COVID-19 SARS-CoV-2 Lisa Gilbert, MD, FAAFP, CTropMed 3/17/20

COVID-19 SARS-CoV-2 Lisa Gilbert, MD, FAAFP, CTropMed 3/17/20.

COVID-19 SARS-CoV-2 2019-nCov HCoV-19. Disease. Virus Name.

7 Human Coronaviruses: 4 normal; 3 “novel”. family: order: Coronaviridae Coronavirinae subfamily: genus: Alpha Beta Gamma Coronavirus Coronavirus Coronavirus NIDOVIRALES Torovirinae Torovirus Bafinivirus Roniviridae Okavirus Arteriviridae Arterivirus.

Coronavirus Structure. Nucleocapsid protein (N) Membrane glycoprotein (M) Spike protein (S) Envelope protein (E) .8 RNA.

Coronavirus Genome. Encodes four or five structural proteins: S – spikes on the outside; mediates receptor binding M – membrane protein; assists viral assembly N – nucleocapsid protein; regulation of viral RNA synthesis, may interact with M protein during virus budding E – small envelope protein; function necessary but not fully understood HE – hemagglutinin-esterase glycoprotein in Beta coronavirus OC43 and HKU1 only; enhances uptake into mucosal cells Video and article on how coronavirus replication in cells occurs: https://www.youtube.com/watch?v=Eeh054-Hx1U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369385/.

Myth 1: Donald Trump Named it Coronavirus. CHANNEL ONE Russia's Channel One has aired a theory linking the coronavirus to President Trump.

Upper Respiratory Infections. Normal human coronaviruses cause 5-10% of common cold/URIs, with outbreaks to 30% of common cold 229E and NL63 (alpha coronaviruses) OC43 and HKU1 (beta coronaviruses) These four predominately attach to receptors in UPPER airway (receptors: aminopeptidase N, dipeptidyl peptidase 4) Seasonality unpredictable (generally winter, but persists year round), different pattern in tropics than temperate regions URI symptoms, croupy or dry cough, rarely pneumonia (except sometimes NL63, but usually just causes croup); Mild diarrhea in infants Don’t forget other URI viruses: Rhinovirus, Influenza A/B, Adenovirus, Parainfluenza, Respiratory syncytial virus, Human metapneumovirus.

“Novel” Coronaviruses. Novel coronaviruses predominantly in LOWER respiratory tract SARS, MERS, SARS-CoV-2 Don’t forget other LRIs: Viral Pneumonia: Influenza (A/B), Adenovirus, Parainfluenza (Type 1-4), Respiratory syncytial virus, Human metapneumovirus, NL63 Typical bacteria CAP: Lobar – Streptococcus pneumoniae , Staphylococcus aureus , Haemophilus influenzae , Moraxella catarrhalis; Gram neg, anaerobic if aspiration Bacterial bronchitis or atypical CAP: Bordetella pertussis, Mycoplasma pneumoniae , and Chlamydia pneumoniae SARS (2002-2003): Contained. CFR 10%. >50% mortality in >60 years. MERS: Not Contained. CFR 35%. Linked to direct camel exposure. High healthcare worker infection and other nosocomial spread Aerosolization during procedures (intubation, nebs, BiPAP, suctioning).

Novel CoV attachment. ACE-2 Receptors Type 2 alveolar cells - highest Bronchial epithelia Tongue > buccal epithelia Upper Intestinal epithelia Myocardial cells Kidney proximal tubule cells Bladder urothelial cells SARS-CoV-2 binds to ACE-2 Receptor 10-20x more strongly than SARS- CoV Question of ADEs (Antibody Dependent Enhancement) Antibodies can create a backdoor enhancement for viral replication Implications on viral replication and vaccine development safety https://www.nature.com/articles/s41368-020-0074-x https://jvi.asm.org/content/94/5/e02015-19.

Myth 2: Only Asian Men Get Coronavirus. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations Yanan Cao Y, Lin Li, Zhimin Feng, Shengqing Wan, Peide Huang, Xiaohui Sun, Fang Wen, Xuanlin Huang, Guang Ning & Weiqing Wang Cell Discovery 6, Article number: 11 (2020) | Cite this article Altmetric I Metrics 62k Accesses 310.

SARS-Cov-2 origin. Bat to a mammal (pangolin?) to human in Nov/Dec 2019 Pangolins used in Chinese medicine Probable link to seafood/exotic animal market Other plausible theory: Wuhan Level 4 Biohazard lab experimental animals sold for human consumption.

[Audio] Published 39 years ago.. Myth 3: COVID-19 was predicted in 1981.

SARS-Cov-2 Transmission. Novel: No herd immunity, No antibodies cross-reacting Incubation 2-14 days (outlier 27 days) Symptom onset median: Day 5-6 from exposure Doubling time: 6-7 days High viral shedding occurs early in disease course, even those with mild symptoms Prolonged shedding noted (unlikely reinfection) ? Up to 23% of transmissions due to pre-symptomatic cases in Shenzen True asymptotic cases apparently only 1% per WHO? Viral load apparently still high Apparently infectious? https://cmmid.github.io/topics/covid19/control-measures/pre-symptomatic-transmission.html https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf.

SARS-Cov-2 Transmission. Respiratory droplets (large - 3 ft, medium - 6 ft) Hand-to-mucus-membrane contact – sticks to skin easily! T-zone: eyes, nose, mouth vulnerable Viable for 3 days on solids (plastics, porcelain, steel); ~24 hours cardboard, dependent also on temperature/humidity; 3 hours if aerosolized Airborne – likely not airborne with cough? But certainly possible with intubation, non-invasive positive pressure ventilation, high flow O2, nebulizer, suctioning ?Fecal/oral? – viral shedding present in stool and diarrhea is common https://www.medrxiv.org/content/10.1101/2020.03.09.20033217v1.full.pdf.

Droplet-borne route Transmitted by Medium or large droplets Ballistic trajectory of. • large droplets Short-range airborne route Transmitted by aerosols airborne route Transmitted by aerosols fomite route • Large droplets (>IOO pm) : Fast deposition due to the domination of gravitational force Medium droplets between 5 and 100 wm Small droplets or droplet nuclei, or aerosols (< 5 pm): Responsible for airborne Fig 4. Illustration of different transmission routes. Small droplets (<5 gm). sometimes called aerosols. are responsible for the stu»rt-range rcnlte. long-range air- borne route. and indirect contact route: large droplets are responsible for the direct spray route and indirect contact route..

Seasonality and Mutation Rate. We don’t know. Some CoV are seasonal in northern hemisphere; MERS is not. High disease burden and outbreaks obscure seasonality. Typical viral mutation rate; see NextStrain for real time gene sequencing: https://nextstrain.org/ Major strain development: L type (more virulent) and S type (wild type/apparent first strain). Lethality difference unclear. Normally viruses become more benign over time. However, delayed symptom onset, delayed time to death, poor access to diagnosis with isolation, contact tracing and quarantine makes deadly strains persist..

Symptoms and Disease Course. Week 1: Fever (77-98%) (intermittent or persistent), Fatigue/Malaise (11-52%), Dry cough (46-82%), dyspnea (3-31%); Less common: Sputum (33%), Myalgia (15%), Headache (13%), Sore throat (14%), Diarrhea (4%), Nausea/Vomiting (5%), Nasal congestion (4%), Hemoptysis (1%) Week 2 (~ day 6-9 of symptoms): ~ 15-20% develop severe dyspnea due to viral pneumonia Hospitalization, supportive care, oxygen Week 2-3: Of hospitalized patients, 1/3 ultimately need ICU care, with up to half needing intubation (i.e. ~5% of total diagnosed cases need ICU) Can rapidly decline (over 12-24 hrs ) from mild hypoxia to frank ARDS Cytokine Storm, Multi-organ failure Late stage sudden cardiomyopathy/viral myocarditis, cardiac shock.

Cormorbidities and Risk Conditions. Age HTN Diabetes Coronary Heart Disease Hep B Cerebrovascular Disease COPD Cancer Children and pregnant women seem to do okay.

Clinical data (1099 cases) - Coronavirus disease 2019 (COVID-19) outbreak Age Patients Non-severe • Severe 5 28.88% Coexisting disorders Patients • Non-severe • Severe Any Hypertension Diabetes Coronary heart Hepatitis B Cerebrovascular m Chronic obstructim Chronic renal dQ Immunodeficiency 0.2% 232% 23.7% 16.2% Symptom or sign • Patients 'Non-severe 'Severe Fever during Cough Fatigue Sputum prod„. Mylgia or art.. Sore throat Chill Nausea or vo„. Nasal conges••• Diarrhea 13.7% Tonsil swelling 12.1% Andrzej 2020 37.6% 15-49 2699% 15.13% 5&64 65+ 1>14 Age.

Diagnosis. Travel History, Exposure and Symptoms most important Person Under Investigation Criteria No specific physical exam findings. Lungs may have rales or rhonchi. Hypoxia, even silent hypoxia, may be present, esp elders. Tachycardia and tachypnea. May present as severe asthma or COPD exacerbation..

Ancillary Studies. Most Common: WBC usually normal, Lymphopenia in 80%, Mild thrombocytopenia Low Procal ; Bacterial coinfection rare CRP and D-Dimer elevated proportionate to severity (marker of poor prognosis); DIC over time Increased ALT/AST to 70-100 range; Occasional increased alk phos Mild elevation of creatinine Generally normal troponin CXR (sensitivity 59%): Bilateral patchy or reticular infiltrates, perihilar infiltrates occasionally CT scan (sensitivity 86%; much better than RT-PCR!) Bilateral diffuse ground glass opacities , multifocal patchy consolidation , interstitial changes Changes prior to severe symptom onset! ECHO: Normal EF prior to late-onset sudden cardiogenic shock with dropping to EF <10% Co-infection rare but possible (5%).

Person Under Investigation (PUI). Clinicians should use their judgment. Most patients with COVID-19 have fever and/or cough or difficulty breathing. Priority may be given to: Hospitalized patients who have signs and symptoms compatible with COVID-19 in order to inform decisions related to infection control precautions. Symptomatic patients such as, older adults and individuals with chronic medical conditions and/or an immunocompromised state (e.g., diabetes, heart disease, receiving immunosuppressive medications, chronic lung disease, chronic kidney disease). Any persons including healthcare personnel , who within 14 days of symptom onset had close contact with a suspect or laboratory-confirmed COVID-19 patient, or who have a history of travel from affected geographic areas within 14 days of their symptom onset..

Person Under Investigation (PUI). Close contact is defined as— a) being within approximately 6 feet (2 meters) of a COVID-19 case for a prolonged period of time; close contact can occur while caring for, living with, visiting, or sharing a healthcare waiting area or room with a COVID-19 case – or – b) having direct contact with infectious secretions of a COVID-19 case (e.g., being coughed on) If such contact occurs while not wearing recommended personal protective equipment or PPE (e.g., gowns, gloves, NIOSH-certified disposable N95 respirator, eye protection), criteria for PUI consideration are met ..

Myth 4: Respiratory Viral Panel tests for this. Generally, RVP tests for: Adenovirus, Coronavirus 229E, Coronavirus HKU1, Coronavirus NL63, Coronavirus OC43 , Human metapneumovirus, Human rhinovirus/enterovirus, Influenza A, subtypes 2009H1N1, H1, H3, Influenza B, Parainfluenza virus types 1, 2, 3 and 4, Respiratory Syncytial Virus. Chlamydophila pneumoniae, Mycoplasma pneumoniae, Bordetella Pertussis in some labs. It does NOT test for COVID-19 (or SARS or MERS).

Testing. RT-PCR: Real-time Polymerase Chain Reaction of RNA Nasal AND Orophangeal Swabs (Collect 2 swabs) Sputum better (but more dangerous to collect?) Stool – not generally used for testing Blood or urine – virus not detected; blood could be tested for IgM, IgG later. DO get (bacterial) blood cultures for any sick patient. PCR ~ 60-80% sensitive A single negative RT-PCR doesn't exclude COVID-19 ( especially if obtained from a nasopharyngeal source or relatively early in the disease course). If RT-PCR is negative but suspicion remains, consider ongoing isolation and re-sampling several days later. Sensitivity from private labs may vary; no data yet. Also dependent on collection technique and timing – early test on asymptomatic may not be accurate.

Testing “Kits”. 1 Cold shipper w/ Refrigerate and Category B labels 2 Ice packs 2 – 3 mL Vials of viral transport media (VTM) 2 Nasopharyngeal Swabs The swabs CANNOT be of cotton or wooden shaft Only synthetic fiber swabs with plastic/aluminum shafts 1 Zip-close biohazard bag 1 95 kPa bags 2 Coronavirus Disease 2019 (COVID-19) Testing Approval Forms.

Outpatient Testing Supplies. Triage by phone or at door to Ascension urgent care. Try to keep patients in car or outside. If patient seen in clinic and needs unexpected testing, put mask on patient, wash hands, leave room. Confirm with preceptor. Go to lab for 2 swabs and biohazard bag. Don PPE: gown, gloves, surgical mask or n95, faceshield Test outside or in car (respect patient privacy). Place in biohazard lab. Lab will place on ice and call St Francis for STAT pick-up. Patient home on isolation (see CDC guidelines). Clean stethoscope, room, etc..

How to collect. How to collect a nasopharyngeal swab https://www.youtube.com/watch?v=DVJNWefmHjE#action=share How to collect an oropharyngeal swab https://www.youtube.com/watch?v=sYWYEAURUl8 Nasopharyngeal AND Oropharyngeal swabs, as separate swabs. If you don’t collect a good sample, it’s a waste of an expensive test and falsely negative! Collect sputum only if patient has productive cough (do not induce cough) Bronchoalveolar lavage is also high risk to healthcare workers. If intubated, collect tracheal aspirate. https://www.cdc.gov/urdo/downloads/SpecCollectionGuidelines.pdf.

Treatment. Mild/moderate symptoms (80%) Outpatient management of symptoms and isolation OTC Tylenol, cough and cold medications Avoid steroids (ICS or oral/IM) unless compelling need (COPD or Asthma Exac ) Possibly avoid ACEI or Ibuprofen – data unclear! Need to protect family members! (Check CDC guidelines) At least 2 weeks isolation? Unclear when viral shedding no longer present. Unclear if we will require two negative tests and/or begin testing IgM IgG.

Treatment. Moderate with risks/severe/critical symptoms (15-20%) Inpatient management and supportive care Obtain Advanced Directives! Offer Chaplain Support for high risk patients. Oxygen by NC (place surgical face mask over NC to reduce aerosolization?) Anticipate rapid progression to High Flow/NRB Avoid NIV/BiPAP/Bronchoscopy if possible (increased aerosolization -> risk to others!) ARDS: Controlled early intubation with airway pressure release ventilation (APRV), Paralysis, Prone positioning, Flolan . Tight connections of ETT and tubing. Avoid fluid blousing, sepsis protocol bolusing . NG tube for feeds (ARDS takes time to resolve) Daily labs: Renal, Mag, CBC with diff, DIC labs, ?LFTs, ?ABG (permissive hypercapnia if needed).

Treatment. Moderate with risks/severe/critical symptoms (15-20%) BiPAP increases risk of areolation due to positive pressure (as would CPAP), AND generally patients needing BiPAP end up needing intubation. Patients do worse on BiPAP compared to HFNC/NRB. If BiPAP is the ONLY option (no vents) or is needed due to COPD, negative pressure room, air filtration, helmet interface..

Treatment. Moderate with risks/severe/critical symptoms (15-20%) Antibiotics, Antifungal probably not helpful (RARE secondary infections) Procal and cultures can guide – discontinue at 48 hours Watch for HAP/VAP Steroid could: 1. increase viral levels, shedding time, lung damage -> ? increase mortality 2. reduce pathological hyper-immune response (beneficial for ARDS) At least NOT high dose pulsed steroids (not Solumedrol or Hydrocortisone) Cardiac: Watch for late onset cardiomyopathy (? Viral myocarditis) with sudden EF <10% leading to cardiogenic shock Be careful if coding patients – high risk to you, low chance of survival See https://emcrit.org/ibcc/COVID19/ for more critical care management!.

Experimental Treatment & Vaccine. Experimental: Lopinavir/Ritonavir ( Kaletra – protease inhibitors) Ribavirin Remdesivir Chloroquine/hydroxychloroquine High dose IV Vitamin C IVIG Serum antibodies of recovered patients Some Vaccine trials in Phase 1 Clinical Trials.

“EVERYTHING WE DO BEFORE A PANDEMIC WILL SEEM ALARMIST. EVERYTHING WE DO AFTER WILL SEEM INADEQUATE” ~ Michael Leavitt.

Epidemiology. “the branch of medicine which deals with the incidence , distribution , and possible control of diseases and other factors relating to health.” Incidence Prevalence R0 and R Case Fatality Rate Mortality Rate Prevention Containment Mitigation Infection, Prevention and Control (IPC).

Epidemiology. Outbreak: “more disease than would be expected” e.g. measles outbreaks Endemic: “diseases that remain in an area naturally” Outbreaks can also occur in endemic areas Endemic diseases can be exported to other places, causing outbreaks Public Health Emergency of International Concern (PHEIC): WHO declares if it 1. constitutes a public health risk to other States 2. potentially requires a coordinated international response Emergency Committee established, unlocks funding, supplies and international response Can also increase stigma, xenophobia, economic harm (tourism) to affected country Epidemic: “regional outbreak of a disease that spreads suddenly and unexpectedly” Pandemic: “worldwide, often rapid, spread of a disease” WHO declares and has implications for activation of worldwide response, national response, World Bank funding, etc..

Basic Reproduction Number ( R 0 ). “Number of cases directly generated by one case in completely susceptible population without interventions” Effective Reproduction Number (R): “number of cases generated by one case with interventions/immunity” Some individuals immunized or already infected/recovered Nonpharmaceutical Interventions (NPI) implemented (social distancing, quarantines, isolation, treatment).

How contagious is the new coronavirus? Scientists measure how contagious a virus is using 'reproduction numbers' • the likely number of people every sick person will infect assuming the whole population is susceptible. CARRIER • —y 0 REPRODUCTION NUMBER Influenza COVID-19 SARS MERS Measles Jm•nes McCmv ard WHO 1.5 4.9 2 to 5 8 20.

Case Fatality Rate. C ase fatality rate/risk/ratio ( CFR) is the ratio of deaths from a certain disease to the total number of people diagnosed with this disease for a certain period of time Deaths/Total Cases = CFR During epidemics, CFR often initially over-estimated as predominantly testing cases that are sicker in hospital (numerator); then CFR is under-estimated as increase testing of mild cases (denominator) that have not yet resolved (recovered or died) Longer time to resolution or death can make CFR look better than it really is until final outcome.

Mortality Rate. Mortality rate (death rate): Number of deaths in general or due to specific cause in particular population per unit of time. e.g. mortality rate of influenza per week is total deaths related to influenza Epidemic threshold: level of incidence (of disease or of death) above which an urgent response is needed; varies by disease. e.g. For influenza, if the mortality rate >7.3% that is, by definition, an epidemic. Once it drops below that, it is no longer epidemic. CFR is 0.1% but the mortality rate per week in the hospital will rise and fall..

Case Fatality rate. COVID-19: 0.7 to 3.4% (>5% in Wuhan itself during peak) Will be higher without access to healthcare, oxygen and ventilators Spanish Influenza 1918: >2.5% Mostly younger people Seasonal Influenza: 0.1-0.2%.

CFR with Comorbidities: 10.5% cardiovascular disease, 7% diabetes, 6% each for chronic respiratory disease, hypertension, and cancer. Case fatality for patients who developed respiratory failure, septic shock, or multiple organ dysfunction was 49%..

Current CFR 3.9 and thoughts about range. CFR 4.0 7.7 5.7 3.4 0.9 0.2 3.6 1.8 1.7 3.5 1.6.

COVID-19 Stats Summary. Median age affected - 50 Deaths: slightly more Males > Females Kids and pregnant women seem to do okay Of total cases 80% mild/moderate 15-20% are severe/critical 2.5 - 10% require ventilator CFR = 0.7% to 7.7% R0 = 2-5.

Possible estimates by Dr Lawler at American Hospital Association meeting.

Underestimation?. R0: 2.5 ; doubling time 7-10 days Community attack rate 30-40% = 96 million Cases requiring hospitalization 5% = 4.8 million Cases requiring ICU 1-2% = 1.9 million Cases requiring vents 1% = 1 million CFR 0.5% = US 488,000 deaths.

Harvard Epidemiologist (Dr Lipsitch ) + current disease ratios.

US Surge Capacity Challenges. Total hospitalizations per year: 34 million (including influenza) Hospital beds (2015): ~ 540,668 staffed beds , of which 94,837 ICU beds (of which 4698 dedicated pediatric ICU, 22,330 neonatal ICU); Per CDC Dr Fauci , 45,000 available ICU beds . Average occupancy: 64-68% Ventilators: ~ 62,188 full-feature mechanical ventilators; 98,738 devices other than full-feature ventilators – BiPAP; some in operating rooms too. 20-40% ICU patients typically need vent support 3.25 – 5.7 million patients need vents for COVID-19 On vent for 2-4 weeks Some would be same patients who would otherwise be hospitalized for other comorbidities. https://www.ncbi.nlm.nih.gov/pubmed/21149215 https://www.sccm.org/Communications/Critical-Care-Statistics.

Kansas Capacity. 11,345 licensed acute care beds of which 8766 staffed beds 1111 nursing home beds 292,953 admissions annually Predictions for COVID-19, based on Harvard and current data: Population: 2.912 million Kansans Community attack rate (40-70%): 1.164-2.038 million Hospital admission (15%): 174,600 - 305,700 Potential Deaths (1-2%): 29,120 – 58,240 (Influenza in Kansas annually only 1438) This assumes access to hospital care/healthcare workers/oxygen/vents https://www.kha-net.org/DataProductsandServices/STAT/HospitalUtilization/ http://www.kdheks.gov/flu/surveillance.htm.

Management of Epidemic. Prevention! Safe public health practices – vaccines, WASH (water, sanitation and hygiene) and IPC (Infection Prevention and Control) measures, Universal Precautions Surveillance systems of WHO, CDC/Ministry of Health, Public/Community Health Containment: Isolation of sick persons, Contact Tracing, Quarantine of exposed persons Mitigation: Nonpharmaceutical interventions Personal – Hand hygiene, Cover cough, Stayi away from sick persons, Avoid Face Social – Social distancing, Canceling mass gatherings/non-essential activities Environmental – Cleaning measures.