SARS-CoV-2 control on a large urban college campus without mass testing.

OBJECTIVE: A small percentage of universities and colleges conducted mass SARS-CoV-2 testing. However, universal testing is resource-intensive, strains national testing capacity, and false negative tests can encourage unsafe behaviors. PARTICIPANTS: A large urban university campus. METHODS: Virus control centered on three pillars: mitigation, containment, and communication, with testing of symptomatic and a random subset of asymptomatic students. RESULTS: Random surveillance testing demonstrated a prevalence among asymptomatic students of 0.4% throughout the term. There were two surges in cases that were contained by enhanced mitigation and communication combined with targeted testing. Cumulative cases totaled 445 for the term, most resulting from unsafe undergraduate student behavior and among students living off-campus. A case rate of 232/10,000 undergraduates equaled or surpassed several peer institutions that conducted mass testing. CONCLUSIONS: An emphasis on behavioral mitigation and communication can control virus transmission on a large urban campus combined with a limited and targeted testing strategy.

CD4+ T-Cell Dysfunction in Severe COVID-19 Disease Is Tumor Necrosis Factor-α/Tumor Necrosis Factor Receptor 1-Dependent.

Rationale: Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers. Objectives: We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable. Methods: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. Measurements and Main Results: In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared with patients with mild disease (P < 0.0001). In severe disease, immunodominant CD4+ T-cell responses to Spike-1 (S1) produced increased in vitro TNF-α (tumor necrosis factor-α) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4+TNF-α+ T-cell responses inversely correlated with absolute CD4+ counts from patients with severe COVID-19 (n = 76; R = -0.797; P < 0.0001). In vitro TNF-α blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4+ T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 (P < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFκB signaling in S1-stimulated CD4+ cells with infliximab treatment. We also evaluated BAL and lung explant CD4+ T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-α compared with peripheral blood mononuclear cells. Conclusions: Together, our findings show CD4+ dysfunction in severe COVID-19 is TNF-α/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-α blockade may be beneficial in severe COVID-19.

Genomic characterization of SARS-CoV-2 from vaccine breakthrough cases in Allegheny County, Pennsylvania.

We performed whole genome sequencing on SARS-CoV-2 from 59 vaccinated individuals from southwest Pennsylvania who tested positive between February and September, 2021. A comparison of mutations among vaccine breakthrough cases to a time-matched control group identified potential adaptive responses of SARS-CoV-2 to vaccination.

Predictive model for severe COVID-19 using SARS-CoV-2 whole-genome sequencing and electronic health record data, March 2020-May 2021.

OBJECTIVE: We used SARS-CoV-2 whole-genome sequencing (WGS) and electronic health record (EHR) data to investigate the associations between viral genomes and clinical characteristics and severe outcomes among hospitalized COVID-19 patients. METHODS: We conducted a case-control study of severe COVID-19 infection among patients hospitalized at a large academic referral hospital between March 2020 and May 2021. SARS-CoV-2 WGS was performed, and demographic and clinical characteristics were obtained from the EHR. Severe COVID-19 (case patients) was defined as having one or more of the following: requirement for supplemental oxygen, mechanical ventilation, or death during hospital admission. Controls were hospitalized patients diagnosed with COVID-19 who did not meet the criteria for severe infection. We constructed predictive models incorporating clinical and demographic variables as well as WGS data including lineage, clade, and SARS-CoV-2 SNP/GWAS data for severe COVID-19 using multiple logistic regression. RESULTS: Of 1,802 hospitalized SARS-CoV-2-positive patients, we performed WGS on samples collected from 590 patients, of whom 396 were case patients and 194 were controls. Age (p = 0.001), BMI (p = 0.032), test positive time period (p = 0.001), Charlson comorbidity index (p = 0.001), history of chronic heart failure (p = 0.003), atrial fibrillation (p = 0.002), or diabetes (p = 0.007) were significantly associated with case-control status. SARS-CoV-2 WGS data did not appreciably change the results of the above risk factor analysis, though infection with clade 20A was associated with a higher risk of severe disease, after adjusting for confounder variables (p = 0.024, OR = 3.25; 95%CI: 1.31-8.06). CONCLUSIONS: Among people hospitalized with COVID-19, older age, higher BMI, earlier test positive period, history of chronic heart failure, atrial fibrillation, or diabetes, and infection with clade 20A SARS-CoV-2 strains can predict severe COVID-19.

Effectiveness of Casirivimab-Imdevimab and Sotrovimab During a SARS-CoV-2 Delta Variant Surge: A Cohort Study and Randomized Comparative Effectiveness Trial.

Importance: The effectiveness of monoclonal antibodies (mAbs), casirivimab-imdevimab and sotrovimab, is unknown in patients with mild to moderate COVID-19 caused by the SARS-CoV-2 Delta variant. Objective: To evaluate the effectiveness of mAb against the Delta variant compared with no mAb treatment and to ascertain the comparative effectiveness of casirivimab-imdevimab and sotrovimab. Design, Setting, and Participants: This study comprised 2 parallel studies: (1) a propensity score-matched cohort study of mAb treatment vs no mAb treatment and (2) a randomized comparative effectiveness trial of casirivimab-imdevimab and sotrovimab. The cohort consisted of patients who received mAb treatment at the University of Pittsburgh Medical Center outpatient infusion centers and emergency departments from July 14 to September 29, 2021. Participants were patients with a positive SARS-CoV-2 test result who were eligible to receive mAbs according to emergency use authorization criteria. Exposure: For the trial, patients were randomized to either intravenous casirivimab-imdevimab or sotrovimab according to a system therapeutic interchange policy. Main Outcomes and Measures: For the cohort study, risk ratio (RR) estimates for the primary outcome of hospitalization or death by 28 days were compared between mAb treatment and no mAb treatment using propensity score-matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospitalization) within 28 days after mAb treatment, where patients who died were assigned -1 day in a bayesian cumulative logistic model adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio (OR) less than 1. Equivalence was defined as a 95% posterior probability that the OR was within a given bound. Results: A total of 3069 patients (1023 received mAb treatment: mean [SD] age, 53.2 [16.4] years; 569 women [56%]; 2046 had no mAb treatment: mean [SD] age, 52.8 [19.5] years; 1157 women [57%]) were included in the prospective cohort study, and 3558 patients (mean [SD] age, 54 [18] years; 1919 women [54%]) were included in the randomized comparative effectiveness trial. In propensity score-matched models, mAb treatment was associated with reduced risk of hospitalization or death (RR, 0.40; 95% CI, 0.28-0.57) compared with no treatment. Both casirivimab-imdevimab (RR, 0.31; 95% CI, 0.20-0.50) and sotrovimab (RR, 0.60; 95% CI, 0.37-1.00) were associated with reduced hospitalization or death compared with no mAb treatment. In the clinical trial, 2454 patients were randomized to receive casirivimab-imdevimab and 1104 patients were randomized to receive sotrovimab. The median (IQR) hospital-free days were 28 (28-28) for both mAb treatments, the 28-day mortality rate was less than 1% (n = 12) for casirivimab-imdevimab and less than 1% (n = 7) for sotrovimab, and the hospitalization rate by day 28 was 12% (n = 291) for casirivimab-imdevimab and 13% (n = 140) for sotrovimab. Compared with patients who received casirivimab-imdevimab, those who received sotrovimab had a median adjusted OR for hospital-free days of 0.88 (95% credible interval, 0.70-1.11). This OR yielded 86% probability of inferiority for sotrovimab vs casirivimab-imdevimab and 79% probability of equivalence. Conclusions and Relevance: In this propensity score-matched cohort study and randomized comparative effectiveness trial, the effectiveness of casirivimab-imdevimab and sotrovimab against the Delta variant was similar, although the prespecified criteria for statistical inferiority or equivalence were not met. Both mAb treatments were associated with a reduced risk of hospitalization or death in nonhospitalized patients with mild to moderate COVID-19 caused by the Delta variant. Trial Registration: ClinicalTrials.gov Identifier: NCT04790786.

Prospective Evaluation of Coronavirus Disease 2019 (COVID-19) Vaccine Responses Across a Broad Spectrum of Immunocompromising Conditions: the COVID-19 Vaccination in the Immunocompromised Study (COVICS).

BACKGROUND: We studied humoral responses after coronavirus disease 2019 (COVID-19) vaccination across varying causes of immunodeficiency. METHODS: Prospective study of fully vaccinated immunocompromised adults (solid organ transplant [SOT], hematologic malignancy, solid cancers, autoimmune conditions, human immunodeficiency virus [HIV]) versus nonimmunocompromised healthcare workers (HCWs). The primary outcome was the proportion with a reactive test (seropositive) for immunoglobulin G to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity. RESULTS: A total of 1271 participants enrolled: 1099 immunocompromised and 172 HCW. Compared with HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (P < .01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus messenger RNA (mRNA)-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman r = 0.89, P < .0001), but in seropositive participants with intermediate antibody levels, neutralization titers were significantly lower in immunocompromised individuals versus HCW. CONCLUSIONS: Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCWs. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency.

The comparative effectiveness of COVID-19 monoclonal antibodies: A learning health system randomized clinical trial.

BACKGROUND: Monoclonal antibodies (mAb) that neutralize SARS-CoV-2 decrease hospitalization and death compared to placebo in patients with mild to moderate COVID-19; however, comparative effectiveness is unknown. We report the comparative effectiveness of bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab. METHODS: A learning health system platform trial in a U.S. health system enrolled patients meeting mAb Emergency Use Authorization criteria. An electronic health record-embedded application linked local mAb inventory to patient encounters and provided random mAb allocation. Primary outcome was hospital-free days to day 28. Primary analysis was a Bayesian model adjusting for treatment location, age, sex, and time. Inferiority was defined as 99% posterior probability of an odds ratio < 1. Equivalence was defined as 95% posterior probability the odds ratio is within a given bound. FINDINGS: Between March 10 and June 25, 2021, 1935 patients received treatment. Median hospital-free days were 28 (IQR 28, 28) for each mAb. Mortality was 0.8% (1/128), 0.8% (7/885), and 0.7% (6/922) for bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively. Relative to casirivimab-imdevimab (n = 922), median adjusted odds ratios were 0.58 (95% credible interval [CI] 0.30-1.16) and 0.94 (95% CI 0.72-1.24) for bamlanivimab (n = 128) and bamlanivimab-etesevimab (n = 885), respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab. INTERPRETATION: Among patients with mild to moderate COVID-19, bamlanivimab-etesevimab or casirivimab-imdevimab treatment resulted in 86% probability of equivalence. No treatment met prespecified criteria for statistical equivalence. Median hospital-free days to day 28 were 28 (IQR 28, 28) for each mAb. FUNDING AND REGISTRATION: This work received no external funding. The U.S. government provided the reported mAb. This trial is registered at ClinicalTrials.gov, NCT04790786.

Performance of the Sofia SARS-CoV-2 Rapid Antigen Test in Symptomatic and Asymptomatic Pediatric Patients.

The sensitivity and specificity of SARS-CoV-2 antigen tests have not been widely assessed in children. We evaluated children presenting to outpatient care with Quidel Sofia SARS-CoV-2 antigen test (Sofia-Ag-RDT) compared against Cepheid Xpert Xpress SARS-CoV-2/Flu/RSV reverse transcriptase-polymerase chain reaction test from November 2020 to April 2021. Sofia-Ag-RDT had the highest sensitivity in symptomatic (82%; 95% confidence interval, 68%-91%) children.

Evaluation of Viral Loads in Patients With SARS-CoV-2 Delta Variant Infection: Higher Loads Do Not Translate Into Different Testing Scenarios.

The Delta SARS-CoV-2 variant is very infectious, and it is spreading quickly during this pandemic. In the study, we compared viral loads estimated by means of the Ct values emerging from RT-PCR swab tests in surging cases infected with the SARS-CoV-2 Delta variant in the fourth wave of COVID-19 with the three prior waves. The data comprised viral loads from positive cases detected within the UPMC health care system in Allegheny County, Pennsylvania. A total of 2059 upper airway samples were collected and tested for SARS-CoV-2 positive by RT-PCR during March 2020 to September 2021. We did not observe significant difference in viral load difference between the third (December 2020 to January 2021) and fourth (June 2021 to September 2021) waves; however, they had the higher viral load than the first (March 2020 to June 2020) and second waves (June 2020 to August 2020). We did find an age-related effect with the elderly presenting with lower viral loads, which was also seen in the earlier waves. However, the level of the viral loads in the fourth wave in the respect of the previous ones was not sufficiently increased to change our testing strategies by means of increased use of rapid antigen tests (RAT).

Evaluation of the ePlex Respiratory Pathogen Panel 2 to detect viral and bacterial pathogens, including SARS-CoV-2 Omicron in nasopharyngeal swabs

The simultaneous detection and specific identification of multiple pathogens from patients exhibiting respiratory symptoms is important for directing pathogen-specific treatments. The ePlex Respiratory Pathogen Panel 2 (ePlex RP2 panel) is a multiplex molecular test for the qualitative detection of many viral and bacterial pathogens including SARS-CoV-2 in respiratory tract infections. The ePlex RP2 panel received FDA emergency use authorization for nasopharyngeal swab specimens collected in viral transport media. In the evaluation using the ePlex RP2, a total of 67 nasopharyngeal swab specimens were compared to the ePlex RP panel and the CDC 2019-nCoV Real-Time RT-PCR assay as the reference methods. The overall agreement of the ePlex RP2 panel was 100%. The ePlex RP2 panel could detect Omicron BA1 and BA2. The ePlex RP2 panel is a rapid, sensitive and specific "specimen-to-answer" platform to detect simultaneously multiple viruses and bacteria in the upper respiratory tract.

Evaluation of the Cepheid Xpert Xpress SARS-CoV-2 test for bronchoalveolar lavage.

Accurate and rapid laboratory tests are essential for the prompt diagnosis of COVID-19, which is important to patients and infection control. The Xpert Xpress SARS-CoV-2 test is a real-time RT-PCR intended for the qualitative detection of nucleic acid from SARS-CoV-2 in upper respiratory specimens. In this study, we assessed the analytical performance characteristics of this rapid test for SARS-CoV-2 in 60 bronchoalveolar lavage (BAL) specimens. BAL is a specimen type that is not authorized under EUA for the Xpert Xpress SARS-CoV-2 test. The limit of detection of the Xpert Xpress SARS-CoV-2 test was 500 copies/ml. The overall agreement of the Xpert Xpress SARS-CoV-2 test was 100%. The Xpert Xpress SARS-CoV-2 test is sensitive and specific to aid in diagnosis of COVID-19 using bronchoalveolar lavage.

Launching a comparative effectiveness adaptive platform trial of monoclonal antibodies for COVID-19 in 21 days.

Outpatient treatments that limit progression to severe coronavirus disease 2019 (COVID-19) are of vital importance to optimise patient outcomes and public health. Monoclonal antibodies (mAb) demonstrated ability to decrease hospitalizations in randomized, clinical trials. However, there are many barriers to mAb treatment such as patient access and clinician education. There are no data comparing efficacy or safety of available mAbs. We sought to rapidly launch an adaptive platform trial with the goals of enhancing access to treatment, regardless of geography and socioeconomic status, and evaluating comparative efficacy and safety of available mAbs. Within 21 days from idea genesis, we allocated mAb treatment to all patients within the context of this clinical trial. Within 2 months, we closed the gap of the likelihood of receiving mAb, conditional on background positivity rate, between Black and White patients (Black patients 0.238; White patients 0.241). We describe trial infrastructure, lessons learned, and future directions for a culture of learning while doing.

Performance of SARS-CoV-2 antigen testing in symptomatic and asymptomatic adults: a single-center evaluation.

BACKGROUND: Antigen testing offers rapid and inexpensive testing for SARS-CoV-2 but concerns regarding performance, especially sensitivity, remain. Limited data exists for use of antigen testing in asymptomatic patients; thus, performance and reliability of antigen testing remains unclear. METHODS: 148 symptomatic and 144 asymptomatic adults were included. A nasal swab was collected for testing by Quidel Sofia SARS IFA (Sofia) as point of care. A nasopharyngeal swab was also collected and transported to the laboratory for testing by Cepheid Xpert Xpress SARS-CoV-2/Flu/RSV RT-PCR (Cepheid). RESULTS: Overall, Sofia had good agreement with Cepheid (> 95%) in adults, however was less sensitive. Sofia had a sensitivity of 87.8% and 33.3% for symptomatic and asymptomatic patients, respectively. Among symptomatic patients, testing > 5 days post symptom onset resulted in lower sensitivity (82%) when compared with testing within 5 days of symptom onset (90%). Of the four Sofia false-negative results in the asymptomatic cohort, 50% went on to develop COVID-19 disease within 5 days of testing. Specificity in both symptomatic and asymptomatic cohorts was 100%. CONCLUSIONS: Sofia has acceptable performance in symptomatic adults when tested < 5 days of symptom onset. Caution should be taken when testing patients with ≥ 5 days of symptoms. The combination of low prevalence and reduced sensitivity results in relatively poor performance of in asymptomatic patients. NAAT-based diagnostic assays should be considered in when antigen testing is unreliable, particularly in symptomatic patients with > 5 days of symptom onset and asymptomatic patients.