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eventually developed an encephalopathy ; but, aftertreatment with A.C.T.H., she recovered completely. Shewas later found to be sensitive to chloramphenicol and

local anaesthetic solution. These features may be due tothe known toxic and allergic properties of drugs con-taining a benzene ring associated with an amino grouping.. A warning is given against an early and optimisticassessment of patients treated with A.C.T.H. or cortisone.

I wish to thank Dr. T. W. Lloyd, medical superintendent ofSt. Wulstan’s Hospital, Malvern, for permission to publishthis case ; Dr. Brian Taylor for undertaking the treatmentwith A.C.T.H.; and Mr. C. G. Bradbury, chief pharmacist, forhis preparation of the skin-test materials.

REFERENCESBedford, P. D. (1952) Brit. med. J. i, 690.Bignall, J. R., Crofton, J. W., Thomas, J. A. B. (1951) Ibid, i, 554.Campbell, A. H., Neufeld, O. G. (1951) Med. J. Aust. 38, 725.Cayley, F. E. de W. (1950) Lancet, i, 447.Climie, H. (1950) Ibid, ii, 308.Fergusson, A. G., McIntyre, J. P., Gemmell, A. R. (1952) Brit. med. J.

i, 855.Hildebrand, G., Marquardt, P. (1950) Klin. Wschr. 28, 319.Kracke, R. R., Parker, F. P. (1934) J. Lab. clin. Med. 19, 799.Landsborough, D. (1951) Brit. med. J. i, 884.Lehmann, J. (1949) Dis. Chest. 16, 684.Long, D. A., Miles, A. A., Perry, W. L. M. (1951) Lancet, i, 1085 ;

Ibid, p. 1392 ; Ibid, ii, 902.Long, J. B., Favour, C. B. (1950) Bull. Johns Hopk. Hosp. 87, 186.Rocha e Silva, M. (1952) Brit. med. J, i, 779.Roussar, N. J. (1952) Ibid, p. 360.Steel, S. J. (1952) Ibid, p. 415.Veterans Administration Quarterly Report, January, 1950. Washing-

ton, D.C.

MULTIPLE PUNCTURE WITH

B.C.G. AND VOLE BACILLUS VACCINEA COMPARATIVE TRIAL

I. MILLS HALLM.D. Lond., M.R.C.P.

CONSULTANT PHYSICIAN, GERMAN HOSPITAL AND TILBURY

AND RIVERSIDE HOSPITAL ; PHYSICIAN IN CHARGE B.C.G.,UNIVERSITY COLLEGE HOSPITAL, LONDON

J. A. H. WYLIEM.A. Oxfd, M.D. Lond, D.Phil. Oxfd

UNIVERSITY DEMONSTRATOR, SIR WILLIAM DUNN SCHOOL OF

PATHOLOGY, UNIVERSITY OF OXFORD

IN view of the encouraging results obtained withvole bacillus as an antigen in laboratory animals andin cattle (Wells and Brooke 1940, Griffith and Dalling1940) and the extension of the use of this antigen toman by Wells in 1940, we decided to compare the resultsof vaccination with B.C.G. and with vole bacillus bythe same technique in comparable series of people.

Previous work with the vole bacillus had shown thatintradermal injection led to a high incidence of chroniculceration when doses similar to those of .c.G. vaccinewere used. More recently, therefore, all the vaccina-tions with vole vaccine had been done by multiplepuncture as described by Birkhaug (1944) and Wells(1946). To make the results as comparable as possibleit was decided to use the same technique with B.C.G.

and thus to eradicate one variable. Since an ulceration-rate of about 5% had been. noted when B.C.G. vaccinewas given intradermally by one of us (1. M. H.), thistrial also served to illustrate whether the complicationswere less when multiple puncture was used and whether

Fig. I-Multiple-puncture spring gun with needles fully protruded (in.

practice a protrusion of 2 mm. is used).

Fig. 2-Usual reaction to multiple-puncture vaccination with vole

bacillus or with B.C.G.

the conversion-rate suffered in any way from thisdifferent technique.

METHOD

The apparatus (fig. 1) is a modification of the originadesign of Birkhaug.* * Since the vole bacillus has beenshown repeatedly to be more virulent than B.C.G.

(Griffith and Dalling 1940, Wells 1949, Wylie 1952,Wells and Wylie 1952), a suspension of B.o.G. 20 mg.per ml. was used as opposed to a suspension of volebacillus 2 mg. per ml.

’

The communities selected for these comparable trialsconsisted of (1) medical students in their second year ofstudy at University College, London ; (2) nurses fromthe preliminary training school at University CollegeHospital, London ; and (3) children in three specialschools of the Royal Eastern Counties, under thedirection of Dr. R. M. Bates, director of education andmedical superintendent. Mantoux tests were madeon all the subjects. Only those who were definitelynegative to 100 units of Old Tuberculin were selectedfor vaccination. All these persons had their chests

radiographed before vaccination to exclude "any earlylesion which had not yet produced Mantoux conversion,and also to recognise and record any other radiologicalfinding which, after vaccination, might be mistakenfor a recent active focus. Altogether 197 persons werevaccinated in our present series. - :-

The medical students and nurses were selected at

random, odd numbers receiving one vaccine, and evennumbers the other. The children attending the specialschools were selected more carefully because of consider-able variation in their home conditions and the risk ofexposure to tuberculosis when they went home for theholidays. With the aid of the schools authorities thehome conditions were graded, and in each group halfthe children received vole-bacillus vaccine, and the otherhalf B.C.G. vaccine. The ages in each group were about

equal. All these persons were tuberculin-tested with10 units of Old Tuberculin six or seven weeks aftervaccination and, if negative to this, again with 100units of Old Tuberculin.. To these were added a groupof medical students at Oxford vaccinated .with volebacillus by the same technique.The site of vaccination was usually over the brachial

portion of the deltoid muscle, but in nurses and womenstudents the anterolateral surface of the thigh was

preferred. The skin was cleansed with 70% alcoholfollowed by etheor to remove all surface grease. A circleof tissue paper t of’ the same diameter as the end-plateof the apparatus was soaked in the vaccine and appliedsmoothly to the skin surface. The forty needles of theapparatus were previously adjusted so that they pro-truded 2 mm. beyond the flat surface after release of thespring. The needles were then withdrawn, the flat end-21 Manufactured by Mast & (-!o., Tjongworth lioad, Oxford, from the

ol il by Mr. S. BV. l3usll. -

f C. ] 05 . ’Lens Tissue,’. manuta.ctvu’cd by J. Barcham Green,Maidstoue, Rent.

-

609

plate was applied firmly over the disc of the tissue paper,and the needles were released. The end-plate andneedles- were next immersed in boiling water for tenseconds after each vaccination.This description of the procedure may sound rather

formidable but no pain is felt, the sensation beingsimilar to a light tap by a blunt instrument. As arule there is no immediate impression left, but occasionallya few pinpoint-haemorrhages may appear.

RESULTS

Local ReactionUsually nothing is visible at the site of vaccination

for about three weeks, after which period small papulesbegin to appear (fig. 2). In this eruptive stage a slightitching is often experienced’; where this may give riseto scratching, as in children, the local application of’Amethocaine’ ointment is effective. In most cases

the papules remain discrete, and only rarely does the

overlying skin break down to form a scab. The papulesare static for some weeksor months and finally fadeaway, either disappearingentirely or leaving a fewminute depressed scars.

Where there has beentrauma from scratching,secondary infection may beintroduced, and some of thepapules may then coalesce.This condition respondsreadily to the local applica-tion of sulphonamides orof penicillin cream. Theseverer reactions (fig. 3)are seen more often with

Fig. 3-More severe reaction tomultiple-puncture vaccinationwith vole bacillus.

-1 2L1’G 3UUII IJLLOHJ 01 mil W1L11

vole bacillus, illustrating its greater virulence.In the present series no such ulceration was observed,

but discrete papules and occasional scabs were observedamong those receiving vole-bacillus vaccine. The rosetteof papules was sometimes incomplete, owing either toirregularity of pressure upon the instrument or to

unequal sharpness of the needles.In only one case in this series was there any enlargement of

local lymph-glands : in a child attending a special schoolan enlarged lymph-gland appeared six weeks after vaccina-tion with vole bacillus, and later became fluctuant, buteventually subsided without ulceration after the administra-tion of p-aminosalicylic acid 3 g. three times a day for fiveweeks.

Conversion-rate .

Table i shows the conversion rate after seven weeks ofthe whole series. As will be seen, one person vaccinatedwith vole bacillus and one person vaccinated with B.C.G.had not converted by this time, thus giving the figuresof 98-23% conversion-rate for vole-bacillus vaccineand 97-62% conversion-rate for B.C.G. vaccine.The vole-bacillus vaccine’s greater virulence and

greater power for producing Mantoux conversion are

illustrated in table 11, which shows that after sevenweeks 70% of persons vaccinated with vole bacilluswere positive to 10 units of Old Tuberculin, comparedwith 45-24% of those vaccinated with B.c.G.Some of the special-school children were tested after

an interval of four weeks to see if there was any differencein the speed of conversion between the two vaccines.The results of this are set out in table ill, which shows

TABLE I-CONVERSION-RATE AFTER SEVEN WEEKS IN WHOLESERIES

Vaffinf I No. I No. I No. not Conversion-Vaccine vaccinated converted converted rate (%)

TABLE II——DIFFERENCE OF TITRE OF CONVERSION TO OLD

TUBERCULIN SEVEN WEEKS AFTER VACCINATION

that the conversion-rate of the children vaccinated withvole bacillus was 100%, whereas that of the childrenvaccinated with s.c.G: was 97-83%. This differenceis not significant.

DISCUSSION

It cannot be overemphasised that a - prophylacticprocedure against any infectious disease should be carriedout with the minimum of immediate or remote dis-comfort compatible with efficacy. Where the proceduredoes not produce certain immunity and is still on trial,as with antituberculous vaccine, this is of even greater-importance. Wilson (1947) has rightly pointed outthat undesirable sequelae of antituberculous vaccinationmay well give rise to revulsion against the alreadyaccepted preventive measures exemplified by smallpoxvaccination and diphtheria immunisation.The present series confirms the findings of Wells

(1946, 1949) and Wylie (1952) that the vole-bacillusvaccination by multiple puncture has an extremely lowincidence of complications. It also seems clear, althoughthe series is small, that B.C.G. vaccination by the samemethod is attended by a negligible complication-rate.One of us (I. M. H.), from personal observation of morethan 500 B.C.G. intradermal vaccinations, has recordedulceration in 6%, enlargement of regional lymph-glandsin 4%, and a breaking down gland in 1%, whereas in

TABLE III-CONVERSION-RATE OF SPECIAL-SCHOOL CHILDRENAFTER FOUR WEEKS

Vaccine I No. vaccinated I No. converted

the present series no such sequelae were noted and theconversion-rate was strictly comparable. -

We have confirmed the findings of Birkhaug (1944)that an appreciably denser suspension of B.C.G. isrequired for the multiple-puncture technique than thatused as a routine for intradermal inoculation. Somespeculation may arise about the small amount of tissuereaction provoked by the use of the heavier suspensionof B.C.G. Although it is impossible to estimate quanti-tative differences, probably the number of organismsintroduced by multiple puncture is less than by intra-dermal injection. It would be reasonable to suggest,however, that it is the relative number per unit area oftissue in contact with the bacillus which is important,and that in the widely scattered punctures the organismsare taken up more readily than when a single intra-dermal dose is administered, where those organisms in theperiphery of the bleb only are in direct contact with thetissue cells.

Reference has already been made to the almostidentical conversion-rate in the two series ; but, thoughthe over-all conversion-rate is strictly comparable, thegreater potency of the vole bacillus is suggested notonly by the results of tuberculin testing with 10 unitsof Old Tuberculin but also by the formation of rathermore scabs at the site of vaccination with vole-bacillusvaccine and the enlargement of axillary -lymph-glandsin one case. These observations confirm those of-

610

Birkhaug (1946), but we do not agree with his condusionsregarding the safety of the vole bacillus as an antigen.Though encouraging evidence of the value of the vole

bacillus as an antigen is accumulating from experimentson animals (Young and Paterson 1949, Wells and Wylie1952) and in human trials (Wells 1949, Wylie 1952),it is too early to say whether the slightly severer reactionproduced is justified by a longer persistence of sensitivityor a greater degree of increased resistance. Only follow-up over several years can determine these importantfacts.

SUMMARY

The immediate effects of vaccination by multiplepuncture with vole bacillus and B.c.G. are compared. _A suspension of B.C.G. 20 mg. per ml. was used for this

technique without any complication arising.. Coilversion-rates to 100 units Old Tuberculin after four

weeks were very high (95-100%).The local reaction following vaccination with the

strength of suspension used in each case was slightlygreater and more persistent with vole bacillus than with- B.C.G. With both antigens there were less initial dis-comfort and fewer undesirable sequelae than occur

with intradermal injection.The administration of B.c.G. by multiple punctureappears in a distinctly advantageous light comparedwith the intradermal route.

After seven weeks the conversion-rate to 10 units OldTuberculin was appreciably higher with vole bacillusthan with B.C.G.

-

We wish to acknowledge our gratitude for their interestand cooperation to Dr. R. M. Bates, F.R.c.s., D.P.M., directorof education, Royal Eastern Counties Special Schools, andto the staffs of these schools ; to the Faculty of MedicalSciences, University College, London; and to the nursesof University College Hospital. Our thanks are also due toDr. Knud Tolderlund, of the State Serum Institute, Copen-hagen, Denmark, for most generously supplying to one ofus (1. M. H.) a suspension of B.C.G. 20 mg. per ml. for theseand future trials ; and finally to Dr. A. Q. Wells for guidanceand criticism.

REFERENCES

Birkhaug, K. (1944) Acta med. scand. 117, 274.— (1946) Amer. Rev. Tuberc. 54, 41.

Griffith, A. S., Dalling, T. (1940) J. Hyg., Camb. 40, 673.Wells, A. Q. (1946) Spec. Rep. Ser. med. Res. Coun., Lond. no. 259.- (1949) Lancet, ii, 53.— Brooke, W. S. (1940) Brit. J. exp. Path, 21, 104.— Wylie, J. A. H. (1952) Ibid, 33, 405.

Wilson, G. S. (1947) See Brit. med. J. ii, 465.Wylie, J. A. H. (1952) to be published.Young, J. A., Paterson, J. S. (1949) J. Hyg., Camb. 47, 40.

TEMPORAL ARTERITIS TREATED WITH

A.C.T.H.J. V. AVELING

M.B. Lond.MEDICAL OFFICER, BUSHEY AND DISTRICT HOSPITAL

F. HARWOOD STEVENSONM.D. Lond., M.R.C.P.

PHYSICIAN, ROYAL NATIONAL ORTHOPÆDIC HOSPITAL AND

BUSHEY AND DISTRICT HOSPITAL

PATHOLOGICAL reports made by Dr. H. C. Moore onarterial sections from three cases of temporal arteritis(Jennings 1948) suggested that adrenocorticotropichormone (A.C.T.H.) might be of value. He described a

collagenous degeneration of the media with secondaryintimal hypertrophy and fibrous thickening of theadventitia. There was a cellular reaction, lymphocyticand histiocytic, with some giant cells and in two casesan eosinophil reaction.

Vascular complications are a risk with A.C.T.H. therapy,but in the case reported here the patient was severely illand the risk of death was already by no means negligible.She was closely watched for fluid retention and rise ofblood-pressure, but neither of these took place.

CASE-RECORD

A married woman, aged 71, was seen late in May, 1952,with a history of six weeks’ bilateral frontal and temporalheadaches, giddiness especially on looking upwards, and amoderate impairment of hearing. Weakness of legs and backhad developed, and in the week before admission to hospitalshe had become drowsy, disoriented in time and space, andmildly aphasic. The headaches included an internal ache anda feeling that she had tender swellings on her scalp and thatthe softest pillow was like a bag of coals.On examination her scalp was everywhere very tender, and

there was exquisite pain when her hard non-pulsating temporalarteries were even lightly touched. She was slightly drowsyand pale and looked ill. She was mildly anaemic but apyrexial.Her blood-pressure was 160/80 mm. Hg. There were no signsof focal disease of the nervous system except an inconstantdiplopia on looking to either side.

Treatrnent and Progress.-The patient was admitted to theBushey.and District Hospital and given A.C.T.H. 10 mg. six-hourly from June 4. An effective eosinopenia was produced.After three days the pain lessened, and after five days it wasincomparably better. Her sight, which had been blurred, hadimproved, she could hear better, and her speech was muchclearer. She certainly looked brighter and was eating well.After eight days’ treatment she was sitting up in bed readingand had almost no pain and " nothing to complain about,"Her hand, she said, was just rather shaky and the power poorfor writing. The dosage of A.C.T.H. was then reduced to7.5 mg. eight-hourly and, after a further four days, to ,5 mg.eight-hourly, because the symptoms seemed to be controlled.However, after two days of this last dosage the pain returned;and on June 21 the dosage was increased to 7-5 mg. eight-hourly. Within twenty-four hours the pain had again ceased,and the patient’s hearing, which had deteriorated,-was a!sobetter. From then on, with the same dosage,, she made goodprogress, and after 31/2 weeks’ treatment the temporal arteries,though still hard, nodulated, and pulseless, were no longertender. After four weeks’ treatment the injections were

stopped. There was no recurrence of symptoms, and sixweeks later the patient was well and doing her normal householdwork.

COMMENT

All the symptoms described by this patient beforetreatment was started have been reported before, some-times with pathological evidence of arterial involvementboth within and outside the skull (Hoyt et al. 1941,Post and Sanders 1944, Cooke et al. 1945, Kremer 1946,Robertson 1947, Jennings 1948).The symptoms of temporal arteritis commonly coii-

tinue for several months. It appears to us that A.C.T.H.exerted a real effect on this case inasmuch as (1) the verysevere and worsening symptoms were relieved withinthree days ; (2) the symptoms recurred when the dosagewas dropped below 7-5 mg. t.d.s. but were again promptlyrelieved when the dose was raised to that level; and(3) after a further month’s treatment the withdrawal ofA.C.T.11. was not followed by a relapse. "

REFERENCES

Cooke, W. T., Cloake, P. C. P., Govan, A. D. T., Colbeck, J. C.(1945) Quart. J. Med. 15, 47.

Hoyt, L. H., Perera, G. A., Kauvar, A. J. (1941) New Engl. J. Med.225, 283.

Jennings, G. H. (1948) Brit. med. J. i, 443.Kremer, M. (1946) Proc. R. Soc. Med. 40, 84.Post, L. T., Sanders, T. E. (1944) Amer. J. Ophthal. 27, 19.Robertson, K. (1947) Brit. med. J. ii, 168.

"... What is social science ? Critics have posed thisquestion, often as a challenge and sometimes ironically, withthe implication that only those entities which can be measuredon the centimeter-gram-second scale are admissible to thedomain of authentic science. But surely the criterion in

evaluating a subject for systematic study is not the degree towhich it is measurable in exact quantitative terms, but thedegree to which it contributes to man’s knowledge of himselfas a part of nature or alternatively the degree to which itaffects man’s well-being."ŅCuissTER I. BARNARD, RockefellerFoundation Review for 1950 & 1951 ; p. 57.