Cytomegalovirus Replication Within the Lung Allograft Is Associated With Bronchiolitis Obliterans Syndrome

Abstract

Early studies reported cytomegalovirus (CMV) pneumonitis as a risk factor for development of bronchiolitis obliterans syndrome (BOS) following lung transplantation. While improvements in antiviral prophylaxis have resulted in a decreased incidence of CMV pneumonitis, molecular diagnostic techniques allow diagnosis of subclinical CMV replication in the allograft. We hypothesized that this subclinical CMV replication was associated with development of BOS. We retrospectively evaluated 192 lung transplant recipients (LTR) from a single center between 2001 and 2009. Quantitative (PCR) analysis of CMV viral load and histological evidence of CMV pneumonitis and acute cellular rejection was determined on 1749 bronchoalveolar lavage (BAL) specimens and 1536 transbronchial biopsies. CMV was detected in the BAL of 41% of LTR and was significantly associated with the development of BOS (HR 1.8 [1.1-2.8], p = 0.02). This association persisted when CMV was considered more accurately as a time-dependent variable (HR 2.1 [1.3-3.3], p = 0.003) and after adjustment for significant covariates in a multivariate model. CMV replication in the lung allograft is common following lung transplantation and is associated with increased risk of BOS. As antiviral prophylaxis adequately suppresses CMV longer prophylactic strategies may improve long-term outcome in lung transplantation.

CMV: Prevention, Diagnosis and Therapy

“…Citations are examples supporting these statements and are not meant to include all references on this topic. Additional references can be found in the comprehensive review by Freeman (5) General indirect effects-elevated risks Bacterial infections (19,134,135) Fungal infection (19,26) Viral infections (summarized in (6)) PTLD (136) Cardiovascular events (137) New-onset diabetes mellitus after transplantation (138,139) Immunosenescence (140) Acute rejection (36,37,134) Mortality (19,134,(141)(142)(143)(144) Transplant-specific indirect effects Chronic allograft nephropathy and/or allograft loss after renal transplant (19,145,146) Accelerated hepatitis C recurrence after liver transplant (147) Hepatic artery thrombosis after liver transplant (144,148,149) Allograft vasculopathy after cardiac transplant (150,151) Bronchiolitis obliterans after lung transplant (37,141,143) hereafter referred to as D+/R−). Preemptive therapy is defined as serial testing done weekly or biweekly for the first few months after transplant or after treatment of rejection, with treatment dose antiviral therapy initiated once a certain defined positive threshold is reached.…”

“…Overall, PV16000 showed that once daily oral valganciclovir was noninferior and as clinically effective and well tolerated as oral ganciclovir for CMV prevention in high-risk SOT recipients. A trial of valganciclovir versus oral ganciclovir in lung transplant recipients showed a higher rate of bronchiolitis obliterans syndrome and bacterial tracheobronchitis in those on oral ganciclovir (36); another similar trial showed much lower rates of CMV pneumonitis in those on valganciclovir compared with oral ganciclovir prophylaxis (37).…”

Recognition of Distinct Cross-Reactive Virus-Specific CD8+ T Cells Reveals a Unique TCR Signature in a Clinical Setting

“…However, even in the current era, we and others have reported that significant rates of subclinical CMV reactivation can still occur in the lung allograft, and that these are associated with both acute episodes of CMV pneumonitis in the short term and chronic rejection associated bronchiolitis obliterans syndrome and decreased patient survival in the longer term (2,3). Poorer clinical outcomes in solid organ transplantation have long been associated with ubiquitous DNA viruses such as CMV and EBV, but it was previously thought that this was largely a result of a direct viral effect and/or the amplification of underlying alloreactivity (3)(4)(5)(6)(7). However, a more contemporary theory links these two possibilities together by focusing on circulating antiviral memory T cell pools toward latent DNA viruses (8)(9)(10)(11) and the cross-reactive capacity of a subset of these memory pools to recognize unrelated HLA molecules (12)(13)(14)(15)(16)(17)(18)(19).…”

“…Over the past two decades, prophylactic antiviral strategies in the early months after lung transplantation have greatly reduced the clinical impact of CMV reactivation and disease (1). However, even in the current era, we and others have reported that significant rates of subclinical CMV reactivation can still occur in the lung allograft, and that these are associated with both acute episodes of CMV pneumonitis in the short term and chronic rejection associated bronchiolitis obliterans syndrome and decreased patient survival in the longer term (2,3). Poorer clinical outcomes in solid organ transplantation have long been associated with ubiquitous DNA viruses such as CMV and EBV, but it was previously thought that this was largely a result of a direct viral effect and/or the amplification of underlying alloreactivity (3)(4)(5)(6)(7).…”

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

“…In lung transplant patients, a relationship between CMV infection and CLAD has been reported in some studies (32,35,48) but not in all (53,54). CMV infection was identified as a significant risk factor for developing CLAD in a study from Australia (hazard ratio [HR] 2.1, p ¼ 0.003) (35) but not in a study from Canada (HR 1.04, p ¼ 0.89) (55). Across studies analyzing the influence of CMV on the incidence of CLAD, the universal use of prolonged antiviral prophylaxis has been consistently associated with lower risk of BOS (55,56).…”