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The influence of the donor (D) and recipient (R) pre-transplant Epstein-Barr Virus (EBV) serostatus on transplant outcomes (overall survival, relapse-free survival, relapse incidence, non-relapse mortality, acute and chronic GVHD) in 12,931 patients with lymphomas or chronic malignancies undergoing allogeneic hematopoietic cell transplant (allo-HCT) between 1997- 2016 was analyzed. In multivariate analysis, the risk of development of chronic GVHD was increased for EBV R+/ D+ (HR = 1.26; p = 0.003), R+/D- (HR = 1.21; p = 0.044), and R-/D + (HR = 1.21; p = 0.048) in comparison to R-/D- transplants. No significance was shown for other transplant outcomes; however, in univariate analysis, EBV-seropositive patients receiving grafts from EBV-seropositive donors (EBV R+/D+ transplants) had inferior transplant outcomes in comparison to EBV-seronegative recipients of grafts from EBV-seronegative donors (EBV R-/D-): inferior overall survival ( 59.6% vs 65.9%), inferior relapse-free survival (51.1% vs 57.5%), increased incidence of chronic GVHD (49.5% vs 41.8%), and increased incidence of de novo chronic GVHD (30.5% vs 24.0%). In conclusion, an EBV-negative recipient with lymphoma or chronic malignancy can benefit from selection of an EBV-negative donor in context of chronic GVHD, while there are no preferences in donor EBV serostatus for EBV-seropositive recipient.

Mantle cell lymphoma (MCL) is a rare form of non-Hodgkin's lymphoma (NHL) with a median overall survival (OS) of approximately 3-5 years. Systematic literature reviews (SLRs) identified efficacy and safety data for first-line therapies, reported in randomised controlled trials (RCTs) and non-randomised interventional studies (NRISs). Nine and 20 independent studies were included in the RCT and NRISs SLRs, respectively. Differences in the regimens and patient outcomes varied according to patient age and suitability for autologous stem cell transplantation (ASCT). In elderly patients ineligible for transplant, OS ranged from 40 months to 69.6 months. In young transplant-eligible patients, OS ranged from 53 months to 152.4 months. Despite the paucity of directly comparable evidence on the efficacy and safety of MCL therapies, these SLRs highlight that MCL remains a difficult NHL subtype to treat, with short survival highlighting the unmet need for newer treatments that improve patient outcomes.

Aim To assess the role of imaging in the early management of encephalitis and the agreement on findings in a well-defined cohort of suspected encephalitis cases enrolled in the Prospective Aetiological Study of Encephalitis conducted by the Health Protection Agency (now incorporated into Public Health England). Materials and methods Eighty-five CT examinations from 68 patients and 101 MRI examinations from 80 patients with suspected encephalitis were independently rated by three neuroradiologists blinded to patient and clinical details. The level of agreement on the interpretation of images was measured using the kappa statistic. The sensitivity, specificity, and negative and positive predictive values of CT and MRI for herpes simplex virus (HSV) encephalitis and acute disseminated encephalomyelitis (ADEM) were estimated. Results The kappa value for interobserver agreement on rating the scans as normal or abnormal was good (0.65) for CT and moderate (0.59) for MRI. Agreement for HSV encephalitis was very good for CT (0.87) and MRI (0.82), but only fair for ADEM (0.32 CT; 0.31 MRI). Similarly, the overall sensitivity of imaging for HSV encephalitis was ∼80% for both CT and MRI, whereas for ADEM it was 0% for CT and 20% for MRI. MRI specificity for HSV encephalitis between 3–10 days after symptom onset was 100%. Conclusion There is a subjective component to scan interpretation that can have important implications for the clinical management of encephalitis cases. Neuroradiologists were good at diagnosing HSV encephalitis; however, agreement was worse for ADEM and other alternative aetiologies. Findings highlight the importance of a comprehensive and multidisciplinary approach to diagnosing the cause of encephalitis that takes into account individual clinical, microbiological, and radiological features of each patient., Highlights • We assessed the role of imaging in encephalitis. • We assessed the agreement between raters on scan interpretation. • Diagnosis for herpes simplex encephalitis (HSE) was good. • Agreement was worse for ADEM and other alternative aetiologies. • HSE can be dismissed if MRI normal 72 hours after neurological symptom onset (with negative CSF tests).

Background Adenovirus infection is a potentially serious complication of allogeneic hematopoietic stem cell transplantation (HSCT) and has been reported to occur more frequently following T-cell-depleted reduced-intensity HSCT. However, the true incidence and clinical significance as well as the relationship of disease to viremic titer remain unclear due to wide variation in study populations and methodology. Methods We performed weekly surveillance blood testing by quantitative polymerase chain reaction on all adult recipients of alemtuzumab-based reduced-intensity HSCT at our institution between January 2008 and January 2011. We collated this with clinical data on treatment and outcomes of adenovirus infection. Results Of 116 HSCT patients analyzed, 14 (12.1%) had adenoviremia with a titer >200 copies/mL. Median time to first detectable titer was 28 days post-HSCT (range, 10-347), and median time to maximum titer was 49 days (range, 16-368). Underlying disease diagnosis (lymphoid > myeloid) and recipient cytomegalovirus (CMV) serostatus (positive > negative) were significantly correlated with adenoviremia. Only 5 patients (with high peak titers of 99 000-2 500 000 copies/mL) received cidofovir; 1 died from complications relating to adenovirus and concurrent CMV infection. Conclusions We detected adenoviremia at quantifiable levels in only 12.1% of HSCT patients. Attributable mortality was low (0.9% of the entire cohort, 7% of those with adenoviremia) because even infections associated with high viral titers responded to reduction in immunosuppression and treatment with cidofovir in the majority. The clinical significance of adenoviral infection in patients receiving alemtuzumab-based HSCT appears to be less than that previously reported, and only rarely does infection lead to significant morbidity and mortality.

The laboratory diagnostic strategy used to determine the etiology of encephalitis in 203 patients is reported. An etiological diagnosis was made by first-line laboratory testing for 111 (55%) patients. Subsequent testing, based on individual case reviews, resulted in 17 (8%) further diagnoses, of which 12 (71%) were immune-mediated and 5 (29%) were due to infection. Seventy-five cases were of unknown etiology. Sixteen (8%) of 203 samples were found to be associated with either N -methyl- d -aspartate receptor or voltage-gated potassium channel complex antibodies. The most common viral causes identified were herpes simplex virus (HSV) (19%) and varicella-zoster virus (5%), while the most important bacterial cause was Mycobacterium tuberculosis (5%). The diagnostic value of testing cerebrospinal fluid (CSF) for antibody was assessed using 139 samples from 99 patients, and antibody was detected in 46 samples from 37 patients. Samples collected at 14 to 28 days were more likely to be positive than samples taken 0 to 6 days postadmission. Three PCR-negative HSV cases were diagnosed by the presence of virus-specific antibody in the central nervous system (CNS). It was not possible to make an etiological diagnosis for one-third of the cases; these were therefore considered to be due to unknown causes. Delayed sampling did not contribute to these cases. Twenty percent of the patients with infections with an unknown etiology showed evidence of localized immune activation within the CNS, but no novel viral DNA or RNA sequences were found. We conclude that a good standard of clinical investigation and thorough first-line laboratory testing allows the diagnosis of most cases of infectious encephalitis; testing for CSF antibodies allows further cases to be diagnosed. It is important that testing for immune-mediated causes also be included in a diagnostic algorithm.

During 2009, a new strain of A/H1N1 influenza appeared and became pandemic. A prospective study was performed to collect data regarding risk factors and outcome of A/H1N1 in hematopoietic stem cell transplant recipients. Only verified pandemic A/H1N1 influenza strains were included: 286 patients were reported, 222 allogeneic and 64 autologous recipients. The median age was 38.3 years and the median time from transplant was 19.4 months. Oseltamivir was administered to 267 patients and 15 patients received zanamivir. One hundred and twenty-five patients (43.7%) were hospitalized. Ninety-three patients (32.5%) developed lower respiratory tract disease. In multivariate analysis, risk factors were age (OR 1.025; 1.01-1.04; P=0.002) and lymphopenia (OR 2.49; 1.33-4.67; P

Two patients with the characteristic high human herpesvirus 6 (HHV-6) DNA loads in peripheral blood caused by chromosomally integrated (CI) virus received a haematopoietic stem cell transplant (HSCT) from a donor without CI HHV-6. Both patients died in consequence of cytomegalovirus (CMV) pneumonitis. At autopsy, high amounts of CMV DNA were detected in lungs but at much lower levels in other organs. In contrast HHV-6 DNA was detected at high levels throughout the organs with the exception of donor-derived haematopoietic tissue. In individuals with chromosomal integration, HHV-6 DNA is found in every tissue of recipient origin indicating inheritance through the germ line.

A large simultaneous outbreak of respiratory syncytial virus (RSV) and parainfluenza type 3 (PIV-3) infections occurred on an adult hematology unit. Implementation of enhanced infection control was complicated by cocirculation of the two different viruses, with prolonged viral shedding from infected patients, and placed great pressure on health care staff; of 27 infected hematopoietic stem cell transplant patients, 9 died, and the unit was closed for 2 months. Retrospective molecular investigation of the virus strains involved in the outbreak was performed by analyzing part of the fusion gene of PIV-3 and part of the glycoprotein gene of RSV. Reverse transcription-PCR on nasopharyngeal aspirates from patients infected before and during the simultaneous outbreak generated amplicons for sequence analysis. A single strain of RSV and a single strain of PIV-3 had spread from person to person within the unit; 7 patients were infected with RSV, 22 were infected with PIV-3, and 4 were infected with both viruses. The PIV-3 outbreak had started at the beginning of August 3 months before the RSV outbreak; it had arisen when PIV-3 was introduced from the community by a patient and passed to another patient, who became chronically infected with the identical strain and, in spite of being nursed in isolation, was most likely the source from which widespread infection occurred in November. Had these early cases been linked to a common PIV-3 strain at the time of diagnosis, enhanced infection control precautions might have prevented the eventual extensive spread of PIV-3, making it much easier to deal with the later RSV outbreak.

The prevalence and concentration of human herpesvirus 6 (HHV-6) DNA in the cerebrospinal fluid (CSF) of the immunocompetent in primary infection was compared with that in viral chromosomal integration. Samples from 510 individuals with suspected encephalitis, 200 young children and 310 older children and/or adults, and 12 other patients were tested. HHV-6 DNA concentration (log 10 copies/ml) was measured in CSF, serum, and whole blood using PCR. Serum HHV-6 immunoglobulin G antibody was measured by indirect immunofluorescence. Primary infection was defined by antibody seroconversion and/or a low concentration of HHV-6 DNA (10 copies/ml) in a seronegative serum. Chromosomal integration was defined by a high concentration of viral DNA in serum (≥3.5 log 10 copies/ml) or whole blood (≥6.0 log 10 copies/ml). The prevalences of CSF HHV-6 DNA in primary infection and chromosomal integration were 2.5% and 2.0%, respectively, in the young children (10 copies/ml) was significantly lower than that of 21 patients with viral chromosomal integration (4.0 log 10 copies/ml). Only HHV-6B DNA was found in primary infection, whereas in viral integration, 4 patients had HHV-6A and 17 patients HHV-6B. Apart from primary infection, chromosomal integration is the most likely cause of HHV-6 DNA in the CSF of the immunocompetent. Our results show that any diagnosis of HHV-6 encephalitis or other type of active central nervous system infection should not be made without first excluding chromosomal HHV-6 integration by measuring DNA load in CSF, serum, and/or whole blood.

Patients undergoing haemopoietic stem cell transplants (HSCT) are at high risk of varicella zoster virus (VZV) reactivation, with a significant incidence of dissemination. This study reports a retrospective analysis of 247 allogeneic HSCT recipients receiving anti-viral prophylaxis with low-dose oral aciclovir 400 mg/day, administered until immunosuppression was discontinued and the CD4(+) cell count exceeded 200/mm(3). Viral reactivation was successfully suppressed by aciclovir prophylaxis, with only one case of breakthrough infection. The cumulative incidence of zoster infection at 1 year post transplant was 2% and at 5 years 34%. In all, 64 patients discontinued prophylaxis. Zoster developed in 26 of these, giving a cumulative incidence of infection at 1 year after stopping aciclovir of 39% and at 3 years 44%. Infection occurred in a localised dermatomal distribution in 93% of cases. This supports previous findings that aciclovir prophylaxis prevents early VZV reactivation, although the long-term incidence is not affected as infection occurs once prophylaxis is discontinued. Such infection, however, is mild and localised. This study does not support the idea that use of such low-dose aciclovir regimens reduces the zoster incidence by permitting subclinical reactivation during prophylaxis, and therefore the re-establishment of protective anti-viral immunity.

BACKGROUND The use of a cytomegalovirus (CMV)-seronegative donor for a CMV-seronegative allogeneic hematopoietic stem cell transplant (HSCT) recipient is generally accepted. However, the importance of donor serostatus in CMV-seropositive patients is controversial. METHODS A total of 49 542 HSCT patients, 29 349 seropositive and 20 193 seronegative, were identified from the European Group for Blood and Marrow Transplantation database. Cox multivariate models were fitted to estimate the effect of donor CMV serological status on outcome. RESULTS Seronegative patients receiving seropositive unrelated-donor grafts had decreased overall survival (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.06-1.21; P < .0001) compared with seronegative donors, whereas no difference was seen in patients receiving HLA-matched sibling grafts. Seropositive patients receiving grafts from seropositive unrelated donors had improved overall survival (HR, 0.92; 95% CI, .86-.98; P < .01) compared with seronegative donors, if they had received myeloablative conditioning. This effect was absent when they received reduced-intensity conditioning. No effect was seen in patients grafted from HLA-identical sibling donors. The same association was found if the study was limited to patients receiving transplants from the year 2000 onward. CONCLUSIONS We confirm the negative impact on overall survival if a CMV-seropositive unrelated donor is selected for a CMV-seronegative patient. For a CMV-seropositive patient, our data support selecting a CMV-seropositive donor if the patient receives a myeloablative conditioning regimen.

Purpose of review This review evaluates publications on human herpesvirus 6 (HHV-6) encephalitis recognizing firstly that HHV-6A and HHV-6B are separate species with differing properties, and secondly the phenomenon of chromosomal integration; this occurs in a minority of persons and the complete viral genome of either HHV-6A or HHV-6B is present in every nucleated cell in the body. Although chromosomal integration has not been associated with disease, the resulting very high level of viral DNA in human tissues and blood has sometimes been wrongly misinterpreted as active infection. Recent findings No disease has been linked to HHV-6A, whereas HHV-6B may cause encephalitis. Encephalitis due to primary HHV-6B infection in young children is commonly reported from Japan, but very rarely elsewhere in the world, suggesting a genetic predisposition. Reports of HHV-6A or HHV-6B encephalitis in immunocompetent older children/adults are most likely due to chromosomal integration and not active infection. HHV-6B reactivation is well established as causing limbic encephalitis after haematopoietic stem cell transplantation, particularly after receipt of cord blood; the outcome is poor and preventive strategies are ineffective. Summary Understanding the pathophysiology of HHV-6B encephalitis remains incomplete, especially regarding young children. Clinical trials of antiviral therapy are warranted for treatment and prevention of HHV-6B encephalitis after transplantation.

Community-acquired respiratory virus infections are a cause of mortality after stem cell transplantation (SCT). A prospective study was performed at 37 centers to determine their frequency and importance. Additional cases were also collected to allow the analysis of risk factors for severe infection. Forty episodes were collected in the prospective study and 53 additional episodes through subsequent case collection. The frequency of documented respiratory virus infections was 3.5% among 819 allogeneic and 0.4% among 1154 autologous SCT patients transplanted during the study period. The frequency of lower respiratory tract infections (LRTI) was 2.1% among allogeneic and 0.2% among autologous SCT patients. The mortality within 28 days from diagnosis of a respiratory viral infection was 1.1% among allogeneic SCT while no autologous SCT patient died. The deaths of five patients (0.6%) were directly attributed to a respiratory virus infection (three RSV; two influenza A). On multivariate analysis, lymphocytopenia increased the risk for LRTI (P = 0.008). Lymphocytopenia was also a significant risk factor for LRTI in patients with RSV infections. The overall mortality in RSV infection was 30.4% and the direct RSV-associated mortality was 17.4%. For influenza A virus infection, the corresponding percentages were 23.0% and 15.3%. This prospective study supports the fact that community-acquired respiratory virus infections cause transplant-related mortality after SCT.

Summary:The prophylactic and pre-emptive use of ganciclovir(GCV) both reduce significantly the incidence of CMVdisease after sibling BMT but it is unclear which ofthese strategies is best for volunteer unrelated donor(VUD) BMT patients. We reviewed 49 consecutivepatients, who received a T-depleted VUD BMT (fromMarch 1990 to March 1996) for the treatment of CMLin chronic phase, and were CMV seropositive beforetransplant or had a CMV seropositive donor. Patientswere conditioned with cyclophosphamide (120 mg/kgfor 2 days) and total body irradiation (13.2–14.4 Gy).Prophylaxis for GVHD was cyclosporin A and metho-trexate with ex vivo or in vivo T cell depletion. Twenty-seven patients received pre-emptive GCV if CMV infec-tion was detected by short-term culture before day+120post BMT. Twenty-two patients received prophylacticGCV from engraftment until day +120 post BMT. Theprobabilities of CMV infection and disease occurring by1 year post-BMT were greater in the pre-emptive GCVgroup than in the prophylactic GCV group (73.8% and64.0% vs 53.1% and 30.0%, respectively; P =0.04 and0.07). The incidence of death from CMV disease wassimilar in both groups (3/12 (25%) vs 3/10 (30%),respectively) and there was no difference in 1 year sur-vival (55.6% vs 54.2%, respectively). New strategies areurgently required for the prevention of CMV diseaseafter T-depleted VUD BMT.Keywords: volunteer unrelated donor bone marrowtransplant; cytomegalovirus; ganciclovir; pre-emptive;prophylacticCytomegalovirus (CMV) disease, especially pneumonitis,remains a major cause of morbidity and mortality afterBMT.

Summary Background Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with encephalitis in England. Methods Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. Findings We identified 203 patients with encephalitis. Median age was 30 years (range 0–87). 86 patients (42%, 95% CI 35–49) had infectious causes, including 38 (19%, 14–25) herpes simplex virus, ten (5%, 2–9) varicella zoster virus, and ten (5%, 2–9) Mycobacterium tuberculosis ; 75 (37%, 30–44) had unknown causes. 42 patients (21%, 15–27) had acute immune-mediated encephalitis. 24 patients (12%, 8–17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7–65) and varicella zoster virus (two patients; 20%, 2–56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups—nine (56%, 30–80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR=3·44). Interpretation Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. Funding The Policy Research Programme, Department of Health, UK.

Background. A retrospective study of the clinical, epidemiologic, and virologic features of norovirus gastroenteritis in 12 adult allogeneic hematopoietic stem cell transplant (HSCT) recipients.Methods. Norovirus infection was diagnosed by reverse-transcriptase polymerase chain reaction. Strains were genotyped by nucleic acid sequence of the most highly conserved region of the norovirus gene encoding the capsid S (shell) domain.Results. Ten of 12 patients presented with vomiting of short duration, but diarrhea was present in all. The median time from onset to norovirus diagnosis was 1 month (range, 0.25-6.0 months). Eleven patients were receiving immunosuppression when norovirus infection was diagnosed: 8 for graft-versus-host disease (GVHD) in an organ other than gut, 1 for previous gut GVHD, and 2 for presumed gut GVHD that proved to be norovirus gastroenteritis. Six patients required enteral or parenteral nutrition for severe weight loss. In 10 patients, diarrhea lasted a median of 3 months (range, 0.5-14 months) and virus was shed at a high level throughout. The remaining 2 patients died after 4 months of diarrhea (one died of unrelated complications, and the other died of malnutrition). The noroviruses found were GII (untyped), GII-3, GII-4, and GII-7 in 1, 1, 9, and 1 patients, respectively. Eleven of the 12 patients had acquired their infection in the community. Phylogenetic analysis of the GII-4 strains demonstrated that all differed.Conclusions. Noroviruses are a hitherto unsuspected cause of prolonged morbidity and mortality in adults after allogeneic HSCT. The use of reverse-transcriptase polymerase chain reaction to detect high viral load levels in feces distinguishes norovirus gastroenteritis from gut GVHD.

Fluorescent in situ hybridization (FISH) was used to investigate the chromosomal integration sites of human herpesvirus 6 (HHV-6) in phytohemagglutinin-stimulated leukocytes and B lymphocytes from Epstein-Barr virus transformed lymphoblastoid cell lines (LCLs). Five different chromosomal integration sites were found in nine individuals. Only one site was identified in each individual, each site was in the vicinity of the telomeric region and was on either the p or q arm of only one of the two chromosome homologues. The sites were 9q34.3, 10q26.3, 11p15.5, 17p13.3, and 19q 13.4, of which three have not been previously identified. For 9q34.3 the site of integration was further mapped using a locus-specific probe for 9q34.3 together with a pan-telomeric probe and both co-localized with the HHV-6 signal. Similarly an arm-specific telomeric probe for 19q co-localized with the HHV-6 signal. It was therefore concluded that the site of integration is actually within the telomere. The number of viral DNA copies/cell was calculated in blood, LCL cells and hair follicles and was one or more in every case for each of the nine individuals. This result was confirmed by FISH where 100% of cells gave an HHV-6 signal. These findings add to previous reports suggesting that integrated HHV-6 DNA is found in every cell in the body and transmitted vertically. Finally, including our data, worldwide seven different chromosomal sites of HHV-6 integration have now been identified. Large epidemiological studies of chromosomal integration are required to identify further telomeric sites, geographical or racial variation and possible clinical consequences.

Purpose We investigated the effect of Epstein-Barr virus (EBV) serostatus on the overall outcome of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Patients and Methods The study included 11,364 patients who underwent allogeneic peripheral-blood or bone marrow transplantation for acute leukemia between 1997 and 2012. We analyzed the impact of donor and recipient EBV serologic status on overall survival, relapse-free survival, relapse incidence, nonrelapse mortality, and incidence of graft-versus-host disease (GVHD) after allo-HSCT. Results Patients receiving grafts from EBV-seropositive donors had the same overall survival as patients who received grafts from EBV-seronegative donors (hazard ratio [HR], 1.05; 95% CI, 0.97 to 1.12; P = .23). Seropositive donors also had no influence on relapse-free survival (HR, 1.04; 95% CI, 0.97 to 1.11; P = 0.31), relapse incidence (HR, 1.03; 95% CI, 0.94 to 1.12; P = .58), and nonrelapse mortality (HR, 1.05; 95% CI, 0.94 to 1.17; P = .37). However, in univariate analysis, recipients receiving grafts from seropositive donors had a higher risk of chronic GVHD than those with seronegative donors (40.8% v 31.0%, respectively; P < .001; HR, 1.42; 95% CI, 1.30 to 1.56). When adjusting for confounders, higher risk was identified for both acute and chronic GVHD. In seronegative patients with seropositive donors, the HR for chronic GVHD was 1.30 (95% CI, 1.06 to 1.59; P = .039). In seropositive patients with seropositive donors, the HR was 1.24 (95% CI, 1.07 to 1.45; P = .016) for acute GVHD and 1.43 (95% CI, 1.23 to 1.67; P < .001) for chronic GVHD. Seropositive patients with seronegative donors did not have an increased risk of GVHD. Conclusion Our data suggest that donor EBV status significantly influences development of acute and chronic GVHD after allo-HSCT.

Previously it was thought that in the immunocompetent human herpesvirus-6 [HHV-6] DNA was present transiently in serum during early primary infection but not thereafter. In this study, HHV-6 serum IgG avidity was detected by immunofluorescence and HHV-6 variants A/B [HHV-6A/B] serum DNA by semi-quantitative PCR [titre-log(10) copies/ml] in: (a) young children3 years old from an encephalitis Survey, and a control Anonymised Serum Bank and (b) children/adults referred for diagnosis. The results showed that 11 out of 15 children [all2 years] with primary infection proven by seroconversion had transient low levels of serum HHV-6B DNA [mean titre 2.6]. However, 3.3% (6/184) of Survey Children had significantly higher levels [mean titre 5.3; 2 HHV-6A; 4 HHV-6B; P0.001]. Similarly high level serum DNA [mean titre 4.0; 4 HHV-6A; 6 HHV-6B] was found in 1.5% (10/653) of the Serum Bank Children. Moreover, seven young children3 years old [four Survey Children and three referred for diagnosis] had high titre serum HHV-6 DNA [mean 4.8] persisting i.e., in all available samples [median 186 days]. Three older children3 years old and 4 adults [3 of whom were the mothers of 3 of the young children with persisting HHV-6] also had persisting high titre viral DNA [mean 4.2; median 108 days]. Thus in contrast to acute primary infection, where only HHV-6B DNA is found transiently, both HHV-6A and B DNA persist in serum at high titre in occasional individuals of all ages. The significance of this newly described phenomenon in relation to diagnosis, clinical consequences and congenital infection are discussed.

Numerous outbreaks of adenovirus infection from different types of health care settings, except a hematology unit, have been reported. This is the first report describing an outbreak of adenovirus infection causing diarrhea among adult hematopoietic stem cell transplant recipients. Six of 21 patients from the outbreak cohort were affected with diarrhea. Electron microscopy, cell culture, and direct DNA sequencing of amplicons generated from stool and blood samples were used to investigate this outbreak. Electron microscopy and cell culture detected adenovirus in stools from symptomatic patients. DNA sequencing of amplicons generated from stool samples confirmed nosocomial transmission of infection from a single index case. The outbreak strain was also detected in plasma of four of these patients, suggesting systemic infection. The outbreak strain was identified as type 12. Standard infection control measures were effective to control this outbreak.

Adenoviruses are emerging as a major cause of infectious complications after allogeneic transplantation. We evaluated the incidence and outcome of symptomatic adenovirus infection or adenovirus disease after alemtuzumab-based reduced-intensity conditioning in 86 consecutive patients. The overall probability of adenovirus disease was 18.4% (11/86 patients). Five patients died of progressive adenovirus disease, and this was the most important infectious cause of mortality in this cohort. The probability of nonrelapse mortality was 49% in patients with adenovirus disease compared with 25.5% in those without (P = .007). The severity of lymphocytopenia and continuation of immunosuppressive therapy were the most important risk factors for progressive adenovirus disease and death. In contrast, patients who were not receiving immunosuppressive therapy or had had it reduced or withdrawn cleared the virus. We also detected a correlation between the lack of preemptive anti-cytomegalovirus (CMV) therapy for CMV reactivation and the risk of progressive adenovirus disease (P = .05). Our findings highlight the emergence of adenovirus as an important posttransplantation pathogen even after reduced-intensity conditioning and demonstrate the effect of the severity of lymphocytopenia, anti-CMV prophylaxis, and immunosuppressive therapy on the outcome of adenovirus disease.

A human herpesvirus 7 (HHV-7) indirect immunofluorescence antibody avidity test was developed and used with an existing human herpesvirus 6 (HHV-6) antibody avidity test to detect and distinguish low-avidity antibodies to HHV-6 and HHV-7 and hence the respective primary infections. With sera from 269 British children aged 0 to 179 weeks, the tests showed that most (10 of 98 serum samples [13%]) HHV-6 low-avidity antibody was found in the first year of life, whereas for HHV-7, most (18 of 101 serum samples [20%]) HHV-7 low-avidity antibody was found in the second year of life. Five children had low-avidity antibodies to both viruses. Of nine Japanese children with previously serologically proven primary HHV-6 or HHV-7 infections, eight had low-avidity antibody only to the relevant virus, but one child had low-avidity antibodies to HHV-6 and HHV-7. The avidity tests were applied to five British children and further proof of viral infection was sought by the detection of specific DNA in serum or plasma, and saliva or cerebrospinal fluid. In two children who had low-avidity antibody to HHV-7 but who were seronegative for HHV-6, only HHV-7 was found. Both viruses were detected in one child with low-avidity HHV-7 antibody and high-avidity HHV-6 antibody. In two children with low-avidity antibodies to both viruses, HHV-6 and HHV-7 DNAs were found, confirming dual primary infections and excluding antibody cross-reactivity.

Two consecutive nosocomial outbreaks of parainfluenza 3, in which 5 of 15 infected patients died, occurred in an adult bone marrow transplant unit. Parainfluenza 3 strain variation was assessed by reverse transcription-PCR sequencing of part of the parainfluenza 3 F gene, including the noncoding region, directly from clinical samples. Sequence data from the outbreaks were compared with those from 15 other parainfluenza 3 isolates circulating concurrently in the community; altogether, 13 strains which fell into three lineages were identified. Four immunosuppressed patients shed virus persistently for between 1 and 4 months without change in sequence. The first outbreak lasted 4 months and involved three parainfluenza 3 strains, and one persistently infected patient was implicated as the source of infection for three others. The second outbreak lasted for 1 month but involved only one strain. These data indicate that introduction of community parainfluenza 3 strains to the bone marrow transplant unit was followed by person-to-person transmission within the unit rather than reintroduction of virus from the community.

To compare the short- and medium-term complications (particularly infection) of bone marrow transplantation for chronic myeloid leukemia in patients with HLA-identical sibling donors or volunteer unrelated donors.Retrospective review of two cohorts of patients.Tertiary referral center.One hundred three patients with chronic myeloid leukemia in first chronic phase.Patients were treated with bone marrow transplantation using marrow from HLA-identical siblings (n = 57) and volunteer donors (n = 46).In total, 68 patients survived a median of 22 months from bone marrow transplant (range, 7 to 81 months). The actuarial probabilities of overall survival and leukemia-free survival at 2 years for the sibling donor group were 73% (95% CI, 60% to 86%) and 72% (CI, 60% to 84%), respectively, and for the volunteer donor group, 47% (CI, 31% to 63%) and 42% (CI, 26% to 58%) (P = 0.07 and 0.05, respectively). However, after adjustment for duration of disease, overall and disease-free survival in the two donor groups did not differ significantly. A major problem was an increased incidence of severe viral infection in the volunteer unrelated donor group (19 episodes in 16 of 46 patients compared with 7 episodes in 7 of 57 sibling donor patients, P = 0.01). The actuarial incidence of chronic graft-versus-host disease (GVHD) was higher in volunteer unrelated donor patients (77% [CI, 63% to 91%] compared with 49% [CI, 35% to 63%]; P = 0.02) but that of acute GVHD was not. The median performance status of the survivors in the volunteer donor group is similar to that in the sibling donor group. The incidence of hematologic relapse in both groups so far is low.Results appear to justify the continued use of volunteer donors in chronic-phase chronic myeloid leukemia, but infection and chronic GVHD are still major problems.