Interstitial lung disease incidence and mortality in the UK and the European Union: an observational study, 2001–2017

Principal findings

In this observational study of ILD across the EU and UK between 2001 and 2017, we have shown an overall increasing incidence of ILD across most countries for both men and women. In most countries, men have greater incidence and mortality compared to women, a difference which persists throughout the observation period. Further, despite overall increases in mortality between 2001 and 2017, there have been decreases in mortality for men and women in the majority of countries at the end of the observation period. The MIR of ILD is flattening or decreasing in most countries, with negative trends in MIR for men and women in the majority of countries in Europe.

The principal aim of this investigation was to obtain current estimates of the burden of ILD across Europe. Specifically, we sought to understand the changes in incidence and mortality over the past two decades because this time period has seen much development in the classification, diagnosis and management of various ILDs. Providing a comprehensive look at incidence and mortality from ILD across Europe, this report will serve as a useful benchmark for current burden of ILD and for monitoring future progress in the management of this heterogeneous group of chronic lung diseases.

Comparison with prior studies

The majority of reports to date have attempted to provide estimates of incidence and mortality in ILDs utilising primary physician surveys, large health system databases or surveys of respiratory physicians. These previous reports have focused on single health systems and are unable to make strong comparisons in incidence and mortality between countries or health systems. For instance, Kornum et al. [20] performed an analysis of a national health database in Denmark and reported adjusted incidence rates of ILD of approximately 2.91 per 100 000 population while another study from the same country reported annual incidence of 4.1 per 100 000 population cohort [21]. These estimates are similar to the incidence estimated in other health systems including Greece, which had a reported incidence of 4.63 per 100 000 population [22], and significantly higher than the incidence reported recently in France at 1.94 per 100 000 population [23]. These data highlight significant differences in estimates of incidence of ILDs between health systems and no prior study has attempted to make direct comparisons between countries as we have done in the current report.

Previously, our research group assessed mortality from IPF across Europe [11]. We demonstrated that across most of the EU, the mortality from IPF was increasing between 2001 and 2014. This report was limited, however, in that we were unable to estimate incidence rates and it was not possible to demonstrate whether increases in mortality from IPF were related to increased awareness and identification of IPF, or whether mortality was increasing independent of incidence. One previous report has also shown increasing incidence and prevalence of IPF in the UK over a similar period [24]. As a result, we planned the current study to better estimate both incidence and mortality from ILD (inclusive of IPF) and to estimate the changes in mortality relative to changing incidence over a similar observation period. Here, our data suggest that over the past two decades, there have been marginal increases in the overall incidence of ILD and greater increases in mortality during the time period.

Despite this, we observed significant decreasing trends in ILD mortality and in MIRs in multiple countries during the most recent 5 years of observation. Specifically, we observed statistically significant negative trends in mortality for 21 countries (75%) for men and in 24 countries (86%) for women for trends ending in 2017. Further, using MIR to understand recent management of this chronic lung disease, we demonstrated that there were significant decreasing trends in MIR in 23 countries (82%) for men and in 23 countries (82%) for women. Although our study assessed ILD broadly, this finding is important because there have been advances in the treatment of IPF with the introduction of anti-fibrotic agents in the EU from as early as 2012 [3, 4]. The approval of anti-fibrotic agents was a significant event in the treatment of IPF because, for the first time, therapeutic agents were available to slow the progression of lung fibrosis and reduce mortality. Although our data are observational in nature and we are unable to make causal statements, IPF constitutes a significant portion of ILD diagnoses with estimates of nearly 20% of all ILDs related to IPF [2], and our study suggests decreases in mortality from ILD after the introduction of anti-fibrotic agents in multiple health systems. Future investigations should, therefore, aim to clarify whether the observed decreases in mortality from ILD are, in fact, driven by improved management of IPF during this period. Furthermore, while no one particular feature has been identified as causal in the development of ILD including sarcoidosis, there are multiple potential explanations for the between-country differences observed in our study. Previous reports of sarcoidosis, for example, have highlighted geographic differences related to sarcoidosis incidence which are potentially associated with geographic features including higher latitudes and sunlight exposure, exposure to coastal or rural areas, and agricultural employment or exposure to environmental antigens. Other ILDs may have other associated risk factors: e.g. hypersensitivity pneumonitis may have greater burden in areas with high agricultural employment, and IPF has been associated with greater exposure to environmental particulates (e.g. particles with a 50% cut-off aerodynamic diameter of 2.5 µm), as well as having strong associations with lifestyle factors such as tobacco smoke and with other comorbid conditions such as gastro-oesophageal reflux disease. Our study was not designed to assess each of these potential contributors and although it is unlikely that any one of these additional variables is the single explanatory factor for the observed differences, we have highlighted these additional potential variables as future work may help to elucidate the individual relationships with ILD morbidity and mortality across Europe.

Strengths and weaknesses of the study

The major strengths of this report are the total number of countries observed and the total duration of the observation period for analysis. We used standardised estimates of incidence and mortality, which allows us to make comparisons between countries by removing the influence of country-specific demographics on these variables. Most previous reports have focused on the epidemiology of ILD within a single health system or with shorter observation periods. Furthermore, we have also used MIR as a marker of performance in management of ILD.

Despite these strengths, there are several limitations that must be considered when interpreting the results of this observational study. First, the data attained are applicable solely for the purpose of identification and comparison of ILD between the EU countries and the UK and, as such, causal relationships cannot be drawn. We acknowledge that confounding variables beyond the scope of discussion will have differential effects by country on the data presented from this observational study: using sex-specific, age-standardised mortality and incidence rates attempts to account for some confounding of demography. Next, our data represent the broad category of ILD, which comprises diseases with heterogeneous clinical features and diagnosis, with variations in management and prognosis. Individuals with sarcoidosis, for example, may carry the diagnosis through lymph node biopsy but lack pulmonary involvement until late stages (i.e. stage IV) of the disease. Owing to the manner in which GBD reports their data, we are unable to ascertain specific features of trends relating to specific causes of ILD such as IPF, and by including sarcoidosis we may potentially underestimate the true mortality burden from other ILDs. Future work should attempt to characterise trends in individual ILD aetiologies. As outlined above, there is variation in the reporting of data quality between European countries that may also influence the results of this study. We attempted to address this limitation by performing a sub-group analysis with data restricted to those countries with a 5-star rating in order to improve comparability (supplementary material).

Conclusion

Over the past two decades, there have been increases in the incidence and mortality of ILD in Europe. Recent trends, however, demonstrate decreases in mortality from ILD in the majority of European countries for both men and women. These data support the ongoing improvements in the diagnosis and management of ILD.