Drug-induced Lung Disease Research Articles

How Drugs Affect The Lungs

Drug-induced lung disease is a major source of iatrogenic injury. The numbers of drugs that adversely affect the respiratory system continues to increase and more than 350 (and still counting) have been identified and their effects pose a great challenge to all physicians. Awareness of drug-induced pulmonary disease is essential to make a proper diagnosis for management of such patients. Here we review the various drugs known to induce lung injury and the various patterns of injury seen.

Drug-Induced Lung Disease

Drug-induced lung disease may present with a variety of histopathologic features, and numerous therapeutic agents have been reported to cause an acute or chronic pulmonary reaction. A lung biopsy might be performed, so that the pathologist receives a specimen in which drug reaction is included in the differential diagnosis. The surgical pathologist should be aware of and able to diagnose the many common histologic patterns, including chronic interstitial pneumonia, organizing pneumonia, diffuse alveolar damage, pulmonary eosinophilia, pulmonary veno-occlusive disease, pulmonary hemorrhage/vasculitis, pulmonary edema, pulmonary hypertension, granulomatous inflammation, and pleural disease. Other common conditions associated with these patterns of injury should be excluded, making radiologic findings and clinical information also necessary for the diagnosis of drug-induced lung disease.

AUTOPSY-PROVEN CAUSES OF DEATH IN LUNGS OF PATIENTS IMMUNOCOMPROMISED BY SECONDARY INTERSTITIAL PNEUMONIA

To present the more frequent associations found in autopsies of immunocompromised patients who developed secondary interstitial pneumonia as well as the risk of death (odds ratio) in having specific secondary interstitial pneumonia according to the cause of immunocompromise. From January 1994 to March 2004, 17,000 autopsies were performed at Hospital das Clínicas, São Paulo University Medical School. After examining the pathology report review, we selected 558 of these autopsies (3.28%) from patients aged 15 years or more with primary underlying diseases who developed radiologically diffuse infiltrates of the lung during their hospital course and died after secondary interstitial pneumonia (bronchopneumonia, lobar pneumonia, interstitial pneumonia, diffuse alveolar damage, pulmonary recurrence of underlying disease, drug-induced lung disease, cardiogenic pulmonary edema, or pulmonary embolism). Histology slides were reviewed by experienced pathologists to confirm or not the presence of secondary interstitial pneumonia. Statistical analysis included the Fisher exact test to verify any association between histopathology and the cause of immunocompromise; a logistic regression was used to predict the risk of death for specific histological findings for each of the independent variables in the model. Secondary interstitial pneumonia was histologically represented by diffuse interstitial pneumonitis ranging from mild nonspecific findings (n = 213) to a pattern of diffuse alveolar damage (n = 273). The principal causes of immunocompromise in patients with diffuse alveolar damage were sepsis (136 cases), neoplasia (113 cases), diabetes mellitus (37 cases), and transplantation (48 cases). A high risk of death by pulmonary edema was found for patients with carcinoma of colon. Similarly, in patients with lung cancer or cachexia, A high risk of death by bronchopneumonia (OR = 3.6; OR = 2.6, respectively) was found. Pulmonary thromboembolism was associated with an appreciable risk of death (OR = 2.4) in patients with arterial hypertension. The risk of death was also high in patients presenting hepatic cancer (OR = 2.5) or steroid therapy (OR = 2.4) who developed pulmonary hemorrhage as the histological pattern of secondary interstitial pneumonia . The risk of death by lung metastasis was also elevated (OR = 1.6) for patients that were immunosuppressed after radiotherapy. Patients with secondary immunosuppression who developed secondary interstitial pneumonia during treatment in hospital should be evaluated to avoid death by diffuse alveolar damage, pulmonary edema, bronchopneumonia, lung hemorrhage, pulmonary thromboembolism, or lung metastasis. The high-risk patients are those immunosuppressed by hematologic disease; those under steroid treatment; or those with colon or hepatic carcinoma, cachexia, or arterial hypertension.

2) Types of Drug-induced Lung Diseases and the Keypoints in Their Diagnosis

2) Types of Drug-induced Lung Diseases and the Keypoints in Their Diagnosis

3. Clinical Types and Imaging of Drug-induced Lung Diseases

薬剤性肺障害のCTによる画像パターンは7型に分類される．この画像パターンには，実際の病理像を反映するものではないこと，再現性は決して高いものではないこと，画像パターンを実際の病理診断名と混同し，治療反応性予後等を病理診断名に基づくものと同様に議論してしまうこと等の問題点が存在する．しかしながら形態学的な疾患パターンを記述するには極めて便利で，また厳密に適用すればある程度予後を反映しうる．

2. Approach to the Diagnosis of Drug-induced Lung Diseases

薬剤性肺炎の診断は，肺障害が薬剤投与との時間的関連があり，他の原因を除外できることから得られる．その病像は多様であり，KL-6などが有用である場合もあるが，本疾患を常に念頭におき，添付文書などの情報を参照するなど基本に忠実な診療が早期診断につながる．起因薬剤の同定はしばしば困難であり，確定のためにチャレンジテストやリンパ球刺激試験が行われるが，種々の問題があり有用性は限られているのが現状である．

2) Types of Drug-induced Lung Diseases and the Keypoints in Their Diagnosis

2) Types of Drug-induced Lung Diseases and the Keypoints in Their Diagnosis

Toxicidade pulmonar induzida pela rapamicina

Drug induced lung diseases (DILD) are an increasingly cause of morbidity. Many drugs have been described, causing several patterns of injury. Sirolimus is an immunosuppressive agent increasingly used in renal and other solid organ transplantation. Pulmonary toxicity has been recognised as a potential complication associated to this medication. Interstitial pneumonitis and more rarely alveolar haemorrhage have been described. The authors describe 4 cases (3 men and 1 woman) between 46–71 years, transplanted three years ago (1 patient) and 7 years ago (3 patients). All of them were medicated with micofenolato mofetil, prednisone and sirolimus. All patients had fever at admission, 3 patients had dyspnoea and 2 productive cough. Diffuse pulmonary infiltrates with basal predominance in HRCT scan were present in the four patients. BAL showed lymphocytic alveolitis in 3 cases, however with a different CD4/CD8 ratio. In additio to lymphocytosis, neutrophilia was observed in 2 patients. One patient showed serious alveolar haemorrhage in BAL. Pulmonary infections were ruled out by specific BAL staining and cultures. After drug suspension, all patients showed a clear improvement. These case studies show some diversity in clinical presentation and in the features of some exams, namely in BAL. This may suggest different underlying pathophysiology entities induced by sirolimus.

Toxicidade pulmonar induzida pela rapamicina

Drug induced lung diseases (DILD) are an increasingly cause of morbidity. Many drugs have been described, causing several patterns of injury. Sirolimus is an immunosuppressive agent increasingly used in renal and other solid organ transplantation. Pulmonary toxicity has been recognised as a potential complication associated to this medication. Interstitial pneumonitis and more rarely alveolar haemorrhage have been described. The authors describe 4 cases (3 men and 1 woman) between 46-71 years, transplanted three years ago (1 patient) and 7 years ago (3 patients). All of them were medicated with micofenolato mofetil, prednisone and sirolimus. All patients had fever at admission, 3 patients had dyspnoea and 2 productive cough. Diffuse pulmonary infiltrates with basal predominance in HRCT scan were present in the four patients. BAL showed lymphocytic alveolitis in 3 cases, however with a different CD4/CD8 ratio. In additio to lymphocytosis, neutrophilia was observed in 2 patients. One patient showed serious alveolar haemorrhage in BAL. Pulmonary infections were ruled out by specific BAL staining and cultures. After drug suspension, all patients showed a clear improvement. These case studies show some diversity in clinical presentation and in the features of some exams, namely in BAL. This may suggest different underlying pathophysiology entities induced by sirolimus.Rev Port Pneumol 2006; XII (6): 715-724

Interstitial lung disease: are we missing formes frustes of connective tissue disease?

Patients with connective tissue disease (CTD) may encompass a variety of respiratory manifestations, including: pleural disease; pulmonary hypertension; bronchial or bronchiolar disease; interstitial pneumonia; restrictive lung disease secondary to musculo-skeletal changes; and iatrogenic drug-induced lung disease. Patients also have an increased risk of opportunistic infections, often favoured by corticosteroids and/or immunosuppressive or immunomodulatory therapy 1, 2. The respective frequency of manifestations, their clinical and radiological presentations, response to treatment, and outcome are dependent on the underlying CTD. Rheumatoid arthritis may be responsible for a broad spectrum of manifestations, including: pleural effusion; chronic interstitial pneumonia; lung rheumatoid nodules; bronchiectasis; obstructive ventilatory defect due to constrictive bronchiolitis; laryngeal involvement; and opportunistic infections, such as mycobacterial infections facilitated by anti-tumour necrosis factor-α treatments. Systemic sclerosis may be commonly associated with chronic interstitial pneumonia (especially in patients with diffuse systemic sclerosis and anti-topoisomerase-1 antibodies), or pulmonary arterial hypertension (most frequently, but not exclusively, in patients with limited systemic sclerosis with anti-centromere antibodies), with both contributing to the unfavourable prognosis of the disease 3. Although less frequent among CTDs than rheumatoid arthritis and systemic sclerosis, the spectrum of idiopathic inflammatory myopathy (including dermatomyositis, polymyositis, and amyopathic dermatomyositis) may give rise to a variety of respiratory manifestations, which represent a common cause of death in these patients. These include interstitial lung disease (ILD), aspiration pneumonia, ventilatory failure secondary to diaphragmatic dysfunction 4, and rarely, acute respiratory distress syndrome, pleural effusion, pneumothorax, pulmonary hypertension 5, diffuse alveolar haemorrhage, and dyspnoea due to dermatopolymyositis-related cardiac disease 2, 6. In addition, some manifestations may be the consequence of treatment, such as drug-induced pneumonitis and opportunistic infections. First described in 1986 7, the high frequency of pneumomediastinum in dermatomyositis has been better appreciated more recently 8. The association of ILD and …

Sirolimus-Induced Pulmonary Hypersensitivity Associated With a CD4 T-Cell Infiltrate

The differential diagnosis of pulmonary infiltrates after solid-organ transplantation presents a broad differential diagnosis including opportunistic infections and drug-induced lung disease. We report an adult liver transplant recipient who had breathlessness and pulmonary infiltrates following the introduction of sirolimus, and in whom transbronchial biopsy demonstrated a granulomatous interstitial pneumonitis and an organizing pneumonia with a CD4 T-cell infiltrate suggesting a T-helper cell-associated reaction to a processed sirolimus protein complex. Withdrawal of sirolimus produced a rapid clinical and radiologic improvement. This case indicates that with the increasing use of sirolimus, clinicians need to be aware of pulmonary hypersensitivity from this agent.

Drug-Induced Lung Diseases: Most Common Reaction Patterns and Corresponding High-Resolution CT Manifestations

Drug-induced lung disease is an increasingly common cause of morbidity and mortality. The diagnosis is based on clinical history and consistent radiologic findings. Lung biopsy is performed in a small percentage of cases. High-resolution CT may demonstrate parenchymal abnormalities in patients with normal radiographs and provides a better depiction of the pattern and distribution of findings. Knowledge of the most common high-resolution CT manifestations and the corresponding histologic patterns is important for early recognition and proper management of drug-induced lung disease.

Drug-induced lung disease: Diagnosis and treatment

Drug-induced lung disease: Diagnosis and treatment

Juvenile rheumatoid arthritis and bronchiolitis obliterans organized pneumonia

Diverse pleuropulmonary manifestations, including pleural effusion, rheumatoid nodulosis, fibrosis, obliterans brochiolitis, bronchiectasias, vasculitis, drug-induced lung disease, and obliterans bronchiolitis with organized pneumonia, have been described in patients with rheumatoid arthritis (RA). Bronchiolitis obliterans organized pneumonia (BOOP) is an uncommon condition described in patients with RA but not in juvenile RA (JRA). We described a patient with JRA who developed a BOOP.

WEB Trawl

This month we consider two European web sites that are of international interest. The first provides data on drug induced lung disease, the second collects and provides data on antimicrobial resistance in Europe. http://www.pneumotox.comBased in France, at the University Hospital in Dijon, the group running this web site collect together papers dealing with drug induced lung disease. On accessing the home page, the user can select which language they wish to use (a choice of English, French, or Spanish is provided). The home page also provides links to two different search methods. Firstly, the user can search by generic drug name; by the name alone, or with different patterns of lung damage that may occur. Alternatively, they may search by clinical or radiological pattern of lung involvement. Whichever search method is used, the user is provided with a list of published papers dealing with the drug in question and, as appropriate, lung conditions it has been associated with. It is stated on the web site that the list of papers provided is not necessarily exhaustive, but some indication is given of the number of known cases of association between the drug in question and the given condition. Although superficially this seems a simple web site, it in fact provides a wealth of useful information. Information is updated regularly, and a date on which the site was last updated (last month at the time of writing) is stated. Use of the web site is unrestricted and its content will be of interest to doctors and other healthcare professionals in a wide variety of disciplines.

Imagerie des pneumopathies médicamenteuses iatrogènes

Drug-induced lung diseases are an increasingly frequent cause of morbidity. Over 350 drugs are now recognized as being implicated in drug-induced lung diseases. Early diagnosis is critical. Discontinuing the drug may result in regression of the adverse effect. Diagnosis is based on a history of drug exposure with a temporal relationship between the introduction of the drug and the onset of symptoms, histologic evidence of lung damage and exclusion of other causes of lung injury. Unfortunately there is no specific test available. Histologic and radiologic findings are often non specific and diagnosis can be difficult. Drugs can cause a constellation of distinct patterns of respiratory involvement and all anatomic compartments of the lungs may be involved. The most common patterns are : non specific interstitial pneumonia and fibrosis, pulmonary eosinophilia, hypersensitivity pneumonitis, pulmonary edema with or without diffuse alveolar damage, bronchiolitis obliterans organizing pneumonia, pulmonary hemorrhage and vasculitis. It is important to be familiar with their common radiologic appearances.

Imagerie des pneumopathies médicamenteuses

The frequency of drug-induced lung toxicity is increasing. Diagnosis is complex due to numerous involved drugs and to various anatomo-clinical manifestations. Radiograph and lung CT scans are important tools for the diagnosis. Drug-induced lung diseases mainly include oedema with or without diffuse alveolar damage, pulmonary hemorrhage, non specific interstitial pneumonia, organizing pneumonia, hypersensitivity reaction, eosinophilic pneumonia and obliterative bronchiolitis. For each of these manifestations, we reviewed the drugs most frequently involved, the radiographic appearance and CT findings. The main lung radiologic manifestations, were described in the most common drugs that cause lung toxicity such as bleomycin, busulfan, cyclophosphamide, methotrexate, amiodarone, nitrofurantoin, gold salts and minocycline.

Collagen vascular disease-related lung disease: high-resolution computed tomography findings based on the pathologic classification.

Collagen vascular disease (CVD) can cause a variety of lung abnormalities, including usual interstitial pneumonia, nonspecific interstitial pneumonia, organizing pneumonia, diffuse alveolar damage, lymphoid interstitial pneumonia, bronchiectasis, constrictive bronchiolitis, follicular bronchiolitis, alveolar hemorrhage, pulmonary hypertension, and drug-induced lung disease. The frequency of each lung disease is different among underlying CVDs. Although high-resolution computed tomography (HRCT) findings of lung disease are often nonspecific, there are some characteristic HRCT findings for some lung diseases based on pathologic findings.

Upper Lobe Pulmonary Fibrosis Associated With High-Dose Chemotherapy Containing BCNU for Bone Marrow Transplantation

Upper lobe fibrotic lung disease is most often associated with sarcoidosis, Langerhans cell histiocytosis, silicosis, and other pneumoconioses but is usually not associated with drug-induced lung disease. Carmustine (BCNU) is a chemotherapeutic agent known to cause pulmonary toxicity. The radiographic pattern is usually diffuse bilateral lung disease predominantly in the lung bases. Upper lobe fibrotic disease associated with BCNU has been reported to occur in children treated for central nervous system gliomas. Often the lung disease occurs years after the exposure. Despite the widespread use of BCNU in the treatment of malignancy in adults, to our knowledge, the complication of upper lobe fibrotic disease has not been reported in adults. We describe a patient who presented with pneumothorax and bilateral upper lobe pulmonary fibrosis that we believe was due to BCNU given for bone marrow transplantation as part of therapy for breast cancer. Bilateral upper lobe pulmonary fibrosis can be associated with chemotherapeutic drugs.

Drug-Induced Lung Disease: A Pragmatic Classification Incorporating HRCT Appearances

Drug-induced lung disease frequently poses a diagnostic challenge. Knowledge of common radiological patterns of lung involvement and corresponding histopathologic diagnoses can facilitate management of individual patients. We outline a framework for understanding radiological and histologic patterns of drug-induced lung disease. Diffuse forms of drug-induced lung disease include processes that mimic acute respiratory distress syndrome (ARDS) and diffuse alveolar hemorrhage. These patterns of drug-induced lung disease are especially common in patients receiving cytotoxic chemotherapeutic agents. Chronic forms of drug-induced lung disease include many of the interstitial pneumonias seen more commonly in patients with idiopathic disease. Bronchiolitis obliterans organizing pneumonia and eosinophilic pneumonia are nonspecific patterns of drug-induced lung disease that are radiologically and histologically indistinguishable from their idiopathic counterparts. In some patients organizing pneumonia and eosinophilic pneumonia mimic the radiological appearance of neoplastic disease.