Bronchiolitis Obliterans Syndrome Complicating Lung or Heart-Lung Transplantation

John A. Belperio, MD; Kathleen Lake, PharmD; Henry Tazelaar, MD; Michael P. Keane, MD; Robert M. Strieter, MD; Joseph P. Lynch, III, MD

Disclosures

Semin Respir Crit Care Med. 2003;24(5) 

In This Article

Risk Factors for BO

Acute allograft rejection is undoubtedly the most important risk factor for OB, but not all patients experiencing BO have prior episodes of clinically evident or documented AR. Several additional possible risk factors have been identified in various publications, but results are conflicting. These hypothetical risk factors (discussed in detail following here) include CMV infection, human leukocyte antigen (HLA) mismatching, non-CMV infections, organizing pneumonia, and airway or allograft ischemia. The dominant risk factors for BO identified in several single-center studies are summarized in Table 5 .[9,25,27]

Acute Allograft Rejection

Acute allograft rejection is the single most important risk factor for BO and BOS.[6,11,22,25] The association of AR and BO may be difficult to assess because some degree of AR (typically mild) occurs in up to 90% of patients within 3 months of transplantation[18,22] and cofactors may potentiate the impact of AR.[9,25] The link between AR and BOS is clearer in the following circumstances: multiple episodes of AR,[9] severe episodes of AR (> grade 2), cumulative episodes of AR by a quantitative scoring system,[27,75] and episodes of late AR.[6,25,27,75] Other influences, such as HLA mismatching or CMV pneumonia may play contributory roles (discussed following here).

Lymphocytic Bronchitis/Bronchiolitis

Several groups have confirmed that LBB is a risk factor for BOS,[25,26,27] particularly at later time points posttransplant.[27] In one study, 12 of 13 patients with LBB developed BOS, at a median interval of 159 days after detecting LBB.[25]

Cytomegalovirus

CMV is a risk factor for AR in LTRs[76] and may increase the risk for BOS.[9,25,75,77] However, data are conflicting.[8] Four studies comprising 543 LTRs found significant associations between either BO or BOS onset and CMV pneumonia in univariate analyses.[9,75,78,79] In contrast, four studies comprising > 400 LTRs found no such associations.[22,25,27,42] One study found that symptomatic CMV pulmonary infection was a significant risk factor for development of BOS (RR 3.2, p = 0.0001) and OB (RR 3.6, p = 0.0005),[75] whereas asymptomatic CMV had no effect. Early studies affirming a relationship between CMV pneumonia and chronic rejection[80] led to more aggressive prophylactic strategies utilizing ganciclovir for patients at high risk for CMV. Following use of prophylactic ganciclovir, several groups reported declines in the incidence of both CMV and BOS.[81,82,83] The role of CMV was supported by one study showing that ganciclovir resistance was associated with earlier BOS onset.[84] In contrast, a recent retrospective study found that prophylaxis for CMV infection did not influence the incidence of BOS.[8] Rates of BOS at 3 and 5 years posttransplantation were similar regardless of CMV serological status. Among donor negative/recipient negative (D-/R-) recipients, the most significant risk factor for developing BOS was ≥ 3 episodes of AR (p = 0.02).[8] Although data are conflicting, it is likely that severe, symptomatic CMV infections predispose to BOS, primarily by potentiating AR.

The mechanism(s) by which CMV may lead to allograft rejection are likely complex. CMV increases EC HLA Class I and II expression[85] and increases production of proinflammatory cytokines (e.g., interferon-γ, tumor necrosis factor-α, and interleukin-4 and -6).[76] CMV also shares nucleic acid sequence homology with the β-2 microglobulin chain of major histocompatibility complex (MHC) class I[86] and between the immediate-early (I-E) gene of CMV and the β-chain of HLA-DR.[87] Endothelialitis generated by CMV infection[88] may be involved in the pathogenesis of OB. Despite the link between CMV and both acute and chronic rejection, additional mechanisms are likely more important.

Histocompatibility Loci (MHC)

The importance of HLA matching for long-term outcome after LT remains uncertain.[6] HLA matching has been proven to have beneficial effects on rejection rates and graft survival in kidney[89] and heart transplant recipients,[90,91] but data among LTRs are limited.[6,9,75,92,93] Some single-center studies among LTRs found no association between HLA mismatches and OB or BOS.[25,27,94] By contrast, in some retrospective studies, marked mismatches were associated with higher rates of late graft failure and BO.[9,75,92,93,95,96] Although the role of HLA mismatching remains controversial, the largest study to date [comprising 3,549 LTRs from the United Network for Organ Sharing (UNOS)/ISHLT Registry database] found no significant association between HLA mismatching and development of BOS.[97] This lack of association likely reflects the fact that a great majority of LTRs (95.4%) have more than two mismatches.[97] This high degree of HLA mismatching reflects the need to harvest lung organs within a few hours, precluding HLA matching between donors and recipients prior to transplantation.

Airway Ischemia

Nonimmune injury to the lung allograft is a hypothetical risk factor for BOS. In this context, primary graft dysfunction, disruption of the bronchial arterial supply, ischemia-reperfusion injury, prolonged ischemic time, cardiopulmonary bypass (CPB), or acute injury to lung or bronchial anastomoses have been considered as plausible risk factors for subsequent BOS. Primary allograft dysfunction occurs in 13 to 35% of LTRs and is associated with hypoxemia, diffuse alveolar damage (DAD) on lung biopsy or necropsy, and a high mortality rate.[98,99,100,101] The mechanisms responsible for primary graft dysfunction are likely multifactorial. Hypothetical (albeit unproven) mechanisms include ischemia-reperfusion injury, inadequate organ preservation techniques, prolonged graft ischemia, CPB, and diffuse cytokine release. In humans, ischemia-reperfusion injury adversely affects early graft function and survival.[98,100] In a rat model, ischemia-reperfusion injury was associated with enhanced MHC class II expression in the lung tissue,[102] which may increase the risk for allograft rejection. Preexisting inflammation or cytokine release may precipitate injury to the allograft. In a recent prospective study, elevated IL-8 levels in donor lungs were associated with poor initial graft function in the recipient and an increase in mortality.[103] Enhanced intrapulmonary cytokine release may follow brain death, in both humans[104] and animals,[105] raising the possibility that cytokines in the donor lung(s) may cause allograft injury. However, there is no compelling evidence that early graft injury affects the frequency or time of onset of BOS. A recent review of 323 LTRs found that early allograft dysfunction (as evidenced by histological evidence of DAD on lung biopsies) was not associated with an increased incidence of BOS or earlier onset of BOS at long-term follow-up compared with LTRs without DAD.[100] Further, neither CPB nor length of cold ischemic time correlated with the risk of DAD.[100] The role of CPB in potentiating lung injury has been debated. CPB may recruit circulating neutrophils and increase circulating cytokines (thereby potentiating lung injury),[102] but CPB may attenuate injury by allowing control of pulmonary artery pressure during reperfusion.[106]

Prolonged cold ischemic time has been considered as a theoretical risk factor for BOS. However, several studies in human LTRs found that increased ischemic times (> 5-6 hours) were not associated with higher incidences in BOS,[73,107,108,109] episodes of AR,[110,111,112,113] or mortality.[9,27,107,108,110,111,114,115,116]

Ischemia due to interruption of the bronchial arterial supply after implantation of the graft is a potential, albeit unproven, cause of small airway injury. One study identified airway ischemia (identified bronchoscopally) as a risk factor for BOS (p < 0.04),[79] but the role of airway ischemia in the pathogenesis of BOS is uncertain.[5,6]

Nonimmune causes of acute lung injury (e.g., acute respiratory distress syndrome) may promote a pro fibrotic milieu, eliciting pulmonary fibrosis.[117] In a rat model of heterotrophic tracheal allograft, severe epithelial injury led to progressive fibrosis and obliteration of the airway lumen.[118] Additional studies are required to determine whether early injury to the lung allograft (immune or nonimmune) influences the risk of BOS.

Infections (Other Than CMV)

A few studies found that infectious episodes other than CMV increased the risk of BOS.[6,9] Single-center studies cited associations between BOS and: pulmonary infections[9]; bacterial, fungal, or Pneumocystis carinii pneumonia[25]; and late bacterial pneumonia.[94] A study from Germany noted clustering of cases of BOS in the winter months (January to March), suggesting that infections may be a trigger for BOS onset.[119] Investigators from the University of Minnesota noted that symptomatic community respiratory virus (CRV) infections (e.g., respiratory syncytial, parainfluenza, and influenza viruses) involving the lower respiratory tract predispose to high-grade BOS ($ stage 3) (RR 2.3, p = 0.04), whereas upper respiratory tract involvement or asymptomatic infections had no effect.[120] Further, the risk for developing CVR infections was increased in patients with preexisting BO or BOS. These data are intriguing because parainfluenza virus infection of allografts aggravated chronic rejection in a rat LT model.[121] It is possible that CRV and BOS have synergistic roles in advancing small airways disease in LTRs. However, the role of viral infections in precipitating or aggravating BOS is controversial; two studies showed no effect of non-CMV infections on BOS risk.[26,122]

Other Potential Risk Factors

Factors that have been evaluated and shown not to be risk factors for BOS include donor gender or age;[9,25,26,79] type of transplant (i.e., single, double, or heart-lung);[6,25] underlying disease[123]; requirement for CPB[79,124] or postoperative mechanical ventilation[27]; induction therapy with cytolytic agents;[25,125] time listed[75]; and bronchial stenosis.[27]

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