Reply to Giménez et al

To the Editor—We thank Giménez et al for sharing their data on the correlation between cytomegalovirus (CMV) DNAemia and CMV-specific CD8⁺ T-cell counts. Monitoring of CMV cell-mediated immunity (CMV-CMI) has been studied as a strategy to guide the management of CMV infection in recipients of solid organ transplants [1] or for prediction of CMV reactivation or protection in recipients of hematopoietic cell transplants [2]. Diverse techniques to measure and evaluate CMV-CMI have subsequently emerged and include the enzyme-linked immunospot CMV assay that quantifies interferon γ (IFN-γ)–producing CD8⁺ and CD4⁺ T cells specific to CMV antigens pp65 and IE1 [2, 3]; the QuantiFERON-CMV kit, which quantifies IFN-γ produced by CMV-specific CD8⁺ T cells [4]; and intracellular cytokine staining and enumeration by flow cytometry of CD8⁺ T cells stimulated by antigens IE1 and pp65 [5].

Giménez et al found no correlation between CMV-specific CD8⁺ T-cell counts at the onset of CMV DNAemia or at peak CMV loads. We agree with Giménez et al about the many dissimilarities between their study and ours, including the different assays used for CMV-CMI monitoring and the lack of head-to-head comparison to identify the most reliable assay for guiding management of CMV infection in hematopoietic cell transplant recipients. In addition to these dissimilarities, a few additional factors might have influenced the differences between their conclusions and ours. First, as acknowledged by the authors, their small sample size of 9 patients with initial episodes of CMV reactivation and 11 recurrent episodes precludes further analysis to control for cofounders, such as corticosteroid use and graft-versus-host disease. Second, the timing of the immunological monitoring remains the unique paramount aspect in any assay used to assess or predict CMV infection. For clarification, in our study we only considered the first episode when progression to clinically significant CMV infection occurred as defined a priori (ie, the CMV event) and correlated with CMV-specific pp65 and IE1 spot counts that preceded the CMV event by 1–2 weeks before progression but >48 hours before the event [3]. Results of immunological surveillance at the time of CMV DNAemia or within 48 hours of reactivation may be misinterpreted as the CMV-CMI, and the magnitude of the CD8⁺ T-cell responses might not be a consequence of CMV reactivation. Third, in our study, high-risk patients such as cord blood transplant recipients were excluded, as these patients may require preemptive therapy at the first sign of reactivation, before attainment of a certain predefined threshold for CMV load, as the likelihood of CMV-specific T-cell recovery within the first year after transplantation is meager and most probably not protective against progression to CMV infection [6].

Again, we thank Giménez et al for their comments. We believe that monitoring CMV-CMI in clinical practice can guide clinicians in the management of CMV infection, but further interventional studies are needed.

Notes

Financial support. This work was supported by Oxford Immunotec and the National Cancer Institute, National Institutes of Health (award P30CA016672; used the Clinical Trials Support Resource).

Disclaimer Oxford Immunotec did not participate in the analysis and/or the interpretation of the data.

Potential conflicts of interest. R. F. C. has served as a consultant to Oxford Immunotec, Merck, Chimerix, Shire, and Astellas and received research funding from Oxford Immunotec, Merck, Novartis, Shire, and Chimerix. E. A.-H. has received research funding from Oxford Immunotec. L. E. certifies no potential conflicts of interest.

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