“A little knowledge is a dangerous thing”

Dr John Ng (9th April 2020)

Acknowledgement: Dr David Pham The Pandemic

 COVID-19

 Coronavirus Disease 2019

 Enveloped, positive sense, single-stranded, RNA virus

 “Crown-like” appearance on electron microscopy

 Aetiological agent formally designated SARS-CoV-2

 COVID-19 chosen to avoid associations with any ethnic group, geographical location or animal species while still being easily pronounceable Wang et al Lancet 2020 Public health emergency of international concern 30/01/20 Pandemic declared by WHO 11/03/2020 1,341,907 confirmed cases 07/04/2020 – www.jhu.edu 74,746 confirmed deaths 07/04/2020 – www.jhu.edu The Infodemic

 Social media is driving the spread of so much information and misinformation that WHO has described this as an “infodemic”

 WHO has launched its own information platform specifically to “myth-bust” fake news The Infodemic

 Media misinformation that consuming alcohol (whiskey) kills COVID-19 resulted in ~300 deaths in Iran and Turkey plus numerous cases of blindness due to methanol poisoning from “bootleg” alcohol  Innumerable “scientific” reports are being published in “pre-print” formats such as “medRxiv” without editorial oversight or peer review

 ie – there is lots of dodgy data! Question 1

 What is the sensitivity?

 Short answer – unknown but a figure of ~75% has been widely promulgated in the media originating from an ED blog called “EMCrit” Question 1 Question 1 Question 1

 Dodgy data!

 “Studies” are both “pre-prints”

 Both retrospective

 Both used inappropriate gold standards

 No assessment of collection adequacy

 Sensitivities cannot be correct

 Currently no validation; no standardization; no good gold standard Question 1

 If no sensitivity, are we missing COVID-19? Question 1

 What if the sensitivity really is 75%?

 Test positivity rate is 2.1% (2686/126146) (5/4/20)

 21 cases detected; 7 cases missed per 1000 patients if tested once

 26 (26.3) cases detected; 2 (1.7) cases missed per 1000 patients if tested two times therefore 200 additional tests to detect 1 more case

 28 (27.6) cases detected; 0 (0.4) cases missed per 1000 patients if tested three times therefore 286 (285.7) additional tests to detect 1 more case Question 1

 Low test positivity means low inherent sensitivity is not overcome simply by repeating test

 Only repeat the PCR if there is a high clinical index of suspicion (eg travel; contact; suspicious radiology; consistent disease without an alternate diagnosis; etc) otherwise this simply wastes tests

 Do not repeat the PCR simply because a negative result does not exclude disease (true for all tests) Question 2

 Asymptomatic testing?

18 patients Zou et al NEJM 2020 Question 2

 Asymptomatic testing?

82 patients Pan et al LIJ 2020 Question 2

 Limited available data

 Yield for COVID-19 PCR testing is best during the first week of symptoms

 COVID-19 PCR could be positive 24 hours before symptoms develop

 For an incubation period up to 14 days, PCR will be falsely negative for the majority of the asymptomatic period and waste tests

 Generally not useful to test while asymptomatic Question 3

 Are asymptomatic patients contagious?

 Unknown if only contagious if viral shedding

 If “yes” then asymptomatic patients only contagious in the 24 hours prior to symptoms

1 asymptomatic transmission Question 3

88yo male infected by asymptomatic family members Question 3

Asymptomatic patient 1 infected 5 family members Bai et al JAMA 2020 Question 3

Rothe et al NEJM 2020 - patient was actually symptomatic! Question 3

Du et al pre-print EID June 2020

59/468 (12.6%) negative serial intervals Question 3

 More dodgy data!

 Proof of asymptomatic COVID-19 spread limited to case reports

 Impact of asymptomatic COVID-19 spread limited to modelling

 ?1/8 cases due to asymptomatic spread

 Modelling needs to be replicated or demonstrated by actual cases Question 4

 Are droplet precautions sufficient?

Long et al J Evid Based Med 2020 Question 4

 COVID-19 secondary attack rates

 3-10% for household members (WHO-China joint mission report)

 10.5% (2/19) for household members

 No (0/426) non household, close contact (10 minutes within 6 feet) acquired COVID-19 Question 4

 “Pre-print” report

 Household secondary attack rate 15%

 Ro number 0.4 (2-3 otherwise) Question 4

 85% close contact (10 minutes within 2m) with surgical mask &15% close contact with N95 mask

 No transmissions Ng et al Ann Int Med 2020 Question 4

 No good data to support N95 over surgical masks for COVID-19

 Limited data supports efficacy of surgical masks (droplet precautions) in preventing COVID-19 infection Question 5

 What is the role of cloth masks? (as now advised by the American CDC) Question 5

 What is the role of cloth masks? (as now advised by the American CDC) Question 5

RR 13 Vs medical mask; RR 6.64 Vs control; very wide confidence intervals; results only significant for ILI  Cloth clearly inferior to a medical mask Question 5 Question 5 Question 5

 Cloth masks are not a substitute for surgical or N95 masks

 Indirect evidence that might protect the wearer

 Indirect evidence that might protect from the wearer

 Theoretical risk of harm from false reassurance and self contamination

 Might be better than nothing in extremis (public relations exercise?) Question 6

 Are there specific COVID-19 treatments?

 Short answer – no

 Beware misinformation! (eg whisky)

 Agents under investigation include convalescent immunoglobulin; lopinavir/ritonavir; chloroquine or hydroxychloroquine; tocilizumab; etc Question 6

 Convalescent immunoglobulin

Original SARS

Mair-Jenkins et al JID 2015 Question 6

 Convalescent immunoglobulin

“25g/day for 5 days” “200ml”

 Two small case series; no controlled studies Question 6

 Lopinavir/ritonavir

2 case series of 75 and 41 SARS patients compared with historical controls only Question 6

• 22 HCWs exposed to MERS compared to 21 HCWs exposed to MERS at 4 other hospitals who did not get PEP Question 6 Question 6

 Lopinavir/ritonavir – no significant benefit

400/100mg bd 14 days Question 6

 Chloroquine or hydroxychloroquine

Hydroxychloroquine is more inhibitory than chloroquine in vitro Vs SARS-CoV2 in Vero cell culture Question 6

 Chloroquine or hydroxychloroquine

 80 patients given hydroxychloroquine 200mg tds for 10 days + azithromycin 500mg then 250mg daily for 4 days

 No controls; rationale for azithromycin unclear Question 6

 Chloroquine or hydroxychloroquine

83% reduction in NP viral load by day 8 Question 6

 Tocilizumab

 IL-6 receptor monoclonal

 Pre-print (on chinaXiv)

 Case series of 21 patients (no controls) who recovered on tocilizumab 400mg single dose

 Concurrent lopinavir + methylprednisone Question 7

 How will this all end?

 Short answer – by the development of herd either through natural infection or

 Long answer – development of immunity is unknown Question 7

 Evidence for reinfection

 Media reports of a Japanese man and woman who have re-tested positive after testing negative

 Pre-print report of 38/262 patients re-testing positive

 Pre-print report of 4 macaque monkeys resistant to COVID-19 reinfection Question 7

 Immunity Passport?

 Widely reported in German, UK and Australian media as a means to clear cases Question 7

 Immunity Passport?

 Unknown if detectable antibody equates with protections – use for late diagnosis Final Thoughts

QUESTIONS?