Effect of conversion from intravenous to oral administration on cyclosporine exposure in pediatric allogeneic hematopoietic stem cell transplantation

Effect of conversion from intravenous to oral administration on cyclosporine exposure in pediatric allogeneic hematopoietic stem cell transplantation | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 22 October 2025 V1 Latest version Share on Effect of conversion from intravenous to oral administration on cyclosporine exposure in pediatric allogeneic hematopoietic stem cell transplantation Authors : Wang Junyan 0009-0008-3356-1660 , Zhang Meng , Wang Lingkun , Yang Jufei , Huang Lingfei , and Miao Jing [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176112036.68711033/v1 125 views 101 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Aim To evaluate the effect of converting administration route from intravenous to oral on cyclosporine exposure in pediatric allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Methods Children underwent allo-HSCT and administered with cyclosporine for the prevention of graft-versus-host disease (GvHD) were included. The cyclosporine trough concentration (C 0 ), the trough concentration-dose ratio (CDR), and the conversion ratio of switching from intravenous to oral administration were evaluated. Meanwhile, factors related to the bioavailability of cyclosporine were also investigated. Results A total of 67 children with 280 concentrations were involved. The conversion ratio of switching from intravenous to oral administration was approximately 1:2, and a significant decrease in cyclosporine CDR (110.5 vs 41.4 mg/kg per μg/L, P <0.001) was observed. The overall bioavailability of cyclosporine was approximately 35 %. Age and increased transaminases had significantly impact on cyclosporine bioavailability, with coefficient of -10.18 (95% CI: -17.07, -3.29, P =0. 004) and -21.18 (95% CI: -26.72, -15.65, P <0.001), respectively, while gender, conversion date, oral formulation, oral mucositis, diarrhea and concomitant antifungal agents presented no significant impact. Conclusions A conversion ratio of 1:3 was more appropriate for pediatric allo-HSCT recipients when switching cyclosporine from intravenous to oral administration. Children younger than 3 years or with increased transaminases had significantly lower cyclosporine bioavailability. Cyclosporine concentration should be monitored more frequently during the conversion period. Effect of conversion from intravenous to oral administration on cyclosporine exposure in pediatric allogeneic hematopoietic stem cell transplantation Wang Junyan 1 , Zhang Meng 1 , Wang Lingkun 1 , Yang Jufei 1 , Huang Lingfei 1 , Miao Jing 1 1 Department of Pharmacy, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310052, China; Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China 1. What is already known about this subject: The optimal dose conversion ratio of cyclosporine when alter the administration route from intravenous to oral remains inconclusive in children. Few studies have investigated the factors related to the cyclosporine bioavailability in pediatric allo-HSCT recipients. 2. What this study adds: A conversion ratio of 1:3 seemed more appropriate for pediatric allo-HSCT recipients when switching cyclosporine from intravenous to oral administration. Children under 3 years old or with increased transaminases had significantly lower cyclosporine bioavailability. Cyclosporine concentration should be monitored more frequently during the conversion period. Abstract Aim To evaluate the effect of converting administration route from intravenous to oral on cyclosporine exposure in pediatric allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Methods Children underwent allo-HSCT and administered with cyclosporine for the prevention of graft-versus-host disease (GvHD) were included. The cyclosporine trough concentration (C 0 ), the trough concentration-dose ratio (CDR), and the conversion ratio of switching from intravenous to oral administration were evaluated. Meanwhile, factors related to the bioavailability of cyclosporine were also investigated. Results A total of 67 children with 280 concentrations were involved. The conversion ratio of switching from intravenous to oral administration was approximately 1:2, and a significant decrease in cyclosporine CDR (110.5 vs 41.4 mg/kg per μg/L, P <0.001) was observed. The overall bioavailability of cyclosporine was approximately 35 %. Age and increased transaminases had significantly impact on cyclosporine bioavailability, with coefficient of -10.18 (95% CI: -17.07, -3.29, P =0. 004) and -21.18 (95% CI: -26.72, -15.65, P <0.001), respectively, while gender, conversion date, oral formulation, oral mucositis, diarrhea and concomitant antifungal agents presented no significant impact. Conclusions A conversion ratio of 1:3 was more appropriate for pediatric allo-HSCT recipients when switching cyclosporine from intravenous to oral administration. Children younger than 3 years or with increased transaminases had significantly lower cyclosporine bioavailability. Cyclosporine concentration should be monitored more frequently during the conversion period. KEYWORDS pediatric allogeneic hematopoietic stem cell transplantation, cyclosporine, bioavailability, conversion ratio Introduction Cyclosporine is an immunosuppressant extensively used for the prevention and treatment of graft-versus-host disease (GvHD) in pediatric allogeneic hematopoietic stem cell transplantation (allo-HSCT). 1,2 Lower trough concentration (C 0 ) of cyclosporine in the early period post-transplantation is significantly associated with higher risk of acute GvHD (aGvHD). 3,4 Besides, cyclosporine has a narrow therapeutic range and large inter- and intra-individual pharmacokinetic variability, 5 mainly due to its erratic absorption and diverse metabolic capability in patients. Therefore, therapeutic drug monitoring (TDM) of cyclosporine is strongly recommended, and frequent monitoring is needed in the early period of HSCT, to ensure cyclosporine C 0 in the appropriate range. 2 In the early period of allo-HSCT, patients may experience oral mucositis, nausea, or diarrhea after the conditioning regimen, and are unable to take oral medications. Therefore, cyclosporine is first administered intravenously in those patients 6 . After 2 - 4 weeks post-transplantation, cyclosporine is then converted from intravenous to oral administration when the mucous membrane has recovered. 6 The recommended conversion ratio from intravenous to oral administration is 1:2. 7 However, several studies, mostly based on adults, have reported that various factors, including gastrointestinal inflammation and coadministration of antifungal agents, 8,9 may have impact on it. Therefore, the optimal conversion ratio remains uncertain, especially for children. Triazole antifungal agents are commonly used in allo-HSCT post-transplantation for prophylaxis of invasive fungal infection. 10 They are inhibitors of cytochrome P450 3A4 (CYP3A4) enzymes, 11 which are also responsible for cyclosporine metabolism. 5 Therefore, the cyclosporine concentration increases when co-administered with triazole antifungal agents. 12 Several studies have reported that fluconazole, voriconazole, posaconazole, and other non-azole agents have different effects on cyclosporine pharmacokinetics during the conversion period from intravenous to oral. 9,13,14 Besides, since cyclosporine is primarily absorbed and metabolized in the intestine and liver, it is not clear whether its bioavailability is affected by diarrhea or changes in liver function of patients. As far as we know, only one study reported that gastrointestinal inflammation caused by mucositis or diarrhea increases the cyclosporine exposure in 7 children undergoing bone marrow transplantation. 8 Whether liver function alteration has an impact on the cyclosporine bioavailability during administration route switching remains unclear. Our study aims to evaluate the change of cyclosporine concentration in Chinese HSCT children during the conversion period from intravenous to oral administration, and to investigate the factors related to the cyclosporine bioavailability. Materials and methods Patients A retrospective and single-center study was conducted at Children’s Hospital, Zhejiang University School of Medicine in China. Children received allo-HSCT and administered with cyclosporine for the prevention of GvHD were enrolled from January 2019 to March 2022. Children experienced conversion from intravenous to oral administration of cyclosporine, and with at least one steady-state C 0 measured during the last intravenous and first oral dosage, were included. Children with incomplete documentation or had cyclosporine C 0 lower than the limit of quantitation were excluded. The study was approved by the Ethics Committee of the Children’s Hospital, School of Medicine, Zhejiang University (2021-IRB-197) and conducted in accordance with the Declaration of Helsinki. Drug regimens All patients were administered with cyclosporine combined with methotrexate and mycophenolate mofetil as a standard GvHD prophylaxis regimen. Cyclosporine (Sandimmun ® , 50 mg/mL, Novartis) was first administered intravenously the day before HSCT by infusion, and switched to oral formulation, including soft gelatin capsule (Neocyspin ® , 25 mg/capsule, Huadong Medicine) and solution (Neocyspin ® , 100 mg/mL, Huadong Medicine) as appropriate. Cyclosporine was dosed twice daily during the intravenous and oral administration. The dosage of cyclosporine was adjusted according to the C 0 drawn by TDM. The recommended therapeutic level was 200 - 300 μg/L during the first 3 - 4 weeks. Moreover, antifungal agents, including posaconazole, voriconazole, or other non-azole agents, were empirically used as antifungal prophylaxis for all patients. Cyclosporine quantitation Whole blood samples were collected at 12 hours after infusion in intravenous administration, or before the morning dose in oral administration from patients who achieved steady-state concentration. The cyclosporine C 0 was measured by chemiluminescent microparticle immunoassay (ARCHITECT I1000SR, Abbott Laboratories, Chicago, IL). The quantitative range of the assay was 30.0 - 1500.0 μg/L, and the total precision was less than 15%. Concentrations lower than the limit of quantification (30.0 μg/L) were excluded in the analysis. Clinical data collection The gender, age, body weights of patients, conversion date, oral formulation, concomitant antifungal agents, daily doses, and concentrations of cyclosporine were collected. The weight-adjusted daily dose and trough concentration-dose ratio (CDR) of cyclosporine were calculated. The percentage of patients with cyclosporine C 0 lower than 200 μg/L, 200 - 300 μg/L, and higher than 300 μg/L was analyzed. The bioavailability of cyclosporine was calculated by dividing the cyclosporine CDR of intravenous by that of oral administration. The laboratory variables of liver function, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) of patients during conversion, were collected. Those patients with at least one parameter three-fold higher than the upper limit of normal reference were considered as having increased transaminases. The occurrence of oral mucositis, diarrhea, and aGvHD was collected according to the electronic medical records. Statistical analysis All analyses were performed using SPSS software (version 24.0, IBM, Armonk, NY, USA) and GraphPad Prism (version 8.0, GraphPad Software, CA, USA). Continuous data were presented as median and range, and categorical data were presented as frequencies and proportions (%). The cyclosporine C 0 and CDR of patients during intravenous and oral administration were compared using the Mann-Whitney test. The impact of factors related to cyclosporine bioavailability, including gender, age, conversion date, oral formulation, concomitant antifungal agents, oral mucositis, diarrhea, and increased transaminases, was evaluated by general linear model. Difference with P < 0.05 was considered to be statistically significant. Patients demographic A total of 67 patients (38 boys and 29 girls) were included in the study. The demographic of patients was summarized in Table 1. The median age of the patients was 7.6 years, and the median body weight was 22.8 kg. Twelve children (17.9%) were aged under 3 years old. The ALT and AST of patients during conversion were 25.0 (5.0-169.0) U/L and 21.0 (7.0-122.0) U/L, respectively. Approximately one in four patients was diagnosed with acute myeloid leukemia (AML), and one in five patients was severe aplastic anemia (SAA). The percentages of patients received stem cells derived from cord blood, bone marrow, and peripheral blood were 28.4%, 10.4%, and 61.2%, respectively. Approximately 73% of the patients were administered with posaconazole, followed by voriconazole and other non-azole antifungal agents. The median day of switching cyclosporine from intravenous to oral administration was 19 days posttransplant. TABLE 1 Patients characteristics Patients（Male/Female） 67 (38/29) Age, years 7.6 (0.4 - 14.7) Weight, kg 22.8 (6.1 - 59.3) ALT, U/L 25.0 (5.0 - 169.0) AST, U/L 21.0 (7.0 - 122.0) Diagnosis SAA 21 (31.3 %) AML 24 (35.8 %) ALL 5 (7.5 %) HLH 3 (4.5 %) WAS 4 (6.0 %) others 10 (14.9 %) Stem cell source Cord blood 19 (28.4 %) Bone marrow 7 (10.4 %) Peripheral blood 41 (61.2 %) Donor related 41 (61.2 %) unrelated 26 (38.8 %) Day of switching from intravenous to oral posttransplant/days 19 (11 - 29) Co-medicated antifungal drug Posaconazole 49 (73.1 %) Voriconazole 10 (14.9 %) Non-azoles 8 (12.0 %) Oral mucositis 19 (28.4 %) Diarrhea 11 (16.4 %) Increased transaminases 3 (4.5 %) ALT alanine aminotransferase, AST aspartate aminotransferase, SAA severe aplastic anemia, AML acute myeloid leukemia, ALL acute lymphatic leukemia, HLH Hemophagocytic lymphohistiocytosis, WAS Wiskott-Aldrich syndrome Bioavailability and concentrations of cyclosporine A total of 280 cyclosporine concentrations were collected, including 162 from intravenous and 118 from oral administration. The mean daily dose of intravenous and oral administration was 2.0 and 4.0 mg/kg, and the overall conversion ratio was 1:2 (Figure 1A), and the bioavailability of cyclosporine after conversion was 35.1% (95% CI: 35.0 - 42.8%). The median cyclosporine C 0 of all patients was significantly reduced by 28.7 % when switching from intravenous to oral administration (234.1 μg/L vs 167.0 μg/L, P <0.001) (Figure 1B). The percentage of patients with cyclosporine C 0 between 200 - 300 μg/L reduced from 56.2 % to 27.1 %, while patients with C 0 lower than 200 μg/L increased from 32.7 % to 67.0 % (Figure 1C), and approximately 30 % of them were below 100 μg/L. Additionally, the CDR of cyclosporine was also significantly reduced by 62.6 % during conversion from intravenous to oral administration (110.5 mg/kg per μg/L vs 41.4 mg/kg per μg/L, P <0.001) (Figure 1D). FIGURE 1 Cyclosporine concentrations during intravenous and oral administration A: The cyclosporine trough concentrations during intravenous and oral administration. B: The percentage of cyclosporine concentration cyclosporine during intravenous and oral administration The role of antifungal agents For patients co-medicated with posaconazole, voriconazole and other non-azole antifungal agents, the median cyclosporine CDR were 110.9 mg/kg per μg/L, 106.1 mg/kg per μg/L, and 108.2 mg/kg per μg/L during intravenous administration, respectively, then reduced to 43.5 mg/kg per μg/L, 49.9 mg/kg per μg/L, and 24.8 mg/kg per μg/L when transferring to oral administration (Figure 2A). For patients with posaconazole, voriconazole, and non-azoles, the cyclosporine bioavailability was 38.9% (95% CI: 36.1 - 45.3%), 31.0% (95% CI: 23.1 - 43.7%), and 30.7% (95% CI: 20.5 - 49.3%), respectively, and no significant difference was observed ( P =0.242) (Figure 2B). FIGURE 2 The impact of antifungal agents on the bioavailability of cyclosporine during transition from intravenous to oral Bioavailability of cyclosporine According to the results of univariate analysis, age, concomitant antifungal agents, and increased transaminases were observed to have a potential impact on the cyclosporine bioavailability ( P <0.1), while gender, conversion date, oral formulation, oral mucositis, and diarrhea were not associated with it. Then in the multivariate analysis, age younger than 3 years old and increased transaminases were proved to be independent factor significantly influencing cyclosporine bioavailability, with coefficient of -10.18 (95% CI: -17.07, -3.29, P =0. 004) and -21.18 (95% CI: -26.72, -15.65, P <0.001), respectively, whereas concomitant antifungal agents presented no significant impact ( P =0.142) (Table 3). TABLE 3 Factors associated with cyclosporine bioavailability Coefficient (95% CI) p -value Coefficient (95% CI) p -value Gender Male reference Female 1.36 (-6.54, 9.25) 0.736 Age <3 years -11.68 (-19.47, -3.90) 0.003 -10.18 (-17.07, -3.29) 0.004 ≥3 years reference reference Conversion date 0.31 (-0.50, 1.13) 0.455 Oral formulation Soft gelatin capsule reference Solution 1.79 (-6.50, 10.07) 0.673 Antifungal agent 0.066 0.142 Posaconazole reference reference Voriconazole -7.30 (-16.87, 2.26) 0.135 -7.15 (-15.24, 0.94) 0.083 Non-azoles -5.76 (-17.77, 6.26) 0.348 -7.38 (-19.20, 4.44) 0.221 Oral mucositis No reference Yes 1.86 (-7.04, 10.76) 0.682 Diarrhea No reference Yes -2.27 (-11.74, 7.20) 0.639 Increased transaminases No reference reference Yes -19.80 (-24.01, -15.58) <0.001 -21.20 (-27.73, -12.66) <0.001 Incidence of aGvHD Among all the 67 patients, grade Ⅰ-Ⅳ aGvHD was seen in 18 children, with a median onset time of 41 days post-transplantation. For patients with aGvHD, the cyclosporine bioavailability was 36.6%, slightly lower than that without aGvHD (39.8%). Nevertheless, no significant association between the cyclosporine bioavailability and the incidence of aGvHD was observed ( P =0.471). Discussion Cyclosporine-based immunosuppressive regimen is the first-line treatment for the prevention of GvHD in pediatric allo-HSCT. Conversion cyclosporine from intravenous to oral administration is common during the treatment, and the conversion ratio in pediatric allo-HSCT is empirically decided based on the data from adults. 7 However, a few studies have reported that the bioavailability of cyclosporine in pediatric allo-HSCT is lower than in adults. 8,15 Therefore, the optimal conversion ratio for children needs to be further evaluated. Our present study attempted to investigate the potential factors influencing the bioavailability of cyclosporine in pediatric allo-HSCT during the transition from intravenous to oral administration, and provide a more appropriate conversion ratio of cyclosporine for children. Our study proved that switching the route of cyclosporine administration significantly reduced the cyclosporine concentration, in accordance with the earlier studies. 9,13,14 Besides, the cyclosporine concentration decreased lower than expected, even though the dose had been doubled. The overall bioavailability of cyclosporine is approximately 35%, lower than the previous studies in adults (58%-80%), 9,13,14 but similar to the findings in children (43%). 16 Therefore, according to our results, a conversion ratio of 1:3 was more appropriate for pediatric allo-HSCT recipients when switching cyclosporine from intravenous to oral administration. Our study observed that age and increased transaminases contributed to the aforementioned lower bioavailability. Patients younger than 3 years old had lower cyclosporine bioavailability during the transition period. Similar results were reported by Hpoou 15 in a group of young children aged under 3 years (1.1-2.5 years) old undergoing renal transplantation, and the cyclosporine bioavailability was low (21.8%). The reasons might be due to the small bowel length of young children, and the resulting less absorption of cyclosporine. 8,15 Besides, the clearance of cyclosporine was reported to be age-related. 17,18 Younger children had higher cyclosporine clearance and lower trough concentration, therefore, lower oral bioavailability was observed. The underlying reason for the age-related difference in clearance may be the age-dependent increase in protein binding rate 17 and developmental changes in metabolic enzymes and transporters in children. 19 Meanwhile, increased transaminases were observed to significantly reduce the cyclosporine bioavailability. The elevation of transaminase levels indicated liver injury in patients. Since the absorption of cyclosporine depends on bile secretion in the liver, 20 and its metabolism is mediated by liver enzymes and transporters, 21 the impairment of liver function may cause changes in cyclosporine exposure by affecting various stages of the pharmacokinetic process. However, there are only 3 patients with increased transaminases in our study, which may have implications for the reliability of the findings. Therefore, the effect of increased transaminase levels on the cyclosporine exposure and its potential mechanisms needs to be investigated by further studies with larger samples. No significant impact of azole antifungal agents on cyclosporine exposure was observed, unlike previous studies. Atiq 14 reported that patients co-administered with voriconazole had higher cyclosporine bioavailability of nearly 100%, when compared to those with fluconazole or without azole co-medication. Similar results were reported by Kimura 9 that cyclosporine bioavailability was much higher in patients with voriconazole (87%) than those with other antifungal agents (fluconazole, itraconazole, and micafungin). The published studies compared the influence of voriconazole and fluconazole or other non-azole antifungal agents such as micafungin. As known for us, voriconazole is a stronger CYP3A4 inhibitor than fluconazole, 22 and contributes to the higher cyclosporine exposure and bioavailability. However, in our study, patients were cotreated with voriconazole and posaconazole. Voriconazole is reported to be a more potent CYP3A4 inhibitor than posaconazole, but posaconazole is an inhibitor of P-glycoprotein (P-gp) and may increase the absorption of cyclosporine by inhibiting the export of cyclosporine out of the cell. 22,23 Therefore, the cyclosporine bioavailability of patients co-administered with voriconazole and posaconazole were comparable in our study. Moreover, the influence of gender, conversion date, oral formulation, oral mucositis, and diarrhea on cyclosporine bioavailability was also evaluated, but no significant impact was observed. The soft gelatin capsule and oral solution of cyclosporine were bioequivalent according to our findings, consistent with the previous study. 16 Besides, there was no influence of oral mucositis or diarrhea on the cyclosporine exposure in our study. Mucositis and diarrhea might cause gastrointestinal inflammation, which was reported to increase the cyclosporine bioavailability because of increased capillary permeability, decreased P-gp and CYP3A4 function, decreased gut motility, and prolonged absorption in the intestinal. 8,24 However, decreased cyclosporine absorption was also reported in patients with diarrhea, which was related to a relatively small absorptive window in the proximal small intestine. 25 Therefore, due to the counteracting effects, diarrhea presented no significant impact on the cyclosporine bioavailability. There are several limitations in our study. First, our study was retrospective designed in a single center, and the patient number in subgroups was small. The effect of factors, including increased transaminase levels and contaminant azoles, on the conversion period could not be fully evaluated due to the limited sample size. Second, the cyclosporine bioavailability was calculated based on CDR, rather than the ratio of area under the concentration-time curve (AUC) and dose. The AUC is definitely a more accurate parameter representing cyclosporine exposure. However, it is difficult to collect serial blood samples from children to calculate the AUC. Although the trough concentration is widely accepted in cyclosporine TDM, further studies should be conducted to evaluate the bioavailability based on AUC. Finally, our results were generated based on the cyclosporine formulation from Novartis and Huadong Medicine. Whether they are applicable to the agents of other manufacturers still warrants further investigation. Conclusions In conclusion, our study recommended a conversion ratio of 1:3 for pediatric allo-HSCT recipients when switching cyclosporine from intravenous to oral administration during the treatment. Age younger than 3 years and with increased transaminases were significantly associated with lower cyclosporine bioavailability. Cyclosporine concentration should be monitored more frequently during the conversion period. AUTHOR CONTRIBUTIONS Wang Junyan, Huang Lingfei and Miao Jing contributed to research conception and design, Wang Junyan and Zhang Meng collected and cleaned the data, Wang Junyan analysed the data, interpreted the results and wrote the manuscript, Wang Junyan, Zhang Meng, Wang Lingkun, Yang Jufei, Huang Lingfei and Miao Jing contributed to results interpreting, manuscript review and revision. All the authors have approved the final version of the manuscript. CONFLICT OF INTEREST STATEMENT All authors declare no conflicts of interest. DATA AVAILABILITY STATEMENT The data supporting the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available for protection of patients’ privacy. REFERENCES 1. 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Authors Affiliations Wang Junyan 0009-0008-3356-1660 Zhejiang University School of Medicine Children's Hospital National Clinical Research Center for Child Health View all articles by this author Zhang Meng Zhejiang University School of Medicine Children's Hospital National Clinical Research Center for Child Health View all articles by this author Wang Lingkun Zhejiang University School of Medicine Children's Hospital National Clinical Research Center for Child Health View all articles by this author Yang Jufei Zhejiang University School of Medicine Children's Hospital National Clinical Research Center for Child Health View all articles by this author Huang Lingfei Zhejiang University School of Medicine Children's Hospital National Clinical Research Center for Child Health View all articles by this author Miao Jing [email protected] Zhejiang University School of Medicine Children's Hospital National Clinical Research Center for Child Health View all articles by this author Metrics & Citations Metrics Article Usage 125 views 101 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Wang Junyan, Zhang Meng, Wang Lingkun, et al. 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