Clin Rheumatol DOI 10.1007/s10067-013-2484-z

CASE BASED REVIEW

Alveolar haemorrhage in eosinophilic granulomatosis and polyangiitis (Churg-Strauss) L. Yalakki Jagadeesh & S. R. Sangle & H. Verma & D. D’Cruz

Received: 30 October 2013 / Revised: 23 December 2013 / Accepted: 30 December 2013 # Clinical Rheumatology 2014

Abstract We describe two patients of alveolar haemorrhage in patients with eosinophilic granulomatosis with polyangiitis (eGPA). This report adds to the evidence that pulmonary haemorrhage is a rare but severe manifestation of eGPA. It may not be associated with positive ANCA antibodies and requires aggressive treatment. Keywords Churg-Strauss . Eosinophilic . Granulomatosis . Polyangiitis . Pulmonary haemorrhage . Vasculitis

Background Eosinophilic granulomatosis and polyangiitis (eGPA, previously called Churg-Strauss syndrome) is a multisystem disorder characterised by chronic rhinosinusitis, asthma and peripheral blood eosinophilia, peripheral neuropathy, cardiomyopathy and occasionally renal involvement [1]. Pulmonary haemorrhage observed in granulomatosis with polyangiitis (Wegener’s, GPA) is seldom seen in eGPA [2]. We report two cases of alveolar haemorrhage in patients with eGPA. Patient 1 A 46-year-old woman was diagnosed with eGPA 5 years ago based on the history of late onset asthma, arthralgia, peripheral Yalakki Jagadeesh L and Sangle SR are first authors L. Y. Jagadeesh : S. R. Sangle : H. Verma : D. D’Cruz The Lupus Research Unit, The Rayne Institute, Lambeth Wing, St Thomas’ Hospital, London SE1 7EH, UK D. D’Cruz (*) The Louise Coote Lupus Unit, Gassiot House, St. Thomas’ Hospital, London SE1 7EH, UK e-mail: david.d'[email protected]

blood eosinophilia, lacrimal gland biopsy which showed eosinophilia and positive perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) and myeloperoxidase antibodies. She was admitted with a 5-day history of breathlessness, haemoptysis and arthralgia. During this admission, she had a rash on her lower limbs, pain over the nasal bridge and lower limb paraesthesiae. On examination, her peak flow had reduced to 190 l/min (baseline 360) and there was a purpuric rash distributed over the lower limbs. She had symmetrical peripheral neuropathy in her lower limbs. Investigations showed raised inflammatory markers with C reactive protein 188 mg/l, haemoglobin 10.3 g/dl and recurrent eosinophilia. A chest radiograph demonstrated widespread airspace opacity within the left upper and lower lobes and focal opacity within the right upper lobe. Computed tomography (CT) of the chest showed multifocal centrilobular nodules with surrounding ground glass opacity, some in the subpleural distribution and areas of more confluent airspace consolidation and ground glass opacity, consistent with pulmonary haemorrhage (Fig. 1). She was unable to perform pulmonary function test on admission but subsequent pulmonary function test showed a normal transfer factor. Bronchoalveolar lavage confirmed haemorrhage with serial aspirate. It showed no organisms on microscopy and culture. Tests for acid-fast bacilli were negative. Treatment was started with intravenous methyl prednisolone 500 mg on alternate days and intravenous cyclophosphamide infusions 500 mg fortnightly for six pulses. Her chest Xray improved with treatment and she was discharged on oral prednisolone. Patient 2 A 25-year-old female was admitted with a 10-day history of increasing breathlessness, haemoptysis and chest

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Fig. 1 Axial CT at the level of the main bronchi demonstrating ground glass opacity and more focal air space consolidation within the left lower lobe

pain. She was diagnosed with adult onset asthma with persistent peripheral eosinophilia. Sputum samples for acid-fast bacilli were negative. Stool samples for ova, cyst and parasites were negative. Serology for strongyloides, filariasis and schistosomiasis was negative. Anti-neutrophil cytoplasmic antibodies (ANCA), skin prick tests for Aspergillus precipitins were negative. She previously had two hospital admissions over 2 years for probable pneumonia requiring intravenous antibiotics, steroids and inhalers. On admission, chest examination showed left upper zone crepitations. Investigations showed persistent peripheral eosinophilia. Repeat vasculitic screen including ANCA were negative. CT pulmonary angiogram showed upper zone ground glass opacity, more extensive within the left upper zone . Bronchoscopy showed chronic inflammatory changes consistent with eosinophilic pneumonia. She was started on oral prednisolone 30 mg daily with a follow up in 4 weeks post discharge. Shortly after discharge, she represented to the emergency department with haemoptysis, chest pain and breathlessness. Investigations showed raised white cell count with eosinophilia (5.0×109), chest X-ray showed bilateral consolidation, more extensive on the left (Fig. 2). A repeat bronchoscopy revealed erythema and mucosal pitting consistent with chronic inflammation. Bronchoalveolar lavage showed numerous eosinophils and no evidence of malignancy or infection. Biopsy showed haemosiderin laden macrophages indicating haemorrhage and also chronic inflammatory changes. Immunological investigations showed negative ANCA and raised IgE levels. The patient was diagnosed with an acute flare of eosinophilic pneumonia with a diagnosis of eGPA and commenced

Fig. 2 Chest X-ray showing bilateral pulmonary infiltrates in a patient with eGPA

on intravenous methyl prednisolone (500 mg) × 3 infusions and cyclophosphamide 500 mg fortnightly for six doses over the next 3 months. She made an excellent clinical recovery, eosinophil count improved and repeat chest X-ray showed resolution of consolidation.

Discussion EGPA is defined as granulomatous inflammation with eosinophilia involving medium- and small-sized vessels. Its manifestations are varied but it usually presents with adult onset asthma, eosinophilia, nasal polyps and skin rashes. In severe cases, it may be associated with eosinophilic cardiomyopathy, gut vasculitis and severe mononeuritis multiplex. It is not uncommon to see eosinophilic tissue infiltrates [3]. It can occur at all ages but is commonly observed in the third and fourth decades. It is less common than GPA and microscopic polyangiitis (MPA). eGPA is usually classified under ANCA-associated vasculitides (AAV) due to its similarity with other AAV such as GPA and MPA. The prevalence of ANCA in eGPA varies widely but is estimated to be approximately 40 %, which is much lower than in GPA or MPA (75–95 %). Most patients w i t h e G PA h a v e P - A N C A w i t h s p e c i f i c i t y f o r myeloperoxidase [4]. ANCA positivity is associated with renal disease and pulmonary haemorrhage [4]. A large study by a French group reported that ANCA positive eGPA patients have severe disease, frequent relapses and poor prognosis as compared to ANCA negative patients [5]. A recent prospective study by Vaglio et al. showed raised IgG4 levels in active eGPA as compared to quiescent eGPA, GPA, healthy

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individuals and patients with atopic asthma. The levels of IgG4 correlate with Birmingham Vasculitis Activity Score and organ involvement. It is not clear whether IgG4 plays any role in pathogenesis of eGPA or a potential biomarker of eGPA [6]. The most common manifestation of eGPA is respiratory tract involvement seen in approximately 60 % of patients and includes allergic rhinitis, nasal polyps and adult onset asthma. Less common respiratory manifestations are eosinophilic pneumonitis, pulmonary infiltrates and alveolar haemorrhage [3]. Pulmonary vasculitis is characterised by inflamed arterioles, capillaries and lung parenchyma. Diffuse alveolar haemorrhage (DAH) is commonly seen in small vessel vasculitis and is a severe manifestation of pulmonary vasculitis [7]. The most common cause is MPA followed by GPA. It is quite rare in patients with polyarteritis nodosa, Takayasu’s arteritis and Behcet’s disease. Other diseases associated with DAH are systemic lupus erythematosus, Goodpasture’s syndrome and Henoch-Schonlein purpura. Less common causes are idiopathic, drug or toxin-induced DAH. Alveolar haemorrhage is rarely seen in eGPA. The radiological features of pulmonary vasculitis are extremely variable and include vessel wall thickening, nodular or cavitating lesions, ground glass opacities and consolidation. Parenchymal opacification in a peripheral or random distribution is the most common manifestation of eGPA, although nonspecific [8]. Chest radiographs are useful for the diagnosis of pulmonary vasculitis; however, they often fail to show the exact pattern and extent of parenchymal abnormality and high-resolution CT is considered a more useful diagnostic tool [9]. Both our patients with eGPA presented with DAH and pulmonary infiltrates, and alveolar lavage confirmed eosinophilic infiltrates and haemorrhage. One patient had positive ANCA antibodies. The second patient had raised IgE levels with negative ANCA antibodies. Both our patients were too ill on presentation for pulmonary function tests and it was not possible to measure transfer factor. They required cyclophosphamide and methyl prednisolone pulses to achieve remission. There is no established protocol for the treatment of eGPA patients with DAH. Corticosteroids and immunosuppressive therapy are used, especially in patients

with severe forms of the disease with renal, cardiac, pulmonary and gastrointestinal manifestations, who are at increased risk of mortality [10].

Conclusion Pulmonary haemorrhage is a rare but severe manifestation of eGPA. It may not be associated with positive ANCA antibodies and requires aggressive treatment.

Disclosures None.

References 1. Sinico RA, Bottero P (2009) Churg-Strauss angiitis. Best Pract Res Clin Rheumatol 23(3):355 2. Kostianovsky A, Hauser T, Pagnoux C, Cohen P, Daugas E, Mouthon L et al (2012) Alveolar haemorrhage in ANCAassociated vasculitides: 80 patients’ features and prognostic factors. Clin Exp Rheumatol 30(1 Suppl 70):S77–S82 3. Della Rossa A, Baldini C, Tavoni A, Tognetti A, Neglia D, Sambuceti G et al (2002) Churg-Strauss syndrome: clinical and serological features of 19 patients from a single Italian centre. Rheumatology (Oxford) 41:1286–1294 4. Sinico RA, Di Toma L, Maggiore U, Bottero P, Radice A, Tosoni C et al (2005) Prevalence and clinical significance of anti-neutrophil cytoplasmic antibodies in Churg-Strauss. Arthritis Rheum 52:2926– 2935 5. Comarmond C, Pagnoux C, Khellaf M, Cordier JF, Hamidou M, Viallard JF et al (2012) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)—clinical characteristics and long-term follow-up of the 383 patients enrolled in the FVSG cohort. Arthritis Rheum. doi:10.1002/art.37721 6. Augusto V, Strehl JD, Bernhard M et al (2012) IgG4 immune response in Churg-Strauss syndrome. Ann Rheum Dis 71:390–393 7. Fishbein GA, Fishbein MC (2011) Lung vasculitis and alveolar haemorrhage: pathology. Semin Respir Crit Care Med 32:254–263 8. Worthy SA, Müller NL, Hansell DM, Flower CDR (1998) ChurgStrauss syndrome: the spectrum of pulmonary CT findings in 17 patients. AJR 170:297–300 9. Castañer E, Alguersuari A, Gallardo X, Andreu M, Pallardó Y, Mata JM et al (2010) When to suspect pulmonary vasculitis: radiologic and clinical clues. Radiographics 30:33–53 10. Guillevin L (2012) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Presse Med 41(10):1004–1013

Alveolar haemorrhage in eosinophilic granulomatosis and polyangiitis (Churg-Strauss).

We describe two patients of alveolar haemorrhage in patients with eosinophilic granulomatosis with polyangiitis (eGPA). This report adds to the eviden...
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