Distinct EBV and CMV reactivation patterns following antibody-based immunosuppressive regimens in patients with severe aplastic anemia

The natural history of EBV and CMV reactivation and the potential for serious complications following antibody-based immunosuppressive treatment for bone marrow failure syndromes in the absence of transplantation is not known. We monitored blood for EBV and CMV reactivation by polymerase chain reaction (PCR) weekly in 78 consecutive patients (total of 99 immunosuppressive courses) with aplastic anemia. Four regimens were studied: (1) HC, horse ATG/cyclosporine; (2) HCS, horse ATG/CsA/sirolimus; (3) RC, rabbit ATG/CsA; and (4) CP, alemtuzumab. There were no cases of EBV or CMV disease, but EBV reactivation occurred in 82 (87%) of 94 and CMV reactivation in 19 (33%) of 57 seropositive patients after starting immunosuppression. The median peak EBV copies were higher in the RC group when compared with HC, HCS, and alemtuzumab (P < .001). The median duration of PCR positivity for EBV was higher in the RC group compared with HC, HCS, and alemtuzumab (P = .001). Subclinical reactivation of both EBV and CMV is common and nearly always self-limited in patients with bone marrow failure receiving immunosuppression; different regimens are associated with different intensity of immunosuppression as measured by viral load and lymphocyte count; and viral reactivation patterns differ according to immunosuppressive regimens.     

Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma

We compared antithymocyte globulin (ATG) with alemtuzumab in 73 patients with multiple myeloma, who underwent reduced conditioning with melphalan/fludarabine, followed by allogeneic stem cell transplantation from human leucocyte antigen-matched or -mismatched unrelated donors. The ATG group had more prior high-dose chemotherapies (P < 0.001), while bone marrow was used more as the stem cell source in the alemtuzumab group (P < 0.001). Alemtuzumab resulted in faster engraftment of leucocytes (P = 0.03) and platelets (P = 0.02) and in a lower incidence of acute graft versus host disease (GvHD) grades II-IV (24% vs. 47%, P = 0.06). More cytomegalovirus (CMV) seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs. 47%, P = 0.001). The cumulative incidence of treatment-related mortality at 2 years was 26% [95% confidence interval (CI) = 12-37%] for ATG vs. 28% (95% CI = 15-55%) for alemtuzumab, P = 0.7. There was no significant difference in the estimated 2-year overall and progression-free survival between ATG and alemtuzumab: 54% (95% CI: 39-75%) vs. 45% (95% CI: 28-73%) and 30% (95% CI: 16-55%) vs. 36% (95% CI: 20-62%) respectively. In multivariate analysis, treatment with alemtuzumab had a higher risk for relapse (hazard ratio: 2.37; P = 0.05) while killer immunoglobulin-like receptor (KIR)-ligand mismatch was protective for relapse (P < 0.0001). We conclude that alemtuzumab produced less acute GvHD, but higher probability of relapse. The data implicated a major role of KIR-ligand mismatched transplantation in multiple myeloma.     

Immune reconstitution to cytomegalovirus following partially matched‐related donor transplantation: impact of in vivo T‐cell depletion and granulocyte colony‐stimulating factor‐primed peripheral blood/bone marrow mixed grafts

Cytomegalovirus (CMV) infection and delayed immune reconstitution remains a serious obstacle for successful partially matched‐related donor transplantation (PMRD). We evaluated 42 patients for the development of CMV‐specific CD8+ T lymphocytes (CTL_CMV) following granulocyte colony‐stimulating factor‐primed peripheral blood (PB) and bone marrow (BM) with anti‐thymocyte globulin (ATG)‐based PMRD. PMRD recipients achieved a high frequency, proliferation capacity, and interferon‐γ response of CTL_CMV at 1 year post transplantation. CTL_CMV with the central memory CD45RO+CD62L+ cell phenotype expanded in PB and BM‐resident CTL_CMV displayed distinct phenotypes when CMV was reactivated. Although the incidence of CMV reactivation was high in PMRD patients (87.67%), only 11.90% of them developed CMV disease. In conclusion, after PMRD using mixed grafts with ATG‐based conditioning, immune recovery to CMV seems to be early and fast, thereby reducing the incidence of CMV disease.     

Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: Real‐world experience

Cytomegalovirus (CMV) is associated with significant morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) patients. We evaluated the efficacy of letermovir as primary and secondary prophylaxis in 53 CMV‐seropositive hematopoietic stem cell transplant recipients. 70% of patients were at high risk for CMV reactivation and disease (primarily ex vivo T‐cell–depleted HCT [n = 18; 34%] or haploidentical T‐replete HCT [n = 12; 23%]). This was a retrospective, single‐center study which identified patients transplanted between January 2018 and June 2018. Patients were followed through September 2018. The primary outcome was the incidence of clinically significant CMV infection (CMV viremia requiring preemptive treatment or CMV disease). Primary letermovir prophylaxis started at a median of 7 days (range, 7‐40) after allo‐HCT. The median duration of primary letermovir prophylaxis was 116 days (range, 12‐221). With primary prophylaxis in 39 patients, the observed CMV reactivation rate was 5.1%. Twenty‐nine patients continued primary prophylaxis beyond 14 weeks with a reactivation rate of 3.4%. No recurrent reactivation was seen with secondary prophylaxis of an additional 14 patients. Our experience demonstrates the efficacy of letermovir in a real‐world setting for CMV prevention for the first 14 weeks and continued efficacy when given longer than 14 weeks after allogeneic stem cell transplantation or as secondary prophylaxis.     

L‐index as a novel index to evaluate both the intensity and duration of lymphopenia after allogeneic hematopoietic stem cell transplantation

We retrospectively investigated L‐index, which evaluates both the intensity and duration of lymphopenia after allogeneic hematopoietic stem cell transplantation (HSCT) (n = 50). L‐index was defined as the area over the lymphocyte curve during lymphopenia (absolute lymphocyte count < 700/μL). We calculated the L‐index from the start of conditioning to day 30 – L‐index(30) – and to day 100 – L‐index(100) – after HSCT. Multivariate analysis revealed that human leukocyte antigen mismatched donor, female gender, and non‐lymphoid disease were significantly associated with high L‐index(30). Grade III–IV acute graft‐versus‐host disease, alemtuzumab‐containing regimen, and non‐lymphoid disease were identified as independent significant factors for high L‐index(100). Cytomegalovirus (CMV) antigenemia was detected > 3 cells/2 slides by C10/11 method in 30 patients (CMV‐AG ≥ 3 group) and was not detected in 20 patients (CMV‐AG < 3 group). Although no significant difference was seen in absolute lymphocyte count on day 30 between the 2 groups, the L‐index(30) was significantly higher in the CMV‐AG ≥ 3 group than in the CMV‐AG < 3 group (P = 0.050). L‐index(30) was identified as an independent factor on CMV reactivation in multivariate analysis, when it was treated as a dichotomous variable with a cut‐off value of 22,318, determined by receiver operating characteristic curve analysis. In conclusion, both the intensity and duration of lymphopenia in early phase after HSCT evaluated on the basis of L‐index(30) showed significant association with CMV reactivation.     

Low-dose alemtuzumab vs. standard policy for prevention of graft-versus-host disease in unrelated and related allogeneic stem cell transplantation—a matched pair analysis

Antibody-mediated in vivo T cell depletion is common prior to unrelated (URD) or mismatched allogeneic stem cell transplantation (alloSCT) and optional in HLA-identical sibling (FAM) alloSCT. While anti-thymocyte globulin (ATG) is the current standard, alemtuzumab is an alternative. The optimal dose of alemtuzumab has not been defined. This retrospective analysis compares low-dose alemtuzumab with ATG in URD alloSCT and with no antibody in FAM alloSCT. Twenty-eight patients treated with alemtuzumab (10 mg; HLA mismatch, 20 mg) were matched to 28 patients who have either received ATG (URD) or no antibody (noAB) according to disease, disease stage, age, transplant type and risk state. Both groups were compared for engraftment, outcome, disease-free (DFS) and overall survival (OS), graft-versus-host disease (GvHD), freedom from GvHD (ffGvHD) and transplant-related mortality (TRM). No significant differences were found between the groups for leukocyte engraftment, GvHD, ffGvHD, TRM, DFS and OS. There was a trend for reduction of cGvHD by alemtuzumab (p?=?0.05). A transplant-type stratified subanalysis consolidated equivalency of alemtuzumab and ATG in URD-SCT and indicates possible superiority of low-dose alemtuzumab compared to noAB in FAM-SCT. Low-dose alemtuzumab, as part of conditioning regimen prior to alloSCT, is safe and comparable to standard ATG. Prospective trials, particularly comparing alemtuzumab vs. noAB in FAM alloSCT, should be conducted.     

Immune reconstitution and cytomegalovirus infection after allogeneic stem cell transplantation: the important impact of in vivo T cell depletion

We analyzed cytomegalovirus (CMV) infection risk factors and immune reconstitution kinetics in 89 patients after allogeneic stem cell transplantation (allo-SCT). The use of alemtuzumab for in vivo T cell depletion (TCD) had, besides the donor/recipient CMV serostatus, the strongest influence on the CMV infection risk in univariate and multivariate analyses. In comparison to without use of in vivo TCD, the CMV infection risk [hazard ratio (HR)] was 4.82-fold after TCD with alemtuzumab, but only 1.40-fold after TCD with antithymocyte globulin (ATG). Alemtuzumab strongly depressed CD4⁺ and CD8⁺ T cell reconstitution, whereas ATG only delayed CD4⁺ T cell reconstitution. Considering the reconstitution kinetics of CD4⁺ and CD8⁺ T cells, CMV-specific CD8⁺ T cells, NK cells and the IgG concentration, only a low day +60 NK cell count (≤161 versus >161/μl) was significantly associated with CMV infection development (HR 2.92, p = 0.034). CMV-specific CD8⁺ T cells were detected in 57% of patients with a CMV-seropositive donor, but in none of the patients with a CMV-seronegative donor on day +30 (p = 0.01). Our data indicate that the type of in vivo TCD (alemtuzumab or ATG) differentially influences both the CMV infection risk and CD4⁺/CD8⁺ T cell reconstitution kinetics in patients after allo-SCT.     

Effect of ATG‐F on B‐cell reconstitution after hematopoietic stem cell transplantation

Antithymocyte globulin Fresenius (ATG‐F) is used before hematopoietic stem cell transplantation to prevent graft rejection and graft‐versus‐host disease in patients with HLA‐matched unrelated donors or mismatched volunteers. However, little is known about the effect of ATG‐F on the reconstitution of B‐cell subsets. Sixty‐seven patients were longitudinally studied at day 15, day 30, and then monthly after hematopoietic stem cell transplantation. Conditioning regimes included ATG‐F, which was infused at days 3, 2 and 1 at a dosage of 10 mg/kg/d. Twenty‐seven patients received conditioning regimes without ATG. ATG‐treated patients showed a significant delay of CD19+ B cells in the early recovery period. The absolute numbers of circulating CD19+ B cells were significantly lower (P < 0.05) up to 5 months post‐transplantation compared to non‐ATG patients. The recovery of the memory compartment was delayed in both groups and did not reach normal values 1‐year post‐transplantation. ATG‐treated patient showed significantly lower absolute numbers of circulating CD27+ memory B cells in the first‐month after transplantation compared to non‐ATG patients. In conclusion, treatment with ATG in the conditioning regime of patients undergoing allogeneic hematopoietic stem cell transplantation leads to a significant delay of CD19+ B cells. Thus, ATG seems also to negatively influence B‐cell immune reconstitution.     

Recipient‐donor KIR ligand matching prevents CMV reactivation post‐haploidentical T cell‐replete transplantation

Licensed natural killer (NK) cells have been demonstrated to have anti‐cytomegalovirus (CMV) activity. We prospectively analysed the human leucocyte antigen typing of donor‐recipient pairs and the killer cell immunoglobulin–like receptor (KIR) typing of donors for 180 leukaemia patients to assess the predictive roles of licensed NK cells on CMV reactivation post‐T‐cell‐replete haploidentical stem cell transplantation. Multivariate analysis showed that donor‐recipient KIR ligand graft‐versus‐host or host‐versus‐graft direction mismatch was associated with increased refractory CMV infection (Hazard ratio = 2·556, 95% confidence interval, 1·377–4·744, P = 0·003) post‐transplantation. Donor‐recipient KIR ligand matching decreased CMV reactivation [51·65% (46·67, 56·62%) vs. 75·28% (70·87, 79·69%), P = 0·012], refractory CMV infection [17·58% (13·77, 21·40%) vs. 35·96% (31·09, 40·82%), P = 0·004] and CMV disease [3·30% (1·51, 5·08%) vs. 11·24% (8·04, 14·43%), P = 0·024] by day 100 post‐transplantation. In addition, the percentage of γ‐interferon expression on donor‐derived NK cells was significantly higher in the recipients among the recipient‐donor pairs with a KIR ligand match compared with that in the recipients among the pairs with a KIR ligand graft‐versus‐host or host‐versus‐graft direction mismatch on days 30 and 100 post‐transplantation (P = 0·036 and 0·047, respectively). These findings have suggested that donor‐recipient KIR ligand matching might promote the NK cell licensing process, thereby increasing NK cell‐mediated protection against CMV reactivation.     

Impact of early NK cell recovery on development of GvHD and CMV reactivation in dose-reduced regimen prior to allogeneic PBSCT

Dose-reduced allogeneic peripheral blood stem cell transplantation (PBSCT) is a therapeutic approach for patients with haematological malignancies who are not eligible for conventional allogeneic PBSCT. We analysed early development of lymphocyte subpopulations and the occurrence of cytomegalovirus (CMV) reactivation and acute graft-versus-host reaction (GvHD) in patients undergoing the protocol according to Slavin vs conventionally treated patients. Lymphocyte status prior to conditioning and at day +30 after allogeneic PBSCT was determined in 24 out of 51 patients who received conventional allogeneic PBSCT (eg cyclophosphamide plus total body irradiation) and compared with 27 patients being treated according to the Slavin protocol (fludarabine, busulphan and ATG). There is a significant delay in CD4 (T helper) cell development and consecutive lower CD4/CD8 ratios and a better reconstitution of CD8 (T cytotoxic) and NK (natural killer) cells after the Slavin protocol. Patients undergoing this protocol and no, or only grade I, acute GvHD show an even better NK cell reconstitution compared to patients with grade II-IV GvHD. A low CD4/CD8 ratio represents a CMV risk factor only in conventionally treated patients with grade 0-I GvHD, while after preparative regimen according to the Slavin protocol, the NK/CD8 ratio might be a marker for the prediction of CMV reactivation in addition to CMV risk status.     

Cytomegalovirus appendicitis after hematopoietic stem cell transplantation

We present the case of a young man with acute lymphoblastic leukemia who developed cytomegalovirus (CMV) appendicitis after receiving alemtuzumab for acute refractory graft‐versus‐host disease after allogeneic hematopoietic stem cell transplantation (HSCT). CMV appendicitis is a rare complication; and we are reporting the first case to our knowledge of CMV appendicitis following HSCT. Our case highlights the importance of recognition of CMV viral reactivation following the use of alemtuzumab. Using a preemptive strategy of checking CMV PCR, with initiation of early effective treatment on detection of CMV replication, may be appropriate following use of alemtuzumab in hematologic malignancies in patients after HSCT.     

Infectious complications associated with alemtuzumab use for allogeneic hematopoietic stem cell transplantation: comparison with anti-thymocyte globulin

Objectives. To evaluate the incidence of infectious complications after receiving alemtuzumab as part of a conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in Korean patients.
Methods. From November 2004 to January 2006, 12 patients who received alemtuzumab-based conditioning regimens for allogeneic HSCT were evaluated retrospectively until death or until the end of the follow-up in July 2007; they were compared with 18 patients who received rabbit anti-thymocyte globulin (ATG)-containing conditioning regimens from January 2002 to January 2006.
Results. Post-engraftment infections occurred more frequently in the alemtuzumab recipients than in the ATG recipients; the mean number of infections, excluding cytomegalovirus (CMV) infections, per patient during the follow-up period was 2.6±1.4 vs. 1.0±0.8 ( P =0.003), respectively. Although there was no statistical difference in the cumulative incidence of CMV  infection between the 2 groups (91.7% vs. 55.6%, P =0.381), the alemtuzumab recipients had a higher incidence of CMV  diseases (41.6% vs. 0%, P =0.0006) and a higher recurrence rate of CMV infection (90.0% vs. 27.3%, P =0.008) than did the ATG recipients, irrespective of the dose of alemtuzumab. Hemorrhagic cystitis (HC) (66.7% vs. 16.7%, P =0.009) and BK virus-associated HC (41.7% vs. 5.6%, P =0.026) developed more frequently in the alemtuzumab recipients. The all-cause mortality rate was not significantly different between the alemtuzumab and the ATG recipients (75% vs. 55.6%, P =0.28).
Conclusion. Alemtuzumab recipients had a high incidence of CMV disease as well as BK virus-associated HC compared with the ATG recipients. The dose of alemtuzumab should be tailored to patients' risk; in addition, the implementation of the appropriate prophylaxis for CMV and early detection strategies for BK virus are recommended.     

Safety of pre‐engraftment prophylactic foscarnet administration after allogeneic stem cell transplantation

K. Ishiyama, T. Katagiri, K. Ohata, K. Hosokawa, Y. Kondo, H. Yamazaki, A. Takami, S. Nakao. Safety of pre‐engraftment prophylactic foscarnet administration after allogeneic stem cell transplantation. Transpl Infect Dis 2011. All rights reserved Abstract: Human herpesvirus‐6 (HHV‐6) is a major cause of limbic encephalitis with a dismal prognosis after allogeneic hematopoietic stem cell transplantation (SCT). Because our previous trial of preemptive therapy with foscarnet sodium (phosphonoformic acid; PFA) failed to prevent HHV‐6 encephalitis, we conducted a prospective study to examine the safety of prophylactic PFA administration and elucidate the changes in the plasma HHV‐6 DNA levels in the early post‐SCT period. Plasma HHV‐6 DNA was measured thrice weekly from day 6. PFA, 90 mg/kg/day, was administered from days 7 to 21 after bone marrow or peripheral blood SCT and to day 25 after umbilical cord blood transplantation. Of the 10 patients enrolled, 2 dropped out of the study, 1 because of early death, and 1 with a low glomerular filtration rate. Grade 3 or greater adverse events occurred in 9 of the 10 prophylactic PFA patients and in 7 of the 10 control patients who had clinical backgrounds similar to the study subjects and underwent SCT during the same period. Neurological disorders developed in none of the study subjects but in 4 of the 10 control patients, including 2 with HHV‐6 encephalitis. HHV‐6 reactivation occurred in 3 of the 10 study subjects. The prophylactic PFA regimen was thus safe and it may reduce the risk of limbic encephalitis, but is not considered to be potent enough to prevent HHV‐6 reactivation.     

Evaluation of risk of symptomatic cytomegalovirus reactivation in myeloma patients treated with tandem autologous stem cell transplantation and novel agents: a single‐institution study

The introduction of proteasome inhibitors and/or immunomodulators in the treatment of myeloma has led to an increase in viral infections, particularly in the Herpesviridae family. Previous studies about the risk of cytomegalovirus (CMV) reactivation after autologous stem cell transplantation (ASCT) have examined the clinical outcome after the first ASCT; however, only 1 study to date has investigated the risk of CMV reactivation after a second transplantation. To address this issue, we performed a retrospective chart review on 78 consecutive myeloma patients (median age 56 years) who underwent a tandem non‐CD34⁺ selected ASCT after induction treatment with either conventional chemotherapy (n = 42) or with novel agents (n = 36), respectively. All subjects had been mobilized and conditioned with cyclophosphamide plus granulocyte colony‐stimulating factor and melphalan alone, respectively. CMV DNA load in the blood has been determined by polymerase chain reaction in the case of a clinical suspicion of CMV reactivation; therefore, routine monitoring was not performed. Considering the outcome of both the first and the second transplantations, we observed a total of 13 episodes of symptomatic CMV reactivation (13/156, 8%), in 12 subjects (12/78, 15%), all successfully treated. Eight subjects experienced a CMV reactivation after the first ASCT (8/78, 10%); however, only 1 of them (1/8, 12%) experienced a CMV reactivation after the second transplantation. Conversely, 4 CMV reactivations (6%) were observed after the second transplantation in the group of 70 patients who did not experience a CMV reactivation after the first ASCT. No statistically significant difference was observed between first and second ASCT (8/78, 10% vs. 5/78, 6%; P = 0.767). Univariate analysis showed that a pre‐transplant treatment with novel agents was the only baseline factor significantly associated with the occurrence of post‐ASCT CMV symptomatic reactivation after the first transplant (odds ratio [OR]: 9.897; 95% confidence interval [CI]: 1.154–84.840; P = 0.021) but not after the second transplant (OR: 5.125; 95% CI: 0.546–48.119; P = 0.115). No end‐organ disease or primary infection was documented. Our data suggest that second transplantation does not increase the risk of CMV reactivation in our patient population, when compared with the first one, and confirm the role of a pre‐transplant treatment with novel agents as a risk factor for CMV symptomatic reactivation.     

Surveillance of active human cytomegalovirus infection in hematopoietic stem cell transplantation (HLA sibling identical donor): search for optimal cutoff value by real-time PCR

Background  

Human cytomegalovirus (CMV) infection still causes significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, it is extremely important to diagnosis and monitor active CMV infection in HSCT patients, defining the CMV DNA levels of virus replication that warrant intervention with antiviral agents in order to accurately prevent CMV disease and further related complications.     

Epstein-Barr virus reactivation in a patient treated with anti-thymocyte globulin for severe aplastic anemia

Epstein-Barr virus (EBV) infection and reactivation is an increasing complication in immune deficient patients, particularly after allogeneic hematopoietic stem cell transplantation (HSCT). Therapy with anti-thymocyte globulin (ATG) is associated with higher incidence of EBV-related disease in HSCT patients, but this risk is not documented in patients receiving ATG for severe aplastic anemia (SAA). We describe the case of a patient who developed an EBV infection, with the clinical features of an infectious mononucleosis, after immune suppression with cyclosporine and two courses of ATG for SAA.     

Systemic lupus erythematosus in adults is associated with previous Epstein‐Barr virus exposure

Objective

The possible molecular mimicry of the Epstein‐Barr virus (EBV) peptide PPPGRRP by the peptide PPPGMRPP from Sm B′/B of the human spliceosome is consistent with the possibility that EBV infection is related to the origin of systemic lupus erythematosus (SLE) in some patients. Association of EBV exposure with SLE was therefore tested for and subsequently found in children and adolescents (odds ratio [OR] 49.9, 95% confidence interval [95% CI] 9.3–1,025, P < 10⁻¹¹). These results were confirmed at the level of EBV DNA (OR > 10, 95% CI 2.53–∞, P < 0.002). Much smaller seroconversion rate differences were found against 4 other herpes viruses. Herein, we extend these studies to adults and test the hypothesis that EBV infection is associated with adult SLE.

Methods

We selected 196 antinuclear antibody–positive adult SLE patients (age ≥20 years) and 2 age‐, race‐, and sex‐matched controls per patient. SLE patients and matched controls were tested for evidence of previous infection with EBV, cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV‐1 and HSV‐2), or varicella‐zoster virus (VZV) by standardized enzyme‐linked immunosorbent assays.

Results

Of the 196 lupus patients tested, all but 1 had been exposed to EBV, while 22 of the 392 controls did not have antibodies consistent with previous EBV exposure (OR 9.35, 95% CI 1.45–∞, P = 0.014). No differences were observed between SLE patients and controls in the seroconversion rate against CMV, HSV‐2, or VZV.

Conclusion

These new data from adults, along with the many suggestive features of EBV infection, are consistent with the contribution of this infection to the etiology of SLE.

     

HHV‐6 in liver transplantation: A literature review

Human herpesvirus 6 (HHV‐6A and HHV‐6B) can cause primary infection or reactivate from latency in liver transplant recipients, which can result in a variety of clinical syndromes, including fever, hepatitis, encephalitis and higher rates of graft dysfunction as well as indirect effects including increased risks of mortality, CMV disease, hepatitis C progression and greater fibrosis scores. Although HHV‐6 infection is currently diagnosed by quantifying viral DNA in plasma or blood, biopsy to demonstrate histopathological effects of HHV‐6 remains the gold standard for diagnosis of end‐organ disease. HHV‐6 reactivation may be restricted to the infected organ with no evidence of active infection in the blood. HHV‐6 infections in liver transplant patients are mostly asymptomatic, but clinically significant tissue‐invasive infections have been treated successfully with ganciclovir, foscarnet or cidofovir. Inherited chromosomally integrated HHV‐6 (ciHHV‐6), in either the recipient or the donor organ, may create confusion about systemic HHV‐6 infection. Recipients with inherited ciHHV‐6 may have an increased risk of opportunistic infection and graft rejection. This article reviews the current scientific data on the clinical effects, risk factors, pathogenesis, diagnosis and treatment of HHV‐6 infections in liver transplant recipients.     

The use of ATG abrogates the antileukemic effect of cytomegalovirus reactivation in patients with acute myeloid leukemia receiving grafts from unrelated donors

Several studies provided evidence of a consistent antileukemic effect induced by cytomegalovirus (CMV) replication in acute myeloid leukemia (AML) patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), however the use of antithymocyte globulin (ATG) as graft‐versus‐host disease prophylaxis, may potentially abrogate the protective effect of CMV infection. To address this issue, we retrospectively analyzed the risk of relapse in a cohort of 101 patients with AML who received grafts from an unrelated donor after a conditioning regimen including ATG. The cumulative incidence of CMV reactivation, evaluated by RT qPCR, was 59% at 12 months, and 93% of CMV reactivations occurred within the first 100 days post HSCT. The 5‐year cumulative incidence of relapse in patients with CMV reactivation was 29% compared with 37% for patients without CMV reactivation, and the only factor associated with a reduced 5‐year cumulative incidence of relapse was the disease status at HSCT (P < 0.001). In the multivariable model adverse cytogenetics (HR 2.42, 95% CI 1.02‐5.72; P = 0.044) and acute GVHD (HR 3.36, 95% CI 1.32‐8.54; P = 0.011) were independent risk factors for reducing overall survival (OS), while the presence of chronic GVHD was associated with a better OS (HR 0.37, 95% CI 0.15‐0.89; P = 0.027). CMV replication was not an independent risk factor for OS (HR 1.06, 95% CI 0.07‐15.75; P = 0.965). In Conclusion, the results of present study suggest that relapse prevention in patients with AML receiving T‐cell depleted HSCT using ATG do not benefit from CMV reactivation. Am. J. Hematol. 90:E117–E121, 2015. © 2015 Wiley Periodicals, Inc.