Host determinants of infectiousness in smear-positive patients with pulmonary tuberculosis

Background Epidemiologic data suggests that only a minority of tuberculosis (TB) patients are infectious. Cough aerosol sampling is a novel quantitative method to measure TB infectiousness. Methods We analyzed data from three studies conducted in Uganda and Brazil over a 13-year period. We included sputum acid fast bacilli (AFB) and culture positive pulmonary TB patients and used a cough aerosol sampling system (CASS) to measure the number of colony-forming units (CFU) of Mycobacterium tuberculosis in cough-generated aerosols as a measure for infectiousness. Aerosol data was categorized as: aerosol negative (CFU = 0) and aerosol positive (CFU > 0). Logistic regression models were built to identify factors associated with aerosol positivity. Results M. tuberculosis was isolated by culture from cough aerosols in 100/233 (43%) TB patients. In an unadjusted analysis, aerosol positivity was associated with fewer days of antituberculous therapy before CASS sampling (p = .0001), higher sputum AFB smear grade (p = .01), shorter days to positivity in liquid culture media (p = .02), and larger sputum volume (p = .03). In an adjusted analysis, only fewer days of TB treatment (OR 1.47 per 1 day of therapy, 95% CI 1.16-1.89; p = .001) was associated with aerosol positivity. Conclusion Cough generated aerosols containing viable M. tuberculosis, the infectious moiety in TB, are detected in a minority of TB patients and rapidly become non-culturable after initiation of antituberculous treatment. Mechanistic studies are needed to further elucidate these findings.publishersversionpublishe

Airborne Infection with Bacillus anthracis—from Mills to Mail

The lack of identified exposures in 2 of the 11 cases of bioterrorism-related inhalation anthrax in 2001 raised uncertainty about the infectious dose and transmission of Bacillus anthracis. We used the Wells-Riley mathematical model of airborne infection to estimate 1) the exposure concentrations in postal facilities where cases of inhalation anthrax occurred and 2) the risk for infection in various hypothetical scenarios of exposure to B. anthracis aerosolized from contaminated mail in residential settings. These models suggest that a small number of cases of inhalation anthrax can be expected when large numbers of persons are exposed to low concentrations of B. anthracis. The risk for inhalation anthrax is determined not only by bacillary virulence factors but also by infectious aerosol production and removal rates and by host factors

Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study.

BACKGROUND: The emergence of programmatically incurable tuberculosis threatens to destabilise control efforts. The aim of this study was to collect prospective patient-level data to inform treatment and containment strategies. METHODS: In a prospective cohort study, 273 South African patients with extensively drug-resistant tuberculosis, or resistance beyond extensively drug-resistant tuberculosis, were followed up over a period of 6 years. Transmission dynamics, infectiousness, and drug susceptibility were analysed in a subset of patients from the Western Cape using whole-genome sequencing (WGS; n=149), a cough aerosol sampling system (CASS; n=26), and phenotypic testing for 18 drugs (n=179). FINDINGS: Between Oct 1, 2008, and Oct 31, 2012, we enrolled and followed up 273 patients for a median of 20·3 months (IQR 9·6-27·8). 203 (74%) had programmatically incurable tuberculosis and unfavourable outcomes (treatment failure, relapse, default, or death despite treatment with a regimen based on capreomycin, aminosalicylic acid, or both). 172 (63%) patients were discharged home, of whom 104 (60%) had an unfavourable outcome. 54 (31%) home-discharged patients had failed treatment, with a median time to death after discharge of 9·9 months (IQR 4·2-17·4). 35 (20%) home-discharged cases were smear-positive at discharge. Using CASS, six (23%) of 26 home-discharged cases with data available expectorated infectious culture-positive cough aerosols in the respirable range (<5 μm), and most reported inter-person contact with suboptimal protective mask usage. WGS identified 17 (19%) of the 90 patients (with available sequence data) that were discharged home before the diagnosis of 20 downstream cases of extensively drug-resistant tuberculosis with almost identical sequencing profiles suggestive of community-based transmission (five or fewer single nucleotide polymorphisms different and with identical resistance-encoding mutations for 14 drugs). 11 (55%) of these downstream cases had HIV co-infection and ten (50%) had died by the end of the study. 22 (56%) of 39 isolates in patients discharged home after treatment failure were resistant to eight or more drugs. However, five (16%) of 31 isolates were susceptible to rifabutin and more than 90% were likely to be sensitive to linezolid, bedaquiline, and delamanid. INTERPRETATION: More than half of the patients with programmatically incurable tuberculosis were discharged into the community where they remained for an average of 16 months, were at risk of expectorating infectious cough aerosols, and posed a threat of transmission of extensively drug-resistant tuberculosis. Urgent action, including appropriate containment strategies, is needed to address this situation. Access to delamanid, bedaquiline, linezolid, and rifabutin, when appropriate, must be accelerated along with comprehensive drug susceptibility testing. FUNDING: UK Medical Research Council, South African Medical Research Council, South African National Research Foundation, European & Developing Countries Clinical Trials Partnership, Oppenheimer Foundation, Newton Fund, Biotechnology and Biological Sciences Research Council, King Abdullah University of Science & Technology

Treatment outcomes of new tuberculosis patients hospitalized in Kampala, Uganda: a prospective cohort study.

BACKGROUND: In most resource limited settings, new tuberculosis (TB) patients are usually treated as outpatients. We sought to investigate the reasons for hospitalisation and the predictors of poor treatment outcomes and mortality in a cohort of hospitalized new TB patients in Kampala, Uganda. METHODS AND FINDINGS: Ninety-six new TB patients hospitalised between 2003 and 2006 were enrolled and followed for two years. Thirty two were HIV-uninfected and 64 were HIV-infected. Among the HIV-uninfected, the commonest reasons for hospitalization were low Karnofsky score (47%) and need for diagnostic evaluation (25%). HIV-infected patients were commonly hospitalized due to low Karnofsky score (72%), concurrent illness (16%) and diagnostic evaluation (14%). Eleven HIV uninfected patients died (mortality rate 19.7 per 100 person-years) while 41 deaths occurred among the HIV-infected patients (mortality rate 46.9 per 100 person years). In all patients an unsuccessful treatment outcome (treatment failure, death during the treatment period or an unknown outcome) was associated with duration of TB symptoms, with the odds of an unsuccessful outcome decreasing with increasing duration. Among HIV-infected patients, an unsuccessful treatment outcome was also associated with male sex (P = 0.004) and age (P = 0.034). Low Karnofsky score (aHR = 8.93, 95% CI 1.88 - 42.40, P = 0.001) was the only factor significantly associated with mortality among the HIV-uninfected. Mortality among the HIV-infected was associated with the composite variable of CD4 and ART use, with patients with baseline CD4 below 200 cells/µL who were not on ART at a greater risk of death than those who were on ART, and low Karnofsky score (aHR = 2.02, 95% CI 1.02 - 4.01, P = 0.045). CONCLUSION: Poor health status is a common cause of hospitalisation for new TB patients. Mortality in this study was very high and associated with advanced HIV Disease and no use of ART

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis.

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

What is in a cough?

Objective/background: The aims of this talk are to: (a) provide an overview of our method of collecting, quantifying, and sizing infectious aerosols of Mycobacterium tuberculosis; and (b) to review data indicating that cough aerosol cultures of M. tuberculosis are the best predictors of infection and incident disease among household contacts of persons with active tuberculosis (TB). New infection was defined as tuberculin skin test conversion. Methods: We developed a cough aerosol sampling system by placing two Andersen cascade impactor viability samplers inside a cylinder into which patients cough via connector tubing. We recruited sputum acid fast bacilli (AFB) smear-positive patients from the tuberculosis clinic and wards at Mulago Hospital in Kampala, Uganda. Patients were asked to cough as strongly and frequently as they comfortably could for two 5-min sessions of coughing. Results: In a cohort of 96 sputum culture positive index TB cases, 43 (45%) produced culture-positive cough aerosols. Household contacts of TB patients who produced high aerosols (≥10colony forming units (CFU)) were more likely to have a new infection compared with contacts with low aerosol CFU (1–9CFU) and aerosol-negative cases (69%, 25%, and 30%, respectively, p = 0.009). In adjusted multivariate analyses, high cough aerosols were the only predictor of new TB infection (odds ratio [OR] 4.81; 1.20–19.23). In a follow-up (median 3.9 years) of this cohort, 369 (84%) of the contacts could be traced; eight (2%) had developed TB disease. Incident TB disease was associated with larger bacillary load in sputum measured by days to positive in liquid culture (OR 7.9; 0.7–70.5), exposure to a high-aerosol TB case patient (OR 6.0, 1.4–25.2) and marginally to HIV infection in the contact (OR 7.2; 0.7–70.5). Cough aerosol studies of TB patients in Brazil and South Africa are ongoing and appear to be finding similar proportions of cough aerosol cultures among TB patients (personal communication). Conclusion: Cough aerosol cultures of M. tuberculosis are the best predictors of infectiousness and predict incident TB disease among sputum smear-positive patients in Uganda. We propose that cough aerosol cultures are a better surrogate of inhaled dose than sputum smear