key: cord-1046521-g266ttng
authors: Lawandi, Alexander; Warner, Sarah; Sun, Junfeng; Demirkale, Cumhur Y; Danner, Robert L; Klompas, Michael; Gundlapalli, Adi; Datta, Deblina; Harris, Aaron M; Morris, Sapna Bamrah; Natarajan, Pavithra; Kadri, Sameer S
title: Suspected SARS-CoV-2 Reinfections: Incidence, Predictors, and Healthcare Use among Patients at 238 U.S. Healthcare Facilities, June 1, 2020- February 28, 2021
date: 2021-08-05
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab671
sha: a2dda1a384f5035f49e519d31cda25a5f855cb97
doc_id: 1046521
cord_uid: g266ttng

In a retrospective cohort study, among 131,773 patients with previous COVID19, reinfection with SARS-CoV-2 was suspected in 253(0.2%) patients at 238 U.S. healthcare facilities between June 1, 2020- February 28, 2021. Women displayed a higher cumulative reinfection risk. Healthcare burden and illness severity were similar between index and reinfection encounters.

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

The United States encountered the heaviest burden of SARS-CoV-2 infections globally in 2020 with over 30 million infected. These individuals are a large group at risk for reinfection, as the durability of immunity offered by natural infection beyond 6 months remains unclear [1] . Understanding the ongoing risk of reinfection with SARS-CoV-2 is critical to guide appropriate personal safety and public health measures.

Several studies consistently indicate SARS-CoV-2 reinfection to be a relatively rare occurrence, with frequencies ranging between 0.02% and 1.0% [2, 3] . A Danish surveillance study covering 69% of the population of Denmark suggested reinfection frequency of 0.65% [4] . The U.S. lacks population surveillance data on this topic; evidence thus far is limited to two smaller retrospective cohort studies that similarly found suspected reinfections occurred infrequently at 0.7% [5, 6] . However one study [5] was limited to a single health care system in 2 U.S. states and the other [6] ended follow up in November 2020, prior to the period of heaviest incident cases during the 3 rd wave of the pandemic (December 2020-January 2021). We therefore sought to leverage observational clinical and administrative data from electronic medical records and included data from the first full year of the U.S. pandemic to retrospectively determine the incidence and healthcare utilization of suspected SARS-CoV-2 reinfection and the evolution and predictors of reinfection risk over time.

The Premier TM Healthcare Database (PHD) contains administrative data on inpatient and outpatient discharges from over 800 centers across 48 U.S. states. All adult patients age >18 years who received SARS-CoV-2 PCR testing at a participating healthcare facility from March 1, 2020, through February 28, 2021, were identified from a subset of 247 healthcare facilities that also submits clinical data from the TheraDoc TM clinical surveillance systems. This research activity was reviewed by the U.S. Suspected reinfection was defined as a patient with ≥2 positive SARS-CoV-2 polymerase chain reaction (PCR) test results ≥90 days apart [7] . The last recorded positive PCR test result (for the index encounter) was used as the start date for the 90-day interval prior to the reinfection risk period. Patients whose index positive SARS-CoV-2 PCR test result occurred after November 30, 2020, were excluded to allow a minimum of 90 days of follow up within the study period. Demographic and clinical characteristics of patients with a sole SARS-CoV-2 infection vs those with a suspected reinfection were compared using Fisher's Exact test while McNemar's test was used to compare the initial versus potential reinfection encounters. An alluvial plot was constructed for 1-to-1 comparison between the care settings of index vs suspected reinfection encounters. Univariate comparisons of cumulative risk were made for age (age <65 vs ≥65 years), gender (male vs female), U.S. census region, and high vs low (< vs ≥ median) monthly SARS-CoV-2 testing frequency for each healthcare facility. These variables were included in a multivariable Cox proportional hazards model to further assess their association with higher cumulative reinfection risk. M a n u s c r i p t criteria for suspected reinfection (0.2% of patients with a positive result, 10.0% of patients who were retested), corresponding to a reinfection rate of 4.96 per 10,000 person-months of potentially exposed time. Demographic characteristics are shown in Table 1 A c c e p t e d M a n u s c r i p t Women were at higher risk for reinfection (HR for suspected reinfection in women vs men, 1.579, 95% CI 1.283-1.941, p < 0.0001, eFigure 2C, eTable 1). There was no significant difference in cumulative risk of reinfection between patients <65 versus ≥65 years of age, nor by geographic region, nor by testing rate.

In this study, COVID-19 reinfections were rarely detected in healthcare facilities in the United States during the first 9 months of risk for reinfection, and reinfection currently appears to account for a small portion of morbidity, mortality and healthcare resource burden in the U.S. Our results complement existing evidence from international surveillance and other U.S. -and non-U.S.-based studies on the topic [4] [5] [6] . The SARS-CoV-2 reinfection rate of 0.2% in our study is lower than reported in two previous smaller U.S. studies (both reported <0.7% reinfection rates) [5, 6] , likely reflecting differences in study populations, inclusion criteria, reinfection definitions, and follow-up times, but collectively reinforce a common theme that reinfection risk remains low.

In this study, there was a higher rate of suspected reinfection in women as compared to men, which has not been previously reported and contrasts with previously published sex-specific infection rates [8] . However, a recent report has identified that women have more breakthrough infections with SARS-CoV-2 post vaccination than men [9] . The mechanistic basis for this female gender predilection for reinfection and vaccination breakthroughs warrants investigation. In contrast to a population surveillance study in Denmark [4] , age ≥65 years was not identified as a significant risk factor for reinfection in our relatively larger study although a non-significant trend of increased risk with older age was observed upon longer follow up. Our results did not identify any geographic differences in reinfection rates, stratified by month (data not shown). While locally circulating SARS-A c c e p t e d M a n u s c r i p t CoV-2 variants can pose increased transmissibility or higher risks of evading previously established immunity, variants of concern were not identified in the United States until late in the time frame of this analysis [10, 11] .

There were some notable similarities between the index infection and suspected reinfection encounters of COVID-19 in the same patient, including similar frequencies of ICD-10 diagnostic coding for common COVID-19 symptoms and acute respiratory failure, distributions of care setting and inpatient COVID-19-targeted medication use. While coding for clinical features might provide an incomplete account of actual frequency, at least our study suggests patients tend not to be markedly sicker on subsequent episodes, which has prognostic and resource implications.

This study has strengths. Our study population includes the largest number of individuals with COVID-19 in whom the risk of reinfection has been examined to date -over 10-fold larger than other contemporaneous studies [4] [5] [6] , and the first multi-healthcare system analysis to capture potential reinfections occurring during the third wave of the pandemic in the United States. We identified suspected reinfections spanning a range of care settings, periods of high and low community transmission, and a long follow-up period. Lastly, as vaccination only became available to the general population towards the end of our study period, the impact of vaccination on the reinfection rates identified here is likely negligible.

Our study also has limitations. First, without any genome sequencing data to confirm reinfection, our study relies on renewed PCR positivity in a previously infected patient as a marker of reinfection.

Some positive test results could represent persistent viral shedding from the index infection, including from patients with impaired immunity (less than 5% of the cohort), though our A c c e p t e d M a n u s c r i p t requirement of a minimum 90-day interval between positive PCRs likely minimized this [12] .

Conversely, given the plethora of SARS-CoV-2 testing avenues in the U.S., we likely missed test results obtained outside of healthcare facilities reporting to Premier Inc. Furthermore, all patients reinfected and coming to medical attention prior to the 90-day cut-off would also have been missed.

As such, our 0.2% estimate of the frequency of reinfection is more likely to be an underestimate of all reinfections but more closely captures the frequency of patients that seek medical attention.

Second, survival bias and the administrative nature of the patient-level data might preclude rigorous assessments of comparisons of illness severity. Third, we were unable to determine the indication for SARS-CoV-2 testing and cannot distinguish among clinically indicated, exposure-based, and routine admissions-based testing.

Overall, these results are encouraging from a public health perspective as the burden of symptomatic and/or acutely ill patients with suspected reinfection was low. Variants-of-concern and the possible waning of immunity over time might lead to a higher burden of reinfection in the future. Ongoing surveillance will be critical.

Funding: Intramural Research Program of the NIH Clinical Center M a n u s c r i p t 

Immunity to SARS-CoV-2: Lessons Learned

Assessment of the risk of SARS-CoV-2 reinfection in an intense re-exposure setting

Risk of reinfection after seroconversion to SARS-CoV-2: A population-based propensity-score matched cohort study

Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study

Reinfection Rates among Patients who Previously Tested Positive for COVID-19: a Retrospective Cohort Study

Re-infection with SARS-CoV-2 in Patients Undergoing Serial Laboratory Testing

Investigative Criteria for Suspected Cases of SARS-CoV-2 Reinfection (ICR)

Sex differences in susceptibility, severity, and outcomes of coronavirus disease 2019: Cross-sectional analysis from a diverse US metropolitan area

COVID-19 Vaccine Breakthrough Infections Reported to CDC -United States

SARS-CoV-2 Variants of Concern in the United States-Challenges and Opportunities

Emergence of SARS-CoV-2 B.1.1.7 Lineage -United States

Virological assessment of hospitalized patients with COVID-2019

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 Restricted to comorbidities present on admission and associated with increased risk for severe COVID-19. Sickle cell disease, cystic fibrosis, and cirrhosis were not excluded, but none were found in the reinfection cohort. A c c e p t e d M a n u s c r i p t Figure 1