Tuberculosis In sub-Saharan Africa Research Articles

High granulocyte/lymphocyte ratio and paucity of NKT cells defines TB disease in a TB-endemic setting

Most people infected with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) actually maintain a strong immune response and are able to control bacterial growth (deemed latently infected (LTBI)), while approximately 10% progress to disease resulting in almost 2 million deaths per year. Determining the immune 'footprint' at specific stages of infection and disease will allow for better diagnostics, treatments and ultimately development of new vaccine candidates. In this study we performed multi-factorial flow cytometry on fresh blood from 56 TB cases, 46 Tuberculin Skin Test (TST) positive (LTBI) and 39 TST negative household contacts. We found a highly significant increase in granulocytes and decrease in B cells and invariant (Valpha24+Vbeta11+) NKT cells in TB cases compared to TST+ contacts (p<0.0001, p=0.007 and p=0.01 respectively) which were restored to LTBI levels following 6 months of TB treatment. Using support vector analysis, we found a combination of granulocyte and lymphocyte and/or NKT cell proportions allowed almost 90% correct classification into M. tuberculosis infection or disease. This work has important public health benefits in regards to diagnosis and treatment of TB in sub-Saharan Africa and in furthering our understanding of the requirements for protective immunity to TB.

Intensified Case Finding for Tuberculosis in Prevention of Mother-to-Child Transmission Programs: A Simple and Potentially Vital Addition for Maternal and Child Health

The intersection of HIV and tuberculosis (TB) poses a serious threat to HIV-infected women and their children. The majority of patients with TB in sub-Saharan Africa are infected with HIV and together the overlapping epidemics synergistically accelerate illness and death. Escalating case rates increased mortality and the recent emergence of extensively drug-resistant TB highlights how catastrophic a once preventable and curable disease has become among people with HIV/AIDS. The HIV epidemic requires new strategies to control TB in high-burden areas especially as women of reproductive age are disproportionately affected by the epidemic. Intensified case finding for TB has the potential to reduce morbidity and mortality for people living with HIV especially pregnant women their families and infants. (excerpt)

Human Flavin-Containing Monooxygenase 2.1 Catalyzes Oxygenation of the Antitubercular Drugs Thiacetazone and Ethionamide

The second-line antitubercular drugs thiacetazone (TAZ) and ethionamide (ETA) are bioactivated by the mycobacterial enzyme EtaA. We report here that human flavin-containing monooxygenase 2.1 (FMO2.1), which is expressed predominantly in the lung, catalyzes oxygenation of TAZ. The metabolites generated, the sulfenic acid, sulfinic acid, and carbodiimide derivatives, are the same as those produced by EtaA and human FMO1 and FMO3. Two of the metabolites, the sulfenic acid and carbodiimide, are known to be harmful to mammalian cells. FMO2.1 also catalyzes oxygenation of ETA, producing the S-oxide. We have developed a novel spectrophotometric assay for TAZ oxygenation. The assay was used to determine kinetic parameters for TAZ oxygenation catalyzed by human FMO1, FMO2.1, and FMO3 and by EtaA. Although the K(M) values for the four enzyme-catalyzed reactions are similar, k(cat) and, consequently, k(cat)/K(M) (the specificity constant) for FMO2.1-catalyzed TAZ oxygenation are much higher than those of FMO1, FMO3, or EtaA. This indicates that FMO2.1 is more effective in catalyzing TAZ oxygenation than are the other three enzymes and thus is likely to contribute substantially to the metabolism of TAZ, decreasing the availability of the prodrug to mycobacteria and producing toxic metabolites. Because of a genetic polymorphism, Europeans and Asians lack FMO2.1. However, in sub-Saharan Africa, a region in which tuberculosis is a major health problem, a substantial proportion of individuals express FMO2.1. Thus, our results may explain some of the observed interindividual differences in response to TAZ and ETA and have implications for the treatment of tuberculosis in sub-Saharan Africa.

Extensively drug-resistant tuberculosis in sub-Saharan Africa: an emerging public-health concern

The extensively drug-resistant tuberculosis (XDR-TB) categorisation has been developed as a phenotypic description of those TB strains that are resistant to most conventional anti-TB drugs. While widely accepted to have significant incidence in those areas, such as Eastern Europe, that have high levels of multidrug resistance, recent reports have described a cluster of XDR-TB cases in the KwaZulu-Natal province of South Africa. With very high case-fatality rates in this setting and a paucity of potential treatment options, concerns have grown about the possibility of an outbreak of highly lethal TB occurring in areas where TB prevalence, generally, is at its highest. In this article, we review previously documented case series of XDR-TB, and examine questions around the likelihood of rapid XDR-TB expansion in sub-Saharan Africa. We analyse how current TB control measures in the area might cope with such a challenge, and identify new areas for focus within the research and development community.

Multidrug-resistant tuberculosis.

BackgroundWith almost 9 million new cases each year, tuberculosis remains one of the most feared diseases on the planet. Led by the STOP-TB Partnership and WHO, recent efforts to combat the disease have made considerable progress in a number of countries. However, the emergence of mutated strains of Mycobacterium tuberculosis that are resistant to the major anti-tuberculosis drugs poses a deadly threat to control efforts. Multidrug-resistant tuberculosis (MDR-TB) has been reported in all regions of the world. More recently, extensively drug resistant-tuberculosis (XDR-TB) that is also resistant to second line drugs has emerged in a number of countries. To ensure that adequate resources are allocated to prevent the emergence and spread of drug resistance it is important to understand the scale of the problem. In this article we propose that current methods of describing the epidemiology of drug resistant tuberculosis are not adequate for this purpose and argue for the inclusion of population based statistics in global surveillance data.DiscussionWhereas the prevalence of tuberculosis is presented as the proportion of individuals within a defined population having disease, the prevalence of drug resistant tuberculosis is usually presented as the proportion of tuberculosis cases exhibiting resistance to anti-tuberculosis drugs. Global surveillance activities have identified countries in Eastern Europe, the former Soviet Union and regions of China as having a high proportion of MDR-TB cases and international commentary has focused primarily on the urgent need to improve control in these settings. Other regions, such as sub-Saharan Africa have been observed as having a low proportion of drug resistant cases. However, if one considers the incidence of new tuberculosis cases with drug resistant disease in terms of the population then countries of sub-Saharan Africa have amongst the highest rates of transmitted MDR-TB in the world. We propose that inclusion of population based statistics in global surveillance data is necessary to better inform debate on the control of drug resistant tuberculosis.SummaryRe-appraisal of global MDR-TB data to include population based statistics suggests that the problem of drug resistant tuberculosis in sub-Saharan Africa is more critical than previously perceived.

Child sexual abuse, HIV, and tuberculosis in sub-Saharan Africa: a case report from rural Cameroon

Most people affected by HIV and tuberculosis live in sub-Saharan Africa where young adults have the highest incidence of both diseases. HIV transmission routes are well established in most adults and young children but are sometimes unclear in older children and teenagers. Sexual abuse may play an important role in this age group. A 12-year-old boy presented to a hospital in rural northwest Cameroon with a one-year history of productive cough and weight loss despite multiple antibiotics. On consultation there were night sweats and decreased appetite no rigors or haemoptysis respiratory rate was 28 breaths per minute blood pressure was 80/60mmHg temperature was 36.6°C and pulse was 100 beats per minute. He appeared chronically ill with submandibular lymphadenopathy bilateral coarse breath sounds and mild clubbing. (excerpt)

The epidemic of HIV-associated tuberculosis in sub-Saharan Africa: does this also impact non-HIV-infected individuals?

Annual tuberculosis notification rates have increased two to threefold in many countries in sub-Saharan Africa as a result of the HIV epidemic [1]. Despite huge increases in the incidence of HIV-associated tuberculosis, existing studies have differing conclusions as to whether this is causing increased transmission to non-HIV-infected individuals. Community-based studies have reported no or limited impact on tuberculosis notifications among the non-HIV-infected population [2,3], whereas data from Kenya suggest that the annual risk of tuberculosis infection has increased [4]. Two studies from South African gold mines differ; one reported substantial increases in tuberculosis among both HIV-infected and non-infected workers [5], whereas the other found no increase among non-infected workers [6]. Understanding the transmission of tuberculosis in African populations with high HIV prevalence is important for the further development of disease control strategies. We therefore read with interest the study recently reported by Egwaga and colleagues [7]. Their aim was to assess the impact of the HIV epidemic on tuberculosis transmission in Tanzania, and analysed the trend in the annual risk of tuberculosis infection using tuberculin skin testing among a randomized sample of children aged 6–14 years. This large well-conducted study reported trends in the annual risk of tuberculosis infection from 1983 to 2003, and found that despite substantial increases in HIV-associated tuberculosis notifications, the annual risk of tuberculosis infection among children decreased. The authors concluded that the overall population level effect of HIV on tuberculosis transmission is limited [7]. These data are helpful and provide some welcome news for tuberculosis control programmes. However, an important question is whether annual risk of tuberculosis infection data among children adequately reflect the overall transmission of tuberculosis within the community. Studies in high tuberculosis prevalence communities in South Africa, for example, have shown that much tuberculosis transmission occurs outside the home and is related to patterns of social interaction among adults such as that occurring in drinking hostels [8,9]. The annual risk of tuberculosis infection data among children, although important, may provide a limited insight into transmission risk among the adult population. We have recently reported on the devastating impact of HIV on the epidemiology of tuberculosis in a peri-urban community in South Africa, which has a well-functioning tuberculosis control programme [10]. Here the antenatal HIV seroprevalence has increased over 10 years to approximately 30%, and annual tuberculosis notification rates for the community exceeded 1400/100 000 in 2004. However, despite these huge increases in the overall community burden of tuberculosis, no significant change in tuberculosis rates has occurred among children aged 0–9 years, a finding that is consistent with those of Egwaga and colleagues [7]. However, we also reported an evolving tuberculosis epidemic among adolescents in the same community [10]. Adolescence has traditionally been described as the ‘golden period’ during which the risk of developing active tuberculosis is very low. However, in this community, rates have steadily risen from zero in 1996/1997 to 436/100 000 in 2003/2004; only a proportion of these cases were HIV associated. It thus seems that in this community the tuberculosis epidemic is spilling over into those traditionally at lowest risk. Moreover, more recently acquired data suggest that overall rates among non-HIV-infected young adults in this community are also rising, despite the maintenance of good treatment outcomes in the local tuberculosis service. Therefore, we suspect that the trend in the annual risk of tuberculosis infection data among children may provide a limited insight into the impact of HIV on the tuberculosis epidemic in this population as this is a highly age-specific effect and has not significantly affected children.

Low plasma selenium concentrations, high plasma human immunodeficiency virus load and high interleukin-6 concentrations are risk factors associated with anemia in adults presenting with pulmonary tuberculosis in Zomba district, Malawi

Although anemia is common among adults with pulmonary tuberculosis and human immunodeficiency virus (HIV) infection in sub-Saharan Africa, the factors contributing to its pathogenesis have not been well characterized. To characterize the antioxidant micronutrient status, interleukin-6 (IL-6) concentrations, and HIV load in relationship with anemia in adults with pulmonary tuberculosis. Zomba district, Malawi. Erythropoietin, IL-6, plasma HIV load, and markers of micronutrient status (hemoglobin (Hb), plasma concentrations of retinol, alpha-tocopherol, carotenoids, ferritin, zinc, and selenium) were measured in 500 adults who presented with pulmonary tuberculosis in Zomba Central Hospital, Malawi. Among 370 HIV-positive and 130 HIV-negative adults, the prevalence of anemia was 88 and 77%, respectively (P = 0.002), and moderate to severe anemia (Hb < 80 g/l) occurred in 30 and 15%, respectively (P = 0.001). Geometric mean IL-6 concentration was 21.1 pg/ml, with no difference between HIV-positive and -negative adults. The erythropoietin response to anemia was not different between adults with elevated IL-6 and those with lower IL-6 concentrations. In a multivariate logistic regression model, HIV load, and lower plasma selenium concentrations were associated with moderate to severe anemia. In a final multivariate linear regression model, IL-6, plasma HIV load, and plasma selenium concentrations were associated with Hb concentrations. This study suggests that low selenium concentrations, high HIV load, and high IL-6 concentrations are associated with anemia in adults with pulmonary tuberculosis in sub-Saharan Africa.

A re-examination of the potential impact of preventive therapy on the public health problem of tuberculosis in contemporary sub-Saharan Africa

Background. To estimate the effect size of tuberculosis preventive therapy (PT) on the public health problem of tuberculosis in contemporary sub-Saharan Africa. Methods. A compartmental flow model that considers high levels of tuberculosis and human immunodeficiency virus (HIV) infection in contemporary sub-Saharan Africa was used to assess the impact of PT on the prevalence of tuberculosis and tuberculosis-associated mortality. Results. Model implementation shows that giving PT to 25% of HIV-positive individuals with latent tuberculosis infection (LTBI) leads to a 3.9% reduction in the prevalence of tuberculosis in 10 years and a 5.1% reduction in 20 years. This intervention also prevents a cumulative total of 3.0% of tuberculosis-associated deaths in a decade and 5.5% in two decades. Doubling PT coverage to 50% approximately doubles the effect size, suggesting a linear relationship within the 20-year period. The effect size is slightly sensitive to changes in level of HIV transmission, level of tuberculosis transmission, and level of case detection and treatment cure rates in the population. Conclusions. Contrary to suggestions by previous authors that PT can significantly reduce the public health problem of tuberculosis in sub-Saharan Africa, this model-based analysis suggests that the impact of PT on tuberculosis in the population is likely to be small.

Adult tuberculosis overview: African versus Western perspectives.

Tuberculosis is currently an enormous global health problem. In industrialized countries in Western Europe and North America, tuberculosis case rates are low and an increasing proportion of cases now occur in foreign-born individuals and in marginalized populations, including the homeless, prisoners, drug users, and persons with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS). In contrast, the burden of tuberculosis in sub-Saharan Africa continues to grow, largely fueled by the HIV pandemic and poor public health infrastructure. Use of the World Health Organization's (WHO) directly observed therapy, short course (DOTS) strategy has been successful in improving outcomes and preventing the emergence of acquired drug resistance in several African countries; however, case rates are increasing throughout most of the region. It is clear that control of tuberculosis in Africa is closely linked to control of HIV and AIDS. Substantial external donor support and innovative approaches to enhance interactions between HIV/AIDS prevention and treatment efforts and tuberculosis control programs will be needed to improve the current tuberculosis situation in Africa. The purpose of this review is to provide a synopsis of recent developments in these areas and to serve as a reference source for interested readers.

Tuberculosis in sub-Saharan Africa: A regional assessment of the impact of the human immunodeficiency virus and National Tuberculosis Control Program quality

Background: The effect of the human immunodeficiency virus (HIV) epidemic on tuberculosis (TB) has been evaluated for certain countries in sub-Saharan Africa. However, no multi-country comparisons have been performed of the magnitude of the changes in TB case rates and the roles of the HIV epidemic and national TB control program (NTP) quality in these changes. Methods: We examined trends in TB case rates after 1985 for 20 sub-Saharan African countries, and also from 1975–1984 for 10 of these countries (core countries). Average annual changes in TB case rates after 1985 were stratified by 1992 urban low-risk HIV seroprevalence and by NTP quality, as determined by a survey of international TB experts. Results: Case rates in the core countries decreased by an average of −1.6% per year prior to 1985, but increased by an average of +7.0% per year after 1985 (+7.7% per year after 1985 in all 20 countries). Average annual case rates after 1985 increased approximately twice as fast in countries with high vs low or intermediate HIV seroprevalence ratings. In both the core countries and all 20 countries, the average annual rate of rise in case rates after 1985 decreased as NTP quality rating increased. This relationship persisted even after stratification by HIV seroprevalence rating. Conclusions: TB case rates have increased in sub-Saharan Africa since 1985. These increases were relatively greater as HIV seroprevalence increased, and relatively lower as NTP quality increased. Improving NTP quality is essential to mitigate the resurgence of TB in the HIV era.

Drug resistant tuberculosis in sub-Saharan Africa: An estimation of incidence and cost for the year 2000

Setting: Rwanda Objectives: To evaluate the tuberculosis (TB) drug resistance in Rwanda on smear positive sputa, collected prospectively at the start of the National TB programme, before the start of any treatment or retreatment. To adapt the scenarios of Schulzer et al (1992) to the data from Rwanda, in order to obtain an estimation of the number of drug resistant and multi-drug resistant (MDR) TB cases expected by the year 2000. Design: A total of 298 specimens (236 randomly selected new cases and 62 retreated cases), collected between January 1991 and June 1993, were sent to Belgium in 1% cetylpyridinium chloride. Drug resistance was determined using the proportion method. Results: MDR, i.e. resistance to at least rifampicin (R) and isoniazid (H), was observed in 3 (1.3%) out of 236 new cases and in 4 (6.5%) out of 62 retreated cases. For new cases, single drug resistance to H, R and ethambutol (E) was 3%, 0.4% and 4.2% respectively; for retreated cases it was 14.5%, 1.6% and 6.5% respectively. Based on the estimate of the size of the TB problem in sub-Saharan Africa by the year 2000 (Schulzer), we calculated that the region should expect between 15 543 and 223 417 cases of MDR, all forms combined (between 2.3 and 32.7 per 100 000 inhabitants), by the end of the century. Conclusion: The results from Rwanda during the period studied do not appear dramatic. However, for some other developing countries, they may just represent the tip of the iceberg. Rapid recognition of resistance to the major antituberculosis agents is essential for control of TB. Integration of an MDR increase factor into the TB budget would not dramatically increase the total TB budget. Our data urgently point to the need for drug resistance surveys, followed by continuous drug resistance monitoring in high TB prevalence areas.

Tuberculosis and HIV infection in sub-Saharan Africa.

To review the epidemiologic, clinical, and pathological characteristics and the public health implications of human immunodeficiency virus (HIV)-associated tuberculosis in sub-Saharan Africa. Published medical literature (English and French) and proceedings of international and African conferences on the acquired immunodeficiency syndrome (AIDS). Selection by the authors of articles most pertinent to HIV infection and tuberculosis in Africa and internationally. Direct reporting of quantitative data (eg, HIV seroprevalence levels) and of qualitative descriptions and conclusions from selected literature. High rates (20% to 67%) of HIV infection in patients with tuberculosis have been reported from East, West, Central, and Southern Africa. An increase in tuberculosis cases has been reported at the same time as the emergence of AIDS in several countries. Autopsies in Abidjan, Ivory Coast (Côte d'Ivoire), have shown tuberculosis as the most frequent opportunistic infection in patients dying of AIDS. Clinical differences in patients with tuberculosis who were HIV-positive and HIV-negative are reviewed, the most important being a greatly increased mortality rate in HIV-associated disease. Access to HIV testing is required for firm diagnosis, for clinical care and counseling, and for public health surveillance. The epidemiology of tuberculosis has been profoundly influenced by the epidemic of HIV infection in sub-Saharan Africa. Greatly increased human and material resources are required for this neglected problem in international health.