key: cord-0788508-7zfs0tpj
authors: Suleyman, Geehan; Fadel, Raef; Brar, Indira; Kassab, Rita; Khansa, Rafa; Sturla, Nicholas; Alsaadi, Ayman; Latack, Katie; Miller, Joseph; Tibbetts, Robert; Samuel, Linoj; Alangaden, George; Ramesh, Mayur
title: Risk factors associated with hospitalization and death in COVID-19 breakthrough infections
date: 2022-03-07
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofac116
sha: 4161dc802f7d0e3e457ef6132a619b42ff0609da
doc_id: 788508
cord_uid: 7zfs0tpj

BACKGROUND: Characterization of COVID-19 vaccine breakthrough infections are limited. We aim to characterize breakthrough infections and identify risk factors associated with outcomes. METHODS: This was a retrospective case series of consecutive fully vaccinated patients with SARS-CoV-2 in a multi-center academic center in Southeast Michigan, between December 30, 2020 and September 15, 2021. RESULTS: 982 patients were identified; mean age was 57.9, 565 (59%) were female, 774 (79%) white, 255 (26%) healthcare workers (HCWs). Median number of comorbidities was 2; 225 (23%) were immunocompromised. BNT162b2 was administered to 737 (75%) individuals. Mean time to SARS-CoV2 detection was 135 days. The majority were asymptomatic or exhibited mild-to-moderate disease, 154 (16%) required hospitalization, 127 (13%) had severe-critical illness, and 19 (2%) died. Age (odds ratio [OR] 1.14 [95% CI, 1.04-1.07]; p<0.001), cardiovascular disease (OR 3.02 [95% CI, 1.55-5.89; p=0.001), and immunocompromised status (OR 2.57 [95% CI, 1.70-3.90]; p<0.001) were independent risk factors for hospitalization. Additionally, age (OR 1.06 [95% CI, 1.02-1.11]; p=0.006) was significantly associated with mortality. HCWs (OR 0.15 [95% CI, 0.05-0.50]; p = 0.002) were less likely to be hospitalized, and prior receipt of BNT162b2 was associated with lower odds of hospitalization (OR 0.436 [95% CI, 0.303-0.626]; p<0.001) and/or death (OR 0.360 [95% CI, 0.145-0.898]; p=0.029). CONCLUSION: COVID-19 vaccines remain effective at attenuating disease severity. However, patients with breakthrough infections necessitating hospitalization may benefit from early treatment modalities and COVID-19 mitigating strategies, especially in areas with substantial or high transmission rates.

Vaccination against SARS-CoV-2 is highly effective at preventing disease progression and mortality and leading strategy to change the trajectory of the coronavirus 2019 (Covid- 19) pandemic worldwide. Randomized clinical trials demonstrated high vaccine efficacies (>94%) for the mRNA-based vaccines against Covid-19 (1, 2) . Several other studies have redemonstrated their high effectiveness among various patient populations against severe disease, hospitalization, and death in real-world data (3) (4) (5) (6) (7) (8) . Early surveillance data from a nationwide mass vaccination campaign in Israel suggested that two doses of BNT162b2 were effective against overall infection, severe disease, hospitalization and death (3) . More recently, a large multi-state analysis of more than 63,000 medical visits showed that Covid-19 vaccines remained effective against Covid-19-related hospitalizations and ambulatory visits (6) .

However, COVID-19 mRNA vaccine effectiveness (VE) in preventing laboratoryconfirmed COVID-19 has declined due to waning immunity and/or variant immune evasion, especially during the Omicron-predominant period (9) . During a 6-month follow-up of the BNT162b2 mRNA Covid-19 Vaccine clinical trial, VE gradually declined; VE was 96.2% (95% confidence interval *CI+, 93.3 to 98.1) ≥ 7 days, and 83.7% (95% CI, 74.7 to 89.9) 4 months after the second dose (10) . Moreover, lower VE in preventing COVID-19-related hospitalization has been observed among older adults and high-risk groups (4, 11) . Despite the emergence of breakthrough infections, the cumulative COVID-19-associated hospitalization rate remained 12-times higher in unvaccinated persons compared to vaccinated individuals. Moreover, an unvaccinated individual had significantly greater risk of testing positive for SARS-CoV2 and dying from COVID-19 (12). As of December 2021, the M a n u s c r i p t 6 Centers for Disease Control and Prevention (CDC) has reported rates as high as 130 per 100,000 COVID-19 breakthrough infections among fully vaccinated persons, with a low hospitalization and mortality rates (12). Studies characterizing breakthrough infections among the general patient population across all age groups and outcomes with respect to hospitalization, intensive care unit (ICU) admission, need for invasive mechanical ventilation (IMV) and mortality are limited. Previous studies in unvaccinated and vaccinated individuals have shown that age and multiple comorbid conditions are associated with disease progression and adverse outcomes (7, 11, 13) . Further studies are needed to identify specific characteristics that are associated with disease progression in breakthrough infections and determine which individuals may benefit from additional vaccine doses and therapeutic modalities and mitigating COVID-19 strategies. Therefore, we aimed to describe SARS-CoV-2 breakthrough infections, risk factors associated with disease progression and outcomes among our patient population.

This was a case series of consecutive patients, including healthcare workers (HCWs), diagnosed with COVID-19 vaccine breakthrough or post-vaccine infections in Henry Ford

Health System (HFHS), a comprehensive, integrated, health care organization that includes 5 hospitals and 9 emergency departments (EDs) in Southeast Michigan, from December 30, 2020 (two weeks after the introduction of a COVID-19 vaccine) to September 15, 2021. In our health system, HCWs exhibiting symptoms and/or signs consistent with COVID-19 infection and exposed asymptomatic HCWs were referred to employee health for SARS-CoV-2 testing; however, routine asymptomatic testing was not performed.

A c c e p t e d M a n u s c r i p t 7 A vaccine breakthrough infection was defined as detection of SARS-CoV-2 ≥14 days after receipt of two doses of mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech), or one dose of JNJ78436735 (Janssen), confirmed by state immunization registry. Patients with positive polymerase chain reaction (PCR) for SARS-CoV-2 in a respiratory specimen were included. The first SARS-CoV-2 test within this eligibility period was used. Partially vaccinated participants (<14 days since completing the primary series or not completing the series before the specimen collection date) were excluded.

We performed a retrospective review of the electronic health records (EHR) using Epic ® to obtain data on a standardized data collection form. Demographic data, chronic comorbid conditions, prior COVID-19 infection, SARS-CoV-2 test results, severity of illness, vaccine type and date, prior Covid-19 history, receipt of monoclonal antibody (MAB), hospital admission status and clinical outcomes were evaluated. The viral load as expressed by the PCR cycle threshold (Ct) was obtained from the microbiology laboratory when available.

Race/ethnicity data were collected in EHR by self-report using standard classification.

Based on the most recent recorded body mass index (BMI), obesity was defined as a BMI ≥ 30 kg/m2 and morbid obesity as BMI ≥40 (14). Comorbidities associated with higher risk of developing severe outcomes of COVID-19 (15) were extracted using the International Classification of Diseases (ICD) 10 codes. Vaccination status, including specific vaccine type and vaccination dates, was extracted, and verified in state immunization registry. Possible reinfection was defined as an infection in a person with a specimen collected ≥90 days after a positive SARS-CoV-2 diagnostic test, based on current CDC guidelines. Severity of illness was determined using established guidelines (16) , and patients were grouped into the Cardiovascular disease was defined as presence or history of cardiomyopathy, coronary artery disease (CAD), or congestive heart failure (CHF). Substance use disorder was defined as use of cocaine, heroin, marijuana, alcohol use > 3 drinks per day or moderate-severe alcohol dependence. Missing data for substance abuse and alcohol use was excluded from final analysis.

The primary outcomes included COVID-19-associated hospitalization and mortality. COVID-19-related hospitalization was defined as hospitalization in a symptomatic person within 30 days of a SARS-CoV-2 positive specimen collection. COVID-19-related mortality occurred in a person with a documented COVID-19 diagnosis who died as a result of or from complications of COVID-19 disease.

Secondary outcomes were ICU admission, need for IMV, 30-day readmission and LOS.

We used descriptive statistics to characterize the patient cohort. We display frequency and count data for categorical variables and mean, and standard deviation, along 

The study was approved by the Institutional Review Board of HFHS, Detroit, Michigan.

Informed consent was waived given that the study exclusively used deidentified data. Table 1 summarizes the baseline characteristics and outcomes of the entire cohort.

The mean time from final vaccine dose to SARS-CoV-2 detection was 135 days (SD 61) among the entire cohort, with no significant difference between hospitalized and nonhospitalized patients. Patients vaccinated with BNT162b2 exhibited the most days free from COVID-19 breakthrough infection (138 ± 62 days) as compared to both mRNA1273 (131 ± 49 days) and JNJ78436735 (99 ± 47 days) vaccination (p<0.001). Figure 1 Table 4 demonstrates these findings.

We describe 982 fully vaccinated individuals with vaccine breakthrough COVID-19 infections in our health system over a 9-month period. Most breakthrough infections occurred during the Delta surge. The majority of patients were asymptomatic or had mild to hospitalizations in this study. However, the proportion of patients with severe COVID-19 outcome in our cohort was higher.

The dramatic change in the number of breakthrough infections since July 2021 in our study is likely multifactorial and may be due to the emergence of the more contagious Delta variant and waning vaccine immunity over time as previously reported (10, 11, (18) (19) (20) (21) (22) ; the Delta variant became the dominant strain in Michigan, accounting for 99% of all viral samples sequenced since the last week in July 2021. In addition, lifting of the mask mandate and restrictions on July 1, 2021, in Michigan may also have resulted in greater community exposure risk. As of July 7th, we stopped testing fully vaccinated asymptomatic patients or those who had recovered from COVID on admission or for procedures. It is possible that there were additional asymptomatic breakthrough infections that were not detected.

Risk factors for disease progression and hospitalization in our study are similar to those previously reported for the unvaccinated and vaccinated individuals (7, 13, 15, 17, 18, (23) (24) (25) (26) (27) (28) (29) (30) (31) . Our hospitalized patients were also older and had a higher prevalence of preexisting conditions. A third of our immunocompromised patients were A c c e p t e d M a n u s c r i p t 13 hospitalized. In the multivariate analysis, older age, cardiovascular disease, including CHF, and immunocompromised status were associated with increased odds of hospitalization.

Older age is a well-established risk factor for infection and disease progression and has been associated with breakthrough hospitalization (7, 13, 17, 18, (23) (24) (25) (26) (27) (28) (29) (30) (31) .

Certain comorbidities, including CHF, CKD, DM, malignancy, are also associated with higher risk of developing severe COVID-19 (13, 17, 18, (23) (24) (25) (26) (27) (28) (29) . In a report published during the early stages of the pandemic, the mean (SD) number of comorbidities of hospitalized patients was 3.2 (1.8) compared with 1.9 (1.7) in patients who were not hospitalized 20.8 to 82.6%) compared to those without immunosuppression (91.3%; 95% CI: 85.6 to 94.8%) (26) . In a recently published multistate analysis of more than 89,000 hospitalized patients, the VE of the mRNA vaccines against COVID-19-associated hospitalization was 77% (95% CI= 74%-80%) in the immunocompromised adults compared with 90% (95% CI = 89%-91%) in the immunocompetent adults, irrespective of age. Moreover, VE varied across this patient population and ranged from 59% in SOT or BMT patients to 81% in patients with a rheumatologic or inflammatory disorder (32). This was further supported by another study A c c e p t e d M a n u s c r i p t 14 that demonstrated the association between mRNA vaccination and reduced risk of COVID-19 hospitalization was notably weaker in the immunocompromised patient population (7) .

Comparative data on secondary outcomes (LOS, ICU level care, need for IMV, readmission) and mortality in hospitalized patients with breakthrough infections are limited (6, 7, 17, (25) (26) (27) 33) . Our findings support the observations of earlier studies for ICU level care (6, 7) . In a large multistate study involving adults ≥50 years of age, 2,470 of 15,581 or 16% of patients with breakthrough infections required ICU level care (6) .

Overall mortality among those with breakthrough infections was low (17) . However, mortality was 12% among our hospitalized patients and 15% among those with severe or critical COVID-19. This is in contrast to a recent study where the need for IMV was 7.7% and mortality 6.3% among 142 hospitalized patients (7) . Our patients who expired from COVID-19 had mean age >75 years and had higher prevalence of underlying comorbidities, in addition to longer time from final vaccine dose to SARS-CoV-2 detection. In the multivariable analysis, age was the only risk factor associated with mortality. This may be attributed to lower immune response to vaccines and waning immunity.

In our study, prior receipt of BNT162b2 vaccine was associated with significantly lower odds of breakthrough hospitalization compared to receipt of JNJ78436735 or mRNA1273 vaccine and mortality, independent of age, HCW status, and other variables.

Interestingly, this contrasts with previous studies that reported higher VE in mRNA1273 (5, 7, 17, 20) . Thirty percent of our cohort were HCW with mean age of 45 years, which may have affected the results; however, our overall study population contained diverse group of patients. HFHS expanded the BNT162b2vaccine to the elderly and immunocompromised patients after prioritizing our HCWs early on. These groups are known to have a less robust A c c e p t e d M a n u s c r i p t 15 response to vaccines with possible waning immunity overtime and are at higher risk for severe COVID-19 (19) .

To conclude, the odds of COVID-19-related hospitalization after breakthrough infection increased in older adults, patients who were immunocompromised or had multiple comorbidities and decreased in HCWs and those who received BNT162b2. Despite vaccination, older age remained a significant risk factor for mortality. Thus, patients who are older, have underlying comorbidities or are immunocompromised may benefit from early treatment modalities and COVID-19 mitigating strategies, especially in areas with substantial or high transmission rates.

The findings in this report are subject to several limitations. It was a retrospective study conducted at a single large health system in Southeast Michigan; however, a diverse patient population was included in the study. It is possible that not all breakthrough infections were captured in our health system, including those who had at-home or MinuteClinic testing, which might introduce selection bias. This was less of a concern since Epic was integrated with other health care systems who utilized EHR. Moreover, patients who are asymptomatic or mildly symptomatic may not seek testing and be underrepresented. We did not measure immunity or report VE in our cohort due to multiple prior studies having assessed this. We did not compare risk factors and outcomes in hospitalized patients (alive vs dead) due to the small sample size. In addition, the primary goal of this investigation was to characterize and describe demographics and outcomes of breakthrough infections, so no control group was used. This limits the conclusions that can A c c e p t e d M a n u s c r i p t 27 

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Potential Conflict of Interest: There are no conflicts of interest to report.Funding Source: There are no funding sources to report.

A c c e p t e d M a n u s c r i p t 18 A c c e p t e d M a n u s c r i p t