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UNEXPLAINED JAUNDICE

THE LANCETLONDON: : SATURDAY, JANUARY 16, 1943

IN 1937 the CHIEF MEDICAL OFFICER of the Ministryof Health wrote 1 of a disquieting series of cases ofinfective jaundice reported to him. Most of themwere mild but a small number died with classical

symptoms of acute necrosis of the liver. On inquiryit was found that some of the patients, having been incontact with measles, had been given convalescentmeasles serum of a certain batch. Unused remainderof this batch was found to be sterile and non-toxicand the situation offered a pretty problem for thediagnostic acumen of the central health department.The scope of the problem has been widened by reportsof similar happenings in the Americas with yellow-fever vaccine and other excitants, already discussedin our leader columns (Oct. 31, 1942). Elsewhere inthis issue is a closely reasoned summary, prepared bymedical officers of the Ministry, of what is now knownabout this homologous serum jaundice. The factsavailable at present indicate that the blood or blood-products of certain individuals possess some factorwhich when inoculated into certain other individualswill produce symptoms of varying degrees of severity.It may be a fleeting disturbance to a few liver cellswith resulting mild symptoms of gastro-intestinal dis-turbance with bile in the urine for a day ; moresevere cases may have skin lesions in the form ofurticaria or erythema multiforme, pains in the joints,splenomegaly, and frank icteric coloration of scleraand skin. Many of these patients have high icteruswith remarkably little loss of appetite. A very small

proportion of those affected die with acute atrophy ofthe liver. Those who recover do so, it seems, withlittle or no residual damage to the liver. Whether theincriminated product contained liquid human serum,reconstituted dried serum or plasma the clinical

picture has been the same.At the time of the earlier " outbreaks " it was sug-

gested that the condition was epidemic catarrhaljaundice, but this idea has been discarded because ofthe much longer incubation period of the disease underdiscussion. The possibility that yellow-fever viruswas to blame has also been eliminated. Whateverthe causative agents may be, they are exceedinglypotent despite the long incubation period ; in someof the yellow-fever vaccine cases each man receivednot more than 0’05 c.cm. serum. Oddly enough thisamount subcutaneously has produced more disturb-ance than several hundredfold by transfusion. Thefact that children given convalescent serum as a pro-tection against measles came off badly may be relatedto the relatively large dose. In contrast is the lowincidence in children following injection of vaccinein Brazil.3 Another curious variant is the extremerange of severity among an apparently uniform groupof men inoculated with the same material. Whenthis occurs in epidemic infective hepatitis it is

1. Rep. med. Offr Minist. Hlth, Lond. 1937.2. Findlay, G. M. and MacCallum, F. O. Trans. R. Soc. trop. Med.

Hyg. 1937, 31, 297.3. Fox, J. P., Manso, C., Penna, H. A. and Para, M. Amer. J. Hyg.

1942, 36, 68.

explained by assuming different degrees of exposure,but this can hardly apply to a group receiving thesame intravenous injection from a pool of liquidplasma.>! In the light of this wide range in signs,symptoms and severity in different countries-letalone the variety of exciting agents : yellow-fevervaccine, human serum and plasma-are we then rightin gathering them together like this as a singleentity ? Whether they indeed result from the actionof a common causative agent has yet to be proven.Clinically they have been distinguished from casesof catarrhal jaundice by the triad of joint pains,splenomegaly and erythema multiforme. But inseveral accounts 2 3 there has been no mention ofskin lesions or joint pains, and splenomegaly does notseem to have been a notable feature of the yellow-fevervaccine cases. We must not overlook, however, thatmany of these cases were only studied retrospectively,weeks after the beginning of the illness, when signs mayhave been forgotten-or were no longer recognisable.

Frankly the evidence is not yet ready for a grandjury to be sure of a prima-facie case for trial, and themain reason for the publication of the Ministry’smemo at this stage is to put the medical professionon its guard against the possible occurrence ofjaundice following the use of human blood or blood-products. POPE had a prevision of the natureof the quest when he wrote 6 " All seems infectedthat th’ infected spy, as all looks yellow to thejaundic’d eye." Much of the delay in getting to theroot of this problem has been the failure to realise itsexistence, so that many of the data in each outbreakhad to be collected in retrospect. If the condition

appears to be infrequent it may become commoner iflooked out for more carefully. The cases set out inthe memo which followed transfusion with recon-

stituted dried serum might have been overlooked hadthey not all occurred in one hospital where a house-physician had seen some of the convalescent serumcases. Practitioners unaware of the possibility wouldnot relate an attack of anorexia, nausea and jaundicewith a transfusion given two to six months before.Cases transfused from a common lot of blood mighthave dispersed widely in the interval. For example,one man who developed jaundice ten weeks aftertransfusion had during the short period since his

discharge from hospital had no known -contact withanother case. Investigation showed that of the fourothers who were transfused from the same pool, whileone was alive and well, three were dead without

apparent liver damage within less than ten weeks-and none of the original blood was left for examina-tion. One of the main hindrances in investigatingthese cases has been the lack of clinical data and ofan exact record of the material used for transfusion.

All attempts at animal transmission 3 7 have beenunsuccessful, but there are still many who pin theirfaith on a virus aetiology. The possibility of findingthe cause in some altered or peculiar protein in certainbloods has been seen by LEVINE and STATE whorecord fatal anaphylactic reactions in 20% of a groupof 109 people transfused with a certain plasma. These

4. Chesney, G. J. E., Hawley, W., MacFarlane, A. and Stegman, A.Unpublished communication.

5. Soper, F. L. and Smith, H. H. Amer. J. Trop. Med. 1938, 18, 111.6. An Essay on Criticism, Part II, line 358.7. Findlay, G. M., MacCallum, F. O., and Murgatroyd, F. Trans.

R. Soc. trop. Med. Hyg. 1939, 32, 575.8. Levine, M. and State, D. Science, 1942, 96, 68.

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patients were found to be hypersensitive to intra-dermal injection of one or more monovalent samplesof plasma, and when transfused they developed head-ache, dyspnoea, epigastric distress, chills, fever andurticaria. Transfer of dermal sensitivity from react-ing to non-reacting patients was readily effected. But

nearly all the outbreaks have followed the use ofpooled serum or plasma and no-one has yet reporteda history of jaundice in any donor of an incriminatedbatch. While the mixing of many samples may some-times result in an incompatibility for certain indivi-duals, the pooling on the other hand may be the meansof neutralising one or two virus-containing samplesby a number of immune ones. If however the agentis really a virus it is difficult to understand how thesame noxa can be highly virulent for children in oneepisode and almost avirulent in another. The lowincidence reported in the large groups who receivedbad batches of yellow-fever vaccine suggests that,whatever may be the agent, a high proportion ofindividuals in the USA and Brazil are immune or

resistant to it.It is to be hoped that all this lively research will

bear fruit in the coming months. Meanwhile, bywatchful eye and accurate recordirig of clinical andlaboratory data on the part of all’ who are usingblood or blood products, it should be possible toidentify and eliminate suspicious batches and this intime should give some clue to the conundrum.These inquirers will be stimulated by learning of theprodigious amount of work done by the backroomdoctors at the Ministry.

FAILURE OF LACTATIONA PHYSIOLOGICAL breakdown such as occurs when

breast-feeding fails is not only unsatisfactory for thewomen immediately concerned but, repeated on alarge scale, may prove disastrous for the race or

section of the race which it affects. The decline in

-breast-feeding in this country. has been a matter forcritical comment in the past decade, the general feel-ing left by such reports being that mothers are

increasingly unwilling to cooperate or frankly unableto cope with the physiological situation. Elsewherein this issue Dr. MARGARET ROBINSON analvses 1100consecutive examples of breast-feeding prematurelydiscontinued. In 40% no reason for the failure wasoffered by the mothers and no cause could be foundon examination. Breast abscess, cracked nipple,acute illness and debility of the mother made up thechief morbid reasons for weaning. Over 100 mothersin the series refused to feed their babies ; the-environ-ment was wrong in less than 10% and the baby wasblamed in nearly 14%, although clearly the digestivesymptoms which led to weaning were usually due toan already declining lactation. Approaching the sub-ject from another angle, a subcommittee of theBritish Pædiatric Association recently investigatedthe effect of modern labour conditions on breast-

feeding in Birmingham.1 . There it was possible tocompare a survey made before the war with one madein 1942 and it is reported that the incidence of breast-feeding has not been materially affected by the periodof open hostilities. This is satisfactory as far as it

goes, but the report also shows that only 50% ofwomen are prepared to continue breast-feeding their1. Where Dr. A. V. Neale secured the help of Drs. Ethel Cassie,

Frances Braid and Mila Pierce.

baby for longer than three months. It may be truethat it is in the early months that natural feedingmatters most, but it is certainly true that the diffl-culties in successful breast-feeding have mostly beenovercome by the third month, so that from the

physiological aspect breast-feeding ought to be easilycontinued. Of the influences adverse to breast.

feeding in Birmingham the report picks out one

important group. "

Doctors," it states, " are still

responsible for weaning babies more than any othersingle factor. They still take babies off the breastwhenever there is any difficulty, rather than take thetrouble to go into the whole difficult question ofsuccessful breast-feeding." Yet in Liverpool ROBIN-SON only blames the doctor in 4 instances out of her1100 cases. Clearly some other factors must be atwork. GORDON in a recent study 2 of some socialaspects of infant feeding eliminates air-raids andevacuation as possible accelerating factors in thewholesale decline now taking place ; and he is alsoable to show that although the place of breast-feedinghas largely been taken by dried milk, the distributionof dried milk at the infant welfare centres has, perchild, diminished over the period studied (1920 to1938) during which the decline in breast-feeding hasoccurred.

°

Since social and environmental factors appear toplay a minor part it seems logical to seek a physio-logical reason for a physiological failure. This has beenattempted by Dr. H. K. WALLER, whose contributionin this issue will repay careful study. WALLER startsfrom the well-known fact that many mothers who failto feed their babies appear to have had plenty of milkin the early days of lactation. Putting all the

responsibility on the baby to " empty " the breasts

in the early stages is unsatisfactory, because it is nota simple question of suction. Something more isinvolved and in the veterinary world experts areagreed that the outflow is dependent on a reflexmechanism. HAMMOND suggests 3 that in the cowthis takes the form of a reflex venous engorgement,produced by stimulation of the teats, exerting pres-sure on the fat-laden milk in the alveoli and finesttubules, and forcing it into the larger ducts andsinuses. He used an ingenious method of fractionalmilking and fat analysis to prove his thesis and thishas been followed by WALLER in the human subjectwith similar results. The vascular element of the

theory is not essential : smooth muscle is present inthe human breast, certainly around the large lacti-ferous ducts and also to some extent around thealveoli-a specialised type of myo-epithelial tissue ofectodermal origin. The clinical significance of thisconception of what WALLER terms a draught reflexis of great importance. Clearly it is a delicate thingwhich must be carefully cherished in the early stagesof lactation ; as WALLER puts it, the reflex mightrespond to methods of conditioning less crude andhaphazard than those to which it is commonly sub-jected. In a contribution to the Banting memorialnumber of the Canadian Medical Association Journal,GUNTHER indicates that workers at the BantingResearch Foundation have reached similar conclusionsand she enumerates many factors which may inhibitthe essential reflexes. Clearly the whole technique of

2. Gordon. I. Arch. Dis. Childh. 1942, 17, 139.3. Hammond, J. Vet. Rec. 1936, 16, 519.4. Gunther, M. Canad. med. Ass. J. 1942, 47, 410.