title: Low cytomegalovirus-specific T-cell counts at reactivation are associated with progression to high-level viremia or disease in seropositive recipients of hematopoietic cell grafts from seropositive but not seronegative donors.
abstract: OBJECTIVE
  Identifying patients who spontaneously resolve cytomegalovirus (CMV) reactivation could spare these patients from the toxicity of antiviral drugs such as ganciclovir. The role of CMV-specific T cells in clearing CMV viremia in patients who do not receive ganciclovir has not been evaluated. We assessed this in patients with CMV viremia between 50 and 50 000 genome copies/mL, because our threshold for initiating ganciclovir is 50 000 copies/mL.
  
  
  METHODS
  We enumerated CMV-specific T cells in 39 CMV seropositive hematopoietic cell transplantation (HCT) recipients within 4 days of the first positive CMV polymerase chain reaction (PCR). CMV-specific T cells were defined as cells that upon stimulation with CMV lysate or pp65 overlapping peptides produced interferon (IFN)-γ, tumor necrosis factor (TNF)-α or interleukin (IL)-2, alone or in combination.
  
  
  RESULTS
  Among Donor (D+), Recipient (R+) patients, unifunctional CMV-specific CD4 T-cells were higher in patients who spontaneously resolved CMV viremia (did not receive ganciclovir) versus those who progressed (received ganciclovir) (median 0.20 versus 0.02/μL lysate-stimulated cells, P < 0.05, and 0.26 versus 0.05/μL pp65 peptide-stimulated cells, P<0.05). Among D- R+ patients, there was no difference between patients with spontaneous resolution or progression; all subsets of CMV-specific T cells measured were barely detectable, in both patients with spontaneous resolution and those with progression.
  
  
  CONCLUSIONS
  Among D+ R+ patients (but not D- R+ patients), high CMV-specific CD4 T-cell counts identify patients who can spontaneously resolve CMV reactivation. In D- R+ patients, immune mechanisms other than T cells may control the progression from reactivation to high-level viremia/disease.
authors.affiliation: Department of Medicine, University of Calgary, Calgary, Alberta, Canada. mhoeghpe@ucalgary.ca
authors.forename: Mette
authors.initials: M
authors.lastname: Hoegh-Petersen
authors.forename: Lina
authors.initials: L
authors.lastname: Roa
authors.forename: Yiping
authors.initials: Y
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.forename: Alejandra
authors.initials: A
authors.lastname: Ugarte-Torres
authors.forename: Polly
authors.initials: P
authors.lastname: Louie
authors.forename: Kevin
authors.initials: K
authors.lastname: Fonseca
authors.forename: Faisal
authors.initials: F
authors.lastname: Khan
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.forename: Jan
authors.initials: J
authors.lastname: Storek
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D003587:Cytomegalovirus / Q000276:immunology / Q000472:pathogenicity; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000821:virology*; D018450:Disease Progression; D015774:Ganciclovir / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D008875:Middle Aged; D014019:Tissue Donors; D014766:Viremia / Q000473:pathology*; D014775:Virus Activation / Q000276:immunology; D017735:Virus Latency
chemical_list: D007371:Interferon-gamma; D015774:Ganciclovir