Characterizing Long COVID in Children and Adolescents

ImportanceMost research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment.ObjectiveTo identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC.Design, setting, and participantsMulticenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history.ExposureSARS-CoV-2 infection.Main outcomes and measuresPASC and 89 prolonged symptoms across 9 symptom domains.ResultsA total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents.Conclusions and relevanceThis study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges

Correlated Template-Switching Events during Minus-Strand DNA Synthesis: a Mechanism for High Negative Interference during Retroviral Recombination

Two models for the mechanism of retroviral recombination have been proposed: forced copy choice (minus-strand recombination) and strand displacement-assimilation (plus-strand recombination). Each minus-strand recombination event results in one template switch, whereas each plus-strand recombination event results in two template switches. Recombinant proviruses with one and more than one template switches were previously observed. Recombinants with one template switch were generated by minus-strand recombination, while recombinants containing more than one template switch may have been generated by plus-strand recombination or by correlated minus-strand recombination. We recently observed that retroviral recombination exhibits high negative interference whereby the frequency of recombinants containing multiple template-switching events is higher than expected. To delineate the mechanism that generates recombinants with more than one template switch, we devised a system that permits only minus-strand recombination. Two highly homologous vectors, WH204 and WH221, containing eight different restriction site markers were used. The primer binding site (PBS) of WH221 was deleted; although reverse transcription cannot initiate from WH221 RNA, it can serve as a template for DNA synthesis in heterozygotic virions. After one round of retroviral replication, the structures of the recombinant proviruses were examined. Recombinants containing two, three, four, and five template switches were observed at 1.4-, 10-, 65-, and 50-fold-higher frequencies, respectively, than expected. This indicates that minus-strand recombination events are correlated and can generate proviruses with multiple template switches efficiently. The frequencies of recombinants containing multiple template switches were similar to those observed in the previous system, which allowed both minus- and plus-strand recombination. Thus, the previously reported high negative interference during retroviral recombination can be caused by correlated template switches during minus-strand DNA synthesis. In addition, all examined recombinants contained an intact PBS, indicating that most of the plus-strand DNA transfer occurs after completion of the strong-stop DNA

Impact of Discharge Components on Readmission Rates for Children Hospitalized with Asthma.

OBJECTIVES: To describe hospital-based asthma-specific discharge components at children\u27s hospitals and determine the association of these discharge components with pediatric asthma readmission rates. STUDY DESIGN: This is a multicenter retrospective cohort study of pediatric asthma hospitalizations in 2015 at children\u27s hospitals participating in the Pediatric Health Information System. Children ages 5 to 17 years were included. An electronic survey assessing 13 asthma-specific discharge components was sent to quality leaders at all 49 hospitals. Correlations of combinations of asthma-specific discharge components and adjusted readmission rates were calculated. RESULTS: The survey response rate was 92% (45 of 49 hospitals). Thirty-day and 3-month adjusted readmission rates varied across hospitals, ranging from 1.9% to 3.9% for 30-day readmissions and 5.7% to 9.1% for 3-month readmissions. No individual or combination discharge components were associated with lower 30-day adjusted readmission rates. The only single-component significantly associated with a lower rate of readmission at 3 months was having comprehensive content of education (P \u3c .029). Increasing intensity of discharge components in bundles was associated with reduced adjusted 3-month readmission rates, but this did not reach statistical significance. This was seen in a 2-discharge component bundle including content of education and communication with the primary medical doctor, as well as a 3-discharge component bundle, which included content of education, medications in-hand, and home-based environmental mitigation. CONCLUSIONS: Children\u27s hospitals demonstrate a range of asthma-specific discharge components. Although we found no significant associations for specific hospital-level discharge components and asthma readmission rates at 30 days, certain combinations of discharge components may support hospitals to reduce healthcare utilization at 3 months

Significant Hepatic Involvement in Patients with Ornithine Transcarbamylase Deficiency

OBJECTIVE: To determine the frequency of significant liver injury and acute liver failure (ALF) in patients with ornithine transcarbamylase deficiency (OTCD), the most common urea cycle defect (UCD). STUDY DESIGN: A historical cohort study was performed. Charts were reviewed at two centers to assess the proportion of 71 individuals with OTCD who had evidence of ALF (INR ≥ 2.0), liver dysfunction (INR 1.5–1.99), or hepatocellular injury (AST/ALT≥ 250 IU/L). RESULTS: 57% of the 49 patients with symptomatic OTCD had liver involvement: 29% met the criteria for ALF, 20% had liver dysfunction, and 8% had isolated hepatocellular injury. The proportion with ALF was greatest in those with more severe OTCD, including neonates with markedly elevated ammonia levels (> 1,000 μmol/L). Some patients with severe liver involvement (INR ≥ 2.0 and AST/ALT > 1,000 IU/L) had only moderate hyperammonemia (100 – 400 μmol/L). ALF was the initial presenting symptom of OTCD in at least 3 of 49 symptomatic OTCD patients. CONCLUSIONS: Episodes of hepatocellular injury, liver dysfunction, and ALF were identified in a high proportion of individuals with symptomatic OTCD. The more severely affected OTCD patients had a higher likelihood of ALF. The diagnosis of a UCD should be considered in unexplained ALF, liver dysfunction or hepatocellular injury