Respiratory syncytial virus‐associated acute respiratory illness in adult non‐immunocompromised patients: Outcomes, determinants of outcomes, and the effect of oral ribavirin treatment

Abstract Background Respiratory syncytial virus (RSV) is an increasingly common cause of respiratory illness in adult non‐immunocompromised patients. Oral ribavirin was reported to improve outcomes of RSV infection in immunocompromised patients. This study aimed to determine the outcomes of non‐immunocompromised patients hospitalized with RSV‐associated acute respiratory illnesses (RSV‐ARI), the factors independently associated with the outcomes and the effect of oral ribavirin treatment. Methods This retrospective, observational cohort study included 175 adults admitted to the hospital with virologically confirmed RSV‐ARI during 2014–2019. Severe ARI was identified using Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) criteria for severe community‐acquired pneumonia. The primary outcome was all‐cause mortality within 30 days after enrollment. A multivariable Cox model was performed to identify significant predictors of mortality. Results Mean age was 76 ± 12.7 years. Seventy‐eight (44.6%) patients met the diagnostic criteria for severe ARI. Thirty‐six (20.6%) patients required invasive mechanical ventilation, and 11 (6.3%) required vasopressor. Ninety‐nine (56.6%) patients received oral ribavirin treatment, and 52 (29.7%) received systemic corticosteroids. Forty‐one (23.4%) patients had evidence of bacterial infection. Overall mortality was 7.4%. Mortality among patients with non‐severe ARI and severe ARI was 1.04% and 15.4%, respectively. Estimated glomerular filtration rate <50 ml/min/1.73 m2, severe ARI, systemic corticosteroids, and bacterial infection were independently associated with higher risk of mortality. Treatment with oral ribavirin was the only factor associated with reduced mortality (adjusted HR: 0.19, 95% CI: 0.04–0.9, P = 0.03). Conclusion RSV‐ARI may result in significant mortality and health care utilization. Treatment with oral ribavirin may improve survival in these patients.


| INTRODUCTION
Respiratory syncytial virus (RSV) is increasingly recognized as a common cause of acute respiratory illness (ARI) in adults. [1][2][3][4][5] Among adults admitted to the hospital with RSV-associated acute respiratory illness (RSV-ARI), 10%-31% require intensive care and 3%-17% need mechanical ventilation. 4 The reported RSV-associated morbidity, mortality, and health care utilization were comparable with those observed in patients with influenza infection. 3,6,7 Antiviral treatment, coexisting bacterial infection, and corticosteroids were reported to significantly influence survival in influenza patients. 8 However, the relative impact of these factors on the clinical outcomes of patients with RSV-ARI remains unclear. The antiviral treatment options are limited in RSV infection. Aerosolized ribavirin is approved for the treatment of RSV in pediatric patients. In adult population, the use of ribavirin is off-label and has been limited to severely immunocompromised transplant recipients. The reported clinical outcomes in those patients were favorable based mainly on observational data. 9,10 Due to the high cost of aerosolized ribavirin and the occupational risk to healthcare workers exposed to this form of ribavirin, many centers use oral ribavirin instead. 11 Most studies that have compared oral and inhaled ribavirin have shown similar efficacy. [12][13][14] However, reports of oral ribavirin's efficacy in adult nonimmunocompromised RSV are comparatively scarce. [15][16][17] Whether the data that we currently have about the effect of oral ribavirin can be applied to general adult population still needs to be determined. Even though oral ribavirin has not yet been approved for adult use in RSV, it is used to treat adult patients with severe RSV-ARI at our center. RSV infection is associated with airway inflammation and increased airway responsiveness and may trigger exacerbation of chronic airway diseases. Corticosteroids are widely prescribed for bronchospasm, which is commonly associated with RSV infection. 3,18 To increase our understanding of RSV-ARI, this study sets forth to determine the outcomes of patients hospitalized with RSV-ARI, the factors independently associated with the outcomes, and the effect of oral ribavirin treatment on patient outcomes.

| STUDY DESIGN AND METHODS
We performed a retrospective single-center study of a cohort of adults hospitalized with RSV-ARI during January 2014 to April 2019 at a 2300-bed university-based national tertiary referral center in Bangkok, Thailand. Patients with RSV infection were identified from our center's inpatient database using the ICD-10 code related to RSV infection (J12.1: RSV pneumonia; J20.5: Acute bronchitis due to RSV; B97.4: RSV as the cause of diseases classified elsewhere). RSV infection was defined by a positive reverse transcription polymerase chain reaction (RT-PCR) to any of the following samples: pharyngeal swab, nasal swab, nasopharyngeal aspirate, sputum, or bronchoalveolar lavage (BAL). Patients with RSV infection that met all of the following criteria were included: age ≥18 years; admitted from outside the hospital with signs or symptoms of ARI, defined as two or more respiratory symptoms, including cough, dyspnea, pleuritic chest pain, and/or respiratory distress; and diagnosis of RSV infection within 48 h after admission. Patients who were pregnant, who had received immunosuppressants or long-term corticosteroid therapy, or who had concomitant acquired immunodeficiency syndrome were excluded.

| Data collection
Electronic and written medical records were reviewed for all patients.
A protocol for data collection was applied in all cases. Information that was collected included age, gender, comorbidities (pulmonary, cardiovascular, liver, renal, neoplasms, and diabetes), functional status (independent or dependent functional status), time of illness onset, and hospital admission. The following clinical data at admission were recorded: presenting symptoms and signs, mental alterations, heart rate, respiratory rate, and blood pressure. The need for non-invasive or invasive mechanical ventilation or vasopressors within 48 h of hospital admission was assessed. Chest radiographic findings were also documented (infiltrates, number of lobes affected, unilateral versus bilateral affection, and pleural effusion). The chest radiographs at admission were retrospectively reviewed by three independent physicians (two pulmonologists and one radiologist) with all interpreters blinded to all clinical information and outcomes. The images were then collectively interpreted so that a consensus determination could be reached and documented. The recorded laboratory data included complete blood count, chemical parameters, and arterial blood gas analysis. If the results of arterial blood gas analysis were unavailable, the PaO 2 was inferred from the oxygen saturation as measured by pulse oximetry (SpO 2 ). 19 All microbiological studies for bacterial infection, including blood cultures, sputum cultures, pleural fluid cultures, or BAL cultures, at admission and during the course of hospitalization were recorded. Etiologic diagnosis was considered positive in the following situations: isolation of a respiratory pathogen in a usually sterile specimen (blood and pleural fluid) or bacterial growth in BAL fluid (≥10 4 cfu/ml) or a predominant microorganism isolated from a sputum sample (>25 polymorphonuclear leukocytes and <10 squamous cells per low-power field) with moderate or high quantity.

| Medication treatment
Four types of medications prescribed during admission were recorded.
Ribavirin treatment referred to the administration of ribavirin for one or more doses during the study illness, including timing of initiation and dosing. Systemic corticosteroids use was defined as any intended therapeutic use of corticosteroids (parenteral or enteral routes) for the study illness for ≥24 h during hospitalization. Replacement doses and inhalation treatment were excluded. Inhaled bronchodilator used to treat the study illness for ≥24 h. Antibiotic referred to the initial antibiotic prescribed within the first 24 h.

| Definitions
Severe ARI was defined according to Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) criteria for severe community-acquired pneumonia (CAP) 20 (Table S1). Bacterial coinfection was defined in patients having one or more positive cultures of a known respiratory pathogen thought to be causing a true infection from blood and/or a respiratory sample (sputum, BAL, or pleural fluid) collected within 2 days of admission. Bacterial superinfection was defined in patients having one or more positive cultures of a known respiratory pathogen from blood and/or a respiratory sample collected more than 2 days after admission. Adequate antibiotic therapy was defined as treatment with at least one agent to which all recovered isolates were susceptible in vitro. Non-respiratory nosocomial infection was defined in patients having one or more positive cultures with a bacterial pathogen thought to be causing a true infection from non-respiratory sources collected more than 2 days after admission.

| Outcomes
The primary outcome was all-cause mortality within 30 days after admission. The secondary outcome was the duration of hospitalization by assessing the number of days alive and outside the hospital (hospital-free days) within 30 days after hospital admission. Factors affecting duration of hospitalization were analyzed using time-to-event analyses. Univariate and multivariate Cox regression analyses were performed to identify factors independently associated with the time to hospital discharge alive within 30 days after admission, with patients who were not discharged at day 30 or death before day 30 were considered as right censored at day 30. A lower HR (HR < 1) indicates a lower probability of hospital discharge alive and therefore increased duration of hospitalization. Kaplan-Meier curves were used to illustrate time to hospital death and time to hospital discharge alive. All statistical analyses were two-sided, and a P value <0.05 was considered to be statistically significant. All statistical analyses were performed using SPSS Statistics software version 20 (SPSS, Inc., Chicago, IL, USA).

| RESULTS
A total of 175 adult patients with community-acquired RSV-ARI were included in this study ( Figure 1). All cases occurred during the rainy and winter season in Thailand ( Figure 2). The mean age was 76 AE 12.7 years, and 165 (94.3%) patients had one or more coexisting medical conditions. One hundred and fifty-nine (90.6%) patients had infiltrates on chest radiograph (Table 1). Seventy-eight (44.6%) patients met the diagnostic criteria for severe ARI. Thirty-six (20.6%) patients required invasive mechanical ventilation, 11 (6.3%) required vasopressor, and 56 (32%) were classified as severe ARI by IDSA/ATS minor criteria for severe CAP. Seven (4%) patients required invasive mechanical ventilation later during the course of hospitalization.
Clinical outcomes according to ARI severity are shown in Table 2.
Of those, 64 (64.6%) received treatment within 24 h after admission, and 89 (89.9%) received treatment within 48 h after admission. The most common dosing regimen prescribed was 600-mg loading, followed by 200 mg three times a day for 7 days. Patients who were likely to receive treatment with ribavirin were patients with chronic lung diseases, severe ARI, and patients who had infiltrates on chest radiograph (Table 3). There was no document of serious adverse event related to ribavirin leading to cessation of treatment. Compared with patients who did not receive ribavirin, patients who received ribavirin tended to have lower hemoglobin level during hospitalization. Nevertheless, there was no significant difference in blood transfusion requirement and the change of white blood cell count (Table 3). Fiftytwo (29.7%) patients received treatment with systemic corticosteroids, and 157 (89.7%) patients received inhaled bronchodilator therapy during hospitalization. Patients who received treatment with ribavirin were more likely to receive treatment with systemic corticosteroids or inhaled bronchodilator ( Table 3). The clinical outcomes associated with these medication treatments are shown in Table 2.  Table 2.

| Outcomes
Overall mortality within 30 days was 7.4%. Mortality among patients with non-severe ARI and severe ARI was 1.04% and 15.4%, respectively. Multivariate Cox regression analysis revealed estimated glomerular filtration rate (eGFR) < 50 ml/min/1.73 m 2 , severe ARI, systemic corticosteroids, and bacterial infection to be independent predictors of 30-day mortality. Ribavirin treatment was the only factor independently associated with lower risk of mortality (Table 4 and Figure 4).
Patient demographic data and clinical characteristics and associated hospital-free days are shown in Tables S2-S4. Multivariate analysis revealed severe ARI, systemic corticosteroids, bacterial infection, lower hemoglobin, bronchodilator use, and non-respiratory nosocomial infection to be independently associated with longer time to F I G U R E 1 Flow chart of included patients with community-acquired RSVassociated ARI. ARI, acute respiratory illness; RSV, respiratory syncitial virus hospital discharge alive within 30 days after admission (Table 4 and

| DISCUSSION
We found the RSV-ARI patients to be older adults with many coexisting medical conditions. The mortality rate was 7.4%, which is comparable with previously reported mortality rates of 6%-13% in patients hospitalized with RSV infection. 3,4,6,7,[21][22][23] We also found that treating these infections requires substantial health care utilization. The average length of stay was 9 days, and approximately 25% of patients required invasive mechanical ventilation.
Disease severity at admission, low eGFR, bacterial infection, and systemic corticosteroids use were associated with increased mortality. Treatment with oral ribavirin was the only factor associated with reduced mortality. Factors previously reported to be associated with mortality in patients hospitalized with RSV infection were advanced age, 6 6 and bacterial coinfection. 6,[24][25][26] There is currently no scoring system specifically designed to assess the severity of patients hospitalized with RSV infection. We used IDSA/ATS criteria for severe CAP to define severe ARI due to its good performance for identifying patients at risk for deterioration or escalation of care, ICU admission, and mortality. 20 Moreover, these criteria are based mainly on severity of pneumonia rather than other factors, such as age or comorbidities, and they are simple to apply.   Currently, the standard of care for the management of RSV infection in adults is mainly limited to supportive care. To our knowledge, the present study is the first to evaluate the effect of oral ribavirin in non-immunocompromised adults with RSV-ARI. Oral ribavirin treatment was associated with a reduction in mortality of nonimmunocompromised adults with RSV-ARI. Ribavirin had no effect in the univariate model. This may be explained by indication bias characterized by physicians treating more severe patients with ribavirin.
Nevertheless, ribavirin therapy had no effect on duration of hospitalization. The reason for this is suggested to be a consequence of improved survival of more severe patients as a result of their being treated with ribavirin. Similar to the findings in other studies, oral ribavirin appears to be a safe and well-tolerated treatment. [12][13][14] The strengths of this study include a homogeneous cohort of adult, non-immunocompromised patients with community-acquired visualization.

FUNDING INFORMATION
This research received no specific grants from any funding agency in the public, commercial, or non-profit sectors.
F I G U R E 4 Kaplan-Meier estimates for overall mortality (A) and discharge alive from hospital (B) within 30 days after admission for patients receiving ribavirin treatment and those not receiving ribavirin treatment. The adjusted hazard ratio (aHR) is provided with the 95% CI and P value from the multivariate Cox regression model (for details, see Table 4)

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.12971.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

SUPPORTING INFORMATION
Additional supporting information may be found in the online version of the article at the publisher's website.