845

THE LANCET

Congenital Cytomegalovirus Infection—More Problems

CYTOMEGALOVIRUS (C.M.V.) is the commonest

known microbiological cause of brain damage in

infancy.l Infection by c.M.v. is particularly commonduring pregnancy, for 3-6% of pregnant womenexcrete virus in their urine 2-5 and an even greaterproportion via the cervix. The incidence of viruriaand cervical excretion increases progressively fromtrimester to trimester.4-6 In patients of differentethnic groups in Pittsburgh, the overall incidence ofviruria was similar (about 4%), but cervical excretionwas much more common among Navajo Indians

(14%) than among Blacks (5%) or Whites (4%).5Pregnant Japanese women had even higher rates ofcervical c.M.v. excretion-10% and 28% during thesecond trimester and at term, respectively. 6 c.M.v.

may also be excreted in breast milk: Australianworkers have shown that 27% of apparently healthyrecently delivered, seropositive women have viro-lactia.7 Nevertheless, although intrauterine c.M.v.

infection may damage the fetus, there is no evidenceas yet to suggest that infection acquired during birthor in the immediate postnatal period is harmful.

c.M.v. is a member of the herpes group of viruses,and in common with these viruses it is not eliminatedafter primary infection, but remains latent. Virus

may be reactivated later, particularly in immuno-compromised hosts or during pregnancy. Indeed,investigations of cell-mediated immunity suggest thatpregnancy itself, perhaps because of hormonal

changes, is associated with a "

physiological immuno-suppression ".8,9 About three-quarters of c.M.v.

infections during pregnancy result from reactivationof latent virus; but, although the major risk to thefetus is believed to arise from primary infections,9,lothere have been three reports of congenitally acquiredinfections in consecutive pregnancies. ll--13 It is en-couraging that follow-up revealed no abnormality intwo of the secondborn infants, the third having a mildhepatomegaly at the age of three months.121. Stern, H., Elek, S. D., Booth, J. C., Fleck, D. G. Lancet, 1969, ii, 443.2. Hildebrandt, R. J., Sever, J. L., Margileth, A. M., Callagan, D. A.

Am. J. Obstet. Gynec. 1967, 98, 1125.3. Feldman, R. A. Am. J. Dis. Child. 1969, 117, 517.4. Reynolds, D. W., Stagno, S., Hosty, T. S., Tiller, M., Alford,

C. A. New Engl. J. Med. 1973, 289, 2.5. Montgomery, R., Youngblood, L., Medearis, D. N., Jr. Pediatrics,

1972, 49, 524.6. Numazaki, Y., Yano, N., Morizuka, T., Takai, S., Ishida, N.

Am. J. Epidem. 1970, 91, 410.7. Hayes, K., Danks, D. M., Gibas, H., Jack, I. New Engl. J. Med.

1972, 287, 177.8. St. Hill, C. A., Finn, R., Denye, V. Br. med. J. 1973, iii, 513.9. Thong, Y. H., Steele, R. W., Vincent, M. M., Hensen, S. A.,

Bellanti, J. A. New Engl. J. Med. 1973, 289, 604.10. Hanshaw, J. B. in Intrauterine Infections (Ciba Fdn Symp. 10);

p. 38. Amsterdam, 1973.11. Embil, J. A., Ozere, R. L., Haldane, E. V. J. Pediat. 1970, 77, 417.12. Krech, U., Konjajev, Z., Jung, M. Helv. pœdiat. Acta, 1971,

26, 355.13. Stagno, S., Reynolds, D. W., Lakeman, A., Charamella, L. J.,

Alford, C. A. Pediatrics, 1973, 52, 788.

What are the chances of and the risks associatedwith primary infections in pregnancy ? Serologicalinvestigations in London 14 and in Manchester 15have shown that about 40-45% of women of child-bearing age are susceptible-roughly double thenumber who are susceptible to rubella. Furthermore,in contrast to rubella, there is little to pinpointinfection, since c.M.v. infections in otherwise healthyindividuals are generally subclinical. Primary infec-tion occurs in about 1% of pregnancies, and virologi-cal work on newborn infants indicates that the risk

.

of fetal infection in such pregnancies is of the orderof 50%, infections being more common during thefirst two trimesters.14 On this basis it can be calcu-lated that about 4000 c.M.v.-infected babies are

delivered annually in England and Wales. HANSHAWcalculated that 5-15% of infants infected in uterosustain central-nervous-system damage,16,17 and ifhis results are generally applicable, at least 200-600babies who will eventually show evidence of c.M.v.-induced damage are born each year in England andWales. 14 But even this may be a considerableunderestimate of the extent of the problem, andfurther carefully conducted combined virological andclinical investigations on congenitally infected infants,extending over many years and designed to detectsubtle defects, are essential if the real impact ofcongenitally acquired infection is to be determined.Two newly reported long-term follow-up investi-

gations are of interest since they provide rather

contrasting findings. 15 infected but clinicallynormal babies followed up in Cleveland did not have

any substantial physical or psychological defects byfour years of age,18 but a follow-up in Alabama on16 apparently normal infants also with infection atbirth revealed that, by the time the children werebetween two and six years, 9 had some degree ofsensorineural deafness, particularly at high frequen-cies, although most had reasonable hearing. 19Although sensorineural hearing loss may be associatedwith cytomegalic inclusion disease itself 20 its asso-ciation with otherwise inapparent infection had notpreviously been reported. In this series the c.M.v.-infected children also had a trend towards subnormal

intelligence. It is not surprising that progressive,although subtle, damage may be detected postnatallyeven though infection is inapparent at birth, sincevirus replication which begins in utero persists wellinto childhood; thus, most patients in this seriesexcreted virus up to the age of four. But even carefulclinical and psychometric assessment may be aninsensitive index of intellectual damage, for it is

14. Stern, H., Tucker, S. M. Br. med. J. 1973, ii, 268.15. Walker, G. H., Tobin, J. O’H. Archs Dis. Childh. 1970, 45, 513.16. Hanshaw, J. B. J. infect. Dis. 1971, 123, 555.17. Melish, M. E., Hanshaw, J. B. Am. J. Dis. Child. 1973, 126, 190.18. Kumar, M. L., Nankervis, G. A., Gold, E. New Engl. J. Med.

1973, 288, 1370.19. Reynolds, D. W., Stagno, S., Stubbs, K. G., Dahle, A. J., Living-

ston, M. M., Saxon, S. S., Alford, C. A. ibid. 1974, 290, 291.20. Strauss, M. Davis, G. L. Ann. Otol. Rhinol. Lar. 1973, 82, 577.

846

possible that many c.M.v.-infected children, althoughappearing in every way normal, will nevertheless fallshort of their genetically determined potential.Might a vaccine make congenitally acquired c.M.v.

infection a preventable disease ? ELEK and STERNhave developed a c.M.v. vaccine by passage of theAdl69 virus strain in human diploid-cell cultures.21When it was given subcutaneously to seronegativeadult volunteers, neutralising and complement-fixingantibodies developed, but the virus was not excretedand no serious side-effects occurred. Although theseresults are encouraging, further information isawaited on the duration of antibody persistence andon protection against antigenically variant strains aswell as closely related ones.Any new vaccine raises anxieties, not least in those

responsible for its development and early trials, andwith a c.M.v. vaccine there are certain uniqueproblems. Unlike vaccine strains of poliovirus,rubella, and measles, herpes viruses are not eliminatedbut persist in a potentially infectious state. Theymay induce malignant lymphoproliferative disease inanimals 22-26 and perhaps in man. They are closelyassociated with, although as yet not proven to bethe direct cause of, such tumours as Burkitt lym-phoma 27,28 (at least in the tropics) and nasopharyn-geal carcinoma (E.B. virus) 27,29 and perhaps car-cinoma of the cervix (herpes, type 2).30 Whetherc.M.v. is associated with human malignant lympho-proliferative disease is unknown, but the possibilitydeserves serious thought, since c.M.v. transformshamster fibroblasts,31 stimulates host-cell D.N.A.

synthesis,32 and induces neo-antigens on the surfaceof infected cells,33 all of which are characteristic

properties of oncogenic D.N.A. viruses. On the other

hand, most individuals will acquire natural infectionin due course, and it may seem reasonable to give acalculated dose of virus to susceptible individualswho may later be at risk of acquiring an intrauterineinfection. But could laboratory manipulation enhancethe oncogenic potential of c.M.v., perhaps by pro-ducing large numbers of defective virus particles orby modifying host responses ? It may be too easyto conclude, on existing evidence, that the develop-21. Elek, S. D., Stern, H. Lancet, 1974, i, 1.22. Churchill, A. F., Biggs, P. M. Nature, 1967, 215, 528.23. Granoff, A. in Oncogenesis and Herpesviruses; p. 171. Lyons, 1972.24. Hsiung, G. D., Kaplow, L. S. J. Virol. 1969, 3, 355.25. Melendez, L. V., Daniel, M. D., Hunt, R. D., Frazer, C. E. O.,

Garcia, F. G., King, N. W., Williamson, M. E. J. natn. CancerInst. 1970, 44, 1175.

26. Melendez, L. V., Hunt, R. D., Daniel, M. D., Frazer, C. E. O.,Barahona, H. H., Garcia, F. G., King, N. W. in Oncogenesis andHerpesviruses; p. 451. Lyons, 1972.

27. Henle, G., Henle, W., Diehl, V. Proc. natn. Acad. Sci. U.S.A.1968, 59, 94.

28. Burkitt, D. P. J. natn. Cancer Inst. 1969, 42, 19.29. Henle, W., Henle, G. Ho, H.-C., Burtin, P., Cachin, Y., Clifford,

P., De Schryver, A., De-Thé, G., Diehl, V., Klein, G. ibid.1970, 44, 225.

30. Rawls, W. E., Tompkins, W. A. F., Figueroa, M. E., Melnick,J. L. Science, 1968, 161, 1255.

31. Albrecht, T., Rapp, F. Virology, 1973, 55, 53.32. Jeors, S. C.-St., Albrecht, J. B., Funk, F. D., Rapp, F. J. Virol.

1974, 13, 353.33. The, T. H., Langenhuysen, M. M. A. C. Clin. exp. Immun. 1972,

11, 475.

ment and testing ofc.M.v. vaccines is premature; buthow long will it be before we can say reasonablyconfidently that the advantages of preventing this

disease, the commonest known microbial cause ofmental retardation, outweigh the hypothetical risk ofneoplastic disease ? It seems that c.M.v. infection

provides many problems, not the least of which nowis its prevention.

Immunotherapy for Acute MyeloidLeukæmia

ATTEMPTS to immunise cancer patients withtumour cells or extracts have been made many timessince the turn of the century,1,2 and until lately theresults have been consistently disappointing. Never-theless, there is impressive circumstantial evidencefrom clinical sources,3 and direct evidence from

experimental work, that tumour growth may beinfluenced by immunological reactivity, and that theimmunocompetent cells of the host recognise tumourcells as " foreign " because of the presence on theirsurface membrane of macromolecules not found onthe surface membrane of normal adult cells. This

surprising conclusion seems totally at variance withthe everyday clinical experience of cancer as a diseasein which the tumour cells seem to be accepted aspart of the host and to thrive without restraint. If,from the inception of the growth, the tumour cellsare immunogenic, why are they not destroyed bythe immune reaction they provoke ? One obvious

explanation would be that the victims of cancer areimmunoincompetent. There is indeed a highincidence of malignant disease in several conditionsassociated with severe immunodeficiency,5 but ifcancer arose exclusively in immunodeficient hosts theprospects for immunotherapy would be bleak indeed.The general view now is that cancer usually arisesin immunologically competent hosts and that at a

critical stage in its early development the balancebetween the strength of the immunological defencesand that of the antigenic challenge of the growingtumour is irreversibly upset in favour of the tumour.An early explanation was that antigenic sites on thesurface of the tumour cells were protected fromimmunological attack by a coating of antibody notitself capable of damaging the cells. 6 Later, smallamounts of antibody were found to repress the

expression of antigens on the cell surface.’The nature of the antigens on the surface of

tumour cells and the mechanism of their impact onthe immunological defences of the host are immensely1. von Leyden, V. E., Blumenthal, F. Dt. med. Wschr. 1902, 28, 36.2. Coca, A. F., Dorrance, G. M., Lebredo, M. G. Z. Immun.-Forsch.

exp. Ther. 1912, 13, 543.3. Currie, G. A. in Modern Trends in Oncology, 1 (edited by R. W.

Raven); p. 127. London, 1973.4. Old, L. J., Boyse, E. A. A. Rev. Med. 1964, 15, 167.5. Good, R. A. Proceedings of the Non-Hodgkin’s Lymphoma

Symposium, London, October, 1973 (in the press).6. Kaliss, N. Cancer Res. 1958, 18, 902.7. Boyse, E. A., Old, L. J. A. Rev. Genet. 1969, 3, 269.