covid-19 at lhsc · 2020-06-04 · outline •review of covid-19 literature •focus on clinical...

Covid-19 at LHSC:An ID Physician’s Perspective

Dr. Megan Devlin, MD, FRCPC

Infectious Diseases, Assistant Professor

April 2nd, 2020

Some Notes:

• No Disclosures

• ZOOM Etiquette:• Mute your Microphone• Please save your questions for the end

• ID is piece, Multiple Stakeholders in this outbreak• Disagreement/Differing opinions common• New Data becoming rapidly available

• (April 1st was my cutoff)

• Evolving Guidelines and Shortages

Outline

• Review of Covid-19 literature• Focus on Clinical Course

• Risk Factors/Prognosis

• Therapeutics

• Discussion of ID/ASP plan for therapeutics

• Tips for Admitting, Managing and Discharging COVID+ or Presumed COVID patients

• Review of Clinical Characteristics of Admitted patients at LHSC

Hierarchy of COVID Literature

Basics of SARS-CoV-2

• +RNA virus, BetaCorona• Related to SARS-CoV-1• Transmitted Droplet/Contact, Ability to Aerosolize with specific procedures

• Some asymptomatic or pauci-symptomatic transmission

• To Date Worldwide (as of April 1 afternoon):• 927,986 Cases, 46,491 Deaths

• Canada:• 9,005 Cases, 105 Deaths

• Ontario:• 2,392 Cases, 37 Death (Mar. 31st)

Natural History

• Incubation Period: 5 days (~ 3-7 days)• Onset of Dyspnea: 7-8 days• Onset of symptoms to requiring mechanical

ventilation (12-14 days)• Recovery 2 weeks for mild, 3-6 weeks for

severe

• Viral Shedding:• Typically 10 Days in those recovered (from onset of

illness) (Severe disease ~20 days)• PCR detectable in stool, but unable to culture

(?Viable virus)

Zhou L. NEJM. 2020. Zhou F. Lancet. 2020.

Testing – PCR Based

In House (LHSC):

• E-gene – Envelope gene (more sensitive)

• RdRP-gene - RNA Dependent RNA Polymerase

• Running ~140 tests/day, ?Increased

• On NP, BAL, ET Aspirate, NOT on Stool

• TAT < 24hours

Test Ordered in Community (outside hospital) PHO

• Sensitivity: 70% for NP - Chinese Numbers, (Wang. JAMA. 2020)• Increased Sensitivity for lower respiratory specimens (96% for BAL)

• Specificity

Serologic Studies??

If E-gene positive,RdRP negative = INCONCLUSIVE

Only target being tested at PHO

Mild – Severe – Critical Disease

Mild Disease

• Non-Pneumonia/

• Mild-pneumonia

Severe

• Dyspnea

• RR >30

• Sat < 93%

• P/F < 300

81 % 14 %

Critical

• Respiratory Failure,

• Septic Shock

• MOD

5 %

Wu Z. JAMA. 2020.

Predictors for Severe Disease

Clinical

• Age (>50) OR 2.61 - 95% CI, 2.29-2.98

• Sex (Male) OR 1.34 - 95% CI, 1.195-1.521

• Smoking 1.73 95% CI 1.146-2.626

• Comorbidities• Any OR = 2.635, 95% CI 2.098-3.309

• CKD, OR = 6.017; 95% CI, 2.192-16.514

• COPD, OR = 5.323; 95% CI, 2.613-10.847

• Cerebral Vascular Disease, OR = 3.219; 95% CI, 1.486-6.972

Laboratory

• Lymphopenia

• Thrombocytopenia

• LDH

• CRP

• D-Dimer• *all for P < 0.001

• IL-6 Levels?

Zhou et al. Lancet . 2020.Ma C. PRE-PRINT. 2020, Metanalysis.

Prognostic Factors

• Old age (≥ 60 yrs) RR = 9.45; 95% CI, 8.09-11.04

• Higher qSOFA score (Zhou)

• Cardiovascular disease RR = 6.75; 95% CI, 5.40-8.43

• In Zhou for CAD OR (Univariate) – 21.40 (95% CI

• Hypertension RR = 4.48; 95% CI, 3.69-5.45

• Diabetes RR = 4.43; 95% CI, 3.49-5.61

• * All Independent prognostic factors

• CKD

• Need more data re: Malignancy, Immunocompromised population

Zhou F et al. Lancet . 2020.Ma C. PRE-PRINT. 2020, Meta-analysis.

Comparing CFR: SARS, COVID-19 and Influenza

Ruan, S. Lancet ID. 2020.

Notes on Clinical Characteristics

• 1/3 early GI symptoms?• More end organ disease, longer disease course• Some ONLY had GI symptoms (Han et al. AGJ. 2020)

• Cardiac: 19.7% “cardiac injury” in hospitalized patients, independent risk factor for mortality (51.2% vs 4.5%)

• Hypercoaguable state or DIC?• Those with elevated D-Dimer ?Therapeutic Anticoagulation• ?Improved outcomes if on anticoagulation? (Tang, JTH, 2020)

Tang N et al. Journal Thrombosis & Hemostasis. 2020.

Shi S et al. JAMA Cardiology. 2020.

Han et al. AGJ. 2020

Covid in Pregnancy

• No (?) reports of pregnant women requiring ventilation

• 3 Case reports of vertical transmission (Case series of 33 babies born to Covid + mothers)• Mothers delivered under Negative Pressure/Local Infection Control

Precautions• Neonates developed Pneumonia, NO Deaths

• Neonatal swabs NP and rectal swab + SARS-CoV-2

• ?Increased Preterm Labour

• Breastfeeding: 6 mothers breast milk tested negative

Zeng. JAMA Pediatrics. 2020.

Notes for Clinicians Admitting Presumptive Covid-19 patients

• At Admission:• Record O2 sat at room air• CBC, lytes, Cr, Liver Enzymes (ALT),

LDH, CRP, Troponin• Look for Markers of Severe Disease:

• Lymphopenia, Tropinitis, CRP, LDH• D-Dimer*

• NP Swab for COVID• ECG (if therapy started, monitor QTc)• CXR (Consider CT, US)

• Therapeutics:• Minimal Fluids (unless AKI, Cr)• Continue ACE/ARB if already on

• Consider Non-Covid issues (consider more than one illness)

• Code Status

• Infection Control: Droplet/Contact precautions• Practice your Donning and Doffing

• ?Notifying CCOT

• ?ABG if Sat <95%

?Standard Order Set

Imaging

Thomas, A. CMAJ. 2020.

CT US

Notes for Managing Patients

@leorahorwitzmd

GIM, NYU

Specific Therapeutics for Covid-19

Therapeutics for Consideration

Antivirals

• Anti-Retroviral (Protease Inhibitors):• Lopinavir/ritonavir• Darunavir/ritonair

• RNA Polymerase• Remdesivir

• Ribavirin

Other• Hydroxychloroquine

• (Plus Azithromycin)• (Plus Zinc and Azithromycin)

• Colchicine, Losartan

• Convalescent Plasma

• Anti IL-6 Therapy

Less Access/Experience in Canada

Anti Viral

• Favipravir

• Arbidol

Online as of Mar. 17

NEJM LPV/r in Severe Covid

• Jan. 18 – Feb. 23, 2020• Randomized, Controlled, Open-label trial• Included (n=199):

• SARS-CoV-2 + , Sat <94% at room air or PF <300• Excluded: Allergy, Cirrhosis, major Drug Interaction, HIV, Pregnancy, Cirrhosis

• Intervention: Lopinavir/ritonavir 400/100mg BID x 14 days vs Standard of Care

• End-points: • Primary: Time to Clinical improvement

• (Defined: Discharge from Hospital or 2 point improvement on a ordinal scale)

Cao, B et al. NEJM. 2020.

Caveats/Questions

• Patients received 1 st dose of LPV/r at 14 days

• ?Would Lopinavir/ritonavir given earlier result in a more significant benefit?

• Lopanivir/r: • Adverse Events (Nausea, Vomiting, Diarrhea)

• Drug-Drug interactions (Ritonavir “Booster” – Midazolam)


Hydroxychloroquine

• Rationale:• In vitro activity against SARS-CoV-2

• Especially when combined with Remdesivir

• Anti-Inflammatory Properties

• Chloroquine: Malaria

• Safety:• N&V, Dizziness, Headache, QT prolonging (w/ other agents), retinal disease,

Study Design

• Non-Randomized Controlled Trial in Marseille, France

• n = 26 intervention arm, 16 in control arm (alternate sites)• HCQ used• Azithromycin added at the discretion of the physician (n = 6)

• Endpoint – Viral Clearance (PCR Status at Day 6)• 41% were male, mean age 45

• 6 patients in treatment arm (HCQ) not included in analysis due to stopping therapy:• 3 transferred to ICU, 1 Death, 1 Nausea, 1 left hospital

HCQ Chinese Trial – Preprint (Mar. 31st, 2020)• Study Design:

• Double-blind, randomized parallel-group trial (1:1) • Recruitment: 4 to 28 February 2020• Location: Renmin University Hospital, Wuhan (single-centre)

• Inclusion:• Age ≥18y & CoV-2 confirmed by PCR • Pneumonia confirmed by chest CT • Not severely ill

• Intervention: Hydroxychloroquine 400 mg/d for 5 days (n=31)• Intervention: 200mg/d x 5 day• Control: usual care (n= 31)

• Outcome: • Time to clinical Recovery (body temperature), • CT Chest at D0 and D6

Chen Z, et al. PREPRINT. 2020.

• Intervention Group 2 (HCQ 200mg) missing

• Underpowered

A Note on HCQ OD

• Chloroquine/hydroxychloroquine OD: • Charcoal if <2h - expect rapid CNS/CVS crash;

• Tube early

• Diazepam 2 mg/kg over 30" then 1-2 mg/kg/d

• Epi 0.25 μg/kg/min, titrate to SBP ≥90

• NaHCO₃ or 3% NS for ↑QRS

• Avoid meds that ↑QT

• Watch for ↓K⁺ (shift); don't overcorrect

Ref: WikiTox

#chloroquinegate

Convalescent Plasma

Donors:

• Recovered from SARS-CoV-2

Convalescent Plasma

Shen C. JAMA. 2020

Colchicine

• Colchicine Coronavirus SARS-CoV2 Trial (COLCORONA) (COVID-19)• Montreal Heart Institute, clinicaltrials.gov

• COVID +• Randomized, double-blind, placebo-controlled, multi-center study.

Following signature of the informed consent form, approximately 6000 subjects meeting all inclusion and no exclusion criteria will be randomized to receive either colchicine or placebo (1:1 allocation ratio) for 30 days. Follow-up phone or video assessments will occur at 15 and 30 days following randomization for evaluation of the occurrence of any trial endpoints or other adverse events.

• Goal: 6000 participants

Evolution of ID LHSC Guidelines

• Week of Mar. 16: Document Created: Dr. Shalhoub and Michael Juba (ID pharmacy)• For Severe Cases: Kaletra, HCQ• For ICU: Remdesivir Application• Active work to be involved in RCTs: WHO and CATCO

• Week of Mar. 24:• HCQ alone or Nothing• For ICU: Tocilizumab• Active work to be involved in RCTs: WHO and CATCO

• Week of Mar. 30th:• Discretion of ID Physician• https://intra.lhsc.on.ca/antimicrobial-stewardship/covid-19-resources

https://intra.lhsc.on.ca/antimicrobial-stewardship/covid-19-resources


https://intra.lhsc.on.ca/antimicrobial-stewardship


https://intra.lhsc.on.ca/antimicrobial-stewardship

Summary of Literature for Therapy as of April 1Therapy Level of Available Evidence LHSC Access to drug? RCT Opportunity?

LPV/r Open label RCT in severe COVID - NEJM 2020

Liquid – Very limitedTablets (*If Crushing tablets reduce AUC < 40%)

WHO Solidarity/CATCO

Remdesivir In Vitro Data ?Compassionate Access for Pregnancy and Pediatric?

Closed to centers in Canada

HCQ RCT from Wuhan (PREPRINT) Yes, for now WHO Solidarity/CATCO

PEP Trials forthcoming

HCQ/Azithromycin Open label, non-randomized(n = 26), serious methodological flaws

Yes Join Raoult, Vive La France Libre

IL-6 Inhibitors(Tocilizumab/Sarilumab)

Case Series n=11 (PREPRINT Cost 4,500/vial Being explored

Colchicine N/A Yes Trial in Montreal

Convalescent Plasma JAMA (n=5 Cases Series) Looking into it Help!

Other:Losartan Trial in US

Hot off the Press (This AM)

• LHSC - Will be a WHO SOLIDARITY Site:• 4 arms:

• HCQ• LPV/r• Remdesivir• Control

• Both ICU/Admitted Patients• Ethics Approval Pending

• 2 HCQ as PEP Trials:• 1 for HCW• 1 for LTCF patients

Thanks to Seema, Michael Silverman, Sarah Shalhoub, Geriatric Division (M. Borrie)

ACE-inhibitors and COVID

Vaduganathan M, NEJM. 2020.

My Thoughts on Therapeutics

• Need to be studied in RCT when possible• Like many respiratory viral illness, therapy may be limited value

• Focus on • Control of Community Spread (Public Health Interventions)

• Physical Distancing, Access to Testing• Preventing Nosocomial Spread, Protecting HCW

• ?Testing for Every Admitted patient• Cohorting of Covid+ Patients• PPE SUPPLY• Surge Capacity

Tips on Discharging Patients

• Notify Public Health• Typically already in discussion

• Instructions on how to Self-Isolate• https://www.publichealthontario.ca/-/media/documents/ncov/factsheet-covid-19-how-to-self-

isolate.pdf?la=en• How are they getting home?• What does their home situation look like?

• Community Self-isolation removed:• Symptoms resolved (fever) AND• 14 days from onset of symptoms in community

• To remove from precaution in hospital: Symptoms resolved AND 2 negative swabs 24 hours apart

https://www.publichealthontario.ca/-/media/documents/ncov/factsheet-covid-19-how-to-self-isolate.pdf?la=en

Resources

• COVID: • Covidprotocols.org

• MLHU Website – Local Data:• Biweekly updates for community physicians (GPs)

• Train yourself in ICU level care:• https://www.quickicutraining.com/

https://www.quickicutraining.com/

Looking for people to follow on Twitter?

• ID/Aggregation of Published Studies• @mugecevik

• GIM Clinicians:• @FralickMike @DavidJuurlink (Clin

Pharm)

• ASP/IPAC• @ASPPhysician

• Clinical Trials:• @DrToddLee

• Mathematical Modelers• @DFisman @BogochIsaac

Covid-19 @ LHSCA Review of Cases

Clinical Covid at LHSC – 1 (As of 04.01)University Hospital – Mar. 16-27

Case Demographics PresumedLocation ofAcquisition

Therapy Received CRP atadmission

LOS (Days) Outcome

1 24 yo MT2DM

Community HCQ x 5 daysLPV/r x 4 days

72.0 6 Discharged in stable condition

2 74 yo MT2DM, HTN, CKD

Travel(Portugal)

HCQ x 5 daysLPV/r x 5 daysApplied for Remdesivir –DeclinedPipTazo

314.0 10t/f Mar. 18

Deceased (Mar. 27th)Vent on t/f from Strathroy, Requiring Dialysis

3 68 yo M T2DM, NAFLD

Community HCQ x 5 daysLPV/r C

196.8 A Mar. 23 Vent PAD #2,

4 37 yo M Travel (US) HCQ x 5 days 14.0 2 Discharged in stable condition

*(Admitted Patients not HCW)

Both pts attended Teen Challenge MeetingRequired/Requiring ICU level care

Clinical Covid at LHSC - 2University Hospital (~Mar. 25-29)

Case Demographics PresumedLocation ofAcquisition

Therapy Received CRP at admission

LOS (Days) Outcome

5 75 yo M HTN

Travel (Spain) Supportive 36.2 A Mar. 25 Admitted, requiringSupplemental O2

6 53yo M Community Supportive 12.2 4 Discharged in Stable Condition

7 62 yo F Community xx 110.6 A Mar . 27 Admitted, requiringSupplemental O2

8 21 yo F Community(Travel to Toronto)

Supportive 212.8 A Mar. 28 Ventilated x _ days

9 85 yo FParkinson’s Disease

Community (NH – Henley Place)

SupportiveCeftriaxone

120.0 A Mar. 29 Admitted, requiringSupplemental O2


Clinical Covid at LHSC - 3University Hospital (Mar. 29 – present)Case Demographics Presumed

Location ofAcquisition

Therapy Received

CRP at admission

LOS (Days) Outcome

10 73yo F Travel (Philippines) Supportive 180.2 A Mar. 30Presented Mar. 22

Vented PAD 1

11 82yo MHTN, CLL

Community (LRCP volunteer)

Ceftriaxone,Doxycycline

18.7 A Mar. 30 Supplemental O2

12 66 yo F CHF, COPD, HTN, Obesity

Community/ ?Nosocomial(A @ UH Jan. 25-Mar. 18th)

281 A Mar. 30 Vented PAD 0

13 73yo FCHF, T4

Travel (US) Supportive 31.4 A Mar. 31

14 76 yo MStroke, HTN, etc

Travel (US) Supportive 154.9 A Mar. 31

15 91yo FT2DM, HTN, etc

Community(Retirement home)

N/A A Mar. 29 CCU


Married

Clinical Covid at LHSC - 4University Hospital (Mar. 29 – present)Case Demographics Presumed


Therapy Received

CRP at admission

LOS (Days) Outcome

16 81 y MStroke, HTN

Travel (Brazil) Supportive,Ceftriaxone/Azithromycin

77.6 A Mar. 31 Supplemental O2

17 48 y FNo CM

Community(International students)

Supportive,Ceftriaxone/Azithromycin

131.5 A Mar. 30 Vented PAD 0


Clinical Covid at LHSC - 5Victoria Hospital

Case Demographics Presumed Location ofAcquisition


LOS (Days) Outcome

1 32 yo F Travel (US) Supportive 15.6 3 Discharged in Stable Condition

2 67 yo FCMML

Community HCQLopinavir/rRemdesivir

96.5 A Mar. 19th

Presented x 1 Mar. 17

Vented PAD 1

3 45 yo FMild Asthma

Travel (St. Maarten)

LPV/rHCQ

N/A A Mar. 22nd Vented, PAD Day 0

4 68 yo MHTN, T2DM, etc

Community (Wife Travel)

Supportive,PTZ/Azithromycin

274.7 t/f Mar. 27 Vented on t/ft/f from South Huron

5 67 yo M Hepatitis B

Community (Works at Loblaws)

Ceftriaxone/Azithromycin

171.3 A Mar. 29th AIRVO as of Mar. 31st

6 56 yo FeGPA, T2DM, CKD, etc

Community Supportive,PTZ

236.1 A Mar. 29th Vented, PAD 0


Clinical Covid at LHSC - 6Victoria HospitalCase Demographics Presumed



LOS (Days) Outcome

7 47yo FCervical Cancer

Community N/A A Mar. 24 Requiring Supplemental O2

8 56 yo FHTN

Community Supportive,Ceftriaxone

46.2 A Mar. 30 Requiring High flow O2

9 60 yo MOSA, HTN

Community 61.7 A Mar. 31


Total Confirmed as of April 1st ~3PM Confirmed• Total Number of Cases Admitted

at LHSC: 26• (UH – 17, Vic – 9)

• Male - 12/26

• % Community Acquired: 65%• (17/26)

• % Travel Acquired: 35%

CRP At Admission

• If CRP > 100• 9/12 in ICU – 75%

• CRP < 100:• 2/11 in ICU – 18%

Advocacy• Preventing Community Spread

• PPE Supply: Occurring at Local, Provincial, National Levels• (N95>Surgical/Isolation Masks, Gowns)

• Staff Wellness & Time away

• Administrative/Planning: Surge Planning

COVID Hospital Hierarchy of Needs

Summary

• Increasing Numbers of Patients of LHSC with COVID• ?Mid April Peak?

• Current data to support specific therapies is limited, more forthcoming

• Active work to be involved in RCTs

Thanks &Questions

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covid-19 at lhsc · 2020-06-04 · outline •review of covid-19 literature •focus on clinical...

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