John W. Gnann

Viral encephalitis: familiar infections and emerging pathogens

Significant advances have been made in our understanding of the natural history and pathogenesis of viral encephalitides. The development of PCR has greatly increased our ability to diagnose viral infections of the central nervous system, particularly for herpes and enteroviral infections. Advancing knowledge has led to the recognition that some encephalitides can be reliably prevented by vaccination (eg, Japanese encephalitis and rabies). For other pathogens such as the arboviruses, the focus has been on prevention by vector control. Finally, effective therapy has been established for a very limited number of viral infections (eg, acyclovir for herpes simplex encephalitis). Other potentially useful treatments, such as pleconaril for enteroviral meningoencephalitis are under clinical evaluation. We review current understanding of viral encephalitides with particular reference to emerging viral infections and the availability of existing treatment regimens.

Acyclovir: A Decade Later

REPORTS of the clinical efficacy of acyclovir, a selective and specific inhibitor of herpesvirus replication, appeared in the literature a decade ago. Acyclovir has become the most widely prescribe...

Varicella-Zoster Virus: Atypical Presentations and Unusual Complications

Varicella-zoster virus (VZV) is the etiologic agent of varicella (primary infection) and herpes zoster (reactivation of latent infection). Although varicella is most often a relatively benign and self-limited childhood illness, the disease can be associated with a variety of serious and potentially lethal complications in both immunocompetent and immunocompromised persons. One complication of varicella that appears to be increasing in frequency is serious bacterial soft tissue infections caused by group A streptococci. Issues related to management of varicella become especially complex when varicella involves pregnant women or susceptible neonates. Herpes zoster can be associated with a variety of neurologic complications, including a syndrome of delayed contralateral hemiparesis. Neurologic complications of herpes zoster, including chronic encephalitis, occur with increased frequency in AIDS patients. VZV retinitis is a potentially sight-threatening complication that occurs in both immunocompetent and immunocompromised persons. Current knowledge regarding pathogenesis and antiviral therapy is reviewed.

Efficacy, Safety, and Tolerability of Herpes Zoster Vaccine in Persons Aged 50–59 Years

BACKGROUND Herpes zoster (HZ) adversely affects individuals aged 50-59, but vaccine efficacy has not been assessed in this population. This study was designed to determine the efficacy, safety, and tolerability of zoster vaccine for preventing HZ in persons aged 50-59 years. METHODS This was a randomized, double-blind, placebo-controlled study of 22 439 subjects aged 50-59 years conducted in North America and Europe. Subjects were given 1 dose of licensed zoster vaccine (ZV) (Zostavax; Merck) and followed for occurrence of HZ for ≥1 year (mean, 1.3 years) postvaccination until accrual of ≥96 confirmed HZ cases (as determined by testing lesions swabs for varicella zoster virus DNA by polymerase chain reaction). Subjects were followed for all adverse events (AEs) from day 1 to day 42 postvaccination and for serious AEs (SAEs) through day 182 postvaccination. RESULTS The ZV reduced the incidence of HZ (30 cases in vaccine group, 1.99/1000 person-years vs 99 cases in placebo group, 6.57/1000 person-years). Vaccine efficacy for preventing HZ was 69.8% (95% confidence interval, 54.1-80.6). AEs were reported by 72.8% of subjects in the ZV group and 41.5% in the placebo group, with the difference primarily due to higher rates of injection-site AEs and headache. The proportion of subjects reporting SAEs occurring within 42 days postvaccination (ZV, 0.6%; placebo, 0.5%) and 182 days postvaccination (ZV, 2.1%; placebo, 1.9%) was similar between groups. CONCLUSIONS In subjects aged 50-59 years, the ZV significantly reduced the incidence of HZ and was well tolerated. CLINICAL TRIALS REGISTRATION NCT00534248.

A randomized, open-label study to evaluate the safety and pharmacokinetics of human hepatitis C immune globulin (Civacir) in liver transplant recipients

Chronic hepatitis C is the most common indication for liver transplantation, but viral recurrence is universal and progressive graft injury occurs in most recipients. Our aim was to assess the safety, pharmacokinetics (PK), and antiviral effects of high doses of a human hepatitis C antibody enriched immune globulin product (HCIG) in patients undergoing liver transplantation for chronic hepatitis C. This was a multicenter, randomized, open‐label, controlled trial conducted at 4 transplant centers in the United States. A total of 18 patients with chronic hepatitis C, who underwent liver transplantation, were randomized to receive low‐dose HCIG (75 mg/kg) or high‐dose HCIG (200 mg/kg), or no treatment. A total of 17 infusions of HCIG were administered in each treated patient over 14 weeks using a time‐dependent dosing strategy based on the PK of anti‐hepatitis B immune globulin in liver transplant recipients. Hepatitis C virus levels, liver enzymes, and liver biopsies were obtained serially throughout the study period. PK profiles of HCV antibodies were determined on days 4, 10, and 98. HCIG infusions were safe and tolerated. The infusion rate could not be maximized because of symptoms for 18% to 30% of the doses. The half‐life of HCIG was extremely short immediately after transplantation but was gradually prolonged. In the high‐dose group, serum alanine aminotransferase (ALT) levels normalized in most subjects and no patient developed hepatic fibrosis. However, serum HCV RNA levels were not suppressed at either dose. In conclusion, HCIG, an anti‐HCV enriched immune globulin product, appears to be safe in patients with chronic hepatitis C undergoing liver transplantation. Further studies are required to determine whether the drug has beneficial effects in this group of patients. (Liver Transpl 2005;11:941–949.)

Randomized Controlled Multicenter Trial of Aerosolized Ribavirin for Respiratory Syncytial Virus Upper Respiratory Tract Infection in Hematopoietic Cell Transplant Recipients

BACKGROUND Respiratory syncytial virus infection of the upper airways may progress to fatal pneumonia in hematopoietic cell transplant recipients. The safety and efficacy of aerosolized ribavirin in preventing disease progression is unknown. METHODS In a multicenter prospective trial, hematopoietic cell transplant recipients with respiratory syncytial virus infection of the upper airways were randomized to receive ribavirin (2 g 3 times daily) or supportive care for 10 days. The primary end point was progression to radiographically proven pneumonia. Secondary end points included virologically proven respiratory syncytial virus pneumonia, viral load changes, and safety. RESULTS Fourteen patients were randomized to 1 of 2 treatment arms. The trial was discontinued after 5 years because of slow accrual. Pneumonia at 1 month after randomization occurred in 1 of 9 patients who received ribavirin and in 2 of 5 patients who received supportive care (P=.51); virologically proven respiratory syncytial virus pneumonia occurred in 0 of 9 and 2 of 5 patients, respectively (P=.11). At 10 days after randomization, the average viral load decreased by 0.75 log10 copies/mL in ribavirin recipients, compared with a viral load increase of 1.26 log10 copies/mL in untreated patients (P=.07). No discontinuations of ribavirin therapy because of adverse effects occurred during 84 drug administrations. Rates of adverse events were similar in both groups. CONCLUSIONS Preemptive aerosolized ribavirin treatment appeared to be safe, and trends of decreasing viral load over time were observed. However, proof of efficacy remains elusive in hematopoietic cell transplant recipients.

Long-Term Persistence of Zoster Vaccine Efficacy

BACKGROUND The Shingles Prevention Study (SPS) demonstrated zoster vaccine efficacy through 4 years postvaccination. A Short-Term Persistence Substudy (STPS) demonstrated persistence of vaccine efficacy for at least 5 years. A Long-Term Persistence Substudy (LTPS) was undertaken to further assess vaccine efficacy in SPS vaccine recipients followed for up to 11 years postvaccination. Study outcomes were assessed for the entire LTPS period and for each year from 7 to 11 years postvaccination. METHODS Surveillance, case determination, and follow-up were comparable to those in SPS and STPS. Because SPS placebo recipients were offered zoster vaccine before the LTPS began, there were no unvaccinated controls. Instead, SPS and STPS placebo results were used to model reference placebo groups. RESULTS The LTPS enrolled 6867 SPS vaccine recipients. Compared to SPS, estimated vaccine efficacy in LTPS decreased from 61.1% to 37.3% for the herpes zoster (HZ) burden of illness (BOI), from 66.5% to 35.4% for incidence of postherpetic neuralgia, and from 51.3% to 21.1% for incidence of HZ, and declined for all 3 outcome measures from 7 through 11 years postvaccination. Vaccine efficacy for the HZ BOI was significantly greater than zero through year 10 postvaccination, whereas vaccine efficacy for incidence of HZ was significantly greater than zero only through year 8. CONCLUSIONS Estimates of vaccine efficacy decreased over time in the LTPS population compared with modeled control estimates. Statistically significant vaccine efficacy for HZ BOI persisted into year 10 postvaccination, whereas statistically significant vaccine efficacy for incidence of HZ persisted only through year 8.

Diagnosis and Assessment of Pain Associated With Herpes Zoster and Postherpetic Neuralgia

UNLABELLED Accurate evaluation of pain plays a critical role in identifying new interventions for the treatment and prevention of herpes zoster and postherpetic neuralgia (PHN). Different types of pain and other sensory symptoms are found in patients with herpes zoster, and these vary greatly with respect to their presence, location, duration, intensity, and quality. The results of recent studies of herpes zoster and PHN and the development of new methods for assessing neuropathic pain provide a foundation for diagnosing and assessing the pain associated with herpes zoster. We review the results of recent research to identify the essential components that must be considered in developing an evidence-based description of pain associated with herpes zoster and PHN. PERSPECTIVE Comprehensive assessments of pain are necessary for clinical research on the epidemiology, natural history, pathophysiologic mechanisms, treatment, and prevention of pain in herpes zoster and PHN.

The epidemiological, clinical, and pathological rationale for the herpes zoster vaccine.

Worldwide, herpes zoster (HZ) affects millions of patients (particularly older adults) annually and causes significant suffering due to acute and chronic pain, or postherpetic neuralgia (PHN). The objective of this article is to explain the rationale for the HZ vaccine by summarizing data on the epidemiology of HZ in the immunocompetent host, with a focus on recent incidence and risk factor studies; to review information on the burden of HZ; and to discuss the challenges of lessening the morbidity of the disease. The incidence and severity of HZ and PHN are highest in older adults. Given the central nervous system damage caused by HZ, the difficulty of adequately treating HZ to prevent PHN, and the intractability of PHN, the advent of the HZ vaccine appears to be a crucial innovation for preventing HZ and PHN.

Herpes Zoster: Risk Categories for Persistent Pain

Acute neuritis and persistent pain are the most significant clinical manifestations of herpes zoster and are end points for clinical trials therapy. In an acyclovir and prednisone study, patients were categorized according to pain severity and number of lesions at presentation. Risk categories were defined according to the magnitude of risk ratios (RRs) and a comparison of Kaplan-Meier survival estimates. For acute neuritis and zoster-associated pain, RRs defined rate of resolution. Patients who presented with severe or incapacitating pain and a large number of lesions were less likely to achieve resolution of both acute neuritis and zoster-associated pain (RR, 18.0; 95% confidence interval [CI], 6. 6-48.6, and RR, 5.3; 95% CI, 4.2-17.2, respectively). These analyses identify the subgroups of patients for whom aggressive interventions are most strongly indicated.