Comparison of risk factors for SARS-CoV-2 infection among healthcare workers during Omicron and Delta dominance periods in Japan

Abstract

Background

The risk factors for coronavirus disease (COVID-19) among healthcare workers (HCWs) might have changed since the emergence of the highly immune evasive Omicron variant.

Aim

To compare the risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among HCWs during the Delta- and Omicron-predominant periods.

Methods

Using data from repeated serosurveys among the staff of a medical research centre in Tokyo, two cohorts were established: Delta period cohort (N = 858) and Omicron period cohort (N = 652). The potential risk factors were assessed using a questionnaire. Acute/current or past SARS-CoV-2 infection was identified by polymerase chain reaction or anti-nucleocapsid antibody tests, respectively. Poisson regression was used to calculate the risk ratio (RR) of infection risk.

Findings

The risk of SARS-CoV-2 infection during the early Omicron-predominant period was 3.4-fold higher than during the Delta-predominant period. Neither working in a COVID-19-related department nor having a higher degree of occupational exposure to SARS-CoV-2 was associated with an increased infection risk during both periods. During the Omicron-predominant period, infection risk was higher among those who spent ≥30 min in closed spaces, crowded spaces, and close-contact settings without wearing mask (≥3 times versus never: RR: 6.62; 95% confidence interval: 3.01–14.58), whereas no such association was found during the Delta period.

Conclusion

Occupational exposure to COVID-19-related work was not associated with the risk of SARS-CoV-2 infection in the Delta or Omicron period, whereas high-risk behaviours were associated with an increased infection risk during the Omicron period.

Introduction

The Omicron variant of SARS-CoV-2 has been identified in 192 countries, and is the dominant lineage globally, representing 97% of variant cases reported at the end of May 2022 [1]. This variant has caused an exponential growth in COVID-19 incidence [[2], [3], [4]]. Consequently, the immense demand for healthcare services poses an increased occupational risk for healthcare workers (HCWs) to be infected [5]. Therefore, identifying both occupational and non-occupational risk factors among HCWs during the circulation of this variant is crucial for controlling and minimizing the risk of infection [6,7].

Studies among HCWs during the early phase of the COVID-19 pandemic (before the Omicron variant) showed that engagement in the care of patients with COVID-19 and inappropriate use of personal protective equipment were major occupational risk factors, whereas close contact with patients with COVID-19 in daily life was among the important community risk factors [6,[8], [9], [10]]. However, the relative importance of each risk factor might have changed over time, especially after the emergence of the Omicron variant with giant mutations in the post-vaccination era. Epidemiological evidence is lacking among HCWs, and risk factors vary over time during the circulation of different dominant variants [11]. Addressing this issue would form the basis for an effective strategy to protect HCWs against circulating variants.

During the COVID-19 pandemic, using data from repeated serological surveys among staff of a national medical and research institution in Tokyo, we built two cohorts with exposure to Delta- and Omicron-dominant waves. The objective of the present study was to identify the risk factors for SARS-CoV-2 infection among HCWs in each period and to compare the relative importance of the risk factors in terms of their prevalence and impact.

Methods

Study setting

The National Centre for Global Health and Medicine (NCGM) has played a leading role in the prevention and control of COVID-19 in Japan. Based on the specific mission of the NCGM on the COVID-19 control campaign, a project with repeated surveys, including the laboratory antibody test, was conducted to survey the antibodies among the NCGM staff [12,13]. The progress of this project is shown in Figure 1 , and the present study was conducted from July 2020 to March 2022 with five rounds of surveys. In each survey, we invited participants to donate venous blood samples and complete an online questionnaire. Venous blood samples were used for immunological testing, and serum separation was performed at the laboratory in the NCGM on the same day as sample collection. This study was approved by the NCGM ethics committee. Written informed consent was obtained from all participants.

Figure 1.

Timeline of antibody surveys, vaccine dates among National Center for Global Health and Medicine staff, and changes in the number of newly confirmed COVID-19 cases in Japan.

NCGM also conducted a vaccination campaign for the staff since March 2021, which was before the third-round survey in June 2021, and most vaccinated NCGM staff received two doses before the third-round survey; whereas the booster shot was provided since December 2021, which was during the period of the fourth-round survey at the end of December 2021.

Cohort definition

In this study, we established two cohorts to investigate potential infection risk factors during the Omicron- and Delta-predominant periods. The selection and exclusion processes for the two cohorts are presented in Figure 2 . A total of 2683 staff participated in the survey in June 2021 (baseline of cohort 1); of these, 895 attended the follow-up survey in December 2021. The Delta-predominant epidemic occurred between the two surveys. Of these, 37 participants who were positive on SARS-CoV-2 anti-nucleocapsid antibody test at baseline or in any previous survey or who reported a COVID-19 history at baseline were excluded, leaving 858 participants in cohort 1 (Supplementary Appendix). A total of 919 staff participated in the survey in December 2021 (baseline of cohort 2); of these, 704 attended the follow-up survey in March 2022. The Omicron-predominant epidemic occurred between the two surveys. Of these, 52 participants who were positive on SARS-CoV-2 anti-nucleocapsid antibody test at baseline or in any previous survey or who reported a COVID-19 history at baseline were excluded, leaving 652 participants in cohort 2.

Figure 2.

Flowchart of the study design and participant selection.

Detection of SARS-CoV-2 infection

The outcome was the incidence of SARS-CoV-2 infection, which was defined as positive on anti-nucleocapsid antibody test at the end of each period or on polymerase chain reaction (PCR) or antigen test during each period. For serological tests, we qualitatively measured IgG (Abbott Architect) and total antibodies (Roche Elecsys Anti-SARS-CoV-2) against the nucleocapsid protein. Seropositivity was defined as the positive detection of IgG or total antibodies according to the manufacturers' instructions (positive IgG threshold: ≥1.4 (S/C); total antibody positive threshold: ≥1.0 (Col)) [14]. The sensitivity was 100% for the Abbott assay and 99.5% for the Roche assay [15,16]. Data on the history of PCR or antigen positivity were retrieved from the COVID-19 staff registry in the Infection Control Office at NCGM. In NCGM, PCR test for the staff has been done only for those who had symptoms suggestive of COVID-19 or who had close contact with patients with COVID-19, while some staff (mainly hospital staff) have participated, on a voluntary basis, in a regular self-monitoring programme using an antibody test kit from January 2022 onward (cohort 2 period).

Covariates

Risk factors evaluated in this investigation included demographic characteristics (sex and age), occupational factors (job category, affiliated department, and degree of possible exposure to SARS-CoV-2), close contact with COVID-19 patients in the past two months (contact in the hospital, contact at home, and contact both in the hospital and at home), adherence to infection prevention practices, high-risk behaviours in the past two months (the frequency of spending ≥30 min in the closed spaces, crowded spaces, and close-contact setting (3Cs) and having dinner in a group of ≥5 people for >1 h), and vaccination status. The main clinical symptoms indicative of COVID-19 within the last two months were assessed (common cold-like symptoms lasting ≥4 days, high fever, severe fatigue, dyspnoea, and loss of sense of taste or smell). Follow-up data were used for all of the above variables, except vaccination status, for which baseline data were used.

Age was classified into three groups: <30, 30–39, and ≥40 years. Job was classified into three groups: doctors, nurses, and others (allied health professionals, administrative, technical, or research staff). The affiliated departments were dichotomized into COVID-19- and non-COVID-19-related department. The degree of possible exposure to SARS-CoV-2 was classified into three categories: low (not engaged in COVID-19-related work), moderate (engaged in COVID-19-related work without heavy exposure to SARS-CoV-2), and high (heavily exposed to SARS-CoV-2). Adherence to infection prevention practices was classified as low, moderate, and high according to the four questions we asked: ‘keeping social distance’, ‘wearing masks’, ‘not touching eyes, noses, and mouths’, and ‘washing or sanitizing hands’. Each question has four response options: ‘not at all’ and ‘rarely’, ‘often’, and ‘always’. Zero was assigned to ‘not at all’ and ‘rarely’, 1 to ‘often’, and 2 to ‘always’. Total score was summarized ranging from 0 to 8. Adherence to infection prevention practices was classified as low (0–4), moderate (5–6), and high (7–8) according to the total score. The frequency of spending ≥30 min in the 3Cs without masks was classified into three groups: never, 1–2 times, and ≥3 times, and the frequency of having dinner in a group of ≥5 people for >1 h was classified into two groups: never and ≥1 time. The vaccination status was classified into two groups in cohort 1: none and first/second dose, and four groups in cohort 2: none, first/second dose, booster before the Omicron pandemic, and booster after the Omicron pandemic.

Statistical analysis

Participant characteristics and infection cases (%) were presented as the number of categorical variables in each cohort. In risk factor analysis, we estimated risk ratio (RR) with a 95% confidence interval (CI) using robust Poisson regression models. Model 1 was adjusted for sex and age. Model 2 was fully adjusted for all the above-mentioned covariates except clinical symptoms. Sensitivity analyses were also conducted in both cohorts by excluding patients who received a booster dose before each pandemic during the follow-up period. All reported P-values were two-tailed, and the level of significance was set at P < 0.05. All statistical analyses were performed with the Stata 16 software (Stata Corp LLP, College Station, TX, USA).

Ethical approval

Written informed consent was obtained from all participants and the study procedure was approved by the NCGM Ethics Committee (approval number: NCGM-G-003598).

Results

Baseline characteristics

In cohort 1, the mean age (standard deviation) was 33 (9) years, 77.0% were female, 67.9% were nurses, 18.1% worked in a COVID-related department, and 29.0% were involved in high degree of possible exposure to SARS-CoV-2 (Table I ). Similar demographic characteristics were observed in cohort 2. The proportion of those who had close contact with COVID-19 patients in the hospital was 3.4% in cohort 1 and 2.1% in cohort 2, whereas those who had contact at home were 0.8% and 1.8% in cohorts 1 and 2, respectively. High-risk behaviours decreased from cohort 1 to cohort 2: the proportion of spending ≥30 min in the 3Cs without masks (≥1 time) decreased from 30.0% to 15.5%, and the proportion of having dinner in a group of ≥5 people for >1 h decreased from 21.8% to 8.0%. Regarding the main clinical symptoms, the proportion of high fever and severe fatigue decreased from cohort 1 to cohort 2 (high fever: 7.0% versus 4.6%; and severe fatigue: 7.8% versus 6.4%), whereas other symptoms were similar in both cohort 1 and cohort 2. The vaccination coverage (defined as at least one dose of the COVID-19 vaccine) increased from 93.2% in cohort 1 to 99.1% in cohort 2.

Table I.

Demographic characteristics in cohorts 1 and 2

Characteristics	Cohort 1 (June 2021 to December 2021)		Cohort 2 (December 2021 to March 2022)
	No.	%	No.	%
Study sample	858	100.0	652	100.0
Sex
Men	197	23.0	132	20.2
Women	661	77.0	520	79.8
Age range (years)
<30	440	51.3	314	48.2
30–39	231	26.9	176	27.0
≥40	187	21.8	162	24.8
Job category
Doctor	114	13.3	67	10.3
Nurse	583	67.9	447	68.6
Othersa	161	18.8	138	21.2
Affiliated department
Non-COVID-19	703	81.9	538	82.5
COVID-19	155	18.1	114	17.5
Degree of possible exposure to SARS-CoV-2
Low	394	45.9	271	41.6
Moderate	215	25.1	174	26.7
High	249	29.0	207	31.7
Close contact with COVID-19 patients
No close contact	822	95.8	625	95.9
Contact in the hospitalb	29	3.4	14	2.1
Contact at homec	7	0.8	12	1.8
Contact in the hospital and at home	0	0.0	1	0.2
Score of adherences to infection-prevention practices in the past one month
Low	143	16.7	105	16.1
Moderate	405	47.2	284	43.6
High	310	36.1	263	40.3
High-risk behaviours in the past two months
Spending ≥30 min in the 3Cs without mask
Never	601	70.0	551	84.5
1–2 times	159	18.5	83	12.7
≥3 times	98	11.4	18	2.8
Having dinner in a group of ≥5 people for >1 h
Never	671	78.2	600	92.0
≥1 time	187	21.8	52	8.0
Major clinical symptoms indicative of COVID-19
Common cold-like symptom lasting ≥4 days
No	768	89.5	588	90.2
Yes	90	10.5	64	9.8
High fever
No	798	93.0	622	95.4
Yes	60	7.0	30	4.6
Severe fatigue
No	791	92.2	610	93.6
Yes	67	7.8	42	6.4
Dyspnoea
No	840	97.9	635	97.4
Yes	18	2.1	17	2.6
Loss of sense of taste or smell
No	845	98.5	645	98.9
Yes	13	1.5	7	1.1
Vaccination status
None	58	6.8	6	0.9
One or two doses	800	93.2	21	3.2
Booster before Omicron pandemic	NA	NA	503	77.1
Booster after the Omicron pandemic	NA	NA	122	18.7

3Cs, closed spaces, crowded places, and close-contact settings; NA, not applicable.

^aOthers include allied healthcare professionals, administrative staff, staff working in the laboratory and research institution, etc.

^bClose contact with COVID-19 patients or coworkers.

^cClose contact with COVID-19 family members or cohabitants.

SARS-CoV-2 infection

During six months of follow-up in cohort 1 and three months in cohort 2, 2.2% and 7.4% of the staff were infected, respectively (Table II ). No repeated infections were reported in both cohorts. Compared to cohort 1, the infection rate in cohort 2 increased, especially among women, nurses, workers in non-COVID-19-related departments, and those with low and moderate degrees of exposure to SARS-CoV-2. Regarding close contact, the infection rate among those who had close contact with COVID-19 patients in the hospital increased from 3.4% in cohort 1 to 21.4% in cohort 2. In contrast, the infection rate among those who had close contact with COVID-19 patients at home was similar in cohort 1 (42.8%) and cohort 2 (41.7%). All infected staff who had close contact in the hospital were nurses in the non-COVID-related department in both cohort 1 and cohort 2. Additionally, all these infections were related to close contact with patients with COVID-19. Regarding high-risk behaviours, increased infection risks were observed among individuals who spent ≥30 min in the 3Cs without masks (1–2 times: from 1.9% in cohort 1 to 9.6% in cohort 2; ≥3 times: from 2.4% in cohort 1 to 38.9% in cohort 2), and those who had dinner in a group of ≥5 people for >1 h (from 2.7% in cohort 1 to 11.5% in cohort 2).

Table II.

Robust Poisson regression models to estimate the association between risk factors and the SARS-CoV-2 infections

Characteristics	Cohort 1 (June 2021 to December 2021)			Cohort 2 (December 2021 to March 2022)
	Infection No. (%)	RR (95% CI)		Infection No. (%)	RR (95% CI)
		Model 1a	Model 2b		Model 1a	Model 2b
Sex
Men	9 (4.6)	Ref.	Ref.	7 (5.3)	Ref.	Ref.
Women	10 (1.5)	0.30 (0.12–0.76)	0.39 (0.14–1.07)	41 (7.9)	1.50 (0.67–3.36)	0.60 (0.19–1.90)
Age range (years)
<30	11 (2.5)	Ref.	Ref.	22 (7.0)	Ref.	Ref.
30–39	5 (2.2)	0.74 (0.26–2.11)	0.66 (0.21–2.07)	16 (9.1)	1.35 (0.72–2.51)	1.17 (0.56–2.45)
≥40	3 (1.6)	0.52 (0.14–1.94)	0.23 (0.05–1.27)	10 (6.2)	0.94 (0.44–1.99)	0.96 (0.45–2.02)
Job category
Doctor	4 (3.5)	0.79 (0.21–2.21)	0.83 (0.24–2.84)	1 (1.5)	0.55 (0.06–5.25)	0.64 (0.08–5.22)
Nurse	9 (1.5)	0.65 (0.24–1.80)	0.29 (0.07–1.10)	43 (9.6)	4.87 (1.48–16.04)	3.81 (1.07–13.64)
Othersc	6 (3.7)	Ref.	Ref.	4 (2.9)	Ref.	Ref.
Affiliated department
Non-COVID-19	14 (2.0)	Ref.	Ref.	40 (7.4)	Ref.	Ref.
COVID-19	5 (3.2)	1.69 (0.64–4.46)	1.96 (0.58–6.60)	8 (7.0)	0.91 (0.44–1.88)	0.90 (0.41–1.96)
Degree of possible exposure to SARS-CoV-2
Low	8 (2.0)	Ref.	Ref.	25 (9.2)	Ref.	Ref.
Moderate	5 (2.3)	1.04 (0.32–3.41)	1.04 (0.31–3.55)	14 (8.1)	0.90 (0.48–1.70)	0.97 (0.49–1.91)
High	6 (2.4)	0.89 (0.31–2.58)	0.57 (0.23–1.43)	9 (4.4)	0.49 (0.23–1.03)	0.61 (0.29–1.28)
Close contact with COVID-19 patients
No close contact	15 (1.8)	Ref.	Ref.	39 (6.2)	Ref.	Ref.
Contact in the hospitald	1 (3.4)	2.45 (0.31–19.14)	4.35 (0.44–42.68)	3 (21.4)	3.31 (1.17–9.37)	3.35 (1.09–10.31)
Contact at homee	3 (42.8)	51.70 (16.39–77.49)	24.65 (7.84–163.09)	5 (41.7)	7.27 (3.34–15.83)	7.53 (2.90–19.56)
Contact in the hospital and at home	0 (0.0)	NA	NA	1 (100.0)	24.16 (9.50–61.45)	7.79 (1.92–31.68)
Score of adherences to infection prevention practices in the past one month
Low	3 (2.1)	Ref.	Ref.	10 (9.5)	Ref.	Ref.
Moderate	8 (2.0)	1.03 (0.28–3.88)	0.90 (0.23–3.53)	22 (7.7)	0.78 (0.38–1.60)	0.97 (0.46–2.06)
High	8 (2.6)	1.35 (0.36–5.15)	1.12 (0.20–6.22)	16 (6.1)	0.62 (0.28–1.34)	0.78 (0.33–1.88)
High-risk behaviours in the past two months
Spending ≥30 min in the 3Cs without mask
Never	14 (2.3)	Ref.	Ref.	33 (6.0)	Ref.	Ref.
1–2 times	3 (1.9)	0.68 (0.20–2.36)	0.47 (0.13–1.68)	8 (9.6)	1.65 (0.80–3.42)	1.96 (0.96–3.99)
≥3 times	2 (2.0)	0.87 (0.21–3.66)	0.85 (0.20–3.65)	7 (38.9)	6.19 (3.13–12.24)	6.62 (3.01–14.58)
Having dinner in a group of ≥5 people for >1 h
Never	14 (2.1)	Ref.	Ref.	42 (7.0)	Ref.	Ref.
≥1 time	5 (2.7)	1.05 (0.34–3.22)	1.12 (0.31–4.01)	6 (11.5)	1.70 (0.75–3.82)	0.88 (0.34–2.33)
Major clinical symptoms indicative of COVID-19
Common cold-like symptom lasting ≥4 days
No	11 (1.4)	Ref.	Ref.	18 (3.1)	Ref.	Ref.
Yes	8 (8.9)	6.36 (2.52–16.09)	5.84 (2.49–13.73)	30 (46.9)	15.12 (8.87–25.80)	16.08 (8.90–29.06)
High fever
No	14 (1.8)	Ref.	Ref.	36 (5.8)	Ref.	Ref.
Yes	5 (8.3)	4.55 (1.67–12.45)	5.34 (1.90–15.03)	12 (40.0)	6.97 (4.06–11.96)	5.38 (2.81–10.28)
Severe fatigue
No	13 (1.6)	Ref.	Ref.	30 (4.9)	Ref.	Ref.
Yes	6 (9.0)	5.40 (2.10–13.86)	5.27 (2.04–13.60)	18 (42.9)	8.80 (5.39–14.38)	8.83 (4.99–15.64)
Dyspnoea
No	14 (1.7)	Ref.	Ref.	40 (6.3)	Ref.	Ref.
Yes	5 (27.8)	18.54 (7.58–45.36)	19.69 (5.76–67.37)	8 (47.1)	7.92 (4.23–14.83)	7.45 (3.62–15.36)
Loss of sense of taste or smell
No	13 (1.5)	Ref.	Ref.	43 (6.7)	Ref.	Ref.
Yes	6 (46.2)	31.22 (14.73–66.15)	39.72 (14.09–111.99)	5 (71.4)	11.55 (6.66–20.03)	7.09 (3.49–14.41)
Vaccination status
None	1 (1.7)	0.87 (0.11–6.68)	1.41 (0.15–13.16)	1 (16.7)	0.78 (0.11–5.53)	0.85 (0.18–4.06)
One or two doses	18 (2.3)	Ref.	Ref.	5 (23.8)	Ref.	Ref.
Booster before Omicron pandemic	NA	NA	NA	34 (6.8)	0.30 (0.13–0.70)	0.57 (0.20–1.66)
Booster after the Omicron pandemic	NA	NA	NA	8 (6.6)	0.29 (0.11–0.79)	0.65 (0.20–2.12)

RR, risk ratio; CI, confidence interval; NA, not applicable; 3Cs, closed spaces, crowded places, and close-contact settings.

^aSex and age were adjusted in model 1.

^bSex, age, job category, affiliated department, occupational risk degree of SAR-CoV-2 infection, close contact with COVID-19 cases, high-risk behaviours, and vaccination status were adjusted in model 2.

^cOthers include allied healthcare professionals, administrative staff, staff working in the laboratory and research institution, and so on.

^dClose contact with COVID-19 patients or coworkers.

^eClose contact with COVID-19 family members or cohabitants.

Risk factors of SARS-CoV-2 infection

Table II shows the association between risk factors and risk of SARS-CoV-2 infection. In a fully adjusted model (model 2), compared with participants other than doctors and other job category, nurses were associated with a lower, albeit statistically non-significant, infection risk in cohort 1 (RR: 0.29; 95% CI: 0.07–1.10); but with a higher infection risk (RR: 3.81; 95% CI: 1.07–13.64) in cohort 2. Those who had close contact with COVID-19 cases in the hospital had a non-significantly higher infection risk in cohort 1 (RR: 4.35; 95% CI: 0.44–42.68), and this association became weaker in cohort 2 (RR: 3.35; 95% CI: 1.09–10.31). Close contact with COVID-19 cases at home was associated with a higher infection risk in cohort 1 (RR: 24.65; 95% CI: 7.84–163.09), but this association became weaker in cohort 2 (RR: 7.53; 95% CI: 2.90–19.56). Those who spent ≥30 min in the 3Cs without masks were associated with an increased infection risk in cohort 2 (≥3 times: RR: 6.19; 95% CI: 3.13–12.24) but a decreased infection risk in cohort 1 (≥3 times: RR 0.85; 95% CI: 0.20–3.65) although the decrease was not statistically significant. There was a suggestion of decreasing trend in the risk of infection with the increasing adherence to the infection prevention practice scores in cohort 2 (moderate: RR: 0.97; 95% CI: 0.46–2.06; high: RR: 0.78; 95% CI: 0.33–1.88) but not in cohort 1. Regarding clinical symptoms, compared with the results in cohort 1, associations in cohort 2 were stronger for common cold-like symptoms lasting ≥4 days (RR in cohort 1 versus cohort 2: 5.84 versus 16.08), and severe fatigue (RR in cohort 1 versus cohort 2: 5.27 versus 8.83); but weaker for dyspnoea (RR in cohort 1 versus cohort 2: 19.69 versus 7.45) and loss of sense of taste or smell (RR in cohort 1 versus cohort 2: 39.72 versus 7.09). In cohort 2, participants who received a booster shot were associated with a lower, albeit statistically non-significant, infection risk compared with those who received the one/two doses (booster shot before the Omicron pandemic: RR: 0.57; 95% CI: 0.20–1.66; booster shot after the Omicron pandemic: RR: 0.65; 95% CI: 0.20–2.12).

Similar results were observed in cohort 1 after excluding 296 participants who received a booster dose during the follow-up period and in cohort 2 after excluding 28 participants who received a booster dose during the follow-up period Table III .

Table III.

Sensitivity analysis of the association between risk factors and the SARS-CoV-2 infections

Characteristics	Cohort 1 (June 2021 to December 2021)				Cohort 2 (December 2021 to March 2022)
	Total no.	Infection No. (%)	RR (95% CI)		Total no.	Infection No. (%)	RR (95% CI)
			Model 1a	Model 2b			Model 1a	Model 2b
Study sample	562	12 (2.2)			530	40 (7.6)
Sex
Men	143	5 (3.5)	Ref.	Ref.	113	4 (3.5)	Ref.	Ref.
Women	419	7 (1.7)	0.47 (0.14–1.58)	0.38 (0.10–1.40)	417	36 (8.6)	2.51 (0.91–6.88)	1.03 (0.25–4.29)
Age range (years)
<30	295	7 (2.4)	Ref.	Ref.	225	16 (17.1)	Ref.	Ref.
30–39	151	2 (1.3)	0.52 (0.11–2.50)	0.34 (0.07–1.76)	150	14 (9.3)	1.43 (0.73–2.81)	1.14 (0.53–2.45)
≥40	116	3 (2.6)	0.93 (0.22–3.90)	0.36 (0.08–1.68)	155	10 (6.5)	1.04 (0.48–2.24)	0.97 (0.44–2.16)
Job category
Doctor	81	2 (2.5)	0.66 (0.11–3.96)	0.58 (0.12–2.72)	50	1 (2.0)	2.54 (0.15–41.49)	2.85 (0.23–35.30)
Nurse	344	6 (1.7)	0.80 (0.20–3.23)	0.22 (0.03–1.57)	364	38 (10.4)	14.92 (1.60–138.47)	10.28 (1.12–94.54)
Othersc	137	4 (2.9)	Ref.	Ref.	116	1 (0.9)	Ref.	Ref.
Affiliated department
Non-COVID-19	481	9 (1.9)	Ref.	Ref.	437	33 (7.6)	Ref.	Ref.
COVID-19	81	3 (3.7)	2.38 (0.70–8.12)	6.68 (1.11–40.18)	93	7 (7.5)	0.98 (0.45–2.12)	0.93 (0.41–2.14)
Degree of possible exposure to SARS-CoV-2
Low	254	6 (2.4)	Ref.	Ref.	221	22 (10.0)	Ref.	Ref.
Moderate	142	3 (2.1)	0.78 (0.17–3.60)	0.84 (0.15–4.58)	147	11 (7.5)	0.80 (0.40–1.61)	0.88 (0.43–1.82)
High	166	3 (1.8)	0.63 (0.15–2.65)	0.44 (0.16–1.18)	162	7 (4.3)	0.47 (0.20–1.09)	0.54 (0.25–1.16)
Close contact with COVID-19 patients
No close contact	542	10 (1.8)	Ref.	Ref.	504	31 (6.2)	Ref.	Ref.
Contact in the hospitald	16	0 (0.0)	NA	NA	12	3 (25.0)	3.75 (1.35–10.43)	4.35 (1.35–13.98)
Contact at homee	4	2 (50.0)	48.50 (11.95–196.90)	172.14 (25.28–1171.96)	13	5 (38.5)	7.60 (3.56–16.25)	2.92 (3.09–21.11)
Contact in the hospital and at home	0	0 (0.0)	NA	NA	1	1 (100.00)	43.17 (11.67–159.69)	2.92 (2.59–87.18)
Score of adherences to infection-prevention practices within recent one month
Low	101	1 (1.0)	Ref.	Ref.	84	8 (9.5)	Ref.	Ref.
Moderate	260	6 (2.3)	2.43 (0.27–21.43)	1.81 (0.14–24.06)	231	17 (7.4)	0.71 (0.31–1.58)	0.87 (0.34–2.24)
High	201	5 (2.5)	2.57 (0.38–23.18)	2.92 (0.18–46.37)	215	15 (7.0)	0.69 (0.30–1.64)	0.86 (0.40–1.86)
High-risk behaviors within recent two months
Spending ≥30 min in the 3Cs without mask
Never	401	10 (2.5)	Ref.	Ref.	444	27 (6.1)	Ref.	Ref.
1–2 times	106	1 (0.9)	0.33 (0.04–2.65)	0.39 (0.04–3.62)	71	6 (8.5)	1.41 (0.62–3.24)	1.79 (0.82–3.91)
≥3 times	55	1 (1.8)	0.71 (0.10–5.37)	1.14 (0.10–12.55)	15	7 (46.7)	7.26 (3.71–14.21)	9.02 (4.30–18.93)
Having dinner in a group of ≥5 people for >1 h
Never	454	9 (2.0)	Ref.	Ref.	488	35 (7.2)	Ref.	Ref.
≥1 time	108	3 (2.8)	1.26 (0.29–5.56)	1.02 (0.18–18.20)	42	5 (11.9)	1.71 (0.71–4.13)	0.93 (0.32–2.70)
Major clinical symptoms indicative of COVID-19
Common cold-like symptom lasting ≥4 days
No	501	5 (1.0)	Ref.	Ref.	476	15 (3.2)	Ref.	Ref.
Yes	61	7 (11.5)	13.22 (4.12–42.37)	11.13 (3.54–35.00)	54	25 (46.3)	13.84 (7.77–24.64)	14.03 (7.20–27.33)
High fever
No	522	8 (1.5)	Ref.	Ref.	507	31 (6.1)	Ref.	Ref.
Yes	40	4 (10.0)	6.77 (2.07–22.11)	7.78 (1.97–30.79)	23	9 (39.1)	6.09 (3.33–11.13)	7.81 (3.58–17.06)
Severe fatigue
No	514	7 (1.3)	Ref.	Ref.	495	24 (4.8)	Ref.	Ref.
Yes	48	5 (45.5)	8.53 (2.85–25.54)	8.42 (2.08–34.11)	35	16 (45.7)	9.27 (5.49–15.67)	9.51 (4.74–19.06)
Dyspnoea
No	551	7 (1.3)	Ref.	Ref.	513	32 (6.2)	Ref.	Ref.
Yes	11	5 (50.0)	37.91 (14.73–97.58)	61.66 (9.74–390.19)	17	8 (47.1)	8.03 (4.14–15.59)	61.66 (9.74–390.19)
Loss of sense of taste or smell
No	552	7 (1.3)	Ref.	Ref.	523	35 (6.7)	Ref.	Ref.
Yes	10	5 (50.0)	43.83 (15.86–121.16)	68.86 (6.73–704.87)	7	5 (71.4)	10.43 (5.90–18.43)	8.61 (2.47–30.02)
Vaccination status
None	21	1 (4.8)	0.90 (0.12–6.69)	1.74 (0.17–18.20)	6	1 (16.7)	0.75 (0.11–5.22)	0.84 (0.15–4.59)
One or two doses	541	11 (2.0)	Ref.	Ref.	21	5 (23.8)	Ref.	Ref.
Booster before Omicron pandemic	NA	NA	NA	NA	503	34 (6.8)	0.31 (0.14–0.72)	0.72 (0.22–2.35)

RR, risk ratio; CI, confidence interval; NA, not applicable; 3Cs, closed spaces, crowded places, and close-contact settings.

^aSex and age were adjusted in model 1.

^bSex, age, job category, affiliated department, occupational risk degree of SAR-CoV-2 infection, close contact with COVID-19 cases, high-risk behaviours, and vaccination status were adjusted in model 2.

^cOthers include allied healthcare professionals, administrative staff, staff working in the laboratory and research institution, etc.

^dClose contact with COVID-19 patients or coworkers.

^eClose contact with COVID-19 family members or cohabitants.

Discussion

To our knowledge, this is the first study to directly compare risk factors of SARS-CoV-2 infection among HCWs in the Delta and Omicron periods in the same target population. Working in a COVID-19-related department and having a higher occupational risk of infection were not associated with an increased risk of infection during the spread of either variant. More than 40% of staff who lived with a household member with COVID-19 were infected during both periods, whereas the infection rate among staff who had close contact in the hospital was low during the Delta period (3.4%), but increased during the Omicron period (21.4%). Risky behaviours (positive) and adherence to infection prevention practices (inverse) were associated with infection risk only during the Omicron wave.

The present finding of no increased risk of infection among the staff in COVID-19-related departments, or of being at higher risk of occupational exposure to SARS-CoV-2 during the Delta- and Omicron-predominant waves, contradicts some previous studies that report a higher infection risk among staff working in COVID-19-related departments [[17], [18], [19]]. However, the findings of a few other studies are consistent with our findings, which include our previous observations among NCGM staff prior to the emergence of these variants, demonstrating that staff at high occupational risk would be safe as long as appropriate prevention measures were adopted [12,13,20]. In the NCGM, multiple infection control measures have been adopted to protect frontline HCWs since the early phase of the pandemic, including the provision of personal protective equipment, training programmes for taking care of COVID-19 patients, and management and support policies for COVID-19 patients [21]. The present finding lends further support to the effectiveness of these measures in the protection of frontline HCWs even after the emergence of the variants with high immune evasion properties.

During the observation period, among a few staff members who had close contact with patients with COVID-19 in the hospital during both periods of Delta (3.4%, N = 29) and Omicron (2.1%, N = 14), the infection rate was much higher during Omicron (21.4%) than during the Delta variant (3.4%). This finding is consistent with the high transmission and evasion properties of the Omicron variant [[22], [23], [24]]. Regarding occupational background for the infected staff who had close contact in the hospital (cohort 1: N = 1; cohort 2: N = 3), they were all nurses working for non-COVID-related departments, suggesting that virus transmission in the hospital might have occurred through colleague or inpatient in general wards, but not in COVID-19 specific wards. In the NCGM, all inpatients were tested for SARS-CoV-2 infection at admission. Owing to the high false-negative rate of initial PCR assays for COVID-19 (12%), infection control measures must be strengthened in hospitals, including general wards, during the virus pandemic with high transmission potential to prevent nosocomial infections [25].

During the follow-up period, close contact with a family member with COVID-19 was rare (Delta 0.8%, N = 7 versus Omicron 1.8%, N = 12); however, infection rates were very high (Delta 42.8% versus Omicron 41.7%). Our results were in line with existing data showing high household transmission rates of COVID-19 in the USA (29%), Canada (49%), and the UK (43%), which have been attributed to less mask use, low ventilation, and difficulty of isolation at home [[26], [27], [28], [29], [30]]. In Japan, infections among children have markedly increased after the emergence of variants, especially Omicron, putting HCWs living with children at higher risk of infection than before [[31], [32], [33], [34]]. The expansion of vaccine coverage among the younger generation is a priority issue to prevent HCWs living with school-age children against household infection.

Spending long hours in a crowded location has been indicated as a high-risk situation for clustered infections [35]. In the present study, such high-risk behaviour was associated with an increased infection rate during the Omicron-predominant wave, but not during the Delta wave. Similarly, there was a suggestion to decrease the risk of infection by increasing adherence to infection prevention practices during Omicron, but not Delta, predominance. These results emphasize the importance of avoiding risky behaviours and adhering to standard infection prevention practices during pandemics of high immune evasive variants, even in the post-vaccination era.

This study has several strengths. We identified the infection cases using two sources of diagnostic information: an in-house registry of COVID-19 patients and a serological survey. Serological data are useful for capturing all infections, including undiagnosed ones, and may be particularly important during the epidemic of the Omicron variant infection, which is characterized by asymptomatic or mild symptoms and is more likely to be left undiagnosed. Additionally, we used data from repeated serological surveys, which enabled us to make a direct comparison of risk factors for infection between different periods of variant dominance. Our study has some limitations. First, we were aware of the selective participation in cohort 2. According to the in-house registry, clustered infections among nurses occurred in non-COVID departments during the Omicron-predominant epidemic, suggesting the presence of staff-to-staff transmission; however, these nurses did not participate in the end survey of cohort 2. Due to this selective participation, the present study was not suitable for assessing the risk associated with close contact with staff members with COVID-19. Second, the exposure status could have changed during follow-up. For instance, some participants received a booster dose during follow-up, leading to misclassification of the vaccine status. However, the results remained unchanged after excluding those who received a booster dose during follow-up in both cohorts. Third, the number of infections was relatively small in cohort 2 (N = 48), making it difficult to detect a modest and statistically significant risk. Finally, this study was conducted at a single national medical institution designated for COVID-19; therefore, the findings may not be generalizable to other settings.

In conclusion, there was a 3.4-fold increase in the risk of SARS-CoV-2 infection from the Delta- to Omicron-predominant period. Occupational factors were not associated with the risk of SARS-CoV-2 infection in both periods, whereas high-risk behaviour and poor adherence to infection prevention practices were associated with an increased risk of infection during the Omicron period. Greater emphasis should be placed on extra-hospital infection when planning infection control measures for HCWs during the epidemic of highly immune-evasive SARS-CoV-2 variants.

Conflict of interest statement

None declared.

Funding sources

This work was supported by the NCGM COVID-19 Gift Fund (grant number 19K059) and the Japan Health Research Promotion Bureau Research Fund (grant number 2020-B-09). Abbott Japan and Roche Diagnostics provided reagents for the anti-nucleocapsid antibody assays.

Appendix A. Supplementary data

The following is the Supplementary data to this article.