COVID-19 Precautions Recommended by Dr Nishtha Singh Saans doctor in Jaipur

1. The New Work TimeCYTOKINE STORMThe Coronavirus patients Betrayed by their ownImmune systemsA” cytokine storm’’ becomes an all-too-frequent phenomenon , particularly among the young. But treatments are being tested. The immune system keeps raging after the virus is no longer a threat 15% of all severely ill COVID-19 patients: younger patients more often- - Diagnosed by elevated Interleukin -6, interferon gamma, TNF alpha Elevated Ferritin levels may be the most simple and specific test Tocilzumab , Sarilumab in severe cases HCQS in milder cases

2. Tocilizumab / Actemra (Roche) • An IL-6 receptor antagonist • FDA approved treatment in: • Severe , active ,RA • CAR T cell induced cytokine release storm - - • IL-6 drives overactive inflammatory response in lungs of severely ill COVID-19 patients

3. Chloroquine / HCQS • CHLOROQUINE: a widely used anti-malarial • HYDROXYCHLOROQUINE: less toxic analogue • Both have immunomodulatory effects • Old drugs: in use over > 50 years • Safe drugs: In WHO list of safe and essential medicines. • Widely used: > 5 million prescriptions / year in U.S alone (2018)

4. Safety • Whilst majority of patients require no special caution - - • Dangerous hemolysis in patients with G6PD deficiency • Gastric side effects • Caution in diabetics • Significant drug interactions • Risk of cardiac arrhythmias (by QTc prolongation)

5. Anecdotal evidence for HCQS • Doctors in Wuhan observed patients with SLE on HCQS did not seem to develop COVID-19 • None of wuhan hospital’s dermatology department’s 80 lupus patients were infected • They hypothesized that ‘’ this may be due to long-term use of HCQS ‘’ • Anecdotal case reports of its use in the previous SARS outbreak in 2002-2003

6. Virology Journal • Chloroquine is a potent inhibitor of SARS coronavirus infected and spread martin J Vincent1, Eric Bergero,n2, Suzanne Benjannet2, Bobbie R Erickson1, Pierre E Rollin1, Thomas G Ksiazek1, Nabil G Seidah2 and Stuart T Nichol* 1.Chloroquine is effective in preventing the spread of SARS Co V in cell culture. 2.Favourable inhibition of virus spread observed when cells were treated with chloroquine either prior to or after SARS Co V infection.

7. Cellular evidence for HCQS • I) pH related: • An acidic pH at the surface of the host cell facilitates coronavirus entry • HCQS alters pH at cell membrane surface thus inhibiting fusion of virus to cell membrane ie inhibiting endocytosis • II) Other antiviral mechanisms: • Inhibits nucleic acid replication • Glycosylation of viral proteins • Inhibits virus assembly, virus particle transport, virus release • III) Other receptor mechanisms: • May involve ACE2 cellular receptor inhibition

8. Clinical Infectious Diseases • In vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of severe Acute Respiratory Syndrome Coronavirus 2 (SARS –CoV-2) xueting Yao, Fei Ye ,Miao Zhang, Cheng Cui, Baoying Huang, PeihuaNiu, Xu Liu, Li Zhao, Erdan Dong, Chunli Song… Show more Author Notes PK study which showed: 1) HCQS more effective than Chloroquine in inhibitory effect on COVID-19 2) Reaches high lung concentration 3) Optimal dose: 400mg bid on Day 1, than 200mg Day 2 - 5

9. Results: after 5 days of HCQS • Overall faster TTCR • Faster improvement in cough • Faster improvement in temperature • Faster imp • None progressed to severe disease (4 in the non- HCQS group) ‘’Our results confirm the short- term efficacy of HCQS in the treatment of COVID-19 pneumonia’’

10. Group de veille coronavirus {GVC} • ACTUALITES – ARTICLES SCIENTIFIQUES Int J of Antimicrobial Agents 2020 Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study 28 mars 2020 Source : Mediterranee Infection Auteur : Philippe Gautret and AI. Corresponding author: Didier Raoult • 80 hospitalized COVID-19 patients: • Rx with HCQS 200 mg TDS for 10 days + Azithromycin for 5 days

11. Results: too good to be true? • Clinical improvement in all but 2 of the 80 patients • Rapid decline in nasopharyngeal viral PCR load by Day 8: 93% • Viral cultures from resp samples negative by Day 5: 97% • Allowed rapid discharge from contagious wards after mean stay of 5 Days

12. Reply to Gautret et al. 2020: A Bayesian reanalysis of the effects ofhydroxychloroquine and azithromycin on viral carriage in patients with COVID-19 Oliver J Hulme. Eric – Jan Wagenmakers. Per Damkier. ChristofferFugl Madelung. Hartwig Roman Siebner. JannikHelweg – Larsen. Quentin Gronau. Thomas Lars Benfield. Kristoffer H Madsen

13. Criticism • Small size • No control limb • Physicians not blinded • Milder cases only • Selection bias could have skewed data • 6 patients dropped out: their data excluded from analysis- - • PCR tests not consistently performed • Conflicts of interest • Promoted on YouTube, Fox News by author/colleagues before review A deeply flawed study ‘’The article does not meet the society’s expected standard’’ Int J Antimicrob Agents

14. ‘This is insane!’ Many scientists lament Trump’s embrace of risky malaria drugs for coronavirus ‘’Let’s put our work into running score proper trials, and see if this effect holds up in well- Conducted studies,’’ Dahly says

15. ‘’ To those who say we need 30 multi center studies and 1000 patients I say when you have a Rix that works against zero others, this should become a benchmark. It is unethical not to administer it. It’s that simple’’ ‘’The evidence is anecdotal. The president is talking abut hope .My job, as a scientist, is to prove, without a doubt, that a drug is not only safe by that it actually works.’’