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1.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-321928

ABSTRACT

Large Phase 3 clinical trials of the two FDA-approved COVID-19 vaccines, mRNA-1273 (Moderna) and BNT162b2 (Pfizer/BioNTech), have demonstrated efficacies of 94.1% (n = 30,420, 95% CI: 89.3-96.8) and 95% (n = 43,448, 95% CI: 90.3-97.6) in preventing symptomatic COVID-19, respectively. Given the ongoing vaccine rollout to healthcare personnel and residents of long-term care facilities, here we provide a preliminary assessment of real-world vaccination efficacy in 62,598 individuals from the Mayo Clinic and associated health system (Arizona, Florida, Minnesota, Wisconsin) between December 1st 2020 and February 8th 2021. Our retrospective analysis contrasts 31,299 individuals receiving at least one dose of either vaccine with 31,299 unvaccinated individuals who are propensity-matched based on demographics, location (zip code), and number of prior SARS-CoV-2 PCR tests. Administration of two COVID-19 vaccine doses was 89.0% effective in preventing SARS-CoV-2 infection (95% CI: 69.1-97.2%) with onset at least 36 days after the first dose. Furthermore, vaccinated patients who were subsequently diagnosed with COVID-19 had significantly lower 14-day hospital admission rates than propensity-matched unvaccinated COVID-19 patients (3.7% vs. 9.2%;Relative Risk: 0.4;p-value: 0.007). Building upon the previous randomized trials of these vaccines, this study demonstrates their real-world effectiveness in reducing the rates of SARS-CoV-2 infection and COVID-19 severity among individuals at highest risk for infection.

2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-319897

ABSTRACT

Background: Real-world clinical data to support the use of casirivimab-imdevimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) is needed. This study aimed to assess the outcomes of casirivimab-imdevimab treatment of mild to moderate COVID-19.Methods: A retrospective cohort of 696 patients who received casirivimab-imdevimab between December 4, 2020 and April 9, 2021 was compared to a propensity-matched control of 696 untreated patients with mild to moderate COVID-19 at Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin. Primary outcome was rate of hospitalization at days 14, 21 and 28 after infusion.Findings: The median age of the antibody-treated cohort was 63 years (interquartile range, 52-71);45·5% were ≥65 years old;51·4% were female. High-risk characteristics were hypertension (52·4%), body mass index ≥35 (31·0%), diabetes mellitus (24·6%), chronic lung disease (22·1%), chronic renal disease (11·4%), congestive heart failure (6·6%), and compromised immune function (6·7%). Compared to the propensity-matched untreated control, patients who received casirivimab-imdevimab had significantly lower all-cause hospitalization rates at day 14 (1·2% vs 3·4%;Odds Ratio [OR], 0·26;95% confidence interval (CI): 0·11-0·64), day 21 (1·2% vs 4·2%;OR, 0·22;95% CI: 0·09-0·52), and day 28 (1·3% vs 4·9%;OR, 0·21;95% CI: 0·09-0·48). Rates of intensive care unit admission and mortality at days 14, 21 and 28 were similarly low for antibody-treated and untreated groups.Interpretation:Among high-risk patients with mild to moderate COVID-19, casirivimab-imdevimab treatment was associated with a significantly lower rate of hospitalization.Funding Information: This work was funded by an intramural grant from Mayo Clinic to RRR.Declaration of Interests: CP, AP, AV, and PL are employees of nference and have financial interests in the company. JCO is supported by grants from nference, and is a paid consultant for Elsevier, Inc. and Bates College. ADB is supported by grants from NIAID (grants AI110173 and AI120698) Amfar (#109593) and Mayo Clinic (HH Shieck Khalifa Bib Zayed Al-Nahyan Named Professorship of Infectious Diseases). ADB is a paid consultant for Abbvie and Flambeau Diagnostics, is a paid member of the DSMB for Corvus Pharmaceuticals and Equilium, owns equity for scientific advisory work in Zentalis and Nference, and is founder and President of Splissen therapeutics. RRR is supported by research grants from Regeneron, Roche, Gilead and the Mayo Clinic, and is a member of DSMB for Novartis. All other have nothing to disclose. Ethics Approval Statement: The Mayo Clinic Institutional Review Board approved this study. Informed consent was waived and patients without research authorization were excluded.

3.
Med (N Y) ; 3(1): 28-41.e8, 2022 Jan 14.
Article in English | MEDLINE | ID: covidwho-1559964

ABSTRACT

Background: mRNA coronavirus disease 2019 (COVID-19) vaccines are safe and effective, but increasing reports of breakthrough infections highlight the need to vigilantly monitor and compare the effectiveness of these vaccines. Methods: We retrospectively compared protection against symptomatic infection conferred by mRNA-1273 and BNT162b2 at Mayo Clinic sites from December 2020 to September 2021. We used a test-negative case-control design to estimate vaccine effectiveness (VE) and to compare the odds of symptomatic infection after full vaccination with mRNA-1273 versus BNT162b2, while adjusting for age, sex, race, ethnicity, geography, comorbidities, and calendar time of vaccination and testing. Findings: Both vaccines were highly effective over the study duration (VEmRNA-1273: 84.1%, 95% confidence interval [CI]: 81.6%-86.2%; VEBNT162b2: 75.6%, 95% CI: 72.2%-78.7%), but their effectiveness was reduced during July-September (VEmRNA-1273: 75.6%, 95% CI: 70.1%-80%; VEBNT162b2: 63.5%, 95% CI: 55.8%-69.9%) as compared to December-May (VEmRNA-1273: 93.7%, 95% CI: 90.4%-95.9%; VEBNT162b2: 85.7%, 95% CI: 81.4%-88.9%). Adjusted for demographic characteristics, clinical comorbidities, time of vaccination, and time of testing, the odds of experiencing a symptomatic breakthrough infection were lower after full vaccination with mRNA-1273 than with BNT162b2 (odds ratio: 0.60; 95% CI: 0.55-0.67). Conclusions: Both mRNA-1273 and BNT162b2 strongly protect against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It is imperative to continue monitoring and comparing available vaccines over time and with respect to emerging variants to inform public and global health decisions. Funding: This study was funded by nference.

4.
J Clin Invest ; 131(19)2021 10 01.
Article in English | MEDLINE | ID: covidwho-1448085

ABSTRACT

BACKGROUNDClinical data to support the use of bamlanivimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) are needed.METHODS2335 Patients who received single-dose bamlanivimab infusion between November 12, 2020, and February 17, 2021, were compared with a propensity-matched control of 2335 untreated patients with mild to moderate COVID-19 at Mayo Clinic facilities across 4 states. The primary outcome was the rate of hospitalization at days 14, 21, and 28.RESULTSThe median age of the population was 63 years; 47.3% of the bamlanivimab-treated cohort were 65 years or more; 49.3% were female and 50.7% were male. High-risk characteristics included hypertension (54.2%), BMI greater than or equal to 35 (32.4%), diabetes mellitus (26.5%), chronic lung disease (25.1%), malignancy (16.6%), and renal disease (14.5%). Patients who received bamlanivimab had lower all-cause hospitalization rates at days 14 (1.5% vs. 3.5%; risk ratio [RR], 0.41), 21 (1.9% vs. 3.9%; RR, 0.49), and 28 (2.5% vs. 3.9%; RR, 0.63). Secondary exploratory outcomes included lower intensive care unit (ICU) admission rates at days 14 (0.14% vs. 1%; RR, 0.14), 21 (0.25% vs.1%; RR, 0.25), and 28 (0.56% vs.1.1%; RR. 0.51) and lower all-cause mortality at days 14 (0% vs. 0.33%), 21 (0.05% vs. 0.4%; RR,0.13), and 28 (0.11% vs. 0.44%; RR, 0.26). Adverse events were uncommon with bamlanivimab, occurring in 19 of 2355 patients, and were most commonly fever (n = 6), nausea (n = 5), and lightheadedness (n = 3).CONCLUSIONSAmong high-risk patients with mild to moderate COVID-19, treatment with bamlanivimab was associated with a statistically significant lower rate of hospitalization, ICU admission, and mortality compared with usual care.FUNDINGMayo Clinic.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19 , Hospitalization , SARS-CoV-2/metabolism , Administration, Intravenous , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/mortality , Disease-Free Survival , Female , Humans , Intensive Care Units , Male , Middle Aged , Risk Factors , Survival Rate
5.
EClinicalMedicine ; 40: 101102, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1377701

ABSTRACT

BACKGROUND: Real-world clinical data to support the use of casirivimab-imdevimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) is needed. This study aimed to assess the outcomes of casirivimab-imdevimab treatment of mild to moderate COVID-19. METHODS: A retrospective cohort of 696 patients who received casirivimab-imdevimab between December 4, 2020 and April 9, 2021 was compared to a propensity-matched control of 696 untreated patients with mild to moderate COVID-19 at Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin. Primary outcome was rate of hospitalization at days 14, 21 and 28 after infusion. FINDINGS: The median age of the antibody-treated cohort was 63 years (interquartile range, 52-71); 45·5% were ≥65 years old; 51.4% were female. High-risk characteristics were hypertension (52.4%), body mass index ≥35 (31.0%), diabetes mellitus (24.6%), chronic lung disease (22.1%), chronic renal disease (11.4%), congestive heart failure (6.6%), and compromised immune function (6.7%). Compared to the propensity-matched untreated control, patients who received casirivimab-imdevimab had significantly lower all-cause hospitalization rates at day 14 (1.3% vs 3.3%; Absolute Difference: 2.0%; 95% confidence interval (CI): 0.5-3.7%), day 21 (1.3% vs 4.2%; Absolute Difference: 2.9%; 95% CI: 1.2-4.7%), and day 28 (1.6% vs 4.8%; Absolute Difference: 3.2%; 95% CI: 1.4-5.1%). Rates of intensive care unit admission and mortality at days 14, 21 and 28 were similarly low for antibody-treated and untreated groups. INTERPRETATION: Among high-risk patients with mild to moderate COVID-19, casirivimab-imdevimab treatment was associated with a significantly lower rate of hospitalization. FUNDING: Mayo Clinic.

6.
NPJ Digit Med ; 4(1): 117, 2021 Jul 27.
Article in English | MEDLINE | ID: covidwho-1328860

ABSTRACT

Understanding the relationships between pre-existing conditions and complications of COVID-19 infection is critical to identifying which patients will develop severe disease. Here, we leverage ~1.1 million clinical notes from 1803 hospitalized COVID-19 patients and deep neural network models to characterize associations between 21 pre-existing conditions and the development of 20 complications (e.g. respiratory, cardiovascular, renal, and hematologic) of COVID-19 infection throughout the course of infection (i.e. 0-30 days, 31-60 days, and 61-90 days). Pleural effusion was the most frequent complication of early COVID-19 infection (89/1803 patients, 4.9%) followed by cardiac arrhythmia (45/1803 patients, 2.5%). Notably, hypertension was the most significant risk factor associated with 10 different complications including acute respiratory distress syndrome, cardiac arrhythmia, and anemia. The onset of new complications after 30 days is rare and most commonly involves pleural effusion (31-60 days: 11 patients, 61-90 days: 9 patients). Lastly, comparing the rates of complications with a propensity-matched COVID-negative hospitalized population confirmed the importance of hypertension as a risk factor for early-onset complications. Overall, the associations between pre-COVID conditions and COVID-associated complications presented here may form the basis for the development of risk assessment scores to guide clinical care pathways.

7.
Med (N Y) ; 2(8): 965-978.e5, 2021 08 13.
Article in English | MEDLINE | ID: covidwho-1294062

ABSTRACT

BACKGROUND: As the coronavirus disease 2019 (COVID-19) vaccination campaign unfolds, it is important to continuously assess the real-world safety of Food and Drug Administration (FDA)-authorized vaccines. Curation of large-scale electronic health records (EHRs) enables near-real-time safety evaluations that were not previously possible. METHODS: In this retrospective study, we deployed deep neural networks over a large EHR system to automatically curate the adverse effects mentioned by physicians in over 1.2 million clinical notes between December 1, 2020 and April 20, 2021. We compared notes from 68,266 individuals who received at least one dose of BNT162b2 (n = 51,795) or mRNA-1273 (n = 16,471) to notes from 68,266 unvaccinated individuals who were matched by demographic, geographic, and clinical features. FINDINGS: Individuals vaccinated with BNT162b2 or mRNA-1273 had a higher rate of return to the clinic, but not the emergency department, after both doses compared to unvaccinated controls. The most frequently documented adverse effects within 7 days of each vaccine dose included myalgia, headache, and fatigue, but the rates of EHR documentation for each side effect were remarkably low compared to those derived from active solicitation during clinical trials. Severe events, including anaphylaxis, facial paralysis, and cerebral venous sinus thrombosis, were rare and occurred at similar frequencies in vaccinated and unvaccinated individuals. CONCLUSIONS: This analysis of vaccine-related adverse effects from over 1.2 million EHR notes of more than 130,000 individuals reaffirms the safety and tolerability of the FDA-authorized mRNA COVID-19 vaccines in practice. FUNDING: This study was funded by nference.


Subject(s)
COVID-19 , Drug-Related Side Effects and Adverse Reactions , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Mass Vaccination , RNA, Messenger , Retrospective Studies , SARS-CoV-2 , United States , United States Food and Drug Administration
8.
Med (N Y) ; 2(8): 979-992.e8, 2021 08 13.
Article in English | MEDLINE | ID: covidwho-1284376

ABSTRACT

BACKGROUND: Two US Food and Drug Administration (FDA)-authorized coronavirus disease 2019 (COVID-19) mRNA vaccines, BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna), have demonstrated high efficacy in large phase 3 randomized clinical trials. It is important to assess their effectiveness in a real-world setting. METHODS: This is a retrospective analysis of 136,532 individuals in the Mayo Clinic health system (Arizona, Florida, Iowa, Minnesota, and Wisconsin) with PCR testing data between December 1, 2020 and April 20, 2021. We compared clinical outcomes for a vaccinated cohort of 68,266 individuals who received at least one dose of either vaccine (nBNT162b2 = 51,795; nmRNA-1273 = 16,471) and an unvaccinated control cohort of 68,266 individuals propensity matched based on relevant demographic, clinical, and geographic features. We estimated real-world vaccine effectiveness by comparing incidence rates of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR testing and COVID-19-associated hospitalization and intensive care unit (ICU) admission starting 7 days after the second vaccine dose. FINDINGS: The real-world vaccine effectiveness of preventing SARS-CoV-2 infection was 86.1% (95% confidence interval [CI]: 82.4%-89.1%) for BNT162b2 and 93.3% (95% CI: 85.7%-97.4%) for mRNA-1273. BNT162b2 and mRNA-1273 were 88.8% (95% CI: 75.5%-95.7%) and 86.0% (95% CI: 71.6%-93.9%) effective in preventing COVID-19-associated hospitalization. Both vaccines were 100% effective (95% CIBNT162b2: 51.4%-100%; 95% CImRNA-1273: 43.3%-100%) in preventing COVID-19-associated ICU admission. CONCLUSIONS: BNT162b2 and mRNA-1273 are effective in a real-world setting and are associated with reduced rates of SARS-CoV-2 infection and decreased burden of COVID-19 on the healthcare system. FUNDING: This study was funded by nference.


Subject(s)
COVID-19 Vaccines , COVID-19 , COVID-19/epidemiology , Humans , RNA, Messenger/genetics , Retrospective Studies , SARS-CoV-2/genetics , United States/epidemiology , United States Food and Drug Administration
10.
EClinicalMedicine ; 34: 100793, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1144586

ABSTRACT

BACKGROUND: Consecutive negative SARS-CoV-2 PCR test results are being considered to estimate viral clearance in COVID-19 patients. However, there are anecdotal reports of hospitalization from protracted COVID-19 complications despite such confirmed viral clearance, presenting a clinical conundrum. METHODS: We conducted a retrospective analysis of 222 hospitalized COVID-19 patients to compare those that were readmitted post-viral clearance (hospitalized post-clearance cohort, n = 49) with those that were not re-admitted post-viral clearance (non-hospitalized post-clearance cohort, n = 173) between February and October 2020. In order to differentiate these two cohorts, we used neural network models for the 'augmented curation' of comorbidities and complications with positive sentiment in the Electronic Hosptial Records physician notes. FINDINGS: In the year preceding COVID-19 onset, anemia (n = 13 [26.5%], p-value: 0.007), cardiac arrhythmias (n = 14 [28.6%], p-value: 0.015), and acute kidney injury (n = 7 [14.3%], p-value: 0.030) were significantly enriched in the physician notes of the hospitalized post-clearance cohort. INTERPRETATION: Overall, this retrospective study highlights specific pre-existing conditions that are associated with higher hospitalization rates in COVID-19 patients despite viral clearance and motivates follow-up prospective research into the associated risk factors. FUNDING: This work was supported by Nference, inc.

11.
Cell Death Discov ; 7(1): 55, 2021 Mar 15.
Article in English | MEDLINE | ID: covidwho-1135657

ABSTRACT

Intensive care unit (ICU) admissions and mortality in severe COVID-19 patients are driven by "cytokine storms" and acute respiratory distress syndrome (ARDS). Interim clinical trial results suggest that the corticosteroid dexamethasone displays better 28-day survival in severe COVID-19 patients requiring ventilation or oxygen. In this study, 10 out of 16 patients (62.5%) that had an average plasma IL-6 value over 10 pg/mL post administration of corticosteroids also had worse outcomes (i.e., ICU stay >15 days or death), compared to 8 out of 41 patients (19.5%) who did not receive corticosteroids (p-value = 0.0024). Given this potential association between post-corticosteroid IL-6 levels and COVID-19 severity, we hypothesized that the glucocorticoid receptor (GR or NR3C1) may be coupled to IL-6 expression in specific cell types that govern cytokine release syndrome (CRS). Examining single-cell RNA-seq data from BALF of severe COVID-19 patients and nearly 2 million cells from a pan-tissue scan shows that alveolar macrophages, smooth muscle cells, and endothelial cells co-express NR3C1 and IL-6, motivating future studies on the links between the regulation of NR3C1 function and IL-6 levels.

12.
EClinicalMedicine ; 33: 100774, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1120898

ABSTRACT

BACKGROUND: Coagulopathies are a major class among COVID-19 associated complications. Although anticoagulants such as unfractionated Heparin and Enoxaparin are both being used for therapeutic mitigation of COVID associated coagulopathy (CAC), differences in their clinical outcomes remain to be investigated. METHODS: We analyzed records of 1,113 patients in the Mayo Clinic Electronic Health Record (EHR) database who were admitted to the hospital for COVID-19 between April 4, 2020 and August 31, 2020, including 19 different Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin. Among this patient population, we compared cohorts of patients who received different types of anticoagulants, including 441 patients who received unfractionated Heparin and 166 patients who received Enoxaparin. Clinical outcomes at 28 days were compared, and propensity score matching was used to control for potential confounding variables including: demographics, comorbidities, ICU status, chronic kidney disease stage, and oxygenation status. Patients with a history of acute kidney injury and patients who received multiple types of anticoagulants were excluded from the study. FINDINGS: We find that COVID-19 patients administered unfractionated Heparin but not Enoxaparin have higher rates of 28-day mortality (risk ratio: 4.3; 95% Confidence Interval [C.I.].: [1.8, 10.2]; p-value: 8.5e-4, Benjamini Hochberg [BH] adjusted p-value: 2.1e-3), after controlling for potential confounding factors. INTERPRETATION: This study emphasizes the need for mechanistically investigating differential modulation of the COVID-associated coagulation cascades by Enoxaparin versus unfractionated Heparin. FUNDING: This work was supported by Nference, inc.

13.
J Med Virol ; 93(7): 4303-4318, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1118166

ABSTRACT

Here we analyze hospitalized andintensive care unit coronavirus disease 2019 (COVID-19) patient outcomes from the international VIRUS registry (https://clinicaltrials.gov/ct2/show/NCT04323787). We find that COVID-19 patients administered unfractionated heparin but not enoxaparin have a higher mortality-rate (390 of 1012 = 39%) compared to patients administered enoxaparin but not unfractionated heparin (270 of 1939 = 14%), presenting a risk ratio of 2.79 (95% confidence interval [CI]: [2.42, 3.16]; p = 4.45e-52). This difference persists even after balancing on a number of covariates including demographics, comorbidities, admission diagnoses, and method of oxygenation, with an increased mortality rate on discharge from the hospital of 37% (268 of 733) for unfractionated heparin versus 22% (154 of 711) for enoxaparin, presenting a risk ratio of 1.69 (95% CI: [1.42, 2.00]; p = 1.5e-8). In these balanced cohorts, a number of complications occurred at an elevated rate for patients administered unfractionated heparin compared to patients administered enoxaparin, including acute kidney injury, acute cardiac injury, septic shock, and anemia. Furthermore, a higher percentage of Black/African American COVID patients (414 of 1294 [32%]) were noted to receive unfractionated heparin compared to White/Caucasian COVID patients (671 of 2644 [25%]), risk ratio 1.26 (95% CI: [1.14, 1.40]; p = 7.5e-5). After balancing upon available clinical covariates, this difference in anticoagulant use remained statistically significant (311 of 1047 [30%] for Black/African American vs. 263 of 1047 [25%] for White/Caucasian, p = .02, risk ratio 1.18; 95% CI: [1.03, 1.36]). While retrospective studies cannot suggest any causality, these findings motivate the need for follow-up prospective research into the observed racial disparity in anticoagulant use and outcomes for severe COVID-19 patients.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/mortality , Enoxaparin/therapeutic use , Healthcare Disparities , Heparin/therapeutic use , Thrombosis/prevention & control , Anticoagulants/adverse effects , Blood Coagulation/drug effects , COVID-19/blood , COVID-19/drug therapy , Enoxaparin/adverse effects , Female , Heparin/adverse effects , Hospitalization , Humans , Male , Middle Aged , Retrospective Studies , SARS-CoV-2 , Thrombosis/drug therapy
14.
Sci Rep ; 11(1): 4741, 2021 02 26.
Article in English | MEDLINE | ID: covidwho-1104539

ABSTRACT

Clinical studies are ongoing to assess whether existing vaccines may afford protection against SARS-CoV-2 infection through trained immunity. In this exploratory study, we analyze immunization records from 137,037 individuals who received SARS-CoV-2 PCR tests. We find that polio, Haemophilus influenzae type-B (HIB), measles-mumps-rubella (MMR), Varicella, pneumococcal conjugate (PCV13), Geriatric Flu, and hepatitis A/hepatitis B (HepA-HepB) vaccines administered in the past 1, 2, and 5 years are associated with decreased SARS-CoV-2 infection rates, even after adjusting for geographic SARS-CoV-2 incidence and testing rates, demographics, comorbidities, and number of other vaccinations. Furthermore, age, race/ethnicity, and blood group stratified analyses reveal significantly lower SARS-CoV-2 rate among black individuals who have taken the PCV13 vaccine, with relative risk of 0.45 at the 5 year time horizon (n: 653, 95% CI (0.32, 0.64), p-value: 6.9e-05). Overall, this study identifies existing approved vaccines which can be promising candidates for pre-clinical research and Randomized Clinical Trials towards combating COVID-19.


Subject(s)
COVID-19/prevention & control , Adolescent , Adult , Aged , COVID-19/epidemiology , Child , Child, Preschool , Female , Haemophilus Vaccines/therapeutic use , Humans , Immunization , Infant , Influenza Vaccines/therapeutic use , Male , Measles-Mumps-Rubella Vaccine/therapeutic use , Middle Aged , Pneumococcal Vaccines/therapeutic use , Poliovirus Vaccines/therapeutic use , Protective Factors , SARS-CoV-2/isolation & purification , Vaccines, Conjugate/therapeutic use , Viral Hepatitis Vaccines/therapeutic use , Young Adult
15.
Cell Death Discov ; 6(1): 138, 2020 Dec 02.
Article in English | MEDLINE | ID: covidwho-962237

ABSTRACT

Longitudinal characterization of SARS-CoV-2 PCR testing from COVID-19 patient's nasopharynx and its juxtaposition with blood-based IgG-seroconversion diagnostic assays is critical to understanding SARS-CoV-2 infection durations. Here, we retrospectively analyze 851 SARS-CoV-2-positive patients with at least two positive PCR tests and find that 99 of these patients remain SARS-CoV-2-positive after 4 weeks from their initial diagnosis date. For the 851-patient cohort, the mean lower bound of viral RNA shedding was 17.3 days (SD: 7.8), and the mean upper bound of viral RNA shedding from 668 patients transitioning to confirmed PCR-negative status was 22.7 days (SD: 11.8). Among 104 patients with an IgG test result, 90 patients were seropositive to date, with mean upper bound of time to seropositivity from initial diagnosis being 37.8 days (95% CI: 34.3-41.3). Our findings from juxtaposing IgG and PCR tests thus reveal that some SARS-CoV-2-positive patients are non-hospitalized and seropositive, yet actively shed viral RNA (14 of 90 patients). This study emphasizes the need for monitoring viral loads and neutralizing antibody titers in long-term non-hospitalized shedders as a means of characterizing the SARS-CoV-2 infection lifecycle.

16.
Elife ; 92020 08 17.
Article in English | MEDLINE | ID: covidwho-721626

ABSTRACT

Temporal inference from laboratory testing results and triangulation with clinical outcomes extracted from unstructured electronic health record (EHR) provider notes is integral to advancing precision medicine. Here, we studied 246 SARS-CoV-2 PCR-positive (COVIDpos) patients and propensity-matched 2460 SARS-CoV-2 PCR-negative (COVIDneg) patients subjected to around 700,000 lab tests cumulatively across 194 assays. Compared to COVIDneg patients at the time of diagnostic testing, COVIDpos patients tended to have higher plasma fibrinogen levels and lower platelet counts. However, as the infection evolves, COVIDpos patients distinctively show declining fibrinogen, increasing platelet counts, and lower white blood cell counts. Augmented curation of EHRs suggests that only a minority of COVIDpos patients develop thromboembolism, and rarely, disseminated intravascular coagulopathy (DIC), with patients generally not displaying platelet reductions typical of consumptive coagulopathies. These temporal trends provide fine-grained resolution into COVID-19 associated coagulopathy (CAC) and set the stage for personalizing thromboprophylaxis.


Subject(s)
Betacoronavirus/isolation & purification , Blood Coagulation Disorders/diagnosis , Blood Coagulation Tests , Blood Coagulation , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Aged , Betacoronavirus/pathogenicity , Biomarkers/blood , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/virology , COVID-19 , COVID-19 Testing , Coronavirus Infections/blood , Coronavirus Infections/virology , Disease Progression , Female , Fibrinogen/metabolism , Host Microbial Interactions , Humans , Leukocyte Count , Longitudinal Studies , Male , Middle Aged , Pandemics , Platelet Count , Pneumonia, Viral/blood , Pneumonia, Viral/virology , Predictive Value of Tests , Reproducibility of Results , Retrospective Studies , SARS-CoV-2 , Time Factors
17.
Elife ; 92020 07 07.
Article in English | MEDLINE | ID: covidwho-635065

ABSTRACT

Understanding temporal dynamics of COVID-19 symptoms could provide fine-grained resolution to guide clinical decision-making. Here, we use deep neural networks over an institution-wide platform for the augmented curation of clinical notes from 77,167 patients subjected to COVID-19 PCR testing. By contrasting Electronic Health Record (EHR)-derived symptoms of COVID-19-positive (COVIDpos; n = 2,317) versus COVID-19-negative (COVIDneg; n = 74,850) patients for the week preceding the PCR testing date, we identify anosmia/dysgeusia (27.1-fold), fever/chills (2.6-fold), respiratory difficulty (2.2-fold), cough (2.2-fold), myalgia/arthralgia (2-fold), and diarrhea (1.4-fold) as significantly amplified in COVIDpos over COVIDneg patients. The combination of cough and fever/chills has 4.2-fold amplification in COVIDpos patients during the week prior to PCR testing, in addition to anosmia/dysgeusia, constitutes the earliest EHR-derived signature of COVID-19. This study introduces an Augmented Intelligence platform for the real-time synthesis of institutional biomedical knowledge. The platform holds tremendous potential for scaling up curation throughput, thus enabling EHR-powered early disease diagnosis.


Subject(s)
Clinical Laboratory Techniques/methods , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Adult , Betacoronavirus/isolation & purification , COVID-19 , COVID-19 Testing , Chills/epidemiology , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Diarrhea/virology , Dysgeusia/virology , Female , Fever/virology , Humans , Male , Middle Aged , Myalgia/virology , Olfaction Disorders/virology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , Polymerase Chain Reaction , SARS-CoV-2
18.
Elife ; 92020 05 28.
Article in English | MEDLINE | ID: covidwho-401507

ABSTRACT

The COVID-19 pandemic demands assimilation of all biomedical knowledge to decode mechanisms of pathogenesis. Despite the recent renaissance in neural networks, a platform for the real-time synthesis of the exponentially growing biomedical literature and deep omics insights is unavailable. Here, we present the nferX platform for dynamic inference from over 45 quadrillion possible conceptual associations from unstructured text, and triangulation with insights from single-cell RNA-sequencing, bulk RNA-seq and proteomics from diverse tissue types. A hypothesis-free profiling of ACE2 suggests tongue keratinocytes, olfactory epithelial cells, airway club cells and respiratory ciliated cells as potential reservoirs of the SARS-CoV-2 receptor. We find the gut as the putative hotspot of COVID-19, where a maturation correlated transcriptional signature is shared in small intestine enterocytes among coronavirus receptors (ACE2, DPP4, ANPEP). A holistic data science platform triangulating insights from structured and unstructured data holds potential for accelerating the generation of impactful biological insights and hypotheses.


Subject(s)
Coronavirus Infections/virology , Libraries, Medical , Pneumonia, Viral/virology , Receptors, Virus/metabolism , Animals , Betacoronavirus/genetics , Betacoronavirus/metabolism , COVID-19 , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Gene Expression Profiling , Humans , Knowledge Discovery , Mice , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Receptors, Coronavirus , Receptors, Virus/chemistry , Receptors, Virus/genetics , SARS-CoV-2
19.
Elife ; 92020 05 26.
Article in English | MEDLINE | ID: covidwho-378182

ABSTRACT

Molecular mimicry is an evolutionary strategy adopted by viruses to exploit the host cellular machinery. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site, absent in any previous coronavirus sequenced, resulting in the striking mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic alteration of ENaC-α causes aldosterone dysregulation in patients, highlighting that the FURIN site is critical for activation of ENaC. Single cell RNA-seq from 66 studies shows significant overlap between expression of ENaC-α and the viral receptor ACE2 in cell types linked to the cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular characterization with cleavage signatures of 178 proteases highlights proteolytic degeneracy wired into the SARS-CoV-2 lifecycle. Evolution of SARS-CoV-2 into a global pandemic may be driven in part by its targeted mimicry of ENaC-α, a protein critical for the homeostasis of airway surface liquid, whose misregulation is associated with respiratory conditions.


Viruses hijack the cellular machinery of humans to infect their cells and multiply. The virus causing the global COVID-19 pandemic, SARS-CoV-2, is no exception. Identifying which proteins in human cells the virus co-opts is crucial for developing new ways to diagnose, prevent and treat COVID-19 infections. SARS-CoV-2 is covered in spike-shaped proteins, which the virus uses to gain entry into cells. First, the spikes bind to a protein called ACE2, which is found on the cells that line the respiratory tract and lungs. SARS-CoV-2 then exploits enzymes called proteases to cut, or cleave, its spikes at a specific site which allows the virus to infiltrate the host cell. Proteases identify which proteins to target based on the sequence of amino acids ­ the building blocks of proteins ­ at the cleavage site. However, it remained unclear which human proteases SARS-CoV-2 co-opts and whether its cut site is similar to human proteins. Now, Anand et al. show that the spike proteins on SARS-CoV-2 may have the same sequence of amino acids at its cut site as a human epithelial channel protein called ENaC-α. This channel is important for maintaining the balance of salt and water in many organs including the lungs. Further analyses showed that ENaC-α is often found in the same types of human lung and respiratory tract cells as ACE2. This suggests that SARS-CoV-2 may use the same proteases that cut ENaC-α to get inside human respiratory cells. It is possible that by hijacking the cutting mechanism for ENaC-α, SARS-CoV-2 interferes with the balance of salt and water in the lungs of COVID-19 patients. This may help explain why the virus causes severe respiratory symptoms. However, more studies are needed to confirm that the proteases that cut ENaC-α also cut the spike proteins on SARS-CoV-2, and how this affects the respiratory health of COVID-19 patients.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/virology , Epithelial Sodium Channels/metabolism , Molecular Mimicry , Peptide Hydrolases/metabolism , Pneumonia, Viral/virology , Viral Envelope Proteins/metabolism , Viral Proteins/metabolism , Angiotensin-Converting Enzyme 2 , Betacoronavirus/genetics , Betacoronavirus/pathogenicity , COVID-19 , Epithelial Sodium Channels/genetics , Host-Pathogen Interactions , Humans , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Proteolysis , SARS-CoV-2 , Substrate Specificity , Viral Envelope Proteins/genetics , Viral Proteins/genetics
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