Update on Respiratory Syncytial Virus

WITH THE HIGH prevalence of respiratory syncytial virus (RSV) in the U.S. and globally, it’s a wonder this sometimes deadly illness isn’t better known or more talked about. RSV is recognized as one of the most common causes of childhood illness.¹ It is the most common cause of lower respiratory tract infections in children, with most infants infected before 1 year of age and virtually all children infected by 2 years of age.² Depending on the source, there are between 57,0002 to 120,0003 children under 5 years of age in the U.S. requiring hospitalization each year due to RSV, resulting in approximately 4,500 deaths.⁴ But RSV also affects adults, especially older adults and those with compromised immune systems. In adults over age 65 years, RSV results in approximately 177,000 hospitalizations and 14,000 deaths.²

RSV is a very highly contagious illness spread via respiratory secretions through contact with infected people or contaminated objects or surfaces.³ Discovered in 1956, RSV is a member of the family Paramyxoviridae and the subfamily Pneumovirinae. The enveloped RNA virus has two main types (subgroups A and B) and many subtypes (strains); however, the clinical significance of the different strains remains unclear.^1,5 What is clear is that this pervasive illness is avoidable, despite there is still no vaccine to prevent it. Therefore, with little awareness of RSV and how to prevent it, government and other healthcare entities are prioritizing research to better understand it and to develop a preventive vaccine.

Causes of RSV

Because there are many different strains, no one has full immunity to RSV, and some people have many RSV infections throughout life. 5 In the U.S. and other countries with similar climates, RSV infections generally occur during the fall, winter and spring, but that can vary from year to year.⁶

Those infected with RSV are usually contagious for between three days and eight days, although some infants and people with weakened immune systems can be contagious for as long as four weeks.⁷ The incubation period ranges from two days to eight days, but usually is between four days and six days.⁵

RSV spreads easily in crowded areas such as child care facilities, preschools and nursing homes through both direct and indirect contact with infected persons. Infection can occur when infectious particles make contact with mucous membranes of the eyes, mouth or nose, and even through the inhalation of secretory respiratory droplets. And, because infectious particles can survive for more than six hours on objects and surfaces, infection can occur by touching them and rubbing the eyes, nose or mouth.⁵

Symptoms and Progression of RSV

Symptoms of RSV in adults and older, healthy children are typically mild and mimic the common cold. In most infants, symptoms are similar to a bad cold with fever, prominent runny nose and nasal congestion lasting between one week and two weeks. Some babies and young children also develop symptoms of bronchiolitis or pneumonia.³ In very young infants, irritability, decreased activity and breathing difficulties may be the only symptoms, but infection without symptoms is rare among infants.^8,9

Those at increased risk of severe and, sometimes, life-threatening RSV infections include:¹⁰

• infants younger than 6 months old;
• younger children, especially under 1 year of age, who were born prematurely or who have an underlying condition such as congenital heart or lung disease;
• children with weakened immune systems such as those undergoing chemotherapy or transplantation;
• infants in crowded child care settings;
• older adults;
• adults with asthma, congestive heart failure or chronic obstructive pulmonary disease; and
• people with immunodeficiency disorders, certain transplanted organs, leukemia or HIV/AIDS.

Complications that typically happen with those who are more at risk of severe RSV infections include hospitalization, pneumonia or bronchiolitis, middle ear infection (mostly in infants and young children), asthma (developing later in life) and recurring infections.¹¹

The majority of children hospitalized for RSV are under 6 months old. When hospitalized, they most commonly require supplemental oxygen, IV fluids and pulmonary inhalation therapy.³ In a study of adult patients hospitalized with laboratory-confirmed RSV infection, pneumonia was found in 42.3 percent, bacterial superinfection in 12.5 percent and cardiovascular complications in 14.3 percent. Additionally, 11.1 percent developed respiratory failure requiring ventilator support. All-cause mortality at 30 days and 60 days was 9.1 percent and 11.9 percent, respectively, with pneumonia the most common cause of death.¹²

Preventing RSV

Without a vaccine yet available to prevent RSV, individuals need to be aware of steps they can take to avoid infection and passing on infection. Of course, it isn’t always possible to prevent the spread of RSV since it is often spread during the early stages of illness prior to the development of severe symptoms.

Frequent handwashing and not sharing cups, glasses or utensils can decrease the spread of RSV. Those experiencing cold-like symptoms should cover their coughs and sneezes, wash hands frequently and correctly (with soap and water for 20 seconds), avoid sharing cups and eating utensils, refrain from kissing others and clean contaminated surfaces such as doorknobs. Interaction with children at high risk for developing severe disease should also be avoided.

Hospitals and doctor offices can play a role by paying strict attention to contact precautions such as handwashing and wearing gowns and gloves.^3,7

Previously, RSV immune globulin intravenous was available as passive immunization to protect against RSV infection. However, it is no longer being manufactured.¹³ In 1998, though, the U.S. Food and Drug Administration approved palivizumab (Synagis) to help prevent severe RSV; it is given as a monthly injection during RSV season. According to the American Academy of Pediatrics guidelines, the following are candidates for palivizumab prophylaxis:¹³

• infants younger than 24 months who have hemodynamically significant congenital heart disease (cyanotic or acyanotic lesions) or who have chronic lung disease and are off oxygen or pulmonary medications for less than 6 months at the start of RSV season;
• premature infants born at 28 weeks’ gestational age or less who are younger than 1 year old at the start of RSV season (once treatment is initiated, it should continue throughout the season and not stop at 1 year of age);
• premature infants born at 29 weeks’ to 32 weeks’ gestational age who are younger than 6 months old at the start of RSV season (once treatment is initiated, it should continue throughout the season and not stop at age 6 months); and
• infants born at 32 weeks’ to 35 weeks’ gestational age who are younger than 3 months old at the start of or during RSV season and who either attend child care or have one or more siblings or other children younger than 5 years old living permanently in the same household (prophylaxis should be provided only until age 3 months).

It should be noted that palivizumab is prescribed only for high-risk infants to help prevent severe RSV infection. And, it’s expensive, so insurance companies often have strict guidelines that limit for whom they will pay for the medication.³

Diagnosing RSV

Nonspecific lab tests for children who experience nonsevere symptoms include complete blood count, serum electrolyte concentrations, urinalysis and oxygen saturation. For therapeutic diagnosis, specific tests include cell culture, antigen-revealing techniques, polymerase chain reaction (PCR) assay and molecular probes.¹³

Cell culture is typically supplemental to antigen detection tests since the latter’s sensitivity generally ranges from 80 percent to 90 percent. And, while antigen detection tests are generally reliable in young children, they are less useful in older children and adults. It’s also recommended that, for optimal results, experienced lab technicians be consulted for cell culture because of its thermolability. Reverse transcription-PCR (RT-PCR) assays, which often exceed the sensitivity of antigen detection methods, should be considered when testing older children and adults because they may have low viral loads in their respiratory specimens.⁸

Treating RSV The mainstay therapy for RSV is supportive care such as acetaminophen to treat fever and, in cases of bacterial complication, an antibiotic.¹⁴ While corticosteroids are sometimes prescribed, clinical data doesn’t support their use to treat RSV.¹³

For severe cases of RSV, hospitalization may be needed to provide intravenous fluids and humidified oxygen. Infants and children may need mechanical ventilation to ease breathing.¹³ Pharmacologic therapies include bronchodilators such as albuterol (ProAir HFA, Proventil-HFA, Ventolin HFA) to relieve wheezing, alpha agonists, a nebulized form of ribavirin (Virazole) and an injection of epinephrine or a form of epinephrine that can be inhaled through a nebulizer.¹⁴

Ongoing Research

As of this writing, there are 21 open studies investigating treatments for and potential vaccines to prevent RSV in infants and older adults.¹⁵

Outside of these trials, one important area of research centers on identifying which infants are at greater risk of severe RSV infection so that they are treated more aggressively. In recent years, scientists have made significant progress in better understanding adult lung diseases by studying lung tissue. However, because infants are so fragile, attempting to obtain lung samples is unsafe. But, a recent study conducted at the University of Rochester Medical Center (URMC), which could lead to much more precise diagnosis of RSV and other infant lung diseases, found that cells from an infant’s nose are remarkably similar to those found in the lungs. Nasal cells can be captured through a simple swab of the nostril. “An infant with RSV could potentially have their nasal cells tested to determine if they are among the small group that will develop a severe response that might require hospitalization,” said Thomas Mariani, PhD, professor of pediatrics at URMC. “Additionally, we could potentially use this method to examine other at-risk infants such as those born prematurely who face a greater risk for lung disease throughout life and identify which of those children should be treated more aggressively.”¹⁶

While developing a vaccine that would prevent RSV in all people is what is ultimately needed, despite repeated efforts, no vaccine has yet been effective. Interestingly, though, scientists at Vanderbilt University Medical Center (VUMC) working with colleagues in California and Pennsylvania believe they have discovered why the virus has been so difficult to neutralize. They found that competition among antibodies for binding the same viral site can interfere with effective neutralization of the virus. Using palivizumab (the drug licensed to prevent serious RSV complications in high-risk infants), which targets the antigenic site II of the RSV F protein that fuses the viral particle to its target cell in the lung, they found that the target cell undergoes a dramatic structural rearrangement and reveals another, previously concealed binding site next to site II. In essence, the neutralizing antibody essentially binds to the new site instead of the target site. According to the researchers, the answer may be to design a vaccine strategy that identifies and produces neutralizing monoclonal antibodies that target only site II and not the entire F protein.¹⁷

Today, two RSV fusion (F) nanoparticle vaccines, both manufactured by Novovax, are in Phase III clinical trials.¹⁸

Looking Ahead

Understanding and preventing RSV is a priority. In August 2015, the National Institutes of Health launched a new study to help understand infection in healthy adults to aid development of RSV medicines and vaccines. The study will enroll up to 60 healthy men and nonpregnant women ages 18 years to 50 years who will receive a drop of liquid containing RSV in each nostril and remain hospitalized in isolation for one to two weeks, during which time they will be monitored for development and progression of disease. Results are expected sometime in 2017.¹⁹

Today is an exciting time as vaccines progress in clinical trials to protect against RSV. In June, the Advisory Committee on Immunization Practices’ RSV Vaccines Working Group presented an update that outlined the status of preventive measures against RSV, as well as its goals in relation to adults aged 60 years and older and those with underlying medical conditions. The update points out how much progress has been made since 2003, when only one live-attenuated vaccine was in Phase I trials, to the one now approved for high-risk infants, and the 11 others in clinical trials, four of which are in Phase II and III trials.¹⁸

With nearly 19,000 deaths each year due to RSV, it can only be hoped that this illness will one day be much less prevalent, if not eliminated altogether.