title: Clinically-based determination of safe DNAemia cutoff levels for preemptive therapy or human cytomegalovirus infections in solid organ and hematopoietic stem cell transplant recipients.
abstract: Transplantation Centers using human cytomegalovirus (HCMV) antigenemia-based preemptive therapy will need to replace in the near future the antigenemia assay with a more standardized and automatable assay, such as a molecular assay quantifying HCMV DNA in blood (DNAemia). Thus, in view of replacing antigenemia with clinically safe cutoff values, DNAemia levels corresponding to antigenemia cutoffs guiding HCMV preemptive therapy were determined retrospectively in solid organ and hematopoietic stem cell transplant recipients (HSCTR) using an "in-house" quantitative PCR (QPCR) method. Since preemptive therapy had prevented appearance of HCMV disease in all patients tested, DNA cutoffs determined retrospectively had to be considered as safe clinically as antigenemia cutoffs used prospectively. However, in solid organ transplant recipients (SOTR), initiating preemptive therapy upon an antigenemia cutoff of 100 pp65-positive leukocytes, a DNAemia cutoff of 300,000 copies/ml blood had positive and negative predictive values of >90%, indicating that a DNAemia cutoff could achieve, in terms of prevention of HCMV disease, the same clinical results as the antigenemia cutoff. In HSCTR, initiating preemptive therapy upon first antigenemia positivity, a DNAemia cutoff of 10,000 copies/ml blood had a positive predictive value of >90%, indicating that the great majority of patients treated under the antigenemia guidance would have been treated also using this DNA cutoff. On the other hand, the negative predictive value of 28.6% indicated that two out of three HSCTR had been treated under the antigenemia guidance having the same levels of viral DNA as the untreated patients. The data suggest that a quantitative cutoff could be adopted as a guiding criterion for preemptive therapy also in HSCTR. Regression analysis allowed to determine the DNAemia (corresponding to QPCR) cutoff values for two commercial assays tested both in solid organ and HSCTR. Retrospective DNAemia cutoff values will be verified for safety in prospective trials.
authors.affiliation: Servizio di Virologia, IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Lilleri
authors.forename: Fausto
authors.initials: F
authors.lastname: Baldanti
authors.forename: Marta
authors.initials: M
authors.lastname: Gatti
authors.forename: Francesca
authors.initials: F
authors.lastname: Rovida
authors.forename: Luca
authors.initials: L
authors.lastname: Dossena
authors.forename: Simona
authors.initials: S
authors.lastname: De Grazia
authors.forename: Maria
authors.initials: M
authors.lastname: Torsellini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gerna
mesh_terms: D000956:Antigens, Viral / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use*; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification*; D003586:Cytomegalovirus Infections / Q000175:diagnosis* / Q000188:drug therapy / Q000517:prevention & control* / Q000821:virology; D004279:DNA, Viral / Q000097:blood*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D016377:Organ Transplantation / Q000009:adverse effects*; D016133:Polymerase Chain Reaction / Q000379:methods; D011183:Postoperative Complications; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D014766:Viremia / Q000235:genetics / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D000998:Antiviral Agents; D004279:DNA, Viral