953LEADING ARTICLES

Facts about B.C.G.

THE LANCETLONDON: SATURDAY, MAY 10, 1952

AFTER the late war an international programmeof mass B.c.G. vaccination was initiated by theJoint Enterprise, formed by UNICEF, the DanishRed Cross, the Norwegian Relief for Europe, and theSwedish Red Cross. The Tuberculosis ResearchOffice of W.H.O. was established in Copenhagen tostudy the problems brought to light during the earlystages of this vast campaign ; and some of the resultsof investigations during the past two years are

described in this issue by Dr. CARROLL PALMER,the director. Many have not yet been published,partly because much of the work had to be repeatedwhen the early findings were found to differ so muchfrom what is generally accepted about B.C.G. To

supplant traditional beliefs the evidence must beexcellent. That brought forward by Dr. PALMERseems to be unassailable ; the experiments were

carefully planned, methodically executed, and accu-rately analysed. Had similar experiments been carriedout years ago when B.C.G. vaccination was in its infancy,the confusion and controversy that have hamperedits development might have been averted.The tuberculin skin reaction is indispensable in the

study and practice of B.C.G. vaccination. Despite itsmany inherent limitations, it gives a quantitativeguide to the tuberculin hypersensitivity of the skin.Until lately, however, very little attention was paidto the accuracy of the test. MEYER et al.1 have nowshown that with experienced testers the experimentalerror in the observed size of the skin induration has astandard deviation of about 2 mm. Thus, where thediameter of the indurated area is 10 mm.,about30 %of testsunder these conditions will be recorded as above 12 mm. orbelow 8 mm. A diameter of 6 mm. is commonly takenas the lower limit of a " positive " reaction ; and theremay be some support for this convention in Dr. PALMER’Sevidence that the frequency-distribution of the skinreactions’of large numbers of persons to the same doseof tuberculin shows two peaks with between them aregion of very low frequency around a diameter of6 mm. By this definition of a " positive " reaction,MEYER and his colleagues found that 10 % of peoplewith a " negative " reaction on one arm had a " positive "reaction on the other. The experimental error withinexperienced testers and between testers of variedskill is likely to be great. Indeed, in the Medical ResearchCouncil’s tuberculin survey 2 variations between testersWere so great that degrees of sensitivity in differentparts of the country could not be compared, and itWas possible to measure infection only by the total1, positives," irrespective of whether a jelly test or anintradermal test was used. This sufficed for the mainpurpose of this particular survey, but much valuableinformation was probably lost by the differences ininterpretation. For many research purposes the record-

1. Meyer, S. N., Hougen, A., Edwards, P. Publ. Hlth Rep., Wash1951, 66, 561.

2. Medical Research Council, Lancet, April 19, 1952, p. 775.

ing of "positive" reactions is insufficient. The W.H.O.workers have measured the level of tuberculin sensitivityin different groups by the mean diameter of the reactions ;and in this way they have investigated accurately someof the factors affecting the capacity of B.c.G. to producehypersensitivity. All tuberculin testing was done withpurified protein derivative (P.P.D.), which has obviousadvantages over Old Tuberculin. (GREEN 3 has pointedout that p.r.D. is less difficult to standardise and easierand less expensive to make.) The doses of P.P.D. wererecorded in terms of tuberculin units (T.u.)-a simplesystem that avoids the cumbersome method of tenfolddilutions and numerous ciphers, one T.u. being equivalentto 0-00002 mg. of reference standard P.P.D.

It is usually thought that .c.G. vaccine has tobe kept cold and used very soon after preparation,that the potency of the vaccine can be adjusted byslightly changing the concentration of bacilli, andthat large numbers of living organisms are neededto evoke satisfactory hypersensitivity. These beliefs,it now seems, are ill founded. EDWARDS andGELTING,4 working for W.H.O. in collaboration withthe Joint Enterprise and the State Serum Institute,Copenhagen, have shown that the capacity of thevaccine to cause hypersensitivity is little altered bystorage for two months at 2°-4°C. After storageat 20°C for the same period the vaccine still producedwhat would normally be regarded as satisfactorytuberculin hypersensitivity ; and even storage fora few days at 37°C had very little effect. It was

suggested that the hypersensitivity from the storedvaccine might be temporary, but a year after vaccina-tion there was no substantial evidence of this. B.C.G.

vaccine can therefore be stored at moderate tempera-tures for quite long periods without much loss of

potency. EDWARDS and G ELTING 5 have also shownthat, while sensitivity is not so great after vaccinationwith diluted vaccine, small changes in the concentra-tion have hardly any effect, and even halving theconcentration may reduce by only 1 mm. the meandiameter of the skin reactions. Moreover, the effectof dilution differs with different batches of vaccine,and one vaccine cannot always be made comparablewith another by adjusting the amount of B.c.G.

in each dose. PALMER describes as perhaps the mostinteresting and important investigations those on

mixtures of living and dead bacilli. Vaccine containing1 part of living and 255 parts of heat-killed vaccineproduced strong hypersensitivity 10 weeks aftervaccination, which persisted after a year. Heat-killed vaccine alone gave rise to only a low level ofsensitivity ; but even this was comparable with thatrecorded with presumed living vaccine in one countryduring the mass campaign. Thus large numbers ofliving bacilli are not necessary for

"

satisfactory "

hypersensitivity. This -may be the most importantfinding ; but the most surprising is that the allergy-producing potency of B.c.G. vaccine was halved byexposure to sunlight in Denmark for only one hour.6 gSuch deterioration may account for many of the

unexpected results of vaccination projects throughoutthe world. The W.H.O. workers, therefore, haveshown that the allergy-producing potency of B.C.G.vaccine is little reduced by the factors that were

thought to be damaging, and greatly reduced byone that has only occasionally been mentioned.3. Green, H. H. Ibid, 1951, ii, 500.4. Edwards, L. B., Gelting, A. S. Bull. World Hlth Org. 1950, 3, 1.5. Edwards, L. B., Gelting, A. S. Ibid, p. 279.6. Edwards, L. B., Tolderlund, K. Ibid, 1952, 5, 245.

954

One might be tempted to conclude that B.c.G.

is too variable and unstable for use in large immunisa-tion campaigns ; but the data so far collected relate

only to the ability of the vaccine to produce tuberculinhypersensitivity. The relation of immunity to hyper-sensitivity is unknown, and the extent of immunitycannot be inferred from the skin hypersensitivity.Moreover, as PALMER says : "In many places in theworld today vaccination is almost all that can bedone to control tuberculosis, and B.c.G. is certainlythe best known, the most promising, and the mostacceptable immunising agent at our disposal." Thecontroversy about the efficacy of this vaccine in thecontrol of tuberculosis will be ended only by accumula-ting facts. Dr. PALMER’S report shows how efficientlysuch facts are being gathered by internationalresearch.

1. Brody, S. Biogenetics and Growth. New York, 1945.2, Kleiber, M. Physiol. Res. 1947, 27, 511.3. Galvao, P. E. J. appl. Physiol. 1948, 1, 385, 389.4. Cullumbine, H. Ibid, 1949, 2, 640.5. Quenoille, M. H., Boyne, A. W., Fisher, W. B., Leitch, I. Com-

monwealth Bureau of Animal Nutrition. Technical com-

munication no. 17. 1951. 6s.

Standards for Basal MetabolismAT the beginning of this century the German

physiologist RUBNER propounded the natural lawthat the heat generated by the metabolism of theresting individual is proportional to the surface-areaof the body. This has proved a useful conception,which brings the metabolic rate of such differentanimals as the mouse and the horse approximatelywithin the same range. It has also been used for

predicting the normal basal metabolic rate (B.M.B.)in clinical examinations. But in the past few years ithas become evident that, though the surface-area

predicts the B.M.R. well enough, other measurements,which are easier to make and involve no elaborateformulae, predict as accurately or even more so.

For example, a good’ approximation is said to be

given by a simple power of the weight-a powerbetween 0-7 and 0-8 being ordinarily used in thecalculation.1-4Accurate knowledge of the normal B.M.R., and its

variation with sex, age, race, stature, and environ-ment, is valuable for two practical reasons. Firstly,the post-war food shortages in many lands and theincreasing world population have stimulated studiesof human energy requirements and of the basic

physiological concepts behind such estimates. In

persons not employed in heavy manual work, the basalmetabolism may contribute up to half the total energyrequirements. Clearly, it is essential to have accuratefigures for the B.M.R. before estimating the food neededby various population groups. Secondly, the clinicianwho is called upon to treat a patient with an abnormalB.M.R. wants to know the normal value for a similar

person under the same living conditions. In assessingdisorders of the thyroid gland it is particularlyimportant to know the limits of the patient’s ownnormal range.At the suggestion of Dr. W. R. AYKROYD,

director of the Division of Nutrition of the Food and

Agriculture Organisation, Dr. I. LEITCH and a teamfrom the Commonwealth Bureau of Animal Nutritionand Aberdeen University have reassessed the normalB.M.R. in relation to sex, stature, age, climate, andrace.5 z They first collected details of just over 8600

B.M.1L measurements, of which roughly half had beenmade in people between the ages of 17 and 39. Bymeans of multiple regression coefficients, they corre-lated B.M.R. with height, weight, surface-area, tempera.ture, and humidity, and they have drawn up predictiontables for practical use. The B.M.R. of women wasfound to be almost exactly seven-eighths that of menof the same height and weight : between boys andgirls the difference was slightly less. The effect of sizewas more complicated than either that of surface-area or of any simple function of height or weight. Inthis respect two main racial groups were defined-agroup belonging to North America and Northern

Europe, and a group belonging to India, China, andJapan. The two groups gave very different regressionequations, and accordingly four prediction tables weredrawn up-one for men and one for women in each

group. Italians showed the same pattern as the

American-European group, but with a higher averagerate of metabolism. The Eskimo, the AmericanIndian, and the Polynesian fell most easily into theAsiatic group, but their mean B.M.R. was higher thanthat of most of its members. Data for Australianaborigines were very variable. The authors seem tohave found no systematic study of either African orAmerican Negroes.The prediction tables were prepared, for a mean

annual temperature of 70°F and a relative humidityof 75%. Starting from these points, the. B.M.R. variedinversely with the temperature at the rate of 4 caloriesper °F in men and boys, and 3-5 calories in women andgirls. It varied directly with humidity ; in males by3 calories for a 1 % rise in humidity, and by slightlyless in females. Maximum effects were observed whenthe climate was hot and dry or cold and wet. Whenall other variables had been taken into account, adultsof both sexes and all race groups, and American-

European children, conformed to the rule that theB.M.R. declines at the rate of 3% every ten yearsfrom the age of 3 to ages over 80. This is a higherrate of decline than has been reported in the past.There was no evidence of a significant change at

puberty. When the observed rates, both in groupsand in individuals in different parts of the world, werecompared with predictions from the new tables andwith previous estimates based on surface-area and

body-weight, the tables showed the greater accuracy.Moreover, the tables and the correction factors forclimate and age are easy to understand and simpleto use.

In this issue we publish new standards set out byDr. J. D. ROBERTSON and Dr. D. D. REID from astatistical analysis of the observedB.M.R. of 987 malesand 1323 females. All these estimations were carriedout personally by RoBERTSON in London over the lasttwenty years, using a rigidly standardised technique.They prefer to express their results in terms of body-surface, and for practical use they give a table showingthe expected mean, and upper and lower limits ofnormal, for each age and for both sexes. Curvesrepresenting the relation between B.M.R. per unitof surface-area and age show how closely the observedfigures agree with the calculated expected mean.

There are some interesting differences between thestandards based on the observations of one man inLondon and those based on data from different source