs, statins, rituximab, mTOR inhibitors Alveolar macrophage pneumonia Diffuse or patchy ground glass, often peripheral; fine reticulation; could have cysts or emphysema Amiodarone, nitrofurantoin, mTOR inhibitors Acute fibrinous and organizing pneumonia Patchy or mass-like consolidations, ground glass; perilobular pattern Chemotherapy, ICIs, sirolimus Eosinophilic pneumonia Acute: diffuse ground glass with or without septal thickening; chronic: photographic negative of edema because of peripheral consolidation Nitrofurantoin, minocycline, nonsteroidal antiinflammatory drugs, amiodarone, antibiotics ICIs immune checkpoint inhibitors

Immune Checkpoint Inhibitors

In recent years, immune checkpoint inhibitors (ICIs) have become a key component of cancer therapy with an expanding range of approved treatments across a wide range of malignancies [ 5 , 20 – 22 ]. Their use has particularly increased as first-line options for both early and advanced stages of non-small cell lung cancer (NSCLC), demonstrating improved overall survival [ 23 – 26 ]. However, their rising prevalence has also highlighted an association with lung toxicities appearing as sarcoid-like granulomatosis, pleural effusion, exacerbation of obstructive lung disease, and most notably, checkpoint inhibitors pneumonitis (CIP) [ 27 ].

CIP is a serious immune-related adverse event (irAE) associated with ICI therapy, particularly anti-PD-1/PD-L1 treatments. It is the most common cause of death among the ICI-related adverse effects [ 28 ].

Initially, CIP incidence was thought to be low, with clinical trials reporting rates under 6%. However, several retrospective studies have suggested that the real-world incidence of CIP may be significantly higher than that reported in clinical trials. Risk factors include the type of agent (PD-1/PD-L1 inhibitors more than CTLA-4 inhibitors), combination therapies, radiotherapy, and tumor type, with patients with NSCLC being at higher risk [ 14 ].

Checkpoint inhibitors pneumonitis typically presents with dyspnea, cough, and hypoxemia. Diagnosis relies on clinical evaluation and imaging, particularly when respiratory symptoms appear within the expected timeframe after treatment initiation (days to weeks, with a median onset of 2–3 months), although no specific radiological features define the condition [ 5 , 14 , 27 , 28 ]. The basic imaging signs of CIP include ground-glass opacity (GGO), consolidation, interlobular septal thickening, distraction branch expansion, nodules, and reticular shadow [ 15 , 29 ] (Fig. 1 ). Fig. 1 A A 75-year-old woman with diagnosis of lung adenocarcinoma developed new-onset consolidative areas, ground-glass opacities, and reticulations on HRCT scan imaging following treatment with pembrolizumab. B An 81-year-old man with lung adenocarcinoma exhibited ground-glass opacities, pulmonary edema, and pleural effusion on imaging after receiving pembrolizumab therapy

Differential diagnosis is critical to exclude infections, tumor progression, or alveolar hemorrhage. BAL frequently reveals lymphocytosis and may serve as a valuable adjunct to differentiate checkpoint-inhibitor-related pneumonitis (CIP) from infectious etiologies. The use of serologic markers has been explored for CIP diagnosis and prediction, requiring clarity on the context of their application:

On the one hand, elevated interleukin 6 (IL-6), IL-10, lactate dehydrogenase (LDH), and reduced albumin (ALB) and absolute lymphocyte count (ALC) are associated with CIP in patients with lung cancer. These parameters represent clinically accessible peripheral blood biomarkers, validated in retrospective, observational studies. Their measurement can be performed when CIP is clinically suspected. Furthermore, high IL-6 and low ALB levels at onset are significantly correlated with severe CIP and poor prognosis. On the other hand, elevated levels of anti-CD74 autoantibodies have been found to be a potential predictor of CIP development. However, the determination of these autoantibodies is not included in routine clinical tests and requires special equipment, placing them strictly within a research context, pending further validation in prospective studies [ 30 – 32 ].

Similarly, a decrease in eosinophils has been closely correlated with CIP, especially in high-grades cases. The ratio of eosinophil percentage at the onset of CIP compared with its baseline level serves as a key marker for differentiating it from bacterial pneumonia and cancer progression. These findings emphasize the potential of serologic markers in improving early diagnosis and treatment decisions, warranting further research [ 33 , 34 ].

Treatment involves discontinuation of ICI and initiation of systemic corticosteroids for patients with moderate-to-severe CIP. Approximately 70–80% of CIP cases respond to glucocorticoids (GCS), typically requiring treatment for 6–12 weeks, while refractory cases may necessitate additional therapies [ 14 , 15 ]. Some patients who do not respond to GCS may require additional therapies. Intravenous immunoglobulin (IVIG) is particularly preferred in patients with suspected or concurrent infection [ 14 ]. Interleukin 6 receptor inhibitors, such as tocilizumab, have also shown promise; studies report that more than 80% of grade 3–4 irAEs were successfully controlled by combination therapy with GCS and tocilizumab [ 35 ]. Some practice guidelines suggest the use of antitumor necrosis factor antibody (TNF-alpha), such as infliximab, and immunosuppressors such mycophenolate mofetil and cyclophosphamide; however, more studies are needed to clarify their role in the management of (Fig. 2 ) [ 15 ]. Fig. 2 Management algorithm for immune checkpoint inhibitor (ICI)-related pneumonitis. This flowchart outlines the diagnostic and therapeutic approach to patients receiving ICI therapy who present with respiratory symptoms such as cough, dyspnea, or hypoxemia. Following an initial assessment, pneumonitis is classified into grades on the basis of symptom severity. Management depends on severity and may include holding or discontinuing ICI therapy, initiating corticosteroids, hospital admission, and bronchoscopy in severe cases [ 14 , 15 ]

Chimeric Antigen Receptor T-Cell Therapy

Chimeric antigen receptor T-cell (CAR-T) therapy uses genetically modified T cells to recognize tumor-specific antigens and trigger a cytotoxic immune response [ 36 , 37 ]. This innovative treatment has revolutionized cancer care and is expanding to lymphomas and multiple myeloma, but its broader use is limited by the challenge of managing severe adverse effects [ 6 , 38 – 42 ].

Pulmonary complications have been primarily associated with cytokine release syndrome (CRS), which is the most common adverse effect, with an incidence ranging between 60% and 90% [ 6 , 43 , 44 ]. These complications are more frequent in patients with higher-grade CRS, with the most common being hypoxia, pleural effusion, pulmonary embolism, and pulmonary edema [ 45 , 46 ]. Inflammatory toxicities in CAR-T therapy are driven by elevated cytokines such as Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), IL-6, IL-1β, and C-reactive protein (CRP). Although rare, there have been reported cases of CAR-T on-target off-tumor lung toxicity when normal tissues expressing the target antigen are attacked, triggering severe pulmonary injury, cytokine release, and potentially fatal multiorgan failure [ 47 ]. Current treatment strategies focus on managing these effects by reducing inflammation with GCS or cytokine blockade with anti-IL6 therapy, though immunosuppression may reduce CAR-T cell efficacy [ 10 ]. In a case series report of three patients who also had diffuse large B-cell lymphoma and received CAR-T therapy, at between 3- and 12-months post-treatment, all patients experienced febrile cough and varying degrees of dyspnea. CT scans revealed diffuse GGO and consolidations, indicative of an organizing pneumonia (OP) pattern. After ruling out infection and lymphoma relapse, CAR-T cell-induced lung toxicity was diagnosed. Two patients improved with corticosteroids, while the third, also diagnosed with polyarthritis, responded well to tocilizumab [ 45 , 47 ]. This case series underscores that pulmonary complications from CAR-T therapy can emerge later, resembling those seen after allogeneic hematopoietic stem cell transplantation, highlighting the need for accurate diagnosis and tailored management of post-CAR-T lung toxicities [ 16 , 48 – 51 ].

Biological Agents

Biological agents have emerged as a transformative treatment for a variety of diseases, as they are a key component in cancer immunotherapy and autoimmune disease treatments [ 1 ]. They are increasingly recognized as a cause of drug-induced interstitial lung disease (DI-ILD), with tumor necrosis factor inhibitors (TNFi) such as etanercept, infliximab, adalimumab, certolizumab, golimumab, and anti-CD20 drugs such as rituximab being those most implicated [ 1 , 7 , 52 , 53 ]. Pulmonary fibrosis associated with TNFi therapy remains a rare condition, typically presenting with dry cough, dyspnea, and radiographic or high-resolution CT (HRCT) infiltrates, with its prevalence still not well defined but increasingly documented in case reports and database analyses [ 11 , 54 ].

Studies suggest that TNF-alpha plays a dual role in interstitial lung disease (ILD) during TNF inhibitor therapy, related to the imbalance between profibrotic and antifibrotic effects of TNF-alpha [ 11 ]. Absence of TNF-alpha led to accelerated pulmonary fibrosis due to inhibition of apoptosis of inflammatory cells; in addition, TNF-alpha promotes IL-1 and interferon (IFN) expression to inhibit fibroblast multiplication [ 11 ]. In contrast, TNF-alpha can promote fibrosis by increasing TGF-β1 expression in the lungs, activating specific fibroblasts pathways and directly stimulating myofibroblasts collagen synthesis [ 11 , 55 ].

Patients with rheumatoid arthritis (RA) are particularly susceptible to TNFi-induced ILD, which typically appears after about 26 weeks of treatment and is associated with a 29% mortality rate, 70% of which occurs within the first 5 weeks. The most common imaging pattern is nonspecific interstitial pneumonia (NSIP), with older women and those with preexisting ILD at highest risk [ 11 , 56 – 58 ].

Factors associated with DI-ILD in patients with RA have been widely discussed due to the possibility of bias, since it is difficult to establish whether ILD is an extraarticular RA manifestation or is directly due to TNFi use [ 11 , 56 ].

A study in patients with RA showed that levels of glycoprotein Krebs von den Lungen-6 (KL-6) were higher in patients with ILD events (339 ± 172 versus 29 ± 372 U/mL, p < 0.05), but not in the absence of an ILD event (388 ± 347 versus 360 ± 226 U/mL, p = 0.528), suggesting that KL-6 could be a surrogate marker of ILD development in patients with RA [ 58 , 59 ].

TNFi are commonly employed to treat refractory sarcoidosis, with infliximab being an established treatment for disease unresponsive to corticosteroids or second-line agents [ 60 ]; nevertheless, one of the drug-induced reactions of this treatment is paradoxically a sarcoid-like pulmonary disease [ 59 , 60 ]. TNFi stimulate granulomatous formation by enhancing Th1 responses and IFN-gamma levels, with impaired clearance of P. acnes potentially sustaining granulomatous inflammation [ 59 ]. Pulmonary sarcoidosis and pulmonary granulomatous nodules have also been reported in patients with Crohn’s disease treated with infliximab, etanercept, and adalimumab [ 59 , 61 , 62 ]. In addition, rare pulmonary complications have also been reported with TNF inhibitors, including uncommon cases of alveolar hemorrhage and thrombotic events [ 54 ].

Pulmonary complications of biological agents are rare but notable, particularly with rituximab, which can induce new-onset ILD (often presenting as organizing pneumonia or acute lung injury) typically within 3 months of treatment initiation, with incidence rates ranging from 0.01% to 0.03% in early studies to 3.7–10% in post-marketing reports [ 1 , 56 , 63 ].

Rituximab-induced ILD is more commonly reported in male patients with lymphoma in their fifth and sixth decades, whereas in patients with RA, responses are heterogeneous, with some developing ILD and others showing clinical improvement. This divergence may be explained by the underlying pathophysiology of RA-ILD, where follicular B cell hyperplasia and plasma cell infiltration of the interstitial space suggest a potential therapeutic benefit from B cell-targeted treatments in selected cases [ 64 ].

Lung HRCT usually shows bilateral involvement with diffuse or patchy consolidations and GGO, fibrosis, alveolar hemorrhage, or pleural effusions [ 63 ]. Rituximab-induced pulmonary toxicity can range from subclinical diffusion lung capacity of carbon monoxide (DLCO) reductions (observed in 22% of asymptomatic patients after an average of 26 weeks of treatment) to overt hypoxemia with a restrictive pattern, particularly in patients with prior smoking, glucocorticoid use, or previous rituximab exposure [ 64 , 65 ]. There are several postulated mechanisms for rituximab induced ILD such as: prolonged B-cell depletion that may disrupt lymphocyte interactions leading to dysregulation of cytotoxic T lymphocytes, leucostasis, release of inflammatory cytokines such as TNF-alfa and cytotoxic substances, and tumor lysis syndrome [ 63 , 64 ]. As with other drug-induced lung toxicities, suspected rituximab-induced pulmonary toxicity should be managed by discontinuing the drug, providing supportive respiratory care, and initiating GCS [ 63 , 64 ].

Other Relevant Drugs

Amiodarone

Amiodarone, an iodinated benzofuran derivative and the most widely used antiarrhythmic for supraventricular and ventricular arrhythmias, is associated with pulmonary toxicity, with an incidence ranging from 1% to 17% [ 1 ]. The main risk factors include advanced age, high cumulative of > 100–150 g or daily doses > 400 mg, prolonged treatment, and preexisting pulmonary disease [ 3 , 8 , 66 ].

Amiodarone-induced pulmonary injury primarily results from direct toxicity due to pulmonary accumulation of the drug and its active metabolite, desethylamiodarone, which generates oxidative stress and induces cellular apoptosis [ 3 , 8 , 9 ]. Additionally, an immune-mediated response involving CD8 + T cells is proposed, contributing to various inflammatory and fibrotic pulmonary patterns [ 3 , 8 , 9 ].

The diagnosis is challenging due to the lack of specific clinical and radiological features, and it is primarily a diagnosis of exclusion. A comprehensive clinical evaluation, assessment of drug exposure, and rigorous exclusion of alternative causes such as infections, heart failure, or malignancy, are essential [ 1 , 2 , 12 ]. Diagnostic approaches typically combine HRCT, which may reveal nonspecific patterns ranging from GGO or consolidations to advanced fibrosis (Fig. 3 ), with pulmonary function tests that often show a restrictive pattern and decreased DLCO. Additional supportive findings may include lymphocytic alveolitis with CD8 + predominance on BAL and elevated serum biomarkers such as KL-6 and surfactant proteins (SP-A, SP-D), although their lack of specificity limits their diagnostic utility [ 1 , 2 , 12 ]. Fig. 3 A Imaging of an 81-year-old man receiving amiodarone demonstrated peribronchovascular ground-glass opacities with consolidations, compatible with organizing pneumonia. B In a 91-year-old man, imaging demonstrated reticular abnormalities and ground-glass opacities, radiologically consistent with a nonspecific interstitial pneumonia–organizing pneumonia overlap pattern

The primary treatment for amiodarone-induced lung toxicity is prompt drug discontinuation, considering alternative antiarrhythmic therapy when indicated, with systemic corticosteroids reserved for moderate-to-severe or rapidly progressive cases, followed by careful tapering [ 1 – 3 , 12 , 13 ].

Nitrofurantoin

Nitrofurantoin, a broad-spectrum antibiotic, is commonly used for urinary tract infection (UTI) treatment and prophylaxis [ 67 – 69 ]. Pulmonary toxicity occurs predominantly in women (85–94%) because of their increased incidence of recurrent urinary tract infections and consequent greater exposure to nitrofurantoin, and is acute in most cases, typically developing within 1–2 weeks of therapy (earlier with reexposure) [ 70 ]. Subacute or chronic forms arise after ≥ 1 month of treatment. Symptoms include fever, dyspnea, cough, and often peripheral eosinophilia [ 68 – 71 ].

Imaging shows diffuse ground-glass opacities (GGO) in acute disease, while chronic toxicity may demonstrate GGO, consolidation, reticulation, or traction bronchiectasis [ 70 , 71 ]. Management involves immediate drug withdrawal, with glucocorticoids reserved for severe or progressive cases; prognosis is usually favorable, though fatal ILD can occur [ 67 , 70 , 72 – 78 ].

Methotrexate

Methotrexate (MTX), the most widely used disease-modifying antirheumatic drug, is central to the treatment of rheumatoid arthritis, autoimmune diseases, and certain malignancies, but its use is limited by unpredictable pulmonary toxicity [ 1 , 79 , 80 ]. The incidence of MTX-induced lung disease is challenging to establish due to nonspecific features, concurrent exposure to other pneumotoxic agents, and preexisting lung involvement related to the underlying disease [ 56 , 81 ]. Hypersensitivity pneumonitis is the most typical manifestation, though organizing pneumonia and pleural effusion are also described [ 82 – 84 ].

Clinical onset can be acute, subacute (most frequent), or chronic. Acute pneumonitis presents with rapidly progressive cough, dyspnea, fever, malaise, and chest pain, while subacute disease shows a more gradual onset; mild eosinophilia occurs in up to half of patients. Imaging typically demonstrates diffuse parenchymal opacities, GGO or consolidations, septal thickening, and ill-defined centrilobular nodules [ 56 , 79 , 85 ].

Diagnosis requires integration of clinical, radiological, BAL, and sometimes histological findings, with exclusion of alternative causes. Withdrawal of MTX generally results in recovery, though corticosteroids may be needed. The prognosis is overall favorable and determined by response to treatment, yet persistent abnormalities and fatal outcomes have been reported [ 56 , 84 , 86 ].

Other Anticancer Drugs

Classical chemotherapy agents are well known to cause lung toxicity, affecting up to 20% of patients [ 86 ]. These drugs include alkylating agents, antimetabolites, and antibiotics such as bleomycin [ 1 ]. Pulmonary injury results primarily from epithelial damage due to the destruction of type II pneumocytes, accompanied by capillaritis and capillary leak that can progress to noncardiogenic pulmonary edema, eventually leading to organizing pneumonia (OP) or pulmonary fibrosis. Clinical presentation is often subtle and nonspecific, with symptoms such as cough, fatigue, dyspnea, fever, and weight loss emerging within 1–6 months of treatment initiation. Diagnosis requires careful clinical evaluation, exclusion of infectious complications, and a high degree of suspicion, such as physical examination, pulmonary function, laboratory markers, and HRCT. The findings are usually nonspecific and difficult to distinguish from toxicities induced by other cancer therapies or infections [ 87 ].

Among chemotherapy agents, bleomycin is the most extensively studied and recognized for its direct pulmonary toxicity. Besides fibrosis, it may induce alveolitis, OP, and hypersensitivity pneumonitis. The risk of bleomycin-induced lung disease increases with genetic predisposition, older age, preexisting lung disease, high cumulative doses (> 550 U), and bolus administration. These findings underscore the complexity of diagnosing and managing chemotherapy-induced lung injury (Fig. 4 ) [ 88 ]. Fig. 4 A High-resolution CT scan imaging in a 35-year-old woman with Hodgkin’s lymphoma demonstrated bilateral ground-glass opacities and patchy consolidations, suggestive of bleomycin-induced lung injury. B A 42-year-old man with a history of germ cell tumor developed ground-glass opacities and patchy consolidations on imaging following completion of bleomycin therapy, findings radiologically compatible with organizing pneumonia secondary to drug-induced pulmonary toxicity

Antibody–drug conjugates (ADCs) constitute a rapidly expanding class of targeted oncologic therapies, with more than 100 currently under clinical investigation and 12 agents approved by the U.S. Food and Drug Administration. Structurally, ADCs are composed of a monoclonal antibody conjugated to a cytotoxic payload via a chemical linker, thereby enabling selective delivery of cytotoxic agents to tumor cells on the basis of differential antigen expression, while aiming to minimize off-target effects. This design seeks to enhance the therapeutic window compared with conventional chemotherapy. However, its clinical applicability remains constrained by dose-limiting toxicities affecting nonmalignant tissues. Importantly, ILD has emerged as clinically significant toxicity, with trastuzumab deruxtecan carrying a black box warning due to the risk of these potentially pulmonary complications (Fig. 5 ). Considerable research is ongoing to elucidate the mechanisms underlying these adverse effects and to develop strategies to improve tolerability and therapeutic efficacy [ 89 ]. Fig. 5 Imaging in a 56-year-old woman with breast cancer showed bilateral ground-glass opacities and small consolidative foci after trastuzumab deruxtecan therapy, consistent with organizing pneumonia

Management and Prognosis

In general, management of DI-ILD generally involves high-dose corticosteroids, usually prednisone (0.5–1 mg/kg/day for mild-to-moderate cases), with tapering individualized on the basis of clinical and radiological severity. Severe or refractory cases may require additional immunosuppressants and supportive care, though optimal dosing and duration remain uncertain [ 12 , 14 , 15 , 62 – 64 ].

Prognosis varies with radiological patterns and underlying disease, being poorest in diffuse alveolar damage (DAD), and more favorable in OP, NSIP, and pneumonitis. While some patients recover after drug withdrawal and corticosteroids, many experience persistent or progressive disease, with mortality ranging from 14% to 51% in oncology and from 0% to 41% in noncancer populations [ 12 , 62 – 64 ]. Ongoing clinical, radiological, and functional follow-up is essential to assess and monitor recovery and detect long-term complications, including pulmonary fibrosis [ 1 , 2 , 12 , 13 ].

Conclusions

Drug-induced ILD (DI-ILD) is a significant but often underrecognized complication of pharmacologic therapies, with incidence expected to rise alongside the expanding use of immunotherapies, biologics, and targeted anticancer agents. Early recognition and timely management are critical due to the heterogeneous clinical and radiological presentations, requiring high clinical suspicion, exclusion of alternative causes, and integration of imaging, laboratory, and sometimes bronchoscopic findings.

However, the diagnostic process remains inherently challenging: no single clinical, radiologic, or laboratory feature is pathognomonic, and the available tools—though essential for narrowing the differential diagnosis—present notable limitations in sensitivity, specificity, and interpretability.

Moreover, the expanding use of immune checkpoint inhibitors and CAR T-cell therapies, while offering substantial therapeutic benefit, has introduced distinctive and sometimes severe patterns of pulmonary toxicity. Their increasing use reinforces the need for careful risk–benefit assessment, structured surveillance, and prompt evaluation of new respiratory symptoms.

Management should be individualized according to lung involvement severity, with prompt drug withdrawal and corticosteroids as the mainstay, and additional immunomodulators or respiratory support for severe cases. As highlighted throughout this review, optimal management of DI-ILD relies on a multidisciplinary approach integrating pulmonology, radiology, oncology, and when necessary, pathology to ensure accurate diagnosis and coordinated treatment. Future efforts in DI-ILD should focus on identifying reliable prognostic and predictive biomarkers, developing standardized diagnostic and monitoring protocols, and conducting prospective studies and registries to improve understanding of disease mechanisms and optimal management.

Acknowledgements

We thank the patients for providing consent for the use of their radiologic images.

Medical Writing/Editorial Assistance

No professional medical writing or editorial assistance was used. The authors used the free versions of Consensus and Google Scholar to support literature searching. These tools were used solely to support reference discovery; they did not generate, summarize, or edit any part of the manuscript or figures.

Author Contributions

Josmar Jesvi Ríos Poveda: conceptualization, methodology, investigation, writing—original draft, and writing—review and editing; Manuela Herrera Tamayo: methodology, investigation, writing—original draft, and writing—review and editing; Juan José Zapata Huizi: methodology, investigation, data curation, writing—original draft, and writing—review and editing; Jacobo Sellares: conceptualization, supervision, project administration, and funding acquisition; Fernanda Hernández-González: validation, formal analysis, resources, data curation, writing—review and editing, and supervision.

Funding

This study was funded by the Instituto de Salud Carlos III (ISCIII) through the projects PI23/00924 and co-funded by the European Union, SEPAR, SOCAP, FUCAP, and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). No funding was received for the publication of this article.

Data Availability

All data generated or analyzed during this study are included in this published article.

Declarations

Conflict of Interest

Fernanda Hernández-González and Jacobo Sellares report honoraria for lectures, educational events, and support for attending meetings from Roche, Boehringer-Ingelheim, Aztra Zeneca, Gebro, and GSK outside the submitted work. J.S. discloses consulting fees from Boehringer-Ingelheim and Alofarma, and grants from Roche and Boehringer-Ingelheim, all outside the submitted work. Jacobo Sellares is an editorial board member of Pulmonary Therapy. Jacobo Sellares was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. The remaining authors, Josmar Jesvi Ríos Poveda, Manuela Herrera Tamayo, and Juan José Zapata Huizi, have nothing to disclose.

Ethical Approval

This narrative review is based on previously published studies and does not include any new studies with human participants or animals performed by the authors. The manuscript includes deidentified radiological images from the authors’ clinical practice. In accordance with the policies of the Hospital Clínic de Barcelona, this activity does not constitute human subjects research and institutional review board/ethics committee approval was not required. Written informed consent for publication of the images was obtained from all patients.

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