FeNO measurements in childhood asthma management did not improve the proportion of symptom-free days, but did result in fewer asthma exacerbations associated with an increased leukotriene receptor antagonist use and an augmentation of the inhaled corticosteroid doses.

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STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti–IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

Background: Respiratory infections are major causes of morbidity and mortality, but determinants of susceptibility are poorly defined. We studied whether and to what extent immunologic and genetic factors are associated with increased susceptibility to respiratory infections. Methods: We evaluated the prevalence of IgA, IgM, IgG, and IgG subclass deficiencies, impairment in the antibody response against pneumococcal polysaccharides, G2m(n) allotypes, Fc␥RIIa polymorphisms, partial C2 and partial C4 deficiency, promoter polymorphisms in MBL2, and lymphocyte subset deficiencies in a control population and in consecutive children with recurrent respiratory infections. Results: IgA and/or IgG subclass deficiency was found in 27 of 55 patients (49%) and 6 of 43 controls (14%) (P ‫؍‬ 0.0006). An impaired antibody response to polysaccharides was found in 7 patients (19%) and in 0 of 37 controls (P ‫؍‬ 0.002). The Gm(n)marker was absent in 25 of 55 patients (45%) and 6 of 42 controls (14%) (P ‫؍‬ 0.009). The MBL2 variants O/O, A/O, and A/A occurred in 9, 14, and 32 of the 55 patients, respectively, and in 1, 19, and 23 of the 43 controls, respectively (P ‫؍‬ 0.05). There was no increase in the prevalence of partial C4 deficiency, C2 deficiency, lymphocyte subset deficiency, or Fc␥RIIa polymorphism in the patients compared to the controls. A combination of at least 2 immune defects was found in 31 of 55 patients (56%) and in 4 of 42 controls (11.6%) (P <0.0001). Conclusion: Specific antipolysaccharide antibody deficiency, IgA and/or IgG subclass deficiency, Gm(n) allotype, and MBL2 genotype are susceptibility factors for recurrent respiratory infections, and coexistence of sev-

Background: Measurement of postimmunization antibody response to pneumococcal capsular polysaccharide (caps-PS) is the standard method to identify deficiency of antipolysaccharide antibody production. However, no standardized criteria have been defined for classification of patients into responders or nonresponders to caps-PS. Methods: We vaccinated 37 healthy children and 39 healthy adults with Pneumovax ® and measured the anti-caps-PS antibody response to 5 serotypes. We also measured antipneumococcal antibody titers in 82 patients with increased susceptibility to airway infection. The ELISA was performed according to the 3rd-generation assay format. 3, 4, 9N, 18C, and 19F, respectively. In 96% of healthy individuals, antibody responses higher than the cutoff concentration were seen for at least 3 of the 5 serotypes. Nine of 82 patients (11%) failed to mount an adequate antibody response for at least 4 of the 5 serotypes tested, whereas only 1 control (1.3%) failed to do so. Conclusion:The cutoffs for antibody responses to caps-PS identified in this study appear useful for identi-