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B.C.G.: the Next Phase
385
When
THE LANCET LONDON;SATURDAY, SEPT. 14, 1946
B.C.G.: the Next Phase BY his social experience through the centuries, European man has acquired a fair resistance to tuberculosis ; but until the introduction of
B.c.G.
vaccine the bacteriologist had failed to add one cubit to its stature. From the " brownish-clear fluid which is durable in and for itself," which KocH called tuberculin, to the bacillus which CA3.nzTTE and GtrEBJN isolated from " lait du Nocard," the tale of these vaccines is a long one, and it is written in the textbooks for those to read who wish. But most of these vaccines belong to the past; they are dead,
both
metaphorically
and
literally, excepting only
B.C.G.
Introduced by CALMETTE shortly after the first world war as a means of protecting children born in tuberculous households in Paris, B.C.G. vaccine has passed through several critical phases. Oral which was first was too administration, employed, and came to a dramatic end the under haphazard of Lubeck for which it was affair, opprobrium the not in fact responsible. Subcutaneous and intracutaneous inoculations followed, but caused many cold abscesses at the site of inoculation. Quite recently B.C.G. has successfully negotiated the trial of two new transcutaneous methods-a scarification and a multiple-puncture technique. As to its real efficacy, many international discussions have raised the temperature amongst the critics, and no useful purpose would be served at this late stage by going over all the arguments which concerned the experts in the Health Organisation of the League of Nations. Four facts, however, stand out from the mass of official reports and protocols of experiments : (1) the Calmette-Guerin bacillus is harmless to man; (2) inoculation with it increases resistance to tuberculosis ; (3) the degree and duration of this immunity have not yet been precisely determined; but (4), like the immunity conferred by other bacterial vaccines, it is not permanent. An impressive array of information collected from various parts of the world has recently been set forth by the European regional office of UNRRAand in a memorandum, prepared by Prof. W. H. TYTLER,2 which has been presented to health departments jointly by various tuberculosis organisations.3 These bodies have made it clear that informed opinion is in favour of
a clinical trial of B.c.G. in this and country, they also advocate a single source of under official control. Because of the earlier supply bacteriological reports on the unstable virulence of the bacillus, and because of the Lubeck incident, stress has rightly been laid on the care with which the vaccine should be prepared by the laboratories.
now
1. Bulletin of Communicable Diseases and Medical Notes,
1946,
4, 708. 2. Memorandum on B.C.G. prepared for Tuberculosis Association, Joint Tuberculosis Council, and National Association for the Prevention of Tuberculosis, 1946; see Lancet, July 27, p. 138. 3. See Lancet, July 27, p. 125.
a vaccine is made of living micro-organisms, almost as much concern, however, should be felt about its care when it is no longer under the watchful eye of the bacteriologist who has prepared it. The subcutaneous and transcutaneous methods of giving B.c.G. have been pioneered chiefly in Scandinavia. The Norwegians began with tuberculin-negative nurses and then went on to immunise groups of the general population. Later B.c.G. was introduced for the Norwegian forces in Britain, and between 3500 This group deserves and 4000 were inoculated. mention because it the is special only large body of persons immunised while living in this country ; but so far as we know the results have not yet been It has been claimed that the vaccine published. " a standardised innocuous primary infection," gives but the UNRRA bulletin emphasises what is regarded as a contra-indication to its use-namely, a latent allergy in the individual. It points out that
" In Scandinavia nurses undergoing B.C.G. vaccination are completely segregated; there is an antevaccinal period of isolation, during which all the
requisite preliminary investigations,
are
made, viz.,
tuberculin testing, radiography, ascertainment of home conditions to eliminate the possibility of recent infection. Thereafter the vaccination is carried out and, one month later, the individual is tuberculin tested. Should the reaction prove negative, the individual is segregated for another month and again tuberculin tested." .
If these difficulties have been overcome in Norway, there is no reason why they should not be tackled here, but with the present shortage of staff they will not be easily surmounted. The memorandum presented to the health departments advocates a trial-purely voluntary-with selected groups of people who are exposed to unusual risks of tuberculous infection. Those who - work in hospital-medical students, nurses, and domestics-come to mind at once ; and these groups certainly lend themselves to medical supervision, though not all their members are employed very long in one place. In the industries with a high incidence of tuberculosis it might be less easy to arrange appropriate trials ; while children in tuberculous households in this country do not in general run such serious risks as they did in Paris when the vaccine was introduced. The primary of an whether should be to determine object inquiry B.C.G. vaccine will give in Britain the satisfactory results claimed for it in Scandinavia, in Canada, and in some other parts of the world. It should be borne in mind that tests on a small scale in New York, where the conditions more closely resemble those of the large British cities, have not been strikingly favourable : moreover, the clinical picture of tuberculosis varies in different countries, racial resistance differs, and neither social circumstances nor antituberculosis measures are the same. Granted therefore that the vaccine is efficacious, it will not necessarily produce dramatic results in this country where infection is already under fair control, and where spontaneous arrest of the disease is very common : it is more likely to do conspicuous good in the devastated and hungry parts of Europe where ordinary precautions have broken down and cannot be restored for a long time ; or in the tropics. There are some, indeed, who consider it mere wishful thinking to suppose that prophylactic vaccination will hasten
386
.
i of the biliary and pancreatic tracts to the slow disappearance of tuberculosis from ouranastomoses it fear that deflect us the intestine no sphincters, and their ostia must even from more have and midst, may fundamental efforts at eradication. As Prof. ARNOLD therefore be kept away from the main stream of RICH has pointed out, however, a disease which still digesting food ; unless this is contrived, by admitting kills twice as many individuals as any other during bile and pancreatic juice to the jejunum proximal the productive period of life cannot be regarded as to the gastric opening, ascending cholangitis and will result from reflux of food up the nearly defeated. There is as yet no easy way to over so channels and the proximal jejunum will inveterate an but it is not victory enemy, respective too much to hope that immunisation, if wisely be denied the protection from the gastric juice handled, will prove a useful weapon. provided by an alkaline flow from above. Opinion The clinical trial of B.C.G. which we hope soon to differs as to whether radical pancreatoduodenectomy should be done in one or two stages. The advocates see in this country should be placed in the hands of of the one-stage operation argue that the double a body such as the Medical Research Council which has the experience, equipment, and personnel for risk of two operations is avoided, that vascular work on a sufficient scale. Only the most carefully adhesions at the second and more difficult stage compiled figures in significant quantity will satisfy are sidestepped, and that the patients, though deeply the statisticians. The question also arises whether jaundiced, can be carried safely through by sufficient it should be confined to B.C.G. The vole bacillus preparation, particularly with vitamin K. The’two. discovered by A. Q. WELLS shortly before the war4 stage protagonists hold that these patients are too ill to stand a major procedure without preliminary is running the Calmette-Guerin organism very close, in and BIRKHAUG’S latest experiments suggest that biliary decompression;- they do not find adhesions 5 a problem at the second stage if the gall-bladder animals its immunising properties are as high.5 is anastomosed to the jejunum. WHIPPLE,7 doyen of pancreatic surgeons and Excision of the Head of the Pancreas an advocate of the one-stage operation, has lately HOPES of a radical treatment for carcinoma of the distilled his wisdom in a formula for the operation. pancreas were first raised in 1899 when HALSTED For an ampullary growth the abdomen is entered excised a segment of the duodenum and part of the through a right rectus incision from the costal margin the umbilicus. After a general survey, the peripancreas for an ampullary growth; but progress to toneum is incised to the right of ’the duodenum, was sporadic until, in 1935, WHIPPLE, PARSONS, which is elevated to determine the mobility of the and MULLINSg initiated a systematic study. Since then reports of excision of the duodenum and panpancreatic head, and the configuration of the uncinate creatic head for carcinoma have become almost process is studied. If the growth appears operable, the common bile-duct is divided behind the duodenum. commonplace in America. stomach is transected proximal to the pylorus, Apart from the rare islet-cell tumour, malignant The and from growths of the head of the pancreas may be classified the the origin of the gastroduodenalandartery The cut. hepatic artery revealed, ligated, according to their site in two main varieties : carci- duodenum is divided to the duodenojejund proximal noma of the ampulla of Vater or its immediate tributaries grows slowly and gives rise to early flexure (this stage must be modified if the uncinate encircles the superior mesenteric vessels); jaundice, whereas carcinoma of the head of the process the and inferior pancreaticoduodenal artery is secured. pancreas proper is more common, more malignant, cut across at the junction of the The is pancreas and gives rise to jaundice somewhat later. A radical head and the body, and the splenic vessels, portal resection of either type necessitates removal not only and superior mesenteric vessels are dissected of the pancreatic head but also of the duodenum, . vein, because the lymphatic and blood supplies of the off, drawing the pancreatic head to the right. The pylorus, duodenum, lower end of common bile-duct, two organs are inseparable. So bold an extirpation head of pancreas are now removed en bloc. (involving as it does the division and repair of the and A loop of jejunum is brought up and anastomosed intestinal, biliary, and pancreatic tracts) would to stomach, pancreatic stump, and cut lower scarcely be possible without the recent advances end the of from below upwards, so that the bile-duct, in chemotherapy, the discovery of vitamin K, and is the most distal in the jejunum. gastric opening the excellence of resuscitative and anaesthetic techIt seems easier than be supposed to insert a niques. The problems of the actual excision are small rubber tube intomight the pancreatic duct which is anatomical and are largely concerned with avoiding dilated and to thrust the tube from obstruction, damage to blood-vessels essential to life. The repair a small hole into the lumen of the jejunum; which follows has its special difficulties. The thorniest through the of then sutured cut is to the jejunal edge pancreas this is the treatment of the pancreatic stump ; is inserted the wall. A drain and abdomen closed. continues to secrete the most powerful proteolytic WHIPPLE attaches to the of use great importance enzyme in the body, and mere closure of the cut silk the because is throughout operation, catgut end has led, through sloughing and digestion of and he readily digested by escaping any trypsin ; damaged tissues and sutures, to external fistulae thinks that the gall-bladder should never be used and-still worse---to internal leaking. What remains to anastomose the biliary tract to the intestineof the pancreas must therefore be anastomosed to an unavoidable expedient in the two-stage operation. the jejunum, into which it can secrete. The new What are the results ? WHIPPLE in 1945 8 reported 4. Wells, A. Q. Lancet, 1937, i, 1221, 1233. that he had done 8 two-stage operations with an 5. Birkhaug, K. Amer. Rev. Tuberc. 1946, 53, 411 ; see Lancet,
pancreatitis
July 6, p. 17. 6. Whipple, A. O., Parsons, W. B., Mullins, C. R. 1935, 102, 763.
Ann.
Surg.
7. Whipple, A. O. Surg. Gynec. Obstet. 1945, 8. Whipple, A. O. Ann. Surg. 1945, 121, 847.
82, 623.
"
When
THE LANCET LONDON;SATURDAY, SEPT. 14, 1946
B.C.G.: the Next Phase BY his social experience through the centuries, European man has acquired a fair resistance to tuberculosis ; but until the introduction of
B.c.G.
vaccine the bacteriologist had failed to add one cubit to its stature. From the " brownish-clear fluid which is durable in and for itself," which KocH called tuberculin, to the bacillus which CA3.nzTTE and GtrEBJN isolated from " lait du Nocard," the tale of these vaccines is a long one, and it is written in the textbooks for those to read who wish. But most of these vaccines belong to the past; they are dead,
both
metaphorically
and
literally, excepting only
B.C.G.
Introduced by CALMETTE shortly after the first world war as a means of protecting children born in tuberculous households in Paris, B.C.G. vaccine has passed through several critical phases. Oral which was first was too administration, employed, and came to a dramatic end the under haphazard of Lubeck for which it was affair, opprobrium the not in fact responsible. Subcutaneous and intracutaneous inoculations followed, but caused many cold abscesses at the site of inoculation. Quite recently B.C.G. has successfully negotiated the trial of two new transcutaneous methods-a scarification and a multiple-puncture technique. As to its real efficacy, many international discussions have raised the temperature amongst the critics, and no useful purpose would be served at this late stage by going over all the arguments which concerned the experts in the Health Organisation of the League of Nations. Four facts, however, stand out from the mass of official reports and protocols of experiments : (1) the Calmette-Guerin bacillus is harmless to man; (2) inoculation with it increases resistance to tuberculosis ; (3) the degree and duration of this immunity have not yet been precisely determined; but (4), like the immunity conferred by other bacterial vaccines, it is not permanent. An impressive array of information collected from various parts of the world has recently been set forth by the European regional office of UNRRAand in a memorandum, prepared by Prof. W. H. TYTLER,2 which has been presented to health departments jointly by various tuberculosis organisations.3 These bodies have made it clear that informed opinion is in favour of
a clinical trial of B.c.G. in this and country, they also advocate a single source of under official control. Because of the earlier supply bacteriological reports on the unstable virulence of the bacillus, and because of the Lubeck incident, stress has rightly been laid on the care with which the vaccine should be prepared by the laboratories.
now
1. Bulletin of Communicable Diseases and Medical Notes,
1946,
4, 708. 2. Memorandum on B.C.G. prepared for Tuberculosis Association, Joint Tuberculosis Council, and National Association for the Prevention of Tuberculosis, 1946; see Lancet, July 27, p. 138. 3. See Lancet, July 27, p. 125.
a vaccine is made of living micro-organisms, almost as much concern, however, should be felt about its care when it is no longer under the watchful eye of the bacteriologist who has prepared it. The subcutaneous and transcutaneous methods of giving B.c.G. have been pioneered chiefly in Scandinavia. The Norwegians began with tuberculin-negative nurses and then went on to immunise groups of the general population. Later B.c.G. was introduced for the Norwegian forces in Britain, and between 3500 This group deserves and 4000 were inoculated. mention because it the is special only large body of persons immunised while living in this country ; but so far as we know the results have not yet been It has been claimed that the vaccine published. " a standardised innocuous primary infection," gives but the UNRRA bulletin emphasises what is regarded as a contra-indication to its use-namely, a latent allergy in the individual. It points out that
" In Scandinavia nurses undergoing B.C.G. vaccination are completely segregated; there is an antevaccinal period of isolation, during which all the
requisite preliminary investigations,
are
made, viz.,
tuberculin testing, radiography, ascertainment of home conditions to eliminate the possibility of recent infection. Thereafter the vaccination is carried out and, one month later, the individual is tuberculin tested. Should the reaction prove negative, the individual is segregated for another month and again tuberculin tested." .
If these difficulties have been overcome in Norway, there is no reason why they should not be tackled here, but with the present shortage of staff they will not be easily surmounted. The memorandum presented to the health departments advocates a trial-purely voluntary-with selected groups of people who are exposed to unusual risks of tuberculous infection. Those who - work in hospital-medical students, nurses, and domestics-come to mind at once ; and these groups certainly lend themselves to medical supervision, though not all their members are employed very long in one place. In the industries with a high incidence of tuberculosis it might be less easy to arrange appropriate trials ; while children in tuberculous households in this country do not in general run such serious risks as they did in Paris when the vaccine was introduced. The primary of an whether should be to determine object inquiry B.C.G. vaccine will give in Britain the satisfactory results claimed for it in Scandinavia, in Canada, and in some other parts of the world. It should be borne in mind that tests on a small scale in New York, where the conditions more closely resemble those of the large British cities, have not been strikingly favourable : moreover, the clinical picture of tuberculosis varies in different countries, racial resistance differs, and neither social circumstances nor antituberculosis measures are the same. Granted therefore that the vaccine is efficacious, it will not necessarily produce dramatic results in this country where infection is already under fair control, and where spontaneous arrest of the disease is very common : it is more likely to do conspicuous good in the devastated and hungry parts of Europe where ordinary precautions have broken down and cannot be restored for a long time ; or in the tropics. There are some, indeed, who consider it mere wishful thinking to suppose that prophylactic vaccination will hasten
386
.
i of the biliary and pancreatic tracts to the slow disappearance of tuberculosis from ouranastomoses it fear that deflect us the intestine no sphincters, and their ostia must even from more have and midst, may fundamental efforts at eradication. As Prof. ARNOLD therefore be kept away from the main stream of RICH has pointed out, however, a disease which still digesting food ; unless this is contrived, by admitting kills twice as many individuals as any other during bile and pancreatic juice to the jejunum proximal the productive period of life cannot be regarded as to the gastric opening, ascending cholangitis and will result from reflux of food up the nearly defeated. There is as yet no easy way to over so channels and the proximal jejunum will inveterate an but it is not victory enemy, respective too much to hope that immunisation, if wisely be denied the protection from the gastric juice handled, will prove a useful weapon. provided by an alkaline flow from above. Opinion The clinical trial of B.C.G. which we hope soon to differs as to whether radical pancreatoduodenectomy should be done in one or two stages. The advocates see in this country should be placed in the hands of of the one-stage operation argue that the double a body such as the Medical Research Council which has the experience, equipment, and personnel for risk of two operations is avoided, that vascular work on a sufficient scale. Only the most carefully adhesions at the second and more difficult stage compiled figures in significant quantity will satisfy are sidestepped, and that the patients, though deeply the statisticians. The question also arises whether jaundiced, can be carried safely through by sufficient it should be confined to B.C.G. The vole bacillus preparation, particularly with vitamin K. The’two. discovered by A. Q. WELLS shortly before the war4 stage protagonists hold that these patients are too ill to stand a major procedure without preliminary is running the Calmette-Guerin organism very close, in and BIRKHAUG’S latest experiments suggest that biliary decompression;- they do not find adhesions 5 a problem at the second stage if the gall-bladder animals its immunising properties are as high.5 is anastomosed to the jejunum. WHIPPLE,7 doyen of pancreatic surgeons and Excision of the Head of the Pancreas an advocate of the one-stage operation, has lately HOPES of a radical treatment for carcinoma of the distilled his wisdom in a formula for the operation. pancreas were first raised in 1899 when HALSTED For an ampullary growth the abdomen is entered excised a segment of the duodenum and part of the through a right rectus incision from the costal margin the umbilicus. After a general survey, the peripancreas for an ampullary growth; but progress to toneum is incised to the right of ’the duodenum, was sporadic until, in 1935, WHIPPLE, PARSONS, which is elevated to determine the mobility of the and MULLINSg initiated a systematic study. Since then reports of excision of the duodenum and panpancreatic head, and the configuration of the uncinate creatic head for carcinoma have become almost process is studied. If the growth appears operable, the common bile-duct is divided behind the duodenum. commonplace in America. stomach is transected proximal to the pylorus, Apart from the rare islet-cell tumour, malignant The and from growths of the head of the pancreas may be classified the the origin of the gastroduodenalandartery The cut. hepatic artery revealed, ligated, according to their site in two main varieties : carci- duodenum is divided to the duodenojejund proximal noma of the ampulla of Vater or its immediate tributaries grows slowly and gives rise to early flexure (this stage must be modified if the uncinate encircles the superior mesenteric vessels); jaundice, whereas carcinoma of the head of the process the and inferior pancreaticoduodenal artery is secured. pancreas proper is more common, more malignant, cut across at the junction of the The is pancreas and gives rise to jaundice somewhat later. A radical head and the body, and the splenic vessels, portal resection of either type necessitates removal not only and superior mesenteric vessels are dissected of the pancreatic head but also of the duodenum, . vein, because the lymphatic and blood supplies of the off, drawing the pancreatic head to the right. The pylorus, duodenum, lower end of common bile-duct, two organs are inseparable. So bold an extirpation head of pancreas are now removed en bloc. (involving as it does the division and repair of the and A loop of jejunum is brought up and anastomosed intestinal, biliary, and pancreatic tracts) would to stomach, pancreatic stump, and cut lower scarcely be possible without the recent advances end the of from below upwards, so that the bile-duct, in chemotherapy, the discovery of vitamin K, and is the most distal in the jejunum. gastric opening the excellence of resuscitative and anaesthetic techIt seems easier than be supposed to insert a niques. The problems of the actual excision are small rubber tube intomight the pancreatic duct which is anatomical and are largely concerned with avoiding dilated and to thrust the tube from obstruction, damage to blood-vessels essential to life. The repair a small hole into the lumen of the jejunum; which follows has its special difficulties. The thorniest through the of then sutured cut is to the jejunal edge pancreas this is the treatment of the pancreatic stump ; is inserted the wall. A drain and abdomen closed. continues to secrete the most powerful proteolytic WHIPPLE attaches to the of use great importance enzyme in the body, and mere closure of the cut silk the because is throughout operation, catgut end has led, through sloughing and digestion of and he readily digested by escaping any trypsin ; damaged tissues and sutures, to external fistulae thinks that the gall-bladder should never be used and-still worse---to internal leaking. What remains to anastomose the biliary tract to the intestineof the pancreas must therefore be anastomosed to an unavoidable expedient in the two-stage operation. the jejunum, into which it can secrete. The new What are the results ? WHIPPLE in 1945 8 reported 4. Wells, A. Q. Lancet, 1937, i, 1221, 1233. that he had done 8 two-stage operations with an 5. Birkhaug, K. Amer. Rev. Tuberc. 1946, 53, 411 ; see Lancet,
pancreatitis
July 6, p. 17. 6. Whipple, A. O., Parsons, W. B., Mullins, C. R. 1935, 102, 763.
Ann.
Surg.
7. Whipple, A. O. Surg. Gynec. Obstet. 1945, 8. Whipple, A. O. Ann. Surg. 1945, 121, 847.
82, 623.
"