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      Background Rates of Adverse Events of Special Interest for COVID-19 Vaccine Safety Monitoring in the United States, 2019–2020

      research-article
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      Vaccine
      Published by Elsevier Ltd.
      background rates, vaccine safety surveillance, COVID-19, adverse events, AESI, Adverse Event of Special Interest, AMI, Acute Myocardial Infarction, BEST, CBER Biologics Effectiveness and Safety, BHI, Blue Health Intelligence, CBER, Center for Biologics Evaluation and Research, CI, Confidence Interval, CMS, Centers for Medicare & Medicaid Services, DIC, Disseminated Intravascular Coagulation, DVT, Deep Vein Thrombosis, EHR, Electronic Health Record, EUA, Emergency Use Authorization, FDA, Food and Drug Administration, GBS, Guillain-Barré Syndrome, ICD-10-CM/PCS, International Classification of Diseases, Tenth Revision, Clinical Modification/Procedure Coding System , IR, Incidence Rate, IRR, Incidence Rate Ratio, ITP, Immune Thrombocytopenia, PE, Pulmonary Embolism, SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2, TTS, Thrombosis with Thrombocytopenia Syndrome

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          Abstract

          Background

          The U.S. Food and Drug Administration (FDA) Biologics Effectiveness and Safety (BEST) Initiative conducts active surveillance of adverse events of special interest (AESI) after COVID-19 vaccination. Historical incidence rates (IRs) of AESI are comparators to evaluate safety.

          Methods

          We estimated IRs of 17 AESI in six administrative claims databases from January 1, 2019, to December 11, 2020: Medicare claims for adults ≥65 years and commercial claims (Blue Health Intelligence®, CVS Health, HealthCore Integrated Research Database, IBM® MarketScan® Commercial Database, Optum pre-adjudicated claims) for adults <65 years. IRs were estimated by sex, age, race/ethnicity (Medicare), and nursing home residency (Medicare) in 2019 and for specific periods in 2020.

          Results

          The study included >100 million enrollees annually. In 2019, rates of most AESI increased with age. However, compared with commercially insured adults, Medicare enrollees had lower IRs of anaphylaxis (11 vs. 12–19 per 100,000 person-years), appendicitis (80 vs. 117–155), and narcolepsy (38 vs. 41–53). Rates were higher in males than females for most AESI across databases and varied by race/ethnicity and nursing home status (Medicare). Acute myocardial infarction (Medicare) and anaphylaxis (all databases) IRs varied by season. IRs of most AESI were lower during March–May 2020 compared with March–May 2019 but returned to pre-pandemic levels after May 2020. However, rates of Bell’s palsy, Guillain-Barré syndrome, narcolepsy, and hemorrhagic/non-hemorrhagic stroke remained lower in multiple databases after May 2020, whereas some AESI (e.g., disseminated intravascular coagulation) exhibited higher rates after May 2020 compared with 2019.

          Conclusion

          AESI background rates varied by database and demographics and fluctuated in March–December 2020, but most returned to pre-pandemic levels after May 2020. It is critical to standardize demographics and consider seasonal and other trends when comparing historical rates with post-vaccination AESI rates in the same database to evaluate COVID-19 vaccine safety.

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          Long-term cardiovascular outcomes of COVID-19

          The cardiovascular complications of acute coronavirus disease 2019 (COVID-19) are well described, but the post-acute cardiovascular manifestations of COVID-19 have not yet been comprehensively characterized. Here we used national healthcare databases from the US Department of Veterans Affairs to build a cohort of 153,760 individuals with COVID-19, as well as two sets of control cohorts with 5,637,647 (contemporary controls) and 5,859,411 (historical controls) individuals, to estimate risks and 1-year burdens of a set of pre-specified incident cardiovascular outcomes. We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care). Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease.
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            Delay or Avoidance of Medical Care Because of COVID-19–Related Concerns — United States, June 2020

            Temporary disruptions in routine and nonemergency medical care access and delivery have been observed during periods of considerable community transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) ( 1 ). However, medical care delay or avoidance might increase morbidity and mortality risk associated with treatable and preventable health conditions and might contribute to reported excess deaths directly or indirectly related to COVID-19 ( 2 ). To assess delay or avoidance of urgent or emergency and routine medical care because of concerns about COVID-19, a web-based survey was administered by Qualtrics, LLC, during June 24–30, 2020, to a nationwide representative sample of U.S. adults aged ≥18 years. Overall, an estimated 40.9% of U.S. adults have avoided medical care during the pandemic because of concerns about COVID-19, including 12.0% who avoided urgent or emergency care and 31.5% who avoided routine care. The estimated prevalence of urgent or emergency care avoidance was significantly higher among the following groups: unpaid caregivers for adults* versus noncaregivers (adjusted prevalence ratio [aPR] = 2.9); persons with two or more selected underlying medical conditions † versus those without those conditions (aPR = 1.9); persons with health insurance versus those without health insurance (aPR = 1.8); non-Hispanic Black (Black) adults (aPR = 1.6) and Hispanic or Latino (Hispanic) adults (aPR = 1.5) versus non-Hispanic White (White) adults; young adults aged 18–24 years versus adults aged 25–44 years (aPR = 1.5); and persons with disabilities § versus those without disabilities (aPR = 1.3). Given this widespread reporting of medical care avoidance because of COVID-19 concerns, especially among persons at increased risk for severe COVID-19, urgent efforts are warranted to ensure delivery of services that, if deferred, could result in patient harm. Even during the COVID-19 pandemic, persons experiencing a medical emergency should seek and be provided care without delay ( 3 ). During June 24–30, 2020, a total of 5,412 (54.7%) of 9,896 eligible adults ¶ completed web-based COVID-19 Outbreak Public Evaluation Initiative surveys administered by Qualtrics, LLC.** The Human Research Ethics Committee of Monash University (Melbourne, Australia) reviewed and approved the study protocol on human subjects research. This activity was also reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. †† Respondents were informed of the study purposes and provided electronic consent before commencement, and investigators received anonymized responses. The 5,412 participants included 3,683 (68.1%) first-time respondents and 1,729 (31.9%) persons who had completed a related survey §§ during April 2–8, 2020. Among the 5,412 participants, 4,975 (91.9%) provided complete data for all variables in this analysis. Quota sampling and survey weighting ¶¶ were employed to improve cohort representativeness of the U.S. population by gender, age, and race/ethnicity. Respondents were asked “Have you delayed or avoided medical care due to concerns related to COVID-19?” Delay or avoidance was evaluated for emergency (e.g., care for immediate life-threatening conditions), urgent (e.g., care for immediate non–life-threatening conditions), and routine (e.g., annual check-ups) medical care. Given the potential for variation in interpretation of whether conditions were life-threatening, responses for urgent and emergency care delay or avoidance were combined for analysis. Covariates included gender; age; race/ethnicity; disability status; presence of one or more selected underlying medical conditions known to increase risk for severe COVID-19; education; essential worker status***; unpaid adult caregiver status; U.S. census region; urban/rural classification ††† ; health insurance status; whether respondents knew someone who had received a positive SARS-CoV-2 test result or had died from COVID-19; and whether the respondents believed they were at high risk for severe COVID-19. Comparisons within all these subgroups were evaluated using multivariable Poisson regression models §§§ with robust standard errors to estimate prevalence ratios adjusted for all covariates, 95% confidence intervals, and p-values to evaluate statistical significance (α = 0.05) using the R survey package (version 3.29) and R software (version 4.0.2; The R Foundation). As of June 30, 2020, among 4,975 U.S. adult respondents, 40.9% reported having delayed or avoided any medical care, including urgent or emergency care (12.0%) and routine care (31.5%), because of concerns about COVID-19 (Table 1). Groups of persons among whom urgent or emergency care avoidance exceeded 20% and among whom any care avoidance exceeded 50% included adults aged 18–24 years (30.9% for urgent or emergency care; 57.2% for any care), unpaid caregivers for adults (29.8%; 64.3%), Hispanic adults (24.6%; 55.5%), persons with disabilities (22.8%; 60.3%), persons with two or more selected underlying medical conditions (22.7%; 54.7%), and students (22.7%; 50.3%). One in four unpaid caregivers reported caring for adults who were at increased risk for severe COVID-19. TABLE 1 Estimated prevalence of delay or avoidance of medical care because of concerns related to COVID-19, by type of care and respondent characteristics — United States, June 30, 2020 Characteristic No. (%)† Type of medical care delayed or avoided* Urgent or emergency Routine Any %† P-value§ %† P-value§ %† P-value§ All respondents 4,975 (100) 12.0 — 31.5 — 40.9 — Gender Female 2,528 (50.8) 11.7 0.598 35.8 <0.001 44.9 <0.001 Male 2,447 (49.2) 12.3 27.0 36.7 Age group, yrs 18–24 650 (13.1) 30.9 <0.001 29.6 0.072 57.2 <0.001 25–44 1,740 (35.0) 14.9 34.2 44.8 45–64 1,727 (34.7) 5.7 30.0 34.5 ≥65 858 (17.3) 4.4 30.3 33.5 Race/Ethnicity White, non-Hispanic 3,168 (63.7) 6.7 <0.001 30.9 0.020 36.2 <0.001 Black, non-Hispanic 607 (12.2) 23.3 29.7 48.1 Asian, non-Hispanic 238 (4.8) 8.6 31.3 37.7 Other race or multiple races, non-Hispanic¶ 150 (3.0) 15.5 23.9 37.3 Hispanic, any race or races 813 (16.3) 24.6 36.4 55.5 Disability** Yes 1,108 (22.3) 22.8 <0.001 42.9 <0.001 60.3 <0.001 No 3,867 (77.7) 8.9 28.2 35.3 Underlying medical condition†† No 2,537 (51.0) 8.2 <0.001 27.9 <0.001 34.7 <0.001 One 1,328 (26.7) 10.4 33.0 41.2 Two or more 1,110 (22.3) 22.7 37.7 54.7 2019 household income, USD <25,000 665 (13.4) 13.9 0.416 31.2 0.554 42.8 0.454 25,000–49,999 1,038 (20.9) 11.1 30.9 38.6 50,000–99,999 1,720 (34.6) 12.5 30.5 41.1 ≥100,000 1,552 (31.2) 11.2 33.0 41.4 Education Less than high school diploma 65 (1.3) 15.6 0.442 24.7 0.019 37.9 0.170 High school diploma 833 (16.7) 12.3 28.1 38.1 Some college 1,302 (26.2) 13.6 29.7 40.3 Bachelor's degree 1,755 (35.3) 11.2 34.8 43.6 Professional degree 1,020 (20.5) 10.9 31.2 39.5 Employment status Employed 3,049 (61.3) 14.6 <0.001 31.5 0.407 43.3 <0.001 Unemployed 630 (12.7) 8.7 34.4 39.5 Retired 1,129 (22.7) 5.3 29.9 33.8 Student 166 (3.3) 22.7 30.5 50.3 Essential worker status§§ Essential worker 1,707 (34.3) 19.5 <0.001 32.4 0.293 48.0 <0.001 Nonessential worker 1,342 (27.0) 8.4 30.3 37.3 Unpaid caregiver status¶¶ Unpaid caregiver for adults 1,344 (27.0) 29.8 <0.001 41.0 <0.001 64.3 <0.001 Not unpaid caregiver for adults 3,631 (73.0) 5.4 27.9 32.2 U.S. Census region*** Northeast 1,122 (22.6) 11.0 0.008 33.9 0.203 42.5 0.460 Midwest 936 (18.8) 8.5 32.0 38.7 South 1,736 (34.9) 13.9 29.6 40.7 West 1,181 (23.7) 13.0 31.5 41.5 Rural/Urban classification††† Urban 4,411 (88.7) 12.3 0.103 31.5 0.763 41.2 0.216 Rural 564 (11.3) 9.4 30.9 38.2 Health insurance status Yes 4,577 (92.0) 12.4 0.036 32.6 <0.001 42.3 <0.001 No 398 (8.0) 7.8 18.4 24.8 Know someone with positive test results for SARS-CoV-2§§§ Yes 989 (19.9) 8.8 0.004 40.7 <0.001 46.6 <0.001 No 3,986 (80.1) 12.8 29.2 39.5 Knew someone who died from COVID-19 Yes 364 (7.3) 10.1 0.348 41.4 <0.001 46.3 0.048 No 4,611 (92.7) 12.2 30.7 40.5 Believed to be in group at high risk for severe COVID-19 Yes 981 (19.7) 10.0 0.050 42.5 <0.001 49.4 <0.001 No 3,994 (80.3) 12.5 28.8 38.8 Abbreviations: CI = confidence interval; COVID-19 = coronavirus disease 2019; USD = U.S. dollars. * The types of medical care avoidance are not mutually exclusive; respondents had the option to indicate that they had delayed or avoided more than one type of medical care (i.e., routine medical care and urgent/emergency medical care). † Statistical raking and weight trimming were employed to improve the cross-sectional June cohort representativeness of the U.S. population by gender, age, and race/ethnicity according to the 2010 U.S. Census. § The Rao-Scott adjusted Pearson chi-squared test was used to test for differences in observed and expected frequencies among groups by characteristic for avoidance of each type of medical care (e.g., whether avoidance of routine medical care differs significantly by gender). Statistical significance was evaluated at a threshold of α = 0.05. ¶ “Other” race includes American Indian or Alaska Native, Native Hawaiian or Pacific Islander, or Other. ** Persons who had a disability were defined as such based on a qualifying response to either one of two questions: “Are you limited in any way in any activities because of physical, mental, or emotional condition?” and “Do you have any health conditions that require you to use special equipment, such as a cane, wheelchair, special bed, or special telephone?” https://www.cdc.gov/brfss/questionnaires/pdf-ques/2015-brfss-questionnaire-12-29-14.pdf. †† Selected underlying medical conditions known to increase the risk for severe COVID-19 included in this analysis were obesity, diabetes, high blood pressure, cardiovascular disease, and any type of cancer. Obesity is defined as body mass index ≥30 kg/m2 and was calculated from self-reported height and weight (https://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/index.html). The remaining conditions were assessed using the question “Have you ever been diagnosed with any of the following conditions?” with response options of 1) “Never”; 2) “Yes, I have in the past, but don’t have it now”; 3) “Yes I have, but I do not regularly take medications or receive treatment”; and 4) “Yes I have, and I am regularly taking medications or receiving treatment.” Respondents who answered that they have been diagnosed and chose either response 3 or 4 were considered as having the specified medical condition. §§ Essential worker status was self-reported. ¶¶ Unpaid caregiver status was self-reported. Unpaid caregivers for adults were defined as having provided unpaid care to a relative or friend aged ≥18 years at any time in the last 3 months. Examples provided to survey respondents included helping with personal needs, household chores, health care tasks, managing a person’s finances, taking them to a doctor’s appointment, arranging for outside services, and visiting regularly to see how they are doing. *** Region classification was determined by using the U.S. Census Bureau’s Census Regions and Divisions. https://www2.census.gov/geo/pdfs/maps-data/maps/reference/us_regdiv.pdf. ††† Rural-urban classification was determined by using self-reported ZIP codes according to the Federal Office of Rural Health Policy definition of rurality. https://www.hrsa.gov/rural-health/about-us/definition/datafiles.html. §§§ For this question, respondents were asked to select the following statement, if applicable: “I know someone who has tested positive for COVID-19.” In the multivariable Poisson regression models, differences within groups were observed for urgent or emergency care avoidance (Figure) and any care avoidance (Table 2). Adjusted prevalence of urgent or emergency care avoidance was significantly higher among unpaid caregivers for adults versus noncaregivers (2.9; 2.3–3.6); persons with two or more selected underlying medical conditions versus those without those conditions (1.9; 1.5–2.4); persons with health insurance versus those without health insurance (1.8; 1.2–2.8); Black adults (1.6; 1.3–2.1) and Hispanic adults (1.5; 1.2–2.0) versus White adults; young adults aged 18–24 years versus adults aged 25–44 years (1.5; 1.2–1.8); and persons with disabilities versus those without disabilities (1.3; 1.1–1.5). Avoidance of urgent or emergency care was significantly lower among adults aged ≥45 years than among younger adults. FIGURE Adjusted prevalence ratios* , † for characteristics § , ¶ , ** , †† associated with delay or avoidance of urgent or emergency medical care because of concerns related to COVID-19 — United States, June 30, 2020 Abbreviation: COVID-19 = coronavirus disease 2019. * Comparisons within subgroups were evaluated using Poisson regressions used to calculate a prevalence ratio adjusted for all characteristics shown in figure. † 95% confidence intervals indicated with error bars. § “Other” race includes American Indian or Alaska Native, Native Hawaiian or Pacific Islander, or Other. ¶ Selected underlying medical conditions known to increase the risk for severe COVID-19 were obesity, diabetes, high blood pressure, cardiovascular disease, and any type of cancer. Obesity is defined as body mass index ≥30 kg/m2 and was calculated from self-reported height and weight (https://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/index.html). The remaining conditions were assessed using the question “Have you ever been diagnosed with any of the following conditions?” with response options of 1) “Never”; 2) “Yes, I have in the past, but don’t have it now”; 3) “Yes I have, but I do not regularly take medications or receive treatment”; and 4) “Yes I have, and I am regularly taking medications or receiving treatment.” Respondents who answered that they have been diagnosed and chose either response 3 or 4 were considered as having the specified medical condition. ** Essential worker status was self-reported. For the adjusted prevalence ratios, essential workers were compared with all other respondents (including those who were nonessential workers, retired, unemployed, and students). †† Unpaid caregiver status was self-reported. Unpaid caregivers for adults were defined as having provided unpaid care to a relative or friend aged ≥18 years to help them take care of themselves at any time in the last 3 months. The figure is a forest plot showing the adjusted prevalence ratios for characteristics associated with delay or avoidance of urgent or emergency medical care because of concerns related to COVID-19, in the United States, as of June 30, 2020. TABLE 2 Characteristics associated with delay or avoidance of any medical care because of concerns related to COVID-19 — United States, June 30, 2020 Characteristic Weighted* no. Avoided or delayed any medical care aPR† (95% CI†) P-value† All respondents 4,975 — — — Gender Female 2,528 Referent — — Male 2,447 0.81 (0.75–0.87)§ <0.001 Age group, yrs 18–24 650 1.12 (1.01–1.25)§ 0.035 25–44 1,740 Referent — — 45–64 1,727 0.80 (0.72–0.88)§ <0.001 ≥65 858 0.72 (0.64–0.81)§ <0.001 Race/Ethnicity White, non-Hispanic 3,168 Referent — — Black, non-Hispanic 607 1.07 (0.96–1.19) 0.235 Asian, non-Hispanic 238 1.04 (0.91–1.18) 0.567 Other race or multiple races, non-Hispanic¶ 150 0.87 (0.71–1.07) 0.196 Hispanic, any race or races 813 1.15 (1.03–1.27)§ 0.012 Disability** Yes 1,108 1.33 (1.23–1.43)§ <0.001 No 3,867 Referent — — Underlying medical condition†† No 2,537 Referent — — One 1,328 1.15 (1.05–1.25)§ 0.004 Two or more 1,110 1.31 (1.20–1.42)§ <0.001 Education Less than high school diploma 65 0.72 (0.53–0.98)§ 0.037 High school diploma 833 0.79 (0.71–0.89)§ <0.001 Some college 1,302 0.85 (0.78–0.93)§ 0.001 Bachelor's degree 1,755 Referent — — Professional degree 1,020 0.90 (0.82–0.98)§ 0.019 Essential workers vs others§§ Essential workers 1,707 1.00 (0.92–1.09) 0.960 Other respondents (nonessential workers, retired persons, unemployed persons, and students) 3,268 Referent — — Unpaid caregiver status¶¶ Unpaid caregiver for adults 1,344 1.64 (1.52–1.78)§ <0.001 Not unpaid caregiver for adults 3,631 Referent — — U.S. Census region*** Northeast 1,122 Referent — — Midwest 936 0.93 (0.83–1.04) 0.214 South 1,736 0.90 (0.82–0.99)§ 0.028 West 1,181 0.99 (0.89–1.09) 0.808 Rural/Urban classification††† Urban 4,411 1.00 (0.89–1.12) 0.993 Rural 564 Referent — — Health insurance status Yes 4,577 1.61 (1.31–1.98)§ <0.001 No 398 Referent — — Know someone with positive test results for SARS-CoV-2§§§ Yes 989 1.22 (1.12–1.33)§ <0.001 No 3,986 Referent — — Knew someone who died from COVID-19 Yes 364 0.99 (0.88–1.12) 0.860 No 4,611 Referent — — Believed to be in a group at high risk for severe COVID-19 Yes 981 1.33 (1.23–1.44)§ <0.001 No 3,994 Referent — — Abbreviations: aPR = adjusted prevalence ratio; CI = confidence interval; COVID-19 = coronavirus disease 2019. * Statistical raking and weight trimming were employed to improve the cross-sectional June cohort representativeness of the U.S. population by gender, age, and race/ethnicity according to the 2010 U.S. Census. † Comparisons within subgroups were evaluated using Poisson regressions used to calculate a prevalence ratio adjusted for all characteristics listed, as well as a 95% CI and p-value. Statistical significance was evaluated at a threshold of α = 0.05. § P-value calculated using Poisson regression among respondents within a characteristic is statistically significant at levels of p<0.05. ¶ “Other” race includes American Indian or Alaska Native, Native Hawaiian or Pacific Islander, or Other. ** Persons who had a disability were defined based on a qualifying response to either one of two questions: “Are you limited in any way in any activities because of physical, mental, or emotional condition?” and “Do you have any health conditions that require you to use special equipment, such as a cane, wheelchair, special bed, or special telephone?” https://www.cdc.gov/brfss/questionnaires/pdf-ques/2015-brfss-questionnaire-12-29-14.pdf. †† Selected underlying medical conditions known to increase the risk for severe COVID-19 were obesity, diabetes, high blood pressure, cardiovascular disease, and any type of cancer. Obesity is defined as body mass index ≥30 kg/m2 and was calculated from self-reported height and weight (https://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/index.html). The remaining conditions were assessed using the question “Have you ever been diagnosed with any of the following conditions?” with response options of 1) “Never”; 2) “Yes, I have in the past, but don’t have it now”; 3) “Yes I have, but I do not regularly take medications or receive treatment”; and 4) “Yes I have, and I am regularly taking medications or receiving treatment.” Respondents who answered that they have been diagnosed and chose either response 3 or 4 were considered as having the specified medical condition. §§ Essential worker status was self-reported. For the adjusted prevalence ratios, essential workers were compared with all other respondents (including those who were nonessential workers, retired, unemployed, and students). ¶¶ Unpaid caregiver status was self-reported. Unpaid caregivers for adults were defined as having provided unpaid care to a relative or friend aged ≥18 years at any time in the last 3 months. Examples provided to survey respondents included helping with personal needs, household chores, health care tasks, managing a person’s finances, taking them to a doctor’s appointment, arranging for outside services, and visiting regularly to see how they are doing. *** Region classification was determined by using the U.S. Census Bureau’s Census Regions and Divisions. https://www2.census.gov/geo/pdfs/maps-data/maps/reference/us_regdiv.pdf. ††† Rural/urban classification was determined by using self-reported ZIP codes according to the Federal Office of Rural Health Policy definition of rurality. https://www.hrsa.gov/rural-health/about-us/definition/datafiles.html. §§§ For this question, respondents were asked to select the following statement, if applicable: “I know someone who has tested positive for COVID-19.” Discussion As of June 30, 2020, an estimated 41% of U.S. adults reported having delayed or avoided medical care during the pandemic because of concerns about COVID-19, including 12% who reported having avoided urgent or emergency care. These findings align with recent reports that hospital admissions, overall emergency department (ED) visits, and the number of ED visits for heart attack, stroke, and hyperglycemic crisis have declined since the start of the pandemic ( 3 – 5 ), and that excess deaths directly or indirectly related to COVID-19 have increased in 2020 versus prior years ( 2 ). Nearly one third of adult respondents reported having delayed or avoided routine medical care, which might reflect adherence to community mitigation efforts such as stay-at-home orders, temporary closures of health facilities, or additional factors. However, if routine care avoidance were to be sustained, adults could miss opportunities for management of chronic conditions, receipt of routine vaccinations, or early detection of new conditions, which might worsen outcomes. Avoidance of both urgent or emergency and routine medical care because of COVID-19 concerns was highly prevalent among unpaid caregivers for adults, respondents with two or more underlying medical conditions, and persons with disabilities. For caregivers who reported caring for adults at increased risk for severe COVID-19, concern about exposure of care recipients might contribute to care avoidance. Persons with underlying medical conditions that increase their risk for severe COVID-19 ( 6 ) are more likely to require care to monitor and treat these conditions, potentially contributing to their more frequent report of avoidance. Moreover, persons at increased risk for severe COVID-19 might have avoided health care facilities because of perceived or actual increased risk of exposure to SARS-CoV-2, particularly at the onset of the pandemic. However, health care facilities are implementing important safety precautions to reduce the risk of SARS-CoV-2 infection among patients and personnel. In contrast, delay or avoidance of care might increase risk for life-threatening medical emergencies. In a recent study, states with large numbers of COVID-19–associated deaths also experienced large proportional increases in deaths from other underlying causes, including diabetes and cardiovascular disease ( 7 ). For persons with disabilities, accessing medical services might be challenging because of disruptions in essential support services, which can result in adverse health outcomes. Medical services for persons with disabilities might also be disrupted because of reduced availability of accessible transportation, reduced communication in accessible formats, perceptions of SARS-CoV-2 exposure risk, and specialized needs that are difficult to address with routine telehealth delivery during the pandemic response. Increasing accessibility of medical and telehealth services ¶¶¶ might help prevent delay of needed care. Increased prevalences of reported urgent or emergency care avoidance among Black adults and Hispanic adults compared with White adults are especially concerning given increased COVID-19-associated mortality among Black adults and Hispanic adults ( 8 ). In the United States, the age-adjusted COVID-19 hospitalization rates are approximately five times higher among Black persons and four times higher among Hispanic persons than are those among White persons ( 9 ). Factors contributing to racial and ethnic disparities in SARS-CoV-2 exposure, illness, and mortality might include long-standing structural inequities that influence life expectancy, including prevalence and underlying medical conditions, health insurance status, and health care access and utilization, as well as work and living circumstances, including use of public transportation and essential worker status. Communities, health care systems, and public health agencies can foster equity by working together to ensure access to information, testing, and care to assure maintenance and management of physical and mental health. The higher prevalence of medical care delay or avoidance among respondents with health insurance versus those without insurance might reflect differences in medical care-seeking behaviors. Before the pandemic, persons without insurance sought medical care much less frequently than did those with insurance ( 10 ), resulting in fewer opportunities for medical care delay or avoidance. The findings in this report are subject to at least five limitations. First, self-reported data are subject to recall, response, and social desirability biases. Second, the survey did not assess reasons for COVID-19–associated care avoidance, such as adherence to public health recommendations; closure of health care provider facilities; reduced availability of public transportation; fear of exposure to infection with SARS-CoV-2; or availability, accessibility, and acceptance or recognition of telemedicine as a means of providing care in lieu of in-person services. Third, the survey did not assess baseline patterns of care-seeking or timing or duration of care avoidance. Fourth, perceptions of whether a condition was life-threatening might vary among respondents. Finally, although quota sampling methods and survey weighting were employed to improve cohort representativeness, this web-based survey might not be fully representative of the U.S. population for income, educational attainment, and access to technology. However, the findings are consistent with reported declines in hospital admissions and ED visits during the pandemic ( 3 – 5 ). CDC has issued guidance to assist persons at increased risk for severe COVID-19 in staying healthy and safely following treatment plans**** and to prepare health care facilities to safely deliver care during the pandemic. †††† Additional public outreach in accessible formats tailored for diverse audiences might encourage these persons to seek necessary care. Messages could highlight the risks of delaying needed care, especially among persons with underlying medical conditions, and the importance of timely emergency care. Patient concerns related to potential exposure to SARS-CoV-2 in health care settings could be addressed by describing facilities’ precautions to reduce exposure risk. Further exploration of underlying reasons for medical care avoidance is needed, including among persons with disabilities, persons with underlying health conditions, unpaid caregivers for adults, and those who face structural inequities. If care were avoided because of concern about SARS-CoV-2 exposure or if there were closures or limited options for in-person services, providing accessible telehealth or in-home health care could address some care needs. Even during the COVID-19 pandemic, persons experiencing a medical emergency should seek and be provided care without delay ( 3 ). Summary What is already known about this topic? Delayed or avoided medical care might increase morbidity and mortality associated with both chronic and acute health conditions. What is added by this report? By June 30, 2020, because of concerns about COVID-19, an estimated 41% of U.S. adults had delayed or avoided medical care including urgent or emergency care (12%) and routine care (32%). Avoidance of urgent or emergency care was more prevalent among unpaid caregivers for adults, persons with underlying medical conditions, Black adults, Hispanic adults, young adults, and persons with disabilities. What are the implications for public health practice? Understanding factors associated with medical care avoidance can inform targeted care delivery approaches and communication efforts encouraging persons to safely seek timely routine, urgent, and emergency care.
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              Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting

              Background Preapproval trials showed that messenger RNA (mRNA)–based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a good safety profile, yet these trials were subject to size and patient-mix limitations. An evaluation of the safety of the BNT162b2 mRNA vaccine with respect to a broad range of potential adverse events is needed. Methods We used data from the largest health care organization in Israel to evaluate the safety of the BNT162b2 mRNA vaccine. For each potential adverse event, in a population of persons with no previous diagnosis of that event, we individually matched vaccinated persons to unvaccinated persons according to sociodemographic and clinical variables. Risk ratios and risk differences at 42 days after vaccination were derived with the use of the Kaplan–Meier estimator. To place these results in context, we performed a similar analysis involving SARS-CoV-2–infected persons matched to uninfected persons. The same adverse events were studied in the vaccination and SARS-CoV-2 infection analyses. Results In the vaccination analysis, the vaccinated and control groups each included a mean of 884,828 persons. Vaccination was most strongly associated with an elevated risk of myocarditis (risk ratio, 3.24; 95% confidence interval [CI], 1.55 to 12.44; risk difference, 2.7 events per 100,000 persons; 95% CI, 1.0 to 4.6), lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000 persons; 95% CI, 64.1 to 89.3), appendicitis (risk ratio, 1.40; 95% CI, 1.02 to 2.01; risk difference, 5.0 events per 100,000 persons; 95% CI, 0.3 to 9.9), and herpes zoster infection (risk ratio, 1.43; 95% CI, 1.20 to 1.73; risk difference, 15.8 events per 100,000 persons; 95% CI, 8.2 to 24.2). SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000 persons; 95% CI, 5.6 to 15.8) and of additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia. Conclusions In this study in a nationwide mass vaccination setting, the BNT162b2 vaccine was not associated with an elevated risk of most of the adverse events examined. The vaccine was associated with an excess risk of myocarditis (1 to 5 events per 100,000 persons). The risk of this potentially serious adverse event and of many other serious adverse events was substantially increased after SARS-CoV-2 infection. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.)
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                Author and article information

                Journal
                Vaccine
                Vaccine
                Vaccine
                Published by Elsevier Ltd.
                0264-410X
                1873-2518
                8 November 2022
                8 November 2022
                Affiliations
                [a ]IBM Consulting, Bethesda, MD, USA
                [b ]Acumen LLC, Burlingame, CA, USA
                [c ]U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Silver Spring, MD, USA
                [d ]Gevity Inc, an Accenture Company, Ottawa, Canada
                [e ]Centers for Medicare & Medicaid Services, Baltimore, MD, USA
                [f ]IQVIA, Falls Church, VA, USA
                [g ]Optum Epidemiology, Boston, MA, USA
                [h ]Aetna, Blue Bell, PA, USA
                [i ]HealthCore, Inc, Wilmington, DE, USA
                [j ]Department of Economics, Stanford University, Stanford, CA, USA
                Author notes
                [* ]Corresponding author.
                [1]

                These authors contributed equally to this work.

                Article
                S0264-410X(22)01373-1
                10.1016/j.vaccine.2022.11.003
                9640387
                36404170
                741218b6-419c-45fe-8c1a-05215b6e3e84
                © 2022 Published by Elsevier Ltd.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 24 August 2022
                : 31 October 2022
                : 2 November 2022
                Categories
                Article

                Infectious disease & Microbiology
                background rates,vaccine safety surveillance,covid-19,adverse events,aesi, adverse event of special interest,ami, acute myocardial infarction,best, cber biologics effectiveness and safety,bhi, blue health intelligence,cber, center for biologics evaluation and research,ci, confidence interval,cms, centers for medicare & medicaid services,dic, disseminated intravascular coagulation,dvt, deep vein thrombosis,ehr, electronic health record,eua, emergency use authorization,fda, food and drug administration,gbs, guillain-barré syndrome,icd-10-cm/pcs, international classification of diseases, tenth revision, clinical modification/procedure coding system,ir, incidence rate,irr, incidence rate ratio,itp, immune thrombocytopenia,pe, pulmonary embolism,sars-cov-2, severe acute respiratory syndrome coronavirus 2,tts, thrombosis with thrombocytopenia syndrome

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