194 LETTERS TO THE EDITOR
To what extent serologic cross-reactivity may be reflected at the clinical level remains essentially unanswered. However, although the existence of a selective type of cashew or pistachio allergy cannot be excluded on the basis of the present study, the lack of even a single patient with proof of selective allergy or tolerance to only 1 of the 2 Anacardiaceae nuts corroborates the notion that extensive cross-reactivity applies at the clinical level as well. It may therefore be especially prudent for physicians to advise strict avoidance of both Anacardiaceae members, if clinical reactivity to either nut is documented. Bearing in mind the close phylogenetic relationship of the 2 allergenic sources and the present data, recognition of a cashew/pistachio allergy syndrome may be appropriate. Detection of IgE to Ana o 3 may serve as a highly accurate diagnostic marker for both arms of this apparently dual entity, significantly improving specificity over conventional, whole-extract serologic testing. To geographically and demographically explore the generalizability of our findings, further studies on different populations are required. We thank Helena Ekoff for performing the serologic analyses reported and € Jonas Ostling and Ulrika Magnusson for developing the recombinant allergen used in the study. Savvas Savvatianos, MDa Anastasios P. Konstantinopoulos, MDa Borg Ase a, PhDb George Stavroulakis, MDa Jonas Lidholm, PhDb Magnus P. Borres, MD, PhDb,c Emmanouil Manousakis, MDa Nikolaos G. Papadopoulos, MD, PhDa,d From athe Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece; bThermo Fisher Scientific, Uppsala, Sweden; cthe Department of Maternal and Child Health, Uppsala University, Uppsala, Sweden; and dthe Centre for Paediatrics and Child Health, Institute of Human Development, University of Manchester, Manchester, United Kingdom. E-mail: [email protected]. Disclosure of potential conflict of interest: S. Savvatianos has received payment for lectures from Thermo Fisher Scientific. A. Borg a, J. Lidholm, and M. P. Borres are employed by Thermo Fisher Scientific. N. G. Papadopoulos has received research support from GlaxoSmithKline, Nestle, and Merck; has received payment for the development of educational presentations from Abbvie, Sanofi, Menarini, and Meda; has consultant arrangements with GlaxoSmithKline, Abbvie, Novartis, Menarini, Meda, and ALK-Abello; and has received payment for lectures from Novartis, Allergopharma, Uriach, GlaxoSmithKline, Stallergenes, and MSD. The rest of the authors declare that they have no relevant conflicts of interest. REFERENCES 1. Clark AT, Anagnostou K, Ewan PW. Cashew nut causes more severe reactions than peanut: case-matched comparison in 141 children. Allergy 2007;62:913-6. 2. Sicherer SH, Mu~ noz-Furlong A, Godbold JH, Sampson HA. US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up. J Allergy Clin Immunol 2010;125:1322-6. € 3. Vetander M, Helander D, Flodstrom C, Ostblom E, Alfven T, Ly DH, et al. Anaphylaxis and reactions to foods in children—a population-based case study of emergency department visits. Clin Exp Allergy 2012;42:568-77. 4. Hourihane JO, Harris H, Langton-Hewer S, Kilburn SA, Warner JO. Clinical features of cashew allergy. Allergy 2001;56:252-3. 5. Maloney JM, Rudengren M, Ahlstedt S, Bock SA, Sampson HA. The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy. J Allergy Clin Immunol 2008;122:145-51. 6. Clark AT, Ewan PW. Interpretation of tests for nut allergy in one thousand patients, in relation to allergy or tolerance. Clin Exp Allergy 2003;33:1041-5. 7. Klemans RJ, van Os-Medendorp H, Blankestijn M, Bruijnzeel-Koomen CA, Knol EF, Knulst AC. Diagnostic accuracy of specific IgE to components in diagnosing peanut allergy: a systematic review. Clin Exp Allergy 2015;45: 720-30.
J ALLERGY CLIN IMMUNOL JULY 2015
8. Masthoff LJ, Mattsson L, Zuidmeer-Jongejan L, Lidholm J, Andersson K, Akkerdaas JH, et al. Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults. J Allergy Clin Immunol 2013;132:393-9. 9. Ebisawa M, Brostedt P, Sj€olander S, Sato S, Borres MP, Ito K. Gly m 2S albumin is a major allergen with a high diagnostic value in soybean-allergic children. J Allergy Clin Immunol 2013;132:976-8, e1-5. Available online May 8, 2015. http://dx.doi.org/10.1016/j.jaci.2015.03.037
T-cell regulation during viral and nonviral asthma exacerbations To the Editor: Asthma is a common chronic inflammatory disease of the airways characterized by recurrent episodes of airway inflammation and following cycles of tissue repair and regeneration.1 Asthma exacerbations are defined as episodes of progressive increase in shortness of breath, cough, wheezing, and chest tightness, or a combination of these symptoms, accompanied by decreases in expiratory airflow that can be quantified by measurement of lung function. Factors contributing to exacerbations of asthma symptoms include respiratory infections (viral, bacterial, and atypical), allergens (aeroallergens and food allergens), exposures (occupational allergens and drugs), and miscellaneous factors (b-adrenergic receptor polymorphisms and nonrespiratory factors).2 The immune mechanisms underlying acute episodes of asthma are poorly understood, and whether factors contributing to asthma exacerbations for different reasons engage distinct immune pathways has been studied in the present study. In patients with asthma, airway inflammation is driven by T cells, with the most important role attributed to TH2 cells and their cytokines. There is growing evidence that not only TH2 cells have been associated with the development and progression of asthma but also TH17 cells might be involved by supporting the recruitment and survival of neutrophils, which were detected in sputum of subjects with asthma exacerbations and severe persistent asthma.1 Furthermore, data on the function of regulatory T (Treg) cells in asthma in humans are largely incomplete and quite inconsistent, although their role in allergen tolerance and allergen-specific immunotherapy has been intensively studied.3 To address these questions in a clinical setting, we used multicolor flow cytometry for the evaluation of phenotypical changes in CD41 T cells in subjects with asthma during acute episodes and stable asthma compared with the control group. The clinical characteristics of subjects are summarized in Table E1 in this article’s Online Repository at www.jacionline.org. Viruses were determined in the induced sputum during exacerbation. Rhinovirus (n 5 6), metapneumovirus (n 5 1), parainfluenza-2 virus and metapneumovirus (n 5 1), and parainfluenza-1 and respiratory syncytial virus (n 5 1) were identified in 9 virus-induced asthma exacerbation cases. Our data demonstrate that Treg cells analyzed according to the gating of CD31CD41 CD251CD1272FOXP31 and Helios1 cells (Fig 1, A) exhibit a major change during asthma exacerbations. Higher numbers of Treg cells in peripheral blood were found in subjects with stable asthma than in healthy controls. In contrast, during asthma exacerbations, the number of Treg cells was significantly reduced than during stable asthma (Fig 1, B). In addition, the frequency of Treg cells positively correlated
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LETTERS TO THE EDITOR 195
FIG 1. Decreased frequency of Treg cells during asthma exacerbations. A, Treg cells were identified in CD31CD41 T-cell gate on the basis of the expression of CD25 and CD127 as well as intracellular FOXP3 and Helios. B, The percentage of CD31CD41CD251CD1272 (Treg cells) was significantly decreased in asthma exacerbations. C, The frequency of Treg cells positively correlates with FEV1%. During asthma exacerbations, the percentage of FOXP31Helios1 Treg cells was reduced (D) and was positively correlated with FEV1% (E). HC, Healthy control; no-VEx, nonviral exacerbated asthma; SA, stable asthma; VEx, viral exacerbated asthma.
with predicted percentage of FEV1 (FEV1%) (Fig 1, C). Increased frequency of Treg cells in subjects with stable asthma could be due to corticosteroid treatment, as previously reported in adult subjects with asthma.4 The speed of kinetics of decrease and recovery of Treg cells during asthma exacerbations and stabilization is difficult to predict without a longitudinal study.
The evaluation of migratory properties of Treg cells is limited by lack of availability of suitable markers for homing to lungs.5 In the present study, we used CCR7 as a marker for migratory properties of Treg cells toward central lymphatic organs as a marker for exit from peripheral organs (see Fig E1 in this article’s Online Repository at www.jacionline.org).5 These data show a
196 LETTERS TO THE EDITOR
J ALLERGY CLIN IMMUNOL JULY 2015
FIG 2. Distinct cytokine profile of CD31CD41 T cells in asthma exacerbations. A, IL-4–producing CD31CD41 T cells. B, IL-10–producing CD31CD41 T cells. C, IL-17A–producing CD31CD41 T cells. D, IL-22–producing CD31CD41 T cells. E, IFN-g–producing CD31CD41 T cells. HC, Healthy control; no-VEx, nonviral exacerbated _ .05, **P < _ .01, and ***P < _ .001. asthma; SA, stable asthma; VEx, viral exacerbated asthma. *P
To what extent serologic cross-reactivity may be reflected at the clinical level remains essentially unanswered. However, although the existence of a selective type of cashew or pistachio allergy cannot be excluded on the basis of the present study, the lack of even a single patient with proof of selective allergy or tolerance to only 1 of the 2 Anacardiaceae nuts corroborates the notion that extensive cross-reactivity applies at the clinical level as well. It may therefore be especially prudent for physicians to advise strict avoidance of both Anacardiaceae members, if clinical reactivity to either nut is documented. Bearing in mind the close phylogenetic relationship of the 2 allergenic sources and the present data, recognition of a cashew/pistachio allergy syndrome may be appropriate. Detection of IgE to Ana o 3 may serve as a highly accurate diagnostic marker for both arms of this apparently dual entity, significantly improving specificity over conventional, whole-extract serologic testing. To geographically and demographically explore the generalizability of our findings, further studies on different populations are required. We thank Helena Ekoff for performing the serologic analyses reported and € Jonas Ostling and Ulrika Magnusson for developing the recombinant allergen used in the study. Savvas Savvatianos, MDa Anastasios P. Konstantinopoulos, MDa Borg Ase a, PhDb George Stavroulakis, MDa Jonas Lidholm, PhDb Magnus P. Borres, MD, PhDb,c Emmanouil Manousakis, MDa Nikolaos G. Papadopoulos, MD, PhDa,d From athe Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece; bThermo Fisher Scientific, Uppsala, Sweden; cthe Department of Maternal and Child Health, Uppsala University, Uppsala, Sweden; and dthe Centre for Paediatrics and Child Health, Institute of Human Development, University of Manchester, Manchester, United Kingdom. E-mail: [email protected]. Disclosure of potential conflict of interest: S. Savvatianos has received payment for lectures from Thermo Fisher Scientific. A. Borg a, J. Lidholm, and M. P. Borres are employed by Thermo Fisher Scientific. N. G. Papadopoulos has received research support from GlaxoSmithKline, Nestle, and Merck; has received payment for the development of educational presentations from Abbvie, Sanofi, Menarini, and Meda; has consultant arrangements with GlaxoSmithKline, Abbvie, Novartis, Menarini, Meda, and ALK-Abello; and has received payment for lectures from Novartis, Allergopharma, Uriach, GlaxoSmithKline, Stallergenes, and MSD. The rest of the authors declare that they have no relevant conflicts of interest. REFERENCES 1. Clark AT, Anagnostou K, Ewan PW. Cashew nut causes more severe reactions than peanut: case-matched comparison in 141 children. Allergy 2007;62:913-6. 2. Sicherer SH, Mu~ noz-Furlong A, Godbold JH, Sampson HA. US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up. J Allergy Clin Immunol 2010;125:1322-6. € 3. Vetander M, Helander D, Flodstrom C, Ostblom E, Alfven T, Ly DH, et al. Anaphylaxis and reactions to foods in children—a population-based case study of emergency department visits. Clin Exp Allergy 2012;42:568-77. 4. Hourihane JO, Harris H, Langton-Hewer S, Kilburn SA, Warner JO. Clinical features of cashew allergy. Allergy 2001;56:252-3. 5. Maloney JM, Rudengren M, Ahlstedt S, Bock SA, Sampson HA. The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy. J Allergy Clin Immunol 2008;122:145-51. 6. Clark AT, Ewan PW. Interpretation of tests for nut allergy in one thousand patients, in relation to allergy or tolerance. Clin Exp Allergy 2003;33:1041-5. 7. Klemans RJ, van Os-Medendorp H, Blankestijn M, Bruijnzeel-Koomen CA, Knol EF, Knulst AC. Diagnostic accuracy of specific IgE to components in diagnosing peanut allergy: a systematic review. Clin Exp Allergy 2015;45: 720-30.
J ALLERGY CLIN IMMUNOL JULY 2015
8. Masthoff LJ, Mattsson L, Zuidmeer-Jongejan L, Lidholm J, Andersson K, Akkerdaas JH, et al. Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults. J Allergy Clin Immunol 2013;132:393-9. 9. Ebisawa M, Brostedt P, Sj€olander S, Sato S, Borres MP, Ito K. Gly m 2S albumin is a major allergen with a high diagnostic value in soybean-allergic children. J Allergy Clin Immunol 2013;132:976-8, e1-5. Available online May 8, 2015. http://dx.doi.org/10.1016/j.jaci.2015.03.037
T-cell regulation during viral and nonviral asthma exacerbations To the Editor: Asthma is a common chronic inflammatory disease of the airways characterized by recurrent episodes of airway inflammation and following cycles of tissue repair and regeneration.1 Asthma exacerbations are defined as episodes of progressive increase in shortness of breath, cough, wheezing, and chest tightness, or a combination of these symptoms, accompanied by decreases in expiratory airflow that can be quantified by measurement of lung function. Factors contributing to exacerbations of asthma symptoms include respiratory infections (viral, bacterial, and atypical), allergens (aeroallergens and food allergens), exposures (occupational allergens and drugs), and miscellaneous factors (b-adrenergic receptor polymorphisms and nonrespiratory factors).2 The immune mechanisms underlying acute episodes of asthma are poorly understood, and whether factors contributing to asthma exacerbations for different reasons engage distinct immune pathways has been studied in the present study. In patients with asthma, airway inflammation is driven by T cells, with the most important role attributed to TH2 cells and their cytokines. There is growing evidence that not only TH2 cells have been associated with the development and progression of asthma but also TH17 cells might be involved by supporting the recruitment and survival of neutrophils, which were detected in sputum of subjects with asthma exacerbations and severe persistent asthma.1 Furthermore, data on the function of regulatory T (Treg) cells in asthma in humans are largely incomplete and quite inconsistent, although their role in allergen tolerance and allergen-specific immunotherapy has been intensively studied.3 To address these questions in a clinical setting, we used multicolor flow cytometry for the evaluation of phenotypical changes in CD41 T cells in subjects with asthma during acute episodes and stable asthma compared with the control group. The clinical characteristics of subjects are summarized in Table E1 in this article’s Online Repository at www.jacionline.org. Viruses were determined in the induced sputum during exacerbation. Rhinovirus (n 5 6), metapneumovirus (n 5 1), parainfluenza-2 virus and metapneumovirus (n 5 1), and parainfluenza-1 and respiratory syncytial virus (n 5 1) were identified in 9 virus-induced asthma exacerbation cases. Our data demonstrate that Treg cells analyzed according to the gating of CD31CD41 CD251CD1272FOXP31 and Helios1 cells (Fig 1, A) exhibit a major change during asthma exacerbations. Higher numbers of Treg cells in peripheral blood were found in subjects with stable asthma than in healthy controls. In contrast, during asthma exacerbations, the number of Treg cells was significantly reduced than during stable asthma (Fig 1, B). In addition, the frequency of Treg cells positively correlated
J ALLERGY CLIN IMMUNOL VOLUME 136, NUMBER 1
LETTERS TO THE EDITOR 195
FIG 1. Decreased frequency of Treg cells during asthma exacerbations. A, Treg cells were identified in CD31CD41 T-cell gate on the basis of the expression of CD25 and CD127 as well as intracellular FOXP3 and Helios. B, The percentage of CD31CD41CD251CD1272 (Treg cells) was significantly decreased in asthma exacerbations. C, The frequency of Treg cells positively correlates with FEV1%. During asthma exacerbations, the percentage of FOXP31Helios1 Treg cells was reduced (D) and was positively correlated with FEV1% (E). HC, Healthy control; no-VEx, nonviral exacerbated asthma; SA, stable asthma; VEx, viral exacerbated asthma.
with predicted percentage of FEV1 (FEV1%) (Fig 1, C). Increased frequency of Treg cells in subjects with stable asthma could be due to corticosteroid treatment, as previously reported in adult subjects with asthma.4 The speed of kinetics of decrease and recovery of Treg cells during asthma exacerbations and stabilization is difficult to predict without a longitudinal study.
The evaluation of migratory properties of Treg cells is limited by lack of availability of suitable markers for homing to lungs.5 In the present study, we used CCR7 as a marker for migratory properties of Treg cells toward central lymphatic organs as a marker for exit from peripheral organs (see Fig E1 in this article’s Online Repository at www.jacionline.org).5 These data show a
196 LETTERS TO THE EDITOR
J ALLERGY CLIN IMMUNOL JULY 2015
FIG 2. Distinct cytokine profile of CD31CD41 T cells in asthma exacerbations. A, IL-4–producing CD31CD41 T cells. B, IL-10–producing CD31CD41 T cells. C, IL-17A–producing CD31CD41 T cells. D, IL-22–producing CD31CD41 T cells. E, IFN-g–producing CD31CD41 T cells. HC, Healthy control; no-VEx, nonviral exacerbated _ .05, **P < _ .01, and ***P < _ .001. asthma; SA, stable asthma; VEx, viral exacerbated asthma. *P
