Probing the Mechanisms Underlying the Transport of the Vinca Alkaloids by P-glycoprotein.

The efficacy of many cancer drugs is hindered by P-glycoprotein (Pgp), a cellular pump that removes drugs from cells. To improve chemotherapy, drugs capable of evading Pgp must be developed. Despite similarities in structure, vinca alkaloids (VAs) show disparate Pgp-mediated efflux ratios. ATPase activity and binding affinity studies show at least two binding sites for the VAs: high- and low-affinity sites that stimulate and inhibit the ATPase activity rate, respectively. The affinity for ATP from the ATPase kinetics curve for vinblastine (VBL) at the high-affinity site was 2- and 9-fold higher than vinorelbine (VRL) and vincristine (VCR), respectively. Conversely, VBL had the highest Km (ATP) for the low-affinity site. The dissociation constants (KDs) determined by protein fluorescence quenching were in the order VBL < VRL< VCR. The order of the KDs was reversed at higher substrate concentrations. Acrylamide quenching of protein fluorescence indicate that the VAs, either at 10 µM or 150 µM, predominantly maintain Pgp in an open-outward conformation. When 3.2 mM AMPPNP was present, 10 µM of either VBL, VRL, or VCR cause Pgp to shift to an open-outward conformation, while 150 µM of the VAs shifted the conformation of Pgp to an intermediate orientation, between opened inward and open-outward. However, the conformational shift induced by saturating AMPPNP and VCR condition was less than either VBL or VRL in the presence of AMPPNP. At 150 µM, atomic force microscopy (AFM) revealed that the VAs shift Pgp population to a predominantly open-inward conformation. Additionally, STDD NMR studies revealed comparable groups in VBL, VRL, and VCR are in contact with the protein during binding. Our results, when coupled with VAs-microtubule structure-activity relationship studies, could lay the foundation for developing next-generation VAs that are effective as anti-tumor agents. A model that illustrates the intricate process of Pgp-mediated transport of the VAs is presented.

Drug-Induced Conformational Dynamics of P-Glycoprotein Underlies the Transport of Camptothecin Analogs.

P-glycoprotein (Pgp) plays a pivotal role in drug bioavailability and multi-drug resistance development. Understanding the protein's activity and designing effective drugs require insight into the mechanisms underlying Pgp-mediated transport of xenobiotics. In this study, we investigated the drug-induced conformational changes in Pgp and adopted a conformationally-gated model to elucidate the Pgp-mediated transport of camptothecin analogs (CPTs). While Pgp displays a wide range of conformations, we simplified it into three model states: 'open-inward', 'open-outward', and 'intermediate'. Utilizing acrylamide quenching of Pgp fluorescence as a tool to examine the protein's tertiary structure, we observed that topotecan (TPT), SN-38, and irinotecan (IRT) induced distinct conformational shifts in the protein. TPT caused a substantial shift akin to AMPPNP, suggesting ATP-independent 'open-outward' conformation. IRT and SN-38 had relatively moderate effects on the conformation of Pgp. Experimental atomic force microscopy (AFM) imaging supports these findings. Further, the rate of ATPase hydrolysis was correlated with ligand-induced Pgp conformational changes. We hypothesize that the separation between the nucleotide-binding domains (NBDs) creates a conformational barrier for substrate transport. Substrates that reduce the conformational barrier, like TPT, are better transported. The affinity for ATP extracted from Pgp-mediated ATP hydrolysis kinetics curves for TPT was about 2-fold and 3-fold higher than SN-38 and IRT, respectively. On the contrary, the dissociation constants (KD) determined by fluorescence quenching for these drugs were not significantly different. Saturation transfer double difference (STDD) NMR of TPT and IRT with Pgp revealed that similar functional groups of the CPTs are accountable for Pgp-CPTs interactions. Efforts aimed at modifying these functional groups, guided by available structure-activity relationship data for CPTs and DNA-Topoisomerase-I complexes, could pave the way for the development of more potent next-generation CPTs.

Varicella in the neonatal ICU due to the Varicella vaccine Oka strain.

BACKGROUND: Varicella vaccination of non-immune post-partum women is recommended to reduce the risk of chickenpox in mothers and their infants. Though rare, transmission of the varicella vaccine strain vOka can occur from recent vaccinees to non-immune contacts who usually develop mild chickenpox. METHODS/RESULTS: Here we describe an infant hospitalized in the neonatal ICU with vaccine-strain varicella due to transmission from their mother who received the varicella vaccine post-partum. We describe the infection prevention and control strategies implemented to prevent further transmission. CONCLUSION: Vaccine-strain varicella transmission from mother to infant is a rare event and its occurrence in the neonatal ICU setting can be challenging. Anticipatory guidance for mothers vaccinated in the postpartum period and support of parents of an infected infant are recommended.

Baseline characteristics and comorbidities in the CAnadian REgistry for Pulmonary Fibrosis.

BACKGROUND: The CAnadian REgistry for Pulmonary Fibrosis (CARE-PF) is a multi-center, prospective registry designed to study the natural history of fibrotic interstitial lung disease (ILD) in adults. The aim of this cross-sectional sub-study was to describe the baseline characteristics, risk factors, and comorbidities of patients enrolled in CARE-PF to date. METHODS: Patients completed study questionnaires and clinical measurements at enrollment and each follow-up visit. Environmental exposures were assessed by patient self-report and comorbidities by the Charlson Comorbidity Index (CCI). Baseline characteristics, exposures, and comorbidities were described for the overall study population and for incident cases, and were compared across ILD subtypes. RESULTS: The full cohort included 1285 patients with ILD (961 incident cases (74.8%)). Diagnoses included connective tissue disease-associated ILD (33.3%), idiopathic pulmonary fibrosis (IPF) (24.7%), unclassifiable ILD (22.3%), chronic hypersensitivity pneumonitis (HP) (7.5%), sarcoidosis (3.2%), non-IPF idiopathic interstitial pneumonias (3.0%, including idiopathic nonspecific interstitial pneumonia (NSIP) in 0.9%), and other ILDs (6.0%). Patient-reported exposures were most frequent amongst chronic HP, but common across all ILD subtypes. The CCI was ≤2 in 81% of patients, with a narrow distribution and range of values. CONCLUSIONS: CTD-ILD, IPF, and unclassifiable ILD made up 80% of ILD diagnoses at ILD referral centers in Canada, while idiopathic NSIP was rare when adhering to recommended diagnostic criteria. CCI had a very narrow distribution across our cohort suggesting it may be a poor discriminator in assessing the impact of comorbidities on patients with ILD.

Ten-year trends in direct costs of asthma: a population-based study.

INTRODUCTION: There is little information on recent trends in the economic burden of asthma. Our objective was to estimate the excess costs of asthma and their trend in British Columbia, Canada, from 2002 to 2011. METHODS: A retrospective cohort of individuals aged 5-55 years was constructed from the provincial administrative health databases, consisting of patients with physician-diagnosed asthma and a propensity-score-matched comparison sample from the general population. Total direct medical costs were calculated as the sum of hospitalizations, outpatient visits and medication costs, adjusted to 2012 Canadian dollars ($). Excess costs were defined as the difference in costs between the asthma and comparison groups. RESULTS: A total of 341 457 individuals (mean age at entry 27.3, 54.1% female) were equally divided into the asthma and comparison groups. Excess costs in patients with asthma were $1028.0 (95% CI $982.7-$1073.4) per patient-year (PY). Medications contributed to the greatest share of excess costs ($471.7/PY), whereas hospitalization and outpatient costs were, respectively, $272.2/PY and $284.1/PY. Only $192.9/PY was attributable to asthma itself. There was a 2.9%/year increase in excess costs (P < 0.001), a combination of asthma-attributable costs declining by 0.8%/year while nonasthma excess costs increasing by 3.8%/year. The most dramatic trend was observed in asthma-related outpatient costs, which decreased by %6.6/year. CONCLUSIONS: A significant share of excess costs in asthma is not attributable to the disease itself. The pattern of costs changed significantly during the study period. The burden of comorbid conditions should be considered in developing evidence-based policies for management of patients with asthma.

The differences in short- and long-term varicella-zoster virus (VZV) immunoglobulin G levels following varicella vaccination of healthcare workers measured by VZV fluorescent-antibody-to-membrane-antigen assay (FAMA), VZV time-resolved fluorescence immunoassay and a VZV purified glycoprotein enzyme immunoassay.

Healthcare workers (HCWs) reporting no history of varicella frequently receive varicella vaccination (vOka) if they test varicella-zoster virus (VZV) immunoglobulin G (IgG) negative. In this study, the utilities of VZV-IgG time-resolved fluorescence immunoassay (VZV-TRFIA) and a commercial VZV-IgG purified glycoprotein enzyme immunoassay (gpEIA) currently used in England for confirming VZV immunity have been compared to the fluorescent-antibody-to-membrane-antigen assay (FAMA). A total of 110 HCWs received two doses of vOka vaccine spaced 6 weeks apart and sera collected pre-vaccination (n = 100), at 6 weeks post-completion of vaccination (n = 86) and at 12-18 months follow-up (n = 73) were analysed. Pre-vaccination, by FAMA, 61·0% sera were VZV IgG negative, and compared to FAMA the sensitivities of VZV-TRFIA and gpEIA were 74·4% [95% confidence interval (CI) 57·9-87·0] and 46·2% (95% CI 30·1-62·8), respectively. Post-completion of vaccination the seroconversion rate by FAMA was 93·7% compared to rates of 95·8% and 70·8% determined by VZV-TRFIA and gpEIA, respectively. At 12-18 months follow-up seropositivity rates by FAMA, VZV-TRFIA and gpEIA were 78·1%, 74·0% and 47·9%, respectively. Compared to FAMA the sensitivities of VZV-TRFIA and gpEIA for measuring VZV IgG following vaccination were 96·4% (95% CI 91·7-98·8) and 74·6% (95% CI 66·5-81·6), respectively. Using both FAMA and VZV-TRFIA to identify healthy adult VZV susceptibles and measure seroconversion showed that vOka vaccination of HCWs is highly immunogenic.

Glucocorticoid-induced osteoporosis management among seniors, by year, sex, and indication, 1996-2012.

UNLABELLED: We identified that glucocorticoid-induced osteoporosis management (bone mineral density testing or osteoporosis treatment) among seniors improved among men (2 to 23 %) and women (10 to 48 %) between 1996 and 2007, and then remained relatively stable through to 2012. Differences were also noted by indication (from a low of 21 % for respiratory conditions to a high of 41 % for rheumatic conditions). PURPOSE: The aim of our study was to describe the proportion of chronic oral glucocorticoid (GC) users that receive osteoporosis management (bone mineral density test or osteoporosis treatment) by sex and over time. METHODS: We identified community-dwelling older adults initiating chronic oral GC therapy in Ontario using pharmacy data from 1996 to 2012. Chronic GC use was defined as greater than or equal to two oral GC prescriptions dispensed and ≥450 mg prednisone equivalent over a 6-month period. Osteoporosis management within 6 months of starting chronic GC therapy was examined by sex, year, indication for therapy, and osteoporosis management history. Results were summarized using descriptive statistics. RESULTS: We identified 72,099 men and 95,975 women starting chronic oral GC therapy (mean age = 74.9 years, SD = 6.5). Approximately two thirds of patients (65 %) received ≥900 mg within the 6-month chronic use window. GC-induced osteoporosis management increased from 2 to 23 % (men) and 10 to 48 % (women) between 1996 and 2007, and then remained relatively stable through to 2012. A higher proportion of patients with prior osteoporosis management were managed within 6 months (56 % men, 67 % women) of chronic GC use, compared to patients without prior management (12 % men, 23 % women). Patients with rheumatic disease were managed most commonly (41 %), and patients with respiratory conditions were managed least commonly (21 %). CONCLUSIONS: GC-induced osteoporosis management improved significantly over time for both sexes yet remains low. Significant care gaps by sex and between clinical areas represent a missed opportunity for fracture prevention among patients requiring chronic GC therapy.

Hypersomnia subtypes, sleep and relapse in bipolar disorder.

BACKGROUND: Though poorly defined, hypersomnia is associated with negative health outcomes and new-onset and recurrence of psychiatric illness. Lack of definition impedes generalizability across studies. The present research clarifies hypersomnia diagnoses in bipolar disorder by exploring possible subgroups and their relationship to prospective sleep data and relapse into mood episodes. METHOD: A community sample of 159 adults (aged 18-70 years) with bipolar spectrum diagnoses, euthymic at study entry, was included. Self-report inventories and clinician-administered interviews determined features of hypersomnia. Participants completed sleep diaries and wore wrist actigraphs at home to obtain prospective sleep data. Approximately 7 months later, psychiatric status was reassessed. Factor analysis and latent profile analysis explored empirical groupings within hypersomnia diagnoses. RESULTS: Factor analyses confirmed two separate subtypes of hypersomnia ('long sleep' and 'excessive sleepiness') that were uncorrelated. Latent profile analyses suggested a four-class solution, with 'long sleep' and 'excessive sleepiness' again representing two separate classes. Prospective sleep data suggested that the sleep of 'long sleepers' is characterized by a long time in bed, not long sleep duration. Longitudinal assessment suggested that 'excessive sleepiness' at baseline predicted mania/hypomania relapse. CONCLUSIONS: This study is the largest of hypersomnia to include objective sleep measurement, and refines our understanding of classification, characterization and associated morbidity. Hypersomnia appears to be comprised of two separate subgroups: long sleep and excessive sleepiness. Long sleep is characterized primarily by long bedrest duration. Excessive sleepiness is not associated with longer sleep or bedrest, but predicts relapse to mania/hypomania. Understanding these entities has important research and treatment implications.

Chronic stressors and trauma: prospective influences on the course of bipolar disorder.

BACKGROUND: Exposure to life stress is known to adversely impact the course of bipolar disorder. Few studies have disentangled the effects of multiple types of stressors on the longitudinal course of bipolar I disorder. This study examines whether severity of chronic stressors and exposure to trauma are prospectively associated with course of illness among bipolar patients. METHOD: One hundred and thirty-one participants diagnosed with bipolar I disorder were recruited through treatment centers, support groups and community advertisements. Severity of chronic stressors and exposure to trauma were assessed at study entry with in-person interviews using the Bedford College Life Event and Difficulty Schedule (LEDS). Course of illness was assessed by monthly interviews conducted over the course of 24 months (over 3000 assessments). RESULTS: Trauma exposure was related to more severe interpersonal chronic stressors. Multiple regression models provided evidence that severity of overall chronic stressors predicted depressive but not manic symptoms, accounting for 7.5% of explained variance. CONCLUSIONS: Overall chronic stressors seem to be an important determinant of depressive symptoms within bipolar disorder, highlighting the importance of studying multiple forms of life stress.

Comparative study of the standard fluorescent antibody to membrane antigen (FAMA) assay and a flow cytometry-adapted FAMA assay to assess immunity to varicella-zoster virus.

A flow cytometry-adapted fluorescent antibody to membrane antigen (FAMA) assay to detect IgG antibodies against varicella-zoster virus (VZV) was developed and tested in 62 serum samples, showing 90.32% accuracy obtained from a receiver operating characteristic (ROC) curve with a 0.9125 (95% confidence interval [CI], 0.829 to 1.00) area below the curve compared to the result with standard FAMA.

Population diversity in batches of the varicella Oka vaccine.

The Oka vaccine is a live attenuated vaccine for the prevention of varicella. Although the vaccine differs from the progenitor virus by over 40 mutations, only three of these are fixed, the rest being a mixture of the wildtype and the vaccine allele. To examine the extent of this variability between two of the three commercially available vaccine preparations, we analysed the vaccine/wildtype allele frequencies present at fifteen vaccine loci in five preparations each from two different manufacturers of the vOka vaccine. Our results suggest that differences in manufacturing processes between the two companies have resulted in significant variation in the frequencies of the vaccine/wildtype alleles in their vaccines. Yet despite these differences, the allele frequencies in the vaccines from the two companies are strongly correlated. We discuss the significance of these findings and the role of evolutionary processes that influence the production of this live attenuated vaccine.

Evaluation of the time resolved fluorescence immunoassay (TRFIA) for the detection of varicella zoster virus (VZV) antibodies following vaccination of healthcare workers.

Determination of varicella zoster virus (VZV) immunity in healthcare workers without a history of chickenpox is important for identifying those in need of vOka vaccination. Post immunisation, healthcare workers in the UK who work with high risk patients are tested for seroconversion. To assess the performance of the time-resolved fluorescence immunoassay (TRFIA) for the detection of antibody in vaccinated as well as unvaccinated individuals, a cut-off was first calculated. VZV-IgG specific avidity and titres six weeks after the first dose of vaccine were used to identify subjects with pre-existing immunity among a cohort of 110 healthcare workers. Those with high avidity (≥ 60%) were considered to have previous immunity to VZV and those with low or equivocal avidity (<60%) were considered naive. The former had antibody levels ≥ 400 mIU/mL and latter had levels < 400 mIU/mL. Comparison of the baseline values of the naive and immune groups allowed the estimation of a TRFIA cut-off value of > 130 mIU/mL which best discriminated between the two groups and this was confirmed by ROC analysis. Using this value, the sensitivity and specificity of TRFIA cut-off were 90% (95% CI 79-96), and 78% (95% CI 61-90) respectively in this population. A subset of samples tested by the gold standard Fluorescence Antibody to Membrane Antigen (FAMA) test showed 84% (54/64) agreement with TRFIA.

The effect of injections of botulinum toxin type A combined with casting on the equinus gait of children with cerebral palsy.

Our aim was to evaluate the effect of adding inhibitory casting to the treatment of young children with cerebral palsy who received injections of botulinum neurotoxin A (BoNT-A) to gastrocnemius for equinus gait. Of the 20 patients in the series, 11 in group A had inhibitory casts applied on the day of the first set of BoNT-A injections and nine in group B did not have casting. Both groups received another BoNT-A injection four months later. The patients were followed for eight months and examined at five intervals. Both groups showed significant improvement in gait parameters and function (p < 0.0001) and selective motor control (p = 0.041, - 0.036) throughout the study. Group A had significantly better passive dorsiflexion of the ankle (p = 0.029), observational gait score (p = 0.006) and selective motor control (p = 0.036). We conclude that the addition of inhibitory casting enhances and prolongs the results of treatment and mainly influences the passive range of movement, while BoNT-A mostly influences the dynamic motion. The second injection further improved the results of most parameters. The gross motor function measure, the selective motor control test and the modified Tardieu scale correlated well with the results of treatment. We recommend the use of inhibitory casting whenever augmentation of the effect of treatment with BoNT-A is needed.

Identifying individuals with physcian diagnosed COPD in health administrative databases.

Chronic Obstructive Pulmonary Disease (COPD) is a common chronic respiratory disease responsible for significant morbidity and mortality. Population-based health administrative databases provide a powerful and unbiased way of studying COPD in the population, however, their ability to accurately identify patients with this disease must first be confirmed. The objective was to validate population-based health administrative definitions of COPD. Previously abstracted medical records of adults over the age of 35 randomly selected from primary care practices in Ontario, Canada were reviewed by an expert panel to establish if an individual did or did not have a diagnosis of COPD. These reference designations were then linked to each individual's respective health administrative database record and compared with predefine health administrative data definitions of COPD. Concepts of diagnostic test evaluation were used to calculate and compare their test characteristics. The most sensitive health administrative definition of COPD was 1 or more ambulatory claims and/or 1 or more hospitalizations for COPD that yielded a sensitivity of 85.0% (95% confidence interval 77.0 to 91.0) and a specificity of 78.4% (95% confidence interval 73.6 to 82.7). As number of ambulatory claims in the definition increased, sensitivity decreased and specificity increased. Individuals with COPD can be accurately identified in health administrative data, and therefore it may be used to create an unbiased population cohort for surveillance and research. This offers a powerful means of generating evidence to inform strategies that optimize the prevention and management of COPD.

Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine.

BACKGROUND: A double-blind, placebo-controlled trial that involved 38,546 subjects > or =60 years old demonstrated efficacy of a high-potency live-attenuated Oka/Merck varicella-zoster virus (VZV) vaccine. The trial included an immunology substudy to determine the relationship of VZV-specific immune responses to vaccination and clinical outcome. METHODS: The immunology substudy enrolled 1395 subjects at 2 sites where blood samples obtained prior to vaccination, at 6 weeks after vaccination, and at 1, 2, and 3 years thereafter were tested for VZV-specific cell-mediated immunity (VZV-CMI) by gamma-interferon ELISPOT and responder cell frequency assays and for VZV antibody by glycoprotein ELISA. RESULTS: VZV-CMI and VZV antibodies were significantly increased in vaccine recipients at 6 weeks after vaccination. The vaccine-induced increases in VZV-CMI persisted during the 3 years of follow-up, although their magnitude decreased over time. The magnitude of these VZV-specific immune responses was greater in subjects 60-69 years old than in subjects > or =70 years old. CONCLUSIONS: The zoster vaccine induced a significant increase in VZV-CMI and VZV antibody. The magnitude and duration of the boost in VZV-CMI in vaccine recipients and the relationship of this boost to age paralleled the clinical effects of the vaccine observed during the efficacy trial. These findings support the hypothesis that boosting VZV-CMI protects older adults against herpes zoster and postherpetic neuralgia.

Gender, victimization, and psychiatric outcomes.

BACKGROUND: Although gender differences in rates of internalizing disorders, particularly depression, are well documented, the causes of these differences are not well understood. One influential hypothesis [Cutler & Nolen-Hoeksema, Sex Roles (1991), 24, 425-438] proposes that higher rates of depression in females compared to males may be partially attributable to gender differences in the effects of childhood sexual abuse. The present study has evaluated this possibility by reviewing evidence for gender moderating the effects of childhood victimization on psychiatric outcomes. METHOD: Literature search using PsycINFO and Medline, applying the following inclusion criteria: publication from 1996 to 2006, community-based sampling, adequate male-to-female sample ratio, use of clearly defined psychiatric outcomes, and a statistical test of gender differences in the effects of childhood victimization on psychiatric outcomes. RESULTS: Thirty studies met inclusion criteria. Overall, the results were mixed. Nearly half of all studies find no gender differences. In studies that do observe gender differences, victimization tends to be associated with higher psychiatric risk in females in studies with adult samples, whereas in samples of youth, victimization tends to be associated with higher psychiatric risk in males. With respect to outcome, when gender differences were observed, outcomes were distributed across both internalizing and externalizing categories for both genders. CONCLUSIONS: The gender differences in prevalence rates of internalizing disorders, such as depression, do not appear to be attributable to differential effects of childhood victimization.

Cholesterol dependence of varicella-zoster virion entry into target cells.

The entry of inhaled virions into airway cells is presumably the initiating step of varicella-zoster infection. In order to characterize viral entry, we studied the relative roles played by lipid rafts and clathrin-mediated transport. Virus and target cells were pretreated with agents designed to perturb selected aspects of endocytosis and membrane composition, and the effects of these perturbations on infectious focus formation were monitored. Infectivity was exquisitely sensitive to methyl-beta-cyclodextrin (M beta CD) and nystatin, which disrupt lipid rafts by removing cholesterol. These agents inhibited infection by enveloped, but not cell-associated, varicella-zoster virus (VZV) in a dose-dependent manner and exerted these effects on both target cell and viral membranes. Inhibition by M beta CD, which could be reversed by cholesterol replenishment, rapidly declined as a function of time after exposure of target cells to VZV, suggesting that an early step in viral infection requires cholesterol. No effect of cholesterol depletion, however, was seen on viral binding; moreover, there was no reduction in the surface expression or internalization of mannose 6-phosphate receptors, which are required for VZV entry. Viral entry was energy dependent and showed concentration-dependent inhibition by chlorpromazine, which, among other actions, blocks clathrin-mediated endocytosis. These data suggest that both membrane lipid composition and clathrin-mediated transport are critical for VZV entry. Lipid rafts are likely to contribute directly to viral envelope integrity and, in the host membrane, may influence endocytosis, evoke downstream signaling, and/or facilitate membrane fusion.

Reasons patients present to the emergency department might change during epidemics and be a valuable component of a disease surveillance system.

We hypothesize that the frequency of reasons patients present to the emergency department will change during epidemics and might be a valuable component of a disease surveillance system. We found support for this hypothesis over a two-year period with high frequency days of fever clustering during two periods of increased hospital influenza activity, but not during any other period during the two-years. This methodology appears to be superior to the previous use of triage nurses defining patients with symptom complexes. Such a system could result in online monitoring, be independent of the medical personnel (use of admission secretary), and might be able to identify various epidemics including increased hospital disease activity due to bio-terror attacks, influenza, and food poisoning. This would have important implications for limiting the spread of disease and for the acute planning of distribution of medical resources. Studies are warranted in various settings to determine whether or not changes in the daily frequencies of reasons patients present to the ED will allow identification of epidemics.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.