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Transmissão recente da infecção pelo complexo Mycobacterium tuberculosis na região de saúde de Lisboa e Vale do Tejo em 2003
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Orientador(es)
Resumo(s)
Em Portugal, são raros os estudos que avaliam a frequência e os factores de transmissão
da infecção pelo Mycobacterium tuberculosis. Com a finalidade de contribuir para um
melhor conhecimento sobre a transmissão recente da infecção pelo Mycobacterium
tuberculosis, realizou-se um estudo de base populacional sobre a diversidade molecular
de estirpes de Mycobacterium tuberculosis, isoladas de indivíduos residentes na Região
de Saúde de Lisboa e Vale do Tejo em 2003, que permitiu responder a algumas questões
sobre o padrão de transmissão da infecção da infecção pelo Mycobacterium tuberculosis
e sobre os factores demográficos, sócio-comportamentais e clínicos associados a essa
transmissão.
Objectivos
Com este trabalho pretendeu-se:
1) Avaliar a sensibilidade dos sistemas de vigilância epidemiológica dos casos
incidentes por tuberculose;
2) Caracterizar a epidemiologia da tuberculose e analisar a correlação entre a
incidência observada e os indicadores demográficos, clínicos e de
desenvolvimento concelhio respectivos;
3) Identificar os factores demográficos, sócio-comportamentais e clínicos
associados aos padrões de susceptibilidade aos antituberculosos de 1.ª linha;4) Caracterizar a diversidade molecular das estirpes de Mycobacterium
tuberculosis, identificar os factores demográficos, sócio-comportamentais e
clínicos associados, bem como analisar a correlação entre a incidência observada
e a frequência de agrupamentos moleculares.
Material, População e Métodos
Foi utilizado um modelo de estudo observacional, transversal ou ecológico, com uma
componente analítica.
A população em estudo incluiu todos os indivíduos com tuberculose diagnosticada em
2003, residentes na Região de Lisboa e Vale do Tejo, e notificada a pelo menos uma das
três fontes de dados de morbilidade por tuberculose em Portugal (Sistema de Vigilância
da Tuberculose (SVIG-TB), Doenças de Declaração Obrigatória (DDO) e Sistema de
Vigilância da Resistência aos Antibacilares (VigLab-Tuberculose). Sob esta população,
e para responder aos objectivos propostos, o projecto de investigação foi dividido em
quatro partes.
Na 1.ª parte, a avaliação da sensibilidade dos sistemas de vigilância foi realizada através
da técnica de captura-recaptura, aplicada às três fontes de dados mencionadas e
utilizando modelos log-lineares.
Na 2.ª parte, a descrição das características demográficas, sócio-comportamentais e
clínicas da população em estudo foi feita através do cálculo de frequências absolutas e
relativas e recorreu-se ao teste de homogeneidade do qui-quadrado para comparar as
distribuições destas características por distrito de residência. Para a análise da
correlação entre as taxas de incidência por concelho de residência e os indicadores
demográficos, clínicos e de desenvolvimento concelhio respectivos, recorreu-se ao
coeficiente de correlação linear de Pearson e à aplicação de modelos de regressão linear
múltipla.Na 3.ª parte, a análise univariada entre os padrões de susceptibilidade aos
antituberculosos de 1.ª linha e os factores demográficos, sócio-comportamentais e
clínicos em estudo foi efectuada pelo teste de qui-quadrado e teste exacto de Fisher. A
intensidade de associação foi avaliada pelo cálculo dos Odds ratio e respectivos
intervalos de confiança. A análise multivariada foi efectuada por regressão logística
binária, utilizando o modelo computacional Forward stepwise para ajustamento dos
Odds ratio relativamente a potenciais variáveis de confundimento e para definição do
modelo final de predição. Foi assumido um nível de significância estatística de p≤ 0,05
e intervalos de confiança de 95,0%.
Na 4.ª e última parte do estudo, foi realizada a caracterização molecular das estirpes
isoladas de Mycobacterium tuberculosis através da técnica Mycobacterial Interspersed
Repetitive Units-Variable Number Tandem Repeats (MIRU-VNTR). Aplicou-se a
análise univariada e multivariada descrita anteriormente para os determinantes
demográficos, sócio-comportamentais e clínicos e a frequência de agrupamentos
moleculares da infecção por Mycobacterium tuberculosis na Região de Saúde de Lisboa
e Vale do Tejo em 2003. A taxa de transmissão recente foi calculada subtraindo o
número de agrupamentos moleculares ao número de isolados nos agrupamentos
moleculares, o que depois foi dividido pelo número total de isolados do complexo
Mycobacterium tuberculosis. A análise de correlação entre a taxa de incidência de
tuberculose por concelho de residência e a proporção de indivíduos em agrupamento
molecular foi feita usando o coeficiente de correlação linear de Pearson e o seu
respectivo teste de significância. Para determinar os padrões de tendência destas
características recorreu-se à regressão linear simples e à regressão linear quadrática.Resultados Principais
Na Região de Lisboa e Vale do Tejo, em 2003, foram declarados 1758 casos de
tuberculose e a taxa de incidência observada foi de 50,6/100.000 habitantes (IC95%
48,3-53,1/100.000 habitantes).
Em relação à 1.ª parte do projecto de investigação, a sensibilidade dos três sistemas de
vigilância em simultâneo foi de 95,0% (IC95% 92,9-96,7).
Na 2.ª parte, o estudo ecológico realizado indicou que a variação da taxa de incidência
de tuberculose por concelho de residência depende da distribuição dos estabelecimentos
prisionais (β=25,595; p=0,001) e também da infecção pelo VIH (β=0,547; p=0,004).
Em relação à 3.ª parte do trabalho, observaram-se 6,0% (55/923) dos casos de
tuberculose multirresistente. A análise multivariada indicou que os casos de
retratamento (OR 15,985; IC95% 4,376-58,390) e os prestadores de cuidados de saúde
(OR 12,339; IC95% 2,400-63,429) tinham um risco acrescido de multirresistência.
Relativamente à 4.ª parte, os resultados sobre a caracterização molecular mostraram que
pertencer a um agrupamento molecular está simultaneamente associado aos doentes
nascidos fora de Portugal (OR 0,532; IC95% 0,334-0,847), aos doentes com tuberculose
pulmonar (OR 2,756; IC95% 1,273-5,967) e aos doentes infectados pelo VIH (OR
1,779; IC95% 1,087-2,912). A taxa de agrupamento molecular encontrada foi de 54,2%.
No estudo ecológico realizado, verificou-se a existência de uma correlação entre a taxa
de incidência de tuberculose por concelho de residência e o pertencer aos maiores
agrupamentos moleculares (coeficiente de correlação de Pearson R:-0,623; p=0,003).Conclusões e Recomendações
Com este estudo foi evidente a necessidade de se desenvolver um sistema único e
integrado de vigilância epidemiológica da infecção pelo Mycobacterium tuberculosis.
Os resultados obtidos vieram igualmente demonstrar a associação entre a incidência de
tuberculose e a incidência de infecção VIH nos estabelecimentos prisionais e, ainda,
alertar para a importância da transmissão da multirresistência na prática clínica,
justificando-se, assim, o desenvolvimento de programas de vigilância e controlo
específicos para conter a transmissão da infecção pelo Mycobacterium tuberculosis nas
prisões e nos serviços de saúde. Foi ainda confirmada a pertinência de se iniciar a
caracterização molecular sistemática da infecção pelo Mycobacterium tuberculosis,
dirigida a grupos populacionais específicos ou a comunidades fechadas, como
complemento às investigações epidemiológicas.
Palavras chave: tuberculose; técnica de captura-recaptura; sensibilidade da vigilância
epidemiológica; epidemiologia molecular; Mycobacterial Interspersed Repetitive Units-
Variable Number Tandem Repeats (MIRU-VNTR); estudos ecológicos; tuberculose
multirresistente; tuberculose extensivamente resistente; infecção pelo VIH; tuberculose
em estabelecimentos prisionais; tuberculose em profissionais de saúde; transmissão
recente da infecção pelo Mycobacterium tuberculosis.
There are few studies in Portugal assessing the frequency and factors of transmission of Mycobacterium tuberculosis infection. In order to contribute to a better knowledge of the recent transmission of Mycobacterium tuberculosis infection, a population-based study was undertaken on the molecular diversity of Mycobacterium tuberculosis strains, isolated from individuals living in the Health Region of Lisboa and Vale do Tejo in 2003. The study made possible some answers about the pattern of transmission of infection of Mycobacterium tuberculosis and the demographic, social-behavioural, and clinical factors associated with this transmission. Objectives This study sought to: 1) Assess the sensitivity of the epidemiological systems of surveillance of incident cases of tuberculosis; 2) Characterize the epidemiology of tuberculosis and analyze the correlation between the observed incidence and its respective demographic, clinical, and local development factors; 3) Identify the demographic, social-behavioural, and clinical factors associated to the patterns of susceptibility in anti-tuberculosis first-line drugs; 4) Characterize the molecular diversity of strains of Mycobacterium tuberculosis in order to identify the associated demographic, social-behavioural, and clinicalfactors, as well as analyzing the correlation between the observed incidence and the frequency of molecular clusters. Material, Population, and Methods We used a type of observational study, cross-section or ecological, with an analytical component. The studied population included all individuals with a diagnosis of tuberculosis in 2003, living in the Health Region of Lisboa and Vale do Tejo who were notified to at least one of the three sources of data on morbidity from tuberculosis in Portugal (Sistema de Vigilância da Tuberculose (SVIG - TB), Doenças de Declaração Obrigatória (DDO) and Sistema de Vigilância da Resistência aos Antibacilares (VigLab-Tuberculose)). Aiming the initial established objectives, the research project was divided into four parts. Part 1 measures the sensitivity of surveillance systems, which was performed using the technique of capture-recapture applied to the three data sources mentioned above and using log-linear models. Part 2 includes the description of demographic characteristics, social-behavioural, and clinical aspects of the studied population, calculated through absolute and relative frequencies and tested using the homogeneity chi-square test to compare the distributions of these characteristics by district residence. For the correlation analysis between the incidence rates by county of residence and the demographic, clinical and local development factors, both Pearson linear correlation coefficient and multiple linear regression models were applied. In Part 3, the univariate analysis between the patterns of susceptibility to the first-line anti-tuberculosis drugs and the demographic, social-behavioural, and clinical factors under study was performed by using the chi-square test and Fisher's exact test. The intensity of association was assessed by calculating the Odds ratio and their respectiveconfidence intervals. Multivariate analysis was performed by binary logistic regression using the computational Forward stepwise procedure, so as to adjust the Odds ratio controlling for potential confounding variables, and also to define the final prediction model. A statistical significance level of 5% and confidence intervals of 95.0% were assumed. In the 4th – and last– part of the study, the molecular characterization was performed on the isolated strains of Mycobacterium tuberculosis through the technique Mycobacterial interspersed Repetitive Unit-Variable Number Tandem repeats (MIRU-VNTR). The univariate and multivariate analysis described above were applied to determine the demographic, social-behavioural, and clinical determinants, as well as the molecular clusters of infection with Mycobacterium tuberculosis in the Health Region of Lisboa and Vale do Tejo in 2003. The rate of recent transmission was calculated by subtracting the number of molecular groups from the number of isolated molecular clusters and finally dividing by the total number of isolates of the Mycobacterium tuberculosis complex. The analysis of correlation between the incidence rate of tuberculosis by county of residence and the proportion of individuals in molecular groups was done using the Pearson’s linear correlation coefficient and its significance test. To determine the patterns of these features simple linear regression and quadratic regression models were applied. Main results In the Health Region of Lisboa and Vale do Tejo, in 2003, 1758 cases of tuberculosis were notified. The observed incidence rate was 50.6 per 100,000 inhabitants (CI95% 48.3-53.1/100,000 inhabitants). In the 1st part of the research project, the simultaneous sensitivity of the three monitoring systems was 95.0% (CI95% 92.9-96.7).In part 2, the ecological study conducted indicated that the variation in the incidence rate of tuberculosis by county of residence depends upon the distribution of penal facilities (β=25.595; p=0.001) and HIV infection (β=0.547; p=0.004). In the 3rd part of the study, there were 6.0% (55/923) of cases of multi-drug-resistant tuberculosis. Multivariate analysis indicated that cases of re-treatment (OR15.985; 95% CI 4.376-58.390) and health-care providers (OR12.339; 95% CI 2.400-63.429) experienced an increased risk of multidrug resistance. The fourth part of the study included the results of the molecular characterization, and provided evidence that belonging to a molecular cluster is associated with foreign-born patients (OR 0.532; 95% CI 0.334-0.847), patients with pulmonary tuberculosis (OR 2.756; 95% CI 1.273 -5.967) and HIV-infected patients (OR 1.779; 95% CI 1.087- 2.912). The rate of molecular clustering was 54.2%. In the ecological study, we established a correlation between the incidence rate of tuberculosis by county of residence and the fact that one belongs to the larger molecular clusters (Pearson correlation coefficient R: -0.623; p=0.003). Conclusions and Recommendations According to this study, the need of development of a unique and integrated epidemiological surveillance system for Mycobacterium tuberculosis infection was widely demonstrated. The obtained results also demonstrated the association between the incidence of tuberculosis and the incidence of HIV infection in penal facilities. We also warn about the importance of transmission of multidrug resistance in clinical practice, thereby justifying the development of specific surveillance and control sysyems, in order to contain the transmission of Mycobacterium tuberculosis infection both in penal and health facilities. I addition, there is evidence that systematic molecularcharacterization must be implemented, targeting specific population groups or closed communities, as a complement to epidemiological research. Keywords: tuberculosis; technique of capture-recapture; sensitivity of surveillance, molecular epidemiology; Mycobacterial interspersed Repetitive Unit-Variable Number Tandem repeats (MIRU-VNTR); ecological studies; multiresistant tuberculosis; extensively resistant tuberculosis; HIV infection, tuberculosis in prisons; tuberculosis in health care professionals; recent transmission of Mycobacterium tuberculosis infection.
There are few studies in Portugal assessing the frequency and factors of transmission of Mycobacterium tuberculosis infection. In order to contribute to a better knowledge of the recent transmission of Mycobacterium tuberculosis infection, a population-based study was undertaken on the molecular diversity of Mycobacterium tuberculosis strains, isolated from individuals living in the Health Region of Lisboa and Vale do Tejo in 2003. The study made possible some answers about the pattern of transmission of infection of Mycobacterium tuberculosis and the demographic, social-behavioural, and clinical factors associated with this transmission. Objectives This study sought to: 1) Assess the sensitivity of the epidemiological systems of surveillance of incident cases of tuberculosis; 2) Characterize the epidemiology of tuberculosis and analyze the correlation between the observed incidence and its respective demographic, clinical, and local development factors; 3) Identify the demographic, social-behavioural, and clinical factors associated to the patterns of susceptibility in anti-tuberculosis first-line drugs; 4) Characterize the molecular diversity of strains of Mycobacterium tuberculosis in order to identify the associated demographic, social-behavioural, and clinicalfactors, as well as analyzing the correlation between the observed incidence and the frequency of molecular clusters. Material, Population, and Methods We used a type of observational study, cross-section or ecological, with an analytical component. The studied population included all individuals with a diagnosis of tuberculosis in 2003, living in the Health Region of Lisboa and Vale do Tejo who were notified to at least one of the three sources of data on morbidity from tuberculosis in Portugal (Sistema de Vigilância da Tuberculose (SVIG - TB), Doenças de Declaração Obrigatória (DDO) and Sistema de Vigilância da Resistência aos Antibacilares (VigLab-Tuberculose)). Aiming the initial established objectives, the research project was divided into four parts. Part 1 measures the sensitivity of surveillance systems, which was performed using the technique of capture-recapture applied to the three data sources mentioned above and using log-linear models. Part 2 includes the description of demographic characteristics, social-behavioural, and clinical aspects of the studied population, calculated through absolute and relative frequencies and tested using the homogeneity chi-square test to compare the distributions of these characteristics by district residence. For the correlation analysis between the incidence rates by county of residence and the demographic, clinical and local development factors, both Pearson linear correlation coefficient and multiple linear regression models were applied. In Part 3, the univariate analysis between the patterns of susceptibility to the first-line anti-tuberculosis drugs and the demographic, social-behavioural, and clinical factors under study was performed by using the chi-square test and Fisher's exact test. The intensity of association was assessed by calculating the Odds ratio and their respectiveconfidence intervals. Multivariate analysis was performed by binary logistic regression using the computational Forward stepwise procedure, so as to adjust the Odds ratio controlling for potential confounding variables, and also to define the final prediction model. A statistical significance level of 5% and confidence intervals of 95.0% were assumed. In the 4th – and last– part of the study, the molecular characterization was performed on the isolated strains of Mycobacterium tuberculosis through the technique Mycobacterial interspersed Repetitive Unit-Variable Number Tandem repeats (MIRU-VNTR). The univariate and multivariate analysis described above were applied to determine the demographic, social-behavioural, and clinical determinants, as well as the molecular clusters of infection with Mycobacterium tuberculosis in the Health Region of Lisboa and Vale do Tejo in 2003. The rate of recent transmission was calculated by subtracting the number of molecular groups from the number of isolated molecular clusters and finally dividing by the total number of isolates of the Mycobacterium tuberculosis complex. The analysis of correlation between the incidence rate of tuberculosis by county of residence and the proportion of individuals in molecular groups was done using the Pearson’s linear correlation coefficient and its significance test. To determine the patterns of these features simple linear regression and quadratic regression models were applied. Main results In the Health Region of Lisboa and Vale do Tejo, in 2003, 1758 cases of tuberculosis were notified. The observed incidence rate was 50.6 per 100,000 inhabitants (CI95% 48.3-53.1/100,000 inhabitants). In the 1st part of the research project, the simultaneous sensitivity of the three monitoring systems was 95.0% (CI95% 92.9-96.7).In part 2, the ecological study conducted indicated that the variation in the incidence rate of tuberculosis by county of residence depends upon the distribution of penal facilities (β=25.595; p=0.001) and HIV infection (β=0.547; p=0.004). In the 3rd part of the study, there were 6.0% (55/923) of cases of multi-drug-resistant tuberculosis. Multivariate analysis indicated that cases of re-treatment (OR15.985; 95% CI 4.376-58.390) and health-care providers (OR12.339; 95% CI 2.400-63.429) experienced an increased risk of multidrug resistance. The fourth part of the study included the results of the molecular characterization, and provided evidence that belonging to a molecular cluster is associated with foreign-born patients (OR 0.532; 95% CI 0.334-0.847), patients with pulmonary tuberculosis (OR 2.756; 95% CI 1.273 -5.967) and HIV-infected patients (OR 1.779; 95% CI 1.087- 2.912). The rate of molecular clustering was 54.2%. In the ecological study, we established a correlation between the incidence rate of tuberculosis by county of residence and the fact that one belongs to the larger molecular clusters (Pearson correlation coefficient R: -0.623; p=0.003). Conclusions and Recommendations According to this study, the need of development of a unique and integrated epidemiological surveillance system for Mycobacterium tuberculosis infection was widely demonstrated. The obtained results also demonstrated the association between the incidence of tuberculosis and the incidence of HIV infection in penal facilities. We also warn about the importance of transmission of multidrug resistance in clinical practice, thereby justifying the development of specific surveillance and control sysyems, in order to contain the transmission of Mycobacterium tuberculosis infection both in penal and health facilities. I addition, there is evidence that systematic molecularcharacterization must be implemented, targeting specific population groups or closed communities, as a complement to epidemiological research. Keywords: tuberculosis; technique of capture-recapture; sensitivity of surveillance, molecular epidemiology; Mycobacterial interspersed Repetitive Unit-Variable Number Tandem repeats (MIRU-VNTR); ecological studies; multiresistant tuberculosis; extensively resistant tuberculosis; HIV infection, tuberculosis in prisons; tuberculosis in health care professionals; recent transmission of Mycobacterium tuberculosis infection.
Descrição
Palavras-chave
Saúde pública Saúde e desenvolvimento Epidemiologia Micobactérias Mycobacterium tuberculosis Lisboa
Contexto Educativo
Citação
Editora
Instituto de Higiene e Medicina Tropical