medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021.

The copyright holder for this preprint

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

A 1 to 1000 SARS-CoV-2 reinfection proportion in members of a large

healthcare provider in Israel: a preliminary report

Authors:

Galit Perez, MN MA1; Tamar Banon2, MSc; Sivan Gazit1, MD MA; Shay Ben Moshe3,1,

MSc; Joshua Wortsman, MD 1; Daniel Grupel3, MD; Asaf Peretz, MD4; Amir Ben Tov,

MD2,5; Gabriel Chodick, PhD MHA2, 5; Miri Mizrahi-Reuveni MD MHA 6; Tal Patalon, MD2

1
Kahn Sagol Maccabi (KSM) Research & Innovation Center, Maccabi Healthcare
Services, Israel.
2
Maccabitech Institute for Research and Innovation, Maccabi Healthcare Services, Tel
Aviv, Israel.
3
Ben-Gurion University, Beer Sheva, Israel.
4
Internal Medicine COVID-19 Ward, Samson Assuta Ashdod University Hospital,
Ashdod Israel.
5
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
6
Health Division, Maccabi Healthcare Services, Tel Aviv, Israel.

Corresponding author: Galit Perez

[email protected]

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 1
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

Abstract

With more than 100 million confirmed COVID-19 cases as of March 2021,

reinfection is still considered to be rare. In light of increasing reports of reinfected

COVID-19 patients, the need to better understand the real risk for reinfection is critical,

with potential effects on public health policies aimed at containing the spread of SARS-

CoV-2. In this descriptive preliminary report, we conducted a large-scale assessment on

the country level of the possible occurrence of COVID-19 reinfection within the

members of a large healthcare provider in Israel. Out of 149,735 individuals with a

documented positive PCR test between March 2020 and January 2021, 154 had two

positive PCR tests at least 100 days apart, reflecting a reinfection proportion of 1 per

1000. Given our strict inclusion criteria, we believe these numbers represent true

reinfection incidence in MHS and should be clinically regarded as such.

Introduction

In the ongoing effort to understand and control the coronavirus disease 2019

(COVID-19) global pandemic, one of the key questions that should be explored is how

effectively the immune response protects a host from being re-infected with the Severe

Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)[1]. The answer to this

question has many implications including understanding if there is a real possibility to

obtain herd immunity as well as significantly influencing policy-making in COVID-19

afflicted regions. This is particularly true when considering policy pertaining to social

distancing practices and mask-wearing by individuals who were infected and recovered

2
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

from SARS-CoV-2 [2]. The widespread assumption that recovered patients develop a

protective immune response has heavily influenced both research and policy-making,

however, recent documentation of re-infected COVID-19 patients could potentially affect

public health policies aimed at containing the spread of SARS-CoV-2.

With more than 100 million confirmed COVID-19 cases as of March 2021,

reinfection is still considered to be a rare event[3, 4]. In light of increasing reports of

reinfected COVID-19 patients, the need to better understand the real risk for reinfection

is critical, with potential effects on public health policies aimed at containing the spread

of SARS-CoV-2.

With the earliest cases of reinfection emerging in June 2020[3], there is increasing

documentation of patients who have been re-infected with SARS-CoV-2[5]. Re-infection

has been determined either by genetic sequencing[1, 5], which verifies that patients have

been infected with two genetically distinct isolates of COVID-19, or by real-time

polymerase chain reaction (PCR), demonstrating a newly positive PCR test months

following recovery from COVID-19[5, 6].

Several studies have indicated that re-infected patients typically experience

milder symptoms during their second infection, possibly explained by priming of their

adaptive immune response[7, 8]. However, case reports of individuals who have suffered

a significantly more severe disease course during re-infection have also been

documented[5].

Admittedly, it is not surprising that there would be re-infections with SARS-CoV-2, as

this phenomenon is known to occur with other coronaviruses[6]. Various strains of

coronaviruses are responsible for the common cold and research displayed that the

3
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

immune response to these viruses tend to develop quickly and wane over time which

allows for re-infection to take place[2]. Although reinfections typically occur within one to

three years with other coronaviruses, the increased re-exposure rate to SARS-CoV-2

may decrease the impact of the protective immune response and significantly shorten

the time required for re-infection[2, 6].

Within the Israeli population, at least one re-infection case has been documented, in

August 2020[9]. Further research is therefore required to determine whether this case is

an outlier or rather represents a trend of possible SARS-CoV-2 re-infection in the Israel

population.

This descriptive preliminary report aims to perform a large-scale assessment on

the country level of the possible occurrence of COVID-19 reinfection within the

members of a large healthcare provider in Israel.

Methods

Data Source

This study was conducted using data from the Maccabi Healthcare Services

(MHS) central computerized database, the second largest state-mandated not-for-profit

healthcare provider in Israel, containing more than 2.5 million members (approximately

25% of the population) and is a representative sample of the Israeli population. This

fully computerized database captures all information on patient interaction (including

demographics, visits, diagnoses, procedures and more).

4
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

Study population and design

In this retrospective cohort study, individuals were included if they had two

positive PCR results, at least 100 days apart, from March 16, 2020 until January 27,

2021. The 100 days marker was selected in order to reduce the chance of prolonged

shedding. The study was approved by the MHS institutional review board.

Variables and definitions

The cohort was described by age (mean and standard deviation [±SD]), sex,

socioeconomic status (SES), Immunocompromised registry (i.e. included in the MHS

registry or not), the days between PCR tests (mean [±SD]), and COVID-19 related

symptoms (±10 days from PCR test result), hospitalization and mortality. COVID-19

related symptoms included fever, cough, breathing difficulties, diarrhea, changes in the

senses of taste or smell, fatigue, sore throat and headache.

Individuals' ages were calculated at first positive PCR test date. SES of

members' residential area was based on a score ranked with 1 (lowest) to 10 built for

commercial purposes by Points Location Intelligence using geographic information

systems and data such as expenditures related to retail chains, credit cards and

housing. This score is highly correlated with SES measured by the Israel Central

Bureau of Statistics[10]. SES was categorized into low (1-4), medium (5-6) and high (7-

10).

The MHS Immunocompromised Registry captures all members with at least one

of the following treatments or diagnoses: organ or bone marrow transplant,

immunosuppressive treatment (oncologic or other), advanced kidney disease

5
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

(advanced chronic kidney disease, dialysis, Nephrotic Syndrome), Asplenia or any

records of immunosuppression drug purchase.

COVID-19 related symptoms were described as present at first or second PCR

test result. Among individuals with a COVID-19 related hospital record, those with a

hospitalization within 10 days of their first or second positive PCR test were accounted

for and described.

Descriptives

In addition to individual characteristics, the number of individuals (i.e. individual

counts) were assessed and displayed in figures. Age distribution was presented, as

reinfection counts, by ranges of 10 years. Distribution of the second positive PCR test

was displayed per month. Lastly, the number of days between first and second positive

PCR test was evaluated and shown by ranges of 50 days (with a minimum of 100 to

149 days).

6
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

Results

A total of 149,735 individuals in MHS had a record of a positive PCR test

between March 2020 and January 2021. Among them 154 MHS members had two

positive PCR tests at least 100 days apart and were included in this study, amounting to

0.1% proportion of reinfection. In this cohort, 73 individuals (47.4%) had symptoms at

both PCR positive events. Members' characteristics are displayed in Table 1.

Age distribution is presented in Figure 1, where the highest count was among

individuals aged 10 to 19 years old. The monthly distribution (Figure 2) displayed that

the first reinfection (1 member) occurred in July 2020, where the reinfection counts peak

in January 2021 (99 members). The distribution of days between first and second

positive PCR (Figure 3) shows that 30 individuals were reinfected more than 200 days

following their first positive PCR test.

7
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

Discussion

A yet unanswered question is the definition of COVID-19 reinfection. While clear

cut cases exist, namely two different clinical occasions with two distinct sequenced

viruses, relying solely on these will likely cause a massive under-estimation of the

reinfection phenomena. Different criteria have been suggested and used in studies,

trying to identify true reinfections using easier-to-obtain information and separate those

with cases of prolonged viral shedding[11, 12].

This descriptive preliminary report strongly suggests that COVID-19 reinfections

have occurred in MHS in Israel. Out of 149,735 individuals with a documented positive

PCR test between March 2020 and January 2021, 154 had two positive PCR tests at

least 100 days apart, reflecting a reinfection proportion of 1 per 1000. We believe these

numbers represent true reinfection incidence in MHS and should be clinically regarded

as such.

Admittedly, without genome sequencing, COVID-19 reinfections cannot be

conclusively determined; however, we chose a very strict 100-day period and risk

factors previously shown to be associated with prolonged viral shedding (especially

mechanical ventilation, late hospital admission and immunosuppression) were not

prevalent in the population meeting our inclusion criteria [13-15]. In addition, 73 members

(47.4%) reported symptoms at two positive PCR tests, suggesting they showed clinical

signs of COVID-19 reinfection at both events. The presence of symptoms also

reinforces the suggested reinfection among members. We are conducting further

research to verify our inclusion criteria.

8
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

The peak reinfection counts from January 2021 (Figure 3) should also be

addressed. A possible hypothesis for the elevated reinfection counts may refer to the

presence of different COVID-19 strains. Multiple genetically distinct variants of SARS-

CoV-2 have been documented[16] around the world, as coronavirus mutations were

identified in Israel in late November (according to the Israeli Ministry of Health)[17] and

become widespread in January[18-20]. Correlations between strains and the risk of

reinfection should be studied further.

Lastly, the demonstrated age distribution, which suggests higher counts of

reinfection among younger individuals, differs from previous analyses that display

reinfection rates irrespective of patient age and gender[3]. Possible explanations include

behavioral factors, namely the lack of social distancing and mask-wearing that may

account for an increased exposure and therefore possible increased risk of reinfection.

Limitations

Although this research displays new information on reinfected COVID-19

individuals in Israel, the study has some limitations. First, the conservative definition of

reinfections (i.e. minimum 100 days between positive PCR tests) may have excluded

some reinfected members from this study. Furthermore, members in the cohort were

not evaluated further than preliminary assessments, mainly counts and proportions.

Further research should be performed as more data is collected, followed by statistic

modeling and predictive analyses between reinfection groups.

9
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

Conclusions

This study describes real-world data of SARS-CoV-2 reinfection in a large-scale

population cohort. Reinfection proportion, albeit small, is not insignificant; as time

passes the potential for reinfection increases. Given our strict inclusion criteria, we

believe these numbers represent true reinfections in MHS and should be clinically

regarded as such.

Health policymakers should acknowledge the possibility of reinfection and

reconsider the differential message to recovered population.

10
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

References

1. Iwasaki, A., What reinfections mean for COVID-19. The Lancet Infectious
Diseases, 2021. 21(1): p. 3-5.
2. Edridge, A.W., et al., Human coronavirus reinfection dynamics: lessons for
SARS-CoV-2. MedRxiv, 2020.
3. Hall, V.J., et al., Do antibody positive healthcare workers have lower SARS-CoV-
2 infection rates than antibody negative healthcare workers? Large multi-centre
prospective cohort study (the SIREN study), England: June to November 2020.
medRxiv, 2020: p. 2021.01. 13.21249642.
4. de Vrieze, J., Reinfections, still rare, provide clues on immunity. 2020, American
Association for the Advancement of Science.
5. Dickson, M., R.A. Mathews, and G.G. Menon, ANALYSIS OF COVID-19
REINFECTION RATES AND ITS UNDERLYING CAUSES: A SYSTEMATIC
REVIEW.
6. Pal, R. and M. Banerjee, Are people with uncontrolled diabetes mellitus at high
risk of reinfections with COVID-19? Primary care diabetes, 2021. 15(1): p. 18-20.
7. Priyanka, O.P.C. and I. Singh, Protective immunity against COVID-19:
Unravelling the evidences for humoral vs. cellular components. Travel Medicine
and Infectious Disease, 2021. 39: p. 101911.
8. Osman, A.A., M.M. Al Daajani, and A.J. Alsahafi, Re-positive COVID-19 PCR
test: could it be a reinfection? New microbes and new infections, 2020: p.
100748.
9. Nachmias, V., et al., The first case of documented Covid-19 reinfection in Israel.
IDCases, 2020. 22: p. e00970.
10. Israel Centeral Bureau of Statistics, 1995 Census of Population and Housing
1998: Jerusalem.
11. Tomassini, S., et al., Setting the criteria for SARS-CoV-2 reinfection–six possible
cases. The Journal of Infection, 2020.
12. CDC. Reinfection. 2020 Oct. 27, 2020 March 4, 2020]; Available from:
https://www.cdc.gov/coronavirus/2019-ncov/php/reinfection.html.
13. Dou, P., et al., Serial CT features in discharged COVID-19 patients with positive
RT-PCR re-test. European journal of radiology, 2020. 127.
14. Li, J., et al., Case report: viral shedding for 60 days in a woman with COVID-19.
The American journal of tropical medicine and hygiene, 2020. 102(6): p. 1210-
1213.
15. Xu, K., et al., Factors associated with prolonged viral RNA shedding in patients
with coronavirus disease 2019 (COVID-19). Clinical Infectious Diseases, 2020.
71(15): p. 799-806.
16. Pachetti, M., et al., Emerging SARS-CoV-2 mutation hot spots include a novel
RNA-dependent-RNA polymerase variant. Journal of translational medicine,
2020. 18: p. 1-9.
17. Ministry of Health. Another Case of the UK Variant Found. 2020 24.12.2020
05.03.2021]; Available from: https://www.gov.il/en/Departments/news/24122020-
03.

11
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

18. Ministry of Health. 18 Positive Samples of the English Variant ("The British
Mutation") of the Coronavirus Detected. 2021 01.01.2021 05.03.2021]; Available
from: https://www.gov.il/en/Departments/news/01012021-01.
19. Ministry of Health. 30 Cases of the South African Variant Detected So Far. 2021
27.01.2021 05.03.2021]; Available from:
https://www.gov.il/en/Departments/news/27012021-03.
20. Staff, T., Virus czar: With COVID-19 mutations, third lockdown may not be
Israel’s last, in The Times of Israel. 2021.

12
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

Tables and Figures

Table 1. Descriptive results for individuals with COVID-19 reinfections in MHS

Individual Characteristics COVID-19 Reinfections

(n=154)

Age (mean [±SD]) 31.5 (19.7)

Sex, male (%) 94 (61.0%)

SES (%) Low 93 (60.4%)

Medium 40 (26.0%)

High 21 (13.6%)

Immunocompromised (%) 5 (3.2%)

Days between PCRs (mean [±SD]) 165.7 (57.6)

Symptoms (%) 1st PCR test 109 (70.8%)

2nd PCR test 98 (63.6%)

Both PCR tests 73 (47.4%)

Hospitalizations (%) 1st PCR test 11 (7.1%)

2nd PCR test 4 (2.6%)

Both PCR tests 0 (0%)

Death (%) 1 (0.6%)

13
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

Figure 1. Age distribution among individuals with a COVID-19 reinfection (n=154)

14
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

Figure 2. Monthly distribution of second positive PCR test among individuals with a

COVID-19 reinfection (n=154)

15
medRxiv preprint doi: https://doi.org/10.1101/2021.03.06.21253051; this version posted March 8, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
All rights reserved. No reuse allowed without permission.

Figure 3. Distribution of days between first and second positive PCRs among

individuals with a COVID-19 reinfection (n=154)

16