Advantage of First-Line Therapeutic Drug Monitoring-Driven Use of Infliximab for Treating Acute Intestinal and Liver GVHD in Children: A Prospective, Single-Center Study.

The high serum concentrations of TNF-α characterize acute graft-versus-host disease (aGVHD), for which infliximab treatment may be beneficial. In 28 pediatric patients, four doses of 10 mg/kg infliximab every seven days were administered after steroid failure (Standard Group, n = 14) or as a first-line therapy (Early Group, n = 14). Population pharmacokinetic analyses and evaluation of serum cytokines were performed. After two months of treatment, complete response in gastrointestinal and liver aGVHD was achieved in 43% and 100% of patients in the Standard and Early groups, respectively. During follow-up, four patients in the Standard Group (but none in the Early Group) experienced an aGVHD recurrence. Viral infections occurred more frequently in the Standard Group after the fifth dose. Infliximab clearance did not differ between groups or according to treatment outcome for each organ involved in aGVHD, whereas serum levels of cytokines significantly differed. Therefore, present findings show that use of first-line, TDM-driven infliximab to treat aGVHD in children may result in better clinical outcomes and tolerability, with a different pattern of cytokines generated according to the moment of beginning of treatment.

Defibrotide impact on the acute GVHD disease incidence in pediatric hematopoietic stem cell transplant recipients.

Despite advances in acute graft-versus-host disease (aGVHD) prophylaxis, current pharmacological approaches fail to prevent aGVHD. The protective effect of defibrotide on GVHD incidence and GVHD-free survival has not been sufficiently studied. 91 pediatric patients included in this retrospective study were divided into two groups based on defibrotide use. We compared the incidence of aGVHD and chronic GVHD-free survival between the defibrotide and control groups. The incidence and severity of aGVHD were significantly lower in patients who received defibrotide prophylactic administration than in the control group. This improvement was observed in the liver and intestinal aGVHD. No defibrotide prophylaxis benefit was observed in the prevention of chronic GVHD. The pro-inflammatory cytokine levels were significantly higher in the control group. Our findings suggest that prophylactic administration of defibrotide in pediatric patients significantly reduces the incidence and severity of aGVHD, with a modification of cytokine pattern, both strongly coherent with the protective drug's action. This evidence adds to pediatric retrospective studies and preclinical data suggesting a possible defibrotide role in this setting.

Druggable monogenic immune defects hidden in diverse medical specialties: Focus on overlap syndromes.

In the last two decades two new paradigms changed our way of perceiving primary immunodeficiencies: An increasing number of immune defects are more associated with inflammatory or autoimmune features rather than with infections. Some primary immune defects are due to hyperactive pathways that can be targeted by specific inhibitors, providing innovative precision treatments that can change the natural history of diseases. In this article we review some of these "druggable" inborn errors of immunity and describe how they can be suspected and diagnosed in diverse pediatric and adult medicine specialties. Since the availability of precision treatments can dramatically impact the course of these diseases, preventing the development of organ damage, it is crucial to widen the awareness of these conditions and to provide practical hints for a prompt detection and cure.

Intranasal dexmedetomidine and intranasal ketamine association allows shorter induction time for pediatric sedation compared to intranasal dexmedetomidine and oral midazolam.

BACKGROUND: Non-painful diagnostic procedures require an inactive state for a prolonged time, so that sedation is often needed in younger children to perform the procedures. Our standard of care in this setting consists of the association between oral midazolam (0.5 mg/kg) and intranasal dexmedetomidine (4 mcg/kg). One of the limits of this approach is that the onset of action is quite delayed (up to 55 min) and poorly predictable. We chose to compare this association with intranasal-ketamine and intranasal-dexmedetomidine. METHODS: This is a "pre-post" study. The study population included the first forty children receiving sedation with the "new" combination intranasal ketamine (3 mg/kg) and intranasal dexmedetomidine (4 mcg/kg) compared to a historical cohort including the last forty children receiving sedation with our standard of care combination of intranasal dexmedetomidine (4mcg/kg) and oral midazolam (0,5 mg/kg). RESULTS: The association intranasal dexmedetomidine and intranasal ketamine allowed for a significantly shorter sedation induction time than the combination intranasal dexmedetomidine and oral midazolam (13,5 min versus 35 min). Both group's cumulative data showed a correlation between age and sedation effectiveness, with younger children presenting a higher success rate and shorter induction time (p 0,001). CONCLUSIONS: This study suggests that the ketamine and dexmedetomidine intranasal association may have a shorter onset of action when compared to intranasal dexmedetomidine and oral midazolam.

Why does SARS-CoV-2 hit in different ways? Host genetic factors can influence the acquisition or the course of COVID-19.

The identification of high-risk factors for the infection by SARS-CoV-2 and the negative outcome of COVID-19 is crucial. The genetic background of the host might account for individual responses to SARS-CoV-2 infection besides age and comorbidities. A list of candidate polymorphisms is needed to drive targeted screens, given the existence of frequent polymorphisms in the general population. We carried out text mining in the scientific literature to draw up a list of genes referable to the term "SARS-CoV*". We looked for frequent mutations that are likely to affect protein function in these genes. Ten genes, mostly involved in innate immunity, and thirteen common variants were identified, for some of these the involvement in COVID-19 is supported by publicly available epidemiological data. We looked for available data on the population distribution of these variants and we demonstrated that the prevalence of five of them, Arg52Cys (rs5030737), Gly54Asp (rs1800450) and Gly57Glu (rs1800451) in MBL2, Ala59Thr (rs25680) in CD27, and Val197Met (rs12329760) in TMPRSS2, correlates with the number of cases and/or deaths of COVID-19 observed in different countries. The association of the TMPRSS2 variant provides epidemiological evidence of the usefulness of transmembrane protease serine 2 inhibitors for the cure of COVID-19. The identified genetic variants represent a basis for the design of a cost-effective assay for population screening of genetic risk factors in the COVID-19 pandemic.

The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers.

Type I disorders of glycosylation (CDG), the most frequent of which is phosphomannomutase 2 (PMM2-CDG), are a group of diseases causing the incomplete N-glycosylation of proteins. PMM2-CDG is an autosomal recessive disease with a large phenotypic spectrum, and is associated with mutations in the PMM2 gene. The biochemical analysis of mutants does not allow a precise genotype⁻phenotype correlation for PMM2-CDG. PMM2 is very tolerant to missense and loss of function mutations, suggesting that a partial deficiency of activity might be beneficial under certain circumstances. The patient phenotype might be influenced by variants in other genes associated with the type I disorders of glycosylation in the general population.