MASTERCLASS Series editor: John Axford

Asthma and epididymitis: the calm before thestorm

Gerald H M George, John S Axford

Case reportA 17 year old Asian college student presentedwith a two month history of arthralgia, arthritisof his ankles and wrists, numbness of his feetand weight loss. He had a history, for the previ-ous month, of epididymo-orchitis treated atanother hospital.

He had been investigated for abdominal painand weight loss by plain abdominal radiogra-phy, abdominal ultrasound scan and rectalbiopsy. Results were all normal. The symptomswere associated with a poor appetite but nohistory of nausea, vomiting or diarrhoea. Nodefinite diagnosis was reached.

He had a painful left ankle with associatednumbness of the lateral aspect of his left foot.He felt generally weak and lethargic. He subse-quently developed right ankle discomfort andswelling and bilateral wrist swelling and pain.

Past medical history included allergic rhinitisand asthma, since childhood, for which he wastreated regularly with beclomethasone andsalbutamol inhalers.

Clinical examination on presentation re-vealed a thin, unwell, feverish patient. He was160 cm tall and weighed 43 kg. His feverpersisted during the early stages of hisadmission to hospital. Hand examinationrevealed splinter haemorrhages, macular pig-mented lesions on the palmar surface of hishands, and subcutaneous nodules at bothelbows. He had a tachycardia with a softejection systolic murmur and his blood pres-sure was normal. His chest was clear andabdomen soft and non-tender with no palpableorgans or masses. Central nervous systemexamination was normal. Peripheral nervoussystem examination revealed an asymmetricalsubjective light touch sensory diminution inthe lower limbs below the knees and absentankle jerk reflexes bilaterally. Plantar reflexeswere both flexor. There was grade 3/5 weaknessof dorsiflexion at both ankles. Urine analysiswas negative for blood and protein.

InvestigationsLaboratory investigations showed: haemo-globin 15.0 g/dl, leucocyte count 21.5 × 109/1,platelets 461 × 109/1, erythocyte sedimentationrate (ESR) 146 mm 1st h, and C reactive pro-tein (CRP) 37 mg/l. Serum urea, creatinine,electrolytes, liver function tests, bone biochem-istry, creatine kinase and angiotensin convert-

ing enzyme were all normal. Rheumatoidfactor was 490 iu/l (normal <20 iu/l), ANAweak positive, anti double stranded DNA andanti- ENA antibodies negative, and cANCAweak positive but negative for proteinase 3 andmyeloperoxidase.

Further investigations were as follows: therewas an eosinophilia of 14.8 × 109/1. IgE wasmarkedly raised with an initial level of 540 ku/llater peaking at 5118 ku/1. Serial bloodcultures were sterile. Trans-thoracic echocar-diogram demonstrated a mass on the mitralvalve chordae tendinae. Radiographs of hands,feet, chest and abdominal ultrasound scan werenormal. Microscopy of initial left elbow nodulebiopsy showed the presence of granulomatoustissue with necrosis. Subsequent skin biopsyfrom a subcutaneous nodule at the right shoul-der was consistent with a leucocytoclastic vas-culitis. EMG revealed an increased latency ofthe right and left lateral, and right medial pop-liteal knee to ankle motor nerve conductionwith reduced amplitude. Right radial sensory,right ulnar and median motor nerve conduc-tion were normal.

DiVerential diagnosis1 Sub-acute bacterial endocarditis, in view ofhis fever, weight loss, murmur and echocardio-gram findings. The mass on the mitral valvechordae tendinae was initially considered to besupportive of a diagnosis of infective endocar-ditis in keeping with the clinical context ofpresentation. However, after two subsequentechocardiograms, the lesion was deemed to beconsistent with probable ruptured chordaetendinae. There was neither valvular regurgita-tion nor other evidence of infective endocardi-tis.2 Rheumatoid arthritis with vasculitis, in viewof his arthralgia, arthritis, nodules at bothelbows, and positive rheumatoid factor. Initialskin biopsy was consistent with a rheumatoidnodule. The skin showed focal depigmentationwith lymphocytes and histiocytic aggregates inthe upper dermis, and some altered collagen.The leucocytoclastic biopsy specimen had fea-tures of patchy basal degeneration with occa-sional dyskaryotic cells in the epidermis. Therewas focal ulceration and the dermis showedperivascular and periadnexal active chronicinflammation with focal fibrinoid change in avessel with prominent nuclear dust indicating aleucocytoclastic vasculitis.

Ann Rheum Dis 1999;58:731–736 731

Academic Unit forMusculo-skeletalDiseases, St George’sHospital MedicalSchool, London

Correspondence to:Dr G H M George,Department ofRheumatology, St HelierHospital, Wrythe Lane,Carshalton, SurreySM5 IAA

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3 Other vasculitides such as Churg-Strausssyndrome (CSS), in view of asthma, allergicrhinitis, arthralgia, arthritis, and neurologicalfindings.

Evidence for CSS(1) The presence of asthma was the mostdiscriminative criterion in segregating CSSfrom other forms of vasculitis in the ACR(American College of Rheumatology) criteriaclassification series.1 As in this case, asthmaoften precedes the other features of CSS byseveral years and up to as long as 30 years.2 Itcommonly occurs in the fourth decade in lifeand its severity and frequency increases beforethe systemic manifestations of CSS.3 Remis-sion of asthma often coincides with the onset ofmanifestations of systemic features of CSS butrelapse may occur in the post-vasculitic phase.2

Allergic rhinitis, as in this case, sinusitis, andnasal polyps are common upper airwaysassociations in CSS.

(2) Arthralgia and arthritis are common inCSS, may be flitting in nature, and tend tooccur during the vasculitic phase of the illnessas occurred in this case. Similarly myalgia iscommon but myositis is rare.1 3 4 Rheumatoidfactor (RF) has been noted to be positive, usu-ally in low titres but occasional high concentra-tions have been reported.2 3 IgG and IgMserum RF have been observed to be transientlyraised in the vasculitic phase of the illness. Thiscoincides with a transient increase in theconcentrations of interleukin 6 (IL6), suggest-ing that RF and IL6 may be important in thepathogenesis of the vasculitis of CSS.5

(3) A mononeuritis multiplex of the lowerlimbs was confirmed by EMG. Vascularneuropathy presents with either a mononeuritismultiplex or, symmetrical or asymmetricalsensori-motor neuropathy. In a review ofvasculitis selectively aVecting the peripheralnervous system, most had a mononeuritis mul-tiplex or asymmetrical neuropathy and somehad a symmetrical neuropathy.6 Mononeuritismultiplex is usually a necrotising vasculitiswhereas a distal neuropathy is probably relatedto vasa nervorum micro-circulation occlusion.

Shintani reported a case of third nerve palsyand mononeuritis multiplex associated withCSS.7 Cranial nerve palsies are unusual in CSSand the most frequent cranial nerve lesionobserved is an ischaemic optic neuritis. In thiscase there were no cranial nerve palsies butthere was a mononeuritis multiplex confirmedby nerve conduction studies.

The traditional format ACR criteria for CSSlists neuropathy as being 75% sensitive and79.8% specific for CSS against other definedvasculitis syndromes. The neuropathy may be amononeuropathy, mononeuritis multiplex orpolyneuropathy. Neuropathy lies third in theorder of sensitivity in the diagnosis of CSS.1

(4) Examination of the diVerential leucocytecount revealed marked eosinophilia of 14.8 ×109/1. Eosinophilia is essential to the diagnosisof CSS. However there are other situationswhere eosinophilia may be related to arthralgia,vasculitis and autoimmune rheumatic diseases.In a review of 265 British cases of Wegener’s

granulomatosis, eosinophilia was a frequentlaboratory feature though it was not a prerequi-site for diagnosis.8 Eosinophilia myalgia syn-drome, which shares features with eosinophilicfasciitis and other variants of systemic sclerosis,is characterised by peripheral bloodeosinophilia.9 Blood eosinophilia may bepresent in localised scleroderma and coincideswith active disease.10 Eosinophilia has beenreported in rheumatoid arthritis, both relatedand unrelated to drug treatment.11 12 In somecases eosinophilia has been suggested as amarker of extra-articular manifestations ofrheumatoid arthritis.13 On a rarer note, Espinoreported a case of eosinophilic myositis associ-ated with vasculitis and symmetrical polyneu-ropathy, presenting as myalgia, muscle weak-ness and eosinophilia.14 The pulmonaryeosinophilias, reviewed elsewhere,15–17 are adiverse group of disorders characterised bypulmonary infiltrates, rich in eosinophils andusually associated with a peripheral blood eosi-nophilia.

In the ACR classification criteria for CSS,the presence of eosinophilia was the secondmost useful criterion in segregating CSS fromother forms of vasculitis.1 This was further spe-cific if the eosinophilia was >10% on a whiteblood cell diVerential smear as occurred inmost patients. An eosinophilia of >10% was95% sensitive and 96.6% specific for CSScompared with other defined vasculitis syn-dromes. The current reported case had aneosinophilia of >10%. This value varied withdisease activity, normalising with clinical re-mission of disease activity.

(5) The IgE was markedly raised. In theseries of patients recruited by the ACR to cre-ate criteria for the classification of CSS, IgEconcentrations were raised in all patients inwhom it was measured. Concentrations rangedfrom 184–2200 units/ml.1 Lanham et al ob-served raised IgE in 75% of patients, both intheir series and in the accompanying literaturesearch review.3 This was particularly so in thevasculitic phase of CSS with normal concentra-tions in remission. Raised IgE concentrationswere observed in this case report, and IgE isimplicated in the pathogenesis of asthma andallergic rhinitis as well as vasculitis.18

(6) The skin and histology findings weresupportive of CSS. Seventy per cent of patientswith CSS have skin involvement.3 19 Anycombination of papules, macules, nodules andpapulovesicles may occur. Three categories oflesions are recognised: erythematous maculo-papules resembling erythema multiforme(40%); haemorrhagic lesions ranging frompetechiae to often palpable extensive ecchy-moses (45%); cutaneous and subcutaneousnodules (20%), often tender, persistent andresolve with scarring. Nodules histologicallyshow the characteristic granuloma of CSS. Aneosinophilic infiltrate progresses into granu-loma formation, beginning with necrosis withina densely packed cluster of eosinophils. Thenecrotic core enlarges with inclusion of colla-genous stroma, and epithelioid and giant cellsappear around the core to produce a palisadingformation several cells thick. The type of

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granuloma seen in CSS may be seen in otherdisorders, including rheumatoid arthritis,polyarteritis nodosa, systemic lupus erythema-tosus, sub-acute bacterial endocarditis, lym-phoproliferative disorders and chronic activehepatitis.20

Histological examination of the other skinlesions in CSS is usually of a small vesselleucocytoclastic vasculitis, with a predomi-nance of neutrophils. The second biopsy in thiscase was consistent with a leucocytoclastic vas-culitis.

Other notable features of CSS relevant tothis caseEPIDIDYMITIS

It can only be assumed that the episode in thiscase may be related to the diagnosis of CSS.Epididymitis as a manifestation of ARD is rare.However, there have been several case reportsand case series of this. Wright21 reported ontwo cases in which epididymitis heralded theonset of more severe visceral organ damage. Inour case, the presentation of epididymitis wasat a diVerent hospital and so the precise aetiol-ogy is unknown. Shurbaji22 described ninecases of testicular vasculitis identified fromsurgical and necropsy files. In three cases thiswas the initial presentation of polyarteritisnodosa (PAN), one of these being as epidi-dymitis. In two separate cases testicular vascu-litis proceeded systemic PAN. There was onecase of Goodpastures syndrome and three inci-dental findings without diseases associatedwith vasculitis. Kroegel23 reported a case ofgranulomatous epididymitis occurring beforethe development of asthma and eosinophilia inCSS. The consensus of opinion would there-fore be that epididymitis as a manifestation ofCSS is rare.

CARDIAC INVOLVEMENT

Cardiac manifestations of CSS are best dem-onstrated by echocardiography. Mitral regurgi-tation is common.24 25 In this case there was thepresence of ruptured chordae tendinae, whichmay be a preceding factor in the progression tomitral regurgitation. Vasculitis of the coronaryarteries may occur with all the expected conse-quences of this.25–27 Pericarditis and pericardialeVusion may occur in 25% but these are notsensitive enough features to be included in thediagnostic criteria.1 There may be congestivecardiac failure or restrictive cardiomyopathy.28

Cardiac disease accounts for 48% of deathsattributable to CSS.3

Cardiac granulomas are commonly found atnecropsy and cardiac failure featured in theseries studied for the ACR criteria.1 3 29 Withthe advent of corticosteroid and immunosup-pressive treatment, improved diagnostic meth-ods and awareness of cardiac involvement inCSS, the prognosis of CSS determined by car-diac disease should improve.30

GASTROINTESTINAL MANIFESTATIONS

Gastrointestinal involvement is frequent inCSS. Symptoms range from abdominal painand diarrhoea, to haemorrhage and perfora-

tion. The causes include eosinophilic infiltra-tion of the bowel wall and mesenteric vasculi-tis, the former being rare.31

This case had been investigated for abdomi-nal pain before presentation at our centre.There were no specific findings and theabdominal pain settled before presentationwithout further recurrence.

RENAL DISEASE

Renal disease in CSS is mild and rarelyprogresses to renal failure.2 3 This provides adistinguishing feature when compared withpolyarteritis nodosa and Wegener’s granuloma-tosis. In this case, renal function has remainednormal throughout the duration of the disease.In the series studied by Lanham, 49% had mildor moderate renal disease but only 9% (onepatient) had renal failure.4 Histologically thelesions vary. The original findings of Churgand Strauss were of focal glomerular lesions, adiVuse or focal interstitial nephritis, and necro-tising vasculitis with granulomatous nodules.Lanham on the other hand found a focalsegmental glomerulonephritis, with necrotisingfeatures, including crescents in some cases.The case of renal failure, in that series, reversedwith corticosteroids and immunosuppressivetreatment, demonstrating the less aggressivenature of renal disease as compared withpatients with Wegener’s granulomatosis.Necrotising glomerulonephritis in CSS areoften associated with p-ANCA.32

PRESENCE OF ANCA ANTIBODIES

Anti-neutrophil cytoplasmic antibodies(ANCA) are neither specific nor sensitive in thediagnosis of CSS.33 However, CSS is stronglyassociated with ANCA, the frequency beingapproximately 50%.34 In a study by Guillevin,67% of patients with CSS had positive ANCAtitres. Most were perinuclear ANCA (pANCA)positive.35 Others have found thisassociation36 37 but the value of serial ANCAmeasurements for the monitoring of treatmenteYcacy has not yet been established.38 Thiscase is unusual as a weak positive cytoplasmicANCA (cANCA) staining pattern was ob-tained but with no detectable antibody toserine proteinase 3 (PR3). On repeated occa-sions in this case, ANCA staining was negative,suggesting the initial weak positive result mayhave been a non-specific finding associatedwith the inflammatory process especially in thelight of the absence of antibodies to PR3.

Initial managementAfter investigations and the exclusion andtreatment of possible infection, the diagnosis ofChurg-Strauss syndrome was made. The pa-tient was prescribed 30 mg prednisolone dailyand this was subsequently increased to 40 mgdaily. Azathioprine was added initially at 50 mgdaily and increased to a maintenance dose of100 mg daily (equivalent to >2 mg/kg/day) toconsolidate treatment of his symptoms ofarthralgia and lethargy, and as a corticosteroidsparing agent. There was subsequent improve-ment in his overall condition and the patientwas discharged from hospital.

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Subsequent presentationSix months after presentation the patientdeveloped sudden onset headache, nausea,vomiting and deteriorating level of conscious-ness. He had a Glasgow coma score of 9/15.Eye opening scored 2/4, verbal response 2/5and motor response 5/6. Motor response local-ised on the left side and flexed on the right side.Pupils were 4 mm and non-reactive to light.Blood pressure was 130/80. Computed tomog-raphy of the head scan showed a large left syl-vian fissure intra-cerebral haemorrhage ex-tending to the left frontal lobe, left lateralventricle and 3rd ventricle. Laboratory investi-gations at this time showed: Haemoglobin 10.3g/dl, leucocyte count 16.8 × 109/1, eosinophils1 × 109/1, ESR 104 mm 1st h, CRP 105 mg/l.Urea and electrolytes were normal. On thisoccasion IgE was not measured.

Subsequent managementThe patient required intubation, ventilationand a frontal ventriculostomy. A cerebral angio-gram at the time showed no evidence ofarteriovenous malformation (AVM), aneurysmor vasculitis (fig 1B), as did a subsequent angio-gram six weeks later. Magnetic resonanceimaging of the brain demonstrated the haem-atoma but once again no evidence of vasculitisor AVM (fig 1A). He has since received intenseneurophysiotherapy, speech therapy, and occu-pational therapy. He continues to make agradual recovery with residual right sidedweakness, and a mild receptive and expressivedysphasia.

Cerebral haemorrhageCerebral haemorrhage as a complication ofCSS has been described but is rare. This case isunique in that there was no documentedevidence of cerebral vasculitis, AVM, cerebralaneurysm or hypertension. Liou described asimilar case in a patient with uncontrolled

blood pressure.39 Chang in a case reportdescribed intra-ventricular and subarachnoidhaemorrhage resulting from necrotising vascu-litis of the choroid plexus.47 Lanham,3 in aseries of 16 patients, reported 25% of cases ofCNS disease but did not specify cerebralhaemorrhage as a cause.

The cause of cerebral haemorrhage in thiscase may have been attributable to isolatedareas of vasculitis not demonstrated on MRI orcerebral angiography but there is no conclusiveproof as to its aetiology.

Further treatment and progressAfter his cerebral haemorrhage a decision wasmade to treat with further immunosuppressionand a course of intermittent intravenous cyclo-phosphamide, at a dose of 10 mg/kg, wasstarted. To date the patient has not suVered arelapse of vasculitis and has tolerated immuno-suppression with no iatrogenic problems.

DiscussionGENERAL FEATURES OF CSS

CSS is of unknown aetiology. It was firstdescribed by Churg and Strauss in 1951 from aseries of necropsy findings29 and the pathogen-esis is believed to be a proliferation of activatedeosinophils producing a cascade of aberranttissue responses.19 CSS is increasingly beingrecognised but epidemiological studies aresparse. Case series have been published thatprovide valuable information on the features ofthe disease.1 3 29 The incidence was found to be1.3% in a large collection of patients withvasculitis.41 In an epidemiological study of anethnically homogenous population of 414 000adults from 1988 to 1994, the annual incidenceof CSS was 2.4/million.42 There is an equal sexdistribution and onset is reported to bebetween 20 and 40 years of age in the seriesdescribed by Lanham, but varied with a rangeof 16–74 in the ACR series (mean age 50

Figure 1 (A) Magnetic resonance imaging demonstrates a proton density axial image andmagnetic resonance imaging angiography to show the Circle of Willis and middle cerebralarteries. There is a large mass in the frontoparietal region that is maximal in size at thelevel of the body of the lateral ventricle. The mass is of high signal intensity on protondensity imaging and there is evidence of mass eVect on the ipsilateral ventricle. Signalchange is seen in the adjacent white matter, suggesting a degree of oedema. The appearancesare in keeping with a large intracerebral haematoma. (B) Magnetic resonance imagingangiogram shows displacement of vessels secondary to the haematoma.

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years). The mean age of onset of vasculitis was38 years in both series. Lanham described aphasic pattern to the presentation of CSS. Thepro-dromal phase consists of allergic diseaseconsisting of asthma, often preceded by allergicrhinitis. The second phase is characterised byperipheral blood eosinophilia and eosinophilictissue infiltrates. The infiltrative disease mayrecur over a period of years, but is often inter-rupted by a life threatening vasculitic phase ofthe illness. The patient described in this reportseemed to follow this pattern with a history ofasthma and allergic rhinitis since childhoodbefore the more systemic manifestations of thedisease.

DIAGNOSTIC CRITERIA

The ACR and Lanham criteria for the diagno-sis of CSS are widely accepted.1 3 Using theACR criteria, the diagnosis can be made by thetraditional method of fulfilling a proportion ofcriteria from a list or by using the classificationtree method of fulfilling a progression of crite-ria. The latter method starts with the presenceof asthma as the most important criterion andis proceeded by eosinophilia of >10% and his-tory of allergy. By this method sensitivity was95% and specificity 99.2% when comparedwith other forms of vasculitis.

Table 1 shows the features used in the tradi-tional method. Four positive of the six listedcriteria constitutes a diagnosis of CSS with asensitivity of 85% and a specificity of 99.7%.

TREATMENT

Corticosteroids are the mainstay of treatmentin CSS. Corticosteroids alone result in remis-sion of the disease in particular the vasculitis,eosinophilia, IgE, and symptoms of allergicrhinitis and asthma. The response is good but ithas been suggested that consideration ofimmunosuppression, in the form of cyclophos-phamide, should depend on prognosticfactors.43 In addition cyclophosphamide shouldbe reserved for cases in which there is a failureto respond to corticosteroids or disease relapse.Consideration of the organs involved and theseverity of their involvement should be takeninto account. Factors indicating poor prognosisare renal symptoms (glomerulonephritis orrenal insuYciency), gastrointestinal tract in-volvement, cardiomyopathy, central nervoussystem involvement, weight loss >10% of bodyweight, or age >50 years old. These factorswere identified in a retrospective cohort of 165patients studied.43 In a review of 45 cases byFortin, renal and cardiac involvement wereconfirmed as poor prognostic factors insystemic necrotising vasculitis.44 The possible

role of plasma exchange was explored by Guil-levin et al in a prospective randomised trial with62 patients.45 They found that combined treat-ment with prednisone, cyclophosphamide, andplasma exchanges, was not superior to pred-nisone and cyclophosphamide alone in patientswith factors indicating poor prognosis.

OUTCOME

The reported survival rate in CSS has beenreported as 90% at one year, and 62% at fiveyears, by Chumbley.2 Guillevin46 reported a75% five year survival. Compared with PAN,the outcome in CSS is favourable. A retrospec-tive data review of 13 patients with PAN and 12patients with CSS showed that patients withCSS had a lower mean damage index score, alower disability score and a higher pain score.47

CSS patients had fewer relapses and a lowermortality rate.

SUMMARY

We have provided a review of the many clinicaland laboratory features with which CSS couldpresent. In addition, we have cited thedevastating but rare complication of cerebralhaemorrhage and the need for immunosup-pression to control disease activity to preventsuch life threatening consequences.

1 Masi AT, Hunder GG, Lie JT, et al. The American college ofrheumatology 1990 criteria for the classification of Churg-Strauss syndrome (Allergic granulomatosis and angiitis).Arthritis Rheum 1990;33:1094–100.

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Table 1 1990 criteria for the classification of CSS (traditional format), their sensitivityand specificity versus other defined vasculitis syndromes, and features in this reported case(adapted from reference 1)

Criterion Sensitivity (%) Specificity (%) Reported case features

Asthma 100 96.3 YesEosinophilia >10% 95 96.6 YesNeuropathy, mono or poly 75 79.8 YesPulmonary infiltrates, non-fixed 40 92.4 NoParanasal sinus abnormality 85.7 79.3 NoExtra-vascular eosinophils 81.3 84.4 No

Key messages+ Incidence—1. 3% of patients with vascu-

litis+ Prevalence—2.4/million in general popu-

lation+ Main clinical features

Asthma/allergic rhinitisNeuropathyArthralgiaSkin involvement

+ Laboratory featuresEosinophiliaRaised IgE

+ TreatmentCorticosteroidsCyclophosphamide may be required

+ Prognosis

Five year survival approximately 62 to 75%

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