COVID-19: A Global Threat to the Nervous System

Authors: Igor J. Koralnik MD,Kenneth L. Tyler MD 07 June 2020 Annals of NeurologyVolume 88, Issue 1 p. 1-11

Abstract

In less than 6 months, the severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) has spread worldwide infecting nearly 6 million people and killing over 350,000. Initially thought to be restricted to the respiratory system, we now understand that coronavirus disease 2019 (COVID-19) also involves multiple other organs, including the central and peripheral nervous system. The number of recognized neurologic manifestations of SARS-CoV-2 infection is rapidly accumulating. These may result from a variety of mechanisms, including virus-induced hyperinflammatory and hypercoagulable states, direct virus infection of the central nervous system (CNS), and postinfectious immune mediated processes. Example of COVID-19 CNS disease include encephalopathy, encephalitis, acute disseminated encephalomyelitis, meningitis, ischemic and hemorrhagic stroke, venous sinus thrombosis, and endothelialitis. In the peripheral nervous system, COVID-19 is associated with dysfunction of smell and taste, muscle injury, the Guillain-Barre syndrome, and its variants. Due to its worldwide distribution and multifactorial pathogenic mechanisms, COVID-19 poses a global threat to the entire nervous system. Although our understanding of SARS-CoV-2 neuropathogenesis is still incomplete and our knowledge is evolving rapidly, we hope that this review will provide a useful framework and help neurologists in understanding the many neurologic facets of COVID-19. ANN NEUROL 2020;88:1–11 ANN NEUROL 2020;88:1–11

The novel coronavirus, now called severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2), is the agent of coronavirus disease 2019 (COVID-19), that was first diagnosed on December 8, 2019, in a patient in the city of Wuhan in central China. Common symptoms of COVID-19 include fevercoughfatigue, and shortness of breath. Whereas most affected individuals have no or minor symptoms, some go on to develop pneumonia, acute respiratory distress syndrome (ARDS), and succumb from multiple organ failure. On January 30, 2020, the World Health Organization (WHO) declared it a Public Health Emergency of international concern. It has been estimated that the number of infected individuals during the early epidemic doubled every 2.4 days, and the R0 value, or number of people that can be infected by a single individual, may be as high as 4.7 to 6.6.1 After spreading throughout China, the disease took hold in Europe and the United States, and in view of this alarming development and the rapid growth of cases, public health officials in many jurisdictions ordered people to shelter in place beginning with the state of California on March 19, 2020. As of May 29, 2020, there have been 5.88 million confirmed cases in 188 countries and 363,000 reported deaths, and most countries are in various phases of relaxing quarantine requirements while continuing some social distancing measures.

What are coronaviruses and what makes SARS-CoV-2 so contagious? Coronaviruses, which have a diameter of approximately 100 nm, are named after their crown-like appearance on electron microscopy. They infect many animal species and are part of the family of Coronaviridae that contain four distinct Genera. Coronaviruses are positive strand, single stranded ribonucleic acid (+ss-RNA) viruses. They have the largest genome of all RNA viruses, approximately 30 kilobases in length. The full sequence of SARS-CoV-2 was published on January 7, 2020, and revealed that it is was a β-coronavirus, similar to other human coronaviruses that are responsible for 15% of all cases of acute viral nasopharyngitis, also known as “common cold.”2 However, SARS-CoV-2 contains unique sequences, including a polybasic cleavage site in the spike protein, which is a potential determinant of increased transmissibility.3

Coronaviruses have caused deadly outbreaks in the past. The first one caused by SARS-CoV, occurred in China in 2003 and affected approximately 8,000 people, with a 10% mortality rate. The Middle-East Respiratory Syndrome (MERS) outbreak began in Saudi Arabia in 2012, and affected 2,500 individuals with a 35% mortality rate. SARS-CoV-2 has approximately 80% sequence homology with SARS-CoV, but 96% homology with a bat coronavirus and 92% with a pangolin coronavirus, suggesting it arouse in animals and then spread between species to humans. The spike protein of SARS-CoV-2 binds to its cellular receptor, the angiotensin converting enzyme 2 (ACE2), which also acts as receptor for SARS-CoV. Viral entry occurs after proteolytic cleavage of the spike protein by the transmembrane protease TMPRSS2. ACE2 is expressed abundantly in lung alveolar cells, but also in many cell types and organs in the body, including the cerebral cortex, digestive tract, kidney, gallbladder, testis, and adrenal gland.4

Experience with the neurological complications of MERS and SARS provides a framework for considering both reported and potential neurological complications with SARS-CoV-2 and COVID-19.510 In both MERS and SARS, significant neurological complications were fortunately extremely rare. Reported cases of neurological disease suggests a minimum incidence of ~1:200 cases (MERS) -1:1,000 cases (SARS). It is important to recognize, however, that the total number of confirmed cases of MERS and SARS together is only ~10,500 cases. It is likely that the sheer numeracy of COVID-19 compared to MERS and SARS, with nearly 6 million cases reported worldwide to date, will bring out a broader spectrum of neurological manifestations. In MERS and SARS neurological disease could be considered in three major categories: (1) the neurological consequences of the associated pulmonary and systemic diseases, including encephalopathy and stroke, (2) direct central nervous system (CNS) invasion by virus, including encephalitis, and (3) postinfectious and potentially immune-mediated complications, including Guillain-Barre syndrome (GBS) and its variants and acute disseminated encephalomyelitis (ADEM).

Neurological Complications of Systemic COVID-19

In a review of 214 patients hospitalized in 3 dedicated COVID-19 hospitals in Wuhan, China, 36% of patients had nerurologic.11 These were further subdivided into those thought to reflect CNS, peripheral nervous system (PNS), and skeletal muscle injury. Overall, 25% of patients had symptoms considered as evidence of CNS dysfunction, including dizziness (17%), headache (13%), impaired consciousness (7.5%), acute cerebrovascular disease (3%), ataxia (0.5%), and seizures (0.5%). Confirming this low incidence of seizures, no cases of status epilepticus or new onset seizures were reported in a large cohort of over 304 hospitalized patients with COVID-19 in Hubei Province, China,12 although there have been isolated case reports describing seizures at presentation in both adult and pediatric patients with COVID-19.1314

In the series by Mao and colleagues,11 the patients were subdivided based on the severity of their pneumonia and pulmonary impairment, and among those with “severe” disease (n = 88) the incidence of CNS symptoms was higher (31%) compared to the non-severe group (21%), although the results were not statistically significant (p = 0.09). Although all the categorized CNS symptoms occurred more frequently in patients with severe disease compared to non-severe disease, only impaired consciousness (15% in severe vs 2% in non-severe, p < 0.001) and acute cerebrovascular disease (5.7% vs 0.8%; p = 0.03) were significantly different between the two groups. Diagnostic studies were limited, but the impairment of consciousness seems most consistent with encephalopathy. Not surprisingly, when compared to those with non-severe disease, the severe cohort were older (58 ± 15 years vs 49 ± 15 years), and more likely to have comorbidities, including hypertension, diabetes, malignancy, cardiac, cerebrovascular, or kidney disease (48% vs 33%; p = 0.03). The severe group also had more evidence of systemic inflammation, including elevated C-reactive protein (CRP; median 37 mg/L) and D-dimer (median 0.9 mg/L) compared to non-severe cases, and were also more likely to have evidence of hepatic (elevated alanine and aspartate aminotransferases) and renal (elevated BUN and creatinine) dysfunction.

A second survey of 58 hospitalized patients (median age 63 years) with COVID-19 ARDS at Strasbourg University Hospital found that 69% of patients had agitation, 67% had corticospinal tract signs, and 36% had a “dysexecutive” syndrome with difficulty in concentration, attention, orientation, and following commands.15 All patients studied (11/11) had evidence of frontal hypoperfusion on arterial spin label and dynamic susceptibility-weighted perfusion magnetic resonance imaging (MRI). Only seven patients had a cerebrospinal fluid (CSF) examination, none had a pleocytosis, and none had SARS-CoV-2 RNA detected by reverse transcriptase-polymerase chain reaction (RT-PCR). One patient did have elevated immunoglobulin G (IgG) levels and “mildly” elevated total protein. CSF specific oligoclonal bands (OCBs) were not detected, but one patient had “mirror pattern” OCBs in CSF and serum.

In a study of MRI abnormalities in patients in the intensive care unit (ICU) with COVID-19, 21% (50/235) of patients developed neurological symptoms.16 In this group of neurologically symptomatic patients, only 27 had MRIs performed, and of these 44% (12/27) had new acute findings. Surprisingly, 56% (15/27) had no new MRI changes. The most common new abnormalities were multifocal areas of cortical fluid-attenuated inversion recovery (FLAIR) signal (10/12), accompanied in three patients by areas of increased FLAIR signal in the subcortical and deep white matter. One patient each had new transverse sinus thrombosis and acute middle cerebral artery infarction. Five of the 10 patients with cortical FLAIR abnormalities had a CSF examination, and none of these patients had a pleocytosis elevated IgG index, or OCBs (0/3 tested), although 4 patients had an elevated protein (mean 80 mg/dl; range = 60–110). RT-PCR for SARS-CoV-2 was negative in all 5 cases tested. In another MRI series of critically ill patients on mechanical ventilation, many were found to have confluent T2 hyperintensities and restricted diffusion in the deep and subcortical white matter, in some cases, accompanied by punctate microhemorrhages in the juxtacortical and callosal white matter that resembled findings seen in delayed post-hypoxic leukoencephalopathy.17

The mechanism of encephalopathy in COVID-19 remains to be determined. From available studies, COVID-19 encephalopathy seems to be more common in patients with more severe disease, associated comorbidities, evidence of multi-organ system dysfunction, including hypoxemia, and renal and hepatic impairment, and elevated markers of systemic inflammation. Virus is not detected in CSF by RT-PCR and pleocytosis is usually absent. Some patients may have altered perfusion detectable by MRI, others have leukoencephalopathy with or without punctate microhemorrhages. This group needs to be distinguished from patients with encephalitis (who have a pleocytosis) and postinfectious immune-mediated encephalitis (see below).

In a series of five consecutive patients with COVID-19 with delayed awakening post-mechanical ventilation for ARDS, MRI showed enhancement of the wall of basal skull arteries without enlargement of the vessel wall or stenosis. Toxic-metabolic derangements and seizures were ruled out, CSF SARS-CoV-2 RT-PCR was negative in all and they showed marked improvement in alertness 48 to 72 hours after treatment with methylprednisolone 0.5 g/days iv for 5 days. These findings suggest that an endothelialitis rather than a vasculitis was responsible for the encephalopathy.18 Direct infection of endothelial cells by SARS-CoV-2 and associated endothelial inflammation has been demonstrated histologically in postmortem specimens from a variety of organs, which did not include the brain.19

However, in an autopsy series, including examination of the brain, of 20 patients with COVID-19, six had microthrombi and acute infarctions and two focal parenchymal infiltrates of T-lymphocytes, whereas the others mainly had minimal inflammation and slight neuronal loss without acute hypoxic–ischemic changes in most cases. There was no evidence of meningoencephalitis, microglial nodules, or viral inclusions, including in the olfactory bulbs and brainstem, and no demyelination. ACE2 was expressed in lung and brain capillaries. All cases had evidence of systemic inflammation.20

A second major manifestation of systemic COVID-19 disease is acute cerebrovascular disease. In the study by Mao and colleagues,11 this was present in 6 of the 214 (3%) hospitalized cases, but 5 of the 6 events occurred in those with severe disease (incidence 6%; p = 0.03 vs non-severe disease).11 Five of the six reported events were ischemic strokes, and one was hemorrhagic. In the review of cases at Strasbourg University Hospital,15 3 of 13 (23%) had cerebral ischemic stroke. In a single center retrospective study from China of 221 patients hospitalized with COVID-19, 13 had acute strokes, including 11 ischemic, 1 hemorrhagic, and 1 venous sinus thrombosis.21 The stroke patients were older, had more comorbidities, including diabetes, hypertension, and a prior stroke, and elevated inflammatory markers, including D-dimer and CRP. Another review of six consecutive patients with COVID-19 admitted to the National Hospital in Queen Square with stroke, noted that occlusions typically involved large vessels and often occurred in multiple vascular territories.22 In 5 of 6 cases, the strokes occurred 8 to 24 days after onset of COVID-19 symptoms. All patients had a highly prothrombotic state with very high D-dimer levels and elevated ferritin. Five of the six patients had detectable lupus anticoagulant, suggesting another potential prothrombotic mechanism for stroke in COVID-19. Anticardiolipin IgA and antiphospholipid IgA and IgM antibodies directed against β2-glycoprotein-1 were also found in three patients with COVID-associated multiple territory large vessel infarctions.23 Finally, a postmortem MRI study showed subcortical micro- and macro-bleeds (two decedents), cortico-subcortical edematous changes evocative of posterior reversible encephalopathy syndrome (PRES; one decedent), and nonspecific deep white matter changes (one decedent).24

Although initial reports emphasized acute cerebrovascular disease in older patients with COVID-19, a recent report described five cases of large vessel stroke as a presenting feature of COVID-19 in younger individuals, two of whom lacked classic stroke risk factors.25 These patients ranged in age from 33 to 49 years. Two of the five patients had diabetes, one of whom had had a mild prior stroke, and one had hypertension and dyslipidemia. The infarcts involved large vessel territories, including the middle cerebral artery (3), posterior cerebral artery (1), and internal carotid artery (1). Two patients had preceding COVID-19 symptoms, including fever, chills, cough, and headache; one patient had only lethargy. Surprisingly, two of the five patients had no COVID-19-related symptoms preceding their stroke presentation. These five patients had elevated prothrombin (range = 12.8–15.2 seconds) and activated partial thromboplastin times (range = 25–42.7 seconds), elevated fibrinogen (range = 370–739 mg/dl), D-dimer (range = 52–13,800 ng/ml) and ferritin (range = 7–1,564 ng/ml) consistent with a hypercoagulable state and the presence of disseminated intravascular coagulation (DIC).

COVID-19 cerebrovascular disease seems to be predominantly ischemic and to involve large vessels. In older individuals, it reflects the underlying severity of systemic disease as well as the hyperinflammatory state, whereas in younger patients, it seems to be due to hypercoagulopathy. Children with a Kawasaki disease-like multisystem inflammatory syndrome (MIS) have recently been described.2627 Patients with Kawasaki disease can develop cerebral vasculopathy and forms of neurological involvement, and in one series of 10 COVID-19 associated cases of MIS, two patients had meningeal symptoms.27 As noted, in addition to hypercoagulable states, SARS-CoV-2 can infect and injure endothelial cells. However, it remains to be determined whether virus-induced injury to endothelial cells (a vasculopathy) or even true vasculitis contributes to COVID-19 related cerebrovascular syndromes, and this determination will require additional detailed vessel imaging and neuropathological analyses. Similarly, the number of cases is too small to determine the comparative therapeutic benefit, if any, of antiplatelet or anticoagulant drugs or immunomodulatory therapies in COVID-19 associated neurovascular syndromes.

Neuroinvasion by SARS-CoV-2

In contrast to encephalopathy, in which evidence for direct invasion by virus of the CNS is absent, encephalitis occurs when direct invasion of the CNS by virus produces tissue injury and neurological dysfunction. Evidence for direct invasion of the CNS was seen in patients with SARS. Xu and colleagues described a fatal case in a 39-year-old man with delirium that progressed to somnolence and coma.10 At postmortem, the SARS-CoV antigen was detected in brain tissue by immunohistochemistry (IHC) and viral RNA by in situ hybridization (ISH). SARS-CoV virions were seen by transmission electron microscopy of brain tissue inoculated cell culture. In a postmortem analysis of four patients with SARS, low level infection of cerebral neurons with SARS-CoV (1–24% of cells) was seen in the cerebrum in all four cases by IHC and ISH, although none of the cases had virus detected in the cerebellum.28

By definition, encephalitis is an inflammatory process, with supportive evidence, including the presence of a CSF pleocytosis and elevated protein. However, in studies of transgenic mice expressing the human SARS-CoV receptor, ACE2, infection with SARS-CoV was associated with viral entry into the CNS, spread within the CNS, and neuronal injury with relatively limited inflammation.29 This suggests the possibility that, in some cases of SARS-CoV-2 CNS invasion, that signs of inflammation could be modest or even absent. Regardless of the presence or absence of inflammation, diagnostic studies may show evidence of either a generalized or focal CNS process, including areas of attenuation on computed tomography (CT), hyperintense signal on FLAIR, or T2-weighted sequences on MRI, and focal patterns, including seizures on electroencephalogram (EEG). Definitive evidence supporting direct viral invasion would include a positive CSF RT-PCR for SARS-CoV-2, demonstration of intrathecal synthesis of SARS-CoV-2-specific antibodies, or detection of SARS-CoV-2 antigen or RNA in brain tissue obtained at biopsy or autopsy.

Cases meeting strict criteria for encephalitis resulting from direct SARS-CoV-2 are currently extremely rare, although several plausible case reports have now surfaced. Moriguchi et al described a 24-year-old man with COVID-19 disease who developed nuchal rigidity, progressively decreased consciousness (Glasgow Coma Scale [GCS] = 6), and generalized seizures.30 CSF showed a slight mononuclear predominant pleocytosis (12 cells/μl3) and elevated opening pressure (>320 mm H20). Neuroimaging showed hippocampal and mesial temporal increased FLAIR signal and the CSF RT-PCR was positive for SARS-CoV-2. Unfortunately, studies to exclude other viral etiologies of encephalitis were limited. A second case involved a 41-year-old woman with headache, fever, a new onset seizure, and photophobia and nuchal rigidity, followed by hallucinations and disorientation. A head CT scan was normal and MRI was not performed. An EEG showed generalized slowing. The CSF examination showed a lymphocytic pleocytosis (70 cells/μl; 100% lymphocytes), and elevated protein (100 mg/dl), and a positive SARS-CoV-2 RT-PCR.3132

Several cases have emerged in which patients had inflammatory features consistent with encephalitis, but who did not have evidence of direct viral CNS invasion. Bernard-Valnet et al reported on two patients with “meningoencephalitis concomitant to SARS-CoV2.”33 These patients had nuchal rigidity, altered mental status, mild CSF lymphocytic pleocytosis (17–21 cells/μl3 on initial lumbar puncture [LP]), and mildly elevated CSF protein (46–47 mg/dl). However, in both patients, the MRI was normal and neither patient had a positive CSF RT-PCR for SARS-CoV-2. Similarly, Pilotto et al describe a 60-year-old man with COVID-19 who developed confusion, irritability, and then apathy progressing to “akinetic mutism” with nuchal rigidity.34 The CSF showed a mild lymphocytic pleocytosis (18 cells/μl3) and elevated protein (70 mg/dl). An EEG showed generalized slowing with an anterior predominance. The CT and MRI were normal, and CSF RT-PCR was negative twice for SARS-CoV-2. Although treated with a wide variety of medications, this patient showed improvement coincident to administration of high dose methylprednisolone.34 Another study reported on six critically ill patients with severe ARDS, elevated inflammatory markers, and depressed consciousness and/or agitation, who were considered to have “autoimmune meningoencephalitis.”35 No patient had a CSF pleocytosis but five had elevated CSF protein (52–131 mg/dL) and three had an MRI that showed cortical hyperintensities with sulcal effacement. There were no controls but patients were felt to have responded to plasma exchange. In one report, a patient with neuropsychiatric symptoms and COVID-19 had a “hematic” CSF tap with 960 “red and white blood cells” and an elevated protein (65 mg/dL) and detectable N-methyl-D-aspartate (NMDA) receptor antibodies. This currently isolated case also raises the possibility that COVID-19 may trigger auto-antibody production.36

The available studies suggest that SARS-CoV-2 can rarely produce a true encephalitis or meningoencephalitis with associated evidence of direct viral invasion of the CNS. The failure to detect virus in CSF in the other reported cases, despite evidence of inflammation as evidenced by CSF pleocytosis and elevated protein, raises the possibility that some cases of COVID-19 encephalitis may occur in the absence of direct virus invasion, and could potentially result from immune-mediated inflammatory mechanisms (see below). It is important to realize that techniques, including detection of intrathecal SARS-CoV-2 antibody synthesis or of viral antigen or nucleic acid in brain tissue, may establish evidence for viral invasion when CSF RT-PCR studies are negative. For example, detection of intrathecal antibody synthesis is significantly more sensitive than CSF nucleic acid amplification tests for diagnosis of both West Nile Virus neuroinvasive disease and Enterovirus (EV)-D68 associated acute flaccid myelitis (AFM).3739 In the case of EV-D68-associated AFM, nasopharyngeal and throat swabs are frequently positive for virus by RT-PCR when obtained early after disease onset, yet, CSF RT-PCR tests are only positive in a small minority (<3%) of cases.40 The sensitivity of SARS-CoV-2 RT-PCR in properly performed nasopharyngeal swabs for detection of acute COVID-19 is high, but data are currently too limited to evaluate sensitivity of this technique in CSF in patients with neurological disease.

Post-Infectious and Immune-Mediated Complications of SARS-CoV-2

The identification of postinfectious complications of SARS-CoV-2 would be expected to temporally lag behind those resulting from acute infection. Occasional cases of GBS and its variants and of ADEM were reported after MERS and SARS.579 Reports are now emerging of similar associations with COVID-19 and GBS, and with GBS variants, including the Miller-Fisher syndrome.4146 The largest series to date, describes five patients.47 In this series, all patients developed GBS 5 to 10 days following COVID-19 symptom onset. The clinical presentation included bilateral multi-limb flaccid weakness with areflexia. Three patients had associated respiratory failure and two had associated facial weakness. MRI showed caudal root nerve enhancement in two cases and enhancement of the facial nerve in a third case. The CSF was normocellular in all five cases, and had an elevated protein consistent with albuminocytological dissociation in three cases. Electrophysiological studies showed reduced compound motor amplitudes and prolonged distal latencies, and the overall pattern was felt to be consistent with demyelination in two cases and axonal neuropathy in three cases. Fibrillation potentials were seen by electromyography (EMG) acutely in three patients and later in a fourth patient. None of the patients had SARS-CoV-2 detected in the CSF by RT-PCR. Antiganglioside antibodies were absent in the three tested patients. All patients received intravenous immunoglobulin (ivIG) and one plasma exchange, although improvement was noted in only two cases (one “mild improvement” only).

Cases of acute necrotizing encephalopathy (ANE) have been reported in COVID-19.4849 One patient was a 50-year-old woman with COVID-19 confirmed by nasopharyngeal RT-PCR who developed altered mental status and MRI and CT findings typical of ANE, including bilateral thalamic lesions. Unfortunately, CSF studies were limited and CSF RT-PCR testing for SARS-CoV-2 was not performed. A second case occurred in a 59-year-old woman with aplastic anemia who developed seizures and reduced consciousness 10 days after onset of her COVID-19 symptoms.49 The mechanism behind ANE remains unknown, and either direct viral or postinfectious inflammatory processes have been postulated to play a role, and many cases have been reported after upper respiratory infections, including influenza. Some patients have mutations in RAN binding protein-2 (RANBP2), indicating that host genetic factors may also play a role in susceptibility.

Rare cases of ADEM were associated with MERS.6 The first case of “COVID-19 associated disseminated encephalomyelitis” was reported in a 40-year-old woman.50 This individual had COVID-19 symptoms followed 11 days later by dysarthria, dysphagia, facial weakness, and a gaze preference. A chest X-ray showed pneumonia and nasopharyngeal RT-PCR was positive for SARS-CoV-2. Head CT showed multiple areas of patchy hypoattenuation and an MRI showed areas of increased FLAIR and T2 signal in the subcortical and deep white matter that were felt to be consistent with demyelination. Her CSF was normal. A second reported case was in a 54-year-old woman who developed seizures and neurological deterioration (GCS = 12) and had chest X-ray lesions consistent with COVID-19 and a positive nasopharyngeal RT-PCR for SARS-CoV-2.51 Her MRI showed multiple periventricular T2 hyperintense, nonenhancing, lesions in the white matter of the cerebrum, brainstem, and spinal cord consistent with multifocal demyelination. Her CSF studies were unremarkable, including a negative CSF RT-PCR for SARS CoV-2. She was treated with high dose dexamethasone and her symptoms gradually resolved. A single case of acute flaccid myelitis has also been described in COVID-19.52 This patient developed upper limb weakness and a flaccid areflexic lower limb paralysis, urinary and bowel incontinence, and a T10 sensory level. Unfortunately, neither spine imaging nor CSF studies were available so the mechanism remains unknown. The most convincing example of ADEM-like pathology associated with COVID-19 was in a 71-year-old man who developed symptoms immediately following coronary bypass graft surgery that progressed to respiratory failure and a hyperinflammatory state. A postmortem examination showed brain swelling and disseminated hemorrhagic lesions and subcortical white matter pathology with perivenular myelin injury but also necrotic blood vessels and perivascular inflammation. The lesions had features of both acute hemorrhagic leukoencephalitis and of acute disseminated encephalomyelitis.53

The rarity of postinfectious potentially immune-mediated cases following COVID-19 other than GBS and its variants, and the general paucity of details, makes their status unclear. The cases of ADEM-like illness are hard to distinguish from some of the patients with acute encephalopathy and associated MRI white matter lesions, but can be differentiated from cases of encephalitis by the absence of CSF pleocytosis. GBS is a common neurological disease even in the absence of COVID-19, and identifying the magnitude of the COVID-19 risk and association will require better epidemiological data. However, the 5 cases of GBS occurring in a population of 1,000 to 1,200 patients with COVID-19 seen over a 1 month period by Toscano et al in Northern Italy suggest an incidence that is much higher than that can be expected in the general population (~1/100,000 person-years).54 The mechanism of pathogenesis will need to be identified, and the efficacy of conventional therapies, including ivIG and plasma exchange, evaluated.

Other COVID-19 Related Neurological Disorders

One of the more striking reported symptom manifestations in patients with COVID-19 is loss or perturbation of smell (anosmia or hyposmia) and/or taste (dysgeusia). The frequency of these symptoms, their specificity as a potential diagnostic clue for COVID-19 infection as opposed to influenza or other symptomatologic similar diseases, and their implication for understanding viral pathogenesis all remain uncertain. In the Wuhan COVID-19 series, impairment of smell was noted in 5% and of taste in 6% of the 214 hospitalized patients.11 It is likely that the frequency was under-represented due to incomplete evaluations in these hospitalized sick patients. A later study of 31 patients, suggested that disorders of taste occurred in 81% of COVID-19 cases (46% anosmia, 29% hyposmia, and 6% dysosmia) and disorders of taste in 94% (ageusia 45%, hypogeusia 23%, and dysgeusia 26%).55 The average duration of smell and taste disorders in the COVID-19 cases was 7.1 ± 3.1 days. A multicenter European study of 417 cases with “mild-to-moderate” COVID-19 disease found a similarly high frequency of olfactory dysfunction (86%), with 80% of those affected having anosmia and 20% hyposmia.56 Approximately 70% of patients had recovered within 8 days of symptom onset. It has been suggested that olfactory and/or gustatory dysfunction may be indicative of neuro-invasion and provide a route from the nasopharynx or oropharynx to cardiorespiratory centers in the medulla, based on studies of transgenic mice expressing the human SARS virus receptor (ACE2) and infected with SARS-CoV, however, no evidence supporting host entry via this pathway yet exists in man.29 The transient nature of the dysfunction in most patients would seem to make direct viral infection and subsequent killing of olfactory or gustatory neurons unlikely. MRI of the olfactory bulb was normal in one RT-PCR confirmed patient with anosmia.57

In the Wuhan COVID-19 series, 11% of patients were reported to have evidence of skeletal muscle injury (defined as a creatine kinase [CK] >200 U/L and skeletal muscle pain).11 Injury was significantly more common in patients with “severe” disease (19%) compared to non-severe disease (5%; p < 0.001). Unfortunately, almost no clinical details were provided beyond the presence of associated muscle pain. Subsequently two reports have emerged of rhabdomyolysis as either a presenting feature or a late complication of COVID-19.5859 One patient had limb pain and weakness with a peak CK of ~12,000 U/L and myoglobulin >12,000 μg/L, and the other had a peak CK of 13,581 U/L. Neither patient had muscle biopsy performed. The mechanism of injury remains to be determined.

Immunopathogenesis of SARS-CoV-2 and Implication for Management and Treatment of Neurologic Manifestations

One of the most puzzling features of SARS-CoV-2 infection is that it is asymptomatic or associated with minor symptoms in approximately 80% of patients, especially children and young adults, whereas 20% will develop COVID-19 with various degrees of severity. Can knowledge gathered on SARS-CoV inform us about the immunopathogenesis of SARS-CoV-2? A successful production of type I interferon (IFN) response is a key first line defense for suppressing replication of many neurotropic viruses at the site of entry and dissemination. SARS-CoV suppresses type I IFN response and downstream signaling using multiple strategies, and this dampening is closely associated with disease severity.60

Because SARS-CoV-2 shares an overall genomic similarity of 80% with SARS-CoV and uses the same receptor, it is reasonable to expect that the innate immune mechanisms involved in pathogenesis will be similar for the two viruses. SARS-CoV has developed multiple strategies to evade the innate immune response in order to optimize its replication capacity.61 It seems likely that SARS-CoV-2 uses the same strategy. The magnitude of the immune response against SARS-CoV-2 needs to be precisely calibrated to control viral replication without triggering immunopathogenic injury. A hyperinflammatory response likely plays a major role in ARDS and, in a subset of children, may contribute to the development of a Kawasaki-like multisystem inflammatory disorder.20 In a mouse model of SARS, rapid SARS-CoV replication and delay in IFN-I signaling led to inflammatory monocyte–macrophage accumulation, resulting in elevated lung cytokine/chemokine levels and associated vascular leakage and lethal pneumonia. This “cytokine storm,” in turn, was associated with a decrease in T cell counts and suboptimal T cell responses to SARS-CoV infection.62

The same pattern is found in 522 patients with COVID-19, where the number of total T cells, CD4+ and CD8+ T cells, were dramatically reduced, especially in those requiring ICU care, and T cell numbers were negatively correlated to serum IL-6, IL-10, and TNF-α concentration. Conversely, patients in the disease resolution period showed reduced IL-6, IL-10, and TNF-α levels and restored T cell counts.63 These data were corroborated by other groups who also noticed a decrease in type 1 interferon response in severely affected patients.6465 It has been suggested that reduced and delayed IFN gamma production (“too little and too late”) in the lungs and depletion of both CD4+ and CD8+ T cells may combine to potentiate viral injury, by reducing control of viral replication and enhancing the upregulation of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-10 (“cytokine storm”), and that it may be the immune dysregulation as much or more than the direct viral infection that results in pulmonary epithelial cell injury, and similar mechanisms could be operative in the CNS.66

What are the possible mechanisms for the apparent immune dysregulation seen in those patients and could they have a role in the neuropathogenesis of COVID-19? The source of cytokines found in the serum in unclear, but they could be produced by lung macrophages. IL-6 could also come from infected neurons, as seen in a transgenic mouse model of SARS-Cov.29 A high level of circulating cytokines, in turn, could lead to lymphocytopenia. TNF-α, a pro-inflammatory cytokine, may cause T cell apoptosis via interacting with its receptor, TNFR1, which expression is increased in aged T cells.6768 IL-6, that has both pro-inflammatory and anti-inflammatory properties, contributes to host defense in response to infections. However, continual synthesis of IL-6 has been shown to play a pathological role in chronic inflammation and infection.6970 IL-10, an inhibitory cytokine that prevents T cell proliferation, can also induce T cell exhaustion. Interestingly, patients with COVID-19 have high levels of the PD-1 and Tim-3 exhaustion markers on their T cells.63 In turn, decreased numbers of CD4+ and CD8+ T lymphocytes will considerably weaken the cellular immune response to SARS-CoV-2 in severe cases, allowing further viral replication. This can be compounded by the use of corticosteroids. Of note, a study in convalescent patients with SARS-CoV showed that CD8+ T cell responses were more frequent and had a greater magnitude of response than CD4+ T cells.71 Finally, one autopsy series of patients with COVID-19 showed histological features suggestive of secondary hemophagocytic lymphohistiocytosis (sHLH), also known as macrophage activation syndrome. This syndrome is characterized by an imbalance of innate and adaptive immune responses with aberrant activation of macrophages, and a blunted adaptive immune response.20

This dysregulated immune response may have a role in the pathogenesis of the COVID-19 encephalopathy. High levels of circulating pro-inflammatory cytokines can cause a confusion and alteration of consciousness, whereas a weakened T cell response may be unable to eliminate virus-infected cells in the brain causing further neurologic dysfunction. Careful studies of the CSF cytokine profile and T cell response to SARS-CoV-2 as well as postmortem studies, including CNS and muscle tissues, are urgently needed to better understand the neuropathogenesis of COVID-19. These will help inform whether therapeutic strategies aimed at blocking pro-inflammatory cytokines, including the IL-6 inhibitors tocilizumab and sarilumab, could have a beneficial effect on encephalopathy or whether corticosteroids that dampened the adaptive cellular immune response to viruses are contra-indicated. As we strive to find medications to counter the deleterious inflammatory state triggered by SARS-CoV-2, lessons can also be learned from COVID-19 outcomes in patients with neurological diseases, such as multiple sclerosis or myasthenia gravis, treated with immunomodulatory therapies.

Although we are only starting to grasp the complexity of SARS-CoV-2 biology, it is already apparent that COVID-19 causes a global threat to the entire nervous system, both through its worldwide distribution and multifactorial pathogenic mechanisms (Fig). As we hope for a vaccine or a cure, neurologists will play an important role in diagnosing, investigating, and treating the many neurologic manifestations of COVID-19 (Table).72

Details are in the caption following the image
FIGURE 1Open in figure viewerPowerPointMechanisms of severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) neuropathogenesis. SARS-CoV-2 pathogenic effects on the nervous system are likely multifactorial, including manifestations of systemic disease, direct neuro-invasion of the central nervous system (CNS), involvement of the peripheral nervous system (PNS) and muscle, as well as through a postinfectious, immune-mediated mechanism. MOF = multi-organ failure; GBS = Guillain-Barre syndrome. *CNS inflammation (CSF pleocytosis and proteinorrachia) with no evidence of direct viral infection of CNS; §direct evidence of viral invasion (reverse transcriptase-polymerase chain reaction positive [RT-PCR+], biopsy); ADEM = acute disseminated encephalomyelitis; ANE = acute necrotizing encephalopathy. [Color figure can be viewed at www.annalsofneurology.org]

TABLE 1. Neurologic Conditions Associated with SARS-CoV-2 Infection

Disease entityPresentationSupportive Neurodiagnostic testingPathogenesis
EncephalopathyAltered mental statusMRI: non-specificEEG: abnormal (slow)CSF: nl cells and ProCSF SARS-CoV-2 RT-PCR: NEGMultiple organ failureHypoxemiaSystemic InflammationEndothelialitis
EncephalitisAltered mental status and CNS dysfunctionMRI: non-specific (? WM changes)EEG: abnormal (slow, +focal)CSF: pleocytosis & elev. ProCSF SARS-CoV-2 RT-PCR: NEGCNS inflammation
Viral encephalitisAltered mental status and CNS dysfunctionMRI: new abnormalityEEG: abnormal (slow, ±focal)CSF: Pleocytosis and elev. ProCSF SARS-CoV-2 RT-PCR: POSBrain Tissue: POS (Ag or RNA)Brain parenchymal neuro-invasion
Viral meningitisHeadache, nuchal rigidityMRI: meningeal enhancement, CSF: pleocytosis & elev. ProCSF SARS-CoV-2 RT PCR: POSSubarachnoid invasion
StrokeFocal motor or sensory deficitMRI: ischemia or bleed, abnormal coagulation factors, increased inflammatory markersCoagulopathy
Anosmia/ageusiaOlfactory or taste dysfunctionAbnormal smell/taste tests? Peripheral vs central neuro-invasion
ADEMHeadache, acute neurologic symptomsMRI: hyperintense FLAIR lesions with variable enhancementPostinfectious
Guillain-Barre syndromeFlaccid muscle weaknessCSF: increased protein, nl WBC CSF SARS-CoV-2 RT-PCR: NEGEMG/NCS: abnormalPostinfectious
Muscle injuryMyalgiaCK elevatedMyopathy or myositis?
  • ADEM = acute disseminated encephalomyelitis; CNS = central nervous system; CK= creatinine kinase; CSF = cerebrospinal fluid; EEG = electroencephalogram; EMG = electromyogram; FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging; NCS = nerve conduction study; NEG = negative; POS = positive; pro = protein; RT-PCR = reverse transcriptase-polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome-coronavirus type 2; WBC = white blood cell; WM = white matter.

New Omicron BA.4 and BA.5 Sublineages May Evade Vaccines, Natural Immunity. What Experts Say

Authors: Mint Newsletters April 29, 2022

  • The BA.4 and BA.5 sublineages appear to be more infectious than the earlier BA.2 lineage
  • The sub-lineages have been detected in seven of South Africa’s nine provinces and 20 countries worldwide

New omicron sublineages, discovered by South African scientists this month, are likely able to evade vaccines and natural immunity from prior infections, the head of gene sequencing units that produced a study on the strains said, according to Bloomberg report.

It is important to note that the BA.4 and BA.5 sublineages appear to be more infectious than the earlier BA.2 lineage, which itself was more infectious than the original omicron variant, Tulio de Oliveira, the head of the institutes, said.

Omicron sublineages  mutated to evade immunity

  • As almost all South Africans either having been vaccinated against the coronavirus or having had a prior infection the current surge in cases means that the strains are more likely to be capable of evading the body’s defenses rather than simply being more transmissible, de Oliveira said.
  • There are “mutations in the lineages that allow the virus to evade immunity,” he said in a response to queries. “We expect that it can cause reinfections and it can break through some vaccines, because that’s the only way something can grow in South Africa where we estimate that more than 90% of the population has a level of immune protection.”
  • South Africa is seen as a key harbinger of how the omicron variant and its sublineages are likely to play out in the rest of the world. South African and Botswanan scientists discovered omicron in November and South Africa was the first country to experience a major surge of infections as a result of the variant.
  • The new sublineages account for about 70% of new coronavirus cases in South Africa, de Oliveira said in a series of Twitter postings. 
  • “Our main scenario for Omicron BA.4 and BA.5 is that it increases infections but that does not translate into large hospitalizations and deaths,” he said.
  • So far, the sublineages have been detected in seven of South Africa’s nine provinces and 20 countries worldwide. 

Covid Could Be Surging in the U.S. Right Now and We Might Not Even Know It

Authors: Madison Muller – April 10, 12:12 PM Bloomberg

The rise of Covid cases in some regions of the U.S., just as testing efforts wane, has raised the specter that the next major wave of the virus may be difficult to detect. In fact, the country could be in the midst of a surge right now and we might not even know it.

Testing and viral sequencing are critical to responding quickly to new outbreaks of Covid. And yet, as the country tries to move on from the pandemic, demand for lab-based testing has declined and federal funding priorities have shifted. The change has forced some testing centers to shutter while others have hiked up prices in response to the end of government-subsidized testing programs.  People are increasingly relying on at-home rapid tests if they decide to test at all. But those results are rarely reported, giving public health officials little insight into how widespread the virus truly is. 

“There’s always more spread than we can detect,” said Abraar Karan, an infectious disease physician at Stanford University.  “That’s true even more so now than earlier in the pandemic.” 

Despite groundbreaking scientific advances like vaccines and antivirals, public health experts say the U.S.’s Covid defenses appear to be getting weaker as time goes on, not stronger.

“We’re in a worse position,” said Julia Raifman, an assistant professor of health law, policy and management at Boston University School of Public Health. “We’ve learned more about the virus and how to address it, and then we haven’t done what we need to do to address it.”

In late February, the Centers for Disease Control and Prevention began relying on hospital admissions and ICU capacity to determine community-level risk. That was a change from relying on Covid case counts and the percentage of positive tests, which are widely considered a better snapshot of how much virus is circulating in a given community. Several states, including Arizona, Hawaii, Nevada and Ohio have now completely stopped reporting daily Covid data to the CDC, making it more difficult to gauge the progression of the pandemic in those states.

According to the CDC, the majority of the country is still considered low risk. Public health experts argue this is misleading though, given hospitalization and death generally occur days to weeks after initial infection. Without widespread testing, that could make it impossible to detect a surge until it’s too late to do anything about it. 

“CDC is understating and downplaying cases,” said Gregg Gonsalves, an infectious disease expert at Yale’s School of Public Health. “Their alarm bells won’t go off until we see a rise in hospitalizations and deaths, which are lagging indicators.”

Transmissible Variant

Though omicron tends to cause milder symptoms for healthy, vaccinated people, its transmissibility led to such a huge spike in cases that it caused hospitalization rates to break previous pandemic records. The variant was also responsible for a record number of children going to the hospital. Black people were hospitalized at twice the rate of White people during the surge in New York. Vaccines are extremely effective at preventing severe disease if not always at preventing cases, one of the reasons metrics shifted toward hospitalizations to judge the state of the virus. But failing to track cases creates a blind spot. Experts say it is critical to continue to track them in order to protect vulnerable communities and respond to new waves of the virus before the health system gets overwhelmed.

In recent weeks, cases have started to tick up in places like New York, Massachusetts and in Chicago, but conflicting public messaging has caused confusion. National leaders have largely declared victory over the virus, but some local governments are starting to again urge caution. New York City delayed lifting a mask mandate for kids under 5 years of age due to rising cases and the city’s health commissioner recommended New Yorkers return to masking indoors.

Still, even in New York things look vastly different than during the start of prior surges. Gone are the days of long testing lines and sold out antigen tests. And all over the country, pop-up testing centers, once a pandemic mainstay, are starting to disappear. Though state-run testing facilities have continued to operate in some regions, people without health insurance are facing high prices. And as of March 22, the  U.S. Health Resources and Services Administration is no longer accepting reimbursement claims from health providers for Covid testing either.

At the same time, at-home rapid testing has increased. The problem is, the CDC does not require people to report positive at-home test results so it’s rare the results of at-home tests are factored into public health data.

“We are probably underestimating the number of infections we are having now because many of the infections are either without symptoms or minimally symptomatic and you will miss people that do it at home,” Anthony Fauci, the top medical adviser to President Joe Biden, told Bloomberg TV on Wednesday. 

Daily Covid Diagnostic Test Volume | Tests sequenced by labs in the U.S. and reported to the CDC

© BloombergDaily Covid Diagnostic Test Volume | Tests sequenced by labs in the U.S. and reported to the CDC

In New Jersey, for example, Stacy Flanagan, the director of health and human services for Jersey City, said that in the last three months she’s had just two people call to report positive at-home tests. Cases are continuing apace in the city with an average of 64 new cases per day, according to health department data.  That’s almost double the number of daily cases reported a month ago. 

“We’ve heard from only a handful of conscientious people who call us and say, ‘I’ve done a home test and it’s positive,’” said Dave Henry, the health officer for more than a dozen towns in Monmouth County, New Jersey.

Public health experts are left to piece together data from a variety of sources. For Rick Bright, a virologist and CEO of the Rockefeller Foundation’s Pandemic Prevention Institute, that means using the CDC data as well as a number of other sources to understand Covid’s spread. “Unfortunately, we still have to go to a handful of sites to try to patch together what’s really happening across the country.”

Other metrics such as wastewater surveillance and even air sampling may eventually become helpful alternatives in understanding how much virus is circulating in a community. For weeks, sewer data has shown cases are increasing in some regions of the U.S. — foreshadowing the uptick in positives that places like New York and Massachusetts are now seeing.

In the nation’s capital, more than 50 people who attended the elite Gridiron Club dinner on April 2 have tested positive for the coronavirus, the Washington Post reported — at least 8 percent of those who attended. The list of the infected includes the U.S. attorney general, Commerce secretary, aides to Vice President Kamala Harris and first lady Jill Biden, and the sister of the president. 

Speaker of the House Nancy Pelosi, who didn’t attend the dinner, has also tested positive, raising concern about time she spent in proximity to President Biden prior to her diagnosis.

Home Testing

The White House maintains there’s enough data about Covid in circulation to catch the next surge. Tom Inglesby, senior policy advisor for Biden’s Covid-19 Response Team, said the CDC gets 850,000 lab-based test results every day, which he believes is sufficient to detect trends in the positivity rate and variant prevalence. 

“It is true that there is a larger shift now to switch to over-the-counter testing, that’s definitely happening,” Inglesby said during a panel discussion.  “There are various efforts underway to try to assess whether people might be willing to voluntarily report some fraction of those tests that are being performed at home.” One biotech company, Ellume, has rolled out an at-home test and app that automatically reports positive tests to the CDC through a secure, HIPAA-compliant connection. 

Meanwhile the CDC has pledged to ramp up its wastewater surveillance efforts. The agency does not yet have data from sites in every state, so even getting access to some of the sampling already underway could be useful. Environmental surveillance, like many other tools to track Covid, may be at risk without additional funding from Congress. On Tuesday, lawmakers  reached an agreement to re-allocate $10 billion to pandemic preparedness, which press secretary Jen Psaki said would fund “the most immediate needs” such as antivirals and tests.  But that bill has yet to clear the Senate.

“The information we are getting from the CDC is going to be less reliable, more spotty, and lose momentum,” Bright said. “There’s really big concerns about the lack of sustainable financing to keep the momentum going and finish the job for the surveillance we’re building for pandemic prevention.”

There could be a lesson from the 1918 flu pandemic. After cases started to go down following the first two waves of the influenza virus, public sentiment shifted and many health measures were lifted. But in 1919, at the tail end of the pandemic, a fourth wave hit New York city, causing deaths to spike higher than they had during prior waves, according to a government funded study. 

“These late waves of the pandemics are sometimes the deadliest because people have given up,” said Gonsalves from Yale. 

COVID cases rise again in half the states

Change in reported COVID-19 cases per 100k people in the last two weeks

March 23 to April 5, 2022

Half of the states are seeing COVID case numbers rise again while nationwide totals continue to fall.

The big picture: The Omicron subvariant known as BA.2 is the dominant strain circulating around the U.S., accounting for almost three out of every four cases.

By the numbers: Overall, cases dropped 5% across the U.S. to an average of about 28,700 cases from an average of more than 30,000 cases two weeks ago.

  • Three states — Alaska, Vermont and Rhode Island — had more than 20 new cases per 100,000 people.
  • Nine states — Utah, Montana, South Dakota, Kansas, Louisiana, Iowa, Arkansas, Indiana and Tennessee — had three or fewer new cases per 100,000 people.

Between the lines: Deaths fell to an average of 600 a day, down 34% from just over 900 a day two weeks ago.

What we’re watching: While U.S. officials have said they aren’t expecting a significant rise in hospitalizations or deaths, there have been signs of hospitalizations rising among older individuals in the U.K., the Guardian reported.

  • Since those numbers lag behind new cases, we won’t have a clear view of that impact in the U.S. for a few weeks.
  • The highly contagious subvariant surged through parts of Europe but probably will spare many Americans, thanks in part to this winter’s Omicron surge.

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The Epidemiology, Transmission, and Diagnosis of COVID-19

Authors: By: Neesha C. Siriwardane & Rodney Shackelford, DO, Ph.D. April 15, 2020

Introduction to COVID-19

Coronaviruses are enveloped single-stranded RNA viruses of the Coronaviridae family and order Nidovirales (1). The viruses are named for their “crown” of club-shaped S glycoprotein spikes, which surround the viruses and mediate viral attachment to host cell membranes (1-3). Coronaviruses are found in domestic and wild animals, and four coronaviruses commonly infect the human population, causing upper respiratory tract infections with mild common cold symptoms (1,4). Generally, animal coronaviruses do not spread within human populations, however rarely zoonotic coronaviruses evolve into strains that infect humans, often causing severe or fatal illnesses (4). Recently, three coronaviruses with zoonotic origins have entered the human population; severe acute respiratory syndrome coronavirus-2 (SARS) in 2003, Middle Eastern respiratory syndrome (MERS) in 2012, and most recently, coronavirus disease 2019 (COVID-19), also termed SARS-CoV-2, which the World Health Organization declared a Public Health Emergency of International Concern on January 31st, 2020 (4,5). 

COVID19 Biology, Spread, and Origin

COVID-19 replicates within epithelial cells, where the COVID-19 S glycoprotein attaches to the ACE2 receptor on type 2 pneumocytes and ciliated bronchial epithelial cells of the lungs. Following this, the virus enters the cells and rapidly uses host cell biochemical pathways to replicate viral proteins and RNA, which assemble into viruses that in turn infect other cells (3,5,6). Following these cycles of replication and re-infection, the infected cells show cytopathic changes, followed by various degrees of pulmonary inflammation, changes in cytokine expression, and disease symptoms (5-7). The ACE2 receptor also occurs throughout most of the gastrointestinal tract and a recent analysis of stool samples from COVID-19 patients revealed that up to 50% of those infected with the virus have a COVID-19 enteric infection (8).

COVID-19 was first identified on December 31st, 2020 in Wuhan China, when twenty-seven patients presented with pneumonia of unknown cause. Some of the patients worked in the Hunan seafood market, which sold both live and recently slaughtered wild animals (4,9).  Clusters of cases found in individuals in contact with the patients (family members and healthcare workers) indicated a human-to-human transmission pattern (9,10). Initial efforts to limit the spread of the virus were insufficient and the virus soon spread throughout China. Presently COVID-19 occurs in 175 countries, with 1,309,439 cases worldwide, with 72,638 deaths as of April 6th, 2020 (4). Presently, the most affected countries are the United States, Italy, Spain, and China, with the United States showing a rapid increase in cases, and as of April 6th, 2020 there are 351,890 COVID-19 infected, 10,377 dead, and 18,940 recovered (4).  In the US the first case presented on January 19th, 2020, when an otherwise healthy 35-year-old man presented to an urgent care clinic in Washington State with a four-day history of a persistent dry cough and a two-day history of nausea and vomiting.  The patient had a recent travel history to Wuhan, China. On January 20th, 2020 the patient tested positive for COVID-19.  The patient developed pneumonia and pulmonary infiltrates, and was treated with supplemental oxygen, vancomycin, and remdesivir. By day eight of hospitalization, the patient showed significant improvement (11). 

Sequence analyses of the COVID-19 genome revealed that it has a 96.2% similarity to a bat coronavirus collected in Yunnan province, China. These analyses furthermore showed no evidence that the virus is a laboratory construct (12-14). A recent sequence analysis also found that COVID-19 shows significant variations in its functional sites, and has evolved into two major types (termed L and S). The L type is more prevalent, is likely derived from the S type, and may be more aggressive and spread more easily (14,15). 

Transmission

While sequence analyses strongly suggest an initial animal-to-human transmission, COVID-19 is now a human-to-human contact spread worldwide pandemic (4,9-11). Three main transmission routes are identified; 1) transmission by respiratory droplets, 2) contract transmission, and 3) aerosol transmission (16). Transmission by droplets occurs when respiratory droplets are expelled by an infected individual by coughing and are inhaled or ingested by individuals in relatively close proximity.  Contact transmission occurs when respiratory droplets or secretions are deposited on a surface and another individual picks up the virus by touching the surface and transfers it to their face (nose, mouth, or eyes), propagating the infection. The exact time that COVID-19 remains infective on contaminated surfaces is unknown, although it may be up to several days (4,16). Aerosol transmission occurs when respiratory droplets from an infected individual mix with air and initiate an infection when inhaled (16). Transmission by respiratory droplets appears to be the most common mechanism for new infections and even normal breathing and speech can transmit the virus (4,16,17). The observation that COVID-19 can cause enteric infections also suggests that it may be spread by oral-fecal transmission; however, this has not been verified (8). A recent study has also demonstrated that about 30% of COIVID-19 patients present with diarrhea, with 20% having diarrhea as their first symptom. These patients are more likely to have COVID-19 positive stool upon testing and a longer, but less severe disease course (18).  Recently possible COVID-19 transmission from mother to newborns (vertical transmission) has been documented. The significance of this in terms of newborn health and possible birth defects is currently unknown (19). 

The basic reproductive number or R0, measures the expected number of cases generated by one infection case within a population where all the individuals can become infected. Any number over 1.0 means that the infection can propagate throughout a susceptible population (4). For COVID-19, this value appears to be between 2.2 and 4.6 (4,20,21). Unpublished studies have stated that the COVID10 R0 value may be as high as 6.6, however, these studies are still in peer review. 

COVID-19 Prevention

There is no vaccine available to prevent COVID-19 infection, and thus prevention presently centers on limiting COVID-19 exposures as much as possible within the general population (22). Recommendations to reduce transmission within community include; 1) hand hygiene with simultaneous avoidance of touching the face, 2) respiratory hygiene, 3) utilizing personal protective equipment (PPE) such as facemasks, 4) disinfecting surfaces and objects that are frequently touched, and 5) limiting social contacts, especially with infected individuals  (4,9,17,22). Hand hygiene includes frequent hand-washing with soap and water for twenty seconds, especially after contact with respiratory secretions produced by activities such as coughing or sneezing. When soap and water are unavailable, hand sanitizer that contains at least 60% alcohol is recommended (4,17,22). PPE such as N95 respirators are routinely used by healthcare workers during droplet precaution protocols when caring for patients with respiratory illnesses. One retrospective study done in Hunan, China demonstrated N95 masks were extremely efficient at preventing COVID-19 transfer from infected patients to healthcare workers (4,22-24). It is also likely that wearing some form of mask protection is useful to prevent COVID19 spread and is now recommended by the CDC (25). 

Although transmission of COVID-19 is primarily through respiratory droplets, well-studied human coronaviruses such as HCoV, SARS, and MERS coronaviruses have been determined to remain infectious on inanimate surfaces at room temperature for up to nine days. They are less likely to persist for this amount of time at a temperature of 30°C or more (26). Therefore, contaminated surfaces can remain a potential source of transmission. The Environmental Protection Agency has produced a database of appropriate agents for COVID-19 disinfection (27). Limiting social contact usually has three levels; 1) isolating infected individuals from the non-infected, 2) isolating individuals who are likely to have been exposed to the disease from those not exposed, and 3) social distancing. The later includes community containment, were all individuals limit their social interactions by avoiding group gatherings, school closures, social distancing, workplace distancing, and staying at home (28,29). In an adapted influenza epidemic simulation model, comparing scenarios with no intervention to social distancing and estimated a reduction of the number of infections by 99.3% (28). In a similar study, social distancing was estimated to be able to reduce COVID-19 infections by 92% (29). Presently, these measured are being applied in many countries throughout the world and have been shown to be at least partially effective if given sufficient time (4,17,30). Such measures proved effective during the 2003 SARS outbreak in Singapore (30). 

Symptoms, Clinical Findings, and Mortality 

On average COVID-19 symptoms appear 5.2 days following exposure and death fourteen days later, with these time periods being shorter in individuals 70-years-old or older (31,32). People of any age can be infected with COVID-19, although infections are uncommon in children and most common between the ages of 30-65 years, with men more affected than women (32,33). The symptoms vary from asymptomatic/paucisymptomatic to respiratory failure requiring mechanical ventilation, septic shock, multiple organ dysfunction, and death (4,9,32,33). The most common symptoms include a dry cough which can become productive as the illness progresses (76%), fever (98%), myalgia/fatigue (44%), dyspnea (55%), and pneumoniae (81%), with less common symptoms being headache, diarrhea (26%), and lymphopenia (44%) (4,32,33). Rare events such as COVID-19 acute hemorrhagic necrotizing encephalopathy have been documented and one paper describes conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, or increased secretions in 30% of COVID-19 patients (34,35). Interestingly, about 30-60% of those infected with COVID-19 also experience a loss of their ability to taste and smell (36). 

The clinical features of COVID-19 include bilateral lung involvement showing patchy shadows or ground-glass opacities identified by chest X-ray or CT scanning (34). Patients can develop atypical pneumoniae with acute lung injury and acute respiratory distress syndrome (33). Additionally, elevations of aspartate aminotransferase and/or alanine aminotransferase (41%), C-reactive protein (86%), serum ferritin (63%), and increased pro-inflammatory cytokines, whose levels correlate positively with the severity of the symptoms (4,31-33,37-39).

About 81% of COVID-19 infections are mild and the patients make complete recoveries (38). Older patients and those with comorbidities such as diabetes, cardiovascular disease, hypertension, and chronic obstructive pulmonary disease have a more difficult clinical course (31-33,37-39). In one study, 72% of patients requiring ICU treatment had some of these concurrent comorbidities (40). According to the WHO 14% of COVID-19 cases are severe and require hospitalization, 5% are very severe and will require ICU care and likely ventilation, and 4% will die (41). Severity will be increased by older age and comorbidities (4,40,41). If effective treatments and vaccines are not found, the pandemic may cause slightly less than one-half billion deaths, or 6% of the world’s population (41). Since many individuals infected with COVID-19 appear to show no symptoms, the actual mortality rate of COIVD-19 is likely much less than 4% (42). An accurate understanding of the typical clinical course and mortality rate of COVID-19 will require time and large scale testing.         

COVID-19 Diagnosis

COVID-19 symptoms are nonspecific and a definitive diagnosis requires laboratory testing, combined with a thorough patient history.  Two common molecular diagnostic methods for COVID-19 are real-time reverse polymerase chain reaction (RT-PCR) and high-throughput whole-genome sequencing.  RT-PCR is used more often as it is cost more effective, less complex, and has a short turnaround time. Blood and respiratory secretions are analyzed, with bronchoalveolar lavage fluid giving the best test results (43). Although the technique has worked on stool samples, as yet stool is less often tested (8,43). RT-PCR involves the isolation and purification of the COVID-19 RNA, followed by using an enzyme called “reverse transcriptase” to copy the viral RNA into DNA. The DNA is amplified through multiple rounds of PCR using viral nucleic acid-specific DNA primer sequences. Allowing in a short time the COVID-19 genome ti be amplified millions of times and then easily analyzed (43). RT-PCR COVID-19 testing is FDA approved and the testing volume in the US is rapidly increasing (44,45). The FDA has also recently approved a COVID-19 diagnostic test that detects anti-COVID-19 IgM and IgG antibodies in patient serum, plasma, or venipuncture whole blood (43). As anti-COVID-19 antibody formation takes time, so a negative result does not completely preclude a COVID-19 infection, especially early infections. Last, as COVID-19 often causes bilateral pulmonary infiltrates, correlating diagnostic testing results with lung chest CT or X-ray results can be helpful (4,31-33,37-39).  

Testing for COVID-19 is based on a high clinical suspicion and current recommendations suggest testing patients with a fever and/or acute respiratory illness. These recommendations are categorized into priority levels, with high priority individuals being hospitalized patients and symptomatic healthcare facility workers. Low priority individuals include those with mild disease, asymptomatic healthcare workers, and symptomatic essential infrastructure workers. The latter group will receive testing as resources become available (41,46,47). 

COVID-19 Possible Treatments

Presently research on possible COVIS-19 infection treatments and vaccines are underway (48). At the writing of this article many different drugs are being examined, however any data supporting the use of any specific drug treating COVID-19 is thin as best. A few drugs that might have promise are:  

Hydroxychloroquine

Hydroxychloroquine has been used to treat malarial infections for seventy years and in cell cultures it has anti-viral effects against COVID-19 (49). In one small non-randomized clinical trial in France, twenty individuals infected with COVID-19 who received hydroxychloroquine showed a reduced COVID-19 viral load, as measured on nasopharyngeal viral carriage, compared to untreated controls (50). Six individuals who also received azithromycin with hydroxychloroquine had their viral load lessened further (50). In one small study in China, a similar drug (chloroquine) was superior in reducing COVID-19 viral levels in treated individuals compared to untreated control individuals (51).  These results are preliminary, but promising. 

Remdesivir

Remdesivir is a drug that showed value in treating patients infected with SARS (52). COVID-19 and SARS show about 80% sequence similarity and since Remdesivir has been used to treat SARS, it might have value in treating COVID-19 (52). These trials are underway (48). Remdesivir was also used to treat the first case of COIVD-19 identified within the US (11). There are many other drugs being examined to treat COVID-19 infections, however, the data on all of them is presently slight to none, and research has only begun. There is an enormous research effort underway, and progress should be rapid (48). 

Conclusion

Our understanding of COVID-19 is changing extremely rapidly and new findings come out daily. Combating COVID-19 effectively will require multiple steps; including slowing the spread of the virus through socially isolating and measures such as hand washing. The development of effective drug treatments and vaccines is already a priority and rapid progress is being made (48). Additionally, many areas of the world, such as South American and sub-Saharan Africa, will be affected by the COVID-19 pandemic and are likely to have their economies and healthcare systems put under extreme stress. Dealing with the healthcare crisis in these countries will be very difficult. Lastly, several recent viral pandemics (SARS, MERS, and COVID-19) have come from areas where wildlife is regularly traded, butchered, and eaten in conditions that favor the spread of dangerous viruses between species, and eventually into human populations. The prevention of new viral pandemics will require improved handling of wild species, better separation of wild animals from domestic animals, and better regulated and lowered trade in wild animals, such as bats, which are known to be a risk for carrying potentially deadly viruses to human populations (53). 

References

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Eyes can be infected by COVID-19: 4 things to know

Authors: Gabrielle Masson – Wednesday, May 19th, 2021 Print 

Cells in the eye can be directly infected by SARS-CoV-2, the virus that causes COVID-19, according to findings published May 17 by ScienceDirect. 

Below are four things to know about COVID-19 infections of the eye:

1. Researchers exposed adult human eyes to SARS-CoV-2 in an in vitro stem cell model and then studied them after 24 hours. The virus is able to infect surface cells of the eye, the researchers found. Ocular surface cells, particularly the limbus, were particularly susceptible to infection, while the central cornea was less vulnerable.

2. Researchers are currently trying to determine if the virus can be spread through the eyes, Timothy Blenkinsop, PhD, study author and assistant professor of cell, developmental and regenerative biology at New York City-based Mount Sinai Health System, told Becker’s. While aerosol transmission is thought to be the primary route of spread, viral particles detected in ocular fluid suggest the eye may be a vulnerable point of viral entry. However, scientists don’t have evidence to back the theory up yet, in part because it is difficult to develop experiments where nasal infections don’t complicate the results. 

3. To prevent the transmission of COVID-19, people in dense areas that aren’t well ventilated would benefit from eye protection. Front-line providers should definitely have eye protection, Dr. Blenkinsop said, which is already fairly standard in the U.S.  

4. Other studies have found a significant number of patients with severe COVID-19 experience abnormal nodules of the eye. Three recent reports showed retinal findings, such as hemorrhages, cotton wool spots, dilated veins or tortuous vessels, are possibly tied to COVID-19.

What is OC43?

Authors: By Benedette Cuffari, M.Sc.Reviewed by Emily Henderson, B.Sc.

In an effort to further understand and predict the health effects that can arise following infection by SARS-CoV-2, which is the infection that causes the disease COVID-19, many researchers have reevaluated the pathogenesis associated with coronaviruses that have already been identified. One type of coronavirus that has infected individuals around the world is HCoV-OC43.

A history of coronaviruses

In 1965, the first human coronavirus (HCoV) strain, which was eventually named B814, was identified from a patient’s nasal discharge. Since then, over 30 different HCoV strains have been isolated, the most notable of which include HCoV-229E, HCoV-NL63, HCoV-HLU1, and HCoV-0C43.

In addition to the aforementioned human-infecting coronavirus strains, several highly pathogenic zoonotic strains such as the severe acute respiratory syndrome coronavirus (SARS-CoV) of 2002, the Middle East respiratory syndrome coronavirus (MERS-CoV) of 2011 and the novel coronavirus COVID-19 that has, as of June 18, 2020, infected 8.24 million people and claimed the lives of over 446,000 thousand individuals around the world.

Classification of HCoV-OC43

Within the virus order of Nidiovirules is the suborder of Cornidovirineae. Within Cornidovirineae are two subfamilies known as Letovirinae and Orthocoronairinae.

All coronaviruses are within the subfamily of Orthocornavirinae; however, specific coronavirus strains can be further classified into one of four genera including Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. Whereas HCoV and HCoV-NL63 are found in the Alphacoronavirus genus, HCoV-OC43, as well as HCoV-HKU1, MERS-CoV, SARS-CoV and SARS-CoV-2 are all classified within the Betacoronavirus genus.

How does HCoV-OC43 enter cells?

The entry of HCoV-OC43 into human cells is largely achieved through the caveolin-1-dependent pathway of endocytosis; however, virus-containing vesicles at the cell surface can also undergo scission to also penetrate human cells.

Notably, while host factors like interferon-inducible transmembrane proteins (IFITMs) often prevent the entry of coronaviruses like HCoV-229E, -NL63, SARS-CoV and MERS-CoV from entering cells through its various antiviral functions, IFITM2 and IFITM3 promote the entry and subsequent infection of HCoV-OC43 into human cells.

For More Information: https://www.news-medical.net/health/What-is-OC43.aspx

Worse Than the Disease? Reviewing Some Possible Unintended Consequences of the mRNA Vaccines Against COVID-19

Authors: Stephanie Seneff1and Greg Nigh21Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge MA, 02139, USA, E-mail: seneff@csail.mit.edu

ABSTRACT

Operation Warp Speed brought to market in the United States two mRNA vaccines, produced by Pfizer and Moderna. Interim data suggested high efficacy for both of these vaccines, which helped legitimize Emergency Use Authorization (EUA) by the FDA. However, the exceptionally rapid movement of these vaccines through controlled trials and into mass deployment raises multiple safety concerns. In this review we first describe the technology underlying these vaccines in detail. We then review both components of and the intended biological response to these vaccines, including production of the spike protein itself, and their potential relationship to a wide range of both acute and long-term induced pathologies, such as blood disorders, neurodegenerative diseases and autoimmune diseases. Among these potential induced pathologies, we discuss the relevance of prion-protein-related amino acid sequences within the spike protein. We also present a brief review of studies supporting the potential for spike protein “shedding”, transmission of the protein from a vaccinated to an unvaccinated person, resulting in symptoms induced in the latter. We finish by addressing a common point of debate, namely, whether or not these vaccines could modify the DNA of those receiving the vaccination. While there are no studies demonstrating definitively that this is happening, we provide a plausible scenario, supported by previously established pathways for transformation and transport of genetic material, whereby injected mRNA could ultimately be incorporated into germ cell DNA for transgenerational transmission. We conclude with our recommendations regarding surveillance that will help to clarify the long-term effects of these experimental drugs and allow us to better assess the true risk/benefit ratio of these novel technologies.

For More Information: https://ijvtpr.com/index.php/IJVTPR/article/view/23/51

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

COV-2 Transmission Analyzing Genomics

Authors:Trevor Bedford, PhD

The news of infections caused by a novel coronavirus, and the everyday use of the names SARS-CoV-2 and COVID-19, became widespread around February. But, the question of how long the virus had already been present in the United States before that time has remained unknown. Now, a team of researchers has reconstructed some of the early transmissions of the virus. By analyzing the genomic sequences of SARS-CoV-2 samples from infected patients in Washington State, they suggest that most early SARS-CoV-2 infections derive from a single introduction in late January or early February, sparking rapid community transmission of the virus that went undetected for several weeks before this community spread became evident.

For More Information: https://www.genengnews.com/news/early-sars-cov-2-transmission-reconstructed-using-genomics/

https://science.sciencemag.org/content/370/6516/571