A severe systemic inflammatory reaction following therapy with montelukast (Singulair®)

Lasse G. Gøransson and Roald Omdal

Department of Medicine, Central Hospital of Rogaland, Stavanger, Norway

Keywords: eosionophilia; glomerulonephritis; leukotriene antagonist



   Introduction
 Top
 Introduction
 Case
 Discussion
 Conclusion
 References
 
Recent reports describe Churg-Strauss syndrome in asthma patients being treated with zafirlukast, a potent, orally administered leukotriene-receptor antagonist [1]. Similar reactions have been reported with montelukast [2]. We report a case with glomerulonephritis and hypereosinophilia after use of montelukast (Singulair®).



   Case
 Top
 Introduction
 Case
 Discussion
 Conclusion
 References
 
A 46-year-old, non-smoking, Asiatic woman with asthma was hospitalized. She had a 3-year history of moderate persistent asthma and for the last year she had experienced multiple exacerbations that required treatment with prednisolone. She had been on therapy with budesonid, formoterol, and terbutalin, and in January 1998 she was also started on therapy with montelukast (Singulair®). She had a marked improvement in her asthma symptoms.

In May 1998 the patient noted an increase in her asthma symptoms, and she developed fever, muscle pain, and an erythematous exanthem on hands and feet. Pneumonia was suspected, and she was treated with azithromycin and amoxicillin for 2 weeks without amelioration of her symptoms.

On admission to hospital she had a leucocyte count in peripheral blood of 16.8x109/l, with 7.38x109/l eosinophils (42.6%), C-reactive protein 208 mg/l, erythrocyte sedimentation rate 92 mm/h, and serum creatinine 85 µmol/l which increased to 170 µmol/l. Antineutrophil cytoplasmic antibody (ANCA) determined as anti-myeloperoxidase (MPO), was strongly positive (>80 U/l), and other immunological and routine biochemical tests including blood cultures were negative. She had microscopic haematuria, hyaline, granular and erythrocyte casts, and a 24-h urinary protein excretion of 1.6 g. Chest X-ray was negative. Renal biopsy demonstrated a necrotizing glomerulonephritis with crescent formation without deposits of IgM, IgG, IgA, C1q or C3a, a marked interstitial infiltrate with tissue eosinophils, and normal blood vessels. A blind muscular biopsy from the lateral vastus muscle showed no signs of vasculitis.

Therapy with montelukast (Singulair®) was discontinued, she received intravenous pulse therapy with methylprednisolone, and she was also started on prednisolone 10 mg/day. She had an immediate improvement of her symptoms, and the eosinophilia quickly disappeared. After 4 months of therapy with low-dose corticosteroids she had a normal creatinine of 98 µmol/l and a persistent proteinuria in non-nephrotic range (2+ by dipstick).



   Discussion
 Top
 Introduction
 Case
 Discussion
 Conclusion
 References
 
Both montelukast and zafirlukast has proved to be effective and well tolerated [24]. However, there are a number of case reports describing a Churg-Strauss like syndrome in patients treated with leukotriene antagonists [1]. A prominent feature of all cases is a markedly elevated eosinophil count in peripheral blood.

Churg-Strauss syndrome is a systemic vasculitis characterized by the presence of asthma, hypereosinophilia and necrotizing vasculitis with extravascular granulomas and tissue infiltration by eosinophils. Renal involvement is not uncommon, and on renal biopsies focal segmental glomerulonephritis with necrotizing features and crescent formation is the predominant findings, whereas extravascular granulomas and eosinophilic infiltrates are uncommon [5]. A positive ANCA (MPO) is associated with the syndrome [6].

In contrast to other reports, Churg-Strauss syndrome could not be documented in our patient. However, a condition with severe systemic inflammation, positive p-ANCA, hypereosinophilia and glomerulonephritis started after administration of montelukast. It is unlikely that azithromycin or amoxicillin triggered the inflammatory reaction since the treatment was started after the beginning of the patient's symptoms. The patient has been followed for 4 months, and she is still on treatment with 7.5 mg prednisolone daily. She has no signs of disease except for a persistent proteinuria in non-nephrotic range.



   Conclusion
 Top
 Introduction
 Case
 Discussion
 Conclusion
 References
 
This patient illustrates a case with a marked and severe inflammatory reaction characterized by eosinophilia and glomerulonephritis which might have been triggered by the leukotriene receptor antagonist, montelukast.



   Notes
 
Correspondence and offprint requests to: Dr Lasse Gøransson, Department of Medicine, Division of Nephrology, Central Hospital of Rogaland, Stavanger PB 8100, N-4068 Stavanger, Norway. Back



   References
 Top
 Introduction
 Case
 Discussion
 Conclusion
 References
 

  1. Wechsler M, Garpestad E, Flier S, et al. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. J Am Med Assoc1998; 279: 455–457[Abstract/Free Full Text]
  2. Lipworth B. Leukotriene-receptor antagonists. Lancet1999; 353: 57–62[ISI][Medline]
  3. Malmstrom K, Rodriguez-Gomez G, Guerra J et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. Ann Intern Med1999; 130: 487–495[Abstract/Free Full Text]
  4. Suissa S, Dennis R, Ernst P, Sheehy O, Wood-Dauphinee S. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med1997; 126: 177–183[Abstract/Free Full Text]
  5. Clutterbuck E, Evans D, Pusey C. Renal involvement in Churg-Strauss syndrome. Nephrol Dial Transplant1990; 5: 161–167[Abstract]
  6. Guillevin L, Cohen P, Gayraud M, Lhote F, Jarrousse B, Casassus P. Churg-Strauss syndrome. Clinical study and long-term follow up of 96 patients. Medicine (Baltimore)1999; 78: 26–37[ISI][Medline]
Received for publication: 28.10.99
Revision received 25. 2.00.



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