Severity grading system for acute allergic reactions—time for validation and assessment of best practices

Abstract

A challenge in the allergy and immunology field has been the development and implementation of a universally accepted consensus severity grading system for acute allergic reactions that is applicable to all patient populations and considers the perception and needs of all stakeholders. There is consensus that a universal classification system and common language will be beneficial to all stakeholders, leading to standardization of patient monitoring, improve management and safety comparisons of clinical trials and immunotherapy approaches, identify best clinical practices, and possibly determine the most appropriate emergency treatment. In the current issue, Dribin et al1Dribin T.E. Schnadower D. Spergel J.M. Campbell R.L. Shaker M. Neuman M.I. et al.Severity grading system for acute allergic reactions: a multidisciplinary Delphi study.J Allergy Clin Immunol. 2021; 148: 173-181Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar as part of a 21-member multidisciplinary panel of allergy and emergency care experts applied the Delphi technique to develop a consensus-based grading system for acute allergic and nonallergic reactions. The classification system is based on the principle that the severity of acute allergic reactions is a continuum from a mild allergic reaction to anaphylactic shock. The classification system is organized into a grading and subgrading system, making it intuitive and straightforward to be applied to daily clinical practice while being sufficiently detailed and differentiating of signs and symptoms in reaction severity for research purposes. A current limitation of the grading system is that it has not undergone dissemination, validation, and comparative analyses to determine the utility of these criteria for best clinical practice and research purposes. Given that there are already a number of acute allergic reaction classification systems described and others being formulated, it would seem timely that the invested organizations (National Institutes of Health, European Academy of Allergology and Clinical Immunology, American Academy of Asthma, Allergology and Clinical Immunology, American College of Allergy, Asthma and Immunology, and World Allergy Organization [WAO]) and stakeholders come together to assess the interrater reliability, generalizability, practicality of the classification systems, and best clinical practices. Acute allergic reactions (AARs) are rapid in onset, can be biphasic, and occur on a severity continuum from mild symptoms (urticaria, tingling or itching of lips or throat, sneezing rhinorrea) to the potentially life-threatening severe form of anaphylactic shock.2Shaker M.S. Wallace D.V. Golden D.B.K. Oppenheimer J. Bernstein J.A. Campbell R.L. et al.Anaphylaxis—a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis.J Allergy Clin Immunol. 2020; 145: 1082-1123Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar From 2008 to 2016, emergency department visits for anaphylaxis in the United States have doubled across all ages and tripled among children, and patients do not appear adequately equipped to manage future reactions.3Wood R.A. Camargo Jr., C.A. Lieberman P. Sampson H.A. Schwartz L.B. Zitt M. et al.Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States.J Allergy Clin Immunol. 2014; 133: 461-467Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar AARs can occur following exposure to various triggers (foods, medications, and biological compounds) in a broad range of environments (eg, home, school, and health care). The challenge with AARs is that they do not always present with a constant constellation of symptoms, and the severity of an individual’s reaction following exposure to the trigger is not necessarily predicted by clinical history or previous reactions. The rapid onset and unpredictable nature of AARs adversely affect the health-related quality of life of patients, parents, and families, leading to significant anxiety and restrictive daily activities.4van der Velde J.L. Dubois A.E. Flokstra-de Blok B.M. Food allergy and quality of life: what have we learned?.Curr Allergy Asthma Rep. 2013; 13: 651-661Crossref PubMed Scopus (28) Google Scholar A key element in the management of AARs is the accurate assessment and communication of reaction severity between the different stakeholders. Given the variability in health care and research settings, a universal and common language using standardized and straightforward terminology and definitions is needed to enable comparison of safety outcomes associated with different patient practices and therapeutic interventions and research activities (eg, clinical trials). Furthermore, a common classification system will strengthen communication between third-party stakeholders (patient advocacy groups, disease registries, food and drug industries, legislative bodies, and government agencies and regulators), enhancing public education, support service resources, and legislative bodies public health communications. This has led to significant efforts by the World Allergy and Immunology community to develop a universally accepted consensus acute allergic reaction grading system.5Cox L.S. Sanchez-Borges M. Lockey R.F. World Allergy Organization Systemic Allergic Reaction Grading System: is a modification needed?.J Allergy Clin Immunol Pract. 2017; 5: 58-62.e5Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar However, to date no one consensus grading system has been universally accepted and implemented. Previous classifications have been limited by lack of granularity and inability to distinguish between clinical important phenotypes, nonspecific terminology, impracticality, subjective clinical outcomes, trigger and mode of exposure specificity, and narrowed focus of reaction. Other classifications required rate of onset, definition of specific symptoms and signs, organ involvement to a specific grade, and incorporation of therapeutic usage with a rate of responsiveness.5Cox L.S. Sanchez-Borges M. Lockey R.F. World Allergy Organization Systemic Allergic Reaction Grading System: is a modification needed?.J Allergy Clin Immunol Pract. 2017; 5: 58-62.e5Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar In efforts to overcome these issues, Dribin et al using the Delphi methodological approach developed a consensus criterion to describe the development of a severity grading system for AARs for use in clinical care and research. The 21-member multidisciplinary panel of experts in the field of anaphylaxis included allergists, immunologists, and general pediatric emergency medicine specialists based on expert recommendations, published research, and membership in national research networks and/or anaphylaxis interest groups. A 9-panel subgroup served as a writing group that (1) reviewed the literature search to assess the strengths and limitations of previous grading systems; (2) developed criterion attributes for an optimal grading system including how the acute allergic reaction grading system should be structured and used in clinical care and research; and (3) created and revised a draft grading system based on telephone and electronic communications as part of the multiple rounds feedback. The Delphi technique was originally developed in the 1950s to obtain a reliable consensus of opinion from a group of experts to forecast the impact of technology on warfare and is widely used in business, educational, social sciences, and health care domains.6Veugelers R. Gaakeer M.I. Patka P. Huijsman R. Improving design choices in Delphi studies in medicine: the case of an exemplary physician multi-round panel study with 100% response.BMC Med Res Methodol. 2020; 20: 156Crossref PubMed Scopus (10) Google Scholar The method involves an iterative process of having a group of experts anonymously reply to a series of questions interspersed with controlled feedback including group statistical responses, with the goal of reducing the range of responses and converging on an expert consensus. The anonymity among panelists is an advantage because it protects against individual and professional dominance bias and also permits panel members to reappraise their opinion on the basis of judgments presented by other panel members. However, whether the iterative process and reduction in variance of responses over multiple rounds reflects reasoned acceptance of a position or related to conformity pressures remains unclear. Disadvantages of this approach include design and quality of execution, lengthy time process, and participation dropout and accuracy of data. Dribin et al’s consensus system is organized into a grading system and a subgrading system. The grading system includes objective symptoms for different organ systems to ensure intuitive and straightforward application for clinical care. The 24-point subgrading system is a modification of that developed by Sampson et al to score reaction severity during oral food challenges and provides the ability to account for the entirety of symptoms within each organ system and assign a final severity grade on the basis of severity of organ system involvement. This subgrading system will be applicable for clinical research purposes. The authors achieved the newly developed grading system with 95.2% overall agreement and the subgrading system with a 90.5% overall agreement. No individual component had less than 80% agreement. The consensus for each item and the overall system was reached after one Delphi round with a consensus threshold of greater than 65% agreement. Meta-analysis of methodological features of Delphi in 26 previous study types in forecasting, policy, and technique comparison revealed on average of approximately 3.3 Delphi rounds per study.6Veugelers R. Gaakeer M.I. Patka P. Huijsman R. Improving design choices in Delphi studies in medicine: the case of an exemplary physician multi-round panel study with 100% response.BMC Med Res Methodol. 2020; 20: 156Crossref PubMed Scopus (10) Google Scholar In the Dribin study, consensus was reached after a single Delphi round, indicating that that there was significant degree of “pregroup” conformity between Dribin et al. Whether the lack of disparity reflects size and diversification within the 21-member multidisciplinary panel of experts remains unclear. Ingeniously, the authors also included an abridged pocket guide version of the grading system intended to promote easy use in clinical care. It is important to note that the Delphi methodology was not used when creating the pocket guide. Therefore, there was no assessment or consensus of the prioritization of the content in the abridged version; however, this version will enhance accessibility and utilization. The authors recognize that there are limitations with the proposed grading system including that (1) the grading system was developed to evaluate the severity of AARs and not chronic or nonallergic conditions; (2) that the grading system and definitions specific to it do not include every possible symptom; (3) that it is not intended to dictate patient-level management decisions; and (4) that the 24 elements in the grading system are somewhat complex and may need decision-support tools to be fully functional. Like other previous grading systems for acute adverse reactions, this grading system will need validation and possible refinement. However, as often happens with these grading systems, they are assessed in isolation by expert panels from a spectrum of health care settings and are challenged by subjective case scenarios without comprehensive quantitated evidence-based assessment or side-by-side comparison with other grading systems to determine validity, appropriate application, and best practice. It would seem appropriate at this time that the invested organizations (National Institutes of Health, European Academy of Allergology and Clinical Immunology, American Academy of Asthma, Allergology and Clinical Immunology, American College of Allergy, Asthma and Immunology, and WAO) come together and develop an international multidisciplinary panel of experts and perform a post hoc analysis of the current and emerging classification systems for adverse severe reactions. Inclusion of patient-centered studies to assess the interrater reliability of key symptoms and their association with patient-related outcomes, practicality, generalizability, and value to stakeholders would seem warranted. Vidal at al7Vidal C. Rodríguez Del Río P. Gude F. Casale T. Cox L. Just J. et al.Comparison of international systemic adverse reactions due to allergen immunotherapy.J Allergy Clin Immunol Pract. 2019; 7: 1298-1305.e3Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar performed a post hoc analysis aimed at investigating the practicality of proposed classification systems for systemic adverse reactions during allergen immunotherapy. The authors assessed international classifications proposed by the European Academy of Allergology and Clinical Immunology, the American Academy of Asthma, Allergology and Clinical Immunology/American College of Allergy, Asthma and Immunology, and the WAO using data provided by the longitudinal European Survey on Systemic Adverse Reactions in Allergen Immunotherapy (EASSI) based on daily clinical practice in 3 countries in Europe. The authors identified disparities in mild and moderate systemic adverse reactions in the different grading systems; however, overall, there was a good correlation between the EASSI-severity grading system and others. The number of system organ classes involved in the reaction best correlated with the WAO2010 and WAO2017 grading systems. Despite the lower correlation between WAO and EASSI-severity grading systems compared with others, the WAO grading system provided the best correlation among these classifications. Similar analyses have been performed for allergic rhinitis. One of the challenges associated with the development of a universally accepted severity grading system for acute adverse reactions is the lack of reliable biomarkers. Other allergic diseases such as asthma have quantitative measures including lung function tests (FEV1, forced vital capacity, and peak expiratory flow) that correlate with asthma exacerbations and have been integrated into the grading classification of asthma severity. Currently, there is no reliable biomarker for acute adverse reactions.8Beck S.C. Wilding T. Buka R.J. Baretto R.L. Huissoon A.P. Krishna M.T. Biomarkers in human anaphylaxis: a critical appraisal of current evidence and perspectives.Front Immunol. 2019; 10: 494Crossref PubMed Scopus (32) Google Scholar Previous studies have analyzed markers of mast cell activation such as histamine, tryptase, and chymase to predict severity of AARs. Increased serum total mast cell tryptase is diagnostic, and serum tryptase and histamine correlate with severity.9Stone S.F. Cotterell C. Isbister G.K. Holdgate A. Brown S.G. Elevated serum cytokines during human anaphylaxis: identification of potential mediators of acute allergic reactions.J Allergy Clin Immunol. 2009; 124: 786-792.e4Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar However, increased tryptase or histamine levels are not observed in all cases of acute adverse reactions. Other biomarkers that have been shown to be elevated during acute adverse reactions include chymase, carboxypeptidase A3, CCL-2, and basophils.8Beck S.C. Wilding T. Buka R.J. Baretto R.L. Huissoon A.P. Krishna M.T. Biomarkers in human anaphylaxis: a critical appraisal of current evidence and perspectives.Front Immunol. 2019; 10: 494Crossref PubMed Scopus (32) Google Scholar However, only CCL-2 has been shown to correlate with the severity of the reaction.10Vantur R. Rihar M. Koren A. Rijavec M. Kopac P. Bidovec-Stojkovic U. et al.Chemokines during anaphylaxis: the importance of CCL2 and CCL2-dependent chemotactic activity for basophils.Clin Transl Allergy. 2020; 10: 63Crossref PubMed Scopus (2) Google Scholar Development of a universally accepted and implemented grading system is likely to aid in the identification of reliable biomarkers that can more quantitatively assess severity of acute adverse reactions. Dribin et al have developed a consensus-based comprehensive grading classification system for acute adverse reactions for use in clinical care and research, adding to the growing number of classification systems. This classification system reinforces important principles and addresses a number of shortcomings of other classification systems. However, as with other systems, this classification system will require rigorous examination and comparative analyses with the goal of developing a universal language for all stakeholders to improve clinical care practices, facilitate research to better understand the disease processes, and improve current and novel therapeutics. I thank members of the Mary H. Weiser Food Allergy Center and the Division of Experimental Pathology at the University of Michigan Medicine for thoughtful discussions. Severity grading system for acute allergic reactions: A multidisciplinary Delphi studyJournal of Allergy and Clinical ImmunologyVol. 148Issue 1PreviewThere is no widely adopted severity grading system for acute allergic reactions, including anaphylactic and nonanaphylactic reactions, thus limiting the ability to optimize and standardize management practices and advance research. Full-Text PDF