An analysis of factors determining the risk of disease following infection must take into consideration both the virulence of the causative organism and the immune defenses of the infected person. In this context it is important to determine whether those who remain healthy have a genetically endowed high level of resistance to tuberculosis or whether resistance is affected by environmental or other exogenous factors that are subject to change and, perhaps, to modification or correction.

The mechanisms of virulence of the tubercle bacillus are poorly understood and, although determinants of virulence have been described, it has proved very difficult to establish the relative importance of these in human tuberculosis. Although
experimental animals such as the guinea pig or rabbit have been used to quantify the virulence of tubercle bacilli, much doubt has been shed on the relevance of these studies to human infection. For example, some strains of Mycobacterium tuberculosis originating from South India and others that are resistant to isoniazid are of very low virulence in the guinea pig yet, apparently, fully virulent in humans.


The relative impact of innate, largely genetically determined, specific and non-specific immune defences and the impact of  the environmental factors must be considered in relation to the disease ratio. Natural selection The concept that the process of natural selection was responsible for the sharp decline in the incidence of tuberculosis in
the developed nations over the 20th century has been widely debated. While some argue that better social conditions were responsible for the changes, others, citing the evidence presented above, maintain that social improvements do not give the
complete explanation for the observed declines. The possibility that natural selection played at least some role in this decline in the pre-chemotherapeutic era cannot therefore be dismissed. It has been postulated on the basis of a hypothetical
model of the rise and fall of tuberculosis in a previously uninfected population that, following the introduction of the disease into a community, the incidence would increase rapidly over the first half century to several hundred cases per hundred thousand of the population annually. It would thereafter decline to around 5/100 000 some 150 years after the peak of  incidence, a decline of 4.7% annually. This predicted course of the disease closely reflects the observed epidemiological  changes in Western Europe over the previous two centuries.

The global spread of tuberculosis
Different populations across the globe are at different stages in the pandemic of tuberculosis. The white population of  Western Europe,t after a 200 year history of the disease, would appear to be at or near the end of the epidemic, but the populations of the developing nations are only half way down the slope with a "natural" annual incidence of tuberculosis of 100-200/100 000. It has been suggested therefore that tuberculosis occurred sporadically in dispersed populations well adapted to their environment but increased substantially in prevalence when these peoples were subjected to stress and overcrowding. Major social change may therefore be more important than natural genetic selection in determining the observed behavior of tuberculosis in a population.

Acquired factors affecting susceptibility to tuberculosis

Any condition which compromises the integrity of the immune responses predisposes to the development of active tuberculosis and to an adverse outcome. In recent years, HIV infection has emerged as the most important and prevalent predisposing factor
for tuberculosis worldwide. Other immuno-compromising factors include congenital immuno-deficiencies, high dose steroid therapy, cytotoxic drugs, immunosuppressive drugs, protein-calorie malnutrition, acute viral infections especially measles in
children, schistosomiasis, renal failure, liver failure, haematological malignancies and other cancers, diabetes mellitus, and local lung damage due to smoking or industrial dust disease.


Protective immunity and delayed type hypersensitivity

In addition to genetic factors, there is increasing evidence that the pattern of immune reactivity in tuberculosis, leading to protection or tissue destroying hypersensitivity, is influenced by environmental factors. Several studies have shown that the outcome of infection by M tuberculosis is dependent on the maturation pattern, Th1 and Th2, of the helper T cells.
Protective immunity is associated with Th1 cytokine mediated macrophage activation and granuloma formation but a superimposed Th2 response elicits tissue destroying delayed hypersensitivity reactions. This crucial difference in immune reactivity is
related to the cytokine regulated effect of tumour necrosis factor (TNF) on the tissues at the site of the lesions. Thus, while TNF plays a key role in the development of the granuloma in a Th1 mediated response, Th2 associated cytokines, by a
direct or indirect mechanism, render tissues at the site of the immune reaction extremely sensitive to killing by TNF. This  pattern of reactivity causes massive tissue necrosis and pulmonary cavity formation.

It is therefore important to determine what factors are responsible for the undesirable superimposition of the Th2 component in the immune responses in tuberculosis. The Th2 component may be induced by endogenous hormonal factors, particularly the
balance between the two major adrenocortical hormones, glucocorticoids and dehydro-epiandrosterone (DHEA). Glucocorticoids favour Th2 maturation and, as levels are increased by stress, this could provide an explanation for the claims that stress
reduces resistance to tuberculosis. In addition, there is evidence that Th1 and Th2 responses to M tuberculosis are determined by immunologically effective contact with antigens of environmental mycobacteria. The nature and extent of such contact varies from region to region and is thought to be responsible for the very significant regional differences in the protective efficacy of BCG.

Variations in the incidence of tuberculosis within geographical regions

In addition to the genetic and environmental factors contributing to resistance and susceptibility to tuberculosis, consideration must be given to the socioeconomic factors responsible for the very great differences in the incidence of tuberculosis within countries. Tuberculosis has long been considered a disease of the poor and socially disadvantaged. A radiographic survey of homeless people seeking temporary shelter over two Christmas periods in London revealed active tuberculosis in 2% of them.A study in Liverpool showed that tuberculosis was closely associated with deprivation throughout the electoral wards of the city,and in Birmingham tuberculosis was found to be linked to poverty in the indigenous white population but not among the Asian population.

In general, higher rates of tuberculosis are seen in recent immigrants than in those who have been resident in the UK for longer periods. Within the Indian subcontinent ethnic group, rates in those aged 35 years or over and resident in the country for less than 5 years before presenting with disease were over 1000/100 000, and a recent survey has shown that rates in those classified as Black African now exceed those from the Indian subcontinent ethnic group.

The relatively high incidence of extrathoracic manifestations of tuberculosis in the Indian subcontinent ethnic group has been referred to above. This has not been adequately explained. As a similar high proportion of non-respiratory disease is observed in AIDS patients, it has been postulated that immigration might be associated with some form of acquired immunodeficiency. One distinct possibility is the lowering of serum vitamin D (25 hydroxycholecalciferol) levels up to tenfold that occurs in immigrants from developing countries after arrival in the relatively sunless United Kingdom . This
vitamin is an important mediator of macrophage activation which is central to protective immunity in tuberculosis; indeed,this explains the claimed success of cod liver oil and sunlight in the treatment of tuberculosis in the pre-chemotherapeutic era. 53 Thus, infected people might have latent tuberculosis while in their own country but develop active disease when their vitamin D levels fall.

The relationship between vitamin D and susceptibility to tuberculosis is, as mentioned above, affected by genetic factors. In
India a study of the wives of men with tuberculosis suggested that the homozygous TT vitamin D receptor (VDR) genotype was associated with resistance and the tt genotype with susceptibility to the disease. The expression of the impact of VDR genotype may be accentuated by vitamin D deficiency. This was the case in a predominantly vegetarian population of Gujarati Asians resident in west London . Those with serum vitamin D levels too low for detection had an almost tenfold increase in their risk of active tuberculosis.Although there was no independent association between the VDR genotype and the risk of tuberculosis, the combination of the TT/Tt VDR genotype and vitamin D deficiency was associated with disease and a combination of the tt genotype and undetectable serum vitamin D had a fivefold stronger association with disease

Factors influencing bacillary persistence

One of the most important factors in the development of tuberculosis is the poorly understood ability of the tubercle bacillus to persist in the tissues for long periods of time. Very recent evidence has cast interesting new light on the factors which may influence bacillary persistence. The use of polymerase chain reaction (PCR) to detect DNA specific for M tuberculosis in cadaveric lungs has shown that this bacterium can persist intracellularly without histological evidence of tuberculosis lesions. M tuberculosis DNA is situated, not only in macrophages, but also in other cells not normally regarded
as phagocytic such as type II pneumocytes, endothelial cells, and fibroblasts. These cells, rather than the healed granuloma,might offer protected sites for persistent bacilli. These findings contradict the dominant view that latent organisms exist in old classic tuberculosis lesions and have relevance to strategies aimed at eliminating latent and persistent bacilli.