Progress and Challenges in the Prevention, Diagnosis, and Management of Cytomegalovirus Infection in Transplantation

Abstract

Hosts with compromised or naive immune systems, such as individuals living with HIV/AIDS, transplant recipients, and fetuses, are at the highest risk for complications from cytomegalovirus (CMV) infection. Despite substantial progress in prevention, diagnostics, and treatment, CMV continues to negatively impact both solid-organ transplant (SOT) and hematologic cell transplant (HCT) recipients. In this article, we summarize important developments in the field over the past 10 years and highlight new approaches and remaining challenges to the optimal control of CMV infection and disease in transplant settings.

Keywords: antiviral agents; clinical trials; cytomegalovirus; diagnostics; immune monitoring; immunocompromised hosts; transplant infectious diseases; transplantation; vaccines.

FIG 1

Predictive models of positive (A) and negative (B) predictive values with thresholds of 100, 500, and 1,000 IU/ml across a range of cytomegalovirus (CMV) pneumonia prevalences in patients who underwent bronchoalveolar lavage for evaluation of pulmonary infiltrates (132 patients with CMV pneumonia and 118 controls with non-CMV pneumonia). (Reproduced from reference with permission of Oxford University Press.)

FIG 2

Cumulative incidence of overall mortality in survivors at day 100 (n = 832) stratified by the maximum cytomegalovirus viral load before day 100 (A) and multivariable Cox proportional-hazard models assessing maximum cytomegalovirus viral load before day 100 as a risk factor for overall mortality (B). Covariates for overall mortality models were age, donor relation, transplantation year, underlying disease, disease risk, hemopoietic stem cell transplantation-specific comorbidity index score, neutropenia before day 100, and cytomegalovirus viremia after day 100 (time dependent). CI, confidence interval. (Reproduced from reference with permission of Elsevier.)

FIG 3

CMV prevention strategies in HCT, including potential combined approaches. Red circles indicate weekly monitoring for CMV viremia; open circles indicate test time points that yielded viral loads below the threshold for the initiation of antiviral therapy, while filled shapes indicate test time points with values above this threshold. Black arrows indicate the administration of antivirals as preemptive therapy (PET). Black bars indicate the administration of antivirals as prophylaxis. Blue triangles indicate the administration of a dose of vaccine. All strategies include clinical surveillance. IM, immune monitoring; Exp, experimental; Tx, therapy. ^a, vaccination of transplant donor and/or recipient; ^b, various vaccination schedules have been used; ^c, see references , , and .

FIG 4

CMV prevention strategies in SOT, including potential combined approaches. Red circles indicate weekly monitoring for CMV viremia; open circles indicate test time points that yielded viral load below the threshold for the initiation of antiviral therapy, while filled shapes indicate test time points with values above this threshold. Black arrows indicate the administration of antivirals as preemptive therapy (PET). Black bars indicate the administration of antivirals as prophylaxis. Blue and purple triangles indicate the administration of a dose of vaccine or monoclonal antibodies (mAb), respectively. All strategies include clinical surveillance. LiT, liver transplant; LT, lung transplant; PCR, CMV viral load monitoring by PCR; IM, immune monitoring; Exp, experimental. ^a, see reference ; ^b, see reference ; ^c, see reference ; ^d, the dotted line represents the duration of prophylaxis for lung transplantation.

FIG 5

Drug resistance-associated mutations in CMV genes. CMV gene mutation maps for UL54, UL97, and UL56 show structural domains and the locations of identified resistance mutations. Color-coding indicates the resistance phenotype (A and B) and the degree of resistance conferred (C). GCVr, ganciclovir resistant; CDVr, cidofovir resistant; FOSr, foscarnet resistant; MBV-R, maribavir resistant; ZF, zinc finger; LZ, leucine zipper; NLS, nuclear localization signal; EC50, 50% effective concentration. (Reproduced from reference with permission of Elsevier.)