TETANUS IN WAR AND PEACE
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204 of thrombosis or disturbance at the site of operation, though a careful watch will have to be kept for any abnormality appearing in later years. The conception and execution of Crafoord’s attack on what has hitherto seemed ’an unassailable problem must be regarded as an outstanding achievement which opens up further possibilities in the realm of active therapy. ANIMAL TESTS OF LIVER EXTRACTS THE assay of the anti-pernicious-anaemia factor in liver fractions by a test on animals would obviously be preferable to the present method of testing on patients with pernicious anaemia, but repeated attempts to find a suitable test have failed, for two main reasons : first, it has not been possible to induce true pernicious anaemia in animals (the monkeys used by Wills and Stewart had a nutritional anaemia) ; and secondly, the tests have rested on a reticulocyte response which, at best, rose little above the limit of normal variation. Jacobson and Williams 1 at Cambridge, using splenectomised rabbits, are the latest to claim that they have answered the problem. In these animals the reticulocyte count rarely rises spontaneously above 3-5%, whereas injection of a liver extract known to be active for pernicious anaemia produces a rise to 5-6% ; the smallest dose required to produce this response gives a measure of the activity. The presence of tricresol, or filtration through a Seitz pad, seriously interferes with the test. The results can be repeated, and as a rule comparable rises are obtained when an extract is given to several animals. The animals are not anaemic, and there is no evidence of any interference with normal erythropoiesis ; the liver apparently stimulates normal erythropoiesis to greater activity ; comparatively large doses have to be used and a negative result may indicate only low concentration of the anti-anaemic factor. - Liver extracts are known to contain many other substances besides the anti-anaemic factor, and Jacobson and Williams 2 have therefore attempted to find out how far the test is specific. Negative results with ascorbic acid, thiamine, calcium- pantothenate, nicotinamide, biotin, and lactoflavin were obtained. Amino-acids, like histidine and a proprietary peptone, were likewise ineffective ; iron produced a response only with a very large dose. Pterins were also tested, since these sub- stances have been found in the pigment granules in the argentaffine cells of the alimentary tract, which appear to be connected with the production of the anti- pernicious-anaemia principle ; leucopterin and xantho- pterin, both natural and synthetic, were found to produce reticulocyte responses comparable to those obtained with liver extract in the splenectomised rabbits. But pterins are not known to be active in pernicious anaemia. Castle and others have incubated xanthopterin with gastric juice, and the resultant substance had no demonstrable anti-pernicious-anaemia activity ; there are, however, several references to the stimulant effect of pterins on erythropoiesis in animals with either nutritional or post-haemorrhagic anaemia. The test appears to be based on a fallacy, for, although some experiments indicate that the spleen may retard the release of cells from the bone-marrow, there is no real evidence that splenic extracts inhibit erythropoiesis ; their use in human polycythaemia vera long ago accom- panied onion extract and other treatments into oblivion. There remains the difficulty of obtaining a readably significant increase of reticulocytes in a non-anaemic animal-the difference between 3-5% and 5-0% may be statistically significant, but in practice it is only 15 reticulocytes in the 1000 cells counted, so exceptional care will be needed in deciding what is or is not a reticulo- 1. Jacobson, W., Williams, S. M. J. Path. Bact. 1945, 57, 101. 2. Ibid, p. 423. 3. Castle, W. B., et al. Science, 1944, 100, 81. cyte. Finally, the results with the pterins inevitably suggest that what is being estimated is nof the anti- pernicious-anaemia factor but something else associated with it in an unknown manner. Jacobson and Williams will not be surprised if hsematologists, after so many disappointments in this line, are not excited about their results. But the experiments are likely to be repeated, because the test may at least make it possible to select the batches of liver extract that are worth clinical trial. TETANUS IN WAR AND PEACE TETANUS, like gas-gangrene, is caused by an anaerobic sporing bacillus whose natural habitat is the bowel of animals and the spores of which persist in faecal-soiled earth or dust. Both infections have been much more common in war than in peace, for the deep penetrating dirt-contaminated wound of the soldier seems to facilitate infection with the sporing anaerobes more than the bruises that accompany street or factory accidents. Indeed, the primary focus of tetanic infection may be so small as to -be entirely overlooked and the conditions which favour germination of tetanus spores are still imperfectly understood. The spores may lie latent in the tissues for long periods, and Clostridium tetani, like other anaerobic pathogens, may be present in wounds without being associated with active infection. Sepsis and the toxins of other clostridia predispose to infection, but whether by lowering oxidation-reduction potential or by preventing phagocytosis of tetanus spores is still in dispute. The incidence of tetanus in the first year of the 1914-18 war was 9 per 1000 wounded, a figure which after the routine use of prophylactic tetanus antitoxin was reduced to less than 1 per 1000. By contrast, the ‘ average annual number of fatal cases of tetanus in 1927-37 was 126-6, which with a case-fatality of 40-50% must mean that tetanus develops in a very small pro- portion of the accidents that occur every year. Yet the infection is so horrible and so difficult to treat in its florid state that every possible means of preventing it must be utilised in peace as well as in war. The use of tetanus toxoid in two doses of 1 -0 c.cm. at an interval of not less than 6 weeks was shown by Boyd 1 to produce an active immunity, and at the outbreak of war in 1939 a high proportion of our Armed Forces had already been actively immunised against tetanus. Later a boost- ing dose of tetanus toxoid was given at intervals of 6-12 months after the primary inoculations, to maintain the antibodies at as high a level as possible, and in addition any soldier who was wounded was given 3000 units of antitoxin, repeated weekly for 4 weeks in those not actively immunised. That this policy had its due reward is demonstrated by Boyd’s 2 analysis of figures for the African and European campaigns. Thus the incidence for the B.L.A. was only 6 per 100,000 wounded, which may be compared with a rate of 147 per 100,000 during the 1914-18 war. Higher rates (43 and 22 per 100,000) were recorded in the B.E.F. and M.E.F., but these infections mostly arose among the small percentage of men who were not actively immunised. The few cases of tetanus in men who received both primary and boosting inoculations seemed to be related to the failure in antibody production which occurs in a small proportion of people, and which probably justified the British injunction to give prophylactic doses of tetanus anti- toxin to every wounded man. The success and safety of active immunisation against tetanus has impressed America, where this infection has always been a bogy from the days when it used to affect a fair number of Fourth of July revellers ; and indeed deaths from tetanus have lately exceeded those from diphtheria in some American States. A combination of tetanus and diph- 1. Boyd, J. S. K. J. R. Army med. Cps, 1938, 70, 289. 2. Lancet, Jan. 26, 1946, p. 113.
Transcript of TETANUS IN WAR AND PEACE
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of thrombosis or disturbance at the site of operation,though a careful watch will have to be kept for anyabnormality appearing in later years. The conceptionand execution of Crafoord’s attack on what has hithertoseemed ’an unassailable problem must be regarded as
an outstanding achievement which opens up furtherpossibilities in the realm of active therapy.
ANIMAL TESTS OF LIVER EXTRACTS
THE assay of the anti-pernicious-anaemia factor inliver fractions by a test on animals would obviously bepreferable to the present method of testing on patientswith pernicious anaemia, but repeated attempts to find asuitable test have failed, for two main reasons : first,it has not been possible to induce true pernicious anaemiain animals (the monkeys used by Wills and Stewart hada nutritional anaemia) ; and secondly, the tests haverested on a reticulocyte response which, at best, roselittle above the limit of normal variation. Jacobsonand Williams 1 at Cambridge, using splenectomisedrabbits, are the latest to claim that they have answeredthe problem. In these animals the reticulocyte countrarely rises spontaneously above 3-5%, whereas injectionof a liver extract known to be active for perniciousanaemia produces a rise to 5-6% ; the smallest doserequired to produce this response gives a measure of theactivity. The presence of tricresol, or filtration througha Seitz pad, seriously interferes with the test. Theresults can be repeated, and as a rule comparable risesare obtained when an extract is given to several animals.The animals are not anaemic, and there is no evidence ofany interference with normal erythropoiesis ; the liverapparently stimulates normal erythropoiesis to greateractivity ; comparatively large doses have to be usedand a negative result may indicate only low concentrationof the anti-anaemic factor. -
Liver extracts are known to contain many othersubstances besides the anti-anaemic factor, and Jacobsonand Williams 2 have therefore attempted to find out howfar the test is specific. Negative results with ascorbicacid, thiamine, calcium- pantothenate, nicotinamide,biotin, and lactoflavin were obtained. Amino-acids,like histidine and a proprietary peptone, were likewiseineffective ; iron produced a response only with a verylarge dose. Pterins were also tested, since these sub-stances have been found in the pigment granules in theargentaffine cells of the alimentary tract, which appearto be connected with the production of the anti-
pernicious-anaemia principle ; leucopterin and xantho-pterin, both natural and synthetic, were found to producereticulocyte responses comparable to those obtained withliver extract in the splenectomised rabbits. But pterinsare not known to be active in pernicious anaemia. Castleand others have incubated xanthopterin with gastricjuice, and the resultant substance had no demonstrableanti-pernicious-anaemia activity ; there are, however,several references to the stimulant effect of pterins onerythropoiesis in animals with either nutritional or
post-haemorrhagic anaemia.The test appears to be based on a fallacy, for, although
some experiments indicate that the spleen may retardthe release of cells from the bone-marrow, there is noreal evidence that splenic extracts inhibit erythropoiesis ;their use in human polycythaemia vera long ago accom-panied onion extract and other treatments into oblivion.There remains the difficulty of obtaining a readablysignificant increase of reticulocytes in a non-anaemicanimal-the difference between 3-5% and 5-0% may bestatistically significant, but in practice it is only 15
reticulocytes in the 1000 cells counted, so exceptionalcare will be needed in deciding what is or is not a reticulo-
1. Jacobson, W., Williams, S. M. J. Path. Bact. 1945, 57, 101.2. Ibid, p. 423.3. Castle, W. B., et al. Science, 1944, 100, 81.
cyte. Finally, the results with the pterins inevitablysuggest that what is being estimated is nof the anti-pernicious-anaemia factor but something else associatedwith it in an unknown manner. Jacobson and Williamswill not be surprised if hsematologists, after so manydisappointments in this line, are not excited about theirresults. But the experiments are likely to be repeated,because the test may at least make it possible to selectthe batches of liver extract that are worth clinical trial.
TETANUS IN WAR AND PEACE
TETANUS, like gas-gangrene, is caused by an anaerobicsporing bacillus whose natural habitat is the bowel ofanimals and the spores of which persist in faecal-soiledearth or dust. Both infections have been much morecommon in war than in peace, for the deep penetratingdirt-contaminated wound of the soldier seems to facilitateinfection with the sporing anaerobes more than thebruises that accompany street or factory accidents.Indeed, the primary focus of tetanic infection may be sosmall as to -be entirely overlooked and the conditionswhich favour germination of tetanus spores are still
imperfectly understood. The spores may lie latent inthe tissues for long periods, and Clostridium tetani,like other anaerobic pathogens, may be present inwounds without being associated with active infection.Sepsis and the toxins of other clostridia predispose toinfection, but whether by lowering oxidation-reductionpotential or by preventing phagocytosis of tetanus sporesis still in dispute.The incidence of tetanus in the first year of the 1914-18
war was 9 per 1000 wounded, a figure which after theroutine use of prophylactic tetanus antitoxin wasreduced to less than 1 per 1000. By contrast, the ‘average annual number of fatal cases of tetanus in1927-37 was 126-6, which with a case-fatality of 40-50%must mean that tetanus develops in a very small pro-portion of the accidents that occur every year. Yetthe infection is so horrible and so difficult to treat inits florid state that every possible means of preventingit must be utilised in peace as well as in war. The useof tetanus toxoid in two doses of 1 -0 c.cm. at an intervalof not less than 6 weeks was shown by Boyd 1 to producean active immunity, and at the outbreak of war in1939 a high proportion of our Armed Forces had alreadybeen actively immunised against tetanus. Later a boost-ing dose of tetanus toxoid was given at intervals of 6-12months after the primary inoculations, to maintain theantibodies at as high a level as possible, and in additionany soldier who was wounded was given 3000 units ofantitoxin, repeated weekly for 4 weeks in those not
actively immunised. That this policy had its duereward is demonstrated by Boyd’s 2 analysis of figuresfor the African and European campaigns. Thus theincidence for the B.L.A. was only 6 per 100,000 wounded,which may be compared with a rate of 147 per 100,000during the 1914-18 war. Higher rates (43 and 22 per100,000) were recorded in the B.E.F. and M.E.F., butthese infections mostly arose among the small percentageof men who were not actively immunised. The fewcases of tetanus in men who received both primary andboosting inoculations seemed to be related to the failurein antibody production which occurs in a small proportionof people, and which probably justified the Britishinjunction to give prophylactic doses of tetanus anti-toxin to every wounded man. The success and safetyof active immunisation against tetanus has impressedAmerica, where this infection has always been a bogyfrom the days when it used to affect a fair number ofFourth of July revellers ; and indeed deaths from tetanushave lately exceeded those from diphtheria in someAmerican States. A combination of tetanus and diph-
1. Boyd, J. S. K. J. R. Army med. Cps, 1938, 70, 289.2. Lancet, Jan. 26, 1946, p. 113.
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theria toxoids is now being recommended in the U.S.A.for the immunisation of children, and in Britain a
case has been made out for the active immunisationof agricultural workers against tetanus. In civilian
practice reliance is usually placed on passiveimmunisation, although the prophylactic injection oftetanus antitoxin for accident cases in outpatient depart-ments is not by any means a universal procedure.
Other forms of tetanus infection that often attract
publicity are the postoperative, which is reckoned toconstitute 5-10% of all cases, and the puerperal, whichwas recently the subject of inquiry by a committeeof the Royal College of Obstetricians and Gyneecologists.3A high proportion of cases of puerperal tetanus followabortion, and it seems reasonable to conclude that inmany of them the infection was derived from unsterilisedcotton-wool or cellulose wadding used as packs. Thesematerials commonly harbour tetanus spores,4 and thedanger of unsterilised dressings was recently demon-strated by the astonishing report of 5 fatal cases oftetanus within 15 days among women who had beenattended by the same abortionist." Postoperativetetanus, most common after abdominal operations, hasoften been blamed on catgut or contamination fromthe bowel, but catgut has very rarely been found guilty,and in this country human carriers of tetanus spores arevery uncommon. 6Another more likely source of tetanus infection is
dust coming more or less directly from the street or fromcultivated land. Kerrin7 showed that domestic animals,and particularly dogs, are frequent carriers of tetanusspores, while Fildes 8 found the organism in 57 out of79 samples of soil from cultivated fields. During therecent war many surgical theatres were protected withsandbags (often containing more earth than sand),and the possibility of anaerobic infection from theseanti-blast devices was recognised. Last week (p. 152)Robinson, McLeod, and Downie reported two probableinstances of dust-borne tetanus following surgical opera-tion, one in a sanatorium where the windows of the
operating-theatre opened on to grazing pasture (01. tetaniwas isolated both from the dust of the theatre andfrom the adjacent field) ; the other following an opera-tion for haemorrhoids where the catgut and dressingsseemed to be satisfactory but the dust of the theatretaken 11 days after operation yielded toxigenic C7. tetani.Examination of dust in 15 other operating-theatresyielded only one positive result-from the theatreadjacent to that in which the case of haemorrhoidshad been operated on. However, the positive findingsindicate that dust must be regarded as a possible sourcefor yet another infection (it has already been circum-stantially incriminated in such diseases as scarlet fever,diphtheria, psittacosis, and, experimentally, tuber-
culosis), and measures must be taken to obviate thisadmittedly small but real risk of postoperative dust-borne tetanus. Operating-theatres are often not suffi-
ciently isolated from much-trodden corridors. Anair-lock should separate the theatre from such corridors,and new methods of ventilation are needed whereby apositive pressure of air is maintained in the theatreto prevent dust being aspirated into it. Dust-layingmeasures and the use of special theatre footwear shouldalso be enforced. Where some of these recommenda-tions cannot easily be put into practice, the surgeonshould consider the wider use of prophylactic tetanusantitoxin, particularly after bowel and gynaecologicaloperations.
3. Report of the Tetanus Committee, Royal College of Obstetriciansand Gynæcologists, 1941.
4. Pulvertaft, R. J. V. Brit. med. J. 1937, i, 441.5. Bush, W. L. J. Amer. med. Ass. 1941, 116, 2750.6. Kerrin, J. C. Brit. J. exp. Path. 1928, 9, 69.7. Ibid, 1929, 10, 370.8. Fildes, P. System of Bacteriology in Relation to Medicine,
London, 1929, vol. III, p. 321.
FUTURE OF DERMATOLOGY
THE Royal College of Physicians of London last weekpublished an interim report from its committee on
dermatology,’ who are here concerned with the medicalstaff, beds, and ancillary services needed for a compre-hensive dermatological service. In a National HealthService, they point out, the demands made on dermato-logical departments will be greater than at present, formore patients will be referred to special departments bypractitioners and more patients will want to have
specialist advice. The provision they recommend is
necessary, they believe, if standards of training-andpresumably facilities for practice and research-are to beraised to a level that will give the best results in termsof health.Assuming that, for purposes of organisation, the
country will be divided into regions, whose dermatologicalcentre will be in or attached to a university hospital(in London, a teaching hospital), the committee recom-mend that the head of each central department shouldbe of professorial rank and his appointment a full-timeone. His staff should include a dermatologist of readerstatus, two full-time registrars, and two resident medicalofficers, and a number of clinical assistants should alsobe appointed. The members of this department wouldbe available for consultation with dermatologists through-out the region, and in certain circumstances by dermato-logists of other regions. Facilities for pathological andbiochemical investigation, and for physical therapy, mustbe to hand ; a cadre of special personnel will be requiredfor nursing, secretarial, and other duties ; and either inthe university hospital or in an easily accessible hospitalthere should be a block of 50 beds for dermatological cases.In addition, in every area of population of 100,000 or250,000 persons a secondary dermatological centre shouldbe established. This would be staffed by one seniordermatologist with assistants of the status of chief
clinical assistants, the size of the staff depending on thedensity of population round any given centre andwhether the area is industrial or rural. In sparselypopulated districts small outlying hospitals could beused for collecting patients suffering from cutaneousdiseases, and beds could be provided in one of eachgroup of these establishments, which specialists from thesecondary centres should visit when required. Thecommittee think it important to have rehabilitationcentres for skin cases, and they discuss the purposes thecentre would fulfil-omitting, however, to mention thepioneer work done in this connexion by the Army duringthe war. They conclude their report by quoting a
statement by Sir Archibald Gray that there are at
present 85 part-time dermatologists of consulting rankin active work in England, Wales, and Scotland,and some 30 doctors in charge of skin clinics whoare either general physicians or general practitioners.On the basis of the committee’s recommendationsthe National Health Service will require no fewer than250 dermatologists; and if some work only half-timethe number will be larger.
Evidently the committee have been impressed by thepaucity of the facilities for inpatient treatment forcutaneous diseases, and would like to see more centralisa-tion than at present, especially in teaching hospitals.
Undoubtedly by the use of modern methods of therapy,under controlled conditions, much of the gross wastageof drugs, dressings, and time which now occurs in manyareas will be obviated, and much human suffering willbe prevented ; it has often been noted that while a man
1. The members are Lord Moran, P.R.C.P. (chairman), Dr. HenrylBlacCormac (vice-chairman), Sir Archibald Gray, Dr. H. BB.Barber, Dr. A. C. Roxburgh, Dr. R. B. Mumford, Dr. G. B.Dowling, Dr. M. Sydney Thomson, Dr. R. T. Brain, Dr. J. T.Ingram, Dr. W. N. Goldsmith, Dr. J. E. M. Wigley, Dr.R. M. B. MacKenna, Dr. L. Forman (hon. secretary), Dr. B. C.Tate, and Dr. J. H. Twiston Davies.
