key: cord-1002919-meybzp9v
authors: Watkins, Louise K Francois; Mitruka, Kiren; Dorough, Layne; Bressler, Sara S; Kugeler, Kiersten J; Sadigh, Katrin S; Birhane, Meseret G; Nolen, Leisha D; Fischer, Marc
title: Characteristics of Reported Deaths Among Fully Vaccinated Persons with COVID-19 —United States, January–April 2021
date: 2022-01-29
journal: Clin Infect Dis
DOI: 10.1093/cid/ciac066
sha: 557dcfb9b2d9af26a3245b2093a7b0551f66e281
doc_id: 1002919
cord_uid: meybzp9v

BACKGROUND: COVID-19 vaccines are highly efficacious, but SARS-CoV-2 infections post-vaccination occur. We characterized COVID-19 cases among fully vaccinated persons with an outcome of death. METHODS: We analyzed COVID-19 cases voluntarily reported to CDC by US health departments during January 1, 2021–April 30, 2021. We included cases among U.S. residents with a positive SARS-CoV-2 test ≥14 days after completion of an authorized primary vaccine series and who had a known outcome (alive or death) as of May 31, 2021. When available, specimens were sequenced for viral lineage and death certificates were reviewed for cause(s) of death. RESULTS: Of 8,084 reported COVID-19 cases among fully vaccinated persons during the surveillance period, 245 (3.0%) died. Compared with patients who remained alive, those who died were older (median age 82 years vs. 57 years, P <0.01), more likely to reside in a long-term care facility (51% vs. 18%, P <0.01), and more likely to have at least one underlying health condition associated with risk for severe disease (64% vs. 24%, P <0.01). Among 245 deaths, 191 (78%) were classified as COVID-19-related. Of 106 deaths with available death certificates, COVID-19 was listed on 81 (77%). There were no differences in the type of vaccine administered or the most common viral lineage (B.1.1.7). CONCLUSIONS: COVID-19 deaths are rare in fully vaccinated persons, occurring most commonly in those with risk factors for severe disease, including older age and underlying health conditions. All eligible persons should be fully vaccinated against COVID-19 and follow other prevention measures to mitigate exposure risk.

confirmed these findings. [2] [3] [4] [5] [6] [7] [8] [9] Real-world data provided further evidence that these vaccines are highly effective in preventing hospitalizations and deaths from severe COVID-19. [10] [11] [12] [13] [14] [15] High vaccine effectiveness against severe COVID-19 is maintained even following infection with the SARS-CoV-2 Delta variant, demonstrating the continued critical role of vaccines in controlling the pandemic. [16] [17] [18] [19] [20] [21] [22] Because no vaccine is 100% effective, SARS-CoV-2 infections among fully vaccinated persons are expected and have been documented. [23] [24] [25] [26] [27] [28] [29] However, fully vaccinated people remain at much lower risk for hospitalization or death than unvaccinated or partially vaccinated people with similar risk factors.[1, 17-20, 30, 31] 

For this analysis, a COVID-19 case in a fully vaccinated person was defined as the detection of SARS-CoV-2 RNA or antigen in a respiratory specimen collected from the person ≥14 days after receipt of recommended primary series of an FDA-authorized or approved COVID-19 vaccine. Cases meeting this definition that were reported to CDC by April 30, 2021 were included in this analysis if outcomes (i.e., alive or dead from any cause) were known as of May 31, 2021. Cases were excluded if a previous positive SARS-CoV-2 test was documented within 45 days of the first post-vaccination positive test, if information on the vaccine manufacturer or administration dates was missing, or if the schedule was inconsistent with CDC recommendation (i.e., receipt of two doses of vaccines from different manufacturers or spacing of doses shorter than 4-day grace period of manufacturer's recommendations).

[33] This activity was conducted consistent with applicable federal law and CDC policy, and was determined to be non-research and exempt from further institutional review board review at CDC 1 .

Data were collected from state health departments and managed through a REDCap secure platform and data capture tools hosted at CDC. [ For cases with an outcome of death, health departments reported whether the cause was COVID-19-related and how this determination was made (e.g., death certificate, medical records, medical examiner, provider report). We reviewed death certificates (i.e., U.S. Standard Certificate of Death Rev 11/2003) and medical records when available to verify the cause(s) of death and completed missing or unreported information. When the death certificate was available for review, the death was classified as COVID-19-related if COVID-19 was listed as an immediate or underlying cause of death (Part I) or as a significant condition contributing to death (Part II). If COVID-19 was not listed on the death certificate or the death certificate was not available for review, the death was still classified as COVID-19-related if the health department reported it to be COVID-19-related based on their review of the death certificate or medical examiner or provider report. We documented all conditions listed on the death certificate (Part I and Part II) for both COVID-19related and COVID-19-unrelated deaths.

We used descriptive statistics to assess the demographic characteristics, clinical features and course, and SARS-CoV-2 lineage of fully vaccinated people with COVID-19. We compared cases with an outcome of death versus alive, and cases where cause of death was deemed COVID-19-related versus unrelated. Distributions of categorical variables were compared using chi-square or Fisher exact tests.

Distributions of continuous variables were compared using Wilcoxon rank sum tests. A P-value <0.05 was considered significant. All analyses were performed using SAS version 9.4 (SAS Institute, Cary NC). Compared with patients who lived, those who died were older (median age 82 vs. 57 years, P <0.01), more commonly male (51% vs. 34%, P <0.01), a resident of a nursing home or long-term care facility (51% vs. 18%, P <0.01), and had ≥1 underlying medical condition associated with risk for severe disease (64% vs. 24%, P <0.01) ( Table 1) . The most common underlying conditions were the same in both groups but were more common among those who died: diabetes (44% vs. 18%, P <0.01), chronic renal disease (37% vs. 7%, P <0.01), and immunosuppressing condition (33% vs. 7%, P <0.01) (data not shown). Patients who died compared with those who lived were more likely to have COVID-19-like symptoms (84% vs. 63%, P <0.01), to require hospitalization (79% vs. 12%, P <0.01) A c c e p t e d M a n u s c r i p t and intensive care (54% vs 18% among those hospitalized, P <0.01), and to experience symptoms associated with severe disease such as fever (40% vs. 22%, P <0.01), shortness of breath (67% vs. 24%, P <0.01), and difficulty breathing (51% vs. 15%, P <0.01). Milder symptoms, including headache (19% vs. 24%, P <0.01), sore throat (6% vs. 32%, P <0.01), runny nose (23% vs. 62%, P <0.01), and loss of smell or taste (9% vs. 29%, P <0.01) were more common among patients who lived (data not shown). There were no significant differences between the two groups in the type of vaccine administered.

SARS-CoV-2 sequence data were available for 54 (22%) of 245 patients who died, and 945 (12%) of 7,839 patients who lived (Supplemental Table) . The Alpha (B.1.1.7) lineage was the most common among both patients who died and those who lived (43% vs. 41%), and the breakdown of variants being monitored did not differ significantly between groups (P=0.34). The median Ct value among those specimens with sequence data was lower (associated with higher levels of viral genetic material) for those who died (median 18. Of the 245 total deaths, 191 (78%) were classified as COVID-19-related, 41 (17%) were classified as not COVID-19-related, and 13 (5%) could not be classified. COVID-19-relatedness was determined by review of death certificates for 106 (46%) patients and reported by state health public health officials for the remainder; the most common sources of information used by health officials were death certificates, medical records, and reports from medical examiners or other healthcare professionals. Patients whose deaths were deemed COVID-19-related had similar distributions of age, sex, and race/ethnicity to those whose deaths were not considered COVID-19related. However, compared with patients with non-COVID-19-related deaths, patients with COVID-19-related deaths were less likely to be residents of a long-term care facility (46% vs. 76%, P <0.01) and more likely to have at least one underlying medical condition (69% vs. 47%, P=0.01) or A c c e p t e d M a n u s c r i p t symptoms of COVID-19 (90% vs. 57%, P <0.01), to be hospitalized (83% vs. 68%, P <0.01), or to have SARS-CoV-2 sequence data available (26% vs. 7%, P <0.01), although not more likely to be infected with a variant being monitored (Table 2) .

Of the 106 (43%) death certificates available for review, 72 (68%) listed COVID-19 in the chain of events leading to the immediate cause of death, 9 (8%) listed COVID-19 as a contributing condition, and 25 (24%) did not have COVID-19 listed on the death certificate. Other common causes of death listed on the available death certificates included other respiratory conditions, cardiovascular conditions, diabetes, and sepsis (Table 3) . Of note, among 25 patients for whom COVID-19 was not listed on the death certificate, 8 (32%) had documentation of either pneumonia or respiratory failure.

Of the 245 patients who died, nearly all had at least one underlying condition, resided in a long-term care facility or nursing home, or had advanced age. Only two deaths occurred in patients who were younger than age 50 and had no reported underlying conditions, and only one was classified as a case of COVID-19-related death, with an immediate cause of death of septic shock reported on the death certificate.

In this analysis of COVID-19 cases among fully vaccinated persons voluntarily reported during January-April 2021, we found that COVID-19 deaths occurred more commonly among persons with risk factors for severe disease, including older age (especially among those aged >75 years) and underlying health conditions such as diabetes, chronic renal disease, and immunosuppressing condition. These deaths represented a very small proportion of the reported COVID-19 cases among fully vaccinated persons and occurred among the over 100 million Americans fully vaccinated during the same period.

[1] The characteristics and causes of death in fully vaccinated patients resembled those who died of COVID-19 pre-vaccination, [37, 38] highlighting the M a n u s c r i p t This analysis is subject to several limitations. First, our findings may not be generalizable because the passive surveillance system for COVID-19 cases among fully vaccinated persons did not receive case reports from all states, represented a time before the widespread circulation of the Delta variant, and focused on a period before vaccines were approved for use in children under age 16 or were widely available to adults at lower risk of occupational exposure or at lower risk of severe COVID. Second, fully vaccinated individuals with COVID-19 who died after May 31, 2021, could have been misclassified as alive in this analysis; however, given the additional month of follow-up time allowed, we expect these misclassifications to be rare. Third, we did not obtain symptom onset date.

This could have led to the inappropriate inclusion of some patients who contracted COVID-19 before becoming fully vaccinated. Furthermore, we were unable to assess the Ct value in relation to illness onset, although the viral load is known to vary according to the timing of testing. Fourth, the methods and timing of testing were not standardized across laboratories. Ct values may differ with the type of test, limiting the usefulness of Ct value as a marker for viral load. Also, more severe cases might have been diagnosed earlier, resulting in lower Ct values. Fifth, missing data were more common among patients who lived, which could have affected comparisons with patients who died.

Finally, SARS-CoV-2 lineage (all cases) and death certificates (among patients who died) were only available for a small number of cases. Nevertheless, this analysis adds to our understanding of the most severe cases of COVID-19 in fully vaccinated individuals.

COVID-19 vaccines are safe and effective, but COVID-19 cases among fully vaccinated individuals will continue to occur, particularly while community transmission remains high. Deaths among fully vaccinated persons were most common among older adults (especially those over age 75 years) and those with at least one underlying health condition during the early post-vaccination period before widespread transmission of the Delta variant B.1.617.2 (January-April 2021). Our findings highlight the importance of complete vaccination of all persons eligible for COVID-19 M a n u s c r i p t

for Disease Control and Prevention. COVID data tracker

Safety and efficacy of the BNT162b2 mRNA Covid-19

Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine

Safety and efficacy of single-dose Ad26.COV2.S vaccine against Covid-19

BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting

COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): A prospective, multicentre, cohort study

Safety of the BNT162b2 mRNA Covid-19 vaccine in a nationwide setting

Effectiveness of mRNA Covid-19 vaccine among U.S. health care personnel

Prevention and attenuation of Covid-19 with the BNT162b2 and mRNA-1273 vaccines

Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a campaign in Israel: An observational study using national surveillance data

Short-term impact of nursing home SARS-CoV-2 vaccinations on new infections, hospitalizations, and deaths

Reduction in COVID-19 Patients requiring mechanical ventilation Following Implementation of a National COVID-19 Vaccination Program -Israel

The initial impact of a national BNT162b2 mRNA COVID-19 vaccine rollout

Decreases in COVID-19 cases, emergency department visits, hospital admissions, and deaths among older adults following the introduction of COVID-19 vaccine -United States

Effectiveness of SARS-CoV-2 mRNA vaccines for preventing Covid-19 hospitalizations in the United States

Effectiveness of COVID-19 mRNA vaccines against COVID-19-associated hospitalization -five Veterans Affairs Medical Centers

Hospitalizations associated with COVID-19 among children and adolescents -COVID-NET, 14 states

Interim estimates of COVID-19 vaccine effectiveness against COVID-19-associated emergency department or urgent care clinic encounters and hospitalizations among adults during SARS-CoV-2 B.1.617.2 (Delta) variant predominance -Nine states

New COVID-19 cases and hospitalizations among adults, by vaccination status

Monitoring incidence of COVID-19 cases, hospitalizations, and deaths, by vaccination status -13

Sustained effectiveness of Pfizer-BioNTech and Moderna vaccines against COVID-19 associated hospitalizations among adults -United States

SARS-CoV-2 vaccine protection and deaths among US veterans during 2021

Centers for Disease Control and Prevention. COVID-19 vaccine breakthrough infections reported to CDC -United States

Postvaccination SARS-CoV-2 infections among skilled nursing facility residents and staff members

COVID-19 outbreak associated with a SARS

1 lineage variant in a skilled nursing facility after vaccination program -Kentucky

SARS-CoV-2 infection after vaccination in health care workers in California

Covid-19 breakthrough infections in vaccinated health care workers

Outbreak of SARS-CoV-2 infections, Including COVID-19 vaccine breakthrough infections, associated with large public gatherings -Barnsy

SARS-CoV-2 infections and hospitalizations among persons aged ≥16 years, by vaccination status

Vaccination reduces need for emergency care in breakthrough COVID-19 infections: A multicenter cohort study

Research electronic data capture (REDCap)-A metadata-driven methodology and workflow process for providing translational research informatics support

Centers for Disease Control and Prevention. SARS-CoV-2 Variant Classifications and

Characteristics of persons who died with COVID-19

Death Certificate-Based ICD-10 Diagnosis Codes for COVID-19 Mortality Surveillance -United States

BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully-vaccinated hospitalized COVID-19 patients in Israel

A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 2 Consisting of pregnancy, diabetes, chronic renal disease, chronic liver disease, autoimmune disease, immunosuppressing condition, or use of immunosuppressing medications A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 6 23 (22) 16 (20) 7 (28) ARDS = acute respiratory distress syndrome; COPD = chronic obstructive pulmonary disease 1 Refers to Part I of the death certificate: "Enter the chain of events--diseases, injuries, or complications--that directly caused the death." 2 Refers to Part II of the death certificate: "Enter other significant conditions contributing to death but not resulting in the underlying cause given in Part I." 3 Includes myocardial infarction, coronary artery disease, and peripheral vascular disease 4 Other cardiovascular conditions: aortic valve replacement (1); arteriosclerosis (1); sick sinus syndrome (1); supraventricular tachycardia (1) 5 Other chronic conditions include: diabetes (18) , chronic renal disease (13), dementia (12) , leukemia or lymphoma (12) , liver disease (7), solid tumor cancer (3), alcohol abuse (2), obesity (2), rheumatoid arthritis (2), anemia (1), asthma (1), kidney and liver transplant (1), myotonic muscular dystrophy (1), polymyalgia rheumatica (1), protein calorie malnutrition (1), seizure disorder (1), tobacco abuse (1) A c c e p t e d M a n u s c r i p t