Differential host responses within the upper respiratory tract and peripheral blood of children and adults with SARS-CoV-2 infection (preprint)

Age is among the strongest risk factors for severe outcomes from SARS-CoV-2 infection. We sought to evaluate associations between age and both mucosal and systemic host responses to SARS-CoV-2 infection. We profiled the upper respiratory tract (URT) and peripheral blood transcriptomes of 201 participants (age range of 1 week to 83 years), including 137 non-hospitalized individuals with mild SARS-CoV-2 infection and 64 uninfected individuals. Among uninfected children and adolescents, young age was associated with upregulation of innate and adaptive immune pathways within the URT, suggesting that young children are primed to mount robust mucosal immune responses to exogeneous respiratory pathogens. SARS-CoV-2 infection was associated with broad induction of innate and adaptive immune responses within the URT of children and adolescents. Peripheral blood responses among SARS-CoV-2-infected children and adolescents were dominated by interferon pathways, while upregulation of myeloid activation, inflammatory, and coagulation pathways was observed only in adults. Systemic symptoms among SARS-CoV-2-infected subjects were associated with blunted innate and adaptive immune responses in the URT and upregulation of many of these same pathways within peripheral blood. Finally, within individuals, robust URT immune responses were correlated with decreased peripheral immune activation, suggesting that effective immune responses in the URT may promote local viral control and limit systemic immune activation and symptoms. These findings demonstrate that there are differences in immune responses to SARS-CoV-2 across the lifespan, including between young children and adolescents, and suggest that these varied host responses contribute to observed differences in the clinical presentation of SARS-CoV-2 infection by age.

Using natural language processing and structured medical data to phenotype patients hospitalized due to COVID-19 (preprint)

To identify patients who are hospitalized because of COVID-19 as opposed to those who were admitted for other indications, we compared the performance of different computable phenotype definitions for COVID-19 hospitalizations that use different types of data from the electronic health records (EHR), including structured EHR data elements, provider notes, or a combination of both data types. And conduct a retrospective data analysis utilizing chart review-based validation. Participants are 586 hospitalized individuals who tested positive for SARS-CoV-2 during January 2022. We used natural language processing to incorporate data from provider notes and LASSO regression and Random Forests to fit classification algorithms that incorporated structured EHR data elements, provider notes, or a combination of structured data and provider notes. Results: Based on a chart review, 38% of 586 patients were determined to be hospitalized for reasons other than COVID-19 despite having tested positive for SARS-CoV-2. A classification algorithm that used provider notes had significantly better discrimination than one that used structured EHR data elements (AUROC: 0.894 vs 0.841, p < 0.001), and performed similarly to a model that combined provider notes with structured data elements (AUROC: 0.894 vs 0.893). Assessments of hospital outcome metrics significantly differed based on whether the population included all hospitalized patients who tested positive for SARS-CoV-2 versus those who were determined to have been hospitalized due to COVID-19. This work demonstrates the utility of natural language processing approaches to derive information related to patient hospitalizations in cases where there may be multiple conditions that could serve as the primary indication for hospitalization.

Asthma and the Risk of SARS-CoV-2 Infection Among Children and Adolescents (preprint)

Importance: More than 4 million SARS-COV-2 infections have occurred among children and adolescents in the United States. Risk factors for SARS-CoV-2 infection among children remain poorly defined. Objective: To evaluate the association between asthma and the risk of SARS-CoV-2 infection among children. Design: Retrospective cohort study Setting: A large, integrated health system in central North Carolina. Participants: Children 5 to 17 years of age with a Durham County address and at least one health care encounter in the Duke University Health System between March 1, 2017, and February 28, 2020. Exposure: Diagnosis of asthma Main Outcomes and Measures: The primary outcome was SARS-CoV-2 infection identified by PCR testing of a respiratory sample collected between March 1, 2020, and October 31, 2020. We matched children with asthma 1:1 to children without asthma using propensity scores and used Poisson regression to evaluate the association between asthma and the risk of SARS-CoV-2 infection. We assessed for effect modification of this association by inhaled corticosteroid prescription and comorbid atopic diseases. Results: Of 49,455 children, 6,515 (13%) met criteria for a diagnosis of asthma; all children with asthma were matched to a control child without asthma for a final cohort of 13,030 children. Median (interquartile range) age was 11.0 (8.0, 14.0) years, 56% were male, and 78% were non-White. A diagnosis of asthma was associated with a decreased risk of SARS-CoV-2 infection [risk ratio (RR): 0.67, 95% confidence interval (CI): 0.49-0.92]. This association tended to be stronger in children with asthma who were prescribed inhaled corticosteroids (RR: 0.60, 95% CI: 0.38-0.94) or who had comorbid atopic diseases (RR: 0.59, 95% CI: 0.39-0.88). Of the 66 children with asthma who developed SARS-CoV-2 infection, none required hospitalization for COVID-19. Conclusions and Relevance: Children with asthma had a lower risk of SARS-CoV-2 infection, particularly children prescribed an inhaled corticosteroid or with comorbid atopic diseases. Further studies are needed to explore the complex relationship between asthma, inhaled corticosteroids, and SARS-CoV-2.

Reduced Pediatric Urgent Asthma Utilization and Exacerbations During the COVID-19 Pandemic (preprint)

Background and Objectives: The COVID-19 pandemic has had a profound impact on healthcare access and utilization, which could have important implications for children with chronic diseases, including asthma. We sought to evaluate changes in healthcare utilization and outcomes in children with asthma during the COVID-19 pandemic. Methods: We used electronic health records data to evaluate healthcare use and asthma outcomes in 3,959 children and adolescents, 5-17 years of age, with a prior diagnosis of asthma who had a history of well child visits and encounters within the healthcare system. We assessed all-cause healthcare encounters and asthma exacerbations in the 12-months preceding the start of the COVID-19 pandemic (March 1, 2019-February 29, 2020) and the first 12-months of the pandemic (March 1, 2020-February 28, 2021). Results: All-cause healthcare encounters decreased significantly during the pandemic compared to the preceding year, including well child visits (48.1% during the pandemic vs. 66.6% in the prior year; p < 0.01), emergency department visits (9.7% vs. 21.0%; p < 0.01), and inpatient admissions (1.6% vs. 2.5%; p < 0.01), though there was over a 100-fold increase in telehealth encounters. Asthma exacerbations that required treatment with systemic steroids also decreased (127 vs. 504 exacerbations; p < 0.01). Race/ethnicity was not associated with changes in healthcare utilization or asthma outcomes. Conclusion: The COVID-19 pandemic corresponded to dramatic shifts in healthcare utilization, including increased telehealth use and improved outcomes among children with asthma. Social distancing measures may have also reduced asthma trigger exposure.

Asymptomatic or mild symptomatic SARS-CoV-2 infection elicits durable neutralizing antibody responses in children and adolescents (preprint)

As SARS-CoV-2 continues to spread globally, questions have emerged regarding the strength and durability of immune responses in specific populations. In this study, we evaluated humoral immune responses in 69 children and adolescents with asymptomatic or mild symptomatic SARS-CoV-2 infection. We detected robust IgM, IgG, and IgA antibody responses to a broad array of SARS-CoV-2 antigens at the time of acute infection and 2 and 4 months after acute infection in all participants. Notably, these antibody responses were associated with virus neutralizing activity that was still detectable 4 months after acute infection in 94% of children. Moreover, antibody responses and neutralizing activity in sera from children and adolescents were comparable or superior to those observed in sera from 24 adults with mild symptomatic infection. Taken together, these findings indicate children and adolescents with mild or asymptomatic SARS-CoV-2 infection generate robust and durable humoral immune responses that are likely to protect from reinfection.

Age-related changes in the upper respiratory microbiome are associated with SARS-CoV-2 susceptibility and illness severity (preprint)

Children are less susceptible to SARS-CoV-2 and typically have milder illness courses than adults. We studied the nasopharyngeal microbiomes of 274 children, adolescents, and young adults with SARS-CoV-2 exposure using 16S rRNA gene sequencing. We find that higher abundances of Corynebacterium species are associated with SARS-CoV-2 infection and SARS-CoV-2-associated respiratory symptoms, while higher abundances of Dolosigranulum pigrum are present in SARS-CoV-2-infected individuals without respiratory symptoms. We also demonstrate that the abundances of these bacteria are strongly, and independently, associated with age, suggesting that the nasopharyngeal microbiome may be a potentially modifiable mechanism by which age influences SARS-CoV-2 susceptibility and severity.

SARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study (preprint)

BACKGROUNDChildren with SARS-CoV-2 infection typically have mild symptoms that do not require medical attention, leaving a gap in our understanding of the spectrum of illnesses that the virus causes in children. METHODSWe conducted a prospective cohort study of children and adolescents (<21 years of age) with a SARS-CoV-2-infected close contact. We collected nasopharyngeal or nasal swabs at enrollment and tested for SARS-CoV-2 using a real-time PCR assay. RESULTSOf 382 children, 289 (76%) were SARS-CoV-2-infected. SARS-CoV-2-infected children were more likely to be Hispanic (p<0.0001), less likely to have a history of asthma (p=0.009), and more likely to have an infected sibling contact (p=0.0007) than uninfected children. Children ages 6-13 years were frequently asymptomatic (38%) and had respiratory symptoms less often than younger children (30% vs. 49%; p=0.008) or adolescents (30% vs. 59%; p<0.0001). Compared to children ages 6-13 years, adolescents more frequently reported influenza-like (61% vs. 39%; p=0.002), gastrointestinal (26% vs. 9%; p=0.003), and sensory symptoms (43% vs. 9%; p<0.0001), and had more prolonged illnesses [median (IQR) duration: 7 (4, 12) vs. 4 (3, 8) days; p=0.004]. Despite the age-related variability in symptoms, we found no differences in nasopharyngeal viral load by age or between symptomatic and asymptomatic children. CONCLUSIONSHispanic ethnicity and an infected sibling close contact are associated with increased SARS-CoV-2 infection risk among children, while a history of asthma is associated with decreased risk. Age-related differences in the clinical manifestations of SARS-CoV-2 infection must be considered when evaluating children for COVID-19 and in developing screening strategies for schools and childcare settings.