Associations between comorbidities, their treatment and survival in patients with interstitial lung diseases – a claims data analysis

Interstitial lung diseases (ILDs) comprise around 200 different rare diseases that are mostly associated with high mortality but are heterogeneous regarding aetiology, prognosis, and treatment [1].

Recent clinical trials have created a sound basis for improved pharmaceutical treatment of patients with idiopathic pulmonary fibrosis (IPF) [2, 3]. However, the transferability of corresponding findings to routine care settings remains slightly uncertain [4]. This has also been highlighted in other diseases such as chronic obstructive pulmonary disease (COPD), in which comorbidities play a significant role in management decisions and clinical outcome [5]. Assuming that a similar interaction between comorbidity and outcomes in various ILD subtypes exists, more research is currently being conducted. These investigations are urgently recommended because the relationships between an index disease (here: ILD) and comorbidities include conditions that occur incidentally (e.g. arterial hypertension) as well as potential risk factors (e.g. gastro-oesophageal reflux) or complications respectively sequelae of the index disease (e.g. pulmonary hypertension). These different interaction modes therefore introduce a high level of complexity [6].

Available evidence suggests that comorbidities substantially affect disease progression and survival in IPF [7, 8], but information on other ILD subtypes is sparse [9, 10]. Moreover, previous research has often focused on distinct conditions [11‐14] instead of the patients’ entire comorbidity burden [15‐17] and, consequently, has tended to disregard the effects of pharmaceutical comorbidity management [8, 10, 18‐21]. Against this background, we assessed the baseline comorbidity profile of patients diagnosed with different ILD subtypes with a particular emphasis on the impact of distinct comorbid conditions and their respective pharmaceutical treatments on mortality. Since this study is the first to elucidate the associations of treated vs. untreated comorbidity and mortality in distinct ILD subtypes this new aspect may improve patient-centred ILD management.

Our study emphasizes the relevance of comorbidities and their consequent treatment across various ILDs. The results obtained through this study suggest the need for improving comprehensive pharmaceutical comorbidity management in ILDs, with a particular emphasis on the treatment of ILD-relevant comorbid conditions such as COPD (54.0% untreated) and GERD (35.1% untreated). Moreover, we perceived ILD subtype-specific comorbidity profiles. In this regard, the current ICD-10 coding system needs to be acknowledged as not being sufficiently differentiated to precisely separate distinct fibrosing ILDs from one another. Therefore, patients in the IIP and the other fibrosing ILDs group may be substantially more heterogeneous than in the other subtypes. Although within less frequent subtypes sample size issues might explain the observed differences, the LASSO method, which selects conditions based on relevance and not just on significance, provided first insights into subtype-specific comorbidity management approaches.

As expected, highly prevalent, potentially age-associated comorbid conditions were not necessarily those with the strongest impact on survival [35‐37]. Yet generally, we observed a clinically meaningful association with a higher mortality risk in the case of untreated distinct comorbidities. This emphasizes the need for active screening for and treatment of comorbidity in distinct ILDs. This might be highlighted by using the example of PH, which is recognised as a marker of diseases progression and prognosis in ILDs. PH frequently complicated the course of many ILDs depicted in our data and was identified as a crucial impact factor for all subtypes but radiation-associated pneumonitis. However, the advantage of specific PH drugs remains unclear. Recent trials have not only failed to demonstrate a benefit of PH-drugs but even reported potential detrimental effects in IPF [38]. Thus, treatment options are limited. Our data show that most patients are treated according to clinical practice with diuretics (96% of treated PH patients), while the use of PH drugs is low (14% of treated PH patients). Only in the subgroup of CTD-ILD and PH did 57% of the treated patients receive specific PH drugs that complied with current guidelines [39].

‘COPD’, ‘treated hypertension’, rheumatoid arthritis/connective tissue disorders’, and ‘OSAS’ were positively associated with survival in the complete cohort, but this was generally not the case on the level of the distinct ILD strata. Observations regarding ‘COPD’ and ‘treated hypertension’ might be explained by an early detection bias. This means that individuals with a known chronic condition are under frequent medical control, which increases the likelihood of earlier ILD diagnosis or that symptoms related to the comorbid condition yield an earlier detection of the ILD. In part, this explanation also applies to ‘rheumatoid arthritis/connective tissue disorders’ that can manifest as CTD-ILDs. Yet from a clinical point of view, this comorbidity should not occur in other subtypes. In contrast, a recent study concerning OSAS reports that CPAP therapy enhances the capability of IPF patients to perform activities of daily living, and the authors also proposed a mitigating effect on mortality [40], which corresponds with our own observation on the general impact of OSAS.

In addition to investigating the associations of comorbidity prevalence and its treatment to survival, we analysed the independent impact of distinct comorbidity-related drugs. Currently, the role of anti-acid treatment is particularly under discussion [7, 8, 41, 42]. As reported before for IPF [7], we could not find an association between anti-acid treatment and improved survival among the distinct ILDs, yet we simultaneously observed an independent negative impact of anti-acid drugs in other fibrosing ILDs and sarcoidosis, as previously shown for IPF [8]. Reverse causality must be considered as an explanatory factor to solve this apparent contradiction.

At the subtype level, we found no association between antiplatelet drugs and survival [8]. Yet, there was a positive impact of heparin (−derivates) in IIP, other fibrosing ILDs, sarcoidosis, and pneumoconiosis, but vitamin-K antagonists had no significant impact on survival in any subtype (except for radiation-associated pneumonitis). This needs to be further investigated, as recent analyses report a detrimental association between anticoagulants and survival or disease progression [20, 43, 44]. These studies focus on warfarin and IPF, whereas we studied all forms of vitamin-K antagonists and heparins within several ILD subtypes. Apparently, the role of anticoagulants is not entirely understood and a detailed examination of different drug entities is urgently required, especially for subtypes other than IPF. Here, particularly the role of NOACs – which were not included in our analyses as only 413 (1.1%) patients received corresponding prescriptions – should be further investigated.

Although our observed positive impact of drugs for the treatment of cardiovascular diseases supports recent studies claiming benefits for statin therapy [21, 45], the results of our analysis should be cautiously interpreted. Different patient groups and methodological approaches hamper a sound between-study comparison and our research focuses on a claims data-based study [46].

Compared with studies from specialized ILD centres [7, 8], our study displayed more frequent age-associated comorbidities (e.g., arterial hypertension, IHD, diabetes). Possibly, this display represents an incorporation of diagnoses from primary, secondary, and tertiary care, where priority setting for distinct conditions is assumed to be different. Additionally, different patient cohorts introduce substantial variation in regards to comorbidity prevalence [16]. Thus, direct comparisons are a sensitive issue. Moreover, the comorbidity burden was assessed based on ICD-10 codes, which could produce potential coding errors [47]. Furthermore, the coding practice may be triggered to some extent by remuneration relevance. One example could be the observed high prevalence of COPD, for which additional payments exist in the form of disease management programme bonuses. To ensure sound comorbidity diagnosis, we restricted our analysis to confirmed diagnoses and required the multiple documentation of comorbidity diagnoses within SA1. Given the high concordance between the main analysis and SA1, we assume that the risk of false-positive comorbidity diagnoses is of subordinated relevance.

Currently, the ICD coding system does not allow differentiation between different IIPs and other fibrosing ILDs. Since the documented codes could not be validated with medical files, the possibility exists that some of the patients may have been misclassified. To some extent, this possibility is supported by the unexpectedly high proportion of individuals with eosinophilic pneumonia as well as by the high share of individuals with comorbid 'rheumatoid arthritis/connective tissue disorders' in non-CTD-ILDs. Here, the assignment of individuals with polyarthropathy to other subtypes than CTD may result due to the coding requirement that CTD-ILD should only be diagnosed in the presence of systemic connective tissue disorders (ICD-10 codes M33-M335) but not in the case of polyarthropathy (ICD10-code M11-M14). Indeed, we observed a particularly high prevalence of polyarthropathy in the heterogeneous subtypes of other fibrosing ILDs and IIP and only within these two subtypes 'rheumatoid arthritis/connective tissue disorders' presented a significant association with survival. This suggests that the assignment to distinct ILD-subtypes is more in accordance with coding requirements than with a clinical perspective on aetiology, which might affect conclusions on the associations between comorbidity presence and mortality. This underscores that thorough differential diagnostic of patients with ILDs is essential to initiate appropriate ILD management.

To avoid using a misdiagnosis, we only allowed confirmed ILD diagnoses by medical specialists combined with related diagnostic procedures, applied specific code combinations (radiation-associated pneumonitis + diagnosis of malignacy, CTD + diagnosis of autoimmune disease), and, lastly, we disregarded patients diagnosed with multiple forms of ILDs. Although misclassification of subtypes cannot be excluded, the results of the main analysis correlated well with those of SA2 that applied a prospective validation of the initial ILD diagnosis. Therefore, we are convinced that a misclassification of subtypes does not crucially affect the associations found between comorbidity and survival.

Due to the lack of information on clinical parameters from the claims data, we could not account for the severity of the ILDs or that of comorbidities [46]. However, not included in our data was the baseline information on lung function. Disease severity remains a major impact factor on survival in ILDs. Therefore, this baseline information on lung function should be considered as an effect modificator because FVC and DLCO are established predictors for survival, e.g. in IPF [48] or SSc-related ILD [49]. Additional knowledge lacking from the claims data were reliable ICD codes for lifestyle factors such as smoking, dietary habits, and physical activity. These factors could not be incorporated into the analyses.

Moreover, the decision to pharmaceutically treat a comorbid condition depends on many factors such as the medical need for treatment, the potential interactions of treatment regimens, the patients’ individual performance status, and patient/physician preferences. Without the connection to medical files, the aspect of confounding by indication is clearly acknowledged to avoid potential misconclusions on treatment recommendations. However, even a connection with medical files cannot eliminate issues of adherence, meaning that the prescription of a distinct drug is not necessarily linked to the medication intake by the patient.

Likewise, we limited our research to baseline comorbidity only and did not incorporate newly occurring conditions in the course of the ILD. By this, further relevant conditions may have been disregarded. For example, Hyldgaard et al. have shown that substantial comorbidities are diagnosed after IPF-diagnosis but they only observed an additional mortality risk for late onset of cardiovascular diseases and not for other conditions [7]. Hence, baseline comorbidity restriction may presumably only affect the magnitude of HRs but not general statements on significance of the comorbidities reported.

Last, the nature of this analysis does not allow a distinction between ILD-related and non-ILD-related mortality. Indeed, all-cause mortality might not reflect the impact of distinct comorbid conditions on ILD-related mortality comprehensively. In particular, the effects of conditions that present substantial disease-specific lethality might be overestimated. Given recent evidence on an enhanced mortality effect of combined ILD and lung cancer [12, 50], it seems justified to assume corresponding interactions for other conditions as well.

In contrast, claims data remain less prone to selection bias than primary data-based cohorts. Thus, a realistic picture of comorbidity burden and treatment practice in daily routine care can be assumed. Moreover, large sample sizes enable analysis of the comorbidity profiles of rare ILD subtypes for which reference literature is sparse.

For enhanced ILD-management thorough comorbidity assessment seems paramount: We based our assessment on the Elixhauser Index which was amended by ILD-relevant comorbidities (‘GERD’, ‘OSAS’, ‘PH’, and ‘lung cancer’). Other than the often applied Carlson Index [36], the Elixhauser Index more stringently addresses chronic conditions related to high morbidity but not necessarily to high mortality [26]. Thus, our approach seems superior in the field of ILDs, which are quite heterogeneous regarding their survival prognosis.

To further alleviate management decisions, we finally disentangled untreated and treated comorbidity in regards to comorbidity-relevant drugs. In our opinion, this approach appears to be preferable to a simple prevalence-based analysis (comorbidity yes/no) that might fail to detect the peculiar relevance of pharmaceutical comorbidity management.

In conclusion, improved management of comorbidities in ILDs should address all survival-relevant conditions and not be limited to risk factors and sequelae. Consequently, more stringent pharmaceutical treatment seems to be advisable because our analyses provide first insights that untreated comorbidity tends to affect survival in the various ILDs more detrimentally than treated comorbidity. However, since insurance claims data do not address clinical characteristics of ILD patients comprehensively, further analyses of clinical cohorts with more differentiated information on ILD subtype and disease severity is needed. To improve patient benefit meaningfully, detailed longitudinal investigations of the mutual interactions between comorbidity and its treatment at the substance level should be encouraged. In parallel, a stronger emphasis could be dedicated to evaluating the benefits of non-pharmacological disease management.