Elmhurst Grand Rounds COVID19 March 18 2020 Peter

Elmhurst Grand Rounds COVID-19 March 18, 2020 Peter Hongdau Liu (based on presentation by Allen Zhong)

COVID-19 Timeline (so far…) December 2019 Dec 7/8: “First” case - - Cluster of respiratory infections linked to seafood market in Wuhan Novel SAR-co. V-2 virus isolated as cause of pneumonia clusters Dec 31: WHO China announces outbreak January 2020 Jan 8: coronavirus announced as causative pathogen Jan 13: first case outside China - Thailand Jan 20: first case in US Jan 30: declared “public health emergency of international concern” February 2020 March 2020 Feb 3: Diamond Princess Mar 1: first NY case outbreak Feb 11: new disease named COVID-19 Feb 20: China confirms 74000+ cases, 2000+ deaths - Hotspots in Iran, Italy, and South Korea Mar 11: WHO declares Pandemic

SARS-Co. V-2 Virology v Coronaviruses- family within nidovirales order • Replication via m. RNA v Sub-divided into 4 coronavirus genera: alpha, beta, delta, gamma • Human Co. V’s are alpha and beta (MERS, SARS, COVID-19) v Medium-sized +ss. RNA v SARS-Co. V animal reservoir- horseshoe bat • Intermediate host- civet cats and raccoon dogs in wet markets v Human coronavirus suspected to present in about 13% of pneumonias • Less frequent than rhinovirus and influenza

Spike proteins (S) SARS-Co. V-2 Virology v 4 essential proteins for replication • Spike (S), nucleocapsid (N), membrane (M), envelope (E) v Nucleocapsid (N) Membrane (M) and Envelope (E) Life cycle: • S protein binds ACE 2 receptor on Type 2 • • pneumocytes Membrane merges with host, host RNA polymerase used to translate proteins Viral proteins released ACE 2

Cell nucleus Viral RNA Viral proteins

Previously Famous Coronaviruses SARS-Co. V 2002 -2003 v v v Isolated Spring 2003 Bats primary reservoir Transmitted by close contact • v Effective infection control proved key to stopping the 2013 epidemic 14 -15% fatality rate MERS-Co. V (Middle East) 2012 v v v Identified in Suadi Arabia 2012 Camels primary reservoir Transmitted by very close contact v From unprotected care to a patient v 35% fatality rate

SARS-Co. V Pathophysiology v SARS > diffuse alveolar damage • Extensive edema, hyaline membrane formation v v Affected cells: • Intestinal • Tubular epithelial • Neurons • Immune cells Indirect injury to other organs: • Cytokine storm • Lymphopenia

COVID-19 Routes of Transmission v Person-to-Person • Virus cultured from resp secretions, blood, stool • Close contact (within 6 ft) • Respiratory droplets when infected person coughs • • • v or sneezes Likely do not linger in air Most contagious when most symptomatic Transmission of asymp pts reported Contaminated surfaces or objects • Droplets on surfaces, unlikely to be main source of • transmission SAR-Co. V found on contaminated surfaces up to 6 -9 days, Et. OH solutions deactivated within 1 min

Detectable virus Aerosols: 3 hrs • t½ 1. 1 hrs Copper: 4 hrs • t½ 0. 7 hrs Cardboard: 24 hrs • t½ 3. 4 hrs Plastic: 2 -3 days • t½ 6. 8 hrs Stainless Steel: 2 -3 days • t½ 5. 6 hrs

COVID-19 Epidemiology v Based on Wuhan’s first 425 cases • R 0 - ~2. 5 -2. 9 (# of cases doubling • • every 7 days) Seasonal influenza: R 0 1 -2 1918 Pandemic Flu: R 0 2 -3 • <1, epidemic will burn out • >1, epidemic will grow exponentially v Mean incubation period 5. 2 days up to 12. 5 days • 95% CI of 4. 1 to 7 days v Mean infection period 2. 3 days

Epidemiology of COVID-19 in Wuhan R=1. 25 R=0. 32 R=3. 88 Population size: 11 M

Epidemiology of COVID-19 in Wuhan First case Spring Festival Travel Start of Cordon Sanitaire Mobile Hospitals launched

Epidemiology of COVID-19 in Wuhan R=3. 88 R=3. 87 Blue = projected trajectory if no prevention had continued

Epidemiology of COVID-19 in Wuhan R=1. 25 Blue = projected trajectory if this intervention had continued v Traffic ban, social distancing and home quarantining reduced the R 0 from 3. 88 to 1. 25 … but was not good enough Start of Cordon Sanitaire

Epidemiology of COVID-19 in Wuhan Blue = projected trajectory if this intervention continues R=0. 32 Start of Cordon Sanitaire Launch of mobile hospitals v Wuhan required home-quarantine, traffic ban, controlled groceries… v PLUS: designated hospitals + designated hotels for healthcare workers + PPE

Centralized Quarantine Strategies After Feb 1, 2020 Group 1 Test positive Mobile Cabin Hospitals (converted from stadiums or conference centers ) (Mild/moderate cases) If progressed to be severe Transported to regular hospitals, e. g. , ICU Group 2 Group 3 Suspected cases (cases with symptoms) Centrally quarantined in designated hotels Have Fever Centrally quarantined in designated hotels If confirmed case Group 4 Close contacts with confirmed or suspected cases Centrally quarantined in designated hotels or university dorms

COVID-19 Maps CDC. Gov https: //www. cdc. gov/coronavirus/2019 -ncov/cases-in-us. html Johns Hopkins University CSSE COVID-19 Map https: //gisanddata. maps. arcgis. com/apps/opsdashboard/index. html#/bda 7594740 fd 4 0299423467 b 48 e 9 ecf 6 Infection 2020. com covidtracking. com

Washington (03/17/20) Kings County: 488 cases, 43 † Snohomish County: 200 cases, 4 † New York (03/17/20) NY County: 644 cases, 7 † Westchester County: 380 cases, 0 † Nassau County: 140 cases, 1 † Suffolk Count: 97 cases, 3 † California (03/17/20) LA County: 144 cases, 1 † Santa Clara County: 155 cases, 4 †

COVID-19 Locally, per CDC (as of March 17, 2020) v USA v • Total cases: 5923 • Total deaths: 100 v By source of exposure • Travel related: 229 • Close contact: 245 • Under investigation: 3752 NY State • Total cases: 1374 • Total deaths: 13 v NYC • Total cases: 644 • Total deaths: 12

COVID-19 Risk Factors v 191 pts up to Jan. 31 in Wuhan • Retrospective review of 2 Wuhan hospitals • 137 discharged • 54 died v 48% co-morbidity • Hypertension (30%) • Diabetes (36%) • CAD (15%) v Risk factors in-hospital death • Older age (OR 1. 1, 95% CI 1. 03 -1. 17 per year, p= 0. 0043) • Higher SOFA score (5. 65, 2. 61 -12. 23) • D-dimer > 1 ug/m. L (18. 42, 2. 64 -128. 55) on admission • Median duration of viral shedding- 20 days (IQR 17 -24) in survivors • Longest 37 days

COVID-19 Clinical Course: Survivors vs Non-survivors

COVID-19 Clinical Presentation v Asymptomatic Patients • Princess Diamond cruise - all screened, 17% positive, half asymptomatic • Case series of 24 asymptomatic pts • 50% had ground-glass opacities/patchy shadowing on CT and 20% had other atypical imaging v Symptomatic • Pneumonia- fever, cough, dyspnea, and bilateral infiltrates on CXR/CT • Clinical features at onset of illness of 138 pts in Wuhan • Fever (99%) • Fatigue (70%) • Dry cough (59%) • Anorexia (40%) • Myalgias (35%) • Dyspnea (31%) • ARDS in 20% and mechanical ventilation in 12. 3% • Median time from first symptom to dyspnea- 5 days, admission 7, ARDS 8.

COVID-19 Clinical Presentation v China CDC Data of 72, 314 pts through Feb 11, 2020 Severity of disease • Mild (no or mild pneumonia) - 81% • Severe (dyspnea, hypoxia, >50% lung involvement on imaging within 1 -2 days) - 14% • Critical (resp failure, shock, multiorgan dysfunction)- 5% • Mortality- 2. 3%, all in critical group v Age Range • Median age: 49 -56 • Symptomatic infection children uncommon • 2% infections age 20 or less

COVID-19 Mortality Rate

COVID-19 Clinical Presentation: Labs v CBC: WBC usually normal • Lymphopenia (most common) (0. 8 – 1) • Both leukopenia and leukocytosis seen • Mild thrombocytopenia (>100 k) Elevated LFT’s in 30% High d-dimer and severe lymphopenia associated w/ mortality Procalcitonin <0. 5 in 95% of patients (Guan et al NEJM) v Labs overall unlikely to be “tremendously helpful” v v v

COVID-19 Clinical Presentation: Imaging CT v Ground-glass opacities (GGO) (86. 1%) v Mixed GGO and consolidation (64. 4%) v Vascular enlargement in the lesion (71. 3%) v Peripheral distribution (87. 1%) v Bilateral involvement (82. 2%) v Lower lung predominant (54. 5%) v Multifocal (54. 5%) CXR v Bilateral interstitial pneumonia v Bilateral infiltrates common w/ gravitational distribution

COVID-19 Clinical Presentation: CT Imaging

COVID-19 Clinical Presentation: CT vs Lung ultrasound

COVID-19 Diagnostic Testing v Diagnosis made via real time RT-PCR of sputum/swabs • E and Rd. Rp gene assays - 71 -95% sensitivity Chest CT evidence of viral pneumonia may precede positive RT-PCR test results – so PCR results should not overrule symptoms and CT findings

COVID-19 Testing v Gene Targets • ORF 1 ab and N • Rd. RP, E, N • ORF 1 b-nsp 14, N • Spike protein v In-house vs Commercial • Lap. Corp, Quest Diagnostics • UW, Stanford • CDC tests • Roche FDA emergency use authorization for 400, 000 test kits v US testing ~37, 000 per day

COVID-19 Testing

COVID-19 Treatment Strategies v Initial eval - early recognition, immediate isolation, infection control • Contact history v Encourage over the phone evaluation for testing v Limited testing, triage testing for: (per CDC) • Hospitalized w/ S&Sx (infection control) • Symptomatic w/ high risk factors (>65 y/o, • comorbidities, immunocompromised) High exposure risk (recent travel, healthcare worker who contact w/in 14 days) w/in 14 days of symptom onset

Effects of Multiple Interventions on Epidemics 1918 Flu Pandemic v Philadelphia • • • v v v First case Sep 17, 1918 Held a city-wide parade Sep 28, 1918 Only implement closures Oct 3 Peak weekly death rate: 257/100, 000 Total death rate: 719/100, 000 St. Louis • • v v First case Oct 5, 1918 Social distancing Oct 7, 1918 Peak weekly death rate: 31/100, 000 Total death rate: 347/100, 000

#FLATTENTHECURVE

COVID-19 Treatment Strategies v Home care - mild infections, quarantine • v Limit hospital burden Hospital care - severe disease, supplemental oxygen • HFNC and NIPPV- risks include aerosol-generating procedures • Require special isolation precautions v Respiratory distress • Intubation, mechanical ventilation • ECMO has been used v Adjuncts • Glucocorticoids are NOT indicated (except when w/ other • indications, i. e. COPD exacerbation) Increased mortality with influenza and delayed viral clearance in MERS

CDC Infection Control / PPE

COVID-19 Infection Control / PPE v Of the 42, 000 external healthcare workers who went to Wuhan after the strict adoption of full PPE: • 0 out of 42, 000 were infected PPE WORKS

COVID-19 Treatment Strategies v Management of severe COVID-19: O 2 therapy and monitoring v Supplemental O 2 w/ SARI and resp distress, hypoxemia, or shock, target Sp. O 2 > 94% v Close monitoring for signs of clinical deteriorating, progressive resp failure, sepsis, respond with supportive care v Early warning scores (NEWS 2) v Follow labs for liver injury, AKI, cardiac injury, or shock v Conservative fluid management when no evidence of shock v Management of co-infections v Empiric antimicrobials within 1 hour of identification of sepsis- CAP, HCAP, influenzas and deescalate based on micro and clinical judgement v Management of septic shock v Bolus 250 -500 m. L bolus and assess fluid status (peds: 10 -20 ml/kg) up to 30 ml/kg fluid in first 3 hours v Adults target MAP > 65 w/ vasopressors if unresponsive to fluids

COVID-19 Critical Care Course v 52/710 pts admitted to ICU in Wuhan between Dec to Jan 26 2020 • Mean age - 52 (SD 13. 3 yrs) • 40% chronic illness • 98% w/ fever • 32 (61. 5%) died • Median time from admission to death was 7 days (IQR 3 -11, max 28) v Non-survivors • Older (64. 6 yrs vs. 51. 9) • More ARDS (81% vs. 45%) • More on vents (94% vs. 35%) v End organ damage rates in whole cohort • ARDS (67%) • AKI (29%) • Cardiac injury (23%) • Liver dysfunction (29%) • Pneumothorax (2%) • Hospital-acquired infection (13. 5%)

Respiratory Failure / ARDS Management v v Recognize hypoxemic respiratory failure in a patient with resp distress refractory to standard O 2 therapy, provide O 2/vent • Intubate w/ airborne precautions v Prone ventilation for 12 -16 hrs v Higher PEEP in moderate to severe ARDS (Pa. O 2/Fi. O 2 <150) Low tidal volumes (4 -8 ml/kg of predicted body weight), lower inspiratory pressures (plateau pressure <30 cm. H 2 O) v Paralysis not recommended v ECMO can be considered if refractory to above interventions • • • v Permissive hypercapnia Deep sedation to control respiratory drive and achieve tidal volume targets Kids: plateau pressure <28 w/ lower p. H 7. 15 -7. 3. TV- 3 -8. Conservative fluid management

COVID-19 Investigational Therapies Remdesivir v v Lopinavir-Ritonavir Nucleotide analog that inhibits RNA polymerase complex and blocks replication Initially made for SARS-Co. V Activity against SARS-Co. V 2 in vitro and animals Clinical Trial (est. primary completion date 4/10/20) Remdesivir v v Combined protease inhibitor In vitro activity against SARS-Co. V Clinical Trial Others: Chloroquine, hyddroxycholorquin, interferon beta, and convalescent serum Lopinavir

COVID-19 Investigational Therapies v v Known effective antivirals: ribavirin, interferon, lopinavir, corticosteroids, nitazoxanide, nafamostat, favipiravir In vitro in Vero E 6; quantified by RT-PCR and immunofluorescence of NP Remdesivir EC 50 = 0. 77µM Chloroquine EC 50 = 1. 13µM

Remdesivir and Chloroquine against SARS-Co. V-2 v Remdesivir • Adenosine analog: incorporates into nascent viral RNA • Results in pre-mature termination • Functions at post-viral entry stage • Pre-clinical dose: 10 mg/kg v Chloroquine v Anti-malarial, autoimmune drug v Increases endosomal p. H required for viral/cell fusion v Functions at both entry and post-entry stages v Pre-clinical dose: 500 mg

Chloroquine against SARS-Co. V-2 Vero E 6 cells pretreated w/ chloroquine Post-infection treated cells: ED 50 = 4. 4µM

Chloroquine against SARS-Co. V-2 v Chinese clinical trials in 10 hospitals • 100 patients in Wuhan, Jingzhou, Guangzhou, Beijing, Shanghai • “Thus far, results from more than 100 patients have demonstrated that chloroquine phosphate is superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus negative conversion, and shortening the disease course according to the news briefing. ”

Surgical Procedures During COVID-19 [Recommendations for general surgery clinical practice in novel coronavirus pneumonia situation] 2020 Feb 14, PMID: 32057212 v Consensus recommendations from the General Surgery Branch of the Wuhan Medical Association v Confirmed cases should be arranged for isolation in designated hospitals v Risk of laparoscopy theoretically high (reduced lung volume, increased airway pressure, worse post-op lung functional recovery), but no data yet [Surgical treatment for esophageal cancer during the outbreak of COVID-19] 2020 Feb 27, PMID: 32105052 v Beijing Thoracic Surgery group

[Recommendations for general surgery clinical practice in novel coronavirus pneumonia situation] PMID: 32057212 Pre-Op v Designated negative pressure room (-5 Pa) v “ 3 -Level Protection” Double-layer hats, N 95, goggles/masks, double-layer sterile gloves, surgical gowns Intra-Op v Rapid Sequence Intubation v Low TV frequent ventilation, gauze to cover nose and mouth v Bovie: lowest effect power, smoke evacuator v Avoid mixed gas generated by cutting tissue Post-Op v Disposable sheets on beds, Cl disinfectant v Laminar flow peroxyacetic acid fumigation v >30 min disinfection time, closed >2 hr v v Patients should go to negative pressure rooms Patients with cough and fever after surgery should be isolated and re-tested Patients at higher risk for DVTs from prolonged hospitalization Can be cleared if 2 consecutive negative tests in asymptomatic patients