Further development of prevention, treatment options for RSV required

According to the CDC, the majority of children in the US will have contracted a respiratory syncytial virus infection by their second birthday — a statistic so large it would seem almost routine. In most infants, respiratory syncytial virus causes mild, coldlike symptoms that subside in 1 to 2 weeks. For premature infants and children with special health care needs, however, respiratory syncytial virus represents a serious risk for infection that can cause pneumonia or bronchiolitis.

Like influenza, pertussis and varicella, respiratory syncytial virus (RSV) affects almost everyone, both children and adults, at some point in time.

“By 12 months of age, 50% of all children have been infected with RSV and by 24 months of age almost all children have been infected at least once, and many of them more than once,” H. Cody Meissner, MD, chief of the division of pediatric infectious diseases at Tufts Medical Center in Boston and an Infectious Diseases in Children Editorial Board member, said in an interview. “We continue to experience RSV throughout life. This is partly due to the fact that the immune response does not work very well in protecting against RSV infection.”

Each year, approximately 2.1 million children aged younger than 5 years require medical attention for an RSV infection, as reported by the AAP. Of these, 25% are seen and treated in the ED, while an estimated 70% are assessed and treated in a pediatric office.

Young and small children are the most severely affected by RSV. Infants aged 2 months have the highest hospitalization rate for RSV, almost twice as high as the rate of the next highest risk group — children aged 1 month.

Overall, approximately 2% to 3% of infants are hospitalized for RSV during their first year of life, according to the AAP.

Chronological age is the most significant risk factor for RSV hospitalization, as 58% to 64% of RSV hospitalizations among children occur in the first 5 months of life.

Premature infants, children aged younger than 2 years with congenital heart or chronic lung disease and children with compromised immune systems due to a medical condition or treatment are at highest risk for severe RSV disease, according to the CDC.

Despite these overwhelming numbers, successful, safe and universal treatment and vaccine prevention methods have yet to be developed. This may be because RSV infection is unlike other common infections in that it does not confer protective immunity, and patients can be reinfected with RSV, noted Jeffrey S. Kahn, MD, PhD, the Sarah M. and Charles E. Seay chair of pediatric infectious diseases at the University of Texas Southwestern Medical Center.

“RSV has an unusual ability to inhibit the immune response so that the host does not produce an optimal immune response that protects against subsequent infections, such as with measles or chickenpox,” Meissner said.

Due to the virus’ complexity, management, treatment and prevention methods that specifically target RSV are limited.

Management of RSV infection

Currently, supportive or symptomatic care is the most common way to manage RSV infection.

“There is very little we can do to alter the course of disease once a child has RSV,” Shawn L. Ralston, MD, section chief of inpatient pediatrics at the Geisel School of Medicine at Dartmouth University, told Infectious Diseases in Children. “Essentially, we have to support the patient until they get through it on their own.”

The approach to RSV has changed little since the virus was discovered in the 1950s, according to Kahn. Quality of care may have improved since then but diagnostic methods are not significantly different.

“If a child needs oxygen, they get oxygen. If the child is not taking in enough fluids, they should receive fluids,” Michael T. Brady, MD, chair of the AAP’s Red Book Committee, told Infectious Diseases in Children.

An antiviral for RSV does exist, ribavirin, but it comes with drawbacks that make it an uncommon treatment method.

Ribavirin was approved in the 1980s for treatment of RSV-related hospitalization and severe disease, and at one point, it was endorsed by the AAP. However, review of subsequent medical literature indicated ribavirin was not effective in treating the infection.

“Today, if ribavirin is used, it is used in well-defined situations,” Pedro A. Piedra, MD, of the department of pediatric medicine, infectious disease, at Texas Children’s Hospital and an Infectious Diseases in Children Editorial Board member, said in an interview. The drug is administered as an aerosol and is cumbersome to deliver, Meissner said. Children sit in a plastic hood and breathe in the aerosol mixture, which leaves a powder over exposed surfaces.

“Ribavirin has potential teratogenic effects for individuals exposed to the drug and because it is delivered as an aerosol, individuals caring for the child may be exposed,” Kahn said.

Concerns about safety and cost have contributed to the diminished appeal of ribavirin, and it is not used among the majority of healthy infants or at-risk infants, according to Piedra. However, the drug remains a treatment option for severely immunocompromised adults and children who may develop life-threatening RSV infection.

An experimental RSV vaccine was developed in the 1960s, but it had extremely poor results in clinical trials. When exposed to natural infection, children who received the vaccine were more likely to have severe RSV disease compared with children who received a parainfluenza vaccine.

“To some extent, that experience has set RSV vaccine development back years, if not decades,” according to Kahn.

In addition, the population that would benefit most from an RSV vaccine — infants aged 3 months and younger — generally do not respond well to vaccines.

“Producing a protective response in young infants has always been challenging, regardless of what vaccine is being used,” Kahn said.

Inducing a protective immune response against RSV within the first 3 months of life is likely to be difficult, noted Meissner. Further clinical challenges lie in the fact that clinicians do not yet have a complete understanding of the pathogenic mechanisms that underlie RSV which could shed light on the spectrum of the disease.

“We do not have a vaccine because we do not have a complete understanding of why we had so much trouble formulating a safe and effective vaccine in the 1960s,” Brady said. “Fortunately, new technologies in the past 2 decades have helped advance our understanding of the virus, and I think there are a handful of good vaccine candidates that will be available in the not-too-distant future.”

Prevention methods

Perhaps as a result of the decades-long struggle with treatment methods, a few prominent prevention methods do exist for RSV.

Infection prevention and control strategies are a common approach to preventing exposure to infection, particularly in hospitals. Because RSV is spread by nasal droplets, infection control is an effective method to prevent spread of the disease.

“Infection prevention and control strategies are the optimal ways to ensure RSV does not spread from an infected child to an uninfected child, particularly in the hospital setting,” Kahn said. “We know that contact precautions are usually what are required to prevent spread.”

Considering that there is no vaccine for RSV, infection prevention strategies are the most common way to prevent RSV among healthy children. However, this approach is not guaranteed, as preventing a child from touching contaminated surfaces without then touching their mouth, nose or face can be challenging.

Due to the nature of RSV and that children’s risk for disease is highest during the first 3 months of life, keeping children out of day care until they are aged older than 3 months may be an effective prevention method.

“Day care is an optimal environment for circulating many infectious organisms,” Piedra said. “Attending day care would likely increase risk for RSV infection.”

Unfortunately, not attending day care or postponing day care entrance until after a child is aged older than 3 months or the typical RSV season has ended may not be an option for many families.

Additionally, having siblings who attend day care or grammar school can increase a child’s risk for RSV. Children who attend school may encounter the disease just as a child would at day care. Then the exposed child comes home and plays with their baby sibling and unknowingly increases the risk for infection transmission.

Limiting children’s exposure to secondhand smoke is another prevention method that can be utilized outside the hospital setting. Secondhand smoke exposure impacts lung function, according to Brady, and thus increases risk for more severe RSV disease.

“Many parents will say they only smoke outside, but if you smell their clothes, it is apparent they carry the smoke with them. Then perhaps they pick up their child and rest them on their shoulder,” he said. “There is still opportunity for the infant to be exposed to secondhand smoke.”

These prevention strategies can be utilized for all children, no matter their inherent risk for severe respiratory disease.

Palivizumab prophylaxis for RSV infection

Another prevention method, a humanized mouse immunoglobulin monoclonal antibody called palivizumab (Synagis, MedImmune), is available for use against RSV among children, but only for those considered at high risk for RSV.

Palivizumab was licensed by the FDA in June 1998, based on results from the Impact-RSV trial, a randomized, placebo-controlled, double blind trial conducted during the 1996 to 1997 RSV season. The trial included 1,501 infants and children born preterm, at or before 35 weeks gestation, some of whom had chronic lung disease of prematurity. Trial results demonstrated a RSV hospitalization rate of 10.6% among children who received placebo and 4.8% among children who received prophylaxis, indicating a reduction of 5.8% in RSV hospitalizations (P<.001).

A second randomized, double blind, placebo-controlled trial conducted from 1998 to 2002 assessed safety and efficacy of palivizumab prophylaxis among 1,287 children with hemodynamically significant congenital heart disease. Children who received placebo had an RSV hospitalization rate of 9.7% compared with 5.3% among children who received palivizumab, indicating a reduction of 4.4% (P<.003).

However, AAP guidelines for palivizumab prophylaxis for RSV infection have become increasingly specific since the drug was licensed, with the most recent AAP guidance published in August 2014.

“The major focus of updated guidance was based on new epidemiology in order to better define populations who are truly at higher risk for RSV,” Brady said.

Since the last update to guidance in 2012, new data have become available regarding RSV seasonality, palivizumab pharmacokinetics, incidence of bronchiolitis hospitalizations, effects of gestational age and other risk factors on RSV hospitalization and mortality rates among children hospitalized with RSV.

“New data indicated that children born at 30 to 36 weeks gestation who did not have any chronic lung or cardiac disease had similar or slightly increased risk for RSV hospitalization,” according to Brady. “Rates were slightly increased but not statistically significant. However, hospitalization rates became very different for infants born at less than 30 weeks gestation, suggesting a clear break point as to who is really at high risk.”

As a result, palivizumab prophylaxis is recommended for infants born before 29 weeks gestation, and otherwise healthy infants born at or after 29 weeks gestation should not receive palivizumab prophylaxis, according to the AAP.

Twenty-one AAP sections, plus committees and groups from outside the AAP, collaborated to create the most recent palivizumab prophylaxis guidelines.

Compared with previous guidelines, chronic lung disease and heart disease have specific definitions that more closely match what neonatologists and cardiologists consider to seriously increase risk for RSV, thus narrowing the population of children for whom palivizumab is intended.

For example, changes were made to recommendations for Alaska natives, Navajo and White Mountain Apache Indians to increase their eligibility for palivizumab due to logistical issues the population may have in reaching a hospital to receive the treatment.

Although palivizumab has been shown to effectively reduce RSV hospitalizations, the population for which palivizumab prophylaxis is recommended is increasingly limited for a number of other reasons.

“Palivizumab is quite difficult to make, it requires a significant amount of expertise, and therefore it costs a great deal,” according to Ralston.

There are conflicting study results regarding the cost-effectiveness of palivizumab. Analyses sponsored by the manufacturer indicate a cost neutrality or cost-savings, while independently conducted analyses show that the cost of palivizumab exceeds the economic benefit of hospital avoidance, even among high-risk children, according to the AAP. However, differences in study design and base case assumptions used in the study model may explain the contrasting study findings.

Even so, the cost associated with administering five monthly doses of palivizumab, the dosage the drug is licensed for, is approximately the same as the cost of hospitalization, Brady noted.

The studies used to support the licensing of palivizumab used hospitalization as their endpoint. While palivizumab prevents hospitalization, it is only 55% effective in preventing infection and does not prevent the need for mechanical ventilation or the risk for death, according to Brady.

Furthermore, vaccine surveillance data from the CDC indicates that one hospitalization is prevented for every 1,000 children who received palivizumab.

“The burden of disease being prevented by Synagis is so small that it is difficult to justify its use,” Meissner said. “Generally we say about 2% to 3% of all babies are hospitalized with RSV in the first year of life. At least 80% of hospitalizations occur among healthy, full-term babies who do not fall into any risk category. Even if we administered prophylaxis to every high-risk child, it would have very little impact on RSV hospitalizations.”

Essentially, palivizumab is intended by the AAP for use only among children whose lives could potentially be threatened by RSV infection.

“In order to be prudent stewards of the delivery of medical care, we should target the children where the medication is indicated — children who are at high risk for severe lower respiratory tract disease,” Brady said.

The prevention methods for RSV leave something to be desired, particularly for otherwise healthy children. Many of these strategies are not guaranteed to be successful. This extremely prevalent disease is in need of management and treatment development, according to clinicians.

Looking to the future: Antivirals and vaccines

When asked what the field of RSV really needs, many physicians say a vaccine.

“If we really want to make a difference for children, a vaccine needs to be developed,” Brady said. “This is a significant infection; almost all children are infected with RSV by the age of 2 years, and it results in approximately 50,000 hospitalizations per year with numerous visits to the ED and pediatrician. A vaccine is the answer, and we are getting closer, but we are not there yet.”

Despite the anxiety caused by the failure of an RSV vaccine in the 1960s, promising vaccine candidates are on the horizon, according to Kahn.

“There are a number of experimental vaccines in clinical trials, some in phase 2 or phase 3, on a variety of different platforms — attenuated viruses, subunit vaccines — and some of them look very promising,” he told Infectious Diseases in Children.

Unfortunately, creating a vaccine that successfully protects infants and children from RSV does come with challenges. Children who are most at risk for infection and hospitalization are aged younger than 3 months, and it may be difficult to produce an immune response within an infant so that they are protected during the 3-months when they are most at risk. Previous experiences with vaccines have proven this difficult for other infections.

To that end, maternal immunization is another vaccination approach within the pipeline. In November 2014, the FDA granted fast track designation to an RSV F-protein nanoparticle vaccine candidate from Novavax, intended to protect infants from RSV via maternal immunization. Several vaccines, including tetanus, pertussis and seasonal influenza, utilize maternal immunization to provide infection protection to infants.

In September 2014, Novavax initiated a study among pregnant women to assess safety and immunogenicity of their RSV-F vaccine, determine transfer of vaccine-induced antibodies to infants and evaluate safety of RSV-specific antibody levels in infants through the age of 18 months.

“It may be a reasonable strategy to induce high levels of antibodies in the mother that will be protective to the child in the first few months of life, when children are at highest risk for RSV,” Kahn said.

Treatment methods for RSV are another developing area of research, according to Piedra. In addition to vaccination, a successful and effective treatment may reduce disease transmission while alleviating symptoms.

“Development of antivirals is advancing,” he said. “A recent publication from Gilead [Sciences] showed promise for their fusion protein inhibitor. A variety of monoclonal antibodies, what I would consider next-generation monoclonal antibodies, are also being developed for longer-term circulation so as to not require monthly doses.”

The possibilities of developing antivirals are encouraging, clinicians say, as managing RSV can be challenging due to the lack of effective treatment methods.

“As a hospitalist, finding a medication or therapy that is effective during illness, once the child has gotten sick, is a major challenge within the field of respiratory viruses,” Ralston said.

Often, children who are seen in the ED or hospital are 3 to 5 days into their disease, according to Kahn, and as a result, antiviral therapy may be less effective.

“We know the virus can induce a great amount of inflammation. Based on experiences with ribavirin and even palivizumab, even if viral replication can be combated, inflammation is not significantly affected. We either need rapid diagnostics so that antivirals can be used much earlier in infection or perhaps an anti-inflammatory, though steroids do not typically work on RSV.”

Although there has not been significant change regarding RSV management and treatment methods since the virus was discovered, there is significant movement in the field today.

“We have a much greater understanding of the molecular structure of the virus, of the epidemiology of the virus, and we have insight into what may be required for protection,” Piedra said. “There is a lot of optimism in the field for RSV vaccines, but as always, time will tell if a vaccine truly comes to fruition.”

References:

AAP Committee on Infectious Diseases. Pediatrics. 2014;doi:10.1542/peds.2014-1666.
CDC. RSV infection and incidence. Available at: www.cdc.gov/rsv/about/infection.html. Accessed Dec. 26, 2014.

For more information:

Michael T. Brady, MD, can be reached at 700 Children’s Drive, Columbus, OH 43205.
Jeffrey S. Kahn, MD, PhD, can be reached at 5323 Harry Hines Blvd, Dallas, TX 75235.
H. Cody Meissner, MD, can be reached at 800 Washington Street, Boston, MA 02111; email: cmeissner@tuftsmedicalcenter.org.
Pedro A. Piedra, MD, can be reached at the Department of Molecular Virology & Microbiology, MS BCM 280, One Baylor Plaza, Houston, TX 77030.
Shawn L. Ralston, MD, can be reached at 1 Medical Drive, Lebanon, NH 03745; email: shawn.l.ralston@dartmouth.edu.