Induced Interstitial Lung Disease Research Articles

Iguratimod reduces B-cell secretion of immunoglobulin to play a protective role in interstitial lung disease

ObjectiveOur study aimed to investigate the effect of Iguratimod (IGU) on bleomycin (BLM)-induced interstitial lung disease (ILD). MethodsThe pulmonary fibrosis model group mice were developed by intratracheal injection of BLM. Mice were divided into two groups at random: (1) Control group (BLM group) – endotracheal BLM (BLM, 3.5 mg/kg, Kayaku, Japan) plus an intraperitoneal injection of normal saline, and (2) BLM + IGU group – intratracheal BLM (same as the control group) + IGU intraperitoneal injection (50 mg/kg/d). The alveolar lavage fluid, histopathology/immunohistochemistry, imaging, and other tests were performed on days 7, 14, 21, and 28 after injection. ResultsLung function, including Compliance (Crs),Tissue damping (G), Static compliance (Cst), Inspiratory capacity (IC), Elastance (Ers), Tissue elastance (H) and Respiratory system resistance (Rrs) in mice, was improved by IGU. IGU reduced BLM-induced changes in pulmonary fibrosis and pulmonary inflammation, as shown in histological examination.Collagen production and inflammatory damage in the lungs caused by BLM were also reduced by IGU. IGU reduced the expression of immunoglobulin IgG and type I collagen in BLM-induced pulmonary fibrosis mice by inhibiting the production of B cells and immunoglobulin, and also delayed the deterioration of imaging changes. ConclusionIGU inhibits immunoglobulin secretion by B cells to relieve pulmonary inflammation and fibrosis. IGU also plays a protective role in the lung in ILD.

Rituximab Induced Interstitial Lung Disease Diagnosis, Treatment Outcome, and Risk’s Factor, a Place for Transbronchial Pulmonary Cryobiopsy

Rituximab (RTX) is a mouse/human chimeric anti-CD20 IgG1 monoclonal antibody, approved in late 1998 by the FDA. Effectively used as a single agent or combined with a chemotherapy regimen to treat lymphoma, RTX is a significant step forward in the arsenal treatment of idiopathic thrombocytopenic purpura, systemic lupus erythematous, rheumatoid arthritis, and autoimmune hemolytic anemia. Side effects of RTX are commonly seen during the first infusion in up to 50% of patients and include fever, chills, and rigors. These side effects are generally transient and related to the tumor burden, probably due to a greater degree of complement activation and proinflammatory cytokine release. Severe lung toxicity like cryptogenic organizing pneumonia, pneumonitis, and interstitial lung diseases are infrequent, with most of the knowledge coming from case reports.

Pre-existing interstitial lung abnormalities are risk factors for immune checkpoint inhibitor-induced interstitial lung disease in non-NSCLC cancers.

e15171 Background: Immune check point inhibitor (ICI) induced interstitial lung disease (ICI-ILD) is a clinically serious and life-threatening toxicity. Pre-existing ILD has been reported to be a risk factor for ICI-ILD in patients with non-small cell lung cancer (NSCLC). In addition, we have previously reported that interstitial lung abnormality (ILA) is also a risk factor for the ICI-ILD. Therefore, we investigated whether any patient characteristics, including ILA, were risk factors for ICI-ILD in patients with non-NSCLC cancers. Methods: Head and neck cancer, malignant melanoma, oral cavity cancer, renal cell carcinoma or gastric cancer patients who received anti PD-1 antibody (Nivolumab or Pembrolizumab) at Hiroshima University Hospital from December 2015 to May 2019 were enrolled. Information on patient characteristics before anti-PD-1 antibody administration, including chest CT findings and laboratory data, were obtained. Results: Two hundred patients were enrolled, and 20 (10%) developed ICI-ILD. Grade1 was observed in 15 patients, grade2 in 3, and grade3 and 5 in 1. There was no significant difference in the background factors between patients with and without ICI-ILD. On the other hand, the proportion of patients with ILA was significantly higher in the patients with ICI-ILD than those without (P < 0.01). Furthermore, univariate logistic regression analysis revealed ILA was the risk factor for ICI-ILD (p < 0.01), and multivariate logistic regression analysis showed that GGA or reticulation in ILA was an independent risk factor for ICI-ILD (p = 0.016, 0.011). Conclusions: Pre-existing ILA is a risk factor for ICI-ILD, and GGA or reticulation in ILA is an independent risk factor for ICI-ILD in patients with non-NSCLC cancers. Therefore, we should pay more attention to the development of ICI-ILD in patients with ILA, especially GGA or reticulation.

Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low–Expressing Advanced Breast Cancer: Results From a Phase Ib Study

PURPOSETrastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload. A dose escalation and expansion phase I study evaluated the safety and activity of T-DXd in patients with advanced HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization−) breast cancer (ClinicalTrials.gov identifier: NCT02564900) are reported.PATIENTS AND METHODSEligible patients had advanced/metastatic HER2-low–expressing breast cancer refractory to standard therapies. The RDE of 5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor activity and safety were assessed.RESULTSBetween August 2016 and August 2018, 54 patients were enrolled and received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated (median, 7.5 prior therapies). The confirmed objective response rate by independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered fatal events associated with T-DXd–induced interstitial lung disease (ILD)/pneumonitis as determined by an independent adjudication committee.CONCLUSIONThe novel HER2-targeted ADC, T-DXd, demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were GI or hematologic in nature. ILD is an important identified risk and should be monitored closely and proactively managed.

Whole genome sequencing to identify predictive markers for the risk of drug-induced interstitial lung disease.

Drug-induced interstitial lung disease (DIILD) is a serious side effect of chemotherapy in cancer patients with an extremely high mortality rate. In this study, to identify genetic variants with greater risk of DIILD, we carried out whole genome sequencing (WGS) of germline DNA samples from 26 patients who developed DIILD, and conducted a case-control association study between these 26 cases and general Japanese population controls registered in the integrative Japanese Genome Variation Database (iJGVD) as a screening study. The associations of 42 single nucleotide variants (SNVs) showing P < 0.0001 were further validated using an independent cohort of 18 DIILD cases as a replication study. A further combined analysis of the screening and replication studies showed a possible association of two SNVs, rs35198919 in intron 1 of the chromosome 22 open reading frame 34 (C22orf34) and rs12625311 in intron 1 of the teashirt zinc finger homeobox 2 (TSHZ2), with DIILD (Pcombined = 1.87 × 10−5 and 5.16 × 10−5, respectively). Furthermore, in a subgroup analysis of epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI)-induced interstitial lung disease (ILD), we observed seven candidate SNVs that were possibly associated with ILD (P < 0.00001). This is the first study to identify genetic markers for the risk of DIILD using WGS. Collectively, our novel findings indicate that these SNVs may be applicable for predicting the risk of DIILD in patients receiving chemotherapy.

Pre-existing interstitial lung abnormalities are risk factors for immune checkpoint inhibitor-induced interstitial lung disease in non-small cell lung cancer.

Approximately 5% of non-small cell lung cancer (NSCLC) patients develop immune checkpoint inhibitor (ICI)-induced interstitial lung disease (ICI-ILD), 10% of whom die. However, there are no established risk factors for its occurrence. Interstitial lung abnormalities (ILA) are areas of increased lung density on lung computed tomography (CT) in individuals with no known ILD. This study retrospectively investigated whether any patient characteristics, including ILA, were risk factors for ICI-ILD in patients with NSCLC. NSCLC patients who received anti-programmed death (PD)-1 antibody treatment at our hospital between September 2015 and December 2017 were enrolled. Information on patient characteristics before anti-PD-1 antibody administration, including chest CT findings and laboratory data, were obtained. Among 83 enrolled patients, the incidence of ICI-ILD was 16.9% (14/83). All ICI-ILD cases developed by the third line of treatment. The incidence of ICI-ILD was significantly higher in patients with pre-existing ILA than that in those without (p = 0.007). Furthermore, patients with ground glass attenuation (GGA) in ILA had a higher incidence of ICI-ILD than that in those without (p < 0.001). In univariate logistic analysis, ILA were significant risk factors for ICI-ILD (p = 0.005). Multivariate logistic analysis revealed that only GGA in ILA was a significant risk factor for ICI-ILD (p < 0.001). Pre-existing ILA are risk factors for ICI-ILD and GGA in ILA is an independent risk factor for ICI-ILD. Therefore, we should be more aware of the development of ICI-ILD in patients with ILA, especially those with GGA.

Le nivolumab peut-il être utilisé dans les fibroses pulmonaires idiopathiques ?

Anti-PD1 immunotherapies have become an essential treatment for bronchial cancer. According to published studies, PD1 and PD-L1 inhibitors have a better toxicity profile than chemotherapy. Nevertheless, some immune related toxicities can be potentially severe, such as induced interstitial lung disease (ILD). Currently, ILD patients are excluded from clinical trials using immunotherapy in lung cancer. IPF is the most frequent and severe form of ILD. Lung cancer represents a major complication of this disease and to date few data exist on the safety of immunotherapy in this context. We report 3 cases of IPF with lung cancer treated by nivolumab. All had a clinically mild to moderate IPF. The patients had received at least one line of chemotherapy before nivolumab and had progressive, metastatic lung cancer. Two patients experienced rapid cancer progression without immune toxicities. The third had a partial response but developed grade III immune colitis that led to discontinuation of the treatment. None developed lung toxicity or worsening of IPF on CT during follow-up, and death was always related to progression of the cancer. In our series of three patients with IPF, nivolumab was well tolerated with regard to their pulmonary condition. As inflammation and autoimmunity are probably marginal mechanisms in the pathogenesis of IPF, we do not believe that the presence of IPF should definitely disqualify potential candidates for treatment with nivolumab. Decisions should be taken, case-by-case, in selected patients without severe IPF and with no evidence of autoimmunity. In view of the epidemiology of lung cancer in IPF and the critical role of immunotherapy in the management of lung cancer, studies of prospective cohorts are urgently needed in this population.

Diagnosis and treatment of imatinib-induced interstitial lung disease and literatures review

Objective To investigate the diagnosis and treatment of imatinib induced interstitial lung disease (ILD), providing clinical reference for early diagnosis, treatment and alternative medicine selection, and improving the prognosis of patients. Methods On 3 June 2016, a case of imatinib induced ILD who was admitted to Department of Hematology, West China Hospital, Sichuan University was included in this study. The patient was diagnosed with chronic myeloid leukemia (CML) and started therapy of imatinib on 15 December 2015. When the patient was admitted, bone marrow morphology, cytogenetic, medical imageological and pathological examination were conducted and diagnosis was made base on those test results and patient′s medical history and medication history. Then imatinib discontinued on 6 July 2016 and started 30 mg/d prednisone therapy on 29 July 2016 with 6-month duration. Switched to nilotinib 300 mg twice daily on 20 December 2016. Follow-up (up to 5 September 2017) was performed to monitor the efficacy. Clinical features, diagnosis and treatment of this patient were analyzed retrospectively, and related literatures were reviewed. Results ① When the patient was admitted, results of bone marrow morphology, genetic examinations were all within normal range. Chest high resolution (HR) CT scan revealed lung marking increased, disordered, and blurred; and there were diffusely distributed multiple ground glass opacity, small patchy, and fibrous stripes. Results of lung puncture biopsy suggested chronic inflammation changed with fibrous tissue hyperplasia. ② Patient was diagnosed with imatinib-induced ILD. ③ Patient suspended imatinib were treated with prednisone, and the symptoms of cough and anhelation were significantly improved. After 6 weeks, the chest HRCT indicated a significant decrease in the bilateral lung lesions. After 6 months of nilotinib application, no significant abnormalities were observed in bone marrow morphology, genetic examination and HRCT results. And complete cytogenetic remission (CCyR) and deep molecular remission were achieved. The patient was well tolerated during follow-up. Conclusions The appearance of dyspnea after imatinib treatment should be considered the possibility of imatinib-induced ILD. Early diagnosis, discontinuation of imatinib and application of glucocorticoid can significantly improve prognosis of imatinib-induced ICD. In this case report, the patient with imatinib-induced ILD who was switched to nilotinib was well tolerated and CML treatment response was good, which could provide a reference for the clinical medication of CML. Key words: Imatinib; Interstitial pneumonia; Glucocorticoid; Nilotinib; Diagnosis

Successful treatment of non-small-cell lung cancer with afatinib and a glucocorticoid following gefitinib- and erlotinib-induced interstitial lung disease: A case report.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)-induced interstitial lung disease (ILD) may be a life-threatening condition that may develop during treatment of lung cancer patients harboring EGFR mutations. We herein present the case of a 41-year-old female patient diagnosed with lung adenocarcinoma with an EGFR mutation (exon 19 deletion). The patient was treated with gefitinib followed by erlotinib and developed ILD induced by both EGFR-TKIs; furthermore, the patient acquired resistance to EGFR-TKI treatment. A repeat biopsy revealed a T790M mutation, which is associated with resistance to first-generation EGFR-TKIs, along with an exon 19 deletion identified by cytology of the pleural fluid. Treatment with afatinib and prednisolone resulted in tumor shrinkage, without worsening of the ILD. The present case demonstrated that combination treatment with afatinib and a glucocorticoid may be effective for the treatment of lung cancer patients who develop EGFR-TKI-induced ILD.

Ibrutinib Induced Interstitial Lung Disease

Ibrutinib Induced Interstitial Lung Disease

Rituximab Induced Interstitial Lung Disease in Patients with Non-Hodgkin’s Lymphoma: A Clinical Study of Six Cases and Review of the Literature

Background. Rituximab-induced lung disease (R-ILD) is a rare entity that should be considered in patients treated with rituximab who present with dyspnea, fever, and cough but no clear evidence of infection. Aim. The aim of this prospective longitudinal study is to describe the clinical presentation, management, and response to rechallenge in patients diagnosed with rituximab induced ILD over a period of one year. Results. Out of sixteen patients with CD20 positive non-Hodgkin’s lymphoma who received rituximab along with standard chemotherapy, six patients developed features suggestive of R-ILD. Four (66.6%) of these patients had diffuse large B cell lymphoma. The median time of presentation of R-ILD was after the 3rd cycle of chemotherapy. Three patients (50%) presented with acute onset of high fever, dyspnea, and dry cough while the remaining three presented with insidious onset of dyspnea and dry cough. An infectious etiology for the respiratory illness was ruled out in all patients with an exhaustive work-up. Four patients (66.6%) responded to corticosteroid treatment and supplemental oxygen. One patient required mechanical ventilation and succumbed to ILD while another required prolonged supplemental oxygen. Two (33.3%) of patients were successfully rechallenged with rituximab under cover of corticosteroids. Conclusions. Rituximab induced lung disease is a rare but potentially fatal pulmonary toxicity which requires a high index of suspicion for early diagnosis and treatment.

Interstitial Lung Disease Induced by Targeted Therapy for Non-Small Cell Lung Cancer: A Review of Diagnosis, Workup, and Management

Targeted therapies are being increasingly used for cancer treatments and had been proven to improve clinical outcomes. Although targeted therapies demonstrate survival benefit in particular patient populations, they may also increase the frequency of treatment-related toxicities and morbidity. The pulmonary toxicities, especially drug induced-interstitial lung disease (ILD), have emerged as critical adverse drug reactions which are potentially fatal.The main managment of targeted therapy-induced ILD includes drug discontinuation and corticosteroid therapy, but no standard guideline for the treatment of targeted therapy-induced ILD was established. Clinical physicians must cautiously weigh the benefits and risks of targeted therapies causing ILD in order to provide optimal treatments and favorable outcomes. Relevant clinical information regarding management of targeted therapy-induced ILD was reviewed in this article.

Interstitial lung diseases after leflunomide use in nephropathy: an analysis of reported cases in Chinese literature

Leflunomide (LEF)-induced interstitial lung disease (ILD) has been reported in patients with rheumatoid arthritis. In China, LEF is used off-label for the treatment of nephropathy. Systemic review of the Chinese literature from 1999 to June 2010 for case reports and case series of LEF-induced ILD in nephropathy patients. We identified seven cases of LEF-induced ILD (three males and four females), with an average age of 45.9 years (range: 9-69 years). Six cases had primary nephrotic syndrome and one had Henoch-Schoenlein purpura. Four cases had diagnoses of renal pathology. Five patients were given loading doses of LEF, followed by a maintenance dose of 10-30 mg/day. The mean duration of LEF use was 62.9 ± 33.0 days (range: 20-120 days). The mean accumulated dose of LEF was 1192.5 mg (range: 830-1800 mg). LEF therapy was considered effective in four patients. Four patients died (57.1%), three of whom had developed fevers. All three male patients died and both of the young patients died. The mean duration of LEF treatment was 83 days for patients who died and 37 days for survivors. LEF-induced ILD in patients with nephropathy usually occurred after ∼2 months of treatment and an accumulated dose of 1192.5 mg. Duration of LEF use, male sex, young age and fever seemed to increase the risk of mortality.

Rituximab Induced Interstitial Lung Disease.

Interstitial lung disease (ILD) secondary to monoclonal antibodies and tyrosine-kinase inhibitors have been reported. However, little is known about rituximab induced ILD. We report two cases of R-ILD.CASE 1: A 63 year-old man with DLBCL presented for cycle 6 of R-CHOP complaining of 10 days of dyspnea and fever. Prior to initiation of therapy, he had a normal lung exam along with computerized tomography (CT) of the chest. After three cycles of R-CHOP, repeat CT scans of the chest revealed a favorable response to treatment and continued disease-free lung fields. He had tachypnea, tachycardia, and a normal lung examination. Pulse oximetry on room air was 76%. A helical CT of the chest demonstrated diffuse bilateral pneumonitis with no evidence of pulmonary embolus. Bronchoscopy with bronchoalveolar lavage and biopsy revealed no infection. Biopsy showed evidence of alveolar damage and interstitial fibrosis. He responded to corticosteroids and was discharged home with supplemental oxygen. Two months later, he did not require supplemental oxygen. A CT scan of the chest showed almost complete resolution of his interstitial disease. Pulmonary function tests revealed a mild restrictive pattern with a severe diffusion defect.CASE 2: A 61 year-old man with DLBCL presented with 3 days of dyspnea, fever and cough. He was on cycle five, day 14 of R-CHOP. Prior to starting therapy, lung examination was normal and a CT of the chest showed no lung abnormalities. He had tachypnea, tachycardia, and inspiratory crackles on lung examination. Arterial blood gas revealed a pO2 of 45 mmHg. He was admitted to the hospital and started on broad spectrum antibiotics and corticosteroids. A helical CT of the chest revealed a diffuse interstitial lung pattern bilaterally consistent with interstitial pneumonitis and no pulmonary embolus. A bronchoscopy with bronchoalveolar lavage showed no infection. A lung biopsy could not be performed because of severe hypoxia. The patient required mechanical ventilation. After one week of intensive treatment the patient expired.DISCUSSION: Respiratory complications of rituximab include increased cough, rhinitis, brochospasm, dyspnea, and sinusitis. However, R-ILD is very rare. The pathogenesis of R-ILD is largely unknown. Potential explanations for R-ILD may include a direct injury to the lung tissues, unlikely, as well as the induction of cytotoxic substances. Rituximab acts by binding CD20+ B cells. Toxicity and efficacy are related to events after binding which include B cell signaling, complement activation, direct apoptosis, and antibody dependent cellular cytotoxicity. Complement activation and cytokine secretion, in particular, seems to be the causative factors in side effects associated with infusion reactions. Because of the increasing use of rituximab for a variety of disorders, it is important to recognize and appropriately treat possible fatal toxicities. Our patients presented with dyspnea and fever. In the absence of an infectious etiology further evaluation with a high-resolution CT scan of the chest or bronchoscopy with BAL and biopsy should be pursued. If evaluation suggests an ILD without clear evidence of infection, corticosteroids should be initiated and further treatment with rituximab discontinued.CONCLUSION: With the increasing use of rituximab and other monoclonal antibodies, clinicians must be aware of this rare but potentially fatal complication.