Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphoinositide 3-kinase (PI3K), result in hyperactivation of the PI3K–AKT–mechanistic target of ...rapamycin pathway and underlie a novel inborn error of immunity. Affected subjects exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or cytomegalovirus infection, and increased incidence of B-cell lymphoproliferation, lymphoma, or both. Mechanisms underlying disease pathogenesis remain unknown.
Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in patients with PIK3CD GOF mutations, identify key molecules required for cell-mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this and other EBV-opathies.
We studied the consequences of PIK3CD GOF mutations on the generation, differentiation, and function of CD8+ T cells and natural killer (NK) cells, which are implicated in host defense against infection with herpesviruses, including EBV.
PIK3CD GOF total and EBV-specific CD8+ T cells were skewed toward an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion and increased susceptibility to reactivation-induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF mutations. NK cells in patients with PIK3CD GOF mutations also exhibited perturbed expression of differentiation-associated molecules. Both CD8+ T and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, programmed death ligand 1/2, and CD70.
PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8+ T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance.
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Gain-of-function (GOF) mutations in PIK3CD cause a primary immunodeficiency characterized by recurrent respiratory tract infections, susceptibility to herpesvirus infections, and impaired antibody ...responses. Previous work revealed defects in CD8+ T and B cells that contribute to this clinical phenotype, but less is understood about the role of CD4+ T cells in disease pathogenesis.
We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4+ T-cell function.
We performed detailed ex vivo, in vivo, and in vitro phenotypic and functional analyses of patients' CD4+ T cells and a novel murine disease model caused by overactive PI3K signaling.
PI3K overactivation caused substantial increases in numbers of memory and follicular helper T (TFH) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human TFH cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a TFH cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4+ T cells also acquired an aberrant TFH phenotype and provided poor help to support germinal center reactions and humoral immune responses by antigen-specific wild-type B cells. The increase in numbers of both memory and TFH cells was largely CD4+ T-cell extrinsic, whereas changes in cytokine production and TFH cell function were cell intrinsic.
Our studies reveal that CD4+ T cells with overactive PI3K have aberrant activation and differentiation, thereby providing mechanistic insight into dysfunctional antibody responses in patients with PIK3CD GOF mutations.
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Vancomycin has been in clinical use for over 60 years, but it is still not clear what dose should be given to children. Effective treatment with vancomycin requires a serum concentration well above ...the minimum inhibitory concentration (MIC) of the bacteria being treated. This is predicted by the area under the concentration curve (AUC) divided by the MIC being >400 (AUC/MIC). Recent concerns about increasing MIC in staphylococci have lead to recommendations to aim for higher trough vancomycin levels (15–20 mg/L). In current practice, most children do not achieve these trough levels. Modelling and pharmacokinetic studies in children suggest these trough levels may not be necessary if the MIC of the organisms is 1 mg/L or less. Further, large-scale studies are needed to determine the most appropriate dosing of vancomycin in children. While awaiting these, it is time to consider moving to 15 mg/kg 6 h as a standard starting regime for vancomycin. It is also vital to determine the MIC of the organism being treated, as this may give some guidance about suitable trough levels to be aimed for. There is currently little evidence to guide the use of loading doses or continuous vancomycin infusions in children.
Autoimmunity is observed in 40% of the patients manifesting as hemolytic anemia, vasculitis, neutropenia, inflammatory bowel disease, or IgA nephropathy.1 The pathogenesis of autoimmunity is complex. ...Contrastingly, the adult CI revealed a 2-year overall survival rate of 43%.6 It is important to note that prospective validation studies of CIs in malignant or nonmalignant diseases have not been validated. ...accurately defining the risk of a second RIC transplant in an adolescent with adult comorbidity was exceedingly difficult and mandated an ethics discussion. ...the case highlights how, even in the setting of a CI of 6, it is possible to achieve remission of this refractory condition using nonmyeloablative conditioning.
This abstract provides an evidence-based approach to the detection of post-HSCT BOS in children. The background discusses the high occurrence of pulmonary complications post-HSCT, particularly BOS, ...and the conflicting recommendations for surveillance. A multinational panel of experts conducted a systematic review of the literature to answer six questions regarding surveillance and evaluation of post-HSCT BOS in children. The panel used the Grading of Recommendations, Assessment, Development, and Evaluation approach to rate the quality of evidence and strength of recommendations. The recommendations address the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS, and propose new diagnostic criteria. The document also highlights considerations for implementing each recommendation and identifies areas for future research.
Patients may develop autoimmunity, lymphoproliferation, and malignancy.2 Transmembrane activator and calcium-modulating and cyclophilin ligand interactor (TACI), encoded by TNFRSF13B, is mutated in ...10% cases of CVID.3 TACI is important in B-lymphocyte activation and plasma cell differentiation, and it plays an important role in central B-lymphocyte tolerance.4 TACI-deficient mice experience increased lymphomas and autoimmune phenomena including a lupuslike condition with autoantibody production.5 A number of TNFRSF13B mutations are described in patients with CVID, most commonly heterozygous p.C104R and p.A181E mutations, each found in 4% to 5% of the patients with CVID,6,7 who develop splenomegaly and autoimmune phenomena more frequently than do patients with other mutations, including CD8 lymphoproliferation described in a patient with a heterozygous p.104C>R TNFRSF13B mutation.8 We report a patient with 22q11 deletion and heterozygous p.104C>R TNFRSF13B mutation who developed granulomatous-lymphocytic interstitial lung disease (GLILD) and other widespread granulomatous-lymphocytic disease, although no peripheral CD8 lymphoproliferation. Patients with CVID harboring TNFRSF13B mutations more frequently develop splenomegaly and autoimmune phenomena.7 Heterozygous p.104C>R alleles are associated with antibody deficiency, reduced CD19+CD27+IgM-IgD- B lymphocytes, lymphoproliferation, and autoimmune complications.7 However, many individuals carrying a TNFRSF13B mutation do not develop CVID, because in many individuals, peripheral B-lymphocyte tolerance can be established despite a defective central B-lymphocyte tolerance checkpoint.4 Although one heterozygous TNFRSF13B mutation alone is insufficient to induce the development of CVID, the combination of another defect (22q11 deletion), associated with autoimmunity, may have been sufficient in our patient, either because some genes deleted in the 22q11 region, such as TBX1 or CRKL, implicated in thymic development, act as a TNFRSF13B modifier, or the cellular immunodeficiency associated with 22q11 deletion acted in synergy with the defect caused by the TNFRSF13B mutation.4 The immunopathology of granulomatous disease in PID is unclear.
A single-center experience of catheter-related blood stream infections in children undergoing hematopoietic stem cell transplant for primary immunodeficiency is described. The rate of definite ...central venous catheter infections was 5.31/1000 line days. Staphylococcus epidermidis was the most commonly identified organism. Teicoplanin resistance occurred in 17% of S. epidermidis infections. The central catheter was removed in 21% of infections.
How to use... eye swabs Drew, Richard J; Cole, Theresa S; Newman, William
Archives of disease in childhood. Education and practice edition,
06/2015, Letnik:
100, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Conjunctivitis is a very common presentation to general practitioners and general paediatricians. The investigation of conjunctivitis can be a significant cost to microbiology laboratories due to the ...high volume of samples that can be submitted, particularly from patients in the community. The key issue is to send eye swabs in clinical situations where it can make a difference to management, and limiting the use of eye swabs in routine cases of conjunctivitis which are likely to be due to viruses. For investigation of neonatal conjunctivitis we recommend sending a bacterial swab for routine culture, and also a swab for molecular detection of Chlamydia trachomatis and Neisseria gonorrhoeae. In older children with mild conjunctivitis no swab is necessary unless there is marked conjunctival injection. In this article we also highlight patient populations that require specialist tests to be sent as part of their assessment such as contact lens wearers and sexually active teenagers.
Purpose
The aim of this systematic review was to review studies that existed from 1993 to 2012 regarding antimicrobial treatment options of paediatric neurosurgical shunt.
Methods
Studies were ...identified from MEDLINE, Scopus and Cochrane databases using a search strategy that was registered on the PROSPERO database. Studies were included if they had two or more patients, aged less than 18 years, and also specified the organism and antimicrobial treatment that was used.
Results
The search yielded 2,985 articles, and 76 articles were suitable for full review. In the final qualitative analysis, only eight studies were included, involving 86 participants. The most common antimicrobial regimens for Gram-positive infections was intravenous and intrathecal vancomycin (
n
= 7), followed by intravenous vancomycin monotherapy.
Conclusion
This systematic review has shown that there are no prospective randomised studies of antimicrobial treatment options for paediatric neurosurgical patients in the last 20 years, and larger prospective studies are urgently required for this serious infection. There is some limited case series showing the benefits of certain antimicrobials such as vancomycin and ceftriaxone, but a larger case series or randomised controlled trial is required, particularly to establish the benefit, if any, of additional intraventricular antimicrobials.
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