Mechanisms of Risk for Sulfonamide Hypersensitivity

Hypersensitivity (HS) reactions to sulfonamide antibiotics occur uncommonly, but with potentially severe clinical manifestations. A familial predisposition to sulfonamide HS is suspected, but robust predictive genetic risk factors have yet to be identified. Strongly linked genetic polymorphisms have been used clinically as screening tests for other HS reactions prior to administration of high-risk drugs. The purpose of this study was to evaluate for genetic risk of sulfonamide HS in the immunocompetent population using genome-wide association. Ninety-one patients with symptoms after trimethoprim-sulfamethoxazole (TMP-SMX) attributable to "probable" drug HS based on medical record review and the Naranjo Adverse Drug Reaction Probability Scale, and 184 age- and sex-matched patients who tolerated a therapeutic course of TMP-SMX, were included in a genome-wide association study using both common and rare variant techniques. Additionally, two subgroups of HS patients with a more refined clinical phenotype (fever and rash; or fever, rash and eosinophilia) were evaluated separately. For the full dataset, no single nucleotide polymorphisms were suggestive of or reached genome-wide significance in the common variant analysis, nor was any genetic locus significant in the rare variant analysis. A single, possible gene locus association (COL12A1) was identified in the rare variant analysis for patients with both fever and rash, but the sample size was very small in this subgroup (n=16), and this may be a false positive finding. No other significant associations were found for the subgroups. No convincing genetic risk factors for sulfonamide HS were identified in this population. These negative findings may be due to challenges in accurately confirming the phenotype in exanthematous drug eruptions, or to unidentified gene-environment interactions influencing sulfonamide HS. Reprinted under PLOS ONE's open access license, CC-BY (http://www.plos.org/open-access).]]>
Study DocumentsCASES Inclusion: Administration of TMP-SMX for at least 5 days prior to the adverse event Documentation of one or more new clinical signs after starting TMP-SMX, including fever with or without eosinophilia, skin rash, increases in liver enzyme activities, hyperbilirubinemia, blood dyscrasias (anemia, leukopenia or thrombocytopenia), pneumonitis, myocarditis, aseptic meningitis, polyarthritis, acute interstitial nephritis, toxic epidermal necrolysis, or Stevens-Johnson syndrome Lack of other clinical explanation for the adverse event Resolution of clinical signs with discontinuation of TMP-SMX alone Exclusion: Gastrointestinal symptoms such as nausea, vomiting or diarrhea, in absence of other symptoms described above Acute anaphylactoid reactions were excluded Immunocompromised patients, including those with HIV infection or undergoing immunosuppressive chemotherapy CONTROLS Inclusion: Administration of a course of TMP-SMX at a standard therapeutic daily dosage for at least 10 days, with adequate follow-up in the medical record to indicate that the drug was taken and tolerated without adverse event. ]]>
2010 - Medical records from Marshfield Clinic Personalized Medicine Research Project, Marshfield, WI were retrospectively reviewed to identify the initial 198 patients (99 hypersensitive, 99 controls) for the study. All patients initially retrieved had been previously genotyped. 2013/14 - An additional 99 control patients were retrospectively identified from the Marshfield Clinic. 96 of these were underwent additional genotyping at the University of Wisconsin Biotechnology Center. 2015 - Genome-wide association study performed for all 297 patients; 275 included in final analysis.]]>