Lymphotropic herpesviruses in allogeneic bone marrow transplantation

Human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), Epstein-Barr virus (EBV), and human cytomegalovirus (CMV) DNA were repeatedly assayed in peripheral blood leukocytes from 37 allogeneic bone marrow transplant (BMT) patients by polymerase chain reaction. Before BMT, HHV- 6 DNA was detected in 8 (22%) patients. HHV-7, EBV, and CMV DNA were detected in 21 (57%), 10 (27%), and 1 (3%) patient, respectively. After BMT, HHV-6 DNA was detected in 26 (70%), HHV-7 in 21 (57%), EBV in 28 (76%), and CMV in 21 (57%) patients. Thirty-two (87%) patients were positive with more than one virus. HHV-6, HHV-7, and EBV DNA were found earlier than CMV DNA in most patients after BMT. The proportions of HHV- 6-positive samples during the first 3 months after BMT were higher in the patients with either delayed granulocyte engraftment (P = .04, Fisher's exact test) or delayed platelet engraftment (P = .001, Fisher's exact test). The HHV-6 DNA in samples from the patients with delayed engraftment was confirmed to be variant B. The detection of any lymphotropic herpesvirus was not related to the development of acute graft-versus-host disease (aGVHD). High-dose acyclovir (ACV) prophylaxis significantly (P < .01) reduced the proportion of HHV-6- positive samples and tended to lower HHV-6 DNA levels (P = .06). Our data indicate that HHV-6 variant B can inhibit marrow engraftment and that high-dose ACV may be beneficial to engraftment after BMT by preventing HHV-6 reactivation. No relation between the proportions of HHV-7-, EBV-, and CMV-positive samples in the first 3 months and engraftment or aGVHD was found.     

The utility of plasma polymerase chain reaction for human herpes virus-6 among pediatric bone marrow transplant recipients: results of a pilot study

We evaluated the utility of plasma polymerase chain reaction (PCR) for surveillance of human herpes virus 6 (HHV-6) infection among pediatric bone marrow transplant (BMT) recipients. We used a prospective, non-interventional design involving a study group and controls. BMT recipients and healthy controls were evaluated. BMT subjects had HHV-6 PCR done biweekly for 12 weeks post transplantation, while a single PCR test was done on controls. For the PCR assay, EDTA blood was collected and DNA extracted from whole blood and cell-free plasma using standard procedures. The PCR was first performed on DNA from whole blood and if a positive result was obtained, the test was repeated on the DNA from the plasma. Thirty BMT recipients (13 autologous and 17 allogeneic) were enrolled, on whom a total of 156 PCR tests were performed, while six tests were done on six healthy controls. The median age of BMT subjects was 6.2 years (range 0.5-17.5 years). The median age of the control subjects was 6.6 years (range 2-10 years). Among asymptomatic BMT patients who had PCR surveillance, the positivity rate was 3.3% (1/30) on whole blood and 0% (0/30) on plasma. None of the six healthy subjects had a positive PCR test on whole blood. During the period of the surveillance study, 14 patients had diagnostic evaluations for HHV-6 disease because of clinical symptoms. Two of these patients were diagnosed with disease associated with HHV-6 (graft failure and encephalitis) and had positive PCR tests on whole blood and plasma and whole blood and cerebrospinal fluid, respectively. We conclude that despite the fact that HHV-6 seropositivity rates are high among children, the frequency of HHV-6 plasma PCR positivity is low in pediatric BMT subjects who are asymptomatic for HHV-6 disease. Given that a positive test on plasma is consistent with active infection, this increases the utility of the PCR test as a diagnostic aid in evaluating syndromes presumed to be due to HHV-6 in pediatric bone marrow transplant recipients.     

Human Herpesvirus 6 Variant B Infection in Adult Patients after Unrelated Cord Blood Transplantation

Human herpesvirus 6 variant B (HHV-6B) infection was studied in 23 adult patients who underwent cord blood transplantation (CBT). HHV-6B DNA was detected by quantitative polymerase chain reaction analysis after CBT in the sera from 15 patients (65%) at day 14 or 15 (week 2), from 16 patients (70%) at day 21 or 22 (week 3), and from 3 patients (13%) at day 28 or 29 (week 4). HHV-6B DNAemia was found in none of the 20 patients examined at day 7 or 8 (week 1). The overall incidence of HHV-6B DNAemia reached 87% (20 of 23 patients). This incidence was much higher than after unrelated bone marrow transplantation (19%, P < .0001). In CBT patients, positive HHV-6B DNAemia at week 3 was significantly associated with early skin rash (88% versus 14%, P < .005) and grade II-IV acute graft-versus-host disease (aGVHD) (69% versus 14%, P < .05). In contrast, positive HHV-6B DNAemia at week 2 was associated with neither skin rash nor aGVHD. Prospective large-scale studies are needed to determine the role of HHV-6 infection in CBT patients.     

Detection of active human herpesvirus-6 infection in the brain: correlation with polymerase chain reaction detection in cerebrospinal fluid

One-half of bone-marrow transplant (BMT) and stem-cell transplant recipients have reactivation of latent human herpesvirus (HHV)-6 2-4 weeks after transplant. Although the detection of viral DNA, RNA, and antigen in brain material confirmed active HHV-6 variant B infection, peak viral loads in cerebrospinal fluid (CSF) and serum occurred 2-4 weeks before death and decreased to low levels before or at autopsy. All autopsy samples consistently demonstrated HHV-6 active infection in the hippocampus. Astrocytic cells positive for viral antigen provided support for an HHV-6-specific tropism for hippocampal astrocytes. HHV-6 DNA in CSF and serum may not reflect the level of active viral infection in the brain after BMT.     

Detection of herpesvirus type 6 by polymerase chain reaction in blood donors: random tests and prospective longitudinal studies

Summary. In order to evaluate the prevalence of HHV-6 in blood donors, we examined 112 persons by polymerase chain reaction (PCR) and ELISA. HHV-6 antibodies could be detected in 107/111 (96.4%) of the donors. The median ELISA antibody level was 0.451 (range 0.056–0.914). 14 individuals (12.5%) were PCR positive in either oral lavage fluid, urine or buffy coat. Six persons (5.4%) were PCR positive in buffy coat samples. The prospective longitudinal analysis of 11 donors for periods between 7 and 13 weeks revealed that 4/6 persons who were initially PCR negative had positive tests in 9/63 weeks studied. Two persons were consistently PCR positive over the whole observation period of 12 and 13 weeks. HHV-6 variants could be determined in 14 persons as variant A in nine and variant B in five cases. These observations emphasize the high prevalance of HHV-6 and suggest that some blood donors carry detectable concentrations of the virus and therefore may be a source for transmission of HHV-6. The finding of positive PCR in antibody negative individuals suggests that antibody determination may not be sufficient to identify potentially infectious persons.     

Successful treatment of human herpesvirus-6 encephalitis after bone marrow transplantation

We report two cases of human herpesvirus-6 (HHV-6)-associated encephalitis in patients after BMT. Both patients reported distinct neurological symptoms with disorientation, sleepiness and loss of short-term memory. Diagnosis was based on PCR analysis of the cerebrospinal fluid (CSF) positive for HHV-6 variant B-DNA. After institution of therapy with foscarnet in both cases, neurological symptoms improved and in one patient clearance of HHV-6-DNA from CSF was demonstrated. These cases show that HHV-6 infection has to be considered in patients with neurological symptoms following BMT and effective treatment of HHV-6 encephalitis is possible if instituted early.     

Human herpesvirus 6 is an important pathogen in infectious lung disease after allogeneic bone marrow transplantation

Two hundred and ten bronchoalveolar lavage (BAL) samples were obtained from 50 patients 10 days before and on defined days after allogeneic bone marrow transplantation (BMT). The samples were examined for human cytomegalovirus (HCMV) and human herpesvirus-6 (HHV-6) by polymerase chain reaction (PCR). Fifteen patients (30%) had a positive result for HCMV in at least one sample and 25 (50%) were positive for HHV-6 in at least one sample. Five patients developed HCMV-associated interstitial pneumonia (HCMV-IP) within 100 days after allogeneic BMT. Four of these patients were positive for both HCMV and HHV-6. Conspicuous HHV-6 positivity was detected in BAL samples obtained because of respiratory symptoms. No association was found between detection of HHV-6 and acute graft-versus-host disease. Engraftment failure or a delay in engraftment was observed in none of the 50 patients. The data from this study indicate that HHV-6 is a pathogen in HCMV-associated, as well as in non-HCMV-associated infectious lung disease after BMT.     

Correlation between HHV-6 infection and skin rash after allogeneic bone marrow transplantation

We investigated whether a causal relationship exists between human herpesvirus 6 (HHV-6) and skin rash resembling acute graft-versus-host disease (GVHD) following bone marrow transplantation (BMT). Isolation of HHV-6 was used to monitor active HHV-6 infection in this study. We analyzed 25 episodes of skin rash in 22 recipients. All recipients were seropositive for HHV-6 before BMT. The onset of skin rash started prior to 30 days post transplantation (group A) in 15 of 25 cases, but after that (group B) in the remaining 10 cases. Twenty-five skin tissue samples were obtained from 22 recipients. The HHV-6 genome was detected in four of 15 skin samples from group A, but not detected in those from group B. HHV-6 was isolated from 11 of 22 recipients around 2 to 3 weeks after BMT (range 14 to 28 days after BMT). HHV-6 was isolated at a time between 10 days before and after the onset of skin rash (skin rash-related viremia) in nine cases in group A. Meanwhile, no skin rash-related viremia was observed in group B. Of the four recipients with positive detection of HHV-6 genome in their skin tissue (group A), two had HHV-6 viremia at the same time. The association between the timing of HHV-6 infection and the onset of skin rash was analyzed statistically. HHV-6 viremia (skin rash-related viremia) was found in nine of 15 (60%) cases in group A, compared with none of 10 (0%) cases in group B. This difference was statistically significant (P = 0.008). Moreover, HHV-6 infection (skin rash-related viremia and/or positive detection of HHV-6 DNA in skin tissue) was demonstrated in 11 of 15 (73.3%) cases in group A, compared with none of 10 (0%) cases in group B (P = 0.001). Thus, this study suggests that HHV-6 may be involved in the development of skin rash in the first month after allogeneic BMT.     

High levels of human herpesvirus 6 DNA in peripheral blood leucocytes are correlated to platelet engraftment and disease in allogeneic stem cell transplant patients

The aim of this study was to correlate human herpesvirus (HHV)-6 viral load with clinical symptoms in allogeneic stem cell transplant (SCT) patients. Seventy-four patients were monitored during the first 3 months after SCT using a qualitative polymerase chain reaction (PCR) for HHV-6 DNA. HHV-6 was detected in 181 out of 494 samples (36%) from 58 (78%) patients. These 181 samples were analysed using a quantitative competitive PCR. DNA could be quantified from 146 out of 181 samples (80.6%). The HHV-6 viral load was highest at 4 weeks compared with 8 weeks (P < 0.001) and 12 weeks (P = 0.01) after SCT. Three patients had HHV-6 encephalitis and one patient had hepatitis. The HHV-6 DNA levels were higher in patients with HHV-6 than in those without HHV-6 (P = 0.01). Patients who received grafts from unrelated or HLA-mismatched family donors had significantly higher HHV-6 DNA levels than patients who received grafts from matched sibling donors (P < 0.001). In a multiple regression model, unrelated donor grafts (P < 0.001) and use of intravenous immunoglobulin prophylaxis (P = 0.04) influenced HHV-6 DNA levels. HHV-6 viral load was significantly correlated with delayed platelet engraftment in both univariate (P < 0.01) and multivariate analysis, and to the number of platelet transfusions.     

Evaluation of CMV/human herpes virus-6 positivity in bronchoalveolar lavage fluids as early detection of acute GVHD following BMT: evidence of a significant relationship

We evaluated the relationship between CMV and human herpes virus-6 (HHV-6) reactivation and the incidence of grades 2 to 4 acute GVHD post BMT. Bronchoalveolar lavage fluid (BALF) samples extracted from 54 BMT recipients on post-BMT day 35 were analyzed by PCR for detection of CMV DNA, HHV-6 DNA and CMV plus HHV-6 DNA. CMV DNA was detected in 26 patients and 13 (50%) developed grades 2 to 4 acute GVHD. Of the 28 who were CMV negative, only six (21.4%) developed grades 2 to 4 acute GVHD. HHV-6 was detected in 18 patients, and 11 (61.1%) developed grades 2 to 4 acute GVHD. Of the 36 who were HHV-6 negative, only eight (22.2%) developed grades 2 to 4 acute GVHD. CMV and HHV-6 were detected in 13 patients, and eight (61.5%) developed grades 2 to 4 acute GVHD. Of the 23 who were negative for both CMV and HHV-6, only three (13%) developed grades 2 to 4 acute GVHD. In all experiments, the difference between the groups was significant (P<0.05, P<0.05 and P<0.01, respectively). We conclude that herpes virus infection, in particular CMV concurrent with HHV-6 reactivation, is predictive of moderate to severe acute GVHD.     

Human herpesvirus 6 infection inhibits specific lymphocyte proliferation responses and is related to lymphocytopenia after allogeneic stem cell transplantation

Human herpesvirus 6 (HHV-6) infection and the HHV-6-specific lymphocyte proliferation response were studied longitudinally in 24 patients in the first 3 months after allogeneic stem cell transplantation (allo-SCT). HHV-6 DNAemia was analyzed by a nested PCR method, and the HHV-6-specific lymphocyte proliferation responses were evaluated with a standard lymphocyte proliferation assay. All patients who responded to HHV-6 GS (variant A) antigen also responded to HHV-6 Z29 (variant B) antigen, and a response to HHV-6 Z29 antigen was detected more often than to HHV-6 GS antigen after allo-SCT (P = 0.048). HHV-6 DNA was detected in more patients after than before transplantation (P = 0.01) and in more patients with acute GVHD grades II-IV than those without (P = 0.009). An HHV-6-specific proliferative response was more often detected in patients without, than in those with persistent HHV-6 infection (three consecutively positive PBL samples; P < 0.001). Patients with persistent HHV-6 infection had lower lymphocyte counts from the 8th week after transplantation than those without (P = 0.03). No HHV-6-specific proliferation responses were detected in the three patients who developed HHV-6 disease. HHV-6 infection was associated with persistent lymphocytopenia and might thereby inhibit immune function.     

Evidence of active herpesvirus 6 (variant-A) infection in patients with lymphadenopathy in Belém, Pará, Brazil

A total of 323 patients with lymphadenopathy were selected in Belém, Brazil, between January 1996 and December 2001, and screened for the presence of human herpesvirus-6 (HHV-6) IgM- and--IgG antibodies by enzyme-linked immunosorbent assay (ELISA). When seroprevalence is analyzed by gender, similar rates are found for female (60.6%) and male (55.7%) individuals. Seventy-seven (23.8%) patients were HHV-6-IgM-and--IgG-positive (IgM+ subgroup), with positivity rates of 29.7% and 17.7% (p = 0.0007) for female- and male individuals, respectively. Sera from a subgroup (n = 120) of these subjects, with high HHV-6 antibody levels (either IgM+ or IgG+ reactivities), were subsequently processed for the presence of HHV-6 DNA by polymerase chain reaction (PCR)/nested PCR. Active infections (IgM+ and/or IgG+ high levels specific antibodies plus detection of viral DNA) were diagnosed in 20/77 (20.0%) and 8/43 (18.6%); subgroup of the 120 individuals suspected of having HHV-6 suggestive recent infection. All (n = 28) cases of active infection were found to be associated with HHV-6 variant-A (HHV-6A), as detectable by PCR/nested PCR, using variant-specific primer that amplify regions of 195 base pairs (bp) (HHV-6A) and 423 bp (HHV-6B). Rates of HHV-6 DNA detection between female and male patients were similar (p > 0.05) in the IgM+ and IgG+ groups: 20.4% versus 35.7% and 25.0% versus 13.0%, respectively. HHV-6 DNA was detected across < or = 5 through 41-50-year age-groups for patients whose serum samples were IgM+, with rates ranging from 7.7% (female subjects aged < or = 5 years) to 80.0% (male, 11-20 years). Among patients whose serological status was IgG+, HHV-6 DNA was detected in < or = 5, 6-10, 21-30 and > 50 age-groups at rates that ranged from 15.4% (male, < or = years of age) to 100.0% (female aged 11-20 years). Swelling cervical lymph nodes were the most common sign, accounting for 9 (32.0%) cases in each gender group. Among patients (n = 28) with active infection by HHV-6A variant, duration of symptoms lasted 1-5 days in 35.7% of subjects, whereas in 64.3% of them the disease lasted 6-20 days. Our data suggest that it is worth seeking for HHV-6 infection whenever a patient (infant or adult) presents with lymphadenopathy as a prominent symptom in the course of an acute febrile illness.     

The impact of cyclosporin A on acute graft-versus-host disease after allogeneic bone marrow transplantation in children and adolescents with acute lymphoblastic leukemia

Experimental and clinical data demonstrate an antileukemia effect of acute graft-versus-host disease (aGVHD). In all, 58 pediatric patients with acute lymphoblastic leukemia (ALL) who had received an allogeneic bone marrow transplant (BMT) at our institution were retrospectively analyzed for a correlation between the development of aGVHD and leukemic relapse. Probability of relapse after 5 (3) years was 13% (7%) in patients developing grade II-IV aGVHD vs 30% in patients with grade 0 or I aGVHD. There was a trend for a difference of the point estimates at 3 years, but no overall significance because of an unusual late relapse. Moreover, we analyzed the impact of cyclosporin A (CsA) on aGVHD in a subgroup of 22 children who had received a matched sibling donor (MSD) BMT. An increased dose of CsA within the first 2 weeks after BMT led to decreased occurrence and severity of aGVHD (P=0.035). The cumulative CsA dose appeared to have more impact than the average CsA whole-blood levels within the first 2 weeks and than the CsA dose given from day 15 to 40. In this subgroup, no life-threatening aGVHD or death from aGVHD occurred. In all cases (6/22), leukemic relapse was the cause of death. We therefore suggest that there is a relation between dose of CsA and relapse rate in childhood ALL transplanted from a MSD.     

Inverse relationship between human herpesvirus-6 and -7 detection after allogeneic and autologous stem cell transplantation.

Human herpesvirus-6 (HHV-6) and -7 were analyzed in 25 and 18 patients with allogeneic (allo) and autologous (auto) stem cell transplantation (SCT), respectively, by weekly examination of viral DNA in peripheral mononuclear cells using semiquantitative PCR and serologic tests up to 12 weeks after SCT. HHV-6 DNA was detected in 29.6% and 27.9% of samples after allo- and auto-SCT, respectively. The proportions of HHV-6-DNA-positive samples increased in week 3 and 4 after allo-SCT, and in week 1 to 3 after auto-SCT. The frequency of HHV-7 DNA detection, however, was higher after auto-SCT (24.7%) than allo-SCT (12.8%) (P 10(2) copies of HHV-6 DNA (/10(5) cells) on two consecutive occasions were allo-SCT recipients and three showed clinical episodes. Conversely, three of five patients with continuous reactivation of HHV-7 were auto-SCT recipients. Thus, the frequencies of HHV-6 and -7 DNA detection showed an inverse relationship comparing allo- and auto-SCT, suggesting a different mechanism may regulate HHV-6 and -7 reactivation.     

Human herpesvirus 6 viremia in bone marrow transplant recipients: clinical features and risk factors

Human herpesvirus 6 (HHV-6) infection was studied in 82 bone marrow transplant (BMT) recipients (72 allogeneic, 10 autologous). All recipients and 30 donors were seropositive for HHV-6 antibody at the time of bone marrow transplantation. Thirty-one recipients (37.8%) had HHV-6 viremia 2-4 weeks after transplantation. The incidence of HHV-6 viremia was significantly higher among allogeneic BMT recipients than in autologous BMT recipients (P=.011). Therefore, the following analyses of allogeneic BMT recipients were carried out (n=72). Geometric mean antibody titers (log(10)) were significantly higher in recipients without viremia than in those with viremia (1.84+/-0.39 vs. 1.61+/-0.42; P=.022). Logistic regression analysis demonstrated that leukemia or lymphoma is an independent risk factor (P=.031) for HHV-6 viremia. Rash occurring within 1 month after transplantation was observed in 17 (54.8%) of 31 recipients with HHV-6 viremia but in only 8 (19.5%) of 41 recipients without HHV-6 viremia (P=.001).     

Human herpesvirus 6 positive Reed-Sternberg cells in nodular sclerosis Hodgkin lymphoma

Classical Hodgkin lymphoma (HL) exhibits a bi-modal age distribution that suggests an infectious aetiology. However, most cases of nodular sclerosis HL (NSHL) are Epstein-Barr virus (EBV) negative (60-90%). Previous studies regarding human herpesvirus 6 (HHV-6) positivity of HL have led to conflicting results. In order to clarify this situation, we examined NSHL biopsies for the presence and distribution of HHV-6 by immunohistochemistry (IHC), polymerase chain reaction (PCR), and fluorescence in situ hybridization (FISH). PCR identified HHV-6 DNA in 86% of NSHL cases. As HHV-6 DNA was also identified in most cases of reactive lymphoid hyperplasia, we sought to localize the virus to specific cells by IHC, which detected HHV-6 in Reed-Sternberg (RS) cells of nearly half (48%) of NSHL cases. Dual CD30/HHV-6 immunostaining confirmed HHV-6 immunoreactivity in CD30+ RS cells, and HHV-6 PCR positivity was confirmed in laser capture microdissection-isolated CD30+ RS cells. FISH demonstrated multiple copies of HHV-6 genome in scattered cells. In contrast, EBV+ RS cells were identified in only 24% of the cases. HHV-6+ cases trended toward a younger age than EBV+ cases. These results conclusively demonstrate that RS cells in many cases of NSHL are HHV-6 positive, and suggest that HHV-6 may play a role in NSHL pathogenesis, particularly in younger patients with EBV-negative disease.     

Human herpesvirus 6 in biopsies from patients with gastrointestinal symptoms after allogeneic stem cell transplantation

Gastrointestinal complications are frequent after allogeneic stem cell transplantation (allo-SCT). Main differential diagnoses are graft-versus-host disease (GvHD) and viral infections. In this retrospective analysis, we included 50 patients with severe vomiting or diarrhea in the first year after allo-SCT. One hundred two biopsies obtained by colonoscopy or endoscopy of the upper gastrointestinal tract were analysed by conventional histology for signs of GvHD and by qualitative polymerase chain reaction (PCR) for viral DNA of human herpesvirus 6 (HHV-6) and other virus of the herpes family. DNA of HHV-6 was detected in 38 of 75 initial samples (51%) and in 19 of 27 follow-up biopsies (70%). In the initial samples (n = 75), HHV-6 DNA was detected in 20/37 (54%) biopsies in the presence of GvHD compared to 18/38 (47%) biopsies without signs of GvHD. At the time of the first endoscopic investigation, most patients received antiviral prophylaxis with aciclovir. None of the follow-up biopsies was HHV-6 DNA negative after antiviral treatment with aciclovir, foscarnet or ganciclovir. By univariate analysis, no risk factor for HHV-6 detection could be demonstrated. In this cohort of patients with severe gastrointestinal complications, there was no significant difference in the overall survival between patients with or without HHV-6 DNA detection in the gastrointestinal tract. In summary, the detection of HHV-6 DNA had no impact on overall survival. Moreover, antiviral therapy against HHV-6 was without effect. Thus, positive PCR results in GI tract samples do not necessarily reflect reactivation of HHV-6. Further studies are needed to define the significance of HHV-6 for GI tract symptoms after allo-SCT.     

Human herpesvirus-6 infection in bone marrow transplantation.

Twenty-five pediatric patients who received bone marrow transplantation (BMT) were studied prospectively to determine the relationship between BMT and human herpesvirus-6 (HHV-6) infection by the virus isolation from peripheral blood and/or bone marrow and by determining neutralizing antibodies to HHV-6 during the 2 months following BMT. All of the 25 donors and the recipients were immune to HHV-6 at the time of BMT and the virus was not isolated from them. HHV-6 was isolated from peripheral blood and/or bone marrow mononuclear cells in ten (40%) of the 25 recipients between day 14 and day 22 of BMT, but not from any other day. Two additional recipients showed a significant increase in the antibody titer. Thus, infection with HHV-6 was confirmed in 12 (48%) of the 25 recipients. Four of the 12 developed skin rashes; three of these four had a febrile episode when the virus was isolated, whereas none of the remaining 13 developed the skin rash. These results suggest a frequent infection with HHV-6 only a few weeks after BMT and a close association between the infection with the virus and the development of skin rashes.     

Prognostic value of quantitative Kaposi sarcoma--associated herpesvirus load in posttransplantation Kaposi sarcoma

Reactivation of human beta-herpesviruses (cytomegalovirus [CMV], human herpesvirus [HHV]-6, and HHV-7) in nonimmunocompromised hosts is rare. Because these viruses are susceptible to reactivation by cytokines and stress-related mechanisms, the incidence of their reactivation was investigated among 120 patients during stress related to critical illness and compared with findings among 50 healthy volunteers. Human beta-herpesvirus DNA was found in 65% of critically ill patients (60% men; mean age, 63 years) who required admission to an intensive care unit for medical (40%) or surgical (53%) indications or trauma (7%). HHV-6 reactivation was higher in critically ill patients than in healthy volunteers (54/101 vs. 0/50; P=.001). All patients except 1 were confirmed as HHV-6 variant A (mean virus load, 5066 copies/10(6) peripheral blood leukocytes). The reactivation of HHV-6A did not affect disease severity and outcome. No significant reactivation of HHV-7 or CMV was demonstrated among the critically ill patients. These findings contribute to the less-defined epidemiology of HHV-6A infection.