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Common variable immune deficiency (CVID) is a heterogenous group of disorders characterized by varying degrees of hypogammaglobulinemia, recurrent infections, and autoimmunity. Currently, pathogenic variants are identified in approximately 20-30% of CVID cases. Here we report a 3-generation family with autosomal dominant Common Variable Immunodeficiency (CVID) diagnosed in 9 affected individuals. Although primary immune deficiency panels and exome sequencing were non-diagnostic, whole genome sequencing revealed a novel, pathogenic c.499C > T: p.His167Tyr variant in IKZF1, a critical regulator of B cell development. Functional testing done through pericentromeric heterochromatin localization and light shift chemiluminescent electrophoretic mobility shift assay confirmed the variant's deleterious effect via a haploinsufficiency mechanism. Our findings expand the spectrum of known IKZF1 mutations and contribute to a more comprehensive understanding of CVID's genetic heterogeneity. Furthermore, this case underscores the importance of considering whole genome sequencing for comprehensive genetic diagnosis when concern for a monogenic inborn errors of immunity is high.
Assuntos
Imunodeficiência de Variável Comum , Fator de Transcrição Ikaros , Linhagem , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Éxons/genética , Fator de Transcrição Ikaros/genética , Mutação , Sequenciamento Completo do Genoma , Pré-Escolar , Adolescente , IdosoRESUMO
BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.
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Doenças do Sistema Imunitário , Síndromes de Imunodeficiência , Criança , Humanos , Autoimunidade/genética , Estudos de Coortes , Mutação com Ganho de Função , Síndromes de Imunodeficiência/genética , Mutação , Fator de Transcrição STAT3/genética , Proliferação de Células , LinfócitosRESUMO
PURPOSE OF REVIEW: Asthma is a frequently encountered chronic medical condition encountered in paediatrics, affecting 7% of children under the age of 18 in the United States. Although asthma is one of the more common conditions that is associated with wheezing, there is a broad differential diagnosis to consider. The purpose of this review is to describe other causes of wheezing outside of asthma in a paediatric population and discuss diagnostic and management strategies to consider when evaluating a child or adolescent with wheezing. RECENT FINDINGS: The characteristics of the wheezing along with other associated signs and symptoms can be helpful in narrowing the differential diagnosis. The age and the past medical history of the patient are also important aspects to consider when determining next steps in the evaluation and management of paediatric wheezing. In addition to considering other causes of wheezing, it is often necessary to assess for the presence of underlying asthma, and recently updated asthma guidelines from the National Heart, Lung and Blood Institute provide a graded review of various recommendations for making the diagnosis and managing asthma in the clinical setting. SUMMARY: It is important to maintain a broad differential diagnosis when evaluating a paediatric patient with wheezing.
Assuntos
Asma , Pediatria , Adolescente , Asma/complicações , Asma/diagnóstico , Asma/terapia , Criança , Diagnóstico Diferencial , Humanos , Sons Respiratórios/etiologia , Estados UnidosRESUMO
PURPOSE OF REVIEW: To provide clinicians with an understanding of risk factors associated with fatal anaphylaxis, and to promote individualized management plans with patients based upon key aspects of their clinical history. RECENT FINDINGS: While anaphylaxis can affect a significant percentage of the general population, death from anaphylaxis remains a rare outcome. The presence of asthma and peanut or tree nut allergy is associated with higher risk for severe or fatal anaphylaxis from foods. Specific triggers (medications, venom), underlying comorbid conditions, age, and use of some medications can also impact risk and warrant different counseling and management strategies. Anaphylaxis is a rapidly progressive systemic reaction with multiple different causes and encompasses a wide degree of severity in clinical presentation and risk for future episodes. Individualized management, discussion of risk, and shared decision making should occur with each patient and in consideration of their personal risk factors.
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Anafilaxia , Hipersensibilidade , Anafilaxia/diagnóstico , Anafilaxia/epidemiologia , Anafilaxia/etiologia , Anafilaxia/mortalidade , Humanos , Hipersensibilidade/etiologia , Fatores de RiscoRESUMO
This review summarizes some of the most significant advances in asthma research over the past year. We first focus on novel discoveries in the mechanism of asthma development and exacerbation. This is followed by a discussion of potential new biomarkers, including the use of radiographic markers of disease. Several new biologics have become available to the clinician in the past year, and we summarize these advances and how they can influence the clinical delivery of asthma care. After this, important findings in the genetics of asthma and heterogeneity in phenotypes of the disease are explored, as is the role the environment plays in shaping the development and exacerbation of asthma. Finally, we conclude with a discussion of advances in health literacy and how they will affect asthma care.
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Asma , Animais , Antiasmáticos/uso terapêutico , Asma/diagnóstico por imagem , Asma/tratamento farmacológico , Asma/genética , Asma/imunologia , Produtos Biológicos/uso terapêutico , Biomarcadores , Suplementos Nutricionais , Letramento em Saúde , Disparidades em Assistência à Saúde , HumanosAssuntos
Mutação em Linhagem Germinativa , Sepse , Humanos , Criança , Testes Genéticos , Sepse/diagnóstico , Sepse/genética , Células GerminativasRESUMO
Asthma is one of the most common chronic health conditions that affect children and adults. It is associated with many comorbid conditions, particularly those along the allergic spectrum, such as atopic dermatitis, allergic rhinitis, and food allergy. The relationship between asthma and food allergies involves prognosis, management, and understanding of risk for severe reactions. Both conditions are heterogeneous and can change over time, which necessitates an individualized approach toward counseling and management. Long-standing associations of an increased risk for food allergy fatality in individuals who have asthma is not as straightforward or concrete as previously believed. It is important for clinicians to have a current understanding of the evidence about the relationship between asthma and food allergy to participate in shared decision-making and counseling with patients. This review will offer background and new perspective surrounding the nuanced relationship of asthma and food allergy.
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The field of Immunology is one that has undergone great expansion in recent years. With the advent of new diagnostic modalities including a variety of genetic tests (discussed elsewhere in this journal), the ability to diagnose a patient with a primary immunodeficiency disorder (PIDD) has become a more streamlined process. With increased availability of genetic testing for those with suspected or known PIDD, there has been a significant increase in the number of genes associated with this group of disorders. This is of great importance as a misdiagnosis of these rare diseases can lead to a delay in what can be critical treatment options. At times, those options can include life-saving medications or procedures. Presentation of patients with PIDD can vary greatly based on the specific genetic defect and the part(s) of the immune system that is affected by the variation. PIDD disorders lead to varying levels of increased risk of infection ranging from a mild increase such as with selective IgA deficiency to a profound risk with severe combined immunodeficiency. These diseases can also cause a variety of other clinical findings including autoimmunity and gastrointestinal disease.
Assuntos
Deficiência de IgA , Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Autoimunidade/genética , Testes Genéticos , Humanos , Deficiência de IgA/complicações , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/genéticaRESUMO
BACKGROUND: Although many egg- and milk-allergic children tolerate baked egg (BE) and baked milk (BM), reactions elicited by these oral food challenges (OFCs) can be severe. Previous studies comparing BE and BM reactions to other OFC reactions are limited. OBJECTIVE: To compare the clinical features of reactions to BE and BM with other OFCs to promote challenge safety. METHODS: A retrospective review of OFCs eliciting objective reactions to BE, BM, lightly cooked egg (CE), fresh cow's milk (CM), peanut (PN), and tree nuts (TN) which were performed at a tertiary referral center from June 1, 2017, to June 1, 2019. RESULTS: We identified 174 OFCs conducted in 158 subjects, age 6 to 187 months (34 BE, 19 BM, 14 CE, 25 CM, 52 PN, and 30 TN). TN reactors were older than BE (P = .049) and PN (P < .01) reactors and had a higher frequency of persistent asthma than PN-reactive subjects (P = .02). Mucocutaneous symptoms occurred less frequently during BE (56%) and BM (42%) OFCs compared with other OFCs (P < .05). Lower respiratory tract reactions were increased during BM (37%) versus BE (12%), CM (8%), and PN (12%) OFCs (P < .05). Epinephrine was administered to more BE (44%) and TN (50%) than PN (17%) OFCs (P < .01). New reaction manifestations developed 60 minutes or later after OFC termination during 29% BE and 21% BM versus 0% PN OFCs (P < .05). One-third of anaphylactic reactions to BE began more than 60 minutes after OFC termination. CONCLUSIONS: BE and BM challenge reactions differed phenotypically from other OFC reactions, including significantly increased frequencies of new symptoms beginning 60 minutes or later after challenge termination. Consider amended dose-escalation and prolonged observation after BE and BM OFCs.
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Anafilaxia , Hipersensibilidade a Leite , Alérgenos , Anafilaxia/epidemiologia , Animais , Bovinos , Criança , Feminino , Humanos , Imunoglobulina E , Leite , Hipersensibilidade a Leite/diagnóstico , Hipersensibilidade a Leite/epidemiologia , Estudos RetrospectivosRESUMO
CARMIL2 deficiency is a rare combined immunodeficiency (CID) characterized by defective CD28-mediated T cell co-stimulation, altered cytoskeletal dynamics, and susceptibility to Epstein Barr Virus smooth muscle tumors (EBV-SMTs). Case reports associated with EBV-SMTs are limited. We describe herein a novel homozygous CARMIL2 variant (c.1364_1393del) in two Saudi Arabian male siblings born to consanguineous parents who developed EBV-SMTs. CARMIL2 protein expression was significantly reduced in CD4+ T cells and CD8+ T cells. T cell proliferation on stimulation with soluble (s) anti-CD3 or (s) anti-CD3 plus anti-CD28 antibodies was close to absent in the proband, confirming altered CD28-mediated co-signaling. CD28 expression was substantially reduced in the proband's T cells, and was diminished to a lesser degree in the T cells of the younger sibling, who has a milder clinical phenotype. Defects in both T and B cell compartments were observed, including absent central memory CD8+ T cells, and decreased frequencies of total and class-switched memory B cells. FOXP3+ regulatory T cells (Treg) were also quantitatively decreased, and furthermore CD25 expression within the Treg subset was substantially reduced. These data confirm the pathogenicity of this novel loss-of-function (LOF) variant in CARMIL2 and expand the genotypic and phenotypic spectrum of CIDs associated with EBV-SMTs.
Assuntos
Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/fisiologia , Proteínas dos Microfilamentos/genética , Doenças da Imunodeficiência Primária/genética , Linfócitos T/fisiologia , Antígenos CD28/metabolismo , Células Cultivadas , Citoesqueleto/metabolismo , Humanos , Ativação Linfocitária , Masculino , Linhagem , Arábia Saudita , Irmãos , Tumor de Músculo LisoRESUMO
Chronic granulomatous disease (CGD) is a rare but serious primary immunodeficiency with varying prevalence and rates of X-linked and autosomal recessive disease worldwide. Functional defects in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex predispose patients to a relatively narrow spectrum of bacterial and fungal infections that are sometimes fastidious and often difficult to identify. When evaluating and treating patients with CGD, it is important to consider their native country of birth, climate, and living situation, which may predispose them to types of infections that are atypical to your routine practice. In addition to recurrent and often severe infections, patients with CGD and X-linked female carriers are also susceptible to developing many non-infectious complications including tissue granuloma formation and autoimmunity. The DHR-123 oxidation assay is the gold standard for making the diagnosis and it along with genetic testing can help predict the severity and prognosis in patients with CGD. Disease management focuses on prophylaxis with antibacterial, antifungal, and immunomodulatory medications, prompt identification and treatment of acute infections, and prevention of secondary granulomatous complications. While hematopoietic stem-cell transplantation is the only widely available curative treatment for patients with CGD, recent advances in gene therapy may provide a safer, more direct alternative.
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Atopic dermatitis (AD) is a chronic, relapsing disease that typically manifests in childhood and improves with age. Studies have demonstrated that the presence of AD increases the risk of developing food allergy, allergic rhinitis, and asthma later in life. Although children with AD are more likely to produce allergen-specific immunoglobulin E, there is conflicting evidence that allergen avoidance improves disease severity. Furthermore, food-elimination diets in patients with AD may increase the risk of developing immediate, life-threatening reactions to the removed food. The most effective treatments of AD aim to repair and protect the skin barrier and decrease inflammation.
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Dermatite Atópica/etiologia , Alérgenos/administração & dosagem , Alérgenos/imunologia , Animais , Dermatite Atópica/diagnóstico , Dermatite Atópica/prevenção & controle , Dermatite Atópica/terapia , Gerenciamento Clínico , Suscetibilidade a Doenças , Predisposição Genética para Doença , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/etiologia , Hipersensibilidade/prevenção & controle , Hipersensibilidade/terapiaAssuntos
Anafilaxia , Hipersensibilidade Alimentar , Testes Cutâneos , Humanos , Anafilaxia/diagnóstico , Hipersensibilidade Alimentar/diagnóstico , Masculino , Feminino , Adulto , Criança , Alérgenos/imunologia , Adolescente , Pré-Escolar , Sensibilidade e Especificidade , Pessoa de Meia-Idade , Adulto JovemRESUMO
Epinephrine is the only effective treatment for anaphylaxis but studies routinely show underutilization. This is especially troubling given the fact that fatal anaphylaxis has been associated with delayed administration of epinephrine. Many potential barriers exist to the proper use of epinephrine during an anaphylactic reaction. This article will explore both patient-and physician-related factors, as well as misconceptions that all contribute to the underuse of epinephrine for the treatment of anaphylaxis.
RESUMO
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency that is caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The disease presents in most patients initially with infection, especially of the lymph nodes, lung, liver, bone, and skin. Patients with CGD are susceptible to a narrow spectrum of pathogens, and Staphylococcus aureus, Burkholderia cepacia complex, Serratia marcescens, Nocardia species, and Aspergillus species are the most common organisms implicated in North America. Granuloma formation, most frequently in the gastrointestinal and genitourinary systems, is a common complication of CGD and can be seen even before diagnosis. An increased incidence of autoimmune disease has also been described in patients with CGD and X-linked female carriers. In patients who present with signs and symptoms consistent with CGD, a flow cytometric dihydrorhodamine neutrophil respiratory burst assay is a quick and cost-effective way to evaluate NADPH oxidase function. The purpose of this review is to highlight considerations for and challenges in the diagnosis of CGD.
Assuntos
Doença Granulomatosa Crônica/diagnóstico , Diagnóstico Diferencial , Feminino , Granuloma/etiologia , Doença Granulomatosa Crônica/complicações , Humanos , Masculino , Mutação , Micoses/etiologia , NADPH Oxidases/genética , NADPH Oxidases/fisiologia , Nitroazul de TetrazólioRESUMO
The impact of gut microbiome on human development, nutritional needs, and disease has become evident with advances in the ability to study these complex communities of microorganisms, and there is growing appreciation for the role of the microbiome in immune regulation. Several studies have examined associations between changes in the commensal microbiota and the development of asthma, allergic rhinitis, and asthma, but far less have evaluated the impact of the microbiome on the development of food allergy. This article reviews the human gastrointestinal microbiome, focusing on the theory and evidence for its role in the development of IgE-mediated food allergy and other allergic diseases.