Characteristics and outcomes of patients hospitalized for infection with influenza, SARS-CoV-2 or respiratory syncytial virus in the season 2022/2023 in a large German primary care centre

Lower respiratory tract infections are a common cause of hospitalization and significantly contribute to morbidity and mortality particularly in young children and older adults [1, 2]. Among the viral causes, Respiratory Syncytial Virus (RSV) and various strains of Influenza, particularly Influenza A, have been most prominent for a long time [3‐5]. Starting in early 2020, SARS-CoV-2 dominated this type of infection, while the role of previously relevant viruses became minor or even disappeared, although this impression might have been favoured by the practice of regular testing for SARS-CoV-2. Those papers that addressed other viruses during this time confirmed the predominant role of SARS-CoV-2 [6, 7]. Consequently, nearly all comparisons of the disease burden between viruses were based on historical data [8‐10].

Starting in the summer of 2022, the formerly prevalent viruses reappeared, e.g. in terms of Influenza or in terms of RSV, particularly in children [11‐13], and a very recent study used data from the same season 2022/2023 to compared Influenza and SARS-CoV-2 [14]; RSV was not included in this analysis. As shown by many studies, the risk from SARS-CoV-2 declined over time, possibly due to the prevalence of less harmful variants [15‐17], improved immunity due to infection or vaccination, and advances in the management of Covid-19 patients. In addition, the population at risk may have changed over time. Thus, in-time comparisons are of great value.

The re-appearance of infections with previously prevalent viruses renders it possible to compare disease burden, characteristics of patients at risk, treatment and outcome under comparable conditions. Hospitalized patients are of interest not only due to their disease severity but also, because availability, validity and comparability of data are probably higher than for non-hospitalized patients.

Based on these considerations, we studied infections with Influenza A/B, RSV and SARS-CoV-2 in recent time (October 2022 to February 2023) in patients of a large primary care hospital located in a region known as former Covid-19 hotspot [18, 19] covering the full range of age from newborns to very old individuals.

In this study, the clinical characteristics and outcomes of patients hospitalized with Influenza A, SARS-CoV-2 or RSV between October 1st 2022 and February 28th 2023 were analysed to assess differences and similarities. Its strength is the simultaneous collection of most recent data. This was enabled by the fact that the high numbers of the major infections allowed a direct comparison, whereas nearly all previous studies relied upon data from different seasons. In children and adolescents, the comparatively high disease burden from RSV that is well known from the past was essentially confirmed. In adults, the three infections had a similar impact on the relative risk for ICU admission and in-hospital mortality; although differences were not statistically significant, values were highest for RSV. In terms of clinical and treatment characteristics, respiratory symptoms, a history of obstructive airway disease, non-invasive ventilation and low-flow oxygen supply were most frequent for RSV. Taken together, our findings indicate that in the season 2022/2023 all three infections played an important role in hospitalized adult patients. In particular, they underline that RSV is worth of further attention not only in children.

In the beginning of 2020, SARS-CoV-2 became the dominant respiratory viral infection worldwide with regard to hospitalization rate and mortality [20]. During this time, the incidence of other respiratory viruses, particularly RSV and Influenza, appeared to decrease drastically [6, 7]. Since then, however, the impact of SARS-CoV-2 has declined, as reflected in a reduction of mortality [14], which was already visible when comparing the first and second wave of Covid-19 in 2020/2021 [18]. In parallel, respiratory viruses including Influenza and RSV reappeared, particularly RSV in children [11‐13]. We confirmed this in both young and adult patients for the season 2022/2023. The large number of hospitalized patients enabled a comparison in the same population at the same time. The season 2022/2023 also provided the most recent information on Influenza, SARS-CoV-2 and RSV, which might be relevant for predicting future developments.

Previous comparisons between SARS-CoV-2, Influenza and RSV based on data from different times indicated both similarities and differences. A recent study from Germany [21], that examined outcomes and patients’ characteristics in the three types of infection between 2017 and 2020, found a higher risk of ICU admission and hospital death for RSV compared to Influenza A, whereas the risk for SARS-CoV-2 was even higher. In addition, the RSV patients were more likely to have COPD or CKD. Our findings from 2022/2023, i.e. a much later time, confirmed the high risk from RSV particularly in COPD patients, but did not find an elevated risk from SARS-CoV-2.

Another study from Switzerland compared the outcomes of patients infected with Influenza from 2018 to 2022 and with SARS-CoV-2 in 2022 [22]. There was no difference in the risk of ICU admission, but mortality was higher for SARS-CoV-2 than for Influenza (7% vs. 4.4%). Similar observations regarding SARS-CoV-2 versus Influenza were made in a recent study on the outcomes of the last season from October 2022 to January 2023 [14]. Again, SARS-CoV-2 was associated with higher mortality risk than Influenza, but the results also showed that the difference had decreased compared to 2020 (SARS-CoV-2: 6% versus 17–20% in 2020, Influenza: 3.7% versus 3.8% in 2020).

These data again underline that the mortality of Covid-19 patients decreased over time. Our data agree with this regarding ICU admission and length of ICU stay in adults. They also showed a difference between the two infections regarding mortality, irrespective of the fact, whether all patients were included or only those, in whom the infection was considered to be the likely cause of their hospital stay. The differences in mortality between the total group and the subgroup were, however, considerable (see Additional file 2: Table S5), underlining the need for taking into account the type of approach in the comparison of numerical data. Importantly, our comparison showed that relationship between the infection groups essentially remained the same, thus our conclusion appeared robust.

When comparing RSV and Influenza, a study from the US [23] published in 2019 reported higher morbidity and mortality in RSV patients. On average, RSV patients were more likely to have congestive heart failure and COPD, and they had a higher risk for ICU admission. Our findings (see Table 2, Table 3, Additional file 2: Table S5) are in accordance with this, but additionally place SARS-CoV-2 at an intermediate position between the other two viruses, with more similarities to RSV than to Influenza A.

In order to identify differences between viruses in the risk profile of patients in the most recent season, we included a comprehensive analysis of comorbidities in adults. Consistent with previous reports [21, 23], adults hospitalized with RSV had the greatest frequency of comorbidities, especially heart failure, rheumatic disease, COPD and asthma, as well as the status of immunosuppression. In the SARS-CoV-2 group, only PAD was more frequent. The higher frequency of comorbidities in RSV patients was supported by the higher median of the sum of comorbidities. Among adults, the SARS-CoV-2 group was the oldest on average, followed by RSV and Influenza A. As comorbidities are often linked to age, we assessed whether the different patterns of comorbidities were due to the differences in age. This was not the case, suggesting intrinsic age-independent risk profiles for the three infections.

The respiratory symptoms cough and dyspnoea were most prevalent in RSV patients, followed by Influenza A, and lowest with SARS-CoV-2. These observations are in line with results of a comparison covering different seasons [21]. Taken together with the higher frequency of obstructive airway diseases in RSV patients, the findings point at RSV but not SARS-CoV-2 as being primarily associated with clinical affectation of the lung.

While the primary outcomes ICU admission and mortality did not show marked differences between the three major infection groups in adults, we observed differences regarding the frequency of NIV, of low-flow oxygen supply during hospital stay and of oxygen supply upon admission. The highest percentages were found in the RSV group, the lowest in the SARS-CoV-2 group. The median length of the hospital stay was similar between groups, but patients infected with SARS-CoV-2 showed a right skewed distribution and based on this a statistically significantly longer hospital stay compared to RSV patients.

The overall pattern of differences between infections had two aspects. First, the burden from respiratory impairments appeared to be highest with RSV, underlining previous findings that RSV remains to be a serious concern in adults, particularly in the elderly and those with pre-existing medical conditions [21, 23‐25]. In comparison, SARS-CoV-2 and Influenza A appeared to have a more systemic impact. Despite these differences, we could identify common risk factors in a comprehensive analysis of ICU admission and mortality. The strongest predictor for both outcomes was oxygen supplementation upon admission, while comorbidities did not play a role, except malignant disease for ICU admission. Regarding ICU, vital parameters were also relevant. For SARS-CoV-2, renal function played an important role, in accordance with our previous findings [18, 19, 26].

It demonstrated the overwhelming role of the requirement for initial oxygen supply for later ICU admission, and in addition younger age, male sex, malignant diseases, increased heart rate, decreased body temperature, and lower oxygen saturation. The predictors of higher in-hospital mortality were slightly different. The role of initial oxygen supplementation was confirmed, but at the same time a reduction in eGFR played a role, while reduced oxygen saturation showed only a tendency.

One of the advantages of our study may be that we covered the whole spectrum of patients’ ages and that the population of hospitalized patients comprised a large number of children and adolescents, in whom the dominant role of RSV was clearly visible. This was reflected by the findings regarding prevalence of infection, length of stay, admission to ICU, as well as high-flow and low-flow oxygen therapy. When restricting the analysis to young children of age less than 3 years, essentially the same results were obtained as for the total group of children and adolescents. We did not analyse the data from children and adolescents further, as RSV has already been discussed in many publications.

This retrospective study has a number of limitations. First, it does not allow causal inferences but only provides associations. In particular, we could not address the potential interaction between infection and severity of comorbidities beyond the regression analyses performed. Moreover, it is a single-centre study, and there is no guarantee that our findings must be valid for other regions. However, they are well compatible with historical data, suggesting their validity. Moreover, data limited to hospitalized patients cannot quantify the overall burden from the infections; for this, epidemiological studies are needed. As a strength, however, this limitation allowed for the collection of a large set of high-quality data in a well-defined population. A further advantage was that information from previous waves of Covid-19 from the same region was available for comparison [18, 19, 26]. A noteworthy limitation was the fact, that hospitalized patients were routinely tested for SARS-CoV-2 upon admission, while the (combined) testing for Influenza A/B and RSV was performed only in case of clinical hints on their potential involvement, both upon admission and during the stay. In case of any uncertainties, however, these hints were taken seriously and the appropriate tests were performed, thus in the sensitivity analysis we not only excluded patients of the SARS-CoV-2 group. Importantly, the sensitivity analysis demonstrated that differences in the indications of tests did not play a role regarding the relationship between infections. The only relevant bias might have been that patients with Influenza A or RSV infection were not recognized and not tested at all but this was unlikely due to the broad indication for testing. Due to incomplete data on patients after discharge from hospital, partly caused by legal issues in Germany, mortality referred to in-hospital mortality and may not reflect the overall mortality of viral infections. Based on previous analyses [18, 19, 26], however, we have reason to assume that mortality after discharge from the RoMed hospital did not play a significant role for the comparative analysis.

In conclusion, the comparison of infections with Influenza, SARS-CoV-2 and RSV in the same season 2022/2023 in hospitalized patients showed no major differences in the rates of ICU admissions and mortality of adult patients. Overall, SARS-CoV-2 was most frequent. The adult RSV group had the highest frequencies of comorbidities, especially obstructive airway diseases, and of respiratory symptoms. Moreover, the need for oxygen supply, appearing as unfavourable indicator, was most frequent for RSV, both in adults and in children/adolescents. The data indicate a tendency for relatively higher disease burden from RSV compared to Influenza and SARS-CoV-2 in all age groups and suggest that it could be worthwhile to consider vaccination against RSV particularly in the elderly.