Performance of Existing and Novel Symptom- and Antigen Testing-Based COVID-19 Case Definitions in a Community Setting

Point-of-care antigen tests are an important tool for SARS-CoV-2 detection, but they are less clinically sensitive than real-time reverse-transcription PCR (RT-PCR), impacting their efficacy as screening procedures. Our goal in this study was to see whether we could improve this sensitivity by considering antigen test results in combination with other relevant information, namely exposure status and reported symptoms. In November of 2020, we collected 3,419 paired upper respiratory specimens tested by RT-PCR and the Abbott BinaxNOW antigen test at two community testing sites in Pima County, Arizona. We used symptom, exposure, and antigen testing data to evaluate the sensitivity and specificity of various symptom definitions in predicting RT-PCR positivity. Our analysis yielded 6 novel multi-symptom case definitions with and without antigen test results, the best of which overall achieved a Youdens J index of 0.66, as compared with 0.52 for antigen testing alone. Using a random forest as a guide, we show that this definition, along with our others, does not lose the ability to generalize well to new data despite achieving optimal performance in our sample. Our methodology is broadly applicable, and we have made our code publicly available to aid public health practitioners in developing or fine- tuning their own screening rules.

Transmission potential of vaccinated and unvaccinated persons infected with the SARS-CoV-2 Delta variant in a federal prison, July-August 2021

BackgroundThe extent to which vaccinated persons who become infected with SARS-CoV-2 contribute to transmission is unclear. During a SARS-CoV-2 Delta variant outbreak among incarcerated persons with high vaccination rates in a federal prison, we assessed markers of viral shedding in vaccinated and unvaccinated persons. MethodsConsenting incarcerated persons with confirmed SARS-CoV-2 infection provided mid-turbinate nasal specimens daily for 10 consecutive days and reported symptom data via questionnaire. Real-time reverse transcription-polymerase chain reaction (RT-PCR), viral whole genome sequencing, and viral culture was performed on these nasal specimens. Duration of RT-PCR positivity and viral culture positivity was assessed using survival analysis. ResultsA total of 978 specimens were provided by 95 participants, of whom 78 (82%) were fully vaccinated and 17 (18%) were not fully vaccinated. No significant differences were detected in duration of RT-PCR positivity among fully vaccinated participants (median: 13 days) versus those not fully vaccinated (median: 13 days; p=0.50), or in duration of culture positivity (medians: 5 days and 5 days; p=0.29). Among fully vaccinated participants, overall duration of culture positivity was shorter among Moderna vaccine recipients versus Pfizer (p=0.048) or Janssen (p=0.003) vaccine recipients. ConclusionsAs this field continues to develop, clinicians and public health practitioners should consider vaccinated persons who become infected with SARS-CoV-2 to be no less infectious than unvaccinated persons. These findings are critically important, especially in congregate settings where viral transmission can lead to large outbreaks.

Characteristics of children and antigen test performance at a SARS-CoV-2 community testing site

BackgroundPerformance characteristics of SARS-CoV-2 antigen tests among children are limited despite the need for point-of-care testing in school and childcare settings. We describe children seeking SARS-CoV-2 testing at a community site and compare antigen test performance to real-time reverse transcription-polymerase chain reaction (RT-PCR) and viral culture. MethodsTwo anterior nasal specimens were self-collected for BinaxNOW antigen and RT-PCR testing, along with demographics, symptoms, and exposure information from individuals [≥]5 years at a community testing site. Viral culture was attempted on residual antigen or RT-PCR positive specimens. Demographic and clinical characteristics, and the performance of SARS-CoV-2 antigen tests, were compared among children (<18 years) and adults. ResultsAbout one in ten included specimens were from children (225/2110); 16.4% (37/225) were RT-PCR positive. Cycle threshold values were similar among RT-PCR positive specimens from children and adults (22.5 vs 21.3, p=0.46) and among specimens from symptomatic and asymptomatic children (22.5 vs 23.2, p=0.39). Sensitivity of antigen test compared to RT-PCR was 73.0% (27/37) among specimens from children and 80.8% (240/297) among specimens from adults; among specimens from children, specificity was 100% (188/188), positive and negative predictive value were 100% (27/27) and 94.9% (188/198) respectively. Virus was isolated from 51.4% (19/37) of RT-PCR positive pediatric specimens; all 19 had positive antigen test results. ConclusionsWith lower sensitivity relative to RT-PCR, antigen tests may not diagnose all positive COVID-19 cases; however, antigen testing identified children with live SARS-CoV-2 virus.

Description of a University COVID-19 Outbreak and Interventions to Disrupt Transmission, Wisconsin, August - October 2020.

University settings have demonstrated potential for COVID-19 outbreaks, as they can combine congregate living, substantial social activity, and a young population predisposed to mild illness. Using genomic and epidemiologic data, we describe a COVID-19 outbreak at the University of Wisconsin (UW)-Madison. During August - October 2020, 3,485 students tested positive, including 856/6,162 students living in residence halls. Case counts began rising during move-in week for on-campus students (August 25-31, 2020), then rose rapidly during September 1-11, 2020. UW-Madison initiated multiple prevention efforts, including quarantining two residence halls; a subsequent decline in cases was observed. Genomic surveillance of cases from Dane County, where UW-Madison is located, did not find evidence of transmission from a large cluster of cases in the two residence halls quarantined during the outbreak. Coordinated implementation of prevention measures can effectively reduce SARS-CoV-2 spread in university settings and may limit spillover to the community surrounding the university.

Performance of Repeat BinaxNOW SARS-CoV-2 Antigen Testing in a Community Setting, Wisconsin, November-December 2020

Repeating the BinaxNOW antigen test for SARS-CoV-2 by two groups of readers within 30 minutes resulted in high concordance (98.9%) in 2,110 encounters. BinaxNOW test sensitivity was 77.2% (258/334) compared to real-time reverse transcription-polymerase chain reaction. Repeating antigen testing on the same day did not significantly improve test sensitivity while specificity remained high.

Quantitative Comparison of SARS-CoV-2 Nucleic Acid Amplification Test and Antigen Testing Algorithms: A Decision Analysis Simulation Model

BackgroundAntigen tests for SARS-CoV-2 offer advantages over nucleic acid amplification tests (NAATs, such as RT-PCR), including lower cost and rapid return of results, but show reduced sensitivity. Public health organizations continue to recommend different strategies for utilizing NAATs and antigen tests in various settings. There has not yet been a quantitative comparison of the expected performance of these strategies. MethodsWe utilized a decision analysis approach to simulate the expected outcomes of six algorithms for implementing NAAT and antigen testing, analogous to testing strategies recommended by public health organizations. Each algorithm was simulated 50,000 times for four SARS-CoV-2 infection prevalence levels ranging from 5% to 20% in a population of 100000 persons seeking testing. Primary outcomes were number of missed cases, number of false-positive diagnoses, and total test volumes. Outcome medians and 95% uncertainty ranges (URs) were reported. ResultsAlgorithms that use NAATs to confirm all negative antigen results minimized missed cases but required high NAAT capacity: 92,200 (95% UR: 91,200-93,200) tests (in addition to 100,000 antigen tests) at 10% prevalence. Substituting repeat antigen testing in lieu of NAAT confirmation of all initial negative antigen tests resulted in 2,280 missed cases (95% UR: 1,507-3,067) at 10% prevalence. Selective use of NAATs to confirm antigen results when discordant with symptom status (e.g., symptomatic persons with negative antigen results) resulted in the most efficient use of NAATs, with 25 NAATs (95% UR: 13-57) needed to detect one additional case at 10% prevalence compared to exclusive use of antigen tests. ConclusionsNo single SARS-CoV-2 testing algorithm is likely to be optimal across settings with different levels of prevalence and for all programmatic priorities; each presents a trade-off between prioritized outcomes and resource constraints. This analysis provides a framework for selecting setting-specific strategies to achieve acceptable balances and trade-offs between programmatic priorities and constraints. DisclaimerThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention.

SARS-CoV-2 detection by rRT-PCR on self-collected anterior nares swabs or saliva compared with clinician-collected nasopharyngeal swabs--Denver and Atlanta, August--November, 2020

Nasopharyngeal swabs (NPS) collected by trained healthcare professionals are the preferred specimen for SARS-CoV-2 testing. Self-collected specimens might decrease patient discomfort, conserve healthcare resources, and be preferred by patients. During August - November 2020, 1,806 adults undergoing SARS-CoV-2 testing in Denver, Colorado and Atlanta, Georgia, provided self-collected anterior nares swabs (ANS) and saliva specimens before NPS collection. Compared to NPS, sensitivity for SARS-CoV-2 detection by rRT-PCR appeared higher for saliva than for ANS (85% versus 80% in Denver; 67% versus 58% in Atlanta) and higher among participants reporting current symptoms (94% and 87% in Denver; 72% and 62% in Atlanta, for saliva and ANS, respectively) than among those reporting no symptoms (29% and 50% in Denver; 50% and 44% in Atlanta, for saliva and ANS, respectively). Compared to ANS, saliva was more challenging to collect and process. Self-collected saliva and ANS are less sensitive than NPS for SARS-CoV-2 detection; however, they offer practical advantages and might be most useful for currently symptomatic patients.

Performance of Existing and Novel Surveillance Case Definitions for COVID-19 in the Community

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), presents with a broad range of symptoms. Existing COVID-19 case definitions were developed from early reports of severely ill, primarily hospitalized, patients. Symptom-based case definitions that guide public health surveillance and individual patient management in the community must be optimized for COVID-19 pandemic control. MethodsWe collected daily symptom diaries and performed RT-PCR on respiratory specimens over a 14-day period in 185 community members exposed to a household contact with COVID-19 in the Milwaukee, Wisconsin and Salt Lake City, Utah metropolitan areas. We interpreted the discriminatory performance (sensitivity, specificity, predictive values, F1 score, Youdens index, and prevalence estimation) of individual symptoms and common case definitions according to two principal surveillance applications (i.e., individual screening and case counting). We also constructed novel case definitions using an exhaustive search with over 73 million symptom combinations and calculated bias-corrected and accelerated bootstrap confidence intervals stratified by children versus adults. FindingsCommon COVID-19 case definitions generally showed high sensitivity (8696%) but low positive predictive value (PPV) (3649%; F1 score 5263) in this community cohort. The top performing novel symptom combinations included taste or smell dysfunction. They also improved the balance of sensitivity and PPV (F1 score 7880) and reduced the number of false positive symptom screens. Performance indicators were generally lower for children (<18 years of age). InterpretationExisting COVID-19 case definitions appropriately screened in community members with COVID-19. However, they led to many false positive symptom screens and poorly estimated community prevalence. Absent unlimited, timely testing capacity, more accurate case definitions may help focus public health resources. Novel symptom combinations incorporating taste or smell dysfunction as a primary component better balanced sensitivity and specificity. Case definitions tailored specifically for children versus adults should be further explored. FundingThis research was wholly supported by the U.S. Centers for Disease Control and Prevention. DisclaimerThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSCoronavirus disease 2019 (COVID-19) incidence has accelerated globally over the last several months. As the full spectrum of clinical presentations has come into clearer focus, symptom-based clinical screening and case surveillance has also evolved. Preliminary understanding of the clinical manifestation of COVID-19 was driven primarily by descriptions of hospitalized patients, as early testing algorithms prioritized more severely ill persons with classic lower respiratory symptoms and fever. Since then, more data from ambulatory settings have emerged. We searched PubMed from 1 December 2019 to 21 August 2020 for studies that assessed the diagnostic performance of case surveillance definitions for COVID-19. We found no studies examining the discriminatory performance of case surveillance definitions among contacts with mild to moderate symptoms with documented exposure to persons with COVID-19. Nonetheless, we found nine highly relevant studies: seven original reports and two review articles. Five original studies evaluated individual, self-reported symptoms (two among healthcare workers in the United States, one among healthcare workers in the Netherlands, and one online survey for the general public in Somalia) and concluded that using dysfunction of taste or smell for routine COVID-19 screening likely had utility. The fifth study had a similar conclusion based on self-reported symptoms and laboratory results collected via smartphone from the general public in the United States and the United Kingdom. Another original study modeled the substantial effect that multiple revisions to the COVID-19 case definition had on the reported disease burden in the Chinese population. Lastly, an original study illustrated the shift in discriminatory performance of established influenza surveillance case definitions for influenza between adults and children. Age-specific differences in case definition performance may also apply to COVID-19. Two articles reviewed predictive algorithms to define outpatient COVID-19 illness and risk of hospitalization. The reviewed studies were limited in that they were either restricted to individual signs or symptoms, or they incorporated blood tests or imaging that required in-person access to medical care. Added value of this studyThe discriminatory performance of case surveillance definitions for COVID-19 is important for implementing effective epidemic mitigation strategies. Our study illustrates the performance of case definitions in community members with household exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based solely on symptom profiles. Prior work overrepresented healthcare workers or otherwise studied non-representative populations, and they did not examine across the age spectrum. Our study also provides a novel framework for refining definitions. Using 15 symptoms associated with COVID-19 for all contacts regardless of disease status, we systematically evaluated the discriminatory performance of individual symptoms and previously defined case surveillance definitions across ages and according to two core surveillance applications: 1) screening non-hospitalized individuals to prioritize public health interventions, and 2) estimating the number of non-hospitalized persons with COVID-19 (i.e., community-based syndromic surveillance). We also constructed novel symptom combinations that effectively performed both functions and improved upon widely used case surveillance definitions that may help to target interventions in the absence of unlimited laboratory diagnostic capacity. Our analyses highlight the importance of ongoing re-evaluation of symptom-based surveillance definitions to suit the intended purpose and population under surveillance. Based on our results, which were derived from household members of all ages, case surveillance definition performance may improve if developed separately for adults and children. Implications of all the available evidenceCase definitions for COVID-19 should be tailored to maximize the discriminatory performance dependent upon its intended use. Existing COVID-19 case definitions screened in most community members with COVID-19, but also yielded a high number of false positive results. When unlimited, timely diagnostic testing is not available symptom combinations with improved accuracy (i.e., more balanced sensitivity and specificity) may help focus resources, such as recommending self-isolation among community contacts.

Loss of Taste and Smell as Distinguishing Symptoms of COVID-19

Olfactory and taste dysfunctions have emerged as symptoms of COVID-19. Among individuals with COVID-19 enrolled in a household study, loss of taste and/or smell was the fourth most commonly reported symptom (26/42; 62%), and among household contacts, it had the highest positive predictive value (83%; 95% CI: 55-95%) for COVID-19. These findings support consideration of loss of taste and/or smell in possible case identification and testing prioritization for COVID-19.