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Publication
Madeira dengue outbreak: a tool to study primary symptomatic and asymptomatic infections
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Abstract(s)
A febre da dengue é uma arbovirose que emergiu nas últimas décadas como uma séria
ameaça à saúde mundial, colocando em risco quase metade da população mundial. A
infeção por qualquer um dos quatro serotipos do vírus da dengue (DENV-1-4) resulta
num amplo espectro de situações, desde infeções assintomáticas até doença severa que
pode ser fatal. O desfecho assintomático parece ser o mais comum, podendo
representar até 90% das infeções. Diferenças na virulência e capacidade de infeção de
diferentes serotipos/genótipos de DENV, conjuntamente com a variabilidade genética
dos hospedeiros, mecanismos de imunidade treinada e de tolerância à doença, são
possíveis justificações para o desfecho assintomático e são extensivamente discutidos
nesta tese.
Entre 2012 e 2013 ocorreu o primeiro e único surto de DENV-1 na ilha da Madeira,
providenciando a oportunidade de investigar a resposta humoral em infeções primárias,
bem como o seu impacto na saúde desta população exposta pela primeira vez ao DENV.
Neste trabalho demonstra-se que os indivíduos que desenvolveram infeções
assintomáticas durante o surto apresentam níveis muito baixos ou indetetáveis de
anticorpos contra DENV-1 oito anos após a infeção. Por outro lado, as infeções
sintomáticas parecem ter resultado numa resposta humoral forte, com níveis elevados
de anticorpos contra DENV-1, e atividade neutralizante contra DENV-2. Sugerindo uma
proteção não só homotípica, mas possivelmente também contra infeções heterotípicas.
O impacto do surto de dengue no estado de saúde desta população, estudado através
da caracterização retrospetiva dos sintomas experienciados durante o período de
infeção, evidenciou que a maioria dos sintomas e as suas frequências são semelhantes
às descritas noutros estudos e compatíveis com o desfecho menos severo característico
de infeções primárias, exceto para os sintomas hemorrágicos, que foram mais
frequentes do que se antecipava. Igualmente, verificou-se que as manifestações clínicas
a longo termo ocorreram mais frequentemente e foram mais persistentes do que
inicialmente pensado, influenciando o estado de saúde e bem-estar de uma porção
considerável da população infetada. A análise adicional de parâmetros clínicos e
laboratoriais, contribuiu para o conhecimento da dimensão clínica do surto de dengue
na Madeira. Não obstante o desfecho clínico moderado, foram também encontradas alterações laboratoriais sobretudo hematológicas e hepáticas, assim como sinais
sugestivos de dengue severa em 5 pacientes, sugerindo um quadro de severidade
relativamente amplo em infeções primárias.
Este trabalho conduziu a um melhor conhecimento da resposta humoral e do impacto
clínico de uma infeção por DENV-1 numa população nunca anteriormente exposta a
qualquer DENV.
Dengue fever (DF) is an arboviral disease that has emerged as a serious worldwide public health threat in the last decades, endangering almost half of the world’s population. Infection with any of the four known serotypes of dengue virus (DENV-1-4) results in a broad spectrum of outcomes, ranging from asymptomatic to severe life-threatening illness. The asymptomatic outcome is thought to be the most common, which may reach up to 90% of all infections. Differences in virulence and infection capacity of the different DENV serotypes/genotypes, coupled with the host’s genetic variability and mechanisms of trained immunity and disease tolerance, are likely determinants for the asymptomatic outcome of these infections and are thoroughly discussed in this thesis. A primary and unique DENV-1 outbreak occurred in Madeira Island between 2012 and 2013, providing the opportunity to investigate the humoral immune response in primary infections, and the clinical impact of the outbreak on this naïve population. This first exposure of this population to DENV-1 is shown herein to have prompted a weak long term humoral immune response in asymptomatic cases, with very low or undetectable DENV-specific antibody levels eight years post-infection. Conversely, symptomatic cases seem to have resulted in strong humoral responses, with high DENV-specific antibody levels, and cross-protective activity against DENV-2. These results suggest that symptomatic infections result in long-term immunity against homologous reinfection and maybe even against heterologous infection. Concerning the impact of the outbreak on the health status of this naïve population, a retrospective characterization of the symptoms experienced throughout the entire infection period revealed that most symptoms and their frequencies are in line with previous studies and are compatible with the milder outcome of primary infections, except for hemorrhagic symptoms, which were more common than anticipated. As for potential long-term manifestations, these occurred more frequently and persisted longer than previously thought, impacting the health status and well-being of a considerable proportion of the infected population. Further analysis of clinical, hematological, and biochemical parameters contributed to elucidate the clinical burden of the Madeira dengue outbreak. Despite the general mild clinical outcome, both hematological and liver abnormalities were also found, in both adults and children, with 5 patients presenting signs compatible with severe dengue, suggesting a broader range of severity in primary infections. Overall, this work allowed for a better understanding of the humoral immune response and the clinical impact of a DENV-1 primary infection, in a naïve population.
Dengue fever (DF) is an arboviral disease that has emerged as a serious worldwide public health threat in the last decades, endangering almost half of the world’s population. Infection with any of the four known serotypes of dengue virus (DENV-1-4) results in a broad spectrum of outcomes, ranging from asymptomatic to severe life-threatening illness. The asymptomatic outcome is thought to be the most common, which may reach up to 90% of all infections. Differences in virulence and infection capacity of the different DENV serotypes/genotypes, coupled with the host’s genetic variability and mechanisms of trained immunity and disease tolerance, are likely determinants for the asymptomatic outcome of these infections and are thoroughly discussed in this thesis. A primary and unique DENV-1 outbreak occurred in Madeira Island between 2012 and 2013, providing the opportunity to investigate the humoral immune response in primary infections, and the clinical impact of the outbreak on this naïve population. This first exposure of this population to DENV-1 is shown herein to have prompted a weak long term humoral immune response in asymptomatic cases, with very low or undetectable DENV-specific antibody levels eight years post-infection. Conversely, symptomatic cases seem to have resulted in strong humoral responses, with high DENV-specific antibody levels, and cross-protective activity against DENV-2. These results suggest that symptomatic infections result in long-term immunity against homologous reinfection and maybe even against heterologous infection. Concerning the impact of the outbreak on the health status of this naïve population, a retrospective characterization of the symptoms experienced throughout the entire infection period revealed that most symptoms and their frequencies are in line with previous studies and are compatible with the milder outcome of primary infections, except for hemorrhagic symptoms, which were more common than anticipated. As for potential long-term manifestations, these occurred more frequently and persisted longer than previously thought, impacting the health status and well-being of a considerable proportion of the infected population. Further analysis of clinical, hematological, and biochemical parameters contributed to elucidate the clinical burden of the Madeira dengue outbreak. Despite the general mild clinical outcome, both hematological and liver abnormalities were also found, in both adults and children, with 5 patients presenting signs compatible with severe dengue, suggesting a broader range of severity in primary infections. Overall, this work allowed for a better understanding of the humoral immune response and the clinical impact of a DENV-1 primary infection, in a naïve population.
Description
Keywords
Febre da dengue Infeção assintomática DENV-1 Fatores de hospedeiro Resposta humoral Desfecho clínico Sintomas persistentes Madeira (Portugal) Dengue fever Asymptomatic infection Host factors Antibody response Clinical outcome Persistent symptoms Biological Sciences . Faculdade de Ciências da Vida