Antonio Volpi

Transmission of human herpesvirus 8: an update.

Purpose of review Human herpesvirus 8 is associated with neoplastic diseases in the immunocompromised host, including Kaposis sarcoma, multicentric Castleman disease and primary effusion lymphoma. Acquisition and control of human herpesvirus 8 infection have not yet been fully elucidated. This review focuses on the most recent findings on human herpesvirus 8 transmission. Recent findings Horizontal transmission by saliva appears the most common route not only in families in endemic regions, but also among high-risk groups in Western countries. Vertical, sexual, and blood and transplant-related transmission, however, remain of significant concern worldwide. Novel approaches to standardize and optimize the assessment of human herpesvirus 8 infection have been reported. New insights on the host immune cell mechanisms devoted to the control of human herpesvirus 8 infection have also been presented. Summary The increasing knowledge about the routes of human herpesvirus 8 transmission, which appear now more similar to those of other more ubiquitous human herpesviruses (i.e. Epstein–Barr virus and cytomegalovirus), the growing efforts in improving laboratory diagnosis and the caution in the research of new biological associations are the major recent findings. They constitute a fundamental background for directing more appropriate future research and achieving more stringent evidence useful for the control of human herpesvirus 8 spread and for the management of human herpesvirus 8-related diseases.

Inflammatory cytokines stimulate vascular smooth muscle cells locomotion and growth by enhancing α5β1 integrin expression and function

The formation of atherosclerotic lesions requires the migration of vascular smooth muscle cells from the media into the intima of the artery and their proliferation. These events, which are preceded and accompanied by inflammation, are modulated by integrin receptors linking vascular smooth muscle cells to extracellular matrix molecules. Among them, fibronectin induces vascular smooth muscle cells to acquire the phenotype they show in the atherosclerotic plaque. Here we show that amounts of interleukin-1 beta, tumor necrosis factor alpha and interferon-gamma as possibly released by activated immune cells infiltrating atherosclerotic lesions, upregulate vascular smooth muscle cell expression of the alpha5beta1 integrin, a fibronectin receptor. This improves vascular smooth muscle cell capability of migrating toward soluble or anchored fibronectin and of adhering to immobilized fibronectin. The latter effect, in turn, augments vascular smooth muscle cell proliferative response to mitogens, as suggested by the increase of intracellular pH. Finally, the effects that inflammatory cytokines have on vascular smooth muscle cell locomotion and growth, are specifically blocked by anti-alpha5beta1 antibodies. As fibronectin and alpha5beta1 levels are augmented in vivo in the atherosclerotic plaques, these findings support the use of integrin antagonists as potential adjuvants in atherosclerosis treatment.

Management of herpes zoster and post-herpetic neuralgia now and in the future.

Herpes zoster (HZ; shingles)--a reactivation of the latent varicella zoster virus (VZV)--can cause significant morbidity. Its major complication is pain, particularly post-herpetic neuralgia (PHN). We will review the current management strategies available for the treatment of both acute HZ and PHN, including antiviral drugs, analgesic agents, anticonvulsants, tricyclic antidepressants and topical therapies. New molecules in development that show improved activity against VZV are also covered, and new drug targets are outlined. The role of translational neuroscience in moving towards a goal of finding disease-modifying treatments will be examined.

Clinical and psychosocial correlates of post-herpetic neuralgia

Post‐herpetic neuralgia is the most challenging and debilitating complication of herpes zoster in the immunocompetent host. Because the effect of treatment is disappointing once the syndrome has developed, it is important to know which factors predict post‐herpetic neuralgia occurrence to facilitate selection of herpes zoster patients with a higher risk of developing neuralgia and undertake preventative strategies. The present study aimed at identifying demographic, clinical and psychosocial correlates of post‐herpetic neuralgia in a sample of 219 immunocompetent patients, who were examined by dermatologists in private practice in Italy and who completed a questionnaire designed to evaluate their clinical and psychosocial profile at the time of clinical diagnosis of herpes zoster and at a follow‐up visit 6 months later. In a univariate analysis, post‐herpetic neuralgia was associated significantly with older age, longer duration of prodromal pain, greater acute pain intensity, greater extent of rash, presence of abnormal sensations and use of systemic antiviral therapy. Compared to the values at herpes zoster onset, at the follow‐up visit patients with post‐herpetic neuralgia presented with similar high mean scores of pain intensity, anxiety and depression and greatly reduced quality of life, whereas patients without neuralgia presented with improved scores. In a multivariate model, older age, greater acute pain intensity, greater extent of rash and longer duration of prodromal pain were independently associated with post‐herpetic neuralgia. The results of this study may help physicians to identify patients with a higher risk of developing post‐herpetic neuralgia and undertaking preventative strategies. J. Med. Virol. 80:1646–1652, 2008.

Predictors of pain intensity and persistence in a prospective Italian cohort of patients with herpes zoster: relevance of smoking, trauma and antiviral therapy

BackgroundHerpes zoster (HZ) is a common disease, characterized by rash-associated localized pain. Its main complication, post-herpetic neuralgia (PHN), is difficult to treat and may last for months to years in the wake of rash resolution. Uncertainties remain as to the knowledge of predictors of HZ-related pain, including the role of antiviral therapy in preventing PHN in ordinary clinical practice. This prospective cohort study was aimed at investigating pain intensity at HZ presentation and its correlates, as well as the incidence of PHN and its predictors.MethodsPatients diagnosed with HZ were consecutively enrolled by a network of Italian General Practitioners and Hospital Units in the health district of Pescara, Italy, over two years. Uncertain cases were referred for microbiological investigation. Data were collected through electronic case report form (e-CRFs) at enrolment and at 1, 3, 6 and 12 months after enrolment. Pain intensity was coded on a five-degree semi-quantitative scale at each time point. PHN was defined as pain of any intensity during follow-up and quantified using an area-under-the-curve (AUC) method.ResultsFour hundred and forty-one patients composed the final sample. Mean age was 58.1 years (SD = 20.4 years); 43.5% of patients were males; 7.9% did not receive prescription of antivirals. Intense/very intense pain at presentation was reported by 25.2% of patients and was significantly associated with female gender, older age, cigarette smoking, trauma and/or surgery at HZ site (logistic regression). PHN was diagnosed in 51.2% of patients at one month and in 30.0% of patients at three months. PHN was significantly associated with pain intensity at presentation, age, smoking, trauma and missed antiviral prescription (generalized estimating equations model). The same factors were also independent predictors of the overall pain burden as described by the AUC method (linear regression).ConclusionsSmoking, traumas and surgery at the HZ site emerged as new predictors of both HZ-related pain intensity and persistence, opening new perspectives in the prevention of HZ-related pain. An independent line of evidence was provided for the efficacy of antiviral therapy in preventing PHN and reducing total pain burden.

A Systematic Analysis of Host Factors Reveals a Med23-Interferon-λ Regulatory Axis against Herpes Simplex Virus Type 1 Replication

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome.

A prospective study comparing quantitative Cytomegalovirus (CMV) polymerase chain reaction in plasma and pp65 antigenemia assay in monitoring patients after allogeneic stem cell transplantation

BackgroundLow levels of Cytomegalovirus (CMV) viral load are frequently detected following allogeneic stem cell transplantation (SCT) and CMV disease may still develop in some allogeneic SCT patients who have negative pp65-antigenemia (pp65-Ag) or undetectable DNA. Pp65Ag is a sensitive method to diagnose CMV infection. Quantitative CMV-DNA PCR assay in plasma has been proposed to monitor CMV infection in SCT patients. We evaluated the clinical utility of pp65Ag and PCR assay in plasma of SCT recipients.MethodsIn a prospective longitudinal study, 38 consecutive patients at risk of CMV infection (donor and/or recipient CMV seropositive) were weekly monitored for CMV infection by both quantitative CMV-PCR in plasma (COBAS AMPLICOR CMV MONITOR) and pp65 Ag, during the first 100 days after SCT.ResultsA total of 534 blood samples were simultaneously analysed for pp65Ag and PCR. Overall, 28/38 patients (74%) had active CMV infection within 100 days from SCT. In 16 patients, CMV was first detected by pp65 Ag alone; in 5 patients by both methods and in 6 by PCR assay alone; one patient had CMV biopsy-proven intestinal disease without pp65Ag and PCR assays positivity before CMV disease. Overall, three patients developed intestinal CMV disease (7.9%): one had negative both pp65Ag and PCR assays before CMV disease, one had disease and concomitant positivity of both methods, while in the remaining patient, only pp65Ag was positive before CMV disease.ConclusionPlasma PCR(COBAS AMPLICOR CMV MONITOR) and pp65Ag assays were effective in detecting CMV infection, however, discordance between both methods were frequently observed. Plasma PCR and pp65Ag assays may be complementary for diagnosis and management of CMV infection.

No Evidence of Family History as a Risk Factor for Herpes Zoster in Patients with Post-Herpetic Neuralgia

Little is known about reactivation of latent varicella zoster virus as herpes zoster in individuals with no underlying immunosuppression. Risk factors include age, sex, ethnicity, exogenous boosting of immunity from varicella contacts, underlying cell‐mediated immune disorders, mechanical trauma, psychological stress, and immunotoxin exposure. An association between herpes zoster and family history of zoster has been proposed. A case‐control study involving patients affected by post‐herpetic neuralgia, which usually follows more severe acute herpes zoster, was performed. The patients with post‐herpetic neuralgia were enrolled at the Pain Clinic of the Policlinico Tor Vergata in Rome, Italy, within 1 year from the onset of acute zoster. The controls matched for sex and age were chosen among healthy subjects without a history of herpes zoster presenting at the Internal Medicine Outpatient Clinic for hypertension in the same time period. All the participants in the study gave informed consent and were interviewed by medically trained and blinded investigators using a questionnaire. Similar proportions of the patients and the controls reported a family history of herpes zoster irrespective of the degree of relationship, i.e., 17.4% and 18.2%, respectively, by analyzing only the first‐degree relatives [RR 1.03 (CI 95%: 0.78–1.37)], and 28.4% and 29.6%, respectively, by analyzing the total number of relatives [RR 1.03 (CI 95%: 0.81–1.31)]. Further and larger prospective cohort studies are needed to ascertain whether a family history of herpes zoster is really an independent predictor of zoster in different geographical settings. J. Med. Virol. 82:1007–1011, 2010.

Preventing and managing herpes zoster: key actions to foster healthy aging

Population aging is the demographic phenomenon characterizing all countries in the world, and it is challenging the national infrastructures, in particular health systems. However, aging itself is not associated with increased medical spending, but disability and comorbidity that affect older individuals are the actual drivers for health expenditures. Therefore, if people age in better health, medical spending may be significantly reduced. Preventative interventions proved to be effective in reducing/preventing disease and disability and often found to be cost effective, include diet and exercise interventions, medications, routine disease screenings, and immunizations. Vaccination can protect older citizens against life-threatening diseases, such as influenza, pneumococcal infections, tetanus, and against diseases which adversely impact their quality of life, such as herpes zoster (HZ). Including HZ vaccination in its citizens’ lifetime immunization calendar can reinforce Europe’s commitment toward active, healthy aging. This paper outlines the consensus statement of a group of Italian experts on HZ.

Frequency of Herpes Zoster Recurrence

To the Editor: We read with great interest the study by Yawn et al,1 published in the February 2011 issue of Mayo Clinic Proceedings, which found that the frequency of herpes zoster (HZ) recurrence in a community population was higher than previously reported. The reported results are somewhat unexpected. It is generally accepted that the lifetime incidence of a second episode of HZ in immunocompetent individuals is between 1% and 5% and that the recurrence is typically many years after the first episode. A number of issues need to be clarified about the study by Yawn et al before the relevance of these findings can be determined. First, the diagnosis of HZ in the study by Yawn et al1 was established clinically. The clinical diagnosis of HZ can be difficult and is subject to error. In a zoster prevention study,2 HZ was ruled out by laboratory testing (polymerase chain reaction or viral culture) in 24% of patients with a clinical diagnosis of HZ, suggesting that clinical diagnosis can on occasion be incorrect. No previous unreported case of HZ was revealed in closeout interviews with patients in that study.2 Similarly, a prospective study of HZ diagnoses by general practitioners in the United Kingdom found 17% of diagnoses to be incorrect.3 More specifically, of the 230 patients diagnosed clinically as having HZ, only 204 cases were confirmed by immunofluorescence and/or polymerase chain reaction. Of the 26 patients who had no evidence of HZ on laboratory tests, 10 patients had herpes simplex, and the rest had other dermatological diseases.3 In the study by Yawn et al,1 only 25% of the recurrent episodes were confirmed by laboratory analysis, but it is unclear whether the first episode was also confirmed by laboratory results. We recently conducted a study of 173 patients (median age, 75 years) with postherpetic neuralgia. In these patients, the median duration of postherpetic neuralgia was 23 months (range, 2-207 months).4 None of the patients presented with HZ during the follow-up visit or had a history of HZ. We realize that the number of people involved is low compared with the cohort in the study by Yawn et al, but they presented with both the main risk factors that, according to that study, predict the likelihood of recurrences. Another point in need of clarification is the choice by Yawn et al to include in the analysis the 139 individuals (8.3% of the total population sample) who were immunocompromised at the time of the index HZ episode.1 It is known that the risk of HZ and its recurrence is increased in persons with a compromised immune system. Indeed, HZ rates of 29.4 to 51.5 per 1000 person-years have been reported among adults infected with the human immunodeficiency virus,5 and high rates have also been reported in persons with systemic lupus erythematosus, rheumatoid arthritis, granulomatosis with polyangiitis (Wegener), and inflammatory bowel disease.5 For most of these conditions, data are insufficient to determine how much of the risk is attributable to the underlying disease vs its treatment. Hence, the inclusion of immunocompromised people may represent a bias. Finally, the authors discuss the possibility of an innate (possibly genetic) predisposition for HZ, which has received attention in studies of HZ in families. We have recently examined the possibility that a family history of HZ represents a risk factor for zoster development, but our findings could not confirm the hypothesis.4 Given the ready availability and the safety profile of the HZ vaccine, we agree that it is important to identify additional categories of people who could benefit from it. However, in our opinion, well-designed prospective studies are needed to ascertain the real likelihood of recurrences in the general population.