Prediction of pediatric peanut oral food challenge outcomes using machine learning.

Background: Clinical testing, including food-specific skin and serum IgE level tests, provides limited accuracy to predict food allergy. Confirmatory oral food challenges (OFCs) are often required, but the associated risks, cost, and logistic difficulties comprise a barrier to proper diagnosis. Objective: We sought to utilize advanced machine learning methodologies to integrate clinical variables associated with peanut allergy to create a predictive model for OFCs to improve predictive performance over that of purely statistical methods. Methods: Machine learning was applied to the Learning Early about Peanut Allergy (LEAP) study of 463 peanut OFCs and associated clinical variables. Patient-wise cross-validation was used to create ensemble models that were evaluated on holdout test sets. These models were further evaluated by using 2 additional peanut allergy OFC cohorts: the IMPACT study cohort and a local University of Michigan cohort. Results: In the LEAP data set, the ensemble models achieved a maximum mean area under the curve of 0.997, with a sensitivity and specificity of 0.994 and 1.00, respectively. In the combined validation data sets, the top ensemble model achieved a maximum area under the curve of 0.871, with a sensitivity and specificity of 0.763 and 0.980, respectively. Conclusions: Machine learning models for predicting peanut OFC results have the potential to accurately predict OFC outcomes, potentially minimizing the need for OFCs while increasing confidence in food allergy diagnoses.

Racial and Socioeconomic Disparities Exist in Patients Pursuing Peanut Oral Immunotherapy.

BACKGROUND: Oral immunotherapy (OIT) is a promising treatment for food allergy. Prior studies demonstrate significant differences among food-allergic individuals across race, ethnicity, and socioeconomic groups. Disparities in OIT have not been evaluated. OBJECTIVE: We assessed disparities in the use of OIT in patients with peanut allergy based on race, ethnicity, and socioeconomic status at a single academic medical center. METHODS: We identified 1028 peanut-allergic patients younger than 18 years receiving care in the University of Michigan food allergy clinics. Of these, 148 patients who underwent peanut OIT (treatment group) were compared with the 880 patients who avoided peanut (control group). Pertinent demographic and socioeconomic characteristics were compared. RESULTS: There were no differences in gender or ethnicity between the OIT and control groups. However, Black patients comprised 18% of the control group but only 4.1% of the OIT treatment group (P < .0001). The proportion of patients with private insurance was significantly higher in the treatment group compared with the control group (93.2% vs 82.2%, P = .0004). Finally, the neighborhood affluence index, a census-based measure of the relative socioeconomic prosperity of a neighborhood, was significantly higher in the OIT group than the control group (0.51 ± 0.18 vs 0.47 ± 0.19, P = .015), whereas the neighborhood disadvantage index, a census-based measure of the relative socioeconomic disadvantage of a neighborhood, was significantly lower (0.082 ± 0.062 vs 0.10 ± 0.093, P = .020). CONCLUSIONS: Significant racial and economic disparities exist at our institution between peanut-allergic individuals who receive OIT and those who do not. Efforts to understand the basis for these disparities are important to ensure that patients have equitable access to OIT.

Genetic and Immunological Pathogenesis of Atopic Dermatitis.

Type 2 immune-mediated diseases give a clear answer to the issue of nature (genetics) versus nurture (environment). Both genetics and environment play vital complementary roles in the development of atopic dermatitis (AD). As a key component of the atopic march, AD demonstrates the interactive nature of genetic and environmental contributions to atopy. From sequence variants in the epithelial barrier gene encoding FLG to the hygiene hypothesis, AD combines a broad array of contributions into a single syndrome. This review will focus on the genetic contribution to AD and where genetics facilitates the elicitation or enhancement of AD pathogenesis.

Transepidermal water loss rises before food anaphylaxis and predicts food challenge outcomes.

BACKGROUNDFood allergy (FA) is a growing health problem requiring physiologic confirmation via the oral food challenge (OFC). Many OFCs result in clinical anaphylaxis, causing discomfort and risk while limiting OFC utility. Transepidermal water loss (TEWL) measurement provides a potential solution to detect food anaphylaxis in real time prior to clinical symptoms. We evaluated whether TEWL changes during an OFC could predict anaphylaxis onset.METHODSPhysicians and nurses blinded to the TEWL results conducted and adjudicated the results of all 209 OFCs in this study. A study coordinator measured TEWL throughout the OFC and had no input on the OFC conduct. TEWL was measured 2 ways in 2 separate groups. First, TEWL was measured using static, discrete measurements. Second, TEWL was measured using continuous monitoring. Participants who consented provided blood samples before and after the OFCs for biomarker analyses.RESULTSTEWL rose significantly (2.93 g/m2/h) during reactions and did not rise during nonreacting OFCs (-1.00 g/m2/h). Systemic increases in tryptase and IL-3 were also detected during reactions, providing supporting biochemical evidence of anaphylaxis. The TEWL rise occurred 48 minutes earlier than clinically evident anaphylaxis. Continuous monitoring detected a significant rise in TEWL that presaged positive OFCs, but no rise was seen in the OFCs that resulted in no reaction, providing high predictive specificity (96%) for anaphylaxis against nonreactions 38 minutes prior to anaphylaxis onset.CONCLUSIONSDuring OFCs, a TEWL rise anticipated a positive clinical challenge. TEWL presents a monitoring modality that may predict food anaphylaxis and facilitate improvements in OFC safety and tolerability.

Evolution of Food Protein-Induced Enterocolitis Syndrome (FPIES) Index Trigger Foods and Subsequent Reactions After Initial Diagnosis.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy treated by trigger food avoidance and supportive care. Whether the prevalence of different trigger foods is changing with evolving food introduction patterns is unknown. The rate and nature of subsequent reactions after initial diagnosis have not been fully studied. OBJECTIVE: We sought to characterize how trigger foods have changed over time and investigate the nature of subsequent reactions after initial diagnosis. METHODS: We collected data regarding patients' FPIES reactions from 347 patients seen in the University of Michigan Allergy and Immunology clinic for FPIES from 2010 to 2022. Inclusion criteria consisted of pediatric patients diagnosed with FPIES by an allergist based on international consensus guidelines. RESULTS: Most foods including less commonly cited FPIES triggers increased in frequency over time. The most common index trigger was oat. A total of 32.9% (114 of 347) patients experienced a subsequent reaction after education on trigger avoidance and safe home introduction of new foods, with 34.2% (41 of 120) of subsequent reactions to new triggers at home and 45% (54 of 120) to known triggers at home. Of patients reacting subsequently, 28% (32 of 114) experienced a subsequent reaction necessitating an emergency department visit. The most common new subsequent reaction triggers were egg and potato, whereas peanut most commonly triggered reactions on oral food challenge. CONCLUSIONS: The risk profile of FPIES triggers may be evolving over time, though high-risk FPIES foods remain common. The subsequent reaction rate after counseling indicates that home food introduction poses risk. This study highlights the need for improved safety of new food introduction and/or prediction methods for FPIES to help prevent potentially dangerous home FPIES reactions.

Wild-type SARS-CoV-2 neutralizing immunity decreases across variants and over time but correlates well with diagnostic testing.

Importance: The degree of immune protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants provided by infection versus vaccination with wild-type virus remains unresolved, which could influence future vaccine strategies. The gold-standard for assessing immune protection is viral neutralization; however, few studies involve a large-scale analysis of viral neutralization against the Omicron variant by sera from individuals infected with wild-type virus. Objectives: 1) To define the degree to which infection versus vaccination with wild-type SARS-CoV-2 induced neutralizing antibodies against Delta and Omicron variants.2) To determine whether clinically available data, such as infection/vaccination timing or antibody status, can predict variant neutralization. Methods: We examined a longitudinal cohort of 653 subjects with sera collected three times at 3-to-6-month intervals from April 2020 to June 2021. Individuals were categorized according to SARS-CoV-2 infection and vaccination status. Spike and nucleocapsid antibodies were detected via ADVIA Centaur® (Siemens) and Elecsys® (Roche) assays, respectively. The Healgen Scientific® lateral flow assay was used to detect IgG and IgM spike antibody responses. Pseudoviral neutralization assays were performed on all samples using human ACE2 receptor-expressing HEK-293T cells infected with SARS-CoV-2 spike protein pseudotyped lentiviral particles for wild-type (WT), B.1.617.2 (Delta), and B.1.1.529 (Omicron) variants. Results: Vaccination after infection led to the highest neutralization titers at all timepoints for all variants. Neutralization was also more durable in the setting of prior infection versus vaccination alone. Spike antibody clinical testing effectively predicted neutralization for wild-type and Delta. However, nucleocapsid antibody presence was the best independent predictor of Omicron neutralization. Neutralization of Omicron was lower than neutralization of either wild-type or Delta virus across all groups and timepoints, with significant activity only present in patients that were first infected and later immunized. Conclusions: Participants having both infection and vaccination with wild-type virus had the highest neutralizing antibody levels against all variants and had persistence of activity. Neutralization of WT and Delta virus correlated with spike antibody levels against wild-type and Delta variants, but Omicron neutralization was better correlated with evidence of prior infection. These data help explain why 'breakthrough' Omicron infections occurred in previously vaccinated individuals and suggest better protection is observed in those with both vaccination and previous infection. This study also supports the concept of future SARS-CoV-2 Omicron-specific vaccine boosters.

Acute systemic myeloid inflammatory and stress response in severe food allergic reactions.

INTRODUCTION: Food allergic reactions can be severe and potentially life-threatening and the underlying immunological processes that contribute to the severity of reactions are poorly understood. The aim of this study is to integrate bulk RNA-sequencing of human and mouse peripheral blood mononuclear cells during food allergic reactions and in vivo mouse models of food allergy to identify dysregulated immunological processes associated with severe food allergic reactions. METHODS: Bulk transcriptomics of whole blood from human and mouse following food allergic reactions combined with integrative differential expressed gene bivariate and module eigengene network analyses to identify the whole blood transcriptome associated with food allergy severity. In vivo validation immune cell and gene expression in mice following IgE-mediated reaction. RESULTS: Bulk transcriptomics of whole blood from mice with different severity of food allergy identified gene ontology (GO) biological processes associated with innate and inflammatory immune responses, dysregulation of MAPK and NFkB signalling and identified 429 genes that correlated with reaction severity. Utilizing two independent human cohorts, we identified 335 genes that correlated with severity of peanut-induced food allergic reactions. Mapping mouse food allergy severity transcriptome onto the human transcriptome revealed 11 genes significantly dysregulated and correlated with severity. Analyses of whole blood from mice undergoing an IgE-mediated reaction revealed a rapid change in blood leukocytes particularly inflammatory monocytes (Ly6Chi Ly6G- ) and neutrophils that was associated with changes in CLEC4E, CD218A and GPR27 surface expression. CONCLUSIONS: Collectively, IgE-mediated food allergy severity is associated with a rapid innate inflammatory response associated with acute cellular stress processes and dysregulation of peripheral blood inflammatory myeloid cell frequencies.

Novel insights into atopic dermatitis.

Recent research into the pathophysiology and treatment of atopic dermatitis (AD) has shown notable progress. An increasing number of aspects of the immune system are being implicated in AD, including the epithelial barrier, TH2 cytokines, and mast cells. Major advances in therapeutics were made in biologic cytokine and receptor antagonists and among Janus kinase inhibitors. We focus on these areas and address new insights into AD epidemiology, biomarkers, endotypes, prevention, and comorbidities. Going forward, we expect future mechanistic insights and therapeutic advances to broaden physicians' ability to diagnose and manage AD patients, and perhaps to find a cure for this chronic condition.

IL-4 receptor alpha signaling alters oral food challenge and immunotherapy outcomes in mice.

BACKGROUND: Food allergy diagnosis and management causes a number of social and emotional challenges for individuals with food allergies and their caregivers. This has led to increased interest in developing approaches to accurately predict food allergy diagnosis, severity of food allergic reactions, and treatment outcomes. However, the utility of these approaches is somewhat conflicting. OBJECTIVE: We sought to develop and utilize a murine model that mimics the disease course of food allergy diagnosis and treatment in humans and to identify biomarkers that predict reactivity during food challenge (FC) and responsiveness during oral immunotherapy (OIT) and how these outcomes are modified by genetics. METHODS: Skin-sensitized intestinal IL-9 transgenic (IL9Tg) and IL9Tg mice backcrossed onto the IL-4RαY709F background received a single intragastric exposure of egg antigen (ovalbumin), underwent oral FC and OIT; food allergy severity, mast cell activation, and ovalbumin-specific IgE levels were examined to determine the predictability of these outcomes in determining reactivity and treatment outcomes. RESULTS: Subcutaneous sensitization and a single intragastric allergen challenge of egg antigen to BALB/c IL9Tg mice and Il4raY709F IL9Tg induced a food allergic reaction. Enhanced IL-4Rα signaling altered the symptoms induced by the first oral exposure, decreased the cumulative antigen dose, increased the severity of reaction during oral FC, and altered the frequency of adverse events and OIT outcomes. Biomarkers after first oral exposure indicated that only the severity of the initial reaction significantly correlated with cumulative dose of oral FC. CONCLUSION: Collectively, these data indicate that single nucleotide polymorphisms in IL-4Rα can alter clinical symptoms of food allergic reactions, severity, and reactive dose during FC and OIT, and that severity of first reaction can predict the likelihood of reaction during FC in mice with IL-4Rα gain of function.

Mild SARS-CoV-2 Illness Is Not Associated with Reinfections and Provides Persistent Spike, Nucleocapsid, and Virus-Neutralizing Antibodies.

Uncertainty exists whether mild COVID-19 confers immunity to reinfection. Questions also remain regarding the persistence of antibodies against SARS-CoV-2 after mild infection. We prospectively followed at-risk individuals with and without SARS-CoV-2 for reinfection and monitored the spike and nucleocapsid antibodies. This prospective cohort study was conducted over two visits, 3 to 6 months apart, between May 2020 and February 2021. Adults with and without COVID-19, verified by FDA EUA-approved SARS-CoV-2 RT-PCR assays, were screened for spike and nucleocapsid antibody responses using FDA EUA-approved immunoassays and for pseudoviral neutralization activity. The subjects were monitored for symptoms, exposure to COVID-19, COVID-19 testing, seroconversion, reinfection, and vaccination. A total of 653 subjects enrolled; 129 (20%) had a history of COVID-19 verified by RT-PCR at enrollment. Most had mild disease, with only three requiring hospitalization. No initially seropositive subjects experienced a subsequent COVID-19 infection during the follow-up versus 15 infections among initially seronegative subjects (infection rates of 0.00 versus 2.05 per 10,000 days at risk [P = 0.0485]). In all, 90% of SARS-CoV-2-positive subjects produced spike and nucleocapsid responses, and all but one of these had persistent antibody levels at follow-up. Pseudoviral neutralization activity was widespread among participants, did not decrease over time, and correlated with clinical antibody assays. Reinfection with SARS-CoV-2 was not observed among individuals with mild clinical COVID-19, while infections continued in a group without known prior infection. Spike and nucleocapsid COVID-19 antibodies were associated with almost all infections and persisted at stable levels for the study duration. IMPORTANCE This article demonstrates that people who have mild COVID-19 illnesses and produce antibodies are protected from reinfection for up to 6 months afterward. The antibodies that people produce in this situation are stable for up to 6 months as well. Clinical antibody assays correlate well with evidence of antibody-related viral neutralization activity.

NLRP3-Inflammasome Inhibition during Respiratory Virus Infection Abrogates Lung Immunopathology and Long-Term Airway Disease Development.

Respiratory syncytial virus (RSV) infects most infants by two years of age. It can cause severe disease leading to an increased risk of developing asthma later in life. Previously, our group has shown that RSV infection in mice and infants promotes IL-1ß production. Here, we characterized the role of NLRP3-Inflammasome activation during RSV infection in adult mice and neonates. We observed that the inhibition of NLRP3 activation using the small molecule inhibitor, MCC950, or in genetically modified NLRP3 knockout (Nlrp3-/-) mice during in vivo RSV infection led to decreased lung immunopathology along with a reduced expression of the mucus-associated genes and reduced production of innate cytokines (IL-1ß, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-ß. NLRP3-inflammasome inhibition or deletion diminished Th2 cytokines and inflammatory cell infiltration into the lungs. Furthermore, NLRP3 inhibition or deletion during early-life RSV infection led to reducing viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation. Here, we demonstrated the critical role of NLRP3-inflammasome activation in RSV immunopathology and the related long-term airway alteration. Moreover, these findings suggest the NLRP3-inflammasome as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.

Prevalence of mastocytosis and Hymenoptera venom allergy in the United States.

BACKGROUND: Mastocytosis is a risk factor for Hymenoptera venom anaphylaxis (HVA). Current guidelines recommend measuring tryptase in patients with HVA and that those with mastocytosis pursue lifelong venom immunotherapy (VIT). Available data on HVA and mastocytosis largely derive from European single-center studies, and the prevalence of HVA with and without mastocytosis in the United States is unknown. OBJECTIVE: We sought to determine the prevalence of HVA and mastocytosis in the United States using an insurance claims database and evaluate the impact of mastocytosis on VIT in patients with HVA in a US cohort. METHODS: The IBM Watson Database, consisting of insurance claims from approximately 27 million US patients in 2018, was queried to identify patients with HVA and/or mastocytosis. Furthermore, a retrospective study of 161 patients undergoing VIT between 2015 and 2018 at the University of Michigan was conducted. RESULTS: In the IBM Watson Database, the prevalence of HVA was 167 per 100,000 (0.167%) and the prevalence of mastocytosis 10 per 100,000 (0.010%) overall and 97 per 100,000 (0.097%) among those with HVA. Mastocytosis showed a 9.7-fold increase among patients with HVA versus the general population. In the U-M cohort, 2.6% of patients with VIT had mastocytosis. Tryptase level did not correlate with venom reaction severity but was higher in patients with systemic VIT reactions. CONCLUSIONS: We observed a lower US HVA prevalence than previously reported. Mastocytosis was more common in US patients with HVA, though at lower rates than previously reported. In patients with VIT there was no correlation between tryptase level and reaction severity.

Accurate point-of-care serology tests for COVID-19.

BACKGROUND: As COVID-19 vaccines become available, screening individuals for prior COVID-19 infection and vaccine response in point-of-care (POC) settings has renewed interest. We prospectively screened at-risk individuals for SARS-CoV-2 spike and nucleocapsid protein antibodies in a POC setting to determine if it was a feasible method to identify antibody from prior infection. METHODS: Three EUA-approved lateral flow antibody assays were performed on POC finger-stick blood and compared with serum and a CLIA nucleocapsid antibody immunoassay. Variables including antibody class, time since PCR, and the assay antigen used were evaluated. RESULTS: 512 subjects enrolled, of which 104 had a COVID-19 history and positive PCR. Only three PCR-positive subjects required hospitalization, with one requiring mechanical ventilation. The POC results correlated well with the immunoassay (93-97% sensitivity) and using serum did not improve the sensitivity or specificity. CONCLUSIONS: Finger-stick, POC COVID-19 antibody testing was highly effective in identifying antibody resulting from prior infections in mildly symptomatic subjects. Using high-complexity serum immunoassays did not improve the screening outcome. Almost all individuals with COVID-19 infection produced detectable antibodies to the virus. POC antibody testing is useful as a screen for prior COVID-19 infection, and should be useful in assessing vaccine response.

Inhibition of uric acid or IL-1ß ameliorates respiratory syncytial virus immunopathology and development of asthma.

BACKGROUND: Respiratory syncytial virus (RSV) affects most infants early in life and is associated with increased asthma risk. The specific mechanism remains unknown. OBJECTIVE: To investigate the role of uric acid (UA) and IL-1ß in RSV immunopathology and asthma predisposition. METHODS: Tracheal aspirates from human infants with and without RSV were collected and analyzed for pro-IL-1ß mRNA and protein to establish a correlation in human disease. Neonatal mouse models of RSV were employed, wherein mice infected at 6-7 days of life were analyzed at 8 days postinfection, 5 weeks postinfection, or after a chronic cockroach allergen asthma model. A xanthine oxidase inhibitor or IL-1 receptor antagonist was administered during RSV infection. RESULTS: Human tracheal aspirates from RSV-infected infants showed elevated pro-IL-1ß mRNA and protein. Inhibition of UA or IL-1ß during neonatal murine RSV infection decreased mucus production, reduced cellular infiltrates to the lung (especially ILC2s), and decreased type 2 immune responses. Inhibition of either UA or IL-1ß during RSV infection led to chronic reductions in pulmonary immune cell composition and reduced type 2 immune responses and reduced similar responses after challenge with cockroach antigen. CONCLUSIONS: Inhibiting UA and IL-1ß during RSV infection ameliorates RSV immunopathology, reduces the consequences of allergen-induced asthma, and presents new therapeutic targets to reduce early-life viral-induced asthma development.

Uric acid pathway activation during respiratory virus infection promotes Th2 immune response via innate cytokine production and ILC2 accumulation.

Respiratory syncytial virus (RSV) infects a majority of infants and can cause severe disease leading to increased risk to develop asthma later in life. In the present studies we detected high levels of uric acid pathway components during RSV infection and examined whether they altered the pathogenesis of RSV infection. Inhibition of uric acid (UA) pathway activation during RSV infection in airway epithelial cells using XOI decreased the expression of IL-33, thymic stromal lymphopoietin (TSLP), and CCL2. In addition, treatment of RSV infected bone marrow-derived macrophages with XOI decreased production of IL-1ß. Thus, UA activation of different cell populations contributes different innate immune mediators that promote immunopathogenesis. When mice were treated with XOI or interleukin-1 receptor antagonist (IL1-ra) during RSV infection decreased pulmonary mucus was observed along with significantly reduced numbers of ILC2 and macrophages, accompanied by decreased IL-33 in bronchoalveolar lavage of the treated mice. These findings provide mechanistic insight into the development of RSV immunopathology and indicate that xanthine metabolites and UA are key immunoregulator molecules during RSV infection. Moreover, these findings suggest uric acid and IL-1ß as possible therapeutic targets to attenuate severe RSV disease.

An 82-year-old man with recurrent angioedema.

Angioedema is a potentially life-threatening swelling condition that can occur either in isolation or in the context of other syndromes, e.g., anaphylaxis. Angioedema is typically asymmetric, lasts for hours to days, is not gravity dependent, and is often nonpitting. Recurrent angioedema is typically associated with histaminergic and bradykinin-mediated causes, some of which can indicate underlying etiologies with high morbidity or mortality. The differential diagnosis for acute angioedema can include anaphylaxis, chronic urticaria with angioedema, medications such as angiotensin-converting-enzyme inhibitors, hereditary C1 esterase inhibitor defects, and acquired defects; however, the cause is often idiopathic, and effective therapy can be elusive. In this article, we described a unique etiology of a case of isolated recurrent angioedema that improved when the possible underlying cause was successfully treated.

New Insights into Clonal Mast Cell Disorders Including Mastocytosis.

Mastocytosis is a heterogeneous group of neoplasms that involve the clonal expansion of mast cells into one or more organ systems, which typically involves the skin and hematopoietic systems. Systemic mastocytosis consists of a multifocal infiltration of mast cells into various noncutaneous tissue sites, especially the bone marrow. Diagnosis requires tissue confirmation, and algorithms have been developed to assist clinicians in this process. The current classification system focuses on delineating prognostic categories. Therapeutic approaches include symptomatic management, prevention of complications, and, in advanced disease, cytoreductive therapy.