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Expert opinion: Focus on RSV

Dexter Wiseman is a registrar at Royal Brompton and Harefield NHS Trust, London, but has also been working at the National Heart and Lung Institute based at Imperial College, where he has just submitted a PhD. Part of his research involved working with the RESCEU (REspiratory Syncytial virus Consortium in EUrope) Project, a European group investigating the burden of respiratory syncytial virus (RSV) across Europe, with a work package focusing on older adults with chronic lung disease.

We had the pleasure of speaking with him about his work, the condition, and how he feels research will progress in the future.

Please tell us about RSV?

Dr Wiseman explained that respiratory syncytial virus (RSV) is an RNA virus that was first discovered in the 1950s and found to be pathogenic, initially in chimpanzees but then also in humans. There are two common strains – A and B – that differ in the proteins present on the viral membrane. The virus is spread via respiratory droplets and has an incubation period of four to five days. Dr Wiseman added that although the virus enters via the nasopharyngeal route, ‘it can also be transmitted through the conjunctival membrane and then spreads into the lower airways and replicates in the ciliated cells.’ The resultant humoral and T cell immune response causes cell necrosis, pushing the debris into the airways. Interestingly, he also described how in a healthy adult, human challenge study with the virus, where bronchoscopy was performed before and after infection, it was found that ‘even when the symptoms had subsided from RSV, there was still evidence of macroscopic inflammation, so that RSV might be doing a lot more than we realised when it comes to inflammation.’ A further problem among those who become infected with RSV, Dr Wiseman continued, was that that immunity to the virus is short-lived, so that individuals remain susceptible to re-infection throughout their life. In fact, he mentioned how other human challenge studies have suggested that an individual can be susceptible to re-infection in as little as two months after their initial infection. Why immunity wanes so quickly he says is still unclear, although what is known is that among older adults both immunosenescence and inflammaging can be detrimental such that their immune system appears to work against them with respect to the virus.

RSV displays a seasonality for infection, which is traditionally from October to March, although due to the COVID-19 pandemic and greater hand hygiene and the use of face masks, the seasonality was disrupted. Nevertheless, he noted that in countries such as Australia, where there has been a lot of epidemiological work on RSV, while some evidence has revealed a winter spike in cases, it seems that RSV might no longer being following its traditional pattern.

What are the main symptoms of RSV?

Dr Wiseman said that the symptoms of RSV are very non-specific, which poses a diagnostic challenge for clinicians, making it difficult to differentiate RSV from other more common viral infections. Typically, he says, adults would present with ‘nasal congestion, sore throat, cough, shortness of breath, sputum, wheeze and fever. They will also get headache, fatigue and myalgia.’ He mentioned how a study conducted in the pre-COVID era found that the symptomology of several different viral infections was broadly similar, so that making a diagnosis of RSV based solely on symptoms was impossible. While RSV can be identified through PCR testing, if this is not performed within the first few days of symptom onset, the result if often negative (i.e., a false negative) in older adults. This, he explained was a phenomenon encountered in one of his COPD trials where patients were asked to keep a symptom diary and record when they developed any specific symptoms such as a runny nose. As Dr Wiseman explained, ‘as they [patients] become more unwell, short of breath, having a cough with productive sputum, they would test negative on PCR but when we did the serology, we would find that they did have an RSV illness.’

Given the non-specific nature of the symptoms, what is known about the prevalence of RSV?

Although as Dr Wiseman explained, pretty much everyone will have had exposure to RSV by the age of 2, ‘we don’t really know much about the burden of RSV or what it does from older childhood to  adulthood where people are healthy, and that’s a very understudied area.’ Nevertheless, the information that is available does suggest that RSV has a considerable burden upon adults. He mentioned a 2015 meta-analysis undertaken of studies in Western countries that found a prevalence of 1.5 million acute cases of RSV, of which 200,000 required hospitalisation. Furthermore, a seminal 2005 paper revealed that RSV led to an estimated 14,000 deaths every year in the USA among older adults and which was significantly greater than the 1 to 500 deaths per year among US children. Other analyses have demonstrated that the burden of RSV increases with age, such that an estimated 1 hospitalisation per 10,000 cases in those aged 65 years and older can be expected to occur, although this increases to 5 per 10,000 cases in those over 80 years of age.

Dr Wiseman also described how RSV is known to be a trigger of COPD and asthma exacerbations. He said that a recent study in older adults ‘had estimated a prevalence of around 6% per year in community dwelling older adults’ when testing was done with nasal swabbing and a PCR test, together with serology to diagnose RSV throughout two seasons. He added that an interesting observation from this study was how the duration of symptoms was 19 days, and that in a third of cases a visit to a physician was required.

While it is possible for anyone to become infected with RSV, Dr Wiseman explained how there are risk factors associated with a poor outcome such as a longer symptom duration, hospitalisation or even death. These include chronic lung conditions, e.g., COPD, asthma, chronic heart conditions such as heart failure, and being immunocompromised. He added that a further complication for heart disease patients is that RSV ‘promotes the increase of certain inflammatory markers such as IL-6 and tumour necrosis factor that can promote plaque destabilisation and can mean that some of these patients end up with an MI [myocardial infarction] from RSV.’ He cited another vulnerable group was care home residents due to the highly contagious nature of RSV and who are generally older and have a number of comorbidities.

Might RSV levels reduce in the coming years because people are now more wary of respiratory viruses because of COVID-19?

Dr Wiseman felt that COVID-19 mitigation strategies such as mask-wearing and self-isolation once an individual develops respiratory symptoms might help reduce the future spread of RSV. However, because immunity to RSV is often short-lived, individuals are still at an increased risk because they become ‘immune-naïve to RSV again and it is known that people with higher quantities of antibodies to the F protein in their blood are less likely to have symptomatic illness with RSV.’ He cited early data from Australia that has revealed how ‘RSV has kicked up post-COVID much more so than influenza’, although recent molecular studies have shown that RSV now has fewer strains so that the heterogeneity of RSV has decreased significantly. Precisely what long-term effect this might have remains unclear, however.

What management strategies are available for patients?

Dr Wiseman said that at the present time there are no specific interventions for adults infected with RSV, either in the community or hospital. Treatment is therefore symptomatic and directed towards any underlying comorbidities, which tend to worsen due to the infection. He mentioned how infected patients’ oxygen levels can drop, warranting supplementary oxygen, and as their condition deteriorates, either non-invasive or mechanical ventilation might be needed. The virus effects can reduce patients’ blood pressure, necessitating additional fluids and, in some cases, inotropes, and typically worsens both chronic heart failure and COPD. Additionally, infection with RSV, especially in those with an underlying lung disease, can lead to a bacterial infection and bacterial pneumonia. Dr Wiseman explained that while RSV can itself cause pneumonia in older patients with a reduced immunity, leading to inflammaging which can be fatal, it is more often the case that an exacerbation of a comorbidity due to infection that is usually the cause of death in most patients.

How useful is screening for RSV?

Currently, Dr Wiseman said many hospitals include RSV on their viral multiplex panel for PCR testing, adding how, while less accurate in the past, point-of-care test kits are now much better at detecting the virus. In clinical studies rather than rely on PCR testing, it is more usual to perform baseline serum samples, and where there is a clinical suspicion of an RSV infection, serum testing is repeated to determine if there is a rise in RSV antibody levels.

Dr Wiseman said that while there is an ongoing debate over the value of screening for RSV, especially given the absence of a specific treatment, he believes that screening does have a value, particularly considering data suggesting worse outcomes from RSV infection compared with influenza and how knowledge of the infecting virus allows clinicians to instigate vigilance measures.  As he explained, with research showing that ‘mortality was greater at one year for those hospitalised with RSV than for those with influenza and because RSV is contagious, if you can identify someone in the care home or the hospital ward having RSV, you might then implement barrier nursing or some procedures to try and stop the spread of the virus to other vulnerable people in the facility.’

What do you see as the barriers to wider RSV screening?

Dr Wiseman thinks that the cost of PCR testing is certainly an important barrier in some countries. However, perhaps a more important factor is simply lack of awareness of the virus among clinicians. He cited research which ‘found that when patients were eventually diagnosed with RSV during their admission, it was only in about a third of those cases that a viral PCR swab at the point of admission was considered.’ He believes there needs to a cultural shift within the medical profession before the diagnosis of RSV is considered more widely, especially among older adults. A further hurdle limiting awareness among medical staff is that unlike influenza, RSV is not a reportable disease, although he said this is slowly changing, and it has already happened in Australia.

With the available data suggesting that patients hospitalised with RSV often have more severe disease, a longer hospital stay, and even higher mortality than those with influenza, now is the time to raise awareness of this under-recognised, yet potentially fatal, viral pathogen

A further obstacle is the lack of availability of point-of-care tests within emergency departments, despite the fact that many currently available panels are multiplexed and able to identify a whole range of viral pathogens including RSV. Dr Wiseman believes there is an argument for point-of-care testing to be carried out in general practice. This, he feels, would be invaluable for the older and more vulnerable adults with viral symptoms and comorbidities, enabling doctors to monitor individuals who test positive for RSV and might also then lowering the threshold for a subsequent hospital admission.

What is the role of anti-viral therapies in RSV?

Dr Wiseman described how studies of anti-virals against RSV have been met with limited success, though there has been some benefit for a subset of patients, e.g., those who are immunosuppressed. However, overall, there is no statistically significant evidence that anti-viral therapy helps with RSV.

How do you see the future progressing with RSV and what would you like to see happening?

Dr Wiseman feels that greater awareness of RSV in older adults would be very important first step but believes that this is already happening with a greater propensity to send PCR swabs for multiplex testing from hospital wards. A further important development will be the introduction of an RSV vaccine. He noted that provisional data appears to be promising in terms of reducing symptom burden and even reducing poorer outcomes, adding more concrete data will arise from Phase IV trials. While anti-virals have not demonstrated much use in patients already infected with RSV, Dr Wiseman thinks there is a need to examine whether the early use of anti-virals could reduce or prevent hospitalisation. He also would like to see the collection of more data on the effect of RSV in younger, healthy adults, particularly given how there is bronchoscopy evidence of residual inflammation even after symptoms have resolved. Dr Wiseman feels that the continued presence of inflammation in the lungs might explain why RSV is such a burden for those with lung diseases, leading to poorer outcomes.

Finally, Dr Wiseman believes that greater awareness of RSV is needed among government bodies and those directing health policy. With the available data suggesting that patients hospitalised with RSV often have more severe disease, a longer hospital stay, and even higher mortality than those with influenza, now is the time to raise awareness of this under-recognised, yet potentially fatal, viral pathogen.

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