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1.
Clin Infect Dis ; 74(4): 584-590, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1709326

ABSTRACT

BACKGROUND: With limited severe acute respiratory syndrome coronavirus (SARS-CoV-2) testing capacity in the United States at the start of the epidemic (January-March 2020), testing was focused on symptomatic patients with a travel history throughout February, obscuring the picture of SARS-CoV-2 seeding and community transmission. We sought to identify individuals with SARS-CoV-2 antibodies in the early weeks of the US epidemic. METHODS: All of Us study participants in all 50 US states provided blood specimens during study visits from 2 January to 18 March 2020. Participants were considered seropositive if they tested positive for SARS-CoV-2 immunoglobulin G (IgG) antibodies with the Abbott Architect SARS-CoV-2 IgG enzyme-linked immunosorbent assay (ELISA) and the EUROIMMUN SARS-CoV-2 ELISA in a sequential testing algorithm. The sensitivity and specificity of these ELISAs and the net sensitivity and specificity of the sequential testing algorithm were estimated, along with 95% confidence intervals (CIs). RESULTS: The estimated sensitivities of the Abbott and EUROIMMUN assays were 100% (107 of 107 [95% CI: 96.6%-100%]) and 90.7% (97 of 107 [83.5%-95.4%]), respectively, and the estimated specificities were 99.5% (995 of 1000 [98.8%-99.8%]) and 99.7% (997 of 1000 [99.1%-99.9%]), respectively. The net sensitivity and specificity of our sequential testing algorithm were 90.7% (97 of 107 [95% CI: 83.5%-95.4%]) and 100.0% (1000 of 1000 [99.6%-100%]), respectively. Of the 24 079 study participants with blood specimens from 2 January to 18 March 2020, 9 were seropositive, 7 before the first confirmed case in the states of Illinois, Massachusetts, Wisconsin, Pennsylvania, and Mississippi. CONCLUSIONS: Our findings identified SARS-CoV-2 infections weeks before the first recognized cases in 5 US states.


Subject(s)
COVID-19 , Population Health , Antibodies, Viral , COVID-19/diagnosis , Enzyme-Linked Immunosorbent Assay , Humans , Immunoglobulin G , SARS-CoV-2 , Sensitivity and Specificity
2.
J Am Heart Assoc ; 11(1): e022010, 2022 01 04.
Article in English | MEDLINE | ID: covidwho-1599177

ABSTRACT

Background Myocardial injury in patients with COVID-19 is associated with increased mortality during index hospitalization; however, the relationship to long-term sequelae of SARS-CoV-2 is unknown. This study assessed the relationship between myocardial injury (high-sensitivity cardiac troponin T level) during index hospitalization for COVID-19 and longer-term outcomes. Methods and Results This is a prospective cohort of patients who were hospitalized at a single center between March and May 2020 with SARS-CoV-2. Cardiac biomarkers were systematically collected. Outcomes were adjudicated and stratified on the basis of myocardial injury. The study cohort includes 483 patients who had high-sensitivity cardiac troponin T data during their index hospitalization. During index hospitalization, 91 (18.8%) died, 70 (14.4%) had thrombotic complications, and 126 (25.6%) had cardiovascular complications. By 12 months, 107 (22.2%) died. During index hospitalization, 301 (62.3%) had cardiac injury (high-sensitivity cardiac troponin T≧14 ng/L); these patients had 28.6%, 32.2%, and 33.2% mortality during index hospitalization, at 6 months, and at 12 months, respectively, compared with 4.1%, 4.9%, and 4.9% mortality for those with low-level positive troponin and 0%, 0%, and 0% for those with undetectable troponin. Of 392 (81.2%) patients who survived the index hospitalization, 94 (24%) had at least 1 readmission within 12 months, of whom 61 (65%) had myocardial injury during the index hospitalization. Of 377 (96%) patients who were alive and had follow-up after the index hospitalization, 211 (56%) patients had a documented, detailed clinical assessment at 6 months. A total of 78 of 211 (37.0%) had ongoing COVID-19-related symptoms; 34 of 211 (16.1%) had neurocognitive decline, 8 of 211 (3.8%) had increased supplemental oxygen requirements, and 42 of 211 (19.9%) had worsening functional status. Conclusions Myocardial injury during index hospitalization for COVID-19 was associated with increased mortality and may predict who are more likely to have postacute sequelae of COVID-19. Among patients who survived their index hospitalization, the incremental mortality through 12 months was low, even among troponin-positive patients.


Subject(s)
COVID-19 , Heart Injuries , COVID-19/complications , COVID-19/therapy , Heart Injuries/epidemiology , Hospitalization , Humans , Prospective Studies , Treatment Outcome , Troponin T/blood
3.
Nat Med ; 27(6): 1012-1024, 2021 06.
Article in English | MEDLINE | ID: covidwho-1472229

ABSTRACT

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.


Subject(s)
Aging/genetics , Communicable Diseases/genetics , Pneumonia/genetics , Sepsis/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Aging/pathology , Biological Specimen Banks , Chromosome Aberrations , Communicable Diseases/complications , Communicable Diseases/microbiology , Digestive System Diseases/epidemiology , Digestive System Diseases/genetics , Digestive System Diseases/microbiology , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Hematologic Neoplasms/complications , Hematologic Neoplasms/genetics , Hematologic Neoplasms/microbiology , Humans , Male , Middle Aged , Mosaicism , Pneumonia/epidemiology , Pneumonia/microbiology , Risk Factors , Sepsis/epidemiology , Sepsis/microbiology , Urogenital Abnormalities/epidemiology , Urogenital Abnormalities/genetics , Urogenital Abnormalities/microbiology , Young Adult
4.
Angew Chem Int Ed Engl ; 60(49): 25966-25972, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1427057

ABSTRACT

Coronavirus disease 2019 (COVID-19) manifests with high clinical variability and warrants sensitive and specific assays to analyze immune responses in infected and vaccinated individuals. Using Single Molecule Arrays (Simoa), we developed an assay to assess antibody neutralization with high sensitivity and multiplexing capabilities based on antibody-mediated blockage of the ACE2-spike interaction. The assay does not require live viruses or cells and can be performed in a biosafety level 2 laboratory within two hours. We used this assay to assess neutralization and antibody levels in patients who died of COVID-19 and patients hospitalized for a short period of time and show that neutralization and antibody levels increase over time. We also adapted the assay for SARS-CoV-2 variants and measured neutralization capacity in pre-pandemic healthy, COVID-19 infected, and vaccinated individuals. This assay is highly adaptable for clinical applications, such as vaccine development and epidemiological studies.


Subject(s)
Antibodies, Neutralizing/immunology , COVID-19/immunology , Neutralization Tests/methods , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Viral/immunology , Antigen-Antibody Reactions , COVID-19/pathology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Humans , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
5.
Nat Med ; 27(3): 454-462, 2021 03.
Article in English | MEDLINE | ID: covidwho-1319036

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread relentlessly, associated with a high frequency of respiratory failure and mortality. Children experience largely asymptomatic disease, with rare reports of multisystem inflammatory syndrome in children (MIS-C). Identifying immune mechanisms that result in these disparate clinical phenotypes in children could provide critical insights into coronavirus disease 2019 (COVID-19) pathogenesis. Using systems serology, in this study we observed in 25 children with acute mild COVID-19 a functional phagocyte and complement-activating IgG response to SARS-CoV-2, similar to the acute responses generated in adults with mild disease. Conversely, IgA and neutrophil responses were significantly expanded in adults with severe disease. Moreover, weeks after the resolution of SARS-CoV-2 infection, children who develop MIS-C maintained highly inflammatory monocyte-activating SARS-CoV-2 IgG antibodies, distinguishable from acute disease in children but with antibody levels similar to those in convalescent adults. Collectively, these data provide unique insights into the potential mechanisms of IgG and IgA that might underlie differential disease severity as well as unexpected complications in children infected with SARS-CoV-2.


Subject(s)
Antibodies, Viral/blood , COVID-19/epidemiology , SARS-CoV-2/immunology , Adolescent , Adult , Age of Onset , Aged , Antibodies, Neutralizing/analysis , Antibodies, Neutralizing/blood , Antibodies, Viral/analysis , Asymptomatic Infections , COVID-19/blood , COVID-19/pathology , Carrier State/blood , Carrier State/epidemiology , Child , Child, Preschool , Cohort Studies , Female , Humans , Immunity/physiology , Immunoglobulin A/blood , Immunoglobulin G/blood , Infant , Infant, Newborn , Male , Middle Aged , Pandemics , Severity of Illness Index , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/epidemiology , Young Adult
6.
Ethn Dis ; 31(3): 407-410, 2021.
Article in English | MEDLINE | ID: covidwho-1318484

ABSTRACT

Purpose: Enhancing the bidirectional benefit of precision medicine research infrastructure may advance equity in research participation for diverse groups. This study explores the use of research infrastructure to provide human-centered COVID-19 resources to participants as a part of their research participation. Design: The All of Us New England (AoUNE) consortium research team developed standardized check-in telephone calls to ask participants about their well-being and share COVID-19 resources. Participants: A total of 20,559 participants in the AoUNE consortium received a COVID-19 check-in call. Methods: Research assistants called participants during March-April 2020, distributed COVID-19 resources to interested participants, and subsequently rated call tone. Results: Of the total cohort participants called, 8,512 (41%) spoke with a research team member. The majority of calls were rated as positive or neutral; only 3% rated as negative. African American and Black as well as Hispanic populations requested COVID-19 resources at higher rates than other groups. Conclusions: Calls made to AoUNE participants were received positively by diverse groups. These findings may have implications for participant-centered engagement strategies in precision medicine research.


Subject(s)
COVID-19 , Population Health , Humans , Precision Medicine , SARS-CoV-2
7.
J Appl Lab Med ; 6(6): 1561-1570, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1291298

ABSTRACT

BACKGROUND: Serological testing provides a record of prior infection with SARS-CoV-2, but assay performance requires independent assessment. METHODS: We evaluated 3 commercial (Roche Diagnostics pan-IG, and Epitope Diagnostics IgM and IgG) and 2 non-commercial (Simoa and Ragon/MGH IgG) immunoassays against 1083 unique samples that included 251 PCR-positive and 832 prepandemic samples. RESULTS: The Roche assay registered the highest specificity 99.6% (3/832 false positives), the Ragon/MGH assay 99.5% (4/832), the primary Simoa assay model 99.0% (8/832), and the Epitope IgG and IgM 99.0% (8/830) and 99.5% (4/830), respectively. Overall sensitivities for the Simoa, Roche pan-IG, Epitope IgG, Ragon/MGH IgG, and Epitope IgM were 92.0%, 82.9%, 82.5%, 64.5% and 47.0%, respectively. The Simoa immunoassay demonstrated the highest sensitivity among samples stratified by days postsymptom onset (PSO), <8 days PSO (57.69%) 8-14 days PSO (93.51%), 15-21 days PSO (100%), and > 21 days PSO (95.18%). CONCLUSIONS: All assays demonstrated high to very high specificities while sensitivities were variable across assays.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , COVID-19 Serological Testing , Humans , Immunoassay , Immunoglobulin G , Immunoglobulin M , Sensitivity and Specificity
9.
Clin Infect Dis ; 74(4): 584-590, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1269569

ABSTRACT

BACKGROUND: With limited severe acute respiratory syndrome coronavirus (SARS-CoV-2) testing capacity in the United States at the start of the epidemic (January-March 2020), testing was focused on symptomatic patients with a travel history throughout February, obscuring the picture of SARS-CoV-2 seeding and community transmission. We sought to identify individuals with SARS-CoV-2 antibodies in the early weeks of the US epidemic. METHODS: All of Us study participants in all 50 US states provided blood specimens during study visits from 2 January to 18 March 2020. Participants were considered seropositive if they tested positive for SARS-CoV-2 immunoglobulin G (IgG) antibodies with the Abbott Architect SARS-CoV-2 IgG enzyme-linked immunosorbent assay (ELISA) and the EUROIMMUN SARS-CoV-2 ELISA in a sequential testing algorithm. The sensitivity and specificity of these ELISAs and the net sensitivity and specificity of the sequential testing algorithm were estimated, along with 95% confidence intervals (CIs). RESULTS: The estimated sensitivities of the Abbott and EUROIMMUN assays were 100% (107 of 107 [95% CI: 96.6%-100%]) and 90.7% (97 of 107 [83.5%-95.4%]), respectively, and the estimated specificities were 99.5% (995 of 1000 [98.8%-99.8%]) and 99.7% (997 of 1000 [99.1%-99.9%]), respectively. The net sensitivity and specificity of our sequential testing algorithm were 90.7% (97 of 107 [95% CI: 83.5%-95.4%]) and 100.0% (1000 of 1000 [99.6%-100%]), respectively. Of the 24 079 study participants with blood specimens from 2 January to 18 March 2020, 9 were seropositive, 7 before the first confirmed case in the states of Illinois, Massachusetts, Wisconsin, Pennsylvania, and Mississippi. CONCLUSIONS: Our findings identified SARS-CoV-2 infections weeks before the first recognized cases in 5 US states.


Subject(s)
COVID-19 , Population Health , Antibodies, Viral , COVID-19/diagnosis , Enzyme-Linked Immunosorbent Assay , Humans , Immunoglobulin G , SARS-CoV-2 , Sensitivity and Specificity
10.
Med (N Y) ; 2(2): 137-148.e4, 2021 02 12.
Article in English | MEDLINE | ID: covidwho-948684

ABSTRACT

BACKGROUND: Small studies have correlated hypertension with pneumonia risk; whether this is recapitulated in larger prospective studies, and represents a causal association, is unclear. METHODS: We estimated the risk for prevalent hypertension with incident respiratory diseases over mean follow-up of 8 years among 377,143 British participants in the UK Biobank. Mendelian randomization of blood pressure on pneumonia was implemented using 75 independent, genome-wide significant variants associated with systolic and diastolic blood pressures among 299,024 individuals not in the UK Biobank. Secondary analyses with pulmonary function tests were performed. FINDINGS: In total, 107,310 participants (30%) had hypertension at UK Biobank enrollment, and 9,969 (3%) developed pneumonia during follow-up. Prevalent hypertension was independently associated with increased risk for incident pneumonia (HR: 1.36; 95% CI: 1.29-1.43; p < 0.001), as well as other incident respiratory diseases. Genetic predisposition to a 5 mm Hg increase in blood pressure was associated with increased risk for incident pneumonia for systolic blood pressure (HR: 1.08; 95% CI: 1.04-1.13; p < 0.001) and diastolic blood pressure (HR: 1.11; 95% CI: 1.03-1.20; p = 0.005). Additionally, consistent with epidemiologic associations, increased blood pressure genetic risk was significantly associated with reduced performance on pulmonary function tests (p < 0.001). CONCLUSIONS: These results suggest that elevated blood pressure increases risk for pneumonia. Maintaining adequate blood pressure control, in addition to other measures, may reduce risk for pneumonia. FUNDING: S.M.Z. (1F30HL149180-01), M.H. (T32HL094301-07), and P.N. (R01HL1427, R01HL148565, and R01HL148050) are supported by the National Institutes of Health. J.P. is supported by the John S. LaDue Memorial Fellowship.


Subject(s)
Hypertension , Pneumonia , Biological Specimen Banks , Blood Pressure/genetics , Genome-Wide Association Study , Humans , Hypertension/epidemiology , Mendelian Randomization Analysis , Pneumonia/epidemiology , Polymorphism, Single Nucleotide , Prospective Studies , United Kingdom/epidemiology , United States
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