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Matteo Bassetti, MD: Hello. I am Dr Matteo Bassetti. I am professor of infectious diseases at the University of Genoa and chief of the Infectious Disease Department in the San Martino University Hospital in Genoa, Italy. Welcome to Medscape's InDiscussion series on COVID-19. Today we'll discuss long COVID and identify what this means, and how to recognize and talk about this with patients and other healthcare providers. What does the future hold? We know that initial concerns about COVID-19 are the immediate risk of hospitalization and death, but it is now known that long-term damage and sequelae can result from it. Long COVID is used to describe patients with both symptomatic COVID-19 and post-COVID syndrome. The presentation can vary greatly between individuals, making diagnosis and treatment very challenging. First, let me introduce my guest, Dr Romain Sonneville. Dr Sonneville is professor of medicine in the Department of Intensive Care Medicine and Department of Infectious Diseases at the Hôpital Bichat Claude-Bernard, Université de Paris, in France. Before we begin our discussion today, what was it that sparked your interest in COVID-19, and what keeps you engaged today?
Romain Sonneville, MD, PhD: Thank you, Dr Bassetti, for the very nice introduction. First of all, we were all concerned about caring for COVID-19 patients at the very early phase of the epidemic. We saw many patients with not only respiratory disease but also with non-respiratory manifestations associated with COVID-19, which made COVID-19 a very intriguing and interesting disease to focus on and study. After the acute phase, we also saw a lot of patients who were supposed to have recovered fully from the disease. Some patients developed or had persistent respiratory symptoms, but also other symptoms that were seen not only in the first week, but in the long term, making this disease very intriguing. The other thing is we saw very atypical forms or different forms of COVID-19 in specific subgroups of patients — those patients with chronic conditions, such as immunocompromised patients. And those patients required even more attention both at the acute phase and long term. So, these reasons made me think that it was a very fascinating disease to study.
Bassetti: Thank you, Romain. Talking about typical complications, I would like to discuss the impact of neurologic complications of COVID-19. What are the typical [neurologic] complications? And regarding the long-term outcomes of these complications, what is the real impact?
Sonneville: That's a very important question. We noticed in the very early phase of the epidemic that some patients with COVID-19 developed neurologic symptoms. We now have data suggesting that approximately 10%-15% of patients develop acute neurologic symptoms. And the most frequent presentation would be presenting with inattention, delirium, or a more severe alteration of consciousness leading to coma and care in the ICU. So, based on systematic reviews and meta-analyses, we know that this presentation occurs in about 10% to 15% of cases. We also know that COVID is a neurotropic virus. COVID can reach the brain and is associated with specific neurologic syndromes in the form of stroke or acute neuroinflammatory disorders, such as meningitis or encephalitis. Less frequently, peripheral nerve involvement, such as muscle weakness or Guillain-Barre syndrome, occurs. These are the typical neurologic presentations you could face when caring for a patient with acute COVID-19 infection.
Bassetti: Do you find any specific risk factors for long COVID? Do you find any pre-COVID risk factors that are associated with a higher risk of long COVID?
Sonneville: This is a very important question, trying to identify what type of patients would develop long COVID after a definite COVID-19 infection. What we know from neurologic complications is that patients with chronic neurologic disorders are at a higher risk of worsening their neurologic condition after a COVID-19 infection. So any patients with pre-existing cognitive impairment or chronic neurologic disorders, such as Parkinson's disease, are at higher risk of worsening their neurologic condition after COVID-19. We also know that patients presenting without neurologic comorbidities but presenting with acute neurologic presentation have a higher risk of persistent disability in the long term, let's say 3 months or 6 months after a COVID-19 infection. That would represent two very different risk factors for the risk of long-term symptoms.
Bassetti: Romain, you already discussed the fact that SARS-CoV-2 is a neurotropic virus. What is the direct relationship between neurologic complications and long COVID?
Sonneville: This is also a very important point, trying to understand whether COVID-19 can induce persistent symptoms in the long term due to its presence in the central nervous system (CNS). We know that this virus is a so-called neurotropic virus, and we had evidence in the very first studies that neuro invasion could occur transsynaptically, and the virus can reach the basal forebrain through the transcribial route. That's the first hypothesis. The other hypothesis is, of course, blood-brain barrier disruption during severe systemic illness. Severe COVID-19 with acute systemic inflammation can be associated with endothelial dysfunction in the form of inflammation, thrombosis, and secondary brain injury. So, those would be the two mechanisms involved in the pathogenesis of neurologic complications at the acute phase and potential consequences in the long term.
Bassetti: You already discussed at the beginning of our podcast the clinical presentations. Do you want to go back to the common clinical presentations, looking not only at the neurologic effects but also at some of the cardiac effects that have been described? Also, what are the social effects of long COVID?
Sonneville: It is now well known that COVID-19 is associated with persistent symptoms in the long term. The most frequent symptoms observed in follow-up cohorts include respiratory symptoms, such as persistent dyspnea, and exertional symptoms in the form of fatigue after exercise or weakness that have very serious consequences in the everyday life of patients who recover from severe COVID-19 requiring hospitalization. In terms of prevalence, these respiratory and cardiac symptoms may be more prevalent than other neurologic symptoms. What we also observed is that some symptoms are difficult to define, such as patients complaining of brain fog or fatigue. These symptoms are really non-specific but are very frequently associated with long COVID.
Bassetti: It is important to know as a clinician that long COVID is managed not only by experts but also by general practitioners (GPs) or non-expert doctors. Do you have anything to suggest about how to do the diagnosis? What do you suggest for the patients who reach doctors with a diagnosis of long COVID or maybe they heard about long COVID from the internet? Do you have any suggestions for colleagues on how to approach long COVID?
Sonneville: First, if you suspect long COVID, I think this diagnosis should be an exclusion diagnosis. Therefore, for a patient complaining of dyspnea, chest pain, and fatigue after COVID-19, you should first rule out common respiratory or cardiac illnesses that are non-COVID specific.
And it's the same for brain symptoms. For instance, cognitive complaints and physical complaints should trigger you to rule out common neurologic problems depending on the age and comorbidities of the patient. You should maybe perform brain imaging or refer the patient to the neurology department for more extensive investigations if you suspect vascular disease or neuroinflammatory disease, for instance. So, the very first step would be to not associate COVID-19 with any symptoms following documented COVID-19 infection.
Bassetti: I have a question regarding epidemiology. I know that there are data from vaccinated people that reveal differences between the Omicron variant and Delta infections. Is it true that there is a big difference in vaccinated people and in the number of long COVID cases in the different populations — vaccinated vs not vaccinated?
Sonneville: Yes, it's true, especially in terms of severe symptoms at the acute phase of infection. We know that the severity of infection is linked to a higher risk of long COVID and prolonged symptoms after COVID-19 infection. And we know that vaccination reduces the number of symptomatic COVID-19 episodes. So, I would say that the epidemiology of vaccinated people with regards to long COVID syndrome clearly differs from the one observed in the non-vaccinated population, both in terms of prevalence and in terms of duration or severity of symptoms.
Bassetti: Regarding the long-term outcomes, what do we know? Do we have any information about the differences among patients who suffer from long COVID for weeks, others for months, and others even for years? Is there any situation or any specific mechanism that allows the patients to have a longer course of long COVID?
Sonneville: I think we don't have all the explanations, but we have some clues from the early phases of the disease where we now have long-term follow up of many months or many years now. We know that the severity of respiratory illness, if we speak in terms of long-term neurologic complications, for instance, is associated with worse cognitive function. More severe respiratory illness is associated with more persistent cognitive dysfunction at 1 and 2 years after the infection as compared to less severe patients. And the other thing is, of course, the weight of comorbidities in terms of symptoms and ability to recover from severe infection. For instance, we know that older patients and patients with multiple comorbidities have a higher risk of worse cognitive outcomes at 1 and 2 years. We now have clear data from the Chinese cohorts supporting this. We also have data suggesting the same association with respect not only to cognitive outcomes but also to functional outcomes, disability, and the ability to regain functional independence in the long term.
Bassetti: Do you have any data about potential treatment options for patients affected by long COVID? As you know, there are several completed and ongoing trials. Could you give us an overview about the treatment options for long COVID?
Sonneville: It is a very tricky question because we know that we don't have any specific treatment — not only for less severe forms of COVID-19 but also for long COVID — apart from supportive care. What we observed at our follow-up clinic focusing on the most severe patients requiring attention, either in the hospital and requiring oxygen or requiring hospitalization in the ICU, was that the most frequent complaints were physical complaints. Patients had weakness or muscle fatigue, those were the most prevalent complaints, and they were far more frequent than cognitive complaints or respiratory symptoms, for instance. This is just our personal experience, but it suggests that we had more problems in patients regaining functional independence than problems associated with cognition, sleep, or psychological problems in general. So, I would say that one of the important ways to treat patients with long COVID is to make sure they don't have physical residual problems. If they do, adequately prescribe occupational or physiotherapy adapted to the patient's status rather than looking for drugs or pharmacologic treatments that have not proven beneficial in this long-term setting.
Bassetti: You are an expert not only in intensive care medicine but also in infectious diseases. Do you think there is any similarity to other viral-onset illnesses, such as myalgic encephalomyelitis (chronic fatigue syndrome) or postural orthostatic tachycardia? Even in the past, we have had a lot of cases of viral-induced post infection. Are there any similarities of COVID to other types of viral infections?
Sonneville: We saw very similar symptoms following COVID-19 to the ones observed after other viral illnesses, such as influenza or other common lower respiratory tract infections. But what we observed is that the risk for developing post-infection symptoms, such as weakness, cognitive impairments, sleep disturbances, and dyspnea, is much higher in post-COVID-19 situations as compared to influenza infection or common respiratory tract infections, for instance. In terms of risk and prevalence, we know that COVID-19 is associated with a much higher risk of symptoms. And this also includes the cardiac symptoms you mentioned, such as autonomic dysfunction or orthostatic hypertension. Why is this so? I think nobody really knows, but it's very intriguing and important to notice that the risk is higher in COVID-19 patients as compared to less severe viral infections.
Bassetti: Thank you very much, Romain. I would like to close this episode by asking you what advice you would share with clinicians treating long COVID, specifically.
Sonneville: My advice would be to pay attention to any symptoms, because we know that COVID-19 can be associated with symptoms of basically any organ of the body. So, if you have one symptom, make sure you don't have other symptoms from other systems, such as the cardiac system or the respiratory system, that may be less symptomatic. And again, rule out the differential diagnosis, and remember that COVID-19 in the long term should be an exclusion diagnosis in this setting. We are caring for an aging population with multiple comorbidities for some patients, and we cannot attribute everything to COVID.
Bassetti: Today we have talked with Dr Romain Sonneville about the pathophysiology and presentation of neurologic complications of COVID-19 and how these complications may impact long-term outcomes. Let me conclude by saying that people with long COVID can have a wide range of symptoms that can last weeks, months, or even years after infection. Sometimes, the symptoms can go away; and sometimes, they come back again. For some people, long COVID can sometimes result in a very long disability. I think it's very important for the management of patients with long COVID to include a multidisciplinary approach with different experts. Thank you for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on COVID-19. This is Dr Matteo Bassetti for InDiscussion.
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Cite this: Identifying and Managing Patients With Long COVID - Medscape - Sep 20, 2023.