Open Forum Infectious Diseases

BackgroundIncreasing evidence on long-term health outcomes following SARS CoV-2 infection shows post-viral symptoms can persist for months. The aim of the present study was to examine the prevalence and outcome predictors of post-viral fatigue and related symptoms 3 and 6 months following infection. MethodsA prospective cohort of patients hospitalized with COVID-19 (n=88) were recruited from a Post-COVID-19 Respiratory Clinic (PCRC) in Vancouver, Canada to examine predictors of long-term fatigue and substantial fatigue. Multivariable logistic and linear regression analysis were used to examine the relationship between patient predictors (medical history at the time of hospitalization and follow-up patient-reported outcome measures) and the presentation of fatigue and substantial fatigue at 3 and 6 months follow-up. ResultsThe number of patients exhibiting fatigue and substantial fatigue was 58 (67%) and 14 (16%) at 3 months and 47 (60%) and 6 (7%) at 6 months post-infection, respectively. Adjusted analysis revealed the number of pre-existing comorbidities to be associated with fatigue (OR 2.21; 95% CI 1.09-4.49; 0.028) and substantial fatigue (OR 1.73; 95% CI 1.06-2.95; 0.033) at 3 months follow-up. Except for shortness of breath, self-care, and time, all follow-up variables were found to be associated with fatigue and substantial fatigue at 3 months follow-up. ConclusionFatigue and substantial fatigue are common, and decrease from 3 to 6 months; however, a significant number of patients continue to exhibit long-term fatigue at 6 months follow-up. Further research is needed to clarify the causality of viral infections and co-factors in the development and severity of fatigue as a symptom and in meeting post-viral fatigue syndrome or ME/CFS diagnostic criteria.

SARS-CoV-2 transmission was investigated between university students and the surrounding community using whole genome sequencing. Fourteen putative transmission clusters were identified. Proximity assessed using ZIP codes showed that clustered cases were more widely dispersed than non-clustered cases, highlighting the need for integrated surveillance, coordinated interventions, and data-driven public health policies.

BackgroundSymptoms of COVID-19 including fatigue and dyspnea, may persist for weeks to months after SARS-CoV-2 infection. This study compared self-reported disability among SARS-CoV-2-positive and negative persons with mild to moderate COVID-19-like illness who presented for outpatient care before widespread COVID-19 vaccination. MethodsUnvaccinated adults with COVID-19-like illness enrolled within 10 days of illness onset at three US Flu Vaccine Effectiveness Network sites were tested for SARS-CoV-2 by molecular assay. Enrollees completed an enrollment questionnaire and two follow-up surveys (7-24 days and 2-7 months after illness onset) online or by phone to assess illness characteristics and health status. The second follow-up survey included questions measuring global health, physical function, fatigue, and dyspnea. Scores in the four domains were compared by participants SARS-CoV-2 test results in univariate analysis and multivariable Gamma regression. ResultsDuring September 22, 2020 - February 13, 2021, 2,712 eligible adults were enrolled, 1,541 completed the first follow-up survey, and 650 completed the second follow-up survey. SARS-CoV-2-positive participants were more likely to report fever at acute illness but were otherwise comparable to SARS-CoV-2-negative participants. At first follow-up, SARS-CoV-2-positive participants were less likely to have reported fully or mostly recovered from their illness compared to SARS-CoV-2-negative participants. At second follow-up, no differences by SARS-CoV-2 test results were detected in the four domains in the multivariable model. ConclusionSelf-reported disability was similar among outpatient SARS-CoV-2-positive and -negative adults 2-7 months after illness onset.

BackgroundUsing a large dataset, we evaluated prevalence and severity of alterations in liver enzymes in COVID-19 and association with patient-centred outcomes. MethodsWe included hospitalized patients with confirmed or suspected SARS-CoV-2 infection from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) database. Key exposure was baseline liver enzymes (AST, ALT, bilirubin). Patients were assigned Liver Injury Classification score based on 3 components of enzymes at admission: Normal; Stage I) Liver injury: any component between 1-3x upper limit of normal (ULN); Stage II) Severe liver injury: any component >= 3x ULN. Outcomes were hospital mortality, utilization of selected resources, complications, and durations of hospital and ICU stay. Analyses used logistic regression with associations expressed as adjusted odds ratios (OR) with 95% confidence intervals (CI). ResultsOf 17,531 included patients, 46.2% (8099) and 8.2% (1430) of patients had stage 1 and 2 liver injury respectively. Compared to normal, stages 1 and 2 were associated with higher odds of mortality (OR 1.53 [1.37-1.71]; OR 2.50 [2.10-2.96]), ICU admission (OR 1.63 [1.48-1.79]; OR 1.90 [1.62-2.23]) and invasive mechanical ventilation (OR 1.43 [1.27-1.70]; OR 1.95 (1.55-2.45).Stages 1 and 2 were also associated with higher odds of developing sepsis (OR 1.38 [1.27-1.50]; OR 1.46 [1.25-1.70]), acute kidney injury (OR 1.13 [1.00-1.27]; OR 1.59 [1.32-1.91]), and acute respiratory distress syndrome (OR 1.38 [1.22-1.55]; OR 1.80 [1.49-2.17]). ConclusionsLiver enzyme abnormalities are common among COVID-19 patients and associated with worse outcomes. Study HighlightsO_ST_ABSWhat is known?C_ST_ABSO_LIAbnormalities in liver enzymes in hospitalized patients with COVID-19 have been described in small, predominantly single-centre studies. C_LIO_LIImpact of such derangements on clinical outcomes are unclear. C_LI What is new here?O_LIIn this large international study, we found that close to 50% of hospitalized patients with COVID-19 have abnormal liver enzymes at admission. C_LIO_LISuch derangements in liver enzymes are associated with worse clinical outcomes (survival, Intensive Care Unit admission and need for invasive mechanical ventilation). C_LIO_LIThey are also associated with the development of complications such as Acute Kidney Injury, Sepsis and Acute Respiratory Distress Syndrome. C_LI

Background: Oseltamivir is an antiviral medication for influenza that can reduce the duration of symptoms and may lower the risk of some complications. Recommendations for use of oseltamivir include in the outpatient setting for individuals at higher risk of developing influenza complications. Objectives: To describe oseltamivir initiation and treatment completion among influenza-positive outpatients and identify factors associated with each. Methods: In a U.S. outpatient household transmission study, index participants with laboratory-confirmed influenza provided up to 12 days of detailed information on medication use. We described oseltamivir initiation among index cases and treatment course completion of [&ge;] 10 doses among cases who initiated oseltamivir. We used unadjusted and adjusted logistic regression to identify factors associated with initiation and course completion. Results: Among 823 enrolled index cases, 324 (39%) initiated oseltamivir treatment. Of 406 persons at higher risk for influenza complications, 172 (42%) initiated treatment. Oseltamivir initiation was lowest among children aged 2 to < 5 years (19%) compared to all other age groups. Among 313 cases who initiated oseltamivir, 42% completed the recommended treatment course of [&ge;] 10 doses. Among 163 individuals at higher risk of influenza complications, 69 (42%) completed the recommended treatment course of [&ge;] 10 doses. Children < 2 years were significantly less likely to complete treatment compared to adults aged 18-50 years (aOR: 0.21, 95% CI: 0.04, 0.78, p= 0.030); reasons for discontinuation could not be determined. Conclusions: These findings reveal differences in oseltamivir treatment in an outpatient setting among groups at higher risk for influenza complications.

Background Although the hemagglutination inhibition (HAI) titer remains the gold standard correlate of protection against influenza, it does not fully capture the broader antibody responses that contribute to immunity. MethodsWe analyzed immune responses in paired pre-infection and convalescent sera from 306 RT-PCR-confirmed A/H3N2 infections from two household studies (2014-18) in Managua, Nicaragua. Antibody responses were measured by HAI and enzyme-linked immunosorbent assays (ELISAs) against full-length hemagglutinin (HA), the HA stalk, and neuraminidase (NA). Participants were classified as HAI responders ([&ge;]4-fold HAI rise), alternate responders (no HAI rise but [&ge;]4-fold boost in [&ge;]1 ELISA), or no-response individuals (no [&ge;]4-fold rise in any assay). We compared demographic, clinical, and pre-infection antibody characteristics across these groups. We also analyzed predictors of an NA response. ResultsOverall, 77% of participants had HAI seroconversion or a 4-fold rise. Among the 23% HAI non-responders, 62% had alternate antibody responses. No-response individuals had the highest pre-infection HAI and full-length HA titers (p < 0.0001), the lowest viral loads, and the fewest fever or influenza like illness (ILI) symptoms (p < 0.01). An NA response was more common among symptomatic individuals (p = 0.0483) and those with low or high baseline NA titers. ConclusionsHigh baseline HAI titers can limit detectable 4-fold rises and are associated with milder illness. Evaluating additional immune responses may capture a more complete picture of the host response to infection, thereby improving surveillance and informing vaccine development.

Infectious gastroenteritis (IGE) is a major cause of pediatric morbidity globally, with viral pathogens accounting for a substantial proportion of cases. While seasonal patterns of viral IGE are well recognized, the association between specific environmental exposures, such as ambient temperature, and viral IGE has not been fully quantified. First, we performed a secondary analysis of data from a prospective, multisite study of children presenting to emergency departments at five medical centers across the continental United States, linking individual level laboratory data to environmental exposures, including temperature, humidity, and air pollutants, measured during the 14 days preceding symptom onset. Mixed-effects logistic regression was applied to evaluate the association between viral IGE and environmental exposures, adjusting for site-level clustering and patient age. Among 868 children with IGE, higher ambient temperature was inversely associated with viral etiology (OR 0.50, 95% CI 0.36-0.68, p < 0.001). We did not find statistically significant associations between other environmental variables and viral IGE. Then, to contextualize these individual-level findings in children, we examined all-ages population-level surveillance data from GermWatch, a regional laboratory testing-based infectious disease surveillance system, which demonstrated concordant declines in viral pathogen detection with increasing temperature. These findings support the association of weather with viral transmission patterns. Incorporating environmental context into clinical decision-making may improve diagnostic stewardship and support more effective resource allocation during periods of increased viral IGE prevalence.

BackgroundLong COVID (LC), also referred to as post-COVID condition, refers to new or worsening symptoms lasting more than three months after SARS-CoV-2 infection. The prevalence of LC, and the impact of co-infection with prevalent pathogens such as Mycobacterium tuberculosis (Mtb), in low- and middle-income countries remain unclear. We aimed to address these gaps in two Mtb-exposed populations. MethodsWe recruited HIV-uninfected pulmonary tuberculosis (TB) patients (n=36) and their household contacts (n=63) in Peru, and healthcare workers (n=202) in Kenya. We collected clinical data using study instruments adapted from a United States based study of LC. Participants were sampled within 2 years of SARS-CoV-2 diagnosis. ResultsIn Peru, 41.4% participants reported LC symptoms, with no TB-associated significant differences in the prevalence or clinical phenotypes of LC. The most common LC symptoms were neurological (e.g., headache and trouble sleeping) and musculoskeletal (e.g., back pain). Kenyan participants reported acute, but no LC symptoms, and reported a decline in the quality of life during acute infection. In Peru, the post-COVID-19 period was associated with a significant decline in all quality-of-life dimensions (p<0.01), except depression and anxiety (p=0.289). ConclusionThis study shows that LC prevalence was high in Peru, where TB status was not linked to LC symptoms. Those with LC reported high levels of musculoskeletal and neurological symptoms. Unexpectedly, healthcare workers in Kenya denied the presence of LC symptoms. These findings highlight the need for long-term follow-up and larger studies in different geographic settings to dissect the impact of TB comorbidity on LC.

ObjectiveTo determine how many people with long COVID also meet diagnostic criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). MethodsWe identified which participants with long COVID also met the Institute of Medicine (IOM) or the 2003 Canadian Consensus Criteria (CCC) for ME/CFS at approximately 6-8 months post-SARS-CoV-2 infection in two cohorts: (1) the JHU COVID Recovery cohort, which enrolled participants within 4 weeks of infection and (2) the Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort, which enriched for participants with long COVID. Neither study administered ME/CFS-specific surveys, so available data elements were mapped onto each ME/CFS diagnostic criteria. ResultsOf 97 JHU participants with long COVID, 5 met IOM criteria and 2 met CCC criteria. Of 281 LIINC participants with long COVID, 51 met the IOM criteria and 29 met the CCC criteria. In LIINC, participants with long COVID meeting ME/CFS criteria were more likely to be female and report a greater number of post-COVID symptoms (p<0.001). ConclusionsThe co-occurrence of ME/CFS symptoms and long COVID suggests that SARS-CoV-2 is a cause of ME/CFS. ME/CFS-specific measures should be incorporated into studies of post-acute COVID-19 to advance studies of post-SARS-CoV-2 onset ME/CFS.

BackgroundRSV is a frequent cause of respiratory illness less often diagnosed outside hospital settings; thus, overall prevalence of RSV-associated illness is under-recognized. Information about presence of RSV among those with chronic conditions is especially needed with recent advances in vaccine development. MethodsParticipants prospectively enrolled in an ambulatory surveillance study of respiratory illness (MFIVE) were tested by RT-PCR for RSV and influenza. Participant and illness characteristics were collected by in-person survey and EMR review. Chronic conditions were characterized by the Multimorbidity-weighted index (MWI). Viral factors, including subtype and viral load, were compared between RSV-A and RSV-B. Multivariate logistic regression models were used to compare participant and illness characteristics between those with RSV and those with influenza. Comparisons were also made across RSV subtypes. ResultsAmong 4,442 individuals enrolled in MFIVE from fall 2017 to spring 2020, 9.9% (n=441) had RSV detected. RSV+ participants with increased viral load had increased odds of illness lasting [&ge;] 7 days [ORadj=2.39 (95% CI: 1.03-5.51) p-value=0.04]. Adults with RSV had higher median MWI scores compared to influenza and RSV/influenza-negative (1.62, 0.40, 0.64, respectively). ConclusionsOur findings support the need for ongoing RSV surveillance, particularly in older adults and those with multimorbidity. Our findings support a recognition of multimorbidity as a significant contributor to RSV-associated MAARI among outpatient adults, with particularly notable impacts among adults under 65.

BackgroundChildren with autoimmune liver disease (AILD) face unique challenges that may impair their health-related quality of life (HRQoL). This multicenter, prospective, longitudinal study evaluated HRQoL over time and identified associated clinical factors. MethodsA total of 162 participants from five centers completed at least one HRQoL assessment. Medical and laboratory data were abstracted within three months of each assessment. Fatigue and pruritus were reported at one center. Generalized linear mixed-effects modeling was used to examine longitudinal associations between HRQoL and clinical variables. ResultsParticipants reported the lowest HRQoL scores in school and emotional domains, while the physical and social domains were less affected. Compared to healthy children, participants with AILD reported lower overall HRQoL. Longitudinal analysis revealed that caregivers of participants with overlap syndrome reported higher emotional, social, psychosocial, and total scores. Paradoxically, children with disease complications had better school scores, possibly due to increased support services. Prednisone use was associated with improved emotional scores, while azathioprine use was associated with lower social scores. Elevated ALT levels were associated with lower HRQoL scores, particularly when reported by caregivers. Disease duration and presence of inflammatory bowel disease were not significantly associated with HRQoL. From one center, fatigue and pruritus were significantly associated with lower HRQoL, especially in the physical, psychosocial, and total domains. Fatigue was also associated with elevated liver enzymes and reduced rates of biochemical remission, suggesting that inflammation may contribute to a disrupted liver-brain axis. ConclusionThese findings underscore the multidimensional impact of AILD on pediatric patients and highlight the need for further research into the pathophysiology of fatigue and potential therapeutic interventions.

BackgroundSurveillance of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a chronic, debilitating multisystem illness, is challenging because ME/CFS can be under-recognized in healthcare settings. MethodsUsing a population-based panel study of 9,820 adult members of Kaiser Permanente Northern California (KPNC), a large, integrated healthcare system, we compared survey-defined ME/CFS-like illness with presence of an ME/CFS diagnosis in the electronic health record (EHR) to evaluate ME/CFS underdiagnosis. ResultsOf those with survey-defined ME/CFS-like illness, an estimated 97.8% (95% confidence interval [CI] 97.1%-98.4%) did not have an ME/CFS diagnosis in the EHR. The group without EHR diagnosis was younger, less likely to identify as white non-Hispanic, and more likely to have developed fatigue in the past three years than the EHR diagnosed group. Both diagnosed and undiagnosed ME/CFS-like illness groups had significantly impaired physical, cognitive, and social functioning, and significantly worse mental health and anxiety than those without ME/CFS-like illness. ConclusionME/CFS is underdiagnosed in the Kaiser Permanente Northern California healthcare system. Enhanced syndromic surveillance that characterizes patients with ME/CFS who have not been diagnosed has the potential to increase timely recognition of ME/CFS.

We evaluated the clinical and socioeconomic burdens of respiratory disease in a cohort of Guatemalan banana plantation workers. All eligible workers were offered enrollment from June 15-December 30, 2020, and annually, then followed for influenza-like illnesses (ILI) through: 1) self-reporting to study nurses, 2) sentinel surveillance at health posts, and 3) absenteeism. Workers with ILI submitted nasopharyngeal swabs for influenza, RSV, and SARS-CoV-2 testing, then completed surveys at days 0, 7, and 28. Through October 10, 2021, 1,833 workers developed 169 ILIs (12.0/100 person-years) and 43 (25.4%) of these ILIs were laboratory-confirmed SARS-CoV-2 (3.1/100 person-years). Workers with SARS-CoV-2-positive ILI reported more anosmia (p<0.01), dysgeusia (p<0.01), difficulty concentrating (p=0.01), and irritability (p=0.01), and greater clinical and well-being severity scores (Flu-iiQ) than test-negative ILIs; they also had greater absenteeism (p<0.01) and lost income (median US$127.1, p<0.01). These results support the prioritization of Guatemalan farm workers for COVID-19 vaccination.

BackgroundEarly in the SARS-CoV-2 pandemic, description of COVID-19 illness among non-hospitalized patients was limited. Data from household cohorts can help reveal the full spectrum of disease and the potential for long-term sequelae, even in non-severe disease. MethodsDaily symptom diaries were collected in a US household cohort of SARS-CoV-2 infection from April to November 2020, during the pre-COVID vaccine period. SARS-CoV-2 nasal viral loads were measured at study entry and weekly until day 21; serologic testing was performed at study entry and day 28. A subset of volunteers underwent an additional assessment 8-10 months later. Participants who met the criteria for early infection--testing antibody-negative at study entry but PCR-positive either at baseline or during follow-up--were included in this analysis (n=143). ResultsDaily symptoms were ascertained in 143 outpatients with acute COVID-19, including 60 index cases who sought testing and 83 of their household contacts. Asymptomatic cases comprised 16% (13/83) of SARS-CoV-2 infections detected among household contacts. Among 119 persons with mild or moderate illness, the number of symptoms peaked 3 or 4 days after symptom onset. Fever and anosmia occurred in nearly half of participants. Symptom severity was associated with increased age, viral load, and cardiovascular disease. Increased BMI was associated with a higher antibody level at day 28, independent of symptom severity. Those with a higher day 28 antibody level were more likely to develop symptoms consistent with post-acute sequelae of SARS-CoV-2 (PASC), also known as long COVID-19, 8-10 months later. ConclusionsFever, anosmia, as well as asymptomatic infection were common features of COVID-19 non-severe illness when the D614G variant circulated in the US, before the availability of vaccines or outpatient therapies. Antibody levels following acute infection were linked to the development of symptoms of PASC 8-10 months later.

BackgroundThere is a need to understand the duration of infectivity of primary and recurrent COVID-19 and identify predictors of loss of infectivity. MethodsProspective observational cohort study with serial viral culture, rapid antigen detection test (RADT) and RT-PCR on nasopharyngeal specimens of healthcare workers with COVID-19. The primary outcome was viral culture positivity as indicative of infectivity. Predictors of loss of infectivity were determined using multivariate regression model. The performance of the US CDC criteria (fever resolution, symptom improvement and negative RADT) to predict loss of infectivity was also investigated. Results121 participants (91 female [79.3%]; average age, 40 years) were enrolled. Most (n=107, 88.4%) had received [&ge;]3 SARS-CoV-2 vaccine doses, and 20 (16.5%) had COVID-19 previously. Viral culture positivity decreased from 71.9% (87/121) on day 5 of infection to 18.2% (22/121) on day 10. Participants with recurrent COVID-19 had a lower likelihood of infectivity than those with primary COVID-19 at each follow-up (day 5 OR, 0.14; p<0.001]; day 7 OR, 0.04; p=0.003]) and were all non-infective by day 10 (p=0.02). Independent predictors of infectivity included prior COVID-19 (adjusted OR [aOR] on day 5, 0.005; p=0.003), a RT-PCR Ct value <23 (aOR on day 5, 22.75; p<0.001), but not symptom improvement or RADT result. The CDC criteria would identify 36% (24/67) of all non-infectious individuals on Day 7. However, 17% (5/29) of those meeting all the criteria had a positive viral culture. ConclusionsInfectivity of recurrent COVID-19 is shorter than primary infections. Loss of infectivity algorithms could be optimized.

BackgroundOral nirmatrelvir/ritonavir is a treatment for COVID-19, but whether treatment during the acute phase reduces the risk of developing Long COVID is unknown. MethodsUsing the Covid Citizen Science (CCS) online cohort, we surveyed individuals who reported their first SARS-CoV-2 positive test between March and August 2022 regarding Long COVID symptoms. We excluded those who were pregnant, unvaccinated, hospitalized for COVID-19, or received other antiviral therapy. The primary exposure was oral nirmatrelvir/ritonavir. The primary outcome was the presence of any Long COVID symptoms reported on cross-sectional surveys in November and December 2022. We used propensity-score models and inverse probability of treatment weighting to adjust for differences in treatment propensity. Our secondary question was whether symptom or test positivity rebound were associated with Long COVID. Results4684 individuals met the eligibility criteria, of whom 988 (21.1%) were treated and 3696 (78.9%) were untreated; 353/988 (35.7%) treated and 1258/3696 (34.0%) untreated responded to the survey. Median age was 55 years and 66% were female. We did not identify an association between nirmatrelvir/ritonavir treatment and Long COVID symptoms (OR 1.15; 95%CI 0.80-1.64). Among n=666 treated with nirmatrelvir/ritonavir who responded who responded to questions about rebound, rebound symptoms or test positivity were not associated with Long COVID symptoms (OR 1.34; 95%CI 0.74-2.41; p=0.33). ConclusionsWithin this cohort, treatment with nirmatrelvir/ritonavir among vaccinated, non-hospitalized individuals was not associated with lower prevalence of Long COVID symptoms or severity of Long COVID. Experiencing rebound symptoms or test positivity is not strongly associated with developing Long COVID.

BackgroundCOronaVirus Disease 2019 (COVID-19) can be challenging to diagnose, because symptoms are non-specific, clinical presentations are heterogeneous, and false negative tests can occur. Our objective was to assess the utility of lymphocyte count to differentiate COVID-19 from influenza or community-acquired pneumonia (CAP). MethodsWe conducted a cohort study of adults hospitalized with COVID-19 or another respiratory infection (i.e., influenza, CAP) at seven hospitals in Ontario, Canada.The first available lymphocyte count during the hospitalization was used. Standard test characteristics for lymphocyte count (x109/L) were calculated (i.e., sensitivity, specificity, area under the receiver operating curve [AUC]). All analyses were conducting using R. ResultsThere were 869 hospitalizations for COVID-19, 669 for influenza, and 3009 for CAP. The mean age across the three groups was 67 and patients with pneumonia were older than those with influenza or COVID19, and approximately 46% were woman. The median lymphocyte count was nearly identical for the three groups of patients: 1.0 x109/L (interquartile range [IQR]:0.7,2.0) for COVID-19, 0.9 x109/L (IQR 0.6,1.0) for influenza, and 1.0 x109/L (IQR 0.6,2.0) for CAP. At a lymphocyte threshold of less than 2.0 x109/L, the sensitivity was 87% and the specificity was approximately 10%. As the lymphocyte threshold increased, the sensitivity of diagnosing COVID-19 increased while the specificity decreased. The AUC for lymphocyte count was approximately 50%. InterpretationLymphocyte count has poor diagnostic discrimination to differentiate between COVID-19 and other respiratory illnesses. The lymphopenia we consistently observed across the three illnesses in our study may reflect a non-specific sign of illness severity. However, lymphocyte count above 2.0 x109/L may be useful in ruling out COVID-19 (sensitivity = 87%).

SARS-CoV-2 seroprevalence was low (<1%) in this large population of healthcare workers (HCWs) across the state of Tennessee (n=11,787) in May-June 2020. Among those with PCR results, 81.5% of PCR and antibody test results were concordant. SARS-CoV-2 seroprevalence was higher among HCWs working in high-community-transmission regions and among younger workers. ImportanceThese results may be seen as a baseline assessment of SARS-CoV-2 seroprevalence among HCWs in the American South during a period of growth, but not yet saturation, of infections among susceptible populations. In fact, this period of May-June 2020 was marked by the extension of renewed and sustained community-wide transmission after mandatory quarantine periods expired in several more populous regions of Tennessee. Where community transmission remains low, HCWs may still be able to effectively mitigate SARS-CoV-2 transmission, preserving resources for populations at high risk of severe disease, and these sorts of data help highlight such strategies.

BackgroundIn the EPIC-HR trial, nirmatrelvir plus ritonavir led to an 88% reduction in hospitalization or death among unvaccinated outpatients with early COVID-19. Clinical impact of nirmatrelvir plus ritonavir among vaccinated populations is uncertain. ObjectiveTo assess whether nirmatrelvir plus ritonavir reduces risk of hospitalization among outpatients with early COVID-19 in the setting of prevalent SARS-CoV-2 immunity and immune evasive SARS-CoV-2 lineages. DesignPopulation-based cohort study analyzed to emulate a clinical trial utilizing two-stage, inverse-probability weighted models to account for anticipated bias in testing and treatment. SettingA large healthcare system providing care for 1.5 million patients in Massachusetts and New Hampshire during Omicron wave (January 1 to May 15, 2022) with staged access and capacity to prescribe nirmatrelvir plus ritonavir. Patients30,322 non-hospitalized adults (87.2% vaccinated) aged 50 and older with COVID-19 and without contraindications to nirmatrelvir plus ritonavir. MeasurementPrimary outcome was hospitalization within 14 days of COVID-19 diagnosis. ResultsDuring the study period, 6036 (19.9%) patients were prescribed nirmatrelvir plus ritonavir and 24,286 (80.1%) patients were not. Patients prescribed nirmatrelvir were more likely to be older, have more comorbidities, and be unvaccinated. Hospitalization occurred in 40 (0.66%) and 232 (0.96%) patients prescribed and not prescribed nirmatrelvir plus ritonavir, respectively. The adjusted risk ratio was 0.55 (95% confidence interval 0.38 to 0.80, p = 0.002). Observed risk reduction was greater among unvaccinated patients and obese patients. LimitationsPotential for residual confounding due to differential access and uptake of COVID-19 vaccines, diagnostics, and treatment. ConclusionsThe overall risk of hospitalization was already low (<1%) following an outpatient diagnosis of COVID-19, but this risk was 45% lower among patients prescribed nirmatrelvir plus ritonavir. FundingNational Institutes of Health (P30 AI060354 and R01 CA236546).

IntroductionThe relationship between SARS-CoV-2 viral dynamics during acute infection and the development of long COVID is largely unknown. MethodsA total of 7361 asymptomatic community-dwelling people enrolled in the Test Us at Home parent study between October 2021 and February 2022. Participants self-collected anterior nasal swabs for SARS-CoV-2 RT-PCR testing every 24-48 hours for 10-14 days, regardless of symptom or infection status. Participants who had no history of COVID-19 at enrollment and who were subsequently found to have [&ge;]1 positive SARS-CoV-2 RT-PCR test during the parent study were recontacted in August 2023 and asked whether they had experienced long COVID, defined as the development of new symptoms lasting 3 months or longer following SARS-CoV-2 infection. Participants cycle threshold values were converted into viral loads, and slopes of viral clearance were modeled using post-nadir viral loads. Using a log binomial model with the modeled slopes as the exposure, we calculated the relative risk of subsequently developing long COVID with 1-2 symptoms, 3-4 symptoms, or 5+ symptoms, adjusting for age, number of symptoms, and SARS-CoV-2 variant. Adjusted relative risk (aRR) of individual long COVID symptoms based on viral clearance was also calculated. Results172 participants were eligible for analyses, and 59 (34.3%) reported experiencing long COVID. The risk of long COVID with 3-4 symptoms and 5+ symptoms increased by 2.44 times (aRR: 2.44; 95% CI: 0.88-6.82) and 4.97 times (aRR: 4.97; 95% CI: 1.90-13.0) per viral load slope-unit increase, respectively. Participants who developed long COVID had significantly longer times from peak viral load to viral clearance during acute disease than those who never developed long COVID (8.65 [95% CI: 8.28-9.01] vs. 10.0 [95% CI: 9.25-10.8]). The slope of viral clearance was significantly positively associated with long COVID symptoms of fatigue (aRR: 2.86; 95% CI: 1.22-6.69), brain fog (aRR: 4.94; 95% CI: 2.21-11.0), shortness of breath (aRR: 5.05; 95% CI: 1.24-20.6), and gastrointestinal symptoms (aRR: 5.46; 95% CI: 1.54-19.3). DiscussionWe observed that longer time from peak viral load to viral RNA clearance during acute COVID-19 was associated with an increased risk of developing long COVID. Further, slower clearance rates were associated with greater number of symptoms of long COVID. These findings suggest that early viral-host dynamics are mechanistically important in the subsequent development of long COVID.