Drug reaction with Eosinophilia and Systemic Symptoms (DRESS) / Drug-induced Hypersensitivity Syndrome (DIHS): a review of current concepts

The Drug Reaction with Eosinophilia and Systemic Symptoms syndrome, also known as Drug Induced Hypersensitivity Syndrome presents clinically as an extensive mucocutaneous rash, accompanied by fever, lymphadenopathy, hepatitis, hematologic abnormalities with eosinophilia and atypical lymphocytes, and may involve other organs with eosinophilic infiltration, causing damage to several systems, especially to the kidneys, heart, lungs, and pancreas. Recognition of this syndrome is of paramount importance, since the mortality rate is about 10% to 20%, and a specific therapy may be necessary. The pathogenesis is related to specific drugs, especially the aromatic anticonvulsants, altered immune response, sequential reactivation of herpes virus and association with HLA alleles. Early recognition of the syndrome and withdrawal of the offending drug are the most important and essential steps in the treatment of affected patients. Corticosteroids are the basis of the treatment of the syndrome, which may be associated with intravenous immunoglobulin and, in selected cases, Ganciclovir. The article reviews the current concepts involving this important manifestation of adverse drug reaction.

Brazilian blood donation eligibility criteria for dermatologic patients

A focused and commented review on the impact of dermatologic diseases and interventions in the solidary act of donating blood is presented to dermatologists to better advise their patients. This is a review of current Brazilian technical regulations on hemotherapeutic procedures as determined by Ministerial Directive #1353/2011 by the Ministry of Health and current internal regulations of the Hemotherapy Center of Ribeirão Preto, a regional reference center in hemotherapeutic procedures. Criteria for permanent inaptitude: autoimmune diseases (>1 organ involved), personal history of cancer other than basal cell carcinoma, severe atopic dermatitis or psoriasis, pemphigus foliaceus, porphyrias, filariasis, leprosy, extra pulmonary tuberculosis or paracoccidioidomycosis, and previous use of etretinate. Drugs that impose temporary ineligibility: other systemic retinoids, systemic corticosteroids, 5-alpha-reductase inhibitors, vaccines, methotrexate, beta-blockers, minoxidil, anti-epileptic, and anti-psychotic drugs. Other conditions that impose temporary ineligibility: occupational accident with biologic material, piercing, tattoo, sexually transmitted diseases, herpes, and bacterial infections, among others. Discussion: Thalidomide is currently missing in the teratogenic drugs list. Although finasteride was previously considered a drug that imposed permanent inaptitude, according to its short halflife current restriction of 1 month is still too long. Dermatologists should be able to advise their patients about proper timing to donate blood, and discuss the impact of drug withdrawal on treatment outcomes and to respect the designated washout periods.

Pair approximation for a model of vertical and horizontal transmission of parasites.

We apply Stochastic Dynamics method for a differential equations model, proposed by Marc Lipsitch and collaborators (Proc. R. Soc. Lond. B 260, 321, 1995), for which the transmission dynamics of parasites occurs from a parent to its offspring (vertical transmission), and by contact with infected host (horizontal transmission). Herpes, Hepatitis and AIDS are examples of diseases for which both horizontal and vertical transmission occur simultaneously during the virus spreading. Understanding the role of each type of transmission in the infection prevalence on a susceptible host population may provide some information about the factors that contribute for the eradication and/or control of those diseases. We present a pair mean-field approximation obtained from the master equation of the model. The pair approximation is formed by the differential equations of the susceptible and infected population densities and the differential equations of pairs that contribute to the former ones. In terms of the model parameters, we obtain the conditions that lead to the disease eradication, and set up the phase diagram based on the local stability analysis of fixed points. We also perform Monte Carlo simulations of the model on complete graphs and Erdös-Rényi graphs in order to investigate the influence of population size and neighborhood on the previous mean-field results; by this way, we also expect to evaluate the contribution of vertical and horizontal transmission on the elimination of parasite. Pair Approximation for a Model of Vertical and Horizontal Transmission of Parasites.

Bicistronic DNA vaccines simultaneously encoding HIV, HSV and HPV antigens promote CD8⁺ T cell responses and protective immunity

Millions of people worldwide are currently infected with human papillomavirus (HPV), herpes simplex virus (HSV) or human immunodeficiency virus (HIV). For this enormous contingent of people, the search for preventive and therapeutic immunological approaches represents a hope for the eradication of latent infection and/or virus-associated cancer. To date, attempts to develop vaccines against these viruses have been mainly based on a monovalent concept, in which one or more antigens of a virus are incorporated into a vaccine formulation. In the present report, we designed and tested an immunization strategy based on DNA vaccines that simultaneously encode antigens for HIV, HSV and HPV. With this purpose in mind, we tested two bicistronic DNA vaccines (pIRES I and pIRES II) that encode the HPV-16 oncoprotein E7 and the HIV protein p24 both genetically fused to the HSV-1 gD envelope protein. Mice i.m. immunized with the DNA vaccines mounted antigen-specific CD8⁺ T cell responses, including in vivo cytotoxic responses, against the three antigens. Under experimental conditions, the vaccines conferred protective immunity against challenges with a vaccinia virus expressing the HIV-derived protein Gag, an HSV-1 virus strain and implantation of tumor cells expressing the HPV-16 oncoproteins. Altogether, our results show that the concept of a trivalent HIV, HSV, and HPV vaccine capable to induce CD8⁺ T cell-dependent responses is feasible and may aid in the development of preventive and/or therapeutic approaches for the control of diseases associated with these viruses.

Studien zur physiologischen Funktion löslicher Zytokinrezeptoren und zur Wirkungsweise viral kodierter Zytokine

Interleukin-6 (IL-6) aktiviert Zielzellen durch Bindung an den Interleukin-6-Rezeptor (IL-6R) und anschließende Homodimerisierung von gp130. IL-6 alleine kann nur Zellen aktivieren, die IL-6R exprimieren, der Komplex aus IL-6 und löslichem IL-6R (sIL-6R) kann gp130 auf Zellen aktivieren, die keinen IL-6R exprimieren. Von gp130 gibt es eine lösliche Form (sgp130), die in Komplexen mit sIL-6R und IL-6 vorliegen kann.Es wurden rekombinante Versionen von sgp130 konstruiert, exprimiert und aufgereinigt. Die sgp130 Proteine inhibieren die sIL-6R-abhängige Stimulation von Zellen, nicht jedoch über membrangebundenen IL-6R vermittelte IL-6-Aktivitäten. sgp130 inhibiert also selektiv sIL-6R-abhängige Antworten und hat keinen Einfluß auf IL-6-Antworten über membrangebundenen IL-6R.Das Genom von Humanem Herpesvirus-8 kodiert für ein virales IL-6 (vIL-6). Um zu klären, ob vIL-6 direkt an IL-6R oder gp130 bindet, wurden Immunpräzipitationen mit radioaktiv markiertem vIL-6 durchgeführt. Dabei zeigte vIL-6 eine direkte Interaktion mit gp130, nicht jedoch mit IL-6R.Die biologische Aktivität von vIL-6 ist IL-6R-unabhängig. Es gibt keinen Unterschied in der Effektivität von vIL-6 bei der Stimulation von Zellen die nur gp130 oder gp130 und IL-6R exprimieren. Die Ergebnisse demonstrieren, daß vIL-6 das erste bekannte Zytokin ist, welches direkt gp130 binden und aktivieren kann.

Genetic and environmental factors associated with the risk of cognitive decline and dementia

AD is the most common age related neurodegenerative disease in the industrialized world. Clinically AD is defined as a progressing decline of cognitive functions. Neuropathologically, AD is characterized by the aggregation of b-amyloid (Ab) peptide in the form of extracellular senile plaques, and hyperphosphorlylated tau protein in the form of intracellular neurofibrillary tangles. These neuropathological hallmarks are often accompanied by abundant microvascular damage and pronounced inflammation of the affected brain regions. In this thesis we investigated several aspects of AD focusing on the genetic aspect. We confirmed that Alpha 1 antichymotrypsin (ACT), an acute phase protein, was associated to AD subjects, being plasma levels higher in AD cases than controls. In addition, in a GWA study we demonstrated that two different gene, Clusterin and CR1 were strongly associated to AD. A single gene association not explain such a complex disease like AD. The goal should be to created a network of genetic, phenotypic and clinical data associated to AD. We used a new algorithm, the ANNs, aimed to map variables and search for connectivity among variables. We found specific variables associated to AD like cholesterol levels, the presence of variation in HMGCR enzyme and the age. Other factors such as the BMI, the amount of HDL and blood folate levels were also associated with AD. Pathogen infections, above all viral infections, have been previously associated to AD. The hypothesis suggests that virus and in particular herpes virus could enter the brain when an individual becomes older, perhaps because of a decline in the immune system. Our new hypothesis is that the presence of SNPs in our GWA gene study results in a genetic signature that might affect individual brain susceptibility to infection by herpes virus family during aging.

Kostimulatorische Rezeptoren in der Aktivierung humaner neutrophiler Granulozyten

Neutrophile Granulozyten spielen eine wichtige Rolle in der ersten Phase der Inflammation. Sie infiltrieren den Infektionsort um den eingedrungenen Erreger zu bekämpfen und Ihre Effektor Funktion auszuführen. Neben den Mustererkennenden Rezeptoren des angeborenen Immunsystems (pattern recognition receptors) werden weitere Rezeptoren auf der Oberfläche von neutrophilen Granulozyten exprimiert, welche zur Aktivierung der Zelle beitragen können. In dieser arbeit wurden der Herpes Virus Entry Mediator (HVEM) und Triggering Receptor expressed on Myeloid Cells-1 (TREM-1) auf neutrophilen untersucht. Für HVEM konnte eine synergistische Aktivierung von neutrophilen Granulozyten im Zusammenspiel mit Toll like Rezeptor (TLR) Liganden nachgewiesen werden. Für TREM-1 konnte ein Vorhandensein eines Liganden auch Thrombozyten beschrieben. Es wurden weiterhin Mechanismen untersucht und beschrieben, welche für die synergistische Aktivierung von neutrophilen Granulozyten verantwortlich sind, welche nach TREM-1 und TLR Stimulation erkennbar ist.

Genetic and environmental factors associated with cardiovascular diseases and acute myocardial infarction

Acute myocardial infarction (AMI) is a multifactorial disease with a complex pathogenesis where lifestyle, individual genetic background and environmental risk factors are involved. Altered inflammatory responses seems to be implicated in the pathogenesis of atherosclerosis. To understand which genes may predispose to increased risk of cardiovascular disease gene polymorphism of immune regulatory genes, and clinical events from the Offs of parents with an early AMI were investigated. Genetics data from Offs were compared with those obtained from healthy subjects and an independent cohort of patients with clinical sporadic AMI. Rates of clinical events during a 24 years follow up from Offs and from an independent Italian population survey were also evaluated. This study showed that a genetic signature consisting of the concomitant presence of the CC genotype of VEGF, the A allele of IL-10 and the A allele of IFN-γ was indeed present in the Offs population. During the 24-year follow-up, Offs with a positive familiarity in spite of a relatively young age showed an increased prevalence of diabetes, ischemic heart disease and stroke. In these patients with the genetic signature the EBV and HHV-6 herpes virus were also investigated and founded. These findings reinforce the notion that subjects with a familial history of AMI are at risk of an accelerated aging of cardiovascular system resulting in cardiovascular events. These data suggest that selected genes with immune regulatory functions and envoronmental factors are part of the complex genetic background contributing to familiarity for cardiovascular diseases.N

BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination

The function of antigen-specific CD8+ T cells, which may protect against both infectious and malignant diseases, can be impaired by ligation of their inhibitory receptors, which include CTL-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). Recently, B and T lymphocyte attenuator (BTLA) was identified as a novel inhibitory receptor with structural and functional similarities to CTLA-4 and PD-1. BTLA triggering leads to decreased antimicrobial and autoimmune T cell responses in mice, but its functions in humans are largely unknown. Here we have demonstrated that as human viral antigen-specific CD8+ T cells differentiated from naive to effector cells, their surface expression of BTLA was gradually downregulated. In marked contrast, human melanoma tumor antigen-specific effector CD8+ T cells persistently expressed high levels of BTLA in vivo and remained susceptible to functional inhibition by its ligand herpes virus entry mediator (HVEM). Such persistence of BTLA expression was also found in tumor antigen-specific CD8+ T cells from melanoma patients with spontaneous antitumor immune responses and after conventional peptide vaccination. Remarkably, addition of CpG oligodeoxynucleotides to the vaccine formulation led to progressive downregulation of BTLA in vivo and consequent resistance to BTLA-HVEM-mediated inhibition. Thus, BTLA activation inhibits the function of human CD8+ cancer-specific T cells, and appropriate immunotherapy may partially overcome this inhibition.

[Infectious bovine rhinotracheitis (IBR) in the canton of Jura: an epidemiological outbreak investigation]

Following an abortion in a beef herd in the summer of 2009, three outbreaks of infectious bovine rhinotracheitis (IBR) were diagnosed in the cantons of Jura and Neuchatel. An epidemiological outbreak investigation was conducted with the aims to identify the source of introduction of the bovine herpes virus 1 (BoHV-1) into the affected herds and to prevent further spread of the disease. The attack rates in the three outbreak farms were 0.89, 0.28 and 0, respectively. BoHV-1 could be isolated from nasal swabs of two animals originating from one of the affected farms. Comparative restriction enzyme analysis revealed slight differences between the isolates of the two animals, but a high similarity to previous BoHV-1 isolates from the canton of Jura, as well as to a French BoHV-1 isolate. This IBR outbreak has shown the importance of reporting and analyzing abortions. The current disease outbreaks recall the main risk factors for the spread of IBR in Switzerland: purchase and movement of bovines and semen of often unknown IBR status.

Human and feline invasive cervical resorptions: the missing link?--Presentation of four cases

This report describes 4 patients presenting with multiple teeth affected by invasive cervical resorption (ICR). The cases came to our attention between 2006 and 2008; previously, no cases of multiple ICR (mICR) had been reported in Switzerland. Characteristics common to all 4 cases included progression of disease over time, similar clinical and radiographic appearance of lesions, and obscure etiology. The histologically assessed teeth showed a similar pattern of tooth destruction, with resorptive lesions being confined to the cervical region. Howship's lacunae and multinucleated, tartrate-resistant acid phosphatase-positive odontoclasts were detected. None of the teeth presented with internal resorption. The positive pulp sensitivity corresponded to the histologic findings, indicating that the pulp tissue resisted degradation even in advanced stages of resorptive lesions. Although mICR is rare in humans, a similar disease known as feline odontoclastic resorptive lesions (FORL) is common in domestic, captive, and wild cats. The etiology of FORL, like that of mICR, remains largely unknown. Because FORL has been associated with feline viruses, we asked our mICR patients whether they had had contact with cats, and interestingly, all patients reported having had direct (2 cases) or indirect (2 cases) contact. In addition, blood samples were taken from all patients for neutralization testing of feline herpes virus type 1 (FeHV-1). Indeed, the sera obtained were able to neutralize (2 cases) or partly inhibit (2 cases) replication of FeHV-1, indicating transmission of feline viruses to humans. Future studies on mICR (and FORL) should evaluate the possible role of a (feline) virus as an etiologic (co-)factor in this disease.

Oral manifestations of HIV/AIDS in China: a review

PURPOSE: The purpose of this study is to review the Chinese-language medical and dental literature from 1982 to 2008 on oral manifestations (OMs) of patients with HIV/AIDS for introducing the spectrum of OMs of the patients in China. MATERIALS AND METHODS: All data were extracted from 18 references which had used diagnostic criteria for HIV/AIDS. Four of the references had used the EC-Clearinghouse classification for oral lesions in HIV infection. The feasible overall rate and 95% confidence interval (95%CI) of the data on OMs were calculated. RESULTS: Risk group analysis revealed that, of 203 patients, 64.3% were men and 35.7% were women (age range, 5 months to 64 years; mean age in three studies, 34.0, 34.3, and 36.1 years). Of these patients, 22.2% were infected by sexual contacts, 11.8% by intravenous drug use (IDU), 59.6% by blood or its products, 2.9% by mother to child transmission, and 3.4% were unclear. In 203 patients, oral candidiasis (OC) was the most common lesion (66%, 95%CI = 59.48-72.52%), followed by herpes simplex (HS) (22.2%, 95%CI = 16.48-27.92%), ulcerative stomatitis (14.8%, 95%CI = 9.92-19.68%), salivary gland disease (11.3%, 95%CI = 6.94-15.66%), oral hairy leukoplakia (OHL) (9.8%, 95%CI = 5.71-13.89%), necrotizing gingivitis (5.9%, 95%CI = 2.66-9.14%), Kaposi's sarcoma (2.9%, 95%CI = 0.59-5.21%), other malignant tumors (2.9%, 95%CI = 0.59-5.21%), and linear gingival erythema (2.0%, 95%CI = 0.07-3.93%). CONCLUSIONS: The spectrum of OMs reported from China is similar to that described in the international literature. Present data are useful to supplement international resources of HIV/AIDS research.

Economic evaluation of varicella vaccination in Swiss children and adolescents

This study explores the effects of three different 2-dose varicella zoster virus (VZV) vaccination strategies in Switzerland. The EVITA model was used to assess clinical benefits and costs of strategies (1) vaccination of 11-15 year old adolescents with a negative or uncertain history for chickenpox, (2) universal vaccination of toddlers at age 1 to 2 years, and (3) strategy 2 plus catch-up vaccination of 11-15 year old susceptible adolescents. The cost-effectiveness analysis compares strategies 2 and 3 versus strategy 1 (current vaccination policy in Switzerland). Probabilities for clinical outcomes and medical resource utilization were derived from a real-world survey among Swiss pediatricians and general practitioners including 236 individuals with VZV infection, published information on varicella complications, and expert opinion. Costs of medical resource utilization represent official Swiss medical tariffs. The model predicts both universal childhood vaccination strategies to be more effective in reducing varicella disease burden compared to strategy 1. Economically, both universal childhood vaccination strategies with or without catch-up result in net savings from the societal perspective reflected by a benefit cost ratio (BCR) of 1.22 or 1.29, respectively. In contrast, the model predicts net costs from the payer perspective (BCR of 0.27 and 0.30, respectively). These economic findings are comparable to those reported from other similar evaluations. However, due to the recent recommendation for using a 2-dose varicella vaccination schedule, our economic results for Switzerland are somewhat less favorable than those for other country analyses in which a less expensive 1-dose vaccination regimen for toddlers has been studied.

[Odynophagia of a young mother]

We report the case of a 34-year old mother presenting in the emergency unit because of fever and odynophagia. Herpetic esophagitis with Herpes simplex virus primoinfection in a immunocompetent patient was diagnosed. The virus was transmitted by her own child which came to be hospitalised because of herpetic stomatitis. In the blood chemistry pancreas enzymes were elevated which we interpreted as herpetic pancreatitis because of coincidence with herpetic esophagitis.

HHV-8 seroprevalence: a global view

BACKGROUND Human herpes virus 8 (HHV-8) is the underlying infectious cause of Kaposi sarcoma (KS) and other proliferative diseases; that is, primary effusion lymphoma and multicentric Castleman disease. In regions with high HHV-8 seroprevalence in the general population, KS accounts for a major burden of disease. Outside these endemic regions, HHV-8 prevalence is high in men who have sex with men (MSM) and in migrants from endemic regions. We aim to conduct a systematic literature review and meta-analysis in order 1) to define the global distribution of HHV-8 seroprevalence (primary objective) and 2) to identify risk factors for HHV-8 infection, with a focus on HIV status (secondary objective). METHODS/DESIGN We will include observational studies reporting data on seroprevalence of HHV-8 in children and/or adults from any region in the world. Case reports and case series as well as any studies with fewer than 50 participants will be excluded. We will search MEDLINE, EMBASE, and relevant conference proceedings without language restriction. Two reviewers will independently screen the identified studies and extract data on study characteristics and quality, study population, risk factors, and reported outcomes, using a standardized form. For the primary objective we will pool the data using a fully bayesian approach for meta-analysis, with random effects at the study level. For the secondary objective (association of HIV and HHV-8) we aim to pool odds ratios for the association of HIV and HHV-8 using a fully bayesian approach for meta-analysis, with random effects at the study level. Sub-group analyses and meta-regression analyses will be used to explore sources of heterogeneity, including factors such as geographical region, calendar years of recruitment, age, gender, ethnicity, socioeconomic status, different risk groups for sexually and parenterally transmitted infections (MSM, sex workers, hemophiliacs, intravenous drug users), comorbidities such as organ transplantation and malaria, test(s) used to measure HHV-8 infection, study design, and study quality. DISCUSSION Using the proposed systematic review and meta-analysis, we aim to better define the global seroprevalence of HHV-8 and its associated risk factors. This will improve the current understanding of HHV-8 epidemiology, and could suggest measures to prevent HHV-8 infection and to reduce its associated cancer burden.