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Original Studies

Defining Risk Factors for Red Man Syndrome in Children and Adults

Myers, Angela L. MD, MPH*; Gaedigk, Andrea PhD; Dai, Hongying PhD*,‡; James, Laura P. MD§; Jones, Bridgette L. MD*,†; Neville, Kathleen A. MD, MS*,†

Author Information
The Pediatric Infectious Disease Journal: May 2012 - Volume 31 - Issue 5 - p 464-468
doi: 10.1097/INF.0b013e31824e10d7

Abstract

Red man syndrome (RMS) is the most common adverse drug reaction (ADR) that occurs with vancomycin with estimated rates of 5–50% in hospitalized subjects, and up to 90% in healthy control subjects.1–5 However, its true incidence remains unknown, and previous studies of RMS in children have described widely varying clinical features.6–10 RMS encompasses a spectrum of symptoms that ranges from a mild reaction such as flushing, urticarial rash and/or pruritis, to a severe reaction that includes generalized erythema, intense pruritis and even hypotension.1,3,10 Although there is general consensus on clinical features included in the symptom complex of RMS, there is no standard definition based on a required constellation of features that constitutes this ADR. The lack of a precise phenotype may account for widely reported estimates of incidence in the literature.

Vancomycin is widely used in children for treatment of serious Gram-positive infections. Recently published methicillin-resistant Staphylococcus aureus guidelines recommend vancomycin as a first-line agent in the setting of serious or invasive methicillin-resistant Staphylococcus aureus infections.11 Therefore, characterization of this ADR is important for optimizing the therapeutic benefit of vancomycin while making use of methods to prevent occurrence of RMS.

RMS is believed to be an anaphylactoid type of reaction due to vancomycin-induced direct mast cell degranulation. It has been shown to be associated with a rise in blood histamine level in some studies; however, conflicting data exist.3–5,12–14 Increasing evidence suggests that altered histamine metabolism may contribute to the pathogenesis of hypersensitivity reactions, including RMS.15–17 Histamine is synthesized from L-histidine and primarily metabolized by histamine N-methyltransferase and diamine oxidase (Fig., Supplemental Digital Content 1, https://links.lww.com/INF/B106).18–20 Both of these enzymes are polymorphically expressed. Several single nucleotide polymorphisms (SNPs) in the H1 and H4 histamine receptors also have been described. It is known that certain SNPs in the H4 receptor, which is expressed on mast cells, are associated with atopic dermatitis and pruritus. It is possible that one or more of these SNPs may contribute to altered function of these receptors.21–23

The purpose of this study was to precisely describe the clinical syndrome, further characterize the epidemiology of RMS, identify risk factors for RMS in pediatric subjects and explore associations between RMS and known SNPs in genes involved in histamine production, response and degradation.

METHODS

Study Design and Participants

Hospitalized subjects between 6 months and 21 years of age who received at least 1 dose of intravenous vancomycin during hospitalization between April 2007 and October 2009 were enrolled. Subjects who continued to receive vancomycin after enrollment were followed prospectively until vancomycin was stopped to monitor for development of RMS, whereas subjects with RMS at the time of enrollment were not followed further.

Initial screening for RMS was based on the presence of one or more of the following signs or symptoms: macular or papular rash, flushing, itching and/or a documented decrease of either systolic or diastolic blood pressure by >10 mm 14;Hg in association with a dose of vancomycin. Confirmation of RMS required the presence of at least 2 of these signs/symptoms. Reactions were then further characterized by extent: local rash, pruritis and flushing were defined as affecting only one body part (eg, face, neck or torso); generalized rash included a combination of ≥3 body parts; and generalized flushing or itch included ≥2 body parts. Involvement of ≥2 extremities was considered generalized regardless of association with other body parts. Presence of generalized symptoms, such as a combination of rash on at least 3 body parts and flushing or itch of at least 2 body parts in any of the above categories was defined as a severe reaction.

Immune deficiency was classified as primary or secondary, and defined by either presence of an underlying diagnosis of an immune system disorder or receipt of treatment with an agent intended to result in immune suppression. Immune suppressive treatment was defined as: (1) therapy of at least 2 weeks duration with corticosteroids (eg, prednisone); (2) at least 1 round of chemotherapy with a myelosuppressive agent; or (3) chronic immune modulator therapy for a rheumatic disease or solid organ transplant (eg, tacrolimus). Medications known to modify histamine responses also were recorded.

The protocol was approved by the institutional review boards of the respective participating centers: Children’s Mercy Hospitals and Clinics, Arkansas Children’s Hospital, Kosair Children’s Hospital and Texas Children’s Hospital. Parental permission was obtained for all subjects, and assent was obtained for subjects ≥7 years of age that were deemed capable by their parent or legal guardian. This trial was registered at clinical trials.gov (# NCT00824122) and with the Pediatric Pharmacology Research Units #10914.

Clinical Methods

Diagnosis of RMS, age, gender, ethnicity, RMS signs and symptoms, previous vancomycin receipt and previous RMS symptomatology were identified through medical record review and parent/nurse report. Cases required confirmation by more than one source (eg, parent and nurse report). Clinical diagnosis for which vancomycin therapy was initiated, chronic comorbid conditions, use of agents with antihistamine properties, leukotriene antagonists, immune suppression, treatment with immunosuppressive agents and treatment for RMS symptoms were obtained from the medical records. Chronic comorbid conditions were categorized as previously described.24

Specific characteristics of vancomycin administration included drug concentration (mg/mL), interruption or slowing of infusion, dosing interval and dose (mg/kg/dose). Intermittent doses of corticosteroids and receipt of blood transfusion within 24 hours before vancomycin initiation was recorded as a possible confounder for the determination of RMS symptoms. Standard practice at each institution included an initial infusion rate of 60 minutes. However, vancomycin infusion rate was not included in the analysis as some patients with previous RMS had initial infusion rates that were prolonged for their course of therapy and some patients with first time RMS symptomatology had a prolonged infusion time at enrollment.

Genotyping Methods

Genomic DNA was isolated from whole blood or saliva using a QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA). The following SNPs were genotyped: HNMT (rs6430764, −1639 C>T; rs2071048, −464 C>T; rs11558538, 314 C>T, Thr105Ile; rs1050900, 3′ UTR A>T), DAO (rs10156191, 47 C>T, Thr16Met; rs1049742, 995 C>T, Ser332Phe; rs1049793, 4107 C>G, His645Asp), HDC (rs17740607, 92 C>T, Met31Thr), H1 (rs901865, −17 C>T) and H4 (rs11665084, 413C>T, Ala138Val). A restriction fragment length polymorphism assay was used to detect H1 rs901865. All other SNPs were detected using predesigned TaqMan assays (Applied Biosystems, Carlsbad, CA).

Further testing of possible gene–gene interactions was performed with multifactor dimensionality reduction (MDR) using previously described techniques.25 MDR in conjunction with other data mining and machine learning techniques offers a strategy to detect possible nonlinear complex gene–gene interactions that is not explained by traditional categorical analysis.19,26 A 1-locus model characterizes the main effect of each SNP whereas a multilocus model investigates the interactions among relevant polymorphisms. The validity and significance of the selected models were assessed by 1000-count permutation testing. MDR was performed using the open source software MDR2.0, and model goodness-of-fit and significance were assessed by software MDRPT1.0.26

Statistical Analysis

χ2 analysis was used to compare categorical variables; Student t test and analysis of variance were used to compare means. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported along with P-values. Wilcoxon rank sum was used for nonparametric testing and logistic regression with backward selection was used to identify the predictive factors related to the development of RMS. Age, ethnicity, vancomycin per kilogram dosing, vancomycin concentration in milligrams per deciliter, previous vancomycin receipt, presence of a chronic comorbid condition, previous RMS and antihistamine use before first dose of vancomycin were included in the multivariate logistic regression model. Antihistamine use during vancomycin treatment and slowed infusion were not included in the model, as these 2 events were more likely to be initiated by the presence of RMS symptomatology. Covariates that were statistically insignificant were removed from the model by stepwise elimination.

An MDR analysis was performed to evaluate the DNA sequence variations and gene–gene interactions associated with the incidence of RMS. Ten SNPs were included as risk factors, and the outcome variable was the development of RMS during vancomycin.

RESULTS

Demographics

A total of 546 subjects were enrolled and had clinical data available (391 Children’s Mercy Hospitals and Clinics, 116 Arkansas, 24 Kosair, and 15 Texas). The RMS rate was 14.1% (77/546; 95% CI: 12–17%), with equal gender distribution (Table 1). The majority of subjects were Caucasian or African American, 79.1% and 12.5%, respectively. Caucasians and other non–African American ethnic groups were more likely to be diagnosed as having RMS symptoms than African American subjects (OR = 12.5, 95% CI [1.7–90.1], P = 0.013; OR = 16.3, 95% CI [2.0–133.7], P = 0.009; Table 1). The median age for all subjects in the study was 6.7 years (range, 0.5–21.8). Subjects with RMS were significantly older at 8.7 years (interquartile range: 4.3–13.3) than subjects without RMS at 6.1 years (interquartile range: 2–13; P = 0.009). Further, children older than 2 years of age were 4.6 times more likely to develop RMS than children under 2 years of age. There was no difference found for development of RMS in those 2–16 years of age versus those >16–21 years of age, or in severity of symptomatology between age groups.

TABLE 1
TABLE 1:
Comparison of Demographic Features, Age, Reason for Vancomycin and CCC in Patients With and Without RMS

Three hundred ninety-nine of 546 (73.1%) children had a chronic comorbid condition. The most common chronic comorbid condition was an oncologic process (183/399; 45.9%). Subjects with underlying chronic comorbid conditions were significantly more likely to develop RMS compared with healthy subjects (OR = 1.8, 95% CI [1.1–3.7], P = 0.032). However, no association was found with any specific chronic comorbid condition and development of RMS. The most frequent diagnoses for which vancomycin was given were suspected or proven bacteremia, 169 of 546 (31%) and pneumonia, 99 of 546 (18.1%) subjects.

Clinical Features

Subjects who had received vancomycin in the past without a history of RMS were not found to be at higher risk of developing RMS than those who had never been exposed. However, subjects with a history of RMS from exposure to vancomycin were more likely to develop RMS with their current vancomycin therapeutic course (43% versus 11%, OR = 6.1, 95% CI [2.0–133.7], P < 0.001).

RMS developed more frequently in subjects who received antihistamines for any reason (eg, antiemetic or sleep aid) before the first dose of vancomycin (22%, 40/185 versus 11%, 37/361; OR = 2.3, 95% CI [1.5–3.9], P < 0.001) than in those who had not received prior antihistamines. In subjects with a history of RMS, those who received an antihistamine before the first vancomycin dose were as likely to develop RMS as those who did not (42.9%, 15/35 versus 44.4%, 8/18; P > 0.05). However, in subjects without history of RMS, those who received an antihistamine before the first vancomycin dose were more likely to develop RMS than those who did not (16.7%, 25/150 versus 8.8%, 29/343; OR = 2.2, 95% CI [1.2, 3.8], P < 0.01).

Twenty-two of 52 subjects who had a history of previous RMS (42.3%) developed recurrent RMS. The majority of subjects with a history of RMS received prophylactic antihistamines before the first dose of vancomycin whether they had recurrent (68.2%) symptomatology or not (66.7%; Fig. 1). There was no difference in the presence or severity of rash (P = 0.81, P = 0.85) and pruritis (P = 0.13, P = 0.23) between subjects who received a dose of antihistamine before vancomycin and those who did not. However, presence and severity of flushing appeared to be modified by antecedent antihistamine use (P = 0.006, P = 0.04) respectively.

FIGURE 1
FIGURE 1:
Flow diagram of patients with and without current RMS and history of RMS, as well as antihistamine and previous vancomycin exposure. Hx, history; RMS Hx (+), RMS history positive; RMS Hx (–), RMS history negative; AH, antihistamine; V, vancomycin.

Pruritis, rash and flushing were common in all subjects who developed RMS. Hypotension was not observed in any subject (Table 2). When evaluating combined symptomatology, 59.7% (46/77) developed itch and rash, 49.4% (38/77) developed rash and flushing, 61% (47/77) developed flushing and itch and 40.3% (31/77) of subjects developed flushing, rash and itching simultaneously. Subjects with recurrent RMS developed similar symptoms of equal severity as subjects with new RMS (Table 2). However, subjects with recurrent RMS were more likely to develop the combination of itch and rash together (Table 2).

TABLE 2
TABLE 2:
Phenotype Characteristics of Patients With Current RMS Without and With a History of RMS

Drug Administration

We also determined the timing of RMS symptom onset, which was available for 61 of 77 (79%) cases. The majority (62%) of subjects with RMS developed symptoms within 30 minutes of infusion initiation, 21% had symptoms between 30 and 60 minutes and 16% had symptoms more than 1 hour into their infusion. Subjects with earlier detection of symptoms were more likely to have their infusion slowed (86% for 0–30 min, 54% for 30–60 min and 20% for >60 min, OR = 5.1, 95% CI [2.2–12.3], P < 0.001).

The incidence of RMS was vancomycin dose (mg/kg) dependent with 8% in subjects who received 10 mg/kg, 16% in subjects who received 15 mg/kg and 27% in subjects who received 20 mg/kg dosing (P = 0.003). Risk of RMS was also associated with the concentration of vancomycin preparations with the 5 mg/mL preparation conferring lower risk of RMS than other preparations, including 10 mg/mL, 50 mg/mL and 100 mg/mL (P < 0.001).

There were no differences among subjects who received intermittent steroid dosing, blood product transfusion before first dose of vancomycin, immune suppressive therapy or leukotriene inhibitors with regard to risk of developing RMS symptomatology.

Covariates that remained significant after multivariate analysis included age >2 years (P = 0.008), vancomycin dose (P = 0.002), previous RMS (P < 0.0001), vancomycin concentration (P = 0.0169) and non-Hispanic African American ethnicity, with decreased risk (P = 0.011). All other univariate factors (previous vancomycin, chronic comorbid conditions and prior antihistamine) did not remain significant in the multivariate analysis, partly due to the correlation among risk factors. For instance, previous RMS was correlated with prior antihistamine; therefore prior antihistamine became insignificant in the multivariate analysis.

Genotype Analysis

Genotype results for all 10 SNPs were obtained on a total of 523 (95.8%) subjects. Twenty-one subjects had no sample available, and 2 samples were of inferior quality. The 995 C>T SNP in the DAO gene was significantly associated with RMS symptomatology in the Caucasian and other non–African American ethnicity categories. Among subjects with RMS symptomatology, 44% were found to have this sequence variation on at least 1 allele compared with 15% who were homozygous for the wild-type allele (P = 0.044). There were no significant associations with any of the other SNPs.

MDR analysis was performed to investigate potential gene–gene interactions associated with the development of RMS. The optimal model at 1 locus, 2-loci and 3-loci were developed, and significance of these selected models was evaluated by testing accuracy and crossing validation counts. The most promising gene–gene interaction was rs1049742 (995 C>T, Ser332Phe) +HDC with testing accuracy at 57% (P = 0.083). However, there was no statistically significant association between development of RMS symptomatology and any sequence variation combinations, partly due to the relatively small sample size and the complex RMS phenotype.

DISCUSSION

RMS associated with vancomycin use has long been recognized as an ADR. However, few systematic investigations have been conducted in pediatric subjects to date. One previous retrospective study evaluated RMS in 650 children who had been exposed to vancomycin, and found a low rate (1.6%) of RMS, which limited their ability to determine risk factors. Other studies included only small numbers of children and revealed wide variations in clinical symptoms of RMS, including hypotension as a common finding, forming the basis for which slowing the infusion has become a common ameliorating practice.7–9 Therefore, the present study is the first to characterize RMS features and risk factors across a large population and to evaluate for a potential SNP association.

The prevalence of RMS found in this study is consistent with the range noted in previous studies,3–5 and our data indicate that vancomycin dose, vancomycin concentration, RMS history, age and ethnicity are risk factors for RMS. It is unclear why patients of African American ethnicity are less likely to develop RMS, although it is possible that rash and flushing are harder to determine in this patient population.

Although antihistamines were commonly used before receipt of the initial vancomycin dose, they were not found to protect subjects from developing RMS or ameliorate rash and pruritis. However, antecedent antihistamine use was associated with statistically significant less flushing in subjects with RMS. Not only were antihistamines not protective for RMS, but administration of an antihistamine for any reason before receiving vancomycin was associated with increased risk of RMS. This observation is somewhat counterintuitive, and a biologically plausible explanation is not readily apparent. However, these findings underscore the complex nature of the RMS reaction and suggest that although the histaminergic pathway is likely involved, alternative inflammatory pathways that may or may not involve histamine release (eg, complement receptor activation on the mast cell) may play a more dominant role.

Genotype analysis for sequence variations in the histamine biotransformation enzymes15–17 and H1 and H4 receptors21–23 revealed 1 SNP with an apparent association of risk for RMS. However, further MDR analysis did not detect a significant association in any combination of subject symptoms and SNPs. This indicates that these particular gene polymorphisms are unlikely to be important determinants of RMS risk.

This study has several limitations. First, the study had both retrospective and prospective components. Clinical data for those patients who already had developed RMS at the time of enrollment were collected retrospectively, whereas subjects who had not developed RMS at enrollment were followed prospectively; thus, we were unable to collect the timing of development of RMS symptoms on all patients. Potential ascertainment bias was mitigated by enrolling subjects solely based on age and current receipt of vancomycin, without regard to previous vancomycin receipt or RMS reaction. Second, our criteria for determining whether a subject developed RMS were stricter than previously published clinical criteria, raising the possibility that we excluded subjects with milder symptomatology. However, our goal was to rigorously define the population of subjects with definite RMS, and the prevalence of RMS in our study was consistent with previous reports. Furthermore, the use of stricter criteria facilitated more rigorous identification of risk factors for developing RMS. Third, although we evaluated all commonly used H1 and H2 antihistamines, as well as other agents with antihistamine and immune suppressant effects in our study,27,28 it is possible that medications, other than the ones we evaluated, could play a role in ameliorating RMS symptomatology (eg, cromolyn sodium). Finally, given the short half-life of these medications, data were not collected regarding the length of antihistamine use. It is possible that longer-term use could play a role in development of RMS or amelioration of symptomatology.

Using a rigorous and specific definition, the prevalence of RMS in a large sample of hospitalized children receiving vancomycin was 14%. Our study suggests that dose (mg/kg) and concentration (mg/mL) of infused vancomycin play a key role in the development of RMS syndrome. To our knowledge this is the first study to report this finding; although previous studies have also shown the development of RMS in the setting of standard 1-hour infusion times, dose and concentration have not been independently evaluated.7,29 Additional risk factors for RMS include RMS history, non–African American ethnicity and age ≥ 2 years. Known genetic polymorphisms of histamine pathway and histamine receptor genes have little influence on risk of RMS. What was unexpected was that pretreatment with an antihistamine did not prevent RMS from developing and did not ameliorate most symptoms once present. However, duration of antihistamine treatment was not collected. Nevertheless, these observations merit confirmation in a prospective controlled study.

ACKNOWLEDGMENTS

The authors acknowledge Katie Klockau and Jackie Riley, both recipients of Summer Scholarships, for their contribution with genotype analysis. The authors also thank Greyson Twist and Liliane Njountché for technical assistance. In addition, the authors are grateful to all research coordinators (University of Arkansas and Arkansas Children’s Hospital, Lee Howard and Leah Dawson; the University of Louisville, Carrie Schanie and Nitya Narayan; Baylor College of Medicine and Texas Children’s Hospital, Christina Lopez and Cynthia Bourdreaux). The authors also thank Janice Sullivan, MD, at the University of Louisville, and Lisa Bomgaars, MD, at Baylor College of Medicine and Texas Children’s Hospital. Finally, the authors acknowledge Dr. Ralph Kauffman for helpful editing of this manuscript.

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Keywords:

vancomycin; histamine; red man syndrome; single nucleotide polymorphisms

Supplemental Digital Content

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