Pulmonary Fibrosis Is Associated with an Elevated Risk of Thromboembolic Disease
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Eur Respir J 2012; 39: 125–132 DOI: 10.1183/09031936.00041411 CopyrightßERS 2012 Pulmonary fibrosis is associated with an elevated risk of thromboembolic disease D.B. Sprunger*,#, A.L. Olson*,#, T.J. Huie*, E.R. Fernandez-Perez*, A. Fischer*, J.J. Solomon*, K.K. Brown*," and J.J. Swigris*," ABSTRACT: Recent epidemiological studies have suggested an increased risk of venous AFFILIATIONS thromboembolism (VTE) in lung fibrosis. Large-scale epidemiological data regarding the risk of *Interstitial Lung Disease Program and Autoimmune Lung Center, VTE in pulmonary fibrosis-associated mortality have not been published. Division of Pulmonary and Critical Using data from the National Center for Health Statistics from 1988–2007, we determined the Care Medicine, National Jewish risk of VTE in decedents with pulmonary fibrosis in the USA. Health, Denver, CO, USA. # We analysed 46,450,489 records, of which 218,991 met our criteria for idiopathic pulmonary These authors contributed equally to the study. fibrosis. Among these, 3,815 (1.74%) records also contained a diagnostic code for VTE. The risk of "These authors contributed equally to VTE in pulmonary fibrosis decedents was 34% higher than in the background population, and 44% the study. and 54% greater than among decedents with chronic obstructive pulmonary disease and lung cancer, respectively. Those with VTE and pulmonary fibrosis died at a younger age than those CORRESPONDENCE A.L. Olson with pulmonary fibrosis alone (females: 74.3 versus 77.4 yrs (p,0.0001); males: 72.0 versus Interstitial Lung Disease Program and 74.4 yrs (p,0.0001)). Autoimmune Lung Center Decedents with pulmonary fibrosis had a significantly greater risk of VTE. Those with VTE and National Jewish Health pulmonary fibrosis died at a younger age than those with pulmonary fibrosis alone. These data F-107 1400 Jackson Street suggest a link between a pro-fibrotic and a pro-coagulant state. Denver CO 80220 KEYWORDS: Epidemiology, idiopathic pulmonary fibrosis, mortality, pulmonary fibrosis, venous USA thromboembolism E-mail: [email protected] Received: March 07 2011 diopathic pulmonary fibrosis (IPF) is the most clots), occurs in lung tissue from patients with IPF Accepted after revision: common of the idiopathic interstitial pneumo- [10]. Data also suggest abnormalities in intrinsic June 17 2011 I nias, and recently published epidemiological anticoagulation pathways: bronchoalveolar lavage First published online: data suggest that the burden of disease is rising. fluid from patients with IPF reveals decreased July 07 2011 The incidence and mortality rates for IPF, and protein C activation [11]. Furthermore, fibrinolysis pulmonary fibrosis (PF) in general, have been in- appears to be dysregulated: models of lung fibrosis creasing steadily [1–6]. IPF is a deadly disease, with have revealed elevated levels of plasminogen a median survival after diagnosis ranging from 3 to activator inhibitor-1, thus promoting fibrin persis- 5 yrs [7], and no therapy other than lung trans- tence [12]. plantation has been shown to prolong survival. Based on these data, we hypothesised that an In a recently conducted epidemiological study of excessive number of VTEs would be found in 920 subjects, an increased risk of venous thrombo- patients with IPF in decedents in the USA from embolism (VTE) was found both before and after 1988–2007, and that among IPF decedents, the the onset of PF [8]. In a separate study that in- presence of VTE would be associated with a youn- ger age of death. cluded all Danish PF patients from 1980–2007, a prior history of VTE was found to increase the risk of developing interstitial lung disease (ILD) [9]. METHODS Although these studies hint at a relationship Database between VTE and PF, large-scale epidemiological Details of the database and methods used have data about the risk of VTE in PF-associated been published previously [6]. Briefly, we used mortality have not been published. the US Multiple Cause-of-Death mortality data- base (National Centre for Health Statistics (NCHS), At the molecular level, activation of the coagulation Centers for Disease Control and Prevention, cascade, via the tissue factor-dependent extrinsic Atlanta, GA, USA) [13], for which the NCHS European Respiratory Journal pathway, and as evidenced by elevated levels of compiles data from all death certificates in the USA Print ISSN 0903-1936 c tissue factor and fibrin (the main component of and releases the figures in annual, public-use files. Online ISSN 1399-3003 EUROPEAN RESPIRATORY JOURNAL VOLUME 39 NUMBER 1 125 PULMONARY FIBROSIS AND PULMONARY VASCULAR DISEASE D.B. SPRUNGER ET AL. For this study, we analysed files from 1988 to 2007 [13, 14]. An diagnosis of IPF. Among these, 3,815 records also contained a annual file contains .2 million decedent records, and each diagnostic code for VTE (table 1), yielding a prevalence of VTE record contains decedent demographics, f20 conditions related in IPF that was significantly greater than in the background to death within a section of the record the NCHS calls the population (1.74% versus 1.31%; p,0.0001). Thus, the overall ‘‘record axis’’, and the ultimate underlying cause of death odds of being diagnosed with a VTE were significantly greater (UCD), defined by the World Health Organization as ‘‘the in decedents with IPF than in decedents in the background disease or injury which initiated the train of events leading to population (overall OR 1.34, 95% CI 1.29–1.38). In the year-by- death’’ [14, 15]. year analysis, the risk of VTE was greater for IPF than in the background population in every year except 2005 (p50.25). From 1988–1998, the NCHS coded conditions related to death using the International Classification of Diseases (ICD)-9 [16]. After stratifying for sex and age, female decedents with IPF in Thereafter, the NCHS coded conditions related to death using age strata 65–74 yrs, 75–84 yrs and o85 yrs, but not ,65 yrs, the ICD-10 [14]. All data contained in these database files have had a significantly greater risk of VTE than the background been de-identified and are publicly recorded; therefore, institu- population (fig. 1). Among male decedents with IPF, the risk of tional review board approval for this study was not required. VTE was significantly greater than the background population for all age strata (fig. 2). Case definitions We included files from any decedent from the USA with IPF, as Using logistic regression, and adjusting for sex, age and year defined by the following ICD codes: from 1988 to 1998, ICD-9 of death, the risk of VTE remained significantly greater in codes 515 (post-inflammatory pulmonary fibrosis (PIPF)) and decedents with IPF than in the background population 515.6 (IPF); and thereafter, ICD-10 code J84.1 (a code that (adjusted OR 1.34, 95% CI 1.29–1.38). Among all decedents, combines both PIPF and IPF). We then excluded patients with males had a significantly lower risk of VTE (OR 0.75, 95% CI record axis codes for any condition that might be associated with 0.74–0.75) than females, and increasing age conferred a slightly secondary PF, including connective tissue diseases, radiation lower, but significant, risk of VTE (OR 0.99, 95% CI 0.99–0.99). fibrosis, asbestosis, pneumoconiosis (including coal workers’ From 1988 to 2007, the overall risk of VTE increased slightly pneumoconiosis, silicosis, talcosis and berylliosis), sarcoidosis with each passing year (OR 1.01, 95% CI 1.01–1.01). and/or extrinsic allergic alveolitis (hypersensitivity pneumo- When interactions between IPF and sex, age and year of death nitis). In addition, we excluded patients with a concurrent were assessed, each two-way interaction was found to be diagnosis of chronic obstructive pulmonary disease (COPD) or statistically significant. The risk of VTE in decedents with IPF lung cancer. We identified three groups for comparison was modified by age, sex and year of death: among decedents purposes: 1) the background population, which included dece- with IPF, increasing age, female sex and later year of death dents without IPF, lung cancer or COPD; 2) decedents with reduced the risk of VTE. b-coefficients, standard errors and p- COPD (but not IPF or lung cancer); and 3) decedents with lung values for the model that included these second-order cancer (but not IPF). VTE disease was defined as either venous interactions are reported in table 2. thrombosis or pulmonary embolism. From 1988 to 1998, we defined venous thrombosis by ICD-9 codes 451–451.8 and 453– We assessed the effects of race and sex on the risk of VTE in 453.9, and pulmonary embolism by ICD-9 code 415.1, while after decedents with IPF compared with the background popula- 1998 we used ICD-10 codes I80–I80.9, I82.8 and I82.9 to define tion. Using logistic regression, we found that the risk of VTE venous thrombosis, and ICD-10 codes I26–I26.9 to define remained greater for IPF decedents than those in the back- pulmonary embolism. Specifics of additional ICD-9 and ICD- ground population when adjusted for ethnicity and race 10 codes are included in the Appendix. (adjusted OR 1.39, 95% CI 1.34–1.43). Among all decedents, when using non-Hispanic Whites as the reference population, Statistical analysis Hispanics and non-Hispanic others (including Asians) had a We used the Chi-squared test (or Mantel–Haenszel statistic lower risk of VTE (OR 0.75, 95% CI 0.74–0.76 and OR 0.56, 95% where appropriate) to determine the risk of VTE in decedents CI 0.54–0.57, respectively), while non-Hispanic Blacks had an with IPF in reference to the three comparator groups. We then elevated risk of VTE (OR 1.33; 95% CI 1.32–1.34).