A. Forestier

A. Le Quellec

A. Maria

A. Schiffman

A.K. Van Kien

E. Delhom

H. Leray-Moragues

I. Serre

J-F Eliaou

P. Guilpain

S. Rivière

T. Vincent

European Respiratory Review

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CORRESPONDENCEAsymptomatic bilateral pulmonary embolism in Churg–Strauss syndromeTo the Editor:Churg–Strauss syndrome (CSS) is a systemic small-sized vesselvasculitis, characterised by severe asthma, transient pulmon-ary infiltrates, and blood and tissue eosinophilia [1]. CSS canaffect several organs, including the lungs, heart, kidneys andperipheral nervous system. Anti-neutrophil cytoplasm auto-antibodies (ANCA) mainly directed against myeloperoxidase(MPO) are detected in ,40% of patients and are associatedwith renal involvement. Several studies have focused onvenous thromboembolic events (VTE), which are an emergingclinical condition in ANCA-associated vasculitides (AAV)[2, 3]. Herein, we report the case of a patient with newlydiagnosed CSS and totally asymptomatic pulmonary embo-lism, and discuss the features, pathogenesis and managementof VTE in CSS.In February 2011, a 61-yr-old male was referred for recentasthenia, diffuse arthromyalgia and blood eosinophilia. Hispast medical history included high blood pressure treated withamlodipine. There were no other risk factors for VTE otherthan age and inflammatory state. His recent history includedlate-onset asthma, which started 1 yr earlier and requiredvarious combined inhaled corticosteroids, bronchodilators andseveral short courses of oral corticosteroids.In early December 2010, the patient complained of generalweakness, weight loss and diffuse myalgia. In late December,another asthma flare-up was successfully treated with a courseof oral prednisolone (1 mg?kg-1 per day for 5 days), which waseffective for both myalgia and weakness. Unfortunately,muscle and joint pain immediately relapsed as soon ascorticosteroids were discontinued, while respiratory symp-toms had improved. In February 2011, a thoracic computedtomography (CT) scan was performed, focusing on theparenchyma not vessels. No lesions were reported. At thesame time, distal paresthesia appeared and subsequentlyconcerned the lower left and upper right limbs. Followingthis, the patient was referred to our department (InternalMedicine A, CHU, Montpellier, France).On admission, the patient did not complain about dyspnoea,cough or chest pain. His blood pressure was 130/80 mmHgand cardiac frequency was 90 beats per min, his temperaturerose to 39uC and his oxygen saturation was 98%. Pulmonaryauscultation did not disclose wheezes or ronchi. Cardiacauscultation and vascular examination were normal and therewas no sign of phlebitis. Neurological examination detecteddysesthesia and hypoesthesia in the right cubital and leftcommon peroneal nerve areas but no objective weakness wasnoted and all reflexes were present. There was no jointswelling or cutaneous eruption. Abdominal examination wasnormal. No hepatosplenomegaly and no enlarged lymph nodewere observed.Blood tests showed a white blood cell count of 14.66109 cellsper L with 5.46109 eosinophils per L (37% of white bloodcells), C-reactive protein (CRP) was 94 mg?L-1, fibrinogen was7.3 g?L-1 and serum creatinine was 123 mmol?L-1 (clearance60 mL?min-1 Modification of Diet in Renal Disease score).Testing for ANCA was highly positive (1/1,600 perinuclear)and anti-MPO antibodies (69 UI?mL-1) were detected byLuminex1 (Luminex Corporation, Austin, TX, USA). Urinesediment analysis showed 2.06103 leukocytes per L witheosinophiluria, and 4.06105 red blood cells per L. Proteinurialevel was 0.55 g per 24 h. Blood and urine cultures remainedsterile. An echocardiogram was normal and systolic pulmon-ary arterial pressure was 25 mmHg. The thoracic CT scan,which had been performed 2 weeks earlier, was then re-read. Itdid not include specific angiosequences, but eventuallydisclosed proximal bilateral pulmonary embolism (fig. 1).Ultrasonography of the lower limb veins did not demonstrateany venous thrombosis. Electromyography confirmed mono-neuritis multiplex involving the right cubital and left commonperoneal nerves. Percutaneous renal biopsy demonstratedpauci-immune extra-capillary crescentic glomerulonephritis,with associated tubulitis and no eosinophilic infiltration withinthe interstitium.CSS with neurological and renal involvement was diagnosedand oral corticosteroids were started (1 mg?kg-1 per dayprednisone). Because of renal involvement, the patient alsoreceived three intravenous pulses of methylprednisolone(15 mg?kg-1 per day for 3 days) and pulses of intravenouscyclophosphamide (0.6 g?m-2). Because bilateral pulmonaryembolism was also diagnosed, an anticoagulant treatment withlow-molecular-weight heparin was immediately started andrapidly switched to oral anticoagulants. Under this regimen,the patient quickly improved and experienced a good outcomeof CSS and pulmonary embolism with 8-month follow-up.Thrombotic factors that could have been implicated in thedevelopment of pulmonary embolism were also investigated.Thoracic and abdominal CT scans did not show any tumourprocess, and no coagulation abnormality could be detected:there was no mutation for pro-thrombin and Factor V Leiden,no anti-thrombin III, protein C or protein S deficiency, nolupus anticoagulant, no anti-cardiolipin antibodies, no anti-b2GP1 antibodies and no hyperhomocysteinaemia.The prevalence of VTE in AAV seems to be higher thanpreviously expected. A specific survey for VTE in CSS yieldeda prevalence of 6.5% in a cohort of 1,130 patients with AAVand of 8.1% in the 232 CSS patients of the study by ALLENBACHEur Respir Rev 2012; 21: 123, 75–77DOI: 10.1183/09059180.00007911CopyrightERS 2012cEUROPEAN RESPIRATORY REVIEW VOLUME 21 NUMBER 123 75et al. [2]. The prevalence of VTE in CSS was not different to thatobserved in granulomatosis with polyangiitis (Wegener’sgranulomatosis) and microscopic polyangiitis. In this cohortof AAV patients, the first VTE was deep venous thrombosis in62.2% of cases, pulmonary embolism in 21.6% of cases, or bothin 16.2% of cases. VTE is not constantly observed at diagnosisof vasculitis. In the cohort of AAV patients reported byALLENBACH et al. [2], the interval between the diagnosis of AAVand the first VTE vary to an extended degree (median (range)5.8 (-2.4–156.0) months). A similar observation is reported inCSS, since VTE can also occur during flare-ups [4] andremission [3].Risk factors for VTE in AAV have not yet been identified. Inthe cohort of ALLENBACH et al. [2], multivariate and univariateanalysis found VTE to be associated with older age at diag-nosis, male sex, previous VTE and stroke with motor deficit.Nephrotic range proteinuria was a risk factor in univariateanalysis. There was no association with CRP level, ANCApositivity and disease activity assessed by the BirminghamVasculitis Activity Score.Similarly, the mechanisms leading to VTE in CSS remain unclearand speculative [5]. No association has been reported with innateor acquired thrombophilia but, to date, such conditions have notbeen well investigated. As mentioned previously, no link wasestablished with ANCA positivity. Similarly to other inflamma-tory diseases, increased amounts of von Willebrand Factor andinterleukin-6 released by endothelial cells, hepatic synthesis ofCRP and fibrinogen may promote platelet aggregation andplasma hypercoagulability. The role of eosinophils is notestablished in the development of VTE and, in the study byALLENBACH et al [2], the similar prevalence of VTE in other AAVclassically devoid of eosinophilia (granulomatosis with poly-angiitis and microscopic polyangiitis) do not argue for a specificrole of these cells. Nevertheless, VTE can occur in the courseof other hypereosinophilic states, such as hypereosinophilicsyndromes, which has been attributed to the pro-thromboticproperties of eosinophil granule proteins. Indeed, eosinophilcationic proteins can bind to Hageman Factor (XII), activate theintrinsic pathway of coagulation and also interfere with antic-oagulant activity of heparin and of endogenous heparan sulfatein vitro [4]. The main oxidative product of eosinophils,hypothiocyanous acid, may also lead to a pro-thrombotic state,through the induction of tissue factor activity in humanumbilical vein endothelial cells [6].Our case illustrates the risk of VTE in CSS, which may bepromoted by inflammatory state and hypereosinophilia. In ourpatient, pulmonary embolism was totally asymptomatic andwas unexpectedly diagnosed on a thoracic CT scan. A delayedor missed diagnosis could have led to respiratory failure anddeath in the present case. Thus, pulmonary embolism may beconsidered as a pitfall in CSS since respiratory signs may befalsely attributed to the vasculitis. Therefore, our observationraises the question of systematic screening for VTE in CSS.We do not reasonably think that angiography CT scans shouldbe performed systematically in this condition. CSS glomerulo-nephritis and renal insufficiency must definitely be taken intoconsideration because of the risk of worsening following theadministration of a contrast agent. Furthermore, incidentalpulmonary embolism is not so uncommon in the generalpopulation (,2.6% of all patients according to a recent meta-analysis) [7] and in the clinical conditions with increased riskof VTE, such as malignant diseases. In these cases, systematicscreening for VTE is not recommended but this screening isfrequently addressed by the necessity for radiological mon-itoring of cancer.In vasculitides, there is no recommendation for VTE to dateand the length of curative anticoagulation remains to beestablished. However, the continuation of anticoagulationcould be proposed until remission, which is usually obtainedwithin 6 months.A. Maria*, P. Guilpain*, A. Forestier*, E. Delhom#, A.Schiffman*, S. Rivière*, A.K. Van Kien", H. Leray-Moragues+, I. Serre1, T. Vincente, J-F. Eliaoue and A. LeQuellec**Service de Médecine Interne A – Maladies Multi-Organiques,Centre de Compétence Maladies Auto-Immunes, #Serviced’Imagerie Médicale, "Service de Médecine Interne et MaladiesVasculaires, eDépartement d’Immunologie, UniversitéMontpellier 1, Hôpital Saint-Eloi, CHRU de Montpellier,+Service de Néphrologie, and 1Service d’Anatomopathologie,Université Montpellier 1, Hôpital Lapeyronie, CHRU deMontpellier, Montpellier, France.Correspondence: P. Guilpain, Service de Médecine Interne A,Hôpital Saint-Eloi, CHRU de Montpellier, 80 avenue AugustinFliche, 34295 Montpellier, Cedex 5, France. E-mail: p-guilpain@chu-montpellier.frStatement of Interest: None declared.FIGURE 1. Thoracic computed tomography scan showing occlusion of theright posterior basal segmental artery.Provenance: Submitted article, peer reviewed.76 VOLUME 21 NUMBER 123 EUROPEAN RESPIRATORY REVIEWREFERENCES1 Pagnoux C, Guilpain P, Guillevin L. Churg–Strauss syndrome. CurrOpin Rheumatol 2007; 19: 25–32.2 Allenbach Y, Seror R, Pagnoux C, et al. High frequency of venousthromboembolic events in Churg–Strauss syndrome, Wegener’sgranulomatosis and microscopic polyangiitis but not polyarteritisnodosa: a systematic retrospective study on 1130 patients. AnnRheum Dis 2009; 68: 564–567.3 Garcia G, Achouh L, Cobarzan D, et al. Severe venous thrombo-embolic disease in Churg–Strauss syndrome. Allergy 2005; 60: 409–410.4 Ames PR, Roes L, Lupoli S, et al. Thrombosis in Churg–Strauss syndrome. Beyond vasculitis? Br J Rheumatol 1996; 35:1181–1183.5 Ames PR, Margaglione M, Mackie S, et al. Eosinophilia andthrombophilia in Churg–Strauss syndrome: a clinical and patho-genetic overview. Clin Appl Thromb Hemost, 16: 628–636.6 Wang JG, Mahmud SA, Thompson JA, et al. The principal eosinophilperoxidase product, HOSCN, is a uniquely potent phagocyteoxidant inducer of endothelial cell tissue factor activity: a potentialmechanism for thrombosis in eosinophilic inflammatory states.Blood 2006; 107: 558–565.7 Dentali F, Ageno W, Becattini C, et al. Prevalence and clinical historyof incidental, asymptomatic pulmonary embolism: a meta-analysis.Thromb Res, 125: 518–522.DOI: 10.1183/09059180.00007911EUROPEAN RESPIRATORY REVIEW VOLUME 21 NUMBER 123 77

Asymptomatic bilateral pulmonary embolism in Churg–Strauss syndrome

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Asymptomatic bilateral pulmonary embolism in Churg–Strauss syndrome

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