Inborn errors of immunity in adulthood.

Inborn errors of immunity (IEIs) are a group of conditions whereby parts of the immune system are missing or dysfunctional. Once thought to primarily be a pediatric disorder, it is now estimated that more than 50% of worldwide incident IEI cases are accounted for by adults. Delayed diagnosis, late symptom onset, and IEI phenocopies can all lead to adult-onset recognition of IEIs. Lack of awareness regarding the diversity of IEI manifestations in adults contributes to diagnostic and treatment delays. Prompt referral to immunology is critical so that patients can receive a precise molecular diagnosis and targeted therapy when available. This article serves as a primer on IEIs in adulthood, highlighting the pathophysiology, epidemiology and clinical features. We present clinical vignettes of three key IEIs to assist clinicians in building illness scripts on their presentations. We provide a framework for the laboratory evaluation of IEIs and their initial treatment, with the aim of improving recognition and management of these conditions.

Summary of the NACI Statement on Public Health Level Recommendations on the Use of Pneumococcal Vaccines in Adults, Including the Use of 15-valent and 20-valent Conjugate Vaccines.

Background: Age and certain medical/social conditions are risk factors for invasive pneumococcal disease (IPD). For prevention of IPD, the National Advisory Committee on Immunization (NACI) has recommended the 23-valent polysaccharide pneumococcal vaccine, PNEU-P-23, for adults 65 years of age and older and adults over 18 years of age living with certain underlying conditions. NACI has also recommended 13-valent conjugate pneumococcal vaccine, PNEU-C-13, for adults; however, in publicly funded programs, this recommendation is limited to individuals with risk factors for IPD. Two new conjugate vaccines, PNEU-C-15 and PNEU-C-20, have been authorized by Health Canada for prevention of IPD in adults. This article summarizes NACI public health recommendations for pneumococcal vaccines in adults given these new conjugate vaccines that provide additional serotype coverage over PNEU-C-13. Methods: Key studies evaluating the immunogenicity and safety of PNEU-C-15 and PNEU-C-20 were reviewed. The Grading of Recommendations, Assessment, Development and Evaluations framework methodology was used to assess the certainty of evidence. Results: The PNEU-C-15 and PNEU-C-20 vaccines showed comparable immune responses, and safety profiles for all mild, moderate, and severe adverse events, to the currently used vaccines. No data were available on the efficacy or effectiveness of PNEU-C-15 or PNEU-C-20. Economic evidence and feasibility assessments supported the use of the PNEU-C-20 vaccine. Conclusion: NACI recommends PNEU-C-20 for adults 65 years of age and older, 50-64 years of age and living with factors placing them at higher risk of pneumococcal disease, and 18-49 years of age with immunocompromising conditions, with PNEU-C-15+PNEU-P-23 an alternative.

Trends in the proportion of women speakers at North American Allergy and Immunology conferences, 2008 to 2020.

BACKGROUND: Women in medicine continue to be underrepresented at medical conferences. Previous studies have evaluated the proportion of invited female speakers across multiple specialties and evaluated factors that may have led to this disparity. The field of Allergy and Immunology has often been excluded and analyses have not illustrated how the trends have changed over the past decade. OBJECTIVE: To evaluate the distribution of invited speakers by gender over time at the 3 largest North American Allergy and Immunology conferences. METHODS: This retrospective longitudinal analysis used conference programs from 2008 to 2020 from the American Academy of Allergy, Asthma, and Immunology (AAAAI), the American College of Allergy, Asthma, and Immunology (ACAAI), and the Canadian Society of Allergy and Clinical Immunology (CSACI). The gender (binary definition, man or woman, based on names, photos, pronouns, from conference programs and institutional profiles) of invited speakers was analyzed as the primary outcome, and planning committee members, and multispeaker sessions as secondary outcomes. These data were compared with publicly available data on the composition of the specialty by gender in the United States and Canada. RESULTS: Women speakers at AAAAI, ACAAI, and CSACI conferences have historically been lower than male speakers and underrepresented compared with specialty composition. However, there has been a significant increase in the proportion of women speakers over time for all 3 conferences individually (AAAAI: 23.7% in 2008, 41.1% by 2020; ACAAI: 16.7% in 2008, 37.3% by 2020; CSACI: 19.4% in 2008, 54.8% by 2020; P < .001 for each) and combined (21.3% in 2008, 40.7% by 2020, P < .001). This trend coincides with a significant increase in women on the planning committee (all conferences: 20% in 2008, 50.6% by 2020; P < .001). There is also a decreasing trend over time for men-only multispeaker sessions. CONCLUSION: This study sheds light on the trends of women speaker representation at Allergy and Immunology conferences and provides clarity on future needs to reach equal representation in this field.

Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay.

BACKGROUND: Helios (encoded by IKZF2), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and immune function. Although predominantly recognised for its role in the development and function of T lymphocytes, particularly the CD4+ regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans. METHODS: We performed detailed phenotypic, genomic and functional investigations on two unrelated individuals with a phenotype of immune dysregulation combined with syndromic features including craniofacial differences, sensorineural hearing loss and congenital abnormalities. RESULTS: Genome sequencing revealed de novo heterozygous variants that alter the critical DNA-binding zinc fingers (ZFs) of Helios. Proband 1 had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios (p.Gly136_Ser191dup) and Proband 2 had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios (p.Gly153Arg). Functional studies confirmed that both these variant proteins are expressed and that they interfere with the ability of the wild-type Helios protein to perform its canonical function-repressing IL2 transcription activity-in a dominant negative manner. CONCLUSION: This study is the first to describe dominant negative IKZF2 variants. These variants cause a novel genetic syndrome characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay.

Cow's milk alternatives for children with cow's milk allergy and beyond.

Cow's milk allergy (CMA) is one of the most common food allergies in the first years of life, with worldwide prevalence estimated to range from 2% to 5%. While the majority of children with CMA will eventually develop tolerance to cow's milk proteins (it is estimated that >75% of children with CMA develop tolerance to cow's milk proteins by the age of 3 years, and >90% develop tolerance by the age of 6 years), the selection of an appropriate cow's milk (CM) alternative for those with CMA is vital to ensure adequate growth and development during childhood. The increasing number of CM alternative products on the commercial market with markedly different nutritional content and micronutrient fortification adds a layer of complexity that can be challenging for both families and clinicians to navigate. This article aims to provide guidance and clarity to Canadian paediatricians and primary care clinicians on recommending the most appropriate, safe, and nutritionally optimal CM alternatives for individuals with CMA, and beyond.

A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency.

Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) and key regulator of immune cell development and function. We report a recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) in seven patients from six unrelated families. The patients exhibited profound susceptibility to opportunistic infections, notably Pneumocystis jirovecii, and presented with agammaglobulinemia. Patients' B cells showed impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation, whereas their T cells contained reduced TH17 and TFH populations and exhibited decreased cytokine production. A knock-in mouse model of heterozygous T95R showed a severe defect in antibody production both at the steady state and after immunization with different types of antigens, consistent with the CID observed in these patients. The IRF4T95R variant maps to the TF's DNA binding domain, alters its canonical DNA binding specificities, and results in a simultaneous multimorphic combination of loss, gain, and new functions for IRF4. IRF4T95R behaved as a gain-of-function hypermorph by binding to DNA with higher affinity than IRF4WT. Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, showcasing a hypomorphic activity of IRF4T95R. Simultaneously, IRF4T95R functions as a neomorph by binding to noncanonical DNA sites to alter the gene expression profile, including the transcription of genes exclusively induced by IRF4T95R but not by IRF4WT. This previously undescribed multimorphic IRF4 pathophysiology disrupts normal lymphocyte biology, causing human disease.

Revaccination and Adverse Event Recurrence in Patients with Adverse Events following Immunization.

OBJECTIVES: To estimate the risk of recurrence of adverse events following immunization (AEFIs) upon revaccination and to determine among patients with suspected vaccine allergy whether allergy skin test positivity was associated with AEFI recurrence. STUDY DESIGN: This prospective observational study included patients assessed in the Canadian Special Immunization Clinic Network from 2013 to 2019 with AEFIs who required revaccination with the vaccine temporally associated with their AEFI. Participants underwent standardized assessment and data collection. Special Immunization Clinic physicians used guidelines to inform their recommendations. Participants were followed up after revaccination to capture AEFI recurrences. Data were transferred to a central database for descriptive analysis. RESULTS: Overall, 588 participants were assessed for 627 AEFIs; 570 (91%) AEFIs occurred in children <18 years of age. AEFIs included immediate hypersensitivity (130/627; 21%), large local reactions (110/627; 18%), nonurticarial rash (51/627; 8%), seizures (26/627; 4%), and thrombocytopenia (11/627; 2%). Revaccination was recommended to 513 of 588 (87%) participants. Among participants recommended and due for revaccination during the study period, 63% (299/477) were revaccinated. AEFI recurrence was 10% (31/299) overall, 31% (15/49) for large local reactions, and 7% (5/66) for immediate hypersensitivity. No recurrence was serious. Among 92 participants with suspected vaccine allergy who underwent skin testing and were revaccinated, the negative predictive value of skin testing for AEFI recurrence was 96% (95% CI 92.5%-99.5%). CONCLUSIONS: Most individuals with AEFIs were safely revaccinated. Among those with suspected vaccine allergy, skin testing may help determine the safety of revaccination.

Inborn errors of immunity manifesting as atopic disorders.

Inborn errors of immunity are traditionally best known for enhancing susceptibility to infections. However, allergic inflammation, among other types of immune dysregulation, occurs frequently in patients with inborn errors of immunity. As such, the term primary atopic disorders (PADs) was recently coined to describe the group of heritable monogenic allergic disorders. It is becoming increasingly important for clinicians to recognize that allergic diseases such as food allergy, atopic dermatitis, and allergic asthma are expressions of misdirected immunity, and in patients who present with severe, early-onset, or coexisting allergic conditions, these can be indications of an underlying PAD. Identifying monogenic allergic disease through next-generation sequencing can dramatically improve outcomes by allowing the use of precision-based therapy targeting the patient's underlying molecular defect. It is therefore imperative that clinicians recognize PADs to be able to provide informed therapeutic options and improve patient outcomes. Here, we summarize the clinical features commonly seen with each of the currently known PADs, identify clinical warning signs that warrant assessment for PADs, and lastly, discuss the benefits of timely diagnosis and management of these conditions.

Diverse clinical features and diagnostic delay in monogenic inborn errors of immunity: A call for access to genetic testing.

BACKGROUND: Inborn errors of immunity (IEIs) are a group of conditions affecting immune system development and function. Due to their clinical heterogeneity and lack of provider awareness, patients suffer from long diagnostic delays that increase morbidity and mortality. Next-generation sequencing facilitates earlier diagnosis and treatment of IEIs, but too often patients are unable to see the benefit of this technology due to gaps in providers' knowledge regarding which patients to test and barriers to accessing sequencing. METHODS: Here, we provide detailed clinical phenotyping and describe the impact of genetic sequencing on a cohort of 43 patients with monogenic IEIs seen in a tertiary care center from 2014 to 2019. Data were abstracted from a chart review, and a panel of clinical immunologists were consulted on the impact of genetic sequencing on their patients. RESULTS: We found that our patients had significant diagnostic delays, averaging 3.3 years; had diverse manifestations of immune system dysfunction; and had demonstrated highly complex medical needs, with on average 7.9 subspecialties involved in their care and 4.9 hospitalizations prior to definitive treatment. Our results also demonstrate the benefits of genetic testing, as it provided the majority of our patients with a diagnosis, and positively impacted their treatment, follow-up, and prognosis. CONCLUSION: This paper expands the paucity of literature on genetically confirmed IEIs in North America and supports the expansion of access to genetic testing for patients with clinical features suggesting IEI, such as those presented in our cohort.

Non-IgE-mediated food allergy: Evaluation and management.

The most common types of non-IgE-mediated food allergy are food protein-induced enterocolitis syndrome (FPIES) and food protein-induced allergic proctocolitis (FPIAP). FPIES presents with delayed refractory emesis, while FPIAP presents with hematochezia in otherwise healthy infants. Acute management of FPIES includes rehydration or ondansetron, or both. No acute management is required for FPIAP. Long-term management of both disorders includes avoidance of the trigger food. The prognosis for both conditions is a high rate of resolution within a few years' time.

L'évaluation et la prise en charge des allergies alimentaires non induites par les IgE.

Le syndrome d'entérocolite induite par les protéines alimentaires et la proctocolite allergique induite par les protéines alimentaires sont les principaux types d'allergies alimentaires non induites par les immunoglobines E. Le syndrome d'entérocolite induit par les protéines alimentaires se manifeste par des vomissements réfractaires tardifs, tandis que la proctocolite allergique induite par les protéines alimentaires se révèle par une hématochézie chez des nourrissons autrement en santé. La prise en charge immédiate du syndrome d'entérocolite induite par les protéines alimentaires inclut la réhydratation, l'ondansétron ou ces deux traitements, mais est inutile pour soigner la proctocolite allergique induite par les protéines alimentaires. À long terme, il faut éviter l'aliment déclencheur pour prendre en charge ces deux affections, dont le pronostic est un fort taux de résolution au bout de quelques années.

Prevention and management of allergic reactions to food in child care centers and schools: Practice guidelines.

Food allergy management in child care centers and schools is a controversial topic, for which evidence-based guidance is needed. Following the Grading of Recommendations Assessment, Development, and Evaluation approach, we conducted systematic literature reviews of the anticipated health effects of selected interventions for managing food allergy in child care centers and schools; we compiled data about the costs, feasibility, acceptability, and effects on health equity of the selected interventions; and we developed the following conditional recommendations: we suggest that child care centers and schools implement allergy training and action plans; we suggest that they use epinephrine (adrenaline) to treat suspected anaphylaxis; we suggest that they stock unassigned epinephrine autoinjectors, instead of requiring students to supply their own personal autoinjectors to be stored on site for designated at-school use; and we suggest that they do not implement site-wide food prohibitions (eg, "nut-free" schools) or allergen-restricted zones (eg, "milk-free" tables), except in the special circumstances identified in this document. The recommendations are labeled "conditional" due to the low quality of available evidence. More research is needed to determine with greater certainty which interventions are likely to be the most beneficial. Policymakers might need to adapt the recommendations to fit local circumstances.