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RIGINAL ARTICLE

ar, Nose and Throat Manifestations of Wegener’s GranulomatosisGranulomatosis With Polyangiitis)�

armelo Morales-Angulo,a Roberto García-Zornoza,a,∗ Sergio Obeso-Agüera,a

aime Calvo-Alén,b Miguel A. González-Gayc

Otorrinolaringología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, SpainReumatología, Hospital Sierrallana, Torrelavega, Cantabria, SpainReumatología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain

eceived 6 November 2011; accepted 2 December 2011

KEYWORDSGranulomatosis withpolyangiitis;Wegener’sgranulomatosis;Ear nose and throat;Incidence

AbstractIntroduction and objectives: Granulomatosis with polyangiitis (GPA), previously calledWegener’s granulomatosis, is a small vessel vasculitis often associated with clinical head andneck manifestations, which are sometimes the presenting symptoms of the disease. The aimof our study was to identify ear, nose and throat (ENT) manifestations associated with GPA andpropose a work-up for the management and diagnosis for patients with suspicion or confirmeddiagnosis of this ENT pathology.Patients and methods: Retrospective review of the medical records of all patients diagnosedwith GPA who were seen at the Department of Otolaryngology from a tertiary public hospitalin Cantabria (Spain) over a 20-year period. Clinical and laboratory data, in particular thoseconcerning ENT manifestations, were retrieved from the patients’ medical records.Results: Twenty-five patients (age range: 30---81 years) were included in the study. Of these,88% had ENT manifestations at some point in the course of the disease. In 28% of the cases,ENT features were the presenting manifestations. The most frequent ENT manifestations weresinonasal symptoms (52%), followed by otological manifestations (32%).Conclusions: Patients with GPA often present with clinical ENT manifestations. Consequently,

routine ENT physical examination must be performed in patients with suspected vasculitis toestablish a diagnosis of GPA or to better determine the degree of organ system involvement inpatients with GPA.© 2011 Elsevier España, S.L. All rights reserved.

� Please cite this article as: Morales-Angulo C, et al. Manifestaciones otorrinolaringológicas en pacientes con granulomatosis deegener (granulomatosis con poliangeitis). Acta Otorrinolaringol Esp. 2012;63:206---11.∗ Corresponding author.

E-mail address: robertozornoza@hotmail.com (R. García-Zornoza).

173-5735/$ – see front matter © 2011 Elsevier España, S.L. All rights reserved.

Ear, Nose and Throat Manifestations of Wegener’s Granulomatosis (Granulomatosis With Polyangiitis) 207

PALABRAS CLAVEGranulomatosiscon poliangeitis;Granulomatosisde Wegener;Manifestaciones ORL

Manifestaciones otorrinolaringológicas en pacientes con granulomatosis de Wegener(granulomatosis con poliangeitis)

ResumenIntroducción y objetivos: La granulomatosis con poliangeitis (GPA), previamente llamada gra-nulomatosis de Wegener, es una vasculitis de pequenos vasos que con frecuencia se asocia a man-ifestaciones clínicas de cabeza y cuello, y en ocasiones constituyen los síntomas de presentaciónde la enfermedad. El objetivo de nuestro estudio fue identificar la afección otorrinolaringológ-ica asociada a dicha enfermedad y proponer un protocolo diagnóstico de los pacientes consospecha clínica o confirmada de la misma.Pacientes y métodos: Se realizó un estudio retrospectivo descriptivo que incluyó los pacientesdiagnosticados de GPA que recibieron asistencia por el Servicio de Otorrinolaringología de unhospital público de tercer nivel de Cantabria. El período de inclusión fue de 20 anos. Se reco-gieron de la historia clínica diferentes variables clínicas concernientes al área de cabeza ycuello.Resultados: Veinticinco pacientes con edades comprendidas entre 30 y 81 anos de edad fueronincluidos en nuestro estudio. El 88% de los mismos presentaron manifestaciones otorrino-laringológicas en algún momento de la evolución de la enfermedad, y en un 28% constituyeronla forma de presentación de la misma. Los síntomas nasosinusales fueron los más frecuentes(52%), seguido de los otológicos (32%). Un paciente desarrolló un carcinoma de nasofaringe3 anos después del tratamiento con ciclofosfamida.Conclusiones: Los pacientes con GPA presentan con frecuencia manifestaciones clínicas decabeza y cuello. Es necesario realizar una exploración sistemática otorrinolaringológica en lospacientes con sospecha o diagnóstico confirmado de GPA, tanto para contribuir al diagnósticode la enfermedad, si esta no estuviese confirmada, como para establecer el grado de afección

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Introduction

Granulomatosis with polyangiitis (GPA), previously known asWegener’s granulomatosis (WG),1 is a systemic autoimmunedisease of unknown aetiology characterised by necrotisinggranulomatous inflammation and vasculitis affecting mainlysmall blood vessels.2 The prevalence of GPA ranges between3 cases per 100 000 inhabitants in the U.S.A.3 and 16 casesper 100 000 inhabitants in southern Sweden.4 A collabora-tive European study suggested that the incidence of GPAhas a North---South gradient, with a higher incidence inScandinavian countries and a relatively lower incidence insouthern Europe.5 In this sense, an epidemiological studyconducted in Galicia described an incidence of 2.95 newcases per 1 000 000 inhabitants/year,6 which is below thatobserved in other European countries such as Norway (12 per1 000 000 inhabitants/year)7 and the UK (8.4 per 1 000 000inhabitants/year).8

The most common ages of presentation of GPA are thesixth and seventh decades of life, but it can appear at anyage, with similar frequency between genders in adult age.9

The clinical manifestations of GPA can be very hetero-geneous, often affecting the upper respiratory tract, lungsand kidneys. Localised forms of the disease in the head andneck region are not exceptional.10,11

The diagnosis of GPA is complex, contributing to a delayin its confirmation and start of treatment. This often resultsin significant sequelae secondary to tissue destruction in

affected areas of the head and neck.12

The aim of our study was to determine the head and neckmanifestations appearing in GPA, with particular emphasison their presentation forms, in order to contribute to early

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iagnosis of the disease, and to propose a protocol for ENTiagnostic evaluation in these patients.

aterials and Methods

e conducted a retrospective study including patients diag-osed with GPA at a public tertiary care hospital in theegion of Cantabria, between January 1991 and April 2011.e reviewed the medical records of patients and col-

ected the main clinical data associated with head and necknvolvement.

The diagnosis of GPA was based on the presence of sus-icious clinical lesions (e.g. head and neck manifestationslong with systemic manifestations) with histological confir-ation of WG or positive antineutrophil antibodies (ANCA).he histopathological criteria of GPA include the presencef necrotising granulomatous inflammation in arterial vesselalls or in the perivascular or extravascular region.10

We excluded from the study those patients with GPAho were not examined at an Otorhinolaryngology Service

ENT). These were generally patients referred from othereographical regions for histological confirmation by lung oridney biopsy.

esults

e reviewed the medical records of 70 patients with gran-

lomatosis or systemic vasculitis. We excluded 30 patientsho suffered a disease other than GPA and 15 patients whoad not been examined by an ENT specialist. Of the 25atients who met the inclusion criteria, 16 were male (64%)

208

Table 1 ENT Manifestations Found in the Series of PatientsSuffering Granulomatosis With Polyangiitis.

ENT symptoms No. of cases, %

Otological involvementSerous otitis 5 (20%)Sensorineural hypoacusis 3 (12%)Chronic otitis media 2 (8%)Facial paralysis 1 (4%)External otitis 1 (4%)

Sinonasal involvementChronic rhinosinusitis 8 (32%)

Epistaxis 5 (20%)Dry rhinitis 4 (16%)

Septal perforation 1 (4%)Nasal ulcer 1 (4%)Nasal swelling 1 (4%)Chronic dacryocystitis 1 (4%)

Retroorbital tumour 0 (0%)‘‘Saddle’’ nose 0 (0%)

Pharyngeal---laryngeal---tracheal involvementSubglottic stenosis 2 (8%)Tracheal stenosis 1 (4%)Pharyngeal tumour 1 (4%)

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Otological manifestations appear in between 6% and

nd 9 were female (36%). Age at diagnosis ranged between0 and 81 years with a mean of 57 years. In total, 88% ofatients presented ENT manifestations during the course ofheir disease, with sinonasal manifestations being the mostrequent (52%).

Table 1 summarises the ENT involvement found. Therst manifestation of the disease was an ENT symptom orign in 28% of patients. A total of 18 patients (72%) suf-ered pulmonary involvement and 10 (40%) suffered renalnvolvement during the course of the disease. Except for

patient who presented granulomatosis localised in theead and neck region manifested as a sinus condition, theest presented systemic involvement. A total of 10 patients40%) underwent head and neck biopsy of suspicious lesions,enerally nasal (only 1 case underwent biopsy of the laryn-eal subglottis). In 5 cases (50% of those conducted in thisegion and 20% of the total patients included in the study)ead and neck biopsy confirmed the presence of the dis-ase by revealing histological criteria consistent with GPA.he 5 positive cases were obtained from biopsies of nasalucosa.A total of 23 patients (92%) underwent an ANCA study

through indirect immunofluorescence or else by ELISA),ith 19 positive (76%) and 4 negative cases (16%). Among

he positive cases, 15 were positive for antiPR3 with cytoplasmic pattern (cANCA) and 4 were positive foryeloperoxidase with a perinuclear pattern (pANCA). Of the

patients with negative ANCA, 1 case presented localisedisease and the remainder suffered systemic involvement.

All patients were treated with immunosuppressants andorticosteroids by the Rheumatology Service and in col-

aboration with the Nephrology Service in cases of renalnvolvement.

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In total, 4 patients (16%) required surgical treatmentor their ENT condition associated with GPA, which hadot responded to medical treatment. Of these, 2 under-ent tracheotomy due to subglottic stenosis (decannulationas not attempted in either case, due to the sever-

ty of stenosis, advanced age and/or general condition), cases underwent tympanic tube placement (including theatient with subglottic stenosis) and another patient under-ent dacryocystorhinostomy due to lachrymal-nasal ductbstruction. None of these patients presented postoperativeomplications.

One patient treated with cyclophosphamide and corti-osteroids developed a nasopharyngeal carcinoma 3 yearsfter diagnosis of GPA. This was treated with concomitanthemotherapy and radiotherapy and the patient is currentlyisease-free (2 years after diagnosis).

iscussion

PA characteristically affects the upper respiratory tract,lthough the lower respiratory tract and kidneys are alsorequently involved, completing the classic triad of thisisease. Pulmonary involvement ranges from asymptomaticulmonary nodules to pulmonary infiltrates and fulmi-ating alveolar haemorrhage.13 The most common renalnvolvement is necrotising segmental glomerulonephritis,lthough proliferative glomerulonephritis is also fre-uently present.14 Renal manifestations may be presentt the time of diagnosis in 18% of patients, althoughatients may develop renal involvement throughout theirvolution.13,15

GPA can also affect various other organs, resulting inrticular, cutaneous (palpable purpura, ulcers, subcuta-eous nodules) or neurological (mononeuritis multiplex,eripheral neuropathy, meningitis) symptoms and consti-utional syndrome (fever, asthenia, anorexia and weightoss).13

The presence of ENT involvement in patients with GPAanges between 72.3% and 99% of cases depending on theerformance or not of systematic head and neck studiespon suspicion or diagnosis of disease, as well as periodiceassessment of new outbreaks.14,16 These figures are similaro that found in the present study, despite its retrospectiveature, which was 88%.

Although in our work ENT manifestations were the firstymptom of the disease in 28% of cases, in other serieshese manifestations were the first symptom of the diseasen between 63% and 72% of cases.17,18

The fact that our study was retrospective coupled withhe absence of a standardised study protocol for theseatients in our service may have underestimated the truencidence of ENT manifestations of the disease. Moreover,ince the course of this clinical entity is marked by fre-uent outbreaks, patients generally alternate silent phasesn which there are no ENT manifestations, with phases ofctivity, and hence the importance of finding ENT symp-oms in the previous history which may have disappeared

6% of patients with GPA. The most frequent are middlear lesions, especially serous otitis. Acute otitis media

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Ear, Nose and Throat Manifestations of Wegener’s Granulom

or chronic otitis media, which develop as a result of thepresence of granulation tissue affecting the Eustachiantube, middle ear or nasopharynx, are less frequent.19

Facial paralysis, including bilateral cases, can also appearassociated with the presence of otomastoiditis.20 Some GPApatients may present sensorineural or mixed hearing loss.13

Although hearing loss is usually described as having rapidonset, progressing over days or weeks and being compatiblewith the profile of typical autoimmune hearing loss, the3 cases in our study who developed it suffered a slowlyprogressive evolution. In fact, we cannot rule out that theirhearing loss was related to other environmental factorsand neither can we confirm that sensorineural hearingloss in these patients had a true connection with GPA. Itis postulated that sensorineural hearing loss is associatedwith the development of vasculitis affecting irrigationof the cochlea or by deposition of immune complexeswithin it.18,19 On the other hand, manifestations affectingthe outer ear are exceptional, although there have beenreports of auricular chondritis similar to those in recurrentpolychondritis.18

Sinonasal manifestations are the most frequent in thehead and neck region as shown in our study, in which 52% ofpatients developed sinonasal symptoms. Typically, patientsrefer non-specific symptoms such as nasal dryness, puru-lent rhinorrhea, epistaxis, pain, smell disorders and nasalobstruction. Physical examination usually reveals the pres-ence of nasal crusts and, occasionally, perforation of theanterior nasal septum. These lesions are often caused byvasculitis of the Kiesselbach area. The sequela known as‘‘saddle nose’’ may occur in advanced stages as a resultof extensive necrosis of the septal cartilage area.21 Theappearance of chronic sinusitis due to obstruction of thedrainage ostium is also a frequent.18

Up to 8% of patients may develop a retroorbital tumour,sometimes by extension of sinus lesions or else by theappearance of primary granulation tissue in that area.13

In 2% of patients, GPA may initially appear as secondaryproptosis.12 However, none of the patients in our seriesdeveloped orbital disease.

Oral manifestations are rare in GPA, with ‘‘strawberry’’gingival hyperplasia being the most characteristic in thisdisease.22 This finding was only observed in 1 patient in ourstudy and represented one of the manifestations observedat the time of diagnosis of the disease which disappearedcompletely after medical treatment with immunosuppres-sants. Deep oral ulcers can also appear in the oropharynxor oral cavity (buccal mucosa, gums and tongue), and therewere 2 cases in our series. Hypertrophy of the parotid andsubmandibular glands is very rare.23 There has been 1 casereport of submandibular gland hypertrophy as the only man-ifestation of GPA.11

Laryngotracheal manifestations are rare, with subglotticstenosis being the most common. These appear in 8%---23%of patients throughout their evolution, representing the firstmanifestation of the disease in between 1% and 6% of cases(4% in our series).23 It is more common when the diagnosisof GPA takes place before 20 years of age.13 Patients with

subglottic or tracheal stenosis may be asymptomatic in ini-tial phases of the disease or suffer dyspnoea with exercise,but sometimes they may eventually develop acute respira-tory obstruction.24 Between 22% and 44% of patients with

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s (Granulomatosis With Polyangiitis) 209

ubglottic stenosis suffer concomitant bronchial stenosis.12

n some cases, subglottic stenosis represents the only mani-estation of the disease, as was the case in 1 of our patients,ho debuted at 70 years of age with subglottic stenosishich required urgent tracheotomy.

Pharyngeal manifestations are exceptional in GPA. Thereas only been 1 case report of retropharyngeal tumours initial manifestation of the disease.25 In our study weound 1 case of asymptomatic non-obstructive pharyngealumour.

The diagnosis of GPA is performed based on sugges-ive clinical symptoms (head and neck manifestations,haracteristics associated with pulmonary and/or renalnvolvement), and is confirmed by a compatible histologi-al study including: presence of small vessel vasculitis andecrotising granulomatous inflammation with giant multinu-leated cells. These may occur together or in isolation. Theresence of positive ANCA may contribute to the diagnosisn histologically dubious cases.

ANCA are antibodies whose target are the 2 main compo-ents of neutrophil granulocytes: PR3 serine and myeloper-xidase. Anti-PR3 antibodies are virtually pathognomonicor WG, while anti-myeloperoxidase antibodies are moreuggestive of other necrotising primary vasculitis, mainlyn microscopic polyangiitis.26 There are 2 types of tests toetect ANCA: immunofluorescence or ELISA (enzyme-linkedmmunosorbent assay). Immunofluorescence distinguishesetween anti-PR3 and anti-myeloperoxidase based on stain-ng pattern: the first are associated with cANCA and theecond with pANCA.14 Detection through ELISA (presencef anti-PR3 or else anti-myeloperoxidase) provides greaterpecificity. However, when both methods are combined, theensitivity and specificity for the diagnosis of GPA increasep to 90% and 98%, respectively.27 Up to 10% of patients withPA present a perinuclear pattern in immunofluorescencessays and up to 20% of patients with active, untreated GPAresent negative ANCA. This percentage increases up to 30%n localised forms of the disease.15,18 In patients with sugges-ive clinical histories and negative cANCA tests, conductingerial serology studies may eventually demonstrate positiveANCA.18

Biopsies of sinonasal lesions represent the best possibil-ty for diagnosis in the head and neck region since theynable extensive sampling (generally, samples over 5 mmre required), thus facilitating the detection of histologi-ally compatible lesions.28 Biopsy of granulation tissue inhe middle ear is rarely diagnostic because of the limitedmount of sample taken for diagnosis, except for those per-ormed in the context of mastoidectomy. Subglottic biopsiesre not very sensitive since it is also difficult to obtain largeamples without causing subsequent scarring sequelae. Inur study, 50% of the samples obtained confirmed the pres-nce of histological lesions compatible with GPA, all of themrom the nasal mucosa.

Conducting complementary tests, such as sinus radiol-gy, is useful in the initial ENT examination since someatients present sinus granulation tissue in the absence ofymptoms. Performing tone audiometry is also useful in thenitial evaluation of patients with GPA or suspected of it,

ince the development of bilateral sensorineural hearing losshroughout the evolution of the disease is not uncommon,s mentioned previously.13

210

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Figure 1 CT scan: destruction of the left maxillary sinus.

Performing computerised tomography (CT) or magneticesonance imaging (MRI) may be indicated in some patientsccording to location of involvement and clinical mani-estations. The most common findings on CT scans of thearanasal sinuses and fossae are the presence of mucosaledema with bone destruction foci in the paranasal sinusesFig. 1), as well as foci of sclerosing osteitis and bone thick-ning in the same location.29 In severe subglottic/trachealtenosis CT and MRI scans may also help to evaluate theharacteristics of lesions. These tests are also indicatedn patients with ear involvement who are unresponsive to

reatment or in cases of facial paralysis.

Table 2 proposes a diagnostic protocol which we believes useful in the initial assessment of patients with suspectedr confirmed diagnosis of GPA.

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Table 2 Evaluation Protocol for Patients With Suspicion or Confir

Type of examination

External examination ‘‘Otoscopy SeAnterior rhinoscopy/nasal endoscopy Na

tisExploration of oral cavity/oropharynx ‘‘Neck exploration PaLaryngotracheal exploration SuRadiography of sinuses SiTone audiometry CoFlow/volume curves LaCT/MRI ear/sinonasal/larynx/trachea Se

grne

Biopsy of sinonasal/ear/subglotticgranulomatous tissue

In

COM, chronic otitis media; CT, computed tomography; GPA, granuloma

C. Morales-Angulo et al.

In general, head and neck manifestations of patientsith GPA usually respond well to immunosuppressive therapy

cyclophosphamide or methotrexate) associated with gluco-orticoids for several months in phases of disease activity.ubsequently, patients require maintenance therapy in qui-scent phases, with methotrexate and azathioprine beingseful, as well as frequent boluses of glucocorticoids toontrol reactivations.18 Monoclonal antibodies against CD20rituximab) can also be useful.30

Surgical treatment does not change the course of theisease, but it can contribute to ameliorate the con-equences of tissue destruction in the head and neckegion. Caution should be exercised before conductingurgical indications in reactivation phases of the diseasehich may subsequently lead to greater sequelae. Inur study, 5 patients required surgical treatment due toisease-related sequelae. Two patients underwent place-ent of transtympanic ventilation tubes without further

omplications, 1 patient underwent dacryocystorhinostomynd 2 patients underwent tracheotomy due to subglottictenosis.

Generally, surgical treatment is not recommended inases of septal perforation. However, ‘‘saddle nose’’an be operated in the remission phase with goodesults.21

Subglottic stenosis only responds to medical treatmentn 20% of patients, with the rest requiring surgical treat-ent, either tracheostomy, dilation with steroid injection,

aser surgery or, in severe cases, laryngotracheoplasty.23

n our series, patients who suffered subglottic stenosisnderwent tracheotomy exclusively due to severe airwaybstruction, with decannulation not being attempted dueo their advanced age.

There have been reports of malignant tumours appearingn patients with GPA treated with cyclophosphamide.31 Oneatient in our series developed a malignant nasopharyngeal

umour. We do not know if it could have been related to theedication.

med Diagnosis of Granulomatosis With Polyangiitis.

Involvement to be ruled out or indicated study

Saddle nose’’, parotid or submandibular gland hypertrophyrous otitis/COM/granulation tissue in middle earsal crusts/septal perforation/granulomatoussue/sinusopathy

Strawberry’’ gingivitis, deep ulcersrotid/submaxillary gland hypertrophybglottic/tracheal stenosisnusopathynductive/mixed/sensorineural hypoacusisryngeal/tracheal stenosislected cases according to suspicion or location ofanulomatous tissue/preoperative evaluation of head andck lesion

non-confirmed GPA cases

tosis with polyangiitis; MRI, magnetic resonance imaging.

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Ear, Nose and Throat Manifestations of Wegener’s Granulom

Conclusions

Patients with GPA often present head and neck mani-festations. It is important to perform a systematic ENTexploration of patients with suspected or confirmed diagno-sis of GPA in order to contribute to an early diagnosis of thesemanifestations so as to prevent secondary complicationswhich would worsen the quality of life of these patients.

Conflict of Interests

The authors have no conflicts of interest to declare.

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