A virus with the characteristics of the respiratory syncytial virus was isolated from the throat of a 6-month-old infant with pneumonia. The illness was accompanied by an eightfold increase in complement-fixation antibody to the Long strain of the respiratory syncytial virus identified by Chanock and colleagues1 and a 16-fold rise in the homologous neutralizing antibody, indicating that the pneumonia was accompanied by infection with this virus. The virus was labile to freezing at −15 to −20°C; isolation was possible from the original unfrozen specimen inoculated immediately or from passage virus pools sealed in glass ampules and stored in the dry ice chest.
Rowe and Michaels2 were the first to publish a report with the title including “respiratory syncytial virus,” the designation suggested earlier by Chanock and Finberg.3 The virus first was isolated from chimpanzees with upper respiratory illnesses by Morris, Blount, and Savage, who called the virus chimpanzee coryza agent (CCA).4 Chanock and Finberg recovered CCA from two children in Baltimore, MD, and suggested the name respiratory syncytial virus (RSV).3 Rowe and Michaels were the second investigators to report the isolation of this virus from young children. Their study not only confirmed the report of Chanock and Finberg but performed temperature stability tests that demonstrated the lability of RSV to freezing at −15°C to −20°C. Beem and colleagues5 made parallel observations of the temperature lability of RSV published at about the same time as the work of Rowe and Michaels. This observation provided an explanation for the low frequency of isolation of RSV by several investigators who were studying acute lower respiratory tract disease in infants and young children. It should be recalled that the viruses commonly isolated from children before that time were enteroviruses and adenoviruses. These viruses were relatively stable after −20°C freeze, and specimens usually were initially frozen, stored in freezers, and then tested in batches in virus diagnostic laboratories in the 1950s. Furthermore, the specimens usually were collected in Hank's balanced salt solution with only a small amount of gelatin as stabilizer that proved to be inadequate. This practice virtually eliminated the possibility of recognizing infections with RSV, although the virus replicated readily in continuous tissue culture lines such as HeLa and HEp-2 cells that were in common use at the time. Rowe and Michaels inoculated their specimen immediately without freezing, and this allowed them to recognize the cytopathic effect that had been described by Chanock and Finberg. With the assistance of Chanock, the identification of the Rowe and Michaels' virus was confirmed, and the child was found to have a significant rise in neutralizing antibodies to RSV.
Bronchiolitis is a common diagnosis today, but in 1959, this condition was not appreciated fully and the clinical designation was not used frequently.6 The illness of the 6-month-old child began with upper respiratory symptoms for 3 days and, when examined in the clinic, she was found to have a rectal temperature of 102°F, with tachycardia, hyperpnea, bilateral subcostal retractions, expiratory wheezing, and rales—all typical for bronchiolitis. Chest roentgenography showed patchy densities in the right lower lung field that were compatible with the diagnosis. Furthermore, it has been shown subsequently that isolation of virus 14 days after onset of bronchiolitis is not unusual.7 Therefore, the illness leading to the first hospitalization probably was associated with the RSV infection; rehospitalization with RSV also would not be unusual. Flattening of the diaphragm pushed the liver below the costal margin and resulted in a perception that the child was in heart failure. No evidence of myocarditis was found.
The infant had no evidence of a bacterial infection or of any other virus infection. The virus isolated was confirmed to be similar to the CCA virus isolated by Chanock and Finberg. The infant had a significant neutralizing antibody rise to her own virus and to the CCA virus of Chanock and Finberg. Thus, the association of the agent to pneumonia (bronchiolitis) was confirmed, and this opened the door to many other studies that have documented the role of RSV as the most important cause of pneumonia and bronchiolitis in infants. Subsequent studies have expanded the role of RSV to include triggering of attacks in asthmatic children and causing exacerbations in adults with chronic obstructive pulmonary disease.8 Fatal pneumonias have occurred in persons with recent bone marrow transplantation. High-risk elderly patients have life-threatening illnesses with RSV infection.
Infection is universal; all children are infected by 2 years of age.8 Reinfection is common, and natural infection does not provide complete protection. Illness can result from reinfection. It is not surprising that vaccine development has been difficult. An effective vaccine should provide better protection than natural infection. Much of the effort has been directed toward development of protection of young infants before the first natural infection. This is difficult because the peak occurrence of bronchiolitis and pneumonia is in the second month of life. Infants younger than 6 months of age do not have an optimal immune response to infection, and maternal antibody may interfere with response during that period. Therefore, it is immunologically inefficient to attempt active immunization during the first 6 months of life.
Some alternatives should be considered. One approach would be passive immunization of infants by increasing the amount of specific antibody transmitted across the placenta. This could be accomplished by immunizing women during the third trimester of pregnancy with a subunit vaccine. Passive immunity would not prevent infection but could prevent lower respiratory disease. Active immunization might be more effective if implemented after 6 months of age. Safety factors limit the approaches possible before that age because of small airway size and the possibility of paradoxic responses to immunization, as occurred with the formalin-inactivated vaccine in the 1960s. Effective primary immunization of older infants would reduce the exposure of the young infants who are at greatest risk of serious infection. Booster immunization of high-risk patients—the same groups currently recommended for influenza immunization—should be achieved. RSV subunit vaccines could be combined with inactivated influenza vaccine for this purpose.
Because of the high rate of infection, the threat of lower respiratory tract involvement, and the poor natural protective response, RSV poses a daunting challenge. Although much has been learned in the past 40 years, we still need information about the correlates of immunity and the protective response. The pioneering work of Chanock and his associates confirmed by Rowe and Michaels has initiated a process that has defined the enormity of the problem. Closure awaits the development of effective prophylactic measures that can be applied for the health of every child.
- Rowe DS,
- Michaels RH
- Morris JA Jr.,
- Blount RE,
- Savage RE
- ↵Hall CB. Respiratory syncytial virus In: Feigin RD, Cherry JD, eds. Textbook of Pediatric Infectious Diseases. 4th ed. Philadelphia, PA: WB Saunders Company; 1998:2084–2111
- ↵Piedra PA, Englund JA, Glezen WP. Respiratory syncytial virus and parainfluenza viruses. In: Richman DD, Whitley RJ, Hayden FG, eds. Clinical Virology. New York, NY: Churchill Livingstone; 1997:787–819
- Copyright © 1998 American Academy of Pediatrics