Sex differences in symptomatology and immune profiles of Long COVID (preprint)

Strong sex differences in the frequencies and manifestations of Long COVID (LC) have been reported with females significantly more likely than males to present with LC after acute SARS-CoV-2 infection1-7. However, whether immunological traits underlying LC differ between sexes, and whether such differences explain the differential manifestations of LC symptomology is currently unknown. Here, we performed sex-based multi-dimensional immune-endocrine profiling of 165 individuals8 with and without LC in an exploratory, cross-sectional study to identify key immunological traits underlying biological sex differences in LC. We found that female and male participants with LC experienced different sets of symptoms, and distinct patterns of organ system involvement, with female participants suffering from a higher symptom burden. Machine learning approaches identified differential sets of immune features that characterized LC in females and males. Males with LC had decreased frequencies of monocyte and DC populations, elevated NK cells, and plasma cytokines including IL-8 and TGF-{beta}-family members. Females with LC had increased frequencies of exhausted T cells, cytokine-secreting T cells, higher antibody reactivity to latent herpes viruses including EBV, HSV-2, and CMV, and lower testosterone levels than their control female counterparts. Testosterone levels were significantly associated with lower symptom burden in LC participants over sex designation. These findings suggest distinct immunological processes of LC in females and males and illuminate the crucial role of immune-endocrine dysregulation in sex-specific pathology.

Risk factors for experiencing Long-COVID symptoms: Insights from two nationally representative surveys (preprint)

BackgroundLong COVID (LC) is a complex and multisystemic condition marked by a diverse range of symptoms, yet its associated risk factors remain poorly defined. MethodsLeveraging data from the 2022 Behavioral Risk Factor Surveillance System (BRFSS) and National Health Interview Survey (NHIS), both representative of the United States population, this study aimed to identify demographic characteristics associated with LC. The sample was restricted to individuals aged 18 years and older who reported a positive COVID-19 test or doctors diagnosis. We performed a descriptive analysis comparing characteristics between participants with and without LC. Furthermore, we developed multivariate logistic regression models on demographic covariates that would have been valid at the time of the COVID-19 infection. ResultsAmong the 124,313 individuals in BRFSS and 10,131 in the NHIS reporting either a positive test or doctors diagnosis for COVID-19 (Table), 26,783 (21.5%) in BRFSS and 1,797 (17.1%) in NHIS reported LC. In the multivariate logistic regression model, we found middle age, female gender, Hispanic ethnicity, lack of a college degree, and residence in non-metropolitan areas associated with higher risk of LC. Notably, the initial severity of acute COVID-19 was strongly associated with LC risk. In contrast, significantly lower ORs were reported for Non-Hispanic Asian and Black Americans compared to Non-Hispanic White. ConclusionsIn the United States, there is marked variation in the risk of LC by demographic factors and initial infection severity. Further research is needed to understand the underlying cause of these observations.

Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naÏve individuals with Long COVID (preprint)

BackgroundLong COVID contributes to the global burden of disease. Proposed root cause hypotheses include the persistence of SARS-CoV-2 viral reservoir, autoimmunity, and reactivation of latent herpesviruses. Patients have reported various changes in Long COVID symptoms after COVID-19 vaccinations, leaving uncertainty about whether vaccine-induced immune responses may alleviate or worsen disease pathology. MethodsIn this prospective study, we evaluated changes in symptoms and immune responses after COVID-19 vaccination in 16 vaccine-naive individuals with Long COVID. Surveys were administered before vaccination and then at 2, 6, and 12 weeks after receiving the first vaccine dose of the primary series. Simultaneously, SARS-CoV-2-reactive TCR enrichment, SARS-CoV-2-specific antibody responses, antibody responses to other viral and self-antigens, and circulating cytokines were quantified before vaccination and at 6 and 12 weeks after vaccination. ResultsSelf-report at 12 weeks post-vaccination indicated 10 out of 16 participants had improved health, 3 had no change, 1 had worse health, and 2 reported marginal changes. Significant elevation in SARS-CoV-2-specific TCRs and Spike protein-specific IgG were observed 6 and 12 weeks after vaccination. No changes in reactivities were observed against herpes viruses and self-antigens. Within this dataset, higher baseline sIL-6R was associated with symptom improvement, and the two top features associated with non-improvement were high IFN-{beta} and CNTF, among soluble analytes. ConclusionsOur study showed that in this small sample, vaccination improved the health or resulted in no change to the health of most participants, though few experienced worsening. Vaccination was associated with increased SARS-CoV-2 Spike protein-specific IgG and T cell expansion in most individuals with Long COVID. Symptom improvement was observed in those with baseline elevated sIL-6R, while elevated interferon and neuropeptide levels were associated with a lack of improvement. Plain language summaryThe impact of the COVID-19 vaccine on vaccine-naive individuals suffering from Long COVID is uncertain. This study assessed the experience and immune signatures of 16 unvaccinated participants with Long COVID. A total of 10 participants had improved health status after vaccination, and one person reported only worsening health. As expected, vaccination increased immune cells and antibodies against the viral spike protein. Immune signatures may prove to be predictors of health status after vaccination. However, given the small number of participants, these initial findings need further validation.

Suicide deaths during the COVID-19 pandemic in the United States, by region, gender and age, March 1, 2020-June 30, 2022 (preprint)

The COVID-19 pandemic imposed substantial mental health stressors leading to concerns about an increased suicide risk. To investigate this issue, we investigated suicide mortality rates in the United States from March 1, 2020, through June 30, 2022, comparing them with data from the pre-pandemic period of January 2015 through February 2020. Suicide mortality in the United States was 3% below expected levels during the study period. However, there was an increased suicide incidence in adults ages 18–34 years. The concerns that the pandemic contributed to an overall marked increase in suicide risk is not supported by this analysis, but young adults did experience an increase.

Internal tremors and vibrations in long COVID: a cross-sectional study (preprint)

Background: Internal tremors and vibrations symptoms have been described as part of neurologic disorders but have not been fully described as a part of long COVID. We compared demographics, socioeconomic characteristics, pre-pandemic comorbidities, and new-onset conditions between people with internal tremors and vibrations as part of their long COVID symptoms and people with long COVID but without these symptoms. Methods: A cross-sectional study, Listen to Immune, Symptom and Treatment Experiences Now (LISTEN), collected data from adults with long COVID. The study sample included 423 participants enrolled between May 2022 and June 2023. Results: The 423 participants had a median age of 46 years (interquartile range, 38-56), 74% were female, 87% were Non-Hispanic White, and 158 (37%) reported "internal tremors, or buzzing/vibration" as a long COVID symptom. Before long COVID, the groups had similar comorbidities. Post-COVID, participants with internal tremors and vibrations had significantly worse health as measured by the Euro-QoL visual analogue scale (median: 40 vs. 50 points, P = 0.007), higher rates of financial difficulties caused by the pandemic and housing insecurity (P < 0.001 for each), and were significantly more likely to have new-onset conditions of mast cell disorders (11% vs. 2.6%), neurologic conditions (22% vs. 8.3%), anxiety (20% vs. 8.7%), and trauma- or stress-related mental health disorders (12% vs. 3.4%) compared with those without internal tremors (Bonferroni-adjusted P < 0.05 for each). Participants with internal tremors also reported significantly higher rates of cardiovascular, gastrointestinal, integumentary, and neurologic long COVID symptoms compared with those without internal tremors (Bonferroni-adjusted P < 0.05 for each). Conclusions and Relevance: Among people with long COVID, those with internal tremors and vibrations have more associated symptoms and worse health status, suggesting it may be associated with a severe phenotype of the condition.

Short- and longer-term all-cause mortality among SARS-CoV-2- infected persons and the pull-forward phenomenon in Qatar (preprint)

Background: Risk of short- and long-term all-cause mortality after a primary SARS-CoV-2 infection is inadequately understood. Methods: A national, matched, retrospective cohort study was conducted in Qatar to assess the risk of all-cause mortality in the national cohort of people infected with SARS-CoV-2 compared with a reference national control cohort of uninfected persons. Associations were estimated using Cox proportional-hazards regression models. Results: Among unvaccinated persons, within 90 days after primary infection, adjusted hazard ratio (aHR) comparing incidence of death in the primary-infection cohort with the infection-naive cohort was 1.19 (95% CI: 1.02-1.39). The aHR was 1.34 (95% CI: 1.11-1.63) in persons more clinically vulnerable to severe COVID-19 and 0.94 (95% CI: 0.72-1.24) in those less clinically vulnerable to severe COVID-19. In subsequent follow-up, the aHR was 0.50 (95% CI: 0.37-0.68). The aHR was 0.41 (95% CI: 0.28-0.58) in months 3-7 after the primary infection and 0.76 (95% CI: 0.46-1.26) in subsequent months. The aHR was 0.37 (95% CI: 0.25-0.54) in persons more clinically vulnerable to severe COVID-19 and 0.77 (95% CI: 0.48-1.24) in those less clinically vulnerable to severe COVID-19. Among vaccinated persons, no evidence was found for differences in incidence of death in the primary-infection versus infection-naive cohorts, even among persons more clinically vulnerable to severe COVID-19. Conclusions: COVID-19 mortality in Qatar appears primarily driven by forward displacement of deaths of individuals with relatively short life expectancy and more clinically vulnerable to severe COVID-19. Vaccination negated the mortality displacement by preventing early deaths.

Two years of COVID-19: Excess mortality by age, region, gender, and race/ethnicity in the United States during the COVID-19 pandemic, March 1, 2020, through February 28, 2022 (preprint)

Introduction Excess mortality does not depend on labeling the cause of death and is an accurate representation of the pandemic population-level effects. A comprehensive evaluation of all-cause excess mortality in the United States during the first two years of the COVID-19 pandemic, stratified by age, sex, region, and race/ethnicity can provide insight into the extent and variation in harm. Methods With Centers for Disease Control and Prevention (CDC)/National Center for Health Statistics (NCHS) data from 2014-2022, we use seasonal autoregressive integrated moving averages (sARIMA) to estimate excess mortality during the pandemic, defined as the difference between the number of observed and expected deaths. We continuously correct monthly expected deaths to reflect the decreased population owing to cumulative pandemic-associated excess deaths recorded. We calculate excess mortality for the total US population, and by age, sex, US census division, and race/ethnicity. Results From March 1, 2020, through February 28, 2022, there were 1.17 million excess deaths in the United States. Overall, mortality was 20% higher than expected during the study period. Of the excess deaths, 799,477 (68%) were among residents aged 65 and older. The largest relative increase in all-cause mortality was 27% among adults ages 18-49 years. Males comprised most of the excess mortality (57%), but this predominance declined with age. A higher relative mortality occurred among non-Hispanic American Indian/Alaskan Native, non-Hispanic Black, non-Hispanic Native Hawaiian and Other Pacific Islander, Hispanic people. Excess mortality differed by region; the highest rates were in the South, including in the population ages ≥65 years. Excess mortality rose and fell contemporaneously with COVID-19 waves. Conclusion In the first two years of the pandemic, the US experienced 1.17 million excess deaths, with greater relative increases in all-cause mortality among men, in American Indian/Alaskan Native, Black and Hispanic people, and the South.

Distinguishing features of Long COVID identified through immune profiling (preprint)

SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID 1–3 . Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions 1–3 ; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Here, 215 individuals were included in an exploratory, cross-sectional study to perform multi-dimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID. Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups, as well as evidence of elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID. Further, unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus. Analysis of circulating immune mediators and various hormones also revealed pronounced differences, with levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups. Integration of immune phenotyping data into unbiased machine learning models identified significant distinguishing features critical in accurate classification of Long COVID, with decreased levels of cortisol being the most significant individual predictor. These findings will help guide additional studies into the pathobiology of Long COVID and may aid in the future development of objective biomarkers for Long COVID.

The uncoupling of all-cause excess mortality from Covid-19 cases and associated hospitalizations in late winter and spring of 2022 in a highly vaccinated state. (preprint)

Introduction: Since March 2020, all-cause excess mortality (the number of all-cause deaths exceeding the baseline number of expected deaths) has been observed in waves coinciding with Covid-19 outbreaks in the United States. We recently described high levels of excess mortality in Massachusetts during the initial 8-week Omicron wave. However, whether excess mortality continued after that period (during which an outbreak of Omicron subvariants occurred) is unknown. Methods: We applied seasonal autoregressive integrated moving averages to five years of pre-pandemic data provided by the Massachusetts Registry of Vital Records and Statistics (MRVRS) to project the weekly populations and expected deaths for the pandemic period. Observed deaths during the pandemic were also provided by MRVRS and are >99% complete for all study weeks. Results: During the 18-week Omicron subvariant period (the week ending February 27, 2022, through June 26, 2022) the incidence of all-cause excess mortality was 0.1 per 100,000-person weeks, corresponding to 148 excess deaths (95%. CI -907 to 1153), representing a 97.1% decrease from the initial Omicron period (during which all-cause excess mortality was 4.0 per 100,000-person-weeks), and a 91.9% reduction from the Delta and Delta-Omicron transition period (during which all-cause excess mortality was 1.5 per 100,000-person-weeks), despite >226,000 reported new Covid-19 cases during the subvariant/spring period. However, Covid-19-associated hospitalizations were observed during the subvariant/spring 2022 period. Conclusion: In a highly vaccinated state with a recent wave of SARS-CoV-2, all-cause excess mortality was uncoupled from new case counts, indicating the possibility of temporary protection from the most severe outcomes related to Covid-19 among high-risk individuals. However, given the possibility of waning immunity and the emerging of new variants, continued monitoring is warranted.

Prevalence of COVID-19 and Long COVID in Collegiate Student Athletes from Spring 2020 to Fall 2021: A Retrospective Survey (preprint)

Symptomatic COVID-19 and post-COVID conditions, also referred to as post-acute sequelae of SARS-CoV-2 (PASC) or Long COVID, have been widely reported in young, healthy people, but their prevalence has not yet been determined in student athletes. We surveyed a convenience sample of 18 collegiate school administrators, representing about 7,000 student athletes. According to their survey responses, 9.8% of student athletes tested positive for COVID-19 in spring 2020 and 25.4% tested positive in the academic year of fall 2020 to spring 2021. About 4% of student athletes who tested positive from spring 2020 to spring 2021 developed Long COVID, defined as new, recurring, or ongoing physical or mental health consequences occurring 4 or more weeks after SARS-CoV-2 infection. This study highlights that Long COVID occurs in healthy collegiate athletes and merits a larger study to determine population-wide prevalence.

Racial and ethnic disparities in COVID-19 vaccinations in the United States during the booster rollout. (preprint)

Background: We sought to quantify whether there were statistically significant disparities along race and ethnicity lines during the early rollout of Covid-19 vaccine booster doses in the United States. We also studied whether such disparities replicated or widened disparities that had already been observed during the initial series rollout as of 2 months earlier (Janssen) or 6 months earlier (Pfizer-BioNTech or Moderna), which comprised the booster-eligible population. Methods: This cross-sectional study of US adults (ages [≥]18 years) used public data from US Centers for Disease Control and Prevention. The observed shares of vaccine doses for each race and ethnicity were compared to the expected shares, predicted based upon the compositions of the booster-eligible and initial series-eligible populations. Results: As of November 16, 2021, 123.5 million US adults were eligible for a booster dose of either the Pfizer-BioNTech, Moderna, or Janssen vaccines. Of these, 21.7 million had received a booster dose, among whom race and ethnicity information was available for 18.8 million booster recipients. A statistically significant higher share of Non-Hispanic White and Non-Hispanic Multiple/Other race individuals had received a booster vaccination than projected based on the composition of the booster-eligible population. A statistically significant lower share of Hispanic, Non-Hispanic American Indian/Alaskan Native, Non-Hispanic Asian, Non-Hispanic Black, and Non-Hispanic Native Hawaiian/Other Pacific Islander individuals had received a booster vaccination than expected based on the booster-eligible population. A secondary analysis of the booster-eligible population found that some of these disparities had already occurred at the time of the initial series. However, the booster campaign widened all of those disparities and added new disparities for Non-Hispanic American Indian/Alaskan Native and Non-Hispanic Native Hawaiian/Other Pacific Islander individuals. Conclusion: Disparities in Covid-19 vaccine administration on race and ethnicity lines occurred during the initial series rollout in the US. However, these disparities were not merely replicated but widened by the early booster rollout.

Internal Tremors and Vibration Symptoms Among People with Post-Acute Sequelae of SARS-CoV-2: A narrative review of patient reports (preprint)

To introduce the perspective of patients who have PASC with vibrations and tremors as a prominent component, we leveraged the efforts by Survivor Corps, a grassroots COVID-19 patient advocacy group, to gather information from people in their Facebook group suffering from vibrations and tremors. Survivor Corps collected 140 emails and 450 Facebook comments from members. From the emails, we identified 22 themes and 7 broader domains based on common coding techniques for qualitative data and the constant comparative method of qualitative data analysis. Facebook comments were analyzed using Word Clouds to visualize frequency of terms. The respondent emails reflected 7 domains that formed the basis of characterizing their experience with vibrations and tremors. These domains were: (1) symptom experience, description, and anatomic location; (2) initial symptom onset; (3) symptom timing; (4) symptom triggers or alleviators; (5) change from baseline health status; (6) experience with medical establishment; and (7) impact on lives and livelihood. There were 22 themes total, each corresponding to one of the broader domains. The Facebook comments Word Cloud revealed that the 10 most common words used in comments were: tremors (64), covid (55), pain (51), vibrations (43), months (36), burning (29), feet (24), hands (22), legs (21), back (20). Overall, these patient narratives described intense suffering, and there is still no diagnosis or treatment available.

Absence of Excess Mortality in a Highly Vaccinated Population During the Initial Covid-19 Delta Period. (preprint)

BackgroundAll-cause excess mortality (the number of deaths that exceed projections in any period) has been widely reported during the Covid-19 pandemic. Whether excess mortality has occurred during the Delta wave is less well understood. MethodsWe performed an observational study using data from the Massachusetts Department of Health. Five years of US Census population data and CDC mortality statistics were applied to a seasonal autoregressive integrated moving average (sARIMA) model to project the number of expected deaths for each week of the pandemic period, including the Delta period (starting in June 2021, extending through August 28th 2021, for which mortality data are >99% complete). Weekly Covid-19 cases, Covid-19-attributed deaths, and all-cause deaths are reported. County-level excess mortality during the vaccine campaign are also reported, with weekly rates of vaccination in each county that reported 100 or more all-cause deaths during any week included in the study period. ResultsAll-cause mortality was not observed after March 2021, by which time over 75% of persons over 65 years of age in Massachusetts had received a vaccination. Fewer deaths than expected (which we term deficit mortality) occurred both during the summer of 2020, the spring of 2021 and during the Delta wave (beginning June 13, 2021 when Delta isolates represented >10% of sequenced cases). After the initial wave in the spring of 2020, more Covid-19-attributed deaths were recorded that all-cause excess deaths, implying that Covid-19 was misattributed as the underlying cause, rather than a contributing cause of death in some cases. ConclusionIn a state with high vaccination rates, excess mortality has not been recorded during the Delta period. Deficit mortality has been recorded during this period.

Breakthrough Symptomatic COVID-19 Infections Leading to Long Covid: Report from Long Covid Facebook Group Poll (preprint)

Vaccines have been shown to be extremely effective in preventing COVID-19 hospitalizations and deaths. However, a question remains whether vaccine breakthrough cases can still lead to Post-Acute Sequelae of SARS-CoV-2 (PASC), also known as Long Covid. To address this question, the Survivor Corps group, a grassroots COVID-19 organization focused on patient support and research, posted a poll to its 169,900 members that asked about breakthrough cases, Long Covid, and hospitalizations. 1,949 people who self-report being fully vaccinated have responded to date. While robust data are needed in a larger, unbiased sample to extrapolate rates to the population, we analyzed the results of this public poll to determine what people were reporting regarding Long Covid after breakthrough infection and to prompt discussion of how breakthrough cases are measured. The poll was posted in the Survivor Corps Facebook group ([~]169,900 members). Of the 1,949 participants who responded to the poll, 44 reported a symptomatic breakthrough case and 24 of those reported that the case led to symptoms of Long Covid. 1 of these 24 cases was reported to have led to hospitalization in addition to Long Covid.

Change in Symptoms and Immune Response in People with Post-Acute Sequelae of SARS-Cov-2 Infection (PASC) After SARS-Cov-2 Vaccination (preprint)

As more people are vaccinated against SARS-CoV-2, many of those already infected are still suffering from Post-Acute Sequelae (PASC). Although there is no current treatment for PASC, reports from patients that the vaccine itself improves, and in some reports, worsens, PASC symptoms may lead to a deeper understanding of the causes of PASC symptoms and viable treatments. As such, we are conducting a study that measures the changes in PASC symptoms after vaccination. We are collecting baseline self-report and biospecimens for immune assays and then are following up with participants to collect the same data at 2-weeks, 6-weeks, and 12-weeks post-vaccination (first dose). Immune assays using blood specimens will include B-cell, T-cell, and myeloid cell panels; evaluation of T-cell responsiveness to SARS-CoV-2 peptides and antigen specific response; autoantibody screening (of IgG, IgM, and IgA antibodies that attack human proteins); and TCR sequencing and antigen mapping of CD8+ T-cells. Mucosal immunity will be measured using saliva specimens. The study aims to provide answers for people with PASC, especially regarding the causes of their symptoms and how the vaccine may affect them, and clues for PASC treatment.

Lipid-Modulating Agents for Prevention or Treatment of COVID-19 in Randomized Trials (preprint)

Coronavirus disease 2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multi-organ manifestations. Lipid modulating agents may be useful in treating patients with COVID-19. They may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglycerides portends worse outcome in patients with COVID-19. Upon a systematic search, 40 RCTs with lipid modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrates RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for management or prevention of COVID-19. This manuscript summarizes the ongoing or completed randomized controlled trials (RCTs) of lipid modulating agents in COVID-19 and the implications of these trials for patient management.

Accuracy of Computable Phenotyping Approaches for SARS-CoV-2 Infection and COVID-19 Hospitalizations from the Electronic Health Record (preprint)

ABSTRACT Objective Real-world data have been critical for rapid-knowledge generation throughout the COVID-19 pandemic. To ensure high-quality results are delivered to guide clinical decision making and the public health response, as well as characterize the response to interventions, it is essential to establish the accuracy of COVID-19 case definitions derived from administrative data to identify infections and hospitalizations. Methods Electronic Health Record (EHR) data were obtained from the clinical data warehouse of the Yale New Haven Health System (Yale, primary site) and 3 hospital systems of the Mayo Clinic (validation site). Detailed characteristics on demographics, diagnoses, and laboratory results were obtained for all patients with either a positive SARS-CoV-2 PCR or antigen test or ICD-10 diagnosis of COVID-19 (U07.1) between April 1, 2020 and March 1, 2021. Various computable phenotype definitions were evaluated for their accuracy to identify SARS-CoV-2 infection and COVID-19 hospitalizations. Results Of the 69,423 individuals with either a diagnosis code or a laboratory diagnosis of a SARS-CoV-2 infection at Yale, 61,023 had a principal or a secondary diagnosis code for COVID-19 and 50,355 had a positive SARS-CoV-2 test. Among those with a positive laboratory test, 38,506 (76.5%) and 3449 (6.8%) had a principal and secondary diagnosis code of COVID-19, respectively, while 8400 (16.7%) had no COVID-19 diagnosis. Moreover, of the 61,023 patients with a COVID-19 diagnosis code, 19,068 (31.2%) did not have a positive laboratory test for SARS-CoV-2 in the EHR. Of the 20 cases randomly sampled from this latter group for manual review, all had a COVID-19 diagnosis code related to asymptomatic testing with negative subsequent test results. The positive predictive value (precision) and sensitivity (recall) of a COVID-19 diagnosis in the medical record for a documented positive SARS-CoV-2 test were 68.8% and 83.3%, respectively. Among 5,109 patients who were hospitalized with a principal diagnosis of COVID-19, 4843 (94.8%) had a positive SARS-CoV-2 test within the 2 weeks preceding hospital admission or during hospitalization. In addition, 789 hospitalizations had a secondary diagnosis of COVID-19, of which 446 (56.5%) had a principal diagnosis consistent with severe clinical manifestation of COVID-19 (e.g., sepsis or respiratory failure). Compared with the cohort that had a principal diagnosis of COVID-19, those with a secondary diagnosis had a more than 2-fold higher in-hospital mortality rate (13.2% vs 28.0%, P<0.001). In the validation sample at Mayo Clinic, diagnosis codes more consistently identified SARS-CoV-2 infection (precision of 95%) but had lower recall (63.5%) with substantial variation across the 3 Mayo Clinic sites. Similar to Yale, diagnosis codes consistently identified COVID-19 hospitalizations at Mayo, with hospitalizations defined by secondary diagnosis code with 2-fold higher in-hospital mortality compared to those with a primary diagnosis of COVID-19. Conclusions COVID-19 diagnosis codes misclassified the SARS-CoV-2 infection status of many people, with implications for clinical research and epidemiological surveillance. Moreover, the codes had different performance across two academic health systems and identified groups with different risks of mortality. Real-world data from the EHR can be used to in conjunction with diagnosis codes to improve the identification of people infected with SARS-CoV-2.

Physical Activity Patterns Among Patients with Intracardiac Remote Monitoring Devices Before, During, and After COVID-19-related Public Health Restrictions (preprint)

ABSTRACT Nationwide public health restrictions due to the coronavirus disease 2019 (COVID-19) pandemic have disrupted people’s routine physical activities, yet little objective information is available on the extent to which physical activity has changed among patients with pre-existing cardiac diseases. Using remote monitoring data of 9,924 patients with pacemakers and implantable cardiac defibrillators (ICDs) living in New York City and Minneapolis/Saint Paul, we assessed physical activity patterns among these patients in 2019 and 2020 from January through October. We found marked declines in physical activity among patients with implantable cardiac devices during COVID-19-related restrictions and the reduction was consistent across age and sex subgroups. Moreover, physical activity among these vulnerable patients did not return to pre-restrictions levels several months after COVID-19 restrictions were eased. Our findings highlight the need to consider the unintended consequences of mitigation strategies and develop approaches to encourage safe physical activity during the pandemic.

Trends in Thoracic Impedance and Arrhythmia Burden Among Patients with Implanted Cardiac Defibrillators During the COVID-19 Pandemic (preprint)

Hospitalizations for acute cardiac conditions have markedly declined during the coronavirus disease 2019 (COVID-19) pandemic, yet the cause of this decline is not clear. Using remote monitoring data of 4,029 patients with implantable cardiac defibrillators (ICDs) living in New York City and Minneapolis/Saint Paul, we assessed changes in markers of cardiac status among these patients and compared thoracic impedance and arrhythmia burden in 2019 and 2020 from January through August. We found no change in several key disease decompensation markers among patients with implanted ICD devices during the first phase of COVID-19 pandemic, suggesting that the decrease in cardiovascular hospitalizations in this period is not reflective of a true population-level improvement in cardiovascular health.

Mortality from injury, overdose and suicide during the 2020 COVID-19 pandemic, March-July, 2020 (preprint)

Introduction: The COVID-19 pandemic has been associated with substantial rates of all-cause excess mortality. The contribution of external causes of death to excess mortality including drug overdose, homicide, suicide, and unintentional injuries during the initial outbreak in the United States is less well documented. Methods Using public data published by the National Center for Health Statistics on February 10, 2021, we measured monthly excess mortality (the gap between observed and expected deaths) from five external causes using national-level data published by National Center for Health Statistics; assault (homicide); intentional self-harm (suicide); accidents (unintentional injuries); and motor vehicle accidents. We used seasonal autoregressive integrated moving average (sARIMA) models developed with cause-specific monthly mortality counts and US population data from 2015-2019 and estimated the contribution of individual cause-specific mortality to all-cause excess mortality from March-July 2020. Results From March-July, 2020, 212,825 (95% CI 136,236-290,776) all-cause excess deaths occurred in the US). There were 8,540 excess drug overdoses (all intents) (95% CI 5,106 to 11,975), accounting for 4% of all excess mortality; 1,455 excess homicide deaths (95% CI 708 to 2202, accounting for 0.7% of excess mortality; 5,492 excess deaths due to unintentional accidents occurred (95% CI 85 to 10,899, accounting for 2.6% of excess mortality. Though a non-significantly 135 (95% CI -1361 to 1,630) more MVA deaths were recorded during the study period, a significant decrease in April (525; 95% CI -817 to -233) and significant increases in June-July (965; 95% CI 348 to 1,587) were observed. Suicide deaths were statistically lower than projected by 2,067 (95% CI 941-3,193 fewer deaths). Meaning Excess deaths from drug overdoses, homicide, and addicents occurred during the pandemic but represented a small fraction of all-cause excess mortality. The excess external causes of death, however, still represent thousands of lives lost. Notably, deaths from suicide were lower than expected and therefore did not contribute to excess mortality.