Quality of life in children receiving treatment for Mycobacterium abscessus otomastoiditis

-Mycobacterium abscessus is a multidrug-resistant nontuberculous mycobacterium capable of causing otomastoiditis and its treatment is complex with frequent adverse events. -Ten children (mean age: 8 years old; 70% males) were treated according to our institutional protocol. -Patients within one-year post-treatment reported a decreased QoL, with GCBI and COMBI scores of -12.91 and 10.94. -In contrast, patients evaluated more than one year after finishing treatment reported an improved QoL by both the GCBI (difference (Δ) = 23.9 points; p > 0.05) and COMBI (Δ = 19.4 points; p = 0.00). -The disease-induced hearing loss is reduced with successful treatment.


| INTRODUC TI ON
Mycobacterium abscessus (M. abscessus) is a rapidly growing nontuberculous mycobacterium (NTM), often dubbed the 'antibiotic nightmare' for its extensive resistance to antibiotics. 1 Pulmonary infections, skin and soft tissue infections are its most frequent clinical manifestations, but otomastoiditis is also an established clinical entity. 2 Treatment is difficult due to the multidrug resistance and lack of international consensus on therapeutic options as well as duration of treatment.
A previous study at our institute suggested a 6-month antibiotic treatment strategy combining systemic and local treatment. 3 This intensive, long-term antibiotic regimen proved effective, but severely affects children's wellbeing. Children need a peripherally inserted central catheter (PICC) for long-term intravenous antibiotics and both surgery and antibiotic treatment may induce hearing loss (HL).
Adverse events (AE) such as nausea and vomiting, myelosuppression, toxic dermatitis and liver toxicity are frequent and the psychosocial impact of the treatment is thought to be the severe. 3 Therefore, the assessment of quality of life (QoL) during and after treatment is important. This study aims to evaluate adverse events and QoL after treatment for M. abscessus otomastoiditis.

| Design
A retrospective analysis of QoL from patients treated for M. abscessus otomastoiditis at our referral centre was performed. Informed consent was obtained from the guardians and children above 12 years old. Guardians and patients were invited by phone. Upon informed consent, QoL questionnaires were sent by mail. The data were saved in an anonymised protected web-based database. This study was approved by the independent regional ethics committee (CMO Arnhem-Nijmegen; file number: 2020-6257).

| Participants
Patients treated between 2013 and January 2020 for M. abscessus otomastoiditis were eligible. The microbiological diagnosis was made based on auramine staining and culture on liquid (Mycobacterium growth indicator tubes; MGIT) and solid (Lowenstein-Jensen) media; drug susceptibility testing was performed by broth microdilution. Patients with insufficient data on presenting symptoms and treatment were excluded. We extracted baseline characteristics (age, gender and predisposing factors), date of diagnosis, onset and related symptoms, audiograms and radiological imaging, date and type of treatment interventions (i.e. surgery and antibiotics), and post-treatment follow-up from the electronic medical files.
Radiological imaging was used as baseline for signs of progression or improvement of the disease. Also, imaging was screened for signs of complications (e.g. osteomyelitis, sinus thrombosis, meningitis or cerebritis).

| Treatment
This treatment strategy consists of an intensive phase using intravenous imipenem-cilastatin and tigecycline and oral treatment with azithromycin and clofazimine ( Table 1). Topical treatment with imipenem-cilastatin and tigecycline eardrops is added for the duration of tympanic membrane perforation. Surgical debridement is performed during the intensive phase. Surgery was performed to obtain cultures (in patients without diagnosis) and to reduce the local infection load by a mastoidectomy and atticotomy. In patients in whom the diagnosis was already confirmed, local antibiotics (imipenem/cilastatin 1 mg/ml, 1:1, and tigecycline 1 mg/ml) was also left in the mastoid cavity. In the more recent cases, ventilation tubes were removed (because of the risk of biofilm formation) and the tympanic membrane was perforated using a laser for subsequent topical treatment.

| Quality of Life Measurement instruments
We applied the Glasgow Children's Benefit Inventory (GCBI) and the Chronic Otitis Media Benefit Inventory (COMBI) QoL questionnaires. 4,5 The GCBI is a validated retrospective questionnaire on QoL in children after treatment in paediatric otolaryngology. [6][7][8] Patients and guardians are supposed to fill out the questionnaire together. It consists of 24 questions on the impact of certain treatment on various social and emotional aspects of a child's life. 5,7 A score of zero is considered as no change before/after treatment. Positive scores mirror good response while negative scores mean the condition has become worse. 5 The four different domains (emotions, physical health, learning and vitality) are evaluated separately. 7 The COMBI is a validated questionnaire to measure, in retrospect, the impact of otitis and related ear problems on QoL.
It consists of 12 questions with 5-scaled answers, in which a score higher than 38.5 means the condition has improved significantly. The Dutch version has also been validated and was used in this study. 4 As both questionnaires do not control for cranial nerve involvement or whether hearing aids were required after intervention, we have added five questions on lasting AE's to the questionnaires (Appendix S1).

| Statistics
An independent t-test was used to compare the QoL scores of patients who have finished the treatment regime <1 year ago and patients who have finished the same regimen at least one year ago.
Pearson correlation or independent t-test was used for possible confounders such as: gender, age, treatment duration, intravenous treatment duration and otorrhea recurrence during follow-up.

| RE SULTS
Ten patients were included. Patient characteristics are presented in Table 2. The actual duration per drug frequently deviated from protocol due to AEs and observed effect (see Figure S1). All patients suffered from conductive hearing loss (CHL) in the infected ear ( Figure 1). On average a significant improvement of 26 dB was

Key points
• Mycobacterium abscessus is a multidrug-resistant nontuberculous mycobacterium capable of causing otomastoiditis and its treatment is complex with frequent adverse events.
• Ten children (mean age: 8 years old; 70% males) were treated according to our institutional protocol.
• Patients within 1-year post-treatment reported a decreased QoL, with GCBI and COMBI scores of −12.91 and 10.94.
• The disease-induced hearing loss is reduced with successful treatment. Note: Timing indicates the moment in which the surgical procedure was performed is relative to the start of the antibiotic treatment. Patient 008 did not undergo major surgery as radiological imaging showed the middle ear to be affected mostly with mild extension to the mastoid.

| Quality of life
Completed questionnaires were returned for nine children (90%).
A total mean GCBI-score of −2.3 (SD ± 19.8) was found. The total mean score and subdomains are presented in Figure 2. The mean COMBI score was 41 (±10.2). Age, gender, (iv) treatment duration and otorrhea recurrence did not impact significantly on COMBI or GCBI scores.
Patients who ended treatment less than 1 year ago had a lower mean GCBI-score compared to patients who finished treatment more

| DISCUSS ION
This study evaluated ten patients who were treated for M. abscessus otomastoiditis and revealed a vast, but presumably temporary QoL reduction after treatment.
The GCBI showed relatively little improvement in QoL after treatment. The GCBI was previously used in children with Bone-Anchored Hearing Aids who showed relatively great QoL improvement after implantation. 5,9 This may be due to side effects and long-term nature of the treatment regimen. The GCBI-scores also suggest that learning and emotion are the most affected by the treatment. Children will miss school for multiple weeks due to hospital admission(s) or AEs.
The COMBI showed a During the treatment period all patients were screened for primary immunodeficiencies and here, mainly humoral immune defects were found in a few cases. Also, these conditions did not affect the QoL per se but could of course have made patients more susceptible to infection.
The key limitations of the current study are the cohort size and the retrospective nature of the QoL assessments. As only 10 patients finished treatment and nine provided QoL data, statistical analysis is less reliable; conversely, a cohort this size with a standardised treatment for a rare but severe infection is unique and yet informative.

ACK N OWLED G EM ENTS
The authors wish to express their gratitude to Philip van Haren and Gitta Romeijn for their contribution in the treatment protocol and patient care. Dr. Rob E. Aarnoutse for his contribution in the treatment protocol.

CO N FLI C T S O F I NTE R E S T
The authors have no relevant financial or non-financial interests to disclose.

AUTH O R S' CO NTR I B UTI O N S
TL, SB and MH designed the work; TL acquired and analysed data; TL drafted the manuscript, SB, MH, JvI, KvA, AJ, SP, HK, JW, TJ, SH revised and approved the manuscript. All agree to be accountable for all aspects of the work.

E TH I C A L A PPROVA L
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the independent regional Ethics Committee of Arnhem-Nijmegen (CMO) (Date:21-02-2020/ No.2020-6257).

F I G U R E 2
Spiderplot showing the GCBI-score including subdomains. The population was divided in a group which finished treatment less than a year ago, and a group which finished treatment 1 year ago or longer. Baseline illustrates a GCBI-score (=0) in which no change is perceive

CO D E AVA I L A B I LIT Y
Not applicable.

CO N S E NT TO PA RTI CI PATE
Informed consent was obtained from all individual participants included in the study.

CO N S E NT FO R PU B LI C ATI O N
Not applicable.
[Correction added on May 31, 2022, after first online publication: Peer review history is not available for this article, so the peer review history statement has been removed.]

DATA AVA I L A B I L I T Y S TAT E M E N T
Data may be available per request.

S U PP O RTI N G I N FO R M ATI O N
Additional supporting information may be found in the online version of the article at the publisher's website.