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1.
JAMA ; 329(22): 1934-1946, 2023 06 13.
Article in English | MEDLINE | ID: covidwho-20243721

ABSTRACT

Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds). Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.


Subject(s)
COVID-19 , SARS-CoV-2 , Female , Adult , Humans , Middle Aged , Male , COVID-19/complications , Prospective Studies , Post-Acute COVID-19 Syndrome , Cohort Studies , Disease Progression , Fatigue
2.
JCI Insight ; 7(13)2022 07 08.
Article in English | MEDLINE | ID: covidwho-1932894

ABSTRACT

BACKGROUNDProlonged 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 biomarkers are points that remain elusive.METHODSAdult SARS-CoV-2 reverse transcription PCR-positive (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 1 year after diagnosis; they completed symptom surveys and underwent blood draws and nasal swab collections at each visit.RESULTSOur cohort (n = 617) ranged from asymptomatic to critical COVID-19 infections. In total, 40% of participants reported at least 1 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 1 month or longer was 214 days. Anti-nucleocapsid IgG level in the first week after positive RT-PCR test and history of lung disease were associated with time to sustained symptom resolution. COVID-19 disease severity, ethnicity, age, sex, and remdesivir use did not affect time to sustained symptom resolution.CONCLUSIONWe found 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 REGISTRATIONClinicalTrials.gov, NCT04373148.FUNDINGNIH UL1TR003142 CTSA grant, NIH U54CA260517 grant, NIEHS R21 ES03304901, Sean N Parker Center for Allergy and Asthma Research at Stanford University, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative, Sunshine Foundation, Crown Foundation, and Parker Foundation.


Subject(s)
COVID-19 , COVID-19/complications , Humans , Immunoglobulin G , SARS-CoV-2 , Post-Acute COVID-19 Syndrome
3.
JAMA Netw Open ; 5(2): e2148988, 2022 02 01.
Article in English | MEDLINE | ID: covidwho-1694842

ABSTRACT

Importance: There is an urgent need to assess the feasibility of COVID-19 surveillance measures in educational settings. Objective: To assess whether young children can feasibly self-collect SARS-CoV-2 samples for surveillance testing over the course of an academic year. Design, Setting, and Participants: This prospective pilot cohort study was conducted from September 10, 2020, to June 10, 2021, at a K-8 school in San Mateo County, California. The research consisted of quantitative data collection efforts: (1) demographic data collected, (2) student sample self-collection error rates, and (3) student sample self-collection time durations. Students were enrolled in a hybrid learning model, a teaching model in which students were taught in person and online, with students having the option to attend virtually as needed. Data were collected under waiver of consent from students participating in weekly SARS-CoV-2 testing. Main Outcomes and Measures: Errors over time for self-collection of nasal swabs such as contaminated swabs and inadequate or shallow swabbing; time taken for sample collection. Results: Of 296 participants, 148 (50.0%) were boys and 148 (50.0%) were girls. A total of 87 participants (29.2%) identified as Asian; 2 (0.6%), Black or African American; 13 (4.4%), Hispanic/Latinx; 103 (34.6%), non-Hispanic White; 87 (29.2%), multiracial; and 6 (2.0%), other. The median school grade was fourth grade. From September 2020 to March 2021, a total of 4203 samples were obtained from 221 students on a weekly basis, while data on error rates were collected. Errors occurred in 2.7% (n = 107; 95% CI, 2.2%-3.2%) of student encounters, with the highest rate occurring on the first day of testing (20 [10.2%]). There was an overall decrease in error rates over time. From April to June 2021, a total of 2021 samples were obtained from 296 students on a weekly basis while data on encounter lengths were collected. Between April and June 2021, 193 encounters were timed. The mean duration of each encounter was 70 seconds (95% CI, 66.4-73.7 seconds). Conclusions and Relevance: Mastery of self-collected lower nasal swabs is possible for children 5 years and older. Testing duration can be condensed once students gain proficiency in testing procedures. Scalability for larger schools is possible if consideration is given to the resource-intensive nature of the testing and the setting's weather patterns.


Subject(s)
COVID-19 Testing , COVID-19/diagnosis , SARS-CoV-2 , Self-Testing , COVID-19/pathology , COVID-19/prevention & control , California , Child , Child, Preschool , Cohort Studies , Epidemics , Feasibility Studies , Female , Humans , Male , Population Surveillance , Prospective Studies , Specimen Handling
4.
Open Forum Infect Dis ; 9(2): ofab646, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1672245

ABSTRACT

Determinants of Post-Acute Sequelae of COVID-19 are not known. Here we show that 83.3% of patients with viral RNA in blood (RNAemia) at presentation were symptomatic in the post-acute phase. RNAemia at presentation successfully predicted PASC, independent of patient demographics, worst disease severity, and length of symptoms.

5.
Clin Infect Dis ; 75(1): e440-e449, 2022 08 24.
Article in English | MEDLINE | ID: covidwho-1493770

ABSTRACT

BACKGROUND: Based on interim analyses and modeling data, lower doses of bamlanivimab and etesevimab together (700/1400 mg) were investigated to determine optimal dose and expand availability of treatment. METHODS: This Phase 3 portion of the BLAZE-1 trial characterized the effect of bamlanivimab with etesevimab on overall patient clinical status and virologic outcomes in ambulatory patients ≥12 years old, with mild-to-moderate coronavirus disease 2019 (COVID-19), and ≥1 risk factor for progressing to severe COVID-19 and/or hospitalization. Bamlanivimab and etesevimab together (700/1400 mg) or placebo were infused intravenously within 3 days of patients' first positive COVID-19 test. RESULTS: In total, 769 patients were infused (median age [range]; 56.0 years [12, 93], 30.3% of patients ≥65 years of age and median duration of symptoms; 4 days). By day 29, 4/511 patients (0.8%) in the antibody treatment group had a COVID-19-related hospitalization or any-cause death, as compared with 15/258 patients (5.8%) in the placebo group (Δ[95% confidence interval {CI}] = -5.0 [-8.0, -2.1], P < .001). No deaths occurred in the bamlanivimab and etesevimab group compared with 4 deaths (all COVID-19-related) in the placebo group. Patients receiving antibody treatment had a greater mean reduction in viral load from baseline to Day 7 (Δ[95% CI] = -0.99 [-1.33, -.66], P < .0001) compared with those receiving placebo. Persistently high viral load at Day 7 correlated with COVID-19-related hospitalization or any-cause death by Day 29 in all BLAZE-1 cohorts investigated. CONCLUSIONS: These data support the use of bamlanivimab and etesevimab (700/1400 mg) for ambulatory patients at high risk for severe COVID-19. Evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants will require continued monitoring to determine the applicability of this treatment. CLINICAL TRIALS REGISTRATION: NCT04427501.


Subject(s)
COVID-19 Drug Treatment , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Child , Humans , Middle Aged , Prognosis , SARS-CoV-2 , Viral Load
6.
JAMA Netw Open ; 4(9): e2125524, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1414844

ABSTRACT

Importance: As of May 2021, more than 32 million cases of COVID-19 have been confirmed in the United States, resulting in more than 615 000 deaths. Anaphylactic reactions associated with the Food and Drug Administration (FDA)-authorized mRNA COVID-19 vaccines have been reported. Objective: To characterize the immunologic mechanisms underlying allergic reactions to these vaccines. Design, Setting, and Participants: This case series included 22 patients with suspected allergic reactions to mRNA COVID-19 vaccines between December 18, 2020, and January 27, 2021, at a large regional health care network. Participants were individuals who received at least 1 of the following International Statistical Classification of Diseases and Related Health Problems, Tenth Revision anaphylaxis codes: T78.2XXA, T80.52XA, T78.2XXD, or E949.9, with documentation of COVID-19 vaccination. Suspected allergy cases were identified and invited for follow-up allergy testing. Exposures: FDA-authorized mRNA COVID-19 vaccines. Main Outcomes and Measures: Allergic reactions were graded using standard definitions, including Brighton criteria. Skin prick testing was conducted to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used for internal validation. Basophil activation testing after stimulation for 30 minutes at 37 °C was also conducted. Concentrations of immunoglobulin (Ig) G and IgE antibodies to PEG were obtained to determine possible mechanisms. Results: Of 22 patients (20 [91%] women; mean [SD] age, 40.9 [10.3] years; 15 [68%] with clinical allergy history), 17 (77%) met Brighton anaphylaxis criteria. All reactions fully resolved. Of patients who underwent skin prick tests, 0 of 11 tested positive to PEG, 0 of 11 tested positive to P80, and 1 of 10 (10%) tested positive to the same brand of mRNA vaccine used to vaccinate that individual. Among these same participants, 10 of 11 (91%) had positive basophil activation test results to PEG and 11 of 11 (100%) had positive basophil activation test results to their administered mRNA vaccine. No PEG IgE was detected; instead, PEG IgG was found in tested individuals who had an allergy to the vaccine. Conclusions and Relevance: Based on this case series, women and those with a history of allergic reactions appear at have an elevated risk of mRNA vaccine allergy. Immunological testing suggests non-IgE-mediated immune responses to PEG may be responsible in most individuals.


Subject(s)
COVID-19 Vaccines/adverse effects , Hypersensitivity/diagnosis , Adolescent , Adult , Aged , COVID-19 Vaccines/therapeutic use , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/epidemiology , Female , Humans , Hypersensitivity/epidemiology , Male , Middle Aged , Risk Factors , United States/epidemiology , United States Food and Drug Administration/organization & administration , United States Food and Drug Administration/statistics & numerical data , Vaccination/adverse effects
7.
J Exp Med ; 218(8)2021 08 02.
Article in English | MEDLINE | ID: covidwho-1269483

ABSTRACT

Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-κB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.


Subject(s)
COVID-19/blood , COVID-19/immunology , Immunity, Innate/physiology , Adult , Aged , COVID-19/genetics , COVID-19/mortality , Case-Control Studies , Cytokines/genetics , Epigenesis, Genetic , Female , Hematopoiesis , Humans , Killer Cells, Natural/pathology , Killer Cells, Natural/virology , Male , Middle Aged , Monocytes/pathology , Monocytes/virology , NF-kappa B/metabolism , Neutrophils/pathology , Neutrophils/virology , Proteomics , Severity of Illness Index , Single-Cell Analysis
8.
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
9.
Clin Infect Dis ; 74(2): 218-226, 2022 01 29.
Article in English | MEDLINE | ID: covidwho-1216637

ABSTRACT

BACKGROUND: The determinants of coronavirus disease 2019 (COVID-19) disease severity and extrapulmonary complications (EPCs) are poorly understood. We characterized relationships between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNAemia and disease severity, clinical deterioration, and specific EPCs. METHODS: We used quantitative and digital polymerase chain reaction (qPCR and dPCR) to quantify SARS-CoV-2 RNA from plasma in 191 patients presenting to the emergency department with COVID-19. We recorded patient symptoms, laboratory markers, and clinical outcomes, with a focus on oxygen requirements over time. We collected longitudinal plasma samples from a subset of patients. We characterized the role of RNAemia in predicting clinical severity and EPCs using elastic net regression. RESULTS: Of SARS-CoV-2-positive patients, 23.0% (44 of 191) had viral RNA detected in plasma by dPCR, compared with 1.4% (2 of 147) by qPCR. Most patients with serial measurements had undetectable RNAemia within 10 days of symptom onset, reached maximum clinical severity within 16 days, and symptom resolution within 33 days. Initially RNAemic patients were more likely to manifest severe disease (odds ratio, 6.72 [95% confidence interval, 2.45-19.79]), worsening of disease severity (2.43 [1.07-5.38]), and EPCs (2.81 [1.26-6.36]). RNA loads were correlated with maximum severity (r = 0.47 [95% confidence interval, .20-.67]). CONCLUSIONS: dPCR is more sensitive than qPCR for the detection of SARS-CoV-2 RNAemia, which is a robust predictor of eventual COVID-19 severity and oxygen requirements, as well as EPCs. Because many COVID-19 therapies are initiated on the basis of oxygen requirements, RNAemia on presentation might serve to direct early initiation of appropriate therapies for the patients most likely to deteriorate.

10.
Prehosp Emerg Care ; : 1-10, 2021 May 06.
Article in English | MEDLINE | ID: covidwho-1165151

ABSTRACT

Objective: Firefighter first responders and other emergency medical services (EMS) personnel have been among the highest risk healthcare workers for illness during the SARS-CoV-2 pandemic. We sought to determine the rate of seropositivity for SARS-CoV-2 IgG antibodies and of acute asymptomatic infection among firefighter first responders in a single county with early exposure in the pandemic. Methods: We conducted a cross-sectional study of clinically active firefighters cross-trained as paramedics or EMTs in the fire departments of Santa Clara County, California. Firefighters without current symptoms were tested between June and August 2020. Our primary outcomes were rates of SARS-CoV-2 IgG antibody seropositivity and SARS-CoV-2 RT-PCR swab positivity for acute infection. We report cumulative incidence, participant characteristics with frequencies and proportions, and proportion positive and associated relative risk (with 95% confidence intervals). Results: We enrolled 983 out of 1339 eligible participants (response rate: 73.4%). Twenty-five participants (2.54%, 95% CI 1.65-3.73) tested positive for IgG antibodies and 9 (0.92%, 95% CI 0.42-1.73) tested positive for SARS-CoV-2 by RT-PCR. Our cumulative incidence, inclusive of self-reported prior positive PCR tests, was 34 (3.46%, 95% CI 2.41-4.80). Conclusion: In a county with one of the earliest outbreaks in the United States, the seroprevalence among firefighter first responders was lower than that reported by other studies of frontline health care workers, while the cumulative incidence remained higher than that seen in the surrounding community.

11.
Infect Control Hosp Epidemiol ; 42(9): 1053-1059, 2021 09.
Article in English | MEDLINE | ID: covidwho-989631

ABSTRACT

OBJECTIVE: We assessed the magnitude of unidentified coronavirus disease 2019 (COVID-19) in our healthcare personnel (HCP) early in the COVID-19 pandemic, and we evaluated risk factors for infection to identify areas for improvement in infection control practice in a northern California academic medical center. METHODS: We reviewed anti-severe acute respiratory coronavirus virus 2 (SARS-CoV-2) receptor-binding domain (RBD) IgG serologic test results and self-reported risk factors for seropositivity among 10,449 asymptomatic HCP who underwent voluntary serology testing between April 20 and May 20, 2020. RESULTS: In total, 136 employees (1.3%) tested positive for SARS-CoV-2 IgG. This included 41 individuals (30.1%) who had previously tested positive for SARS-CoV-2 by nasopharyngeal reverse-transcription polymerase chain reaction (RT-PCR) between March 13 and April 16, 2020. In multivariable analysis, employees of Hispanic ethnicity (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.22-3.46) and those working in environmental services, food services, or patient transport (OR, 4.81; 95% CI, 2.08-10.30) were at increased risk for seropositivity compared to other groups. Employees reporting a household contact with COVID-19 were also at higher risk for seropositivity (OR, 3.25; 95% CI, 1.47-6.44), but those with a work, exposure alone were not (OR, 1.27; 95% CI, 0.58-2.47). Importantly, one-third of seropositive individuals reported no prior symptoms, no suspected exposures, and no prior positive RT-PCR test. CONCLUSION: In this study, SARS-CoV-2 seropositivity among HCP early in the northern California epidemic appeared to be quite low and was more likely attributable to community rather than occupational exposure.


Subject(s)
COVID-19 , Pandemics , California/epidemiology , Delivery of Health Care , Humans , SARS-CoV-2 , Seroepidemiologic Studies
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