Modes of transmission of respiratory syncytial virus

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observed in our patients, deserves further clinical study, and could be a fertile field for immunologic research, possibly enhancing our comprehension of the complex interactions between immunocompetence and neoplastic growth. The authors thank Joseph V. Simone, M.D., St. Jude Children's Hospital, Memphis, Tenn. for his helpful advice and criticism. REFERENCES

1. Sutnick AI, Levine PH, London WT, and Blumberg BS: Frequency of Australia antigen in patients with leukemia in different countries, Lancet 1:1200, 1971. 2. Armitage JO, Burns CP, and Kent TH: Liver disease complicating the management of acute leukemia during remission, Cancer 41:737, 1978. 3. Malone W., and Novak R.: Outcome of hepatitis in children with acute leukemia, Am J Dis Child 134:584, 1980. 4. Barton JC, and Conrad ME: Beneficial effects of hepatitis

The Journal of Pediatrics July 1981

5. 6.

7.

8.

9.

10.

in patients with acute myelogenous leukemia, Ann Intern Med 90:188, 1979. Kaplan EL, and Meier P: J Am Statis Assoc 53:457, 1958. Anderson TW: An introduction to multivariate statistical analysis, New York, 1958, John Wiley & Sons, Inc., Chap~ter 6. Bierman HR, Crile DM, Dod KS, Kelly KH, Petrakis NL, White LP, Shimkin MB: Remission in leukemia of childhood following acute infectious disease. Staphylococcus and streptococcus, varicella and feline panleukopenia, Cancer 61:591, 1953. Paolino W, and Sartoris S: Due casi di leucemia migliorati a seguito di complicanze infettive, Minerva Med 51:3454, 1960. Pelner L, Fowler GA, and Nauts HC: Effects of concurrent infections and their toxins on the course of leukemia, Acta Med Scand (Suppl) 338:47, 1958. Cowan DH, Kouroupis GM, and Leers WD: Occurrence of hepatitis and hepatitis B surface antigen in adult patients with acute leukemia, CMA Journal 112:693, 1975.

Modes of transmission of respiratory syncytial virus Caroline Breese Hall, M.D.,* and R. Gordon Douglas, Jr., M.D., Rochester, N.Y.

RESPIRATORY SYNCYTIAL VIRUS has recently been recognized as a major nosocomial hazard on pediatric wards. '-~ During a community outbreak of RSV infection, up to 40% of contact infants on hospital wards may acquire RSV infection nosocomially? Infection control procedures have been of limited value in reducing the nosocomial spread, especially among hospital personnel? Almost one-half of the staff on our infants' ward have become infected during these outbreaks, and they have appeared to play a role in transmitting the virus. How RSV is actually spread, however, is not clear. The possibility of spread by fomites followed by autoinoculation has been suggested by the demonstration of the survival of RSV in infant secretions on various environmental surfaces for periods up to six hoursr Whether spread by fomites or any other mode of spread actually occurs on a pediatric ward during an RSV From the Departments of Pediatrics and Medicine, University of Rochester School of Medicine and Dentistry. Supported by Contract No. NO1 A I 22503from'the Development and Applications Branch of the National Institute of Allergy and Infectious Disease. *Reprint address: Universityof Rochester Medical Center, Box MED, 601 Elmwood A venue, Rochester, N Y 14642.

outbreak has not been evaluated. The purpose of this study was to determine the possible modes of spread of RSV to young adult volunteers working on a pediatric ward who were exposed in different manners to infants with RSV infection. Abbreviation used RSV: respiratory syncytial virus

]

METHODS Study design. Three routes of transmission of RSV appear possible: (1) by large particles or droplets, (2) by self-inoculation after touching contaminated surfaces (fomites), and (3) by small particle aerosol. In the first route, direct spread by large droplets requires close contact with inoculation of infected secretions into a subject's eye or nose. The second possible route involves indirect spread by fomites, requiring contamination of environmental surfaces with infected secretions, and transfer of infectious virus to the hands after contacting these surfaces, with subsequent self-inoculation. Spread by small particle aerosol would not require close contact with the subject or contaminated surface, as such aerosols contain particles small enough ( < 10 microns) to travel

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Volume 99 Number 1 distances of 6 or more feet. This study was designed to expose young healthy adults in our hospital ward to infants infected with RSV by one of these three routes. Volunteers. Young adult volunteers were determined to be in good health and free of atopic manifestations by history, physical examination, and laboratory studies, which included an SMA-12, complete blood cell count, and a pregnancy test for women. Informed consent was obtained and approved by the Human Investigations Committee of the University of Rochester. Volunteers for the "cuddlers group" were obtained from medical personnel, such as student nurses, who as a part of their training had exposure during one day to the infants on this ward. Volunteers were then divided into three groups: "Cuddlers." Volunteers in this group were exposed to an infected infant over two to four hours by caring for the baby in the usual manner, which included feeding, changing the diaper, and playing with the infant. These volunteers wore gowns, but no masks or gloves. "Touchers." These volunteers were exposed with the infant out of the room by touching surfaces contaminated with the baby's secretions. The objects touched were those usually found about an infant's bed, such as countertops, crib sides, pacifiers, toys, and sometimes an oxygen tent. Volunteers touched the surfaces and then gently rubbed the mucous membranes of their nose or eye. Swabs of these surfaces were obtained at the time of the volunteers' exposure to ensure the presence of infectious virus on at least one of the surfaces contacted by the volunteers. "Sitters. "" This group of volunteers was exposed to an infected baby by sitting at a distance of more than 6 feet from an infant's bed. Volunteers wore gowns and gloves, but no masks. They were allowed to read but to touch nothing else for three hours. Cuddlers could potentially be exposed by any of the three routes of transmission, touchers by means of fomites and self-inoculation only, and sitters only by small particle aerosols. In order to control for possible differences in infectivity among infants, a volunteer from each of the three groups was exposed to each infant, or to his environment in the case of touchers. In addition, volunteers from each group were exposed to more than one infant. Also from the staff on the ward, nasal washes were obtained every two to three days as part of a study to detect nosocomial RSV infection. Monitoring of these cultures indicated that the volunteers were not accidentally exposed to a staff member shedding RSV. After exposure, volunteers were followed for 12 days with daily physical examinations and questionnaires for symptoms of illness. Nasal washes were obtained prior to exposure and daily for 12 days. Blood was obtained from

Brief clinical and laboratory observations

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Table. The proportion of 31 volunteers infected with respiratory syncytial virus according to method of exposure to an infected infant, and the resulting type of illness and incubation period

Volunteers

Cuddlers*

No. exposed No infected Afebrile URIw Febrile URI Asymptomatic Incubation

7 5 3 2 0 4 days

[

Toucherst

Sitters~_

l0 4 3 0 1 5.5 days

14 0 -

*Volunteersexposed by close contactwith infectedinfants. tVolunteersexposed by self-inoculationafter touchingsurfaces contaminated by infectedinfant'ssecretions. :~Volunteersexposed only by sittingat a distanceof over 6 feet from an infected infant. w respiratorytract infection.

each volunteer prior to exposure, and 12 days and four weeks after exposure. Infants. Volunteers were exposed to infants admitted with bronchiolitis or pneumonia during a community outbreak of RSV infection. RSV infection was documented by isolation of virus from a nasal wash obtained just prior to the volunteers' exposure. Virus isolation. Nasal washes obtained prior to the volunteers' exposure were inoculated onto several cell lines, HEp-2, Rhesus monkey kidney, Madin-Darby canine kidney, and human foreskin fibroblasts for viral isolation. All subsequent nasal washes were inoculated immediately onto two cultures of HEp-2 cells for isolation of RSV. The additional cell lines were also utilized for nasal washes of any subjects manifesting illness. Swabs of environmental surfaces about the infants' beds were put into veal infusion broth and inoculated immediately onto HEp-2 cell cultures. RSV was initially identified by its characteristic cytopathic effect and subsequently confirmed by complement fixation testing. Serology. Paired sera of the volunteers were tested for antibody rises by the complement fixation test and the enzyme-linked immunosorbent assay. 7'8 RESULTS Thirty-one volunteers were included in the study; seven in the "cuddlers" group, ten in the "touchers," and 14 in the "sitters" group. As shown in the Table, RSV infection was acquired by the cuddlers and the touchers, but not by the sitters (P < 0.05, Fisher exact test for cuddler versus sitters, and touchers versus sitters). Infection was demonstrated by viral isolation in all of the nine infected subjects and by serology in six (four of the cuddlers and two of the touchers). All of the cuddlers

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Brief clinical and laboratory observations

who became infected developed upper respiratory tract symptoms, which in two people was accompanied by a fever of 38~ for one to two days (Table). Infection in the touchers developed slightly later and was either asymptomatic or accompanied by mild respiratory symptoms consisting of slight nasal congestion or a slightly sore throat for one to three days. The onset of viral shedding in the nine infected subjects occurred on days three to six, with a median of five days. Shedding persisted for a range of one to five days with a median of three days. In each infant's room four to eight surfaces were swabbed to detect infectious virus. From at least one surface contacted by each volunteer, RSV was subsequently recovered. An average of 2.4 of the surfaces tested in an infant's room had detectable virus. DISCUSSION These findings suggest that the spread of RSV may occur by close contact with direct inoculation of large droplets or by self-inoculation after touching contaminated surfaces. Infection does not appear to occur after more distant contact requiring small particle aerosols. In this study the cuddlers could have been infected by both routes-direct inoculation of large droplets and by self-inoculation. We have observed that staff who care for prolonged periods for these infants in isolation commonly touch their eyes or nose, similar to the rate of hand-to-eye or hand-to-nose contact noted to occur during medical grand rounds by Hendley et al. 9 The relative importance in the nosocomial spread of RSV of these two routesself-inoculation versus direct inoculation of large droplets--cannot be determined. This study only indicates that both are possible. The inoculum obtained through direct inoculation of large particles may be greater than that received by contact with contaminated surfaces, since the amount and survival of infectious virus is dependent upon the type of surface, and the fall in titer is rapid on skin." In this and a previous study there is a suggestion that a lower inoculum of RSV is more likely to result in mild illness or asymptomatic infection in adults? ~ For infants, however, the size of the inoculum may be less important, since the infectious dose for infants is likely to be much less than that for adults. Transmission by fomites could, therefore, pose an even greater hazard for the infant. Recognition that these two modes of spread could be operative on hospital wards has potentially important and pragmatic implications for infection control. The infection control procedure that ought to be the most effective is one of the simplest, i.e., handwashing. Although handwashing may also be one of the most difficult procedures to enforce, almost any type of handwashing ought to be

The Journal of Pediatrics June 1981 effective in eradicating RSV, considering its lability and short survival on skin, which is further diminished when the hands are used or rubbedr The use of rubber gloves does not seem advisable, since RSV survives much better on gloves than on skin. In general, nonporous surfaces prolong the survival of RSV. However, infectious virus, even on these surfaces, should be readily eradicated by careful washing. Protection against infection by direct inoculation of staff members caring for infected infants is more difficult. RSV appears to infect via the nose and eye, but not the mouth. I~ Masks, therefore, do not adequately protect against direct or self-inoculation. Since small particle aerosol spread does not appear to be an important route of transmission, isolation of each infected infant may not be necessary. Isolation often is not feasible during an outbreak of RSV infection. Since only small particle aerosols can spread beyond a distance of 3 to 6 feet, infants separated by greater distances should not be at risk from the sneezes or coughs of neighboring infected infants. The possibility that spread could occur via fomites and the hands of staff and family members, of course, would remain no matter what the distance between infants. Currently, therefore, it would seem that infection con-trol procedures for RSV should stress handwashing. Ancillary procedures that may be helpful include the care of contaminated surfaces and gowns, cohorting of staff and infants, and limiting the traffic in and out of the infants' rooms. 4 With limited facilities, isolation rooms might best be reserved for uninfected infants with underlying disease who, should they acquire nosocomial RSV infection, are at high risk for severe disease. 11

REFERENCES

1. Ditchburn RK, McQuillin J, Gardner PS, and Court SDM: Respiratory syncytial virus in hospital cross-infection, Br Med J 3:671, 1971. 2. Gardner PS, Court SDM, Brocklebank JT, Downham MAPS, and Weightman D: Virus cross-infection in pediatric wards, Br Med J 2:571, 1973. 3. Hall CB, Douglas RG Jr, Geiman JM, and Messner MK: Nosocomial respiratory syncytial virus infections, N Engl J Med 293:1343, 1975. 4. Hall CB, Geiman JM, Douglas RG Jr, and Meagher MP: Control of nosocomial respiratory syncytial viral infections, Pediatrics 62:728, 1978. 5. Hall CB, Kopelman AE, Douglas RG Jr, Geiman JM, and Meagher MP: Neonatal respiratory syncytial viral infection, N Engl J Med 300:393, 1979. 6. Hall CB, Douglas RG Jr, and Geiman JM: Possible transmission of fomites of respiratory syncytial virus, J Infect Dis 141:98, 1980. 7. Buynak EB, Weibel RE, Carlson AJ, McLean AA, and Hilleman MR: Further investigation of live respiratory

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B r i e f cfinical and laboratory observations

syncytial virus vaccine administered parenterally, Proc Soc Exp Biol Med 160:272, 1979. Steinhoff MC, Hall CB, and Schnabel KC: Respiratory syncytial virus serology by a simplified enzyme-linked immunosobent assay, J Clin Microbiol 12:447, 1980. Hendley JO, Wenzel RP, and Gwaltney JM Jr: Transmission of rhinovirus colds by self-inoculation, N Engl J Med 288:1361, 1973.

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10. Hall CB, Douglas RG Jr, and Steinhoff MC: Infectivity of respiratory syncytial virus (RSV) by various routes of inoculation, Pediatr Res 13:461, 1979. 11. MacDonald NE, Hall CB, Alexson C, and Manning JA: Respiratory syncytial virus (RSV) infection in infants with congenital heart disease, 20th Interscience Conference on Antimicrobial Agents and Chemotherapy. Sept. 22-24, 1980, Abstract No. 200.

Plasma C-peptide and insulin in neonates, infants, and children Mikael Knip, M.D.,* and Hans K. A]kerblom, M.D.,** Oulu, Finland

TH E C LEAVAG E of proinsulin in the pancreatic beta cells results in an equimolar release of insulin and C-peptide into the portal circulation? In contrast to insulin, C-peptide is removed only to a minor degree by the liver? Hence, the determination of the C-peptide concentration in peripheral blood is a more accurate indicator of insulin secretion than the measurement of plasma insulin concentration. Low peripheral insulin concentrations have been reported in young fasting children, 34 but there is little information on C-peptide levels in the peripheral circulation of young children. The purpose of this study was to analyze the relationship between plasma C-peptide and insulin in children of different ages. SUBJECTS

AND METHODS

We studied 76 infants and children after informed consent was obtained from the parents. A mixed arteriovenous cord sample was collected from 20 vaginally delivered term infants (Group I). Their mean birth weight was 3,504 gm (range 2,690 to 4,250 gin) and mean gestational age 40 weeks (range 38 to 42 weeks). The delivery was induced in 15 of 20 mothers with intravenous infusion of oxytocin in 5% glucose. Group II comprised 12 healthy newborn infants with a mean birth weight of 3,622 gm (range 2,900 to 4,250 gm) and a mean gestational age of 40 weeks (range 38 to 42 weeks). A peripheral blood sample was taken at the mean age of 48 hours (range 36 to 60 hours) after fasting for four hours. Group III comprised 12 normal-weight infants, aged 0.5 to 12 From the Department of Pediatrics, University of Oulu. *Reprint address: Department of Pediatrics, Universityof Oulu, SF-90220 Oulu 22, Finland. **Supported by Sigrid Jusblius Foundation.

0022-3476/81/070103 + 03500.30/0 9 1981 The C. V. Mosby Co.

months (mean 7.0 months). Group IV comprised 12 normal-weight children aged 1.5 to 6.0 years (mean 3.8 years), and Group V 20 normal-weight children aged 6.9 to 15.1 years (mean 10.7 years). The children in Groups III to IV were admitted to hospital for elective surgery and had no endocrine or metabolic diseases. The venous blood samples were obtained preoperatively after fasting for six to ten hours. Abbreviations used IRI: immunoreactive insulin CPR: C-peptide immunoreactivity Plasma C-peptide was determined radioimmunologically using antiserum M 1230 (Novo Research Institute, Denmark)? The sensitivity of the assay was 0.02 nmol/L. The intra-assay and interassay coefficients of variation were 1.8 and 10%, respectively. Plasma immunoreactive insulin was measured using antiserum M 8309 (Novo Research Institute) with a minor modification of the charcoal separation method described by Herbert et al. 6 The sensitivity was 1 mU/L, the intra-assay coefficient of variation being 1.6% and the interassay variation 8.4%. Blood glucose was measured in neonates and infants by the hexokinase method. The statistical evaluation was performed using the nonparametric Kruskall-Wallis oneway analysis of variance and nonparametric correlation analysis (Spearman rank correlation coefficient, rs). For ease of comparison the results are expressed as mean _+ SEM. RESULTS C-peptide, IRI, and molar ratio of C-peptide to IRI in the five age groups are shown in Table I. C-peptide