Factoring in cofactors in the diagnosis and management of anaphylaxis

Abstract

Anaphylaxis is the most severe manifestation of an acute allergic reaction and will occur in approximately 5% of the US population.1Turner PJ Jerschow E Umasunthar T Lin R Campbell DE Boyle RJ Fatal anaphylaxis: mortality rate and risk factors.J Allergy Clin Immunol Pr. 2017; 5: 1169-1178Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar Food allergy is the most common trigger, with approximately 25% to 50% of food reactions in adults resulting in anaphylaxis.2Bartra J Turner PJ Munoz-Cano RM Lin R Campbell DE Boyle RJ Cofactors in food anaphylaxis in adults.Ann Allergy Asthma Immunol. 2023; 130: 733-740Abstract Full Text Full Text PDF Scopus (1) Google Scholar However, even in an individual patient with food allergy, reaction severity to a known food allergen can be unpredictable and variable in severity.3Muñoz-Cano R San Bartolome C Casas-Saucedo R Araujo G Gelis S Ruano-Zaragoza M et al.Immune-mediated mechanisms in cofactor-dependent food allergy and anaphylaxis: effect of cofactors in basophils and mast cells.Front Immunol. 2021; 11623071Crossref Scopus (11) Google Scholar In addition, some individuals may tolerate an allergen exposure in some cases but react in others.3Muñoz-Cano R San Bartolome C Casas-Saucedo R Araujo G Gelis S Ruano-Zaragoza M et al.Immune-mediated mechanisms in cofactor-dependent food allergy and anaphylaxis: effect of cofactors in basophils and mast cells.Front Immunol. 2021; 11623071Crossref Scopus (11) Google Scholar This phenomenon can be partially explained by cofactors, which either increase reaction severity or lower the threshold of reactivity in an individual. Cofactors, which include exercise, various medications, and alcohol, have been identified in up to 30% of anaphylactic reactions in adults (and up to 58% of food anaphylaxis).2Bartra J Turner PJ Munoz-Cano RM Lin R Campbell DE Boyle RJ Cofactors in food anaphylaxis in adults.Ann Allergy Asthma Immunol. 2023; 130: 733-740Abstract Full Text Full Text PDF Scopus (1) Google Scholar,3Muñoz-Cano R San Bartolome C Casas-Saucedo R Araujo G Gelis S Ruano-Zaragoza M et al.Immune-mediated mechanisms in cofactor-dependent food allergy and anaphylaxis: effect of cofactors in basophils and mast cells.Front Immunol. 2021; 11623071Crossref Scopus (11) Google Scholar In some individuals, various cofactors may be required to increase reaction severity or lower reaction threshold.3Muñoz-Cano R San Bartolome C Casas-Saucedo R Araujo G Gelis S Ruano-Zaragoza M et al.Immune-mediated mechanisms in cofactor-dependent food allergy and anaphylaxis: effect of cofactors in basophils and mast cells.Front Immunol. 2021; 11623071Crossref Scopus (11) Google Scholar Cofactors remain poorly understood, poorly described, and likely underrecognized. In the current issue of the Annals of Allergy, Asthma & Immunology, Bartra et al2Bartra J Turner PJ Munoz-Cano RM Lin R Campbell DE Boyle RJ Cofactors in food anaphylaxis in adults.Ann Allergy Asthma Immunol. 2023; 130: 733-740Abstract Full Text Full Text PDF Scopus (1) Google Scholar provide a comprehensive review of different extrinsic cofactors and the mechanisms (when understood) involved in alterations of food allergic reaction severity or threshold. This review focuses on exercise, nonsteroidal anti-inflammatory drugs, alcohol, angiotensin-converting enzyme inhibitors and beta-blockers, lipid-lowering drugs, estrogens, proton pump inhibitors, and sleep deprivation. This review will serve as a pertinent resource for any clinician involved in the workup of food anaphylaxis. Although the authors discuss each cofactor independently, they rightly note that a patient may “even need more than one cofactor to develop a more severe reaction … while either cofactor in isolation may not be needed” to trigger a reaction.2Bartra J Turner PJ Munoz-Cano RM Lin R Campbell DE Boyle RJ Cofactors in food anaphylaxis in adults.Ann Allergy Asthma Immunol. 2023; 130: 733-740Abstract Full Text Full Text PDF Scopus (1) Google Scholar Of note, this review focuses largely on modifiable cofactors and does not provide a comprehensive discussion on nonmodifiable (intrinsic) cofactors including age, sex, and comorbidities.4Poziomkowska-Gęsicka I Kostrzewska M Kurek M Comorbidities and cofactors of anaphylaxis in patients with moderate to severe anaphylaxis. Analysis of data from the anaphylaxis registry for West Pomerania Province, Poland.Int J Eviron Res Public Heal. 2021; 18: 333Crossref Scopus (12) Google Scholar This review has the potential to influence anaphylaxis diagnosis and management. It serves to remind the clinician of the importance of screening for, and evaluating, the presence of cofactors in any individual with anaphylaxis. A high degree of suspicion is necessary when evaluating cofactors as patients may not recall cofactors nor volunteer them. Cofactors may be the reason why a particular patient tolerates a food (or only has a mild reaction) in some instances, but in others has a severe allergic reaction.5Muñoz-Cano R Pascal M Araujo G Goikoetxea MJ Valero AL Picado C et al.Mechanisms, cofactors, and augmenting factors involved in anaphylaxis.Front Immunol. 2017; 8: 1193Crossref PubMed Scopus (56) Google Scholar Cofactors may be the reason a clinical history indicates a strong suspicion of a reaction to a specific food allergen but then there is a negative oral food challenge result.6Shin M Food allergies and food-induced anaphylaxis: role of cofactors.Clin Exp Pediatr. 2021; 64: 393-399Crossref PubMed Scopus (12) Google Scholar In that scenario, a food challenge in the presence of a cofactor could be considered. Cofactors should also be kept in mind for anaphylaxis long-term management. In many cases, such as with medications and alcohol use, cofactors are modifiable and have the potential to reduce severe anaphylaxis risk among our patients. This review is also a reminder to the clinician of gaps in anaphylaxis knowledge. As noted by Bartra et al,2Bartra J Turner PJ Munoz-Cano RM Lin R Campbell DE Boyle RJ Cofactors in food anaphylaxis in adults.Ann Allergy Asthma Immunol. 2023; 130: 733-740Abstract Full Text Full Text PDF Scopus (1) Google Scholar further information elucidating the mechanism for various cofactors is necessary as many are poorly understood. An understanding of mechanisms could serve to identify possible biomarkers or prophylactic therapies for our patient population.3Muñoz-Cano R San Bartolome C Casas-Saucedo R Araujo G Gelis S Ruano-Zaragoza M et al.Immune-mediated mechanisms in cofactor-dependent food allergy and anaphylaxis: effect of cofactors in basophils and mast cells.Front Immunol. 2021; 11623071Crossref Scopus (11) Google Scholar As has been previously postulated, because there is an individual predisposition to cofactor-enhanced anaphylaxis and as most cofactors can influence anaphylaxis severity or threshold, there may be some similar or overlapping pathogenic mechanism.3Muñoz-Cano R San Bartolome C Casas-Saucedo R Araujo G Gelis S Ruano-Zaragoza M et al.Immune-mediated mechanisms in cofactor-dependent food allergy and anaphylaxis: effect of cofactors in basophils and mast cells.Front Immunol. 2021; 11623071Crossref Scopus (11) Google Scholar Studies specific to cofactors in children are also necessary, as the vast majority of studies on cofactors have been conducted in the adult population. Several cofactors, including illness and exercise (or, in a younger pediatric population, active play), warrant prompt and thorough investigation for children, especially as children are increasingly involved in food oral immunotherapy. Food-dependent exercise-induced anaphylaxis has been described among children, an observation that is of concern for children at risk of anaphylaxis, including those who are undergoing immunotherapy.7Nagakura K-I Sato S Asaumi T Yanagida N Ebisawa M Novel insights regarding anaphylaxis in children - with a focus on prevalence, diagnosis, and treatment.Pediatr Allergy Immunol. 2020; 31: 879-888Crossref Scopus (19) Google Scholar Alcohol is an additional cofactor that remains minimally explored in adolescents at risk of anaphylaxis but one that warrants substantial exploration. Adolescents represent an age group that faces the combined risks of increasing rates of alcohol consumption8National Institute on Alcohol Abuse and Alcoholism. Underage drinking. Available at: https://www.niaaa.nih.gov/publications/brochures-and-fact-sheets/underage-drinking on 20230315. Accessed March 15, 2023.Google Scholar and general risk taking. The potential for alcohol as a cofactor and the oft-parallel behavior of smoking, which may exacerbate comorbid asthma, remain poorly elucidated, but theoretically substantial, in this age group. Finally, an additional cofactor for anaphylaxis that warrants investigation among both adults and children is gender. Although differences in estrogens, and more broadly biological sex, have been described,2Bartra J Turner PJ Munoz-Cano RM Lin R Campbell DE Boyle RJ Cofactors in food anaphylaxis in adults.Ann Allergy Asthma Immunol. 2023; 130: 733-740Abstract Full Text Full Text PDF Scopus (1) Google Scholar there is a paucity of data on gender as a cofactor. However, as gender may predict health-related behaviors, ranging from allergen exposure to seeking health care,9De Martinis M Sirufo MM Suppa M Di Silvestre D Ginaldi L Sex and gender aspects for patient stratification in allergy prevention and treatment.In J Mol Sci. 2020; 21: 1535Crossref PubMed Scopus (39) Google Scholar gender (independent of sex) may be an additional cofactor for anaphylaxis. Moving forward, we should consider how we collect, code, and interpret anaphylaxis data. It has been previously described that anaphylaxis triggers are not coded properly in data systems which prevents the opportunity to accurately identify triggers and cofactors. Proper, standardized data collection would further the opportunity to study the impact of cofactors more granularly in the future.10Turner PJ Campbell DE Motosue MS Campbell RL Global trends in anaphylaxis epidemiology and clinical implications.J Allergy Clin Immunol Pract. 2020; 8: 1169-1176Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar In conclusion, this review prompts the clinician to remain broad in the initial diagnostic workup for anaphylaxis and always consider cofactors as a contributing factor. As aptly stated at the end of this review, cofactors should always be evaluated in our patient population to reduce the risk of, and severity of, anaphylaxis. Cofactors in food anaphylaxis in adultsAnnals of Allergy, Asthma & ImmunologyVol. 130Issue 6PreviewAround 25% to 50% of food-induced allergic reactions in adults cause anaphylaxis, and epidemiologic evidence suggests that food is the most common cause of anaphylaxis. Reaction severity is unpredictable, and patients will often experience reactions of variable severity, even to an identical exposure (both dose and allergen). A common explanation for this phenomenon has been the impact of “cofactors”—factors that might contribute to reaction severity independent of the allergen exposure. Cofactors can influence reaction severity in 2 ways: either by reducing the reaction threshold (ie, the dose needed to trigger any symptoms) so that patients have no symptoms in the absence of the cofactor and only react with the cofactor present, or by increasing reaction severity such that individuals have only mild symptoms in the absence of the cofactor, but a more severe reaction when the cofactor is present. Full-Text PDF