Acute exacerbation of chronic fibrosing interstitial pneumonia in patients receiving antifibrotic agents: incidence and risk factors from real-world experience

Patients with progressive CFIP treated with antifibrotic agents (pirfenidone or nintedanib) from 01 Aug 2015 to 31 Aug 2018 with no history of AE were identified at Saiseikai Kumamoto Hospital. All patients received antifibrotic agents as the standard-of-care. Follow-up included an inpatient visit or phone call by a research team member. Date of last follow-up was identified as either date of death, last in-person visit or last research phone call. Data were locked on 30 Sept 2018. Subjects were censored if they [1] experienced no events by 30 Sept 2018 or [2] were lost to follow-up.

Demographic, clinical, and pathological data were collected from electronic medical records. Patients’ pharmacy records were reviewed to determine whether patients were documented as having received corticosteroids, anticoagulant and/or antiplatelet drugs, and H2-blockers or proton-pump inhibitors upon initiating the antifibrotic agent. Corticosteroid dose was expressed as total daily milligrams of prednisone equivalents. The following clinical characteristics were collected for all patients: age upon antifibrotic initiation, gender, time from 1st visit to antifibrotic initiation (months), surgical lung biopsy (yes or no), clinical diagnosis upon starting antifibrotic agents (IPF vs others: chronic hypersensitivity pneumonitis [CHP], collagen vascular disease-associated IP, and unclassifiable), long-term oxygen therapy (no, therapy started prior to antifibrotic agent initiation, or therapy introduced simultaneously with antifibrotic agents), serum KL-6 level, serum lactate dehydrogenase (LDH), Interstitial Lung Disease-Gender, Age, and Physiology (ILD-GAP) score [18], smoking history, and updated Charlson comorbidity index [19]. Baseline pulmonary function testing, right ventricular systolic pressure estimated by echocardiogram (> or ≤ 40 mmHg), serum KL-6, and serum LDH levels at baseline were performed on the day the antifibrotic agent was initiated or within 14 days before the first antifibrotic agent treatment. ILD-GAP scores were calculated from data obtained at the start of antifibrotic agent use. Using the ILD-GAP index, we classified patients into one of three categories based on enrollment values: stage 1 (0–3 points), stage 2 (4–5 points), and stage 3 (6–8 points).

Diagnoses of acute exacerbations of interstitial pneumonia were made in accordance with the definition of acute exacerbation of IPF proposed by Collard et al. [14], which includes both triggered and idiopathic acute exacerbations. IPF was diagnosed by the diagnostic criteria proposed by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association [20] and also included cases confirmed to have features of possible usual interstitial pneumonia (UIP) and traction bronchiectasis on high-resolution computed tomography with no surgical lung biopsy as previously described [21]. Non-IPF was diagnosed after discussing and integrating the clinical, radiological, bronchoalveolar lavage, and pathological findings.

Patients’ baseline characteristics were summarized using percentages for categorical variables and medians and interquartile ranges for continuous variables. Between-group comparisons were performed using the Mann-Whitney rank-sum and Fisher’s exact tests. Time-to-event endpoints were defined as the time from antifibrotic initiation to the first admission of AE. Time-to-end endpoints were estimated using the Kaplan-Meier method based on events and compared with the log-rank test (univariable analysis). Risk factors for time to first AE development and univariate survival were analyzed using the Cox proportional hazards model to determine hazard ratios (HR) and 95% confidence intervals (95%CI). For concomitant medications, multivariable logistic regression was performed for AE risk factors using an a priori covariable of ILD-GAP scores in some covariate.

We used the inverse probability of treatment-weighting analysis using the propensity score calculated from the data at the start of treatment to analyze the pharmacological treatment effect for the AE risk as a sensitivity analysis. All tests were two-sided and performed at a significance level of 0.05. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [22], a graphical user interface for R, version 3.2.2 (The R Foundation for Statistical Computing, Vienna, Austria).

One hundred patients treated with antifibrotic agents without previous history of AE were recruited. Three patients who started antifibrotics after AE were identified and excluded from this analysis.

Table 1 shows the patients’ baseline demographics and clinical characteristics. The study cohort included 75 men and 25 women, and the patients’ median age was 68 years (interquartile range [IQR] 64–73 years). The median follow-up was 17.4 months (IQR 6.6–6.7 months). The median time from first visit to starting antifibrotics was 12 months (IQR 6–36 months). The clinical diagnoses upon starting antifibrotics were IPF (n = 75) and others (n = 25; CHP = 19; collagen-vascular disease-associated [rheumatoid arthritis] =2; unclassified = 4). The baseline median values for percent predicted forced vital capacity (FVC) and percent predicted diffusing capacity of the lung for carbon monoxide (DLCO) were 70.8% (IQR 58.7–82.4%) and 55.9% (IQR 45.1–68.4%), respectively. Patients who had been diagnosed as not-IPF before commencing anti-fibrotic agents were more frequently prescribed corticosteroids than those with an IPF diagnosis at the time of starting anti-fibrotic agents (IPF n = 15 [20%] vs. non-IPF n = 11 [44%]; p = 0.033).

During the follow-up periods, 21 patients experienced AE after antifibrotic agent introduction. Figure 1 shows the cumulative incidence of AE-CFIP. The estimated 1-, 2-, and 3-year AE incidences were 11.4% (95%CI, 6.2–20.3%), 32% (95%CI, 20.7–47,4%), and 36.3% (95%CI, 23.5–53.1%), respectively. Table 2 compares the baseline characteristics and patient outcomes with and without AE. Sex, smoking history, clinical diagnosis, and comorbidity index distributions did not significantly differ between groups. Patients with AE were slightly younger than those without AE, but the percentage of elderly patients did not differ between groups. There was a tendency for patients who developed AEs to have had SLBs (47.6 versus 24.1% p = 0.06); however, the difference was not statistically significant. No AEs were associated with surgical lung biopsy. Patients with AE had decreased lung functions; higher ILD-GAP scores; more frequent use of corticosteroids, PPIs, and long-term oxygen therapy; and longer times from diagnosis to starting antifibrotic agents than did the non-AE group.

Additional file 1: Table S1 lists details of each patient’s baseline characteristics. AE varied seasonally and appeared more frequently during winter.

Table 3 lists risk factors of AE. Decreased baseline lung function (FVC, DLCO), estimated right ventricular systolic pressure over 40 mmHg by echocardiogram, and higher ILD-GAP score and stage were risk of AE. Patients receiving long-term oxygen therapy prior to starting antifibrotics had higher risks of AE (HR 4.8; 95%CI 1.6–14.7; P = 0.006) than did patients who had not received prior oxygen therapy or patients who began both simultaneously. Patients receiving corticosteroids upon beginning antifibrotics had higher risks of AE (adjusted HR 11.3; 95%CI 4.1–32.0; p < 0.0001) than those not receiving corticosteroids, independent of underlying disease severity. Additionally, AE was increased in patients receiving > 10 mg or 1–10 mg prednisone compared with patients not receiving corticosteroids (Fig. 2b).