Understanding the Neurologic Manifestations of COVID-19

RELEASE DATE

January 1, 2021

EXPIRATION DATE

January 31, 2023

FACULTY

Elsen C. Jacob, PharmD, BCPS, BCGP, CPPS
Assistant Professor
Department of Clinical Health Professions
St. John’s University College of Pharmacy and Health Sciences
Queens, New York

FACULTY DISCLOSURE STATEMENTS

Dr. Jacob has no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT

acpePharmacy
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

UAN: 0430-0000-21-006-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

Exam processing and other inquiries to:
CE Customer Service: (800) 825-4696 or cecustomerservice@powerpak.com

DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL

To provide participants with an overview of the neurologic manifestations of coronavirus disease-2019 (COVID-19), including pathophysiology, clinical presentation, public-health impact, and pharmacist’s role in educating and supporting patients and communities.

OBJECTIVES

After completing this activity, the participant should be able to:

  1. Describe severe acute respiratory syndrome coronavirus 2 and COVID-19.
  2. Identify the neurologic sequelae of COVID-19.
  3. Summarize the pathophysiology and clinical manifestations of the neurologic sequelae of COVID-19.
  4. Examine the public-health implications of, and pharmacists’ role in addressing, COVID-19.

ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus that causes coronavirus disease 2019 (COVID-19), has impacted many people worldwide. SARS-CoV-2 primarily affects the respiratory system and has the potential to result in serious illness and death. However, it is now recognized that COVID-19 infection can manifest beyond the respiratory tract. In fact, the neurologic, cardiovascular, renal, hematologic, dermatologic, and gastrointestinal systems may be affected. Neurologic sequelae are wide-ranging and may include loss of taste, loss of smell, acute cerebrovascular disease, seizures, encephalopathy, encephalitis, and Guillain-Barré syndrome. In order to adequately care for patients, it is important for pharmacists to have a good understanding of these neurologic complications.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, was first identified in a patient in Wuhan, China, in December 2019.1 SARS-CoV-2 is the newest of seven coronaviruses that have demonstrated the ability to infect humans, hence the term human coronavirus (HCoV).2,3 First discovered in the 1960s, HCoVs are named for their surface spikes, which resemble crowns. These RNA viruses are positive-sense, single-stranded, enveloped, and large.3,4

The seven human HCoVs that infect humans produce vary in their symptom severity. HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1 typically result in the common cold and mild infections, mainly in immunocompromised individuals; Middle East respiratory syndrome–related coronavirus, SARS-CoV, and SARS-CoV-2 are more likely to cause severe disease, including respiratory failure and death.2,3,5,6 Coronavirus disease 2019 (COVID19) is caused by SARS-CoV-2.2 Since the time that the first cases were reported, the world has witnessed an alarmingly rapid growth in the number of COVID-19 cases, prompting the World Health Organization to declare COVID-19 a pandemic on March 11, 2020.7 A steep global increase in the number of cases of COVID-19 has continued since then, with no clear signs of abating.8 As of December 28, 2020, it was calculated that 80,908,162 million persons worldwide had been infected with SARS-CoV-2 and 1,767,187 persons had lost their lives to COVID-19; in the United States, 19,145,982 individuals had been infected with COVID-19 and 333,239 had succumbed to the disease.9 The health and economic impacts of COVID-19 are wide-ranging and presumably will last for decades to come.

Scientists and clinicians around the world are working to characterize the transmission and pathophysiology of SARS-CoV-2 and the management of COVID-19.10 It is now understood that the virus is transmitted through respiratory droplets, aerosols, and surfaces.6,11 When an individual is exposed to the virus, the virus infects the host’s airway cells by binding to the cell membrane, resulting in viral replication and disease progression.6 In the early stages of the disease, the virus can infect bronchial epithelial cells, endothelial cells, and pneumocytes, causing an inflammatory response.5,6 In later stages, the inflammatory response is magnified, leading to numerous downstream effects.6

Patient response to SARS-CoV-2 is variable. In symptomatic cases, it typically takes an average of 5 days to develop symptoms, with most patients experiencing them by 12 days post exposure.5,6 Symptomatic patients can present with an array of COVID-19 symptoms ranging from mild to severe.6

A fraction of patients remain asymptomatic following infection.6 Early studies reported that more than 40% of patients with confirmed SARS-CoV-2 infection were asymptomatic from the time of testing through follow-up.12 A recent meta-analysis, however, revealed that 17% of cases remain asymptomatic.13 This meta-analysis also found that asymptomatic patients could still transmit the virus, although they had a 42% reduced relative risk of transmission compared with symptomatic patients.13 Presymptomatic transmission, defined as transmission of SARS-CoV-2 to a secondary patient from a source patient who has not yet developed symptoms, has also been identified.14

Mild and moderate COVID-19 symptoms include fever, cough, fatigue, anorexia, nausea, diarrhea, myalgias, loss of smell (anosmia), and loss of taste (ageusia).5,6 Symptoms of severe illness include acute respiratory distress syndrome, lymphopenia, multiorgan failure, cardiac arrhythmias, shock, rhabdomyolysis, and coagulopathy.15 A substantial number of patients may also experience neurologic manifestations of COVID-19.16 Given the scope of these neurologic sequelae and their potential long-lasting effects, this article seeks to elucidate neurologic complications in patients with COVID-19.

Overview of Neurologic Manifestations

A significant number of patients presenting with COVID-19 report neurologic sequelae; in fact, studies have revealed that more than one-third of all COVID-19 patients experience neurologic manifestations.17,18 The neurologic manifestations of the disease can be classified into central nervous system (CNS) symptoms and peripheral nervous system (PNS) symptoms.3,18 More than one-half of patients experiencing neurologic complications present with CNS symptoms, and the remaining patients present with PNS symptoms.18

CNS manifestations of COVID-19 have been reported to include encephalopathy, encephalitis, loss of consciousness, stroke, headache, dizziness, and epilepsy.3,16-22 PNS symptoms include Guillain Barré syndrome (GBS), anosmia, ageusia, and skeletal muscle damage, among others.3,16-22 Although the neurologic manifestations are not fully elucidated, these sequelae are important to understand, as they can have a lasting impact on patients.23

Pathophysiology

SARS-CoV-2 uses its spike protein (S-protein) carboxy-terminal domain to bind to angiotensin-converting enzyme 2 (ACE2), which is now understood to be the functional receptor of the virus.4,24 This interaction initiates complex conformational changes that result in cleavage of the S-protein.24 This leads to subsequent attachment of the virus to the human cell membrane, resulting in endocytosis and entry of the viral genome into the cell.24 The host cell then packages the virus and releases it, thereby advancing the infection and its spread.24 This pathway for human infection was previously noted in SARS-CoV, which is structurally similar to SARS-CoV-2, although the latter has a stronger affinity to ACE2 than to SARS-CoV.4

ACE2 is located in numerous cell types and tissues, including the lungs, small intestines, kidney cells, venous endothelial cells, and arterial smoothmuscle cells in many areas of the body, including the brain.25-27 In the brain, ACE2 receptors are particularly noted in neurons, oligodendrocytes, glial cells, arterial smooth-muscle cells, and endothelial cells.3,18,21 Researchers have discovered SARS-CoV-2 in cerebrospinal-fluid samples and pathological brain tissue.28 Based on the recognition of neurologic sequelae of COVID-19 and the proclivity of SARS-CoV-2 to invade neural tissue by binding to ACE2 located in brain tissue, SARS-CoV-2 is classified as a neurotropic virus.29 To better understand SARS-CoV-2 and its ability to invade neural tissue, scientists have proposed several mechanisms for neurologic invasion and injury in COVID-19.3,16,18,19,21,22,26,27

There are three proposed routes for direct CNS invasion and injury, as well as several suggested mechanisms for indirect neurologic injury.21 The proposed direct CNS mechanisms are 1) infection of the peripheral nerve, which may occur via entry through the olfactory epithelium by way of the olfactory nerve to the olfactory bulb, entry into the neurons in a direct manner, and retrograde transsynaptic transmission; 2) disruption of the blood-brain barrier (BBB); and 3) the Trojan horse entry method, wherein virally infected immune cells covertly pass through the BBB to the CNS.3,21 In addition, the virus can exert injury by way of inflammation, demyelination, endothelial invasion, and hypoxia.21 Regardless of the mechanism of entry and damage, the subsequent neurologic manifestations profoundly impact patients.

Olfactory and Gustatory Dysfunction

Recent loss of smell or taste, which has been reported by patients, is now recognized as a symptom of COVID-19.30,31 In fact, studies suggest that sudden changes in smell or taste may be used as a reasonable indicator of the incidence of COVID-19 spread among individuals and within communities.32 Dysfunctions of smell and taste, which are typically noted in patients with milder disease, are thought to be PNS manifestations.33 Patients may present with varying degrees of changes in olfactory dysfunction, gustatory dysfunction, or both.31,34 Although gustatory (taste) dysfunction and olfactory (smell) dysfunction do not always appear together, there is a significant association between the disorders (P <.001).34 Together, these conditions are referred to as olfactory and gustatory dysfunction (OGD).33 To better understand this phenomenon, the American Academy of Otolaryngology-Head and Neck Surgery has developed a COVID-19 anosmia reporting tool to enable healthcare workers around the world to chronicle COVID-19–related OGD.35

Olfactory dysfunction can present to varying degrees, including anosmia, hyposmia, and parosmia.36 Anosmia is considered the complete loss of smell, hyposmia is a reduced ability to smell, and parosmia is a misrepresentation of smell.36 Gustatory outcomes are also variable, with the potential for ageusia (complete loss of taste), hypogeusia (reduced ability to taste), or dysgeusia (changes in taste).35,36 Studies have revealed that anosmia is present in close to 75% of patients in the early stages of disease, with more than 25% of patients reporting it as the first symptom experienced.33 Furthermore, a meta-analysis noted a prevalence in olfactory dysfunction of 3.2% to 98.3%, with a pooled prevalence of 41%.33 Gustatory dysfunction was found to have a prevalence of 5.6% to 62.7%, with a pooled prevalence of 38.2%.33

Scientists have attempted to elucidate the mechanism of OGD. Unlike other viruses linked to olfactory dysfunction, SARS-CoV-2 does not lead to inflammation of the nasal mucosa, which results in rhinorrhea and olfactory dysfunction.34 Proposed mechanisms include viral entry through the nasal epithelium cells by binding to ACE2 receptor; passage along the olfactory nerve; and arrival at the olfactory bulb located in the CNS, followed by inflammation and damage of the olfactory receptor neuron.3,37,38 In fact, the virus’ primary route of transmission is via the nasal passages, with the olfactory nerve providing easy access to the CNS.28 Gustatory dysfunction is also thought to be related to olfactory dysfunction (i.e., impaired ability to perceive flavor; also known as impaired retronasal olfaction) rather than impaired gustation (i.e., impaired ability to distinguish sweet, salty, sour, and bitter tastes).38 Therefore, both the gustatory impairment and olfactory impairment noted in patients with COVID-19 are likely chemosensory in nature and closely interconnected.38

There are no approved treatments for OGD, and treatment may not be necessary given that spontaneous recovery is typically expected.38,39 For olfactory dysfunction that remains beyond 2 weeks, nonpharmacologic and therapeutic modalities may be reasonable.38 A nonpharmacologic strategy is olfactory training, wherein patients sniff odorants such as rose, cloves, lemon, and eucalyptus for 20 seconds twice daily for 3 months or longer.38 Therapeutic modalities, although lacking in data and nonstandardized, may include oral and intranasal corticosteroids, nasal saline irrigation, intranasal sodium citrate, intranasal vitamin A, omega-3, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and mucolytics.34,38 Some clinicians may also use vitamins, decongestants, L-carnitine, and trace elements in treatment.34 The time to symptom resolution is variable, with most patients experiencing relief in approximately 8 days.40

Guillain-Barré Syndrome

Clinicians have reported a possible association between GBS—a rare, acute, and severe paralytic polyneuropathy—and SARS-CoV-2 infection.41-44 The incidence of GBS is historically noted to be 1.11 per 100,000 patients.42 However, recent literature reveals a 5.41 times increase in reports of GBS following COVID-19.42 Given that GBS generally develops following an infection or other condition that leads to an autoimmune response, it is not a surprising finding in SARS-CoV-2 infection.44

Once identified, GBS has a rapid disease progression.44 GBS is now understood to be a spectrum of diseases with the primary phenotypic subtypes noted as 1) acute inflammatory demyelinating polyneuropathy (AIDP), wherein immunologic attack and injury occur on the myelin sheath, and 2) acute motor axonal neuropathy, wherein the target for immunologic attack and injury is on the nerve axon.44 Scientists have postulated that a potential mechanism for GBS in SARS-CoV-2 is a cross-reaction between epitopes of the SARS-CoV-2 S-protein and gangliosides of peripheral nerves.42 Most known patients with GBS in SARS-CoV-2 have presented with the AIDP phenotype of GBS.41

Studies have reported that, in SARS-CoV-2, patients usually presented with GBS an average of 11.5 days following onset of COVID-19, were more likely be male (64.3%), and had a median age of 57.5 years.41 Findings in patients with GBS included symmetric limb weakness, hyporeflexia, sensory disturbances, and facial palsy.41 These are similar to the symptoms typically seen in AIDP, including sensory symptoms involving cranial nerves and ascending flaccid limb paralysis that is symmetrical with areflexia.45 GBS is life-threatening, with reported pre–SARS-CoV-2 mortality rates of up to 7%.44 Most patients who survive GBS may have continued deficits, including fatigue, pain, dysphagia, paraplegia, and tetraplegia, among others.43,44

Treatment for GBS includes IV immunoglobulin (IVIG) for 5 days or plasma exchange.44 For worsening disease, clinicians may consider repeating treatment with IVIG or corticosteroids.44 Patients with worsening disease may require mechanical ventilation.43,44 In addition, because most patients may experience deficits for months or years following illness, physical therapy and psychosocial support are warranted.44

Recent loss of smell or taste, which has been reported by patients, is now recognized as a symptom of COVID-19. In fact, studies suggest that sudden changes in smell or taste may be used as a reasonable indicator of the incidence of COVID19 spread among individuals and within communities.

Acute Cerebrovascular Disease

Patients with COVID-19 have been noted to have an elevated risk of acute cerebrovascular disease or stroke.3 Studies have found that 5% of hospitalized patients had an acute stroke, with 80% of strokes reported to be ischemic.3,46 In patients presenting with strokes, risk factors included diabetes, hypertension, and older age.19 In postulating the pathophysiology of stroke in COVID-19, researchers have suggested that COVID-19, like other viral infections, may lead to cytokine storms wherein interleukin-6, monocytes, interferons, and other proteins can lead to neuroinflammation, encephalopathy, and stroke.18 Furthermore, patients with COVID-19 are noted to be in a hypercoagulable state, with elevated C-reactive protein and d-dimer levels.3,46

Management of acute ischemic stroke involves understanding the patient’s renal, hepatic, and other organ function, as well as obtaining a coagulation profile including prothrombin time/international normalized ratio, activated partial thromboplastin time, and platelet count. As in the pre–COVID-19 era, patients typically undergo a computed tomography (CT) scan and CT angiography with or without CT perfusion. Mechanical thrombectomy is recommended as per the guidelines for patients with acute ischemic stroke who present within 6 hours of symptoms and with occlusion of the proximal middle cerebral artery or internal carotid artery. In patients who present between 6 and 24 hours, imaging and identification of salvageable tissue should be performed, and mechanical thrombectomy may be recommended in selected patients.46

Encephalopathy and Encephalitis

Patients with COVID-19 may present with impaired consciousness.3 In one study, more than one-third of hospitalized patients experienced this condition.3 These patients may develop encephalopathy or encephalitis, two neurologic conditions that have been observed in COVID-19.46

Encephalopathy involves an alteration in mental status, including agitation, disorientation, somnolence, and confusion.23 It is thought to be a secondary effect of severe disease wherein patients experience hypoxia, cytokine storm, and coagulopathy.28 There are reports of patients experiencing hypoxic brain injury as a consequence of respiratory failure, followed by hypoxic encephalopathy.25 The severity and extent of the disease can vary, and patients may become delirious, obtunded, or comatose.20 In addition to hypoxic encephalopathy, patients may also present with acute necrotizing encephalopathy, a rare condition characterized by brain damage, including hemorrhage.37 Acute necrotizing encephalopathy is thought to be related to the cytokine storm seen in COVID-19 that can cause an alteration in the BBB, resulting in neuroinflammation and encephalopathy.18 Currently, there is no specific guidance for the management of encephalopathy in COVID-19.

Encephalitis is an inflammatory process in which inflammatory lesions develop in the brain tissue, including nerve tissue.18 This process can lead to neuronal damage.18 Unlike encephalopathy, encephalitis is a direct result of SARS-CoV-2.23 Patients can present with loss of consciousness, seizures, facial weakness, ataxia, and diplopia, among other symptoms.18 There is no specific guidance for the management of encephalitis related to COVID-19.

Patients with COVID-19 may present with impaired consciousness. In one study, more than one-third of hospitalized patients experienced this condition. These patients may develop encephalopathy or encephalitis, two neurologic conditions that have been observed in COVID-19.

Headache

Many patients with COVID-19 have reported headache to be one of the first symptoms experienced.20,28 One of most common findings in COVID-19, headache occurred in an average of about 20% of patients in a systematic review but has been reported to be as high as 71%.20,47 More females than males have reported headaches related to COVID-19.47

In studies, patients have described COVID-19– related headaches as moderate-to-severe pain that is throbbing, incapacitating, and associated with photophobia or phonophobia.47 Patients also commonly complain of gastrointestinal symptoms in conjunction with the headache.47 Most patients describe the onset as rapid, with the headache lasting approximately 3 days.47

The mechanism of these headaches, while not fully elucidated, is thought to be related to the neuroinvasion of SARS-CoV-2.47 Scientists have suggested that the virus may invade the trigeminal nerve endings in the nasopharyngeal cavity, resulting in trigeminovascular-system activation.47 The management of headache in COVID-19 is not clearly defined. Clinicians may consider brain imaging if there is concern for secondary causes of headaches, including malignancy, encephalitis, or meningitis.48 Currently, therapeutic modalities are not clearly defined in the literature, although limited data suggest that patients could be appropriately managed with acetaminophen or NSAIDs.47

Other Conditions

In addition to the conditions previously described, patients may also present with several other neurologic conditions, including seizure, myalgia, dysphagia, and dizziness.18,20,28

Post–COVID-19 Syndrome

Following acute COVID-19 illness, patients may experience lingering symptoms, referred to by clinicians as postviral syndrome.49 These symptoms may last for months beyond the onset of infection.49 The illness can be long-lasting, with a mean of 110.9 days noted in one study.50 In fact, to acknowledge the disproportionate length of time beyond acute illness that symptoms may last, patient-advocacy groups refer to patients with post–COVID-19 syndrome as “long haulers.”49

Studies found that patients facing this syndrome were primarily women (75% of patients presenting with postviral syndrome were female), aged approximately 40 years, and without significant medical history.51 Patients with this condition typically experienced mild symptoms of COVID-19, including anosmia and ageusia.51 Patients also experienced fatigue (seen in more than one-half of patients), memory loss (more than one-third of patients), concentration problems (more than one-fourth of patients), and sleep disorders (more than one-third of patients).50 Advocacy groups have described symptoms as a “brain fog” with fatigue in which a previously healthy person is unable to perform daily activities in the same way that he or she could prior to the illness.49

Scientists believe that the postviral syndrome is likely related to dysautonomia, a neurologic condition that is thought to be due to endothelial injury and microangiopathy.51 In fact, brain biopsies of patients with severe COVID-19 support these findings.51 It has also been speculated that this condition may be related to immune triggers, as is the case with GBS.

It has been suggested that post–COVID-19 syndrome may, in fact, be myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS).49 ME/CFS is a complex and debilitating illness characterized by extreme fatigue, postexertional malaise, sleep disorders, trouble concentrating, dizziness, and pain.52 It primarily affects individuals aged 40 to 60 years, and women have a higher incidence.52 ME/CFS carries a significant burden of disease, as it is estimated to affect approximately 2.5 million people, although only 10% of COVID-19 patients have been diagnosed with the condition.52 The healthcare cost of ME/CFS is approximately $24 billion.52 It is important to recognize that scientists have not yet identified the cause of ME/CFS.52 Also, at present there is no targeted therapy for this condition, but nonpharmacologic strategies such as activity management, sleep hygiene, counseling, acupuncture, balanced diet, and meditation may be beneficial.53

Public-Health Implications

The COVID-19 pandemic has had devastating consequences for millions of individuals and communities worldwide. Unfortunately, public-health efforts have not been adequately implemented and therefore have not been successful in protecting all residents of the U.S. The more effective public-health strategies involve educating the public about COVID-19 in order to prevent SARS-CoV-2 infection and the potential long-term consequences of contracting COVID-19. It is essential that the public understand that this disease is not just a respiratory illness; it could permanently affect many other systems, including the neurologic system. Pharmacologic options for neurologic complications are not yet specific or fully defined. Nonetheless, pharmacists are an important part of the solution and can play a role in filling the gap in public-health efforts across the U.S.

The Pharmacist’s Role

Throughout the pandemic, pharmacists have led the way in planning, leading, and operationalizing efforts to adequately care for patients with COVID-19.54 Pharmacists have developed and implemented policies and protocols, led antimicrobial-stewardship teams, conducted research, addressed medication shortages, and provided consultations on evidence-based care to other members of the healthcare team.

As the most accessible members of the healthcare team, as well as medication experts, pharmacists have remained patient-facing throughout the pandemic and have continued to provide communities with essential services.54 Pharmacists have educated patients on the signs and symptoms of COVID-19, have counseled them on symptom management, and have provided guidance on when to seek additional help.54 Furthermore, pharmacists have educated patients on medication therapy for COVID-19 and have amplified public-health measures by conducting COVID-19 testing and encouraging practices such as social distancing, hand-washing, and donning masks.54,55

Pharmacists have provided essential care during the COVID-19 pandemic. With a growing understanding of the prolonged effects—including the neurologic manifestations—of COVID-19, pharmacists will continue to play a key part in educating the public and healthcare colleagues. Given the FDA’s Emergency Use Authorizations for the first two COVID-19 vaccines in December 2020 (with other vaccines in development) and the U.S. government’s announcement of a partnership with community pharmacy to ensure increased access to COVID-19 vaccines, once available, pharmacists will have an even more crucial role in ensuring public health in the months ahead.56-58

Conclusion

The neurologic sequelae of COVID-19 are not well known or understood by the general public or clinicians. Although therapeutic modalities for COVID19 are not clearly defined for most neurologic manifestations of the disease, it is important for pharmacists to be familiar with these complications. In doing so, pharmacists will be able to educate the public and other healthcare professionals about the potential for long-term neurologic manifestations of COVID-19 and refer patients to specialists if further evaluation is needed. Ultimately, in addition to the essential services that they have provided during this pandemic, pharmacists are poised to play an even larger role in combating this disease through robust public-health efforts.

Pharmacists have provided essential care during the COVID-19 pandemic. With a growing understanding of the prolonged effects—including the neurologic manifestations—of COVID-19, pharmacists will continue to play a key part in educating the public and healthcare colleagues.

REFERENCES

1. World Health Organization (WHO). Pneumonia of unknown cause—China. www.who.int/csr/don/05-january-2020-pneumonia-ofunkown-cause-china/en/. Accessed October 23, 2020.

2. CDC. Human coronavirus types. www.cdc.gov/coronavirus/types. html. Accessed October 23, 2020.

3. Zubair AS, McAlpine LS, Gardin T, et al. Neuropathogenesis and neurologic manifestations of the coronaviruses in the age of coronavirus disease 2019: a review. JAMA Neurol. 2020;77(8):1018-1027.

4. Wang Q, Zhang Y, Wu L, et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell. 2020;181(4): 894-904.e9.

5. Gandhi RT, Lynch JB, del Rio C. Mild or moderate Covid-19. N Engl J Med. 2020;383(18):1757-1766.

6. Wiersinga WJ, Rhodes A, Cheng AC, et al. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;324(8):782-793.

7. WHO. WHO Director-General’s opening remarks at the media briefing on COVID-19—11 March 2020. www.who.int/director-general/ speeches/detail/who-director-general-s-opening-remarks-at-the-mediabriefing-on-covid-19---11-march-2020. Accessed October 24, 2020.

8. WHO. WHO Director-General’s opening remarks at the media briefing on COVID-19—23 October 2020. www.who.int/director-general/ speeches/detail/who-director-general-s-opening-remarks-at-the-mediabriefing-on-covid-19---23-october-2020. Accessed October 24, 2020.

9. Johns Hopkins University of Medicine. Coronavirus Resource Center. https://coronavirus.jhu.edu/. Accessed November 2, 2020.

10. WHO. Global scientific community unites to track progress on COVID-19 R&D, identifies new research priorities and critical gaps. www.who.int/news-room/feature-stories/detail/global-scientific-community-unites-to-track-progress-on-covid-19-r-d-identifies-newresearch-priorities-and-critical-gaps. Accessed October 29, 2020.

11. Zhang R, Li Y, Zhang AL, et al. Identifying airborne transmission as the dominant route for the spread of COVID-19. Proc Natl Acad Sci U S A. 2020;117(26):14857-14863.

12. Lavezzo E, Franchin E, Ciavarella C, et al. Suppression of a SARS-CoV-2 outbreak in the Italian municipality of Vo’. Nature. 2020;584(7821):425-429.

13. Byambasuren OB, Cardona M, Bell K, et al. Estimating the extent of asymptomatic COVID-19 and its potential for community transmission: systematic review and meta-analysis. Official J Assoc Med Microbiol Infect Dis Canada. 2020 Oct 9:Epub.

14. Wei WE, Li Z, Chiew CJ, et al. Presymptomatic transmission of SARS-CoV-2—Singapore, January 23–March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(14):411-415.

15. Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med. 2020;383(25):2451-2460.

16. Whittaker A, Anson M, Harky A. Neurological manifestations of COVID-19: a systematic review and current update. Acta Neurol Scand. 2020;142(1):14-22.

17. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-690.

18. Khatoon F, Prasad K, Kumar V. Neurological manifestations of COVID-19: available evidences and a new paradigm. J Neurovirol. 2020;26(5):619-630.

19. Montalvan V, Lee J, Bueso T, et al. Neurological manifestations of COVID-19 and other coronavirus infections: a systematic review. Clin Neurol Neurosurg. 2020;194:105921.

20. Nepal G, Rehrig JH, Shrestha GS, et al. Neurological manifestations of COVID-19: a systematic review. Crit Care. 2020;24(1):421.

21. Nordvig AS, Rimmer KT, Willey JZ, et al. Potential neurological manifestations of COVID-19. Neurol Clin Pract. 2020 Jun 30: Epub.

22. Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID-19. Lancet Neurol. 2020;19(9):767-783.

23. Iadecola C, Anrather J, Kamel H. Effects of COVID-19 on the nervous system. Cell. 2020;183(1):16-27.e1.

24. Shang J, Wan Y, Luo C, et al. Cell entry mechanisms of SARSCoV-2. Proc Natl Acad Sci U S A. 2020;117(21):11727-11734.

25. Khan S, Gomes J. Neuropathogenesis of SARS-CoV-2 infection. eLife. 2020;9:e59136.

26. Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID19 virus targeting the CNS: tissue distribution, host–virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. 2020;11(7):995-998.

27. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020;92(6):552-555.

28. Zhou Z, Kang H, Li S, Zhao X. Understanding the neurotropic characteristics of SARS-CoV-2: from neurological manifestations of COVID-19 to potential neurotropic mechanisms. J Neurol. 2020;267(8):2179-2184.

29. Conde Cardona G, Quintana Pájaro LD, Quintero Marzola ID, et al. Neurotropism of SARS-CoV 2: mechanisms and manifestations. J Neurol Sci. 2020;412:116824.

30. CDC. COVID-19 (coronavirus disease). Symptoms of coronavirus. www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html. Accessed October 29, 2020.

31. Xydakis MS, Dehgani-Mobaraki P, Holbrook EH, et al. Smell and taste dysfunction in patients with COVID-19. Lancet Infect Dis. 2020;20(9):1015-1016.

32. Pierron D, Pereda-Loth V, Mantel M, et al. Smell and taste changes are early indicators of the COVID-19 pandemic and political decision effectiveness. Nat Commun. 2020;11(1):5152.

33. Agyeman AA, Chin KL, Landersdorfer CB, et al. Smell and taste dysfunction in patients with COVID-19: a systematic review and meta-analysis. Mayo Clin Proc. 2020;95(8):1621-1631.

34. Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020;277(8):2251-2261.

35. American Academy of Otolaryngology-Head and Neck Surgery. COVID-19 anosmia reporting tool. www.entnet.org/content/reporting-tool-patients-anosmia-related-covid-19. Accessed November 1, 2020.

36. Mainland JD, Barlow LA, Munger SD, et al. Identifying treatments for taste and smell disorders: gaps and opportunities. Chem Senses. 2020;45(7):493-502.

37. Wenting A, Gruters A, van Os Y, et al. COVID-19 neurological manifestations and underlying mechanisms: a scoping review. Front Psychiatry. 2020;11:860.

38. Whitcroft KL, Hummel T. Olfactory dysfunction in COVID-19: diagnosis and management. JAMA. 2020;323(24):2512-2514.

39. Dell’Era V, Farri F, Garzaro G, et al. Smell and taste disorders during COVID-19 outbreak: cross-sectional study on 355 patients. Head Neck. 2020;42(7):1591-1596.

40. Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March-June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(30):993-998.

41. Uncini A, Vallat JM, Jacobs BC. Guillain-Barré syndrome in SARS-CoV-2 infection: an instant systematic review of the first six months of pandemic. J Neurol Neurosurg Psychiatry. 2020;91(10):1105-1110.

42. Diez-Porras L, Vergés E, Gil F, et al. Guillain-Barré-Strohl syndrome and COVID-19: case report and literature review. Neuromuscul Disord. 2020;30(10):859-861.

43. Carrillo-Larco RM, Altez-Fernandez C, Ravaglia S, Vizcarra JA. COVID-19 and Guillain-Barre syndrome: a systematic review of case reports. Wellcome Open Res. 2020;5:107.

44. Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré syndrome. Lancet. 2016;388(10045):717-727.

45. Scheidl E, Canseco DD, Hadji-Naumov A, Bereznai B. GuillainBarré syndrome during SARS-CoV-2 pandemic: a case report and review of recent literature. J Peripher Nerv Syst. 2020;25(2):204207.

46. Qureshi AI, Abd-Allah F, Al-Senani F, et al. Management of acute ischemic stroke in patients with COVID-19 infection: report of an international panel. Int J Stroke. 2020;15(5):540-554.

47. Toptan T, Aktan Ç, Basarı A, Bolay H. Case series of headache characteristics in COVID-19: headache can be an isolated symptom. Headache. 2020;16(8):1788-1792.

48. Tolebeyan AS, Zhang N, Cooper V, Kuruvilla DE. Headache in patients with severe acute respiratory syndrome coronavirus 2 infection: a narrative review. Headache. 2020;60(10):2131-2138.

49. Rubin R. As their numbers grow, COVID-19 “long haulers” stump experts. JAMA. 2020;324(14):1381-1383.

50. Garrigues E, Janvier P, Kherabi Y, et al. Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19. J Infect. 2020;81(6):e4-e6.

51. Davido B, Seang S, Tubiana R, de Truchis P. Post-COVID-19 chronic symptoms: a postinfectious entity? Clin Microbiol Infect. 2020;26(11):1448-1449.

52. CDC. What is ME/CFS? www.cdc.gov/me-cfs/about/index.html. Accessed November 2, 2020.

53. CDC. Treatment of ME/CFS. www.cdc.gov/me-cfs/treatment/ index.html. Accessed November 3, 2020.

54. Goff DA, Ashiru-Oredope D, Cairns KA, et al. Global contributions of pharmacists during the COVID-19 pandemic. J Am Coll Clin Pharm. 2020;10.1002/jac5.1349.

55. CDC. COVID-19. How to protect yourself & others. www.cdc. gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Accessed November 24, 2020.

56. Zimmer C, Corum J, Wee SL. Coronavirus vaccine tracker. New York Times. www.nytimes.com/interactive/2020/science/coronavirusvaccine-tracker.html. Accessed November 24, 2020.

57. HHS.gov. Trump Administration partners with chain and independent community pharmacies to increase access to future COVID19 vaccines. www.hhs.gov/about/news/2020/11/12/trump-administration-partners-chain-independent-community-pharmacies-increaseaccess-future-covid-19-vaccines.html. Accessed November 24, 2020.

58. FDA. FDA takes additional action in fight against COVID-19 by issuing Emergency Use Authorization for second COVID-19 vaccine. www.fda.gov/news-events/press-announcements/fda-takes-additionalaction-fight-against-covid-19-issuing-emergency-use-authorizationsecond-covid. Accessed December 22, 2020.