Maribavir, brincidofovir and letermovir: Efficacy and safety of new antiviral drugs for treating cytomegalovirus infections.

Cytomegalovirus (CMV) infection is a common complication in immunocompromised patients, especially after hematopoietic stem cell or solid organ transplantation. Therapeutic antiviral options [(val)ganciclovir, foscarnet, cidofovir] are still limited and can expose to severe toxicities. Moreover, prolonged antiviral drug exposure and ongoing viral replication are key factors in the development of antiviral drug resistance. After many years of few tangible advances in terms of new antiviral drugs, we are now experiencing an exciting period characterized by a series of phase III clinical trials incorporating three novel agents: maribavir, brincidofovir, and letermovir. This article summarizes the current state of the prevention and treatment of CMV infections as well as data of investigational drugs in clinical development.

An update on pediatric invasive aspergillosis.

Invasive aspergillosis (IA) is a major cause of morbidity and mortality in immunocompromised adults and children, the number of which has been continuously increasing in the last decades. The purpose of our review was to provide epidemiological, clinical, and biological data and antifungal treatment options in the pediatric population. Several biological assays (galactomannan enzyme immunoassay, ß-D-glucan, detection of Aspergillus spp. DNA) have proven useful adjuncts for the diagnosis of IA in adult studies. However, data on these assays in children is limited by small sample sizes and sometimes conflicting results concerning their sensitivity/specificity. Pediatric treatment recommendations are mainly extrapolated from results of clinical trials performed in adults. It is thus necessary to develop new antifungal formulations specifically adapted to the pediatric population and to evaluate their pharmacokinetic/pharmacodynamic profile, their safety, and their effectiveness in infants and children.

Nocardiosis in transplant recipients.

Nocardiosis is a rare opportunistic infection caused by Nocardia spp., an aerobic actinomycete, that mainly affects patients with cell-mediated immunity defects, such as transplant recipients. Despite recent progress regarding Nocardia identification and changes in taxonomic assignment, many challenges remain for the diagnosis or management of nocardiosis. This opportunistic infection affects 0.04 to 3.5 % of patients with solid organ or hematopoietic stem cell transplantation, depending on the organ transplanted, cytomegalovirus (CMV) infection, corticosteroids dose and calcineurin inhibitors level. Nocardiosis diagnosis relies on appropriate clinical, radiological and microbiological workup that includes the sampling of an accessible involved site and molecular microbiology tools. In parallel, extensive clinical and radiological evaluations are mandatory, including brain imaging, even in the absence of neurological signs. In transplanted patients, differential diagnosis is challenging, with co-infections reported in 20 to 64 % of cases. As the antibiotic susceptibility pattern varies among species, the antimicrobial regimen before species identification should rely on the association of antibiotics active on all species of Nocardia. Bactericidal antibiotics are required in cases of severe or disseminated disease. Furthermore, in transplant recipients, combination therapy is difficult to manage because of cumulative toxicity and interactions with immunosuppressive agents. Because of a high recurrence rate, antibiotic therapy should be prescribed for 6 to 12 months.

Safety of hematopoietic stem cell transplantation from hepatitis B core antibodies-positive donors with low/undetectable viremia in HBV-naïve children.

Scarce data exist on allogeneic hematopoietic stem cell transplantation (HSCT) outcomes in hepatitis B virus (HBV)-naïve recipients from HBV-experienced donors. Long-term follow-up is herein reported for 17 allogeneic HSCT performed in 13 HBV-naïve children from HBc-antibodies-positive donors between 2006 and 2012. Four donors were HBs-antigen-positive, with detectable but low viremia in 2 cases (<2 log10IU/ml). HBV-DNA was undetectable in all transplanted cell products. Recipients' HBV prophylaxis consisted of pre-transplant vaccination, polyvalent immune globulins, specific anti-HBV immune globulins, and/or oral lamivudine in 3, 12, 8, and 8 children, respectively. No case of HBV transmission occurred based on negative close monitoring of recipients' HBV serology and plasma HBV-DNA during a median follow-up of 22 months. In case of undetectable viremia in the donor, prophylaxis with vaccination and/or immune globulins in the recipient seems to be sufficient and lamivudine prophylaxis might be unnecessary to prevent viral transmission. In case of undetectable viremia in the donor, a systematic screening of HBV DNA in the stem cell product might be unnecessary to confirm the low risk of viral transmission. Prior exposure to HBV in the donor should not be considered a contraindication to HSCT.

Dental abnormalities in Schimke immuno-osseous dysplasia.

Described for the first time in 1971, Schimke immuno-osseous dysplasia (SIOD) is an autosomal-recessive multisystem disorder that is caused by bi-allelic mutations of SMARCAL1, which encodes a DNA annealing helicase. To define better the dental anomalies of SIOD, we reviewed the records from SIOD patients with identified bi-allelic SMARCAL1 mutations, and we found that 66.0% had microdontia, hypodontia, or malformed deciduous and permanent molars. Immunohistochemical analyses showed expression of SMARCAL1 in all developing teeth, raising the possibility that the malformations are cell-autonomous consequences of SMARCAL1 deficiency. We also found that stimulation of cultured skin fibroblasts from SIOD patients with the tooth morphogens WNT3A, BMP4, and TGFß1 identified altered transcriptional responses, raising the hypothesis that the dental malformations arise in part from altered responses to developmental morphogens. To the best of our knowledge, this is the first systematic study of the dental anomalies associated with SIOD.

[Lymphohistiocytic activation syndrome and Burkholderia cepacia complex infection in a child revealing chronic granulomatous disease and chromosomal integration of the HHV-6 genome]. / Syndrome d'activation lymphohistiocytaire associé à une infection àBurkholderia cepacia complex chez un nourrisson révélant une granulomatose septique et une intégration génomique du virus HHV-6.

Chronic granulomatous disease (GCD) is characterized by severe infections, notably with Burkholderia cepacia complex (BCC). GCD is rarely complicated by lymphohistiocytic activation syndromes, most often secondary to bacterial or viral infections, in particular human herpes virus 6 (HHV-6). We describe the case of a 10-month-old boy who suffered from multiple organ failure due to a BCC infection and a lymphohistiocytic activation syndrome, leading to diagnosis of GCD. The initial search for HHV-6 was positive and the infection was treated, but the progression and viral sample analysis led to the chromosomal integration of the HHV-6 genome. The child's clinical condition was normal after bone marrow transplantation. This case describes a rare association between GCD and lymphohistiocytic activation syndrome and raises questions about the role played by chromosomal integration of the HHV-6 genome.

From childhood to adulthood: long-term outcome of medulloblastoma patients. The Institut Curie experience (1980-2000).

Medulloblastoma patients treated at the Institute Curie between 1980 and 2000 were reviewed. Only patients whose primary treatment included craniospinal radiation were considered. Surviving patients were identified and evaluated by means of self-report questionnaires using the Health Utility Index (HUI). Psychosocial functioning, employment, and other health-related indicators were recorded. Seventy-three patients were treated during the study period. At a median follow-up from diagnosis of 14.4 years, 49 patients were alive and 45 surviving patients could be contacted. Late sequelae were frequent, particularly neurological deficits (71%) and endocrine complications (52%). Impairments of psychosocial functioning, including employment, driving capacity, independent living, and marital status, were identified in most patients. Most long-term medulloblastoma survivors suffer persistent deficits in several domains, with a significant impact on their psychosocial functioning. These findings reinforce the importance of early intervention programs for all survivors in order to reduce the psychosocial impacts of their disease.

[Immunity and immunosuppression in childhood idiopathic nephrotic syndrome]. / Immunité cellulaire et traitement immunosuppresseur du syndrome néphrotique idiopathique corticosensible.

Steroid sensitive idiopathic nephrotic syndrome is a T-cell disorder characterized by a functional renal impairment. Concluding a still relevant demonstration involving cellular immunity in the pathogenesis of the disease, R. Shalhoub in 1974 suggested a "special role for the thymus" based on the efficiency of steroids and alkylating agents, dramatic recoveries following measles, sensibility to bacterial infection due to a lack of cooperation between T and B cell and association to Hodgkin disease. As a matter of fact, the selected drugs based on medical empirism somehow enhance thymocytes apoptosis and negative selection of T cell, except cyclosporin. Steroids have been the first historical treatment of idiopathic nephrotic syndrome and have steadily been the first-line treatment for 50 years. Their unavoidable ability to induce rapid recovery of proteinuria and long-lasting or definite remission are dependent to a strict compliance to treatment. Indications of steroids-sparing treatments are not that clearcut in patients with steroids intoxication. Objectively, efficiency of levamisole and cyclophosphamide are much more limited than previously reported and cyclosporin nephrotoxicity might severely impair renal function following long-lasting treatment as well as it may paradoxically increase the activity of the disease. An alternate strategy to those currently adopted would use cyclosporin as the first-line steroids-sparing treatment during a very limited period, awaiting favourable ageing of patients and natural dampening activity of the disease to a full efficiency of alkylating agents. Compared to cyclophosphamide and cyclosporin, the relative safety of levamisole is encouraging to a more frequent uses. Its association to a full dose of prednisone in the treatment of the inaugural episode should be investigated. According to the limitations of those therapies, emerging drugs as mycophenolate might be worthwhile in the treatment of nephrotic patients.