Anti-nucleocapsid (N) IgG antibody responses were lower in plasma and oral fluid after SARS-CoV-2 infection in vaccinated patients compared to patients infected prior to vaccination or infected without vaccination. This raises questions about the long-term use of anti-N antibodies as a marker for natural infection for surveillance.

In an outpatient cohort in Maryland, clustering of SARS-CoV-2 positivity within households was high, with 76% of 74 households reporting at least one other symptomatic person and 66% reporting another person who tested SARS-CoV-2 positive. SARS-CoV-2 positivity among household members was associated with larger household size and bedroom sharing.

IntroductionThe incidence of long COVID is substantial, even in people with mild to moderate acute COVID-19. The role of early viral kinetics in the subsequent development of long COVID is largely unknown, especially in individuals who were not hospitalized for acute COVID-19.MethodsSeventy-three non-hospitalized adult participants were enrolled within approximately 48 hours of their first positive SARS-CoV-2 RT-PCR test, and mid-turbinate nasal and saliva samples were collected up to 9 times within the first 45 days after enrollment. Samples were assayed for SARS-CoV-2 using RT-PCR and additional SARS-CoV-2 test results were abstracted from the clinical record. Each participant indicated the presence and severity of 49 long COVID symptoms at 1-, 3-, 6-, 12-, and 18-months post-COVID-19 diagnosis. Time from acute COVID-19 illness onset to SARS-CoV-2 RNA clearance greater or less than 28 days was tested for association with the presence or absence of each of 49 long COVID symptoms at 90+ days from acute COVID-19 symptom onset.ResultsSelf-reported brain fog and muscle pain at 90+ days after acute COVID-19 onset were negatively associated with viral RNA clearance within 28 days of acute COVID-19 onset with adjustment for age, sex, BMI ≥ 25, and COVID vaccination status prior to COVID-19 (brain fog: aRR 0.46, 95% CI 0.22-0.95; muscle pain: aRR 0.28, 95% CI 0.08-0.94). Participants reporting higher severity brain fog or muscle pain at 90+ days after acute COVID-19 onset were less likely to have cleared SARS-CoV-2 RNA within 28 days. The acute viral RNA decay trajectories of participants who did and did not later go on to experience brain fog 90+ days after acute COVID-19 onset were distinct.DiscussionThis work indicates that at least two long COVID symptoms - brain fog and muscle pain – at 90+ days from acute COVID-19 onset are specifically associated with prolonged time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute COVID-19. This finding provides evidence that delayed immune clearance of SARS-CoV-2 antigen or greater amount or duration of viral antigen burden in the upper respiratory tract during acute COVID-19 are directly linked to long COVID. This work suggests that host-pathogen interactions during the first few weeks after acute COVID-19 onset have an impact on long COVID risk months later.

The incidence of long COVID is substantial, even in people who did not require hospitalization for acute COVID–19. The pathobiological mechanisms of long COVID and the role of early viral kinetics in its development are largely unknown. Seventy–three non-hospitalized adult participants were enrolled within approximately 48 hours of their first positive SARS–CoV–2 RT–PCR test, and mid–turbinate nasal and saliva samples were collected up to 9 times within the first 45 days after enrollment. Samples were assayed for SARS–CoV–2 using RT–PCR and additional test results were abstracted from the clinical record. Each participant indicated the presence and severity of 49 long COVID symptoms at 1, 3, 6, 12, and 18 months post–COVID–19 diagnosis. Time from acute COVID–19 illness onset to SARS-CoV-2 RNA clearance greater or less than 28 days was tested for association with the presence or absence of each of 49 long COVID symptoms at 90 or more days from acute COVID–19 symptom onset. Brain fog and muscle pain at 90 or more days after acute COVID–19 onset were negatively associated with viral RNA clearance within 28 days of acute COVID–19 onset with adjustment for age, sex, BMI over 25, and COVID vaccination status prior to COVID–19 (brain fog: aRR 0.46, 95% CI 0.22 – 0.95; muscle pain: aRR 0.28, 95% CI 0.08 – 0.94). This work indicates that at least two long COVID symptoms, brain fog and muscle pain, at 90 or more days from acute COVID–19 onset are specifically associated with longer time to clearance of SARS–CoV–2 RNA from the upper respiratory tract.

Little data exist on long COVID outcomes beyond one year. In a cohort enrolled with mild-moderate acute COVID-19, a wide range of symptoms manifest at 6, 12, and 18 months. Endorsing over 3 symptoms associates with poorer quality of life in 5 domains: physical, social, fatigue, pain, and general health.

Background Sustained molecular detection of SARS-CoV-2 RNA in the upper respiratory tract (URT) in mild to moderate COVID-19 is common. We sought to identify host and immune determinants of prolonged SARS-CoV-2 RNA detection. Methods Ninety-five symptomatic outpatients self-collected mid-turbinate nasal, oropharyngeal (OP), and gingival crevicular fluid (oral fluid) samples at home and in a research clinic a median of 6 times over 1-3 months. Samples were tested for viral RNA, virus culture, and SARS-CoV-2 and other human coronavirus antibodies, and associations were estimated using Cox proportional hazards models. Results Viral RNA clearance, as measured by SARS-CoV-2 RT-PCR, in 507 URT samples occurred a median (IQR) 33.5 (17-63.5) days post-symptom onset. Sixteen nasal-OP samples collected 2-11 days post-symptom onset were virus culture positive out of 183 RT-PCR positive samples tested. All participants but one with positive virus culture were negative for concomitant oral fluid anti-SARS-CoV-2 antibodies. The mean time to first antibody detection in oral fluid was 8-13 days post-symptom onset. A longer time to first detection of oral fluid anti-SARS-CoV-2 S antibodies (aHR 0.96, 95% CI 0.92-0.99, p=0.020) and BMI ≥ 25kg/m2 (aHR 0.37, 95% CI 0.18-0.78, p=0.009) were independently associated with a longer time to SARS-CoV-2 viral RNA clearance. Fever as one of first three COVID-19 symptoms correlated with shorter time to viral RNA clearance (aHR 2.06, 95% CI 1.02-4.18, p=0.044). Conclusions We demonstrate that delayed rise of oral fluid SARS-CoV-2-specific antibodies, elevated BMI, and absence of early fever are independently associated with delayed URT viral RNA clearance.

Background Viral and immune kinetics in mild to moderate COVID-19 are understudied because of challenges inherent in longitudinal sampling of people who are infectious to others, feeling ill, yet are not hospitalized. In particular, sustained molecular detection of SARS-CoV-2 RNA in the upper respiratory tract (URT) in mild to moderate COVID-19 is common and confounds surveillance efforts in the community. We sought to identify host and immune determinants of prolonged SARS-CoV-2 RNA detection via longitudinal viral RNA, virus culture, and plasma and oral fluid antibody sampling in a prospective observational cohort study of adult outpatients with COVID-19. Methods and Findings Samples from 95 non-hospitalized participants ≥ 30 years old with recent COVID-19 diagnosis and known symptom onset date were analyzed. Participants self-collected mid-turbinate nasal, oropharyngeal (OP), and gingival crevicular fluid (oral fluid) samples at home and in a research clinic a median of 6 times over 1-3 months. SARS-CoV-2 RT-PCR performed on 507 URT samples revealed a median time to viral RNA clearance of the URT of 33.5 days. Sixteen nasal-OP samples collected 2-11 days post-symptom onset were virus culture positive out of 183 RT-PCR positive samples tested. All participants but one with positive virus culture were negative for concomitant oral fluid anti-SARS-CoV-2 spike-receptor binding domain (S-RBD) antibodies. The kinetics of oral fluid anti-SARS-Cov-2 antibodies were measured using a multiplex immunoassay. The mean time to first detection of oral fluid anti-SARS-CoV-2 antibodies was 8-13 days post-symptom onset. Associations of symptoms, host demographics, comorbidities, and immune kinetics with time to SARS-CoV-2 RNA clearance were estimated using Cox proportional hazards models. A longer time to first detection of oral fluid anti-SARS-CoV-2 S antibodies was independently associated with a longer time to SARS-CoV-2 viral RNA clearance (aHR 0.96, 95% CI 0.92-0.99, p=0.020). BMI ≥ 25kg/m2 was also independently associated with a longer time to viral RNA clearance (aHR 0.37, 95% CI 0.18-0.78, p=0.009). Fever reported as one of first three COVID-19 symptoms was associated with shorter time to viral RNA clearance (aHR 2.06, 95% CI 1.02-4.18, p=0.044). Plasma titers of neutralizing antibodies, SARS-CoV-2 spike (S) antibodies, and S-receptor binding domain (S-RBD) antibodies were obtained at 1-4 months post-symptom onset. BMI was positively correlated with post-acute plasma SARS-CoV-2-specific neutralizing antibody titer and anti-S-RBD antibody titer. Conclusions In an intensively sampled cohort of 95 adult outpatients with COVID-19, we demonstrate that longer time to first detection of oral fluid SARS-CoV-2-specific antibodies, elevated BMI, and absence of early fever are independently associated with longer time to viral RNA clearance. This work provides insights into the host and immune factors most important for viral clearance in mild to moderate COVID-19.

The administration of high-alert medications requires the use of enhanced systems to prevent errors. One commonly used system relies on independent verification of dose changes by a second clinician, a human double check. This system is inefficient, and while it may reduce, it does not eliminate error. We postulate that the ability to integrate interoperable medication infusion pumps and electronic medical records systems with existing dose adjustment algorithms can improve the safety and efficiency in the delivery of high-alert and other medications. We followed step-wise systems engineering practices to develop and build a novel system, the Smart Agent, to semi-autonomously administer intravenous insulin according to our hospital’s protocol for nurse-managed insulin infusion in the intensive care units. The prototype system used a commercial medication infusion pump and our existing electronic health record. We believe that this model of interoperable systems integration can be incrementally and broadly developed in the future to improve the safety and workflow of medication infusions.