Genetic polymorphisms in vitamin D receptor, vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-γ genes and its association with susceptibility to tuberculosis

Mycobacterium tuberculosis kills more people than any other single pathogen, with an estimated one-third of the world's population being infected. Among those infected, only 10% will develop the disease. There are several demonstrations that susceptibility to tuberculosis is linked to host genetic factors in twins, family and associated-based case control studies. In the past years, there has been dramatic improvement in our understanding of the role of innate and adaptive immunity in the human host defense to tuberculosis. To date, attention has been paid to the role of genetic host and parasitic factors in tuberculosis pathogenesis mainly regarding innate and adaptive immune responses and their complex interactions. Many studies have focused on the candidate genes for tuberculosis susceptibility ranging from those expressed in several cells from the innate or adaptive immune system such as Toll-like receptors, cytokines (TNF-α, TGF-β, IFN-γ, IL-1b, IL-1RA, IL-12, IL-10), nitric oxide synthase and vitamin D, both nuclear receptors and their carrier, the vitamin D-binding protein (VDBP). The identification of possible genes that can promote resistance or susceptibility to tuberculosis could be the first step to understanding disease pathogenesis and can help to identify new tools for treatment and vaccine development. Thus, in this mini-review, we summarize the current state of investigation on some of the genetic determinants, such as the candidate polymorphisms of vitamin D, VDBP, Toll-like receptor, nitric oxide synthase 2 and interferon-γ genes, to generate resistance or susceptibility to M. tuberculosis infection.

Peroral susceptibility of Aedes albifasciatus and Culex pipiens complex mosquitoes (Diptera: Culicidae) from Argentina to western equine encephalitis virus

The transmission cycle of western equine encephalitis (WEE) virus in South America is unknown. A WEE virus strain was isolated from Aedes albifasciatus in Argentina during the WEE epizootic of 1982-83. Also, Culex pipiens from Argentina was reported to be able to transmit WEE virus experimentally, but other results indicate that Cx. pipiens from the USA is refractory to this virus. We determined the susceptibility of Argentina strains of Ae. albifasciatus and Culex pipiens complex mosquites to infection by WEE virus by the oral route. Adult females were fed on chicks infected with a WEE virus strain isolated in Cordoba Province, Argentina, or were fed on a blood/virus suspension. Each mosquito ingested between 10(1.6) to 10(6.4) vero cell plaque-forming units of virus. Each of 28 Ae. albifasciatus was positive for virus from the fourth day postfeeding, and there was evidence for virus replication. In contrast, 0/44 Cx. p. quinquefasciatus and only 1/15 Cx. p. pipiens was positive. Aedes albifasciatus is susceptible to infection by WEE virus and should be considered a potential vector of this virus in Argentina. Both subspecies of Cx. pipiens are refractory to peroral infection by WEE virus and probably do not play a role in the WEE virus cycle in Argentina.

HIV/tuberculosis co-infection: a request for a better surveillance

The increasing endemicity of tuberculosis resulting from causes such as immigration, poverty, a declining public health infrastructure and co-infection by HIV/Mycobacterium tuberculosis, is leading to a change in tuberculosis control programmes. One of the main reasons for the resurgence of tuberculosis is HIV infection - the risk of tuberculosis is greater in HIV patients than in the majority of the population as can be seen from numerous research projects. The need for systematic testing for HIV infection in all tuberculosis patients by undertaking confidential HIV tests on admission to a tuberculosis programme is brought out. This measure would increase the number of cases diagnosed and provide data for better surveillance of the co-infection.

Age transition of tuberculosis incidence and mortality in Brazil

OBJECTIVE: Before the Aids pandemic, demographic transition and control programs prompted a shift in the age of incidence of tuberculosis from adults to older people in many countries. The objective of the study is to evaluate this transition in Brazil. METHODS: Tuberculosis incidence and mortality data from the Ministry of Health and population data from the Brazilian Bureau of Statistics were used to calculate age-specific incidence and mortality rates and medians. RESULTS: Among reported cases, the proportion of older people increased from 10.5% to 12% and the median age from 38 to 41 years between the period of 1986 and 1996. The smallest decrease in the incidence rate occurred in the 30--49 and 60+ age groups. The median age of death increased from 53 to 55 years between 1980 and 1996. The general decline in mortality rates from 1986 to 1991 became less evident in the 30+ age group during the period of 1991 to 1996. A direct correlation between age and mortality rates was observed. The largest proportion of bacteriologically unconfirmed cases occurred in older individuals. CONCLUSIONS: The incidence of tuberculosis has begun to shift to the older population. This shift results from the decline in the annual risk of infection as well as the demographic transition. An increase in reactivation tuberculosis in older people is expected, since this population will grow from 5% to 14% of the Brazilian population over the next 50 years. A progressive reduction in HIV-related cases in adults will most likely occur. The difficulty in diagnosing tuberculosis in old age leads to increased mortality.

Tuberculosis en la Ciudad de la Habana, 1995-1999

OBJETIVO: La tuberculosis es un importante problema mundial de salud que recibe una atención priorizada del Sistema de Salud Cubano. Lo objetivo del trabajo es describir el comportamiento de los indicadores del Programa de Control de Tuberculosis cubano. MÉTODOS: A partir de una revisión de los documentos de la vigilancia de la tuberculosis en los registros del Centro Provincial de Higiene y Epidemiología se expone la infraestructura sanitaria, las estrategias del Programa de Control en la ciudad, se describen las tasas de incidencia, indicadores de localización, diagnóstico y manejo de casos. RESULTADOS: Se hallaron 8 sintomáticos respiratorios por cada mil consultantes de medicina general; la tasa de incidencia de tunerculosis en todas sus formas descendió de 16,4 (1995) a 12,0x105 habitantes (1999); la tuberculosis pulmonar descendió de 15,1 a 10,45 habitantes mientras la tuberculosis extrapulmonar ascendió de 1,3 a 1,6 x 105 habitantes, en igual período. Del total de los casos nuevos, el 40-50% fueron identificados en los policlínicos, el 67% fueron diagnosticados por baciloscopías, el 15,2% por cultivos, el 13.8% sólo por evidencias clínicas y radiológicas; el 0,9% y el 1,5%, respectivamente, fueron diagnosticados por biopsia o hallazgos de necropsia. Los grupos de 15-64 años incrementaron su incidencia en 1996-1997 y disminuyeron en 1998-1999; los casos >64 años de edad disminuyeron progresivamente de 1995 a 1999; en general, la tasa de incidencia de casos disminuyó. La demora promedio entre primeros síntomas y diagnóstico mejoró de 42 días en 1995 a 28,6 en 1999. CONCLUSIONES: La reversión de la tendencia de la notificación de casos nuevos parece haberse detenido en 1996. La situación de los indicadores de tuberculosis revelan cambios satisfactorios en el período analizado.

Distribuição espacial da co-infecção M. tuberculosis/HIV no Estado de São Paulo, 1991-2001

OBJETIVO: Avaliar o padrão espacial de incidência de tuberculose na epidemia de Aids, a fim de verificar a influência do espaço físico na causalidade. MÉTODOS: Foram incluídos os casos de Aids notificados ao Ministério da Saúde, entre 1991 e 2001, provenientes do Estado de São Paulo. Os casos foram estratificados em municípios de residência, em regiões de saúde, em categorias de transmissão de Aids, em sexos e em anos do diagnóstico. Um modelo geoestatístico gaussiano foi usado para construir um mapa temático de risco, utilizando a incidência de tuberculose em casos de Aids como variável de resposta. RESULTADOS: A análise exploratória mostrou dois padrões de incidência de Aids: um, para a capital do Estado, e outro, com risco crescente, para os outros municípios. As regiões mais populosas estão sob maiores riscos de transmissão de tuberculose, mostrando um padrão concordante com o padrão de ocupação do território, do leste para o oeste. As regiões de saúde com os maiores coeficientes de incidência de Aids (por 10 mil habitantes) foram Santos (53,5), São José do Rio Preto (43,1), Ribeirão Preto (42,4) e São Paulo (40,3). As regiões de saúde com maiores incidências de tuberculose em casos de Aids foram Santos (44,9%), Franco da Rocha (39,9%), Osasco (39,6%) e São Paulo (38,9%). CONCLUSÕES: Os resultados permitem concluir que as coordenadas geográficas estão associadas ao risco da tuberculose, mas não de Aids.

Household members and health care workers as supervisors of tuberculosis treatment

OBJECTIVE: To compare tuberculosis cure rates among patients supervised by household members or health care workers. METHODS: Prospective cohort study of 171 patients treated by the program in Vitoria, Southeastern Brazil, from 2004 to 2007. Each patient was followed-up for six months until the end of the treatment. Of the patients studied, a household member supervised 59 patients and healthcare workers supervised 112 patients. Patients' sociodemographic and clinic data were analyzed. Differences between groups were assessed using chi-square test or Student's t-test. Significance level was set at 5%. RESULTS: Most patients had smear positive, culture confirmed pulmonary tuberculosis. Two patients were HIV-positive. There were more illiterate patients in the healthcare-supervised group, in comparison to those supervised by their families (p=0.01). All patients supervised by a household member were cured compared to 90% of the patients supervised by health care workers (p = 0.024). CONCLUSIONS: Successful tuberculosis treatment was more frequent when supervised by household members.

Tuberculosis and latent tuberculosis in prison inmates

OBJECTIVE: To estimate the prevalences of tuberculosis and latent tuberculosis in inmates. METHODS: Observational study was carried out with inmates of a prison and a jail in the State of São Paulo, Southeastern Brazil, between March and December of 2008. Questionnaires were used to collect sociodemographic and epidemiological data. Tuberculin skin testing was administered (PPD-RT23-2TU/0.1 mL), and the following laboratory tests were also performed: sputum smear examination, sputum culture, identification of strains isolated and drug susceptibility testing. The variables were compared using Pearson's chi-square (Χ2) association test, Fisher's exact test and the proportion test. RESULTS: Of the 2,435 inmates interviewed, 2,237 (91.9%) agreed to submit to tuberculin skin testing and of these, 73.0% had positive reactions. The prevalence of tuberculosis was 830.6 per 100,000 inmates. The coefficients of prevalence were 1,029.5/100,000 for inmates of the prison and 525.7/100,000 for inmates of the jail. The sociodemographic characteristics of the inmates in the two groups studied were similar; most of the inmates were young and single with little schooling. The epidemiological characteristics differed between the prison units, with the number of cases of previous tuberculosis and of previous contact with the disease greater in the prison and coughing, expectoration and smoking more common in the jail. Among the 20 Mycobacterium tuberculosis strains identified, 95.0% were sensitive to anti-tuberculosis drugs, and 5.0% were resistant to streptomycin. CONCLUSIONS: The prevalences of tuberculosis and latent tuberculosis were higher in the incarcerated population than in the general population, and they were also higher in the prison than in the jail.

Tuberculosis in indigenous children in the Brazilian Amazon

OBJECTIVE: Assess the epidemiological aspects of tuberculosis in Brazilian indigenous children and actions to control it. METHODS: An epidemiological study was performed with 356 children from 0 to 14 years of age in Rondônia State, Amazon, Brazil, during the period 1997-2006. Cases of TB reported to the Notifiable Diseases Surveillance System were divided into indigenous and non-indigenous categories and analyzed according to sex, age group, place of residence, clinical form, diagnostic tests and treatment outcome. A descriptive analysis of cases and hypothesis test (χ²) was carried out to verify if there were differences in the proportions of illness between the groups investigated. RESULTS: A total of 356 TB cases were identified (125 indigenous, 231 non-indigenous) of which 51.4% of the cases were in males. In the indigenous group, 60.8% of the cases presented in children aged 0-4 years old. The incidence mean was much higher among indigenous; in 2001, 1,047.9 cases/100,000 inhabitants were reported in children aged < 5 years. Pulmonary TB was reported in more than 80% of the cases, and in both groups over 70% of the cases were cured. Cultures and histopathological exams were performed on only 10% of the patients. There were 3 cases of TB/HIV co-infection in the non-indigenous group and none in the indigenous group. The case detection rate was classified as insufficient or fair in more than 80% of the indigenous population notifications, revealing that most of the diagnoses were performed based on chest x-ray. CONCLUSIONS: The approach used in this study proved useful in demonstrating inequalities in health between indigenous and non-indigenous populations and was superior to the conventional analyses performed by the surveillance services, drawing attention to the need to improve childhood TB diagnosis among the indigenous population.

Towards a Unified Theory of Health-Disease: I. Health as a complex model-object

Theory building is one of the most crucial challenges faced by basic, clinical and population research, which form the scientific foundations of health practices in contemporary societies. The objective of the study is to propose a Unified Theory of Health-Disease as a conceptual tool for modeling health-disease-care in the light of complexity approaches. With this aim, the epistemological basis of theoretical work in the health field and concepts related to complexity theory as concerned to health problems are discussed. Secondly, the concepts of model-object, multi-planes of occurrence, modes of health and disease-illness-sickness complex are introduced and integrated into a unified theoretical framework. Finally, in the light of recent epistemological developments, the concept of Health-Disease-Care Integrals is updated as a complex reference object fit for modeling health-related processes and phenomena.

Incremental yield of bronchial washing for diagnosing smear-negative pulmonary tuberculosis

OBJECTIVE To assess the increased diagnostic yield for pulmonary tuberculosis using bronchial washing cultures compared with sputum cultures. METHODS Study conducted with 61 adults in Lima, Peru, from January 2006 to December 2007. The yield of sputum cultures was compared with the yield of acid-fast bacilli smears and cultures of bronchial washing for diagnosing pulmonary tuberculosis in suspected cases of clinical tuberculosis with negative acid fast bacilli sputum smears. RESULTS Twenty seven (95%CI 32;58) of the cases were eventually diagnosed with smear-negative pulmonary tuberculosis. Bronchial washing samples detected 23 (95%CI 72;99) of the smear-negative pulmonary tuberculosis cases compared with 15 (95%CI 37;74) for sputum cultures (p = 0.02). The incremental diagnostic yield of acid fast bacilli smear and culture of bronchial washing specimens over sputum culture was 44% (95%CI 25;65). CONCLUSIONS In function of the epidemiological context and the resources available, bronchoscopy should be deployed as part of a comprehensive work up that optimizes smear-negative pulmonary tuberculosis diagnosis and minimizes risk and costs.

Assessing usual dietary intake in complex sample design surveys: the National Dietary Survey

The National Cancer Institute (NCI) method allows the distributions of usual intake of nutrients and foods to be estimated. This method can be used in complex surveys. However, the user must perform additional calculations, such as balanced repeated replication (BRR), in order to obtain standard errors and confidence intervals for the percentiles and mean from the distribution of usual intake. The objective is to highlight adaptations of the NCI method using data from the National Dietary Survey. The application of the NCI method was exemplified analyzing the total energy (kcal) and fruit (g) intake, comparing estimations of mean and standard deviation that were based on the complex design of the Brazilian survey with those assuming simple random sample. Although means point estimates were similar, estimates of standard error using the complex design increased by up to 60% compared to simple random sample. Thus, for valid estimates of food and energy intake for the population, all of the sampling characteristics of the surveys should be taken into account because when these characteristics are neglected, statistical analysis may produce underestimated standard errors that would compromise the results and the conclusions of the survey.

Tuberculosis Control Program and patient satisfaction, Rio de Janeiro, Brazil

OBJECTIVE To evaluate factors associated with users’ satisfaction in the Tuberculosis Control Program. METHODS A cross-sectional study of 295 patients aged ≥ 18 years, with two or more outpatient visits in the Tuberculosis Control Program, in five cities in the metropolitan region of Rio de Janeiro, RJ, Southeastern Brazil, in 2010. Considering an estimated population of 4,345 patients, the sampling plan included 15 health care units participating in the program, divided into two strata: units in Rio de Janeiro City, selected with probability proportional to the monthly average number of outpatient visits, and units in the other four cities. In the units, four temporal clusters of five patients each were selected with equal probability, totaling 300 patients. A questionnaire investigating the users’ clinical and sociodemographic variables and aspects of care and service in the program relevant to user satisfaction was applied to the patients. Descriptive statistics about users and their satisfaction with the program were obtained, and the effects of factors associated with satisfaction were estimated. RESULTS Patients were predominantly males (57.7%), with a mean age of 40.9 and with low level of schooling. The mean treatment time was 4.1 months, mostly self-administered (70.4%). Additionally, 25.8% had previously been treated for tuberculosis. There was a high level of satisfaction, especially regarding medication provision, and respect to patients by the health professionals. Patients who were younger (≤ 30), those on self-administered treatment, and with graduate level, showed less satisfaction. Suggestions to improve the services include having more doctors (70.0%), and offering exams in the same place of attendance (55.1%). CONCLUSIONS Patient satisfaction with the Tuberculosis Control Program was generally high, although lower among younger patients, those with university education and those on self-administered treatment. The study indicates the need for changes to structural and organizational aspects of care, and provides practical support for its improvement.

Profile and follow-up of patients with tuberculosis in a priority city in Brazil

OBJECTIVE To analyze the cases of tuberculosis and the impact of direct follow-up on the assessment of treatment outcomes.METHODS This open prospective cohort study evaluated 504 cases of tuberculosis reported in the Sistema de Informação de Agravos de Notificação (SINAN – Notifiable Diseases Information System) in Juiz de Fora, MG, Southeastern Brazil, between 2008 and 2009. The incidence of treatment outcomes was compared between a group of patients diagnosed with tuberculosis and directly followed up by monthly consultations during return visits (287) and a patient group for which the information was indirectly collected (217) through the city’s surveillance system. The Chi-square test was used to compare the percentages, with a significance level of 0.05. The relative risk (RR) was used to evaluate the differences in the incidence rate of each type of treatment outcome between the two groups.RESULTS Of the outcomes directly and indirectly evaluated, 18.5% and 3.2% corresponded to treatment default and 3.8% and 0.5% corresponded to treatment failure, respectively. The incidence of treatment default and failure was higher in the group with direct follow-up (p < 0.05) (RR = 5.72, 95%CI 2.65;12.34, and RR = 8.31, 95%CI 1.08;63.92, respectively).CONCLUSIONS A higher incidence of treatment default and failure was observed in the directly followed up group, and most of these cases were neglected by the disease reporting system. Therefore, effective measures are needed to improve the control of tuberculosis and data quality.

Validity and reliability of a health care service evaluation instrument for tuberculosis

OBJECTIVE To evaluate the validity and reliability of an instrument that evaluates the structure of primary health care units for the treatment of tuberculosis.METHODS This cross-sectional study used simple random sampling and evaluated 1,037 health care professionals from five Brazilian municipalities (Natal, state of Rio Grande do Norte; Cabedelo, state of Paraíba; Foz do Iguaçu, state of Parana; Sao José do Rio Preto, state of Sao Paulo, and Uberaba, state of Minas Gerais) in 2011. Structural indicators were identified and validated, considering different methods of organization of the health care system in the municipalities of different population sizes. Each structure represented the organization of health care services and contained the resources available for the execution of health care services: physical resources (equipment, consumables, and facilities); human resources (number and qualification); and resources for maintenance of the existing infrastructure and technology (deemed as the organization of health care services). The statistical analyses used in the validation process included reliability analysis, exploratory factor analysis, and confirmatory factor analysis.RESULTS The validation process indicated the retention of five factors, with 85.9% of the total variance explained, internal consistency between 0.6460 and 0.7802, and quality of fit of the confirmatory factor analysis of 0.995 using the goodness-of-fit index. The retained factors comprised five structural indicators: professionals involved in the care of tuberculosis patients, training, access to recording instruments, availability of supplies, and coordination of health care services with other levels of care. Availability of supplies had the best performance and the lowest coefficient of variation among the services evaluated. The indicators of assessment of human resources and coordination with other levels of care had satisfactory performance, but the latter showed the highest coefficient of variation. The performance of the indicators “training” and “access to recording instruments” was inferior to that of other indicators.CONCLUSIONS The instrument showed feasibility of application and potential to assess the structure of primary health care units for the treatment of tuberculosis.