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The challenge of tuberculosis

P D O Davies DM FRCP  

Tuberculosis Research and Resource Centre (TRRU), Cardiothoracic Centre, Liverpool L14 3PE, UK

E-mail: peter.davies2{at}ccl-tr.nwest.nhs.uk

	INTRODUCTION

TOP INTRODUCTION WHY ARE WE FAILING... A LOW LEVEL OF... LACK OF INTEREST BY... DIAGNOSING TB IS PCR OF VALUE... WHAT ABOUT TREATMENT? THE WORLDWIDE CHALLENGE OF... SO WHAT ARE THE... REFERENCES

 
The most important challenge for tuberculosis (TB) care in the UK today is the re-education of the medical and allied professions in diagnosis and management of the disease. In the first half of 2001 there were an exceptionally large number of outbreaks of TB, one of which with over 70 secondary cases (and still counting) is the largest since the advent of specific chemotherapy. ¹ I often see patients with a diagnosis of TB who have at some point been told by a doctor that they do not have TB. One was even told that nobody gets TB these days. A missed diagnosis of lung infection, specifically TB, is the second most common cause of litigation from a respiratory cause after pulmonary embolus (Evans CC, personal communication). TB is usually missed because it is not considered.

	WHY ARE WE FAILING TO DIAGNOSE TB?

TOP INTRODUCTION WHY ARE WE FAILING... A LOW LEVEL OF... LACK OF INTEREST BY... DIAGNOSING TB IS PCR OF VALUE... WHAT ABOUT TREATMENT? THE WORLDWIDE CHALLENGE OF... SO WHAT ARE THE... REFERENCES

 
There are several reasons for non-diagnosis. First, TB 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 5000 to 7000 in England and Wales since 1987, is confined to certain areas of the country, particularly London. ² In the past 12 years TB has doubled in London, which now contributes more than 40% of UK cases. ³

This means that fewer doctors are experienced in recognizing and managing the disease. Even among specialists in respiratory medicine there can be blindness to TB. A woman of 30 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 and 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 staining for acid-fast bacilli but did not take the important pleural biopsy. The pleural effusion resolved spontaneously, as they nearly always do in primary TB. But almost a year later TB meningitis ensued, the permanent after-effects of which have destroyed her life.

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 information 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 TB he had seen. Not much, was the answer. His teaching hospital was in a well-heeled area of the South of England. Did he think that we were giving our registrars sufficient training in TB? It is difficult when one sees so few cases, was his reply.

I could not help asking 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 a lifetime's work in the district general hospital where he was hoping to get a post. Of course he could hardly be blamed for that, but the professor of medicine or the postgraduate dean could have advised him better—if experience in TB had been thought important.

	A LOW LEVEL OF ACADEMIC INTEREST

TOP INTRODUCTION WHY ARE WE FAILING... A LOW LEVEL OF... LACK OF INTEREST BY... DIAGNOSING TB IS PCR OF VALUE... WHAT ABOUT TREATMENT? THE WORLDWIDE CHALLENGE OF... SO WHAT ARE THE... REFERENCES

 
This brings me to the second reason why TB might be being missed as a diagnosis—an absence of interest by academic, particularly respiratory academic, medicine. There are about 50 professors of respiratory medicine, of whom rather more than half have a principal interest in asthma. The rest are distributed through cancer, chronic obstructive pulmonary disease, fibrosis and occupational lung disease. There is one TB chair with a respiratory interest at a district general hospital in the North West and a chair of microbiology in London occupied by a professor who does some clinical sessions. Of course, physicians other than respiratory specialists can deal with TB but in practice chest physicians deal with 85% of all cases. ⁴

The absence of a critical academic mass of expertise in TB means that there is no independent advice to which government can turn in the event of a crisis. A broader base of expertise might have prevented the questionable decision in August 2002 to withdraw all supplies of BCG so that for three months it was impossible to get a BCG vaccination in the UK (and the Republic of Ireland).

Twenty years ago we were told that asthma was Britain's most rapidly increasing respiratory disease and the number of academic chairs multiplied. Today TB clearly holds that place and the academic silence is curious.

One suspects that the strong academic presence in asthma has much to do with a pharmacological interest. Pharmaceutical companies, who look for diseases of the rich to provide profits, fund most medical research. New drugs for TB, a disease predominantly of the poor, offer little prospect of profit.

This leads me to the third reason for missed diagnosis.

	LACK OF INTEREST BY THE PHARMACEUTICAL INDUSTRY

TOP INTRODUCTION WHY ARE WE FAILING... A LOW LEVEL OF... LACK OF INTEREST BY... DIAGNOSING TB IS PCR OF VALUE... WHAT ABOUT TREATMENT? THE WORLDWIDE CHALLENGE OF... SO WHAT ARE THE... REFERENCES

 
It is nearly forty years since the last new drug for TB was invented—rifampicin. In that time all the drugs in current use for asthma have been invented and in half that time thirty or so antivirals for HIV have come into use. A new consortium for the development of drugs for TB has recently been convened. It promises a new drug in ten years, by which time another 20 million people will have died of TB across the world and incidentally about 4000 in the UK. ⁵

There is one further point about the pharmaceutical industry in connection with the outbreaks of 2001. In the two most extensive the initial index cases were misdiagnosed as asthma. ⁶ How can asthma be mistaken for TB? By believing that any cough in a person under the age of thirty must be asthma.

Pharmaceutical companies are responsible for a great deal of postgraduate medical education in the UK. One sponsored meeting I went to started with a statement by the chairman that asthma was the only treatable respiratory disease in the UK that was increasing. I could not restrain a heckle from the back, ‘What about tuberculosis?’ I recall advertisements even in the BMJ in the 1990s presenting a product for asthma with the caption ‘Cough? Think of asthma.’ I have never seen an advertisement for a TB drug in the UK saying ‘Cough? Think of TB. ’⁷ In fact I have never seen an advertisement for a TB drug in any publication from this country.

We are not going to give patients with TB a fair deal until we find a better way of educating our doctors and allied medical professionals about TB. The British Thoracic Society has been commendable in its regular publication of guidelines^8,9 and the Government has recently taken an interest with its document Getting Ahead of the Curve. ¹⁰ But the information still has to get through to grass-roots level.

	DIAGNOSING TB

TOP INTRODUCTION WHY ARE WE FAILING... A LOW LEVEL OF... LACK OF INTEREST BY... DIAGNOSING TB IS PCR OF VALUE... WHAT ABOUT TREATMENT? THE WORLDWIDE CHALLENGE OF... SO WHAT ARE THE... REFERENCES

 
Infectious TB is very easy to diagnose. All you have to do is send off some sputum and ask the laboratory to look for acid-fast bacilli. As a clinician I depend on my microbiological colleague (or rather the technician who does the work).

A TB clinician needs to be as close to the microbiologist as the surgeon is to the anaesthetist. Some smear-negative pulmonary disease and quite a lot of non-respiratory disease is 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.

	IS PCR OF VALUE IN RAPID DIAGNOSIS?

TOP INTRODUCTION WHY ARE WE FAILING... A LOW LEVEL OF... LACK OF INTEREST BY... DIAGNOSING TB IS PCR OF VALUE... WHAT ABOUT TREATMENT? THE WORLDWIDE CHALLENGE OF... SO WHAT ARE THE... REFERENCES

 
Consider a patient who we think has TB meningitis. We send off cerebrospinal fluid for smear and culture and for polymerase chain reaction (PCR) and we start to treat. The smear is negative, but it is so in 80% of tuberculous meningitis. Then the PCR comes back negative. Do we stop treatment? No we do not, because we think it is tuberculous meningitis clinically and we know about false negatives. ¹¹ 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 tuberculous meningitis, 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 confident 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 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 a patient with 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.

	WHAT ABOUT TREATMENT?

TOP INTRODUCTION WHY ARE WE FAILING... A LOW LEVEL OF... LACK OF INTEREST BY... DIAGNOSING TB IS PCR OF VALUE... WHAT ABOUT TREATMENT? THE WORLDWIDE CHALLENGE OF... SO WHAT ARE THE... REFERENCES

 
Should we use directly observed therapy (DOTS), as WHO says we should?¹² DOTS has five components—government commitment, good drug supply, good microscopy, good recording, and directly observed therapy. DOTS is a means to an end, not an end in itself. The end we seek is cure for over 85% of our patients without 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? Only one centre in the UK has ever published its cure results.¹³ The augmented notification system introduced by the Public Health Laboratory Service at the beginning of 2002 will force us all to reveal our success in treatment or lack of it. At least I can say that in Liverpool we do achieve an 85% or better cure rate, from a mainly self-administered treatment with selective DOTS.

In a small Indian mission hospital that I have visited the completion rate before DOTS was 17% and after one year of DOTS 87%. If it is broken then fix it, and DOTS is that fix.¹⁴

	THE WORLDWIDE CHALLENGE OF TB

TOP INTRODUCTION WHY ARE WE FAILING... A LOW LEVEL OF... LACK OF INTEREST BY... DIAGNOSING TB IS PCR OF VALUE... WHAT ABOUT TREATMENT? THE WORLDWIDE CHALLENGE OF... SO WHAT ARE THE... REFERENCES

 
And that brings me to the real challenge of TB—the wider world. Since the time when we in Europe, and particularly the UK, exported TB to the rest of the world in the early 1800s as a result of industrialization, the total number of cases has been increasing.¹⁵ As a result of demographic changes and of HIV, TB is increasing globally at between 1.5 and 2% a year. There are 8-10 million new cases a year with 2 million deaths. A quarter of these are in India alone. Rates in some African countries exceed 500 per 100 000 a year.¹⁶ That is why TB in the UK is increasing—because of migration to and from the developing world where TB is out of control.¹⁷ There is some good news. Through WHO drug procurement, anti-TB drugs are now cost-free to certain countries and to large NGOs. The expense of the drugs is no longer a barrier. But much greater resources are needed if we are to reduce the global mortality and morbidity from TB.¹⁸

With the global fund for AIDS, TB and malaria, a start has been made in recognizing the devastation caused by these diseases.¹⁹ But the fund is woefully short of money. Less than a tenth of what is needed in the first few years has come forward. This year there is a $2 billion dollar shortfall. Richard Feacham, chairman of the fund, has said that TB is the best placed to benefit because through DOTS the TB control programmes have better structures and endpoints than the other diseases. This is largely thanks to the scientific expertise of the International Union Against Tuberculosis and Lung Disease and the relevant departments of the WHO. New drugs, a new vaccine and cheap rapid methods of diagnosing smear-negative disease are needed.

Even if there are no new drugs or vaccines for TB on the horizon there are continuing advances in diagnostics. A recent paper shows that an enzyme-linked immunospot (ELISPOT) assay to detect T cell specific antigen for M. tuberculosis antigens provides a more accurate test for infection than the tuberculin skin test. This represents a significant improvement on a test which has just celebrated its 110th birthday, while incidentally providing a silver lining to the cloud of England's biggest outbreak of tuberculosis.^1,20

	SO WHAT ARE THE SOLUTIONS?

TOP INTRODUCTION WHY ARE WE FAILING... A LOW LEVEL OF... LACK OF INTEREST BY... DIAGNOSING TB IS PCR OF VALUE... WHAT ABOUT TREATMENT? THE WORLDWIDE CHALLENGE OF... SO WHAT ARE THE... REFERENCES

 
I have pinpointed two major obstacles—lack of medical education in TB within the UK and lack of resources for control internationally. A start could be made within the UK with the creation of two chairs with a specific interest in clinical tuberculosis, one in London and one in a provincial city with high rates of TB (perhaps Leicester or Birmingham). At international level the use of scarce funds should be biased towards TB control. With the exception of antivirals for HIV-positive pregnant mothers, treatment of TB in HIV patients is the most cost-effective intervention in improving life expectancy and quality.²¹ The control of TB now depends more on politics than on science. If the political will was there, the means to control and eradicate TB would soon materialize. At present, too many people, from presidents to prime ministers and from professors of medicine to pharmaceutical companies, have a different agenda.

	Footnotes

 
Note: Peter Davies has acted as an independent advisor to Evans Medical, manufacturer of BCG.

	REFERENCES

TOP INTRODUCTION WHY ARE WE FAILING... A LOW LEVEL OF... LACK OF INTEREST BY... DIAGNOSING TB IS PCR OF VALUE... WHAT ABOUT TREATMENT? THE WORLDWIDE CHALLENGE OF... SO WHAT ARE THE... REFERENCES

 

1. Watson JM, Moss F. TB in Leicester: out of control, or just one of those things? BMJ2001; 322:1133 -4[Free Full Text]

2. Ormerod LP, Charlett A, Gilham C, Darbyshire JH, Watson JM. The geographical distribution of tuberculosis notifications in National Surveys of England and Wales in 1988 and 1993. Thorax1998; 53:176 -81[Abstract/Free Full Text]

3. [http://www.phls.org.uk/topics_az/tb/TB_tables_figures/TB%20Tables%20Index.htm]. Accessed 26 February 2003

4. Ormerod LP, Bentley C. The management of pulmonary tuberculosis notified in England and Wales in 1993. J R Coll Physns1997; 31:662 -5

5. Doherty MJ, Spence DPS, Davies PDO. Trends in tuberculosis in England and Wales; the proportion of deaths from non-respiratory disease is increasing in the elderly. Thorax1995; 50:976 -9[Abstract/Free Full Text]

6. Leese J. Tuberculosis—a 19th century disease in the 21st century. CMO's Update, 31 October 2001, p. 4

7. Davies P. Industry funding in medical education [letter]. Lancet2002; 359:1949 -50

8. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax1998; 53:536 -48[Abstract/Free Full Text]

9. Joint Tuberculosis Committee of the British Thoracic Society. Control and prevention of tuberculosis in the United Kingdom: code of practice 2000. Thorax2000; 55:887 -901[Abstract/Free Full Text]

10. [http://www.doh.gov.uk/cmo/idstrategy/]. Accessed 26 February 2003

11. Barnes PF. Rapid diagnostic tests for tuberculosis: progress but no gold standard. Am J Resp Crit Care Med1997; 155:1497 -8[Medline]

12. [http://www.who.int/gtb/dots/index.htm]. Accessed 26 February 2003

13. Ormerod LP, Horsefield N, Green RM. Tuberculosis treatment outcome monitoring: Blackburn 1988-2000. Int J Tuberc Lung Dis2002; 6:662 -71[Medline]

14. Mathew AJ, Eicher A, Davies PD. Comparison of hospital-checked, directly observed therapy with family supervised and unchecked tuberculosis treatment in a rural setting in North India. Europ Resp J 2002;20(Suppl):1425

15. Davies PDO. Tuberculosis and migration. J R Coll Physns Lond 1995;29:113 -18[Medline]

16. [http://www.who.int/gtb/]. Accessed 26 February 2003

17. Public Health Laboratory Service/British Thoracic Society/Department of Health Collaborative Group. Tuberculosis at the end of the 20th century in England and Wales: results of a national survey in 1998. Thorax2001; 56:173 -9[Abstract/Free Full Text]

18. [http://www.stoptb.org/GDF/default.asp]. Accessed 26 February 2003

19. [http://www.globalfundatm.org/index.html]. Accessed 26 February 2003

20. Ewer K, Deeks J, Alvarez L, et al. Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet2003; 361:1168 -73[Medline]

21. Creese A, Floyd K, Alban A, Guiness L. Cost effectiveness of HIV/Aids interventions in Africa: a systematic review of the evidence. Lancet2002; 359:1635 -42[Medline]

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