Pediatric Annals

Respiratory Syncytial Virus Infection and Cardiopulmonary Disease

Deborah A Laufer, MD; J Edelson, MD

Abstract

Respiratory syncytial virus (RSV) is a ubiquitous cause of epidemic winter respiratory disease in children and adults. Ics best recognized clinical form is bronchiolitis, but it may also cause pneumonia, apnea, respiratory distress, or merely a cold. Its clinical severity is generally greatest in the infant and mildest in the adult. CHnical disease occurs throughout life, but asymptomatic infection probably occurs only in adults.

RSV is the only respiratory virus which occurs in consistent annual outbreaks each year, usually beginning after Thanksgiving and ending in early March. A child under the age of one has about a 50% chance of being infected, and by 3 years of age essentially 100% of children have had at least one infection. During the epidemic period, except when it is interrupted by epidemic influenza, RSV accounts for 90% of the lower respiratory tract disease in preschool children.

Most children weather RSV infection with little problem. However, certain groups of children, including infants under 6 months of age, immunosuppressed children, and children with preexisting cardiac or pulmonary disease, may develop life-threatening disease. These children are much more likely to require hospitalization, intensive care, and mechanical ventilation. Although the risk of long-term morbidity following RSV infection in these children is not known, their case-fatality rate with RSV infection may be 10 to 100 times higher than it is for other children (Table 1).

The life-threatening nature of RSV infection has been best documented in the infant with congenital heart disease. In one study among children in Rochester, New York, who were hospitalized with RSV, those with congenital heart abnormalities had a 37% case-fatality rate, as compared with an estimated rate of under 1% in otherwise healthy children. ' RSV raised the relative risk of fatality among all children with congenital heart disease who required hospital admission from 6.5% to 37%, more than a fivefold nse.

Table

Obviously in patients with underlying cardiac disease, the clinician must carefully assess whether an infectious process, cardiac failure, or both are occurring. Fever and rhinorrhea are not seen in primary congestive heart failure, and increasing heart size and organomegaly are not usually seen in infections with RSV. Although tachypnea and worsening cyanosis may be seen in either condition, their development in association with upper respiratory symptoms must raise the issue of superimposed RSV infection.

LABORATORY DIAGNOSIS

The standard for diagnosis of RSV infection is viral isolation from the respiratory secretions of a symptomatic individual. Although a reliable diagnosis can be made using improved techniques for sample collection and virus cultivation, the role of viral isolation in management is limited as it may take two to three weeks for a positive result. Serologie diagnosis can be made using a complement fixation test, which shows a significant rise in antibody titer to RSV. However, serologie testing for any of the common viral pathogens other than influenza is also slow, unreliable, and has no role in individual patient management.

A more rapid and highly reliable test for RSV is the enzyme-linked immunosorbent assay (ELISA). This sensitive and specific method, which takes only a few hours, can identify viral antigen in nasopharyngeal secretions by using enzyme-tagged antibodies that bind to infected cells and can be identified by a photometric enzyme assay. Several companies now market testing kits that include the reagents and controls as well as the photometric equipment needed to make quantitative readings. Clinical laboratories should be requested to provide these studies during RSV season.

CLINICAL MANAGEMENT

Exposure to RSV in infants with cardiopulmonary disease should be kept to a minimum; therefore, these infants should not be electively admitted to the hospital during…

Respiratory syncytial virus (RSV) is a ubiquitous cause of epidemic winter respiratory disease in children and adults. Ics best recognized clinical form is bronchiolitis, but it may also cause pneumonia, apnea, respiratory distress, or merely a cold. Its clinical severity is generally greatest in the infant and mildest in the adult. CHnical disease occurs throughout life, but asymptomatic infection probably occurs only in adults.

RSV is the only respiratory virus which occurs in consistent annual outbreaks each year, usually beginning after Thanksgiving and ending in early March. A child under the age of one has about a 50% chance of being infected, and by 3 years of age essentially 100% of children have had at least one infection. During the epidemic period, except when it is interrupted by epidemic influenza, RSV accounts for 90% of the lower respiratory tract disease in preschool children.

Most children weather RSV infection with little problem. However, certain groups of children, including infants under 6 months of age, immunosuppressed children, and children with preexisting cardiac or pulmonary disease, may develop life-threatening disease. These children are much more likely to require hospitalization, intensive care, and mechanical ventilation. Although the risk of long-term morbidity following RSV infection in these children is not known, their case-fatality rate with RSV infection may be 10 to 100 times higher than it is for other children (Table 1).

The life-threatening nature of RSV infection has been best documented in the infant with congenital heart disease. In one study among children in Rochester, New York, who were hospitalized with RSV, those with congenital heart abnormalities had a 37% case-fatality rate, as compared with an estimated rate of under 1% in otherwise healthy children. ' RSV raised the relative risk of fatality among all children with congenital heart disease who required hospital admission from 6.5% to 37%, more than a fivefold nse.

Table

TABLE 1CONDITIONS WITH INCREASED RISK OF LIFE-THREATENING RSV INFECTION

TABLE 1

CONDITIONS WITH INCREASED RISK OF LIFE-THREATENING RSV INFECTION

Over the past ten years knowledge has been developed concerning the diagnosis, management, and prevention of RSV infection. This knowledge has important implications for physicians caring for children with chronic pulmonary or cardiac disease, and heralds a new approach to the management of viral lower respiratory tract disease in these high-risk children.

Our aim in this article is to familiarize the physician with the nature of RSV infection in the high-risk child and the approach we at The New York Hospital have adopted to care for these children. We will particularly address the issue of nosocomial spread of RSV, the early clinical recognition of RSV in the high-risk child, new laboratory techniques for the rapid confirmation of RSV infection, and the role of newly approved antivirale in the management of the child with RSV infection.

NOSOCOMIAL INFECTIONS

During infection, RSV is shed in nasal secretions in large quantities and for prolonged periods. Viral excretion is routine until at least the sixth day of infection, and in 50% of infections shedding persists at least ten days.2 In some children, shedding may go on for a week or more after the resolution of clinical symptoms. Viral titers are generally highest in patients less than 1 month of age and in those with radiographie evidence of pulmonary consolidation. Since these are the children most likely to be hospitalized, these facts are of prime importance in understanding the risk of nosocomial spread of the virus during the winter months.

Nosocomial infections with RSV are those occurring in a previously uninfected child who has been hospitalized longer than one week. A study in Rochester found that of 31 susceptible hospitalized infants, 14 (45%) acquired nosocomial RSV infections. 3 The risk of infection increased with each subsequent week of hospitalization, and all infants hospitalized longer than one month eventually acquired RSV. Forty-two percent of staff members also became infected with RSV. A similar study of a neonatal unit showed that during a community outbreak of RSV 35% of neonates hospitalized longer than six days acquired RSV.4 Thirty-four percent of staff members in the neonatal unit also had RSV infections.

The routes of nosocomial transmission of RSV were demonstrated in another study by the Rochester group.5 In this study, three groups of adults were exposed to infants infected with RSV. In the group that only sat in the children's rooms, there were no infections. However, 40% of those who touched objects in the rooms developed RSV infections, and all persons who held the infants became infected. Like the other major respiratory pathogens, with the exception of influenza, RSV is not spread by aerosol but through contact with respiratory secretions either directly by handling the infant or indirectly via fomites.

Efforts to control the nosocomial spread of RSV should therefore concentrate on fomite control and good handwashing rather than such respiratory precautions as masks or gowns. When these infection control practices were instituted, including isolating infants, requiring handwashing between patients, and cohorting staff, the nosocomial rate dropped from 45% to 19%. 6 More recently, this group has reported that with the use of eye-nose goggles the nosocomial rate could be reduced to 9% and infection in hospital staff could be reduced as well.7

Similar patterns of reinfection and spread of RSV were described in children attending a day care program in Chapel Hill, North Carolina.8 The attack rate for at least one infection in these children was 98%; about 65% had three infections. Attacks were generally milder with each reinfection.

These data on the ease of transmission of RSV infection from child to child provide objective evidence confirming the clinical impression of many physicians who were aware of the risk of hospitalizing children during RSV season. Too many physicians have had the experience of hospitalizing a child with congenital heart disease who then acquired fatal RSV infection. In some centers it has become policy to limit elective admission, for example for cardiac catheterization, of high-risk children during the winter months.

CLINICAL PRESENTATION

Although bronchioiitis is the most characteristic presentation of RSV infection, pneumonia is the most common admitting diagnosis for infants hospitalized with RSV infection. These two processes occur together in many patients, with the clinical picture being dominated by one or the other diagnosis depending on the patient 's age, the size of the inoculum, and host immune factors. Other presentations of RSV infection include asthma, respiratory distress, apnea, or cyanosis.

Since the infection begins in conjunctival or nasal mucosa, it is not unusual for the infection to start as an upper respiratory infection with subsequent lower respiratory tract involvement. Infants under 6 months of age with a "winter" cold should be closely observed for signs of progression to the lower respiratory tract, particularly the development of marked tachypnea or respiratory distress. One characteristic symptom of RSV infection is profuse rhinorrhea. At our institution we consider that a dry nose almost rules out RSV infection. Fever is common during the first few days of illness but generally resolves as the infection progresses. A secondary bacterial infection should be considered in any patient with RSV pneumonia who is febrile after the fourth day of illness. Cough and pharyngitis are common, but hoarseness, dyspnea, and difficulty handling secretions are more suggestive of viral croup or bacterial epiglottitis (Table 2).

By the end of the first week of illness, most children have evidence of lower respiratory tract disease. Hypoxemia is common, with respiratory rates over 60 per minute associated with substantial desaturation. Blood gas determinations in infants with RSV on room air have shown that the average arterial oxygen pressure is approximately 50 mmHg.9 Cyanosis, however, occurs in fewer than one third of patients who do not have underlying cardiac or pulmonary disease.

Apneic episodes occur in nearly 20% of infants with RSV infection. These episodes are more frequent in premature infants, particularly if they have a history of previous apneic episodes during the newborn period. Apnea generally occurs early in the course of the illness and rarely lasts more than a few days. The apnea is nonobstructive and is associated with failure of the diaphragm to undergo contraction and displacement.

Infections with RSV1 though uncommon in the newborn, have been documented in children less than 1 month of age. Neonates may have no specific respiratory symptoms but simply exhibit such nonspecific signs of illness as lethargy, poor feeding, and irritability. Some neonates have been described with a clinical picture of viral sepsis with fever, rash, and thrombocytopenia with no respiratory symptoms. Infants over 3 weeks of age generally exhibit more typical symptoms of respiratory disease.

CHEST X-RAYS

Chest x-rays usually show hyperinflation with low, flat diaphragms, a prominent retrosternal space on lateral views, and widened intercostal spaces. Most also show diffuse interstitial infiltrates, although lobar consolidation may occur in up to 10% of cases. In 15% of patients, hyperinflation is the only radiographie sign. Small pleural effusions and hilar adenopathy have occasionally been described, but pneumatoceles and cavitating lesions are not seen in this illness. Although many of the x-ray findings of congestive heart failure may be similar to those of RSV pneumonia, the signs of hyperinflation are not seen in congestive heart failure and should alert the physician to the possibility of respiratory infection.

DIFFERENTIAL DIAGNOSIS

Chlamydial pneumonia is probably the most common disorder with which RSV pneumonia may be confused, occurring in children of the same age and manifesting itself with wheezing and air trapping. Chlamydial disease is a more prolonged and insidious illness, and is not associated with acute respiratory deterioration. Other possibilities include a congenital anomaly of the respiratory tract, the presence of a foreign body, hyperreactive airway disease, or infection with other respiratory agents including parainfluenza viruses, adenovirus, influenza virus, pertussis, or mycoplasma.

Table

TABLE 2CLINICAL CHARACTERISTICS OF RSV INFECTION

TABLE 2

CLINICAL CHARACTERISTICS OF RSV INFECTION

Obviously in patients with underlying cardiac disease, the clinician must carefully assess whether an infectious process, cardiac failure, or both are occurring. Fever and rhinorrhea are not seen in primary congestive heart failure, and increasing heart size and organomegaly are not usually seen in infections with RSV. Although tachypnea and worsening cyanosis may be seen in either condition, their development in association with upper respiratory symptoms must raise the issue of superimposed RSV infection.

LABORATORY DIAGNOSIS

The standard for diagnosis of RSV infection is viral isolation from the respiratory secretions of a symptomatic individual. Although a reliable diagnosis can be made using improved techniques for sample collection and virus cultivation, the role of viral isolation in management is limited as it may take two to three weeks for a positive result. Serologie diagnosis can be made using a complement fixation test, which shows a significant rise in antibody titer to RSV. However, serologie testing for any of the common viral pathogens other than influenza is also slow, unreliable, and has no role in individual patient management.

A more rapid and highly reliable test for RSV is the enzyme-linked immunosorbent assay (ELISA). This sensitive and specific method, which takes only a few hours, can identify viral antigen in nasopharyngeal secretions by using enzyme-tagged antibodies that bind to infected cells and can be identified by a photometric enzyme assay. Several companies now market testing kits that include the reagents and controls as well as the photometric equipment needed to make quantitative readings. Clinical laboratories should be requested to provide these studies during RSV season.

CLINICAL MANAGEMENT

Exposure to RSV in infants with cardiopulmonary disease should be kept to a minimum; therefore, these infants should not be electively admitted to the hospital during the season of peak RSV activity. However, if such an infant develops signs of respiratory tract illness during RSV season, he or she should be promptly evaluated and considered for hospitalization for close observation and specific antiviral therapy.

The use of supplemental oxygen remains a mainstay of initial therapy because all hospitalized children are hypoxic on admission. Unless they are chronically hypercarbic, they are not breathing on an "oxygen drive," and there is no risk in giving them as much supplemental oxygen as they require. The role of bronchodilator use remains unclear, but in the hands of persons experienced in their use in infants, and when appropriate monitoring is available, they may be of real value. Steroids have been shown to have no positive effect on the outcome of RSV infection, and their use should be limited to individuals with respiratory failure.

Secondary bacterial infection in RSV pneumonia is uncommon and does not constitute a reason for using antibiotics in routine cases. However, these children are at risk for developing nosocomial bacterial infections, and this possibility should be considered in a hospitalized child who has recrudescent fever or who undergoes sudden clinical deterioration.

Ribavirin, a synthetic nucleoside closely resembling guanosine, is currently being used in an aerosolized form as specific antiviral therapy for RSV infections in hospitalized patients. Ribavirin appears to act by inhibition of both viral replication and transcription of viral messenger RNA. In double-blind clinical trials, ribavirin has been shown to speed clinical recovery and to decrease the duration and amount of viral shedding in infants and children with RSV bronchiolitis or pneumonia.9 In some children, the use of ribavirin also appears to prevent the development of IgE class antiviral antibodies in respiratory secretions. These antibodies do not seem to be important for recovery from the infection but are thought to play an important role in the syndrome of recurrent bronchospasm associated with reinfection by RSV. Early antiviral therapy may therefore not only treat the acute infection, but also provide prophylaxis against future immunologically mediated bronchospastic disease.

Ribavirin aerosol is delivered by mask, hood, or ventilator for 12 to 18 hours daily, for three to seven days. Studies have shown that therapy speeds the resolution of symptoms and decreases the severity of illness. In a study of patients with bronchiolitis associated with RSV infection, both blinded and nonblinded observers noted more rapid improvement in patients treated with ribavirin.10 Improvement began within the first 24 hours of ribavirin therapy and reached a maximum on day 3. Another study of infants hospitalized with lower respiratory tract disease due to RSV showed that children receiving ribavirin had significantly less severe cough, rales, retractions, and lethargy at the end of therapy than did untreated infants. This finding is of particular importance in patients with pre-existing cardiopulmonary disease.

In a randomized, double-blind, placebo-controlled trial at our institution, the use of ribavirin in treating high-risk children reduced the length of hospitalization and decreased the morbidity of RSV infection.11 Treatment with ribavirin decreased the need for interi' sive care, and with one exception, allowed us to avoid intubation and mechanical ventilation. Similar positive results have recently been reported by Caroline Hall and her colleagues in Rochester.12

We currently use ribavirin in two ways. First, any infant with RSV who is ill enough to require hospitalization is treated with the drug for a period of five days, or until ready for discharge. Second, high-risk children with RSV infection are promptly admitted to the hospital for the early initiation of antiviral therapy. We consider that such early aggressive management in these children is warranted by the ease with which the drug is tolerated, and by the substantial mortalities seen with RSV infection in these children.

REFERENCES

1. MacDonald NE. Hall CB. Suftm SC. et al: Respiratory syncyrial viral infection in infants with congenial heart disease. N En¿} Med 1982; 307:397-400.

2. Hall CB, Douglas RG, Geiman JM: Respiratory- syncytial virus infections in inlarm. Quanlitalion and duration of shedding. J Pediatr 1976; 89:11-15.

3. Hall CB, Douglas RG, Geiman JM: Nosocomial respiratory syncytial vims infections. N Engl Med 1975; 29)4343-13«.

4. Hall CB, Kopelman AE, Douglas RG, ei al: Neonatal respiratory syneytial virus infection. N EnglJ Mei 1979; 300:393-396.

5. Hall CB, Douglas RG: Modes of transmission of respiratory syncytial virus. } ftdiurr 198U 99:100-105.

6. Hall CB, Geiman JM, Douglas RG: Control of nosocomial respiratory syncytial viral infections, ftdiamci 1978: 62:728-732.

7. Gala CL, Hall CB, Schnabel KC. et al· The use of eye-nose goggles to control nosocomial respiratory syncytial virus infection. JAMA 1986; 256:2706-2708.

8. Loda FA1 Glewn WP1 Clyde WA: Respiratory disease in group day care. Pediatrics 1972; 49:428-437.

9. Hall CB, MeBride JT, Walsh EE, et al: Aerosoliied ribavirin treatment of infants with respiratory syncytial viral infection: A randomized double- biind study. N Engl J Med 1983; 308:1443-1447.

10. Taber LH. Knight V. Gilbert BE, et al: Ribavirin aerosol treatment of branch ialiti s associated with respiratory syncytial viral infection in infants. Pediatrics 1983; 72:613-618

11. Spinelli M, Geraci-Ciardullo K, Palumbo PE, er al: Efficacy of ribavirin for treating respiratory syncytial virus (RSV) pneumonia in high-risk infants. feduttr Rei 1985; 19:304A.

12. Hall CB, McBride JT. GaIaCL, et al: Ribavirin treatment of respiratory syncytial viral infection in infants with underlying cardiopulmonary disease. JAMA 1985; 254:3047-3051.

TABLE 1

CONDITIONS WITH INCREASED RISK OF LIFE-THREATENING RSV INFECTION

TABLE 2

CLINICAL CHARACTERISTICS OF RSV INFECTION

10.3928/0090-4481-19870801-10

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