El virus respiratorio sincicial: patógeno de niños... y de grandes / Respiratory syncytial virus: a pathogen for the small ones and the big ones

Desde el descubrimiento del virus respiratorio sincicial (VRS) en 1956, se ha demostrado en todo el mundo su impacto como el principal causante de infecciones respiratorias agudas bajas (IRAB) que requieren hospitalización en el lactante. Posteriormente se ha descrito que una inadecuada respuesta inmune favorece reinfecciones en la infancia. Más recientemente, numerosos trabajos epidemiológicos lo han asociado a IRAB en adultos, especialmente de tercera edad y en ciertos pacientes inmunocomprometidos. Se ha avanzado en el conocimiento de la estructura y función de los diferentes componentes del VRS, lo que ha permitido facilitar su diagnóstico y avanzar en estrategias de desarrollo de antivirales y vacunas. En efecto, el diagnóstico de laboratorio de VRS es muy simple en niños, por su alta excreción viral, pero para demostrar su participación en adultos se requieren técnicas de alta sensibilidad. La patogenia de la infección es muy compleja y muchos aspectos todavía no se han aclarado. Intervienen factores dependientes del virus -cepa, dosis infectiva, capacidad del virus de inhibir la respuesta inmune- y del hospedero humano, como edad, enfermedades concomitantes, integridad del aparato inmune y otros. Se menciona que otros factores como frío, humedad ambiental, contaminación aérea, hacinamiento, también actuarían en combinación con los inicialmente mencionados. Es necesario conocer los mecanismos responsables de la adquisición de inmunidad contra el VRS para entender las estrategias usadas en el intento de desarrollar vacunas, cuyos esfuerzos son todavía infructuosos. Actualmente se conoce bastante del VRS como patógeno de niños. Sin embargo, cada día se documenta más su participación en enfermedades de adultos, por lo que haremos un resumen para promover su consideración como posible patógeno respiratorio.

Since respiratory syncytial virus (RSV) was identified in 1956, its impact as the main cause of severe acute lower respiratory infections in infants has been shown. Studies about RSV immunopathogenesis have demonstrated that the host immune response is important in protecting from re-infections. The presence of RSV in exacerbation of chronic diseases as COPD and bronchial asthma in adults and its severity in cases with immunodeficiency has been also related to an inadequate response. The actual knowledge on the molecular structure and functions of the virus has allowed to improve diagnosis and to develop new strategies for vaccines and antiviral drugs. The etiologic diagnosis in children is easier than in adults due to the higher viral shedding; therefore techniques based on antibody reactions (immunofluorescence, immunocromatography, etc) are good enough in this group. By contrast, in adults, highly sensitive molecular techniques are needed. Although the advances in understanding the pathogenesis process in neonates and infants, many pathogenic factors still need to be elucidated. The virus strains, viral loads and immune response have been described as important players; however, the changes on the host immunity to RSV according to age and co-morbidities associated to severity of illness needs to be explored. RSV has been known as a children pathogen, nowadays this agent is being recognized as an important agent in adults, especially in those with chronic diseases, immunodeficiency and in immune-senescence.

In Hot Pursuit of the First Vaccine Against Respiratory Syncytial Virus

Human respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infection, such as bronchiolitis, bronchitis, or pneumonia, in both infants and the elderly. Despite the global burden of diseases attributable to RSV infection, no clinically approved vaccine is available, and a humanized monoclonal antibody for prophylaxis is not readily affordable in developing countries. There are several hurdles to the successful development of RSV vaccines: immune-vulnerable target populations such as premature infants, pregnant women, and immunocompromised people; safety concerns associated with vaccine-enhanced diseases; repeated infection; and waning memory. To develop successful strategies for the prevention of RSV infection, it is necessary to understand the protective and pathologic roles of host immune responses to RSV infection. In this review, we will summarize the positive and negative relationship between RSV infection and host immunity and discuss strategies for the development of the first successful RSV vaccine.

Aumento de interleuquinas proinflamatorias y de cortisol plasmático en bronquiolitis por virus respiratorio sincicial: relación con la gravedad de la infección / Levels of inflammatory cytokines and plasma cortisol in respiratory syncytial virus bronchiolitis

Background: An increased inflammatory innate response may play a role in pathogenesis of respiratory syncytial virus (RSV) infection. Aim: To quantify pro-inflammatory cytokines (IL-6-IL-8, ÍL-2-P and TNF-a) in nasopharyngeal aspirate (NPA) and plasma, and plasma cortisol in previously healthy infants with RSV bronchiolitis. Patients and Methods: We studied 49 infants aged less than one year of age with RSV bronchiolitis and 25 healthy controls. Severity was defined using a previously described modified score. We quantified interleukins in NPA and plasma by flow cytometry and plasma cortisol by radioimmunoanalysis. Results: Among patients with RSV bronchiolitis, 25 were classified as severe and 24 as moderate or mild. Significantly higher levels ofIL-6 and IL-8 in NPA and plasma and IL-lfi in NPA were found in children classified as severe, when compared to those with moderate or mild disease and controls. There was a positive correlation between IL-6 and cortisol in plasma (r = 0,55; p < 0,0001) and both were correlated with the severity of the disease. Conclusions: RSV bronchiolitis severity was associated with higher levéis of inflammatory interleukins and plasma cortisol.

Respiratory syncitial virus in children with acute respiratory infections.

Objective. To study the nutritional status of children with Respiratory Syncitial virus infection. Methods. One hundred and twenty six children with acute respiratory infection, between the age of 4-24 months, were investigated for RSV infection with bronchiolitis, pneumonia and upper respiratory tract infection. Nasopharyngeal aspirates were collected and cytokine responses were determined by ELISA. Upper respiratory tract infections were detected in 16.66%, bronchiolitis in 30.15% and Pneumonia in 53.17% children. Results. Of the 126 patients, 46.66% children were positive for RSV while 58.33% were negative for RSV. Children with bronchiolitis were more commonly positive for RSV compared to URTI and pneumonia. RSV was almost equally distributed among boys (42.5%) and girls (48.7%). More children were RSV positive when the mean age lesser (8.4 mo) was compared to RSV negative (9.93 mo). Well nourished children and children with normal birth weight had more RSV positives, though not statistically significant. In a sub sample analysis of cytokines done (n=25), Interleukin-2 and Interleukin-8 levels were higher in the RSV positive children and these levels declined after 5 days of illness. Conclusions. RSV is more commonly associated with bronchiolitis in younger infants with normal birth weight or more weight for age (WFA). Proinflammatory cytokine IL-8 was secreted at high concentrations in the nasopharyngeal aspirate in all the children.

Lower respiratory tract infection caused by respiratory syncytial virus in infants: the role played by specific antibodies

INTRODUCTION: Respiratory syncytial virus (RSV) is a major etiological agent of lower respiratory tract infection in infants. Genotypes of this virus and the role of the infants' serum antibodies have yet to be fully clarified. This knowledge is important for the development of effective therapeutic and prophylactic measures. OBJECTIVES: To evaluate the types and genotypes of RSV causing respiratory tract infection in infants, to analyze the association of subtype-specific serum antibodies with the occurrence of infection and to evaluate the presence of subtype-specific antibodies in the infants' mothers and their association with the profile of the childrens' serum antibodies. METHODS: This was a prospective study on infants hospitalized with respiratory infection. Nasopharyngeal secretions were collected for viral investigation using indirect immunofluorescence and viral culture and blood was collected to test for antibodies using the Luminex Multiplex system. RESULTS: 192 infants were evaluated, with 60.9 percent having RSV (73.5 percent- A and 20.5 percent B). Six genotypes of the virus were identified: A5, A2, B3, B5, A7 and B4. The seroprevalence of the subtype-specific serum antibodies was high. The presence and levels of subtype-specific antibodies were similar, irrespective of the presence of infection or the viral type or genotype. The mothers' antibody profiles were similar to their infants'. CONCLUSIONS: Although the prevalence of subtype-specific antibodies was elevated, these antibodies did not provide protection independently of virus type/genotype. The similarity in the profiles of subtype-specific antibodies presented by the mothers and their children was consistent with transplacental passage.

INTRODUÇÃO: O vírus sincicial respiratório é um dos principais agentes etiológicos das infecções do aparelho respiratório inferior em lactentes. Os genótipos deste vírus e o papel dos anticorpos séricos ainda não estão esclarecidos. Este conhecimento é importante para o desenvolvimento de medidas terapêuticas e profiláticas. OBJETIVOS: Avaliar: os tipos e genótipos do vírus sincicial que causam infecção respiratória em lactentes e a associação dos anticorpos séricos subtipo-específicos com a ocorrência de infecção; a presença de anticorpos subtipo-específicos nas mães e sua associação com o perfil de anticorpos da criança. MÉTODOS: Estudo prospectivo incluindo lactentes hospitalizados com infecção respiratória. Foi coletada secreção de nasofaringe para investigação viral usando imunofluorescência indireta e cultivo viral. Foi coletado sangue para pesquisa de anticorpos usando o sistema Luminex Multiplex. RESULTADOS: Avaliados 192 lactentes: 60,9 por cento com vírus sincicial (73,5 por cento - A e 20,5 por cento - B). Seis genótipos de vírus sincicial respiratório foram identificados: A5,A2,B3,B5,A7 e B4. A soroprevalência dos anticorpos subtipos-específicos foi alta. A presença e o nível de anticorpos subtipos-específicos foram semelhantes, independentemente da presença de infecção, tipo e genótipo do vírus. As mães e as crianças apresentaram perfis semelhantes de anticorpos. CONCLUSÕES: A prevalência dos anticorpos subtipos-específicos foi elevada mas estes anticorpos não conferiram proteção, independentemente do tipo/genótipo do vírus. A semelhança dos perfis de anticorpos das mães e das crianças foi compatível com transmissão transplacentária.

Eosinophil Cationic Protein and Chemokines in Nasopharyngeal Secretions of Infants with Respiratory Syncytial Virus (RSV) Bronchiolitis and Non-RSV Bronchiolitis

Bronchiolitis is a risk factor for the development of childhood asthma. Eosinophilic inflammation in airways plays an important role in the pathophysiology of both bronchiolitis and asthma. To investigate this inflammation, we measured the eosinophil cationic protein (ECP), regulated on activation normal T-cell expressed and secreted (RANTES) and eotaxin levels in nasopharyngeal secretions (NPS). Twenty-eight patients with RSV bronchiolitis (RSV group), 11 patients with non-RSV bronchiolitis (non-RSV group) and 7 controls were enrolled in this study. ECP, RANTES, and eotaxin levels were measured by enzyme immunoassays. The ECP level in the NPS of the RSV group was significantly higher than that in the NPS of the non-RSV group and controls. RANTES and eotaxin levels in infants with bronchiolitis were significantly higher than those in the controls, but there was no significant difference between the RSV and non-RSV groups. In conclusion, with regard to eosinophilic airway inflammation, as compared with non-RSV bronchiolitis, RSV bronchiolitis may be more similar to childhood asthma.

Infecções pelo Vírus Sincicial Respiratório em crianças / Respiratory Syncytial Virus Infections in children

As infecções respiratórias agudas são importante causa de morbimortalidade em pediatria em todo o mundo, particularmente nos países em desenvolvimento. As infecções respiratórias são responsáveis por mais de 25 de todo o atendimento médico pediátrico ambulatorial e hospitalar e, em torno de 90 dessas infecções são relacionadas com agentes virais. O vírus sincicial respiratório (VSR)possui distribuição mundial e constitui a causa mais comum de pneumonia viral em crianças com menos de 5 anos de idade. A bronquiolite ou a pneumonia grave têm probabilidade elevada de ocorrência em lactantes com cerca de 6 semanas de idade, com incidência máxima aos 2 meses. A infecção pelo VSR em lactantes e crianças de mais idade resulta em infecção das vias respiratórias menos agressiva do que aquela observada em lactentes com menos de 6 meses de idade. No hemisfério setentrional, os surtos de infecção pelo VSR tendem a terseu pico no inverno. Nas regiões tropicais, as epidemias pelo VSR iniciamîse no outono e vão até a primavera. A reinfecção é freqüente, porém os sintomas resultantes são mais leves, envolvendo as vias aéreas superiores. Nesta revisão são abordados aspectos importantes das infecções respiratórias por VSR relativos às características do VSR, imunidade, transmissão, epidemiologia, clínica e patologia, prevenção, tratamento, e mortalidade

Avances en la prevención de infecciones por virus respiratorio sincicial / Advances in prevention of respiratory syncytial virus infections

El virus respiratorio sincicial (VRS) fue aislado por primera vez en 1955 desde monos de adolescentes con coriza, llamándolo agente de la coriza del chimpancé. Muy pronto el mismo virus se aisló de infantes con bronquiolitis y neumonía siendo reconocido como la causa más común de infección respiratoria baja durante los periodos de invierno en todo el planeta. Dado que este virus tiene predilección por el aparato respiratorio y forma acumulación de grandes células multinucleadas se le rebautizó como virus respiratorio sincicial en 1957 (1). Durante la primera infección por este virus, un 25 a 40 por ciento de los infantes pequeños tiene signos y síntomas de bronquiolitis o neumonía, y de ellos entre 0.5 y 2 por ciento, según distintas series estudiadas, requiere hospitalización. La gran mayoría de estos niños hospitalizados tiene menos de 6 meses de vida (2). El VRS además causas repetidas infecciones a través de la vida, principalmente de la vía aérea superior, como resfríos, otitis, faringitis, etc. Sin embargo, severo compromiso de la vía inferior puede ocurrir a cualquier edad, pero fundamentalmente en niños pequeños y con factores de riesgo como enfermedades crónicas pulmonares, cardíacas o prematuridad. El propósito de esta revisión es dar una visión actualizada de la prevención de infecciones por VRS, tomando como base la aparición de distintas inmunoglobulinas y los avances en el desarrollo de una futura vacuna

Antigenic and Genetic Characterization of Twenty-six Strains of Human Respiratory Syncytial Virus (Subgroup A) Isolated During Three Consecutive Outbreaks in Havana City, Cuba

Twenty-six human respiratory syncytial virus strains (subgroup A) isolated from three outbreaks in Havana City during the period 1994/95, 1995/96 and 1996/97 were analyzed to determine their antigenic and genetic relationships. Analyses were performed by monoclonal antibodies and restriction mapping (N gene) following amplification of the select region of the virus genome by polymerase chain reaction. All isolated strains were classified as subgroup A by monoclonal antibodies and they showed a restriction pattern NP4 that belonged to subgroup A. Thus the results obtained in this work, showed a close relation (100 percent) between antigenic and genetic characterization of the isolated strains in our laboratory. These methods permit the examination of large numbers of isolates by molecular techniques, simplifying the researchs into the molecular epidemiology of the virus

Evaluación de un ultramicroELISA para la detección de la infección por el virus sincitial respiratorio / Evaluation of an ultramicroELISA assay for the detection of infection by the respiratory syncytial virus

Objetivo. El presente trabajo tuvo como objetivo la evaluación de un ensayo de ultramicroELISA (UME) de doble anticuerpo para la detección rápida de anticuerpos IgG al Virus Sincitial Respiratorio (VSR) en monosueros y muestras de sueros pareados. Materiales y métodos. Se evaluaron 1567 muestras de suero por las técnicas de UME y Fijación de Complemento (FC), de ellas 619 eran monosueros de niños menores de 15 años y 474 pares pertenecientes al Programa Nacional de Vigilancia Seroepidemiológica de las Infecciones Respiratorias Agudas. En el UME de doble anticuerpo se utilizó un anticuerpo monoclonal específico a la proteína F del VSR. Resultados. Para los monosueros el UME con respecto a la FC mostró una sensibilidad de 98.9 por ciento, una especificidad de 56.05 por ciento y una coincidencia de 63.9 por ciento. Para los sueros pares la sensibilidad fue de 92.7 porciento, mientras que la especificidad y la coincidencia aumentaron aun 79.3 por ciento y 80.1 por ciento respectivamente. Conclusiones. La utilización del anticuerpo monoclonal permitió la inclusión de preparaciones antigénicas crudas en lugar de fracciones purificadas, disminuyendo notablemente la reactividad obtenida con el control de antígeno. Los resultados obtenidos respaldan la utilización de este método como una herramienta complementaria en estudios seroepidemiológico a gran escala y con fines diagnósticos