Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

Chronic tracheostomy care of ventilator-dependent and -independent children: Clinical practice patterns of pediatric respirologists in a publicly funded (Canadian) healthcare system.

OBJECTIVES: To describe the current clinical practice patterns of Canadian pediatric respirologists at pediatric tertiary care institutions regarding chronic tracheostomy tube care and management of home invasive ventilation. METHODS: A pediatric respirologist/pediatrician with expertise in tracheostomy tube care and home ventilation was identified at each Canadian pediatric tertiary care center to complete a 59-item survey of multiple choice and short answer questions. Domains assessed included tracheostomy tube care, caregiver competency and home monitoring, speaking valves, medical management of tracheostomy complications, decannulation, and long-term follow-up. RESULTS: The response rate was 100% (17/17) with all Canadian tertiary care pediatric centers represented and heterogeneity of practice was observed in all domains assessed. For example, though most centers employ Bivona™ (17/17) and Shiley™ (15/17) tracheostomy tubes, variability was observed around tube change, re-use, and cleaning practices. Most centers require two trained caregivers (14/17) and recommend 24/7 eyes on care and oxygen saturation monitoring. Discharge with an emergency tracheostomy kit was universal (17/17). Considerable heterogeneity was observed in the timing and use of speaking valves and speech-language assessment. Inhaled anti-pseudomonal antibiotics are employed by most centers (16/17) though the indication, agent, and protocol varied by center. Though decannulation practices varied considerably, the requirement of upper airway patency was universally required to proceed with decannulation (17/17) independent of ongoing ventilatory support requirements. CONCLUSION: Considerable variability in pediatric tracheostomy tube care practice exists across Canada. These results will serve as a starting point to standardize and evaluate tracheostomy tube care nationally.

Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation.

Primary atopic disorders are a group of inborn errors of immunity that skew the immune system toward severe allergic disease. Defining the biology underlying these extreme monogenic phenotypes reveals shared mechanisms underlying common polygenic allergic disease and identifies potential drug targets. Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia. Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis. RNA-Seq of JAK1GOF human whole blood, iPSCs, and transgenic zebrafish revealed a shared core set of dysregulated genes involved in IL-4, IL-13, and IFN signaling. Immunophenotypic and transcriptomic analysis of patients carrying a JAK1GOF variant revealed marked Th cell skewing. Moreover, long-term ruxolitinib treatment of 2 children carrying the JAK1GOF (p.A634D) variant remarkably improved their growth, eosinophilia, and clinical features of allergic inflammation. This work highlights the role of JAK1 signaling in atopic immune dysregulation and the clinical impact of JAK1/2 inhibition in treating eosinophilic and allergic disease.

In support of point-of-care social needs screening: The effects of five social determinants on the health of children with chronic diseases in British Columbia.

BACKGROUND: Prior to introducing social needs screening into our subspecialty clinics, we first wanted to understand the health effects of the major social challenges facing children with chronic diseases in British Columbia. METHODS: Using a strict prospective methodology, avoiding use of health databases and proxy end points, we studied the effects of five social health determinants (distance from care, family income, gender, ethnicity, caregiver education), on health outcomes in three groups of children with chronic diseases: cystic fibrosis (CF), type 1 diabetes (T1D), chronic kidney disease (CKD). Social determinant data were collected at a face-to-face interview during a clinic visit. These were correlated with diagnosis-specific health outcomes, measured at the same visit. Main outcomes were: forced expired volume in 1 second (FEV1) (CF group), HbA1c (T1D group), estimated glomerular filtration rate (CKD group). RESULTS: We studied 270 children: 85 CF, 89 T1D and 96 CKD. In all three groups, children from families with annual income less than $45,000 had significantly worse health than those from families above this cut-off. Lower caregiver education was related to worse health in the CKD and T1D groups. We found no adverse health effects associated with distance from subspecialty care, patient ethnicity or gender. CONCLUSION: Even in a prosperous province, family poverty and lack of caregiver education still impose measurable adverse effects on the health of children with chronic diseases. We hope these results help support the integration of social needs screening into routine multidisciplinary outpatient clinics. Early detection of social problems and targeted interventions will hopefully help to equalize health outcomes between children from different social groups.

A review of congenital lung malformations with a simplified classification system for clinical and research use.

PURPOSE: Congenital lung abnormalities are rare malformations increasingly detected early by prenatal ultrasound. Whether management of these frequently asymptomatic lesions should be surgical or conservative is an unresolved issue. The necessary prospective studies are limited by the absence of a widely accepted practical classification system. Our aim was to develop a simple, clinically relevant system for classifying and studying congenital lung abnormalities. MATERIALS AND METHODS: We based our proposed grouping on a detailed analysis of clinical, radiological, and histological data from well-documented cases, plus an extensive review of the literature. RESULTS: The existence of hybrid lesions and common histological findings suggested a unified embryological mechanism-possibly obstruction of developing airways with distal dysplasia. Malformations could be classified by their anatomical and pathological findings; however, a system based on the prenatal ultrasound plus initial chest X-ray findings had greater clinical relevance: Group 1-Congenital solid/cystic lung malformation, Group 2-Congenital hyperlucent lobe, Group 3-Congenital small lung. CONCLUSIONS: Pathological classification is academically important but is unnecessarily complex for clinical and research use. Our simple radiological-based system allows unambiguous comparison between the results of different studies and also guides the choice of necessary investigations specific to each group.

The importance of considering monogenic causes of autoimmunity: A somatic mutation in KRAS causing pediatric Rosai-Dorfman syndrome and systemic lupus erythematosus.

OBJECTIVES: Clinicians need to be aware of the growing list of defined monogenic etiologies of autoimmune diseases. This is particularly relevant when evaluating children, as these rare monogenic forms of autoimmunity tend to present very early in life. METHODS AND RESULTS: By harnessing the transformative power of next generation sequencing, we made the unifying diagnosis of RAS-associated autoimmune leukoproliferative disease (RALD), caused by the somatic gain-of-function p.G13C KRAS mutation, in a boy with the seemingly unrelated immune dysregulatory conditions of Rosai-Dorfman and systemic lupus erythematosus (SLE). CONCLUSIONS: This case expands our understanding of the clinical phenotypes associated with the extremely rare condition of RALD, and emphasizes the importance of always considering the possibility of a monogenic cause for autoimmunity, particularly when the disease manifestations begin early in life and do not follow a typical clinical course.

Predictive Accuracy of Chest Radiographs in Diagnosing Tachypneic Children.

OBJECTIVE: To test the predictive accuracy and reporting reproducibility of digital chest radiographs under low-resource conditions. METHODS: One hundred thirty four tachypneic children who presented to two Indian hospitals were enrolled. Based on review of 16 variables recorded in the Emergency Room (ER) by a senior pediatrician, children were given one of the four clinical diagnoses: pneumonia, wheezy disease, mixed and non-respiratory. Every child also had a digital CXR. It was interpreted by ER physician, pediatrician and two independent radiologists. All used the same standardized interpretation system (one or more of: normal, minor patches, major patches, hyperinflation, lobar change, pleural effusion). RESULTS: The 10 % of CXRs showing pleural effusions reliably predicted pneumonia and disease severity. For all other CXR findings, the correlation between CXR interpretation and clinical diagnosis was moderate to poor. Apart from pleural effusions, inter-observer agreements between interpretations made by ER physician, pediatrician and radiologist were also poor (kappa <0.4). CONCLUSIONS: With the exception of pleural effusions, CXR findings, interpreted by a radiologist, had moderate to poor power to predict respiratory diagnosis or disease severity defined by a pediatrician. Value of CXRs was further reduced by poor inter-observer agreement. When investigating tachypneic children under low-resource conditions, CXRs should be used with a clear understanding of their limitations.

The quality of life of home-ventilated children and their primary caregivers plus the associated social and economic burdens: a prospective study.

BACKGROUND: Despite the obvious challenges faced by families caring for children on home ventilation, there is surprisingly little research into the details of their daily lives. In particular, little is known about the quality of life of the child and caregiver plus the associated social and economic burdens of care. METHODS: We prospectively studied 90 families enrolled in a paediatric home ventilation service in British Columbia. In the clinic, we recorded demographic information, patient acuity score and quality of life for patient and caregiver using standardised questionnaires. Parents then monitored social and financial costs of care at home over the subsequent 8 weeks. These data were collected by telephone at 1 and 2 months. RESULTS: Most children led rich active lives. Camping trips, wheelchair sports and foreign travel were the norm, not the exception. Over 90% assessed the burden of care as mild or moderate. Government support covers medical expenses and home nursing (median 32 h/week, IQR 0-62.5 h). Monthly unreimbursed family expenses were low (median $87.7, IQR $15.3-$472). Despite this, nearly 25% of primary caregivers assessed burden of care as severe and over 50% had chronic illnesses requiring daily medication (principally depression, anxiety and arthritis). Quality of life for children or caregivers did not correlate with income or education. INTERPRETATION: Home ventilation of complex children is a successful strategy but it places significant strain on the primary caregiver. Specific attention to the physical and mental health of the caregiver should be an integral part of the management of home-ventilated children. TRIAL REGISTRATION NUMBER: NCT01863992.

Casting a look at pediatric plastic bronchitis.

OBJECTIVES: To review clinical presentations and management strategies for children with plastic bronchitis. METHODS: Retrospective chart review. RESULTS: Seven patients required rigid bronchoscopy to remove bronchial casts over a 17-year study period. Mean age at presentation was 60 months. Mean follow-up was 53 months. Co-morbidities included: congenital heart disease (n=3), chronic pulmonary disorders (n=2) and sickle cell disease (n=1). 4 patients required multiple bronchoscopies for recurrent casts. Adjunctive topical therapies were administered in all 7 patients, without complication. Rigid bronchoscopy for cast removal was performed in 2 patients who were on extra-corporal membrane oxygenation (ECMO), using special precautions to safeguard the ECMO catheters. CONCLUSIONS: Bronchial casts in children may present acutely or sub-acutely. Recurrent casts are unusual; however, in combination with severe cardiac disease may lead to mortality. Adjunctive topical therapies are still under investigation. Special safeguards for ECMO catheters are imperative. This case series complements and adds to the International Plastic Bronchitis Registry.

Can we distinguish pneumonia from wheezy diseases in tachypnoeic children under low-resource conditions? A prospective observational study in four Indian hospitals.

BACKGROUND: Acute respiratory infections are the commonest cause of mortality and morbidity in children worldwide. A quarter of all deaths occur in India alone. In order to reduce this disease burden, there is a need for better diagnostic criteria, particularly ones allowing early detection of high-risk children. METHODS: We enrolled 516 under 5 year olds, in four Indian hospitals, who met WHO age-dependent tachypnoea criteria for pneumonia at presentation. Patients underwent a protocolised examination assessing 29 items, including history, examination, O2 saturation, plus scores for chest X-ray, auscultation and conscious level. Treatment was determined by the emergency room (ER) physician. All children were reviewed at day 4 by a paediatrician and placed into four diagnostic categories: pneumonia, wheezy disease, mixed and non-respiratory. RESULTS: The majority had wheezy diseases (42.8%). The remainder had pneumonia (35.9%), mixed disease (18.6%) and non-respiratory (2.7%). Best diagnostic predictors for wheezy disease were (auscultation/previous similar episodes) and for pneumonia (auscultation/CXR score). Mortality was 1.6%. Best disease severity predictors were conscious level, weight/age z score and respiratory/pulse rates. INTERPRETATION: Current tachypnoea-based algorithms significantly overdiagnose pneumonia in children and underdiagnose wheezy diseases. Diagnostic accuracy can be improved by various combinations of clinical variables, but the best single diagnostic predictor is auscultation. Simple criteria can also be defined that reliably detect which tachypnoeic children are at high risk of death or deterioration. Management plans based on these protocols could reduce unnecessary antibiotic use, improve the management of wheezy diseases and reduce mortality by earlier identification of high-risk children.

Long-term ventilation in children: longitudinal trends and outcomes.

BACKGROUND: Cross-sectional studies have suggested a rapid expansion in paediatric long-term ventilation (LTV) over the last 20 years but information on longitudinal trends is limited. METHODS: Data were collected prospectively on all patients receiving LTV over a 15-year period (1.1.95-31.12.09) in a single regional referral centre. RESULTS: 144 children commenced LTV during the 15-year period. The incidence of LTV increased significantly over time, with an accompanying 10-fold increase in prevalence due to a significant increase in institution of non-invasive ventilation (NIV). There was no significant increase in invasive ventilation. 5-year survival was 94% overall and was significantly higher for patients on NIV (97%) than invasively ventilated patients (84%). 10-year survival was 91% overall. Although some children were able to discontinue respiratory support (21% at 5 years and 42% at 10 years), the number of patients transitioned to adult services increased significantly over time (26% of total cohort). Patients with neuromuscular disease were less likely to discontinue support than other patients. CONCLUSIONS: The paediatric LTV population has expanded significantly over 15 years. Future planning of paediatric hospital and community services, as well as adult services, must take into account the needs of this growing population.

Bronchial balloon occlusion in children with complex pulmonary air leaks.

Pulmonary air leaks in children are most commonly due to infection or barotrauma. While cases of severe barotrauma are falling because of advances in neonatal care, the incidence of necrotising pneumonia is rising. The majority of air leaks can be managed conservatively, but more severe cases pose a significant challenge to the clinician. The use of occlusive endobronchial balloons is an established anaesthetic technique for a number of indications, but is not widely used in children. We conducted a review over a 12-year period, and report six cases of complex air leaks in which balloon occlusion was used. Balloon occlusion was successful in both cases of bronchopleural fistulae (secondary to severe necrotising pneumonia) and half of the cases of intrapulmonary air leak (due to barotrauma). In the other two cases (due to barotrauma and filamin A deficiency), it was transiently effective. No serious adverse effects or complications were encountered. In selected cases, endobronchial balloons are a useful adjunct in the management of life-threatening bronchopleural fistulae and cystic lung disease. The procedure is non-operative, minimally invasive and reversible. With the increasing incidence of bronchopleural fistulae, this may become an increasingly important therapy.

Superior herniation of the mediastinum presenting as an anterior neck mass on straining.

We report an infant with an anterior neck mass present only on straining. Airway fluoroscopy revealed this to be due to superior mediastinal herniation. Neck masses apparent only during Valsalva maneuver are rare and awareness of the differential diagnosis is important to avoid unnecessary investigation or surgery.

Fifty years of pediatric asthma in developed countries: how reliable are the basic data sources?

Given the difficulties in diagnosing, or even defining, asthma in children, claims of a pediatric asthma epidemic in Canada and other developed countries are accepted with surprisingly little critical examination. We reviewed a broad range of data sources to understand how the epidemic evolved during the last 50 years and also to assess the reliability of the conclusions drawn from that data. We obtained Canadian National and Provincial data from Statistics Canada National Population Health Survey, and the British Columbia Ministry of Health respiratory database. International data were obtained by extensive review of pediatric asthma epidemiological surveys published during the last 50 years. In many developed countries, there have been three separate epidemics involving different aspects of pediatric asthma during the last 50 years: a double peaked mortality epidemic (1960s and 1980s), a hospital admission epidemic (peaked around 1990) and a steadily growing epidemic of children who report asthmatic symptoms on questionnaires. Canadian pediatric rates for asthma mortality (1-2/million/year) and hospital admission (1-2/thousand/year) are low and have fallen for the last 20 years. Rates based on questionnaire studies are high (10-15/hundred) and rose steadily over the same period. Objective reductions in asthma deaths and hospital admission likely reflect improved education and treatment programmes. Current claims of an epidemic based largely on subjective self-reported symptoms require more careful analysis. The possibility that symptom misperception, disease fashions, and poor recall, may be part of the explanation for the current high levels of self-reported symptoms deserves more attention.