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Vaccination against Hepatitis BSERUM hepatitis or, as it is now called, hepatitis

B is a serious and common disease, especially inwarm countries. It is also a danger for patients re-peatedly exposed to blood or certain blood productsand for those who care for them in ward or labora-tory. Its prevalence is high in institutions, especiallythose for the mentally retarded. Measures to pre-vent the disease are therefore urgently sought.MARMION and his colleaguesl have shown howeffective simple methods of screening for HBsAgand good housekeeping can be in controlling thedisease. Indeed the success of these measures in

controlling infection in haemodialysis units in Bri-tain has been very encouraging. Nevertheless, itwould be highly desirable to back up preventivemeasures based on identification of the hazard and

good hygiene by active immunisation. There is

good reason to believe that a vaccine againsthepatitis B could be developed. The infection isknown to be an immunising one; and HBsAb inY-globulin has been shown to prevent the disease,provided its titre is adequate. But there are difficul-ties surrounding the development of a vaccine asoutlined by Professor ZUCKERMAN on p. 1396. De-spite these uncertainties, vaccines are being pre-pared within the limitations of present technologyby a number of workers; and the results obtainedby Professor MAUPAS and his colleagues in Toursare reported on p. 1367 this week.How can the undoubted advantages of a vaccine

be balanced against risks involved? The history ofthe control of infectious diseases is an impressiverecord, but there has been some cost—for exam-ple, several hundred children were paralysed dur-ing the early days of vaccination against poliomye-litis. In March an international meeting3 in Genevadiscussed the ethical and technical questions in-volved in the development of vaccines. The overrid-ing requirement was held to be that the prepara-tion of any vaccine should be technically efficientand open to independent review, which could besecured by national or even international commit-tees. Such committees are often entirely manned byexperts and there was a plea for wider public repre-sentation. Another valuable form of review is pro-vided by the publication of the results of thoseworkers who are developing a vaccine.Some will say that it is premature to attempt to

make an HBsAg vaccine. Because the virus cannot1. Marmion, B. P., Tonkin, R. W. Br. med. Bull. 1972, 28, 169.2. Wilson, G. S. The Hazards of Immunisation. London, 1967.3. Sponsored by the World Health Organisation, the World Medical Associ-

ation, the International Association for Biological Standardisation, theU.S. Public Health Service, and the Council for International Organisa-tions of Medical Sciences.

be grown in the laboratory in cell culture, purityand safety cannot be assured by direct tests. More-over, HBsAg may not contain the antigen neces-sary for protection; and it may contain antigenswhich could cause immunological damage ratherthan clinical immunity. Strong arguments can alsobe put for undertaking trials in a highly selectiveway. HBsAg is readily available from personscarrying it, and donors can be selected by meanswhich reduce risks from the presence of otheragents, as is done with blood-donors in many coun-tries. Techniques for purification can employ bothaffinity chromatography and physical methods toconcentrate the 22 nm particles. There is convinc-ing evidence that heat at 60°C for 10 hours des-troys hepatitis-B virus in plasma and this treat-

ment, combined with another established

inactivating agent, such as formalin, may be con-sidered to add extra security. To another key ques-tion-how important are the dangers of host-speci-fic antigens?-the answer must be that we do notknow. There is assurance in the knowledge thatblood products have been massively used withoutthis type of hazard becoming apparent. Among theblood products used on a large scale is heated plas-ma-protein fraction, which, in the U.S.A. at least,almost always contained HBsAg until about 1972.4 4The most that can be said is that so far the vaccineused by Professor MAUPAS and his colleagues hasbeen associated with none of the possible untowardreactions.

Viral Cross-infections in Children’sWards

ON the children’s ward, hospital-acquired virusinfection can be a calamity. Discomforts and dangersapart, such infections complicate management ofother ills and may add to distress by prolonging thehospital stay. Thus, a child in hospital who

acquires an exanthem such as measles or varicellashould at once be discharged or, failing that, iso-lated. As to the contacts, they should when possiblebe screened for the presence of antibody to thevirus in question (unless there is a clear history ofinfection or of measles vaccination). Susceptiblecontacts over the age of 9-12 months may be pro-tected against measles with attenuated measles vac-cine, provided that this is given within three daysof exposure. 5 Probably this works becausemeasles induced by attenuated vaccine has a

shorter incubation period than naturally acquireddisease; alternatively, the vaccine-induced inter-feron response may inhibit replication of naturalmeasles virus. It may be useful to check pa-tients for the presence of antibodies after this vac-cination, say at 8-10 weeks. Susceptible contacts in4. Pattison, C. P., et al. Am. J. Epidemiol. 1976, 103, 399.5. Marshall, W. C. Unpublished.

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whom measles vaccination is contraindicated-forexample, immunocompromised children or thoseallergic to egg protein-can be protected withhuman immune globulin, provided that this too isgiven within three days of exposure. However, ifsuch children are to remain in hospital, it is wiseto isolate them between the 7th and 21st day aftercontact, since a proportion may have coryzal symp-toms without a rash and excrete virus, thus infect-ing others. Varicella may be particularly severe,occasionally life-threatening, in patients with im-munodeficiency and malignant disorders as well asin children on systemic corticosteroids. With vari-cella-zoster immune globulin, given within 72hours of contact, about a third of such high-riskcontacts will have subclinical infection, most of theothers becoming mildly ill; the incubation periodmay be prolonged by 4 to 5 days.2 Whenever pos-sible, all susceptible children should be dischargedwithin 10 days of contact. If this is impossible,virus transmission in the ward may be prevented bystrict isolation of contacts between the 10th and21st days after contact with the index case. Duringthe 10 days, however, patients can be admitted anddischarged without risk.

Children in an open ward may contract rubella-like illnesses, but, since clinical diagnosis of rubellais often wrong, virological confirmation is needed.Serological studies should be done rapidly to deter-mine the immune status of any visitor who may bepregnant. Any woman who is pregnant and sero-negative should be discouraged from visiting-un-less of course the diagnosis in the index case turnsout to be incorrect. It is also good practice to screenfemale ward staff for rubella antibodies, attenuatedrubella vaccine being offered to those who are

seronegative, not pregnant, and ready to take effec-tive contraceptive measures for two months aftervaccination.

Although measures such as these may controloutbreaks of measles or varicella, the position withrespiratory viral pathogens is different: except withinfluenza there exist no effective active or passiveimmunising agents and cross-infection is more dif-ficult to control. Influenza A, parainfluenzaviruses, and respiratory syncytical virus (R.s.v.)can all cause hospital infections,’-9 R.s.v. being themost important since it is the commonest cause ofacute bronchiolitis and pneumonia in infancy. (Ithas also been implicated as a possible cause of thesudden-infant-death syndrome. 10 ") R.S.V. infectionis particularly likely to be fatal in children withcongenital heart-disease, central-nervous-system6. Gershon, A. A., Steinberg, S., Bruncell, P. A. New Engl. J. Med. 1974, 290,

243.7. Mufson, M. A., Mocega, H. E., Krause, H. E. J. inf. Dis. 1973, 128, 141.8. Gardner, P. S., Court, S. D. M., Brocklebank, J. T., Downham,

M. A. P. S., Weightman, D. Br. med. J. 1973, ii, 571.9. Hall, C. B., Douglas, R. C. Pediatrics, 1975, 55, 673.

10. Downham, M. A. P. S., Gardner, P. S., McQuillin, J., Ferris, J. A. J. Br.med. J. 1975, 235.

11. Ogra, P. L., Ogra, S. S., Coppola, P. R. Lancet, 1975, ii, 387.

malformation, and cystic fibrosis. These conditionsare not uncommon on a paediatric ward; indeed, ina study of deaths in infancy associated with acuterespiratory virus infections, one in three infantshad some such predisposing factor. 12 Studies in New-castle-upon-TyneS-13 and more recently in Roches-ter, New York,t4 have shown, respectively,that 13 of 22 (39%) and 14 of 44 (32%) childrenadmitted to hospital with non-viral diseaseacquired R.S.V. infections whilst in hospital duringperiods of R.s.v. prevalence in the community. 5 of13 (38%) Newcastle children and 4 of 14 (29%)Rochester children had lower-respiratory-tract in-fection. The risk of acquiring R.s.v. cross-infectionincreased with the time spent in hospital. Thus,after a week 45% of contacts were infected andafter a month all had been infected. That R.s.v.cross-infection is common is not surprising, sinceyoung infants often excrete virus for 14 to 20

daysg ’4 and sometimes for up to 36 days." InRochester, infants with R.s.v. cross-infection spenta mean oaf 21.5 days in hospital compared with un-infected contacts’ 9.2 days. Furthermore, largeamounts of virus may be excreted, for 50% of in-fants aged from 1 to 21 months with lower-respira-tory-tract infection caused by R.s. virus excretedbetween 5 and 6 loglo TCIDso of virus per ml ofnasal secretions Perhaps in very young infants adecreased or delayed immunological responseaccounts for prolonged virus excretion. Isolation ofbabies in cubicles reduces but does not eliminatethe risk of R.S.V. cross-infection. Both the Newcas-tle and the Rochester studies suggest that infectionmay be transmitted by ward staff: in Rochester, 10of 24 (42%) doctors, nurses, or medical students onthe ward contracted R.s.v. infection with minor

upper-respiratory-tract involvement. In adults,however, virus excretion is transient, generally last-ing 2-3 days. t4 15

Although infection may have been transmittedfrom infants to both children and staff by small-particle aerosols, R.s.v.-containing aerosols are un-stable at the relative humidity present in most hos-pitals during winter." It is possible thatcross-infection resulted from carriage of contami-nated secretions on the hands or clothing of theward staff. Rhinoviruses have been recovered fromthe hands of patients with colds, contaminationprobably resulting from finger contact with nasalsecretions during nose-blowing, eye-rubbing, or

sneezing.’4 Even among doctors such contami-nation is frequent: during conferences, 1 in 3 doc-tors picked their noses and 1 in 2.7 rubbed their12. Gardner, P. S., Turk, D. C., Aherne, W. A., Bird, T., Holdaway, M. D.,

Court, S. D. M. Br. med. J. 1967, iv, 316.13. Ditchburn, R. K., McQuillin, J., Gardner, P. S., Court, S. D. M. ibid. 1971,

iii, 671.14. Hall, C. B., Douglas, R. G., Geiman, J. M., Messner, M. K. New Engl. J.

Med. 1975, 293, 1343.15.. Hall, C. B., German, J. M., Biggar, R., Kotok, D. I., Hogan, P. M., Douglas,

R. G. ibid. 1976, 294, 414.16. Hall, C. B., Douglas, G., Jr., Geiman, J. M. J. inf. Dis. 1975, 132, 151.17. Rechsteiner, J., Winkler, K. C. J. gen. Virol. 1969, 5, 405.

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eyes.’8 What can be done to reduce R.s.v. cross-in-fection ? Clearly, if R.s. virus is prevalent, admis-sion of highly susceptible children should, if pos-sible, be postponed. For such children already inhospital, the chance of cross-infection may be

reduced by isolation in single-cot cubicles with theward staff wearing gowns and scrupulously wash-ing their hands. GARDNER and his colleagues8 advo-cate isolation of all infants with respiratory symp-toms and febrile convulsions until a virologicaldiagnosis is made. The diagnosis can be establishedby immunofluorescence within a few hours, t9 20but as yet only in a few specialised centres. TheU.S. workers recommend that ward personnel withupper-respiratory-tract infections during periods ofR.s.-virus prevalence should be regarded as havingR.s.-virus infection until proved otherwise, and notallowed to handle young infants, particularly thosein high-risk categories. If the ward has enoughstaff, this makes sense; virus excretion in adults isof short duration.The latest addition to the list of viruses which

may cause severe hospital-acquired infection is therotavirus (reovirus-like particles or "duoviruses").Rotaviruses have a world-wide distribution and aredetected in the stools of about 50% of children withinfantile gastroenteritis (or more in wintermonths).2’ The stability of this virus, together withthe large amounts excreted (e.g., 101-1010 particlesper gramme of faeces during the 4-5-day acutephase of illness), makes environmental contami-nation more or less inevitable and, in the absenceof stringent precautions, cross-infection of suscep-tible contacts is likely. In 1975, 330 rotavirus infec-tions were diagnosed in the Hospital for SickChildren, Toronto, 1 in 5 having been acquired inhospital; during warm months the proportion ofhospital-acquired cases was even higher. The in-fants’ surgical ward was the richest source of hospi-tal-acquired rotavirus infection, and there was

strong evidence that infection was transmitted to

patients by attending staff.22 In nurseries for thenewborn outbreaks of rotavirus infection are notuncommon,23-26 and in some infection is almostendemic. Fortunately, in most neonatal outbreaksthe diarrhoea has been mild or even absent. Studiesin London provide circumstantial evidence that in-fection may have been transmitted to a maternityunit by staff attending both the general children’sward and the newborn nurseries. 27 Hospital-18. Hendley, J. O., Wenzel, R. P., Gwaltney, J. M., Jr. New Engl. J. Med. 1973,

288, 1361.19. McQuillin, J., Gardner, P. S. Br. med. J. 1968, i, 602.20. Gardner, P. S., McQuillin, J. ibid. 1968, iii, 340.21. Lancet, 1975, i, 257.22. Middleton, P. J. Unpublished.23. Chrystie, I. L., Totterdell, B., Baker, M. J., Scopes, J. W., Banatvala, J. E.

Lancet, 1975, ii, 79.24. Cameron, D. J. S., Bishop, R. F., Davidson, G. P., Townley, R. R. W.,

Holmes, I. H., Ruck, B. J. ibid. 1975, ii, 124.25. Murphy, A. M., Albrey, M. B., Hay, P. J. ibid. p. 452.26. Bishop, R. F., Hewstone, A. S., Davidson, G. P., Townley, R. R. W.,

Holmes, I. H., Ruck, B. J. J. clin. Path. 1976, 29, 46.27. Totterdell, B. M., Chrystie, I. L., Banatvala, J. E. Unpublished.

acquired virus infections are always a nuisance andmay sometimes kill children. Reappraisal and tight-ening-up of precautions is never out of place; quiteoften medical staff are the chief offenders. ,

MICROBIAL KILLING BY NEUTROPHILS

WHEN a normal neutrophil begins to engulf a micro-organism there is an immediate increase in oxygen con

I

sumption, hexose-monophosphate-shunt activity, and

hydrogen peroxide and superoxide production.1-3 Hy-drogen peroxide and superoxide are important in thesubsequent killing of the ingested microorganism.4Oxidised nicotinamide adenine nucleotide (N.A.D.) canindirectly stimulate the hexose-monophosphate-shuntpathway and can be involved in production of hydrogenperoxide. Consequently, N.A.D.H oxidase may be the keyto the antimicrobial activity of neutrophils, as is sug-gested by Dr Segal and Dr Peters in the first article thisweek.- As is so often the case, our understanding of what isnormal is illuminated by study of the abnormal. Chronicgranulomatous disease (C.G.D.) is usually fatal in child-hood or early adult life owing to repeated infections withorganisms such as staphylococci and gram-negative rodswhich do not produce hydrogen peroxide.1 5 When neu-trophils from these children ingest organisms there is noburst of oxidative metabolism and no production of hy-drogen peroxide. The defective microbial killing can bepartly corrected by adding hydrogen peroxide to themedium or producing it within the cells by means of glu-cose-oxidase-coated particles.6 These manoeuvres in-crease hexose-monophosphate-shunt activity, suggestingthat the final oxidase is deficient in this disease and feed-back of its products stimulates the shunt pathway. How-ever, there has been considerable controversy as to

which oxidase is really important. Baehner and Kar-novsky7 reported that N.A.D.H oxidase is reduced inC.G.D. but this could not be confirmed by other workers.N.A.D.P.H oxidase was suggested, since N.A.D.P. directlystimulates the hexose-monophosphate pathway.’ 8 9N.A.D. and N.A.D.P. are theoretically interconvertible inhuman neutrophils by means of a transhydrogenase.Another problem was that neither enzyme seems to bein the right place. N.A.D.H oxidase is in the cytoplasmand N.A.D.P.H oxidase is associated with the granules,whereas the important oxidase should be located on themembrane of the phagocytic vacuole so that its metabo-lites are concentrated within the vacuole to act directlyon ingested organisms. Dr Segal and Dr Peters now un-ravel the problem by showing that when N.A.D.H oxi-dase is assayed using a low concentration of N.A.D.Hthen the enzyme is found predominantly on the plasmamembrane. This makes good sense, since it is this mem-brane which is invaginated to form the phagocytic1. Holmes, B., Page, A. R., Good, R. A. J. clin. Invest. 1967, 46, 1422.2. Nathan, D. G., Baehner, R. L., Weaver, D. K. ibid. 1969, 48, 1895.3. Klebanoff, S. J. A. Rev. Med. 1971, 22, 39.4. Klebanoff, S. J. J. biol. Chem. 1974, 249, 3724.5. Baehner, R. L., Johnston, R. B. Pediatrics, 1971, 48, 730.6. Baehner, R. L., Nathan, D. G., Karnovsky, M. L. J. clin. Invest. 1970, 49,

860.7. Baehner, R. L., Karnovsky, M. L. Science, 1968, 162, 1277.8. Patriarca, P., Cramer, R., Moncalvo, S., Rossi, F., Romeo, D. Archs Bio-

chem. Biophys. 1971, 145, 255.9. Hohn, D. C., Lehrer, R. T. J. clin. Invest. 1975, 55, 707.