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O Vírus Sincicial respiratório (HRSV) é um patógeno de grande importância para crianças. É o maior causador de infecções respiratórias agudas e também um dos principais causadores de internações e mortes de crianças menores de 5 anos. Cepas de HRSV com mutações no sítio de ligação do Palivizumab vêm apresentando resistência ao medicamento. Pouco se sabe sobre a prevalência destas mutações em amostras clínicas, apesar de sua potencial importância na patogênese viral. Além disso, existem poucos dados sobre a evolução molecular da proteína F do HRSV, sobretudo no Brasil. O presente estudo tem como objetivo caracterizar fenotipicamente através de ensaios de microneutralização in vitro, cepas oriundas de crianças não tratadas com Palivizumab circulantes em 2013 apresentando mutações na proteína F, mais especificamente relacionadas a potencial resistência nos epítopos de ligação do Palivizumab. Como resultado deste trabalho todas as amostras testadas foram neutralizadas pelo Palivizumab, concluindo-se que as mutações encontradas não conferem resistência ao monoclonal. / Respiratory Syncytial Virus (HRSV) is a pathogen of great importance for children. It is the major cause of acute respiratory infections and also one of the main causes of hospitalizations and deaths of children under 5 years. Strains of HRSV with mutations in the binding site of Palivizumab have been showing resistance to the drug. Little is known about the prevalence of these mutations in clinical samples, despite their potential importance in viral pathology. In addition, there is little data on the molecular evolution of HRSV F protein, especially in Brazil. The present study aims to characterize phenotypically by in vitro microneutralization assays, strains from children not treated with Palivizumab circulating in 2013 showing mutations in F protein, more specifically related to potential resistance in the binding epitopes of Palivizumab. As result of this study all samples tested were neutralized by Palivizumab, concluding that the mutations found did not confer resistance to the monoclonal.

Orientador: Cristina Maria Garcia de Lima Parada Parada / Resumo: O programa de uso da imunoglobulina palivizumabe teve início em 2007 no Estado de São Paulo e em 2013 estendeu-se nacionalmente, sendo destinado a crianças com maior risco para a infecção pelo Virus Sincicial Respiratório (VSR). Desde seu início, o programa permanece sem avaliação sistemática. O objetivo dessa pesquisa foi avaliar o programa de uso da imunoglobulina palivizumabe no Estado de São Paulo. Foram avaliados os 16 locais de aplicação: cinco Centros de Referência para Imunobiológicos Especiais (CRIE) e 11 postos de aplicação existentes no Estado de São Paulo, seguindo o referencial de avaliação proposto por Donabedian. Dados de estrutura e processo foram obtidos por entrevista com os responsáveis pela aplicação da imunoglobulina; para avaliação de resultado foram entrevistadas as mães das crianças do programa, visando identificar a associação entre falha na tomada do palivizumabe e a necessidade de hospitalização em Unidade de Terapia Intensiva por doença ou sintomatologia respiratória no período de sazonalidade do VSR. Participaram desta pesquisa 693 crianças/responsáveis (85,1% da população elegível), que ingressaram no programa entre março e agosto de 2014, sendo a coleta de dados realizada entre março e setembro do mesmo ano. Para análise de resultado foi utilizado o odds ratio pontual e intervalar com intervalo de confiança de 95%, considerando-se associações estatisticamente significativas se p < 0,05. Para avaliação de estrutura foram consideradas 30 variáveis... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

This retrospective cohort study examined risk factors associated with RSV-associated hospitalization (RSV-H) among infants born 32 to 35 weeks gestational age in Nova Scotia. Results were used to develop a clinical instrument (RSV-H scoring tool) that would discriminate between infants at high, moderate and low risk for RSV-H. Identifying the highest-risk infants, (using baseline information to predict RSV-H in the first year of life), would help target cost effective prophylaxis by Palivizumab (Pz), an expensive RSV-specific monoclonal antibody. Significant risk factors, determined by multivariate logistics, included infants born in December, January or February, passive household smoke exposure and household crowding. The scoring tool produced similar RSV-H post-test probabilities (3.1% pre-test probability) between risk groups (5.5% vs. 5.8%) and was unable to target highest risk infants. The tool could be used as an educational guideline for health professionals, outlining the importance of significant risk factors for RSV-H to parents and caregivers.

Respiratory Syncytial Virus (RSV) infection is common among young children. Congenital Heart Disease (CHD) is a risk factor of severe illness and hospitalization. Palivizumab prophylaxis reduces the severity of RSV infection and reduces the risk of hospitalization for children at high risk of severe illness, such as children born premature or with CHD. The aim of this thesis was to evaluate compliance with national guidelines for prophylactic treatment and to study the Relative Risk (RR) of hospitalization due to RSV and unspecified Respiratory Tract Infection (RTI) for children with CHD. In a prospective study, questionnaires were sent to all paediatric cardiology centres in Sweden with questions about prophylactic treatment. Hospitalization rates were retrieved from the national inpatient registry. Heart defects were grouped according to type and the relative risk of hospitalization was calculated for each group and for summer and winter seasons. Half of the patients received prophylactic treatment later than recommended in the guidelines. The risk of hospitalization due to RSV infection was increased (RR=2.06 95% CI 1.6-2.6; p &lt; 0.0001) for children with CHD compared to children without CHD. The RR of hospitalization was also increased for all CHD subgroups, and was further increased during summer for children with the more severe CHD. We conclude that guidelines for prophylactic treatment were not followed and that the risk of hospitalization due to RSV and unspecified RTI was increased for all subgroups of CHD. The risk was increased both during winter and summer and we therefore argue that information to health personnel and parents should include that the risk of severe RTI is present all year round for children with CHD. / Respiratoriskt syncytialvirus (RSV) är det vanligaste förkylningsviruset och de allra flesta barn drabbas före två års ålder. RSV kan leda till allvarlig luftvägsinfektion hos alla barn, men speciellt hos dem med medfött hjärtfel. Någon botande läkemedelsbehandling finns inte för RSV, utan de medicinska insatserna får inriktas mot att mildra sjukdomsförloppet och för svårt sjuka barn krävs sjukhusvård för att exempelvis erhålla syrgasbehandling. Det finns inget vaccin mot RSV, men barn som riskerar att bli svårt sjuka kan behandlas profylaktiskt med en monoklonal antikropp (Palivizumab) som ges som injektion en gång per månad under vintersäsong. Vissa barn med svårt hjärtfel får denna profylaktiska behandling enligt nationella riktlinjer. Vår första studie visade att ungefär hälften av barnen med medfött hjärtfel, aktuella för profylax mot RSV, fick behandlingen senare än vad de nationella riktlinjerna rekommenderade. Denna studie genomfördes via en enkät till alla landets barnkliniker under två vintersäsonger. Vi såg även att något fler barn än förväntat (4.6%) fick RSV-infektion trots profylaktisk behandling och för cirka en tredjedel av dessa barn fördröjdes tiden till hjärtoperation. Behovet av sjukhusvård kan användas som mått på hur svårt ett sjukdomsförlopp är, och baserat på Socialstyrelsens slutenvårdsregister studerade vi alla barn under två års ålder och fann att den relativa risken för sjukhusvård på grund av RSV var högre för barn med hjärtfel än för barn utan hjärtfel (RR=2.06 95% CI 1.6-2.6; p &lt; 0.0001). I vår andra studie, baserad på slutenvårdsregistret, beräknade vi den relativa risken för sjukhusvård på grund av RSV, för barn med olika former av hjärtfel och uppdelat i sommar- och vintersäsong. Risken för sjukhusvård var ökad för alla barn oavsett typ av hjärtfel, och detta gällde såväl under vintern som under sommaren. Barn med de allvarligaste formerna av hjärtfel hade högre risk för sjukhusvård under sommaren jämfört med deras risk under vintern, medan barn med vad som anses vara lättare hjärtfel hade ökad risk för sjukhusvård under hela året, utan någon större skillnad i risk mellan vinter och sommar. Att barn med hjärtfel riskerar att bli svårt sjuka i RSV är väl känt, men våra resultat visar att denna risk även existerar under sommarhalvåret, då det inte är RSV-säsong och då profylax inte ges. Vi fann också att barn med vad som anses vara lättare hjärtfel löper lika stor risk att drabbas av svårare sjukdomsförlopp med sjukhusvård under vintern, som barn med svårare hjärtfel. Att denna information sprids till såväl sjukvårdspersonal som arbetar med denna patientgrupp som till föräldrar med hjärtsjuka barn är viktigt, för att belysa att även dessa barn behöver skyddas, och detta inte bara under vintern och RSV-säsongen.

Introduction: Infants with Bronchopulmonary Dysplasia (BPD) are at higher risk of developing severe RSV Bronchiolitis requiring hospitalisation. Palivizumab Immunoprophylaxis (PIP) was shown to reduce the severity of illness and hence the need for hospitalisation. Currently PIP is recommended for all infants with BPD, but there is little evidence on which infants with BPD would most benefit from PIP. Aim: This study aims to identify the clinical benefit of administering PIP to infants with BPD of different severities and to determine which infants would benefit most from PIP. In order to achieve this, the study also identifies the incidence of BPD, categorised into mild, moderate and severe in infants, in the Greater Manchester Region (GMR).Methods: This is a multi-centre, prospective, observational cohort study, involving 11 hospitals across GMR. Patients were recruited over 2 years, from 1st April 2009 to 31st March 2011. The infants with BPD were recruited and further categorised in various severities, based on Jobe’s BPD classification [Jobe et al 2001]. Patients were followed up for a minimum of one year. Results: The incidence of BPD in the GMR was 5.9 infants per 1000 live births. On categorisation by level of severity, the study found 31% of these to have mild BPD, 39% moderate and 30% severe BPD. Around 60% of infants received PIP in our cohort: one third of mild group, two thirds of moderate and three quarters of severe BPD. The overall proportion of hospitalisation for all the respiratory illnesses in infants with BPD was 44%. The overall incidence of hospitalization secondary to RSV infection was 7.6% of the cohort, and 14.8% due to other respiratory viruses. PIP was most beneficial in infants with moderate BPD (p = 0.016). Infants hospitalised with RSV infection required more admissions to HDU, required a longer duration of supplemental oxygen as well as a longer hospital stay compared to infants hospitalised due to other respiratory viruses and all other respiratory illnesses. Conclusion: This is the first study identifying the incidence of BPD in the GMR, which was lower than expected based on estimates from the JCVI. Both, the distribution of BPD into the various severity categories, as well as the requirement of hospital admission secondary to respiratory illness, were in keeping with published evidence from the USA and UK. PIP practices across North West of England were varied and not compliant with JCVI guidelines. Infants with moderate BPD showed the largest benefit from receiving PIP. This is a novel finding that highlights the need for further research, to determine whether a subgroup of infants might benefit from PIP.

Les virus respiratoires induisent de nombreuses et fréquentes pathologies en pédiatrie avec une morbidité importante. Ces virus sont bien connus car étudiés depuis longtemps mais ils sont en évolution constante. L’apparition des antibiotiques, des antiviraux, des soins intensifs, de la vaccination, les connaissances sur l’hygiène ont transformé l’impact de ces virus sur les populations humaines. Nos modes de vie principalement citadins favorisent la diffusion virale locale par le regroupement de presque tous les enfants dans des crèches ou des écoles. De même l’explosion récente des moyens de transport en particulier aérien qui ont reliés physiquement tous les pays du monde entre eux et qui accentuent la diffusion virale mondiale. Faut-il appliquer les mêmes raisonnements dans tous les pays du monde pour lutter contre ces infections ? Cette thèse apporte de nouvelles connaissances sur ce sujet en se focalisant sur les virus influenza et le virus respiratoire syncytial :1) Pendant la pandémie H1N1 au Canada, la mise en évidence de l’augmentation des hospitalisations des enfants asthmatiques, paradoxalement moins souvent ventilés durant leurs séjours en réanimation pédiatrique.2) L’intérêt de la vaccination contre le virus pandémique H1N1 pour diminuer le recours à la ventilation assistée chez les enfants hospitalisés en réanimation pédiatrique.3) Le Canada n’a pas connu de 3ème vague pandémique en raison d’une campagne vaccinale massive qui bien que tardive, a été efficace même 1 an plus tard.(4) La saisonnalité de la bronchiolite dans les régions tropicales est très différente de celle retrouvée dans les pays tempérés et nécessite de réajuster les recommandations de prise en charge à l’aune des données localesEn décrivant la cinétique et l’impact de la pandémie grippale de 2009 sur les enfants hospitalisés en soins intensifs pédiatriques au Canada d’Octobre 2009 à Mars 2011, en comparant cette cohorte à une cohorte similaire en France Hexagonale, et en décrivant 2 épidémies de VRS en Martinique en 2007 et 2008 pour confronter ces données avec celles décrites dans les pays tempérés, ce travail illustre combien nos connaissances doivent toujours être remises en question du fait de l’évolution du climat, de l’évolution de la société et de l’évolution des connaissances médicales / Respiratory viruses are responsible for much pediatric pathology with significant morbidity. These viruses are well known for a long time but are subject to constant changes. The development of antibiotics, antivirals, intensive care, vaccination, knowledge on hygiene has modified the impact of these viruses on human populations. Our predominantly urban lifestyles support local viral spread by bringing almost all children together in nurseries or schools. In the same way, the large use of modern transport facilities especially air transport (which connect all continents between them) facilitate the world viral spread. In this new environment, should we apply the same medical reasoning all over the world to fight against these infections? This thesis brings new knowledge on this topic, focusing on influenza virus and syncytial respiratory virus:1) During Influenza A(H1N1)pdm09, hospitalizations of children with asthma increase, but they were least often to be ventilated during their pediatric intensive care stay.2) The value of vaccination against the pandemic virus to reduce the use of assisted ventilation in children hospitalized in Pediatric Intensive Care Unit.3) Canada did not experience a third pandemic wave in 2010 because of a massive vaccination campaign that, even late, was effective one year later.4) The bronchiolitis season in the tropics is different from what we know in temperate countries. It is mandatory to adjust management recommendations in the light of regional data.By describing the kinetics and impact of the 2009 influenza pandemic on children in pediatric intensive care in Canada from October 2009 to March 2011, comparing this cohort to a similar cohort in France, and comparing 2 epidemics of VRS in Martinique (French West Indies) in 2007 and 2008 with those that have been carried out in temperate countries, this thesis is an example why we have to constantly question our knowledge because of climate change, change in society and medical knowledge evolution.

Submitted by IVANA REGINA GONÇALVES null (nanaenf82@hotmail.com) on 2016-12-13T18:58:31Z No. of bitstreams: 1 Tese Ivana Goncalves.pdf: 2035441 bytes, checksum: e2a1f49f031767147cf4e472de95ceea (MD5) / Approved for entry into archive by Felipe Augusto Arakaki (arakaki@reitoria.unesp.br) on 2016-12-15T14:52:37Z (GMT) No. of bitstreams: 1 goncalves_ir_dr_bot.pdf: 2035441 bytes, checksum: e2a1f49f031767147cf4e472de95ceea (MD5) / Made available in DSpace on 2016-12-15T14:52:37Z (GMT). No. of bitstreams: 1 goncalves_ir_dr_bot.pdf: 2035441 bytes, checksum: e2a1f49f031767147cf4e472de95ceea (MD5) Previous issue date: 2016-11-18 / O programa de uso da imunoglobulina palivizumabe teve início em 2007 no Estado de São Paulo e em 2013 estendeu-se nacionalmente, sendo destinado a crianças com maior risco para a infecção pelo Virus Sincicial Respiratório (VSR). Desde seu início, o programa permanece sem avaliação sistemática. O objetivo dessa pesquisa foi avaliar o programa de uso da imunoglobulina palivizumabe no Estado de São Paulo. Foram avaliados os 16 locais de aplicação: cinco Centros de Referência para Imunobiológicos Especiais (CRIE) e 11 postos de aplicação existentes no Estado de São Paulo, seguindo o referencial de avaliação proposto por Donabedian. Dados de estrutura e processo foram obtidos por entrevista com os responsáveis pela aplicação da imunoglobulina; para avaliação de resultado foram entrevistadas as mães das crianças do programa, visando identificar a associação entre falha na tomada do palivizumabe e a necessidade de hospitalização em Unidade de Terapia Intensiva por doença ou sintomatologia respiratória no período de sazonalidade do VSR. Participaram desta pesquisa 693 crianças/responsáveis (85,1% da população elegível), que ingressaram no programa entre março e agosto de 2014, sendo a coleta de dados realizada entre março e setembro do mesmo ano. Para análise de resultado foi utilizado o odds ratio pontual e intervalar com intervalo de confiança de 95%, considerando-se associações estatisticamente significativas se p < 0,05. Para avaliação de estrutura foram consideradas 30 variáveis relacionadas a condições preconizadas pelas políticas públicas de saúde e para o processo elencaram-se 10 variáveis relativas aos cuidados com a aplicação e conservação da imunoglobulina e sala de aplicação, sendo em ambos os casos o serviço classificado de acordo com o percentual de desconformidade em: adequado (até 10%), parcialmente adequado (de 10 a 20%) e inadequado (superior a 20%). Apenas dois locais de aplicação (P7 e P9), tiveram estrutura e processo considerados adequados. Apesar de terem estrutura classificada como adequada, nove locais tiveram processo parcialmente adequado (C2, C3, C4, P3 e P10) ou inadequado (C1, P2, P5 e P8). As principais falhas de estrutura foram relativas à climatização, disponibilidade de medicamentos e materiais para uso em caso de choque anafilático, sala exclusiva para aplicação de imunobiológicos e protocolo de uso da palivizumabe disponível e, no caso do processo, a não aplicação da imunoglobulina em crianças hospitalizadas, falta de supervisão do médico durante a aplicação, falha na temperatura de conservação do produto e não aplicação no mês anterior à sazonalidade. De acordo com os resultados, pode-se verificar que o risco de hospitalização em Unidade de Terapia Intensiva por doença/sintomatologia respiratória foi diretamente proporcional ao número de falhas (p=0,007; OR=1,29, IC=1,07-1,56). Conclui-se que a avaliação da estrutura do programa de uso da imunoglobulina palivizumabe no Estado de São Paulo é, em geral, mais favorável que o processo. Os resultados evidenciaram aumento médio da chance de internação por doença/sintomatologia respiratória de 29% a cada falha no recebimento das doses. / The palivizumab immunoglobulin health program was introduced in 2007 in São Paulo State and it was initiated nationally in 2013, aiming at being administered to highly risk children for respiratory syncytial virus infections. Since its beginning, such a program has remained with no systematic evaluation. The objetive of the present research was evaluate the palivizumab immunoglobulin health program in São Paulo State. For doing so, 16 places of palivizumab application in São Paulo State were considered: five of which are reference centers for special immunobiologicals and other 11 places of application. The theoretical framework adopted for the evaluation was the one proposed by Donabedian. Structural and processual data on the program was obtained by interviewing each worker responsible for the immunoglobulin in each application place. As for the evaluation of the program outcomes, the childrens mothers/responsible were also interviewed with the aim of identifying the association between palivizumab dose failure and respiratory-related hospitalizations in the seasonality period of respiratory syncytial virus. A total of 693 children/responsibles (85.1% of the eligible individuals) composed the research, all of which made part of the program in the period March-August of 2014, being the data collection performed between March and September of the same year. The data was analysed by the punctual and intervalar odds ratio, with a confidence interval of 95% and a statistical significance fixed at 5%. To the evaluation of program structure, 30 variables preconized by the public health policies were considerated; regarding the program process, 10 variables related to the immunoglobulin care of application and conservation and room of application were considered. Structure and process were both classificated as its nonconformity rate in: adequate (less than 10%), partially adequate (from 10% to 20%) and inadequate (greater than 20%). Only in two of the application places (P7 and P9) structure and process were found to be inadequate. Despite having an adequate structure, in nine places the process was found to be either partially adequate (C2, C3, C4, P3 and P10) or inadequate (C1, P2, P5 and P8). The main structural failures were the ones related to: climate control, availability of materials and medicines used in anaphylactic shock, exclusive room for immunobiological application and palivizumab usage protocol availability and, regarding the process, the absence of application in hospitalized children, absence of medical care during the immunoglobulin administration, inappropriate temperature for immunoglobulin conservation and absence of application prior to the respiratory syncytial virus seasonality. According to the results, the hospitalization risk in intensive care unit due to respiratory disease and related-symptoms was directly proportional to the number of dose failures (p=0.007; OR=1.29, IC=1.07-1.56). As a conclusion for the evalution, the structure of the São Paulo State palivizumab immunoglobulin health program is in general more favorable than the process. As for the results, they an average increasing of 29% in respiratory-related hospitalizations in intensive unit to each dose failure in palivizumab adminstration.