This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.
Forest W. Arnold, DO, MSc: Hello. This is Dr Arnold. Welcome to season 2 of the Medscape InDiscussion podcast series on respiratory syncytial virus (RSV) in adults. Today we'll discuss long-term outcomes of severe RSV infection in adults. First, let me introduce my guest, Dr Christopher Robinson. He is an associate professor in the Department of Neurology and Neurosurgery at the University of Florida and specializes in neurocritical care. Welcome to the Medscape InDiscussion podcast.
Christopher Robinson, DO, MS: Hello.
Arnold: Let's start generally and narrow our conversation as we go along. First, we have talked at length on this podcast about RSV, but not neurology. What do the two of them have to do with each other?
Robinson: I think in general, we look at RSV as a pulmonary disease, when in reality it's a systemic disease, with the inflammatory reactions that occur and the humoral response to the infection. Like most viruses, this immune response can affect the neurologic system. We know that specific viruses have something called neurotropism, which is the ability to invade the central nervous system (CNS) or peripheral nervous system. RSV falls into the category of one of those types of viruses.
We have some long-standing data on neurologic outcomes as it relates to RSV infection in children, but when it comes to the adult population, the data are quite limited. We know that a small proportion of patients that get infected with RSV can have symptoms such as encephalopathy, encephalitis, and status epilepticus, and a commonly known complication in the pediatric population is central apnea.
Arnold: What are the most common neurologic complications following RSV infection in adults?
Robinson: We don't have a ton of data to speak on this. In a lot of the data that we look at when it comes to outcomes related to viral infection in the neurologic system, there seems to be an interplay between a condition called myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). If you look at the literature on neurologic manifestations of RSV, the pediatric data are quite robust. To date, there are no long-term studies on neurologic outcomes in patients in the chronic phase, following RSV infection. But there are some data to support that patients do suffer from encephalopathy or seizures, and it comes to about 1.5%-1.8% of total patients infected.
When you look at the pathophysiology of why patients with RSV present with neurologic manifestations, there's a category of immune-mediated responses, which are a relative autoimmunity that can occur; we can talk about that a little later. More importantly, there seems to be a secondary effect that is hypoxemia-related, metabolic-related, or cytokine-mediated, which is a lot of what we saw with COVID-19.
Arnold: Okay. CFS stands for "chronic fatigue syndrome," which I think we're familiar with. But ME — tell us what that stands for again?
Robinson: That stands for "myalgic encephalomyelitis," which is essentially a synonym for CFS. These entities have been known since the 1980s. They were largely been written off by the medical community until the presence of long COVID-19, and in fact, in 2021, the US Food and Drug Administration (FDA) committed a substantial amount of money to research on these chronic sequelae of viral diseases. I think the presence of knowledge of this disease is ever increasing, because of the number of patients that are presenting to primary care with "long COVID-19" symptoms. These patients can typically have a variety of symptoms, including chronic fatigue, cerebral blunting, short-term or long-term memory impairment, dysautonomia or autonomic disturbances, poor sleep, and reduced activity levels. These were for a long time written off as sequelae of other diseases or some other nonsomatic complaint. So it's gaining traction in the literature.
Arnold: You've mentioned some of the common neurologic complications like encephalitis, seizures, and status epilepticus. What are some of the extrapulmonary manifestations of RSV?
Robinson: We know specifically, neurologic manifestations can occur. The only cerebrospinal fluid (CSF) data we have for RSV relate to the pediatric population, in which the data are not that robust. You typically see, in the pediatric literature, children with status epilepticus or encephalitis having negative CSF and polymerase chain reaction (PCR) for RSV and more likely related to excitotoxic-type pathology, like febrile seizures. Again, in the adult population, we don't have a robust amount of evidence. We do also have some extrapulmonary evidence of cardiovascular disease or cardiovascular complications in the setting of RSV; that's probably a secondary effect of multiorgan dysfunction in the setting of refractory hypoxemia.
Arnold: So the heart definitely is an area affected by RSV, and the nervous system penetrates every area of the body and every organ, thus, it's no surprise that neurotropic virus like this would be elsewhere other than just the lungs. Does the importance of increased awareness and improved management of RSV in adult populations translate to improved patient outcomes also?
Robinson: I think it does without a doubt. I think there's been a large culture shift across the country and the world, after the COVID-19 pandemic, in patients being more aware of their current medical conditions, promoting a culture of healthiness, and trying to tackle their illnesses in an expedited fashion. I also think it changed the way that we practice medicine systemically and our approach to patients from a holistic standpoint, in that using multidisciplinary care can help these patients. Since 2019, we've seen a large increase in patient's knowledge of their current illness, and an understanding of what the severity of it might be. Taking a glass half full perspective, a positive effect of the pandemic itself is people's own reliance on their healthcare and knowledge of their current disease state. So early recognition in this case is very helpful.
Arnold: When we speak of early identification and appropriate management of neurologic complications in RSV-infected adults, could you share some of the strategies you use to do that?
Robinson: That's a large topic, if I may take some time on this. The etiology is typically multifactorial. We can dichotomize neurologic manifestations into those that are a direct secondary effect from the disease state itself, or those that are a secondary effect from the immune reactivation that occurs from the virus. To date, we don't have any FDA-approved treatments for these neurologic manifestations per se. Typically, if we see a patient that has a seizure or status epilepticus, the classical teaching is that a seizure or status epilepticus is a symptom of another systemic problem. So addressing that systemic problem — whether it be hypoxia or hypoxia-induced brain injury, or a cytokine storm, for example, like we saw with COVID-19 — tackling that head-on as the primary cause will usually result in improvement in the seizure. We use classic EEG technology to identify seizures. We know that in patients that are admitted to the medical intensive care unit, anywhere between 20% and 35% of those patients at any one time are in nonconvulsive status epilepticus, and management of those patients with effective antiepileptic therapy is important.
On the other hand, if we have an immune reactivation–type effect — which we see more commonly in influenza, such conditions as acute necrotizing encephalitis or acute disseminated encephalomyelitis (ADEM), or another condition called MERS (which is not the infectious Middle East respiratory syndrome but rather mild encephalopathy with reversible splenial lesions) — these are immune activation–type disorders, and they typically result in acute demyelination. In those patients we'll typically use immunomodulatory therapy, including steroids, as well as intravenous immune globulin (IVIG) or plasma exchange, to remove the autoantibodies that have occurred.
Speaking about steroids alone, we know that steroids in the setting of acute hypoxic respiratory failure with RSV have not shown benefit beyond placebo. So we only utilize steroid treatment when we have typically MRI-confirmed or CSF-confirmed invasion of the virus. Steroids have not shown any benefit in patients with classic bronchiolitis or bronchial pneumonia with RSV. We use steroids in the setting of neurologic invasion or immune invasion affecting the brain, as it relates to an acute demyelinating disorder in the setting of a viral illness. So this would cross between RSV, influenza, and other viruses, to reduce that immune activity attacking the brain.
Arnold: So the exception is viral invasion, and you can have that with RSV or influenza. How is that diagnosed?
Robinson: That's a good point. We talked about the presence of neurotropism with these viruses. What these CNS disorders are typically not are a reflection of direct viral invasion into the brain. If we look at RSV, influenza, and COVID-19 and we look at neuropathologic studies, we do not tend to find direct invasion or infection of the virus into the brain. What we tend to find is a humoral B-cell reactivation, attacking astrocytes and attacking myelin that result in a secondary neurologic disorder, which is why steroids work.
An interesting paper was just released in The Journal of Infectious Diseases of a study performed in rat models, looking at gray matter in the spinal cord as well as peripheral nerves. The researchers did direct infection with RSV and found that RSV was present and actually invaded the peripheral nerves as well as the spinal roots for up to 30 days after infection. Now, this wasn't done in vivo, but it points to the fact that neurotropism exists. Getting back to your original question, typically when we see these lesions, we will do the workup. We will do CSF sampling. We will look for an inflammatory reaction. We will look for changes in glucose and protein, and we'll do RT-PCR to determine whether there is a presence of a virus. But typically those studies come back normal.
Arnold: You mentioned that there are extrapulmonary manifestations of RSV, and so that makes us consider that there must be multiple specialties involved. I'm wondering about the collaboration between different medical specialties for comprehensive care and management of RSV-infected patients.
Robinson: I think the front line of care for any patient is their primary care physician, and we've had some nice podcasts previously talking to primary care physicians about the impact of RSV and the knowledge behind it. So, astute knowledge and recognition of upper respiratory or severe lower respiratory infection if RSV progresses, via primary care are highly important.
It's also important to note that if a patient does require hospitalization from RSV — which is not uncommon, it's around 200,000 adult patients per year — those patients tend to have specific comorbidities in the literature that predict severe outcomes of RSV. These comorbidities include cardiovascular disease and pulmonary disease, and interestingly, social living status is a predictor of poor outcome in RSV. So when these patients are admitted, the presence of effective pulmonary and cardiovascular care, especially in those that have the comorbidities, as well as critical care if they're having hypoxemia, is vitally important.
This begs a topic which is out of the scope of this podcast, but I think as we move forward in medicine, we're seeing that precision medicine is more adequate than holistic systemic medicine. Utilizing the specialties in the hospital for individual patient care, and targeting what their specific comorbidities are, have been shown to improve outcomes not only in RSV but in multiple medical conditions. So I would suggest that precision medical care as it relates to comorbidities in the primary infection is the way to go.
Arnold: We have learned from long COVID-19 that some inroads have been made with physical therapy and some psychiatric help, but I think for the most part, many physicians, especially primary care physicians, as you mentioned, don't feel like they can do much for COVID-19. I'm wondering about the need for long-term follow-up and monitoring of patients who have experienced neurologic complications due to RSV infection.
Robinson: That's a good question, and I'd like to dichotomize it a bit. Patients that have acute neurologic complications in the hospital, such as seizures or encephalitis, should be followed by a neurologist. I think those patients will probably leave the hospital on antiepileptic therapy — not all, but some. Not all primary care physicians would be comfortable with those medications. So I would suggest that any patient with acute-phase neurologic complications be seen by a neurologist.
The more important topic you're addressing here is the long-term sequelae, the neurologic sequelae, that these patients can have. We know specifically that just the presence of delirium in an intensive care unit (ICU) patient significantly decreases their cognitive outcomes in the first 3-12 months after their ICU stay. If you add a viral infection that has neurotropism, such as RSV or COVID-19, these patients are experiencing long COVID-19 symptoms, which have significant crosstalk with ME/CFS. As you alluded to, there are no FDA-approved interventions for these conditions, and they're quite frustrating to primary care physicians. There are some data to speak of. We know, and we should be familiar, with dysautonomia and how to manage that with some FDA-approved therapies. But beyond that, for cognitive impairment, there is some good evidence to support neurocognitive therapies and social behavior therapies, and then there's some evolving literature as it relates to long COVID-19, in which we see poor cognitive outcomes with reduced serotonin levels. There are some data to support the use of selective serotonin reuptake inhibitors (SSRIs) in patients with these long symptoms, and as most astute clinicians should realize, they're going to be associated comorbidities in patients who are more likely to experience these long neurocognitive symptoms that follow along with ME/CFS.
Arnold: Are there support networks available for these people?
Robinson: Not specifically for RSV, but for the ME/CFS that we keep talking about, there are definitely support networks, diagnostic criteria, and places where you can reach out. I would encourage providers and or patients to look at the FDA website, who's poured a lot of money into this. Although trust in that institution varies among patient populations, it's a nice resource where the patients can go and see and find these support groups. Whether or not they're interested in the medical literature and the research behind it, there are some opportunities there to find groups. I've also had a lot of patients suggest that Facebook groups and social media groups are there. I think regardless of the type of virus you had, the community will be willing to accept you, talk to you, and perhaps walk you through some treatment modalities that work for them.
Arnold: Speaking about risk factors, are there any known risk factors that increase the likelihood of developing these types of sequelae?
Robinson: It's standard among most viral infections and people that get severe RSV — so those with other comorbid factors such as heart failure, pulmonary disease, and social living status. And one thing we haven't mentioned, which has been talked about quite a bit with illness severity, is the immunocompromised patient. Those patients would be more likely to have CNS invasion, have less immune reactivation because they're immunosuppressed, and be more likely to have severe infection and neurologic manifestations secondary to that.
Arnold: Thank you. Today we've talked to Dr Christopher Robinson about RSV in the nervous system. We have learned that RSV is a neurotropic virus attacking nerves that extend all throughout the body, giving manifestations that are more than just in the brain and spinal cord. We've learned and discussed some of the long-term sequelae, and we appreciate you joining us today.
Thank you for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on RSV and adults. This is Dr Arnold, for the Medscape InDiscussion podcast.
Listen to additional seasons of this podcast.
Resources
Respiratory Syncytial Virus Infection
Neurologic Manifestations of Severe Respiratory Viral Contagions
Chronic Fatigue Syndrome (Myalgic Encephalomyelitis)
Excitotoxicity: Still Hammering the Ischemic Brain in 2020
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Cite this: Long-Term Outcomes of Severe RSV Infection in Adults - Medscape - Mar 05, 2024.
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