Estimating the Effect of Coronavirus Disease 2019 (COVID-19) Vaccination and Infection Variant on Post-COVID-19 Venous Thrombosis or Embolism Risk.

Background: Previous research has shown that vaccination reduces risk of post-coronavirus disease 2019 (COVID-19) venous thrombosis or embolism (VTE), but the effect of vaccine boosting on post-COVID-19 VTE risk reduction is unclear. We sought to estimate the effect of COVID-19 vaccination on the risk of post-COVID-19 VTE and to examine if the magnitude of this association differed among variant eras. Methods: We performed a case-control study of Military Health System (MHS) beneficiaries who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2020-2022. Cases were defined as those with medically attended VTE within 90 days after their first positive SARS-CoV-2 test; controls were defined as SARS-CoV-2 infections without incident VTE by 90 days. Multivariate logistic regression estimated the odds of post-SARS-CoV-2 VTE based on pre-COVID-19 vaccine status, adjusting for other VTE risk factors. Results: A total of 4646 MHS beneficiaries were included in this analysis; 1370 received a primary vaccine series and a further 790 received at least 1 booster at time of infection; 71 had VTE within 90 days of SARS-CoV-2 infection. Those who were vaccinated had lower odds of VTE (adjusted odds ratio [95% confidence interval]) compared to the unvaccinated following infection (primary series: 0.28 [.13-.62]; booster dose: 0.06 [.01-.46]). Post-COVID-19 VTE risk was lowest during the Omicron era, but VTEs were too rare to examine for an interaction of variant era and vaccine effect. Conclusions: Among MHS beneficiaries, COVID-19 vaccination was associated with a reduced risk of post-COVID-19 VTE diagnosis; estimated risk reduction was larger among those who received a booster.

SARS-CoV-2 variant replacement constrains vaccine-specific viral diversification.

Coronavirus disease 2019 (COVID-19) vaccine breakthrough infections have been important for all circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant periods, but the contribution of vaccine-specific SARS-CoV-2 viral diversification to vaccine failure remains unclear. This study analyzed 595 SARS-CoV-2 sequences collected from the Military Health System beneficiaries between December 2020 and April 2022 to investigate the impact of vaccination on viral diversity. By comparing sequences based on the vaccination status of the participant, we found limited evidence indicating that vaccination was associated with increased viral diversity in the SARS-CoV-2 spike, and we show little to no evidence of a substantial sieve effect within major variants; rather, we show that rapid variant replacement constrained intragenotype COVID-19 vaccine strain immune escape. These data suggest that, during past and perhaps future periods of rapid SARS-CoV-2 variant replacement, vaccine-mediated effects were subsumed with other drivers of viral diversity due to the massive scale of infections and vaccinations that occurred in a short time frame. However, our results also highlight some limitations of using sieve analysis methods outside of placebo-controlled clinical trials.

SARS-CoV-2 infection is associated with self-reported post-acute neuropsychological symptoms within six months of follow-up.

BACKGROUND: Chronic neuropsychological sequelae following SARS-CoV-2 infection, including depression, anxiety, fatigue, and general cognitive difficulties, are a major public health concern. Given the potential impact of long-term neuropsychological impairment, it is important to characterize the frequency and predictors of this post-infection phenotype. METHODS: The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study is a longitudinal study assessing the impact of SARS-CoV-2 infection in U.S. Military Healthcare System (MHS) beneficiaries, i.e. those eligible for care in the MHS including active duty servicemembers, dependents, and retirees. Four broad areas of neuropsychological symptoms were assessed cross-sectionally among subjects 1-6 months post-infection/enrollment, including: depression (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), fatigue (PROMIS® Fatigue 7a), and cognitive function (PROMIS® Cognitive Function 8a and PROMIS® Cognitive Function abilities 8a). Multivariable Poisson regression models compared participants with and without SARS-CoV-2 infection history on these measures, adjusting for sex, ethnicity, active-duty status, age, and months post-first positive or enrollment of questionnaire completion (MPFP/E); models for fatigue and cognitive function were also adjusted for depression and anxiety scores. RESULTS: The study population included 2383 participants who completed all five instruments within six MPFP/E, of whom 687 (28.8%) had at least one positive SARS-CoV-2 test. Compared to those who had never tested positive for SARS-CoV-2, the positive group was more likely to meet instrument-based criteria for depression (15.4% vs 10.3%, p<0.001), fatigue (20.1% vs 8.0%, p<0.001), impaired cognitive function (15.7% vs 8.6%, p<0.001), and impaired cognitive function abilities (24.3% vs 16.3%, p<0.001). In multivariable models, SARS-CoV-2 positive participants, assessed at an average of 2.7 months after infection, had increased risk of moderate to severe depression (RR: 1.44, 95% CI 1.12-1.84), fatigue (RR: 2.07, 95% CI 1.62-2.65), impaired cognitive function (RR: 1.64, 95% CI 1.27-2.11), and impaired cognitive function abilities (RR: 1.41, 95% CI 1.15-1.71); MPFP/E was not significant. CONCLUSIONS: Participants with a history of SARS-CoV-2 infection were up to twice as likely to report cognitive impairment and fatigue as the group without prior SARS-CoV-2 infection. These findings underscore the continued importance of preventing SARS-CoV-2 infection and while time since infection/enrollment was not significant through 6 months of follow-up, this highlights the need for additional research into the long-term impacts of COVID-19 to mitigate and reverse these neuropsychological outcomes.

Cardiopulmonary exercise testing in younger patients with persistent dyspnea following acute, outpatient COVID-19 infection.

Studies using cardiopulmonary exercise testing (CPET) to evaluate persistent dyspnea following infection with COVID-19 have focused on older patients with co-morbid diseases who are post-hospitalization. Less attention has been given to younger patients with post-COVID-19 dyspnea treated as outpatients for their acute infection. We sought to determine causes of persistent dyspnea in younger patients recovering from acute COVID-19 infection that did not require hospitalization. We collected data on all post-COVID-19 patients who underwent CPET in our clinic in the calendar year 2021. Data on cardiac function and respiratory response were abstracted, and diagnoses were assigned using established criteria. CPET data on 45 patients (238.3 ± 124 days post-test positivity) with a median age of 27.0 (22.0-40.0) were available for analysis. All but two (95.6%) were active-duty service members. The group showed substantial loss of aerobic capacity-average VO2 peak (L/min) was 84.2 ± 23% predicted and 25 (55.2%) were below the threshold for normal. Spirometry, diffusion capacity, high-resolution computed tomography, and echocardiogram were largely normal and were not correlated with VO2 peak. The two most common contributors to dyspnea and exercise limitation following comprehensive evaluation were deconditioning and dysfunctional breathing (DB). Younger active-duty military patients with persistent dyspnea following outpatient COVID-19 infection show a substantial reduction in aerobic capacity that is not driven by structural cardiopulmonary disease. Deconditioning and DB breathing are common contributors to their exercise limitation. The chronicity and severity of symptoms accompanied by DB could be consistent with an underlying myopathy in some patients, a disorder that cannot be differentiated from deconditioning using non-invasive CPET.

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.

A machine learning approach identifies distinct early-symptom cluster phenotypes which correlate with hospitalization, failure to return to activities, and prolonged COVID-19 symptoms.

BACKGROUND: Accurate COVID-19 prognosis is a critical aspect of acute and long-term clinical management. We identified discrete clusters of early stage-symptoms which may delineate groups with distinct disease severity phenotypes, including risk of developing long-term symptoms and associated inflammatory profiles. METHODS: 1,273 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative symptom scores (FLU-PRO Plus) were included in this analysis. We employed machine-learning approaches to identify symptom clusters and compared risk of hospitalization, long-term symptoms, as well as peak CRP and IL-6 concentrations. RESULTS: We identified three distinct clusters of participants based on their FLU-PRO Plus symptoms: cluster 1 ("Nasal cluster") is highly correlated with reporting runny/stuffy nose and sneezing, cluster 2 ("Sensory cluster") is highly correlated with loss of smell or taste, and cluster 3 ("Respiratory/Systemic cluster") is highly correlated with the respiratory (cough, trouble breathing, among others) and systemic (body aches, chills, among others) domain symptoms. Participants in the Respiratory/Systemic cluster were twice as likely as those in the Nasal cluster to have been hospitalized, and 1.5 times as likely to report that they had not returned-to-activities, which remained significant after controlling for confounding covariates (P < 0.01). Respiratory/Systemic and Sensory clusters were more likely to have symptoms at six-months post-symptom-onset (P = 0.03). We observed higher peak CRP and IL-6 in the Respiratory/Systemic cluster (P < 0.01). CONCLUSIONS: We identified early symptom profiles potentially associated with hospitalization, return-to-activities, long-term symptoms, and inflammatory profiles. These findings may assist in patient prognosis, including prediction of long COVID risk.

Obesity-related Changes in Diffusing Capacity and Transfer Coefficient of the Lung for Carbon Monoxide and Resulting Patterns of Abnormality across Reference Equations.

Rationale: In 2017, an American Thoracic Society/European Respiratory Society Task Force report recommended further research on the effects that body mass index (BMI) has on diffusing capacity of the lung for carbon monoxide (DlCO), the transfer coefficient (Kco), and the alveolar volume (VA). Objectives: Our goals were to 1) quantify the magnitude and direction of change to measured and predicted DlCO values as BMI increases in patients free of cardiopulmonary disease and 2) identify how BMI and obesity-related changes differ by reference set. Methods: Using data from a prospective cohort study of service members free of cardiopulmonary disease, we modeled the effect that BMI has on measured values of DlCO, Kco, and VA, after adjusting for age, sex, hemoglobin (Hgb), and height. We then referenced DlCO, Kco, and VA to normal values using four different reference equations. Results: There were 380 patients with data available for analysis, and 130 had a BMI ⩾ 30 kg/m2 (87.7% class I obesity). After controlling for age, sex, Hgb, and height, increased BMI was significantly associated with Kco (ß = 0.09, P < 0.01) and VA (ß = -0.15, P < 0.01) but not DlCO. After adjustment for Hgb, for every 5-kg/m2 increase in BMI, the mean increase in percent predicted (PPD) values ranged from 4.2% to 6.5% and from 5.0% to 7.5% for DlCO and Kco, respectively; and the mean decrease in VA PPD was 3.2-4.0%. In the presence of obesity (BMI ⩾ 30 kg/m2), the prevalence of DlCO and Kco abnormalities dropped by 4.1-12.1% and 0.4-16.3%, respectively, across equations, whereas VA abnormalities increased from 7.7% to 9.9%. Eliminating 163 patients with abnormal trans-thoracic echocardiogram (TEE), high-resolution computed tomographic (HRCT) scan, or Hgb altered the magnitude of relationships, but significance was preserved. Conclusions: In an otherwise healthy population with predominantly class I obesity and normal TTE, HRCT scan, and Hgb, we found that Kco and VA were more affected by BMI than DlCO. Increases in PPD values varied across equations and were modest but significant and could change clinical decision making by reducing sensitivity for detecting gas-exchange abnormalities. BMI and obesity had the smallest effect on Global Lung Function Initiative PPD values.

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.

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.

Unraveling the Treatment Effect of Baricitinib on Clinical Progression and Resource Utilization in Hospitalized COVID-19 Patients: Secondary Analysis of the Adaptive COVID-19 Treatment Randomized Trial-2.

Background: The Adaptive COVID Treatment Trial-2 (ACTT-2) found that baricitinib in combination with remdesivir therapy (BCT) sped recovery in hospitalized coronavirus disease 2019 (COVID-19) patients vs remdesivir monotherapy (RMT). We examined how BCT affected progression throughout hospitalization and utilization of intensive respiratory therapies. Methods: We characterized the clinical trajectories of 891 ACTT-2 participants requiring supplemental oxygen or higher levels of respiratory support at enrollment. We estimated the effect of BCT on cumulative incidence of clinical improvement and deterioration using competing risks models. We developed multistate models to estimate the effect of BCT on clinical improvement and deterioration and on utilization of respiratory therapies. Results: BCT resulted in more linear improvement and lower incidence of clinical deterioration compared with RMT (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95). The benefit was pronounced among participants enrolled on high-flow oxygen or noninvasive positive-pressure ventilation. In this group, BCT sped clinical improvement (HR, 1.21; 95% CI, 0.99 to 1.51) while slowing clinical deterioration (HR, 0.71; 95% CI, 0.48 to 1.02), which reduced the expected days in ordinal score (OS) 6 per 100 patients by 74 days (95% CI, -8 to 154 days) and the expected days in OS 7 per 100 patients by 161 days (95% CI, 46 to 291 days) compared with RMT. BCT did not benefit participants who were mechanically ventilated at enrollment. Conclusions: Compared with RMT, BCT reduces the clinical burden and utilization of intensive respiratory therapies for patients requiring low-flow oxygen or noninvasive positive-pressure ventilation compared with RMT and may thereby improve care for this patient population.

Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.

BACKGROUND: Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19. METHODS: In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168. FINDINGS: Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012). INTERPRETATION: In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered. FUNDING: National Institute of Allergy and Infectious Diseases.

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.

Deconstructing the Treatment Effect of Remdesivir in the Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1: Implications for Critical Care Resource Utilization.

BACKGROUND: The Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1 (ACTT-1) found that remdesivir therapy hastened recovery in patients hospitalized with COVID-19, but the pathway for this improvement was not explored. We investigated how the dynamics of clinical progression changed along 4 pathways: recovery, improvement in respiratory therapy requirement, deterioration in respiratory therapy requirement, and death. METHODS: We analyzed trajectories of daily ordinal severity scores reflecting oxygen requirements of 1051 patients hospitalized with COVID-19 who participated in ACTT-1. We developed competing risks models that estimate the effect of remdesivir therapy on cumulative incidence of clinical improvement and deterioration, and multistate models that utilize the entirety of each patient's clinical course to characterize the effect of remdesivir on progression along the 4 pathways above. RESULTS: Based on a competing risks analysis, remdesivir reduced clinical deterioration (hazard ratio [HR], 0.73; 95% confidence interval [CI]: .59-.91) and increased clinical improvement (HR, 1.22; 95% CI: 1.08, 1.39) relative to baseline. Our multistate models indicate that remdesivir inhibits worsening to ordinal scores of greater clinical severity among patients on room air or low-flow oxygen (HR, 0.74; 95% CI: .57-.94) and among patients receiving mechanical ventilation or high-flow oxygen/noninvasive positive-pressure ventilation (HR, 0.73; 95% CI: .53-1.00) at baseline. We also find that remdesivir reduces expected intensive care respiratory therapy utilization among patients not mechanically ventilated at baseline. CONCLUSIONS: Remdesivir speeds time to recovery by preventing worsening to clinical states that would extend the course of hospitalization and increase intensive respiratory support, thereby reducing the overall demand for hospital care.

Evaluation of Supranormal Spirometry Values With an Obstructive Ratio for Airway Hyperreactivity.

BACKGROUND: Published guidelines on spirometry interpretation suggest an elevated FVC and FEV1 > 100% of predicted with an obstructive ratio may represent a physiological variant. Further evidence is needed on whether this finding indicates symptomatic airways obstruction and what additional evaluation should be done. METHODS: Participants were prospectively enrolled to undergo additional testing for a technically adequate spirometry study with an FEV1 > 90% of predicted, and FEV1/FVC below the lower limit of normal, based on 95th percentile confidence intervals. Further testing consisted of full pulmonary function testing, impulse oscillometry (IOS), post-bronchodilator testing, fractional exhaled nitric oxide (FeNO), and methacholine challenge testing (MCT). RESULTS: A total of 49 patients meeting entry criteria enrolled and completed testing. Thirty-three were considered symptomatic based on clinical indications for initial testing and 16 were considered asymptomatic. Baseline pulmonary function test values were not different between groups while IOS R5 values (% predicted) were higher in the symptomatic group (126.5 ± 0.37 vs 107.1 ± 0.31). Bronchodilator responsiveness on PFT or IOS was infrequent in both groups. There was a 29% positivity rate for MCT in the symptomatic group compared to one borderline study in asymptomatic participants. FeNO was similar for symptomatic, 26.17 ± 31.3 ppb, compared to asymptomatic, 22.8 ± 13.5 ppb (p = 0.93). The dysanapsis ratio was higher in the symptomatic (0.15 ± 0.03) compared to the asymptomatic (0.13 ± 0.02) (p < 0.05). CONCLUSION: Normal FEV1 > 90% of predicted and obstructive indices may not represent a normal physiological variant in all patients. In symptomatic patients, a positive MCT and elevated baseline IOS values were more common than in asymptomatic patients with similar PFT characteristics. These findings suggest that clinicians should still evaluate for airway hyperresponsiveness in patients with exertional dyspnea with airway obstruction and FEV1 > 90% of predicted and consider alternative diagnoses to include a normal physiologic variant if non-reactive.

Performance of the inFLUenza Patient-Reported Outcome Plus (FLU-PRO Plus) Instrument in Patients With Coronavirus Disease 2019.

BACKGROUND: The inFLUenza Patient-Reported Outcome Plus (FLU-PRO Plus) is a patient-reported outcome data collection instrument assessing symptoms of viral respiratory tract infections across 8 body systems. This study evaluated the measurement properties of FLU-PRO Plus in a study enrolling individuals with coronavirus disease 2019 (COVID-19). METHODS: Data from a prospective cohort study (EPICC) in US Military Health System beneficiaries evaluated for COVID-19 was utilized. Adults with symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with FLU-PRO Plus survey information within 1 week of symptom onset were included. Reliability of FLU-PRO Plus was estimated using intraclass correlation coefficient (ICC; 2 days' reproducibility). Known-groups validity was assessed using patient global assessment (PGA) of disease severity. Patient report of return to usual health was used to assess responsiveness (day 1-6/7). RESULTS: Two hundred twenty-six SARS-CoV-2-positive participants were included in the analysis. Reliability among those who reported no change in their symptoms from one day to the next was high for most domains (ICC range, 0.68-0.94 for day 1 to day 2). Construct validity was demonstrated by moderate to high correlation between the PGA rating of disease severity and domain and total scores (eg, total scores correlation: 0.69 [influenza-like illness severity], 0.69 [interference in daily activities], and -0.58 [physical health]). In addition, FLU-PRO Plus demonstrated good known-groups validity, with increasing domain and total scores observed with increasing severity ratings. CONCLUSIONS: FLU-PRO Plus performs well in measuring signs and symptoms in SARS-CoV-2 infection with excellent construct validity, known-groups validity, and responsiveness to change. Standardized data collection instruments facilitate meta-analyses, vaccine effectiveness studies, and other COVID-19 research activities.

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.

Durability of SARS-CoV-2-Specific T-Cell Responses at 12 Months Postinfection.

BACKGROUND: Characterizing the longevity and quality of cellular immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enhances understanding of coronavirus disease 2019 (COVID-19) immunity that influences clinical outcomes. Prior studies suggest SARS-CoV-2-specific T cells are present in peripheral blood 10 months after infection. Analysis of the function, durability, and diversity of cellular response long after natural infection, over a range of ages and disease phenotypes, is needed to identify preventative and therapeutic interventions. METHODS: We identified participants in our multisite longitudinal, prospective cohort study 12 months after SARS-CoV-2 infection representing a range of disease severity. We investigated function, phenotypes, and frequency of T cells specific for SARS-CoV-2 using intracellular cytokine staining and spectral flow cytometry, and compared magnitude of SARS-CoV-2-specific antibodies. RESULTS: SARS-CoV-2-specific antibodies and T cells were detected 12 months postinfection. Severe acute illness was associated with higher frequencies of SARS-CoV-2-specific CD4 T cells and antibodies at 12 months. In contrast, polyfunctional and cytotoxic T cells responsive to SARS-CoV-2 were identified in participants over a wide spectrum of disease severity. CONCLUSIONS: SARS-CoV-2 infection induces polyfunctional memory T cells detectable at 12 months postinfection, with higher frequency noted in those who experienced severe disease.

Post-COVID-19 Pulmonary Fibrosis: Novel Sequelae of the Current Pandemic.

Since the initial identification of the novel coronavirus SARS-CoV-2 in December 2019, the COVID-19 pandemic has become a leading cause of morbidity and mortality worldwide. As effective vaccines and treatments begin to emerge, it will become increasingly important to identify and proactively manage the long-term respiratory complications of severe disease. The patterns of imaging abnormalities coupled with data from prior coronavirus outbreaks suggest that patients with severe COVID-19 pneumonia are likely at an increased risk of progression to interstitial lung disease (ILD) and chronic pulmonary vascular disease. In this paper, we briefly review the definition, classification, and underlying pathophysiology of interstitial lung disease (ILD). We then review the current literature on the proposed mechanisms of lung injury in severe COVID-19 infection, and outline potential viral- and immune-mediated processes implicated in the development of post-COVID-19 pulmonary fibrosis (PCPF). Finally, we address patient-specific and iatrogenic risk factors that could lead to PCPF and discuss strategies for reducing risk of pulmonary complications/sequelae.