Respiratory syncytial virus infection is an underestimated cause of viral pneumoniae in adults

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 inuenza/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 signicant in our cohort and higher in patients with advanced age. Further, we report a signicant increase in detected RSV cases but also in detection rate. Together, these ndings suggest that implementation of a combined inuenza/RSV testing led to a signicant increase in detection rate, supported clinicians establishing the correct diagnosis and allowed a safe and controlled handling of RSV patients.


Introduction
The respiratory syncytial virus (RSV), a single-stranded RNA virus, is primarily known as a major cause of lower respiratory tract infection in infants and young children 1  Previously, an overwhelming amount of studies reported similar rates of hospitalization and mortality of in uenza virus A and B compared to RSV [5][6][7][8] . Similar clinical presentation of both viruses and comparable seasonal characteristics makes a differential diagnosis based on clinical or epidemiological characteristics nearly impossible without adequate diagnostics 9 . Moreover, both viruses can be transmitted by aerosol droplets or direct contact to the virus, such as over fomites 10,11 . Hence, prevention protocols have to be implemented to protect health care workers (HCWs) and prevent disease transmission within health care facilities. Such prevention strategies mainly comprise two aspects.
Firstly, clinicians must be aware of the virus and test for it. Despite overwhelming evidence that RSV is associated with a signi cant disease burden in adults, clinicians' awareness is still low 12,13

Risk Factor Analysis For A Severe Disease Progression
Risk factors for hospitalization in RSV patients were, advanced age (> 65a) (p < 0.001), smokers (p < 0.001), pre-existing cardiac diseases (p = 0.001), preexisting pulmonary disease (p = 0.006), diabetes mellitus type II (p = 0.044), clinical or radiological signs for pneumonia (p = 0.009). Antimicrobial treatment was initiated in 29 of 103 (28.2%) patients. Decision for antimicrobial treatment was based on several factors as demonstrated in Fig. 2. Furthermore, C-reactive protein at admission did signi cantly correlate with hospitalization (p < 0.001) and administration of antimicrobial agents (p < 0.001). Of the patients admitted for in-patient care 15.56% (7 of 45%) needed further treatment and an ICU ward. Risk for ICU admission was higher in patient with preexisting pulmonary disease (p = 0.03), experience of complications (p = 0.001), evidence for pneumonia (p = 0.002) and bacterial superinfection (p = 0.036).
6.67% of hospitalized RSV patients died (3 of 45 patients, overall 2.9% [3 of 103]). Risk for death was higher in patients advanced age (p = 0.048). Table 1. demonstrates the odds-ratios of the risk factors depending on the outcome parameters risk for hospitalization, ICU admission and mortality.

Discussion
This study was conducted to assess the in uence of a newly implemented combined u/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 in uenza season.
Mortality in our cohort was 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 in uence on admission rates to hospital or administration of antimicrobial agents.
When comparing RSV to in uenza, overwhelming evidence showed similar rates of hospitalization, respiratory failure and mortality 7,12 . RSV disease burden was particularly high in patients aged > 75years 6,14  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 . RSV is known to be transmitted by aerosol droplets or direct contact to the virus, such as over contaminated hands or surfaces 15,16 . During winter months RSV and in uenza have their epidemic peaks in Austria, RSV usually a bit later than in uenza virus. As a result, clinicians in emergency rooms and ambulances had to separate patients with respiratory tract infections due to RSV and in uenza quickly and reliably to prevent nosocomial transmission. To tackle this problem, the general diagnostic procedure for RSV was revised in early 2018 by implementing a combined diagnostic assay for in uenza A, in uenza B and RSV. 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%. The clinical presentation of patients with RSV and in uenza is non-speci c and similar, which makes it almost impossible to differentiate between the viruses based on symptoms alone. We believe that the demonstrated increase in detection rate emphasizes these diagnostic di culties and supports the application of combined PCR tests in the clinical practice. At our center all 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.
Apart from the implemented measures, the impact of the test on the clinical reasoning is di cult to quantify. In theory, detection of viral pathogens responsible for pneumonia should reduce administration of antimicrobial treatment. Coinciding data from previously published retrospective studies showed that increased viral testing only partially altered antimicrobial treatment 17,18 . 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 in uence of broad viral testing was often discussed controversially, mostly due to three factors. Firstly, apart from neuraminidase inhibitors for in uenza virus infections no speci c antiviral options exists 19 . Secondly, attempts to provide convincing evidence that broad antiviral testing reduces rates of antimicrobial treatment were unsuccessful 17,18 . 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 di cult. 19 . 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. Finally, the present study was conducted retrospectively. Thus, the study design does not allow conclusions about the outcome of the patients besides the information documented in our system.
In conclusion, we demonstrated that although RSV disease is a well described cause for pneumonia in adults. Implementation of a combined in uenza/RSV test led to a signi cant increase in detection rate, supported clinicians establishing the correct diagnosis and allowed a safe and controlled handling of RSV patients.

Methods
This retrospective cohort analysis assesses the in uence of a newly implemented combined in uenza/RSV RT-PCR test on the clinical practice at a university hospital. The study protocol 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.

Setting Of The Study
The Vienna General Hospital is the largest tertiary care center in Austria, and contributes signi cantly to the medical care of patients with respiratory tract infections during in uenza virus and RSV epidemics.
Here  Redlberger-Fritz contributed for statistical analysis and interpretation of the data. All authors reviewed the manuscript.

Competing interest
The author(s) declare no competing interest. This research did not receive any speci c grant from funding agencies in the public, commercial, or not-for-pro t sectors.

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

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.