outbreak response and case management
TRANSCRIPT
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
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.
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