CHILDHOOD ANAPHYLAXIS: NEW DEVELOPMENTS IN DIAGNOSIS AND TREATMENT

CHILDHOOD_ANAPHYLAXIS_NEW_DEVELOPMENTS _IN_DIAGNOSIS_AND_TREATMENT_kapak

ANAPHYLAXIS WITH BETA-LACTAMS AND NON-STEROIDAL ANTI INFLAMMATORY DRUGS (NSAIDs)

Pınar Şahin1 Mehmet Geyik2

1Ege University, Faculty of Medicine, Department of Pediatric Immunology and Allergic Diseases, İzmir, Türkiye
2Hatay Training and Research Hospital, Department of Pediatric Immunology and Allergic Diseases, Hatay, Türkiye

Şahin P, Geyik M. Anaphylaxis with Beta-Lactams and Non-Steroidal Anti Inflammatory Drugs (NSAIDs). In: Harmancı K, editor. Childhood Anaphylaxis: New Developments in Diagnosis and Treatment. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.79-103.

ABSTRACT

Anaphylaxis is a rapid, multisystem, and potentially fatal hypersensitivity reaction that represents a medical emergency, especially in pediatric cases. While food allergens remain the leading cause of anaphylaxis in children, an increasing number of cases are now linked to medications, with beta-lactam antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) among the most frequently implicated. A comprehensive understanding of these drug-induced reactions—including their underlying immunological mechanisms and clinical nuances—is crucial for prompt recognition and management.

Beta-lactam antibiotics represent the most common drug class associated with pediatric anaphylaxis. The immunologic basis of these reactions is primarily related to the beta-lactam ring, which can stimulate classic IgE-mediated hypersensitivity. Clinical symptoms typically manifest rapidly—within minutes to an hour—and may include urticaria, facial or peripheral angioedema, bronchospasm, hypotension, and gastrointestinal complaints. Diagnosis hinges on clinical context and is supported by skin prick or intradermal testing, and in some instances, serum-specific IgE analysis. Management requires immediate cessation of the suspected drug, intramuscular epinephrine as first-line therapy, and subsequent strict avoidance. Desensitization can be implemented in controlled healthcare settings for patients who require beta-lactam therapy without suitable alternatives.

NSAID-induced anaphylaxis in children presents a more varied clinical spectrum and arises from both immunologic and non-immunologic mechanisms. The most common pathway is Cyclooxygenase (COX)-1inhibition, especially in children with pre-existing chronic urticaria or during viral illnesses. Reactions can range from isolated cutaneous symptoms to full systemic anaphylaxis. Unlike beta-lactam allergies, standardized skin or laboratory tests to confirm NSAID hypersensitivity do not exist, making diagnosis dependent on a clear temporal relationship and clinical judgment. If necessary, oral drug provocation remains the gold standard diagnostic method. Treatment includes the complete avoidance of the implicated NSAID, comprehensive education for families, and the selection of safe alternatives such as paracetamol or COX-2 selective inhibitors. Desensitization or may be considered in rare, unavoidable cases.

This chapter offers a comprehensive overview of beta-lactam and NSAID-induced anaphylaxis in the pediatric population, highlighting pathophysiological mechanisms, clinical recognition, diagnostic approaches, and therapeutic strategies. Increased awareness and personalized management protocols are crucial for improving outcomes and preventing recurrence in children with drug-induced anaphylaxis.

Keywords: Anaphylaxis; Beta-lactam antibiotics; Non-steroidal antiinflammatory drugs (NSAIDs); Drug hypersensitivity; Child; Drug allergy

Referanslar

  1. Muraro A, Worm M, Alviani C, Cardona V, DunnGalvin A, Garvey LH, et al. EAACI guidelines: Anaphylaxis (2021 update). Allergy. 2022;77(2):357-77. [Crossref]  [PubMed]
  2. Pandey N, Cascella M. Beta-Lactam Antibiotics. StatPearls. Treasure Island (FL) ineligible companies. Disclosure: Marco Cascella declares no relevant financial relationships with ineligible companies.: StatPearls Publishing Copyright © 2025, StatPearls Publishing LLC.; 2025.
  3. Caruso C, Valluzzi RL, Colantuono S, Gaeta F, Romano A. -Lactam Allergy and Cross-Reactivity: A Clinician's Guide to Selecting an Alternative Antibiotic. J Asthma Allergy. 2021;14:31-46. [Crossref]  [PubMed]  [PMC]
  4. Waller DG, Sampson AP. 51 Chemotherapy of infections. In: Waller DG, Sampson AP, editors. Medical Pharmacology and Therapeutics (Fifth Edition): Elsevier; 2018:581-629. [Crossref]
  5. Lima LM, Silva BNMd, Barbosa G, Barreiro EJ. -lactam antibiotics: An overview from a medicinal chemistry perspective. European Journal of Medicinal Chemistry. 2020;208:112829. [Crossref]  [PubMed]
  6. Kuriyama T, Karasawa T, Williams DW. Chapter Thirteen Antimicrobial Chemotherapy: Significance to Healthcare. In: Percival SL, Williams DW, Randle J, Cooper T, editors. Biofilms in Infection Prevention and Control. Boston: Academic Press; 2014:209-44. [Crossref]
  7. Lin X, Kück U. Cephalosporins as key lead generation beta-lactam antibiotics. Appl Microbiol Biotechnol. 2022;106(24):8007-20. [Crossref]  [PubMed]  [PMC]
  8. Azevedo J, Gaspar Â, Mota I, Benito-Garcia F, Alves-Correia M, Chambel M, et al. Anaphylaxis to beta-lactam antibiotics at pediatric age: Six-year survey. Allergologia et Immunopathologia. 2019;47(2):128-32. [Crossref]  [PubMed]
  9. Torres MJ, Blanca M. The Complex Clinical Picture of -Lactam Hypersensitivity: Penicillins, Cephalosporins, Monobactams, Carbapenems, and Clavams. Medical Clinics of North America. 2010;94(4):805-20. [Crossref]  [PubMed]
  10. Xing Y, Zhang H, Sun S, Ma X, Pleasants RA, Tang H, et al. Clinical features and treatment of pediatric patients with drug-induced anaphylaxis: a study based on pharmacovigilance data. European Journal of Pediatrics. 2018;177(1):145-54. [Crossref]  [PubMed]  [PMC]
  11. Celiksoy MH, Ulas S, Turan I, Yıldırım I, Ucar OT, Al S. Characteristics of childhood anaphylaxis in different age groups. Allergol Immunopathol (Madr). 2024;52(5):1-5. [Crossref]  [PubMed]
  12. Jeimy S, Ben-Shoshan M, Abrams EM, Ellis AK, Connors L, Wong T. Practical guide for evaluation and management of beta-lactam allergy: position statement from the Canadian Society of Allergy and Clinical Immunology. Allergy, Asthma & Clinical Immunology. 2020;16(1):95. [Crossref]  [PubMed]  [PMC]
  13. Solensky R, Earl HS, Gruchalla RS. Clinical approach to penicillin-allergic patients: a survey. Ann Allergy Asthma Immunol. 2000;84(3):329-33. [Crossref]  [PubMed]
  14. Sobrino-García M, Moreno EM, Muñoz-Bellido FJ, Gracia-Bara MT, Laffond E, Doña I, et al. Analysis of the Costs Associated With the Elective Evaluation of Patients Labelled as Allergic to Beta-Lactams or Nonsteroidal Antiinflamatory Agents. Frontiers in Pharmacology. 2020;11. [Crossref]  [PubMed]  [PMC]
  15. Ariza A, Mayorga C, Fernandez TD, Barbero N, Martín-Serrano A, Pérez-Sala D, et al. Hypersensitivity reactions to -lactams: relevance of hapten-protein conjugates. J Investig Allergol Clin Immunol. 2015;25(1):12-25.
  16. Torres MJ, Adkinson NF, Jr., Caubet J-C, Khan DA, Kidon MI, Mendelson L, et al. Controversies in Drug Allergy: Beta-Lactam Hypersensitivity Testing. The Journal of Allergy and Clinical Immunology: In Practice. 2019;7(1):40-5. [Crossref]  [PubMed]
  17. Bianchi A, Valluzzi R, Crisafulli G, Bottau P, Caimmi S, Franceschini F, et al. Drug-Induced Anaphylaxis in Children. Biomedicines. 2024;12(3). [Crossref]  [PubMed]  [PMC]
  18. Montañez MI, Mayorga C, Bogas G, Barrionuevo E, Fernandez-Santamaria R, Martin-Serrano A, et al. Epidemiology, Mechanisms, and Diagnosis of Drug-Induced Anaphylaxis. Front Immunol. 2017;8:614. [Crossref]  [PubMed]  [PMC]
  19. Park CS, Yang MS, Kang DY, Park HJ, Park SY, Nam YH, et al. Risk factors of beta-lactam anaphylaxis in Korea: A 6-year multicenter retrospective adult case-control study. Şahin, Geyik Anaphylaxis with Beta-Lactams and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) World Allergy Organ J. 2021;14(9):100580. [Crossref]  [PubMed]  [PMC]
  20. Ponvert C, Perrin Y, Bados-Albiero A, Le Bourgeois M, Karila C, Delacourt C, et al. Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests. Pediatric Allergy and Immunology. 2011;22(4):411-8. [Crossref]  [PubMed]
  21. Faria E, Rodrigues-Cernadas J, Gaspar A, Botelho C, Castro E, Lopes A, et al. Drug-induced anaphylaxis survey in Portuguese Allergy Departments. J Investig Allergol Clin Immunol. 2014;24(1):40-8.
  22. Blanca-Lopez N, Atanaskovic-Markovic M, Gomes ER, Kidon M, Kuyucu S, Mori F, et al. An EAACI Task Force report on allergy to beta-lactams in children: Clinical entities and diagnostic procedures. Pediatric Allergy and Immunology. 2021;32(7):1426-36. [Crossref]  [PubMed]
  23. Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al. International Consensus on drug allergy. Allergy. 2014;69(4):420-37. [Crossref]  [PubMed]
  24. Atanaskovic-Markovic M, Gomes E, Cernadas JR, du Toit G, Kidon M, Kuyucu S, et al. Diagnosis and management of drug-induced anaphylaxis in children: An EAACI position paper. Pediatr Allergy Immunol. 2019;30(3):269-76. [Crossref]  [PubMed]
  25. Gomes ER, Brockow K, Kuyucu S, Saretta F, Mori F, Blanca-Lopez N, et al. Drug hypersensitivity in children: report from the pediatric task force of the EAACI Drug Allergy Interest Group. Allergy. 2016;71(2):149-61. [Crossref]  [PubMed]
  26. Arıkoğlu T, Kuyucu S, Caubet JC. New diagnostıc perspectives in the management of pediatrıc beta-lactam allergy. Pediatr Allergy Immunol. 2022;33(3):e13745. [Crossref]  [PubMed]
  27. Moral L, Mori F. Drug provocation tests in children: All that glitters is not gold. Pediatric Allergy and Immunology. 2023;34(8):e14002. [Crossref]  [PubMed]
  28. Doña I, Salas M, Moreno E, Ferrer M, Mayorga C, Torres MJ. An algorithm for the diagnosis of beta-lactam allergy, 2024 update. Allergy. 2025;80(2):633-7. [Crossref]  [PubMed]
  29. Jeimy S, Ben-Shoshan M, Abrams EM, Ellis AK, Connors L, Wong T. Practical guide for evaluation and management of beta-lactam allergy: position statement from the Canadian Society of Allergy and Clinical Immunology. Allergy Asthma Clin Immunol. 2020;16(1):95. [Crossref]  [PubMed]  [PMC]
  30. Romano A, Atanaskovic-Markovic M, Barbaud A, Bircher AJ, Brockow K, Caubet J-C, et al. Towards a more precise diagnosis of hypersensitivity to beta-lactams an EAACI position paper. Allergy. 2020;75(6):1300-15. [Crossref]  [PubMed]
  31. Khan DA, Banerji A, Blumenthal KG, Phillips EJ, Solensky R, White AA, et al. Drug allergy: A 2022 practice parameter update. Journal of Allergy and Clinical Immunology. 2022;150(6):1333-93. [Crossref]  [PubMed]
  32. Pichichero ME. A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients. Pediatrics. 2005;115(4):1048-57. [Crossref]  [PubMed]
  33. Zagursky RJ, Pichichero ME. Cross-reactivity in  -Lactam Allergy. The Journal of Allergy and Clinical Immunology: In Practice. 2018;6(1):72-81.e1. [Crossref]  [PubMed]
  34. Zagursky RJ, Pichichero ME. Cross-reactivity in -Lactam Allergy. J Allergy Clin Immunol Pract. 2018;6(1):72-81. e1. [Crossref]  [PubMed]
  35. Cernadas J, Vasconcelos MJ, Carneiro-Leão L. Desensitization in children allergic to drugs: Indications, protocols, and limits. Pediatric Allergy and Immunology. 2023;34(6):e13965. [Crossref]  [PubMed]
  36. Sullivan TJ, Yecies LD, Shatz GS, Parker CW, Wedner HJ. Desensitization of patients allergic to penicillin using orally administered beta-lactam antibiotics. J Allergy Clin Immunol. 1982;69(3):275-82. [Crossref]  [PubMed]
  37. Yilmaz O, Ertoy Karagol IH, Bakirtas A, Topal E, Celik GE, Demirsoy MS, et al. Challenge-proven nonsteroidal anti-inflammatory drug hypersensitivity in children. Allergy. 2013;68(12):1555-61. [Crossref]  [PubMed]
  38. Çelik G, Pichler WJ, Adkinson NF. Drug allergy. In: Adkinson NF, Bochner BS, Busse WW, Holgate ST, Lemans-ke RF, Simons FER (eds). Middleton's Allergy. 7th ed. China, 2009:1205-26. [Crossref]
  39. Ayuso P, Blanca-López N, Doña I, Torres MJ, GuéantRod-ríguez RM, Canto G, et al. Advanced phenotyping in hypersensitivity drug reactions to NSAIDs. Clin Exp Allergy 2013;43:1097-109. [Crossref]  [PubMed]
  40. Kidon M, Blanca-Lopez N, Gomes E, Terreehorst I, Tanno L, Ponvert C, et al. EAACI/ENDA Position Paper: Diagnosis and management of hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) in children and adolescents. Pediatr Allergy Immunol. 2018 Aug;29(5):469-480. [Crossref]  [PubMed]
  41. Caimmi S, Caimmi D, Bousquet PJ, Demoly P. How can we better classify NSAID hypersensitivity reactions? -Validation from a Large Database. Int Arch Allergy Immunol. 2012;159:306-312. [Crossref]  [PubMed]
  42. Kowalski ML, Asero R, Bavbek S, Blanca M, Blanca-Lopez N, Bochenek G, et al. Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs. Allergy. 2013;68(10):1219-32. [Crossref]  [PubMed]
  43. Blanca-López N, Cornejo-García JA, Plaza-Serón MC, Doña I, Torres-Jaén MJ, Canto G, et al. Hypersensitivity to Nonsteroidal Anti-inflammatory Drugs in Children and Adolescents: Cross-Intolerance Reactions. J Investig Allergol Clin Immunol. 2015;25(4):259-69. [PubMed]
  44. Blanca-López N, Cornejo-García JA, Pérez-Alzate D, Pérez-Sánchez N, Plaza-Serón MC, Doña I, et al. Hypersensitivity Reactions to Nonsteroidal Anti-inflammatory Drugs in Children and Adolescents: Selective Reactions. J Investig Allergol Clin Immunol. 2015;25(6):385-95. [PubMed]
  45. Dibek Mısırlıoğlu E. Ağır İlaç Aşırı Duyarlılık Reaksiyonları: Türkiye Ulusal Rehberi 2020.
  46. Çelik G, Dursun B. İlaç Aşırı Duyarlılık Reaksiyonlarına Yaklaşım:UlusalRehberGüncellemesi2019.
  47. Guvenir H, Dibek Misirlioglu E, Vezir E, Toyran M, Ginis T, Civelek E, et al. Nonsteroidal anti-inflammatory drug hypersensitivity among children. Allergy Asthma Proc. 2015;36(5):386-93. [Crossref]  [PubMed]
  48. Cavkaytar O, Arga M. NSAID Hypersensitivity in the Pediatric Population: Classification and Diagnostic Strategies. J Asthma Allergy. 2022;15:1383-1399. [Crossref]  [PubMed]  [PMC]
  49. Doña I, Moreno E, Pérez-Sánchez N, et al. An algorithm for the diagnosis and treatment of nonsteroidal anti-inflammatory drugs hypersensitivity. Allergy. 2024;79(3):621-639.
  50. Muraro A, Worm M, Alviani C, Cardona V, DunnGalvin A, Garvey LH, Riggioni C et al; European Academy of Allergy and Clinical Immunology, Food Allergy, Anaphylaxis Guidelines Group. EAACI guidelines: Anaphylaxis (2021 update). Allergy. 2022;77(2):357-377. [Crossref]  [PubMed]
  51. Francuzik W, Ruëff F, Bauer A, Bilò MB, Cardona V, Christoff G, et al. Phenotype and risk factors of venom-induced anaphylaxis: A case-control study of the European Anaphylaxis Registry. J Allergy Clin Immunol. 2021;147(2):653662.e9. [Crossref]  [PubMed]
  52. Aurich S, Dölle-Bierke S, Francuzik W, Bilo MB, Christoff G, Fernandez-Rivas M, et al. Anaphylaxis in Elderly Patients-Data From the European Anaphylaxis Registry. Front Immunol. 2019;10:750. [Crossref]  [PubMed]  [PMC]
  53. Hassani A, Ponvert C, Karila C, Le Bourgeois M, De Blic J, Scheinmann P. Hypersensitivity to cyclooxygenase inhibitory drugs in children: a study of 164 cases. Eur J Dermatol. 2008;18(5):561-5.
  54. Gomes ER, Demoly P. Epidemiology of hypersensitivity drug reactions. Curr Opin Allergy Clin Immunol. 2005;5(4):309-16.15985812. [Crossref]  [PubMed]
  55. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-273. [Crossref]  [PubMed]
  56. Erlewyn-Lajeunesse M, Dymond S, Slade I, Mansfield HL, Fish R, Jones O, et al. Diagnostic utility of two case definitions for anaphylaxis: a comparison using a retrospective case notes analysis in the UK. Drug Saf. 2010;33(1):57-64. [Crossref]  [PubMed]
  57. Loprinzi Brauer CE, Motosue MS, Li JT, Hagan JB, Bellolio MF, Lee S, et al. Prospective Validation of the NIAID/ FAAN Criteria for Emergency Department Diagnosis of Anaphylaxis. J Allergy Clin Immunol Pract. 2016 NovDec;4(6):1220-1226. [Crossref]  [PubMed]
  58. Yilmaz Ö, Ertoy Karagöl Hİ, Bakırtaş A. Non-steroidal anti-inflammatory drug hypersensitivity in children. Asthma Allergy Immunology, 2022, 12.3: 123-129.
  59. Jerschow E, Lin RY, Scaperotti MM, McGinn AP. Fatal anaphylaxis in the United States, 1999-2010: temporal patterns and demographic associations. J Allergy Clin Immunol. 2014;134(6):1318-1328.e7. [Crossref]  [PubMed]  [PMC]
  60. Blanca-Lopez N, Cornejo JA, Perez-Sanchez NI, et al. Hypersensitivity reactions to NSAIDs in children. J Allergy Clin Immunol. 2017;139:AB34. [Crossref]
  61. Kowalski ML, Agache I, Bavbek S, Bakirtas A, Blanca M, Bochenek G, et al. Diagnosis and management of NSAID-Exacerbated Respiratory Disease (N-ERD)-a EAACI position paper. Allergy. 2019;74(1):28-39. [Crossref]  [PubMed]
  62. Simon RA. Diagnostic challenge and desensitization protocols for NSAID reactions.
  63. Nizankowska-Mogilnicka E, Bochenek G, Mastalerz L, Swierczyńska M, Picado C, Scadding G, et al. A. EAACI/ GA2LEN guideline: aspirin provocation tests for diagnosis Şahin, Geyik Anaphylaxis with Beta-Lactams and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) of aspirin hypersensitivity. Allergy. 2007;62(10):1111-8. [Crossref]  [PubMed]
  64. Misirlioglu ED, Toyran M, Capanoglu M, Kaya A, Civelek E, Kocabas CN. Negative predictive value of drug provocation tests in children. Pediatr Allergy Immunol. 2014 Nov;25(7):685-90. [Crossref]  [PubMed]
  65. Soyer O, Sahiner UM, Sekerel BE. Pro and Contra: Provocation Tests in Drug Hypersensitivity. Int J Mol Sci. 2017;18(7):1437. [Crossref]  [PubMed]  [PMC]
  66. Demoly P, Kropf R, Bircher A, Pichler WJ. Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity. Allergy. 1999;54(9):999-1003. [Crossref]  [PubMed]
  67. Brockow K, Romano A, Blanca M, Ring J, Pichler W, Demoly P. General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy. 2002;57(1):45-51. [Crossref]  [PubMed]
  68. Barbaud A, Gonçalo M, Bruynzeel D, Bircher A; European Society of Contact Dermatitis. Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions. Contact Dermatitis. 2001;45(6):321-8. [Crossref]  [PubMed]
  69. Blanca M, Torres MJ, García JJ, Romano A, Mayorga C, de Ramon E, Vega JM, et al. Natural evolution of skin test sensitivity in patients allergic to beta-lactam antibiotics. J Allergy Clin Immunol. 1999;103(5 Pt 1):918-24. [Crossref]  [PubMed]
  70. Aberer W, Bircher A, Romano A, Blanca M, Campi P, Fernandez J, et al. European Network for Drug Allergy (ENDA); EAACI interest group on drug hypersensitivity. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy. 2003;58(9):854-63. [Crossref]  [PubMed]
  71. Lee S, Hess EP, Nestler DM, Bellamkonda Athmaram VR, Bellolio MF, Decker WW, et al. Antihypertensive medication use is associated with increased organ system involvement and hospitalization in emergency department patients with anaphylaxis. J Allergy Clin Immunol. 2013;131(4):1103-8. [Crossref]  [PubMed]
  72. de Silva D, Singh C, Muraro A, Worm M, Alviani C, Cardona V, et al.; European Academy of Allergy and Clinical Immunology Food Allergy and Anaphylaxis Guidelines Group. Diagnosing, managing and preventing anaphylaxis: Systematic review. Allergy. 2021;76(5):1493-1506. [Crossref]  [PubMed]
  73. Shaker MS, Wallace DV, Golden DBK, Oppenheimer J, Bernstein JA, Campbell RL, et al. Anaphylaxis 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis. J Allergy Clin Immunol. 2020;145(4):1082-1123. [Crossref]  [PubMed]
  74. Li X, Zhou M, Xia Q, Li J. Parecoxib sodium reduces the need for opioids after tonsillectomy in children: a double-blind placebo-controlled randomized clinical trial. Can J Anaesth. 2016;63(3):268-74. [Crossref]  [PubMed]
  75. Eleftheriou D, Levin M, Shingadia D, Tulloh R, Klein NJ, Brogan PA. Management of Kawasaki disease. Arch Dis Child. 2014;99(1):74-83. [Crossref]  [PubMed]  [PMC]
  76. Cernadas JR, Brockow K, Romano A, Aberer W, Torres MJ, Bircher A, et al. European Network of Drug Allergy and the EAACI interest group on drug hypersensitivity. General considerations on rapid desensitization for drug hypersensitivity a consensus statement. Allergy. 2010;65(11):1357-66. [Crossref]  [PubMed]