Mycobacterium avium complex prosthetic joint infection: A systematic review of the literature and pooled analysis

Abstract

Background

Mycobacterium avium complex (MAC) prosthetic joint infection (PJI) has been rarely reported.

Methods

This study aimed to investigate the epidemiology and outcomes of MAC PJI. A systematic review of the literature regarding the MAC infection following total joint arthroplasty including hip and knee joint was performed. Multiple databases were searched for published English-written articles up to May 2023. Studies that reported cases of PJI by MAC were reviewed.

Results

A total of 17 patients were identified and analyzed from 11 published studies. All patients presented with joint symptom of pain or swelling prior to the diagnosis and MAC was confirmed by culture. The most of the patients (16/17 patients, 94.1%) were noted to have underlying medical condition(s) that might have affected immunity. Treatment consisted of anti-MAC medication therapy only in two patients and anti-MAC medication therapy plus surgery in 15 patients. Among the patients who underwent surgery, 14 patients (82.3%) had removal of the prosthesis including seven patients who had two-stage surgery to have reimplantation of the prosthesis. No relapse of MAC infection was reported despite of one case of relapse of infection caused by different pyogenic bacteria. The rate of overall mortality was 29.4%, however, identified attributable mortality due to MAC infection was low (5.9%).

Conclusion

PJI by MAC is a rare disease. However, MAC needs to be considered in the differential diagnosis in immunocompromised patients presenting with symptoms of PJI. Two-stage exchange arthroplasty may result in successful treatment outcomes without higher risks of relapse of infection if undertaken in association with appropriate active anti-MAC antibiotic therapy.

Keywords

infection arthroplasty treatment

Introduction

It has been acknowledged that an excess of 150 species of Mycobacterium species have been officially recognized to date, encompassing both tuberculous mycobacteria and nontuberculous mycobacteria (NTM)¹ in literature. NTM are known to be distributed in the water, soil, and animals.² Among them, Mycobacterium avium complex (MAC) is the most commonly reported pathogenic NTM species worldwide, including asymptomatic carriers.³ MAC represents a group of indolent mycobacterial species that predominantly manifest as pulmonary infections in immunocompetent individuals, while leading to disseminated infections among immunocompromised patients such as patients with human immunodeficiency (HIV)/acquired immunodeficiency syndrome (AIDS).^4,5

At least 17 Mycobacterium species including M. tuberculosis, M. abscessus, M. chelonae, M. kansasii, M. bovis, and M. fortuitum can be responsible for hip or knee prosthetic joint infection (PJI).⁶ Mycobacterium tuberculosis and NTM PJI have been identified in several cases reported in the literature.^7,8 Among them, M. tuberculosis is the most common causal pathogen. PJI by NTM is considered to be less frequent compared to that caused by M. tuberculosis. Furthermore, instances of PJI attributed to MAC are exceedingly scarce within the NTM-induced PJI spectrum and occur almost exclusively in patients with compromised immune systems.⁴ As these bacteria tend to have indolent growth patterns, the culture period should be extended beyond conventional timeframes given the difficulty of diagnosis. A literature search revealed few reported cases of MAC infection in total joint arthroplasty (TJA).⁶ However, given lack of standardized clinical protocols and recommendations, there are no practical guidelines. While several single-institution experiences addressing this topic are reported in the literature, the notable lack of systemic literature reviews concerning the appropriate management strategies and outcomes of MAC infections following total joint arthroplasty (TJA) serves as a catalyst for undertaking this study.

Our study aimed to assess the epidemiology and therapeutic outcomes of MAC infections subsequent to TJA by employing a review of the literature and aggregated data analysis. Consequently, out study seeks to address: (1) the range of viable treatment options for managing MAC infections following TJA (2) the outcomes associated with these infections as delineated by the respective therapeutic approaches.

Methods

Review of the literature

Multiple databases (Embase, PubMed, Cochrane Library, and Web of Science) were investigated with the key words “arthroplasty”, “replacement”, “periprosthetic”, “Mycobacterium avium”, and “infection” in various combinations. Two autonomous authors conducted the search individually, with each author replicating the search process twice to ensure the process. The initial database exploration was performed on April 10, 2023, followed by an updated search on May 10, 2023, to guarantee precision. Through this repetitive search approach, one additional study⁹ was identified.

Criteria for inclusion and exclusion

The inclusion criteria were (1) studies conducted in human, (2) English-written articles, (3) studies including electronic publications up to May 10, 2023, (4) studies reported cases of infections caused by MAC, (5) both prospective and retrospective studies, (6) cases of infections caused by MAC following arthroplasty, and (7) studies that assessed the outcomes including relapse of infection.

The exclusion criteria were (1) articles without data on patient risk factors for infection (immunocompromising conditions), (2) assessment of any other joints beyond the realm of the hip and knee joint,¹⁰ (3) non-English articles, (4) abstracts only, (5) conference presentations, and (6) native joint infection (septic arthritis) before arthroplasty.^11,12 Given the dearth of substantial evidence pertaining to this topic, our review predominantly encompasses case reports and case series to provide a comprehensive analysis. No limits for the minimum duration of follow-up for patient cohorts in each study were imposed.

The flow of selection

The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guideline¹³ was followed. A total of 67 articles were yielded after the aforementioned databases search. A flow-chart illustrating this process is shown in Figure 1.

Figure 1.

The Systematic review flowchart details the method of retrieval of relevant articles for this study.

A total of 42 articles were identified through the searches. Both abstracts and complete texts of these procured articles were assessed by two independent authors, with thorough evaluations being undertaken for all pertinent articles. Also, the references of the obtained articles were screened for any additional studies that might be missed. Disagreements regarding inclusion were reconciled by deliberative discourse. Finally, a total of 11 publications were included after rigorous exclusion criteria were applied. Studies of MAC infection after TJA mainly appeared following the cases of Isono et al in 1987,¹⁴ despite several previous reports of osteoarticular infection caused by MAC.

Collection of data

Data were collected from the selected articles by two authors, then confirmed by another author. The following variables of data were collected: demographics, underlying host factor for infection, clinical symptom, time to development of symptom(s) after TJA, C-reactive protein (CRP) erythrocyte sedimentation rate (ESR) and erythrocyte sedimentation rate (ESR) at the presentation of infection, diagnosis of MAC infection, surgical management, perioperative and postoperative therapeutic drugs, treatment outcomes including resolution of infection, recurrence of infection, mortality, and other associated complications.

Results

Our systematic review of Web of Science, Embase, Cochrane literature, and PubMed yielded a total of 17 patients from 11 selected studies^{2,4,5,9,14–20} which have been published from 1987 to 2023. Despite the unavailability of exhaustive data, demographic data and other pertinent factors such as preexisting medical conditions, management of infection including surgery and antibiotic therapy, and outcomes including recurrence of infection and death, were extracted. Location of infection, time to development of symptom(s) after arthroplasty, diagnostic method, surgical treatment and postoperative antibiotic therapy were reported in the selected articles and included in the analysis.

Patient population

There were 11 male patients and 5 female patients (gender and age were not clearly reported in one study).¹⁴ The mean age was 66.8 years. The minimum follow-up was 3 months (range, 3–85 months). The information of demographics is shown in Table 1.

Table 1.

Demographic information in the studies (NA, not available).

AuthorReference number	Journal	Year	Country	Gender	Age	Location	Clinical presentation
Maimaiti⁹	Orthop Surg	2023	China	M	65	Knee	Knee pain, sinus tract
Dobos¹⁵	J Bone Jt Infect	2022	USA	M	70	Knee	Knee pain
Dobos¹⁵	J Bone Jt Infect	2022	USA	F	67	Hip	Hip pain
				M	74	Knee	NA
				F	77	Hip	Thigh pain and hip pain
				F	46	Knee	Knee pain
Sixt¹⁶	QJM	2020	France	M	81	Hip	Hip pain and fever
Goldstein²⁰	Emerg Infect Dis	2019	USA	M	76	Knee	NA
				F	77	Knee	NA
				M	83	Knee	NA
Sigler¹⁷	J Bone Jt Infect	2019	USA	M	56	Hip	Malaise and fever
Ingraham⁴	Case Rep Infect Dis	2017	USA	M	79	Hip	Hip pain
Tan²	J Clin Tuberc Other Mycobact Dis	2016	USA	M	73	Knee	Knee pain and swelling
Vergidis¹⁸	Transpl Infect Dis	2012	USA	M	39	Hip	NA
Gupta¹⁹	Transpl Infect Dis	2009	USA	F	67	Hip	Fever, hip pain
McLaughlin⁵	J Bone Joint Surg Br	1994	USA	M	40	Hip	Hip pain
Isono¹⁴	Clin Orthop Relat Res	1987	USA	NA	NA	Hip	Hip pain

Among these patients, nearly all - (16/17 patients, 94.1%) - had underlying medical condition(s) that might have affected immunity (Table 2).

Table 2.

Clinical variable data on the studies (NA, not available; RA, rheumatoid arthritis; OA, osteoarthritis; SLE, systemic lupus erythematosus; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; AIDS, acquired immune deficiency syndrome).

Author	Risk factor for underlying disease	ESR	CRP	Time to symptom	Preoperative joint aspiration culture	Intraoperative tissue culture
Maimaiti	DM, HTN, coronary artery disease	NA	NA	1 month	NA	MAC
Dobos	None	11	0.7	9 years	MAC	MAC
Dobos	RA treated with methotrexate and leflunomide, prior prednisone use	80	4.6	26 years	MAC	MAC
	RA and OA, prior prednisone use	77	8.7	5 months	MAC	MAC
	RA treated with methotrexate and prednisone	95	4	15 years	NA	MAC
	SLE treated with prednisone, refractory B-cell lymphoma treated with chemotherapy	63	46.5	1 year	MAC	NA
Sixt	Myelodysplasia	NA	136	5 years	NA	MAC
Goldstein	Nonspecific autoimmune disease, oral steroids	NA	NA	0 month	NA	NA
	RA treated with prednisone and azathioprine	NA	NA	25 years	NA	MAC
	Malnutrition, prednisone	NA	NA	14 years	NA	MAC
Sigler	Seronegative RA	25	NA	9 years	MAC	MAC
Ingraham	RA treated with prednisone, leflunomide and infliximab	28	5.2	15 years	MAC	NA
Tan	Multiple myeloma, seronegative RA	65	13.5	1 year	MAC	MAC
Vergidis	Renal transplantation with immunosuppression	NA	NA	12 years	NA	MAC
Gupta	Renal transplantation with immunosuppression, SLE	NA	NA	15 years	NA	MAC
McLaughlin	AIDS	NA	NA	20 years	MAC	MAC
Isono	Cardiac, renal transplantation with immunosuppression	NA	NA	7 years	MAC	NA

The analysis of serum levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) at the time of the presentation was difficult due to presence of inconsistencies in documentation. A considerable variation was observed in the prosthesis age at the time of diagnosis of PJI by MAC, with a maximum of 26 years between the infection and implantation of the prosthesis. Presenting symptoms were non-specific. Among the total of 17 patients included in the pooled analysis, the details of the presenting symptoms were available in 12 patients. In these 12 patients, pain was the most common presenting symptom identified in the majority of patients (11/12, 91.7%). However, fever and malaise were the presenting symptoms in one patient. The details of the presenting radiology test results were available in seven patients. Loosening of the hardware in one patient, increased uptake in the periprosthetic soft tissue seen from PET (A fluorodeoxyglucose positron emission tomography) in one patient, abscess or fluid collection or effusion involving the affected joint in four patients, and loculated cystic mass in one patient. MAC was confirmed by culture in all patients. The information of culture media was available in one patient, who had growth of MAC from the liquid broth medium. Joint fluid cultures from the preoperative arthrocentesis yielded positive culture results for nine patients (52.9%). Thirteen patients (76.4%) were diagnosed with MAC infection by intraoperative tissue cultures. Histopathology data was available in two patients, which showed that acid-fast bacilli bacteria in necrotic tissue in one patient and no evidence of acute inflammation in one patient.

Treatment

All patients were treated with active anti-MAC antibiotic therapy, which consisted of 5-drug therapy in one patient, 4-drug therapy in one patient, 3-drug therapy in 14 patients, and two drug therapy in one patient. The most common 3-drug active anti-MAC therapy regimen was ethambutol, rifabutin or rifampin, and clarithromycin or azithromycin. The duration of active anti-MAC antibiotic therapy ranged from 1 month to 84 months. In addition, 14 patients (82.3%) received initial treatment of the prosthesis removal and subsequently underwent either resection arthroplasty (explantation) or exchange arthroplasty (Table 3).

Table 3.

Treatments and outcomes of the studies (NA, not available; SM, streptomycin; AFB, Acid fast bacilli).

Author	Surgical management	Medical management	Duration of active medical treatment (months)	Follow up (months)	Outcome	Further treatment
Maimaiti	Two-stage exchange	Ciprofloxacin, amikacin, azithromycin	NA	85	Clinical cure
Dobos	Spacer exchange	Ethambutol, rifabutin, azithromycin	16	18	Recurrent PJI with Klebsiella aerogenes	Resection arthroplasty
Dobos	Explantation	Ethambutol, rifabutin, azithromycin	12	24	Clinical cure
	Two-stage exchange	Ethambutol, rifabutin -> rifampin, azithromycin	15	24	Clinical cure
	One-stage exchange	Ethambutol, rifampin -> rifabutin, azithromycin	84	84	Died due to pneumonia
	Not done due to neutropenia	Ethambutol, rifabutin -> rifampin, azithromycin	4	4	Died due to lymphoma
Sixt	Explantation, cement spacer	Clarithromycin, ethambutol, rifabutin	1	3	Died due to leukemia
Goldstein	Two-stage exchange	Ethambutol, clofazimine, azithromycin	39	20	Clinical cure
	Two-stage exchange	Ethambutol, moxifloxacin, azithromycin	9	17	Clinical cure
	Two-stage exchange	Ethambutol, rifampin, azithromycin	7	20	Clinical cure
Sigler	Two-stage exchange	Amikacin, ethambutol, rifampin, azithromycin	12	12	Clinical cure
Ingraham	Incision and drainage	Ethambutol, rifampin, clarithromycin	4	6	Positive AFB smear from surgical site after 4 months of medical treatment;Died due to decline quality of life and hospice care
Tan	Two-stage exchange	Ethambutol, clarithromycin for 12 months followed by azithromycin suppression	12	84	Clinical cure
Vergidis	Explantation	Ethambutol, rifabutin, azithromycin	12	NA	Clinical cure
Gupta	Explantation, cement spacer	Ethambutol, rifabutin, azithromycin	12	6	Doing well	Scheduled for reimplantation
McLaughlin	Explantation	Ciprofloxacin, clarithromycin, rifampin, clofazimine, ethambutol	7	5	Died from unknown etiology
Isono	Not done	Ethambutol, rifampin, isoniazied	NA	NA	NA

Seven patients (41.1%) underwent a two-stage exchange arthroplasty, exhibiting variable durations between prosthesis removal and subsequent reimplantation. Six patients underwent resection arthroplasty. One patient had surgical debridement with retention of the implant due to due to comorbidities.⁴ Two patients were only treated with antibiotic therapy without surgery.

Outcomes

A conclusive clinical follow-up report was available for 16 patients (94.1%). The mean duration of follow up after the surgical procedure was 27.4 months, with a range from 3 months to 85 months. No relapse of MAC infection was reported despite of one case of relapse of infection caused by different pyogenic bacteria (Klebsiella aerogenes) after reimplantation of static weight-bearing spacer¹⁵ requiring resection arthroplasty 10 months post-reimplantation. The rate of overall mortality was 29.4% (5 patients, 5/17), however, identified attributable mortality due to MAC infection was low (1 patient, 1/17, 5.9%). Other causes of death were viral pneumonia in one patient and progression of underlying malignancy in two patients (acute myeloid leukemia and diffuse large B cell lymphoma, respectively). Outcome after treatment (antibiotic treatment only) was not clearly reported in one study.¹⁴ Survivors all had removal of the arthroplasty with the two-stage exchange arthroplasty performed in the majority (63.6%). The total duration of active anti-MAC antibiotic therapy among survivors ranged from 7 months to 39 months, with a median of 12 months, interquartile range of 11 months to 15 months. The majority of the survivors had active 3-drug anti-MAC antibiotic therapy (81.8%). Chronic suppression with anti-MAC antibiotic therapy following the active anti-MAC antibiotic therapy was employed in only one survivor patient.

Discussion

PJI by NTM is not well known and poses a significant diagnostic and therapeutic challenge because of limited clinical experience. The prevalence of PJI by NTM may have risks of being on the rise due to the evolution of diagnostic techniques of PJI and widespread use of newer immunosuppressive medications. The purpose of the present study was to assess the epidemiology and the outcomes of MAC infections after joint arthroplasty, which may contribute to the clinical management of PJI by MAC.

Mycobacteria rarely cause PJI, accounting for 0%–0.6% of cases. The most of these cases are known to be caused by M. tuberculosis.²¹ MAC is a nontuberculous mycobacteria which is well known for disseminated invasive infections in immunocompromised patients. In the present study, we evaluated the profile of hip and knee MAC infection cases published in the past 30 years. Since the 1990s, MAC infections of hip and knee joints were increasingly identified in the setting of AIDS.^11,22,23 More recently, various comorbid conditions and multi-organ diseases leading to compromised immune system have been acknowledged as a contributing risk factor for septic arthritis and periprosthetic infections by MAC.²⁴ According to our review, the most of the patients (16/17 patients, 94.1%) were noted to have underlying medical condition(s) that might have affected immunity similar to other studies. Although one patient lacked clearly documented immunologic deficiency, it is plausible that this patient might have had an undiagnosed immunosuppressive host factor, thereby augmenting the risks of acquiring and developing MAC PJI.

In our systematic review, presenting symptoms were non-specific although pain was the most common symptom. The findings of the presenting radiology test were diverse, including the loosening of the hardware, fluid collection, and cystic mass. Thus, it poses a diagnostic challenge, requiring a high index of suspicion. In addition, in the diagnostic evaluation, mycobacterial culture (acid fast bacilli culture with employing both solid and liquid media) should be performed along with the routine bacterial culture to improve diagnostic sensitivity. Joint aspiration from preoperative arthrocentesis and intra-operative tissue cultures were used for detection of MAC PJI infection, and MAC was confirmed by culture in all patients (one patient was diagnosed at another hospital).²⁰ MAC belongs to the category of slow-growing mycobacteria. As an unusual bacterium, NTMs including MAC are not easily diagnosed and often overlooked during the diagnostic procedure due to various reasons. According to one recent study,²⁵ Mycobacterium is predominantly implicated in as many as 43% of culture-negative PJI cases. Therefore, in culture-negative PJI, orthopedic surgeons must keep in mind possibility of atypical microorganisms, especially nontuberculous mycobacteria including MAC.

In addition to rarity of PJI caused by NTM, it also presents considerable challenges in treatment. Existing therapeutic guidelines for pulmonary nontuberculous mycobacteria and typical PJI offer scant information on the proper management of PJI caused by MAC. Successful treatment of infection can be accomplished by a combination of appropriate surgical intervention and medical antibiotic treatment. According to our review, the most commonly employed routine treatment was the surgical removal of all bio-prosthetic components. Surgical debridement without removal of prosthesis is considered to be a controversial matter, given its inherent risk of infection recurrence and was performed in only one patient in our review.⁴ Two cases of MAC prosthetic infection were only treated with antibiotic therapy without surgical intervention due to poor general conditions (neutropenia and thrombocytopenia). Overall, prosthesis removal was performed in 82.3% (14/17) of the cases for the treatment of infection. The risk of relapse of MAC infection after surgery and active anti-MAC antibiotic therapy seemed to be low as no relapse of MAC infection was reported despite of one case of relapse caused by different pyogenic bacteria (Klebsiella aerogenes).¹⁵ The majority of survivors in our analysis had the two-stage revision arthroplasty treated with active anti-MAC antibiotic therapy. Of note, the success rate of pyogenic PJI treated with the two-stage exchange arthroplasty along with systemic antibiotic therapy has been known for 82–100% and 89% for infected knee and hip arthroplasty, respectively.^26,27 Thus, our results suggest that the outcome of PJI by MAC could be comparable to that of pyogenic PJI, particularly if the patients with PJI by MAC are treated with the two-stage exchange arthroplasty along with the anti-MAC antibiotic therapy. Extrapolating from our results, surgical treatment (two-stage revision arthroplasty) combined with appropriate antibiotic therapy can be recommended for the management of PJI by MAC.

As far as we are concerned, there are currently no specific guidelines as regards whether MAC periprosthetic infections ought to be locally managed during surgery (i.e., antibiotic-loaded cement spacer). However, we believe that incorporating antibiotics into the bone cement could be considered, as mycobacterial infections may have a higher risk of other bacterial co-infection.¹⁵ Despite the potential inability of the antibiotic-impregnated bone cement to prevent the recurrence of MAC infection, it may decrease the risk of additional bacterial infection.²⁸

There remains an absence of unified agreement regarding the proper duration and regimen of antibiotics to be systemically employed to treat this formidable condition. A combination of surgery and 6–12 months of active anti-MAC antibiotic therapy for osteoarticular MAC infection was recommend from a previous guideline.³ Although further detailed recommendations regarding the PJI by MAC were not available from the previous guideline,³ a prolonged course (12 months or more in severe infection¹²) of anti-MAC antibiotic therapy is recommended, in addition to surgical intervention including debridement or surgical excision.³ There is a lack of clear evidence suggesting that a shorter duration of antibiotic therapy would yield equally successful outcomes, and recurrence may occur even after the completion of long term combination therapy.¹⁰ Notably, the median duration of active anti-MAC antibiotic therapy among survivors in our study analysis was 12 months. Therefore, the duration of active anti-MAC antibiotic therapy may be considered for approximately 12 months for those who underwent surgery without complication and for longer than 12 months for those who did not have surgery or who found to have complications after the surgery. Although various therapeutic regimens have been employed for the treatment of MAC PJI, no particular standard drug regimen has been demonstrated to possess a superior efficacy compared to others thus far. Until now, macrolide (azithromycin or clarithromycin), ethambutol, and rifampin have been considered the drugs of choice for the treatment in the majority of the reports.^3,10,29 The recent guideline²⁴ for MAC pulmonary disease recommends 3-drug therapy including a macrolide and ethmbutol over 2-drug regimen. Addition of rifamycin such as rifabutin or rifampin may prevent the development of macrolide resistance during the antibiotic therapy.³⁰ Extrapolating from the recent recommendations regarding the pulmonary MAC treatment, a 3-drug regimen consisting of macrolide (azithromycin or clarithromycin), ethambutol, and rifamycin (rifabutin or rifampin) may first be considered for active anti-MAC antibiotic therapy for treatment of PJI by MAC. Given the potential drug interaction from anti-MAC antibiotics, choosing the appropriate antibiotic therapy may require a multidisciplinary approach including infectious diseases physician, clinical pharmacist, and treating orthopedic surgeon. Optimal drug regimen and duration of antibiotic therapy for MAC PJI need to be clarified in the forthcoming research.

There are several limitations to this review that should be considered. First, owing to the limited availability of data on the MAC infection following TJA compared to investigations of other common diseases, we relied significantly on case series in the present study. Second, due to the small number of heterogeneous cohort of patients found in the pooled analysis, we were unable to perform objective statistical comparisons of variables of interest. Furthermore, limited data of histopathology in our analysis showed conflicting results of acid-fast bacilli bacteria in necrotic tissue in one patient and no evidence of inflammation in one patient. These findings might have been secondary to inappropriate sampling of the histopathology sample in the latter as all of surgical tissue samples of that patient grew MAC. Given the small number of the patients with available histopathology data and lack of the occupation or ethnicity data of the patients, it is difficult to draw the conclusion regarding these aspects from the pooled analysis. Nevertheless, the reports of 17 cases represent a considerably large sample size among reports of PJI by MAC. We believe that our review and pooled analysis may provide helpful information and some insights into the profile of MAC hip/knee prosthetic joint infection, including its therapeutic options and associated results.

Conclusion

In conclusion, in culture-negative PJI, NTM including MAC should be considered potential pathogens by orthopedic surgeons, especially in patients with compromised immune systems. In the consideration of MAC PJI treatment, two-stage exchange arthroplasty, in conjunction with appropriate systemic anti-MAC antibiotic therapy, is strongly recommended. Incorporating antibiotics into the bone cement could be added when there is a possibility of subsequent other bacterial infections. Further multicenter research studies, embracing a larger number of patients and ethnic groups, are required to determine the optimal treatment strategies for MAC infection following TJA.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Seung-Ju Kim

Jong Hun Kim

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