310

THE USE OF CORTICOSTEROIDS IN THETREATMENT OF ASTHMA AND

RELATED CONDITIONSBy C. M. FLETCHER, M.D., F.R.C.P.

Senior Lecturer in Medicine, Postgraduate Medical School

The Greek word ' asthma ' means no more than' a hard-drawn or gasping breath.' It may beapplied to the dyspnoea of left ventricular failure,but is more usually taken to indicate bronchialasthma. It is with this sort of asthma that thisarticle is concerned, and for this purpose asthmamay be defined as dyspnoea due to generalizedbronchiolar obstruction characterized clinically bywheezing respiration. It will be assumed that the'diagnosis has been confirmed by the usual in-vestigations, thereby excluding wheezing due tolocalized bronchial obstruction.

Theoretical ConsiderationsAsthma is generally regarded as belonging to the

group of allergic or hypersensitivity reactions andis thought to be due to contraction of bronchiolarmuscles in response to histamine liberated as aresult of local antigen-antibody reactions. Mucosaloedema and hyperaemia and secretion of viscidmucus add to the bronchiolar obstruction. Thepromptness of the response of an asthmatic to aninhaled allergen is such that the asthmatic attackmust be of the immediate rather than the delayedtype of hypersensitivity reaction. Although corti-sone inhibits the delayed type of sensitivity re-action in the skin (Long and Miles, 1950), its effectupon the immediate type of skin reaction toinjected allergens in sensitive subjects has beenreported to be insignificant (Feinberg et al., I95I;Cook et al., I951; Pickering, 1952; Lovell et al.,1953). More recently, however, Holti (1.956) hasshown that cortisone does reduce the skin reactionto injected histamine and Herxheimer (I954) hasshown that the amount of an inhaled allergennecessary to cause an attack of asthma in sensitivesubjects is considerably increased when they areunder cortisone treatment. There is no convincingdemonstration of an impairment of adrenal func-tion in allergic subjects during attacks of asthma(Siegel et al., I956), so that there is no reason tosuppose that the use of these drugs in asthma may

be regarded as replacement therapy; entirely un-physiological doses may be needed to produce aneffect.

Clinical ReportsThe literature on the treatment of asthma

abounds with claims of success for innumerablemethods which have later fallen into disuse afterinitial enthusiasm has worn off, or when controltrials have shown them to be useless. This is partlybecause of the profound importance of psycho-logical factors in inducing or relieving asthma andalso because of the unpredictable course of theuntreated disease. It is therefore necessary to beextremely cautious about accepting claims for thevalue of corticosteroids which, when they werefirst introduced, were hailed with uncritical en-thusiasm as a cure for nearly all the ills to whichmankind is heir and, more especially, as the solu-tion to all the allergist's problems. Early reportson the use of these drugs in asthma were nearly allenthusiastic, but quite uncontrolled. The un-toward side-effects and expense of prolongedadministration were at first the only grounds forhesitation in accepting them as the treatment ofchoice in asthma. Subsequently, controlled trials,almost all carried out in Great Britain, have shownthat the true place of corticosteroids in the treat-ment of asthma is limited. Since the effect of thesedrugs has been shown to be very different in acuteattacks, in persistent asthma, and in asthmaassociated with other pulmonary diseases, the useof the drugs in these three types of case must beconsidered separately.

Acute Asthmatic Attacks and Status AsthmaticusThe early uncontrolled claims of the effective-

ness of corticosteroids in acute asthma (reviewedby Brown, I952) have been substantiated in thiscountry by controlled trials of ACTH (Ball, 1954)and of cortisone (M.R.C., I956b). The latter trialwas carried out on 32 cases in status asthmaticus

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June 1958 FLETCHER: (lse of Corticosteroids in the Treatment of Astlhma and Related Conditions 311

M.R.C. TRIAL OF CORTISONEIN STATUS ASTHMATICUS/o ot cases able to get up without

audible wheeze

8070 - Cortisone 9/ii relapsed60

-

at 3/12uJ 500 40I- 30 f x x 7/14 relapsedz 20 xx at 3/12

10 / Controlcr 0a 30

20100

2 4 6 8 10 14TIME IN DAYS

FI(;. i

that had failed to respond during 24 hours toroutine anti-spasmodic treatment. Fifteen caseswere given cortisone (300 mg. on the first daywith gradual reduction in dosage over io days) and17 were given undistinguishable control tablets.The results in terms of clinical assessment ofvirtual freedom from asthma are summarized inFig. i. There is a highly significant difference inthe response to the cortisone and control tablets.This difference only appears after two days andonly becomes significant after four days. A similardelay in response to ACTH was reported by Balland many other authors. In the M.R.C. trial therewere two failures or withdrawals from the cortisonegroup. One was a woman with mitral stenosis whowent into heart failure and died three months later,and the other was a man with an overwhelmingbronchial infection who died on the fourth day.On the other hand, five failures in the control groupall responded to corticosteroids on removal fromthe trial. Follow-up of these patients after the trialshowed no evidence that the period of treatmenthad lessened the liability to further attacks ofasthma and this conclusion is in agreement withall other reports.

Cases of acute asthma who fail to respond tocorticosteroids fall into three groups. First, thereare those in whom the side-effects of the cortico-steroids prevent persistence with the treatment.Chief among these side-effects in short courses isfluid retention in cases complicated by heartfailure. It may be possible to use prednisolone inthese cases. A rare complication of ACTH therapyis an allergic or anaphylactic reaction to the drugwhich may be fatal (Levin, 1955; Bloom andWolff, 1954; Swift, 1954; Serafini and di Nardo,I955). Because of this possibility and the lack of

any clear evidence that ACTH is superior to theother corticosteroids, I consider that it should onlybe tried when other corticosteroids have failed toproduce a response. Next there are those cases inwhom bronchial infection contributes to the ob-struction. Whenever there is evidence of suchinfection appropriate antibacterial drugs must begiven together with the corticosteroid. Lastly,there are those in which there is no clear explana-tion. Fatal cases of simple asthma are found atpost-mortem to have bronchioles plugged bysecretion and in some cases there may apparentlybe desquamation of ciliated epithelium (Earle,I953). It is not surprising that the bronchialobstruction is irreversible once this condition hasbecome established (Aber et al., I954). The delayin the response to corticosteroids may also beexplained in part by the time taken for these viscidsecretions to be evacuated. For this reason delayin starting treatment with corticosteroids in severeacute asthma may be dangerous.Mlaintenance Treatment of Chronic AsthmaAlthough reports of uncontrolled, trials on the

use of corticosteroids in maintenance treatment ofchronic asthma have been rather less enthusiasticthan reports on its.use in acute asthma, they arenearly all extremely favourable. Table I sum-marizes the results obtained in a number of thesereports. It is impossible to make strict com-parisons between the varying methods of assess-ment used in these papers, but they agree thatthe drugs are beneficial in all but a small pro-portion of cases. Savidge and Brockbank (I954a)were less enthusiastic, though still favourable, asthe result of a controlled trial in which 13 patientswith persistent asthma were given oral cortisoneand 14 similar patients were given a placebo forperiods ranging from four to 80 weeks. Theyfound that six out of the 13 cortisone treated casesderived significant benefit, but only one of the 14control cases derived equal benefit. They con-cluded that some cases of chronic asthma could becontrolled by moderate doses of cortisone. How-ever, their comparison may be criticized on thegrounds that in some of the cases the nature of thetreatment was known to the authors and the dura-tion of treatment was not comparable in the twogroups, being nearly twice as long in the cortisoneas in the control groups. The Medical ResearchCouncil's trial (i956a) was a fully controlled' double blind' trial. Ninety-six patients from sixcentres between the ages of 14 and 60 with asthmaof at least three months' duration and withoutsevere broncho-pulmonary infection were giveneither cortisone or dummy tablets. The dose ofcortisone (or placebo) started at 300 mg., falling toIoo mg. at the end of a week, and thereafter

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POSTGRADUATE MEDICAL JOURNAL

M.R.C. TRIAL OF CORTISONE IN CHRONIC ASTHMA%/o of cases free from Rhonchi ( detaulters included in totdl)

Control

were on IJmgRj.Iy or mure.

O 2 4 6 8 16 24 36TIME IN WEEKS

FIG. 2

dosage was adjusted by individual physicians,according to their assessment of the patient's needs.After 24 weeks the physicians were instructed toattempt-to withdraw the tablets from those patientswho could manage without them and the finalassessment was made 36 weeks after the start ofthe trial. Unfortunately, assessment was purelyclinical and no lung function tests were used. Themost objective means of assessment was by theseverity of rhonchi on auscultation and the resultsobtained by this method are summarized graphic-ally in Fig. 2. The cortisone group showed sig-nificantly greater benefit than the control groupfrom the second to the eighth week, but by thesixteenth week this difference had disappeared,and during the last 20 weeks of the trial thecortisone group were, if anything, less well offthan the controls. (This may have been accountedfor by the fact that some of the severer cases hadbeen removed from the control group and trans-ferred to corticosteroid therapy.) During thetreatment period nine cortisone cases were with-drawn, five because of incidental illnesses, fourof which (two psychoneuroses, one duodenal ulcerand one tuberculous kidney) may have been ex-acerbated by the cortisone. Two were withdrawnbecause of status asthmaticus and two defaulted.Ten control cases were withdrawn, five by defaultand five because of status asthmaticus. The con-clusion is that cortisone is only of short-termbenefit. The steady improvement of the controlcases is notable and the fact that withdrawal of thecontrol tablets was apparently as difficult as with-drawal of cortisone shows the powerful effect ofsuggestion on both patients and doctors. Fig. 3shows that the exercise tolerance reported by thepatients suggested a greater difference between

treated and control groups than did the objectiveassessment. This is perhaps attributable to thepsychological effect of cortisone. However, theeffects on capacity for work were very little dif-ferent in the two groups, nor was there any dif-ference in the need for other treatment in the twogroups. All but five cortisone and four controlcases received other forms of anti-spasmodicsthroughout the trial.The results of this trial have been described in

some detail because of the very real doubt theythrow upon the value of maintenance therapy bycorticosteroids. They indicate the reality of tem-porary benefit, confined to the first two months oftreatment, and they show how difficult it is todistinguish over longer periods between the benefitsof cortisone and that of entirely ineffective tablets.

Treatment of Asthma Associated with Bronchitisand/or EmphysemaIn most reports of the treatment of asthma by

corticosteroids bronchial infection is said to abolishthe benefits of the treatment (Schwartz, I951;Davies and Williams, 1955; Savidge and Brock-bank, 1954). Benefit in cases of emphysema hasbeen slight and where it has been claimed there isconsiderable doubt as to the differential diagnosisof the emphysema from simple asthma (Bicker-man, Beck and Barach, 1955; Galdston et al.,195I; Lukas, I951). In a controlled trial on casesof bronchitis and emphysema during acute ex-acerbations of infection Felix-Davies and Westlake(I956) showed that ACTH had no effect on therate of recovery of ventilatory capacity. Kennedy(1954) found no significant effect of cortisone onthe ventilatory capacity of cases of pneumo-coniosis with bronchospasm. The improvement-in

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June I958 FLETCHER: (,"se of Corticosteroids in the Treatment of Asthma and Related Conditions

REPORTED RESULTS OF CORTICOSTEROID MAINTENANCE THERAPY FOR BRONCHIAL ASTHMA

Author

Six authors collected by Savidgeand Brockbank (I954)Turiaf et al. (1954) .. .Kania and Schmidt (I954)

Arbesman and Richards (1954)

Serafini and di Nardo (1955)

Barach et al. (1955) ......... .

Sheldon et al. (1955)

Taub et al. (1956)

Walton (1956) ..

Drug

CortisoneHydrocortisoneCortisone

Cortisone

ACTH, hydrocortisone orprednisonePrednisone

Prednisone

Prednisone

.% 'T T - -I AU rI, cortisone orhydrocortisone

Results per cent.5'No. of CommentCases

-I9552

IIII

86

''5

30

5 '

'53

'53

Good

73l 64

84

65

76

57

9

30

48

Fair Poor

i6 I I3' 520 5 Some short courses

included24 I2 Occasional ACTH

supplementsI8 6 Some short courses

included40 3 Eighteen had failed

on cortisone8 2 Eleven had failed

on cortisone65 5 Some short courses

and status included50 2 Five failed cases

were all fatal

FIG. 3

dyspnoea presumably depends upon whether it ispredominantly due to reversible bronchial obstruc-tion or to irreversible pulmonary damage.

Side-effectsThe undesirable side-effects of corticosteroids

in asthma are the same as those encountered inother diseases (Bickerman and Barach, I954;Burrage et al., 1955; Irwin et al., I954; Jenkins,'955; Wang et al., I955). They are consideredelsewhere in this series of articles. The danger ofan allergic reaction to ACTH, to which referencehas already been made, is probably greater inasthmatics than in other patients. Apart from thisthere have been a number of reports of deathsoccurring during and after cortisone treatment ofasthma. These have been attributed by someauthors to hypo-adrenalism induced by cortisone(Savidge and Brockbank, I954b), but the un-predictable course of asthma and the fact that fatalstatus asthmaticus may occur even under steroidtreatment makes it difficult to accept this explana-tion. Henneman et al. (I955) investigated theeffects of abrupt cessation of cortisone main-tenance in I9 asthmatics. They observed noprompt return of asthma, though various otherminor symptoms attributable to hypo-adrenalismoccurred which were relieved by intravenoushydrocortisone.

RecommendationsFrom the evidence that has been presented it is

necessary to attempt to derive some conclusionsas to the indications for steroid treatment, theregime that should be adopted and the necessityfor adjuvant therapy. It is clear from most reportsthat only a small minority of asthmatics require

treatment by corticosteroids. Thus, over a periodof nearly two years only 32 cases of status asth-maticus failing to respond to routine treatmentwere obtained from I3 hospitals during theMedical Research Council trial of cortisone. Ball(I954) found that only 20 out of 132 and Johnson(I954) only I4 out of 407 cases of asthma admittedto hospital required ACTH because of failure torespond to routine treatment. These reports weremade at a time when the drugs were in relativelyshort supply and may not be generally applicabletoday. It must be remembered that statusasthmaticus is a dangerous condition which maybe rapidly fatal and that response to corticosteroidsmay be delayed for two days, so that it is risky towait for as long as 24 hours to see whether theymay be required. In severe asthma I recommendthat if, after four hours in hospital, adrenalinaerosol and intravenous aminophyllin have notproduced a significant improvement, cortico-steroids should be given.

It is more difficult to assess the need for thesedrugs in asthmatic attacks, which, while not severeenough to be a threat to life or even to demandadmission to hospital, are nevertheless severelydisabling. The first essential in such cases is toensure full investigation to discover and removepossible environmental causes for the attack,whether psychological or allergic, and then toensure that adequate anti-spasmodic therapy isbeing given. Some cases that are quite resistant toephedrine may obtain relief from choline theo-phyllinate or to a combination of the two, andoccasional cases are encountered who deny relieffrom a hand inhaler with adrenaline or isoprena-line, but who respond promptly when properlyinstructed in the use of the inha-ler. If, despite all

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314 POSTGRADUATE MEDICAL JOURNAL June I958

such methods, -disabling asthma persists, thensteroids should be tried,

Since these drugs are potentially dangerous,especially in chronic cases, it is essential to ensurethat any apparent benefit is really due to the drugitself. It may be due simply to an increase inmorale from the psychological stimulus given bythe drug. This confusion may be avoided bymaking objective measurements of ventilatorycapacity in every case treated. Measurement ofthe one-second forced expiratory volume (FEV.1.0)(Gandevia and Hugh-Jones, 1957) and of its pro-portional relationship to the vital capacity is simpleand provides a sensitive index of changes in ven-tilatory capacity. If a significant increase ofventilatory capacity occurs when steroids arestarted, it may still not be due to the drug itself,but to the patient's knowledge of the reputed effectsof cortisone. This confusion may be avoided bystarting the drug without telling the patient whatit is and without any claims as to its likely benefit.Substitution of indistinguishable dummy tabletswith repeat testing of the ventilatory capacity mayshow whether the effect is psychological or pharma-cological in doubtful cases. If dummy tablets aregiven and the patient thinks they are cortisone (ora similar drug), steps must be taken to ensure thatany other doctor called to treat the patient in anexacerbation will know that the tablets are dum-mies. Lastly, when benefit undoubtedly due to thecorticosteroids has been conferred, every effortshould be made to limit the duration of treatmentor, if a maintenance dose is essential to keep it aslow as possible, so that full dosage may be kept inreserve for acute and dangerous exacerbations.The danger of extension of infection occurring

without overt symptoms under cover of cortisonemust always be kept in mind, more especiallywhen, as in asthma, exacerbations may be associ-ated with bronchopulmonary infections. A chestradiograph will presumably always have beentaken before treatment is started. It should berepeated whenever a fresh course is begun and atregular intervals during maintenance therapybecause of the danger of rapidly progressivetuberculosis. If there is any evidence of infection,either radiological or clinical, appropriate anti-bacterial drugs must be given promptly.There is little doubt that oral prednisolone is

the drug of choice (Barach et al., 1955; Jenkins,1955; Sheldon et al., 1955), although in an acuteemergency it may be preceded by intravenoushydrocortisone to obtain a more rapid response.There are those who prefer to use intravenousACTH on the grounds that the natural- steroidsproduced by the adrenal glands may be moreeffective than any single synthetic drug, but thereis no clear evidence in support of this. There are

certainly some cases which appear -to respond toACTH after having failed on cortisone, but thereverse occurs equally frequently (Arbesman andRichards, I954; Bickerman and Barach, I954;Serafini and di Nardo, I955). There are otherswho like to combine ACTH with prednisolone orcortisone to avoid the atrophic effect of thesedrugs on the adrenal cortex (Arbesman andRichards, I954; Salassa et al., 1953; Taub et al.,1956). This is rather an elaborate way of avoidinga risk which is only encountered if the patientabruptly discontinues taking the drug, which needniever happen, and is, in any case, of doubtfulimportance (Henneman et al., I955). Whenevertreatment is started it is best to begin with alarge dose and then to reduce it over several days:15 mg. of prednisolone may be given six-hourlyat first and each dose may then be reduced by

ing. every other day until 5 mg. are being givenisix-hourly. Thereafter the dose should be moreslowly reduced to find the minimum required forrelief of symptoms, and with the firm intention ofdiscontinuing the drug if at all possible after 4otmore than three months, even though repeatedcourses may often be necessary in some cases.

BIBLIOGRAPHYABER, G. M., CHANDLER, G. N., and HlARTFALL, S. J.

(1954), Brit. "ted. Y., i, i.

ARBESMAN, C. E., aiid RICHARDS, N. B. (1954), A.Allergy,25, 306.

BALL, K. (I954), Lancet, i, i i62.BARACH, A. L., BICKERMAN, FH. A., and-BECK, G. J. (1955),

Dis. Chest, 27, 515.BICKERMAN, H. A., and BARACH, A. L. (1954), A.AllergY,

25, 312.B3ICKERMAN, H. A., BECK, G. S., and BARACH, A. L. (1955),

Y. chron. Dis., 2, 247.BLOOM, A., and WOLFF, F. (1954), Brit. ined. 7., ii, 1354.B3ROWN, E. A. (1952), Ann. Allergy, 10, 356, 496.BU'RRAGE, W. S., RITCHIE, W. B., MANSFIELD, H. C.,

IRWIN, J. W., and RUSSFIELD, A. B. (1955), Ann. intern.Med., 43, 1001.

C'OOKE, R. A., SHERMAN, W. B., MENZEL, A. E. O.,CHAPIN, H. B., HOWELL, C. M., SCOTT, R. B., MYERS,P. A., and DOWNING, L. M. (195I), 7. Allergy, 22, 211.

I)AVIES, B. M., and WILLIAMS, D. A. (0955), Brit. nied. 7.,ii, 293.

EARLE, B. V. (1953), Thorax, 8, 195.FEINBERG, S. M., DANNEBERG, T'. 1'., andl MALKIEL, S.

(195I), 7. Allergy, 22, 195.FELIX-DAVIES, D., anid WES'ITLAKE, I-. K. (u5st), Brit.mied. 7., ii, 780.(GALDSTON, M., WEISENFIELD, S., BENJA.MIIN, B., andt

ROSENBLEkUTH, M. B. (1951), Amer. .7. Med., Io, i68.GANDEVIA, B., and HCGH-JONES, P'. (1957), Thorax, in the

press.1-ENNEMAN, P. H'., W\ANG, D. M. K., IRWVIN, J. XV., andt

BURRAGE, W. S. (1955):jY. Amner. mted. Ass., I58, 384.HERX.HEIMER, H. (954), Brit. med. 7., i, 184.HOLTI, G. (I956), C'lin. .Sci., 15, 41.IRWIN, J. W., HENNFMAN, P. H., WANG, D. M. K., anid

BURRAGE, W. S. (1954), Y. Allergy, 25, 20I.JENKINS, C. M. (I955), Ann. Allergy, I3, 700.JOIINSON, E. H. (1954), Wis. med. 7., 53, 537.KANIA, E., and SCHMIDT, P. 954), MIunch. nied. Wschr., 96,

759.KENNEDY, M. (. S. (I954), Lancet, i, 77.LEVIN, S. J. (1955), Pediatrics, x6, 4i6.LONG, D. A., and MILES, A. A. (1950), Lancet, i, 492.Bibliography continutedi ont paige 3 2 I

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June 1958 SAVAGE: Cortisone and its Analogues in the Treatment of the Rheumatic Diseases 321-

in the blood has proved difficult because of thelarge- amount of plasma required for estimations,but the method of Porter and Silber has becomeestablished.

Important progress in the scientific knowledgeof cortisone metabolism has been made. It hasbeen found that there is a diurnal variation in thelevel of blood hydrocortisone throughout the dayin normal subjects. The mean value is high at8 a.m., though in some people this is delayed tillio a.m., and falls during the next four hours.After a short rise it falls again and is low between4 p.m. and 6 p.m. Studies done throughout thenight have shown a low level at 3 a.m., followed bya rise to the morning peak.

Investigations on rheumatoid patients haveshown that the blood hydrocortisone is high, butthat there are greater fluctuations throughout theday than in normal subjects.Work on the physiological dispositions and

metabolic fate of hydrocortisone in man have beencarried out following intravenous infusion. Innormal subjects the half life in plasma averagedI.9 hours. Following the infusion of tracerquantities of hydrocortisone -4-C I4 metabolitesappears in the plasma in substantial quantity intwo hours. Normal subjects excrete over 90 percent. as urinary metabolites in 72 hours. Liverdisease delays the excretion of hydrocortisone.

The FutureAs the recent advances in the estimation of blood

hydrocortisone levels continue it should soon bepossible to adjust the dosage of the cortisones byscientific calculation instead of by balancing clinicalimprovement against side effects.

However, in spite of the somewhat crude regimewhich has, of necessity, ruled the dosage of cor-

tisone and its analogues since their introduction in1948, a large number of patie-nts who had failed torespond to other treatment and who were crippledwith rheumatoid arthritis have been relieved ofpain and enabled to return to work.

BIBLIOGRAPHYALBRIGHT, F. (1942), The Harry Lectures, Lancaster, Pa. The

Science Printing Company, p. I22.APPLEBY, J. I., GIBSON, G., NORYMBERSKI, J. K., and

STUBBS, R. D. (I955), Biochem. J., 6o, 453.BOLAND, E. W. (1950), Ann. rheuim. Dis., 9, I.BLACK, R. L., YIELDING, K. L., and BUNIM, J. J. (1957),

Y. chron. Dis., 5, 751.BUNIM, J. J., ZIFF, M., and McEWEN, C. (I955), Anier. Y. Mled.,

I8, No. I, 27.COPEMAN, W. S. C., SAVAGE, O., BISHOP, P. M. F., DODDS,

E. C., KELLIE, A. E., STEWART, J. W., GLYNN, J. H. H.,HENLY, A. A., and TWEED, J. M. (I952), Brit. med. J., i,397.

COPEMAN, W. S. C., SAVAGE, 0., DODDS, E. C., GLYN-N,-J. H. H., and FEARNLEY, M. E. (1954), Ibid., i, II09.

COSTE, F., CAYLA, J., and DELBARRE, F. (1953), 'Cortisoneet Corticostimuline (ACTH) en rhumatologie.' Masson, Paris.

ENIPIRE RHEUMATISM COUNCIL TRIAL (I957), A4Wz1.rheum. Dis., I6, No. 3, 277.

FEARNLEY, G. R., BALMFORTH, G. V., and BLATCHLEY, R.(I957), Brit. med. _'., ii, 1263.

FISCHER, F., and BROCHNER-MORTENSEN, K. (1953),Ugeskr. Laeg., 115, 203.

GRAY, S. J., BENSON, J. A., REIFENSTEIN, R. WV., andSPIRO, H. M. (1951;, J. Amer. med. Ass., 147, I529.

GRAY, S. J., BENSON, J. A., Jr., SPIRO, H. M., andREIFENSTEIN, R. W. (I95I), Gastroenterology, Ig, 658.

HENCH, P. S., KENDALL, E. C., SLOCUMB, C. H., andPOLLEY, H. F. (1949), Proc. Mayo Clin., 24, i8i.

HOLLANDER, J. L., BROWN, E. M., Jr., JESSAR, R. A., andBROWN, C. Y. (I95), J7. Amer. med. Ass., I629.

ILLINGWORTH, R. S., LORBER, J., HOLT K. S., RENDLE-SHORT, J., JOWETT, CG. H., and GIBS6N, W. M. (1957),Lancet, ii, 653.

MIEDICAL RESEARCH COUNCIL AND NUFFIELD FOUN-DATION (1954), 'Report of Joint Committee,' Brit. mied. J3.,i, I223.

MEDICAL RESEARCH COUNCIL AND NUFFIELD FOUN-DATION (1957), Ibid., ii, I99.

POPERT, A. J., and DAVIS, P. S. (I958), Lancet, i, 21.PORTER, C. S., and SILBER, R. H. (I950),J. biol. Chenm., I85, 201.SAVAGE, 0., DAVIS, P., CHAPMAN, L., POPERT, A. J.,

ROBERTSON, J. D., and COPEMAN, W. S. C. (a957),Brit. med. _7., ii, I1258.

WN'ARD, L. E., POOLEY, H. F., SLOCUMB, C. H., and HENCH,P. S. (I953), . Amer. med. Ass., 152, 129.

WEST, H. F. (1957), Ann. rheum. Dis., I6, 322.

Riblignrahhv continued from iawe .i-C. AlM Fletcher M1).D F R C.PLOVELL, R. R. H., GOODMAN, H. C., HUDSON, B.

ARMITAGE, P., and PICKERING, G. W. (I953), Clin. Sci.,12, 41.

LUKAS, D. S. ('95I), Amer. Rev. Ttuberc., 64, 279.MEDICAL- RESEARCH COUNCIL (1956a), Lancet, ii, 798;

(i956b), Ibid., ii, 803.PICKERING, G. W. (1952), Brit. med. J., i, I207.SALASSA, R. M., BENNETT, W. A., KEATING, F. R., and

SPRAGUE, R. G. (I953), J. Amer. nmed. Ass., 152, I509.SAVIDGE, R. S., and BROCKBANK, W. (1954a), Lancet, ii, 889;

(a954b), Ibid., ii, 893.SCHWARTZ, E. (I95I), J. Amer. med. Ass., 147, 1734.SERAFINI, U., and DI NARDO, U. (1955), Act. allerg. (Kbh.), 9,

241.

SHELDON, J. M., McLEAN, J. A., and MATHEWS, K. P.(1955),J7. Mich. med. SQc., 54, 08I.

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