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The Editors' Choice
The Editors’ Choice Donald Y. M. Leung, MD, PhD Stanley J. Szefler, MD and the Associate Editors of the JACI
Effect of smoking on asthma treatment The article by Price et al (p 763) explores the use of inhaled corticosteroids and the leukotriene receptor antagonist montelukast in the seldom-studied population of asthmatic patients who smoke cigarettes. Previous research suggests that smoking has a detrimental effect on the efficacy of inhaled corticosteroids for the treatment of asthma. Whereas efficacy studies have demonstrated greater clinical benefit with inhaled corticosteroids than with leukotriene receptor inhibition in nonsmoking asthmatic patients, the randomized controlled trial reported in this article, evaluating asthmatic patients who smoked an average of 0.79 packs per day, demonstrated that both 10 mg of daily
THE JOURNAL OF
Allergy Clinical Immunology AND
VOLUME 131
NUMBER 3
montelukast and 250 lg of the inhaled corticosteroid fluticasone propionate twice daily significantly increased days with asthma control over 6 months compared with placebo but were not statistically different relative to each other. Further analysis demonstrated that patients with a smoking history of 11 pack years or less tended to show more benefit with fluticasone, whereas those with a history of greater than 11 pack years tended to show more benefit with montelukast. These results suggest that smoking attenuates the efficacy of corticosteroids and might be an important consideration in clinical practice. Future research is needed to evaluate corticosteroids and alternative asthma treatments, such as montelukast, to optimize treatment for this patient population.
Get the balance right—therapeutic immune modulation in patients with allergic asthma Asthma is characterized by TH2-type chronic inflammation. The development of allergic diseases like asthma is linked to reduced exposure to environmental pathogens promoting TH1 immune responses during childhood, a concept termed the hygiene hypothesis. Consequently, counteracting the TH2/TH1 imbalance in patients with allergic diseases has emerged as a therapeutic concept. This can be achieved, for example, by stimulation of TH1 immune pathways via Toll-like receptors (TLRs) through use of microbiological compounds. The drug QbG10 is a virus-like particle (a recombinantly produced viral protein shell filled with DNA) and a potent ligand for TLR9. In this issue of the Journal, Beeh et al (p 866) present data from a phase II trial evaluating the effect of subcutaneous QbG10 injection on clinical asthma control in 63 patients with mild-to-moderate asthma receiving stable doses of inhaled corticosteroids. Patients received 4 injections of QbG10 during a 4-week add-on treatment period and then entered an 8-week corticosteroid withdrawal period (with further 3 injections) so that the ability of QbG10 to maintain asthma control versus placebo could be studied. Overall, treatment with QbG10 resulted in greater asthma control and airway caliber over 12
Empiric food avoidance in patients with eosinophilic esophagitis and prolonged disease remission Empiric exclusion of major potential food antigens has recently arisen as a promising medical alternative to swallowed corticosteroids in treating patients with eosinophilic esophagitis (EoE). Lucendo et al (p 797) investigated the prolonged efficacy of empiric food exclusion on adults with EoE: 67 Spanish patients were exclusively treated with a diet avoiding cereals, milk, eggs, fish/seafood, legumes/peanuts, and soy for 6 weeks. Symptom resolution and biopsy normalization were documented in three fourths of the subjects. Sequentially reintroducing all excluded single foods and conducting subsequent endoscopic examinations
J ALLERGY CLIN IMMUNOL
Asthma control (ACQ) and lung function (FEV1) during the stable add-on (week 0-4) treatment and corticosteroid withdrawal (week 4-12) period in patients treated with QbG10 or placebo.
weeks (see Figure). Clinical benefits were accompanied by lower blood eosinophil counts with QbG10, suggesting an antiinflammatory effect. Treatment was well tolerated. These results suggest that TLR9-agonism might represent a novel approach to the treatment of allergic asthma. and biopsies, the authors identified specific food triggers through documenting disease recurrence. After prolonged avoidance of offending foods (milk, wheat, eggs, and legumes being found to be the main EoE triggers), EoE remained quiescent for up to 3 years. Serum specific IgE measurements and skin prick tests performed in each patient before initiation of the diet exhibited an extremely low concordance with the results of food-reintroduction challenges, and therefore the authors suggest that IgE-mediated allergies might be not the main pathophysiologic mechanism leading to EoE but rather a delayed hypersensitivity reaction against common, regularly consumed foods. The question of whether empiric exclusion diets should be tailored to specific areas and based on the staple diets and food sensitization profiles of each patient’s region arises. The present research opens the door to a new, feasible, drug-free maintenance therapy for patients with EoE.
March 2013 Page 683
Primary immunodeficiency and autosomal recessive hyper-IgE: Natural killer cells DOCKed Dedicator of cytokinesis 8 (DOCK8) mutation causes combined immunodeficiency and autosomal recessive hyper-IgE syndrome. Although several abnormalities have been reported in patients with DOCK8 mutations, there is an unusual occurrence of cutaneous viral infections that is not well explained by the immunologic defects ascribed to this syndrome. Because these types of infections are thought to be combated by natural killer (NK) cell– mediated defenses, Mizesko et al (p 840) evaluated 10 patients with DOCK8 deficiency and identified a pervasive defect in NK cell function. Although all patients had NK cells, they were unable to form a normal immunologic synapse with a target cell, which is needed to enable cytotoxicity. NK cells from patients could bind to target cells but did not accumulate actin filaments at the synapse (see Figure). The patients’ findings were recapitulated in an NK cell line in which DOCK8 expression was blocked with short-hairpin RNAs. Cells from DOCK8-deficient patients and knockdown NK cells had normal total actin filament levels, which distinguish this phenotype from that found in NK cells from patients with WiskottAldrich syndrome and suggest that DOCK8 is required for activation-induced access to the actin machinery to enable NK cell function. Overall, the findings identify NK cell deficiency as a clinically relevant component of human DOCK8 deficiency.
Just one word for you: Plastics The rapid increase in asthma prevalence over the past 30 years implicates environmental exposures, but the culprits identified thus far do not fully explain asthma risk. Global production of bisphenol A (BPA) exceeds 6 billion pounds annually, making it one of the world’s highest-production-volume chemicals. BPA is found in toys, drinking containers, dental sealants, water pipes, and food and beverage containers, including containers for infant formula. It has been detected in more than 90% of child urine samples. Studies in mice suggest that exposure to BPA might augment the allergic immune response,
Defective actin accumulation (red) at NK cell immunologic synapses in a DOCK8-deficient patient.
and recently, prenatal BPA exposure was associated with increased odds of childhood wheeze. Donohue et al (p 736) hypothesized that BPA exposure, as assessed from urinary BPA concentrations prenatally and at ages 3, 5, and 7 years, would be associated with increased risk of wheeze and asthma at school age. They found that postnatal urinary BPA concentrations were associated with increased odds of wheeze and asthma and increased levels of exhaled nitric oxide in a birth cohort of school-age children. These findings add to the evidence that environmental exposure to BPA might be associated with adverse respiratory outcomes.
Atopic sensitization in the first year of life The time point of initiation and the subsequent trajectories of atopic sensitization are elusive. The patterns of measureable IgE levels in the first year of life have thus far been described as fluctuating. Moreover, it remains unclear whether early IgE production is determined by external factors. In this issue of the Journal, Depner et al (p 781) show that different subpopulations follow distinct sensitization patterns of detectable IgE. In addition to never-sensitized children, there are children with transient (detectable IgE at birth but not at 12 months), incident (detectable IgE at 12 months but not at birth), or persistent (detectable IgE at birth and 12 months) sensitization; the figure illustrates these separate pathways for sensitization to combinations of inhalant and food allergens. Furthermore, the authors report distinct genetic and environmental factors prenatally and postnatally determining incident sensitization to inhalant and food allergens. Among those determinants were maternal atopy, nutrition, and exposure to a farming environment. These results demonstrate
Page 684 March 2013
Pathways of incident, transient, and persistent sensitization.
that the allergic immune response is shaped early in life. Whether the effects influence disease manifestation and persist into adulthood remains to be seen in subsequent follow-ups of the PASTURE birth cohort.
J ALLERGY CLIN IMMUNOL
Effect of smoking on asthma treatment The article by Price et al (p 763) explores the use of inhaled corticosteroids and the leukotriene receptor antagonist montelukast in the seldom-studied population of asthmatic patients who smoke cigarettes. Previous research suggests that smoking has a detrimental effect on the efficacy of inhaled corticosteroids for the treatment of asthma. Whereas efficacy studies have demonstrated greater clinical benefit with inhaled corticosteroids than with leukotriene receptor inhibition in nonsmoking asthmatic patients, the randomized controlled trial reported in this article, evaluating asthmatic patients who smoked an average of 0.79 packs per day, demonstrated that both 10 mg of daily
THE JOURNAL OF
Allergy Clinical Immunology AND
VOLUME 131
NUMBER 3
montelukast and 250 lg of the inhaled corticosteroid fluticasone propionate twice daily significantly increased days with asthma control over 6 months compared with placebo but were not statistically different relative to each other. Further analysis demonstrated that patients with a smoking history of 11 pack years or less tended to show more benefit with fluticasone, whereas those with a history of greater than 11 pack years tended to show more benefit with montelukast. These results suggest that smoking attenuates the efficacy of corticosteroids and might be an important consideration in clinical practice. Future research is needed to evaluate corticosteroids and alternative asthma treatments, such as montelukast, to optimize treatment for this patient population.
Get the balance right—therapeutic immune modulation in patients with allergic asthma Asthma is characterized by TH2-type chronic inflammation. The development of allergic diseases like asthma is linked to reduced exposure to environmental pathogens promoting TH1 immune responses during childhood, a concept termed the hygiene hypothesis. Consequently, counteracting the TH2/TH1 imbalance in patients with allergic diseases has emerged as a therapeutic concept. This can be achieved, for example, by stimulation of TH1 immune pathways via Toll-like receptors (TLRs) through use of microbiological compounds. The drug QbG10 is a virus-like particle (a recombinantly produced viral protein shell filled with DNA) and a potent ligand for TLR9. In this issue of the Journal, Beeh et al (p 866) present data from a phase II trial evaluating the effect of subcutaneous QbG10 injection on clinical asthma control in 63 patients with mild-to-moderate asthma receiving stable doses of inhaled corticosteroids. Patients received 4 injections of QbG10 during a 4-week add-on treatment period and then entered an 8-week corticosteroid withdrawal period (with further 3 injections) so that the ability of QbG10 to maintain asthma control versus placebo could be studied. Overall, treatment with QbG10 resulted in greater asthma control and airway caliber over 12
Empiric food avoidance in patients with eosinophilic esophagitis and prolonged disease remission Empiric exclusion of major potential food antigens has recently arisen as a promising medical alternative to swallowed corticosteroids in treating patients with eosinophilic esophagitis (EoE). Lucendo et al (p 797) investigated the prolonged efficacy of empiric food exclusion on adults with EoE: 67 Spanish patients were exclusively treated with a diet avoiding cereals, milk, eggs, fish/seafood, legumes/peanuts, and soy for 6 weeks. Symptom resolution and biopsy normalization were documented in three fourths of the subjects. Sequentially reintroducing all excluded single foods and conducting subsequent endoscopic examinations
J ALLERGY CLIN IMMUNOL
Asthma control (ACQ) and lung function (FEV1) during the stable add-on (week 0-4) treatment and corticosteroid withdrawal (week 4-12) period in patients treated with QbG10 or placebo.
weeks (see Figure). Clinical benefits were accompanied by lower blood eosinophil counts with QbG10, suggesting an antiinflammatory effect. Treatment was well tolerated. These results suggest that TLR9-agonism might represent a novel approach to the treatment of allergic asthma. and biopsies, the authors identified specific food triggers through documenting disease recurrence. After prolonged avoidance of offending foods (milk, wheat, eggs, and legumes being found to be the main EoE triggers), EoE remained quiescent for up to 3 years. Serum specific IgE measurements and skin prick tests performed in each patient before initiation of the diet exhibited an extremely low concordance with the results of food-reintroduction challenges, and therefore the authors suggest that IgE-mediated allergies might be not the main pathophysiologic mechanism leading to EoE but rather a delayed hypersensitivity reaction against common, regularly consumed foods. The question of whether empiric exclusion diets should be tailored to specific areas and based on the staple diets and food sensitization profiles of each patient’s region arises. The present research opens the door to a new, feasible, drug-free maintenance therapy for patients with EoE.
March 2013 Page 683
Primary immunodeficiency and autosomal recessive hyper-IgE: Natural killer cells DOCKed Dedicator of cytokinesis 8 (DOCK8) mutation causes combined immunodeficiency and autosomal recessive hyper-IgE syndrome. Although several abnormalities have been reported in patients with DOCK8 mutations, there is an unusual occurrence of cutaneous viral infections that is not well explained by the immunologic defects ascribed to this syndrome. Because these types of infections are thought to be combated by natural killer (NK) cell– mediated defenses, Mizesko et al (p 840) evaluated 10 patients with DOCK8 deficiency and identified a pervasive defect in NK cell function. Although all patients had NK cells, they were unable to form a normal immunologic synapse with a target cell, which is needed to enable cytotoxicity. NK cells from patients could bind to target cells but did not accumulate actin filaments at the synapse (see Figure). The patients’ findings were recapitulated in an NK cell line in which DOCK8 expression was blocked with short-hairpin RNAs. Cells from DOCK8-deficient patients and knockdown NK cells had normal total actin filament levels, which distinguish this phenotype from that found in NK cells from patients with WiskottAldrich syndrome and suggest that DOCK8 is required for activation-induced access to the actin machinery to enable NK cell function. Overall, the findings identify NK cell deficiency as a clinically relevant component of human DOCK8 deficiency.
Just one word for you: Plastics The rapid increase in asthma prevalence over the past 30 years implicates environmental exposures, but the culprits identified thus far do not fully explain asthma risk. Global production of bisphenol A (BPA) exceeds 6 billion pounds annually, making it one of the world’s highest-production-volume chemicals. BPA is found in toys, drinking containers, dental sealants, water pipes, and food and beverage containers, including containers for infant formula. It has been detected in more than 90% of child urine samples. Studies in mice suggest that exposure to BPA might augment the allergic immune response,
Defective actin accumulation (red) at NK cell immunologic synapses in a DOCK8-deficient patient.
and recently, prenatal BPA exposure was associated with increased odds of childhood wheeze. Donohue et al (p 736) hypothesized that BPA exposure, as assessed from urinary BPA concentrations prenatally and at ages 3, 5, and 7 years, would be associated with increased risk of wheeze and asthma at school age. They found that postnatal urinary BPA concentrations were associated with increased odds of wheeze and asthma and increased levels of exhaled nitric oxide in a birth cohort of school-age children. These findings add to the evidence that environmental exposure to BPA might be associated with adverse respiratory outcomes.
Atopic sensitization in the first year of life The time point of initiation and the subsequent trajectories of atopic sensitization are elusive. The patterns of measureable IgE levels in the first year of life have thus far been described as fluctuating. Moreover, it remains unclear whether early IgE production is determined by external factors. In this issue of the Journal, Depner et al (p 781) show that different subpopulations follow distinct sensitization patterns of detectable IgE. In addition to never-sensitized children, there are children with transient (detectable IgE at birth but not at 12 months), incident (detectable IgE at 12 months but not at birth), or persistent (detectable IgE at birth and 12 months) sensitization; the figure illustrates these separate pathways for sensitization to combinations of inhalant and food allergens. Furthermore, the authors report distinct genetic and environmental factors prenatally and postnatally determining incident sensitization to inhalant and food allergens. Among those determinants were maternal atopy, nutrition, and exposure to a farming environment. These results demonstrate
Page 684 March 2013
Pathways of incident, transient, and persistent sensitization.
that the allergic immune response is shaped early in life. Whether the effects influence disease manifestation and persist into adulthood remains to be seen in subsequent follow-ups of the PASTURE birth cohort.
J ALLERGY CLIN IMMUNOL