Frequencies of Adenovirus Types in U.S. Children with Acute Respiratory Illness, 2016-2019

Background. Adenovirus (AdV) is a common cause of acute respiratory illness (ARI). Multiple respiratory AdV types have been identified in humans, but it remains unclear which are the most common in U.S. children with ARI. Methods. We conducted a multicenter, prospective viral surveillance study at seven U.S. children's hospitals, the New Vaccine Surveillance Network, during 12/1/ 16-11/30/19, prior to the COVID-19 pandemic. Children < 18 years of age seen in the emergency department or hospitalized with fever and/or respiratory symptoms were enrolled, and mid-turbinate nasal +/- throat swabs were tested using multiplex respiratory pathogen assays or real time polymerase chain reaction (PCR) test for AdV, respiratory syncytial virus (RSV), human metapneumovirus, rhinovirus/enterovirus (RV), influenza, parainfluenza viruses, and endemic coronaviruses. AdV-positive specimens were subsequently typed using single-plex qPCR assays targeting sequences in the hexon gene specific for types 1-7, 11, 14, 16 and 21. Demographics, clinical characteristics, and outcomes were compared between AdV types. Results. Of 29,381 enrolled children, 2,106 (7.2%) tested positive for AdV. The distribution of types among the 1,330 (63.2%) successfully typed specimens were as follows: 31.7% AdV-2, 28.9% AdV-1, 15.3% AdV-3, 7.9% AdV-5, 5.9% AdV-7, 1.4% AdV-4, 1.2% AdV-6, 0.5% AdV-14, 0.2% AdV-21, 0.1% AdV-11, and 7.0% >=1 AdV type. Most children with AdV-1 or AdV-2 detection were < 5 years of age (Figure 1a). Demographic and clinical characteristics varied by AdV types, including age, race/ethnicity, smoke exposure, daycare/school attendance, and hospitalization (Table 1). Co-detection with other viruses was common among all AdV types, with RV and RSV being the most frequently co-detected (Figure 1b). Fever and cough were the most common symptoms for all AdV types (Figure 2). Children with AdV-7 detected as single pathogen had higher odds of hospitalization (adjusted odds ratio 6.34 [95% CI: 3.10, 12.95], p= 0.027). Conclusion. AdV-2 and AdV-1 were the most frequently detected AdV types among children over the 3-year study period. Notable clinical heterogeneity of the AdV types warrants further surveillance studies to identify AdV types that could be targeted for pediatric vaccine development. (Figure Presented).

Safety and Immunogenicity of SARS-CoV-2 Vaccination in Children with a History of MIS-C

Background. Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare sequela that typically develops 2-6 weeks after SARS-CoV-2 infection. According to CDC recommendations, children who recover from MIS-C should be vaccinated 90 days after diagnosis, but safety and immunogenicity data are lacking. Our aim was to evaluate the safety and immunogenicity of one dose of the BNT162b2 vaccine in children with a history of MIS-C. Methods. We conducted a longitudinal study of children with MIS-C admitted to Monroe Carell Jr. Children's Hospital at Vanderbilt from 7/11/2020 to 3/23/2022. Children were eligible if they met CDC's MIS-C criteria and had blood collected before and after SARS-CoV-2 vaccination. Clinical data were obtained from medical records and injection site and systemic reactions were recorded for a week following SARS-CoV-2 vaccination via memory aids. IgG against SARS-CoV-2 nucleocapsid (N), spike receptor-binding domain (RBD), and spike extracellular domain (ECD)was detected using an enzyme-linked immunosorbent assay. The first anti-RBD and anti-ECD levels prevaccination and post vaccination were compared using the paired-samples t-test. Results. Seven children were included, of whom five were male and five were non-Hispanic White. The first blood sample was collected 3-44 days following admission. The median age at admission was 15.8 years (IQR, 10.5-14.7 years), and the median time from admission to vaccination was 7 months (IQR, 6-8 months). Five children each had injection site or systemic reactions (Figure 1);the majority were mild or moderate and occurred within 2 days of vaccination. Children were followed for a median of 5.6 months (4.3-6.2 months) postvaccination;none developed MIS-C recurrence. Following vaccination, mean anti-RBD and anti-ECD levels increased by 2.0 (1.2-2.9;p < 0.001) and 1.9 (1.2-2.6;p < 0.001) absorbance units, respectively (Figure 2). A sensitivity analysis excluding children with antibody evidence of reinfection (increase in anti-N level >= 0.5) showed similar results. Conclusion. SARS-CoV-2 vaccination is safe and immunogenic in children with a history of MIS-C, with no documented recurrence of MIS-C-like illness. Further studies are needed to determine the optimal timing, safety, and immunogenicity of vaccination following MIS-C.

Command and Control with Human-Machine Teams

The amount of information to analyze in the decision-making process for command and control is increasing past human cognitive limits. The effects of augmenting human information processing with machine-processing capability are not fully understood. This research examined the interdependence between machine and human teammates and its impact on the current command and control structure. The experiment (2X4 repeated measures analysis) was conducted online utilizing Qualtrics and Amazons Mechanical Turk. Each of the 119 participants was asked a set of questions about 34 faces. Participants were asked to identify the category of the face and what reaction they would have, friendly or defensive. This question order was reversed and each of the questions was asked individually. This process was repeated while adding the assistance of a machine teammate. The machine teammate displayed a suggested answer to the first question that the human had to acknowledge before continuing to answer. This research is preliminary. However, conceptually, the additional communication between a human and machine teammate adds time into the command and control process. This interaction may also affect the decision maker by priming the human to an action or through automation bias. Furthermore, reducing information to the human in a human-machine team has significant potential to reduce team situational awareness. Follow-on research is needed before any conclusions can be reached.

Circulation of Rhinovirus/Enterovirus Respiratory Infections in Children during 2020-21 in the United States

Background. Sharp declines in influenza and respiratory syncytial virus (RSV) circulation across the U.S. have been described during the pandemic in temporal association with community mitigation for control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to determine relative frequencies of rhinovirus/ enterovirus (RV/EV) and other respiratory viruses in children presenting to emergency departments or hospitalized with acute respiratory illness (ARI) prior to and during the COVID-19 pandemic. Methods. We conducted a multi-center active prospective ARI surveillance study in children as part of the New Vaccine Surveillance Network (NVSN) from December 2016 through January 2021. Molecular testing for RV/EV, RSV, influenza, and other respiratory viruses [i.e., human metapneumovirus, parainfluenza virus (Types 1-4), and adenovirus] were performed on specimens collected from children enrolled children. Cumulative percent positivity of each virus type during March 2020-January 2021 was compared from March-January in the prior seasons (2017-2018, 2018-2019, 2019-2020) using Pearson's chi-squared. Data are provisional. Results. Among 69,403 eligible children, 37,676 (54%) were enrolled and tested for respiratory viruses. The number of both eligible and enrolled children declined in early 2020 (Figure 1), but 4,691 children (52% of eligible) were enrolled and tested during March 2020-January 2021. From March 2020-January 2021, the overall percentage of enrolled children with respiratory testing who had detectable RV/EV was similar compared to the same time period in 2017-2018 and 2019-2020 (Figure 1, Table 1). In contrast, the percent positivity of RSV, influenza, and other respiratory viruses combined declined compared to prior years, (p< 0.001, Figure 1, Table 1). Figure 1. Percentage of Viral Detection Among Enrolled Children Who Received Respiratory Testing, New Vaccine Surveillance Network (NVSN), United States, December 2016 - January 2021 Table 1. Percent of Respiratory Viruses Circulating in March 2020- January 2021, compared to March-January in Prior Years, New Vaccine Surveillance Network (NVSN), United States, March 2017 - January 2021 Conclusion. During 2020, RV/EV continued to circulate among children receiving care for ARI despite abrupt declines in other respiratory viruses within this population. These findings warrant further studies to understand virologic, behavioral, biological, and/or environmental factors associated with this continued RV/EV circulation.

Persistence of Long COVID in SARS-CoV-2 Confirmed Cases One-Year Post Infection

Background. Regardless of severity of acute SARS-CoV-2 illness, adults infected with SARS-CoV-2 are at risk for post-acute sequelae of COVID-19. Long COVID is typically classified as symptoms lasting greater than four weeks post-infection. We aimed to evaluate the frequency of resolved and unresolved long COVID symptoms in adults residing in greater Nashville, TN. Methods. We conducted a longitudinal cohort study of SARS-CoV-2-positive and exposed individuals from March 20 to May 15, 2020. Participants for this analysis were included if: 1) ≥18 years;2) SARS-CoV-2 positive by molecular or antibody testing;and 3) completed a one-year visit. Demographic and illness information were collected at enrollment, and long COVID symptoms were systematically collected at the one-year survey. Long COVID symptoms are defined as an adult experiencing at least one of the following symptoms four weeks post-infection: fatigue, confusion, loss of smell or taste, shortness of breath, chest pain, cough, muscle aches, inability to exercise, or heart palpitations. Unresolved symptoms are defined as an individual with long COVID still experiencing symptoms at the one-year visit. Results. A total of 115 adults enrolled and completed the one-year survey, of which 63 (54.8%) were SARS-CoV-2-positive, with one asymptomatic individual. Of SARS-CoV-2-positive symptomatic adults, 32 (51%) were female, 5 (88%) were of Hispanic ethnicity, and 58 (92%) were white. At the one-year visit, 33 (52%) reported having long COVID, of which 17 (52%) reported having unresolved symptoms. Fatigue (89%), headache (89%), muscle aches (79%), and cough (77%) were the most common symptoms reported at illness onset (Figure 1). Among 33 adults with long COVID, fatigue (42%), loss of smell (39%), and loss of taste (33%) were most common (Figure 2A). In the 17 individuals with unresolved symptoms, loss of smell (29%) and loss of taste (24%) were commonly reported (Figure 2B). Figure 1. COVID-19 symptoms reported at enrollment (n=62) Figure 2. Long COVID (symptoms lasting ≥ 4 weeks) (n=33) (A) and unresolved long COVID symptoms one-year post-infection (n=17) (B) reported on the one-year survey Conclusion. Half of the adults in our cohort reported long COVID symptoms, with more than quarter of symptoms persisting one-year post-illness. Our findings support that prolonged symptoms up to year after SARS-CoV-2 exposure occur, and future studies should investigate the residual impacts of long COVID symptoms and conditions.

Comparison of Humoral Immune Response to the SARS-CoV-2 BNT162b2 Vaccine between Solid Organ Transplant Recipients and Healthy Controls

Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased morbidity and mortality in immunocompromised individuals, including solid organ transplant recipients (SOTR). Despite being excluded from phase 1-3 SARS-CoV-2 vaccine clinical trials, SOTR were identified as high-risk populations and prioritized for vaccination in public health guidelines. We aimed to evaluate the antibody response to two doses of the BNT162b2 (Pfizer-BioNTech) vaccine in SOTR as compared to healthy controls (HC). Methods. SOTR and HC scheduled to receive two doses of BNT162b2 vaccine and able to complete required follow-up visits were enrolled. Blood specimens were collected from participants before receiving the first and second doses and 21-42 days after the second dose. Enzyme-linked immunosorbent assay (ELISA) was used to detect immunoglobulin G (IgG) to the SARS-CoV-2 spike receptor-binding domain (RBD). Generalized estimating equations with a working independence correlation structure were used to compare anti-RBD IgG levels between SOTR and HC at each study visit and within each group over time. All models were adjusted for age, sex, and pre-vaccination seroreactivity in the ELISA. Results. A total of 54 SOTR and 26 HC were enrolled, with mean (SD) ages of 72 (3.6) and 62 (6.7) years, 61% and 35% were male, and 91% and 88% were white, respectively. The most common organ transplant types were kidney (41%) and liver (37%). All SOTR were receiving calcineurin inhibitors. The median time post-transplantation was 7 years. SOTR had markedly lower mean anti-RBD IgG levels when compared to HC with adjusted mean differences of -0.76 (95%CI: [-1.04, -0.47];p < 0.001) ELISA units (EU) and -1.35 (95%CI [-1.68, -1.01];p < 0.001) EU after the first and second doses, respectively (Figure 1). Both groups had a significant increase in anti-SARS-CoV-2 IgG levels after the second dose. However, the magnitude was lower in SOTR, 0.49 (95%CI [0.31, 0.69];p < 0.001) EU than in HCs, 1.08 (95% CI [0.91, 1.24];p < 0.001) EU. Figure 1. Anti-SARS-CoV-2 RBD IgG levels in solid organ transplant recipients and healthy controls before receiving the BNT162b2 vaccine (baseline), post-vaccine dose 1, and post-vaccine dose 2. Conclusion. Our study showed SOTR mounted weaker humoral immune responses than HC to SARS-CoV-2 vaccines. Given a lower response, SOTR should continue to practice social distancing and masking until data on vaccine efficacy are available in this vulnerable population.

COVID-19 Vaccine Perceptions in Adults from Greater Nashville Tennessee

Background. In December 2020, SARS-CoV-2 vaccines were made available to healthcare workers and soon thereafter offered to the general public according to age and risk of severe illness. Despite widespread access, vaccination rates vary by region, with Tennessee ranking lower than the national average. Therefore, we aimed to survey adults in greater Nashville, TN regarding SARS-CoV-2 vaccine perceptions. Methods. We conducted a cross-sectional study of an ongoing longitudinal cohort of individuals with confirmed and/or suspected SARS-CoV-2 infection and their household contacts with enrollment onset in March 2020. For this analysis, individuals were included if they were ≥ 18 years and available for a one-year follow-up visit. At the one-year visit individuals completed a survey about vaccine preferences, beliefs and risks. Demographic and social characteristics were collected at enrollment. Individuals were considered vaccinated if they had received at least one dose of a SARS-CoV-2 vaccine under FDA emergency use authorization. Vaccine perceptions were compared by SARS-CoV-2-infection and vaccination status using Pearson's chi-squared, alpha=5%. Results. Between April-May 2021, 115 individuals completed the one-year follow-up. Table 1 includes sociodemographic characteristics of adults, of which the majority were vaccinated and were unemployed or in non-essential occupations. Most individuals agreed the SARS-CoV-2 vaccine can prevent infection and hospitalization (Figure 1A & B). Unvaccinated participants more often agreed that those who contracted SARS-CoV-2 should not receive the vaccine (30%), whereas vaccinated persons less often agreed (11%, p< 0.001) (Figure 1A). Additionally, 44% of unvaccinated individuals were neutral or disagreed that benefits of SARS-CoV-2 vaccination outweighed the illness risk, compared to 10% in the vaccinated group, p=0.001 (Figure 1A). Minimal differences of vaccine perceptions were observed between SARS-CoV-2 positive and negative adults (Figure 1B). Conclusion. Although some unvaccinated individuals seemingly perceived the SARS-CoV-2 vaccine offered some protection, research should continue to evaluate the implications of vaccine hesitancy on the COVID-19 pandemic response as we prepare for the upcoming respiratory season.

Severity of seasonal coronavirus acute respiratory illness during infancy associated with respiratory viral co-infection

Background: There are limited data on the clinical characteristics of acute respiratory illness (ARI) in infants due to seasonal coronaviruses (CoV), long-term respiratory outcomes, and how CoV compare to other common viruses. Methods: Prospective cohort study of previously healthy term infants enrolled during hospitalization or acute care outpatient visits (emergency and clinic visits) for ARI from 2004-2008. ARI severity was determined using a 12-point respiratory severity score (RSS), and dichotomous LRTI or URI. ARI viral etiology was determined using real-time PCR for a panel of common respiratory viruses including seasonal CoV NL63, 229E, and OC43. In an exploratory analysis, proportions who subsequently developed childhood asthma were estimated by infection status in infancy. Clinical presentation of infant seasonal CoV infections was compared with published data on SARS-CoV-2 clinical characteristics in infants. Results: Among 665 infants, 28 (4%) had CoV detected. NL63, 229E, and OC43 comprised 25%, 25%, and 61% of detections, respectively, which included mixed-CoV infections. CoV exhibited winter seasonality. Among 28 CoV infections, 19 (68%) infants had co-infection with other viruses (RSV, HRV, influenza). Of 9 CoV-only detections, 2 (22%) were hospitalizations, 7 (78%) were outpatient, 8 (89%) were URI, 0 were bronchiolitis, and 1 (11%) was other diagnosis. Among CoV co-infections, 9 (47%) were hospitalizations, 10 (53%) were outpatient, 6 (32%) were URI, 11 (58%) were bronchiolitis, and 2 (11%) were other diagnoses. Average RSS was higher in infants with CoV co-infection than CoV-only infection (figure). Most common seasonal CoV symptoms were fever, cough, and rhinorrhea. Among those with long-term follow-up, childhood asthma (4-6 years) appeared more prevalent in RSV-only (62/152, 41%) and HRV-only infection groups (33/61, 54%) versus CoV-only (2/6, 33%);however, infants with CoV infection comprised a small proportion. Conclusions: Seasonal CoV represented the fourth most common viral etiology of ARI among infants seeking unscheduled medical care. CoV infection was less severe compared to RSV or HRV. This mild disease presentation is similar to current published reports of SARS-CoV-2 infection in infants. Greater illness severity was associated with CoV coinfection compared to CoV alone;however, CoV-only detection were few. Infants with seasonal CoV were less likely than infants with RSV or HRV to have later childhood long-term respiratory morbidity. These findings highlight the potential influence that respiratory co-pathogens may have in infant SARS-CoV-2 infection severity, and underscore the importance of identifying co-infecting pathogens.