This pilot observational study was conducted in the Department of Pneumonology of Upper Silesian Medical Center, which is a clinical tertiary care hospital. Assessment of QOL was a secondary outcome measure in a multicenter prospective study aimed at determining the characteristics of Polish patients with IPAF [14]. Patient recruitment was conducted in rounds from July 2019 to March 2020 and from April 2021 to December 2021. The pause was caused by the outbreak of the novel coronavirus, when our department was transformed into an infectious diseases ward. We recruited hospitalized adults who had been previously diagnosed with an ILD according to the international guidelines [15-18] .

We recruited 57 individuals among patients hospitalized in our department: 22 with IIPs (13 patients with IPF and 9 patients with idiopathic nonspecific interstitial pneumonia), 19 with CTD-ILDs, and 16 with IPAF. Patients were hospitalized in order to undergo routine check-ups; therefore, they were not additionally burdened. Patients with deafness or other disorders causing disturbance in verbal communication were excluded. In addition, patients who had previously received treatment for ILD and individuals diagnosed with heart failure whose left ventricle ejection fraction measured during transthoracic echocardiography was ≤45% were excluded. To reduce the impact of mobility issues on 6-minute walk distance (6MWD), patients who used any kind of mobility aid or individuals with cognitive impairment were excluded [19].

This article presents the results of a pilot study with a sample size of 57 participants.

According to a simulation by Jenkins and Quintana-Ascensio [20], the minimal sample size can be 8 participants when the groups have low variability. At least one journal now requires a minimum of 5 participants per group for statistical analyses [21]. Ecological studies have been advised to use 10 to 20 participants per predictor [20] or 30 to 45 participants if studying gradients [22].

We aimed to recruit 370 patients for a multicenter study (120 patients in our center) based on an estimated 8000 Polish patients with ILD according to the National Health Fund [23], a confidence level of 95%, and a margin of error of 5%. The number of participants was greater than our initial plans for the pilot study, as many patients are currently hospitalized for inclusion in therapeutic programs for patients with IPF or progressive fibrotic ILD. Moreover, cooperation with a local rheumatological center was also planned.

The minimum sample size was calculated to be 55 participants for linear regression analysis with 1 predictor and assuming a moderate effect (f2=0.15), an α of .05, and a test power of 0.8. With 7 predictors with a strong effect (f2=0.35), the minimum sample size was calculated to be 49 participants.

The degree of dyspnea was measured using the modified Medical Research Council (mMRC) dyspnea scale, with which the severity of dyspnea is assessed on a scale from 0 (dyspneic during strenuous exercise) to 4 (dyspneic when dressing/undressing or unable to leave home due to dyspnea) [24].

Taking into account that no QOL questionnaires are currently validated specifically for ILDs in the Polish population, we used questionnaires designed either for patients with chronic obstructive pulmonary disease (eg, Saint George’s Respiratory Questionnaire [SGRQ]) or individuals undergoing medical interventions (eg, World Health Organization Quality of Life Questionnaire [WHOQOL-BREF]), as these have been validated for use in the Polish-speaking population. CTD-specific questionnaires, such as the Rheumatoid Arthritis Quality of Life Questionnaire, were not used, as they focus specifically on the musculoskeletal symptoms.

To assess QOL, the SGRQ and WHOQOL-BREF were used. The SGRQ is an instrument with weighted responses that are calculated to produce a score for each component of the questionnaire (ie, symptom severity and frequency, activity impairment due to illness, and impacts including the psychological and social effects of dysfunction) as well as a total score. The SGRQ is scaled from 0 (optimal health) to 100 (worst health) [25]. The WHOQOL-BREF is a 26-item version of the WHOQOL-100 assessment. It is a tool to assess QOL in the physical, psychological, social, and environmental domains. Measures are calculated using an algorithm transforming scores to a 0 to 100-point interval. Higher scores correspond to greater perceived QOL [26].

We chose 2 questionnaires to assess QOL in this population in order to determine whether, similar to QOL assessment in chronic obstructive pulmonary disease, they show comparable reliability.

Data show that the Hospital Anxiety and Depression Scale - Modified Version (HADS-M) and Patient Health Questionnaire - 9 (PHQ-9) vary in their ability to categorize the severity of depression, with the PHQ-9 identifying a greater proportion of patients with moderate or severe depression [27]. Therefore, we decided to include these 2 questionnaires in the study design to determine later, in a full-size study, whether there are differences in depression categorization. As the severity of depression impacts the choice of treatment, the choice of the depression questionnaire may impact therapeutical decisions.

Consent to use these instruments was obtained.

Depression and anxiety were assessed using the HADS-M and PHQ-9.

The HADS-M is a self-administered screening tool for depression, anxiety, and aggression. Scores ranging from 11 to 21 are considered indicative of the presence of a disorder [28].

The PHQ-9 is used to diagnose and determine the severity of depression based on the 9 criteria in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition; DSM-IV), and scores ranging from 20 to 27 are indicative of severe depression [29].

Cough was assessed using a visual analog scale (VAS), which is a linear scale where participants are asked to position the severity of cough on the line from 0 mm to 100 mm (no cough to worst cough, corresponding to subjective intensity of the symptom).

Activity capacity was assessed using the 6-minute walk test performed in a corridor 30 meters long [19]. Individuals using any kind of mobility aids or patients with cognitive impairment were excluded from the study.

This observational cross-sectional study was performed according to the principles of the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the Medical University of Silesia (KNW/0022/KB1/130/18/19; date of approval: January 8, 2019). Informed consent forms were provided to every participant, along with information that they could withdraw their consent at any time without any negative impact on their care. Participants gave their consent after after receiving a detailed explanation of the study’s purpose and procedures.

Data collected for this study were anonymous. No compensation was offered to participants in this study.

Statistical analysis was performed using SPSS version 28.0 (IBM Corp). First, analysis of basic description statistics was performed using the Shapiro-Wilk normality test. To evaluate relationships between the variables, Pearson correlation coefficient and Spearman correlation tests were performed. To compare 2 groups, an independent samples t test was performed. To compare 3 groups, univariate analysis was performed. In order to establish which aspects were QOL predictors, multivariate regression analysis was performed. In order to establish the relationships between QOL and pulmonary function test (PFT) parameters, Pearson correlation analysis was performed. In order to determine the relationship between cough VAS and mMRC scores and QOL scores, Spearman correlation analysis was performed. As significance level of .05 was used.

To compare 3 study groups in terms of QOL scores, depression, anxiety, and aggression aspects and activity scores, 1-way ANOVA was performed. To determine the character of differences, a post hoc Bonferroni test was performed.

In order to establish which functional parameters and which aspects of anxiety and depression are QOL predictors, linear regression analysis was performed.

To establish the relationship between treatment duration and QOL and depression and anxiety aspects, Spearman correlation analysis was performed.

The analysis revealed significant intergroup differences in QOL psychological domain scores and PHQ-9 and HADS-M depression scores.

The scores for the psychological domain of QOL were significantly lower in the CTD-ILD and IPAF groups than in the IIP group, indicating worse QOL.

However, the post hoc analysis revealed that the score differences in the HADS-M depression domain were irrelevant.

The results are presented in Table 1.

A significant predictor of QOL (expressed as the SGRQ total score) was the transfer lung capacity for carbon monoxide (TLCO) % predicted value (t₁₄=–3.63, P=.005). A higher TLCO % predicted value was correlated with lower SGRQ scores.

Higher cough VAS scores were correlated with higher SGRQ symptoms scores. The 2 significant predictors for SGRQ activity scores were cough VAS score (t₁₄=2.73, P=.03) and HADS-M anxiety scores (t₁₄=–2.36, P=.046). Higher cough VAS (t₁₃=−5.19, P<.001) and HADS-M anxiety (t₁₃=–4.25, P=.002) scores were correlated with lower QOL, as expressed by scores in the WHOQOL-BREF physical domain. Higher PHQ-9 scores were correlated with lower scores in the WHOQOL-BREF psychological domain (t₁₄=–5.49, P<.001). The results are presented in Table 3.

The analysis revealed that higher SGRQ total scores, which indicate worse QOL, were correlated with shorter 6MWD (t₁₆=–4.20, P<.001) and higher HADS-M aggression scores (t₁₆=2.89, P=.01). For QOL according to the SGRQ symptoms score, the predictors were cough VAS (t₁₆=5.56, P<.001) and mMRC (t₂₀=3.45, P=.004) scores; higher symptom scores were correlated with worse QOL, expressed as a higher SGRQ symptoms score. The cough VAS score was also a predictor of the SGRQ activity score (t₂₀=4.27, P<.001). 6MWD and HADS-M aggression score were predictors of SGRQ impacts scores (P<.001). The results are presented in Table 4.

The mMRC score was a significant predictor of SGRQ total score (t₂₀=2.44, P=.03) and SGRQ activity score (t₂₀=6.93, P<.001).

The 2 significant predictors of SGRQ symptoms scores were 6MWD and PHQ-9 scores (P=.003).

The 2 significant predictors of QOL, as expressed using the WHOQOL-BREF physical domain scores, were cough VAS (P=.02) and mMRC (P=.008) scores. Higher cough VAS (P=.001) and HADS-M anxiety (P=.04) scores were correlated with lower QOL, as expressed using WHOQOL-BREF psychological domain score.

Table 5 shows the results.

Regarding the relationships between QOL and PFT parameters in all study groups (n=57), the Pearson correlation analysis revealed a moderate correlation between forced expiratory volume in 1 second (FEV₁) predicted values and QOL scores in the physical domain of the WHOQOL-BREF questionnaire (r=0.30, P=.02; R=0.25, P=.06). There was also a positive weak correlation between TLCO predicted values and QOL scores in the physical domain of the WHOQOL-BREF questionnaire (r=0.29, P=.03; R=0.05, P=.70).

There was a weak to strong negative correlation between depression scores and WHOQOL-BREF physical domain scores (r=–0.45, P<.001). WHOQOL-BREF physical domain scores correlated negatively with all HADS-M domain scores (depression: r=–0.45, P<.001; anxiety: r=–0.43, P<.001; aggression: r=–0.28, P=.03). WHOQOL-BREF psychological domain scores also correlated negatively with all HADS-M domain scores (depression: r=–0.87, P<.001; anxiety: r=–0.77, P<.001; aggression: r=–0.52, P<.001). There was a moderate negative correlation between the WHOQOL-BREF social relationships score and HADS-M depression (r=–0.47, P<.001), anxiety (r=–0.43, P=.001), and aggression (r=–0.35, P=.008) scores and SGRQ symptoms score (r=–0.42, P=.001). There was a negative moderate to strong correlation between the WHOQOL-BREF environment score and HADS-M depression (r=–0.57, P<.001), anxiety (r=–0.49, P<.001), and aggression (r=–0.48, P<.001) scores. The results are presented in Tables 6 and 7.

ILDs affect multiple aspects of patients’ lives, impairing QOL proportionately to progression of symptoms [30,31]. Enhancing or maintaining QOL, especially in individuals with noncurable QOL, which affects life expectancy, is an important therapeutic goal [9]. IPAF, as a relative novelty, has been associated with some clinical uncertainty, as data regarding its possible progression are scarce [7,32].

To the best of our knowledge, we are the first to evaluate various aspects of QOL in patients with IPAF compared with patients with other ILDs.

According to Yuan et al [33], individuals with CTD-ILD have a lower QOL as measured by the 36-Item Short Form Health Survey (SF-36) physical component score and SGRQ impact, activity, and total domains in comparison with patients with IIP.

In a study with 131 patients with ILD (CTD-ILD, IPF, sarcoidosis, non-IPF IIP) [34], no significant differences in the prevalences of anxiety and depression between the ILD and IPF groups were found.

Interestingly, our pilot study revealed that psychological aspects of QOL were more significantly impaired in the CTD-ILD and IPAF groups than in the IIP group. We are looking forward to an assessment of patients’ mental health on a larger scale in a full-sized study, and we hope that under-recognition of mental health issues in these populations will be addressed in the future.

Similar to other respiratory diseases, we found gender-related differences in the QOL assessment. In all study groups, men had higher QOL scores than women in the psychological, social, and environmental domains of the WHOQOL-BREF; differences in the physical domain scores were not statistically significant. In a study by Han et al [35] with 221 individuals with IPF, the SF-12 mental health, emotional, and social functioning domain scores were significantly better in men than women.

These findings appear interesting in the light of the fact that men tend to have a worse prognosis and lower transplant-free survival with both IPF and non-IPF ILDs [36]. Moreover, men have an increased risk of faster progression of CTD-ILDs, including rheumatoid arthritis [37] and systemic sclerosis [38].

It remains unclear whether biological, gender-associated, or behavioral aspects influence the course of disease progression and perception of QOL and its various aspects.

As expected, higher depression, anxiety, and aggression scores were associated with worse perceived QOL in the psychological, social, environmental, and physical domains of the WHOQOL-BREF.

In a study with patients with IPF, Lee et al [39] revealed that higher depression and anxiety scores on the HADS questionnaire were associated with higher (worse) SGRQ scores. Many studies with patients with ILD have shown that depression and anxiety are common symptoms in this population and that individuals with ILD have a greater risk of developing both depression and anxiety than the general population [34,39]. Similarly, in our study, 48 patients (48/57, 84%) exhibited borderline depression symptoms on the PHQ-9, and 3 patients (3/57, 5%) scored positively for depression; however, in the HADS-M depression domain, 21 patients (21/57, 37%) had borderline results, and 8 patients (8/57, 14%) had positive results. In the multivariate analysis, HADS-M depression scores and PHQ-9 scores were predictors of the psychological composite of QOL (measured with the WHOQOL-BREF), and the HADS-M depression score was also a predictor of the physical composite of QOL. The high percentage of “borderline depression” results in our study population implies the importance of regular screening for depressive symptoms in the disease course.

Only 3 patients in our study received antidepressants (selective serotonin reuptake inhibitors). Interestingly, there are data suggesting a role of serotonin as a profibrotic agent in myofibrolast differentiation and extracellular matrix deposition in not only the cardiac valves or skin but also interstitial lung tissue [40]. Serotoninergic antagonists are studied as potential antifibrotic agents in progressive fibrosing ILD in the course of rheumatoid arthritis and systemic sclerosis [41].

On the other hand, the low percentage of medicated patients draws our attention to the need for routine mental health assessment in all patients with ILD.

Interestingly, the psychological aspects of QOL in the IPAF group were similar to those in the CTD-ILD group and worse than those in the IIP group.

We revealed positive correlations between the predicted values of FEV₁ and TLCO and physical health domain scores of the WHOQOL-BREF in all study groups. These findings are corroborated by the results of a study with 229 patients with ILD by Szentes et al [42], who showed that a higher forced vital capacity (FVC) % predicted value was associated with higher QOL scores in all domains. However, to assess QOL, the authors used the King’s Brief Interstitial Lung Disease (K-BILD) questionnaire, which is a different tool developed for this specific population. However, we could not compare the findings in our population, as the K-BILD has not yet been translated into Polish nor validated in the Polish population.

Surprisingly, there were no correlations between the functional parameter predicted values and QOL aspects with the exception of SGRQ total score and the TLCO predicted value.

Our findings are in line with those summarized in a systematic review of QOL studies with patients with IPF by Swigris et al [43], which revealed rather weak correlations between PFT parameters (FVC, TLCO predicted value) and various aspects of QOL. Naturally, health-related QOL perception is a much more intricate and complicated matter than just an outcome of PFT parameters; strong and unambiguous correlations would imply a lack of usefulness of QOL measurement tools: Why assess QOL with a dedicated instrument if PFTs will suffice to describe it?

IPF, as a frequently studied ILD, has a dyspnea prevalence of 90% at the moment of diagnosis [44]. The high dyspnea burden has a great impact on both QOL and mortality [45].

We demonstrated that subjective evaluation of dyspnea (mMRC scores) and anxiety scores (HADS-M) may be important determinants of various aspects of QOL. This is a reminder for health care professionals to evaluate patients’ mental health and work on strategies leading to effective stress management.

Higher scores on the VAS cough scale and mMRC dyspnea scale in our study were associated with worse perceived QOL for all its aspects in all studied groups.

Dyspnea is one of the most common complaints from patients with ILD [46].

In patients with IPF, the Medical Research Council (MRC) dyspnea score is a significant determinant of survival, along with Tiffeneau index and total lung capacity [47].

An understanding of the influence of psychophysiological health determinants on dyspnea sensation in patient with ILD is still limited. Establishing the relationships of associated psychological and physiological factors in dyspnea in hospitalized individuals with ILDs may contribute to effective management of pulmonary rehabilitation and to improved QOL for these patients. Some studies have revealed that both psychological determinants, such as depression or anxiety [48], and physiological determinants, such as cough occurrence and severity, reduced activity capacity and decline in pulmonary function [49] that occur with dyspnea in a population of patients with chronic respiratory diseases. Multiple attempts have been made to establish the associations between these psychophysiological factors and dyspnea among patients with various ILDs (eg, IPF or CTD-ILD), and their findings were contradictory. Ryerson and Berkeley [50] revealed that FVC is an independent determinant of dyspnea, similar to the findings of Londner et al [51]. Interestingly, Ryerson and Berkeley [50] also revealed that depression was an independent dyspnea predictor in 52 participants with ILDs. This was not corroborated by Sanchez et al [52], who reported that anxiety or depression did not contribute to dyspnea sensation in this population. We think that studies with patients with various entities are necessary to clarify the relationships of psychophysiological determinants of dyspnea.

Our study has its limitations. The QOL assessment was a secondary outcome in a study focused on the identification of diagnostic biomarkers in bronchoalveolar lavage fluid in patients with ILD. The results should also be corroborated in larger populations.

Our study has demonstrated that diagnosis of ILD impacts not only physical but also psychological aspects of QOL. Physical aspects of QOL are far more than a resultant of functional test parameters. Due to the abundance of questionnaires used to assess QOL in chronic diseases, there is a need to validate an ILD-focused questionnaire for the Polish population, which would give an overview about the position of patients with ILD compared with those with other chronic respiratory diseases.