Drug reaction with eosinophilia and systemic symptoms (DRESS)‐associated hemophagocytic lymphohistiocytosis (HLH), an important and underrecognized HLH mimic: A case report

Carter-Febres, Maria; Abbott, Jeff; Cipriano, Sarah D.; Knackstedt, Elizabeth D.; George, Tracy I.; Afify, Zeinab

doi:10.1002/pbc.28657

Cited by 5 publications

(4 citation statements)

References 16 publications

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“…7 In 39/56 (70%) sJIA/AOSD DHR cases, AST-ALT elevation was noted in the absence of macrophage activation syndrome (MAS) or other explanation. Also, cytokine storm during inhibitor treatment, which can be a manifestation of DRESS 1,2,18,19 , was significantly more common in DHR patients than in drug-tolerant sJIA/AOSD (p=8.5×10 −10 ). When MAS occurred during drug treatment, eosinophilia typically preceded this by months, consistent with evolution of DRESS-associated features.…”

Section: Resultsmentioning

confidence: 99%

“…These patients meet classification criteria for DRESS, a potentially fatal, eosinophilic systemic syndrome that can lead to organ failure and can stimulate a cytokine storm. 1,2,18,19 In relatively short-term exposure of KD patients to anakinra, a subset of patients also developed clinical manifestations consistent with drug reaction. In sJIA/AOSD and KD, the drug reactions are delayed type and differ from the immediate, anaphylactic reactions to tocilizumab we observed in association with DLD in sJIA.…”

Section: Discussionmentioning

confidence: 99%

“…Further research is needed to determine underlying mechanisms for DHR to these inhibitors and its relevance in other conditions, particularly inflammatory diseases, in which DRESS/DHR is underrecognized. 2,18…”

Section: Discussionmentioning

confidence: 99%

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Hypersensitivity reactions to IL-1 and IL-6 inhibitors are linked to common HLA-DRB1*15 alleles

Hollenbach

Ombrello

Tremoulet

et al. 2020

Preprint

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In Saper et al (2019), we described systemic JIA patients who developed a high-fatality diffuse lung disease (DLD) while on IL-1 or IL-6 inhibitors. We observed severe delayed drug hypersensitivity reactions (DHR) in a significant subset. Because alleles of the human leukocyte antigen (HLA) loci can mediate DHR, we investigated HLA genotype association with these DHR. We typed subjects treated with these inhibitors: 34 sJIA/DHR/DLD, 11 sJIA/DHR without DLD, 18 drug-tolerant sJIA, and 19 Kawasaki disease (KD) patients in an anti-IL-1(anakinra) trial. We also accessed genotypes from a large sJIA case/control cohort. We first compared White subjects with sJIA/DHR to 550 ancestry-matched sJIA subjects. We found striking enrichments of HLA-DRB1*15:01, HLA-DQA1*01:02, and DQB1*06:02, alleles in near-complete linkage (White individuals). HLA-DRB1*15:01 (as haplotype proxy) was increased in White sJIA subjects with DHR/DLD versus sJIA drug-tolerant controls and was observed upon inclusion of sJIA+DHR-only and KD+DHR White subjects. In our entire cohort regardless of ancestry, 75% carried HLA-DRB1*15:01 or the structurally related DRB1*15:03 and DRB1*15:06, which were absent among drug-tolerant subjects (p=5 x 10-13; Odds Ratio lower bound=20.11). Patients who harbor HLA-DRB1*15 alleles are at high risk of developing DHR to anti-IL-1/IL-6. Our data also suggest DHR maybe a trigger/enhancer of DLD in sJIA patients and support performing prospective HLA screening in sJIA, its adult-onset counterpart, and other inflammatory conditions where these drugs are used, such as KD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hypersensitivity reactions to IL-1 and IL-6 inhibitors are linked to common HLA-DRB1*15 alleles

Hollenbach

Ombrello

Tremoulet

et al. 2020

Preprint

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“…Although the development of a hemophagocytic process in the context of DRESS is not new ( Picard et al, 2013 ; Korbi et al, 2015 ; Penel-Page et al, 2017 ; Rioualen et al, 2017 ; Carter Febres et al, 2021 ), this complication is significantly underdiagnosed. Cohort studies with prospectively collected data on this complication are lacking, but as cytopenia is present in 10–30% of DRESS patients ( Choudhary et al, 2013 ), it is likely that at least a proportion of these patients has concurrent hemophagocytosis.…”

Section: Discussionmentioning

confidence: 99%

Case report: Drug reaction with eosinophilia and systemic symptoms (DRESS)-induced hemophagocytic disorder

Pope

Au²,

Levy³

et al. 2022

Front. Pharmacol.

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Hemophagocytic disorders are severe and life-threatening conditions that can be genetic in origin [i.e., primary hemophagocytic lymphohistiocytosis (HLH)] or result from infections (i.e., secondary hemophagocytic lymphohistiocytosis), rheumatologic disease [i.e., macrophage activation syndrome (MAS)], and less frequently immunodeficiency or metabolic disease. Although rare, drug-induced hemophagocytosis needs to be considered in the work-up as it requires specific management strategies. Most drug-induced hemophagocytic disorders are related to Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). We present the case of a 7-year-old girl who initially presented with fever, maculopapular rash, and unilateral lymphadenopathy, who went on to develop hemophagocytosis secondary to DRESS caused by prolonged combination treatment with amoxicillin/clavulanic acid and trimethoprim/sulfamethoxazole. This case illustrates the importance of considering adverse drug reactions in the evaluations of patients with a hemophagocytic process.

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Piperacillin/tazobactam

2021

Reactions Weekly

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Background: High-level expression of AmpC b-lactamase genes is associated with increased resistance to b-lactam antibiotics. bla CMY-2 is the most prevalent plasmid-encoded AmpC gene found in Escherichia coli worldwide, and the gene is often found on plasmids of the IncI1 replicon type. Replication of IncI1 plasmids is controlled by antisense RNA transcribed from the gene inc, and nucleotide changes in the hairpin loop region of inc have been associated with increased plasmid copy number of IncI1 mini-plasmid constructs. The objective of this study was to determine the mechanism(s) responsible for increased bla CMY-2 expression in three piperacillin/tazobactam-selected E. coli mutant strains with bla CMY-2 encoded on a 100 kb IncI1 plasmid.Methods: Mutants were selected from a clinical E. coli strain by exposure to superinhibitory concentrations of piperacillin/tazobactam. b-Lactam susceptibilities were measured by agar dilution. Relative bla CMY-2 transcript levels, gene copy number and IncI1 plasmid copy number were measured by real-time PCR. The inc gene of all strains was sequenced.Results: Piperacillin/tazobactam MICs were 16-to 128-fold higher for mutant strains than for their parent strain. This increase in MICs correlated with 3-to 13-fold increases in bla CMY-2 gene expression, bla CMY-2 copy number and IncI1 plasmid copy number. Two mutants with 8-and 13-fold increases in IncI1 copy number had single point mutations located within the hairpin loop region of inc.Conclusions: These findings demonstrate that inc point mutations can be associated with increased copy number of a 100 kb IncI1 plasmid, and lead to increased bla CMY-2 expression and piperacillin/tazobactam resistance.

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Drug reaction with eosinophilia and systemic symptoms (DRESS)‐associated hemophagocytic lymphohistiocytosis (HLH), an important and underrecognized HLH mimic: A case report

Cited by 5 publications

References 16 publications

Hypersensitivity reactions to IL-1 and IL-6 inhibitors are linked to common HLA-DRB1*15 alleles

Hypersensitivity reactions to IL-1 and IL-6 inhibitors are linked to common HLA-DRB1*15 alleles

Case report: Drug reaction with eosinophilia and systemic symptoms (DRESS)-induced hemophagocytic disorder

Piperacillin/tazobactam

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