Elsevier

The American Journal of Medicine

Volume 118, Issue 12, December 2005, Pages 1416.e9-1416.e18
The American Journal of Medicine

Clinical research study
Herpes zoster in immunocompromised patients: Incidence, timing, and risk factors

https://doi.org/10.1016/j.amjmed.2005.06.012Get rights and content

Abstract

Purpose

To evaluate the risk factors for herpes zoster as well as the incidence and timing of this complication in patients who were treated with immunosuppression because of active Wegener’s granulomatosis.

Subjects and methods

We studied the 180 Wegener’s granulomatosis patients in the Wegener’s Granulomatosis Etanercept Trial (WGET). Herpes zoster events during WGET were documented prospectively. Follow-up questionnaires were employed to describe the location, treatment, and complication(s) of herpes zoster and its therapy. Univariate and multivariate analyses were performed to evaluate risk factors, including history of herpes zoster, for the occurrence of herpes zoster during the trial. All analyses were based on the time to first occurrence of herpes zoster.

Results

Eighteen patients (10% of the WGET cohort) suffered a total of 19 herpes zoster episodes over a mean follow-up period of 27 months. The annual incidence of herpes zoster in the WGET cohort was 45 cases/1000 patient-years (95% confidence interval [CI]: 27, 70). The median time from enrollment to the occurrence of herpes zoster in the subgroup of patients with that complication was 16.5 months (± 9.4). Fifteen of the 19 herpes zoster events (79%) occurred between months 6 and 36, many months after the period of most intensive immunosuppression. In univariate analyses, history of serum creatinine ≥1.5 mg/dL before enrollment was associated with a relative risk (RR) of 3.0 (95% CI: 1.1, 7.8) for herpes zoster during WGET (P = .03). In multivariate analyses, serum creatinine ≥1.5 mg/dL was associated with an RR of 6.3 (95% CI: 2.0, 19.8; P = .002), and female sex with an RR of 4.6 (95% CI: 1.6, 13.2; P = .004).

Conclusion

Renal dysfunction and female sex were consistently strong risk factors for herpes zoster events in this population. Contrary to expectation, most herpes zoster events did not occur during periods of most intensive immunosuppression. These data may inform studies of interventions designed to prevent herpes zoster in patients on treatment for immune-mediated diseases.

Section snippets

WGET design

WGET was a randomized, double-masked, placebo-controlled trial designed to test the efficacy of etanercept (Enbrel; Amgen Corporation, Thousand Oaks, Calif), a soluble inhibitor of tumor necrosis factor, in combination with conventional therapy for Wegener’s granulomatosis.21 Details of the trial design, the baseline data on the patient cohort, and the overall trial results have been published.12, 21, 22 The primary outcome in WGET was the ability of the experimental medication to maintain

Severe disease

Patients with severe Wegener’s granulomatosis began cyclophosphamide at an initial dose of 2 mg/kg/day (adjusted for renal dysfunction21) and prednisone 0.5-1 mg/kg/day. At the start of therapy, methylprednisolone (1 g/day for 3 days) could also be administered at the investigator’s discretion. After 1 month, a glucocorticoid taper was initiated with the goal of discontinuing prednisone within 6 months of randomization.

Limited disease

Patients who had limited Wegener’s granulomatosis at enrollment began

Demographics of the WGET cohort and subgroups

The mean age of the participants in the WGET cohort was 50 ± 16 years (range: 16-85). Sixty percent of the patients were male and 92% were white. Among the patients with severe disease, 86 (67%) were men and 42 (33%) were women. The baseline characteristics of patients with and without histories of herpes zoster before WGET entry are shown in Table 1. There were 2 patients whose pre-WGET herpes zoster histories were not documented at baseline. Eighteen (10%) of the 180 patients in the WGET cohort

Univariate analyses

The results of univariate analyses are shown in Table 3. History of herpes zoster before WGET was not associated with an increased relative risk (RR) of herpes zoster during the trial (RR = 1.2; P = .81). In univariate analyses, history of serum creatinine ≥1.5 mg/dL before trial enrollment was associated with an RR for herpes zoster of 3.0 during WGET (95% CI: 1.1, 7.8; P = .03). Patients with serum creatinine levels ≥1.5 mg/dL at trial entry had an RR of 3.9 (95% CI: 1.5, 9.8; P = .004). Female sex

Discussion

Our study identifies 2 major risk factors for herpes zoster events in this population. Patients with renal dysfunction at baseline (serum creatinine ≥1.5 mg/dL) were the subset of the WGET cohort at greatest risk for herpes zoster events. This risk factor was consistently strong throughout univariate and multivariate analyses, even those in which cyclophosphamide use and severe disease were included in the model. Thus, renal dysfunction appears to identify Wegener’s granulomatosis patients at

Acknowledgment

Dr. Stone is a Hugh and Renna Cosner Scholar in the Center for Innovative Medicine at Johns Hopkins University.

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    • Cited by (0)

    This study was supported by the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (Contract Number N01-AR-9-2240); The Food and Drug Administration/Office of Orphan Products (Grant Number FD-R-001652-01); General Clinical Research Center Grants M01-RRO-2719 (Johns Hopkins University School of Medicine), M01-RRO-00533 (Boston University), M01-RRO-0042 (The University of Michigan), and M01-RR-30 (Duke University) from the National Center for Research Resources/NIH; and Amgen Corporation, Thousand Oaks, Calif.

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