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1.
Am Soc Clin Oncol Educ Book ; 42: 1-13, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1879288

ABSTRACT

Patients with cancer generally have a higher risk of adverse outcomes from COVID-19, with higher age, male sex, poor performance status, cancer type, and uncontrolled malignant disease as the main risk factors. However, the influence of specific cancer therapies varies and raises concerns during the pandemic. In patients undergoing cancer immunotherapy or other immunosuppressive cancer treatments, we summarize the evidence on outcomes from COVID-19; address the safety, immunogenicity, and efficacy of COVID-19 vaccination; and review COVID-19 antiviral therapeutics for the patient with cancer. Despite higher mortality for patients with cancer, treatment with immune checkpoint inhibitors does not seem to increase mortality risk based on observational evidence. Inhibitory therapies directed toward B-cell lineages, including monoclonal antibodies against CD20 and CAR T-cell therapies, are associated with poor outcomes in COVID-19; however, the data are sparse. Regarding vaccination in patients receiving immune checkpoint inhibitors, clinical efficacy comparable to that in the general population can be expected. In patients undergoing B-cell-depleting therapy, immunogenicity and clinical efficacy are curtailed, but vaccination is not futile, which is thought to be due to the cellular response. Vaccine reactogenicity and toxicity in all groups of patients with cancer are comparable to that of the general population. Preexposure prophylaxis with monoclonal antibodies directed against the viral spike may provide passive immunity for those not likely to mount an adequate vaccine response. If infected, prompt treatment with monoclonal antibodies or oral small molecule antivirals is beneficial, though with oral antiviral therapies, care must be taken to avoid drug interactions in patients with cancer.


Subject(s)
COVID-19 , Neoplasms , Antibodies, Monoclonal/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immune Checkpoint Inhibitors , Immunologic Factors/therapeutic use , Immunotherapy , Neoplasms/drug therapy , SARS-CoV-2 , Vaccination
2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335191

ABSTRACT

ABSTRACT Clinical diagnoses rely on a wide variety of laboratory tests and imaging studies, interpreted alongside physical examination and documentation of symptoms and patient history. However, the tools of diagnosis make little use of the immune system’s internal record of specific disease exposures encoded by the antigen-specific receptors of memory B cells and T cells. We have combined extensive receptor sequence datasets with three different machine learning representations of the contents of immune repertoires to develop an interpretive framework, MAchine Learning for Immunological Diagnosis (Mal-ID) , that screens for multiple illnesses simultaneously. This approach can already reliably distinguish a wide range of disease states, including specific acute or chronic infections, and autoimmune or immunodeficiency disorders, and could contribute to identifying new infectious diseases as they emerge. Importantly, many features of the model of immune receptor sequences are human-interpretable. They independently recapitulate known biology of the responses to infection by SARS-CoV-2 or HIV, and reveal common features of autoreactive immune receptor repertoires, indicating that machine learning on immune repertoires can yield new immunological knowledge.

3.
Sci Rep ; 12(1): 6568, 2022 04 28.
Article in English | MEDLINE | ID: covidwho-1815592

ABSTRACT

Risk stratification for hospitalized adults with COVID-19 is essential to inform decisions about individual patients and allocation of resources. So far, risk models for severe COVID outcomes have included age but have not been optimized to best serve the needs of either older or younger adults. Models also need to be updated to reflect improvements in COVID-19 treatments. This retrospective study analyzed data from 6906 hospitalized adults with COVID-19 from a community health system across five states in the western United States. Risk models were developed to predict mechanical ventilation illness or death across one to 56 days of hospitalization, using clinical data available within the first hour after either admission with COVID-19 or a first positive SARS-CoV-2 test. For the seven-day interval, models for age ≥ 18 and < 50 years reached AUROC 0.81 (95% CI 0.71-0.91) and models for age ≥ 50 years reached AUROC 0.82 (95% CI 0.77-0.86). Models revealed differences in the statistical significance and relative predictive value of risk factors between older and younger patients including age, BMI, vital signs, and laboratory results. In addition, for hospitalized patients, sex and chronic comorbidities had lower predictive value than vital signs and laboratory results.


Subject(s)
COVID-19 , Adult , COVID-19/epidemiology , Hospitalization , Humans , Middle Aged , Retrospective Studies , Risk Factors , SARS-CoV-2 , United States
4.
Clin Infect Dis ; 2022 Feb 25.
Article in English | MEDLINE | ID: covidwho-1713630

ABSTRACT

INTRODUCTION: Most studies of solid organ transplant (SOT) recipients with COVID-19 focus on outcomes within one month of illness onset. Delayed mortality in SOT recipients hospitalized for COVID-19 has not been fully examined. METHODS: We used data from a multicenter registry to calculate mortality by 90 days following initial SARS-CoV-2 detection in SOT recipients hospitalized for COVID-19 and developed multivariable Cox proportional-hazards models to compare risk factors for death by days 28 and 90. RESULTS: Vital status at day 90 was available for 936 of 1117 (84%) SOT recipients hospitalized for COVID-19: 190 of 936 (20%) died by 28 days and an additional 56 of 246 deaths (23%) occurred between days 29 and 90. Factors associated with mortality by day 90 included: age > 65 years [aHR 1.8 (1.3-2.4), p =<0.001], lung transplant (vs. non-lung transplant) [aHR 1.5 (1.0-2.3), p=0.05], heart failure [aHR 1.9 (1.2-2.9), p=0.006], chronic lung disease [aHR 2.3 (1.5-3.6), p<0.001] and body mass index ≥ 30 kg/m 2 [aHR 1.5 (1.1-2.0), p=0.02]. These associations were similar for mortality by day 28. Compared to diagnosis during early 2020 (March 1-June 19, 2020), diagnosis during late 2020 (June 20-December 31, 2020) was associated with lower mortality by day 28 [aHR 0.7 (0.5-1.0, p=0.04] but not by day 90 [aHR 0.9 (0.7-1.3), p=0.61]. CONCLUSIONS: In SOT recipients hospitalized for COVID-19, >20% of deaths occurred between 28 and 90 days following SARS-CoV-2 diagnosis. Future investigations should consider extending follow-up duration to 90 days for more complete mortality assessment.

5.
Clin Infect Dis ; 2021 Aug 19.
Article in English | MEDLINE | ID: covidwho-1707253

ABSTRACT

BACKGROUND: The impact of remdesivir (RDV) on COVID-19 mortality is controversial, and the mortality effect in sub-groups of baseline disease severity has been incompletely explored. The purpose of this study was to assess the association of RDV with mortality in patients with COVID-19. METHODS: In this retrospective cohort study we compared persons receiving RDV to persons receiving best supportive care (BSC). Patients hospitalized between 2/28/20 - 5/28/20 with laboratory confirmed SARS-CoV-2 infection were included when they developed COVID-19 pneumonia on chest radiography, and hypoxia requiring supplemental oxygen or SpO2 ≤ 94% on room air. The primary outcome was overall survival assessed with time-dependent Cox proportional-hazards regression and multivariable adjustment, including calendar time, baseline patient characteristics, corticosteroid use and effects for hospital. RESULTS: 1,138 patients were enrolled including 286 who received RDV, and 852 treated with BSC, 400 of whom received hydroxychloroquine. Corticosteroids were used in 20.4% of the cohort (12.6% in RDV and 23% in BSC). In persons receiving RDV compared to those receiving BSC the HR (95%CI) for death was 0.46 (0.31 - 0.69) in the univariate model, p<0.001 and 0.60 (0.40 - 0.90) in the risk-adjusted model, p=0.014. In the sub-group of persons with baseline use of low-flow oxygen, the HR (95%CI) for death in RDV compared to BSC was 0.63 (0.39 - 1.00), p=0.049. CONCLUSION: Treatment with RDV was associated with lower mortality compared to BSC. These findings remain the same in the subgroup with baseline use of low-flow oxygen.

6.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-318068

ABSTRACT

We describe the establishment and current content of the ImmuneCODE™ database, which includes hundreds of millions of T-cell Receptor (TCR) sequences from over 1,400 subjects exposed to or infected with the SARS-CoV-2 virus, as well as over 135,000 high-confidence SARS-CoV-2-specific TCRs. This database is made freely available, and the data contained in it can be downloaded and analyzed online or offline to assist with the global efforts to understand the immune response to the SARS-CoV-2 virus and develop new interventions.

7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-309036

ABSTRACT

Background: The early months of the COVID-19 pandemic were fraught with much uncertainty and some resource constraint. We assessed the change in survival to hospital discharge over time for intensive care unit patients with COVID-19 during the first three months of the pandemic and the presence of any surge effects on patient outcomes.MethodsRetrospective cohort study using electronic medical record data for all patients with laboratory-confirmed COVID-19 admitted to intensive care units from February 25, 2020 to May 15, 2020 at one of 26 hospitals within an integrated delivery system in the Western United States. Patient demographics, comorbidities and severity of illness were measured along with medical therapies and hospital outcomes over time. Multivariable logistic regression models were constructed to assess temporal changes in survival to hospital discharge during the study period.ResultsOf 620 patients with COVID-19 admitted to the ICU (mean age 63.5 years (SD 15.7) and 69% male), 403 (65%) survived to hospital discharge and 217 (35%) died in the hospital. Survival to hospital discharge increased over time, from 60.0% in the first two weeks of the study period to 67.6% in the last two weeks. In a multivariable logistic regression analysis, the risk-adjusted odds of survival to hospital discharge increased over time (bi-weekly change, adjusted odds ratio [aOR] 1.22, 95%CI 1.04-1.40, P = 0.02). Additionally, an a priori -defined explanatory model showed that after adjusting for both hospital occupancy and percent hospital capacity by COVID-19 positive individuals and persons under investigation (PUI), the temporal trend in risk-adjusted patient survival to hospital discharge remained the same (bi-weekly change, aOR 1.18, 95% CI 1.00 to 1.38, P = 0.04). The presence of greater rates of COVID-19 positive/PUI as a percentage of hospital capacity was, however, significantly and inversely associated with survival to hospital discharge (aOR 0.95, 95% CI 0.92 to 0.98, P < 0.01). ConclusionsDuring the early COVID-19 pandemic, risk-adjusted survival to hospital discharge increased over time for critical care patients. An association was also seen between a greater COVID-19 positive/PUI percentage of hospital capacity and a lower survival rate to hospital discharge.

8.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327521

ABSTRACT

Background It is important to understand how BNT162b2, mRNA-1273, and JNJ-78436735 COVID-19 vaccines, as well as prior infection, protect against breakthrough cases and reinfections. Real world evidence on acquired immunity from vaccines, and from SARS-CoV-2 infection, can help public health decision-makers understand disease dynamics and viral escape to inform resource allocation for curbing the spread of pandemic. Methods This retrospective cohort study presents demographic information, survival functions, and probability distributions for 2,627,914 patients who received recommended doses of COVID-19 vaccines, and 63,691 patients who had a prior COVID-19 infection. In addition, patients receiving different vaccines were matched by age, sex, ethnic group, state of residency, and the quarter of the year in 2021 the COVID-19 vaccine was completed, to support survival analysis on pairwise matched cohorts. Findings Each of the three vaccines and infection-induced immunity all showed a high probability of survival against breakthrough or reinfection cases (mRNA-1273: 0.997, BNT162b2: 0.997, JNJ-78436735: 0.992, previous infection: 0.965 at 180 days). The incidence rate of reinfection among those unvaccinated and previously infected was higher than that of breakthrough among the vaccinated population (reinfection: 0.9%;breakthrough:0.4%). In addition, 280 vaccinated patients died (0.01% all-cause mortality) within 21 days of the last vaccine dose, and 5898 (3.1 %) died within 21 days of a positive COVID-19 test. Conclusions Despite a gradual decline in vaccine-induced and infection-induced immunity, both acquired immunities were highly effective in preventing breakthrough and reinfection. In addition, for unvaccinated patients with COVID-19, those who did not die within 90 days of their initial infection (9565 deaths, 5.0% all-cause mortality rate), had a comparable asymptotic pattern of breakthrough infection as those who acquired immunity from a vaccine. Overall, the risks associated with COVID-19 infection are far greater than the marginal advantages of immunity acquired by prior infection.

9.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327371

ABSTRACT

Background Risk stratification for hospitalized adults with COVID-19 is essential to inform decisions for individual patients and allocation of potentially scarce resources. So far, risk models for severe COVID outcomes have included age but have not been optimized to best serve the needs of either older or younger adults. Additionally, existing risk models have been limited to either small sample sizes, or modeling mortality over an entire hospital admission. Further, previous models were developed on data from early in the pandemic, before improvements in COVID-19 treatment, the SARS-CoV-2 delta variant, and vaccination. There remains a need for early, accurate identification of patients who may need invasive mechanical ventilation (IMV) or die, considering multiple time horizons. Methods This retrospective study analyzed data from 6,906 hospitalized adults with COVID-19 from a community health system with 51 hospitals and 1085 clinics across five states in the western United States. Risk models were developed to predict mechanical ventilation illness or death across one to 56 days of hospitalization, using clinical data collected available within the first hour after either admission with COVID-19 or a first positive SARS-CoV-2 test. The relative importance of predictive risk factors features for all models was determined using Shapley additive explanations. Findings The percentage of patients who required mechanical ventilation or died within seven days of admission to the hospital due to COVID-19 was 10.82%. For the seven-day interval, models for age ≥ 18 and < 50 years reached AUROC 0.80 (95% CI: 0.70-0.89) and models for age ≥ 50 years reached AUROC 0.83 (95% CI: 0.79-0.88). Models revealed differences in the statistical significance and relative predictive value of risk factors between older and younger patients, including age, BMI, vital signs, and laboratory results. In addition, sex and chronic comorbidities had lower predictive value than vital signs and laboratory results. Interpretation For hospitalized adults, baseline data that is readily available within one hour after hospital admission or a first positive inpatient SARS-CoV-2 test can predict critical illness within one day, and up to 56 days later. Further, the relative importance of risk factors differs between older and younger patients.

10.
Lancet Respir Med ; 10(4): 327-336, 2022 04.
Article in English | MEDLINE | ID: covidwho-1665591

ABSTRACT

BACKGROUND: The oral, selective Janus kinase 1/2 inhibitor baricitinib has shown efficacy in studies of hospitalised adults with COVID-19. COV-BARRIER (NCT04421027) was a multinational, phase 3, randomised, double-blind, placebo-controlled trial of baricitinib in patients with confirmed SARS-CoV-2 infection. We aimed to evaluate the efficacy and safety of baricitinib plus standard of care in critically ill hospitalised adults with COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation. METHODS: This exploratory trial followed the study design of COV-BARRIER in a critically ill cohort not included in the main phase 3 trial. The study was conducted across 18 hospitals in Argentina, Brazil, Mexico, and the USA. Participants (aged ≥18 years) hospitalised with laboratory-confirmed SARS-CoV-2 infection on baseline invasive mechanical ventilation or extracorporeal membrane oxygenation were randomly assigned (1:1) to baricitinib (4 mg) or placebo once daily for up to 14 days in combination with standard of care. Participants, study staff, and investigators were masked to study group assignment. Prespecified endpoints included all-cause mortality through days 28 and 60, number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. The efficacy analysis was done in the intention-to-treat population and the safety analysis was done in the safety population. This trial is registered with ClinicalTrials.gov, NCT04421027. FINDINGS: Between Dec 23, 2020, and April 10, 2021, 101 participants were enrolled into the exploratory trial and assigned to baricitinib (n=51) or placebo (n=50) plus standard of care. Standard of care included baseline systemic corticosteroid use in 87 (86%) participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared with placebo (20 [39%] of 51 participants died in the baricitinib group vs 29 [58%] of 50 in the placebo group; hazard ratio [HR] 0·54 [95% CI 0·31-0·96]; p=0·030; 46% relative reduction; absolute risk reduction 19%). A significant reduction in 60-day mortality was also observed in the baricitinib group compared with the placebo group (23 [45%] events vs 31 [62%]; HR 0·56 [95% CI 0·33-0·97]; p=0·027; 44% relative reduction; absolute risk reduction 17%). In every six baricitinib-treated participants, one additional death was prevented compared with placebo at days 28 and 60. The number of ventilator-free days did not differ significantly between treatment groups (mean 8·1 days [SD 10·2] in the baricitinib group vs 5·5 days [8·4] in the placebo group; p=0·21). The mean duration of hospitalisation in baricitinib-treated participants was not significantly shorter than in placebo-treated participants (23·7 days [SD 7·1] vs 26·1 days [3·9]; p=0·050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment groups. INTERPRETATION: In critically ill hospitalised patients with COVID-19 who were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, treatment with baricitinib compared with placebo (in combination with standard of care, including corticosteroids) reduced mortality, which is consistent with the mortality reduction observed in less severely ill patients in the hospitalised primary COV-BARRIER study population. However, this was an exploratory trial with a relatively small sample size; therefore, further phase 3 trials are needed to confirm these findings. FUNDING: Eli Lilly and Company.


Subject(s)
COVID-19 , Extracorporeal Membrane Oxygenation , Adolescent , Adult , Azetidines , COVID-19/drug therapy , Critical Illness , Double-Blind Method , Humans , Purines , Pyrazoles , Respiration, Artificial , SARS-CoV-2 , Standard of Care , Sulfonamides , Treatment Outcome
11.
Open forum infectious diseases ; 8(Suppl 1):S77-S77, 2021.
Article in English | EuropePMC | ID: covidwho-1602523

ABSTRACT

Background T cells are central to the early identification and clearance of viral infections and support antibody generation by B cells, making them desirable for assessing the immune response to SARS-CoV-2 infection and vaccines. We combined 2 high-throughput immune profiling methods to create a quantitative picture of the SARS-CoV-2 T-cell response that is highly sensitive, durable, diagnostic, and discriminatory between natural infection and vaccination. Methods We deeply characterized 116 convalescent COVID-19 subjects by experimentally mapping CD8 and CD4 T-cell responses via antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I and 284 class II viral peptides. We also performed T-cell receptor (TCR) repertoire sequencing on 1815 samples from 1521 PCR-confirmed SARS-CoV-2 cases and 3500 controls to identify shared public TCRs from SARS-CoV-2-associated CD8 and CD4 T cells. Combining these approaches with additional samples from vaccinated individuals, we characterized the response to natural infection as well as vaccination by separating responses to spike protein from other viral targets. Results We find that T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the SARS-CoV-2 T-cell response peaks about 1-2 weeks after infection and is detectable at least several months after recovery. Applying these data, we trained a classifier to diagnose past SARS-CoV-2 infection based solely on TCR sequencing from blood samples and observed, at 99.8% specificity, high sensitivity soon after diagnosis (Day 3–7 = 85.1%;Day 8–14 = 94.8%) that persists after recovery (Day 29+/convalescent = 95.4%). Finally, by evaluating TCRs binding epitopes targeting all non-spike SARS-CoV-2 proteins, we were able to separate natural infection from vaccination with > 99% specificity. Conclusion TCR repertoire sequencing from whole blood reliably measures the adaptive immune response to SARS-CoV-2 soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points, and distinguishes post-infection vs. vaccine immune responses with high specificity. This approach to characterizing the cellular immune response has applications in clinical diagnostics as well as vaccine development and monitoring. Disclosures Thomas M. Snyder, PhD, Adaptive Biotechnologies (Employee, Shareholder) Rachel M. Gittelman, PhD, Adaptive Biotechnologies (Employee, Shareholder) Mark Klinger, PhD, Adaptive Biotechnologies (Employee, Shareholder) Damon H. May, PhD, Adaptive Biotechnologies (Employee, Shareholder) Edward J. Osborne, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ruth Taniguchi, PhD, Adaptive Biotechnologies (Employee, Shareholder) H. Jabran Zahid, PhD, Microsoft Research (Employee, Shareholder) Rebecca Elyanow, PhD, Adaptive Biotechnologies (Employee, Shareholder) Sudeb C. Dalai, MD, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ian M. Kaplan, PhD, Adaptive Biotechnologies (Employee, Shareholder) Jennifer N. Dines, MD, Adaptive Biotechnologies (Employee, Shareholder) Matthew T. Noakes, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ravi Pandya, PhD, Microsoft Research (Employee, Shareholder) Lance Baldo, MD, Adaptive Biotechnologies (Employee, Shareholder, Leadership Interest) James R. Heath, PhD, Merck (Research Grant or Support, Funding (from BARDA) for the ISB INCOV project, but had no role in planning the research or in writing the paper.) Joaquin Martinez-Lopez, MD, PhD, Adaptive Biotechnologies (Consultant) Jonathan M. Carlson, PhD, Microsoft Research (Employee, Shareholder) Harlan S. Robins, PhD, Adaptive Biotechnologies (Board Member, Employee, Shareholder)

12.
Clin Infect Dis ; 73(12): 2193-2204, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1592626

ABSTRACT

BACKGROUND: Data on the characteristics of coronavirus disease 2019 (COVID-19) patients disaggregated by race/ethnicity remains limited. We evaluated the sociodemographic and clinical characteristics of patients across racial/ethnic groups and assessed their associations with COVID-19 outcomes. METHODS: This retrospective cohort study examined 629 953 patients tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a large health system spanning California, Oregon, and Washington between March 1 and December 31, 2020. Sociodemographic and clinical characteristics were obtained from electronic health records. Odds of SARS-CoV-2 infection, COVID-19 hospitalization, and in-hospital death were assessed with multivariate logistic regression. RESULTS: A total of 570 298 patients with known race/ethnicity were tested for SARS-CoV-2, of whom 27.8% were non-White minorities: 54 645 individuals tested positive, with minorities representing 50.1%. Hispanics represented 34.3% of infections but only 13.4% of tests. Although generally younger than White patients, Hispanics had higher rates of diabetes but fewer other comorbidities. A total of 8536 patients were hospitalized and 1246 died, of whom 56.1% and 54.4% were non-White, respectively. Racial/ethnic distributions of outcomes across the health system tracked with state-level statistics. Increased odds of testing positive and hospitalization were associated with all minority races/ethnicities. Hispanic patients also exhibited increased morbidity, and Hispanic race/ethnicity was associated with in-hospital mortality (odds ratio [OR], 1.39; 95% confidence interval [CI], 1.14-1.70). CONCLUSION: Major healthcare disparities were evident, especially among Hispanics who tested positive at a higher rate, required excess hospitalization and mechanical ventilation, and had higher odds of in-hospital mortality despite younger age. Targeted, culturally responsive interventions and equitable vaccine development and distribution are needed to address the increased risk of poorer COVID-19 outcomes among minority populations.


Subject(s)
COVID-19 , Hospital Mortality , Hospitalization , Humans , Retrospective Studies , SARS-CoV-2
14.
Open forum infectious diseases ; 8(Suppl 1):S808-S809, 2021.
Article in English | EuropePMC | ID: covidwho-1564089

ABSTRACT

Background Interventions to reduce mortality in critically ill patients with COVID-19 are a crucial unmet medical need. Baricitinib (BARI) is an oral, selective Janus kinase (JAK)1/JAK2 inhibitor with efficacy in hospitalized adults with COVID-19. Treatment with BARI 4-mg was evaluated in critically ill adult patients with COVID-19 with baseline need for invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). Methods COV-BARRIER (NCT04421027) was a randomized double-blind, placebo-controlled trial in patients with confirmed SARS-CoV-2 infection and elevation of ≥ 1 serum inflammatory marker. In this newly completed substudy, enrolled participants (not previously reported) from 4 countries on IMV or ECMO at study entry were randomly assigned 1:1 to once-daily BARI 4-mg or placebo (PBO) for up to 14 days plus standard of care (SOC), which included baseline systemic corticosteroid use in 86% of patients. The prespecified exploratory endpoints included all-cause mortality and number of ventilator-free days (VFDs) through Day 28. Results Characteristics for 101 participants are shown in Table 1. Treatment with BARI significantly reduced all-cause mortality by Day 28 compared to PBO [39.2% vs 58.0%, respectively;hazard ratio (HR) = 0.54 (95%CI 0.31, 0.96), p=0.030, relative risk (RR) = 0.68 (95%CI 0.45, 1.02);Figure 1A]. One additional death was prevented for every six BARI-treated patients. Significant reduction in mortality was also observed by Day 60 [45.1% vs 62.0%;HR = 0.56 (95%CI 0.33, 0.97), p=0.027, RR = 0.73 (95%CI 0.50, 1.06);Figure 1B]. Patients treated with BARI showed a numerical reduction in the duration of IMV and duration of hospitalization vs PBO and more BARI treated patients recovered (Table 2). No new safety findings were observed (Table 2). Conclusion Treatment with BARI+SOC (corticosteroids) resulted in an absolute risk reduction in mortality of 19% at Day 28 and 17% at Day 60 in patients with COVID-19 who were on IMV or ECMO at enrollment. These results are consistent with the reduction in mortality observed in the less severely ill hospitalized patients in the primary COV-BARRIER study population. Disclosures E. Wesley Ely, MD, CDC (Grant/Research Support)Eli Lilly (Other Financial or Material Support, Unpaid consultant)NIH (Grant/Research Support)VA (Grant/Research Support) Athimalaipet V. Ramanan, FRCP, AbbVie (Consultant, Speaker’s Bureau)Eli Lilly and Company (Consultant, Grant/Research Support, Speaker’s Bureau)Novartis (Consultant, Speaker’s Bureau)Pfizer (Consultant, Speaker’s Bureau)Roche (Consultant, Speaker’s Bureau)Sobi (Consultant, Speaker’s Bureau)UCB (Consultant, Speaker’s Bureau) Cynthia E. Kartman, RN BSN, Eli Lilly and Company (Employee, Shareholder) Stephanie de Bono, MD PhD, Eli Lilly and Company (Employee, Shareholder) Ran Liao, PhD, Eli Lilly and Company (Employee, Shareholder) Maria Lucia B Piruzeli, MD, Eli Lilly and Company (Employee, Shareholder) Sujatro Chakladar, PhD, Eli Lilly and Company (Employee, Shareholder) Vincent Marconi, MD, Bayer (Consultant, Scientific Research Study Investigator)Eli Lilly (Consultant, Scientific Research Study Investigator)Gilead Sciences (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator)

15.
Clin Infect Dis ; 73(11): e4090-e4099, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1561046

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to significant reductions in transplantation, motivated in part by concerns of disproportionately more severe disease among solid organ transplant (SOT) recipients. However, clinical features, outcomes, and predictors of mortality in SOT recipients are not well described. METHODS: We performed a multicenter cohort study of SOT recipients with laboratory-confirmed COVID-19. Data were collected using standardized intake and 28-day follow-up electronic case report forms. Multivariable logistic regression was used to identify risk factors for the primary endpoint, 28-day mortality, among hospitalized patients. RESULTS: Four hundred eighty-two SOT recipients from >50 transplant centers were included: 318 (66%) kidney or kidney/pancreas, 73 (15.1%) liver, 57 (11.8%) heart, and 30 (6.2%) lung. Median age was 58 (interquartile range [IQR] 46-57), median time post-transplant was 5 years (IQR 2-10), 61% were male, and 92% had ≥1 underlying comorbidity. Among those hospitalized (376 [78%]), 117 (31%) required mechanical ventilation, and 77 (20.5%) died by 28 days after diagnosis. Specific underlying comorbidities (age >65 [adjusted odds ratio [aOR] 3.0, 95% confidence interval [CI] 1.7-5.5, P < .001], congestive heart failure [aOR 3.2, 95% CI 1.4-7.0, P = .004], chronic lung disease [aOR 2.5, 95% CI 1.2-5.2, P = .018], obesity [aOR 1.9, 95% CI 1.0-3.4, P = .039]) and presenting findings (lymphopenia [aOR 1.9, 95% CI 1.1-3.5, P = .033], abnormal chest imaging [aOR 2.9, 95% CI 1.1-7.5, P = .027]) were independently associated with mortality. Multiple measures of immunosuppression intensity were not associated with mortality. CONCLUSIONS: Mortality among SOT recipients hospitalized for COVID-19 was 20.5%. Age and underlying comorbidities rather than immunosuppression intensity-related measures were major drivers of mortality.


Subject(s)
COVID-19 , Organ Transplantation , Cohort Studies , Humans , Male , Middle Aged , Organ Transplantation/adverse effects , SARS-CoV-2 , Transplant Recipients
16.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-295408

ABSTRACT

ABSTRACT Background The efficacy and safety of baricitinib, an oral selective Janus kinase 1/2 inhibitor, in addition to standard of care (SOC) in hospitalised adults with COVID-19 is unknown. Methods In this phase 3, global, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America ( ClinicalTrials.gov NCT04421027 ). Hospitalised adults with COVID-19 receiving SOC were randomly assigned (1:1) to once-daily baricitinib 4-mg or placebo for up to 14 days. SOC included systemic corticosteroids in 79·3% of participants (dexamethasone ∼90%). The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28. All-cause mortality by days 28 and 60 were key secondary and exploratory endpoints, respectively. Efficacy and safety analyses included the intent-to-treat and safety populations, respectively. Findings Between June 11, 2020 and January 15, 2021, 1525 participants were randomly assigned to baricitinib 4-mg (n=764) or matched placebo (n=761). Overall, 27·8% of participants receiving baricitinib vs 30·5% receiving placebo progressed (primary endpoint, odds ratio 0·85, 95% CI 0·67-1·08;p=0·18). The 28-day all-cause mortality was 8·1% (n=62) for baricitinib and 13·1% (n=100) for placebo, corresponding to a 38·2% reduction in mortality (hazard ratio [HR] 0·57, 95% CI 0·41-0·78;nominal p=0·0018). The 60-day all-cause mortality was 10·3% (n=79) for baricitinib and 15·2% (n=116) for placebo (HR 0·62, 95% CI 0·47-0·83;p=0·0050). Frequency of serious adverse events (14·7% [n=110] vs 18·0% [n=135]), serious infections (8·5% [n=64] vs 9·8% [n=74]), and venous thromboembolic events (2·7% [n=20] vs 2·5% [n=19]) was similar between baricitinib and placebo, respectively. Interpretation While reduction of disease progression did not achieve statistical significance, treatment with baricitinib in addition to SOC (including dexamethasone) significantly reduced mortality, with a similar safety profile to SOC, in hospitalised COVID-19 participants. Funding Eli Lilly and Company. Research in context Evidence before this study We searched PubMed using the terms “COVID-19”, “SARS-CoV-2”, “treatment”, “baricitinib” and “JAK inhibitor” for articles in English published up to April 31, 2020, regardless of article type. We considered previous and current clinical trials of investigational medications in COVID-19, as well as previous clinical trials of the Janus kinase (JAK)1 and JAK2 inhibitor, baricitinib, before undertaking this study. At the time the COV-BARRIER study was designed, there were no approved therapies for the treatment of COVID-19. Management of COVID-19 was supportive, and limited phase 3 randomised placebo-controlled studies had been completed. Limited phase 2 and 3 data on the antimalarial hydroxychloroquine and protease inhibitor lopinavir/ritonavir were available, and trials investigating the use of the antiviral remdesivir were ongoing. Baricitinib’s mechanism of action as a JAK1 and JAK2 inhibitor was identified as a potential intervention for the treatment of COVID-19 given its known anti-cytokine properties and potential for targeting host proteins for its antiviral mechanism. Additionally, early case series evaluating the efficacy and safety of baricitinib in the hospitalised patient population supported further evaluation of baricitinib as a potential treatment option for hospitalised patients with COVID-19. While COV-BARRIER was enrolling, ACTT-2, a phase 3 study evaluating baricitinib plus remdesivir was completed showing that baricitinib added to remdesivir improved time to recovery and other outcomes. Added value of this study This was the first phase 3 study to evaluate baricitinib in addition to the current standard of care (SOC) and included antivirals, anticoagulants, and cort costeroids. After the earliest publication of the RECOVERY study in June 2020, the treatment of hospitalised patients with COVID-19 changed with the adoption of dexamethasone as SOC. As a result of its design, COV-BARRIER became the first trial to evaluate the benefit/risk of baricitinib when added to the most current SOC (dexamethasone) in these patients. This was a randomised, double-blind, placebo-controlled trial conducted globally in regions with high COVID-19 hospitalisation rates. The reduction in the composite primary endpoint of progression to non-invasive ventilation, high flow oxygen, invasive mechanical ventilation, or death for baricitinib plus SOC (including dexamethasone) compared to placebo plus SOC did not reach statistical significance. However, in a pre-specified key secondary endpoint, treatment with baricitinib reduced 28-day all-cause mortality by 38·2% compared to placebo (HR 0·57, 95% CI 0·41-0·78;nominal p=0·0018);one additional death was prevented per 20 baricitinib-treated participants. The reduction of all-cause mortality with baricitinib was maintained by day 60 in an exploratory analysis. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between baricitinib and placebo, respectively. Implications of all the available evidence In this phase 3 trial, baricitinib given in addition to SOC (which predominantly included dexamethasone) did not reduce a composite endpoint of disease progression, but showed a strong effect on reducing mortality by 28 days, an effect which was maintained by 60 days. In the ACTT-2 study, baricitinib further reduced time to recovery above the background use of remdesivir. Taken together, these findings suggest that baricitinib has synergistic effects to other SOC treatment modalities including remdesivir and dexamethasone. Based on all available evidence, baricitinib is a potentially effective oral treatment option to decrease mortality in hospitalised patients with COVID-19.

17.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-295098

ABSTRACT

Background: Safe, effective, inexpensive treatment for COVID-19 is an urgent unmet medical need. Zinc and resveratrol have been reported to have antiviral activity and resveratrol may increase zinc activity at the site of replication by increasing intracellular zinc concentrations.<br><br>Methods: A 1:1 randomized, placebo-controlled trial of zinc 150 mg plus resveratrol 4 grams daily for 5 days versus placebos in SARS-CoV-2 positive outpatients was carried out 9/21/2020 – 1/22/2021 in Seattle, Washington. Patients were enrolled within four days of testing positive if they had no chronic liver, kidney, or lung disease and did not have hypoxia requiring supplemental oxygen. Viral shedding was followed at days 1-7,10, and 14 with patient self-collected nasal and saliva samples by measuring qRT-PCR for SARS-CoV-2 N gene. Patients filled out a web-based questionnaire on days 1-14 to report symptoms, vital signs and adherence to study intervention.<br><br>Findings: 45 persons consented to enrollment, and 30 (14 treatment;16 placebo) had ≥1 day of the protocol treatment and were evaluable for the primary or secondary outcome. There was no difference in viral shedding between groups. There was a non-statistically significant trend toward more rapid decrease in symptoms in the treatment group. Viral shedding was similar between patient self-collected mid-turbinate nasal swabs and expectorated saliva samples with good correlation, R= 0.67, p<0.001.<br><br>Interpretation: SARS-CoV-2 shedding and COVID-19 symptoms were not statistically significantly decreased by treatment in this small Phase 1/2 pilot study. Viral shedding correlates well between patient-obtained home nasal swab and saliva sampling.<br><br>Clinical Trial Registration Details: Clinical Trials.gov NCT04542993<br><br>Funding Information: This study was funded by the Kaplan Cancer Research Fund.<br><br>Declaration of Interests: JDG reports research support from Lilly, Gilead, and Regeneron;grants from the NIH, BARDA (administered by Merck) and Viracor to his institution;and speaker or consulting personal fees from Lilly, Gilead, and Mylan. All other authors report no conflicts of interest.<br><br>Ethics Approval Statement: The study was approved by the Providence St Joseph Health Care System IRB. Informed consent was obtained with electronic consent forms by the principal investigator.

18.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-294654

ABSTRACT

ABSTRACT Background The oral, selective Janus kinase (JAK)1/JAK2 inhibitor baricitinib demonstrated efficacy in hospitalised adults with COVID-19. This study evaluates the efficacy and safety of baricitinib in critically ill adults with COVID-19 requiring invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). Methods COV-BARRIER was a global, phase 3, randomised, double-blind, placebo-controlled trial in patients with confirmed SARS-CoV-2 infection ( ClinicalTrials.gov NCT04421027 ). This addendum trial added a critically ill cohort not included in the main COV-BARRIER trial. Participants on baseline IMV/ECMO were randomly assigned 1:1 to baricitinib 4-mg (n=51) or placebo (n=50) for up to 14 days in combination with standard of care (SOC). Prespecified endpoints included all-cause mortality through days 28 and 60, and number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. Efficacy and safety analyses included the intent-to-treat and safety populations, respectively. Findings SOC included baseline systemic corticosteroid use in 86% of participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared to placebo (39·2% vs 58·0%;hazard ratio [HR]=0·54 [95%CI 0·31–0·96];p=0·030). One additional death was prevented for every six baricitinib-treated participants. Significant reduction in 60-day mortality was also observed (45·1% vs 62·0%;HR=0·56 [95%CI 0·33–0·97];p=0·027). Baricitinib-treated participants showed numerically more ventilator-free days (8.1 vs 5.5 days, p=0.21) and spent over 2 days less in the hospital than placebo-treated participants (23·7 vs 26·1 days, p=0·050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment arms. Interpretation In critically ill patients with COVID-19 already receiving IMV/ECMO, treatment with baricitinib as compared to placebo (in combination with SOC, including corticosteroids) showed mortality HR of 0·56, corresponding to a 44% relative reduction at 60 days. This is consistent with the mortality reduction observed in less severely ill hospitalised primary COV-BARRIER study population. Funding Eli Lilly and Company. Research in context Evidence before this study We evaluated current and prior studies assessing the efficacy and safety of interventions in patients requiring invasive mechanical ventilation (IMV) and searched current PubMed using the terms “COVID-19”, “SARS-CoV-2”, “treatment”, “critical illness”, “invasive mechanical ventilation”, “baricitinib”, and “JAK inhibitor” for articles in English, published until December 1, 2020, regardless of article type. We also reviewed the NIH and IDSA COVID-19 guidelines and reviewed similar terms on clinicaltrials.gov. When the critical illness addendum study to COV-BARRIER study was designed, there was only one open-label study of dexamethasone showing mortality benefit in hospitalised patients with COVID-19 requiring IMV. Small studies of interleukin-6 inhibitors had shown no effect and larger trials were underway. Guidelines recommended use of dexamethasone with or without remdesivir and recommended against the use of interleukin-6 inhibitors, except in a clinical trial. Overall, there were no reported double-blind, placebo-controlled phase 3 trials which included corticosteroids as part of SOC investigating the efficacy and safety of novel treatments in the NIAID-OS 7 population. Baricitinib’s mechanism of action as a JAK1 and JAK2 inhibitor was identified as a potential intervention for the treatment of COVID-19 given its known anti-cytokine properties and potential antiviral mechanism for targeting host proteins mediating viral endocytosis Data from the NIAID sponsored ACTT-2 trial showed that baricitinib when added to remdesivir improved time to recovery and other outcomes including mortality compared to placebo plus remdesivir. A numerically larg r proportion of participants who received baricitinib plus remdesivir showed an improvement in ordinal scale compared to those who received placebo plus remdesivir at day 15 in participants requiring IMV (NIAID-OS score of 7) at baseline. We designed COV-BARRIER, a phase 3, global, double-blind, randomised, placebo-controlled trial, to evaluate the efficacy and safety of baricitinib in combination with SOC (including corticosteroids) for the treatment of hospitalised adults with COVID-19 who did not require mechanical ventilation (i.e., NIAID-OS 4-6). A significant reduction in mortality was found after 28 days between baricitinib and placebo (HR 0·57, corresponding to a 43% relative reduction, p=0·0018);one additional death was prevented per 20 baricitinib-treated participants. In the more severely ill NIAID-OS 6 subgroup, one additional death was prevented per nine baricitinib-treated participants (HR 0·52, corresponding to a 48% relative reduction, p=0·0065). We therefore implemented an addendum to the COV-BARRIER trial to evaluate the benefit/risk of baricitinib in the critically ill NIAID-OS 7 population and considered the sample size of 100 participants sufficient for this trial. Added value of this study This was the first phase 3 study to evaluate baricitinib in addition to the current standard of care (SOC), including antivirals, anticoagulants, and corticosteroids, in patients who were receiving IMV or extracorporeal membrane oxygenation at enrolment. This was a multinational, randomised, double-blind, placebo-controlled trial in regions with high COVID-19 hospitalisation rates. Treatment with baricitinib reduced 28-day all-cause mortality compared to placebo (HR 0·54, 95% CI 0·31–0·96;nominal p=0·030), corresponding to a 46% relative reduction, and significantly reduced 60-day all-cause mortality (HR 0·56, 95% CI 0·33–0·97;p=0·027);overall, one additional death was prevented per six baricitinib-treated participants. Numerical improvements in endpoints such as number of ventilator-free days, duration of hospitalisation, and time to recovery were demonstrated. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between baricitinib and placebo, respectively. The COV-BARRIER study overall trial results plus these COV-BARRIER addendum study data in mechanically ventilated and ECMO patients provide important information in context of other large, phase 3 randomised trials in participants with invasive mechanical ventilation at baseline. The RECOVERY study reported mortality of 29·3% following treatment with dexamethasone compared to 41·4% for usual care (rate ratio of 0·64, corresponding to a 36% relative reduction) and 49% mortality in participants who received tocilizumab compared to 51% for usual care (rate ratio of 0.93, corresponding to a 7% relative reduction). The ACTT-2 study reported 28-day mortality of 23·1% and 22·6% in the baricitinib plus remdesivir and placebo plus remdesivir groups, respectively, in this critically ill patient population;however, the primary outcome of this trial was time to recovery, so was not powered to detect a change in mortality. Implications of all the available evidence In this phase 3 addendum trial, baricitinib given in addition to SOC (which predominantly included corticosteroids) had a significant effect on mortality reduction by 28 days in critically ill patients, an effect which was maintained by 60 days. These data were comparable with those seen in the COV-BARRIER primary study population of hospitalised patients, but which excluded patients who required IMV or extracorporeal membrane oxygenation at enrolment. These findings suggest that baricitinib has synergistic effects to other SOC treatment modalities including remdesivir and dexamethasone. Based on the available evidence, baricitinib is a novel treatment option to decrease mortality in hospitalised, critically ill patients with COVID-19 even when started late in the disease process after steroids, mechanical ventilat on, and ECMO have already been implemented.

19.
Lancet Respir Med ; 9(12): 1407-1418, 2021 12.
Article in English | MEDLINE | ID: covidwho-1545515

ABSTRACT

BACKGROUND: Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. METHODS: In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT04421027. FINDINGS: Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of -2·7 percentage points (95% CI -7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41-0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47-0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. INTERPRETATION: Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19. FUNDING: Eli Lilly and Company. TRANSLATIONS: For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.


Subject(s)
Azetidines/therapeutic use , COVID-19 , Purines/therapeutic use , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Adenosine Monophosphate/analogs & derivatives , Adrenal Cortex Hormones , Adult , Alanine/analogs & derivatives , Antiviral Agents , Asia , COVID-19/drug therapy , Dexamethasone , Double-Blind Method , Europe , Humans , North America , SARS-CoV-2 , South America , Treatment Outcome
20.
[Unspecified Source]; 2020.
Preprint in English | [Unspecified Source] | ID: ppcovidwho-292804

ABSTRACT

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,015 samples (from 827 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 83.8% [95% CI = 77.6-89.4];Day 8-14 = 92.4% [87.6-96.6]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 96.7% [93.0-99.2]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in vaccine development as well as clinical diagnostics and monitoring.

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