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. 2016 Mar 29;11(3):e0151425.
doi: 10.1371/journal.pone.0151425. eCollection 2016.

Impact of Comorbidities on Mortality in Patients with Idiopathic Pulmonary Fibrosis

Michael Kreuter  1   2 , Svenja Ehlers-Tenenbaum  1 , Karin Palmowski  1 , Jacques Bruhwyler  3 , Ute Oltmanns  1 , Thomas Muley  4   2 , Claus Peter Heussel  5   6   2 , Arne Warth  7   2 , Martin Kolb  8 , Felix J F Herth  1   2
Affiliations

Impact of Comorbidities on Mortality in Patients with Idiopathic Pulmonary Fibrosis

Michael Kreuter et al. PLoS One. .

Abstract

Introduction: Comorbidities significantly influence the clinical course of idiopathic pulmonary fibrosis (IPF). However, their prognostic impact is not fully understood. We therefore aimed to determine the impact of comorbidities, as individual and as whole, on survival in IPF.

Methods: The database of a tertiary referral centre for interstitial lung diseases was reviewed for comorbidities, their treatments, their frequency and survival in IPF patients.

Results: 272 patients were identified of which 12% had no, 58% 1-3 and 30% 4-7 comorbidities, mainly cardiovascular, pulmonary and oncologic comorbidities. Median survival according to the frequency of comorbidities differed significantly with 66 months for patients without comorbidities, 48 months when 1-3 comorbidities were reported and 35 months when 4-7 comorbidities were prevalent (p = 0.004). A multivariate Cox proportional hazard analyses identified other cardiac diseases and lung cancer as significant predictors of death, gastro-oesophageal reflux disease (GERD) and diastolic dysfunction had a significant positive impact on survival. A significant impact of comorbidities associated therapies on survival was not discovered. This included the use of proton pump inhibitors at baseline, which was not associated with a survival benefit (p = 0.718). We also established a predictive tool for highly prevalent comorbidities, termed IPF comorbidome which demonstrates a new relationship of IPF and comorbidities.

Conclusion: Comorbidities are frequent in IPF patients. Some comorbidities, especially lung cancer, mainly influence survival in IPF, while others such as GERD may inherit a more favourable effect. Moreover, their cumulative incidence impacts survival.

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Conflict of interest statement

Competing Interests: Michael Kreuter and his institution received grants and personal fees from InterMune, Roche and Boehringer Ingelheim. Jacques Bruhwyler was in charge of biostatistics and is employed by (CRO ECSOR, Belgium) and was financially supported by the University of Heidelberg through the unrestricted grant by InterMune / Roche. Claus Peter Heussel owns stocks from GSK and received personal fees from Boehringer, Roche, InterMune and research funding from Boehringer Ingelheim. Martin Kolb reported grants and personal fees from Roche, grants and personal fees from Boehringer Ingelheim, personal fees from GSK, personal fees from Gilead, grants from Actelion, grants from Respivert, personal fees from Astra Zeneca, personal fees from Prometic, personal fees from Genoa, outside the submitted work; Thomas Muley reported grants and non-financial support from Roche outside the submitted work. Svenja Ehlers-Tenenbaum, Karin Palmowski, Felix JF Herth and Arne Warth had nothing to disclose in relationship to this publication. Competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Prevalence of comorbidities in relation to survival status (survivors: red bars, non-survivors: blue bars).
The figure also denotes those comorbidities with a significantly (*) different prevalence in non-survivors compared with survivors regardless of their absolute prevalence.
Fig 2
Fig 2. Kaplan-Meier survival curves for patients with (N = 19; median survival 96 months) or without (N = 250; median survival 41 months) (p = 0.026) gastro-oesophageal reflux disease (GERD) and for patients with (N = 42; median survival 19 months) or without (N = 227; median survival 48 months) (p<0.0001) lung cancer.
Fig 3
Fig 3
(A) Kaplan-Meier survival curves as a function of the total number of comorbidities. Survival duration decreased as a function of the number of comorbidities (p = 0.004): median survival of 66, 59, 40, 42, 42, 34, 12 months for 0, 1, 2, 3, 4, 5 and 6 comorbidities, respectively. The number of patients with 7 comorbidities was too low (N = 9) to correctly evaluate survival. (B) Kaplan-Meier survival curves as a function of the number of comorbidities clustered in three categories (0, 1–3, 4–7). Survival duration decreased significantly as a function of the number of comorbidities (p = 0.047): 0 comorbidity (N = 30; median survival 66 months), 1–3 comorbidities (N = 156; median survival 48 months) and 4–7 comorbidities (N = 82; median survival 35 months).
Fig 4
Fig 4. Kaplan-Meier survival curves for patients receiving proton pump inhibitors (PPI) at baseline (n = 76, median survival 48 months) versus patients (n = 193, median survival 42 months) without PPI at baseline (p = 0.718).
Fig 5
Fig 5. Impact of idiopathic pulmonary fibrosis and comorbidities on mortality.
Hazard ratios (HR) have been determined using a predictive multivariate Cox proportional hazards regression model.
Fig 6
Fig 6. Graphic expression (comorbidome) of comorbidities with more than 10% prevalence in the entire cohort, and those comorbidities with the strongest association with mortality (hazard ratio [HR] >1; 95% confidence interval >1; p<0.05).
The area of the circle relates to the prevalence of the disease. The proximity to the centre (mortality) expresses the strength of the association between the disease and risk of death. This was scaled from the inverse of the HR (1/HR). All bubbles associated with a statistically significant increase in mortality are fully inside the dotted orbit (1/HR <1). Bubble colours represent organ systems or disease clusters (cardiovascular = red, pulmonary = green, others = orange).
See this image and copyright information in PMC

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