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Delayed Antimicrobial Hypersensitivity: Immunology and Diagnostics

Adverse drug reactions (ADRs) are undesired and unpredictable effects of therapy that may impact treatment decision-making. In particular, antibiotics (such as sulphonamides and beta-lactams), as well as antiretroviral and hepatitis C antiviral agents, are key causes of T cell-mediated ADRs.
“In an era of increasing antimicrobial resistance and use of broad-spectrum antimicrobial therapy, ensuring patients are assigned the correct ‘allergy label’ is essential,” the authors wrote.
In a review article published in Current Opinion in Infectious Diseases, Katherine C. Konvinse, MD, from Vanderbilt University Medical Center, and colleagues discuss current understanding of the pathogenesis of type IV T cell-dependent immune-mediated ADRs. They also review the evidence for diagnostics for T cell-mediated ADRs.
Immunology of T Cell-Mediated ADRs
T cell-mediated hypersensitivities are immune-mediated ADRs that result in antibiotic “allergy labels” that affect patient outcomes and antibiotic usage. In addition, according to the authors, although genetic susceptibility plays a role in these reactions, given the extent of antimicrobial use, at least half of all severe cutaneous adverse reactions (SCARs) worldwide are associated with antimicrobial agents.
Although the pathogenesis of T cell-mediated immune responses remains controversial, most drug-allergy reactions have been shown to involve T lymphocytes that are specific to a drug. According to the hapten-prohapten model, T cells cannot recognize a low molecular weight drug unless the drug first binds to an endogenous peptide. This complex of the drug and peptide is then processed within the cell, producing chemically modified peptides. When these modified peptides are presented with major histocompatibility complex (MHC), T cells will recognize them as a foreign antigen, and thus, will mount an immune response.
SCARs are often associated with long-term persistence of specific T cells in a patient’s circulation—for more than 20 years after drug exposure in some cases. For example, CD8+ T cells have been identified as important mediators of the blistering and severe immune-mediated ADRs (such as Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]), whereas CD4+ T cells or mixtures of CD4+ and CD8+ T cells are associated with simple exanthema and drug reaction with eosinophilia and systemic symptoms (DRESS).
Although cytokine mediators may vary slightly for each type of ADR, those typically upregulated in these reactions include IL-2, IL-5, IL-13, and IFNγ.
“An understanding of immune mediators is vital for future works measuring cytokines in ex-vivo T cell diagnostics,” the authors stressed.
T Cell Diagnostics
Testing for immune-mediated ADRs is troublesome because testing is not widely available. Furthermore, although traditional methods such as patch
testing and intradermal testing (IDT) are specific in the diagnosis of T cell-mediated ADRs, they have low sensitivity; this means that a negative patch test result cannot be used as the basis for rechallenge to any drug.
Nevertheless, the authors noted that a positive patch test result has high specificity for specific antibiotic-associated immune-mediated ADRs. It may be more useful for DRESS, and less useful for conditions such as SJS and TEN, they added.
Although delayed-IDT can be used to investigate non-SJS/TEN immune-mediated ADRs, this method also lacks sensitivity. In addition, the
highest nonirritating concentrations of drugs for use in this method have not been validated for most agents, the authors said. They also stressed that while a positive delayed-IDT result highly suggests an immune-mediated ADR, a negative result does not exclude an immune-mediated ADR and should not be used as the basis for rechallenge to a drug.

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