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1.
J Allergy Clin Immunol Pract ; 8(1): 24-35, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31950904

RESUMO

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy that manifests with projectile, repetitive emesis that can be followed by diarrhea and may be accompanied by lethargy, hypotonia, hypothermia, hypotension, and metabolic derangements. FPIES usually starts in infancy although onset at older ages is being increasingly recognized. FPIES is not rare, with the cumulative incidence of FPIES in infants estimated to be 0.015% to 0.7%, whereas the population prevalence in the US infants was 0.51%. FPIES diagnosis is challenging and might be missed because of later (1-4 hours) onset of symptoms after food ingestion, lack of typical allergic skin and respiratory symptoms, and food triggers that are perceived to be hypoallergenic. Diagnosis is based on the recognition of symptoms because there are no biomarkers of FPIES. The pathophysiology remains obscure although activation of the innate immune compartment has been detected. Management relies of avoidance of food triggers, treatment of accidental exposures, and periodic re-evaluations with supervised oral food challenges to monitor for resolution. There are no strategies to accelerate development of tolerance in FPIES. Here we review the most important current concepts in epidemiology, pathophysiology, diagnosis, and management of FPIES.

2.
Front Immunol ; 10: 1900, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474985

RESUMO

The rare autoinflammatory disease mevalonate kinase deficiency (MKD, which includes HIDS and mevalonic aciduria) is caused by recessive, pathogenic variants in the MVK gene encoding mevalonate kinase. Deficiency of this enzyme decreases the synthesis of isoprenoid lipids and thus prevents the normal post-translational prenylation of small GTPase proteins, which then accumulate in their unprenylated form. We recently optimized a sensitive assay capable of detecting unprenylated Rab GTPase proteins in peripheral blood mononuclear cells (PBMCs) and showed that this assay distinguished MKD from other autoinflammatory diseases. We have now analyzed PBMCs from an additional six patients with genetically-confirmed MKD (with different compound heterozygous MVK genotypes), and compared these with PBMCs from three healthy volunteers and four unaffected control individuals heterozygous for the commonest pathogenic variant, MVK V377I . We detected a clear accumulation of unprenylated Rab proteins, as well as unprenylated Rap1A by western blotting, in all six genetically-confirmed MKD patients compared to heterozygous controls and healthy volunteers. Furthermore, in the three subjects for whom measurements of residual mevalonate kinase activity was available, enzymatic activity inversely correlated with the extent of the defect in protein prenylation. Finally, a heterozygous MVK V377I patient presenting with autoinflammatory symptoms did not have defective prenylation, indicating a different cause of disease. These findings support the notion that the extent of loss of enzyme function caused by biallelic MVK variants determines the severity of defective protein prenylation, and the accumulation of unprenylated proteins in PBMCs may be a sensitive and consistent biomarker that could be used to aid, or help rule out, diagnosis of MKD.

5.
Allergy ; 74(7): 1352-1363, 2019 07.
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.

6.
J Allergy Clin Immunol Pract ; 7(2): 471-478.e3, 2019 02.
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.

8.
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.


Assuntos
Enterocolite , Hipersensibilidade Alimentar , Austrália , Pré-Escolar , Proteínas na Dieta/efeitos adversos , Enterocolite/diagnóstico , Enterocolite/etiologia , Enterocolite/terapia , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/diagnóstico , Hipersensibilidade Alimentar/terapia , Humanos , Lactente , Guias de Prática Clínica como Assunto , Síndrome
9.
Am J Med Genet C Semin Med Genet ; 175(4): 516-523, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29159871

RESUMO

Immunodeficiency can occur in CHARGE syndrome, with immunophenotypes including reduction in T-cell counts, combined T-B cell defects rarely requiring antibiotic prophylaxis or immunoglobulin replacement, and severe combined immunodeficiency, which is fatal without immune reconstitution. However, the prevalence of immunodeficiency in CHARGE syndrome remains unclear with few prospective studies. In this review, we examine the existing literature covering immunodeficiency associated with CHARGE syndrome, compare these with immunodeficiencies reported in 22q11.2 deletion syndrome (a condition that shares many phenotypic characteristics with CHARGE syndrome) and suggest future research priorities.


Assuntos
Síndrome CHARGE/genética , Síndrome CHARGE/imunologia , Estudos de Associação Genética , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Fenótipo , Animais , Síndrome CHARGE/diagnóstico , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/metabolismo
12.
J Allergy Clin Immunol ; 140(5): 1323-1330, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28427879

RESUMO

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal allergic disorder. Large population-based FPIES studies are lacking. OBJECTIVE: We sought to determine the incidence and clinical characteristics of FPIES in Australian infants. METHODS: An Australia-wide survey (2012-2014) was undertaken through the Australian Paediatric Surveillance Unit, with monthly notification of new cases of acute FPIES in infants aged less than 24 months by 1400 participating pediatricians. RESULTS: Two hundred thirty infants with FPIES were identified. The incidence of FPIES in Australian infants (<24 months) was 15.4/100,000/y. Median age of first episode, diagnosis, and notification were 5, 7, and 10 months, respectively. There was no sex predilection. Seven percent of infants had siblings with a history of FPIES, and 5% reacted during exclusive breast-feeding. Sixty-eight had a single food trigger (20% had 2 and 12% had ≥3 food triggers). The most common FPIES triggers were rice (45%), cow's milk (33%), and egg (12%). Fifty-one percent of infants reacted on their first known exposure. Infants with FPIES to multiple versus single food groups were younger at the initial episode (4.6 vs 5.8 months [mean], P = .001) and more frequently had FPIES to fruits, vegetables, or both (66% vs 21%, P < .0001). Infants exclusively breast-fed for more than 4 months had a trend toward lower rates of FPIES to multiple food groups (23% vs 36%, P = .06). Sixty-four percent of infants with FPIES to multiple foods, which included cow's milk, had coassociated FPIES to solid foods. Forty-two percent of infants with FPIES to fish reacted to other food groups. CONCLUSIONS: FPIES is not rare, with an estimated incidence of 15.4/100,000/y. Rice is the most common food trigger in Australia. Factors associated with FPIES to multiple foods included early-onset disease and FPIES to fruits, vegetables, or both.


Assuntos
Enterocolite/epidemiologia , Hipersensibilidade Alimentar/epidemiologia , Grupos Populacionais , Idade de Início , Alérgenos/efeitos adversos , Alérgenos/imunologia , Animais , Austrália/epidemiologia , Bovinos , Enterocolite/imunologia , Feminino , Hipersensibilidade Alimentar/imunologia , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Oryza/efeitos adversos , Fatores de Risco , Síndrome
14.
J Paediatr Child Health ; 52(9): 889-95, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27650144

RESUMO

AIM: Cryopyrin-associated periodic syndromes (CAPS) encapsulate three auto-inflammatory conditions, ranging in severity from mild (familial cold auto-inflammatory syndrome: FCAS), moderate (Muckle-Wells syndrome: MWS) and severe (neonatal onset multi-inflammatory disorder: NOMID). We aimed to describe the epidemiology, clinical features and outcomes of Australian children and adults with CAPS. METHODS: Patients were identified and clinical data collected through a questionnaire sent during 2012-2013 to clinicians reporting to the Australian Paediatric Surveillance Unit and subscribing to the Australasian Societies for Allergy/Immunology, Rheumatology and Dermatology. RESULTS: Eighteen cases of CAPS were identified (8 NOMID; 8 MWS, 2 FCAS); 12 in children <18 years of age. The estimated population prevalence of CAPS was 1 per million persons. Diagnostic delay was frequent, particularly in those with milder phenotypes (median diagnostic delay in MWS/FCAS 20.6 years compared with NOMID 2.1 years; P = 0.04). Common presenting features included urticaria (100%), periodic fever (78%), arthralgia (72%) and sensorineural hearing loss (61%). Almost all (90%) MWS patients had a family member similarly affected compared with none in the NOMID group (P = 0.004). A significant proportion of patients on anti-interleukin (IL)-1 therapy (n = 13) no longer had systemic inflammation. Only 50% with sensorineural hearing loss had hearing restored on anti-IL-1 therapy. CONCLUSIONS: Although CAPS are rare, patients often endured prolonged periods of systemic inflammation. This is despite almost all MWS patients having family members with similar symptoms and children with NOMID presenting with chronic infantile urticaria associated with multi-system inflammation. Hearing loss in NOMID/MWS was frequent, and reversible in only 50% of cases.


Assuntos
Síndromes Periódicas Associadas à Criopirina/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Criança , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/complicações , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/terapia , Diagnóstico Tardio/estatística & dados numéricos , Feminino , Inquéritos Epidemiológicos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prevalência , Vigilância em Saúde Pública , Adulto Jovem
15.
Immunol Cell Biol ; 94(10): 994-999, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27377765

RESUMO

Mevalonate kinase deficiency (MKD) is caused by mutations in a key enzyme of the mevalonate-cholesterol biosynthesis pathway, leading to recurrent autoinflammatory disease characterised by enhanced release of interleukin-1ß (IL-1ß). It is currently believed that the inflammatory phenotype of MKD is triggered by temperature-sensitive loss of mevalonate kinase activity and reduced biosynthesis of isoprenoid lipids required for the prenylation of small GTPase proteins. However, previous studies have not clearly shown any change in protein prenylation in patient cells under normal conditions. With lymphoblast cell lines from two compound heterozygous MKD patients, we used a highly sensitive in vitro prenylation assay, together with quantitative mass spectrometry, to reveal a subtle accumulation of unprenylated Rab GTPases in cells cultured for 3 days or more at 40 °C compared with 37 °C. This included a 200% increase in unprenylated Rab7A, Rab14 and Rab1A. Inhibition of sterol regulatory element-binding protein (SREBP) activation by fatostatin led to more pronounced accumulation of unprenylated Rab proteins in MKD cells but not parent cells, suggesting that cultured MKD cells may partially overcome the loss of isoprenoid lipids by SREBP-mediated upregulation of enzymes required for isoprenoid biosynthesis. Furthermore, while inhibition of Rho/Rac/Rap prenylation promoted the release of IL-1ß, specific inhibition of Rab prenylation by NE10790 had no effect in human peripheral blood mononuclear cells or human THP-1 monocytic cells. These studies demonstrate for the first time that mutations in mevalonate kinase can lead to a mild, temperature-induced defect in the prenylation of small GTPases, but that loss of prenylated Rab GTPases is not the cause of enhanced IL-1ß release in MKD.


Assuntos
Deficiência de Mevalonato Quinase/enzimologia , Prenilação de Proteína , Proteínas rab de Ligação ao GTP/metabolismo , Linhagem Celular , Criança , Pré-Escolar , Feminino , Humanos , Interleucina-1beta/metabolismo , Marcação por Isótopo , Leucócitos Mononucleares/metabolismo , Masculino , Deficiência de Mevalonato Quinase/patologia , Piridinas/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Temperatura Ambiente , Tiazóis/farmacologia
16.
J Pediatr ; 176: 150-5, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27321065

RESUMO

OBJECTIVE: To evaluate whether central adrenal insufficiency (CAI) is present in CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital hypoplasia, and Ear abnormalities, including deafness) syndrome, a complex malformation disorder that includes central endocrine dysfunction. STUDY DESIGN: Two cross-sectional studies were performed in Dutch (September 2013-February 2015) and Australian (January 2012-January 2014) CHARGE syndrome clinics. Twenty-seven Dutch and 19 Australian patients (aged 16 months-18 years) with genetically confirmed CHARGE syndrome were included. The low-dose adrenocorticotropin (ACTH) test was used to assess CAI in the Dutch cohort. A peak cortisol response less than 18.1 µg/dL (500 nmol/L) was suspected for CAI, and a glucagon stimulation test was performed for confirmation. Australian patients were screened by single measurements of ACTH and cortisol levels. If adrenal dysfunction was suspected, a standard-dose ACTH test was performed. RESULTS: The low-dose ACTH test was performed in 23 patients (median age 8.4 [1.9-16.9] years). Seven patients showed an insufficient maximum cortisol level (10.3-17.6 µg/dL, 285-485 nmol/L), but CAI was confirmed by glucagon stimulation test in only 1 patient (maximum cortisol level 15.0 µg/dL, 415 nmol/L). In the Australian cohort, 15 patients (median age 9.1 [1.3-17.8] years) were screened, and none had CAI. CONCLUSIONS: CAI was not common in our cohorts, and routine testing of adrenal function in children with CHARGE syndrome is not indicated.


Assuntos
Insuficiência Adrenal/etiologia , Síndrome CHARGE/complicações , Adolescente , Insuficiência Adrenal/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Masculino
17.
Paediatr Respir Rev ; 19: 56-61, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26831679

RESUMO

Common variable immunodeficiency is an antibody deficiency that usually presents in childhood with recurrent sino-pulmonary infections. Diagnostic delay is frequent and thus respiratory morbidity is common, ranging from recurrent suppurative bronchitis to bronchiectasis. Immunoglobulin replacement therapy is the mainstay of treatment, whilst prophylactic antibiotic therapy and muco-ciliary clearance are additional treatment options. This review examines the diagnosis and management of respiratory issues in children with CVID.


Assuntos
Imunodeficiência de Variável Comum/complicações , Pneumopatias/etiologia , Pneumopatias/imunologia , Pneumopatias/terapia , Criança , Gerenciamento Clínico , Humanos
18.
J Allergy Clin Immunol Pract ; 4(1): 96-103.e2, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26563674

RESUMO

BACKGROUND: Recurrent sinopulmonary infections are common in children with CHARGE (Coloboma, Heart disease, choanal Atresia, growth/mental Retardation, Genitourinary malformations, Ear abnormalities) syndrome, but no prospective studies on immune function have been conducted. OBJECTIVE: This study aims to examine and compare the immune phenotype of patients with CHARGE syndrome to those with 22q11.2 deletion and healthy controls. METHODS: A total of 21 patients attended a multidisciplinary CHARGE clinic. All patients had CHD7 mutational analysis performed. Patients with CHARGE syndrome had lymphocyte subsets, immunoglobulins (IgG, A, M), functional protein, and polysaccharide vaccine responses measured at initial evaluation. A total of 55 healthy controls were prospectively recruited, whereas 40 patients with 22q11.2 deletion were retrospectively identified through medical records. A separate analysis compared serial lymphocyte counts and ionized calcium levels between patients with CHARGE syndrome and those with 22q11.2 deletion in the first 72 months of life. RESULTS: Despite recurrent childhood ear and chest infections, only 2 children with CHARGE syndrome had an identifiable immune defect (reduced serum IgA). In contrast, T-cell lymphopenia, low immunoglobulin levels, and specific antibody deficiency were noted in patients with 22q11.2 deletion. A greater proportion of patients with 22q11.2 deletion had persistent lymphopenia (57% vs 30%) and hypocalcemia (60% vs 37.5%) compared with patients with CHARGE syndrome in the first 72 months of life. CONCLUSIONS: Although phenotypic overlap exists between CHARGE and 22q11.2 deletion syndromes, no significant immune defects were detected in this cohort of patients with CHARGE syndrome at the time of testing. Lymphopenia and hypocalcemia occur in both conditions early in life, but is more pronounced in patients with 22q11.2 deletion.


Assuntos
Síndrome CHARGE/diagnóstico , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Síndrome de DiGeorge/diagnóstico , Linfócitos/imunologia , Síndrome CHARGE/imunologia , Cálcio/sangue , Criança , Pré-Escolar , Análise Mutacional de DNA , Síndrome de DiGeorge/imunologia , Feminino , Humanos , Imunoglobulinas/sangue , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos
20.
J Allergy Clin Immunol ; 135(5): 1114-24, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25956013

RESUMO

Non-IgE-mediated gastrointestinal food-induced allergic disorders (non-IgE-GI-FAs) account for an unknown proportion of food allergies and include food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), and food protein-induced enteropathy (FPE). Non-IgE-GI-FAs are separate clinical entities but have many overlapping clinical and histologic features among themselves and with eosinophilic gastroenteropathies. Over the past decade, FPIES has emerged as the most actively studied non-IgE-GI-FA, potentially because of acute and distinct clinical features. FPIAP remains among the common causes of rectal bleeding in infants, while classic infantile FPE is rarely diagnosed. The overall most common allergens are cow's milk and soy; in patients with FPIES, rice and oat are also common. The most prominent clinical features of FPIES are repetitive emesis, pallor, and lethargy; chronic FPIES can lead to failure to thrive. FPIAP manifests with bloody stools in well-appearing young breast-fed or formula-fed infants. Features of FPE are nonbloody diarrhea, malabsorption, protein-losing enteropathy, hypoalbuminemia, and failure to thrive. Non-IgE-GI-FAs have a favorable prognosis; the majority resolve by 1 year in patients with FPIAP, 1 to 3 years in patients with FPE, and 1 to 5 years in patients with FPIES, with significant differences regarding specific foods. There is an urgent need to better define the natural history of FPIES and the pathophysiology of non-IgE-GI-FAs to develop biomarkers and novel therapies.


Assuntos
Hipersensibilidade Alimentar/imunologia , Gastroenteropatias/imunologia , Animais , Aleitamento Materno , Gerenciamento Clínico , Feminino , Alimentos/efeitos adversos , Hipersensibilidade Alimentar/diagnóstico , Hipersensibilidade Alimentar/tratamento farmacológico , Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/prevenção & controle , Gastroenteropatias/diagnóstico , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/epidemiologia , Gastroenteropatias/prevenção & controle , Humanos , Imunoglobulina E/imunologia , Lactente , Prevalência
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