Neurologic Manifestations Associations of COVID-19

High-quality epidemiologic data is still urgently needed to better understand neurologic effects of COVID-19.

Authors: Shraddha Mainali, MD; and Marin Darsie, MD VIEW/PRINT PDF

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to prevail as a deadly pandemic and unparalleled global crisis. More than 74 million people have been infected globally, and over 1.6 million have died as of mid-December 2020. The virus transmits mainly through close contacts and respiratory droplets.1 Although the mean incubation period is 3 to 9 days (range, 0-24 days), transmission may occur prior to symptom onset, and about 18% of cases remain asymptomatic.2 The highest rates of coronavirus disease 2019 (COVID-19) in the US have been reported in adults age 18 to 29 and 50 to 64 years, representing 23.8% and 20.5% of cases, respectively.3 Although adults age 65 and older make up only 14.6% of total cases in the US, they account for the vast majority of deaths (79.9%).3 Similarly, men appear to be more vulnerable to the disease, accounting for 69% of intensive care unit (ICU) admissions and 58% of deaths despite nearly equal disease prevalence between men and women.4 In terms of ethnicity, Black Americans account for 15.6% of COVID-19 infections and 19.7% of related deaths, whereas Hispanic/Latinx Americans account for 26.3% of COVID-19 infections and 15.7% of COVID-19 deaths, despite these groups comprising 13.4% and 16.7% of the US population, respectively.3,5

The most commonly reported symptoms are fever, dry cough, fatigue, dyspnea, and anorexia.2 Numerous studies have also reported a spectrum of neurologic dysfunctions, including mild symptoms (eg, headache, anosmia, and dysgeusia) to severe complications (eg, stroke and encephalitis). Despite the prolific reports of neurologic associations and complications of COVID-19 in the face of a raging pandemic with limited resources, there is a significant lack of control for important confounders including the severity of systemic disease, exacerbation or recrudescence of preexisting neurologic disease, iatrogenic complications, and hospital-acquired conditions. Moreover, given the ubiquity of the virus, it is challenging to parse COVID-19–related complications from coexisting conditions. There is an urgent need for high-quality epidemiologic data reflecting COVID-19 prevalence by age, sex, race, and ethnicity on a local, state, national, and international level.

Neurologic and Neuropsychiatric Manifestations of COVID-19

Prevalence estimates of acute neurologic dysfunctions caused by COVID-19 are widely variable, with reports ranging from 3.5% to 36.4%.6 A recent study from Chicago showed that in those with COVID-19 who develop neurologic complications, 42% had neurologic complaints at disease onset, 63% had them during hospitalization, and 82% experienced them during the course of illness.7 Considering the widespread nature of the pandemic, with millions infected globally, neurologic complications of COVID-19 could lead to a significant increase in morbidity, mortality, and economic burden.

People over age 50 with comorbidities (eg, hypertension, diabetes, and cardiovascular disease) are prone to neurologic complications.2,8 Common nonspecific symptoms include headache, fatigue, malaise, myalgia, nausea, vomiting, confusion, anorexia, and dizziness. COVID-19 is known characteristically to affect taste (dysgeusia) and smell (anosmia) in the absence of coryza with variable prevalence estimates ranging from 5% to 85%.9 Since the first report on hospitalized individuals in Wuhan, China, numerous other reports have indicated a spectrum of mild-to-severe neurologic complications, including cerebrovascular events, seizures, demyelinating disease, and encephalitis.8,10-13 As a result of fragmented data from across the world with diverse neurologic manifestations and multiple potential mechanisms of injury, the classification of neurologic dysfunctions in COVID-19 is complex and varies across the literature. Here we present 2 pragmatic classification approaches based on 1) type and site of neurologic manifestations disease categories.

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Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms

Authors: Amy D. Proal1 and Michael B. VanElzakker1,2*

The novel virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of coronavirus disease 2019 (COVID-19). Across the globe, a subset of patients who sustain an acute SARS-CoV-2 infection are developing a wide range of persistent symptoms that do not resolve over the course of many months. These patients are being given the diagnosis Long COVID or Post-acute sequelae of COVID-19 (PASC). It is likely that individual patients with a PASC diagnosis have different underlying biological factors driving their symptoms, none of which are mutually exclusive. This paper details mechanisms by which RNA viruses beyond just SARS-CoV-2 have be connected to long-term health consequences. It also reviews literature on acute COVID-19 and other virus-initiated chronic syndromes such as post-Ebola syndrome or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to discuss different scenarios for PASC symptom development. Potential contributors to PASC symptoms include consequences from acute SARS-CoV-2 injury to one or multiple organs, persistent reservoirs of SARS-CoV-2 in certain tissues, re-activation of neurotrophic pathogens such as herpesviruses under conditions of COVID-19 immune dysregulation, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation issues, dysfunctional brainstem/vagus nerve signaling, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage care for specific patients with the diagnosis.


The novel virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic of coronavirus disease 2019 (COVID-19) (Hiscott et al., 2020). Classic cases of acute COVID-19 are characterized by respiratory symptoms, fever, and gastrointestinal problems (Larsen et al., 2020). However, patients can present with a wide range of other symptoms, including neurological issues suggesting central nervous system (CNS) involvement (Harapan and Yoo, 2021). Acute COVID-19 cases range in length and severity. Many patients are asymptomatic, while others require hospitalization and ventilation (Cunningham et al., 2021). Overall, an average case of COVID-19 lasts between 1 and 4 weeks. However, across the globe, a subset of patients who sustain an acute SARS CoV-2 infection are developing a wide range of persistent symptoms that do not resolve over the course of many months (Carfì et al., 2020Davis et al., 2020Huang C. et al., 2021) (Figure 1). One study of COVID-19 patients who were followed for up to 9 months after illness found that approximately 30% reported persistent symptoms (Logue et al., 2021). These patients are being given the diagnosis Long COVID, post-acute COVID-19 syndrome (PACS), or post-acute sequelae of COVID-19.

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Potential mechanisms of cerebrovascular diseases in COVID-19 patients

Authors: Manxue Lou 1Dezhi Yuan 2 3Shengtao Liao 4Linyan Tong 1Jinfang Li 5Affiliations expand


Since the outbreak of coronavirus disease 2019 (COVID-19) in 2019, it is gaining worldwide attention at the moment. Apart from respiratory manifestations, neurological dysfunction in COVID-19 patients, especially the occurrence of cerebrovascular diseases (CVD), has been intensively investigated. In this review, the effects of COVID-19 infection on CVD were summarized as follows: (I) angiotensin-converting enzyme 2 (ACE2) may be involved in the attack on vascular endothelial cells by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), leading to endothelial damage and increased subintimal inflammation, which are followed by hemorrhage or thrombosis; (II) SARS-CoV-2 could alter the expression/activity of ACE2, consequently resulting in the disruption of renin-angiotensin system which is associated with the occurrence and progression of atherosclerosis; (III) upregulation of neutrophil extracellular traps has been detected in COVID-19 patients, which is closely associated with immunothrombosis; (IV) the inflammatory cascade induced by SARS-CoV-2 often leads to hypercoagulability and promotes the formation and progress of atherosclerosis; (V) antiphospholipid antibodies are also detected in plasma of some severe cases, which aggravate the thrombosis through the formation of immune complexes; (VI) hyperglycemia in COVID-19 patients may trigger CVD by increasing oxidative stress and blood viscosity; (VII) the COVID-19 outbreak is a global emergency and causes psychological stress, which could be a potential risk factor of CVD as coagulation, and fibrinolysis may be affected. In this review, we aimed to further our understanding of CVD-associated COVID-19 infection, which could improve the therapeutic outcomes of patients. Personalized treatments should be offered to COVID-19 patients at greater risk for stroke in future clinical practice.

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The OC43 human coronavirus envelope protein is critical for infectious virus production and propagation in neuronal cells and is a determinant of neurovirulence and CNS pathology

Authors:Jenny K.Stodola1GuillaumeDubois1AlainLe CoupanecMarcDesforgesPierre J.Talbot


Coronavirus structural envelope (E) protein specific motifs involved in protein-protein interaction or in homo-oligomeric ion channel formation are needed for optimal production of recombinant infectious virus.•

Fully functional E protein of HCoV-OC43 is crucial for viral propagation in the CNS and neurovirulence.•

Fully functional E protein of HCoV-OC43 is crucial for efficient viral propagation in the central nervous system and thereby for neurovirulence.


The OC43 strain of human coronavirus (HCoV-OC43) is an ubiquitous respiratory tract pathogen possessing neurotropic capacities. Coronavirus structural envelope (E) protein possesses specific motifs involved in protein-protein interaction or in homo-oligomeric ion channel formation, which are known to play various roles including in virion morphology/assembly and in cell response to infection and/or virulence. Making use of recombinant viruses either devoid of the E protein or harboring mutations either in putative transmembrane domain or PDZ-binding motif, we demonstrated that a fully functional HCoV-OC43 E protein is first needed for optimal production of recombinant infectious viruses. Furthermore, HCoV-OC43 infection of human epithelial and neuronal cell lines, of mixed murine primary cultures from the central nervous system and of mouse central nervous system showed that the E protein is critical for efficient and optimal virus replication and propagation, and thereby for neurovirulence.

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Long-Haul COVID

 Authors: Avindra Nath

Modern medicine has faced its biggest challenge from the smallest of organisms. It is becoming increasingly apparent that many patients who recovered from the acute phase of the SARS-CoV-2 infection have persistent symptoms. This includes clouding of mentation, sleep disturbances, exercise intolerance and autonomic symptoms (table 1). Some also complain of persistent low grade fever and lymphadenopathy. Although there are no peer reviewed papers at the moment on these patients, many news articles have been written about this phenomenon1,,4 and there are Facebook groups with several thousand patients describing these symptoms. They call the illness, “Long-Haul COVID” or “Long-tail COVID.” Many of these patients are health care workers who had massive exposure to the virus early in the pandemic and describe having symptoms for “100+ days.”5

Most of these patients were in excellent health prior to getting infected with SARS-CoV-2. They all had a myriad of symptoms during the acute phase. However as the fever and respiratory symptoms improved, they are left with persistent systemic symptoms some of which are gradually improving but not all are following that course. Still others feel they had nearly recovered from the acute illness and then a few days later, developed a plethora of symptoms that are now persisting. Some describe a cyclical nature to their symptoms where they improve and then worsen every few days. While some were admitted to the hospital due to pulmonary symptoms, the majority were isolated at home. Access to testing and medical care has been limited and most appointments with physicians are being done via telemedicine which has its limitations. Some patients have had extensive testing by internists, infectious disease specialists, cardiologists and pulmonary medicine experts but nothing has been found to explain the symptoms.5 These patients, some of whom are physicians themselves are concerned that they could be stigmatized as being “functional.” Many of these symptoms overlap with those of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).6,7 However one needs to be careful not jump to the conclusion that they have ME/CFS unless other possible causes of their symptoms have been investigated (table 2).

Table 2

The cause of ME/CFS remains unknown despite decades of research on the syndrome. Many patients with ME/CFS similarly report a viral infection as a trigger but since they come to our attention often years after symptom onset, it is impossible to know what may have triggered the symptoms.8 Long-Haul COVID thus represents an excellent opportunity to study the pathophysiology of ME/CFS and in doing so may have broader implications.

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Late Complications of COVID-19; a Systematic Review of Current Evidence

Authors: SeyedAhmad SeyedAlinaghi,1Amir Masoud Afsahi,2Mehrzad MohsseniPour,1Farzane Behnezhad,3Mohammad Amin Salehi,1Alireza Barzegary,4Pegah Mirzapour,1Esmaeil Mehraeen,5,* and Omid Dadras6



COVID-19 is a new rapidly spreading epidemic. The symptoms of this disease could be diverse as the virus can affect any organ in the body of an infected person. This study aimed to investigate the available evidence for long-term complications of COVID-19.


This study was a systematic review of current evidence conducted in November 2020 to investigate probable late and long-term complications of COVID-19. We performed a systematic search, using the keywords, in online databases including PubMed, Scopus, Science Direct, Up to Date, and Web of Science, to find papers published from December 2019 to October 2020. Peer-reviewed original papers published in English, which met the eligibility criteria were included in the final report. Addressing non-human studies, unavailability of the full-text document, and duplicated results in databases, were characteristics that led to exclusion of the papers from review.


The full-texts of 65 articles have been reviewed. We identified 10 potential late complications of COVID-19. A review of studies showed that lung injuries (n=31), venous/arterial thrombosis (n=28), heart injuries (n=26), cardiac/brain stroke (n=23), and neurological injuries (n=20) are the most frequent late complications of COVID-19.

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Long covid—mechanisms, risk factors, and management

Authors: Harry Crook, research assistant1,  Sanara Raza, research assistant1,  Joseph Nowell, research assistant1,  Megan Young, clinical research officer1,  Paul Edison, clinical senior lecturer, honorary professor12


Since its emergence in Wuhan, China, covid-19 has spread and had a profound effect on the lives and health of people around the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 million deaths. Recent evidence has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-2 infection, and this condition is now coined long covid by recognized research institutes. Studies have shown that long covid can affect the whole spectrum of people with covid-19, from those with very mild acute disease to the most severe forms. Like acute covid-19, long covid can involve multiple organs and can affect many systems including, but not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive impairment, sleep disturbances, symptoms of post-traumatic stress disorder, muscle pain, concentration problems, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.


Coronavirus disease 2019 (covid-19) has spread across the world. As of 4 July 2021, more than 183 million confirmed cases of covid-19 have been recorded worldwide, and more than 3.97 million deaths have been reported by the World Health Organization .1 The clinical spectrum of covid-19 ranges from asymptomatic infection to fatal disease.23 The virus responsible for causing covid-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enters cells via the angiotensin-converting enzyme 2 (ACE2) receptor.4 Once internalized, the virus undergoes replication and maturation, provoking an inflammatory response that involves the activation and infiltration of immune cells by various cytokines in some patients.5 The ACE2 receptor is present in numerous cell types throughout the human body, including in the oral and nasal mucosa, lungs, heart, gastrointestinal tract, liver, kidneys, spleen, brain, and arterial and venous endothelial cells, highlighting how SARS-CoV-2 can cause damage to multiple organs.67

The impact of covid-19 thus far has been unparalleled, and long term symptoms could have a further devastating effect.8 Recent evidence shows that a range of symptoms can remain after the clearance of the acute infection in many people who have had covid-19, and this condition is known as long covid. The National Institute for Health and Care Excellence (NICE) defines long covid as the symptoms that continue or develop after acute covid-19 infection and which cannot be explained by an alternative diagnosis. This term includes ongoing symptomatic covid-19, from four to 12 weeks post-infection, and post-covid-19 syndrome, beyond 12 weeks post-infection.9 Conversely, The National Institutes of Health (NIH) uses the US Centers for Disease Control and Prevention (CDC) definition of long covid, which describes the condition as sequelae that extend beyond four weeks after initial infection.10 People with long covid exhibit involvement and impairment in the structure and function of multiple organs.11121314 Numerous symptoms of long covid have been reported and attributed to various organs, an overview of which can be seen in fig 1. Long term symptoms following covid-19 have been observed across the spectrum of disease severity. This review examines the long term impact of symptoms reported following covid-19 infection and discusses the current epidemiological understanding of long covid, the risk factors that may predispose a person to develop the condition, and the treatment and management guidelines aimed at treating it.

Multi-organ complications of covid-19 and long covid. The SARS-CoV-2 virus gains entry into the cells of multiple organs via the ACE2 receptor. Once these cells have been invaded, the virus can cause a multitude of damage ultimately leading to numerous persistent symptoms, some of which are outlined here.

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Inflammatory brain injury higher in men with acute COVID-19, finds study

Authors: By Dr. Liji Thomas, MD

The coronavirus disease 2019 (COVID-19) pandemic has been associated with both short- and long-term neurologic complications, including stroke, brain fog and persistent tiredness.

A new study concludes that the effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the central nervous system are due to the endothelial injury and inflammation that this produces in the brain.Study: Markers of brain and endothelial Injury and inflammation are acutely and sex specifically regulated in SARS-CoV-2 infection. Image Credit: Ralwell / ShutterstockStudy: Markers of brain and endothelial Injury and inflammation are acutely and sex specifically regulated in SARS-CoV-2 infection. Image Credit: Ralwell / Shutterstock

A preprint version of the study is available on the medRxiv* server, while the article undergoes peer review.

Study aims

Since the beginning of the pandemic, it has become clear that men are often more affected by COVID-19, with a higher likelihood of severe illness and a greater chance of death.

The current study focused on assessing brain injury markers (BIM) within 48 hours of hospitalization and at three months later.

BIMs are recognized as being valid indicators of injury to nerve cells and astrocytes, in human immunodeficiency virus (HIV) infection, sepsis and cardiac arrest. The current study focused on six, namely, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), S100B, ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), Syndecan-1 and microtubule-associated protein 2 (MAP 2).

The scientists also examined levels of two markers of endothelial injury (Intercellular Adhesion Molecule 1, ICAM-1 and Vascular Cell Adhesion Molecule 1, VCAM-1) and of inflammation, in the form of cytokines or chemokines.

These were measured in hospitalized patients and in controls in a single hospital in Houston, Texas, USA. None of them had chronic lung, heart, neurological or psychiatric disease, cancer, or any disabling condition.

Increased markers of endothelial and brain injury

The researchers found that within 48 hours of hospitalization, that is, during the acute phase, patients had higher markers of brain injury like MAP2 and NSE than controls. The mean levels showed an increase of 60% to 145%, depending on the individual marker, relative to the controls.

Of these markers, MAP2 is a sign of dendritic injury, and was high at both acute and chronic time points. It has previously been shown to be high after traumatic brain injury and predicts long-term outcomes.

NSE is found in nerve cells and indicates damage. S100B is found in astrocytes and is high in traumatic brain injury and in strokes. Thus, this combination of BIMs shows combined nerve cell and astrocytic injury in COVID-19, worse in men than in women.

However, all markers had returned to normal at three months from hospitalization.

Markers of endothelial injury were also higher with acute infection, with the mean levels being two and three times higher than in controls, for ICAM1 and VCAM1, respectively. These were not assessed at three months.

The endothelial marker ICAM1 is released in response to IL-1b and TNFα. The effects are increased leukocyte adhesion, which reduces the barrier’s integrity and promotes leakage from the blood vessels.

Cytokines and chemokines were also much higher, in some cases, in acute infection, but others showed a decrease. Of 38 chemokines and cytokines evaluated, seven were high, while two were low. Again, these reverted to normal levels at three months.  

TNFα is a potent inflammatory mediator. Its elevation in this context indicates that the vascular injury is probably inflammatory in origin and not due to viral injury.

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Bell’s Palsy as a Late Neurologic Manifestation of COVID-19 Infection

Authors: Ibiyemi O. OkeOlubunmi O. OladunjoyeAdeolu O. OladunjoyeAnish PaudelRyan Zimmerman


Bell’s palsy is acute peripheral facial nerve palsy; its cause is often unknown but it can be triggered by acute viral infection. Coronavirus disease 2019 (COVID-19) infection commonly presents with respiratory symptoms, but neurologic complications have been reported. A few studies have reported the occurrence of facial nerve palsy during the COVID-19 pandemic. We present a case of Bell’s palsy in a 36-year-old man with COVID-19 infection and a past medical history of nephrolithiasis. He presented to the emergency room with a day history of sudden right facial weakness and difficulty closing his right eye four weeks following a diagnosis of COVID-19 infection. Physical examination revealed right lower motor neuron facial nerve palsy (House-Brackmann grade IV). Serologic screen for Lyme disease, human immunodeficiency virus (HIV), and herpes simplex virus (HSV) 1 and 2 were negative for acute infection; however, neuroimaging with MRI confirmed Bell’s palsy. He made remarkable improvement following treatment with a course of valacyclovir and methylprednisolone. This case adds to the growing body of literature on neurological complications that should be considered when managing patients with COVID-19 infection.


Bell’s palsy is an acute peripheral lower motor neuron (LMN) facial nerve palsy leading to weakness on one side of the face without any other neurologic abnormalities on examination. The cause is often unknown; however, herpes simplex virus isoform 1 (HSV 1) and/or herpes zoster virus (HZV) reactivation is thought to be the most likely cause [1]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the novel virus that causes coronavirus disease 2019 (COVID-19). It was first identified in Wuhan, a city in Hubei province of China, in December 2019.

There are a few theories on the neuropathogenesis of COVID-19, which include the binding of coronavirus to angiotensin-converting enzyme 2 (ACE2) receptors, which are widely distributed on glial cells and neurons [2,3]. Dubé et al. postulated in their study with animal models that there is axonal transport of human coronavirus (HCoV) OC43 protein into the nervous system [4]. These two mechanisms may lead to nerve damage through direct injury, autoimmunity, and ischemia of the vasa nervorum or inflammatory demyelination [5,6].

Facial nerve palsy may be the first presentation of COVID-19 and it may occur within a few days of its diagnosis [7-13]. We present a patient with a unilateral LMN facial nerve palsy four weeks after a diagnosis of COVID-19 infection.

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Long-Term Neurologic Symptoms Emerge in COVID-19

— Hospitalized patients show deficits including cognitive impairment 6 months later

Authors: by Judy George, Senior Staff Writer, MedPage Today January 7, 2021share to facebookshare to twittershare to linkedinemail article

Long-term neurologic manifestations were seen in more than a third of patients hospitalized with SARS-CoV-2 infection, a prospective study in Italy showed.

In a group of hospitalized COVID-19 patients with no prior neurologic disease, 37.4% showed abnormalities on neurologic exam 6 months later — most commonly cognitive deficits, hyposmia, and postural tremor — according to Alessandro Padovani, MD, PhD, of the University of Brescia, and co-authors. The findings were reported in a medRxiv preprint and have not undergone peer review.

Patients also noted fatigue, memory impairment, and sleep disorders, Padovani said. “The severity of SARS-CoV-2 infection was an important predictor, together with age and premorbid condition, of long-term neurological symptoms and features in the cohort.”

The findings are important for long-term management of COVID-19 patients, he told MedPage Today. “They showed that the severity of SARS-CoV-2 infection may impact on neurological sequelae, but also that the symptoms reported do not always reflect neurological features at examination.”

The study is one of the first to look specifically for new long-term neurologic manifestations in COVID-19 patients who were hospitalized. Earlier research showed that 87% of patients hospitalized with COVID-19 reported persistence of at least one lingering symptom, notably fatigue and dyspnea, 60 days after discharge. Fatigue and dyspnea also were the most prevalent symptoms reported during infection and at 3-month follow-up in an analysis of both hospitalized and non-hospitalized COVID-19 patients.

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