Pediatric Pulmonology 49:E21–E24 (2014)

Case Report

Refractory Otitis Media: An Unusual Presentationof Childhood Granulomatosis With Polyangiitis

Preena Uppal, MBBS, DCH, MD (Paeds),1,2 Jonny Taitz, MBChB, FCP, FRACP,1,2

Brynn Wainstein, MBChB, FRACP, PHD,2,3 Marlene Soma, BSc (Med) MBBS, FRACS,2,4

Yvonne Belessis, MBBS (Hons), FRACP, MPH, PhD,2,5 andPaul Gray, MBChB, B.A Hons, FRACP, FRCPA

2,3*

Summary. Childhood granulomatosis with polyangiitis (cGPA), previously known as Wegener’s

granulomatosis, is a rare, potentially fatal necrotizing vasculitis, the symptoms of which overlap

with infection. We present a 16-year-old girl who, following 6 months of treatment for persistent

middle ear effusion with progressive sensorineural hearing loss, developed rapidly progressing

pneumonia, with pleural effusion, and multiple cavitatory lung lesions. Investigations demon-

strated high titer c-ANCA and nasal septal biopsy confirmed the diagnosis of cGPA. This case

highlights the difficulty in diagnosing cGPA and the potentially life-threatening consequences of

failing to do so. Pediatr Pulmonol. 2014; 49:E21–E24. � 2013 Wiley Periodicals, Inc.

Key words: Wegener’s granulomatosis; chronic otitis media; hearing loss; atypical

pneumonia; childhood vasculitis.

Funding source: none reported.

INTRODUCTION

Childhood granulomatosis with polyangiitis (cGPA),previously known as Wegener’s Granulomatosis, is apredominately small vessel vasculitis, with an estimatedchildhood incidence of <1 per 2 million per year.1 Theclinical presentation of cGPA is varied and the diagno-sis may be missed unless a high index of suspicion ismaintained. We present the case of a teenager with anatypical presentation of chronic otitis media, which wassubsequently diagnosed as cGPA, where delay to diag-nosis led to life-threatening respiratory involvement.

CASE REPORT

A 16-year-old girl presented to our tertiary pediatrichospital with a 3 week history of fever, persistent coughproductive of lightly blood stained sputum, and rightsided pleuritic chest pain. Her symptoms had worseneddespite 2 weeks of oral antibiotic therapy prescribed byher general practitioner, for suspected community ac-quired pneumonia.

In addition, prior to the onset of respiratory symp-toms, she had a history of presumed left middle ear in-fection over the preceding 6 months, having not beenprone to otological problems earlier in life. She had pre-sented with ear fullness and reduced hearing with anaudiogram demonstrating a mild to severe mixed

conductive and sensorineural hearing loss. This hadbeen treated with multiple courses of antibiotics and cor-ticosteroids, including nasal corticosteroids, and whenshe failed to respond, she proceeded to myringotomywith grommet insertion. Subsequent audiological testing

1Department of General Pediatrics, Sydney Children’s Hospital Network,

Randwick, Australia.

2School of Women’s and Children’s Health, University of New South

Wales, Australia.

3Department of Immunology, Sydney Children’s Hospital Network,

Randwick, Australia.

4Department of Ear, Nose, and Throat Surgery, Sydney Children’s Hospi-

tal Network, Randwick, Australia.

5Department of Respiratory Medicine, Sydney Children’s Hospital Net-

work, Randwick, Australia.

Conflict of interest: None.

*Correspondence to: Paul Gray, MBChB, B.A Hons, FRACP, FRCPA,

Department of Immunology, Sydney Children’s Hospital, 61 High Street,

Randwick, NSW 2031, Australia.

E-mail: paul.gray@sesiahs.health.nsw.gov.au

Received 27 August 2012; Accepted 15 November 2012.

DOI 10.1002/ppul.22746

Published online 28 January 2013 in Wiley Online Library

(wileyonlinelibrary.com).

� 2013 Wiley Periodicals, Inc.

unexpectedly showed progression of the sensorineuralcomponent of her hearing loss. Given the atypical courseof presumed otitis media, a CT scan of the sinuses, mid-dle ear, and mastoids was performed, to look for evi-dence of a mass lesion such as acoustic neuroma orretrocochlear tumour underlying symptoms, howeverthis showed only inflammatory changes. She would nothave been considered at exposure risk for atypical infec-tion such as tuberculosis or lyme disease. She was re-ferred on to a specialist with specific otologicalexpertise for further investigation and management.

By the time she was admitted to hospital she had lost10% of her body weight over and appeared extremelyunwell. She was tachypnoeic and orthopnoeic with arespiratory rate of 50/min and oxygen saturation of92% in room air. There was reduced air entry and bron-chial breath sounds over the right lung, but no fingerclubbing. She reported reduced hearing on the left sidewhich pure tone audiogram subsequently confirmed asa profound sensorineural hearing loss, with a mild lossat higher frequencies in the right ear.

Initial investigations showed elevated inflammatorymarkers, including neutrophil leukocytosis, C-reactiveprotein (CRP) ¼ 286 mg/L (N < 7), and erythrocytesedimentation rate (ESR) ¼ 138 mm/hr (N < 15).Blood cultures, sputum for bacterial culture and acid fastbacilli and tuberculin skin test were negative. A chest X-ray (CXR) showed ill-defined rounded opacities scat-tered throughout the right lung with possible cavitationin the lower zone in addition to opacification in the rightsuperior mediastinum (Fig. 1A). Contrast enhanced com-puted tomography (CT) scan of the chest revealed multi-ple cavitating lung lesions associated with right lowerlobe consolidation, mediastinal and hilar lymphadenopa-thy, and a moderate-sized pleural effusion (Fig. 1B).

She was commenced on broad spectrum intravenousanti-biotics with antifungal therapy added when shefailed to respond to treatment, and her sputum culture

isolated Candida albicans. However, she underwentfurther clinical and radiological progression with wors-ening respiratory distress, increasing oxygen require-ment, significant haemoptysis and extensive right lowerand middle lobe consolidation, prompting an immunol-ogy review. At this time an additional history was eluci-dated, with the patient describing mild intermittentepistaxis with nasal obstruction over several months,which had been attributed to nasal corticosteroid treat-ment. She was noted to have a hyponasal quality to herspeech, and direct anterior rhinoscopy demonstratedsignificant nasal mucosal inflammation, crusting, andulceration. Given the history of otitis media, hearingloss, nasal symptoms, and lower respiratory disease, adiagnosis of cGPA was considered. Anti-neutrophil cy-toplasmic antibody (ANCA) test identified a cyto-plasmic pattern (c-ANCA titre 1:100), the relevance ofwhich was confirmed by the presence of anti-protein-ase-3 (anti-PR3) antibodies by enzyme linked immuno-sorbent assay (ELISA). Nasal biopsy demonstratednecrotising granulomata with prominent small vesselvasculitis consistent with cGPA. Urinary examinationwas normal other than very mild proteinuria and renalbiopsy was not performed. Ophthalmology and cardiacexaminations, including echocardiography were normal.

Immunosuppressive therapy was initiated in the formof pulse methylprednisolone 1 g/day � 3 days withconcurrent intravenous cyclophosphamide 500 mg/M2.She responded with decreasing oxygen requirement,resolution of haemoptysis and improved radiologic ap-pearance. Prior to discharge baseline lung function test-ing including spirometry, body plethysmography, anda diffusion study was performed. This revealed mildrestrictive lung disease with impaired diffusion(FVC ¼ 75%, FEV1/FVC ¼ 97%, and DLCO ¼ 49%).Unfortunately, repeat Pure Tone audiogram confirmedpersistent profound unilateral hearing loss in the left earwith no significant improvement (Fig. 2). She was

Fig. 1. Chest radiograph (a) shows ill-defined opacities with possible cavitations, while con-

trast enhanced computed tomography (CECT) scan (b) of chest shows cavitating lung lesions

associated with right lower lobe consolidation.

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treated with cyclophosphamide 750 mg/M2 initiallyfortnightly changing to monthly over a 6-month period,along with concurrent weaning dose of oral predniso-lone. She remains in remission on azathioprine as amaintenance agent.

DISCUSSION

This case report highlights some of the specific diffi-culties associated with diagnosing childhood granuloma-tosis with polyangiitis (cGPA), as well as the importanceof considering an inflammatory aetiology when manag-ing apparently refractory infective symptoms.

cGPA is one of a number of systemic vasculitides thatcan potentially effect children and which should there-fore always be included in the differential diagnosis ofcomplex inflammatory presentations. The more commonvasculitis syndromes in childhood include HenochSchonlein purpura and Kawasaki disease,2 while polyar-teritis nodosa and Takayasu’s arteritis occur only rarely.3

cGPA effects small vessels and has an incidence of 1per 2 million children per year1 and affects predominate-ly older children, with a female predominance.4

Presentations of cGPA may be localized to one organor may involve many organs from the time of onset.3

Common features include constitutional symptoms, sino-nasal and lower respiratory inflammation, renal disease,4,5

and ANCA positivity.5 Presentations involving isolatedotitis/mastoiditis, eye or cutaneous manifestations, areless common but well documented.5 The degree of in-volvement of any given organ can vary greatly, withlower airway involvement ranging from asymptomatic(one-third of patients) to acute and fulminant alveolarhemorrhage with respiratory failure.4–6 Common lung

presentations include multiple pulmonary nodules withcavitations and confluent areas of airspace opacity. Renaldisease involving a pauci-immune glomerulonephritis isalso common at diagnosis and frequently presents as partof a pulmonary-renal syndrome. Loss of renal function iscommon and rarely completely reversible.4,5 Otitis can re-sult in either conductive of sensorineural hearing loss, andlaryngotracheobronchial stenosis is more common at pre-sentation in children than adults.7

The variable presentation and rarity of cGPA meansthat it may be overlooked when searching for a cause ofinflammatory symptoms, as happened in the currentcase. Diagnostic delays commonly occur with childhoodGPA5 with the median time period from symptom onsetto diagnosis being reported as 2.7 months.4 Multipleattempts have been made to improve diagnostic criteria,using features including clinical symptomatology, thesize of vessel involved (predominately small), the pres-ence of ANCA antibodies, or the presence of necrotizingvasculitis with granuloma formation on light microsco-py. Currently the preferred criteria are those set out inthe EULAR/PRINTO/PRES criteria for the classificationof childhood vasculitides.3 In brief, a diagnosis of cGPArequires three of the following features: abnormal urinal-ysis, granulomatous inflammation on biopsy, nasal sinusinflammation, subglottic, tracheal, or endobronchialstenosis, an abnormal chest X-ray or CT and ANCAstaining by indirect immunofluorescence confirmed aspositive for either anti-PR3 or anti-MPO antibody.3

While the pathogenesis of GPA is uncertain, evidencefrom animal models and the fact that B-cell targetedtherapies are efficacious, supports a pathogenic rolefor anti-nuclear cytoplasmic (ANCA) antibodies.8 Theprognosis in the pre-treatment era was grave and even

Fig. 2. Pure tone audiogram showing profound hearing loss in the left ear.

Granulomatosis With Polyangiitis Complex Case E23

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with the emergence of effective treatment with steroidsand cyclophosphamide, the average patient can expectto suffer a significant number of relapses with both dis-ease and treatment associated morbidity,9 There is con-siderable hope that the emergence of newer biologictherapies may alter the outcome,10 with the anti-CD20monoclonal antibody, rituximab, proving equivalence tocyclophosphamide in adult primary ANCA-associatedvasculitis, and superiority in inducing remission follow-ing relapse in adult patients.11

The current case highlights a number of importantpoints regarding the diagnosis of inflammatory diseasesin general and GPA in particular. The occurrence ofmiddle ear effusion in an older child may suggest anumber of common diagnoses, including Eustachiantube dysfunction, acute otitis media or otitis media witheffusion (‘‘glue ear’’), however the latter diagnosiswould be unusual in a teenager who had not previouslybeen affected by this condition.

The presence of middle ear inflammation with pro-gressive sensorineural deafness in this setting shouldsuggest an inflammatory cause with cGPA being high onthe list of differentials. Otic disease in GPA may be pres-ent for months before pulmonary or renal manifestations,and its prompt recognition and treatment is needed topreserve auditory function and prevent involvement ofother organs. Other differentials include infective toxicneuropathy, a neoplastic cause such as acoustic neuroma,retrocochlear, or even postnasal space tumour, while im-mune diseases such as Cogan’s syndrome or Tubulointer-stitial Nephritis with Uveitis (TINU) are exceedinglyrare. Finally, while there were multiple reasons to poten-tially suspect cGPA in this case, failure to respond tomultiple courses of antibiotics and the presence of cavi-tating lung disease in an immunocompetent patientpointed strongly towards a diagnosis of GPA or anotherANCA-associated vasculitis such as microscopic polyan-giitis or Churg–Strauss syndrome. Any patient presentingwith refractory airway inflammatory disease should bequestioned about the presence of nasal or sinus symp-toms including epistaxis and the development of nasalspeech and direct rhinoscopy performed to identify nasalpassage inflammation.

CONCLUSION

We have presented the case of a teenager with an atyp-ical course of GPA where delay in diagnosis led to thedevelopment of life-threatening respiratory involvement.The report highlights the importance of looking beyondinfectious causes of sinopulmonary disease, particularlywhen there is failure to isolate an organism, to respondto anti-microbial therapy, or where certain features (newonset deafness and pulmonary cavitation) point towards amore complex etiology.

KEY POINTS

(1) cGPA is a major organ and/or life threatening dis-ease, in which early diagnosis and treatment mayprevent life threatening consequences and irrevers-ible organ damage.

(2) Sinonasal, otic, or renal inflammatory disease, inparticular when combined with pulmonary fea-tures, are important flags for the diagnosis ofcGPA or another ANCA positive vasculitis.

(3) While pneumonia is overwhelmingly the mostcommon cause of lung consolidation, the presenceof haemoptysis or pulmonary cavitation alongwith failure of treatment response to broad spec-trum antibiotics, must always raise the possibilityof a vasculitis.

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