Reflux-induced collagen type v sensitization: potential mediator of bronchiolitis obliterans syndrome

Abstract

Background: Lung transplantation continues to have poor long-term survival partly because of the high incidence of bronchiolitis obliterans syndrome (BOS). Gastroesophageal reflux disease (GERD) has been implicated in BOS pathogenesis. We investigated the role of collagen type V [col(V)] sensitization in this process.

Methods: Only primary lung transplant recipients were included. Reflux status was assessed with pH monitoring, impedance plethysmography, and esophagogastroduodenoscopy. Sensitivity to col(V) was determined with trans vivo delayed-type hypersensitivity reaction (DTH). Kaplan-Meier analyses were performed.

Results: Of the 54 recipients, 26 had proven GERD. There were no significant between-group differences in diagnosis; donor and recipient age; sex; ischemic time; single vs bilateral; human leukocyte antigen A, B, and DR matching cytomegalovirus status; acute rejections; or mean follow-up period. The mean DTH response in the GERD group was 25.7 x 10(-4) inches vs 18.3 x 10(-4) inches in the non-GERD group (P = .023). There was a significant reduction in BOS-free survival in the GERD group for both BOS-I (GERD+, 28.3%; GERD-, 86.6%; P = .0001) and BOS-II/III (GERD+, 66.2%; GERD-, 91.7%; P = .0374). A second cohort of 53 patients awaiting lung transplantation also was assayed. The mean DTH response in the GERD group was 24.0 x 10(-4) inches vs 13.1 x 10(-4) inches in the non-GERD group (P = .003). There were no differences in age or sex.

Conclusions: GERD is strongly associated with the development of BOS after primary lung transplantation. Col(V) sensitization is associated with reflux and BOS and may play an intermediary role in the pathogenesis of BOS. Trials using col(V) reactivity to assess the impact of antireflux procedures in patients with lung transplantation and idiopathic pulmonary fibrosis are warranted.

Figure 1.

BOS-free survival based on reflux status in 54 patients after primary lung transplantation. Solid lines denote the positive gastroesophageal reflux disease (GERD) group (n = 26); dotted lines represent the group with no objective evidence of GERD (n = 28). Patients with objectively proven reflux had significantly worse BOS-free survival for both low-grade BOS (A) and high-grade BOS (B) over the 7-year study period. BOS = bronchiolitis obliterans syndrome; BOS-I = low-grade BOS; BOS-II/III = high-grade BOS.

Figure 2.

BOS-free survival (A) and overall survival (B) after primary lung transplantation based on trans vivo delayed-type hypersensitivity (TV-DTH) reactivity to collagen type V [col(V)]. Solid lines denote TV-DTH+ (n = 20); dotted lines represent TV-DTH− (n = 34). Patients sensitized to col(V) were significantly more likely to develop severe BOS after transplantation. Additionally, col(V) reactivity was associated with a higher mortality after lung transplantation. See Figure 1 legend for expansion of other abbreviation.

Figure 3.

Fifty-three patients before lung transplantation were analyzed while on the transplantation wait list. Reflux status was objectively confirmed as previously described in the “Materials and Methods” section. Patients with idiopathic pulmonary fibrosis (n = 15) had a significantly higher proportion of GERD (solid bars) than all other conditions (n = 38) (A). Additionally, patients with proven reflux (solid bars, n = 17) had a significant and specific response to col(V) not seen in the group with no objective evidence of GERD (dotted bars, n = 36) (B). This response was near the magnitude of the positive recall antigen Epstein-Barr virus. There was no response to collagen type II. AAD = α1-antitrypsin deficiency; CF = cystic fibrosis; col(II) = collagen type II; col(V) = collagen type V; EBV = Epstein-Barr virus; IPF = idiopathic pulmonary fibrosis. See Figure 1 legend for expansion of other abbreviations.