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TUBERCULOSIS AS A GLOBAL PROBLEM OF BIOLOGICAL SECURUTY

Professor V. Gergert

Central Research Institute of Tuberculosis

Could tuberculosis be considered a disease, presenting a major threat for the biological security of the population?

There exists no unequivocal answer to this question.

The mere fact of discussions, arising round this problem, emphasizes not only the complexity of the problem, but also the theoretical possibility of developing or even deliberate construction of this dangerous situation.

Comparatively slow development of tuberculosis, as compared to many other highly dangerous diseases, as well as far non-absolute susceptibility of humans to this infection, make it difficult to imagine the way of it`s usage as a weapon. Nevertheless, there exists a theoretical possibility of attempting to deliberately induce an epidemic in a certain region of the world or a given country.

There is no need in detailed description of the ways of enhancing the aggressiveness of mycobacteria and in this way accelerating the tuberculosis disease course, leading to death. Rather it is reasonable to feature some simple arguments, favoring the idea of it`s feasibility.

Mycobacterium tuberculosis can be viewed as a source of hazard because of it`s high contagious capacity. Two thirds of the world population are infected via alimentary rout or inhaled aerosol.

It is well known, that tuberculosis can progress in the form of a rapidly and unrestricted disease, known as rapid consumption. This form of tuberculosis was most common in the so called pre-antibacterial era, but it becomes increasingly frequent at present. As a rule it`s progress is accompanied by rapid and massive spread of caseose, multiple areas of lung tissue destruction, high level of toxicity and lethality.

This fulminant infection could be, in part, accounted for by the genetics of the host macroorganism. Specifically, strains of mice, resistant and susceptible to mycobacterial infection were established, and certain loci, responsible for susceptibility were identified. In humans infection with mycobacteria and the disease progression were shown to be associated with several genes encoding for HLA class I and II specificities.
Rapid progression of the disease could also be associated to pathogenicity, virulence and the amount of mycobacteria in the infecting dose. These features of the pathogen can influence the host-pathogen relationship, elevating the threshold of susceptibility to tuberculosis.

Are there any ways for inducing a high level of virulence in mycobacteria? Very probably yes. And here is an example to confirm this statement.

The widely known BCG strain of mycobacteria was obtained following multiple passages of a virulent mycobacterium in a culture medium, containing beef bile, that is long term growing in quite unfavorable conditions - to diminish the bacillus virulence.

Hence, one can assume, that it is possible to increase the bacillus virulence by growing the pathogen in optimal environmental conditions, for instance, by making serial passages in animal species with absolute susceptibility to tuberculosis. Obviously, wild strains of mycobacteria can strengthen their virulence by natural selection in infected animals and humans, genetically highly susceptible to tuberculosis. The high virulence being reached, the bacilli can spread widely by infecting hosts with genetically determined low susceptibility.
Molecular genetic technologies have presented approaches to determine the genomic regions, differing in virulent and avirulent strains and BCG. These regions could be an object of precise analysis in any attempt to enhance the bacillus virulence.

Studies on variations in mycobacterial genotypes are under way. These could give the possibility of choosing the most aggressive family of mycobacteria. Though no reliable data on association of virulence with differing genotypes are available as yet, it is known, that mono- and multidrug resistance are more frequent among W and Beijing genotype mycobacteria - the two strains mostly widespread in Russia, and there is some evidence of severe disease prevalence in groups of patients, infected with these strains.

Additionally, the latter genotype is widespread in high prevalence countries of South-East Asia, in some territories of Russia - Samara district and Tuva Republic ( up to 70%)- and in prisons, where morbidity and mortality have reached immensely high levels.

These data reconsidered from the viewpoint of biological security, mycobacteria bearing the mentioned genotypes could be the first line candidates to be used with the aims of aggression.

Enhanced severity of active tuberculosis also depends on a number of factors of the host resistance, including immunologically associated.

Low effectiveness of protective immunity gives basis not only for tuberculosis gaining severity, but also for the development of drug resistance in mycobacterial strains.

The effectiveness of protective immunity , in it's turn, is associated with numbers of T-helper type I cells, profile of secreted cytokines and enhanced cytopathic effects.

The productive immune response appears disturbed in cases of overexpansion of T-helper type 2 cells. This is illustrated by low level of protective immunity and accumulation of cytokines, in part, TNF, promoting the development of necrosis and tissue destruction, which altogether leads to progression of tuberculosis.

The details of the regulatory mechanisms are unclear, but they could include dependence on mycobacterial antigen processing by macrophages and presentation to lymphocytes. Certain mycobacterial antigens are capable of ruling the immune response preferentially to activate T-helper 1 or T-helper 2 type cells. This is an important factor, able to modulate resistance.

Social and ecological-environmental factors tend to suppress resistance to mycobacterial infection. Crisis in the economy of the country was one of the reasons for transition of most part of the population into low-income group.

Unsatisfactory ecology and local ethnic conflicts, leading to massive migration of population groups, favor the development of conditions, necessary for widespreading the infection by most virulent mycobacterial strains.
As a result we witness an established milieu, favorable for the development of tuberculosis epidemic in the country. This could be illustrated by epidemiologic data on tuberculosis in Russia in recent 10-12 years.

Table 1. Morbidity due to tuberculosis in Russia

Years 1992 1995
1998
2000
2002
Cases per 100000 pulsation 35,8 57,8 76,0 90,7 86,1

In 2000 a 2.5 times rise in morbidity was observed. Morbidity in the adult group was as high as 103,0 indicating the start of an epidemic in this age group. The highest level of morbidity - 153,4 - was found in the most socially and economically active age group ( 25-34 years age).

Table 2. Mortality due to tuberculosis

Years 1991
1994
1996
2000
2002
Cases per 100000 pulsation 8,1 14,4 17,8 20,5 21,5

Mortality increase reached 2,6 times.
The most unsatisfactory regions by morbidity and mortality ( 127,8 and 31,9 ) are
the Ural, , the Far East and Siberia Federal Districts.

Morbidity and mortality in prisons are really threatening - 2783,0 ( 31,6 times high as compared to the mean figures for Russia ) and 137,7 ( 8,8 times high ).

The situation with tuberculosis is even more worsened by the fact that the scope of the population, regularly undergoing prophylactic examination for tuberculosis, diminished from 75,4% in 1985 to 53,8% in 2002.

Failure of early detection leads to ineffective treatment for tuberculosis. Thus, the percentage of patients with closure of the cavities as a result of treatment diminished from 83% to 63% and abacillation of patients - from 90% to 75% during last 14 years. Additional quantities of patients with fibrotic-cavity tuberculosis (which indicates transition of the disease into a chronic form) appear every year as a consequence of inadequate treatment. This additional cohort of chronic patients increases each year. Thus, in 1992 transition of tuberculosis into a chronic form occurred in 6779 patients, while in 2001 this occurred in 22731 patient.

The proportion of cases with primary infection with drug resistant mycobacteria is also growing. The mean value for Russia is 8,9%, while in separate regions each second patient gets infected with drug resistant bacilli (50,5% in Krasnoyarsk region), which makes therapy still more difficult.

Summarizing conclusions.

The problem of tuberculosis in Russia has reached a highly dangerous level, illustrated by signs of epidemic, developing in individual regions.

Ethnic conflicts and migration of the population tend to increase the rate of infection.
The aggressiveness of mycobacteria being increased, tuberculosis affects more individuals, supposed to be genetically more resistant.

Low standards of life and unsatisfactory ecology diminish resistance to tuberculosis in the population. Clinical course of contemporary tuberculosis has obtained features of the disease in the pre-antibacterial era.
Treatment of tuberculosis is often ineffective.

The proportion of newly detected patients infected by drug resistant mycobacteria, is growing.

Finally, for occasional (or, maybe non-occasional) reasons, Russia, together with some other countries represents a convenient base for the development and large scale spread of tuberculosis epidemic.

Urgent measures needed to change the situation.

Many of these measures are well known.

Rise in the standards of life of the citizens is a prerequisite to building up a system of measures, preventing tuberculosis spread. This goal is difficult to achieve since it is associated with the level of economy of the state. Possibly, these measures should be applied first to smear-positive patients.

Prophylaxis of tuberculosis is certainly a very important problem. Special attention should be paid to the development of a chemical or a more efficient live vaccine. It is obvious, that chemical vaccines should contain a complex of immunodominant antigens, including, possibly, antigens, associated with virulence factors.

Early detection of tuberculosis is necessary for preventing the growth in the rate of newly diagnosed developed forms of tuberculosis, epidemiologically dangerous and presenting problems during therapy. This approach should include intensified case finding on the one hand, and developing a simple, reproducible and time saving screen tests for tuberculosis.

Construction of a range of novel antimycobacterial drugs. This is really necessary in connection with the increased rate of infection by drug resistant mycobacteria and by the known fact that existing drugs can promote selection of drug resistant mycobacteria in the patient.

It is highly important to develop measures and drugs aimed at stimulation of host resistance to tuberculosis.

It is necessary to develop and support research in mycobacterial genetics, in part, studies on mutations, leading to altered virulence and inducing drug resistance in mycobacteria.

Search for immunodominant mycobacterial antigens is important for developing new vaccines and diagnostic screen tests for tuberculosis. This field is not very effectively explored, hence additional efforts are necessary here.

Studies on the mechanisms and expression of genetic differences in host resistance to tuberculosis.

Studies on the mechanisms of local protective responses in tuberculosis. This could give basis for regulation of these responses through immunomodulating treatments, which is especially important in patients with HIV infection.

These are some of the numerous ways to attract all possible efforts (including financial ones) aimed at successful struggle against tuberculosis in Russia and worldwide.

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Proceedings of First Russian Workshop on Biological Security
Copyright © Committee of Scientists for Global Security and Arms Control