Acute exacerbations of fibrosing interstitial lung disease associated with connective tissue diseases: a population-based study

Background Acute exacerbation (AE) is the major cause of morbidity and mortality in patients with idiopathic pulmonary fibrosis (IPF). AEs also occur in other forms of fibrosing interstitial lung disease (fILD). The clinical features and prognosis of AE patients with connective tissue diseases (CTDs) associated-ILD has not been fully described. Methods We retrospectively reviewed 177 patients with either IPF or a characterized CTD-ILD admitted to Nanjing Drum Tower Hospital with an AE from January 2010 to December 2016. Results The study cohort included 107 subjects with AE-IPF and 70 cases with AE-CTD-ILD. Female gender, prior use of corticosteroid and immunosupressants, lower serum albumin, higher D-dimer level, TLC% pred, survival, and treatment with immunosupressants and caspofungin were more common in the CTD-ILD group (all p<0.05). The incidences of AE-CTD-ILD and AE-IPF were similar in our single center (p = 0.526). TLC% pred was the risk factor for AE after ILD diagnosis for 1 year in CTD patients (p = 0.018). Log-rank tests showed patients with CTD-ILD had a significantly lower mortality rate compared with IPF patients after AEs (p = 0.029). No significant difference in survival was noted among CTD subgroups (p = 0.353). The survival was negatively correlated with WBC count, LDH and CT score, (p = 0.006, p = 0.013 and p = 0.035, respectively), and positively correlated with PaO2/FiO2 ratio (p<0.001) in the CTD-ILD group. WBC count and PO2/FiO2 ratio were the independent predictors for survival in AE-CTD-ILD after adjusting for other clinical variates in Cox regression Models (p = 0.038 and p < 0.001, respectively). Conclusions The clinical characteristics of patients with AE-CTD-ILD differed from those with AE-IPF, while AE incidences were similar between the two groups. Subjects with AE-CTD-fILD tended to have a better prognosis, and WBC count and PO2/FiO2 ratio were the independent survival predictors for these patients.


Background
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive scarring disease of the lung characterized by worsening dyspnea and lung function over time [1,2]. Some patients will experience an acute, clinically significant respiratory deterioration characterized by widespread alveolar abnormality [3]. Acute exacerbations (AEs) are a major cause of mortality of patients with IPF. The incidence of AE-IPF ranges from 4 to 20% per year among IPF patients in reported clinical trials [4][5][6][7][8], and up to one-half of IPF patients die from AE [9]. In most cases, in-hospital mortality rate was up to 50% [7]. The etiology of AE-IPF is still unknown. Recent evidence suggests that causes of acute lung injury (ALI) and histopathologic diffuse alveolar damage (DAD) such as infection, aspiration, surgery and air pollution exposure could contribute to the development of AE-IPF [3,10,11]. Low forced vital capacity (FVC), diffusing capacity for carbonmonoxide (DLCO) and baseline oxygenation were known risk factors for AE [7,10,[12][13][14]. Lower baseline FVC and DLCO and more extensive CT abnormalities at the time of AE and worse oxygenation were predictors of mortality [7,8,15]. The elevated levels of Kerbs von Lungen-6 and leptin in peripheral blood could be the risk and prognostic factors for AE-IPF [16,17].
Recently, AE has also been shown to occur in fibrosing interstitial lung diseases (fILD) other than IPF, such as connective tissue disease (CTD) associated ILD, idiopathic nonspecific interstitial lung disease and chronic hypersensitivity pneumonias [18][19][20][21][22]. Park et al. reported AE in CTD-ILD was similar to AE-IPF and most common in older patients with rheumatoid arthritis (RA) [18]. Suda et al. suggested that AE occurred mostly with RA-ILD with a usual interstitial pneumonia (UIP) pattern [19]. Toyoda et al. showed some AE cases in patients with CTD had good response to corticosteroid [23]. To date, there are few reports of AE in CTD-ILD patients. The incidence, clinical characteristics and prognosis of AE patients in CTD-ILD have yet to be fully elucidated.
We conducted a retrospective study of AE in CTD-ILD and IPF in our single center. The aims were to clarify the occurrence, clinical characteristics and prognosis of patients with CTD-ILD who developed AE, and to identify risk and predictive factors in Chinese population.

Study subjects
This retrospective cohort study was approved by the Ethics Committee of Nanjing Drum Tower Hospital and conducted in compliance with the Helsinki Declaration (1989) (NO.2016-160-01). We retrospectively reviewed 3280 new patients with ILD admitted to our hospital from January 2010 to December 2016, and 177 consecutive patients with an AE of underlying fILD were enrolled in our study (Fig. 1). The follow-up period was from 6 months to 7 years. The final cohort included 107 cases of AE-IPF and 70 cases of AE-CTD-ILD. All subjects had an underlying UIP or possible UIP pattern on chest high resolution computed tomography (HRCT) as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines [1,2]. The diagnosis of the underlying CTD and interstitial pneumonia with autoimmune features (IPAF) was according to the established criteria [23][24][25][26][27][28][29][30]. IPAF means patients with ILD that had features of autoimmunity, yet falling short of a characterizable CTD, was included in CTD-ILD. The definition of AE was based on the updated international criteria for AE-IPF [3]. Briefly, AE-IPF and AE-CTD-fILD were defined as an acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality with: ① Previous or concurrent diagnosis of IPF or a characterized CTD-fILD; ② Acute worsening or development of dyspnea typically 1 month duration; ③ CT with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with UIP or possible UIP pattern; ④ Deterioration not fully Fig. 1 Flow chart of included patients explained by cardiac failure or fluid overload [3]. All baseline and follow-up clinical data and chest imaging findings were obtained from hospital medical records. Vital status was obtained from medical records or telephone interview. Baseline clinical variables were obtained at the time of AE. The pulmonary function tests (PFTs) were conducted up to 1 month prior or after the initial diagnosis as AE-PF.

HRCT scanning
Chest HRCT examination was performed within 24 h of the diagnosis of respiratory failure with 1.0-1.5 mm thick sections with appropriate window settings (window width: 1600, window level: − 600). The findings were blindly reviewed and scored by two senior radiologists without any knowledge of clinical data. The images were assessed for the presence and extent of ground glass opacity, consolidation, traction bronchiectasis, reticulation, honeycombing and emphysema. The overall extent of abnormalities was determined for per lung using a 4point scale (0 = no involvement, 1 = 1-25% involvement, 2 = 26-50% involvement, 3 = 51-75% involvement, and 4 = 76-100% involvement) according to the published studies [31,32]. The HRCT of each case was evaluated as UIP pattern and possible UIP (P-UIP) pattern. Those with an inconsistent with UIP pattern were excluded from this study [1,33].

Statistical analysis
Data are presented as mean ± standard deviation (SD) for continuous variables or percentages for categorical variables. Chi-squared and Fisher's exact tests were used for categorical data, and the unpaired t-test and Kruskal-Wallis test were used for continuous data. A multivariate Cox regression model was used to identify significant variables capable of predicting AE or acting as prognostic factors. Bivariate correlation analysis was used to identify the relationship between total survival time and clinical variables. The incidence of AE was obtained from the Kaplan-Meier (K-M) survival curve by treating AE as the death variable. Survival was also evaluated using the log rank test. P < 0.05 was considered to represent statistical significance. Statistical analyses were performed by using IBM SPSS version 19 (SPSS, Inc., Chicago IL, USA) and Prism version 5 (GraphPad, SanDiego, CA, USA).

Clinical characteristics
The baseline clinical features of subjects with AE-CTD-fILD (n = 70) and AE-IPF (n = 107) were summarized in Table 1. The average ages were similar. Female gender, prior use of corticosteroid and immunosupressants were more common in the CTD-ILD group (p<0.001, p = 0.011 and p<0.001, respectively). Serum albumin (ALB), D-dimer and TLC% pred also differed between the two groups (p<0.001, p = 0.023 and p = 0.012, respectively). Subjects with AE-CTD-ILD were treated with immunosupressants and caspofungin more frequently than AE-IPF subjects after AEs (p<0.001 and p = 0.009, respectively).

AE occurrence in patients with CTD-ILD
The incidence of AE-IPF in patients with idiopathic interstitial pneumonia (IIP) was 3.97-11.06% (6.67%) and the incidence of AE-CTD-fILD in CTD-ILD cases was 1.92-7.89% (5.99%) per year in our single center from January 2010 to December 2016 ( Fig. 2A). The difference of AE occurrence between the two groups was not significant (p = 0.526) (Fig. 2B).
In univariate Cox analysis, prior corticosteroids use was the independent risk factor for AE among in subjects with CTDs after ILD diagnosis for 1 year (HR: 0.415, 95% CI: 0.215-802, p = 0.009), and pulmonary arterial hypertension (PAH) was the independent risk factor for AE occurrence in IPF patients (HR: 0.959, 95% CI: 0.921-1.000, p = 0.048) ( Table 2). After considering the clinical significance and adjusting other clinical variables, prior corticosteroids and immunosuppressant use, FVC, TLC% pred, PAH and body mass index (BMI) were included in the multivariate Cox analysis. The findings showed only TLC% pred was associated with the occurrences of AE among CTD-ILD patients (HR: 0.668, 95% CI: 0.505-0.938; p:0.018). However, none of above clinical variables could predict the occurrence of AE in AE-IPF group (Table 2).

Prognostic factors
Bivariate correlation analysis demonstrated that overall survival time was negatively correlated with WBC counts, LDH, and CT score (r = − 0.323, p = 0.006; r = − 0.296, p = 0.013 and r = − 0.252, p = 0.035), respectively, and positively correlated to PaO 2 /FiO 2 (r = 0.407, < 0.001) in AE-CTD-ILD group. In AE-IPF group, the findings were similar to CTD-ILD patients except for a negative correlation with the maximal dosage of corticosteroid and no correlation with PaO 2 /FiO 2 ( Table 3).

Discussion
The present study retrospectively compared the clinical, chest imaging and follow-up data between 70 subjects with AE-CTD-ILD and 107 subjects with AE-IPF. The clinical features of patients with AE-CTD-ILD differed from those of AE-IPF. Subjects with AE-CTD-ILD had a better survival than AE-IPF patients, while the survival of AE cases in the CTD subgroups didn't show any difference. WBC count and PO 2 /FiO 2 ratio could predict the survival of AE-CTD-ILD patients independently.
Recently, the definition and diagnostic criteria of AE-IPF have been updated. IPF patients manifesting an acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality on chest imaging or histopathology should be considered as having an AE [3]. Data showed that a potential infectious aetiology is up to one-third of patients with ILD and acute respiratory decline [22]. The updated criteria of AE-IPF do not exclude respiratory infection [3]. The causes of acute lung injure (ALI) including infection, aspiration, drugs and surgery may lead to events that are indistinguishable from idiopathic AE of IPF [3]. These events are further classified into "triggered" (ie, postprocedure, drug toxicity, infection, aspiration) or "idiopathic" (ie, no inciting event identified) AEs in the updated guideline [3].
The published reports about AE in patients with CTD-ILD have been relatively small series and show inconsistent results. The incidence of AE in RA-UIP was about 11.1-20% [18,19]. The mild elevation of mean PAH was very common in CTD-ILD patients [34]. Suda et al. suggested that the clinical characteristics of AE in CTD-ILD were similar to those of IPF with high mortality [19].  Park and Suda reported that AE occurred mostly with RA-UIP with poor outcome [18,19]. Song and Huie suggested that CTD-UIP group was younger, included more women and nonsmokers, and showed better survival than the IPF-UIP group [7,22]. The current study was based on the updated criteria of Collard about AE-IPF [3] and comprised a 177 cases of AE patients with IPF and CTD-ILD. The findings showed that the clinical features, treatment and prognosis of patients with AE-CTD-ILD differed from those with AE-IPF and published reports [7,8,18,35]. The incidence of AE in IPF patients has been reported in a number of studies. Due to different definition and diagnostic criteria of AE, AE incidence in IPF varied greatly, estimated to be in the range of 4-20% per year [4][5][6][7][8]. In patients with CTD-ILD, Suda et al. revealed an  overall AE incidence of 7.2% and a 1-year incidence of 1.25% [19]. Compared with AE-IPF, the incidence of AE in CTD-ILD seemed to be lower [19]. In our single center, AE incidence was about 5% in all new ILD patients about 6% per year in those with CTD-ILD. AE incidence of fILD patients in our study is similar to the published reports of IPF population in other countries [4][5][6][7][8]. IPF patients with physiologically and functionally advanced disease are thought to be at higher risk of AE [3]. However, little is known about the causative factors of AE in patients with CTD-ILD. In CTD-ILD patients, age and SS overlapped with PM/DM were the independent risk factors for AE [19,36]. In our study, AE occurrence in CTD-ILD patients within 1 year after ILD diagnosis was weakly associated with TLC% pred, likely due to the limited sample size. A larger sample prospective study of AE-CTD-ILD is therefore needed to clarify this complication. The poor survival of patients with AE-IPF is a great challenge. The MST of these patients was about 3-4 months [6,7]. Nearly half of patients with AE-IPF died in the hospital, and patients with both definite AE-IPF and suspected AE-IPF had a similar clinical outcome [6,7,22]. The published reports on AE-CTD-ILD differ from AE-IPF and include a relatively small number of cases. Tachikawa et al. concluded that the survival of AE-CTD-ILD was better than that of advanced IPF (90-day mortality at 33% vs. 69%) [37]. Huie et al. suggested that IPF patients had a lower rate of survival as compared with patients with non-IPF fibrotic disease after acute respiratory decline [22]. Suda et al. suggested that AE incidence in CTD-ILD was similar to that of IPF with poor prognosis [19]. In our cohort study, the overall survival was significant better in subjects with AE-CTD-ILD than AE-IPF cases, despite their similar short-term survival. Usui Y.et al. reported that systemic inflammatory response (SIRS) was the most significant predictor for in-hospital mortality in patients with AE of chronic fILD including IPF and non-IPF [38]. Infection at AE was thought to determine the short-term survival in these patients. In current study, the inflammatory indicators, WBC counts, CRP, LDH and CT scores didn't show any difference between the two groups, implying that infection was similar between the two groups. So, the similar short-term survival may be associated with the similar infection in the two groups [38]. The better overall survival in CTD-ILD patients may be associated with the favorable response to corticosteroids treatment [23]. Yoshimura et al. also suggested that the diagnosis of IPF might predict a favorable prognosis in patients with chronic fILD [39], thereby a better survival in AE-CTD-fILD. The lack of difference in overall survival among different CTD subgroups may be due to the small sample size in our study.
A number of factors including lower baseline FVC and DLCO, extensive CT abnormalities and CT pattern, worse oxygenation, higher bronchoalveolar lavage neutrophil and lymphocyte percentages at the time of AE were reported to be associated with the survival of patients with AE-IPF [7,8,15,32,40,41]. Literature also indicated that described age, TLC, honeycombing score and higher initial MPAP were the independent prognostic factors in AE-CTD-ILD [34,35]. In current study, WBC count and PO 2 /FiO 2 ratio could predict the survival of patients with AE-CTD-ILD after adjusting for other clinical variables. Now, infection has been regarded as one of the causes for AE in IPF patients [3]. WBC is a non-specific inflammation marker of infection. Infection with elevated WBC counts was correlated with the poor clinical outcomes in AE-CTD-fILD patients in our study. Low PO 2 /FiO 2 ratio could account for the severity of hypoxia and clinical condition at AE, which indicated patients with more severe condition when AE occurred would have worse prognosis. The different risk factors of prognosis in the two groups may be due to the underlying diseases and the conditions at AE occurrence.
Although there is no effective therapy for AE-IPF, supportive care including supplemental oxygen and palliation of symptoms are regarded as important treatment modality. The use of MV is controversial [1,3]. Corticosteroids are recommended but with somewhat low-quality evidence [1,3]. There is no consensus on the dosage and course of therapy. A slight survival benefit was reported for the treatment of AE-IPF combining cyclosporine with systemic glucocorticoids as compared to that without cyclosporine in a small retrospective study [41]. The therapy of steroids combined with cyclophosphosphamide for patients with AE-CTD-ILD appeared better than those without any immunosuppressant [7,42]. However, there is no evidence supporting the benefit of a specific immunosuppressant. Addition of intravenous thrombomodulin and polymyxin B immobilized fiber column perfusion to conventional treatment was shown to improve the survival in patients with AE-IPF [39,41]. Rituximab combined with plasma exchange and intravenous immunoglobulin also showed certain benefits [42]. All patients in our study used corticosteroids after AEs, but the maximal dosage was different for each case according to the clinical severity and the extent of damage on chest CT. The overall survival time was not correlated with the maximal dosage of methylprednisolone both in CTD-ILD and IPF patients when AE occurred. So, we speculated that the higher dosage of corticosteroids would not be beneficial for AE patients, and the clinical outcomes of AE patients with pulmonary fibrosis mainly depend on the underlying clinical conditions and the extent of lung injury at AE.
The current study has some limitations. It was designed retrospectively and the stable cases of pulmonary fibrosis were not available as controls. Histological evidence was not available for the diagnosis of pulmonary fibrosis. It was unable to get the exact number of cases with IPF patients. A definite cause of death was not available for each case, although most patients died of AE. A prospective, multicenter, multinational study of a larger cases cohort would be helpful to provide enough data for the epidemiology in AE-CTD-ILD.

Conclusions
In summary, the current study demonstrated that the clinical characteristics of patients with AE-CTD-ILD differed from those of AE-IPF. The incidence of AE-CTD-ILD was similar to that of AE-IPF. Subjects with AE-CTD-fILD had a better prognosis than those with AE-IPF. However, the survival of AE patients in each group was identical. WBC count and PO 2 /FiO 2 were the independent predictors for the survival in patients with CTD-fILD. A higher dosage of corticosteroids would not be beneficial for the survival of fILD patien.
Additional file 1: Table S1. Comparison of the CPS at different time after AE.