Surveillance of respiratory syncytial virus infections in adults, Austria, 2017 to 2019

Respiratory syncytial virus (RSV) testing is generally available in most care centres, but it is rarely performed because clinicians’ seldom suspect RSV to be the underlying pathogen in adults with respiratory disease. Here, we evaluate the impact of broad combined influenza/RSV testing on the clinical practice. Overall, 103 patients were tested positively for RSV. Our study indicates that positively tested patients were mostly of advanced age and suffered from chronic diseases. Mortality was significant in our cohort and higher in patients with advanced age. Further, we report a significant increase in detected RSV cases but also in detection rate. Together, these findings suggest that implementation of a combined influenza/RSV testing led to a significant increase in detection rate, supported clinicians establishing the correct diagnosis and allowed a safe and controlled handling of RSV patients.

demonstrates the investigated collective and performed analysis. For the data analysis demographic parameters (age, sex, body-mass index, co-morbidities and history of smoking), microbiological data (urinary antigen testing, bloodculture, bronchoalveolar lavage fluid culture), radiological data (evidence of pneumonia), laboratory parameters (haemoglobin, thrombocytes, leucocytes, creatinine, bilirubin and C-reactive protein), treatment procedures (admission to hospital, administration of antibiotics, admission to ICU) and mortality data were retrospectively extracted from the electronic patient information system. Firstly, diagnostic approach of RSV was compared between the surveillance period 2018 (period before combined influenza/RSV testing), defined as week 40 of 2017 to week 30 of 2018, and the surveillance period 2019 (period with influenza/RSV testing in place), defined as week 40 of 2018 to week 30 of 2019. Secondly, demographic data, handling of the patients and outcome were described.  19,20 . Baseline characteristics of participants are summarized as frequencies and proportions for categorical data and as means and standard deviations or medians and interquartile for metric data. The hypothesis testing was performed by Chi-Square test for categorical variables and Student's t tests or Mann-Whitney tests for metric data. To illustrate correlations between categorical variables, a Pearson-correlation is performed for normally distributed variables, as well as Spearman's Rho for non-parametric variables. Statistical significance was defined as p < 0.05.

Ethics declaration.
The study protocol of this retrospective analysis was approved by the Ethics Committee of the Medical University of Vienna, Austria (ECS 1523/2019) and all study-related procedures were conducted according to the declaration of Helsinki. Due to the retrospective study design, informed consent was waived by the Ethics Committee of the Medical University Vienna.

Descriptive analysis of RSV patients.
In total 103 patients with RSV infection were included into the analysis. Baseline characteristics are highlighted in Table 1. The median age of our cohort was 57 years and female and male patients were equally affected. Most of the patients suffered from comorbidities, such as cardiac illness (n = 54), pulmonary illness (n = 33), oncological disease (n = 24), type 2 diabetes mellitus (n = 20) and terminal dialysis-dependent kidney insufficiency (n = 13). 19 patients were solid-organ transplant recipients. Nearly half of the cohort (43.7%) required in-hospital care. Risk factors for hospitalization in RSV patients were, advanced age (> 65a) (p < 0.001), smokers (p < 0.001), comorbidities (p < 0.001), clinical or radiological signs for pneumonia (p = 0.009) and signs for superinfection (0.014) (supplementary Table 2). Inpatients had   table 3). Complications during hospitalization were most frequently worsening of pulmonary disease, such as COPD exacerbation in 16 patients, followed by cardiac decompensation in two patients. Superinfections were reported in 5 patients. Streptococcus pneumoniae detected by rapid urine antigen testing was the most common pathogen, followed by Klebsiella pneumoniae detected in blood culture (n = 1), Enterococcus faecalis detected in blood culture (n = 1) and Aspergillus fumigatus detected in a bronchoalveolar lavage fluid culture (n = 1). Antimicrobial treatment was initiated in 29 of 103 (28.2%) patients. Decision for antimicrobial treatment was based on several factors as demonstrated in Fig. 3. Further, antimicrobial treatment was more likely to administered in patients with higher CRP values (no antibiotics prescribed CRP = 1.28 mg/dl [0.52-2.9], antibiotics prescribed CRP = 9 mg/dl [4.56-17.3]; p < 0.001]).
Of the patients admitted for in-patient care 15.56% (7/45) needed further treatment and an ICU ward. Patients with preexisting pulmonary (p = 0.03), complications of RSV infection (p = 0.001), pneumonia (p = 0.002) and bacterial superinfection (p = 0.036) were more likely to be admitted to ICU. Overall 2.9% of the patients died. Age over 65 was associated with higher odds for death.

Discussion
This study was conducted to assess the influence of a newly implemented combined flu/RSV test at the biggest tertiary care center in Austria. As expected, introduction of the test revealed that RSV is responsible for a substantial fraction of severe respiratory illnesses in adults during influenza season. Mortality in our cohort was www.nature.com/scientificreports/ high, and was even higher in patients with advanced age. Despite early and broad testing of our patients we were not able to safely discern any influence on admission rates to hospital or administration of antimicrobial agents. Previously published studies demonstrated a particularly high disease burden of RSV disease burden in patients aged > 75years 6,21 . Consistent with previous reports, our patients were mostly of advanced age and suffered from chronical diseases, such as respiratory illness, cardiac illness, type 2 diabetes mellitus, oncological diseases or were solid-organ transplant recipients. Previous reports have demonstrated rates of bacterial superinfections in up to 15% of RSV cases 7 . In our cohort 11.1% of the patients suffered from superinfection. Most frequently reported pathogens were Streptococcus pneumoniae, Klebsiella pneumoniae, Enterococcus faecalis and Aspergillus fumigatus. Bacterial superinfections were associated with increased need for hospitalization and need for ICU admission.
Despite an increasing number of reports highlighting the disease burden of RSV in adults, awareness of many health care providers to adults seems to be low 12,13 . The clinical presentation of patients with RSV and influenza is non-specific and similar, which makes it almost impossible to differentiate between the viruses based on symptoms alone. Furthermore, RSV and influenza virus A and B epidemics show similar seasonality with most synchronized peaks in temperate regions. Chronological sequence of the viruses' peak incidence differs depending on the country and is not necessarily consistent from year-to-year 22 . In Austria, the RSV epidemic starts later than influenza virus A 15,16 . As a result, clinicians in emergency rooms and ambulances had to separate patients with respiratory tract infections due to RSV and influenza quickly and reliably to prevent nosocomial transmission. We demonstrate that a combined test led to an expected increase in performed tests and detected cases, but also to an increase in detection rate from 2.6 to 4.6%. We believe that the demonstrated increase in Listed factors were inpatient care (yes/no), evidence for pneumonia (defined as radiological evidence for pneumonia), complications (respiratory complications and bacterial or fungal superinfections), comorbidities (cardiac disease, pulmonary disease, type 2 diabetes mellitus, oncological disease, terminal dialysis-dependent kidney insufficiency and solid-organ transplant recipients), bacterial superinfections (bacterial growth in blood cultures) and age > 65a (yes/no). www.nature.com/scientificreports/ detection rate emphasizes these diagnostic difficulties and supports the application of combined PCR tests in the clinical practice. Broad testing did change the management of patients. Positively tested patients were admitted to distinct wards and had to remain in quarantine for 5 days. Further, health care workers in contact with those patients had to wear personal protective equipment. Herewith we achieved a save and controlled handling of RSV patients. Although, the implemented strategies suggest a reduction of nosocomial infection, the study design does not allow causative conclusions. Apart from the implemented measures, the impact of the test on the clinical reasoning is difficult to quantify. In theory, detection of viral pathogens responsible for pneumonia should reduce administration of antimicrobial treatment and prevent nosocomial infections. Coinciding data from previously published retrospective studies showed that increased viral testing only partially altered antimicrobial treatment 23,24 . Here, we demonstrate that reasoning for ab treatment depends on multiple factors such as an elevated CRP, clinical and radiological indication for pneumonia, as well as age of the patient rather than on the clinicians' knowledge about RSV/test result.
Due to increasing availability and potency of viral diagnostic tools, viruses are increasingly detected as a cause for pneumonia world-wide. Clinical influence of broad viral testing was often discussed controversially, mostly due to three factors. Firstly, apart from neuraminidase inhibitors for influenza virus infections no specific antiviral options exists 25 . Secondly, attempts to provide convincing evidence that broad antiviral testing reduces rates of antimicrobial treatment were unsuccessful 23,24 . Thirdly, interpretation of naso-pharyngeal swabs poses a challenge of its own as the detected virus could be responsible for co-existing upper respiratory tract colonization or an actual pneumonia pathogen, making diagnosis difficult 25 . The above points should not be interpreted in the sense that testing is unnecessary, but rather that further research is urgently necessary to improve diagnostic procedures and the availability of treatment options. Currently, however, the biggest argument for broad-based testing remains the prevention of the spread of disease and protection of HCWs.
We acknowledge several limitations. First, our control group of patients with unknown RSV status was relatively small, as we only detected 10 additional cases. Hence, we only compared 10 patients from season 2018 to 103 cases in season 2019 in terms of clinical practice and reasoning, which is a limiting factor of our study. However, it is plausible clinicians' select antimicrobial treatment based on multiple factors such as CRP, indication for pneumonia, age and not only on a test result. Furthermore, the assessed 191 samples corresponded to all samples during the suspected peak of RSV season in 2018, week 8 to 12. Hence, analysis of other periods would have been associated with increased efforts regrading costs and time. Secondly, we did not broadly test patients after the isolation period and cannot ultimately conclude if implemented strategies proved feasible in reducing risk of transmission after the isolation period. Thirdly, the present study was conducted retrospectively. Hence, study results were depended on the quality of documentation done by clinicians and does not allow conclusion about consequences not documented as, such as source of infection (nosocomial versus community acquired) and quality of care performed.
In conclusion, we demonstrated that although RSV disease is a well described cause for pneumonia in adults. Implementation of a combined influenza/RSV test led to a significant increase in detection rate, supported clinicians establishing the correct diagnosis and allowed a safe and controlled handling of RSV patients.

Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.