Activity Transcript

Peter J.M. Openshaw, FRCP, FMedSci: Hello, I'm Peter Openshaw, Professor of Experimental Medicine at the National Heart and Lung Institute in Imperial College London. A very warm welcome to this program, which is titled, "Current Clinical Challenges of RSV in Older Adults: The Hidden Foe."

So joining me today is Stefan Gravenstein. He is the David S. Greer Professor of Geriatric Medicine and is the Director of the Division of Geriatrics and Palliative Care at Brown University in Providence, Rhode Island, United States. So a very warm welcome to you Stefan.

What we're going to talk about today are the challenges in recognizing RSV infection and in making the diagnosis of RSV infection in older adults. And we're going to be focused on the patient profiles of individuals susceptible to severe RSV infection, and particularly be talking about the problems that there are in diagnosis in elderly persons.

Now, when I started working on RSV many, many years ago, it was really thought of as a disease of infancy and childhood, and there hasn't been nearly as much research in the impact of RSV in older adults historically. But I think in recent years, that has all changed and it's become evident that all adults are susceptible to reinfection with RSV throughout life. And indeed, older adults particularly say those over the age of 65, are particularly adversely affected by RSV infection in a way that we just didn't understand a few decades ago.

So there's a real lack of recommended specific treatments for RSV and associated illnesses in older adults; no vaccine currently, although we are very optimistic that there may soon be vaccines. And there's also a lack of awareness amongst clinicians generally, about the great importance of RSV in the elderly.

In terms of the disease that it causes, it's a very common infection. It probably accounts for something like 10.6% in 1 study of hospitalizations for pneumonic disease; about 11% of the admissions in patients with chronic obstructive pulmonary disease (COPD); in 1 study 5.4% of the admissions for chronic heart failure, and about 7.2% for those with asthma amongst people over the age of 65 and so that includes many high-risk patients.

The data from adult RSV season surveillance programs, which have been assembled between 1975 and 1995, routinely used viral culture specimens to identify RSV and came up with a prevalence rate of about 7% in the population at that time. So I think it's now increasingly recognized as a cause of exacerbation of those chronic medical conditions.

So the burden of RSV acute respiratory infection (ARI) in adults with comorbidities is becoming increasingly evident. incidence of an RSV symptomatic acute respiratory infection in adults with comorbidities may be as high as almost 37.6 per 1000 persons in 1 particular study. And the seasonal incidence rate is given as 28.4 per 1000 persons per season. So a very significant cause of morbidity.

The in-hospital case fatality ratio is also very high. In 1 study in industrialized countries, it was 11.7%. So, that's a very high fatality rate in those who have been hospitalized. The likelihood of experiencing RSV-ARI for those with any comorbidity compared to those without, gives an odds ratio of 4.1 in 1 particular study, although in a more complicated statistical analysis, that figure was 1.1. So an increase in the frequency of those with comorbidities.

So Stefan, can I come over to you now and ask you, so in patients with RSV, what are the characteristics and predictors of hospitalization, particularly in older adults?

Stefan Gravenstein, MD, MPH: When we think about what the typical older adult has, hypertension and so forth, these pose no greater risk, but specifically for the things that drive hospitalization, underlying lung disease and heart disease and kidney disease are sort of the leaders. So you already mentioned COPD, emphysema. You've mentioned heart failure; chronic kidney disease, probably because of the immune suppression that comes with that. If they've had prior pneumonia, which may also underline these other conditions; just being older and immune suppressive conditions, and hematological malignancies are probably the leading driver of that, but immunosuppressing drugs are in this group too, and then finally stroke.

Dr Openshaw: So Dr Gravenstein as a geriatrician, can you tell us how we should define the elderly? Is it just on age or what?

Dr Gravenstein: Yes, obviously it's a leading question and older folks are certainly more susceptible, just purely cause of age and immune senescence, but with age somewhere around age 50 or so, we also start acquiring additional disorders. So the older we get, the more heterogeneous we become, collecting diabetes and lung disease and other kinds of things that also change susceptibility.

Those things are really interesting in part because the older adult has susceptibility that is not just related to their anatomy. Their mucociliary escalator isn't as efficient as it is in a small child, as an example. It isn't just because of their underlying other conditions like heart and lung disease. It also relates to their prior exposure to RSV. So when they present, they present quite differently and much of that presentation is related to the immune senescence.

Dr Openshaw: So Stefan, can I ask you a bit more about that immune senescence? So why does an RSV infection behave so differently in older adults compared to other age groups?

Dr Gravenstein: So specifically from the immune senescence standpoint, as we age our T cells change. We have a reduced number of naive T cells and new T cells. We have reduced B cell stimulation; the T cells that are turning on these B cells to make a specific antibody. The B cells themselves make less antibody. They make less neutralizing antibody, lower quality antibody, less avidity, less of the isotype switched antibody repertoire.

And meanwhile, the pool of memory cells has been increasing and those memory cells also are somewhat different. They produce a little less interferon gamma and cytokines and that means when we get that acute infection, the cytokine kick when we were younger, or when we were children, isn't quite the same. We have a lower rate of rise of those cytokines that can produce fever and a lower absolute antigen and a slower decline. So older folks start looking sicker a little bit more slowly, and they stay sicker longer because of that delayed clearing. The illness that might clear in a space of a week or 2 in younger adults or kids might take weeks or months to fully recover.

Then finally dendritic cells, these cells that present antigens to T cells, aren't quite as functional in older groups. They aren't able to process and present the antigens in quite the same way and migrate to the infected site, the lung in this case. So all of these things together change the clinical presentation of the acute illness quite a bit for older adults.

Dr Openshaw: Well, thank you very much. Yes. So in patients with RSV, what are the characteristics and the predictors of hospitalization?

Dr Gravenstein: So things that influence both the functions of the lungs and immune system, I think are the main drivers. So function of the lung, if you already have underlying lung disease, like COPD, emphysema, asthma, heart failure is sort of the cousin of this; immune changes with age, which also come with COPD, CKD, older age; if you have hematologic malignancies; if you're on immunosuppressive drugs are, again, things that change this risk for hospitalization.

Finally, if you've had prior pneumonia, which might be a marker of any of these other things, or just underlying risk to the lung itself, or stroke, which might include aspiration risk or prothrombotic risk that comes with acute infection, these collectively increase the risk of hospitalization.

Given all these things that older adults tend to present with as a risk for hospitalization, what are the symptoms that we get when they come in?

Dr Openshaw: Well, I think from the virological point of view, we can say that RSV really is a specialist in replicating in the ciliated cells within the respiratory tract. That results in respiratory symptoms and precipitates the presentation, both in primary and secondary care.

Now, there was a study going back to 2014, that was a study of adults over the age of 50 with RSV. In that study, almost all of them, 99% had cough, but only 61% had fever and 67% were wheezing. So I think it's important to look out for lone cough as a presentation of RSV in that older adult group.

There was another study more recently in 2020, looking at adults with RSV in Korea. They found broadly similar sorts of results. In patients over the age of 65, about 65% had fevers, 65% coughs, so not quite at such a high rate there, but often it was productive of sputum, that was 68%. Only 15% had symptoms that you might associate with a cold of rhinorrhea and 41% were short of breath and had dyspnea.

Now, Walsh in 2017, did a really nice summary of symptoms of outpatients over the age of 65 with RSV. In that group, there was more nasal congestion. That was present in 83%, cough in 79%, and sputum in 64%. So only a small proportion of those had dyspnea or fever, and wheeze was much less common.

So I think in summary, if you look at the symptoms in older adults, they're quite non-specific. And I think it really means that we need to have quite a low threshold for considering RSV in adults presenting with those diverse types of symptoms.

Dr Gravenstein: Yes, and those are different than in kids, right? So in kids, they have almost the same number of airways that we have as older adults. So when they start getting an infection, they get bronchoconstriction, and are more likely to wheeze and sound croupy early on, whereas that doesn't happen as much in older adults.

Dr Openshaw: Yes, so the disease in older adults is much more insidious really. It's harder to diagnose, it's less obviously associated with virus replication in the upper respiratory tract, and it's often missed.

So I think it's clear that diagnosis is a real issue. And often clinical diagnosis isn't possible because it's hard to distinguish from other viral diseases. And indeed the virus may actually not be present in the upper respiratory tract at the time that they present to hospital, particularly in the later stages when their lung function might be deteriorating.

I think that it's also important to mention that there isn't a great incentive to diagnosing RSV in the absence of any specific treatment that can be directed at the virus at the present time. Of course, that may change with the advent of antivirals and other types of maybe immune-modifying treatments, which might in the future be used against RSV at specific stages. So many cases, particularly in primary care are going to go undiagnosed at the moment.

It is possible to use polymerase chain reaction, but the cost is quite high. That's not really going to be a sensible alternative, particularly in resource-poor settings and the result in any case may be negative by the time they present. So this really highlights why research on the topic of adult RSV is so important in order to get a really full understanding of disease.

Dr Gravenstein: I think it changes our testing paradigm a bit too. Now, in the era of COVID when somebody presents with respiratory symptoms, we are challenged with even going beyond the differential of SARS-CoV-2 infection to all these other things like RSV.

And I think there's a need to start thinking more broadly about our diagnostic approach, because it influences diagnostic stewardship. At the moment, somebody gets a SARS-CoV-2 test and they test negative, whether it's PCR or whether it's antigen, there's a fair chance that you get it at the wrong moment and maybe it misses the diagnosis because you test it too early or too late and so forth. And if at that same moment you had been looking for other infections like RSV or flu, if that test were to come back for the other diagnosis, although you could have dual infection, it's still relatively uncommon, you can stop your search for additional infections and start appropriate treatment if it's available.

I think that brings us also to a feature of antibiotic stewardship. So getting it right means that we won't unnecessarily use antibiotics that otherwise we might be inclined to use because they look sick and you're not sure what you're treating and so you start this empiric therapy that might be unnecessary.

It reminds me in the long-term care setting, there was 1 study that suggested that potentially three-quarters of the antibiotics prescribed are potentially inappropriate. So, having a multiplex test or PCR with RSV and coronavirus and flu and so forth, might actually get us there better, and identifying a virus 40% more often could really help us.

So as a geriatrician, I spend a lot of time thinking about the long-term care setting where the implications of spread of infection is different than in the home setting, because there's lots of vulnerable people at risk living together. And I think there's 2 things that sort of come to mind. One of them is, we did this study from 2011 to 2017, where we were looking at these 6 seasons and the attribution of RSV to new infections, cardiorespiratory infections, producing hospitalization was almost identical to flu across various age groups.

So I think we forget and we often don't even consider RSV in our differential because we have nothing available to treat it. So if we're looking for COVID, which we can now treat; we're looking for flu, which we can now treat; we can give the correct diagnosis and treatment, but if there's RSV, you'll know that those things aren't important and we can manage them supportively.

Dr Openshaw: So Stefan, can I ask you to just sum up, what are the main challenges as you see them to the diagnosis and management of RSV in elderly people?

Dr Gravenstein: Yes, I think the front end of that is this -- we have to think about it. It has to be in our differential. It's under-recognized and underdiagnosed. And because we can't clinically distinguish it from other important causes of upper and lower respiratory tract infections, we really have to start thinking about changing our testing paradigm. And that might be especially important when there's a context to other people they might infect, much like we do with SARS-CoV-2.

So awareness of this and the value of multiplex testing, I think is going sort of get advanced here and that facilitates antimicrobial stewardship, diagnostic stewardship, and in a long-term care setting, improving workforce and resource stability in these under-resourced environments. So we still need an approach for primary prevention of course, but we have to know that there's something we can prevent.

Dr Openshaw: Well, thank you, Stefan. So I think just to sum up what we've been discussing, I think it's very clear that RSV causes a substantial morbidity and mortality in older adults. It's underdiagnosed, it's underestimated, particularly in primary care, but the burden is probably approximately equal to the burden caused by influenza in hospitalized patients. This is especially so in those with comorbidities, particularly those who are immunosuppressed, those with chronic heart or lung conditions are particularly at risk. And if you look in the round, RSV is now estimated to cause something like 177,000 hospitalizations per year in the US, in those aged over 65.

So I'd just like to thank Stefan Gravenstein, again for his participation. It's been a very interesting discussion. I'd like to thank you the audience as well for participating in this activity. Please continue on to answer the questions that follow and then to complete the evaluation. Thank you.

This is a verbatim transcript and has not been copyedited.