Background
Idiopathic pulmonary fibrosis (IPF) is a rare, fibrosing interstitial lung disease (ILD) characterized by progressive loss of lung function, dyspnea, and deteriorating quality of life [
1,
2]. Most commonly, patients with IPF are male and aged > 60 years at first presentation [
3]. The prognosis for patients with IPF is poor, with median survival estimates of 2 to 5 years following diagnosis [
4,
5]. Estimating the precise incidence and prevalence of IPF is challenging, given the limited availability of epidemiological data and lengthy diagnostic process.
Although a standardized, internationally accepted diagnostic pathway for IPF exists [
3], misdiagnosis as well as delayed diagnosis and treatment often occur [
4,
6]. Despite the recent approval of two antifibrotic drugs, pirfenidone and nintedanib, which delay disease progression and may be associated with improved survival [
7], prognosis remains poor [
3,
8,
9].
Currently, data on the epidemiology and health economic burden of IPF in Germany are sparse. Wälscher et al. (2020) showed that over a 5-year observation period, more than four out of five ILD patients were hospitalized, with Frank et al. (2019) reporting hospitalizations to be the main driver for both total and ILD-associated costs [
10,
11]. However, both studies used data collected between 2009 and 2014, and neither focused specifically on IPF.
Against this background, the current claims data study provides greater insight into the epidemiology, healthcare resource utilization (HCRU) and cost, and disease course of IPF in Germany. It describes the demographic and clinical characteristics of incident patients with IPF in Germany and reports current incidence, prevalence, and all-cause mortality rates. Furthermore, this study maps HCRU (including antifibrotic and non-antifibrotic therapy) and provides a detailed description of the associated direct costs. Finally, using proxies for disease deterioration, IPF disease progression is assessed.
Discussion
There is a substantial gap in knowledge relating to the epidemiology, economic burden, and disease course of IPF worldwide. Our retrospective claims data study in Germany aimed to address this gap by describing the demographic and clinical characteristics of patients with IPF, providing updated epidemiological data, assessing disease progression, and estimating the HCRU and costs associated with this disease.
Between 2015 and 2019, 1737 incident IPF patients were identified. Following adjustments for age differences compared with the German SHI population, cumulative incidence was estimated to be between 9.6 and 10.9 and point prevalence between 21.7 and 24.1 per 100,000 individuals for 2016–2019. The point prevalence showed a slight upward trend, whereas the cumulative incidence was stable. There are no current population-based incidence or prevalence rates for IPF in Germany, and substantial variation is reported in data from other countries. In a review of 34 studies from 21 countries published between 1968 and 2012, Hutchinson et al. [
28] reported incidence estimates of 3–9 cases per 100,000 individuals per year in Europe and North America. The German Guideline for Diagnosis and Management of IPF from 2013 reported prevalence estimates of 2–29 cases per 100,000 individuals [
29]. Compared with these estimates, our data suggest a relatively high incidence and prevalence of IPF in Germany. It should be noted that Saxony and Thuringia are rural compared with other German regions. The current population in these regions may be less affected by air pollution, which is a recognized risk factor for the incidence and acute exacerbation of IPF [
30,
31]. However, historical pollution levels in Saxony and Thuringia may have been higher, as both regions were part of the German Democratic Republic, in which pollutant emissions were previously extremely high [
32‐
34]. The socio-economic disparities that still exist between German states may limit how representative these incidence and prevalence rates are for Germany as a whole; however, mortality in most age groups has been shown to converge across the former East–West political divide [
35,
36].
Our IPF population was older, predominantly male and demonstrated a high burden of comorbidities [
15,
37]. Hypertension, COPD, ischemic heart disease, heart failure, type 2 diabetes, GERD, and asthma, which have all been identified as important IPF comorbidities [
1,
10,
37,
38], were prevalent. However, it is common for pulmonary fibrosis to be misdiagnosed as heart disease, COPD, or asthma, which might result in an overestimation of comorbidity numbers [
39]. The high proportion of hospitalizations for pulmonary diseases also suggests delayed diagnosis of IPF.
Data on HCRU for patients with IPF in Germany are sparse. Wälscher et al. [
10] reported that 86% of incident ILD patients were hospitalized over a 5-year observation period (2009–2014). In our study, for the same follow-up period, a higher percentage of patients with IPF (93%) were hospitalized, consistent with the characterization of IPF as a more serious form of ILD. Within 5 years of the initial IPF diagnosis, approximately one-tenth of patients had been treated with antifibrotic agents in our sample. This is low when compared with other reports. Behr et al. [
7] found that around half of German patients with IPF received either nintedanib or pirfenidone. However, Behr et al. [
7] used registry data from specialized ILD centers, whereas our claims dataset represents a broader population of patients with IPF, which could explain this difference. Another reason for the low use of pirfenidone and nintedanib in our sample could be the fact that diffusion to routine care takes time and these medications were only approved in Germany in 2012 and 2015, respectively.
Our study highlights the economic burden of IPF, with healthcare costs per patient three times higher than the average yearly healthcare expenditure per insured individual in Germany [
40]. Hospitalizations and medication were the main cost drivers, with more than half of the total all-cause direct costs for newly diagnosed patients with IPF caused by hospitalizations and almost one-third by medications. For IPF-related direct costs, medication accounted for around half of total costs and hospitalizations for more than one-third. Frank et al. [
11] examined the economic burden of ILDs (IPF and sarcoidosis) and their associated comorbidities using a claims dataset that covered about one-third of the German population. This study looked at an earlier period (2009–2014) and distinguished between all-cause costs and ILD-related costs. The mean annual per capita healthcare costs for patients with IPF were lower than our study (€12,111 vs €15,721), which can partly be explained by the rise in per capita healthcare expenditure and price levels. The study’s findings are consistent with our own, as hospital costs were the main driver of total costs, followed by medication. By contrast, the study from Frank et al. [
11] found that medication accounted for only 13.9% of ILD-related costs, compared with 49.4% of IPF-related costs in our study. Although IPF is the most common subtype of fibrosing ILD, a direct comparison of these two studies is not appropriate. However, some of the differences may result from the earlier time period examined by Frank et al. [
11], as pirfenidone and nintedanib only became available in 2012 and 2015, respectively. Over the last decade, there has been an increase in the cost of antifibrotic agent prescriptions in Europe due to these licenses [
8].
We report a 5-year survival probability of around 50%, whereas a Swedish study using similar inclusion criteria for IPF (ICD-10 code of J84.1, aged ≥ 40 years) reported a rate of approximately 30% over the same duration, and a median survival time of 2.6 years [
15]. Our results are consistent with an Australian IPF registry data study, which estimated the cumulative mortality rate 1, 2, 3, and 4 year(s) after diagnosis at 5%, 24%, 37%, and 44% (vs 15%, 26%, 35%, and 41% in our study), respectively [
38]. Using German registry data, Behr et al. [
7] reported the 1- and 2-year mortality rates for patients with or without antifibrotic therapy as 13% vs 54% and 38% vs 79%, respectively. Global estimates for median survival are approximately 2–5 years [
4,
5], indicating a comparatively high overall survival in our sample.
In line with historical international guidelines for the management of patients with IPF [
17], a high percentage of patients using LTOT after initial diagnosis were identified, with the 25th percentile reached after 6.9 months and the median after 55.1 months. To our knowledge, there are no studies analyzing LTOT use among patients with IPF using time-to-event analysis. Recent German studies based on registry data reported LTOT use of 33.1% and 32.3% among patients with IPF, with a mean disease duration of 2.3 and 2.0 years, respectively [
1,
41].
Our study suggests a relatively rapid worsening of health in newly diagnosed patients with IPF. A US claims data study from 2016 found an all-cause hospitalization risk of 39% within 1 year of IPF diagnosis, with a US registry study from 2020 reporting a 30% hospitalization risk for the same period [
42,
43]. By contrast, the 1-year probability of all-cause, non-elective hospitalization was 63% in our sample. Hospitalization rates for ILD patients in Germany have been reported to be higher than those for patients with IPF in the US [
10]. This could be explained by the different inclusion criteria used by Wälscher et al. [
10], and different referral and hospitalization patterns between the US and Europe. These authors also used German claims data, reporting a median time from initial IPF diagnosis to the first ILD-related hospitalization of around 15 months [
10], whereas in our analysis the median time from initial IPF diagnosis to the first IPF-related hospitalization was not reached after 5 years. This could be explained by the use of a wider list of ILD codes used by Wälscher et al. [
10] to define ILD.
Limitations
A number of limitations, some of which are inherent to retrospective claims database analyses, were identified in the current study. This includes the information contained in the AOK PLUS dataset. Direct measures of functional status, such as forced expiratory volume in one second, forced vital capacity, and 6-min walk test, are not included. As a result, proxies were used to describe disease deterioration. German claims data do not report specific clinical reasons for hospitalizations, containing only ICD-10 codes. Inpatient rehabilitation is only partially covered in German claims data, as SHI only supports rehabilitation outside of the workforce, with rehabilitation of the working population covered by statutory pension insurance. As such, the number of rehabilitation days and associated costs in this study are likely to be an underestimation. Considering the mean age of patients with IPF in our sample, we do not believe this bias to be large. A further drawback of German claims data is the lack of information on drugs dispensed from hospital pharmacies, as well as nursing and sick leave costs; these latter two add to the indirect economic burden of disease.
There are also limitations with respect to how information is reported in the AOK PLUS dataset. For example, outpatient diagnoses and costs are not linked to single visits but are reported by individual physicians per quarter. The total number of IPF-related visits and related costs may therefore be misestimated, if invoiced by the same physician. A drawback in identifying IPF patients via the ICD-GM-10 code J84.1, is that this code includes a range of ILDs such as diffuse pulmonary fibrosis, fibrosing alveolitis (cryptogenic) (both formerly used instead of IPF), and Hamman-Rich syndrome. The code can also include other idiopathic interstitial pneumonias such as nonspecific interstitial pneumonia. A proportion of the IPF cases identified by this study might therefore potentially be misclassified, which could be a reason for the relatively high prevalence and incidence numbers reported, compared with other studies outside of Germany. However, as IPF is the most common fibrosing ILD, possible misclassification of the case definition is reduced [
8]. The risk of possible misclassification was further reduced by excluding patients with diagnoses suggestive of ILDs other than IPF (Additional file
1: Table S1). Furthermore, it is not possible to unambiguously disentangle the individual contribution of distinct, potentially life-limiting diseases in the multimorbid patient to the outcomes observed. In this context, overlapping, interacting symptoms and complications of IPF and co-existing diseases (e.g., cardiovascular diseases) are assumed to detrimentally affect assignment to as well as rates, timing and costs of IPF-related hospitalizations. This is an unsolved methodological issue for any diagnosis-based uncontrolled study.
Finally, some limitations are unrelated to the dataset. Prescriptions for both drugs containing nintedanib in Germany (Ofev and Vargatef) were included to estimate the prevalence of antifibrotic therapy as a treatment against IPF; however, Vargatef is only licensed for lung cancer. Our sample contains patients diagnosed with both IPF and lung cancer, yet the rationale for a specific prescription is unknown. As such, Vargatef was considered to be antifibrotic therapy in this analysis.
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