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first task of the new social medicine advocated by Ryle.A person harbouring tubercle bacilli would then belooked upon in the same light as a carrier of typhoidor a case of smallpox.

I recognise that there are many difficulties to over-come before this aim is achieved, but it will never beachieved unless clearly envisaged and worked for. Whatis required now is not a

"

statistically satisfactory trial "of B.C.G., but the imaginative leadership of a campaignin which all weapons-tuberculin-testing, mass radio-graphy, clinical treatment (including chemotherapy),and immunisation with B.c.G.-will be used in an attemptto reduce mortality from the most important singlecause of death in Great Britain.

Summary1. Work on tuberculosis in cattle shows that the

disease can be controlled over large areas when thetuberculin test is used as a diagnostic .agent and allefforts are concentrated on breaking the chain ofinfection.

2. The control of human tuberculosis is obviouslymuch more complex, because far less control can beexerted over the individual. Though chemotherapymay eventually come to play an important part, B.C.G.is the one specific weapon that can now help to reducethe number of infected persons and the severity of newinfections.

3. B.C.G. has been available for twenty-five years,but we have done almost no work in Great Britain onthe standardisation of the vaccine or methods of using itin man.

4. There still appears to be little official enthusiasmfor the use of B.C.G. in Great Britain.

(a) Quite different standards of evidence are used when

discussing the value of B.c.G. and when discussingthe value of other immunological procedures or of

pasteurisation.(b) It is stated that there are no properly controlled trials

demonstrating the value of the vaccine in man. Thisstatement is unjustified. The suggestion that civilisedraces will not respond to B.c.G. as well as native racesrespond also has little foundation : indeed the reverseis more probably correct.

5. There is abundant evidence that B.C.G. increasesresistance to tuberculosis in experimental animals, andthis increased resistance is for all practical purposesassociated with the development of allergy. An allergicresponse is the criterion of successful B.c.G. immunisation,and there are very good reasons for regarding allergyin immunised persons as direct practical proof ofincreased resistance.

6. There seems to be no justification for withholdingB.C.G. vaccine from people who want to use it or for

exposing tuberculin-negative girls to tuberculous patientsin order to obtain statistically satisfactory evidence ofits value. The evidence supporting the use of B.C.G.

is already better than the evidence supporting any otherimmunological procedure in man. Data collected ina table indicate that B.C.G. may cause a fivefold reductionin the morbidity and mortality of tuberculosis, whichwould be well worth achieving if only for the

economy it would mean in surgical and sanatoriumtreatment.

7. Veterinarians and farmers have decided that bovinetuberculosis shall be eradicated in ten to twenty years.Human tuberculosis remains the most important singlecause of death in this country. What is requiredis not so much an " adequate trial " of B.c.G.,as a campaign which will begin a new " sanitaryrevolution " and control of the last of the greatzymotic diseases in Great Britain.

MR. FRANCIS : REFERENCES

Aronsen, J. D. (1948) Amer. Rev. Tuberc. 58, 255.— Palmer, C. E. (1946) Publ. Hlth Rep., Wash. 61, 802.

Birkhaug, K. (1948) Bull. N.Y. Acad. Med. 24, 412.Bruns, E. H. (1920) Amer. Rev. Tuberc. 4, 370.Budd, W. (1863) Variola Ovina, Sheep’s Small Pox, or the laws of

contagious epidemics illustrated by an experimental type.Pp. 33. Also published in Brit. med. J. ii, 141.

Editorial (1947) Brit. med. J. ii, 873.— (1949a) Ibid, i, 624.— (1949b) Tubercle, 30, 49.— (1949c) Ibid, p. 97.

Ferguson, R. G., Simes, A. B. (1949) Ibid, p. 5.Francis, J. (1947) Bovine Tuberculosis including a Contrast with

Human Tuberculosis. London.— (1949) Infection with the bovine tubercle bacillus including

its control and a comparison between certain aspects of tuber-culosis in man and cattle. (Awaiting publication.)

Harries, E. H. R. (1930) Lancet, i, 802.Hedvall, E. (1942) Acta med. scand. suppl. 135, pp. 4-196.Heimbeck, J. (1936) Tubercle, 18, 97.Holm, J. (1941) Acta tuberc. scand. 15, 370.

— (1946) Publ. Hlth Rep., Wash. 61, 1298.— Holm, M. (1945) Acta. tuberc. scand. 19, 71

Holmes, M. J. (1937) Med. J. Aust. ii, 813.Hyge, T. V. (1947) Acta tuberc. scand. 21, 1.Jensen, K. A. (1946) Ibid, 20, 1.Kayne, G. G. (1942) Proc. R. Soc. Med. 35, 483.

— (1943) Brit. med. J. i, 777.Long, E. R. (1942) Amer. Rev. Tuberc. 45, 616.Madsen, T., Holm, J., Jensen, K. A. (1942) Acta med. scand. suppl. 6

p. 176.Magnusson, H. (1942) Ibid, suppl. 135, pp. 199-239.Malmross, H. (1947) Amer. Rev. Tuberc. 56, 267.

— (1948) Brit. med. J. i, 1129.Medlar, E. M. (1948) Amer. Rev. Tuberc. 58, 583.Myers, J. A. (1946a) Tuberculosis among Children and Young

Adults. Springfield, Ill.— (1946b) Publ. Hlth Rep., Wash. 61, 1563.— (1947) Amer. Rev. Tuberc. 57, 107.

Nieman, I. S., Loewinsohn, E. (1947) Ibid, 56, 27.Olsen, H. C. (1943) Acta tuberc. scand. suppl. 11.Pagel, W .(1948) in Kayne, Pagel, and O’Shaughnessy’s " Pulmonary

Tuberculosis." Oxford.Paterson, R. G. (1947) Publ. Hlth Rep., Wash. 62, 336.Price, D. S. (1949) Tubercle, 30, 11.Rainey, W. (1944) Vet. J. 100, 233, 245.Ryle, J. A. (1948) Changing Disciplines. Oxford.Sigurdsson, J. (1945) Acta tuberc. scand., suppl. 15.Stocks, P. (1949) Tubercle, 30, 50.Topley, W. W. C., Wilson, G. S. (1946) Principles of Bacteriology

and Immunity. London.Tytler, W. H. (1946) Memorandum on B.C.G., presented to the

Minister of Health.Wallgren, A. (1948) Brit. med. J. i, 1126.Wilson, G. S. (1942) Pasteurisation of Milk. London.

— (1947) Brit. med. J. ii, 855.Wingfield, R. C. (1942) Proc. R. Soc. Med. 36, 39.Wolff, G. (1940) Amer. Rev. Tuberc. 42, 1, 214.

SEQUELÆ OF INFECTIVE HEPATITIS INCHILDREN

REVIEW OF TWELVE CASES

W. G. WYLLIEM.D. Edin., F.R.C.P.

PHYSICIAN, HOSPITAL FOR SICK CHILDREN,GREAT ORMOND STREET, LONDON

MARGARET E. EDMUNDSM.B. Lond., M.R.C.P., D.C.H.

RESEARCH ASSISTANT, INSTITUTE OF CHILD HEALTH; LATE

MEDICAL REGISTRAR AT THE HOSPITAL

MANY recent reports have drawn attention to the

relatively high incidence of cirrhosis following infectivehepatitis among adults, especially troops, during thewar years. Records of chronic hepatic damage, possiblyleading to a fatal termination, among children are

scarce. The power of hepatic regeneration may begreater in childhood than in adult life, yet the presentseries of cases with sequelae is composed of twelvechildren aged 31/2-12 years ; all except one were seenbetween 1942 and 1945, and six died.

Epidemics of infective hepatitis chiefly affectingchildren have been recorded, in this country, by Pickles(1930), Glover and Wilson (1931), Montford (1934),and Frazer (1935). There were no fatalities, and

apparently all recoveries were complete, though Picklesmentions one patient who did not recover for two months.Commenting on these, Barber (1937) remarked thatinfective hepatitis was most infectious to children, themajority of whom recovered completely, but that "theseapparently simple cases of jaundice should be treated

554

with respect." In the past, death in childhood frominfective hepatitis has been rare. One case, in a girlaged 11 years, is described by Morgan and Brown (1927),and another, in a girl aged 31,1, years, by Findlay andDunlop (1932). Both of these showed acute yellowatrophy. There is some evidence that in recent yearsthe virulence of infective hepatitis has increased, possiblyaided by amino-acid deficiencies in war-time diet (seeHimsworth’and Glynn 1944) and by mixing and concen-tration of groups of the population. THE LANCET (1948),discussing the sequels, puts the case-mortality of epidemicjaundice at about 1 in 500, possibly higher, and reaffirmsthat it is a condition never to be taken lightly.

It seems to be possible for chronic liver damage tofollow non-icteric attacks of infective hepatitis (Lawrence1946, Kelsall et al. 1947). The apparent clinical severityof the initial attack certainly bears no relation to thelikelihood of sequelae. ,

It has been established by aspiration biopsies (Roholmand Iversen 1939, Dible et al. 1943) that the primarylesions of infective hepatitis are periportal cellularinfiltration and hepatic-cell degeneration or necrosis

beginning in the centre of the lobule. In severe cases,widespread necrosis or yellow atrophy occurring earlymay end fatally or may be compensated for by multiplenodular hyperplasia. In such cases a later decompensa-tion may terminate in a recurrence of acute or subacutenecrosis.The late effects, based on Sherlock’s (1948) aspiration

biopsy and necropsy material and on the necropsyfindings of Lucke (1944) and Cullinan (1936), may begraded as follows :

(1) Complete restoration of the hepatic lobule, providedits reticulin framework is undamaged.

(2) Periportal (zonal) fibrotic scarring, which usually dis-appears or may be progressive.

(3) A fine diffuse portal cirrhosis, which may be obstructive,leading to gastric or oesophageal haemorrhages.

(4) Multiple nodular hyperplasia replacing massive necrosis.(5) Acute or subacute liver necrosis ending in one of the

chronic forms. ’

According to Lucke (1944), histological signs ofregeneration begin to appear about the tenth day of theillness, and it is interesting that, in the patient dying ofacute yellow atrophy in whom there was no attemptat repair, it was at about this time that clinicaldeterioration set in.

FATAL CASES

In the six fatal cases of our series the symptoms lastedfrom 11 days to 5 years. The liver in the case of theshortest duration showed acute yellow atrophy. Sub-acute necrosis, with multiple nodular hyperplasia, wasthe feature of cases of longer duration. The classicalportal type of cirrhosis was not seen in this series (cf.,Sherlock 1948).Case 1.-A boy, aged 31! years, had an illness lasting

11 days, in which he was jaundiced and had malaise, vomiting,dark urine; and pale stools. On the ninth day he hadintermittent bouts of abdominal pain and became comatoseand restless, with exaggeration of tendon-reflexes and extensorplantar reflexes. His abdomen became grossly distended,and he had a hsematemesis a few hours before death..Necropsy.-The liver was much smaller than normal for

the boy’s age, and weighed 390 g. The cut surface hada yellowish-pink ground-glass appearance. Histologicallythere was acute hepatic necrosis without signs of nodularregeneration.

The patient’s elder brother had had a bilious attack, withlight stools and dark urine, 41- /2weeks before the onset of thepatient’s illness.

’

Case 2.—A boy, aged 7 years, had a history of vomitingand dark urine, 8 weeks before death, followed in a week byjaundice and pale stools but no loss of appetite. His liverwas tender and reached four finger-breadths below thecostal margin, and the tip of his spleen was palpable. Histerminal state was characterised by vomiting, inability to see

clearly, restlessness passing into coma, neck rigidity, extensorplantar reflexes, sudden decrease in the size of the liver, andfinal haematemesis.

.Aecrop.—The liver was small, with well-marked subacuteliver atrophy, and there were multiple haemorrhages in thelungs and mesentery.Case 3.-A boy, aged 11 years, had an illness lasting 10

weeks, starting with sickness and malaise, and succeeded byjaundice, after which he felt well in himself for a time, exceptfor some epistaxes and muscular pains in the first fortnightof his illness. In the fourth week his abdomen became verydistended, with prominence of the superficial veins, well-marked ascites, and oedema of the abdominal wall and legs ;the liver and spleen could not be palpated. Paracentesiswas done four times, with removal of 54, 60, 200, and 210 oz.The boy felt comfortable and ate well, but in the eighth weekof illness he became deeply jaundiced and his temperaturerose gradually. There were no terminal cerebral signs.

Necrop&bgr;y.-The liver weighed 720 g. and showed a grosslyirregular surface ; on section there were irregular nodules ofolive-green tissue and microscopy showed multiple nodularhyperplasia, with terminal necrosis.Case 4.-A boy, aged 10 years, had had an attack of

jaundice 10 weeks previously, with a rash resembling rubella,nausea, sickness for a week before the appearance of jaundice,dark urine, and pale stools. He had not been free from

jaundice since but had improved and then relapsed. He had

bruising and petechiae for a week and bleeding from gumsin the last 2.days. Liver and spleen were impalpable. Therewas terminal intracranial haemorrhage. The serum-bilirubinlevel was 2 mg. per 100 ml.Necropsy.-The liver weighed 1030 g., was moderately

firm, and showed multiple nodular hyperplasia and subacutenecrosis.

Case 5.-A boy, aged 121/2 years, had had, at the age of7 years, an attack of jaundice which had lasted 17 weeksand been followed by recurrent attacks of abdominal pain andjaundice and by profuse melsena on three occasions. Hisliver had a hard edge, felt at the costal margin ; his spleen wasgrossly enlarged down to the level of the umbilicus ; andhe had ascites and telangiectasia on his face and trunk. Hisserum-bilirubin level was 10’4 mg. per 100 ml. He had terminal

epistaxis, melaena, spasticity of limbs, and coma.Necropsy.-His liver weighed 1140 g. and was coarsely

nodular, the nodules being bile-stained and the interveningfibrotic tissue pink. His spleen weighed 1000 g. The’liveron section showed a late stage of subacute necrosis.No varicosities were found; haemorrhage was due to

hypoprothrombinaemia.The next case is an example of multiple nodular hyper-

plasia with terminal necrosis, possibly following a sub-clinical hepatitis. It is included because the pathologicalfindings were similar to those in the preceding cases.Case 6.-A boy, aged 8 years, had been in good health

up to July, 1948, when he developed abdominal pains, pallor,and temperature for a few days. Since then he had beenunwell, lost half a stone in weight, and passed pale stoolson several occasions. He had had frequent epistaxes for12 months.When first seen in September, 1948, he presented icteric

conjunctivae ; protuberant abdomen, with free nuid demon-strable ; liver firm and hard ; liver and spleen both extendingthree finger-breadths below the costal margin ; and spidernaevi on wrists, knees, and trunk. The serum-bilirubin levelwas 3-7 mg. per 100 ml. Paracentesis abdominalis was requiredtwice. A liver biopsy by laparotomy showed a tawny-coloured hobnailed liver. Microscopically areas both ofnecrosis and of multiple nodular hyperplasia were present.On Nov. 25, 1948, the jaundice greatly increased, the

temperature rose to 103°F, oedema spread to sacrum andankles, and the patient became drowsy, vomited alteredblood, and died. The duration of the hepatic symptoms was5 months or more but difficult to assess, because the onsetwas non-icteric.

This case closely resembles one of Cullinan’s (1936),a boy, aged 12 years, who first had jaundice on the daybefore his death, but whose liver at necropsy- showedcirrhosis and long-standing nodules.The remaining six cases demonstrate in children three

possible forms of sequeloe following infective hepatitis:

555

(1) delayed recovery of the liver ; (2) compensatedcirrhosis ; and (3) compensated cirrhosis in a possiblenon-icteric case.

DELAYED RECOVERY

Case 7.-A girl, aged 6 years in April, 1943, when first seen,had in September, 1942, been off her food and sick, and hadbecome jaundiced at the end of about a week. She hadrecovered but subsequently had recurrent attacks of nausea,belly-ache, and sometimes a yellow colour lasting for 2-3days. Her urine contained bile. The edge of her liverwas felt three finger-breadths below the costal margin ; herspleen was not palpable ; she was apparently in good health ;her serum-bilirubin level was 0-6 mg. per 100 ml., and aTakata reaction was strongly positive. In June, 1943,her liver was clinically normal, and her Takata .Case 8.-A girl, aged 3 years, had vomiting, abdominal

pain, and dark urine, and became jaundiced for 2 weeks inOctober, 1942. Intermittent bouts of abdominal upsetcontinued. She was again jaundiced in May, 1946, and hada further relapse in June. The symptoms all disappeared,and in December, 1946, her liver was " only just palpable."Her spleen was not felt, and the child appeared to be in goodhealth.

It is possible that some cirrhosis may be present, inspite of clinical and biochemical recovery, in cases 7 and 8.

COMPENSATED CIRRHOSIS

Case 9.-A boy, aged 5 years, was first seen on Jan. 20,1943, with 10 days’ history of malaise, frequent vomiting,deep jaundice, dark urine, pale stools, one hoematemesis, andone epistaxis. After admission his temperature rangedfrom 99 to 103°F for a fortnight. He was drowsy and hada blotchy reddish-purple rash on his arms and face for 4 days.His liver and spleen were both firm and enlarged. He hadbeen in contact with infective hepatitis at school. He hadconsiderable ansemia : Hb 56%, red cells 3,600,000 per c.mm.-The jaundice lasted 3 weeks, but the liver and spleen were stillhard and enlarged when the patient was discharged home inApril, 1943.He was readmitted subsequently five times up to January,

1946, with bouts of vomiting and diarrhoea, or headache,epistaxes, and haematemesis, or pyrexia and abdominal

pains. Latterly the liver was recorded as " small " and the

spleen as just palpable. The patient has subsequently goneto America and is said to be in good health.Case 10.-A boy, aged 21/2 years when first he became

jaundiced in September, 1944, had had a normal infancy.His stools were pale, urine dark, liver enlarged down to theumbilicus, and spleen palpable. The jaundice disappeared,but the Takata-Ara test was strongly positive in October,1944. In December, 1944, the patient had a relapse, withreappearance of jaundice for a short time. On subsequentexaminations up to December, 1948, his liver and spleen werestill firm and enlarged ; he has had occasional epistaxesbut is said to be lively and well. A Takata reaction onDec. 6, 1948, was negative.Case 11.—A girl, aged 10 years, first seen in 1943, had had

recurrent attacks of abdominal pains associated with vomitingand pale stools for 5 years. She was slightly jaundiced andhad yellow conjunotivse ; her urine contained bile. After afatty meal she had considerable abdominal pain: A chole-

cystogram was negative. The edge of her liver was not felt,but tenderness was present in her right hypochrondrium.Her serum-bilirubin level was 3-2 mg. per 100 ml. ; itdiminished to 1 mg. per 100 ml., and the jaundice disappeared.The Takata reaction changed from + + to _j. Since leavinghospital the patient has not been traced.

SEQUEL IN A POSSIBLE NON-ICTERIC CASE

Case 12.-A girl, aged 6 years, sister to six healthy children,was noted in 1943 to be developing considerable enlargementof the abdomen, the firm rounded edge of her liver beingeasily felt, and her spleen palpable on inspiration. Laparotomyhad been done at another hospital a month before she wasseen here, and " cirrhosis of the liver " had been foundwith about 11/2 pints of straw-coloured fluid. There was nofree fluid on admission here, and she had never been yellow.The Wassermann reaction and Mantoux test were negative,and the Takata-Ara + +. Since discharge the childremains well, and was last seen on Jan. 10, 1949, when her

liver was enlarged and hard, the tip of her spleen palpable.and the Takata reaction J.

The condition in cases 6 and 12, both with non-ictericonset, can, we think, be related tentatively to a precedingattack of subclinical infective hepatitis.

DISCUSSION

In our cases of compensated cirrhosis we have beenunable to obtain serial estimations of the indirect vanden Bergh and other tests of hepatic function. Altschuleand Gilligan (1944) found some residual enlargement ofthe liver and a raised serum-bilirubin level in nine ofthirty-six unselected patients examined 1-29 yearsafter acute infective hepatitis.As regards prognosis, we have found no means of tell-

ing, during the initial illness, whether an individual

patient is going to do well or badly. Biochemical testsof liver function have not been found to help in thisrespect. This is in accordance with Sherlock’s (1948)findings, though Roholm and Iversen (1939) have foundthat a strongly positive Takata-Ara reaction early inthe disease is of some significance.The clinical picture, again, gives no indication of the

outcome. In all but two cases nausea, vomiting, or

abdominal pain preceded the jaundice. In case 1 the

jaundice preceded the intestinal symptoms by some days,but this has not been so in the other reported cases ofacute yellow atrophy in infective hepatitis. In case 10also the jaundice came first.

Ascites, though indicating severe liver damage, is notnecessarily associated with a fatal outcome. It occurredin three fatal cases and one non-fatal case in this series.Other cases of recovery following ascites are reported(Sherlock 1948). Lucke (1944) reports its occurrence

in the final phase of two-thirds of his series of 125 fatalcases.

It is not clear why ascites develops. Cullinan (1936) ,assumes that it is due to portal obstruction, since somepatients also had melena and hsematemesis. This doesnot seem to be the entire explanation, since it occursin the absence of other obstructive signs. Lucke suggeststhat it may also be due to a change in the plasma-proteinsor to interference with the water-storage capacity ofthe liver. Fearnley’s (1947) case is interesting in thatthe ascites was reduced by giving intravenous plasma-protein, even after the serum-protein level had beenrestored to 7 g. per 100 ml.

SUMMARY

The relation of chronic hepatic damage to infectivehepatitis in children is discussed.Twelve cases of infective hepatitis are reported, six

of them fatal, to illustrate the possible sequels.There is apparently no means of telling, in the initial

attacks of jaundice, which patient will recover andwhich will not.

We acknowledge our thanks to Dr. W. W. Payne for hishelp in the biochemical studies.

REFERENCES

Altschule, M. D., Gilligan, D. R. (1944) New Engl. J. Med. 231, 315.Barber, H. (1937) Brit. med. J. i, 67.Cullinan, E. R. (1936) St Bart’s Hosp. Rep. 69, 55.Dible, J. H., McMichael, J., Sherlock, S. P. V. (1943) Lancet, ii,

402.Fearnley, G. R. (1947) Ibid, i, 137.Findlay, G. M., Dunlop, J. L. (1932) Brit. med. J. i, 652.Frazer, E. M. R. (1935) Ibid, i, 701.Glover, J. A., Wilson, J. (1931) Lancet, i, 722.Himsworth, H. P., Glynn, L. E. (1944) Clin. Sci. 5, 93.Kelsall, A. R., Stewart, A., Witts, L. J. (1947) Lancet, ii, 195.Lancet (1948) i, 873.Lawrence, J. S. (1946) Lancet, i, 41.Lucke, B. (1944) Amer. J. Path. 20, 471.Montford, T. M. (1934) Brit. med. J. i, 330.Morgan, M. T., Brown, H. C. (1927) Rep. publ. Hlth med. Subj.,

Lond. no. 42.Pickles, W. N. (1930) Brit. med. J. i, 944.Roholm, K., Iversen, P. (1939) Acta path. microbiol. scand. 16, 427.Sherlock, S. (1948) Lancet, i, 817.