July 1976 TheJournalofPED1ATRICS
11
Respiratory syncytial virus infections in infants." Quantitation and duration of shedding Infants hospitalized with respiratory syncytial virus infection were studied to delineate the quantitative shedding patterns and duration o f shedding o f RSV. Nasal wash specimens collected daily from 19 infants contained a mean maximal titer o f 4.34 loglo 50% tissue culture infective doses per milliliter. On admission, the mean titer was' 4.14 log~o TCID~o, with no consistent decline until after Day 6. The mean duration of shedding for 23 patients until they were virus negative was 6. 7 days with a range of 1 to 21 days. Quantities o f R S V shed were significantly greater in infants less than one month o f age and in infants with evidence of~pulmonary consolidation on chest roentgenogram. Shedding extended for a significantly longer time in infants with lower respiratory tract disease than in those with clinical manifestations limited to the upper respiratory tract.
Caroline Breese Halk M.D.,* R. Gordon Douglas, Jr., M.D., and Joyce M. Geiman, B.S., R o c h e s t e r , N . Y.
RESPIRATORY SYNCYTIAL VIRUS is the most frequent agent of acute lower respiratory tract disease in young infants and is often associated with a considerably high morbidity rate. 1-e In an attempt to better understand the pathogenesis and transmission of RSV infection, we have been interested in delineating the quantitative shedding patterns of infants with RSV lower respiratory tract disease, In a previous study, we observed that such infants tended to shed RSV in high titers and for prolonged periods of time. 7 Most infants continued to shed the virus at the time of discharge from the hospital. Hence, the total duration of shedding could not be estimated. In addition, all the infants studied during the same outbreak were similar in age and type of clinical illness: moderate to severe lower respiratory tract disease. The present study From the Departments' o f Pediatrics and Medicine, Infectious Disease Unit, University o f Rochester School of' Medicine. Supported by a eontract (NOI-AI-22503) from the Infectious Disease Branch, Nattonal Institute o f Allergy and Infectious Disease, National Institutes o f Health. *Reprint address: Departments of Pediatrics and Medicine, Infec!ious Disease Unit, Box 695, University of Rochester School of Medicine, 601 Elmwood Ave., Rochester, N. Y. 14642.
was, therefore, designed to extend these previous observations by including infants with a wider spectrum of illness and age. The daily quantities of virus shed by hospitalized infants with acute lower respiratory tract disease were determined, as well as the total duration of shedding by infants with upper and lower respiratory tract disease, respectively. These patterns were then examined in relation to severity of disease. Abbreviations used RSV: respiratory syncytial virus TCID~,,,: tissueculture infective dose
METHODS Subjects. Specimens for viral cultures were obtained on children under 3 years of age admitted with acute respiratory tract disease to Strong Memorial Hospital during a two-month period in the winter of 1975 when RSV was epidemic in the community. Collection of specimens. Nasal wash specimens were collected by described methods, 8 as soon as possible after admission and thereafter every one to three days throughout the infant's hospitalization. On approximately one-third of the patients, nasal washes were obtained daily for virus titrations. Infants who appeared to be
Vol. 89, No. 1, pp. 11-15
12
Hall, Douglas, and Geiman
The Journal of Pediatrics July 1976
RSV NASAL WASH TITERS e:TITER OF PATIENT --:MEAN
_-..
. . . .
-o-
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DAY OF HOSPITALIZATION Fig. 1. Distribution of titers of RSV in 19 infants' nasal washes (in logloTCID,,o)according to each day of hospitalization. The mean of the titers for each day is represented by the horizontal line.
shedding virus at the time of discharge were, when possible, followed at home. Nurses obtfiined nasal wash specimens and inoculated cell cultures in the home. Viral isolation and titrations. The admission wash was inoculated onto: a HEp-2 line especially sensitive to RSV (obtained from Flow Laboratories, Bethesda, Md.), rhesus monkey kidney, human embryonic kidney, and human embryonic lung (WI-38) cell cultures. Titrations were performed in HEp-2 cells by described methods. 8 Cultures were read daily for the characteristic cytopathic effects of RSV. The titer was calculated by the SpearmanKarber metho& and expressed as log10 TCIDso/ml. RESULTS Patients. A total of 59 patients hospitalized during the 1974-75 community outbreak of RSV infection were proved.to have RSV infection. The children were between the ages of 10 days and 18 months except for two patients, aged 2 and 4 years. The median age was 4 months, and 62.7% were male. Thirty-nine of the children had pneumonia with or without bronchiolitis, 5 had bronchiolitis alone, and 15 had upper respiratory tract illnesses, including otitis media. Forty-nine per cent had underlying diseases, mostly cardiopulmonary or neurologic. Nineteen of these patients were chosen to be studied by performing titers on their daily nasal wash specimens. These infants were arbitrarily selected to include those with lower respiratory tract disease of variable clinical severity, and with variable ages, including five under one month of age. They ranged in age from 12 days to l r months with a median of 3 months. Fifteen were less than 6 months of age, and 13 were male. All of these infants
had roentgenographic evidence of lower respiratory tract disease, 17 had pneumonia, and two had bronchiolitis. These infants were hospitalized from 2 to 37 days with a median of 11 days. Of the 59 patients, 23, including 10 from whom daily titers were obtained, were followed in the hospital or at home until they ceased shedding RSV. Their ages ranged from 10 days to 2 years, with a median age of 4 months. Thirteen were male. Eighteen had pneumonia, and five had upper respiratory tract illnesses. Quantitative shedding of virus. From 15 of the 19 infants who had,:ciaily nasal washes, an initial specimen was obtained for titering within 36 hours of admission, on their first or sr hospital day. The mean of these admission titers was 4.14 log10 (or 1.38 x l04) TCID~0/ml. In 12 of these infants the maximal titer was achieved on the first or second day of hospitalization. In seven infants, however, the maximal titer was not achieved until the third to sixth day of hospitalization. The mean maximal titer was 4.34 loglo TCID~0/ml, which is not significantly different from the mean admission titer (t = 0.70; p = > 0.25). The distribution of the titers of the infants' nasal washes by day of hospitalization is shown in Fig. 1. Although the mean titer decreased on Days 2 and 3, this was a consistent finding in only five individual patients. The quantity of virus shed was evaluated in relation to age, sex, and severity of illness. The influence of age on maximal RSV titer was examined b y dividing the 19 infants into two groups at each month of age. A significant correlation between the youngest infants and greatest quantities of virus shed was found. The five infants under
Volume 89 Number 1
R S V infections in infants
13
45198% Patient with Positive RSV Culture [Z~ Patient with Negative RSV Culture 1
40 35 30 z i,I
25 la_ O
IOO%
ee 2 0 lad II1
94% 100%
Io
56%
67% 67% I'--'Ir ~ l 8 o %
l I
l
l
2
l
3
l
4
l 5
l 6
l
l
7
l
8
l
9
l I0
I
II
DAY
12
OF
I
13
1 l l l 14 15 16 17
I
18
1 lt"-I I I 19 2 0 21 2 2 23 2 4
I-'-I 25 26 27 28
HOSPITALIZATION
Fig. 2. Frequency of RSV shedding according to hospital day in children with lower respiratory tract disease.
one month of age had a mean maximal titer of 5.00 loglo TCID~0/ml compared to 4.08 loglo TCID~0/ml for those over one month of age (t -- 2.65; p = < 0.01). When infants 2 months old or less were compared to those over 2 months of age, the difference in mean maximal titers was less (4.58 versus 4.00 log10 TCID~o/ml) (t = 1.46; p = > 0 . 0 5 and 0.05 and < 0.10). Neither duration of hospitalization nor the presence of underlying cardiopulmonary disease could be related to the amount of RSV shed. Duration of shedding. The proportion of infants with lower respiratory tract disease who shed RSV is depicted in Fig. 2 according to day of hospitalization. Although lhe
number of patients available for testing progressively declined, because of discharge, 96% of infants tested shed RSV throughout the first nine days. The 23 patients, who were followed for their entire period of shedding RSV, shed virus from 1 to 21 days, with a mean of 6.7 days. The girls tended to shed longer than the boys, mean 9.0 days compared to 5.08 days (t = 1.53; p = > 0.05 and < 0.10). The duration of shedding was also examined in relation to the infants' age, type of illness, and clinical findings related to severity of illness. No significant correlation with age could be found. Infants with lower respiratory tract disease, however, did shed for a significantly longer period (mean 8.4 days) than those with upper respiratory illness (mean 1.4 days) (t = 2.71; p = < 0.01). Although infants hospitalized for longer periods tended to have more prolonged shedding of RSV, the correlation was not statistically significant. Infants with less than three weeks of hospitalization shed 5.7 days compared to 8.2 days for those hospitalized longer (t = 0.947; p > 0.15). For infants hospitalized less than four weeks compared to those hospitalized for four weeks or more, mean shedding was 5.9 compared to 9.2 days (t = 1.09; p > 0.10 and < 0.15). Roentgenographic evidence of pulmonary consolidation was statistically correlated with prolonged RSV
14
Hall, Douglas, and Geiman
shedding. The six infants with a consolidated lobe shed RSV for an average 11.5 days compared to 5.2 days for those without consolidation (t = 2.35; p = < 0.025). Overt cyanosis or documented hypoxia, however, could not be similarly related to the period of shedding (t = 1.03; p = > 0.15). The seven infants with underlyflag cardiopulmonarj disease tended to shed RSV longer (9.9 days) than the 16 previously well infants (5,4 days) (t = 1.61; p = > 0.05 and < 0.10). COMMENT This study not only tends to confirm our previous observations that infants shed RSV in large quantities and for prolonged periods of time, but suggests that these findings may be related to age and severity of illness. The amount of virus shed was greatest in the youngest infants, especially those less than one month of age. This is interesting in view of the observations that infants under one month of age contract RSV disease much less commonly.' .... The greater quantities of RSV shed by infants during this period suggest that the low attack rate cannot be explained by their possessing a greater ability or immune function to limit viral replication. Indeed, the larger quantities of RSV shed during this first month of life might be related to an incompetency of the very young infant to produce secretory antibody or a local cellmediated response, both of which may be important in controlling viral spread. 11,~2 Scott and Gardener 1~ observed that 68% of children with RSV disease produce a rise in secretory neutralizing antibody. However, they do not note if infants in the first few weeks of life are less likely to produce this response. This first month of life is, however, when passively acquired serum neutralizing antibody levels would be highest. If the amount of RSV shed could be correlated with the level of serum antibody, Chanock and colleaguesTM hypothesis that the presence of maternal antibody is detrimental to the infant with RSV disease might be supported. However, subsequent studies by these workers have not shown a correlation between the level of serum neutralizing antibody and severity of disease, as indicated by duration of hospitahzation. 4 In our study, RSV shedding tended to be greater and prolonged in infants with more severe RSV pulmonary disease and with underlying cardiopulmonary disease. Infants with underlying diseases, especially congenital heart disease, have been noted to be more at risk for acquiring severe or fatal illness with RSV. 1~ However, the explanation for this is unclear. Our findings might suggest that severity of illness may be related to whatever host defense mechanisms are effective in curtailing the spread and multiplication of the virus in the respiratory tract.
The Journal of Pediatrics July 1976
Production of interferon, as well as specific secretory antibody and cell-mediated immunity, may be important. These defense mechanisms may not only be generally slower but more variable in development than serum antibody, explaining why some infants at varying months of age may have more severe RSV disease. Correlation of severity of disease with quantity of virus shed also suggests that the latter might be a characteristic worth studying in the evaluation of modes of prophylaxis or treatment. Thus, low quantities of RSV shed after immunization with experimental live vaccines may correlate with attenuation. In Kim and colleagues '16 trial of a temperature-sensitive RSV vaccine in young children, the greatest quantities of vaccine virus were shed by the eight youngest infants (6 months to 1 year of age) who had the lowest levels of serum neutralizing antibody prior to immunization. It was in this group also that the greatest clinical reactivity to immunization occurred. Second, determining the amount of wild virus shed might also be useful as a marker of efficacy of an experimental vaccine after challenge with wild RSV. The large amount of virus shed in the nasal secretions, and the prolonged period of shedding suggest that RSV infections spread readily. This has been substantiated epidemiologically by the studies in Washington, D.C., that estimate that approximately half of all infants will contract RSV during the first epidemic in the community?" ~7 Infants with lower respiratory tract disease, according to our findings, would be the most likely disseminators. During a recent community outbreak of RSV infection, we observed that, if a few babies were admitted to the infants' ward with RSV lower respiratory tract disease, RSV spread readily among both contact infants and ward'personnel? 6 Hence, infants hospitalized with respiratory disease during periods of prevalence of RSV in the community should be considered a potential hazard and isolated. REFERENCES
1. Chanock RM, and Parrott RH: Acute respiratory disease in infancy and childhood: present understanding and prospects for prevention, Pediatrics 36:21, 1965. 2. Glezen WP, and Denny FW: Epidemiology of acute lower respiratory disease in children, N Engl J Med 288:498, 1973. 3. Kim HW, Arrobio JO, Brandt CD, Jeffries BC, Pyles G, Reid JL, Chanock RM, and Parrott RH: Epidemiology of respiratory syncytial virus infection in Washington, D.C.I. Importance of the virus in different respiratory tract syndromes and temporal distribution of infection, Am J Epidemiol 98:216, 1973. 4. Parrott RH, Kim HW, Arrobio JO, Hodes DS, Murphy BR, Brandt CD, Camargo E, and Chanock RM: Epidemiology of respiratory syncytial virus infection in Washington, D.C.
Volume 89 Number 1
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6.
7.
8.
9. 10.
11.
12.
II. Infection and disease with respect to age, immunologic status, race and sex, Am J Epidemiol 98:289, 1973. Brandt CD, Kim HW, Arrobio JO, Jeffries BC, Wood SC, Chanock RM, and Parrott RH: Epidemiology of respiratory syncytial virus infection in Washington, D.C. III. Composite analysis of eleven consecutive yearly epidemics, Am J Epidemiol 98:355, 1973. Mufson MA, Krause HE, Mocega HE, and Dawson FW: Viruses, Mycoplasma pneumoniae and bacteria associated with lower respiratory tract disease among infants, Am J Epidemiol 91:192, 1970. Hall CB, Douglas RG Jr, and Geiman JM: Quantitative shedding patterns of respiratory syncytial virus in infants, J Infect Dis 132:151, 1975. Hall CB, and Douglas RG Jr: Clinically useful method for the isolation of respiratory syncytial virus, J Infect Dis 131:1, 1975. Finney DJ: Statistical methods in biological assay, London, 1952, Charles Griffin and Company,~, p 524. Jacobs JW, Peacock DB, Corner:BD, Caul ED, and Clarke SKR: Respiratory syncytial and other viruses associated with respiratory disease in infants, Lancet 1:871, 1971. Mills J V, Van Kirk JE, Wright PF, and Chanock RM: Experimental respiratory syncytial virus infection of adults, J Immunol 107:123, 1971. Jurgensen PF, Olsen GN, Johnson JE III, Swenson EW,
R S V infections in infants
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14.
15.
16.
17.
18.
15
Ayoub EM, Henney CS, and Waldman RH: Immune response of the human respiratory tract. II. Cell-mediated immunity in the lower respiratory tract to tuberculin and mumps and influenza viruses, J Infect Dis 128:730, 1973. Scott R, and Gardner PS: The local antibody response to R.S. virus infection in the respiratory tract, J Hyg 72:111, 1974. Chanock RM, Parrott RH, Kapikian AZ, Kim HW, and Brandt CD: Possible role of immunological factors in pathogenesis of RSV virus lower respiratory tract disease, in Pollard M, editor: Perspectives in virology. IV, New York, 1968, Academic Press, Inc, pp 125-135. Gardner PS, Turk DC, Aherne WA, Bird T, Holdaway MD, and Court SDM: Deaths associated with respiratory tract infections in childhood, Br Med J 4:316, 1967. Kim HW, Arrobio JO, Brandt CD, Wright P, Hodes D, Chanock RM, and Parrott RH: Safety and antigenicity of temperature sensitive (Ts) mutant respiratory synoytial virus (RSV) in infants and children, Pediatrics 52:56, ]973. Parrott RH, Kim HW, Brandt CD, and Chanock RM: Respiratory syncytial virus in infants and children, Prev Med 3:473, 1974. Hall CB, Douglas RG Jr, Geiman JM, and Messner MK: Nosocomiat respiratory syncytial virus infections, N Engl J Med 293:1343, 1975.
11
Respiratory syncytial virus infections in infants." Quantitation and duration of shedding Infants hospitalized with respiratory syncytial virus infection were studied to delineate the quantitative shedding patterns and duration o f shedding o f RSV. Nasal wash specimens collected daily from 19 infants contained a mean maximal titer o f 4.34 loglo 50% tissue culture infective doses per milliliter. On admission, the mean titer was' 4.14 log~o TCID~o, with no consistent decline until after Day 6. The mean duration of shedding for 23 patients until they were virus negative was 6. 7 days with a range of 1 to 21 days. Quantities o f R S V shed were significantly greater in infants less than one month o f age and in infants with evidence of~pulmonary consolidation on chest roentgenogram. Shedding extended for a significantly longer time in infants with lower respiratory tract disease than in those with clinical manifestations limited to the upper respiratory tract.
Caroline Breese Halk M.D.,* R. Gordon Douglas, Jr., M.D., and Joyce M. Geiman, B.S., R o c h e s t e r , N . Y.
RESPIRATORY SYNCYTIAL VIRUS is the most frequent agent of acute lower respiratory tract disease in young infants and is often associated with a considerably high morbidity rate. 1-e In an attempt to better understand the pathogenesis and transmission of RSV infection, we have been interested in delineating the quantitative shedding patterns of infants with RSV lower respiratory tract disease, In a previous study, we observed that such infants tended to shed RSV in high titers and for prolonged periods of time. 7 Most infants continued to shed the virus at the time of discharge from the hospital. Hence, the total duration of shedding could not be estimated. In addition, all the infants studied during the same outbreak were similar in age and type of clinical illness: moderate to severe lower respiratory tract disease. The present study From the Departments' o f Pediatrics and Medicine, Infectious Disease Unit, University o f Rochester School of' Medicine. Supported by a eontract (NOI-AI-22503) from the Infectious Disease Branch, Nattonal Institute o f Allergy and Infectious Disease, National Institutes o f Health. *Reprint address: Departments of Pediatrics and Medicine, Infec!ious Disease Unit, Box 695, University of Rochester School of Medicine, 601 Elmwood Ave., Rochester, N. Y. 14642.
was, therefore, designed to extend these previous observations by including infants with a wider spectrum of illness and age. The daily quantities of virus shed by hospitalized infants with acute lower respiratory tract disease were determined, as well as the total duration of shedding by infants with upper and lower respiratory tract disease, respectively. These patterns were then examined in relation to severity of disease. Abbreviations used RSV: respiratory syncytial virus TCID~,,,: tissueculture infective dose
METHODS Subjects. Specimens for viral cultures were obtained on children under 3 years of age admitted with acute respiratory tract disease to Strong Memorial Hospital during a two-month period in the winter of 1975 when RSV was epidemic in the community. Collection of specimens. Nasal wash specimens were collected by described methods, 8 as soon as possible after admission and thereafter every one to three days throughout the infant's hospitalization. On approximately one-third of the patients, nasal washes were obtained daily for virus titrations. Infants who appeared to be
Vol. 89, No. 1, pp. 11-15
12
Hall, Douglas, and Geiman
The Journal of Pediatrics July 1976
RSV NASAL WASH TITERS e:TITER OF PATIENT --:MEAN
_-..
. . . .
-o-
3 9
oo
oo
~
io
o
o
~
o
o
9
~
o o
9
9
OlD
2 oo
~
-
-
o
e
--
o
o
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0
~
I
1
3
I
I
5
I
l
I
7
I
9
I
I
II
I
I
I
13
I
15
)
I
17
I
l
19
I
I
21
DAY OF HOSPITALIZATION Fig. 1. Distribution of titers of RSV in 19 infants' nasal washes (in logloTCID,,o)according to each day of hospitalization. The mean of the titers for each day is represented by the horizontal line.
shedding virus at the time of discharge were, when possible, followed at home. Nurses obtfiined nasal wash specimens and inoculated cell cultures in the home. Viral isolation and titrations. The admission wash was inoculated onto: a HEp-2 line especially sensitive to RSV (obtained from Flow Laboratories, Bethesda, Md.), rhesus monkey kidney, human embryonic kidney, and human embryonic lung (WI-38) cell cultures. Titrations were performed in HEp-2 cells by described methods. 8 Cultures were read daily for the characteristic cytopathic effects of RSV. The titer was calculated by the SpearmanKarber metho& and expressed as log10 TCIDso/ml. RESULTS Patients. A total of 59 patients hospitalized during the 1974-75 community outbreak of RSV infection were proved.to have RSV infection. The children were between the ages of 10 days and 18 months except for two patients, aged 2 and 4 years. The median age was 4 months, and 62.7% were male. Thirty-nine of the children had pneumonia with or without bronchiolitis, 5 had bronchiolitis alone, and 15 had upper respiratory tract illnesses, including otitis media. Forty-nine per cent had underlying diseases, mostly cardiopulmonary or neurologic. Nineteen of these patients were chosen to be studied by performing titers on their daily nasal wash specimens. These infants were arbitrarily selected to include those with lower respiratory tract disease of variable clinical severity, and with variable ages, including five under one month of age. They ranged in age from 12 days to l r months with a median of 3 months. Fifteen were less than 6 months of age, and 13 were male. All of these infants
had roentgenographic evidence of lower respiratory tract disease, 17 had pneumonia, and two had bronchiolitis. These infants were hospitalized from 2 to 37 days with a median of 11 days. Of the 59 patients, 23, including 10 from whom daily titers were obtained, were followed in the hospital or at home until they ceased shedding RSV. Their ages ranged from 10 days to 2 years, with a median age of 4 months. Thirteen were male. Eighteen had pneumonia, and five had upper respiratory tract illnesses. Quantitative shedding of virus. From 15 of the 19 infants who had,:ciaily nasal washes, an initial specimen was obtained for titering within 36 hours of admission, on their first or sr hospital day. The mean of these admission titers was 4.14 log10 (or 1.38 x l04) TCID~0/ml. In 12 of these infants the maximal titer was achieved on the first or second day of hospitalization. In seven infants, however, the maximal titer was not achieved until the third to sixth day of hospitalization. The mean maximal titer was 4.34 loglo TCID~0/ml, which is not significantly different from the mean admission titer (t = 0.70; p = > 0.25). The distribution of the titers of the infants' nasal washes by day of hospitalization is shown in Fig. 1. Although the mean titer decreased on Days 2 and 3, this was a consistent finding in only five individual patients. The quantity of virus shed was evaluated in relation to age, sex, and severity of illness. The influence of age on maximal RSV titer was examined b y dividing the 19 infants into two groups at each month of age. A significant correlation between the youngest infants and greatest quantities of virus shed was found. The five infants under
Volume 89 Number 1
R S V infections in infants
13
45198% Patient with Positive RSV Culture [Z~ Patient with Negative RSV Culture 1
40 35 30 z i,I
25 la_ O
IOO%
ee 2 0 lad II1
94% 100%
Io
56%
67% 67% I'--'Ir ~ l 8 o %
l I
l
l
2
l
3
l
4
l 5
l 6
l
l
7
l
8
l
9
l I0
I
II
DAY
12
OF
I
13
1 l l l 14 15 16 17
I
18
1 lt"-I I I 19 2 0 21 2 2 23 2 4
I-'-I 25 26 27 28
HOSPITALIZATION
Fig. 2. Frequency of RSV shedding according to hospital day in children with lower respiratory tract disease.
one month of age had a mean maximal titer of 5.00 loglo TCID~0/ml compared to 4.08 loglo TCID~0/ml for those over one month of age (t -- 2.65; p = < 0.01). When infants 2 months old or less were compared to those over 2 months of age, the difference in mean maximal titers was less (4.58 versus 4.00 log10 TCID~o/ml) (t = 1.46; p = > 0 . 0 5 and 0.05 and < 0.10). Neither duration of hospitalization nor the presence of underlying cardiopulmonary disease could be related to the amount of RSV shed. Duration of shedding. The proportion of infants with lower respiratory tract disease who shed RSV is depicted in Fig. 2 according to day of hospitalization. Although lhe
number of patients available for testing progressively declined, because of discharge, 96% of infants tested shed RSV throughout the first nine days. The 23 patients, who were followed for their entire period of shedding RSV, shed virus from 1 to 21 days, with a mean of 6.7 days. The girls tended to shed longer than the boys, mean 9.0 days compared to 5.08 days (t = 1.53; p = > 0.05 and < 0.10). The duration of shedding was also examined in relation to the infants' age, type of illness, and clinical findings related to severity of illness. No significant correlation with age could be found. Infants with lower respiratory tract disease, however, did shed for a significantly longer period (mean 8.4 days) than those with upper respiratory illness (mean 1.4 days) (t = 2.71; p = < 0.01). Although infants hospitalized for longer periods tended to have more prolonged shedding of RSV, the correlation was not statistically significant. Infants with less than three weeks of hospitalization shed 5.7 days compared to 8.2 days for those hospitalized longer (t = 0.947; p > 0.15). For infants hospitalized less than four weeks compared to those hospitalized for four weeks or more, mean shedding was 5.9 compared to 9.2 days (t = 1.09; p > 0.10 and < 0.15). Roentgenographic evidence of pulmonary consolidation was statistically correlated with prolonged RSV
14
Hall, Douglas, and Geiman
shedding. The six infants with a consolidated lobe shed RSV for an average 11.5 days compared to 5.2 days for those without consolidation (t = 2.35; p = < 0.025). Overt cyanosis or documented hypoxia, however, could not be similarly related to the period of shedding (t = 1.03; p = > 0.15). The seven infants with underlyflag cardiopulmonarj disease tended to shed RSV longer (9.9 days) than the 16 previously well infants (5,4 days) (t = 1.61; p = > 0.05 and < 0.10). COMMENT This study not only tends to confirm our previous observations that infants shed RSV in large quantities and for prolonged periods of time, but suggests that these findings may be related to age and severity of illness. The amount of virus shed was greatest in the youngest infants, especially those less than one month of age. This is interesting in view of the observations that infants under one month of age contract RSV disease much less commonly.' .... The greater quantities of RSV shed by infants during this period suggest that the low attack rate cannot be explained by their possessing a greater ability or immune function to limit viral replication. Indeed, the larger quantities of RSV shed during this first month of life might be related to an incompetency of the very young infant to produce secretory antibody or a local cellmediated response, both of which may be important in controlling viral spread. 11,~2 Scott and Gardener 1~ observed that 68% of children with RSV disease produce a rise in secretory neutralizing antibody. However, they do not note if infants in the first few weeks of life are less likely to produce this response. This first month of life is, however, when passively acquired serum neutralizing antibody levels would be highest. If the amount of RSV shed could be correlated with the level of serum antibody, Chanock and colleaguesTM hypothesis that the presence of maternal antibody is detrimental to the infant with RSV disease might be supported. However, subsequent studies by these workers have not shown a correlation between the level of serum neutralizing antibody and severity of disease, as indicated by duration of hospitahzation. 4 In our study, RSV shedding tended to be greater and prolonged in infants with more severe RSV pulmonary disease and with underlying cardiopulmonary disease. Infants with underlying diseases, especially congenital heart disease, have been noted to be more at risk for acquiring severe or fatal illness with RSV. 1~ However, the explanation for this is unclear. Our findings might suggest that severity of illness may be related to whatever host defense mechanisms are effective in curtailing the spread and multiplication of the virus in the respiratory tract.
The Journal of Pediatrics July 1976
Production of interferon, as well as specific secretory antibody and cell-mediated immunity, may be important. These defense mechanisms may not only be generally slower but more variable in development than serum antibody, explaining why some infants at varying months of age may have more severe RSV disease. Correlation of severity of disease with quantity of virus shed also suggests that the latter might be a characteristic worth studying in the evaluation of modes of prophylaxis or treatment. Thus, low quantities of RSV shed after immunization with experimental live vaccines may correlate with attenuation. In Kim and colleagues '16 trial of a temperature-sensitive RSV vaccine in young children, the greatest quantities of vaccine virus were shed by the eight youngest infants (6 months to 1 year of age) who had the lowest levels of serum neutralizing antibody prior to immunization. It was in this group also that the greatest clinical reactivity to immunization occurred. Second, determining the amount of wild virus shed might also be useful as a marker of efficacy of an experimental vaccine after challenge with wild RSV. The large amount of virus shed in the nasal secretions, and the prolonged period of shedding suggest that RSV infections spread readily. This has been substantiated epidemiologically by the studies in Washington, D.C., that estimate that approximately half of all infants will contract RSV during the first epidemic in the community?" ~7 Infants with lower respiratory tract disease, according to our findings, would be the most likely disseminators. During a recent community outbreak of RSV infection, we observed that, if a few babies were admitted to the infants' ward with RSV lower respiratory tract disease, RSV spread readily among both contact infants and ward'personnel? 6 Hence, infants hospitalized with respiratory disease during periods of prevalence of RSV in the community should be considered a potential hazard and isolated. REFERENCES
1. Chanock RM, and Parrott RH: Acute respiratory disease in infancy and childhood: present understanding and prospects for prevention, Pediatrics 36:21, 1965. 2. Glezen WP, and Denny FW: Epidemiology of acute lower respiratory disease in children, N Engl J Med 288:498, 1973. 3. Kim HW, Arrobio JO, Brandt CD, Jeffries BC, Pyles G, Reid JL, Chanock RM, and Parrott RH: Epidemiology of respiratory syncytial virus infection in Washington, D.C.I. Importance of the virus in different respiratory tract syndromes and temporal distribution of infection, Am J Epidemiol 98:216, 1973. 4. Parrott RH, Kim HW, Arrobio JO, Hodes DS, Murphy BR, Brandt CD, Camargo E, and Chanock RM: Epidemiology of respiratory syncytial virus infection in Washington, D.C.
Volume 89 Number 1
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