Trends in mortality from idiopathic pulmonary fibrosis in the European Union: an observational study of the WHO mortality database from 2001–2013

Discussion

In this observational study of the WHO mortality database we report age-standardised death rates (ASDR) from IPF of 3.8 per 100 000 for males and 1.5 per 100 000 for females across the EU. There are substantial differences in IPF mortality rates between member states although there is an overall increase in mortality from IPF in most EU countries. Four countries (Denmark, Austria (males only), Croatia (males only) and Romania (females only)) demonstrated a decrease in mortality from IPF during the observation period. The greatest increases in IPF mortality were observed in the UK, Finland and Portugal. The greatest percentage increases occurred in countries that had comparatively low rates of IPF mortality, notably Lithuania, the Czech Republic and Croatia (females only). There is a persistent sex–mortality gap in most countries, a difference which appears to be increasing over time.

Our finding of increasing overall mortality attributed to IPF is consistent with previous reports [8, 21] and is likely to reflect an increase in the incidence of the disease across the EU. An increase in IPF incidence may be a true biological phenomenon, given the well-described ageing of the world population. Recent investigations have suggested that IPF is a disease of accelerated lung ageing [22] and cellular senescence, a hallmark of ageing, is increased in IPF lungs and appears to play an important role in disease pathogenesis [23]. Furthermore, aged mice are more susceptible to experimental lung fibrosis [24] and epidemiological data also indicate that the incidence of IPF rises with advancing age [6, 20, 25].

Alternatively, the increasing mortality from IPF may be in keeping with increased recognition and diagnosis of the disease, as previously described [7, 26]. Navaratnam et al. [21] modelled IPF incidence using a UK General Practitioner database and identified an increase in the incidence of IPF. They also assessed death registry data and found consistent findings between the independent databases [21]. Levels of specialist knowledge and equipment for the diagnosis of IPF have increased with time and this may account for some of the observed increase in rates of diagnosis and reporting of mortality from this condition. Another potential contributing factor may be the spread of high-resolution scanners in the last two decades, which is reported to have contributed to increasing diagnosis rates [12]. Furthermore, Organisation for Economic Co-operation and Development (OECD) statistics indicate that the availability of computed tomography (CT) scanners has increased in Europe [27]. There have also been changes in diagnostic criteria for IPF over time, with the first guidelines published in 2000 and then modified in 2011 [13], which may further impact case identification.

An increase in mortality among the IPF population could also contribute to the increasing mortality rates observed; however, in the absence of a European-wide database, it is difficult to scientifically address this possibility. Although efforts have been made to generate a Europe-wide registry [28], the results are not yet comprehensive. While the WHO mortality database used in this study is unique in that it captures population-level mortality statistics, future investigations in mortality from IPF would be enhanced with a resource that provides similar population-level statistics on incidence and prevalence. Such a resource would allow investigators to assess whether changes in mortality statistics from IPF are driven primarily by increasing incidence of IPF or whether changes in mortality are limited to the IPF population alone. While the dataset used in the current study does not directly address IPF incidence, it may be a useful proxy for examining population-level diagnostic trends.

Previous studies have highlighted geographical variations in IPF mortality [8]. Potential explanations for the geographical variation may include environmental and genetic factors. Smoking is one of the most important risk factors for IPF; however, countries with higher IPF mortality rates have similar or lower rates of smoking to those with lower IPF mortality rates [29]. Despite the genetic similarity across EU member states, it is possible that genetic differences may contribute to the geographical variation in IPF incidence, as has been suggested elsewhere [30]. In addition, a study in the United States has demonstrated lower mortality from IPF in the black population [31]. Kaunisto et al. have argued that regional differences are likely to be due to heterogeneity of data collection [32]; however, this heterogeneity is reported to be between studies rather than between countries using a unified database. Other approaches have involved using clinical registries and survey data, approaches which are likely to involve significant selection bias. These studies are, however, likely to have higher levels of case validation than is present in national death registries based on death certificate data.

In population studies IPF is frequently found to be more prevalent in males than in females [11, 20]. A previous report found similar mortality rates to our findings for the period 2005–2008 and supported a male-to-female mortality ratio of ∼2:1 in the UK [21]. In the current study, we observe a sex–mortality gap that is present in most EU countries and this sex–mortality difference appears to be increasing over time. Our finding of an increasing difference between men and women is in contrast to other health conditions, where we have observed a narrowing of sex-related mortality differences, for example in cardiovascular disease [14] and some cancers [15, 33]. However, whereas in most other health conditions a sex–mortality difference may be attributed to different patterns in smoking and hazardous drinking [34], previous studies have suggested that these behaviours do not contribute to IPF mortality [35].

There are several limitations that should be considered when interpreting the results of this study. As with any registry data, the accuracy of the mortality rates is dependent upon the quality of death certification and there is always potential for the true cause of death to be different from that recorded. Although we have chosen to use data from the WHO mortality database, which ensures data quality through careful evaluation prior to inclusion, coding practices may vary between countries and over time, potentially limiting the utility of geographic and temporal comparisons. Despite these potential limitations, the WHO database is a valuable resource for exploring diagnostic trends. While we acknowledge that there may be variation between countries in adopting new iterations of consensus diagnostic criteria, we have chosen to focus on changes over time in IPF mortality rates rather than differences between countries with respect to crude mortality rate. Furthermore, we restricted our analysis to ICD-10 codes and defined IPF as J84.1, which has been used previously for epidemiological studies of IPF [9]. Since these data reflect the study period 2001–2013, and given that the idiopathic interstitial pneumonias were reclassified in 2013 [36] and the diagnostic criteria were refined in 2011 [13], our report may reflect a heterogeneous group of ILDs rather than relating exclusively to IPF. An additional limitation of this study is that it is not likely to account for changes in IPF mortality due to the introduction of the novel antifibrotic agents pirfenidone and nintedanib. Pirfenidone was first approved for use in the EU in 2011 but was not available in most member states until 2012. Therefore, its effect on IPF mortality in the last observation period (2011–2013) is likely to be minimal. Furthermore, nintedanib was not approved in the EU until 2015 while, at the end of our observation period, the combination of prednisolone/azathioprine/N-acetylcysteine was demonstrated to increase mortality [37] and is no longer recommended. Any resulting decrease in mortality is thus unlikely to have been observed in these data.

In summary, IPF mortality rates appear to be increasing across the EU and this increase may reflect a greater prevalence of the disease, driven in part by case identification. In the absence of a Europe-wide registry it is not possible to assess the survival of patients with IPF, thus highlighting the need to develop such a resource. IPF mortality rates are higher in males than in females and this disparity appears to be increasing in size. While this may reflect local coding practices, there is substantial variation between countries in the number of deaths recorded with IPF as the primary cause.