Correspondence *University of Texas Southwestern Medical Center, Veterans Affairs North Texas Healthcare System, MC 111G1, 4500 South Lancaster Road, Dallas, TX 75216-7167, USA

Email susan.hedayati@utsouthwestern.edu

The case

A 36-year-old white male with a several-year history of urticaria, chronic cough, allergic rhinitis and sinusitis presented to the emergency room with cramping abdominal pain, bloating, and dark and watery diarrhea, all of which had begun 1 week previously. The patient had a 20-pack-year history of smoking, but he denied using any prescription, over-the-counter or herbal medications. He also had a fever, as well as generalized myalgias and arthralgias. Upon physical examination, the patient's temperature was 38.8 °C (101.8 °F), his blood pressure was 144/89 mmHg, his pulse rate was 111 beats per minute, his respiratory rate was 20 breaths per minute, and his pulse oximetry showed oxygen saturation of 93% on room air. Bibasilar pulmonary rales, moderate lower extremity edema and a diffuse maculopapular rash involving both lower legs and feet were noted.

Blood analysis revealed leukocytosis (30,800 cells/mm³; reference range 3–11,000 cells/mm³) with an elevated eosinophil level (8.1%; reference range 0–4%), thrombocytosis (870,000 cells/mm³; reference range 150–400,000 cells/mm³) and anemia (hemoglobin 97 g/l; reference range 135–180 g/l). The patient's blood urea nitrogen level was 6.38 mmol/l (reference range 2.5–6.7 mmol/l), and his serum creatinine level was 123 mol/l (reference range 70–150 mol/l). Abdominal CT with intravenous contrast revealed thickening of the distal duodenum and jejunum, and subcentimeter mesenteric and retroperitoneal lymphadenopathy. Other pertinent findings included a low partial pressure of oxygen (58 mmHg) and reduced oxygen saturation (89% on room air) as measured in the patient's arterial blood. A urine sediment examination revealed the presence of numerous white blood cells and dysmorphic red blood cells, but no casts. The protein:creatinine ratio of a spot urine sample was 2.9, and the patient's erythrocyte sedimentation rate (ESR) was greater than 120 mm/h (reference range 10–20 mm/h).

The patient was admitted to the hospital. Initial blood cultures grew Staphylococcus epidermidis in two of four samples, and a urine culture grew contaminants, so empirical antibiotic therapy was initiated. However, all subsequent cultures, including those from stool samples, tested negative for bacterial and fungal pathogens, and, therefore, antibiotic therapy was discontinued. Chest radiography and CT showed cardiomegaly and bilateral patchy pulmonary infiltrates. Esophagogastroduodenoscopy revealed an ulcerated duodenojejunal mass; a biopsy of the mass showed acute and chronic inflammation. A skin biopsy of the patient's lower extremities revealed subepidermal vesicular dermatitis with infiltration by lymphocytes, eosinophils and neutrophils. A mesenteric lymph node biopsy did not yield an adequate sample for analysis.

A renal ultrasound showed that the patient had normal-sized kidneys but not hydronephrosis. Serologic investigations, including tests for antinuclear antibody, antibodies against rheumatoid factor, hepatitis B and C, HIV types 1 and 2, antiglomerular basement membrane antibody, and antineutrophil cytoplasmic antibodies (ANCA) directed against myeloperoxidase and proteinase 3, were all negative. The patient's complement levels were normal. Serologic testing for syphilis, and serum and urine protein electrophoresis to test for monoclonal gammopathy were also all negative.

A renal biopsy revealed the presence of eleven glomeruli, none of which were globally sclerotic. Three glomeruli had segmental fibrinoid necrosis of capillary tufts surrounded by early crescents (Figure 1). The remaining eight glomeruli were histologically unremarkable. The biopsy also revealed interstitial fibrosis and mild focal tubular atrophy, as well as mild interstitial edema with heavy infiltration of lymphocytes, plasma cells and eosinophils (Figure 2). Immunofluorescence studies did not reveal any immunoglobulins or complement components. No electron-dense deposits were noted on electron microscopy. The final diagnosis was pauci-immune focal necrotizing glomerulonephritis consistent with Churg–Strauss syndrome.

Figure 1 The renal biopsy reveals a glomerular segment with deeply acidophilic, fibrinoid necrosis surrounded by a small cellular crescent.

There is also a substantial interstitial infiltrate composed of lymphocytes, plasma cells and many eosinophils. Hematoxylin and eosin stain; original magnification 200.

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Figure 2 High-magnification photomicrograph of the renal biopsy sample showing extensive interstitial inflammation with numerous eosinophils.

There is some tubulitis and tubular injury. Hematoxylin and eosin stain; original magnification 400.

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The patient began treatment with intravenous methylprednisolone 1 g daily for 3 days. Oral clotrimazole (10 mg four times daily) and combined oral sulfamethoxazole and trimethoprim (400 mg and 80 mg, respectively, once daily) were given for prophylaxis against candidiasis and Pneumocystis carinii pneumonia, respectively. Clinical improvement was observed within 48 h; the patient's fever, leukocytosis, eosinophilia and hematuria all decreased. The patient's diarrhea and abdominal pain that had been present on admission were resolved. Treatment with cyclophosphamide in addition to steroids was considered given the poor prognostic factors present in the patient (proteinuria >1 g/day and gastrointestinal involvement), but the patient left the hospital against medical advice and was lost to follow-up despite several attempts to contact him. Loss to follow-up also prevented repeat testing for ANCA, a repeat biopsy of the duodenal mass (to determine whether it was lymphoproliferative and, thus, perhaps related to the eosinophilia), the conducting of a bronchoscopy (to detect possible alveolar hemorrhage) and measurement of the patient's serum IgE levels (which are sometimes raised in Churg–Strauss syndrome), all of which would have been advisable to confirm the diagnosis.

Discussion of diagnosis

Churg–Strauss syndrome

The syndrome of "allergic granulomatosis and angiitis" was first described in 1951 by Churg and Strauss in a report of 13 autopsies.¹ The 1994 Chapel Hill Consensus Conference on the nomenclature of systemic vasculitides defined Churg–Strauss syndrome as a granulomatous inflammation involving the respiratory tract in combination with necrotizing vasculitis of both small-sized and medium-sized blood vessels, asthma and eosinophilia.² The incidence of Churg–Strauss syndrome in the general population is approximately 0.5–6.8 per million, the mean age at diagnosis is 48 years and the male to female distribution is 1:1.³

Churg–Strauss syndrome progresses via three successive stages: the 'prodromal phase', involving asthma and/or allergic rhinitis, with or without sinus polyposis; the 'eosinophilic phase', which is characterized by eosinophil infiltration into tissues such as the lungs, heart and gastrointestinal tract, with or without granulomas; and finally the 'systemic phase', during which necrotizing vasculitis develops in the skin, kidneys and peripheral nerves.³ This final phase usually occurs 3–4 years after the onset of asthma.³

The clinical presentation of Churg–Strauss syndrome is variable and can involve any organ system, but pulmonary involvement is the hallmark of Churg–Strauss syndrome, with asthma reported in 98% of cases and pulmonary infiltrates in 50% of patients.³ Allergic rhinitis is reported in about 70% of patients. Neurologic manifestations, which include peripheral neuropathy, occur in about 50% of patients, and cardiac involvement, usually in the form of myocarditis or pericarditis, occurs in 60%. Gastrointestinal involvement is found in about 50% of patients, and symptoms range from abdominal pain and diarrhea to eosinophilic gastroenteritis, an irritable-bowel-syndrome-like condition.⁴ Skin manifestations, most commonly palpable purpura, affect 40–70% of patients and can also include urticaria, maculopapular rash and subcutaneous nodules.³

Approximately one-third of patients with Churg–Strauss syndrome display renal involvement as indicated by a raised serum creatinine level; of these, about one-fifth have rapidly progressive renal failure (Table 1).^{1, 5, 8} Patients with renal involvement usually present with nephritic urinary sediment, although nephrotic syndrome has also been reported.³

Table 1 Prevalence of renal disease in Churg–Strauss syndrome.

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Laboratory evaluation in patients with Churg–Strauss syndrome often shows eosinophilia, but this finding is not universal.⁹ Less-specific findings include normocytic anemia, elevated ESR and raised serum IgE levels.⁹ ANCA, usually directed against myeloperoxidase, are found in only about 35–50% of patients with Churg–Strauss syndrome.^{7, 10, 11, 12} ANCA-negative patients usually present with eosinophilic tissue infiltration involving the heart and the gastrointestinal tract, whereas ANCA-positive patients tend to present with small-vessel vasculitis in the form of glomerulonephritis, pulmonary hemorrhage or mononeuritis multiplex.¹¹ This difference suggests that the pathogenic mechanisms of ANCA-negative and ANCA-positive Churg–Strauss syndrome are different.^{7, 10, 11, 12} However, the role of ANCA in the development of Churg–Strauss syndrome remains hypothetical at present (Figure 3).¹⁰ In the ANCA-negative subset of patients, the pathogenesis of Churg–Strauss syndrome is thought to be mediated by cytotoxic products of eosinophils.^{3, 7, 12}

Figure 3 Postulated pathogenesis of ANCA-mediated pauci-immune vasculitis.

Abbreviations: ANCA, antineutrophil cytoplasmic antibodies; MPO, myeloperoxidase; PR3, proteinase 3; ROS, reactive oxygen species.

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Various diagnostic criteria are available for the classification of small-vessel vasculitis such as Churg–Strauss syndrome, but the most specific appear to be those formulated by the American College of Rheumatology (Box 3).¹³ The presence of at least four of the six criteria indicates that Churg–Strauss syndrome is very likely to be the correct diagnosis (85% sensitivity and 99.7% specificity in the original sample of 20 patients reported by Masi et al.).¹³

Box 3 American College of Rheumatology criteria^a for classification of Churg–Strauss syndrome.¹³

• Asthma
• Eosinophilia >10%
• Neuropathy
• Pulmonary infiltrates
• Paranasal sinus abnormality
• Extravascular eosinophil infiltration on biopsy

^AThe presence of at least four of the six criteria indicates that Churg–Strauss syndrome is very likely to be the correct diagnosis.

The patient described here had both typical and atypical features of Churg–Strauss syndrome. In line with the American College of Rheumatology classification criteria, he had eosinophilia (albeit below the 10% threshold), pulmonary infiltrates, allergic rhinitis and sinusitis, and extravascular eosinophil infiltration of the skin and kidney. He also had urticaria, rash, gastrointestinal involvement, normocytic anemia and elevated ESR, all of which are commonly reported in patients with Churg–Strauss syndrome. Like most patients with renal involvement, he had a nephritic urinary sediment.

The patient presented with a maculopapular rash, which is a rare skin manifestation of Churg–Strauss syndrome.³ The skin biopsy showed subepidermal vesicular dermatitis, which is consistent with dermatitis herpetiformis, a condition not previously reported in association with Churg–Strauss syndrome. Unlike some other cases, the patient had no neurologic manifestations. Most importantly, he displayed no asthma symptoms and exhibited ANCA-negative glomerulonephritis. Although the patient reported chronic cough, he denied a prior diagnosis of asthma or use of a -adrenoceptor agonist inhaler. Fewer than 10 reported cases of Churg–Strauss syndrome have occurred in the absence of asthma.⁹ Of the two that were associated with rapidly progressive glomerulonephritis, both were ANCA-positive.^{14, 15} We acknowledge that vasculitis might simply have preceded the onset of asthma in the patient described here. However, the finding of glomerulonephritis, a typical manifestation of ANCA-positive Churg–Strauss syndrome, questions the concept that the pathogenesis of the ANCA-negative disease differs from that of the ANCA-positive disease. As ANCA negativity has not previously been reported in the absence of asthma, we planned to repeat serologic testing for ANCA, but the patient was lost to follow-up.

Treatment and management

The treatment of Churg–Strauss syndrome is very similar to that of other pauci-immune vasculitides, and is divided into three stages: induction of remission (defined as the resolution of clinical and biological manifestations of active vasculitis, including an inactive urine sediment); maintenance of remission; and treatment of relapse. Monitoring the response to induction therapy is best achieved by clinical evaluation as well as by repeated evaluation of eosinophilia and ESR, and by urinanalysis in those with renal involvement.³ The level or presence of ANCA is not a good marker of disease activity, nor does it seem to influence the likelihood of remission, relapse or death; therefore, it should not be used to guide therapy.^{7, 16}

As with the other pauci-immune vasculitides, intravenous and oral glucocorticoids are the mainstay of therapy for induction, maintenance and treatment of relapse, and the patient described here was initially treated with intravenous methylprednisolone. Addition of oral or intravenous cyclophosphamide can be considered if one or more poor prognostic factors are present at induction, if steroids fail to induce remission or if relapse occurs.^{3, 17} In a study of 342 patients with Churg–Strauss syndrome and polyarteritis nodosa, the French Vasculitis Study Group identified five factors associated with a poor outcome (Box 4).¹⁸ Patients who had none of these risk factors had a 5-year mortality of 12%, and 93% of these patients achieved remission with intravenous corticosteroids followed by oral corticosteroids alone; however, relapse was common (35% in the first year), and one-third of the patients required additional treatment with cyclophosphamide or azathioprine.¹⁹ In the presence of one risk factor, 5-year mortality was 25.9%, and if two or more factors were present, 5-year mortality increased to 46%.¹⁸ Given that upon hospital admission the patient reported here had two of the risk factors reported in Box 4 (proteinuria >1 g/day and gastrointestinal involvement), cyclophosphamide therapy was considered in addition to steroids at the start of therapy. However, the patient left the hospital against medical advice and has not contacted his physicians since.

A study of 48 patients with Churg–Strauss syndrome and at least one poor prognostic factor at baseline found no significant difference in major relapse rates when intravenous cyclophosphamide was administered in either 12 or 6 pulses, but there was a significantly higher number of mild relapses in the 6-pulse than in the 12-pulse group.²⁰ The authors concluded that 12 cyclophosphamide pulses were better than 6 pulses to control severe Churg–Strauss syndrome. The risk:benefit ratio should be considered when contemplating the administration of a higher number of cyclophosphamide pulses, given the associated drug toxicity. In patients with ANCA-associated vasculitis, remission can be maintained over 18 months as effectively by cyclophosphamide as by azathioprine, both administered orally.^{11, 21} One study reported less-serious adverse events with azathioprine compared with cyclophosphamide (10% versus 18%), even though the study was not specifically designed to detect such differences.²¹ Switching from cyclophosphamide to azathioprine after remission to reduce drug toxicity is, therefore, an option.

Jayne et al. studied standard treatment plus either plasma exchange or intravenous pulses of methylprednisolone in patients who had severe ANCA-associated vasculitis.²² The addition of plasma exchange conferred no survival benefit over addition of intravenous methylprednisolone, but the former was associated with better renal outcomes among patients with severe renal dysfunction at presentation; 81% of the plasma exchange group versus 61% of the methylprednisolone group were dialysis-free at 1 year (P <0.01). Intravenous immunoglobulin might be helpful, in combination with steroids, cyclophosphamide and plasmapheresis, at maintaining remission, but this finding has yet to be confirmed.²³ Rituximab, a chimeric antibody against the B cell antigen CD20, is currently being studied in the Rituximab for ANCA-associated Vasculitis (RAVE) trial; the antibody is being used in combination with steroids and being compared to the cyclophosphamide–steroid combination treatment for induction of remission in ANCA-associated vasculitides including Churg–Strauss syndrome.

Conclusions

Churg–Strauss syndrome is challenging to diagnose because of its highly variable presentation. Renal involvement is not universal and rapidly progressive glomerulonephritis is uncommon. This patient seems to be the first reported nonasthmatic case of ANCA-negative Churg–Strauss syndrome with necrotizing glomerulonephritis. The presence of glomerulonephritis in the absence of ANCA raises questions about the differences in the pathogenesis of ANCA-negative and ANCA-positive Churg–Strauss syndrome that have been postulated on the basis of differences in organ involvement.¹⁰ Treatment of Churg–Strauss syndrome should be started early in the course of the disease, and poor prognostic factors should prompt the addition of cyclophosphamide to glucocorticoid therapy.

Acknowledgments

The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Subject areas under which this article appears: Glomerular diseases (glomerulonephritis, FSGS, cryoglobulinemia)