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six months of vaccination on 814 farms out of anestimated number of 460,000 treated herds, and inabout 60 % of these outbreaks it was due to the incursionof a type of virus different from that used in the prepara-tion of the vaccine. Waldmann (1942) claims that theimmunity lasts at least six, and usually eight, months.

Despite the efforts of Continental workers and thehigh claims made for the vaccine, there occurred in theReich more than 89,000 outbreaks of foot-and-mouthdisease during 1940-41, when facilities for the prepara-

tion of vaccine were presumably at their maximum. Anadsorbed vaccine inactivated in the presence of anisolewas described by Vianello (1940) and has been used inItaly. These adsorbed vaccines have been used on avery large scale because there happened to be a severeepidemic of foot-and-mouth disease when they werebeing tested experimentally and there was a greatdemand for a vaccine. Unfortunately there is littleevidence to show that they are superior to formolisedlymph, which is much simpler to prepare. -

While this work was going on, Graub used exactly thesame methods as those used in the preparation of crystal-violet swine-fever vaccine to prepare a vaccine againstfoot-and-mouth disease (Graub 1938, Graub et al. 1940).After considering all the available evidence the Foot-and-Mouth Disease Research Committee decided toconduct experiments on the crystal-violet blood vaccineat Pirbright (Cabot 1945). This vaccine is even simplerto prepare than that made from the formolised lymphand epithelium ; the crystal-violet blood mixturerequired only a few days’ incubation at 37 °C to becomeinactive. It produced a good immunity lasting aboutsix months in cattle. There is evidence (Cabot 1945)that many outbreaks of foot-and-mouth disease in thiscountry are due to feeding pigs with swill containinginfected meat from the Argentine. The crystal-violetvaccine is now being tested in that country, and pre-liminary successful results have’been reported (Vieraand Castelo 1944).

NEWCASTLE DISEASE

Work on immunisation against Newcastle disease hasbeen reviewed by Francis (1947). The chick embryoprovides a better source of virus for the preparation ofvaccines than does the hatched bird ; and though thetissues of the embryo contain a lower titre of virusthan do the fluids they are equally antigenic. Formolisedvaccines seem to be more effective than those inactivatedby other means, including ultraviolet rays ; vaccines inacti-vated in the presence of crystal-violet are not antigenic.lyer and Dobson (1940) found, rather surprisingly,that passage of the virus on the chorio-allantois pro-duces attenuation for the hatched bird, and it appearsthat this attenuated strain is being used with successfor immunising poultry in India. American workershave confirmed this attenuation but think that thesafest method of immunisation is to prolong the shortimmunity produced with formolised vaccines by aninjection of the attenuated virus. Chicks hatched fromeggs laid by immune birds do not respond to vaccina-tion, because of the passive immunity transferred by thevolk sac.

DOG DISTEMPER

The work of Laidlaw and Dunkin (1928) on dogdistemper is too well known to require detailed discussion.Green (1945) reported experiments indicating that 50passages of distemper virus in ferrets considerablylowered its virulence for young foxes and dogs.

SUMMARY OF THE FACTS

The work on the production of vaccines againstswine fever, rinderpest, and foot-and-mouth disease hasbeen closely linked. In all these diseases the bloodand internal organs contain fairly high titres of virus,and in swine fever both of them produce quite goodvaccines when suitably inactivated. In rinderpest, andprobably in dog distemper, the blood is useless as anantigen, but in foot-and-mouth disease it is much moreeffective than the internal organs. In Newcastle diseasethough the embryo contains a lower virus titre than dothe fluids it is equally antigenic.The serum (virus) simultaneous method of vaccina-

tion produces a strong and lasting immunity against

rinderpest, swine fever, and dog distemper, but infoot-and-mouth disease a proper balance of virus andserum cannot be achieved ; often either no immunityis produced or overt disease develops.

In Newcastle disease, rinderpest, and possibly dog dis-temper, but not in the other diseases, modified liveviruses can be used for vaccination.Formalin is a good, and probably the best, inactivating

agent in rinderpest, dog distemper, and foot-and-mouthdisease (when infected epithelium and vesicle fluid areused). In Newcastle disease it is probably superior toultraviolet rays as an inactivating agent. With rinder-pest, foot-and-mouth disease, and swine fever highlyantigenic vaccines can be prepared if infective materialis incubated in the presence of glycerol, erystal-violet,or eucalyptus, but it has not been demonstrated, as ithas with formalin, that the process is anything morethan a simple heat inactivation, these substances merelyhelping to reduce bacterial contamination. There canbe no doubt that the virus in most of these vaccinesis " dead," and’immunity is not due to multiplication .of virus but to the antigenicity of killed virus protein.

Pigs and chicks from immune mothers do not respondto vaccination during the first few weeks of life, becausethey have received antibodies via the placenta andyolk sac respectively.

REFERENCES

Bedson, S. P., Maitland, H. B., Burbury, Y. M. (1927) SecondProgress Report of Foot-and-Mouth Disease Research Commit-tee. London.

Cabot, D. A. E. (1945) Vet. Rec. 57, 375.Doyle, T. M. (1942) Vet. J. 98, 51.Edwards, J. T. (1927) Trans. 7th Congr. Far East Ass. trop. Med.

3, 699.Fogedby, E. F. (1939) Vet. Rec. 51, 1307.Francis, J. (1941) Ibid, 53, 622.

— (1946) Ibid, 58, 501.— (1947) Ibid, 59, 437.

Gräub, E. (1938) Schweiz. Arch. Tierheilk. 80, 524.- Zschokke, W., Saxer, E. (1940) Ibid, 82, 461.

Green, R. G. (1945) Amer. J. Hyg. 41, 7.Hansen, A., Schmidt, S., Oerskov, J. (1936) C.R. Soc. Biol. Paris,

123, 717.Harbo, J. (1940) Skand. VetTidskr. 30, 411.Iyer, S. G., Dobson, N. (1940) Vet. Rec. 52, 889.Laidlaw, P. P., Dunkin, G. W. (1928) J. comp. Path. 41, 1, 209.McBryde, C. N., Cole, C. G. (1936) J. Amer. vet. med. Ass. 89, 652.Matthews, H. T., Doyle, T. M. (1943) J. comp. Path. 53, 121.Schmidt, S. (1936) Rev. Immunol. 2, 580.- Hansen, A. (1936a) C.R. Soc. Biol. Paris, 121, 1236. — — (1936b) Ibid, p. 1242.- Oerskov, J. (1935) Acta path. microbiol. scand. 12, 262.- - Hansen, A. (1936) C.R. Soc. Biol. Paris, 123; 721.

Toussieng, E. (1944) Maanedsskr. Dyrlaeg. 56, 49.— Fogedby, E. F., Frenkel, H. S., van Waveren, G. (1938)

Bull. Off. int. Epizoot. 16, 205.Vallée, H., Carré, H., Rinjard, P. (1926) Rev. gén. Med. vét. 35, 129.Vianello, G. (1940) Azione vet. 9, 132.Viera, O., Castelo, M. (1944) Rev. Med. vet., B. Aires, 26, 114.Waldmann, O. (1930) Proc. 11th int. vet. Congr. 2, 37.

— (1938) Dtsch. tierärztl. Wschr. 46, 569.- (1942) Berl. Münch. tierärztl. Wschr. July, p. 221.- Koebe, K., Pyl, G. (1937) Bull. Off. int. Epizoot. 13, 825.- Reppin (1935) Z. Infektkr. Haustiere, 47, 283.

STREPTOMYCIN TRIALS

PRELIMINARY REPORT

AN account of the Medical Research Council’s first trialsof streptomycin was given at a meeting of the Tubercu-losis Association on Feb. 20.

Dr. GEOFFREY MARSHALL said that it had been decidedto test streptomycin in three types of disease : (1) tuber-culous meningitis ; (2) acute miliary tuberculosis ; and(3) one type of pulmonary tuberculosis. In the last groupit was obviously difficult to obtain a conclusive answerwithin a reasonable time ; and the first aim had beento work on a more or’less uniform group where clinicianswould not ordinarily wish to undertake other forms oftreatment. Thus the group selected had been youngadults with rapidly advancing bilateral lesions of whichcavitation was not a prominent feature. Great care

had been exercised in selection both by clinicians andstatisticians ; and where other forms of treatment hadbeen deemed necessary during the course of streptomycin,the case had been withdrawn from the trial.

Altogether, the cases treated with streptomycin inthese first trials in 1947 numbered : tuberculous

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meningitis, 138 ; acute miliary tuberculosis, 31 ,andpulmonary tuberculosis, 55. The drug was now also

being tested in tracheobronchial ulceration and as an"umbrella" in thoracic surgery: and in another seriesvariations in the rhythm of treatment were being tried inan attempt to circumvent the development of resistance.

TUBERCULOUS MENINGITIS

Prof. NORMAN CAPON, reporting on trials in youngchildren with tuberculous meningitis at one centre,emphasised that the daily intrathecal injections werean ordeal for patients and a strain on the staff. For

early diagnosis the identification of early choroidal

changes had proved helpful.Streptomycin resistance had developed in only 1 of 29

cases treated. The amount given was 0.6-1.0 g. daily,in four separate intramuscular injections ; and in addi-tion 0.1 g. was administered intrathecally. All patientshad had intrathecal injections despite the drug’s irritanteffect ; the present aim was to give streptomycin forseveral months by the intramuscular route, and toadminister it intrathecally for a week at a time withintervals between. In 4 cases with block, streptomycinhad been given into the ventricles ; and 1 survivor hadreceived it intracisternally without ill effects. Toxiceffects had not been many or serious, but 1 survivorwas deaf. Surprisingly, said Professor Capon, childrenwho had recovered clinically sometimes had a grosslyabnormal cerebrospinal fluid (C.S.F.). Did this meanthat the terminal results would be less satisfactory thanwas hoped ? Would not healing in itself be a dangerin the long run ?

Dr. HONOR SMITH, from experience of streptomycinfor tuberculous meningitis in children and adults at onecentre, concluded that the intrathecal route was essential.Intramuscular injections should be continued for sixto nine months and intrathecal for five to six weeks.In fatal cases necropsy had revealed a dense mass ofexudate filling the interpeduncular fossa and spreadingupwards. Occlusion of the cisterna ambiens resulted inobstruction of the c.s.F. circulation and in hydrocephalusof the communicating type. This exudate hindered

streptomycin from reaching the interpeduncular fossa.There was, moreover, occlusion of arteries in the exudate ;and arteriography in one of these cases showed occlusionof the anterior cerebral artery and an attenuated fillingof the middle cerebral. Other components of this"

interpeduncular syndrome " were oculomotor palsyand manifestations of hypothalamic disturbance. Such

changes might be observed in non-fatal as well as fatalcases ; and it seemed that they might be reversed.

Lately instillation of streptomycin into the cisternachiasmatica had been undertaken, but so far it was

impossible to judge results. Clinical experience indicatedthat no patient was too ill to treat ; the prognosis couldbe decided better by the patient’s progress under treat-ment than by his primary condition. In doubtful casesit was difficult to know whether to await a firm

diagnosis, by identification of the bacillus, before start-ing treatment. In one fatal case, where the diagnosis wasestablished at necropsy, twenty-eight cultures had beennegative. Probably it was best to start treatment imme-diately, before the brain had been irreparably damaged.. PULMONARY TUBERCULOSIS

Dr. DOUGLAS SMITH, commenting on streptomycintreatment in young adults unsuitable for collapse therapy,observed that in some cases streptomycin resistance didnot develop. Why should this be ? It seemed thatresistance was most likely to develop in the presence ofcavitation. With regard to toxicity, vestibular disturb-ance was common ; there might be nausea, vomiting,and nystagmus, but after about three weeks these

symptoms usually abated somewhat.

Dr. RICHARD BRENT said that under treatment somecases of pulmonary tuberculosis improved for two orthree months and then relapsed. Tests indicated thatusually drug resistance developed in eight to twelveweeks ; cessation of clinical improvement and the onsetof resistance usually coincided.

Dr. J. W. CROFTON said that in cases responding tostreptomycin therapy the first evidence of improvementwas an increased sense of well-being, and radiologicalimprovement lagged behind clinical improvement. Among31 cases treated with the drug toxic symptoms had beennoted as follows : local pain 12, rash 4, nausea, &c., 9,giddiness 11, mouth numbness 3, and eosinophilia 11.

Objective tests revealed labyrinthine disturbance monthsafter the end of treatment; this disturbance was besttested by asking the patient to walk down a straight linewith his eyes shut. In no case had reactions beensevere enough to necessitate interruption of treatment.

PATHOLOGY

Dr. ROBERT CRUICKSHANK said that in tests on sputumevidence of resistance in tubercle bacilli appearedbetween five and twelve weeks after the start of treat-ment. Not too much importance should, however, beattached to these findings ; it was true that the pro-portion of resistant strains increased, but qualitativetests were misleading.

Dr. I. A. B. CATHIE said that in tuberculous meningitisthe chloride content of the C.S.F. was often no guide to thediagnosis ; the most reliable indicator in the c.s.F. wasa reduced and falling sugar content. In children atGreat Ormond Street the daily dosage was determinedon the basis of 0-01-0-02 g. per lb. body-weight. The

protracted increase in protein content sometimes observedwas a streptomycin effect ; and streptomycin itself alsocaused an increase in the c.s.F. polymorphs. Improve-ment was sometimes heralded by a fall in the cell contentand a rise in the protein content of the c.s.F. At first,the blood-sedimentation rate almost always fell; but therate increased again if the condition was not responding.

RESULTS

Dr. MARC DANIELS described the organisation of thesetrials, which were designed to use a very limited supplyof the drug to the best advantage, with a reasonablehope of reaching statistically valid conclusions.

Preliminary results given by Dr. Daniels justified theconclusion that streptomycin is a powerful weapon inthose forms of tuberculosis which hitherto have beenalmost invariably fatal, though the long-term results arestill in question; and that it is a useful adjuvant in someother forms of the disease. The first full report on themeningitis cases is to appear shortly, and this will befollowed by reports on the miliary and pulmonary series.

... The long-term patient is the chronic patient ofyesterday’s terminology, who was popularly thought to behopeless in prognosis and therefore a useless burden on

society. We are supposed to know better today. This typeof patient claims medical attention for a relatively longer-period of time, but not necessarily for an endless period oftime. The same illness may produce short-term or long-termeffects, depending on the patient and his various natural andacquired defenses against illness. The difference between theshort and the long-term patient is thus seen to have beenartificially set. There is, in fact, no sharp line of demarcationbetween the two.... The phenomenon of clinical urgencymay be subjective, objective, or both. From the standpointof hospital response, short-term illness is more objective thansubjective, while long-term illness is more subjective thanobjective. In the former case we respond to the call almostinstinctively ; in the latter case we seldom respond, even afterrepeated knocking at our doors."-Dr. E. M. BLUESTONE;Bull. Amer. Coll. Surg., September, 1947.