European Journal of Internal Medicine xxx (xxxx) xxx

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Characteristics and clinical outcomes of patients with COVID-19 recurrent infection during the
omicron variant predominance

Dear Editor, covariates to assess recurrent infections, hospitalizations, and death

while addressing the changes in vaccination status throughout the study
Reinfections with severe acute respiratory syndrome coronavirus 2
period. We considered subjects as vaccinated if 14 days or more had
(SARS-CoV-2), the virus responsible for coronavirus disease 2019
elapsed from their last mRNA vaccine dose [7]. The Cox
(COVID-19), were considered an uncommon event during the pre-
proportional-hazards regression model was adjusted for demographics,
omicron period of the pandemic [1,2]. However, during the omicron
and clinical covariates selected a priori based on clinical significance.
period [3], reinfections with SARS-CoV-2 became increasingly common
We used a P-value of less than 0.05 to indicate statistical significance in
[4]. Relatively early in the pandemic, risk factors such as age, obesity,
all analyses. R statistical software, version 4.0.2 (R Foundation), was
and chronic illness played a significant role in the severity of COVID-19
used for all analyses. The Soroka University Medical Center institutional
[5]; however, their relevance to reinfections in the omicron period re­
research review board approved the study (SOR 0288–22) and granted a
mains unknown. Here we describe the results of a nationwide study
waiver of informed consent.
aimed at assessing the clinical characteristics and the hospitalization
Of 2,966,451 eligible CHS members, 1,280,649 (43.2%) had at least
and mortality of people reinfected with COVID-19 during the omicron
one documented SARS-CoV-2 infection throughout the study, and
variant predominance timeframe.
111,417 (8.7%) were diagnosed with a recurrent infection during the
We conducted a retrospective cohort study based on electronic
omicron variant predominance. Of the 111,417 members who were
medical records data for all Clalit Health Services (CHS) members. This
reinfected, 91,814 (82.4%) had a pre-omicron/omicron reinfection, and
large healthcare organization provides services for approximately 4.8
19,603 (17.6%) had an omicron/omicron reinfection. The median time
million people (51% of the Israeli population). We collected data from
for the pre-omicron/omicron reinfection was 399.6 (IQR 340.1–502.3)
March 1, 2020, the beginning of the COVID-19 pandemic in Israel, until
days, and for omicron/omicron reinfection was 164.4 (IQR
September 20, 2022, the introduction of the omicron booster vaccine in
146.5–181.9) days. Most comorbidities were similar between the pri­
Israel. The study included all members of CHS aged ≥16 years with
mary infection groups, but the hospitalizations and death rates were
confirmed SARS-CoV-2 infection, either by quantitative reverse-tran­
significantly lower during the omicron predominance. The administra­
scriptase–polymerase-chain-reaction (RT-qPCR) or by a medically su­
tion of mRNA vaccines was associated with a lower risk for recurrent
pervised rapid antigen test. The omicron variant became the most
infections. Among the patients diagnosed with a first infection, 37,045
prevalent among SARS-CoV-2 variants in Israel on December 19, 2021.
(3.2%) were hospitalized, compared to 1,595 (1.4%) in the recurrent
Therefore, we defined recurrent infection as a positive SARS-CoV-2 test
infection (p<0.001, Table 1). The hospitalization rates were lower in the
result, either PCR or an antigen test, starting from December 19, 2021,
pre-omicron/omicron reinfection group compared to the omicron/om­
and performed at least 90 days after the primary infection [6]. Recurrent
icron reinfection group, 1,147 (1.2%) and 448 (2.3%), respectively
infections were further divided according to the variant of the primary
(p<0.001). The adjusted hazard ratio for omicron/omicron reinfection
infection. The pre-omicron/omicron group was defined as those with a
was 0.1 (95% [CI], 0.1–0.1), compared to the pre-omicron/omicron
pre-omicron variant primary infection followed by an omicron variant
reinfection (Table 2). The adjusted hazard ratio of the principal risk
reinfection, and the omicron/omicron group as those with two in­
factors associated with COVID-19 hospitalization due to recurrent
fections during the omicron variant predominance. We did not evaluate
infection was age above 80 (5.1, 95% [CI], 4.3 to 6.1, compared to
further infections after the second infection. COVID-19-associated hos­
younger than 65), immunocompromised state (3.0, 95% [CI], 2.6 to
pitalization was defined as a hospitalization reported to the Israeli
3.4), chronic kidney disease (CKD, 2.0, 95% [CI], 1.7 to 2.3), diabetes
Ministry of Health as COVID-19-related hospitalization. Similarly,
(1.7, 95% [CI], 1.5 to 1.9), chronic obstructive pulmonary disease (1.7,
COVID-19-related death was defined as death reported to the Israeli
95% [CI], 1.4 to 1.9), and hypertension (1.4, 95% [CI], 1.2 to 1.7,
Ministry of Health as COVID-19 related death. Data were extracted using
Table 2). Compared to the pre-omicron/omicron reinfection, hospitali­
the Clalit Research Data sharing platform powered by MDClone.
zation with omicron/omicron reinfection had an adjusted hazard ratio
For patients with a primary infection before September 20, 2021, 90
of 2.0 (95% CI, 1.7 to 2.3, Table 2). The overall mortality rate from
days prior to the beginning of the omicron predominance period in
COVID-19 was 70.2 per 10,000 in patients with any primary infection
Israel, follow-up started on December 19, 2021, the beginning of the
compared to 13.6 per 10,000 with recurrent infection (Table 1). The
omicron predominance period. For patients with a primary infection
mortality rates, when dividing the primary infection according to pre-
after September 20, 2021, the follow-up period started 90 days after the
omicron and omicron variants, were 202.3 and 26.8 per 10,000,
primary infection. Follow-up for all outcomes started at the later of 90
respectively. The adjusted hazard ratio for death in recurrent infections
days after primary infection or December 19, 2021. We used a multi­
for patients with an immunocompromised state was 4.0 (95% [CI], 2.8
variable Cox proportional-hazards regression model with time-varying

https://doi.org/10.1016/j.ejim.2023.05.017
Received 4 May 2023; Accepted 11 May 2023
Available online 15 May 2023
0953-6205/© 2023 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Ran Abuhasira et al., European Journal of Internal Medicine, https://doi.org/10.1016/j.ejim.2023.05.017
R. Abuhasira et al. European Journal of Internal Medicine xxx (xxxx) xxx

Table 1
Baseline characteristics and outcomes of the study cohort.
Primary COVID-19 infection only (N = 1,169,232) Recurrent COVID-19 infection (N = 111,417)

Age (years, mean ± SD) 45.8 ± 17.9 42.3 ± 16.4

16–64, No. (%) 954,057 (81.6%) 98,609 (88.5%)
65–79, No. (%) 162,890 (13.9%) 9,280 (8.3%)
80+, No. (%) 52,285 (4.5%) 3,528 (3.2%)
Female sex, No. (%) 660,181 (56.5%) 70,573 (63.3%)
Population sector, No. (%)
General Jewish 891,605 (76.3%) 79,066 (71.0%)
Arab 217,941 (18.6%) 23,312 (20.9%)
Other 59,686 (5.1%) 9,039 (8.1%)
Socioeconomic status
Very High 100,491 (8.6%) 5,740 (5.2%)
High 311,191 (26.6%) 22,917 (20.6%)
Medium 368,997 (31.6%) 38,481 (34.5%)
Low 281,668 (24.1%) 34,181 (30.7%)
Very Low 47,976 (4.1%) 4,281 (3.8%)
Unknown 58,909 (5.0%) 5,817 (5.2%)
Clinical risk factors, No. (%)
Diabetes 161,404 (13.8%) 13,154 (11.8%)
Chronic obstructive pulmonary disease 57,390 (4.9%) 4,744 (4.3%)
Asthma 127,783 (10.9%) 12,989 (11.7%)
Chronic kidney failure 51,388 (4.4%) 39,27 (3.5%)
Hypertension 266,702 (22.8%) 20,645 (18.5%)
Ischemic heart disease 81,000 (6.9%) 5,523 (5.0%)
Chronic heart failure 34,034 (2.9%) 2,623 (2.4%)
Obesity 603,474 (51.6%) 57,164 (51.3%)
Lung cancer 2813 (0.2%) 173 (0.2%)
Malignancies 71,353 (6.1%) 5,123 (4.6%)
Cerebrovascular event 51,641 (4.4%) 3,985 (3.6%)
Immunocompromiseda 39,594 (3.4%) 3,981 (3.6%)
Current or former smoking 384,303 (32.9%) 31,386 (28.2%)
Nirmatrelvir/ritonavir treatment (primary infection) 27,434 (2.3%) 646 (0.6%)
Nirmatrelvir/ritonavir treatment (recurrent infection) – 1,732 (1.6%)
Number of COVID-19 vaccines prior to infection, No. (%)
0 263,542 (22.5%) 31,142 (28.0%)
1 19,354 (1.7%) 31,022 (27.8%)
2 188,345 (16.1%) 23,110 (20.7%)
3 585,720 (50.1%) 21,452 (19.3%)
4 112,271 (9.6%) 4,691 (4.2%)
Outcomes of infection
COVID-19 related hospitalization (primary infection), No. (%) 37,045 (3.2%) 4,467 (4.0%)
COVID-19 related hospitalization (recurrent infection), No. (%) – 1,595 (1.4%)
COVID-19 related death, No. (%) 8,212 (0.7%) 151 (0.1%)
a
According to CDC definition. COVID-19 – coronavirus disease 2019.

to 5.7). Compared to the pre-omicron/omicron reinfection, death with
omicron/omicron reinfection had an adjusted hazard ratio of 1.9 (95%
CI, 1.3 to 2.8, Table 2).
We demonstrated higher hospitalizations and mortality rates in
omicron/omicron reinfection than pre-omicron/omicron reinfection. A
study from North Carolina showed that primary infection with an omi­
cron variant is protective against hospitalization and death associated
with reinfection [8]. However, that study reported missing data for these
outcomes and did not account for comorbidities and the immune status
of the patients. The fact that patients with omicron reinfection had far
worse outcomes may be explained by the difference in subvariants be­
tween the primary infection and the reinfection and by the immuno­
compromised state of the patients that developed a severe outcome from
omicron reinfection and could not mount an efficient immunologic
response. Another explanation might be that patients infected with an
omicron variant were less likely to be tested again for COVID-19 after a
relatively short time, except for the most severe clinical cases. This
relatively short time interval between the infections may also contribute
to the severity of illness, as some patients did not fully recover from their
primary infection.
Among immunocompromised patients infected with an omicron
variant, studies have shown that compared to pre-omicron variants,
there is a reduced severity of COVID-19 outcomes; nevertheless, these
patients still have higher morbidity and mortality rates than the general
population [9]. In a study that evaluated patients in the intensive care
unit with an omicron infection, the main difference between those with
and without immunosuppression was mortality, while other complica­
tions and aspects of the treatment were similar [10]. Our results show
that in reinfected individuals, regardless of the variant of the primary
infection, the overall rates of hospitalization and mortality were low and
that immunosuppression and age are the most critical risk factors.
Most studies that assessed recurrent infections during the omicron
period addressed the effectiveness of vaccines and previous immunity to
protect from recurrent infections, but the clinical outcomes and char­
acteristics were rarely assessed at the population level. Therefore, we
have used an extensive national database with real-world data to focus
on the profile of patients that still require special attention in the current
stage of the pandemic. Furthermore, we used a refined definition of an
immunocompromised state determined by the Centers for Disease
Control and Prevention (CDC) and relevant specifically to patients with
COVID-19. Nevertheless, our study has limitations. First, the rate of
reinfections is challenging to assess when testing is not mandated. Sec­
ond, viral genome sequencing data were unavailable; therefore, we
could not attribute the results to a specific subvariant of omicron.
However, as asymptomatic infection or very mild infection is of less
clinical interest, we can safely assume that all patients admitted with
severe COVID-19 were tested. Third, comparing patients infected with
omicron and pre-omicron is potentially confounded by unmeasured

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R. Abuhasira et al. European Journal of Internal Medicine xxx (xxxx) xxx

Table 2
Association between patient characteristics and recurrent infection with an omicron variant or the associated hospitalization or death.
Characteristic Recurrent infection with an omicron Hospitalization with recurrent Death with recurrent infection
variant infection

Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI)

Unadjusted Adjusted Unadjusted Adjusted Unadjusted analysis Adjusted analysis

analysis analysis analysis analysis

Age group
16–64 Reference
65–79 0.77 (0.75–0.78) 0.79 6.44 (5.72–7.25) 2.83 17.14 7.53
(0.77–0.81) (2.42–3.31) (10.65–27.59) (4.17–13.59)
80+ 1.09 (1.05–1.13) 0.95 16.39 5.08 87.67 27.5
(0.92–0.99) (14.5–18.53) (4.26–6.05) (56.98–134.88) (15.04–50.28)
Male sex 0.76 (0.75–0.77) 0.7 (0.69–0.71) 1.11 (1.01–1.23) 0.92 1.33 (0.97–1.84) 1.0 (0.71–1.42)
(0.83–1.03)
Clinical risk factors
Diabetes 0.98 (0.96–1) 0.92 (0.9–0.94) 5.24 (4.74–5.8) 1.67 7.13 (5.18–9.81) 1.28 (0.89–1.82)
(1.47–1.89)
Chronic obstructive pulmonary disease 1.02 (0.99–1.05) 0.99 5.53 (4.87–6.27) 1.65 6.5 (4.42–9.56) 1.23 (0.79–1.9)
(0.96–1.02) (1.42–1.91)
Asthma 1.09 (1.07–1.11) 1.09 1.57 (1.38–1.79) 0.98 1.16 (0.73–1.86) 0.67 (0.4–1.12)
(1.07–1.11) (0.85–1.13)
Chronic kidney failure 1.09 (1.06–1.13) 1.16 10.73 2.0 (1.74–2.3) 21.8 (15.79–30.09) 2.34 (1.6–3.42)
(1.12–1.21) (9.59–12.01)
Hypertension 0.98 (0.96–0.99) 1.08 (1.06–1.1) 5.78 (5.23–6.38) 1.43 14.48 (9.96–21.05) 1.38 (0.82–2.31)
(1.23–1.66)
Ischemic heart disease 0.93 (0.91–0.96) 1.06 6.66 (5.94–7.47) 1.08 10.16 (7.25–14.23) 0.85 (0.57–1.26)
(1.03–1.09) (0.93–1.25)
Chronic heart failure 1.11 (1.07–1.15) 1.04 11.68 1.69 19.65 1.71 (1.14–2.57)
(0.99–1.08) (10.33–13.2) (1.45–1.97) (13.92–27.74)
Obesity 1.03 (1.02–1.04) 1.01 (1–1.03) 1.34 (1.21–1.48) 0.87 1.26 (0.91–1.73) 0.77 (0.55–1.07)
(0.78–0.96)
History of stroke or transient ischemic attack 1.08 (1.05–1.11) 1.18 6.55 (5.77–7.44) 1.29 12.73 (9.02–17.96) 1.5 (1.04–2.17)
(1.14–1.22) (1.12–1.49)
Immunocompromised a 1.24 (1.21–1.28) 1.27 6.92 (6.11–7.84) 2.97 (2.6–3.39) 12.29 (8.69–17.38) 3.96 (2.76–5.67)
(1.23–1.32)
Current or former smoking 0.87 (0.85–0.88) 1.05 1.33 (1.2–1.48) 1.03 1.87 (1.35–2.58) 1.53 (1.07–2.17)
(1.04–1.07) (0.92–1.15)
Nirmatrelvir/ritonavir treatment for reinfection – 0.98 0.37 (0.24–0.56) 0.88 0.26 (0.06–1.04)
(0.65–1.48) (0.22–3.57)
Omicron/omicron reinfection vs. pre-omicron/ 0.12 (0.12–0.13) 0.13 2.59 (2.3–2.91) 2.0 (1.74–2.3) 3.98 (2.78–5.69) 1.9 (1.27–2.84)
omicron reinfection (0.12–0.13)
Number of vaccinations prior to infection
0 Reference
1 1.26 (1.24–1.28) 0.92 (0.9–0.93) 0.61 (0.52–0.7) 0.64 0.41 (0.21–0.78) 0.44 (0.23–0.85)
(0.55–0.74)
2 0.51 (0.5–0.52) 0.54 0.91 (0.78–1.05) 0.71 1.16 (0.69–1.94) 0.78 (0.46–1.31)
(0.53–0.55) (0.61–0.82)
3 or 4 0.25 (0.24–0.25) 0.8 (0.78–0.81) 1.66 (1.46–1.88) 0.55 3.53 (2.33–5.35) 0.74 (0.47–1.16)
(0.47–0.63)
a
According to CDC definition. SARS-CoV-2 – severe acute respiratory syndrome coronavirus 2.

patient characteristics associated with lower infection risk since those
whose first infection was with omicron avoided infection for two years.
Fourth, data about oxygen support, use of specific COVID-19 medica­
tions during hospitalizations, mechanical ventilation, or rate of inten­
sive care unit admissions were unavailable.
In conclusion, our study demonstrated that recurrent infection with
COVID-19 is common during the omicron variant predominance, and
the main risk factors for death are older age, CKD, heart failure, and an
immunocompromised state. In addition, primary infection with an om­
icron variant is protective against omicron/omicron reinfection but in
those who are reinfected is associated with a higher risk for hospitali­
zation and death than a pre-omicron/omicron reinfection.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The authors declare they have no conflict of interest.
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