Background: Although well described in adults, there are scarce and heterogeneous data on the diagnosis and management of chronic urticaria (CU) in children (0-18 years) throughout Europe. Our aim was to explore country differences and identify the extent to which the EAACI/GA²LEN/EDF/WAO guideline recommendations for paediatric urticaria are implemented. Methods: The EAACI Taskforce for paediatric CU disseminated an online clinical survey among EAACI paediatric section members. Members were asked to answer 35 multiple choice questions on current practices in their respective centres. Results: The survey was sent to 2,773 physicians of whom 358 (13.8%) responded, mainly paediatric allergists (80%) and paediatricians (49.7%), working in 69 countries. For diagnosis, Southern European countries used significantly more routine tests (e.g., autoimmune testing, allergological tests, and parasitic investigation) than Northern European countries. Most respondents (60.3%) used a 2nd generation antihistamine as first- line treatment of whom 64.8% up dosed as a second- line. Omalizumab, was used as a second line treatment by 1.7% and third-line by 20.7% of respondents. Most clinicians (65%) follow EAACI/WAO/GA2LEN/EDF guidelines when diagnosing CU, and only 7.3% follow no specific guidelines. Some clinicians prefer to follow national guidelines (18.4%, mainly Northern European) or the AAAAI practice parameter (1.7%). Conclusions: Even though most members of the Paediatric Section of EAACI are familiar with the EAACI/WAO/GA2LEN/EDF guidelines, a significant number do not follow them. Also, the large variation in diagnosis and treatment strengthens the need to re-evaluate, update and standardize guidelines on the diagnosis and management of CU in children.
Potential protective effects of breast milk and amniotic fluid against novel coronavirus SARS-CoV-2.Authors: April Rees1, Stephen Turner2, Catherine Thornton1*1 Institute of Life Science, Swansea University Medical School, Swansea, Wales, UK, SA2 8PP2 University of Aberdeen, The Institute of Applied Health Sciences, Aberdeen, Scotland, UK AB24 3FXDisclosure: The authors report no conflict of interest.Funding: This work was supported by the EPSRC Impact Acceleration Account at Swansea University and the Welsh Government Sêr Cymru III Tackling COVID-19 initiative.*Corresponding author:Professor Cathy ThorntonILS1, Swansea University Medical SchoolSingleton CampusSwansea UniversitySwansea, Wales, UKSA2 8PPTelephone: 01792 602122Email: firstname.lastname@example.orgKeywords: Breast milk, amniotic fluid, SARS-CoV-2, neonateWord count: 769
Background: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of updating the guidelines on the diagnosis and management of food allergy. The existing guidelines are based on a systematic review of the literature until 30th September 2012. Therefore, a new systematic review must be undertaken to inform the new guidelines. This systematic review aims to assess the accuracy of index tests to support the diagnosis of IgE-mediated food allergy. Methods: The databases Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID) will be searched for diagnostic test accuracy studies from 1st October 2012 to 30th June 2021. Inclusion and exclusion criteria will be used to select appropriate studies. Data from these studies will be extracted and tabulated, and then reviewed for risk of bias and applicability using the QUADAS-2 tool. All evaluation will be done in duplicate. Studies with a high risk of bias and low applicability will be excluded. Meta-analysis will be performed if there are three or more studies of the same index test and food. Results: A protocol for the systematic review and meta-analyses is presented and was registered using Prospero prior to commencing the literature search. Discussion: Oral food challenges are the reference standard for diagnosis but involve considerable risks and resources. This protocol for systematic review aims to assess the accuracy of various tests to diagnose food allergy, which can be useful in both clinical and research settings.
Title :Shrimp-Allergic Patients in a Multi-Food Oral Immunotherapy TrialAuthors :Diem-Tran I. Nguyen MD1, Sayantani B. Sindher MD2,3, R. Sharon Chinthrajah MD2,3, Kari Nadeau MD PhD2,3, Carla M. Davis MD1,41Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States2Sean N. Parker Center for Allergy and Asthma Research, Stanford University, Palo Alto, CA, USA3Division of Pulmonary, Allergy and Critical Care Medicine, Dept of Medicine, Stanford, CA, USA.4Section of Immunology, Allergy and Retrovirology, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, United StatesCorresponding Author:Carla M. Daviscarlad@bcm.eduWord Count: 978To the Editor:Shellfish allergy is one of the most common food allergies in the United States accounting for approximately 25% of adulthood and 20% of childhood food allergies (FA).1,2Of the different types of shellfish, shrimp are considered the most allergenic. The prevalence of shellfish allergy in children is substantial at 1.3% and may result in a greater prevalence in the adult population (3%) given that shellfish allergies have a low rate of spontaneous resolution.2,3Shrimp allergy (SA) is a leading cause of severe food reactions and results in high rates of healthcare usage.4Nearly 50% of patients with SA experience at least one lifetime food allergy related Emergency Department visit, yet only 42% of adults and 61% of children with SA reported having a physician confirmed diagnosis.1,2The lack of physician confirmation of SA is concerning given the potentially life threatening consequences of accidental exposure.5Currently, there is no cure and the only management strategies are avoidance and treatment for severe reactions with epinephrine.6 However, avoidance can be difficult due to the high incidence of cross-contamination, requiring strict dietary limitations.Oral immunotherapy (OIT) has emerged as a promising treatment for FA. In OIT, patients ingest increasing doses of the allergenic food with the goal of achieving desensitization so that reactions are less severe. Once a maintenance dose is achieved, the allergen needs to be regularly ingested to preserve the desensitized state. Although OIT has been recently approved by the FDA for peanut allergies, there has been little data in shrimp allergic patients. In this case-series, we discuss a subset of three patients who received shrimp OIT as part of a phase II, multi-food, omalizumab-facilitated OIT clinical trial.Multi-food allergic patients were recruited to a multi-site clinical trial between January 1 and November 30, 2016. Full details of trial design, inclusion criteria, and exclusion criteria have been previously reported.7Patients initially underwent testing with skin prick testing (SPT), specific IgE testing, and double-blind placebo-controlled food challenge (DBPCFC) to confirm their allergy to their culprit foods. To be included, patients were required to have a positive SPT of> 6 mm wheal diameter, specific IgE> 0.35 kU/L, a total IgE <2,000 kU/L, and a clinical reaction with DBPCFCs at < 125 mg dose.Patients enrolled in this clinical trial received 0.016 mg/kg (IU/mL) omalizumab per month or 0.008 mg/kg (IU/mL) every two weeks (based on asthma dosing guidelines)7 from week 1-16. At week 8, multi-food OIT was started and escalated under an investigator-supervised multi-OIT up-dosing regimen to reach a maintenance dose of > 1g of each allergen. Participants who reached maintenance by week 28-29 were randomized and received week 30 DBPCFC to assess desensitization to the allergenic foods. Patients were then randomized to one of three arms: high dose maintenance (1000 mg), low dose maintenance (300 mg), or placebo (0 mg). This randomized dose was dispensed at the last week 30 DBPCFC and consumed until week 36. At week 36, DBPCFC was repeated to assess sustained unresponsiveness with differing daily doses of protein.A total of 70 patients were enrolled, with three found to have SA. Their demographic data and baseline characteristics are detailed in Table 1. All three patients also had asthma, allergic rhinitis, and atopic dermatitis. Each had a convincing clinical history, elevated total IgE, and positive SPT to a mixture of white, brown, and pink shrimp extract from Greer. The diagnosis was confirmed by a reaction during DBPCFC withLitopenaeus setiferus shrimp flour that was manufactured at a Good Manufacturing Practice facility at Stanford University.Clinical outcomes and adverse events are detailed in Table 2. All 3 patients tolerated dose escalation without serious adverse events or epinephrine requirement, were able to achieve maintenance dose, and did not have an allergic reaction at the Week 30 DBPCFC. Patient A was randomized to the placebo treatment arm while the other two patients were randomized to the 300 mg maintenance OIT arm. At Week 36, Patient A and Patient B had sustained unresponsiveness to 12,000 mg of shrimp extract. Patient C did not follow-up for assessment.It is encouraging that all 3 shrimp allergic patients in this multi-food OIT clinical trial were able to reach maintenance dose OIT (> 1g), and 2 out of 3 had no reaction with the 12g DBPCFC dose at Week 30. These results suggest that OIT is a potentially efficacious treatment for SA and warrants further study. There is little data on the optimal shrimp allergen product, dose escalation regimen, and adjunct therapies such as omalizumab to achieve desensitization.There are several known target allergens that contribute to SA. The first major allergen is tropomyosin, a heat-stable, actin-binding protein found in both muscle and non-muscle cells. Tropomyosin has been implicated as the source of significant cross-reactivity between species of mollusks, crustaceans, and non-shellfish such as cockroaches and mites.8,9Other shrimp allergens that have been identified include arginine kinase, myosin light chain, sarcoplasmic calcium-binding protein, hemocyanin, and troponin C.8,9 It is possible that patients with allergies to different shrimp components may have varied responses to OIT, and thus additional research is necessary to determine which patient subgroups are most likely to benefit from shrimp OIT.Our case series is limited by small sample size, with only three patients receiving shrimp OIT and two following up at week 36. Although all patients appeared to develop short-term tolerance by week 30, it is unclear how durable this response would be with long-term follow up. Furthermore, there are risks associated with OIT.SA is a common and serious food allergy that is underdiagnosed and often lifelong. There are currently no effective treatments other than strict avoidance, which can be difficult to achieve and lead to poor quality of life. Our case series presents initial evidence suggesting that shrimp OIT may be an effective strategy of addressing grave reactions faced by SA patients. Larger studies need to be performed to validate these findings.References :1. Gupta, R. S. et al.Prevalence and Severity of Food Allergies Among US Adults. JAMA Netw Open 2, e185630 (2019).2. Wang, H. T., Warren, C. M., Gupta, R. S. & Davis, C. M. Prevalence and Characteristics of Shellfish Allergy in the Pediatric Population of the United States. J. Allergy Clin. Immunol. Pract. 8, 1359–1370.e2 (2020).3. Zotova, V. et al.Low resolution rates of seafood allergy. J. Allergy Clin. Immunol. Pract. 7, 690–692 (2019).4. Ross, M. P. et al.Analysis of food-allergic and anaphylactic events in the National Electronic Injury Surveillance System. J. Allergy Clin. Immunol.121, 166–171 (2008).5. Tuano, K. T. S. et al. Improved diagnostic clarity in shrimp allergic non-dust-mite sensitized patients. Allergy Asthma Proc. 39, 377–383 (2018).6. Davis CM, Gupta RS, Aktas ON, Diaz V, Kamath SD, Lopata AL. Clinical Management of Seafood Allergy. J Allergy Clin Immunol Pract. 2020 Jan;8(1):37-44.7. Andorf, S. et al. A Phase 2 Randomized Controlled Multisite Study Using Omalizumab-facilitated Rapid Desensitization to Test Continued Discontinued Dosing in Multifood Allergic Individuals.EClinicalMedicine 7, 27–38 (2019).8. Faber, M. A. et al.Shellfish allergens: tropomyosin and beyond. Allergy 72, 842–848 (2017).9. Ruethers T, Taki AC, Johnston EB, Nugraha R, Le TTK, Kalic T, McLean TR, Kamath SD, Lopata AL. Seafood allergy: A comprehensive review of fish and shellfish allergens. Mol Immunol. 2018 Aug;100:28-57.
Castleman disease is a rare, heterogeneous disorder that driven by proinflammatory responses. Human herpes virus-8 has a major role in pathogenesis of multicentric Castleman disease. There is also a subgroup of cases, human herpes virus-8 negative, idiopathic multicentric Castleman disease. The role of primary immunodeficiencies in idiopathic Castleman disease are poorly described. DOCK8 deficiency is a combined primary immunodeficiency. It has a broad clinic spectrum including atopy, autoimmunity and cancer. We present a 10-year-old, DOCK8 deficient patient. He had giant lobular capillary hemangiomas on his neck, iliac and gluteal regions and multiple lymphadenopathies. Abdominal lymph node pathology revealed hyaline vascular type Castleman disease and human herpes virus-8 staining was negative. His lesions were shown to be infected with orf virus. Our case is the first case to relate idiopathic multicentric Castleman disease and DOCK8 deficiency; also, very unusual presentation of orf virus infection in humans.
BACKGROUND: Lymphopenia is a hallmark of multisystem inflammatory syndrome in children (MIS-C). We aimed to characterize lymphocyte subsets’ shifts and their correlations with other severity markers of MIS-C. METHODS: In this prospective cross-sectional study, we performed peripheral lymphocyte phenotyping in 32 patients with MIS-C. We analyzed lymphocyte subsets at three time-points of the disease: the acute (A), convalescent (B), and recovery (C) phases. Based on age-normalized lymphocyte counts, we distinguished two groups of patients: “the mild” and “the severe”. In addition, we examined differences between these groups regarding other severity markers. RESULTS: In phase A, 84% of children had lymphopenia. Decreased absolute counts of CD3, CD4, and CD8 cells were observed in, respectively, 88%, 72%, and 84% of patients. The natural killer cells were decreased in 63% and CD19 in 59% of children. “The severe” group had significantly higher procalcitonin and troponin I levels and lower platelets and albumin. Moreover, “the severe” group had hypotension more frequently (73% vs. 20%, p=0.008). In phase B, all lymphocyte counts increased, and 32% of children had lymphocytosis. The increase of CD3, CD4, and CD8 counts correlated with some laboratory severity markers (hemoglobin, procalcitonin, D-dimer, lactate dehydrogenase, N-terminal prohormone of brain natriuretic peptide, albumin), but not with steroid use. In phase C, most children had normal lymphocyte counts. CONCLUSIONS: Substantial shifts in lymphocyte counts during MIS-C apply most to T lymphocytes and correlate with the disease severity markers, particularly hypotension prevalence. A proportion of children with MIS-C develops transient lymphocytosis during convalescence.
Background: Inherited chronic mucocutaneous candidiasis (CMC) is often caused by inborn errors of immunity, impairing the response to, or the production of IL-17A and IL-17F. About half of the cases carry STAT1 gain-of-function (GOF) mutations. Only few patients have been reported with mutations of TRAF3IP2, a gene encoding the adaptor ACT1 essential for IL-17-receptor(R) -signaling. We investigated a 10-year-old girl with CMC, carrying a heterozygous variant of STAT1 and compound heterozygous variants of TRAF3IP2. Methods: By flow cytometry STAT1 levels and phosphorylation (CD14+) as well as IL-17A-, IL-22-, IFN-γ- and IL-4-production (memory CD4+ T cells) were determined. ACT1 expression and binding to IL-17RA by western blot and co-immunoprecipitation in HEK-293T cells transfected with plasmids encoding wild-type or mutant HA-tagged ACT1 and Flag-IL-17RA. We evaluated IL-17A response using an NF-κB-driven luciferase reporter system in HEK-293T cells, and by measuring GRO-α secretion by fibroblasts. Results: A likely non-pathogenic STAT1 variant (c.1363G>A/p.V455I) was identified by next generation sequencing., STAT1 expression and phosphorylation upon IFN- were normal. We also found compound heterozygous variants (c.1325A>G/p.D451G and c.1335delA/p.K454fs11*) of TRAF3IP2. By overexpression, despite normal protein expression, and impaired (K454fs11*) or normal (D451G) interaction with IL-17RA, both mutant alleles resulted in an impaired NF-κB-activation. Patient’s fibroblasts displayed abolished GRO-α secretion upon IL-17A. Finally, ex vivo CD4+ T cells showed increased IL-17A, IL-22, and IL-4, and normal-low IFN-γ expression upon stimulation. Conclusion: We identify novel compound heterozygous variants of TRAFP3IP2 causing autosomal recessive ACT1 deficiency in a child with CMC, and provide a review of the current literature.
Background: TYK2 deficiency is a rare Primary immunodeficiency disease caused by loss of function mutations of TYK2 gene, which is initially proposed as a subset of Hyper IgE syndrome (HIES). However, accumulating evidence suggest TYK2 deficient patients do not necessarily present with HIES characteristics, indicating a vacuum of knowledge on the exact roles of TYK2 in human immune system. Method: Pathogenic effects of patients were confirmed by qRT-PCR, western blot and protein stability assays. The responses to cytokines including IFN-α/β/γ, IL-6, IL-10, IL12 and IL-23 of peripheral blood mononuclear cells (PBMCs) from these patients were detected by western blot, qRT-PCR and flow cytometry. The differentiation of T and B cells were detected by flow cytometry. Results: We describe five more TYK2 deficient cases presenting with or without hyper IgE levels, atopy and distinct pathogen infection profile, which are caused by novel TYK2 mutations. These mutations were all found by high throughout sequencing and confirmed by Sanger sequencing. The patients showed heterogenous responses to various cytokine treatments, including IFN-α/β/γ, IL-6, IL-10, IL12 and IL-23. The homeostasis of lymphocytes is also disrupted. Conclusion: Based on our findings, we propose that TYK2 works as a multi-tasker in orchestrating various cytokines signaling pathways, differentially combined defects of which account for the expressed clinical manifestations.
Complete blood count profiles in children with eczema herpeticumTo the Editor,Eczema herpeticum (EH) is a significant infectious complication of atopic dermatitis (AD) and may lead to serious problems including keratitis, viremia and meningitis (1). The clinical diagnosis of EH may be challenging as the morphology of EH may be mistaken for AD exacerbation and bacterial infection (2). Difficulty in diagnosis may impact treatment decisions while confirmatory testing for herpes simplex virus (HSV) is pending.Previous studies have investigated the association between EH and common laboratory values but have largely been inconclusive. One study in young adults found EH associated with lymphopenia and elevated IgE (3). Another study in children found no relationship between EH and serum total IgE, eosinophil count, or vitamin D level (4).A complete blood count (CBC) is a common test often obtained when there is concern for more severe infection. In this study, we investigated whether CBC profiles can be utilized to distinguish hospitalized children with EH from AD patients with bacterial infections or AD exacerbation.Electronic medical records were reviewed for patients 18 years and younger hospitalized with a primary diagnosis of AD between 2003 to 2018 using International Classification of Diseases -9 and -10 codes (5). The study has been approved by the Institution Review Board at Children’s Hospital Los Angeles. Patients were sorted into the EH group if there was a positive HSV polymerase chain reaction (PCR) swab from skin lesions. Subjects who had bacterial infections or AD exacerbation were classified based on clinical history, physical examination findings and discharge diagnosis as previously described (5). Briefly, patients with a discharge diagnosis of cellulitis, skin abscess, bacteremia, osteomyelitis, septic arthritis or endocarditis were classified into bacterial infections whereas those with generalized, severe eczema exacerbation with documented outpatient treatment failure were classified into AD exacerbation. A CBC obtained within 48 hours of admission was utilized. Multivariate linear regression model was used to assess the effect of EH on the CBC profile adjusting for patient age and gender. Statistical significance was set at 5% level with two-sided test throughout the analysis. All statistical computations were done by Stata/SE 16.0 (StataCorp, College Station, TX).130 subjects with an admission CBC were included in the study. Twenty-two (17%) had EH based on positive HSV PCR. Forty-nine (38%) had AD exacerbation while fifty-nine (45%) had bacterial infectious complications such as cellulitis, skin abscess, bacteremia, osteomyelitis or septic arthritis.EH patients had significantly lower mean admission white blood cell count (WBC, 9.7 ± 6.4 vs. 15.7 ± 9.1 vs 15.9 ± 6.8;p= <0.0001), absolute neutrophil count (ANC, 4.9 ± 5.0 vs. 5.7 ± 4.7 vs. 9.0 ± 5.6; p =0.01), and absolute lymphocyte count (ALC, 3.5 ± 1.8 vs. 6.4 ± 4.6 vs. 4.9 ± 3.4; p =0.003), as compared to AD exacerbation and bacterial infection, respectively (Table 1). When compared to published reference ranges (6), 13.6% of those with EH, 2% of those with AD exacerbation, and 0% of those with bacterial infection had absolute leukopenia for age (WBC under lower limit of normal) (Table 2A). 4.5% of those with EH, 6.1% of those with AD exacerbation, and 0% of those with bacterial infection had absolute neutropenia for age (Table 2B). 22.7% of patients with EH demonstrated absolute lymphopenia for age (Table 2C). In comparison, 10.2% of those with AD exacerbation and 13.6% of those with bacterial infection had absolute lymphopenia for age.EH is a skin infection caused by HSV that can lead to serious complications including ocular and systemic infections. Therefore, accurate diagnosis is important in determining appropriate treatments. The initiation of acyclovir for EH is based on clinical impression, as test results such as PCR and culture are not immediately available. Our current findings may have clinical implications for treatment when CBC profiles are taken together with physical examination as EH may be difficult to distinguish from some bacterial skin infections. For example, streptococcal pustulosis may present with punched scalloped borders that mimic EH (2).Large studies of EH in children are rare. Our results corroborate Wollenberg et al ’s finding that lymphopenia is more pronounced in patients with EH (3). Lymphopenia in the setting of a normal white blood cell count in EH patients may be a finding related to HSV infection, as another article studying the effect of HSV infection (not specifically EH) on CBC parameters also found lower lymphocyte counts in those with HSV (7).In conclusion, our results show that leukopenia or lymphopenia in light of clinical suspicion of EH may help clinicians in their treatment decision. Our study has limitation in that it is based on hospitalized patients and may not apply to an outpatient setting.Keywords: acyclovir, eczema herpeticum, CBC, lymphopenia, leukopenia, neutropeniaGrace Chan, MDa, Choo Phei Wee, MSb, Peck Y. Ong, MDc,daDivision of General Pediatrics, Children’s Hospital Los AngelesbBiostatistics core, The Saban Research Institute, Children’s Hospital Los Angeles, and Southern California and Clinical Translation Science Institute, University of Southern California.cDivision of Clinical Immunology and Allergy, Children’s Hospital Los Angeles.dKeck School of Medicine, University of Southern California, Los Angeles, CaliforniaThis study was funded in part by a Merit Award from The Saban Research Institute at Children’s Hospital Los Angeles to PYO. CPW is supported in part by NIH/NCRR SC-CTSI Grant UL1 TR000130 (Biostatistics core, CHLA/USC).The authors have no conflicts of interest to declare.Address correspondence to: Peck Y. Ong, MD, Division of Clinical Immunology and Allergy, Children’s Hospital Los Angeles, 4650, Sunset Blvd, MS# 75, Los Angeles, CA 90027. Tel: 323-361-2501. Email: email@example.com
Abstract Background: There has been no trial evaluating the psychopathology in breastfeeding mothers of infants with food allergy (FA). Objective: To investigate the effect of dietary elimination on maternal psychopathology, specifically stress/anxiety and mother-to-infant bonding and explore the importance of sociodemographic features on these variables. Methods: Breastfeeding mothers following an elimination diet due to FA in their children aged 1-to-12 months were compared with the healthy controls. Physician-diagnosed FA group were divided into IgE-, non-IgE-mediated and infants with some minor symptoms which were not enough to make the diagnosis of FA were classified as Indecisive symptoms for FA group. Mothers completed standardized questionnaires including Symptom Checklist 90R, Beck Depression/Anxiety Inventories (BDI/BAI), Postpartum Bonding Questionnaire (Bonding). Results: Of 179 mother-infants, 64 were healthy, 89 were FA, 16 were indecisive symptoms for FA. The mean age of the mothers and infants were 31.1±4.7 years and 6.3±3.6 months. The physician diagnosed FA groups had higher scores for anxiety (p=0.008), anger (p=0.042), depression (p<0.001), obsession (p=0.002), phobia (p=0.008), somatization (p=0.002) and general symptom index (GSI) (p=0.001), BDI (p<0.001), BAI (p=0.008) and Bonding [attachment (p=0.001), anger (p=0.019) and total (p=0.036)] than the healthy. The indecisive symptoms for FA group had a similar score pattern to physician-diagnosed FA except interpersonal sensitivity, BDI and attachment. Conclusion: Breastfeeding mothers of infants with FA were anxious, depressive and had many psychopathologies which affected bonding. Interventions targeting negativity in caregivers’ social relationships are urgently needed.
Background: Chemokines are important mediators in immune cell recruitment, contributing to allergy development. However, extensive studies of chemokines in the circulation in relation to the presence and development of allergic diseases remain scarce. Our aim was to investigate associations of circulating allergy-related chemokines with development of asthma and sensitisation cross-sectionally and longitudinally in a population-based cohort. Methods: The chemokines CCL17, CCL22, CXCL10, CXCL11 and CCL18 were measured in plasma samples from children in the Manchester Asthma and Allergy Study. Samples were available from cord blood at birth (n=376), age 1 (n=195) and 8 years (n=334). Cross-sectional and longitudinal association analyses were performed in relation to asthma and allergic sensitisation, as well as allergic phenotype clusters previously derived using machine learning in the same study population. Results: In children with asthma and/or allergic sensitisation, CCL18 levels were consistently elevated at ages 1 and/or 8 years. In a longitudinal model including information on asthma from 4 time-points (ages 5, 8, 11 and 16 years), we observed a significant association between increasing CCL18 levels at age 1 and a higher risk of asthma from early school age to adolescence (OR=2.9, 95% CI 1.1-7.6, p=0.028). We observed similar associations in longitudinal models for allergic sensitisation. Asthma later in life was preceded by increased CXCL10 levels after birth, and decreased CXCL11 levels at birth. Conclusion: Elevated CCL18 levels throughout childhood precede the development of asthma and allergic sensitisation. The Th1-associated chemokines CXCL10 and CXCL11 also associated with development of both outcomes, with differential temporal effects.
Background: Internationally, the COVID-19 pandemic severely curtailed access to hospital facilities for those awaiting elective/semi elective procedures. For allergic children in Ireland, already waiting up to 4yr for an elective oral food challenge (OFC), the restrictions signified indefinite delay. At the time of the initiative there were approx 900 children on the Chidren’s Health Ireland(CHI) waiting list. In July 2020, a project was facilitated by short term(6wk) access to an empty COVID stepdown facility built, in a hotel conference centre, commandeered by the Health Service Executive Ireland(HSE). The aim was to the achieve rapid rollout of an off-site OFC service, delivering high throughput of long waiting patients, while aligning with hospital existing policies and quality standards, international allergy guidelines and national social distancing standards. Methods: The working group engaged key stakeholders to rapidly develop an offsite OFC facility. Consultant Paediatric Allergists, Consultant Paediatricians, trainees and Allergy Clinical Nurse Specialists were seconded from other duties. The facility was already equipped with hospital beds, bedside monitors(BP, Pulse, Oxygen saturation) bedside oxygen. All medication and supplies had to be brought from the base hospital. Daily onsite consultant anaesthetic cover was resourced and a resuscitation room equipped. Standardised food challenge protocols were created. Access to onsite hotel chef facilitated food preparation. A risk register was established. Results: After 6wks planning, the remote centre became operational on 7/9/20, with the capacity of 27 OFC/day. 474 challenges were commenced, 465 (98%) were completed, 9(2%) were inconclusive. 135(29.03%) OFC were positive, 25(5%) causing anaphylaxis. No child required advanced airway intervention. 8 children were transferred to the base hospital. The CHI allergy waiting list was reduced by almost 60% in only 24 days. Conclusions: OFCs remain a vital tool in the care of allergic children, with their cost saving and quality of life benefits negatively affected by delay in their delivery. This project has shown it is possible to have huge impacts on a waiting list efficiently, effectively and safely with good planning and staff buy in – even in a pandemic. Adoption of new, flexible and efficient models of service delivery will be important for healthcare delivery in the post-COVID-19 era.
Dietary diversity during infancy and the association with childhood food allergen sensitization Authors: Kate Maslin PhD1,2, Kaci Pickett MSc3, Suzanne Ngo3,4 MD, William Anderson3,4 MD, Taraneh Dean PhD2,5, Carina Venter PhD2,3,4School of Nursing and Midwifery, University of Plymouth, Plymouth, UK.The David Hide Asthma and Allergy Centre, St. Mary’s Hospital, Isle of Wight, UKUniversity of Colorado School of Medicine, Colorado, USAAllergy and Immunology Section, Children’s Hospital Colorado, Colorado, USAUniversity of Brighton, Brighton, UKRunning title: Dietary diversity and food sensitization
Graded home introduction of egg is safe, well received and cost effective when managing childhood egg allergyTo the Editor,In Australia, an IgE mediated allergy to egg is a common food allergy in children.1-2 The 2011 HealthNuts study determined that 8.9% of children in Australia have an egg allergy.1-2IgE mediated allergy to egg can be mild and most children may outgrow this by 4-5 years of age.3-4 Almost 80% of children with IgE mediated egg allergy are tolerant of egg in a baked form with wheat being used as a matrix.1,3 Turner et al. suggests that the outcome of baked egg challenges can be unpredictable and can lead to anaphylaxis even in children with prior mild symptoms.5 Tolerance to baked egg is generally confirmed by a baked egg food challenge in hospital after which patients are encouraged to introduce baked egg products at home.6 Patients are reassessed and subsequently undergo a lightly cooked egg challenge in hospital where resolution is confirmed if successful.6Whereas there is evidence that majority of children with an egg allergy are tolerant to baked egg, there is debate as to whether it can reduce the duration of egg allergy.7-9 Recently, Gotesdyner et al found that a structured graded exposure using baked egg followed by lightly cooked egg compared to complete avoidance helped achieve tolerance to egg.3 Their findings suggest that an egg ladder may promote a faster resolution of egg allergy. However, due to the case control study design and small sample size definite conclusions could not be drawn.3Our Paediatric Allergy Service is a busy tertiary level clinic with more than 2000 outpatient interactions annually. To reduce the burden on tertiary resources, an egg tolerance ladder was developed (Appendix 1). It has been offered to patients considered low risk which includes (but is not limited to) patients with a single food allergy; mild or no eczema; mild, well controlled or no coexisting asthma; and/or a history of IgE mediated egg allergy without anaphylaxis. It has been designed to allow slow introduction of baked egg followed by foods containing small amounts of cooked egg and finally lightly cooked egg at home. Support throughout the home introduction process is provided by the treating team via email and phone contact.The aim of this study was to evaluate the use of this structured “egg ladder” with regards to its safety as well as user satisfaction and barriers that arose in negotiating it. We also attempted to determine potential risk factors which increased likelihood of clinical reaction to foods containing egg and rates of eventual tolerance to lightly cooked and raw egg achieved in the home environment. This study was approved by the Ethics Committee at John Hunter Children’s Hospital (2020/ETH01192).Patients with mild to moderate IgE mediated egg allergy aged 0-18 years seen in the Paediatric Allergy Clinic and commenced on an egg tolerance ladder by the Paediatric Immunologist were recruited retrospectively. Verbal and written education on the use of the ladder had been provided at the time of clinic review. Patients were excluded from home introduction if they had a history of anaphylaxis to any food containing egg or a non-IgE mediated egg allergy.A file audit identified a total of 98 patients for inclusion in this study who had been commenced on the egg ladder between September 2018 and June 2020. Patients were contacted by email and phone, and offered participation in a telephone survey to evaluate the use of the egg tolerance ladder. Almost half (47 patients) consented to the study. At the time of commencing the egg ladder, patients had a mean age of 40 months (IQR: 12-60 months). Six children did not have a skin prick test (SPT). The majority were sensitised with a mean SPT of 3.1mm. Most (66%) had at least one atopic comorbidity and almost half had more than one food allergy. The vast majority (87.2%) of patients commenced the egg ladder at home. This includes 23 patients already tolerant to baked egg prior to clinic presentation, based on clinical history. Only 3 (6%) used the resources of an inpatient challenge.Patients had spent an average of 15.5 months (IQR: 9-21.5 months) on the ladder. At the time of review, 43% of patients had completed the egg ladder but interestingly, four parents believed their child was still allergic to egg. The mean age of commencement on the egg ladder was higher than expected (40 months), and around the age a child is expected to outgrow an allergy to egg.3-4 Despite this, many patients reported reactions while using the egg ladder. A mild reaction was reported by 18 (38%) parents, 16 required treatment and of those one was given adrenaline. This child was 6 years of age, had an isolated egg allergy and small skin test (3.5mm). They reacted to Step 5 and have continued Step 4 at home successfully. Both families reporting a severe reaction recommenced the ladder and were able to subsequently progress successfully to Step 5 or 6. The majority had a mild skin response (rash or hives). Skin testing was a poor differentiator for clinical reaction with 38% of those with negative skin testing reporting a mild reaction with baked egg.Parental satisfaction was high with 78.7% satisfied or very satisfied with the egg ladder. Most of the remaining families were neutral with no families dissatisfied with the ladder use. Many stated that they valued the structured approach of introducing egg which helped identify their child’s level of tolerance, and allowed them to progress at their own pace. A number of parents identified the main barrier to progressing the ladder was the taste and/or texture of egg after successfully completing the ladder and subsequent difficulty maintaining regular lightly cooked egg in the diet. These families continued egg as an ingredient in cooked or baked food.There were some limitations to this study. Firstly, this was a retrospective small sized survey and some patients were unable to accurately recall timelines. As a voluntary survey there is also a risk of ascertainment bias. Baseline patient demographics (age, sex, SPT size, comorbid allergy diagnoses) of non-responders were compared to the study cohort with no significant differences identified. The initial education on commencing on the egg ladder was provided by multiple clinicians and information therefore was unable to be standardised. As expected, a number of patients at the time of the survey were still navigating the egg ladder and therefore had not had enough time to reach their individual threshold to determine if their child had outgrown their allergy. This may lead to under-reporting of egg tolerance on the ladder. Finally, follow up or assistance with the egg ladder was not provided unless the parent contacted the team. This may have resulted in less children completing the ladder due to parental anxiety over mild reactions.We have shown that the use of a structured egg ladder for egg allergic children without a history of anaphylaxis can be safe, is well tolerated and is a positive experience for families. It can prevent time consuming and costly inpatient supervised challenges unnecessarily consuming valuable and scarce resources in busy allergy clinics. Future prospective studies will help establish the role of home egg introduction in childhood egg allergy management in both tertiary and secondary health care settings.Conflicts of InterestNo conflicts to be declared.Leah Thomas1Jan Belcher1Rachael Phillips1Kahn Preece, MBBS, FRACP1Rani Bhatia, MBBS, FRACP11Department of Paediatric Allergy and Immunology, John Hunter Children’s Hospital, Newcastle, AustraliaReferences1. Osborne NJ, Koplin JJ, Martin PE, et al. Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants. Journal of Allergy and Clinical Immunology. 2011;127:668-76.2. Dang TD, Peters RL, Koplin JJ, et al. Egg allergen specific IgE diversity predicts resolution of egg allergy in the population cohort HealthNuts. Allergy. 2019; 74: 2.3. Gotesdyner L, Zeldin Y et al. A structured graduated protocol with heat denatured eggs in the treatment of egg allergy. Pediatric Allergy and Immunology. 2019;30:824-832.4. Leonard SA, Sampson HA, Sicerer SH, et al. Dietary baked egg accelerates resolution of egg allergy in children. Journal of Allergy and Clinical Immunology. 2012;13:2.5. Turner PJ, Mehr S, Joshi P et al. Safety to food challenges to extensively heated egg in egg-allergic children: a prospective cohort study. Pediatric Allergy and Immunology. 2013;24:450-455.6. Clark A, Islam S, King Y. A longitudinal study of resolution of allergy to well-cooked and uncooked egg. Clinical & Experimental Allergy. 2011;41:706-712.7 Lambert R, Grimshaw K, Elis B et al. Evidence that eating baked egg or milk influences egg or milk allergy resolution: A Systematic Review. Clin Exp Allergy. 2017;47(6):829-837.8. Upton J, Nowak-Wegrzyn A. The impact of baked egg and baked milk diets on IgE and Non-IgE mediated allergy. Clinical Reviews in Allergy & Immunology. 2018;55(2):118-138.9. Leonard SA, Caubet JC, Kim, JS, Groetch M, Wegrzyn AN. Baked Milk- and Egg-Containing Diet in the Management of Milk and Egg Allergy. Journal of Allergy and Clinical Immunology. 2015;1:13 – 23.
Background: The ‘old friends’ hypothesis posits that reduced exposure to previously ubiquitous microorganisms is one factor involved in the increased rates of allergic diseases. Cytomegalovirus (CMV) may be one of the “old friends” hypothesized to help prevent allergic diseases. We sought to elucidate whether early-life CMV infection is associated with childhood atopy via perturbations of the gut microbiota. Methods: Participants were recruited from a population-based birth cohort (CHILD study) and followed prospectively until age five years in four Canadian cities. A total of 928 participants provided stool microbiome data, urine for CMV testing, skin-prick tests, and questionnaires-based detailed environmental exposures. CMV infection was assessed in the first year of life while the main outcome was defined by persistent sensitization to any allergen at ages 1, 3, and 5 years. Results: Early CMV infection was associated with increased beta and decreased alpha diversity of the gut microbiota. Both changes in diversity measures and early CMV infection were associated with persistent allergic sensitization at age 5 years (aOR= 2.08; 95%CI: 1, 4.33). Mediation analysis demonstrated that perturbation of gut microbial composition explains 30% of the association. Conclusions: Early-life CMV infection is associated with an alteration in the intestinal microbiota, which mediates the effect of the infection on childhood atopy. This work indicates that preventing CMV infection would not put children at increased risk of developing atopy. Rather, a CMV vaccine, in addition to preventing CMV-associated morbidity and mortality, might reduce the risk of childhood allergic diseases.