Background
Fibrotic interstitial lung diseases (ILDs) encompass a wide variety of disorders that can be related to underlying connective tissue disease (CTD), occupational or environmental exposures, or an unknown cause [
1]. Commonly reported fibrotic ILD subtypes include idiopathic pulmonary fibrosis (IPF), CTD-associated ILD (CTD-ILD), idiopathic non-specific interstitial pneumonia (NSIP), and chronic hypersensitivity pneumonitis (HP). Limited epidemiologic data are available for fibrotic ILDs other than IPF, and the heterogeneity and relative rarity of these ILD subtypes are significant barriers to research.
Comorbid conditions are increasingly described amongst ILD patients. Data suggest an increased prevalence of several comorbidities in patients with IPF compared to the general population [
2]. These comorbidities contribute to the high economic burden, substantial morbidity, and early mortality of IPF. Recent studies have described comorbidities in international cohorts of patients with IPF [
3‐
6]; however, there are minimal data for non-IPF fibrotic ILDs.
The CAnadian REgistry for Pulmonary Fibrosis (CARE-PF) is a multi-center, prospective registry designed to study the natural history of fibrotic ILD in a Canadian population [
7]. This is the largest cohort of ILD patients in Canada and among the largest internationally, with the goal of providing valuable insight into the characteristics, management, and outcomes of these relatively rare diseases. The aim of this sub-study was to describe the baseline characteristics, risk factors, and comorbidities of patients enrolled in CARE-PF during the first 18 months of patient recruitment.
Discussion
We described the baseline characteristics, risk factors, and comorbidities of patients with fibrotic ILD enrolled during the first 18 months of CARE-PF, a multicenter prospective registry inclusive of all fibrotic ILD subtypes that is amongst the largest registries of its kind. CTD-ILD, IPF, and unclassifiable ILD made up 80% of ILD diagnoses at ILD referral centers in Canada, while idiopathic NSIP was rare when adhering to previously recommended diagnostic criteria. Comorbidities were frequent, with limited ability of the CCI to represent the extent and spectrum of comorbid diseases in this population.
Prospective registries can provide insight into ‘real world’ disease epidemiology, natural history, treatments, and outcomes. They are particularly useful when studying heterogeneous and rare diseases such as fibrotic ILDs; however, many registries have focused only on IPF with limited data for other fibrotic ILD subtypes. In our registry, CTD-ILD was the most frequent diagnosis (33.3%), followed by IPF (24.7%) and unclassifiable ILD (22.3%). In contrast, a recently published large prospective ILD registry from India found HP was the most common ILD subtype (47.3%), followed by a much lower frequency of CTD-ILD (13.9%) and IPF (13.7%) [
19]. Older epidemiologic data describe similarly variable frequencies of ILD diagnoses. This wide variability is likely multifactorial, related to clinical setting and study design, genetic and geographic heterogeneity, populations with variable risk factors, differences in diagnostic approach, and changes in diagnostic criteria over time.
We report a higher percentage of unclassifiable ILD and a lower percentage of idiopathic NSIP compared to many other ILD cohorts. The frequency of unclassifiable ILD in our cohort (25% of incident cases) is at the high end of reported values in the literature, which have ranged from 0.2 to 24% [
19‐
22]. Some discrepancy may be attributed to referral bias, the complexity of cases assessed at our recruitment sites, or the relatively short duration of follow-up without ample time for evolution of some cases to a defined ILD subtype; however, it is likely that the diagnostic criteria used in our study play an important role. We adhered to strict guideline-based criteria whenever possible, most notably requiring biopsy confirmation of idiopathic NSIP as suggested in a previous American Thoracic Society document [
12]. A diagnosis of chronic HP required a minimum of two out of three domains (clinical, radiological, pathological) to be met, which likely contributed to the lower percentage seen in our cohort (7.5%). Chronic HP was a frequent leading differential diagnosis amongst those with unclassifiable ILD, suggesting the use of different diagnostic criteria for HP may impact its reported prevalence within our cohort. We also considered IPAF to be a subgroup of unclassifiable ILD given the absence of a formal recommendation for this entity to be considered a specific clinical diagnosis [
14]. These approaches resulted in a high frequency of unclassifiable ILD in our cohort, as well as a very low frequency of idiopathic NSIP (0.9%). In contrast, idiopathic NSIP was diagnosed in 8.5% of patients in an Indian registry that did not require a SLB for diagnosis [
19], and was a frequent differential diagnosis in our patients with unclassifiable ILD. It is therefore unclear if we have underestimated the prevalence of idiopathic NSIP or if it has been over-diagnosed in other cohorts. Regardless, the high frequency of unclassifiable cases after a SLB and multidisciplinary discussion in our cohort highlights the limitations of current diagnostic algorithms and the challenges clinicians face when determining ILD subtype [
13]. The extent to which this influences individual patient management and outcomes requires further study.
Many observational studies have suggested links between various environmental exposures and multiple subtypes of ILD. The strength of association varies between exposure and disease, with strong etiologic links established for diseases such as HP, asbestosis, and silicosis [
8,
23,
24]. While direct causal links are difficult to establish, exposures such as cigarette smoke, metal dusts, and farming have been frequently associated with IPF [
8]. Patient-reported exposures in our cohort were common in all diagnoses, with organic exposures more frequently endorsed than inorganic ones. Not surprisingly, organic exposures were most frequent in chronic HP. Organic exposures were also reported by over 50% of patients with IPF, which is higher than reported in other registries [
4], and possibly related to our broad definition of exposures that included items such as down feathers, musty smell, and standing water. One-quarter of IPF patients also endorsed an inorganic exposure, which is similar to the reported frequency in the German INSIGHTS-IPF registry [
4].
The high frequency and importance of comorbidities in patients with ILD is increasingly recognized. Studies suggest increased healthcare costs and physician visits in ILD patients compared to matched controls [
2,
25], with most studies focusing on patients with IPF and little information available for patients with other ILD subtypes. Patient-reported comorbidities were common in our cohort, with GERD (26.6%), COPD (23.1%), diabetes (15.2%), and OSA (14.5%) most frequently endorsed. The prevalence of comorbidities in patients with IPF was similar to previously described cohorts [
4]. We found that the frequency of comorbidities was lower in sarcoidosis compared to other diagnoses, likely reflecting the younger age of this group. The CCI was highest in CTD-ILD, reflecting the additional point that these patients received for a diagnosis of CTD. Removing CTD from the index, mean CCI was lowest in patients with CTD-ILD, likely reflecting the younger age of these patients. Although the CCI is a validated tool that predicts 1-year mortality in older adults [
15], it has never been specifically validated in patients with ILD. We chose to include the CCI in CARE-PF given the lack of an alternative validated comorbidity index for ILD at the time of study design, it’s extensive use and validation in other chronic diseases [
26‐
28] and validated use in health services research [
29‐
31]. However, the CCI had a very narrow distribution across our cohort of fibrotic ILD, suggesting it may be a poor discriminator in assessing the impact of comorbidities on patients with ILD. Additionally, the CCI does not capture all comorbidities that are relevant in ILD such as GERD and OSA. Furthermore, the CCI fails to account for functional limitation, which is increasingly recognized as an important component of frailty and a strong predictor of mortality in many chronic diseases [
32‐
35].
Our study has several limitations. First, CARE-PF is a prospective multicenter cohort of patients seen at specialized ILD centers and may not be representative of a general ILD population. While each site is a regional referral center and accepts patients from wide geographic areas, long travel times are a logistical barrier to many patients in northern and rural Canada. Second, we standardized the diagnostic approach for some ILDs that lack diagnostic criteria in order to maintain consistency across enrollment sites; however, our pre-specified approach may be different than that taken in some settings. Third, some of the data were based on patient report, including exposure history and some comorbidities, which could result in over- or under-reporting. Lastly, we were unable to assess longitudinal data (e.g., lung function decline, hospitalizations, mortality) due to the short duration of follow-up. Further analyses in this regard are planned for future studies. Despite these limitations we were able to characterize a large cohort of fibrotic ILD patients, expanding on previous research which has primarily focused on IPF.
Competing interests
KAJ, JM, HM, MK, JHF, GC, CJR, and PW have received grant support for CARE-PF from Boehringer Ingelheim. KAJ has received consultancy fees, speakers honoraria, and travel support from Boehringer Ingelheim and consultancy fees, speakers honoraria, and travel support from Hoffman-La Roche Ltd. CDF has received an unrestricted educational and research Grants from Boehringer Ingelheim. JM has received personal fees from Boehringer Ingelheim and Hoffmann-La Roche ltd. TT has received grants from Ontario Ministry of Health and Long-term Care, Ontario Ministry of the Environment and Climate Change, Canadian Institute for Health Research, Health Canada, and Canadian Respiratory Research Network. MK has received grants from Canadian Pulmonary Fibrosis Foundation, Pulmonary Fibrosis Foundation, Roche Canada, Prometic, Alkermes, and Actelion, personal fees from Boehringer Ingelheim, Roche Canada, GlaxoSmithKline, Gilead, Prometic, and Alkermes and allowance as Chief Editor from the European Respiratory Journal. SS has received personal fees from Astrazeneca, grants, personal fees and other from Boehringer-Ingelheim Canada, grants, personal fees and other from Hoffman La-Roche Canada, other from Medimmune, other from Prometic Canada, other from Sanofi-Aventis, outside the submitted work. NH has received grants and personal fees from Boehringer Ingelheim, grants and personal fees from Roche, grants, personal fees and non-financial support from Actelion, grants, personal fees and non-financial support from Bayer, during the conduct of the study. CJR has received grants from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from Boehringer Ingelheim, grants and personal fees from Hoffmann-La Roche, outside the submitted work.
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