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Untargeted serum metabolomic analysis reveals a role for purinergic signaling in FPIES

Lozano-Ojalvo, Daniel; Chen, Xin; Dunkin, David; Agashe, Charuta; Baker, Mary Grace; Bird, J Andrew; Molina, Elena; Nowak-Wegrzyn, Anna; Berin, M Cecilia
BACKGROUND:Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy with a typical onset in infancy. Symptoms are distinct from IgE-mediated food allergies and include severe repetitive vomiting, lethargy, and pallor. FPIES reactions are associated with Th17 cytokines and a systemic innate immune activation; however, the link between immune activation and symptoms is poorly understood. OBJECTIVE:To use an untargeted metabolomics approach to identify novel pathways associated with FPIES reactions. METHODS:Serum samples were obtained before, during, and after an oral food challenge (OFC) (10 FPIES and 10 asymptomatic subjects), and they were analyzed by untargeted metabolomics. Two-way ANOVA with false discovery rate (FDR) adjustment was used for analysis of metabolites. Stomach and duodenal biopsies from non-FPIES donors were stimulated with adenosine in vitro and serotonin measured by immunoassay. RESULTS:A total of 34 metabolites were increased during symptomatic FPIES OFCs compared to asymptomatic subjects, including inosine and urate of the purine signaling pathway. Expression of purine receptors P2RX7 and P2RY10 and the ectonucleotidase CD73 in peripheral blood was significantly reduced after OFC in FPIES patients. The serotonin metabolite 5-hydroxyindoleacetate was significantly elevated post-reaction. Adenosine stimulation of gastric and duodenal biopsies from non-FPIES donors induced a significant release of serotonin, suggesting a link between purinergic pathway activation and serotonin release. CONCLUSIONS:Activation of the purinergic pathway during FPIES reactions provides a possible mechanism connecting inflammation and vomiting symptoms by triggering serotonin release from gastric and duodenal mucosa. CLINICAL IMPLICATIONS/CONCLUSIONS:The link between gastrointestinal inflammation and FPIES symptoms via adenosine and serotonin suggests novel therapeutic approaches to FPIES by targeting purinergic receptors.
PMID: 36306938
ISSN: 1097-6825
CID: 5359732

Diagnosis and management of food allergy-associated gastroesophageal reflux disease in young children-EAACI position paper

Meyer, Rosan; Vandenplas, Yvan; Lozinsky, Adriana Chebar; Vieira, Mario C; Canani, Roberto Berni; Dupont, Christophe; Uysal, Pinar; Cavkaytar, Ozlem; Knibb, Rebecca; Fleischer, David M; Nowak-Wegrzyn, Anna; Venter, Carina
Gastro-oesophageal reflux (GOR) and food allergy (FA) are common conditions, especially during the first 12 months of life. When GOR leads to troublesome symptoms, that affect the daily functioning of the infant and family, it is referred to as GOR disease (GORD). The role of food allergens as a cause of GORD remains controversial. This European Academy of Allergy and Clinical Immunology (EAACI) position paper aims to review the evidence for FA-associated GORD in young children and translate this into clinical practice that guides healthcare professionals through the diagnosis of suspected FA-associated GORD and medical and dietary management. The task force (TF) on non-IgE mediated allergy consists of EAACI experts in paediatric gastroenterology, allergy, dietetics and psychology from Europe, United Kingdom, United States, Turkey and Brazil. Six clinical questions were formulated, amended and approved by the TF to guide this publication. A systematic literature search using PubMed, Cochrane and EMBASE databases (until June 2021) using predefined inclusion criteria based on the 6 questions was used. The TF also gained access to the database from the European Society of Paediatric Gastroenterology and Hepatology working group, who published guidelines on GORD and ensured that all publications used within that position paper were included. For each of the 6 questions, practice points were formulated, followed by a modified Delphi method consisting of anonymous web-based voting that was repeated with modified practice points where required, until at least 80% consensus for each practice point was achieved. This TF position paper shares the process, the discussion and consensus on all practice points on FA-associated GORD.
PMID: 36282131
ISSN: 1399-3038
CID: 5359092

Are we missing food-protein-induced enterocolitis syndrome in adults?

Bingemann, Theresa A; Anvari, Sara; Bartnikas, Lisa M; Ruffner, Melanie; Nowak-Wegrzyn, Anna
PMID: 36191851
ISSN: 1534-4436
CID: 5351432

Educational resources received by families after successful baked egg/baked milk oral food challenge: An international survey

Hicks, Allison G; Pickett, Kaci; Casale, Thomas B; Cassimos, Dimitrios; Elverson, Wendy; Gerdts, Jennifer; Gray, Sarah; Jones, Carla; LeBovidge, Jennifer; Levin, Michael; Mack, Douglas P; Minshall, Eleanor; Nowak-Wegrzyn, Anna; Pistiner, Michael; Protudjer, Jennifer L P; Said, Maria; Schaible, Allison; Smith, Pete; Vassilopoulou, Emilia; Venter, Carina
PMID: 36184022
ISSN: 2213-2201
CID: 5361432

Acute At-Home Management of Anaphylaxis: 911: What Is the Emergency?

Casale, Thomas B; Wang, Julie; Oppenheimer, John; Nowak-Wegrzyn, Anna
The appropriate at-home management of anaphylaxis begins with patient education on recognition and treatment, especially when and how to use epinephrine. Delayed administration of epinephrine as well as having severe symptoms and needing multiple doses of epinephrine to treat symptoms are risk factors for biphasic anaphylaxis. The successful implementation of at-home management of anaphylaxis requires appropriate patient selection and an algorithmic approach that recommends activation of emergency medical services (EMS) when the patient does not adequately respond to at-home administration of epinephrine or there are extenuating patient-related circumstances. Fortunately, approximately 98% of anaphylactic episodes respond to 2 or fewer doses of epinephrine, the standard prescription used for epinephrine autoinjectors; fatal anaphylaxis is very rare, as low as 0.002 deaths/million person-years; and biphasic reactions are uncommon (∼5%), and only extremely rarely lethal. Thus, most common concerns leading to recommended EMS activation and emergency department visits after epinephrine administration are generally unsubstantiated. Furthermore, emergency department visits do not always lead to better treatment and drive health care costs higher. Open communications with patients and families regarding risks and benefits of at-home management and observation versus EMS activation and emergency department evaluation after epinephrine administration for anaphylaxis are essential. However, we believe the data indicate that it is time to reconsider the often used and taught approach that recommends EMS activation whenever epinephrine is used.
PMID: 35569813
ISSN: 2213-2201
CID: 5284142

Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines update - III - Cow's milk allergens and mechanisms triggering immune activation

Jensen, Sebastian A; Fiocchi, Alessandro; Baars, Ton; Jordakieva, Galateja; Nowak-Wegrzyn, Anna; Pali-Schöll, Isabella; Passanisi, Stefano; Pranger, Christina L; Roth-Walter, Franziska; Takkinen, Kristiina; Assa'ad, Amal H; Venter, Carina; Jensen-Jarolim, Erika
Background/UNASSIGNED:The immunopathogenesis of cow's milk protein allergy (CMPA) is based on different mechanisms related to immune recognition of protein epitopes, which are affected by industrial processing. Purpose/UNASSIGNED:The purpose of this WAO DRACMA paper is to: (i) give a comprehensive overview of milk protein allergens, (ii) to review their immunogenicity and allergenicity in the context of industrial processing, and (iii) to review the milk-related immune mechanisms triggering IgE-mediated immediate type hypersensitivity reactions, mixed reactions and non-IgE mediated hypersensitivities. Results/UNASSIGNED:The main cow's milk allergens - α-lactalbumin, β-lactoglobulin, serum albumin, caseins, bovine serum albumins, and others - may determine allergic reactions through a range of mechanisms. All marketed milk and milk products have undergone industrial processing that involves heating, filtration, and defatting. Milk processing results in structural changes of immunomodulatory proteins, leads to a loss of lipophilic compounds in the matrix, and hence to a higher allergenicity of industrially processed milk products. Thereby, the tolerogenic capacity of raw farm milk, associated with the whey proteins α-lactalbumin and β-lactoglobulin and their lipophilic ligands, is lost. Conclusion/UNASSIGNED:The spectrum of immunopathogenic mechanisms underlying cow's milk allergy (CMA) is wide. Unprocessed, fresh cow's milk, like human breast milk, contains various tolerogenic factors that are impaired by industrial processing. Further studies focusing on the immunological consequences of milk processing are warranted to understand on a molecular basis to what extent processing procedures make single milk compounds into allergens.
PMID: 36185551
ISSN: 1939-4551
CID: 5361472

Qualitative interviews to understand health care providers' experiences of prescribing licensed peanut oral immunotherapy

Anagnostou, Aikaterini; Lawrence, Claire; Tilles, Stephen A; Laubach, Susan; Donelson, Sarah M; Yassine, Mohamed; Nowak-Wegrzyn, Anna
OBJECTIVE:This research sought to explore health care providers' (HCPs) experiences of delivering the first US Food and Drug Administration (FDA) and European Commission (EC) approved peanut oral immunotherapy (peanut OIT; Palforzia). Semi-structured qualitative interviews with HCPs who had initiated treatment with ≥ 3 patients in the first nine months following FDA approval sought to identify challenges faced and successful implementation strategies. RESULTS:Eight allergists and three nurse practitioners from eight sites based in the United States participated. The HCPs included in this research were motivated to implement this novel treatment, however, entered the process with some reservations. HCPs described how successful implementation of peanut OIT requires them to be thoughtful about their clinic's abilities to integrate complex, time-consuming treatments into their daily practice. Prior experience of OIT was deemed beneficial, but not essential for implementation and learning from others' experience was suggested as a way of helping new prescribers overcome perceived and actual implementation challenges. Delivering licensed peanut OIT during the COVID-19 pandemic posed both challenges and unexpected opportunities for implementation. The experiences described have the potential to benefit the wider allergy community by providing practical solutions, successful implementation strategies and opportunities to enhance training and resources.
PMID: 35941597
ISSN: 1756-0500
CID: 5286762

Early Introduction of Allergenic Foods and the Prevention of Food Allergy

Trogen, Brit; Jacobs, Samantha; Nowak-Wegrzyn, Anna
The increasing prevalence of food allergies is a growing public health problem. For children considered high risk of developing food allergy (particularly due to the presence of other food allergies or severe eczema), the evidence for the early introduction of allergenic foods, and in particular peanut and egg, is robust. In such cases, the consensus is clear that not only should such foods not be delayed, but that they should be introduced at approximately 4 to 6 months of age in order to minimize the risk of food allergy development. The early introduction of allergenic foods appears to be an effective strategy for minimizing the public health burden of food allergy, though further studies on the generalizability of this approach in low-risk populations is needed.
PMID: 35807745
ISSN: 2072-6643
CID: 5278462

Broad Cross-Reactive IgA and IgG against Human Coronaviruses in Milk Induced by COVID-19 Vaccination and Infection

Wang, Jiong; Young, Bridget E; Li, Dongmei; Seppo, Antti; Zhou, Qian; Wiltse, Alexander; Nowak-Wegrzyn, Anna; Murphy, Katherine; Widrick, Kaili; Diaz, Nicole; Cruz-Vasquez, Joseline; M Järvinen, Kirsi; Zand, Martin S
It is currently unclear if SARS-CoV-2 infection or mRNA vaccination can also induce IgG and IgA against common human coronaviruses (HCoVs) in lactating parents. Here we prospectively analyzed human milk (HM) and blood samples from lactating parents to measure the temporal patterns of anti-SARS-CoV-2 specific and anti-HCoV cross-reactive IgA and IgG responses. Two cohorts were analyzed: a vaccination cohort (n = 30) who received mRNA-based vaccines for COVID-19 (mRNA-1273 or BNT162b2), and an infection cohort (n = 45) with COVID-19 disease. Longitudinal HM and fingerstick blood samples were collected pre- and post-vaccination or, for infected subjects, at 5 time-points 14-28 days after confirmed diagnosis. The anti-spike(S) and anti-nucleocapsid(N) IgA and IgG antibody levels against SARS-CoV-2 and HCoVs were measured by multiplex immunoassay (mPlex-CoV). We found that vaccination significantly increased the anti-S IgA and IgG levels in HM. In contrast, while IgG levels increased after a second vaccine dose, blood and HM IgA started to decrease. Moreover, HM and blood anti-S IgG levels were significantly correlated, but anti-S IgA levels were not. SARS2 acute infection elicited anti-S IgG and IgA that showed much higher correlations between HM and blood compared to vaccination. Vaccination and infection were able to significantly increase the broadly cross-reactive IgG recognizing HCoVs in HM and blood than the IgA antibodies in HM and blood. In addition, the broader cross-reactivity of IgG in HM versus blood indicates that COVID-19 vaccination and infection might provide passive immunity through HM for the breastfed infants not only against SARS-CoV-2 but also against common cold coronaviruses.
PMID: 35746588
ISSN: 2076-393x
CID: 5282202

Allergen immunotherapy and/or biologicals for IgE-mediated food allergy: A systematic review and meta-analysis

de Silva, Debra; Rodríguez Del Río, Pablo; de Jong, Nicolette W; Khaleva, Ekaterina; Singh, Chris; Nowak-Wegrzyn, Anna; Muraro, Antonella; Begin, Philippe; Pajno, Giovanni; Fiocchi, Alessandro; Sanchez, Angel; Jones, Carla; Nilsson, Caroline; Bindslev-Jensen, Carsten; Wong, Gary; Sampson, Hugh; Beyer, Kirsten; Marchisotto, Mary-Jane; Fernandez Rivas, Montserrat; Meyer, Rosan; Lau, Susanne; Nurmatov, Ulugbek; Roberts, Graham
BACKGROUND:There is substantial interest in immunotherapy and biologicals in IgE-mediated food allergy. METHODS:We searched six databases for randomized controlled trials about immunotherapy alone or with biologicals (to April 2021) or biological monotherapy (to September 2021) in food allergy confirmed by oral food challenge. We pooled the data using random-effects meta-analysis. RESULTS:We included 36 trials about immunotherapy with 2126 mainly child participants. Oral immunotherapy increased tolerance whilst on therapy for peanut (RR 9.9, 95% CI 4.5.-21.4, high certainty); cow's milk (RR 5.7, 1.9-16.7, moderate certainty) and hen's egg allergy (RR 8.9, 4.4-18, moderate certainty). The number needed to treat to increase tolerance to a single dose of 300 mg or 1000 mg peanut protein was 2. Oral immunotherapy did not increase adverse reactions (RR 1.1, 1.0-1.2, low certainty) or severe reactions in peanut allergy (RR 1,6, 0.7-3.5, low certainty), but may increase (mild) adverse reactions in cow's milk (RR 3.9, 2.1-7.5, low certainty) and hen's egg allergy (RR 7.0, 2.4-19.8, moderate certainty). Epicutaneous immunotherapy increased tolerance whilst on therapy for peanut (RR 2.6, 1.8-3.8, moderate certainty). Results were unclear for other allergies and administration routes. There were too few trials of biologicals alone (3) or with immunotherapy (1) to draw conclusions. CONCLUSIONS:Oral immunotherapy improves tolerance whilst on therapy and is probably safe in peanut, cow's milk and hen's egg allergy. More research is needed about quality of life, cost and biologicals.
PMID: 35001400
ISSN: 1398-9995
CID: 5118272