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Vol 17, No 4
Vol 17, No 4 August 2021 ISSN 1708-8569
Review articles
Original articles
Brief report
Letter to the editor
Review articles:
Similarities and differences between multiple inflammatory syndrome in children associated with COVID-19 and Kawasaki disease: clinical presentations, diagnosis, and treatment
  Qing-You Zhang, Bo-Wen Xu, Jun-Bao Du
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been spreading rapidly around the world, while ※multisystem inflammatory syndrome in children§ (MIS-C) is a new type of syndrome that has now been reported in many countries. Similar and different characteristics between KD and MIS-C have been reported in a variety of literature. We aimed to focus on reviewing clinical presentations, diagnosis, and treatment of KD and MIS-C.
Methods: We searched articles in the electronic databases, including the Cochrane Library database, EMBASE, and MEDLINE with the keywords ※multiple inflammatory syndrome§ and/or ※COVID-19§ and/or ※Kawasaki disease§ and ※children§.
Results: Main presentations of MIS-C and KD include fever, rashes, mucous membrane involvement, conjunctivitis, hands and feet erythema/edema, and cervical lymphadenopathy. However, compared with the highest incidence of KD among some Asian countries, MIS-C is common among Black and Hispanic children. MIS-C is common in older children and teenagers, whereas classic KD is common in children under five years of age. Gastrointestinal symptoms, shock, and coagulopathy are common in MIS-C patients but are not common in classic KD. Cardiac manifestations are more common than KD, including myocarditis with cardiac dysfunction and coronary artery dilation or aneurysms. Severe cases in MIS-C present with vasodilated or cardiogenic shock that requires fluid resuscitation, muscular support, and even mechanical ventilation and extracorporeal membrane oxygenation (ECMO), whereas KD rarely presents with these manifestations and requires these treatments. Increased serum ferritin, leukopenia, lymphopenia and thrombocytopenia are common in MIS-C. However,
thrombocytosis is a characteristic feature of KD. Intravenous immunoglobulin (IVIG) and moderate-high dose aspirin are still a standard recommended treatment for KD. In addition to the above-mentioned medications, steroids and biological drugs are frequently used in patients with MIS-C. Most of the children with KD have a good prognosis; however, the longterm clinical outcomes of MIS-C are not clear.
Conclusions: The overall presentation and treatment of MIS-C appear to overlap with KD. However, there are still great differences between the syndromes, and it is controversial to say whether MIS-C is a new entity or is a※severe type§ of KD.
  [Abstract] [Full Text] [PDF]  
Extent, reasons and consequences of off-labeled and unlicensed drug prescription in hospitalized children: a narrative review
  Wasim Shuib, Xin-Yin Wu, Fang Xiao
Background: Off-label and unlicensed prescriptions pose a severe safety concern among the pediatric population. We aimed to summarize the up-to-date evidence on the extent, reasons, and consequences of off-label and unlicensed drugs in hospitalized pediatric patients.
Methods: We systematically searched PubMed, EMBASE, SCOPUS, Web of Science and Google Scholar between 1990 and 2020 in which the last search was conducted on 12 February 2021. We included studies with the following inclusion criteria: (1) observational studies in design; (2) target population was hospitalized pediatric patients whether admitted in the intensive care unit or in the general ward; (3) study reporting the prevalence of off-label, unlicensed prescriptions or both; and (4) published in English.
Results: A total of 47 studies were eligible for inclusion. The proportion of off -label and unlicensed prescriptions ranged from 7.4% to 99.5% and 0.1% to 74.4%, respectively. The most frequent category of off-label prescriptions was prescription outside the age range, with the most commonly reported reason for off-label prescriptions being the lack of information specifically for pediatrics on the drug information leaflets. The consequences of off-label and unlicensed prescriptions ranged from minor and bearable skin reactions to debilitating renal failure, risking deaths.
Conclusions: Off-label and unlicensed prescriptions are extensive and require progressively meditative interventions. However, the pediatric population is currently a ※therapeutic orphan§. Unless adequate pediatric clinical trials and licensed drugs become available, off-label and unlicensed drug prescription should not entirely be banned but rather promoted in an organized manner.
  [Abstract] [Full Text] [PDF]  
Clinical characteristics of COVID-19 in family clusters: a systematic review
  Wen-Liang Song, Ning Zou, Wen-He Guan, Jia-Li Pan, Wei Xu
Background: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) has spread around the world and reports of children during early epidemic period showed features of family clusters. The aim of this study is to assess clinical profiles of COVID-19 in family clusters with children.
Methods: We performed a systematic literature review of English database (PubMed, Web of Science) and Chinese database (※www.cnki.net§, ※www.cqvip.com§ and ※www.Wanfangdata.com.cn§) to identify papers on family clusters of COVID-19 with children and their family members.
Results: Eighteen studies involving 34 children and 98 adults from 28 families were included. Fever, cough and ground-grass opacity change of chest computed tomography (CT) were the dominant features, whereas proportion of asymptomatic infections for children was higher than adults with statistical significance (32.4% and 13.3%, respectively, P < 0.05). Median time of longer incubation period (10 days) and shorter duration of pharyngeal swab nucleic acid test positive period (11 days) were seen in children than adults (7 and 17 days, respectively) with statistical significance (P < 0.05). There were statistically significant differences in lymphopenia, increased C-reactive protein and abnormal chest CT between children and adult patients (P < 0.05). Twenty-seven families reported adults as first case of COVID-19 in family clusters.
Conclusions: The same virus strain can cause milder disease in children compared with their caregivers. Children of COVID-19 were infected by adults in family during the early epidemic period. Asymptomatic patients can transmit the virus.
  [Abstract] [Full Text] [PDF]  
Cerebral palsy in children born after assisted reproductive technology: a meta-analysis
  Fang-Fang Wang, Tao Yu, Xiao-Lu Chen, Rong Luo, De-Zhi Mu
Background: Several studies have assessed the association between cerebral palsy (CP) and assisted reproductive technology (ART), but the results remain controversial. We conducted a meta-analysis to evaluate the risk of CP after ART compared with natural conceptions and to examine CP risk separately in ART singletons, multiples and preterm births.
Methods: Web-based databases (PubMed, Embase, the Cochrane Library, and Web of Science) were searched until November 22, 2020. Studies which compare CP rates after ART with natural conceptions were included. The Newcastle-Ottawa Scale was used to assess the quality of the included studies. Effect estimates were extracted and combined using the fixed-effects or random-effects model depending on the heterogeneity test.
Results: There were nine studies included in the meta-analysis. The included studies were of moderate or high quality. A significantly higher risk of CP [odds ratio (OR) = 2.17, 95% confidence interval (CI) 1.72-2.74] was found in ART children (n = 89,214) compared with naturally conceived children (n = 4,160,745). The significantly higher risk decreased when data were restricted to singletons (OR = 1.36, 95% CI 1.16-1.59) and disappeared when data were restricted to multiples (OR = 1.05, 95% CI 0.86-1.29) or preterm births (OR = 1.53, 95% CI 0.66-3.56). Subgroup and sensitivity analyses indicated that the overall results were robust.
Conclusions: The risk of CP is increased more than two-fold after ART. This increased risk is largely due to increased rates of multiple birth and preterm delivery in ART children.
  [Abstract] [Full Text] [PDF]  
Original articles:
Characteristics of immune and inflammatory responses among different age groups of pediatric patients with COVID-19 in China
  Su-Qiong Ji, Min Zhang, Yong Zhang, Kun Xia, Yuan Chen, Qian Chu, Yong-Chang Wei, Fu-Ling Zhou, Bi-Tao Bu, Hong-Lei Tu, Ya-Yun Cao, Li-Ya Hu
Background: Severe cases of coronavirus disease 2019 (COVID-19) among pediatric patients are more common in children less than 1 year of age. Our aim is to address the underlying role of immunity and inflammation conditions among different age groups of pediatric patients.
Methods: We recruited pediatric patients confirmed of moderate COVID-19 symptoms, admitted to Wuhan Children*s Hospital from January 28th to April 1st in 2020. Patients were divided into four age groups (≒ 1, 1-6, 7-10, and 11-15 years). Demographic information, clinical characteristics, laboratory results of lymphocyte subsets test, immune and inflammation related markers were all evaluated.
Results: Analysis included 217/241 (90.0%) of patients with moderate clinical stage disease. Average recovery time of children more than 6 years old was significantly shorter than of children younger than 6 years (P = 0.001). Reduced neutrophils and increased lymphocytes were significantly most observed among patients under 1 year old (P < 0.01). CD19+ B cells were the only significantly elevated immune cells, especially among patients under 1 year old (cell proportion: n = 12, 30.0%, P < 0.001; cell count: n = 13, 32.5%, P < 0.001). While, low levels of immune related makers, such as immunoglobulin (Ig) G (P < 0.001), IgA (P < 0.001), IgM (P < 0.001) and serum complement C3c (P < 0.001), were also mostly found among patients under 1 year old, together with elevated levels of inflammation related markers, such as tumor necrosis factor 污 (P = 0.007), interleukin (IL)-10 (P = 0.011), IL-6 (P = 0.008), lactate dehydrogenase (P < 0.001), and procalcitonin (P = 0.007).
Conclusion: The higher rate of severe cases and long course of COVID-19 among children under 1 year old may be due to the lower production of antibodies and serum complements of in this age group.
  [Abstract] [Full Text] [PDF]  
Impact of probiotics supplement on the gut microbiota in neonates with antibiotic exposure: an open-label single-center randomized parallel controlled study
  Hui Zhong, Xiang-Geng Wang, Jing Wang, Yan-Jie Chen, Huan-Long Qin, Rong Yang
Background: Antibiotics, a common strategy used for neonatal infection, show consistent effect on the gut microbiota of neonates. Supplementation with probiotics has become increasingly popular in mitigating the loss of the gut microbiota. However, no clear consensus recommending the use of probiotics in the infection of neonates currently exists. This study examined the effects of probiotics on the gut microbiota of infectious neonates when used concurrently with or during the recovery period following antibiotic therapy.
Methods: Fifty-five full-term neonates diagnosed with neonatal infections were divided into the following groups: NI (no intervention, antibiotic therapy only), PCA (probiotics used concurrently with antibiotics), and PAA (probiotics used after antibiotics). The NI group received antibiotic treatment (piperacillin-tazobactam) for 1 week and the PCA group received antibiotic treatment together with probiotics (Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis) for 1 week. The PAA group received antibiotic treatment for 1 week followed by probiotics for 1 week. Fecal samples were collected at four time nodes: newborn, 1 week, 2 weeks, and 42 days after birth. The composition of the gut microbiota was determined by the high-throughput sequencing of 16S rRNA amplicons.
Results: Antibiotic exposure was found to dramatically alter gut microbiota, with a significant decrease of Bifidobacterium and Lactobacillus. The use of probiotics did not restore the overall diversity of the gut microbiota. However, using probiotics simultaneously with the antibiotics was found to be beneficial for the gut microbiota as compared to delaying the use of probiotics to follow treatment with antibiotics, particularly in promoting the abundance of Bifidobacterium.
Conclusions: These results suggest that the early use of probiotics may have a potential ability to remodel the gut microbiota during recovery from antibiotic treatment. However, further study is required to fully understand the long-term effects including the clinical benefits.
  [Abstract] [Full Text] [PDF]  
Increased asprosin is associated with non-alcoholic fatty liver disease in children with obesity
  Lu-Jie Liu, Yu-Rong Kang, Yan-Feng Xiao
Background: Obesity is a common disease among children, often accompanied by a lot of metabolic disease. Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of obesity among children and adolescents. Asprosin has been identified as a new adipokine that is closely associated with hepatic glucose metabolism. However, few data on asprosin in obese children with NAFLD are available. The present study focuses on the relationship between serum asprosin level and NAFLD in children with obesity.
Methods: A total of 110 subjects (71 boys and 39 girls aged 6每18 years) were recruited from the Second Affiliated Hospital of Xi*an Jiaotong University: 36 obese children with NAFLD, 39 obese children without NAFLD and 35 lean controls. Anthropometric parameters and biochemical data were measured, and the concentrations of asprosin were detected by ELISA.
Results: The levels of serum asprosin were significantly higher in obese children, particularly those with NAFLD and were positively correlated with body mass index, waist to height ratio, fasting blood glucose, alanine aminotransferase and tumor necrosis factor-alpha. Furthermore, asprosin was independently associated with NAFLD in binary logistic regression analysis.
Conclusion: Serum asprosin levels were elevated in obese children, especially in those with NAFLD, and were involved in the pathogenesis of NAFLD in children with obesity.
  [Abstract] [Full Text] [PDF]  
Pediatric interfacility transport effects on mortality and length of stay
  Rod M. Shinozaki, Andreas Schwingshackl, Neeraj Srivastava, Tristan Grogan, Robert B. Kelly
Background: We aimed to evaluate the effects of interfacility pediatric critical care transport response time, physician presence during transport, and mode of transport on mortality and length of stay (LOS) among pediatric patients. We hypothesized that a shorter response time and helicopter transports, but not physician presence, are associated with lower mortality and a shorter LOS.
Methods: Retrospective, single-center, cohort study of 841 patients (< 19 years) transported to a quaternary pediatric intensive care unit and cardiovascular intensive care unit between 2014 and 2018 utilizing patient charts and transport records. Multivariate linear and logistic regression analyses adjusted for age, diagnosis, mode of transport, response time, stabilization time, return duration, mortality risk (pediatric index of mortality-2 and pediatric risk of mortality-3), and inotrope, vasopressor, or mechanical ventilation presence on admission.
Results: Four hundred and twenty-eight (50.9%) patients were transported by helicopter, and 413 (49.1%) were transported by ambulance. Physicians accompanied 239 (28.4%) transports. The median response time was 2.0 (interquartile range 1.4每2.9) hours. Although physician presence increased the median response time by 0.26 hours (P = 0.020), neither physician presence nor response time significantly affected mortality, ICU length of stay (ILOS) or hospital length of stay (HLOS). Helicopter transports were not significantly associated with mortality or ILOS, but were associated with a longer HLOS (3.24 days, 95% confidence interval 0.59每5.90) than ambulance transports (P = 0.017).
Conclusions: These results suggest response time and physician presence do not significantly affect mortality or LOS. This may reflect the quality of pre-transport care and medical control communication. Helicopter transports were only associated with a longer HLOS. Our analysis provides a framework for examining transport workforce needs and associated costs.
  [Abstract] [Full Text] [PDF]  
Responsible genes in children with primary vesicoureteral reflux: findings from the Chinese Children Genetic Kidney Disease Database
  Jia-Lu Liu, Qian Shen, Ming-Yan Wu, Guang-Hua Zhu, Yu-Feng Li, Xiao-Wen Wang, Xiao-Shan Tang, Yun-Li Bi, Yi-Nv Gong, Jing Chen, Xiao-Yan Fang, Yi-Hui Zhai, Bing-Bing Wu, Guo-Min Li, Yu-Bo Sun, Xiao-Jie Gao, Cui-Hua Liu, Xiao-Yun Jiang, Sheng Hao, Yu-Lin Kang, Ying-Liang Gong, Li-Ping Rong, Di Li, Si Wang, Duan Ma, Jia Rao, Hong Xu, for Chinese Children Genetic Kidney Disease Database (CCGKDD), ※Internet Plus§ Nephrology Alliance of the National Center for Children*s Care
Background: Primary vesicoureteral reflux (VUR) is a common congenital anomaly of the kidney and urinary tract (CAKUT) in childhood. The present study identified the possible genetic contributions to primary VUR in children.
Methods: Patients with primary VUR were enrolled and analysed based on a national multi-center registration network (Chinese Children Genetic Kidney Disease Database, CCGKDD) that covered 23 different provinces/regions in China from 2014 to 2019. Genetic causes were sought using whole-exome sequencing (WES) or targeted-exome sequencing.
Results: A total of 379 unrelated patients (male: female 219:160) with primary VUR were recruited. Sixty-four (16.9%) children had extrarenal manifestations, and 165 (43.5%) patients showed the coexistence of other CAKUT phenotypes. Eighty-eight patient (23.2%) exhibited impaired renal function at their last visit, and 18 of them (20.5%) developed ESRD at the median age of 7.0 (IQR 0.9每11.4) years. A monogenic cause was identified in 28 patients (7.39%). These genes included PAX2 (n = 4), TNXB (n = 3), GATA3 (n = 3), SLIT2 (n = 3), ROBO2 (n = 2), TBX18 (n = 2), and the other 11 genes (one gene for each patient). There was a significant difference in the rate of gene mutations between patients with or without extrarenal complications (14.1% vs. 6%, P = 0.035). The frequency of genetic abnormality was not statistically significant based on the coexistence of another CAKUT (9.6% vs. 5.6%, P = 0.139, Chi-square test) and the grade of reflux (9.4% vs. 6.7%, P = 0.429). Kaplan每Meier survival curve showed that the presence of genetic mutations did affect renal survival (Log-rank test, P = 0.01). PAX2 mutation carriers (HR 5.1, 95% CI 1.3每20.0; P = 0.02) and TNXB mutation carriers (HR 20.3, 95% CI 2.4每168.7; P = 0.01) were associated with increased risk of progression to ESRD.
Conclusions: PAX2, TNXB, GATA3 and SLIT2 were the main underlying monogenic causes and accounted for up to 46.4% of monogenic VUR. Extrarenal complications and renal function were significantly related to the findings of genetic factors in children with primary VUR. Like other types of CAKUT, several genes may be responsible for isolated VUR.
  [Abstract] [Full Text] [PDF]  
Increasing prevalence and influencing factors of childhood asthma: a cross-sectional study in Shanghai, China
  Ya-Bin Hu, Yi-Ting Chen, Shi-Jian Liu, Fan Jiang, Mei-Qin Wu, Chong-Huai Yan, Jian-Guo Tan, Guang-Jun Yu, Yi Hu, Yong Yin, Jia-Jie Qu, Sheng-Hui Li, Shi-Lu Tong
Background: Asthma has been a global problem, especially in children. We aim to evaluate the contemporary prevalence and influencing factors of asthma among children aged 3-7 years in Shanghai, China.
Methods: A random sample of preschool children was included in this study. The International Study of Asthma and Allergies in Childhood questionnaire was adopted to assess the childhood asthma. Multivariable logistic regression models were used to evaluate the associations between independent variables and childhood asthma.
Results: Of 6389 preschool children who were invited to take part in this study, 6163 (response rate: 96.5%) completed the questionnaire and were included in the analysis. The overall prevalence of asthma was 14.6% which increased more than six folds from 2.1% in 1990. Being male, younger age, preterm delivery, being born in spring or autumn, being delivered by elective cesarean section without indication, miscarriage, high socioeconomic status, having allergy history, and exposure to passive smoking, latex paint, and dust were potential risk factors for childhood asthma. Spending more time outdoors (> 30 min/day), having indoor plants, and cleaning rooms more frequently were potential protective factors.
Conclusions: The prevalence of childhood asthma in Shanghai has increased dramatically during the past three decades. The findings about risk and protective factors of childhood asthma could be used to develop appropriate strategies to prevent and control childhood asthma in Shanghai and in other similar metropolitan cities.
  [Abstract] [Full Text] [PDF]  
Brief report:
Application of Kaiser Sepsis Calculator in culture-positive infants with early onset sepsis
  Gretchen Kopec, Marc Collin, Anirudha Das
Background: Kaiser Sepsis Calculator (KSC) reduces antibiotic use, testing and intravenous infiltrates but there are concerns about the missed early onset sepsis (EOS) cases. We sought to apply the KSC score for culture-positive infants retrospectively in infants born in the last 10 years in our hospital.
Methods: In a retrospective cohort study, the comparison groups were divided into Group A (no antibiotics recommended by KSC) and Group B (antibiotics recommended).
Results: Overall, 17/24 (71%) infants would have been started on antibiotics per KSC but 7/24 (29%) would not. The initial EOS risk was not significantly different between the groups (Group A vs. Group B: 0.44 vs. 0.76, P = 0.41), but the final risk score was (0.33 vs. 9.41, P < 0.001). In Group A (no antibiotics), 3/7 infants became symptomatic between 9 and 42 hours.
Conclusion: There may be a potential delay in starting antibiotics in infants that are asymptomatic at birth while using KSC.
  [Abstract] [Full Text] [PDF]  
A wake-up call to action for smoking cessation interventions
  Farahnak Assadi
  [Abstract] [Full Text] [PDF]  
Letter to the editor:
Mosaic trisomy 12 diagnosed in a female patient: clinical features, genetic analysis, and review of the literature
  Daniela Hainz, Marcus Kr邦ger, Daniela Reber, Karl Mehnert, Theresa Brunet, Gabriele Lederer, Sabine Langer-Freitag, Julia Hoefele
  [Abstract] [Full Text] [PDF]  
World Journal of Pediatric Surgery
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