The challenge of tuberculosis.

Dr. P.D.O.Davies, Consultant Chest Physician, Director Tuberculosis Research and Resource Centre, (TRRU), Cardiothoracic Centre, Liverpool L14 3 PE.

You are probably expecting the standard medical talk at a medical conference with lots of slides and lots of data under subdued lighting and soporific conditions. Well you're not going to get it.

I visited a TB programme in Tomsk, Siberia a few years ago and gave two talks. One was in a teaching hospital with full facilities, slide projector, screen, blackout ,microphone; the works. The second was in a basic field hospital up country with nothing and I gave the talk with no visual aids at all, just sentence by sentence translation. The ex-army driver who came to both lectures said the second was better because he could see my eyes. Perhaps he meant that if I got boring he could get a better shot at me. Anyway today your going to see my eyes, not my slides.

The most important medical challenge facing tuberculosis in this country today is an ignorant medical profession. How was it that last year saw an unprecedented number of outbreaks of tuberculosis, one of which with over 70 secondary cases (and still counting I gather)was the largest since we had specific chemotherapy? Why is it that patient after patient whom I see in Liverpool with a diagnosis of TB has at some point been told by a doctor that they do not have TB? One was even told that nobody gets TB these days. Why is a missed diagnosis of tuberculosis the second commonest cause of litigation after PE from a respiratory cause?
It is because it is tuberculosis is missed because it is not considered.

There are a number of reasons for this. First it is becoming less common across the country as a whole. At the last Notification survey more local authorities were TB free than ever before. The increase in total cases, from 5,000 to 7,000 in England and Wales since 1987 is confined to certain areas of the country particularly London. So fewer doctors are experienced in recognising and managing the disease. Even among specialists in respiratory medicine there is a wonderful blindness to TB.
A lady will be paraplegic for life because a consultant chest physician missed primary TB. The patient was seen as a contact of a case of TB, had a Grade 4 Heaf but a normal chest x-ray. A few months later she was seen at the same clinic with a pleural effusion. The consultant sent sputum for AFB thus failing to send the important pleural biopsy. The pleural effusion eventually resolved as they nearly always do with primary disease. But almost a year later TB meningitis ensued the permanent after affects of which will be with her for life.
Why was this missed? Because we are failing to train even our specialists who should have expertise in TB.

I was at an advisory appointments committee for a consultant Chest Physician a few years ago. There were three candidates. You can tell from that piece of data that it was a while back. The local boy had done all the right things including an 18 months attachment to a hospital in Australia. As the College Assessor I asked him how much tuberculosis he had seen. Not much, was the answer. His teaching hospital was in a well-healed area of the South of England. Did he think that we were giving our registrars sufficient training in tuberculosis? It is difficult when one sees so few cases was his reply.
I could not help asking him whether he had thought of touching down for a weekend in any of the developing countries he had overflown on his way to Australia. A ward round or clinic at the local hospital could have given him as much experience in TB as he would have for the rest of his life in the DGH he was hoping to get a post in.

Of course he could hardly be blamed for that, but the professor of medicine or post-graduate dean who was advising him in gaining training could have. If that person had thought it was important.
Which brings me to the second reason why TB is being missed as a diagnosis; a wonderful absence of interest by Academic, particularly Respiratory Academic medicine.
I have not counted recently but there are approximately 50 professors of respiratory medicine of whom rather more than half have a principal interest in Asthma. The rest are distributed through cancer, COPD, fibrosis and occupational lung disease. The one Chair for TB with a respiratory interest is confined to a District General Hospital in the North West.
Twenty years ago we were told that asthma was Britain's most rapidly increasing respiratory disease and the number of chairs multiplied. Today TB clearly holds that place and the academic silence is deafening.
Tuberculosis has doubled in London in 12 years, which now contributes more than 40% of UK cases. Why is there such a strong academic presence with an asthma interest? Because that is where the money is and as pharmaceutical companies, looking for diseases of those rich enough to afford the drugs and provide profits, fund most medical research.

The absence of a critical academic mass of expertise in tuberculosis means that there is no independent advice which government can turn to in the event of a crisis. Hence the decision in August to withdraw all supplies of BCG so that for three months it has been impossible to get a BCG vaccination in the UK (and the Republic of Ireland.)

Which leads me to the third reason for missed diagnosis: pharmaceutical interest, or the lack of it.
It is nearly 40 years since the last new drug for tuberculosis was invented; rifampicin. In that time all the drugs in current use for asthma have been invented and in half that time the 20 or so Anti-virals for HIV have come into use. A new consortium for the development of new drugs for TB has recently been convened. It promises a new drug in 10 years. By which time another 20 million people will have died of TB across the world and incidentally about 4,000 in the UK.
One further point on the pharmaceutical industry. Back to last year's outbreaks. In the two most extensive, the initial index cases were misdiagnosed as asthma. How can a doctor mistake TB for asthma. By believing that any cough in a person under the age of 30 must be asthma.
Pharmaceutical companies are responsible for a great deal of post-graduate medical education in the country. I recall advertisements in even the British Medical Journal in the 90s presenting a product for asthma with the caption "Cough, think of asthma." I have never seen an advertisement for a TB drug in this country saying " Cough, think of TB."
A publisher who produces small 70 pages paperback books of notes of topics and diseases recently approached me. To publish they rely on a pharmaceutical grant of about $30,000 so for asthma or COPD there is no shortage of sponsorship. But we are still looking for a company willing to fork out for a TB book.
But one cannot blame pharmaceutical companies for doing the job they are supposed to do. Blame can be attached to institutions and individuals responsible for providing a balanced post graduate educational and scientific agenda.

We are not going to give patients with tuberculosis a fair deal in this country until we find a better way of educating our doctors and allied medical professionals about TB.

The thing about TB, at least infectious TB is that it is very easy to diagnose. All you have to do is send off some sputum and ask the lab to look for Acid Fast bacilli. Next point, as a clinician my ability to diagnose TB is as good as my microbiological colleague or rather the MLSO who does the work. A TB clinician needs to be as close to their microbiological roots as the surgeon is to the anaesthetist. Some smear negative pulmonary disease and quite a lot of non-respiratory disease can be very difficult to diagnose. If you are really worried about TB the rule is the same as in any aspect of medicine, get a specimen for diagnostic purposes and then start treatment. And that specimen is for bacteriology, not histology alone.

What about the Polymerase Chain Reacrtion I hear you ask? Any help? Yes but not a lot.
Consider a patient who we think has TB meningitis. We send off CSF for smear and culture and for PCR and we start to treat. The smear is negative, no surprise there but then it is in 80% of TBM. Then the PCR comes back negative. Do we stop treatment? No we don't because we think it is TBM clinically and we know about false negatives. And finally the culture comes back negative too. Do we stop treatment then. Well 20-50% of series suggest the culture may be negative in TBM so having put our hand to the plough we will probably continue. Of course if the PCR is positive and the culture is positive we feel better a bit earlier than without PCR but what if the PCR is positive and the culture is negative? I doubt whether it would make any difference. What of the smear negative pulmonary disease? I would probably continue to treat in the face of negative PCR and think again if the culture came back negative.
When will a PCR result influence my management? If the smear is positive and the PCR and gene probe for TB is negative. Then I probably have an environmental or "atypical" mycobacterial infection on my hands. That will affect my management in that I will change the treatment and wind down the contact tracing if it has started.

So have there been any decent inventions to help the clinician with management? I like the Rifampicin resistant gene. Actually I hate it but the ability to know about rifampicin resistance in a patient within days of making the diagnosis can be wonderfully helpful in planning treatment and of course in infection control.
So no new drugs on the horizon and certainly no new vaccines but at least we have a way of detecting rifampicin resistance, an entirely man-made disaster rapidly.

What about treatment. Should we use DOTS as WHO says we should. In parenthesis please note DOTS has five components; government commitment, good drug supply, good microscopy, good recording, and last but not least, directly observed therapy.
So should we all use DOTS. DOTS is a means to an end not an end in itself. The end we seek is cure for over 85% of our patients and the prevention of creating drug resistance. If we are achieving 85% or better cure then we are doing well whatever our method. But first do we know our cure rates? In Liverpool we know we achieve over 85% cure or completion using mainly a self-administered regimen with some selective DOTS.
But a small Indian mission hospital I have visited had a 17% completion rate before it started its DOTS under the RNTCP programme. In the first complete year it is heading for 87% completion/cure. If it is broken then fix it and DOTS is that fix.

And where should patient be treated? Well at home of course if at all possible. There was recently a call in London for specialised TB wards which was taken by the media as a call for compulsory detention. The trouble is that we have lost our TB wards. In Liverpool we used to have a nice bungalow in the hospital grounds with individual rooms and the patients could come and go as they pleased as long as they were present for the once daily drugs round. Now we have to house our patients up a tower block with no direct access to the outside. No wonder they abscond and the prospect of compulsory detention is suggested.

And that brings me on to the real challenge of TB the wider world. Since we in Europe and particularly the UK exported the new pandemic of TB to the rest of the world in the early 1800s as a result of industrialisation it has been fluctuating wildly. Now with the increase in population and HIV driven immunodeficiency TB is steadily increasing globally at somewhere between 1.5 and 2% a year. There are 8 to 10 million new cases a year with 2 million deaths. A quarter of these is in India alone. Rates in some African countries exceed 500/100,000 a year.
And that is why TB in this country is increasing: because of migration to and from the developing world where tuberculosis is out of control.

There is some good news. Through WHO drug procurement, TB drugs can now be made more or less free to countries and large Non Governmental Organisations. The cost of drugs is no longer a barrier. But much greater resources are needed if we are to reduce the global mortality and morbidity form tuberculosis.
Again some good news there too. There is the global fund for AIDS, tuberculosis and malaria. (GFATM) A start has been made in recognising the devastation caused by these disease. But the fund is woefully short of money. Less than a tenth of what is needed in the first few years has come forward. Next year there is a $2billion dollar shortfall. But Richard Feacham the Chair of the fund says that TB is the best placed to benefit because through DOTS the TB control progammes have better structure and end points than the other diseases. This is largely due to the scientific expertise of the International Union Against Tuberculosis and Lung Disease and the relevant departments of the WHO. We need to extend the DOTS programme but we also know that DOTS alone will not control TB in the presence of HIV.

The threat of MDR TB is there but perhaps not as great as a few years ago when it seemed ready to engulf the world. It is an enormous problem in some areas, particularly the Russian prison system and parts of the former Soviet Union such as the Balkan states. But evidence is that it is not increasing and is probably not as easily transmitted as the fully susceptible strain.

There has been an appeal for anti-virals for HIV patients from Doctors treating them for TB. It must be very dispiriting to cure your HIV patient of TB only to find they become reinfected or die from some other AIDS related illness. But the logistics let alone the expense of providing anti-virals to large numbers of people from the poorest part of the world seem insurmountable. Even in the USA resistance to anti-virals has risen to 15%. We cannot afford drug resistance HIV.

New drugs, a new vaccine and cheap rapid methods of diagnosing smear negative disease are needed. I have a feeling that TB will be last in the queue for these.

In his Dimbleby lecture, given only three months after the September 11 attack, former US President Bill Clinton had some interesting insights on the problem.

"Half the people on earth live on less than two dollars a day. A billion people, on less than a dollar a day. A billion people go to bed hungry every night and a billion and a half people - one quarter of the people on earth - never get a clean glass of water. …
One in four of all the people on earth who die, will die of AIDS, TB, malaria and infections related to diarrhoea. …
I am absolutely confident that we have the knowledge and the means to make the twenty first century the most peaceful, prosperous, interesting time in all human history. The question is whether we have the wisdom and the will."

So what are the solutions?
I have pinpointed two problems, which would be relatively cheap to solve. First within the UK appoint two Chairs with a specific interest in Clinical tuberculosis one in London and one in a provincial city perhaps Leicester or Birmingham.
Secondly at international level bias what monies there are available towards tuberculosis control. With the exception of antivirals for HIV positive pregnant mothers, treating TB in HIV patients is the most cost-effective intervention in improving life expectancy and quality. There has recently been good news from India, TB cure costs $50. A rapid increase in DOTS across this; the highest burden country would be the most cost effective way of using monies from the uderfunded GFATM.

You've had a slideless lecture because all the data in the world will not alter the fact that the control of TB now depends more on politics than science. If the political will was there the means to control and eradicate TB would soon arrive. The problem is that so many people from presidents to prime ministers and from professors of medicine to pharmaceutical companies have a different agenda.

http://www.phls.org.uk/topics_az/tb/TB_tables_figures/TB%20Tables%20Index.htm Accessed 8/11/02

Khatri GR, Frieden TR. Controlling tuberculosis in India. New Eng. J.Med. 2002;347:1420-1425.

Leese J. Tuberculosis-a 19th century disease in the 21st century. CMO,s update Oct31, 2001:4.

Davies P. Industry funding in medical education. (Letter). Lancet 2002;359:1949-1950.

Creese, A., Floyd, K., Alban, A., Guinness, L.
Cost effectiveness of HIV/Aids interventions in Africa: a systematic review
of the evidence. LANCET 2002;359:1635-1642.

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The challenge of tuberculosis.

Infection 2002

A talk given at a meeting held at the Natural Science Museum, sponsored by Aventis. November 14th 2002.