{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T19:00:06Z","timestamp":1776279606056,"version":"3.50.1"},"reference-count":31,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T00:00:00Z","timestamp":1612483200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The dynamics of recovery of cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) and its impact on controlling clinically significant CMV infections following hematopoietic stem cell transplant (HSCT) are rarely reported in pediatric HSCT recipients. In this study, dynamics of recovery of CMV-specific CMI and its clinical significance in controlling CMV viremia and clinically significant CMV infections were assessed in pediatric allogeneic HSCT recipients. All subjects underwent CMV pp65- and IE1-specific enzyme-linked immune absorbent spot (ELISPOT) assays just before transplantation and then monthly until the detection of CMV-specific CMI with \u2265 5 spot-forming cells (SFC) \/ 2.0 \u00d7 10<jats:sup>5<\/jats:sup> cells. Clinically significant CMV infections were defined as CMV diseases, prolonged CMV infections, recurrent CMV infections or late onset CMV infections. Among 52 recipients, 88.5% of recipients recovered CMV-specific CMI with \u2265 5 SFC\/ 2.0 \u00d7 10<jats:sup>5<\/jats:sup> cells at a median of 34 days (interquartile range [IQR]: 29\u201395 days) following HSCT, 55.8% at 30 days following HSCT, and 73.1% at 90 days following HSCT. The presence of CMV-specific CMI before HSCT was the significant factors for the reconstitution of CMV specific CMI after HSCT (adjusted odds ratio [aOR] = 13.33; 95% confidence interval [CI] = 1.21\u2013142.86). After HSCT, 30 recipients experienced CMV viremia, of which 20 were clinically significant CMV infections. The full recovery of CMV-specific CMI with \u2265 50 SFC \/ 2.0 \u00d7 10<jats:sup>5<\/jats:sup> cells after HSCT was the protective factor for the development of clinically significant CMV infections (aOR = 0.13; 95% CI = 0.22\u20130.71). In the haploidentical HSCT recipients, 82.1% recovered CMV-specific CMI at a median of 65 days after HSCT (IQR: 34\u2013118 days) with a tendency to recover their CMV-specific CMI later than did those from non-haploidentical donors (65 days vs. 30 days; <jats:italic>P<\/jats:italic> = 0.001). Clinically significant CMV infections tended to occur more frequently in the haploidentical HSCT recipients compared to those with matched donor HSCT (46.4% vs. 29.2%; <jats:italic>P<\/jats:italic> = 0.205). The full recovery of CMV-specific CMI with \u2265 50 SFC\/2.0 \u00d7 10<jats:sup>5<\/jats:sup> cells after HSCT also lowered the risk of development of clinically significant CMV infections (aOR = 0.08; 95% CI = 0.01\u20130.90). However, transplantation from haploidentical donors was a significant risk factor hampering recovery of CMV-specific CMI (aOR = 0.08; 95% CI = 0.01\u20130.86) and full recovery of CMV-specific CMI (aOR = 0.05; 95% CI = 0.01\u20130.50). Pre-transplant CMV-specific CMI influenced the recovery of CMV-specific CMI, and the full recovery of CMV-specific CMI could be a surrogate marker for preventing clinically significant CMV infections in pediatric HSCT recipients. Immunologic monitoring using ELISPOT assay before and after HSCT helps in identifying patients with a high risk of CMV infection and in controlling CMV infection.<\/jats:p>","DOI":"10.1371\/journal.pone.0246191","type":"journal-article","created":{"date-parts":[[2021,2,7]],"date-time":"2021-02-07T17:53:33Z","timestamp":1612720413000},"page":"e0246191","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Immunologic monitoring of cytomegalovirus (CMV) enzyme-linked immune absorbent spot (ELISPOT) for controlling clinically significant CMV infection in pediatric allogeneic hematopoietic stem cell transplant recipients"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6168-7876","authenticated-orcid":true,"given":"Euri","family":"Seo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun Seok","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung Hwa","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyery","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyung-Nam","family":"Koh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ho Joon","family":"Im","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jina","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,2,5]]},"reference":[{"key":"pone.0246191.ref001","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1086\/339329","article-title":"Definitions of cytomegalovirus infection and disease in transplant recipients","volume":"34","author":"P Ljungman","year":"2002","journal-title":"Clin Infect Dis"},{"key":"pone.0246191.ref002","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1182\/blood.V67.4.1162.1162","article-title":"Cytomegalovirus infection after bone marrow transplantation: an association with acute graft-v-host disease","volume":"67","author":"W Miller","year":"1986","journal-title":"Blood"},{"key":"pone.0246191.ref003","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1086\/338624","article-title":"High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection","volume":"185","author":"WG Nichols","year":"2002","journal-title":"J Infect Dis"},{"key":"pone.0246191.ref004","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1093\/cid\/cis818","article-title":"State-of-the-art monitoring of cytomegalovirus-specific cell-mediated immunity after organ transplant: a primer for the clinician","volume":"55","author":"A Egli","year":"2012","journal-title":"Clin Infect Dis"},{"key":"pone.0246191.ref005","doi-asserted-by":"crossref","first-page":"2468","DOI":"10.1111\/ajt.14347","article-title":"An interventional study using cell-mediated immunity to personalize therapy for cytomegalovirus infection after transplantation","volume":"17","author":"D Kumar","year":"2017","journal-title":"Am J Transplant"},{"key":"pone.0246191.ref006","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1093\/infdis\/jiw064","article-title":"Utility of the enzyme-linked immunospot interferon-gamma-release assay to predict the risk of cytomegalovirus infection in hematopoietic cell transplant recipients","volume":"213","author":"L Nesher","year":"2016","journal-title":"J Infect Dis"},{"key":"pone.0246191.ref007","doi-asserted-by":"crossref","first-page":"e17","DOI":"10.1097\/TP.0b013e318224f263","article-title":"Immunological monitoring for guidance of preemptive antiviral therapy for active cytomegalovirus infection in allogeneic stem-cell transplant recipients: a pilot experience","volume":"92","author":"C Solano","year":"2011","journal-title":"Transplantation"},{"key":"pone.0246191.ref008","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1097\/TP.0b013e31824215db","article-title":"Diagnostic utility of human cytomegalovirus-specific T-cell response monitoring in predicting viremia in pediatric allogeneic stem-cell transplant patients","volume":"93","author":"D Abate","year":"2012","journal-title":"Transplantation"},{"key":"pone.0246191.ref009","doi-asserted-by":"crossref","first-page":"5016","DOI":"10.4049\/jimmunol.1201759","article-title":"Reconstitution of protective immune responses against cytomegalovirus and varicella zoster virus does not require disease development in pediatric recipients of umbilical cord blood transplantation","volume":"189","author":"N Merindol","year":"2012","journal-title":"J Immunol"},{"key":"pone.0246191.ref010","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1111\/j.1365-2141.2005.05800.x","article-title":"Evaluation of cytomegalovirus-specific T-cell reconstitution in patients after various allogeneic haematopoietic stem cell transplantation using interferon-gamma-enzyme-linked immunospot and human leucocyte antigen tetramer assays with an immunodominant T-cell epitope","volume":"131","author":"M Ohnishi","year":"2005","journal-title":"Br J Haematol"},{"key":"pone.0246191.ref011","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1056\/NEJM199810223391702","article-title":"Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype","volume":"339","author":"F Aversa","year":"1998","journal-title":"N Engl J Med"},{"key":"pone.0246191.ref012","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1038\/bmt.2015.132","article-title":"Early recovery of CMV immunity after HLA-haploidentical hematopoietic stem cell transplantation as a surrogate biomarker for a reduced risk of severe infections overall","volume":"50","author":"M Noviello","year":"2015","journal-title":"Bone Marrow Transplant"},{"key":"pone.0246191.ref013","doi-asserted-by":"crossref","first-page":"4063","DOI":"10.1182\/blood.V88.10.4063.bloodjournal88104063","article-title":"Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study","volume":"88","author":"M Boeckh","year":"1996","journal-title":"Blood"},{"key":"pone.0246191.ref014","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1093\/cid\/ciw668","article-title":"Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials","volume":"64","author":"P Ljungman","year":"2017","journal-title":"Clin Infect Dis"},{"key":"pone.0246191.ref015","doi-asserted-by":"crossref","first-page":"e13220","DOI":"10.1111\/petr.13220","article-title":"Quantiferon-cytomegalovirus assay: a potentially useful tool in the evaluation of CMV-specific CD8+ T-cell reconstitution in pediatric hematopoietic stem cell transplant patients","volume":"22","author":"B Paouri","year":"2018","journal-title":"Pediatr Transplant"},{"key":"pone.0246191.ref016","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1086\/597123","article-title":"Human cytomegalovirus-specific T cell reconstitution in young patients receiving T cell-depleted, allogeneic hematopoietic stem cell transplantation","volume":"199","author":"D Lilleri","year":"2009","journal-title":"J Infect Dis"},{"key":"pone.0246191.ref017","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1093\/infdis\/jiy592","article-title":"The ability of a cytomegalovirus ELISPOT assay to predict outcome of low-level CMV reactivation in hematopoietic cell transplant recipients","volume":"219","author":"L El Haddad","year":"2019","journal-title":"J Infect Dis"},{"key":"pone.0246191.ref018","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1182\/blood-2005-11-012864","article-title":"Prospective simultaneous quantification of human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in young recipients of allogeneic hematopoietic stem cell transplants","volume":"108","author":"D Lilleri","year":"2006","journal-title":"Blood"},{"key":"pone.0246191.ref019","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1111\/bjh.12875","article-title":"Relationship between cytomegalovirus (CMV) reactivation, CMV-driven immunity, overall immune recovery and graft-versus-leukaemia effect in children","volume":"166","author":"M Jeljeli","year":"2014","journal-title":"Br J 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Characterization of cytotoxic function of CMVpp65-specific CD8+ T-lymphocytes identified by HLA-tetramers in recipients and donors of stemcell transplants","volume":"74","author":"SF Lacey","year":"2002","journal-title":"Transplantation"},{"key":"pone.0246191.ref021","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/S1083-8791(03)70010-X","article-title":"Reconstitution of T-cell repertoire after autologous stem cell transplantation: influence of CD34 selection and cytomegalovirus infection","volume":"9","author":"KS Peggs","year":"2003","journal-title":"Biol Blood Marrow Transplant"},{"key":"pone.0246191.ref022","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.4110\/in.2018.18.e2","article-title":"The detailed kinetics of cytomegalovirus-specific T cell responses after hematopoietic stem cell transplantation: 1 year follow-up data","volume":"18","author":"S Bae","year":"2018","journal-title":"Immune Netw"},{"key":"pone.0246191.ref023","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/j.1399-3062.2011.00626.x","article-title":"Tetramer monitoring to assess risk factors for recurrent cytomegalovirus reactivation and reconstitution of antiviral immunity post allogeneic hematopoietic stem cell transplantation","volume":"13","author":"S Borchers","year":"2011","journal-title":"Transpl Infect Dis"},{"key":"pone.0246191.ref024","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.bbmt.2010.07.020","article-title":"Donor serostatus has an impact on cytomegalovirus-specific immunity, cytomegaloviral disease incidence, and survival in seropositive hematopoietic cell transplant recipients","volume":"17","author":"A Ugarte-Torres","year":"2011","journal-title":"Biol Blood Marrow Transplant"},{"key":"pone.0246191.ref025","doi-asserted-by":"crossref","first-page":"6465","DOI":"10.1182\/blood-2009-02-203307","article-title":"Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients","volume":"113","author":"W Zhou","year":"2009","journal-title":"Blood"},{"key":"pone.0246191.ref026","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/sj.bmt.1705825","article-title":"Evaluation of intervention strategy based on CMV-specific immune responses after allogeneic SCT","volume":"40","author":"G Avetisyan","year":"2007","journal-title":"Bone Marrow Transplant"},{"key":"pone.0246191.ref027","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1056\/NEJM198509263131301","article-title":"Marrow transplantation from related donors other than HLA-identical siblings","volume":"313","author":"PG Beatty","year":"1985","journal-title":"N Engl J Med"},{"key":"pone.0246191.ref028","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1182\/blood-2011-11-354563","article-title":"Selection of optimal alternative graft source: mismatched unrelated donor, 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Blyth","year":"2016","journal-title":"Virulence"}],"updated-by":[{"DOI":"10.1371\/journal.pone.0294486","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T00:00:00Z","timestamp":1699833600000}}],"container-title":["PLOS 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