INTRODUCTION
An isolated fungal infection of the larynx is less common than fungal infections of the respiratory tract. Primary fungal laryngitis is an extremely rare clinical entity. Larynx is an uncommon location for fungal infections of the body.[1] It often presents with nonspecific clinical symptoms and often gets confused with certain laryngeal diseases such as leukoplakia and other granulomatous lesions of the larynx.[2] Clinical conditions such as prolonged use of antibiotics, inhaled steroids, and laryngopharyngeal reflux (LPR) can predispose to fungal infections of the larynx. It may present with hoarseness of voice, odynophagia, and dyspnea due to laryngeal edema and granulations. The fungal laryngitis often mimics with granulomatous disease, gastroesophageal reflux disease, and malignant lesions.[3] Common fungi causing laryngeal infections are Candida, aspergillosis, cryptococcal, histoplasmosis, and blastomycosis.[4] Due to its nonspecific clinical presentations and mimicking to other laryngeal lesions may be misdiagnosed and often leading to the inappropriate treatment. Clinician and otorhinolaryngologist should be familiar with clinical presentations, diagnosis, and treatment of fungal infections at the uncommon site like larynx. To minimize the misdiagnosis and late treatment of primary fungal laryngitis, this review article is aimed to discuss the etiopathology, clinical presentations, diagnosis, and treatment of primary fungal laryngitis.
METHOD OF LITERATURE OF SEARCH
Research articles regarding primary fungal laryngitis were searched through a multisystemic approach. First, we conducted an online search of the PubMed, Scopus, and Medline databases with the word primary fungal laryngitis. There is a limited research work on primary fungal laryngitis as compared to fungal laryngitis associated with oropharyngeal and pulmonary involvement.
ETIOPATHOLOGY
Low host immunity and impaired protective mucosal barrier of the larynx may lead to infections of the larynx.[5] Primary fungal laryngitis is most commonly seen in immunocompromised patients such as patients with diabetes, advanced age, long-term use of steroid, low CD4 counts, AIDS, leukemia, and aplastic anemia.[6] Prolonged use of inhaled steroids is an important predisposing factor for primary fungal laryngitis. Certain conditions affect the mucosal barriers such as prior radiotherapy, gastroesophageal reflux disorders, inhaled corticosteroids, smoking, and trauma.[7] In case of inhaled corticosteroid therapy, the substantial proportion of molecules gets deposited in the airway when inhaled through dry powered forms. Inhaled corticosteroids are often augmenting colonization of the epithelial surfaces and commonly cause fungal laryngitis and oropharyngeal candidiasis.[8] Fungal infections of the larynx may occur in association with bronchopulmonary fungal infections. It is a common clinical entity among immunocompromised patient; however, the primary fungal infections of the larynx is extremely rare one.[9] Almost all fungal infections of the larynx are secondary to pulmonary or oropharyngeal infections.[10] Aspergillus and Candida are often associated with fungal laryngitis.[11] One study suggests Candida is the most common agent causing fungal laryngitis.[12] Cryptococcus neoformans is a fungus which may cause laryngitis, but it is an extremely rare incidence.[13] The most common site for cryptococcal infection is lungs as this yeast is found in a 2–7 mm encapsulated, airborne form which can be easily inhaled whereas the primary form of cryptococcal infection to the larynx is extremely rare. Aspergillus is a saprophytic fungus and is found in soil. The persons those who are engaged in farming or carpentry occupation may get contaminated by fungus, and this leads to primary aspergillosis of the larynx.[14] Other rare fungi causing fungal laryngitis reported are Cryptococcus, blastomycosis, and histoplasmosis.[15][16] Iatrogenic factors such as radiotherapy, chronic steroid inhalation, and laser treatment may predispose to the localized fungal infections of the larynx.[17] It has been reported that 2% of the patients those receive fluticasone and 1% of patients getting beclomethasone lead to fungal laryngitis.[17] Inhalations of corticosteroids lead to deposition over the larynx particularly on the superior surface of the focal folds, facilitating for colonization of the fungi on the epithelial surfaces.[18] Prolonged use of antibiotics may alter the local bacterial flora and changes the ecological balance between bacteria and fungi, leading to overgrowth of the fungus. Some invasive aspergillosis cases have been reported among patients those had received multiple antibiotics.[19] LPR may cause laryngeal mucosal injury through retrograde acid transit through esophagus, and prolonged use of antibiotic may lower the bacterial burden of the larynx, predisposes the patient to fungal laryngitis.[20] There are different predisposing factors responsible for developing fungal laryngitis, for example, diabetes mellitus, immunosuppressive medications, immunodeficiency, and nutritional deficiency. The intact epithelium of the respiratory tract provides protection of the microbial entry from the outside environment. Vocal abuse may cause repeated frictions of the vocal folds followed by injury to local mucosal barrier and edema which facilitates colonization and invasion of fungal hyphae.[14] Repeated practice of oral sex may be a predisposing factor for fungal laryngitis. By repeated friction, fellatio may lead to injury of the local mucosal membrane and may cause primary fungal laryngitis in immunocompetent persons.[21] It has been observed that Aspergillus fumigatus has a tendency to colonize at the vocal cord cyst and laryngocele.[18][22] Primary laryngeal aspergillosis is often rare in immunocompetent patients in comparison to immunocompromised patients. However, there is an increasing occurrence, and this lesion among immunocompetent patients is now an emerging trend in clinical practice. The etiological factors responsible for this increasing trend among immunocompetent patients include vocal abuse, vocal cord cyst, iatrogenic factors, and occupational factors.[23]
CLINICAL FEATURES
In primary fungal laryngitis, the most common clinical symptom is hoarseness of voice. Other less common clinical presentations of primary fungal laryngitis are variable and include dysphagia, dysphonia, stridor, odynophagia, and respiratory distress. The duration of symptoms vary from few weeks to several months. Clinical examinations of head and neck area are essential to rule out second site of fungal infections. Oral cavity and oropharynx must be checked to rule out any fungal infections. Palpation of the neck nodes should be done to find out any pathological lesions. Fiberoptic nasopharyngolaryngoscopy must be done to reveal the exact laryngeal pathology. Fungal laryngitis often mimic to granulomatous diseases, LPR disease, leukoplakia, and malignancy.[24] The clinical spectrum ranges from localized allergic response to invasive infection.[25] The endoscopic picture of the lesion varies from erythematous, edematous, to leukoplakia [Figure 1]. In fungal laryngitis, video laryngoscopy reveals erythema, edema, hyperkeratosis, adherent white plaques, shallow ulcerations, and grey or white pseudomembranes formation over vocal cords.[26] Although strobovideolaryngoscopy is nonspecific, it gives important data on the integration of mucosal waves of the vocal cords. In the larynx, mucosal edema and erythema even after sufficient therapy for laryngopharyngeal diseases need prompt consideration for fungal laryngitis.[26] The fungal laryngitis often mimic to leukoplakia, carcinoma, LPR disease, and granulomatous disease.[20]
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Figure 1: Fiberoptic nasopharyngolaryngoscopy showing whitish patches on bilateral vocal cords
DIAGNOSIS
The diagnosis of the primary fungal laryngitis is often overlooked in immunocompetent patients as it is usually considered as the disease of the immunocompromised hosts. Fiberoptic nasopharyngolaryngoscopy shows ulceration [Figure 2] or white patches on the vocal folds. Video laryngoscopy is another noninvasive method for seeing the laryngeal lesions where it typically reveals edema, hyperplasia, white patches, and grey or white pseudoepitheliomatosis in patients of primary fungal laryngitis. As vocalization needs vibration of epithelial layer of vocal folds by making mucosal waves, it affects the integration of mucosal waves in fungal laryngitis. Hence, strobovideolaryngoscopy is a better option for assessing the mucosal waves of the vocal folds. Stiffness of the mucosal waves of vocal folds is seen in primary fungal laryngitis.[27] Definitive diagnosis of fungal laryngitis is done by the demonstration of fungal spores, hyphae, or pseudohyphae either by KOH staining, culture, or tissue biopsy [Figure 3]. Biopsy at initial presentation helps to exclude the malignancy and its progression. The characteristic features of histopathological examination are termed as pseudoepitheliomatous hyperplasia.[4] Direct microlaryngoscopy with KOH preparation of the tissue shows 45° Y-shaped dichotomous branching, septate hyphae. Some portion of the tissue can be cultures on Sabouraud dextrose agar. The suspicion of fungal lesion should be informed to the pathologist for appropriate staining as diagnosis could be missed. The role biopsy is controversial but it is useful to rule out malignancy or any other diseases of the larynx or in case of nonresponse to adequate treatment. The confirmation of primary fungal laryngitis can be done from histopathological examination; so, the importance of biopsy should not be underestimated. Histopathological examination of the tissue isa easy and quick way to identify the fungal laryngitis. Gomori methenamine silver, Gram staining, and periodic acid-Schiff are commonly used stains to find out fungi in the cytological specimen. Fungi inside the tissue may appear as hyphae, budding yeast, endosporulating spherules, or mixture of these forms.[28] The diagnosis of fungus is confirmed by seeing fungal spores, hyphae [Figure 4], or pseudohyphae either by culture or tissue biopsy or KOH stain. The Aspergillus hyphae appear as basophilic with hematoxylin and eosin stain. Gram staining is useful for identification of the Candida albicans [Figure 5]. Chest X-ray was done in all cases. Samples from oral cavity and oropharynx were sent for fungal staining. Computed tomography of the neck was done in one case for assessment of laryngeal lesions and airway. The indolent clinical features and laryngoscopic pictures of the fungal laryngitis give a differential diagnosis of neoplastic lesions. Equivocal clinical presentations and histopathological findings such as acanthosis and pseudoepitheliomatous hyperplasia often provide false diagnosis of malignant or premalignant lesions of the larynx. The presence of fungal hyphae may rule out malignant lesions and confirms the diagnosis.[17] Fungal laryngitis is differentiated from fungal colonization, which occurs in the oral cavity. In the oral cavity, the fungal elements deposits on the top of keratinocyte layer whereas there is no such hyperkeratosis or neutrophil infiltration of the upper epithelial layers in the larynx.[2]
Figure 2: Laryngoscopic picture showing ulcerative lesions with whitish patches at anterior part of vocal cords
Figure 3: HPE showing chronic inflammation in sub-epithelial region of the vocal cords along with fungal balls consisting of thin septate hyphae with acute angle confirming aspergillosis (H and E; ×400)
Figure 4: Microscopic view of 48 h culture of Aspergillus (lactophenol cotton blue staining, ×400)
Figure 5: Candida albicans in Gram staining
TREATMENT
Prompt treatment and appropriate measures will prevent the morbidity of fungal laryngitis. It is treated by antifungal drugs and eliminations of risk factors.[29] There is no satisfactory epidemiological data for the incidence of primary fungal laryngitis. In healthy controls, excision of the lesion, stopping prolonged use of antibiotics, voice rest, and applying antifungal agents are considered as an important part of the treatment.[30] Treatment of primary fungal laryngitis is mainly conservative which includes antifungal drugs from oral fluconazole or itraconazole or ketoconazole or topical nystatin to intravenous amphotericin B based on the severity of the lesion.[24] The duration of antifungal treatment vary from 10 days to 1 month depending on the clinical improvement. Videolaryngoscopy should be done in regular interval as it is not uncommon to recur.[24] The first-line antifungal agents differ from local to systemic. Systemic oral antifungal agents such as itraconazole or fluconazole are given daily for 3 or 4 weeks. In immunocompromised patient with noninvasive lesion, first-line treatment is the oral antifungal agent whereas intravenous amphotericin B is useful in patients with significant tissue invasion. In our case, tablet itraconazole 100 mg twice a day for 3 weeks showed symptomatic improvement with resolution of the lesions over the vocal cords. The treatment duration ranges from 1 week to 1 month depending on the extent of the clinical improvement. Early diagnosis and treatment of fungal laryngitis are important for preventing the spread of infection and systemic involvement. Inadequate treatment or misdiagnosis of this lesion can lead to impaired functioning of vocal cords and leads to disability. Sometimes, patient of bronchial asthma is used to inhale corticosteroids for prolonged period. Inhalational corticosteroids are easily available as over-the-counter drugs and patients are using even without prescribed by pulmonologists. Inhalation corticosteroids should be stopped or avoided in case of fungal laryngitis for preventing further spread of the lesions.[31] Although primary fungal laryngitis has nonspecific clinical presentations, it is very important to have a high index of suspiciousness to rule out fungal lesion in the larynx as this is a curable disease. Inhalational corticosteroids are often available in medical stores over the counter where patients use it without monitoring by the pulmonary medicine specialist. Use of this type of inhalational corticosteroids should be in mind for stopping rampant use of the same.
CONCLUSION
Diagnosis of primary fungal laryngitis among immunocompetent patient is usually overlooked as it often mimics to leukoplakia and other granulomatous diseases of the larynx. A high index of suspicion is needed for diagnosis in case of persistent laryngitis failed with conservative treatment. Biopsy from the laryngeal lesion with identification of fungal hyphae is the confirmatory. Prolonged treatment with antifungals and avoidance of predisposing factors are helpful for the treatment of primary fungal laryngitis.
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Conflicts of interest
There are no conflicts of interest.
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