Sickle cell disease: Clinical presentation and management of a global health challenge.

Sickle cell disease is an autosomal recessive, multisystem disorder, characterised by chronic haemolytic anaemia, painful episodes of vaso-occlusion, progressive organ failure and a reduced life expectancy. Sickle cell disease is the most common monogenetic disease, with millions affected worldwide. In well-resourced countries, comprehensive care programs have increased life expectancy of sickle cell disease patients, with almost all infants surviving into adulthood. Therapeutic options for sickle cell disease patients are however, still scarce. Predictors of sickle cell disease severity and a better understanding of pathophysiology and (epi)genetic modifiers are warranted and could lead to more precise management and treatment. This review provides an extensive summary of the pathophysiology and management of sickle cell disease and encompasses the characteristics, complications and current and future treatment options of the disease.

Human herpes virus 6 reactivation: important predictor for poor outcome after myeloablative, but not non-myeloablative allo-SCT.

Hematopoietic SCT (HSCT) is often complicated by viral reactivations. In this retrospective cohort study (January 2004-August 2008), predictors for human herpes virus 6 (HHV6)-reactivation and associations between HHV6-reactivation and clinical outcomes after allogeneic HSCT were studied. HHV6 DNA load in plasma was monitored weekly by quantitative real-time PCR. Associations between the main end point HHV6-reactivation and other end points, that is, acute GVHD (aGVHD) and NRM were analyzed using Cox proportional hazard models. In total, 108 patients receiving either a myeloablative (MA; n=60) or non-myeloablative (NMA; n=48) conditioning regimen were included. Median age was 40 years (range 17-65); median follow-up was 20 months (range 3-36). In 16/60 (27%) patients with MA conditioning regimen, a HHV6 reactivation was observed (mean viral load 50 323 cp/mL) compared with 2/48 (4%) patients with a NMA conditioning regimen with low viral load (mean 1100 cp/mL). In multivariate analysis, MA conditioning was the only predictor for HHV6 reactivation (P=0.02). In addition, HHV6 reactivation was associated with grades 2-4 aGVHD (P<0.001) and NRM (P=0.03). Regular monitoring of HHV6 reactivation after HSCT might be important in MA HSCT patients to enable early initiation of antiviral treatment or to anticipate aGVHD, all of which may improve clinical outcome.

Increased proportion of perforin-expressing CD8+T-cells indicates control of herpesvirus reactivation in children after stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is frequently complicated by viral reactivations. Early diagnosis of viral reactivations and preemptive therapy relies on frequent viralload monitoring. An easy marker of effective cytotoxicity in lymphopenia is lacking and therefore we studied perforin-expression in CD8+T-cells in children following HSCT. Prospectively, we weekly monitored viral loads and perforin-expression of CD8+T-cells in whole blood by FACS, until 4months after HSCT in children. 27 patients were included (median age 4,3, range 0.3-20,1years) of whom 19 developed viral reactivations. These patients showed higher percentages of perforin-expressing CD8+T-cells (17,2%, range 0-63%) than those without (6,8%; range 0-16%) (p=0.001). The increased percentage of perforin-expressing CD8+T-cells coincided with a decrease in viral load with a median interval between maximum viral load and maximum level of perforin-expression of 0,4weeks (range 0.1-7.1). We conclude that perforin-expression in CD8+T-cells may be a marker for effective antiviral T-cell reconstitution early after HSCT in children.

Multicenter external quality assessment of molecular methods for detection of human herpesvirus 6.

The purpose of this study was to evaluate the performance of laboratories for the detection and quantification of human herpesvirus 6 (HHV-6) by an external quality assessment (EQA) evaluation. The HHV-6 EQA panel consisted of eight samples containing various concentrations of HHV-6 type A (strain GS) or type B (strain Z29), two samples containing other herpesviruses (i.e., human cytomegalovirus [HCMV] and Epstein-Barr virus [EBV]), and two HHV-6-negative samples. Panel samples were prepared in human plasma, heat inactivated, and lyophilized. Panel distribution, data management, and analysis were coordinated by Quality Control for Molecular Diagnostics (QCMD), Glasgow, United Kingdom. Fifty-one laboratories participated and submitted 57 data sets. Eleven (19.3%) data sets were generated using conventional in-house assays, 11 (19.3%) data sets using commercial real-time PCR assays, and 35 (61.4%) data sets using in-house real-time PCR assays. The presence of HHV-6 DNA at viral loads exceeding 6,000 copies/ml was detected by all participants, and over 80% of the participants still reported correct qualitative results for the sample containing just over 200 copies/ml. The false-positivity rate was 1.8% for both the negative samples and the samples containing HCMV or EBV DNA. The majority (23/33; 69.7%) of quantitative data sets were generated using in-house real-time PCR assays. The standard deviations of the geometric means of the samples ranged from 0.5 to 0.7 log(10). The results of this first international EQA demonstrate encouraging analytical sensitivity for the detection of HHV-6-DNA in human plasma, although we observed extensive interlaboratory variation of quantitative HHV-6 DNA results. Standardization needs to be improved to allow further elucidation of the clinical significance of HHV-6 loads.

Human herpesvirus type 6 reactivation after haematopoietic stem cell transplantation.

Human herpesvirus type 6 (HHV6) is known to reactivate after hematopoetic stem cell transplantation (HSCT) and has been suggested to be associated with increased mortality and severe clinical manifestations, including graft versus host disease (GvHD). The exact etiological role of HHV6 reactivation in increased morbidity and mortality after HSCT remains unclear. This review will focus on the current available evidence of HHV6 reactivation after HSCT and its immuno-modulatory capacities, with particular emphasis on the severe complication GvHD. At present, no effective specific antiviral treatment for HHV6 reactivation has been identified. The currently available antiviral agents are outlined, as well as possible future strategies for the treatment of HHV6 reactivation. Non-toxic, specific treatment or prevention of HHV6 reactivation might improve the safety and efficacy of the HSCT procedure.

Human herpes virus 6 plasma DNA positivity after hematopoietic stem cell transplantation in children: an important risk factor for clinical outcome.

Human herpes virus 6 (HHV6) is known to reactivate after hematopoietic stem cell transplantation (HSCT), and has been suggested to be associated with severe clinical manifestations in adults. The clinical significance in children remains unclear. We investigated the incidence of HHV6 reactivation in relation to HSCT-associated morbidity and mortality in children. Between January 2004 and May 2006, 58 pediatric patients, median age 7.6 years (range: 0.1-18.1 years), received their first allogeneic HSCT. After HSCT, HHV6, Epstein Barr Virus (EBV), cytomegalovirus (CMV), and adenovirus (AdV)-plasma loads were weekly measured by quantitative PCR. Clinical features, engraftment, graft-versus-host disease (GVHD), and HSCT-associated mortality and morbidity were monitored. HHV6 reactivations were classified in group I (no reactivation), group II (loads <1000 cp/mL) and group III (loads >1000 cp/mL). CMV, EBV, Herpes Simpex Virus, Varicella Zoster Virus, and AdV-reactivations were treated according to local guidelines. HHV6 was treated only when there was clinical suspicion of disease. Thirty-six HLA-identical and 22 HLA nonidentical grafts were transplanted of which 43 were bone marrow or peripheral blood stem cells grafts and 15 were cord blood (CB) grafts. Median follow-up of the patients was 15.5 (1-35) months. HHV6 reactivation occurred in 39 of 58 (67%) patients with 31 of 39 (80%) occurring within the first 30 days post-HSCT. In 26 of 58 (45%) patients (group III), HHV 6 reactivation was significantly associated with higher nonrelapse mortality (P = .02), using multivariate Cox proportional hazard models and grade 2-4 acute GVHD (P = .03) and chronic GVHD (P = .05) in a multivariate logistic regression analysis. HHV6 reactivation is very common after HSCT in children and is associated with serious transplantation-related morbidity and mortality. Although the exact role of HHV6 reactivation after HSCT has to be elucidated, early detection and initiation of therapy might be of benefit.