PIDS Journal Club, December 2019

 

Immune Monitoring of CMV After Transplantation? Refinements in Our Approach Are Necessary.

Reviewing: Paouri B et. al., “Quantiferon-Cytomegalovirus Assay: A Potentially Useful Tool in the Evaluation of CMV-Specific CD8+ T-Cell Reconstitution in Pediatric Hematopoietic Stem Cell Transplant Patients”, Ped. Transplant., 20181

Background

Despite improvements in the detection and management of cytomegalovirus (CMV), morbidity and mortality remain significant in the transplant population. Methods that might improve risk stratification, that might reduce drug toxicity and that might reduce levels of drug resistance are necessary to improve management. Reconstitution of CMV specific immunity in hematopoietic stem cell transplant (HSCT) patients has been associated with control of and protection against CMV reactivation and disease. In this paper, the investigators evaluated the clinical utility of using CMV specific cell mediated immune responses to predict CMV DNAemia in pediatric HSCT patients. 

Methods and Results

Thirty-seven pediatric HSCT patients were followed prospectively. Weekly CMV PCR was performed to look for DNAemia until day 100 and then if clinically indicated. The Quantiferon-CMV assay was performed prior to transplant, early after transplant and at days 30, 90, 180, 270, and 360 after transplant.

The principle behind the Quantiferon-CMV is identical to the Quantiferon-TB. Whole blood is placed in separate tubes with a negative control, a mitogen positive control, and specific CD8 stimulating peptides. After incubation, interferon gamma is measured and can be reported as qualitatively positive, negative, or indeterminate or as a quantitative result. Production of interferon gamma acts as a surrogate for stimulation of CD8 specific T cells, in this case, to CMV.

Prior to transplant, 17 (46%) patients were negative by Quantiferon-CMV, 12 (32%) patients were indeterminate, and 5 (14%) were positive. There was no correlation between pre-transplant cell mediated immunity (CMI) and CMV DNAemia at < 30 days post-transplant. CMV DNAemia occurred in 51% of patients with half of those episodes occurring at < 30 days presumably before full engraftment. Fifteen of these DNAemic patients (40% of total cohort) developed immunity at an average of 82 days’ post-transplant. In those who developed immunity, later reactivation of CMV was lower (15% vs. 53%) than in those who did not develop immunity. In this cohort, acute graft versus host disease (GVHD) did not alter the recovery of CMV immunity.

Critique

The percentage of indeterminate results was high in this cohort and may reflect disease state or conditioning regimen for transplant, as over 50% of the indeterminate samples were drawn in the 1-3 days after transplant. In addition, this method is probably not helpful in the early post-transplant period at least for those with an HSCT. It should, however, be more useful in those receiving a solid organ transplant (SOT) as pre-existing immunity remains after conditioning. The technique appears to have merit and may be useful in the future once larger prospective studies are undertaken.

Conclusions 

Immune monitoring of CMV may help with stratifying patients for episodes of reactivation, as those who recovered CMV immunity were less likely to reactivate in this cohort. However, since most episodes of CMV reactivation occurred before immune reconstitution was expected, the clinical utility of this assay may be limited in HSCT patients to post engraftment. However, CMV immunity prior to transplant in those receiving a SOT, may also predict who will be more likely to control DNAemia. A prospective trial is underway in adult patients (NCT02538172) 2

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Author

Marc Foca, MD

Columbia University Irving Medical Center, New York, NY USA

Peer Reviewers

Joshua Wolf MBBS, PhD, FPIDS, FRACP, St. Jude Children’s Research Hospital, Memphis, TN

Sanjeev Swami MD, The Children’s Hospital of Philadelphia, Philadelphia, PA

References 

  1. PaouriB, Soldatou A, Petrakou E, Theodosaki M, Tsentidis C, Kaisari K, Oikonomopoulou C, Matsas M, Goussetis E. Quantiferon-Cytomegalovirus assay: A potentially useful tool in the evaluation of CMV-specific CD8+ T-cell reconstitution in pediatric hematopoietic stem cell transplant patients. Pediatr Transplant. 2018 Aug;22(5):e13220. doi: 10.1111/petr.13220. Epub 2018 May 18. 
  1. Clinical Trials.gov. Cell Mediated Immunity for Prevention of CMV Disease.

https://clinicaltrials.gov/ct2/show/NCT02538172. Sept. 2015. Accessed Dec. 2019