Drug-induced Lung Research Articles

Role of CT in the detection and management of cancer related complications: a study of 599 patients.

Cancer-related complications (CrC) and any potentially life-threatening findings detected on routine oncological imaging requires urgent intervention and needs proactive management. We conducted a retrospective study to highlight the role of imaging in the detection of CrC on computed tomography (CT)-scan while sharing our experience at a tertiary care cancer hospital. All the reports of the CT scans performed in our department between January 2018 and December 2019 were reviewed and the imaging findings of CrC were recorded. Only the patients who had known malignancy and underwent imaging evaluation at our centre at baseline/follow up/surveillance were included. The clinical details of the patients were recorded and the findings were classified based on the system or organ involved and also on the basis of its impact on clinical management. A total of 14,226 CT scans were performed during the study period, out of which 599 patients had CrC. Most of the CrC were seen involving thorax (265/599, 44.3%) followed by abdomen (229/599, 38.2%) and head and neck (104/599, 17.3%) regions. The commonly encountered CrC were pulmonary infections, superior vena cava obstruction and drug-induced lung changes. CrC have significant impact on the course of management of cancer patients and radiologist plays an important role in early diagnosis and initiation of prompt management of many such patients. CT is an excellent modality for early diagnosis of CrC which guides the oncologist for appropriate treatment.

Incidence and prognostic factors in severe drug-induced interstitial lung disease caused by antineoplastic drug therapy in the real world

PurposeInvestigate the frequency and prognostic factors of severe drug-induced interstitial lung disease (DILD) caused by antineoplastic drugs regardless of cancer types or type of drugs.MethodsFrom 2014 to 2018, we reviewed patients with a history of antineoplastic agents administration in the real-world database of our hospital's electronic medical record and extracted patients who experienced "severe" DILD, requiring hospitalization with treatment or developed during hospitalization and required treatment. We collected patients' backgrounds, clinical and radiological features, laboratory data, treatment, and survival outcomes.Results19,132 cancer patients received antineoplastic drug therapy during the study period, and 120 (0.62%) experienced severe DILD. The incidence of severe DILD in patients with thoracic cancer was highest among the patients included in this analysis (2.52% vs. 0.34% other cancers). Diffuse alveolar damage (DAD) pattern on CT was associated with higher mortality in patients with severe DILD compared with non-DAD pattern (hazard ratio [HR], 11.24; 95% CI, 4.82–26.2). Multivariate analysis revealed that the DAD pattern at diagnosis as severe DILD (HR, 3.59; 95% CI, 1.17–11.03), concurrent/previous interstitial lung disease (HR, 3.20; 95% CI, 1.27–8.10), and ECOG performance status of 2–4 (HR, 3.81; 95% CI, 1.10–13.17) were independent risk factors for mortality in patients with severe DILD.ConclusionsThe frequency of severe DILD was highest in patients with thoracic cancer. The DAD pattern was associated with a poor outcome. From the perspective of DILD, special attention should be paid when administering antineoplastic agents to patients with thoracic cancer.

Drugs associated with drug-induced interstitial lung diseases

Interstitial lesion is one of the causes of respiratory failure. Drugs are a modifiable etiological factor of lung damage. Medications most commonly associated with drug-induced interstitial lung disease include antineoplastic drugs, disease-modifying anti-rheumatic drugs and amiodarone. According to the latest literature data, the previously described link between anti-rheumatic drugs and interstitial lung diseases is very inconsistent. It may even be a protective effect of this group of drugs on the lung tissue. The relationship between statin use and interstitial lesions is also complex and not fully understood. It is necessary to carefully assess the appearance of respiratory tract complaints in patients taking statins as in other groups of patients. Prescription of additional diagnostic methods is necessary to close monitoring and prevention the toxic effect of these drugs. These actions, as well as the potential prescription of steroid therapy and change in the underlying disease treatment approaches, are an important factor in reducing the incidence of respiratory failure in the population.

151-LB: High Risk of Krebs Von Den Lungen-6 (kL-6) Elevation when Dipeptidyl Peptidase-4 Inhibitors and Amiodarone Are Prescribed Simultaneously

Amiodarone-caused pulmonary toxicity including interstitial lung diseases is a well-known side effect and its incidence was reported as approximately 5.7%. Also, dipeptidyl peptidase-4 inhibitors (DPP-4is) recently attracted physicians’ attention as a cause of drug-induced interstitial lung diseases. On the other hand, there must be patients who are prescribed both DPP-4is and amiodarone simultaneously. In this case, they might have an increased risk for interstitial lung disease. Given the lack of clarity regarding the risk for drug induced interstitial lung disease under the combination therapy of DPP-4is and amiodarone, we estimated serum Krebs von den Lungen-6 (KL-6) levels in patients who were prescribed amiodarone without DPP-4is, DPP-4is without amiodarone, and both DPP-4is and amiodarone simultaneously. 47 patients were prescribed amiodarone without DPP-4is (amiodarone group). 44 patients were prescribed DPP-4is without amiodarone (DPP-4is group). 15 patients were prescribed both amiodarone and DPP-4is (DPP-4is and amiodarone group). Elevation in KL-6 levels beyond the upper limit of normal range (reference range; <500 U/mL) was observed in 3 patients in the amiodarone group, 3 patients in DPP-4is group, and 3 patients in DPP-4is and amiodarone group respectively. Thus, the frequency of KL-6 levels beyond the upper limit of normal range in amiodarone group was 6.4%, 6.8% in DPP-4is group, but 20% in DPP-4is and amiodarone group respectively. We confirmed that KL-6 levels were in the normal range before initiating DPP-4is and/or amiodarone administration. Moreover, KL-6 levels were transiently elevated and normalized within one year after DPP-4is and/or amiodarone termination. All of participated patients showed normal study on chest X-ray examination through the observation period. Thus, when physicians prescribe DPP-4is, physicians should probably concern whether patients are prescribed amiodarone. Disclosure J. Okada: None. S. Okada: None. M. Yamada: None.

Fatal interstitial\xa0lung disease associated with Crizotinib pathologically confirmed by percutaneous lung biopsy in a patient with ROS1-rearranged advanced non-small-cell lung cancer: a case report

BackgroundCrizotinib is a multi-target inhibitor approved for the treatment of advanced non-small-cell lung cancer patients with a ROS1 rearrangement. However, interstitial lung disease is a rare but severe and fatal side effect of crizotinib that should lead to immediate discontinuation of the drug. Unfortunately, the pathophysiology, molecular mechanism and risk factors for crizotinib-induced interstitial lung disease remain poorly understood.Case presentationWe first identified and reported interstitial lung disease induced de novo by crizotinib in a 47-year-old female patient who was diagnosed with advanced lung adenocarcinoma with a ROS1 rearrangement in a malignant pleural effusion. Subsequent next-generation sequencing analysis revealed both ROS1 rearrangement and an EGFR exon 19 deletion mutation in lung biopsy specimens, which were histologically confirmed to be interstitial lung disease. Although crizotinib treatment was ceased immediately and a shock treatment with high-dose methylprednisolone as well as other necessary treatment procedures was applied to reverse the interstitial lung disease process, the patient died.ConclusionsThe present case indicates that while treating non-small-cell lung cancer patients with crizotinib, it is important to constantly monitor any newly emerging respiratory symptoms and unexplained imaging changes, which may suggest an adverse effect related to drug-induced interstitial lung disease or even lethality. Histopathology and molecular pathological examination of lung biopsy specimens may help clinicians understand the development mechanism and exclude other causes.

Drug-induced interstitial lung lesions

Drug-induced interstitial lung lesions (DIILL) are one of the most common forms of drug pneumopathy. DIILL account is about 3% in the structure of the entire interstitial lung pathology. Drugs induce various types of lesions of the lung parenchyma, often combining several histopathological patterns. Diagnostics of DIILL deals with many problems, since there are no specific clinical, morphological changes and specific markers. The diagnosis depends on the chronological dependence between taking the drug and the development of symptoms, and is confirmed by an improvement in the general condition of the patients after discontinuation of treatment. The aim of the work was to study the effect of various drugs on the development of DIILL, clinical diagnostic criteria, characteristic CT (computed tomography) and X-ray features, as well as the prognosis of the future course of the disease. We observed 12 patients with DIILL, which were divided into 2 groups: 1st group consisted of 4 patients with amiodarone lung, 2nd group of 8 patients, in which CT of the chest organs revealed an interstitial lesion of the lung tissue in the form of “frosted glass”. This gave us a reason to diagnose DIILL in patients who had CT scan in connection with suspected bronchocarcinoma in 3 patients, prolonged pneumonia in 3 patients and chronic obstructive pulmonary disease in 3 patients with fever. All patients took antibiotics of different groups a long time, ACE inhibitors, beta-blockers. The diagnosis of DIILL was made on the basis of the anamnesis of the patients, the CT data, as well as the positive dynamics of the general condition of the patients after the cancellation of the above medication. Diagnostic difficulties are often caused by late clinical and radiological manifestations or the lack of improvement after stopping the potentially “guilty” drug. However, timely diagnosis of DIILL is extremely important, since in many cases, the cancellation of the medication contributes to the resolution of the pathological process.

Case report: continued treatment with alectinib is possible for patients with lung adenocarcinoma with drug-induced interstitial lung disease

BackgroundAlectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, is a key drug for ALK rearranged lung adenocarcinoma. Interstitial lung disease (ILD) is an important adverse effect of alectinib, which generally requires termination of treatment. However, we treated two patients with drug-induced ILD who continued to receive alectinib.Case presentationPatient 1 was a 57-year-old male with an ALK-rearranged Stage IV lung adenocarcinoma who was administered alectinib as first-line therapy. Computed tomography (CT) detected asymptomatic ground-glass opacity (GGO) on day 33 of treatment. Alectinib therapy was therefore discontinued for 7 days and then restarted. GGO disappeared, and the progression of ILD ceased. Patient 2 was a 64-year-old woman with an ALK-positive lung adenocarcinoma who was administered alectinib as third-line therapy. One year later, CT detected GGO; and she had a slight, nonproductive cough. Alectinib therapy was continued in the absence of other symptoms, and GGO slightly diminished after 7 days. Two months later, CT detected increased GGO, and alectinib therapy was continued. GGO diminished again after 7 days. The patient has taken alectinib for more than 2 years without progression of ILD.ConclusionsCertain patients with alectinib-induced ILD Grade 2 or less may continue alectinib therapy if they are closely managed.

Drug-induced acute lung injury in malignant lymphoma: report of six cases and review of literature

目的 探讨淋巴瘤化疗致弥漫性肺损伤的临床特点、诊断、治疗，加强对该病早期诊断、早期治疗的认识。 方法 对6例化疗后急性弥漫性肺损伤的淋巴瘤患者临床资料进行分析，并复习国内外相关文献。 结果 化疗药物可引起急性弥漫性肺损伤，在化疗1~7个周期时出现，6例患者均以发热为首发症状，2例同时出现干咳，5例在发热后出现气促，肺部CT表现为双肺弥漫性磨玻璃样影，激素治疗效果好，甲基泼尼松龙40~120 mg治疗有效。 结论 化疗药物相关的弥漫性肺损伤早期诊断十分重要，发热为常见首发症状，早期使用糖皮质激素是治疗的关键。

First described case of clomipramine-induced acute eosinophilic pneumonia-like syndrome leading to acute respiratory failure

Drugs are well-known causes of eosinophilic lung disease and patients with drug-induced eosinophilic lung disease can have variable clinical presentations. Clinical features may range from asymptomatic eosinophilic infiltrates to acute eosinophilic pneumonia (AEP)-like syndrome leading to acute respiratory failure. This report describes the first case of clomipramine-induced AEP-like syndrome causing acute hypoxemic respiratory failure which was treated successfully. Considering the increasing usage of tricyclic antidepressants, physicians should be aware of this very rare and life-threatening complication of clomipramine.

The Ratio KL-6 to SLX in Serum for Prediction of the Occurrence of Drug-Induced Interstitial Lung Disease in Lung Cancer Patients with Idiopathic Interstitial Pneumonias Receiving Chemotherapy

We retrospectively evaluated whether the ratio KL-6 to SLX in serum (K/S ratio) before chemotherapy was a predictor for the occurrence of drug-induced interstitial lung disease (D-ILD) in lung cancer patients with idiopathic interstitial pneumonias (IIPs). D-ILD occurred in 8 of 20 IIPs-positive cases and in 14 of 100 IIPs-negative cases (40 vs. 14%, p = .015). In IIPs-positive cases, the high K/S ratio (>20) before first-line chemotherapy had a tendency to increase the risk of D-ILD (p = .085). Serum K/S ratio may be a useful predictor for the occurrence of D-ILD in lung cancer patients with IIPs.

Lung, CNS and musculo-skeletal targeted therapy-induced toxicity: imaging features

By focusing on molecular and cellular changes that are up regulated in cancer, targeted agents may have less severe side effects compared with conventional chemotherapy. However, many of these signaling pathways also exist in healthy cells and targeted therapies can therefore result in specific complications [1-3]. The spectrum of toxicity encountered with the targeted agents includes fatigue, skin rash and mucositis, eye, cardiac and muscle toxicity, drug-induced interstitial lung disease (DILD), posterior reversible encephalopathy syndrome (PRES) and a wide spectrum of gastro-intestinal complications. Nephrotoxic effects such as proteinuria, nephrotic syndrome or hypertension are also seen with agents such as VEGFR or mTOR inhibitors. The DILD imaging appearances encompass a range of patterns including nonspecific ground-glass opacity with and without interlobular septal thickening, multifocal consolidations with or without traction bronchiectasis, flitting subcentimetre nodules with or without ground glass halo, bronchiolitis and pulmonary fibrosis or pleural effusions [4]. Acute respiratory distress syndrome (ARDS) has also been described. The EGFR inhibitors related DILD is an important challenge for their use in lung carcinoma especially in patients with preexisting pulmonary fibrosis. Up to one-sixth of patients taking mammalian target of rapamycin (mTOR) inhibitors get a reversible interstitial pneumonitis [5]. Posterior reversible encephalopathy syndrome (PRES) is an uncommon complication (incidence < 0.1%) of VEGF/VEGFR pathway therapy. Most patients recover fully with discontinuation of the causative agent and supportive management of hypertension and seizures [6]. Intra-cerebral bleeding has also been described with anti-VEGF agents, especially in tumours with a strong hemorrhagic tendency, such as renal-cell carcinoma. On imaging, there is usually symmetrical vasogenic oedema in the occipital and parietal regions. However, PRES can be found in a non-posterior distribution, occurring at watershed areas of vascular territories, including the frontal, inferior temporal, cerebellar and brainstem areas. Increases of creatine kinase (CK) are amongst the most common grade 3-4 toxicity treatment-related adverse events of the Mitogen-activated protein kinase (MEK) inhibitors, although most patients are asymptomatic. Symptoms of CK increase include muscle weakness and myalgia. The true significance especially of asymptomatic CK increases is still unknown. An association between CK elevation and skin rash of novel targeted agents in phase I trials, possibly due to increased CK-BB (brain and skin) expression of keratinocytes was reported by Moreno Garcia et al [7]. With the continuous increase in the use of anti-cancer targeted therapies, it is important for the radiologist to be familiar with the clinical and treatment history and associated complications that may occur, in order to accurately identify drug-related complications and differentiate them from disease progression.

I67. Drug-Induced Interstitial Lung Disease in Patients With RA

RA is associated with an increased risk of serious pulmonary infection. Most observational studies have demonstrated a greater than 2-fold increased risk of serious pulmonary infection in RA. Pulmonary infection is the most prevalent infection associated with RA. There are a number of component risk factors for chronic pulmonary infection in RA: (i) drug therapy; (ii) underlying lung disease; (iii) the RA disease process; (iv) current smoking. (i) Drug therapy in RA: For over half a decade glucocorticoids have been used as immunosuppressive drugs in RA. There is evidence that they increase the risk of serious pulmonary infections up to 4-fold in a dose-dependent manner. The mechanisms behind this greatly increased risk will be discussed further in the presentation. TNF-a inhibitors increase the serious pulmonary infection risk up to 2-fold. If patients need higher dosages of glucocorticoids in addition to treatment with TNF-a inhibitors, their risk of infection is substantial. This combination should be used with caution and if possible avoided in RA patients with additional risk factors for pulmonary infection such as older age, smoking, diabetes and underlying lung disease. The use of rituximab in the context of underlying lung disease and chronic pulmonary infection will be reviewed. The risk benefits of MTX in RA will be discussed in context of known chronic pulmonary disease with the possibility of underlying chronic pulmonary infection. (ii) Underlying lung disease in RA: The most common cause of chronic pulmonary infection in RA is underlying lung disease. The prevalence of underlying lung disease exceeds 50% of the RA population. These underlying lung diseases include chronic obstructive airways disease and interstitial lung disease in RA smokers and bronchiectasis and small airways disease in RA non-smokers. The different pathogens commonly associated with these lung pathologies will be discussed. (iii) RA disease process: RA is associated with citrullination of peptides and the relevance of this to pulmonary infection will be explored further. The concept of NETosis and its potential role in RA disease activity and predisposition to chronic pulmonary infection will be discussed. (iv) Current smoking: Current smoking is a significant risk for acute or chronic pulmonary infection and is particularly relevant to RA as it is a known risk factor for both RA and RA associated interstitial lung disease and an independent risk factor for pulmonary infection. Disclosure statement: D.H. has received funding from Roche, Pfizer and BMS for speaker meetings, advisory boards and educational events.

Combination chemotherapy of intermittent erlotinib with pemetrexed for pretreated patients with advanced non-small cell lung cancer: A phase I dose-finding study.

e18056 Background: Erlotinib and pemetrexed have been approved in second-line treatment for non-small cell lung cancer (NSCLC) and have different mechanisms of action. Their combination could potentially augment the antitumor activity brought by either agent alone. We investigated the safety in combination of erlotinib and pemetrexed in pretreated NSCLC patients. Methods: A phase I dose-finding study was performed in patients with stage III/IV nonsquamous NSCLC whose disease had progressed on or after receiving first-line chemotherapy. This study was registered as UMIN000002900. Patients received 500 mg/m2 of pemetrexed intravenously every 21 days and erlotinib (100 mg in Level 1, 150 mg in Level 2) orally on days 2-16. Results: Twelve patients were recruited. Patient characteristics included median age of 66 (range, 48-78), 9 males, 9 stage IV, 7 adenocarcinoma, and 2 activating mutation-positives in the gene of epidermal growth factor receptor. Treatment was well-tolerated and the recommended dose of erlotinib was fixed on 150 mg. Dose-limiting toxicities were experienced in 3 patients: grade 3 elevation of serum alanine aminotransferase, repetitive grade 4 neutropenia that required the second dose reduction of pemetrexed, and grade 3 diarrhea. None experienced drug-induced interstitial lung disease. Three patients achieved partial response and 5 kept stable disease. Conclusions: Combination chemotherapy of intermittent erlotinib with pemetrexed was well-tolerated with promising efficacy against pretreated advanced nonsquamous NSCLC.

Centrilobular nodules with ground-glass opacities in the lungs

We report the case of a 56 year-old Gabonese man under treatment by candesartan-hydrochlorothiazide for essential hypertension. After 2 months of treatment, he presented with pneumonia and severe respiratory failure. The chest radiography showed centrilobular nodules resembling tumor metastases, but no evidence of a primary tumor. Laboratory and imaging found no evidence of infectious or autoimmune disease. The computed tomography findings led to a diagnosis of diffuse alveolitis. The candesartan treatment was stopped and oral corticosteroid therapy (50 mg/day) initiated. The rapid favorable outcome supports the diagnosis of a drug-induced infiltrative lung disease.

Erlotinib-induced acute interstitial lung disease associated with extreme elevation of the plasma concentration in an elderly non-small-cell lung cancer patient

We herein describe a case of drug-induced interstitial lung disease (ILD) following treatment with erlotinib. The plasma trough concentration of erlotinib at the time of the ILD diagnosis was extremely elevated compared with the plasma maximum concentration on day 1. We hypothesized that this phenomenon was associated with the pharmacodynamic interaction with a concomitant drug. The present case indicates that erlotinib-induced ILD was associated with a high plasma concentration of erlotinib. Oncologists should be aware of the possibility of ILD induced by erlotinib, especially for patients with co-morbidities.

Drug-induced interstitial lung disease (ILD) associated with statins is a "rare but serious" adverse reaction,

Drug-induced interstitial lung disease (ILD) associated with statins is a "rare but serious" adverse reaction,

Protective effect of geranylgeranylacetone, an inducer of heat shock protein 70, against drug-induced lung injury/fibrosis in an animal model

BackgroundTo determine whether oral administration of geranylgeranylacetone (GGA), a nontoxic anti-ulcer drug that is an inducer of heat shock protein (HSP) 70, protects against drug-induced lung injury/fibrosis in vivo.MethodsWe used a bleomycin (BLM)-induced lung fibrosis model in which mice were treated with oral 600 mg/kg of GGA before and after BLM administration. Inflammation and fibrosis were evaluated by histological scoring, hydroxyproline content in the lung and inflammatory cell count, and quantification by ELISA of macrophage inflammatory protein-2 (MIP-2) in bronchoalveolar lavage fluid. Apoptosis was evaluated by the TUNEL method. The induction of HSP70 in the lung was examined with western blot analysis and its localization was determined by immunohistochemistry.ResultsWe confirmed the presence of inflammation and fibrosis in the BLM-induced lung injury model and induction of HSP70 by oral administration of GGA. GGA prevented apoptosis of cellular constituents of lung tissue, such as epithelial cells, most likely related to the de novo induction of HSP70 in the lungs. GGA-treated mice also showed less fibrosis of the lungs, associated with the findings of suppression of both production of MIP-2 and inflammatory cell accumulation in the injured lung, compared with vehicle-treated mice.ConclusionGGA had a protective effect on drug-induced lung injury/fibrosis. Disease-modifying antirheumatic drugs such as methotrexate, which are indispensable for the treatment of rheumatoid arthritis, often cause interstitial lung diseases, an adverse event that currently cannot be prevented. Clinical use of GGA for drug-induced pulmonary fibrosis might be considered in the future.

Tc-99m HMPAO Labeled White Blood Cell Imaging in a Child With Eosinophilic Lung Disease

In radiolabeled leukocyte imaging, Tc-99m HMPAO has a significantly higher selectivity for eosinophils than neutrophils, but this may be clinically meaningful in disorders with eosinophilic infiltration. We present the case of a 2-year-old boy with infection who also developed drug-induced eosinophilic lung disease, as established later by bronchoalveolar lavage and discontinuation of the responsible antistaphylococcal agent. In the investigation of sepsis, diffusely increased pulmonary accumulation of Tc-99m HMPAO labeled leukocytes was observed. These findings were consistent with eosinophilic lung infiltration and underline the importance of clinical and laboratory data in the comprehensive interpretation of Tc-99m HMPAO labeled leukocytes scans.

Managementof drug‐induced interstitial lung disease

AbstractOur series on serious ADRs focusses on rare but potentially fatal drug reactions and how to recognise and avoid them. This article describes the drugs most commonly associated with interstitial lung disease and discusses subsequent management. Copyright © 2006 Wiley Interface Ltd

The Lung in Rheumatoid Arthritis

Drug-induced interstitial lung disease (ILD) is a rare but potentially fatal complication from the disease modifying drugs that we use for rheumatological conditions. Clinical presentation, prevalence and screening for MTX pneumonitis will be focussed upon. Diagnostic criteria for hypersensitivity pneumonitis will be reviewed. The talk will also give an overview of ILD reported with the other commonly used DMARDs as well as biologics. Disclosure statement: J.D. has received grants/research support from the British Lung Foundation (2007).