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.

Oral challenge is performed to confirm an immune-mediated ADR in the event of negative delayed-IDT or negative patch testing, the authors said. However, they emphasized that this method should never be used in patients with SJS, TEN, or DRESS.

The antibiotic lymphocyte transformation test (LTT) measures the proliferation of T cells to a drug in vitro. However, this test is unvalidated and is associated with both false-positive and false-negative results; it is currently only used in research settings.

According to the authors, use of ex-vivo diagnostic techniques—specifically ELISpot, which analyzes antigen-specific, cytokine-producing cells in peripheral blood after a patient is exposed to a drug—holds potential as a new approach to assigning causality in antimicrobial-associated T cell-mediated ADRs; it also has higher sensitivity in detecting drug-specific T cell responses than LTT has. However, ELISpot is also currently used only within research settings.

An understanding of key cytokine mediators involved in the different form of T cell-mediated ADRs will help to further development of these tools, the

authors noted.

Cross Reactivity in T Cell-Mediated Reactions

The authors also highlight the need for clinicians to understand the concept of cross-reactivity based on shared chemical structure among antimicrobial agents—specifically if in-vivo and ex-vivo diagnostics are unavailable. “A knowledge of side chain cross-reactivity aids empirical antibiotic choice in the setting of immune-mediated ADRs,” they emphasized.

Current data indicate that most cross-reactivity in the beta-lactam class of antibiotics occurs because of similarities between agents in their side chain structures. Cross-reactivity and tolerance have also been reported for aminoglycosides, in which ADRs occur more commonly with topical agents than systemic ones, due to contact sensitization. For quinolone antibiotics, delayed immune-mediated ADRs occur less commonly than immediate ADRs occur, and cross-reactivity occurs more frequently between first- and second-generation quinolones than between third- and fourth-generation quinolones. Cross-reactivity also occurs between antibiotic sulfonamides, particularly between sulfasalazine and sulfamethoxazole, the authors noted.

In contrast, however, cross-reactivity between carbapenems or between macrolides seems to be rare. The authors added that cross-reactivity between most classes of antiretrovirals also seems to be very uncommon because these drugs lack structural similarities. Nevertheless, they stressed that patients with a history of severe hypersensitivity to a nonnucleoside reverse transcriptase inhibitor (NNRTI) should be carefully monitored if new NNRTI therapy is started.

The process by which an antibiotic label is assigned, acted on, and maintained remains imprecise, the authors said. As a consequence, “[p]redicting T cell-mediated ADRs via personalized approaches, including human leukocyte antigen-typing, may pave future pathways to safer antimicrobial prescribing guidelines,” they concluded.

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals, and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.