LAUSR

Chronic cough is a common presenting complaint that has a substantial impact on quality of life and healthcare utilisation. Eosinophilic bronchitis, an important cause of chronic cough, is caused by airway inflammation as a result of eosinophilic infiltration. Medications, including leflunomide, are frequently the cause of eosinophilia in the blood as well as in the airway. Hence, leflunomideinduced eosinophilic bronchitis should be considered in the differential diagnosis of cough for all patients to whom this medication is prescribed. A 56-year-old white woman with a history of sarcoidosis was evaluated for persistent, non-productive cough and wheezing 12 months after the initiation of leflunomide. She was a non-smoker without a history of significant exposures. Her sarcoidosis was diagnosed 10 years earlier. It had been well controlled on prednisone until she developed corticosteroid-induced cataracts resulting in discontinuation of prednisone and subsequent worsening of her pulmonary symptoms. At the time of the initial encounter, her vital signs were normal. The rest of her examination was significant only for wheezing on auscultation. Laboratory values were unremarkable except for an immunoglobulin E of 285 Ku/L and peripheral eosinophils of 7.3%. Pulmonary function tests revealed no obstruction or response to bronchodilators. Computed tomography (CT) of the chest demonstrated an interval increase in subcarinal and hilar adenopathy, increased perihilar fibrosis and traction bronchiectasis in the bilateral upper lobes compatible with stage IV sarcoidosis. Cardiac magnetic resonance imaging demonstrated cardiac involvement, but the echocardiogram was normal. The patient was started on leflunomide 10 mg daily as a steroid-sparing agent. She initially tolerated the new medication well and the dose was titrated to 20 mg daily. At the 3-month follow up, she began to complain of a cough that progressively worsened over the next 9 months despite intermittent treatment with prednisone and antibiotics. No changes were noted on chest imaging over this time period. The patient underwent further work up with bronchoscopy, which demonstrated pale yellow bronchial wall plaques. Endobronchial biopsy was performed on the plaques and the samples were sent to pathology where eosinophilic infiltration of the bronchial tissue was confirmed. Leflunomide was promptly discontinued and prednisone restarted at 10 mg daily. The patient reported complete resolution of her pulmonary symptoms 2 weeks after stopping leflunomide. She was transitioned to azathioprine and prednisone was tapered off. Chronic cough is defined as a cough lasting greater than 8 weeks without clear clinical or radiographic evidence of lung disease. The workup for chronic cough has a broad differential diagnosis including infection, reactive airway disease, malignancy, interstitial lung disease and medication side-effects. There can be multiple causes of chronic cough affecting the patient simultaneously; therefore, it is important to explore other possible causes especially when there is an incomplete or lack of response to therapy. This patient’s presentation was without markers of infection. Pulmonary function tests were negative for reactive airway disease. The findings of hilar lymphadenopathy as well as fibrosis on her chest CT were consistent with her history of sarcoidosis. Further investigation with bronchoscopy was indicated and demonstrated pale yellow plaques along the bronchial walls. These findings were consistent with eosinophilic infiltration of the bronchial wall which was later confirmed on pathology. Patients with eosinophilic bronchitis will present with airway inflammation in the absence of airway hypersensitivity. The exact pathophysiology for the development of drug-induced eosinophilic diseases remains unclear. It has been shown that interleukin (IL)-4, IL-5 and eosinophilic cationic protein release in eosinophilic bronchitis are not different from asthma in terms of eosinophil degranulation in the bronchial mucosa and the levels of nitric oxide in expiratory air. Leflunomide, a pyrimidine synthesis inhibitor, is classically used as an immunosuppressive disease-modifying antirheumatic drug with indications for use in the treatment of sarcoidosis. It is cited as a known causative agent of peripheral eosinophilia and eosinophilic pneumonia. However, to our knowledge, a case of leflunomide-induced eosinophilic bronchitis has not yet been reported. After discontinuing leflunomide, the first-line treatment is corticosteroids. Trial of an alternative steroid-sparing agent can be initiated after the symptoms subside. As this case illustrates, chronic cough is a common presenting symptom that has a broad differential diagnosis. Drug-induced eosinophilic bronchitis must be considered in the setting of elevated eosinophils and spirometry negative for reactive airway disease. Leflunomide-induced eosinophilic bronchitis is one of the lesser known causes