Raising the patient’s voice in influenza research and care: a systematic review of patient-reported outcomes

Abstract

Background

Patient-reported outcomes (PROs) enable the evaluation of patients’ perspectives in relation to their health and well-being. This paper reviews PRO instruments, regulatory guidelines, and product labels for influenza and influenza-like illness (ILI) to recommend strategies for their optimal use in clinical research.

Methods

We conducted a systematic literature review of publications and electronic records reporting PROs for influenza and influenza-like illness.

Results

The systematic search identified 112 items, of which 36 were included in the final analysis (20 clinical research publications; two national guidelines; eight influenza intervention product labels; and six PRO instrument descriptions). We identified influenza-specific PRO instruments developed to assess symptom severity and impact of influenza, or the acceptability and safety of influenza interventions; several of these have been used in clinical research, enabling a better understanding of the impact of influenza and influenza interventions. However, further research on the use of influenza-specific PROs in routine care settings is needed.

Conclusions

Based on these findings, we describe opportunities and challenges for PROs and propose recommendations to facilitate wider implementation of PROs in influenza research and patient care.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12879-026-12821-w.

Introduction

Influenza is an acute respiratory infectious disease that spreads easily, with rapid transmission in crowded areas [1, 2]. Influenza affects hundreds of millions of individuals worldwide causing substantial morbidity, with an estimated 294,000 to 518,000 global deaths caused by influenza each year, equating to approximately 2% of all annual respiratory deaths [3]. Acute influenza infection can result not only in a high symptom burden for individuals but can also cause a wide range of severe complications including exacerbation of underlying chronic conditions and increased risk of diseases across organ systems, such as cardiovascular disease [4, 5]. Beyond these severe clinical outcomes, influenza imposes a substantial symptomatic burden—characterized by respiratory and systemic symptoms, such as cough, fever, fatigue, and myalgia—that significantly impairs health-related quality of life and restricts daily activities [6]. Furthermore, this burden translates into considerable economic costs due to workplace absenteeism and productivity loss, with adults missing an estimated 1 to 4 days of work per influenza episode [7].

Patient-reported outcomes (PROs) are a category of health-related endpoints that rely on direct input from patients and can encompass various aspects of their lived experience of conditions, including health status and overall well-being, symptoms, functional abilities, emotional state, quality of life (QoL), and treatment satisfaction [8, 9]. PROs are of fundamental importance to healthcare, as they serve as a valuable means of capturing a patient’s perspective on their health and healthcare experiences, thereby enabling healthcare professionals to provide a more personalized and holistic approach to care and allowing health authorities to make more informed public health decisions [8]. Furthermore, guidance documents from health authorities inform the development, selection, and use of PROs in clinical trials as a way of fostering patient-centered drug and vaccine development [8, 10].

There are numerous examples of generic health status measures that are used across clinical research and by health authorities, such as the widely used EuroQol five dimensions (EQ-5D) and the 36-item short form health survey (SF-36) in their multiple forms [11–13]. Despite the value of such generic PRO instruments, which can allow for the comparison of endpoints across multiple heterogenous indications, they are designed to assess general aspects of health, and so are less sensitive to the capture of disease-specific attributes, potentially underestimating the real value of interventions [9, 14]. Several disease-specific PRO measures are available for the evaluation of some conditions, for example, the European Organization for Research and Treatment of Cancer QLQ-30 [15], and the Hemophilia Treatment Experience Measure (Hemo-TEM) [16]. Use of more targeted PRO instruments such as these may allow for more detailed evaluation of the true impact on patients of a specific disease or condition [17]. Adding a patient-centered perspective to bridge understanding with traditional measures for influenza is particularly important given that patient experiences of influenza can vary substantially from person-to-person [1].

The objective of this study is to comprehensively review Patient-Reported Outcome (PRO) instruments for influenza and influenza-like illness (ILI), encompassing existing measures, regulatory guidelines, and product labels. By evaluating this landscape from a broad perspective—including current clinical applications and health authority requirements—this paper aims to identify gaps and provide actionable recommendations for the effective implementation of PROs in influenza research.

Methods

Eligibility criteria

In this systematic literature review, eligible records included [1]: psychometric validation studies of PRO instruments for influenza/ILI [2]; clinical trials and observational studies implementing these PROs; and [3] regulatory documents (guidelines, approved product labels) describing PRO utilization. We excluded animal studies, reviews without primary data, and publications not available in English.

Information sources and search strategy

A systematic search was conducted from June to October 2023 across the MEDLINE database and COA-specific databases from the ePROVIDE platform. ePROVIDE is a centralized, subscription-based library managed by Mapi Research Trust that hosts comprehensive resources on Clinical Outcome Assessments (COAs). Within this platform, three specific databases were consulted: PROQOLID, which catalogs descriptive and psychometric information on existing COA instruments; PROLABEL, which indexes international drug labels containing COA claims; and PROINSIGHT, which compiles regulatory guidelines and critical reviews. These resources enabled the collection of data on PROs in influenza research studies, as well as regulatory guidelines for their utilization and inclusion in product labels for influenza interventions. Following the PICO (Population, Intervention, Comparison, Outcome) framework [18], the search prioritized broad coverage of the condition to capture all management strategies. Consequently, the overarching Medical Subject Heading (MeSH) terms “Influenza, Human” and “Influenza” were selected to serve as catch-all categories for therapeutic interventions (antivirals and symptomatic treatments), ensuring that no relevant treatment studies were excluded. The specific term “influenza vaccines” was explicitly added to ensure high sensitivity for prophylaxis-related PROs (e.g., injection site pain), which might otherwise be distinct from disease symptomology. Additional keywords included: “patient-reported outcome measures”, “influenza-like illness”, “Influenza Impact Wellbeing Scale”, “Influenza Symptom Severity Scale”, “vaccinees’ perception of injection”, “Influenza Intensity and Impact Questionnaire”, “Respiratory Intensity and Impact Questionnaire”, and “InFLUenza Patient-Reported Outcome”.

Study selection and data extraction

Two reviewers (EMM and PMA) conducted independent assessments of all references according to the search eligibility criteria. Full texts of references were comprehensively screened to identify relevant literature. Any discrepancies or disputes regarding eligibility were resolved through discussion between the two reviewers. The information extracted from the identified articles included: publication year, objective(s), target population, instrument, covered domains, timepoint collection, and principal findings. A formal risk of bias assessment of the included clinical trials was not performed, as the primary objective was to identify the utilization of PRO instruments rather than to synthesize intervention efficacy. Instead, an evaluation of the psychometric properties reported in the included PRO validation papers was performed, as this was considered more relevant for the objectives of this review.

Results

Study selection and characteristics

The literature search identified a total of 112 items: 57 articles from MEDLINE and 55 items (17 articles; 38 electronic records) from the ePROVIDE platform (PROQOLID, PROLABEL, and PROINSIGHT). A comprehensive overview of the search process is shown in the PRISMA diagram (Fig. 1).

Fig. 1.

PRISMA flow diagram of the article selection process in the systematic literature review. PRO: patient-reported outcome

Following removal of duplicated articles (n = 11), application of the pre-specified eligibility criteria and a comprehensive full-text evaluation, 20 articles and 16 electronic records were included in the final analysis. Sixty-five records were excluded; the reasons for exclusion were: no PRO endpoint was included, the study design was not the target, and the population was not the target.

Two influenza-related instruments were excluded: the first because it measures observer-reported outcomes rather than PROs (the Canadian Acute Respiratory Illness and Flu Scale [CARIFS], developed to assess symptom severity and impact of acute respiratory diseases in children ≤12 years old and subsequent impact on their caregivers); the second because the caregiver was the target population rather than the patient (the Care-ILI-QoL questionnaire, developed to assess the quality of life of caregivers of children with ILI).

Of the 36 items included in the final analysis, 20 articles described the development, psychometric properties, or clinical application of PRO instruments (Table 1) [6, 19–37], two were regulatory documents guiding the use of PROs in influenza clinical trial design [38, 39], and eight indicated the inclusion of PROs in the clinical section of product label claims (Table 2) [40–47]. The remaining six records detailed digital descriptions of the eligible PROs; these records were used to detail the domain(s) of PRO instruments but are not discussed

Table 1.

Identified PRO instruments used in influenza clinical research

PRO instrument	Domain(s) of PRO instrument	Author, year	Study population	Timepoint for PRO instrument
Symptom severity
Influenza Symptom Severity (ISS) scale	Respiratory symptoms (three items), systemic symptoms (eight items)	Osborne RH, et al. 2000 [19]	Adults (≥18 years old) with ILI	Daily for 8 days
		Treanor JJ, et al. 2000 [20]	Adults (18 to 65 years) with acute influenza	Twice daily for 21 days
InFLUenza Patient-Reported Outcome (FLU-PRO)	Nose (four items), throat (three items), eyes (three items), chest/respiratory (seven items), gastrointestinal (four items), body/systemic (11 items)	Powers JH, et al. 2016 [21]	Adults (≥18 years old) with laboratory-confirmed influenza	Within 14 days of diagnosis
		Powers JH, et al. 2018 [22]	Adults (≥18 years old) with acute influenza symptoms	Daily for up to 14 days
		Powers JH, et al. 2018 [23]	Adults (≥18 years old) with acute influenza	Daily for 14 days
		Han A, et al. 2018 [24]	Healthy adults (18 to 40 years old)	The evening of Day −1 and the morning of Day 0 (preintervention) and then twice daily for 14 days and once on Day 28
		Hershberger E, et al. 2019 [25]	Adults (18 to 65 years old) with laboratory-confirmed influenza	Daily for 10 days
		Hsieh YH, et al. 2021 [26]	Adults (≥18 years old) with laboratory-confirmed influenza	Daily for 14 days
		Han A, et al. 2021 [27]	Healthy adults (18 to 45 years old)	Not specified
		Leroux-Roels I, et al. 2022 [28]	Healthy adults (18 to 65 years old)	Up to 180 days post-vaccination
InFLUenza Patient-Reported Outcome Plus (FLU-PRO Plus)	Nose (four items), throat (three items), eyes (three items), chest/respiratory (seven items), gastrointestinal (four items), body/systemic (11 items), senses (loss of taste and smell)	Gander J, et al. 2022 [29]	Adults (≥18 years old) with ILI or COVID-19	Daily for 14 days
		Chrenka E, et al. 2023 [30]	Adults (≥18 years old) with ILI or COVID-19	Daily for 14 days
Symptom severity and impact on quality of life
Influenza Impact Wellbeing Scale (IIWS)	Health (one item), sleep quality (one item), ability to perform usual activities (one item)	Osborne RH, et al. 2000 [19]	Adults (≥18 years old) with ILI	Daily for 8 days
		Treanor JJ, et al. 2000 [20]	Adults (18 to 65 years) with acute influenza	Twice daily for 21 days
Influenza Intensity and Impact Questionnaire (FluiiQ™)	Respiratory symptoms (three items), systemic symptoms (seven items), impact on daily activities (six items), impact on emotions (four items), impact on others (five items)	Osborne RH, et al. 2011 [6]	Adults (≥18 years old) with ILI	Daily for 14 days
		van Essen GA, et al. 2014 [31]	Elderly adults (≥65 years old) with ILI	Daily for 15 days
Respiratory Infection Intensity and Impact Questionnaire (RiiQ™)	Respiratory and systemic influenza symptoms (13 items), impact on quality of life (16 items)	Falsey A, et al. 2021 [32]	Adults (≥18 years old) hospitalized with ARTI	During hospitalization (48 hours after enrollment/early discharge and within 2 days before discharge) and post-discharge
		Osborne RH, et al. 2023 [33]	Adults (≥18 years old) with ARI or hospitalized with RSV	During ARI and follow-up (specific timings differed for each of three trials included)
Impact of influenza vaccination
Vaccinees’ Perception of Injection (VAPI)	Bother from injection-site reactions (six items), arm movement (four items), sleep (four items), acceptability (two items) + five individual items	Chevat C, et al. 2009 [34]	Adults (18 to 60 years old) or elderly adults ( > 60 years old)	21 days post-vaccination
		Hernández-Guerra M, et al. 2012 [35]	Adults (≥18 years old) with chronic hepatitis C	21 days post-vaccination
		Durando P, et al. 2012 [36]	Elderly adults ( > 60 years old)	21 days post-vaccination
Adverse Drug Reaction (ADR) Questionnaire	Adverse events	Dos Santos JP, et al. 2023 [37]	Adults (≥18 years old) and children ( > 6 months old)	7 days post-vaccination

ARI: acute respiratory infection, ARTI: acute respiratory tract infection, COVID-19: coronavirus disease 2019, ILI: influenza-like illness, PRO: patient-reported outcome, RSV: respiratory syncytial virus

Table 2.

Identified PRO instruments described in product labels of influenza interventions

Regulatory agency	Drug	Approval year	PRO endpoint of interest	PRO instrument(s) utilized
US FDA	Relenza (zanamivir) [40]	1999	Time to alleviation or improvement of influenza symptoms	Unknown PRO instrument (five symptoms)
	Tamiflu (oseltamivir) [41]	1999	Time to alleviation of influenza symptoms	Unknown PRO instrument (seven symptoms assessed using a 4-point scale, twice daily) Unknown PRO instrument and assessment type
	Rapivab (peramivir) [42]	2014	Time to alleviation or resolution of influenza symptoms	Unknown PRO instrument (seven symptoms assessed using a 4-point scale, twice daily) Unknown PRO instrument and assessment type
	Xofluza (baloxavir marboxil) [43]	2018	Time to alleviation or improvement of influenza signs and symptoms	Unknown PRO instrument (seven symptoms assessed using a 4-point scale, twice daily)
EMA	Tamiflu (oseltamivir) [44]	2002	Time to alleviation of influenza symptoms	Unknown PRO instrument and assessment type
	Alpivab (peramivir) [45]	2018	Time to alleviation or resolution of influenza symptoms	Unknown PRO instrument (seven symptoms assessed using a 4-point scale, twice daily) Unknown PRO instrument and assessment type
	Dectova (zanamivir) [46]	2019	Fever, upper respiratory tract illness and total symptoms scores	Unknown PRO instrument and assessment type
	Xofluza (baloxavir marboxil) [47]	2022	Time to alleviation or improvement of influenza symptoms	Unknown PRO instrument (seven symptoms) Unknown PRO instrument (seven symptoms)

EMA: European Medicine Agency, PRO: patient-reported outcome, US FDA: United States Food and Drug Administration

PRO instruments in influenza clinical research

Several PRO instruments have been developed, undergone psychometric testing, and subsequently been used in influenza clinical trials (Table 1). These broadly fall into the following categories of assessment: influenza symptom severity [19–30], influenza symptom severity and the impact of influenza [6, 19, 20, 31–33], and the impact of influenza interventions [34–37].

Assessing the severity of influenza

Influenza symptom severity scales are disease-specific PRO instruments that capture the intensity, frequency, and duration of symptoms associated with influenza (e.g. cough, nasal congestion, sore throat, headache, fever, muscle aches, and fatigue). Such tools for use in adults include the discontinued influenza symptom severity (ISS) scale [19, 20], and the more recently developed InFLUenza Patient-Reported Outcome (FLU-PRO) and FLU-PRO Plus questionnaires [21–23, 29]. FLU-PRO is a sixdomain (eyes, nose, throat, chest/respiratory, gastrointestinal, and body/systemic), 32item questionnaire that was developed to examine influenza symptoms, and includes a 5point Likert-type scale scoring system ranging from 0 to 4, to allow measurement of both symptom presence and severity [23]. The FLU-PRO questionnaire has been used in multiple phase 2 studies, including a double-blind, placebo-controlled study on the safety and efficacy of a monoclonal antibody (VIS410) [25], and a randomized, double-blind study on the immunogenicity and safety of a nucleoprotein-based influenza vaccine (OVX836) [28]. Results from clinical studies suggest that FLU-PRO scores are reliable and responsive to change, and FLU-PRO has high adherence and low responder burden [22–24]. The FLU-PRO questionnaire was subsequently modified into the FLU-PRO Plus by adding a seventh domain for sense items (e.g. loss of sense of smell) during the COVID-19 pandemic [29]. Using this modified questionnaire, three symptom clusters successfully discriminated patients with COVID-19 from non-COVID-19 illness and were associated with quality of life and predicted symptom duration [30].

Assessing the severity and impact of influenza

Symptom severity scales have been developed to allow self-reporting of the impact of influenza on patients’ daily lives and emotions. These PRO tools include the Influenza Intensity and Impact Questionnaire (FluiiQ™), developed from the discontinued ISS scale and influenza impact wellbeing scale (IIWS) following thorough psychometric work, and the Respiratory Infection Intensity and Impact Questionnaire (RiiQ™), further evaluated and adapted from the FluiiQ™ [6, 32]. The FluiiQ^TM and RiiQ^TM items are scored using a 4-point scale ranging from 0 to 3, with higher scores denoting worse symptoms and impact [6, 32].

The FluiiQ™ is a five-domain, 25-item PRO tool, which was developed through concept mapping with patients who had recently experienced influenza and through interviews with clinicians [6]. The grounded concept mapping process allowed patients to report their full range of experience of influenza infection, and resulted in the generation of two symptom severity scales (respiratory and systemic) and three impact of influenza scales (impact on daily activities, emotions, and others) [6]. The FluiiQ™ was found to have strong psychometric properties, including excellent evidence of construct validity, reliability, and responsiveness [6]. It has been applied in a range of settings, including in randomized clinical trials to assess the efficacy of inactivated trivalent seasonal influenza vaccines [31].

As mentioned, the FluiiQ™ was further evaluated and adapted into the RiiQ™ to strengthen its application in a broader range of respiratory infections in adults (including respiratory syncytial virus) [32]. The RiiQ™ consequently includes all scales used in FluiiQ^TM (symptom severity and impact of respiratory infection), but with a respiratory symptoms scale that has increased reliability [32]. However, this RiiQ™ validation paper was conducted in populations with Respiratory Syncytial Virus (RSV) or undifferentiated acute respiratory infections (ARI), rather than a dedicated influenza cohort. In two later trials including an influenza, RSV and Human Metapneumovirus (HMPV) cohorts, the RiiQ™ demonstrated construct validity, reliability, and responsiveness, including expected associations with clinical ratings and the 5-level EQ-5D [32, 48].

Assessing the safety and acceptability of influenza interventions

PRO tools have also been developed to assess the safety, perceptions, and acceptance of influenza interventions. This review identified the Vaccinees’ Perception of Injection (VAPI) questionnaire, developed to capture the most immediate side effects of vaccination and a patient’s general attitude to acceptability of vaccination [34–36], and an unknown adverse drug reaction (ADR) questionnaire, used once in the context of safety surveillance of an influenza vaccine [37].

The VAPI questionnaire is a self-administered questionnaire used to assess the acceptance of influenza vaccination and consists of domains measuring bother from injection-site reactions, arm movement, sleep, and acceptability [34]. The psychometric properties of the VAPI questionnaire include face and construct validity, with its scales demonstrating good reliability for assessing the acceptability of vaccine injection [34]. The VAPI questionnaire has subsequently been used in studies assessing the acceptability of influenza vaccines [34–36], although further confirmatory factor analysis would be beneficial to confirm the scoring algorithm and determine if items could be removed, prior to recommending its use.

The ADR questionnaire was a general questionnaire consisting of a comprehensive list of adverse events [37]. Insufficient response scales, limited to the presence or absence of the event, and lack of details regarding its development and psychometric properties suggest that future enhancements are needed to the ADR questionnaire before its use in future clinical settings.

Additional information on the general purpose and procedures for validating and testing the reliability of PRO instruments, along with a description of the key psychometric properties of the PRO instruments described earlier from the papers in which the measures were originally developed, can be found in the Supplementary File S1 [6, 21, 23, 34].

PRO instruments described in product labels and regulatory guidelines

This systematic review extended beyond clinical research studies to also identify descriptions of PROs in regulatory documents, specifically product labels for influenza interventions, limited to those from the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) [40–47], and regulatory guidelines for clinical trial design [38, 39].

As displayed in Table 2, the US FDA and EMA have each approved four influenza interventions over the period from 1999 to 2022 that reference PROs in the clinical section of the product labels. All identified results relate to interventions with the aim of relieving the symptoms of influenza infection [40–47]. The most frequently reported PRO endpoint of interest among these product labels was time to improvement or alleviation of influenza symptoms, including cough, sore throat, nasal congestion, headache, feverishness, myalgia, and fatigue [40–43, 45, 47]. In most studies described within the product labels, the self-reported PRO instrument was unknown, but often comprised tools that used a 4-point response scale range (e.g. “none”, “mild”, “moderate”, “severe”) [41–43, 45]. Although the specific instrument was not named in the product labels, its structural characteristics—specifically the 4-point scale—strongly suggest it is the Influenza Symptom Severity Scale (ISS). This hypothesis is further supported by the temporal alignment between the FDA’s initial regulatory assessments for antivirals (1999) and the subsequent publication of the ISS (2000) [19, 41]. Furthermore, the frequency of PRO administration was not consistently reported. While a twice-daily schedule was explicitly described in some cases [41–43, 45], the majority of product labels—particularly those from the EMA—did not specify the frequency of symptom assessment [6, 23].

The systematic literature search also identified two regulatory documents from the US FDA that described the use of PROs in the design of influenza clinical trials [38, 39]. In the US FDA (2011) regulatory document ‘Influenza: Developing Drugs for Treatment and/or Prophylaxis’, PROs are recommended for measuring the signs and/or symptoms of influenza as both primary (antiviral medications) and secondary (prophylaxis treatment) endpoints [38]. In particular, industry sponsors are encouraged to provide evidence for the ability of interventions to directly measure how a patient feels, functions, or survives, potentially using self-assessments (e.g. use of diary cards) [38]. In the US FDA (2021) regulatory document ‘Clinical Outcome Assessment (COA) Compendium’, PROs are recommended for consideration in trials assessing antivirals for the treatment of influenza [39].

Discussion

In this systematic literature review, we utilized both a general database (MEDLINE) and COA-specific databases (PROQOLID, PROLABEL, and PROINSIGHT) to identify research studies or regulatory documents that mentioned or provided descriptions of the use of PRO instruments in the context of influenza or ILI. We identified articles and electronic records describing the development, validity testing, and use of PRO instruments in influenza clinical research and patient care, regulatory documents describing use of PROs in the design of influenza clinical trials, and several product labels for influenza interventions which mentioned the use of such instruments. Based on these findings, we can describe the advantages and challenges of using influenza-specific PRO instruments and provide recommendations for their wider implementation in influenza clinical research and care.

There are several advantages of using PROs in influenza clinical research and care. PROs allow/provide: 1) the early detection of complications and tracking of influenza (for example, by identifying signs of improvement or deterioration in individual patients), 2) a holistic understanding of the impact of influenza (including an assessment of what matters most to patients with influenza, and how they are feeling), 3) research insights for personalized patient care, and 4) endpoints that can be used in the development or safety monitoring of improved interventions for influenza.

Influenza symptoms often manifest suddenly, transiently, and can vary substantially from person to person [1, 2]. The symptom severity PRO instruments (e.g. FLU-PRO) enable severity scoring of symptoms beyond just their presence, and allow for continued active reporting of symptom severity from their onset (e.g. once or twice daily) [21]. Importantly, such instruments may enable the early detection of influenza complications or worsening of symptoms, allowing healthcare providers to promptly identify signs of deterioration and intervene in a timely manner to prevent progression of illness to a more severe stage.

PRO instruments can allow a holistic understanding of the impact of influenza on patients and provide research insights for personalized, patient-centered care, allowing healthcare professionals and researchers to understand the broader implications of influenza disease beyond physical signs and laboratory values [8]. The development of influenza disease-specific tools such as the RiiQ™, which include measures for both symptom severity and the impact of influenza on the patient, are important for improving understanding of a patient’s condition and the support that they may require [32]. Traditional trial metrics, such as infection rates, severe clinical outcomes (for example, hospitalization) or death, fail to capture the full impact of the disease on patients [9]. However, the specific utility of PROs varies depending on the intervention type. In vaccine and prevention trials, PROs are critical for capturing reactogenicity and assessing whether breakthrough infections are attenuated in severity—nuances that binary outcomes like ‘infection status’ miss. Conversely, for disease-modifying therapies and symptomatic treatments, PROs shift from complementary to central, as the primary therapeutic goal is often the direct alleviation of the symptomatic burden and the restoration of daily functioning. Moreover, current safety monitoring often focuses solely on the presence or absence of adverse events, whereas PRO metrics provide a deeper understanding of the severity of symptomatic adverse reactions by using ordinal or continuous response scales [9]. As a result, healthcare decisions may potentially become more collaborative between patients and healthcare professionals, and tailored to an individual’s needs [8, 49]. Another feature of symptom severity PRO tools is that they allow comparison of symptoms of influenza with other respiratory diseases. For example, the RiiQ™ has been used to compare symptoms of influenza, RSV, and HMPV [32] and the FLU-PRO Plus questionnaire was recently used to distinguish between COVID-19 and non-COVID-19 ILI in adults [29, 30]. In doing so, these PRO tools have the potential to be implemented in joint respiratory disease trials or monitoring settings, facilitate comparisons of outcomes across respiratory diseases for decision-making, provide a supportive, preliminary identification of the disease in the absence of formal laboratory testing, and promote patient-centric, tailored treatments and interventions to alleviate the burden of specific respiratory diseases.

Influenza-specific PRO instruments also have an important role in clinical research in elucidating the efficacy and safety profiles of influenza interventions, both as primary and secondary endpoints. For example, the FLU-PRO and FluiiQ™ have been used in multiple randomized clinical trials of influenza interventions [25, 28, 31]. The importance of PRO measures in determining the benefit-risk ratio of influenza interventions is highlighted by the inclusion of PRO data in the clinical section of the product labels of multiple US FDA- and EMA-approved antiviral medications [40–47]. Indeed, several regulatory documents aimed at informing the design of influenza clinical trials recommend the inclusion of PROs focusing on influenza symptoms as secondary endpoints [38, 39].

There are, however, several challenges regarding use of PRO instruments in influenza research and care, including content validity and reliability, patient compliance and data collection, privacy and confidentiality, and equitable access [9, 50–53]. A major challenge for successful implementation of PROs in influenza research is the selection of an appropriate instrument; it is vital to consider both the content validity (i.e. degree of how much the measure of interest is captured) and the reliability (i.e. degree of reproducibility) in the intended context of use [9], avoiding to generalize the instrument psychometric properties out of the clinical trial setting in which they were originally assessed [17, 52]. Sensitivity to change or responsiveness and thresholds for meaningful change are also important measurement characteristics to be considered [9, 52]; these are particularly useful in clinical care settings where treatment decisions would be based on changes in the PRO scores [9, 17].

Establishing validity in truly representative samples presents a logistical challenge unique to influenza management. Since the majority of influenza cases are mild to moderate and self-managed at home without medical consultation, validation studies that recruit exclusively from clinical or hospital settings inevitably suffer from selection bias. This over-representation of severe cases may result in psychometric properties that are not generalizable to the broader community population, potentially leading to ceiling or floor effects when these instruments are applied in real-world, decentralized settings [52].

While patients are the primary source of information regarding their symptoms in influenza, measurement bias can be introduced if instruments are not robustly designed. Specifically, long recall periods can lead to recall bias, and ambiguous item wording may result in inconsistent interpretation of items. Consequently, the use of rigorous, reliable, and well-defined PRO instruments is essential to minimize these sources of variance and ensure accurate data capture [50]. Implementing PROs in influenza research requires navigating challenges specific to the acute and widespread nature of the disease. Biases are particularly pronounced in acute respiratory infections; selection bias may occur if patients with mild symptoms deem reporting unnecessary, while those with severe fever-induced malaise or fatigue may be too incapacitated to comply with frequent data entry [52, 54]. Furthermore, the cognitive impact of high fever and systemic symptoms can hinder a patient’s ability to comprehend complex items, necessitating the use of rigorous cognitive interviewing during instrument development to ensure questions remain clear even during acute illness [51, 52]. Burden and accessibility must also be viewed through the lens of influenza’s epidemiology. While digital tools enable real-time tracking of rapidly evolving symptoms, reliance on technology may exclude older adults—a primary risk group for severe influenza—due to lower digital literacy [53]. Consequently, minimizing respondent burden through brief, optimized instruments and offering flexible delivery modes (e.g., mixed paper/digital) is crucial to maintain compliance without exhausting the patient [53]. Finally, given that influenza morbidity peaks in young children and frail elderly populations, self-reporting is often unfeasible. In these contexts, Observer-Reported Outcomes (ObsROs) are not merely alternatives but essential tools to capture the disease burden and caregiver impact in the most vulnerable high-risk groups [55].

This study is subject to limitations. Primarily, the work was conducted and finalized in 2023; given the rapid evolution of clinical research, new and updated evidence and PRO instruments, or revised care guidelines may have emerged in the intervening period. Furthermore, as with any systematic literature review, there is a risk that relevant studies were inadvertently excluded, particularly those published in languages other than English or indexed in databases not consulted during our search strategy. Finally, while the paper outlines recommendations for integrating PROs into routine care, the practical challenges of standardization and interoperability within diverse health record systems may limit the immediate generalizability of these proposals to all healthcare settings.

Based on the findings of the systematic literature review and the authors’ clinical experience, we propose several recommendations to facilitate the wider implementation of PROs in influenza clinical research and care (Table 3).

Table 3.

Author recommendations based on findings of the systematic review and the authors’ clinical experience

Recommendation	Notes
Recommendation #1: Integrate PRO assessments into routine clinical care.	Routine collection of patient-symptom and -well-being data complements traditional metrics (e.g., infection rates) to enable personalized interventions. Future research could assess the feasibility of integrating such endpoints in various influenza clinical settings.
Recommendation #2: Leverage PRO data to enhance public immunization campaigns.	Use PRO findings to communicate vaccine benefits beyond just “preventing infection” (e.g., reduced symptom severity, improved quality of life). Additionally, use PROs to identify public concerns regarding side effects to better target vaccination messaging.
Recommendation #3: Standardize PRO endpoints in influenza trials and regulatory submissions.	Pharmaceutical developers should adhere to SPIRIT-PRO guidelines and regulatory standards (FDA/EMA) by including both generic and disease-specific PROs in trial protocols. This standardization is critical for comparing efficacy across different influenza seasons and strains, ensuring data compatibility for meta-analyses of antivirals and vaccines.
Recommendation #4: Prioritize validation of PRO instruments for specific influenza populations and contexts.	Do not assume an instrument validated in one influenza or respiratory symptom setting applies to another. Researchers must verify the psychometric properties (validity and reliability) of PRO tools in the influenza-targeted setting before deployment. See Supplementary File 1 for detailed data on the validity and reliability of the PROs identified in this review.

EMA: European Medicine Agency, FDA: United States Food and Drug Administration, PRO: patient-reported outcome

Conclusions

In conclusion, PROs provide a patient-centered perspective that complement traditional clinical metrics for influenza. This systematic literature review identified several PRO instruments that have been used in clinical trials to assess the severity of influenza symptoms and impact of influenza, as well as the acceptability and safety of influenza interventions. We also identified the inclusion of PRO results in the clinical section of label claims for various influenza interventions and FDA guidelines that recommend the inclusion of PROs in influenza clinical trial designs, highlighting the increasing importance and acceptance of PROs. However, beyond clinical trial settings, studies are needed to better understand how PROs may enhance routine care in real-world clinical settings. The results of this systematic literature review can help to inform and guide healthcare professionals, patients, decision-makers, and clinical researchers on the advantages and challenges of PROs and recommendations for the integration of such tools in influenza clinical research and care.

Electronic supplementary material

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Abbreviations

CARIFS

Canadian Acute Respiratory Illness and Flu Scale

COA

Clinical Outcome Assessment

EMA

European Medicines Agency

EQ-5D

EuroQol five dimensions

FDA

Food and Drug Administration

Hemo-TEM

Hemophilia Treatment Experience Measure

FLU-PRO

InFLUenza Patient-Reported Outcome

FluiiQ™

Influenza Intensity and Impact Questionnaire

ILI

Influenza-like illness

ISS

Influenza symptom severity

IIWS

Influenza impact wellbeing scale

MeSH

Medical Subject Heading

PRO

Patient-reported outcomes

QoL

Quality of life

RiiQ™

Respiratory Infection Intensity and Impact Questionnaire

SF-36

36-item short form health survey

VAPI

Vaccinees’ Perception of Injection

Author contributions

EMM and PMA: Performed the systematic literature review, wrote the manuscript, and reviewed and approved changes. BAFM, CG, JBH: Participated in the critical assessment of literature findings, wrote sections of the manuscript, and reviewed the accuracy of the information.

Funding

This publication was funded by Sanofi.

Data availability

This is a review paper and thus no experimental or clinical data have been generated.

Declarations

Ethical approval

Not applicable.

Consent for publication

Not applicable.

Competing interests

EMM, PMA, BAFM, and CG received consulting fees from Sanofi. JBH is an employee of Sanofi (a company that develops and commercializes influenza vaccines) and own stocks of the company.