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ORIGINAL ARTICLE
Wegeners granulomatosis: A challenging disease
forotorhinolaryngologists
GABRIELLA CADONI1, DALIA PRELAJADE2, ELENA CAMPOBASSO3, LEA
CALO1,
STEFANIA AGOSTINO1, RAFFAELE MANNA3 & GAETANO PALUDETTI1
Departments of Otorhinolaryngology,1
Catholic University of the Sacred Heart, Rome, Italy,2Kaunas
Medical University,
Kaunas, Lithuania and 3Department of Medicine, Catholic
University of the Sacred Heart, Rome, Italy
AbstractConclusions. Diagnosis of Wegeners granulomatosis (WG)
can be delayed because of its aspecific presenting
symptoms.Detection of serum circulating antineutrophil cytoplasm
antibodies (c-ANCAs), in combination with histology, permits oneto
identify WG at an early stage and to implement stage-adapted
therapy. c-ANCA levels may also help to evaluate theresponse to
medical therapy. Recently, the quality of life of WG patients has
been improved by administering cotrimoxazolein order to prevent
infections and recurrent diseases during the remission period.
Objective. WG is of special significance tothe
otorhinolaryngologist because it is often initially limited to the
upper respiratory tract before becoming systemic. Theaim of this
paper was to describe a series of WG patients and underline the
difficulties involved in diagnosing and treatingthis challenging
disease. Material and methods. This was a prospective study in 23
consecutive patients with head and neckmanifestations of WG (17
systemic, 6 limited). Diagnosis was performed by means of both
c-ANCAs detection usingindirect immunofluorescence and histology in
biopsy specimens. Treatment consisted of daily cyclophosphamide
(CYC;2 mg/kg/day) and glucocorticoids (prednisone; 1 mg/kg/day). If
an improvement or toxic events occurred, CYC wasdiscontinued and
methotrexate was started. If, during remission of the disease, low
serum c-ANCAs levels were detected,CYC was suspended and
cotrimoxazole (1 g/day) was introduced. Results. Serum c-ANCAs
detection was positive for all
patients. Biopsy was diagnostic from the beginning in 19/23
cases. The six patients with limited WG did not show aprogression
to systemic disease. Only 3 patients with a diagnosis of delayed
systemic WG died, whereas 19/23 patients werealive with good
control of relapses.
Keywords: Circulating antineutrophil cytoplasm antibodies,
cotrimoxazole, cyclophosphamide, methotrexate, tumor necrosis
factor inhibitors, Wegeners granulomatosis
Introduction
Wegeners granulomatosis (WG) is a systemic dis-
ease characterized by necrotizing granulomas and
vasculitis of small vessels. It has been over half a
century since Wegener [1,2] first described a groupof patients
who presented with upper airways disease
and died of renal failure. In 1954, Godman and
Churg [3] delineated three criteria for WG: necro-
tizing granulomatous lesions of the upper airways,
vasculitis and glomerulonephritis.
WG is a relatively rare disease, with an incidence
that varies from 5 to 15 cases per million people.
Higher incidences have been reported in northern
compared to southern Europe [4]. The average age
at initial diagnosis is 20/40 years; no gender
predominance has been reported [5 /7].
The etiology is unknown, although certain drugs,
infections, environmental toxins and also genetic
factors have been implicated. Some drugs, such
aspropylthiouracil [8] and monocycline [9], are clearly
associated with vasculitis. Infectious agents have
frequently been implicated as initiators of vasculitis,
and nasal carriage of Staphylococcus aureus has
been documented in WG [10,11]. As far as environ-
mental factors are concerned, silica has repeatedly
been mentioned as an etiologic agent in small-vessel
vasculitis [12].
Correspondence: Gaetano Paludetti, MD, Department of
Otorhinolaryngology, Catholic University of the Sacred Heart, Largo
A. Gemelli, 8, IT-00168
Rome, Italy. E-mail: [email protected]
Acta Oto-Laryngologica, 2005; 125: 1105 /1110
(Received 3 September 2004; accepted 2 December 2004)
ISSN 0001-6489 print/ISSN 1651-2551 online # 2005 Taylor &
Francis
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WG is associated with the presence of circulating
antineutrophil cytoplasm antibodies (c-ANCAs),
whose target autoantigens are primarily contained
within azurophil granules. Recent findings [13 /15]
demonstrate that c-ANCAs are best demonstrated in
WG by using a combination of indirect immuno-
fluorescence of normal peripheral blood neutrophilsand an ELISA
that detects ANCAs specific for
proteinase 3 (PR3). The most widely accepted
pathogenetic model suggests that c-ANCAs-acti-
vated cytokine-primed neutrophils induce microvas-
cular damage and a rapid escalation of inflammation
with recruitment of mononuclear cells. Although all
studies on c-ANCAs target cells have concentrated
on the neutrophils, there is evidence that monocytes
also express PR3, and that c-ANCAs-induced
monocyte activation can lead to release of mediators
[16].
In its classic form, WG involves three regions:
the head and neck; lung; and kidney. Some patients
develop a disease restricted to only one or two of
these target areas, the so-called limited form of
WG. There is a high prevalence of head and neck
manifestations (72.3 /99%) [5,17 /20].
Nasal obstruction, pain, ulceration, edema, dis-
charge, an altered sense of smell, epistaxis and
deformity are manifestations of nasosinusal involve-
ment of WG. The commonest site of active nasal
disease is the area of the Kiesselbacch locus, where
one can see necrosis of the septal cartilage. The
typical WG saddle nose deformity often ensues,
but does not necessarily indicate the presence of anactive
disease. The remaining mucosa and turbinates
are also frequently involved [18,21,22].
Otological symptoms can represent the onset of
WG in 20 /25% of cases, whereas aural lesions may
develop during the course of the disease in 14 /45%
of cases [23 /28]. In the former situation, conductive
or mixed uni- or bilateral hearing loss associated
with other objective signs of otitis media with
effusion can be the presenting features. Granuloma-
tous obstruction of the Eustachian tube often con-
stitutes the pathological basis of the disease.
Sensorineural hearing loss due to vascular damage[29], deposits
of immune complexes at the cochlear
site or granulomatous involvement of the cochlear
nerve [30] are less frequent.
Facial palsy occurs in association with middle ear
disease, but is extremely rare as a presenting sign
[31]; it usually improves with cytotoxic therapy, but
is often permanent when middle ear surgery has
been incorrectly performed or treatment has been
delayed. In a very few instances other cranial nerves,
such as the IXth, Xth and XIth, are affected [32,33].
The peculiar gingival hyperplasia known as
strawberry gum is pathognomic, but occasionally
presents in the early stages of WG [34]. Deep
mucosal ulcers of the tongue, cheek, gingiva and
palate are also rare but distinct signs.
Occasionally, patients develop severe subglottic
stenosis. According to the National Institutes of
Health experience [35], subglottic stenosis was
present in 16% of patients, half of whom needed atracheostomy.
Laryngeal symptoms of subglottic
stenosis in WG patients are stridor, pain, dyspnea,
wheezing and altered phonation [5,36,37].
Material and methods
A total of 23 patients affected by WG (14 females, 9
males; median age 48 years; male:female ratio 0.64)
were included in our study between 1990 and 2001.
A total of 6/23 patients presented with limited WG
(Table I): 2 had a laryngeal localization, 3 had a
nasosinusal involvement and 1 had unilateral facialpalsy as the
presenting symptom.
A total of 17/23 patients presented with systemic
WG (Table II). At the time of presentation, 16/17
showed renal involvement, with nephritis in only 4
cases; 10/17 had pulmonary lesions, 8 had ocular
inflammation and there were 4 peripheral neuropa-
thies. Three patients presented in an advanced stage
of disease due to a delayed diagnosis.
Diagnosis of WG was performed by serum
c-ANCAs detection using an indirect immunofluor-
escence technique and by histopathologic identifica-
tion of granulomatous inflammation, multinucleated
giant cells, necrosis and vasculitis in biopsy speci-
mens. Biopsy was not performed in the one case of
facial palsy.
At our department the standard medical treatment
for WG consists of daily cyclophosphamide (CYC)
and glucocorticoids. In 22/23 patients, oral CYC
was started at a dosage of 2 mg/kg/day, as a single
dose given in the morning, together with oral
prednisone at a dosage of 1 mg kg/day. If a sig-
nificant improvement or toxic events occurred, CYC
was discontinued, methotrexate (MTX) was started
and prednisone was tapered. During the period of
therapy, a blood cell count was obtained to evaluate
toxic effects and the dosage of CYC was adjusted
downward.
Patients were followed up once a month from the
time of diagnosis; at each evaluation, a physical
examination and a laboratory assessment (complete
blood count, determination of the erythrocyte sedi-
mentation rate, renal and hepatic function and
c-ANCA, and urinalysis) were performed.
One patient with limited WG (laryngeal) who
refused CYC was treated with oral MTX at a dosage
of 0.3 mg/kg, together with oral prednisone.
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Results
Head and neck localizations were present in all 17
systemic WG patients: 10 of them had a nasosinusal
involvement, 11 had mixed hearing loss associated
with serous otitis media in 9 cases and chronic
hyperplastic otitis media in 2, and 1 had progressive
bilateral sensorineural hearing loss. Of the six
patients with limited WG, two had dysphonia and
dyspnea with a subglottic laryngeal localization and
one needed a tracheotomy for respiratory distress;
three with nasosinusal involvement suffered with
nasal obstruction, crusts and purulent secretions,
bloody discharge and pain, and in one case a
progressive saddle nose deformity occurred; one
patient showed unilateral facial palsy as the present-
ing symptom, in association with clinical features of
bilateral serous otitis media.
Serum c-ANCAs detection was positive for all 23
patients (Table II). C-ANCAs positivity as a unique
finding was conclusive for an early diagnosis of WG
for the patient with unilateral facial palsy as the
presenting symptom. One patient with hyperplastic
chronic mastoiditis underwent a tympanoplasty
before c-ANCAs positivity and a kidney biopsy
permitted us to make a definitive diagnosis of
systemic WG.
The first biopsy was diagnostic in 19/23 cases
(Table II). Laryngeal and inferior turbinate biopsies
were positive in two and three cases, respectively
with limited WG. For patients with systemic symp-
toms and serum c-ANCAs positivity, an inferior
turbinate biopsy proved diagnostic in eight cases;
three had a positive lung biopsy after negative
kidney (n0/2) and mastoid (n0/1) biopsies; one
other lung biopsy was positive; five kidney biopsies
were positive.
During the first month of follow-up, 7/22 patients
stopped taking CYC due to toxicity and were
administered steroids; 3 of them relapsed and
MTX was added to the regimen. The six patients
with limited WG did not show a progression to
systemic involvement of the disease.
If, during remission of the disease, low serum c-
ANCA levels were detected, CYC was suspended
and cotrimoxazole (1 g/day) was introduced.
The one patient who refused standard therapy was
lost to follow-up (range 0 /132 months). Only 3
patients with a delayed diagnosis of systemic WG
died, whereas 19/23 patients were alive with a good
control of relapses with standard therapy.
Discussion
WG is an uncommon disease which is hard to
identify. Since its first description in 1936 it has
undergone significant changes in terms of its diag-
nosis and treatment. It has special significance to the
otorhinolaryngologist because the disease is initially
limited to the upper respiratory tract before becom-
ing systemic [23,25,27,38,39].
The systemic form of WG is more frequent than
the localized one [40] but since determination of c-
ANCAs was introduced as a diagnostic tool, in
combination with histology, an increasing number
of cases have been identified at an early stage [22].
Such early identification is of great importance in
order to implement stage-adapted therapy.
In our experience, diagnosis of some cases of WG
can be delayed because of the aspecific presenting
symptoms. The resistance of WG to traditional
medical treatment, and the worsening of symptoms,
encouraged us to perform new diagnostic immune
tests and histology; sometimes, occasional histologi-
cal findings of granulomatous inflammation induced
us to consider WG in the differential diagnosis.
In the literature, the specificity of c-ANCAs for
diagnosing WG has been widely discussed. Negativ-
ity of c-ANCA tests does not necessarily exclude the
diagnosis of WG [41], as they can become positive
during the course of the disease. The application of
c-ANCAs testing as a clinical diagnostic tool is still
regarded as controversial [15]. In our series, c-
ANCAs positivity was the determining factor for
diagnosis, even if histology was aspecific. Never-
theless, for a correct diagnostic interpretation of
Table I. Details of patients with limited WG (c-ANCAs were
detected in all patients).
Patient
no.
Nasosinusal
localization Larynx Cranial nerves Biopsy
Follow-up period
(months)
1 Rhinitis Inferior turbinate 108
2 Rhinosinusitis Inferior turbinate 120
3 Saddle nose Inferior turbinate 96
4 Hipoglottic Laryngeal 60
5 Glottic Laryngeal 0
6 VIIth cranial nerve palsy 120
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serological data it is necessary to carefully assess the
clinical /pathological relationship.
c-ANCA levels have been also used to evaluate the
response to medical therapy; as in other reports,
their levels were lower during the periods of remis-
sion. The close relationship between antibody titer
and the clinical course suggests a possible role of
antibodies in the pathogenesis of the disease [38,42].
The poor prognosis of WG was marginally im-proved by the use of
steroids and cytotoxic agents
(CYC, MTX). Conventional treatment with CYC
and glucocorticoids is limited by the occurrence of
toxic events. The interruption of CYC administra-
tion and its substitution by MTX is associated with a
higher rates of recurrences, as was seen in 8/23
patients in our series.
A less toxic treatment for systemic WG [43] can
be considered for cases diagnosed early. Anti-in-
flammatory doses of steroids can be used in localized
WG, whereas cytotoxic drugs together with immu-
nosuppressive doses of steroids can be administered
when WG becomes a systemic disease. Fever and
joint pain can characterize the evolution of WG from
a localized to a generalized disease.
Recently, the quality of life of WG patients was
improved by administering cotrimoxazole in order to
prevent infections and recurrent diseases during the
remission period [44]. Because of the apparent
correlation between infection and WG activation,
the management of infections, especially thosecaused by S.
aureus, requires special attention,
especially for the localized variant of WG, and
cotrimoxazole is considered the drug of choice for
the prevention of relapses [22]. Moreover, cotrimox-
azole may be worth trying not only during the initial
stage of WG but also for the generalized disease
when the patient is not acutely ill [45].
In our series only three patients died, all of whom
had delayed diagnosis and treatment.
Plasmapheresis or plasma exchange has occasion-
ally been used in rapidly progressive glomerulone-
phritis [46], and hemodialysis with CYC and
Table II. Details of patients with systemic WG (c-ANCAs were
detected in all patients).
Patient
no.
Nasosinusal
localization Middle ear Kidney Lung Eye PNS Biopsy
Follow-up
period
(months)
1 Serous otitis Proteinuria Parenchymal
lesion
Brachial
palsy
Inferior
turbinate
102
2 Rhinitis SNHL Glomerulonephritis Parenchymal
lesion
Conjunctivitis Kidney 8
3 Sinusitis,
saddle nose
Serous otitis Nephrosis Granuloma Kidney,
inferior
turbinate
48
4 Rhinosinusitis Proteinuria Dacryoadenitis Paresthesiae
Inferior
turbinate
35
5 Serous otitis Episcleritis 91
6 Serous otitis Proteinuria Inferior
turbinate
98
7 Serous otitis Proteinuria Conjunctivitis Neuropathy
Inferior
turbinate
97
8 Saddle nose Chronic otitis Proteinuria Radiopaque
area
Lung,
mastoid
103
9 Sinusitis Serous otitis Microhematuria Radiopaque
area
Inferior
turbinate
51
10 Sinusitis Serous otitis Hemoglobinuria Parenchymal
lesion
Episcleritis Inferior
turbinate
90
11 Chronic otitis Hemoglobinuria Kidney 71
12 Sinusitis Serous otitis Proteinuria Conjunctivitis Neuropathy
Inferior
turbinate
91
13 Proteinuria Parenchymal
lesion
Lung 87
14 Sinusitis Serous otitis Nephrosis Temporary
blindness
Kidney 57
15 Maxillary
sinusitis
Glomerulonephritis Radiopaque
area
Kidney,
lung
6
16 Sinusitis Serous otitis Proteinuria Radiopaque
area
Kidney,
lung
3
17 Proteinuria Radiopaque
area
Episcleritis Kidney 123
SNHL0/sensorineural hearing loss; PNS0/peripheral nervous
system.
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steroids has been performed in WG complicated by
pregnancy [47].
In a recent study [48], an improvement in
refractory WG was achieved with two tumor necrosis
factor inhibitors (infliximab and etanercept) and the
immunosuppressant 15-deoxyspergualin.
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