Second acute exacerbation of fibrotic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis

Introduction

Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) has been found to occur multiple times (1). Patients with fibrotic hypersensitivity pneumonitis (HP) experienced a lower incidence of the first AE and a higher 90-day survival rate after the first AE compared to those with IPF (2). However, the incidence, risk factors, and 90-day survival rate associated with the second AE in patients with fibrotic HP and those with IPF remain unclear. This study focused on investigating the clinical characteristics of the second AE in patients with fibrotic HP and those with IPF. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-195/rc).

Methods

Data collection

This was a single-center, and retrospective study. Patients with histopathological diagnose of fibrotic HP or IPF between January 2005 and June 2023 were included. The diagnosis of fibrotic HP followed the 2020 American Thoracic Society (ATS)/ the Japan Respiratory Society (JRS)/the Asociación Latinoamericana de Tórax (ALAT) Clinical Practice Guidelines (3). Patients with a moderate confidence or higher diagnostic confidence, including histopathological findings by surgical lung biopsy (SLB) or transbronchial lung cryobiopsy (TBLC), were diagnosed with fibrotic HP. Patients with IPF were diagnosed according to the 2011 or 2018 the ATS/the European Respiratory Society (ERS) IPF statement, including histopathological findings by SLB and TBLC (4,5). The choice of guidelines depended on the timing of the IPF diagnosis. Patients with fibrotic HP and those with IPF were diagnosed through multidisciplinary discussion (MDD). AE was defined according to the 2016 International Working Group Report on the diagnostic criteria for AE of IPF (6). Patients with fibrotic HP and those with IPF who survived for at least 2 weeks after the first AE were included for the investigation of the second AE.

After evaluating the cumulative incidence of the first AE in patients with fibrotic HP and those with IPF, the incidence, risk factors, and survival rate of the second AE were analyzed. The baseline was defined as 4 weeks (±2 weeks) after the first AE. Patients were followed until June 2024.

Erector spinae muscle (ESM) measurements

The cross-sectional area of the ESM (ESMcsa) was measured on high-resolution computed tomography (HRCT) images at the lower margin of the twelfth thoracic vertebra using Ziostation2 (AMIN Corporation, Tokyo, Japan). Evaluation methods were based on previous studies (7,8). The left and right ESMs were identified, manually shaded, and the cross-sectional areas of both muscles were calculated and summed to determine the total ESMcsa.

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the committee of the Kanagawa Cardiovascular and Respiratory Center (No. KCRC-24-0013, August 14, 2024). The requirement for patient consent was waived owing to the retrospective nature of the study, and high levels of anonymity were ensured.

Statistical analysis

The unpaired t-test was used to compare continuous variables between the two groups. Additionally, the 2×2 contingency tables were analyzed using the Pearson’s Chi-squared test. The Kaplan-Meier curves and the log-rank test were applied to analyze survival and time to AE. Cox hazard regression analysis was used to compare the time to event. Parameters with a P value of <0.1 in the univariate Cox hazard regression analysis were included in the multivariate Cox hazard regression analysis. All statistical analyses were conducted using BellCurve for Excel (Social Survey Research Information Co., Ltd., Tokyo, Japan).

Results

Patient characteristics

For investigation of the second AE, 39 patients with fibrotic HP and 61 patients with IPF were included, respectively (Figure 1). The mean ages of the fibrotic HP group were 73.1 years and the mean age of IPF group was 70.1 years; 51% and 85% of patients with fibrotic HP and those with IPF, respectively, were male (Table 1). In patients with fibrotic HP and those with IPF, mean serum Krebs von den Lungen-6 (KL-6) levels were 2,467 and 1,845 U/mL, while mean ESMcsa/body surface area (BSA) was 15.5 and 16.4 respectively. SLB was performed in 72% of patients with fibrotic HP and 70% of patients with IPF. No significant differences were observed between the two groups in terms of age, body mass index (BMI), ESMcsa/BSA, KL-6 level, C-reactive protein, serum albumin level. The fibrotic HP group exhibited significantly lower BSA compared with the IPF group (1.574 vs. 1.649 m², P=0.03). Based on the HRCT criteria for the usual interstitial pneumonia (UIP) pattern proposed in the 2011 ATS/ERS/JRS/ALAT statement (4), the HRCT pattern in the IPF group was classified as UIP pattern in 23 patients (38%), possible UIP pattern in 26 (43%), and inconsistent with UIP pattern in 12 (19%).

Figure 1 Flowchart of included patients. AE, acute exacerbation; HP, hypersensitivity pneumonitis; IPF, idiopathic pulmonary fibrosis.

At baseline, defined as 4 weeks after the first AE, there were no significant differences between the fibrotic HP and IPF groups in the frequency of prednisolone (PSL) or immunosuppressant use. Furthermore, the average daily dose of PSL was 26 mg/day in both the fibrotic HP and IPF groups. Regarding immunosuppressant use, 7 of 11 patients in the fibrotic HP group received cyclosporine, with 4 receiving tacrolimus. In the IPF group, 10 of 25 patients received ciclosporin and 15 received tacrolimus. At baseline, 16 patients with fibrotic HP and 27 patients with IPF received antifibrotics. The inciting antigen for fibrotic HP was identified as avian in 6 patients, and unknown in 33.

Incidence of the first AE

In 425 patients with fibrotic HP, the cumulative first AE rates from diagnosis were 2.6% at 1 year and 4.3% at 2 years. In 335 of patients with IPF, the corresponding 1- and 2-year rates were 5.1% and 8.9%, respectively. The cumulative incidence of the first AE in fibrotic HP group was significantly lower than that in IPF group [hazard ratio (HR) =0.561, 95% confidence interval (CI): 0.383–0.821, P=0.003] (Figure 2).

Figure 2 Cumulative incidence of the first AE in patients with fibrotic HP and those with IPF. AE, acute exacerbation; CI, confidence interval; HP, hypersensitivity pneumonitis; HR, hazard ratio; IPF, idiopathic pulmonary fibrosis.

The second AE incidence

In fibrotic HP group, the second AE incidence rates at 1 and 2 years from the baseline (defined as 4 weeks after the first AE) were 23% and 50%, respectively. In the IPF group, these incidence rates of the second AE were 29% and 32% at 1 and 2 years, respectively, with no significant difference compared to fibrotic HP group (HR =1.084, 95% CI: 0.550–2.140, P=0.82) (Figure 3).

Figure 3 Cumulative incidence of the second AE from the baseline in patients with fibrotic HP and those with IPF. AE, acute exacerbation; CI, confidence interval; HP, hypersensitivity pneumonitis; HR, hazard ratio; IPF, idiopathic pulmonary fibrosis.

Multivariate analysis identified baseline serum KL-6 levels as a risk factor for the second AE in fibrotic HP, whereas baseline serum KL-6 levels and ESMcsa/BSA were risk factors in IPF (Tables 2,3). Among 39 patients with fibrotic HP and 61 patients with IPF, elevated serum KL-6 levels (≥2,000 U/mL) at 4 weeks after the first AE were associated with an increased risk of the second AE (HR =3.266, 95% CI: 1.648–6.472, log-rank test, P<0.001). The 90-day survival rates after the second AE were 69% in patients with fibrotic HP and 50% in those with IPF, respectively, with no significant difference observed (HR =0.503, 95% CI: 0.232–1.091, log-rank test, P=0.07) (Figure 4).

Figure 4 Ninety-day survival from the second AE onset in patients with fibrotic HP and those with IPF. AE, acute exacerbation; CI, confidence interval; HP, hypersensitivity pneumonitis; HR, hazard ratio; IPF, idiopathic pulmonary fibrosis.

For patients with fibrotic HP during a second AE, treatment included antigen avoidance in 2, methylprednisolone (mPSL) pulse therapy in 11, mPSL pulse therapy with tacrolimus in 2, and mPSL pulse therapy with intravenous cyclophosphamide (IVCY) in 1. For patients with IPF, treatment included mPSL pulse therapy in 14, mPSL pulse therapy with tacrolimus in 1, mPSL pulse therapy with IVCY in 1, mPSL pulse therapy with ciclosporin in 1, IVCY alone in 1, mPSL pulse therapy with polymyxin B-immobilized fiber column direct hemoperfusion in 1, and best supportive care in 1. No significant differences were observed in second AE treatment strategies between fibrotic HP group and IPF group (P=0.69). In HP group, the second AE occurred in 1 of 7 patients with bird-related HP and in 15 of 33 patients with an unknown inciting antigen.

Survival in patients with fibrotic HP and IPF

Median survival from baseline was 38.8 and 35.4 months in fibrotic HP group and IPF group, respectively, with no significant difference detected (HR =0.680, 95% CI: 0.413–1.122, log-rank test, P=0.13) (Figure 5).

Figure 5 Overall survival from 4 weeks after the first AE in patients with fibrotic HP and those with IPF. AE, acute exacerbation; CI, confidence interval; HP, hypersensitivity pneumonitis; HR, hazard ratio; IPF, idiopathic pulmonary fibrosis.

In patients with fibrotic HP, from baseline, measured 4 weeks after the first AE, the causes of death included AE in 4 patients, disease progression in 14, alveolar hemorrhage in 1 patient, pulmonary embolism in 1, unknown causes in 4, and other causes in 2. Among patients with IPF, deaths were attributed to AE in 14 patients, disease progression in 19, aspiration pneumonia in 3, heart failure in 2, unknown causes in 5, and others cause in 2. Among patients who experienced a second AE, a third AE occurred in 6 of 16 patients with fibrotic HP (38%) and 4 of 20 patients with IPF (20%).

Discussion

In this study, the incidence of the first AE differed significantly between fibrotic HP group and IPF group; however, no significant difference was found in the second AE incidence between the fibrotic HP group and IPF group. Additionally, baseline KL-6 levels were identified as a risk factor for the second AE in both the fibrotic HP group and IPF group.

A previous study showed that, the first AE incidence was 3% at 1 year and 6% at 2 years for fibrotic HP group, compared with 8% at 1 year and 13% at 2 years for IPF group, indicating a marked difference (2). Consistent with this, this study revealed a significant difference in the first AE incidence between fibrotic HP group and IPF group. However, no significant difference was found in the second AE incidence between the two groups. Sánchez-Díez et al. reported that serum KL-6 levels were correlated with exposure to the inciting antigen in patients with HP (9). This study indicated that baseline serum KL-6 levels were identified as a risk factor for the second AE in fibrotic HP group; the second AE occurred in 45% of patients with fibrotic HP with an unknown inciting antigen. Therefore, patients might have sustained exposure to the inciting antigen following the first AE.

In this study, the cumulative incidence of the second AE over a 5-year period was 75.2% in the IPF group. In a 5-year prospective study, Tsubouchi et al. reported that the incidences of multiple AEs as 33.0% 27.9% for IPF group and idiopathic interstitial pneumonia group other than IPF group (1). Tsubouchi et al. used the time of diagnosis as the baseline, whereas this study used the onset of 4 weeks after the first AE as the baseline, which may explain the difference in incidence rates of the second AE. Additionally, the requirement for histopathological confirmation of IPF in the current study likely included many atypical cases which suggests that a number of patients with HRCT findings of atypical IPF were included. The inconsistent with UIP patterns based on HRCT pattern classifications was as high as 20%. Moreover, patients with mild disease who could tolerate histopathological evaluation were commonly included. Despite these factors, IPF diagnoses in this study show relatively high confidence owing to histopathological confirmation and MDD.

A prior study reported 90-day survival rates of 75% and 64% for patients with fibrotic HP and those with IPF (2). In contrast, this study found 90-day survival rates after the second AE were 69% and 50% in patients with fibrotic HP and those with IPF, with no significant difference observed. These findings might suggest that the prognosis following the second AE in patients with fibrotic HP is comparable to those with IPF. Most patients in both groups were already receiving ≥20 mg/day PSL after the first AE, and additional therapy, including mPSL pulse therapy or immunosuppressants, and increased doses of PSL during the second AE might have been less effective.

Previous studies identified various risk factors for the first AE in fibrotic HP, including low forced vital capacity at diagnosis, low diffusing capacity for carbon monoxide, high BMI, low percentage of lymphocytes in bronchoalveolar lavage (BAL), and the presence of UIP patterns in HRCT (2,10,11). In this study, BMI was not identified as a risk factor for the development of the second AE. Additionally, owing to limited availability of pulmonary function tests and bronchoscopy after the first AE, neither lymphocyte percentages in BAL nor pulmonary function tests were analyzed for the risk factors of second AE. Notably, in real-world practice, pulmonary function tests and bronchoscopy are often avoided because of respiratory deterioration following the first AE.

Few reports currently exist on risk factors associated with the development of the second AE. We identified ESMcsa/BSA as a risk factor of the second AE in addition to baseline of serum KL-6 levels in patients with IPF. Moreover, in patients with IPF, measuring ESMcsa/BSA with HRCT scan, which is relatively less invasive, might predict the onset of the second AE. ESMcsa/BSA, a parameter used to assess skeletal muscle mass, demonstrated to be a useful predictor of prognosis in patients with IPF (12-16). A previous study reported additionally showed that low ESMcsa was also related to high 90-day mortality rate in patients with the first AE (17). Although many studies have reported the association between the ESMcsa and mortality in IPF, few have investigated its relationship with the risk of AE (14,15). In contrast, other surrogate markers of frailty, such as weight loss and low BMI, have been reported as risk factors for the first AE in patients with IPF (18,19). Our findings indicate that ESMcsa/BSA was also a potential predictor of the second AE. However, parameters that assess frailty, such as ESMcsa/BSA, are prognostic indicators, and their relevance as risk factors for AE is not yet clear. Therefore, parameters that assess frailty might not be the direct cause of AE, but might reflect phenomena associated with poor prognosis. In this study, only 20 patients with IPF experienced the second AE, suggesting that the results should be interpreted with caution. Further large-scale studies are warranted to determine whether ESMcsa/BSA is a reliable risk factor for the second AE.

In this study, only patients who underwent pathological examination were included, which likely resulted in a higher proportion of patients with mild disease. Previous reports have shown a 1-year AE incidence rate ranging from 5% to 14% in patients with IPF (20,21). The incidence of AE within one year after diagnosis among patients with IPF in this study was 5.1%. The low incidence of the first AE suggests that many of the included patients were in the early or mild stages of disease. In the international diagnostic guidelines for IPF and fibrotic HP, pathological examination is not mandatory (3,5). Therefore, studies including patients with severe disease who cannot undergo pathological examination are desirable. However, since the survival rate after the first AE is low in severe patients, accumulating sufficient numbers of patients with severe IPF for investigation of the second AE is considered challenging (21,22).

This study had several limitations. First, this was a single-center, retrospective study, and all patients underwent pathological examinations, which might have led to potential bias in patient selection. However, this study included patients who underwent TBLC as well as SLB, allowing for the selection of patients with a relatively high level of diagnostic confidence. Second, treatments for patients with fibrotic HP and those with IPF varied at baseline, including PSL and immunosuppressants. These treatments might have influenced both survival outcomes and the second AE incidence. However, no significant differences were observed between the two groups in the frequency of PSL or immunosuppressant use at baseline, which was defined as 4 weeks after the first AE. The influence of initial treatments during the first AE, such as mPSL pulse therapy or IVCY, on the development of the second AE cannot be excluded. Third, no established international guideline for the definition of AE in fibrotic HP exists. In this study, the definition of AE in fibrotic HP was based on the same criteria used for AE in IPF, outlined in the 2016 International Working Group Report (6). However, further discussion is necessary to establish a standardized definition of AE in patients with fibrotic HP.

Conclusions

In contrast to the first AE, no significant difference in the second AE incidence was observed between fibrotic HP and IPF groups. Additionally, levels of serum KL-6 measured 4 weeks after the first AE were identified as a risk factor for the second AE in both fibrotic HP and IPF groups

Acknowledgments

The authors would like to thank Enago (www.enago.jp) for the professional English language review.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-195/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-195/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-195/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-195/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the committee of the Kanagawa Cardiovascular and Respiratory Center (No. KCRC-24-0013, August 14, 2024). The requirement for patient consent was waived owing to the retrospective nature of the study, and high levels of anonymity were ensured.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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