Acute lymphoblastic leukemia is the main type of leukemia in children. An infectious etiology has been suspected and the role of the Human herpesvirus-6 (HHV-6) has been suggested. Several studies have tried to establish a link between HHV-6 infections and hematological malignancies, with discordant results. The potential role of HHV-6 in the pathogenesis of pediatric acute lymphoblastic leukemia was investigated. HHV-6 genome copy number was measured by quantitative real-time PCR (RQ-PCR) in bone marrow or peripheral blood samples obtained from 36 children (median age = 4 years) with B acute lymphoblastic leukemia (n = 31) and T acute lymphoblastic leukemia (n = 5) at diagnosis and during complete remission. Positive samples were further characterized to define viral variant, A or B. A total of 24.7% of samples were positive for HHV-6 genome: 13.9% were leukemia samples and 34.1% were complete remission samples. Viral load was low with values lower at diagnosis (median viral copy number = 22.9) than at complete remission (median copy number = 60.1). Among the 17 patients with positive samples, 15 were typed as B-variant whereas 2 could not be typed. These results argue against a role of HHV6 infection in the development of pediatric acute lymphoblastic leukemia. They also suggest that HHV-6 may infect latently bone marrow progenitors but seems not able to infect leukemic cells, raising again the question of the mechanism of virus fusion and entry. This observation shows that a reactivation may be observed during complete remission supporting the possibility of virus reactivation in immunocompromised hosts.
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Background Pneumococcal conjugate vaccine (PCV) implementations led to major changes in serotype distribution and antibiotic resistance in carriage, accompanied by changes in antibiotic consumption. Objectives To assess the dynamic patterns of antimicrobial non-susceptibility across non-PCV13 serotypes following PCV implementations. Methods We conducted a quasi-experimental interrupted time series analysis based on a 17 year French nationwide prospective cohort. From 2001 to 2018, 121 paediatricians obtained nasopharyngeal swabs from children with acute otitis media who were aged 6 months to 2 years. The main outcome was the rate of penicillin-non-susceptible pneumococci (PNSP), analysed by segmented regression. Results We enrolled 10 204 children. After PCV13 implementation, the PNSP rate decreased (−0.5% per month; 95% CI −0.9 to −0.1), then, after 2014, the rate slightly increased (+0.7% per month; 95% CI +0.2 to +1.2). Global antibiotic use within the previous 3 months decreased over the study period (−22.2%; 95% CI −33.0 to −11.3), but aminopenicillin use remained high. Among the main non-PCV13 serotypes, four dynamic patterns of penicillin susceptibility evolution were observed, including unexpected patterns of serotypes emerging while remaining or even becoming penicillin susceptible. In contrast to PNSP strains, for these latter patterns, the rate of co-colonization with Haemophilus influenzae increased concomitant with their emergence. Conclusions In a context of continuing high antibiotic selective pressure, a progressive increase in PNSP rate was observed after 2014. However, we highlighted an unexpected variability in dynamic patterns of penicillin susceptibility among emerging non-PCV13 serotypes. Antibiotic resistance may not be the only adaptive mechanism to antimicrobial selective pressure, and co-colonization with H. influenzae may be involved.
Hodgkin's lymphoma (HL) in children and adolescents is highly curable, but children are at risk of long-term toxicity. The MDH-03 guidelines were established in order to decrease the burden of treatment in good-responder patients, and this report should be considered a step toward further optimization of treatment within large collaborative trials. We report the therapy and long-term outcomes of 417 children and adolescents treated according to the national guidelines, which were applied between 2003 and 2007 in France. The patients were stratified into three groups according to disease extension. Chemotherapy consisted of four cycles of VBVP (vinblastine, bleomycin, VP16, prednisone) in localized stages (G1/95 pts/23%), four cycles of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone, adriamycin, bleomycin, vinblastine) cycles in intermediate stages (G2/184 pts/44%) and three cycles of OPPA (vincristine, procarbazine, prednisone, adriamycin) plus three cycles of COPP in advanced stages (G3/138 pts/33%). Radiation therapy of the involved field was given to 97% of the patients, with the dose limited to 20 Gy in good responders (88%). With a median follow-up of 6.6 years, the 5-year event-free survival (EFS) and overall survival (OS) were 86.7% (83.1-89.7%) and 97% (94.5-98.1%), respectively. EFS and OS for G1, G2, and G3 were 98% and 100%, 81% and 97%, and 87% and 95%, respectively. Low-risk patients treated without alkylating agents and anthracycline had excellent outcomes and a low expected incidence of late effects. Intensification with a third OPPA cycle in high-risk group patients, including stage IV patients, allowed for very good outcomes, without increased toxicity.
4480 Post-transplant lymphoproliferative disorder (PTLD) caused by Epstein Barr Virus (EBV) is a severe complication in allogeneic hematopoietic stem cell transplantation (HSCT). Rituximab is an effective treatment, now commonly used as early therapy against B-cell PTLD and preemptive treatment of EBV reactivation. In first trials, rituximab was considered to have little adverse events. As exposure to this therapy is increasing worldwide, special toxicities are recognized including prolonged hypogammaglobulinemia (PH). Few details are known about duration and severity of rituximab induced low serum immunoglobulin status, especially in pediatric population treated with this drug for PTLPD after HSCT. This retrospective study was conducted in one pediatric HSCT center (Robert Debré Hospital, Paris, France). Between December 2008 and June 2011, among 138 transplanted children, 39 children received rituximab (Mabthera®, Roche, Paris, France) for either EBV reactivation or B-cell PTLD. 28 children were then followed for immune status more than 12 months after rituximab based therapy. Median age at HSCT was 7 years (range 1 to 18). There were 17 males and 11 females. Indications for HSCT were hematological malignancy (n=17), sickle cell disease (n=3), B thalassemia (n=1), severe aplastic anemia (n=4) and inherited bone marrow failure (n=3). 23 children underwent 1 HSCT, 4 children received 2 while 1 received 3 HSCT. They received HSCT from either MSD (n=10), 9 to 10/10 HLA MUD (n=16), haploidentical familial donor (n=1) or unrelated 5/6 cord blood (n=1). PH was defined as serum Ig G level < 3.3g/l (1 year old), < 5g/l (1 to 5 year old), < 5.5 g/l (5 to 15 years old) and <6.5 g/l after 15 years old or serum IgM level < 0.5g/l, more than 12 months after HSCT. IV-Ig replacement therapy was used when serum immunoglobulin level was under the median range for age. Median duration of hypogammaglobulinemia was 13 months (range 0 to 38): 60% (17/28) of patients had PH that last in 3 cases more than 24 months (24, 27 and 38 months) after HSCT. 6 children still have a low immunoglobulin status. Among patients with PH, 6 underwent HSCT from 9/10 MUD, 1 from haploidentical family donor and 1 from unrelated cord blood. 3 patients received 2 HSCT and 1 patient 3 HSCT. 10 children with PH had abnormal levels of immunoglobulin before rituximab therapy. Regarding B-cell reconstitution, normalization of B cell count for age was obtained in every child, by a median time of 7.5 months (range 5 to 19) after HSCT in PH cases and 7 months (range 4 to 9) in non PH cases. Among patients with PH, 5 presented repeated lower or upper respiratory track infections (vs. 1 without PH). 2 had pancytopenia secondary to a Parvovirus B 19 infection, 1 presented an extensive VZV infection 17 month after HSCT, and 1 had Pneumocystis jirovecii pneumonia 9 month after HSCT. 1 child presented invasive aspergillosis 8 months after HSCT and 2 months after IV-Ig supplementation interruption. Although rituximab induces almost complete depletion of normal B lymphocytes in peripheral blood for an average of 6–9 months, prolonged serum immunoglobulin suppression is unusual. However, PH has been reported in patients treated with rituximab in association with chemotherapy, or after either autologous or allogeneic HSCT. In some of these studies, phenotypical analysis of B cell recovery help to find abnormalities in naïve B cell differentiation into memory B cells and plasma cells. It may help to explain that normalization of B-cell count is not systematically followed by a rapid increase in immunoglobulin. It seems that during the period of post HSCT immune reconstitution, rituximab could affect, in association with other immunosuppressive factors, not only B cell quantity but also B cell quality. PH may be then a frequent event as we report in our study. Consequences of PH on infection severity and frequency are controversial. Infectious complications secondary to rituximab-associated PH are rare but some are reported as a fatal invasive aspergillosis, frequent pulmonary infections, parvovirus or VZV infections. We also report such severe infections in our patients with PH. Thus, every EBV-PTLD patient treated with rituximab must be monitored closely with regard to serum Ig levels and probably have to receive IV-Ig supplementation, even if its interest remains unproved. B-cell sub-population monitoring may probably help to understand mechanism of PH and identify high-risk patients. Disclosures: No relevant conflicts of interest to declare.
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