June 08,2023

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Clinical Reports

Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection
- SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.
Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms
- Persistent depressive symptoms, often accompanied by cognitive symptoms, commonly occur after COVID-19 illness (hereinafter termed COVID-DC, DC for depressive and/or cognitive symptoms). In patients with COVID-DC, gliosis, an inflammatory change, was suspected, but measurements of gliosis had not been studied in the brain for this condition. This case-control study conducted at a tertiary care psychiatric hospital in Canada from April 1, 2021, to June 30, 2022, compared TSPO VT of specific brain regions in 20 participants with COVID-DC with that in 20 healthy controls. The TSPO VT was measured with fluorine F 18–labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) PET. The TSPO VT was measured in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus. Symptoms were measured with neuropsychological and psychological tests, prioritizing outcomes related to striatal function. The study population included 40 participants (mean [SD] age, 32.9 [12.3] years). The TSPO VT across the regions of interest was greater in persons with COVID-DC compared with healthy control participants. The difference was most prominent in the ventral striatum. Motor speed on the finger-tapping test negatively correlated with dorsal putamen TSPO VT, and the 10 persons with the slowest speed among those with COVID-DC had higher dorsal putamen TSPO VT than healthy persons by 2.3. In this case-control study, TSPO VT was higher in patients with COVID-DC. Greater TSPO VT is evidence for an inflammatory change of elevated gliosis in the brain of an individual with COVID-DC. Gliosis may be consequent to inflammation, injury, or both, particularly in the ventral striatum and dorsal putamen, which may explain some persistent depressive and cognitive symptoms, including slowed motor speed, low motivation or energy, and anhedonia, after initially mild to moderate COVID-19 illness.
Long COVID Clinical Phenotypes Up to Six Months After Infection Identified by Latent Class Analysis of Self-Reported Symptoms
- This was a multicenter, prospective study of symptomatic adults tested for SARS-CoV-2 with prospectively collected data on general symptoms and fatigue-related symptoms up to six-months post-diagnosis. Using LCA, we identified symptomatically homogenous groups among participants with COVID-19 (COVID-positive) and among others without COVID-19 (COVID-negative) at each time period for both general and fatigue-related symptoms. Among 5,963 baseline participants (4,504 COVID-positive and 1,459 COVID-negative), 4,056 had three-month and 2,856 had six-month data at the time of analysis. Researchers identified four distinct phenotypes of post-COVID conditions at three- and six-months for both general and fatigue-related symptoms; minimal symptom groups represented 70% of participants at three and six months. When compared with the COVID-negative cohort, COVID-positive participants had higher occurrence of loss of taste and smell, as well cognition problems. There was substantial class-switching over time; those in one symptom class at three months were equally likely to remain or enter a new phenotype at six months. Researchers identified distinct classes of post-COVID phenotypes for general and fatigue-related symptoms. Most participants had minimal or no symptoms at three and six months follow-up. Significant proportions of participants changed symptom groups over time, suggesting that symptoms present during the acute illness may differ from prolonged symptoms and that post-COVID conditions may have a more dynamic nature than previously recognized.

Antiviral Therapeutics and Vaccines

Effectiveness of COVID-19 Treatment With Nirmatrelvir–Ritonavir or Molnupiravir Among U.S. Veterans: Target Trial Emulation Studies With One-Month and Six-Month Outcomes
- Eighty-seven percent of participants were male; the median age was 66 years, and 18% were unvaccinated. Compared with matched untreated control participants, those treated with nirmatrelvir–ritonavir (n = 9607) had lower 30-day risk for hospitalization (22.07 vs. 30.32 per 1000 participants; risk difference [RD], −8.25 [95% CI, −12.27 to −4.23] per 1000 participants) and death (1.25 vs. 5.47 per 1000 participants; RD, −4.22 [CI, −5.45 to −3.00] per 1000 participants). Among persons alive at day 31, reductions were seen in 31- to 180-day incidence of death (hazard ratio, 0.66 [CI, 0.49 to 0.89]) but not hospitalization (subhazard ratio, 0.90 [CI, 0.79 to 1.02]). Molnupiravir-treated participants (n = 3504) had lower 30-day and 31- to 180-day risks for death (3.14 vs. 13.56 per 1000 participants at 30 days; RD, −10.42 [CI, −13.49 to −7.35] per 1000 participants; hazard ratio at 31 to 180 days, 0.67 [CI, 0.48 to 0.95]) but not hospitalization. A difference in 30-day or 31- to 180-day risk for hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. The date of COVID-19 symptom onset for most veterans was unknown. Nirmatrelvir–ritonavir was effective in reducing 30-day hospitalization and death. Molnupiravir was associated with a benefit for 30-day mortality but not hospitalization. Further reductions in mortality from 31 to 180 days were observed with both antivirals.

Epidemiology

Estimates of SARS-CoV-2 Seroprevalence and Incidence of Primary SARS-CoV-2 Infections Among Blood Donors, by COVID-19 Vaccination Status
- SARS-CoV-2 hybrid immunity (immunity derived from both previous infection and vaccination) has been reported to provide better protection than that from infection or vaccination alone. By the third quarter of 2022, an estimated 96.4% of persons aged ≥16 years in a longitudinal blood donor cohort had SARS-CoV-2 antibodies from previous infection or vaccination, including 22.6% from infection alone and 26.1% from vaccination alone; 47.7% had hybrid immunity. Hybrid immunity prevalence was lowest among adults aged ≥65 years. Low prevalence of infection-induced and hybrid immunity among older adults, who are at increased risk for severe disease if infected, reflects the success of public health infection prevention efforts while also highlighting the importance of this group staying up to date with recommended COVID-19 vaccination, including at least 1 bivalent dose.
Smart Thermometer–Based Participatory Surveillance to Discern the Role of Children in Household Viral Transmission During the COVID-19 Pandemic
- This cohort study of a voluntary US cohort tracked data from participatory surveillance using commercially available thermometers with a companion smartphone app from October 2019 to October 2022. Eligible participants were individuals with temperature measurements in households with multiple members between October 2019 and October 2022 who opted into data sharing. Proportion of household transmissions with a pediatric index case and changes in transmissions during school breaks were assessed using app and thermometer data. A total of 862 577 individuals from 320 073 households with multiple participants (462 000 female [53.6%] and 463 368 adults [53.7%]) were included. The number of febrile episodes forecast new COVID-19 cases. Within-household transmission was inferred in 54 506 (15.4%) febrile episodes and increased from the fourth pandemic period, March to July 2021 (3263 of 32 294 [10.1%]) to the Omicron BA.1/BA.2 wave (16 516 of 94 316 [17.5%]; P < .001). Among 38 787 transmissions in 166 170 households with adults and children, a median (IQR) 70.4% (61.4%-77.6%) had a pediatric index case; proportions fluctuated weekly from 36.9% to 84.6%. A pediatric index case was 0.6 to 0.8 times less frequent during typical school breaks. The winter break decrease was from 68.4% (95% CI, 57.1%-77.8%) to 41.7% (95% CI, 34.3%-49.5%) at the end of 2020 (P < .001). At the beginning of 2022, it dropped from 80.3% (95% CI, 75.1%-84.6%) to 54.5% (95% CI, 51.3%-57.7%) (P < .001). During summer breaks, rates dropped from 81.4% (95% CI, 74.0%-87.1%) to 62.5% (95% CI, 56.3%-68.3%) by August 2021 (P = .02) and from 83.8% (95% CI, 79.2%-87.5) to 62.8% (95% CI, 57.1%-68.1%) by July 2022 (P < .001). These patterns persisted over 2 school years. In this cohort study using participatory surveillance to measure within-household transmission at a national scale, we discerned an important role for children in the spread of viral infection within households during the COVID-19 pandemic, heightened when schools were in session, supporting a role for school attendance in COVID-19 spread.
Changing Severity and Epidemiology of Adults Hospitalized With Coronavirus Disease 2019 (COVID-19) in the United States After Introduction of COVID-19 Vaccines, March 2021–August 2022
- Among adults (≥18 years) hospitalized with laboratory-confirmed, acute COVID-19 between 11 March 2021, and 31 August 2022 at 21 hospitals in 18 states, those hospitalized during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron-predominant period (BA.1, BA.2, BA.4/BA.5) were compared to those from earlier Alpha- and Delta-predominant periods. Demographic characteristics, biomarkers within 24 hours of admission, and outcomes, including oxygen support and death, were assessed. Among 9825 patients, median (interquartile range [IQR]) age was 60 years (47–72), 47% were women, and 21% non-Hispanic Black. From the Alpha-predominant period (Mar–Jul 2021; N = 1312) to the Omicron BA.4/BA.5 sublineage-predominant period (Jun–Aug 2022; N = 1307): the percentage of patients who had ≥4 categories of underlying medical conditions increased from 11% to 21%; those vaccinated with at least a primary COVID-19 vaccine series increased from 7% to 67%; those ≥75 years old increased from 11% to 33%; those who did not receive any supplemental oxygen increased from 18% to 42%. Median (IQR) highest C-reactive protein and D-dimer concentration decreased from 42.0 mg/L (9.9–122.0) to 11.5 mg/L (2.7–42.8) and 3.1 mcg/mL (0.8–640.0) to 1.0 mcg/mL (0.5–2.2), respectively. In-hospital death peaked at 12% in the Delta-predominant period and declined to 4% during the BA.4/BA.5-predominant period. Compared to adults hospitalized during early COVID-19 variant periods, those hospitalized during Omicron-variant COVID-19 were older, had multiple co-morbidities, were more likely to be vaccinated, and less likely to experience severe respiratory disease, systemic inflammation, coagulopathy, and death.
National Trends in Anticoagulation Therapy for COVID-19 Hospitalized Adults in the United States: Analyses of the National COVID Cohort Collaborative
- Using the National COVID Cohort Collaborative, researchers conducted a retrospective cohort study (2020-2022) to assess AC use patterns and identify factors associated with therapeutic AC employing modified Poisson regression. Among 162,842 hospitalized COVID-19 patients, 64% received AC and 24% received therapeutic AC. Therapeutic AC use declined from 32% in 2020 to 12% in 2022, especially after December 2021. Therapeutic AC predictors included age (relative risk (RR), 1.02 [95% confidence interval (CI), 1.02-1.02] per year), male (RR, 1.29 [1.27-1.32]), Non-Hispanic Black (RR, 1.16 [1.13-1.18]), obesity (RR, 1.48 [1.43-1.52]), increased length of stay (RR, 1.01; [1.01-1.01] per day), and invasive ventilation (RR, 1.64 [1.59-1.69]). Vaccination (RR, 0.88 [0.84-0.92]) and higher Charlson Comorbidity Index (CCI) (RR, 0.98 [0.97-0.98]) were associated with lower therapeutic AC. Overall, two thirds of hospitalized COVID-19 patients received any AC and a quarter received therapeutic dosing. Therapeutic AC declined after the introduction of the Omicron variant. Predictors of therapeutic AC included demographics, obesity, LOS, invasive ventilation, CCI, and vaccination, suggesting AC decisions driven by clinical factors including COVID-19 severity, bleeding risks, and comorbidities.
Coronary microvascular health in symptomatic patients with prior COVID-19 infection: an updated analysis
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with endothelial dysfunction. Researchers aimed to determine the effects of prior coronavirus disease 2019 (COVID-19) on the coronary microvasculature accounting for time from COVID-19, disease severity, SARS-CoV-2 variants, and in subgroups of patients with diabetes and those with no known coronary artery disease. Cases consisted of patients with previous COVID-19 who had clinically indicated positron emission tomography (PET) imaging and were matched 1:3 on clinical and cardiovascular risk factors to controls having no prior infection. Myocardial flow reserve (MFR) was calculated as the ratio of stress to rest myocardial blood flow (MBF) in mL/min/g of the left ventricle. Comparisons between cases and controls were made for the odds and prevalence of impaired MFR (MFR < 2). Researchers included 271 cases matched to 815 controls (mean ± SD age 65 ± 12 years, 52% men). The median (inter-quartile range) number of days between COVID-19 infection and PET imaging was 174 (58–338) days. Patients with prior COVID-19 had a statistically significant higher odds of MFR <2 (adjusted odds ratio 3.1, 95% confidence interval 2.8–4.25 P < 0.001). Results were similar in clinically meaningful subgroups. The proportion of cases with MFR <2 peaked 6–9 months from imaging with a statistically non-significant downtrend afterwards and was comparable across SARS-CoV-2 variants but increased with increasing severity of infection. The prevalence of impaired MFR is similar by duration of time from infection up to 1 year and SARS-CoV-2 variants, but significantly differs by severity of infection.