Apparent Risks of Postural Orthostatic Tachycardia Syndrome Diagnoses After COVID-19 Vaccination and SARS-Cov-2 Infection.

Postural orthostatic tachycardia syndrome (POTS) has been previously described after SARS-CoV-2 infection; however, limited data is available on the relation of POTS with COVID-19 vaccination. Here we show in a cohort of 284,592 COVID-19 vaccinated individuals using a sequence-symmetry analysis, that the odds of POTS are higher 90 days after vaccine exposure than 90 days prior to exposure, and that the odds for POTS are higher than referent conventional primary care diagnoses, but lower than the odds of new POTS diagnosis after SARS-CoV-2 infection. Our results identify a possible association between COVID-19 vaccination and incidence of POTS. Notwithstanding the probable low incidence of POTS after COVID-19 vaccination, particularly when compared to SARS-Cov-2 post-infection odds which were five times higher, our results suggest that further studies, are needed to investigate the incidence and etiology of POTS occurring after COVID-19 vaccination.

Serological response to vaccination in post-acute sequelae of COVID.

BACKGROUND: Individuals with post-acute sequelae of COVID (PASC) may have a persistence in immune activation that differentiates them from individuals who have recovered from COVID without clinical sequelae. To investigate how humoral immune activation may vary in this regard, we compared patterns of vaccine-provoked serological response in patients with PASC compared to individuals recovered from prior COVID without PASC. METHODS: We prospectively studied 245 adults clinically diagnosed with PASC and 86 adults successfully recovered from prior COVID. All participants had measures of humoral immunity to SARS-CoV-2 assayed before or after receiving their first-ever administration of COVID vaccination (either single-dose or two-dose regimen), including anti-spike (IgG-S and IgM-S) and anti-nucleocapsid (IgG-N) antibodies as well as IgG-S angiotensin-converting enzyme 2 (ACE2) binding levels. We used unadjusted and multivariable-adjusted regression analyses to examine the association of PASC compared to COVID-recovered status with post-vaccination measures of humoral immunity. RESULTS: Individuals with PASC mounted consistently higher post-vaccination IgG-S antibody levels when compared to COVID-recovered (median log IgG-S 3.98 versus 3.74, P < 0.001), with similar results seen for ACE2 binding levels (median 99.1 versus 98.2, P = 0.044). The post-vaccination IgM-S response in PASC was attenuated but persistently unchanged over time (P = 0.33), compared to in COVID recovery wherein the IgM-S response expectedly decreased over time (P = 0.002). Findings remained consistent when accounting for demographic and clinical variables including indices of index infection severity and comorbidity burden. CONCLUSION: We found evidence of aberrant immune response distinguishing PASC from recovered COVID. This aberrancy is marked by excess IgG-S activation and ACE2 binding along with findings consistent with a delayed or dysfunctional immunoglobulin class switching, all of which is unmasked by vaccine provocation. These results suggest that measures of aberrant immune response may offer promise as tools for diagnosing and distinguishing PASC from non-PASC phenotypes, in addition to serving as potential targets for intervention.

Review of Immunologic Manifestations of COVID-19 Infection and Vaccination.

We herein summarize currently available and clinically relevant information regarding the human immune responses to SARS-CoV-2 infection and vaccination, in relation to COVID-19 outcomes with a focus on acute respiratory distress syndrome (ARDS) and myocarditis.

Outcomes of Extremely Prolonged (> 50 d) Venovenous Extracorporeal Membrane Oxygenation Support.

OBJECTIVES: There has been a sustained increase in the utilization of venovenous extracorporeal membrane oxygenation (ECMO) over the last decade, further exacerbated by the COVID-19 pandemic. We set out to describe our institutional experience with extremely prolonged (> 50 d) venovenous ECMO support for recovery or bridge to lung transplant candidacy in patients with acute respiratory failure. DESIGN: Retrospective cohort study. SETTING: A large tertiary urban care center. PATIENTS: Patients 18 years or older receiving venovenous ECMO support for greater than 50 days, with initial cannulation between January 2018 and January 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred thirty patients were placed on venovenous ECMO during the study period. Of these, 12 received prolonged (> 50 d) venovenous ECMO support. Eleven patients (92%) suffered from adult respiratory distress syndrome (ARDS) secondary to COVID-19, while one patient with prior bilateral lung transplant suffered from ARDS secondary to bacterial pneumonia. The median age of patients was 39 years (interquartile range [IQR], 35-51 yr). The median duration of venovenous ECMO support was 94 days (IQR, 70-128 d), with a maximum of 180 days. Median time from intubation to cannulation was 5 days (IQR, 2-14 d). Nine patients (75%) were successfully mobilized while on venovenous ECMO support. Successful weaning of venovenous ECMO support occurred in eight patients (67%); 6 (50%) were bridged to lung transplantation and 2 (17%) were bridged to recovery. Of those successfully weaned, seven patients (88%) were discharged from the hospital. All seven patients discharged from the hospital were alive 6 months post-decannulation; 83% (5/6) with sufficient follow-up time were alive 1-year after decannulation. CONCLUSIONS: Our experience suggests that extremely prolonged venovenous ECMO support to allow native lung recovery or optimization for lung transplantation may be a feasible strategy in select critically ill patients, further supporting the expanded utilization of venovenous ECMO for refractory respiratory failure.

Mechanically Ventilated Patients With Coronavirus Disease 2019 Had a Higher Chance of In-Hospital Death If Treated With High-Flow Nasal Cannula Oxygen Before Intubation.

BACKGROUND: The impact of high-flow nasal cannula (HFNC) on outcomes of patients with respiratory failure from coronavirus disease 2019 (COVID-19) is unknown. We sought to assess whether exposure to HFNC before intubation was associated with successful extubation and in-hospital mortality compared to patients receiving intubation only. METHODS: This single-center retrospective study examined patients with COVID-19-related respiratory failure from March 2020 to March 2021 who required HFNC, intubation, or both. Data were abstracted from the electronic health record. Use and duration of HFNC and intubation were examined' as well as demographics and clinical characteristics. We assessed the association between HFNC before intubation (versus without) and chance of successful extubation and in-hospital death using Cox proportional hazards models adjusting for age, sex, race/ethnicity, obesity, hypertension, diabetes, prior chronic obstructive pulmonary disease or asthma, HCO 3 , CO 2 , oxygen-saturation-to-inspired-oxygen (S:F) ratio, pulse, respiratory rate, temperature, and length of stay before intervention. RESULTS: A total of n = 440 patients were identified, of whom 311 (70.7%) received HFNC before intubation, and 129 (29.3%) were intubated without prior use of HFNC. Patients who received HFNC before intubation had a higher chance of in-hospital death (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.06-4.05). No difference was found in the chance of successful extubation between the 2 groups (0.70, 0.41-1.20). CONCLUSIONS: Among patients with respiratory failure from COVID-19 requiring mechanical ventilation, patients receiving HFNC before intubation had a higher chance of in-hospital death. Decisions on initial respiratory support modality should weigh the risks of intubation with potential increased mortality associated with HFNC.

Association of COVID-19 Vaccination With Risk for Incident Diabetes After COVID-19 Infection.

This cohort study compares the risk of new-onset hypertension, hyperlipidemia, and diabetes before and after COVID-19 infection among patients who were vaccinated vs unvaccinated before infection.

Excess risk for acute myocardial infarction mortality during the COVID-19 pandemic.

The COVID-19 pandemic has had a detrimental impact on the healthcare system. Our study armed to assess the extent and the disparity in excess acute myocardial infarction (AMI)-associated mortality during the pandemic, through the recent Omicron outbreak. Using data from the CDC's National Vital Statistics System, we identified 1 522 669 AMI-associated deaths occurring between 4/1/2012 and 3/31/2022. Accounting for seasonality, we compared age-standardized mortality rate (ASMR) for AMI-associated deaths between prepandemic and pandemic periods, including observed versus predicted ASMR, and examined temporal trends by demographic groups and region. Before the pandemic, AMI-associated mortality rates decreased across all subgroups. These trends reversed during the pandemic, with significant rises seen for the youngest-aged females and males even through the most recent period of the Omicron surge (10/2021-3/2022). The SAPC in the youngest and middle-age group in AMI-associated mortality increased by 5.3% (95% confidence interval [CI]: 1.6%-9.1%) and 3.4% (95% CI: 0.1%-6.8%), respectively. The excess death, defined as the difference between the observed and the predicted mortality rates, was most pronounced for the youngest (25-44 years) aged decedents, ranging from 23% to 34% for the youngest compared to 13%-18% for the oldest age groups. The trend of mortality suggests that age and sex disparities have persisted even through the recent Omicron surge, with excess AMI-associated mortality being most pronounced in younger-aged adults.

Evidence of premature lymphocyte aging in people with low anti-spike antibody levels after BNT162b2 vaccination.

SARS-CoV-2 vaccines have unquestionably blunted the overall impact of the COVID-19 pandemic, but host factors such as age, sex, obesity, and other co-morbidities can affect vaccine efficacy. We identified individuals in a relatively healthy population of healthcare workers (CORALE study cohort) who had unexpectedly low peak anti-spike receptor binding domain (S-RBD) antibody levels after receiving the BNT162b2 vaccine. Compared to matched controls, "low responders" had fewer spike-specific antibody-producing B cells after the second and third/booster doses. Moreover, their spike-specific T cell receptor (TCR) repertoire had less depth and their CD4+ and CD8+T cell responses to spike peptide stimulation were less robust. Single cell transcriptomic evaluation of peripheral blood mononuclear cells revealed activation of aging pathways in low responder B and CD4+T cells that could underlie their attenuated anti-S-RBD antibody production. Premature lymphocyte aging may therefore contribute to a less effective humoral response and could reduce vaccination efficacy.

Awareness of SARS-CoV-2 Omicron Variant Infection Among Adults With Recent COVID-19 Seropositivity.

Importance: Some individuals who were infected by the SARS-CoV-2 Omicron variant may have been completely unaware of their infectious status while the virus was actively transmissible. Objective: To examine awareness of infectious status among individuals during the recent Omicron variant surge in a diverse and populous urban region of Los Angeles County. Design, Setting, and Participants: This cohort study analyzed the records of adult employees and patients of an academic medical center who were enrolled in a longitudinal COVID-19 serological study in Los Angeles County, California. These participants had 2 or more serial anti-nucleocapsid IgG (IgG-N) antibody measurements at least 1 month apart, with the first occurring after the end of a regional Delta variant surge (September 15, 2021) and a subsequent one occurring after the start of a regional Omicron variant surge (December 15, 2021). Adults with evidence of new SARS-CoV-2 infection occurring during the Omicron variant surge period through May 4, 2022, were included in the present study sample. Exposures: Recent Omicron variant infection as evidenced by SARS-CoV-2 seroconversion. Main Outcomes and Measures: Awareness of recent SARS-CoV-2 infection was ascertained from review of self-reported health updates, medical records, and COVID-19 testing data. Results: Of the 210 participants (median [range] age, 51 (23-84) years; 136 women [65%]) with serological evidence of recent Omicron variant infection, 44% (92) demonstrated awareness of any recent Omicron variant infection and 56% (118) reported being unaware of their infectious status. Among those who were unaware, 10% (12 of 118) reported having had any symptoms, which they attributed to a common cold or other non-SARS-CoV-2 infection. In multivariable analyses that accounted for demographic and clinical characteristics, participants who were health care employees of the medical center were more likely than nonemployees to be aware of their recent Omicron variant infection (adjusted odds ratio, 2.46; 95% CI, 1.30-4.65). Conclusions and Relevance: Results of this study suggest that more than half of adults with recent Omicron variant infection were unaware of their infectious status and that awareness was higher among health care employees than nonemployees, yet still low overall. Unawareness may be a highly prevalent factor associated with rapid person-to-person transmission within communities.

How useful are body mass index and history of diabetes in COVID-19 risk stratification?

OBJECTIVE: This study examines the value of risk stratification by documented diagnosis of diabetes and objectively measured height and weight (BMI) in COVID-19 severity and mortality in a large sample of patients in an urban hospital located in Southern California. METHODS: Data from a retrospective cohort study of COVID-19 patients treated at Cedars-Sinai Medical Center between March 8, 2020, and January 25, 2021, was analyzed. Sociodemographic characteristics and pre-existing conditions were extracted from electronic medical records. Univariable and multivariable logistic regression models identified associated risk factors, and a regression causal mediation analysis examined the role of diabetes in the association between obesity and illness severity. All analyses were stratified by age (<65 and ≥65). RESULTS: Among individuals <65yo, diabetes accounted for 19-30% of the associations between obesity and COVID-19 illness severity. Among patients ≥65yo, having a BMI <18.5 was a risk factor for mortality regardless of diabetes history. CONCLUSION: Our findings have clinical implications in documenting which patients may be at elevated risk for adverse outcomes. More in-depth prospective studies are needed to capture how glycemic regulation may influence prognosis.

Demographic and clinical characteristics associated with variations in antibody response to BNT162b2 COVID-19 vaccination among healthcare workers at an academic medical centre: a longitudinal cohort analysis.

OBJECTIVES: We sought to understand the demographic and clinical factors associated with variations in longitudinal antibody response following completion of two-dose regiment of BNT162b2 vaccination. DESIGN: This study is a 10-month longitudinal cohort study of healthcare workers and serially measured anti-spike protein IgG (IgG-S) antibody levels using mixed linear models to examine their associations with participant characteristics. SETTING: A large, multisite academic medical centre in Southern California, USA. PARTICIPANTS: A total of 843 healthcare workers met inclusion criteria including completion of an initial two-dose course of BNT162b2 vaccination, complete clinical history and at least two blood samples for analysis. Patients had an average age of 45±13 years, were 70% female and 7% with prior SARS-CoV-2 infection. RESULTS: Vaccine-induced IgG-S levels remained in the positive range for 99.6% of individuals up to 10 months after initial two-dose vaccination. Prior SARS-CoV-2 infection was the primary correlate of sustained higher postvaccination IgG-S levels (partial R2=0.133), with a 1.74±0.11 SD higher IgG-S response (p<0.001). Female sex (beta 0.27±0.06, p<0.001), younger age (0.01±0.00, p<0.001) and absence of hypertension (0.17±0.08, p=0.003) were also associated with persistently higher IgG-S responses. Notably, prior SARS-CoV-2 infection augmented the associations of sex (-0.42 for male sex, p=0.08) and modified the associations of hypertension (1.17, p=0.001), such that infection-naïve individuals with hypertension had persistently lower IgG-S levels whereas prior infected individuals with hypertension exhibited higher IgG-S levels that remained augmented over time. CONCLUSIONS: While the IgG-S antibody response remains in the positive range for up to 10 months following initial mRNA vaccination in most adults, determinants of sustained higher antibody levels include prior SARS-CoV-2 infection, female sex, younger age and absence of hypertension. Certain determinants of the longitudinal antibody response appear significantly modified by prior infection status. These findings offer insights regarding factors that may influence the 'hybrid' immunity conferred by natural infection combined with vaccination.

New-Onset Atrial Fibrillation in Patients Hospitalized With COVID-19: Results From the American Heart Association COVID-19 Cardiovascular Registry.

BACKGROUND: New-onset atrial fibrillation (AF) in patients hospitalized with COVID-19 has been reported and associated with poor clinical outcomes. We aimed to understand the incidence of and outcomes associated with new-onset AF in a diverse and representative US cohort of patients hospitalized with COVID-19. METHODS: We used data from the American Heart Association COVID-19 Cardiovascular Disease Registry. Patients were stratified by the presence versus absence of new-onset AF. The primary and secondary outcomes were in-hospital mortality and major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, stroke, cardiogenic shock, and heart failure). The association of new-onset AF and the primary and secondary outcomes was evaluated using Cox proportional-hazards models for the primary time to event analyses. RESULTS: Of the first 30 999 patients from 120 institutions across the United States hospitalized with COVID-19, 27 851 had no history of AF. One thousand five hundred seventeen (5.4%) developed new-onset AF during their index hospitalization. New-onset AF was associated with higher rates of death (45.2% versus 11.9%) and MACE (23.8% versus 6.5%). The unadjusted hazard ratio for mortality was 1.99 (95% CI, 1.81-2.18) and for MACE was 2.23 (95% CI, 1.98-2.53) for patients with versus without new-onset AF. After adjusting for demographics, clinical comorbidities, and severity of disease, the associations with death (hazard ratio, 1.10 [95% CI, 0.99-1.23]) fully attenuated and MACE (hazard ratio, 1.31 [95% CI, 1.14-1.50]) partially attenuated. CONCLUSIONS: New-onset AF was common (5.4%) among patients hospitalized with COVID-19. Almost half of patients with new-onset AF died during their index hospitalization. After multivariable adjustment for comorbidities and disease severity, new-onset AF was not statistically significantly associated with death, suggesting that new-onset AF in these patients may primarily be a marker of other adverse clinical factors rather than an independent driver of mortality. Causality between the MACE composites and AF needs to be further evaluated.

Differences in SARS-CoV-2 Vaccine Response Dynamics Between Class-I- and Class-II-Specific T-Cell Receptors in Inflammatory Bowel Disease.

T-cells specifically bind antigens to induce adaptive immune responses using highly specific molecular recognition, and a diverse T-cell repertoire with expansion of antigen-specific clones can indicate robust immune responses after infection or vaccination. For patients with inflammatory bowel disease (IBD), a spectrum of chronic intestinal inflammatory diseases usually requiring immunomodulatory treatment, the T-cell response has not been well characterized. Understanding the patient factors that result in strong vaccination responses is critical to guiding vaccination schedules and identifying mechanisms of T-cell responses in IBD and other immune-mediated conditions. Here we used T-cell receptor sequencing to show that T-cell responses in an IBD cohort were influenced by demographic and immune factors, relative to a control cohort of health care workers (HCWs). Subjects were sampled at the time of SARS-CoV-2 vaccination, and longitudinally afterwards; TCR Vß gene repertoires were sequenced and analyzed for COVID-19-specific clones. We observed significant differences in the overall strength of the T-cell response by age and vaccine type. We further stratified the T-cell response into Class-I- and Class-II-specific responses, showing that Ad26.COV2.S vector vaccine induced Class-I-biased T-cell responses, whereas mRNA vaccine types led to different responses, with mRNA-1273 vaccine inducing a more Class-I-deficient T-cell response compared to BNT162b2. Finally, we showed that these T-cell patterns were consistent with antibody levels from the same patients. Our results account for the surprising success of vaccination in nominally immuno-compromised IBD patients, while suggesting that a subset of IBD patients prone to deficiencies in T-cell response may warrant enhanced booster protocols.

Review of Immunologic Manifestations of COVID-19 Infection and Vaccination.

We herein summarize currently available and clinically relevant information regarding the human immune responses to SARS-CoV-2 infection and vaccination, in relation to COVID-19 outcomes with a focus on acute respiratory distress syndrome (ARDS) and myocarditis.

Seasonal COVID-19 surge related hospital volumes and case fatality rates.

BACKGROUND: Seasonal and regional surges in COVID-19 have imposed substantial strain on healthcare systems. Whereas sharp inclines in hospital volume were accompanied by overt increases in case fatality rates during the very early phases of the pandemic, the relative impact during later phases of the pandemic are less clear. We sought to characterize how the 2020 winter surge in COVID-19 volumes impacted case fatality in an adequately-resourced health system. METHODS: We performed a retrospective cohort study of all adult diagnosed with COVID-19 in a large academic healthcare system between August 25, 2020 to May 8, 2021, using multivariable logistic regression to examine case fatality rates across 3 sequential time periods around the 2020 winter surge: pre-surge, surge, and post-surge. Subgroup analyses of patients admitted to the hospital and those receiving ICU-level care were also performed. Additionally, we used multivariable logistic regression to examine risk factors for mortality during the surge period. RESULTS: We studied 7388 patients (aged 52.8 ± 19.6 years, 48% male) who received outpatient or inpatient care for COVID-19 during the study period. Patients treated during surge (N = 6372) compared to the pre-surge (N = 536) period had 2.64 greater odds (95% CI 1.46-5.27) of mortality after adjusting for sociodemographic and clinical factors. Adjusted mortality risk returned to pre-surge levels during the post-surge period. Notably, first-encounter patient-level measures of illness severity appeared higher during surge compared to non-surge periods. CONCLUSIONS: We observed excess mortality risk during a recent winter COVID-19 surge that was not explained by conventional risk factors or easily measurable variables, although recovered rapidly in the setting of targeted facility resources. These findings point to how complex interrelations of population- and patient-level pandemic factors can profoundly augment health system strain and drive dynamic, if short-lived, changes in outcomes.