To the Editor: We read with interest the latest epidemiological survey by Lebbe et al. (1Lebbe C Porcher R Marcelin AG et al.Human herpesvirus 8 (HHV8) transmission and related morbidity in organ recipients.Am J Transplant. 2013; 13: 207-213Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), assessing the risk of HHV8 transmission after solid organ transplantation in a French cohort of liver, kidney or heart recipients, by applying different serological and molecular tests (i.e. either latent or lytic IFA, and quantitative PCR), as well as providing helpful information on some life-threating cases of HHV8-related diseases. During the last decade, using the same multiple assays, we have similarly performed two multicentric, prospective HHV8 screening studies on previously unreported Italian transplant cohorts (Table 1). The former from the North Italian Transplant (NIT) group and the Gruppo Italiano Trapianto Midollo Osseo (GITMO) enrolled 367 donor/recipient pairs from 2001 to 2003 (referred as NIT-GITMO Study), while the latter from the Regione Emilia-Romagna—Progetto Regione-Università included 525 recipients and 249 donors, enrolled from 2008 to 2012 (referred as RER-PRU Study). Here, we briefly report our data (Table 1) and focus on some main points emerging from recent literature on this topic (1Lebbe C Porcher R Marcelin AG et al.Human herpesvirus 8 (HHV8) transmission and related morbidity in organ recipients.Am J Transplant. 2013; 13: 207-213Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 2Francès C Marcelin AG Legendre CH et al.The impact of preexisting or acquired Kaposi sarcoma herpesvirus infection in kidney transplant recipients on morbidity and survival.Am J Transplant. 2009; 9: 2580-2586Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 3Pietrosi G Vizzini G Pipitone L et al.Primary and reactivated HHV8 infection and disease after liver transplantation: A prospective study.Am J Transplant. 2011; 11: 2715-2723Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar).Table 1:Summary data on HHV8 infection and related diseases, derived from two Italian transplant cohort studiesNIT-GITMO studyRER-PRU studyEnrollment period2001–20032008–2012Applied HHV8-specific assays1Patients were considered HHV8-seropositive when samples resulted + with at least two HHV8-specific assays. All recipients and donors were tested once at baseline (pre-transplant) to assess HHV8 seroprevalence in different groups and then, to identify HHV8 seroconversions, the recipients in D+/R− groups were tested at least every 4 months, for 36–48 months or until positive. Seropositive patients were monitored by HHV8 Q-PCR at least monthly.Latent IFA, lytic IFA, lytic EIA, Q-PCRLatent IFA, lytic IFA, lytic EIA, Q-PCRRecipientsNumber per organ typeHHV8 seroprevalenceNumber per organ typeHHV8 seroprevalenceKidney1037.7%Kidney26010.4%Liver16518.1%Liver22820.6%BM/PBSC998.1%Heart378.1%Total36712.5%Total52515.0%DonorsTotal3634.4%Total2494.0%HHV8 seroconversion in D+/R− group: 14.3%2Assessed in kidney recipients.HHV8 seroconversion in D+/R− group: 19.0%HHV8-related diseasesAfter primary infectionAfter reactivationAfter primary infectionAfter reactivation4KS5 KS1 PEL3 KS1 PEL1 MCD1 BM aplasiaKS, Kaposi’s sarcoma; PEL, primary effusion lymphoma; MCD, multicentric Castleman’s disease; BM, bone marrow.1 Patients were considered HHV8-seropositive when samples resulted + with at least two HHV8-specific assays. All recipients and donors were tested once at baseline (pre-transplant) to assess HHV8 seroprevalence in different groups and then, to identify HHV8 seroconversions, the recipients in D+/R− groups were tested at least every 4 months, for 36–48 months or until positive. Seropositive patients were monitored by HHV8 Q-PCR at least monthly.2 Assessed in kidney recipients. Open table in a new tab KS, Kaposi’s sarcoma; PEL, primary effusion lymphoma; MCD, multicentric Castleman’s disease; BM, bone marrow. Although HHV8 seroconversion was not infrequent in HHV8-negative patients receiving HHV8-infected grafts (D+/R− group), seroconversion rates were quite variable, ranging from 21% to 32% in the French cohorts (1Lebbe C Porcher R Marcelin AG et al.Human herpesvirus 8 (HHV8) transmission and related morbidity in organ recipients.Am J Transplant. 2013; 13: 207-213Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar,2Francès C Marcelin AG Legendre CH et al.The impact of preexisting or acquired Kaposi sarcoma herpesvirus infection in kidney transplant recipients on morbidity and survival.Am J Transplant. 2009; 9: 2580-2586Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar), showing high frequencies of HHV8 seroreversion and transient seropositivity, to 14% and 19% in our NIT-GITMO and RER-PRU cohorts, respectively (without available data on HHV8 seroreversion). Altogether, these data suggest that the detection of serum anti-HHV8 antibodies may be tricky and highly transient in posttransplant immunosuppressed patients, further exposing the actual lack of a gold-standard serological test. Moreover, this underlines the unmet clinical need for reliable and cost-effective monitoring tools, able to identify posttransplant patients at higher risk to develop HHV8 primary infection and/or HHV8-related diseases (either neoplastic or non-neoplastic). In this view, the recent surveys showed that HHV8 viremia screening by quantitative PCR, while less sensitive than serological tests to identify patients infected after transplantation, seems to become clinically useful when able to reveal the occurrence and evolution of highly-active viremic events, frequently associated with severe HHV8-related complications (1Lebbe C Porcher R Marcelin AG et al.Human herpesvirus 8 (HHV8) transmission and related morbidity in organ recipients.Am J Transplant. 2013; 13: 207-213Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 2Francès C Marcelin AG Legendre CH et al.The impact of preexisting or acquired Kaposi sarcoma herpesvirus infection in kidney transplant recipients on morbidity and survival.Am J Transplant. 2009; 9: 2580-2586Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 3Pietrosi G Vizzini G Pipitone L et al.Primary and reactivated HHV8 infection and disease after liver transplantation: A prospective study.Am J Transplant. 2011; 11: 2715-2723Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). In line with these observations, we found that less than half of seroconverted patients eventually developed at least one positive viremia (HHV8-DNA >100 copies/mL) during our long-term follow-up. Of note, we detected positive HHV8 viremias in 6 out of 16 patients with HHV8-associated diseases, due to primary infections (3/7 cases) or viral reactivations (3/9 cases), yielding a positive predictive value of 20%. In addition to serial HHV8-DNA measurements, an immunological monitoring of protective HHV8-specific T cells (recently found to be significantly associated with disease control) (4Lambert M Gannagé M Karras A et al.Differences in the frequency and function of HHV8-specific CD8 T cells between asymptomatic HHV8 infection and Kaposi sarcoma.Blood. 2006; 108: 3871-3880Crossref PubMed Scopus (58) Google Scholar,5Riva G Luppi M Barozzi P Forghieri F Potenza L. How I treat HHV8/KSHV-related diseases in posttransplant patients.Blood. 2012; 120: 4150-4159Crossref PubMed Scopus (72) Google Scholar) may also provide valuable information for the clinical management of HHV8-seropositive recipients or patients with Kaposi’s sarcoma in remission, to guide timely modifications of immunosuppressive treatments. Further investigations are warranted to define the positive predictive value of HHV8 viral loads combined with HHV8-specific T cell enumeration in high-risk HHV8-seropositive posttransplant patients. The authors thank the Gruppo Italiano Trapianto di Midollo Osseo (GITMO), the North Italian Transplant (NIT) group and Dr. Lorenza Ridolfi from the Centro Riferimento Trapianti dell’Emilia-Romagna (CRT-ER), for active collaboration. This work was supported by grants from the Regione Emilia-Romagna—Programma di ricerca Regione-Università (RER-PRU 2007–2009, to M.L.); the Associazione Italiana per la Ricerca sul Cancro (AIRC, IG 10811, to M.L.); and the Ministero dell’Istruzione, Università e della Ricerca (MIUR, PRIN2009, to M.L.). The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

The immune cell function assay (ICFA) and de novo anti-donor-specific HLA antibodies (DSA) have been proposed as assays for immune monitoring in renal transplantation, but longitudinal studies examining the modification of both parameters over time and their relation with clinical events are lacking. We prospectively measured longitudinal changes in ICFA and DSA levels in 55 kidney transplant recipients over 3-year follow-up (534 visits) and analyzed their relation with the risk of developing acute rejections or infections. Seven patients (12.7%) developed biopsy-proven acute rejection, and 20 (36.4%) developed viral infections. At 3 years posttransplant, 28% of the patients had developed de novo DSA. ICFA levels peaked at 1-2 months posttransplant (p = 0.005) and leveled off thereafter. They were not associated with the risk of acute rejections, viral infections or development of de novo DSA. Instead, the incidence of de novo DSA was higher in patients who previously had viral infections (adjusted-odds ratio of de novo DSA associated with prior infections: 6.03 [95% CI, 1.64-22.06; p = 0.007]). Our prospective, longitudinal study does not support using ICFA to quantify the immune risk in kidney transplantation. Further studies are needed to confirm the relationship between viral infections and the subsequent development of de novo DSA.