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2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-313371

ABSTRACT

Background: Prolonged symptoms after SARS-CoV-2 infection are well-documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with serologic biomarkers remain elusive. Methods: Adult inpatient and outpatient SARS-CoV-2 RT-PCR positive patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1-3 months for up to one year after diagnosis;they completed symptom surveys and underwent sampling procedures (blood draw and nasal swab) at each visit. Findings: Our cohort (n=617) ranged from asymptomatic to critical COVID-19 infections. 40% of participants reported at least one symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days, median time from diagnosis to sustained symptom resolution with no recurring symptoms for one month or longer was 214 days. Serum anti-nucleocapsid IgG level in the first week of infection was predictive of time to symptom resolution. A prior diagnosis of lung disease was associated with longer time to symptom resolution. COVID-19 disease severity, ethnicity, sex, cytomegalovirus (CMV) seropositivity, and remdesivir use did not affect time to sustained symptom resolution. More than 90% of participants had SARS-CoV-2-specific antibody>1000 AU/mL nine months after diagnosis. Interpretation: Our findings showed that all disease severities had a similar risk of developing post-COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration. Trial Registration: National clinical trial database NCT04664309.Funding: NIH CTSA grant, U54 NIH Grant, R21 NIEHS, Sean N Parker Center for Allergy and Asthma Research at Stanford University, the Sunshine Foundation, the Crown Foundation, and the Parker Foundation.Declaration of Interest: Dr. Boyd received support for the current manuscript from Meso Scale Discovery and NIH;418 received consulting fees by Regeneron for expert testimony, has stocks or stock options in 419 AbCellera Biologics;Dr. Chinthrajah reports grants from NIAID, CoFAR, Aimmune, DBV 420 Technologies, Astellas, Regeneron, Stanford Maternal and Child Health Research Institute 421 (MCHRI), and FARE. She is an Advisory Board Member at Alladapt Therapeutics, Novartis, 422 Genentech, Sanofi, Allergenis, and Nutricia;Dr. Manisha Desai received support from Chan 423 Zuckerberg Foundation;Dr. Maecker received grants or contracts from NIH, Bill & Melinda 424 Gates Foundation, Ionis Corporation, Amgen Corporation;Consulting fees from Magarray Corp;425 payment or honoraria from UCLA, UC Davis;leadership or fiduciary role at Cytek SAB;stocks 426 or stock options at BD Biosciences;Dr. Nadeau reports grants from National Institute of Allergy and Infectious Diseases (NIAID), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Environmental Health Sciences (NIEHS), and Food Allergy Research & Education (FARE);Director of World Allergy Organization (WAO) , Advisor at Cour Pharma, Consultant for Excellergy, Red tree ventures, and Phylaxis, Co-founder of Before Brands, Alladapt, Latitude, and IgGenix;and National Scientific Committee member at Immune Tolerance Network (ITN), and National Institutes of Health (NIH) clinical research centers, outside the submitted work;patents include, “Mixed allergen composition and methods for using the same”, “Granulocyte-based methods for detecting and monitoring immune system disorders”, “Methods and Assays for Detecting and Quantifying Pure Subpopulations of White Blood Cells in Immune System Disorders,” and “Methods of isolating allergen-specific antibodies from humans and uses thereof”;Dr. Benjamin Pinsky received grants or contracts for the present manuscript from MesoScale Diagno tics;Dr. Angele Rogers was a Clinical Trials Advisory Board Member for Merck;Dr. Sindher reports support for the present manuscript from the NIH, Regeneron, DBV Technologies, Aimmune, Novartis, CoFAR, FARE, participated on a DSMB for Astra Zeneca, DBV, and received payment or honorarium from FARE;Neera Ahuja, Maja Artandi, Linda Barman, Catherine Blish, Andra Blomkalns, William Collins, MacKenzie Cox, Linda Geng, Xiaolin Jia, Megan Mahoney, Monali Manohar, Ruth O’hara, Rajan Puri, Katharina Roltgen, Laura Vaughan, Samuel Yang, Shu Cao, Iris Chang, Hena Din, Evan Do, Andrea Fernandez, Alexandra Lee, Natasha Purington, Yael Rosenberg-Hasson, Theo Snow, Daniel Solis, Michelle Verghese, and Yingjie Weng have no conflict of interest.Ethical Approval: This study was reviewed and approved by the Stanford Administrative Panel on Human Subjects in Medical Research.

3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-309904

ABSTRACT

Background: It is unclear if asthma and its allergic phenotype are risk factors for hospitalization or severe disease from SARS-CoV-2.Methods: All patients testing positive for SARS-CoV-2 between March 1 and September 30, 2020, were retrospectively identified and characterized through electronic analysis at Stanford. A sub-cohort was followed prospectively to evaluate long-term COVID-19 symptoms.Findings: 168,190 patients underwent SARS-CoV-2 testing, and 6,976 (4·15%) tested positive. In a multivariate analysis, asthma was not an independent risk factor for hospitalization (OR 1·12 [95% CI 0·86, 1·45], p=0·40). Among SARS-CoV-2 positive asthmatics, allergic asthma lowered the risk of hospitalization and had a protective effect compared to non-allergic asthma (OR 0·52 (0·28, 0·91), p=0·026);there was no association between baseline medication use as characterized by GINA and hospitalization risk. Patients with severe COVID-19 disease had lower eosinophil levels during hospitalization compared to patients with mild or asymptomatic disease, independent of asthma status (p=0.0014). In a patient sub-cohort followed longitudinally, asthmatics and non-asthmatics had similar time to resolution of COVID-19 symptoms, particularly lower respiratory symptoms.Interpretation: Asthma is not a risk factor for more severe COVID-19 disease. Allergic asthmatics were half as likely to be hospitalized with COVID-19 compared to non-allergic asthmatics. Lower levels of eosinophil counts (allergic biomarkers) were associated with more severe COVID-19 disease trajectory. Recovery was similar among asthmatics and non-asthmatics with over 50% of patients reporting ongoing lower respiratory symptoms three months post-infection.Trial Registration Information: Sub-cohort analysis performed among those enrolled in a prospective, longitudinal study (NCT# 04373148),Funding Statement: The Sean N. Parker Center for Allergy and Asthma Research, Stanford University, Sunshine Foundation, Crown Foundation, Parker Foundation.Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Ethics Approval Statement: This study was reviewed and approved with a waiver of consent by the Stanford Administrative Panel on Human Subjects in Medical Research.

4.
Clin Ther ; 43(11): 1877-1893.e4, 2021 11.
Article in English | MEDLINE | ID: covidwho-1506541

ABSTRACT

PURPOSE: In the Phase III COV-BARRIER (Efficacy and Safety of Baricitinib for the Treatment of Hospitalised Adults With COVID-19) trial, treatment with baricitinib, an oral selective Janus kinase 1/2 inhibitor, in addition to standard of care (SOC), was associated with significantly reduced mortality over 28 days in hospitalized patients with coronavirus disease-2019 (COVID-19), with a safety profile similar to that of SOC alone. This study assessed the cost-effectiveness of baricitinib + SOC versus SOC alone (which included systemic corticosteroids and remdesivir) in hospitalized patients with COVID-19 in the United States. METHODS: An economic model was developed to simulate inpatients' stay, discharge to postacute care, and recovery. Costs modeled included payor costs, hospital costs, and indirect costs. Benefits modeled included life-years (LYs) gained, quality-adjusted life-years (QALYs) gained, deaths avoided, and use of mechanical ventilation avoided. The primary analysis was performed from a payor perspective over a lifetime horizon; a secondary analysis was performed from a hospital perspective. The base-case analysis modeled the numeric differences in treatment effectiveness observed in the COV-BARRIER trial. Scenario analyses were also performed in which the clinical benefit of baricitinib was limited to the statistically significant reduction in mortality demonstrated in the trial. FINDINGS: In the base-case payor perspective model, an incremental total cost of 17,276 US dollars (USD), total QALYs gained of 0.6703, and total LYs gained of 0.837 were found with baricitinib + SOC compared with SOC alone. With the addition of baricitinib, survival was increased by 5.1% and the use of mechanical ventilation was reduced by 1.6%. The base-case incremental cost-effectiveness ratios were 25,774 USD/QALY gained and 20,638 USD/LY gained; a "mortality-only" scenario analysis yielded similar results of 26,862 USD/QALY gained and 21,433 USD/LY gained. From the hospital perspective, combination treatment with baricitinib + SOC was more effective and less costly than was SOC alone in the base case, with an incremental cost of 38,964 USD per death avoided in the mortality-only scenario. IMPLICATIONS: In hospitalized patients with COVID-19 in the United States, the addition of baricitinib to SOC was cost-effective. Cost-effectiveness was demonstrated from both the payor and the hospital perspectives. These findings were robust to sensitivity analysis and to conservative assumptions limiting the clinical benefits of baricitinib to the statistically significant reduction in mortality demonstrated in the COV-BARRIER trial.


Subject(s)
COVID-19 , Adult , Azetidines , COVID-19/drug therapy , Cost-Benefit Analysis , Humans , Purines , Pyrazoles , Quality-Adjusted Life Years , SARS-CoV-2 , Standard of Care , Sulfonamides , United States
5.
Nat Commun ; 12(1): 5417, 2021 09 14.
Article in English | MEDLINE | ID: covidwho-1410404

ABSTRACT

COVID-19 is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. Here we develop three protein arrays to measure IgG autoantibodies associated with connective tissue diseases, anti-cytokine antibodies, and anti-viral antibody responses in serum from 147 hospitalized COVID-19 patients. Autoantibodies are identified in approximately 50% of patients but in less than 15% of healthy controls. When present, autoantibodies largely target autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes. A subset of autoantibodies targeting traditional autoantigens or cytokines develop de novo following SARS-CoV-2 infection. Autoantibodies track with longitudinal development of IgG antibodies recognizing SARS-CoV-2 structural proteins and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.


Subject(s)
Autoantibodies/immunology , COVID-19/immunology , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Aged , Antibodies, Antinuclear/blood , Antibodies, Antinuclear/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Autoantibodies/blood , Autoantigens/immunology , Connective Tissue Diseases/immunology , Cytokines/immunology , Female , Hospitalization , Humans , Immunoglobulin G/blood , Male , Middle Aged , SARS-CoV-2/pathogenicity , Viral Proteins/immunology
7.
Allergy ; 77(1): 173-185, 2022 01.
Article in English | MEDLINE | ID: covidwho-1255322

ABSTRACT

BACKGROUND: It is unclear whether asthma and its allergic phenotype are risk factors for hospitalization or severe disease from SARS-CoV-2. METHODS: All patients over 28 days old testing positive for SARS-CoV-2 between March 1 and September 30, 2020, were retrospectively identified and characterized through electronic analysis at Stanford. A sub-cohort was followed prospectively to evaluate long-term COVID-19 symptoms. RESULTS: 168,190 patients underwent SARS-CoV-2 testing, and 6,976 (4.15%) tested positive. In a multivariate analysis, asthma was not an independent risk factor for hospitalization (OR 1.12 [95% CI 0.86, 1.45], p = .40). Among SARS-CoV-2-positive asthmatics, allergic asthma lowered the risk of hospitalization and had a protective effect compared with non-allergic asthma (OR 0.52 [0.28, 0.91], p = .026); there was no association between baseline medication use as characterized by GINA and hospitalization risk. Patients with severe COVID-19 disease had lower eosinophil levels during hospitalization compared with patients with mild or asymptomatic disease, independent of asthma status (p = .0014). In a patient sub-cohort followed longitudinally, asthmatics and non-asthmatics had similar time to resolution of COVID-19 symptoms, particularly lower respiratory symptoms. CONCLUSIONS: Asthma is not a risk factor for more severe COVID-19 disease. Allergic asthmatics were half as likely to be hospitalized with COVID-19 compared with non-allergic asthmatics. Lower levels of eosinophil counts (allergic biomarkers) were associated with a more severe COVID-19 disease trajectory. Recovery was similar among asthmatics and non-asthmatics with over 50% of patients reporting ongoing lower respiratory symptoms 3 months post-infection.


Subject(s)
Asthma , COVID-19 , Asthma/diagnosis , Asthma/epidemiology , COVID-19 Testing , Humans , Phenotype , Retrospective Studies , SARS-CoV-2
8.
N Engl J Med ; 384(9): 795-807, 2021 03 04.
Article in English | MEDLINE | ID: covidwho-972740

ABSTRACT

BACKGROUND: Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known. METHODS: We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15. RESULTS: A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003). CONCLUSIONS: Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Azetidines/therapeutic use , COVID-19/drug therapy , Purines/therapeutic use , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/therapeutic use , Adult , Aged , Alanine/adverse effects , Alanine/therapeutic use , Antiviral Agents/adverse effects , Azetidines/adverse effects , COVID-19/mortality , COVID-19/therapy , Double-Blind Method , Drug Therapy, Combination , Female , Hospital Mortality , Hospitalization , Humans , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/therapeutic use , Male , Middle Aged , Oxygen Inhalation Therapy , Purines/adverse effects , Pyrazoles/adverse effects , Respiration, Artificial , Sulfonamides/adverse effects , Treatment Outcome
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