John M. Grange

The global emergency of tuberculosis: what is the cause?

The treatment of tuberculosis is cheap and highly effective, yet worldwide the disease remains a serious cause of illness and death; so serious as to have been declared a ‘global emergency’ in 1993. It is principally a disease of poverty, with 95% of cases and 98% of deaths occurring in developing countries. The incidence of tuberculosis is increasing worldwide, partly due to poverty and inequity and partly to the HIV/AIDS pandemic, which greatly increases the risk of infection proceeding to overt disease. Around 30% of AIDS-related deaths are due to tuberculosis. The emergence of multidrug resistant tuberculosis (MDRTB) is an increasing threat to tuberculosis control. Although treatable with alternative drugs, the cost is enormous and, accordingly, not undertaken in many poor nations. While the overall global incidence of MDRTB is low, it occurs in certain ‘hotspots’ including Russian prisons. Due to adverse socio-economic factors, London has not escaped the general rise in incidence and, without the introduction of active control strategies, there could be a serious epidemic as occurred in New York City ten years ago which required an enormous financial outlay for its control. In view of the global emergency of tuberculosis, the WHO ‘Stop TB’ campaign has called for the universal adoption of its directly observed therapy, short course (DOTS) strategy. Also, through the Massive Effort Against Diseases of Poverty, several international agencies are urging the establishment of effective control programmes worldwide. London should take the lead and set an example.

Treatment of tuberculosis: present status and future prospects

Over recent years, tuberculosis (TB) and disease caused by human immunodeficiency virus (HIV) have merged in a synergistic pandemic. The number of new cases of TB is stabilizing and declining, except in countries with a high prevalence of HIV infection. In these countries, where HIV is driving an increase in the TB burden, the capacity of the current tools and strategies to reduce the burden has been exceeded. This paper summarizes the current status of TB management and describes recent thinking and strategy adjustments required for the control of TB in settings of high HIV prevalence. We review the information on anti-TB drugs that is available in the public domain and highlight the need for continued and concerted efforts (including financial, human and infrastructural investments) for the development of new strategies and anti-TB agents.

Impact of vaccinations and infectious diseases on the risk of melanoma—evaluation of an EORTC case–control study

A significant correlation between a reduced risk of melanoma and BCG and vaccinia vaccination in early childhood or infectious diseases later in life has already been reported from the FEBrile Infections and Melanoma (FEBIM) multicentre case-control study. This correlation is further evaluated in this study based on 603 incident cases of malignant melanoma and 627 population controls in six European countries and Israel by means of a joint analysis of the influence of vaccinations and infectious diseases. In addition, the previously unconsidered impact of influenza vaccinations is evaluated for the whole study population. The strong effects of the frequently given BCG and vaccinia vaccinations in early childhood, as well as of uncommon previous severe infectious diseases, were apparently not cumulative. With the Odds Ratio (OR) being set at 1 in the absence of vaccinations and infectious diseases, the OR dropped to 0.37 (95% Confidence Interval (CI): 0.10-1.42) when subjects had experienced one or more severe infectious diseases, associated with a fever of > 38.5 degrees C, and had not been vaccinated with BCG or vaccinia. The OR was 0.29 (CI: 0.15-0.57) in those who had had a severe infectious disease and were vaccinated with either BCG or vaccinia and 0.33 (CI: 0.17-0.65) for those with 1 or more severe infectious diseases and who had received both vaccinations. We conclude that both vaccinations as well as previous episodes of having a severe infectious disease induced the same protective mechanism with regards to the risk of melanoma. Because of a masking effect by the vaccinia vaccination, the protective effect of the BCG vaccination and of certain infectious diseases against cancer has remained undetected. The vaccinations contributed more to the protection of the population than a previous episode of having an infectious disease. In view of the termination of vaccinations with vaccinia in all countries and of BCG in many of them, these findings call for a re-evaluation of vaccination strategies.

Viewpoint: Scientific dogmas, paradoxes and mysteries of latent Mycobacterium tuberculosis infection

Worldwide, there are nearly 10 million new cases of active TB and 1.8 million associated deaths every year. WHO estimates that one‐third of the world’s population is infected with Mycobacterium tuberculosis (Mtb), forming a huge latent Mtb global reservoir. This renders the prospect of ever eliminating Mtb from the human race almost impossible. Several controversial issues regarding host‐pathogen interactions and existing prevention and eradication strategies for latent Mtb infections need to be critically re‐examined. In this viewpoint, widely held assumptions on Mtb latency and isoniazid monotherapy and chemoprophylaxis are challenged. We highlight the need for future research to resolve these issues and to develop evidence‐based strategies for better understanding of equilibrium and escape of Mtb in the human body, eventually leading to global recommendations for elimination of the latent Mtb state through informed policy and practice. Until such strategies and policies are realized, WHO and TB experts will have to settle for global TB control rather than eradication.

The use of mycobacterial adjuvant-based agents for immunotherapy of cancer

A heat-killed preparation of Mycobacterium vaccae (SRL172) has been shown, in recent studies, to be effective in the treatment of adenocarcinoma of the lung and renal cell cancer. It is postulated that the mechanisms of this form of immunotherapy is, at least in part, due to immune regulation, reflected in the selective enhancement of Th1 and down-regulation of Th2 T cell activity. These beneficial effects are attributed to the ability of adjuvants in the bacterial cell walls to modify and optimise the response to antigens shared by the bacteria and stressed host tissues, resulting in the destruction of cancer cells by programmed cell death or apoptosis. The M. vaccae-induced apoptosis appears to be most effective against carcinomas, perhaps especially those of glandular tissue, in contrast to pyrexia-induced necrosis which is most effective against tumours of mesodermal origin. In view of the great range of adjuvants, especially in the genus Mycobacterium and related genera, it may prove possible to develop a range of immunotherapeutic agents with useful activity against a wide range of cancers.

Tuberculosis in disadvantaged groups.

Tuberculosis remains predominantly a disease of the disadvantaged and marginalized. The incidence of the disease is increasing in many industrially developed countries, particularly among the poor, ethnic minorities, prisoners and other institutionalized persons, and the socially isolated and hard to reach groups. Strengthening of the tuberculosis services is required to care for these groups. Millions of people in the developing nations are disadvantaged by poverty and inequity, and recent health sector reforms have not always been entirely in their interest. A further serious problem is the HIV/AIDS pandemic, which not only facilitates the spread of tuberculosis but, by its associated stigma, leads to delayed treatment seeking and poor adherence to therapy. In recent times, emphasis has moved away from didactic principles of tuberculosis “control” to community-and patient-centered health services, based on analysis of local factors affecting case finding and adherence to therapy.

Tuberculosis in association with HIV/AIDS emerges as a major nonobstetric cause of maternal mortality in Sub-Saharan Africa.

Every year, approximately 250 000 African women die during pregnancy, delivery, or the puerperium. Maternal mortality rates due to infectious diseases in Sub‐Saharan Africa now supersede mortality from obstetric causes. Evidence is accumulating that tuberculosis associated with HIV/AIDS, malaria, sepsis, and other opportunistic infections are the main infectious causes of maternal deaths. Screening for these killer infections within prenatal healthcare programs is essential at this stage to prevent and treat causes of maternal mortality. The combination of proven effective interventions that avert the greatest number of maternal deaths should be prioritized and expanded to cover the greatest number of women at risk, and incorporated into a “prophylaxis and treatment community package of care.” The effectiveness of these “packages of care” will need to be determined subsequently. Maternal deaths from tuberculosis are now on the increase in the UK, and due diligence and watchful surveillance are required in European prenatal services.

Multidrug-resistant tuberculosis—can the tide be turned?

Despite continued control efforts, tuberculosis remains a leading cause of illness and death worldwide, with more cases today than at any previous time in history. Not only is there a global increase in the disease itself, there is a worrying rise in the number of cases resistant to the two principal antituberculosis drugs, isoniazid and rifampicin--so called multidrug resistance.

Reflections on the white plague.

Tuberculosis continues to be one of the leading causes of morbidity and mortality from infectious disease worldwide. When WHO declared tuberculosis a global emergency in 1993, the initial response from the international community was sluggish and inadequate. A resurgence of the disease, the emergence of multidrug-resistant and extensively drug-resistant strains, and the detrimental effect of the concurrent tuberculosis and HIV/AIDS epidemics on national control programmes in sub-Saharan Africa have all occurred despite the availability of effective combination treatment regimens. On the positive side, funding agencies and donor governments are at long last taking a serious interest in investing in tuberculosis research priorities defined by the Stop TB Partnership. Although this investment introduces optimism for eventual control of the White Plague, past failures remind us not to be complacent.

The tuberculosis pandemic: implications for health in the tropics

Among infectious diseases, tuberculosis is the leading cause of death, killing around 3 million people each year. Most cases occur in young adults but it is also a major cause of illness and death in children. The problem has been exacerbated in recent years by the HIV pandemic and by the emergence of multidrug resistance. Co-infection with HIV greatly enhances the risk of overt tuberculosis and in 1999 it is expected that tuberculosis will account for 30% of the predicted 2.5 million AIDS-related deaths. By inducing clinically and radiologically atypical forms of tuberculosis, and by increasing pressure on diagnostic facilities by sheer numbers, serious diagnostic difficulties are increasingly occurring in both adults and children in the tropics. At the present time, 2% of all cases of tuberculosis are multidrug resistant but, as the treatment of such cases is often grossly inadequate in many tropical countries, their frequency will doubtless grow. There are no simple solutions to the global emergency of tuberculosis: clearly there is a need for better use of available control measures but there is also a need to reach a much clearer understanding of the underlying immune phenomena in this disease so as to develop more effective vaccines and therapeutic agents. Finally, it cannot be ignored that tuberculosis is a disease of poverty--95% of cases and 98% of deaths due to it occur in the developing nations--and thus a major control measure is a resolution of the gross inequities in health care provision both between and within nations.