Impact of respiratory syncytial virus disease on quality of life in adults aged ≥50 years: A qualitative patient experience cross‐sectional study

Abstract Background Information about the impact of respiratory syncytial virus (RSV) on quality of life in older adults is limited. This study characterized the patient experience of RSV illness in USA older adults and assessed the content validity of the InFLUenza Patient Reported Outcome (FLU‐PRO) in this population. Methods This qualitative, non‐interventional, cross‐sectional study included hybrid concept elicitation and cognitive debriefing interviews with 30 individuals (age ≥50 years) with polymerase chain reaction‐confirmed RSV diagnosed within 6 months of screening. Targeted literature review was first conducted to inform the development of interview materials. Webcam or telephone interviews were conducted by qualitative researchers using a semistructured interview guide. Interview transcripts were coded and analyzed using Excel and NVivo software. Results All participants reported impacts on daily activities, social activities, and relationships during RSV disease. Physical functioning was impaired in 25 (83%) participants, and 18 (60%) reported not engaging in leisure activities/hobbies. All nine participants who were working reported major impacts on work. Most (n = 28; 93%) described emotional impacts. A majority (n = 19; 63%) reported symptoms lasting beyond the acute disease stage from a week to >1 month. Symptom concepts reported generally matched FLU‐PRO items and domains. Cognitive debriefing indicated that FLU‐PRO was easy to understand and captured participants' experiences of RSV illness. Conclusions This study indicates that RSV disease in adults aged ≥50 years in the USA has substantial impacts on daily life and that the concepts included in FLU‐PRO are appropriate and fit for purpose as a measure of RSV symptoms in this population.


| INTRODUCTION
Human respiratory syncytial virus (RSV) is a major pathogen in pediatric populations, and reinfection may occur throughout life.
Given similar host response, common symptoms of RSV infection are similar to those of other respiratory viruses, including cough, blocked/runny nose, sore throat, and trouble breathing. 1 Research in older adults (specifically, aged ≥65 years) indicates RSV as an important pathogen in winter respiratory illness. 2 In the United States of America (USA), annual RSV incidence is 1-7% in adults aged ≥50 years. 3,4 The risk of RSV infection requiring medical attention 4 or hospitalization/emergency department attendance 5

increases with
age, and a majority of individuals aged 50-64 years, hospitalized with RSV, report ≤1 chronic comorbidity. 6 Groups at high risk of severe RSV illness include older adults (especially aged ≥65 years), adults with chronic heart or lung disease, and adults with weakened immune systems. 7 RSV infection requiring hospitalization in older adults may result in prolonged functional decline. A recent study of 39 patients aged ≥60 years, hospitalized with RSV infection in the USA, and with functional assessment data at 2 months of follow-up showed that 23% of older adults required a higher care level at discharge, and activities of daily living scores were decreased at 2 months compared with baseline in 36%. 8 Frail older adults are especially vulnerable to functional decline following infection. 9 However, although RSV illness is recognized as an important disease in older adults, there is limited qualitative evidence exploring older adult patients' experiences with RSV illness and its impact on quality of life (QoL).
Exploring the symptoms and QoL impact of RSV illness in older adults needs a valid patient-reported outcome (PRO) measure that can capture patients' experiences of RSV. The InFLUenza Patient Reported Outcome (FLU-PRO; Leidos Biomedical Research, USA) is a PRO measure developed to assess symptoms of viral respiratory illness in adults. 10 The measure contains 32 items in six domains, which evaluate the severity, in the past 24 h of symptoms, in the nose (four items), throat (three items), eyes (three items), chest/respiratory (seven items), gastrointestinal (four items), and body/systemic (11 items), and has been shown to produce scores that are well defined, reliable, valid, and responsive to change in influenza-positive and influenza-negative adults. 11,12 Clinical symptom concepts are similar across respiratory viral illnesses in older adults, indicating that the FLU-PRO could be suitable for use in RSV. The reliability and validity of FLU-PRO as an outcome measure has been demonstrated in a Phase II clinical trial of an experimental RSV vaccine in adults aged ≥60 years. 13 This indicates that the FLU-PRO measurement properties have been validated in an older adult RSV population, although qualitative content validation has been lacking until the present study. Concept elicitation and cognitive debriefing are recommended as important steps toward establishing content validity in any PRO measure by the USA Food and Drug Administration (FDA) 14 and the leading professional society for health economics and outcomes research, the International Society for Pharmacoeconomics. 15 The objectives of the present study were twofold: first, to characterize the patient experience and QoL impacts during and after an episode of RSV illness in USA older adults (aged ≥50 years) and identify concepts of importance to measure in this population, to inform the development of a conceptual model of RSV illness, including both proximal and distal impacts. Proximal impacts refer to health effects resulting directly from RSV symptoms, for example, difficulty in breathing having an impact on physical functioning. Distal impacts refer to those beyond the direct results of RSV symptoms, such as impacts on emotional or social functioning. The second objective is to assess the content validity of the FLU-PRO as a tool for capturing the patient experience (symptom presence, severity, and frequency) of RSV illness in older adults.

| Study design
This qualitative, cross-sectional, non-interventional, observational study included hybrid concept elicitation and cognitive debriefing interviews with 30 individuals (age ≥50 years) who had RSV within 6 months of screening. A targeted literature review was first conducted to inform the development of the conceptual model, the study protocol, and supporting materials for the qualitative interviews that were subsequently submitted to an independent review board. Figure 1 shows an overview of the study design.

| Literature review
PubMed was searched for articles published between September 2009 and September 2019 that focused on patient-reported concepts of RSV burden, impacts on QoL, risk factors, signs, symptoms, treatments, and comorbid or chronic conditions associated with RSV (Appendix S1). In addition, relevant sources from the reference lists of selected manuscripts were reviewed, and unstructured searches using Google Scholar and RSV support/advocacy group websites were used to fill in any gaps. 1 Only English-language publications were included.

| Sample size and saturation analysis
The sample size was estimated with the intent to reach saturation, 14,17 when further interviews no longer introduce new concepts or themes. Previous research has suggested that 97% of symptom concepts emerge by the 20th interview. 18 As this study included sample quotas related to age, ranging from 50 to over 80 years, the sample size was set at 30 participants to maximize the likelihood of capturing at least 97% of key concepts within an older adult population. Saturation analysis was conducted using a process examining concepts and themes across sets of consecutive interviews. 15,17,19 Transcripts were coded in six sets of five transcripts each. An initial coding structure was determined after coding the first set and modified to account for new concepts that emerged while coding each subsequent set.

| Recruitment and screening
Potential participants were screened by telephone, and those who were interested were asked to provide a physician-confirmed polymerase chain reaction diagnosis of RSV, received within the past 6 months, to be eligible. Participants were also required to be aged ≥50 years; live in the USA; be able to read, write, and fully understand the English language; and be willing and able to participate in an interview for 90 min.

| Study procedures
All participants read and signed an informed consent form prior to their scheduled interview. Interviews were conducted between January 8, 2020, and March 20, 2020, by experienced and trained qualitative researchers using a semistructured interview guide. The guide included a list of instructions for the interviewer to ensure that each interview was conducted consistently. All interviews were conducted via telephone or webcam and audio recorded. Following the concept elicitation segment of the interview, which explored participants' descriptions of their experiences of RSV, a cognitive debriefing exercise was conducted where participants completed the FLU-PRO using the think-aloud method. 20 Participants then answered a set of structured queries, to gather patient feedback on all elements of the FLU-PRO, including instructions, items, response options, and recall period.
Audio files of interviews were transcribed verbatim. All interview transcripts were content coded by two trained qualitative analysts and confirmed by the principal investigator. Three transcripts (10%) were double coded to ensure reliability between coders. Discrepancies between coders were reviewed, discussed, and resolved by the research team in scheduled consensus meetings.

| Concept elicitation
Concept elicitation data were coded and analyzed using constant comparison 21,22 in accordance with grounded theory analysis methods. 17,23 Concepts emerging from participants, that is, rather than imposing an a priori theory, were identified. All transcripts were reviewed using NVivo qualitative research software

| Cognitive debriefing
Cognitive debriefing data, from the same set of patients, were coded and analyzed using a Microsoft Excel database to systematically summarize participants' feedback on the understandability and relevance of the instrument. Codes were assigned to each patient-reported issue according to its likely impact on comprehension and validity of data and whether the issue was reported spontaneously by participants.

| Demographic and clinical characteristics
A total of 30 interviews were conducted, and the demographic and clinical characteristics of the respondents are summarized in Table 1.
The sample included 15 individuals 50-64 years of age, 12 individuals 65-79 years of age, and 3 individuals ≥80 years of age (Table 1). Most participants (n = 18; 60%) reported at least one comorbid condition such as asthma, chronic obstructive pulmonary disease (COPD), congestive heart failure, hypertension, emphysema, and irritable bowel syndrome representing the real-world population with RSV disease. Most participants (n = 22; 73%) had been treated in the outpatient setting. Eight (27%) had been treated in the hospital/emergency room, including four adults aged ≥65 years who had been hospitalized. Table S1 summarizes the number of codes identified in each set of transcripts. Of the 65 codes identified in total, 58 (89%) were identified in the first set and a further 5 (8%) in the second and third sets.

| Saturation analysis
Few new concepts of importance emerged in the last sets, suggesting that 30 interviews were sufficient to reach saturation. Table 2 presents the RSV symptoms reported by participants during the interview, spontaneously or when probed. Symptoms generally matched those listed in the FLU-PRO. Gastrointestinal symptoms such as diarrhea and vomiting were reported by 12 (40%) and 7 (23%) participants, respectively. These symptoms were concentrated in participants aged ≥65 years; 10 (83%) reports of diarrhea and 5 (71%) reports of vomiting were in this age group.

| Signs and symptoms
The symptoms reported as most bothersome were coughing (n = 12; 40%), trouble breathing (n = 11; 37%), fever or feverish (n = 8; 27%), and body aches or pains (n = 7; 23%). There were 52 signs/symptoms reported in total, 20 of which were not described by participants using the same language as FLU-PRO items, such as fever or feverish, fatigue or lack of energy, wheezing, shortness of breath, chest pain, ear pain or pressure, and hoarseness. However, as confirmed by patients during cognitive debriefing, many of these additional symptoms were captured by existing items in FLU-PRO. For example, all participants reporting wheezing (n = 13) and shortness of breath (n = 12) reported that "trouble breathing" in the FLU-PRO

| Impacts on QoL
All 30 participants reported impacts of RSV illness on productivity. Eighteen (60%) reported decreased vitality that resulted in not engaging in leisure activities or hobbies. All nine participants who were working reported major impacts on work, for example: So, I was at work, you know, during that time but after that, after I went to see the doctor and then I took about another ten days off ….
Time off work ranged from 3 days to 3 weeks, typically on the advice of a healthcare provider. Those who remained at work or returned before symptoms had fully resolved reported reduced productivity and efficiency at work due to lack of energy. Sleep disruptions at night were reported by 22 (73%) participants, for example: Sleeping was horrible because the coughing just constantly, all night long, kept coughing ….
A majority of participants (n = 19; 63%) reported symptoms, such as cough, throat irritation, and tiredness, that lingered beyond the acute disease stage from a week to over a month and reported that it was more difficult to recover from RSV than previous respiratory illnesses they had experienced. Half of the participants (n = 15) described current impacts, at the time of the interview, on physical functioning, leisure activities, productivity, relationships or social activities, and emotional functioning.

| Cognitive debriefing: Participants' feedback on FLU-PRO
All participants reported that the FLU-PRO instructions were easy to understand, and the 24-h recall period would be easy to remember.
Most (n = 27; 90%) indicated that the length was appropriate. The majority of participants (n = 22; 73%) reported they would be able to complete the questionnaire during different stages of RSV illness, whereas eight (27%) reported that it may be difficult to complete during the worst phase of their RSV illness.
Most reported that the items accurately reflected their RSV symptoms. Of the 32 symptoms in the FLU-PRO instrument, 29 were reported as relevant by at least half the participants (Table S2).
Gastrointestinal symptoms such as stomachache (47%), vomiting (37%), and diarrhea (47%) were less commonly reported. Eight participants (27%) reported difficulty with answering "stomachache," because they considered their abdominal muscles being sore or tight from coughing, having an empty stomach from lack of appetite, or medication side effects. Two participants reported that the FLU-PRO did not miss any symptoms, but it would be helpful to include additional questions to capture their whole experience including impacts on daily life, treatment experiences, illness phases encountered, and their environment during their RSV illness. These participants enjoyed sharing their experience with the interviewer and wanted a way to capture this full experience as part of the instrument. The FLU-PRO includes three sets of response options evaluating concept intensity and frequency: • not at all, a little bit, somewhat, quite a bit, and very much; • never, rarely, sometimes, often, and always; and • 0 times, 1 time, 2 times, 3 times, and 4 or more times.
All participants found the second and third sets easy to understand, and all except one found the first set easy to understand.
Nineteen of the 29 participants who were asked (66%) reported that the FLU-PRO comprehensively captured their experiences with no missing symptoms. Eight different participants reported missing symptoms, but these symptoms varied across the interviews. Three participants mentioned preferring the inclusion of one specific question regarding fever rather than answering the fever symptoms listed in the FLU-PRO like "felt hot," "felt cold," and "chills or shivering"; however, participants were accurately able to describe their fever using these existing items in the FLU-PRO.
Eight additional signs and symptoms were reported, each by a single participant, and included wheezing, general malaise, dry skin, constipation, itchy nose, fatigue, lack of energy, and chest pain.
Although the participants described the sound of their breathing as "wheezing," which is a sign not a symptom, what they felt was the symptom of "trouble breathing." As wheeze is a medical term used to describe the presence of adventitious sound, and which may also be confused with other sounds such as crackles and rhonchi, it is more appropriate that this sign is assessed by a trained medical practitioner, rather than self-reported in a PRO. Even in a medical setting, there can be disagreement on the classification of these sounds. 25 Some of these signs and symptoms, such as general malaise and lack of energy, are already included in the FLU-PRO using different language.   John H. Powers III https://orcid.org/0000-0002-5150-5119 ENDNOTE 1 A report from the National Foundation for Infectious Diseases was added to the literature review using this approach. 16