Coronavirus and the Nervous System

What is SARS-CoV-2 and COVID-19?

Coronaviruses are common causes of usually mild to moderate upper respiratory tract illnesses like the common cold, with symptoms that may include runny nose, fever, sore throat, cough, or a general feeling of being ill. However, a new coronavirus called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) emerged and spread to cause the COVID-19 pandemic.

COVID-19, which means Coronavirus disease 2019, is an infectious disease that can affect people of all ages in many ways. It is most dangerous when the virus spreads from the upper respiratory tract into the lungs to cause viral pneumonia and lung damage leading to Acute Respiratory Distress Syndrome (ARDS). When severe, this impairs the body’s ability to maintain critical levels of oxygen in the blood stream—which can cause multiple body systems to fail and can be fatal.

What do we know about the effects of SARS-CoV-2 and COVID-19 on the nervous system?

Much of the research to date has focused on the acute infection and saving lives. These strategies have included preventing infection with vaccines, treating COVID-19 symptoms with medicines or antibodies, and reducing complications in infected individuals.

Research shows the many neurological symptoms of COVID-19 are likely a result of the body’s widespread immune response to infection rather than the virus directly infecting the brain or nervous system. In some people, the SARS-CoV-2 infection causes an overreactive response of the immune system which can also damage body systems. Changes in the immune system have been seen in studies of the cerebrospinal fluid, which bathes the brain, in people who have been infected by SARS-CoV-2. This includes the presence of antibodies—proteins made by the immune system to fight the virus—that may also react with the nervous system. Although still under intense investigation, there is no evidence of widespread viral infection in the brain. Scientists are still learning how the virus affects the brain and other organs in the long-term. Research is just beginning to focus on the role of autoimmune reactions and other changes that cause the set of symptoms that some people experience after their initial recovery. It is unknown if injury to the nervous system or other body organs cause lingering effects that will resolve over time, or whether COVID-19 infection sets up a more persistent or even chronic disorder.

What are the immediate (acute) effects of SARS-CoV-2 and COVID-19 on the brain?

Most people infected with SARS-CoV-2 virus will have no or mild to moderate symptoms associated with the brain or nervous system. However, most individuals hospitalized due to the virus do have symptoms related to the brain or nervous system, most commonly including muscle aches, headaches, dizziness, and altered taste and smell. Some people with COVID-19 either initially have, or develop in the hospital, a dramatic state of confusion called delirium. Although rare, COVID-19 can cause seizures or major strokes. Muscular weakness, nerve injury, and pain syndromes are common in people who require intensive care during infections. There are also very rare reports of conditions that develop after SARS-CoV-2 infection, as they sometimes do with other types of infections. These disorders of inflammation in the nervous system include Guillain-Barré syndrome (which affects nerves), transverse myelitis (which affects the spinal cord), and acute necrotizing leukoencephalopathy (which affects the brain).

Bleeding in the brain, weakened blood vessels, and blood clots in acute infection

The SARS-CoV-2 virus attaches to a specific molecule (called a receptor) on the surface of cells in the body. This molecule is concentrated in the lung cells but is also present on certain cells that line blood vessels in the body. The infection causes some arteries and veins—including those in the brain—to  become thin, weaken, and leak. Breaks in small blood vessels have caused bleeding in the brain (so-called microbleeds) in some people with COVID-19 infection. Studies in people who have died due to COVID-19 infection show leaky blood vessels in different areas of the brain that allow water and a host of other molecules as well as blood cells that are normally excluded from the brain to move from the blood stream into the brain. This leak, as well as the resulting inflammation around blood vessels, can cause multiple small areas of damage. COVID-19 also causes blood cells to clump and form clots in arteries and veins throughout the body. These blockages reduce or block the flow of blood, oxygen, and nutrients that cells need to function and can lead to a stroke or heart attack.

stroke is a sudden interruption of continuous blood flow to the brain. A stroke occurs either when a blood vessel in the brain becomes blocked or narrowed or when a blood vessel bursts and spills blood into the brain. Strokes can damage brain cells and cause permanent disability. The blood clots and vascular (relating to the veins, capillaries, and arteries in the body) damage from COVID-19 can cause strokes even in young healthy adults who do not have the common risk factors for stroke.

COVID-19 can cause blood clots in other parts of the body, too. A blood clot in or near the heart can cause a heart attack. A heart attack orInflammation in the heart, called myocarditis, can causeheart failure, and reduce the flow of blood to other parts of the body. A blood clot in the lungs can impair breathing and cause pain. Blood clots also can damage the kidneys and other organs.

Low levels of oxygen in the body (called hypoxia) can permanently damage the brain and other vital organs in the body. Some hospitalized individuals require artificial ventilation on respirators. To avoid chest movements that oppose use of the ventilator it may be necessary to temporarily “paralyze” the person and use anesthetic drugs to put the individual to sleep. Some individuals with severe hypoxia require artificial means of bringing oxygen into their blood stream, a technique called extra corporeal membrane oxygenation (ECMO). Hypoxia combined with these intensive care unit measure generally cause cognitive disorders that show slow recovery.

Diagnostic imaging of some people who have had COVID-19 show changes in the brain’s white matter that contains the long nerve fibers, or “wires,” over which information flows from one brain region to another. These changes may be due to a lack of oxygen in the brain, the inflammatory immune system response to the virus, injury to blood vessels, or leaky blood vessels. This “diffuse white matter disease” might contribute to cognitive difficulties in people with COVID-19. Diffuse white matter disease is not uncommon in individuals requiring intensive hospital care but it not clear if it also occurs in those with mild to moderate severity of COVID-19 illness.

For More Information: https://www.ninds.nih.gov/Current-Research/Coronavirus-and-NINDS/nervous-system

Clinical Outcomes for Patients With Anosmia 1 Year After COVID-19 Diagnosis

Authors: Marion Renaud, MD1Claire Thibault, MD1Floriane Le Normand, MD1et al

Introduction

Since the pandemic was declared in early 2020, COVID-19–related anosmia quickly emerged as a telltale sign of infection.1,2 However, the time course and reversibility of COVID-19–related olfactory disorders, which may persist and negatively affect patients’ lives, require further study. To clarify the clinical course and prognosis, we followed a cohort of patients with COVID-19–related anosmia for 1 year and performed repeated olfactory function evaluations for a subset of patients.Methods

This cohort study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Participants provided written informed consent. The study was approved by the ethics committee of the University Hospitals of Strasbourg.

In April 2020, we published a study1 about a cohort of patients with polymerase chain reaction–proven COVID-19 with acute smell loss (lasting >7 days). Over the course of 1 year, at 4-month intervals, patients were asked to complete a survey, and their olfactory function was assessed by psychophysical testing (the threshold and identification tests; Sniffin’ Sticks Test; Burghardt).3 Hyposmic or anosmic patients were followed until objective olfactory recovery (normal results were defined as those at or above the 10th percentile). Data analysis was performed from June 2020 to March 2021.Results

We evaluated 97 patients (67 women [69.1%]; mean [SD] age, 38.8 [11.5] years) with acute smell loss beyond 7 days. Of these patients, 51 (52.6%) underwent both subjective and objective olfactory test, and 46 (47.4%) underwent subjective assessment alone (Figure). After subjective assessment at 4 months, 23 of 51 patients (45.1%) reported full recovery of olfaction, 27 of 51 patients (52.9%) reported partial recovery, and 1 of 51 patients (2.0%) reported no recovery. On psychophysical testing, 43 of 51 patients (84.3%) were objectively normosmic, including 19 of 27 (70.0%) who self-evaluated as only partially recovered (all patients who self-reported normal return of smell were corroborated with objective testing) (Table). The remaining 8 patients (15.7%) with persistent subjective or objective loss of smell were followed up at 8 months, and an additional 6 patients became normosmic on objective testing. At 8 months, objective olfactory assessment confirmed full recovery in 49 of 51 patients (96.1%). Two patients remained hyposmic at 1 year, with persistent abnormalities (1 with abnormal olfactory threshold and 1 with parosmia causing abnormal identification). Among those who underwent subjective assessment alone, 13 of 46 patients (28.2%) reported satisfactory recovery at 4 months (7 with total and 6 with partial recovery), and the remaining 33 patients (71.7%) did so by 12 months (32 with total and 14 with partial recovery).

For More Information: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2781319

Parosmia post COVID-19: an unpleasant manifestation of long COVID syndrome

As we begin to slowly unravel the mystery hidden behind the current pandemic, novel clinical manifestations are emerging ceaselessly following SARS-CoV-2. Olfactory dysfunction, which has become one of the sought-after clinical features of COVID-19, has been associated with less severe disease manifestation.1 Yet, the previously deemed ‘fortunate’ patients with olfactory dysfunction who successfully recovered from COVID-19 are now being afflicted by another sinister condition known as parosmia, which is found to be more debilitating than loss of smell. Parosmia or distortion of smell is currently regarded as one of the long COVID-19 syndrome or chronic COVID-19 syndrome. Carfi et al found that 87.4% of patients in their study who recovered from COVID-19 had at least one persistent symptom with loss of smell among them.2 However, recent reports have discovered that a number of patients with loss of smell or anosmia regained their smell, yet surprisingly this time, the smell was distorted. The magical aroma of coffee had turned into a nightmare as coffee began to smell pungent like gasoline and favorite dishes were turning to smell more like rotten food or garbage, which inadvertently affects taste as food becomes almost unpalatable. The word parosmia is taken from the Greek words: para and osme (smell) which is defined as a distortion of smell with the presence of odorant, whereas phantosmia is a condition when there is a distortion of smell with the absence of odorant. Anosmia, on the other hand, means complete loss of smell. As of the latest report, three hypotheses exist to explain the pathophysiology of olfactory dysfunction secondary to COVID-19, which include: (1) Mechanical obstruction ensuing the inflammation around the olfactory cleft, which prevents the odorants from binding with the olfactory receptors,3 (2) infection of the ACE-2 expressing supporting cell, mainly the sustentacular cell of the olfactory epithelium4 and (3) direct invasion of olfactory neurons by SARS-CoV-2, which impedes the olfaction transmission.5

For More Information: https://pmj.bmj.com/content/postgradmedj/early/2021/03/31/postgradmedj-2021-139855.full.pdf

Age-dependent appearance of SARS-CoV-2 entry sites in mouse chemosensory systems reflects COVID-19 anosmia-ageusia symptoms

Authors: Julien Brechbühl,Ana Catarina Lopes,Dean Wood,Sofiane Bouteiller,Aurélie de Vallière,Chantal Verdumo, and Marie-Christine Broillet

Abstract

COVID-19 pandemic has given rise to a collective scientific effort to study its viral causing agent SARS-CoV-2. Research is focusing in particular on its infection mechanisms and on the associated-disease symptoms. Interestingly, this environmental pathogen directly affects the human chemosensory systems leading to anosmia and ageusia. Evidence for the presence of the cellular entry sites of the virus, the ACE2/TMPRSS2 proteins, has been reported in non-chemosensory cells in the rodent’s nose and mouth, missing a direct correlation between the symptoms reported in patients and the observed direct viral infection in human sensory cells. Here, mapping the gene and protein expression of ACE2/TMPRSS2 in the mouse olfactory and gustatory cells, we precisely identify the virus target cells to be of basal and sensory origin and reveal the age-dependent appearance of viral entry-sites. Our results propose an alternative interpretation of the human viral-induced sensory symptoms and give investigative perspectives on animal models.

Introduction

The Corona Virus Disease 2019 (COVID-19) has federated worldwide scientific efforts for understanding the viral epidemiological mechanisms of the coronavirus 2 (SARS-CoV-2) that causes this severe acute respiratory syndrome. In humans, the viral syndrome is characterized by an increased mortality rate in aged and/or comorbidity patients associated with the upper respiratory infection symptoms, such as severe respiratory distress13. In addition to its major impact, COVID-19 is associated by its direct alteration of human olfaction and gustation, in absence of substantial nasal inflammation or coryzal signs, resulting to anosmia and ageusia in up to 77% of the patients47. While these sensory symptoms are well established and intensely affect everyday behaviors8,9, the precise related mechanisms remain elusive10.

The target cells of the virus share a molecular signature: the concomitant cellular expression of the angiotensin-converting enzyme 2 (ACE2) and of its facilitating transmembrane serine protease 2 (TMPRSS2), which plays a crucial role for the interaction of viral spike proteins with the host cell1113. Paradoxically, these entry sites seem to be lacking in sensory cells1418, while a direct SARS-CoV-2 contamination has been observed both in humans and rodents19,20, requesting further investigations to explain the sensory-associated symptoms2124. Therefore, the characterization of the animal model is necessary prior to its use to understand the causality underling the viral-induced sensory symptoms.

The use of mice is indeed limited for epidemiological studies due to their absence of hands, which, with aerosols, are the foremost passages of interindividual viral transmission25, as well as their published lack of SARS-CoV-2 ACE2-spike protein affinity26,27. Nevertheless, the ease of production of genetically modified mice and their scientific availability, as well as their well-studied and specialized chemosensory systems2830, make them a valuable ally for the development of potential prophylactic and protective treatments related to these sensory symptoms.

Thus, we aimed here at characterizing the potential viral entry sites across mouse sensory systems. We found SARS-CoV-2 entry cells to be of different origins depending on the sensory systems. In summary, the virus could target cells involved in tissue regulation such as the supporting cells of the olfactory receptor neurons and the regenerative basal cells but also, specifically, the chemosensory cells of both gustatory and olfactory systems. We finally revealed that the emergence of viral entry sites in sensory and basal cells only occurs with age, which could explain both, the observed COVID-19 long-lasting effects and the age-dependent sensory-symptomatology in human.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282876/

Virology, transmission, and pathogenesis of SARS-CoV-2

Authors: Muge Cevik, clinical lecturer2,  Krutika Kuppalli, assistant professor3,  Jason Kindrachuk, assistant professor of virology4,  Malik Peiris, professor of virology5

What you need to know

  • SARS-CoV-2 is genetically similar to SARS-CoV-1, but characteristics of SARS-CoV-2—eg, structural differences in its surface proteins and viral load kinetics—may help explain its enhanced rate of transmission
  • In the respiratory tract, peak SARS-CoV-2 load is observed at the time of symptom onset or in the first week of illness, with subsequent decline thereafter, indicating the highest infectiousness potential just before or within the first five days of symptom onset
  • Reverse transcription polymerase chain reaction (RT-PCR) tests can detect viral SARS-CoV-2 RNA in the upper respiratory tract for a mean of 17 days; however, detection of viral RNA does not necessarily equate to infectiousness, and viral culture from PCR positive upper respiratory tract samples has been rarely positive beyond nine days of illness
  • Symptomatic and pre-symptomatic transmission (1-2 days before symptom onset), is likely to play a greater role in the spread of SARS-CoV-2 than asymptomatic transmission
  • A wide range of virus-neutralizing antibodies have been reported, and emerging evidence suggests that these may correlate with severity of illness but wane over time.

Since the emergence of SARS-CoV-2 in December 2019, there has been an unparalleled global effort to characterize the virus and the clinical course of disease. Coronavirus disease 2019 (covid-19), caused by SARS-CoV-2, follows a biphasic pattern of illness that likely results from the combination of an early viral response phase and an inflammatory second phase. Most clinical presentations are mild, and the typical pattern of covid-19 more resembles an influenza-like illness—which includes fever, cough, malaise, myalgia, headache, and taste and smell disturbance—rather than severe pneumonia (although emerging evidence about long term consequences is yet to be understood in detail).1 In this review, we provide a broad update on the emerging understanding of SARS-CoV-2 pathophysiology, including virology, transmission dynamics, and the immune response to the virus. Any of the mechanisms and assumptions discussed in the article and in our understanding of covid-19 may be revised as further evidence emerges.

For More Information: https://www.bmj.com/content/371/bmj.m3862