Churg-Strauss syndrome

Clinicohistologic Evaluation of Steroids and Immunosuppressive Therapy

Treatment of cardiac dysfunction associated with Churg-Strauss syndrome (CSS) is empiric since the histologic findings provided by endomyocardial biopsy are rare and often nondiagnostic. Myocardial necrotizing vasculitis presenting as restrictive cardiomyopathy has not been reported before. A case of CSS, presenting with fever and progressive heart failure due to pericarditis, eosinophilic endomyocarditis, and myocardial necrotizing vasculitis, is reported. Cardiac involvement assessed by noninvasive (cardiac two-dimensional echocardiogram and nuclear magnetic resonance [NMR] imaging) and invasive (cardiac catheterization, angiography, and biopsy) studies showed a moderate degree of pericardial effusion and left ventricular (LV) dysfunction (ejection fraction 0.40), severe diastolic dysfunction (increased right and LV filling pressure with a dip and plateau pattern) and a severe reduction of cardiac index (1.6 L/min/[m.sup.2]). Histologic characteristics showed marked eosinophilic infiltration of the endocardium and myocardium with myocitolysis and fibrinoid necrosis of arterioles, venules, and capillaries. Combination therapy of steroids and cyclophosphamide resulted in both a clinical (regression of pericardial effusion, normalization of systolic and diastolic dysfunction, and increase of cardiac index to 2.8 L/min/[m.sup.2]) and histologic (sequential endomyocardial biopsies at 1, 3, and 6 months of follow-up) resolution of cardiac involvement. No recurrences were registered at 12-month follow-up with the patient receiving a maintenance drug regimen.

(CHEST 1998; 114:1484-1489)

Key words: Churg-Strauss syndrome; heart failure; myocardial necrotizing vasculitis

Abbreviations: CI = cardiac index; CSS = Churg-Strauss syndrome; 2D-ECHO = two-dimensional echocardiography; LV = left ventricular; NMR = nuclear magnetic resonance

Churg-Strauss syndrome (CSS), also known as allergic granulomatous angiitis, is a multisystem disease with an unknown cause.[1] Its diagnostic criteria were established in 1990 by the American College of Rheumatology;[2] the main clinical characteristics are prominent eosinophilia with asthma or allergic rhinitis associated with a systemic vasculitis. Cardiac involvement has been found in up to 64%[3] of autopsy cases, while mortality attributed to cardiac causes ranged from 27 to 48% in two postmortem studies.[3,4] Cardiac pathologic findings derive essentially from postmortem examinations and include eosinophilic pericarditis, interstitial myocarditis, and epicardial coronary vasculitis, usually with no valvular involvement. Necrotizing angiitis of intramural coronary vessels giving rise to a restrictive cardiomyopathy has not previously been described either at postmortem or in the clinical setting of CSS. Moreover, only one case of eosinophilic myocarditis has been diagnosed by endomyocardial biopsy[5] as all other studies were nondiagnostic.[6-8] The efficacy of steroid or immunosuppressive therapy or both to reverse CSS cardiac localization, has, therefore, essentially an empiric basis, while in the context of necrotizing myocardial vasculitis, this efficacy is unknown.

Sequential cardiac NMR imaging, angiography, and endomyocardial biopsy were carried out, and it was subsequently demonstrated that steroids combined with immunosuppressive therapy, have a remarkable efficacy in a patient with CSS presenting with progressive heart failure due to severe eosinophilic infiltration of the endocardium, myocardium, and pericardium with necrotizing vasculitis of intramural vessels.

CASE REPORT

A 52-year-old man was admitted to the hospital because of fever (39.5 [degrees] C), chest pain, cough, and expiratory dyspnea. The patient had suffered three episodes of pericardial effusion in the last 16 months that responded successfully to steroids. He had suffered from bronchial asthma for the last 7 years and had undergone a nasal polypectomy in 1991 without recurrences. He denied a history of drug allergy. At physical examination, the patient was orthopnoeic with severe bronchospasm. Heart auscultation revealed tachycardia with reduced cardiac sounds. BP was 110/80 mm Hg with no evidence of paradox pulse. The ECG showed sinus tachycardia (110 beats per minute); low QRS voltages and absence of R waves in the inferior and [V.sub.1] through [V.sub.3] leads. The jugular veins were enlarged with the jugular pulse being dominated by a rapid y and x wave descent as well as by prominence of a wave. A moderate liver and spleen distension with mild peripheral edema was apparent, while no abnormalities of the nervous system were observed. Some days after admission the patient complained of visual disturbances, and a brain scan and NMR imaging documented multifocal ischemic damage of the posterior territory of a thromboembolic origin.

MATERIALS AND METHODS

Laboratory Investigation

Results of laboratory tests are presented in Table 1. Bonemarrow biopsy showed a marked, presence (48%) of eosinophils in different phases of maturation (blast cells, 2%), characteristic of reactive eosinophilia. Serologic tests were negative for cox-sackie virus and adenovirus, HIV-1, HIV-2, Mycoplasma pneumoniae, Chlamydia psittaci, Aspergillus, and Echinococcus granulosus. No fecal parasites were found.

(*) ESR -- erythrocyte sedimentation rate; PCP = plasma cationic protein; ANA = antinuclear antibodies; p-ANCA = perinuclear antineutrophil cytoplasmic antibodies.

Imaging Studies

A chest x-ray film showed interstitial infiltrates in the apical region of both lungs and an enlargement in cardiac silhouette with pulmonary congestion. The two-dimensional echocardiogram (2D-ECHO) revealed diffuse moderate wall hypokinesia with an increased thickness of the cardiac walls that was particularly pronounced at the apex, where there was an image compatible with the presence of a stratified thrombus (Table 2). A moderate echogenic pericardial effusion without hemodynamic evidence of tamponade was present. Doppler echocardiography showed a marked abnormality of diastolic function with shortening of the isovolumic relaxation period, increased and rapid E wave, enhanced E/A wave ratio, and shortening of the deceleration time. The NMR study confirmed the presence of pericardial effusion and ruled out any pericardial primary mass or metastatic involvement; furthermore, small, round hyperintense foci were clearly recognized along with diffuse left myocardial thickening (mean end-diastolic thickness, 1.8 cm) on fat suppressed images (Fig 1, upper panel). These data were highly suggestive of myocardial infiltration by an inflammatory process. An apical stratified thrombus was evident in the left ventricle. Using manual tracing of endocardial and epicardial contours on the end-systolic frames of the multislice short axis cine sequence, the left ventricular (LV) mass was calculated, the value being clearly abnormal (312 g). The patient then underwent invasive cardiac examinations (catheterization, coronary angiography, left and right ventriculography and right ventricular endomyocardial biopsy). Pulmonary and intracavity pressures were elevated, exhibiting a dip and plateau diastolic pattern with overlapping values in the four cardiac chambers. Cardiac index (CI) was depressed (Table 2). Ventricular angiography showed a reduced end-diastolic volume with diffusely thickened walls and moderate reduction of cardiac contractility. Coronary angiography was normal.

Table 2--Echocardiographic and Hemodynamic Characteristics of the Patient Before and After 1 Month of Steroid and Immunosuppressive Treatment(*)

(*) IVS = interventricular septum; PSP = pulmonary systolic pressure; RV = right ventricle; RA = right atrium; LA = left atrium; AO = aorta.

[Figure 1 ILLUSTRATION OMITTED]

Histologic Studies

Three right ventricular endomyocardial biopsy specimens were removed and processed for histologic study following the conventional technique and staining (hematoxylin-eosin, Miller's Elastic van Gieson, Masson's trichrome). In addition, a special stain (carbol-chromatrope)[9] for identifying eosinophils and their intracellular granules was used. The interstitium was markedly increased due to extensive inflammatory infiltrates represented mainly by eosinophils and, to a lesser extent, by lymphocytes, histiocytes, mast cells, and some plasma cells. The infiltrates were in close proximity to the myocytes, which showed focal evidence of myocytolysis mostly around the myocardial vessels (including arterioles, venules, and capillaries) many of which exhibited some fibrinoid necrosis (Fig 2). No evidence of a reparative process was observed in fibroelastic tissue stains. The endocardium also was thickened due to infiltration by eosinophils. The clinical and histologic data were consistent with CSS associated with pericarditis, endomyocarditis, and myocardial necrotizing vasculitis.

[Figure 2 ILLUSTRATION OMITTED]

Treatment and Follow-up

As soon as the histologic diagnosis became available, therapy with high doses of steroids (methylprednisolone, 1 g daily for 3 consecutive days, followed by prednisone, 1 mg/kg daily for 3 months) was started along with oral administration of cyclophosphamide (2 mg/kg daily). This was followed by the dramatic disappearance of eosinophils from the blood (to less than 500/ [mm.sup.3]) and the progressive improvement of systemic and cardiac conditions. In particular, the fever subsided, the lung infiltrates disappeared, and the pericardial effusion decreased. Heart rate decreased to 80 beats per minute and the QRS voltages increased on the ECG and ST-T wave alterations improved. 2D-ECHO showed an improvement of systolic function with reduced thickness of cardiac walls (Table 2). Doppler study of mitral valve flow evidenced a reduction of E wave with reduced E/A wave ratio and a normalization of isovolumic relaxation period and of deceleration time. As a result of the documentation of brain ischemia and thrombus formation in the left ventricular apex, treatment with an oral anticoagulant (dicumarol) was started to maintain the international normalized ratio between 2.5 and 3.5. The patient was discharged and followed up every 3 weeks with a physical examination, an ECG, 2D-ECHO, and routine blood and chemical analysis. At 1, 3, and 6 months, the patient was readmitted in order to undergo another cardiac NMR, catheterization, angiography (biventricular), and biopsy. After the first hemodynamic follow-up, the intracavity pressures decreased to normal values, with normalization of CI (Table 2). NMR imaging revealed that the thickness had reduced to 1.5 em and the myocardial mass had decreased by 25% (from 312 to 225 g) (Fig 1, lower panel). After the first control biopsy, no inflammatory infiltrates were observed in the interstitium or around the intramural vessels, while some focal areas of replacement fibrosis were documented with some vessels showing fibrotic repair of the wall (Fig 3). The endocardium was severely focally thickened but free of superimposed eosinophil infiltration or thrombus. Prednisone treatment at the 3-month follow-up was reduced to 0.33 mg/kg daily and withdrawn at 5 months following a tapering dose schedule, while cyclophosphamide therapy was continued for 1 year. Tapering of prednisone dosage and withdrawal were based on blood film and myocardial histologic findings, showing normalization of eosinophil count and resolution of myocardial vasculitis and eosinophil infiltration, respectively. LV parietal thrombi were not registered at 2D-ECHO and NMR imaging after 6 months of treatment with oral anticoagulants; this treatment with anticoagulants then was maintained for 12 months. At the 12-month follow-up, the patient was still symptom-free, and an echocardiogram showed normal cardiac volumes and function.

[Figure 3 ILLUSTRATION OMITTED]

DISCUSSION

A case of CSS presenting with fever and progressive heart failure due to pericarditis, eosinophilic endomyocarditis, and necrotizing myocardial vasculitis, has been reported. The hemodynamic pattern was that of a restrictive cardiomyopathy as shown by cardiac catheterization, Doppler 2D-ECHO and NMR imaging. The histologic analysis documented extensive eosinophilic infiltration of the endocardium and myocardium with focal myocytolysis. Involvement of intramural vessels was widespread and included fibrinoid necrosis of arterioles (Fig 2), venules, and capillaries. The results of treatment in patients with myocardial necrotizing vasculitis are poorly understood because this condition occurs only rarely. Systemic necrotizing vasculitis due to polyarteritis nodosa, Wegener's granulomatosis or CSS, which accounts for 20% of cases,[9] has a severe clinical impact with a mortality rate at 5 years of greater than 85% in untreated patients,[10] mostly due to cardiac causes.[11] However, after steroid treatment this figure has been reduced to 48%[10] and to 25% at 5 years following the introduction of a combination therapy of steroids and immunosuppressive drugs.[12] In the patient reported here, the combination of steroids and cyclophosphamide, in association with oral anticoagulants, resulted in a marked improvement in systolic (LV ejection fraction from 40 to 55%) and diastolic function with normalization of cardiac filling pattern and pressures and CI (from 1.6 to 2.8 L/min/[m.sup.2]). NMR imaging revealed that LV myocardial wall thickness decreased, with diminution of the LV myocardial mass by 25% and lysis of the LV thrombus. In sequential endomyocardial biopsies, eosinophilic infiltrates disappeared rapidly from the endocardium, myocardium, and intramural vessels, with the inflammatory process progressing to a healed phase. Although recurrences are common in systemic necrotizing vasculitis, accounting for up to 52% at 18 months,[13] the patient in this report continued to improve on a maintainance drug regimen, and this improvement was still apparent at the 12-month follow-up. In conclusion, the manifestation of CSS may include myocardial necrotizing vasculitis with severe heart failure which can be reversed clinically and histologically, if recognized early, by a combination therapy of steroids and cyclophosphamide.

REFERENCES

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[3] Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol 1951; 27:277-301

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[8] Lanham JG, Cooke S, Davies J, et al. Endomyocardial complication of the Churg-Strauss syndrome. Postgrad Med J 1985; 61:341-344

[9] Fauci AS, Katz P, Haynes BF, et al. Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med 1979; 301:235-238

[10] Frohnert PP, Sheps SG. Long-term follow-up study of periarteritis nodosa. Am J Med 1967; 43:8-14

[11] Lanham JG, Elkon KB, Pusey CD, et al. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine 1984; 63:65-81

[12] Guillevin L, Guittard T, Bletry O, et al. Systemic necrotizing angiitis with asthma: causes and precipitating factors in 43 cases. Lung 1987; 165:165-172

[13] Gordon M, Luqmani RA, Adu D, et al. Relapses in patients with a systemic vasculitis. Q J Med 1993; 86:779-789

(*) From the Departments of Cardiology (Drs. Frustaci, Chimenti, and Maseri), Internal Medicine (Drs. Gentiloni and Gasbarrini), and Radiology (Natale), Universita Cattolica del Sacro Cuore, Rome, Italy.

Manuscript received November 10, 1997; revision accepted March 30, 1998.

Correspondence to: Andrea Frustaci, MD, FCCP, Istituto di Cardiologia Universita Cattolica del Sacro Cuore, Largo Gemelli 8, 00168 Rome, Italy

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