Asthma associated with worsening leg ulcer: a case of vasculitis in primary care. (Case Report).

Abstract: A 71-year-old black woman was admitted to the hospital with a 2-month history of a nonhealing leg ulcer. Her medical history included diabetes mellitus type 2, congestive heart failure, allergic rhinitis, and asthma. The patient's asthma was labile and steroid-dependent until 2 years before admission, at which time zafirlukast therapy was started. On further questioning, the patient revealed a 6-month history of malaise and a 40-lb weight loss. A physical examination showed a 2-cm Stage 3 ulcer on the medial aspect of the right ankle with diminished sensation in both feet and left footdrop. Electromyography revealed mononeuritis multiplex. The patient's white blood cell count was 11,100/[mm.sup.3] with 60% eosinophils. A sural nerve biopsy showed vasculitis consistent with Churg-Strauss syndrome. One week after prednisone therapy was initiated, the patient's foot strength was nearly normal and her eosinophilia had resolved. Although ChurgStrauss syndrome is a rare disorder, in the setting of asthma and multiple disparate signs and symptoms, the broad diagnostic category of serious vasculitic illness should be considered.

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Churg-Strauss syndrome (CSS) is a rare form of small-vessel vasculitis with an incidence of 2.4 to 3.3 per 1 million population. (1) Symptoms usually appear between 20 and 40 years of age, with a slight predominance in men. The 1990 American College of Rheumatology classification criteria for CSS are as follows: 1) asthma; 2) eosinophilia of more than 10%; 3) mononeuropathy, including mononeuritis multiplex or polyneuropathy; 4) paranasal sinus abnormality; 5) nonfixed pulmonary infiltrates; and 6) extravascular eosinophils evidenced on biopsy. (2) The presence of four or more of these criteria yields a sensitivity of 85% and a specificity of 99.7%. (3) Constitutional symptoms such as malaise, anorexia, weight loss, cardiac involvement including congestive heart failure, and skin lesions are also common in CSS. The cause of CSS is unknown, but several reports of drug-related disease have been published. (1,4) Isolated cases of CSS have been documented in association with estrogen replacement therapy, the use of free-base cocaine, and macrolides. (3) The occurrence of CSS in patients with asthma undergoing leukotriene receptor antagonist (LTA) therapy was determined to be related to the unmasking of an underlying vasculitic syndrome because of steroid sparing rather than a direct cause and effect. (1,5-8) CSS is a rare disease requiring early and accurate diagnosis followed by immunosuppressive therapy to prevent severe clinical deterioration. We present this case to emphasize that in a patient with multisystem disease and nonspecific symptoms, particularly in association with asthma, vasculitis needs to be considered.

Discussion

This case met four of the six American College of Rheumatology criteria for the diagnosis of CSS: 1) asthma, 2) eosinophilia (60%), 3) mononeuritis multiplex, and 4) extravascular eosinophils in sural nerve biopsy. The constellation of late-onset severe asthma, history of zafirlukast use, marked eosinophilia, and recent foot drop served as the impetus for an aggressive workup in this case.

Pulmonary involvement may be seen in 96 to 100% of patients with CSS in the form of asthma, pleural effusions, or nonfixed patchy infiltrates on chest films. The neurologic findings may be either mononeuritis multiplex or polyneuropathy in 66 to 75% of patients. Cardiac involvement is known to be a major cause of mortality and morbidity in patients with CSS. Manifestations may include cardiac arrest, valvular heart disease, congestive heart failure, pericardial effusion, acute or chronic pericarditis, and eosinophilic endomyocarditis. (9) Although we cannot rule out a possible silent ischemic episode or minimize the potential therapeutic effect of the angiotensin-converting enzyme inhibitor in our patient, impressive improvement of her left ventricular EF in response to steroid treatment strongly suggests that cardiac involvement was part of her vasculitic syndrome. In contrast to our case, patients' response to steroids in CSS-associated cardiomyopathy at a late stage is reported to be limited, (3,9) althoug h it is remarkable in the setting of neuropathy.

The cause of CSS is unknown, although isolated cases of CSS have been associated with various medications, including LTAs. However, the incidence of CSS in patients undergoing LTA therapy was found to be comparable to that in patients with asthma as a whole (approximately 60 cases/I million patients/yr). (1,5) Most likely, systemic manifestations of CSS are unmasked with LTAs because of the steroidsparing effect. (1) As in our case, vasculitis progresses cryptically because the patient's asthma is improved by LTAs, whereas the eosinophilic process invades other organs slowly. The duration of treatment with LTA therapy before the onset of symptoms was 2 years in our patient, compared with 2 to 7 months in patients described in previous case reports. (1,4,10)

CSS has a three-phase clinical pattern: a prodromal phase of allergic disease, peripheral eosinophilia and eosinophilic tissue infiltration, and a life-threatening vasculitic phase. (11) Our patient's course was consistent with this pattern. Her asthma and allergic rhinitis had been diagnosed 4 years earlier, mild eosinophilia had developed 2 years earlier, and then she had severe manifestations of CSS.

Treatment with oral corticosteroids is known to be effective in patients with CSS. Myocardial involvement and severe gastrointestinal involvement were reported to be predictors of poor prognosis, (4) and the addition of immunosuppressive treatment such as cyclophosphamide is recommended. (12) High doses of interferon a can maintain remission in patients who have responded incompletely to cyclophosphamide. (12) Our patient responded so dramatically to prednisone therapy that other immunosuppressive treatments have yet to be considered.

Conclusion

Early recognition followed by immunosuppressive therapy is essential in patients with CSS. Five-year survival ranges from 62 to 79%, with higher mortality strongly associated with cardiac, gastrointestinal, and renal involvement. (3) In the setting of asthma and multiple, disparate systemic signs and symptoms, the broad diagnostic category of serious vasculitic illness should be considered.

Accepted July 10, 2002.

References

(1.) Wechsler ME, Finn D, Gunawardena D, Westlake R, Barker A, Haranath SP, et al. Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma. Chest 2000;117:708-713.

(2.) Masi AT, Hunder CG, Lie JT, Michel BA, Bloch DA, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990;33:1094-1100.

(3.) Ramakrishna G, Midthun DE. Churg-Strauss syndrome. Ann Allergy Asthma Immunol 2001;86:603-6l3.

(4.) Anonymous. Case records of the Massachusetts General Hospital: Weekly clinicopathological exercises--Case 30-2000: A 25-year-old man with asthma, cardiac failure, diarrhea, and weakness of the right hand. N Engl J Med 2000;343:953-961.

(5.) Spector SL. Safety of antileukotriene agents in asthma management. Ann Allergy Asthma Immunol 2001;86(6 Suppl 1):18-23.

(6.) Cranmer LD, Warrington KJ, Ytterberg SR. 61-year-old man with dyspnea and bilateral foot drop. Mayo Clin Proc 2002;77:363-366.

(7.) Kinoshita M, Shiraishi T, Koga T, Ayabe M, Rikimaru T, Oizumi K. Churg-Strauss syndrome after corticosteroid withdrawal in an asthmatic patient treated with pranlukast. J Allergy Clin Immunol 1999;103:534-535.

(8.) Mukhopadhyay A, Stanley NN. Churg-Strauss syndrome associated with montelukast. Postgrad Med J 2001;77:390-391.

(9.) Ramakrishna G, Connolly HM, Tazelaar HD, Mullany CJ, Midthun DE. Churg-Strauss syndrome complicated by eosinophilic endomyocarditis. Mayo Clin Proc 2000;75:631-635.

(10.) Wechsler ME, Garpestad E, Flier SR, Kocher O, Weiland DA, Polito AJ, et al. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. JAMA 1998;279:455-457.

(11.) Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: A clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore) 1984;63:65-81.

(12.) Solans R, Bosch JA, Perez-Bocanegra C, Selva A, Huguet P, Alijotas J, et al. Churg-Strauss syndrome: Outcome and long-term follow-up of 32 patients. Rheumatology (Oxford) 2001 ;40:763-771.

RELATED ARTICLE: Key Points

* A presentation of asthma with a disparate constellation of symptoms such as nonhealing leg ulcer or neuropathy should trigger consideration of vasculitis as a primary diagnosis.

* Leukotriene receptor antagonists can unmask the manifestations of Churg-Strauss syndrome because of their steroid-sparing effect.

* Cardiac involvement is a poorly recognized manifestation of Churg-Strauss syndrome that is linked to major morbidity as a result of the disease.

Case Report

A 71-year-old black woman was admitted to the hospital with a nonhealing leg ulcer that had been present for 2 months and had continued to progress despite local skin care and oral antibiotics. Her medical history included diet-controlled diabetes mellitus type 2, allergic rhinitis, and asthma of 4 years' duration with two episodes of status asthmaticus. Five months before this admission, the patient had been hospitalized with acute congestive heart failure and left pleural effusion. A two-dimensional echocardiogram showed global hypokinesis with an ejection fraction (EF) less than 25%. On further questioning, the patient reported fatigue, malaise, early satiety, anorexia, and a 40-lb weight loss during the past 6 months. Numbness and tingling in the lower extremities also were reported and were presumed to be due to diabetic neuropathy. She denied fevers, chills, night sweats, or skin rash. Her medications included benazepril, digoxin, furosemide (Lasix; Aventis Pharmaceuticals, Inc., Bridgewater, NJ), aspir in, lansoprazole, metoclopramide, amitriptyline, albuterol, salmeterol, ipratropium inhalers, and zafirlukast.

At admission, it was noted that the patient had bilateral varicose veins and a 2-cm Stage 3 ulcer on the medial aspect of the right ankle, without any purulent drainage. There was diminished sensation to pinprick in the feet bilaterally, with motor function of 4/5 in plantarflexion and 2/5 in dorsiflexion of the left foot. The findings of electromyographic nerve conduction studies of the lower extremities were consistent with mononeuritis multiplex. A complete blood cell count showed a white blood cell count of 11,000/[mm.sup.3] with 60% eosinophils, and the patient's immunoglobulin E level was 503 IU/ml (normal,...0-180 IU/ml). The results of liver and renal function tests, thyroid function tests, and urinalysis were normal, but the patient's total serum protein value was 7.3 g/dl, her albumin value was 2.3 g/dl, and her erythrocyte sedimentation rate was 51 mm/h with negative tests for antinuclear antibody and rheumatoid factor. Serum protein electrophoresis showed a polyclonal gammopathy. The test for anti -hepatitis B surface antibody was positive. Tests for anti-hepatitis C virus, human immunodeficiency virus, cryoglobulins, and antineutrophil cytoplasmic antibodies, including both antimyeloperoxidase and anti-[PR.sub.3], were all negative. Stool tests were negative for occult blood, ova, and parasites. The chest and abdominal computed tomographic scans were unremarkable. Repeated two-dimensional echocardiography showed that the patient's EF had decreased to 20%, with severe hypokinesis and mild tricuspid regurgitation, mitral regurgitation, and aortic regurgitation. A skin ulcer biopsy revealed superficial and deep dermis perivascular dermatitis with fibrosis. A sural nerve biopsy revealed severe loss of large and small myelinated axons, as well as perivascular inflammation with predominance of plasma cells and eosinophils consistent with vasculitis (Figs. 1 and 2).

Zafirlukast therapy was discontinued, and prednisone therapy was started at 60 mg/d. One week after the initiation of therapy, motor function in the left foot improved to 5/5 in plantarflexion and 4/5 in dorsiflexion. The patient's easinophilia had resolved (white blood cell count, 4,200/ [mm.sup.3] easinophils, 2%). Her erythrocyte sedimentation rate decreased to 39 mm/h. The patient's appetite increased, and she gained 6 lb. After 6 months of treatment, repeated two-dimensional echocardiography showed an EF of 40 to 45%.

From the Internal Medicine Program, Moses Cone Hospital, Greensboro, NC.

Reprint requests to Samuel Cykert, MD, Internal Medicine Office, Moses Cone Hospital, 1200 N. Elm Street, Greensboro, NC 27401. Email: [e-mail]

Copyright [C] 2003 by The Southern Medical Association

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