Pediatrics

Respiratory syncytial virus infection

Are you sure your patient has respiratory syncytial virus infection? What are the typical findings for this disease?

For a discussion of bronchiolitis, the most common manifestation of lower respiratory tract infection in infants, please see the Bronchiolitis chapter.

The major emphasis of this chapter will be the role of respiratory syncytial virus (RSV) infection in the childhood population that has undergone hematopoietic or solid organ transplantation. In addition, immunodeficiency states, including the condition of the cancer patient who is undergoing chemotherapy, will be discussed.

Table I.

Factors associated with risk for the development and spread of RSV
Family size
Crowded living conditions
Older siblings in school or day-care
Attendance in day-care
Lack of breast feeding
Exposure to cigarette smoke
Birth in the months prior to the onset of the RSV season
Healthcare workers
Elderly patients in nursing homes
Multiple births

The World Health Organization estimates that 33.8 million new episodes annually of RSV-associated lower respiratory tract illness (LRTI) occurred worldwide in children younger than 5 years of age. The WHO also estimated that there are 3.4 million episodes severe enough to require hospitalization.

There are two facets of RSV infection. First is an upper respiratory infection that includes symptoms of a common cold with rhinorrhea and nasal congestion. A low grade fever is possible and cough is often present.

Infants < 2 years of age and immunocompromised children who acquire RSV infection are at risk for bronchiolitis and pneumonia that can be severe. The second facet of RSV infection is progression from upper respiratory to lower respiratory infection; this may be rapid, and the onset of respiratory failure is associated with a poor prognosis.

  1. The most common symptoms of lower respiratory involvement include cough, retractions, and wheeze.

  2. Although wheeze may be dominant, the development of pneumonia is associated with crackles, which may be extensive.

Factors associated with more severe disease

The following is a list of conditions associated with more severe RSV disease:

  • Prematurity

  • Age less than 3 months

  • Male gender

  • Low socioeconomic status

  • Indoor smoke pollution

  • Malnutrition

  • Chronic lung disease of infancy (bronchopulmonary dysplasia)

  • Hemodynamically significant congenital heart disease

  • Immune deficiency problems, especially severe combined immunodeficiency disorder (SCID) and HIV/AIDS

  • Severe neuromuscular disorders

  • Solid organ transplant patients, especially lung transplantation

  • Hematopoietic transplants (bone marrow and stem cell)

  • Cancers, especially in patients undergoing chemotherapy

What other disease/condition shares some of these symptoms?

Upper and lower respiratory infections may result from a wide variety of viral, bacterial, fungal, and protozoal organisms. Immunocompromised children and adolescents need to be followed closely because of the rapidity of spread from upper to lower airway.

What caused this disease to develop at this time?

  • RSV has multiple subtypes, but immunity is short-lived, and as a result, recurrent infection is common throughout childhood.

  • Awareness of the seasonality of RSV is important. This varies with both geographic and climatic factors. The best resource on the timing of RSV seasons is from the CDC website, reporting from the National Respiratory and Enteric Virus Surveillance System (NREVSS): http://www.cdc.gov/surveillance/nrevss/rsv/. It is important to be aware of the RSV season in each community. Most communities in North America will have a defined season with onset in October/November and lasting 5 months.

  • After the age of 2 years, respiratory syncytial virus (RSV) no longer causes a lower respiratory tract infection in the child who has a normal immune system. Despite the fact that RSV is the most common cause of hospitalization for lower respiratory tract infection (LRTI) in the first 2 years, the virus typically only causes an upper respiratory infection after 2 years of age.

  • There is increasing evidence that after the age of 65 years, RSV infection is associated with significant morbidity and mortality.

  • Between the age of 2 and 5 years, the presence of co-morbid conditions, especially chronic lung disease, congenital heart disease and immune deficiency, increases the risk of severe RSV infection. Children and adolescents with cancer and hematopoietic disorders are most at risk for severe RSV infection. Additional co-morbid conditions include chronic lung and symptomatic congenital heart disease. HIV infection is a potential problem, but even during the RSV season the prevalence of LRTI associated with HIV is less than expected.

  • Particularly in developing countries, malnutrition and diarrhea increases the risk of severe respiratory infection associated with RSV.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • There are 4 main methods to confirm the presence of RSV. Confirmation of the presence of RSV, however, does not necessarily mean that it is causing disease.

  • Viral culture is an important method for confirmation, but the results of culture are not available for several days so that it is not a clinically useful test.

  • The most common test used in the hospital situation is the rapid viral antigen test. There are various useful immunoassays, mostly involving immunofluorescent techniques that provide a result potentially in under an hour (perhaps 30 minutes). These tests are not as sensitive or specific as culture methods or polymerase chain reaction tests.

  • Polymerase chain reaction (PCR) is highly specific and sensitive and, while formerly a research tool, it is increasingly used in the clinical situation. Results are available in a few hours.

  • Newer tests that can be used for screening, even in a physician's office, utilize rapid immunochromatographic techniques and are relatively economical. Examples are the BinaxNOW® RSV Test Kit and ClearView RSV Rapid Test Kit.

  • During influenza season, it is possible for influenza and RSV to coexist. Although the usual influenza season typically affects the young (infants) and the old (over 65 years of age), epidemic forms of influenza including H1N1 may cause disease in children and young adults. The co-infection likely causes more severe disease.

  • Bacterial co-infection has also been reported to cause pneumonia complicating RSV infection. This co-infection is more common in children with co-morbid conditions, including lung and heart disease. The most common bacterial co-infections are pneumococcus and Staphylococcus aureus.

Would imaging studies be helpful? If so, which ones?

  • The lower respiratory tract illness caused by RSV is typically bronchiolitis in the first 2 years of life. The routine use of chest radiography is discouraged. However, in the immune compromised child, pneumonia, which may be complicated, is more usual. As a result, chest radiograph may be indicated. Other imaging techniques are not indicated unless complicated pneumonia is present, in which case CT scan may be helpful. If there is a pleural effusion, an ultrasound is indicated, but pleural effusions are not typical of RSV infection and imply secondary bacterial pneumonia.

If you are able to confirm that the patient has respiratory syncytial virus infection, what treatment should be initiated?

Supportive care is the mainstay of treatment for bronchiolitis. Parents should be instructed in assessment and provision of basic supportive measures, as symptoms may progress over the course of the illness. Assessment and clearance of the upper airway using suction can improve respiratory distress, particularly in young infants who are obligate nasal breathers.

Oxygenation should be assessed using pulse oximetry, and oxygen should be provided to keep saturation levels greater than 90%. Transient episodes of hypoxemia may resolve with positioning and suctioning. Use of continuous pulse oximetry can detect self-limited hypoxemic episodes that may result in prolongation of hospital stay; continuous monitoring can be discontinued as an infant improves. Studies of home oxygen for stable infants with bronchiolitis have demonstrated safety in high-altitude locales.

Hydration status should be assessed and appropriate intervention provided. Most infants with bronchiolitis can continue to feed by mouth. For severely ill infants, fluid can be provided by the nasogastric or intravenous route. Intake and output should be assessed, as free water retention can be a complication of bronchiolitis and other pulmonary disorders.

Routine chest physiotherapy was not demonstrated to be beneficial in one small study.

Bronchodilators: The use of bronchodilators such as albuterol, salbutamol or epinephrine is not recommended.

Hypertonic saline: Limited evidence suggests that use of repeated doses of nebulized hypertonic saline (usually 3%) given to children hospitalized with bronchiolitis may reduce length of stay. Studies have not found a benefit to this therapy in outpatient (emergency department) settings.

The child who is immunocompromised and develops an upper respiratory tract infection may be a candidate for immediate treatment if RSV is diagnosed. The reason is that once lower respiratory tract infection has taken hold, the mortality rate is significant. Patients who have undergone hematopoietic transplantation, especially stem cell transplant recipients, are at significant risk for severe life-threatening RSV infection. In addition, solid organ transplant patients, especially lung transplant recipients, are at risk for severe RSV disease. Supportive care and close monitoring are indicated for these patients. Oxygen may be required to keep the saturation greater than 90%. Close follow-up is necessary because of the potential rapid onset of respiratory failure.

Options for treatment include ribavirin, palivizumab and intravenous immunoglobulin (IVIG).

  • Ribavirin is a guanosine analog that has activity against RNA and DNA viruses. It is approved for treatment of lower respiratory infection in high-risk infants and children when delivered in the aerosol form. It can be delivered intravenously or orally.

  • Ribavirin has been shown to be useful in preventing progression from upper respiratory infection associated with RSV to a lower respiratory tract infection in the patients who are immunosuppressed following transplantation (hematopoietic and solid). It also may be indicated in patients who are undergoing chemotherapy for cancer. Although controlled studies have not confirmed the results, various combinations of ribavirin have been tried. These include adding intravenous palivizumab and/or IVIG. Although controlled studies have not been reported, the results appear to be positive.

    In addition, if RSV is treated before it causes lower respiratory tract infection, the results are clearly better in terms of both morbidity and mortality. Ribavirin is delivered by small particle aerosol generator (SPAG). In adults, it is recommended to give a daily dose of 6 grams delivered at a concentration of 20 mg/mL over 18 hours. An alternative regimen, which appears to be similarly efficacious, is to use 60 mg/mL for 2 hours, each 8 hours.

    The duration of ribavirin treatment in various studies ranges from 5 to 21 days. Shorter durations (5-10 days) have been used for the treatment of upper respiratory infections, whereas the longer durations were used for LRTI in high-risk and neutropenic patients.

  • Palivizumab is approved for the prevention of severe RSV infection in high-risk infants. (See Bronchiolitis chapter.) It is given during the RSV season as a monthly intramuscular injection for 3-5 months using a dose of 15 mg/kg. In the treatment of children who are immunosuppressed and have RSV-associated upper or lower respiratory infection, palivizumab has been given intravenously. It appears to be safe, and is given as an adjunct to ribavirin, but its efficacy has not been proven in controlled clinical trials.

  • Studies have demonstrated the efficacy of RSV-IVIG in preventing severe lower respiratory tract infection in high risk infants, but there were significant side effects, particularly in patients who could not tolerate the fluid load. RSV-IVIG is no longer available in the United States. At the present time, IVIG is used in the management of hematopoietic transplant patients with RSV-associated infection.

    Studies in immunocompetent and immunocompromised animal models have shown that IVIG and RSV-IVIG prevent RSV replication in lung tissues, antibody response, and lymphocyte infiltration in the lungs, reduce viral loads in pulmonary tissues, and prevent subsequent development of illness. (see reference below: Shah 2011)

What are the adverse effects associated with each treatment option?

Ribavirin

There is a black box warning concerning ribavirin, particularly for infants who require mechanical ventilation. There are multiple reports of acute respiratory deterioration, probably as a result of precipitation of the drug. The warning goes on to say that it is not indicated for use in adults. Animal studies have demonstrated that it has the potential to be teratogenic. There has not been confirmation of teratogenicity in humans, but that may be because caregivers are aware of the potential and appropriate precautions have been taken.

Despite these comments, the risk/reward benefit has been demonstrated in adults who have been immunosuppressed following hematopoietic and solid organ transplantation. Infection with RSV that is not recognized or aggressively treated is associated with significant mortality.

Additional side effects of ribavirin include headache and conjunctivitis. Allergy to ribavirin is unusual.

Ribavirin is usually administered by nebulization using the SPAG unit. Intravenous ribavirin has been used in Europe when lung consolidation is present. It has been shown to be well tolerated, although some patients develop hemolysis or leukopenia.

Oral ribavirin has been shown to be well tolerated, but in some patients anemia develops.

Palivizumab appears to be safe in both the pediatric and adult populations. It does not prevent infection, but rather, reduces its impact. One of the major considerations has been cost, which for a fully grown person would amount to $10,000 per injection and may need to be repeated monthly if the patient is neutropenic.

What are the possible outcomes of respiratory syncytial virus infection?

Outcomes for infants with bronchiolitis are generally good, although the short-term burden on the child and family can be significant. About 1 in 10 infants with bronchiolitis is hospitalized for supportive care. The risk for severe disease, such as the need for mechanical ventilation, is increased among infants with underlying cardiopulmonary disease, immunodeficiency, prematurity, and young age (<2-3 months). Mortality from bronchiolitis has remained low over recent decades, at about 2.2/100,000 live births.

Recovery from bronchiolitis can require weeks; the median duration of symptoms has been estimated at 12 days, but up to 20% of children continue to have intermittent cough at 3 weeks after onset of illness. A long-term association with increased risk for asthma in later childhood has been demonstrated for infants with severe bronchiolitis requiring hospitalization, although it is unclear if this is a complication of bronchiolitis or an underlying characteristic of the child.

If the child or adolescent is undergoing chemotherapy or is post-transplant, the potential for mortality is significant. This is particularly so if lower respiratory infection develops.

Available antiviral treatments include ribavirin, IVIG and palivizumab. The complications of these therapies are relatively minor when appropriate precautions are taken. The potential to prevent passage of RSV infection from the upper to the lower airway may improve the potential to survive.

What causes this disease and how frequent is it?

  • Although the first description of probable RSV bronchiolitis was 150 years ago, the next major report was from Adams (1941) of an epidemic in 1937 of viral pneumonitis that involved 32 infants with 9 deaths. Adams followed a second epidemic in Minnesota in 1941, and a third in Los Angeles in 1961. RSV was isolated from several infants in the 1961 epidemic, and although it cannot be proven that the 1937 and 1941 epidemics were caused by RSV, Adams noted the clinical similarities.

  • In 1955 at the Walter Reed Army Institute of Research, JA Morris recovered a virus from the nasal secretions of monkeys who had sneezing and mucopurulent nasal discharge. The new virus was named chimpanzee coryza agent (CCA). Convalescent CCA antibodies were found in a number of co-workers at Walter Reed, and the agent was described and named respiratory syncytial virus (RSV) by Robert Chanock. Dr. Chanock recognized the relationship between CCA and the human respiratory virus that he found in infants with bronchiolitis and pneumonia. The virus was named RSV because of the multinucleated giant cells that were surrounded by large syncytia.

  • The RSV story would not be complete without mention of Dr. Caroline Breese Hall, who documented its seasonality, the epidemic nature of RSV, the clinical features, and its nosocomial spread. She and her colleagues conducted many of the early studies of the use of ribavirin as therapy for RSV infection. Use of this agent is problematic in infants, but it has found use in children and adults who are immunocompromised.

  • During the first two years of life, between 95% and 100% of all infants will have acquired infection with RSV. The incidence in the at-risk population after 2 years of age is not known. During the first two years of life, perhaps 30% of infants will develop bronchiolitis and 3% require hospitalization.

  • The incidence of RSV infection in the population of patients who are immune suppressed varies considerably.

How do these pathogens/genes/exposures cause the disease?

N/A

What complications might you expect from the disease or treatment of the disease?

In the first 2 years of life, the mortality rate for infants who have RSV / LRTI and do not have a co-morbid condition is very low. Infants who have RSV bronchiolitis and chronic lung disease or hemodynamically significant congenital heart disease requiring intensive care have a potential mortality rate of 2%-3%.

A recently published meta-analysis estimated that 66,000 to 199,000 children younger than 5 years of age died from RSV-associated LRTI in one year (2005), with 99% of these occurring in developing countries.

Are additional laboratory studies available; even some that are not widely available?

Bronchoscopy with bronchoalveolar lavage may be indicated in patients with lower respiratory tract infection. Patients who require intensive care are more at risk to have RSV with coexistent organisms, including other viruses, bacteria or fungi.

How can respiratory syncytial virus infection be prevented?

The only preventive therapy available to prevent severe RSV disease is the monoclonal antibody palivizumab, which is FDA-approved only for high-risk infants, especially preterm babies, and infants with chronic lung disease or hemodynamically significant congenital heart disease.

Important strategies to reduce the spread of RSV include hand cleanliness and avoidance of exposure to RSV-positive patients.

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