Precision symptom phenotyping identifies early clinical and proteomic predictors of distinct COVID-19 sequelae.

BACKGROUND: Post-COVID conditions (PCC) are difficult to characterize, diagnose, predict, and treat due to overlapping symptoms and poorly understood pathology. Identifying inflammatory profiles may improve clinical prognostication and trial endpoints. METHODS: 1,988 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative post-COVID symptom scores were included in this analysis. Among participants who reported moderate-to-severe symptoms on surveys collected 6-months post-SARS-CoV-2 infection, principal component analysis (PCA) followed by K-means clustering identified distinct clusters of symptoms. RESULTS: Three symptom-based clusters were identified: a sensory cluster (loss of smell and/or taste), a fatigue/difficulty thinking cluster, and a difficulty breathing/exercise intolerance cluster. Individuals within the sensory cluster were all outpatients during their initial COVID-19 presentation. The difficulty breathing cluster had a higher likelihood of obesity and COVID-19 hospitalization compared to those with no/mild symptoms at 6-months post-infection. Multinomial regression linked early post-infection D-dimer and IL-1RA elevation to fatigue/difficulty thinking, and elevated ICAM-1 concentrations to sensory symptoms. CONCLUSIONS: We identified three distinct symptom-based PCC phenotypes with specific clinical risk factors and early post-infection inflammatory predictors. With further validation and characterization, this framework may allow more precise classification of PCC cases and potentially improve the diagnosis, prognostication, and treatment of PCC.

Surveillance outcomes of respiratory pathogen infections during the 2021-2022 season among U.S. Military Health System beneficiaries, October 3, 2021-October 1, 2022.

The Department of Defense Global Respiratory Pathogen Surveillance Program conducts continuous surveillance for influenza, severe acute respiratory syndrome 2 (SARS-CoV-2), and other respiratory pathogens at 104 sentinel sites across the globe. These sites submitted 65,475 respiratory specimens for clinical diagnostic testing during the 2021-2022 surveillance season. The predominant influenza strain was influenza A(H3N2) (n=777), of which 99.9% of strains were in clade 3C.2a1b.2a2. A total of 21,466 SARSCoV-2-positive specimens were identified, and 12,225 of the associated viruses were successfully sequenced. The Delta variant predominated at the start of the season, until December 2021, when Omicron became dominant. Most circulating SARS-CoV-2 viruses were subsequently held by Omicron sublineages BA.1, BA.2, and BA.5 during the season. Clinical manifestation, obtained through a self-reported questionnaire, found that cough, sinus congestion, and runny nose complaints were the most common symptoms presenting among all pathogens. Sentinel surveillance can provide useful epidemiological data to supplement other disease monitoring activities, and has become increasingly useful with increasing numbers of individuals utilizing COVID-19 rapid self-test kits and reductions in outpatient visits for routine respiratory testing.

Antigenic cartography using hamster sera identifies SARS-CoV-2 JN.1 evasion seen in human XBB.1.5 booster sera.

Antigenic assessments of SARS-CoV-2 variants inform decisions to update COVID-19 vaccines. Primary infection sera are often used for assessments, but such sera are rare due to population immunity from SARS-CoV-2 infections and COVID-19 vaccinations. Here, we show that neutralization titers and breadth of matched human and hamster pre-Omicron variant primary infection sera correlate well and generate similar antigenic maps. The hamster antigenic map shows modest antigenic drift among XBB sub-lineage variants, with JN.1 and BA.4/BA.5 variants within the XBB cluster, but with five to six-fold antigenic differences between these variants and XBB.1.5. Compared to sera following only ancestral or bivalent COVID-19 vaccinations, or with post-vaccination infections, XBB.1.5 booster sera had the broadest neutralization against XBB sub-lineage variants, although a five-fold titer difference was still observed between JN.1 and XBB.1.5 variants. These findings suggest that antibody coverage of antigenically divergent JN.1 could be improved with a matched vaccine antigen.

Decreased Self-reported Physical Fitness Following SARS-CoV-2 Infection and the Impact of Vaccine Boosters in a Cohort Study.

Background: The long-term effects of coronavirus disease 2019 (COVID-19) on physical fitness are unclear, and the impact of vaccination on that relationship is uncertain. Methods: We compared survey responses in a 1-year study of US military service members with (n = 1923) and without (n = 1591) a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We fit Poisson regression models to estimate the association between history of SARS-CoV-2 infection and fitness impairment, adjusting for time since infection, demographics, and baseline health. Results: The participants in this analysis were primarily young adults aged 18-39 years (75%), and 71.5% were male. Participants with a history of SARS-CoV-2 infection were more likely to report difficulty exercising (38.7% vs 18.4%; P < .01), difficulty performing daily activities (30.4% vs 12.7%; P < .01), and decreased fitness test (FT) scores (42.7% vs 26.2%; P < .01) than those without a history of infection. SARS-CoV-2-infected participants were at higher risk of these outcomes after adjusting for other factors (unvaccinated: exercising: adjusted risk ratio [aRR], 3.99; 95% CI, 3.36-4.73; activities: aRR, 5.02; 95% CI, 4.09-6.16; FT affected: aRR, 2.55; 95% CI, 2.19-2.98). Among SARS-CoV-2-positive participants, full vaccination before infection was associated with a lower risk of post-COVID-19 fitness impairment (fully vaccinated: exercise: aRR, 0.81; 95% CI, 0.70-0.95; activities: aRR, 0.76; 95% CI, 0.64-0.91; FT: aRR, 0.87; 95% CI, 0.76-1.00; boosted: exercise: aRR, 0.62; 95% CI, 0.51-0.74; activities: aRR, 0.52; 95% CI, 0.41-0.65; FT: aRR, 0.59; 95% CI, 0.49-0.70). Conclusions: In this study of generally young, healthy military service members, SARS-CoV-2 infection was associated with lower self-reported fitness and exercise capacity; vaccination and boosting were associated with lower risk of self-reported fitness loss.

Clustered cases of human adenovirus types 4, 7, and 14 infections in US Department of Defense Beneficiaries during the 2018-2019 season.

Human adenoviruses (HAdV) are genetically diverse and can infect a number of tissues with severities varied from mild to fatal. HAdV types 3, 4, 7, 11, 14, 21, and 55 were associated with acute respiratory illnesses outbreaks in the United States and in other countries. The risk of outbreaks can be effectively controlled by HAdV vaccination or mitigated by screening and preventive measures. During the influenza season 2018-2019, the DoD Global Respiratory Pathogen Surveillance Program (DoDGRS) received 24 300 respiratory specimens. HAdV samples that produced positive cytopathic effects in viral cultivation were subjected to next-generation sequencing for genome sequence assembly, genome typing, whole genome phylogeny, and sequence comparative analyses. A variety of HAdV types were identified in this study, including HAdV types 1-7, 14, 55, and 56. HAdV types 4, 7, and 14 were found in clustered cases in Colorado, Florida, New York, and South Carolina. Comparative sequence analyses of these isolates revealed the emergence of novel genetic mutations despite the stability of adenovirus genomes. Genomic surveillance of HAdV suggested possible undetected outbreaks and shed light on prevalence, genetic divergence, and viral evolution of HAdV. Continued surveillance will inform risk assessment and countermeasures.

Persistent COVID-19 Symptoms at 6 Months After Onset and the Role of Vaccination Before or After SARS-CoV-2 Infection.

Importance: Understanding the factors associated with post-COVID conditions is important for prevention. Objective: To identify characteristics associated with persistent post-COVID-19 symptoms and to describe post-COVID-19 medical encounters. Design, Setting, and Participants: This cohort study used data from the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases With Pandemic Potential (EPICC) study implemented in the US military health system (MHS); MHS beneficiaries aged 18 years or older who tested positive for SARS-CoV-2 from February 28, 2020, through December 31, 2021, were analyzed, with 1-year follow-up. Exposures: SARS-CoV-2 infection. Main Outcomes and Measures: The outcomes analyzed included survey-reported symptoms through 6 months after SARS-CoV-2 infection and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis categories reported in medical records 6 months following SARS-CoV-2 infection vs 3 months before infection. Results: More than half of the 1832 participants in these analyses were aged 18 to 44 years (1226 [66.9%]; mean [SD] age, 40.5 [13.7] years), were male (1118 [61.0%]), were unvaccinated at the time of their infection (1413 [77.1%]), and had no comorbidities (1290 [70.4%]). A total of 728 participants (39.7%) had illness that lasted 28 days or longer (28-89 days: 364 [19.9%]; ≥90 days: 364 [19.9%]). Participants who were unvaccinated prior to infection (risk ratio [RR], 1.39; 95% CI, 1.04-1.85), reported moderate (RR, 1.80; 95% CI, 1.47-2.22) or severe (RR, 2.25; 95% CI, 1.80-2.81) initial illnesses, had more hospitalized days (RR per each day of hospitalization, 1.02; 95% CI, 1.00-1.03), and had a Charlson Comorbidity Index score of 5 or greater (RR, 1.55; 95% CI, 1.01-2.37) were more likely to report 28 or more days of symptoms. Among unvaccinated participants, postinfection vaccination was associated with a 41% lower risk of reporting symptoms at 6 months (RR, 0.59; 95% CI, 0.40-0.89). Participants had higher risk of pulmonary (RR, 2.00; 95% CI, 1.40-2.84), diabetes (RR, 1.46; 95% CI, 1.00-2.13), neurological (RR, 1.29; 95% CI, 1.02-1.64), and mental health-related medical encounters (RR, 1.28; 95% CI, 1.01-1.62) at 6 months after symptom onset than at baseline (before SARS-CoV-2 infection). Conclusions and Relevance: In this cohort study, more severe acute illness, a higher Charlson Comorbidity Index score, and being unvaccinated were associated with a higher risk of reporting COVID-19 symptoms lasting 28 days or more. Participants with COVID-19 were more likely to seek medical care for diabetes, pulmonary, neurological, and mental health-related illness for at least 6 months after onset compared with their pre-COVID baseline health care use patterns. These findings may inform the risk-benefit ratio of COVID-19 vaccination policy.

Understanding "Hybrid Immunity": Comparison and Predictors of Humoral Immune Responses to Severe Acute Respiratory Syndrome Coronavirus 2 Infection (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19) Vaccines.

BACKGROUND: Comparison of humoral responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinees, those with SARS-CoV-2 infection, or combinations of vaccine/ infection ("hybrid immunity") may clarify predictors of vaccine immunogenicity. METHODS: We studied 2660 US Military Health System beneficiaries with a history of SARS-CoV-2 infection-alone (n = 705), vaccination-alone (n = 932), vaccine-after-infection (n = 869), and vaccine-breakthrough-infection (n = 154). Peak anti-spike-immunoglobulin G (IgG) responses through 183 days were compared, with adjustment for vaccine product, demography, and comorbidities. We excluded those with evidence of clinical or subclinical SARS-CoV-2 reinfection from all groups. RESULTS: Multivariable regression results indicated that vaccine-after-infection anti-spike-IgG responses were higher than infection-alone (P < .01), regardless of prior infection severity. An increased time between infection and vaccination was associated with greater post-vaccination IgG response (P < .01). Vaccination-alone elicited a greater IgG response but more rapid waning of IgG (P < .01) compared with infection-alone (P < .01). BNT162b2 and mRNA-1273 vaccine-receipt was associated with greater IgG responses compared with JNJ-78436735 vaccine-receipt (P < .01), regardless of infection history. Those with vaccine-after-infection or vaccine-breakthrough-infection had a more durable anti-spike-IgG response compared to infection-alone (P < .01). CONCLUSIONS: Vaccine-receipt elicited higher anti-spike-IgG responses than infection-alone, although IgG levels waned faster in those vaccinated (compared to infection-alone). Vaccine-after-infection elicits a greater humoral response compared with vaccine or infection alone; and the timing, but not disease severity, of prior infection predicted these post-vaccination IgG responses. While differences between groups were small in magnitude, these results offer insights into vaccine immunogenicity variations that may help inform vaccination timing strategies.

Antigenic cartography of well-characterized human sera shows SARS-CoV-2 neutralization differences based on infection and vaccination history.

The rapid emergence of SARS-CoV-2 variants challenges vaccination strategies. Here, we collected 201 serum samples from persons with a single infection or multiple vaccine exposures, or both. We measured their neutralization titers against 15 natural variants and 7 variants with engineered spike mutations and analyzed antigenic diversity. Antigenic maps of primary infection sera showed that Omicron sublineages BA.2, BA.4/BA.5, and BA.2.12.1 are distinct from BA.1 and more similar to Beta/Gamma/Mu variants. Three mRNA COVID-19 vaccinations increased neutralization of BA.1 more than BA.4/BA.5 or BA.2.12.1. BA.1 post-vaccination infection elicited higher neutralization titers to all variants than three vaccinations alone, although with less neutralization to BA.2.12.1 and BA.4/BA.5. Those with BA.1 infection after two or three vaccinations had similar neutralization titer magnitude and antigenic recognition. Accounting for antigenic differences among variants when interpreting neutralization titers can aid the understanding of complex patterns in humoral immunity that informs the selection of future COVID-19 vaccine strains.

Surveillance trends for SARS-CoV-2 and other respiratory pathogens among U.S. military health system beneficiaries, 27 September 2020­2 October 2021

Laboratory-based respiratory pathogen surveillance for SARS-CoV-2 and other respiratory pathogens was conducted in the 2020-2021 surveillance season among U.S. Military Health System (MHS) beneficiaries through the Department of Defense Global Respiratory Pathogen Surveillance Program (DoDGRPSP). Sentinel and participating sites submitted 96,660 specimens for clinical diagnostic testing. A total of 12,282 SARS-CoV-2 positive cases were identified, and 7,286 of the associated viruses were successfully sequenced. Two overlapping waves of SARS-CoV-2 activity were observed during the season. The B.1.1.7 (Alpha) lineage was dominant during February 2021 through May 2021. By July 2021, and continuing through the rest of the season, B.1.617.2/AY.x (Delta) lineage predominated and by September 2021 comprised 100% of identified SARS-CoV-2 lineages. The emergence of SARS-CoV-2 coincided with substantial reductions in the circulation of seasonal influenza viruses and most other non-SARS-CoV-2 respiratory pathogens. A total of 4,426 non-SARS-CoV-2 respiratory pathogens were identified, including 71 influenza. Of the 71 influenza positives, 64 were successfully sequenced. The majority of influenza strains sequenced belonged to influenza A(H3N2) clades 3C.2a1b.2a2. The most common non-SARSCoV-2 respiratory pathogen detected was rhinovirus/enterovirus (n=3,058).

Establishment of SARS-CoV-2 genomic surveillance within the Military Health System during 1 March-31 December 2020.

This report describes SARS-CoV-2 genomic surveillance conducted by the Department of Defense (DoD) Global Emerging Infections Surveillance Branch and the Next-Generation Sequencing and Bioinformatics Consortium (NGSBC) in response to the COVID-19 pandemic. Samples and sequence data were from SARS-CoV-2 infections occurring among Military Health System (MHS) beneficiaries from 1 March to 31 December 2020. There were 1,366 MHS samples sequenced from 10 countries, 36 U.S states or territories, and 5 Geographic Combatant Commands, representing approximately 2% of DoD cases in 2020. Genomes from these samples were compared with other public sequences; observed trends were similar to those of Centers for Disease Control and Prevention national surveillance in the U.S. with B.1, B.1.2, and other sub-lineages comprising the dominant variants of SARS-CoV-2. Sequence data were used to monitor transmission dynamics on U.S. Navy ships and at military training centers and installations. As new variants emerge, DoD medical and public health practitioners should maximize the use of genomic surveillance resources within DoD to inform force health protection measures.

COVID-19 Patient-Reported Symptoms Using FLU-PRO Plus in a Cohort Study: Associations With Infecting Genotype, Vaccine History, and Return to Health.

Background: Patient-reported outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are an important measure of the full burden of coronavirus disease (COVID). Here, we examine how (1) infecting genotype and COVID-19 vaccination correlate with inFLUenza Patient-Reported Outcome (FLU-PRO) Plus score, including by symptom domains, and (2) FLU-PRO Plus scores predict return to usual activities and health. Methods: The epidemiology, immunology, and clinical characteristics of pandemic infectious diseases (EPICC) study was implemented to describe the short- and long-term consequences of SARS-CoV-2 infection in a longitudinal, observational cohort. Multivariable linear regression models were run with FLU-PRO Plus scores as the outcome variable, and multivariable Cox proportional hazards models evaluated effects of FLU-PRO Plus scores on return to usual health or activities. Results: Among the 764 participants included in this analysis, 63% were 18-44 years old, 40% were female, and 51% were White. Being fully vaccinated was associated with lower total scores (ß = -0.39; 95% CI, -0.57 to -0.21). The Delta variant was associated with higher total scores (ß = 0.25; 95% CI, 0.05 to 0.45). Participants with higher FLU-PRO Plus scores were less likely to report returning to usual health and activities (health: hazard ratio [HR], 0.46; 95% CI, 0.37 to 0.57; activities: HR, 0.56; 95% CI, 0.47 to 0.67). Fully vaccinated participants were more likely to report returning to usual activities (HR, 1.24; 95% CI, 1.04 to 1.48). Conclusions: Full SARS-CoV-2 vaccination is associated with decreased severity of patient-reported symptoms across multiple domains, which in turn is likely to be associated with earlier return to usual activities. In addition, infection with the Delta variant was associated with higher FLU-PRO Plus scores than previous variants, even after controlling for vaccination status.

Waning Vaccine Protection against Influenza among Department of Defense Adult Beneficiaries in the United States, 2016-2017 through 2019-2020 Influenza Seasons.

The objective of this study was to assess inactivated influenza vaccine effectiveness (VE) by time since vaccination in adults aged ≥ 18 years using a test-negative design. All data were obtained from the US Department of Defense Global Respiratory Pathogen Surveillance Program over four influenza seasons, from 2016-2017 through 2019-2020. Analyses were performed to estimate VE using a generalized linear mixed model with logit link and binomial distribution. The adjusted overall VE against any medically attended, laboratory-confirmed influenza decreased from 50% (95% confidence interval (CI): 41-58%) in adults vaccinated 14 to 74 days prior to the onset of influenza-like illness (ILI), to 39% (95% CI: 31-47%) in adults vaccinated 75 to 134 days prior to the onset of ILI, then to 17% (95% CI: 0-32%) in adults vaccinated 135 to 194 days prior to the onset of ILI. The pattern and magnitude of VE change with increasing time since vaccination differed by influenza (sub)types. Compared to VE against influenza A(H1N1)pdm09 and influenza B, the decrease of VE against influenza A(H3N2) was more pronounced with increasing time since vaccination. In conclusion, based on the analysis of 2536 influenza-positive cases identified from 7058 adults over multiple influenza seasons, the effectiveness of inactivated influenza vaccine wanes within 180 days after 14 days of influenza vaccination.

SARS-CoV-2 Genome-Based Severity Predictions Correspond to Lower qPCR Values and Higher Viral Load.

The 2019 coronavirus disease (COVID-19) pandemic has demonstrated the importance of predicting, identifying, and tracking mutations throughout a pandemic event. As the COVID-19 global pandemic surpassed one year, several variants had emerged resulting in increased severity and transmissibility. Here, we used PCR as a surrogate for viral load and consequent severity to evaluate the real-world capabilities of a genome-based clinical severity predictive algorithm. Using a previously published algorithm, we compared the viral genome-based severity predictions to clinically derived PCR-based viral load of 716 viral genomes. For those samples predicted to be "severe" (probability of severe illness >0.5), we observed an average cycle threshold (Ct) of 18.3, whereas those in in the "mild" category (severity probability <0.5) had an average Ct of 20.4 (P=0.0017). We also found a nontrivial correlation between predicted severity probability and cycle threshold (r = -0.199). Finally, when divided into severity probability quartiles, the group most likely to experience severe illness (≥75% probability) had a Ct of 16.6 (n = 10), whereas the group least likely to experience severe illness (<25% probability) had a Ct of 21.4 (n = 350) (P=0.0045). Taken together, our results suggest that the severity predicted by a genome-based algorithm can be related to clinical diagnostic tests and that relative severity may be inferred from diagnostic values.

Circulating Trends of Influenza and Other Seasonal Respiratory Viruses among the US Department of Defense Personnel in the United States: Impact of the COVID-19 Pandemic.

The objective of this study was to evaluate the impact of the COVID-19 pandemic on the circulation of influenza and other seasonal respiratory viruses in the United States. All data were obtained from the US Department of Defense Global Respiratory Pathogen Surveillance Program over five consecutive respiratory seasons from 2016-2017 through to 2020-2021. A total of 62,476 specimens were tested for seasonal respiratory viruses. The circulating patterns of seasonal respiratory viruses have been greatly altered during the pandemic. The 2019-2020 influenza season terminated earlier compared to the pre-pandemic seasons, and the 2020-2021 influenza season did not occur. Moreover, weekly test positivity rates dramatically decreased for most of the seasonal respiratory viruses from the start of the pandemic through spring 2021. After the easing of non-pharmaceutical interventions (NPIs), circulations of seasonal coronavirus, parainfluenza, and respiratory syncytial virus have returned since spring 2021. High rhinovirus/enterovirus activity was evident throughout the 2020-2021 respiratory season. The findings suggest a strong association between the remarkably changed activity of seasonal respiratory viruses and the implementation of NPIs during the COVID-19 pandemic. The NPIs may serve as an effective public health tool to reduce transmissions of seasonal respiratory viruses.

SARS-CoV-2 BA.1 variant is neutralized by vaccine booster-elicited serum but evades most convalescent serum and therapeutic antibodies.

The rapid spread of the highly contagious Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) along with its high number of mutations in the spike gene has raised alarms about the effectiveness of current medical countermeasures. To address this concern, we measured the neutralization of the Omicron BA.1 variant pseudovirus by postvaccination serum samples after two and three immunizations with the Pfizer/BioNTech162b2 SARS-CoV-2 mRNA (Pfizer/BNT162b2) vaccine, convalescent serum samples from unvaccinated individuals infected by different variants, and clinical-stage therapeutic antibodies. We found that titers against the Omicron variant were low or undetectable after two immunizations and in many convalescent serum samples, regardless of the infecting variant. A booster vaccination increased titers more than 30-fold against Omicron to values comparable to those seen against the D614G variant after two immunizations. Neither age nor sex was associated with the differences in postvaccination antibody responses. We also evaluated 18 clinical-stage therapeutic antibody products and an antibody mimetic protein product obtained directly from the manufacturers. Five monoclonal antibodies, the antibody mimetic protein, three antibody cocktails, and two polyclonal antibody preparations retained measurable neutralization activity against Omicron with a varying degree of potency. Of these, only three retained potencies comparable to the D614G variant. Two therapeutic antibody cocktails in the tested panel that are authorized for emergency use in the United States did not neutralize Omicron. These findings underscore the potential benefit of mRNA vaccine boosters for protection against Omicron and the need for rapid development of antibody therapeutics that maintain potency against emerging variants.

Mass COVID-19 patient screening using UvsX and UvsY mediated DNA recombination and high throughput parallel sequencing.

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV), is a highly infectious RNA virus. A percentage of patients develop coronavirus disease 2019 (COVID-19) after infection, whose symptoms include fever, cough, shortness of breath and fatigue. Acute and life-threatening respiratory symptoms are experienced by 10-20% of symptomatic patients, particularly those with underlying medical conditions. One of the main challenges in the containment of COVID-19 is the identification and isolation of asymptomatic/pre-symptomatic individuals. A number of molecular assays are currently used to detect SARS-CoV-2. Many of them can accurately test hundreds or even thousands of patients every day. However, there are presently no testing platforms that enable more than 10,000 tests per day. Here, we describe the foundation for the REcombinase Mediated BaRcoding and AmplificatioN Diagnostic Tool (REMBRANDT), a high-throughput Next Generation Sequencing-based approach for the simultaneous screening of over 100,000 samples per day. The REMBRANDT protocol includes direct two-barcoded amplification of SARS-CoV-2 and control amplicons using an isothermal reaction, and the downstream library preparation for Illumina sequencing and bioinformatics analysis. This protocol represents a potentially powerful approach for community screening of COVID-19 that may be modified for application to any infectious or non-infectious genome.

Anatomical Site, Viral Ribonucleic Acid Abundance, and Time of Sampling Correlate With Molecular Detection of Severe Acute Respiratory Syndrome Coronavirus 2 During Infection.

BACKGROUND: Nasopharyngeal (NP) swabs are the standard for SARS-CoV-2 diagnosis. If less invasive alternatives to NP swabs (eg, oropharyngeal [OP] or nasal swabs [NS]) are comparably sensitive, the use of these techniques may be preferable in terms of comfort, convenience, and safety. METHODS: This study compared the detection of SARS-CoV-2 in swab samples collected on the same day among participants with at least one positive PCR test. RESULTS: Overall, 755 participants had at least one set of paired swabs. Concordance between NP and other swab types was 75% (NS), 72% (OP), 54% (rectal swabs [RS]), and 78% (NS/OP combined). Kappa values were moderate for the NS, OP, and NS/OP comparisons (0.50, 0.45, and 0.54, respectively). Highest sensitivity relative to NP (0.87) was observed with a combination of NS/OP tests (positive if either NS or OP was positive). Sensitivity of the non-NP swab types was highest in the first week postsymptom onset and decreased thereafter. Similarly, virus RNA quantity was highest in the NP swabs as compared with NS, OP, and RS within two weeks postsymptom onset. OP and NS performance decreased as virus RNA quantity decreased. No differences were noted between NS specimens collected at home or in clinic. CONCLUSIONS: NP swabs detected more SARS-CoV-2 cases than non-NP swabs, and the sensitivity of the non-NP swabs decreased with time postsymptom onset. While other swabs may be simpler to collect, NP swabs present the best chance of detecting SARS-CoV-2 RNA, which is essential for clinical care as well as genomic surveillance.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA Vaccine-Breakthrough Infection Phenotype Includes Significant Symptoms, Live Virus Shedding, and Viral Genetic Diversity.

Little is known about severe acute respiratory syndrome coronavirus 2 "vaccine-breakthrough" infections (VBIs). Here we characterize 24 VBIs in predominantly young healthy persons. While none required hospitalization, a proportion endorsed severe symptoms and shed live virus as high as 4.13 × 103 plaque-forming units/mL. Infecting genotypes included both variant-of-concern (VOC) and non-VOC strains.

COVID-19 Outcomes Among US Military Health System Beneficiaries Include Complications Across Multiple Organ Systems and Substantial Functional Impairment.

BACKGROUND: We evaluated clinical outcomes, functional burden, and complications 1 month after coronavirus disease 2019 (COVID-19) infection in a prospective US Military Health System (MHS) cohort of active duty, retiree, and dependent populations using serial patient-reported outcome surveys and electronic medical record (EMR) review. METHODS: MHS beneficiaries presenting at 9 sites across the United States with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test, a COVID-19-like illness, or a high-risk SARS-CoV-2 exposure were eligible for enrollment. Medical history and clinical outcomes were collected through structured interviews and International Classification of Diseases-based EMR review. Risk factors associated with hospitalization were determined by multivariate logistic regression. RESULTS: A total of 1202 participants were enrolled. There were 1070 laboratory-confirmed SARS-CoV-2 cases and 132 SARS-CoV-2-negative participants. In the first month post-symptom onset among the SARS-CoV-2-positive cases, there were 212 hospitalizations, 80% requiring oxygen, 20 ICU admissions, and 10 deaths. Risk factors for COVID-19-associated hospitalization included race (increased for Asian, Black, and Hispanic compared with non-Hispanic White), age (age 45-64 and 65+ compared with <45), and obesity (BMI≥30 compared with BMI<30). Over 2% of survey respondents reported the need for supplemental oxygen, and 31% had not returned to normal daily activities at 1 month post-symptom onset. CONCLUSIONS: Older age, reporting Asian, Black, or Hispanic race/ethnicity, and obesity are associated with SARS-CoV-2 hospitalization. A proportion of acute SARS-CoV-2 infections require long-term oxygen therapy; the impact of SARS-CoV-2 infection on short-term functional status was substantial. A significant number of MHS beneficiaries had not yet returned to normal activities by 1 month.

Variants in SARS-CoV-2 associated with mild or severe outcome.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic is a global public health emergency causing a disparate burden of death and disability around the world. The viral genetic variants associated with outcome severity are still being discovered. METHODS: We downloaded 155 958 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from GISAID. Of these genomes, 3637 samples included useable metadata on patient outcomes. Using this subset, we evaluated whether SARS-CoV-2 viral genomic variants improved prediction of reported severity beyond age and region. First, we established whether including genomic variants as model features meaningfully increased the predictive power of our model. Next, we evaluated specific variants in order to determine the magnitude of association with severity and the frequency of these variants among SARS-CoV-2 genomes. RESULTS: Logistic regression models that included viral genomic variants outperformed other models (area under the curve = 0.91 as compared with 0.68 for age and gender alone; P < 0.001). We found 84 variants with odds ratios greater than 2 for outcome severity (17 and 67 for higher and lower severity, respectively). The median frequency of associated variants was 0.15% (interquartile range 0.09-0.45%). Altogether 85% of genomes had at least one variant associated with patient outcome. CONCLUSION: Numerous SARS-CoV-2 variants have 2-fold or greater association with odds of mild or severe outcome and collectively, these variants are common. In addition to comprehensive mitigation efforts, public health measures should be prioritized to control the more severe manifestations of COVID-19 and the transmission chains linked to these severe cases.Lay summary: This study explores which, if any, SARS-CoV-2 viral genomic variants are associated with mild or severe COVID-19 patient outcomes. Our results suggest that there are common genomic variants in SARS-CoV-2 that are more often associated with negative patient outcomes, which may impact downstream public health measures.