Tuberculosis of the SpineTHE treatment of pulmonary tuberculosis is

soundly based on the results of controlled clinicaltrials. Unfortunately it is not always effective. Butif it fails the fault lies with the physician, the patient,or the medical services; failure is not due to inade-

quacy of the drugs or deficiencies of research. Withother forms of tuberculosis the position is different.Few controlled trials have been done. Treatment isoften empirical, the drugs being used largely to

supplement traditional procedures. Tuberculosisof the spine, for instance, has for long been treatedby rest, immobilisation in plaster jackets, and surgicalprocedures such as debridement—removal from thevertebral bodies of caseous material, sloughs, andsequestra. But no one knew whether these were

necessary or whether chemotherapy by itself wassufficient. In 1958 good results were reported fromNigeria with only outpatient chemotherapy. 1,2 Incountries without adequate medical services this is,indeed, all that can be offered to the patients. Hos-

pitals and surgical teams are expensive and prolongedimmobilisation is uneconomic. It was clearlyimportant to find out whether the expense andeconomic loss were necessary. In 1963 the MedicalResearch Council began, through its Tuberculosisand Chest Diseases Unit, to study the problem.The first three reports have now been published.

Spinal tuberculosis is not common. To obtain

enough patients within a reasonable period it was

necessary to go to countries with a high prevalenceof the disease. The trials have been done in Korea,Rhodesia, South Africa, and Hong Kong. Patientswith lesions of the cervical or sacral vertebrae wereexcluded ; so the conclusions relate only to thetreatment of tuberculosis of the thoracic spine.In Masan in South Korea a controlled comparisonwas made between outpatient chemotherapy withoutrestriction of activity and inpatient chemotherapyfor the first 6 months with rest in bed but withoutmechanical restraint. 3 At the end of 3 years(including 1½ years of chemotherapy) 88% of thosetreated as outpatients and 84% of those treated inhospital had had a favourable response. Thus, 6months in bed produced no benefit. In Pusan, alsoin South Korea, outpatient chemotherapy with andwithout restraint by a plaster-of-paris jacket wasassessed. After 3 years the response was assessedas favourable in 86% treated with a jacket and 82%without, the small difference not being statistically1. Konstam, P. G., Konstam, S. T. J. Bone Jt Surg. 1958, 40B, 26.2. Konstam, P. G., Blesovsky, A. Br. J. Surg. 1962, 50, 26.3. Medical Research Council. J. Bone Jt Surg. 1973, 55B, 678.4. Medical Research Council. Tubercle, 1973, 54, 261.

significant. Thus, mechanical restraint produced nobenefit. In the third study, in Bulawayo, Rhodesia,débridement and chemotherapy were compared withoutpatient chemotherapy alone.6 After the same

period the response was favourable in 85% withdébridement and in 86",, without. Thus, thisform of surgical procedure conferred no benefit.Another surgical procedure, débridement with bonegrafting, is also being studied by controlled trials inSouth Africa and Hong Kong.The planning and execution of these trials seem

impeccable. The conclusions drawn from them can,and should, be accepted and acted upon. Properlyprescribed and adequately controlled chemotherapyis all that is required for routine treatment of tuber-culosis of the thoracic spine. Complications mayneed other measures, but, for the uncomplicated case,rest in bed, plaster jackets, and debridement areunnecessary. The basic chemotherapy regimen wasisoniazid and p-aminosalicylic acid (P.A.S.) for 18months. Within each of the trials there was a sub-

sidiary comparison to find out whether an initial

supplement of daily streptomycin improved results.It did not. The bacterial population of the lesionsbeing much smaller than in cavitated pulmonarytuberculosis, the emergence of bacterial drug-resist-ance was not a limiting factor. Nevertheless, in cer-tain circumstances-for example, in patients witha history of previous unsuccessful chemotherapyand in countries with a high prevalence of resistantstrains in the population-a three-drug combinationseems advisable because of the risk of initial resistance.The results, measured by exacting standards includingfull physical activity, radiographic stability, absenceof abscesses and sinuses, or nervous-system in-

volvement, were very good. They might be furtherimproved if another bactericidal drug, rifampicin,were used instead of P.A.S. Unfortunately, in thedeveloping countries, where the need for simplifiedtreatment is greatest, the continuing high cost ofthis drug precludes its widespread use.The importance of these M.R.C. trials lies not only

in the immediate benefits they can bring to patientswith tuberculosis of the spine by easing the burdenof being treated, but also in the remote benefits toothers through extending the rigorous discipline ofcontrolled clinical trials into new areas. Greatcredit is due not only to the team that organised andcoordinated these international investigations, butalso to the many surgeons and physicians whosubmitted to the irksome restraints of such controlledstudies. Chest physicians in Britain and in othercountries have become accustomed during the past25 years to exercising the self-discipline required forcooperative controlled trials. Their cooperation hasbeen well rewarded by results. Extension to inter-national cooperation in controlled trials for surgicalproblems of tuberculosis is a major advance. There

5. Medical Research Council. J. trop. Med. Hyg. 1974, 77, 72.

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is still much scope for research even in the diminish-ing sphere of extra pulmonary tuberculosis-and evengreater scope for controlled trials of other surgicalprocedures.

Microbial-antigen DetectionFOR diagnosis of infections, microbial-antigen

detection may have three advantages over culture-speed ; indication of pathogenicity; and inferenceof the presence of microbes that will not grow invitro. Speedy diagnosis is sometimes vital, andantigen detection can be very quick: by gel-diffusionagainst a potent antiserum variola antigen can bedetected in blister fluid within hours. GREENWOODand his co-workers 1 using counterimmunoelectro-phoresis found meningococcal antigen within 45minutes in the cerebrospinal fluid of 41 patients:only 17 specimens contained visible bacteria but all 41proved to be culture-positive. As to pathogenicity,some bacterial species, especially in the respiratorytract, may be of doubtful import: thus, Streptococcuspneumonice and Hcemophilus infiuenzœ may benormal flora and Pseudomonas œruginosa a harmlesssurface coloniser; alternatively, all three may be

highly pathogenic. In chronic infections serum

antibodies may give a clue to the relevance of suchspecies,2 but they are unlikely to help in the acutecase. The presence of antigen, on the other

hand, may suggest a heavy bacterial load, and soimply infection. VERHOEF and JONES 3 found a rela-tion between presence of pneumococcal antigens insputum, the number of viable pneumococci,and the severity of the disease; but, in the experienceof SPENCER and SAVAGE,4 patients with postoperativeproductive coughs were as likely to have antigen intheir sputum as those with pneumonia. Lastly,antigen detection may be the only way to diagnoseinfection if the causal organism cannot be isolated.Absence of growth in vitro could be due to factorssuch as an inadequate inoculum, previous therapy,overgrowth by. commensals, and lack of a suitableculture system. Cryptococcal antigen has beendetected in cerebrospinal fluid which was culture-negative (presumably because the inoculum was toosmall) and the patients responded to specific therapy.5 The diagnosis of primary pneumonia is often con-fused by growth of commensals or by previous anti-biotic treatment-pathogens were only found in aquarter of the patients in one survey 6—but pneumo-coccal antigen has been detected in sputum even aftertreatment.? Hepatitis-B virus is a good example of a1. Greenwood, B. M., Whittle, H. C., Dominic-Rajkovic, O. Lancet,

1971, ii, 519.2. Burns, M. W., May, J. R. ibid. 1968, i, 270.3. Verhoef, J., Jones, D. M. ibid. 1974, i, 879.4. Spencer, R. C., Savage, M. A. ibid. p. 988.5. Goodman, J. E., Kaufman, L., Koenig, M. G. New Engl. J. Med.

1971, 285, 434.6. Spencer, R. C., Philp, J. R. Lancet, 1973, ii, 349.7. Tugwell, R., Greenwood, B. M. ibid. 1974, i, 95.

non-cultivatable microbe, and screening requirementshave given rise to intensive research into detection ofHBAg.

Australia antigen was discovered by double diffu-sion in agar gel, a technique which may take severaldays to complete and can detect microgrammes ofantigens. This has been supplanted by discontinuouscountercurrent immunoelectrophoresis 8 (osmo-phoresis), which is quicker and more sensitive.Techniques under evaluation for screening includereverse passive agglutination of antibody-coatedlatex particles or turkey erythrocytes, inhibition ofpassive hsemagglutination, and radioimmunoassay.Radioimmunoassay can detect picogrammes of

antigens. The methods all depend on potent andspecific antisera. Many commercial antisera are madefor other purposes and may be inadequate.9 A tech-nique for general diagnostic use should be specific,sensitive, easy, quick, and cheap. Discontinuouscountercurrent immunoelectrophoresis is feasiblebecause standard equipment is used, some commercialantisera are available, and speedy results are obtained.BARTRAM and others 10 have evaluated the sensitivityand specificity of this technique by testing sera

from patients with pneumococcal pneumonia andbronchitis or sundry bacteraemias, and also extractsof various bacterial cultures. They used a range ofhome-made and commercial antisera. Pneumococcal

antigen was found in 54% of the patients with

pneumonia but in none of the controls. Bacter-semic patients often had the relevant antigen in theirblood; and antigen was present, too, in the blood of11 out of 12 patients with severe pseudomonasinfections. Thus their results were highly specific,but of variable sensitivity. Tests with laboratorycultures revealed various cross-reactions; some

pneumococcal antisera reacted with four other species.They concluded that the difference between the in-

’

vivo and in-vitro results was due to the higher antigenconcentrations in vitro and that, although their in-

’

vivo results were specific, occasional cross-reactions’ might occur. These are encouraging and important’

observations which require amplification before thetechnique comes into routine use. A more sensitivetechnique could well be less specific because of cross-reactions, which may be due to natural antibodiesin the antiserum or to sharing of antigens by different

.

bacterial species. Pools of antisera may be needed to.

make the method practicable, but would also reducethe specificity.

.

Rapid diagnosis of severe infections can be life-

saving. Most clinicians can recall the death of a

patient within 24 hours of admission in whom:, bacterial cultures subsequently revealed an unsuspec-

ted diagnosis. Antigen detection may be one way ofavoiding this. There are other possibilities, however.8. Wallis, C., Melnick, J. L. Appl. Microbiol. 1971, 21, 867.9. Coonrod, J. T., Rytel, M. W. Lancet, 1972, i, 1154.

10. Bartram, C. E., Crowder, J. G., Beeler, B., White, A. J. Lab. clin.Med. 1974, 83, 591.