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Medical Journal Review

July 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.

Cluster analysis of nasal cytokines during rhinovirus infection identifies different immunophenotypes in both children and adults with allergic asthma
Muehling LM, Heymann PW, Carper H et al.
Clinical & Experimental Allergy 2022; Published online ahead of print (16 May)

As is well known, infection with rhinovirus (RV) is a major risk factor for disease exacerbations in patients with allergic asthma. Thus, to better understand the pathophysiology occurring during exacerbation, the authors examined cytokines in the noses of children who were experimentally infected with RV in order to identify immunophenotypes that may link to virus-induced episodes. Through analysis of a core set of 7 cytokines (IL-6, CXCL8/IL-8, IL-15, EGF, G-CSF, CXCL10/IP-10 and CCL22/MDC) they found higher levels in children with acute wheeze versus those with stable asthma or controls. Multivariate analysis identified two clusters that were enriched for acutely wheezing children; one displaying high viral load (“RV high”) with robust secretion of CXCL10, and the other displaying high IgE with elevated EGF, CXCL8 and both eosinophil- and neutrophil-derived mediators. Broader assessment of 39 cytokines confirmed that children with acute wheeze were not deficient in type 1 anti-viral responses. Analysis of 18 nasal cytokines in adults with asthma who received RV challenge identified two clusters; one that was “RV-high” and linked to robust induction of anti-viral cytokines and anti-IgE; and the other associated with more severe symptoms and a higher inflammatory state featuring eosinophil and neutrophil factors. The authors note that these disparities in cytokine profiles may reflect the ability to regulate anti-viral responses.

Blocking the IL-4/IL-13 Pathway: Potential Mechanisms and Clinical Outcomes
Olaguibel JM, Sastre J, Rodríguez JM, Del Pozo V
Journal of Investigational Allergology and Clinical Immunology 2022;32(3):165-180

Hypereosinophilia has been observed in 4%-25% of patients treated with the IL-4/IL-13 pathway blocker dupilumab and is transient in most cases, although there have been reports of persistent cases of symptomatic hypereosinophilia consistent with eosinophilic granulomatosis with polyangiitis (EGPA), eosinophilic pneumonia, eosinophilic vasculitis, and sudden worsening of asthma symptoms. It should be noted that cases of EGPA have been reported with all biologics, including anti–IL-5 agents, and with leukotriene receptor antagonist. In many cases, EGPA appears during tapering of systemic corticosteroids or after switching from an anti–IL-5 biologic to dupilumab, suggesting that systemic corticosteroids or the anti–IL-5 agent were masking vasculitis. This review investigates plausible mechanisms of dupilumab-induced hypereosinophilia and review cases of symptomatic hypereosinophilia associated with dupilumab. The authors note that blockade of the IL-4/IL-13 pathway reduces eosinophil migration and accumulation of blood by inhibiting eotaxin-3, VCAM-1, and TARC without simultaneously inhibiting eosinophilopoiesis in bone marrow. When choosing the optimal biologic, it seems necessary to consider the presence of hypereosinophilia (>1500/µL), in which case an anti–IL-5/IL-5R agent is preferable. The authors recommend that when switching from an anti–IL-5/5R to an anti–IL-4/13R agent, blood eosinophils and clinical progress should be closely monitored. The authors suggest that dual therapy with anti–IL-5/5R and anti–IL4/IL-13R agents may be needed for optimal control, since both the IL-5 and the IL-4/IL-13 pathways can simultaneously contribute to airway inflammation.

Genetic Associations and Architecture of Asthma-COPD Overlap
John C, Guyatt AL, Shrine N, Packer R et al
Chest 2022;161(5):1155-1166 (28 January)

In trying to better understand asthma-COPD overlap, the authors examined the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma by performing a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank. They found eight novel signals (P < 5 x 10–8 ) for asthma-COPD overlap. The authors note that these signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. The authors suggest that these signals may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

The Multidimensional Burden of Atopic Dermatitis Among Adults: Results From a Large National Survey
Elsawi R, Dainty K, Smith Begolka W et al
JAMA Dermatology 2022; Published online (29 June)

In this study, Elsawi and colleagues utilized multivariable ordinal regression analysis to assess associations between demographic and clinical variables and patient-reported overall atopic dermatitis (AD) impact through a survey of 1065 subjects of diverse age. Of the group, 489 (46%) participants reported low-moderate AD impact scores (2-3), 544 (51%) reported high-significant impact scores (4-5), whereas 32 (3%) reported no association of AD with disease. The authors found that variables strongly associated with overall impact scores were current AD severity (moderate: OR, 4.13; 95% CI, 2.94-5.79; severe: OR, 13.63; 95% CI, 8.65-21.50 vs mild), and time spent managing AD (11-20 hours: OR, 2.67; 95% CI, 1.77-4.03, >21 hours: OR, 5.34; 95% CI, 3.22-8.85, vs <5 hours).

Long-Term Natural History of Severe Asthma Exacerbations and Their Impact on the Disease Course
Lee TY, Petkau J, Sadatsafavi M
Annals of the American Thoracic Society 2022;19(6):907-915

To investigate the long-term natural history of asthma among patients who are hospitalized for asthma for the first time in terms of the risk of future severe exacerbations and heterogeneity in this risk across patients. Lee and colleagues mined the administrative health databases of British Columbia, Canada (January 1, 1997 to March 31, 2016), to create an incident cohort of patients with at least one asthma exacerbation that required inpatient care. Through this they estimated the 5-year cumulative incidence of severe exacerbations after successive numbers of previous events and employed a joint frailty model to investigate the extent of between-individual variability in exacerbation risk and the associations of each exacerbation with the rate of subsequent events. Analyses were conducted separately for pediatric (<14 years old) and adult (>14 years old) patients. This analysis included 3,039 pediatric (mean age at baseline, 6.4; 35% female) and 5,442 (mean age at baseline, 50.8; 68% female) adult patients. The 5-year rates of severe exacerbations after the first three events were 0.16, 0.29, and 0.35 for the pediatric group, and 0.14, 0.33, and 0.49 for the adult group. Both groups exhibited substantial variability in patient-specific risks of exacerbation: the mid-95% interval of 5-year risk of experiencing a severe exacerbation ranged from 11% to 24% in pediatric patients and from 8% to 40% in adult patients. After controlling for potential confounders, the first follow-up exacerbation was associated with an increase of 79% (95% confidence interval [CI], 11–189%) in the rate of subsequent events in the pediatric group, whereas this increase was 188% (95% CI, 35–515%) for the adult group. The authors conclude that after the first severe exacerbation, the risk of subsequent events is substantially different among patients and the number of previous severe exacerbations carries nuanced prognostic information about future risk.

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