Environmental and Genetic Risk Factors of Congenital Anomalies: an Umbrella Review of Systematic Reviews and Meta-Analyses

BackgroundThe prevalence of congenital anomalies in newborns in South Korea was 272.9 per 100,000 in 2005, and 314.7 per 100,000 in 2006. In other studies, the prevalence of congenital anomalies in South Korea was equivalent to 286.9 per 10,000 livebirths in 2006, while it was estimated 446.3 per 10,000 births during the period from 2008 to 2014. Several systematic reviews and meta-analyses analyzing the factors contributing to congenital anomalies have been reported, but comprehensive umbrella reviews are lacking.MethodsWe searched PubMed, Google Scholar, Cochrane, and EMBASE databases up to July 1, 2019, for systematic reviews and meta-analyses that investigated the effects of environmental and genetic factors on any type of congenital anomalies. We categorized 8 subgroups of congenital anomalies classified according to the 10th revision of the International Statistical Classification of Diseases (ICD-10). Two researchers independently searched the literature, retrieved the data, and evaluated the quality of each study.ResultsWe reviewed 66 systematic reviews and meta-analyses that investigated the association between non-genetic or genetic risk factors and congenital anomalies. Overall, 269 associations and 128 associations were considered for environmental and genetic risk factors, respectively. Congenital anomalies based on congenital heart diseases, cleft lip and palate, and others were associated with environmental risk factors based on maternal exposure to environmental exposures (air pollution, toxic chemicals), parental smoking, maternal history (infectious diseases during pregnancy, pregestational and gestational diabetes mellitus, and gestational diabetes mellitus), maternal obesity, maternal drug intake, pregnancy through artificial reproductive technologies, and socioeconomic factors. The association of maternal alcohol or coffee consumption with congenital anomalies was not significant, and maternal folic acid supplementation had a preventive effect on congenital heart defects. Genes or genetic loci associated with congenital anomalies included MTHFR, MTRR and MTR, GATA4, NKX2-5, SRD5A2, CFTR, and 1p22 and 20q12 anomalies.ConclusionThis study provides a wide perspective on the distribution of environmental and genetic risk factors of congenital anomalies, thus suggesting future studies and providing health policy implications.     

Analysis of Critical COVID-19 Cases Among Children in Korea

BackgroundCoronavirus disease 2019 (COVID-19) is generally asymptomatic or mild in otherwise healthy children, however, severe cases may occur. In this study, we report the clinical characteristics of children classified as critical COVID-19 in Korea to provide further insights into risk factors and management in children.MethodsThis study was a retrospective case series of children < 18 years of age classified as critical COVID-19. Cases were identified by the Korea Disease Control and Prevention Agency surveillance system and medical records were reviewed. Critical COVID-19 was defined as cases with severe illness requiring noninvasive (high flow nasal cannula, continuous positive airway pressure, or bilevel positive airway pressure) or invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO) or continuous renal replacement therapy (CRRT), between January 20, 2020 and October 7, 2021.ResultsAmong 39,146 cases diagnosed with COVID-19 in subjects < 18 years of age, eight cases (0.02%) were identified as critical COVID-19. The median age was 13 years (range 10 month–17 years) and male-to-female ratio was 1:1. Three children had underlying diseases; one child has asthma and major depressive disorder, one child had Lennox-Gastaut syndrome and one child had mental retardation and was newly diagnosed with type 2 diabetes mellitus with the diagnosis of COVID-19. Among the eight children, seven were obese (body mass index range [BMI] median 29.3, range 25.9–38.2, weight-for-length > 97% for infant) and one was overweight (BMI 21.3). All patients had fever, six patients had dyspnea or cough and other accompanied symptoms included sore throat, headache, lethargy and myalgia. Radiologic findings showed pneumonia within 1–8 days after symptom onset. Pneumonia progressed in these children for 2–6 days and was improved within 5–32 days after diagnosis. Among the eight critical cases, remdesivir was administered in six cases. Steroids were provided for all cases. Inotropics were administered in one case. Six cases were treated with noninvasive mechanical ventilator and three required mechanical ventilator. One case required ECMO due to acute respiratory distress syndrome. All cases were admitted to the intensive care unit and admission period ranged from 9–39 days. Among all critical COVID-19 cases < 18 years of age, there were no fatal cases.ConclusionTo develop appropriate policies for children in the COVID-19 pandemic, it is important to monitor and assess the clinical burden in this population.     

Risk Factors of Outcomes of COVID-19 Patients in Korea: Focus on Early Symptoms

BackgroundCoronavirus disease 2019 (COVID-19) has spread around the globe, and it is important to determine the risk factors of death in the general population. Our study aimed to determine the risk factors of death and severe illness requiring supplemental oxygen therapy based on the demographic and clinical characteristics of COVID-19 patients in Korea.MethodsIn this study, we used data provided by the Korea Disease Control and Prevention Agency (KDCA) and analyzed a total of 5,068 patients with COVID-19, excluding 19 pregnant women and 544 individuals with missing data. We performed logistic regression analysis to determine the impact of early symptoms on survival and severe disease. Logistic regression models included sex, age, number of comorbidities, symptoms on admission, blood pressure, heart rate, and body temperature as explanatory variables, and death and oxygen therapy as outcome variables.ResultsLogistic regression analyses revealed that the male sex, older age (≥ 60 years), higher number of comorbidities, presence of symptoms on admission, heart rate ≥ 120 bpm, and body temperature ≥ 37.5°C presented with higher risk of in-hospital death and oxygen therapy requirement. Conversely, rhinorrhea and headache were associated with a low risk of death and oxygen therapy requirement. The findings showed that cough, sputum, and fever were the most common symptoms on admission, while 25.3% of patients with COVID-19 were asymptomatic.ConclusionCOVID-19 patients with high-risk early symptoms on admission, such as dyspnea and altered mental status, and those without low-risk symptoms of rhinorrhea and headache should be included in priority treatment groups.     

Comprehensive Rehabilitation in Severely Ill Inpatients With COVID-19: A Cohort Study in a Tertiary Hospital

BackgroundThis study aimed to investigate the effects of comprehensive rehabilitation management on functional recovery and examine the correlation between clinical parameters and improvements in functional outcomes in severe-to-critical inpatients with coronavirus disease 2019 (COVID-19) in a tertiary hospital.MethodsPost-acute COVID-19 patients who had a World Health Organization (WHO) ordinal scale of 5–7, underwent intensive care, and received comprehensive rehabilitation management, including exercise programs, nutritional support, dysphagia evaluation, and psychological care were included. The appendicular skeletal muscle mass index (SMI), Medical Research Council sum score, handgrip strength, number of repetitions in the 1-minute sit-to-stand test, gait speed, Berg Balance Scale (BBS), and Functional Ambulation Classification (FAC) were evaluated at hospital stay, discharge, and 1-month follow-up. The correlation between the rehabilitation dose and improvement in each outcome measure was analyzed.ResultsOverall, 37 patients were enrolled, of whom 59.5% and 32.4% had a score of 6 and 7 on the WHO ordinal scale, respectively. Lengths of stay in the intensive care unit and hospital were 33.6 ± 23.9 and 63.8 ± 36.5 days. Outcome measures revealed significant improvements at discharge and 1-month follow-up. The SMI was significantly increased at the 1-month follow-up (6.13 [5.24–7.76]) compared with that during the hospital stay (5.80 [5.39–7.05]). We identified dose-response associations between the rehabilitation dose and FAC (ρ = 0.46) and BBS (ρ = 0.50) scores. Patients with older age, longer hospitalization, longer stay at the intensive care unit, longer duration of mechanical ventilation, tracheostomy, a more depressive mood, and poorer nutritional status revealed poorer improvement in gait speed at the 1-month follow-up.ConclusionComprehensive rehabilitation management effectively improved muscle mass, muscle strength, and physical performance in severe-to-critical COVID-19 patients. Dose-response relationship of rehabilitation and functional improvement emphasizes the importance of intensive post-acute inpatient rehabilitation in COVID-19 survivors.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT05104411","term_id":"NCT05104411"}}NCT05104411     

Predicting Factors of Severe COVID-19 in Patients With Asthma: A Korean National Cohort Study

As there are limited data on the disease course of and factors predicting severe coronavirus disease 19 (COVID-19) in patients with asthma, this study aims to perform a detailed analysis of the clinical course of asthmatic patients with COVID-19 and evaluate factors related to severe infection. Of the 5,628 patients confirmed with COVID-19, 128 (2.3%) had asthma. Among the 128 asthmatic patients, 32 (25%) had severe COVID-19 and 96 (75%) had non-severe COVID-19. Among asthmatic patients, those with severe COVID-19 were significantly older and had more dyspnea and fever, more comorbidities, and lower lymphocyte and platelet counts than those with non-severe COVID-19. In multivariable logistic regression analysis, chronic obstructive pulmonary disease (adjusted odds ratio [aOR], 6.49; 95% confidence interval [CI], 1.18–41.81), low lymphocyte proportion (aOR, 0.91; 95% CI, 0.86–0.97), and low platelet count (aOR, 0.99; 95% CI, 0.98–0.99) were independently associated with severe COVID-19.     

Risk factors associated with COVID-19-associated pulmonary aspergillosis in ICU patients: a French multicentric retrospective cohort

ObjectivesThe main objective of this study was to determine the incidence of invasive pulmonary aspergillosis (IPA) in patients with coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU), and to describe the patient characteristics associated with IPA occurrence and to evaluate its impact on prognosis.MethodsWe conducted a retrospective cohort study including all successive COVID-19 patients, hospitalized in four ICUs, with secondary deterioration and one or more respiratory samples sent to the mycology department. We used a strengthened IPA testing strategy including seven mycological criteria. Patients were classified as probable IPA according to the European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group Education and Research Consortium (MSGERC) classification if immunocompromised, and according to the recent COVID-19-associated IPA classification otherwise.ResultsProbable IPA was diagnosed in 21 out of the 366 COVID-19 patients (5.7%) admitted to the ICU and in the 108 patients (19.4%) who underwent respiratory sampling for deterioration. No significant differences were observed between patients with and without IPA regarding age, gender, medical history and severity on admission and during hospitalization. Treatment with azithromycin for ≥3 days was associated with the diagnosis of probable IPA (odds ratio 3.1, 95% confidence interval 1.1–8.5, p = 0.02). A trend was observed with high-dose dexamethasone and the occurrence of IPA. Overall mortality was higher in the IPA patients (15/21, 71.4% versus 32/87, 36.8%, p < 0.01).ConclusionIPA is a relatively frequent complication in severe COVID-19 patients and is responsible for increased mortality. Azithromycin, known to have immunomodulatory properties, may contribute to increase COVID-19 patient's susceptibility to IPA.     

The Usefulness of Rare Blood Group Systems in the Risk Determination for Severe COVID-19

The newly identified human coronavirus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), based on a detailed analysis of clinical manifestation. It was reported that blood type O individuals were less likely to become infected by SARS-CoV, while blood type A individuals have an increased risk of severe illness. The Forssman antigen, or Forssman glycolipid synthase (FS), was first described in 1911 by John Frederick Forssman. Blood type A/B glycosyltransferases (AT/BTs) and Forssman glycolipid synthase (FS) are encoded by the evolutionarily related ABO (A/B alleles) and GBGT1 genes. In this article, based on published studies about the pathogenesis of the COVID-19, we hypothesize the possible relationship between the COVID-19 infection and rare blood type systems, such as the Forssman antigen system.     

Relationship Between Androgen Deprivation Therapy for Prostate Cancer and Risk of SARS-CoV-2 Infection: A Systematic Review and Meta-Analysis

BackgroundSeveral cohort studies have explored the relationship between androgen deprivation therapy (ADT) and the severity of coronavirus disease 2019 (COVID-19). This study aimed to characterize the relationship between ADT and the severity of COVID-19 in patients with prostate cancer.MethodsA systematic search was conducted using PubMed, Embase, and Cochrane Library databases from the inception of each database until February 31, 2020. Patients with prostate cancer who were treated with ADT were assigned to treatment group while those patients who were not treated with ADT were assigned to the control group. Outcomes were severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) positivity, hospitalization, intensive care unit (ICU) admission, and death. The risk of bias was evaluated using ROBINS-I (Risk Of Bias In Non-randomized Studies of Interventions) tool.ResultsThree studies with qualitative synthesis were included. Finally, two studies with quantitative synthesis having a total of 44,213 patients were included for the present systematic review. There was no significant difference in SARS-CoV-2 positive rate (odds ratio [OR], 0.52; 95% confidence intervals [Cis], 0.13–2.09; P = 0.362), hospitalization (OR, 0.52; 95% CIs, 0.07–3.69; P = 0.514), ICU admission (OR, 0.93; 95% CIs, 0.39–2.23, P = 0.881), or death (OR, 0.88; 95% CIs, 0.06–12.06; P = 0.934) between ADT and non-ADT groups.ConclusionQualitative and quantitative analyses of previous studies revealed no significant effect of ADT on COVID-19. However, more studies with higher quality that explore biochemical and immunological factors involved are needed to confirm this finding in the future.     

A Clinical Risk Score to Predict In-hospital Mortality from COVID-19 in South Korea

BackgroundEarly identification of patients with coronavirus disease 2019 (COVID-19) who are at high risk of mortality is of vital importance for appropriate clinical decision making and delivering optimal treatment. We aimed to develop and validate a clinical risk score for predicting mortality at the time of admission of patients hospitalized with COVID-19.MethodsCollaborating with the Korea Centers for Disease Control and Prevention (KCDC), we established a prospective consecutive cohort of 5,628 patients with confirmed COVID-19 infection who were admitted to 120 hospitals in Korea between January 20, 2020, and April 30, 2020. The cohort was randomly divided using a 7:3 ratio into a development (n = 3,940) and validation (n = 1,688) set. Clinical information and complete blood count (CBC) detected at admission were investigated using Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression to construct a predictive risk score (COVID-Mortality Score). The discriminative power of the risk model was assessed by calculating the area under the curve (AUC) of the receiver operating characteristic curves.ResultsThe incidence of mortality was 4.3% in both the development and validation set. A COVID-Mortality Score consisting of age, sex, body mass index, combined comorbidity, clinical symptoms, and CBC was developed. AUCs of the scoring system were 0.96 (95% confidence interval [CI], 0.85–0.91) and 0.97 (95% CI, 0.84–0.93) in the development and validation set, respectively. If the model was optimized for > 90% sensitivity, accuracies were 81.0% and 80.2% with sensitivities of 91.7% and 86.1% in the development and validation set, respectively. The optimized scoring system has been applied to the public online risk calculator (https://www.diseaseriskscore.com).ConclusionThis clinically developed and validated COVID-Mortality Score, using clinical data available at the time of admission, will aid clinicians in predicting in-hospital mortality.     

PICU危重患儿预后危险因素分析

目的 通过对我院近4年来150例PICU危重患儿的病例进行剖析,总结影响预后的相关因素。方法 收集150例2014年3月~2018年5月于我院PICU住院治疗危重患儿的临床资料作为研究对象,按预后不同,分为生存组97例和终点事件组53例,对比两组患儿在降钙素原、乳酸脱氢酶、血钙、血乳酸及血 pH 值水平的差异。结果 两组患儿的年龄和性别比较,差异无统计学意义（P＞0.05）。生存组患儿降钙素原、乳酸脱氢酶和血乳酸分别为（0.72±0.31）ng/ml、（75.43±28.88）IU/L和（4.71±1.88）mmol/L,均低于终点事件组的（1.98±0.92）ng/ml、（119.2±49.89）IU/L和（8.46±2.98）mmol/L;血钙和血pH值分别为（1.41±0.55）mmol/L和（7.23±0.20）,高于终点事件组的（1.13±0.42）mmol/L和（7.05±0.15）,差异均具有统计学意义（P＜0.05）。结论 对于降钙素原、乳酸脱氢酶、血乳酸明显升高,血钙值低和严重酸中毒患儿,生存质量及预后差,死亡风险上升,这些临床指标对PICU危重患儿预后具有重要的临床指导意义。     

Autism Spectrum Disorder and Obesity in Children: A Systematic Review and Meta-Analysis

IntroductionChildren and adolescents with autism spectrum disorder (ASD) appear to be at greater risk of excess weight gain. The aim of this systematic review and meta-analysis was to examine whether children with ASD have a greater prevalence of obesity and whether the prevalence of ASD is higher in children with obesity.MethodsWe conducted a systematic search on PubMed, Scopus, and PsychINFO until May 21, 2021. We used the meta package in the R in order to calculate the pooled prevalence and relative risk of obesity in children with ASD.ResultsWe found 20 eligible studies investigating the prevalence of obesity in children with ASD, with the prevalence ranging from 7.9 to 31.8% and from 1.4 to 23.6% among controls. All but three studies originated from the USA. The proportion of children with obesity in ASD populations was 17% (95% confidence interval [CI]: 13–22). The relative risk of obesity in children with ASD compared with control children was 1.58 (95% CI: 1.34–1.86). There were no controlled studies reporting on the prevalence of ASD in children with obesity.ConclusionChildren and adolescents with ASD have a higher prevalence of obesity than healthy controls. There is a need for further prevalence studies of obesity in children with ASD, especially outside the USA, since the few European studies carried out have failed to show a significant difference between obesity prevalence in children with and without ASD. There is no knowledge at all regarding the prevalence of ASD among children with obesity.     

Clinical Characteristics of COVID-19: Risk Factors for Early Oxygen Requirement after Hospitalization

BackgroundSome coronavirus disease 2019 (COVID-19) patients initially present with early oxygen demand, requiring more medical resources, and some develop severe conditions, while others worsen later in their clinical course. Whether the nature of the two groups is the same but in the spectrum of different diagnostic time points is not certain.MethodsHospitalized COVID-19 patients who needed oxygen therapy from February to November 2020 were included in the study. The patients were divided into early and late groups based on the time when the oxygen requirement occurred. Basic and epidemiologic characteristics were compared. Clinical variables were analyzed in both groups.ResultsA total of 164 patients needed oxygen therapy, 94 of whom were in the early group and 70 of whom were in the late group. The early and late groups had similar baseline characteristics except age (median age, 73 vs. 67 years), uncertain exposure history (50% vs. 31.4%) and the time from the onset of illness to admission (median, 5 vs. 2 days). Multivariate analysis showed that age > 65 years (OR, 4.65), symptom onset > 5 days (OR, 9.13) and several clinical manifestations, such as febrile sensation (OR, 6.01), dyspnea (OR, 30.0), C-reactive protein > 1 mg/dL (OR, 7.87) and chest X-ray abnormality (OR, 8.15), were predictive factors in the early group. The early group required more intensive care such as mechanical ventilation care, extracorporeal membrane oxygenation and death (29.8% vs. 14.3%, P = 0.002).ConclusionOlder age, especially > 65 years, and a delay of over 5 days from the onset of illness to admission were associated with early oxygen demand in COVID-19 patients. Interventions for earlier diagnosis of elderly people may benefit clinical outcomes.     

Severity-Adjusted Dexamethasone Dosing and Tocilizumab Combination for Severe COVID-19

PurposeReal-world experience with tocilizumab in combination with dexamethasone in patients with severe coronavirus disease (COVID-19) needs to be investigated.Materials and MethodsA retrospective cohort study was conducted to evaluate the effect of severity-adjusted dosing of dexamethasone in combination with tocilizumab for severe COVID-19 from August 2020 to August 2021. The primary endpoint was 30-day clinical recovery, which was defined as no oxygen requirement or referral after recovery.ResultsA total of 66 patients were evaluated, including 33 patients in the dexamethasone (Dexa) group and 33 patients in the dexamethasone plus tocilizumab (DexaToci) group. The DexaToci group showed a statistically significant benefit in 30-day clinical recovery, compared to the Dexa group (p=0.024). In multivariable analyses, peak FiO₂ within 3 days and tocilizumab combination were consistently significant for 30-day recovery (all p<0.05). The DexaToci group showed a significantly steeper decrease in FiO₂ (-4.2±2.6) than the Dexa group (-2.7±2.6; p=0.021) by hospital day 15. The duration of oxygen requirement was significantly shorter in the DexaToci group than the Dexa group (median, 10.0 days vs. 17.0 days; p=0.006). Infectious complications and cellular and humoral immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the convalescence stage were not different between the two groups.ConclusionA combination of severity-adjusted dexamethasone and tocilizumab for the treatment of severe COVID-19 improved clinical recovery without increasing infectious complications or hindering the immune response against SARS-CoV-2.     

A Case Report for Severe COVID-19 in a 9-Year-Old Child Treated with Remdesivir and Dexamethasone

Coronavirus disease 2019 (COVID-19) is generally milder in children than in adults, and a substantial proportion of children with the disease have asymptomatic infections. Remdesivir is recommended for severe COVID-19. To date, there are little data on the outcomes of remdesivir treatment in children. We report a case of severe COVID-19 in a previously healthy but obese (body mass index, 27.6; 99.8^th percentile of the age) 9-year-old boy treated with remdesivir and dexamethasone. The patient had pneumonia at the time of diagnosis and required supplemental oxygen due to hypoxia one day after diagnosis. The patient developed respiratory distress as his pneumonia progressed rapidly. Therefore, remdesivir with dexamethasone therapy was initiated on hospital day 2. Supplemental oxygen was gradually weaned on hospital day 6 and stopped on hospital day 9. Significant improvement in pneumonic consolidations on chest X-ray was noted on hospital day 8. The patient was discharged on hospital day 21. We did not observe any adverse effects of remdesivir therapy and successfully treated a 9-year-old child with severe COVID-19.     

Epidemiology and Outcome of Out-of-Hospital Cardiac Arrests during the COVID-19 Pandemic in South Korea: A Systematic Review and Meta-Analyses

PurposeTo evaluate the effect of coronavirus disease 2019 (COVID-19) on out-of-hospital cardiac arrest (OHCA) outcomes in South Korea, we conducted systematic review and meta-analysis.Materials and MethodsMEDLINE, Embase, KoreaMed, and Korean Information Service System databases were searched up to June 2022. We included observational studies and letters on OHCA during the COVID-19 pandemic and compared them to those before the pandemic. Epidemiologic characteristics, including at-home OHCA, bystander cardiopulmonary resuscitation, unwitnessed arrest, use of an automated external defibrillator (AED), shockable cardiac rhythm, and airway management, were evaluated. Survival and favorable neurological outcomes were extracted. We conducted a meta-analysis of each characteristic and outcome.ResultsSix studies including 4628 OHCA patients were included in this study. The incidence of at-home OHCA significantly increased and the AED use decreased during the COVID-19 pandemic compared to before the pandemic [odds ratio (OR), 1.29; 95% confidence interval (CI), 1.08–1.55; I²=0% and OR, 0.74; 95% CI, 0.57–0.97; I²=0%, respectively]. Return of spontaneous circulation after OHCA, survival, and favorable neurological outcomes during and before the pandemic did not differ significantly (OR, 0.90; 95% CI, 0.71–1.13; I²=37%; OR, 0.74; 95% CI, 0.43–1.26; I²=72%; OR, 0.77; 95% CI, 0.43–1.37; I²=70%, respectively).ConclusionDuring the COVID-19 pandemic in South Korea, the incidence of at-home OHCA increased and AED use decreased among OHCA patients. However, survival and favorable neurological outcomes did not significantly differ from before the pandemic. This insignificant effect of the pandemic on OHCA in South Korea could be attributed to the slow increase in patient count in the early days of the pandemic.OSF Registry (DOI: 10.17605/OSF.IO/UGE9D).