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4.
JCI Insight ; 52019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31021819

RESUMO

Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αß T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.

5.
J Allergy Clin Immunol Pract ; 7(2): 471-478.e3, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30722841

RESUMO

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is frequently misdiagnosed and subject to diagnostic delay. Profuse vomiting, the cardinal feature of acute FPIES, may occur in more common pediatric disorders such as gastroenteritis and sepsis. OBJECTIVES: We sought to determine differentiating features at acute presentation between FPIES, gastroenteritis, and sepsis in young children presenting to an emergency department (ED) with profuse vomiting. METHODS: We conducted a retrospective case-control study of children aged 6 months to 4 years with a diagnosis of acute FPIES who had presented to ED and compared the clinical features, vital signs, and routine laboratory studies of this cohort to similarly aged children presenting to ED with vomiting diagnosed with bacterial/viral gastroenteritis or bacterial sepsis. RESULTS: A total of 181 acute FPIES ED presentations were compared with 55 gastroenteritis and 36 bacterial sepsis ED presentations. Children with FPIES were more likely to present with lethargy, floppiness, and pallor. Compared with children with FPIES, children with sepsis were likely to present with fever, tachycardia, tachypnea, and diarrhea, whereas those with gastroenteritis were likely to present with fever, diarrhea, and blood in stools. Normal C-reactive protein (CRP), leucocytosis, lymphocytosis, thrombocytosis, low MPV, and an elevated albumin/globulin ratio were more commonly seen in FPIES than in sepsis or gastroenteritis. No other clinical or laboratory markers examined reliably distinguished between the 3 disease groups. CONCLUSIONS: In the young vomiting child, lethargy, floppiness, pallor without fever, and normal CRP should alert clinicians to a possible diagnosis of FPIES. In contrast, a highly elevated CRP is not a feature of FPIES, and in such cases an alternative diagnosis must be considered.

6.
Allergy ; 74(7): 1352-1363, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30762884

RESUMO

BACKGROUND: Commercial allergen extracts for allergy skin prick testing (SPT) are widely used for diagnosing fish allergy. However, there is currently no regulatory requirement for standardization of protein and allergen content, potentially impacting the diagnostic reliability of SPTs. We therefore sought to analyse commercial fish extracts for the presence and concentration of fish proteins and in vitro IgE reactivity using serum from fish-allergic patients. METHODS: Twenty-six commercial fish extracts from five different manufacturers were examined. The protein concentrations were determined, protein compositions analysed by mass spectrometry, followed by SDS-PAGE and subsequent immunoblotting with antibodies detecting 4 fish allergens (parvalbumin, tropomyosin, aldolase and collagen). IgE-reactive proteins were identified using serum from 16 children with confirmed IgE-mediated fish allergy, with focus on cod, tuna and salmon extracts. RESULTS: The total protein, allergen concentration and IgE reactivity of the commercial extracts varied over 10-fold between different manufacturers and fish species. The major fish allergen parvalbumin was not detected by immunoblotting in 6/26 extracts. In 7/12 extracts, five known fish allergens were detected by mass spectrometry. For cod and tuna, almost 70% of patients demonstrated the strongest IgE reactivity to collagen, tropomyosin, aldolase A or ß-enolase but not parvalbumin. CONCLUSIONS: Commercial fish extracts often contain insufficient amounts of important allergens including parvalbumin and collagen, resulting in low IgE reactivity. A comprehensive proteomic approach for the evaluation of SPT extracts for their utility in allergy diagnostics is presented. There is an urgent need for standardized allergen extracts, which will improve the diagnosis and management of fish allergy.

7.
JAMA ; 321(10): 946-955, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30794314

RESUMO

Importance: There are currently no approved treatments for peanut allergy. Objective: To assess the efficacy and adverse events of epicutaneous immunotherapy with a peanut patch among peanut-allergic children. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted at 31 sites in 5 countries between January 8, 2016, and August 18, 2017. Participants included peanut-allergic children (aged 4-11 years [n = 356] without a history of a severe anaphylactic reaction) developing objective symptoms during a double-blind, placebo-controlled food challenge at an eliciting dose of 300 mg or less of peanut protein. Interventions: Daily treatment with peanut patch containing either 250 µg of peanut protein (n = 238) or placebo (n = 118) for 12 months. Main Outcomes and Measures: The primary outcome was the percentage difference in responders between the peanut patch and placebo patch based on eliciting dose (highest dose at which objective signs/symptoms of an immediate hypersensitivity reaction developed) determined by food challenges at baseline and month 12. Participants with baseline eliciting dose of 10 mg or less were responders if the posttreatment eliciting dose was 300 mg or more; participants with baseline eliciting dose greater than 10 to 300 mg were responders if the posttreatment eliciting dose was 1000 mg or more. A threshold of 15% or more on the lower bound of a 95% CI around responder rate difference was prespecified to determine a positive trial result. Adverse event evaluation included collection of treatment-emergent adverse events (TEAEs). Results: Among 356 participants randomized (median age, 7 years; 61.2% male), 89.9% completed the trial; the mean treatment adherence was 98.5%. The responder rate was 35.3% with peanut-patch treatment vs 13.6% with placebo (difference, 21.7% [95% CI, 12.4%-29.8%; P < .001]). The prespecified lower bound of the CI threshold was not met. TEAEs, primarily patch application site reactions, occurred in 95.4% and 89% of active and placebo groups, respectively. The all-causes rate of discontinuation was 10.5% in the peanut-patch group vs 9.3% in the placebo group. Conclusions and Relevance: Among peanut-allergic children aged 4 to 11 years, the percentage difference in responders at 12 months with the 250-µg peanut-patch therapy vs placebo was 21.7% and was statistically significant, but did not meet the prespecified lower bound of the confidence interval criterion for a positive trial result. The clinical relevance of not meeting this lower bound of the confidence interval with respect to the treatment of peanut-allergic children with epicutaneous immunotherapy remains to be determined. Trial Registration: ClinicalTrials.gov Identifier: NCT02636699.


Assuntos
Alérgenos/administração & dosagem , Arachis/imunologia , Dessensibilização Imunológica/métodos , Hipersensibilidade a Amendoim/terapia , Adesivo Transdérmico , Administração Cutânea , Criança , Pré-Escolar , Intervalos de Confiança , Método Duplo-Cego , Ingestão de Alimentos/imunologia , Feminino , Humanos , Masculino , Hipersensibilidade a Amendoim/imunologia , Adesivo Transdérmico/efeitos adversos , Resultado do Tratamento
9.
Med J Aust ; 210(2): 89-93, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30636277

RESUMO

INTRODUCTION: The Australasian Society of Clinical Immunology and Allergy, the peak professional body for clinical immunology and allergy in Australia and New Zealand, develops and provides information on a wide range of immune-mediated disorders, including advice about infant feeding and allergy prevention for health professionals and families. Guidelines for infant feeding and early onset allergy prevention were published in 2016, with additional guidance published in 2017 and 2018, based on emerging evidence. MAIN RECOMMENDATIONS: When the infant is ready, at around 6 months, but not before 4 months, start to introduce a variety of solid foods. (This is not a strict window of introduction but rather a recommendation not to delay the introduction of solid foods beyond 12 months.) Introduce peanut and egg in the first year of life in all infants, regardless of their allergy risk factors. Hydrolysed (partially and extensively) formula is no longer recommended for the prevention of allergic disease. CHANGES IN MANAGEMENT A RESULT OF THE GUIDELINES: The guidelines specifically recommend introducing solid foods at around 6 months of age and introducing peanut and egg in the first year of life in all infants to prevent allergy development. Hydrolysed formula is no longer recommended for prevention of allergic disease. A new document outlining the reasons for and the method of peanut introduction to high risk infants is available for health professionals.

10.
Med J Aust ; 210(2): 94-99, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30656696

RESUMO

Food protein-induced enterocolitis syndrome (FPIES) is a poorly understood non-IgE gastrointestinal-mediated food allergy that predominantly affects infants and young children. Cells of the innate immune system appear to be activated during an FPIES reaction. Acute FPIES typically presents between one and 4 hours after ingestion of the trigger food, with the principal symptom being profuse vomiting, and is often accompanied by pallor and lethargy. Additional features can include hypotension, hypothermia, diarrhoea, neutrophilia and thrombocytosis. In Australia, the most commonly reported foods responsible for FPIES are (in descending order) rice, cow's milk, egg, oats and chicken. Most children with FPIES react to only one food trigger, and thus, avoidance of multiple foods is often not indicated. FPIES is often misdiagnosed as sepsis or gastroenteritis. However, a diagnosis of FPIES is favoured if there is rapid resolution of symptoms within hours of presentation, an absence of fever, and a lack of a significant rise in C-reactive protein at presentation. Diagnosis is often hampered by the lack of awareness of FPIES, absence of reliable biomarkers, the non-specific nature of the presenting symptoms, and the delay between allergen exposure and symptoms. Although some national peak allergy bodies have attempted to improve the diagnosis and management of FPIES, up until 2017 there were no internationally agreed guidelines for its diagnosis and management.

11.
Artigo em Inglês | MEDLINE | ID: mdl-30523652

RESUMO

Food allergy and anaphylaxis is increasing in Australian children, and anaphylaxis is relatively common in Australian schools. This review aims to provide an overview of current policies and practices for anaphylaxis management in Australian schools, including approaches to risk mitigation and anaphylaxis training. We reviewed literature related to anaphylaxis training in the school setting published between 2010 and 2018. Current anaphylaxis policies/guidelines were obtained from Australian education and health departments, and reports of suspected anaphylaxis and adrenaline autoinjector (AAI) use for 2016-2017 were obtained from education departments where available. Our review of policies/guidelines across Australian jurisdictions indicates inconsistent approaches to anaphylaxis management training. Almost half of Australian school anaphylaxis events required a general-use AAI, administered to students not identified as at risk of anaphylaxis. Development of clear, evidence-based, consistent guidelines related to anaphylaxis management and training in the school setting is imperative to minimise risk.

12.
Nutrients ; 10(9)2018 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-30420587

RESUMO

Human milk provides essential substrates for the optimal growth and development of a breastfed infant. Besides providing nutrients to the infant, human milk also contains metabolites which form an intricate system between maternal lifestyle, such as the mother's diet and the gut microbiome, and infant outcomes. This study investigates the variation of these human milk metabolites from five different countries. Human milk samples (n = 109) were collected one month postpartum from Australia, Japan, the USA, Norway, and South Africa and were analyzed by nuclear magnetic resonance. The partial least squares discriminant analysis (PLS-DA) showed separation between either maternal countries of origin or ethnicities. Variation between countries in concentration of metabolites, such as 2-oxoglutarate, creatine, and glutamine, in human milk, between countries, could provide insights into problems, such as mastitis and/or impaired functions of the mammary glands. Several important markers of milk production, such as lactose, betaine, creatine, glutamate, and glutamine, showed good correlation between each metabolite. This work highlights the importance of milk metabolites with respect to maternal lifestyle and the environment, and also provides the framework for future breastfeeding and microbiome studies in a global context.

13.
Arch Dis Child ; 2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279157

RESUMO

BACKGROUND: Chronic conditions are the leading cause of mortality, morbidity and disability in children. However, children and caregivers are rarely involved in identifying research priorities, which may limit the value of research in supporting patient-centred practice and policy. OBJECTIVE: To identify priorities of patients, caregivers and health professionals for research in childhood chronic conditions and describe the reason for their choices. SETTING: An Australian paediatric hospital and health consumer organisations. METHODS: Recruited participants (n=73) included patients aged 8 to 14 years with a chronic condition (n=3), parents/caregivers of children aged 0 to 18 years with a chronic condition (n=19), representatives from consumer organisations (n=13) and health professionals including clinicians, researches (n=38) identified and discussed research priorities. Transcripts were thematically analysed. RESULTS: Seventy-eight research questions were identified. Five themes underpinned participants' priorities: maintaining a sense of normality (enabling participation in school, supporting social functioning, promoting understanding and acceptance), empowering self-management and partnership in care (overcoming communication barriers, gaining knowledge and skills, motivation for treatment adherence, making informed decisions, access and understanding of complementary and alternative therapies),strengthening ability to cope (learning to have a positive outlook, preparing for home care management, transitioning to adult services), broadening focus to family (supporting sibling well-being, parental resilience and financial loss, alleviating caregiver burden), and improving quality and scope of health and social care (readdressing variability and inequities, preventing disease complications and treatment side effects, identifying risk factors, improving long-term outcomes, harnessing technology, integrating multidisciplinary services). CONCLUSION: Research priorities identified by children, caregivers and health professionals emphasise a focus on life participation, psychosocial well-being, impact on family and quality of care. These priorities may be used by funding and policy organisations in establishing a paediatric research agenda.

15.
Clin Case Rep ; 6(7): 1241-1245, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29988644

RESUMO

Cryopyrin-associated periodic syndrome (CAPS) is a monogenetic auto-inflammatory disorder with systemic manifestations. Innate immune system aberrance is seen in both CAPS and erythema nodosum and this case may point to a previously unknown association. In pediatric patients with EN and systemic features, the possibility of underlying CAPS should be considered.

16.
J Immunol ; 200(12): 3970-3980, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29720424

RESUMO

Recent evidence suggests early environmental factors are important for gut immune tolerance. Although the role of regulatory T (Treg) cells for gut immune homeostasis is well established, the development and tissue homing characteristics of Treg cells in children have not been studied in detail. In this article, we studied the development and homing characteristics of human peripheral blood Treg cell subsets and potential mechanisms inducing homing molecule expression in healthy children. We found contrasting patterns of circulating Treg cell gut and skin tropism, with abundant ß7 integrin+ Treg cells at birth and increasing cutaneous lymphocyte Ag (CLA+) Treg cells later in life. ß7 integrin+ Treg cells were predominantly naive, suggesting acquisition of Treg cell gut tropism early in development. In vitro, IL-7 enhanced gut homing but reduced skin homing molecule expression in conventional T cells, whereas IL-2 induced a similar effect only in Treg cells. This effect was more pronounced in cord compared with adult blood. Our results suggest that early in life, naive Treg cells may be driven for gut tropism by their increased sensitivity to IL-2-induced ß7 integrin upregulation, implicating a potential role of IL-2 in gut immune tolerance during this critical period of development.

18.
J Allergy Clin Immunol Pract ; 6(2): 367-375, 2018 Mar - Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29524992

RESUMO

Given the prevalence and impact of childhood food allergy, there is increasing interest in interventions targeting disease prevention. Although interventions such as early introduction of dietary peanut have demonstrated efficacy in a small number of well-conducted randomized clinical trials, evidence for broader effectiveness and successful implementation at a population level is still lacking, although epidemiological data suggest that such strategies are likely to be successful, at least for peanut. In this commentary, we explore the issues of translating evidence of efficacy studies (performed under optimal conditions) to make policy recommendations at a population level, and highlight potential benefits, harms, and unintended consequences of making population-based recommendations on the basis of randomized controlled trials. We discuss the complexity and barriers to effective primary and secondary prevention intervention implementation in resource-poor settings.

19.
BMJ Open ; 8(1): e020232, 2018 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-29391374

RESUMO

INTRODUCTION: Atopic diseases, including food allergy, have become a predominant cause of chronic illness among children in developed countries. In Australia, a rise in hospitalisations among infants coded as anaphylaxis to foods coincided with the replacement of whole-cell pertussis (wP) vaccine with subunit acellular pertussis (aP) vaccine on the national immunisation schedule in the late 1990s. Atopy is characterised by a tendency to mount T helper type 2 (Th2) responses to otherwise innocuous environmental antigens. Compared with infants who receive aP as their first pertussis vaccine, those who receive wP appear less likely to mount Th2 immune responses to either vaccine or extraneous antigens. We therefore speculate that removal of wP from the vaccine schedule contributed to the observed rise in IgE-mediated food allergy among Australian infants. METHODS AND ANALYSIS: This is a retrospective individually matched case-control study among a cohort of Australian children born from 1997 to 1999, the period of transition from wP to aP vaccines; we include in the cohort children listed on Australia's comprehensive population-based immunisation register as having received a first dose of either pertussis vaccine by 16 weeks old. 500 cohort children diagnosed as having IgE-mediated food allergy at specialist allergy clinics will be included as cases. Controls matched to each case by date and jurisdiction of birth and regional socioeconomic index will be sampled from the immunisation register. Conditional logistic regression will be used to estimate OR (±95% CI) of receipt of wP (vs aP) as the first vaccine dose among cases compared with controls. ETHICS AND DISSEMINATION: The study is approved by all relevant human research ethics committees: Western Australia Child and Adolescent Health Services (2015052EP), Women's and Children's Hospital (HREC/15/WCHN/162), Royal Children's Hospital (35230A) and Sydney Children's Hospital Network (HREC/15/SCHN/405). Outcomes will be disseminated through publication and scientific presentation. TRIAL REGISTRATION NUMBER: NCT02490007.


Assuntos
Hipersensibilidade Alimentar/etiologia , Esquemas de Imunização , Vacina contra Coqueluche/efeitos adversos , Vacinação , Coqueluche/prevenção & controle , Adolescente , Anticorpos Antibacterianos/sangue , Antígenos , Estudos de Casos e Controles , Protocolos Clínicos , Vacina contra Difteria, Tétano e Coqueluche , Vacinas contra Difteria, Tétano e Coqueluche Acelular , Feminino , Hipersensibilidade Alimentar/sangue , Humanos , Imunoglobulina E/sangue , Lactente , Masculino , Vacina contra Coqueluche/classificação , Projetos de Pesquisa , Estudos Retrospectivos , Fatores de Risco , Austrália Ocidental
20.
J Paediatr Child Health ; 54(5): 551-555, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29363215

RESUMO

AIMS: To examine reports of anaphylaxis in Australasia from consumption of packaged food products with or without precautionary allergen labelling (PAL), where the known allergen triggers were not a listed ingredient. METHODS: A questionnaire was sent to all members of the Australasian Society of Clinical Immunology and Allergy (n = 548). Participants were asked to complete a survey reporting whether they have had seen any patients over the last 3 months reporting anaphylaxis following ingestion of a packaged food where the suspected food allergen was not a listed ingredient. RESULTS: Of the n = 548 members approached, n = 198 responded (response rate 36.1%).There were 14 reports of anaphylaxis to packaged foods (where the suspected allergen was not a listed ingredient), which met the case definition from a total of 198 respondents over the 9-month period. Of those reactions, 50.0% (confidence interval 95% 21-78) were reported from foods that did not have a PAL statement, and 50.0% (confidence interval 95% 21-78) were due to peanuts. CONCLUSION: Anaphylaxis to undeclared allergens was not rare and did not appear to depend on whether the product was labelled with precautionary advice. There is currently no reliable labelling system that can inform food-allergic consumers of safer food choices. Improvements in the regulation of food labelling with PAL are required.

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