Respiratory syncytial virus (RSV) infection: An overview

Respiratory syncytial virus (RSV) is a common, ubiquitous and contagious viral pathogen that infects the respiratory tract of most children by two years of age. RSV is an RNA pneumovirus of the Paramyxoviridae family, and humans are
the only natural host.

RSV is primarily a childhood infection; however, it may occur at any age and can be most severe in infants under one year of age, the immunocompromised, and in people aged 65 years and older.^3,7 It infects 90 per cent of children within the first two years of life and frequently re-infects older children and adults.¹⁰

RSV infection can present as a variety of clinical syndromes including upper respiratory tract infections, bronchiolitis, pneumonia, exacerbations of asthma and viral-induced wheeze.¹ Worldwide, it is estimated that RSV is responsible for approximately 33 million lower respiratory tract illnesses, three million hospitalisations, and up to 199,000 childhood deaths annually. The majority of deaths are in resource-limited countries.¹⁰ In medium and high resource countries, the RSV mortality rate in infants is almost nine times that of influenza.⁷

RSV has been shown to account for 22 per cent of all episodes of acute lower respiratory tract infection in children globally, with the greatest burden of severe disease requiring hospitalisation in infants under one year and particularly those under six months of age.^2,5

For most babies and young children the infection is mild, presenting with cold-like symptoms which usually last one
to two weeks, but for a small percentage, RSV infection can lead to serious and sometimes life-threatening problems,
such as pneumonia or bronchiolitis.⁴ The chance of developing severe infection is highest for premature babies, children less than 10 weeks old, children aged under two years with congenital heart or chronic lung disease, and infants and young children with a weak immune system or who are immunocompromised.^3,4

Adults with weakened immune systems and those aged 65 years and older are also at increased risk of developing severe RSV disease. Approximately one-in-20 older people develop RSV infection each year. Overcrowding, smoking and passive smoking are recognised risk factors for infection.³

RSV infection has been a notifiable disease in Ireland since January 2012, and RSV activity in Ireland is monitored by the Health Protection Surveillance Centre (HPSC).³
According to the HPSC (2020), nearly all children have been infected with RSV at least once, by two years of age. Most cases are not specifically diagnosed as RSV; however, the infection causes 80 per cent of bronchiolitis and 20 per cent of pneumonia cases in young children and RSV is a significant cause of infection and outbreaks in hospitals, neonatal units, day units, and nursing homes.³

RSV infections occur in a seasonal pattern in temperate climates with epidemics from October to April.7
Outbreaks typically occur in the winter months with the highest numbers of infections usually reported in December and January every year. The sharp winter peak varies little in timing or size from year to year, in contrast to influenza.³

There is only one serotype of RSV, but it is classified into two strains, A and B, with differences consisting of variation in thenstructure of several structural membrane proteins, most especially the attachment protein.10 One of the two major antigenic subgroups of RSV A or B, usually predominates each season.7 RSV typically spreads via hands, fomites and the airborne aerosol route. It spreads from person to person by aerosol droplets through coughing or sneezing, and is also spread through direct contact by touch. RSV can survive on surfaces and objects for 24 hours and spread can occur indirectly through contact with contaminated hands.^1,4 Handwashing is the most effective infection control procedure.

Incubation period and symptoms

The incubation period for RSV-infected individuals ranges from three-to-eight days, but immunocompromised patients with severe infection may shed virus for up to four weeks. The frequent occurrence of mild or asymptomatic infection in otherwise healthy individuals makes infection control challenging.⁷

After inoculation into the nasopharyngeal or conjunctival mucosa, the virus rapidly spreads into the respiratory tract,
where it targets its preferred growth medium, apical ciliated epithelial cells. There it binds to cellular receptors using the RSV-G glycoprotein and uses the RSV-F fusion glycoprotein to fuse with host cell membranes and insert its nucleocapsid into the host cell to begin its intracellular replication.¹⁰

Symptoms include: Fever, rhinorrhoea, pharyngitis, nasal congestion, sneezing, coughing which can be croupy or barking in nature, tachypnoea, sore throat, wheeze, decreased appetite, and ear infections in children. In very young infants, irritability, decreased activity and breathing difficulties may be the only symptoms of infection.

Lower respiratory tract infections, such as pneumonia or pneumonitis, are most likely to occur during a child’s first
infection with RSV and may develop in 30-to-70 per cent of those with a first infection. Typically, only between 1 and 3
per cent of infected infants require hospitalisation.⁷

The infectious period lasts from shortly before onset to one week post the onset of symptoms. Most children recover in eight-to-15 days. Even after recovery, however, very young infants and children with weakened immune systems can
continue to spread the virus for one-to-three weeks. Immunity is incomplete and short-lived. Repeated RSV respiratory
infections can occur, although these are usually mild and become less common with increasing age.³,⁷

Bronchiolitis is an inflammatory process in the small airways of the lungs and is the most common clinical syndrome
associated with RSV infection. It typically presents in infants under one year of age, but may be diagnosed in children up to two years old, and is characterised by a short history of low-grade fever, cough, coryza, dyspnoea, and reduced feeding. The symptoms usually peak in clinical severity between day three and five of the illness. RSV bronchiolitis presents a significant clinical burden. In the UK, infection with RSV is responsible for up to 80 per cent of all cases of bronchiolitis, similar to that of 65-to-70 per cent in the US.³,⁸

In older children, RSV typically presents as an upper respiratory tract infection, viral pneumonia, episodic viral-induced wheeze or an acute exacerbation of asthma. Viral pneumonia is a common illness with five million cases reported globally in children annually. A meta-analysis of nine studies involving over 4,000 children investigating viruses identified by polymerase chain reaction (PCR), found that RSV was the causative organism in 11 per cent of community-acquired pneumonia cases.⁶

Diagnosis

Diagnosis of RSV includes a thorough medical history and a physical exam. A chest x-ray may be requested and blood and urine tests may be carried out to rule out a bacterial infection or other conditions. Differential diagnosis can include asthma, bronchiolitis, influenza, croup, bronchitis and pneumonia.¹⁰ Respiratory viral testing may be used in a clinical setting to increase confidence in the diagnosis of a viral, rather than bacterial, cause for respiratory illness. RSV can be detected in nasopharyngeal aspirate, broncho-alveolar lavage, sputum, or swabs from the nose and throat by using real-time PCR, immunofluorescence, ELISA and growth in cell culture. Reverse transcriptase-PCR (RT-PCR) assays are currently the gold standard in RSV testing and are available commercially.

These are more sensitive than antigen detection and virus isolation methods. The sensitivity of antigen detection tests ranges from 80-to-90 per cent in children, but is less sensitive in adults. Serological tests are used less for routine diagnosis and more for seroprevalence and epidemiological studies.³,⁷

Vaccination

There is currently no vaccine available against RSV infection. Palivizumab, which is a humanised mouse monoclonal antibody specific for the F protein of RSV, provides passive immunity against RSV. Palivizumab inhibits RSV binding to host cells and prevents fusion of infected cells with adjacent cells. It is authorised in Ireland for the prevention of serious lower respiratory tract disease requiring hospitalisation caused by RSV in children at high risk for RSV disease.⁷

Palivizumab prophylaxis reduces the absolute risk of RSV hospitalisation from about 10-to-5 per cent for premature babies, infants with chronic lung disease and haemodynamically significant congenital heart disease, particularly when complicated by large left-to-right shunts, and pulmonary hypertension. It does not reduce mortality or the need for mechanical ventilation.⁷,³

Palivizumab is given as an intramuscular injection monthly (up to five doses) during the RSV season. As it is very expensive and has a half-life of 18-to-21 days, meaning monthly injections are required to maintain protective titres, cost-benefit analyses limit its use to only the most vulnerable infants, those born prematurely with moderate or severe BPD, haemodynamically significant, acyanotic congenital heart disease, severe combined immunodeficiency or infants with other severe chronic lung conditions or requiring long-term ventilation.⁹

Differences in epidemiology, practice setting, healthcare systems and drug cost have resulted in variability in palivizumab recommendations and use nationally and internationally.

Treatment and prevention

The mainstay of treatment for the vast majority of RSV infections is supportive including rest, fluids and paracetamol, but passive preventive immunisation is available for at-risk children, including premature infants and infants with a history of cardiac, pulmonary, or neuromuscular diseases. Those with severe respiratory illness require hospitalisation, oxygen therapy, IV fluids and ventilatory support in the form of a high-flow nasal cannula, CPAP, or intubation, and mechanical ventilation.⁷,¹⁰

Ribavirin is the only licensed antiviral medication for the specific treatment of RSV infection, but due to drug toxicity,
including bone marrow suppression and potential carcinogenicity and teratogenicity and minimal clinical benefit, it
has not been recommended for routine clinical use.⁹

Ribavirin may be considered for a small number of patients and treatment of RSV with ribavirin must be done under the supervision of an infection specialist, such as a consultant microbiologist or an infectious disease specialist.³

Other treatment modalities for bronchiolitis have been tried in the past and have failed to show broad, reproducible efficacy on clinically significant outcomes in RSV and bronchiolitis. These include albuterol, epinephrine, steroids, hypertonic saline, antibiotics, and chest physical therapy, and routine use of these interventions is not recommended.¹⁰ Antibiotics are not effective against RSV and it is important that unnecessary antibiotics are discontinued once a diagnosis is confirmed, to avoid adverse drug reactions and antibiotic resistance.³

Although palivizumab may help prevent serious complications of RSV infection, it is not used to treat RSV infection. Infants who are recovering from RSV bronchiolitis can continue to have respiratory symptoms including cough and post-bronchiolitis wheeze for several weeks/months. There is no evidence for the use of steroids, montelukast or other medications in preventing these symptoms, but the acute episodes often respond to anti-asthma medication.⁹

Highrisk infants with other co-morbidities may require longer admission and some may even require mechanical ventilation. However, the majority of children with RSV make a full recovery and have an excellent outcome. The majority of children who need hospital admission are usually discharged in several days. Some infants with RSV may develop wheezing, but recent studies do not show an increased risk of asthma.¹⁰

Prevention and patient education is key, and frequent, careful handwashing is the most important measure in preventing the spread of RSV. Respiratory etiquette should be properly maintained and people with cold/flu-like symptoms should cover their nose and mouth preferably with a tissue or cough and sneeze into their elbow and wash their hands afterwards for at least 20 seconds or use an alcohol-based rub/gel. Used tissues should be properly disposed of. Sharing utensils with persons who have RSV illness should be avoided and cleaning contaminated surfaces such as door handles may help stop the spread of RSV.³

Parental smoking is a known risk factor for RSV infection in infancy, and parents or carers who smoke should be offered smoking cessation advice and encouraged to stop smoking. Breastfeeding also offers some protection against RSV infection.⁹

Persons with RSV should not attend crèches, school, work and non-residential institutions until well. It is important to
prevent young infants, frail older persons and immunocompromised people coming into contact with individuals with
respiratory infection.⁹

In the hospital setting, RSV transmission can be prevented by managing children with RSV together in the same
ward, paying strict attention to handwashing guidelines, using barrier precautions and avoiding overcrowding through
restriction of visitors.³

Several studies have shown that strict infection control practices including hand hygiene, the use of personal protective equipment when necessary, timely detection and isolating or cohorting infants with RSV infection can reduce nosocomial RSV infection rates by 39-to-67 per cent.⁹

RSV research and outlook

The management of RSV disease in infants and children is primarily supportive with antiviral medications reserved for the most vulnerable.10 Palivizumab continues to be the only effective prophylactic medication licensed for use, however, its high cost prevents it from being used in all infants. The development of a well-tolerated, clinically effective and cost-effective RSV vaccine and therapeutic agent remains a global health priority. It is likely that a licensed RSV vaccine is several years away, however, given the burden of RSV infection and the associated costs globally there is much ongoing research into the development of a well-tolerated and effective vaccine.

The main target populations for vaccination include infants, school-age children, pregnant women and older adults. Multiple different vaccine approaches are being considered including live-attenuated chimeric, whole-inactivated, particle-base, subunit, nucleic acid, and gene-based vectors. There are also ongoing efforts to develop long-acting monoclonal antibodies for infants.²
Three agents; ribavirin, IVIG and palivizumab, have been extensively used and investigated as antiviral treatments for
RSV. To date none have proven unequivocally beneficial, and effective treatments and research continues into future therapies. At least 14 anti-RSV treatment products are undergoing phase 1 and 2 clinical trials, of which five have included paediatric patients. Novel therapeutic molecules developed to date include fusion inhibitors, non-fusion inhibitors, polymerase inhibitors, antibodies, nucleoside analogues, small-interfacing RNAs, and a benzodiazepine.

They have various targets on RSV, such as the F protein, RNA polymerase, nucleoprotein, and nucleocapsid mRNA. It is hoped that one of these products will become a licensed treatment for RSV infection in children and adults over the coming years.² The development of a successful treatment or prophylactic agent has the potential to revolutionise the care and outcome for severe RSV infections in the world’s most vulnerable infant population.

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