The prognosis of IPF is poor, with a reported 5-year survival rate of 20–40% [10]. In CFIP, diagnostic imaging with HRCT or surgical biopsy/cryobiopsy is used for pathological diagnosis to differentiate between IPF and nonspecific interstitial pneumonia. Meanwhile, owing to the invasive nature of surgical biopsy/cryobiopsy and the advanced skills required for these procedures, pathological diagnosis is often avoided despite the need to make a differential diagnosis between IPF and idiopathic nonspecific interstitial pneumonia, except for cases exhibiting typical usual interstitial pneumonia (UIP). Accordingly, the reported prognostic predictors of CFIP were mostly investigated in relation to IPF.
In CFIP cases, serial changes in the FVC are considered the best markers for monitoring disease progression [9]. In the present study, no significant differences were observed between the poor and good prognosis groups regarding FVC and %FVC at the time of BAL, suggesting that comparing these two groups is appropriate in evaluating the biomarker levels in BALF.
Performing pulmonary function examination in older people and patients with advanced respiratory failure can be rendered as challenging. Preferably, prognosis is predicted based on the tests performed at the time of initial medical examination, rather than by evaluating progress through serial changes in prognostic markers, such as the FVC.
In clinical practice, it is meaningful to examine prognostic markers in patients other than those diagnosed with typical IPF by HRCT or those diagnosed with IPF by surgical biopsy and to identify prognostic markers in patients with CFIP. However, to date, no previous study has comprehensively examined BALF.
Prognostic serum biomarkers for CFIP have been reported in several studies, although there is insufficient evidence regarding their use in daily clinical practice. Concerning KL-6, serial changes in its serum levels are associated with prognosis in patients with IPF [2, 3]. Moreover, patients with a serum KL-6 level of ≥ 1000 U/mL [4–6], a serum SP-D level of ≥ 250 ng/mL [7], and a serum SP-A level of ≥ 80 ng/mL [8] have poor prognoses. Meanwhile, Raghu et al. reported that those markers had no correlation with prognosis [11]. In the present study, although no differences were observed between the poor and good prognosis groups, the median serum KL-6, SP-D, and SP-A levels at the initial visit were ≥ 1000 U/mL, ≥ 250 ng/mL, and ≥ 80 ng/mL, respectively, in the poor prognosis group. Although there is no consensus regarding the serum markers, we considered the examined population in the present study to be valid.
Few previous studies have examined BALF. McCormack et al. reported that, in IPF, patients who died within 2 years had a lower BALF SP-A/PL compared with those who survived, and patients with low BALF SP-A/PL levels had poor prognoses according to the survival curves [12]. While the present study mainly investigated patients with CFIP, the analysis, which was limited to confirmed IPF cases, revealed the highest prognostic performance for the BALF SP-A level, consistent with the findings of a previous report. Although no correlation was observed between the BALF KL-6 level and prognosis, the BALF/serum ratio of SP-D, which is also a surfactant, was significantly lower in the poor prognosis group. This finding may indicate that SP-D, being more hydrophilic compared to SP-A, has a greater propensity to transfer into the serum [13]. Our findings are of high clinical significance, as similar results were obtained in patients with CFIP excluding those with HRCT- or pathologically-diagnosed UIP.
We previously reported that, in patients with IIP and UIP diagnosed by surgical biopsy, the SP-A expression in the lesion tissue significantly decreased in patients with a poor prognosis [14]. Takezaki et al. performed a genomic analysis of families with familial IPF and reported that mutations in the gene encoding SFTPA1, one of the constituent molecules of SP-A, cause hyposecretion of SFTPA1 from type II alveolar epithelial cells, thereby increasing the sensitivity of type II alveolar epithelial cells to necroptosis and possibly leading to pulmonary fibrosis [15]. This suggests that patients with decreased BALF SP-A levels may have had increased necroptosis of type II alveolar epithelial cells, which may have led to the progression of pulmonary fibrosis, resulting in their poor prognosis. Moreover, SP-A has also been reported to induce a natural immune effect [16]; thus, it is possible that the decrease in the production of SP-A in type II alveolar epithelial cells may have concurrently caused pulmonary infection and induced acute exacerbation and worsened the prognosis.
The present study had some limitations. First, the sample size was small as BAL was not performed in all patients with CFIP. This decision stemmed from the established diagnostic criteria for typical IPF, where imaging findings often suffice, making BAL unnecessary. In addition, BAL was performed in selected patients potentially exhibiting higher activity levels relative to others in the overall population of patients with CFIP. Second, this study was conducted at a single center. Thus, future studies with a larger sample size are needed. Third, it was not possible to pathologically diagnose all patients for whom a definitive diagnosis of UIP could not be made using HRCT. Despite these limitations, we believe that our findings are significant as they suggest the potential usefulness of BAL SP-A measurement in predicting the prognosis for patients with CFIP given the large number of cases, in which surgical biopsy is not feasible in clinical practice.