Nasopharyngeal Mycobacterium abscessus Infection: A Case Report and Literature Review

Introduction

Nontuberculous mycobacteria (NTM) are a group of mycobacteria distinct from tuberculosis and leprosy, with approximately 200 species identified to date.¹ The incidence of NTM disease has increased in recent years, surpassing that of tuberculosis in Japan.² NTM are ubiquitous environmental organisms found in various locations, including soil and water. Immunocompromised individuals and individuals with genetic disorders are more prone to acquire NTM infections.³ However, immunocompetent individuals may also acquire NTM infections. NTM primarily cause lung diseases; however, extrapulmonary NTM infections, including skin infections, superficial lymphadenitis, and disseminated lesions, are common in immunosuppressed patients. Although NTM infections of the head and neck region – such as otitis media – have been reported, the number of patients who developed pharyngeal/laryngeal NTM infections were few.

Rapidly growing mycobacteria (RGM) are more frequently associated with extrapulmonary NTM infections than with pulmonary NTM infections.⁴ Mycobacterium abscessus (M. abscessus) is a type of RGM and is divided into three subspecies: M. abscessus subsp. abscessus, M. abscessus subsp. massiliense, and M. abscessus subsp. bolletii. Most M. abscessus subsp. abscessus and M. abscessus subsp. bolletii carry the erythromycin ribosomal methylase [erm(41)] gene which confers resistance to macrolide antibiotics and are therefore treatment resistant.⁵ Mycobacterium abscessus complex (MABC) causes extrapulmonary lesions on the skin (skin and soft tissue infections), bones, central nervous system, eyes, and blood.⁶

Herein, we report a rare case of a patient who tested positive for M. abscessus on three succeeding sputum culture tests without developing any lung lesions; M. abscessus in the nasopharynx was diagnosed after performing a close examination. In addition, whole-genome sequencing of M. abscessus was performed, and a literature review of NTM infections of the pharynx and larynx was conducted.

Case Presentation

A 41-year-old woman with a history of cough variant asthma and chronic sinusitis visited her primary care physician in October 2020 with a complaint of bloody sputum. Upon consultation, she was not provided with any immunosuppressive medications, including inhaled corticosteroids. The patient repeatedly underwent nasal irrigation and gargling. Despite treatment with clarithromycin, amoxicillin, and amoxicillin/clavulanic acid, she continued to experience symptoms and increased purulent sputum production. In December 2020, the patient underwent further examinations at a general hospital. Chest computed tomography (CT) did not show any obvious abnormalities, while three sputum culture tests consistently detected the presence of M. abscessus.

She was referred to our department in April 2021 and tested positive for M. abscessus subsp. abscessus on sputum culture. She had worsening symptoms of possible posterior rhinorrhoea (phlegm dripping into the throat) and showed mild sinusitis on sinus CT; hence, M. abscessus infection of the sinuses was suspected. Nasal endoscopy did not show any abnormalities in the nasal cavity, such as purulent nasal discharge. Polymerase chain reaction (PCR) tests for Mycobacterium tuberculosis/NTM and acid-fast bacilli (AFB) cultures of the nasal secretions yielded negative results.

Positron emission tomography/computed tomography (PET/CT), performed in June 2021 to identify the focus of infection, showed 18-fluorodeoxyglucose accumulation with a maximum standardized uptake value of 3.5 in the right nasopharyngeal wall (Figure 1a). Laryngeal endoscopy revealed purulent discharge in the right nasopharynx (Figure 1b). Initially, the purulent nasopharyngeal discharge showed positive results on smear test but negative for AFB on culture test. Repeat culture tests of purulent discharge collected by laryngeal endoscopy were performed; the purulent discharge collected in December 2021 tested positive for M. abscessus subsp. abscessus leading to a diagnosis of M. abscessus disease of the nasopharynx. Drug susceptibility tests indicated that the isolate was susceptible to amikacin and resistant to macrolides (Table 1). Specimens collected from the patient’s kitchen and bathroom tested negative for AFB.

Table 1 Antimicrobial Drug Susceptibility

Figure 1 PET/CT and Laryngeal endoscopy findings before and after antibiotic therapy. Abbreviations: PET/CT, positron emission tomography/computed tomography; FDG, F-fluorodeoxyglucose; SUV max, maximum standardized uptake value. Notes: FDG accumulation with an SUV max value of 3.5 noted in the right nasopharyngeal wall (a). Laryngeal endoscopy showing purulent discharge and inflammation in the right nasopharynx (b). Purulent discharge and inflammation in the nasopharynx disappeared after antibiotic therapy (c). FDG accumulation in the right nasopharyngeal disappeared after antibiotic therapy (d).

The patient was hospitalized and treated with amikacin, imipenem/cilastatin, azithromycin, and clofazimine for 28 days. After discharge, the patient was treated with amikacin, azithromycin, clofazimine, and sitafloxacin, a new fluoroquinolone, for four months. Since sitafloxacin’s minimum inhibitory concentration for M. abscessus is reported to be low, it is used in clinical settings in Japan.⁷ The posterior rhinorrhoea improved, and laryngeal endoscopy performed in February 2022 revealed the absence of purulent discharge in the nasopharynx (Figure 1c). In addition, both sputum smear and culture tests yielded negative results at the end of the patient’s treatment. PET/CT performed in May 2022 confirmed the disappearance of the previously observed abnormal accumulation in the right nasopharyngeal wall (Figure 1d). The patient was followed up in an outpatient clinic and revealed no evidence of recurrence. Whole-genome sequencing of M. abscessus subsp. abscessus constitutively isolated from the patient revealed that all strains belonged to a phylogenetic cluster, ABS-GL4 (Figure 2a). The pairwise SNP distance between these isolates was less than 10 SNPs (Figure 2b). Mutations in the 23S rRNA (rrl) gene conferring macrolide resistance were not detected in these isolates, but they carried the functional erm(41) gene (Figure 2a), which was expected to induce macrolide resistance. In addition, the strains did not harbour the known A1375G substitution in the 16S rRNA (rrs) gene, which confers amikacin resistance (Figure 2a).

Figure 2 Whole-genome sequencing of M. abscessus isolates from our patient. Abbreviation: SNP, single nucleotide polymorphisms. Notes: All strains analysed in this study (KO1157_R1, KO1157_S1, KO1216, KO4696, and KO4697) belonged to the ABS-GL4 cluster (a). The maximum SNP distances between KO1157_R1, KO1157_S1, KO1216, KO4696, and KO4697 were approximately 10 (b). The SNP distance between KO1157_R1 (rough morphotype) and KO1157_S1 (smooth morphotype) was 7.

Discussion and Conclusions

We report a case of a patient with M. abscessus infection in the nasopharynx. Based on endoscopy and PET/CT findings, the patient was diagnosed with M. abscessus infection confined to the nasopharynx without lung involvement. After initial treatment with amikacin, imipenem/cilastatin, azithromycin, and clofazimine, and maintenance treatment with azithromycin, clofazimine, and sitafloxacin, the patient achieved sputum smear- and culture-negative conversion with improvement of symptoms and endoscopic and PET/CT findings.

Although the precise mode of M. abscessus transmission is not fully understood, M. abscessus, which is prevalent in soil and aquatic environments, is thought to be transmitted to hosts with specific risk factors. These risk factors include being diagnosed with a human immunodeficiency virus infection, having genetic abnormalities in the interferon gamma pathway, using tumour necrosis factor inhibitors, having had previous exposure to broad-spectrum antimicrobials, and smoking. Individuals with lung conditions, such as cystic fibrosis (CF) and bronchiectasis, are also at an increased risk.⁸ Although none of these risk factors were present in our patient, she repeatedly underwent nasal irrigation and gargling, which may have contributed to the occurrence of infection. However, the tap water sample collected from her bathroom and kitchen showed negative results on smear and culture tests.

M. abscessus causes extrapulmonary lesions on the skin (skin and soft tissue infections), bones, central nervous system, eyes, and blood.^6,9 Infections of the upper respiratory tract, such as those of the pharynx, rarely occur, with sinusitis being the most common type of upper respiratory tract infection caused by NTM.^10,11 Moreover, the only types of pharyngeal NTM infection identified were nasopharyngitis, reported by Oki et al,¹² and hypopharyngitis/laryngitis, reported by Hussin et al.¹³

The M. abscessus complex is resistant to disinfectants used to minimize the risk of infection during surgery and other procedures. Therefore, they can cause postsurgical and postprocedural infections.⁵ Oki et al reported a case of M. abscessus nasopharyngitis resulting from the transmission of bacteria from contaminated medical devices that were only washed with tap water, which had been used during repeat nasopharyngeal abrasive therapy for pharyngitis.¹² Our patient had no history of dental or otolaryngological treatments.

In cases of NTM infection without lung lesions, the diagnosis of sinusitis should not be based solely on the history of sinusitis or mild CT findings. Instead, a thorough examination of the nasopharyngeal region should be conducted to detect the presence of infection. Moreover, NTM sinusitis should be distinguished from pharyngeal/laryngeal NTM disease, as the treatment approaches for these two conditions differ significantly. Surgical debridement is the preferred treatment for NTM sinusitis,¹⁴ while antibiotics are the primary treatment for pharyngeal/laryngeal NTM infection.

We conducted a thorough review of the existing literature. By searching the PubMed database, we identified English articles (Table 2) related to pharyngeal and laryngeal NTM infections. This condition is rare, with only eight cases reported to date, including the case reported here. Of the seven other cases, one involved infection of the pharynx alone,¹² one involved infection of both the pharynx and larynx,¹³ and five involved infection of the larynx alone.^15–19 All patients were female, had a median age of 45 years (range: 30–81 years), and only two showed abnormal findings on chest CT.

Table 2 Clinical Characteristics of Eight Patients

Of the three patients with pharyngeal infection, our patient and that reported by Oki et al¹² had a history of physical irritation of the pharynx caused by nasal irrigation and nasopharyngeal abrasive therapy, respectively. Among the five patients with laryngeal lesions only, four had a history of steroid therapy, and two were administered with inhaled steroids. Irritation of the pharyngeal mucosa and the use of immunosuppressive agents, including steroids, may be potential risk factors for pharyngeal and laryngeal NTM infection. However, immunocompetent patients with no history of immunosuppressive therapy can also be susceptible to nasopharyngeal Mycobacterium abscessus infection.

The strains identified included Mycobacterium kansasii in two patients, M. abscessus subsp. abscessus in one patient, Mycobacterium abscessus subspecies massiliense in one patient, Mycobacterium malmoense in one patient, Mycobacterium fortuitum in one patient, and Mycobacterium avium in one patient. Three patients were infected with RGM.

Of the eight patients, seven responded well to treatment, while one died. The treatment duration varied widely among the patients, ranging from 12 to 17 months.

Although NTM infections are traditionally thought to be acquired from the environment, previous studies have suggested that they may be transmitted directly or indirectly to patients with cystic fibrosis.²⁰ According to Bryant et al,²⁰ identical or nearly identical M. abscessus clones (clusters) have been isolated from patients with cystic fibrosis in a wide range of locations across the United States, Europe, and Australia, thus suggesting the possibility of a recent outbreak of patient-to-patient transmission of M. abscessus within the cystic fibrosis patient community. More than ten such clones, also referred to as clusters, were identified in M. abscessus subsp. abscessus and five in M. abscessus subsp. massiliense. Among these clusters, M. abscessus subsp. abscessus clusters 1 and 2 and M. abscessus subsp. massiliense cluster 1, which were isolated from patients in the United States, Europe, and Australia, were regarded as the dominant circulating clones (DCC) 1, 2, and 3 owing to their capacity for intercontinental transmission.²⁰

In the present study, whole-genome sequencing of M. abscessus isolates from our patient was performed. All strains analysed in this study (KO1157_R1, KO1157_S1, KO1216, KO4696, and KO4697) belonged to the ABS-GL4 cluster. The ABS-GL4 strains were widely isolated from non-CF patients in East Asia and from CF patients in European countries but have not been reported to be the major lineage in either region.^20,21 Analysis of drug resistance genes revealed that our strains lacked T28C sequevar and had no rrl and rrs mutation.^22–24 The profile of drug resistance genes predicts inducible macrolide resistance and amikacin sensitivity, which corresponds to the clinical course of the present case and the drug susceptibility test.

ABS-GL4 is a lineage that differs from DCC1 (Absc. 1) and DCC2 (Absc. 2) described by Bryant et al in 2016,¹⁹ and is closely related to Absc. 8 and 13 reported in the same study. The ABS-GL4 cluster has spread to East Asia and Europe and has no erm(41) T28C sequence.²¹ A T-to-C substitution at position 28 (T28C) in erm(41) makes the gene non-functional, thus leading to the recovery of macrolide susceptibility.^25,26 Therefore, more intensive treatments should be considered for patients infected with ABS-GL4 strains lacking the erm(41) T28C sequence.

The maximum SNP distances between KO1157_R1, KO1157_S1, KO1216, KO4696, and KO4697 were approximately 10. The SNP distance between KO1157_R1 (rough morphotype) and KO1157_S1 (smooth morphotype) was 7 SNPs (Figure 2), suggesting that these strains are identical clones despite having different morphotypes.

M. abscessus complex pulmonary disease (MABC-PD) is a severe infection. According to the report by Kwak et al, the overall treatment success rate for MABC-PD is 45.6%, with success rates of 33.0% for M. abscessus subsp. abscessus and 56.7% for M. abscessus subsp. massiliense.²⁷

Because M. abscessus infection in the nasopharyngeal region rarely occurs, and no clinical guidelines have been established for managing this disease, our patient was treated in accordance with the guidelines for treating M. abscessus pulmonary disease.

The ATS/ERS/ESCMID/IDSA (American Thoracic Society/European Respiratory Society/European Society of Clinical Microbiology and Infectious Diseases/Infectious Diseases Society of America) clinical practice guidelines recommend a regimen consisting of three or more antimicrobial agents for the initial phase of therapy based on in vitro drug susceptibility. Even in patients with macrolide-resistant M. abscessus pulmonary disease, the guidelines suggest a macrolide-containing regimen, although macrolides should be used because of their immunomodulatory properties and are not considered active drugs in the multidrug regimen.

For the initial phase of therapy, the recommended parenteral agents are amikacin, imipenem (or cefoxitin), and tigecycline, whereas the recommended oral agents are azithromycin (or clarithromycin), clofazimine, and linezolid. The recommended agents for continuation-phase therapy are azithromycin (or clarithromycin), clofazimine, linezolid, and inhaled amikacin.⁹ Our patient received amikacin, imipenem, azithromycin, and clofazimine in the initial phase of therapy, and azithromycin, clofazimine, and sitafloxacin in the maintenance phase.

The incidence of pharyngeal and laryngeal NTM is expected to increase with the increasing use of immunosuppressive drugs. If sputum is positive for NTM and chest imaging shows an absence of abnormal findings, NTM infection of the upper respiratory tract, including the pharynx and larynx, should be considered as the differential diagnosis. As NTM infection of the upper respiratory tract may respond well to antimicrobial therapy, aggressive treatment rather than follow-up should be considered.

We encountered a case of M. abscessus infection localized to the nasopharynx in an adult with no history of immunosuppression or use of immunosuppressive drugs, which was completely cured with medical therapy alone. As no guidelines have been established for the treatment of NTM disease of the upper respiratory tract, the patient was treated in accordance with the treatment guidelines for M. abscessus pulmonary disease. Further studies on NTM infections of the upper respiratory tract are needed to clarify the pathogenesis of the disease and establish more effective therapies.