Comparative assessment of reported symptoms of influenza, respiratory syncytial virus, and human metapneumovirus infection during hospitalization and post‐discharge assessed by Respiratory Intensity and Impact Questionnaire

Abstract Background The hospitalized acute respiratory tract infection (HARTI) study used the Respiratory Intensity and Impact Questionnaire (RiiQ™) Symptom Scale, derived from FluiiQ™, to assess and compare the burden of respiratory infection symptoms for patients with influenza, respiratory syncytial virus (RSV), and human metapneumovirus (hMPV) infection, with or without core risk factors (CRF) (age ≥65; chronic heart, renal, obstructive pulmonary disease; asthma). Methods This was a prospective cohort study in adult patients hospitalized with acute respiratory tract infection (40 centers, 12 countries) during two consecutive influenza/RSV/hMPV seasons (2017–2019). The RiiQ™ Symptom Scale and EuroQol 5‐Dimensions 5‐Levels (EQ‐5D‐5L) were assessed by interview at two timepoints during hospitalization and at 1, 2, and 3 months post‐discharge. Results Mean lower respiratory tract (LRT) symptom scores were higher for RSV and hMPV participants compared to influenza at 48 h after enrollment/early discharge (p = 0.001) and 3 months post‐discharge (p = 0.007). This was driven by LRT symptoms, including shortness of breath (SOB) (p < 0.01) and wheezing (p < 0.01) during hospitalization, and SOB (p < 0.05) and cough (p < 0.05) post‐discharge. Participants with CRF reported more moderate‐to‐severe SOB (p < 0.05) and wheezing (p < 0.05) compared to CRF(−) participants post‐discharge. EQ‐5D‐5L scores were moderately associated with RiiQ™ LRT and systemic symptoms domains. Conclusions Results from the HARTI study suggest that in the study population, LRT symptoms were more severe for RSV and hMPV groups and for patients with CRF. RiiQ™ Symptom Scale scores shows a moderate association with EQ‐5D‐5L indicating that the RiiQ™ may provide useful insights and offer advantages over other measures for use in interventional RSV adult clinical studies.

Respiratory syncytial virus (RSV) causes acute respiratory tract infection (ARTI) that presents with similar symptoms to influenza and results in substantial morbidity and mortality, particularly among older adults aged ≥65 years; however, there is limited evidence of symptom burden associated with RSV in adults. [3][4][5] PROs that are designed for influenza are often used or adapted for patients with RSV and other ARTIs. 2  The clinical diagnosis of ARTI and the decision to hospitalize the patient were made according to local standard of care (SOC) practices.
The enrollment period followed the local respiratory viral infection seasonal progression. Participants were consented and enrolled in the main study within 24 h after admission. Viral testing was done as part of SOC or by study-specific molecular diagnostic test if not performed as SOC. Participants with influenza (capped to 380 consecutive subjects), RSV, or hMPV infection confirmed by reverse transcriptionpolymerase chain reaction were invited to enroll in the substudy, which comprised a hospitalization phase with 3 visits (enrollment, 48 h after enrollment/early discharge, and up to 2 days prior to discharge), and follow-up telephone interviews at 1, 2, and 3 months post-discharge ( Figure 1). Additional details on study design have been presented elsewhere. 9

| Data collection
The RiiQ™ was developed from the FluiiQ™ and assesses lower respiratory tract (LRT), upper respiratory tract (URT), and systemic symptoms (Table 1) The EQ-5D-5L measures health-related quality of life (HRQoL) for cost-effectiveness analysis based on five dimensions (Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression) rated on five levels ranging from "No Problems" to "Extreme Problems." 11 In addition, the EQ-5D Visual Analog Scale (EQ-VAS) records a participant's self-rated health overall. 12 Clinical information and PROs were collected during hospitalization and post-discharge. The RiiQ™ Symptom Scale and EQ-5D-5L were administered as interviews during hospitalization (at 48 h after enrollment/early discharge and within 2 days before discharge) and follow-up. If the participant was discharged within less than 72 h from the enrollment visit (early discharge), post-baseline assessments were performed on the day of discharge, so the assessment within 2 days before discharge was not available. If the participant could not be interviewed, RiiQ™ Symptom Scale and EQ-5D-5L were not assessed.

| Statistical analysis
The RiiQ™ symptoms domain scores were calculated by averaging the individual symptom severity scores. At each visit, RiiQ™ symptom scores were summarized overall, by pathogen, and by presence of core risk factors (CRF) (age ≥65 years, chronic obstructive pulmonary disease [COPD], asthma, chronic heart or chronic renal disease) for progression to severe disease and presence of long-term sequalae and compared among groups using Kruskal-Wallis test. Individual RiiQ™ symptom scores were compared among pathogens and by presence/ absence of CRF (as a binary variable, irrespective of the number of CRFs reported) using Fishers Exact Test to compare symptom severity. P values were not adjusted for multiple comparisons. The EQ-5D-5L Index Value was calculated by assigning a level code of 1-5 ("No Problems" to "Extreme Problems") to each of the 5 dimensions, and the health state obtained was then mapped to a single index value by using the crosswalk value set available for the United Kingdom. 13 Scatterplots with Spearman correlation coefficients compared RiiQ™ Symptom Scale scores with EQ-VAS score and EQ-5D-5L index scores at 48 h after enrollment/early discharge and 1, 2, and 3 months post-discharge.

| RESULTS
Of the 3861 main study participants, 366 (9.5%) influenza-positive, 238 (6.2%) RSV-positive, and 100 (2.6%) hMPV-positive participants were enrolled in the substudy. The mean (SD) age of substudy F I G U R E 1 Respiratory Intensity and Impact Questionnaire (RiiQ™) and EQ-5D-5L responders at substudy assessment by time of assessment and pathogen. EQ-5D-5L: EuroQol 5 Dimensions 5 Levels; hMPV: Human Metapneumovirus; RiiQ™: Respiratory Intensity and Impact Questionnaire; RSV: Respiratory Syncytial Virus. This figure presents the number of responders (and % of total pathogen group enrolled in substudy) at each assessment timepoint for the patient-reported outcomes of interest (RiiQ and EQ-5D-5L). a If a participant was hospitalized for a short period (i.e., <72 h) or transferred to another ward, an early discharge assessment was performed on the day of discharge and 75.3% of participants at 1, 2, and 3 months post-discharge, respectively ( Figure 1).

| DISCUSSION
The HARTI substudy aimed to describe the disease burden in adults hospitalized with influenza, RSV, and hMPV infection during hospitalization and up to 3 months post-discharge. The novel RiiQ™ Symptom Scale was used to describe participants' self-rated symptom severity. RiiQ™ Symptom Scale scores demonstrated significantly increased symptom severity for participants with either RSV or hMPV infection compared to those with influenza. This was particularly driven by the LRT domain. At 48 h after enrollment/early discharge, a significantly greater frequency of moderate-to-severe wheezing and SOB for RSV and hMPV compared to influenza was observed. Additionally, at 3 months post-discharge, significant differences persisted with more moderate-to-severe SOB and cough observed for RSV and hMPV infected patients. These results suggest that wheezing is an important component of the patient-reported symptoms related to RSV, hMPV and influenza. Compared with influenza, more severe LRT symptoms were reported for RSV and hMPV participants during F I G U R E 6 Frequency of participants with moderate-to-severe symptoms by presence of CRF and visit. CRF: Core risk factors (age ≥65, chronic heart or renal disease, chronic obstructive pulmonary disease [COPD], asthma). 95% Confidence intervals calculated using Wilson's method. p values based on Fisher-exact test: * p < 0.05; ** p < 0.01; *** p < 0.001. If a participant was hospitalized for a short period (i.e., <72 h) or transferred to another ward, an early discharge assessment was performed on the day of discharge. RiiQ™ data were available for 599 (85.0%) participants at 48 h after enrollment/early discharge, 249 (35.3%) participants at 2 days before discharge (for those hospitalized >3 days), and 558 (  À0.44). The EQ-5D-5L Index Value and EQ-VAS have previously been shown to be associated with other disease-specific questionnaires, including the Chronic Respiratory Disease Questionnaire. 16 LRT and systemic symptoms, domains as measured using RiiQ™, appear to be F I G U R E 7 Association between Respiratory Intensity and Impact Questionnaire (RiiQ™) score and EQ-5D-5L index value score over time. EQ-5D-5L = EuroQol 5 Dimensions 5 Levels; RiiQ™ = Respiratory Intensity and Impact Questionnaire. Small random jitter is applied to the data points to allow for a clearer view on the data points. Spearman correlation coefficient (R) is presented. A linear regression line (with 95% confidence interval) is added to aid visualization. Co-infections (N = 5) were excluded. EQ-5D-5L Index Value Scores <0 indicate a health state worse than death (likely due to underlying conditions) moderately associated with poor health status, as measured using EQ-5D-5L.
A limitation of this study is that the first PRO assessment was administered 48 h after the pathogen was identified and the enrollment of the patient in the substudy was confirmed. The frequency of moderate-to-severe symptoms may have been greater at hospital admission; future studies may explore whether a greater difference would be observed among the three pathogen groups at the time of pathogen diagnosis, when symptoms may be most severe. Assessments performed at 48 h after enrollment were pooled with those performed at early discharge (roughly 10% of the analysis set); inclusion of early discharge patients (<3 days) may have resulted in less severe disease observed at this timepoint. By study design, having an evaluation 48 h after enrollment, the second one 48 h before discharge would be performed only for patients with longer hospitalization. The "within 2 days before discharge" time point had considerable missing data, due to the challenges of operational implementation of the last assessment prior to discharge; however, the compliance with PRO data collection was high for the time points before and after the hospital discharge. The pre-infection symptoms were not available; therefore, one cannot distinguish between the long-term respiratory disease sequela and symptoms related to the underlying chronic condition for the CRF(+) group (e.g., age ≥65 years, COPD, asthma).
Overall, results from the HARTI study allow for comparative assessment of symptoms between the 3 most common viral respiratory pathogens and provide novel evidence regarding symptom severity and HRQoL burden for influenza, RSV, and hMPV. The RiiQ™ is currently being used in clinical development for RSV vaccine and antiviral studies, and the data presented in this manuscript support continued use of the RiiQ™ for characterization of these patients. 8

| CONCLUSION
The majority of hospitalized influenza, RSV and hMPV patients were older than 65 years, with the RSV group slightly older compared with influenza group. RiiQ™ showed greater incidence of moderate-tosevere LRT symptoms for RSV and hMPV compared with influenza.
Additionally, presence of CRF was associated with greater moderateto-severe symptom burden during hospitalization and post-discharge compared to those without CRF, with significantly higher LRT and systemic symptom domain scores at 1, 2, and 3 months postdischarge. The association between RiiQ™ Symptom Scale and EQ-5D-5L is encouraging and warrants further exploration of RiiQ™ for pharmaceuticals development.

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