Saliva antibody profiles are associated with reaction threshold and severity of peanut allergic reactions.

BACKGROUND: Reaction threshold and severity in food allergy are difficult to predict, and noninvasive predictors are lacking. OBJECTIVE: We sought to determine the relationships between pre-challenge levels of peanut (PN)-specific antibodies in saliva and reaction threshold, severity, and organ-specific symptoms during PN allergic reactions. METHODS: We measured PN-specific antibody levels in saliva collected from 127 children with suspected PN allergy before double-blind, placebo-controlled PN challenges in which reaction threshold, severity, and symptoms were rigorously characterized. Low threshold (LT) PN allergy was defined as reaction to <300 mg of PN protein cumulatively consumed. A consensus severity grading system was used to grade severity. We analyzed associations between antibody levels and reaction threshold, severity, and organ-specific symptoms. RESULTS: Among the 127 children, those with high pre-challenge saliva PN IgE had higher odds of LT PN allergy (odds ratio [OR] 3.9, 95% CI 1.6-9.5), while those with high saliva PN IgA:PN IgE ratio or PN IgG4:PN IgE ratio had lower odds of LT PN allergy (OR 0.3, 95% CI 0.1-0.8; OR 0.4, 95% CI 0.2-0.9). Children with high pre-challenge saliva PN IgG4 had lower odds of severe PN reactions (OR 0.4, 95% CI 0.2-0.9). Children with high saliva PN IgE had higher odds of respiratory symptoms (OR 8.0, 95% CI 2.2-26.8). Saliva PN IgE modestly correlated with serum PN IgE levels (Pearson r = 0.31, P = .0004). High and low saliva PN IgE levels further distinguished reaction threshold and severity in participants stratified by serum PN IgE, suggesting endotypes. CONCLUSIONS: Saliva PN antibodies could aid in noninvasive risk stratification of PN allergy threshold, severity, and organ-specific symptoms.

ICOS agonist vopratelimab modulates follicular helper T cells and improves B cell function in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is an immune defect characterized by hypogammaglobulinemia and impaired development of B cells into plasma cells. As follicular helper T cells (TFH) play a central role in humoral immunity, we examined TFH cells in CVID, and investigated whether an inducible T cell co-stimulator (ICOS) agonist, vopratelimab, could modulate TFH, B cell interactions and enhance immunoglobulin production. CVID subjects had decreased TFH17 and increased TFH1 subsets; this was associated with increased transitional B cells and decreased IgG+ B and IgD-IgM-CD27+ memory B cells. ICOS expression on CVID CD4+ T cells was also decreased. However, ICOS activation of CD4+ T cells by vopratelimab significantly increased total CVID TFH, TFH2, cell numbers, as well as IL-4, IL-10 and IL-21 secretion in vitro. Vopratelimab treatment also increased plasma cells, IgG+ B cells, reduced naïve & transitional B cells and significantly increased IgG1 secretion by CVID B cells. Interestingly, vopratelimab treatment also restored IgA secretion in PBMCs from several CVID patients who had a complete lack of endogenous serum IgA. Our data demonstrate the potential of TFH modulation in restoring TFH and enhancing B cell maturation in CVID. The effects of an ICOS agonist in antibody defects warrants further investigation. This biologic may also be of therapeutic interest in other clinical settings of antibody deficiency.

IL4Rα and IL17A Blockade Rescue Autoinflammation in SOCS1 Haploinsufficiency.

By inhibition of JAK-STAT signaling, SOCS1 acts as a master regulator of the cytokine response across numerous tissue types and cytokine pathways. Haploinsufficiency of SOCS1 has recently emerged as a monogenic immunodysregulatory disease with marked clinical variability. Here, we describe a patient with severe dermatitis, recurrent skin infections, and psoriatic arthritis that harbors a novel heterozygous mutation in SOCS1. The variant, c.202_203delAC, generates a frameshift in SOCS1, p.Thr68fsAla*49, which leads to complete loss of protein expression. Unlike WT SOCS1, Thr68fs SOCS1 fails to inhibit JAK-STAT signaling when expressed in vitro. The peripheral immune signature from this patient was marked by a redistribution of monocyte sub-populations and hyper-responsiveness to multiple cytokines. Despite this broad hyper-response across multiple cytokine pathways in SOCS1 haploinsufficiency, the patient's clinical disease was markedly responsive to targeted IL4Rα- and IL17-blocking therapy. In accordance, the mutant allele was unable to regulate IL4Rα signaling. Further, patient cells were unresponsive to IL4/IL13 while on monoclonal antibody therapy. Together, this study reports a novel SOCS1 mutation and suggests that IL4Rα blockade may serve as an unexpected, but fruitful therapeutic target for some patients with SOCS1 haploinsufficiency.

Multiscale study of the oral and gut environments in children with high- and low-threshold peanut allergy.

BACKGROUND: The oral and gut microbiomes have each been associated with food allergy status. Within food allergy, they may also influence reaction thresholds. OBJECTIVE: Our aim was to identify oral and gut microbiota associated with reaction thresholds in peanut allergy. METHODS: A total of 59 children aged 4 to 14 years with suspected peanut allergy underwent double-blind, placebo-controlled food challenge to peanut. Those children who reacted at the 300-mg or higher dose of peanut were classified as high-threshold (HT), those who reacted to lower doses were classified as low-threshold (LT), and those children who did not react were classified as not peanut allergic (NPA). Saliva and stool samples collected before challenge underwent DNA isolation followed by 16S rRNA sequencing and short-chain fatty acid measurement. RESULTS: The 59 participants included 38 HT children and 13 LT children. Saliva microbiome α-diversity (Shannon index) was higher in LT children (P = .017). We identified saliva and stool microbiota that distinguished HT children from LT children, including oral Veillonella nakazawae (amplicon sequence variant 1979), which was more abundant in the HT group than in the LT group (false discovery rate [FDR] = 0.025), and gut Bacteroides thetaiotaomicron (amplicon sequence variant 6829), which was less abundant in HT children than in LT children (FDR = 0.039). Comparison with NPA children revealed consistent ordinal trends between these discriminating species and reaction thresholds. Importantly, many of these threshold-associated species were also correlated with short-chain fatty acid levels at the respective body sites, including between oral V nakazawae and oral butyrate (r = 0.57; FDR = 0.049). CONCLUSION: Findings from this multiscale study raise the possibility of microbial therapeutics to increase reaction thresholds in children with food allergy.

Case Series: Convalescent Plasma Therapy for Patients with COVID-19 and Primary Antibody Deficiency.

Patients with primary antibody deficiency are at risk for severe and in many cases for prolonged COVID-19. Convalescent plasma treatment of immunocompromised individuals could be an option especially in countries with limited access to monoclonal antibody therapies. While studies in immunocompetent COVID19 patients have demonstrated only a limited benefit, evidence for the safety, timing, and effectiveness of this treatment in antibody-deficient patients is lacking. Here, we describe 16 cases with primary antibody deficiency treated with convalescent plasma in four medical centers. In our cohort, treatment was associated with a reduction in viral load and improvement of clinical symptoms, even when applied over a week after onset of infection. There were no relevant side effects besides a short-term fever reaction in one patient. Longitudinal full-genome sequencing revealed the emergence of mutations in the viral genome, potentially conferring an antibody escape in one patient with persistent viral RNA shedding upon plasma treatment. However, he resolved the infection after a second course of plasma treatment. Thus, our data suggest a therapeutic benefit of convalescent plasma treatment in patients with primary antibody deficiency even months after infection. While it appears to be safe, PCR follow-up for SARS-CoV-2 is advisable and early re-treatment might be considered in patients with persistent viral shedding.

Multidimensional study of the oral microbiome, metabolite, and immunologic environment in peanut allergy.

BACKGROUND: The oral mucosa is the initial interface between food antigens, microbiota, and mucosal immunity, yet, little is known about oral host-environment dynamics in food allergy. OBJECTIVE: Our aim was to determine oral microbial, metabolic, and immunologic profiles associated with peanut allergy. METHODS: We recruited 105 subjects (56 with peanut allergy and 49 healthy subjects) for salivary microbiome profiling using 16S ribosomal RNA sequencing, short-chain fatty acid (SCFA) metabolite assays using liquid chromatography/mass spectrometry, and measurement of oral secreted cytokines using multiplex assays. Analyses within and across data types were performed. RESULTS: The oral microbiome of individuals with peanut allergy was characterized by reduced species in the orders Lactobacillales, Bacteroidales (Prevotella spp), and Bacillales, and increased Neisseriales spp. The distinct oral microbiome of subjects with peanut allergy was accompanied by significant reductions in oral SCFA levels, including acetate, butyrate, and propionate, and significant elevation of IL-4 secretion. Decreased abundances of oral Prevotella spp and Veillonella spp in subjects with peanut allergy were significantly correlated with reduced oral SCFA levels (false discovery rate < 0.05), and increased oral Neisseria spp was correlated with lower oral SCFA levels (false discovery rate < 0.05). Additionally, oral Prevotella spp abundances were correlated with decreased local secretion of TH2-stimulating epithelial factors (IL-33 and thymic stromal lymphopoietin) and TH2 cytokines (IL-4, IL-5, and IL-13), whereas oral Neisseria spp abundance was positively associated with a TH2-skewed oral immune milieu. CONCLUSION: Our novel multidimensional analysis of the oral environment revealed distinct microbial and metabolic profiles associated with mucosal immune disturbances in peanut allergy. Our findings highlight the oral environment as an anatomic site of interest to examine host-microbiome dynamics in food allergy.

Clinical Outcomes and Immunologic Characteristics of Coronavirus Disease 2019 in People With Human Immunodeficiency Virus.

We performed a retrospective study of coronavirus disease 2019 (COVID-19) in people with human immunodeficiency virus (PWH). PWH with COVID-19 demonstrated severe lymphopenia and decreased CD4+ T cell counts. Levels of inflammatory markers, including C-reactive protein, fibrinogen, D-dimer, interleukin 6, interleukin 8, and tumor necrosis factor α were commonly elevated. In all, 19 of 72 hospitalized individuals (26.4%) died and 53 (73.6%) recovered. PWH who died had higher levels of inflammatory markers and more severe lymphopenia than those who recovered. These findings suggest that PWH remain at risk for severe manifestations of COVID-19 despite antiretroviral therapy and that those with increased markers of inflammation and immune dysregulation are at risk for worse outcomes.

Markers of Immune Activation and Inflammation in Individuals With Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

BACKGROUND: The biological processes associated with postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are unknown. METHODS: We measured soluble markers of inflammation in a SARS-CoV-2 recovery cohort at early (<90 days) and late (>90 days) timepoints. We defined PASC as the presence of 1 or more coronavirus disease 2019 (COVID-19)-attributed symptoms beyond 90 days. We compared fold-changes in marker values between those with and without PASC using mixed-effects models with terms for PASC and early and late recovery time periods. RESULTS: During early recovery, those who went on to develop PASC generally had higher levels of cytokine biomarkers including tumor necrosis factor-α (1.14-fold higher mean ratio [95% confidence interval {CI}, 1.01-1.28]; P = .028) and interferon-γ-induced protein 10 (1.28-fold higher mean ratio [95% CI, 1.01-1.62]; P = .038). Among those with PASC, there was a trend toward higher interleukin 6 levels during early recovery (1.29-fold higher mean ratio [95% CI, .98-1.70]; P = .07), which became more pronounced in late recovery (1.44-fold higher mean ratio [95% CI, 1.11-1.86]; P < .001). These differences were more pronounced among those with a greater number of PASC symptoms. CONCLUSIONS: Persistent immune activation may be associated with ongoing symptoms following COVID-19. Further characterization of these processes might identify therapeutic targets for those experiencing PASC.

COVID-19 prevalence and outcomes in patients receiving biologic therapies at an infusion center in New York City.

To better understand COVID-19 infection in patients receiving biologic and immunomodulatory therapies, we evaluated prevalence and outcomes for symptomatic cases of COVID-19 at a large therapeutic infusion center in New York City during the height of the pandemic. 2074 patients received treatment with biologic infusions at our center between March and May 2020, and 34 patients developed symptomatic COVID-19 infection, for an overall low rate of 1.64%. The majority of infections and deaths were in a small subset of patients with a primary immunodeficiency. Patients with inflammatory or autoimmune conditions requiring biologic therapies tended to have mild cases. Higher inflammatory responses were observed in patients who died.

Discharge in Pandemic: Suspected Covid-19 patients returning to the Emergency Department within 72 hours for admission.

INTRODUCTION: Coronavirus disease 2019 (Covid-19) has led to unprecedented healthcare demand. This study seeks to characterize Emergency Department (ED) discharges suspected of Covid-19 that are admitted within 72 h. METHODS: We abstracted all adult discharges with suspected Covid-19 from five New York City EDs between March 2nd and April 15th. Those admitted within 72 h were then compared against those who were not using descriptive and regression analysis of background and clinical characteristics. RESULTS: Discharged ED patients returning within 72 h were more often admitted if suspected of Covid-19 (32.9% vs 12.1%, p < .0001). Of 7433 suspected Covid-19 discharges, the 139 (1.9%) admitted within 72 h were older (55.4 vs. 45.6 years, OR 1.03) and more often male (1.32) or with a history of obstructive lung disease (2.77) or diabetes (1.58) than those who were not admitted (p < .05). Additional associations included non-English preference, cancer, heart failure, hypertension, renal disease, ambulance arrival, higher triage acuity, longer ED stay or time from symptom onset, fever, tachycardia, dyspnea, gastrointestinal symptoms, x-ray abnormalities, and decreased platelets and lymphocytes (p < .05 for all). On 72-h return, 91 (65.5%) subjects required oxygen, and 7 (5.0%) required mechanical ventilation in the ED. Twenty-two (15.8%) of the study group have since died. CONCLUSION: Several factors emerge as associated with 72-h ED return admission in subjects suspected of Covid-19. These should be considered when assessing discharge risk in clinical practice.

The gut microbiome in food allergy.

OBJECTIVE: To review observational human, murine, and interventional trial studies that have examined the gut microbiome in food allergy, and to provide perspective on future investigations in this field. DATA SOURCES: A review of the published literature was performed with PubMed, and clinical studies catalogued at ClinicalTrials.gov were also reviewed. STUDY SELECTIONS: The most recent relevant studies, seminal works, and topical clinical trials were selected. RESULTS: Gut dysbiosis likely precedes the development of food allergy, and the timing of such dysbiosis is critical. Gut microbiota associated with individual food allergies may be distinct. Murine models support the importance of gut microbiota in shaping immune maturation and tolerance. Gut microbiota may affect food allergy susceptibility by modulating type 2 immunity, influencing immune development and tolerance, regulating basophil populations, and promoting intestinal barrier function. Ongoing and future interventional trials of probiotics, prebiotics, synbiotics, and fecal microbiota transfer will help translate our understanding of the gut microbiome in food allergy to clinical practice. Future work in this area will include deepening of current research foci, as well as expansion of efforts to include the virome, mycobiome, and interactions between the microbiome, host, and environment. Robust and consistent study designs, multidimensional profiling, and systems biology approaches will enable this future work. CONCLUSION: By advancing research on the microbiome in food allergy, we can further our understanding of food allergy and derive new approaches for its prevention and therapy.

Microbial Adjuncts for Food Allergen Immunotherapy.

PURPOSE OF REVIEW: Food allergen immunotherapy may benefit from adjunct therapies to enhance safety and efficacy. We review preclinical studies investigating the effects of probiotics and other microbial-based interventions on oral tolerance, describe the human clinical trial evidence thus far for microbial adjuncts, and discuss steps for translating research findings in this area to clinical therapy. RECENT FINDINGS: Murine studies support that microbial-based interventions confer protection against sensitization and may augment treatment efficacy for food allergy. Microbial adjunct therapies can promote regulatory T cells and modulate Th1 vs. Th2 responses. There is a wide array of novel modalities utilizing microbial components. Ongoing efforts are focused on translating preclinical data into potential treatments. Probiotics, prebiotics, and microbial components have all been examined as microbial adjunct therapies in murine models of food allergy. The effects of probiotics appear to be strain-specific. Prebiotics and bacterial components are innovative modalities to modulate oral tolerance. Better characterization of dysbiosis in human cohorts with food allergy, deeper mechanistic understanding of microbial adjunct therapies, safety evaluation, and careful clinical trial design will be crucial for the development of microbial adjuncts for food allergen immunotherapy. Microbial adjunct therapies have the potential to enhance the efficacy, safety, and durability of food allergen immunotherapy.

Role of the Microbiome in Food Allergy.

PURPOSE OF REVIEW: Resident microbial communities likely modify risk for allergic disorders, including food allergy. We review epidemiologic studies linking microbial exposures to food allergy risk and discuss the mechanisms by which the microbiome may modulate oral tolerance. We additionally address ongoing translational efforts in human microbiome studies. RECENT FINDINGS: Epidemiologic studies and murine models support that altered microbial exposures and colonization in early life modify food allergy risk. Differential microbiota confer protection or susceptibility to food allergy by modulating the regulatory tone of the mucosal immune system. Recent efforts are focused on the identification of bacterial strains necessary for oral tolerance in human and microbial-based clinical trials. Early childhood appears to be critical for the colonization of a diverse microbiota necessary for the induction and maintenance of oral tolerance. Identification and functional evaluation of protective commensal microbes will inform strategies for the prevention and treatment of food allergy.

Detection of SARS-CoV-2 Antibodies in Immunoglobulin Products.

BACKGROUND: For patients with primary antibody deficiency, the first line of therapy is replacement with immunoglobulin (Ig) products. Prior to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, Ig products did not contain antibodies with specificity for this virus, and there have been limited data on the antibodies present in the Ig products in current use. OBJECTIVE: To quantitatively examine SARS-CoV-2 antibodies in current Ig products. METHODS: We examined 142 unique lots of 11 different Ig products intended for intravenous and/or subcutaneous delivery for IgG-binding activities against recombinant SARS-CoV-2 receptor binding domain, spike, and nucleocapsid proteins by enzyme-linked immunosorbent assays. In addition, to assess functionality, 48 of these unique lots were assessed for their ability to inhibit the variants SARS-CoV-2 Ancestral, Alpha, Beta, Delta, and Omicron spike binding to angiotensin-converting enzyme 2 (ACE2). RESULTS: Significantly increased antibody values were observed for products manufactured after the year 2020 (expiration dates 2023-2024), as compared with Ig products before 2020 (prepandemic). Sixty percent and 85% of the Ig products with expiration dates of 2023 and 2024 were positive for antibody to SARS-CoV-2 proteins, respectively. The area under the curve values were significantly higher in products with later expiration dates. Later dates of expiration were also strongly correlated with inhibition of ACE2-binding activity; however, a decline in inhibition activity was observed with later variants. CONCLUSIONS: Overall, more recent Ig products (expiration dates 2023-2025) contained significantly higher binding and inhibition activities against SARS-CoV-2 proteins, compared with earlier, or prepandemic products. Normal donor SARS-CoV-2 antibodies are capable of inhibiting ACE2-binding activities and may provide a therapeutic benefit for patients who do not make a robust vaccine response.

Seeking Relevant Biomarkers in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiency. More than 50% of patients in some series suffer from autoimmune or inflammatory complications (the "CVID+" phenotype), and these are not adequately addressed by current treatments. Despite major advancements in genetics, the pathogenesis of the CVID+ phenotype has remained unexplained for most patients, necessitating the need for relevant biomarkers in both the clinic and research settings. In the clinics, reduced isotype-switched memory B cells (≤ 0.55% of B cells) and reduced T cells (CD4) can be utilized to identify those with increased complication risks. Additionally, condition-specific markers have also been suggested for lymphoma (normal or elevated IgM) and progressive interstitial lung disease (increased BAFF, normal or elevated IgM). Additional biomarkers have provided insights into disease pathogenesis, demonstrating wider systemic inflammation (increased LBP, sCD14, and sCD25; expanded ILC3), mucosal defects (increased zonulin, I-FABP), and perhaps reduced anti-inflammatory capability (reduced HDL) in CVID. Most recently, efforts have revealed elevated circulating bioactive bacterial DNA levels - marking microbial translocation and potentially linking the causation of multiple inflammatory changes previously observed in CVID. The implementation of high throughput profiling techniques may accelerate the search of relevant biomarker profiles in CVID and lead to better clinical risk stratification, revealing disease insights, and identifying potential therapeutic targets.

SARS-COV-2 infections in inborn errors of immunity: A single center study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19). One of the main topics of conversation in these past months in the world of immunology has been the issue of how patients with immune defects will fare if they contract this infection. To date there has been limited data on larger cohorts of patients with Inborn Errors of Immunity (IEI) diagnosed with COVID-19. Here, we review the data of COVID-19 infections in a single center cohort of 113 patients from the Mount Sinai Immunodeficiency program, who had 132 infections between January 2020 and June 2022. This included 56 males and 57 females, age range 2 - 84 (median 42). The mortality rate was 3%. Comparison between admitted patients revealed a significantly increased risk of hospitalization amongst the unvaccinated patients, 4% vaccinated vs 40% unvaccinated; odds ratio 15.0 (95% CI 4.2 - 53.4; p <0.00001). Additionally, COVID anti-spike antibody levels, determined in 36 of these patients post vaccination and before infection, were highly variable.