Impact of newborn screening for SCID on the management of congenital athymia.

BACKGROUND: Newborn screening (NBS) programs for severe combined immunodeficiency facilitate early diagnosis of severe combined immunodeficiency and promote early treatment with hematopoietic stem cell transplantation, resulting in improved clinical outcomes. Infants with congenital athymia are also identified through NBS because of severe T-cell lymphopenia. With the expanding introduction of NBS programs, referrals of athymic patients for treatment with thymus transplantation have recently increased at Great Ormond Street Hospital (GOSH) (London, United Kingdom). OBJECTIVE: We studied the impact of NBS on timely diagnosis and treatment of athymic infants with thymus transplantation at GOSH. METHODS: We compared age at referral and complications between athymic infants diagnosed after clinical presentation (n = 25) and infants identified through NBS (n = 19) who were referred for thymus transplantation at GOSH between October 2019 and February 2023. We assessed whether age at time of treatment influences thymic output at 6 and 12 months after transplantation. RESULTS: The infants referred after identification through NBS were significantly younger and had fewer complications, in particular fewer infections. All deaths occurred in the group of those who did not undergo NBS, including 6 patients before and 2 after thymus transplantation because of preexisting infections. In the absence of significant comorbidities or diagnostic uncertainties, timely treatment was achieved more frequently after NBS. Treatment when younger than age 4 months was associated with higher thymic output at 6 and 12 months after transplantation. CONCLUSION: NBS contributes to earlier recognition of congenital athymia, promoting referral of athymic patients for thymus transplantation before they acquire infections or other complications and facilitating treatment at a younger age, thus playing an important role in improving their outcomes.

Infliximab Reverses Symptoms and May Protect from Developing Chronic Restrictive Ophthalmopathy in Children with Familial Orbital Myositis: A Case Report.

BACKGROUND: Orbital myositis is a rare sporadic eye disease associated with extraocular eye muscle inflammation. To date, there have been two reports of familial orbital myositis (FOM), which demonstrate partially penetrant autosomal dominant inheritance. CASES: We report six new Australian cases of FOM, four of whom extend one of the reported pedigrees, as well as a separate mother and daughter manifesting orbital myositis, which constitutes a third report of familial occurrence. We can confirm that the disease has onset in childhood, appearing to go into remission in adult life, and that the inflammation is corticosteroid-responsive. However, one patient went on to develop permanent diplopia in upgaze. We also report two children suffering chronic pain and diplopia who demonstrated complete resolution of symptoms with the anti-TNF-α monoclonal infliximab. CONCLUSION: Uncontrolled FOM in childhood may result in permanent extraocular eye muscle damage, while TNF-α blockade provides an excellent steroid-sparing effect.

Standardized testing and written communication improve patient understanding of beta-lactam allergy testing outcomes: A multicenter, prospective study.

Background: Historical penicillin allergy is commonly reported, but the lack of standardized allergy clinic practices may diminish the ability to delabel beta-lactam allergy appropriately. Objective: We sought to improve beta-lactam allergy testing and patient understanding of their antibiotic allergy status by standardizing testing and communication practices between 7 adult and pediatric hospital centers. Methods: Phase 1 prospectively described the beta-lactam allergy testing practices at each center. Following this, practice was standardized to achieve a defined panel of skin testing reagents, pro forma result letters for patients and referring doctors, and provision of medical alert jewelry to those with confirmed allergy. Testing outcomes and patient perception regarding allergy status 8 weeks postassessment were compared before (phase 1) and after standardization (phase 2). Primary outcomes were the percentage of participants delabeled after testing, and concordance rates between participant perception of their allergy status and their status as determined by the treating physician at 8-week follow-up. Results: Of 195 adult and pediatric participants (median age, 50 years; 21.5% <18 years; 36.9% males), 75% were delabeled of their beta-lactam allergy. No patient experienced anaphylaxis related to any beta-lactam delabeling testing. In phase 1, 75% of participants received written results, 52% were informed verbally, and 48% received results in more than 1 form. All phase 2 participants received written results (P < .01), 61% received verbal results from a physician as well (P > .05). At 8-week follow-up, 54% of phase 1 participants had concordant perceptions of their allergy status as the testing team versus 91.6% in phase2 (P < .001). Of the 17 participants who were delabeled and treated with a beta-lactam antibiotic during the 8-week follow-up period, there were no reported allergic reactions, although 1 participant experienced anaphylaxis following exposure to amoxicillin-clavulanic acid 1 year after delabeling. Conclusions: Standardization of testing and written patient information improved short-term patient perception of beta-lactam allergy status.

Factors influencing reintroduction of peanut and tree nuts after negative oral food challenges in children.

BACKGROUND: Compliance with reintroduction of foods after a negative oral food challenge (OFC) is variable. Ongoing avoidance of tolerated foods is associated with recurrence of allergy and a reduced quality of life. OBJECTIVE: To determine the proportion of children who reintroduced peanut or tree nuts after a negative OFC and to describe factors that influenced decisions regarding reintroduction or avoidance of nonallergic (negative) nuts. METHODS: Families of children that had undergone an OFC for peanut or tree nuts at Sydney Children's Hospital were invited to participate. Consenting families were sent an online questionnaire. RESULTS: The response rate to the questionnaire was 64%. More than 85% of respondents had introduced all or some of the negative nuts after the OFC and most had maintained at least some regular exposure in the child's diet at the time of the study. The age at diagnosis of the nut allergy and an awareness of the benefit of introducing foods after a negative OFC were significantly (P < .05) associated with introducing negative nuts. There was improved quality of life in those that introduced negative nuts. CONCLUSION: Most families introduced or attempted to introduce negative nuts after a negative OFC. Educating families on the benefits of introducing foods after a negative OFC result is an important factor contributing to successful reintroduction.

Added Diagnostic Value of Peanut Component Testing: A Cross-Sectional Study in Australian Children.

BACKGROUND: Peanut components are widely used in clinical practice; however, their utility to predict challenge outcome in the Australian children, outside of infants, is not well studied. OBJECTIVE: Can peanut component testing predict outcome of challenge in peanut-allergic children. METHODS: All children attending peanut challenges, regardless of previous allergic reactions to peanut or sensitization (skin prick test or peanut IgE) alone, were recruited. Serum collected before the challenge was analyzed for peanut IgE and Ara h 1, 2, 3, 6, 8, and 9 (ImmunoCap). RESULTS: Of the 222 children recruited, 89 (40%) were allergic on oral food challenge. Ara h 2 and 6 performed similarly to peanut IgE and skin prick test in predicting challenge outcome (area under the curve, 0.84-0.87). No baseline clinical characteristics, including past history, predicted challenge outcome. By logistic regression, degree of polysensitization to Ara h 1, 2, or 3 increased the odds of allergic reaction at oral food challenge at 0.35 and 1.0 kUA/L cutoff levels (P < .001 for both). All 11 children sensitized (>0.35 kUA/L) to Ara h 1, 2, and 3 reacted to peanut challenge. Degree of polysensitization at more than 1.0 kUA/L was associated with a lower cumulative eliciting dose (P = .016) and with severity of allergic reaction on challenge (P = .007). CONCLUSIONS: In our cohort, sensitization to the combination of Ara h 1, 2, and 3 was highly predictive of peanut allergy. Overall, only Ara h 2 as individual component most correlated with severity of reaction at challenge and adrenaline use. Ara h 8 and 9 were not useful in predicting challenge outcome.

Skin testing with ultra-heat-treated (UHT) cow's milk in children with cow's milk allergy.

BACKGROUND: A large proportion of cow's milk (CM)-allergic children are able to tolerate extensively heated forms of CM such as baked goods. Little is known about whether ultra-heat-treated (UHT) forms of cow's milk are immunologically similar to extensively heated cow's milk and therefore may be tolerated by these children. OBJECTIVE: To determine whether skin test wheal size using UHT CM was significantly different from other forms of CM and CM extracts. METHODS: Children presenting for oral food challenges with either extensively heated or unheated cow's milk underwent skin prick test (SPT) to commercial CM, UHT CM, evaporated CM, and fresh whole CM. The results were compared between groups of children. RESULTS: At study exit, only 14% of children were avoiding all forms of CM, compared with 70% at study entry. No difference was seen in the mean SPT results for UHT CM between those children that could tolerate heated CM compared with those that could not. The mean SPT result for casein was significantly lower in those that could tolerate heated CM. However, within the group of heated milk-tolerant children, the mean SPT for UHT CM was significantly lower than the SPT for fresh whole CM. CONCLUSION: Ultra-heat-treated CM does not behave significantly differently from other forms of CM when evaluated by SPT in heated milk-allergic vs heated milk-tolerant children. This suggests that UHT CM is not sufficiently immunologically different from unheated CM to be tolerated by heated CM-tolerant children.

A Mutation Outside the Dimerization Domain Causing Atypical STING-Associated Vasculopathy With Onset in Infancy.

BACKGROUND: Mutations in the gene encoding stimulator of interferon genes (STING) underlie a type I interferon (IFN) associated disease, STING-associated vasculopathy with onset in infancy (SAVI). Patients suffer cutaneous vasculopathy and interstitial lung disease, but are not known to suffer life-threatening infection. CASE: We describe a child who presented with Pneumocystis jirovecii pneumonia in early life, from which he recovered. He went on to suffer failure to thrive, developmental delay, livedo reticularis, and vesicular rash, but without cutaneous vasculitis, and with normal C-reactive protein and erythrocyte sedimentation rates. At 3 years of age, he developed life-threatening pulmonary hypertension. METHODS: Whole genome sequencing (WGS) was performed using the Illumina HiSeqX10 platform and the Seave platform was used for bioinformatic analysis. mRNA expression of IFN-stimulated genes and inflammatory cytokines from peripheral blood mononuclear cells was determined by quantitative polymerase chain reaction. Luciferase assay was used to model IFNß and NF-κB activity in vitro. RESULTS: WGS revealed a de novo mutation p.Arg284Ser in STING at an amino acid previously associated with SAVI. Although this mutation did not fall in the dimerization domain (DD), mRNA analysis revealed constitutive IFN-gene activation consistent with an interferonopathy, which correlated to STING activation in vitro. The patient was treated with corticosteroids and the JAK inhibitor Ruxolitinib, resulting in a rapid improvement of pulmonary hypertension, general well-being, and resolution of the IFN gene signature. However, he did go on to evolve a nasal septal erosion suggesting incomplete control of disease. CONCLUSION: This case provides molecular evidence to support the p.Arg284Ser variant in STING exerting pathogenicity through a gain-of-function mechanism. The lack of cutaneous vasculitis or elevated systemic inflammatory markers, and the occurrence of an opportunistic infection are notable, and raise the possibility that variants outside the STING DD may potentially manifest with an atypical SAVI phenotype. Nevertheless, there was an objective clinical improvement in response to JAK inhibition.

Bullying in Australian children and adolescents with food allergies.

BACKGROUND: Food allergy is an increasing concern worldwide. The significant impact of food allergies on quality of life and bullying has been well described in international studies. No studies have yet investigated the occurrence of bullying in children and adolescents with food allergies in the Australian population. This study aimed to characterize and examine the frequency of bullying and describe those most responsible and the effects of the bullying on the victims. METHODS: Questionnaires were developed based on those used in previous studies and were distributed throughout paediatric allergy clinics. Children and adolescents aged 10-19 with food allergies were recruited to complete the questionnaire independently, whilst parents completed the questionnaire on behalf of their children aged 5-9 with food allergies. The data were tabulated and analysed using descriptive statistics. RESULTS: Ninety-three questionnaires were completed. Overall, 39 (42%) children experienced some form of bullying. This was higher in the older children and adolescent group, where 53% (18/34) were bullied. In addition, 23% (21/93) of the cohort were bullied or teased specifically because of their allergy. Food allergens had been used in the bullying in 24 cases, but no child reported being forced to eat foods to which they were allergic. Two adolescents experienced allergic reactions. CONCLUSIONS: This study highlights that those with food allergy are subject to a high degree of bullying. This risk of bullying for children with food allergy indicates a significant social problem that requires addressing to positively assist these children.

Haematopoietic stem cell transplantation for primary immunodeficiency syndromes: A 5-year single-centre experience.

AIM: Haematopoietic stem cell transplantation (HSCT) is a central therapy in the treatment of primary immunodeficiency diseases (PIDs). Over the past 5 years, outcomes have been greatly improved due to earlier diagnosis, improved donor availability, advancements in graft manipulation and the use of less toxic preparative regimens. We present a 5-year audit of HSCT for PID at a single Australian tertiary hospital. METHODS: Retrospective case note review identified diagnosis, pre-transplant medical morbidity, transplant protocol, engraftment, adverse events, post-transplant immune reconstitution and general health. RESULTS: A total of 22 patients with PID underwent 24 HSCTs at our institution between 2012 and 2016. The most common indications were severe combined immunodeficiency, chronic granulomatous disease and familial haemophagocytic lymphohistiocytosis, with a genetic diagnosis in all but two patients. Reduced intensity or reduced toxicity conditioning was used in 91% of cases, and 75% of the donors were unrelated. Transplant-related mortality at day +100 was 9.5%, and cumulative overall survival was 86%. There were three mortalities, all secondary to viral infection, one of which occurred in the context of graft failure. Two patients remained on immune support, with the remainder achieving adequate immune reconstitution. CONCLUSIONS: The outcomes for HSCT for PIDs performed at Sydney Children's Hospital were in line with the world's best practice. HSCT should be considered a potential therapeutic option for all Australian PID patients with a valid disease indication.

Bullying and quality of life in children and adolescents with food allergy.

Food allergy is an increasing phenomenon in Australia, with most recent reports of food allergy occurring in 1 in 12 children. A number of studies have demonstrated that children and adolescents with food allergies experience a decreased quality of life across a number of domains. More recent evidence suggests that this population also experiences an increased occurrence of bullying compared to similar school-aged children. Some individuals have reported being bullied because of their allergies, whilst others have reported specific allergy-related-bullying, such as being touched with foods that they are allergic to or having their food being intentionally contaminated with an allergen. Where there may be a risk of severe anaphylaxis, this is of great concern. This article reviews the current literature on bullying in populations of children and adolescents with food allergies. Several papers worldwide have investigated this, providing evidence of its occurrence in North America, Canada, Italy and Japan.

Repeat oral food challenges in peanut and tree nut allergic children with a history of mild/moderate reactions.

BACKGROUND: In peanut and tree nut allergic children a history of anaphylaxis is associated with subsequent severe reactions. OBJECTIVE: We aimed to prospectively rechallenge peanut and tree nut allergic children with a history of mild/moderate reactions to assess their allergy over time. METHODS: In this cohort study peanut and tree nut allergic children with a history of mild/moderate reactions during a controlled oral challenge were invited to have a follow-up oral challenge to the same food at least 1 year later. RESULTS: Twenty-six children participated in the study. The mean time interval between the first and second challenge for all participants was 35.5 months. Peanut or tree nut allergy resolved in 38.5% of participants. Those with persistent peanut or tree nut allergy showed a decrease in their reaction threshold and/or increased severity in 81% of cases. There were no demographic features or skin test results that were predictive of changes in severity over time. CONCLUSION: Peanut and tree nut allergic children with a history of mild/moderate reactions who remained allergic demonstrated a high rate of more severe reactions and/or reduced thresholds upon rechallenge over a year later, however, the rate of resolution of allergy in this group may be higher than previously reported.

Refractory otitis media: an unusual presentation of childhood granulomatosis with polyangiitis.

Childhood granulomatosis with polyangiitis (cGPA), previously known as Wegener's granulomatosis, is a rare, potentially fatal necrotizing vasculitis, the symptoms of which overlap with infection. We present a 16-year-old girl who, following 6 months of treatment for persistent middle ear effusion with progressive sensorineural hearing loss, developed rapidly progressing pneumonia, with pleural effusion, and multiple cavitatory lung lesions. Investigations demonstrated high titer c-ANCA and nasal septal biopsy confirmed the diagnosis of cGPA. This case highlights the difficulty in diagnosing cGPA and the potentially life-threatening consequences of failing to do so.

Salicylate elimination diets in children: is food restriction supported by the evidence?

A review of case notes from our Sydney-based paediatric allergy services, between 1 January 2003 and 31 December 2011, identified 74 children who had been prescribed diets that eliminated foods containing natural salicylates before attending our clinics. The most common indications for starting the diets were eczema (34/74) and behavioural disturbances (17/74) including attention deficit hyperactivity disorder (ADHD). We could find no peer-reviewed evidence to support the efficacy of salicylate elimination diets in managing these diseases. We do not prescribe these diets, and in a survey of European and North American food allergy experts, only 1/23 respondents used a similar diet for eczema, with none of the respondents using salicylate elimination to treat ADHD. A high proportion (31/66) of children suffered adverse outcomes, including nutritional deficiencies and food aversion, with four children developing eating disorders. We could find no published evidence to support the safety of these diets in children. While this uncontrolled study does not prove a causal relationship between salicylate elimination diets and harm, the frequency of adverse events appears high, and in the absence of evidence of safety or efficacy, we cannot recommend the use of these diets in children.

Clinical, molecular, and cellular immunologic findings in patients with SP110-associated veno-occlusive disease with immunodeficiency syndrome.

BACKGROUND: Mutations in the SP110 gene result in infantile onset of the autosomal recessive primary immunodeficiency disease veno-occlusive disease with immunodeficiency syndrome (VODI), which is characterized by hypogammaglobulinemia, T-cell dysfunction, and a high frequency of hepatic veno-occlusive disease. OBJECTIVES: We sought to further characterize the clinical features, B-lineage cellular immunologic findings, and molecular pathogenesis of this disorder in 9 patients with new diagnoses, including 4 novel mutations from families of Italian, Hispanic, and Arabic ethnic origin. METHODS: Methods used include clinical review; Sanger DNA sequencing of the SP110 gene; determination of transfected mutant protein function by using immunofluorescent studies in Hep-2 cells; quantitation of B-cell subsets by means of flow cytometry; assessments of B-cell function after stimulation with CD40 ligand, IL-21, or both; and differential gene expression array studies of EBV-transformed B cells. RESULTS: We confirm the major diagnostic criteria and the clinical utility of SP110 mutation testing for the diagnosis of VODI. Analysis of 4 new alleles confirms that VODI is caused by reduced functional SP110 protein levels. Detailed B-cell immunophenotyping demonstrated that Sp110 deficiency compromises the ability of human B cells to respond to T cell-dependent stimuli and differentiate into immunoglobulin-secreting cells in vitro. Expression microarray studies have identified pathways involved in B-lymphocyte differentiation and macrophage function. CONCLUSION: These studies show that a range of mutations in SP110 that cause decreased SP110 protein levels and impaired late B-cell differentiation cause VODI and that the condition is not restricted to the Lebanese population.

Parental satisfaction with oral peanut food challenges; perception of outcomes and impact on management of peanut allergy.

Oral peanut food challenges (OPFC) are the 'gold standard' for diagnosing peanut allergy in children. However, there are few data on parental perception of such challenges. We aimed to investigate the parental experience of and satisfaction with OPFC and reported dietary management of children with a history of peanut allergy following OPFC. Telephone interviews were conducted with parents of children who had undergone an open-label OPFC at a specialist paediatric allergy centre. Forty-six of 76 eligible parents participated. Of those parents, 54% were very satisfied with the OPFC. The highest levels of satisfaction were reported in relation to (i) clarification of the severity of the child's peanut allergy (ii) the support provided by staff and (iii) determining the child was tolerant of peanut or assessed to be at low risk of anaphylaxis from accidental peanut exposure. When the outcome of the challenge was perceived to be equivocal, levels of parental satisfaction were lower. Other areas of dissatisfaction included difficulties inducing peanut ingestion, parental distress at seeing their child unwell and perception of inadequate follow-up. Ninety-four per cent of parents could not remember the amount of peanut ingested, and 24% could not remember whether management advice was given after the OPFC or reported that none was given. Reported compliance with recalled advice to avoid peanut was found in all cases but one, whilst recalled advice to reintroduce peanuts following a negative challenge was followed in 5/9 cases. Although 12 parents reported that their child had an allergic reaction caused by accidental exposure to peanut since the OPFC, only four were certain peanut was the cause. Comprehensive education, counselling and follow-up subsequent to an OPFC are required. Parents of children whose challenge outcome is inconclusive should be targeted for support.

Prediction of anaphylaxis during peanut food challenge: usefulness of the peanut skin prick test (SPT) and specific IgE level.

Cutoffs (decision points) of the peanut skin prick test (SPT) and specific IgE level for predicting peanut allergy have been proposed. It is not known whether decision points indicating a significant risk of severe reactions on challenge differ from those indicating probable allergy. We aimed at determining the usefulness of allergy tests for predicting the risk of anaphylaxis on challenge following the ingestion of up to 12 g of peanut in peanut-sensitized children. Children attending the Allergy Clinic who had a positive peanut SPT and completed open-label in-hospital peanut challenges were included. The challenge protocol provided for challenges to be continued beyond initial mild reactions. Eighty-nine in-hospital peanut challenges were performed. Thirty-four were excluded as the challenge was not completed, leaving 55 for analysis. Children who completed the challenge and did not react (n = 28) or reacted without anaphylaxis (n = 6) represented the comparison group (n = 34). The study group comprised 21 children whose challenge resulted in anaphylaxis. The mean peanut SPT wheal size and specific IgE level were associated with the severity of reactions on challenge. Among the 21 children, who developed anaphylaxis, in only 3 cases was anaphylaxis the initial reaction. Unexpectedly, a history of anaphylaxis was not predictive of anaphylaxis on challenge. Anaphylaxis developed at cumulative doses of peanut ranging from 0.02 to 11.7 g. Provided that a fixed amount of peanut is ingested, available tests for peanut allergy may assist in predicting the risk of anaphylaxis during challenge in peanut-sensitized children.

Insulin allergy desensitization with simultaneous intravenous insulin and continuous subcutaneous insulin infusion.

Persistent 'IgE-mediated' insulin allergy (type 1 allergy) (1), unresponsive to changes in insulin type or the use of antihistamines, necessitates desensitization. A number of case reports (2-7) and recent reviews (8, 9) have demonstrated that desensitization can be achieved with continuous subcutaneous insulin infusion (CSII), but in type 1 diabetes mellitus, the need to slowly increase insulin dose from sub-therapeutic levels competes with the need for glycaemic control and suppression of ketogenesis. Tolerance to intravenous (IV) insulin despite persistent life-threatening allergic reactions to subcutaneous human insulin (bolus or CSII) has been recently described (10). We present the cases of two unrelated 9-yr-old boys with persistent generalized urticarial reactions to subcutaneous injections of all available insulin types, despite treatment with oral antihistamines. After failed rapid desensitization to insulin delivered by either subcutaneous injection or CSII, the concurrent use of IV insulin allowed desensitization to CSII over 5-6 d.

Rituximab for lymphoproliferative disease prior to haematopoietic stem cell transplantation for X-linked severe combined immunodeficiency.

Lymphoproliferative disease (LPD) is a complication of congenital and acquired immunodeficiency states. There are a number of treatment options for LPD arising after haematopoietic stem cell or solid organ transplantation including reduction of immunosuppression, targeted therapies, such as the anti-CD20 monoclonal antibody, rituximab, and EBV specific cytotoxic lymphocytes. Treatment of LPD in children with congenital immunodeficiency syndromes remains unsatisfactory and is associated with a high mortality rate. We recently managed an infant found to have polymorphic LPD concurrent with X-linked severe combined immunodeficiency (SCID). Haematopoietic stem cell transplantation (HSCT) had to be deferred because of progressive LPD. Treatment with rituximab resulted in regression of the LPD following which the patient received a 5/6 HLA matched umbilical cord blood (UCB) transplant. The patient remains well 20 months following transplantation. Rituximab treatment may have a useful role in the control of LPD associated with congenital immunodeficiency prior to HSCT.