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Outcome of hospitalized influenza and COVID-19 inpatients in different phases of the SARS-CoV-2 pandemic. A single-centre retrospective case-control study.
The virulence of SARS-CoV-2 changed during the pandemic. To provide a rationale for treatment priorities of respiratory infections and the adaption of in-house infection control strategies, we evaluated the outcome parameters treatment on an intensive care unit (ICU), requirement of mechanical ventilation (MV), requirement of extracorporeal membrane oxygenation (ECMO) and death for inpatients either infected with the influenza virus or SARS-CoV-2 during the wild type, alpha, delta, omicron BA.1/2 and omicron BA.5 waves of the pandemic.
Design
Single-centre retrospective case-control study.
Setting
Tertiary hospital in Germany.
Participants
1316 SARS-CoV-2-infected adult inpatients and 218 adult inpatients with seasonal influenza infection.
Methods
Demographic data, outcome parameters and underlying comorbidities of patients were obtained from the hospital information system. Multivariate regression analysis was performed for the assessment of significant associations between risk factors and outcome variables.
Results
Compared to influenza-infected inpatients, SARS-CoV-2-infected inpatients showed significantly evaluated rates for in-hospital mortality, admission to ICU and MV in the wild type, alpha and delta wave and for ECMO in the wild type wave. In the Omicron BA.1/BA.2 and Omicron BA.5 waves, SARS-CoV-2-infected inpatients did not show significantly increased risk of in-hospital mortality, admission to ICU, MV or ECMO compared to influenza- infected inpatients. Length of hospital stay of SARS-CoV-2-infected inpatients decreased from 10.8 to 6.2 days which is below that of influenza-infected inpatients (8.3 days).
Conclusions
Treatment capacities should be shared equally between SARS-CoV-2 and influenza virus infections and at least regarding the severity of infections similar levels of infection control could be applied.
Influenza and COVID-19 are both contagious acute respiratory infections. Influenza is caused by the influenza A and B viruses. Annual seasonal influenza epidemics result in three to five million cases of severe illness and up to half a million deaths per year. Symptoms of an influenza infection may include abrupt onset of respiratory symptoms, myalgia, or fever. In most cases, patients recover within one week, but some can experience severe complications, as bacterial pneumonia and acute respiratory distress syndrome (ARDS). For prophylaxis, different influenza vaccines are available and for the treatment of infections, antiviral drugs targeting the virus surface glycoprotein neuraminidase can be used.(
Common symptoms of COVID-19, which is caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), include fever, cough, chest discomfort, olfactory and gustatory disturbances and in severe cases, dyspnoea and bilateral lung infiltration. Vaccination against SARS-CoV-2 can provide partial protection against infection, whereby the protective effect depends on the vaccine, the number of vaccination doses, the time of the last vaccination dose and the virus variant of SARS-CoV-2. For treatment of COVID-19, different intravenous and oral antiviral drugs are available. Furthermore, convalescent plasma may be an option for treatment, especially in patients with immunosuppression.(
Maßnahmen zur Bewältigung der COVID-19-Pandemie in Deutschland: nichtpharmakologische und pharmakologische Ansätze [Measures to cope with the COVID-19 pandemic in Germany: nonpharmaceutical and pharmaceutical interventions].
) Retrospectively, the pandemic can be classified in phases dominated by specific SARS-CoV-2 variants. In Germany, the wild type variant of SARS-CoV-2 was dominant until calendar week (CW) 08/2021. It was followed by the alpha variant (from CW 9 to CW 23/2021) and the delta variant (from CW 31 to CW 51/2021) in a third and fourth wave. Subsequently, the infection process in Germany was determined by different Omicron variants (fifth wave - BA.1/BA.2 dominated from CW 52/2021 to CW 21/2022 and sixth wave - BA.5 dominated since CW 22/2022).(
After very low influenza incidences in Germany in 2020 and 2021, in late 2022, a ‘twindemic’ situation was present and large number of inpatients infected with influenza or COVID-19 had to be treated simultaneously in our hospital. Since the simultaneous presence of both viruses can also be expected in the next years, we performed a head-to-head comparison of the outcome parameters of inpatients with COVID-19 and influenza in order to better prioritize treatment capacities and the level of required infection control precautions for both diseases.
Methods
Setting
The University Hospital Magdeburg is a tertiary hospital located in central Germany. It has approximately 4700 staff members and treats about 50,000 inpatients annually. In 2020 and 2021, SARS-CoV-2-positive patients were treated in dedicated COVID-19 isolation wards (both - normal units under the management of the infectious diseases department and intensive care units led by the anaesthesiology department). In 2022, there was an increasing change in strategy towards treating SARS-CoV-2-positive patients in single bedrooms (if possible with anteroom) on general wards according to the underlying admission diagnosis. PCR admission screening of all inpatients for SARS-COV-2 was established in May 2020 and is still in progress.
Data collection
Data processing was based on retrospectively obtained pseudonymized patient data and did not include any experiments involving human participants (including the use of tissue samples). The requirement for informed consent was waived by the Ethics Committee of the University Hospital Magdeburg. Lists of all SARS-COV-2 and influenza virus-positive inpatients were available in the section infection control from routine hospital surveillance. Demographic data (age, gender), outcome parameters (treatment on an intensive care unit (ICU), requirement of mechanical ventilation (MV), requirement of extracorporeal membrane oxygenation (ECMO) and death), underlying comorbidities, main diagnosis and date of admission and discharge were obtained from our Hospital Information System for each case. The assignment of a case to the corresponding SARS-CoV-2 wave was based on the admission date according to Tolksdorf et al.(
Case control study, inclusion and exclusion criteria
Adult inpatients between January 2018 and December 2022 who had a positive SARS-CoV-2 or influenza PCR result before or within five days after admission were included. Patients were excluded if they were pre-treated for more than 24 hours in another acute hospital before admission to our hospital, as these patients are a pre-selected group and might have an increased risk of a severe course of the disease. Characteristics of SARS-CoV-2 and influenza virus-positive patients are shown in Table I.
Table ICharacteristics and outcomes of all inpatients with SARS-CoV-2 or influenza infection (all)/ subgroup of patients with acute respiratory main diagnosis (RMD).
In individual cases, it was difficult to decide whether a patient died or required ICU treatment, MV or ECMO due to the course of the infection or because of an underlying disease. In the latter case, the infection is considered only a secondary diagnosis. For this reason, a multivariate regression analysis was performed for both - inpatients with a positive influenza virus or SARS-CoV-2 test as well as for the subgroup of patients with acute respiratory tract infection as main diagnosis (including icd-10 codes J04, J06, J10, J11, J12, J15, J18, J22, J80, J96, J98). Patients in this subgroup are further referred to as patients with COVID-19 or influenza-related respiratory main diagnosis (RMD).
Statistics
Data analyses were performed using Microsoft Excel 2016. Multivariate regression analysis was used for the assessment of significant associations between risk factors (predominant SARS-CoV-2 variant/ influenza, age, gender, diabetes mellitus, arterial hypertension, cancer, renal failure, haematological malignancies, neurological disorders, chronic respiratory diseases, chronic heart disease) and outcome variable (admission to ICU, MV, ECMO, death). A significance level of p < 0.05 was considered statistically significant. We decided not to employ a Bonferroni correction because of the explorative character of our study and because the outcome variables death, ICU, MV and ECMO are not strictly independent, e.g. inpatients with MV or ECMO are always on ICU.
Results
Characteristics of patients with SARS-CoV-2 and influenza infection are shown in Table I. Seventy-four percent of all influenza virus-positive inpatients had an influenza-related RMD within the observation period. While at the beginning of the pandemic most SARS-CoV-2-positive patients had a COVID-19-related RMD (wild type waves: 73%, alpha wave: 80%; delta wave: 76%), in 2022 SARS-CoV-2-positive patients were more often admitted with other main diagnoses and COVID-19-related RMD decreased to 30% in the omicron BA.1/2 wave and 25% during the omicron BA.5 wave, respectively. During the pandemic, the mean length of hospital stay of patients with a COVID-19-related RMD decreased from 11.2 days in the wild type waves to 7.2 days in the omicron BA.5 wave, which is below the mean length of hospital stay of patients with an influenza-related respiratory main diagnosis (7.7 days). The mean age of inpatients with a COVID-19 related RMD initially decreased from 67.6 years during the wild type waves to 64.7 years during the alpha wave and subsequently increased steadily to 76.0 years in the current omicron BA.5 wave. The mean age of inpatients hospitalized with an influenza-related RMD was 69.4 years over the period from 2018 to 2022.
In-house mortality of patients with COVID-19-related RMD dropped from 22.7% at the beginning of the pandemic to 12.1% in the BA.5 wave which is close to the mortality of patients with an influenza-related RMD (10.5%), especially when considering the higher age of these COVID-19 inpatients in the last omicron wave. ICU admission rate dropped from 33.6% to 3.3% and MV rate subsided from 25.0% to 2.2% in inpatient with COVID-19-related RMD and is now below ICU admission rate (5.8%) and MV rate (2.3%) of inpatients with an influenza-related RMD (Table I).
The results of the multivariate regression analysis of risk factors for the outcomes death, admission to ICU, MV and ECMO are shown in Table II and Figure 1. In summary, during the SARS-COV-2 wild type waves mortality (p < 0.005) as well as the risk of ICU admission (p < 0.005), MV (p < 0.005) and ECMO (p < 0.005) were significantly higher in all SARS-COV-2-positive patients than in all influenza virus-positive patients. In the following alpha and delta waves, significantly higher rates of mortality (alpha: p < 0.005; delta: p < 0.05), admission to ICU (each p < 0.005) and MV (each p < 0.05) were found in SARS-CoV-2-positive patients compared to influenza virus-positive patients, but no significant differences were found for the outcome parameter ECMO. In the omicron BA.1/2 and BA.5 waves no significant difference in mortality, ICU dependency, MV or ECMO could be found between SARS-CoV-2- and influenza virus-positive patients.
Table IIMultivariate regression analysis of risk factors for the outcomes death, admission to ICU, mechanical ventilation (MV), and extracorporeal membrane oxygenation (ECMO) for either all patients positive for SARS-CoV-2 or influenza and the subgroup of patients with acute respiratory main diagnosis (RMD) only.
Factor
Outcome
Acute Respiratory main diagnosis only
All patients positive for SARS-CoV-2 or influenza
Coefficient
Standard error
P-value
Coefficient
Standard error
P-value
SARS-CoV-2 - wild type wave compared to influenza
Death
0.143
0.050
0.004
0.112
0.032
0.001
ICU
0.269
0.050
0.000
0.193
0.032
0.000
MV
0.225
0.040
0.000
0.151
0.024
0.000
ECMO
0.053
0.018
0.004
0.040
0.009
0.000
SARS-CoV-2 - Alpha wave compared to influenza
Death
0.101
0.052
0.053
0.116
0.035
0.001
ICU
0.148
0.052
0.005
0.109
0.035
0.002
MV
0.081
0.042
0.051
0.055
0.026
0.033
ECMO
0.009
0.019
0.629
0.008
0.010
0.418
SARS-CoV-2 - Delta wave compared to influenza
Death
0.092
0.052
0.078
0.085
0.035
0.014
ICU
0.150
0.053
0.004
0.103
0.035
0.003
MV
0.085
0.042
0.042
0.051
0.026
0.046
ECMO
0.020
0.019
0.284
0.015
0.010
0.134
SARS-CoV-2 - Omicron BA.1, BA.2 wave compared to influenza
Death
0.028
0.053
0.599
0.021
0.028
0.449
ICU
0.026
0.053
0.630
0.014
0.028
0.616
MV
0.005
0.042
0.900
0.008
0.021
0.713
ECMO
0.002
0.019
0.909
0.000
0.008
0.972
SARS-CoV-2 - Omicron BA.5 wave compared to influenza
Figure 1Multivariate regression analysis of risk factors for the outcomes death, admission to ICU, mechanical ventilation and extracorporeal membrane oxygenation (ECMO) in all SARS-CoV-2 and influenza virus-positive patients (solid bars) and the subgroup of SARS-CoV-2 and influenza virus-positive patients with acute respiratory main diagnosis (open bars). Error bars indicate standard error from the mean. Asterisks indicate p values of p < 0.05 (*) and p < 0.005 (**) respectively.
Considering only the subgroups of patients with COVID-19/influenza related RMD, in the wild type waves we found significantly elevated rates of mortality, admission to ICU, MV and ECMO (each p < 0.005) in COVID-19 patients compared to influenza patients (Figure 1). In the further course of the pandemic, there were still significant elevated rates of admission to ICU (p < 0.005) in the alpha wave and of admission to ICU (p < 0.005) and MV (each p < 0.05) in the delta wave in COVID-19 patients compared to influenza patients (Figure 1, Table I).
In addition, we evaluated the outcome parameters in different age groups (Figure 2). In the Omicron BA.5 wave, patients with COVID-19 related RMD of all three age groups (18-57 years, 58-77 years, 78-97 years) showed equal or lower rates of ICU admission, MV and ECMO compared to patients with influenza-related RMD. Considering mortality in the BA.5 wave, patients with COVID-19 related RMD showed increased mortality in the age group 58-77 years and decreased mortality in the age group 78-97 years compared to patients with influenza.
Figure 2Relative disease severity of SARS-CoV-2 variants compared to influenza in different age groups. Upper left chart: ICU admission rate in SARS-CoV-2-positive patients with respiratory main diagnosis compared to all influenza virus-positive patients with respiratory main diagnosis (as baseline) in three different age groups (white bar: 18-57 years, grey bar 58-77, black bar 78-97 years). Upper right chart: Need of mechanical ventilation in SARS-CoV-2-positive patients with respiratory main diagnosis compared to all influenza virus-positive patients with respiratory main diagnosis (as baseline) in three different age groups (white bar: 18-57 years, grey bar 58-77, black bar 78-97 years). Lower left chart: Need of extracorporeal membrane oxygenation in SARS-CoV-2-positive patients with respiratory main diagnosis compared to all influenza virus-positive patients with respiratory main diagnosis (as baseline) in three different age groups (white bar: 18-57 years, grey bar 58-77, black bar 78-97 years). Lower right chart: In-house mortality in SARS-CoV-2-positive patients with respiratory main diagnosis compared to all influenza virus-positive patients with respiratory main diagnosis (as baseline) in three different age groups (white bar: 18-57 years, grey bar 58-77, black bar 78-97 years).
During the wild type, the alpha and the delta waves we found significantly higher mortality and ICU admission rates in SARS-CoV-2-positive patients compared to influenza virus-positive patients, while we found no significant differences in these outcome parameters during the omicron BA.1/2 and BA.5 waves.
Significantly increased mortality rates of hospitalized COVID-19 patients compared to hospitalized influenza patients have already been reported within the SARS-CoV-2 wild type waves of the pandemic.(
Comparative evaluation of clinical manifestations and risk of death in patients admitted to hospital with covid-19 and seasonal influenza: cohort study.
Comparison of the characteristics, morbidity, and mortality of COVID-19 and seasonal influenza: a nationwide, population-based retrospective cohort study.
) In these previous studies from the USA, France, Germany and Belgium in-hospital mortality rates for patients with wild type SARS-CoV-2 infection ranged from 14.0% to 20.0% while in-hospital mortality rates for patients with influenza virus infection ranged from 5.0% to 9.8%. In our study the mortality rates for SARS-CoV-2- and influenza virus-infection were 19.3% and 8.8%, respectively, and thus were in the expected previously reported range.
The ICU admission rates in these studies ranged from 15.0% to 36.8% for COVID-19 patients during the wild type waves and from 10.8% to 24% for influenza patients, the mechanical ventilation rates ranged from 9.7% to 15.0% for COVID-19 patients during the wild type waves and from 4.0% to 9.0% for influenza patients. While the ICU admission rate (27.3%) and the MV rate (18.2%) for our SARS-CoV-2-positive patients are in the previously reported range, the rates for our influenza virus-positive inpatients are slightly lower (ICU rate: 7.1% and MV rate 2.7%). This could be at least in part explained by the fact that the average age of influenza patients who died without being transferred to an intensive care unit was 83 years. Many of these patients were multimorbid and had explicitly expressed their opposition to intensive care measures.
The mortality rate of our SARS-CoV-2-positive inpatients decreased from 15.0% in the delta wave to 7.0% in the omicron BA.5 wave. This reduction of 53.3% is in line with the observations of other studies(
Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study.
Mortality Risk Among Patients Hospitalized Primarily for COVID-19 During the Omicron and Delta Variant Pandemic Periods - United States, April 2020-June 2022.
) that described a reduction in mortality rate between 44.4% and 61.7% between the delta and the omicron variant of SARS-CoV-2.
Compared to the delta wave, we saw a 40% and 58.5% reduction in the ICU admission rate of SARS-CoV-2-psoitive inpatients in the BA.1/2 and BA.5 omicron waves, respectively. Bouzid et al. (
) described a 75% reduction in the ICU admission rate between the delta and early omicron wave in hospitals in France. Adjei et al. reported a reduction of 14.4% between delta and the early omicron phase and of 46.8% between delta and the late omicron phase in the USA.
Compared to the delta wave, we observed a 58.7% and 78.7% reduction in the MV rate of SARS-CoV-2-positive patients in the BA.1/2 and BA.5 omicron waves, respectively. Bouzid et al. (
) described a 52% reduction in the ICU admission rate between the delta and the early omicron wave in France. Adjei et al. reported a reduction of 22.4% between delta and the early omicron phase and of 65% between delta and the late omicron phase in the USA.
Interestingly, patients with COVID-19 related RMD showed, compared to patients with influenza, increased mortality in the age group 58-77 years and decreased mortality in the age group 78-97 years in the BA.5 wave. However, due to the small sample size (five patients died in this age group during the BA.5 wave) and the severe pre-existing comorbidities of some of these patients this might be a statistical outlier. Further studies would be needed to corroborate this observation.
Our study has some limitations. First, this is a retrospective study. While the patient demographics and outcome variables are quite reliable, there is some uncertainty in the complete coverage of the listed comorbidities. Furthermore, in the first SARS-CoV-2 wave, a larger proportion of oligosymptomatic patients were probably hospitalized over a longer period, as at the beginning of the pandemic there was no possibility to isolate these patients in care facilities, such as nursing homes. While PCR admission screening of all inpatients has been in place for SARS-COV-2 since May 2020, testing for influenza was only performed on symptomatic patients throughout the observation period. As a result, asymptomatic inpatients with influenza often are not detected, which can lead to an overestimation of disease severity in influenza patients. In order to consider this, we conducted a corresponding subgroup analysis for inpatients with RMD, which corroborated the general analysis of all virus-positive inpatients. In addition, due to the retrospective nature of the study the impact of the vaccination status on the patient’s outcome could not be examined more closely, as the vaccination status was only sporadically recorded in the patient files.
Our data show, that regarding the severity of infections it would be justified to apply similar levels of infection control. For the implementation of infection control measures in hospitals, however, transmissibility is also important in addition to pure disease severity. Thus, a disease that has a lower mortality but a significantly higher transmissibility can ultimately lead to more nosocomial deaths. For this reason, these data on the relative severity of both infections should not be used as a basis for uncritically dispensing SARS-CoV-2 infection control measures.
Conclusions
Compared to influenza virus-positive inpatients, SARS-CoV-2 BA.1/2 and BA.5-positive inpatients do not show a significantly increased risk of in-hospital mortality, ICU admission, MV or ECMO. Against this background, health care system resources should be shared equally between the two diseases.
Acknowledgements
No funds were received in support of this manuscript. The authors declare that they have no competing interests.
Maßnahmen zur Bewältigung der COVID-19-Pandemie in Deutschland: nichtpharmakologische und pharmakologische Ansätze [Measures to cope with the COVID-19 pandemic in Germany: nonpharmaceutical and pharmaceutical interventions].
Comparative evaluation of clinical manifestations and risk of death in patients admitted to hospital with covid-19 and seasonal influenza: cohort study.
Comparison of the characteristics, morbidity, and mortality of COVID-19 and seasonal influenza: a nationwide, population-based retrospective cohort study.
Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study.
Mortality Risk Among Patients Hospitalized Primarily for COVID-19 During the Omicron and Delta Variant Pandemic Periods - United States, April 2020-June 2022.
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