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Medical Journal Review

October 2022

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

T2-high asthma phenotypes across lifespan
Maison N, Omony J, Illi S et al
European Respiratory Journal 2022;60(3):2102288

While it is common practice in adults to personalise asthma treatment based upon T2 phenotypes, it is unclear whether such classification is achievable in children. The purpose of this study was to define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages by examining the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls). In this study extensive clinical characterisation (questionnaires, blood differential count, allergy testing, and lung function and sputum induction [in adults]) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28.

Based on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: “atopy-only”, “eosinophils-only”, “T2-high” (eosinophilia + atopy) and “T2-low” (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2 years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (p<0.0001) and, from school age onwards, by increased production of IL-5 after anti-CD3/CD28 stimulation of whole blood.

Overall, the study demonstrates that through easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype and potentially these patients may benefit from therapy with biologicals even at a young age.

Association between aluminum exposure from vaccines before age 24 months and persistent asthma at age 24 to 59 months
Daley MF, Reifler LM, Glanz JM et al
Academic Pediatrics 2022;In press (28 September)

In this study by Daley and colleagues the authors examined the association between exposure from vaccines before age 24 months and persistent asthma at age 24 to 59 months via a retrospective cohort study conducted in the Vaccine Safety Datalink (VSD). Vaccination histories were used to calculate cumulative vaccine-associated aluminum in milligrams (mg). The authors defined asthma as 1 inpatient or 2 outpatient asthma encounters, and ≥2 long-term asthma control medication dispenses.

The cohort examined included 326,991 children, among whom 14,337 (4.4%) had eczema. For children with and without eczema, the mean (standard deviation [SD]) vaccine-associated aluminum exposure was 4.07 mg (SD 0.60) and 3.98 mg (SD 0.72), respectively. Among children with and without eczema, 6.0% and 2.1%, respectively, developed persistent asthma. Among children with eczema, vaccine-associated aluminum was positively associated with persistent asthma (aHR 1.26 per 1 mg increase in aluminum, 95% CI 1.07, 1.49); a positive association was also detected among children without eczema (aHR 1.19, 95% CI 1.14, 1.25).  Overall, they demonstrated that a positive association was found between vaccine-related aluminum exposure and persistent asthma. The authors note the small effect sizes identified and the potential for residual confounding require additional study for validation.

Are blood cytokines reliable biomarkers of allergic disease diagnosis and treatment responses?
Radonjic-Hoesli S, Pavolv N, Simon HU, Simon D
Journal of Allergy and Clinical Immunology 2022;150(2):251-258

The development of targeted therapies for allergic diseases reinforces the need for biomarkers supporting disease diagnosis and management has increased. In this review article, the authors critically examine the literature regarding the use of cytokine measurements in association with disease diagnosis and management. The authors note that among the variety of potential cytokines, thymus and activation-regulated chemokine stands out and can indeed serve as a biomarker of atopic dermatitis. Unfortunately, both biologic characteristics and technical issues determine the reliability and limit the use of blood cytokines as biomarkers.

Reduced miR-146a-5p is a Biomarker of Infant Respiratory Diseases Contributing to Immune Dysregulation in Small Airway Epithelial Cells
Rodrigo-Muñoz JM, Gil-Martínez M, Lorente-Sorolla C et al
Cells 2022;11(17):2746 (2 September)

Respiratory diseases such as bronchiolitis, and wheezing episodes, are highly important during infancy due to their potential chronicity. Immune response dysregulation is critical in perpetuating lung damage. Epigenetic modifications including microRNA (miRNA) post-transcriptional regulation are among the factors involved in alleviating inflammation. In this study Rodrigo-Muñoz and colleagues evaluated the expression of miR-146a-5p in order to study epigenetic regulation of the immune response. miR-146a-5p has previously been described as a negative regulator of immunity, in infants with respiratory diseases. To do so, they examined nasopharyngeal aspirate (NPA) obtained from infants with bronchiolitis (ongoing and post-disease) or with wheezing episodes in addition to healthy controls. Virus presence was determined by nested PCR, while miRNA and gene expression were studied in cells from NPAs using qPCR. Healthy small airway epithelial cells (SAECs) were used as an in vitro model. We observe a reduction in miR-146a-5p expression in infants with either of the two diseases compared to controls, suggesting the potential of this miRNA as a disease biomarker. Post-bronchiolitis, miR-146a-5p expression was found to increase, though without reaching levels of healthy controls. MiR-146a-5p expression correlates inversely with the immune-related gene PTGS2, while its expression correlates directly with TSLP. In heathy donor when SAECs are stimulated by poly:IC, the authors found an increase in miR-146a-5p, with wounds having a synergistic effect.  Overall, this indicates that infants with respiratory diseases present reduced miR-146a-5p expression, which possibly affects immune dysregulation.

A clinician's guide for administration of high-concentration and facilitated subcutaneous immunoglobulin replacement therapy in patients with primary immunodeficiency diseases
Epland K, Suez D, Paris K
Allergy Asthma & Clinical Immunology 2022/18(1):87 (30 September)

Immunoglobulin replacement therapy is the standard-of-care treatment for patients with primary immunodeficiency diseases who have impaired antibody production and function. Clinicians and patients have the option of intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG), with each route offering different potential benefits. The authors of this practical review note that IVIG requires fewer infusion sites and less frequent infusions than some formulations of SCIG. However, SCIG does not require venous access, is associated with fewer systemic adverse infusion reactions than IVIG, and can independently be self-administered at home. The authors stress the importance of tailoring treatment experiences to the needs of the individual may improve treatment adherence and quality of life for patients with primary immunodeficiency diseases.


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