Outcomes from patients with presumed drug resistant tuberculosis in five reference centers in Brazil.

BACKGROUND: The implementation of rapid drug susceptibility testing (DST) is a current global priority for TB control. However, data are scarce on patient-relevant outcomes for presumptive diagnosis of drug-resistant tuberculosis (pDR-TB) evaluated under field conditions in high burden countries. METHODS: Observational study of pDR-TB patients referred by primary and secondary health units. TB reference centers addressing DR-TB in five cities in Brazil. Patients age 18 years and older were eligible if pDR-TB, culture positive results for Mycobacterium tuberculosis and, if no prior DST results from another laboratory were used by a physician to start anti-TB treatment. The outcome measures were median time from triage to initiating appropriate anti-TB treatment, empirical treatment and, the treatment outcomes. RESULTS: Between February,16th, 2011 and February, 15th, 2012, among 175 pDR TB cases, 110 (63.0%) confirmed TB cases with DST results were enrolled. Among study participants, 72 (65.5%) were male and 62 (56.4%) aged 26 to 45 years. At triage, empirical treatment was given to 106 (96.0%) subjects. Among those, 85 were treated with first line drugs and 21 with second line. Median time for DST results was 69.5 [interquartile - IQR: 35.7-111.0] days and, for initiating appropriate anti-TB treatment, the median time was 1.0 (IQR: 0-41.2) days. Among 95 patients that were followed-up during the first 6 month period, 24 (25.3%; IC: 17.5%-34.9%) changed or initiated the treatment after DST results: 16/29 MDRTB, 5/21 DR-TB and 3/45 DS-TB cases. Comparing the treatment outcome to DS-TB cases, MDRTB had higher proportions changing or initiating treatment after DST results (p = 0.01) and favorable outcomes (p = 0.07). CONCLUSIONS: This study shows a high rate of empirical treatment and long delay for DST results. Strategies to speed up the detection and early treatment of drug resistant TB should be prioritized.

Different immunosuppressive mechanisms in multi-drug-resistant tuberculosis and non-tuberculous mycobacteria patients.

Previous studies have demonstrated that cells from both multi-drug-resistant tuberculosis (MDR-TB) and non-tuberculous mycobacteria (NTM) patients respond poorly to mycobacterial antigens in vitro. In the present study, we compared the in vitro response of cells isolated from sensitive TB (NR-TB)-, MDR-TB- and NTM-infected patients. Analysis of T cell phenotype ex vivo revealed that both MDR-TB and NTM patients present an increased percentage of CD4(+) CD25(+-) forkhead box protein 3 (FoxP3)(+) and CD4(+) CD25(+) CD127(-) regulatory T (T(reg) ) cells when compared to NR-TB. Increased numbers of T(reg) cells and interleukin (IL)-10 serum levels were detected in MDR-TB, whereas elevated serum transforming growth factor (TGF)-ß was found in the NTM group. Cells of MDR-TB patients stimulated with early secretory antigenic target (ESAT)-6, but not purified protein derivative (PPD), showed a lower frequency of CD4(+) /interferon (IFN)-γ(+) T cells and enhanced CD4(+) CD25(+) FoxP3(+) , CD4(+) CD25(+) CD127(-) and CD4(+) CD25(+) IL-10(+) T cell population. In addition, increased IL-10 secretion was observed in cultured MDR-TB cells following ESAT-6 stimulation, but not in NR-TB or NTM patients. In vitro blockade of IL-10 or IL-10Rα decreased the CD4(+) CD25(+) FoxP3(+) frequencies induced by ESAT-6 in MDR-TB, suggesting a role of IL-10 on impaired IFN-γ responses seen in MDR-TB. Depletion of CD4(+) CD25(+) T lymphocytes restored the capacity of MDR-TB T cells to respond to ESAT-6 in vitro, which suggests a potential role for T(reg) /T regulatory 1 cells in the pathogenesis of MDR-TB. Together, our results indicate that although the similarities in chronicity, NTM- and MDR-TB-impaired antigenic responses involve different mechanisms.

Detection of in vitro interferon-gamma and serum tumour necrosis factor-alpha in multidrug-resistant tuberculosis patients.

Multidrug-resistant tuberculosis (MDR-TB) is known as having a poor prognosis with a weak response to therapy and very high death rates. The aim of this work was to assess the immune response to the RD1-encoded antigen ESAT-6 of Mycobacterium tuberculosis in MDR-TB patients and compare to non-resistant (NR) TB patients and healthy controls (HC). Evaluation of interferon (IFN)-gamma production showed that, although 55% of the MDR patients were responsive to ESAT-6, they produced lower IFN-gamma levels (553 +/- 11 pg/ml) when compared to NR-TB (1179 +/- 163 pg/ml; P < 0.05) but not to controls (412 +/- 65.7 pg/ml). Differences in the response to ESAT-6 and to its overlapping peptides mixture were also significant between MDR versus treated pulmonary NR-TB. Furthermore, a very low rate of response to PPD (23.5%) and to Ag85B (33.3%) was noted in MDR-TB patients as compared to the other groups. To determine the inflammatory response in patients' groups, detection of tumour necrosis factor (TNF)-alpha was assessed in their sera before and during chemotherapy. Mean TNF-alpha levels in MDR-TB (43.8 +/- 9 pg/ml) paralleled those found in treated pulmonary, and it was significantly different (P < 0.05) from the values found in untreated NR and HC. Interestingly, secretion of IFN-gamma and TNF-alpha were predominant in MDR patients who presented with bilateral pulmonary lesions and lung cavitation. The present data indicate that the overall immune response to mycobacterial antigens is decreased in resistant TB and the major role inflammatory cytokines may play in perpetuating pulmonary tissue damage.

Tuberculosis and HIV infection in Brazil -- update and overview.

PIP: In Brazil, tuberculosis (TB) has become an important public health problem with approximately 90,000 cases reported annually. Compounding the TB problem is the interaction of the growing HIV/AIDS epidemic with TB, with potential implications for intranosocomial transmission to immunodeficient patients and health care workers, as well as for the emergence of multidrug-resistant strains. The increased number of reported TB cases is attributed to the deterioration in socioeconomic conditions, the decentralization and restructuring of local TB programs, and the HIV epidemic. TB is the third most common AIDS-defining event; hence, increase in TB cases could be attributed to coinfection with HIV. To this effect, the Tuberculosis and AIDS Programs created a joint committee in order to define national guidelines for the prevention, case management, and treatment of HIV-associated TB. These guidelines recommend 1) preventive therapy with Isoniazid (300 mg daily for 6 months); and 2) Rifampicin-Isoniazid-Pyrazinamide daily for 2 months plus Rifampicin-Isoniazid for the following 7 months for those with active TB. In addition to these strategies, Bacillus-Calmette Guerin vaccination is mandatory for newborns and children under age 4 years, especially for all HIV positive asymptomatic newborns of HIV-infected or AIDS mothers.^ieng

Cost effectiveness of antituberculosis interventions.

The treatment of tuberculosis (TB) is ranked as the most cost effective of all therapeutic programmes in terms of cost per year of life saved. Nevertheless, TB kills or debilitates more adults aged between 15 and 59 years than any other disease in the world; furthermore, about 2 to 4% of the burden of disease, 7% of all deaths and 26% of all preventable deaths are directly attributable to TB. About one-third of the world's population is infected with the TB bacillus. In the developing world, more women of childbearing age die from TB than from causes directly associated with pregnancy and childbirth. The death of adults in their prime, who are parents, community leaders and producers in most societies, causes a particularly onerous burden besides being a serious public health problem. In the poorest countries, where the magnitude of the TB problem is greatest, those TB control strategies that are economically feasible tend to be less effective. Therefore, in low and middle income countries, cost-effectiveness considerations aimed at prioritising resource allocation in the health sector in general, and in TB control programmes in particular, are of paramount importance. Operationally, the main components of a TB control programme are: (i) detection and treatment of TB; and (ii) prevention of TB through BCG vaccination and chemoprophylaxis. Priority should be given to ensuring that TB patients complete their prescribed course of chemotherapy. Adequate treatment is the most effective way of preventing the spread of TB and the emergence of drug resistance. This article reviews evidence of the effectiveness and cost effectiveness of different approaches to TB care, particularly those that are applicable to low income countries, in both HIV-infected and noninfected patients. Financial implications and ways to implement directly observed therapy for TB in large urban areas are discussed, and the need to address some relevant operational issues is highlighted. The current role of chemoprophylaxis and BCG vaccination is also reviewed.

Estudo de obitos infantis por pneumonia por meio de inquerito domiciliar: Segunda fase de investigacao / Study of infantilis deaths by pneumonia by mean of inquiry domiciliary

Foi realizada uma investigacao domiciliar junto aos familiares de 154 criancas menores de 5 anos que morreram por pneumonia em Porto Alegre, entre abril de 1987 e marco de 1988; incluiu 91,67% dos obitos que ocorreram no periodo. Detectaram-se diferencas entre as informacoes constantes na Declaracao de Obito e as obtidas atraves das entrevistas. O numero de mortes domiciliares foi de 69 (44,80%) casos e 19 (12,34%) criancas morreram antes de 24 horas deinternacao. Ocorreram 66 (42,86%) obitos em hospital. Discutem-se as causas e suas possiveis associacoes entre elas para a ocorrencia da morte ser hospitalar ounao, fazendo uma extrapolacao a outros estados do pais .