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




123

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




123

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




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




123

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£)




123

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£)




123

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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12Infectious granulomatous laryngitis a retrospective