Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.

Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement. These findings suggest that individually rare JAK1 GoF variants may underlie an emerging syndrome with more common presentations of autoimmune and inflammatory disease (JAACD syndrome). More broadly, individuals who present with such conditions may benefit from genetic testing for the presence of JAK1 GoF variants.

Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms.

Serum tryptase is a biomarker used to aid in the identification of certain myeloid neoplasms, most notably systemic mastocytosis, where basal serum tryptase (BST) levels >20 ng/mL are a minor criterion for diagnosis. Although clonal myeloid neoplasms are rare, the common cause for elevated BST levels is the genetic trait hereditary α-tryptasemia (HαT) caused by increased germline TPSAB1 copy number. To date, the precise structural variation and mechanism(s) underlying elevated BST in HαT and the general clinical utility of tryptase genotyping, remain undefined. Through cloning, long-read sequencing, and assembling of the human tryptase locus from an individual with HαT, and validating our findings in vitro and in silico, we demonstrate that BST elevations arise from overexpression of replicated TPSAB1 loci encoding canonical α-tryptase protein owing to coinheritance of a linked overactive promoter element. Modeling BST levels based on TPSAB1 replication number, we generate new individualized clinical reference values for the upper limit of normal. Using this personalized laboratory medicine approach, we demonstrate the clinical utility of tryptase genotyping, finding that in the absence of HαT, BST levels >11.4 ng/mL frequently identify indolent clonal mast cell disease. Moreover, substantial BST elevations (eg, >100 ng/mL), which would ordinarily prompt bone marrow biopsy, can result from TPSAB1 replications alone and thus be within normal limits for certain individuals with HαT.

X-Linked Agammaglobulinemia: Infection Frequency and Infection-Related Mortality in the USIDNET Registry.

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by mutations in the Bruton tyrosine kinase (BTK) gene leading to B lymphocyte deficiency and susceptibility to infection. A potential benefit of earlier diagnosis and treatment initiation on morbidity and mortality in XLA is incompletely understood. In the USIDNET Registry, we describe infection frequency and infection-related mortality in patients with XLA and their relationship to age of diagnosis and treatment initiation. Among the 231 XLA patients enrolled in the Registry, respiratory infections (N = 203, 88%) were the most commonly reported. Among those deceased (N = 20) where cause of death was known (N = 17), mortality was attributed to infection in most (N = 12, 71%). Chronic lung disease, often a consequence of repeated lower respiratory tract infection (LRTI), was also a frequent complication associated with mortality (N = 9, 53%). Age of diagnosis in years was lower for those without LRTI compared to those with (median 1.5 [IQR 0.5-3.3] vs. median 3.0 [IQR 1.0-5.0], p = 0.0026) and among living patients compared to deceased (median 1.8 [IQR 0.5-5.0] vs. median 2.7 [IQR 1.6-6.0], p = 0.04). Age at treatment initiation in years was lower among those without LRTIs compared to those with (median 1.0 [IQR 0.4-2.4] vs. median 2.8 [IQR 1.0-5.4], p = 0.0006). For every year increase in age at start of therapy, the odds of experiencing a LRTI was 1.216 (OR 1.216, 95% CI 1.048-1.411, p = 0.01). Given the expected finding of reduced LRTIs and mortality among those with earlier age at diagnosis, our study findings support inclusion of XLA in newborn screening programs.

A formula-fed infant with profound dehydration, cerebral venous sinus thrombosis, and intracranial hemorrhage.

Background: Chronic food protein-induced enterocolitis syndrome (FPIES) is a cell-mediated gastrointestinal food hypersensitivity described almost exclusively in infants fed cow's milk or soy formula. A timely diagnosis is challenging due to a number of factors, including broad differential diagnoses, absence of specific biomarkers, and delayed symptom onset. Objective: This report aimed to highlight how the severity of presentation can further impede a timely diagnosis in chronic FPIES. Methods: A case of presumed chronic FPIES to soy with previously unreported complications of intracranial hemorrhage and cerebral venous sinus thrombosis was described. Results: We reported a case of a female infant fed a soy formula who presented during the third week of life with intermittent and progressive emesis, diarrhea, and lethargy, which culminated in severe dehydration, with early hospital course complications of seizures, intracranial hemorrhage, and cerebral venous sinus thrombosis. Although not recognized until weeks into the hospital course, many of the presenting symptoms and laboratory abnormalities were characteristic of chronic FPIES. An ultimate consideration of FPIES led to transition to amino acid-based formula and gradual resolution of gastrointestinal symptoms. Close outpatient follow-up was essential in facilitating subsequent age-appropriate solid food introduction. Conclusion: The severity of presentation in FPIES can represent an additional barrier to a timely diagnosis. Early consideration of this entity in the differential diagnosis of patients with typical FPIES features, regardless of the additional presence of atypical and severe complications, may help with more timely recognition and intervention. In addition, there is an increased need for close follow-up as an outpatient in severe FPIES cases.

Lymphoproliferative Disease in CVID: a Report of Types and Frequencies from a US Patient Registry.

PURPOSE: Lymphoproliferative disease in common variable immunodeficiency disease (CVID) is heterogeneous in pathogenesis and ranges from non-malignant lymphoid hyperplasia to lymphoma. METHODS: The United States Immunodeficiency Network (USIDNET) patient registry was queried for lymphoproliferative diseases reported in CVID patients. Diagnoses included as possible manifestations of lymphoproliferation included lymphadenopathy, lymphoid hyperplasia, lymphocytic inflammation, lymphocytosis, and gammopathy. RESULTS: Among 1091 CVID patients, lymphoproliferative conditions were reported in 17.2% (N = 188). These conditions included lymphadenopathy (N = 192, 12.3%), lymphoid hyperplasia or lymphocytic inflammation (N = 50, 4.6%), lymphocytosis (N = 3, 0.3%), and gammopathies (N = 3, 0.3%). Of the 188 patients with lymphoproliferative conditions, 15 (8%) also had a diagnosis of lymphoma, while the remaining 173 (92%) did not. Nine (4.8%) had a diagnosis of non-lymphomatous malignancy including basal cell carcinoma (N = 3, 1.6%), thyroid carcinoma (N = 2, 1.1%), gynecologic cancer (N = 2, 1.1%), testicular cancer (N = 1), and vocal cord carcinoma (N = 1). CVID patients with lymphoma were older than patients with lymphoproliferative disease who did not have a diagnosis of lymphoma at the time of analysis (median age 49 vs. 35 years, p = 0.005). CVID patients with lymphoproliferative disease had 2.5 times higher odds of having chronic lung disease compared with those with lymphoma (OR = 0.4, p = 0.049). There were no significant differences in the frequency of autoimmune, gastrointestinal, hepatic, or granulomatous disease between these populations. CONCLUSIONS: While CVID patients are at increased risk for lymphoma, lymphoproliferation may be observed in the absence of a concurrent hematologic or solid tumor malignancy.

Allergen-Specific Immunotherapies for Food Allergy.

With rising prevalence of food allergy (FA), allergen-specific immunotherapy (AIT) for FA has become an active area of research in recent years. In AIT, incrementally increasing doses of inciting allergen are given with the goal to increase tolerance, initially through desensitization, which relies on regular exposure to allergen. With prolonged therapy in some subjects, AIT may induce sustained unresponsiveness, in which tolerance is retained after a period of allergen avoidance. Methods of AIT currently under study in humans include oral, sublingual, epicutaneous, and subcutaneous delivery of modified allergenic protein, as well as via DNA-based vaccines encoding allergen with lysosomal-associated membrane protein I. The balance of safety and efficacy varies by type of AIT, as well as by targeted allergen. Age, degree of sensitization, and other comorbidities may affect this balance within an individual patient. More recently, AIT with modified proteins or combined with immunomodulatory therapies has shown promise in making AIT safer and/or more effective. Though methods of AIT are neither currently advised by experts (oral immunotherapy [OIT]) nor widely available, AIT is likely to become a part of recommended management of FA in the coming years. Here, we review and compare methods of AIT currently under study in humans to prepare the practitioner for an exciting new phase in the care of food allergic patients in which improved tolerance to inciting foods will be a real possibility.

Autoimmune Cytopenias and Associated Conditions in CVID: a Report From the USIDNET Registry.

PURPOSE: Autoimmune cytopenia is frequently a presenting manifestation of common variable immune deficiency (CVID). Studies characterizing the CVID phenotype associated with autoimmune cytopenias have mostly been limited to large referral centers. Here, we report prevalence of autoimmune cytopenias in CVID from the USIDNET Registry and compare the demographics and clinical features of patients with and without this complication. METHODS: Investigators obtained demographic, laboratory, and clinical data on CVID patients within the USIDNET Registry. Patients were considered to have autoimmune cytopenia if they had a diagnosis of hemolytic anemia, immune thrombocytopenia (ITP), or autoimmune neutropenia. Baseline characteristics and associated complications of those with autoimmune cytopenia (+AC) and those without (-AC) were compared. RESULTS: Of 990 CVID patients included in the analysis, 10.2% (N = 101) had a diagnosis consistent with autoimmune cytopenia: ITP was diagnosed in 7.4% (N = 73), hemolytic anemia in 4.5% (N = 45), and autoimmune neutropenia in 1% (N = 10). Age at diagnosis, gender, and baseline Ig values did not differ between the +AC and -AC groups. The +AC group was significantly more likely to have one or more other CVID-associated non-infectious complications (OR = 2.9; 95%-CI: 1.9-4.6, P < 0.001), including lymphoproliferation, granulomatous disease, lymphomas, hepatic disease, interstitial lung diseases, enteropathy, and organ-specific autoimmunity. CONCLUSIONS: Autoimmune cytopenias are a common manifestation in CVID and are likely to be associated with other non-infectious CVID-related conditions. In light of prior studies showing increased morbidity and mortality in CVID patients with such complications, a diagnosis of autoimmune cytopenia may have prognostic significance in CVID.

Time Trends in Food Allergy Diagnoses, Epinephrine Orders, and Epinephrine Administrations in New York City Schools.

OBJECTIVES: To assess time trends in food allergy diagnoses, epinephrine autoinjector (EAI) prescriptions, and EAI administrations in the school setting. STUDY DESIGN: In this retrospective study, deidentified student data from the New York City Department of Health and Mental Hygiene, which oversees >1 million students in 1800 schools, were provided to investigators. Data from school years 2007-2008 to 2012-2013 pertaining to diagnoses of food allergy, student-specific EAI orders, and EAI administrations among students in New York City were analyzed for trends over time, via the use of ORs and χ2 calculation. RESULTS: The prevalences of providing physician documentation of food allergy and EAI orders, and the incidence of EAI administrations, all increased approximately 3-fold over the years of the study. Of 337 EAI administrations, more than one-half used stock EAI, and three-quarters were for students without a student-specific order preceding the incident. CONCLUSIONS: The rise in food allergy diagnoses, EAI prescriptions, and EAI administrations suggest either a true increase in allergic disease, increased reporting, and/or, in the case of EAI administrations, increased appropriate use. As the majority of EAI administrations used stock supply, availability of nonstudent-specific stock EAI appears vital to management of anaphylaxis in schools. Collaboration between physicians, families, and schools is needed to identify students at risk for severe allergic reactions and to ensure preparedness and availability of EAI in the event of anaphylaxis.

Oral Immunotherapy for Food Allergies.

Oral immunotherapy (OIT) is a promising investigational therapy for food allergy. Clinical trials in peanut, milk, egg, and wheat allergy provide evidence that OIT can effectively desensitize a majority of individuals to a food allergen. While a portion of subjects demonstrate sustained unresponsiveness, the majority regain sensitivity with allergen avoidance. The safety and tolerability of OIT continue to limit its use in some patients. Virtually all studies report adverse reactions that are more frequent during dose escalation but may also occur during maintenance therapy. Recent studies have identified adjunctive therapies (such as omalizumab) which may mitigate adverse effects. There is a paucity of data on the long-term safety and efficacy of OIT. Further study is required before OIT is ready for routine clinical practice. This review is intended to provide the reader with an up-to-date understanding of OIT, including its mechanisms, efficacy, safety profile, and potential utility in clinical practice.

Food Protein-Induced Enterocolitis Syndrome, Allergic Proctocolitis, and Enteropathy.

Food protein-induced enterocolitis (FPIES), allergic proctocolitis (FPIAP), and enteropathy (FPE) are among a number of immune-mediated reactions to food that are thought to occur primarily via non-IgE-mediated pathways. All three are typically present in infancy and are triggered most commonly by cow's milk protein. The usual presenting features are vomiting with lethargy and dehydration in FPIES; bloody and mucous stools in FPIAP; and diarrhea with malabsorption and failure to thrive in FPE. Diagnosis is based on convincing history and resolution of symptoms with food avoidance; confirmatory diagnostic testing other than food challenge is lacking. The mainstay of management is avoidance of the suspected inciting food, with interval challenge to assess for resolution, which usually occurs in the first years of life. Studies published in the past few years clarify common presenting features, report additional culprit foods, address potential biomarkers, and suggest new management strategies.