Health-related quality of life (HRQOL), or one's quality of life as it relates to health status or disease, is increasingly recognized as an important patient centered-outcome by leading health organizations (1, 2)¹. HRQOL is a subjective, dynamic, and multidimensional concept that includes domains representative of an individual patients' goals, values, and beliefs (3, 4). Over the past several decades, various conceptual models of HRQOL have contributed to our study of HRQOL in human disease (2, 5–7). These models provide an essential structure for conceptualization of HRQOL, including both the positive and negative aspects, and are often used as a guide for research and practices that promote improved HRQOL in different populations of interest (8). HRQOL frameworks most commonly focus on the physical and psychosocial impacts of health or disease on an individual's ability to live what they consider to be a fulfilling life (9). HRQOL amongst those who share the same or different chronic diseases is often very personal and subjective. This subjectivity will vary even more depending on a person's cultural background and environment. The various domains of HRQOL (e.g., psychosocial, physical etc.) that we intend to measure therefore should ideally be considered in the context of an individual's culture and value system (10, 11). This adds a level of complexity to measurement of HRQOL as we are compelled to recognized that these constructs will differ across different cultural, religious, and socioecological contexts (12). The processes of linguistic and cross-cultural adaptation have allowed for improved measurement of HRQOL across different cultures and languages.

During the past decade, HRQOL has gained much traction as a priority endpoint in the Interstitial Lung Disease (ILD) community. ILD is a group of heterogeneous parenchymal lung diseases with various clinical courses, many of which may be progressive, fibrotic, life altering, and eventually fatal (13, 14). Patients and ILD experts alike have vocalized the importance prioritizing HRQOL as a top area of focus in research studies and clinical practice (15, 16). Though a few therapies are documented to slow progression of disease [as measured by forced vital capacity (FVC)] in idiopathic pulmonary fibrosis (IPF) and the progressive fibrotic form of other ILDs, there is now much interest in how our interventions effectively slow deterioration in HRQOL (17, 18).

Patient Reported Outcome Measures (PROMs) that measure HRQOL gather information directly from the patient (without interpretation by a clinician or anyone else) about their perspective of the quality of their life in the context of their disease and it's treatments (19, 20). There are several PROMs that have undergone validation testing to measure HRQOL in ILD. The most commonly used instruments in the past few decades were originally intended for use in other respiratory diseases, while a handful of newer instruments have been developed for use specifically in ILD and pulmonary fibrosis (21). These “condition” or “disease-specific” PROMs are intended to capture more nuanced information about the impact of living with ILD that is most pertinent to patients with this particular chronic respiratory disease (e.g., breathlessness, cough, fatigue, aspects of psychological well-being) (22). Despite the ILD-targeted items in these instruments, one must be cognizant of the interpretation of the wording of these items for those from other cultures or countries in which the instrument was not developed. For example, dyspnea, or breathlessness is a common ILD symptom that impacts HRQOL. There are various qualitative aspects of this symptom are interpreted differently across different languages and cultures (23–25).

Here we introduce the concept of measuring HRQOL around the world, and as it pertains to specifically to ILD with a focus on linguistics, regional and environmental factors, health literacy and health-care systems, and race, ethnicity, religion and spirituality. We will describe the process of cross-cultural adaptation, the work that has been performed to cross-culturally validate PROMs in ILD, and the potential challenges and opportunities for the future study of HRQOL in ILD on a global scale.

HRQOL generally reflects each individual's perspective on their own health and is widely accepted as one of the most important patient-centered outcomes. HRQOL measures the impact a chronic disease and its treatment have on several domains of one's life and is largely influenced by cultural and spiritual backgrounds. Therefore, it is expected that the concept of HRQOL will differ across communities within a nation, as well as between countries. Given the growing number of international clinical trials and large population health studies it is increasingly important to recognize the global factors that influence accurate measurement of HRQOL, and how to potentially address them. This section focuses on general considerations for assessing HRQOL in chronic illness, which is pertinent when we consider measurement in ILDs.

In the past several decades, the measurement of HRQOL has garnered significant attention as an important endpoint in clinical trials and public health research (51). With the increasing number of multi-country, multi-center trials that are conducted in clinical research there is a growing need for HRQOL measures that can be administered in countries with various languages of origin and amongst different cultural groups where disease expression and health-care system usage may vary (52). In order to administer an HRQOL instrument appropriately in a new country or culture, the instrument must not only possess linguistic equivalence, but must also capture the cultural differences in disease expression and perception of HRQOL (27, 28). This allows investigators to collect accurate information about HRQOL of the whole population in one study (when several countries are represented) and to compare results across different studies both nationally and internationally (53). Development of a new PROM is a rigorous and time intensive process (20). It may take years to gather enough data to prove the instrument possesses adequate validity to use in a clinical trial, often with stringent regulatory approval criteria that must be met (54). Rather than develop a brand-new instrument for each distinct language and culture, current practice is to perform “cross cultural adaptation.” This process facilitates the translation of existing and well-validated instruments in a manner that allows the instrument to retain its psychometric properties in a culturally distinct population (55).

There is overwhelming agreement that an instrument should not be simply translated word for word into another linguistic context, as this can compromise the cultural integrity and equivalence of the findings (56). However, there is not a standardized protocol for linguistic validation or cross cultural adaptation, therefore risking poor translation and compromised research data (57, 58).

Several approaches to cross cultural adaptation have been suggested with the goal of maximizing validity and reliability of the instrument that is to be translated into the “target” (or new) language. The Translation and Cultural Adaptation Group (TCA) of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) task force put forth recommendations for translation and cultural adaptation of PROs in the research community based upon review of the literature and multidisciplinary expert consensus (59). Their recommended approach includes stages of translation and validations testing that require both forward and backwards translation, harmonization that allows for concept equivalence between the source and target language versions of the instrument, review by an expert committee, and cognitive debriefing to assess comprehensibility and cognitive equivalence of the translation by interviewing patients from the target population (60, 61). While the ISPOR task force guidelines provide a rigorous approach to translation, they provide less guidance on further psychometric testing to perform beyond translation and assessment of content validity.

In 1991, the international quality of life assessment (IQOLA) project was established to translate and validate the short-form 36-item health survey (SF-36) (28, 62, 63). The IQOLA project group guidelines encompass a three-stage process that incorporates further psychometric testing; (1) rigorous translation and evaluation process, (2) formal psychometric testing of the assumptions underlying item scoring and construction of multi-item scales, and (3) studies evaluating the equivalence of interpretations across countries (64, 65). Their project with the SF-36 transferred an existing generic HRQOL questionnaire to another culture, a process termed “sequential development”. On the other hand, in 1990s, the World Health Organization (WHO) developed the WHO Quality of Life assessment instrument (WHOQOL) simultaneously in fifteen different centers worldwide (2). This type of approach helps to ensure equivalence of concepts at each stage as the questionnaire is developed in multiple languages at the same time, a process termed “simultaneous development”. In the 1980-1990s, the European Organization for Research and Treatment of Cancer (EORTC) and the EuroQol Group developed the quality of life questionnaire (QLQ-C30), and the EuroQol-5 dimensions (EQ-5D), respectively (66–68). These questionnaires were generated in one language and then forward and backward translated into multiple languages by multinational discussions, a “parallel development” approach. With these historical developments, various HRQOL questionnaire translations are available for clinical trials, daily clinical practice, population studies, and health economic evaluations around the world.

Several patient-reported outcome measures (PROMs) have been adapted for use in ILDs. The PROMs utilized in ILD research and practice are mainly categorized into three groups: (1) disease-specific HRQOL, (2) generic HRQOL, and (3) domain-specific instruments (69). These instruments are ideally chosen as endpoints in research according to the objective of the study and characteristics of the study population. Each of the most common PROMs administered in ILD are at different stages of validation, translation, cross-cultural adaptation, and level of use in clinical trials (Table 1). Here we provide an overview of the current state of cross-cultural adaptation of PROMs in ILD.

Despite the great strides that have been made to highlight the importance of HRQOL in ILD in the past two decades, there are still many opportunities to internationally and cross culturally improve its measurement. The ILD-specific HRQOL questionnaires (e.g., K-BILD, ATAQ-IPF, or L-IPF/L-PF) are designed to measure the nuanced impacts of ILD on HRQOL more precisely than generic instruments. A limited number of translations and cross-cultural adaptations have been performed on these instruments making them less generalizable for use in a larger international study compared to others that may be less ILD specific, but have been around longer and are more widely established (99–102, 105, 107, 108, 149). For example, questionnaires developed for COPD (e.g., SGRQ) are not specific to ILD, but have a large number of translations and are relatively-well-validated in ILD (70–92). More studies are needed to continue to linguistically validate and cross culturally adapt the new ILD disease-specific instruments. To standardize this process internationally, it will require global consensus and a collaborative approach (95).

There is little information on the international equivalence of the methods we use to validate PROMs, e.g., how we calculate internal consistency, construct validity including correlation with other parameters, and responsiveness. The various global concepts that impact HRQOL have the potential to affect the interpretation of PROMs. These diversities may contribute to different interpretation of the items in a single questionnaire amongst various communities and countries. Although no formal method has been established to address this possibility, subgroup analyses of multinational clinical trials may support the validity of each questionnaire across these communities and nations if similar results are obtained (154–156). We must also recognize that a PROM is ideally chosen to measure a certain outcome based upon the context and objective of the research study. This means that one questionnaire that is deemed appropriate for one trial design may not be the same questionnaire that is ideal for another, even if they are both measuring HRQOL. This adds another layer of complexity for multi-national studies as one must not only choose an instrument that will capture information about HRQOL in multiple languages and cultures, but they must also be comfortable that the instrument is measuring the constructs that are important to answer their particular question.

To date, trials testing medications developed for use in fibrotic ILDs have overwhelmingly targeted the halt of disease progression as reflected by pulmonary function, exercise tolerance, or progression-free survival (82, 103, 115, 157). As disease-specific HRQOL PROMs generally reflect changes in these parameters, these have characteristically been chosen for use in those clinical trials (77, 98, 100). As patient-centered research in ILD expands, future interventions may target the more disease-specific symptoms (e.g., cough, dyspnea, fatigue) (158–160). For these clinical trials, domain-specific PROMs focusing on each symptom may likely be chosen as the primary endpoint and therefore these instruments will need to be adapted for use cross-culturally.

The guidelines for development of PROMs are not internationally unified. Regulatory agencies such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have released PROM development guidance as we increasingly recognize the importance of including these measures in clinical trials (161, 162). Recent PROMs including the K-BILD and L-IPF/L-PF adhered strictly to their guidelines during the process of developments (99, 107). Although there is no question that these guidelines are well-established and rigorous, it is necessary to verify whether the same methodology can be adapted in non-English speaking countries where there are different cultural components as well as potentially different resources available.

Finally, we need to consider the international inequalities of HRQOL itself. As discussed in this review, many individual factors are closely associated with a patient's health status. In fact, the global burdens of ILD measured by disability-adjusted life years (DALYs), which is calculated as the number of years lost due to disability or early death, are known to greatly vary across the countries (163). The level of HRQOL impairment may differ in each country, even if the disease severity assessed by pulmonary function is the same. Therefore, an understanding of the baseline health status in any individual country is important. If there is a large difference in the baseline health status between groups, then the evaluation of relative change in each individual or group should be considered. Multinational consortia of researchers with expertise in PROMs and who study HRQOL are needed in order to begin to address some of these gaps on an international level.

HRQOL is an increasingly important end point in ILD amongst patients, clinicians, and researchers alike. As our understanding of the disease and its possible therapies expands, we are rapidly accelerating opportunities for clinical trial conduct across the globe. While we have made great strides in the measurement of HRQOL in ILD, we have many opportunities to improve our measurement across cultures and countries. We have identified several ways in which HRQOL may be interpreted differently across the globe and highlighted potential mechanisms for translation and cross-cultural adaptation of HRQOL PROMs, both in general and in ILD. By recognizing these important differences and working together with our colleagues and patients across the globe we have the opportunity to improve the way we study and report HRQOL which will have a substantial impact on the conduct of multinational studies and interventions in the future.

KA and AS contributed equally to the conception and writing of this manuscript. Both authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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