SMJ

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Volume 75, Number 9, September 2023

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ORIGINAL ARTICLE REVIEW ARTICLE

Siriraj Medical Journal

The world-leading biomedical science of Thailand

ORIGINAL ARTICLE‌

612

Influence of Online Dating Apps on Sexual Risk Behaviors among Homosexual and Bisexual Adolescents and Youths in Thailand: An Online Cross-sectional Survey

SMJ

Siriraj Medical Journal

The world-leading biomedical science of Thailand

Volume 75 Number 9

September 2023

Chaloempong Thunyapipat, Supinya In-iw, Boonying Manaboriboon

622 Increased Serum Neutrophil Lymphocyte Ratio Raises the Risk for Peripheral Diabetic Neuropathy in Type 2 Diabetes Mellitus Patients

Anak Agung Ayu Agung Pramaswari, I Made Oka Adnyana, I Putu Eka Widyadharma, Ketut Suastika

629 Outcomes of Per-Oral Endoscopic Myotomy in the Treatment of Esophageal Achalasia: Over One Hundred Cases in a Single Tertiary Center

Kannikar Laohavichitra, Jerasak Wannaprasert, Thawee Ratanachu-ek

638 Bedaquiline Effect Towards QT Interval in Drug Resistant Tuberculosis (DR-TB): A Systematic Review

Arya Marganda Simanjuntak, Rahmadini Aulia, Dhewa Triguna Banjarnahor, Riski Dimas Harianja

646 Evaluating Risk Factors for Cumulative Life Course Impairment in Psoriasis using Patient-Acceptable Symptom State and European Quality of Life 5 Dimensions (EQ-5D)

Leena Chularojanamontri, Chanisada Wongpraparut, Narumol Silpa-archa, Chayada Chaiyabutr, Supisara Wongdama, Praveena Chiowchanwisawakit

655 The Efficacy of Preoperative Tamsulosin on Ureteroscopy Access in Pediatrics: A Systematic Review and Meta-Analysis

Nicholas Andrian Singgih, Jacinda Risha Oktaviani, Raden Honggo Pranowo Sampurno Secodiningrat, William Adipurnama, Egi Edward Manuputty, Kevin Tandarto

665 Integrative Health Promotion Model in Leprosy Prevention and Control Programs to Improve Quality of Life for Leprosy Survivors

Reny Nugraheni, Bhisma Murti, Muhammad Eko Irawanto, Endang Sutisna Sulaeman, Eti Poncorini Pamungkasari

674 Validity and Reliability of a Thai Behavioral and Emotional Screening tool for Children with Enuresis (TBEST-E)

Varis Manomaivong, Prakasit Wannapaschaiyong, Sudarat Sirisakpanit, Jeeranan Kantasorn, Jariya Tarugsa, Nuntawan Piyaphanee, Sasitorn Chantaratin

680 Predicting Progression to Hypervascular HCC in Hypovascular Hypointense Nodules in Gadoxetic Acid-enhanced MR Images in Patients with Chronic Liver Disease

688

Radiopharmaceuticals for Positron Emission Tomography Imaging of Amyloid: Research and Clinical Applications in Thailand

Tossaporn Siriprapa, Tanyaluck Thientunyakit, Juri Gelovani

REVIEW ARTICLE

Wanwarang Teerasamit, Suchanya Hongpinyo, Ranista Tongdee, Voraparee Suvannarerg

SMJ

SIRIRAJ MEDICAL JOURNAL

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Executive Editor: Apichat Asavamongkolkul Editorial Director: Aasis Unnanuntana

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Varut Lohsiriwat, Mahidol University, Thailand

Andrew S.C. Rice, Imperial College London, UK

International Editorial Board

Morris Solomon Odell, Monash University, Australia

Anusak Yiengpruksawan, The Valley Robotic Institute, USA Barbara Knowles, The Jackson Laboratory, USA Christopher Khor, Singapore General Hospital, Singapore Ciro Isidoro, University of Novara, Italy

David S. Sheps, University of Florida, USA

David Wayne Ussery, University of Arkansas for Medical Sciences, USA Davor Solter, The Jackson Laboratory, USA

Dennis J. Janisse, Medical College of Wisconsin, USA

Dong-Wan Seo, University of Ulsan College of Medicine, Republic of Korea Folker Meyer, Argonne National Laboratory, USA

Frans Laurens Moll, University Medical Center Ultrecht, Netherlands

G. Allen Finley, Delhousie University, Canada

George S. Baillie, University of Glasgow, United Kingdom

Gregory Bancroft, London School of Hygiene of Tropical Medicine, United Kingdom Gustavo Saposnik, St. Michael’s Hospital, Canada

Harland Winter, Harvard Medical School, USA

Hidemi Goto, Nagoya University Graduate School of Medicine, Japan Ichizo Nishino, National Institute of Neuroscience NCNP, Japan Intawat Nookaew, University of Arkansas for Medical Sciences, USA James P. Doland, Oregon Health & Science University, USA

John Damian Smith, Texas A&M University-San Antonio, USA John Hunter, Oregon Health & Science University, USA

Juri Gelovani, Wayne State University, USA

Karl Thomas Moritz, Swedish University of Agricultural Sciences, Sweden Kazuo Hara, Aichi Cancer Center Hospital, Japan

Keiichi Akita, Tokyo Medical and Dental University Hospital, Japan Kym Francis Faull, David Geffen School of Medicine, USA

Kyoichi Takaori, Kyoto University Hospital, Japan Marcela Hermoso Ramello, University of Chile, Chile Marianne Hokland, University of Aarhus, Denmark

Matthew S. Dunne, Institute of Food, Nutrition, and Health, Switzerland Mitsuhiro Kida, Kitasato University & Hospital, Japan

Moses Rodriguez, Mayo Clinic, USA

Nam H. CHO, Ajou University School of Medicine and Hospital, Republic of Korea Nima Rezaei, Tehran University of Medical Sciences, Iran

Noritaka Isogai, Kinki University, Japan

Paul James Brindley, George Washington University, USA

Pauline Mary Rudd, National Institute for Bioprocessing Research and Training Fosters Avenue Mount Merrion Blackrock Co., Dublin, Ireland

Peter Hokland, Aarhus University Hospital, Denmark

Philip A. Brunell, State University of New York At Buffalo, USA Philip Board, Australian National University, Australia

Richard J. Deckelbaum, Columbia University, USA Richard W. Titball, University of Exeter, USA Robert W. Mann, University of Hawaii, USA

Robin CN Williamson, Royal Postgraduate Medical School, United Kingdom Sara Schwanke Khilji, Oregon Health & Science University, USA

Seigo Kitano, Oita University, Japan

Shomei Ryozawa, Saitama Medical University, Japan Shuji Shimizu, Kyushu University Hospital, Japan

Stanlay James Rogers, University of California, San Francisco, USA Stephen Dalton, University of Georgia, USA

Sue Fletcher, Murdoch University, Australia

Tai-Soon Yong, Yonsei University, Republic of Korea Tomohisa Uchida, Oita University, Japan

Victor Manuel Charoenrook de la Fuente, Centro de Oftalmologia Barraquer, Spain Vincent W.S. Chan, University of Toronto, Canada

Wen-Shiang Chen, National Taiwan University College of Medicine, Taiwan Wikrom Karnsakul, Johns Hopkins Children’s Center, USA

Yasushi Sano, Director of Gastrointestinal Center, Japan Yik Ying Teo, National University of Singapore, Singapore Yoshiki Hirooka, Nagoya University Hospital, Japan

Yozo Miyake, Aichi Medical University, Japan Yuji Murata, Aizenbashi Hospital, Japan

Ampaiwan Chuansumrit, Mahidol University, Thailand Anuwat Pongkunakorn, Lampang Hospital, Thailand Jarupim Soongswang, Mahidol University, Thailand Nopphol Pausawasdi, Mahidol University, Thailand Nopporn Sittisombut, Chiang Mai University, Thailand Pa-thai Yenchitsomanus, Mahidol University, Thailand Pornchai O-Charoenrat, Mahidol University, Thailand Prapon Wilairat, Mahidol University, Thailand Puttinun Patpituck, Mahidol University, Thailand Rungroj Krittayaphong, Mahidol University, Thailand Saranatra Waikakul, Mahidol University, Thailand

Editorial Board

Sayomporn Sirinavin, Mahidol University, Thailand Suneerat Kongsayreepong, Mahidol University, Thailand Supakorn Rojananin, Mahidol University, Thailand Surapol Issaragrisil, Mahidol University, Thailand

Suttipong Wacharasindhu, Chulalongkorn University, Thailand Vasant Sumethkul, Mahidol University, Thailand

Vitoon Chinswangwatanakul, Mahidol University, Thailand Watchara Kasinrerk, Chiang Mai University, Thailand Wiroon Laupattrakasem, Khon Kaen University, Thailand Yuen Tanniradorn, Chulalongkorn University, Thailand

Journal Manager: Nuchpraweepawn Saleeon, Mahidol University, Thailand

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Office: His Majesty the King’s 80th Birthday Anniversary 5th December 2007 Building (SIMR), 2nd Fl., Room No.207 Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand Tel: 02-419-2888 Fax: 02-411-0593 E-mail: sijournal92@gmail.com

Influence of Online Dating Apps on Sexual Risk Behaviors among Homosexual and Bisexual Adolescents and Youths in Thailand: An Online Cross-sectional Survey

Chaloempong Thunyapipat, M.D.*, Supinya In-iw, M.D.**, Boonying Manaboriboon, M.D.**

*Department of Pediatric, Maharat Nakhon Ratchasima Hospital, Nakhon Ratchasima 30000, Thailand, **Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

ABSTRACT

Objective: The internet and social media enhance communication, education, and social connection among users; however, some adverse effects on health are notable, particularly sexual risk engagement and mood problems. Mobile dating applications (apps)/websites facilitate high sexual-risk access, particularly among lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals. Recognition of the characteristics of using these platforms and identifying factors related to high sexual risk among LGBTQ youths will facilitate both targeting of those at risk and subsequent intervention.

Materials and Methods: Adolescents and youths were invited to voluntarily join this study, scan the QR code, and anonymously complete the questionnaires. These validated questionnaires were launched online via a popular platform among LGBTQs during 2017-2018. Multiple logistic regression was employed to identify factors independently associated with high sexual risk among study subjects.

Results: Of 360 participants (mean age: 21±2.8 years, range: 11-25), 60.8% self-reported as homosexual, and the rest were bisexual. Median dating app/website usage was 2 (range 1-10). Two-thirds (62.8%) met partners from those e-platforms, and most (79.6%) developed a sexual relationship. Over half (52.2%) did not use a condom, and one-third (30.6%) abused substances during sex. Poor condom compliance, multiple partners, and substance use were strongly associated with individuals who used >2 apps for longer than 3 years. Depression susceptibility was 32.2%, and was related to condom-use failure (p=0.01).

Conclusion: Among LGBTQs, the greater the number and longer time exposed to dating apps/websites, the higher the number of sexual risk behaviors. Moreover, unsafe sex increased among individuals at risk for depression.

Keywords: Bisexual; dating apps; homosexual; men who have sex with men (MSM); social media (Siriraj Med J 2023; 75: 612-621)

INTRODUCTION

Social media offers numerous benefits and perceived advantages for adolescents, including improved health literacy and communication skills. However, its excessive use can lead to undeniable social and medical problems,1

such as cyberbullying, internet addiction, sleep problems, depression,2 and increasing exposure to pornography and sexual risk behaviors.1 In particular, social network dating in which individuals met online resulted in increased possibility of random, impromptu sexual encounters,

Corresponding Author: Boonying Manaboriboon

E-mail: boonying.man@mahidol.ac.th, drboonying@gmail.com

Received 14 July 2023 Revised 11 August 2023 Accepted 13 August 2023 ORCID ID:http://orcid.org/0000-0002-1219-950X https://doi.org/10.33192/smj.v75i9.264171

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

which, in turn, led to unplanned, unprotected, and undiscerned sexual intercourse and sexual behaviors. Among men who have sex with men (MSM), high- risk sexual activity is frequently linked to substance abuse. Notably, misuse of prescription analgesic pills and muscle relaxants was significantly associated with engaging in receptive unprotected anal intercourse.3 Other substances were used to enhance sexual stamina while performing anal sex, such as phosphodiesterase type 5 inhibitor.4 Extensive social media use correlated with high-risk sexual activities. Smith LW et al. found a growing association between exposure to sexually explicit websites or “sexting” by young people and condomless sexual intercourse (SI), recent sexual activity, alcohol and drug use prior to SI, and having multiple recent sexual partners.5 Furthermore, adolescents who shared sexual photos were more likely to have low self-esteem than their demographically similar peers.6

Sexting posed a specific risk to the MSM and bisexual population, as they extensively used geo-social mobile dating apps, granting greater access to potential sexual partners who lived nearby or were currently in close proximity. Previous research found that men who used online dating apps were more likely to seek sexual encounters rather than romantic relationships.7 Moreover, the length of use of these dating apps was associated with increased likelihood of high-risk condomless anal intercourse.8 Therefore, individuals who used geo-social apps for finding sexual partners were at greater risk for sexually transmitted infections, such as gonorrhea and chlamydia infection, when compared to individuals who met their partners in person.9

Sexual risk behaviors were also associated with patterns of geo-social dating app usage. Men who reported using 3 or more websites or apps to meet sex partners were significantly more likely to report anal intercourse and condomless anal sex within the past 3 months.10 Finally, the use of such technology was also associated with increased likelihood of having sex exchanged for food, drugs, or a place to stay within the past 3 months.11 In Thailand, the use of online social networking

has become increasingly popular over the past decade. The use of social media apps also increased from 33.2% to 86.8% in 2013 and 2016, respectively.12,13 At the same time, increased sexual health risks were well-reported, especially among sexual minorities. It was estimated that there are 185,000 MSMs living in metropolitan Bangkok, and more than 75,600 transgenders living in Thailand. The median HIV prevalence among these two groups was estimated at 9.15% and 12.7%, respectively. A 2015 study by UNICEF found that 39% of young transgender

people had commercial sex. Moreover, although condom use among MSMs and transgenders remained high at 82-84%, new infections had not declined14, and the rate of HIV transmission in young MSMs aged less than 25-years-old remained 12.1%.4 As such, the impact of mobile dating apps on this particular phenomenon remain unknown.

The study aimed to assess the association between mobile dating app usage and sexual risk behaviors among Thai homosexual and bisexual adolescents and youths. It also evaluated the links between sexual risk behaviors, self-esteem, and depression in the participants.

MATERIALS AND METHODS

Participants

We conducted a cross-sectional survey among adolescents and youths aged 11 – 25 years who identified themselves as homosexual, bisexual, or queer. Survey data was obtained during 17 May 2017 to 16 May 2018. Research posters were placed in large medical care centers in Bangkok, including the Adolescent Clinics at Siriraj Hospital and Ramathibodi Hospital, the Gender Variation Clinic at Ramathibodi Hospital, the Silom clinic at the Hospital for Tropical Diseases, the MSM Clinic at Bangrak Hospital, the Tangerine Clinic at the Thai Red Cross AIDS Research Center, and at the Rainbow Sky Association of Thailand Health Center. Study participants were also recruited via an advertisement in a popular online forum (www.pantip.com), and in an online chat room (www.lovecarestation.com). Those who were interested could voluntarily access the survey via a conspicuously visible QR code. Once logged in, the study information was visible, and participants were asked to complete a 62-item electronic questionnaire (provided in Thai), which took about 15-20 minutes to complete. Participants could decide whether they wanted to continue or not. Study consent was automatically obtained by way of a participant’s voluntary decision to response the survey. Due to the anonymous log-in process, parental consent for participants aged less than 18 years was not required. Upon completion of the survey, a gift of 100 Thai baht in the form of a LINE pre-paid card (US$ 3.2) was sent to the email address provided by each participant. For sample size calculation, no previous study had reported the correlation coefficient value for this population. Considering other similar studies with 90-350 participants, the sample size for this study was set to at least 350.

The research methodology for this study was approved by the Ethical Review Board of the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand [COA no. Si 264/2017] prior to initiation of the study.

Measurement

Survey questions were designed to collect demographic and lifestyle data, apps or website usage patterns, and sexual risk behaviors. Collected data included age, sexual orientation, marital status, education, occupation, and household income. Dating apps or website usage patterns within the previous 12 months were obtained using the number of apps or websites (multiple selectable choices with spaces for naming all dating apps or websites used), onset and duration of knowing apps, purpose of use, online day(s), online time(s), duration of use on weekdays, and duration of use on weekends. Sexual risk behaviors included inconsistent condom use, number of partners within the previous one and twelve months, number of previous partners, history of sexual transmitted infections (STIs), and history of substance use during sexual intercourse (SI). The developed questions were then tested for content validity by three experts (a child and adolescent psychiatrist, a gynecologist, and an adolescent medicine physician). The questions were then put to 33 unidentified participants to check for reliability and internal validity. The Cronbach’s alpha coefficient was

0.95. Rosenberg Self-Esteem Scale, Thai version15 with 10 items was used to assess the self-esteem of all participants (Cronbach’s alpha: 0.86), with a higher score indicating higher self-esteem. Groups with low, moderate, and high self-esteem were classified by mean score. For depression screening, the 20-item self-report Center for Epidemiologic Studies-Depression Scale (CES-D), Thai version16 was used. A score higher than 22 indicated a person at risk for depression (Cronbach’s alpha: 0.86). The completed questionnaires were analyzed.

Statistical analysis

The descriptive data were shown as mean plus/ minus standard deviation, median and range, or number and percentage. Chi-square and independent t-tests were used to test differences between two groups, and statistical significance was defined as p-value less than or equal to 0.05. To identify association between mobile dating apps or website usage patterns and sexual risk behaviors, we used Spearman’s correlation coefficient

(r). The factors associated with sexual risk behaviors were reported as crude and adjusted odds ratio with their respective 95% confidence interval (CI). Multiple logistic regression models were constructed for each exposure of interest, including age, biological sex, sexual orientation, education, occupation, and income, which were all previously found to be associated with sexual risk behaviors. The statistical analyses were conducted using SPSS version 18™ (licensed to Mahidol University).

RESULTS

Targeted recruitment

Out of 401 respondents, 360 completed the survey, resulting in an 89.7% response rate. Of those, 219 (60.8%) self-identified as homosexuals, 110 (30.6%) as bisexuals, and the remaining 31 (8.6%) as queer or not sure about their sexual orientation. Table 1 showed the demographic and lifestyle characteristics of study participants. The mean age was 21 years. The homosexual group was significantly older than the bisexual group (21.3±2.6 vs. 20.6±2.9, respectively; p=0.03). Most participants (75%) were in a relationship prior to the initiation of this study. Over half were studying (55.3%), and 62.8% had low income (<15,000 Thai baht/month).

Dating app or website usage patterns

The median number of dating- apps/websites used by study participants was 2 (range: 1-10). The most popular website for finding sex-partners was Google. The dating apps and websites reported by participants were shown in Fig 1. Weekends were the most common online days, and during 5 to 10 pm was the most popular time period for searching out dating partners (Fig 2). The majority of participants (78.1%) used dating apps to find friends, whereas one-third used them to find sexual partners. Subgroup analysis revealed homosexual males to be significantly more likely than homosexual females to use dating apps to find sex partners (p<0.001). In addition, bisexual males were significantly more likely to use dating apps to find sex partners than homosexual males (p=0.037), while homosexual females were significantly more likely to use these apps to find a partner for a long-term relationship than bisexual females (X2 5.42, p=0.02).

Sexual risk behavior

In our study population, the mean age at first SI was 17.6±2.8 years. About two-thirds (62.8%) of subjects met with persons they found via dating apps, and most of those (79.6%) had SI with their apps partner. Among the homosexual group, males were significantly more likely to meet (p<0.001) and have SI (p<0.001) with an app partners than females. About half (52.2%) reported no condom use during SI with apps partners. About one- third (30.6%) of participants used substances during SI. The most common substance used was alcohol (83.6%). The median number of previous apps partners within 12 months was 4, and the median number of concomitant apps partners (within the previous 30 days) was 1 with a range of 0 to 22. Duration of familiarity with the dating apps was strongly associated with duration of dating

Sexual orientation

TABLE 1. Demographic and lifestyle characteristics of adolescents and youths aged 11-25 years grouped by sexual orientation.

Sexual orientation

TABLE 1. Demographic and lifestyle characteristics of adolescents and youths aged 11-25 years grouped by sexual orientation. (Continue)

* 1 USD = 32.507 Thai baht (2017)

Abbreviations: SD, standard deviation; USD, United States dollars; App(s), application(s); SI, sexual intercourse; STD, sexually transmitted disease; CES-D, Center for Epidemiologic Studies Depression Scale

Fig 1. Dating apps/websites accessed among study adolescents and youths.

Fig 2. Days (a) and times (b) online among subgroup participants.

(a)

(b)

platform use during the weekdays and weekend (p<0.001). Moreover, those who used dating apps during the weekday were also more likely to use them during the weekend (r=0.80, p<0.05) (Table 2). In addition, if a study subject currently had sex partners that they became acquainted with via dating apps, they were significantly more likely to have had app-partners before within that year (r=0.67, p<0.001).

Table 3 showed the factors significantly associated with specific sexual risk behaviors (inconsistent condom use, recent multiple apps sex-partners, and substance use during SI). After adjusting for age, biological sex, sexual orientation, education, occupation, and income, participants who used ≥2 apps/websites were twice as likely to have inconsistent condom use [OR: 2.131, 95% CI: 1.047-4.334], and 2.8 times more likely to use drug

TABLE 2. Spearman’s correlation coefficient of dating app/website usage patterns.

A p-value<0.05 indicates statistical significance* and p<0.01 indicated strongly statistical significance**

TABLE 3. Factors associated with various sexual risk behaviors.

*Adjusted for age, biological sex, gender orientation, education, occupation, and income

A p-value<0.05 indicates statistical significance* and p<0.01 indicated strongly statistical significance**

Abbreviations: OR, odds ratio; CI, confidence interval; SE, standard error; App(s), application(s); SI, sexual intercourse

during SI [OR: 2.807, 95% CI: 1.172-6.725]. History of

no-condom use [OR: 90.348, 95% CI: 26.373-309.509]

and having positive depression screening [OR: 2.436, 95% CI: 1.231-4.821] were factors that had higher odds that a study subject would have sex without barrier method. Moreover, those who used dating apps for a long time and those who practiced unsafe sex (no condom use or use of substances while having sex) also had a higher chance of having multiple sex partners. Lastly, participants who regularly had a minimum of 2 sex partners had a greater probability of taking any substance while having SI [OR: 3.144, 95% CI: 1.487-6.646]. These results strongly confirm that duration of use these kinds of dating apps/ websites, and the number of dating apps used strongly significantly associated with high sexual risk behaviors among homosexual and bisexual adolescents and youths.

Self-esteem and depression

The mean score of the Rosenberg self-esteem scale was 28.9±4.8. Sixty-eight participants (18.1%) showed low self-esteem (scores less than 25) with no statistical difference among the homosexual, bisexual, and queer groups. No association between low self-esteem and sexual risk behaviors was found. Around one-third of each group had positive depression screening. Those at risk for depression were associated with inconsistent condom use (X2 9.05, p<0.01), and were twice as likely to use no condom when compared to the group without depression (OR: 2.61, 95% CI: 1.36-5.02; p<0.01)

(Table 3).

DISCUSSION

This paper described the patterns and relationships specific to geo-social mobile dating apps among the homosexual, bisexual, and queer adolescents and youths in Thailand. Our findings demonstrated that these populations have used several dating apps/websites for a few years, that they spent twice as much time during the weekend compared to during the week, and that they accessed these platforms mostly at night. Interestingly, most of the dating apps/websites used were originally created in English, which suggests that these populations were well- educated or that at least they understood English. This hypothesis was supported by the fact that over 80% of our participants completed at least high school. Extensively use of geo-social mobile dating apps provided greater access to nearby potential sexual partners, which was found to pose a special sexual risk to the MSM, lesbian and bisexual populations. More than three-fourths of our target populations already had a sexual relationship and had their sexual debut by the end of middle adolescence

(at age 17.5-17.8 years). Most participants used mobile dating apps to search for sexual partners, which is similar to previous research. People used online dating apps to seek sexual relationships, and men were more likely to seek out a sexual encounter rather than a romantic relationship.7 However, the Thai youths in this study tended to seek friends and romantic relationships from dating apps more than finding sexual partners when compared to previous study.6 The data from our study showed that the more study participants used these dating apps, the more likely they were to engage in sexual risk behaviors. In addition to inconsistent condom use and unawareness of their partner’s sexual risk, our study identified other high-risk sexual behaviors, such as group sex or ‘sex party or swinging sex’, substance use when having sex, and a large number of sex partners (22 partners in a month or a hundred in a year). Consistent with previous study, we found condomless anal intercourse to be more common among low-education people who spent more time using dating apps.8 In addition, a small number of bisexual and homosexual females reported no condom use during sex, which may be due to a lack of education, unawareness of sexual transmitted disease, or misunderstanding that condom is only for males.17

Compatible with another report18, one-third of our study participants reported using substances while having sex, and alcohol was the most common substance used followed by vasodilator medication (sildenafil), methamphetamine, and cannabis, sequentially. It’s worth noting that cannabis was not legally declared “free” during the study. Access to alcohol was not difficult, but sildenafil required a physician specialist’s prescription, and amphetamine and cannabis were illegal in Thailand, which suggested illegitimate sourcing for all (including under age for alcohol) or most substances. Those using substances were more likely to be employed, bisexual, using many dating apps for a long time, spending more time online, and currently having multiple partners from dating apps. Generally similar to other previous reports19,20, individuals who had positive screening for depression were more likely to demonstrate condom noncompliance. Depression was also shown to increase sexual risk and diminish self-efficacy towards condom use among MSM population.21 In addition to having sex to cope with sadness, when feeling depressed, people had less concentration, which could reduce sexual risk perception that could lead to forgetting to use a condom.22,23

Our study demonstrated association between the use of dating apps/websites and sexual risk behaviors among bisexual and homosexual adolescents and youths population. The more exposure they had to these dating

platforms, the more sexual risk they experienced. Therefore, sexual risk prevention that specifically focuses on dating apps/ websites is suggested. First, exposure to dating apps or sexually explicit websites should be delayed in children and adolescent population. Second, educate children and adolescents to postpone their sexual debut until the appropriate age or relationship, and emphasize the important of a ‘no condom, no sex’ approach to SI decision-making. In addition to family, school was shown to be another effective environment for helping students develop the confidence to say “No” to sex, to understand the consequences of unplanned sex, and how to minimize sexual risk, including substance use.24 Legal mandating of pop-up messages, such as a warning to engage in safe sex, should be considered for dating apps/websites. Finally, early detection of depression and treatment may help to reduce possible future sexual risk.

Limitations

This study has some mentionable limitations. Firstly, since this was a self-report questionnaire-based study, certain recall bias among study participants was possible. Secondly, the authors provided a LINE pre-paid card to participants who provided their email addresses as a token of gratitude for their cooperation. However, this could be seen as a biased incentive favoring a specific group. Thirdly, the authors acknowledged the delayed timing of publication but emphasized that the study’s uniqueness and relevance persist for Thailand and neighboring countries with similar social and cultural norms, contrasting to developed countries where “sexual health/sexuality or gender minorities” issues are more advanced. Lastly, recruiting participants from specific locations serving sexual-minority adolescents and youths may introduce bias towards mental health and substance use issues, potentially inflating their prevalence in the study. In addition to the valuable findings from this study, an additional strength of this study is proof of the effectiveness of the study design. For researchers who set forth to study these same or similar objectives in their respective country (especially in the developing world), we recommend an anonymous online approach that is user-friendly, and the use of an attractive premium that can be rapidly and easily redeemed as a thank you gift to the respondent.

CONCLUSION

The patterns of use of online dating apps/websites was found to be significantly related to high sexual risk behaviors among homosexual and bisexual adolescents and youths. The longer they used and the more they were

exposed to these kinds of apps/websites, the higher the likelihood that they would present sexual risk behaviors, particularly having recent multiple partners, inconsistent condom use, and using substance while having sex. In addition, almost one-fifth of this population had low self-esteem, and around one-third were at-risk for depression, and depression would increase the risk of unsafe sex practices.

ACKNOWLEDGEMENTS

The authors gratefully acknowledge the adolescents and youth that volunteered to participate in this study; Assoc. Prof. Chulathida Chomchai and Mr. Kelvin Jones for their assistance with language editing; and, Ms. Julaporn Pooliam for her assistance with statistical analysis.

Conflict of interest declaration

The authors hereby declare no personal or professional conflicts of interest regarding any aspect of this study.

Funding disclosure

This study was supported by a grant from the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand [grant no. (IO) R016031048].

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7. Goedel WC, Duncan DT. Geosocial-Networking App Usage Patterns of Gay, Bisexual, and Other Men Who Have Sex With Men: Survey Among Users of Grindr, A Mobile Dating App. JMIR Public Health Surveill 2015;1(1):e4.

8. Lorimer K, Flowers P, Davis M, Frankis J. Young men who have sex with men’s use of social and sexual media and sex-risk associations: cross-sectional, online survey across four countries.

   
   

   Sex Transm Infect 2016;92(5):371-6.

9. Beymer MR, Weiss RE, Bolan RK, Rudy ET, Bourque LB, Rodriguez JP, et al. Sex on demand: geosocial networking phone apps and risk of sexually transmitted infections among a cross-sectional sample of men who have sex with men in Los Angeles County. Sex Transm Infect 2014;90(7):567-72.

10. Hirshfield S, Grov C, Parsons JT, Anderson I, Chiasson MA. Social media use and HIV transmission risk behavior among ethnically diverse HIV-positive gay men: results of an online study in three U.S. states. Arch Sex Behav 2015;44(7):1969-78.

11. Young SD, Szekeres G, Coates T. The relationship between online social networking and sexual risk behaviors among men who have sex with men (MSM). PLoS One 2013;8(5):e62271.

12. Thailand Internet User Profile 2013 [Internet]. Electronic transactions development agency (public organization). 2013 [cited 2016 December 20]. Available from: https://www.etda. or.th/publishing-detail/thailand-internet-user-profile-2013-th. html.

13. Thailand Internet User Profile 2016 [Internet]. Electronic transactions development agency (public organization) 2016 [cited 2016 December 20]. Available from: https://www.etda. or.th/publishing-detail/thailand-internet-user-profile-2016-th. html.

14. McKenzie Smith M, Pinto Pereira S, Chan L, Rose C, Shafran

    R. Impact of Well-being Interventions for Siblings of Children and Young People with a Chronic Physical or Mental Health Condition: A Systematic Review and Meta-Analysis. Clin Child Fam Psychol Rev 2018;21(2):246-65.

15. Wongpakaran T, Wongpakaran N. Confirmatory factor analysis of Rosenberg Self-Esteem Scale: A study of Thai student sample. J Psychiatr Assoc Thailand 2011;56:59-70.

16. Trangkasombat U, Larpboonsarp V, Havanond P. CES-D as

    a screen for depression in adolescents. J Psychiatr Assoc Thailand 1997;42(1):2-13.

17. Doull M, Wolowic J, Saewyc E, Rosario M, Prescott T, Ybarra ML. Why Girls Choose Not to Use Barriers to Prevent Sexually Transmitted Infection During Female-to-Female Sex. J Adolesc Health 2018;62(4):411-6.

18. Holloway IW. Substance use homophily among geosocial networking application using gay, bisexual, and other men who have sex with men. Arch Sex Behav 2015;44(7):1799-811.

19. Islam N, Laugen C. Gender differences in depression and condom use among sexually active Canadians. J Affect Disord 2015;174: 511-5.

20. Wim VB, Christiana N, Marie L. Syndemic and other risk factors for unprotected anal intercourse among an online sample of Belgian HIV negative men who have sex with men. AIDS Behav 2014;18(1):50-8.

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22. Shrier LA, Feldman HA, Black SK, Walls C, Kendall AD, Lops C, et al. Momentary affective states surrounding sexual intercourse in depressed adolescents and young adults. Arch Sex Behav 2012;41(5):1161-71.

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Increased Serum Neutrophil Lymphocyte Ratio Raises the Risk for Peripheral Diabetic Neuropathy in Type 2 Diabetes Mellitus Patients

Anak Agung Ayu Agung Pramaswari, M.D*, I Made Oka Adnyana, M.D.*, I Putu Eka Widyadharma, M.D.*, Ketut Suastika, M.D.**

*Department of Neurology, Faculty of Medicine Universitas Udayana, Bali, Indonesia, **Department of Internal Medicine, Faculty of Medicine Universitas Udayana, Bali, Indonesia.

ABSTRACT

Objective: Peripheral diabetic neuropathy (PDN) is among the most prevalent diabetes mellitus (DM) sequelae. PDN is a severe health issue that represents a huge social and economic burden worldwide, is associated with long- term morbidity, and diminishes the quality of life of those affected. The neutrophil-lymphocyte ratio (NLR) is a mixture of the two primary components of chronic inflammatory diseases (high neutrophils and low lymphocytes) that contribute to the production of PDN. This study aimed to demonstrate high serum NRL levels enhance the risk of PDN in type 2 DM patients.

Materials and Methods: This study employed a case-control design, collecting data from the registers and outpatient medical records of Prof. Dr. IGNG Ngoerah General Hospital type 2 DM patients who satisfied the inclusion and exclusion criteria between January 2018 and December 2019. Based on clinical neuropathy and abnormal electrodiagnostic testing, the PDN diagnosis was established. Serum NLR was collected from laboratory tests recorded by a computer.

Results: The Receiver Operating Characteristic (ROC) curve approach determined the NLR cut-off value of 2.18. High NLR substantially increased the incidence of PDN (OR 10.36; 95% CI 3.69-29.07; p≤0.001). Other characteristics evaluated, including duration of diabetes, usage of anti-diabetic medications, uncontrolled diabetes, obesity, hypertension, and dyslipidemia, were not significantly associated with the incidence of PDN. High serum NLR was an independent risk factor for PDN in type 2 DM patients (adjusted OR=10.36; 95% CI: 3.57-29.07; p≤0.001). Conclusion: Based on the findings of this investigation, it was determined that elevated serum NLR increases the risk of PDN events in patients with type 2 DM.

Keywords: Diabetes mellitus; neutrophil-lymphocyte ratio; peripheral diabetic neuropathy; risk factors (Siriraj Med J 2023; 75: 622-628)

INTRODUCTION

One of the most prevalent consequences of diabetes mellitus is peripheral diabetic neuropathy (PDN). PDN is a serious health issue representing a large social and economic burden worldwide, causing long-term morbidity and diminished quality of life for those affected.

The prevalence of diabetes globally is predicted to be around 382 million people, with the number of diabetics expected to reach 629 million by 2045.1 PDN was found in about 10% of DM patients within the first year after diagnosis, rosed to 50% after 25 years. Approximately fifty percent of DM patients experience PDN, thirty

Corresponding Author: Anak Agung Ayu Agung Pramaswari E-mail: agungpramaswari@unud.ac.id

Received 30 May 2023 Revised 14 July 2023 Accepted 18 July 2023 ORCID ID:http://orcid.org/0000-0003-1301-6311 https://doi.org/10.33192/smj.v75i9.263372

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

percent of diabetic patients suffer PDN pain (PDNP), and thirty-nine percent do not obtain treatment or disregard the PDN complaint.2,3 A lack of understanding of the pathophysiology of neuropathy impedes the management of PDN, resulting in suboptimal therapy that leads to long-term morbidity and diminishes the quality of life for patients.4 Peripheral diabetic neuropathy causes balance disturbances and increases the risk of falls, especially in the elderly.5 Foot ulcers are the leading cause of lower limb amputation, affecting around fifty percent of those with neuropathy.3

The neutrophil-lymphocyte ratio (NLR) combines the two primary components of chronic inflammatory disorders (high neutrophils and low lymphocytes). An increased neutrophil count indicates a continuous, nonspecific, damaging inflammatory activity, whereas a low lymphocyte count suggests comparatively insufficient immunological control and dormant immune pathways. Elevated NLR can show the immune system's functioning during chronic inflammatory events.6 NLR as an inflammatory biomarker in type 2 complications involving the macrovascular and microvascular systems Diabetes mellitus is an independent predictor of carotid artery intima-media thickening, and albuminuria compared to other cardiovascular risks factors such as age, male sex, smoking history, duration of diabetes, estimated glomerular filtration rate (eGFR), LDL, albuminuria-creatinine ratio, and HbA1c. NLR is also believed to be indicative of an autonomic vascular imbalance. The sympathetic nerves stimulate granulocyte release, whereas the parasympathetic nerves stimulate lymphocyte release. A greater NLR may imply a greater ratio of sympathetic to parasympathetic activity. In addition to increasing oxygen consumption and releasing proinflammatory cytokines such as IL-6 and TNF-, the sympathetic tone also stimulates smooth muscle and interstitial cell proliferation, accelerating the progression of atherosclerosis.7,8

According to a literature search undertaken by researchers, there is a lack of domestic literature and study examining the association between NLR and the increased risk of microvascular complications of DM, particularly in PDN instances. NLR examination is simple, non-invasive, available in nearly all level one healthcare institutions, and affordable. Based on this and the reviewed theoretical background, a study on a high NLR is recommended to evaluate an increase in the risk of diabetic neuropathy in type 2 diabetes patients at Prof. Dr. IGNG Ngoerah General Hospital, Denpasar.

MATERIALS AND METHODS

This study used a case-control design. Aim of this

study was to prove high NLR as the risk factor of diabetic neuropathy in type 2 diabetes patients. The odds ratio was determined by comparing two groups of subjects with type 2 DM (T2DM) who had PDN (cases) and those without PDN (controls) and then examining the serum NLR in the blood (high or low) recorded in the medical record of neuro polyclinic and internal medicine polyclinic (diabetes center) Prof. Dr. IGNG Ngoerah General Hospital, Denpasar. NLR was measured by dividing the absolute number of neutrophils by the absolute number of lymphocytes. Patients treated from January 2018 to December 2019 were the subjects of the collected data. The study included 85 types 2 DM participants who fulfilled the eligibility requirements and were divided into groups with (42 subjects) and without PDN (43 subjects). This study's sample size fulfilled the minimal sample size requirements, with 39 people in each group.

Inclusion criteria in this research included: (1) patients were diagnosed with type 2 diabetes for under five years,

(2) patients were diagnosed with PDN, (3) patients were between 40 and 80 years old, (4) gender, length of DM, type of diabetic therapy, duration of diabetes treatment, diabetes control status, nutritional status, medical history, connected full blood laboratory test, HbA1c examination, and lipid profile were included in the patient's medical record, (5) patients underwent an electrophysiological evaluation at the electro neuro-myography (ENMG) neuro polyclinic, with data indicating a PDN. The exclusion criteria for cases and controls were: (1) patients had history of chronic kidney disease, HIV infection, morbus hansen, systemic lupus erythematosus, cancer, entrapment neuropathy (carpal tunnel syndrome/CTS, cervical root syndrome/CRS), history of the spinal cord and peripheral nerve trauma, blood disease (myeloproliferative and leukemia), coronary heart disease, cerebrovascular disease, diabetic retinopathy, (2) patients had severe illness and were bleeding profusely, (3) antiretroviral, chemotherapeutic, traditional analgesic, anti-inflammatory, and anti-tuberculosis medicines were administered to individuals with neuropathy, (4) patients had history of hazardous exposure, including alcohol, pesticides, mercury, and organophosphates, are at risk for lead poisoning.

Purposive sampling was used to determine research subjects, with the researcher selecting topics based on subjective and practical considerations. Subjects in medical records that met the eligibility criteria were included in the study until the required number of samples was obtained and homogenous. The age and gender matching procedure was conducted in both groups. The Chi-Square test has

been used to test the null hypothesis in bivariate analyses involving categorical nominal independent variables and unpaired dependent variables. If the requirements for the Chi-Square test are not met, Fisher's test will be conducted. The logistic regression method has been used to examine other categorical variables that may have affected the study's results. Variables included in the multivariate analysis are those with a p-value≤0.25 in the bivariate analysis. The study data will be statistically examined using Windows SPSS version 20.

RESULTS

The case group included 42 subjects with a mean age of 59.9±1.44 years, while the control group had a mean age of 61.37±1.59 years. In both groups, men predominated, with 69% males in the case group. In the control group, the mean HbA1c was greater than in the case group (8.32±0.38 vs 7.90±0.31%). The case group had a higher median NLR value than the control group (2.99 vs 1.94) (Table 1).

TABLE 1. Fundamental characteristics of research participants.

Note: *statistically significant p ≤ 0.05

The total NLR yielded value data with a range of

0.86 to 26.83 and a median of 2.39. The ROC curve demonstrates that the NLR value has a relatively high diagnostic value, as the curve is above the 50% line. The ROC method yielded an AUC value of 77.9% (95% CI: 0.68 - 0.88; p = 0.001). The AUC value of 77.9% indicates appropriate diagnostic capacity from a statistical point of view. The ROC coordinates indicate that the NLR cutoff value of 2.18 utilized in this investigation has a sensitivity of 83.3%, specificity of 67.4%, positive predictive value (PPV) of 71.4%, and negative predictive value (NPV) of 80.5%. The research data were separated into two groups: those with serum NLR levels greater than 2.18 and those lower than 2.18.

Using an NLR cutoff value of 2.18, the relationship between elevated serum NLR as the independent variable and PDN in T2DM patients as the dependent variable was evaluated. The analysis revealed a significant association between high serum NLR and PDN in T2DM patients, with an odds ratio of 10.357 (95%CI = 3.69 – 29.07; p≤0.001), indicating that high serum NLR in T2DM patients increases the risk of PDN by 10.36 times relative to DM patients with low serum NLR in Table 2. The analysis of each component of NLR (neutrophils and lymphocytes) revealed that lymphocytes significantly increased the risk of PDN events in T2DM patients (OR

= 9.07; 95%CI=2.31-34.11; p≤0.001).

A bivariate analysis was performed between PDN in patients with T2DM and duration of DM, types of anti-diabetic drugs (ADD), uncontrolled DM, obesity, hypertension, dyslipidemia, neutrophil levels, and lymphocyte levels. Of all the variables, no significant relationship was found between other variables and PDN in T2DM patients (Table 3).

Multivariate analysis included serum NLR, dyslipidemia, neutrophil levels, and lymphocyte levels with p≤0.25 in bivariate analysis. Serum NLR was an independent risk factor for PDN in DM patients, with an odds ratio of

10.36 (95% CI: 3.57-29.07; p≤0.001) (Table 4).

DISCUSSION

This study performed an age-matching procedure at the outset of the study. However, due to data limitations, an age difference of fewer than 2 years was still included, resulting in a relatively small difference in the mean age between the two groups. This study's findings are consistent with a study by Karki et al.9 and an investigation by Suwannaphant et al.10 which found that the prevalence of PDN was highest among individuals aged 51 to 60. The prevalence and incidence of PDN increased and were directly proportional to age, with the prevalence rising by 3.2% in the 20-30 age group, 11.5% in the 40-59 age group, and 20.4% in the over-60 age group.11,12 It is related to the vascular characteristics of the peripheral nervous system that the prevalence of PDN increases with the age and duration of DM. The peripheral nervous system's reliance on vascular supply makes it susceptible to disruption.13 In this analysis, the average age of DM patients with PDN was 59-60 years, presumably owing to the significant number of patients over 60 with other comorbid diseases. They were excluded at the outset.

In this survey, it was discovered that men predominated in both categories. In China, the prevalence of PDN among women was greater than among men.6 Males are four years more likely than females to develop PDN as a complication of T2DM.14 Compared to previous studies, the variance in this study's proportion of males and females may result from demographic differences

Fig 1. ROC of serum NLR to PDN values.

TABLE 2. Bivariate analysis of NLR, neutrophils, and serum lymphocytes with PDN in DMT2.

Note: *statically significant p ≤ 0.05

TABLE 3. Bivariate analysis of other variables and PDN in patients with DMT2.

Note: DMT2: diabetes mellitus type 2

TABLE 4. Logistic regression multivariate analysis.

Note: *statically significant p<0.05

in the sampling location. The same was discovered for education in secondary school in our study. The difference in results may be because most subjects in this study reside in urban areas and generally have at least a high school education. Those with a high level of education are more aware of complications of DM, such as a PDN, and therefore are more likely to seek medical attention. Work and education are not directly related to the incidence of diabetes mellitus or neurodegenerative disease but rather to the existence of urban residents, the majority of whom are urban residents who have a lifestyle-related association.15 PDN severity correlates linearly with age, body mass index (BMI), and duration of DM, but not with HbA1c in our study.16 In this study, obesity was determined by BMI values and the results did not indicate a statistically significant increase in the risk of adverse events. In previous studies, the BMI had no statistically significant effect on the incidence of PDN in T2DM patients.17,18 Similarly, precise results were obtained for hypertension, possibly due to the large number of DM patients with hypertension at our hospital who had other complicating conditions and thus did not satisfy the criteria for sample collection.

Neutrophils are integrally connected to chronic inflammation, whereas lymphocytes reflect immune regulation pathways. The literature explaining the direct relationship between lymphocytes and the formation of PDN is scarce. Chronic hyperglycemia in DM will increase the release of reactive oxygen species (ROS) from neutrophils and decrease lymphocyte levels. Chronic hyperglycemia also directly causes diminished lymphocyte proliferation. In patients with uncontrolled

type 2 diabetes, decreased lymphocyte proliferation is more prevalent. In type 2 diabetes, the decrease in lymphocyte proliferation is due to the low expression of IL-2 receptors. CD25 deficiency is the cause of the reduced level of IL-2 receptor expression. CD25 is crucial for stimulating the IL-2 receptor to produce T cells. CD25 serves a vital role in expanding T cell cloning after antigen discovery. Antigen stimulation increases IL-2 expression because T cells are the primary proliferating cells in specific immune responses. Low levels of IL-2 inhibit lymphocyte proliferation and differentiation.10 NLR is an independent risk factor for PDN associated with diabetic microangiopathy, which impairs the nutrient supply to neuronal and Schwann cells, resulting in peripheral neuropathy due to nerve degeneration. NLR combines the two primary components of chronic inflammatory disorders (high neutrophils and low lymphocytes).6 High neutrophils were more prevalent in the PDN group, but there was no significant association with an increased risk of PDN.

In contrast, low lymphocytes substantially increased the risk of a PDN incident. Similar lymphopenia has been observed in numerous clinical and experimental studies of people with diabetes with microvascular, macrovascular, and other complications. It may be the result of increased oxidative DNA damage and lymphocyte apoptosis. Diabetes patients exhibited decreased lymphocyte proliferation due to lower IL-2 receptor expression levels. It causes a decrease in lymphocytes and an increase in neutrophils, thereby increasing the NLR.6

This study's strength is the lack of prior research on NLR and the incidence of PDN. NLR has extensively

studied DM microvascular complications such as peripheral arterial disease (PAD), diabetic retinopathy, and diabetic nephropathy.18 Still, its relationship to PDN has not been extensively studied, particularly in Indonesia so this study will add future research references. This study was also conducted by matching by design on confounding variables so that other factors contributing to the incidence of PDN can be controlled and the results of high serum NLR as an independent risk factor for PDN in patients with T2DM can be strengthened. Blood assays for evaluating NLR (a marker of ongoing destructive nonspecific inflammatory processes) or lymphocytes (relatively inactive or insufficient immune regulation) alone are less stable indicators of the functional status of the immune system than the ratio.

The limitation of this study is there were differences in treatment between the two groups, with ENMG examination not being performed in the control group, so a diagnosis of subcutaneous PDN (no visible signs of neuropathy but abnormalities in nerve conduction velocity or abnormal small fiber neuropathy examination) could not be ruled out (no visible symptoms of neuropathy but irregularities in nerve conduction velocity or abnormal small fiber neuropathy examination). In addition, the sample size is limited to a single region, so it cannot be used to characterize the population as a whole. Large-scale research is required to further evaluate the implementation of NLR in predicting PDN.

CONCLUSION

Neutrophil-lymphocyte ratio can be one of the predictors of high risk PDN in T2DM patients. Compared to T2DM patients with low serum NLR, T2DM patients with high blood NLR levels (2.18 mg/dL) had a 10-fold greater chance of developing PDN.

REFERENCES

1. Karuranga, Joao da Rocha Fernandes, Yadi Huang. Eighth edition 2017. IDF Diabetes Atlas, 8th edition. 2017.1-150 p.

2. Rajchgot T, Thomas SC, Wang J-C, Ahmadi M, Balood M, Crosson T, et al. Neurons and Microglia; A Sickly-Sweet Duo in Diabetic Pain Neuropathy. Front Neurosci. 2019;13:25.

3. Hicks CW, Selvin E. Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes. Curr Diab Rep. 2019;19(10):86.

4. Gow D, Moore P. Assessing diabetic peripheral neuropathy in primary care. Best Pract J. 2014;(61):36-47.

5. Vongsirinavarat M. Falls among Older Adults with Type 2 Diabetes Mellitus with Peripheral Neuropathy. Siriraj Med J. 2021;72(2):92-8.

6. Xu T, Weng Z, Pei C, Yu S, Chen Y, Guo W, et al. The relationship between neutrophil-to-lymphocyte ratio and diabetic peripheral neuropathy in Type 2 diabetes mellitus. Medicine (Baltimore). 2017;96(45):e8289.

7. Tracey KJ. The inflammatory reflex. Nature. 2002;420(6917): 853-9.

8. Mohammad WH, Ahmad AB, Al-Maghraby MH, Abdelrhman MZ, Ezzate S. Is neutrophil-lymphocyte ratio a novel biomarker for macrovascular and microvascular complications of type 2 diabetes? Egypt J Intern Med. 2019;31(1):1-7.

9. Karki D, Nagila A, Dhakal N, Chhetri S. Prevalence of peripheral neuropathy in diabetes mellitus and its association with therapy, ethnicity and duration of diabetes mellitus. Asian J Med Sci. 2018;10(1):72-6.

10. Suwannaphant K, Laohasiriwong W, Puttanapong N, Saengsuwan J, Phajan T. Association between Socioeconomic Status and Diabetes Mellitus: The National Socioeconomics Survey, 2010 and 2012. J Clin Diagn Res. 2017;11(7):LC18-LC22.

11. Yang W, Lu J, Weng J, Jia W, Ji L, Xiao J, et al. Prevalence of Diabetes among Men and Women in China. N Engl J Med. 2010; 362(12):1090-101.

12. Bansal D, Gudala K, Muthyala H, Esam HP, Nayakallu R, Bhansali A. Prevalence and risk factors of development of peripheral diabetic neuropathy in type 2 diabetes mellitus in a tertiary care setting. J Diabetes Investig. 2014;5(6):714-21.

13. Yagihashi S, Mizukami H, Sugimoto K. Mechanism of diabetic neuropathy: Where are we now and where to go? J Diabetes Investig. 2011;2(1):18-32.

14. Aaberg ML, Burch DM, Hud ZR, Zacharias MP. Gender differences in the onset of diabetic neuropathy. J Diabetes Complications. 2008;22(2):83-7.

15. Azmiardi A, Tamtomo D, Murti B. Factors Associated with Diabetic Peripheral Neuropathy among Patients with Type 2 Diabetes Mellitus in Surakarta, Central Java. Indones J Med. 2019;4(4):300-12.

16. Amour AA, Chamba N, Kayandabila J, Lyaruu IA, Marieke D, Shao ER, et al. Prevalence, Patterns, and Factors Associated with Peripheral Neuropathies among Diabetic Patients at Tertiary Hospital in the Kilimanjaro Region: Descriptive Cross- Sectional Study from North-Eastern Tanzania. Int J Endocrinol. 2019;2019:1-7.

17. Rahimdel A, Afkhami-ardekani M, Souzani A, Modaresi M. Prevalence of Sensory Neuropathy in Type 2 Diabetic Patients in Iranian Population ( Yazd Province ). Iran J Diabetes Obes. 2009;1(1):30-5.

18. Liu S, Zheng H, Zhu X, Mao F, Zhang S, Shi H, et al. Neutrophil- to-lymphocyte ratio is associated with diabetic peripheral neuropathy in type 2 diabetes patients. Diabetes Res Clin Pract. 2017;130:90-7.

Outcomes of Per-Oral Endoscopic Myotomy in the Treatment of Esophageal Achalasia: Over One Hundred Cases in a Single Tertiary Center

Kannikar Laohavichitra, M.D., Jerasak Wannaprasert, M.D., Thawee Ratanachu-ek, M.D.

Department of Surgery, Rajavithi Hospital, College of Medicine, Rangsit University, Bangkok, Thailand.

ABSTRACT

Objective: To study the outcomes and complications of per-oral endoscopic myotomy (POEM) in patients with esophageal achalasia.

Materials and Methods: This retrospective observational study reviewed the medical records of esophageal achalasia patients who underwent POEM between March 2013 and September 2022. One hundred and eight cases were included.

Results: A total of 108 consecutive patients were included in this study and classified into 4 groups: 30 (27.8%) as type I; 53 (49.1%) as type II; 5 (4.6%) as type III; and 20 (18.5%) as unspecified due to unsuccessful catheter placement across the esophagogastric junction. The mean patient age was 46.10±16.59, 77 (71.3%) patients were female. Ten (9.3%) of the patients had undergone prior treatment, including balloon dilation, POEM, Heller myotomy, and nitroglycerine. Technical success was achieved in 106 (98.1%) cases, clinical success was evaluated only in 88 patients who follow up more than 6 month and the median follow-up time was 20.50 months (range 6-110 months). The clinical success was accomplished in 82 (93.2%), and 26 (24.1%) patients experienced perioperative complications which were significantly associated with anterior myotomy and probably operator learning curve. One patient (1.1%) had recurrent symptoms at 24-month follow up. Gastroesophageal reflux disease (GERD) was found in 19 (21.6%) patients, all of whom responded well to proton pump inhibitors (PPIs).

Conclusion: POEM is effective and safe in long-term treatment of achalasia. Although the incidence of symptomatic GERD was slightly high, the cases were not severe and were well controlled with medication.

Keywords: Per-oral esophageal myotomy; POEM; achalasia; outcomes; complication. (Siriraj Med J 2023; 75: 629-637)

INTRODUCTION

Esophageal achalasia is an esophageal motility disorder characterized by incomplete relaxation of the lower esophageal sphincter (LES), increased LES pressure and lack of normal peristalsis of the esophagus causing symptoms of dysphagia, chest pain, regurgitation and weight loss. Diagnosis and pre-operative evaluations include esophagogastroduodenoscopy (EGD), high-

resolution esophageal manometry (HREM) and barium/ time-barium esophagography (BE/TBE). Various treatments are available for lowering LES pressure, such as nitroglycerine, balloon dilation, and botulinum toxin injection, Heller myotomy and also per-oral endoscopic myotomy (POEM), which was first performed in 2008 by Professor Haruhiro Inoue, who later published his first case series of 17 patients in 2010.1 Since then, many

Corresponding author: Kannikar Laohavichitra E-mail: niphangnga@yahoo.com

Received 12 June 2023 Revised 12 July 2023 Accepted 22 July 2023 ORCID ID:http://orcid.org/0000-0002-7546-1691 https://doi.org/10.33192/smj.v75i9.263612

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

POEM studies, including retrospective single- and multi- center reviews, systematic reviews and meta-analyses, have reported its good clinical outcomes and safety.2-7 Our center first performed POEM in March 2013 and

had conducted 108 of these operations by September 2022. In the early period, all procedures were performed by two experienced endoscopists, who later supervised operations conducted by a further 2 experienced endoscopists. This retrospective observational study aims to analyze the outcomes of our 9-year experience in a single tertiary center in terms of technical and clinical success, as well as perioperative and long-term complications, such as gastroesophageal reflux disease (GERD).

MATERIALS AND METHODS

This study was approved by Institutional Review Board (code: 66054). Medical records were retrospectively reviewed of 108 patients who underwent POEM between March 2013 and September 2022. The study included patients who had undergone the procedure after being diagnosed with achalasia from EGD, BE/TBE and/or HREM results.8-12 The exclusion criteria were factors which identified individuals as unsuitable candidates for POEM, such as those with end-stage achalasia with massive dilated and tortuous esophagus; severe heart or pulmonary disease; coagulopathy; cirrhosis with portal hypertension; and history of previous endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), or radiofrequency ablation (RFA) of esophagus.13,14 The data used for pre-operative evaluation included gender, age, duration of symptoms, prior treatment, pre-operative Eckardt score, barium column height and width recorded at 5 minutes post-swallow from TBE, and integrated relaxation pressure (IRP) from HREM. Achalasia patients were classified into 4 groups: types I, II and III (by manometric patterns characterized with the Chicago Classification), and an unspecified group (patients whose esophageal manometry failed due to unsuccessful catheter placement across the esophagogastric junction).

Further subtypes were classified as non-sigmoid and sigmoid type based on BE/TBE findings.

The procedure began with EGD for esophageal irrigation to eliminate the contents of the esophagus. Mucosal injection and incision were performed to create a submucosal tunnel appropriate for the myotomy technique and planned approach. Two different myotomy approaches were used in our department: anterior, in which the myotomy is performed at 12-1 o’clock; and posterior, at 5-6 o’clock. The choice of operative technique varied in accordance with operator preference or whether a previous myotomy by POEM or Heller technique had

been performed, in which case the opposite approach was utilized. The length of myotomy in the esophagus varied according to the type of achalasia and manometry patterns, plus 2-3 cm in the gastric site. At the end of the procedure, the mucosal incision was closed with clips.1 Technical success was defined as complete performance of all steps.15 Perioperative complications such as hypercarbia, pneumoperitoneum, subcutaneous emphysema, pneumothorax, pleural effusion, mucosal injury, perforation, or bleeding, were recorded. EGD with or without esophagogram was performed the following morning. If all mucosal clips were correctly placed and no leakage was observed, then the patients were allowed a clear liquid diet followed by a full liquid diet on the following day. The patients were discharged when they could tolerate a liquid diet, and they were advised to

resume a soft diet the following week.

Postoperative clinical evaluation was performed using Eckardt score at 1, 3, and 6 months, and then once annually.15 A score of over 3 within 6 months indicated clinical failure, while this score after 6 months was classified as recurrence.16 Testing of HREM and TBE was performed in some patients who had questionable clinical evaluation but no time specific. GERD as a long- term complication was recorded if patients presented with reflux symptoms which were relieved by taking proton pump inhibitors (PPI) or when the results of 24 hours of pH monitoring confirmed acid exposure with pH levels below 4 for over 80 minutes/day or when EGD showed evidence of reflux esophagitis or Barrett’s esophagus.17

Statistical analysis was performed using SPSS version 17.0 (SPSS Inc. Chicago IL, USA), Descriptive statistics were used to characterize populations, categorical variables were presented as number and percentage, and continuous variables were represented by mean ± standard deviation (SD) or median (range) when the data are skewed. Differences in qualitative variables between two groups were analyzed using Chi-squared test or Fisher’s exact test, while either Student’s t-test or Mann-Whitney U test was used to compare continuous variables between two groups. Multivariate analysis was performed with logistic regression model in the “Enter” method.18 Adjusted by surgical technique and subtype of achalasia and a p-value less than 0.05 was considered to be statistically significant.

RESULTS

A total of 108 consecutive patients underwent POEM. Their mean age was 46.10±16.59 years, and the majority were female (77/108, 71.3%). Twenty-nine (26.9%) had

underlying diseases such as hypertension, diabetes mellitus, reactive airway disease (asthma/COPD), hyperthyroid, cardiac arrhythmia (atrial fibrillation, sinus bradycardia, PVC), and others. All conditions were well controlled preoperatively. Thirty patients (27.8%) had achalasia type I, 53 (49.1%) had type II, 5 (4.6%) were type III, and 20 (18.5%) were unspecified type. With regard to subtype classification, 14 (13.0%) were sigmoid and 94 (87.0%) were non-sigmoid type. Median duration of symptoms was 12 months (range 2-240 months). Ninety-eight (90.7%) had had no prior treatment, while 10 patients (9.3%) had undergone previous modalities (2 pneumatic balloon dilations, 5 POEMs (3 POEMs from our hospital who were clinical failure from the first POEMs and 2 POEMs from outside hospital), 1 laparoscopic Heller myotomy, 1 open Heller myotomy, and 1 nitroglycerine). Median Eckardt score was 6 (range 0-10), and median IRP was

31.4 (range 11.5-83.6) mmHg. Preoperative TBE was conducted in 26 patients (24.07%) with median barium height 129.3 (range 34.6-242.7) mm, and median width

36.7 (range 22.8-76.4) mm as shown in Table 1.

With regard to surgical techniques and perioperative outcomes, about the myotomy technique, 26 patients (24.1%) underwent the myotomy technique using anterior approach and 80 patients (74.1%) had the posterior approach, while 2 patients’ operative reports were missing (1.9%). Median myotomy length was 9 (range 2-17) cm, and median operative time was 120 minutes (range 45-295). Technical success was achieved in 106 patients (98.1%), while 2 patients (1.9%) had severe inflammation and fibrosis of esophageal mucosa resulting in failure to create a submucosal tunnel and, therefore, an unsuccessful operation. Perioperative complications occurred in 26 patients (24.1%) as follows: pneumoperitoneum needing intraoperative needle decompression (13), subcutaneous emphysema (4), pneumothorax (2), hypercarbia (4),

perforation (2), mucosal injury (6), hypotension (1),

hypoxia (1), pleural effusion (2) and bleeding (1). All complications were resolved with symptomatic and supportive treatment, except one case of pleural effusion, which required intercostal tube drain insertion. Median length of hospital stay was 9 days (range 4-41).

TABLE 1. Preoperative demographic and clinical characteristics of the study patients.

Characteristics

Total (n=108)

n (%)

Gender

Male 31 (28.7)

Female 77 (71.3)

Age (mean±SD) 46.10±16.59

Underlying Disease

Yes 29 (26.9)

Type of achalasia

Unspecified Achalasia type I/II/III

20 (18.5)

30 (27.8)/ 53 (49.1)/ 5 (4.6)

No 79 (73.1)

Subtype of achalasia

Twenty patients (18.5%) were excluded from clinical outcomes due to follow up period less than 6 months, only the remaining 88 patients were evaluated in clinical outcomes. Median follow-up time was 20.50 months (range 6-110), median post-operative IRP decreased to 17.2 mmHg (range 0.7-73.5), median barium height fell to 30.0 mm (range 0.0-245.8), and median barium width went down to 24.8 (1.7-134.7) mm. Eighty-two patients (93.2%) had improvement of symptoms and Eckhardt score ≤ 3 and were classified as clinical successes, while 6 (6.8%) were categorized as clinical failures, as they developed symptoms and had Eckhardt score > 3 within 6 months. Three of these patients underwent laparoscopic Heller myotomy, while another 3 received POEM (which were included in the analysis as 3 patients who had prior treatment by POEM), and all 6 eventually

achieved clinical improvement. Nineteen patients (21.6%) developed GERD, and all of these improved with daily PPI use. One patient (1.1%) who developed symptoms at 24 months was classified as a case of recurrence and successfully underwent laparoscopic Heller myotomy. According to very low number of technical failure, there was no factor associated with technical success (Table 2). The patients without perioperative complication achieved clinical success higher than the patients with perioperative complication significantly on univariate analysis (p=0.027) as shown in Table 3 but it was not necessary to perform multivariate analysis due to small number of clinical failure. The perioperative complications were significantly associated with the use of the anterior myotomy technique on uni-and multivariate analysis as

shown in Table 4 and Table 5.

TABLE 2. Factors associate with technical success.

*Values were represented as n (%), mean+SD and median (min-max). The p-value from independent samples t-test and chi-square test with significant at p<0.05

**Factors associated with technical success could not be computed in pre-operative IRP, pre-operative time barium swallowing, myotomy site, myotomy length because failure group data was missing.

TABLE 3. Factors associate with clinical success.

*Values were represented as n (%), mean+SD and median (min-max). The p-value from independent samples t-test and chi-square test with significant at p<0.05

TABLE 4. Factors associate with complications.

*Values were represented as n (%), mean+SD and median (min-max). The p-value from independent samples t-test and chi-square test with significant at p<0.05

TABLE 5. Multivariate analysis of factors associated with Complication.

On multivariable analysis by logistic regression model in the “Enter” method. Adjusted by Surgical technique and Subtype of achalasia,

*significance at p<0.05.

DISCUSSION

After the excellent outcomes of the first POEM case series were reported by Professor Inoue in 20101, this procedure became accepted as a good treatment choice for achalasia. In our institute, 108 consecutive cases have been carried out with a good technical success rate of 106/108 (98.1%). The two technical failures, resulting from severe submucosal fibrosis, were unspecified type, one sigmoid and one non-sigmoid subtype. A recently published retrospective review showed that the majority of cases of submucosal fibrosis occur in type I achalasia and proposed a double tunnel method to effectively and safely reduce technical failure during POEM, improving the technical success rate from 68.3% to 98.4%.19

The short-term clinical success rate at 6-month follow up was 82/88(93.2%) patients. There was only one incidence of recurrence which was identified at the 24-month long-term follow up. At the maximum follow- up time of 110 months, the long-term clinical success rate was 92.0%, similar to the findings of two previous systematic reviews, one of which reported clinical success rates at 6-12 months, at 24 months, and at 36 months of 93.2%, 91.5% and 93.1% respectively.7 The other review found pooled clinical success at 30 to 60 months and >60 months of 87% and 84% respectively.6 This suggests that POEM is an effective treatment which yields very good results that can be maintained beyond 5 years.

Concerning about achalasia patients diagnosed despite normal IRP and outcome of treatment, Sanagapalli et al.20 suggested that, to diagnosed a subset of achalasia patients with normal IRP, but impaired LES relaxation can demonstrated by additional provocative tests using rapid drink challenge (RDC), solid swallows during HREM, and/or barium esophagogram, and the outcome of treatment exhibited equivalent to achalasia diagnosed in the conventional fashion. There are 5 patients demonstrated normal IRP in this study, one patient loss follow up and 4 patients had clinical success with a 9-103 month- follow up period.

Even though the median of post-POEM IRP was higher than 15 mmHg (17.2 mmHg) but Eckardt score was lower than 3 can be explained by a multicenter, observational cohort study reported by Hata Y et al.21 studied the associations between post-POEM HREM and the outcomes of POEM. 7% (151 of 2,171 patients) showed residual high post-POEM IRP (≥ 26 mmHg; Starlet [Starmedical Ltd, Tokyo, Japan]) still have comparable clinical outcome with low post-POEM IRP patients. The high pre-POEM IRP and gastric myotomy of ≤ 2 cm were predictive of residual of high post POEM IRP values, and a residual high post-POEM IRP not necessarily mean clinical failure and routine HREM follow-up is not recommended after POEM.

Another factor which may influence the outcome was “prior treatment”. A retrospectively study reported the effect of prior treatment on clinical outcomes with a low rate of major adverse events but increase the risk of clinical failure after POEM.22 In this study, 8 of 10 patients with prior treatment (5 POEM, 2 heller myotomy and 1 nitroglycerine) had minor perioperative complication but not statistically significant (p=0.696) and there was no technical failure and clinical failure in this group which probably due to small number of patients.

Regarding perioperative complications associated with myotomy techniques and practices used in our center, we performed POEM using the anterior approach in the first 16 cases routinely, and then moved on to the posterior approach which was then adopted as the normal technique, where technically feasible, over the next 3 years. Adverse events occurred in a total of 26 cases (24.1%), half of which resulted from use of the anterior approach, 13/26 cases (50.0%) and the majority of these

(10) occurred in the first 16 cases. A randomized pilot study and a narrative review supported the correlation between anterior myotomy and increased risk of mucosal injuries due to its need for greater scope tip angulation23,24, but the majority of findings of randomized clinical trials and systematic reviews have reported comparable outcomes

for the two approaches.25-27 In our study, the significant complications from anterior approach might be from early period of learning curve.28 The minimum threshold number of cases required for an expert interventional endoscopist to reach this plateau was around 13. Another study focusing on training 4 surgeons in the use of POEM found that the number of operations required to reach this plateau was 12 cases, after which significant reductions in dissection speed and perforation were achieved.29

GERD occurred in 19 of 88 patients (21.6%), all of whom were in the clinical success group. Some studies have claimed that the posterior approach probably has a higher incidence of GERD because it involves severance of both the circular and sling or oblique fiber, but the difference has been found to be of only borderline significance in some systematic reviews and meta-analysis.30 In our study, the incidence of GERD was also higher with the posterior (15/67, 22.4%) compared to the anterior approach (4/21, 19.0%), but this difference was also not significant (p=1.00).

Limitation of this study was retrospective study and the small number of patients.

CONCLUSION

POEM is effective and safe as a long-term treatment for achalasia. While perioperative adverse events were associated with anterior myotomy and probably surgeons’ insufficient experience in the use of the technique, these complications responded well to conservative management. Although the incidence of symptomatic GERD was slightly high at 21%, the cases were not severe and were successfully treated with to PPI.

REFERENCES

1. Inoue H, Minami H, Kobayashi Y, Sato Y, Kaga M, Suzuki M, et al. Peroral endoscopic myotomy (POEM) for esophageal achalasia. Endoscopy. 2010;42:265-71.

2. Rai MR, Woo M, Bechara R. The Canadian POEM Experience: The first 50 patients. J Can Assoc Gastroenterol. 2020;4(3): 110-4.

3. Campagna RAJ, Cirera A, Holmstrim AL, Triggs JR, Teitelbaum EN, Carlson DA, et al. Outcomes of 100 Patients More Than 4 Years After POEM for Achalasia. Ann Surg. 2021;273:1135- 40.

4. Crosthwaite GL, Sejka M. Per-oral endoscopic myotomy (POEM): overview and experience of 100 cases by a single surgeon in Australia. Ann Esophagus. 2020;3:12.

5. Gutierrez OIB, Moran RA, Familliari P, Dbouk MH, Costamagna G, Ichkhanian Y, et al. Long-term outcomes of per-oral endoscopic myotomy in achalasia patients with a minimum follow-up of 4 years: a multicenter study. Endosc Int Open. 2020;8(5):E650-E655.

6. Vespa E, Pellegatta G, Chandrasekar VT, Spadaccini M, Patel H, Maselli R, et al. Long-term outcomes of peroral endoscopic

   myotomy for achalasia: a systematic review and meta-analysis. Endoscopy. 2023;55:167-75.

7. Nabi Z, Mandavdhare H, Akbar W, Talukdar R, Nageshwar R. Long-term Outcome of Peroral Endoscopic Myotomy in Esophageal Motility Disorders: A Systematic Review and Meta-analysis. J Clin Gastroenterol. 2023;57:227-38.

8. Boeckxstaens GE, Zaninotto G, Richter JE. Achalasia. Lancet. 2014;383:83-93.

9. Schima W, Stacher G, Pokieser P, Uramitsch K, Nekahm D, Schober E, et al. Esophageal motor disorders: video fluoroscopic and manometric evaluation: a prospective study in 88 symptomatic patients. Radiology. 1992;185:487-91.

10. Boonsomjint W, Maneerattanaporn M, Charoensak A. Correlation between Time Barium Esophagogram and the Eckardt Stage in Achalasia. Siriraj Med J. 2018;70(1):60-5.

11. Kahrilas PJ, Bredenoord AJ, Fox M, Gyawali CP, Roman S, Smout AJ, et al. The Chicago classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil. 2015;27(2):160-74.

12. Bredenoord AJ, Fox M, Kahrilas PJ, Pandolfino JE, Schwizer W, Smout AJ, et al. Chicago classification criteria of esophageal motility disorders defined in high resolution esophageal pressure topography. Neurogastroenterol Motil. 2012;24 Suppl 1:57-65.

13. Cho YK, Kim SH. Current Status of Peroral Endoscopic Myotomy. Clin Endosc. 2018;51:13-8.

14. Modayil R, Stavropoulos SN. POEM Contraindications and Pitfalls. In: Reavis KM. Per Oral Endoscopic Myotomy (POEM). eBook: Springer International Publishing AG; 2017. p.85-121. Doi 10.1007/978-3-319-50051-5_7.

15. Leung LJ, Ma GK, Lee JK, Fukami N, Chang H, Svahn J, et al. Successful Design and Implementation of a POEM Program for Achalasia in an Integrated Healthcare System. Dig Dis Sci. 2023;68(6):2276-84.

16. Xu MM, Kahaleh M. Recurrent symptoms after per-oral endoscopic myotomy in achalasia: Redo, dilate, or operate? A call for a tailored approach. Gastrointest Endosc. 2018;87(1): 102-3.

17. Callahan ZM, Su B, Ujiki M. Management of reflux after peroral endoscopic myotomy. J Xiangya Med. 2019;4(6):1-10.

18. Wayne WD. Biostatistics: A foundation of analysis in the health sciences. 6th ed. New York: John Wiley and Sons; 1995.

19. Nabi Z, Ramchandani M, Chavan R, Basha J, Reddy M, Darisetty S, et al. Double tunnel technique reduces technical failure during POEM in case with severe submucosal fibrosis. Endosc Int Open. 2021;9(9):E1335-E41.

20. Sanagapalli S, Roman S, Hastier A, Leong RW, Patel K, Raeburn A, et al. Achalasia diagnosed despite normal integrated relaxation pressure responds favorably to therapy. Neurogastroenterol Motil. 2019;31(6):e13586.

21. Hata Y, Sato H, Shimamura Y, Abe H, Shiwaku A, Shiota J, et al. Impact of peroral endoscopic myotomy on high-resolution manometry findings and their association with the procedure’s outcomes. Gastrointest Endosc. 2023;97(4):673-83.e2.

22. Liu ZQ, Li QL, Chen WF, Zhang XC, Wu QN, Cai MY, et al. The effect of prior treatment on clinical outcomes in patients with achalasia undergoing peroral endoscopic myotomy. Endoscopy. 2019;51(4):307-16.

23. Ramchandani M, Nabi Z, Reddy DN, Talele R, Darisetty S, Kotla R, et al. Outcomes of anterior myotomy versus posterior myotomy during POEM: a randomized pilot study. Endosc Int Open. 2018;6(2):E190-8.

    
    

24. Nabi Z, Reddy DN. Impacted of modified techniques on outcomes of peroral endoscopic myotomy: A narrative review. Frontiersin. org [Internet]. 2022, Aug, 18 [cited 2023, May,17]. Available from: doi:10.3389/fmed.2022.948299.

25. Khashab M, Sanaei O, Rivory J, Eleftheriadis N, Chu PWYW, Shiwaku H, et al. Peroral endoscopic myotomy: anterior versus posterior approach: a randomized single-blinded clinical trial. Gastrointest Endosc. 2020;91(2):288-97.e7.

26. Mohan BP, Ofosu A, Chandan S, Ramai D, Khan SR, Ponnada S, et al. Anterior versus posterior approach in peroral endoscopic myotomy (POEM): a systematic review and meta-analysis. Endoscopy. 2020;52(4):251-8.

27. Ichkhanian Y, Abimansour JP, Pioche M, Vosoughi K, Eleftheriadis N, Chiu PWY, et al. Outcomes of anterial versus posterior peroral

    endoscopic myotomy 2 years post-procedure: prospective follow-up results from a randomized clinical trial. Endoscopy. 2021;53:462-8.

28. Zein ME, Kumbhari V, Ngamruengphong S, Carson KA, Stein E, Tieu A, et al. Learning curve for peroral endoscopic myotomy. Endosc Int Open. 2016;4(5):E577-82.

29. Gonzalez JM, Meunier E, Debourdeau A, Basile P, Mouel JPL, Caillo L, et al. Training in esophageal peroral endoscopic myotomy (POEM) on an ex vivo porcine model: learning curve study and training strategy. Surg Endosc. 2023;37:2062-9.

30. Mota RCL, Moura EGH, Moura DTH, Bernardo WM, Moura ETH, Brunaldi VO, et al. Risk factors for gastroesophageal reflux after POEM for achalasia: a systematic review and meta-analysis. Surg Endosc. 2021;35(1):383-97.

Bedaquiline Effect Towards QT Interval in Drug Resistant Tuberculosis (DR-TB): A Systematic Review

Arya Marganda Simanjuntak, B.Med*, Rahmadini Aulia**, Dhewa Triguna Banjarnahor, M.D.***, Riski Dimas Harianja****, Indra Yovi, M.D.*

*Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Riau/Arifin Achmad General Hospital, Pekanbaru, Indonesia,

**Faculty of Medicine, Universitas Andalas, Padang, Indonesia, ***Santa Maria Hospital, Pekanbaru, Indonesia, ****Faculty of Medicine, Universitas Riau/Arifin Achmad General Hospital, Pekanbaru, Indonesia.

ABSTRACT

Objective: Bedaquiline is recommended by World Health Organization (WHO) to treat Drug-Resistant Tuberculosis (DR-TB). Bedaquiline is chosen due to its efficacy and safety in numerous studies. One adverse event that could happen is QT interval prolongation, which increases the risk of Torsade de Pointes (TdP) and leads to death. This study aimed to discuss the knowledge on the effect of bedaquiline on before-after and changes of QT interval.

Materials and Methods: This systematic review based on PRISMA guidelines through PubMed, Cochrane, Science Direct, ProQuest, Google Scholar, and Epistemonikos until April 10, 2023. The keywords used was (“Bedaquiline” AND “QT Interval”). We implemented inclusion and exclusion criteria by PICOS framework then assessed the studies by Joanna Briggs Institute (JBI) critical appraisal checklist tools.

Results: From 1.170 articles, eleven articles met the criteria. In total 2,449 patients assessed in this study. Most of the studies carried out treatment duration of 6 months. There was a change in the mean QT interval between 11ms to 52.5ms in patients using bedaquiline from the beginning to the end of treatment. The mean QT interval after treatment ranges from 409.7ms – 464.5ms.

Conclusion: The use of bedaquiline requires attention to the ECG before and during therapy. Regular monitoring is necessary to prevent QT prolongation.

Keywords: Bedaquiline; Drug-Resistant Tuberculosis; QT Interval (Siriraj Med J 2023; 75: 638-645)

INTRODUCTION

Bedaquiline is an anti-tuberculosis drug that is still recommended by the World Health Organization (WHO) today for Multi Drug-Resistant Tuberculosis (MDR-TB).1 MDR-TB is a difficult case to treat and the incidence is increasing. Not only that, the genes of resistant TB that can mutate and present various variants of resistant mutations pose a potential ineffectiveness of current drugs in the future.2 However, Bedaquiline is used because of its good efficacy in treating DR-TB

and is better than kanamycin and bedaquiline could reduce the median time to culture conversion.3,4 Result from clinical trial phase 2 in 2015 showed bedaquiline containing regimen considered well tolerated and led to good outcomes for DR-TB patients.5 But behind a therapy with its efficacy, certainly has side effects that need to be considered in the provision of therapy. Meta- analysis by Lan et al in 2020 revealed the least amount of adverse events leading to long-term drug cessation occurred with bedaquiline (1.7% [0.7 – 4.2]),6 However

Corresponding author: Arya Marganda Simanjuntak E-mail: arya.marganda@gmail.com

Received 18 June 2023 Revised 6 July 2023 Accepted 15 July 2023 ORCID ID:http://orcid.org/0000-0001-8680-7865 https://doi.org/10.33192/smj.v75i9.263683

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

the QT interval prolongation, skin rash, hyperlactatemia, peripheral neuropathy, electrolyte depletion, and hearing loss are some adverse effects that need to be dealt with.7,8 The side effect of QT interval prolongation needs

to be a concern for clinicians before giving the drug to patients. Issues arising from QT interval prolongation will progress to Torsade de Pointes (TdP), a heart arrhythmia that could be fatal and cause the patient to pass away. TdP is a distinctive polymorphic ventricular arrhythmia that is linked to delayed ventricular repolarization as shown by a prolonged QT interval on the surface electrocardiogram.9 A retrospective cohort study by Darmayani et al showed 37.1% patients experienced clinically significant QTcF prolongation from 105 observed subjects.10 Darmayani et al’s suggestion for therapy with bedaquiline is that patients require intensive cardiac monitoring during therapy period.10

The clinical question that will continue to arise is how much change in QT interval can be considered safe during Bedaquiline therapy? It has not yet been established exactly what is the limit or value that clinicians should be concerned about that can be considered “safe”. Some opinions use the limitation that if the QT interval is above 500mm then the patient is stopped on treatment. We

argue that this is potentially dangerous. This is due the risk of arrythmic events increases by 5% for every 10ms increase in the QT interval (normal QTc invervals are approximately 450ms for men and 460ms for women.11 If 500mm is taken as the limit, men have a risk of arrythmia of 25% and 20% in women. Thus, this systematic review aims to discuss the knowledge on the effect of bedaquiline on before-after and changes of QT interval.

MATERIAL AND METHODS

Data sources and search strategy

For reporting in systematic reviews, we used Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and synthesis without meta-analysis. PubMed, Science Direct, Epistemonikos, Cochrane, ProQuest and Google Scholar were all searched for papers. Keywords like “Bedaquiline” AND “QT Interval” were utilized. We incorporate all research: (1) full text, (2) English or Indonesian Language, (3) Display the QT Interval value in numeric form, and (5) last 10 years. The search strategies are described in full in Fig 1. Unpublished data, duplicate research and reviews were disregarded. This systematic review registered at PROSPERO with number: CRD42023393217.

Fig 1. Flow diagram of included studies based on PRISMA flow chart.

Study Selection

Four researchers (AMS, RA, DTB, and RDH) independently evaluated eligibility based on titles and abstracts using the PICO framework (Population = DR-TB; Intervention = Bedaquiline; Compare = Not Specified; Outcome = QT interval). The consensus was reached between investigators to resolve disagreements, or supervisors (IY) were involved when consensus could not be reached.

Data extraction and risk of bias

From each included study, data were taken on: (1) country, (2) study design, (3) population, (4) study size,

(5) Intervention, (6) time on treatment, (7) Regimen,

(8) QT Interval before and after, and (9) QT interval changes. The primary outcome to determine QT interval changes after take Bedaquiline during obervation.

According to the type of articles received, AMS, RA, DTB and RDH examined full-text articles using the Joanna Briggs Institute Critical Appraisal Tool (jbi. global/critical-appraisal-tools). Consensus was reached to resolve the disagreements, or when consensus could not be established, supervisors (IY) were involved.

RESULTS

Study selection

A total of 1.170 studies were identified from the research database (Fig 1). After removing the duplicate records, 14 records were screened and assessed for eligibility. 11 studies were included in the review, after excluding three studies due to out of scope based on inclusion criteria. There are three articles that provide the effects of Bedaquiline in QT Interval but the form of QT interval they provided in categorical form, either

>500ms or <500ms. Therefore we exclude those three articles.

Characteristics of included studies

A total of 1.170 studies were identified from the research database (Fig 1). After removing the duplicate records, and analyze the article based on title, abstract then proceed with full-text, we include 11 studies with 2,449 patients included. The studies we included have various types of study designs such as cohort and clinical trials originating from various countries such as Indonesia, South Africa, America, China, and so on. Patients included in this study were all patients with DR-TB and in some articles were specified according to findings such as Rifampicin-Resistant Tuberculosis (RR-TB), Multi Drug Resistant Tuberculosis (MDR-TB), and others. All studies conducted observations with a

duration of six (6) months and there are some notes from several articles as compiled in Table 1.

QT interval changes in the use of bedaquiline

Of the patients included in this study, 405 out of 2,449 patients (16.5%) had QT Interval problems either QT interval ≥500ms or an increase in QT interval from baseline ≥60ms. Table 2 summarizes the results of each study included in this study including the QT interval values before therapy, after therapy, and the change in QT interval from baseline. The mean QT interval value after treatment with Bedaquiline in each article was rated as safe at <450ms. Only one article by Vandu et al.12, 2022 which in their research found a mean QT interval value of 458.4ms, this according to the degree of QT interval display is considered as QT prolongation degree 1. When looking at the column of QT Interval changes from baseline also in each study can be said to be safe, no study found a mean increase in QT interval from baseline ≥60ms. The highest value of change in QT interval from baseline was 44.5 (23.8 - 63.8) from the study of Lee et al13, 2021. Although on average both the change in QT interval after Bedaquiline therapy and the change in QT interval were said to be good, there were several cases of QT interval prolongation and some had to be discontinued. This shows that Bedaquiline can indeed increase the QT interval, but the number of cases can be said to be small, so it is necessary to monitor the QT interval of patients who are on therapy using Bedaquiline.

Risk of bias

All authors analyze risk-of-bias for every included study based on study design. The cutoff value we set has a risk of bias if it is less than 65%. The mean score of all articles was 89.9% with a lowest score of 84%. Fig 2 displays the JBI score of each article that has been analyzed.

DISCUSSION

Summary and interpretation of findings

This systematic review seeks to analyze the impact of Bedaquiline on QT Interval prolongation in patients with DR-TB. Of the various studies that have been included, the average QT Interval value after six months of observation with Bedaquiline is below 450ms, only two studies report the average post-treatment QT interval is above 450ms, namely Vandu et al., 2022 ranging from

458.4 (SD, 23.7) and Lee et al., 2021 with a median value of 462 (IQR, 443.3 - 492.0). Based on the degree of the average value of the two studies, it is categorized as QT

TABLE 1. Characteristics of the included studies.

Simanjuntak et al.

TABLE 2. Result of selected studies.

TABLE 2. Result of selected studies. (Continue)

Abbreviations: DR-TB: Drug-Resistance Tuberculosis, MDR-TB: Multi Drug Resistance Tuberculosis, RR-TB: Rifampicin Resistance Tuberculosis, XDR-TB: Extensively drug-resistant Tuberculosis, BDQ: Bedaquiline, DLM: Delamanid, Med: Median, IQR: Interquartile Range, SD: Standard Deviation, NA: Not Available, QTcF : QT Interval Friderica Formula

Risk of Bias From Included Studies

Diacon, et al., 2014 Ferlazzo, et al., 2018 Ndjeka, et al., 2022 Lee, et al., 2020 Brust, et al., 2021 Gao, et al., 2021 Isralls, et al., 2021

Darmayani, et al., 2022 Vandu, et al.,2022 Katrak, et al.,2021 Dooley, et al.,2021

75%

80%

85%

90%

95%

100%

Fig 2. JBI scores of articles included in the study

interval Prolongation grade 1. Based on the change in QT Interval from the baseline, all studies assessed the average and there was no average value above 60ms. However, 405 out of 2,449 patients (16.5%) included in this study had QT interval problems ≥500ms or an increase in QT interval from baseline ≥60ms and some of them had to be discontinued.

As a result of this systematic review, it can be interpreted that the use of Bedaquiline may affect the QT Interval in its users, although few of these events have occurred or been reported. However, the use of Bedaquiline should still be cautioned in patients who have cardiovascular system problems, especially arrhythmias. The small number of cases does not mean that no patient will experience it, so clinician care in treating DR-TB patients is needed to ensure patient safety during therapy. Routine evaluation of the patient’s ECG can be a good solution, especially in patients who are suspected of potentially facing adverse effects on the QT interval.

Bedaquiline mechanism on prolonging QT interval

A diarylquinoline called bedaquiline is an excellent treatment for DR-TB. This medication works by specifically inhibiting the mycobacterial ATP synthase enzyme.14 The heart’s hERG potassium channel can be blocked by bedaquiline, which can also influence the incidence of QT interval prolongation.15 According to recent research, the QT interval is also accompanied with lower serum potassium levels and higher serum sodium levels, which may indicate a connection between the cardiac hERG channel and sodium currents and QT interval lengthening.15

Limitation, strength and future research direction

The limitation of this systematic review is that we did an analysis without using any statistics (without meta- analysis) so that a stratification or overall conclusion of the combined research was not obtained. Strength of this study. We summarize the characteristics of this systematic review of the use of Bedaquiline in DR-TB patients for changes in the current QT interval, which can be said to be safe and only a few cases have reported significant problems with the QT interval of its users. So with this systematic review providing evidence of the safety of using Bedaquiline in DR-TB while clinically careful in the condition before the patient received treatment. For future research, it is hoped that it will continue to report if QT interval prolongation occurs when using Bedaquiline and it is expected to be able to carry out a meta-analysis to determine the impact of using Bedaquiline on the QT interval in a combined manner from all existing data.

CONCLUSION

Of all the patients included, 16.5% had problems with the QT interval when using Bedaquiline and some of them had to stop treatment. The use of Bedaquiline is safe for the QT interval but requires the clinician’s attention to the patient before giving the treatment with ECG both before and during therapy. Regular monitoring is important to prevent before QT prolongation occurs so that DR-TB treatment can be safer for patients.

ACKNOWLEDGMENTS

We would like to thank to Dean Faculty of Medicine,

Universitas Riau, Dr.Arfianti, M.Sc, M.Biomed, PhD, for supporting authors to write scientific article and systematic review.

Funding

All authors agree that there is no conflict of Interest. This article does not get any fund from any individuals or organization.

REFERENCES

1. World Health Organization. WHO consolidated guidelines on tuberculosis Module 4: Treatment Drug-resistant tuberculosis treatment 2022 update. 2022.

2. Prammananan T. Distribution of Drug-Resistant Genes Among Thai Multidrug-Resistant Mycobacterium Tuberculosis (MDR- TB) Clinical Isolates. Siriraj Med J. 2011;63(3):102-5.

3. Singh L, Mathibe LJ, Bangalee V. The efficacy of bedaquiline versus kanamycin in multi-drug resistant tuberculosis: A systematic scoping review. Health SA. 2021;26:1708.

4. Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014;371(8):723- 32.

5. Pym AS, Diacon AH, Tang SJ, Conradie F, Danilovits M, Chuchottaworn C, et al. Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur Respir J. 2016;47(2):564-74.

6. Lan Z, Ahmad N, Baghaei P, Barkane L, Benedetti A, Brode SK, et al. Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet Respir Med. 2020;8(4):383-94.

7. Gaida R, Truter I, Peters CA. Adverse effects of bedaquiline in patients with extensively drug-resistant tuberculosis. S Afr J Infect Dis. 2020;35(1):23.

8. Hewison C, Khan U, Bastard M, Lachenal N, Coutisson S, Osso E, et al. Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort. Clin Infect Dis. 2022;75(6): 1006-13.

9. Thomas SHL, Behr ER. Pharmacological treatment of acquired QT prolongation and torsades de pointes. Br J Clin Pharmacol. 2016;81(3):420-7.

10. Darmayani IGAAPS, Ascobat P, Instiaty I, Sugiri YJR, Sawitri N. Bedaquiline Effecton QTIntervalof Drugs-Resistant Tuberculosis Patients: Real World Data. Acta Med Indones. 2022;54(3): 389-96.

11. Khatib R, Sabir FRN, Omari C, Pepper C, Tayebjee MH. Managing drug-induced QT prolongation in clinical practice. Postgrad Med J. 2021;97(1149):452-8.

12. Primadana V, Yovi I, Estiningsih DS. Bedaquiline Correlation to QT Interval Prolongation in DR-TB Patients. Journal of Respirology. 2022;8(3). Available from: https://doi.org/10.20473/

    jr.v8-I.3.2022.140-146

13. Lee HH, Jo KW, Yim JJ, Jeon D, Kang H, Shim TS. Interim treatment outcomes in multidrug-resistant tuberculosis patients treated sequentially with bedaquiline and delamanid. Int J Infect Dis. 2020;98:478-85.

14. Sutherland HS, Tong AST, Choi PJ, Blaser A, Conole D, Franzblau SG, et al. 3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel. Bioorg Med Chem [Internet]. 2019;27(7):1292-

    307. Available from: https://doi.org/10.1016/j.bmc.2019.02.026

15. Li J, Yang G, Cai Q, Wang Y, Xu Y, Zhang R, et al. Safety, efficacy, and serum concentration monitoring of bedaquiline in Chinese patients with multidrug-resistant tuberculosis. Int J Infect Dis. 2021;110:179-86.

16. Dooley KE, Rosenkranz SL, Conradie F, Moran L, Hafner R, von Groote-Bidlingmaier F, et al. QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial. Lancet Infect Dis. 2021;21(7):975-83.

17. Katrak S, Lowenthal P, Shen R, True L, Henry L, Barry P. Bedaquiline for multidrug-resistant tuberculosis and QTc prolongation in California. J Clin Tuberc Other Mycobact Dis. 2021;23:100216.

18. Isralls S, Baisley K, Ngam E, Grant AD, Millard J. QT Interval Prolongation in People Treated With Bedaquiline for Drug- Resistant Tuberculosis Under Programmatic Conditions: A Retrospective Cohort Study. Open Forum Infect Dis. 2021; 8(8):ofab413.

19. Gao JT, Du J, Wu GH, Pei Y, Gao MQ, Martinez L, et al. Bedaquiline-containing regimens in patients with pulmonary multidrug-resistant tuberculosis in China: focus on the safety. Infect Dis Poverty. 2021;10(1):32.

20. Brust JCM, Gandhi NR, Wasserman S, Maartens G, Omar S V, Ismail NA, et al. Effectiveness and Cardiac Safety of Bedaquiline- Based Therapy for Drug-Resistant Tuberculosis: A Prospective Cohort Study. Clin Infect Dis. 2021;73(11):2083-92.

21. Ndjeka N, Campbell JR, Meintjes G, Maartens G, Schaaf HS, Hughes J, et al. Treatment outcomes 24 months after initiating short, all-oral bedaquiline-containing or injectable-containing rifampicin-resistant tuberculosis treatment regimens in South Africa: a retrospective cohort study. Lancet Infect Dis. 2022; 22(7):1042-51.

22. Ferlazzo G, Mohr E, Laxmeshwar C, Hewison C, Hughes J, Jonckheere S, et al. Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study. Lancet Infect Dis. 2018;18(5): 536-44.

23. Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014;371(8):723- 32.

Evaluating Risk Factors for Cumulative Life Course Impairment in Psoriasis using Patient-Acceptable Symptom State and European Quality of Life

5 Dimensions (EQ-5D)

Leena Chularojanamontri, M.D.*, Chanisada Wongpraparut, M.D.*, Narumol Silpa-archa, M.D.*, Chayada Chaiyabutr, M.D.*, Supisara Wongdama, M.D.*, Praveena Chiowchanwisawakit, M.D.**

*Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol. University, Bangkok 10700, Thailand.

**Division of Rheumatology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

ABSTRACT

Objective: To evaluated the health-utility values and risk factors for cumulative life course impairment (CLCI) using Patient Acceptable Symptom State (PASS) and European Quality of Life 5 Dimensions (EQ-5D).

Materials and Methods: This cross-sectional investigation enrolled patients with psoriasis. Patients were asked PASS questions about their overall self-perceived health state, adaptation, and expectations for current, future, and lifelong conditions. The patients also completed EQ-5D.

Results: The mean age of 139 enrolled patients was 45.8 ± 14.4 years, and 57.6% were women. Most cases had chronic plaque psoriasis 121 (87.1%). For current PASS, satisfaction was significantly associated with older age, being married, and lower disease severity. The mean health-utility value and visual analog scale of the 139 patients were 0.89 ± 0.12 and 77.0 ± 17.4, respectively. Patients would not accept their disease if they had moderate to extreme problems in usual activities and depression/anxiety for the future and lifelong. Univariate analysis revealed that depression and usual activities were significantly associated with satisfaction for current PASS, future PASS, and lifelong PASS. Conclusion: Disease severity, age, marital status, problems with usual activities, and depression/anxiety were significantly related to CLCI. These findings may allow physicians to identify psychosocial and psychological aspects of psoriatic patients at high risk for developing CLCI. Early and adequate treatment, good coping strategies, and good social support can prevent a negative impact on CLCI and major life-changing decisions.

Keywords: Cumulative life course impairment; EQ-5D; Patient-acceptable symptom state; Psoriasis; Quality of life (Siriraj Med J 2023; 75: 646-654)

INTRODUCTION

Psoriasis is a common chronic inflammatory skin disease characterized by thick scaly erythematous plaques on the skin, especially in trauma-prone areas.1,2 The condition substantially affects patients’ health-related quality of life (HRQoL) since it can affect daily activities, social functioning, and psychological well-being.3 The

level of HRQoL impairment in psoriasis has been shown to be comparable to some serious medical conditions, such as ischemic heart disease, diabetes, depression, and cancer.4 Furthermore, it has a cumulative impact on a patient’s life course, which sometimes cannot be detected by measuring HRQoL at a specific time point.5 The term “cumulative life course impairment”

Corresponding author: Praveena Chiowchanwisawakit E-mail: praveena.chi@mahidol.ac.th

Received 6 January 2023 Revised 9 May 2023 Accepted 19 July 2023 ORCID ID:http://orcid.org/0000-0002-4253-9229 https://doi.org/10.33192/smj.v75i9.260756

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

(CLCI) was proposed more than a decade ago. It was intended to reflect the overall effects of psoriasis that result in an altered or impaired life potential during the life course of a patient. The dimension of the future is embedded in the CLCI concept, which is considered a key element in the management of lifelong conditions. Understanding the adaptations of patients and their future expectations may allow physicians to provide high-quality patient care. However, this dimension has not been extensively studied in psoriasis.6

Patient Acceptable Symptom State (PASS) is a simple questionnaire that captures the overall self-perceived health state, adaptation, and expectations of individual patients. Three questions are asked:

1. Considering the ways that skin psoriasis affects your functioning, is your current condition satisfactory? (“Current PASS”).

2. Considering the ways that your skin psoriasis is affecting you, if you were to remain in this state for the next few months, would this be satisfactory? (“Future PASS”).

3. If you were to remain for the rest of your life as you were during the last 48 hours, would this be satisfactory? (“Lifelong PASS”).

The answers are recorded as “Yes” or “No,” indicating “satisfaction” and “dissatisfaction,” respectively.7,8

This study aimed to evaluate health-utility (HU) values and risk factors for CLCI using PASS and European Quality of Life 5 Dimensions (EQ-5D).

MATERIALS AND METHODS

This cross-sectional investigation included psoriasis patients with and without psoriatic arthritis (PsA) who attended the Psoriasis Clinic, Outpatient Dermatology Unit, in a tertiary hospital in Thailand. The diagnoses of PsA were confirmed by an expert rheumatologist and were based on the classification criteria for PsA.9 For this study, the inclusion criteria were patients who (i) were 18 years or older; (ii) could read, write, and speak Thai; and (iii) were willing to participate in the study. Patients with psychiatric conditions were excluded. This study was approved by the Institutional Review Board (COA no. Si 156/2020). All methods were performed in accordance with the relevant guidelines and regulations. All patients gave their written informed consent. Details of the following were recorded: demographic and clinical data of patients; the severity of psoriasis (PASI; Psoriasis Area and Severity Index); and treatments. HU values were derived from European Quality of Life-5 Dimensions – 5 Levels (EQ-5D-5L). The completion of EQ-5D-5L, patient global assessment severity (PtGA), and self-assessment

Simplified Psoriasis Index (saSPI-s)10 was carried out by each patient or with the help of a research assistant. The overall health state, adaptation, and expectations of individual patients were investigated using the PASS questions.

EQ-5D-5L

The EuroQoL group introduced EQ-5D-5L in 2009. The Thai version of EQ-5D-5L was validated in 2014.11 EQ-5D-5L consists of a descriptive system and a visual analog scale (EQ-5D VAS).12 The descriptive system has 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and depression/anxiety. In turn, each dimension has 5 levels of impairment: no problems, slight problems, moderate problems, severe problems, and extreme problems.13 The selected levels for each of the 5 dimensions of the descriptive system are combined to derive the HU value for a patient.14 Thai HU values range from -0.28 to 1, with values of 0 and 1 indicating “dead” and “perfect” health, respectively.14 A negative value indicates a state of health that is perceived by a patient as “worse than death”.14 In relation to EQ-5D VAS, it uses a 20-cm vertical numerical scale ranging from 0 to 100, with 0 and 100 representing “the worst” and “the best” imaginable health states, respectively.11

Statistical analysis

Descriptive statistics (frequency, percentage, mean, standard deviation, median, minimum, and maximum) were used to analyze patient characteristics and the variables studied. Fisher’s exact test was used to compare categorical variables. Normally and non-normally distributed data were analyzed using an independent t-test and the Mann–Whitney U test, respectively. The 5 domains of EQ-5D-5L were divided into 2 groups: no to slight problems, and moderate to extreme problems. Subsequently, binary logistic regression with the enter method was used to determine the factors associated with HRQoL for each EQ-5D-5L domain, as well as satisfied PASS. Variables with P values of < 0.2 in a univariate analysis were included in a multivariate analysis. A P value of ≤ 0.05 was considered statistically significant. All statistical analyses were performed using PASW Statistics for Windows (version 18.0; SPSS, Chicago, IL, USA).

RESULTS

A total of 139 patients were involved. Their overall mean age was 45.8 ± 14.4 years, and 57.6% were women (Table 1). Patients who were employed and patients with a bachelor’s or higher degree represented 86.2% and

Chularojanamontri et al.

TABLE 1. Clinical characteristics and EuroQol-5 Dimension-5 Levels (EQ-5D-5L) for current Patient Acceptable Symptom State (PASS), future PASS, and lifelong PASS.

TABLE 1. Clinical characteristics and EuroQol-5 Dimension-5 Levels (EQ-5D-5L) for current Patient Acceptable Symptom State (PASS), future PASS, and lifelong PASS. (Continue)

Abbreviations: EQ-VAS, EuroQol-visual analog scale; PASI, Psoriasis Area and Severity Index; PtGA, Patient Global Assessment; saSPI, self-assessment Simplified Psoriasis Index Bold indicates a statistical significance.

Chularojanamontri et al.

54.7% of the cohort, respectively. In all, there were 121 (87.1%) cases of chronic plaque psoriasis, 9 (6.5%) of

guttate psoriasis, 4 (2.9%) of erythrodermic psoriasis, 3

(2.2%) of pustular psoriasis, and 2 (1.4%) of acrodermatitis continua of Hallopeau. For current PASS, older age, being married, and a lower disease severity were significantly associated with satisfaction with the overall health state. Except for being married, these factors were also significant for future PASS and lifelong PASS.

The mean HU value and the mean EQ-VAS score of the study cohort were 0.89 ± 0.12 and 77.0 ± 17.4, respectively. Eighty-nine patients reported being satisfied for current PASS, future PASS, and lifelong PASS, whereas 13 patients reported dissatisfaction for all stages of PASS. The mean HU score and the mean EQ-VAS score of the 89 patients who reported being satisfied were 0.93 ±

0.09 and 81.2 ± 15, respectively. These were significantly higher than the corresponding values for patients who reported dissatisfaction (n = 13; mean HU score = 0.84

± 0.14, P = 0.003; and mean EQ-VAS = 65.5 ± 19.1,

P = 0.005). Among the 5 dimensions of EQ-5D, the highest percentage of reports of moderate to extreme problems was for pain/discomfort (20.1%), while the lowest percentage was for self-care (4.3%). Pain/discomfort, usual activities, and depression were significant problems that prevented patients from being able to accept their condition if they were still present in the future. Patients reported that they would not accept their disease if moderate to extreme problems in usual activities and depression/anxiety lasted for life.

Although the mean HU value and the mean EQ-VAS of patients without PsA were slightly higher than those of patients with PsA, the differences were not significant (P = 0.203 and P = 0.402, respectively; Table 2). However, the mean EQ-VAS score was significantly different for patients reporting satisfaction and dissatisfaction for current PASS for both the psoriasis and PsA groups. Pain/discomfort, followed by depression, was common among patients without PsA, but pain/discomfort and mobility were the most commonly experienced problems for patients with PsA. Among patients without PsA, those who reported being unhappy for current PASS had significantly lower HU and EQ-VAS scores and more difficulties with their usual activities and depression/ anxiety than patients who stated that they were satisfied for current PASS.

Univariate logistic regression analysis showed that patients who were satisfied for current PASS and future PASS should have no or slight problems performing usual activities, or with pain/discomfort and depression/anxiety (Table 3). The analysis also revealed that having no to

slight problems with usual activities and depression were significantly associated with satisfaction for current PASS, future PASS, and lifelong PASS. Subsequent multivariate analysis showed that no to slight problems with self- care were associated with satisfaction for current PASS. Furthermore, the multivariate analysis found that the EQ-5D-5L domains were not associated with satisfaction for future PASS and lifelong PASS.

DISCUSSION

The concept of CLCI was introduced in 2010. It referred to the cumulative results of the burdens of social stigmatization, physical comorbidities, and psychological comorbidities and their interaction with coping strategies and external factors.5,15 The complex interaction of these key components explains the variations in how each patient experiences life with psoriasis.5 A recent systematic review of the mapping of risk factors for CLCI was conducted in patients with chronic skin diseases such as psoriasis, atopic dermatitis, and hidradenitis suppurativa. The analysis found that such patients are at high risk of developing a lifelong negative impact from their disease.16 Nine of the reviewed studies addressed patients with psoriasis. The severity and comorbidities of the disease were mentioned the most frequently, while only a few studies addressed psychosocial risk factors over time.16 In this study, we used PASS and EQ-5D-5L to assess psychosocial factors over time in patients with psoriasis. Our study showed that satisfaction for current PASS was significantly associated with lower disease severity, older age, and being married. Patients who could accept their disease for a lifetime were significantly older than those who could not. This may be because the coping strategies at different ages are not the same. Middle-aged adults (aged approximately 40 to 59 years) are more likely to use problem-focused coping rather than emotion-focused coping to solve problems.17,18 Problem-focused coping can produce positive effects and minimize CLCI. Furthermore, it is generally accepted that good family and social support play a positive role even though they may not decrease the severity of the disease.19 The results of our study highlight the need to promote problem-focused coping strategies for patients. Moreover, educational programs are needed for family members, friends, and the broad community so that they understand that psoriasis is not a contagious disease and

are more accepting of individuals with the condition.

A systemic review and meta-analysis of EQ-5D for psoriatic patients showed that the mean utility scores of EQ-5D for psoriasis and PsA were 0.82 and 0.76, respectively.20 This was in line with our study, which

TABLE 2. EuroQol-5 Dimension-5 Levels (EQ-5D-5L) and current Patient Acceptable Symptom State (PASS).

Abbreviations: EQ-VAS, EuroQol-visual analog scale; PsA, psoriatic arthritis Bold indicates statistical significance.

Chularojanamontri et al.

TABLE 3. Univariate and multivariate analysis of factors associated with each domain of EuroQol-5 Dimension-5 Levels (EQ-5D-5L).

TABLE 3. Univariate and multivariate analysis of factors associated with each domain of EuroQol-5 Dimension-5 Levels (EQ-5D-5L). (Continue)

Abbreviations: CI, confidence interval; OR, odds ratio; PASI, Psoriasis Area and Severity Index; PASS, Patient Acceptable Symptom State; PtGA, Patient Global Assessment; saSPI, self-assessment Simplified Psoriasis Index

Bold indicates statistical significance.

found that patients with PsA had a lower HRQoL than patients without PsA. Like the systemic review, our investigation also showed that of the 5 dimensions of EQ-5D, pain/discomfort and self-care presented the most and least problems, respectively.20 However, our study added additional information. Specifically, problems with usual activities and depression/anxiety were the most significant for patients with PsA who could not accept those problems in the future (ie, the next few months) nor their lifetime. Depression/anxiety can occur in up to 30% of patients.21 Some studies have shown that severe psoriasis significantly raises the risk of depression.16,22 A connection between the brain and the skin (brain-skin axis) and increased inflammation in psoriasis may be directly related to pathophysiological pathways in depression.23 Nevertheless, depression/anxiety and psychological effects can be severe regardless of disease severity if patients do not have appropriate coping strategies and good social support.24

In conclusion, our study evaluated risk factors for CLCI using the PASS and EQ-5D tools. It showed that a clinical characteristic (disease severity), sociodemographic factors (age and marital status), impaired general health (problems in usual activities), and depression/anxiety were significantly related to CLCI. These findings can help physicians identify psoriatic patients who are at high risk of developing CLCI. Early and adequate treatment, good coping strategies, and good social support can prevent negative impacts on CLCI and major life-changing decisions.

REFERENCES

1. Gelfand JM, Feldman SR, Stern RS, Thomas J, Rolstad T, Margolis DJ. Determinants of quality of life in patients with psoriasis: a study from the US population. J Am Acad Dermatol. 2004;51:704-8.

2. Strober B, Greenberg JD, Karki C, Mason M, Guo N, Hur P, et al. Impact of psoriasis severity on patient-reported clinical symptoms, health-related quality of life and work productivity among US patients: real-world data from the Corrona Psoriasis Registry. BMJ Open. 2019;9:e027535.

3. Basra MK, Hussain S. Application of the dermatology life quality index in clinical trials of biologics for psoriasis. Chin J Integr Med. 2012;18:179-85.

4. Sarkar R, Chugh S, Bansal S. General measures and quality of life issues in psoriasis. Indian Dermatol Online J. 2016;7:481-8.

5. Kimball AB, Gieler U, Linder D, Sampogna F, Warren RB, Augustin M. Psoriasis: is the impairment to a patient’s life cumulative? J Eur Acad Dermatol Venereol. 2010;24:989-1004.

6. Rencz F, Holló P, Kárpáti S, Péntek M, Remenyik É, Szegedi A, et al. Moderate to severe psoriasis patients’ subjective future expectations regarding health-related quality of life and longevity. J Eur Acad Dermatol Venereol. 2015;29:1398-405.

7. Chiowchanwisawakit P, Srinonprasert V, Thaweeratthakul P, Katchamart W. Disease activity and functional status associated

   with health-related quality of life and patient-acceptable symptom state in patients with psoriatic arthritis in Thailand: A cross- sectional study. Int J Rheum Dis. 2019;22:700-7.

8. Chularojanamontri L, Wongpraparut C, Silpa-Archa N, Chaiyabutr C, Apinuntham C, Pruksaeakanan C, et al. Using the patient-acceptable symptom state to evaluate patients’ perspectives of living with psoriasis: A cross-sectional study. Australas J Dermatol. 2021.

9. Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H, et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 2006;54:2665-73.

10. Chularojanamontri L, Griffiths CE, Chalmers RJ. The Simplified Psoriasis Index (SPI): a practical tool for assessing psoriasis. J Invest Dermatol. 2013;133:1956-62.

11. Devlin NJ, Brooks R. EQ-5D and the EuroQol Group: Past, Present and Future. Appl Health Econ Health Policy. 2017;15: 127-37.

12. Yang Y, Brazier J, Longworth L. EQ-5D in skin conditions: an assessment of validity and responsiveness. Eur J Health Econ. 2015;16:927-39.

13. Pattanaphesaj J, Thavorncharoensap M. Measurement properties of the EQ-5D-5L compared to EQ-5D-3L in the Thai diabetes patients. Health Qual Life Outcomes. 2015;13:14.

14. Pattanaphesaj J. Health-related quality of life measure (EQ- 5D- 5L): measurement property testing and its preference-based score in Thai population [Doctoral dissertation]: Mahidol University; 2014.

15. Bhatti ZU, Salek MS, Finlay AY. Major life changing decisions and cumulative life course impairment. J Eur Acad Dermatol Venereol. 2011;25:245-6;author reply 246.

16. von Stülpnagel CC, Augustin M, Düpmann L, da Silva N, Sommer R. Mapping risk factors for cumulative life course impairment in patients with chronic skin diseases - a systematic review. J Eur Acad Dermatol Venereol. 2021;35:2166-84.

17. Richaud de Minzi MC, Sacchi C. Stressful situations and coping strategies in relation to age. Psychol Rep. 2005;97:405-18.

18. Chen Y, Peng Y, Xu H, O’Brien WH. Age Differences in Stress and Coping: Problem-Focused Strategies Mediate the Relationship Between Age and Positive Affect. Int J Aging Hum Dev. 2018; 86:347-63.

19. Idriss SZ, Kvedar JC, Watson AJ. The Role of Online Support Communities: Benefits of Expanded Social Networks to Patients With Psoriasis. Arch Dermatol. 2009;145:46-51.

20. Yang Z, Li S, Wang X, Chen G. Health state utility values derived from EQ-5D in psoriatic patients: a systematic review and meta-analysis. J Dermatolog Treat. 2020:1-8.

21. González-Parra S, Daudén E. Psoriasis and Depression: The Role of Inflammation. Actas Dermosifiliogr (Engl Ed). 2019;110:12-9.

22. Kurd SK, Troxel AB, Crits-Christoph P, Gelfand JM. The risk of depression, anxiety, and suicidality in patients with psoriasis: a population-based cohort study. Arch Dermatol. 2010;146:891-5.

23. Kleyn CE, Schneider L, Saraceno R, Mantovani C, Richards HL, Fortune DG, et al. The effects of acute social stress on epidermal Langerhans’ cell frequency and expression of cutaneous neuropeptides. J Invest Dermatol. 2008;128:1273-9.

24. Mattei PL, Corey KC, Kimball AB. Cumulative Life Course Impairment: Evidence for psoriasis. In: Linder MD, Kimball AB (eds): Dermatological Diseases and Cumulative Life Course Impairment. Curr Probl Dermatol. Basel, Karger, 2013;44:82-90.

The Efficacy of Preoperative Tamsulosin on Ureteroscopy Access in Pediatrics: A Systematic Review and Meta-Analysis

Nicholas Andrian Singgih, M.D.*, Jacinda Risha Oktaviani, M.D.*, Raden Honggo Pranowo Sampurno Secodiningrat, M.D.*, William Adipurnama, M.D.*, Egi Edward Manuputty, M.D.*, Kevin Tandarto, M.D.**

*Department of Urology, Primaya Hospital PGI Cikini, Jakarta, Indonesia. **Faculty of Medicine and Health Science, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia.

ABSTRACT

Objective: The incidence of urolithiasis in pediatrics increases to 4-10% annually. One of the methods for treating urolithiasis is ureteroscopy (URS). The small anatomy in pediatrics often makes the initial URS unsuccessful. Alpha blockers, a drug that can relax the ureteral muscles, is a therapy that can be considered before URS is carried out. The objective of this study is to evaluate the efficacy of preoperative tamsulosin for URS access in pediatrics.

Materials and Methods: We conducted a search using four databases, including PubMed, EBSCO, Cochrane Library, and ProQuest. This study includes randomized controlled trials (RCTs), retrospective and prospective studies, which compared the efficacy of preoperative alpha blockers and placebo or non-placebo controls in pediatrics undergoing ureteroscopy. The outcome of interest was the success rate of URS access and the duration of surgery.

Results: A total of 120 studies were identified from a database search. There were 3 studies included in this review involving 235 patients. The meta-analysis was conducted using a random-effects model. The results of the meta- analysis showed that alpha blockers provided a successful rate of ureteroscopy access in pediatric patients (Odds ratio (OR) 2.73; 95% confidence interval (CI) 1.52 up to 4.91; p=0.0008). Duration of surgery did not show significant results (Mean difference (MD) 3.46; 95% CI -3.59 up to 10.50; p=0.34).

Conclusion: Preoperative administration of tamsulosin may increase the success rate of ureteroscopy access in pediatric patients.

Keywords: Alpha blockers; pediatric; systematic review; tamsulosin; ureteroscopy (Siriraj Med J 2023; 75: 655-664)

INTRODUCTION

The incidence of urolithiasis in children within the past twenty years continues to increase steadily every year with a ratio of 4-10% per year.1 In children it will be difficult to determine the pain experienced, but the symptoms typically in the form of crying, anxiety, vomiting, hematuria, traces of blood or small stones on diapers, or recurrent urinary tract infections (UTI) with painful micturition.2 20% of kidney stones are found in the

ureters which cause discomfort and can result in kidney damage.3 The modality of treatment that can be given is influenced by the location and size of the stone, degree of back-pressure, as well as associated UTI.4 The treatment is in the form of observation, medical expulsive therapy (MET), ureteroscopy (URS), and ureterolithotomy.3 The AUA and the Endourological Society recommend URS and ESWL for patients who have failed MET and may require surgical intervention. URS has been evaluated

Corresponding author: Nicholas Andrian Singgih E-mail: nicholasandrian1606@gmail.com

Received 30 June 2023 Revised 24 July 2023 Accepted 25 July 2023 ORCID ID:http://orcid.org/0000-0002-7331-3070 https://doi.org/10.33192/smj.v75i9.263934

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

as safe for both adults and children, although there is a risk of failure in the initial attempt.1 However, failure rates are higher in children than in adults due to the smaller width of the ureter, making URS challenging in children.1,3

There is controversy regarding the risk of routine prestenting and dilation of balloons to gain ureteral access in children because of the risk of ureteral perforation and ureteral stricture. Ureteral access is often obstructed at the ureteral orifice or intramural ureter, where there are many α1-adrenergic receptors. The presence of alpha blockers can reduce muscle contractions around the ureteral orifice.5 In addition, it can reduce basal tonicity, reduce peristaltic activity and intraluminal tone.3 To our knowledge, there is not much literature about the use of tamsulosin for ureteroscopy in pediatrics. Thus, we conduct a systematic review and meta-analysis to find out the effectiveness of tamsulosin for ureteroscopy access in pediatrics.

MATERIALS AND METHODS

Data sources and literature search strategy

We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020.6 Our search encompassed relevant literature from PubMed, Proquest, EBSCO, and the Cochrane Library databases. We utilized specific search terms such as “alpha blocker”, “alpha adrenergic blocker”, “tamsulosin”, “silodosin”, and “α-blocker” in conjunction with terms like “ureteroscopy”, “ureteroscopic”, and “retrograde intrarenal surgery”. Furthermore, we included terms related to the target population, such as “children”, “adolescence”, “pediatric”, and “school-age children”. To ensure comprehensiveness, we manually examined the reference lists of selected manuscripts for potential articles that met our inclusion criteria.

Eligibility criteria

This systematic review incorporated a variety of study designs, including Randomized Control Trials (RCTs), case-control studies, retrospective cohorts, and prospective cohorts. To be included in this review, studies needed to fulfil specific criteria. Firstly, studies had to compare the use of perioperative alpha blockers with no alpha blockers in the context of ureteroscopy (URS) access. This comparison aimed to examine the potential effects of alpha blockers on the outcomes of interest. Secondly, the study population had to consist of patients who were under the age of 18. Lastly, the reported outcomes of interest included URS success in

the initial attempt and surgical time. Those outcomes were chosen to assess the efficacy and efficiency of utilizing perioperative alpha blockers during URS procedures. To maintain the rigor of our review, we excluded certain types of articles that did not meet our criteria, including case reports, reviews, and conference abstracts, as they were not deemed suitable for inclusion in our analysis.

Data extraction

The data extraction process was carried out independently by 3 reviewers. The data extracted included first author, year of publication, country where the study was conducted, study design, sample sizes, age, sex, body mass index (BMI), stone size, duration of alpha blocker administration, surgical time, and success rate. The primary outcome was the success rate in the initial URS attempt. Secondary outcome was the length of surgical time. Disagreements or discrepancies were discussed by all authors.

Methodological quality and risk of bias assessment

Six reviewers contributed to assessing the quality of bias, with each study independently evaluated by two reviewers using the Newcastle-Ottawa Scale (NOS) for cohort and case-control studies. The NOS is a commonly used tool to assess the quality of non-randomized studies. The maximum score on the NOS is 9. Studies that received a score of 7-9 stars were considered to have a low risk of bias, studies scoring 4-6 stars were considered to have moderate risk, while studies scoring 3 or less stars were considered to have a high risk of bias.7 This rigorous assessment process ensured a comprehensive evaluation of the included studies and provided valuable insights into their methodological quality and potential sources of bias.

Statistical analysis

For the analysis of primary outcomes with dichotomous data, we utilized an OR along with a 95% CI. A p-value below 0.05 was considered statistically significant. This approach allowed us to assess the association between the use of preoperative alpha blockers and the outcomes of interest in a binary manner. On the other hand, secondary outcomes, which involved continuous variables, were analyzed using weighted mean differences (WMD). This method enabled us to compare the differences in means between groups and quantify the effect sizes for these variables. To assess heterogeneity between studies, we calculated the I2 index. If the I2 value exceeded 50%, indicating substantial heterogeneity, we applied the random effects model for the meta-analysis. Conversely, if

the I2 value was below 50%, indicating low heterogeneity, we employed the random-effect model. These models help account for differences across studies and provide a pooled estimate of the effect size. For the statistical analysis, we used RevMan 5.4. software on a Macbook platform. This widely used software facilitated the analysis and synthesis of the data, allowing us to generate forest plots and descriptive narratives to present the outcomes visually and concisely.

RESULTS

Literature search

The comprehensive flow diagram of study selection with subsequent exclusions is presented in Fig 1. A total of 120 studies were found using the search term in four databases. From the first screening, we excluded 42 articles because they did not meet our inclusion criteria from the screening of the title and the abstract. We included

3 suitable English publications in the meta-analysis after removing duplicates and examining the titles, abstracts, and full texts. Of these studies, two were published from the USA and one from Pakistan.

Result of literature extraction Study characteristic

The baseline characteristics of the included studies are presented in Table 1. This study consisted of three articles, including two cohort studies and one case- control study, with a total of 235 participants.1,3,5 The average age in each group ranged from 11.7 to 13.7 years old. The intervention groups received alpha blockers (specifically, tamsulosin), while the control groups did not receive alpha blockers. The duration of alpha blocker administration before the ureteroscopy procedure ranged from 2 to 7 days. All studies utilized tamsulosin as the alpha blocker intervention. The average body mass index

Fig 1. PRISMA flowchart 2020 of the included studies.

TABLE 1. Characteristics of included studies.

(BMI) ranged between 21.2 and 25.2. The average stone size, as reported in the studies, ranged between 2 and 7.44

mm. Based on the length of surgery, the administration of alpha blockers took longer compared to the absence of alpha blockers. The success rate of the three studies indicated that the administration of alpha blockers led to an increased success rate of ureteroscopy access in pediatric patients. There were significant differences of patients’ age, stone and URS size between the two cohort studies.1,5

Quality assessment

Quality assessment was conducted to evaluate the risk of bias using the Newcastle-Ottawa Scale (NOS). The results revealed that the two retrospective studies included in this study obtained a mean total score of 7, while the case-control study obtained a mean total score of 7 as well. These scores indicate that the included studies were considered to be of good quality. The NOS is a widely recognized tool for assessing the quality of non-randomized studies, and its application in this study provides confidence in the reliability and validity of the findings. The high scores obtained by the included studies suggest that they had a low risk of bias and were methodologically robust.7 The NOS assessment is presented in Table 2.

Meta analysis result on the success rate of ureteroscopy access

There was a significant difference in the success rate of ureteroscopy access between the alpha blockers group and the control group, with an odds ratio (OR) of 2.73 (1.52-4.91; 95% confidence interval; p=0.0008). Heterogeneity analysis among the studies yielded an I2 index of 0%. Therefore, a random-effects model was applied based on the collected study heterogeneity. The analysis of the success rate of ureteroscopy access was presented as a forest plot in Fig 2. This funnel plot

showed that it is symmetrical, indicating a low risk of bias (Fig 3).

Meta analysis result on length of surgery

Among the 3 studies included, only 2 studies were measuring the length of surgery. Between the control group and the alpha blocker group, there was no significant difference in surgical time during the ureteroscopy surgery, with a mean difference of 3.46 (-3.59-10.50; 95% confidence interval; p=0.34). The heterogeneity analysis among the studies was low (P=0.79, I2=0%), and a random effect model was used for data synthesis. The analysis of length surgery was presented as a forest plot in Fig 3. This funnel plot showed that it is symmetrical, indicating a low risk of bias (Fig 5).

DISCUSSION

Urolithiasis is a common case, even in children. Recently, several studies have reported an increase in the incidence of pediatric urolithiasis.1,4,5 McGee LM, et al. described the incidence in the last 20 years has been estimated at 4-10%. The increasing incidence of urolithiasis in children has strengthened the evaluation of kidney stone management.1 Pediatrics need a precise identification of the underlying cause and personalized treatments to prevent recurrences of stone formation. It is crucial to see the medical history, find out urinary and dietary habits, perform some tests such as urine and blood tests, as well as analyze urinary stone composition.8 Disease recurrence can be prevented by dietary adjustment and pharmaceutical intervention. Acute management of the condition comprises monitoring with supportive care, medical expulsive therapy (MET), and surgical intervention.9 In the past, treatment for urinary tract stone diseases was performed by open surgeries, but recently there has been a significant drive toward minimally invasive surgery (MIS), such as extracorporeal shockwave lithotripsy (ESWL), ureteroscopy (URS), retrograde intrarenal surgery (RIRS),

Fig 2. The success rate of ureteroscopy access. CI = Confidence Interval

TABLE 2. Newcastle Ottawa Scale for cohort.