558 Thorax 1999;54:558–560

Case reports

Pulmonary eosinophilia associated with

José Franco, María José Artés

Abstract with zafirlukast.2–4 No other modi- drugs are new therapeutic fier has yet been associated with the syndrome. agents that have recently been approved for In this case report we describe an asthmatic the treatment of . Several cases of patient in whom pulmonary eosinophilia devel- eosinophilic conditions including Churg- oped while receiving montelukast therapy. Strauss syndrome have been reported to be associated with zafirlukast, a cysteinyl leu- Case report kotriene type 1 antagonist. So far A 26 year old man with a three year history of no other leukotriene modifier has been asthma had received treatment with salbuta- associated with the syndrome. The case mol, , , and beclo- history is presented of a man with allergic methasone. There was a five year history of rhinitis and asthma who had received with positive skin tests for intermittent pulse therapy with oral house dust mite and cat dander. Because . Pulmonary eosinophilia asthma symptoms were not well controlled, developed while he was receiving treatment treatment was started with fluticasone 1000 µg with montelukast, a chemically distinct daily and twice a day. Allergen cysteinyl leukotriene type 1 receptor an- immunotherapy was also prescribed. Nonethe- tagonist. After discontinuation of montelu- less, short courses of oral prednisone 40 mg or kast therapy and administration of deflazacort 60 mg daily were required on systemic corticosteroids the patient’s several occasions to control asthma exacerba- symptoms reversed rapidly and there was tions. A decision was made to initiate treatment prompt resolution of the pulmonary infil- with montelukast at a dose of 10 mg daily in trates. We believe that cysteinyl leukotriene the evening. Treatment with fluticasone was type 1 receptor antagonists are safe and continued. V e ective drugs for most patients with After approximately four months of treat- asthma but caution is needed for those with ment with montelukast the patient developed more severe disease who require systemic headache, malaise, myalgia, nasal congestion, corticosteroids, especially if they show and fever up to 39ºC. Oral cefuroxime and characteristics of the atypical allergic dia- paracetamol were prescribed. Seven days later thesis seen in the prodromal phase of the patient developed dyspnoea and was Churg-Strauss syndrome. admitted to our hospital. (Thorax 1999;54:558–560) On physical examination there were diVuse Keywords: montelukast; side eVects; pulmonary eosi- wheezes and ronchi. No cutaneous lesions or nophilia arthritis were found. A chest radiograph (fig 1) Department of showed mixed alveolar-interstitial infiltrates in Pneumology the upper lobes. Laboratory findings demon- J Franco The antileukotriene drugs are new therapeutic strated a white blood cell count of 13.9 × 109/l agents which have recently been approved and Department of are now available for the treatment of asthma in Pathology several countries. These drugs include one MJArtés of 5-lipoxygenase, , University Hospital and three chemically distinct cysteinyl leuko- Dr. Peset, Valencia, triene type 1 receptor antagonists, zafirlukast, Spain and montelukast.1 Although clinical studies have shown that Correspondence to: Dr J Franco, Diputado Luis antileukotriene drugs are safe and eVective, the Lucía 19-5, E-46015 results do not yet provide guidelines for their Valencia, Spain. optimal clinical use in the treatment of asthma.1 As the use of these drugs increases, adverse Received 6 January 1999 Returned to authors events occurring at low frequency or in popula- 26 February 1999 tions not examined in clinical trials may become Revised manuscript received manifest.2 Several cases of eosinophilic condi- 12 March 1999 Accepted for publication tions including Churg-Strauss syndrome have Figure 1 Posteroanterior radiograph of the chest showing 16 March 1999 been reported in patients who have been treated mixed alveolar-interstitial infiltrates in both upper lobes. Pulmonary eosinophilia associated with montelukast 559

Despite the lack of systemic vasculitis and a negative ANCA, this patient with his five year history of allergic rhinitis, progressive airways symptoms, and intermittent treatment with oral corticosteroids could have a forme frustre of Churg-Strauss syndrome. Wechsler et al2 reported eight cases of Churg-Strauss syndrome following discontinu- ation of treatment with oral corticosteroids in patients with asthma receiving zafirlukast. The authors speculated that all these patients suVered from a primary eosinophilic infiltrative disorder that was unmasked when steroids were withdrawn. However, in two other cases of Churg-Strauss syndrome associated with zafirlukast therapy34and in the case of pulmo- nary eosinophilia reported in this paper there was no association between withdrawal and the development of the syn- Figure 2 Bronchoalveolar lavage fluid showing a large number of as well as drome. Because all these patients had moder- scant macrophages. Papanicolaou stain; ×40. ate to severe asthma and had received intermit- tent or regular treatment with oral with an fraction of 0.14; the total corticosteroids, they could have been formes IgE level was 527 IU/l and the results of an frustres of Churg-Strauss syndrome whose antineutrophil cytoplasmic antibody (ANCA) manifestations were quelled by prior steroid test were negative. A specimen of arterial treatment.7 blood, drawn while the patient was breathing As this syndrome has not yet been seen in room air, had a pH of 7.45 with oxygen tension patients treated with zileuton, a drug that inhib-

(PaO2) of 8.7 kPa and carbon dioxide tension its leukotriene B4 (LTB4) and cysteinyl leukot-

(PaCO2) of 5.0 kPa. A fibreoptic bronchoscopic rienes (LTC4, LTD4 and LTE4), an alternative examination found no endobronchial lesions. explanation based on the imbalance in leukot- Bronchoalveolar lavage fluid (fig 2) contained riene receptor stimulation has been put macrophages (10%), lymphocytes (10%), and forward.8 Cysteinyl leukotriene type 1 receptor eosinophils (80%). No acid-fast bacilli, fungi, antagonism may have led to increased circulat- or parasites were seen in the lavage fluid. ing LTB4 which has been shown to be a chem- Microscopic examination of a stool specimen oattractant for eosinophils as well as disclosed no parasites. neutrophils.9 Montelukast treatment was discontinued Pulmonary eosinophilia associated with a and treatment with intravenous methylpred- cysteinyl leukotriene type 1 nisolone at a dosage of 60 mg daily was begun. other than zafirlukast suggests that the syn- Both dyspnoea and constitutional symptoms drome may be related to the eVect of improved within a short time. After nine days antileukotriene drugs on leukotriene receptors. of treatment with high dose systemic cortico- Churg-Strauss syndrome is a disorder char- steroids a chest radiograph revealed resolution acterised by hypereosinophilia and systemic of pulmonary infiltrates. vasculitis which occurs in a subset of patients with asthma and allergic rhinitis whose allergic Discussion diathesis is atypical with respect to the late age Montelukast is a potent and selective cysteinyl of onset of symptoms, frequent absence of leukotriene type 1 receptor antagonist with family history, severity of upper respiratory potency and oral activity similar to those of tract disease, and exaggerated eosinophil zafirlukast.5 At a dosage of 10 mg montelukast response.10 The patient described here and the inhibits bronchospasm after allergen or exercise cases of Churg-Strauss syndrome associated challenge and causes clinically significant im- with zafirlukast previously reported could provement in patients with asthma. The toler- belong to this category of patients. We hypo- ability profile of montelukast was similar to that thesise that, in such individuals, cysteinyl of placebo in placebo controlled clinical trials in leukotriene type 1 receptor antagonists can adults and children, and the most common precipitate the phase of the illness character- adverse eVect reported was headache.6 ised by eosinophilic tissue infiltrates or life In the case reported here the temporal rela- threatening systemic vasculitis. tionship between montelukast treatment and We believe that cysteinyl leukotriene type 1 the development of pulmonary eosinophilia receptor antagonists remain safe and eVective suggests a causal association. However, we drugs for most patients with mild to moderate cannot exclude the possibility that the patient asthma but, while the exact causes of the might have developed another eosinophilic syndrome are not well understood, caution is condition such as allergic bronchopulmonary needed for those with more severe disease who aspergillosis even without treatment with mon- require systemic corticosteroids, especially if telukast. The absence of parasites in the stools they show characteristics of the atypical allergic and the bronchoscopic specimens makes para- diathesis seen in the prodromal phase of site induced eosinophilic lung disease unlikely. Churg-Strauss syndrome. 560 Ledson, Convery, Carty, et al

1 O’Byrne PO, Israel E, Drazen JM. in nists. Am J Respir Crit Care Med 1998;157:s214–9. the treatment of asthma. Ann Intern Med 1997;127:472– 6 Markham A, Faulds D. Montelukast. Drugs 1998;56:251–6. 80. 7 Churg J, Churg A. Zafirlukast and Churg-Strauss syn- 2 Wechsler ME, Garpestad E, Flier SR, et al. Pulmonary infil- drome. JAMA 1998;279:1949–50. trates, eosinophilia, and cardiomyopathy following cortico- 8 Honsinger RW. Zafirlukast and Churg-Strauss syndrome. steroid withdrawal in patients with asthma receiving JAMA 1998;279:1949. zafirlukast. JAMA 1998;279:455–7. 3 Katz RS, Papernik M. Zafirlukast and Churg-Strauss 9 Crooks SW, Stockley RA. Leukotriene B4. Int J Biochem Cell syndrome. JAMA 1998;279:1949. Biol 1998;30:173–8. 4 Knoell DL, Lucas J, Allen JN. Churg-Strauss syndrome 10 Lanham JG, Elkon KB, Pusey CD, et al. Systemic vasculitis associated with zafirlukast. Chest 1998;114:332–4. with asthma and eosinophilia: a clinical approach to the 5 Aharony D. Pharmacology of leukotriene receptor antago- Churg-Strauss syndrome. Medicine 1984;63:65–81.

Thorax 1999;54:560–561 Epithelioid haemangioendothelioma

M J Ledson, R Convery, A Carty, C C Evans

Abstract Epithelioid haemangioendothelioma is a rare pulmonary neoplasm with less than 40 cases described world wide. We describe the only case to have presented with hypertrophic pulmonary osteoarthropathy who has been treated with azathioprine and has remained alive and well with no deterioration in pulmonary function since being diagnosed 16 years ago. The progres- sion of the chest radiograph and spiral CT appearances of this rare neoplasm are described, and current views regarding the cellular origin of the neoplasm, its cyto- logical appearance, clinical presentation and prognosis are discussed. (Thorax 1999;54:560–561) Figure 1 Chest radiograph in 1996 revealing multiple irregular unequal bilateral calcified uniformly distributed Keywords: epithelioid haemangioendothelioma; intra- nodular shadowing. vascular sclerosing bronchioalveolar tumour immunoglobulins were all normal. Autoanti- bodies including rheumatoid factor and anti- Epithelioid haemangioendothelioma (EHE) nuclear factor were negative, as was a Mantoux (formerly known as intravascular sclerosing test. The erythrocyte sedimentation rate was bronchioalveolar tumour, IVBAT) is a rare 46 mm in the first hour. Pulmonary function pulmonary neoplasm with less than 40 cases tests revealed a mild restrictive ventilatory described world wide. We have described the defect with lung volumes 70% predicted. Gas first reported case presenting with hyper- transfer was normal. No endobronchial lesions trophic pulmonary osteoarthropathy.1 We now were found at fibreoptic bronchoscopy and a report the progress of this patient who is transbronchial lung biopsy specimen was unique in that she has been treated with unhelpful. The patient therefore underwent an azathioprine and has remained alive and well open lung biopsy via a left thoracotomy. At with no deterioration in pulmonary function operation multiple nodules up to 15 mm in since being diagnosed 16 years ago. diameter were found throughout the lung. Two wedge biopsies were taken from the lingula. All nodules had similar histological appearances Case report which were considered typical of EHE. The Cardiothoracic In April 1981 a 24 year old woman presented As the majority of her symptoms were due Centre, Thomas Drive, to our unit with a six month history of pain and the hypertrophic pulmonary osteoarthropathy Liverpool L14 3PE, UK swelling in her ankles and a six week history of indomethacin was commenced with good M J Ledson mild exertional dyspnoea. On examination her eVect. Azathioprine was also started and the R Convery fingers and toes were grossly clubbed and her patient returned to work. The patient has been A Carty CCEvans wrists and ankles were swollen and tender. reviewed yearly for the past 16 years and her Inspiratory crackles were audible at the left symptoms have remained unchanged. Increas- Correspondence to: base posteriorly. Her chest radiograph, which ing calcification of the nodules was seen radio- Dr C C Evans. had been normal six years earlier, showed mul- logically by 1989, and by 1996 (fig 1) the over- tiple irregular, unequal, bilateral, uniformly all number of nodules remained unchanged Received 14 July 1997 Returned to author distributed, non-calcified nodular shadowing. but their size had decreased to a maximum of 12 September 1997 Radiographs of her wrists and ankles showed 12 mm. A thoracic spiral intravenously en- Revised manuscript received changes of hypertrophic pulmonary osteoar- hanced CT scan was performed in 1997 (fig 2) 5 November 1997 Accepted for publication thropathy. Full blood count, urea and electro- showing innumerable 12 mm calcified nodules 20 November 1997 lytes, liver function tests, calcium, and serum in all areas but more concentrated at the lung