Sutton's law and severe cutaneous adverse drug reactions: Is the money in the blister?

  • Timothy G. Chow
    Correspondence
    Corresponding author: Timothy Chow, MD, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd F04.206, Dallas, TX 75390-9063.
    Affiliations
    Division of Allergy and Immunology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Tex
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  • David A. Khan
    Affiliations
    Division of Allergy and Immunology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Tex
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Open AccessPublished:December 08, 2021DOI:https://doi.org/10.1016/j.jacig.2021.12.001
      Willie Sutton, a convicted bank robber in the 1930s, was once asked why he robbed banks; he responded with his infamous answer, “Because that’s where the money is.” Although in his autobiography Sutton denied ever stating this, curiously his autobiography was titled Where the Money Was.
      • Sutton W.
      • Lynn E.
      Where the money was.
      Although the principle of “go where the money is” has been applied to the disciplines of finance and others, the field of medicine has coined Sutton's law, which recommends proceeding to the diagnostic test that is most likely to provide a diagnosis.
      • Rytand D.A.
      Sutton's or Dock's law?.
      In this issue of the Journal of Allergy and Clinical Immunology: Global, Awad et al suggest that in identifying culprit drugs in severe cutaneous adverse drug reactions (SCARs), “the money” may be in blister cells rather than peripheral blood cells.
      • Awad A.
      • Mouhtouris E.
      • Nguyen-Robertson C.
      • Holmes N.
      • Chua K.
      • Copaescu A.
      • et al.
      Blister fluid as a cellular input for ex vivo diagnostics in drug-induced severe cutaneous adverse reactions improves sensitivity and explores immunopathogenesis.
      SCARs, although uncommon, are associated with significant morbidity and mortality, and identification of the culprit drug often presents a diagnostic challenge for clinicians. Although drug challenge testing remains the criterion standard as a diagnostic procedure for evaluating drug tolerance in suspected drug hypersensitivity reactions, concern for the recurrence of severe clinical manifestations of SCARs has driven the recommendation that direct drug challenges be considered a contraindication in the evaluation of SCARs except in the most extreme circumstances.
      Joint Task Force on Practice Parameters
      Drug allergy: an updated practice parameter.
      As such, there have been significant efforts exploring other in vitro and ex vivo diagnostic tests in the evaluation of SCARs, including patch or delayed intradermal testing, the lymphocyte transformation test, enzyme-linked immunospot (ELISpot) assay, and HLA class I and II typing.
      • Copaescu A.
      • Gibson A.
      • Li Y.
      • Trubiano J.A.
      • Phillips E.J.
      An updated review of the diagnostic methods in delayed drug hypersensitivity.
      One of the more potentially useful emerging tests in relation to identifying drug culprits is the ELISpot. ELISpot assays assess the activation of drug-specific cells by measuring cytokine release when incubated with a suspected drug. The positivity rate for IFN-γ ELISpot from PBMCs has been reported as ranging from 41% to 91%,
      • Copaescu A.
      • Gibson A.
      • Li Y.
      • Trubiano J.A.
      • Phillips E.J.
      An updated review of the diagnostic methods in delayed drug hypersensitivity.
      a range that is influenced by the varying definitions for a positive IFN-γ ELISpot result used across studies. At this point, the IFN-γ ELISpot assay does not appear to be sufficiently sensitive to be used singularly as a diagnostic test, and further studies have investigated its role in conjunction with in vivo testing.
      • Trubiano J.A.
      • Strautins K.
      • Redwood A.J.
      • Pavlos R.
      • Konvinse K.C.
      • Aung A.K.
      • et al.
      The combined utility of ex vivo IFN-gamma release enzyme-linked immunospot assay and in vivo skin testing in patients with antibiotic-associated severe cutaneous adverse reactions.
      ,
      • Copaescu A.
      • Mouhtouris E.
      • Vogrin S.
      • James F.
      • Chua K.Y.L.
      • Holmes N.E.
      • et al.
      The role of in vivo and ex vivo diagnostic tools in severe delayed immune-mediated adverse antibiotic drug reactions.
      For certain drugs and reactions, however, ELISpot assay may have increased sensitivity. Copaescu et al demonstrated that in 22 patients with glycopeptide-induced drug reaction with eosinophilia and systemic symptoms (DRESS), the ELISpot result was positive in 71% of cases, which was higher than in patients with β-lactam–induced DRESS.
      • Copaescu A.
      • Mouhtouris E.
      • Vogrin S.
      • James F.
      • Chua K.Y.L.
      • Holmes N.E.
      • et al.
      The role of in vivo and ex vivo diagnostic tools in severe delayed immune-mediated adverse antibiotic drug reactions.
      Prior studies with the ELISpot assay have utilized PBMCs, but evaluation of the cytokine signature in SCARs has demonstrated a difference between PMBCs and blister fluid cells (BFCs).
      In their aforementioned article, Awad et al
      • Awad A.
      • Mouhtouris E.
      • Nguyen-Robertson C.
      • Holmes N.
      • Chua K.
      • Copaescu A.
      • et al.
      Blister fluid as a cellular input for ex vivo diagnostics in drug-induced severe cutaneous adverse reactions improves sensitivity and explores immunopathogenesis.
      compare IFN-γ ELISpot assays of matched PBMC and BFC samples from 4 patients with confirmed SCARs. There were 2 patients with toxic epidermal necrolysis (TEN), 1 patient with DRESS, and 1 patient with generalized bullous fixed drug eruption. Two patients had a single implicated drug: meloxicam in the case of generalized bullous fixed drug eruption and allopurinol in 1 of the cases of TEN. β-Lactams and vancomycin were potential culprit drugs in the case of the patient with DRESS, whereas trimethoprim-sulfamethoxazole appeared to be the highest-risk agent in the other case of TEN. PBMCs and BFCs were incubated with the representative expected peak serum concentration for a given drug, as well as at a concentration 10- to 20-fold higher. A positive IFN-γ ELISpot assay result was defined as more than 50 spot-forming units per million cells, a definition that is used consistently by this group
      • Trubiano J.A.
      • Strautins K.
      • Redwood A.J.
      • Pavlos R.
      • Konvinse K.C.
      • Aung A.K.
      • et al.
      The combined utility of ex vivo IFN-gamma release enzyme-linked immunospot assay and in vivo skin testing in patients with antibiotic-associated severe cutaneous adverse reactions.
      ,
      • Copaescu A.
      • Mouhtouris E.
      • Vogrin S.
      • James F.
      • Chua K.Y.L.
      • Holmes N.E.
      • et al.
      The role of in vivo and ex vivo diagnostic tools in severe delayed immune-mediated adverse antibiotic drug reactions.
      but may not be directly comparable to the definition in studies using a different IFN-γ ELISpot cutoff.
      Awad et al
      • Awad A.
      • Mouhtouris E.
      • Nguyen-Robertson C.
      • Holmes N.
      • Chua K.
      • Copaescu A.
      • et al.
      Blister fluid as a cellular input for ex vivo diagnostics in drug-induced severe cutaneous adverse reactions improves sensitivity and explores immunopathogenesis.
      report preliminary evidence suggesting that BFC IFN-γ ELISpot assays may offer higher sensitivity than provided by PBMC IFN-γ ELISpot assays. All 4 patient BFC samples demonstrated a positive IFN-γ ELISpot assay result compared with only 1 of the 4 PBMC samples when incubated with parent drug; an additional PBMC sample had a positive IFN-γ ELISpot assay result when incubated with oxypurinol, a metabolite of allopurinol, but not to allopurinol itself. In the patient with DRESS, the BFC IFN-γ ELISpot assay result was positive for ceftriaxone at both concentrations, whereas the PBMC IFN-γ ELISpot assay result was positive only for ceftriaxone at the highest concentration and the results of penicillin and vancomycin testing were negative with both PBMCs and BFCs. Awad et al
      • Awad A.
      • Mouhtouris E.
      • Nguyen-Robertson C.
      • Holmes N.
      • Chua K.
      • Copaescu A.
      • et al.
      Blister fluid as a cellular input for ex vivo diagnostics in drug-induced severe cutaneous adverse reactions improves sensitivity and explores immunopathogenesis.
      also compared the cellular composition of BFCs and PBMCs through flow cytometry and found differences between matched samples, with BFCs enriched for total T cells and IFN-γ–secreting cells compared with PBMCs. This difference may be reflective of enrichment of drug-specific T-cell clones in BFCs, which may be driving the increased sensitivity of BFC assays compared with that of PBMC assays. Fig 1 summarizes some of the data from the Awad et al.
      • Awad A.
      • Mouhtouris E.
      • Nguyen-Robertson C.
      • Holmes N.
      • Chua K.
      • Copaescu A.
      • et al.
      Blister fluid as a cellular input for ex vivo diagnostics in drug-induced severe cutaneous adverse reactions improves sensitivity and explores immunopathogenesis.
      Further study will be needed to characterize and compare these cellular signatures between PBMCs and BFCs in larger populations.
      Figure thumbnail gr1
      Fig 1Performance of IFN-γ ELISpot in SCARs.
      • Awad A.
      • Mouhtouris E.
      • Nguyen-Robertson C.
      • Holmes N.
      • Chua K.
      • Copaescu A.
      • et al.
      Blister fluid as a cellular input for ex vivo diagnostics in drug-induced severe cutaneous adverse reactions improves sensitivity and explores immunopathogenesis.
      ,
      • Trubiano J.A.
      • Strautins K.
      • Redwood A.J.
      • Pavlos R.
      • Konvinse K.C.
      • Aung A.K.
      • et al.
      The combined utility of ex vivo IFN-gamma release enzyme-linked immunospot assay and in vivo skin testing in patients with antibiotic-associated severe cutaneous adverse reactions.
      ,
      • Copaescu A.
      • Mouhtouris E.
      • Vogrin S.
      • James F.
      • Chua K.Y.L.
      • Holmes N.E.
      • et al.
      The role of in vivo and ex vivo diagnostic tools in severe delayed immune-mediated adverse antibiotic drug reactions.
      MPE, Maculopapular exanthema; SJS/TEN, Stevens-Johnson syndrome/toxic epidermal necrolysis.
      Clinicians continue to be limited in the tools available to diagnose SCARs. In this small exploratory study, the findings of Awad et al
      • Awad A.
      • Mouhtouris E.
      • Nguyen-Robertson C.
      • Holmes N.
      • Chua K.
      • Copaescu A.
      • et al.
      Blister fluid as a cellular input for ex vivo diagnostics in drug-induced severe cutaneous adverse reactions improves sensitivity and explores immunopathogenesis.
      encourage further critically needed investigation exploring ways to increase the diagnostic yield of assays such as IFN-γ ELISpot in the evaluation of SCARs and identifying methods of discriminating causal agents for SCARs with multiple suspected drugs. Further studies will need to investigate BFC IFN-γ ELISpot assay in larger cohorts, as well as to compare the performance of BFC IFN-γ ELISpot assay within different SCAR phenotypes and inciting drugs. Furthermore, the practicality of obtaining blister cells in general practice and preservation of viable cells will need to be investigated for such assays to have significant clinical utility.

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