Association of large-airway lymphocytic bronchitis with bronchiolitis obliterans syndrome

Abstract

Rationale: Lung transplantation offers great promise for otherwise terminal lung diseases, but the development of bronchiolitis obliterans syndrome (BOS) continues to limit survival. Although acute rejection and lymphocytic bronchiolitis have been identified as risk factors for the development of BOS, it is unclear whether large-airway lymphocytic inflammation conveys the same risk.

Objectives: We evaluated lymphocytic bronchitis on endobronchial biopsies as a risk factor for BOS and mortality.

Methods: Endobronchial biopsies were collected and graded during surveillance after lung transplantation. We assessed samples with negative cultures collected in the first 90 days from 298 subjects and compared large-airway lymphocytic bronchitis assessed by a 0-2 "E-score" and with standard A and BR pathology scores for acute rejection and small-airway lymphocytic bronchiolitis, respectively.

Measurements and main results: We found surprisingly little association between large- and small-airway lymphocytic inflammation scores from a given bronchoscopy. Endobronchial lymphocytic bronchitis was more prevalent in subjects in BOS stage 0p and BOS stages 1-3 at the time of biopsy. Within 90 days after transplantation, increasing maximum E-score was associated with greater risk of BOS (adjusted hazard ratio, 1.76; 95% confidence interval, 1.11-2.78; P = 0.02) and in this analysis 90-day maximum E-scores were the only score type predictive of BOS (P < 0.01).

Conclusions: These results support a multicenter study to evaluate endoscopic biopsies for the identification of patients at increased risk for BOS. The association of endobronchial lymphocytic inflammation and BOS may have mechanistic implications.

Figure 1.

Large-airway lymphocytic bronchitis was graded according to the following criteria: E0, no chronic inflammation; E1, minimal to mild chronic inflammation with a band of subepithelial lymphocytes and up to occasional intraepithelial lymphocytes; and E2, moderate to severe chronic inflammation with a prominent subepithelial band of lymphocytes, scattered intraepithelial lymphocytes, and at least rare epithelial cell necrosis.

Figure 2.

Enrollment and exclusions for study subjects. Included subjects were transplanted between the date endobronchial biopsies were added as standard of care in March 1997 and November 2011, 90 days before the end of the data collection period. BOS = bronchiolitis obliterans syndrome.

Figure 3.

Maximum E-score in 90 days predicts bronchiolitis obliterans syndrome (BOS). A Kaplan-Meier plot is shown for the development of BOS after transplantation stratified by maximum 90-day E-score. Data were left-truncated at 90 days. The curves are nonoverlapping (P < 0.001 by the Mantel-Cox log-rank test). Increasing E-score was associated with more rapid development of BOS (P < 0.01 by log-rank test for trend).