Cystic fibrosis (CF) is the most common life-shortening autosomal recessive disease affecting Caucasian populations [1]. CF (ICD-10 code E84) is caused by mutations affecting the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which transports chloride ions across epithelial cell membranes [2]. Changes in chloride ion concentration cause thicker exocrine secretions and increased salt concentration throughout the body [1]. In the respiratory tract, where the disease is most detrimental, thickened mucus restricts the airway lumen [2] and impairs clearance of microorganisms, resulting in chronic cough, increased infections, and bronchiectasis [3]. Pulmonary disease can progress to respiratory failure and death [2]. Other common consequences of CFTR mutations include pancreatic insufficiency, impaired intestinal motility, impaired growth, and diabetes [2].

Although life expectancy with CF has improved significantly in the last few decades [4], patients with CF continue to struggle with symptoms that have a profound impact on all areas of life [5]. In addition, daily treatment regimens have become more complex and time-consuming and can require 2-3 hours a day [6]. Traditional physiological parameters that measure disease severity do not capture the impact of symptom and treatment burden on daily functioning. As a result, the assessment of health-related quality of life (HRQOL) in CF has gained prominence as an alternative measure of disease severity and functional limitation [7].

HRQOL has been defined as “an individual’s perception of their position in life” [8]. It is a multidimensional construct that encompasses physical symptoms, daily functioning, psychological well-being, social functioning, and relationships [8]. As these domains are best understood and described by patients themselves, patient-reported outcome measures (PROMs) are commonly used to report HRQOL [6]. PROMs are standardized questionnaires filled out by patients or their proxies [9]. They capture patients’ perceptions of their own well-being [9].

In CF, PROMs are currently used for a variety of purposes including the following: as outcomes in clinical trials, to evaluate the efficacy of new interventions, to measure the effects of disease on patient functioning, or to compare the cost-effectiveness of treatments [10]. However, PROMs can be used most effectively when captured prospectively and longitudinally through routine data collection [11]. Including a PROM within a pre-existing clinical registry is a cost-effective method of HRQOL data collection [11]. When PROMs have been incorporated in national [12] and international [11,13,14] registries for other diseases, they have been used to track treatment outcomes, monitor HRQOL trends, and support benchmarking and quality improvement [15].

The Australian Cystic Fibrosis Data Registry (ACFDR) was established in 1998 and collects clinical data on adult and pediatric patients with CF. Information is collected multiple times a year from specialist clinics [16]. At the end of 2017, the ACFDR held data from 3151 patients [16], estimated to be over 90% of Australian patients with CF [17]. Data collected included patients’ demographics, social functioning, physical health, treatments, hospitalizations, and mortality [16]. Growing interest in the incorporation of PROMs in Australian registries [18] has led to the evaluation of a HRQOL PROM in the ACFDR. This systematic review was planned as the first phase of a project to identify a PROM that would be appropriate to include in ACFDR data collection.

Preliminary searches identified no published data on the use of PROMs in CF clinical registries and no recent systematic reviews summarizing adult and pediatric HRQOL PROMs in CF. Therefore, we planned a systematic review to examine all PROMs currently applied to CF populations to identify whether any PROMs are suitable to incorporate in the ACFDR. We require information on the populations and contexts PROMs are used, their reliability and validity in those populations, and how they are perceived by patients. Information on mode and frequency of PROMs administration is also required. We believe this systematic review will identify a suitable PROM to use in the ACFDR and the best method to implement this PROM.

The primary objective of the proposed systematic review is to identify which PROMs examining HRQOL have been used in adult and pediatric populations with CF and to summarize their psychometric properties. Secondary objectives are to identify how PROMs are administered and assess patient perceptions of PROMs.

Inclusion and exclusion criteria for articles can be found in Textbox 2.

Quantitative (eg, cohort, longitudinal, prospective, retrospective, validation, and case studies) and qualitative studies (eg, phenomenological, grounded theory, and case reports) exploring HRQOL outcomes in patients with CF were included. Mixed methods research articles were also included in the review.

Studies conducted in clinical environments such as acute care (hospital inpatient services and emergency departments) and subacute care (primary health care and outpatient clinics) were included. Patients recruited from databases, patient support groups, and registries were also included.

The primary outcome of interest is to identify which PROMs are currently used in adult and pediatric populations with CF and to summarize the psychometric properties of PROMs (eg, content validity, internal consistency, responsiveness), as assessed for the study population or as stated based on previous studies.

Secondary outcome measures include (1) contexts in which HRQOL PROMs are currently used (eg, interventional studies, prevalence studies, clinical registries); (2) administration methods of PROMs (eg, paper survey, electronic, interview, use of proxy-respondents); and (3) acceptability of PROMs (eg, relevance, ease of use, clarity) as described by authors of the study.

Initial Ovid MEDLINE searches were undertaken to find published studies and reviews relevant to the topic. Keywords and index terms from these articles were recorded and used to develop the final search strategy. The search strategy was finalized in Ovid MEDLINE and adapted as required for other databases using the MeSH trees. The draft search strategy included the terms “patient reported outcome” OR “patient reported outcome measure” OR “self-report*” OR “questionnaire” OR “scale” OR “perception” OR “quality of life” OR “QOL” AND “cystic fibrosis.” The search was restricted to the past 10 years to only include PROMs relevant to the current population with CF.

The following databases were searched: MEDLINE, EMBASE, Scopus, CINAHL (Cumulative Index of Nursing and Allied Health Literature), PsycINFO, and Cochrane Library. A search of the gray literature was not conducted. Bibliographies of all selected studies fulfilling inclusion criteria will be scanned to identify any articles missed by the search.

All studies identified in database searches were compiled in Endnote X7 (Clarivate Analytics). Duplicates were deleted using the Endnote “Remove Duplicates” function and a manual scan of the results. Review documentation and search results were saved and backed up in Monash University’s faculty-allocated network storage (S-drive). Data will only be accessed by the reviewers.

In the first stage of screening, one reviewer (IR) read the titles and abstracts of all studies identified by the search. Studies that met the inclusion criteria were included. During the second stage, two reviewers (IR and RR) read the full texts of the remaining studies and removed any that clearly met the exclusion criteria. Any disagreements that arose were resolved through discussion.

If bibliographies of selected full texts comprised any articles consistent with the inclusion criteria, the full texts of these articles were also considered for inclusion. The number of studies at each stage of the search were recorded using the PRISMA-P flow diagram.

Data was extracted by one reviewer. The information that was extracted from articles is detailed in Textbox 3. Information on methods of PROMs development, target age range, and purposes for which PROMs were developed will be extracted by searching bibliographies for original studies describing PROM development.

The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) risk of bias checklist will be used to evaluate the methodological quality of included studies [20]. This tool has been chosen, as it specifically assesses studies that use PROMs. The tool assesses 10 measurement properties of PROMs (PROM development, content validity, structural validity, internal consistency, measurement invariance, reliability, measurement error, criterion validity, construct validity, and responsiveness). Each property is evaluated against a number of items [20].

Two reviewers will independently appraise studies using the tool. As not all studies describe all properties, only relevant areas of the COSMIN checklist will be applied to each study [20]. Reviewers will rate each item on a 4-point scale denoted as very good, adequate, doubtful, or inadequate. Results will be summarized in a table presenting the lowest score for each property [20]. Any disagreements between reviewers will be resolved through discussion.

A descriptive synthesis of the results will be undertaken in line with the outcomes of this study. Summary tables of characteristics of the included studies and PROMs will be presented. A description of included instruments will be given, along with the contexts in which they were used, how they were administered, and their acceptability to patients. This information will then be used to compare instruments. PROM(s) that may be suitable for inclusion into the ACFDR will be identified by considering the applicability and acceptability of instruments to a population of Australian adult and pediatric patients and caregivers. Quantitative synthesis will not be performed, as the included studies assess different outcomes.

Ethical approval is not required, as primary data was not collected. This project does not require patient or public involvement. Review results will be published in a thesis and peer-reviewed journal and will be presented at conferences. The study has been registered with the International Prospective Register of Systematic Reviews (PROSPERO); registration number CRD42019126931).