Risk factors for an acute exacerbation of idiopathic pulmonary fibrosis

This study examined associations between patient characteristics, serum markers, and BAL fluid cellular constituents and the incidence of AE-IPF and survival in a cohort of IPF patients who were diagnosed based on the official 2011 IPF ATS/ERS/JRS/ALAT Update Statement [2]. A log-rank test showed that treatment with an immunosuppressive agent after diagnosis, baseline cardiovascular diseases, higher GAP stage (?II), higher serum LDH level (?180 U/L), higher serum SP-D level (?194.7 ng/mL), and higher neutrophil (?1.77 %) and eosinophil (?3.21 %) percentages in BAL fluid samples were associated with poor AE-free probability. In the Cox analysis adjusted for treatment with an immunosuppressive agent, baseline cardiovascular diseases, higher GAP stage (?II), and a higher eosinophil percentage (?3.21 %) in BAL fluid samples were predictors of an AE-IPF.

It was reported that the human lung microbiome and any changes in its numbers and composition play important roles in the pathogenesis and progression of lung diseases, including IPF [17, 18]. In addition, it was recently reported that patients with IPF had a higher bacterial load in BAL fluid compared with control subjects and that an increased bacterial load at the time of diagnosis identified patients with more rapidly progressive IPF and those at a higher risk of mortality [19]. The multicenter PANTHER trial found that combination therapy (prednisone, azathioprine, and N-acetylcysteine) was associated with more AEs than a placebo. [20]. The present study also demonstrated that treatment with an immunosuppressive agent was associated with an AE-IPF in the log-rank test and unadjusted Cox analysis. In addition, Papiris et al. recently reported that immunosuppression adversely affected the outcomes of AE-IPFs [21]. These findings imply that treatment with an immunosuppressive agent may increase the bacterial load in the lungs of patients with IPF and lead to an AE-IPF. Further studies are needed to elucidate the association between bacterial load and AE-IPFs. However, baseline cardiovascular diseases, higher GAP stage (?II), and higher eosinophil percentage (?3.21 %) in BAL fluid samples were predictors of an AE-IPF, even after adjustment for treatment with an immunosuppressive agent in the Cox analysis. These risk factors were thought to be independent of treatment with an immunosuppressive agent.

BAL fluid analyses in IPF patients typically show an increase in total cell count, neutrophils (5 %), and eosinophils (5 %) [22]. In the present study, baseline median neutrophil and eosinophil percentages in the BAL fluid of patients who experienced an AE were 7.0 % (IQR: 3.2–10.5 %) and 4.6 % (IQR: 2.1–7.0 %), respectively. These BAL fluid findings were consistent with those previously reported in patients with IPF [22]. This study showed that higher neutrophil (?1.77 %) and eosinophil (?3.21 %) percentages in BAL fluid samples were associated with poor AE-free probability in the log-rank test. In the adjusted Cox analysis, a higher baseline eosinophil percentage (?3.21 %) in BAL fluid samples was a predictor of an AE-IPF. Relative increases in eosinophil and neutrophil percentages in BAL fluid may identify a subset of patients with disease that is more “active” or in an accelerated phase of tissue damage that may predispose them to an AE. Although inflammation is never a prominent histopathological finding in UIP [2], occult sustained eosinophil and neutrophil accumulations in the alveolar space may be key immune effector cells driving the inflammatory response and may play a role in the occurrence of an AE-IPF. Findings of recent studies of high BAL fluid eosinophil and neutrophil percentages in patients with IPF during AEs lend support to this possibility [3, 9]. Tabuena et al. [23] found that BAL fluid neutrophil and lymphocyte counts predicted mortality in current smokers in a study of 81 patients with IPF. Kinder et al. recently reported that each doubling of baseline BAL fluid neutrophil percentage was associated with a 30 % increase in mortality risk in a series of 156 patients with biopsy-proven IPF [24]. These observations also suggest the potential contribution of inflammation in the pathogenesis of IPF. Although the possible role of a chronic inflammatory response has been largely neglected because of the inefficacy of corticosteroids and immunosuppressants in the treatment of IPF [2, 20], further studies focusing on the potential role of inflammation in IPF pathogenesis and AE-IPF occurrence are needed. Current practice and consensus guidelines [2] do not recommend performing BAL for a determination of cellular constituents in BAL fluid at the time of IPF diagnosis. However, the indication for BAL with a cellular analysis may become clearer when effective therapies to prevent an AE-IPF are discovered.

This study showed that a baseline higher GAP stage (?II) was one of the predictors of an AE-IPF and a significant prognostic factor for IPF in the adjusted Cox analysis. This GAP model consists of four baseline variables: gender (G), age (A), and two lung physiology variables (P) (FVC and diffusing capacity for carbon monoxide) [12]. It has been proposed that the GAP model was useful in the prediction of mortality at baseline in patients with IPF [12]. In addition, it was reported that GAP stage III IPF patients tended to have a higher incidence of AEs than stage II and stage I patients [25]. The present findings along with those obtained in previous studies suggest that the GAP staging system could be used as a quick and simple screening method for predicting AE-IPF.

Cardiovascular disease has been reported to be one of the most frequently observed comorbidities in patients with IPF and associated with shortened survival time [26, 27]. However, the impact on AE-IPF has remained unknown. This study showed that baseline cardiovascular disease was not only a prognostic factor for IPF, but also a risk factor for an AE-IPF in the adjusted Cox analysis. Further studies are needed to elucidate the mechanisms of why cardiovascular disease increases the risk of AE-IPF.

SP-D is a lipoprotein complex synthesized mainly by alveolar type II epithelial cells and is secreted into a liquid layer lining the lung epithelium. Increased serum SP-D levels obtained at the time of IPF diagnosis were reported to be associated with increased mortality [28–30]. In the present study, serum SP-D levels obtained at the time of initial diagnosis were associated with AE-free probability in a log-rank test and overall survival in the adjusted Cox analysis. Two mechanisms may contribute to elevated SP-D serum levels in pulmonary fibrosis: (1) an absolute increase in alveolar type II epithelial cells due to diffuse hyperplasia increases at the source of pulmonary SP-D; and (2) epithelial injury and basal membrane leakage may cause spillover into the circulation [28]. Evidence indicates that repetitive injuries to alveolar epithelial cells trigger an exaggerated wound healing response resulting in extensive scar formation, and finally, pulmonary fibrosis [31, 32]. Together with previous observations, the present findings suggest that injuries to alveolar epithelial cells may be one of the important triggers for IPF progression.

In a randomized trial of pirfenidone, a positive treatment effect was demonstrated, including fewer AE-IPF episodes (14 % versus none) [33]. However, a previous study did not reproduce the inhibitory effect of pirfenidone on AE-IPF [34]. In the present study, neither treatment with pirfenidone nor N-acetylcysteine was associated with AE-free probability in a log-rank test. However, this might be due to the small number of patients treated with pirfenidone or NAC in this study. Whether new antifibrotic agents have preventive effects against AE-IPF is an interesting clinical question. Further studies are needed to elucidate this question.

Previously reported conflicting results regarding risk factors for an AE-IPF were probably partly related to the use of multiple AE-IPF definitions. According to previously reported AE-IPF criteria, endotracheal aspirate or BAL fluid should be examined to exclude pulmonary infection, and patients who do not undergo these procedures should be termed as having a “suspected AE” [4]. However, these procedures are often not feasible given the significant hypoxemia typical in an AE-IPF. There is a frequent inability to exclude underlying infection results confidently in a large number of “suspected” AE-IPF cases that cannot be confirmed. Therefore, the definition of AE-IPF in the present study did not include the performance of endotracheal aspirate collection or BAL as an essential component. Collard et al. recently reported that suspected AE-IPF cases were clinically indistinguishable from definite AE-IPF cases, and were associated with similarly high risks of disease progression and short-term mortality in IPF [35]. Ryerson et al. recently proposed expanding the AE-IPF diagnostic criteria by allowing the diagnostic criteria to be met without the performance of invasive procedures (e.g. bronchoscopy) [36]. In fact, the definition of AE-IPF used in recent clinical trials of nintedanib did not include the performance of endotracheal aspirate collection or BAL as essential components, and infection was excluded in accordance with routine clinical practice and microbiologic studies [37]. Therefore, the results obtained in the present study are thought to be practical for the management of patients with IPF in daily clinical settings.

There are some limitations to this study. First, this was a retrospective study with a small number of subjects. Because of the small numbers of AEs and deaths, risk factors and prognostic factors were adjusted only by treatment with an immunosuppressive agent in the multiple Cox analysis. Because the associations among several factors seem to be complex, further study in a larger patient cohort is needed to analyze independent risk factors for AE-IPF and prognostic factors for IPF. Second, although the present study suggests that alveolar inflammation may be one of the key pathways activated prior to the development of an AE-IPF, the precise biological mechanisms of AE-IPF remain unknown. Third, this study included only Japanese patients. Therefore, further studies are needed to ascertain whether these results can be applied equally to other ethnic groups. The relative rarity of AE-IPF suggests that these research questions should be answered by multicenter collaborations.