Outbreak response and case management

John Ferguson

Infectious Diseases, John Hunter Hospital

17/4/2020

Outbreak response - primary goals

• Minimise the number of people becoming infected or sick with COVID-19

• Manage the demand on our health systems

• Reduce morbidity by effective case management

• Help individuals and families to manage their risk

Reducing transmission

• Effective social distancing – based on modelling , high compliance required

• Case detection according to agreed criteria and based on (PCR) test availability

• Tracking down “close” contacts• > 15 mins face to face • > 2 hrs in same room

• Effective case and contacts quarantine

• Large investment in public health personnel and infrastructure – likely to be highly cost effective

Manage the demand on our health systems

• Develop methods for care and supervision of patients at home (o2 saturation monitoring

• Effective IC in the home (may be impractical)

• Identify the higher at risk group and consider hotel accommodation and nursing care there

• Surge capacity for hospitals to isolate and treat cases

• Separate areas for tested suspects awaiting results

• Need to ensure that existing illnesses get managed effectively

• Reduce unnecessary aerosol generating procedures – espnebulisation

Emerging evidence

• Asymptomatic carriage and infective potential

• Culture positivity – post day 8 of illness unlikely to be infectious despite PCR positivity

• Fluctuating PCR detection post recovery

• Utility of serology for diagnosis and testing of immunity

• “Clearance” of infected patients – generally 14 days post sx onset conservative; at least 72 hrs of being asymtomatic without fever (don’t retest)

• HCW risks for acquisition

• Social distancing – models for sequential de-escalation approaches

Case management

General management

• Consider admission if haemodynamically unstable, hypoxaemia (SpO₂ <94% on room air), reduced platelet count, comorbidities or unsuitable home environment.

• Discuss and complete a resuscitation plan for all patients admitted with provisional or confirmed diagnosis of COVID-19, as soon as practicable

• Nurse all patients using contact plus droplet precautions

• Avoid aerosol-generating procedures if possible. Aerosol-generating procedures include nebulised medications, high-flow nasal oxygen, non-invasive ventilation, bronchoscopy, and tracheal intubation

Re-testing of initial negative patients?

• Low to moderate pre-test probability

(e.g. Didn’t meet national testing criteria, firm alternate diagnosis, clinical or epidemiological issues not suggestive, testing of a febrile hospitalised patient admitted for a non-respiratory diagnosis)

• Remove from isolation (amber zone); don’t re-test

• High pre-test probability (judged by COVID consultant on call)• Continue isolation

• Repeat SARS-CoV-2 swab as soon as possible.

Monitoring

• Monitor CRP, FBC, EUC, LFTs, procalcitonin and LDH every 1-3 days, depending on severity

• Perform baseline 12-lead ECG

• Repeat CXR only if clinically indicated (e.g. if patient is deteriorating or has been recently intubated)

• There is no need for routine CT scanning

• If patient is critically unwell, monitor coagulation profile, troponin I and perform bedside echocardiography (where available)

General management

• Supplemental oxygen, starting with nasal prongs (0.5-3l/min) if SpO₂ <94% or significantly below baseline

• Fluid - 1-2 litres of IV fluid per day, only if no oral intake or clinically dehydrated ; nb patients with tachypnoea lose considerable fluid

• If hypotensive, administer 250ml fluid boluses and refer to ICU for vasopressor therapy if patient remains hypotensive after 2-3 boluses.

• Consider antibiotics for bacterial pneumonia if hypoxaemic (SpO₂ <94%), rising procalcitonin, pleural effusion or purulent sputum.

• Commence venous thromboembolism (VTE) prophylaxis as per standard protocols

Adjunctive rx

• There are no proven pharmaceutical treatments for COVID-19 other than supportive care.

• Avoid corticosteroids unless there is an evidence-based indication for them e.g. severe acute exacerbation of COPD or asthma.

• Do not use antivirals outside the context of a randomised controlled trial. No antiviral or immunomodulatory agent has thus far been proven effective in clinical trials, and they may even be harmful and/or in short supply.

Respiratory failure

• Minimise use of high flow nasal prong oxygen as much as possible.

• Use of non-invasive ventilation (NIV) is not recommended for those with confirmed COVID-19. NIV for COVID-19 is associated with a high failure rate, delayed intubation and possibility increased risk of aerosolization with poor mask fit.

• Aim for early intubation and positive pressure ventilation in those who are deteriorating.

45 yr female – local case, DM, morbid obesity, hypertension, IT worker, non smoker

• On admission

• MRSA colonised

13/4/20

• Requiring dialysis

• 80% FIo2

• Tracheostomy today 17/4

15/4/20: Acinetobacter baumannii , Stenotrophomonas in sputum

Mild initial LFT change characteristicAKI from April 3rd

Likely secondary bacterial infection April 5 shown by WCC, PCT and CRP rise

Corticosteroids

• No clear evidence of benefit thus far

• Conflicting data in ARDS in general

• Observational data in COVID from China• May lead to increased viral loads

• Should be used only for evidence-based indications (e.g. COPD exacerbation, refractory shock) in those with COVID

Remdesevir

• Nucleotide pro-drug active against many RNA viruses

• Incorporated into RNA chain by RdRp chain termination

• In-vitro potent inhibition of SARS1, MERS, Ebola

• Effective in mouse model SARS1 and primate MERS only if used early

• IV only (poor PO bioavailability)

• Very limited availability (Gilead) • Stringent compassionate access criteria, and needs importation

• Multiple current large RCTs in COVID19• Multiple countries but not Australia (despite us asking)

Clinical Trials of Remdesivir for Treatment of COVID-19

As of 17th March 2020, there are six randomized clinical trials in hospitalized patients with diagnosed COVID-19

COVID-19Study Design

Location Sponsor Study size (randomization) Study ID Primary endpoint

SevereDouble-blind, placebo-controlled

Wuhan, ChinaCapital Medical

University, ChinaN=453 (2:1)

10d RDV:PlaceboNCT04257656

Time to clinical improvement by Day 28

Mild/ModerateDouble-blind, placebo-controlled

Wuhan, ChinaCapital Medical

University, ChinaN=308 (1:1)

10d RDV:PlaceboNCT04252664

Time to clinical recovery by Day 28

All hospitalized*Double-blind, placebo-controlled

Global NIAIDN=394 (1:1)

10d RDV:PlaceboNCT04280705

Clinical status at Day 15 based on

7-point ordinal scale

SevereOpen-label

Global GileadN=400 (1:1)

10d RDV:5d RDVNCT04292899

Normalization of fever and O2 saturation by

Day 14

ModerateOpen-label

Global GileadN=600 (1:1:1)

10d RDV:5d RDV:SOCNCT04292730 Hospital discharge by

Day 14

All Hospitalized*Double-blind, placebo-controlled

Global WHON=400 (1:1)

10d RDV:PlaceboTBD

Clinical status at Day 15 based on

7-point ordinal scale*Stratified by disease severity at enrollment

RDV, remdesivirThese are the ongoing Remdesivir clinical trials – subjected to be updated.

Please refer to https://clinicaltrials.gov/ and WHO for complete trial informationFOR REACTIVE USE ONLY

Chloroquine/Hydroxychloroquine

• Antimalarials – synthetic derivatives of quinine

• Raise pH inside endosomes (preventing viral entry)

• Hydroxychloroquine more potent in-vitro than chloroquine• CQ EC50=5.47 micromolar; HCQ=0.72 micromolar

• Would need 8 litres of tonic water for potential efficacy against SARS-CoV2

• Large scale RCTs underway for prophylaxis in health care workers (UK, Australia, China, USA)

• Regulatory changes this week• Only specialists allowed to prescribe, for recognised indications

• Anecdotally, many doctors and dentists self-prescribing for prophylaxis

What got Trump all excited?

• Non-randomised study• 36 (42) patients at 2 French

hospitals (6 asymptomatic, 22 URTI, 8 LRTI)

• 20 got HCQ, 16 didn’t (refused or wrong hospital), 6 also got azithromycin

• 6 on HCQ dropped out (5 died or went to ICU) – not included in results

• Control arm had higher viral loads at baseline

• No clinically relevant outcomes

Gautret IJAA 2020

Lopinavir/ritonavir (“Kaletra”)

• HIV Protease inhibitor

• In-vitro MERS and SARS1• low potency viral inhibition at clinically achievable concentrations

• Primate model MERS• Early Rx improved outcomes and reduced viral load

• Human observational data SARS1• Early but not rescue therapy associated with improved outcomes –

confounders++

• Human observational data COVID-19 (China)• No signal of efficacy – messy data

• Open label RCT Lopinavir/rBD(n=99) for 14 days versus standard care (n=100)

• Adults with COVID and O2Sats<94% or P:F ratio<300

• Mortality day 28• 19.2% (Lop) versus 25% (control)

• Lop/r stopped in 14% because of AEs (diarrhoea)

Other

• Antiviral• Faviparavir

• Darunavir

• Immunomodulatory• Interferon 1-beta

• Convalescent serum

• Tocilizumab

• Who to test

• Who to admit (send COVID patients home if not sick)

• Infection control and clearance from precautions

• Don’t forget usual CAP investigations and treatment

• Don’t forget influenza (oseltamivir pending PCRs if sick)

• Avoid NIV and HFNO wherever possible

• Avoid nebulisers

• Do not use antivirals outside the context of a RCT

• Available on PPG, soon to be on internet

• Updated at least weekly