This study demonstrates longitudinal HRQL development in a prospective cohort of patients with ILDs. Our data illustrates that HRQL deteriorated by a clinically relevant amount in a third of the patients after this period. Key predictors for HRQL decline were lower lung function values at baseline across all K-BILD domains. Additionally, older age was a significant determinant in the deterioration of ‘psychological impact’.
Patients who had missing outcomes had lower lung function values at baseline although they had had a shorter disease duration. This could be indicative of progressive fibrosing ILD. Kolb et al described that, progressive fibrosing ILDs are characterized by a rapid decline in lung function, which may have been the cause for the drop out [19]. Moreover, another study describes the patterns of progressive fibrosing ILD and a short disease duration is attributable to this type of ILD [20].
The ILD categories (IPF, sarcoidosis and other) differed in terms of disease duration, number of comorbidities and type of medication. To explain these differences, IPF is a deadly disease, characterized by a short disease duration and high number of comorbidities than any other ILD subtype [21]. Regarding medication, apart from patients with IPF-associated cough or acute exacerbations and those who underwent steroid tapering, the majority of IPF patients received anti-fibrotic therapy, while most patients with other ILD subtypes received immunosuppressant medication.
We observed minimal changes in mean K-BILD scores on the population level after a year. These results are similar to results of the INBUILD trial [22], although the trial only recruited patients with progressive fibrosing ILD. Nevertheless, the baseline patient characteristics in this trial were congruent to those in our study, in terms of age, baseline DLCO % predicted and mean K-BILD scores. Baseline K-BILD scores in this study were 52.5 ± 11.0 and 52.3 ± 9.8 in the nintedanib and placebo arms respectively, (52.8 ± 12.1 in our study). After 52 weeks, the measured score differences were under one unit, similar to our study. The authors, however, did not report on the intra-individual changes in HRQL scores according to pre-specified MCIDs, and we could therefore not make a comparison on this level. Nonetheless, we must consider these small changes. Because a third of the patients worsened in HRQL but the mean K-BILD scores remained the same, it is possible that ILD was characterized by alternating good and bad episodes throughout the 12-month period. At the same time, this could allude to the MCID for K-BILD being too small.
The present study found a relationship between HRQL decline and lung function decline. This is synonymous with previous findings. For example, although the study focused on IPF, Kreuter et al found that an increase in FVC % predicted (beta 0.04, p = 0.006) is a predictor for better HRQL scores [9]. Furthermore, a later analysis in the same population also found higher DLCO % predicted to be associated with higher VAS scores [10]. The only study that included different subtypes of ILD did not find any significant impact of lung function with HRQL, but the study was cross-sectional and thus could not detect these long-term associations [23].
Our study revealed alternating HRQL associations with either baseline FVC % predicted or DLCO % predicted in different K-BILD domains, with DLCO % predicted as an important predictor in respiratory domains and FVC % predicted in the psychological domain. Shortness of breath, dyspnea, is generally associated with HRQL decline [8] and with DLCO % predicted in ILD patients [24]. This could explain why DLCO % predicted was associated with ‘breathlessness and activities’ and ‘chest symptoms’ in our study. Similarly, depression is a common comorbidity in ILD [25] and a study found that depressive symptoms correlate with decline of FVC % predicted in ILD patients [26]. We, therefore, demonstrate either lung function parameters may be used to predict HRQL decline.
Having IPF was linked to less HRQL decline as compared to having sarcoidosis and other ILD subtypes in our study, and there are possible explanations for this. It is known that IPF is associated with substantial morbidity [21] and the prevalence of comorbidities is linked to mortality [27] and HRQL deterioration [9]. In our study, IPF patients had the highest number of comorbidities. We expect that these comorbidities were detected early and managed rapidly, due to the severity of the disease. This in turn could have led to an improvement in overall HRQL. Beyond this, most IPF patients were treated with either nintedanib or pirfenidone. These medications have been shown to slow down lung function decline [6, 28] and we assume IPF patients prescribed either nintedanib or pirfenidone possibly experienced less HRQL deterioration than patients with other ILD subtypes.
We also found higher age to be a determinant of HRQL impairment in ‘psychological impact’ and VAS. It is widely known that functional impairment increases as one ages. This result is consistent with other studies [10].
Patients with secondary education had a significant association with HRQL decline compared to patients with higher education. It is possible that patients with a higher level of education may be able to better assess and understand their prognosis than patients with lower levels of education. Outside of ILD, a study found that lower education levels are associated with unhappiness, poor social relationships and poor self-assessed health [29].
Unexpectedly, the use of immunosuppressant medications was not associated with less HRQL decline. However, this association was present with the linear outcome for K-BILD change score in the ‘psychological’ domain. Immunosuppressive agents are used to treat various forms of ILD. It is believed that they improve the lung pathology [30]. We expected patients on immunosuppressive therapy to therefore have better HRQL scores after 12 months.
Another unanticipated finding was comorbidity burden was not a predictor of HRQL decline. Comorbidities may impact treatment decisions and thus impair HRQL [31, 32]. The association between a higher number of comorbidities and HRQL decline was shown in IPF cohorts [10]. Perhaps, comorbidity burden is more significant in IPF than other ILD subtypes. Also, it is possible that the comorbidities in these two specialized study centers are well managed, and thus, did not determine HRQL decline.
Our first sensitivity analysis demonstrated the robustness of our results, as the main predictors for HRQL, DLCO % predicted and baseline HRQL scores had similar associations. The second sensitivity analysis excluding IPW showed the complete case analysis underestimated certain predictors of HRQL decline due to drop out bias. The associations that diminished can be explained by the characteristics of the dropouts. They had lower FVC % predicted, and the majority had other ILD subtypes. Moreover, the fact that patients who deteriorated were much older explains the difference of these results.
There are some crucial limitations in our study. This study was observational and therefore, we could only report on associations and not on causations. Also, it is to note that K-BILD does not assess some health issues relevant to ILD such as cough. Cough has been shown to negatively influence HRQL in ILD [33]. However, it is possible that cough was indirectly assessed by its impact on “chest symptoms” and “breathlessness and activities”. In addition, our study did not collect data on weight or BMI and physical activity, and these covariates could provide more insight into the patient’s well-being. Furthermore, non-participation bias was a limitation, although this is to be expected in longitudinal studies. One strength is that we are the first to employ K-BILD in a longitudinal analysis in a German cohort with patients diagnosed with different ILD entities. Although the group is heterogeneous, it is important to include otherwise not commonly studied subtypes of ILD because they have differing prognoses and patterns. Lastly, we demonstrate the validity of K-BILD as it captured similar results to the generic VAS.