Hfh Neurology Covid-19 Scientific Advisory Board 03/31/20 Update

HFH NEUROLOGY COVID-19 SCIENTIFIC ADVISORY BOARD 03/31/20 UPDATE

Editorial board: Amer Aboukasem MD, Hassan Aboul Nour MD, Muhammad Affan MD, Owais Alsrouji MD, Ximena Arcila-Londono MD, Gregory Barkley MD, Arun Chandok MD, Alex Bou Chebl MD, Song Chen MS, Michael Chopp PhD, Omar Danoun MD, Elissa Fory MD, Shailaja Gaddam MD, Kavita Grover MD, Mohammed Ismail MD, Holly Lorigan MD, Ghada Mahmoud Mohamed MD, Shaneela Malik MD, Daniel Newman MD, Neepa Patel MD, Phillip Ross MD, Bin Rui PhD, Naganand Sripathi MD, Aarushi Suneja MD, Vibhangini Wasade MD, Iram Zaman MD

Chairs: Gamal Osman MD, Ahmad Riad Ramadan MD

COVID-19 PANDEMIC: THE NUMBERS (as of 3/31/20, confirmed in the symptomatic mother by PCRs. 23 1pm EST) days later, she was delivered by C-section. Two ● World:1 823,479 confirmed cases. Total deaths: hours post-delivery, the baby had positive IgM and 40,635. (CFR 4.93%). Total recovered:166,999 IgG titers but negative PCRs. Importantly, IgM does 1 ● US: 175,669 confirmed cases. Total deaths: not cross the placenta so this was not transmitted 3,424; 661 new deaths in the past 24 hours. immunity.6 Highest number of deaths remains in NY: 932. ● Michigan:2 7,615 confirmed cases. Total deaths: DISCOVERIES IN SARS-COV-2 PATHOGENICITY 259 (CFR 3.4%). 75 new deaths in the past 24 ● Similarly to CoV (SARS epidemic), CoV-2 uses the hours. ACE2 receptor for entry into cells via its spike protein. ● NEW! Peak resource use and peak deaths in the ● ACE2 is expressed in human airway epithelia, lung US is projected on April 15, 2020. Visit parenchyma, vascular endothelium, kidney cells, and covid19.healthdata.org for prediction on deaths, small intestine cells. Also expressed in some need for ICU bed and ventilators.3 neuronal populations - cardiorespiratory centers in ● Evolution of the pandemic:4 The US remains in the brainstem, raphe nucleus, hypothalamus and the acceleration phase of the pandemic with motor cortex. exponential growth of confirmed cases and ● CoV-2, like CoV, may gain access to the CNS via the deaths. The number of deaths increased 2.4 times olfactory receptor neurons (may explain anosmia in the past 4 days. common in these infections), spreading to the olfactory bulbs and then to other parts of the brain via BEST EXPOSURE PREVENTION PRACTICES trans-synaptic transfer (e.g., thalamus, hypothalamus, ● CoV-2 was detected in aerosols for up to 3 hours, 4 brainstem). The medullary cardiorespiratory centers hours on copper, 24 hours on cardboard and 2-3 appear to be highly infected, which may play a role in days on plastic and stainless steel.4 central respiratory failure in these patients.7 ● Continue to perform basic hygiene and apply droplet Coronaviruses infect both neurons and glia. precautions (cover cough, wash hands for at least 20 Neuroinfection, along with the systemic sec, do not touch face/eyes, disinfect the inflammatory response, leads to a breakdown of surroundings with 60-95% alcohol, social distancing the blood-brain barrier and contributes to the of at least 6 feet).5 activation of microglia and astroglia.8 ● Before entering in contact with suspected or known ● Mild disease in 81% of cases, severe disease COVID-19 infected patients, familiarize yourself with (respiratory failure, ARDS, requiring oxygen +/- the donning and doffing procedures. Proper PPE ventilatory support) in 14% cases, and critical disease includes: respirator or facemask (N95, P100; or (shock, MOSD, MOSF) in 5% cases.9 PAPR), gloves, gown, and eye protection (e.g., ● Cytokine storm: A hallmark of severe CoV-2 disease reusable goggles or disposable face shield).5 is the development of a potent “cytokine storm”. This ● A case of possible vertical mother-to-fetus is not unique to COVID-19 and has been described in transmission was reported in China. Infection was MERS and SARS, both of which are closely-related 1 HFH NEUROL COVID-19 SAB UPDATE 3/31/20

coronaviruses. IL-6, a proinflammatory cytokine, is state, and the cytokine storm all contribute to central in this process. direct myocardial injury, mismatch ● Is there a CNS control of the immune system? The myocardial oxygen supply/demand and answer is yes. The autonomic system is an important plaque rupture, leading to increase in the risk modulator of the immune system. Dysregulating the of myocardial infarction, arrhythmias and autonomic system stimulates the inflammatory heart failure. response of both innate and adaptive immune systems. There is strong evidence to support the UPDATES ON SARS-COV2 TESTING direct sympathetic innervation of immune organs ● Per the CDC,16 priority for testing goes to 1) such as the spleen. Sympathetic activation causes hospitalized patients with signs/symptoms compatible splenic cytokine production (IL-1β, IL-2, IL-5, IL-16 with COVID-19, 2) vulnerable patient populations and TGFβ1), whereas vagal nerve stimulation (older adults, immunocompromised state, chronic quiesces the immune response.10 One wonders medical conditions (e.g., HTN, DM, CKD, lung, heart whether blocking the sympathetic outflow may halt or disease), 3) HCP who had close contact with a prevent the development of this exuberant COVID19 suspect or positive patient within 14 days of inflammatory response. symptom onset (close contact= being within 6 feet for ● Important clinical features of the disease: a prolonged period of time or direct contact with ○ A minority of patients will develop hypoxia and secretions of COVID-19 case, while not using deteriorate very quickly, going from oxygen recommended PPE). supplementation by oxygen to high flow nasal ● Methods for sample collection: nasopharyngeal cannula to intubation within a few hours. (NP) swab, tracheal aspirate/BAL (intubated patients, ○ Initial CT chest made the right diagnosis in but increases exposure risk), sputum (induction not 96.1% of cases in one series.11 Most common recommended).17 At this point, HFH only tests via NP findings were ground glass opacities, swabs. consolidations, vascular enlargement, ● rRT-PCR: Almost all diagnostic testing for CoV-2 is interlobular septal thickening, and air done using rRT-PCR. In the US, testing is performed bronchogram sign. by the CDC, hospital and public health laboratories. ○ 2-10% of COVID-19 presented with GI Turnaround time varies, continues to take up to 4-5 symptoms, such as diarrhea, abdominal pain, days due to the low availability of 12 st and vomiting in 2% to 10% of cases. reagents/batching/prioritization. On March 21 , the ○ Elevation of several serum inflammatory markers- FDA approved a point-of-care (POC) test by Cepheid IL-6, ferritin, LDH, CRP, D-dimer, and with a turnaround time of 45 minutes, which should triglycerides, indicating the presence of a potent be commercially available at the end of March.18 cytokine storm and secondary hemophagocytic Abbott has been granted emergency use lymphohistiocytosis. authorization by the FDA for its POC test that will ○ Neutrophil-to-lymphocyte ratio (NLR) of ≥3.13 detect CoV-2 in “as little as 5 min” and “negative predicts disease progression results in 13 min”, making it the fastest POC test ○ Lymphopenia and thrombocytopenia for the virus at this stage. The company claims ○ Myocardial injury: in one study of 416 patients they will produce 5 million tests per month.19 admitted with COVID-19, 20% had evidence of ● Serology: IgM and IgG provide information about the cardiac injury as defined as elevated immune response of the host to the virus antigens. In troponin.13 Patients with underlying one study, antibodies were detected in all patients 5 cardiovascular disease and elevated troponin days after symptom onset. Faster to get results, but were found to have the highest mortality.14 less accurate than PCR. Autopsies have revealed infiltration of ● Immunoassays: monoclonal antibody tests that myocardium by interstitial mononuclear detect viral antigens such as the nucleocapsid (N) inflammatory cells, evidencing a protein, spike protein of the virus or multiple antigens. 15 myocarditis. A RDS, myocarditis, Faster results (20-60 min) but longer to develop and sympathetic hyperactivity, hypercoagulable less accurate than PCR.20

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● FDA has not approved at-home test kits and warns Vessels were patent on CT angiogram and CT the public against the marketing of fraudulent venogram.26 COVID-19 test kits.21 ○ PNS symptoms: In one study, 8.9% of patients ● To date, there is no reliable data on the false positive (hypogeusia, hyposmia, neuralgia).24 Myalgias and false negative rates of the various testing were found in 10.7% of cases. It remains to be methods. seen whether we will encounter cases of ● A South Korea hospital launched a phone-booth-style motor-predominant peripheral neuropathy, CoV-2 testing- a row of 4 negative-pressure, myopathy and rhabdomyolysis, as we saw during single-occupancy plastic booths under a tent outside the SARS pandemic in 2002. So far, no reported the hospital. The patient gets inside the booth and a movement disorders as a result of the infection. consultation takes place with a HCP who, from ● Laboratory findings: Patients with CNS symptoms outside of the booth, can obtain samples via were more likely to have lower lymphocyte and arm-length rubber gloves built into the plastic panel. platelet counts, and elevated BUN levels. There were Process takes about 7 min to complete and the booth no characteristic laboratory findings in patients with is easy to disinfect.22 PNS symptoms. Patients with muscle injury had ● NEW! Kinsa Health smart thermometers are able higher neutrophil counts, lower lymphocyte counts to track fever across the US via a web-based app. and higher CRP levels and D-dimer levels as well as Although it cannot discriminate fever from evidence of multiorgan system failure.24 different etiologies, it can identify new clusters of ● No specific neuroimaging or electrophysiological fever, track fever curve and gauge the response characteristics described in COVID-19 patients yet. to implemented measures such as social distancing. It was first created to track the spread CARING FOR THE NEUROLOGICAL PATIENTS of the flu and a million thermometers have been INFECTED WITH COVID-19 sold since the inception of the company.23 ● Stroke: ○ Cardiovascular comorbidities are prevalent in SARS-COV2 NEUROLOGICAL SYNDROMES COVID-19 patients, similarly to SARS and ● Symptomatology: MERS. These comorbidities increase the risk of ○ CNS symptoms: In one study, 24.8% of cases mortality and morbidity from the infection. (dizziness and headache).24 In another study of ○ With ACE2 serving as the portal for infection, the 221 patients at a single center in China, 5% role of ACE inhibitors (ACEi) or angiotensin cases had AIS, 0.5% CVST and 0.5% ICH.25 receptor blockers (ARB) requires further Ischemic and hemorrhagic strokes, impaired investigation. The American Heart Association consciousness and muscle injury were more recommends at this point continuing ACEi and prevalent in patients with more severe respiratory ARB medications if clinically indicated. 27 In a disease. study of 187 patients hospitalized with ○ NEW! Henry Ford Hospital’s Radiology COVID-19, use of ACEi and ARB were not Department published the first reported case associated with increased mortality, even in of acute hemorrhagic necrotizing the group of patients with higher cardiac encephalopathy in a COVID-19 patient, a injury.28 middle-age female who presented with altered ○ The extent to which a community outbreak of mental status in addition to URI symptoms. infection like COVID-19 stresses other parts of Virology studies were negative for influenza the healthcare system is largely unknown. The and other viruses. CSF could not be tested for question is whether our time metrics for tPA and CoV-2. Non-contrast head CT revealed thrombectomy will be affected by the suspected bithalamic hypoattenuating lesions while or confirmed infectious status of the patient. A brain MRI revealed T2 FLAIR hyperintense study comparing timeline in STEMI patients at a signal with internal hemorrhage in the hospital in Hong Kong showed numerically longer bilateral thalami and medial temporal lobes. median times in all components when compared with historical data from the prior year. The

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largest time difference was in the time from patients at increased risk for breakthrough symptom onset to first medical contact.29 seizures. Therefore, the CDC has included ○ COVID-19 pandemic poses a unique challenge in epilepsy among conditions associated with achieving timely treatment of acute stroke increased risk for serious COVID-19 infection.35 patients with thrombolytics and thrombectomy. It Patients with epilepsy syndromes known to be remains to be seen what impact the pandemic sensitive to fevers such as Dravet Syndrome and will have on adherence to time metrics and genetic epilepsy with febrile seizures plus quality measures. (GEFS+) are likely to be particularly at increased ○ Similarly, with the current strain imposed by the risk for breakthrough seizures in the setting of pandemic on staffing beds and other resources, it COVID-19 infection.36 Use of rescue seizure will be important to study the impact this will have medications can be considered in those patients. on triaging and disposition of patients from the ○ The American Epilepsy Society released a ED. statement recommending the prescriptions be ○ The Society of neuro-interventional surgeons refilled 1 week in advance for 30-day refills and 2 released a guideline statement recommending weeks in advance for 90-day refills.37 CMS has screening for fever and respiratory symptoms made healthcare plans more flexible which in all patients undergoing mechanical included removing prior authorization thrombectomy and having a low threshold for requirements, waiving prescription refill limits, intubation prior to transport to the allowing mail delivery of prescription medications angiography suite. and supporting tele visits.38 ○ Alexandria University in Egypt implemented a ○ Prescribers are advised to review drug interaction protocol of obtaining CT chest with CT protocol in profiles of medications currently used for stroke patients that are suspected COVID 19 treatment of COVID-19 such as positive. hydroxychloroquine with seizure medications and ○ Asian tobacco smokers were found to have use caution when prescribing along with significantly higher ACE2 expression in their hepatically metabolized or hepatotoxic lungs than their non-smoker counterparts. More anti-seizure medications (ASMs).39 A list of the males than females smoke in China and males known drug interactions between ASMs and were more likely to develop severe and critical drugs used for COVID-19 treatment is available COVID. However, this data does not seem to be on the ILAE website as a useful reference for reproduced in Caucasians. More data is needed prescribing clinicians and clinical pharmacists.40 to see whether chronic smoking is an independent risk factor for more severe CoV-2 ● Multiple sclerosis and demyelinating diseases: infection.30 ○ It is important here to distinguish between immunosuppressive and immunomodulatory ● Epilepsy: DMTs. While it is usually ok to continue ○ Animal and human studies have demonstrated immunomodulatory DMTs including IFNs, the neuro-invasive potential of SARS-COV as glatiramer acetate, teriflunomide and dimethyl well as coronavirus strains including HCoV-OC43 fumarate, patients on cell depleting therapies with preferential involvement of the thalamus and including alemtuzumab, ocrelizumab and brainstem.31-33 So far, there have been only rare cladribine are at increased risk for severe reports of encephalitis associated with COVID-19 infections including COVID-19 infections. making it an infrequent cause of new onset National MS Society recommends that the epilepsy.34 decision of continuing or discontinuing DMTs be ○ There is no evidence to suggest that people with taken on an individualized basis, taking into epilepsy are at increased risk than others for account the higher risk of infections associated acquiring COVID-19 infections. However, as with with cell depleting agents and the higher risk of any other viral febrile illnesses, COVID-19 worsening disability among medications including infection may lower seizure threshold and place natalizumab and fingolimod.41

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carbidopa/levodopa must be crushed and given ● MG and LEMS via NG tube. ○ There is no available data yet on the COVID-19 ○ Huntington disease: Patients admitted to the infection risk in MG patients. However, many hospital or ICU must continue with their patients with MG are already on various outpatient regimen of medications. If intubated immunosuppressive/immunomodulatory contact movement disorders physician to therapies and may also have underlying determine if medication (or alternative) should be respiratory muscle weakness which theoretically continued inpatient. places them at increased risk for severe ○ Essential tremor: Those patients treated with COVID-19 infections. primidone may potentially have a drug-interaction ○ A group of International MG experts formed with Remdesivir (there are no known drug MG/COVID-19 work group which recently interactions for this medication reported) released a guideline statement which Primidone is a strong CYP3A4 inducer and a recommends continuing existing medications for week CYP1A2, CYP2A6, CYP2B6 inducer that is patients who are already on them.42 relatively contraindicated with several other ○ They also stated that symptomatic therapies such antiviral therapies. If pharmacist raises concerns as pyridostigmine and 3,4 diaminopyridine do not for drug-drug interaction it is reasonable to hold increase the risk for infection and thus should be primidone for the duration of antiviral therapy continued as well. ○ Other: General recommendations are to continue ○ As for patients receiving infusion therapies all outpatient regimens as prescribed. requiring transport to hospitals or infusion centers, the decision on whether to continue the THERAPIES: YES, MAYBE, NO infusion therapy or not should be individualized ● Therapies targeting viral replication: based on the regional incidence of COVID-19 ○ Lopinavir/ritonavir (LPV/RTV): not and the risk vs benefit of treatment for the recommended; not effective when tested in individual patient. COVID-19 pneumonia (did not change mortality, ○ They also state that there is no evidence of discharge, length of stay).43 No mention of severe increased risk for COVID infection with neurologic sequelae in any of these patients eculizumab therapy. There is also no evidence of ○ Remdesivir (“GS5734”): prodrug of adenosine any increased risk of COVID infection from PLEX analog, promising in cell and animal models or IVIG therapy, but the risk derived from visits to against CoV, crosses BBB in rhesus monkeys healthcare facilities should be considered. [tested in Ebola - also neuro-invasive]; in phase 2 ○ The decision to switch patients to an alternative and 3 human trials,44-46 except for children and immunosuppressive therapy should take into pregnant women with severe disease. Remdisivir account the presence of other comorbid is no longer available for compassionate use but conditions and the risk of viral infection should be should be available for expanded access use balanced against the risk of developing MG crisis soon. when discussing initiating Rituximab therapy. ○ Ribavirin: guanosine analogue, usually Blood draws should be done judiciously in order combined with recombinant interferon. Not to avoid unnecessary hospital visits and patients effective in MERS.47 Looks good in vitro with on immunosuppressive therapies are advised to poor in vivo activity (hard to get high enough practice extra cautious social isolation. serum levels in humans/limited by toxicity). ○ Favipiravir: A viral RNA polymerase inhibitor ● Movement disorders used to treat influenza in Japan.48 A ○ Movement disorders as a complication non-randomized open label trial evaluated its use COVID-19: none reported in the literature. in SARS-COV2 infection in addition to inhaled ○ Parkinson disease: Patients admitted to the interferon-α compared to LPV/RTV therapy. 35 hospital or ICU must continue with their patients received favipiravir compared to 45 outpatient regimen of medications. If intubated patients receiving LPV/RTV. Favipiravir therapy

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was associated with shorter viral clearance time 80 patients receiving HCQ+AZT on 03/27. (median 4 days (IQR 2.5-9) than LPV/RTV 65/80 (81.3%) achieved a favorable outcome. (median 11 days (IQR 8-13) (P<0.001). In 83 % of PCR results turned negative on day 7 addition, 91.4% of patients receiving favipiravir and 93% turned negative on day 8 of demonstrated chest CT improvement compared treatment. However, comparison with a to 62.2% of patients receiving LPV/RTV control group was lacking in this trial. (P=0.004).49 Surprisingly, only 15% of included patients ○ Oseltamivir: A drug approved for influenza A had fever and 4 patients were asymptomatic and B treatment; it inhibits the viral carriers.61 The inclusion of these patients in neuraminidase and, consequently, blocks the this trial in addition to the lack of a control release of viral particles from host cells, reducing group limit the validity of these results. the spread in the respiratory tract. The use of Another pilot trial from China randomized 30 oseltamivir has been reported during the patients to receiving HCQ therapy vs COVID-19 epidemic in China, either with or conventional treatment only. HCQ was not without antibiotics and corticosteroids. superior to standard therapy in achieving viral Oseltamivir is also used in a clinical trial in suppression.62 A larger clinical trial from multiple combinations with chloroquine and China randomized 60 patients to receiving favipiravir.50-53 HCQ vs placebo and demonstrated significant ○ Arbidol (also known as umifenovir) : Approved shortening of body temperature recovery and in Russia and China for the treatment of influenza cough remission times in HCQ arm. In virus infections. Arbidol’s antiviral mechanism addition, 80.6% of patients in the HCQ arm against influenza A and B involves viral fusion demonstrated radiologic improvement of inhibition with the targeted membrane, which pneumonia compared to 54.8% in the control blocks virus entry into the cell. The drug is arm.63 Multiple larger clinical trials are currently currently being investigated in 4 clinical trials in underway assessing the role of China.50,54-58 hydroxychloroquine +/- azithromycin treatment of ○ Hydroxychloroquine (HCQ) +/- azithromycin COVID-19 infections of varying severities as well (AZT): In vitro data has demonstrated efficacy of as for pre-exposure and post-exposure chloroquine and hydroxychloroquine in prophylaxis of healthcare workers.64-68 suppressing SARS-CoV2.59 Based on this data, ○ Teicoplanin: A glycopeptide antibiotic used to Gautret et al. studied the antiviral activity in a treat gram positive infections, active in non-randomized trial that included 20 patients vitro against SARS-CoV2 & other viruses, receiving HCQ 200 mg q8h compared to 16 prevents release of genomic viral RNA and non-matched controls receiving standard of stops viral replication at doses lower than care.60 Viral eradication was assessed via repeat reached in human blood. No human trials PRC nasopharyngeal swab on day 6. Viral yet.69 eradication was achieved in 14/20 (70%) of ○ Baricitinib: JAK1 and JAK2 inhibitor approved patients in the treatment arm compared to 2/16 for treatment of rheumatoid arthritis. Artificial (12.5%) control patients. 6/6 (100%) patients intelligence-based algorithms identified this receiving AZT in addition to HCQ achieved viral medication as a potential treatment for eradication. However, this study was criticized by COVID-19 infections via inhibition of the lack of randomization and lack of blinding as clarithrin-mediated endocystosis and well as the exclusion of three patients who were subsequently viral entry into cells.70 One transferred to ICU and one patient who died clinical trial is currently underway in Italy which could have altered the outcome, in addition investigating its use.71 use of a different PCR cycle threshold for defining ○ Soluble ACE2 molecules: May play a role in positive test than the one adapted by CDC.60 The competitively blocking membrane ACE2 viral same group from Marseille recently reported bindings sites, and subsequently blocking updated results from a larger cohort including

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viral entry and replication.72 No clinical trials successfully discharged from the hospital.79 yet. Based on these data and the state of the current public health crisis, the FDA allowed access to ● Immunosuppressive/Immunomodulatory this treatment through single patient emergency therapies and Passive immunization IND.80 One clinical trial evaluating its role in ○ Tocilizumab: humanized monoclonal antibody COVID-19 infection (NCT04292340) is currently targeting IL6 receptors. A preprint non underway in China as well.81 peer-reviewed case series from China ○ Neutralizing antibodies: Neutralizing antibodies demonstrated clinical improvement in 20/20 and can recognize a wide variety of glycoproteins radiologic improvement in 19/20 (90.5%) patients (GPs) in virus surfaces or the protein shell of a with severe to critical COVID-19 infection.73 There non-enveloped virus. A trial utilizing human are two currently ongoing clinical trials in China immunoglobulin in patients with pneumonia further investigating this drug.74 caused by 2019-nCoV who recovered is currently ○ Sarilumab: Another monoclonal antibody underway. 82 targeting IL6 receptors. A clinical trial evaluating ○ IVIG: Cao et al. reported clinical improvement in its use is currently enrolling patients in New York three cases with severe COVID-19 infection from 75 61 (NCT04315298). China . A clinical trial is currently underway in ○ Eculizumab: Humanized monoclonal antibody China to further assess its utility.83,84 targeting complement protein C5, thus preventing ○ Fingolimod: A sphingosine-1-phosphate the formation of membrane attack complex receptor regulator (FTY720) with an effective (MAC). A clinical trial sponsored by Hudson immunology modulator that is used in multiple Medical is currently underway investigating its sclerosis. Study NCT04280588 aims to determine use in COVID-19 infections of various the efficacy of fingolimod for COVID-19. Currently 85 76 Phase 2. severities. ○ Thalidomide: has an anti-inflammatory action ○ Anakinra: recombinant form of IL1 receptor due to its ability to speed up the degradation of antagonist. This drug is proposed to ameliorate messenger RNA in blood cells and thus reduce the cytokine storm. There are no active trials at tumor necrosis factor-α (TNFα). Furthermore, this point investigating this particular drug, but thalidomide can increase the secretion of one clinical trial is planned in Italy (sponsored by interleukins, such as IL-12, and activate natural 77 SOBI). killer cells. Currently phase 2.86,87 ○ Emapalumab: monoclonal antibody targeting IFN-γ, a proinflammatory cytokine with a central ● International Clinical Trials: There are two large role in various inflammatory processes. No international clinical trials that are currently underway: clinical trials are currently underway evaluating ○ Solidarity trial: A WHO-funded trial enrolling this drug, but one trial is planned in Italy..77 patients into one of 5 treatment arms: remdesivir, ○ Bevacizumab: recombinant humanized chloroquine/hydroxychloroquine, LPV/RTV, monoclonal antibody blocking angiogenesis by LPV/RTV+ IFN-β or standard of care. Countries targeting VEGF receptors. Based on promising participating in the trial include Argentina, data from ARDS trials, a clinical trial was initiated Bahrain, Canada, France, Iran, Norway, South in China to assess its utility in management of Africa, Spain, Switzerland, and Thailand.88 severe or critical COVID-19 pneumonia.78 ○ Discovery trial: A European trial similar to ○ Convalescent plasma: Convalescent plasma Solidarity trial except that hydroxychloroquine is from recovering patients has been used in solely used instead of chloroquine. The trial plans SARS-COV with reported success. One case to enroll 3200 patients from Belgium, France, series from China demonstrated clinical Germany, Luxembourg, the Netherlands, Spain, improvement and viral suppression in 5 patients Sweden, and the UK.88 with COVID-19 infection and ARDS. ARDS resolved in 4/5 patients and three patients were ● Vaccines under development weaned from mechanical ventilation and were

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○ COVID Vaccines Phase 1 clinical trials: vaccine targeting the spike protein, which Currently, there are no FDA-approved the provided a headstart for developing a therapies or vaccines for COVID-19. The vaccine candidate to protect against National Institute of Allergy and Infectious COVID-19. Once the genetic information of Diseases (NIAID) is leading the funding of SARS-CoV-2 became available, the federal research and response to COVID-19, scientists quickly selected a sequence to while some companies in the US are choosing express the stabilized spike protein of the to fund their own COVID-19 research. virus in the existing mRNA platform. Internationally, the UK Medicines and ■ Ad5-nCoV:89,91 China’s CanSino Biologics Healthcare products Regulatory Agency has developed a recombinant CoV-2 (MHRA) and European Medicines Agency vaccine that incorporates the adenovirus (EMA) have called for targeted efforts to type 5 vector (Ad5). Ad5-nCoV is a develop therapies against COVID-19. It could genetically engineered vaccine candidate take between 12-18 months to develop a with the replication-defective adenovirus vaccine ready for market. We will mention the type 5 as the vector to express phase 1 clinical trials here. SARS-CoV-2 spike protein. 89,90 89-92 ■ mRNA-1273: T he investigational ■ ChAdOx1: From The Oxford Vaccine vaccine was developed using mRNA. The Group at the University of Oxford, a investigational vaccine directs the body’s chimpanzee adenovirus vaccine vector cells to express a virus protein that is called ChAdOx1. The team has previously hoped to elicit a robust immune response developed a MERS vaccine. The vaccine to counteract the virus prior cellular entry. is based on an adenovirus vaccine vector The mRNA-1273 vaccine has shown and the SARS-CoV-2 spike protein. It is promise in animal models, and this is the expected to be ready in the coming first trial to examine it in humans. VRC weeks. and Moderna scientists already were working on an investigational MERS

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Glossary

ACE2: angiotensin-converting enzyme-2; AIS: acute ischemic stroke; ARDS: acute respiratory distress syndrome; CNS: central nervous system; CFR: case fatality rate; CKD: chronic kidney disease; CRP: C-reactive peptide; CRR: case recovery rate; CVST: cerebral venous sinus thrombosis; DM: diabetes mellitus; DMT: disease-modifying therapy; HCP: healthcare personnel ; HTN: hypertension; ICH: intracerebral hemorrhage; IVIG: intravenous immunoglobulin; LEMS: Lambert Eaton myasthenic syndrome; MG: myasthenia gravis; PAPR: powered, air-purifying respirator; PLEX: plasma exchange; PNS: peripheral nervous system; PPE: personal protective equipment ; rRT-PCR: real-time reverse transcription-polymerase chain reaction

This HFH COVID-19 Update is intended for the members of the Department of Neurology Henry Ford Hospital. Information concerning COVID-19 is rapidly evolving and the present text represents the authors’ current interpretation, understanding, and evaluation of data at the time of writing. This update does not represent the official position of Henry Ford Hospital regarding COVID-19. For current updates concerning COVID-19, readers should consult the CDC website.