Keywords
Mast cells
Autoimmune thyroid disease
Abstract
Chronic spontaneous urticaria is a condition that persists for more than six weeks, it occurs in the absence of an identifiable triggering factor and from the pathogenic activation of mast cells and basophils. The possibility of autoimmune etiology in up to 40 % of patients is presented, followed by subclinical infections and psychological factors. Two main mechanisms of the pathogenesis of chronic urticaria have been proposed: the former is the dysregulation of intracellular signaling pathways within mast cells and basophils, which leads to defects in the traffic or function of these cells. The latter is the development of autoantibodies against FcεRIα or IgE, in both mast cells and basophils. Numerous autoimmune diseases such as systemic lupus erythematosus, polymyositis, dermatomyositis, and rheumatoid arthritis have been associated with chronic urticaria; however, autoimmune thyroid disease deserves a special mention. A higher prevalence of antithyroid antibodies has been found, regardless of thyroid function (euthyroidism, hypo and hyperthyroidism) in patients with chronic spontaneous urticaria. Several infections have been linked to chronic urticaria. The best evidence is for Helicobacter pylori infection. Finally, stress is associated with the onset of the disease through the activation of the sympathetic and adrenomedullary system and the hypothalamic-pituitary- adrenal axis. Diagnosis may vary in different regions of the world, but the common feature is the completion of a thorough medical history.
References
Poonawalla T, Kelly B. Urticaria : a review. Am J Clin Dermatol. 2009;10(1):9-21. DOI: 10.2165/0128071-200910010-00002
Larenas-Linnemann D, Medina-Ávalos MA, Ortega-Martell JA, Beirana-Palencia AM, Rojo-Gutiérrez MI, Morales-Sánchez MA, et al. Guía mexicana para el diagnóstico y el tratamiento de la urticaria [Mexican guidelines on the diagnosis and treatment of urticaria]. Rev Alerg Mex. 2014;61(Suppl 2):S118-93. Disponible en: https://revistaalergia.mx/ojs/index.php/ram/article/view/49/66
Najib U, Bajwa ZH, Ostro MG, Sheikh J. A retrospective review of clinical presentation, thyroid autoimmunity, laboratory characteristics, and therapies used in patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2009;103(6):496-501. DOI: 10.1016/S1081-1206(10)60266-9.
Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018;73(7):1393-414. DOI: 10.1111/all.13397
Dias GA, Pires GV, Valle SO, Dortas SD, Levy S, França AT, et al. (2016) Impact of chronic urticaria on the quality of life of patients followed up at a university hospital. An Bras Dermatol. 2016;91(6):754-9. DOI: 10.1590/abd1806-4841.20165071
Ferrer, M. Immunological events in chronic spontaneous urticaria. Clin Transl Allergy. 2015;5:30. DOI: 10.1186/s13601-015-0074-7
Church MK, Kolkhir P, Metz M, Maurer M. The role and relevance of mast cells in urticaria. Immunol Rev. 2018;282(1):232-47. DOI: 10.1111/imr.12632
Caproni M, Giomi B, Volpi W, Melani L, Schincaglia E, Macchia D, et al. Chronic idiopathic urticaria: infiltrating cells and related cytokines in autologous serum-induced wheals. Clin Immunol. 2005;114(3):284-92. DOI: 10.1016/j.clim.2004.10.007
Caproni M, Giomi B, Melani L, Volpi W, Antiga E, Torchia D, et al. Cellular infiltrate and related cytokines, chemokines, chemokine receptors and adhesion molecules in chronic autoimmune urticaria: comparison between spontaneous and autologous serum skin test induced wheal. Int J Immunopathol Pharmacol. 2006;19(3):507-15. DOI: 10.1177/039463200601900306
Terhorst D, Koti I, Krause K, Metz M, Maurer M. In chronic spontaneous urticaria, high numbers of dermal endothelial cells, but not mast cells, are linked to recurrent angio-oedema. Clin Exp Dermatol. 2018;43(2):131-6. DOI: 10.1111/ced.13254
Haas N, Toppe E, Henz BM. Microscopic morphology of different types of urticaria. Arch Dermatol. 1998;134(1):41-6. DOI: 10.1001/archderm.134.1.41
Toyoda M, Maruyama T, Morohashi M, Bhawan J. Free eosinophil granules in urticaria: a correlation with the duration of wheals. Am J Dermatopathol. 1996;18(1):49-57. DOI: 10.1097/00000372-199602000-00008
Ying S, Kikuchi Y, Meng Q, Kay AB, Kaplan AP. TH1/TH2 cytokines and inflammatory cells in skin biopsy specimens from patients with chronic idiopathic urticaria: comparison with the allergeninduced late-phase cutaneous reaction. J Allergy Clin Immunol. 2002;109(4):694-700. DOI: 10.1067/mai.2002.123236
Lin RY, Schwartz LB, Curry A, Pesola GR, Knight RJ, Lee HS, et al. Histamine and tryptase levels in patients with acute allergic reactions: an emergency department-based study. J Allergy Clin Immunol. 2000;106(1 Pt 1):65-71. DOI: 10.1067/mai.2000.107600
Bédard PM, Brunet C, Pelletier G, Hébert J. Increased compound 48/80 induced local histamine release from nonlesional skin of patients with chronic urticaria. J Allergy Clin Immunol. 1986;78(6):1121-5. DOI: 10.1016/0091-6749(86)90260-5
Jacques P, Lavoie A, Bédard PM, Brunet C, Hébert J. Chronic idiopathic urticaria: profiles of skin mast cell histamine release during active disease and remission. J Allergy Clin Immunol. 1992;89(6):1139-43. DOI: 10.1016/0091-6749(92)90297-f
Altman K, Chang C. Pathogenic intracellular and autoimmune mechanisms in urticaria and angioedema. Clin Rev Allergy Immunol. 2013;45(1):47-62. DOI: 10.1007/s12016-012-8326-y
Turner H, Kinet JP. Signalling through the high-affinity IgE receptor Fc epsilonRI. Nature. 1999;402(6760 Suppl):B24-30. DOI: 10.1038/35037021
Rossi AB, Herlaar E, Braselmann S, Huynh S, Taylor V, Frances R, et al. Identification of the Syk kinase inhibitor R112 by a human mast cell screen. J Allergy Clin Immunol. 2006;118(3):749-55. DOI: 10.1016/j.jaci.2006.05.023
Gimborn K, Lessmann E, Kuppig S, Krystal G, Huber M. SHIP downregulates FcαRI-induced degranulation at supraoptimal IgE or antigen levels. J Immunol. 2005;174(1):507-16. DOI: 10.4049/jimmunol.174.1.507
Malmros H. Auto-serum test (AST). Nordisk Med. 1946;29(3):150–152.
Leznoff A, Josse RG, Denburg J, Dolovich J (1983) Association of chronic urticaria and angioedema with thyroid autoimmunity. Arch Dermatol. 1983;119(8):636-40. DOI:10.1001/archderm.1983.01650320010007
O’Donnell BF, Francis DM, Swana GT, Seed PT, Kobza Black A, Greaves MW Thyroid autoimmunity in chronic urticaria. Br J Dermatol. 2005;153(2):331-5. DOI: 10.1111/j.1365-2133.2005.06646.x
Grattan CE, Wallington TB, Warin RP, Kennedy CT, Bradfield JW. A serological mediator in chronic idiopathic urticaria--a clinical, immunological and histological evaluation. Br J Dermatol. 1986;114(5):583-90. DOI: 10.1111/j.1365-2133.1986.tb04065.x
Gruber BL, Baeza ML, Marchese MJ, Agnello V, Kaplan AP. Prevalence and functional role of anti-IgE autoantibodies in urticarial syndromes. J Invest Dermatol. 1988;90(2):213-7. DOI: 10.1111/1523-1747.ep12462239
Hide M, Francis DM, Grattan CE, Hakimi J, Kochan JP, Greaves MW. Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med. 1993;328(22):1599-604. DOI: 10.1056/NEJM199306033282204
Niimi N, Francis DM, Kermani F, O’Donnell BF, Hide M, Kobza-Black A Niimi N, Francis DM, Kermani F, O’Donnell BF, Hide M, Kobza-Black A, et al. Dermal mast cell activation by autoantibodies against the high affinity IgE receptor in chronic urticaria. J Invest Dermatol. 1996;106(5):1001-6. DOI: 10.1111/1523-1747.ep12338544
Fiebiger E, Maurer D, Holub H, Reininger B, Hartmann G, Woisetschläger M, et al. Serum IgG autoantibodies directed against the alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients? J Clin Invest. 1995;96(6):2606-12. DOI: 10.1172/JCI118325
Fiebiger E, Hammerschmid F, Stingl G, Maurer D. Anti-FcepsilonRIalpha autoantibodies in autoimmune-mediated disorders. Identification of a structure-function relationship. J Clin Invest. 1998;101(1):243-51. DOI: 10.1172/JCI511
Horn MP, Gerster T, Ochensberger B, Derer T, Kricek F, Jouvin MH, et al. Human anti-FcepsilonRIalpha autoantibodies isolated from healthy donors cross-react with tetanus toxoid. Eur J Immunol. 1999;29(4):1139-48. DOI: 10.1002/(SICI)1521-4141(199904)29:04<1149::AID-IMMU1149>3.0.CO;2-H
Ferrer M, Nakazawa K, Kaplan AP. Complement dependence of histamine release in chronic urticaria. J Allergy Clin Immunol. 1999;104(1):169-72. DOI: 10.1016/s0091-6749(99)70129-6
Kikuchi Y, Kaplan AP. A role for C5a in augmenting IgG-dependent histamine release from basophils in chronic urticaria. J Allergy Clin Immunol. 2002;109(1):114-8. DOI: 10.1067/mai.2002.120954
Kaplan AP, Greaves M. Pathogenesis of chronic urticaria. Clin Exp Allergy. 2009;39(6):777-87. DOI: 10.1111/j.1365-2222.2009.03256.x
Ferrer M, Luquin E, Sanchez-Ibarrola A, Moreno C, Sanz ML, Kaplan AP. Secretion of cytokines, histamine and leukotrienes in chronic urticaria. Int Arch Allergy Immunol. 2002;129(3):254-60. DOI: 10.1159/000066772
Grattan CE, O’Donnell BF, Francis DM, Niimi N, Barlow RJ, Seed PT, et al. Randomized double-blind study of cyclosporin in chronic ‘idiopathic’ urticaria. Br J Dermatol. 2000;143(2):365-72. DOI: 10.1046/j.1365-2133.2000.03664.x
Hollander SM, Joo SS, Wedner HJ. Factors that predict the success of cyclosporine treatment for chronic urticaria. Ann Allergy Asthma Immunol. 2011;107(6):523-8. DOI: 10.1016/j.anai.2011.08.013
Grattan CE, Francis DM, Slater NG, Barlow RJ, Greaves MW. Plasmapheresis for severe, unremitting, chronic urticaria. Lancet. 1992;339(8801):1078-80. DOI: 10.1016/0140-6736(92)90666-q
O’Donnell BF, Barr RM, Black AK, Francis DM, Kermani F, Niimi N, et al. Intravenous immunoglobulin in autoimmune chronic urticaria. Br J Dermatol. 1998;138(1):101-6. DOI: 10.1046/j.1365-2133.1998.02033.x
Kolkhir P, Metz M, Altrichter S, Maurer M. Comorbidity of chronic spontaneous urticaria and autoimmune thyroid diseases: A systematic review. Allergy. 2017;72(10):1440-60. DOI: 10.1111/all.13182
Ulambayar B, Chen YH, Ban GY, Lee JH, Jung CG, Yang EM, et al. Detection of circulating IgG autoantibody to FcεRIα in sera from chronic spontaneous urticaria patients. J Microbiol Immunol Infect. 2020;53(1):141-7. DOI: 10.1016/j.jmii.2017.10.003
Kanani A, Betschel SD, Warrington R. Urticaria and angioedema. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):59. DOI: 10.1186/s13223-018-0288-z
Vasagar K, Vonakis BM, Gober LM, Viksman A, Gibbons SP Jr, Saini SS. Evidence of in vivo basophil activation in chronic idiopathic urticaria. Clin Exp Allergy. 2006;36(6):770-6. DOI: 10.1111/j.1365-2222.2006.02494.x
Natbony SF, Phillips ME, Elias JM, Godfrey HP, Kaplan AP. Histologic studies of chronic idiopathic urticaria. J Allergy Clin Immunol. 1983;71(2):177-83. DOI: 10.1016/0091-6749(83)90096-9
Kay AB, Clark P, Maurer M, Ying S. Elevations in T-helper-2-initiating cytokines (interleukin-33, interleukin-25 and thymic stromal lymphopoietin) in lesional skin from chronic spontaneous (‘idiopathic’) urticaria. Br J Dermatol. 2015;172(5):1294-302. DOI: 10.1111/bjd.13621
Brzoza Z, Grzeszczak W, Rogala B, Trautsolt W, Moczulski D. PTPN22 polymorphism presumably plays a role in the genetic background of chronic spontaneous autoreactive urticaria. Dermatology. 2012;224(4):340-5. DOI: 10.1159/000339332
Baram D, Vaday GG, Salamon P, Drucker I, Hershkoviz R, Mekori YA. Human mast cells release metalloproteinase-9 on contact with activated T cells: juxtacrine regulation by TNF-alpha. J Immunol. 2001;167(7):4008-16. DOI: 10.4049/jimmunol.167.7.4008
Tedeschi A, Asero R, Lorini M, Marzano AV, Cugno M. Plasma levels of matrix metalloproteinase-9 in chronic urticaria patients correlate with disease severity and C-reactive protein but not with circulating histamine-releasing factors. Clin Exp Allergy. 2010;40(6):875-81. DOI: 10.1111/j.1365-2222.2010.03473.x
Puccetti A, Bason C, Simeoni S, Millo E, Tinazzi E, Beri R, et al. In chronic idiopathic urticaria autoantibodies against Fc epsilonRII/CD23 induce histamine release via eosinophil activation. Clin Exp Allergy. 2005;35(12):1599-607. DOI: 10.1111/j.1365-2222.2005.02380.x
O’Donnell BF, O’Neill CM, Francis DM, Niimi N, Barr RM, Barlow RJ, et al. Human leucocyte antigen class II associations in chronic idiopathic urticaria. Br J Dermatol. 1999;140(5):853-8. DOI: 10.1046/j.1365-2133.1999.02815.x
Bozek A, Krajewska J, Filipowska B, Polanska J, Rachowska R, Grzanka A, et al. HLA status in patients with chronic spontaneous urticaria. Int Arch Allergy Immunol. 2010;153(4):419-23. DOI: 10.1159/000316354
Chen J, Tan Z, Li J, Xiong P. Association of HLA-DRB1, DQB1 alleles with chronic urticaria. J Huazhong Univ Sci Technolog Med Sci. 2005;25(3):354-6. DOI: 10.1007/BF02828166
Asero R, Tedeschi A, Riboldi P, Cugno M. Plasma of patients with chronic urticaria shows signs of thrombin generation, and its intradermal injection causes wheal-and-flare reactions much more frequently than autologous serum. J Allergy Clin Immunol. 2006;117(5):1113-7. DOI: 10.1016/j.jaci.2005.12.1343
Cugno M, Tedeschi A, Asero R, Meroni PL, Marzano AV. Skin autoimmunity and blood coagulation. Autoimmunity. 2010;43(2):189-94. DOI: 10.3109/08916930903293086
Kolkhir P, Borzova E, Grattan C, Asero R, Pogorelov D, Maurer M. Autoimmune comorbidity in chronic spontaneous urticaria: A systematic review. Autoimmun Rev. 2017;16(12):1196-208. DOI: 10.1016/j.autrev.2017.10.003
Confino-Cohen R, Chodick G, Shalev V, Leshno M, Kimhi O, Goldberg A. Chronic urticaria and autoimmunity: associations found in a large population study. J Allergy Clin Immunol. 2012;129(5):1307-13. DOI: 10.1016/j.jaci.2012.01.043
Altrichter S, Peter HJ, Pisarevskaja D, Metz M, Martus P, Maurer M. IgE mediated autoallergy against thyroid peroxidase--a novel pathomechanism of chronic spontaneous urticaria? PLoS One. 2011;6(4):e14794. DOI: 10.1371/journal.pone.0014794
Rorsman H. (1962) Basophilic leucopenia in different forms of urticaria. Acta Allergol. 1962;17:168-84. DOI: 10.1111/j.1398-9995.1962.tb02937.x
Pan XF, Gu JQ, Shan ZY. The prevalence of thyroid autoimmunity in patients with urticaria: a systematic review and meta-analysis. Endocrine. 2015;48(3):804-10. DOI: 10.1007/s12020-014-0367-y
Maurer M, Weller K, Bindslev-Jensen C, Giménez-Arnau A, Bousquet PJ, Bousquet J, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy. 2011;66(3):317-30. DOI: 10.1111/j.1398-9995.2010.02496.x
Toubi E, Kessel A, Avshovich N, Bamberger E, Sabo E, Nusem D, et al. (2004) linical and laboratory parameters in predicting chronic urticaria duration: a prospective study of 139 patients. Allergy. 2004;59(8):869-73. DOI: 10.1111/j.1398-9995.2004.00473.x
Caproni M, Volpi W, Giomi B, Cardinali C, Antiga E, Melani L, et al. Chronic idiopathic and chronic autoimmune urticaria: clinical and immunopathological features of 68 subjects. Acta Derm Venereol. 2004;84(4):288-90. DOI: 10.1080/00015550410026939
Goodwin-Tomkinson J. Aetiology of urticaria. Br J Dermatol. 1926;38:431-43. DOI:10.1111/j.1365-2133.1926.tb09242.x
Barber HW. Chronic urticaria and angioneurotic edema due to bacterial sensitisation. Br J Dermatol. 1923;35:209-18. DOI: 10.1111/j.1365-2133.1923.tb09109.x
Wedi B, Raap U, Kapp A. Chronic urticaria and infections. Curr Opin Allergy Clin Immunol. 2004;4(5):387-96. DOI: 10.1097/00130832-200410000-00010
Trachsel C, Pichler WJ, Helbling A. Stellenwert von Laboruntersuchungen und Triggerfaktoren bei der chronischen Urtikaria. Eine retrospektive Studie an 170 Patienten [Importance of laboratory investigations and trigger factors in chronic urticaria]. Schweiz Med Wochenschr. 1999;129(36):1271-9
Sugrañes-Montalván A, Barreto-Suárez E, Nicolau-Pestana E, Quesada-Leyva L. Relación entre infección por Helicobacter pylori y urticaria crónica [Relation between Helicobacter pylori infection and chronic urticaria]. Rev Alerg Mex. 2017;64(4):396-402. DOI: 10.29262/ram.v64i4.283
Wedi B, Wagner S, Werfel T, Manns MP, Kapp A. Prevalence of Helicobacter pylori-associated gastritis in chronic urticaria. Int Arch Allergy Immunol. 1998;116(4):288-94. DOI: 10.1159/000023958
Wedi B. Urticaria. J Dtsch Dermatol Ges. 2008;6(4):306-17. DOI: 10.1111/j.1610-0387.2008.06661.x
69. Leiste A, Skaletz-Rorowski A, Venten I, Altmeyer P, Brockmeyer NH. Urticaria associated with Norovirus infection: report of two cases. J Dtsch Dermatol Ges. 2008;6(7):563-5. DOI: 10.1111/j.1610-0387.2007.06501.x
Ronellenfitsch U, Bircher A, Hatz C, Blum J. Parasiten als Ursache von Urtikaria. Helminthen und Protozooen als Auslöser der Nesselsucht? [Parasites as a cause of urticaria. Helminths and protozoa as triggers of hives?]. Hautarzt. 2007;58(2):133-4, 136-41. DOI: 10.1007/s00105-006-1174-z
Hellgren L, Hersle K. Acute and chronic urticaria. A statistical investigation on clinical and laboratory data in 1.204 patients and matched healthy controls. Acta Allergol. 1964;19:406-20.
Sonoda T, Anan T, Ono K, Yanagisawa S. Chronic urticaria associated with dental infection. Br J Dermatol. 2001;145(3):516-8. DOI: 10.1046/j.1365-2133.2001.04395.x
Buss YA, Garrelfs UC, Sticherling M. Chronic urticaria—which clinical parameters are pathogenetically relevant? A retrospective investigation of 339 patients. J Dtsch Dermatol Ges. 2007;5(1):22-9. DOI: 10.1111/j.1610-0387.2007.06194.x.
Ertam I, Biyikli SE, Yazkan FA, Aytimur D, Alper S. The frequency of nasal carriage in chronic urticaria patients. J Eur Acad Dermatol Venereol. 2007;21(6):777-80. DOI: 10.1111/j.1468-3083.2006.02083.x
Ercolini AM, Miller SD. The role of infections in autoimmune disease. Clin Exp Immunol. 2009;155(1):1-15. DOI: 10.1111/j.1365-2249.2008.03834.x
Wedi B, Liekenbröcker T, Kapp A. Infektassoziation und Serumaktivität bei der chronischen Urtikaria – Ausdruck molekularer Mimikry? [Chronic urticaria-Persistent bacterial infections and serum activity in chronic urticaria--Role of molecular mimicry?]. Allergologie. 2001;24(10):480-90. DOI: 10.5414/ALP24480
Appelmelk BJ, Simoons-Smit I, Negrini R, Moran AP, Aspinall GO, Forte JG, et al. Potential role of molecular mimicry between Helicobacter pylori lipopolysaccharide and Lewis blood group antigens in autoimmunity. Infect Immun. 1996;64(6):2031-40. DOI: 10.1128/iai.64.6.2031-2040.1996
Negrini R, Savio A, Poiesi C, Appelmelk BJ, Buffoli F, Paterlini A, et al. Antigenic mimicry between Helicobacter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis. Gastroenterology. 1996;111(3):655-65. DOI: 10.1053/gast.1996.v111.pm8780570
Hizal M, Tüzün B, Wolf R, Tüzün Y. The relationship between Helicobacter pylori IgG antibody and autologous serum test in chronic urticaria. Int J Dermatol. 2000;39(6):443-5. DOI: 10.1046/j.1365-4362.2000.00979.x
Liekenbröcker T, Koerner M, Kapp A, Wedi B. Korrelation der infektassoziierten chronischen Urtikaria mit positivem autologem Serumtest [Correlation of infect-associated chronic urticaria with positive autologous serum skin test]. Allergologie. 2001;24(10):475-9. DOI: 10.5414/ALP24475
Bakos N, Hillander M. Comparison of chronic autoimmune urticaria with chronic idiopathic urticaria. Int J Dermatol. 2003;42(8):613-5. DOI: 10.1046/j.1365-4362.2003.01759.x
Weiss M, Ingbar SH, Winblad S, Kasper DL. Demonstration of a saturable binding site for thyrotropin in Yersinia enterocolitica. Science. 1983;219(4590):1331-3. DOI: 10.1126/science.6298936
Cunningham MW. Pathogenesis of group A streptococcal infections. Clin Microbiol Rev. 2000;13(3):470-511. DOI: 10.1128/CMR.13.3.470.
Shikhman AR, Greenspan NS, Cunningham MW. A subset of mouse monoclonal antibodies cross-reactive with cytoskeletal proteins and group A streptococcal M proteins recognizes N-acetyl-beta-D-glucosamine. J Immunol. 1993;151(7):3902-13. Disponible en: https://www.jimmunol.org/content/151/7/3902.long
Faé KC, Diefenbach da Silva D, Bilate AM, Tanaka AC, Pomerantzeff PM, Kiss MH, et al. PDIA3, HSPA5 and vimentin, proteins identified by 2-DE in the valvular tissue, are the target antigens of peripheral and heart infiltrating T cells from chronic rheumatic heart disease patients. J Autoimmun. 2008;31(2):136-41. DOI: 10.1016/j.jaut.2008.04.023.
Yang HY, Sun CC, Wu YC, Wang JD. Stress, insomnia, and chronic idiopathic urticaria--a case-control study. J Formos Med Assoc. 2005;104(4):254-63.
Vestergaard C, Deleuran M. Chronic spontaneous urticaria: latest developments in aetiology, diagnosis and therapy. Ther Adv Chronic Dis. 2015;6(6):304-13. DOI: 10.1177/2040622315603951
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright (c) 2022 Revista Alergia México