Drug-induced Lung Disease Research Articles

Acute and subacute idiopathic interstitial pneumonias.

Idiopathic interstitial pneumonias (IIPs) may have an acute or subacute presentation, or acute exacerbation may occur in a previously subclinical or unrecognized chronic IIP. Acute or subacute IIPs include acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP), nonspecific interstitial pneumonia (NSIP), acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) and AE-NSIP. Interstitial lung diseases (ILDs) including connective tissue disease (CTD) associated ILD, hypersensitivity pneumonitis, acute eosinophilic pneumonia, drug-induced lung disease and diffuse alveolar haemorrhage need to be differentiated from acute and subacute IIPs. Despite the severe lack of randomized controlled trials for the treatment of acute and subacute IIPs, the mainstream treatment remains corticosteroid therapy. Other potential therapies reported in the literature include corticosteroids and immunosuppression, antibiotics, anticoagulants, neutrophil elastase inhibitor, autoantibody-targeted treatment, antifibrotics and hemoperfusion therapy. With regard to mechanical ventilation, patients in recent studies with acute and subacute IIPs have shown better survival than those in previous studies. Therefore, a careful value-laden decision about the indications for endotracheal intubation should be made for each patient. Noninvasive ventilation may be beneficial to reduce ventilator associated pneumonia.

Editorial introductions

Editorial introductions

Drug-Induced Lung Disease: Report of Two Cases

Drug-Induced Lung Disease: Report of Two Cases

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.

ニボルマブの初回投与後早期に薬剤性肺障害を発症した肺腺癌の1例

背景．ニボルマブは，非小細胞肺癌に対する2次治療の有効性が認められ適応拡大されたが，合併症の1つとして薬剤性肺障害が報告されている．症例．49歳の男性．肺腺癌に対する7次治療としてニボルマブを開始したが，初回投与8日目に発熱，低酸素血症，胸部CT上すりガラス陰影が出現し，薬剤性肺障害を強く疑った．副腎皮質ステロイドの全身投与により薬剤性肺障害は改善した．また，2か月後でも腫瘍増大の抑制効果を確認した．結論．ニボルマブの単回投与後早期にも薬剤性肺障害が発症しうる．また，ニボルマブ1回のみの投与でも腫瘍増大を抑制できる可能性がある．

Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury.

Identification of signaling pathways that are functional in a specific biological context is a major challenge in systems biology, and could be instrumental to the study of complex diseases and various aspects of drug discovery. Recent approaches have attempted to combine gene expression data with prior knowledge of protein connectivity in the form of a PPI network, and employ computational methods to identify subsets of the protein-protein-interaction (PPI) network that are functional, based on the data at hand. However, the use of undirected networks limits the mechanistic insight that can be drawn, since it does not allow for following mechanistically signal transduction from one node to the next. To address this important issue, we used a directed, signaling network as a scaffold to represent protein connectivity, and implemented an Integer Linear Programming (ILP) formulation to model the rules of signal transduction from one node to the next in the network. We then optimized the structure of the network to best fit the gene expression data at hand. We illustrated the utility of ILP modeling with a case study of drug induced lung injury. We identified the modes of action of 200 lung toxic drugs based on their gene expression profiles and, subsequently, merged the drug specific pathways to construct a signaling network that captured the mechanisms underlying Drug Induced Lung Disease (DILD). We further demonstrated the predictive power and biological relevance of the DILD network by applying it to identify drugs with relevant pharmacological mechanisms for treating lung injury.

Drug-Induced Pulmonary Edema and Acute Respiratory Distress Syndrome in Children

Non-cardiogenic pulmonary edema, and to a lesser extent, Acute Respiratory Distress Syndrome (ARDS) are common clinical manifestations of drug-induced lung diseases. Clinical features and radiographic appearances are generally indistinguishable from other causes of pulmonary edema and ARDS. Typical manifestations include dyspnoea, chest discomfort, tachypnoea, and hypoxemia. Chest radiographs commonly reveal interstitial and alveolar filling infiltrates without cardiomegaly. The laboratory results are usually nonspecific. We illustrate potential aetiologies relating to ARDS and the recognition of mucolytic drug use as one of the pathophysiologic factors of ARDS.

A bilateral pneumonia following Thai herbal inhaler compulsive use

Traditional herbal therapy is often underestimated as a possible cause of drug-induced lung diseases. We report the case of a 51 years old man who developed acute respiratory failure after abuse and misuse of a traditional Thai herbal inhaler. The composition of the herbal therapy was only partially known. However, we supposed that the menthol balm may have been responsible of the pulmonary lipoid inclusions and trans-anethole may have caused diffuse alveolar lung damage.

A 54-Year-Old Man Referred With Nonresolving Pneumonia

A 54-year-old man was referred with nonresolving pneumonia. He had been treated for community-acquired pneumonia 6 weeks earlier. He reported grade 2 dyspnea, malaise, and a nonproductive cough. He had also experienced three episodes of minimal hemoptysis but denied weight loss, fever, or any other constitutional symptoms. He was a nonsmoker and was being treated for dyslipidemia.

Drug induced lung disease - amiodarone in focus

More than 380 medications are known to cause pulmonary toxicity. Selected drugs that are important causes of pulmonary toxicity fall into the following classes: cytotoxic, cardiovascular, anti-inflammatory, antimicrobial, illicit drugs, miscellaneous. The adverse reactions can involve the pulmonary parenchyma, pleura, the airways, pulmonary vascular system, and mediastinum. Drug-induced lung diseases have no pathognomonic clinical, laboratory, physical, radiographic or histological findings. A drug-induced lung disease is usually considered a diagnosis of exclusion of other diseases. The diagnosis of drug-mediated pulmonary toxicity is usually made based on clinical findings. In general, laboratory analyses do not help in establishing the diagnosis. High-resolution computed tomography scanning is more sensitive than chest radiography for defining radiographic abnormalities. The treatment of drug-induced lung disease consists of immediate discontinuation of the offending drug and appropriate management of the pulmonary symptoms. Glucocorticoids have been associated with rapid improvement in gas exchange and reversal of radiographic abnormalities. Before starting any medication, patients should be educated about the potential adverse effects of the drug. Amiodarone is an antiarrhythmic agent used in the treatment of many types of tachyarrhythmia. Amiodarone-caused pulmonary toxicity is a well-known side effect (complication) of this medication. The incidence of amiodarone-induced lung disease is approximately 5-7%.

Patterns of airway involvement in inflammatory bowel diseases.

Extraintestinal manifestations occur commonly in inflammatory bowel diseases (IBD). Pulmonary manifestations (PM) of IBD may be divided in airway disorders, interstitial lung disorders, serositis, pulmonary vasculitis, necrobiotic nodules, drug-induced lung disease, thromboembolic lung disease and enteropulmonary fistulas. Pulmonary involvement may often be asymptomatic and detected solely on the basis of abnormal screening tests. The common embryonic origin of the intestine and the lungs from the primitive foregut, the co-existence of mucosa associated lymphoid tissue in both organs, autoimmunity, smoking and bacterial translocation from the colon to the lungs may all be involved in the pathogenesis of PM in IBD. PM are mainly detected by pulmonary function tests and high-resolution computed tomography. This review will focus on the involvement of the airways in the context of IBD, especially stenoses of the large airways, tracheobronchitis, bronchiectasis, bronchitis, mucoid impaction, bronchial granulomas, bronchiolitis, bronchiolitis obliterans syndrome and the co-existence of IBD with asthma, chronic obstructive pulmonary disease, sarcoidosis and a1-antitrypsin deficiency.

Pneumopathies interstitielles diffuses médicamenteuses au cours des maladies systémiques

Immunosuppressants and immunomodulators are designed to regulate excessive immune response responsible for inflammatory lesions and are prescribed more and more in internal medicine. These drugs are known for their efficiency but with a significant toxicity including interstitial lung disease (ILD). Some factors liable to pulmonary toxicity include advanced age, genetic polymorphism and the existence of prior pulmonary disease. Cytotoxicity and hypersensitivity are the main mechanisms of pulmonary toxicity. There is no universal classification of drug induced-lung disease. Theoretically, drugs may be responsible for all histological aspects of ILD. Methotrexate is the most well-known drug as a provider of ILD with a prevalence of 0.3 to 11.6%. Some cases of ILD have also been reported with the new biologics used in systemic diseases. The diagnostic approach to the suspicion of drug ILD is to eliminate non-medicinal causes of pneumonia including infections and tumors before exploring the clinical symptomatology and the results of imaging and bronchoalveolar lavage cell profile. The analysis of the clinical symptomatology check the compatibility of the chronology of clinical and/or radiological pneumonia with the medication suspected. Subsequently, data from the clinical case are compared with those of the literature. Treatment involves stopping the suspected drug. The use of corticosteroids may be required in case of signs of severity or a lingering evolution.

Adverse reactions to targeted and non-targeted chemotherapeutic drugs with emphasis on hypersensitivity responses and the invasive metastatic switch

More than 100 drugs are used to treat the many different cancers. They can be divided into agents with relatively broad, non-targeted specificity and targeted drugs developed on the basis of a more refined understanding of individual cancers and directed at specific molecular targets on different cancer cells. Individual drugs in both groups have been classified on the basis of their mechanism of action in killing cancer cells. The targeted drugs include proteasome inhibitors, toxic chimeric proteins and signal transduction inhibitors such as tyrosine kinase (non-receptor and receptor), serine/threonine kinase, histone deacetylase and mammalian target of rapamycin inhibitors. Increasingly used targeted vascular (VEGF) and platelet-derived endothelial growth factor blockade can provoke a range of pathological consequences. Many of the non-targeted drugs are cytotoxic, suppressing haematopoiesis as well as provoking cutaneous eruptions and vascular, lung and liver injury. Cytotoxic side effects of the targeted drugs occur less often and usually with less severity, but they show their own unusual adverse effects including, for example, a lengthened QT interval, a characteristic papulopustular rash, nail disorders and a hand–foot skin reaction variant. The term hypersensitivity is widely used across a number of disciplines but not always with the same definition in mind, and the terminology needs to be standardised. This is particularly apparent in cancer chemotherapy where anti-neoplastic drug-induced thrombocytopenia, neutropenia, anaemia, vascular disorders, liver injury and lung disease as well as many dermatological manifestations sometimes have an immune basis. The most insidious of all adverse consequences of targeted therapies, however, are tumour adaptation, increased malignancy and the invasive metastatic switch seen with anti-angiogenic drugs that inhibit the VEGF-A pathway. Adverse reactions to 44 non-targeted and 33 targeted, frequently used, chemotherapeutic drugs are presented together with discussions of diagnosis, premedications, desensitizations and importance of understanding the mechanisms underlying the various drug-induced reactions. There is need for wide-ranging acceptance of what constitutes a hypersensitivity reaction and for allergists to be more involved in the diagnosis, treatment and prevention of chemotherapeutic drug-induced hypersensitivity reactions.

A cohort study of mortality predictors in patients with acute exacerbation of chronic fibrosing interstitial pneumonia

ObjectivesTo assess clinical, laboratory and radiographic findings associated with outcomes and to clarify more practical ways to predict hospital mortality in patients with acute exacerbation (AE) of chronic fibrosing interstitial...

Lung involvement and drug-induced lung disease in patients with rheumatoid arthritis

Interstitial lung disease (ILD) is a common extra-articular manifestation of rheumatoid arthritis (RA) and a significant cause of morbidity and mortality. Usual interstitial pneumonia and nonspecific interstitial pneumonia seem to be the most frequent patterns in RA patients with ILD, although the proportion of patients with usual interstitial pneumonia is higher than among patients with other systemic rheumatic autoimmune diseases. RA patients with ILD most frequently present with chronic symptoms of cough and dyspnea when climbing stairs or walking uphill. A physical examination may reveal inhalatory crackles and a pulmonary function test demonstrates restrictive physiology, often with reduced diffusing capacity. High-resolution computed tomography is generally sufficient to confirm a diagnosis of ILD, although a minority of cases may require a surgical lung biopsy. Conventional disease-modifying antirheumatic drugs such as methotrexate (MTX) or leflunomide (LEF) and biological agents such as TNF-blocking agents or rituximab may trigger or aggravate ILD in RA patients, and infections may contribute to increased mortality in such patients. LEF should not be used in patients with a history of MTX pneumonitis. The prevalence of interstitial pneumonia among RA patients treated with anti-TNF agents ranges from 0.5 to 3%; however, as the evidence that anti-TNF increases or decreases the risk of ILD is controversial, it is not clear whether this indicates more severe RA requiring biological therapy or the effect of exposure to potentially toxic drugs such as MTX or LEF. The development of treatment-related ILD is a paradoxical adverse event, and patients should be warned about this rare but serious complication of biological or disease-modifying antirheumatic drug therapy.

Serum heat shock protein 47 levels in patients with drug-induced lung disease

BackgroundHeat shock protein (HSP) 47 is a collagen-specific molecular chaperone that is required for molecular maturation of various types of collagens. We recently reported that HSP47 serum levels were markedly higher in patients with acute exacerbations of idiopathic pulmonary fibrosis (IPF) when compared with patients with stable IPF, suggesting that serum HSP47 levels correlate with interstitial pneumonia activity. The aim of this study was to evaluate serum HSP47 levels in patients with drug-induced lung disease (DILD).MethodsFindings from high-resolution computed tomographic chest scans of 47 patients with DILD were classified into one of four predominant patterns: organizing pneumonia (OP) (n = 4), nonspecific interstitial pneumonia (NSIP) (n = 24), hypersensitivity pneumonitis (HP) (n = 11), and diffuse alveolar damage (DAD) (n = 8). Serum levels of HSP47, Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-A, and SP-D were measured in these patients.ResultsThe PaO2/fraction of inspired oxygen (FiO2) (P/F) ratios were significantly lower and the alveolar-arterial difference of oxygen (A-a DO2) was significantly higher in the DAD group than in the other groups. Patients with DAD had the worst outcomes among the different subgroups. Patients in the DAD group had significantly higher serum HSP47 levels than those in other groups. Receiver operating characteristic curves revealed that HSP47 was superior to KL-6, SP-A, and SP-D for discriminating between the DAD group and the other groups. The cut-off level for HSP47 that resulted in the highest diagnostic accuracy was 1711.5 pg/mL. The sensitivity, specificity, and diagnostic accuracy were 87.5%, 97.4%, and 95.7%, respectively. Serum levels of HSP47 in the group of patients requiring glucocorticoids were significantly higher than those in patients who experienced clinical improvement without glucocorticoid administration. Serum HSP47 levels also significantly correlated with various respiratory parameters.ConclusionThis study demonstrated that serum HSP47 levels were elevated in patients with DILD with a DAD pattern who had the worst outcomes among the different subgroups, and that this was correlated with P/F ratio and A-a DO2.

Pneumopathies médicamenteuses en réanimation

The diagnosis of drug-induced lung disease (DILD) is a diagnosis of exclusion based on chronological and semiological criteria (intrinsic accountability) as well as bibliographic criteria (extrinsic accountability). In the intensive care unit, DILD incidence is difficult to assess because of the difficulty in obtaining a definitive diagnosis. In case of severe bilateral pneumonia and after ruling out the most common etiologies (infectious and cardiogenic pulmonary edema), DILD should be systematically suspected as involved in about 10% of acute respiratory distress syndromes (ARDS). Out of the 400 drugs known as “pneumotoxic” and mentioned on pneumotox.com website, about one hundred (including amiodarone, chemotherapy, and targeted therapies) has been described as able to result in ARDS.

Distinct immunologic and radiographic patterns in etanercept-induced lung injury

Nonspecific clinical presentation of non-infectious, immune-mediated pulmonary complications of etanercept therapy makes the diagnosis difficult. While bronchoalveolar lavage fluid (BALF) cell analysis is frequently used in diagnosing drug-induced lung disease, BALF patterns in etanercept-induced lung injury (EILI) are not well established. Furthermore, previous reports of EILI diagnosis relied on transbronchial or surgical lung biopsies. Here, we report two patients who developed pulmonary toxicity after etanercept treatment. Both patients were diagnosed with EILI. While one patient presented with CD4+-predominant lymphocytic alveolitis (consistent with a sarcoid-like pattern), the other patient exhibited a CD8+-predominant pattern (consistent with hypersensitivity pneumonitis-like reaction). The different BAL patterns were accompanied by distinct radiographic findings. Both patients significantly improved after etanercept discontinuation and corticosteroid initiation. We propose that EILI can present with distinct immunologic and radiographic phenotypes. In addition, early BALF analysis with lymphocyte immunophenotyping can further define the underlying immunologic abnormalities, and thereby, avoid more invasive procedures.

The Correlation of Body Mass Index, Plasma C-Telopeptidase, and Synovial Fluid Leptin in Osteoarthritis, Before and After Exercise: A Study in Explaining Role of Leptin and Exercise in Osteoarthritis With Obesity and Osteoporosis

s 499 dysplasia for the past 25 years. He did not have any prior history of effusions. The occurrence of recurring effusions with a history of recent use of zoledronic acid points to a diagnosis of this being a rare medication side-effect. A detailed search of literature shows that a few cases have been reported to the FDA after use of zoledronic acid but none have been published. Dyspnea is a listed side effect occurring in 22-27% patients but the etiology is not elucidated. This case highlights the importance of having a high index of clinical suspicion to make a diagnosis of drug induced lung disease. This is especially the case for newer drugs with which we do not have long term data and experience. As the clinical indications for bisphosphonate use continues to expand, it is important for clinicians to prevent, recognize, and manage any possible complications effectively and expeditiously. It also raises awareness to be vigilant for the possibility of a pleural effusion after the use of zoledronic acid as dyspnea is a frequently reported complication. 137 Prevention and Treatment: Osteoporosis Subset BMD Level Odds Ratio (95% CI) All Osteopenia (n 5 8841) T-score -1.5 to -2.4 1.55 (1.38-1.73) Osteoporosis (n55732) T-score -2.5 1.15 (0.99-1.34) Subset NOT on medication at DXA date Osteopenia (n55501) T-score -1.5 to -2.4 1.68 (1.35-2.09) Osteoporosis (n 5 2108) T-score -2.5 1.27 (1.02-1.58) and Other Conditions THE CORRELATION OF BODY MASS INDEX, PLASMA C-TELOPEPTIDASE, AND SYNOVIAL FLUID LEPTIN IN OSTEOARTHRITIS, BEFORE AND AFTER EXERCISE: A STUDY IN EXPLAINING ROLE OF LEPTIN AND EXERCISE IN OSTEOARTHRITIS WITH OBESITY AND

Current Status of Idiopathic Nonspecific Interstitial Pneumonia

Pulmonary pathologists were aware of cases of idiopathic interstitial pneumonia (IIP) that morphologically did not fit Liebow's classification scheme. These cases were labeled as "cellular interstitial pneumonia" or "chronic interstitial pneumonia not otherwise specified." The term nonspecific interstitial pneumonia (NSIP) was first used in relation to a pattern of lung interstitial inflammation seen in association with human immunodeficiency virus (HIV) infection. In 1994 NSIP was used to indicate a group of subacute or chronic interstitial pneumonias characterized morphologically by interstitial inflammation or fibrosis or both, with preservation of the lung architecture and the absence of typical findings for any of the other main categories of IIP (mainly usual interstitial pneumonia, desquamative interstitial pneumonia, and bronchiolitis obliterans organizing pneumonia). Although these patients presented with "nonspecific" lung histology (categorized as cellular and fibrotic variants), and with a broad spectrum of associated clinical conditions, such as connective tissue diseases (CTDs), environmental exposure, and previous acute lung injury, they showed some peculiar clinical aspects, including favorable response to corticosteroid treatment and overall good prognosis.The clinical and radiographic profiles were better defined in the last decade. The NSIP pattern is the histological background of a subacute/chronic interstitial pneumonitis that may be observed in many conditions, including CTD, drug-induced lung disease, hypersensitivity pneumonitis, slowly healing diffuse alveolar damage (DAD), relapsing organizing pneumonia, occupational exposure, immunodeficiency (mainly HIV infection), graft versus host disease (GVHD), familial pulmonary fibrosis, immunoglobulin G4 (IgG4)-related sclerosing disease, with or without overlap features with Rosai-Dorfman disease, multicentric Castleman disease, and myelodysplastic syndrome. Rarely, NSIP is the histology recognized in patients with idiopathic interstitial pneumonitis, in whom efforts to find potential causative exposures are futile. This entity occurs mostly in middle-aged, never-smoker women, with a likely association with an autoimmune background. High-resolution computed tomographic (HRCT) scans typically demonstrate ground-glass attenuation with a bibasilar distribution, or in the fibrotic variant, ground-glass attenuation along with reticular lines and traction bronchiectasis. The prognosis is good compared with idiopathic pulmonary fibrosis (IPF), and therapeutic options include mainly corticosteroids and immunosuppressive agents. Recently a more precise definition of clinical profiles and radiographic findings of idiopathic NSIP allows consideration of less invasive diagnostic procedures (bronchoalveolar lavage, transbronchial lung biopsy). Better understanding of pathogenetic mechanisms might widen the therapeutic horizon giving a role to new therapeutic options in more severe cases.