Transmission dynamics and tuberculosis control among HIV/AIDS patients

Introduction: Les efforts globaux pour contrôler la tuberculose sont présentement restreints par la prévalence croissante du VIH/SIDA. Quoique les éclosions de la tuberculose multi résistante (TB-MDR) soient fréquemment rapportées parmi les populations atteintes du SIDA, le lien entre VIH/SIDA et le développement de résistance n’est pas clair. Objectifs: Cette recherche visait à : (1) développer une base de connaissances concernant les facteurs associés à des éclosions de la TB-MDR parmi les patients atteints du VIH/SIDA; (2) utiliser ce cadre de connaissances pour accroître des mesures préliminaires pour mieux contrôler la tuberculose pulmonaire chez les patients atteints du VIH/SIDA; et (3) afin d’améliorer l’application des ces mesures, affiner les techniques bactériologiques existantes pour Mycobacterium tuberculosis. Méthodologie: Quatre études ont été réalisées : (1) Une étude longitudinale pour identifier les facteurs associés avec une éclosion de la TB-MDR parmi les patients atteints du SIDA qui ont reçu le traitement directement supervisé de courte durée (DOTS) pour la tuberculose pulmonaire au Lima et au Pérou entre 1999 et 2005; (2) Une étude transversale pour décrire différentes étapes de l’histoire naturelle de la tuberculose, la prévalence et les facteurs associés avec la mycobactérie qu’on retrouve dans les selles des patients atteints du SIDA; (3) Un projet pilote pour développer des stratégies de dépistage pour la tuberculose pulmonaire parmi les patients hospitalisés atteints du SIDA, en utilisant l’essaie Microscopic Observation Drug Susceptibility (MODS); et (4) Une étude laboratoire pour identifier les meilleures concentrations critiques pour détecter les souches MDR de M. tuberculosis en utilisant l’essaie MODS. Résultats : Étude 1 démontre qu’une épidémie de TB-MDR parmi les patients atteints du SIDA qui ont reçu DOTS pour la tuberculose pulmonaire ait été causée par la superinfection du clone de M. tuberculosis plutôt que le développement de la résistance secondaire. Bien que ce clone ait été plus commun parmi la cohorte de patients atteints du SIDA, il n’avait aucune différence de risque pour superinfection entre les patients avec ou sans SIDA. Ces résultats suggèrent qu’un autre facteur, possiblement associé à la diarrhée, peu contribuer à la prévalence élevée de ce clone chez les patients atteints du SIDA. Étude 2 suggère que chez la plupart des patients atteints du SIDA il a été retrouvé une mycobactérie dans leurs selles alors qu’ils étaient en phase terminale au niveau de la tuberculose pulmonaire. Or, les patients atteints du SIDA ayant été hospitalisés pendant les deux dernières années pour une autre condition médicale sont moins à risque de se retrouver avec une mycobactérie dans leurs selles. Étude 3 confirme que la tuberculose pulmonaire a été commune à tous les patients hospitalisés atteints du SIDA, mais diagnostiquée incorrectement en utilisant les critères cliniques présentement recommandés pour la tuberculose. Or, l’essaie MODS a détecté pour la plupart de ces cas. De plus, MODS a été également efficace quand la méthode a été dirigée aux patients soupçonnés d’avoir la tuberculose, à cause de leurs symptômes. Étude 4 démontre les difficultés de détecter les souches de M. tuberculosis avec une faible résistance contre ethambutol et streptomycine en utilisant l’essai MODS avec les concentrations de drogue présentement recommandées pour un milieu de culture. Cependant, l’utilité diagnostique de MODS peut être améliorée ; modifier les concentrations critiques et utiliser deux plaques et non une, pour des tests réguliers. Conclusion: Nos études soulèvent la nécessité d’améliorer le diagnostic et le traitement de la tuberculose parmi les patients atteints du SIDA, en particulier ceux qui vivent dans des régions avec moins de ressources. Par ailleurs, nos résultats font ressortir les effets indirects que les soins de santé ont sur les patients infectés par le VIH et qu’ils peuvent avoir sur le développement de la tuberculose.Background: Global efforts to control tuberculosis are currently being hampered by a continuing rise in the prevalence of HIV/AIDS. Although outbreaks of multidrug resistant tuberculosis (MDR-TB) are commonly reported among AIDS populations, the link between HIV/AIDS and the development of drug-resistance remains unclear. Objectives: This thesis aimed to: (1) build a knowledge foundation regarding underlying factors associated with outbreaks of MDR-TB among HIV/AIDS patients; (2) use this knowledge framework to develop preliminary health measures for controlling pulmonary tuberculosis among HIV/AIDS patients; and (3) in an effort to better implement these health measures, refine existing culture-based diagnostics for Mycobacterium tuberculosis. Methods: Four studies were conducted: (1) a longitudinal study to identify the underlying factors associated with an epidemic of MDR-TB among AIDS patients receiving Directly- Observed Therapy Short-course (DOTS) for pulmonary tuberculosis in Lima, Peru between 1999 and 2005; (2) a cross-sectional study to characterize the prevalence and factors associated with gastrointestinal shedding with mycobacteria among AIDS patients at different stages in the natural history of tuberculosis; (3) a pilot study to develop screening strategies for pulmonary tuberculosis among hospitalized HIV/AIDS patients using the Microscopic Observation Drug Susceptibility (MODS) assay; and (4) a laboratory-based study to define the optimal critical concentrations needed for detecting drug resistance in M. tuberculosis using MODS. Results: Study 1 revealed that an epidemic of MDR-TB among AIDS patients receiving DOTS for pulmonary tuberculosis was due to super-infection with a specific clone of M. tuberculosis rather than the development of secondary drug-resistance. Although this epidemic clone was more common among patients in the AIDS cohort, risk of superinfection did not differ between AIDS and non-AIDS patients after adjusting for baseline risk of exposure, suggesting that another factor possibly associated with diarrhea may be contributing to the strain’s high prevalence among AIDS patients. Study 2 showed that the majority of AIDS patients in the later stages of pulmonary tuberculosis exhibited gastrointestinal shedding with mycobacteria. Stool shedding was rare in the absence of pulmonary tuberculosis. AIDS patients were also less likely to shed mycobacteria if they had been hospitalized during the previous two years for another medical condition. Study 3 confirmed that pulmonary tuberculosis was common among hospitalized AIDS patients but frequently misdiagnosed using currently recommended diagnostic algorithms. The MODS assay detected most cases and was equally effective when targeted to patients clinically suspicious for tuberculosis. Study 4 demonstrated that low grade drug resistance in M. tuberculosis to ethambutol and streptomycin was difficult to detect with MODS using currently recommended drug-concentration standards in broth. Its diagnostic utility could be improved by modifying drug-concentration standards, and including two versus one critical concentration well for standardized testing. Conclusion: Our studies underscore the need to improve the diagnosis and treatment of tuberculosis among AIDS patients living in resource-constrained settings, all in an effort to prevent morbidity, mortality and the transmission of drug-resistant strains. They also highlight the indirect effect that general health care among HIV-infected patients can have on the development of tuberculosis

Invasive Group A Streptococcal Infections, Clinical Manifestations and Their Predictors, Montreal, 1995–2002

Specific clinical manifestations of invasive group A streptococcal infection appear to develop not in response to the pathogen, but rather to host or environmental factors

Microscopic-observation drug-susceptibility assay for the diagnosis of TB.

BACKGROUND: New diagnostic tools are urgently needed to interrupt the transmission of tuberculosis and multidrug-resistant tuberculosis. Rapid, sensitive detection of tuberculosis and multidrug-resistant tuberculosis in sputum has been demonstrated in proof-of-principle studies of the microscopic-observation drug-susceptibility (MODS) assay, in which broth cultures are examined microscopically to detect characteristic growth. METHODS: In an operational setting in Peru, we investigated the performance of the MODS assay for culture and drug-susceptibility testing in three target groups: unselected patients with suspected tuberculosis, prescreened patients at high risk for tuberculosis or multidrug-resistant tuberculosis, and unselected hospitalized patients infected with the human immunodeficiency virus. We compared the MODS assay head-to-head with two reference methods: automated mycobacterial culture and culture on Löwenstein-Jensen medium with the proportion method. RESULTS: Of 3760 sputum samples, 401 (10.7%) yielded cultures positive for Mycobacterium tuberculosis. Sensitivity of detection was 97.8% for MODS culture, 89.0% for automated mycobacterial culture, and 84.0% for Löwenstein-Jensen culture (P<0.001); the median time to culture positivity was 7 days, 13 days, and 26 days, respectively (P<0.001), and the median time to the results of susceptibility tests was 7 days, 22 days, and 68 days, respectively. The incremental benefit of a second MODS culture was minimal, particularly in patients at high risk for tuberculosis or multidrug-resistant tuberculosis. Agreement between MODS and the reference standard for susceptibility was 100% for rifampin, 97% for isoniazid, 99% for rifampin and isoniazid (combined results for multidrug resistance), 95% for ethambutol, and 92% for streptomycin (kappa values, 1.0, 0.89, 0.93, 0.71, and 0.72, respectively). CONCLUSIONS: A single MODS culture of a sputum sample offers more rapid and sensitive detection of tuberculosis and multidrug-resistant tuberculosis than the existing gold-standard methods used

Molecular epidemiology of tuberculosis transmission: Contextualizing the evidence through social network theory

Despite a long-standing recognition that factors such as age, gender, and socioeconomic status play a fundamental role in tuberculosis transmission and susceptibility, few molecular epidemiological studies have fully elucidated the etiological mechanisms by which each of these social factors may influence transmission of the disease. In this paper, we propose that in order to achieve this goal, molecular epidemiology must move towards a more holistic approach for disease transmission, thus enabling social theory to be integrated into molecular epidemiological studies on tuberculosis. We then present a social network model to illustrate how molecular and social epidemiology can be combined to study disease transmission patterns, and provide preliminary molecular epidemiological evidence to support the role of social networks in tuberculosis transmission.Tuberculosis Respiratory infection Infectious disease transmission Molecular epidemiology Social networks Holistic health Communicable disease control

Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes

A meta-analysis for response to treatment was undertaken using individual data of multidrug-resistant tuberculosis (MDR-TB) (resistance to isoniazid and rifampicin) patients from 26 centres. The analysis assessed the impact of additional resistance to fluoroquinolones and/or second-line injectable drugs on treatment outcome. Compared with treatment failure, relapse and death, treatment success was higher in MDR-TB patients infected with strains without additional resistance (n=4763; 64%, 95% CI 57-72%) or with resistance to second-line injectable drugs only (n=1130; 56%, 95% CI 45-66%), than in those having resistance to fluoroquinolones alone (n=426; 48%, 95% CI 36-60%) or to fluoroquinolones plus second-line injectable drugs (extensively drug resistant (XDR)-TB) (n=405; 40%, 95% CI 27-53%). In XDR-TB patients, treatment success was highest if at least six drugs were used in the intensive phase (adjusted OR 4.9, 95% CI 1.4-16.6; reference fewer than three drugs) and four in the continuation phase (OR 6.1, 95% CI 1.4-26.3). The odds of success in XDR-TB patients was maximised when the intensive phase reached 6.6-9.0 months duration and the total duration of treatment 20.1-25.0 months. In XDR-TB patients, regimens containing more drugs than those recommended in MDR-TB but given for a similar duration were associated with the highest odds of success. All data were from observational studies and methodologies varied between centres, therefore, the bias may be substantial. Better quality evidence is needed to optimise regimen

Infrequent MODS TB culture cross-contamination in a high-burden resource-poor setting.

One obstacle to wider use of rapid liquid culture-based tuberculosis diagnostics such as the microscopic observation drug susceptibility (MODS) assay is concern about cross-contamination. We investigated the rate of laboratory cross-contamination in MODS, automated MBBacT, and Lowenstein-Jensen (LJ) cultures performed in parallel, through triangulation of microbiologic (reculturing stored samples), molecular (spoligotype/RFLP), and clinical epidemiologic data. At least 1 culture was positive for Mycobacterium tuberculosis for 362 (11%) of 3416 samples; 53 were regarded as potential cross-contamination suspects. Cross-contamination accounted for 17 false-positive cultures from 14 samples representing 0.41% (14/3416) and 0.17% (17/10248) of samples and cultures, respectively. Positive predictive values for MODS, MBBacT (bioMérieux, Durham, NC), and LJ were 99.1%, 98.7%, and 99.7%, and specificity was 99.9% for all 3. Low rates of cross-contamination are achievable in mycobacterial laboratories in resource-poor settings even when a large proportion of samples are infectious and highly sensitive liquid culture-based diagnostics such as MODS are used