Drug-induced Interstitial Lung Disease Research Articles

Diagnosis and Management of Drug-Induced Interstitial Lung Disease in the context of Anti-Cancer Therapy: a Multidisciplinary Viewpoint by Portuguese Experts.

Drug-induced interstitial lung disease (DI-ILD) is a significant complication in patients undergoing treatment with certain anti-cancer therapies, with incidence rates rising, particularly with newer drugs such as trastuzumab-deruxtecan, which may impact their safe and effective use. Although the exact pathophysiological mechanisms remain unknown, and different drugs may induce lung damage through different pathways, the most recognized mechanisms are cytotoxic- and immune-mediated effects. Multidisciplinary teams play a crucial role in the diagnosis, management, and prevention of DI-ILD. Given the wide variability in the onset of DI-ILD, which may occur within the first few days of treatment or months after, patient education and clinician training are essential for early detection and improved outcomes. Moreover, the diagnostic confirmation requires the exclusion of alternative causes through clinical, imaging and bronchoscopy evaluation. Treatment strategies largely depend on the grade of severity of the clinical manifestations of DI-ILD, ranging from interruption or discontinuation of the offending drug to corticosteroid therapy and hospitalization for appropriate monitoring. Nonetheless, further research is needed to better understand the impact of emerging anti-cancer drugs on DI-ILD and to establish standardized management protocols.

The incidence of drug-induced interstitial lung disease caused by epidermal growth factor receptor tyrosine kinase inhibitors or immune checkpoint inhibitors in patients with non-small cell lung cancer in presence and absence of vascular endothelial growth factor inhibitors: a systematic review.

https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=409534, identifier CRD42023409534.

Genetic variants contribute to drug-induced interstitial lung diseases

Genetic variants contribute to drug-induced interstitial lung diseases

Analysis of drug-induced interstitial lung disease caused by herbal medicine using the Japanese Adverse Drug Event Report database

BackgroundDrug-induced interstitial lung disease (DIILD) is a severe adverse event leading to morbidity and mortality. This study evaluated the adverse event indicators of DIILD and time-to-onset profiles following the daily intake of herbal drugs (Scutellariae radix [“ogon” in Japanese], Bupleuri radix [“saiko” in Japanese], and Pinelliae tuber [“hange” in Japanese]) using the Japanese Adverse Drug Event Report database. DIILD was defined in accordance with the Medical Dictionary for Regulatory Activities.MethodsThe Japanese Adverse Drug Event Report database contained 830,079 reports published between April 2004 and April 2023. The association between herbal medicines and DILLD was evaluated using the pharmacovigilance index as the reporting odds ratio (ROR), logistic regression models, propensity score-matching techniques, and Weibull shape parameters.ResultsThe adjusted RORs using multivariate logistic regression models for Scutellariae radix (daily intake), Pinelliae tuber (daily intake), sex (male), age (≥ 60 years), Scutellariae radix (daily intake)*age (≥ 60 years), and Scutellariae radix (daily intake)* Pinelliae tuber (daily intake) were 1.47 (1.36 − 1.59), 1.05 (1.01 − 1.10), 1.45 (1.34 − 1.57), 1.92 (1.74 − 2.11), 3.35 (3.12 − 3.60), and 1.49 (1.46 − 1.53), respectively. DIILD onset profiles were evaluated using the Weibull shape parameter. A logistic plot of daily intake and onset of DIILD was drawn. ROR signals were detected in 32 of 54 herbal medicines, including Scutellariae radix, Bupleuri radix, and Pinelliae tuber. The median duration (days) (interquartile range) to DIILD onset was 36.0 (27.0–63.0) for Saikokaryukotsuboreito, 35.0 (21.0–55.0) for Saireito, and 31.0 (13.5–67.5) for Shosaikoto. The Weibull shape parameter beta (95% confidence interval) values for Saikokaryukotsuboreito, Saireito, and Shosaikoto were 1.36 (1.08–1.67), 1.36 (1.20–1.52), and 1.31 (0.98–1.68), respectively.ConclusionsDIILD demonstrated a dose-dependent to crude drugs. Clinicians should strive for the early detection of DIILD and avoid the inadvertent administration of herbal medicines.

246P Detection of drug-induced interstitial lung disease caused by cancer treatment using electronic nose exhaled breath analysis

246P Detection of drug-induced interstitial lung disease caused by cancer treatment using electronic nose exhaled breath analysis

Anticancer drug-induced interstitial lung disease: a critical appraisal of clinical practice guidelines and consensus statements

ABSTRACT Anticancer drug-induced interstitial lung disease (DIILD) has received increasing clinical attention, and the quality of relevant guidance documents has become critical. Our purpose was to assess the quality of documents for anticancer DIILD and summarize the recommendations. Clinical practice guidelines (CPGs) and consensus statements with recommendations were searched in electronic databases, websites of guideline organizations, and professional societies. The quality of documents was assessed using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) methodology, and the specific recommendations were aggregated and compared. A total of 11 documents were eligible, including 6 CPGs and 5 consensus statements, and the quality of AGREE II assessments differed greatly. The domains of scope and purpose and clarity of presentation received the highest median scores, while the stakeholder involvement domain received the lowest score. Recommendations were inconsistent between documents, particularly regarding the selection of steroid regimens. The methodological quality of the guidance documents needs to be enhanced, especially in the domain of stakeholder involvement. Inconsistencies exist in documents, and further discussions among multidisciplinary experts are needed. Particularly, differences in steroid regimens require attentions, and researches on the risks of adverse events and discovery of precise biomarkers are necessary.

Drug-induced interstitial lung disease

Drug-induced interstitial lung disease

Identification of kynurenine and quinolinic acid as promising serum biomarkers for drug-induced interstitial lung diseases

BackgroundDrug-induced interstitial lung disease (DILD) is a lung injury caused by various types of drugs and is a serious problem in both clinical practice and drug development. Clinical management of the condition would be improved if there were DILD-specific biomarkers available; this study aimed to meet that need.MethodsBiomarker candidates were identified by non-targeted metabolomics focusing on hydrophilic molecules, and further validated by targeted approaches using the serum of acute DILD patients, DILD recovery patients, DILD-tolerant patients, patients with other related lung diseases, and healthy controls.ResultsSerum levels of kynurenine and quinolinic acid (and kynurenine/tryptophan ratio) were elevated significantly and specifically in acute DILD patients. The diagnostic potentials of these biomarkers were superior to those of conventional lung injury biomarkers, Krebs von den Lungen-6 and surfactant protein-D, in discriminating between acute DILD patients and patients with other lung diseases, including idiopathic interstitial pneumonia and lung diseases associated with connective tissue diseases. In addition to identifying and evaluating the biomarkers, our data showed that kynurenine/tryptophan ratios (an indicator of kynurenine pathway activation) were positively correlated with serum C-reactive protein concentrations in patients with DILD, suggesting the potential association between the generation of these biomarkers and inflammation. Our in vitro experiments demonstrated that macrophage differentiation and inflammatory stimulations typified by interferon gamma could activate the kynurenine pathway, resulting in enhanced kynurenine levels in the extracellular space in macrophage-like cell lines or lung endothelial cells. Extracellular quinolinic acid levels were elevated only in macrophage-like cells but not endothelial cells owing to the lower expression levels of metabolic enzymes converting kynurenine to quinolinic acid. These findings provide clues about the molecular mechanisms behind their specific elevation in the serum of acute DILD patients.ConclusionsThe serum concentrations of kynurenine and quinolinic acid as well as kynurenine/tryptophan ratios are promising and specific biomarkers for detecting and monitoring DILD and its recovery, which could facilitate accurate decisions for appropriate clinical management of patients with DILD.

Drug-induced interstitial lung disease: a real-world pharmacovigilance study of the FDA Adverse Event Reporting System from 2004 to 2021.

Drug-induced interstitial lung disease (DILD) is an increasingly common cause of morbidity and mortality. However, due to the lack of specificity, DILD detection remains an unsolved public health challenge. For the first time, we aimed to examine DILD reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to identify demographic characteristics and top drugs associated with DILD at a group level (including age, sex, drug class, and country stratification) and individual drug level. A retrospective analysis of the FAERS database was examined by disproportionality analysis. We reviewed the FAERS database from 2004 to 2021, using search terms 'interstitial lung disease' and sorting cases by generic drug name. The reporting odds ratio, proportional reporting ratio, and Bayesian confidence propagation neural network were calculated as the measure of strength of association. There were 32,821 DILD reports in the FAERS. After excluding reports without age, sex, or country data according to the specific measurement, the median age of patients was 68 (interquartile range: 59), 54.77% were male, and 46.00% of reports came from Japan. The top drug classes related to DILD in the FAERS were antineoplastic, followed by cardiovascular and antirheumatic agents, in varying order in different sexes. Fam-trastuzumab deruxtecan-nxki, ramucirumab, and eribulin were the top three drugs with the highest strength of association. We also found some drugs without DILD in the labels, such as amiodarone, temsirolimus, and ursodiol. There are significant differences in DILD reports in various countries. For example, the United States and France reported more cardiovascular agents, whereas Canada reported more antirheumatic agents. We found the top drugs and drug classes that were associated with DILD in the FAERS, which provides a real-world window for different ages, sexes, and countries to formulate precise pharmacovigilance policies.

Successful Treatment with Ramucirumab Plus Erlotinib following Osimertinib-induced Interstitial Lung Disease: A Case Report.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are key drugs for patients with EGFR mutation-positive non-small-cell lung cancer, and osimertinib is the standard treatment. Although drug-induced interstitial lung disease (ILD) is a remarkable adverse event of EGFR-TKIs, evidence regarding the continuation and re-challenge of EGFR-TKIs after drug-induced severe ILD is lacking. This is the first report of successful switching to ramucirumab plus erlotinib after osimertinib-induced severe ILD in an 81-year-old woman with stage IV lung adenocarcinoma harboring the EGFR L858R mutation in exon 21. These findings suggest that ramucirumab plus erlotinib may be a viable treatment option for osimertinib-induced severe ILD.

Incidence of interstitial lung disease in patients with breast cancer: a nationwide database study in Japan.

Aim: This study estimated the incidence of moderate-to-severe drug-induced interstitial lung disease (ILD) among patients with breast cancer in Japan. Methods: We analyzed a large nationwide database of patients with breast cancer treated with anticancer therapies between 2009 and2022. ILD was identified using diagnostic codes and treatment records. Results: Of the 81,601 patients, 1042 developed ILD requiring corticosteroids, corresponding to an incidence rate of 1.41 per 100 person-years. The incidence varied across years and treatment regimens. Most ILD incidents occurred within the initial 90-day period post-anticancer therapy initiation. Conclusion: Increase in ILD cases and potential risk variations among treatments underlinethe importance of continued monitoring, especially during treatment onset, and ILD management in patients with breast cancer undergoing therapy.

Interstitial lung disease caused by niraparib in ovarian cancer patient: a case report and literature review.

Drug-induced interstitial lung disease (DIILD) is one of the most common and important adverse drug reactions. Still, the details of the clinical presentation of DIILD caused by poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are unknown. A 73-year-old Japanese woman was started on niraparib maintenance therapy after radical surgery and adjuvant chemotherapy for high-grade serous carcinoma originating from the fallopian tube. Forty-seven days after starting niraparib, she presented to the hospital with dyspnea and was diagnosed with DIILD caused by niraparib. The drug was discontinued, and the patient was treated with steroid pulse therapy, and her condition improved. In clinical trials of PARP inhibitors, DIILD was reported in 0.13% of patients with olaparib, but no DIILDs, including pneumonia or pneumonitis, were reported in any patient with niraparib. This is the first report of DIILD caused by niraparib worldwide. In the future, the frequency of DIILD caused by niraparib should be clarified in real-world data.

549P Drug-induced interstitial lung disease in patients with non-small cell lung cancer treated with immunotherapy for postoperative recurrence: Evaluation of CT findings and histopathological findings of the background lung

549P Drug-induced interstitial lung disease in patients with non-small cell lung cancer treated with immunotherapy for postoperative recurrence: Evaluation of CT findings and histopathological findings of the background lung

Drug-Induced Interstitial Lung Disease in a patient treated with a combination of palbociclib and fulvestrant

A 59-year-old patient without a history of pulmonary disease presented with episodes of hemoptysis and acute respiratory failure after being treated for metastatic breast cancer with fulvestrant and palbociclib. The high-resolution chest CT revealed diffuse ground glass opacities and diffuse smooth thickening of the interlobular septa and peribronchovascular interstitium, consistent with drug-induced interstitial lung disease (DIILD). A few days of high-dose steroid treatment increased the patient's PaO2/FiO2 from 75 to 200. Following hospital discharge, the oncologist resumed fulvestrant therapy, with no further adverse events occurring during subsequent follow-up.

Drug-Induced Interstitial Lung Disease in a patient treated with a combination of palbociclib and fulvestrant

A 59-year-old patient without a history of pulmonary disease presented with episodes of hemoptysis and acute respiratory failure after receiving fulvestrant and palbociclib for metastatic breast cancer. The High-Resolution chest CT demonstrated diffuse ground glass opacities, as well as diffuse smooth thickening of the interlobular septa and peribronchovascular interstitium, which are consistent with Drug-Induced Interstitial Lung Disease (DIILD). A few days of high-dose steroid therapy improved the patient's gas exchange from PaO2/FiO2 of 75 to 200. After hospital discharge, the oncologist resumed fulvestrant therapy, with no additional adverse events occurring during the subsequent follow-up.

Drug-induced interstitial lung disease after chemoimmunotherapy for extensive-stage small cell lung cancer

ObjectivesThe combination of chemotherapy and immune checkpoint inhibitors (chemo-ICI) has become the new standard of treatment for extensive-stage small cell lung cancer (ES-SCLC). Recently, slight changes in interstitial shadows, defined as interstitial lung abnormalities (ILA), have been identified. In patients with ES-SCLC who received chemo-ICI, there are limited data on the incidence of drug-induced interstitial lung disease (D-ILD) in daily practice and the association between the development of D-ILD and ILA in the baseline computed tomography (CT). Materials and methodsA multicenter, retrospective study was conducted to investigate the incidence of D-ILD, the risk factors for developing D-ILD, progression-free survival (PFS), and overall survival (OS) in patients with ES-SCLC who received chemo-ICI between August 2019 and November 2021. ResultsThis study enrolled 70 patients (median age, 71 years; including 58 men) from nine institutions in Japan. There were 62 patients (89%) treated with carboplatin/etoposide/atezolizumab and 8 patients treated with carboplatin or cisplatin/etoposide/durvalumab. Twenty-nine patients (41.4%) were found to have ILA at baseline CT. Eleven patients (15.7%) developed D-ILD. The proportion of patients with ILA was significantly higher in the group who developed D-ILD than in the group who did not (9/11 (81.8%) vs. 20/59 (33.9%), respectively, P = 0.0057). In addition, the frequency of ground glass attenuation (GGA) and reticulation was higher in patients who developed D-ILD. There was no significant difference in PFS and OS between patients who developed D-ILD and those who did not (median PFS, 8.0 (95% confidence interval (CI), 5.5–9.5) months vs. 5.0 (95% CI, 4.5–5.6) months, respectively, P = 0.11 and median OS, not reached (NR) (95% CI, 8.7–NR) vs. 18.2 (95% CI, 13.2–NR) months, respectively, P = 0.20). ConclusionThe incidence of D-ILD in patients with ES-SCLC who received chemo-ICI in clinical practice was higher than that in clinical trials. Patients with pre-existing ILA were more likely to develop D-ILD.

Analysis of 12 cases of antineoplastic agents-induced interstitial lung disease.

Objective: To summarize the situation of antineoplastic agents-induced interstitial lung diseases (ILD), provide reference for strengthening clinical management of druginduced interstitial lung diseases (DILD). Methods: We retrospectively investigated the medical records of 12 patients with antineoplastic agents-induced ILD in a hospital between January and December 2020. Data collected included patients' characteristic (gender, age, ECOG PS score, smoking history, primary tumor, concurrent diseases or complications.) and treatment conditions (DILD-causing drugs, clinical symptoms, chest CT, DILD treatment drugs, onset cycle, onset time, severity of DILD, DILD course and prognosis.). Results: The median age of 12 DILD cases was 68%, 66.67% of the patients were male, lung cancer accounted for 58.33% (7/12). DILD was induced by cytotoxicity drugs, targeted drugs and immune checkpoint inhibitors (ICIs), of which ICIs accounted for 66.67% (8/12). Scattered patchy, cord-like, grid-like or flocculent shadows were observed on chest CT, mainly under the pleura of lungs. Once DILD occurs, the suspected antineoplastic agents were stopped and glucocorticoid was given, among which 83.33% (10/12) patients were treated with antibiotics. Finally, 16.67% (2/12) were cured, 33.33% (4/12) were improved, 16.67% (2/12) were not cured and 33.33% (4/12) were dead. Conclusion: Antineoplastic agents-induced ILD is mostly found in elderly male lung cancer patients with smoking history. The clinical symptoms of DILD are diverse and lack of specificity. ICIs-ILD has the characteristic of high incidence and poor prognosis compared with other antineoplastic agents. Comprehensive evaluation before medication, regular review, early and adequate glucocorticoid shock therapy after onset can improve the prognosis of DILD patients.

Drug-induced interstitial lung disease caused by olaparib: three case reports and review of the Japanese Adverse Drug Event Report database and literature

BackgroundOlaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has demonstrated effectiveness in treating ovarian, breast, and other cancers, particularly those with specific molecular subtypes including, but not limited to, BRCA1/2 mutations. Consequently, its utilization is expected to increase in the future. For this reason, it is important to acknowledge the potential for adverse events associated with olaparib, including the relatively rare but significant risk of drug-induced interstitial lung disease (DIILD). Since DIILD can lead to fatal outcomes, its early detection is crucial. The dissemination of knowledge regarding DIILD can be facilitated through case reports; however, specific reports of DIILD caused by olaparib have only been published in Japanese. To the best of our knowledge, this is the first report in English of our experience with three cases of DIILD caused by olaparib.Case presentationCases 1, 2, and 3 involved Japanese women with ovarian cancer who had been receiving olaparib at a dose of 600 mg/day. Case 1, a 72-year-old woman who had been on olaparib for 4 months, and case 2, a 51-year-old woman who had been on olaparib for 8 months, reported fever and general malaise. Chest computed tomography (CT) revealed pale ground glass opacity (GGO) similar to hypersensitivity pneumonitis. The severity grade was 2 in both cases. Case 3, a 78-year-old woman who had been on olaparib for 3 weeks, presented with cough and reported dyspnea on exertion. Chest CT revealed non-specific interstitial pneumonia and organizing pneumonia-like shadows. The severity grade was 4. Olaparib was discontinued in all cases. Case 1 received 0.6 mg/kg of prednisolone due to mild hypoxia, while prednisolone was not administered in case 2 due to the absence of hypoxia. Case 3 received steroid pulse therapy due to severe hypoxia. Olaparib administration was not resumed in any patient.ConclusionDIILD caused by olaparib in Japan, including the present three cases, commonly presents with GGO, similar to hypersensitivity pneumonitis on chest CT. The prognosis for the majority of patients is favorable; however, there have been instances of severe cases. Early recognition of drug-induced lung injury and further accumulation of cases is important.

Diagnostic value of sheath-guided frozen biopsy technique for drug-induced interstitial lung disease

Purpose: To investigate the diagnostic value of sheath-guided frozen biopsy technique for interstitial lung disease (ILD).
 Methods: In this retrospective study, 48 ILD patients of exclusive etiology admitted to Xi’an International Medical Center Hospital between October 1, 2021, and May 31, 2022, were randomly assigned to receive either endobronchial ultrasound with a guide sheath combined with transbronchial cryobiopsy TBCB (TBCB group), or endobronchial ultrasound with a guide sheath combined with transbronchial lung biopsy TBLB (TBLB group).
 Results: The two groups were well-balanced in terms of baseline profiles (p = 0.94). The mean size of tissue blocks was 24.45 ± 2.83 mm2 in TBCB group and 3.58 ± 0.89 mm2 in TBLB group. TBCB and TBLB groups presented with a diagnostic accuracy of 64.00 % (16/25) and 69.57 % (16/23), respectively, while chi-square test demonstrated no significant difference between the two groups (p = 0.683). Chi-square test showed that there was significant difference in the incidence of complications (p = 0.036) as well as the incidence of bleeding (p = 0 .045), but no significant difference in the incidence of pneumothorax between the two groups (p = 0.605).
 Conclusion: There are no significant differences in diagnostic sensitivity, specificity, and accuracy between endobronchial ultrasound sheath-guided frozen lung tissue biopsy and conventional clamped lung tissue biopsy for ILD, but the former has a lower incidence of complication than the latter. It is necessary to conduct a larger clinical study to further validate these findings.

Anticancer–drug-induced interstitial lung disease (DIILD): With great power comes great responsibility.

e18699 Background: DIILD accounts for 3-5% of all ILD cases, with Anticancer agents accounting for 23-51% of all cases, and Case-Fatality Rates of 51.3%. Guidelines for anticancer therapy-related DIILD are lacking. DIILD was not often identified as an adverse event until late in drug development or after launch. Methods: Publications till Feb 2023 were reviewed for incidence, time to onset, prevention and early identification of anticancer DIILD. Results: Highest reportedincidence of DIILD was associated with targeted therapies [mTOR Inhibitors (9.5- 58%), Anti-EGFR (0.9 - 5.9%), MEK inhibitors (2.4%), CDK 4/6 inhibitors (1.6%), PARP inhibitors (0.79%)]; Chemotherapy [Bleomycin (6.8-21%), Gemcitabine(1.1-3.9%), Irinotecan (0.74%)]; ADCs (11.4%); CTLA4 inhibitors (5.44%); and Check-point inhibitors [(CPIs: 1.1-3.6%), PD-1 inhibitors (3.6%), PD-L1 inhibitors (1.3%)]. The rates of DIILD were higher in combinations compared to single-agents. Higher Mortality rates were associated with Anti-EGFR (18-51.3%), Irinotecan (24%), Bleomycin (8.1-23%), Gemcitabine (0-22%), mTOR Inhibitors (0-20%), Check-point inhibitors (all CPIs: 8-9.4%). The time of onset was as early as a week for CPIs (42% occurred within first two months), 28 days for EGFR:TKIs, 60-172 days for MEK Inhibitors, and 14-638 days for ADCs. Risk-mitigation strategies for DIILD: Identification of high-risk patients – (multiple prior lines of therapy, combination therapy, lung comorbidities, poor respiratory reserve, smokers). Early radiological diagnosis accompanied by Monitoringfor early signs of ILD with wearable technology. Conclusions: Research in Genomics and biomarkers to identify patients at risk, development of Artificial Intelligence (AI) algorithms for PFT interpretation, early radiological detection and audiometry analysis are ongoing and urgently needed.