As schools plan for re-opening, understanding the potential role children play in the coronavirus infectious disease 2019 (COVID-19) pandemic and the factors that drive severe illness in children is ...critical.
Children ages 0-22 years with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presenting to urgent care clinics or being hospitalized for confirmed/suspected SARS-CoV-2 infection or multisystem inflammatory syndrome in children (MIS-C) at Massachusetts General Hospital were offered enrollment in the Massachusetts General Hospital Pediatric COVID-19 Biorepository. Enrolled children provided nasopharyngeal, oropharyngeal, and/or blood specimens. SARS-CoV-2 viral load, ACE2 RNA levels, and serology for SARS-CoV-2 were quantified.
A total of 192 children (mean age, 10.2 ± 7.0 years) were enrolled. Forty-nine children (26%) were diagnosed with acute SARS-CoV-2 infection; an additional 18 children (9%) met the criteria for MIS-C. Only 25 children (51%) with acute SARS-CoV-2 infection presented with fever; symptoms of SARS-CoV-2 infection, if present, were nonspecific. Nasopharyngeal viral load was highest in children in the first 2 days of symptoms, significantly higher than hospitalized adults with severe disease (P = .002). Age did not impact viral load, but younger children had lower angiotensin-converting enzyme 2 expression (P = .004). Immunoglobulin M (IgM) and Immunoglobulin G (IgG) to the receptor binding domain of the SARS-CoV-2 spike protein were increased in severe MIS-C (P < .001), with dysregulated humoral responses observed.
This study reveals that children may be a potential source of contagion in the SARS-CoV-2 pandemic despite having milder disease or a lack of symptoms; immune dysregulation is implicated in severe postinfectious MIS-C.
Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening complication that can develop weeks to months after an initial SARS-CoV-2 infection. A complex, time-consuming laboratory ...evaluation is currently required to distinguish MIS-C from other illnesses. New assays are urgently needed early in the evaluation process to expedite MIS-C workup and initiate treatment when appropriate. This study aimed to measure the performance of a monocyte anisocytosis index, obtained on routine complete blood count (CBC), to rapidly identify subjects with MIS-C at risk for cardiac complications. We measured monocyte anisocytosis, quantified by monocyte distribution width (MDW), in blood samples collected from children who sought medical care in a single medical center from April 2020 to October 2020 (discovery cohort). After identifying an effective MDW threshold associated with MIS-C, we tested the utility of MDW as a tier 1 assay for MIS-C at multiple institutions from October 2020 to October 2021 (validation cohort). The main outcome was the early screening of MIS-C, with a focus on children with MIS-C who displayed cardiac complications. The screening accuracy of MDW was compared to tier 1 routine laboratory tests recommended for evaluating a child for MIS-C. We enrolled 765 children and collected 846 blood samples for analysis. In the discovery cohort, monocyte anisocytosis, quantified as an MDW threshold of 24.0, had 100% sensitivity (95% CI 78-100%) and 80% specificity (95% CI 69-88%) for identifying MIS-C. In the validation cohort, an initial MDW greater than 24.0 maintained a 100% sensitivity (95% CI 80-100%) and monocyte anisocytosis displayed a diagnostic accuracy greater that other clinically available hematologic parameters. Monocyte anisocytosis decreased with disease resolution to values equivalent to those of healthy controls. Monocyte anisocytosis detected by CBC early in the clinical workup improves the identification of children with MIS-C with cardiac complications, thereby creating opportunities for improving current practice guidelines.
Background and Objectives Multisystem Inflammatory Syndrome in Children (MIS-C) is an emerging complication of COVID-19 which lacks a definitive diagnostic test and evidence-based guidelines for ...workup. We sought to assess practitioners' preferences when initiating a workup for pediatric patients presenting with symptoms concerning for MIS-C. Methods In a cross-sectional vignette-based survey, providers were presented with clinical vignettes of a patient presenting with 24 h of fever from a community with high rates of COVID-19. Respondents were asked about their general practices in pursuing a workup for potential MIS-C including testing obtained, criteria for diagnosis, and timing to confirm or rule out the diagnosis. Results Most of the 174 respondents were physicians from the United States at academic medical centers. The majority of providers would not initiate MIS-C workup for fever and non-specific symptoms unless the fever lasted more than 72 h. Skin rash, abdominal pain, and shortness of breath were symptoms that raised greatest concern for MIS-C. Most providers would obtain COVID-19 PCR or antigen testing, plus blood work, in the initial workup. The list of laboratory studies providers would obtain is extensive. Providers primarily rely on cardiac involvement to confirm a MIS-C diagnosis, and establishing a diagnosis takes 24-48 h. Conclusions Significant heterogeneity exists amongst providers as to when to initiate the MIS-C workup, the order and content of the workup, and how to definitively diagnose MIS-C. A diagnostic test with high sensitivity and specificity for MIS-C and refined evidence-based guidelines are needed to expedite diagnosis and treatment. Keywords: Pediatric COVID-19, Multisystem inflammatory syndrome in children
Mutations in the RyR2-encoded cardiac ryanodine receptor/calcium release channel and in CASQ2-encoded calsequestrin cause catecholaminergic polymorphic ventricular tachycardia (CPVT1 and CPVT2, ...respectively).
The purpose of this study was to evaluate the extent of genotypic and phenotypic heterogeneity among referrals for CPVT genetic testing.
Using denaturing high-performance liquid chromatography and DNA sequencing, mutational analysis of 23 RyR2 exons previously implicated in CPVT1, comprehensive analysis of all translated exons in CASQ2 (CPVT2), KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), KCNE2 (LQT6), and KCNJ2 (Andersen-Tawil syndrome ATS1, also annotated LQT7), and analysis of 10 ANK2 exons implicated in LQT4 were performed on genomic DNA from 11 unrelated patients (8 females) referred to Mayo Clinic's Sudden Death Genomics Laboratory explicitly for CPVT genetic testing.
Overall, putative disease causing mutations were identified in 8 patients (72%). Only 4 patients (3 males) hosted CPVT1-associated RyR2 mutations: P164S, V186M, S3938R, and T4196A. Interestingly, 4 females instead possessed either ATS1- or LQT5-associated mutations. Mutations were absent in >400 reference alleles.
Putative CPVT1-causing mutations in RyR2 were seen in <40% of unrelated patients referred with a diagnosis of CPVT and preferentially in males. Phenotypic mimicry is evident with the identification of ATS1- and LQT5-associated mutations in females displaying a normal QT interval and exercise-induced bidirectional VT, suggesting that observed exercise-induced polymorphic VT in patients may reflect disorders other than CPVT. Clinical consideration for either Andersen-Tawil syndrome or long QT syndrome and appropriate genetic testing may be warranted for individuals with RyR2 mutation-negative CPVT, particularly females.
The difference in morbidity and mortality between adult and pediatric coronavirus disease 2019 infections is dramatic. Understanding pediatric‐specific acute and delayed immune responses to severe ...acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is critical for the development of vaccination strategies, immune‐targeted therapies, and treatment and prevention of multisystem inflammatory syndrome in children. The goal of this review is to highlight research developments in the understanding of the immune responses to SARS‐CoV‐2 infections, with a specific focus on age‐related immune responses.
To characterize the socioeconomic and racial and/or ethnic disparities impacting the diagnosis and outcomes of multisystem inflammatory syndrome in children (MIS-C).
This multicenter retrospective ...case-control study was conducted at 3 academic centers from January 1 to September 1, 2020. Children with MIS-C were compared with 5 control groups: children with coronavirus disease 2019, children evaluated for MIS-C who did not meet case patient criteria, children hospitalized with febrile illness, children with Kawasaki disease, and children in Massachusetts based on US census data. Neighborhood socioeconomic status (SES) and social vulnerability index (SVI) were measured via a census-based scoring system. Multivariable logistic regression was used to examine associations between SES, SVI, race and ethnicity, and MIS-C diagnosis and clinical severity as outcomes.
Among 43 patients with MIS-C, 19 (44%) were Hispanic, 11 (26%) were Black, and 12 (28%) were white; 22 (51%) were in the lowest quartile SES, and 23 (53%) were in the highest quartile SVI. SES and SVI were similar between patients with MIS-C and coronavirus disease 2019. In multivariable analysis, lowest SES quartile (odds ratio 2.2 95% confidence interval 1.1-4.4), highest SVI quartile (odds ratio 2.8 95% confidence interval 1.5-5.1), and racial and/or ethnic minority background were associated with MIS-C diagnosis. Neither SES, SVI, race, nor ethnicity were associated with disease severity.
Lower SES or higher SVI, Hispanic ethnicity, and Black race independently increased risk for MIS-C. Additional studies are required to target interventions to improve health equity for children.
Our primary aim was to investigate the relationship between LVM and anthropometric measures including lean body mass (LBM) in obese pediatric subjects compared to normal weight controls. A ...retrospective chart review identified subjects 2–18 years old who were normotensive and had normal echocardiograms between 1995 and 2020 at Boston Children’s Hospital. LVM was calculated with the 5/6 area length rule from 2D echocardiograms. LBM was calculated with equations derived from dual-energy X-ray absorptiometry. Of the 2217 subjects who met inclusion criteria, 203 were obese and 2014 had normal weight. The median age was 11.9 (2.0–18.9); 46% were female. The median LVM was 94.5 g (59.3–134.3) in obese subjects vs. 78.0 g (51.5–107.7) in controls. The median LBM was 37.2 kg (18.9–50.6) in obese subjects vs. 30.5 kg (17.6–40.8) in controls. In control and obese subjects, LBM had the strongest correlation to LVM (
R
2
0.86,
P
< 0.001) and (
R
2
0.87,
P
< 0.001), respectively. There was at most a modest correlation between tissue Doppler velocity
z
-scores and LV mass, and the largest was Septal E′
z
-score in obese subjects (
r
= − 0.31,
P
= 0.006). In this cohort, LBM was found to have the strongest relationship to LVM in obese subjects. The largest correlation between tissue Doppler velocity
z
-scores and LV mass was Septal E′
z
-score. Future studies will evaluate which measurements are more closely aligned with clinical outcomes in obese children.
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