Analysis of the shedding of three β-herpesviruses DNA in Polish patients subjected to allogeneic hematopoietic stem cell transplantation: Six-year follow up

BackgroundInfections with human β-herpesviruses are common worldwide and are still frequent in patients after hematopoietic stem cell transplantation. Some data suggest that HHV-6 and HHV-7 could take part in CMV reactivation from latency and/or progression of CMV disease in immunosupressed patients.ObjectivesThe aims of this study were: (1) to summarise retrospectively the results of β-herpesviruses DNA detection in a large group of adult allogeneic haematopoietic stem cell transplant recipients; and (2) to find a potential correlation between viruses belonging to this subfamily.Study designAlloHSCT recipients (N = 142) were examined in the early post-transplant period (median = 89 days). The presence of CMV, HHV-6 and HHV-7 was confirmed through detection and quantification of viral DNA, isolated from 1679 sera samples.ResultsCMV DNA alone was detected in 23.9% of patients, while single HHV-6 and HHV-7 were detected in 14.8% and 9.9% of individuals, respectively. The reactivation of more than one virus was identified in 31% of analysed patients. In cases of concurrent infection, HHV-7 was detected at the same time as HHV-6, and both of them were usually reactivated before CMV. The kinetics of virus reactivation and measured viral load may suggest a potential role of HHV-6 and HHV-7 as co-factors in CMV reactivation.ConclusionsThe observed kinetics of virus reactivation may strongly suggest a potential role of HHV-6 and/or HHV-7 as co-factors of CMV reactivation. The co-infection with these β-herpesviruses could predispose patients after hematopoietic stem cell transplantation to a longer and more severe CMV infection.     

The impact of human herpesvirus 6B reactivation on early complications following allogeneic hematopoietic stem cell transplantation.

Although human herpesvirus 6 (HHV-6) has been considered an important opportunistic and potentially fatal pathogen for allogeneic hematopoietic stem cell transplantation (HSCT), the clinical significance of HHV-6 reactivation remains controversial. In this study, we monitored HHV-6 DNAemia in 72 consecutive allogeneic HSCT recipients by real-time quantitative polymerase chain reaction. A total of 680 peripheral blood specimens were collected from the recipients before HSCT or at weekly intervals after HSCT. As the predominant variant, HHV-6B was detectable at least once in 47.2% (34/72) of HSCT recipients on the median day 21 (range, 7-84 days); HHV-6A reactivation occurred in only 1 recipient (1.4%). Detectable HHV-6B reactivation was associated with increased probability of skin rash by day 30 after HSCT (hazard ratio [HR], 3.68; 95% confidence interval [CI], 1.24-10.92; P = .019), cytomegalovirus (CMV) antigenemia (HR, 2.35; 95%CI, 1.32-4.19; P = .004), and hemorrhagic cystitis (HC) (HR, 2.59; 95%CI, 0.96-6.98; P = .061) by day 100 after HSCT. Neutrophil and platelet engraftment, mortality for 100 days after HSCT were not affected by HHV-6B reactivation. In conclusion, HHV-6 reactivation is a common event, and this study demonstrates a correlation between HHV-6B infection and CMV reactivation, early rash, and possibly increased incidence of HC after transplantation.     

Human cytomegalovirus, human herpesvirus-6 and human herpesvirus-7 in neutropenic patients with fever of unknown origin

Objective  To investigate the appearance of cytomegalovirus (CMV) DNA, human herpesvirus-6 (HHV-6) DNA and human herpesvirus-7 (HHV-7) DNA in plasma as a sign of reactivation and possible causes of fever of unknown origin (FUO) during neutropenia.
Methods  From 134 patients with febrile neutropenia following cytotoxic chemotherapy during the years 1996–2000, 20 severely neutropenic patients (granulocyte count < 0.1 × 10⁹/L) were selected. Ten were patients with bacteremia and ten were patients with FUO. Five samples from each patient were selected at the start of chemotherapy, at the time of blood culture and fever, after 24 and 48 hours of fever, and, finally, after two to three days without fever. Virus DNA was detected by real-time quantitative and nested polymerase chain reaction (PCR).
Results  CMV-DNA was detected in two out of ten FUO-patients in all samples drawn during fever. From another FUO and during two bacteremia episodes, CMV-DNA was detected after 48 hours of fever. DNA from HHV-6 and HHV-7 was not detected in any of the 20 febrile episodes.
Conclusions  HHV-6 and HHV-7 as a possible explanation for FUO in severely neutropenic patients treated with cytotoxic chemotherapy seems not be very likely. However, CMV was identified in 5/20 patients and the febrile episodes in the two FUO-patients with constant DNA-emia may have been caused by a reactivation of CMV. This implies that CMV infection can be expected not only in transplant patients but also in chemotherapy-treated neutropenic patients.     

Quantification of adenovirus DNA in unrelated donor hematopoietic stem cell transplant recipients

BACKGROUND: Adenovirus (AdV) infection is a life threatening condition in immunosuppressed patients. Quantitative AdV assays can improve the clinical management of these patients. OBJECTIVES: To evaluate quantitative measurement of AdV DNA with PCR in blood from hematopoietic stem cell transplant (HSCT) recipients. STUDY DESIGN: Quantitative PCR was used to measure viral DNA levels of AdV in consecutive blood samples from 40 HSCT recipients (27 adults and 13 children) during a 1-year post-engraftment period. All patients received grafts from unrelated donors and were given anti-T-cell antibodies in the conditioning regimen. RESULTS: In the group of 40 patients, six (15%) had detectable AdV DNA in blood for different lengths of time. None of these six patients suffered from severe graft-versus-host disease. In three of the patients a high AdV viral load (>10,000copies/mL) was detected, one of whom also had high viral load of EBV and CMV and one of EBV only. These three patients died within 2 months after detection of ADV viremia. A low AdV viral load (<500copies/mL) was detected in three surviving patients and they did not have concomitant high viral load of neither CMV nor EBV. CONCLUSIONS: AdV viremia was present in 15% of the HSCT recipients and a high AdV viral load was associated with fatal outcome. Screening for AdV DNA with quantitative PCR in blood may be of clinical importance in allogeneic HSCT recipients in order to prevent severe clinical virological complications.     

High incidence of cytomegalovirus, human herpesvirus-6, and Epstein-Barr virus reactivation in patients receiving cytotoxic chemotherapy for adult T cell leukemia

The etiology of cytomegalovirus (CMV), human herpesvirus-6 (HHV-6), and Epstein-Barr virus (EBV) reactivation and the potential for complications following cytotoxic chemotherapy in the absence of allogeneic transplantation are not clearly understood. Patients with adult T cell leukemia (ATL) are susceptible to opportunistic infections. In this study, the incidence, kinetics and clinical significance of reactivation of CMV, HHV-6, and EBV in ATL patients were investigated. Viral DNA in a total of 468 plasma samples from 34 patients was quantified using real-time PCR. The probability of CMV, HHV-6, and EBV reactivation by 100 days after the start of chemotherapy was 50.6%, 52.3%, and 21.6%, respectively. Although most CMV reactivations were self-limited, plasma CMV DNA tended to persist or increase if the CMV DNA levels in plasma reached ≥ 10(4) copies/ml. CMV reactivation was negatively associated with survival, but the P-value for this association was near the borderline of statistical significance (P=0.052). One patient developed fatal interstitial pneumonia concomitant with peak CMV DNA accumulation (1.6 × 10(6) copies/ml plasma). Most HHV-6 and EBV reactivations were self-limited, and no disease resulting from HHV-6 or EBV was confirmed. HHV-6 and EBV reactivation were not associated with reduced survival (P=0.35 and 0.11, respectively). These findings demonstrated that subclinical reactivation of CMV, HHV-6, and EBV were common in ATL patients receiving chemotherapy. There were differences in the viral reactivation patterns among the three viruses. A CMV load ≥ 10(4) copies/ml plasma was indicative of subsequent exacerbation of CMV reactivation and developing serious clinical course.     

儿童造血干细胞移植患者人巨细胞病毒与疱疹病毒6型感染及相互关系

目的 了解儿童造血干细胞移植患者术后人巨细胞病毒与疱疹病毒6型的感染情况以及相互关系.方法 患者为2007年6月至2009年10月间北京儿童医院血液病中心的造血干细胞移植的患儿,患儿术后每周采集外周静脉血,分别应用荧光定量PCR和常规PCR检测患者血清中CMV DNA载量及外周全血中HHV-6,并对HHV-6进行分型.结果 共52例造血干细胞移植患者,636份标本.20例造血干细胞移植患者共52份标本CMV-DNA检测阳性,中位检出时间为术后56d.CMV感染的总发生率为38.5%（20/52）.其中异基因造血干细胞移植CMV感染的发病率为47.6%（20/42）,晚发性CMV感染的发生率为22.2%（6/27）.3例CMV感染患者死亡,其中2例诊断CMV间质性肺炎.14例患者共33份血标本HHV-6 PCR阳性,中位检出时间为术后23d,HHV6感染的总发生率为26.9%（14/52）,其中异基因HSCT患者HHV6感染的发生率为31%（13/42）,且均为B型.20例CMV阳性的造血干细胞移植患者中,有6例发生CMV感染,HHV-6与CMV共感染率为30%（6/20）.结论 儿童造血干细胞移植患者术后CMV感染率和HHV-6感染率均较高,造血干细胞移植术后发生较早的HHV-6感染和发生较晚的CMV感染之间的关系有待进一步研究.     

Development of the loop-mediated isothermal amplification method for rapid detection of cytomegalovirus DNA

Cytomegalovirus (CMV) loop-mediated isothermal amplification (LAMP) was performed on DNA extracted from CMV (AD-169)-, herpes simplex virus (HSV) 1 (KOS)-, HSV-2 (186)-, varicella-zoster virus (Oka-vaccine)-, human herpesvirus (HHV)-6 A (U1102)-, HHV-6 B (Z29)-, and HHV-7 (RK)-infected cells. Although amplified CMV demonstrated typical ladder patterns, no LAMP product was detected in reactions performed with other viral DNAs. The sensitivity of the CMV LAMP was 500 copies/tube, as determined by either agarose gel electrophoresis or turbidity assay. To determine whether CMV LAMP could be used for quantitative analysis of viral DNA, threshold times, defined as the time (in seconds) to reach the threshold level (0.1), were measured by amplification of serial dilutions of the plasmid DNA. The standard curve exhibited a correlation coefficient of 0.944, a slope of -208.1, and a y-intercept of 3261.4. Following these initial validation experiments, we analyzed 180 samples collected serially from 20 pediatric hematopoietic stem cell transplant recipients. Detection of CMV DNA in whole blood (WB) was tested by CMV LAMP and real-time polymerase chain reaction (PCR). When >500 copies/tube (>5000 copies/200 microl of WB) was defined as positive for CMV infection, the sensitivity, specificity, positive predictive value, and negative predictive values of the CMV LAMP were 80.0, 98.9, 66.7, and 99.4%, respectively.     

Detection of beta-herpesviruses in allogenic stem cell recipients by quantitative real-time PCR

The aim of this study was to investigate the clinical impact of reactivation of human herpes virus-6 (HHV-6) and HHV-7 infections in stem cell transplantation recipients, and to examine a possible increase in virulence of the two roseoloviruses when a reactivation of CMV (HHV-5) simultaneously occurs. For this purpose, quantitative real-time PCR systems were developed to assess the viral load of CMV, HHV-6, or HHV-7 in the plasma of haematopoetic stem cell recipients. One hundred and ninety-eight plasma samples from 37 patients who underwent allogeneic stem cell transplantation were tested for CMV, HHV-6, and HHV-7 by a 5'-exonuclease (TaqMan) quantitative real-time PCR. The CMV load obtained by the real-time PCR assay was compared retrospectively with results generated previously with a commercially available test (COBAS AMPLICOR CMV MONITOR Test, Roche). The results suggest that CMV and HHV-6 may be associated with post-transplantation end-organ disease, while HHV-7 reactivation had no impact on the patients included in this study. No evidence for a potential interaction of the roseoloviruses and CMV infections was found.     

Impact of Anti-CMV IgG Titers and CD34 Count Prior to Hematopoietic Stem Cell Transplantation from Alternative Donors on CMV reactivation

Cytomegalovirus (CMV) reactivation remains one of the main infectious complications following hematopoietic stem cell transplantation (HSCT). In this study, we explored the role of anti-CMV antibody titers in HSCT from alternative donors and to compare the risk of CMV reactivation between posttransplant cyclophosphamide-based haploidentical HSCT and antithymocyte globulin-based unrelated donor (URD) HSCT. We included 98 CMV-positive patients, 30 undergoing haploidentical HSCT and 68 undergoing URD HSCT. The majority of patients had a malignant disease (84%), received a myeloablative conditioning regimen (78%), and received a bone marrow graft (90%). The median pretransplantation anti-CMV IgG level was 109 U/mL. With median follow-up of 2.2 years, a total of 72 CMV reactivations occurred in 50 patients. There was no difference in CMV reactivation pattern between haploidentical HSCT recipients and URD HSCT recipients. In multivariable analysis until the first event, the incidence of CMV reactivation was higher in patients with anti-CMV IgG levels >100 U/mL (hazard ratio [HR], 2.38; P = .005) and in patients diagnosed with grade II-IV acute graft-versus-host disease (GVHD) (HR, 10.8; P = .003) after day +50 and lower in patients who received higher doses of CD34 cells (HR, .44; P = .006). In multivariable analysis for recurring events, the incidence of CMV reactivation was higher in patients receiving reduced-intensity conditioning (HR, 1.69: P = .04) and in patients with acute GVHD (HR, 1.88; P = .02), and lower in those who received higher doses of CD34 cells (HR, .55; P = .01). In summary, we have shown that pretransplantation anti-CMV IgG titers are correlated with CMV reactivation risk. More studies are needed to assess how this information can be incorporated in HSCT. The use of high-dose cellular grafts, a modifiable risk factor, also protects against CMV reactivation.     

Detection of human herpesviruses 6 and 7 in heart transplant recipients by a multiplex polymerase chain reaction method

In order to evaluate the possible reactivation of human herpesviruses 6 (HHV-6) and 7 (HHV-7) after heart transplantation, buffy-coat and plasma specimens from 21 transplant patients and 56 healthy blood donors were examined for HHV-6 and HHV-7 DNA by polymerase chain reaction. Human herpesvirus 6 and HHV-7 infection or reactivation has been suggested to play a role in cytomegalovirus disease progression in renal transplant recipients. In the present study, however, no significant difference in the prevalence of HHV-6 and HHV-7 was found between the immunosuppressed and the healthy population; moreover, no viral reactivation was found in the heart transplant recipients.     

HHV-6 and HHV-7 antigenemia related to CMV infection after liver transplantation

BACKGROUND: Betaherpesviruses human herpesvirus-6 and -7 (HHV-6, HHV-7), which are closely related to cytomegalovirus (CMV), have been reported in transplant patients. In this retrospective study, we investigated the occurrence of HHV-6 and HHV-7 antigenemia in relation to symptomatic CMV infection after liver transplantation. METHODS: Sample material from 64 adult liver transplant recipients was included in the study. The patients were monitored weekly for CMV, HHV-6, and HHV-7. CMV infections were diagnosed by pp65-antigenemia and viral cultures. Concomitantly HHV-6 and HHV-7 antigens were demonstrated in peripheral blood mononuclear cells by monoclonal antibodies against both variants A and B and immunoperoxidase staining. Altogether 540 post-transplant blood specimens were analyzed. RESULTS: Nineteen patients (30%) developed symptomatic CMV pp65 antigenemia during the first 3 months (mean 33 days, range 5-62 days) post-transplantation and were treated with intravenous ganciclovir. Concurrent HHV-6 antigenemia was detected in 16/19 (median 9 days, range 6-24 days) and HHV-7 antigenemia 15/19 patients (median 17 days, range 5-58 days) after transplantation. HHV-6 appeared before CMV in most cases (12/16), HHV-7 usually together with CMV. In those cases that HHV-6 preceded CMV antigenemia, it also was a possible cause of graft dysfunction. HHV-7 and CMV were so closely overlapping, that no symptoms could solely be linked with HHV-7. CONCLUSION: HHV-6 and HHV-7 antigenemia usually occurred together with symptomatic CMV infection after liver transplantation. HHV-6 preceded CMV, but HHV-7 appeared together with CMV. Further investigation of the clinical significance of HHV-6 and HHV-7 antigenemia in organ transplant patients is necessary.     

Human herpesvirus-6 and human herpesvirus-7 infections in bone marrow transplant recipients

Human cytomegalovirus (HCMV), human herpesvirus-6 (HHV-6), and human herpesvirus-7 (HHV-7) DNA in peripheral blood leukocytes (PBL) of 61 bone marrow transplant recipients was monitored weekly during the first 12 weeks post-transplantation by a nested polymerase chain reaction (PCR). Thirty-seven (61%), 17 (28%), and 32 (53%) of patients had one or more PBL specimens positive for HCMV, HHV-6 or HHV-7 DNA, respectively. HHV-7 DNA in PBL during the early post-transplant period was associated with a longer time to neutrophil engraftment (mean 28.8 days vs 19.8 days; P = 0.01). In two patients who failed to engraft, HHV-6 DNA and HHV-7 DNA was detected in plasma and PBL, respectively, early in their post-transplant period. Patients with HCMV disease were more likely to have concurrent HHV-7 DNA in PBL prior to onset of disease than were patients with asymptomatic HCMV infection, suggesting that HHV-7 may be a cofactor in the progression from HCMV infection to HCMV disease. In the 17 patients (179 specimens) in whom viral DNA in plasma was studied (in addition to PBL), a positive result was found only in 3. In each, viral DNA in plasma appeared to correlate with clinically significant disease. HHV-7 DNA in plasma was associated with encephalitis in an allograft recipient. J. Med. Virol. 53:295–305, 1997. © 1997 John Wiley & Sons, Inc.     

Rises in antibody to human herpesvirus 6 detected by enzyme immunoassay in transplant recipients with primary cytomegalovirus infection.

Immunoglobulin G to human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) in sera from solid organ recipients was measured by an enzyme-linked immunoassay (ELISA) before and after transplant. The HHV-6 ELISA was developed from glycine extracts of HHV-6-infected and uninfected HSB-2 cells. At a serum dilution of 1:500, 80 (91%) of 88 recipients were seropositive for HHV-6 before transplant, while only 14 (16%) were seropositive for CMV. Posttransplant HHV-6 serologic rises were observed in 38 (43%) recipients; rises in 25 of these recipients were associated with primary CMV infection. Titration of sera revealed much higher HHV-6 titer rises among those with primary CMV infection than among those with CMV reactivation or with no CMV infection. Elevated HHV-6 antibody titers persisted for up to 2 years after primary CMV infection. No correlation was noted between CMV and HHV-6 antibody titers in individual serum samples.     

Monitoring of cytomegalovirus infection in solid-organ transplant recipients by an ultrasensitive plasma PCR assay

Early and accurate monitoring of cytomegalovirus (CMV) infection in solid-organ transplant recipients is of major importance. We have assessed the potential benefit of an ultrasensitive plasma-based PCR assay for renal transplant recipients. The pp65 CMV antigen (pp65 Ag) assay using leukocytes was employed as a routine test for the monitoring of CMV in 23 transplant recipients. We compared the pp65 antigenemia with the CMV load quantified by an ultrasensitive PCR (US-PCR) with a limit of detection of 20 CMV DNA copies/ml of plasma. CMV infection was detected in 215 (67%) of 321 plasma samples by the US-PCR compared with 124 (39%) of 321 samples by the pp65 Ag assay. The US-PCR assay permitted the detection of CMV infection episodes following transplantation a median of 12 days earlier than the pp65 Ag assay. Moreover, during CMV infection episodes, DNA detection by the US-PCR was consistently positive, whereas false negative results were frequently observed with the pp65 Ag assay. We found a good correlation between the two assays, and the peak viral loads were significantly higher in patients with CMV-related complications (median, 5000 DNA copies/ml) than in those without symptoms (1160 DNA copies/ml) (P = 0.048). In addition, patients that did not require preemptive therapy based on the results of the pp65 assay had CMV loads significantly lower (median, 36 DNA copies/ml) than those that needed treatment (median, 4703 DNA copies/ml) (P < 0.001). These observations provided cutoff levels that could be applied in clinical practice. The ultrasensitive plasma-based PCR detected CMV infection episodes earlier and provided more consistent results than the pp65 Ag assay. This test could improve the monitoring of CMV infection or reactivation in renal transplant recipients.     

Prevalence of human herpesvirus 6 antibodies and DNA in allogeneic stem cell transplant patients: two-year single centre experience

INTRODUCTION: Human herpesvirus 6 (HHV-6) has been recognized as a potentially significant pathogen in hemopoietic stem cell transplant (HSCT) recipients. Different clinical manifestations have been described, including fever, skin rash, bone marrow suppression, and encephalitis. MATERIALS AND METHODS: A retrospective review of a group of 26 adult recipients of allogeneic HSCTs was conducted. Serum samples taken before transplant were examined for the presence of specific anti-HHV-6 IgM and IgG antibodies. After transplantation, quantitative real-time PCR was used to determine viral load in plasma samples from days 0-180 post-transplant. RESULTS: HHV-6 DNA was detected in plasma samples in 8 (30%) of the 26 recipients between days 18 and 40 after transplantation. All of them developed fever of unknown origin and over 50% had graft-versus-host disease features. Three individuals from this group died during detectable HHV-6 viremia. Another two recipients showed a single positive PCR result at a later time. Infection with HHV-6 was thus confirmed in 10 (38.5%) of the 26 graft recipients. CONCLUSIONS: There is a high frequency of detectable HHV-6 viral load in stem cell transplant recipients in Poland. Further investigation to monitor HHV-6 reactivation in graft recipients will be important to improve outcome for these patients.     

Pre-Transplant Cytomegalovirus Immunoglobulin G Antibody Levels Could Prevent Severe Cytomegalovirus Infections Post-Transplant in Liver Transplant Recipients: Experience from a Tertiary Care Liver Centre

Background: Humoral immune responses in cytomegalovirus (CMV) are not studied well. Pre-transplant CMV immunoglobulin G (IgG) antibody levels (Pre-Tx IgG) could influence the occurrence of post-transplant CMV infections. Objective: Correlation between pre-Tx IgG and post-Tx risk of acquiring CMV infection was investigated. Materials and Methods: A total of 146 liver Tx recipients, not on CMV prophylaxis, were included. Pre-Tx IgG in donor (D) and recipient (R) were estimated and all the recipients were followed up for 1 year for CMV infections. Results: D+ R+ serostatus was seen in 142 (97.3%) and D− R+ in 4 (2.7%). A total of 113 (77.4%) recipients had pre-Tx IgG of ≥250 AU/ml. Overall, post-Tx CMV infections were seen in 54 (36.9%) recipients. In 32 (59.2%) patients, CMV infection was seen during the 1^st month after TX. Incidences of post-Tx CMV infection in recipients with pre-Tx IgG <250 AU/mL and ≥250 AU/mL were 42.4% and 34.5%, respectively (P = 0.99). Median viral load was significantly higher in patients with pre-Tx IgG <250 AU/ml: 4log10 (R: 2.8–6.6 log 10) copies/ml than those with ≥250 AU/ml: 2.2 log10 (R: 1.6–3.8 log10) copies/ml, P = 0.04. There was no difference in the time of occurrence of CMV infection in both the groups. Concurrent occurrence of rejection and CMV infection was seen in significantly more patients 18/54 (32.7%) than in patients without CMV infection (12/99, 12%, P = 0.002). Conclusions: Higher pre-Tx CMV IgG levels might prevent severe CMV infections post-Tx. Recipients with low pre-Tx CMV titre might be benefitted by CMV prophylaxis or aggressive pre-emptive treatment.     

Association of HHV-6 and HHV-7 reactivation with the development of chronic allograft nephropathy

BackgroundThe long-term effect of HHV-6 and HHV-7 infections on chronic allograft nephropathy (CAN) development after renal transplantation is uncertain.ObjectivesTo determine HHV-6 and HHV-7 reactivation during the post-transplantation period and to evaluate its effect on CAN development in renal transplant patients.Study designEighty-one renal allograft recipients (28 with CAN, 53 with normal transplant function) were studied to determine the frequency of HHV-6 and HHV-7 reactivation during 36.4 ± 7.8 months after renal transplantation using nested PCR. HHV-6 variants were identified using restriction endonuclease analysis. Patients were monitored for the development of CAN.ResultsThe frequency of HHV-6 and/or HHV-7 plasma DNA was significantly higher in CAN patients (25/28, 89.3%) compared to control patients (15/50, 30.0%, p = 0.0001). CAN patients also had an increased incidence of dual active infections (20/25, 80% and 2/15, 13.3%, p = 0.007, respectively). In all 34 HHV-6 positive cases, the HHV-6B variant was identified. The presence of HHV-7 DNA in plasma preceded the presence of HHV-6 DNA. Early development of CAN and graft loss was detected only in patients with simultaneous HHV-6 and HHV-7 plasma DNA.ConclusionsReactivation of HHV-6 and HHV-7 in renal graft recipients is a risk factor for CAN development. The presence of concurrent HHV-6 and HHV-7 DNA in the plasma is an unfavorable prognostic factor.     

Effects of Prophylactic Foscarnet on Human Herpesvirus-6 Reactivation and Encephalitis in Cord Blood Transplant Recipients: A Prospective Multicenter Trial with an Historical Control Group

Cord blood transplantation (CBT) is a distinct risk factor for human herpesvirus-6 (HHV-6) reactivation and HHV-6 encephalitis. In a prospective multicenter trial we investigated the effects of prophylactic foscarnet (90?mg/kg i.v. infusion from days 7 to 27 after CBT) on the occurrence of HHV-6 reactivation, HHV-6 encephalitis, and acute graft-versus-host disease (aGVHD) in CBT recipients. Between 2014 and 2016, 57 patients were included in a foscarnet-prophylaxis group. Outcomes were compared with an historical control group who received CBT between 2010 and 2014 (standard-treatment group, n?=?63). The cumulative incidence of high-level HHV-6 reactivation, defined as plasma HHV-6 DNA ≥ 10⁴ copies/mL, at 60 days after CBT was significantly lower in the foscarnet-prophylaxis group than in the standard-treatment group (18.3% versus 57.3%, P?<?.001). Multivariate analysis revealed that myeloablative preconditioning and standard treatment were significant risk factors for high-level HHV-6 reactivation. The cumulative incidence of HHV-6 encephalitis at 60 days after CBT was not different between the groups (foscarnet-prophylaxis group, 12.4%; standard-treatment group, 4.9%; P?=?.14). The cumulative incidences of grades II to IV and grades III to IV aGVHD at 60 days after CBT were not different between the groups (grades II to IV aGVHD: foscarnet-prophylaxis group, 42.0%; standard-treatment group, 40.5%; P?=?.96; grades III to IV aGVHD: foscarnet-prophylaxis group, 14.5%; standard-treatment group, 14.5%; P?=?1.00). In the setting of this study foscarnet significantly suppressed systemic HHV-6 reactivation in CBT recipients but failed to prevent the development of HHV-6 encephalitis. Suppression of HHV-6 reactivation by foscarnet did not show any effects against the incidence of aGVHD.     

A serological investigation of human herpesvirus 6 infections in liver transplant recipients and the detection of cross-reacting antibodies to cytomegalovirus.

Sera from 50 orthotopic liver transplant recipients were examined for antibodies to human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV), and the findings correlated with the clinical condition of the patients. Both primary and secondary HHV-6 infections were detected serologically following liver transplantation. Interpretation of serological assays is complicated by CMV and HHV-6 antibody cross reactions which were common. Sera from 5 patients became HHV-6 antibody negative following absorption with CMV infected cells. Thirty patients were initially seronegative for HHV-6 antibodies, 12 remained so following transplantation, 5 developed cross reacting antibodies, and 13 seroconverted. The seroconversions occurred at 4 to 8 weeks post-transplant in the same time period as CMV antibody rises. HHV-6 IgM was detected in only 4 of the 13. Of the 7 patients who had serological evidence of active HHV-6 infections but no evidence of CMV infection, 4 (56%) had fever, 1 (14%) hepatitis, 1 (14%) lung dysfunction, and 3 (42%) neurological disorders. In the 12 patients who remained HHV-6 antibody negative, there were fewer fevers and neurological disorders.     

Fatal adult case of severe lymphocytopenia associated with reactivation of human herpesvirus 6.

It has been suggested that immunosuppression associated with human herpesvirus 6 (HHV-6) infection is a result of functional impairment or direct destruction of immunological cells. The ability of the virus to infect and destroy lymphocytes may cause progressive immunodeficiency in an infant with primary HHV-6 infection. An adult patient is described who had a fatal cytomegalovirus (CMV) infection due to severe and prolonged lymphocyte depletion associated with HHV-6 reactivation. The HHV-6 antibody titers were increased significantly after reactivation, and the virus was isolated from his peripheral blood mononuclear cells. The quantity of both HHV-6 and CMV DNA was determined by using real-time PCR in plasma samples collected serially. HHV-6 DNAemia persisted for 1 month, which started just 1 week after the onset of lymphocytopenia. In contrast to HHV-6, CMV DNAemia was detected in the terminal phase of the illness. Thus, HHV-6 reactivation may have been the cause of the severe lymphocyte depletion and fatal CMV infection.