HLA- and immune-mediated adverse drug reactions: Another hit with vancomycin

Serious cutaneous adverse reactions are an important clinical problem caused by a variety of drugs.1Duong T.A. Valeyrie-Allanore L. Wolkenstein P. Chosidow O. Severe cutaneous adverse reactions to drugs.Lancet. 2017; 390: 1996-2011Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar The most serious clinical manifestations are drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis. DRESS, a multisystem hypersensitivity syndrome, is immune mediated and can be associated with mortality rates of up to 10%. Antibiotics are among the most common drugs to cause DRESS. A recent analysis of a large electronic health care record database showed the prevalence of DRESS to be 2.18 per 100,000, with antibiotics responsible for 74% of cases.2Wolfson A.R. Zhou L. Li Y. Phadke N.A. Chow O.A. Blumenthal K.G. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome identified in the electronic health record allergy module.J Allergy Clin Immunol Pract. 2019; 7: 633-640Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar The antibiotics most commonly implicated were vancomycin (39%), β-lactams (23%), fluoroquinolones (4%), tetracyclines (4%), and sulfonamides (3%). There has been increasing interest in antibiotics recently because of the increase in the incidence of antimicrobial resistance (AMR), which has led to grave warnings that this might result in up to 10 million deaths a year by 2050.3O'Neill J. Review on antimicrobial resistance: tackling a crisis for the health and wealth of nations. Review on antimicrobial resistance..https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdfGoogle Scholar Although AMR is largely driven by the overuse of antibiotics in human subjects and animals, other factors also play a role. In many infections multiple antibiotics are administered concomitantly. If a patient has a hypersensitivity reaction, the clinician will not know definitively which antibiotic was responsible for the reaction. Using the precautionary principle, the patient will be labeled as "allergic" to all the administered antibiotics, and for subsequent infections, the patient will be treated with alternative antibiotics, which might have a greater risk of AMR, might be more costly, and might not be the most effective antibiotics. This has been a particular problem with penicillin allergy, which is overdiagnosed (falsely reported to occur in over 90% of those labeled as penicillin allergic) and leads to use of more broad-spectrum antibiotics. A recent United Kingdom–based cohort study showed that documented penicillin allergy led to a greater risk of methicillin-resistant Staphylococcus aureus and Clostridium difficile infection.4Blumenthal K.G. Lu N. Zhang Y. Li Y. Walensky R.P. Choi H.K. Risk of methicillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study.BMJ. 2018; 361: k2400Crossref PubMed Scopus (173) Google Scholar Vancomycin is a glycopeptide antibiotic that is active against gram-positive microbes, including methicillin-resistant S aureus. DRESS caused by vancomycin often manifests as rash, fever, eosinophilia, and renal dysfunction; a recent retrospective case review suggested that the likelihood of renal involvement was at least 2-fold greater than seen in patients with DRESS caused by other drugs.5Madigan L.M. Fox L.P. Vancomycin-associated drug-induced hypersensitivity syndrome (DIHS).J Am Acad Dermatol. 2019; ([Epub ahead of print])Google Scholar In this issue of the Journal, Konvinse et al6Konvinse K.C. Trubiano J.A. Pavlos R. James I. Shaffer C.M. Bejan C.A. et al.HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms.J Allergy Clin Immunol. 2019; 144: 183-192Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar have undertaken a genetic analysis of the HLA region in 23 patients with vancomycin-associated DRESS. They show that 82.6% of cases carried HLA-A*32:01 compared with 6% of the population from Vanderbilt's biorepository, a highly significant finding underlined by their calculations that (1) 19% of the positive group had DRESS within 4 weeks and (2) 75 patients would need to be tested to prevent 1 case of DRESS associated with vancomycin. It is interesting to note that most patients were taking other antibiotics concomitantly, which, as discussed above, can lead to problems in identifying the culprit drug. As with any genetic association, the findings need to be replicated in independent cohorts. However, given the effect size shown, it is likely that this will be a true-positive association. Future studies should also determine whether the same HLA association is observed in patients with hypersensitivity to teicoplanin, another glycopeptide antibiotic, which has been reported to cross-react with vancomycin.7Miyazu D. Kodama N. Yamashita D. Tanaka H. Inoue S. Imakyure O. et al.DRESS syndrome caused by cross-reactivity between vancomycin and subsequent teicoplanin administration: a case report.Am J Case Rep. 2016; 17: 625-631Crossref PubMed Scopus (16) Google Scholar The HLA association identified with vancomycin-associated DRESS is another addition to the striking number of associations that have been identified with hypersensitivity reactions caused by drugs. Indeed, about 30 such HLA associations have been identified since the beginning of this century.8Pirmohamed M. Ostrov D.A. Park B.K. New genetic findings lead the way to a better understanding of fundamental mechanisms of drug hypersensitivity.J Allergy Clin Immunol. 2015; 136: 236-244Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar The drugs implicated have had a wide variety of therapeutic indications (including anti-infectives, such as flucloxacillin, co-amoxiclav, dapsone, abacavir, and nevirapine), have disparate structures, and have affected different organ systems (Fig 1).9Alfirevic A. Pirmohamed M. Genomics of adverse drug reactions.Trends Pharmacol Sci. 2017; 38: 100-109Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Some of these associations have been implemented into clinical practice, with positive benefits including HLA-B*57:01 genotyping before the use of abacavir, HLA-B*15:02 before carbamazepine prescription in Southeast Asian patients, and HLA-B*58:01 before allopurinol, again in some Asian countries.8Pirmohamed M. Ostrov D.A. Park B.K. New genetic findings lead the way to a better understanding of fundamental mechanisms of drug hypersensitivity.J Allergy Clin Immunol. 2015; 136: 236-244Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Given the many advances in the pharmacogenetics of adverse drug reactions (ADRs) over the last 2 decades, a framework for how these tests can be used to improve clinical practice has been proposed.9Alfirevic A. Pirmohamed M. Genomics of adverse drug reactions.Trends Pharmacol Sci. 2017; 38: 100-109Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Although pharmacogenetic tests have largely been used for the prediction and prevention of ADRs, perhaps they can also be used for exclusion of ADRs and stratification of monitoring and diagnosis, as well as pre-emptively and to understand the mechanisms used. This framework is consistent with the suggestion by Konvinse et al6Konvinse K.C. Trubiano J.A. Pavlos R. James I. Shaffer C.M. Bejan C.A. et al.HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms.J Allergy Clin Immunol. 2019; 144: 183-192Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar that HLA testing could be used for risk stratification after starting vancomycin but before the development of DRESS. To facilitate the implementation of HLA testing for ADRs, an HLA gene panel has been developed, which aims to have a turnaround time of 48 hours (Pirmohamed, unpublished) and has been shown to be cost-effective.10Plumpton C.O. Pirmohamed M. Hughes D.A. Cost-effectiveness of panel tests for multiple pharmacogenes associated with adverse drug reactions: an evaluation framework.Clin Pharmacol Ther. 2019; 105: 1429-1438Crossref PubMed Scopus (17) Google Scholar In the context of AMR, pharmacogenomic tests (in combination with other tests, such as the IFN-γ ELISpot, as used by Konvinse et al6Konvinse K.C. Trubiano J.A. Pavlos R. James I. Shaffer C.M. Bejan C.A. et al.HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms.J Allergy Clin Immunol. 2019; 144: 183-192Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar) could be used to identify the culprit drug (when multiple drugs are started in combination) and/or exclude a suspected drug9Alfirevic A. Pirmohamed M. Genomics of adverse drug reactions.Trends Pharmacol Sci. 2017; 38: 100-109Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar and therefore enable patients to receive antibiotics in the future, which might otherwise not have been available if the patient is wrongly labeled as being allergic. In summary, the important finding that HLA-A*32:01 predisposes to vancomycin-associated DRESS adds to the growing evidence of the importance of the HLA region in predisposing to drug hypersensitivity reactions. It also provides an opportunity to prevent these serious ADRs, improve their clinical management, or both, which in the case of antibiotics might have unintended benefits in the fight against AMR. I thank the MRC Centre for Drug Safety Science for support. HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptomsJournal of Allergy and Clinical ImmunologyVol. 144Issue 1PreviewVancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which leads to significant morbidity and mortality and commonly occurs in the setting of combination antibiotic therapy, affecting future treatment choices. Variations in HLA class I in particular have been associated with serious T cell–mediated adverse drug reactions, which has led to preventive screening strategies for some drugs. Full-Text PDF