Impact of forced vital capacity loss on survival after the onset of chronic lung allograft dysfunction

Abstract

Rationale: Emerging evidence suggests a restrictive phenotype of chronic lung allograft dysfunction (CLAD) exists; however, the optimal approach to its diagnosis and clinical significance is uncertain.

Objectives: To evaluate the hypothesis that spirometric indices more suggestive of a restrictive ventilatory defect, such as loss of FVC, identify patients with distinct clinical, radiographic, and pathologic features, including worse survival.

Methods: Retrospective, single-center analysis of 566 consecutive first bilateral lung recipients transplanted over a 12-year period. A total of 216 patients developed CLAD during follow-up. CLAD was categorized at its onset into discrete physiologic groups based on spirometric criteria. Imaging and histologic studies were reviewed when available. Survival after CLAD diagnosis was assessed using Kaplan-Meier and Cox proportional hazards models.

Measurements and main results: Among patients with CLAD, 30% demonstrated an FVC decrement at its onset. These patients were more likely to be female, have radiographic alveolar or interstitial changes, and histologic findings of interstitial fibrosis. Patients with FVC decline at CLAD onset had significantly worse survival after CLAD when compared with those with preserved FVC (P < 0.0001; 3-yr survival estimates 9% vs. 48%, respectively). The deleterious impact of CLAD accompanied by FVC loss on post-CLAD survival persisted in a multivariable model including baseline demographic and clinical factors (P < 0.0001; adjusted hazard ratio, 2.73; 95% confidence interval, 1.86-4.04).

Conclusions: At CLAD onset, a subset of patients demonstrating physiology more suggestive of restriction experience worse clinical outcomes. Further study of the biologic mechanisms underlying CLAD phenotypes is critical to improving long-term survival after lung transplantation.

Figure 1.

CONSORT diagram describing study cohort derivation and physiologic CLAD phenotype classification. BOS = bronchiolitis obliterans syndrome; CLAD = chronic lung allograft dysfunction; DUMC = Duke University Medical Center; PFT = pulmonary function test; R-CLAD = restrictive chronic lung allograft dysfunction. *Malignancy coincident with PFT decline (n = 13), significant airway stenosis (n = 1), uncontrolled infection (n = 3), significant pleural disease (n = 5), unreliable PFT data (n = 1). ^†Criteria applied to CLAD onset PFT, FVC_Best is defined as the average of the two FVCs associated with the two PFTs used in FEV₁ baseline calculation for CLAD diagnosis.

Figure 2.

A spirometric pattern characterized by loss of forced vital capacity, which may be suggestive of restrictive physiology (R-CLAD), on the onset of CLAD was associated with worse survival, compared with BOS physiology. One- and 3-year survival estimates for R-CLAD and BOS were 40 and 9% in contrast to 73 and 48%, respectively. Median time to death in the R-CLAD and BOS groups was 309 and 1,070 days, respectively. BOS = bronchiolitis obliterans syndrome; CLAD = chronic lung allograft dysfunction; R-CLAD = restrictive chronic lung allograft dysfunction.

Figure 3.

Unadjusted Kaplan-Meier curves for survival after CLAD by severity and timing of CLAD onset within each of the physiologic phenotypes. Early-onset CLAD was not associated with worse survival after CLAD onset within R-CLAD (A), but did have a significant deleterious impact on post-CLAD survival among patients presenting with BOS physiology (B). The severity of CLAD onset did not impact survival within either the R-CLAD (C) or BOS (D) groups. BOS = bronchiolitis obliterans syndrome; CLAD = chronic lung allograft dysfunction; R-CLAD = restrictive chronic lung allograft dysfunction.