The search for a tuberculosis vaccine: an elusive quest?

The precise mechanisms of protective immunity and pathogenesis of tuberculosis (TB) are poorly understood. Yet, many efforts are underway to develop new, more effective vaccines against Mycobacterium tuberculosis. This development appears to be predicated upon the assumption that natural acquired immunity to TB exists. In this paper we review the evidence for such immunity, explore the hypothesis that disease progression is due to some, often transient, immunological dysfunction, and discuss its relevance for vaccine development. Several mechanisms for such an immune dysfunction are proposed, including the recently suggested involvement of viral co-infections. Developing vaccines for such co-infections may be a new challenge for TB control.     

Finding patients eligible for antiretroviral therapy using TB services as entry point for HIV treatment

OBJECTIVE: To estimate the proportion of antiretroviral therapy (ART) eligible adults (15-49 years) with tuberculosis potentially identifiable through tuberculosis services using a CD4 count below 350 cells/mm3 as cut-off value for ART initiation. METHODS: Using TB notification rate data, HIV seroprevalence data, and estimates of the size of the adult population (15-49 years) in 18 sub-Saharan African countries with an HIV seroprevalence of > 5%, calculations of the number of ART eligible adults with tuberculosis presenting to tuberculosis services were made. Assumptions were made on the tuberculosis notification rates in the age-group 15-49 years, the HIV-infected population with a CD4 count below 350 cells/mm3 and the relative risk of developing tuberculosis, and average duration from HIV infection to death. The probability of having a CD4+ count below 350 cells/mm3 given a diagnosis of tuberculosis was estimated using Bayes' theorem, and estimates of the number of patients with a CD4 count below 350 cells/mm3 identifiable through tuberculosis were made. The number needed to screen to identify one ART eligible patient through tuberculosis services was estimated for each country. RESULTS: ART eligible adults with tuberculosis potentially identifiable through tuberculosis services in the 18 countries ranged from 2% to 18% of the total HIV-infected adult population with a CD4+ count below 350 cells/mm3 and would average 10% of all such HIV patients. The number needed to screen to identify ART eligible patients through tuberculosis services ranged from 1.4 to 4.2, against 8.6 to 65.4 if adults aged 15-49 are randomly screened for low CD4 counts. CONCLUSION: Tuberculosis services are an important entry point for identifying ART eligible patients. Given that dually infected patients identified through tuberculosis services contributed to 10% of the HIV-infected adult population with a CD4 cell count below 350 cells/mm3 in the 18 sub-Saharan African countries, major efforts are required beyond the tuberculosis services in detecting patients that should benefit from ART. However, the low number needed to screen gives opportunity to use tuberculosis services in AIDS control and ART scaling-up programmes.     

The impact of the HIV epidemic on tuberculosis transmission in Tanzania

OBJECTIVE: To assess the impact of the HIV epidemic on tuberculosis transmission in Tanzania by estimating the trend in annual risk of tuberculosis infection (ARTI) over the period 1983-2003. DESIGN: Tuberculin survey among school children aged 6-14 years, randomly selected by cluster sampling. METHODS: Primary outcome was the ARTI among children without a BCG vaccination scar. To obtain time trends, data were reanalysed from three previous surveys carried out at intervals of 5 years since 1983, using identical methods and definitions. RESULTS: Of 96,226 children included in the analysis (74% of those enrolled), 10,239 (11%) had no BCG scar. The ARTI was 0.68% (95% confidence interval 0.55-0.81). Despite a doubling of notification rates of smear-positive tuberculosis since 1983, this represents an average annual decline since the first survey of 2.7% (P < 0.001). The declining trend in ARTI was observed in 17 of 20 regions, with no association between this trend and region-specific prevalence of HIV infection among patients with tuberculosis (P = 0.575). A similar decline in ARTI was observed among children with a BCG scar and for various ways of estimating the prevalence of tuberculosis infection from the distribution of skin test reactions. CONCLUSION: Despite substantial increases in tuberculosis incidence, the overall population-level effect of the HIV epidemic on tuberculosis transmission in Tanzania has been limited. This suggests that in the presence of a strong control programme, the HIV epidemic has limited impact on tuberculosis transmission.     

No decrease in annual risk of tuberculosis infection in endemic area in Cape Town,South Africa

Objective To estimate the change in annual risk of tuberculosis infection (ARTI) in two neighbouring urban communities of Cape Town, South Africa with an HIV prevalence of approximately 2%, and to compare ARTI with notification rates and treatment outcomes in the tuberculosis (TB) programme. Methods In 1998–1999 and 2005, tuberculin skin test surveys were conducted to measure the prevalence of Mycobacterium tuberculosis infection and to calculate the ARTI. All 6 to 9‐year‐old children from all primary schools were included in the survey. Notification rates and treatment outcomes were obtained from the TB register. Results A total of 2067 children participated in the survey from 1998 to 1999 and a total of 1954 in 2005. Based on a tuberculin skin test cut‐off point of 10 mm, the ARTI was 3.7% (3.4–4.0%) in the 1998–1999 survey and 4.1% (3.8–4.5%) in 2005. The notification rate for pulmonary TB increased significantly from 646 per 100 000 in 1998 to 784 per 100 000 in 2002. In Ravensmead, there was no significant change in ARTI [first survey: 3.5% (3.1–3.9%), second survey: 3.2% (2.9–3.6%)], but in Uitsig the ARTI increased significantly from 4.1% (3.6–4.6%) to 5.8% (5.2–6.5%). The difference in ARTI between the two areas was associated with differences in reported case rates and the proportion of previously treated cases. Conclusion Tuberculosis transmission remains very high in these two communities and control measures to date have failed. Additional measures to control TB are needed.     

A cornerstone of heart failure treatment is not effective in experimental right ventricular failure

Background

Right ventricular (RV) failure due to increased pressure load causes significant morbidity and mortality in patients with congenital heart diseases and pulmonary arterial hypertension. It is unknown whether renin–angiotensin–aldosterone-system (RAAS) inhibition (the cornerstone of left ventricular failure treatment) is effective in RV failure. We investigated the effects of combination treatment of aldosterone-blocker eplerenone + angiotensin II receptor blocker losartan (Ep/Lo) on RV remodeling and function in a model of RV failure due to increased pressure load.

Methods and results

Rats (n = 48) were randomized for pulmonary artery banding (PAB) or sham surgery and for losartan (20 mg/kg/d) + eplerenone (100 mg/kg/d) treatment (Ep/Lo) or vehicle (VEH). RV function was assessed by echocardiography and pressure–volume analysis at 5 and 11 weeks, or at the occurrence of clinical RV failure symptoms necessitating termination.PAB resulted in RV failure in all rats, as defined by reduced cardiac output, RV stroke volume, increased RV end diastolic pressure and liver congestion as well as RV fibrosis, hypertrophy and reduced capillary density. Clinical RV failure necessitated termination in 5/12 PAB–VEH rats. Angiotensin II type 1-receptor expression in the RV was reduced in PAB rats indicating local RAAS activation. Treatment of PAB rats with Ep/Lo significantly lowered arterial pressures, but had no significant effect on RV function, remodeling or survival compared to PAB–VEH rats.

Conclusions

RAAS inhibition does not beneficially affect experimental RV failure due to chronic pressure load. This is of high clinical relevance, because it indicates that the RV response to RAAS inhibition might fundamentally differ from that of the LV.     

Multidrug-resistant tuberculosis, People's Republic of China, 2007-2009

We conducted a case-control study to investigate risk factors for multidrug-resistant tuberculosis (MDR TB) in the People's Republic of China. Genotyping analysis was used to estimate the percentage of cases from recent transmission among 100 MDR TB case-patients hospitalized during April 2007-July 2009. Molecular subtyping of isolates showed that 41% of MDR TB strains clustered. Beijing genotype was found in 94% of the MDR TB isolates and 79% of the pan-susceptible isolates. In multivariate analysis, MDR TB was independently associated with Beijing genotype, retreatment for TB, symptoms lasting >3 months before first evaluation at the hospital, lack of health insurance, and being a farmer (vs. being a student). MDR TB was associated with Beijing genotype and lower socioeconomic status. A large percentage of MDR TB cases seemed to result from recent transmission. Early detection, effective treatment, and infection control measures for MDR TB are needed to reduce transmission.     

Health-seeking behaviour among adults with prolonged cough in Vietnam

Objective To assess health‐seeking behaviour among adults with prolonged cough in a population‐based, nationally representative sample in Vietnam. Methods Cross‐sectional survey conducted from September 2006 to July 2007. All inhabitants aged ≥15 years were invited for screening for cough, history of tuberculosis (TB) treatment and chest X‐ray (CXR) examination. TB suspects, defined as any survey participant with CXR abnormalities consistent with TB, or productive cough for more than 2 weeks or TB treatment either currently or in the preceding 2 years submitted sputum specimens for smear examination and culture and provided information on health‐seeking behaviour in an in‐depth interview. Results Of 94 179 persons participating in the survey, 4.6% had prolonged productive cough. Forty‐four percentage of those had sought health care and reported pharmacies (35%), commune health posts (29%), public hospitals (24%) and private physicians (10%) as first point of contact. Only 7% had undergone sputum smear examination. Of TB suspects with prolonged productive cough, 2.9% were diagnosed with TB; 10.2% of these reported smear and 21.9% reported X‐ray examination when visiting a health care facility. The average patient delay was 4.1 weeks (95% CI: 3.9–4.4) among cough suspects and 4.0 weeks (95% CI: 3.1–4.9) among TB cases. Conclusions In this Vietnamese survey, nearly half of persons with cough for more than 2 weeks had visited a health care provider. The commonest first health facility contacted was the pharmacy. Sputum smears were rarely examined, except in the provincial TB hospital. Our findings highlight the need to improve diagnostic practices by retraining health staff on the performance of sputum examination for TB suspects.