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.

Background: The prevalence of food allergies (FA) in children increased rapidly at the turn of the century. The EuroPrevall study identified Germany as a country with very high prevalence of FA at that time. Using two large German birth cohorts we provide an update of the status quo ten years later. Methods: KUNO Kids and Ulm SPATZ Health studies are two ongoing prospective birth cohorts. Information on FA was obtained by questionnaires at birth and after 6, 12 and 24 months. Univariate logistic regression analyses were performed to investigate risk factors during pregnancy, birth and early childhood. Results: In 1139 and 1006 children from KUNO Kids and SPATZ the point prevalence of parent-reported FA symptoms at the ages of 1 and 2 years was 13.2% and 13.9 % in KUNO Kids. Doctor’s diagnosed FA at 1 and 2 years was 2.4% and 2.7% in KUNO Kids and 2.3% and 3% in SPATZ. Cow’s milk and citrus fruits were most frequently suspected by parents to cause FA symptoms. Atopy in the child was associated with a higher frequency of FA at any time, whereas atopy in first degree relatives was only associated with FA at year 1. Smoke exposure during pregnancy was a risk for FA at age 2. Conclusion: The prevalence of food allergy seems to have plateaued in the last 10 years in Germany. FA is often suspected by parents but only rarely diagnosed by oral food challenge. Risk factor analysis may help to establish personalized health approaches.

FOOD PROTEIN–INDUCED ENTEROCOLITIS SYNDROME IN PRETERM NEWBORNS

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 protected]

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.

Main Text FileUsefulness of thymus and activation-regulated chemokine (TARC) for FPIES diagnosis

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.

A document by Marguerite Lawler. Click on the document to view its contents.

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.

Background: Dysregulation of eicosanoids is associated with asthma and a composite of oxylipins, including exhaled LTB4, characterizes childhood asthma. While FeNO has been used as the standard for monitoring steroid responsiveness, the potential utility of eicosanoids in monitoring the therapeutic outcomes remains unclear. We aimed to examine the levels of major eicosanoids representing different metabolic pathways in exhaled breath condensates (EBCs) of children with asthma during exacerbation and after treatment. Methods: Levels of 6 exhaled eicosanoid species in asthmatic children and healthy subjects were evaluated using ELISA. Results: In addition to those previously reported, including LTB4, the levels of exhaled 15-HETE, but not TXB2, showed significant difference between asthmatics (N=318) and healthy controls (N=97), particularly the severe group showed the lowest levels of exhaled 15-HETE. Receiver Operating Characteristic (ROC) analyses revealed similar distinguishing power for the levels of 15-HETE, FEV1 and FeNO, whilethe 15-HETE/LTB4 ratio was significantly lower in subjects with severe asthma (p<0.01). Analysis of asthmatics (N=75) during exacerbation and convalescence showed significant improvement in lung function (FEV1; p<0.001), but not FeNO, concomitant with significantly increased levels of 15-HETE (p<0.001) and reduced levels of TXB2 (p<0.05) after therapy, particularly for those who at the top 30% level during exacerbation. Further, decreased LTB4 and LXA4 at convalescence were noted only in those at the top 30 percentile during exacerbation. Conclusion: The exhaled 15-HETE was found to discriminate childhood asthma while decreased levels of exhaled TXB2 and increased levels of 15-HETE were prominent after treatment.

Background: Quantifying age trends in healthcare costs of pediatric asthma leads to better understanding of the natural history of the disease and informed decision-making on the allocation of healthcare resources. Methods: We identified children with incident asthma from the health administrative data of British Columbia, Canada (Jan 1998 to Dec 2015), and followed them from their first diagnosis of asthma or wheezing until age 18. We estimated direct medical costs (in 2016 Canadian dollars [$]), including inpatient and outpatient encounters and pharmacy costs, attributed to asthma (primary outcome) and other respiratory diseases (secondary outcome). We assessed the impact of sex and socioeconomic status on age trends, adjusting for calendar effect. Results: The final analysis included 44,552 children with asthma (62% boys). From age 0 to 18, costs of asthma/wheezing and other respiratory conditions decreased from $1,036 to $29/child-year, and from $1,145 to $31/child-year, respectively. Children under 3 years of age incurred 4–fold higher costs for asthma/wheezing and other respiratory conditions. In particular, costs of asthma hospitalizations were 10 times higher in this age group compared to older children. Age trends were generally similar between sex groups and across socioeconomic status. However, medication costs for asthma/wheezing decreased in boys, whereas those in girls declined during childhood but increased during adolescence. Conclusions: The highest costs of pediatric asthma are concentrated in children younger than 3. Age trends were generally consistent between sex and across socioeconomic status.

A document by Jana Eckert. Click on the document to view its contents.