The present study demonstrated the clinical courses and outcomes of AE-FILD and included one of the largest published cohorts of patients with AE-FILD. To our knowledge, this is the first study to describe the clinical course of AE-FILD with a focus on patients experiencing a second attack.
Our study revealed a high mortality rate and a heterogeneous course of AE-FILD. Approximately 40% of patients who developed AE-FILD died within 90 days, which is consistent with previous reports11,14,15. Notably, approximately 80% of patients with AE-FILD responded to treatment at least once; however, approximately 30% of these patients experienced a relapse of their respiratory condition. This indicates the need for careful attention to a possible deterioration of the respiratory condition even after improvement following treatment for AE-FILD.
We identified two major courses leading to death in patients with AE-FILD: cases without a response to initial steroid therapy and those that responded to treatment at least once but died due to a second attack or complications. Among the patients who experienced second attacks or complications, 63.9% (n = 46) died within 90 days. Of all the patients who died of AE-FILD, approximately 40% responded to treatment at least once. Considering these results, we identified a need to differentially treat these disease courses to improve the prognosis of AE-FILD. For patients who do not respond to treatment, it is necessary to consider drugs other than steroids, which are commonly used in the initial treatment of AE-FILD25. It is of interest that a clinical trial of new agents for AE-IPF has recently appeared26. For patients who respond to treatment at least once, we identified a need to improve early preventive treatment against a second attack. This might require studies on prednisolone dose reduction or new therapies, including antifibrotic drugs. In addition to such clinical studies, mechanistic studies are needed to determine the cause of the observed relapses.
Our findings revealed several prognostic factors for AE-FILD. Low P/F ratio, high serum LDH level at AE diagnosis, and high serum CRP level at AE diagnosis were associated with 90-day mortality, which is consistent with previous findings11,22,27,28. Furthermore, multivariate analysis revealed that a second attack was an independent prognostic factor in patients who responded to treatment at least once. Moreover, the second attacks occurred in the early period after initial treatment and were strongly associated with early death; specifically, 28 patients in the second-attack group who died within 90 days died 10.5 days (median) after the onset of the second attack. This phenomenon has not been studied. Given their relatively high incidence and extremely high mortality rate, there is a need to consider the importance of second attacks.
Compared with the responder group, the second-attack group showed significantly higher serum LDH levels at AE onset. The median serum LDH was 328.0 IU/L in patients who responded at least once, with an IQR of 263.0–419.5 IU/L. Patients were divided into four quartiles (≤ 419.5, ≥ 328.0 and < 419.5, ≥ 263.0 and < 328.0, and < 263.0). In each group, 19 (28.8%), 18 (26.5%), five (7.6%), and four (6.2%) patients had second attacks, respectively. The precise reason for the association of LDH with a second attack is unclear. However, we identified a need for increased vigilance for respiratory deterioration if the baseline LDH levels are found to be high, even if the patient initially responds to treatment.
This study has several limitations. First, the fact that this study was conducted at only two institutions introduced a potential selection bias. Second, this was a retrospective study and included some cases (n = 2, 0.6%) with early loss to follow-up. Third, almost all included patients were of a single ethnicity (Japanese), which may limit the generalizability of the results. However, a strength of our study was the use of a large sample.