Fungal laryngitis management in immunocompetent patients: a systematic review

Introduction

Fungal laryngitis occurring in an immunocompetent host is an elusive entity. Typically, patients will present with lingering dysphonia, which despite over-the-counter topical remedies, lifestyle changes and voice rest, have not resolved. Broadly, fungal infections of the upper aerodigestive tract are classically seen in immunosuppressed individuals, due to inherent immune dysfunction [i.e., human immunodeficiency virus (HIV) infection, diabetes mellitus, malignancy] or secondary to medications.

Fungal laryngeal infections are a much less frequent presentation in the immunocompetent individual. In these patients, if the diagnosis is not considered early, it is easily missed and mismanaged, as it often masquerades as malignancy or granulomatous disease (1,2).

The objective of this mixed methods literature review was to identify which treatment regimens have been implemented for the treatment of fungal laryngitis in an immunocompetent patient. The review investigated in detail patient demographics, pathogens cultured, treatment utilized, extent of follow up and symptom resolution. We present this article in accordance with the PRISMA reporting checklist (available at https://www.theajo.com/article/view/10.21037/ajo-24-8/rc) (3).

Methods

Procedure

Due to the limited nature of published research on the topic, a mixed-methods review was used. A systematic review of the literature was performed to identify the relevant articles. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Ethics approval was not sought due to the nature of this article being a systematic literature review. There were no randomized control trials identified on the topic and due to the heterogeneity of different causative pathogens coupled with the lack of large-scale case series, only a qualitative analysis was performed.

Search strategy

An electronic systematic search of PubMed, EMBASE, Scopus, Web of Science, Wiley Online Library, SpringerLink Library, and the Cochrane Library was conducted. The search terms used were: (Fungal OR Candida OR Candidiasis OR Aspergillus OR Aspergillosis OR Cryptococcus OR Histoplasmosis OR Mucormy* OR Blastomy* OR Yeast OR Thrush OR Fungi) AND (Larynx OR Laryngitis OR Vocal Cords OR Vocal Folds OR Voice Or Glottis) AND (Treatment OR Management OR Surgery OR procedure OR Medication OR Anti-fungal). Only articles published between 6^th June 2003 and 6^th June 2023 and those in English were included.

Eligibility criteria

The inclusion and exclusion for this review were made deliberately stringent. To ensure included papers were specific in all aspects of treatment, follow up and outcome.

Inclusion criteria

• Published in English.
• Published within the last 20 years.
• Detailed information on management and treatment was provided.
• States pathogen cultured.
• If medication was used, route, dosage and duration of therapy.

Exclusion criteria

• Immune suppressive disorders [including diabetes mellitus, HIV and acquired immunodeficiency syndrome (AIDS)].
• Immune suppressive oral/intravenous (IV) medication (i.e., prednisone, tacrolimus etc.).
• The follow-up period is not defined.
• Outcome not stated at the end of treatment course.
• Active cancer.
• Previous head or neck cancer.
• Concomitant bacterial infection (including the glottis, respiratory tract as well as systemic).
• Previous radiation therapy to the head or neck region.
• Articles based on retrospective chart reviews (where all individual patient data and specific patient treatment are not described).

Type of intervention

Oral anti-fungal and/or surgical intervention.

Outcome measured

Resolution of symptoms was measured as complete resolution without recurrence after treatment.

Study selection

Two independent reviewers (Y.H.L. and N.W.) conducted the title and abstract screening and full-text review. Papers that were in contention were reviewed by a third independent reviewer (A.W.) and a consensus decision was made for inclusion.

Data extraction

The data was then extracted from the relevant articles independently (A.W. and M.E.) using a standardized template. Details including type of study, gender, age, predominant symptoms, intervention used, dose of intervention (if applicable), organism grown, duration of treatment, follow-up period, primary outcome and if recurrence occurred were recorded.

Data standardization

For the data extracted from each paper, the following standardizations were applied to allow meaningful analysis. All measurements of time were converted to weeks, and articles in which units of time were measured in months were converted to weeks by multiplication of months by 4.35 (weeks). Inhaled corticosteroid (ICS) use was recorded as either yes or no, irrespective of dosage. Cigarette smoking history was recorded as either yes, no, or ex- regardless of cigarettes smoked per day and pack-year history.

Risk of bias assessment

As there was only a qualitative analysis done due to the lack of published literature, specifically randomized control trials, the risk of bias for each paper included was assessed using the JBI Checklist for Case Reports (4). Evaluations were completed by two reviewers (A.W. and N.W.) and discussed to ensure there was a consensus reached for each domain.

Statistical analysis

Due to the absence of any randomized control trials, it was deemed that the data set was too heterogeneous for quantitative analysis and only suitable for a qualitative review.

Results

Search

The initial search yielded 1,669 articles from PubMed, 1,211 articles from EMBASE, 76 articles from Scopus, 83 articles from Wiley Online Library, 63 articles from SpringerLink Library, 60 articles from Web of Science and 0 from the Cochrane Library. Cumulating to 3,162 studies being identified. Four hundred and seventy-one duplicates were removed before screening. A total of 2,691 articles were then screened by title and abstract, and 2,457 papers were removed due to not meeting inclusion and exclusion criteria. Two hundred and thirty-four studies were assessed at full-text eligibility, 203 of which were excluded. Thirty-one articles were included in the data extraction (see Figure 1).

Figure 1 Eligibility flow. Results from database search. Figure created with the use of: an R package and Shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and Open Synthesis Campbell Systematic Reviews (5).

Two articles were considered as near-misses. Firstly, Gumussoy et al. in 2019, a retrospective case-control study, met all criteria, except excluded on the basis that patients with diabetes mellitus were included in the study population as well as the patients who had recurrence were not clearly defined nor were their co-morbidities and measures of symptom resolution (6). Secondly, Mesolella et al. in 2021, case report, met all criteria, except excluded on the basis that no causative pathogen was definitively identified, rather a presumptive diagnosis was made, and the patient was treated empirically (7).

All 31 studies were case-based, 4 were case series and 27 were single case reports (Table 1). The total patient group was 34. All 34 patients were treated with an oral antifungal. All 34 patients had a form of laryngoscopy with biopsies (whether that be via channel scope biopsy or microlaryngoscopy). Further, the majority of the patients 20 (58.8%) had some form of radiological chest imaging, either in the form of a chest X-ray or computed tomography (CT) scan. No patients had excision/ablation of the lesions.

Study information

The frequency of publication origin was as follows: India 10 (32.3%), USA 7 (22.6%), China 4 (12.9%), Brazil 3 (9.7%), Australia 2 (6.5%), Canada 1 (3.2%), France 1 (3.2%), Israel 1 (3.2%), Japan 1 (3.2%), Nepal 1 (3.2%).

Risk of bias assessment

All 31 articles were assessed. There were 27 case reports and although there were 4 case series included, none were true structured case series, rather all were a collation of case reports. As such the JBI Checklist for Case Reports was used for all papers (4). One paper was deemed borderline in terms of information provided to satisfy the eligibility criteria for inclusion (17). Table 2 outlines the critical appraisal for each paper.

Study objectives

In all 31 studies, the primary outcome was to measure symptom resolution. This was assessed with a combination of symptom history and/or direct visualization with fibreoptic nasal endoscopy.

Pathogen and intervention

Antifungals were administered to all patients in the 31 studies analysed. All but one received oral therapy, with one receiving IV therapy. Each study and patient had varying dosage regimes dependent on the pathogen cultured (see Table 3).

For Aspergillus fumigatus and Aspergillus spp., which was found in 16 patients, the most common treatment was itraconazole (15/16) and in one patient voriconazole. The mean daily cumulative dose for itraconazole was 350 mg (range, 200 to 800 mg) with a mean duration of treatment being 3.97 weeks (range, 1 to 8.7 weeks) in adults. The paediatric patient (12-year-old male) was treated with 100 mg for 3 weeks. The patient who received voriconazole received 400 mg daily for 1.14 weeks.

For Blastomycosis dermatitidis and Blastomycosis spp., which was found in 3 patients, the most common treatment was fluconazole (2/3) and in one patient itraconazole (1/3). Both patients received fluconazole 400 mg for 26.1 weeks. For itraconazole the patient received 100 mg for 4 weeks followed by 200 mg for 16 weeks for a total duration of 20 weeks.

Candida spp. was cultured in 1 patient, the treatment consisted of 200 mg of fluconazole daily for 2 weeks.

In patients that grew Cryptococcus neoformans (4) and Cryptococcus spp. (4), all patients received treatment with fluconazole with one patient receiving a mixed regime with itraconazole. All patients received 400 mg with a mean treatment duration of approximately 30.7 weeks (range, 13 to 47.8 weeks). For the patient who received both itraconazole and fluconazole, the treatment consisted of 400 mg itraconazole for 6 weeks followed by 400 mg fluconazole for 10 weeks.

For Histoplasma capsulatum (6) all patients but one received itraconazole, and all patients treated with itraconazole received 200 mg with a mean treatment duration of approximately 24.6 weeks (range, 8.7 to 39.1 weeks). One patient received IV amphotericin B at an average of 0.583 mg/kg for 8.7 weeks.

Lastly, for the one patient who cultured Paracoccidiodes brasiliensis, itraconazole was used at 400 mg daily for 21.7 weeks.

Outcomes

Given that the studies identified were a combination of single case reports and case series the follow-up and measure of outcomes was acceptable. All studies followed up on patients’ post-intervention to assess for resolution of symptoms, there was no recurrence detected in the follow-up periods in the included studies. The success of treatment was measured as symptom resolution in all the studies.

Symptom resolution

The main presenting symptom was vocal hoarseness or dysphonia (in isolation or combination with another symptom), which was present in 31 (91.2%) patients. This was followed by dysphagia or odynophagia in 7 (20.6%) patients, weight loss in 5 (14.7%), shortness of breath in 3 (8.8%), cough in 1 (2.9%) and stridor in 1 (2.9%). All patients had complete resolution of symptoms with a single course of oral antifungals after the causative pathogen was identified.

Patient factors

By combining the total patients across all papers, common patient factors involved in the development of fungal laryngitis were found. Ten (29%) used ICS for either asthma or chronic obstructive pulmonary disease (COPD). Eight (24%) of patients were documented as being active or ex-smokers at the time of diagnosis. And two (6%) were documented to have gastro-oesophageal reflux disorder. There was a higher incidence in females 20 (58.8%) compared to 14 (41.2%) males.

Adverse effects

One of 31 studies reported patient adverse effects. In Tsang et al. in 2022 (35), a 66-year-old male experienced cardiac toxicity (drug-induced heart failure) from 200 mg (daily dose) of itraconazole after 5 months. The itraconazole was ceased and cardiac function returned to baseline. This patient grew Blastomycosis spp. and had complete symptom resolution even though treatment ceased before the planned 6 months of total duration.

Discussion

The development of fungal infections of the upper aerodigestive tract is traditionally thought to be exclusively a disease entity of the immunosuppressed patient. In the case of Candida spp., an otherwise commensal flora of the gastrointestinal tract, it capitalizes on impaired cell-mediated immunity (39). In this review, the use of ICS was found to be the strongest correlating factor to the development of fungal laryngitis in the otherwise immunocompetent host, followed by active or previous tobacco use. The impact of corticosteroids on the mucosal lining microbiome is well-researched. Oral “thrush” is a common side effect following the use of ICS especially in patients who do not practice adequate puffer hygiene, that is the use of a spacer and mouth rinsing after corticosteroid puffer use (40). Though the exact mechanism for how ICS causes fungal infection of the larynx remains unclear, it is likely secondary to a similar process. Similarly, the exact mechanism of how cigarette smoking leads to mucosal fungal infection is not fully understood, hypothesis exists to suggest that there may be localized epithelial alterations such as depressed activity of leukocytes (41).

At our centre, amphotericin B lozenges have been used as a first-line treatment for suspected fungal laryngitis, with the rationale that oral dissipation will lead to some topicalization of the supra-glottis. Although there are no therapeutic guidelines for fungal laryngitis, there exist guidelines for fungal infection of the oesophagus and oropharynx. In the first instance for oropharyngeal infections, it is recommended to use dissipating antifungal preparations, if refractory to this then fluconazole 100–200 mg orally for 7 to 14 days and up to 28 days for refractory disease. For fungal oesophagitis, a similar regime is suggested, 200 to 400 mg for 14 days and up to 28 days for refractory disease (42). This review identifies the importance of identification of the causative organism and targeted anti-fungal use rather than empirical.

In Aspergillus fumigatus infections, whether this be in the lungs or sinuses, itraconazole is the established choice of anti-fungal therapy. Multiple studies have shown it is reliably effective at treating even invasive fungal disease with a low adverse effect burden (43,44). It is also the choice agent in bronchopulmonary aspergillus infections (44). Voriconazole has also been shown to be an effective choice for the treatment of invasive fungal infections, with evidence that it provided better responses, improved survival and fewer side effects compared to amphotericin B in invasive aspergillosis (45).

For pulmonary blastomycosis the agent recommended by the Infectious Disease Society of America (IDSA) is oral itraconazole in mild to moderate disease, and in severe disease amphotericin B (IV) (46). There is also evidence for the use of fluconazole at the higher 400 mg daily dose for non-life-threatening blastomycosis, Pappas et al. in 1997 showed 89% of patients were successfully treated with 8.9 months of therapy (47).

In Candida infections, fluconazole is an established treatment in both oropharyngeal and bronchopulmonary candidiasis (48). Similarly, literature shows that fluconazole is the most suitable agent for pulmonary cryptococcosis (49,50). There is growing evidence of increasing fluconazole resistance in cryptococcal species with higher doses being required to maintain efficacious treatment (51-53).

Itraconazole is an effective treatment for Histoplasma capsulatum, with Wheat et al. in 1995 showing 85% (N=59) of disseminated disease in the setting of AIDS response (54). Itraconazole is also the recommended agent by the IDSA for histoplasmosis (55). Itraconazole is also the choice agent for paracoccidioidomycosis (56,57).

In combination with commencing targeted anti-fungal therapy; in the 10 patients that were taking ICS, 5 (50%) either had the dosage reduced or ceased (9,21,31,37). Whether this had a meaningful impact on the patient’s recovery remains unclear.

This review examined 31 papers published between 2003 and 2023. The majority (32.6%) of the cases originated from India. Assessed with the American Society of Plastic Surgeons Levels of Evidence for Prognostic Studies, all included papers in this review were Level V evidence (58). Although 4 papers appeared to be Level IV, due to the unstructured nature and no clear indication a true case series was done, it was deemed to be Level V. In two such ‘case series’ only one case met the eligibility criteria and as such other patients included in these papers were excluded. Only 2 articles explicitly stated either adverse effects were encountered or that there were no adverse effects (27,35). One article used vague language when describing if any adverse effects occurred (29). One of the articles was on a paediatric patient, which; to avoid confounding, was reported on separately and not included in the analysis with other patients (who cultured the same pathogen). A meta-analysis was unable to be performed due to no randomized controlled trials being published on the topic.

With the quality of evidence in mind, certain inferences can still be drawn due to the limited heterogeneity in treatment protocols implemented. In the studies analysed, all adhered to evidence-based and previously clinically validated anti-fungal agents for each different pathogen cultured (see Table 4). All studies demonstrated that fungal glottic infections respond to treatment like other body sites. Further, surgical procedures with the intent to excise or ablate were not performed routinely in the studies analysed, indicating, that oral anti-fungal medications are sufficient for control and more extensive procedures are seemingly not needed. The duration of treatment varied greatly between cases with the same causative pathogen. This likely relates to the limited knowledge available on treatment duration and correlation to symptom resolution. Most authors continued treatment to an arbitrary time point with continuous symptoms and clinical assessment (via flexible nasal endoscopy) which was sufficient to prevent recurrence.

In terms of oral anti-fungal medications, generally, the “-azole” class of antifungals are well tolerated. Common adverse effects include gastrointestinal side effects, such as abdominal pain, diarrhoea, and nausea (59-61). Very rarely there can be cardiac reactions, as seen by Tsang et al. in 2022 in their study (35).

Based on the available literature on the topic, and commonality in the treatment paradigm, we propose the diagnostic algorithm found in Figure 2 for the management of fungal laryngitis in an immunocompetent patient.

Figure 2 Diagnostic paradigm of suspected fungal laryngitis in an immunocompetent patient. FNE, flexible nasal endoscopy; GORD, gastro-oesophageal reflux disease; ICS, inhaled corticosteroid.

Conclusions

There is a need for an evidence-based treatment for fungal laryngitis, especially in immunocompetent individuals. In current practice, most management protocols are based on anecdotes, with practitioners often commencing topical lozenges. Fungal laryngitis in the immunocompetent patient is a scarce entity and as such a poorly researched field. To date, no randomized control trials on the topic have been conducted. However, the case reports and case series performed provide evidence that treatment with established oral anti-fungal agents targeted for each pathogen is both safe and effective for treating fungal laryngitis. Further research is certainly required, optimally in a randomized setting with a large patient cohort with a standardized oral antifungal treatment regime and follow-up duration to make this assertion more robust, though this is exceptionally challenging due to the rarity of the condition as well as heterogeneity of pathogen grown.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://www.theajo.com/article/view/10.21037/10.21037/ajo-24-8/rc

Peer Review File: Available at https://www.theajo.com/article/view/10.21037/ajo-24-8/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://www.theajo.com/article/view/10.21037/ajo-24-8/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Ethics approval was not required due to the study being a systematic review of previously published data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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