Tuberculosis

TUBERCULOSIS

Tuberculosis (TB) is a major cause of death and morbidity worldwide, particularly where poverty, malnutrition and poor housing prevail. Human infection is acquired by inhalation of Mycobacterium tuberculosis or M. bovis. Tuberculosis is primarily a disease of the lungs, causing chronic infection of the lower respiratory tract, but may spread to other sites or proceed to a generalized infection (miliary tuberculosis). Active disease can result either from a primary infection or from a subsequent reactivation of aquiescent infection. Following inhalation, the mycobacteria are taken up by alveolar macrophages where they survive and multiply. Circulating macrophages and lymphocytes, attracted to the site, carry the organism to local lymph nodes where a cell-mediated immune response is triggered. The host, unable to eliminate the pathogen, contains the bacteria within small granulomas or tubercles. If high numbers of mycobacteria are present then the cellular responses can result in tissue necrosis. The tubercles contain viable pathogens that may persist for the remaining life of the host. Reactivation of the healed primary lesions is thought to account for over two-thirds of all newly reported cases of the disease.

The incidence of TB in the UK declined 10-fold between 1948 and 1992, to just over 5000 new cases being notified each year. Those most at-risk include pubescent children, health service staff and individuals intending to stay for more than 1 month in countries where TB is endemic. However, since 1994 there has been a gradual increase in the number of notified cases in England and Wales to approximately 7000 new cases per year which can be associated with age group (20-45-year-olds more susceptible), sex (males slightly more susceptible), geographical region and ethnicity. The rise in notifications can be attributed to a number of different factors, including increased immigration from countries where TB is more prevalent, crowded conditions (e.g. prisons, hostels, wards, etc.), a greater number of susceptible individuals now in society (e.g. substance abusers, immuno-compromised individuals) and limited training for GPs in recognizing the symptoms of TB. Fortunately this latter issue has now been addressed, along with the re-emergence of TB research programmes.

A live vaccine is required to elicit protection against TB and both antibody and cell-mediated immunity are required for protective immunity. Vaccination with BCG (bacille Calmette-Gu érin), derived from an attenuated M. bovis strain, is commonly used in countries where TB is endemic. The vaccine was introduced in the UK in 1953. Efficacy in the UK has been shown to be over 70%, with protection lasting at least 15 years. In other countries, where the general state of health and well-being of the population is less than in the developed world, the efficacy of the vaccine has been shown to be markedly lower than this.

Because of the risks of adverse reaction to the vaccine by individuals who have already been exposed to the disease, a sensitivity test must be carried out before immunization with BCG. A Mantoux skin test assesses an individual’s sensitivity to a purified protein derivative (PPD) prepared from heat-treated antigens (tuberculin) extracted from M. tuberculosis. A positive test implies past infection or past, successful immunization. Those with strongly positive tests may have active disease and should be referred to a chest clinic. However, many people with active TB, especially disseminated TB, seroconvert from a positive to a negative skin test. Results of the skin test must therefore be interpreted with care.

Much debate surrounds the use of BCG vaccine, a matter of some importance, considering that TB kills around 3 million people annually and that drug-resistant strains have emerged. Although the vaccine has demonstrated some efficacy in preventing childhood TB, it has little prophylactic effect against post primary TB in those already infected. One solution is to bring forward the BCG immunization to include neonates. Immunization at 2-4 weeks of age will ensure that immunization precedes infection, and also negates the requirement for a skin test. Passive, acquired maternal antibody to TB is unlikely to interfere with the effectiveness of the immunization as immunity relates primarily to a cell-mediated response. Alternative strategies involve improvement of the vaccine, possibly through the introduction into the BCG strain of genes that encode protective antigens of M. tuberculosis.

The current UK policy (introduced in September 2005) is to reserve the BCG vaccine for those considered to be at highest risk based on location or familial links to TB endemic areas. As such, this targeted approach will seek to immunize all infants in areas where the incidence of TB is 40 or more per 100 000; infants with at least one parent or grandparent who was born in a country with a TB incidence of 40 or more per 100 000; previously un-vaccinated new immigrants from high-prevalence countries for TB; those who have lived in the same household or had prolonged, close contact with someone with TB; or at-risk workers (doctors, nurses, social workers, etc.).