Postgraduate Medical Journal (March 1984) 60, 187-193

Trends in tuberculosis

K. M. CITRONM.D., F.R.C.P.

Brompton Hospital, London SW3

One of the major medical advances of the 20thcentury has been the discovery of anti-tuber-culosis drugs capable of curing almost every patientsuffering from the disease. The application ofchemo-therapy in technically advanced countries has re-sulted in a spectacular decline of tuberculosis. Incontrast, in developing countries there has been littleimprovement since mass chemotherapy has failedbecause of lack of money, medical and paramedicalpersonnel and inadequate health education.

Trends in tuberculosis have been ones of successand failure, and changing epidemiology. Recentresearch and progress in tuberculosis has beenconcerned mainly with the design and application ofchemotherapy programmes suitably adapted to thewidely differing medical, financial and social needsof different communities.

Epidemiology of tuberculosis

Developing countries

In developing countries there has been an increasein the number of people suffering from tuberculosissince the population has doubled during the last threedecades and control measures have been inadequateto deal with the increasing number of patients.Estimates suggest that throughout the world everyyear 10 million people develop tuberculosis and atleast 3 million die of it, most of these being in thedeveloping countries.

Britain

Tuberculosis, previously a major cause of illnessand death among young people, is now relatively rarein the young. This has led to the erroneous belief thattuberculosis is almost eradicated in Britain. This isnot so and there remain a number ofhigh risk groupsin the community, especially the elderly white maleand refugees and immigrants coming from Asia andother high prevalence countries (Citron, Raynes andBerrie, 1981). A survey of tuberculosis notifications inEngland and Wales during 1978/79 revealed great

differences in the incidence in various ethnic groups(Medical Research Council, 1980) (Fig. 1). The ratesof notification of respiratory tuberculosis in people ofIndian subcontinent ethnic origin (Indian, Pakistaniand Bangladeshi), were 30 times greater than in thewhite population. For non-respiratory tuberculosisthe rates were 70 times greater. These differencesbetween the ethnic groups may, in part, reflect thehigh incidence of the disease in the countries fromwhich the immigrants come. However this is unlikelyto be the major reason. Chest radiography of Asianimmigrants on entry to Britain reveals little pulmo-nary tuberculosis. Clinically pulmonary tuberculosisappears to occur frequently after the immigrantshave been in Britain for some time, the risks beingparticularly high during the first 5 years of theirresidence (British Thoracic and Tuberculosis Associ-ation, 1975). Factors that have been thought tocontribute to the development of tuberculosis aftersettling in the country include the reduction of hostresistance by the stresses and strains of recentimmigration, and the effect of vitamin D deficiencywhich is common among some immigrants. Inaddition there is the higher risk of infection associ-ated with living in immigrant communities in U.K.The Indian subcontinent ethnic group comprise

less than 2% of the population of England and Walesbut contribute almost one third of respiratory andmore than one half non-respiratory notifications.However, they have less extensive pulmonary diseaseand are less infectious than the white ethnic group.For every sputum-smear-positive patient of Indiansubcontinent origin there are four among whitepatients. The main source of infection in U.K.remains the elderly white male. These men wereusually infected in youth, the disease remainingquiescent for years, becoming reactivated in middleor old age. Many of these men are smokers and mayhave cough or sputum, and are therefore thought tobe bronchitic. This acceptance of chronic respiratorysymptoms may contribute to the late diagnosis ofpulmonary tuberculosis at a stage when it is exten-sively cavitated and highly infectious.

copyright. on July 19, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.60.701.187 on 1 March 1984. D

ownloaded from

K. M. Citron

400-

300-

200-

100

White West Chinese African Arab Pakistani & IndianIndian Bangladesbi

FIG. 1. Tuberculosis notifications among various ethnic groups in England and Wales.

Tuberculosis prevention and control

CasefindingCase finding with effective chemotherapy dimin-

ishes the source of infection in a community. In mostdeveloping countries case finding is 'passive', and isrestricted to diagnosing patients who present withrespiratory symptoms. In developed countries activecase finding is practised. It concentrates on examin-ing the high risk groups, which in Britain includemiddle-aged white males, vagrants and Asian immi-grants. These immigrants should be examined assoon as possible after they have reached their place ofabode. There are considerable variations in theannual notifications in England and Wales where theaverage rate is 18 per 100,000 but in the Indiansubcontinent ethnic group it is 380. There are greatregional variations in Britain. In one region a figureof 1,132 per 100,000 was recorded among immi-grants. Regional differences are mainly due to thedistribution of immigrants and it is important thatthe priorities for health care staff are varied accord-ing to the needs of the community (Medical ResearchCouncil, 1982).

Hospitalization and segregation

The only source of tuberculous infection is, forpractical purposes, a person with pulmonary tubercu-losis in whose sputum tubercle bacilli are present insufficient numbers to be seen on direct examinationof sputum smears (sputum smear positive). Patientswhose smears are negative are non-infectious, eventhough cultures may be positive, and do not requiresegregation.Chemotherapy with regimens including rifampicin

abolish infectivity rapidly and long before thedisappearance of acid-fast bacilli from sputum

smears. The number of tubercle bacilli in the sputumwhich are alive as shown by growth on culture, fallby 99% after the first 2 weeks of chemotherapy(Jindani et al., 1980). Hence patients can be regardedas non-infectious after 2 weeks of effective chemo-therapy and segregation need not be continuedbeyond this time providing chemotherapy is takenregularly.Home treatment exposes close family contacts to a

negligible risk of infection due to the rapid abolitionof infectivity by chemotherapy. Controlled studieshave shown that home treatment does not submitthose contacts to a significant risk of infection oncechemotherapy is started (Toman, 1979). The thera-peutic results of well-supervised home treatmenthave been shown to be as good as that obtained byhospital treatment (Fox, 1977). However in spite ofconvincing evidence that most patients can beeffectively and safely treated at home, the majority ofpatients with pulmonary tuberculosis in England andWales are admitted to hospital for the purposes ofdiagnosis, treatment, segregation or for social rea-sons.

BCG vaccination

In Britain BCG vaccination is provided for schoolchildren aged 10-14 years. Recent epidemiologicalstudies have shown this to be highly effective inpreventing tuberculosis (British Thoracic Associa-tion, 1980a.) There are regions which currently havea low prevalence of tuberculosis but BCG should notbe abandoned for children living in these regions,because they may subsequently visit or work inregions where there is a much higher prevalence oftuberculosis such as London and the industrial citiesof the Midlands where the risk of infection is muchgreater than in the place of their schooling. BCG

188

copyright. on July 19, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.60.701.187 on 1 March 1984. D

ownloaded from

Trends in tuberculosis 189

vaccination is also recommended for infants whoseparents are of Indian subcontinent ethnic origin, andfor children of this ethnic group as soon as possibleafter their arrival in U.K. The reason for thisrecommendation is that the incidence of tuberculosisin children of this ethnic group compared with that ofwhite children is 50 times greater if they are bornabroad and 20 times greater if born in Britain.Although a study in India failed to demonstrate thevalue of BCG in that country, there is no good reasonto doubt the efficacy of BCG given in U.K. toimmigrants from India (World Health Organization,1980).

Anti-tuberculosis chemotherapy

The practice of chemotherapy is currently under-going considerable change and there are wide varia-tions in drug regimens used depending upon theneeds of different communities and of individualpatients. For many years there was almost universaluse of so called standard chemotherapy. This consistsof isoniazid with a companion drug to prevent theemergence of drug resistance, this companion drugbeing either ethambutol, PAS or thiacetazone. Strep-tomycin was given as a third drug for the first 2 or 3months of treatment (Table 1). The total duration ofchemotherapy had to be 18 months if relapse was tobe minimized. Although the success of this regimenunder the conditions of meticulously controlledclinical trials could be shown to be 100%, in contrastobservations under service programme conditionsshowed it to be much less satisfactory. In severaldeveloping countries more than 50% of patientsdefaulted before the end of the regimen. In developedcountries, including Scotland and U.S.A., long-termsurveillance showed that there was an appreciablefailure rate (Fox, 1983a). These observations stressedthe importance of studying chemotherapy regimensin two ways. Firstly by meticulously conductedcontrolled trials to show the potential of the regimen.Secondly by testing it under service programmeconditions in the different circumstances of differentcountries to evaluate its efficacy in the varied social,

medical and financial conditions of the communitybeing investigated.

There are two main causes of failure of standardchemotherapy. One is irregular daily self medication.To overcome this problem programmes of totallysupervised intermittent medication are now avail-able. Another cause of failure is default before theend of the full course of chemotherapy. Short coursechemotherapy offers special advantages here. Theadvantages of both fully supervised and short coursechemotherapy may be combined. Much research hasbeen devoted to designing programmes suitable forthe differing needs of various communities and theindividual needs of patients with special problemslikely to lead to poor compliance such as alcoholism,vagrancy or a nomadic life style (Citron and Girling,1983).

Short course chemotherapyIn standard duration chemotherapy, combinations

of bactericidal and bacteriostatic drugs are continueduntil the bacterial population is effectively elimi-nated, a process which requires at least 18 months.Short course chemotherapy depends upon the use ofspecial drugs which have sterilizing properties thatkill the persisting organisms responsible for relapseafter the end of chemotherapy. In addition bacterici-dal drugs are used to kill the rapidly dividingorganisms, together with bacteriostatic drugs whosemain role is to prevent the emergence of drugresistance. The cardinal drugs in short-course chemo-therapy are isoniazid (H) rifampicin (R) and pyra-zinamide (Z) (Fox, 1981). Isoniazid is the mostbactericidal and is continued throughout the regi-men. Rifampicin is less bactericidal but its bacterici-dal action is very rapid so that it is able to killdormant bacilli that start to metabolize for only briefperiods of time, thus helping to remove the persisters.Pyrazinamide has a low bactericidal action but isimportant because it probably acts on persistingorganisms living intracellularly inside macrophages,or in the walls of tuberculous cavities and acts as animportant sterilizing drug. It has a low activity in

TABLE 1. Long-course regimens

Initial intensive phaseTotal duration of regimen

Drugs Duration Continuation phase (months)

Daily regimensSHE (P or T) 2-3 months HE (P or T) 18RHE (P or T) 2-3 months HE (P or T) 18Intermittent regimensSHE (P or T) 2-3 months HS twice weekly 18SHR 2 weeks HR twice weekly 12

Drugs in Table 1 and 2: H= isoniazid; R= rifampicin; Z = pyrazinamide; S = streptomycin;E= ethambutol; P= PAS; T = thiacetazone.

copyright. on July 19, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.60.701.187 on 1 March 1984. D

ownloaded from

190 K. M. Citron

preventing drug resistance. Recent studies suggest itsuse is maximized when given for the first 2 months ofa regimen, and there is little value in continuing thedrug longer. Streptomycin (S) is bactericidal andethambutol (E) is bacteriostatic. Neither are likely tocontribute much to short course chemotherapy,although they may have a role where initial resis-tance to isoniazid or streptomycin exists.A landmark in the history of tuberculosis chemo-

therapy research was attained when the East Afri-can/British Medical Research Council reported theirstudy of daily SHR given for 6 months to hospital-ized patients. This report and subsequent ones haveshown that in terms of bacteriological quiescence andrelapse rate in the subsequent 5-year follow-up, the6-month regimen proved as good as anything at-tained by standard 18-month chemotherapy. Thispioneer study showed the practicability of short-course chemotherapy and prompted many otherstudies.

Nine-month daily regimen

In 1973 the British Thoracic Association launcheda national multicentre study in which HR was givendaily for durations of 6, 9, 12 or 18 months togetherwith an initial third drug for the first 2 months, eitherstreptomycin (S) or ethambutol (E). Drugs weregiven according to the normal practise of the manyparticipating physicians with no special instructionsfor monitoring self medication. The study wastherefore undertaken in the normal service pro-gramme conditions. The 9-month regimen was foundto be highly satisfactory and in a 4-year post-chemotherapy follow-up the results were as good asany that had been previously studied. Ethambutolwas as satisfactory as streptomycin, as the third drug

in the initial intensive phase, so that the difficulties ofusing streptomycin can be avoided. The currentlyrecommended regimen by the British ThoracicSociety is HR for 9 months with E for the first 2months. Daily drug doses are H 300 mg, R 600 mg forpatients weighing over 50 kg and 450 mg for thoseweighing less and E 25 mg/kg for the first 2 monthsonly (British Thoracic Association, 1980b) (Table 2).

Six-month daily regimenIn a British Thoracic Association multicentre

study, 6-month regimens were given using HR dailyfor 6 months and during the 2-month initial intensivephase, pyrazinamide was used together with a fourthdrug which was either streptomycin or ethambutol(SHRZ2/HR, EHRZ2/HR). These were comparedwith the standard 9-month regimen EHR/HR (Table2). Both 6-month regimens were as successful as the9-month. The 6-month regimen had the advantagethat it was shorter and cheaper and caused morerapid sputum conversion, than the 9-month regimen.It was not associated with more hepatotoxicity thanthe control regimen and is more likely to curepatients who abscond early because it containspyrazinamide, a valuable sterilizing drug (BritishThoracic Association, 1982).The dose of pyrazinamide is 1-5 g daily if the

patient weighs less than 50 kg, 2 g daily if the patientweighs 50-74 kg and 2-5 g daily if the patient weighs75 kg or more. The dose of streptomycin is 1 g dailybut for patients over 40 years or under 50 kg isreduced to 0 75 g.

Further shortening of regimens

Much research is now concerned with investigatingregimens shorter than 6 months. So far none of them

TABLE 2. Short-course regimens

Initial intensive phase TotalContinuation phase duration

Drugs and Duration of regimenfrequency (months) Drugs and frequency (months)

Daily RegimensEHR daily 2 HR daily 9SHR daily 2 HR daily 9SHRZ daily 2 HR daily 6EHRZ daily 2 HR daily 6SHRZ daily 2 H daily 8

Intermittent RegimensSHRZ 3 times weekly 6 - 6EHRZ 3 times weekly 6 - 6SHRZ 3 times weekly 2 HR 3 times weekly 6SHRZ daily 2 HR 2 times weekly 6

Drugs in Table 1 and 2: H = isoniazid; R= rifampicin; Z= pyrazinamide;S=streptomycin; E=ethambutol; P=PAS; T=thiacetazone.

copyright. on July 19, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.60.701.187 on 1 March 1984. D

ownloaded from

Trends in tuberculosis

have proved as effective as the 6-month regimen.Nevertheless remarkable results are obtained withdaily SHRZ given for 3 months in advanced pulmo-nary tuberculosis curing 85%. However to ensure100% success, a duration of about 6 months seems tobe necessary even for sputum smear negative cases(Fox, 1981). The results of further research in whichboth microbial drugs and host resistance are manipu-lated may provide exciting advances.

Fully supervised intermittent therapyChemotherapy is likely to fail if the patient does

not take the drugs regularly as prescribed. Givingevery dose under full supervision ensures complianceand becomes practical when given intermittently.Fully supervised intermittent regimens are usuallyeasy to arrange in urban communities where patientscan attend for their drugs 2 or 3 times weekly.

Isoniazid and streptomycin given twice weekly for18 months have been widely used (Table 1). Whenisoniazid is given intermittently, it is essential that ahigh dose of isoniazid 15 mg/kg is used withpyridoxine 5 mg per dose to prevent isoniazidtoxicity. The advantages of intermittency and shortcourse can be combined (Table 2). A particularlyuseful regimen is SHRZ or EHRZ 3 times weeklysupervised for 6 months, successfully used in HongKong (Hong Kong/BMRC, 1981). Another usefulregimen is SHRZ 3 times weekly for 2 monthsfollowed by HR 3 times weekly, the regimen totalling6 months. Alternatively SHRZ daily for the first 2months with HR twice weekly, the regimen totalling6 months (Table 2).

Special aspects of chemotherapyCost

Severe lack of finance for tuberculosis control andtreatment is a major problem in many developingcountries. Mass chemotherapy can only be under-taken with the cheapest regimens (Aquinas andTodd, 1983). Standard long-course chemotherapy(isoniazid with PAS or thiacetazone for 18 monthswith streptomycin for the first few weeks) is cheapbut efficacy is low because of lack of patient co-operation. Short-course chemotherapy is more effec-tive but more expensive, but the cost-efficacy is likelyto be high. SHRZ daily for 2 months followed by Hdaily for another 6 months is cheap and effective.SHRZ 3 times a week for 2 months followed by HR 3times weekly for a total duration of 6 months is also agood cheap regimen.

It is unrealistic to use 100% regimens which aregenerally unacceptable and have a high default rate.A shorter but potentially less effective regimen maycure more patients. Thus SHRZ daily for 2 months islikely to cure 80% of patients, and be very acceptable.

Relapses occur with sensitive organisms and can beretreated with the same regimen.

Administrative aspects of mass chemotherapy

However effective a chemotherapy regimen maybe it will fail if it is not taken correctly by the patient.Mass chemotherapy is as much an exercise inadministration as it is in medicine. The use ofproperly trained administrators and paramedicalworkers is essential in attaining successful masschemotherapy. The use of paramedical staff workingin remote rural situations dealing with basic medicalcare including tuberculosis, has proved to be highlysuccessful in some communities, hence the impor-tance of training appropriate staff for this type ofwork.The cure of tuberculosis is more than the prescrip-

tion of drugs. It requires careful outpatient monitor-ing both by interrogation during outpatient atten-dances and checking urine for presence of drugs byeither red colour for rifampicin or by paper strip testfor isoniazid. Sputum cultures taken towards the endof chemotherapy should be negative. Serial drugsensitivity testing and chest X-rays are of little valuein the routine management of patients with pulmo-nary tuberculosis during chemotherapy.

Patients likely to be uncooperative

Patients who are alcoholic, psychiatrically dis-turbed, or lead a vagrant or nomadic life, are unlikelyto be reliable in self-medication. They need carefulsupervision and usually require fully supervisedintermittent medication for as short a period aspossible. SHRZ or EHRZ given 3 times weekly for 6months is often acceptable for these people. It is oftenwise to use SHRZ daily initially for as long as thepatient will co-operate, since this ensures the highestpercentage of cure should the patient abscond beforethe end of 6 months, this regimen being curative inabout 80%/o of patients when given for only 2 months.

Toxicity

Early studies of pyrazinamide using doses higherthan those now recommended revealed much hepa-totoxicity. However a study in which it was given in adose of 30-40 mg/kg daily for 2 months comparedwith a similar regimen without pyrazinamide,showed no increased hepatotoxicity which could beattributed to pyrazinamide (British Thoracic Asso-ciation, 1981). Pyrazinamide appears to be relativelywell tolerated by most alcoholics. Rifampicin com-pared with isoniazid is remarkably free from sideeffects and although a proportion of patients willshow elevation of liver enzymes during chemo-therapy, clinical symptoms and signs of liver disease

191

copyright. on July 19, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.60.701.187 on 1 March 1984. D

ownloaded from

192 K. M. Citron

are very rare. Early studies of intermittent rifampicinshowed frequent febrile reactions, but later studiesusing lower doses of 600 or 900 mg given twice orthree times weekly caused few and mild reactions. Ifreactions occur they can usually be overcome bygiving rifampicin more frequently. Rifampicin is apowerful hepatic microsomal liver enzyme inducer,resulting in important drug interaction. Oestrogensare more rapidly metabolized hence rendering inef-fective oestrogen-containing oral contraceptives. Thedosage of corticosteroids needs to be doubled inpatients receiving rifampicin in order to compensatefor the more rapid hepatic metabolization of corti-costeroids.

Renalfailure

Rifampicin and isoniazid are metabolized by theliver and can be given in normal doses to patients inrenal failure with safety. In contrast ethambutol andstreptomycin are eliminated mainly by the kidneysand must be avoided in patients with renal failure.

Pregnancy

Ethambutol and rifampicin given in large doses inanimals are teratogenic. However in woman there isno good evidence that teratogenicity has occurred. Ifthere is a risk it would be during the first trimester ofpregnancy and hence the drugs are best avoided atthis time. However if pregnancy occurs whilst awoman is receiving anti-tuberculosis chemotherapy,the pregnancy is unlikely to be diagnosed muchbefore the 12th week, and if the pregnancy isadvanced beyond this time there is little risk ofcontinuing the drug. Patients who are more than 12weeks pregnant can be given the usual anti-tubercu-losis drugs with the exception of streptomycin, whichcan cause 8th nerve damage in the foetus, and PASwhich may cause foetal goitre.

Non-pulmonary tuberculosis

The duration of chemotherapy for non-pulmonarytuberculosis should usually be 18 months since thereis as yet insufficient evidence from studies of short-course chemotherapy to judge the efficacy of short-course chemotherapy in these conditions.Lymph node tuberculosis is notoriously unpredic-

table in its response to chemotherapy. Lymph nodeenlargement or abscess formation is not uncommonduring chemotherapy which appears otherwise satis-factory. Pus from lymph nodes which break downduring chemotherapy almost never yield living tuber-cle bacilli. Caseation and abscess formation may bedue to immunological response to tuberculo-proteincontained within the lymph node. Because of inabil-ity to clear dead tubercle bacilli from lymph nodes,

immunologically reactive products from the bacillimay persist in the nodes for a prolonged period. Thesituation is very different from that found in the lungwhere dead tubercle bacilli are cleared by expectora-tion in sputum and by other means. This fact possiblyaccounts for the more favourable response of pul-monary tuberculosis. However with prolongedchemotherapy the final outcome in lymph nodetuberculosis is usually entirely satisfactory (Campbelland Dyson, 1979).

Tuberculous meningitis

This remains a very dangerous condition. All thedrugs which give good levels in the cerebrospinalfluid should be given. The drugs of choice arepyrazinamide, rifampicin, isoniazid and ethambutolgiven in maximum doses. The role of intrathecalstreptomycin is contentious but it is probably advis-able in the more advanced cases. Corticosteroids areprobably valuable for advanced cases, although theevidence for this is anecdotal, since no controlledstudies have been made.

Conclusion

A wide variety of effective chemotherapy pro-grammes is now available to suit the differentrequirements of various communities and of indivi-dual patients. In the world as a whole however, thenumber of cases of tuberculosis continues to increaseespecially in some developing countries. In develop-ing countries efforts are needed to apply newregimens of chemotherapy, including short-courseand fully supervised programmes, in order to im-prove the often unsatisfactory results ofmass chemo-therapy. Research is needed to explore the use ofestablished drugs in new regimens, and to discovernew drugs which act either on the tubercle bacillus orupon host resistance. It is important that the results ofresearch are widely and effectively disseminated soinfluencing practising clinicians worldwide to bringthe treatment of patients up to date. (Fox, 1983b).Programmes for administering BCG to the new-bornin high risk communities need to be intensified.

In the developed countries, unfamiliarity withtuberculosis may result in the disease being diag-nosed too little or too late. It is important to maintainmedical expertise for prevention and treatment oftuberculosis in these countries, as well as tostrengthen efforts to combat the disease in certainhigh risk groups in the community.

References

AQUINAS, M. & TODD, D. (1983) Particular problems of tuberculosisin developing countries. Oxford Textbook of Medicine. S.212 (Ed.D.J. Weatherall, J.G.G. Ledingham and D.A. Warrell). OxfordUniversity Press, London.

copyright. on July 19, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.60.701.187 on 1 March 1984. D

ownloaded from

Trends in tuberculosis 193

BRITISH THORACIC AND TUBERCULOSIS ASSOCIATION (1975) Tu-berculosis among immigrants related to length of residence inEngland and Wales. British Medical Journal, 3, 698.

BRITISH THORACIC ASSOCIATION (1980a) Effectiveness of BCGvaccination in Great Britain. British Journal of Diseases of theChest, 74, 215.

BRITISH THORACIC ASSOCIATION (1980b) Short course chemo-therapy in pulmonary tuberculosis. Third report. Lancet, i, 1182.

BRITISH THORACIC ASSOCIATION (1981) A controlled trial of sixmonths chemotherapy in pulmonary tuberculosis. First report.British Journal of Diseases of the Chest, 75, 141.

BRITISH THORACIC ASSOCIATION (1982) A controlled trial of sixmonths chemotherapy in pulmonary tuberculosis. Second report.American Review of Respiratory Disease, 126, 460.

CAMPBELL, I.A. & DYSON, A.J. (1979) Lymph node tuberculosis: astudy of treatment 18 months after completion of chemotherapy.Tubercle, 60, 95.

CITRON, K.D. & GIRLING, D.J. (1983) Tuberculosis. OxfordTextbook of Medicine 5.237. (Ed. D.J. Weatherall, J.G.G. Led-ingham and D.A. Warrell). Oxford University Press, London.

CITRON, K.M., RAYNES, R.H. & BERRIE J.R.H. (1981) Topics ofourtime. 3. Tuberculosis today. Her Majesty's Stationery Office,London.

Fox, W. (1977) The modem management of pulmonary tuberculo-sis. Proceeding of Royal Society of Medicine, 70, 4.

Fox, W. (1981) Whither short-course chemotherapy? British Journalof Diseases of the Chest, 75, 331.

Fox, W. (1983a) Compliance of patient and physician: experienceand lessons from tuberculosis-1. British Medical Journal, 287, 33.

Fox, W. (1983b) Compliance of patient and physician: experienceand lessons from tuberculosis-2. British Medical Journal, 287,101.

HONG KONG. CHEST SERVICES/BRITISH MEDICAL RESEARCHCOUNCIL (1981) Controlled trial of four thrice-weekly regimensand a daily regimen, all given for 6 months for pulmonarytuberculosis. Lancet, i, 171.

JINDANI, A., ABER, V.R., EDWARDS, E.A. & MITCHISON, D.A.(1980) The early bactericidal activity of drugs in patients withpulmonary tuberculosis. American Review of Respiratory Disease,121, 939.

MEDICAL RESEARCH COUNCIL (1980) National survey of tuberculo-sis notifications in England and Wales 1978-79. British MedicalJournal, 281, 895.

MEDICAL RESEARCH COUNCIL (1982) The geographical distributionof tuberculosis notifications in a national survey of England andWales (1978-1979). Tubercle, 63, 75.

TOMAN K. (1979) Tuberculosis case-finding and chemotherapy.Questions and answers. Geneva: World Health Organisation. No.219.

WORLD HEALTH ORGANIZATION (1980) Vaccination against tuber-culosis. World Health Organization Technical Report Service,Geneva.

copyright. on July 19, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.60.701.187 on 1 March 1984. D

ownloaded from