Background Ataxia telangiectasia (AT) is a multisystem DNA-repair disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. Patients with AT have reduced B- and T-cell numbers and ...a highly variable immunodeficiency. ATM is important for V(D)J recombination and immunoglobulin class-switch recombination (CSR); however, little is known about the mechanisms resulting in antibody deficiency severity. Objective We sought to examine the immunologic mechanisms responsible for antibody deficiency heterogeneity in patients with AT. Methods In this study we included patients with classical AT plus early-onset hypogammaglobulinemia (n = 3), classical AT (n = 8), and variant AT (late onset, n = 4). We studied peripheral B- and T-cell subsets, B-cell subset replication history, somatic hypermutation frequencies, CSR patterns, B-cell repertoire, and ATM kinase activity. Results Patients with classical AT lacked ATM kinase activity, whereas patients with variant AT showed residual function. Most patients had disturbed naive B-cell and T-cell homeostasis, as evidenced by low cell numbers, increased proliferation, a large proportion CD21low CD38low anergic B cells, and decreased antigen receptor repertoire diversity. Impaired formation of T cell–dependent memory B cells was predominantly found in patients with AT plus hypogammaglobulinemia. These patients had extremely low naive CD4+ T-cell counts, which were more severely reduced compared with those seen in patients with classical AT without hypogammaglobulinemia. Finally, AT deficiency resulted in defective CSR to distal constant regions that might reflect an impaired ability of B cells to undergo multiple germinal center reactions. Conclusion The severity of the antibody deficiency in patients with AT correlates with disturbances in B- and T-cell homeostasis resulting in reduced immune repertoire diversity, which consequently affects the chance of successful antigen-dependent cognate B-T interaction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Despite many efforts at reduction, cerebrospinal fluid (CSF) shunt infections are a major cause of morbidity in shunt surgery, occurring in 5-15% of cases. To attempt to reduce the shunt infection ...rate at our institution, we added topical vancomycin (intrashunt and perishunt) to our existing shunt infection prevention protocol in 2012.
We performed a retrospective cohort study comparing all shunted patients in January 2010 to December 2011 without vancomycin (control group, 263 procedures) to all patients who underwent shunt surgery between April 2012 and December 2015 with vancomycin (intervention group, 499 procedures).
The overall shunt infection rate significantly decreased from 6.8% (control group) to 3.0% (intervention group) (p = 0.023, absolute risk reduction 3.8%, relative risk reduction 56%). Multivariate logistic regression analysis confirmed that the addition of topical vancomycin showed that cases treated under a protocol of topical vancomycin were associated with a decreased shunt infection rate (odds ratio OR 0.49 95% CI 0.25-0.998; p = 0.049). Age < 1 year was associated with an increased risk of infection (OR) 4.41, 95% CI 2,10-9,26; p = 0.001). Time from surgery to infection was significantly prolonged in the intervention group (p = 0.001).
Adding intraoperative vancomycin to a shunt infection prevention protocol significantly reduces CSF shunt infection rate.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neonates, especially preterm neonates, have the highest risk of sepsis of all age groups. Transient immaturity of the neonatal immune system is an important risk factor. Neonates suffer from ...hypogammaglobulinemia as nor IgA nor IgM is transferred over the placenta and IgG is only transferred over the placenta late in gestation. In addition, neutrophil numbers and complement function are also decreased. This mini-review focuses on strategies to improve neonatal host-defense. Both clinical and preclinical studies have attempted to boost neonatal immunity to lower the incidence of sepsis and improve outcome. Recent advances in the development of (monoclonal) antibodies show promising results in preclinical studies but have yet to be tested in clinical trials. Strategies to increase complement activity seem efficient
but potential disadvantages such as hyperinflammation have held back further clinical development. Increase of neutrophil numbers has been tested extensively in clinical trials but failed to show improvement in mortality. Future research should focus on clinical applicability of promising new prevention strategies for neonatal sepsis.
Ataxia‐telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and ...an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classic ataxia‐telangiectasia phenotype, a variant phenotype exists with partly overlapping but some distinctive disease characteristics. This guideline summarizes frequently encountered medical problems in the disease course of patients with classic and variant ataxia‐telangiectasia, in the domains of neurology, immunology and infectious diseases, pulmonology, anaesthetic and perioperative risk, oncology, endocrinology, and nutrition. Furthermore, it provides a practical guide with evidence‐ and expert‐based recommendations for the follow‐up and treatment of all these different clinical topics.
What this paper adds
Recommendations for the clinical management of patients with ataxia‐telangiectasia.
Many health issues must be taken into account.
This review is commented on by Whitehouse on page 670 of this issue.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Aims
The palatability of a new paediatric formulation of valaciclovir was assessed in children and their parents: non‐inferiority of the new paediatric formulation (test formulation) compared to the ...reference formulation was investigated.
Methods
In vivo palatability testing was performed in a randomized, two‐period, multicentre, cross‐over study. Children and their parents scored the liking of the new paediatric valaciclovir formulation and the reference formulation on a 100 mm visual analogue scale (VAS). To support formulation development and palatability testing, electronic tongue measurements were applied.
Results
The electronic tongue measurement indicated taste‐masking capabilities for three different formulations in the developmental phase. A glycerol‐based formulation was further tested and compared to the reference formulation prepared out of crushed and suspended tablets. The mean difference (95% CI) in VAS scores between both formulations, as indicated by the children (n = 20), was 2.4 (−8.5, 13) mm, in favour of the new paediatric valaciclovir formulation. The mean (95% CI) difference in VAS scores indicated by the parents (n = 20) was −0.9 (−12, 9.8) mm.
Conclusion
The palatability of the new paediatric valaciclovir formulation was considered non‐inferior to the reference formulation prepared out of crushed tablets. We were able to optimize the study design and number of children to be included in the palatability testing by using electronic tongue measurements.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Patients with an IgG subclass deficiency (IgSD) ± specific polysaccharide antibody deficiency (SPAD) often present with recurrent infections. Previous retrospective studies have shown that ...prophylactic antibiotics (PA) and immunoglobulin replacement therapy (IRT) can both be effective in preventing these infections; however, this has not been confirmed in a prospective study.
Objective
To compare the efficacy of PA and IRT in a randomized crossover trial.
Methods
A total of 64 patients (55 adults and 9 children) were randomized (2:2) between two treatment arms. Treatment arm A began with 12 months of PA, and treatment arm B began with 12 months of IRT. After a 3-month bridging period with cotrimoxazole, the treatment was switched to 12 months of IRT and PA, respectively. The efficacy (measured by the incidence of infections) and proportion of related adverse events in the two arms were compared.
Results
The overall efficacy of the two regimens did not differ (
p
= 0.58, two-sided Wilcoxon signed-rank test). A smaller proportion of patients suffered a related adverse event while using PA (26.8% vs. 60.3%,
p
< 0.0003, chi-squared test). Patients with persistent infections while using PA suffered fewer infections per year after switching to IRT (2.63 vs. 0.64,
p
< 0.01).
Conclusion
We found comparable efficacy of IRT and PA in patients with IgSD ± SPAD. Patients with persistent infections during treatment with PA had less infections after switching to IRT.
Clinical Implication
Given the costs and associated side-effects of IRT, it should be reserved for patients with persistent infections despite treatment with PA.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aim
This study investigated febrile children with petechial rashes who presented to European emergency departments (EDs) and investigated the role that mechanical causes played in diagnoses.
Methods
...Consecutive patients with fever presenting to EDs in 11 European emergency departments in 2017–2018 were enrolled. The cause and focus of infection were identified and a detailed analysis was performed on children with petechial rashes. The results are presented as odds ratios (OR) with 95% confidence intervals (CI).
Results
We found that 453/34010 (1.3%) febrile children had petechial rashes. The focus of the infection included sepsis (10/453, 2.2%) and meningitis (14/453, 3.1%). Children with a petechial rash were more likely than other febrile children to have sepsis or meningitis (OR 8.5, 95% CI 5.3–13.1) and bacterial infections (OR 1.4, 95% CI 1.0–1.8) as well as need for immediate life‐saving interventions (OR 6.6, 95% CI 4.4–9.5) and intensive care unit admissions (OR 6.5, 95% CI 3.0–12.5).
Conclusion
The combination of fever and petechial rash is still an important warning sign for childhood sepsis and meningitis. Ruling out coughing and/or vomiting was insufficient to safely identify low‐risk patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Streptococcus pneumoniae and Neisseria meningitidis are pathogens that frequently colonize the nasopharynx in an asymptomatic manner but are also a cause of invasive bacterial infections mainly in ...young children. The complement system plays a crucial role in humoral immunity, complementing the ability of antibodies to clear microbes, thereby protecting the host against bacterial infections, including S. pneumoniae and N. meningitidis. While it is widely accepted that complement deficiencies due to rare genetic variants increase the risk for invasive bacterial infection, not much is known about the common genetic variants in the complement system in relation to disease susceptibility. In this review, we provide an overview of the effects of common genetic variants on complement activation and on complement-mediated inflammation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
DNA double‐strand break repair via non‐homologous end joining (NHEJ) is involved in recombination of immunoglobulin and T‐cell receptor genes. Mutations in NHEJ components result in ...syndromes that are characterized by microcephaly and immunodeficiency. We present a patient with lymphopenia, extreme radiosensitivity, severe dysmaturity, corpus callosum agenesis, polysyndactily, dysmorphic appearance, and erythema, which are suggestive of a new type of NHEJ deficiency. We identified two heterozygous mutations in LIG4. The p.S205LfsX29 mutation results in lack of the nuclear localization signal and appears to be a null mutation. The second mutation p.K635RfsX10 lacks the C‐terminal region responsible for XRCC4 binding and LIG4 stability and activity, and therefore this mutant might be a null mutation as well or have very low residual activity. This is remarkable since Lig4 knockout mice are embryonic lethal and so far in humans no complete LIG4 deficiencies have been described. This case broadens the clinical spectrum of LIG4 deficiencies.
In a patient with severe dysmaturity, primordial dwarfism, and neurological abnormalities, we identified two heterozygous mutations in LIG4. The p.S205LfsX29 mutant was only expressed in the cytoplasm and therefore represented a null mutation. The second mutant (p.K635RfsX10) was expressed in the nucleus, but lacks an important domain necessary for its stability, implying that this mutant has probably very low residual activity. This study shows that the clinical spectrum of LIG4 deficiency is broadened with a new clinical phenotype.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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