RSV burden

What is RSV?

Infections with respiratory syncytial virus (RSV) are common and in healthy individuals usually result in coughs or colds with mild symptoms¹. However, in high-risk populations, RSV can result in bronchitis (inflammation of the airway), bronchiolitis (inflammation of the small airways) and pneumonia (inflammation of the lungs) requiring hospitalisation^2,3.

Severe RSV infection most often affects young infants as well as older adults, and adults with comorbidities; severe RSV can be life-threatening^2,4,5

The majority of children will have been infected with RSV by the age of two years, but the incidence of RSV infections in adult populations is unclear^1,2,5,6. This is likely due to misdiagnosis, because of unspecific symptoms that are shared with other respiratory infections, and a lack of routine screening for RSV, which may be driven by the absence of an approved therapy for adults, and the view that the symptoms of RSV are mild and manageable^1,3.

Due to limited data on adults with RSV, it is likely that the full burden of this potentially life-threatening infection is underestimated³

RSV

Now known to be a leading cause of paediatric lower respiratory tract infections (LRTIs), RSV was first identified as a cause of bronchiolitis in babies and children in the 1960s^7–9. RSV is a member of the Pneumoviridae subfamily of the Paramyxoviridae virus family, along with the viruses that cause influenza, mumps and measles^1,6,10. RSV is an enveloped RNA virus, consisting of a single-stranded RNA genome, within a membrane^10–12.

The RNA genome encodes 11 proteins involved in infection and virus replication, which are given alphabetical names^10–12. Some have roles in viral replication, but two key proteins (named F and G) are involved in infecting host cells^10,13. Indeed, protein G has been found to bind to a cell surface molecule (CX3CR1) found in human epithelia airway cells, and this interaction controls levels of infection of host cells grown in laboratories^14,15. Protein F plays a role in viral entry and fusion between infected and neighbouring healthy cells, resulting in syncytia (a mass of cytoplasm containing multiple nuclei)⁶. The F and G proteins are the only two antigens involved in inducing a neutralising antibody response by the infected individual¹².

Two subtypes of RSV are in existence, A and B, which vary in terms of the structure of protein G, and can influence disease severity^10,16.

Transmission of RSV and the RSV season

RSV is transmitted by droplets and secretions from infected individuals¹. The virus can survive on hard surfaces for 4–7 hours and on skin for 20 minutes^1,6.

RSV is highly contagious with an incubation period of approximately 4.4 days^6,17

RSV is a seasonal infection, with variations occurring according to the climate of the region in question⁶. In the Northern hemisphere, RSV season usually occurs between October/November and March/April, with the highest numbers of infections in December (Figure 1)^1,6.

Figure 1. Seasonal variation in influenza and respiratory syncytial virus in a Canadian population, and in the COVID-19 era (Adapted¹⁸). RSV, respiratory syncytial virus.

In more Southerly regions, the season may begin earlier and last for longer, and in tropical regions of South America, Asia and Africa, the RSV season is more variable in terms of onset, duration and peak^6,19. Much of the available data on the RSV season is from industrialised countries, with temperate climates. In order to prepare for and appropriately manage patients during regional RSV seasons, specific surveillance programmes are needed to understand how regional climate changes affect the timing and number of infections¹⁹.

There is also evidence from France and South Africa that lockdowns and social restrictions, such as those associated with the COVID-19 pandemic, may affect the timing of RSV epidemics and the populations affected, and this must further be accounted for when developing strategies to manage RSV^20,21.

RSV pathophysiology

Information on how RSV causes disease comes from biopsies of people with RSV, post-mortem examinations of people who died with RSV, and animal models of RSV infection¹³.

RSV enters the body through the epithelium lining the respiratory tract, and replicates first in the upper region of the throat behind the nose, and then spreads through the lower respiratory tract leading to infection in the lungs. Virus entry stimulates immune responses that trigger cell death and lysis of infected cells. Activated T cells produce signalling molecules (known as proinflammatory cytokines), which contribute to disease progression in the respiratory system, resulting in inflammation of the lungs, overproduction of mucus and bronchial hyperactivity. As the infection resolves, inflammation and mucus secretions are reduced, and memory T cells persist in the lungs and in circulation¹³.

RSV symptoms

The overproduction of mucus and bronchial effects cause RSV symptoms, which begin in the nose and upper respiratory tract, and may progress to the LRTIs bronchiolitis, bronchitis and pneumonia

Early RSV symptoms in infants and children may include a cold, with a runny nose, decreased appetite or ear infection (otitis media)^1,2,22,23. In the majority of cases, early symptoms are mild²³.

Infants and children who progress to more severe RSV, may present with bronchiolitis or pneumonia⁶.

Adults with RSV can present with mild cold symptoms, such as a blocked nose, cough, fever and lethargy. Severe symptoms may also develop, such as pneumonia, acute bronchitis, or worsening of asthma or chronic obstructive pulmonary disease (Figure 2)^24–26.

Figure 2. Symptoms of bronchiolitis, pneumonia and acute bronchitis^{6,23,27–29.} RSV, respiratory syncytial virus.

More on RSV diagnosis

RSV epidemiology

As with other seasonal respiratory viruses, RSV is very common. Between 50% and 60% of infants are affected before the age of one year, and over 80% of children have been infected with RSV by the age of two years^1,6. A global systematic review estimated there to be an annual incidence of 33.1 million acute LRTIs caused by RSV in children under 5 years old in 2015⁴.

Immunity to RSV is not sustained and reinfections are common^1,2. The immunity provided by an initial RSV infection is not sufficient to prevent reinfections throughout life^1,2. It may be that RSV has developed mechanisms to evade the immune system upon reinfection¹⁰.

A review and meta-analysis of global data estimates that in 2015, 1.5 million adults aged 65 years or older living in industrialised countries experienced an acute respiratory infection caused by RSV, with an incidence of 6.7 cases per 1,000 per year⁵

RSV is not routinely screened for, and with symptoms that overlap with influenza, it is possible that patients may be misdiagnosed or receive a primary diagnosis of LRTI if not specifically tested for RSV^3,30,31. Further, if symptoms are manageable, a laboratory diagnosis may not be considered necessary¹. The lack of an approved treatment for RSV in adults may also reduce the impetus to test. Many studies are based on hospitalised patients, and are expected to underestimate the total numbers of people within a population who are infected^5,32.

Meet the experts

Professor Peter Openshaw

Professor of Experimental Medicine at Imperial College London, UK. Professor Openshaw is a respiratory physician and mucosal immunologist, studying how the immune system both protects against viral infection but also causes disease.

Dr Stephanie Ascough

Academic Immunologist in the Department of Infectious Disease at Imperial College London. Dr Ascough is involved in early phase clinical vaccine trials and experimental infection challenges carried out by her group. She investigates innate, humoral and cell-mediated immunity in respiratory viral infections.

What is the burden of RSV?

Respiratory syncytial virus (RSV) has a negative impact on the lives of severely affected patients, due to the requirement for hospitalisation, potential long-term symptoms and high mortality rates (Figure 3).

Figure 3. Estimated global hospitalisations and mortality from lower respiratory infections caused by RSV in 2015^4,5. RSV, respiratory syncytial virus.

Burden of RSV in children

RSV is the most common cause of lower respiratory tract infections (LRTIs) in children and is also the most common cause of pneumonia in children aged under 18 years, present in 28% of children hospitalised due to pneumonia in a US surveillance study^7,33. Acute bronchiolitis symptoms are the most common complication in children infected with RSV, affecting 85% of patients aged ≤1 year, up to 77.5% of infected children <2 years old, and 31% of infected children aged 2–5 years²².

A systematic review has reported that 3.2 million children aged <5 years and 1.4 million infants <6 months across the world were hospitalised with RSV in 2015 (Figure 4)⁴

Figure 4. Hospitalisation rates by age for RSV infection in developing and industrialised countries (Adapted^4,5). *Total individuals.

Hospitalisation rates associated with RSV infection in infants are approximately 15.6 times higher than those caused by influenza infections³⁴.

In severe cases of RSV, intensive care is required, with ventilatory support. In premature infants with RSV and children aged <2 years old, intensive care may be required in up to 48.4% of patients and 17.5% of patients, respectively²². The requirement for ventilatory support could be as high as 34% in premature infants under 90 days old³⁵.

A systematic review also estimates that 59,600 children <5 years (27,300 infants <6 months) died from RSV infections globally in 2015⁴. This mortality burden is not evenly distributed, with over 90% of infections and deaths in developing countries, where otherwise healthy infants experience complications, such as bacterial sepsis and collapsed lung (pneumothorax), possibly due to limited treatment availability^3,36.

Following RSV infection, some children experience recurrent wheezing, persistent lung problems or asthma^22,33,37,38. Recurrent wheezing has a negative impact on health-related quality of life, as assessed using the HRQoL questionnaire in children aged 3 years who had been infected with RSV prior to 13 months of age, not only affecting the respiratory system, but also the gastrointestinal tract and sleep³⁹. Allergic rhinoconjunctivitis is also more common in children who have had RSV infections prior to the age of 1 year compared with controls (P=0.004)⁴⁰.

Burden of RSV in adults

Hospitalisation from RSV infections in adults and older adults appear to be less frequent compared to infants; however, data on RSV infection in adult populations is sparse in comparison with paediatric data^4,5.

A global systematic review and meta-analysis estimates that in 2015, RSV was responsible for 336,000 adult hospitalisations, and 14,000 deaths in adults aged 65 years or older, with a mortality rate of 1.6% in industrialised countries and 9.1% in developing countries⁵

Adults aged between 50 and 64 years had a mortality rate of 1.4% in industrialised countries and 2.5% in developing countries⁵.

A retrospective cohort study of adults with RSV in hospital found that 42.3% had pneumonia, and 21.9% had acute bronchitis²⁵. Patient outcomes are worse for people aged over 60 years with RSV than for people with influenza (Figure 5).

Figure 5. Comparison of outcomes of patients with influenza and patients with RSV⁴¹. ICU, intensive care unit; RSV, respiratory syncytial virus.

Further studies in Europe and the US reported mortality rates and/or intensive care admission rates similar to or higher than those of influenza^32,42. A study in New York hospitals found that 16.4% of patients admitted with RSV required admission to intensive care, while a further 12.4% needed ventilatory support⁴³.

Even following discharge from hospital, poorer patient outcomes have been reported with RSV, with 15.1% of patients needing an increased level of care compared with requirements prior to admission^43,44

Respiratory symptoms of hospitalised RSV patients, such as wheezing, shortness of breath and cough measured using the Respiratory Intensity and Impact Questionnaire (RiiQ^TM), have been found to be worse than for patients with influenza, both at discharge (P=0.001) and 3 months post-discharge (P=0.007)⁴⁵.

Socioeconomic impact of RSV

Beyond the patient, the burden extends to caregivers and society as a whole due to healthcare expenditure and use of resources (Figure 6).

Figure 6. Healthcare resources and costs, and caregiver impact^{22,25,32,46–51}. RSV, respiratory syncytial virus. *Compared with patients with other respiratory infections.

RSV has been estimated to be the cause of 2.2% of all primary care visits for children under 5 years of age in the US, and 3.2% of specialist clinician visits²². Antibiotic treatment rates for acute bronchiolitis caused by RSV are 24.9% in children ≤18 months and 46.8% in children >18 months, and corticosteroid treatment rates are up to 16.8%²².

A study in Spain has reported that the costs of managing an episode of acute bronchiolitis can be up to €1,169, and the management of long-term wheezing can be up to €5,608, with costs more than double those associated with other causes of bronchiolitis^22,47. Higher costs are associated with intensive care, ventilation and extended stays in hospital, and infants infected with RSV continue to have high healthcare cost in the year following infection^48,51.

As with other data on RSV, there is more information on infected paediatric populations than on adults.

Antibiotics and oral corticosteroids are needed in 43% and 21%, respectively, of patients aged over 21 years with RSV and congestive heart failure or chronic pulmonary disease³².

The burden of RSV has been reported as similar to that of non-pandemic influenza, and the costs of managing RSV in adults aged over 60 years are thought to be at least as high as that for managing influenza ($16,034 vs $15,163)^32,52

What are the risk factors for severe RSV?

Given the patient and socioeconomic burden of respiratory syncytial virus (RSV) in paediatric and adult populations, an understanding of risk factors is required to help to isolate high-risk individuals and identify patients at risk of a severe infection.

Risk factors for RSV infection in infants and children

The risk of infants or children experiencing a severe RSV infection or requiring admission to hospital is affected by a range of medical and socioeconomic factors (Figure 7).

Figure 7. Risk factors for severe RSV or admission to hospital in infants and children^{22,23,33,36,53,54}. RSV, respiratory syncytial virus.

Risk factors for RSV infection in adults Risk factors for the development of severe RSV in adults are associated with age and pre-existing medical conditions (Figure 8).

Figure 8. Risk factors for severe RSV or admission to hospital in adults^24,55–57. RSV, respiratory syncytial virus.

RSV diagnosis

References

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