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CASO CLÍNICO

InTRoduCTIon

Eosinophilic granulomatosis with polyangiitis (EGPA),also known as Churg-Strauss Syndrome, is a rare sys-temic vasculitis, characterized by necrotizing eosi -nophilic and granulomatous tissue infiltration, whichcan affect small and medium-sized vessels. Respirato-ry involvement with presentation of rhinitis and/orasthma is practically universal. Although cardiac in-volvement is less common, it is the main cause of mor-bidity and mortality of this pathology1, 2.

CASe RepoRT

A 65-year-old caucasian woman, with a past medicalhistory of allergic rhinosinusitis since the age of 27, wasfollowed by a pneumologist for a recent diagnosis ofasthma and recurrent periods of exacerbation treatedwith montelukast, fluticasone/formoterol and hydro -xyzine. She was admitted in the emergency departmentpresenting a lancinating neuropathic pain and asym-metrical lower limb oedema more pronounced on theleft side with 2 days of duration. Fifteen days prior shedeveloped multiple purpuric lesions and dysesthesiasof the upper and lower limbs (Figure 1). The patient re-ported unproductive cough, with no chest pain, dys -pnea or palpitations. She denied fever or other consti-tutional complaints.

On admission to the rheumatology department, thepatient presented hemodynamic stability, saturation98% and body temperature 36.5ºC. Cardiac ausculta-tion showed rhythmic beats, without murmurs andpulmonary auscultation revealed diffused wheezingand inspiratory basilar crackles. Some petechiae andpurpuric lesions were evident at the palmar and dorsalside of the hands and feet with extension to the preti -bial region bilaterally. A muscular strength deficit wasalso found- right hand flexion grade 3 and left foot dor-siflexion grade 4 - and a hypoesthesia area in the right

1 Rheumatology, São João Hospital Centre; 2 Cardiology, São João Hospital Centre; 3 Cardiology, São João Hospital Centre; Medical Faculty, Universityof Porto; 4 Rheumatology, São João Hospital Centre; Medical Faculty, Uni-versity of Porto;

Silent acute myocarditis in eosinophilic granulomatosis with polyangiitis

Ferreira RM1, Madureira P1, Pinho T2, Martins E3, Pimenta S4, Costa L1

ACTA REUMATOL PORT. 2018;43:309-313

ABSTRACT

Eosinophilic granulomatosis with polyangiitis is a raremultisystemic disorder, characterized by necrotizingvasculitis affecting small to medium-sized vessels, as-sociated with asthma and eosinophilia. Cardiac in-volvement is the most important predictor of mortali-ty and it seems to be more frequent in anti–neutrophilcytoplasmic antibodies-negative patients. Cardiomyo -pathy and congestive heart failure can occur but asignif icant proportion of patients are asymptomatic. Wepresent a case of this condition in a 65-year-old wo manwith a past medical history of rhinosinusitis and recentepisodes of asthma, that developed palpable purpura,sensory deficiency and excruciating pain mainly in thelower limbs. A significant hypereosinophilia and ele-vated troponin level were found, although she had notcardiac symptomatology. Cardiovascular magnetic re sonance revealed late gadolinium enhancement anda severe reduction of the left ventricular ejection frac-tion. Mononeuritis multiplex was documented and di-agnosis was confirmed by biopsy. Complementary car-diac investigation is mandatory in any patient with sus-picion of eosinophilic granulomatosis with polyangii -tis. Early detection and the appropriate treatment arecrucial due to the possible life-threatening manifesta-tions.

Keywords: Churg-strauss syndrome; Eosinophilicgranulomatosis with polyangiitis;

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palm and left foot.A complete blood count standed out leukocytosis of

18.8x10�/L with hypereosinophilia of 11.28 x 10�/L

(59.8%), without anemia (hemoglobin 14,7g/dL) orthrombocytopenia (platelets 234 x10�/L). The ery-throcyte sedimentation rate was 35mm/hr and the C-reactive protein of 147.2mg/L. Despite the absenceof chest pain or other cardiac symptoms, serum tro-ponin I level was markedly increased to 11429ng/L(normal <16) and also muscle enzymes were elevated- aspartate aminotransferase 133U/L, alanine amino-transferase 51U/L, lactate dehydrogenase 782U/L, cre-atine kinase 1579U/L, aldolase 28U/L, myoglobin575ng/mL, creatine kinase-MB 123ng/mL. B-type na-triuretic peptide (BNP) was increased by 543pg/mL aswell as the serum IgE level (843kU/L). Renal functionwas preserved (creatinine 0,75mg/dL, urea 26mg/dL,creatinine clearance 73ml/min), urinalysis and lipidprofile were normal. Anti-neutrophil cytoplasmic an-tibodies (ANCA) and anti-nuclear antibodies were ab-sent. Serological tests for Epstein Barr, Parvovirus B19,Cytomegalovirus, syphilis, hepatitis B and C and HIVwere negative. Blood cultures were sterile.

The electrocardiogram documented sinus tachy-cardia of 114bpm and left bundle branch block (Figu -re 2). Transthoracic echocardiography revealed mode -rate to severe left ventricular systolic dysfunction(LVSD) with ejection fraction ~32%, mild to moderatemitral regurgitation and a small volume pericardial ef-fusion. Cardiac catheterization ruled out coronary di -sease. Cardiac magnetic resonance confirmed the seve -

FIGuRe 1. Palpable purpuric lesions on the lower limbs of thepatient

FIGuRe 2. Electrocardiogram of the patient showing sinus tachycardia, heart rate 114bpm and left bundle branch block

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re LVSD. On T2-weighted sequence no areas of hy-perintensity suggestive of myocardial oedema werefound, although a low image quality of that sequencewas noticed. Post-contrast imaging clearly showed alate gadolinium enhancement pattern of subendocar-dial predominance and also in the papillary muscles,compatible with fibrosis and suggestive of a vasculiticprocess (Figure 3). The chest computed tomographyscan revealed some subsegmental atelectasis of thelower lobes, without consolidations or nodularities.She presented a moderate obstructive pattern on thespirometry - forced vital capacity 1.64L (1.71-3.12),forced expiratory volume in 1 second 1.07L(1.39-2.64), tiffeneau index 56%, maximum mid expiratoryflow 75/25 22%, without arterial blood gas changes(pH 7.4, pO2 81.7mmHg, pCO2 36.4mmHg, HCO324.9mmol/L, satO2 95.2%).

Electromyography of the upper and lower limbsrecorded low amplitude nerve conduction, fitting withan acute multiple mononeuropathy. Doppler ultra-sound test showed no signs of recent venous throm-bosis. Due to the high diagnostic suspicion of EGPApresenting with major organ involvement, immuno-suppressive therapy was instituted on the 2nd day ofhospitalization with 3 pulses of methylprednisolone1g/day, followed by oral prednisolone 1mg/kg/day andcyclophosphamide 1g/month. Montelukast was sus-pended. In addition, she started treatment with biso-prolol, acetylsalicylic acid, gabapentin and integrateda functional rehabilitation program. A rapid decreaseof the inflammatory parameters was seen, as well asnormalization of eosinophilia and muscle enzymes de-

cline. Subsequently, the patient was submitted to suralnerve and muscle biopsy. The histological exam revea -led a severe asymmetric neuropathy with signs ofactivi ty (findings of demyelination of nerve fibers andaxonal degeneration). The muscle tissue expressedvery slight alterations. Although no granulomas or in-filtrates were found in the sample, the characteristicsdescribed were consistent with a vasculitic process.The clinical condition of the patient significantly im-proved, with progressive regression of cutaneous le-sions and a dramatic recovery of sensitivity and mus-cular strength. After 5 months of follow-up, theechocardiographic re-evaluation demonstrated a pre-served left ventricular function (ejection fraction~55%).

dISCuSSIon

EGPA is included in the heterogeneous group of vascu -litis associated with ANCA. It typically manifests in the5th decade of life, with identical sex distribution. Clas-sically, the syndrome occurs in three sequential pha ses.The initial or prodromal phase is characterized by thepresence of allergic rhinitis, sinusitis, nasal polyps andasthma. The latter often of adult-onset and difficultcontrol. The second phase is marked by peripheraleosinophilia and tissue eosinophilic infiltration. Fi-nally, the third phase can progress to potentially life-threatening vasculitic lesions, involving multiple or-gans, such as the heart and nervous system1-3.

Despite de absence of ANCA antibodies, our case

FIGuRe 3. Long and short-axis of cardiac magnetic resonance imaging images showing patchy subendocardial late gadoliniumenhancement in the left ventricule (arrows)

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fulfils the American College of Rheumatology classifi-cation criteria for EGPA: past medical history of asth-ma, eosinophilia> 10%, mononeuropathy and alte -rations of the paranasal sinuses4. To respect to histo-logical findings of muscle and nerve biopsy, althoughtypical eosinophilic infiltration was not found in thetissue sample, we underline that the procedure wasperformed fifteen days after initiating glucocorticoidand immunosuppressive treatment which can influen -ce the results.

The underlying pathophysiological mechanisms ofthe vasculitis and its frequent association with asthmaare still poorly understood. The hypothesis of a causalrelationship between the exposure to anti-leu -kotrienes, such as montelukast, and the developmentof the syndrome have been discussed over the years.Some speculations point to the unmasking of EGPA asa result of steroids tapering or discontinuation, enabledby the newer asthma therapeutics introduction. How-ever, in other cases, there is a temporal relationshipwith the use of these anti-asthmatics in patients notpreviously medicated with corticosteroids. Due to thisunclear association, we chose to discontinue mon-telukast as recommended by the literature3, 5.

Recent studies have showed some particularities ofcardiac involvement in EGPA, which may be importantin the patient clinical approach. The cardiovascularmanifestations can occur in approximately 15 to 60%of cases and are variable. The disease has been associ-ated with pericarditis, myocarditis, pericardial effu-sion, acute coronary syndrome, heart failure, valvu-lopathy, intracardiac thrombi, arterial hypertensionand electrical conduction disorders1,2,6,7. Nevertheless,its course can often be silent, as it happened in the casedescribed. We emphasize that the patient had no car-diac symptoms since her hospital admission. This fin -ding is consistent with the study developed by RobetM. Dennert et al., which reported that in the absenceof symptoms and major electrocardiographic abnor-malities, cardiac involvement could still be detectedby echocardiography or cardiac magnetic resonanceimaging (MRI) in 38% of the cases7.

In fact, MRI has emerged as the gold standard ima -ging test, due to its ability to assess a detailed anatomi -cal description of the cardiac lesions. The techniqueallows the identification of pericardial leaflets inflam-mation, microvasculature changes, the existence of in-traventricular thrombi, inflammation and/or fibrosisof myocardial tissue and detection of late gadoliniumenhancement, despite the meaning of some findings

remain to be defined. Myocardial fibrosis appears todevelop rapidly during the course of the disease and,consequently, an aggressive and immediate immuno-suppressive treatment may be warranted, in order toprevent progression to chronic heart failure1,2,6. In thiscase, an endomyocardial biopsy was not performed,to avoid the inherent risks of an invasive techniqueand a delay of treatment initiation, since the wholeclinical picture was very characteristic of EPGA andthe myocardial involvement was supported by cardiacMRI.

Hypereosinophilia is the hallmark of the pathology,whereas ANCA, predominantly antimyeloperoxidase,are found in only 30-40% of the patients. Besides that,its prevalence seems to vary according to major organsinvolvement. Some series have shown that negativityfor ANCA is more common in cardiac involvement,on the other hand, the presence of positive ANCA ismore frequent in renal and neurological involvement.The data regarding cardiac complications also point toan association with higher serum eosinophilia (per-centage> 20%), especially in myocarditis. The signifi-cant increase in intravascular eosinophilic prolifera-tion that progressed to the infiltration of extravascularspace, namely the cardiac muscle, seems to representthe pathogenic phenomenon. All these aspects sup-port the analytical and clinical phenotype of the casepresented1,8,9.

We therefore suggest the laboratory analysis of BNPand cardiac muscle enzymes, especially troponin I, inthe initial approach, even in asymptomatic patients.Complementary imaging investigation is mandatoryto evaluate cardiac function and structure, with chestx-ray, electrocardiogram and echocardiogram, in anypatient with suspected EGPA. Cardiac catheterizationcan be used to exclude coronary abnormalities and car-diac MRI is a useful non-invasive modality to confirmmyocardial involvement. ANCA assay should be per-formed, but its result deserves a careful interpretation,since clinical characteristics seem to differ according tothis antibodies status remembering that their positi -vity is not imperative for establishing the diagnosis1,2,7.

Assessment of organ involvement is also extremelyimportant for the therapeutic decisions. Steroid the -rapy constitutes the first-line treatment. The choice ofconcomitant immunosuppressants is dictated by thespectrum of manifestations. For remission-induction,cyclophosphamide is recommended in patients withsevere systemic manifestation, as observed in the pre-sented case with cardiac and neurologic involvement,

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but in non-organ-threatening EGPA either methotre -xate or mycophenolate mofetil can be used10. TheFrench Vasculitis Study Group Cohort identified somepoor prognostic factors, such as age> 65 years, cardiacinvolvement, gastrointestinal manifestations or renalfailure, and for some authors cardiomyopathy remainsthe main independent predictor of mortality in thispathology9, 11.

It is peremptory to perform a careful investigationin the suspicion of EGPA, because of its multisystemicinvolvement and the challenge of possible occult clini -cal manifestations. An early diagnosis is similarly es-sential given the association of cardiac involvementwith poor prognosis and the efficacy of immunosup-pressive therapy recommended in the treatment of thisvasculitis.

CoRReSpondenCe To

Raquel Miriam dos Santos Ferreira Rheumatology Department, Centro Hospitalar São JoãoPorto, Portugal E-mail: rakelmiriam@gmail.com

ReFeRenCeS

1. Mahr A, Moosig F, Neumann T, Szczeklik W, Taille C, Vaglio A,et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): evolutions in classification, etiopathogenesis, asses-sment and management. Curr Opin Rheumatol. 2014;26(1):16-23.

2. Dunogue B, Pagnoux C, Guillevin L. Churg-strauss syndrome:clinical symptoms, complementary investigations, prognosisand outcome, and treatment. Semin Respir Crit Care Med.2011;32(3):298-309.

3. Weller PF, Plaut M, Taggart V, Trontell A. The relationship of as-thma therapy and Churg-Strauss syndrome: NIH workshopsummary report. J Allergy Clin Immunol. 2001;108(2):175--183.

4. Masi AT, Hunder GG, Lie JT, Michel BA, Bloch DA, Arend WP,et al. The American College of Rheumatology 1990 criteria forthe classification of Churg-Strauss syndrome (allergic granulo-matosis and angiitis). Arthritis and Rheumatism. 1990;33:1094–1100.

5. McDanel DL, Muller BA. The linkage between Churg-Strausssyndrome and leukotriene receptor antagonists: fact or fiction?Therapeutics and Clinical Risk Management. 2005;1(2):125–140.

6. Cereda AF, Pedrotti P, De Capitani L, Giannattasio C, Roghi A.Comprehensive evaluation of cardiac involvement in eosino -philic granulomatosis with polyangiitis (EGPA) with cardiacmagnetic resonance. Eur J Intern Med. 2017;39:51-56.

7. Dennert RM, van Paassen P, Schalla S, Kuznetsova T, Alzand BS,Staessen JA, et al. Cardiac involvement in Churg-Strauss syn-drome. Arthritis Rheum. 2010;62(2):627-634.

8. Qiao L, Gao D. A case report and literature review of Churg--Strauss syndrome presenting with myocarditis. Medicine (Bal-timore). 2016;95(51):e5080.

9. Comarmond C, Pagnoux C, Khellaf M, Cordier JF, Hamidou M,Viallard JF, et al. Eosinophilic granulomatosis with polyangii-tis (Churg-Strauss): clinical characteristics and long-term fol-low-up of the 383 patients enrolled in the French VasculitisStudy Group cohort. Arthritis Rheum. 2013;65(1):270-281.

10. Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T,et al. EULAR/ERA-EDTA recommendations for the manage-ment of ANCA-associated vasculitis. Ann Rheum Dis.2016;75(9):1583-1594.

11. Guillevin L, Pagnoux C, Seror R, Mahr A, Mouthon L, Le Tou-melin P, et al. The Five-Factor Score revisited: assessment ofprognoses of systemic necrotizing vasculitides based on theFrench Vasculitis Study Group (FVSG) cohort. Medicine (Bal-timore). 2011;90(1):19-27.