Reply
Authors: David A. Khan, Kimberly G. Blumenthal
Journal: Journal of Allergy and Clinical Immunology (2024)

We thank Watts1Watts T.J. Grading immediate drug reactions: adopting a robust diagnostic approach.J Allergy Clin Immunol. 2024; 153 (xx-xx)Google Scholar for his interest in our article "United States Drug Allergy Registry (USDAR) grading scale for immediate drug reactions."2Khan D.A. Phillips E.J. Accarino J.J. Gonzalez-Estrada A. Otani I.M. Ramsey A. et al.United States Drug Allergy Registry (USDAR) grading scale for immediate drug reactions.J Allergy Clin Immunol. 2023; 152: 1581-1586Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar He raises 3 separate concerns for consideration that on behalf of the USDAR Study Team, we are happy to address. The first concern relates to the time frame used to define immediate reactions as within 6 hours of the last drug administration. This time frame was used on the basis of the International Consensus on drug allergy definition of immediate drug reactions.3Demoly P. Adkinson N.F. Brockow K. Castells M. Chiriac A.M. Greenberger P.A. et al.International Consensus on drug allergy.Allergy. 2014; 69: 420-437Crossref PubMed Scopus (747) Google Scholar In the scenario of a patient with a history of a penicillin allergy who develops 10 hives 5 to 6 hours following a challenge, the severity of this reaction would indeed be a grade 1 reaction. We agree that IgE-mediated reactions to penicillin usually occur within minutes of exposure; however, more delayed urticarial reactions to penicillin that are mediated by IgE have been well documented since the 1960s and were termed accelerated reactions by Levine.4Levine B.B. Redmond A.P. Voss H.E. Zolov D.M. Prediction of penicillin allergy by immunological tests.Ann N Y Acad Sci. 1967; 145: 298-309Crossref PubMed Scopus (25) Google Scholar Importantly, the USDAR grading scale is intended to grade the severity of reactions, not necessarily to confirm a diagnosis. As noted in our article,2Khan D.A. Phillips E.J. Accarino J.J. Gonzalez-Estrada A. Otani I.M. Ramsey A. et al.United States Drug Allergy Registry (USDAR) grading scale for immediate drug reactions.J Allergy Clin Immunol. 2023; 152: 1581-1586Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar a grade 1 reaction is "suggestive of a potential immediate reaction," the reaction with the lowest likelihood of a true drug allergy. We would agree with Watts1Watts T.J. Grading immediate drug reactions: adopting a robust diagnostic approach.J Allergy Clin Immunol. 2024; 153 (xx-xx)Google Scholar that in a patient with a low risk and remote history of a reaction to penicillin who develops this type of grade 1 reaction to a penicillin challenge, a repeat challenge or placebo-controlled challenge may be considered to confirm a diagnosis.5Khan D.A. Banerji A. Blumenthal K.G. Phillips E.J. Solensky R. White A.A. et al.Drug allergy: a 2022 practice parameter update.J Allergy Clin Immunol. 2022; 150: 1333-1393Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar The use of this USDAR scale for confirming diagnosis of true drug allergy requires confirmation through future studies that are planned by the USDAR. The second concern relates to reactions in patients with nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NSAID-ERD). We agree that rhinoconjunctivitis occurs commonly in patients with NSAID-ERD. However, NSAID-ERD is a unique form of drug hypersensitivity that does not align with other immediate drug reactions. The diagnosis of NSAID-ERD can often be determined by clinical factors, which led the most recent Drug Allergy Practice Parameter to recommend against oral challenge to confirm a diagnosis in patients with high diagnostic certainty.5Khan D.A. Banerji A. Blumenthal K.G. Phillips E.J. Solensky R. White A.A. et al.Drug allergy: a 2022 practice parameter update.J Allergy Clin Immunol. 2022; 150: 1333-1393Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Nevertheless, patients with NSAID-ERD could have the severity of their reactions graded by the USDAR scale, in which case rhinoconjunctivitis symptoms, which are mild and not life-threatening, would not be captured. The third concern raised is that certain delayed-type hypersensitivity reactions (eg, fixed drug eruptions) can present with more rapid symptoms, typically subsequent to reexposure. As noted in the article, this USDAR grading scale is not indicated for use for delayed reactions. The reactions of most patients with fixed drug eruptions can be differentiated from other more immediate drug reactions on the basis of clinical features, as a result of which use of this severity scale would be excluded. As this is still a proposed grading scale that has achieved USDAR consensus but has not been validated, additional studies must determine how commonly this scenario occurs and whether specific additional exclusion requirements will need to be made. Although the USDAR grading schema for immediate drug reactions improves on prior schemata, validation studies are needed. The use of this scale to aid in diagnosis will also require further study. Supported by the National Institutes of Health (grant R34 AI134569). Disclosure of potential conflict of interest: D. A. Khan receives grant support from the NIH and royalties from Elsevier and UpToDate. K. G. Blumenthal receives grant support from the NIH/National Institute ofAllergy and Infectious Diseases (grant R01AI150295), Phadia Ab (Thermo Fisher Scientific), and the Massachusetts General Hospital; personal fees for legal case review from Weekly Schulte Valdes Murman Tonelli, Piedmont Liability Trust, Vasios Kelly and Stollo PA, and Publix Supermarkets; and royalties from UpToDate, outside the submitted work. Grading immediate drug reactions: Adopting a robust diagnostic approachJournal of Allergy and Clinical ImmunologyPreviewI read with great interest the article by Khan et al,1 which proposes a severity grading system for immediate drug reactions developed by the US Drug Allergy Registry (USDAR) investigators. They describe a grading scale from 0 to 4 that is intended primarily for use with drug challenges and ranges from effectively "no immediate reaction" (a negative challenge result) to severe anaphylactic shock. Khan et al1 comment that grades 1 to 4 meet the criteria for a positive drug challenge result and may be considered drug allergy; they conclude that this system needs validation (internal/external) before knowing its overall clinical usefulness. Full-Text PDF