Human herpesvirus-6 (HHV-6) infection is increasingly recognized among allogeneic hematopoietic stem cell transplantation (HSCT) recipients, with 30% at risk of reactivation in the haploidentical setting. It has been associated with encephalitis, acute graft-versus-host disease, and graft failure. Here we report 2 cohorts of pediatric haploidentical manipulated HSCT in which, despite many differences, HHV-6 reactivation and disease occurred with very high incidence compared with data reported in the literature and represented the main early post-transplant infectious complication compared with other viral, bacterial, or fungal infections. The 2 cohorts were recruited at the pediatric transplant centers of Perugia (n = 13), Barcelona (n = 10), and Madrid (n = 15). All patients received myeloablative conditioning regimens and 2 different types of ex vivo graft manipulation: CD34 selection and regulatory T cell/conventional T cell infusion in 13 patients and CD45RA T cell depletion in 25 patients. Antiviral prophylaxis was acyclovir in 33 and foscarnet in 5 patients. HHV-6 DNAemia was checked by quantitative or qualitative PCR. In vitro experiments demonstrated that donor CD4 T cells are the reservoir of HHV-6 and suggested a role of the graft composition in both transplant settings (rich in CD4 T cells) in the high rate of HHV-6 infections. All patients presented very early HHV-6 DNAemia after transplantation, and although viremic, 9 patients (24%) developed symptomatic limbic encephalitis. All patients responded to antiviral treatment, and none died of infection, although 2 experienced long-term neurologic sequelae (22%). Moreover, 6 patients presented organ involvement in absence of other causes: 1 hepatitis, 1 pneumonia, 2 gastroenteritis, and 2 multiorgan involvement(1 encephalitis, pneumonia, and gastritis; 1 pneumonia and enteritis). Incidences of other viral, bacterial, and fungal diseases were lower in both cohorts. In vitro, HHV-6 was found to infect only CD4 fraction of the graft. Co-culturing CD4 T cells with CD56 natural killer (NK) cells eliminated the virus, demonstrating the main role of NK cells in the antiviral immune response. All 38 pediatric patients undergoing these manipulated haploidentical HSCTs showed HHV-6 reactivation, and 14 of 38 developed HHV-6 disease with similar features in terms of timing, morbidity, response to treatment, and outcome. The graft composition in both transplant platforms, rich in CD4 T cells and poor in NK cells, seems to play a key role. HHV-6 DNAemia surveillance was useful to diagnose and treat preemptively HHV-6 infection.

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Glucose-6-phosphate isomerase (GPI, EC 5.3.1.9) is a dimeric enzyme that catalyzes the reversible isomerization of glucose-6-phosphate to fructose-6-phosphate, the second reaction step of glycolysis. GPI deficiency, transmitted as an autosomal recessive trait, is considered the second most common erythro-enzymopathy of anaerobic glycolysis, after pyruvate kinase deficiency. Despite this, this defect may sometimes be misdiagnosed and only about 60 cases of GPI deficiency have been reported. GPI deficient patients are affected by chronic non-spherocytic hemolytic anemia of variable severity; in rare cases, intellectual disability or neuromuscular symptoms have also been reported. The gene locus encoding GPI is located on chromosome 19q13.1 and contains 18 exons. So far, about 40 causative mutations have been identified. We report the clinical, hematological and molecular characteristics of 12 GPI deficient cases (eight males, four females) from 11 families, with a median age at admission of 13 years (ranging from 1 to 51); eight of them were of Italian origin. Patients displayed moderate to severe anemia, that improves with aging. Splenectomy does not always result in the amelioration of anemia but may be considered in transfusion-dependent patients to reduce transfusion intervals. None of the patients described here displayed neurological impairment attributable to the enzyme defect. We identified 13 different mutations in the GPI gene, six of them have never been described before; the new mutations affect highly conserved residues and were not detected in 1000 Genomes and HGMD databases and were considered pathogenic by several mutation algorithms. This is the largest series of GPI deficient patients so far reported in a single study. The study confirms the great heterogeneity of the molecular defect and provides new insights on clinical and molecular aspects of this disease.

In pediatric patients undergoing a first mobilization, the incidence of poor mobilization was 17%. Failure of mobilization resulted in an increase in health costs and a longer hospitalization for those who underwent autologous stem cell transplantation.