Household Transmission Dynamics of Asymptomatic SARS-CoV-2-Infected Children: A Multinational, Controlled Case-Ascertained Prospective Study.

BACKGROUND: Asymptomatic SARS-CoV-2 infection in children is highly prevalent but its acute and chronic implications have been minimally described. METHODS: In this controlled case-ascertained household transmission study, we recruited asymptomatic children <18 years with SARS-CoV-2 nucleic acid testing performed at 12 tertiary care pediatric institutions in Canada and the United States. We attempted to recruit all test-positive children and 1 to 3 test-negative, site-matched controls. After 14 days' follow-up we assessed the clinical (ie, symptomatic) and combined (ie, test-positive, or symptomatic) secondary attack rates (SARs) among household contacts. Additionally, post-COVID-19 condition (PCC) was assessed in SARS-CoV-2-positive participating children after 90 days' follow-up. RESULTS: A total of 111 test-positive and 256 SARS-CoV-2 test-negative asymptomatic children were enrolled between January 2021 and April 2022. After 14 days, excluding households with co-primary cases, the clinical SAR among household contacts of SARS-CoV-2-positive and -negative index children was 10.6% (19/179; 95% CI: 6.5%-16.1%) and 2.0% (13/663; 95% CI: 1.0%-3.3%), respectively (relative risk = 5.4; 95% CI: 2.7-10.7). In households with a SARS-CoV-2-positive index child, age <5 years, being pre-symptomatic (ie, developed symptoms after test), and testing positive during Omicron and Delta circulation periods (vs earlier) were associated with increased clinical and combined SARs among household contacts. Among 77 asymptomatic SARS-CoV-2-infected children with 90-day follow-up, 6 (7.8%; 95% CI: 2.9%-16.2%) reported PCC. CONCLUSIONS: Asymptomatic SARS-CoV-2-infected children, especially those <5 years, are important contributors to household transmission, with 1 in 10 exposed household contacts developing symptomatic illness within 14 days. Asymptomatic SARS-CoV-2-infected children may develop PCC.

Population-level changes in perinatal death for pregnancies prior to and during the COVID-19 pandemic: A pregnancy cohort analysis.

BACKGROUND: Results of population-level studies examining the effect of the COVID-19 pandemic on the risks of perinatal death have varied considerably. OBJECTIVES: To explore trends in the risk of perinatal death among pregnancies beginning prior to and during the pandemic using a pregnancy cohort approach. METHODS: This secondary analysis included data from singleton pregnancies ≥20 weeks' gestation in Alberta, Canada, beginning between 5 March 2017 and 4 March 2021. Perinatal death (i.e. stillbirth or neonatal death) was the primary outcome considered. The risk of this outcome was calculated for pregnancies with varying gestational overlap with the pandemic (i.e. none, 0-20 weeks, entire pregnancy). Interrupted time series analysis was used to further determine temporal trends in the outcome by time period of interest. RESULTS: There were 190,853 pregnancies during the analysis period. Overall, the risk of perinatal death decreased with increasing levels of pandemic exposure; this outcome was experienced in 1.0% (95% confidence interval [CI] 0.9, 1.0), 0.9% (95% CI 0.8, 1.1) and 0.8% (95% CI 0.7, 0.9) of pregnancies with no overlap, partial overlap and complete pandemic overlap respectively. Pregnancies beginning during the pandemic that had high antepartum risk scores less frequently led to perinatal death compared to those beginning prior; 3.3% (95% CI 2.7, 3.9) versus 5.7% (95% CI 5.0, 6.5) respectively. Interrupted time-series analysis revealed a decreasing temporal trend in perinatal death for pregnancies beginning ≤40 weeks prior to the start of the COVID-19 pandemic (i.e. with pandemic exposure), with no trend for pregnancies beginning >40 weeks pre-pandemic (i.e. no pandemic exposure). CONCLUSION: We observed a decrease in perinatal death for pregnancies overlapping with the COVID-19 pandemic in Alberta, particularly among those at high risk of these outcomes. Specific pandemic control measures and government response programmes in our setting may have contributed to this finding.

Microbial Etiologies and Clinical Characteristics of Children Seeking Emergency Department Care Due to Vomiting in the Absence of Diarrhea.

BACKGROUND: As children with isolated vomiting are rarely able to provide a specimen suitable for routine pathogen testing, we have limited knowledge about their infecting pathogens. METHODS: Between December 2014 and August 2018, children <18 years old with presumed acute gastroenteritis who presented to 2 emergency departments (EDs) in Alberta, Canada, were recruited. Eligible participants had ≥3 episodes of vomiting and/or diarrhea in a 24-hour period, <7 days of symptoms, and provided a rectal swab or stool specimen. We quantified the proportion of children with isolated vomiting in whom an enteropathogen was identified, and analyzed clinical characteristics, types of enteropathogens, resources used, and alternative diagnoses. RESULTS: Of the 2695 participants, at the ED visit, 295 (10.9%), 1321 (49.0%), and 1079 (40.0%) reported having isolated diarrhea, vomiting and diarrhea, or isolated vomiting, respectively. An enteropathogen was detected most commonly in those with vomiting and diarrhea (1067/1321; 80.8%); detection did not differ between those with isolated diarrhea (170/295; 57.6%) and isolated vomiting (589/1079; 54.6%) (95% confidence interval of the difference: -3.4%, 9.3%). Children with isolated vomiting most often had a virus (557/1077; 51.7%), most commonly norovirus (321/1077; 29.8%); 5.7% (62/1079) had a bacterial pathogen. X-rays, ultrasounds, and urine tests were most commonly performed in children with isolated vomiting. Alternate etiologies were most common in those with isolated vomiting (5.7%; 61/1079). CONCLUSIONS: The rate of enteropathogen identification in children with isolated vomiting using molecular diagnostic tests and rectal swabs is substantial. Molecular diagnostics offer an emerging diagnostic strategy in children with isolated vomiting.

Pregnancy Outcomes after ZIKV Infection in French Territories in the Americas.

BACKGROUND: The risk of congenital neurologic defects related to Zika virus (ZIKV) infection has ranged from 6 to 42% in various reports. The aim of this study was to estimate this risk among pregnant women with symptomatic ZIKV infection in French territories in the Americas. METHODS: From March 2016 through November 2016, we enrolled in this prospective cohort study pregnant women with symptomatic ZIKV infection that was confirmed by polymerase-chain-reaction (PCR) assay. The analysis included all data collected up to April 27, 2017, the date of the last delivery in the cohort. RESULTS: Among the 555 fetuses and infants in the 546 pregnancies included in the analysis, 28 (5.0%) were not carried to term or were stillborn, and 527 were born alive. Neurologic and ocular defects possibly associated with ZIKV infection were seen in 39 fetuses and infants (7.0%; 95% confidence interval, 5.0 to 9.5); of these, 10 were not carried to term because of termination of pregnancy for medical reasons, 1 was stillborn, and 28 were live-born. Microcephaly (defined as head circumference more than 2 SD below the mean for sex and gestational age) was detected in 32 fetuses and infants (5.8%), of whom 9 (1.6%) had severe microcephaly (more than 3 SD below the mean). Neurologic and ocular defects were more common when ZIKV infection occurred during the first trimester (24 of 189 fetuses and infants [12.7%]) than when it occurred during the second trimester (9 of 252 [3.6%]) or third trimester (6 of 114 [5.3%]) (P=0.001). CONCLUSIONS: Among pregnant women with symptomatic, PCR-confirmed ZIKV infection, birth defects possibly associated with ZIKV infection were present in 7% of fetuses and infants. Defects occurred more frequently in fetuses and infants whose mothers had been infected early in pregnancy. Longer-term follow-up of infants is required to assess any manifestations not detected at birth. (Funded by the French Ministry of Health and others; ClinicalTrials.gov number, NCT02916732 .).

Prevalence of congenital microcephaly and its risk factors in an area at risk of Zika outbreaks.

BACKGROUND: Prevalence of neonatal microcephaly in populations without Zika-epidemics is sparse. The study aimed to report baseline prevalence of congenital microcephaly and its relationship with prenatal factors in an area at risk of Zika outbreak. METHODS: This study included singletons born after 24 gestational weeks in 2017-2018 at four hospitals in Guangzhou, China. Microcephaly was defined as a head circumference at birth >3SD below the mean for sex and gestational age. Prevalence of microcephaly was estimated by binomial exact method. Multivariable logistic regression was used to examine the associations of microcephaly with prenatal factors. The population attributable fraction (PAF) for associated risk factors was calculated. RESULTS: Of 46,610 live births included, 154 (3.3, 95% CI 2.8-3.9 per 1000 live births) microcephalies were identified. Maternal hepatitis B virus carriers (HBV, OR 1.80, 95% CI 1.05-3.10) and primipara (OR 2.68, 95% CI 1.89-3.81) had higher risk of having a microcephalic baby. Higher prevalence of microcephaly was observed in women who had premature labor (OR 1.98, 95% CI 1.17-3.34) and had a baby with fetal growth restriction (OR 16.38, 95% CI 11.81-22.71). Four identified factors (HBV, primiparity, preterm labor, and fetal growth restriction) contributed to 66.4% of the risk of microcephaly. CONCLUSIONS: The prevalence of microcephaly in Guangzhou was higher than expected. This study identified four prenatal risk factors that, together, contributed to two-thirds of the increased risk of microcephaly. This is the first reported association between maternal HBV carrier status and microcephaly.

Antenatal predictors of stem cell content for successful umbilical cord blood donation.

PURPOSE: The most important HLA-independent factor for the selection of cord blood units (CBU) for hematopoietic stem cell transplantation is the total nucleated cell (TNC) count over 150 × 107 as a surrogate marker for stem cell content. The purpose of this prospective study was to define prenatal clinical predictors for TNC count that would help to identify successful CBU donors before the onset of active labor. METHODS: This was a prospective analysis of 594 CBUs, collected from all eligible term singleton pregnancies at Basel University Hospital between 4/2015 and 9/2016 analyzing several maternal and fetal factors. The impact of these factors on TNC count (< 150 × 107 cells vs. ≥ 150 × 107 cells) of the CBUs was modeled in a multivariate analysis. RESULTS: A total of 114 (19.2%) CBUs had a TNC count of ≥ 150 × 107. In a ROC analysis there was no significant difference between the AUC of all prenatal factors (AUC 0.62) and estimated fetal birth weight by ultrasound alone (AUC 0.62). For women planning a trial of labor a recruitment cut-off at an estimated birth weight of 3300 g would allow 72.6% of all donors with sufficient TNC count to be recruited and 22.8% of all collected CBUs would have a sufficient TNC count for banking. For women planning for elective CS a cut-off of 3400 g would allow 71.4% of all donors with sufficient TNC count to be recruited and 22.7% of all collected CBUs would have sufficient TNC count for banking. CONCLUSION: The estimated fetal birth weight within 2 weeks of delivery by ultrasound as single parameter can be considered at the time of recruitment to estimate the chances of a successful CBU donation.

A Clinical Epidemiology and Molecular Attribution Evaluation of Adenoviruses in Pediatric Acute Gastroenteritis: a Case-Control Study.

The objective of this study was to characterize the etiological role of human adenovirus (HAdV) serotypes in pediatric gastroenteritis. Using a case-control design, we compared the frequencies of HAdV serotypes between children with ≥3 episodes of vomiting or diarrhea within 24 h and <7 days of symptoms (i.e., cases) and those with no infectious symptoms (i.e., controls). Stool samples and/or rectal swabs underwent molecular serotyping with cycle threshold (Ct) values provided by multiplex real-time reverse transcription-PCR testing. Cases without respiratory symptoms were analyzed to calculate the proportion of disease attributed to individual HAdV serotypes (i.e., attributable fraction). Between December 2014 and August 2018, adenoviruses were detected in 18.8% (629/3,347) of cases and 7.2% (97/1,355) of controls, a difference of 11.6% (95% confidence interval [CI], 9.6%, 13.5%). In 96% (95% CI, 92 to 98%) of HAdV F40/41 detections, the symptoms could be attributed to the identified serotype; when serotypes C1, C2, C5, and C6 were detected, they were responsible for symptoms in 52% (95% CI, 12 to 73%). Ct values were lower among cases than among controls (P < 0.001). HAdV F40/41, C2, and C1 accounted for 59.7% (279/467), 17.6% (82/467), and 12.0% (56/467) of all typed cases, respectively. Among cases, Ct values were lower for F40/41 serotypes than for non-F40/41 serotypes (P < 0.001). HAdV F40/41 serotypes account for the majority of HAdV-positive gastroenteritis cases, and when detected, disease is almost always attributed to infection with these pathogens. Non-F40/41 HAdV species have a higher frequency of asymptomatic infection and may not necessarily explain gastroenteritis symptoms. Real-time quantitative PCR may be useful in differentiating asymptomatic shedding from active infection.

Update on nonantibiotic therapies for acute gastroenteritis.

PURPOSE OF REVIEW: The aim of this review is to provide an update of nonantibiotic therapies for acute gastroenteritis (AGE), focusing on antiemetics and probiotics. RECENT FINDINGS: The mainstay of therapy for nonsevere AGE remains oral rehydration therapy (ORT). Recent randomized controlled trials and metaanalyses have further strengthened the evidence-base supporting single-dose ondansetron administration in emergency departments to facilitate ORT based on evidence that it safely reduces intravenous fluid administration and hospitalization rates. Intravenous ondansetron administration and multiple-dose use should be avoided. A bimodal release ondansetron formulation was shown to improve outcomes in adolescents and adults with AGE in one study, but further evidence is required to support use. Recent large trials evaluating probiotic administration demonstrated a lack of benefit and guidelines that recommend their use should reevaluate their positions in light of this evidence. Furthermore, caution should be exercised when use is considered in high-risk populations and settings. SUMMARY: The benefits, dosing/route, and target populations most likely to benefit from ondansetron have been further clarified. Optimization of the real-life effectiveness of this therapy will require implementation strategies. Recent high-quality evidence showing a lack of efficacy and potential harm associated with probiotic use suggests that routine use for AGE should be discouraged.

Comparison of the INTERGROWTH-21st standard and a new reference for head circumference at birth among newborns in Southern China.

BACKGROUND: Previous studies proposed that there were racial or ethnic disparities in fetal growth, challenging the use of international standards in specific populations. This study was to evaluate the validity of applying the INTERGROWTH-21st standard to a Chinese population for identifying abnormal head circumference (HC), in comparison with a newly generated local reference. METHODS: There were 24,257 singletons delivered by low-risk mothers in four perinatal health-care centers in Southern China. New HC reference was constructed and comparison in distribution of HC categories was performed between the INTERGROWTH-21st standard and new reference after applying these two tools in study population. Logistic regression was used to examine the association between abnormal HC and adverse neonatal outcomes. RESULTS: There were 4.40% of the newborns identified with microcephaly (HC > 2 standard deviation below the mean) using the INTERGROWTH-21st standard, comparing to the proportion of 2.83% using new reference. The newborns identified with microcephaly only by the INTERGROWTH-21st standard were not at a higher risk of adverse neonatal outcome, compared with those identified as non-microcephaly by both tools (OR 0.73, 95% CI 0.47-1.13). CONCLUSION: The new HC reference may be more appropriate for newborn assessment in Chinese populations than the INTERGROWTH-21st standard.

Risk of hepatitis B virus reactivation with direct-acting antivirals against hepatitis C virus: A cohort study from Egypt and meta-analysis of published data.

BACKGROUND & AIMS: Hepatitis B virus (HBV) reactivation in chronic hepatitis C (CHC) patients treated with direct-acting antivirals (DAAs) became an issue. However, its frequency has been poorly estimated, because of the varying definitions used and evaluation of heterogeneous study populations, including those concurrently treated for HBV. METHODS: We prospectively followed HBV surface antigen (HBsAg)-positive Egyptians undergoing interferon-free DAAs, to estimate the risk of HBV reactivation and HBV-related hepatitis. We also conducted a meta-analysis to estimate the reactivation risk using published data obtained from a systematic review of PubMed/Embase, in addition to our Egyptian data. We applied a standard definition of HBV reactivation proposed by the international liver associations (APASL and AASLD). RESULTS: Of 4471 CHC patients, 35 HBsAg-positive patients started interferon-free DAAs without HBV nucleos(t)ide analogues in our Egyptian cohort. Ten experienced HBV reactivation (28.6%), of whom 1 developed hepatitis (10.0%). Our systematic review identified 18 papers. The pooled reactivation risk in HBsAg-positive patients was 18.2% (95% CI: 7.9%-30.7%) without HBV therapy and 0.0% (95% CI: 0.0%-0.0%) with HBV nucleos(t)ide analogue. The pooled risk of hepatitis in those with HBV reactivation was 12.6% (95% CI: 0.0%-34.7%). The pooled reactivation risk in HBsAg-negative, antibody to HBV core antigen-positive (anti-HBc-positive) patients was negligible (0.1%, 95% CI: 0.0%-0.3%), irrespective of the presence of antibody to HBsAg (anti-HBs). CONCLUSIONS: We confirmed high HBV reactivation risk in HBsAg-positive patients undergoing DAAs, with only a minority developing clinically important hepatitis. The risk is negligible for HBsAg-negative anti-HBc-positive patients.

The prevalence of hepatitis C virus infection in Egypt 2015: implications for future policy on prevention and treatment.

BACKGROUND & AIMS: In 2015, a national Egyptian health issue survey was conducted to describe the prevalence of hepatitis C virus (HCV) infection. In this paper, we describe the HCV burden in 2015, compare the results with the national survey conducted in 2008, and discuss the implications of the new findings on prevention of HCV in Egypt. METHODS: A multistage probability sampling approach was used, similar to the national demographic survey conducted in 2008. More than 90% of sampled individuals complied with the interview and provided blood samples. RESULTS: In the 15-59-year age groups, the prevalence of HCV antibody was found to be 10.0% (95% CI 9.5-10.5) and that of HCV RNA to be 7.0% (95% CI 6.6-7.4). In children, 1-14 years old, the prevalence of HCV antibody and HCV RNA were 0.4% (95% CI 0.3-0.5) and 0.2% (95% CI 0.1-0.3) respectively. Approximately, 3.7 million persons have chronic HCV infection in the age group 15-59 in 2015. An estimated 29% reduction in HCV RNA prevalence has been seen since 2008, which is largely attributable to the ageing of the group infected 40-50 years ago during the mass schistosomiasis treatment campaigns. Prevention efforts may have also contributed to this decline, with an estimated 75% (95% CI 6-45) decrease in HCV incidence in the 0-19 year age groups over the past 20 years. CONCLUSIONS: These findings can be used to shape future HCV prevention policies in Egypt.

In vivo efficacy of artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated falciparum malaria: an open-randomized, non-inferiority clinical trial in South Kivu, Democratic Republic of Congo.

BACKGROUND: Between 2009 and 2012, malaria cases diagnosed in a Médecins sans Frontières programme have increased fivefold in Baraka, South Kivu, Democratic Republic of the Congo (DRC). The cause of this increase is not known. An in vivo drug efficacy trial was conducted to determine whether increased treatment failure rates may have contributed to the apparent increase in malaria diagnoses. METHODS: In an open-randomized non-inferiority trial, the efficacy of artesunate-amodiaquine (ASAQ) was compared to artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria in 288 children aged 6-59 months. Included children had directly supervised treatment and were then followed for 42 days with weekly clinical and parasitological evaluations. The blood samples of children found to have recurring parasitaemia within 42 days were checked by PCR to confirm whether or not this was due to reinfection or recrudescence (i.e. treatment failure). RESULTS: Out of 873 children screened, 585 (67 %) were excluded and 288 children were randomized to either ASAQ or AL. At day 42 of follow up, the treatment efficacy of ASAQ was 78 % before and 95 % after PCR correction for re-infections. In the AL-arm, treatment efficacy was 84 % before and 99.0 % after PCR correction. Treatment efficacy after PCR correction was within the margin of non-inferiority as set for this study. Fewer children in the AL arm reported adverse reactions. CONCLUSIONS: ASAQ is still effective as a treatment for uncomplicated malaria in Baraka, South Kivu, DRC. In this region, AL may have higher efficacy but additional trials are required to draw this conclusion with confidence. The high re-infection rate in South-Kivu indicates intense malaria transmission. Trial registration NCT02741024.

Impact of SARS-CoV-2 Infection on the Association Between Laboratory Tests and Severe Outcomes Among Hospitalized Children.

Background: To assist clinicians with identifying children at risk of severe outcomes, we assessed the association between laboratory findings and severe outcomes among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected children and determined if SARS-CoV-2 test result status modified the associations. Methods: We conducted a cross-sectional analysis of participants tested for SARS-CoV-2 infection in 41 pediatric emergency departments in 10 countries. Participants were hospitalized, had laboratory testing performed, and completed 14-day follow-up. The primary objective was to assess the associations between laboratory findings and severe outcomes. The secondary objective was to determine if the SARS-CoV-2 test result modified the associations. Results: We included 1817 participants; 522 (28.7%) SARS-CoV-2 test-positive and 1295 (71.3%) test-negative. Seventy-five (14.4%) test-positive and 174 (13.4%) test-negative children experienced severe outcomes. In regression analysis, we found that among SARS-CoV-2-positive children, procalcitonin ≥0.5 ng/mL (adjusted odds ratio [aOR], 9.14; 95% CI, 2.90-28.80), ferritin >500 ng/mL (aOR, 7.95; 95% CI, 1.89-33.44), D-dimer ≥1500 ng/mL (aOR, 4.57; 95% CI, 1.12-18.68), serum glucose ≥120 mg/dL (aOR, 2.01; 95% CI, 1.06-3.81), lymphocyte count <1.0 × 109/L (aOR, 3.21; 95% CI, 1.34-7.69), and platelet count <150 × 109/L (aOR, 2.82; 95% CI, 1.31-6.07) were associated with severe outcomes. Evaluation of the interaction term revealed that a positive SARS-CoV-2 result increased the associations with severe outcomes for elevated procalcitonin, C-reactive protein (CRP), D-dimer, and for reduced lymphocyte and platelet counts. Conclusions: Specific laboratory parameters are associated with severe outcomes in SARS-CoV-2-infected children, and elevated serum procalcitonin, CRP, and D-dimer and low absolute lymphocyte and platelet counts were more strongly associated with severe outcomes in children testing positive compared with those testing negative.

Severe Outcomes Associated With SARS-CoV-2 Infection in Children: A Systematic Review and Meta-Analysis.

Objective: To estimate the proportion of SARS-CoV-2 infected children experiencing hospitalization, intensive care unit (ICU) admission, severe outcomes, and death. Data Sources: PubMed, Embase, and MedRxiv were searched for studies published between December 1, 2019 and May 28, 2021. References of relevant systematic reviews were also screened. Study Selection: We included cohort or cross-sectional studies reporting on at least one outcome measure (i.e., hospitalization, ICU admission, severe outcomes, death) for ≥100 children ≤21 years old within 28 days of SARS-CoV-2 positivity; no language restrictions were applied. Data Extraction and Synthesis: Two independent reviewers performed data extraction and risk of bias assessment. Estimates were pooled using random effects models. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Main Outcomes and Measures: Percentage of SARS-CoV-2 positive children experiencing hospitalization, ICU admission, severe outcome, and death. Results: 118 studies representing 3,324,851 SARS-CoV-2 infected children from 68 countries were included. Community-based studies (N = 48) reported that 3.3% (95%CI: 2.7-4.0%) of children were hospitalized, 0.3% (95%CI: 0.2-0.6%) were admitted to the ICU, 0.1% (95%CI: 0.0-2.2%) experienced a "severe" outcome and 0.02% (95%CI: 0.001-0.05%) died. Hospital-based screening studies (N = 39) reported that 23.9% (95%CI: 19.0-29.2%) of children were hospitalized, 2.9% (95%CI: 2.1-3.8%) were admitted to the ICU, 1.3% (95%CI: 0.5-2.3%) experienced a severe outcome, and 0.2% (95%CI: 0.02-0.5%) died. Studies of hospitalized children (N = 31) reported that 10.1% (95%CI: 6.1-14.9%) of children required ICU admission, 4.2% (95%CI: 0.0-13.8%) had a severe outcome and 1.1% (95%CI: 0.2-2.3%) died. Low risk of bias studies, those from high-income countries, and those reporting outcomes later in the pandemic presented lower estimates. However, studies reporting outcomes after May 31, 2020, compared to earlier publications, had higher proportions of hospitalized patients requiring ICU admission and experiencing severe outcomes. Conclusion and Relevance: Among children tested positive for SARS-CoV-2, 3.3% were hospitalized, with rates being higher early in the pandemic. Severe outcomes, ICU admission and death were uncommon, however estimates vary by study population, pandemic timing, study risk of bias, and economic status of the country. Systematic Review Registration: PROSPERO, identifier [CRD42021260164].

Consequences of In Utero Zika Virus Exposure and Adverse Pregnancy and Early Childhood Outcomes: A Prospective Cohort Study.

We aimed to describe adverse pregnancy outcomes among women who had symptomatic, RT-PCR-confirmed ZIKV infection and early childhood outcomes among their infants. We enrolled pregnant women with symptomatic, RT-PCR-confirmed ZIKV infection in a prospective cohort study, and their infants in a prospective pediatric cohort study. We defined adverse pregnancy and early childhood outcomes based on selected neurologic, ophthalmologic, auditory, musculoskeletal, and anthropometric abnormalities. We used RT-PCR and serologic tests to determine the ZIKV infection status of the child. Between 10 March and 24 November 2016, we enrolled 546 pregnant women with RT-PCR-confirmed ZIKV infection. The overall risk of adverse pregnancy and early childhood outcomes possibly related to in utero ZIKV exposure was 15.7% (95% CI: 12.8-19.0), distributed as follows: 3.6% (95% CI: 2.3-5.6) severe sequelae or fatality; 2.7% (95% CI: 1.6-4.5) major abnormalities; 9.4% (95% CI:7.1-12.2) mild abnormalities. The risk of severe sequelae or fatality was higher when ZIKV infection occurred during the first trimester (7.0%), compared to the second (2.7%) or third trimester (1.4%) (p = 0.02). Among the infants for whom ZIKV infection status could be determined, the vertical transmission rate was 3.0% (5/167) (95% CI: 1.1-7.2). Among pregnant women with symptomatic, RT-PCR-confirmed ZIKV infection, severe or major pregnancy or early childhood outcomes were present in 6.3% of fetuses and infants. Severe outcomes occurred more frequently in fetuses and infants whose mothers had been infected in the first trimester.

Corticosteroids and Other Treatments Administered to Children Tested for SARS-CoV-2 Infection in Emergency Departments.

OBJECTIVE: We sought to determine if corticosteroid administration is associated with a SARS-CoV-2 nucleic acid test-positive result and to describe therapies administered to SARS-CoV-2 infected children. METHODS: We collected cross-sectional data from participants recruited in 41 pediatric emergency departments (ED) in 10 countries between March 2020 and June 2021. Participants were <18 years old, had signs or symptoms of, or risk factors for acute SARS-CoV-2 infection, and had nucleic acid testing performed. To determine if SARS-CoV-2 test status was independently associated with corticosteroid administration, we used a multivariable conditional logistic regression model matched by study site to compare treatments administered based on SARS-CoV-2 test and disposition status. This analysis was repeated for the subgroup of study participants who were hospitalized. RESULTS: 30.3% (3,121/10,315) of participants were SARS-CoV-2-positive. Although remdesivir was more commonly administered to SARS-CoV-2-positive children, use was infrequent (25/3120 [0.8%] vs 1/7188 [0.01%]; P = .001). Corticosteroid use was less common among SARS-CoV-2-positive children (219/3120 [7.0%] vs 759/7190 [10.6%]; P < .001). Among hospitalized children, there were no differences in provision of inotropes, respiratory support, chest drainage or extracorporeal membrane oxygenation between groups. Corticosteroid administration was associated with age, history of asthma, wheezing, study month, hospitalization and intensive care unit admission; it was not associated with a positive SARS-CoV-2 test result overall (aOR: 0.91; 95%CI: 0.74, 1.12) or among the subgroup of those hospitalized (aOR: 1.04; 95%CI: 0.75, 1.44). CONCLUSIONS: Few disease-specific treatments are provided to SARS-CoV-2-positive children; clinical trials evaluating therapies in children are urgently needed.

Outcomes of SARS-CoV-2-Positive Youths Tested in Emergency Departments: The Global PERN-COVID-19 Study.

Importance: Severe outcomes among youths with SARS-CoV-2 infections are poorly characterized. Objective: To estimate the proportion of children with severe outcomes within 14 days of testing positive for SARS-CoV-2 in an emergency department (ED). Design, Setting, and Participants: This prospective cohort study with 14-day follow-up enrolled participants between March 2020 and June 2021. Participants were youths aged younger than 18 years who were tested for SARS-CoV-2 infection at one of 41 EDs across 10 countries including Argentina, Australia, Canada, Costa Rica, Italy, New Zealand, Paraguay, Singapore, Spain, and the United States. Statistical analysis was performed from September to October 2021. Exposures: Acute SARS-CoV-2 infection was determined by nucleic acid (eg, polymerase chain reaction) testing. Main Outcomes and Measures: Severe outcomes, a composite measure defined as intensive interventions during hospitalization (eg, inotropic support, positive pressure ventilation), diagnoses indicating severe organ impairment, or death. Results: Among 3222 enrolled youths who tested positive for SARS-CoV-2 infection, 3221 (>99.9%) had index visit outcome data available, 2007 (62.3%) were from the United States, 1694 (52.6%) were male, and 484 (15.0%) had a self-reported chronic illness; the median (IQR) age was 3 (0-10) years. After 14 days of follow-up, 735 children (22.8% [95% CI, 21.4%-24.3%]) were hospitalized, 107 (3.3% [95% CI, 2.7%-4.0%]) had severe outcomes, and 4 children (0.12% [95% CI, 0.03%-0.32%]) died. Characteristics associated with severe outcomes included being aged 5 to 18 years (age 5 to <10 years vs <1 year: odds ratio [OR], 1.60 [95% CI, 1.09-2.34]; age 10 to <18 years vs <1 year: OR, 2.39 [95% CI 1.38-4.14]), having a self-reported chronic illness (OR, 2.34 [95% CI, 1.59-3.44]), prior episode of pneumonia (OR, 3.15 [95% CI, 1.83-5.42]), symptoms starting 4 to 7 days prior to seeking ED care (vs starting 0-3 days before seeking care: OR, 2.22 [95% CI, 1.29-3.82]), and country (eg, Canada vs US: OR, 0.11 [95% CI, 0.05-0.23]; Costa Rica vs US: OR, 1.76 [95% CI, 1.05-2.96]; Spain vs US: OR, 0.51 [95% CI, 0.27-0.98]). Among a subgroup of 2510 participants discharged home from the ED after initial testing and who had complete follow-up, 50 (2.0%; 95% CI, 1.5%-2.6%) were eventually hospitalized and 12 (0.5%; 95% CI, 0.3%-0.8%) had severe outcomes. Compared with hospitalized SARS-CoV-2-negative youths, the risk of severe outcomes was higher among hospitalized SARS-CoV-2-positive youths (risk difference, 3.9%; 95% CI, 1.1%-6.9%). Conclusions and Relevance: In this study, approximately 3% of SARS-CoV-2-positive youths tested in EDs experienced severe outcomes within 2 weeks of their ED visit. Among children discharged home from the ED, the risk was much lower. Risk factors such as age, underlying chronic illness, and symptom duration may be useful to consider when making clinical care decisions.

Post-COVID-19 Conditions Among Children 90 Days After SARS-CoV-2 Infection.

Importance: Little is known about the risk factors for, and the risk of, developing post-COVID-19 conditions (PCCs) among children. Objectives: To estimate the proportion of SARS-CoV-2-positive children with PCCs 90 days after a positive test result, to compare this proportion with SARS-CoV-2-negative children, and to assess factors associated with PCCs. Design, Setting, and Participants: This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2-positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2-negative controls. Exposure: SARS-CoV-2 detected via nucleic acid testing. Main Outcomes and Measures: Post-COVID-19 conditions, defined as any persistent, new, or recurrent health problems reported in the 90-day follow-up survey. Results: Of 8642 enrolled children, 2368 (27.4%) were SARS-CoV-2 positive, among whom 2365 (99.9%) had index ED visit disposition data available; among the 1884 children (79.7%) who completed follow-up, the median age was 3 years (IQR, 0-10 years) and 994 (52.8%) were boys. A total of 110 SARS-CoV-2-positive children (5.8%; 95% CI, 4.8%-7.0%) reported PCCs, including 44 of 447 children (9.8%; 95% CI, 7.4%-13.0%) hospitalized during the acute illness and 66 of 1437 children (4.6%; 95% CI, 3.6%-5.8%) not hospitalized during the acute illness (difference, 5.3%; 95% CI, 2.5%-8.5%). Among SARS-CoV-2-positive children, the most common symptom was fatigue or weakness (21 [1.1%]). Characteristics associated with reporting at least 1 PCC at 90 days included being hospitalized 48 hours or more compared with no hospitalization (adjusted odds ratio [aOR], 2.67 [95% CI, 1.63-4.38]); having 4 or more symptoms reported at the index ED visit compared with 1 to 3 symptoms (4-6 symptoms: aOR, 2.35 [95% CI, 1.28-4.31]; ≥7 symptoms: aOR, 4.59 [95% CI, 2.50-8.44]); and being 14 years of age or older compared with younger than 1 year (aOR, 2.67 [95% CI, 1.43-4.99]). SARS-CoV-2-positive children were more likely to report PCCs at 90 days compared with those who tested negative, both among those who were not hospitalized (55 of 1295 [4.2%; 95% CI, 3.2%-5.5%] vs 35 of 1321 [2.7%; 95% CI, 1.9%-3.7%]; difference, 1.6% [95% CI, 0.2%-3.0%]) and those who were hospitalized (40 of 391 [10.2%; 95% CI, 7.4%-13.7%] vs 19 of 380 [5.0%; 95% CI, 3.0%-7.7%]; difference, 5.2% [95% CI, 1.5%-9.1%]). In addition, SARS-CoV-2 positivity was associated with reporting PCCs 90 days after the index ED visit (aOR, 1.63 [95% CI, 1.14-2.35]), specifically systemic health problems (eg, fatigue, weakness, fever; aOR, 2.44 [95% CI, 1.19-5.00]). Conclusions and Relevance: In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older.

Comparison of Publication of Pediatric Probiotic vs Antibiotic Trials Registered on ClinicalTrials.gov.

Importance: The published evidence in support of probiotic use is conflicting, which may be a result of selective publication of probiotic trials. Objectives: To compare the proportion of registered trials that evaluate pediatric probiotics vs those that evaluate antibiotics that are published and to identify study-related factors associated with publication status. Design, Setting, and Participants: This cross-sectional study evaluated eligible trials registered in ClinicalTrials.gov, an online clinical trials registry, from July 1, 2005, to June 30, 2016. Eligible studies included participants younger than 18 years, evaluated a probiotic or 1 of the 5 most commonly prescribed antibiotics in children and adolescents, and randomized study participants. All searches were updated and finalized as of September 9, 2020. Exposures: Probiotic or antibiotic. Main Outcomes and Measures: The primary outcome was study publication status. In addition, exposure status (probiotic vs antibiotic), trial result, and funding source were assessed for independent association with publication status. Whether study design elements, publication journal impact factor, and the interval from study completion to publication differed by exposure status were also evaluated. Results: A total of 401 unique trials (265 probiotic and 136 antibiotic) met eligibility criteria. A greater proportion of antibiotic compared with probiotic studies were published (83 [61.0%] vs 119 [44.9%]; difference, 16.1% [95% CI, 5.8%-25.9%]). After adjustment for funding source, blinding, and purpose, studies evaluating an antibiotic were more likely to be published (odds ratio, 2.1 [95% CI, 1.3-3.4]). No other covariates included in the model were independently associated with publication status. Antibiotic trials, compared with probiotic trials, were more likely to have a therapeutic purpose (114 [83.8%] vs 117 [44.2%]; difference, 39.6% [95% CI, 31.1%-48.3%]) and to be multicenter (46 [33.8%] vs 46 [17.4%]; difference, 16.5% [95% CI, 7.5%-25.7%]). The median impact factor of the journals in which the studies were published was higher for the antibiotic trials (7.2 [IQR, 2.8-20.5] vs 3.0 [IQR, 2.3-4.2]; P < .001). The median number of days to publication did not differ between the probiotic and antibiotic trials (683 [IQR, 441-1036] vs 801 [IQR, 550-1183]; P = .24). Conclusions and Relevance: The findings of this cross-sectional study suggest that probiotic studies are less likely to be published than antibiotic trials. No other study characteristics were associated with publication status. This finding raises concerns regarding the results of meta-analyses of probiotic trials.