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Probiotics supplement in children with severe hand, foot, and mouth disease

Probiotics supplement in children with severe hand, foot, and mouth disease Background: Severe hand, foot, and mouth disease (HFMD) is an acute infectious disease caused by infection with serotypes of Enterovirus A, most commonly by enterovirus A71 and coxsackievirus A16. Clinical symptoms usually include fever, malaise, rashes on hands and feet, and oral vesicles. Of note, severe and even life-threatening complications can develop rapidly in young children, such as acute pulmonary edema, cardiopulmonary failure, aseptic meningitis, encephalitis and acute flaccid paralysis. Probiotics supplement have been demonstrated play a positive role as a therapeutic approaches for modulation of gut microbiota. This study aims to systematically investigate the efficacy and safety of probiotics for children with severe HFMD. Methods: All randomized controlled trials related to probiotics and severe HFMD will be searched in 9 electronic databases (PubMed, Cochrane Library, Embase, ClinicalTrails, China National Knowledge Infrastructure, Sino Med, ScienceDirect, VIP, and Wanfang Data databases) from their inception to November 2019. The primary outcome is total effective rate, fever clearance time, rash regression time, remission time of neurological symptoms, and clinical cure time. Two researchers will perform the study selection, data extraction, and assessment of risk of bias independently. RevMan software (version 5.3) will be used for data synthesis. Results: The findings of this study will be published in a peer-reviewed journal. Conclusion: The study will provide evidence to judge whether probiotics is an effective therapeutic intervention for severe HFMD. PROSPERO registration number: PROSPERO CRD42019152946. Abbreviations: CI = confidence interval, CNKI = China National Knowledge Infrastructure, GRADE = Grading of Recommendations, HFMD = hand, foot and mouth disease, ORs = Odds ratios, RCTs = randomized controlled trials, SMD = standardized mean difference, WMD = weighted mean difference. Keywords: hand foot and mouth disease, meta-analysis, probiotics, systematic review [2] [3] coxsackievirus-A16 (CV-A16), and mostly affects children. 1. Introduction The majority of HFMD cases are mild or typically asymptomatic, Hand, foot, and mouth disease (HFMD) is an infectious but severe and potentially life-threatening central nervous system gastrointestinal disease with characteristic features of fever, oral (CNS) complication such as encephalitis, meningitis, acute flaccid [1] ulcers, and vesicular rashes on the hands, feet, and buttocks, paralysis (AFP), myocarditis, and pulmonary edema have also caused primarily by human enterovirus-A71 (EV-A71) and [4–6] been reported. According to the national infectious disease direct network reports from China, from the year 2010 to 2012, the average annual incidence of HFMD was estimated 0.12%, HZ, LZ, JX and WW have contributed equally to this work. about 1.1% of which developed into severe cases, and the This work is supported by the National Natural Science Foundation of China [7] (81804219), National Key Research and Development Plan (2017YFC1703503), mortality of HFMD was 0.03%. Although the inactivated and National Social Science Fund of China (NO.17BTQ063). EV71 vaccine has been widely used to vaccinate infants and The funder had no role in the design, execution, or writing of the study. young children in several provinces of mainland China and has The authors have no conflicts of interest to disclose. shown to be effective at protecting them from EV71-associated a b Nanjing University of Chinese Medicine, Nanjing, China, University College severe HFMD, the number of severe cases is still large, posing a London, London, England. threat to infants and young children in rural areas of Asia-Pacific [3,8–10] Correspondence: Wenting Wen, Luxia Wei, Nanjing University of Chinese region. Medicine, No. 138 Xianlin Avenue, Nanjing, Jiangsu, China In recent years, the effect of probiotics on severe HFMD has (e-mail: wwt305@163.com, 289533469@qq.com). raised concern, and some clinical randomized controlled trials Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc. (RCTs) have been performed to observed the treatment effect. This is an open access article distributed under the Creative Commons Most trials have concluded that probiotics is efficient and, at least Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and in part, beneficial biochemical criteria. Considering the uncom- reproduction in any medium, provided the original work is properly cited. pleted and contradictory results from clinical RCTs, the effect of How to cite this article: Zhang H, Zhang L, Xie J, Wen W, Wei L, Nie B. probiotics on severe HFMD needs further discuss. The purpose of Medicine 2019;98:45(e17939). this systematic review and meta-analysis is to systematically Received: 14 October 2019 / Accepted: 15 October 2019 evaluate the efficacy and safety of probiotics on children with severe HFMD. http://dx.doi.org/10.1097/MD.0000000000017939 1 Zhang et al. Medicine (2019) 98:45 Medicine 2. Methods 2.3.3. Processing missing data. When experimental data are missing or inadequate, we will attempt to contact the original 2.1. Inclusion criteria for study selection author of the study by e-mail or telephone to obtain sufficient and 2.1.1. Types of studies. All randomized controlled trials comprehensive data. Incomplete data will be discarded if (RCTs) evaluating the use of probiotics in the treatment of sufficient data cannot be retrieved. children with severe HFMD will be included without language limitations. 2.3.4. Risk of bias assessment. Two reviewers (HZ and JX) will evaluate the methodological quality of the including studies 2.1.2. Types of participants. Standard diagnosis of severe using the Cochrane Collaboration’s tool. Each study will be HFMD children will be included in analysis, regardless of their evaluated for validity based on the following 7 aspects: random gender, ethnicity, and background, according to the clinical sequence generation, allocation concealment, blinding of partic- guidelines. ipants and personnel, blinding of outcome assessment, incom- 2.1.3. Types of interventions. In this study, the intervention plete data assessment, selective outcome reporting, and other received by children with severe HFMD in the experimental sources of bias. group will be probiotics, while the control group will be 2.3.5. Heterogeneity assessment and statistical analysis. administered other therapy or placebo. Review Manager 5.3 software will be utilized for statistical 2.1.4. Outcomes. Primary outcomes are the differences between analysis on the basis of homogeneity of the included trials. probiotic and control groups immediately after treatment in: Weighted mean differences (WMDs) and 95% CIs will be used for analysis when units are the same, while standardized mean 1. Total effective rate; differences (SMDs) and 95% CIs will be used when units are 2. Fever clearance time; different. The I statistic will be utilized for assessing the 3. Rash regression time; heterogeneity of the included trials. A fixed-effect model will be 4. Clinical cure time; applied to calculate the pooled statistics in the absence of 5. Remission time of neurological symptoms; substantial heterogeneity (I <50% and P≥.1). Conversely, if 6. Incidence of adverse effects. statistical heterogeneity is identified (I >50% or P<.1), the causes of the heterogeneity will be identified first by subgroup analysis. If the heterogeneity cannot be readily explained, a 2.2. Search strategy random effects model will be interpreted with caution. 2.2.1. Electronic searches. Nine databases (PubMed, Cochrane Library, Embase, ClinicalTrails, China National 2.3.6. Subgroup analysis. If significant heterogeneity is ob- Knowledge Infrastructure, Sino Med, ScienceDirect, VIP, and served in the included studies, subgroup analysis will be Wanfang Data databases) will be searched from their inception performed based on interventions, controls, and outcome to November 2019 without language restrictions. Two reviewers measurements. (HZ and LZ) will independently search the studies. Any differences will be resolved through discussion with a third author (WW). 2.3.7. Assessment of reporting biases. If there are a sufficient Search strategy of PubMed was as follows: number of articles (>10) included under the same endpoint addressing the same question, a funnel plot will be used to 1. probiotics measure publication bias. 2. (hand, foot and mouth disease) OR HFMD 3. Step 1 AND step 2. 2.3.8. Sensitivity analysis. If sufficient test data are available, sensitivity analysis will be performed to determine whether the 2.2.2. Searching other resources. Potential eligible studies will conclusion is robust. be searched for relevant conference proceedings and reference 2.3.9. Grading of quality of evidence. The Grading of lists of previously published reviews. Recommendations Assessment, Development, and Evaluation will be utilized for assessing the quality of evidence for the main 2.3. Data collection and analysis outcomes. The quality of evidence will be categorized as high, 2.3.1. Study selection. The selection process will be summarized moderate, low, or very low. according to PRISMA flow diagram. Two reviewers (HZ and LZ) will independently search and evaluate every relevant study 2.3.10. Ethics and dissemination. Ethics approval is not according to the Cochrane Handbook. They will screen the required because the data will not include individual patient retrieved literaturebyreading the titles and abstracts. The full text data and, therefore, will not incur raise any privacy issues. The of relevant literature will then be read, and the studies will be results of this systematic review will be disseminated only in a selected in accordance with the inclusion criteria. Any disagree- peer-reviewed publication. ments will be resolved by discussion with the third reviewer (WW). 3. Discussion 2.3.2. Data extraction. Two reviewers (HZ and JX) will use a [1] data extraction form to extract data on participants, randomiza- Severe HFMD is an implication of many risk factors. Previous tion, interventions, outcomes, duration, follow-up, reasons for studies have confirmed the role of dysbiosis of the gut microbiota discontinuation, number of treatment-related adverse events, in severe HFMD, and probiotics could be beneficial for children author information, and conflicts of interest. Another reviewer with severe HFMD. This study aims to systematically investigate (LZ) will double check the extracted data. Any discrepancies the efficacy and safety of the probiotics for children with should be resolved by negotiation between the 2 reviewers with severe HFMD. The findings will provide further evidence for the the help of a third author (WW). management of severe HFMD. 2 Zhang et al. Medicine (2019) 98:45 www.md-journal.com [3] Xing W, Liao Q, Viboud C, et al. Hand, foot, and mouth disease in Author contributions China, 2008-12: an epidemiological study. The Lancet Infectious Conceptualization: Wenting Wen, Luxia Wei, Bo Nie. diseases 2014;14:308–18. [4] Ooi MH, Wong SC, Lewthwaite P, et al. Clinical features, diagnosis, and Data curation: Wenting Wen, Haibo Zhang, Lei Zhang, Jiadong management of enterovirus 71. Lancet Neurol 2010;9:1097–105. Xie. [5] Chan LG, Parashar UD, Lye MS, et al. Deaths of children during an Formal analysis: Wenting Wen, Haibo Zhang, Lei Zhang, outbreak of hand, foot, and mouth disease in Sarawak, Malaysia: clinical Jiadong Xie. and pathological characteristics of the disease. For the Outbreak Study Funding acquisition: Jiadong Xie, Luxia Wei. Group. Clin Infect Dis 2000;31:678–83. [6] Centers for Disease Control and Prevention (CDC).Deaths among Writing – original draft: Wenting Wen, Haibo Zhang. children during an outbreak of hand, foot, and mouth disease -Taiwan, Writing – review & editing: Luxia Wei. republic of China, April–July 1998. MMWR Morb Mortal Wkly Rep Wenting Wen orcid: 0000-0002-3930-818X. 1998;47:629–32. [7] Zhang D, Li R, Zhang W, et al. A case-control study on risk factors for severe hand, foot and mouth disease. Sci Rep 2017;7:40282. [8] Li R, Liu L, Mo Z, et al. An inactivated enterovirus 71 vaccine in healthy References children. N Engl J Med 2014;370:829–37. [1] Fang Y, Wang S, Zhang L, et al. Risk factors of severe hand, [9] Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection foot and mouth disease: a meta-analysis. Scand J Infect Dis in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med 2014;46:515–22. 1999;341:929–35. [2] Xu Y, Wu YF, Luo HH, et al. Acute kidney injury secondary to severe [10] Van Pham H, Hoang TNA, Duong HT, et al. Clinical characteristics of hand, foot and mouth disease caused by enterovirus-A71: hypertension is hand, foot and mouth disease in Daklak Province, Vietnam and a common. J Trop Pediatr 2019;65:510–3. associated factors of severe cases. Virusdisease 2017;28:430–3. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Medicine Pubmed Central

Probiotics supplement in children with severe hand, foot, and mouth disease

Medicine , Volume 98 (45) – Nov 11, 2019

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Publisher
Pubmed Central
Copyright
Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.
ISSN
0025-7974
eISSN
1536-5964
DOI
10.1097/MD.0000000000017939
Publisher site
See Article on Publisher Site

Abstract

Background: Severe hand, foot, and mouth disease (HFMD) is an acute infectious disease caused by infection with serotypes of Enterovirus A, most commonly by enterovirus A71 and coxsackievirus A16. Clinical symptoms usually include fever, malaise, rashes on hands and feet, and oral vesicles. Of note, severe and even life-threatening complications can develop rapidly in young children, such as acute pulmonary edema, cardiopulmonary failure, aseptic meningitis, encephalitis and acute flaccid paralysis. Probiotics supplement have been demonstrated play a positive role as a therapeutic approaches for modulation of gut microbiota. This study aims to systematically investigate the efficacy and safety of probiotics for children with severe HFMD. Methods: All randomized controlled trials related to probiotics and severe HFMD will be searched in 9 electronic databases (PubMed, Cochrane Library, Embase, ClinicalTrails, China National Knowledge Infrastructure, Sino Med, ScienceDirect, VIP, and Wanfang Data databases) from their inception to November 2019. The primary outcome is total effective rate, fever clearance time, rash regression time, remission time of neurological symptoms, and clinical cure time. Two researchers will perform the study selection, data extraction, and assessment of risk of bias independently. RevMan software (version 5.3) will be used for data synthesis. Results: The findings of this study will be published in a peer-reviewed journal. Conclusion: The study will provide evidence to judge whether probiotics is an effective therapeutic intervention for severe HFMD. PROSPERO registration number: PROSPERO CRD42019152946. Abbreviations: CI = confidence interval, CNKI = China National Knowledge Infrastructure, GRADE = Grading of Recommendations, HFMD = hand, foot and mouth disease, ORs = Odds ratios, RCTs = randomized controlled trials, SMD = standardized mean difference, WMD = weighted mean difference. Keywords: hand foot and mouth disease, meta-analysis, probiotics, systematic review [2] [3] coxsackievirus-A16 (CV-A16), and mostly affects children. 1. Introduction The majority of HFMD cases are mild or typically asymptomatic, Hand, foot, and mouth disease (HFMD) is an infectious but severe and potentially life-threatening central nervous system gastrointestinal disease with characteristic features of fever, oral (CNS) complication such as encephalitis, meningitis, acute flaccid [1] ulcers, and vesicular rashes on the hands, feet, and buttocks, paralysis (AFP), myocarditis, and pulmonary edema have also caused primarily by human enterovirus-A71 (EV-A71) and [4–6] been reported. According to the national infectious disease direct network reports from China, from the year 2010 to 2012, the average annual incidence of HFMD was estimated 0.12%, HZ, LZ, JX and WW have contributed equally to this work. about 1.1% of which developed into severe cases, and the This work is supported by the National Natural Science Foundation of China [7] (81804219), National Key Research and Development Plan (2017YFC1703503), mortality of HFMD was 0.03%. Although the inactivated and National Social Science Fund of China (NO.17BTQ063). EV71 vaccine has been widely used to vaccinate infants and The funder had no role in the design, execution, or writing of the study. young children in several provinces of mainland China and has The authors have no conflicts of interest to disclose. shown to be effective at protecting them from EV71-associated a b Nanjing University of Chinese Medicine, Nanjing, China, University College severe HFMD, the number of severe cases is still large, posing a London, London, England. threat to infants and young children in rural areas of Asia-Pacific [3,8–10] Correspondence: Wenting Wen, Luxia Wei, Nanjing University of Chinese region. Medicine, No. 138 Xianlin Avenue, Nanjing, Jiangsu, China In recent years, the effect of probiotics on severe HFMD has (e-mail: wwt305@163.com, 289533469@qq.com). raised concern, and some clinical randomized controlled trials Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc. (RCTs) have been performed to observed the treatment effect. This is an open access article distributed under the Creative Commons Most trials have concluded that probiotics is efficient and, at least Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and in part, beneficial biochemical criteria. Considering the uncom- reproduction in any medium, provided the original work is properly cited. pleted and contradictory results from clinical RCTs, the effect of How to cite this article: Zhang H, Zhang L, Xie J, Wen W, Wei L, Nie B. probiotics on severe HFMD needs further discuss. The purpose of Medicine 2019;98:45(e17939). this systematic review and meta-analysis is to systematically Received: 14 October 2019 / Accepted: 15 October 2019 evaluate the efficacy and safety of probiotics on children with severe HFMD. http://dx.doi.org/10.1097/MD.0000000000017939 1 Zhang et al. Medicine (2019) 98:45 Medicine 2. Methods 2.3.3. Processing missing data. When experimental data are missing or inadequate, we will attempt to contact the original 2.1. Inclusion criteria for study selection author of the study by e-mail or telephone to obtain sufficient and 2.1.1. Types of studies. All randomized controlled trials comprehensive data. Incomplete data will be discarded if (RCTs) evaluating the use of probiotics in the treatment of sufficient data cannot be retrieved. children with severe HFMD will be included without language limitations. 2.3.4. Risk of bias assessment. Two reviewers (HZ and JX) will evaluate the methodological quality of the including studies 2.1.2. Types of participants. Standard diagnosis of severe using the Cochrane Collaboration’s tool. Each study will be HFMD children will be included in analysis, regardless of their evaluated for validity based on the following 7 aspects: random gender, ethnicity, and background, according to the clinical sequence generation, allocation concealment, blinding of partic- guidelines. ipants and personnel, blinding of outcome assessment, incom- 2.1.3. Types of interventions. In this study, the intervention plete data assessment, selective outcome reporting, and other received by children with severe HFMD in the experimental sources of bias. group will be probiotics, while the control group will be 2.3.5. Heterogeneity assessment and statistical analysis. administered other therapy or placebo. Review Manager 5.3 software will be utilized for statistical 2.1.4. Outcomes. Primary outcomes are the differences between analysis on the basis of homogeneity of the included trials. probiotic and control groups immediately after treatment in: Weighted mean differences (WMDs) and 95% CIs will be used for analysis when units are the same, while standardized mean 1. Total effective rate; differences (SMDs) and 95% CIs will be used when units are 2. Fever clearance time; different. The I statistic will be utilized for assessing the 3. Rash regression time; heterogeneity of the included trials. A fixed-effect model will be 4. Clinical cure time; applied to calculate the pooled statistics in the absence of 5. Remission time of neurological symptoms; substantial heterogeneity (I <50% and P≥.1). Conversely, if 6. Incidence of adverse effects. statistical heterogeneity is identified (I >50% or P<.1), the causes of the heterogeneity will be identified first by subgroup analysis. If the heterogeneity cannot be readily explained, a 2.2. Search strategy random effects model will be interpreted with caution. 2.2.1. Electronic searches. Nine databases (PubMed, Cochrane Library, Embase, ClinicalTrails, China National 2.3.6. Subgroup analysis. If significant heterogeneity is ob- Knowledge Infrastructure, Sino Med, ScienceDirect, VIP, and served in the included studies, subgroup analysis will be Wanfang Data databases) will be searched from their inception performed based on interventions, controls, and outcome to November 2019 without language restrictions. Two reviewers measurements. (HZ and LZ) will independently search the studies. Any differences will be resolved through discussion with a third author (WW). 2.3.7. Assessment of reporting biases. If there are a sufficient Search strategy of PubMed was as follows: number of articles (>10) included under the same endpoint addressing the same question, a funnel plot will be used to 1. probiotics measure publication bias. 2. (hand, foot and mouth disease) OR HFMD 3. Step 1 AND step 2. 2.3.8. Sensitivity analysis. If sufficient test data are available, sensitivity analysis will be performed to determine whether the 2.2.2. Searching other resources. Potential eligible studies will conclusion is robust. be searched for relevant conference proceedings and reference 2.3.9. Grading of quality of evidence. The Grading of lists of previously published reviews. Recommendations Assessment, Development, and Evaluation will be utilized for assessing the quality of evidence for the main 2.3. Data collection and analysis outcomes. The quality of evidence will be categorized as high, 2.3.1. Study selection. The selection process will be summarized moderate, low, or very low. according to PRISMA flow diagram. Two reviewers (HZ and LZ) will independently search and evaluate every relevant study 2.3.10. Ethics and dissemination. Ethics approval is not according to the Cochrane Handbook. They will screen the required because the data will not include individual patient retrieved literaturebyreading the titles and abstracts. The full text data and, therefore, will not incur raise any privacy issues. The of relevant literature will then be read, and the studies will be results of this systematic review will be disseminated only in a selected in accordance with the inclusion criteria. Any disagree- peer-reviewed publication. ments will be resolved by discussion with the third reviewer (WW). 3. Discussion 2.3.2. Data extraction. Two reviewers (HZ and JX) will use a [1] data extraction form to extract data on participants, randomiza- Severe HFMD is an implication of many risk factors. Previous tion, interventions, outcomes, duration, follow-up, reasons for studies have confirmed the role of dysbiosis of the gut microbiota discontinuation, number of treatment-related adverse events, in severe HFMD, and probiotics could be beneficial for children author information, and conflicts of interest. Another reviewer with severe HFMD. This study aims to systematically investigate (LZ) will double check the extracted data. Any discrepancies the efficacy and safety of the probiotics for children with should be resolved by negotiation between the 2 reviewers with severe HFMD. The findings will provide further evidence for the the help of a third author (WW). management of severe HFMD. 2 Zhang et al. Medicine (2019) 98:45 www.md-journal.com [3] Xing W, Liao Q, Viboud C, et al. Hand, foot, and mouth disease in Author contributions China, 2008-12: an epidemiological study. The Lancet Infectious Conceptualization: Wenting Wen, Luxia Wei, Bo Nie. diseases 2014;14:308–18. [4] Ooi MH, Wong SC, Lewthwaite P, et al. Clinical features, diagnosis, and Data curation: Wenting Wen, Haibo Zhang, Lei Zhang, Jiadong management of enterovirus 71. Lancet Neurol 2010;9:1097–105. Xie. [5] Chan LG, Parashar UD, Lye MS, et al. Deaths of children during an Formal analysis: Wenting Wen, Haibo Zhang, Lei Zhang, outbreak of hand, foot, and mouth disease in Sarawak, Malaysia: clinical Jiadong Xie. and pathological characteristics of the disease. For the Outbreak Study Funding acquisition: Jiadong Xie, Luxia Wei. Group. Clin Infect Dis 2000;31:678–83. [6] Centers for Disease Control and Prevention (CDC).Deaths among Writing – original draft: Wenting Wen, Haibo Zhang. children during an outbreak of hand, foot, and mouth disease -Taiwan, Writing – review & editing: Luxia Wei. republic of China, April–July 1998. MMWR Morb Mortal Wkly Rep Wenting Wen orcid: 0000-0002-3930-818X. 1998;47:629–32. [7] Zhang D, Li R, Zhang W, et al. A case-control study on risk factors for severe hand, foot and mouth disease. Sci Rep 2017;7:40282. [8] Li R, Liu L, Mo Z, et al. An inactivated enterovirus 71 vaccine in healthy References children. N Engl J Med 2014;370:829–37. [1] Fang Y, Wang S, Zhang L, et al. Risk factors of severe hand, [9] Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection foot and mouth disease: a meta-analysis. Scand J Infect Dis in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med 2014;46:515–22. 1999;341:929–35. [2] Xu Y, Wu YF, Luo HH, et al. Acute kidney injury secondary to severe [10] Van Pham H, Hoang TNA, Duong HT, et al. Clinical characteristics of hand, foot and mouth disease caused by enterovirus-A71: hypertension is hand, foot and mouth disease in Daklak Province, Vietnam and a common. J Trop Pediatr 2019;65:510–3. associated factors of severe cases. Virusdisease 2017;28:430–3.

Journal

MedicinePubmed Central

Published: Nov 11, 2019

References