Allergic manifestations of inborn errors of immunity and their impact on the diagnosis: A worldwide study.

Background: Allergies have long been observed in Inborn Errors of Immunity (IEI) and might even be the first presentation resulting in delayed diagnosis or misdiagnosis in some cases. However, data on the prevalence of allergic diseases among IEI patients are limited and contradictory. Objective: To provide a worldwide view of allergic diseases, across a broad spectrum of IEI, and their impact on the timely diagnosis of IEI. Methods: This is a worldwide study, conceived by the World Allergy Organization (WAO) Inborn Errors of Immunity Committee. A questionnaire was developed and pilot-tested and was sent via email to collect data from 61 immunology centers known to treat pediatric and/or adult IEI patients in 41 countries. In addition, a query was submitted to The United States Immunodeficiency Network (USIDNET) at its website. Results: Thirty centers in 23 countries caring for a total 8450 IEI patients responded. The USIDNET dataset included 2332 patients. Data from responders showed that a median (IQR) of 16.3% (10-28.8%) of patients experienced allergic diseases during the course of their IEI as follows: 3.6% (1.3-11.3%) had bronchial asthma, 3.6% (1.9-9.1%) atopic dermatitis, 3.0% (1.0-7.8%) allergic rhinitis, and 1.3% (0.5-3.3%) food allergy. As per the USIDNET data, the frequency of allergy among IEI patients was 68.8% (bronchial asthma in 46.9%). The percentage of IEI patients who presented initially with allergic disorders was 8% (5-25%) and diagnosis delay was reported in 7.5% (0.9-20.6%). Predominantly antibody deficiencies had the highest frequency of allergic disease followed by combined immunodeficiency with a frequency of 40.3% (19.2-62.5%) and 20.0% (10-32%) respectively. As per the data of centers, anaphylaxis occurred in 25/8450 patients (0.3%) whereas per USIDNET dataset, it occurred in 249/2332 (10.6%); drugs and food allergy were the main causes in both datasets. Conclusions: This multinational study brings to focus the relation between allergic diseases and IEI. Major allergies do occur in IEI patients but were less frequent than the general population. Initial presentation with allergy could adversely affect the timely diagnosis of IEI. There is a need for policies to raise awareness and educate primary care and other referring specialties on the association of allergic diseases with IEI. This study provides a network among centers for future prospective studies in the field.

The "Golden Hours" Algorithm For the Management of the Multisystem Inflammatory Syndrome in Children (MIS-C).

The global concern of increasing number of children presenting with multisystem inflammatory syndrome in children (MIS-C) related to the coronavirus disease (COVID-19) has escalated the need for a case-oriented clinical approach that provides timely diagnosis and management. The aim of this study is to share our experience in managing 64 MIS-C patients of North African ethnicity guided by a risk-based algorithm. Sixty-four patients met the inclusion criteria, 19 (30%) patients were categorized as mild and moderate risk groups and cared for in an isolation ward and 45 patients who belonged to the high-risk group (70%) were admitted to the pediatric intensive care unit (PICU). Positive laboratory evidence of COVID-19 was found in 62 patients. Fever and dysfunction in 2 or more organs were confirmed in all cases (100%). Fifty patients (78%) presented with gastrointestinal symptoms, meanwhile only 10 patients (16%) had respiratory manifestations. Cardiac involvement was reported in 55 (86%) cases; hypotension and shock were found in 45 patients (70%) therein circulatory support and mechanical ventilations were needed for 45 and 13 patients respectively. Intravenous immunoglobulins (IVIG) were used for all cases and methylprednisolone was used in 60 patients (94%). Fifty-eight (91%) patients were discharged home after an average of 9 days of hospitalization. The mortality rate was 9% (6 patients). Conclusion. A single Egyptian center experience in the management of MIS-C patients guided by a proposed bed side algorithm is described. The algorithm proved to be a helpful tool for first-line responders, and helped initiate early treatment with IVIG.

Breast milk interleukin-7 and thymic gland development in infancy.

PURPOSE: Interleukin-7 (IL-7) is known to be important for lymphocyte development. We sought to investigate the maternal breast milk IL-7 expression to explore its impact on thymus development in infants. METHODS: We conducted a prospective study on three groups of healthy infants classified into exclusively breast-fed (n = 19), formula-fed (n = 17) and mixed-fed (n = 19) infants. They were investigated at 2, 4 and 6 months of age for thymic indices by ultrasonography, T lymphocyte subsets enumeration by flowcytometry and breast milk IL-7 levels. RESULTS: Thymic indices were higher at the age of 2 and 6 months in the exclusively breast-fed infants (mean ± SD 22.4 ± 2.1, 26.2 ± 2.7 mm3, respectively) and mixed-fed infants (mean ± SD 22 ± 3.2, 25 ± 3.2, respectively) as compared to formula-fed infants (mean ± SD 17.9 ± 3.7, 21.6 ± 3.9 respectively); p < 0.001. In the exclusively breast-fed infants, IL-7 levels correlated positively to thymic indices and CD3+ T cell numbers at 2 months of age. Positive correlations were elicited in the mixed-fed group at 2, 4 and 6 months of age for thymic indices and at 6 months for CD3+ cells. CONCLUSION: Breast milk and/or its IL-7 content have a significant positive impact on thymic development. Our conclusions are limited by the sample size and short duration of follow-up. What is known is that breast milk has a trophic role in thymic development and contains IL-7. What is new is that there is positive correlation between breast milk IL-7 concentration and thymic development and lymphocyte output; variation of IL-7 levels with type of feeding (exclusive breast feeding/mixed breast and formula feeding) and with time postnatally.

Vitamin D Increases Percentages of Interleukin-10 Secreting Regulatory T Cells in Children with Cow's Milk Allergy.

Cow's milk allergy (CMA) is known to be either IgE- or non-IgE mediated. Regulatory T (Treg) cell defect is involved in the pathogenesis of both types. Vitamin D has been suggested to improve the generation of allergen-specific Treg cell populations with the potential to provide safe and long-term alleviation of disease symptoms. This study aimed to assess Vitamin D status in children with physician-diagnosed CMA and to investigate the effect of in vitro cultivation with Vitamin D on the percentage of antigen-driven CD4+CD25highFoxp3+IL10+ Treg cells following in vitro stimulation of cells with cow's milk allergen in culture. This cross-sectional study included 20 children with CMA and 20 healthy age and sex-matched children as a control group. All patients were subjected to clinical evaluation, cow's milk skin prick test (SPT), cow's milk elimination and oral re-challenge test in patients with negative cow's milk SPT and in those with gastrointestinal presentation, measurement of serum Vitamin D level and assessment of the percentage of antigen-driven CD4+CD25highFoxp3+IL10+ Treg cells in response to stimulation with cow's milk allergen extract with and without Vitamin D in culture. Vitamin D deficiency was detected in 80% of children with CMA. Percentage of Foxp3+ and IL10+ co-expression on Treg cells was significantly increased after stimulation with cow's milk allergen extract in the presence of Vitamin D. A significant positive correlation was observed between serum Vitamin D level and percentage of antigen-driven CD4+CD25highFoxp3+IL10+ Treg cells as well as level of Foxp3+ and IL10+ co-expression on Treg cells at baseline (control cultures without stimulation) and after PBMCs stimulation with cow's milk allergen extract in the presence of Vitamin D. Re-stimulation with cow's milk allergen extract was performed in vitro in order to evaluate milk-induced immune stimulation and regulation. In conclusion, patients with CMA whether IgE- or non-IgE mediated had Vitamin D deficiency with a decreased number of CD4+CD25highFoxp3+IL10+ Treg cells which increased after in vitro addition of Vitamin D with increased Foxp3 and IL10 co-expression.

Characterization of T and B cell repertoire diversity in patients with RAG deficiency.

Recombination-activating genes 1 and 2 (RAG1 and RAG2) play a critical role in T and B cell development by initiating the recombination process that controls the expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the RAG1 and RAG2 genes in humans cause a broad spectrum of phenotypes, including severe combined immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (BCR) repertoire in 12 patients with RAG mutations presenting with Omenn syndrome (n = 5), leaky SCID (n = 3), or CID-G/AI (n = 4). Restriction of repertoire diversity skewed usage of variable (V), diversity (D), and joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V, D, and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework to better understand the phenotypic heterogeneity of RAG deficiency.

Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.

Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.

A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency.

BACKGROUND: The recombination-activating gene (RAG) 1/2 proteins play a critical role in the development of T and B cells by initiating the VDJ recombination process that leads to generation of a broad T-cell receptor (TCR) and B-cell receptor repertoire. Pathogenic mutations in the RAG1/2 genes result in various forms of primary immunodeficiency, ranging from T(-)B(-) severe combined immune deficiency to delayed-onset disease with granuloma formation, autoimmunity, or both. It is not clear what contributes to such heterogeneity of phenotypes. OBJECTIVE: We sought to investigate the molecular basis for phenotypic diversity presented in patients with various RAG1 mutations. METHODS: We have developed a flow cytometry-based assay that allows analysis of RAG recombination activity based on green fluorescent protein expression and have assessed the induction of the Ighc locus rearrangements in mouse Rag1(-/-) pro-B cells reconstituted with wild-type or mutant human RAG1 (hRAG1) using deep sequencing technology. RESULTS: Here we demonstrate correlation between defective recombination activity of hRAG1 mutant proteins and severity of the clinical and immunologic phenotype and provide insights on the molecular mechanisms accounting for such phenotypic diversity. CONCLUSIONS: Using a sensitive assay to measure the RAG1 activity level of 79 mutations in a physiologic setting, we demonstrate correlation between recombination activity of RAG1 mutants and the severity of clinical presentation and show that RAG1 mutants can induce specific abnormalities of the VDJ recombination process.

Evaluation of banana hypersensitivity among a group of atopic egyptian children: relation to parental/self reports.

PURPOSE: To evaluate the frequency of banana sensitization and allergy among a group of atopic Egyptian children in relation to parental/self reports. METHODS: This is a case-control study included 2 groups of allergic children with and without history of banana allergy, each included 40 patients. They were subjected to skin prick test (SPT) using commercial banana allergen extract and prick-prick test (PPT) using raw banana, in addition to measuring the serum banana-specific IgE. Oral banana challenge was performed in suspected cases. RESULTS: Banana allergy was diagnosed in 3 (7.5%) patients based on positive history of allergy on exposure to banana, positive SPT/PPT and elevated banana-specific IgE. The 3 patients had bronchial asthma with exacerbation upon banana exposure. The PPT results conform with those of SPT both in diagnosis of banana allergy and in the skin reactivity to banana. Serum banana-specific IgE was detectable in the whole studied sample with higher serum level among those without history of banana allergy (P=0.005). Oral banana challenge was negative for 20 patients with history of banana allergy and positive serum banana-specific IgE but negative SPT and PPT. CONCLUSIONS: Self/parental reports of banana allergy is high while the actual banana allergy is uncommon. The PPT seems as reliable as SPT in diagnosis of banana allergy unlike specific IgE which reflects sensitization rather than allergy. Oral food challenge remains the most helpful tool for diagnosis of food allergy in suspected cases.

Clinical predictors of primary immunodeficiency diseases in children.

PURPOSE: To promote awareness of primary immunodeficiency (PID), the "10 warning signs" of PID and an immunodeficiency-related (IDR) score were developed. However, their efficiency in identifying PID cases was not sufficiently evaluated in clinical practice. The objective of this study was to test the validity of the 10 warning signs and IDR score in identifying PID among children with recurrent infections at a tertiary pediatric hospital in Egypt. METHODS: A retrospective analysis of the medical records of 204 patients was performed. Of these patients, 92 had defined PID diseases and 112 were considered non-PID cases because investigations were inconclusive. RESULTS: Demonstrating two warning signs and an IDR score of 6 led to sensitivities of 94 and 66%, respectively, and specificities of 64 and 75%, respectively, in identifying PID cases. The strongest predictor of PID was family history that, if combined with the need for intravenous antibiotics, recurrent deep-seated infections, and failure to thrive, could identify 81% of PID patients. A family history of PID, sibling death, and/or parental consanguinity would predict 92% of combined immunodeficiencies, 92% of phagocyte defects, 87% of well-identified immunodeficiency syndromes, and 84% of antibody deficiency if the need for intravenous antibiotics is considered in the latter. CONCLUSIONS: The 10 warning signs and IDR score do not aid in an early diagnosis of severe PID. Educational campaigns should target pediatricians aiming to increase PID awareness and to address family history of PID, parental consanguinity, and previous sibling death as key predictors of PID in communities with a high prevalence of consanguineous marriages.

A rare association between leukocyte adhesion deficiency type I and psoriasis in humans.

The ß2 integrins are expressed exclusively on leukocytes and participate in many immune and inflammatory processes. This subfamily comprises four heterodimeric glycoproteins with a common ß-subunit, designated ß2 (CD18). Spontaneous mutations of the CD18 gene result in leukocyte adhesion deficiency type I (LAD-I). Low level of CD18 expression has also been implicated in the pathogenesis of psoriasis. We here describe a child with recurrent skin infections without pus formation, persistent gingivitis and periodontitis. His blood counts showed persistent leukocytosis (neutrophilia). CD11b expression was defective on neutrophils, while that of CD18 was normal. So, our patient represents a mild variant of LAD-I with possible dysfunctional CD18. Moreover, he developed psoriasis with reduced CD18 expression on CD4(+) T-cells. Psoriasiform dermatitis has been described before in association with LAD-I, however, clinically and histologically confirmed psoriasis in association with LAD-I has been described only in CD18 hypomorphic mice. Therefore, our patient represents the first clinically and histopathologically documented association between LAD-I and psoriasis in humans. It lends support to the role of ß2 integrins in the etiopathogenesis of psoriasis.