Management of cerebral azole-resistant Aspergillus fumigatus infection : a role for intraventricular liposomal-amphotericin B

Objectives: In the pre-azole era, central nervous system (CNS) infections with Aspergillus had a dismal outcome. Survival improved with voriconazole but CNS infections caused by azole-resistant Aspergillus fumigatus preclude its use. Intravenous liposomal-amphotericin B (L-AmB) is the preferred treatment option for azole-resistant CNS infections but has suboptimal brain concentrations. Methods: We describe three patients with biopsy-proven CNS aspergillosis where intraventricular L-AmB was added to systemic therapy. Two patients with azole-resistant aspergillosis and one patient with azole-susceptible CNS aspergillosis were treated with intraventricular L-AmB at a dose of 1 mg weekly. Results: We describe three patients successfully treated with a combination of intravenous and intraventricular L-AmB. All three patients survived but one patient developed serious headaches, most likely not related to this treatment. Conclusions: Intraventricular L-AmB may have a role in the treatment of therapy-refractory CNS aspergillosis when added to systemic therapy. (C) 2020 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy

High interpatient variability of treosulfan exposure is associated with early toxicity in paediatric HSCT: a prospective multicentre study

Treosulfan-based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drug's relationship with regimen-related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30 g/m2, administered over 3 consecutive days in infants <1 year old (n = 12) and 42 g/m2 in children ≥1 year old (n = 65). Mean day 1 treosulfan exposure was 1744 ± 795 mg*h/l (10 g/m2) and 1561 ± 511 mg*h/l (14 g/m2), with an inter-individual variability of 56 and 33% in the respective groups. High treosulfan exposure (>1650 mg*h/l) was associated with an increased risk of mucosal [Odds ratio (OR) 4·40; 95% confidence interval (CI) 1·19–16·28, P = 0·026] and skin toxicity (OR 4·51; 95% CI 1·07–18·93, P = 0·040). No correlation was found between treosulfan exposure and the early clinical outcome parameters: engraftment, acute graft-versus-host disease and donor chimerism. Our study provides the first evidence in a large cohort of paediatric patients of high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long-term disease-specific outcome and late treatment-related toxicity

Campylobacter jejuni bacteremia and Helicobacter pylori in a patient with X-linked agammaglobulinemia

We describe a 15-year-old patient with X-linked agammaglobulinemia who developed malabsorption and bacteremia due to infection of Helicobacter pylori and Campylobacter jejuni. The Campylobacter bacteremia was only recognized after subculturing of blood culture bottles that failed to signal in the automated system. After 2 weeks of treatment with meropenem and erythromycin for 4 weeks, the patient developed a relapse of bacteremia 10 months later with a high level erythromycin resistant C. jejuni. Sequencing revealed an A2058C mutation in the 23 S rRNA gene associated with this resistance. Treatment with doxycycline for 4 weeks finally resulted in complete eradication. This case report illustrates the importance for physicians to use adapted culture methods and adequate prolonged therapy in patients with an immunodeficiency. A summary of published case reports and series of patients with hypogammaglobulinemia or agammaglobulinemia with Campylobacter or Helicobacter bacteremia is given

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome

BACKGROUND AND OBJECTIVE: Alemtuzumab (Campath®) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing. METHODS: A population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2-19 years, receiving a cumulative intravenous dose of 0.2-1.5 mg/kg, and treated between 2003 and 2015 in two centers. RESULTS: Alemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance. CONCLUSION: The current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab

Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients.

Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2-28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5-16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. HCT is a definitive cure for DADA2 with > 95% survival

Hematopoietic stem cell transplantation rescues the hematological, immunological and vascular phenotype in DADA2

Deficiency of adenosine deaminase 2 (DADA2) is caused by biallelic deleterious mutations in CECR1. DADA2 results in variable autoinflammation and vasculopathy (recurrent fevers, livedo reticularis, polyarteritis nodosa, lacunar ischemic strokes and intracranial hemorrhages), immunodeficiency and bone marrow failure. TNF-α blockade is the treatment of choice for the autoinflammation and vascular manifestations. Hematopoietic stem cell transplantation (HSCT) represents a potential definitive treatment. We present a cohort of 14 patients from 6 countries who received HSCT for DADA2. Indication for HSCT was bone marrow dysfunction or immunodeficiency. Six of 14 patients had vasculitis pre-HSCT. The median age at HSCT was 7.5 years. Conditioning regimens were myeloablative (9), and reduced intensity (5). Donors were HLA-matched sibling (n=1), HLA-matched unrelated (n=9), HLA-mismatched unrelated (n=3), and HLA haploidentical sibling (n=1). All patients are alive and well with no new vascular events and resolution of hematological and immunological phenotype at a median follow-up of 18mo (range 5mo to 13yr). Plasma ADA2 enzyme activity normalized in those tested post-HSCT (7/7), as early as D+14 (myeloid engraftment). Post-HSCT hematological autoimmunity (cytopenias) was reported in 4 patients, acute graft versus host disease (GvHD) grade 1 in 2, grade 2 in 3 and grade 3-4 in 1, and moderate chronic GvHD in 1 patient. In conclusion, in 14 patients, HSCT was an effective and definitive treatment for DADA2

Immunity against Neisseria meningitidis Serogroup C in the Dutch Population before and after Introduction of the Meningococcal C Conjugate Vaccine

Contains fulltext : 88187.pdf (publisher's version ) (Open Access)BACKGROUND: In 2002 a Meningococcal serogroup C (MenC) conjugate vaccine, with tetanus toxoid as carrier protein, was introduced in the Netherlands as a single-dose at 14 months of age. A catch-up campaign was performed targeting all individuals aged 14 months to 18 years. We determined the MenC-specific immunity before and after introduction of the MenC conjugate (MenCC) vaccine. METHODS AND FINDINGS: Two cross-sectional population-based serum banks, collected in 1995/1996 (n = 8539) and in 2006/2007 (n = 6386), were used for this study. The main outcome measurements were the levels of MenC polysaccharide(PS)-specific IgG and serum bactericidal antibodies (SBA) after routine immunization, 4-5 years after catch-up immunization or by natural immunity. There was an increasing persistence of PS-specific IgG and SBA with age in the catch-up immunized cohorts 4-5 years after their MenCC immunization (MenC PS-specific IgG, 0.25 microg/ml (95%CI: 0.19-0.31 microg/ml) at age 6 years, gradually increasing to 2.34 microg/ml,(95%CI: 1.70-3.32 microg/ml) at age 21-22 years). A comparable pattern was found for antibodies against the carrier protein in children immunized above 9 years of age. In case of vaccination before the age of 5 years, PS-specific IgG was rapidly lost. For all age-cohorts together, SBA seroprevalence (> or =8) increased from 19.7% to 43.0% in the pre- and post-MenC introduction eras, respectively. In non-immunized adults the SBA seroprevalence was not significantly different between the pre- and post-MenC introduction periods, whereas PS-specific IgG was significantly lower in the post-MenC vaccination (GMT, age > or =25 years, 0.10 microg/ml) era compared to the pre-vaccination (GMT, age > or =25 years, 0.43 microg/ml) era. CONCLUSION: MenCC vaccination administered above 5 years of age induced high IgG levels compared to natural exposure, increasing with age. In children below 14 months of age and non-immunized cohorts lower IgG levels were observed compared to the pre-vaccination era, whereas functional levels remained similar in adults. Whether the lower IgG poses individuals at increased risk for MenC disease should be carefully monitored. Large-scale introduction of a MenCC vaccine has led to improved protection in adolescents, but in infants a single-dose schedule may not provide sufficient protection on the long-term and therefore a booster-dose early in adolescence should be considered

Hematopoietic cell transplantation in severe combined immunodeficiency : The SCETIDE 2006-2014 European cohort

Publisher Copyright: © 2021 The AuthorsBackground: Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. Objective: We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. Methods: HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. Results: Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P 0.5 × 10e3/μL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. Conclusion: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.Peer reviewe

Association between the magnitude of intravenous busulfan exposure and development of hepatic veno-occlusive disease in children and young adults undergoing myeloablative allogeneic hematopoietic cell transplantation

Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dos-ing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative con-ditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, high-est 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 mg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg x h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two addi-tional alkylators (63.7%, n = 444), cumulative busulfan exposure (78 mg x h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan expo-sure did not further increase this risk. Transplantation and immunomodulatio