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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
THE JOURNAL OF
Allergy Clinical Immunology AND
VOLUME 126
NUMBER 1
Vitamin D insufficiency increases the risk for severe asthma exacerbations Because of its beneficial role in respiratory tract infections and immune system modulation, it has been hypothesized that vitamin D status might affect the risks for exacerbations. In this issue, Brehm et al (p 52) show that children with initial circulating vitamin D levels of 30 ng/mL or less (vitamin D insufficiency) have a 50% greater risk for severe exacerbation over the course of a 4-year clinical trial of asthma treatment than children with circulating vitamin D levels of 30 ng/mL or greater (vitamin D sufficiency) at the start of the trial. The authors also investigated the joint effects of vitamin D status and randomization to inhaled corticosteroids (ICSs; see Figure). They found that compared with children who were randomized to ICSs and who had vitamin D sufficiency at the start of the trial, children who either had vitamin D insufficiency but were randomized to ICSs or had vitamin D sufficiency but were not receiving ICSs had 70% increased risks for severe exacerbations; children who had vitamin D sufficiency and who were not receiving ICSs had the
Oral peanut immunotherapy in children with peanut-induced anaphylaxis The only treatment option for peanut allergy is strict avoidance. However, accidental ingestion followed by allergic reactions is common because of the widespread use of peanuts. As reported in this issue of the Journal, Blumchen et al (p 83) investigated the efficacy and safety of oral immunotherapy (OIT) in children with peanut-induced anaphylaxis. Twentythree children with IgE-mediated peanut allergy confirmed by means of positive double-blind, placebo-controlled food challenge (DBPCFC) results were recruited. After receiving OIT after a 7-day rush protocol with roasted peanut, most of the
Vitamin D insufficiency, ICS use, and risk for severe asthma exacerbations.
highest risks for exacerbations. The authors conclude that sufficient vitamin D status decreases the risk for asthma exacerbations and might potentiate the beneficial effects of corticosteroids. children did not tolerate a protective dose of at least 500 mg of peanut. After continuation with a long-term protocol with daily peanut intake and biweekly dose increases, 14 of the 23 patients finally reached the protective dose; however, mild-to-moderate side effects were common. OIT was discontinued in 4 patients because of adverse events. Threshold levels at final DBPCFCs were increased significantly in comparison with those at DBPCFCs before OIT. In general, a long-term protocol for OIT seems to be a quite safe and effective treatment to protect many patients with peanut allergy against accidental reactions. However, until the risk/benefit ratio has been further evaluated in larger controlled studies, OIT for patients with peanut allergy cannot be considered a therapeutic strategy for routine clinical practice.
A roadmap to prevent milk allergy The World Health Organization recommends exclusive breast-feeding up to 6 months of age. In a large (>13,000 newborns) prospective study on the incidence and risk factors for IgE-mediated cow’s milk allergy (IgE-CMA), Katz and colleagues (p 77) from Tel Aviv University in Israel report several novel findings. They note that the incidence of IgE-CMA is less than commonly reported and measures only 0.5%. In addition, they observed a lack of cross-reactivity to soy in their patients with IgE-CMA. Finally, and perhaps most importantly, they note that early complementary introduction of cow’s milk protein (CMP) was protective against the development of IgECMA. As they illustrate (see Figure), there are 3 well-defined periods for the risk of IgE-CMA. IgE-CMA risk was very low (0.05%; green; group I) in infants introduced to CMP during the first 14 days of life, increased with CMP introduction age (yellow; group II), and peaked at 105 to 194 days of age (1.75%; red; group III). Thus although breast milk should still be considered the nutritional staple of the infant, health organizations
Page 50 July 2010
Regular exposure to CMP and risk of milk allergy.
should consider how to incorporate these findings into their future recommendations.
J ALLERGY CLIN IMMUNOL
Respiratory tract viral infections are common in patients with hypogammaglobulinemia Patients with primary hypogammaglobulinemia have recurrent bacterial infections. It is generally thought that they are not more prone to respiratory tract viral infections than immunocompetent subjects. Kainulainen et al (p 120) conducted a prospective, 12month longitudinal study designed to capture respiratory tract viral infections that occurred in 12 adult patients with primary hypogammaglobulinemia. Nasal swab and induced sputum samples were provided by the subjects every 3 months, irrespective of the symptoms, and at the onset of acute respiratory tract
infection. Viruses were identified through use of PCR tests for 15 respiratory viruses. The patients had a median of 5 episodes of respiratory tract infection, this being significantly more than in the spouses who served as control subjects. Rhinovirus was the most common virus, and it was positive in one third of the infections. Interestingly, some patients had recurrent and persistent rhinoviral infections. Rhinovirus was found both as a sole pathogen and together with bacteria. The most long-acting persistence of the same rhinovirus, confirmed with sequencing, was 4 months in a patient with X-linked agammaglobulinemia; this compared with shedding of 1 to 2 weeks in immunocompetent adults. The observations raise interesting questions about the role of humoral immunity in defense of respiratory tract viral infections.
Increased numbers of sputum myeloid and plasmacytoid dendritic cells in allergic asthmatic subjects Dendritic cells (DCs) are professional antigen-presenting cells that mediate the response to inhaled allergens. Although animal models have demonstrated the distinct roles of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in patients with allergic asthma, it is still uncertain whether the concept of proallergic mDCs and anti-allergic pDCs translates from animals to human beings. As reported in this issue of the Journal, Dua et al (p 133) demonstrate for the first time that both mDCs and pDCs increase in the sputum of allergic asthmatic subjects 24 hours after allergen challenge in comparison with diluent (see Figure). Furthermore, a significant increase in immature (chemokine receptor [CCR] 6+) mDCs occurred 72 hours after allergen challenge. Allergen challenge also increased sputum levels of the CCR6 ligand (macrophage inflammatory protein 3a) in comparison with baseline values. These results are consistent with the hypothesized role for mDCs in allergen presentation and the induction of allergeninduced airway inflammation. The appearance of pDCs is also consistent with a possible role in the resolution of allergen-induced airway inflammation. Continued research into DC biology, including its migration and function, will be fundamental in improving our understanding of the mechanisms of allergic asthma.
Kinetics of sputum mDCs (A) and pDCs (B) after inhalation of allergen versus diluent.
A sting in the tail of chemokine receptor 3 Chemokine receptor (CCR) 3 is a receptor expressed on the surfaces of eosinophils, basophils, and TH2 lymphocytes and directs the migration of these cells to sites of allergic inflammation at which the eotaxin chemokines are generated. Several small-molecule antagonists of CCR3 have been described in the literature as prototypic therapeutic treatments for allergic diseases. In this issue, Wise et al (p 150) describe the effects of a naturally occurring polymorphism that encodes a single point mutation (L324P) within the carboxyl tail of the receptor. This mutation results in the intracellular trapping of CCR3 (see Figure); consequently, cells expressing the mutant CCR3 are unresponsive to eotaxins. The authors postulate that this suggests an interaction between the carboxyl terminus of CCR3 and 1 or more unidentified chaperones that are crucial for the export of nascent CCR3 to the cell surface. The requirement for chaperones might explain previous difficulties in expressing CCR3 in some in vitro systems, and their successful identification might
J ALLERGY CLIN IMMUNOL
L324P-CCR3 (red) is trapped in an intracellular location and fails to traffic to the cell surface.
provide alternative strategies for the successful antagonism of CCR3.
July 2010 Page 51
THE JOURNAL OF
Allergy Clinical Immunology AND
VOLUME 126
NUMBER 1
Vitamin D insufficiency increases the risk for severe asthma exacerbations Because of its beneficial role in respiratory tract infections and immune system modulation, it has been hypothesized that vitamin D status might affect the risks for exacerbations. In this issue, Brehm et al (p 52) show that children with initial circulating vitamin D levels of 30 ng/mL or less (vitamin D insufficiency) have a 50% greater risk for severe exacerbation over the course of a 4-year clinical trial of asthma treatment than children with circulating vitamin D levels of 30 ng/mL or greater (vitamin D sufficiency) at the start of the trial. The authors also investigated the joint effects of vitamin D status and randomization to inhaled corticosteroids (ICSs; see Figure). They found that compared with children who were randomized to ICSs and who had vitamin D sufficiency at the start of the trial, children who either had vitamin D insufficiency but were randomized to ICSs or had vitamin D sufficiency but were not receiving ICSs had 70% increased risks for severe exacerbations; children who had vitamin D sufficiency and who were not receiving ICSs had the
Oral peanut immunotherapy in children with peanut-induced anaphylaxis The only treatment option for peanut allergy is strict avoidance. However, accidental ingestion followed by allergic reactions is common because of the widespread use of peanuts. As reported in this issue of the Journal, Blumchen et al (p 83) investigated the efficacy and safety of oral immunotherapy (OIT) in children with peanut-induced anaphylaxis. Twentythree children with IgE-mediated peanut allergy confirmed by means of positive double-blind, placebo-controlled food challenge (DBPCFC) results were recruited. After receiving OIT after a 7-day rush protocol with roasted peanut, most of the
Vitamin D insufficiency, ICS use, and risk for severe asthma exacerbations.
highest risks for exacerbations. The authors conclude that sufficient vitamin D status decreases the risk for asthma exacerbations and might potentiate the beneficial effects of corticosteroids. children did not tolerate a protective dose of at least 500 mg of peanut. After continuation with a long-term protocol with daily peanut intake and biweekly dose increases, 14 of the 23 patients finally reached the protective dose; however, mild-to-moderate side effects were common. OIT was discontinued in 4 patients because of adverse events. Threshold levels at final DBPCFCs were increased significantly in comparison with those at DBPCFCs before OIT. In general, a long-term protocol for OIT seems to be a quite safe and effective treatment to protect many patients with peanut allergy against accidental reactions. However, until the risk/benefit ratio has been further evaluated in larger controlled studies, OIT for patients with peanut allergy cannot be considered a therapeutic strategy for routine clinical practice.
A roadmap to prevent milk allergy The World Health Organization recommends exclusive breast-feeding up to 6 months of age. In a large (>13,000 newborns) prospective study on the incidence and risk factors for IgE-mediated cow’s milk allergy (IgE-CMA), Katz and colleagues (p 77) from Tel Aviv University in Israel report several novel findings. They note that the incidence of IgE-CMA is less than commonly reported and measures only 0.5%. In addition, they observed a lack of cross-reactivity to soy in their patients with IgE-CMA. Finally, and perhaps most importantly, they note that early complementary introduction of cow’s milk protein (CMP) was protective against the development of IgECMA. As they illustrate (see Figure), there are 3 well-defined periods for the risk of IgE-CMA. IgE-CMA risk was very low (0.05%; green; group I) in infants introduced to CMP during the first 14 days of life, increased with CMP introduction age (yellow; group II), and peaked at 105 to 194 days of age (1.75%; red; group III). Thus although breast milk should still be considered the nutritional staple of the infant, health organizations
Page 50 July 2010
Regular exposure to CMP and risk of milk allergy.
should consider how to incorporate these findings into their future recommendations.
J ALLERGY CLIN IMMUNOL
Respiratory tract viral infections are common in patients with hypogammaglobulinemia Patients with primary hypogammaglobulinemia have recurrent bacterial infections. It is generally thought that they are not more prone to respiratory tract viral infections than immunocompetent subjects. Kainulainen et al (p 120) conducted a prospective, 12month longitudinal study designed to capture respiratory tract viral infections that occurred in 12 adult patients with primary hypogammaglobulinemia. Nasal swab and induced sputum samples were provided by the subjects every 3 months, irrespective of the symptoms, and at the onset of acute respiratory tract
infection. Viruses were identified through use of PCR tests for 15 respiratory viruses. The patients had a median of 5 episodes of respiratory tract infection, this being significantly more than in the spouses who served as control subjects. Rhinovirus was the most common virus, and it was positive in one third of the infections. Interestingly, some patients had recurrent and persistent rhinoviral infections. Rhinovirus was found both as a sole pathogen and together with bacteria. The most long-acting persistence of the same rhinovirus, confirmed with sequencing, was 4 months in a patient with X-linked agammaglobulinemia; this compared with shedding of 1 to 2 weeks in immunocompetent adults. The observations raise interesting questions about the role of humoral immunity in defense of respiratory tract viral infections.
Increased numbers of sputum myeloid and plasmacytoid dendritic cells in allergic asthmatic subjects Dendritic cells (DCs) are professional antigen-presenting cells that mediate the response to inhaled allergens. Although animal models have demonstrated the distinct roles of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in patients with allergic asthma, it is still uncertain whether the concept of proallergic mDCs and anti-allergic pDCs translates from animals to human beings. As reported in this issue of the Journal, Dua et al (p 133) demonstrate for the first time that both mDCs and pDCs increase in the sputum of allergic asthmatic subjects 24 hours after allergen challenge in comparison with diluent (see Figure). Furthermore, a significant increase in immature (chemokine receptor [CCR] 6+) mDCs occurred 72 hours after allergen challenge. Allergen challenge also increased sputum levels of the CCR6 ligand (macrophage inflammatory protein 3a) in comparison with baseline values. These results are consistent with the hypothesized role for mDCs in allergen presentation and the induction of allergeninduced airway inflammation. The appearance of pDCs is also consistent with a possible role in the resolution of allergen-induced airway inflammation. Continued research into DC biology, including its migration and function, will be fundamental in improving our understanding of the mechanisms of allergic asthma.
Kinetics of sputum mDCs (A) and pDCs (B) after inhalation of allergen versus diluent.
A sting in the tail of chemokine receptor 3 Chemokine receptor (CCR) 3 is a receptor expressed on the surfaces of eosinophils, basophils, and TH2 lymphocytes and directs the migration of these cells to sites of allergic inflammation at which the eotaxin chemokines are generated. Several small-molecule antagonists of CCR3 have been described in the literature as prototypic therapeutic treatments for allergic diseases. In this issue, Wise et al (p 150) describe the effects of a naturally occurring polymorphism that encodes a single point mutation (L324P) within the carboxyl tail of the receptor. This mutation results in the intracellular trapping of CCR3 (see Figure); consequently, cells expressing the mutant CCR3 are unresponsive to eotaxins. The authors postulate that this suggests an interaction between the carboxyl terminus of CCR3 and 1 or more unidentified chaperones that are crucial for the export of nascent CCR3 to the cell surface. The requirement for chaperones might explain previous difficulties in expressing CCR3 in some in vitro systems, and their successful identification might
J ALLERGY CLIN IMMUNOL
L324P-CCR3 (red) is trapped in an intracellular location and fails to traffic to the cell surface.
provide alternative strategies for the successful antagonism of CCR3.
July 2010 Page 51