This retrospective study showed that high doses of corticosteroids are beneficial in most cases of AE-ILD, especially in cases of AE-non-IPF ILD, but not in cases of AE-IPF. Survival improved when doses of prednisolone higher than 1 mg/kg were administered.
The immediate outcome of AE is very poor; the median survival is 2.2 months from onset, and half of the patients die during hospitalization4,6. Furthermore, about 50% of patients need admission to an intensive care unit4. However, the optimal treatment for AE-IPF remains undetermined. A recent retrospective study showed that pirfenidone combined with corticosteroids and recombinant human thrombomodulin may improve survival in patients with AE-IPF (55% in patients with pirfenidone vs 34% in control group, p = 0.042)13. Most experts14 administer systemic corticosteroids with or without immunosuppressants, but the various drug regimens used in these two treatment approaches have not been evaluated in randomized controlled trials. Hence, the recommendation of corticosteroid treatment is based on low-quality evidence12. However, most patients are treated with high-dose immunosuppression therapy, typically with pulses of 500–1000 mg of methylprednisolone daily for 3 days3,6. The 2018 Japanese IPF treatment guidelines suggest that patients with AE-IPF should be treated with corticosteroids, including pulse therapy15. This is contradicted by the results of Mengshu et al.,16 who reported that high doses of corticosteroids are not beneficial for AE-ILD patients, and that the clinical outcomes of patients with AE-IPF mainly depend on the underlying clinical condition and the extent of lung injury from the AE. Thus, there remains a lack of consensus regarding proper treatment of AE-ILD.
Feghali-Bostwick et al.17 showed that patients with IPF frequently have autoantibodies and self-reactive CD4 T cells, thus fulfilling the diagnostic criteria for an autoimmune disease18. Moreover, there is a component of inflammation in AE-IPF19. Therefore, some patients respond to corticosteroids20. However, a recent study from 2020 showed no evidence that corticosteroids improve the outcome of patients with AE-IPF admitted to the hospital; furthermore, the results indicated that corticosteroid use following an exacerbation may contribute to reduced overall survival21. Our study showed the same results in AE-IPF cases.
The 90-day mortality rate in this study was relatively low (25.6% in the IPF group and 15.4% in the non-IPF ILD group) compared to other studies (mortality rate: 50–80%)10,22. The patients in our study were mainly diagnosed with mild ARDS (median P/F ratio: 223.4), and pirfenidone was administered in 41.6% (n = 54) of IPF patients before AE. A higher survival rate has been reported for patients with AE-IPF who were administered pirfenidone (55%) compared to those not administered pirfenidone (34%; p = 0.042)13. Recent developments in ARDS and sepsis management, as well as the use of high corticosteroid doses, may contribute to reduced mortality rates in this patient group.
Non-IPF ILD is also associated with autoimmunity, and thus has potential to respond well to corticosteroid treatment. According to the abovementioned mechanism of ILD, it could be speculated that corticosteroids would be effective in cases of AE-non-IPF ILD, but not in cases of AE-IPF.
AE-ILD can be precipitated by a variety of factors1. Viral infections, air pollution, aspiration, transfusions, drugs, or surgery, all leading to acceleration of the fibro-proliferative response, have been postulated as triggers of AE-ILD. However, the specific factors that cause some patients with ILD and not others to develop AE are unknown3,23. Although an infectious trigger could explain why some patients develop AE and others do not, no firm associations between bacterial or viral infections (including Epstein-Barr virus, cytomegalovirus, and human herpesvirus 8) and AE have been identified6. Our study identified 50 cases of AE-ILD triggered by bacterial, fungal, or viral infections. These patients had a worse survival outcome (90-day mortality of 22% compared to 15.8% in the non-triggered AE cases), although the difference was not statistically significant. However, triggered AE-ILD cases showed a more severe clinical course, including lower P/F ratios and higher lactate levels. Depending on the severity of the disease, fluid resuscitation, antibiotic use, initial ventilator care, sepsis management, and corticosteroid therapy could be needed.
Huie et al. suggested that patients with IPF have a lower survival rate after an acute respiratory decline as compared to patients with non-IPF fibrotic disease24. Pathophysiologically, AE-ILD resembles an acute lung injury, which presents histopathologically as diffuse alveolar damage in most cases25. A number of factors (including low baseline FVC and DLCO, extensive CT abnormalities and the involvement pattern, low oxygenation, and high bronchoalveolar lavage fluid neutrophil and lymphocyte percentages at the time of AE) have been reported as associated with survival of patients with AE-IPF3,26,27. However, this study could not demonstrate the significance of the radiologic and cellular pattern of bronchoalveolar lavage fluid because of a small sample size.
Patients who required mechanical ventilation from the beginning had a significantly higher mortality rate, possibly due to individual differences in the response to oxygen and steroid therapy in the setting of AE. Further studies are needed to assess individual differences in the response to oxygen and steroid therapy.
The present study had several limitations. First, this study analyzed data of a single tertiary center. Second, although we tried to obtain complete data by reviewing medical records, not all patients underwent a complete examination (e.g., missing microbiologic studies) at the initial visit to the ED. Third, we could not analyze long-term complications of corticosteroid therapy; therefore, we could not identify whether their use led to adverse outcomes such as opportunistic infections.
Despite the limitations, this study provides useful evidence for proper initial management and for decision-making regarding corticosteroid use in patients with AE-non-IPF ILD. Determining the corticosteroid dose and the administration modality (pulse therapy or routine high-dose steroids) is always difficult because of the potential side effects of corticosteroids. A larger-sample prospective study of patients with AE-ILD is, therefore, needed to address these limitations.