Our study aimed to provide evidence supporting treatment with corticosteroids for fibrotic HP. We demonstrated that corticosteroids improved survival and inhibited radiologic fibrotic progression and %FVC decline in the matched cohort, which was primarily composed of patients with ILD without extensive fibrosis. Our analyses suggest that the early initiation of treatment with corticosteroids may benefit patients with fibrotic HP.
This is the first report to demonstrate the survival benefit associated with treatment with corticosteroids in patients with fibrotic HP. The analysis showed better survival in the PDN group, after matching for pulmonary function and the radiologic presence of fibrosis, which are recognized as predictive of mortality. Indeed, reduced FVC is also recognized as a predictor of mortality in patients with fibrotic HP [25]. The presence of honeycombing is an established prognostic factor in patients with various fibrotic ILDs, including HP [4, 19, 22]. A previous report evaluating the effectiveness of corticosteroids for the treatment of fibrotic HP failed to demonstrate a survival benefit of corticosteroids in a cohort with a lower FVC and a relatively high frequency of the presence of honeycombing in the treatment group [7]. Consistent with this finding, the PDN group in our entire cohort, which similarly consisted of more patients with advanced progression of ILD, with a lower FVC and more radiologic evidence of fibrosis, had a worse survival rate than the group that was not treated with PDN. These differences in underlying characteristics between the groups seemed to lead to the underestimation of the effectiveness of treatment. Notably, the matched cohort consisted of many patients with earlier stages of ILD, with lower scores for fibrosis. Therefore, our results may be applicable only to patients with ILD without extensive fibrosis. Whether corticosteroids yield therapeutic benefits for HP patients with extensive fibrosis remains unclear.
Regarding the radiographic assessment, the scores for the fibrotic components of reticulation, traction bronchiectasis and honeycombing were surprisingly stable in the PDN group; in addition, the scores for the acute inflammatory findings of GGA and consolidation improved in the PDN group. In contrast, all these components worsened in most patients in the non-PDN group. This result indicates that corticosteroids may slow the progression of fibrosis, which is feasible, given that immune-mediated inflammation in HP is a target of anti-inflammatory medications. There have been several reports of the reversal of traction bronchiectasis and reticulation with treatment, although these fibrotic components typically worsen over time. In an analysis of nonspecific interstitial pneumonia that compared the extent of HRCT findings between the initial and later timepoints, some instances of traction bronchiectasis in the early stage were reversed, which was presumably attributable to the collapse of the surrounding peripheral lung parenchyma [26]. In addition, reticulation, which is primarily associated with fibrosis, was slightly improved by pharmacological therapy in some patients [27]. It is possible that the progression of these fibrotic components could be slowed by treatment with corticosteroids, which was supported by our findings regarding the annual changes in HRCT scores. These observations imply that treatment with corticosteroids may benefit patients in the early stages of fibrotic HP due to its inhibitory effect on fibrotic progression and ameliorating effect on acute inflammation.
With respect to the effect of treatment on pulmonary function, our results showed that treatment with corticosteroids improved pulmonary function over the course of two years. It is plausible that the reduction in the extent of GGA led to an improvement in pulmonary function in our cohort, as the scores for GGA decreased after the initiation of corticosteroids in many patients. As reported previously, the resolution of GGA primarily reflects lymphocytic inflammation that is linked to an improvement in pulmonary function in patients with fibrosing lung diseases [28, 29]. Meanwhile, our result was inconsistent with a previous report, which showed no effect of treatment with corticosteroids in patients with fibrotic HP [7]. The inconsistency may be attributed to the duration of the treatment period, as the mean treatment duration was half a year in that previous study, while corticosteroids were used continuously over the observation period in our study. Whether a response of pulmonary function to treatment leads to a survival benefit remains unclear, given that the PDN group in the entire cohort also experienced a posttreatment improvement in FVC, although the mortality rate was high. This clinical question needs to be investigated further.
Evidence supporting the benefits of treatment with corticosteroids for fibrotic HP has been lacking thus far. Given that HP is an immune-mediated disease, treatment with antiinflammatory agents such as corticosteroids may be a reasonable option even when fibrotic lesions are dominant findings on HRCT. We demonstrated that the PDN group in the matched cohort of patients with mild to moderate fibrosis had improved survival and slower radiologic fibrotic progression, while in the entire cohort, including the population with advanced fibrotic progression, the PDN group did not have better survival. Therefore, treatment with corticosteroids may need to be initiated before fibrosis becomes advanced. Mild to moderate fibrosis was identified as a therapeutic target based on the baseline variables of %FVC > 50%, maximum reticulation score < 4, and maximum traction bronchiectasis score < 3 in the majority of the population in our matched cohort. In addition, the population with extensive GGA, which is suggestive of a more abundant inflammatory process, may benefit from treatment with corticosteroids, as might patients with acute inflammatory HP. In our matched analysis, the total GGA score decreased dramatically after treatment, which may have been related to the improved outcomes. In addition, the presence of GGA was associated with improved survival in a multivariate model with adjustment for honeycombing in patients with chronic HP [30]. A recent review proposed that signs of active inflammation, including extensive GGA, were indications for the initiation of immunosuppressive therapy in fibrotic HP patients [5]. Based on this evidence, we suggest that patients with HP with mild to moderate fibrosis and evidence of GGA could be a promising target population for treatment with corticosteroids.
With regard to the pharmacological options for the treatment fibrotic HP, whether antifibrotic agents or immunosuppressants, including corticosteroids and other agents, should be selected remains to be discussed. There have been no head-to-head comparison studies between these interventions yet, and it would be interesting to conduct such studies in the future. In the latest report, nintedanib, a major antifibrotic agent, reduced the rate of ILD progression in patients with chronic fibrosing ILDs with progressive phenotypes, including patients with fibrotic HP [31, 32]. However, the primary outcome of that study focused on pulmonary function decline instead of survival, which was not statistically identified in the analysis of secondary outcome. In contrast, another previous study reported that mycophenolate mofetil or azathioprine for the management of chronic HP failed to yield positive outcomes with regard to pulmonary function and survival [33]. In our cohort, 33% of the group treated with corticosteroids was subsequently treated with other immunosuppressive agents, which could have contributed to the observed clinical improvement. We believe that the corticosteroids were the cause of the favorable outcomes in our analysis. However, intensive immunosuppressive therapy using corticosteroids and other immunosuppressants as a first-line option may be worth examining.
This study has several limitations. First, the matched cohort was small. This is mainly because the patients with progressed ILD were mostly receiving a therapeutic intervention, and we could not collect more patients for inclusion in the non-PDN group. Therefore, the results in the present study need to be verified in a larger cohort before being broadly applied. Second, it remains unclear whether the unmatched patients in this study who had severe disease and a high mortality rate benefits from corticosteroids. Exploring different matching strategies and outcomes may help overcome these limitations. Third, a quantitative scoring system was not adopted in this study, although such systems have been commonly used to more precisely estimate the extent of HRCT abnormalities. Instead, we used a semiquantitative assessment due to the ease of measurement and utility in clinical practice. Finally, the optimal dose and duration of therapy and the risk of adverse events were not discussed in this study. The mean initial dosage of corticosteroids in our cohort was approximately 0.5 mg/kg daily on an individual tapering schedule without complete withdrawal over the clinical course, which resulted in improved survival in the matched cohort. Whether a lower dose of corticosteroids results in a different outcome may be a question of interest with respect to the need to minimize the long-term adverse effects of therapy.