Genetic Polymorphisms Associated With Histamine Disposition in Children With Vancomycin Associated Red Man Syndrome (RMS)

Vancomycin has been utilized as an antimicrobial therapeutic agent for serious gram positive infections for more than half a century.The pharmacokinetics of vancomycin has been well studied, and in general there are few side effects from this medication. The most common side effect that occurs with receipt of vancomycin is red man syndrome (RMS), which is also known as red neck, or red person syndrome.1 RMS encompasses a spectrum that ranges from a mild reaction such as flushing, urticarial rash, pruritis, to a severe reaction that includes generalized erythema,intense pruritis, and even hypotension. RMS has been estimated to occur in 5- 50% of hospitalized patients who receive this drug.

RMS is considered an anaphylactoid type of reaction that is due to mast cell degranulation with a concomitant rise in blood histamine levels. The resultant symptomatology varies from mild itching and erythematous rash to a more generalized reaction with hypotension. This reaction has been shown to be modified by pre-treatment with various types of antihistamines including diphenhydramine and cimetidine.

There is now evidence to suggest that altered histamine metabolism contributes to the pathogenesis of various disorders. Histamine is almost exclusively metabolized by the enzymes histamine N-methyltranserase (HNMT)and diamine oxidase (DAO) both of which are polymorphically expressed in people with varying frequencies.HNMT catalyzes the N- methylation of histamine. This is the predominant pathway for histamine metabolism,accounting for 50-80% of its biotransformation. Diamine oxidase (DAO) likely contributes in a significant manner of the remaining metabolism of histamine as only 2-3% of this autocoid is excreted unchanged in the urine. It is plausible that allelic variants of HNMT and/or DAO may contribute to histmaminergic reactions in a given patient with resultant propagation of its pharmacologic effects, and that polymorphically expressed enzymes primarily responsible for terminating the pharmacologic activity of histamine (via biotransformation)may play a crucial role in determining disease phenotype for disorders (e.g., RMS) where histamine is a key mediator.

This is a prospective study that will be conducted over a one year period of time. Eligible patients will be identified by a search of patients who are receiving vancomycin therapy throughout the study period. Chart review/patient interview will then be performed to identify patients who developed symptomatology consistent with RMS while receiving vancomycin infusion. For the purposes of this study, red man syndrome (RMS) will be defined as: erythematous rash, flushing of the face, neck, or torso, itching, or a lowering of systolic or diastolic blood pressure by >10mm/hg. A subset of patients who remained asymptomatic throughout their vancomycin therapy will also be evaluated as a control group.