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Using Antibiotics “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 antibody 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 immunity either through natural infection or vaccination 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?.
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