Case 3 -

Pergolide-induced Fibrous Pleuritis in a Patient with Asbestos Exposure Francoise Galateau-Salle Centre Hospitalier Universitaire Caen, France

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Click here to download handout in 1-up pdf format for the current section (1.53 MB) Click here to download handout in 6-up pdf format for the current section (460 KB) Case History A 59-year-old white man, a storekeeper in a car factory, was transferred to our institution for evaluation of bilateral pleural effusion, with increasing dyspnea, cough, and fatigue. He also complained of fever, drenching night sweats and progressive body weight loss (8 kg in 3 months). The patient had a previous history of systemic hypertension treated by Valsartan and hydrochlorothiazide and additionally Parkinson's disease. The CT scan confirmed the presence of bilateral pleural effusion and showed diffuse bilateral pleural thickening and rounded atelectasis. Laboratory data showed a normal WBC count with 21 % lymphocytes, proteins:73 g/L, C Reactive protein:138 mg/L, sedimentation rate:107 mm and LDH:652 (N:165 to 420). Thoracentesis disclosed bloody fluid with protein of 39 g/L and a normal adenosine desaminase activity. Cytology showed no evidence of malignancy. Case 3 - Slide 1 Representative slide from the pleurectomy Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Figure 1 The CT Scan schowed bilateral pleural effusions, diffuse pleural thickening and rounded atelectasis. Case 3 - Figure 2 Severe diffuse thickened and fibrotic pleura with serofibrinous exudate at the surface. Case 3 - Figure 3 Some plump, atypical fibroblasts were deeply seated with few mitosis Case 3 - Figure 4 At higher magnification, immunohistochemistry showed AE1/3 positive cells under effusion, and positive spindle cells parallel to the surface. Diagnosis: Pergolide-induced fibrous pleuritis in a patient with asbestos exposure. Gross Description: Pleurectomy: 10 samples of tissue 0.6 to 15, 6 cm in maximum dimension. The pleural thickening range from 0.1 to 0.3 cm. The pleura was white and firm. Microscopic Description At the surface there is a serofibrinous pleuritis. The submesothelial connective tissue shows a diffuse pleural fibrosis with a background of fibroblasts and myofibroblasts parallel to the surface with greater cellularity immediately beneath the surface layer. Some fibroblasts are plump, atypical and few are deeply seated, but distinct zonation is observed which is associated with long capillaries oriented perpendicular to the pleural surface. Rare inflammatory cells are evident. Discussion The differential diagnosis of an exudative effusion with pleural fibrosis included malignancy, infection (eg,tuberculosis), benign asbestosis pleural effusion and drug reactions (table 1). Churg lists [1] the diagnostic criteria for the separation from benign to malignant mesothelial proliferations (organizing effusions versus desmoplastic malignant mesothelioma): 1) Organizing pleurisy ( fibrous pleuritis) show zonation with high cellularity and cytologic atypia underneath the surface pleural layer and progressive loss of cellularity with increasing fibrosis toward the chest wall, whereas diffuse sarcomatoid mesothelioma and desmoplastic mesothelioma, usually unilateral, show an absence of zonation with a high cellularity and cellular atypia more prominent toward the chest wall;2) elongated capillaries perpendicular to the pleural surface are observed in organizing effusions but usually, are not a feature of malignant sarcomatoid or desmoplastic mesothelioma. 3) Absence of invasion of fat and adjacent tissues ( not present in our case); 4) Absence of bland necrosis and cellular storiform pattern. Necrosis is usually not seen in benign reaction of the pleura except in association with infection and tuberculosis. Tuberculosis was excluded in view of the absence of necrotizing epithelioid and giant cell granulomas. Moreover tuberculosis seemed unlikely given the negative findings with multiple cultures, a normal adenosine desaminase activity, and absence of parenchymal lesions. Diffuse pleural fibrosis in relation to asbestos exposure was possible in this patient, since he was a storekeeper in a car factory. This disorder, usually involves the visceral pleura though this is often adherent to the parietal pleura, is believed to follow benign asbestos effusion. Diffuse pleural fibrosis may be unilateral or bilateral and the pleural thickening can range from few millimeters to a centimeter or more [2]. Ultimately the diagnosis of pergolide-associated pleural fibrosis was based on the response to the removal of the drug. It is possible that pre-existing occult asbestos pleural lesions, or even asbestos exposure, increases the risk of developing pergolide-pleural fibrosis [3, 4]. Drug induced pleural disease (table 2) is an uncommon event compared to drug-induced parenchymal lung disease, and often undiagnosed [5]. Drug effect are believed to be causal of the pleural disease, when exposure appears to induce pleural disease, when the pleural response remits on discontinuation of the drug and when pleural disease recurs with re-exposure to the same drug. Since the first description of pleural adverse effects of drugs in the pleura by Cooper et al, in 1986, more than 30 drugs are believed to have caused pleural disease. These included well known cardiovascular agents such as practolol, amiodarone, and minoxidil; ergoline drugs such as methysergide and bromocriptine; sclerosing agents such as sodium morrhuate and absolute alcohol and chemotherapeutic agents such as bleomycin, mitomycin, procarbazine, methotrexate, cyclophosphamide, and docexatel. Nitrofurantoin and Dantrolene, used as a skeletal muscle relaxant, may also cause pleural fibrosis as late sequelae. Other classes of drugs (procainamide/hydralazine) are expected to cause lupus-like pleuritis. The pathogenic mechanisms [6] include 1) hypersensitivity or allergic reaction; 2) direct toxic effect;3) increased oxygen free radical production; 4)suppression of anti-oxydant defenses;5) chemical-induced inflammation. Pergolide is an ergot–derived dopamine agonized used in Parkinson's disease and increasingly, in restless legs syndrome. Pergolide has been reported to cause retroperitoneal fibrosis. The mechanism by which the ergot derivatives produce fibrosis remains obscure. Questions have been raised as to whether this represents a serotonergic effect of this medications, as serotonin has been shown to cause fibrosis [7] . Immunopathogenic mechanism is an other possibility. A pergolide-induced fibrous pleuritis should be considered in a patient presenting with bilateral pleural disease which is associated with fever, weight loss and inflammatory syndrome. Nowadays, some authors [7] recommend not using ergot-derivatives such as Pergolide for Parkinson's disease and switch to non ergot dopamine agonists, in patients with a previous history of asbestos exposure. Table 1 - Cause of organizing effusion (pleural fibrosis) Diffuse visceral and parietal fibrosis Recurrent exudative effusion (non specified) Asbestos exposure Collagen-vascular disease Drug reactions Fibrothorax Pleural fibrosis secondary to asbestos exposure Pleural fibrosis secondary to renal disease Pleural fibrosis secondary to infections Pleural fibrosis secondary to trauma. Table 2 - Drugs and the pleura (adapted from Lorlock et al, Chest 1999) Cardiovascular agents. Amiodarone Minoxidil Practolol Ergoline drugs Bromocriptine Methysergide Pergolide Sclerotherapeutic agents Sodium Morrhuate/absolute alcohol Pleural fluid eosinophilia Nitrofurantoin Dantrolene Valproic Acid Propylthiouracil Isotretinoin Chemotherapeutic agents Bleomycin Mitomycin Procarbazine Methotrexate Cyclophosphamide Other agents Acyclovir Clozapine D-penicillamine Granulocyte-stimulating factor Interleukin-2 Itraconazole L-Tryptophan Simvastin Drugs induced pleuritis Procainamide Hydralazine Other drugs References Churg A, Colby TV, Cagle P, Corson J, Gibbs AR, Gilks B, Grimes M, Hammar S, Roggli V, Travis WD. The Separation of benign from malignant mesothelial proliferations. Am J Sug Pathol. 2000;24:1183-1200. Stephens M, Gibbs AR, Pooley FD, Wagner JC. Asbestos induced pleural fibrosis: pathology and mineralogy. Thorax. 1987; 42:583. Hillerdal G, Lee J, Blomkvist A, Rask –Andersen A, Uddenfeldt M, Kovi H, Rasmussen E. Pleural disease during treatment with bromocriptine in patients previously exposed to asbestos.Eur Respir J. 1997;10:2711-5. McElvaney NG, Wilcox PG, Churg A, Fleetham JA. Pleuropulmonary disease during Bromocriptine treatment of Parkinson's disease. Arch Intern Med. Morelock SY, Sahn SA. Drugs and the pleura. Chest, 1999; 116:212-221. Huggins JT, Sahn SA. Drug-induced pleural disease. Clin Chest Med, 2004;25:141-153. Tintner R, Manian P, Gauthier P, Jankovic J. Pleuropulmonary fibrosis after long term treatment with the dopamine agonist pergolide for Parkinson disease. Arch Neurol, 2005;62:1290-5.