Azathioprine for remission maintenance in anti-interferon-γ autoantibody-associated immunodeficiency syndrome- a retrospective single-center cohort study.

Background

Anti-interferon-gamma autoantibodies (Anti-IFN-γ Aab) associated with adult-onset immunodeficiency disease are prevalent in 0.5–1 per million of the general population worldwide. Two-thirds of patients with this disease are diagnosed in the Southeast Asian region, which includes Thailand and Taiwan [ 1 ]. The median age of disease onset is 50 years [ 1 , 2 ]. Patients with Anti-IFN-γ Aab disease often develop difficult-to-treat recurrent infections, particularly involving nontuberculous mycobacteria (NTM), Salmonella spp., Burkholderia pseudomallei , Cryptococcus neoformans , Talaromyces marneffei , Histoplasma spp., Toxoplasma spp., Pneumocystis jirovecii , and varicella-zoster virus [ 3 , 4 ]. The organs involved in the Anti-IFN-γ Aab include the lymph nodes, skin, blood, lungs, bones, and joints [ 1 ].

The disease is chronic in nature and may persist despite long-term treatment with antimicrobial drugs. About 30% of patients may experience side effects from prolonged use of antimicrobial drugs [ 4 , 5 ]. Some patients may also be at risk of acquiring new infections, even if they have been previously infected. Based on a 36-item short-form survey for evaluating quality of life, patients with active infection exhibit impaired physical functions, role limitations from physical problems, general health problems, bodily pain, limited social functioning, role limitations from emotional problems, and mental health limitations [ 6 ]. However, patients whose infections are controlled exhibit an improved quality of life [ 7 ]. The mortality rate in patients with Anti-IFN-γ Aab disease ranges from 0 to 24%, and mortality results mostly from infections [ 1 ].

In a previous prospective cohort pilot study involving patients who were refractory to antimicrobial treatment, 80% responded to adjunctive immunosuppressive therapy with either rituximab or intravenous cyclophosphamide (IVCY). These patients were able to maintain remission for up to two years [ 5 ]. However, the risk of increased disease relapse was observed in patients who discontinued immunosuppressive drugs.

Azathioprine (AZA) is an antiproliferative immunosuppressive drug in which active metabolites of mercaptopurine (6-MP) and thioguanine (6-TGN) inhibit DNA synthesis, thus inducing cytotoxicity, particularly in leukocytes and lymphocytes [ 8 ]. AZA has the clinical efficacy to prevent relapse and maintain remission in autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease, and in organ transplant recipients [ 9 – 11 ]. Adverse reactions to AZA, such as mild fatigue, nausea, and liver toxicity, have been reported in 15%–28% of patients [ 12 ]. However, AZA is safe during pregnancy [ 13 ]. Compared to anti-CD20, AZA is considered an inexpensive treatment option and is more convenient to administer in an outpatient setting when maintenance immunosuppressive therapy is indicated.

The primary purpose of this study is to explore the disease-free survival time until relapse in patients with Anti-IFN-γ Aab disease who received maintenance therapy with AZA compared to those without AZA maintenance therapy. The secondary outcome is to assess the safety of AZA in this population.

Materials and methods

A retrospective observational study was conducted at Ramathibodi Hospital, Bangkok, Thailand, from January 1, 2019 to December 31, 2023.

Ethical considerations

The study complied with the Declaration of Helsinki. Ethical approval (No. MURA2023/354) was granted by the Research Committee of the Faculty of Medicine Ramathibodi Hospital, Mahidol University, and the requirement for informed consent was waived because of the retrospective nature of the study.

Data collection

The participants were drawn from a hospital’s cohort Anti-IFN-γ Aab registry database. All patients in this cohort received care through a multidisciplinary approach that involved both infectious disease specialists and immunologists. Typically, each patient was evaluated by both teams to create a personalized care plan that combined antimicrobial management with decisions regarding immunosuppressive therapy. This collaborative model ensured a thorough assessment and optimized treatment outcomes. A total of 53 patients were diagnosed with Anti-IFN-γ Aab disease. Of these, 8 patients who did not receive AZA were excluded for the following reasons: 4 patients had died – 2 due to COVID-19 infection, 1 from Salmonella bloodstream infection, and 1 from disseminated nontuberculous mycobacterial infection; 2 patients were lost to follow-up, and 1 patient was referred to another hospital. An additional 16 patients were excluded as they were still undergoing induction therapy at the time of data collection. The study inclusion criteria were as follows: patients diagnosed with Anti-IFN-γ Aab disease who received AZA maintenance therapies, and patients who received only induction therapies and were in clinical remission. Most patients who did not receive AZA were diagnosed before 2016, when IVCY or rituximab-based regimens were more commonly used. In contrast, those diagnosed after 2016 were more likely to receive AZA maintenance therapy. The median year of diagnosis for the AZA group was 2017 (IQR: 2016–2018), while for the non-AZA group, it was 2016 (IQR: 2016–2017). The median follow-up duration since diagnosis was 6.57 years (range: 6.13–7.61 years) for the AZA group and 7.85 years (range: 6.68–8.36 years) for the non-AZA group. These differences in follow-up duration reflect changes in treatment practices over time rather than differences in disease severity. The average follow-up duration, preferably from the start of AZA maintenance therapy to the last follow-up, is 3.63 ± 0.99 years. Patients who received other immunosuppressive drug maintenance therapies for a diagnosis other than Anti-IFN-γ Aab disease, organ transplant recipients, hematopoietic stem cell transplant recipients, receipt of systemic chemotherapy for any malignancy condition, and diagnosis of human immunodeficiency (HIV) were excluded.

The patients’ demographic and clinical data were collected, including the age of disease onset, duration from diagnosis, infection episodes, isolated pathogens, organ involvement, treatment regimen, treatment guidelines for antimicrobial agents, availability, duration of antimicrobial agent use, and duration of disease remission. Laboratory biomarkers, including white blood cell count, C-reactive protein (CRP) and interleukin-6 (IL-6) levels, and erythrocyte sedimentation rate (ESR), were determined. Anti-IFN-γ Aab inhibition titers were evaluated by certified immunology laboratory at the Division of Immunology, Faculty of Medicine Ramathibodi Hospital, Mahidol University using the method according to Khositnithikul et al. [ 14 ] before initiating immunosuppressive drug treatment during the active disease stage and after receiving AZA for at least six months. Laboratory staff had no influence on patients’ treatment plans.

AZA was prescribed as maintenance therapy after clarifying disease remission following induction regimens or conventional antimicrobial treatments. The initial dose of AZA was 50 mg daily, and subsequent dose adjustments were evaluated by clinical and laboratory biomarkers that indicated clinical remission, including white blood cell count, CRP, and IL-6 levels.

Patients in the non-AZA group consisted of individuals who underwent only induction immunosuppressive therapy without subsequent maintenance treatment. The decision to forgo maintenance therapy was based on the treating physician’s assessment and the patient’s preferences. This strategy aimed to minimize unnecessary immunosuppression and reduce the risk of potential adverse effects since some physicians recognized the absence of solid recommendations for long-term immunosuppressive therapy in this patient population. These patients did not receive azathioprine or other immunosuppressive agents after induction, as they had already achieved sustained clinical remission and normalization of inflammatory biomarkers. All patients continued to receive close clinical and laboratory follow-ups to monitor for relapse, ensuring adherence to ethical standards of patient care.

Definitions

Disease remission was defined as (1) recovery of all the symptoms reported before treatment; (2) resolution of the previous infection determined by physical examination, radiographic findings, and/or microbiological studies; and (3) normalization of CRP and IL-6 (i.e., CRP < 5 mg/L and IL-6 < 7 pg/mL). Patients who did not meet these criteria were deemed to have active disease. Relapse was defined as the development of new symptoms suggestive of active disease, such as fever or lymphadenopathy, with or without microbiological or radiological confirmation, accompanied by a rise in inflammatory biomarkers. Induction therapy was defined as immunosuppressive treatment administered during the active phase of disease to control disseminated infections (e.g., cyclophosphamide or rituximab. Maintenance therapy was defined as ongoing immunosuppressive treatment, specifically AZA, initiated after the achievement of clinical remission.

Safety and adverse effects were systematically evaluated during each outpatient visit. Monitoring included regular assessments of white blood cell counts, liver and kidney function tests, and documentation of any clinical adverse events, typically conducted every 4 to 6 weeks during the first 3 months, and then every 3 months thereafter. All potential drug-related side effects were actively monitored and recorded at each follow-up visit. Records of safety and adverse events were assessed using the Common Terminology Criteria for Adverse Events version 5.0.

Statistical analyses

Statistical analysis was conducted using Stata version 18.0 (StataCorp, 2023, College Station, TX). Continuous variables were presented as mean ± standard deviation (SD) or median with interquartile range (IQR), based on the data distribution assessed by the Shapiro–Wilk test. Categorical variables were summarized as frequencies and percentages. To compare groups, the Mann–Whitney U test or independent t-test was used for continuous variables, while Fisher’s exact test or chi-square test was applied for categorical variables.

Relapse-free survival was analyzed using the Kaplan–Meier method, with differences between groups assessed by the log-rank test. Factors related to relapse were further evaluated using a Cox proportional hazards regression model, adjusted for baseline anti-IFN-γ autoantibody titers, duration of antimicrobial treatment, and induction regimens. All statistical tests were two-tailed, and p-values of less than 0.05 were deemed statistically significant.

Results

A total of 29 patients with Anti-IFN-γ Aab disease were surveyed. Of these, 15 patients received AZA maintenance therapy after the induction course, and 14 patients received only immunosuppressive drug induction therapy.

Patient demographics

Table 1 shows the patients’ demographic data, isolated microorganisms, and treatments provided. There was no statistical difference in age, sex, or episode of infection before the initiation of immunosuppressive drug treatment, identified pathogens, and clinical presentation between patients in the AZA maintenance therapy group and those in the group without AZA maintenance therapy. The median year of diagnosis for the AZA group was 2017 (IQR: 2016–2018), while for the non-AZA group, it was 2016 (IQR: 2016–2017). The median follow-up duration since diagnosis was 6.57 years (range: 6.13–7.61 years) for the AZA group and 7.85 years (range: 6.68–8.36 years) for the non-AZA group. These differences in follow-up duration reflect changes in treatment practices over time rather than differences in disease severity. The average follow-up duration, preferably from the start of AZA maintenance therapy to the last follow-up, is 3.63+0.99 years. Patients in the non-AZA group received more intensive induction therapy, with a higher number of intravenous cyclophosphamide and combined rituximab plus cyclophosphamide cycles ( p = 0.040 and p = 0.030, respectively), whereas rituximab monotherapy use did not differ between groups. Corticosteroid treatment was observed only in the AZA group (26.7%), with no significant differences in treatment duration or cumulative dose between groups ( p = 0.100 and p = 0.120, respectively).

AZA maintenance therapy group

In the AZA maintenance therapy group ( n = 15) with the mean dose of prescribed AZA was 0.85 ( ± 0.13) mg/kg/day or 50 mg/day, 9 (60%) patients were female, and the average age at disease onset was 52.1 (± 9.2) years. Eleven (73.4%) patients had a history of three or fewer episodes of disease relapse/recurrent infections. NTM was the most common opportunistic infectious agent in 13 (86.7%) patients, which included M. abscessus in 6 (40.0%) patients. The lymph node was the most frequently involved organ in 8 (53.3%) patients, followed by the skin in 6 (40%) patients and the lungs in 5 (33.3%) patients.

Regarding the induction stage treatment regimen, rituximab (RTX) was used in 5 (33.3%) patients, followed by IVCY in 4 (26.7%) patients, and combined RTX + IVCY in 3 (20.0%) patients. Three patients (20%) responded to conventional antimicrobial treatment and did not require induction therapy; AZA was initiated as maintenance upon diagnosis based on the physician’s and patient’s decision-making. Four (26.7%) patients received prednisolone, prescribed for hemolytic anemia in two patients and reactive arthritis in the other two. The median dose of prednisolone was 5.95 (5.16–7.41) mg/day, with a median duration of 276 (219–1172.25) days.

During maintenance therapy with AZA, breakthrough disease remission was observed in 4 (26.67%) patients. The median time from remission to relapse was 758 (571.5, 1,021) days. AZA was discontinued when patients met the criteria for active disease. Two patients developed M. abscessus infections, presenting with lymphadenopathy; one of these patients also experienced a concurrent Salmonella infection. Additionally, another patient had elevated inflammatory biomarkers, including CRP and IL-6, but no identifiable pathogen was found. A subgroup analysis comparing patients who relapsed with those who did not while receiving AZA maintenance therapy showed no statistically significant differences, as illustrated in Table 1 .

Group without AZA maintenance therapy

In this group, 7 (50%) patients were female; the average age at disease onset was 57.1 (± 12.6) years. Three or fewer episodes of relapse/recurrent infections occurred in 10 (71.4%) patients. NTM was the most common cause of opportunistic infections in all patients, with M. abscessus infection in 7 (50%) patients. The lymph node was the most involved organ in 8 (57.1%) patients, followed by the lungs and skin, each in 6 (42.9%) patients.

Regarding the induction stage treatment regimen, RTX was used in 9 (64.3%) patients, followed by combined RTX + IVCY in 3 (21.4%) patients and IVCY in 2 (14.3%) patients.

All patients who received solely induction regimens experienced relapse of infection, with a median duration from remission of 410 days (238.75, 602.5) days.

Clinical outcomes

Time to disease relapse

The Kaplan–Meier survival analysis of time to disease relapse in patients who received AZA maintenance therapy compared to those who did not receive AZA maintenance therapy is shown in Fig. 1 . Patients were censored at their last follow-up or date of relapse. No deaths or losses to follow-up were reported during the study period. The cumulative 50% relapse-free survival rate for the AZA group was 3.99 years, while it was 0.88 years for those without AZA treatment.

Covariate-adjusted survival curve estimation was performed for antimicrobial treatment durations, Anti-IFN-γ Aab inhibition titers before AZA initiation, and induction regimens, as shown in Table 1 . AZA as a maintenance treatment drug had a hazard ratio of 0.096 ( p = 0.006, 95%CI: 0.018–0.507).

Duration of antimicrobial treatment

The median duration of antimicrobial treatment for patients in the AZA group (IQR) was 338 (221–657) days, compared to 118.5 (0–227) days in the group without AZA ( p = 0.123).

Comparison of anti–IFN-γ titer reduction between patients with and without azathioprine maintenance therapy

The AZA group demonstrated a greater reduction in anti-IFN-γ titers, with a median log 10 change of -3.70 (-4.35, -0.65), compared to the non-AZA group, which had a median log 10 change of -1.30 (-2.65, -0.30), as illustrated in Fig. 2 . However, this difference did not reach statistical significance ( p = 0.42).

At the end of the study period, Anti-IFN-γ Aab inhibition titers in all patients in the AZA group were 1:5,000 or lower, and 7 (46.6%) patients showed negative results. In the group without AZA, the Anti-IFN-γ Aab inhibition titer in 7 (50%) patients was positive at 1:10,000, and 3 (21.4%) patients had positive titers of 1:50,000 or higher.

Safety and adverse events

Safety and adverse effects were assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. No adverse effects were documented in the AZA group.

Discussion

Adult-onset immunodeficiency caused by Anti-IFN-γ Aab is prevalent in Asian countries [ 1 ]. The unique presentation of this condition is a chronic infection that is difficult to control with antimicrobial therapy alone [ 4 ]. Frequently, RTX is prescribed to eliminate excessive Anti-IFN-γ Aab production, with the aim of normalizing the host’s immune response to the infection [ 4 , 15 , 16 ].

A study from Thailand reported that some patients benefited from IVCY therapy during the active disease stage and that many achieved faster disease remission compared to patients on conventional RTX therapy [ 5 ]. However, the disease relapsed when either RTX or IVCY was discontinued after the induction phase. In real-life settings, attending physicians seek different immunosuppressive modalities to maintain disease remission and reduce patients’ risk of acquiring opportunistic infections during long-term care. Using IVCY and RTX for maintenance therapy at longer intervals than those administered during active disease may not be an ideal strategy, as patients require a hospital visit for intravenous drug treatments, and RTX remains a high-cost drug in resource-limited settings.

AZA is considered an inexpensive immunosuppressive agent in Thailand. It has been widely used for various autoimmune diseases and organ transplants despite being less common, according to a favorable safety profile [ 9 – 11 ]. The current study reviewed the effectiveness of AZA maintenance therapy following induction regimens in patients with Anti-IFN-γ Aab disease. The data indicated that AZA extended the duration of disease remission and reduced the relapse rate.

The Kaplan–Meier survival analysis revealed that patients on AZA maintenance treatment had a median 50% cumulative relapse-free survival time of 3.99 years, compared to 0.88 years in patients who did not receive AZA. The extended remission period observed in the AZA group suggests that the agent may have effectively suppressed the underlying mechanisms that cause disease relapse. Factors that are likely to affect disease remission, including antimicrobial treatment durations, Anti-IFN-γ Aab inhibition titers before AZA treatment initiation, and induction regimens, were estimated from the adjusted survival curves, and the results showed a hazard ratio of 0.096 ( p = 0.006, 95%CI: 0.018–0.507). Antimicrobial regimens were tailored based on the severity of infections and the clinical response, while low-dose corticosteroids were prescribed in selected cases for autoimmune manifestations. These factors may have contributed to variability in relapse outcomes and should be addressed in future prospective studies with standardized treatment protocols.

However, this variability reflects real-life medical practice, where there are uncertainties due to the absence of standardized treatment guidelines for certain infectious agents and the anti-IFN-γ Aab associated with adult-onset immunodeficiency.

In this study, AZA maintenance treatment was administered to modulate the patients’ immune status. At the end of the study, a reduction in Anti-IFN-γ Aab titers was observed in the AZA group. The Anti-IFN-γ Aab titer became negative in seven patients (46%) after treatment. This was not observed in the group without AZA. This reduction in Anti-IFN-γ Aab titers suggests that maintenance therapy with AZA may have progressively inhibited the production of Anti-IFN-γ Aab. A previous study found that Anti-IFN-γ Aab titer was related to disease activity, as a lower titer was associated with a higher chance of remission [ 17 , 18 ]. Underlying this finding is the hypothesis that Anti-IFN-γ Aab binds to IFN-γ, thus impairing the IL-12- IFN-γ pathway, causing susceptibility to opportunistic infective agents, particularly NTM [ 19 ]. Conversely, suppressing Anti-IFN-γ Aab production maintains an intact IL-12–IFN-γ pathway, thereby reducing the risk of infections.

AZA was prescribed as maintenance therapy after clarifying disease remission following induction regimens or conventional antimicrobial treatments. The initial dose of AZA was 50 mg daily, and subsequent dose adjustments were evaluated by clinical and laboratory biomarkers that indicated clinical remission, including white blood cell count, CRP, and IL-6 levels [ 5 ]. The average dose of AZA in our study was 0.85 (± 0.13) mg/kg/day or 50 mg/day, which is slightly lower than the doses commonly used in other autoimmune diseases, which typically range from 1 to 2.5 mg/kg/day or 50–100 mg/day [ 20 ]. The lower average dose of azathioprine reflects a cautious titration approach, as TPMT and NUDT15 genotyping were not performed universally. Dose adjustments were made based on individual clinical responses, safety monitoring (including CBC, liver, and renal function), and biomarkers of disease activity such as CRP, ESR, IL-6, and anti–IFN-γ titers.

A combination of prednisolone and AZA was administered as an optional maintenance therapy in some patients. Oral prednisolone was prescribed in 4 (26.7%) patients in the AZA group with a median dose of 5.95 (5.16–7.41) mg/day for 276 (219–1172.25) days. However, Yang et al. reported that high prednisolone doses and long-term use increased the risk of opportunistic infections [ 21 ]. Two (50%) patients who received oral prednisolone had breakthrough infections.

The results of our study posed major implications for managing Anti-IFN-γ Aab disease, particularly for individuals who are unable to afford anti-CD20 or anti-CD38 therapies. While bortezomib depletes plasma cells directly, which leads to a reduction in Anti-IFN-γ Aab levels, it has little to no effect on conditions characterized by true polyclonal antibody responses. Many immune-associated illnesses, such as multiple myeloma and immune thrombocytopenia, may display “polyclonal” antibodies in laboratory tests; however, the pathogenic antibody population is primarily oligoclonal or driven by autoreactive plasma cells, making bortezomib’s mechanism relevant in these contexts [ 22 ]. In contrast, AZA exerts a broader suppression of lymphocytes, making it a safer and more practical option for long-term maintenance therapy. This may make AZA more suitable for treating anti-IFN-γ antibody disease. However, there remains a knowledge gap regarding whether the antibodies involved in this condition are derived from monoclonal or polyclonal sources. Moreover, AZA has been reported to be an effective treatment in IgG4-related diseases, according to Pretis et al. AZA maintenance therapy in such a study was able to prevent relapses in autoimmune pancreatitis when prescribed alongside prednisone [ 23 ]. A clinical study performed by Chawansantati et al. discovered that Anti-IFN- Aab in Chiang Mai, the Northern Thailand province, predominantly demonstrated IgG1 and IgG4 subtypes [ 24 ]. Therefore, AZA might have a positive impact on IgG4-associated illnesses, including Anti-IFN-γ Aab disease, to some extent. AZA could potentially be a viable alternative strategy for preventing disease relapses. However, breakthrough infections were observed during the AZA treatment. Our study revealed that 4 (26.67%) patients in the AZA group experienced disease relapse during maintenance therapy. Therefore, clinical and biomarker follow-ups are essential for early relapse detection and appropriate treatment adjustments.

There is limited data on the use of combination therapy with AZA and biologic agents, such as rituximab or infliximab, for patients with adult-onset immunodeficiency associated with anti–IFN-γ autoantibodies. This study utilized these agents sequentially—rituximab was used for induction, followed by AZA or other immunosuppressants for maintenance—to sustain remission and prevent relapse. The potential synergistic effect of using AZA and rituximab together, which has been observed in inflammatory bowel disease to reduce immunogenicity and prolong the efficacy of biologics, has not yet been systematically evaluated in cases of anti–IFN-γ autoantibody disease. Further prospective studies would be beneficial in determining the safety and efficacy of such combination regimens [ 25 ].

Safety and adverse effects are major concerns when treating patients with Anti-IFN-γ Aab disease, considering their immunocompromised status. However, in this study, AZA did not exhibit any adverse events during maintenance treatment.

The limitations of this study are as follows.

Its retrospective observational design and small sample size.

Diverse duration and regimens of antimicrobial therapy among study groups may affect the natural history of Anti-IFN-γ Aab disease differently and interfere with the interpretation of AZA therapy’s effects.

Lack of initial Anti-IFN-γ Aab titers for comparison before AZA therapy has been initiated; therefore, dynamic changes of the individual’s titers were not witnessed, and the titers at the last available measurement within the study window may not reflect the pure effect of AZA therapy.

Minor side effects may have been underreported or not systematically recorded.

In this study, none of the patients received alternative oral immunosuppressive agents such as mycophenolate mofetil or methotrexate. As a result, a comparative analysis to confirm the efficacy of AZA monotherapy during the maintenance phase was not feasible due to the limited number of participants, which reflects the rarity of adult-onset immunodeficiency associated with anti–IFN-γ autoantibodies.

However, data were derived from a cohort registry database of Anti-IFN-γ Aab, which enhanced the reliability and validity of the findings. Randomized controlled trials should be conducted in future studies to provide more evidence.

Conclusion

AZA was associated with prolonged remission in Anti-IFN-γ Aab disease, significantly extending the duration of disease remission and reducing relapse rates. Despite the occurrence of some breakthrough infections, AZA demonstrated a favorable safety profile.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

None.

Abbreviations

Anti-interferon-gamma autoantibody

Azathioprine

C-reactive protein

Erythrocyte sedimentation rate

Interferon-gamma

Interleukin-6

Interleukin-12

Interquartile range

Intravenous cyclophosphamide

6-mercaptopurine

6-thioguanine

Author contributions

WL and PR conceptualized the study. WL and PR designed the study protocol. WL and SO performed data extraction. WL and PR verified the data. WL and CA performed the data analysis. WL and PR drafted the paper, with critical inputs from PP, PN, and PC. All authors had full access to all the data in the study, critically revised the manuscript, accepted responsibility to submit for publication, and gave approval for the final version to be published.

Funding

Open access funding provided by Mahidol University. This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

Data supporting the conclusions of this article are included within the article. The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The study complied with the Declaration of Helsinki. Ethical approval (No. MURA2023/354) was granted by the Research Committee of the Faculty of Medicine Ramathibodi Hospital, Mahidol University, and the requirement for informed consent was waived because of the retrospective nature of the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Supplementary Materials

Supplementary Material 1

Data Availability Statement

Data supporting the conclusions of this article are included within the article. The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request.