Bronchodilator Response: Utility and Implications in Patients Undergoing Hematopoietic Stem Cell Transplantation

Abstract

Background:

Bronchodilator response (BDR) assessment is routinely included in pulmonary evaluation before hematopoietic cell transplantation (HCT), but its prognostic significance remains uncertain. Recent European Respiratory Society/American Thoracic Society (ERS/ATS) criteria changes complicate interpretation.

Research Question:

To examine associations between BDR and clinical outcomes in HCT recipients and compare prognostic utility of traditional versus revised BDR criteria.

Study Design and Methods:

In this single-center study of 1,255 adult allogeneic HCT recipients (2005–2021), we assessed BDR using both 2005 criteria (≥12% and ≥200 mL increase in FEV₁/FVC) and 2022 criteria (>10% of predicted increase). Primary outcomes included bronchiolitis obliterans syndrome (BOS) development, 120-day ICU admission, and survival.

Results:

Among patients (58% male, mean age 51.3±13.6 years), positive BDR frequency was low (11.5% by 2005 criteria, 14.2% by 2022 criteria), with high concordance (>94%). BDR did not predict BOS development, with similar pre-transplant FEV₁ responses between patients who later developed BOS and those who did not (5.0% vs. 4.9%, p=0.841). Unadjusted analyses showed pre-transplant BDR positivity using 2005 criteria was associated with increased mortality (HR=1.45, p=0.006) and ICU admission (HR=1.65, p=0.005), but these associations did not persist after adjusting for baseline FEV₁ (aHR=1.17, p=0.275; aHR=1.09, p=0.648).

Interpretation:

BDR testing provides minimal additional prognostic information beyond baseline lung function assessment in HCT recipients and does not predict BOS development. Our findings support that BOS represents a fibroproliferative process distinct from disorders characterized by airway hyperresponsiveness, suggesting bronchodilator testing could be eliminated from standard HCT protocols without compromising risk assessment.

Introduction

In the context of hematopoietic cell transplantation (HCT), pulmonary function tests (PFTs) have well-established value in risk stratification both before and after transplantation.[9, 10] Pre-transplant pulmonary function parameters, particularly FEV₁, FVC, and diffusing capacity (DLCO), are strongly associated with post-transplant pulmonary complications and overall survival.[10, 11] PFT monitoring after transplantation plays a crucial role in detecting bronchiolitis obliterans syndrome (BOS), a potentially devastating non-infectious pulmonary manifestation of chronic graft-versus-host disease that affects approximately 5–10% of allogeneic HCT recipients.[12–14] BOS represents a significant cause of morbidity and mortality post-HCT, with five-year survival rates of close to 50% following diagnosis.[15] As early identification and intervention may substantially improve outcomes in BOS, there is considerable clinical interest in identifying sensitive predictive markers. The current NIH consensus diagnostic criteria for BOS have known limitations in sensitivity for early disease detection, particularly when a patient’s baseline FEV₁ is well above the lower limit of normal.[16]

Bronchodilator response (BDR) represents a fundamental component of pulmonary function testing (PFT), providing insight into airway hyperresponsiveness and the reversibility of airflow obstruction.[1, 2] The 2005 American Thoracic Society and European Respiratory Society (ATS/ERS) guidelines established BDR as an increase in either forced expiratory volume in one second (FEV₁) or forced vital capacity (FVC) of both ≥12% and ≥200 mL from baseline values.[3] The 2022 ERS/ATS interpretation standards introduced a revised calculation using the predicted FEV₁ as the denominator and defining a positive BDR as an increase in either FEV₁ or FVC by ≥10%.[4] This departure from the prior definition aimed to reduce age, height and lung size bias. Previous studies using the 2005 BDR calculation have shown a correlation between BDR and mortality outcomes.[5] However, whether this change in calculation method impacts associated clinical outcomes has not been thoroughly examined, and several studies have called into question the diagnostic and prognostic utility of BDR testing.[6–8] By evaluating whether BDR assessment can enhance risk stratification and facilitate earlier intervention, this study addresses a critical gap in pulmonary monitoring approaches for this vulnerable patient population, potentially informing more targeted screening and management strategies. Despite increasing awareness of BDR’s limitations in differentiating between airway diseases, the potential value of BDR as a treatable trait - rather than a diagnostic criterion - warrants exploration in the HCT population.[6]

Our study investigates whether BDR – assessed both prior to transplantation and at defined intervals post-transplantation – may function as a predictive marker for the subsequent development of BOS and other pulmonary complications in HCT recipients. Our primary hypothesis is that pre-transplant BDR is not predictive of BOS development, though we also explore whether post-transplant changes in BDR might signal early bronchial pathology. Additionally, we compare the traditional BDR definition (2005 criteria: ≥12% and ≥200 mL) against the recently adopted criterion (2022 criteria: ≥10% of predicted) within this specific clinical context.

Methods

This is a single-center retrospective cohort study of HCT recipients at Mayo Clinic, Rochester, MN. Research ethics approval was obtained through the Mayo Clinic Institutional Review Board (#13–002869), which waived the requirement for written informed consent. This manuscript is written in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist (Supplemental Table E1).

Setting and Participants

Eligible subjects consisted of consecutive adults (≥18 years of age), who had undergone allogeneic HCT at Mayo Clinic in Rochester (Minnesota). Only subjects with a pre-transplant spirometry test performed with BD administration were included. Patients were excluded if they did not provide research authorization. All spirometry measurements were performed by a trained pulmonary function technician in the Mayo Clinic Pulmonary Function Laboratory. This laboratory performs the requisite quality assurance with daily calibrations and regular biologic quality control checks.[3, 17, 18] ERS/ATS technical standards and expert recommendations were followed for test performance and interpretation [19].

Bronchodilator response – measurement and calculation

BDR testing was performed according to ATS/ERS standardized protocols.[4, 19] Following baseline spirometry measurements, patients received two puffs of a standard albuterol metered dose inhaler using a spacer device. Post-bronchodilator spirometry was performed 15 minutes after medication administration. BDR was assessed using two established criteria:

1. The 2022 ERS/ATS recommended threshold, which defines a positive bronchodilator response as a change of >10% relative to the predicted value for either FEV1 or FVC, with predicted values determined using the Global Lung Function Initiative (GLI) Global reference equations.[20] Specifically, this calculation was performed using the following formula was: BDR (% predicted) = [(Post-BD value - Pre-BD value) / Predicted value] × 100.

2. The 2005 ATS/ERS criteria, which defined a positive response as both an absolute increase of ≥200 mL AND a ≥ 12% improvement from baseline in either FEV1 or FVC, calculated as: BDR (% baseline) = [(Post-BD value - Pre-BD value) / Pre-BD value] × 100.[21]

Data retrieval

Data was retrieved from the electronic healthcare record (EHR) using data warehouses shared across Mayo Clinic (Mayo Data Explorer), an institutional PFT database for pulmonary function measures, and site-specific Hematology databases that included details regarding patient disease, chemotherapy exposures and conditioning chemotherapy regimens.[22, 23] Manual chart review was used to supplement data retrieval where needed. Prior studies have outlined the use of these databases for this and similar cohorts.[10, 24–31] There were no missing baseline characteristic or PFT data for the patients included in the study.

Outcomes

The study examined three primary endpoints: 1) BOS diagnosis, 2) overall survival, and 3) early post-transplant ICU admission. To establish BOS diagnosis, comprehensive chart reviews were conducted independently by two reviewers from a panel of three investigators (R.E., H.Y. and M.H.T.). Diagnostic criteria adhered to the 2014 National Institutes of Health (NIH) Consensus Statement for chronic graft-versus-host disease (cGVHD) following allogeneic HCT [16]. These criteria encompassed: a) FEV₁ below 75% of predicted value with an irreversible decline of ≥10% within a 2-year period, b) FEV₁/VC ratio below 0.7 or lower than normal limits, c) confirmed absence of infection, and d) at least one of the following: (i) established cGVHD diagnosis, (ii) evidence of air trapping on expiratory chest computed tomography (CT) imaging, or (iii) residual volume measurements indicating air trapping on PFTs. Of 111 BOS cases, 93 met all four criteria with 18 patients meeting three of four criteria with both the treating clinician’s assessment and the reviewing physicians’ evaluation concurring that these patients had BOS. Sensitivity analyses were performed using only those patients who met all four NIH criteria to ensure consistency of findings. This diagnostic approach has been validated in our previous work.[30]

For survival analysis, patient outcomes were tracked for a median follow-up duration of 5.9 years. Regarding ICU admissions, we limited our observation window to 120 days post-transplant. This time frame was selected because patients in our transplant program typically remain near the transplant center for approximately 100 days post-HCT for close monitoring, supportive care, and regular clinical evaluations. After this period, patients return to their homes and visit the center only for scheduled follow-up appointments. The 120-day cutoff was therefore implemented to capture all ICU admissions occurring at our facility while avoiding potential selection bias that might arise from incomplete capture of hospitalizations occurring at local facilities near these patients’ homes during later follow-up periods.[10]

Statistical analyses

Descriptive statistics were calculated for demographic and clinical variables, with continuous variables reported as mean ± standard deviation or median with interquartile range (IQR) as appropriate. Categorical variables were summarized using counts and percentages. Comparisons between groups (e.g., BOS vs. non-BOS) were performed using two-sample t-tests or Wilcoxon rank-sum tests for continuous variables and chi-square or Fisher’s exact tests for categorical variables.

BDR was assessed using both the 2005 and 2022 criteria. Concordance between these criteria was evaluated at pre-transplant, day 100, and 1-year timepoints using 2×2 contingency tables. McNemar’s test was used to assess the significance of discordance patterns between criteria. The area under the receiver operating characteristic curve (AUROC) was calculated to evaluate the predictive performance of BDR for subsequent BOS development.

Survival analyses were conducted using Kaplan-Meier methods, with differences between groups assessed using log-rank tests. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. For the cumulative incidence of ICU admission within 120 days post-transplant, competing risk analyses were performed with death as a competing risk, and differences between groups were assessed using Gray’s test.[32] Sub-distribution hazard ratios were estimated using Fine-Gray competing risks regression models.[33–35] Survival analyses and ICU cumulative incidence analyses were adjusted for baseline lung function: FEV₁ in the primary analysis with FVC in a sensitivity analysis. Due to collinearity between FEV1 and FVC, both metrics were not used in Cox regression models. For BOS development as an outcome, we conducted competing risk analyses with death as a competing event. The cumulative incidence function (CIF) was estimated to describe the probability of BOS occurrence over time while accounting for the competing risk of death. Differences in CIFs between BDR-positive and BDR-negative groups were assessed using Gray’s test. Sub-distribution hazard ratios (sHRs) with 95% CIs were estimated using Fine-Gray competing risks regression models to quantify the association between BDR status and BOS development while accounting for the competing risk of death. These analyses were performed separately for both BDR criteria (2005 and 2022) at pre-transplant and day 100 timepoints.

The association between BDR and BOS development was examined at multiple timepoints (pre-transplant, day 100, and 1-year) using logistic regression models. For longitudinal analyses of changes in BDR over time, mixed-effects models were used to account for repeated measurements and missing data.

JMP Pro software (SAS Institute, Cary, NC) was used for data collection and handling. Data analysis was performed in R 4.3.3 (R Foundation for Statistical Computing, Vienna, Austria) using the R Studio 2024.03 integrated development environment (PBC, Boston, MA). Specific packages used include tidyverse, survival, cmprsk, arsenal and pROC.[36–40]

Results

Cohort description

Between January 1, 2005, and December 31, 2021, 1,255 of the 1,368 patients that underwent allogeneic HCT were included (Supplemental Figure E1). Of 113 who were not included, 35 declined consent, 48 did not have pre-transplant pulmonary function testing performed, and had 30 had spirometry performed without bronchodilator administration (most common reason: patient declined). Mean age was 51.3 ± 13.6 years with 57.8% males and 42.2% females (Table 1). The most common diagnoses were acute myelogenous leukemia (38.8%), myelodysplastic/myeloproliferative disorders (21.6%), and acute lymphoblastic leukemia (13.6%). Transplant donors were evenly split between unrelated (47.2%) and related (46.9%) sources, with smaller numbers of cord unit (3.4%) and haploidentical (2.7%) donors. Baseline pulmonary function was within normal limits, with mean FEV₁ of 99.9% predicted (mean Z-score 0.00 ± 1.08) and mean FVC of 103.8% predicted (mean Z-score 0.24 ± 1.03). Of 1255 patients, 111 (8.8%) went on to develop BOS at a median of 12.6 (IQR: 8.0, 21.4) months after transplantation. A sensitivity analysis excluding those patients with three out of four NIH criteria is outlined in Supplemental Table E2.

Table 1.

Baseline characteristics of study participants stratified by BOS status.

	No BOS (N=1144)	BOS (N=111)	Total (N=1255)	SMD
Age	51.3 (13.6)	52.1 (13.1)	51.3 (13.6)	0.059
Sex				0.044
Female	480 (42.0%)	49 (44.1%)	529 (42.2%)
Male	664 (58.0%)	62 (55.9%)	726 (57.8%)
Race				0.129
Asian	25 (2.2%)	1 (0.9%)	26 (2.1%)
Black/African American	14 (1.2%)	0 (0.0%)	14 (1.1%)
Caucasian	1043 (91.2%)	108 (97.3%)	1151 (91.7%)
Other/Mixed Race	27 (2.4%)	1 (0.9%)	28 (2.2%)
Unknown / Choose Not to Disclose	35 (3.1%)	1 (0.9%)	36 (2.9%)
Ethnicity				0.088
Hispanic or Latino	21 (1.8%)	1 (0.9%)	22 (1.8%)
Not Hispanic or Latino	1005 (87.8%)	103 (92.8%)	1108 (88.3%)
Unknown / Choose Not to Disclose	118 (10.3%)	7 (6.3%)	125 (10.0%)
Donor Type				0.110
Cord Unit	42 (3.7%)	1 (0.9%)	43 (3.4%)
Haploidentical	31 (2.7%)	1 (0.9%)	32 (2.5%)
Related	533 (46.6%)	55 (49.5%)	588 (46.9%)
Unrelated	538 (47.0%)	54 (48.6%)	592 (47.2%)
Diagnosis				0.318
Acute lymphoblastic leukemia	148 (12.9%)	23 (20.7%)	171 (13.6%)
Acute myelogenous leukemia	435 (38.0%)	52 (46.8%)	487 (38.8%)
Aplastic Anemia	21 (1.8%)	1 (0.9%)	22 (1.8%)
Chronic myelogenous leukemia	45 (3.9%)	6 (5.4%)	51 (4.1%)
Hodgkin lymphoma	6 (0.5%)	3 (2.7%)	9 (0.7%)
Immune Disorder	24 (2.1%)	0 (0.0%)	24 (1.9%)
Leukemia, Other	86 (7.5%)	2 (1.8%)	88 (7.0%)
Malignancy, Other	1 (0.1%)	0 (0.0%)	1 (0.1%)
MM/PCD	71 (6.2%)	0 (0.0%)	71 (5.7%)
Myelodysplastic/myeloproliferative disorders	249 (21.8%)	22 (19.8%)	271 (21.6%)
Myeloproliferative Disease	15 (1.3%)	1 (0.9%)	16 (1.3%)
Non-Hodgkin lymphoma	43 (3.8%)	1 (0.9%)	44 (3.5%)
Conditioning				0.239
BEAM	2 (0.2%)	0 (0.0%)	2 (0.2%)
Busulfan + Fludarabine	67 (5.9%)	10 (9.0%)	77 (6.1%)
Cyclophosphamide + ATG	7 (0.6%)	0 (0.0%)	7 (0.6%)
Cyclophosphamide + Busulfan	169 (14.8%)	13 (11.7%)	182 (14.5%)
Cyclophosphamide + Fludarabine	6 (0.5%)	0 (0.0%)	6 (0.5%)
Cyclophosphamide + Fludarabine + TBI	54 (4.7%)	5 (4.5%)	59 (4.7%)
Cyclophosphamide + TBI	244 (21.3%)	27 (24.3%)	271 (21.6%)
Fludarabine + Busulfan	51 (4.5%)	6 (5.4%)	57 (4.5%)
Fludarabine + Busulfan + Melphalan	2 (0.2%)	0 (0.0%)	2 (0.2%)
Fludarabine + TBI	96 (8.4%)	3 (2.7%)	99 (7.9%)
Fludarabine/Campath	2 (0.2%)	0 (0.0%)	2 (0.2%)
Melphalan	10 (0.9%)	0 (0.0%)	10 (0.8%)
Melphalan + Fludarabine	340 (29.7%)	42 (37.8%)	382 (30.4%)
Melphalan + Fludarabine + TBI	30 (2.6%)	3 (2.7%)	33 (2.6%)
Melphalan + TBI	39 (3.4%)	0 (0.0%)	39 (3.1%)
Other	12 (1.0%)	2 (1.8%)	14 (1.1%)
Thiotepa + Fludarabine + Busulfan	3 (0.3%)	0 (0.0%)	3 (0.2%)
Unknown	10 (0.9%)	0 (0.0%)	10 (0.8%)
FEV1, L	3.22 (0.82)	3.14 (0.76)	3.22 (0.82)	0.107
FEV1, % predicted	100.10 (16.43)	98.09 (14.41)	99.92 (16.27)	0.123
FEV1 Z-score	0.02 (1.09)	−0.12 (0.96)	0.00 (1.08)	0.127
FVC, L	4.16 (1.04)	4.14 (1.01)	4.16 (1.03)	0.022
FVC, % predicted	103.78 (15.61)	103.69 (14.72)	103.77 (15.53)	0.006
FVC Z-score	0.24 (1.03)	0.23 (0.98)	0.24 (1.03)	0.006
Time to BOS (months; median [IQR])	--	12.6 [8.0, 21.4]	--

Data are presented as mean (standard deviation) or count (percentage) as appropriate. The study included 1,255 patients who underwent allogeneic hematopoietic cell transplantation (HCT) between 2005–2021, of whom 111 (8.8%) developed bronchiolitis obliterans syndrome (BOS). Baseline pulmonary function was similar between groups. Time to BOS diagnosis was 12.6 months (IQR: 8.0, 21.4) after transplantation. P-values were calculated using Wilcoxon rank-sum tests for continuous variables and Fisher’s exact tests (for expected cell counts <5) or chi-square tests for categorical variables.

Abbreviations: BOS: Bronchiolitis obliterans syndrome; MM/PCD: Multiple myeloma/plasma cell dyscrasia; BEAM: Bis-chloroethylnitrosurea, etoposide, arabinosylcytosine, melphalan; ATG: anti-thymocyte globulin; TBI: Total body irradiation; FEV1: Forced expiratory volume in 1 second; L: Liters; FVC: Forced vital capacity; IQR: Interquartile range. SMD = Standardized Mean Difference.

Bronchodilator Response Characteristics

Overall bronchodilator responsiveness was low. At the pre-transplant evaluation, percent predicted change in FEV₁ and FVC after BD administration was similar between patients who later developed BOS and those who did not (FEV₁: 5.0% vs. 4.9%, p=0.841; FVC: 1.8% vs. 1.7%, p=0.829; Table 2). Using 2022 criteria, positive FEV₁ BDR was observed in 9.9% of BOS patients compared to 11.2% of non-BOS patients (Figure 1, p=0.792). At day 100 post-transplant, BDR characteristics remained similar between groups. At 1-year post-transplant, patients who had or went on to develop BOS did not have a higher frequency of positive BDR by FEV₁ criteria. The only metric that differed between the two groups was a higher rate of positive FVC BDR specifically using 2005 criteria (7.6% vs. 1.6%, p<0.001). A positive BDR by either FEV₁ or FVC criteria was a poor predictor of subsequent BOS using either pre-transplant PFTs or day +100 PFTs (Figure 2). AUROC was close to 0.5 using both 2005 and 2022 criterion for a positive response (Supplemental Figure E2). The BDR did not meaningfully change between pre-transplant, day +100 and 1-year post-transplant (Supplemental Figure E3). Sensitivity analyses showed consistent results and are outlined in Supplemental Table E3 and Supplemental Figures E4 – E6. Among BOS patients, longitudinal analysis showed declining positive FEV₁ BDR rates over time (10.0% pre-transplant, 7.5% at day 100, 2.3% at 1-year using 2022 criteria), and PFTs performed within 30 days of BOS diagnosis showed no increase in bronchodilator responsiveness compared to pre-transplant assessments (3.6% at BOS diagnosis vs. 10.0% pre-transplant, p = 0.14), indicating that BDR does not emerge as a marker of evolving BOS.

Table 2.

Bronchodilator response characteristics at different timepoints stratified by BOS status.

Time Point	Parameter	Metric	No BOS (n = 1144)	BOS (n = 111)	P-value
Pre-Transplant	FEV1 BDR	BDR percent (%)	4.9 ± 4.2	5.0 ± 4.0	0.841
		Positive BDR - 2022 criteria (%)	11.2%	9.9%	0.792
		Positive BDR - 2005 criteria (%)	7.6%	9.0%	0.730
	FVC BDR	BDR percent (%)	1.7 ± 3.9	1.8 ± 3.9	0.829
		Positive BDR - 2022 criteria (%)	2.6%	3.6%	0.532
		Positive BDR - 2005 criteria (%)	1.9%	1.8%	1.000
Day 100	FEV1 BDR	BDR percent (%)	4.5 ± 4.1	4.2 ± 4.1	0.501
		Positive BDR - 2022 criteria (%)	8.8%	8.4%	1.000
		Positive BDR - 2005 criteria (%)	6.1%	7.6%	0.665
	FVC BDR	BDR percent (%)	1.6 ± 3.7	2.2 ± 3.7	0.050
		Positive BDR - 2022 criteria (%)	1.9%	1.7%	1.000
		Positive BDR - 2005 criteria (%)	1.5%	1.7%	0.697
1-Year	FEV1 BDR	BDR percent (%)	4.2 ± 4.0	3.5 ± 3.8	0.068
		Positive BDR - 2022 criteria (%)	7.2%	3.4%	0.130
		Positive BDR - 2005 criteria (%)	5.5%	8.4%	0.280
	FVC BDR	BDR percent (%)	1.5 ± 3.8	2.1 ± 4.3	0.139
		Positive BDR - 2022 criteria (%)	2.1%	5.0%	0.082
		Positive BDR - 2005 criteria (%)	1.6%	7.6%	<0.001*

Data are presented as mean ± standard deviation or percentage as appropriate. Bronchodilator response (BDR) was assessed using both 2005 ATS/ERS criteria (≥12% and ≥200 mL improvement from baseline) and 2022 ATS/ERS criteria (≥10% of predicted value improvement). No significant differences in pre-transplant or day 100 BDR were observed between patients who later developed BOS and those who did not. At 1-year post-transplant, patients with BOS had a significantly higher rate of positive FVC BDR by 2005 criteria (7.6% vs 1.6%, p<0.001).

Abbreviations: BOS: Bronchiolitis obliterans syndrome; BDR: Bronchodilator response; FEV1: Forced expiratory volume in 1 second; FVC: Forced vital capacity; BDR: bronchodilator response

Figure 1. Distribution of bronchodilator response in FEV1 and FVC at pre-transplant, day 100, and 1-year assessments, stratified by BOS status.

Histograms show the frequency distribution of bronchodilator response (expressed as percent change) for forced expiratory volume in 1 second (FEV1, top panels) and forced vital capacity (FVC, bottom panels). Vertical dashed red lines indicate the 10% threshold used in the 2022 ATS/ERS criteria for positive BDR. No significant differences in FEV1 BDR were observed between BOS and non-BOS groups at any timepoint.

Figure 2. Cumulative Incidence of BOS Stratified by Bronchodilator Response.

Competing risk analysis with death as competing event. The top panels display pre-transplant pulmonary function tests (PFTs) using 2005 BDR criteria (left) and 2022 BDR criteria (right). The bottom panels display day 100 post-transplant PFTs using 2005 BDR criteria (left) and 2022 BDR criteria (right). Sub-distribution hazard ratios (sHR) with 95% confidence intervals and p-values are displayed for each analysis. No significant difference in cumulative incidence of BOS was observed between patients with positive BDR (orange lines) and those without BDR (blue lines) at either timepoint using either criteria.

Concordance between 2005 and 2022 BDR criteria

Analysis of bronchodilator response (BDR) criteria concordance across multiple timepoints revealed consistently high agreement between the 2005 and 2022 criteria. At pre-transplant assessment (n=1,255), concordance was 94.6% with 68 discordant cases (5.4%). When discordance occurred, the 2022 criteria were more likely to classify patients as positive (56 cases of 2005-/2022+ vs 12 cases of 2005+/2022-, representing 82.4% vs 17.6% of discordant cases; p < 0.001). At day 100 post-transplant (n=811 tests done with bronchodilator), concordance was 96.8% with 26 discordant cases (3.2%), maintaining a similar pattern of discordance (80.8% 2005-/2022+ vs 19.2% 2005+/2022-; p = 0.003). At the 1-year timepoint (n=601 tests done with bronchodilator), concordance remained high at 96.3% with 22 discordant cases (3.7%). At this timepoint, there was no difference in the pattern of discordance (40.9% 2005-/2022+ versus 59.1% 2005+/2022-; p = 0.52).

Analysis of 428 patients with known cause of death showed no significant differences between BDR discordant (n=24) and concordant (n=404) groups. Among discordant cases, respiratory failure (33% vs 39% in concordant), malignancy progression (25% vs 31%), infection (13% vs 10%), and GVHD (8% vs 7%) were the primary causes of death (p=0.665). Similarly, among 290 patients requiring ICU care within 120 days post-transplant, admission causes were comparable between discordant (n=16) and concordant (n=274) groups, with respiratory failure (25% vs 31%), sepsis (25% vs 23%), and supraventricular tachycardia (19% vs 16%) being most common. Despite the 2022 BDR criteria classifying more patients as positive at pre-transplant and day 100, this discordance does not significantly impact mortality or ICU admission patterns.

Bronchodilator response and other outcomes

Given the association of BDR and mortality in those with pulmonary disease, we evaluated rates of ICU admission and overall survival in those undergoing HCT using pre-transplant BDR as a predictor. For overall survival (Figures 3 and 4), unadjusted analyses showed that pre-transplant BDR using the 2005 criteria was associated with reduced survival (HR=1.45, 95% CI: 1.11–1.88, p=0.006), whereas the 2022 criteria were not (HR=1.13, 95% CI: 0.88–1.44, p=0.339). However, after adjusting for baseline FEV₁ percent predicted, this association was no longer significant for either the 2005 criteria (Adj. HR=1.17, 95% CI: 0.88–1.55, p=0.275) or the 2022 criteria (Adj. HR=1.01, 95% CI: 0.79–1.3, p=0.920). Similar results were observed when analyses were adjusted for baseline FVC percent predicted (Supplemental Figures E7–8), though the 2005 criteria approached statistical significance (Adj. HR=1.3, 95% CI: 1–1.69, p=0.054). A positive BDR at day 100 post-transplant was not associated with survival using either the 2005 (Adj. HR=0.74, 95% CI: 0.43–1.27, p=0.273) or the 2022 (Adj. HR=0.98, 95% CI: 0.64–1.5, p=0.920) criteria when adjusted for FEV₁. Results were similar when adjusted for FVC (Supplemental Figures E7–8).

Figure 3. Impact of a Positive Bronchodilator Response on Overall Survival and ICU Admission Rates.

All analyses adjusted for FEV₁ % predicted at the relevant timepoint (Pre-Tx or Day 100). Panels A-B show overall survival stratified by 2005 BDR criteria at pre-transplant (A) and day 100 (B). Panels C-D show overall survival stratified by 2022 BDR criteria at pre-transplant (D) and day 100 (E). Panels C and F show cumulative incidence of ICU admission within 120 days post-transplant stratified by 2005 (C) and 2022 (F) BDR criteria. Adjusted hazard ratios (Adj. HR) with 95% confidence intervals and p-values are displayed for each analysis. Blue lines represent patients without BDR, and orange lines represent patients with positive BDR.

Figure 4. Hazard Ratios for Positive Bronchodilator Response.

Forest plot showing hazard ratios for positive bronchodilator response using both 2005 and 2022 criteria at pre-transplant (pre-Tx) and day 100 timepoints. Results are shown for both unadjusted analyses (blue) and analyses adjusted for FEV₁ percent predicted (orange). Vertical dashed line represents HR = 1 (no effect). Points to the right of this line indicate increased risk, while points to the left indicate reduced risk.

For short-term outcomes (Figures 3 and 4), unadjusted analyses showed that patients with a positive pre-transplant BDR using the 2005 criteria had a higher cumulative incidence of ICU admission within the first 120 days (HR=1.65, 95% CI: 1.17–2.34, p=0.005). After adjusting for baseline FEV₁ percent predicted, this association was no longer significant (Adj. HR=1.09, 95% CI: 0.75–1.59, p=0.648). The 2022 criteria were not predictive of ICU admission in either unadjusted (HR=1.19, 95% CI: 0.86–1.67, p=0.295) or adjusted analyses (Adj. HR=1.0, 95% CI: 0.71–1.4, p=0.983). When adjusting for baseline FVC instead of FEV₁ (Supplemental Figures E7–8), there was no association between positive BDR by 2005 criteria and ICU admission (Adj. HR=1.35, 95% CI: 0.95–1.93, p=0.094).

Discussion

Our study provides a comprehensive evaluation of bronchodilator response testing in allogeneic HCT recipients, systematically examining its relationship with BOS development, overall survival, and early ICU admission. The findings demonstrate that BDR offers limited clinical utility in this patient population, with no predictive value for BOS development and no significant prognostic value for other outcomes after accounting for baseline lung function.

The relatively low prevalence of BDR observed in pre-transplant testing aligns with expectations for a population with limited established obstructive lung disease, though this prevalence appears lower than suggested by previous limited studies.[41, 42] Importantly, we found no difference in pre-transplant BDR between patients who later developed BOS and those who did not, suggesting that pre-existing airway hyperresponsiveness does not predispose HCT recipients to subsequent development of BOS. This observation challenges previous hypotheses that pre-existing airway hyperresponsiveness might predispose HCT recipients to post-transplantation airway complications or serve as an early marker of susceptibility.[43, 44] Instead, our data suggest that the pathophysiological mechanisms underlying BOS development may be distinct from those associated with bronchodilator responsiveness, aligning with evidence that BOS represents a complex fibroproliferative process initiated by epithelial injury rather than primarily a disorder of airway smooth muscle hyperreactivity.[45] Unfortunately, as in patients with asthma and chronic obstructive pulmonary disease, the formulation, dose, and route of bronchodilator administration used during spirometry is not standardized; and similar to patients with other forms of obstructive lung dysfunction, the clinical implication of positive BDR remains uncertain.

Our observation that BDR characteristics remained similar between BOS and non-BOS groups at both day 100 and 1-year post-transplant provides compelling evidence that BDR response is not a characteristic feature of evolving BOS. The only notable difference was a higher rate of positive FVC BDR using 2005 criteria at 1-year post-transplant among patients who had or went on to develop BOS. This isolated finding is of unclear significance and may reflect a restrictive component that can accompany early BOS or related pulmonary complications.[46–50]

While initial unadjusted analyses suggested an association between positive pre-transplant BDR using the 2005 criteria and both reduced overall survival and increased ICU admission rates, these associations were no longer significant after adjusting for baseline FEV₁ percent predicted. This indicates that the apparent prognostic value of BDR was primarily driven by underlying differences in baseline lung function rather than by bronchodilator responsiveness itself. The borderline significance observed when adjusting for baseline FVC instead of FEV₁ for both survival and ICU admission using 2005 criteria is more likely to represent a Type 1 error than a true physiological relationship, particularly given the lack of consistency across other analyses and criteria.

The high concordance (>94%) between the 2005 and 2022 BDR criteria across all assessed timepoints indicates that these different thresholds identify overlapping populations in clinical practice, especially in a cohort where most patients do not have positive bronchodilator testing. In cases of discordance, the 2022 criteria demonstrated greater sensitivity, more frequently classifying patients as BDR-positive, consistent with its design intention. However, neither criteria demonstrated meaningful prognostic utility after accounting for baseline lung function, suggesting that the additional complexity of bronchodilator testing adds little value to standard pulmonary function assessment in this population. Our observed BDR prevalence was lower than some previous reports in HCT populations, likely reflecting our rigorous single-laboratory testing environment that minimizes technical variability. Prior studies were smaller with wider confidence intervals around their prevalence estimates due to limited sample sizes: our observed rates may actually fall within the confidence intervals of these earlier studies despite appearing numerically different.

Our findings have several important clinical implications. First, they indicate that routine bronchodilator testing as part of pre-transplant and post-transplant PFT assessment offers minimal additional prognostic information beyond standard spirometric parameters. This suggests that bronchodilator testing could potentially be eliminated from standard HCT-related pulmonary function protocols without compromising clinical risk assessment, streamlining testing procedures for patients and reducing healthcare costs. Second, our results provide further evidence that the pathophysiology of BOS is distinct from that of reversible airway obstruction, reinforcing the need for continued investigation into the specific mechanisms of post-HCT BOS.

Our study has several strengths, including its large sample size, comprehensive pulmonary function testing conducted systematically at multiple timepoints, and rigorous outcome ascertainment. Sensitivity analyses showed consistency when evaluating both those patients who met all four NIH criteria for BOS, as well as those who met three out of four criteria. This study also has several limitations that we attempted to address through our study design and analytical approach. As a single-center study, our findings may not generalize to all HCT populations, though our large sample size (n=1,255) and comprehensive follow-up enhance statistical power and internal validity. Our systematic, protocol-driven PFT assessments rather than symptom-driven testing minimized selection bias, while standardized, automated search criteria for outcome ascertainment reduced classification bias. The 120-day ICU analysis window was specifically chosen to capture events during the period when patients remain near the transplant center, minimizing incomplete capture bias that could occur from late hospitalizations at local facilities. We employed competing risk analyses to appropriately handle the competing event of death when analyzing BOS and ICU outcomes. While we lacked some clinical details that could influence BDR interpretation, our standardized single-laboratory testing environment with rigorous quality control protocols minimized technical variability that could affect results.

Interpretation

In conclusion, our findings suggest that bronchodilator response testing, using either the 2005 or 2022 ATS/ERS criteria, provides little to no additional prognostic value beyond standard lung function assessment in HCT recipients. BDR has no utility for predicting BOS development, and its apparent associations with overall survival and early complications are largely explained by differences in baseline lung function. These results challenge the routine inclusion of bronchodilator testing in pre-transplant and post-transplant pulmonary function assessment for HCT recipients, suggesting that simplified protocols focusing on baseline spirometric measures would maintain adequate prognostic accuracy while reducing testing burden. Future research should focus on identifying more specific predictive markers for BOS and other pulmonary complications following allogeneic HCT.

Highlights.

• Bronchodilator testing shows minimal prognostic value in HCT recipients beyond baseline PFTs

• No difference in pre-transplant BDR between patients who developed BOS vs those who did not

• 2005 and 2022 BDR criteria show high concordance (>94%) across all timepoints

• Apparent BDR associations with outcomes disappear after adjusting for baseline FEV1

• Results suggest BDR testing could be eliminated from standard HCT protocols

Abbreviation List

ATG

Anti-thymocyte globulin

ATS

American Thoracic Society

AUROC

Area under the receiver operator characteristic curve

BD

Bronchodilator

BDR

Bronchodilator response

BEAM

Bis-chloroethylnitrosurea, etoposide, arabinosylcytosine, melphalan

BOS

Bronchiolitis obliterans syndrome

cGVHD

Chronic graft-versus-host disease

CI

Confidence interval

CT

Computed tomography

DLCO

Diffusing capacity of the lung for carbon monoxide

EHR

Electronic healthcare record

ERS

European Respiratory Society

FEV₁

Forced expiratory volume in 1 second

FVC

Forced vital capacity

GLI

Global Lung Function Initiative

HCT

Hematopoietic cell transplant

HR

Hazard ratio

ICU

Intensive care unit

IQR

Interquartile range

MM/PCD

Multiple myeloma/plasma cell dyscrasia

NIH

National Institutes of Health

PFT

Pulmonary function testing

STROBE

Strengthening the Reporting of Observational Studies in Epidemiology

TBI

Total body irradiation

VC

Vital capacity