Germline TET2 loss of function causes childhood immunodeficiency and lymphoma.

Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.

Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort.

BACKGROUND: Primary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests. METHODS: The diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries. RESULTS: Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry DNAH5 or DNAH11 mutations), Arab (42% of families carry CCDC39 or CCDC40 mutations) and South Asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results. CONCLUSIONS: This study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening.

Evaluation of asthma control, parents' quality of life and preference between AeroChamber Plus and AeroChamber Plus Flow-Vu spacers in young children with asthma.

OBJECTIVE: The AeroChamber Plus (AC) valved holding chamber has been enhanced to include the Flow-Vu (FV) inspiratory flow indicator that provides visual inhalation feedback during use. We have investigated if FV alters asthma control and whether parents accept it. METHODS: At visit 1, children with asthma, age 1-5 years, used an AC with their pressurised metered dose inhaler and 2 weeks later (visit 2) they were randomised to use either AC or FV. Subjects returned 6 (visit 3) and 12 (visit 4) weeks later. The Asthma Control (ACQ) and Paediatric Asthma Caregiver's Quality of Life (PACQLQ) questionnaires were scored at each visit, and their peak inhalation flow (PIF) when they used their spacer was measured. RESULTS: Forty participants in each group completed the study. There was no difference in the ACQ scores from visits 2 to 4 between the two groups. The improvements in the PACQLQ scores were greater in the FV group (p = 0.029). The mean difference (95% confidence interval) for the change from visits 2 to 4 between FV and AC groups was 0.05 (-0.33, 0.43) and 0.39 (0.035, 0.737) for the ACQ and PACQLQ, respectively. Most parents preferred the FV (p < 0.001). There was no difference in the PIF rates at each visit and between the two spacers. CONCLUSIONS: There was no change in asthma control of the young children but that of their parents improved. Parents preferred the FV and this could be related to their improved perception of their children's asthma control by better PACQLQ scores.

Inhalation characteristics of asthma patients, COPD patients and healthy volunteers with the Spiromax® and Turbuhaler® devices: a randomised, cross-over study.

BACKGROUND: Spiromax® is a novel dry-powder inhaler containing formulations of budesonide plus formoterol (BF). The device is intended to provide dose equivalence with enhanced user-friendliness compared to BF Turbuhaler® in asthma and chronic obstructive pulmonary disease (COPD). The present study was performed to compare inhalation parameters with empty versions of the two devices, and to investigate the effects of enhanced training designed to encourage faster inhalation. METHODS: This randomised, open-label, cross-over study included children with asthma (n = 23), adolescents with asthma (n = 27), adults with asthma (n = 50), adults with COPD (n = 50) and healthy adult volunteers (n = 50). Inhalation manoeuvres were recorded with each device after training with the patient information leaflet (PIL) and after enhanced training using an In-Check Dial device. RESULTS: After PIL training, peak inspiratory flow (PIF), maximum change in pressure (∆P) and the inhalation volume (IV) were significantly higher with Spiromax than with the Turbuhaler device (p values were at least <0.05 in all patient groups). After enhanced training, numerically or significantly higher values for PIF, ∆P, IV and acceleration remained with Spiromax versus Turbuhaler, except for ∆P in COPD patients. After PIL training, one adult asthma patient and one COPD patient inhaled <30 L/min through the Spiromax compared to one adult asthma patient and five COPD patients with the Turbuhaler. All patients achieved PIF values of at least 30 L/min after enhanced training. CONCLUSIONS: The two inhalers have similar resistance so inhalation flows and pressure changes would be expected to be similar. The higher flow-related values noted for Spiromax versus Turbuhaler after PIL training suggest that Spiromax might have human factor advantages in real-world use. After enhanced training, the flow-related differences between devices persisted; increased flow rates were achieved with both devices, and all patients achieved the minimal flow required for adequate drug delivery. Enhanced training could be useful, especially in COPD patients.

Overcoming challenges in the management of primary ciliary dyskinesia: the UK model.

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease associated with bronchiectasis, chronic rhinosinusitis, infertility and situs inversus. Estimates of prevalence vary widely, but is probably between 1:10,000- 1:40,000 in most populations. A number of observational studies indicate that access to services to diagnose and manage patients with PCD vary both between and within countries. Diagnosis is often delayed and frequently missed completely. The prognosis of patients with PCD is variable, but evidence suggests that it is improved by early diagnosis and specialist care. This article briefly reviews the literature concerning PCD and the evidence that specialist care will improve healthcare outcomes. The article specifically refers to a new national service in the UK.

Respiratory morbidity, healthcare utilisation and cost of care at school age related to home oxygen status.

UNLABELLED: The aim of the study was to determine whether respiratory morbidity, lung function, healthcare utilisation and cost of care at school age in prematurely born children who had bronchopulmonary dysplasia (BPD) were influenced by use of supplementary oxygen at home after neonatal intensive care unit discharge. Healthcare utilisation and cost of care in years 5 to 7 and respiratory morbidity (parent-completed respiratory questionnaire) and lung function measurements at least at age 8 years were assessed in 160 children. Their median gestational age was 27 (range 22-31) weeks and 65 of them had received supplementary oxygen when discharged home (home oxygen group). The home oxygen group had more outpatient attendances (p = 0.0168) and respiratory-related outpatient attendances (p = 0.0032) with greater related cost of care (p = 0.0186 and p = 0.0030, respectively), their cost of care for prescriptions (p = 0.0409) and total respiratory related cost of care (p = 0.0354) were significantly greater. There were, however, no significant differences in cough, wheeze or lung function results between the two groups. CONCLUSION: Prematurely born children who had BPD and supplementary oxygen at home after discharge had increased healthcare utilisation at school age. Whether such children require greater follow, in the absence of excess respiratory morbidity, merits investigation.

Cow's milk protein allergy.

CMPA is a common food allergy that presents with diverse manifestations affecting more than one body system. Early recognition of the condition and prompt initiation of dietary elimination of cow's milk protein is important. A future challenge with cow's milk protein can confirm a positive diagnosis.

Clinical features and management of children with primary ciliary dyskinesia in England.

OBJECTIVE: In England, the National Health Service commissioned a National Management Service for children with primary ciliary dyskinesia (PCD). The aims of this study were to describe the health of children seen in this Service and compare lung function to children with cystic fibrosis (CF). DESIGN: Multi-centre service evaluation of the English National Management PCD Service. SETTING: Four nationally commissioned PCD centres in England. PATIENTS: 333 children with PCD reviewed in the Service in 2015; lung function data were also compared with 2970 children with CF. RESULTS: Median age at diagnosis for PCD was 2.6 years, significantly lower in children with situs inversus (1.0 vs 6.0 years, p<0.001). Compared with national data from the CF Registry, mean (SD) %predicted forced expiratory volume in one second (FEV1) was 76.8% in PCD (n=240) and 85.0% in CF, and FEV1 was lower in children with PCD up to the age of 15 years. Approximately half of children had some hearing impairment, with 26% requiring hearing aids. Children with a lower body mass index (BMI) had lower FEV1 (p<0.001). One-third of children had positive respiratory cultures at review, 54% of these grew Haemophilus influenzae. CONCLUSIONS: We provide evidence that children with PCD in England have worse lung function than those with CF. Nutritional status should be considered in PCD management, as those with a lower BMI have significantly lower FEV1. Hearing impairment is common but seems to improve with age. Well-designed and powered randomised controlled trials on management of PCD are needed to inform best clinical practice.

Prenatally diagnosed congenital lung malformations-A long-term outcome study.

AIM: To report the natural history of a cohort of children with prenatally diagnosed congenital lung malformations (CLM) which we set out to manage expectantly. METHODS: Retrospective review of children born between 1995 and 2013 with a CLM identified on prenatal ultrasound. Prenatal ultrasound data were analyzed along with patient medical records, radiology, and pathology. RESULTS: One hundred fifty-nine newborns with a fetal lung lesion were identified during the study period. All infants were live born. Twenty-eight (18%) newborns were symptomatic, 17 with transient symptoms, and 11 with persistent symptoms. The latter all underwent lobectomy in the neonatal period with two postoperative deaths. One hundred thirty-one asymptomatic newborns plus the 17 babies with transient symptoms (148 total) were followed during childhood for a median of 6.0 years (0.1-19.2 years). Twenty-one children (13% of the original cohort of 159) became symptomatic at a median age of 2.5 years (9 months-5 years 8 months) with infection and underwent CLM resection. No child became symptomatic after the age of 5 years 8 months. One hundred twenty-seven children remained symptom free during follow-up for a median of 5.75 years (1 month-19 years). We saw no instance of malignancy in the resected specimens. CONCLUSIONS: This study adds further evidence that most children born with CLM identified prenatally are asymptomatic at birth and the majority will remain asymptomatic during childhood. We recommend follow-up to the age of 10 years.

Carbamazepine Improves Apneic Episodes in Congenital Central Hypoventilation Syndrome (CCHS) With a Novel PHOX2B Exon 1 Missense Mutation.

ABSTRACT: Pathogenic variants in Paired-Like Homeobox 2B (PHOX2B) gene cause congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by absent or reduced ventilatory response to hypoxia and hypercapnia. The focus of management in CCHS is optimizing ventilation. Thus far, no medication has proved effective in improving ventilation. Most CCHS cases are caused by polyalanine repeat expansion mutations. Non-polyalanine repeat expansion mutations are the cause in 8% of cases and result in a more severe clinical presentation. PHOX2B has 3 exons. Exon 3 of PHOX2B is the most common location for CCHS-causing mutations. Thus far, only 9 CCHS-causing mutations have been reported in exon 1, 8 of which were nonsense mutations. We report a child with CCHS who was found to have a novel heterozygous missense variant in exon 1; c.95A > T. Improvement in his apneic episodes was observed following treatment with carbamazepine.

The inhalation characteristics of patients when they use different dry powder inhalers.

BACKGROUND: The characteristics of each inhalation maneuver when patients use dry powder inhalers (DPIs) are important, because they control the quality of the emitted dose. METHODS: We have measured the inhalation profiles of asthmatic children [CHILD; n=16, mean forced expiratory volume in 1 sec (FEV1) 79% predicted], asthmatic adults (ADULT; n=53, mean predicted FEV1 72%), and chronic obstructive pulmonary disease (COPD; n=29, mean predicted FEV1 42%) patients when they inhaled through an Aerolizer, Diskus, Turbuhaler, and Easyhaler using their "real-life" DPI inhalation technique. These are low-, medium-, medium/high-, and high-resistance DPIs, respectively. The inhalation flow against time was recorded to provide the peak inhalation flow (PIF; in L/min), the maximum pressure change (ΔP; in kPa), acceleration rates (ACCEL; in kPa/sec), time to maximum inhalation, the length of each inhalation (in sec), and the inhalation volume (IV; in liters) of each inhalation maneuver. RESULTS: PIF, ΔP, and ACCEL values were consistent with the order of the inhaler's resistance. For each device, the inhalation characteristics were in the order ADULT>COPD>CHILD for PIF, ΔP, and ACCEL (p<0.001). The results showed a large variability in inhalation characteristics and demonstrate the advantages of ΔP and ACCEL rather than PIFs. Overall inhaled volumes were low, and only one patient achieved an IV >4 L and ΔP >4 kPa. CONCLUSION: The large variability of these inhalation characteristics and their range highlights that if inhalation profiles were used with compendial in vitro dose emission measurements, then the results would provide useful information about the dose patients inhale during routine use. The inhalation characteristics highlight that adults with asthma have greater inspiratory capacity than patients with COPD, whereas children with asthma have the lowest. The significance of the inhaled volume to empty doses from each device requires investigation.

Saline in acute bronchiolitis RCT and economic evaluation: hypertonic saline in acute bronchiolitis - randomised controlled trial and systematic review.

BACKGROUND: Acute bronchiolitis is the most common cause of hospitalisation in infancy. Supportive care and oxygen are the cornerstones of management. A Cochrane review concluded that the use of nebulised 3% hypertonic saline (HS) may significantly reduce the duration of hospitalisation. OBJECTIVE: To test the hypothesis that HS reduces the time to when infants were assessed as being fit for discharge, defined as in air with saturations of > 92% for 6 hours, by 25%. DESIGN: Parallel-group, pragmatic randomised controlled trial, cost-utility analysis and systematic review. SETTING: Ten UK hospitals. PARTICIPANTS: Infants with acute bronchiolitis requiring oxygen therapy were allocated within 4 hours of admission. INTERVENTIONS: Supportive care with oxygen as required, minimal handling and fluid administration as appropriate to the severity of the disease, 3% nebulised HS every ± 6 hours. MAIN OUTCOME MEASURES: The trial primary outcome was time until the infant met objective discharge criteria. Secondary end points included time to discharge and adverse events. The costs analysed related to length of stay (LoS), readmissions, nebulised saline and other NHS resource use. Quality-adjusted life-years (QALYs) were estimated using an existing utility decrement derived for hospitalisation in children, together with the time spent in hospital in the trial. DATA SOURCES: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and other databases from inception or from 2010 onwards, searched ClinicalTrials.gov and other registries and hand-searched Chest, Paediatrics and Journal of Paediatrics to January 2015. REVIEW METHODS: We included randomised/quasi-randomised trials which compared HS versus saline (± adjunct treatment) or no treatment. We used a fixed-effects model to combine mean differences for LoS and assessed statistical heterogeneity using the I (2) statistic. RESULTS: The trial randomised 158 infants to HS (n = 141 analysed) and 159 to standard care (n = 149 analysed). There was no difference between the two arms in the time to being declared fit for discharge [median 76.6 vs. 75.9 hours, hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.75 to 1.20] or to actual discharge (median 88.5 vs. 88.7 hours, HR 0.97, 95% CI 0.76 to 1.23). There was no difference in adverse events. One infant developed bradycardia with desaturation associated with HS. Mean hospital costs were £2595 and £2727 for the control and intervention groups, respectively (p = 0.657). Incremental QALYs were 0.0000175 (p = 0.757). An incremental cost-effectiveness ratio of £7.6M per QALY gained was not appreciably altered by sensitivity analyses. The systematic review comprised 15 trials (n = 1922) including our own. HS reduced the mean LoS by -0.36 days (95% CI -0.50 to -0.22 days). High levels of heterogeneity (I (2) = 78%) indicate that the result should be treated cautiously. CONCLUSIONS: In this trial, HS had no clinical benefit on LoS or readiness for discharge and was not a cost-effective treatment for acute bronchiolitis. Claims that HS achieves small reductions in LoS must be treated with scepticism. FUTURE WORK: Well-powered randomised controlled trials of high-flow oxygen are needed. STUDY REGISTRATION: This study is registered as NCT01469845 and CRD42014007569. FUNDING DETAILS: This project was funded by the NIHR Health Technology Assessment (HTA) programme and will be published in full in Health Technology Assessment; Vol. 19, No. 66. See the HTA programme website for further project information.

Vascular ring diagnosis following respiratory arrest.

Vascular rings can present with non-specific respiratory and/or oesophageal symptoms. Early diagnosis requires a high index of suspicion. This case report describes an uncommon acute presentation of a vascular ring. We report a thriving 14-month-old child with a long history of recurrent wheeze and 'noisy breathing'. He presented acutely with food bolus impaction in the oesophagus which led to a respiratory arrest. Oesophagoscopy and bronchoscopy suggested vascular ring anomaly. A contrast-enhanced CT scan demonstrated a right-sided aortic arch with left ligamentum arteriosum encircling the oesophagus and airway. The ligament was ligated and divided. At follow-up 6 months later, the infant had mild persistent stridor but was otherwise well.

The RCPCH care pathway for food allergy in children: an evidence and consensus based national approach.

AIMS: The Royal College of Paediatrics and Child Health (RCPCH) Science and Research Department was commissioned by the Department of Health to develop national care pathways for children with allergies; food allergy is the second pathway. The pathways focus on defining the competences required to improve the equity of care received by children with allergic conditions. METHOD: The food allergy pathway was developed by a multidisciplinary working group and was based on a comprehensive review of the evidence. The pathway was reviewed by a broad group of stakeholders including the public and approved by the Allergy Care Pathways Project Board and the RCPCH Clinical Standards Committee. The National Institute of Health and Clinical Excellence simultaneously established a short guideline review of community practice for children with food allergy; close communication was established between the two groups. RESULTS: The results are presented in two sections: a pathway algorithm and the competences. The entry points are defined and the ideal pathway of care is described from initial recognition and confirmed diagnosis through to follow-up. CONCLUSIONS: The range of manifestations of food allergy/intolerance is much more diverse than hitherto recognised and diagnosis can be problematic as many patients do not have classical IgE mediated disease. The pathway provides a guide for training and development of services to facilitate improvements in delivery as close to the patient's home as possible. The authors recommend that this pathway is implemented locally by a multidisciplinary team with a focus on creating networks.