Predictors of forced vital capacity response to immunosuppression in fibrotic hypersensitivity pneumonitis: a retrospective cohort analysis of 203 patients

Introduction

Hypersensitivity pneumonitis (HP) is a diffuse interstitial lung disease (ILD) associated with prolonged and repeated exposure to inhaled sensitizing antigens (1,2). Several causative antigens can exaggerate this hypersensitivity response, including environmental avian, mold, or bacterial proteins and other organic and inorganic compounds (3). A prior international diagnostic guideline proposes the classification of disease into fibrotic and non-fibrotic presentations, given differences in outcome and potential response to antigen avoidance and immunosuppression (2). Additionally, immune mechanisms in fibrotic hypersensitivity pneumonitis (f-HP), including switching from a T-helper 1 to T-helper 2 immune response and exhaustion of antigen-specific T cells, may suggest less inflammation than seen in acute or non-fibrotic subtypes (4). Consequently, the treatment of f-HP with immunosuppression remains controversial.

The current treatment of f-HP is based on observational studies and expert opinion in the absence of well-designed controlled trials and real-world challenges with patient selection and indication bias. In addition to avoiding potential causative antigens, corticosteroids (CS) remain an initial mainstay of treatment for f-HP. Only one randomized controlled trial conducted in acute farmer’s lung several decades ago demonstrated short-term improvement in diffusing capacity for carbon monoxide (DLCO) at one month (5). Later observational studies remain mixed regarding the benefit of CS in those with fibrotic diseases. De Sadeleer et al. found no mortality benefit or differences in forced vital capacity (FVC) or DLCO with CS treatment (6). In contrast, a later study by Ejima et al. demonstrated decreased mortality in patients treated with prednisolone compared to untreated patients matched by age, sex, smoking status, baseline pulmonary function test (PFT), and computed tomography (CT) findings (7). This study found significantly improved FVC in f-HP patients treated with prednisolone.

Steroid-sparing agents (SSA), mycophenolate mofetil (MMF) and azathioprine (AZA), are alternative options for medical treatment in patients requiring additional maintenance or long-term immunosuppression. The benefit of SSA in f-HP is limited to observational studies thus far showing no significant improvement in FVC, however, slowing of FVC decline and potential improvement in DLCO have been reported (8-11).

Given varied mechanisms of reduced inflammation and mixed treatment outcomes in observational studies, treatment response may not be achievable in all patients with f-HP. FVC is a well-established marker of disease progression or treatment responsiveness in patients with ILD (12-14). We conducted a large retrospective study of f-HP patients treated with CS and/or SSA to determine clinical predictors of short-term functional response as defined by changes in percent-predicted FVC (FVC%). Such assessments may better engage patient selection and avoid adverse treatment effects. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1492/rc).

Methods

Subject selection

The study is a single-center retrospective cohort involving adult patients seen at Mayo Clinic from January 2005 through December 2022. A computer-assisted search of the electronic medical record was performed using the term “hypersensitivity pneumonitis” in multiple search fields, including clinical notes, radiology and histopathology reports, and ICD-9/ICD-10 diagnostic codes. Individual patient records identified from screening were comprehensively reviewed for diagnostic confidence based on the 2020 American Thoracic Society (ATS)/Japanese Respiratory Society (JRS)/Asociación Latinoamericana de Tórax (ALAT) clinical practice guideline (2). Fibrosis was defined by radiologic evidence of reticulation with or without traction bronchiectasis or honeycombing on chest CT as reviewed by the authors and indicated in the original reading radiologist report. Patients were included if PFT was obtained at baseline and up to three to nine months while on treatment with CS or SSA (MMF or AZA). Patients were considered ‘new’ diagnosis if the diagnosis of f-HP was not established at the time clinical referral and no prior treatment had been initiated. ‘Established’ diagnoses were those where diagnosis had been made prior to institutional referral, with or without prior use of CS or SSA but not on active treatment. Patients were excluded if (I) diagnostic confidence level was less than 50%; (II) were on antifibrotics at the time of this assessment, or did not receive documented medical treatment (CS, MMF, AZA, or other SSA). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Mayo Clinic (approval No. 20-000211; 11/15/2022). All study participants provided a priori consent for their de-identified clinical information to be included or reviewed for the purposes of research.

Data collection and primary outcome

Baseline characteristics including age, sex, smoking status, causative antigen exposure history, serum IgG against specific antigens (5 avian proteins, 8 mold, and 3 bacterial species), f-HP CT pattern, extent of radiologic findings including ground glass mosaic attenuation (3-density sign), and honeycombing, histopathologic findings, treatment type (CS +/− SSA), and PFTs at baseline (FVC% and DLCO%) and after treatment were collated. Suspected or documented ‘identifiable causative antigen’ was defined as positive serum precipitin antibodies to avian, mold, or bacterial antigens with suspected environmental exposure, or negative serologic testing but suggestive environmental exposure by history (2). Antigen avoidance was defined as clinician documented effort to abstain from environmental or occupational exposure, including removing or abating inciting sources of exposure or abstaining from suspected environments. The primary study outcome of positive treatment response was defined as absolute increase in FVC% ≥5% within three to 9 months of any immunosuppressive therapy.

Statistical analysis

Summarized statistics were presented as mean with standard deviation (SD) or median with 25–75% interquartile range (IQR) for continuous variables and frequency with percentages for categorical variables. Group comparison of baseline characteristics were stratified by treatment response (positive vs. no-change or decline in FVC% after treatment). Baseline clinical characteristics associated with positive treatment response were identified using univariable and multivariable logistic regression. Subgroup analysis of patients with new and pre-existing diagnoses f-HP diagnoses was performed to assess individual group predictors of treatment response. Comparison of mean FVC% findings in patients initially treated with CS followed by SSA (MMF or AZA) was completed using paired t-tests between time points. All regression models were adjusted for a priori covariables of age, sex, baseline FVC%, and diagnosis status (new or incident vs. pre-existing). Two-tailed P values <0.05 were considered statistically significant with analysis completed using R [R core Team (2021) www.R-project.org/].

Results

Patient characteristics

A total of 377 patients with f-HP and diagnostic confidence levels greater than 50% were identified. After protocolized exclusions, 203 were included for analysis (Figure 1).

Figure 1 Patient selection and enrollment. ALAT, Asociación Latinoamericana de Tórax; ATS, American Thoracic Society; HP, hypersensitivity pneumonitis; JRS, Japanese Respiratory Society.

Of these, 51% were male, with a mean age of 64.8±11.4 years (Table 1). Forty-eight percent were prior or active smokers with baseline FVC% and DLCO% of 62.1±16.4 and 45±13.9, respectively. Potential causative antigens were identified in 132 patients (65%). The most common exposure type was bird or avian protein (N=66), followed by exposure to fungal contamination in the home or workplace (N=26) and exposure to farm environments (N=22). Diagnostic confidence for f-HP, f-HP CT pattern, frequency of diagnostic procedures and histopathologic findings, were similar between those with and without positive treatment response. Male sex (36% vs. 84%, P=0.004) and radiologic honeycombing (12% vs. 28%, P=0.01) occurred less frequently in those with positive treatment response, with newer or incident cases (61% vs. 40%, P=0.007). Treatment types (CS or SSA) and frequency of documented antigen avoidance (37% vs. 34%, P=0.66) were no different between treatment responsive and non-responsive groups. Median time between baseline and follow-up FVC% after treatment initiation was 168 days or 5.6 months [IQR, 120–212 days (range, 4 to 7.1 months)].

Predictors of treatment response

Treatment response (absolute increase in FVC% ≥5 within 3 to 6 months of treatment initiation) was seen in 59 patients (29%). Univariable and multivariable logistic regression analyses for treatment response for the whole cohort are presented in Table 2. Male sex [adjusted OR =0.36, 95% confidence interval (CI): 0.18–0.69, P=0.003], radiologic honeycombing (adjusted OR =0.37, 95% CI: 0.15–0.90, P=0.03), and higher baseline FVC% (adjusted OR =0.97, 95% CI: 0.95–0.99, P=0.01) were associated with lower likelihoods of treatment response, while treatment in newly diagnosed patients was associated with a higher likelihood (adjusted OR =2.59, 95% CI: 1.35–5.09, P=0.005). Identifiable suspected antigens (unadjusted OR =1.48, 95% CI: 0.22–0.76, P=0.24) and antigen avoidance (unadjusted OR =1.15, 95% CI: 0.61–2.16, P=0.66) were not associated with treatment response.

On subgroup analysis of new vs established cases of f-HP presenting for treatment, treatment response was seen in 38% of those with newly diagnosed disease (N=94) (Table 3). Of these, 88 received CS, four MMF, and two AZA. A lower likelihood of treatment response was seen again in male patients with higher baseline FVC% (adjusted OR =0.31, 95% CI: 0.12–0.76, P=0.01 and 0.97, 95% CI: 0.93–0.99, P=0.02, respectively), while radiologic honeycombing was no longer associated with a lower likelihood of treatment response (unadjusted OR =0.36, 95% CI: 0.10–1.10, P=0.07). Identifiable causative antigens (unadjusted OR =0.76, 95% CI: 0.31–1.90, P=0.55) and antigen avoidance (unadjusted OR =1.03, 95% CI: 0.46–2.53, P=0.85) were not associated with treatment response.

On subgroup analysis of 109 patients with pre-existing or established f-HP diagnosis, treatment response was 21% (Table 4). Seventeen patients received CS, 48 MMF, and 44 AZA, with a median time from diagnosis to treatment initiation of 9.8 months (25–75% IQR, 3.9–25.0). All patients received CS at some point before study inclusion. An identifiable causative antigen was the only variable predictive of treatment response in this subgroup (adjusted OR =3.52, 95% CI: 1.22–11.85, P=0.02), with male sex, radiologic honeycombing, and higher baseline FVC% no longer associated with treatment response. Notably, antigen avoidance (unadjusted OR =1.01, 95% CI: 0.35–2.67, P=0.99) was still not associated with acute treatment response.

Figure 2 demonstrates mean FVC% in 76 patients with known f-HP treated for disease progression with CS followed by SSA. A continued decrease in mean FVC% on CS was observed, with a pre-treatment baseline mean of 64.5±13.7, dropping to a mean of 60.5±15.3 after treatment (P=0.007). However, further FVC% decline was not observed with transition to SSA over the ensuing six months (mean FVC% 60.5±15.3 and 59.5±16.2, pre- and post-treatment, respectively; P=0.23).

Figure 2 Change in FVC% in patients with previously diagnosed fibrotic hypersensitivity pneumonitis receiving corticosteroids followed by steroid-sparing agent for disease progression (N=76). FVC%, percent-predicted forced vital capacity.

Discussion

In this retrospective analysis of 206 patients receiving immunosuppressive treatment for f-HP, there was a response rate of 29% at three to nine months. Those with newly diagnosed disease had a higher response rate compared to those with pre-existing or established diagnoses (38% vs. 21%, adjusted OR =2.59, 95% CI: 1.35–5.09; P=0.005). Male sex, radiologic honeycombing, and higher baseline FVC were also associated with lower likelihoods of treatment response for the cohort as a whole. On subgroup analysis, newly diagnosed male patients with higher baseline FVC% were less likely to respond, whereas identifiable antigen exposure was a significant predictor of treatment response in those with established disease. Documented antigen avoidance to known or suspected exposures did not appear to be associated with greater treatment response in either cohort, despite identifiable antigen exposure being predictive in those with established disease. Initial CS also did not appear to slow or stop FVC decline in such patients, with subsequent transition to SSA appearing to slow or stop lung function decline in the ensuing 6 months.

Since active inflammation may be less evident in f-HP compared to acute disease, rationale for the immediate and/or long-term use of immunosuppressive agents remains unclear. Our study found that male patients with higher baseline FVC% and radiologic honeycombing were less likely to respond to immunosuppressant therapy. After stratification by new versus established diagnoses, these covariables were not as predictive in those with previously treated or established disease. Male sex is a known variable for predicting survival outcomes in patients with ILDs (15,16), contributing, for example, to the GAP and GAP-ILD index models (17,18). Although not previously reported as a predictor of treatment response, previous studies have also demonstrated association of male sex with worse outcomes in chronic or fibrotic HP (19,20). Underlying mechanisms for this remain unclear, with the potential role of estrogen in fibrotic progression being explored in animal models, as highlighted by one study where decreased fibrosis was seen in female and male rats treated with estrogen compared to untreated males and ovariectomized females (21).

Radiologic honeycombing was associated with a decreased likelihood of treatment response in our study. Honeycombing often represents advanced or end-stage fibrotic disease less amenable to anti-inflammatory or immunosuppressive therapies, as compared to the ground-glass, micronodular, or mosaic changes seen in acute disease (22,23). Immunosuppressive agents may see less effect as immune responses transition from T-helper 1 to T-helper 2 pathways and more fibroproliferative disease (1). Clinical studies have shown no improvement in fibrotic changes after CS treatment in f-HP (7,8).

Higher baseline FVC was associated with a lower likelihood of treatment response in our study. This association appears to be driven by patients with new diagnoses of f-HP as compared to those with existing or established disease. As newly diagnosed patients are treatment naive, a lower baseline FVC might represent more acute inflammation and portend greater opportunity for improvement than those with higher FVC and less underlying lung injury. In contrast, baseline FVC in patients with pre-existing diagnoses may have already optimized FVC response to prior treatment regimens, with higher numbers suggesting established response with less opportunity for improvement. Again, short term changes in lung function including decline in FVC from 5% to 10% at one year have been associated with worse outcomes in patients with f-HP (14,24).

Antigen identification and avoidance are primary management strategies in f-HP. Prior studies suggest antigen removal or avoidance may contribute to improved survival even in those with fibrotic disease (25,26). Antigen identification was a predictor of potential treatment response in patients with established disease in our cohort, though was not predictive in those with newly diagnosed or previously untreated disease. Additionally, documented antigen avoidance did not appear to be associated with treatment response in either cohort. Explanations for this include limited or waning impact from antigen identification and avoidance on lung function in those with established disease who may have already benefited from this before undergoing treatment (26), with mixed or combined effect of both avoidance and medical treatment in those with newly diagnosed disease (6). Notably, current predictors of FVC% treatment outcomes for our cohort as a whole (male sex, presence of honeycombing, and baseline FVC%) and among subgroup analyses of new or incident vs established diagnoses, remained so even after adjusting for identifiable antigens or antigen avoidance. While antigen identification and avoidance are critical to the management of acute and f-HP, its impact may be limited in terms of assessing acute treatment responsive as defined by FVC%, or be difficult to accurately define with less immediate relevance in those with established fibrotic disease (3,7).

Lastly, our study also revealed a higher treatment response rate in newly diagnosed patients compared to those with pre-existing or established diagnoses. As described above, all patients with pre-existing diagnoses of f-HP in our study were treated previously with CS prior to receiving current CS or SSA treatment, with inflammation possibly already suppressed. However, our study found that transitioning from initial CS to SSA appeared to stabilize FVC despite prior decline during the CS-only treatment period. Similarly, Morisset et al. demonstrated no significant increase in FVC after 12 months of SSA treatment (10), while Adegunsoye et al. showed SSA may slow FVC decline compared to previous CS treatment (11).

Our study has several limitations. First, as a retrospective design, non-protocolized follow-up may lead to missing data or variable time point measurements. Our study assessed treatment responses up to nine months, which might not predict or represent longer-term outcomes such as 24 or 48 months from diagnosis. However, change in FVC% before and after SSA treatment in our study was similar to that of previous studies (10,11). Second, we focused on treatment response as defined by change in FVC% and no other clinical outcomes such as reversal or stability of fibrotic and non-fibrotic radiologic findings, respiratory-related quality of life, adverse treatment effects, and mortality. Future studies assessing these variables alone or in conjunction as composite endpoints should be considered. Third, we could not completely exclude potential confounding factors such as concurrent treatment with both CS and SSA therapies, duration of or unknown exposure to causative antigens with lack of antigen avoidance. Finally, selection bias may be present given the lack of a standard indication for initiating treatment, particularly among patients with pre-existing diagnoses who may have demonstrated prior stability but now have new or acute functional or radiologic progression. Such patients may often have more severe or progressive disease with less treatment response.

Conclusions

In patients with f-HP, the overall treatment response rate was 29% at three to nine months of follow-up, with a significantly lower response rate in those with pre-existing disease undergoing prior treatment or observed due to initial stability. Male sex, radiologic honeycombing, and higher baseline FVC were associated with a lower likelihood of treatment response. For established disease with progression treated initially with CS followed by SSA, SSA appeared to stabilize or slow lung function decline despite initial progression on CS only.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1492/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1492/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1492/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1492/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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Mayo Clinic (approval No. 20-000211; 11/15/2022). All study participants provided a priori consent for their de-identified clinical information to be included or reviewed for the purposes of research.

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/.

References

1. Vasakova M, Morell F, Walsh S, et al. Hypersensitivity Pneumonitis: Perspectives in Diagnosis and Management. Am J Respir Crit Care Med 2017;196:680-9. [Crossref] [PubMed]
2. Raghu G, Remy-Jardin M, Ryerson CJ, et al. Diagnosis of Hypersensitivity Pneumonitis in Adults. An Official ATS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med 2020;202:e36-69. [Crossref] [PubMed]
3. Petnak T, Moua T. Exposure assessment in hypersensitivity pneumonitis: a comprehensive review and proposed screening questionnaire. ERJ Open Res 2020;6:00230-2020. [Crossref] [PubMed]
4. Barrera L, Mendoza F, Zuñiga J, et al. Functional diversity of T-cell subpopulations in subacute and chronic hypersensitivity pneumonitis. Am J Respir Crit Care Med 2008;177:44-55. [Crossref] [PubMed]
5. Kokkarinen JI, Tukiainen HO, Terho EO. Effect of corticosteroid treatment on the recovery of pulmonary function in farmer's lung. Am Rev Respir Dis 1992;145:3-5. [Crossref] [PubMed]
6. De Sadeleer LJ, Hermans F, De Dycker E, et al. Effects of Corticosteroid Treatment and Antigen Avoidance in a Large Hypersensitivity Pneumonitis Cohort: A Single-Centre Cohort Study. J Clin Med 2018;8:14. [Crossref] [PubMed]
7. Ejima M, Okamoto T, Suzuki T, et al. Efficacy of treatment with corticosteroids for fibrotic hypersensitivity pneumonitis: a propensity score-matched cohort analysis. BMC Pulm Med 2021;21:243. [Crossref] [PubMed]
8. Kypreos M, de Boer E, Ellington G, et al. Clinical predictors of physiologic change after treatment with immunosuppression in hypersensitivity pneumonitis. PLoS One 2024;19:e0313540. [Crossref] [PubMed]
9. Noh S, Yadav R, Li M, et al. Use of leflunomide in patients with chronic hypersensitivity pneumonitis. BMC Pulm Med 2020;20:199. [Crossref] [PubMed]
10. Morisset J, Johannson KA, Vittinghoff E, et al. Use of Mycophenolate Mofetil or Azathioprine for the Management of Chronic Hypersensitivity Pneumonitis. Chest 2017;151:619-25. [Crossref] [PubMed]
11. Adegunsoye A, Oldham JM, Fernández Pérez ER, et al. Outcomes of immunosuppressive therapy in chronic hypersensitivity pneumonitis. ERJ Open Res 2017;3:00016-2017. [Crossref] [PubMed]
12. Newton CA, Thenappan A, Liu GY, et al. Performance Characteristics for Physiological Measures of Progressive Pulmonary Fibrosis. Am J Respir Crit Care Med 2025;211:1867-75. [Crossref] [PubMed]
13. Veit T, Barnikel M, Crispin A, et al. Variability of forced vital capacity in progressive interstitial lung disease: a prospective observational study. Respir Res 2020;21:270. [Crossref] [PubMed]
14. Gimenez A, Storrer K, Kuranishi L, et al. Change in FVC and survival in chronic fibrotic hypersensitivity pneumonitis. Thorax 2018;73:391-2. [Crossref] [PubMed]
15. Pandit P, Perez RL, Roman J. Sex-Based Differences in Interstitial Lung Disease. Am J Med Sci 2020;360:467-73. [Crossref] [PubMed]
16. Zaman T, Moua T, Vittinghoff E, et al. Differences in Clinical Characteristics and Outcomes Between Men and Women With Idiopathic Pulmonary Fibrosis: A Multicenter Retrospective Cohort Study. Chest 2020;158:245-51. [Crossref] [PubMed]
17. Ryerson CJ, Vittinghoff E, Ley B, et al. Predicting survival across chronic interstitial lung disease: the ILD-GAP model. Chest 2014;145:723-8. [Crossref] [PubMed]
18. Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med 2012;156:684-91. [Crossref] [PubMed]
19. Fernández Pérez ER, Kong AM, Raimundo K, et al. Epidemiology of Hypersensitivity Pneumonitis among an Insured Population in the United States: A Claims-based Cohort Analysis. Ann Am Thorac Soc 2018;15:460-9. [Crossref] [PubMed]
20. Lima MS, Coletta EN, Ferreira RG, et al. Subacute and chronic hypersensitivity pneumonitis: histopathological patterns and survival. Respir Med 2009;103:508-15. [Crossref] [PubMed]
21. Latoche JD, Ufelle AC, Fazzi F, et al. Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice. Environ Health Perspect 2016;124:1199-207. [Crossref] [PubMed]
22. Tateishi T, Ohtani Y, Takemura T, et al. Serial high-resolution computed tomography findings of acute and chronic hypersensitivity pneumonitis induced by avian antigen. J Comput Assist Tomogr 2011;35:272-9. [Crossref] [PubMed]
23. Salisbury M, Gross BH, Chughtai A, et al. Radiologic Phenotype Is a Better Predictor of Clinical Course than Clinical Diagnosis in Patients with Hypersensitivity Pneumonitis and Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2018;197:A1102.
24. Macaluso C, Boccabella C, Kokosi M, et al. Short-term lung function changes predict mortality in patients with fibrotic hypersensitivity pneumonitis. Respirology 2022;27:202-8. [Crossref] [PubMed]
25. Robertshaw MJ, Gorman A, Glazer CS, et al. Effect of antigen removal in hypersensitivity pneumonitis. BMC Pulm Med 2024;24:398. [Crossref] [PubMed]
26. Petnak T, Thongprayoon C, Baqir M, et al. Antigen identification and avoidance on outcomes in fibrotic hypersensitivity pneumonitis. Eur Respir J 2022;60:2101336. [Crossref] [PubMed]