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.

A document by Muhammad Khalid. Click on the document to view its contents.

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. [email protected] 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.

Transcriptome changes during peanut oral immunotherapy and omalizumab treatmentTo the Editor,Peanut allergy is a common food allergy and the main cause of anaphylaxis among children1. In recent years, oral immunotherapy has emerged as a promising treatment for children with different IgE-mediated food allergies, although safety issues must be considered2. The main aim of immunotherapy is to induce tolerance or desensitization to an allergen which otherwise causes an allergic reaction. For oral immunotherapy this means ingesting the allergen in a controlled manner with gradually increasing dosages. Specifically, peanut oral immunotherapy (pOIT) is able to induce tolerance/desensitization3. While the pathogenesis of food allergy in general is relatively well-studied4, mechanisms of OIT-induced tolerance are not well understood. Omalizumab (anti-IgE) used as treatment for severe allergic asthma and other IgE-driven allergies, can facilitate OIT initiation5, however, little is known about the involved mechanisms, including possible changes at the transcriptional level. We therefore investigated transcriptional changes in whole blood using RNA-sequencing profiles during omalizumab treatment and pOIT in participants from the FASTX (Food Allergen Suppression Therapy with Xolair ®) study previously described in detail elsewhere5.In brief, peanut-allergic adolescents (n=23 of whom 17 completed the study, age 12-18 years) were started on omalizumab (baseline) and treated for at least 8 weeks before starting pOIT (pOIT start) while on omalizumab. The peanut-dose was gradually increased during the 8 weeks until reaching a maintenance dose. Guided by a basophil activation test (BAT/CD-sens)6 after 8 weeks on the maintenance dose, participants decreased the omalizumab dose by 50% (maintenance) and continued to decrease the omalizumab dose if pOIT was tolerated. Eleven patients were able to tolerate pOIT without omalizumab protection for >8 weeks and then passed an open peanut food challenge (final); 6 patients could not discontinue omalizumab, but blood samples were obtained for analysis after 2-3 years of omalizumab treatment (final); 6 patients dropped out of the study. RNA-sequencing was performed on whole blood at baseline, pOIT start, maintenance and final time-points using the NovaSeq 6000 platform. DESeq2 was used for differential expression analysis of the omalizumab effect and a linear mixed-effect model for analyses during pOIT in combination with omalizumab (pOIT+O) after adjustment for treatment outcome and cell type. A complete description of the treatment protocol and method is given in Appendix S1.General characteristics of the study participants at baseline can be found in Table S1 . To elucidate if omalizumab treatment alone induced alterations in peripheral blood gene expression, we investigated the two first timepoints, baseline and pOIT start, however no significant differences were observed (Figure S1 ). In the longitudinal analysis (pOIT start to final), 680 genes associated with pOIT+O at nominal p <0.005 (Table S2 ). The Gene Ontology (GO) biological process of the up- and down-regulation of these 680 genes are presented in Figure 1A,B . Upregulation of 337 genes were linked to GO terms “protein regulation and modification”, while “neutrophil degranulation, immune response, phagocytosis, and metabolic process” were among the top terms for the downregulated 343 genes. Out of the 680 genes, 16 were differentially expressed at false discovery rate (FDR) adjusted p<0.05 (Table 1, Figure S2 ). The three genes with the largest negative and positive coefficients, respectively, are displayed in Figure 1C,D ; downregulation of ASGR2 ,GPBAR1 and HM13, and upregulation of USP44 ,ICOS and CDKN2AIP . Finally, we evaluated the enrichment of 680 pOIT+O-associated genes, relative to peripheral blood gene expression associated with acute peanut allergic reactions in a recently published clinical study by Watson et al using the same p-value cut-off (p<0.005)7. Out of our 680 significant genes, 108 genes overlapped with the differentially expressed genes in Watson et al7, mostly with opposite direction, Penrichment = 0.0095 (Figure 2 ).Our results demonstrate that omalizumab treatment alone does not induce alterations in whole blood gene expression in patients with severe food allergy. This is not surprising given that these patients were unexposed to peanut allergen at the time of blood sampling, and any concomitant asthma, rhinitis or eczema were well controlled. However, the longitudinal analysis during pOIT+O identified up- and downregulation of several immune-related genes. CD278/ICOS (Inducible T-cell costimulatory) is expressed on activated T-cells and appears to play a role in directing effector T-cell differentiation and responses during inflammatory conditions8. ICOS-expression on T regulatory cells and T follicular helper cells may be involved in the allergic disease mechanism9. In the pathway analyses, we observed significant enrichment for several GO biological process terms related to T-cell function and immune responses. Notably, we have previously described alterations in T-cell polyclonal in vitroactivation during pOIT +O in the FASTX study10. Comparing our findings with data described by Watson et al7 , suggests that pOIT+O may alter the expression level of many genes that were found activated during an acute peanut allergy reaction.The main limitations of this study are lack of any control subjects and small sample size. Moreover, further studies are needed to evaluate the long-term biological effect of pOIT+O.In conclusion, omalizumab treatment alone does not alter the transcriptional signature in peripheral blood of peanut allergic patients, but during pOIT+O, several immune-related signatures were observed. These results may provide insights into mechanisms of allergen tolerance.

A document by Natasha Correa. Click on the document to view its contents.

Conflict of interestThe authors declare no conflicts of interest.

Background: Anaphylaxis is a significant health burden in most Western countries but there is little published data on the incidence and pattern of anaphylaxis in Asia. We aim to determine the incidence rate and pattern of anaphylaxis over the past decade among the paediatric population in Hong Kong. Methods: Medical records of patients presenting with allergy-related symptoms during the period 2010 to 2019 were examined. Paediatric patients aged below 18 years who fulfilled the diagnostic criteria for anaphylaxis laid out by the NIAID/FAAN were analysed. Incidence rates were calculated using population statistics as the denominator. All information pertaining to the anaphylaxis events and patients’ characteristics were retrieved using standardized data collection forms. Results: The overall 10-year estimated incidence of anaphylaxis was 7.70 per 100,000 person-years, with a rising trend of anaphylaxis incidence across time. Food-induced anaphylaxis accounted for the majority of hospital presentation, of which peanut and shellfish were the top food triggers in our population. Comorbid asthma and young age were risk factors associated with wheeze at presentation. Misdiagnosis of anaphylaxis occurred in up to half the anaphylaxis cases and adrenaline was only utilised in 45% of cases. Conclusions: An increasing trend of anaphylaxis incidence over the past decade is evident in Hong Kong children, with a discrepantly low accuracy in diagnosis and suboptimal management of anaphylaxis. There is a pressing need to heighten public and physicians’ awareness of the distinctive features of anaphylaxis in the paediatric age group.

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.