The complexity of tuberculosis

Among all the infectious diseases of humans those causing the most deaths at present (the so-called big three) are AIDS, tuberculosis and malaria. Tuberculosis is an illness which is not so present in the consciousness of inhabitants of the developed world since its main effects are in developing countries. It is important to realize that about 95 % of TB infections are latent (asymptomatic) and that they often become active after many years. About one third of the population of the world is infected with the pathogen Mycobacterium tuberculosis and this represents a massive silent health problem. For these figures and a general introduction to tuberculosis see the lectures of John McKinney at http://ascb.org/ibioseminars.

McKinney points out two differences between tuberculosis and most other infectious diseases. One is that the relevant timescales for the epidemiology are much longer (many years rather than a few weeks). Another is that TB does not confer lasting immunity so that even if someone has completely recovered from the disease they can be affected by it again. He discusses this in the context of standard mathematical descriptions of epidemics such as the SEIR model mentioned in a previous post.

There is a vaccine against TB which has been around for the best part of a century, the BCG vaccine. McKinney gives a list of its good properties which few vaccines against any disease can compete with. Unfortunately it has a key weakness – it is very often ineffective. What exactly goes wrong does not seem to be understood but given the lack of lasting immunity under natural conditions it is not surprising that there is a problem. If a vaccine for TB almost always worked it would be making the human immune system react more effectively than it does in response to a real infection and this is a tall order.

Most cases of TB can be cured using antibiotics but the treatment is very demanding, combining several drugs and lasting several months. It is hard to ensure that patients finish the whole course of treatment and this is particularly difficult in the context of developing countries. Why is so difficult to combat M. tuberculosis using antibiotics? One reason seems to be that there are different populations of the bacterium and that any one drug is only effective against some of these populations. In his lectures McKinney discusses what might distinguish these populations. It is not enough to suppose that it only depends on the different niches available in the body. Even in an infection of a cell culture heterogeneity in the properties of the bacteria can be observed. If a particular drug is applied the time dependence of the population indicates the presence of more than one type of bacteria being killed at different rates. McKinney suggests that the explanation of this may require a stochastic component. Fluctuations in the state of individual bacteria may lead to some of them entering a dynamical process which takes them to another state. This may lead to populations of bacteria in two distinct states. Modelling this kind of behaviour requires something more sophisticated than the ODE of standard population dynamics.

Another interesting point mentioned by McKinney is the interaction between TB and AIDS. In one direction this is easy to understand. In the presence of AIDS the compromised immune system is not capable of controlling a latent TB infection and the disease is activated. The other direction is more mysterious. Apparently the presence of a TB infection speeds up the evolution of an HIV infection to the state where AIDS occurs.

Added note: a new TB vaccine which is a modification of the BCG vaccine has just started phase I clinical trials in humans. More information can be found in a press release of the Max Planck Society.

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