Course of FEV(1) after onset of bronchiolitis obliterans syndrome in lung transplant recipients

Abstract

Rationale: Bronchiolitis obliterans syndrome (BOS), defined by loss of lung function, develops in the majority of lung transplant recipients. However, there is a paucity of information on the subsequent course of lung function in these patients.

Objectives: To characterize the course of FEV(1) over time after development of BOS and to determine the predictors that influence the rate of functional decline of FEV(1).

Methods: FEV(1)% predicted (FEV(1)%pred) trajectories were studied in 111 lung transplant recipients with BOS by multivariate, linear, mixed-effects statistical models.

Measurements and main results: FEV(1)%pred varied over time after BOS onset, with the steepest decline typically seen in the first 6 months (12% decline; p < 0.0001). Bilateral lung transplant recipients had significantly higher FEV(1)%pred at BOS diagnosis (71 vs. 47%; p < 0.0001) and at 24 months after BOS onset (58 vs. 41%; p = 0.0001). Female gender and pretransplant diagnosis of idiopathic pulmonary fibrosis were associated with a steeper decline in FEV(1)%pred in the first 6 months after BOS diagnosis (p = 0.02 and 0.04, respectively). A fall in FEV(1) greater than 20% in the 6 months preceding BOS (termed "rapid onset") was associated with shorter time to BOS onset (p = 0.01), lower FEV(1)%pred at BOS onset (p < 0.0001), steeper decline in the first 6 months (p = 0.03), and lower FEV(1)%pred at 2 years after onset (p = 0.0002).

Conclusions: Rapid onset of BOS, female gender, pretransplant diagnosis of idiopathic pulmonary fibrosis, and single-lung transplantation are associated with worse pulmonary function after BOS onset.

Figure 1.

Course of FEV₁% predicted (FEV₁%pred) after bronchiolitis obliterans syndrome (BOS) onset in lung transplant recipients. FEV₁%pred for the average patient profile adjusted for age, pretransplant diagnosis, time-to-BOS, type of transplant, transplant date, and 6-month pre-BOS relative change in FEV₁ (rapid vs. gradual onset of BOS) is shown. Numbers of patients at the onset of each time interval are displayed at the bottom. The rate of decline of FEV₁%pred changed significantly during the first 2 years after BOS onset (p < 0.0001). The steepest decline was seen in the first 6 months (12% decline; p < 0.0001). The decline between 6 and 12 months was also significant (4% decline; p = 0.01).

Figure 2.

Gender-specific course of FEV₁%pred after BOS onset in lung transplant recipients. Trajectories for FEV₁%pred after BOS onset for male and female patients are shown, adjusted for age, pretransplant diagnosis, time-to-BOS, type of transplant, transplant date, and 6-month pre-BOS relative change in FEV₁ (rapid vs. gradual onset of BOS)_. The declining trajectory between 0 and 6 months was significantly less steep for male versus female patients (p = 0.02). This difference remained significant after adjusting for the FEV₁ value at BOS onset (p = 0.046). Numbers of male and female patients at the onset of each time interval are displayed at the bottom.

Figure 3.

Course of FEV₁%pred after BOS onset in lung transplant recipients by pretransplant diagnosis. Trajectories for FEV₁%pred after BOS onset for patients with pretransplant diagnosis of idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are shown, adjusted for age, gender, time-to-BOS, type of transplant, transplant date, and 6-month pre-BOS relative change in FEV₁ (rapid vs. gradual onset of BOS). The steeper decline during the 6 months after BOS onset for recipients with IPF compared with those with COPD was statistically significant when adjusted for age, gender, time-to-BOS, type of transplant, transplant date, and 6-month pre-BOS relative change in FEV₁ (p = 0.04). Numbers of patients with COPD and IPF at the onset of each time interval are displayed at the bottom.

Figure 4.

Course of FEV₁%pred after BOS onset in lung transplant recipients by type of transplant. Course for FEV₁%pred after BOS onset for single- (SLT) and bilateral lung transplant (BLT) recipients are shown, adjusted for age, gender, time-to-BOS, pretransplant diagnosis, transplant date, and 6-month pre-BOS relative change in FEV₁ (rapid vs. gradual onset of BOS)_. The steeper slope seen in BLT recipients during the first 6 months was not significant when adjusted for differences in FEV₁%pred at BOS onset (p = 0.17). Twenty-four months after BOS onset, BLT recipients maintained a 42% higher FEV₁%pred compared with SLT recipients (p = 0.0001). Numbers of SLT and BLT recipients at the onset of each time interval are displayed at the bottom.

Figure 5.

Course of FEV₁%pred after BOS onset in lung transplant recipients by pre-BOS FEV₁ change (rapidity of BOS onset). FEV₁ values at the BOS onset date and FEV₁ values collected approximately 6 months earlier were used to calculate percent change in the 6 months before BOS onset. Patients with 20% or greater change in the 6 months before BOS onset were defined as having a rapid course of BOS onset; the remaining patients were defined as experiencing a gradual onset. Both FEV₁%pred trajectories are adjusted for age, gender, pretransplant diagnosis, time-to-BOS, transplant date, and type of transplant. Patients with rapid onset had an 18% lower FEV₁%pred at onset compared with gradual-onset patients (p < 0.0001). These patients continued to exhibit a steeper decline in FEV₁%pred during the first 6 months of BOS after adjusting for gender, age, type of transplant, pretransplant diagnosis, time-to-BOS, transplant date, and baseline FEV₁%pred at BOS onset (p = 0.03). FEV₁%pred at 24 months after BOS onset was higher in the patients with gradual versus rapid onset (p = 0.0002). Numbers of patients with gradual-onset and rapid-onset BOS at the onset of each time interval are displayed at the bottom.

Figure 6.

(A) Course of FEV₁%pred after BOS onset in lung transplant recipients by time-to-BOS. Time of BOS onset was defined as “early” if the onset of BOS occurred within 2 years of transplantation; otherwise it is termed “late.” Both FEV₁%pred trajectories are adjusted for age, gender, pretransplant diagnosis, type of transplant, transplant date, and 6-month pre-BOS relative change in FEV₁ (rapid vs. gradual onset of BOS). At 24 months after BOS onset, patients with early onset had a lower FEV₁%pred compared with patients with late onset (p = 0.01). (B) The estimated interaction of time-to-BOS onset and the rapidity of onset (rapid vs. gradual). All trajectories are adjusted for other significant variables, including age, gender, pretransplant diagnosis, transplant date, and type of transplant. Lowest to highest post-BOS FEV₁%pred patterns over time belonged to patients with early and rapid onset of BOS, followed by patients with rapid onset and late BOS, gradual onset and early BOS, and, finally, gradual onset and late BOS. Numbers of patients with late and early BOS, and those with gradual-onset (late and early) and rapid-onset (late and early) BOS at the onset of each time interval are displayed at the bottom.

Figure 7.

Estimated interaction of rapidity of BOS onset (rapid vs. gradual) with gender (males vs. females) and type of transplantation (bilateral lung transplant [BLT] vs. single-lung transplant [SLT]). Trajectories for these interactions are adjusted for the remaining significant variables including age, pretransplant diagnosis, time-to-BOS onset, transplant date, and type of transplant (A) or gender (B). Particularly poor prognosis for male patients and BLT recipients with rapid BOS onset compared with their gradual-onset counterparts is noted. Numbers of male and female patients with gradual and rapid BOS, and those with gradual-onset (BLT and SLT) and rapid-onset (BLT and SLT) BOS at the onset of each time interval are displayed at the bottom.