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• What is unique about subjects with atopic dermatitis who get eczema herpeticum?
• Urinary leukotriene E4 in subjects with sleep apnea
• Does sleep apnea worsen asthma control?
• Significant increase of allergic sensitization in schoolchildren
• The hyper-IgE syndrome: Distinct genetic forms, common TH17 deficiency
• Toll-like receptors 7 and 9 are defective in subjects with common variable immunodeficiency
• Copyright

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What is unique about subjects with atopic dermatitis who get eczema herpeticum? 

A subset of subjects with atopic dermatitis (AD) is at increased risk for certain viral infections. The condition called eczema herpeticum (EH), which is caused by a serious and extensive skin infection with the herpes simplex virus, was the focus of a National Institute of Allergy and Infectious Diseases–funded study reported in this issue of the Journal by Beck et al (p 260). The authors established a registry of more than 900 cases (including subjects with AD with and without a history of EH [ADEH⁺ and ADEH⁻ subjects, respectively], as well as healthy control subjects). They found that ADEH⁺ subjects have more severe skin disease, an earlier age of onset, more frequent history of other allergic disorders (eg, asthma or food allergy), and immunologic indicators suggestive of a more atopic predisposition. The herpes simplex virus–susceptible group (ADEH⁺) was more commonly sensitized to allergens, especially perennial and food allergens. ADEH⁺ subjects had skin infections with Staphylococcus aureus and appeared to be more susceptible to skin infections with other microbes than subjects without a history of EH (ADEH⁻ subjects). Further studies are underway to identify biomarkers or genetic signatures that will identify the subjects with AD at risk for these severe skin infections.

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• Subjects with AD with a history of EH (ADEH⁺) had higher total IgE levels and greater Eczema Area and Severity Index scores than subjects with AD who never had EH (ADEH⁻).

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Urinary leukotriene E₄ in subjects with sleep apnea 

Obstructive sleep apnea (OSA) syndrome is often associated with obesity and cardiovascular diseases. Low-grade inflammation might partly explain the relationship between OSA and cardiovascular events, but the respective contribution of intermittent hypoxia and obesity is unknown. Cysteinyl leukotriene (CysLT) pathways are proinflammatory lipid mediators that might play a role in the onset of cardiovascular diseases. Leukotriene (LT) E₄ is the major urinary metabolite of the CysLT pathway and provides a validated marker of in vivo whole-body synthesis of CysLT production. As reported in this issue of the Journal, Stanke-Labesque et al (p 364) demonstrated that urinary LTE₄ concentrations were increased in subjects with OSA and that body mass index (regression coefficient, 3.33; P = .001; see panel A of Figure) and, to a lesser extent, percentage of time spent with an oxygen saturation of less than 90% (regression coefficient, 1.01; P = .001) were the main determinants of this urinary LTE₄ production. Moreover, the authors demonstrated that continuous positive airway pressure therapy reduced urinary LTE₄ concentrations in subjects with OSA with normal weight but not in overweight and obese patients (see panel B of the Figure). These observations suggest that CysLTs could contribute to the cardiovascular morbidity associated with OSA and that a systematic weight loss management strategy might be desirable in addition to continuous positive airway pressure.

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• LTE₄ urinary excretion in relation to obesity and hypoxia.

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Does sleep apnea worsen asthma control? 

Previous work has suggested that OSA might contribute to poor asthma control. To further evaluate this, Julien et al (p 371) performed overnight sleep studies (polysomnography) in 3 groups of subjects to test the hypothesis that the prevalence and severity of sleep apnea would be greater among subjects with severe asthma than among subjects with moderate asthma and nonasthmatic control subjects (n = 26 per group). OSA, defined by an Apnea-Hypopnea Index of 15 or more events per hour of sleep, was present in 23 (88%) of 26 subjects with severe asthma, 15 (58%) of 26 subjects with moderate asthma, and 8 (31%) of 26 nonasthmatic control subjects (P < .001, χ² test). The prevalence was significantly higher among subjects with severe asthma in comparison with the other 2 groups and tended to be higher among subjects with moderate asthma than among nonasthmatic control subjects. Nocturnal oxygenation was significantly worse among subjects with severe asthma than among control subjects, and sleep apnea severity was significantly worse for both asthmatic groups than for control subjects. The dramatically higher prevalence of OSA among subjects with severe asthma provides new support for the concept that sleep apnea contributes to poor asthma control. These results suggest that recognition and treatment of sleep apnea might be an important element in improving asthma management.

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Significant increase of allergic sensitization in schoolchildren 

Recent studies indicate that the previously reported increase of asthma and allergic diseases might have stabilized. However, most studies are based on questionnaire data, and there is a lack of studies of time trends performed with objective measurements. In northern Sweden, Rönmark et al (p 357) have studied changes in the prevalence of allergic sensitization in children during a 10-year period. Two large cohorts of children 7 to 8 years old were recruited and examined in 1996 and 2006, respectively, through use of identical methods. The children were skin prick tested with 10 relevant airborne allergens, and the parents completed an expanded International Study of Asthma and Allergies in Childhood questionnaire. The skin prick test results were confirmed by means of analyses of specific IgE antibodies. The authors concluded that the prevalence of allergic sensitization increased 45% in these ages over the 10-year period (see Figure). In parallel, no increase in allergy symptoms was seen, possibly because of decreases in environmental tobacco smoke and respiratory tract infections. The authors' results strengthen the different influence of environmental factors on allergic sensitization and clinical symptoms, respectively. The large increase in sensitization may, however, predict an increase in the incidence of asthma and allergic diseases in pre-teenage and teenage subjects. The new cohort will be accurately followed by the research group.

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• Significant increase in allergic sensitization among 7- and 8-year-old children in northern Sweden from 1996 to 2006.

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The hyper-IgE syndrome: Distinct genetic forms, common T_H17 deficiency 

The hyper-IgE syndrome (HIES) is a multisystem disorder characterized by recurrent staphylococcal abscesses, candidiasis, skeletal and mesenchymal abnormalities, and increased IgE levels. Heterozygous missense mutations in the transcription factor signal transducer and activator of transcription gene (STAT3) underlie the autosomal dominant form of HIES (AD-HIES). STAT3 mutations in subjects with AD-HIES impair the generation of T_H17 cells (see Figure), which protect against bacterial and fungal infections. A few patients with an AD-HIES–like phenotype do not have STAT3 mutations. There also exists an autosomal recessive form of HIES (AR-HIES) that lacks the skeletal abnormalities but exhibits heightened susceptibility to some viral infections. Al Khatib et al (p 342) found that patients with HIES with normal STAT3 genes, including all those with a phenotype of AR-HIES, do exhibit impaired T_H17 differentiation but at steps distal to those affected by STAT3 mutations. Thus distinct genetic defects in patients with HIES affect a common T-cell effector pathway.

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• IL-17 production by hyper-IgE syndrome subjects with (mut) or without (wt) STAT3 mutations.

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Toll-like receptors 7 and 9 are defective in subjects with common variable immunodeficiency 

Common variable immunodeficiency (CVID) is a genetically complex disease of antibody deficiency accompanied by reduced to absent numbers of peripheral blood memory B cells and loss of plasma cells. However, the underlying molecular abnormalities have not yet been identified in most patients. Toll-like receptor (TLR) stimulation has been shown to activate normal B-cell proliferation and immunoglobulin production, but Yu et al (p 349) found that TLR7-, TLR7/8-, or TLR9-stimulated CVID memory B cells fail to proliferate, differentiate, upregulate AID expression, or produce immunoglobulins. TLR7-activated plasmacytoid dendritic cells from subjects with CVID also failed to produce IFN-α; however, reconstitution of this cytokine induced TLR7-mediated B-cell proliferation and class switching in some subjects with CVID. In contrast, TLR3 stimulation, which signals though an alternate MyD88-independent pathway, resulted in normal IFN-β expression by fibroblasts from subjects with CVID. PBMCs from subjects with CVID produced normal proinflammatory cytokine levels after stimulation with a panel of TLR ligands, indicating that these defects are not due to generalized TLR dysfunction in subjects with CVID. These data suggest that the specific impairment of TLR7- and TLR9-mediated signaling and associated IFN-α deficiency might in part account for the hypogammaglobulinemia and B-cell abnormalities in subjects with CVID.