Rheumatic fever – pathogenesis and vaccine

Há um amplo espectro de doenças causadas por estreptococos do grupo A (GAS), e estas são consideradasum problema de saúde pública em países em desenvolvimento, com aproximadamente 600 milhões de casos/ano. As infecções causadas por GAS podem ocasionardoenças invasivas como faringite e pioderma com seqüelas auto-imunes graves como a febre reumática (FR) e glomerulonefrite. A FR acomete principalmente crianças e jovens, inicia com poliartrite na maioria dos casos. Tem como sequelas principais a coreia de Sydenham e a doençareumática cardíaca (DRC), considerada a forma mais grave da doença e caracterizada por lesões cardíacas valvares progressivas e permanentes, que necessitam de cirurgias cardíacas para correção valvular, com alto custo para os Sistemas de Saúde, no mundo. A presente revisão descreve os principais mecanismos desencadeadores das lesões reumáticas no coração e o desenvolvimento da vacinacontra o Streptococcus pyogenes para prevenção das principais sequelas decorrentes das streptococcias.Group A streptococci (GAS) infections are considered a public health problem in developing countries, with about 600 million cases per year and are responsible for an wide spectrum of diseases, mainly invasive diseases as pharyngitis and pyoderma that lead to rheumatic fever (RF) and glomerulonephritis autoimmune sequelae. RF affects children and young adults, and presents different manifestations such as rheumatic heart disease (RHD), Sydenham chorea, erythema marginatum, subcutaneous nodules. RHD is considered the most serious complications leading to cardiac valvular lesions characterized by progressive and permanent heart-valve damage, which entails high cost to the Healthy System around the world. In the present review we described the mechanisms that lead to rheumatic heart lesions and the development of a vaccine against Streptococcus pyogenes

Correction to: Prognostic influence of prior chronic obstructive pulmonary disease in patients admitted for their first episode of acute heart failure

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New technologies and emergency department excellence

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Streptococcus pyogenes strains in Sao Paulo, Brazil: molecular characterization as a basis for StreptInCor coverage capacity analysis

Abstract\ud \ud Background\ud Several human diseases are caused by Streptococcus pyogenes, ranging from common infections to autoimmunity. Characterization of the most prevalent strains worldwide is a useful tool for evaluating the coverage capacity of vaccines under development. In this study, a collection of S. pyogenes strains from Sao Paulo, Brazil, was analyzed to describe the diversity of strains and assess the vaccine coverage capacity of StreptInCor.\ud \ud \ud Methods\ud Molecular epidemiology of S. pyogenes strains was performed by emm-genotyping the 229 isolates from different clinical sites, and PCR was used for superantigen profile analysis. The emm-pattern and tissue tropism for these M types were also predicted and compared based on the emm-cluster classification.\ud \ud \ud Results\ud The strains were fit into 12 different emm-clusters, revealing a diverse phylogenetic origin and, consequently, different mechanisms of infection and escape of the host immune system. Forty-eight emm-types were distinguished in 229 samples, and the 10 most frequently observed types accounted for 69 % of all isolates, indicating a diverse profile of circulating strains comparable to other countries under development. A similar proportion of E and A-C emm-patterns were observed, whereas pattern D was less frequent, indicating that the strains of this collection primarily had a tissue tropism for the throat. In silico analysis of the coverage capacity of StreptInCor, an M protein-conserved regionally based vaccine candidate developed by our group, had a range of 94.5 % to 59.7 %, with a mean of 71.0 % identity between the vaccine antigen and the predicted amino acid sequence of the emm-types included here.\ud \ud \ud Conclusions\ud This is the first report of S. pyogenes strain characterization in Sao Paulo, one of the largest cities in the world; thus, the strain panel described here is a representative sample for vaccine coverage capacity analysis. Our results enabled evaluation of StreptInCor candidate vaccine coverage capacity against diverse M-types, indicating that the vaccine candidate likely would induce protection against the diverse strains worldwide.“Conselho Nacional de Desenvolvimento Científico e Tecnológico” [CNPq 557814/2009-0]“Fundação de Amparo à Pesquisa do Estado de Sao Paulo” [FAPESP 2007/59262-3

Identification, expression, purification and characterization of new allergens from the Polybia paulista wasp venom

As hipersensibilidades do tipo I são caracterizadas por um grupo heterogêneo de manifestações clínicas que atingem mais de 30% da população mundial. Novas reatividades a alérgenos regionais brasileiros têm sido descritas e muitas fontes ainda não são totalmente conhecidas. Dentre os alérgenos mais prevalentes estão os venenos de insetos. A vespa regional Polybia paulista (Hymenoptera vespidae) é endêmica no sudeste do Brasil e é responsável por acidentes graves, causando reações alérgicas que podem levar ao choque anafilático. Alguns componentes dos venenos de vespas de diferentes espécies apresentam mimetismo molecular ou biológico, podendo gerar reação imunológica cruzada, mas muitas vezes não são os responsáveis pelo desencadeamento da resposta alérgica. Isto ocasiona falha no diagnóstico e consequentemente no tratamento indicado, a imunoterapia alérgeno-específica. Diante desses fatos e do grande número de pacientes que procuram o Serviço de Imunologia Clínica e Alergia do Hospital das Clínicas de São Paulo (HCFMUSP) com manifestações clínicas de alergias a ferroadas de insetos, foi desenvolvida uma sistemática de investigação clínica e laboratorial, com ênfase na abordagem proteômica, para identificar e caracterizar físico-química e imunologicamente novos alérgenos do veneno da vespa Polybia paulista e estudar potenciais reatividades cruzadas com alérgenos já conhecidos. Vinte e um pacientes com história de anafilaxia a venenos de vespa foram selecionados para participar do estudo. Foram realizados testes cutâneos e in vitro com veneno de Polistes spp. disponível comercialmente e com o veneno da Polybia paulista, produzido seguindo o protocolo padronizado anteriormente. Os resultados mostraram que a maioria dos pacientes apresentam IgE específica para os dois venenos com maior reatividade ao veneno de Polybia e que o padrão de proteínas reconhecidas entre os dois venenos é diferente, evidenciando a necessidade de veneno de Polybia paulista na prática clínica nas regiões cuja vespa está presente. Foram identificadas mais de 2000 proteínas no extrato total do veneno de Polybia paulista e algumas proteínas alergênicas ainda não descritas. Dentre elas foi identificada uma nova isoforma ao antígeno 5 da vespa Polybia scutellaris relatada como hipoalergênica. A molécula foi produzida na forma recombinante com conformação adequada, pela primeira vez em E. coli. O alérgeno, registrado na IUIS como Poly p 5, foi reconhecido por IgEs no soro dos pacientes testados e apresenta reatividade cruzada com outros antígenos 5 homólogos. Testes de desgranulação de basófilos em linhagem celular de ratos mostraram que o Poly p 5 induziu pouca desgranulação, indicando seu potencial hipoalergênicoType I hypersensitivity is characterized by heterogeneous clinical manifestations and specialists estimate that today around 30% of the general population suffers from an allergic disease. New allergens are being reported and some sources are not yet identified. Insect venoms are amongst the most prevalent allergen sources. The social wasp Polybia paulista (Hymenoptera vespidae) is endemic in the southeastern of Brazil and is responsible for serious accidents due to their venomous stings, causing allergic reactions that can lead to anaphylactic shock. Several components presenting molecular or biological mimicry can be found in different species of wasps and lead to a cross-immunological reaction but they are not always responsible for the allergic manifestations. Therefore, diagnostic and consequently immunotherapy is unsuccessful, since specific allergen identification is crucial. Considering the high number of patients attended at the \"Serviço de Imunologia Clínica e Alergia do Hospital das Clínicas de São Paulo\" with clinical manifestations of allergies not yet determined or barely studied, an approach involving a systematic clinical, laboratorial and investigative practice through a proteomic analysis was created to identify and characterize new allergens of Polybia paulista venom. Twenty-one patients with clinical history of anaphylaxis to Hymenoptera venoms were selected for this work. Cutaneous and in vitro tests were performed using Polistes venom commercially available as well as Polybia paulista venom, produced following a published protocol. The results shows that the majority of the patients has specific IgE for both venoms with biggest reactivity to Polybia paulista venom and the protein profile recognized in these venoms is different. More than 2000 proteins were identified in the whole venom extract of Polybia paulista and some of the allergenic proteins are not yet described in this venom. Among them, a new isoform that is similar to antigen 5 from Polybia scutellaris, already known as hypoallergenic. The molecule was produced as a recombinant properly folded for the first time in E. coli. The allergen, registered at IUIS as Poly p 5, was recognized by IgEs in the sera of 50% of the patients tested and has cross-reactivity with other homologs of antigen 5. Basophil degranulation tests in rat lineage cells showed that Poly p 5 induced little degranulation, indicating the hypoallergenic potential of this molecul

\"in vitro\" analysis of the coverage capacity of the vaccine under development against most frequent strains of Streptococcus pyogenes

O Streptococcus pyogenes (Grupo A de Lancefield) é uma bactéria Gram positiva e beta-hemolítica, responsável por infecções, tais como Faringite, Sepse, Fasciíte Necrotizante e Síndrome do Choque Tóxico Estreptocócico. Indivíduos suscetíveis podem desenvolver sequela não supurativa auto-imune pós-estreptocócica, como a Febre Reumática, Doença Reumática Cardíaca e a Glomerulonefrite Aguda. A proteína M é o principal antígeno bacteriano. Consiste em aproximadamente 450 resíduos de aminoácidos dispostos em quatro regiões (A, B, C e D), contendo alguns blocos de repetições. As regiões C e D são conservadas e a N-terminal (regiões A e B) é polimórfica. Atualmente, existem mais de 250 genótipos de emm conhecidos em todo o mundo, de acordo com o Centers for Disease Control and Prevention. Há vários anos, o desenvolvimento de uma vacina contra S. pyogenes (StreptInCor - identificação médica) foi iniciado, com base na região conservada da proteína M, com o objetivo de proteger o indivíduo vacinado contra infecções estreptocócicas, sem causar reações autoimunes. No presente estudo foi analisada a capacidade \"in vitro\" de anticorpos anti-StreptInCor neutralizarem/opsonizarem as cepas de S. pyogenes mais freqüentes em São Paulo, através da análise do reconhecimento das cepas por soros de camundongos imunizados com StreptInCor. Também foi avaliada por Western blotting a presença de anticorpos de reação cruzada dirigidos ao tecido cardíaco valvular humano. Anticorpos anti-StreptInCor foram capazes de neutralizar/opsonizar, pelo menos, cinco diferentes cepas mostrando que a imunização com StreptInCor pode ser eficaz contra várias cepas de S. pyogenes, assim como prevenir a infecção e sequelas subsequentes, sem causar reações auto-imunes.Streptococcus pyogenes (Group A) is a Gram positive and beta-hemolytic bacteria, responsible for infections such as Pharyngitis, Sepsis, Necrotizing Fasciitis and Streptococcal Toxic Shock Syndrome. Susceptible individuals may develop post-streptococcal non-suppurative autoimmune sequelae such as Rheumatic Fever, Rheumatic Heart Disease and Acute Glomerulonephritis. The M protein is the major bacterial antigen. It consists of approximately 450 amino acid residues arranged in four regions (A, B, C and D), containing some repeated blocks. C and D regions are conserved and the N-terminus (regions A and B) is polymorphic. Currently there are over 250 known emm genotypes worldwide, according to the Centers for Disease Control and Prevention. Several years ago the development of a vaccine against S. pyogenes (StreptInCor - medical identification) was initiated, based on the M protein conserved region, aiming to protect against streptococcal infections without causing autoimmune reactions. In the present study we analyzed the \"in vitro\" ability of anti-StreptInCor antibodies to neutralize/opsonize the most frequent S. pyogenes strains in Sao Paulo by examining the strains recognition by sera from StreptInCor immunized mice. We also evaluated the presence of cross reactive antibodies directed to the human heart valve tissue by Western blotting. Anti-StreptInCor antibodies were able to neutralize/opsonize at least 5 strains, showing that the immunization with StreptInCor can be effective against several S. pyogenes strains as well as preventing infection and subsequent sequelae, without causing autoimmune reactions

Manifestação cutânea isolada da COVID-19 conduzida por telemedicina

Objetivos: Este artigo é um relato de caso de uma paciente com diagnóstico confirmado de COVID-19 que teve avaliação médica realizada por telemedicina. Esta paciente apresentou manifestação cutânea isolada e foi avaliada por clínico geral remotamente, com diagnóstico e tratamento orientados. A avaliação correta da manifestação cutânea da COVID-19 é um desafio, e a viabilidade do diagnóstico por telemedicina ainda é incerta. Nosso objetivo é demonstrar a eficácia da teleconsulta em uma manifestação dermatológica durante a pandemia. Material e Métodos: Compilação retrospectiva de dados do prontuário da paciente e assinatura do termo de consentimento livre e esclarecido para o relato. Resultados: A apresentação clínica inicial foi de máculas pruriginosas difusas pelo abdome, que motivou a paciente a procurar atendimento presencial em pronto-socorro no primeiro dia de sintomas. A hipótese inicial foi de reação alérgica não especificada. Devido ao contexto da pandemia foram realizados exames de sangue e RT-PCR (swab nasofaríngeo) para COVID-19. A paciente recebeu alta medicada com antialérgico e com orientação para ser checar resultado dos exames em 24h e ter reavaliação médica se necessário. Ela foi reavaliada por telemedicina no dia seguinte, houve confirmação do diagnóstico de infecção aguda por COVID-19 (swab positivo), não houve manifestação de outros sintomas e foi possível reavaliar com precisão as lesões cutâneas remotamente. A lesão examinada por vídeo era compatível com rash morbiliforme difuso com angioedema local. A paciente recebeu orientações específicas conforme diretriz institucional e manutenção do tratamento sintomático dermatológico. Após 3 semanas, em nova reavaliação por telemedicina, houve confirmação da resolução do quadro cutâneo e ausência de outros sintomas neste período. Conclusão: A avaliação médica por telemedicina permitiu a interpretação da lesão cutânea elementar, tomada de decisão e orientação adequada. A manifestação cutânea isolada pode ser uma manifestação da COVID-19 e é factível de ser diagnosticada por teleconsulta, reforçando a necessidade de expansão do programa de telemedicina para avaliação inicial de pacientes agudos.Objectives: This paper is a case report of a COVID-19 patient with a confirmed diagnosis of COVID-19 who had a medical evaluation by Telemedicine (TM). She presented with an isolated cutaneous manifestation and was examined by a remote general practitioner, having diagnosis and treatment guided. The correct evaluation of COVID-19 cutaneous manifestation is a challenge, and the feasibility of TM diagnosis is still uncertain. We aim to demonstrate the effectiveness of teleconsultation in a dermatological manifestation during a pandemic. Material and Methods: Retrospective data compilation from patient’s medical record and the patient signed the consent form. Results: The initial clinical presentation was a diffuse pruritic macules in the abdomen, which motivated the patient to seek face-to-face care in the emergency department on the first day of symptoms. The initial hypothesis was an unspecified allergic reaction. Due to the context of the pandemic, blood tests and RT-PCR (nasopharyngeal swab) were performed for COVID-19. The patient was discharged medicated with an anti allergy and instructed to check the results of the test within 24 hours and have a medical reassessment if necessary. She was re-evaluated by TM the following day, the diagnosis of acute infection by COVID-19 was confirmed (swab positive), there was no manifestation of other symptoms and it was possible to accurately re-evaluate the skin lesions remotely. The patient had a diffuse morbilliform rash with local angioedema. The patient received specific orientations according to institutional guidelines and maintenance of dermatological symptomatic treatment. After 3 weeks, in a new reassessment by TM, there was confirmation of the resolution of the skin condition and absence of other symptoms during this period. Conclusion: The medical evaluation by TM allowed the interpretation of the elementary skin lesion, decision making and adequate guidance. The isolated cutaneous manifestation can be a manifestation of COVID-19 and it is feasible to be diagnosed by teleconsultation, reinforcing the need to expand the MT program for the initial evaluation of acute patients

Analysis of the coverage capacity of the StreptInCor candidate vaccine against Streptococcus pyogenes

Streptococcus pyogenes is responsible for infections as pharyngitis, sepsis, necrotizing fasciitis and streptococcal toxic shock syndrome. The M protein is the major bacterial antigen and consists of both polymorphic N-terminal portion and a conserved region. In the present study, we analyzed the in vitro ability of StreptInCor a C-terminal candidate vaccine against S. pyogenes to induce antibodies to neutralize/opsonize the most common S. pyogenes strains in Sao Paulo by examining the recognition by sera from StreptInCor immunized mice. We also evaluated the presence of cross-reactive antibodies against human heart valve tissue. Anti-StreptInCor antibodies were able to neutralize/opsonize at least 5 strains, showing that immunization with StreptInCor is effective against several S. pyogenes strains and can prevent infection and subsequent sequelae without causing autoimmune reactions