Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2023;13(4):e2023307 1 Factors Affecting Topical Treatment Success in Pediatric Scabies Cases: A Cross-Sectional Study Muazzez Cigdem Oba1, Defne Ozkoca2, Rana Basara Sahin3, Didem Senses Kazan4, Gaye Guldiken5, Beril Kara Esen6 1 Department of Dermatology, Health Sciences University, Sancaktepe Sehit Prof. Dr. Ilhan Varank Research and Training Hospital, Istanbul, Turkey 2 Department of Dermatology, Zonguldak Atatürk State Hospital, Zonguldak, Turkey 3 Department of Dermatology, Menemen District State Hospital, Izmir, Turkey 4 Department of Dermatology, Kutahya Evliya Celebi Research and Training Hospital, Kutahya, Turkey 5 Department of Dermatology, Artvin Hopa State Hospital, Artvin, Turkey 6 Esenler District Health Directorate, Republic of Türkiye Ministry of Health, Istanbul, Turkey Key words: children, permethrin, scabies, sulfur, treatment Citation: Oba MC, Ozkoca D, Basara Sahin R, Senses Kazan D, Guldiken G, Kara Esen B. Factors Affecting Topical Treatment Success In Pediatric Scabies Cases: A Cross-Sectional Study. Dermatol Pract Concept. 2023;13(4):e2023307. DOI: https:// doi.org/10.5826/dpc.1304a307 Accepted: September 20, 2023; Published: October 2023 Copyright: ©2023 Oba et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Muazzez Cigdem Oba, MD, Department of Dermatology, Health Sciences University, Sancaktepe Sehit Prof. Dr. Ilhan Varank Research and Training Hospital, Istanbul, Turkey. Email: muazzez.oba@istanbul.edu.tr Patient Consent Statement: All patients legal representants gave written consent to participate in the study. Introduction: Scabies is a common disease that affects the pediatric population. Treatment failure and relapse occur frequently in children. Objectives: We aimed to identify the factors that affect topical treatment success in pediatric scabies patients. Methods: A multicenter cross-sectional study was conducted from April 2022 to December 2022. Pediatric scabies cases were classified as belonging to either the treatment failure (TF) group or the treatment success (TS) group. Results: We enrolled 170 patients for the study. In the TF group, the presence of symptomatic house- hold members and referrals from physicians other than dermatologists were more common (both P < 0.001), and relapse rates and total symptom duration were higher (P = 0.007, P < 0.001, respec- tively). Regarding treatment agents, 5% permethrin was more commonly used in the TF group (71.1% versus 25%; P < 0.001). The proportion of patients treated with sulfur preparations was significantly ABSTRACT 2 Original Article | Dermatol Pract Concept. 2023;13(4):e2023307 Introduction Scabies is a significant global healthcare issue, with a rising incidence and reported outbreaks [1,2]. Treatment failure occurs in approximately one third of the cases of scabies, which possibly contributes to the increasing incidence of the disease in developed countries [3]. Epidemiologic data shows that the most common age range of scabies cases is 10–29 years [4]. Children represent a special population, as there are delays in their diagnosis, and they are frequently insufficiently treated [1]. Thus, treat- ment failure and relapse are frequent in children. In clinical practice, authors have observed a growing number of pediatric scabies cases presenting to dermatology outpatient clinics. To improve treatment outcomes, risk fac- tors for treatment failure should be identified and addressed. Objectives In this study, we aimed to identify the factors that affect top- ical treatment success in pediatric scabies patients presenting to dermatology outpatient clinics. Methods Study Design A multicenter cross-sectional national study was performed from May 2022 to December 2022 on pediatric scabies cases presenting to dermatology outpatient clinics in five different cities. The study was approved by the ethics committee of Sancaktepe Sehit Prof.Dr.Ilhan Varank Research and Train- ing Hospital (no. 38 12-04-2022) and performed in accor- dance with the principles of the Declaration of Helsinki. Written informed consent was obtained from the legal repre- sentatives of the pediatric patients. Patient Population All consecutive pediatric scabies cases were prospectively en- rolled to the study at the time of the outpatient dermatology visit. Patients were classified as belonging to either the treat- ment failure (TF) group or the treatment success (TS) group. Treatment failure cases were diagnosed both clinically and dermatoscopically by the presence of burrows despite topical therapies that had persisted for at least one month. The diag- nosis of the treatment success group was made according to previous patient medical records along with patient history (eg, previous involvement of predilection sites and presence of postinflammatory changes). Data Collection During the dermatology outpatient visit, the following pa- rameters were recorded for each enrolled patient: age, sex, presence of atopic diathesis, travel history, presence of pruri- tus, duration of symptoms, number of household members, number of children in the household, presence of symptom- atic household members, prescribed treatment, referring physician, number of relapses, and application errors. The latter included lack of treatment of close contacts, lack of reapplication, local application of topical products, inap- propriate concentration of topical products, inappropriate quantity of topical products, and lack of head and neck treatment of infants. Statistical Analysis We used SPSS version 21 for the statistical analyses. Median and interquantile range (IQR) values were noted in descrip- tive analyses for continuous variables, and percentages were noted for categorical variables. A Mann–Whitney U test was performed to compare continuous variables between the two groups, whereas categorical variables were compared with the chi-square test and Fischer exact test when appropriate. higher in the TS group (60.7% versus 16.9%; P < 0.001). Misapplication of topical therapy was sig- nificantly more common in the TF group (P < 0.001), with statistically significant errors being (i) lack of treatment of close contacts (p<0,001), (ii) single application (P < 0.001), and (iii) local application (P = 0.027). A multivariate analysis revealed that TS was mainly associated with (i) the presence of at- opy (odds ratio [OR] 6.12, 95% CI: 1.39–27.04), (ii) the absence of symptomatic household members (OR 6.31, 95% CI: 2.14–18.63), and (iii) presentation to a dermatologist rather than another spe- cialist (OR 6.51, 95% CI: 2.11–20.13). The use of permethrin negatively affected treatment success (OR 0.22, 95% CI: 0.07–0.71). Conclusions: Pediatric scabies patients should be treated before other family members become infest- ed and with topicals other than permethrin. In addition, awareness of scabies needs to be increased among non-dermatologists. Original Article | Dermatol Pract Concept. 2023;13(4):e2023307 3 Using variables with P values < 0.25 in univariate analy- ses, factors affecting TS were analyzed with logistic regres- sion analysis. A P value of less than 0.05 was considered significant. Results We enrolled 170 pediatric patients for the study, which in- cluded the TF group (N = 142, 83.5%) and the TS group (N = 28, 16.5%). All patients in the TF group had associ- ated pruritus at referral, and severe pruritus was significantly more commonly present in the TF group (P < 0.001) than in the TS group. The TS group (25%) included significantly more patients with atopic diathesis than the TF group (9.2%; P = 0.026). The presence of symptomatic household members Table 1. Patient characteristics. Treatment failure N = 142 Treatment success N = 28 P Sex N (%) Female 71(50) 17(60.7) 0.3 Male 71(50) 11(39.3) Pruritus N (%) None 0 19(67.9) <0.001 Mild 33(23.2) 7(25) Severe 109(76.8) 2(7.1) Travel history N (%) Yes 130(91.5) 25(89.3) 0.716 No 12(8.5) 3(10.7) Atopy N (%) No 129(90.8) 21(75) 0.026 Yes 13(9.2) 7(25) Symptomatic household members N (%) Present 20(14.1) 17(60.7) <0.001 Absent 122(85.9) 11(39.3) Age (year) median (IQR) 7 (3.75-12) 6 (3.25-13.25) 0.784 Number of household members Median (IQR) 5(4-5) 4 (4-4) 0.081 Number of children in the household Median (IQR) 2 (2-3) 2(2-2) 0.141 Duration of symptoms before first therapy Median (IQR) 30 (15-30) 20 (11-30) 0.083 Total symptom duration Median (IQR) 60 (56.25-120) 60 (32.5-60) 0.007 Number of relapses Median (IQR) 1 (1-2) 0 (0-0) <0.001 IQR = interquartile range was also more common in the TF group (85.9%) than the TS group (39.3%; P < 0.001). Sociodemographic factors, includ- ing number of household members and number of children in the household and duration of symptoms before the first therapy, did not seem to affect treatment results (Table 1). The TF group had significantly higher relapse rates and to- tal symptom duration (P = 0.007 and 0.001, respectively; Table 1). Patients were also classified according to the spe- cialty of the referring physicians. The proportion of patients treated solely by dermatologists was greater in the TS group than the TF group (71.4% versus 20.4%; P < 0.001; Table 2). Regarding errors in application of topical therapy, 96,5% of the patients in the TF group had made at least one error, whereas all except one patient in the TS group had applied the prescription correctly (P < 0.01). A list of 4 Original Article | Dermatol Pract Concept. 2023;13(4):e2023307 Table 2. Specialty distribution of pediatric patients treated for scabies. Treatment failure N = 142 N (%) Treatment success N = 28 N (%) P Referring specialist before presentation to dermatology Emergency physician 24(16.9) 1(3.6) 0.082 General practitioner 53(37.3) 4(14.3) 0.018 Pediatrician 42(29.6) 4(14.3) 0.096 Dermatologist alone 29(20.4) 20(71.4) <0.001 Table 3. Application errors of topical therapy. Treatment Failure N = 142 N (%) Treatment Success N = 28 N (%) P Application error Present 137(96.5) 1(3.6) <0.001 Application errors Close contacts not treated 73(51.4) 0(0.0) <0.001 Lack of reapplication 57(40.1) 0(0.0) <0.001 Local application 21(14.8) 0(0.0) 0.027 Inappropriate dosage 16(11.3) 1(3.6) 0.312 Inappropriate quantity 14(9.9) 0(0.0) 0.130 Lack of head-neck treatment of infants 6(4.2) 0(0.0) 0.591 application errors can be found in Table 3. In the TF group, statistically significant errors were the following: (i) close contacts were not treated (P < 0.001), (ii) reapplication in the first week was not performed (P < 0.001), and (iii) treatment was not applied to the whole body (P = 0.027). Regarding the referring physician, patients treated solely by dermatologists made significantly fewer application errors (Table 4). Patients without atopic diathesis (83.3%) were more prone to make errors in the application of topicals than atopic patients (65%), with a borderline statistical difference (P = 0.066). Regarding treatment agents (Table 5), 5% permethrin lotion was more commonly used in the TF group than in the TS group (71.1% versus 25%; P < 0.001). However, the ratio of patients treated with sulfur preparations was significantly higher in the TS group (60.7% versus 16.9%; P < 0.001). Univariate and Multivariate Analyses Univariate and multivariate analyses were performed to iden- tify the factors associated with treatment success (Table 6). The predictors of treatment success were (i) the presence of atopy (odds ratio [OR] 6.12, 95% CI: 1.39–27.04), (ii) the absence of symptomatic household members (OR 6.31, 95% CI: 2.14–18.63), and (iii) presentation to a dermatolo- gist rather than another specialist (OR 6.51, 95% CI: 2.11– 20.13). The use of permethrin lotion negatively affected treatment success (OR 0.22, 95% CI: 0.07–0.71). Conclusions The present study focuses on factors affecting treatment suc- cess of anti-scabietic topical treatments in pediatric popula- tion. We identified presence of atopy, absence of symptomatic household members and presentation to dermatologists rather than other specialties as predictors of treatment suc- cess whereas use of permethrin lotion negatively affected treatment success. Several studies have previously investi- gated risk factors of treatment failure in scabies, focusing on different treatment methods and clinical features. In a multicenter study conducted in France, monotherapy with topical benzyl benzoate and a single intake of oral ivermec- tin were identified as predictors of treatment failure in mul- tivariate analyses [3]. Lee et al reported that limited mobility and topical steroid use before diagnosis were associated with treatment failure in topical permethrin treatment [5]. Boralevi et al studied the clinical characteristics of pe- diatric scabies according to age. They reported a history of Original Article | Dermatol Pract Concept. 2023;13(4):e2023307 5 Table 4. Specialty distribution of pediatric patients treated for scabies according to presence of application errors. Application error Absent N = 32 N (%) Present N = 138 N (%) P Referring specialist before presentation to dermatology Emergency physician 1(3.1) 24(17.4) 0.05 General practitioner 5(15.6) 52(37.7) 0.017 Pediatrician 6(18.8) 40(29) 0.226 Dermatologist alone 21(65.6) 28(20.3) <0.001 Table 5. Topical therapy agents used in treatment failure and treatment success groups. Treatment failure N = 142 N (%) Treatment success N = 28 N (%) P Topical therapy agent Permethrin 5% lotion 101(71.1) 7(25) <0.001 Permethrin 5% cream 9(6.3) 0(0.0) 0.358 Wilkinson ointment (sulfur 12.5%., tar 12.5%)) 26(18.3) 5(17.9) 0.955 Sulfur in vaseline 24(16.9) 17(60.7) <0.001 Other (benzyl benzoate, balsam of Peru) 4(2.8) 1(3.6) 1.000 Table 6. Factors associated with treatment success in univariate and multivariate analyses. Univariate Multivariate OR %95CI P OR %95CI P Sex (ref. Female) Male 0.65 0.28-1.48 0.302 0.37 0.12-1.20 0.098 Age (year) 1.02 0.94-1.10 0.683 1.05 0.95-1.16 0.364 Atopy (ref. Present) Absent 3.31 1.18-9.25 0.023 6.12 1.39-27.04 0.017 Symptomatic household members (ref. Present) Absent 9.43 3.86-23.04 <0.001 6.31 2.14-18.63 0.001 Presentation to dermatologist alone (ref. No) Evet 9.74 3.9-24.34 <0.001 6.51 2.11-20.13 0.001 Use of permethrin lotion (ref. No) Yes 0.14 0.53-0.34 <0.001 0.22 0.07-0.71 0.011 CI = 95% confidence Interval; OR = odds ratio;, ref. = reference category.Nagelkerke R2:0,491, Hosmer and Lemeshow:0,689 atopic dermatitis in 12.8% of 323 pediatric patients, mainly in patients under 15 years of age. A very similar proportion of pediatric patients in our cohort (11.8%) had atopy. These children with atopic diathesis were found to respond better to therapies. We hypothesized that parents of atopic children would have better compliance with topical therapies. In fact, in our series, patients with atopic diathesis made fewer er- rors in the application of topical therapies than non-atopic patients. Our study showed that the presence of symptomatic household members decreased treatment success. In ad- dition, total symptom duration was significantly longer in the TF group. We can conclude that the identification and treatment of the disease before its propagation is associated with better treatment outcomes. In this regard, prompt and correct recognition of the disease by all specialists is im- portant, as scabies patients also present to general practi- tioners, pediatricians, and emergency departments [6,7]. In 6 Original Article | Dermatol Pract Concept. 2023;13(4):e2023307 The limitations of our study include a lack of longitu- dinal follow-up with the patients and a relatively small TS group, as patients typically present to dermatology outpa- tient clinics with persistent infection. In conclusion, in line with previous reports of perme- thrin resistance, pediatric scabies cases should be prescribed with topicals other than permethrin, preferably sulfur con- taining preparations. Pediatric patients should be treated promptly before other family members are affected. Special care should be taken in topical treatment of scabies patients without atopic diathesis as they are more prone to make ap- plication errors. In addition, awareness of scabies treatment needs to be increased among non-dermatologists. References 1. Sunderkötter C, Wohlrab J, Hamm H. Scabies: Epidemiology, Diagnosis, and Treatment. Dtsch Arztebl Int. 2021;118(41): 695-704. DOI: 10.3238/arztebl.m2021.0296. PMID: 34615594. PMCID: PMC8743988. 2. Özden MG, Ertürk K, Kartal SP, et al. An extraordinary outbreak of scabies in Turkey. J Eur Acad Dermatol Venereol. 2020;34(12), e818-e820. DOI: 10.1111/jdv.16699. PMID: 32491243. 3. Aussy A, Houivet E, Hébert V, et al. Risk factors for treatment failure in scabies: a cohort study. Br J Dermatol. 2019;180(4):888-893. DOI: 10.1111/bjd.17348. PMID: 30376179. 4. Lassa S, Campbell MJ, Benett CE. Epidemiology of sca- bies prevalence in the U.K. from general practice records. Br J Dermatol. 2011;164(6):1329–1334. DOI: 10.1111/j.1365 -2133.2011.10264.x. PMID: 21574970. 5. Lee SK, Kim JH, Kim MS, Lee UH. Risk factors for scabies treat- ment resistance: a retrospective cohort study.  J Eur Acad Der- matol Venereol. 2022;36(1):126-132. DOI: 10.1111/jdv.17713. PMID: 34592030. 6. Albakri L, Goldman RD. Permethrin for scabies in children. Can Fam Physician.  2010;56(10):1005-1006. PMID:  20944041. PMCID: PMC2954078. 7. Tripathi R, Knusel KD, Ezaldein HH, Bordeaux JS, Scott JF. Emergency Department Visits due to Scabies in the United States: A Retrospective Analysis of a Nationally Representative Emer- gency Department Sample. Clin Infect Dis. 2020;70(3):509-517. DOI: 10.1093/cid/ciz207. PMID: 30874793. 8. Sunderkötter C, Feldmeier H, Fölster-Holst R, et al. S1 guide- lines on the diagnosis and treatment of scabies – short version. J Dtsch Dermatol Ges. 2016;14(11):1155-1167. DOI: 10.1111 /ddg.13130. PMID: 27879074. 9. Yürekli A. Is there a really resistance to scabies treatment with permethrin? In vitro killing activity of permethrin on Sarcoptes scabiei from patients with resistant scabies. Der- matol Ther. 2022;35(3):e15260. DOI:  10.1111/dth.15260. PMID: 34897912. 10. Mayer KE, Biedermann T, Posch C. European scabies challenge: what about permethrin-resistant mites?  Eur Acad Dermatol Ve- nereol. 2022;36(9):e712-e713. DOI: 10.1111/jdv.18181. PMID: 35470925. our cohort, the majority of patients (71.8%) were referred to dermatology outpatient clinics by non-dermatologists. How- ever, patients treated solely by dermatologists had better treatment outcomes than those referred by other specialists. Treatment application errors were also less common in pa- tients treated solely by dermatologists. We stress that aware- ness of the proper treatment of scabies needs to be increased among general practitioners, pediatricians, and emergency physicians. At the time of the study, oral ivermectin was unavail- able in our country; thus, all patients in our study cohort were only treated with topical therapies. Topical permetrin is the first-line therapy for scabies in children [8]. Although in vitro results prove its effectiveness [9], longer exposure times are required for its effectiveness, and widespread clin- ical resistance is frequently reported [10]. In fact, the ob- servations of Mazzatenta et al in daily practice led them to modify the standard treatment regimen of permethrin 5% cream at days 0 and 7 to twice or thrice the weekly regi- men [11]. Even with the latter modified permethrin regimen, the authors report treatment failure in 2 out of 3 patients. Thus, it seems necessary to change or at least modify the first-line treatment of scabies [11]. Combined therapy with oral ivermectin and topical benzyl benzoate seems to be the best therapeutic approach, with 100% treatment success in newly diagnosed patients and patients unresponsive to per- methrin [12]. In infants weighing less than 15 kg, topical ivermectin is recommended [13]. According to our data, per- methrin lotion negatively affected treatment success. We sug- gest that sulfur-containing topicals should be preferred over permethrin lotion in pediatric scabies cases. Improper application of topical agents is a common problem in scabies. In a prospective study that included 21 young patients who were clearly instructed on how to ap- ply topical therapies, all patients made application errors. Of note, predilection sites such as ankles, interdigital spaces, and the sacral region were insufficiently treated in 62%, 33%, and 24% of patients, respectively [14]. This study shows the important pitfall of topical therapies, as the rates of misapplication could be higher in children. In our study, 81% of our patients had made at least one application error with topical treatment. Statistically significant errors were the lack of treatment of close contacts, lack of reapplication on first week, and local application of the treatment. Our results were consistent with a descriptive study involving 31 scabies patients with treatment failure in which persistence of infestation was linked to insufficient treatment of close contacts, absence of a repeated treatment, and insufficient efficacy of the available treatments [15]. Original Article | Dermatol Pract Concept. 2023;13(4):e2023307 7 era of permethrin resistance. J Eur Acad Dermatol Venereol. 2022;36(7):e557–9. DOI: 10.1111/jdv.18026. PMID: 35188996. 14. Nemecek R, Stockbauer A, Lexa M, Poeppl W, Mooseder G. Ap- plication errors associated with topical treatment of scabies: an observational study. J Dtsch Dermatol Ges. 2020;18(6):554-559. DOI: 10.1111/ddg.14122. PMID: 32469466. 15. De Sainte Marie B, Mallet S, Gaudy-Marqueste C, et al. Gales en échec de traitement : étude observationnelle [Therapeutic fail- ure in scabies: An observational study]. Ann Dermatol Venereol. 201;143(1):9-15. DOI: 10.1016/j.annder.2015.10.588. PMID: 26651923. 11. Mazzatenta C, Piccolo V, Argenziano G, Bassi A. Is Scabies be- coming less sensitive to permethrin therapy? J Eur Acad Derma- tol Venereol. 2021;35(9):e607-e609. DOI: 10.1111/jdv.17339. PMID: 33974300. 12. Bassi A, Piccolo V, Mazzatenta C. One-shot” combined therapy with oral ivermectin and local benzyl benzoate: is the current best therapeutic option in the era of permethrin resistant sca- bies?  Travel Med Infect Dis. 2023;53:102585. DOI: 10.1016/j .tmaid.2023.102585. PMID: 37149241. 13. Bassi A, Piccolo V, Argenziano G, Mazzatenta C. Topical iver- mectin: an off-label alternative to treat neonatal Scabies in the