The start of the vaccination campaign against COVID-19 raised high hopes of being able to control the pandemic, and the incidence in Germany initially fell. With the advent of the delta variant, however, a new wave of infection developed. The proportion of vaccinated persons among infected persons increased and during the rise of the subsequent omicron variant reached 80% (1). The vaccination breakthroughs led to doubts in the general population regarding vaccine efficacy, and the milder courses associated with the omicron variant simultaneously raised questions as to whether it was actually necessary. The present study aimed to compare the inpatient course of non-vaccinated, vaccinated, and boosted patients infected with SARS-CoV-2 under both variants.
Acknowledgments
Translated from the original German by Birte Twisselmann, PhD.
Footnotes
Conflict of interest statement Prof Kuhlen is a senior employee with Helios, with share options in the Fresenius group. He is also the chair of the scientific advisory board of the IQM.
The remaining authors declare that no conflict of interests exists.
Methods
This retrospective observational cohort study included patients with SARS-CoV-2 infection that was confirmed by polymerase chain reaction (PCR), who were admitted as inpatients between 1 September 2021 and 31 March 2022 and were documented in Helios’s own surveillance program iNOK.
Since the start of the pandemic, patients with COVID-19 have been documented in this company-wide intranet-based database, and their immunization status has been recorded since 1 September 2022. The data were linked to claims data by using a double pseudonymized hospital case number, and information about the risk factors sex, age, and comorbidities as well as the outcome parameters—stay in intensive care, ventilation, and death—was derived from these. A surrogate parameter for patients who actually were sick from COVID-19 as opposed to just infected, we analyzed the rate of patients with severe acute respiratory infection (SARI). Exclusion criteria were age <18 years and incomplete datasets. For the immunization status we applied the currently valid criteria from the Robert Koch Institute (RKI) (1). Data on comorbidities were combined in the Elixhauser comorbidity index (2). The parameter mechanical ventilation included invasive and non-invasive ventilation. Mortality was defined as death during the same inpatient stay. Patients transferred into hospitals outside the Helios group were excluded from the mortality calculation. According to the weekly bulletins of the RKI concerning the development of variants in Germany, patients admitted to hospital up to 31 December 2021 were allocated to the delta cohort and from 1 January 2022 to the omicron cohort.
Results
We included 10 902 patients aged 18–104 years from 69 Helios hospitals. 8156 patients (75%) were from the time period when delta was the dominant variant, and 2746 (25%) from when omicron was dominant. Non-immunized patients were younger than patients who had had the prime series or booster immunizations and had fewer comorbidities (table 1). In non-immunized patients, SARI was coded for more cases, they were more commonly admitted to intensive care and received mechanical ventilation more often. Mortality did not differ significantly during the delta dominant period whereas during omicron it was higher in non-immunized patients. The rate of immunized patients among those infected increased notably during the transition from delta dominance to omicron dominance. Immunized patients were younger during the omicron dominant period and had fewer comorbidities. In people who had had a booster vaccine, SARI was coded the least frequently, in the delta cohort as well as in the omicron cohort. Intensive care stay, ventilation, and death were rarer during the omicron dominant period. In the multivariable analyses for intensive care stay, ventilation, and hospital mortality, comorbidities and male sex were independent risk factors (table 2). Although age was the most important risk factor for dying, the probability for a stay in intensive care and ventilation was lower with rising age. Lacking immunization increased the risk for a stay in intensive care, ventilation, and death. Booster vaccination also led to a reduced risk of ventilation or death compared with the vaccination. Infection with the delta variant was associated with an increased risk of a negative disease course compared with infection with the omicron variant.
Table 1. Patient characteristics and inpatient course by immunization status.
| Not immunized | Vaccinated (primary series) | Boosted | |
| Number (N = 10 902) – rate n (%) | |||
| Delta | 4181 (51.3 %) | 3640 (44.6 %) | 335 (4.1 %) |
| Omicron | 1029 (37.5 %) | 934 (34.0 %) | 783 (28.5 %) |
| Age – years (mean ± standard deviation) | |||
| Delta | 60.4 ± 19.0 | 72.4 ± 15.0 | 76.7 ± 14.6 |
| Omicron | 57.9 ± 21.0 | 61.0 ± 20.7 | 71.4 ± 17.2 |
| Sex – number of men (rate) | |||
| Delta | 2147 (51.4 %) | 2018 (55.4 %) | 169 (50.4 %) |
| Omicron | 468 (45.5 %) | 474 (50.7 %) | 415 (53.0 %) |
| Elixhauser comorbidity index (mean ± SD) | |||
| Delta | 8.6 ± 10.4 | 11.9 ± 11.9 | 12.4 ± 11.6 |
| Omicron | 7.9 ± 10.3 | 8.8 ± 11.0 | 10.2 ± 11.1 |
| SARI – number (rate) | |||
| Delta | 3153 (75.4 %) | 2241 (61.6 %) | 182 (54.3 %) |
| Omicron | 604 (58.7 %) | 363 (38.9 %) | 288 (36.8 %) |
| Admission to ICU – number (rate) | |||
| Delta | 1198 (28.7 %) | 925 (25.4 %) | 73 (21.8 %) |
| Omicron | 225 (21.9 %) | 150 (16.1 %) | 179 (22.9 %) |
| Mechanical ventilation – number (rate) | |||
| Delta | 1026 (24.5 %) | 580 (15.9 %) | 40 (11.9 %) |
| Omicron | 168 (16.3 %) | 59 (6.3 %) | 52 (6.6 %) |
| In-hospital mortality – number (rate) | |||
| Delta | 700 (18.4 %) | 659 (19.3 %) | 63 (20.2 %) |
| Omicron | 125 (13.0 %) | 66 (7.4 %) | 61 (8.4 %) |
ICU, intensive care unit; OR, odds ratio; SARI, severe acute respiratory infection; SD, standard deviation
Table 2. Multivariable analyses for admission to intensive care. ventilation. and in-hospital mortality.
| OR [95% CI]. P value | |
| Admission to intensive care | |
| Male sex | 1.67 [1.52; 1.83]. < 0.001 |
| Age | 0.91 [0.86; 0.96]. < 0.001 |
| Elixhauser comorbidity index | 1.77 [1.69; 1.86]. < 0.001 |
| Not immunized vs basic immunization | 1.49 [1.34; 1.65]. < 0.001 |
| Basic immunization vs booster vaccination | 0.89 [0.74; 1.06]. = 0.194 |
| Delta vs omicron | 1.48 [1.31; 1.65]. < 0.001 |
| Mechanical ventilation | |
| Male sex | 1.86 [1.67; 2.07]. < 0.001 |
| Age | 0.91 [0.86; 0.97]. = 0.004 |
| Elixhauser comorbidity index | 1.75 [1.66; 1.85]. < 0.001 |
| Not immunized vs basic immunization | 2.30 [2.04; 2.59]. < 0.001 |
| Basic immunization vs booster vaccination | 1.32 [1.03; 1.69]. = 0.027 |
| Delta vs omicron | 1.95 [1.68; 2.27]. < 0.001 |
| In-hospital mortality | |
| Male sex | 1.74 [1.54; 1.96]. < 0.001 |
| Age | 2.78 [2.54; 3.04]. < 0.001 |
| Elixhauser comorbidity index | 1.74 [1.64; 1.85]. < 0.001 |
| Not immunized vs basic immunization | 1.97 [1.74; 2.24]. < 0.001 |
| Basic immunization vs booster vaccination | 1.30 [1.04; 1.64] = 0.024 |
| Delta vs omicron | 1.82 [1.55; 2.15]. < 0.001 |
OR, odds ratio; 95% CI, 95% confidence interval
Discussion
Protection against a severe course of COVID-19 as conferred by vaccination has already been confirmed in real world studies (4– 5). Our study shows that even in hospital inpatients, vaccination has a protective effect as regards mortality, intensive care, and ventilation. Booster vaccinations increases protection compared with prime series immunization only. The protective effect continues to be relevant in spite of the more favorable disease course of infections with the omicron variant. Age was associated with a higher mortality risk but a lower risk for admission to intensive care and ventilation. The cause might be a differentiated indication for maximal therapy in the oldest age groups. Furthermore, in older age groups, more comorbidities are present that may have led to hospital admission. In immunized patients in the omicron cohort, SARI affected fewer than half of the patients. It can be assumed that—especially in this group—many patients were not admitted to hospital or treated in intensive care or died because of COVID-19, but, rather, with it. This means that the protective effect of immunization is probably greater than ascertained in this study. Our study shows the dependancy of the disease course in inpatients with COVID-19 immunization and the dominant variant. It applies to inpatients only. For this reason we cannot draw any conclusions about the effectiveness of immunization in the general population. We included only completed cases. Patients still receiving treatment at the end of the study were not included, which may have introduced bias. Optimization of therapeutic guidelines may have contributed to the improved outcome during the omicron dominant period. Patients were assigned to the delta or omicron cohort on the basis of timings, which is imprecise; variants were not determined. Factors such as different treatments and care levels of the hospitals were not recorded and may have affected the results. The Elixhauser comorbidity index does not take into account that comorbidities that increase the risk for a severe course may have different effects for delta and omicron.
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