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Observations on the etiology of acute bronchiolitis in infants
864
T h e Journal of P E D I A 2" R I C S
Observations on the etiology of acute broncln'olitis in infants The etiology of acute bronehiolitis was investigated by comparing the viruses and bacteria isolated [rom the upper respiratory tract o[ 58 children with bronchiolitis and 128 healthy controls. The only virus demonstrated in significant relation to this syndrome was respiratory syncytial virus which was isolated from 55 per cent o[ the bronchiolitis patients and from none of the controls. Pneumococci, hemolytic streptococci, and Hemophilus influenzae were [ound with corr@arable frequency in both groups. There was significantly less [requent isolation o[ alpha hemolytic streptococci and Staphylococcus aureus and more [requent isolation o[ organisms of the coli-aerogenes group [rom the patients with bronchiolitis as compared with the controls.
Marc Beem, M.D., F. H. Wright, M.D.,* Dorcas M. Fasan; M.S., Rosalie Egerer, B.S., and Mafalda Oehme, B.S. C t-I t C A G O ,
ILL.
A c u T ~ bronchiolitis is a syndrome of respiratory tract obstruction at the bronchiolar level, accompanied ,by varying degrees of atelectasis, pneumonitis, and tracheobronchitis. 1 Although seen in patients of all ages and caused by such diverse factors as infection, inhalation of irritating substances,
From the Department o[ Pediatrics, University of Chicago School o[ Medicine. Aided by Grant E 1800 from the National Institutes o[ Health, and grants [rom The United Fund of Harvey, Ill., and the United Fund o[ Downers Grove, Ill. ~:'Address," DeDartment of Pediatrics, University of Chicago School o[ Medicine, Bobs Roberts Memorial Hospital for Children, 920 E. 59th St., Chicago 37, IlL
and allergy, tile majority of patients with bronchiolitis are children in the first 2 years of life in whom an infectious etiology is suggested by factors such as antecedent mild respiratory symptoms in the patient, concurrent mild respiratory illness in other members of the family, and, sometimes, the epidemic occurrence of such illnesses. >~ Sell s has presented observations indicating that infection with H e m o p h i l u s influenzae may play a role in this illness, but other observers G, ~, ~ have failed to find this or other bacteria in significant relationship to cases under their observation. A viral etiology, suggested by m a n y of the epidemiologic, clinical, and pathologic features of this syn-
Volume 61 Number 6
Etiology of acute bronchiolitis
and adenoviruses, were not found with significant frequency in either the bronchiolitis or control patients. 3. No significant differences were evident in the prevalence of pneumococci, hemolytic streptococci, and H. in#uenzae in the bronchiolitis and control groups.
drome, has been sought by methods capable of showing evidence of infection by such viruses as myxoviruses (influenza A, B, parainfluenza 1, 2, 3) adenoviruses, or psittacosis.4-s These efforts have resulted in the occasional demonstration of adenoviruses in such patients but the majority of cases have remained without definitive etiology. The information in the present report is derived from studies of acute respiratory disease in which the viral and bacterial respiratory floras of children with acute respiratory infections were compared with those of well children. During the winter and spring of 1958-1959 and 1959-1960, 424 children with acute respiratory illness and 282 well children were so observed. Fiftyeight of the sick children had bronchiolitis. They were seen during a 5 month period in each year of the study and all but 4 were less than 2 years of age. A comparison of the data on these 58 children and 128 of the controls who matched them in respect to age and time of sampling revealed: 1. A high proportion of the patients with bronchiolitis yielded the respiratory syncytial (R.S.) virus on culture (originally decribed by Morris, Blount, and Savage 1~ as the chimpanzee coryza agent). None of the controls did so. 2. Other viruses, particularly myxoviruses
METHODS A detailed .account of methods has been presented? 1 Briefly, children were considered to have an acute respiratory illness if they had experienced an abrupt change in their state of health which was associated with signs and symptoms of inflammation of the respiratory tract. A diagnosis of bronchiotitis was made when, in the course of such an illness, evidence of bronchiolar obstruction developed, provided that there were no additional findings indicating pulmonary consolidation and there was no history of a similar episode in the past. Children in the control group were patients seen in the clinic and hospital who were free of respiratory illness. Material obtained by swabbing the nose and oropharynx of these patients was used for attempts at bacterial and virus isolation. For bacterial studies the swabs were immersed in nutrient broth and subsequently used for the inoculation of fresh sheep blood and chocolate agar plates and blood broth
BRONGHIOLITIS
PATIENTS
•]-
NO
p ; " ~ - RS
Fig. 1.
NOV.
DEC,
JAN.
FEB,
1958-
1959
8 65
MAR.
APR.
MAY
NOV.
DES.
RS VIRUS VIRUS
JAR.
ISOLATION
ISOLATION
FEB,
1959-1960
MAR.
APR,
MAY
866
Beem et al.
December 1962
Table I. Viruses isolated from the respiratory tracts of children
No. of patients yielding indicated virus
t ora-I ara-I "ara-I Diagnosis Acute respiratory infection 424 patients Controls 282 patients
R.S.virus InfluenzaAo~ influenzalinfluenza[influenzal 2
3
IC~ v~rus Adeno-virusGroup B Uniden-tiffed
87
2
2
3
8
11
I
12
1
0
0
0
1
1
0
0
tubes. Bacterial identification was made through observation of colony morphology, production of hemolysis~ appropriate subculture, and slide staining. For viral studies the swabs were immersed in a salt solution containing horse serum and antibiotics; this fluid, without prior freezing, was inoculated into tubes containing established sheets of HEp-2 cells. About half of the specimens were also inoculated into secondary human kidney cells and secondary monkey kidney cells prepared and maintained as described by H a m r e 2 ~ Cell cultures were observed for the development of cytopathic changes or hemadsorption for a total period of 28 days. This usually required one or more passages. Virus identifications were made by inhibition of cytopathic effect or hemadsorption with type-specific immune serum. RESULTS
A variety of long-known and recently recognized respiratory viruses 1~ are demonstrable by the cell culture systems used. These include myxoviruses (influenza A and B, parainfluenza 1, 2, 3, and 4), adenoviruses, R.S. virus, reoviruses, and certain viruses similar to enteroviruses which have been found in association with acute respiratory illness. The various agents recognized in this study are indicated in Table I, which shows the isolations from the respiratory tracts of children with all varieties of acute respiratory tract infections observed during the period of the study. These were R.S. virus, influenza A:2, parainfluenza 1, 2, and 3, adenovirus (types 1, 2, 3, 5, 7), and Coxsackie virus Group, B, type 2. In addition there were 12 strains of virus which were not
specifically identified. The viral isolates from the infants with bronchiolitis and from their controls, matched according to age and time of sampling, are summarized in Table II. Adenovirus (type 7) was isolated from only one of the bronchiolitis patients and parainfluenza 3 was isolated from one of the controls. R.S. virus, on the other hand, was isolated from 32 of the 58 children with bronchiolitis (55 per cent) but was never demonstrated in an infant who was free of respiratory illness. ~ No characteristics of illness were noted which permitted a clinical distinction between R.S. virus positive and negative bronchiolitis patients. Clinical laboratory findings on 28 of the R.S. virus positive patients showed the following mean values: leukocyte count 11,300 (_+ 4,700) per cubic millimeter, polymorphonuclear leukocytes 35 per cent and lymphocytes 59 per cent. No atypical lymphocytes were noted. These values did not differ significantly from those of patients in the R.S. virus negative bronchiolitis group. The bacteria identified in tile respiratory tract cultures are shown in Table III. Infants who had received antimicrobial therapy within a period of 2 weeks preceding the culture were omitted from tabulations of bacteriologic findings. Since no significant differences were evident on comparison of the virus positive and virus negative bronchiolitis patients, both groups are compared
"X'Paired sera were available fron, 18 of the 32 patients from whom virus was isolated. Significant rises in neutralizing antibody titers were demonstrated in 10 of the 18 sera, a rate of seroconversion comparable to that previously reported for young infants with R.S. virus infection, al
Volume 61 Number 6
Etiology o[ acute bronchiolitis
from the bronchiolitis group is consistent with the experience of others, cited above, that adenoviruses may bear an occasional relationship to bronchiolitis but are not involved in the majority of cases. Although the myxoviruses, particularly parainfluenza 1 and 3, have been shown to be important causes of severe lower respiratory tract infections in young children, 13-1~ none were demonstrated in the patients with bronchiolitis during the period of this study. The role of bacteria in the illnesses of the patients in this study remains open to question. The methods used for identifying H. influenzae were less sensitive than those used by others who have reported evidence for association of this group of organisms with this syndrome so that it must be concluded that, although this correlation was not confirmed in the course of the present experience, it was also not refuted, particularly in respect to bronchiolitis which may occur at other times, in other places. The significance of the more frequent isolation of organisms of the coli-aerogenes group is under further study. Although this could reflect a causal relationship between these organisms and bronchiolitis, consideration should also be given to other possibilities such as a change in the respiratory tract environment resulting from the virus infection which favors the growth of these organisms. Similar factors might be responsible for the less frequent isolation of Staph. aureus from the bronchiolitis patients than from controls.
Table II. Virus isolations from patients with bronchiolitis and from healthy controls No. of patients with virus Diagnosis Bronchiolitis 58 patients Controls 128 patients
Para- 3 Adenoinfluenza virus
R.S. virus
0
1
32
i
0
0
867
with the controls. It is evident that Diplococcus pneurnoniae and hemolytic streptococci were isolated from the control and bronchiolitis patients with comparable frequency. This was also true of H. influenzae. There were significantly fewer isolations of alpha hemolytic streptococci and Staph. aureus from the bronchiolitis group. The only bacteria identified with greater frequency in infants with bronchio.litis than in the controls were organisms of the coli-aerogenes group. DISCUSSION
With the use of a study approach in which children with bronchiolitis and children without respiratory illness were compared in respect to the bacteria and viruses demonstrable in their respiratory tracts, the agent showing the most extensive relationships to illness was the R.S. virus. More than half the infants with bronchiolitis observed during these two winters yielded R.S. virus while none of a larger number of controls did so. The isolation of but a single adenovirus
Table III. Bacterial findings in patients without recent antimicrobial therapy Pneumococci
Diagnosis Bronchiolitis 36 patients
No. I % I0
Controls 127 patients 33 Difference between bronchiolitis and control groups Standard error of difference
Beta hemolytic strep. No.[ %
H. influenzae
Alpha hemolytic strep,
No
No.l
28
2
6
5
14
19 53
26
11
9
21
17
106 83
-3
-31
2
-3
7.9
Staph. aureus
Coliaerogenes
No I%
No.l%
18 50 115
91 -41 7.3
20
56
25
20 +36 8.5
868
Beem et al.
Although some of the virus negative patients may have had R.S. infections that were unidentified, the monthly incidence of virus positive and virus negative cases which is depicted in Fig. 1 is quite dissimilar. This suggests that the virus negative patients probably represent bronchiolitis of other etiology. Possibly non-R.S, virus associated cases were due to a variety of endemic agents such as parainfluenza 1 and 3, H. in/tuenzae, and other as yet unidentified agents; the methods used in this study were not sufficiently sensitive to reveal such a relationship. Certain facts which are becoming apparent concerning the natural history of R.S. virus infections suggest that the association of this agent with a significant portion of cases of bronchiolitis will not prove to be a unique or isolated finding. That R.S. virus infection can produce this syndrome is indicated by this and other observations. TM 1~ It would also appear that this agent makes a frequent appearance in metropolitan areas and at such times succeeds in reaching children in preschool age groups. Thus presence of this virus has been observed in each of 3 successive years in the Chicago area 17 as well as in Washington, D. C. is Also a survey of sera from children residing in the Chicago metropolitan area indicates that most of them have antibodies to this agent by the age of 6 years. 17 A factor which may contribute to this widespread and early infection is the apparent ability of R.S. virus to reinfect some individuals and cause a virus shedding, if not a symptomatic infection. This has been observed in experimental infections in volunteers z9 and also in naturally occurring infections? 7 Such immune and epidemiologic characteristics enhance the possibility that first infection with this agent will be experienced during the years of Iife in which the greatest incidence of bronchiolitis occurs. To what extent the development of this syndrome in the course of such infections is determined by factors of the host, virus, or synergistic action between virus and other microorganisms remains to be determined.
December t962
SUMMARY
During the winter and spring of 19581959 and 1959-1960, 58 children with bronchiolitis and 128 healthy control children matched for time and age were observed in the clinics and wards of the Bobs Roberts Memorial Hospital of the University of Chicago Hospital and Clinics. Attempts at virus isolations by methods capable of demonstrating the presence of a variety of recognized respiratory viruses revealed only R.S. virus in significant relationship t o this syndrome. R.S. virus was isolated from 55 per .cent of the patients with bronchiolitis and from none of the controls. No distinctive clinical characteristics of R.S. virus-associated bronchiolitis were rec,ognized. The bacterial flora of the nose and throat in bronchiotitis and control patients was similar in respect to the presence of pneumococci, hemolytic streptococci, and H. in~tuenzae. Alpha hemolytic streptococci and Staph. aureus were isolated from the bronchiolitis patients less frequently than from the controls, while organisms of the coliaerogenes group were isolated with signifi,cantly greater frequency from the bronchiolitis patients than from the control group.
REFERENCES
1. Nelson, W. E., and Smith, L. W.: Generalized obstructive emphysema in infants, J. P~DIAr. 26: 36, 1946. 2. Adams, John M.: Primary virus pneumonitis with cytoplasmic inclusion bodies, J. A, M. A. 116: 925, 1941. 3. Greengard, Joseph, Bayaraft, W. B., and Frank, Louis S.: Observations on pneumonia of infants at Cook County Hospital season of 1941, Illinois M. J. 80: 391, 1941. 4. Garrow, D. H., and Fawcett, J. W.: Epidemic bronchltis in children, Brit. M. J. 2: 795, 1953. 5. Heycock, J. B., and Noble, T. C.: An epidemic of acute bronehiolitis of infancy, Brit M. J. 1: 438, 1956. 6. Ross, E., Wiswell, G. B., Faulkner, R., MacLeod, A., Handforth, C. P., and VanRooyen, C. E." Epidemic bronchiolitis of infants, Nova Scotia, 1956, Postgrad. Med. 22: 87, 1957. 7. Disney, M. E., Sandiford, B. R., and Wolff,
Volume 61
8. 9.
10.
11.
12.
13.
Number 6
j.: Epidemic bronchiolitis in infants, Brit. M. J. 1: 1407, 1960. Sell, S. It.: Some observations on acute bronchiolitis in infants,.A. M. A. J. Dis. Child. 100: 7, 1960. High, Robert H.: Bronchiolitis, "An acute respiratory infection characterized by generalized obstructive emphysema and respiratory distress," Pedlar. Clin. North America, Feb. (Nov.), 183, 1957. Morris, J. A., Bloant, R. E., Jr., and Savage, R. E.: Recovery of cytopathogenic agent from chimpanzees with coryza, Proc. Soc. Exper. Biol. &Med, 92: 544, 1956. Beem, Marc, Wright, F. tI., Hamre, Dorothy, Egerer, Rosalie, and Oehme, Mafalda: Association of the chimpanzee coryza agent with acute respiratory disease in children, New England J. Med. 263: 523, 1960. Hamre, 'D., and Procknow, J. J.: Virological studies on acute respiratory disease in young adults. I. Isolation of ECHO 28, Proc. Soc. Exper. Biol. & Med. 107: 770, 1961. Chanoek, R. M., and Johnson, K. M.: Infectious disease: Respiratory viruses, in Annual review of medicine, Palo Alto, Calif., 1961, Annual Reviews, Inc., vol. 12, pp. 1-18.
Etiology o[ acute brorLchiolitis
86 9
14. Chanock, R. M., Vargosko, A., Luckey, A., Cook, M. K., Kapikian, A. Z., Reichelderfer, T., and Parrott, R. It.: Association of hemadsorption viruses with respiratory illness in childhood, J. A . M. A. 169: 548, 1959. 15. Kapikian, A. Z., Chanock, R. M., Bell, J. A., Reichelderfer, T. E., and Huebner, R. J.: A study of the hemadsorption viruses (parainfluenzae) and other viruses in children with and without respiratory disease, Pediatrics 26: 243, 1960. 16. Chanock, R. M., Kim, Hyun Wha, Vargosko, A. J., Deleva, A., Johnson, K. M., Cumming, C., and Parrott, R. H.: Respiratory syncytiaI virus. I, J. A. M. A. 176: 647, 1961. 17. Beem, Marc: Unpublished data. 18. Parrott, Robert I-t., Vargosko, A. J., Kim, Hyun Wha, Cumming, C., Turner, H., Huebner, R. J., and Chanock, R. M.: Respiratory syncytial virus. II, J. A. M. A. 176: 653, 1961. 19. Kravetz, H. M., Knight, V., Chanock, R. M., Morris, J. A., Johnson, K. M., Rifkind, D., and Utz, J. P.: Respiratory syncytial virus. III, J. A. M. A. 176: 657, 1961.
T h e Journal of P E D I A 2" R I C S
Observations on the etiology of acute broncln'olitis in infants The etiology of acute bronehiolitis was investigated by comparing the viruses and bacteria isolated [rom the upper respiratory tract o[ 58 children with bronchiolitis and 128 healthy controls. The only virus demonstrated in significant relation to this syndrome was respiratory syncytial virus which was isolated from 55 per cent o[ the bronchiolitis patients and from none of the controls. Pneumococci, hemolytic streptococci, and Hemophilus influenzae were [ound with corr@arable frequency in both groups. There was significantly less [requent isolation o[ alpha hemolytic streptococci and Staphylococcus aureus and more [requent isolation o[ organisms of the coli-aerogenes group [rom the patients with bronchiolitis as compared with the controls.
Marc Beem, M.D., F. H. Wright, M.D.,* Dorcas M. Fasan; M.S., Rosalie Egerer, B.S., and Mafalda Oehme, B.S. C t-I t C A G O ,
ILL.
A c u T ~ bronchiolitis is a syndrome of respiratory tract obstruction at the bronchiolar level, accompanied ,by varying degrees of atelectasis, pneumonitis, and tracheobronchitis. 1 Although seen in patients of all ages and caused by such diverse factors as infection, inhalation of irritating substances,
From the Department o[ Pediatrics, University of Chicago School o[ Medicine. Aided by Grant E 1800 from the National Institutes o[ Health, and grants [rom The United Fund of Harvey, Ill., and the United Fund o[ Downers Grove, Ill. ~:'Address," DeDartment of Pediatrics, University of Chicago School o[ Medicine, Bobs Roberts Memorial Hospital for Children, 920 E. 59th St., Chicago 37, IlL
and allergy, tile majority of patients with bronchiolitis are children in the first 2 years of life in whom an infectious etiology is suggested by factors such as antecedent mild respiratory symptoms in the patient, concurrent mild respiratory illness in other members of the family, and, sometimes, the epidemic occurrence of such illnesses. >~ Sell s has presented observations indicating that infection with H e m o p h i l u s influenzae may play a role in this illness, but other observers G, ~, ~ have failed to find this or other bacteria in significant relationship to cases under their observation. A viral etiology, suggested by m a n y of the epidemiologic, clinical, and pathologic features of this syn-
Volume 61 Number 6
Etiology of acute bronchiolitis
and adenoviruses, were not found with significant frequency in either the bronchiolitis or control patients. 3. No significant differences were evident in the prevalence of pneumococci, hemolytic streptococci, and H. in#uenzae in the bronchiolitis and control groups.
drome, has been sought by methods capable of showing evidence of infection by such viruses as myxoviruses (influenza A, B, parainfluenza 1, 2, 3) adenoviruses, or psittacosis.4-s These efforts have resulted in the occasional demonstration of adenoviruses in such patients but the majority of cases have remained without definitive etiology. The information in the present report is derived from studies of acute respiratory disease in which the viral and bacterial respiratory floras of children with acute respiratory infections were compared with those of well children. During the winter and spring of 1958-1959 and 1959-1960, 424 children with acute respiratory illness and 282 well children were so observed. Fiftyeight of the sick children had bronchiolitis. They were seen during a 5 month period in each year of the study and all but 4 were less than 2 years of age. A comparison of the data on these 58 children and 128 of the controls who matched them in respect to age and time of sampling revealed: 1. A high proportion of the patients with bronchiolitis yielded the respiratory syncytial (R.S.) virus on culture (originally decribed by Morris, Blount, and Savage 1~ as the chimpanzee coryza agent). None of the controls did so. 2. Other viruses, particularly myxoviruses
METHODS A detailed .account of methods has been presented? 1 Briefly, children were considered to have an acute respiratory illness if they had experienced an abrupt change in their state of health which was associated with signs and symptoms of inflammation of the respiratory tract. A diagnosis of bronchiotitis was made when, in the course of such an illness, evidence of bronchiolar obstruction developed, provided that there were no additional findings indicating pulmonary consolidation and there was no history of a similar episode in the past. Children in the control group were patients seen in the clinic and hospital who were free of respiratory illness. Material obtained by swabbing the nose and oropharynx of these patients was used for attempts at bacterial and virus isolation. For bacterial studies the swabs were immersed in nutrient broth and subsequently used for the inoculation of fresh sheep blood and chocolate agar plates and blood broth
BRONGHIOLITIS
PATIENTS
•]-
NO
p ; " ~ - RS
Fig. 1.
NOV.
DEC,
JAN.
FEB,
1958-
1959
8 65
MAR.
APR.
MAY
NOV.
DES.
RS VIRUS VIRUS
JAR.
ISOLATION
ISOLATION
FEB,
1959-1960
MAR.
APR,
MAY
866
Beem et al.
December 1962
Table I. Viruses isolated from the respiratory tracts of children
No. of patients yielding indicated virus
t ora-I ara-I "ara-I Diagnosis Acute respiratory infection 424 patients Controls 282 patients
R.S.virus InfluenzaAo~ influenzalinfluenza[influenzal 2
3
IC~ v~rus Adeno-virusGroup B Uniden-tiffed
87
2
2
3
8
11
I
12
1
0
0
0
1
1
0
0
tubes. Bacterial identification was made through observation of colony morphology, production of hemolysis~ appropriate subculture, and slide staining. For viral studies the swabs were immersed in a salt solution containing horse serum and antibiotics; this fluid, without prior freezing, was inoculated into tubes containing established sheets of HEp-2 cells. About half of the specimens were also inoculated into secondary human kidney cells and secondary monkey kidney cells prepared and maintained as described by H a m r e 2 ~ Cell cultures were observed for the development of cytopathic changes or hemadsorption for a total period of 28 days. This usually required one or more passages. Virus identifications were made by inhibition of cytopathic effect or hemadsorption with type-specific immune serum. RESULTS
A variety of long-known and recently recognized respiratory viruses 1~ are demonstrable by the cell culture systems used. These include myxoviruses (influenza A and B, parainfluenza 1, 2, 3, and 4), adenoviruses, R.S. virus, reoviruses, and certain viruses similar to enteroviruses which have been found in association with acute respiratory illness. The various agents recognized in this study are indicated in Table I, which shows the isolations from the respiratory tracts of children with all varieties of acute respiratory tract infections observed during the period of the study. These were R.S. virus, influenza A:2, parainfluenza 1, 2, and 3, adenovirus (types 1, 2, 3, 5, 7), and Coxsackie virus Group, B, type 2. In addition there were 12 strains of virus which were not
specifically identified. The viral isolates from the infants with bronchiolitis and from their controls, matched according to age and time of sampling, are summarized in Table II. Adenovirus (type 7) was isolated from only one of the bronchiolitis patients and parainfluenza 3 was isolated from one of the controls. R.S. virus, on the other hand, was isolated from 32 of the 58 children with bronchiolitis (55 per cent) but was never demonstrated in an infant who was free of respiratory illness. ~ No characteristics of illness were noted which permitted a clinical distinction between R.S. virus positive and negative bronchiolitis patients. Clinical laboratory findings on 28 of the R.S. virus positive patients showed the following mean values: leukocyte count 11,300 (_+ 4,700) per cubic millimeter, polymorphonuclear leukocytes 35 per cent and lymphocytes 59 per cent. No atypical lymphocytes were noted. These values did not differ significantly from those of patients in the R.S. virus negative bronchiolitis group. The bacteria identified in tile respiratory tract cultures are shown in Table III. Infants who had received antimicrobial therapy within a period of 2 weeks preceding the culture were omitted from tabulations of bacteriologic findings. Since no significant differences were evident on comparison of the virus positive and virus negative bronchiolitis patients, both groups are compared
"X'Paired sera were available fron, 18 of the 32 patients from whom virus was isolated. Significant rises in neutralizing antibody titers were demonstrated in 10 of the 18 sera, a rate of seroconversion comparable to that previously reported for young infants with R.S. virus infection, al
Volume 61 Number 6
Etiology o[ acute bronchiolitis
from the bronchiolitis group is consistent with the experience of others, cited above, that adenoviruses may bear an occasional relationship to bronchiolitis but are not involved in the majority of cases. Although the myxoviruses, particularly parainfluenza 1 and 3, have been shown to be important causes of severe lower respiratory tract infections in young children, 13-1~ none were demonstrated in the patients with bronchiolitis during the period of this study. The role of bacteria in the illnesses of the patients in this study remains open to question. The methods used for identifying H. influenzae were less sensitive than those used by others who have reported evidence for association of this group of organisms with this syndrome so that it must be concluded that, although this correlation was not confirmed in the course of the present experience, it was also not refuted, particularly in respect to bronchiolitis which may occur at other times, in other places. The significance of the more frequent isolation of organisms of the coli-aerogenes group is under further study. Although this could reflect a causal relationship between these organisms and bronchiolitis, consideration should also be given to other possibilities such as a change in the respiratory tract environment resulting from the virus infection which favors the growth of these organisms. Similar factors might be responsible for the less frequent isolation of Staph. aureus from the bronchiolitis patients than from controls.
Table II. Virus isolations from patients with bronchiolitis and from healthy controls No. of patients with virus Diagnosis Bronchiolitis 58 patients Controls 128 patients
Para- 3 Adenoinfluenza virus
R.S. virus
0
1
32
i
0
0
867
with the controls. It is evident that Diplococcus pneurnoniae and hemolytic streptococci were isolated from the control and bronchiolitis patients with comparable frequency. This was also true of H. influenzae. There were significantly fewer isolations of alpha hemolytic streptococci and Staph. aureus from the bronchiolitis group. The only bacteria identified with greater frequency in infants with bronchio.litis than in the controls were organisms of the coli-aerogenes group. DISCUSSION
With the use of a study approach in which children with bronchiolitis and children without respiratory illness were compared in respect to the bacteria and viruses demonstrable in their respiratory tracts, the agent showing the most extensive relationships to illness was the R.S. virus. More than half the infants with bronchiolitis observed during these two winters yielded R.S. virus while none of a larger number of controls did so. The isolation of but a single adenovirus
Table III. Bacterial findings in patients without recent antimicrobial therapy Pneumococci
Diagnosis Bronchiolitis 36 patients
No. I % I0
Controls 127 patients 33 Difference between bronchiolitis and control groups Standard error of difference
Beta hemolytic strep. No.[ %
H. influenzae
Alpha hemolytic strep,
No
No.l
28
2
6
5
14
19 53
26
11
9
21
17
106 83
-3
-31
2
-3
7.9
Staph. aureus
Coliaerogenes
No I%
No.l%
18 50 115
91 -41 7.3
20
56
25
20 +36 8.5
868
Beem et al.
Although some of the virus negative patients may have had R.S. infections that were unidentified, the monthly incidence of virus positive and virus negative cases which is depicted in Fig. 1 is quite dissimilar. This suggests that the virus negative patients probably represent bronchiolitis of other etiology. Possibly non-R.S, virus associated cases were due to a variety of endemic agents such as parainfluenza 1 and 3, H. in/tuenzae, and other as yet unidentified agents; the methods used in this study were not sufficiently sensitive to reveal such a relationship. Certain facts which are becoming apparent concerning the natural history of R.S. virus infections suggest that the association of this agent with a significant portion of cases of bronchiolitis will not prove to be a unique or isolated finding. That R.S. virus infection can produce this syndrome is indicated by this and other observations. TM 1~ It would also appear that this agent makes a frequent appearance in metropolitan areas and at such times succeeds in reaching children in preschool age groups. Thus presence of this virus has been observed in each of 3 successive years in the Chicago area 17 as well as in Washington, D. C. is Also a survey of sera from children residing in the Chicago metropolitan area indicates that most of them have antibodies to this agent by the age of 6 years. 17 A factor which may contribute to this widespread and early infection is the apparent ability of R.S. virus to reinfect some individuals and cause a virus shedding, if not a symptomatic infection. This has been observed in experimental infections in volunteers z9 and also in naturally occurring infections? 7 Such immune and epidemiologic characteristics enhance the possibility that first infection with this agent will be experienced during the years of Iife in which the greatest incidence of bronchiolitis occurs. To what extent the development of this syndrome in the course of such infections is determined by factors of the host, virus, or synergistic action between virus and other microorganisms remains to be determined.
December t962
SUMMARY
During the winter and spring of 19581959 and 1959-1960, 58 children with bronchiolitis and 128 healthy control children matched for time and age were observed in the clinics and wards of the Bobs Roberts Memorial Hospital of the University of Chicago Hospital and Clinics. Attempts at virus isolations by methods capable of demonstrating the presence of a variety of recognized respiratory viruses revealed only R.S. virus in significant relationship t o this syndrome. R.S. virus was isolated from 55 per .cent of the patients with bronchiolitis and from none of the controls. No distinctive clinical characteristics of R.S. virus-associated bronchiolitis were rec,ognized. The bacterial flora of the nose and throat in bronchiotitis and control patients was similar in respect to the presence of pneumococci, hemolytic streptococci, and H. in~tuenzae. Alpha hemolytic streptococci and Staph. aureus were isolated from the bronchiolitis patients less frequently than from the controls, while organisms of the coliaerogenes group were isolated with signifi,cantly greater frequency from the bronchiolitis patients than from the control group.
REFERENCES
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