12infectious granulomatous laryngitis a retrospective
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8/7/2019 12Infectious granulomatous laryngitis a retrospective
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Eur Arch Otorhinolaryngol
DOI 10.1007/s00405-007-0533-4
123
LARYNGOLOGY
Infectious granulomatous laryngitis: a retrospective
study of 24 cases
Leonardo Silva · Edward Damrose · Fernanda Bairão ·
Mayra L. Della Nina · James C. Junior ·
Henrique Olival Costa
Received: 20 June 2007 / Accepted: 29 October 2007
© Springer-Verlag 2007
Abstract The diagnostic and treatment of verrucous
lesions of the larynx involves a high level of suspicion by
the physician attending the patient. The causes may go
from unspeciWc laryngitis to neoplasia and granulomatous
diseases. This kind of lesion is uncommon and the presen-
tation aspects may vary broadly. The lesions in larynx are
signiWcant source of morbidity. The onset of symptoms is
insidious and the diagnosis is usually delayed. Symptoms
include dysphonia, dyspnea, dysphagia and odynophagia.
Proper treatment depends upon tissue biopsy, identiWcation
of the causative organism, and the appropriate pharmaco-
therapy. As there are few papers presenting the clinical fea-
tures of infectious granulomatous laryngitis (IGL) as
leishmaniasis, tuberculosis and paracoccidiodomycosis
aV ecting the larynx, we considered important to show the
experience of a big Brazilian Laryngology Service in deal-
ing with this potential worldwide problem. We present a
retrospective chart review showing our institution’s experi-
ence with IGL focusing in the diagnostic, treatment and
prognosis aspects. Twenty-four patients were identiWed.
Mycobacterium tuberculosis and Paracoccidiodis brasili-
ensis accounted for ten cases each, and Leishmania brazili-
ensis the remaining four. Hoarseness was the most common
symptom of infection. Up to one-third of patients with
laryngeal involvement lacked laryngeal symptoms. The
average delay from onset of symptoms to diagnosis was
7 months. All patients underwent direct laryngoscopy and
biopsies. Caseating granulomas was the key histopatho-
logic Wnding. IdentiWcation of the causative organism was
uncommon. No evidence of concomitant malignancy was
seen on biopsy. Despite treatment, almost 40% of patients
had permanent sequelae of infection, including hoarseness,
dyspnea, and dysphagia. Mycobacterium tuberculosis, P.
brasiliensis, and L. braziliensis accounted for all cases of
IGL. Patients may have laryngeal infection but lack laryn-
geal symptoms. Prompt diagnosis relies upon a high index
of suspicion, especially when evaluating patients from
endemic areas. Given the degree of tissue destruction,
which accompanies infection, timely intervention may be
important in the prevention of late sequelae. Despite appro-
priate therapy, a signiWcant number of patients may have
permanent sequelae of infection.
Keywords Granulomatous · Laryngitis · Clinical aspects
Introduction
Infectious granulomatous laryngitis (IGL) is an uncommon
yet important cause of chronic laryngitis. Because of its rar-
ity, it may be overlooked in the diV erential diagnosis of
voice disorders [1–4]. Its spectrum of presentation may
vary, from hoarseness, to dysphagia and odynophagia [5–
7]. In Brazil, Mycobacterium tuberculosis , Paracoccidiodis
L. Silva (&) · H. O. Costa
Department of Otolaryngology,
Santa Casa Medical School, Rua Martiniano de Carvalho,
864, suite 1001, Bela Vista, São Paulo, SP 01321 000, Brazile-mail: [email protected]
E. Damrose
Stanford Voice Center, Stanford, CA, USA
F. Bairão · M. L. D. Nina
Otolaryngology Resident,
Santa Casa Medical School, São Paulo, SP, USA
J. C. Junior
Otolaryngology Resident Stanford Voice Center,
Stanford, CA, USA
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brasiliensis, and Leishmania braziliensis are the most com-
mon causative agents of ILG. A delay in the diagnosis of
IGL may lead to inadequate or incorrect treatment, and
worsened prognosis [7, 8]. When the causative agent is, for
example, tuberculosis, delaying the diagnosis could lead to
serious consequences regarding transmission of the disease
to other individuals [4].
As the global community is becoming increasingly moreconnected, the regional infectious diseases are being shared
through the entire world, leading to a public health concern
[9–11].
While the organism responsible for the infection may not
necessarily be seen microscopically, the hallmark histologi-
cal Wnding in ILG is that of the caseating granuloma [12,
13]. This particular type of inXammatory reaction is only
encountered in a select number of diseases. Thus, the iden-
tiWcation of the classic chronic granulomatous inWltrate by
tissue biopsy is an important part of the ILG work out.
Physical Wndings of laryngeal involvement by ILG are
variable, and there is no single speciWc feature that could
call for the diagnostic of the infection. Every compartment
of the larynx can be aV ected, along with adjacent sites in
the head and neck such as the nasal and oral cavities.
Therefore, a high index of clinical suspicion is necessary
for the proper and timely diagnosis of the disease [5].
As the recognition of the disease depends upon the pre-
vious clinical experience of the physician, and being the
ILG an uncommon medical situation, the aim of this study
was to share the experience gathered by our institution, pre-
senting a retrospectively review of the clinical aspects and
outcome of 24 patients diagnosed with ILG.
Materials and methods
Permission to conduct this study was given by the Institu-
tional Clinical Research Committee of the Central Hospi-
tal of Santa Casa Medical School of São Paulo, in Brazil.
A retrospective chart review was performed from 1997 to
2006 for patients diagnosed with ILG. The charts were
reviewed for the following information: gender, age, pre-
senting complaints and symptoms, laryngeal Wndings on
laryngoscopy, and the period of time between the onset of
symptoms and diagnosis. Charts were also reviewed for
the response to therapy and persistent sequelae or symp-
toms.
Patients underwent a complete head and neck examina-
tion including Xexible laryngoscopy. Chest radiography
was performed to evaluate the pulmonary involvement. All
patients subsequently underwent direct laryngoscopy to
evaluate carefully the extent of laryngeal involvement, to
obtain a tissue specimen for pathological analysis, and to
exclude the possibility of malignancy.
Treatment
Patients found to have M. tuberculosis subsequently under-
went combined therapy with rifampin (10 mg/kg/day), hid-
razide (10 mg/kg/day), and pyrazinamide (35 mg/kg/day)
for 2 months, followed by 4 months of rifampin (10 mg/kg/
day) and hidrazide (10 mg/kg/day).
In patients diagnosed with paracoccidioidomycosis,treatment was accomplished with sulfamethoxazole
(800 mg bid) for a minimum of 3 months. Treatment was
continued until complete resolution of laryngeal and chest
lesions. Patients not responding to sulfamethoxazole some-
times require treatment with amphotericin B. All patients in
this series responded to treatment with sulfamethoxazole.
Patients diagnosed with leishmaniasis were treated with
methyl glucamine antimoniate 20 mg/kg/day given intra-
muscularly as 20–30 day cycles. Patients typically undergo
three to four cycles until a complete clinical response is
observed. Patients were considered cured when all systemic
symptoms have resolved and there was no evidence of
residual lesions.
Results
Twenty-four patients with ILG were identiWed between
1997 and 2006, divided as follows: 10 patients with tuber-
culosis, 10 with leishmaniasis, and 4 with paracoccidioido-
mycosis. There were 17 males and 7 females. The average
age at diagnosis was 37.8 years for tuberculosis (range 7–
58 years), 47.9 years for leishmaniasis (range 23–65 years)
and 44 years for paracoccidioidomycosis (range 39–
48 years). Etiology, symptoms and initial site of presenta-
tion are summarized in Table 1.
All patients were found to have laryngeal involvement,
although not all patients presented with laryngeal symp-
toms as the initial complaint. The average time to diagnosis
from the initial onset of symptoms was 7 months (range
1 month to 2 years) although the time varied according to
the organism (tuberculosis, 1–20 months; paracoccidiod-
omycosis, 8–24 months; leishmaniasis, 4–9 months).
All patients underwent direct laryngoscopy with biop-
sies. Histopathology in 20 patients (83.3%) revealed non-
caseating granulomas with chronic inXammation, but no
organisms. In the remaining four patients (16.7%) the caus-
ative organism could be seen, and in all of these cases it
was paracoccidiodomycosis.
Dysphonia was the most frequent post-treatment symp-
tom (Table 2). Nine of 24 patients (37.8%) had permanent
sequelae of infection despite therapy (Table 3). One patient
required a tracheostomy for subglottic stenosis, Wve
patients had permanent dysphonia secondary to vocal fold
scarring, one patient acquired a vocal fold paresis, and two
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patients had persistent dysphagia or odynophagia. The
remaining 15 patients developed complete resolution of
their laryngeal disease, with no further evidence of laryn-
geal abnormality found on repeat endoscopy.
Discussion
In this series, M. tuberculosis, P. brasiliensis, and L. brazi-
lienses accounted for all cases of IGL. When dealing with
infectious diseases with signiWcant transmission rates,
prompt diagnosis and treatment is essential to prevent the
spread of infection to others.
The delay between the onset of the symptoms and the
diagnosis reXects the access to health care services and the
timeliness of the diagnosis. In our study, the minimum
period of time to reach a diagnosis was 1 month with a
maximum of 2 years. In the majority of cases a diagnosis
was established within 8 months of the onset of symptoms.
Poor access to medical care, the ineYciency of the
health care system, and the insidious nature of early disease
all may contribute to a delay in diagnosis and treatment.
In the diagnosis of granulomatous laryngitis, the diV er-
ential diagnosis includes other infectious entities such as
blastomycosis, hanseniasis, syphilis, coccidioidomycosis,
actinomycosis, and histoplasmosis; non-infectious disor-
ders such as sarcoidosis, lupus erythematosus and
Wegener’s granulomatosis; and neoplasias [7, 14–21]. Tis-
sue biopsy is key in the establishment of the diagnosis, and
also in ruling out associated neoplasia [16, 20].
The causative organism may be seen in the tissue speci-
men [8, 21, 22]. All patients in this series underwent tissue
biopsy. In all patients, histology revealed caseating granu-
lomas and chronic inXammation, but only in the four
Table 1 Distribution of organ-
isms, symptoms and presenting
site of head and neck involve-
ment
Organism Number of
patients (%)
Symptom
( N , %)
Presenting site
of involvement
( N , %)a
Laryngeal
lesion
Mycobacterium tuberculosis 10 (41.7) Dysphonia
Dyphasia
Odynophagia
Dyspnea
Nose
Mouth
Larynx
Pharyx
Supraglottis
Glottis
Subglottis
Leishmania braziliensis 10 (41.7) Dysphonia
Dyphasia
Odynophagia
Dyspnea
Nose
Mouth
Larynx
Pharyx
Supraglottis
Glottis
Subglottis
Paracoccidiodes brasiliensis 4 (16.7) Dysphonia
Dyphasia
Odynophagia
Dyspnea
Nose
Mouth
Larynx
Pharyx
Supraglottis
Glottis
Subglottis
a All patients had laryngeal
involvement, but not all patients
presented with laryngitis as the
initial complaint
Nose 5 20.8%; Mouth 2 8.4%;
Larynx 16 66.6%; Neck 1 4.2%;
Silva 3
Table 2 Distribution of post-
treatment symptomsOrganism Dyspnea Dysphonia Dysphagia Odynophagia
Mycobacterium tuberculosis 1(10%) 5(50%) 1(10%) 0
Leishmania braziliensis 1(25%) 1(25%) 1(25%) 0Paracoccidiodes brasiliensis 0 1(10%) 0 0
Table 3 Complications of
infectionPatient Organism Percent
(%)aOutcome
1 Leishmania braziliensis Subglottic stenosis, tracheostomy dependence
2 Leishmania braziliensis Bilateral vocal fold scarring, permanent dysphonia
3 Leishmania braziliensis 30 Chronic dysphagia
4 Mycobacterium tuberculosis Bilateral vocal fold scarring, permanent dysphonia
5 Mycobacterium tuberculosis Bilateral vocal fold scarring, permanent dysphonia
6 Mycobacterium tuberculosis Bilateral vocal fold scarring, permanent dysphonia
7 Mycobacterium tuberculosis Bilateral vocal fold scarring, permanent dysphonia
8 Mycobacterium tuberculosis 50 Chronic odynophagia
9 Paracoccidiodes brasiliensis 25 Bilateral vocal fold scarring, permanent dysphonia
a Percent of total patients infect-
ed by a given organism
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patients diagnosed with paracoccidioidomycosis was the
organism seen. Several biopsies demonstrated epithelial
hyperplasia with atypia, but no patient was found to have a
concomitant malignancy, as has been reported in other
series [21, 22].
Histologically, all tissue samples should reveal caseating
granulomas (Fig. 1a). Ziehl Neelsen stain may be used to
identify M. tuberculosis (Fig. 1b). Paracoccidiodis brasili-ensis can be seen as a spherical element on routine hema-
toxylin/eosin staining (Fig. 2a) but the Wnding of the marine
pilot’s wheel with Grogott’s stain is pathognomonic for P.
brasiliensis (Fig. 2b). A robust inXammatory reaction and
neovascularization can be seen with L. brazieliensis infec-
tion (Fig. 3a), and Giemsa staining can reveal the organism
(Fig. 3b).
In general, laryngeal tuberculosis and paracoccidioido-
mycosis develop secondarily from primary pulmonary
infection. Laryngeal infection occurs through direct inocu-
lation of the larynx by aerosolized droplets containing the
organism. In leishmaniasis, laryngeal infection is secondary
to contamination from the nasal and oropharyngeal mucous
membranes. Thus, laryngeal involvement by tuberculosis
and paracoccidioidomycosis is said to be an ascendant pro-
cess, while that by leishmaniasis is thought to be a descen-
dant process [24–26]. Therefore, the site of initial infection
is helpful in determining the diagnosis, with nasal involve-
ment seen initially with leishmaniasis, and pulmonary
involvement seen initially with M. tuberculosis and P.
brazieliensis.Laryngeal tuberculosis shows a predilection for adult
males, and rarely occurs in children [27, 28]. Although
tuberculosis is highly contagious, its incidence of laryngeal
infection in this series was equal to that of paracoccidioido-
mycosis. Some authors consider a chest X-ray and laryn-
geal biopsy to be the most valuable diagnostic tests for
laryngeal tuberculosis, with a diagnostic accuracy that
approaches 100% [29]. A milliary inWltrate and cavitary
lesions in the apices of the lungs can be seen in patients
with acute tuberculosis. Although laryngeal tuberculosis in
Fig. 1 a The caseating granuloma with epithelioid and giant cells as
seen in M. tuberculosis infection (100£). b Ziehl Neelsen staining
demonstrating numerous M. tuberculosis bacilli (arrows) (1,000£)
Fig. 2 a Spherical fungal elements of paracoccidioidomicosis (ar-
rows) interspersed among granulomas and chronic inXammatory cells
(400£). b Grogott (silver) staining revealing the marine pilot’s wheelappearance of paracoccidioidomicosis (1,000£)
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general is associated with signiWcant lung disease, the chest
X-ray can be normal when destruction of pulmonary tissue
has not had an opportunity to progress signiWcantly, as can
be seen in children [28].
In the setting of advanced pulmonary disease, cytology
can reveal the organism in sputum or gastric Xuid cytology.
The most common deep infectious mycosis in Latin
America, paracoccidioidomycosis causes an acute intersti-
tial pneumonitis after inhalation of the fungus. A chronicform can surface many years after initial infection. The dis-
ease is endemic to many regions of the United States,
Europe and Asia [16, 24, 30]. The disease most commonly
aV ects adults between the ages of 29 and 49, and children
only rarely.
Males are 14 times more likely to be aV ected than
females. Apparently, this diV erence is due to a greater
exposure to the agent, mainly among the male rural worker
population, and possibly due to a protective action of estro-
gen [24]. Some experimental studies have shown the in
vitro inhibiting action of 17- estradiol on the transforma-
tion of the yeast mycelium and the existence of a receptor
for 17- estradiol in the yeast’s cytoplasm [31].
Most patients with laryngeal paracoccidioidomycosis
have concomitant active lung infection, although isolated
laryngeal infection can also occur. Laryngeal involvement
may be diV use or localized, and when localized may resem-
ble a carcinoma. Dissemination from the lungs occursthrough the bloodstream or directly by infection from pul-
monary secretions [23]. The disease can show long latent
periods, with some patients having developed active dis-
ease as long as 30 years after leaving endemic areas [32].
The clinical presentations of tuberculosis and paracoccidi-
oidomycosis are similar and may be diYcult to diV erentiate
from each other. Fever, cough, and weight loss are common
in both disease states, and both diseases aV ect men in of
lower socio economic standing. Both diseases behave path-
ologically similar, with primary lung infection ascending to
involve the larynx secondarily. Laryngeal symptoms are
identical and include dysphonia, odynophagia and dyspnea
[33]. Cavitary lesions and interstitial inWltrates can be seen
on chest X-ray, and usually involve the central and basal
portions of the lungs. Unlike tuberculosis, the apices are
usually spared.
Leishmaniasis is the second most common parasitary
condition in the world, with 600,000 new cases per year
[34]. In the western hemisphere the highest prevalence is in
Brazil, with 65,000 new cases diagnosed annually [34–36].
In the last few years, the epidemiology of the disease has
changed, with a shift in the patient population from those
that live in areas undergoing active deforestation, to those
residing in the outskirts of large urban centers and rural
areas that have already been deforested. Leishmaniasis
involves the mucous membranes of the nasal and oral cavi-
ties Wrst, before descending to involve the larynx. Because
pulmonary involvement is not seen in the disease, the chest
X-ray is normal. The Wndings of nasal lesions and a normal
chest X-ray are therefore extremely helpful in distinguish-
ing leishmaniasis from tuberculosis and paracoccidioido-
mycosis.
While all patients responded to therapy and were cured
of their disease, almost 40% of our patients experienced
permanent sequelae as a result of IGL. Hoarseness was usu-
ally secondary to atrophy of the vocal folds and loss of the
mucosal wave. Two patients experienced dysphagia follow-
ing apparent clinical resolution of active disease, but the
etiology as to the exact nature of the dysphagia has
remained uncertain.
Subglottic stenosis was seen in one patient, which
required placement of a tracheostomy. While most patients
who present with IGL will be eV ectively treated with no
long term laryngeal sequelae, it is important to recognize
this clinical entity and institute prompt treatment in order to
Fig. 3 a InXamatory reaction with intensive neovascular formation
and abundant plasmacitic cells as seen in leishmaniasis (400£). b Gi-
emsa staining demonstrating the organism L. braziliensis (arrows)(1,000£)
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minimize injury to the laryngeal tissues as well as to mini-
mize the opportunity for spread of the disease to other indi-
viduals [37].
Conclusions
Mycobacterium tuberculosis, P. brasiliensis, and L. brazili-ensis accounted for all cases of IGL. Patients may have
laryngeal infection but lack laryngeal symptoms. Prompt
diagnosis relies upon a high index of suspicion, especially
when evaluating patients from endemic areas. Given the
degree of tissue destruction which accompanies infection,
timely intervention may be important in the prevention of
late sequelae. Despite appropriate therapy, a signiWcant num-
ber of patients may have permanent sequelae of infection.
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