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).

Seasonality of Microbiology of Combat-related Wound Infections in Afghanistan

Background: We examined the seasonality of wounds and wound infections, including occurrence of multidrug resistance, among combat casualties injured in Afghanistan. Methods: The Trauma Infectious Disease Outcomes Study is a retrospective observational study of infectious complications among military personnel wounded during deployment (06/09-12/14). Wound cultures obtained ≤7 days following injury in Afghanistan were assessed. Epidemiologic, clinical, and microbiologic data were analyzed by injury season [winter (1 Dec-28/29 Feb), spring (1 Mar-31 May), summer (1 Jun-31 Aug), and fall (1 Sep-30 Nov)]. Multidrug-resistant (MDR) determinations for Gram-negative and Gram-positive organisms were per standardized definitions. Results: The study population included 316 patients with a median of 3.5 (IQR 3-5) days from injury to initial culture. Gram-negatives (N=188, 59.5%) were more commonly isolated from wound cultures in summer (N=81, 43.1%) and fall (N=57, 30.3%) versus winter (N=18, 9.6%) and spring (N=32, 17%) (p< 0.001). The MDR Gram-negatives (N=69, 21.8%) were more common in summer (N=26, 37.7%), and fall (N=26, 37.7%) versus winter (N=3, 4.3%) and spring (N=14, 20.3%) (p=0.028). Wound infections were diagnosed in 198 (63%) patients. The pattern for infecting Gram-negative isolates (N=143, 72.2%, Table 1) was similar to that of overall Gram-negative isolates: summer (79.5%) and fall (83.6%;p< 0.001);MDR Gram-negatives (summer, 25.6%) and (fall, 41.8%;p=0.015). Escherichia coli and Enterobacter spp. were the most common infecting Gram-negative bacilli with no significant difference across the seasons. There was a higher proportion of infecting Acinetobacter baumannii isolates in the summer and fall compared to winter and spring. Infecting Gram-positive isolates (N=128, 65%) were not significantly different by season. Anaerobes associated with infections were also identified (N=30, 15%) with a higher proportion in the winter compared to summer, fall, and spring (p=0.036). Conclusion: Gram-negatives, including MDR Gram-negative infecting organisms, were more common in summer/fall months in service members injured in Afghanistan. This may have implications for empiric antibiotic coverage during these months. Disclosures: David R. Tribble, DrPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response.

Epidemiology and Timing of Infectious Complications from Battlefield-Related Burn Injuries

Background: Thermal injury alters the host response, making burn patients more susceptible to infections. In fact, infections represent the most frequent complication and cause of mortality in burn patients. We describe the epidemiology, clinical characteristics, timing, and outcomes of infections among wounded military personnel with burns. Methods: Data were collected through the Trauma Infectious Disease Outcomes Study, an observational study of US service members injured in Iraq and Afghanistan (6/09-12/14). Patients who sustained ≥1 burn injury and were admitted to the Burn Center at Brooke Army Medical Center were included in the analysis. Infections were defined using standardized criteria. For patients with multiple infections, only the initial infection was assessed. Results: Among 144 burn patients, 99% were males and 62% had combat-related burns with a median total body surface area (TBSA) of 6% (IQR 3-14%) thermally injured. Infections were diagnosed in 26 (18%) patients with pneumonia being the predominant initial syndrome (N=16, 62%), followed by skin and soft-tissue infections (N=6, 23%), bloodstream infections (N=3, 12%), and intra-abdominal infections (N=1, 4%). Median number of days to each of these initial infecting syndromes were 4 (IQR 3-5), 7 (IQR 4-12), 7 (IQR 6-7), and 17 (IQR 17-17) days, respectively. Patients with infections were more severely injured with greater TBSA (median 31 vs 5) and Baux scores (median 59 vs 29), and were more likely to have combat trauma, inhalation injury, require mechanical ventilation, and have longer time to definitive grafting (Table 1). Microbiology of initial infections varied with 35% of patients having polymicrobial infections (Table 2). Gram-negative organisms were recovered from 20 (77%) patients, of whom 20% had a multidrug-resistant Gram-negative. Gram-positive organisms and fungi were identified in 42% and 8% of patients, respectively. Conclusion: Improved understanding of risk factors and the timing of infections in this unique population is critical for effective management. Patients with infections were more severely injured, had higher rates of inhalational injury, and longer days to definitive grafting. Initial infections were more commonly pneumonia. Disclosures: David R. Tribble, DrPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response.

HBM4EU feasibility studies: Lessons learned in combining health and human biomonitoring studies : Hanna Tolonen

Background The European Human Biomonitoring Initiative (HBM4EU) is a program protecting humans from the health effects of chemicals. The goal of HBM4EU is to make use of human biomonitoring (HBM) to assess human exposure to chemicals in Europe to better understand the associated health effects for citizens and to improve chemical risk assessment. Harmonisation and sustainable implementation of the HBM programme across Europe are important aims. In parallel to HBM studies, health examination surveys (HESs), dietary surveys, and disease specific health surveys are conducted in many European countries. In HESs, information collected by questionnaire(s) is supplemented with physical examinations and analysis of biomarkers from biological samples. HBM and HES use similar sample and data collection methods and infrastructures hence combining the two is being explored. Methods Within HBM4EU, three feasibility studies (Finland, Germany, and UK/England) were conducted to evaluate opportunities and obstacles in combining HBM and health studies. We describe the contents and differences of these feasibility studies, and discuss the matters of shared benefits, obstacles, and lessons learned. Results Benefits of combining HBM and HESs include the use of shared infrastructures, participants receiving additional health information from HES, and higher participation rates. Obstacles can be encountered when obtaining ethical approval and during time-consuming and complicated preparatory phases. Recruitment of participants and low participation rates are common concerns and designing participant-friendly questionnaires is important. Unexpected events such as the COVID-19 pandemic can cause challenges to studies. Furthermore, experiences from several countries demonstrated that long-term funding for combined studies can be difficult to obtain. Conclusions In the future, incorporating HBM modules into HESs can provide a feasible and cost-effective method to conduct HBM studies. Key messages • The European Human Biomonitoring Initiative (HBM4EU) protects humans from the health effects of chemicals in Europe. HBM4EU uses human biomonitoring (HBM) to evaluate human exposure to chemicals. • In addition to HBM studies, health examination surveys (HESs) are conducted. In the future, incorporating HBM modules into HESs can provide a feasible and cost-effective method to conduct HBM studies.

Immunogenicity and Reactogenicity of COVID-19 mRNA Vaccines in Allogeneic Stem Cell Transplant Recipients

Background. Allogeneic stem cell transplant (SCT) recipients are at an increased risk of poor outcomes from COVID-19. While the mRNA-1273 (Moderna) and BNT162b2 (Pfizer) COVID-19 mRNA vaccines are highly immunogenic in the general population, the immune response in SCT recipients is poorly understood. We characterized the immunogenicity and reactogenicity of COVID-19 mRNA vaccines in a cohort of SCT patients. Methods. We performed a prospective cohort study of 16 allogeneic SCT patients and 23 healthy controls. Blood samples for both cohorts were collected prior to first vaccination (baseline), at the time of second vaccination, and approximately 28 days post-second vaccination. Anti-Spike (S), anti-S1, anti-receptor binding domain (RBD), and anti-Nucleocapsid (N) IgG levels were measured quantitatively from plasma using a multiplexed single molecule array (Simoa) immunoassay. Reactogenicity was captured for the SCT cohort via a self-reported post-vaccination diary for 7 days after each dose. Results. Demographics and SCT recipients' characteristics are shown in Table 1. In the SCT cohort, we observed a significantly lower anti-S (p< 0.0001), S1 (p< 0.0001), and RBD (p< 0.0001) IgG responses as compared to healthy controls, both at the time of dose 2 and 28 days post-vaccine series (Fig 1). Overall, 62.5% of SCT recipients were responders after vaccine series completion, as compared to 100% of healthy controls (Fig 2). While no patients had a reported history of COVID-19 diagnosis, 2 patients in the SCT cohort had elevated anti-S IgG levels and 1 showed elevated anti-N at baseline. 10/16 participants in the SCT cohort completed at least one post-vaccination diary. Local and systemic reactions were reported by 67% and 22% of participants, respectively, after dose 1, and 63% and 50% after dose 2 (Figure 3). All reported events were mild. Anti-Spike (A), anti-S1 (B), anti-RBD (C), and anti-nucleocapsid (D) IgG titers were measured at baseline, time of second dose, and approximately 28 days after second vaccination. IgG levels were measured quantitatively using multiplexed single molecule array (Simoa) immunoassays, and are reported as Normalized Average Enzymes per Bead (AEB). Allogeneic stem cell transplant recipients (mauve) showed significantly lower anti-S, S1, and RBD IgG responses as compared to healthy controls (mint). Low titers of anti-N IgG demonstrates no history of COVID-19 natural infection during the course of the study. 10 allogeneic stem cell transplant recipients completed at least one diary for 7 days after vaccination. Reactions after dose 1 are shown in light blue, and reactions after dose 2 are shown in dark blue. Local reactions (A) were reported by 67% (6/9) of participants after dose 1, and 63% (5/8) after dose 2. Systemic reactions (B) were reported by 22% (2/9) of participants after dose 1, and 50% (4/8) after dose 2. All reported events were mild (Grade 1). Conclusion. Among SCT recipients, mRNA COVID-19 vaccines were well-tolerated but less immunogenic than in healthy controls. Further study is warranted to better understand heterogeneous characteristics that may affect the immune response in order to optimize COVID-19 vaccination strategies for SCT recipients. Figure 2: Response Rate to COVID-19 Vaccination An internally validated threshold for responders was established using pre-pandemic sera from healthy adults. A positive antibody response was was defined as individuals with anti-Spike IgG levels above the 1.07 Normalized AEB threshold.

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.

Metabolic Syndrome Is Associated With Worse Outcomes in SARS-CoV-2 Positive Emergency Department Patients

Study Objective: Increased body mass index (BMI) and metabolic syndrome (MetS) have been associated with adverse outcomes in numerous diseases. However, the role of BMI and MetS in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection remains unclear. We sought to examine the associations of increased BMI and MetS on several clinical outcomes in all ED patients tested for SARS-CoV-2 and then in the subset of COVID positive patients only. Methods: The REgistry of potential COVID-19 in emERgency care (RECOVER) is an observational study of SARS-CoV-2 tested patients from 155 US EDs. Inclusion criteria were a nucleic acid test at index visit. Body mass was categorized per CDC designations ie, BMI 18.5 to <25 kg/m2, 25 to <30 kg/m2, 30 to <35 kg/m2, 35 to <40 kg/m2 and ≥40 kg/m2. The presence of metabolic syndrome was defined as having 3 or more defining characteristics per the electronic medical record at the time of index visit;these included an elevated BMI (≥30 kg/m2), hyperlipidemia, hypertension, and diabetes. We used multivariable logistic regression to test for associations of several variables (including BMI, MetS, age, sex, race, ethnicity, and smoking) on the following clinical outcomes, first comparing SARS-CoV-2 positive and SARS-CoV-2 negative patients (N=27, 051) and then in the COVID+ subset (N=14, 056): hospital admission, intensive care unit (ICU) care, intubation, 30-day mortality and 30-day new or recurrent venous thromboembolism (VTE). Results: We report that BMI ≥ 30 kg/m2 was associated with SARS-CoV-2 test positivity (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.08-1.20). Analysis of BMI ≥ 40 kg/m2 revealed a stronger association with test positivity (OR 1.24, 95% CI 1.14-1.35). By contrast, MetS was not associated with testing positive (OR 0.95, 95% CI 0.89-1.01) in the overall cohort. In COVID+ patients, BMI ≥ 40 kg/m2 was associated with ICU care (adjusted odds ratio [aOR] 1.97;95% CI 1.65-2.35), intubation (aOR 2.69;95% CI 2.22-3.26) and mortality (aOR 1.50;95% CI 1.22-1.84). MetS was associated with worsened clinical outcomes: hospital admission (aOR 2.11;95% CI 1.89-2.37), ICU care (aOR 1.58;95% CI 1.40-1.78), intubation (aOR 1.46;95% CI 1.28-1.66), mortality (aOR 1.29;95% CI 1.13-1.48) and VTE (aOR 1.51;95% CI 1.07-2.13). Conclusions: In this large nationwide sample of ED patients undergoing SARS-CoV-2 testing, we report that BMI ≥ 30 kg/m2, BMI ≥ 40 kg/m2 and not MetS was associated with SARS-CoV-2 test positivity. Multivariable analysis in COVID positive patients only revealed significant associations of BMI ≥ 40 kg/m2 with three outcomes (ICU care, intubation and mortality) and of MetS with five outcomes (hospital admission, ICU care, intubation, mortality and VTE).

Comparison of Singleplex qPCR and the Luminex MAGPIX Platform for the Detection of Viral Pathogens

Background: Various respiratory molecular assays are available, each with different characteristics and advantages that make them uniquely valuable. The objective of this study was to compare rates of viral detection using singleplex and multiplex platforms in a research setting. Methods: A prospective viral surveillance study was conducted in Davidson County, TN. Infants under one year who presented with fever and/or respiratory symptoms were enrolled from the outpatient, emergency department and inpatient settings. Nasal swabs were collected and tested for influenza A (FluA), influenza B (FluB), human metapneumovirus (MPV), respiratory syncytial virus A and B (RSVA and RSVB), human adenovirus (AdV), parainfluenza 1, 2, 3, and 4 (PIV1-4) and SARS-2-CoV by both singleplex qPCR and the Luminex NxTAG Respiratory Pathogen and NxTAG CoV Extended panels. The rhinovirus/enterovirus, human bocavirus, Chlamydophila pneumoniae, Mycoplasma pneumoniae and coronavirus HKU1, NL63, 229E and OC43 results from the Luminex panel were excluded because singleplex qPCR was not performed on those targets. For singleplex qPCR results, cycle threshold (Ct) values were used as a surrogate for viral load, with a higher Ct value indicating a lower viral load. Results: A total of 112 nasal specimens were tested by both singleplex qPCR and Luminex, of which 65 were positive for at least one virus by either platform and 56 had a virus detected on both platforms (Figure 1). Seven specimens were positive by singleplex qPCR only and two were positive by Luminex only (Figure 1). The targets positive by singleplex qPCR only included FluB, RSVA, AdV and PIV2 and those positive by Luminex only included FluA H1N1 and RSVB (Figure 2). Specimens that were positive only on the singleplex assay had a higher average Ct value than those that were positive on both assays, indicating a lower viral load (Figure 3). Figure 1 Figure 2 Figure 3 Conclusion: The multiplex assay identified 89% of the total viruses detected while singleplex qPCR identified 97% of the total viruses detected. Lower viral loads may contribute to false negative results on the multiplex platforms. Future studies with larger sample sizes are needed in order validate our findings.

18FDG-PET/CT findings in COVID-19: a single centre retrospective radiological review.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the infectious disease COVID-19, was declared a global pandemic in March 2020. As radiology departments recommence 18FDG-PET/CT imaging, it is likely that both asymptomatic and specific symptomatic patients with COVID-19 infection will be imaged, particularly if the disease becomes endemic in the UK. We review the clinical scenarios where 18FDG-PET/CT could be performed in COVID-19 positive patients. Our local protocol for safely scanning known COVID-19 positive patients is described, highlighting considerations for other departments. We present the findings from a series of known COVID-19 positive patients and two further asymptomatic cases evaluated with18FDG-PET/CT. Classic, indeterminate, normal and non-COVID-19 manifestations on both the 18FDG-PETand low dose CT component are described as an aid for radiologists and nuclear medicine physicians when reporting 18FDG PET/CT.