Detection of Bronchiolitis Obliterans Syndrome after Pediatric Hematopoietic Stem Cell Transplantation: An Official American Thoracic Society Clinical Practice Guideline.

Background: Many children undergo allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignant and nonmalignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common noninfectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent NIH workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. Methods: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of, post-HSCT BOS in children. A systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. Results: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. Conclusions: This document provides an evidence-based approach to the detection of post-HSCT BOS in children while also highlighting considerations for the implementation of each recommendation. Further, the document describes important areas for future research.

Diagnosis of Post-Hematopoietic Stem Cell Transplantation Bronchiolitis Obliterans Syndrome in Children: Time for a Rethink?

Hematopoietic stem cell transplantation (HSCT) is undertaken in children with the aim of curing a range of malignant and nonmalignant conditions. Unfortunately, pulmonary complications, especially bronchiolitis obliterans syndrome (BOS), are significant sources of morbidity and mortality post-HSCT. Currently, criteria developed by a National Institutes of Health (NIH) working group are used to diagnose BOS in children post-HSCT. Unfortunately, during the development of a recent American Thoracic Society (ATS) Clinical Practice Guideline on this topic, it became apparent that the NIH criteria have significant limitations in the pediatric population, leading to late diagnosis of BOS. Specific limitations include use of an outdated pulmonary function testing reference equation, a reliance on spirometry, use of a fixed forced expiratory volume in 1 second (FEV1) threshold, focus on obstructive defects defined by FEV1/vital capacity, and failure to acknowledge that BOS and infection can coexist. In this review, we summarize the evidence regarding the limitations of the current criteria. We also suggest potential evidence-based ideas for improving these criteria. Finally, we highlight a new proposed criteria for post-HSCT BOS in children that were developed by the authors of the recently published ATS clinical practice guideline, along with a pathway forward for improving timely diagnosis of BOS in children post-HSCT.

Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Antimicrobial treatment options for neurosurgical ventricular shunt infections in children from 1993 to 2012: a systematic review.

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.

Cognitive ability in children with chronic granulomatous disease: a comparison of those managed conservatively with those who have undergone hematopoietic stem cell transplant.

Chronic granulomatous disease (CGD) is a primary immunodeficiency managed conservatively or with hematopoietic stem cell transplant. Studies have shown people with CGD and those transplanted for primary immunodeficiencies have lower than average cognitive ability. In this study, IQ in children with CGD and those transplanted for it was within the normal range.

Pediatric focal intracranial suppuration: a UK single-center experience.

PURPOSE: Brain abscess (BA) and subdural empyema (SDE) are uncommon but clinically important conditions in childhood. Treatment involves surgery and prolonged courses of antibiotics. There is no consensus on the optimal approach. The objective was to review management and outcome of BA and SDE in a single UK center. METHODS: This retrospective case notes review of children with brain abscess or subdural empyema admitted to a tertiary pediatric infectious diseases and neurosurgical center from 2001 to 2009. RESULTS: Forty-two children were included in the study; 17 children were with BA, 23 with SDE, and two both with BA and SDE. The causative factors found in 88 % of the patients were most commonly sinusitis and meningitis with congenital heart disease and immunocompromise unusual. Streptococcus anginosus group organisms were most common; 10 % of the children had a resistant pathogen and 86 % had surgical intervention. Fifteen patients with BA underwent surgery; nine of these patients underwent burrhole aspiration, three had craniotomy, two had stereotactic surgery, and one had endoscopic aspiration. Remaining 19 patients with SDE underwent surgery: seven had burrhole aspiration, 11 underwent craniotomy, and one had aspiration via the anterior fontanel. The most common antibiotic regime was cefotaxime, metronidazole, and amoxicillin. Mean duration of treatment was 14.4 weeks. Mean time until normalization of C reactive protein was 23 days. Survival was 95 % and 20 % had ongoing neurological sequelae. CONCLUSIONS: BA and SDE remain important childhood infections in the UK. Antibiotics are essential in the management of these cases. Empiric antibiotic choices require knowledge of likely pathogens and local resistance. Selected infections can be treated without surgical intervention. Long courses of antibiotics were administered. Outcome is good, and neurological sequelae were less common than found in previous series.

Central venous catheter-related blood stream infections in children undergoing hematopoietic stem cell transplant for primary immunodeficiency and other nonmalignant disorders.

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.

Clinical experience in T cell deficient patients.

T cell disorders have been poorly understood until recently. Lack of knowledge of underlying molecular mechanisms together with incomplete data on long term outcome have made it difficult to assess prognosis and give the most effective treatment. Rapid progress in defining molecular defects, improved supportive care and much improved results from hematopoietic stem cell transplantation (HSCT) now mean that curative treatment is possible for many patients. However, this depends on prompt recognition, accurate diagnosis and careful treatment planning.This review will discuss recent progress in our clinical and molecular understanding of a variety of disorders including: severe combined immunodeficiency, specific T cell immunodeficiencies, signaling defects, DNA repair defects, immune-osseous dysplasias, thymic disorders and abnormalities of apoptosis.There is still much to discover in this area and some conditions which are as yet very poorly understood. However, with increased knowledge about how these disorders can present and the particular problems each group may face it is hoped that these patients can be recognized early and managed appropriately, so providing them with the best possible outcome.