Objectives

Update • COVID-19 – the virus • Testing • PPE • Management • Lessons Learned

COVID-19

• Clinical presentation • Mortality • Transmission • Vaccine

Clinical Presentations

• Hypoxia (as low as 75%) – without dyspnea – does not correlate with the CXR findings – auscultation may be normal

• Bilateral interstitial pneumonia – totally asymptomatic patients

• Cardiac involvement – myocarditis, pericarditis, new onset CHF /AF

• Other – encephalopathy – renal failure from dehydration – DKA

Mortality Rate

Mortality rate:1-2%- maybe lower Europe: > 10% ?? Variables: • testing capacity • patient population • healthcare infrastructure • Inoculum • genetic factors?

Droplet or Airborne Spread?

NEJM 2020 doi: 10.1056/NEJMc2004973 • dispersed SARS-2 virus with three-jet Collison nebulizer into a Goldberg

drum high-powered machine not reflective normal human cough conditions

Nebraska study doi.org/10.1101/2020.03.23.20039446. • biosafety isolation rooms- mild disease • significant environmental contamination • viral RNA but no viable virus found in air samples

WHO- March 2020 • spread by droplet- not airborne

– Exception: AGMPs

Asymptomatic Transmission

Can Pets Get COVID-19?

Potential for Vaccine Options: • live, attenuated vaccine

– can evolve in the host, potentially recapturing virulence • inactivated (part /whole )virus - heat or chemicals

– higher /repeat doses often required to achieve needed degree of protection.

Newer technologies • recombinant vaccine

– spike protein on the surface of Sars-CoV-2 • most likely to provoke an immune reaction

– extract genetic code →insert in bacterial/yeast genome →large quantities spike protein.

OR • bypass the protein step →insert genetic instruction in messenger RNA

Cautious Optimism for Vaccine

1960s - RSV vaccine • aggravate symptoms in infants who eventually caught the virus SARS -1 vaccine • made things worse in animal models • later modified /now repurposed for Sars-CoV-2

– safety testing to rule out the risk of enhanced disease

Global health expert: Jonathan Quick The End of Epidemics (2018) “Virus biology and vaccines technology could be the limiting factors, but politics and economics are far more likely to be the barrier to immunisation.”

Testing

Options:

• PCR • Serology

IH COVID 19 Testing

KGH laboratory – testing started March 17/20 • high throughput PCR system

• capacity to test up to 400 specimens/day • PCR assay detects 3 gene targets in SARS-CoV-2:

– N gene – RdRp gene – E gene

5185 tests done in Interior Health Testing criteria (plans to expand) • inpatients • healthcare workers • long term care residents • clusters

0

20

40

60

80

100

120

140

160

180

Jan 1 to 7 Jan 8 to 14 Jan 15 to 21 Jan 22 to 28 Jan 29 toFeb4

Feb 5 to 11 Feb 12 to 18 Feb 19 to 25 Feb 26 toMar3

Mar 4 to 10 Mar 11 to 17Mar 18 to 24Mar 25 to 31 Apr1 to 5

Influenza A Virus Influenza B Virus Respiratory Synctial Virus Metapneumovirus Parainfluenza Virus Adenovirus Rhinovirus COVID-19 virus (2019-nCoV)

Number of IH lab viral specimens positive by week

KGH started regional COVID testing

0

20

40

60

80

100

120

140

160

180

Jan 1 to 7 Jan 8 to 14 Jan 15 to 21 Jan 22 to 28 Jan 29 toFeb4

Feb 5 to 11 Feb 12 to 18 Feb 19 to 25 Feb 26 toMar3

Mar 4 to 10 Mar 11 to 17 Mar 18 to 24 Mar 25 to 31 Apr1 to 5

Influenza A Virus Influenza B Virus Respiratory Synctial Virus Metapneumovirus Parainfluenza Virus Adenovirus Rhinovirus COVID-19 virus (2019-nCoV)

Number of IH lab viral specimens positive by week

KGH started regional COVID testing

PCR Test

Specificity: excellent Sensitivity: 70-75% • very sensitive analytically – detects < 10 copies of RNA • not a transport/ stability issue • patient specific issue • negative test does not rule out infection • lower respiratory specimens superior in patients with pneumonia Limitations: • molecular test- does not guarantee viable virus • qualitative not quantitative • swab availability • reagent availability

Clinical Case

56 year old male March 25- admitted with pneumonia

– increasing cough/SOB/fever several days – RR >30, O2 sat 87% RA, increased WOB

Lab: • Blood work:

• Normal CBC (no lymphopenia) • D-dimer 669 • LDH 1480

• NP swab - COVID/Flu PCR • Chest Xray

CXR on admission Bibasilar patchy airspace disease

Follow up

Patient transferred to ICU – supplemental O2 given but not intubated

Microbiology results:

Mar 25: NP swab: indeterminate • 1/3 gene targets- very weak positive • sent to BCCDC for further testing

Mar 26: sputum referred to BCCDC Mar 27: NP swab: negative Mar 29: throat swab: negative

Follow up

Mar 25 NP swab: – confirmed by BCCDC as indeterminate (weak +)

Mar 26 sputum: – highly positive (BCCDC - April 1)

Patient: • clinically improved- recovering on ward • NP swab – still indeterminate

Inpatients: order upper and lower respiratory specimens • NP swab • sputum or endotracheal aspirate

Serology • IgM/ IgG • seroconversion at 7-11 days Unknowns: • is protection full/partial? • length of protective immunity? • cross reactivity with other coronaviruses/ RNA viruses

– studies pre-COVID - concerning Usefulness: • serological surveillance / retrospective scope of pandemic • potential source of prophylactic/therapeutic neutralizing antibodies • shield immunity

PPE

• Routine precautions • AGMPs • Donning/ doffing • Shortage of PPE

https://www.interiorhealth.ca/YourEnvironment/CommunicableDiseaseControl/covid19/IH-PH-COV-323%20Optimal%20Use%20of%20Personal%20Protective%20Equipment%20(PPE) 3Apr2020.pdf

https://www.interiorhealth.ca/YourEnvironment/CommunicableDiseaseControl/covid19/IH-PH-COV-332%20Memo_Resources%20for%20donning%20and%20doffing%20PPE%20_03Apr2020.pdf

https://www.interiorhealth.ca/YourEnvironment/CommunicableDiseaseControl/covid19/IH-PH-COV-263%20Memo%20COV1D-19%20UPDATE%20-%20Collection%20of%20Disposable%20N95%20Masks_27Mar2020.pdf

PPE shortage

Management

• ED flow • Treatment options • Other modalities • Isolation algorithms

https://www.interiorhealth.ca/YourEnvironment/CommunicableDiseaseControl/covid19/IH-PH-COV-334%20COVID-19_ED_HOT_COLD_Algorithm_03Apr%202020.pdf

https://www.interiorhealth.ca/YourEnvironment/CommunicableDiseaseControl/covid19/IH-PH-COV-335%20COVID-19%20ED%20Isolation%20and%20Testing_03Apr2020.pdf

Antiviral drugs proposed o lopinavir-ritonavir (Kaletra®) o chloroquine/hydroxychloroquine o remdesivir (investigational)

Immunomodulatory Drugs:

– tocilizumab (non-formulary)

Convalescent Plasma Therapy (CPT)

Treatment for COVID-19

• protease inhibitor indicated to treat HIV-1 infection • in vitro activity against coronaviruses

1 RCT / some case reports • RCT ( China) unblinded, not placebo controlled • 199 COVID-19 inpatients with severe pneumonia March 18, 2020 N Engl J Med 2020; DOI: 10.1056/MEJMoa2001282 • no difference in time to clinical improvement (7-point scale) • no difference in mortality, viral load, drug-induced ADRs Conclusion: lopinavir-ritonavir did not improve outcomes in severe COVID-19 pneumonia

Lopinavir-Ritonavir

Chloroquine /Hydroxychloroquine

Quinine derivatives Treatment: • malaria • anti-inflammatory - rheumatoid arthritis / lupus • extra-intestinal amebiasis Antiviral action:

– interfere with viral trafficking within cells inhibiting coronavirus replication

Adverse effects • potential QT prolongation • liver toxic effects • Immune modulating effects on IL-2

Case-controlled trial (France) - 42 inpatients with COVID-19 (any severity) • hydroxychloroquine 200 mg PO TID x 10 days ± azithromycin

March 19 Int J Antimicrob Agent 2020: doi.org/10.1016/ijantimicag.2020.105949 Primary outcome: nasopharyngeal viral clearance • Day 6 clearance higher in treatment vs. control group (70% vs. 12.5%, P=0.001) • No other outcomes reported (e.g. clinical improvement, mortality)

RCT comparing chloroquine to placebo (unpublished study)- China

• hospitalized patients with COVID-19 disease News briefing Biosc Trends 2020; DOI 10.5582/bst.2020.01047 • inhibited exacerbation of pneumonia /improved lung imaging/ promoted

virus-negative conversion/ shortened the disease course

Chloroquine/Hydroxychloroquine

Experimental, broad-spectrum antiviral • Gilead Sciences for treatment of the Ebola virus infection Trav Med Infect Dis 2020; doi.org/10.1016/j.tmaid/2020/1010615

• inhibits coronavirus RNA polymerase • ongoing clinical trials in China and US • Health Canada SAP & Gilead

– compassionate use in selected hospitalized patients

Remdesivir

Trav Med Infect Dis 2020; doi.org/10.1016/j.tmaid/2020/1010615

Monoclonal antibody (anti-human interleukin-6) – rheumatoid arthritis, juvenile idiopathic arthritis and giant cell arteritis

Not antiviral: - management of the “cytokine storm” seen with severe COVID-19

Case series Inclusion: 21 inpatients with severe COVID-19 pneumonia chinaXiv: 202003.00026v1. www.chinaxiv.org.user.download

Results: patients improved with normalization/improvement of:

• body temperature • improved O2 saturation • lower O2 requirements

Tocilizumab

– plasma from recovered COVID-19 patients • antibodies to treat new cases of COVID-19

– variable effectiveness for: • SARS coronavirus • Avian influenza A (H5N1) and influenza H1N1 Design: systemic review of 8 observational trials • Inclusion: CPT (varying doses) for SARS-CoV (2003) Results: • mortality: ARR 7% (95% CI -2.39-18.68) to 23% (95% CI 5.59-42.02)

(comparative studies) and 0-12.5% (non-comparative studies) • LOS: discharge by day 22 better / early treatment beneficial

Convalescent Plasma Therapy

J Infect Dis 2015; 211:80-90

Oseltamivir – used to treat and prevent influenza A&B – no coronavirus antiviral activity – avoid unless influenza suspected

Corticosteroids – based on use in influenza, MERS and SARS

• higher risk mortality, secondary infections, delayed viral lung clearance – avoid unless exacerbation of asthma/COPD, septic shock with risk benefit

analysis

Other Therapies

World Health Organization. Clinical management of severe acute respiratory infection (SARI)when COVID-19 is suspected. Interim guidance 13March2020. V1.2

NSAIDS, ACE-inhibitors and ARBs • upregulation of angiotensin converting enzyme-2 (ACE-2) expressed

on epithelial cells of the lung, intestine, kidney and blood vessels • coronaviruses bind to target cells in these tissues using ACE-2 Hypothesized: Do NSAIDS, ACE-I / ARBs facilitate COVID-19 ? • WHO - no evidence to avoid NSAIDS in COVID-19 • Hypertension Canada - no evidence to avoid ACE-I /ARBs for

hypertensive /heart disease patients in COVID-19

ACE receptors may actually be protective to minimize lung injury

Other considerations

Lessons Learned

• China- self isolation/ family clusters • South Korea- vigorous testing/ isolation • Italy- family clusters/ healthcare infrastructure/ isolation

Masks for everyone??

Lessons learned

With reduced mobility, but no change in transmission, outbreak expected to peak in April 2020