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• In utero smoke exposure diminishes the benefit of inhaled corticosteroids
• Pubertal stages are not associated with sex difference throughout puberty
• Eczema and increased serum IgE levels: Something other than atopic dermatitis?
• MicroRNAs might contribute to skin inflammation in patients with atopic dermatitis
• Asthma and rhinitis coexist in children independently of allergy
• Hematopoietic stem cell transplantation: The treatment of choice for primary immunodeficiencies?
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In utero smoke exposure diminishes the benefit of inhaled corticosteroids 

In utero smoke (IUS) exposure has been associated with increased prevalence of asthma and reduced lung function in healthy children. There are few data about the effect of IUS on lung function of children given a diagnosis of asthma. Using longitudinal data from the Childhood Asthma Management Program, Cohen et al (p 491) demonstrate that asthmatic children exposed to IUS had reduced improvement in airway responsiveness over time in comparison with asthmatic children who were not exposed to IUS. Furthermore, the authors found that IUS-exposed children had an attenuated response to inhaled corticosteroids in comparison with unexposed children (see Figure). The authors conclude that IUS exposure leads to a decreased age-related improvement in airway responsiveness and attenuates the benefit from inhaled corticosteroids among children with asthma. These observations raise interesting questions about the potential mechanisms of these adverse findings, and they re-emphasize the importance of preventing this exposure among pregnant women.

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• Reduced effect of budesonide among IUS-exposed children (B) in comparison with unexposed children (A).

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Pubertal stages are not associated with sex difference throughout puberty 

It has long been established that asthma occurs more frequently in boys during childhood and more frequently in female subjects during adulthood. It has not been studied prospectively whether this sex shift in asthma during puberty runs parallel with pubertal stages. As reported by Vink et al (p 498), a longitudinal cohort of 2,230 boys and girls followed through puberty did not show differences in asthma prevalence between boys and girls at ages 11.1 years and 13.6 years, whereas at 16.3 years of age, more female than male subjects had asthma (6.2% and 4.3%, respectively). This higher asthma prevalence at age 16.3 years was related to a higher asthma incidence and lower asthma remission in female subjects in comparison with male subjects during this follow-up. The study did not show an association between parent-reported pubertal stages and asthma prevalence. In addition, pubertal stages were not associated with asthma-related phenotypes (total IgE levels and peak expiratory flow decrease during the shuttle run test). If sex hormone changes do not differentially affect boys and girls in the development of asthma, then other factors have to contribute, such as sex differences in physical lung growth from birth into adulthood, leading to a smaller airway diameter in relation to lung volume in female subjects in comparison with that seen in male subjects at age 16 years.

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Eczema and increased serum IgE levels: Something other than atopic dermatitis? 

In a multicenter study Schimke et al (p 611) investigated a large cohort of patients with increased IgE levels and eczema suspected of having hyper-IgE syndrome (HIES) with the aim to differentiate autosomal dominant (AD)-HIES from atopic dermatitis. AD-HIES is a primary immunodeficiency characterized by Staphylococcus aureus abscesses, recurrent pneumonia, increased serum IgE levels, and eczema. Because eczema and increased serum IgE levels are hallmarks of AD-HIES and atopic dermatitis and several specific findings of HIES develop with age, clinical diagnosis can be very difficult. The association of AD-HIES with mutations in the gene encoding the signal transducer and activator of transcription 3 (STAT3) makes a molecularly defined diagnosis possible. However, in view of costs and logistics, should all patients with increased IgE levels and eczema undergo STAT3 mutation analysis? Using a cohort of patients from multiple tertiary centers, these investigators identified heterozygous STAT3 mutations in more than half of them and explored multiple variants for correlation analysis. Comparing clinical, immunologic, and molecular genetic data from these patients, the authors defined 7 key findings selected from the National Institutes of Health scoring system originally designed for the clinical definition of HIES. In addition, they showed a strong correlation between low T_H17 cell counts and the presence of a STAT3 mutation, providing a useful method to differentiate AD-HIES from atopic dermatitis and other primary immunodeficiency syndromes characterized by increased IgE levels and eczema, such as Wiskott-Aldrich syndrome, Netherton syndrome, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. As demonstrated by this approach, careful clinical observation combined with genetic analysis contributes to early diagnosis and effective therapy.

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MicroRNAs might contribute to skin inflammation in patients with atopic dermatitis 

MicroRNAs (miRNAs) are a recently discovered group of short noncoding RNAs that regulate biological functions by suppressing the expression of protein-coding genes. Deregulated miRNA expression has been found in human diseases; however, our knowledge about the potential role of miRNAs in immune-mediated diseases is limited. In this issue Sonkoly et al (p 581) show deregulated miRNA expression in atopic dermatitis lesions compared with healthy skin and identify miR-155, an miRNA with critical functions in immune homeostasis, as one of the most upregulated miRNAs. The authors demonstrate that dermal infiltrating cells, including CD4⁺ T cells, were responsible for increased levels of miR-155 in patients with atopic dermatitis (see Figure). miR-155 was induced by T-cell activation signals in vitro and trigger factors of atopic dermatitis in vivo. The authors identify cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), an important negative regulator of T-cell activation, as a direct target for miR-155 and demonstrate that suppression of CTLA-4 by miR-155 in T_H cells is accompanied by an increased proliferative response. These results suggest that overexpression of miR-155 in atopic dermatitis lesions might contribute to chronic skin inflammation by increasing the proliferative response of T_H cells. miR-155 and other miRNAs identified in this study represent potential therapeutic targets in patients with atopic dermatitis.

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• miR-155 is overexpressed in atopic dermatitis skin.

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Asthma and rhinitis coexist in children independently of allergy 

As reported in this issue of the Journal, Chawes et al (p 567) aimed to characterize the relation between asthma and allergic versus nonallergic rhinitis together with intermediary asthma end points in 290 7-year-old children from the Danish Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohort. They found that asthma is similarly associated and equally frequent in children with allergic and nonallergic rhinitis (see Figure). This underlines the need to test for asthma in all children presenting symptoms of persistent rhinitis independently of allergy and suggests a link between upper and lower airway disease beyond an allergy-driven mechanism. Moreover, children with asthma and allergic rhinitis presented with bronchial hyperresponsiveness and increased levels of fractional exhaled nitric oxide in contrast to the normal bronchial responsiveness and normal fractional exhaled nitric oxide levels seen in children with asthma and nonallergic rhinitis. This warrants increased awareness of children with coexisting asthma and allergic rhinitis because they exhibit signs of bronchial inflammation from early childhood and suggests different subtypes of asthma in children with allergic and nonallergic rhinitis. Together, the authors' observations lend support to the concept of a close connection between upper and lower airway disease from an unknown nonallergic mechanism in addition to a common allergy-driven process.

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• Associations among asthma, allergic rhinitis, and nonallergic rhinitis in 290 children 7 years of age.

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Hematopoietic stem cell transplantation: The treatment of choice for primary immunodeficiencies? 

Primary immunodeficiency has been treated with hematopoietic stem cell transplantation (HSCT) for more than 40 years. An expanding number of conditions are treated. Refinement of HLA tissue-typing methods, ready availability of new stem cell sources, improved methods of isolating hematopoietic stem cells, and use of less toxic chemotherapy conditioning regimens have improved survival. With experience of HSCT concentrated in a few centers of excellence, the chance of successful treatment with cure of disease and long-term survival has increased. There are few large studies reporting the outcome of HSCT for these patients. Gennery et al (p 602) have analyzed patients' data collected in the Stem Cell Transplantation for Immunodeficiencies in Europe registry over 3 periods: before 1995, 1995-1999, and 2000-2005. For 699 patients with severe combined immunodeficiencies (SCIDs), transplantation at less than 6 months of age, use of genoidentical and phenoidentical donors, absence of respiratory impairment, or viral infection before transplantation were associated with better prognosis. For 783 patients with non-SCID primary immunodeficiency, the 4-year survival in 2000-2005 was markedly improved and was better when an unrelated rather than phenoidentical donor was used. These data support screening programs to facilitate the early diagnosis of SCIDs. Analysis of the long-term outcome for disease-specific groups is now required.