Finally both The Times of India (18th June 2020) and The Indian Express (19th June 2020) have cited an editorial published by the Indian Journal of Medical Research that all mathematical models on the Covid-19 pandemic were incorrect, and worse carry a “strong element of bias.”

 

Sadly the edit does not provide any further elaboration on this “bias”. It was expected that the authors dived deep into their “bias” hypothesis. Especially because of the fact that the numbers sprayed by the doomsayers have just not materialised. The exaggeration was so obvious that it took ones breath away. Data from all over the world kept pouring in that mortality in Covid-19 ranged around 1-2 infected per thousand, at times even less than this. But the doom sayers persisted with their doom and gloom predictions as recently as this week.

 

Astonishingly the doomsayers have been provided platforms by the media all these months. The predictions made for terrifying headlines. The protocol in the media was rapidly established, the bigger the numbers for people infected , the greater would be force the force behind the news stories published and interviews recorded.

 

Editors scrambled without exception to provide more and more sensational headlines. No one questioned the source of these deeply flawed models. Neither has this editorial. The authors of the editorial need to answer as to why they presume there was a strong bias by the modellers ? What is a weak “bias?” What were the forces behind the “bias?” Does it really matter whether the modellers were from the university of Kurukshetra or the University of Washington? Was there any influence of these modellers with “bias” on the ICMR?

 

Who funds these newly established non governmental centres for disease control in India? These are some hard questions that need to be checked. Did the media inadvertently provide publicity to these modellers? Or were they hand in glove? Did the editors not realise that despite large-scale infectivity the death rate of the SARS-CoV-2 was very low amongst Indians. As opposed to death rate in Western countries of 3 figures per million, the Indian death rate has been a single digit per million of the population.

 

As of today there have been 12,605 deaths in India at a rate of 9 per million. A remarkably low number but true. There is always the probability that a considerable number of these deaths may be with Covid-19 virus as a bystander, rather than because of it. The modellers however has predicted lakhs of deaths.

 

Unfortunately these modellers were taken at face value, and not unlike the rest of the world, the government was compelled to over react. Who wants lakhs of deaths on their watch? Certainly no sane or responsible government. The English government responded to the Imperial college “document” as did we to our own brilliant modellers. The repercussions will be felt far and wide and sadly for a long time.

 

It is so obvious that lakhs of business lie ruined, lakhs of people were forced to literally walk thousands of kilometres back to their villages. Hundreds succumbed in the ordeal. Little girls walked bare feet hundreds of kilometres to drop dead due to exhaustion and starvation. Many got ploughed down by vehicles as they trudged home in utter despair. The harrowing list of miseries is endless.

 

But despite the clearly visible and palpable sufferings of lakhs of people the media refused to suspend sensationalism around Covid-19. The interviews kept coming, guests repeated ad nauseam that millions would be infected by SARS-CoV-2. That millions would get infected is so obvious that repeating this fact again and again is downright stupid or deliberate scare mongering.

 

The number of infected people infected so far are 381,485. Any public health student will know that in reality at least 10 times this number are actually infected. There is considerable serological data from across the globe ascertaining to the fact that at least 10 times more people are infected that those detected by a positive RT-PCR test. We therefore have at least 3.8 million people infected.

 

3.8 or 4 million people infected seems like a huge number till we bear in mind that we have 1,350 million people in our country. This implies that only 0.296% of our population has been infected by Covid-19. The mainstream and alternate media however keeps drumming the “millions” number.

 

When you keep repeating the “millions’ figure, knowing very well that as the denominator expands the mortality rate gets lowered there is a strong chance that some agenda is at play. Sensationalism for 4 weeks my be considered an inadvertent error, but to keep flogging a weakening horse over months becomes more than suspicious.

 

Why an online so called alternative media magazine priding itself on objectivity repeatedly invite doomsayers for interviews is downright baffling if not suspicious. There is neither science nor any substance in the interviews.

 

I have been repeatedly (in my blogs, videos and interviews ) underscoring the low mortality rate in Covid-19 patients. This was not based on astrology but on painstaking evidence gathered from peer reviewed medical literature. Above all there was absolutely no agenda. It certainly was not for applause or being in the spot light. The panic was becoming both visible and palpable, the ramifications of the fear will cast a large shadow for years to come.

 

According to the Swiss Policy Research the overall lethality of Covid-19 is about 0.1% as per the latest immunological and serological studies. Thus in the range of a strong seasonal flu.

 

The overall mortality in in the range of a strong flu season in countries like the UDS,UK, and also Sweden ( without a lockdown). In country like Germany, Austria and Switzerland overall mortality is in the range of a mild flu season.

 

Upto 80% of test positive cases remain without symptoms. Even among 70-79 year old, about 60% remain symptom free. Almost 95% patients develop moderate symptoms.

 

Importantly 60% of people may have cellular background immunity to Covid-19 due to previous common colds (coronavirus infection).

 

The average age of people dying is 80 years and 96% of these have  chronic illnesses.

 

When people sit down to write about these times centuries from now, they surely will notice that more people died of fear of this virus than by the virus itself.

 

A lot of this fear has been fuelled by the modellers and the media. Mercifully  some in the  print media have finally realised that the mathematical models presented all these months are manifestly incorrect.

 

https://youtu.be/5ZYmDgAu5Zg

 

Antivirals can definitely play a role in management of Covid-19 patients. The only 2 drugs with randomised trials so far are Interferon and Remdesivir. Interferon should be given before 7 days of symptom onset. The very few patients that do not recover may need tocilizumab which acts against interleukin-6 receptors.Only one injection may be needed. The aircraft carrier Theodore Roosevelt has demonstrated that 60% of infected patients remain asymptomatic, 60% develop antibodies and above all only 1 sailor succumbed out of the 1100 infected.

Hence case fatality rate is less than 0.1% in young and fit sailors. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial

Published Online The Lancet; May 8, 2020 https://doi.org/10.1016/ S0140-6736(20)31042-4

 

Remdesivir for the Treatment of Covid-19 — Preliminary Report

J.H. Beigel, K.M. Tomashek, L.E. Dodd, A.K. Mehta, B.S. Zingman, A.C. Kalil, E. Hohmann, H.Y. Chu, A. Luetkemeyer, S. Kline, D. Lopez de Castilla, R.W. Finberg, K. Dierberg, V. Tapson, L. Hsieh, T.F. Patterson, R. Paredes, D.A. Sweeney, W.R. Short, G. Touloumi, D.C. Lye, N. Ohmagari, M. Oh, G.M. Ruiz-Palacios, T. Benfield, G. Fätkenheuer, M.G. Kortepeter, R.L. Atmar, C.B. Creech, J. Lundgren, A.G. Babiker, S. Pett, J.D. Neaton, T.H. Burgess, T. Bonnett, M. Green, M. Makowski, A. Osinusi, S. Nayak, and H.C. Lane, for the ACTT-1 Study Group Members* This article was published on May 22, 2020, at NEJM.org.

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19

Jason D. Goldman, M.D., M.P.H., David C.B. Lye, M.B., B.S., David S. Hui, M.D., Kristen M. Marks, M.D., Raffaele Bruno, M.D., Rocio Montejano, M.D., Christoph D. Spinner, M.D., Massimo Galli, M.D., Mi-Young Ahn, M.D., Ronald G. Nahass, M.D., Yao-Shen Chen, M.D., Devi SenGupta, M.D., Robert H. Hyland, D.Phil., Anu O. Osinusi, M.D., Huyen Cao, M.D., Christiana Blair, M.S., Xuelian Wei, Ph.D., Anuj Gaggar, M.D., Ph.D., Diana M. Brainard, M.D., William J. Towner, M.D., Jose Muñoz, M.D., Kathleen M. Mullane, D.O., Pharm.D., Francisco M. Marty, M.D.,Karen T. Tashima, M.D., George Diaz, M.D., and Aruna Subramanian, M.D., for the GS-US-540-5773 Investigators*

This article was published on May 27, 2020, at NEJM.org. DOI: 10.1056/NEJMoa2015301

medRxiv preprint doi: https://doi.org/10.1101/2020.05.29.20117358.this version posted June 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Tocilizumab for COVID-19 Tocilizumab for treatment of mechanically ventilated patients with COVID-19 Emily C Somers, PhD ScM1,2,3*, Gregory A Eschenauer, PharmD4*, Jonathan P Troost, PhD5, Jonathan L Golob, MD PhD1, Tejal N Gandhi, MD1, Lu Wang, PhD6, Nina Zhou, MS6, Lindsay A Petty, MD1, Ji Hoon Baang, MD1, Nicholas O Dillman, PharmD7, David Frame, PharmD4, Kevin S Gregg, MD1, Dan R Kaul, MD1, Jerod Nagel, PharmD7, Twisha S Patel, PharmD7, Shiwei Zhou, MD1, Adam S Lauring, MD PhD1, David A Hanauer, MD MS8, Emily Martin, PhD9, Pratima Sharma, MD MS1, Christopher M Fung, MD10, Jason M Pogue, PharmD4

Effective treatment of severe COVID-19 patients with tocilizumab

Xiaoling Xua,1,2, Mingfeng Hanb,1, Tiantian Lia, Wei Sunb, Dongsheng Wanga, Binqing Fuc,d, Yonggang Zhouc,d, Xiaohu Zhengc,d, Yun Yange, Xiuyong Lif, Xiaohua Zhangb, Aijun Pane, and Haiming Weic,d,2

www.pnas.org/cgi/doi/10.1073/pnas.2005615117

 

Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in severe patients with COVID-19

S. Sciascia1,2, F. Aprà2, A. Baffa1,2, S. Baldovino1,2, D. Boaro2, R. Boero2, S. Bonora2, A. Calcagno2, I. Cecchi1,2, G. Cinnirella2, M. Converso2, M. Cozzi1,2, P. Crosasso2, F. De Iaco2, G. Di Perri2, M. Eandi3, R. Fenoglio1,2, M. Giusti2, D. Imperiale2, G. Imperiale2, S. Livigni2, E. Manno2,

Newspapers need to desist from sensational headlines; columnists ought to restrict themselves to facts, mortality in India is indeed lower than other countries; probably because of some form of hidden and unknown immunity. The undeniable fact is that few die from Covid-19 in India as compared to other nations. Either one supports extended lockdown or welcomes the easing of lockdown. One cannot demand both in the same breath.

 

References:-

 

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Published Online,The Lancet. May 29, 2020 https://doi.org/10.1016/ S0140-6736(20)31182-X

 

Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID-19 infection Shaoqing Leia, Fang Jiangb,c, Wating Sua, Chang Chend, Jingli Chene, Wei Meif, Li-Ying Zhana, Yifan Jiaa, Liangqing Zhangg, Danyong Liug, Zhong-Yuan Xiaa,*, Zhengyuan Xiab,c,g,*

EClinicalMedicine. https://doi.org/10.1016/j.eclinm.2020.100331

 

https://youtu.be/XmUbSXT7qPE

 

 

It is amusing to watch professional conspiracy theorists touting the use of hydroxychloroquine (HCQ) for treating Covid-19 patients. They invite “scientists” who bemoan the fact that HCQ is being deliberately ignored by the globalists. The invitees are perfectly respectable people who have impeccable credentials but they are not into clinical medicine. Hence their declaration that the pandemic can be resolved by a few HCQ tablets is laughable.

 

 

Sadly a US company owned by an Indian doctor provided fraudulent data to the Lancet that suggested HCQ not only was not effective but actually harmful in patients with Covid-19. The discrepancies in the data did not go unnoticed and the paper had to be retracted by the authors. The first author unabashedly of the Lancet paper spoke to some journalists that he believed in the principles of Gandhiji ! This was of course before the cat got out out of the bag.

 

 

The conspiracy theorists have had a rollicking time pointing out the flaws and untruths of the Lancet paper. There is a constant “I told you so” being unleashed to the public. Even the mainstream media picked up the retraction. This was headlines news in most Indian newspapers as also American outlets.

 

 

But then all at once 2 “gold standard” randomised trials have come out with their numbers. One has already been published in the most prestigious journal , The are England Journal of Medicine. The researchers report no difference in prevention Covid-19 in 800 participants exposed to a confirmed case. Adverse effects such as loose motions and were significantly more common in the group given HCQ, but there were no deaths or arrhythmias. Only 2 participants had to be admitted in hospital.

 

 

The WHO must be in a dilemma as to what to do now. It had suspended the HCQ arm in its multi centre SOLIDARITY trial because of the Lancet paper. But resumed with HCQ soon after news of retraction of the paper.

 

 

Within days the Minnesota University randomised paper showing no evidence of efficacy got published. Now close on the heels of the NEJM paper we are informed by researchers in Oxford University that they are stopping the HCQ arm in the mammoth RECOVERY randomised trial. The British scientists have been urged by the regulatory committee to halt the HCQ trial as there has been no difference in clinical outcomes with HCQ as compared to placebo in patients admitted for Covid-19. RECOVERY assessed more than 1500 patients on HCQ with 3132 patients provided normal care.

 

 

The malaria pill did not help patients of Covid-19 admitted in hospital get better or survive more.

 

 

“These data convincingly rule out any meaningful mortality benefit of hydroxychloroquine in patients hospitalized with COVID-19,” said the researchers from Oxford. RECOVERY is a randomised trial. Mortality was 26% in the HCQ cohort as compared to 24% in the standard treatment group, after 28 days. The high mortality rate probably suggests that thesis patients were too far gone to have been helped by HCQ. But there is no escaping the fact that HCQ failed to deliver in this large randomised trial. Full results are still to be published.

 

 

Even hospital stay ws not reduced by HCQ. The researchers of RECOVERY are studying more than 11000 patients with Covid-19 who have been randomised to get 6 experimental treatments compared with usual care; the other arms of RECOVERY have lopinovir/ritonivir, azithromycin, a common steroid, convalescent plasma and an anti-inflammatory medicine called toclizumab. Results are awaited.

 

 

One has to to wait for the reaction of the WHO. Does it continue with its observational trial of HCQ ? Maybe it shall because of the fear of adverse trolling. And what about the more than 200 ongoing trials with HCQ. Do they modify or suspend their protocol ? HCQ is today known more than any other drug regarding treatment of Covid-19 treatment.

 

 

HCQ is touted as the “game changer”  and the “magic drug.”  The ICMR sans any shred of evidence touts it for post exposure prophylaxis. The directive is that all essential service personnel pop in the malaria pill, along with exposed people.

 

 

However Dr Martin Landray deputy chief investigator of the RECOVERY trial and professor of medicine and epidemiology told The Guardian “If you are admitted to hospital, don’t take hydroxychloroquine.”

 

 

“It doesn’t work,” he added.

 

 

There definitely will be scrutiny of the bank accounts of the Oxford researchers by you know who. They must be scrambling right now.

Facing the House of Lords , Neil Ferguson,  also known now as “Professor Lockdown,” responded that “lockdowns are a crude policy.” A remarkable turnaround. Of course they are , when they shatter the lives of crores of people. After the damage has been done Professor Lockdown advises a more targeted approach would have been more appropriate. The predictions that there would be 20 to 22 lakh deaths in the US, 5 to 8 lakh deaths in the UK and 70,000 to 100,000 in Sweden were dangerously way off the mark. We have the death figures with us , and these are substantially lower than what the models suggested. Sweden has had 4562 deaths, far less than the 70000 to 10000 predicted; and WITHOUT lockdown

 

 

 

 

When one looks back it is obvious the entire Indian media was deriving great pleasure in publishing interviews with “public health workers” who out did one another in predicting dooms day scenarios. One after the other they came up with astronomical death rates that ran into lakhs of deaths due to Covid-19. The corridors would be full of patients they said. The result is that the Indian public is paralysed with fear. The enlightened “editors” living on a completely different moral pedestal left no stone unturned in amplifying the terror.

 

One had expected better sense from the “alternate media” in this country, but they turned out to be the biggest culprits. Scare mongering is as natural to them as breathing. The number of deaths by Covid-19 are in dispute but there is little doubt that viewership rocketed directly in proportion to the dread spread.

 

One can wake up a sleeping person but how do you wake a man who pretends to sleep. The damage is done. Crocodile tears are being copiously shed for the misery of the lakhs who got displaced and lost their livelihoods. There is no need for elaboration, the catastrophe is there for all to see. The contribution of the media to the disaster is immensely worrying. There is some sadistic pleasure in providing death rates every day.

 

Sweden without a lockdown has not recorded more than 4500 deaths , which is less than the UK that suffered a rather stiff lockdown. The prime minister of Norway is on record saying that she had panicked initially and wished she had to some extent followed the Swedish model. The Swedes are probably close to some form of herd immunity with the icing of the least damaged economy in any European country. England faces a 14% drop in its GDP in 2020; such a recession was last seen in 1706.

 

 

Sweden kept its schools open. Children below 16 continued with school; bars and restaurants did not shutter down. The public was coaxed to follow simple common sense rules of social distancing, washing hands, and good hygiene. The Swedish public rose upto to the occasion. The government however made one big error, it failed to protect the elderly staying in care homes. The death count would have been considerably less had the government secured the elderly.

 

Almost half of deaths in other European countries are to be blamed again on the negligence regarding old folks in care homes.

 

It is also being realised that 30-40% excess deaths have been collateral damage. These are deaths not associated to Covid-19 but to people not seeking attention on time. A significant amount of deaths have been due to heart attacks at home. A lot of people feared going to hospitals because of their belief they would catch the SARS-CoV-2 virus or because there was no means of transport. Procedures in Cath labs across the globe have dropped by at least 40%. A lot of people are suffering angina silently and are resigned to their fate.

 

The psychological toll on people is yet to be estimated, but damage surely has been done. Anxiety and depression is rife in people corralled in their homes for months. Near absence of exercise, anxiety and mental stress must be accelerating plaque or blockage formation in coronary arteries. Minor strokes may be being ignored.

 

The second killer is cancer. The commonest are breast, lung, prostate and colon. Not necessarily in that order. Hundreds of people must be unaware that cancer in them has advanced to a more serious stage that may put their lives in peril. They however have not been able to get a consult and in many treatment has been postponed or denied altogether.

 

Who would have dreamt that the diminutive pill containing chloroquine would catch the attention of the entire world. Chloroquine was discovered in 1934 by a German scientist and became the drug of choice for treating malaria. I too took it when I was a third year student in medical college. I have never forgotten the dose since. Hydroxychloroquine (HCQ) , a sister drug, is currently used in auto immune disease such as lupus and rheumatoid arthritis. HCQ is able to quell immunity that attacks its own body in these 2 diseases. Donald Trump touted HCQ as a “game changer” in March. The result was a surge of 2000% in the prescription. Most doctors in the world were soon swallowing HCQ as a means of prophylaxis, that is as prevention from Covid-19. The ICMR issued an advisory on HCQ for post exposure prophylaxis without citing a single study. This was amazing stuff, far far away from evidence based science as we know it.

 

Observational studies published in leading journals did to show any clinical advantage with chloroquine or HCQ. These trials included a sizeable number of patients. A Spanish trial that included 700 patients of rheumatoid or lupus failed to show the slightest difference in those patients receiving HCQ or those not given the pill.

 

A Korean trial similarly failed to demonstrate efficacy of HCQ in an observational study of 300 people exposed to a confirmed patient of Covid-19.

 

Two papers from the US with more than a thousand patients did not demonstrate advantage with HCQ.

 

The largest observational paper that included 96000 patients form 671 hospitals across 6 continents also did not shown any improvement with HCQ, but suggested there may be harm. This paper is now being challenged for providing dodgy data. The editor of the Lancet has commissioned a third party audit to confirm the results. France has banned HCQ whilst Italy and Spain recommend use only in a clinical trial or in hospital setting.

 

The WHO had suspended the HCQ arm in the ongoing SOLIDARITY trial but has resumed it since yesterday. The New York Times and other leading newspapers of the world carry stories on the Lancet paper. Whether this will it be a storm in the teacup remains to be seen ?

 

Currently at least 200 ongoing trials on HCQ in patients with Covid-19. The results are awaited. Quite a few should be randomised. International trials are ongoing in the UK, France , the US and at the WHO. Results are eagerly expected in a few weeks or few months.

 

 

 

The new corona virus has taken a toll on the reputation of the authors of the big paper published in the Lancet. An independent audit has exposed flaws in data collection. The first author Dr. Mandeep Mehra has been compelled to retract the paper.

 

“It is now clear to me that in my hope to contribute to this research during a time of great need, I did not do enough to ensure that the data source was appropriate for this use,” Dr. Mandeep Mehra, lead author of the two studies, said in a statement to The New York Times.

 

“We can no longer vouch for the veracity of the primary data sources,” Mandeep Mehra of Brigham and Women’s Hospital, Frank Ruschitzka of University Hospital Zurich, and Amit Patel of University of Utah said in a statement issued by the Lancet. “Due to this unfortunate development, the authors request that the paper be retracted.”

 

Meanwhile, on Wednesday, researchers reported results of the first gold-standard clinical trial of hydroxycholoroquine in Covid-19, concluding that it did not prevent infections any better than placebo. This was published in the NEJM.

 

So far only 2 double blind randomised trials have been published. A Brazilian study published in JAMA showed that high dose chloroquine was as effective a slow dose chloroquine but lethality was much greater with the higher dose. The authors of the paper instead of appreciation faced death threats. The son of the Brazilian president with 2 million Twitter followers termed the study fake and the handiwork of the opposition political party. The principal author was compelled to go underground.

 

 

 

Yesterday the second double blind study on post exposure prophylaxis in 800 exposed people was published in the New England Journal of Medicine. The conclusion was that HCQ did not provide any benefit in preventing infection. Both groups ( HCQ and control ) developed Covid -19 to the same extent ; only 2 patients needed hospitalisation , one from each group, no patient died. The researchers concede that the population studied was 40 years and not all patients were confirmed by the RT-PCR test.

 

 

The jury is still out on HCQ. We have to wait for more randomised trials to fill this huge gap. HCQ is cheap and made in the tons in India. It has shown activity against the virus in experimental conditions. But the chasm from the petri dish to the human body can be massive. The signal so far is that HCQ may not be the “game changer.”

 

India has recorded 6200 deaths over 6 months , at 4 per million population.

 

The “intellectuals” however had anticipated 20 lakh ( 2 million) deaths .

 

Extraordinary prescience , or covert agenda !

A simple description of immunity in the body.

Sweden’s approach to Covid-19 does not appear to be the wrong move.

 

https://youtu.be/8lkb_NWjbbM

 

The lockdown is being lifted. It is imperative that we do not permit fearmongers to operate amongst us. We should get back to normalcy employing common sense precautions.

 

 

https://youtu.be/bZzyOMFwBW8

 

Chloroquine has been around since 1984 and not 100 uyaers vas suggested by the ICMR. It has been used to treat malaria all these years but not Covid-19. The big Lancet observational study has documented increased death with hydroxychloroquine and chloroquine. The WHO has suspended HCQ in its SOLIDARITY trial. The French health ministry has outright banned use of HCQ. But the ICMR without any published data insist on touting the efficacy of HCQ in post exposure prophylaxis to prevent Covid-19.

 

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis Mandeep R Mehra, Sapan S Desai, Frank Ruschitzka, Amit N Patel Published Online May 22, 2020 https://doi.org/10.1016/ S0140-6736(20)31180-6 ;The Lancet.

 

ARTICLE IN PRESS International Journal of Antimicrobial Agents xxx (xxxx) xxx Contents lists available at ScienceDirect International Journal of Antimicrobial Agents journal homepage: www.elsevier.com/locate/ijantimicag [m5G;April 25, 2020;22:47 ] Short Communication Can post-exposure prophylaxis for COVID-19 be considered as an outbreak response strategy in long-term care hospitals? Sun Hee Leea,1, Hyunjin Sonb,1, Kyong Ran Peckc.

 

medRxiv preprint doi: https://doi.org/10.1101/2020.05.19.20101832.this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Serologic responses to SARS-CoV-2 infection among hospital staff with mild disease in eastern France Samira FAFI-KREMER1,2,*,, Timothée BRUEL3,*, Yoann MADEC4, Rebecca GRANT4, Laura TONDEUR4, Ludivine GRZELAK3,5, Isabelle STAROPOLI3, François ANNA6, Philippe SOUQUE7, Catherine SCHMIDT-MUTTER8, Nicolas COLLONGUES8,14, Alexandre BOLLE8, Aurélie VELAY1,2 , Nicolas LEFEBVRE9, Marie MIELCAREK10, Nicolas MEYER10,11, David REY 12, Pierre CHARNEAU6,7, Bruno HOEN13, Jérôme De SEZE8,14, Olivier SCHWARTZ3,** and Arnaud FONTANET4,15,**

 

medRxiv preprint doi: https://doi.org/10.1101/2020.04.30.20085613.this version posted May 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Humoral immune response and prolonged PCR positivity in a cohort of 1343 SARS-CoV 2 patients in the New York City region Authors: Ania Wajnberg MD, Mayce Mansour, MD, Emily Leven, MD, Nicole M. Bouvier, MD, Gopi Patel, MD, Adolfo Firpo, MD, Rao Mendu, PhD, Jeffrey Jhang, MD, Suzanne Arinsburg, DO, Melissa Gitman, MD MPH, Jane Houldsworth, PhD, Ian Baine, MD PhD, Viviana Simon, MD PhD, Judith Aberg, MD, Florian Krammer, PhD, David Reich, MD, Carlos Cordon-Cardo, MD, PhD Author affiliations: Icahn School of Medicine at Mount Sinai, New York NY

 

 

Data on mortality is coming in fast and furious. It is more our less clear that the mortality figure of 3.4% by the WHO was highly exaggerated. As was the 0.9 to 1% by the Imperial College, London. The infection fatality rate (IFR)is ranging from 0.2 to 0.4% across the globe. The Iranians have provided a figure off 0.12% , while the Germans have noted an IFR of 0.36%. Stanford University too reports 0.17% fatality while the University of Southern California suggests 0.2%. The mortality in India per million is one of the lowest in the world at 3 per million. The total number of cases so far are 139049 with 4024 deaths, giving a crude mortality of 2.89%. The number of infections should be at least 10 times more , hence the Indian infection fatality rate will be around 0.28 % to 0.028%; this is more or less akin to the mortality figures form other nations.

 

The deaths per million are strikingly less in Asian countries than Europe, China is 3, Bangladesh is 1, Pakistan is 5, Singapore is 4, Indonesia has 5, Japan is 5, South Korea is 5, and Malaysia is at 4 per million. The substantial difference in mortality can only be speculated upon, maybe younger population groups or higher local temperatures.

 

One should not worry too much on the increase in new number of cases in India. The prevalence is still reassuringly low, and even if there is a surge in new cases , we inch towards “herd Immunity.” I would prefer to term it “public” or “people” or even “community immunity” rather than herd immunity because the word “herd” is associated more with animals. A herd of elephants.deer, cows, horses, or sheep. We are people and not sheeple. A group of humans is better termed a clan of humans. I would not mind “clan immunity.”

 

The testing has been ramped up, so there is a bigger number of new cases each day. But a new case means an infection , not a death warrant. The majority of people will be asymptomatic or mildly symptomatic. Most of the patients landing up in hospital will be treated by oxygen alone. Till some time back 5-6% required intensive care management with high mobility and mortality. But with greater knowledge of the virus and treatment protocols this should be considerably lowered. We know that SARS-CoV-2 peaks very soon after symptom onset. Unlike SARS and MERS, in which the viral load peaks after a week, Covid -19 is characterised by the viral load at its highest within a week of symptom onset. The common flu is also accompanied by an early peak of viral load. The trick therefore will be to use an antiviral as soon as possible after onset of symptoms in patient with Covid-19.

 

 

A large double blind randomised trial including almost 1100 patients with CVovid-19 has reported significantly shortened recovery time with remdesivir as compared to placebo, from 15 to 11 days. There was also a rent towards lower mortality with remdesivir. Remedesivir acts against the enzyme polymerase that is essential for the replication of the Covid-19 virus. Interestingly remdesivir did not work in hepatitis nor was it very successful against ebola. Remdesivir, however, is currently considered the most promising therapeutic drug against Covid-19. There are other on going randomised trials with remdesivir and results are awaited. It is hoped that good sense prevails with the company manufacturing remdesivir; it keeps the price within reach of the common man. Bangladesh has already begun manufacturing the medicine by virtue of a special arrangement with Gilead, there should be similar understanding with Indian companies. Remdesivir was unable to reduce mortality below 5% (it did bring it down to 7%) in the trial, but this may have been because almost 25% patients were hooked to ventilators. Remdesivir was probably given too late in them. Patients reach the stage of ventilator support after the viral load has begun to diminish but the body has unleashed a wayward immunity response against itself, this is called the cytokine storm. The immune system attacks the lungs and other organs in the patients body with a vengeance. The antiviral now becomes incapable of treating the pathology.

Gilead Sciences has signed non-exclusive, licensing agreement with five generic manufacturers to expand access to its experimental antiviral drug remdesivir for Covid-19 patients.

The licensees include Mylan, Cipla, Hetero Labs and Jubilant Life Sciences in India, as well as Ferozsons Laboratories in Pakistan. The companies will be able to manufacture and distribute remdesivir in 127 countries.

However,  a senior scientist at the Indian Council of Medical Research (ICMR) has said that “it will consider using the drug if Indian firms are able to make it,” as per the BBC. The ICMR continues with its antics.

 

 

The other interesting randomised trial has emerged from Hong Kong. The researchers successfully cut down recovery time to 7 days alone with the use of a triple therapy combination. The troika consisted of lopinavir/ ritonavir (anti HIV), ribavarin (anti hepatitis C) and interferon versus lopinovir/ritonavir alone. The time to become negative for virus was only 7 days in the triple combination group as opposed to 12 days in the control group. Symptoms were alleviated in 4 days and there was suppression of interleukin levels. Raised interleukin levels indicate a grossly inflammatory state within the body. Treatment was given within 7 days from symptom onset. The researchers concluded that treatment with interferon should be initiated as soon a possible, definitely within a week of becoming ill. Interferon is considered the backbone of the triple combination treatment. The researchers have earlier shown reduction in mortality with the triple combination in patients with SARS. In the Covid-19 study, patients given triple therapy tested negative in 7 days as compared to 12 days in controls. Symptom duration was reduced from 8 to 4 days. The triple therapy worked when used early and probably will not give equally good results in patients on ventilators.

 

 

Two studies, one from Germany and the other from Singapore have confirmed that infective viral shedding is upto 10 days only. A patient may shed virus or be positive for as long as 6 weeks but will not be infective. After 10 days the PCR test is picking up dead virus. Till 10 days subgenomic messenger RNA can be seen in the Covid-19 virus, indicating that the virus can be isolated, cultured and above all is infective. If the virus ceases to be infective after 10 days , the protocol of 2 consecutive negative PCR tests becomes redundant. The viral load may be high after 10 days but the virus is not infective. Despite virus detection by PCR, the virus is not viable after 10 days. The PCR may detect high viral loads but the person concerned is not infective after 10 days of symptom onset.

 

 

The PCR test is best described by the inventor himself. Kary Mullis writes in his autobiography “Dancing naked in the minefield” that he figured out the PCR test one night as he drove back to his home with his future wife. He gives a nice analogy. Picking up a number plate of a car from the moon would be next to impossible. But this could be made easier if somehow the number plate was multiplied millions or billions of times. The human DNA is like a very long number plate. The SARS-CoV-2 has a genome or telephone number of 30000 numbers. Mullis imagined that a fragment of the DNA could be split into 2 by an enzyme, “polymerase.” The two fragments could again be split into two and then again into two; the reaction could go on. After 10 cycles we would have a thousand fragments , after 20 cycles a million and after 30 cycles a billion. It would become easier to identify the target fragment after this magnitude of amplification. Mullis called it the “polymerase chain reaction” and soon the PCR test came into being. It could not only be helpful in solving crimes but could also be used to study the DNA of an animal that existed 40,000 years ago. The PCR test is used to detect the presence of the Covid-19 virus. The test is not infallible because errors in collection of sample and transportation can account for a negative test. But more about the fact that the PCR test can be quite fallible some time later.

The take home message is that combination antiviral treatment is a must in Covid-19, and this should be begun within a week of symptom onset. But selection of the patient who would most benefit from treatment  remains unclear.

 

 

 

India has one of the lowest death rate at 3 per million population; there is as of now no evidence that hydroxychloroquine is effective for prophylaxis; the ICMR provides no reference in its advisory ; vaccines are being tested at “warp speed”; lets hope one works.

 

• Published: 24 April 2020

The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin

• Ehud Chorin

Nature Medicine (2020)Cite this article

 

 

 

 

 

 

The health ministry of India for some inexplicable reasons expanded yesterday the indications of prophylactic hydroxychloroquine (HCQ) on flimsy data, despite a huge observational study of 96000 patients with Covid-19 published yesterday in The Lancet concluding that HCQ is ineffective and could be even hazardous in treating Covid-19.

Why wait for a vaccine if HCQ is so effective ???

 

JAMA Netw Open. 2020;3(4):e208857. doi:10.1001/jamanetworkopen.2020.8857 OriginalInvestigation |

InfectiousDiseases Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection A

 

Randomized Clinical Trial www.thelancet.com Published online May 22, 2020 https://doi.org/10.1016/S0140-6736(20)31180-6

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis Mandeep R Mehra, Sapan S Desai, Frank Ruschitzka, Amit N Patel

 

 

 

 

How do you envisage sports being conducted after the lockdown is lifted ? The masks may remain mandatory; as also the social distancing. You will have to stay 6 feet away from colleagues and strangers. Even your own family if they live elsewhere. So how do you play cricket? What rules do you modify? How far behind does Dhoni have to stay behind to ensure a stumping does not go waste? Ashwin and Kuldeep Yadav may become a trifle ineffective. How far away do the slip fielders position themselves from one another. The questions become starker with contact sport. You could watch the beautiful game from your homes, but how does the soccer player stay 6 feet away from the defender? Do you change the architecture of stadiums for athletics? How do you get the 100 m race run and ensure the athletes are in their lanes 6 feet away form one another? These are complex issues that need to be anticipated right now. Maybe the think tanks want to vaporise sports away for good. As you can see running a 5000 m or a cross-country race will become a near impossibility. Runners do get to jostle as they compete in these races that are both fascinating and thrilling to watch. Boxing and wrestling will evaporate away. German Bundesliga has done a first, organised a football match in a stadium devoid of spectators. The Germans have done it by testing all players and officials. We had the eerie spectacle of a goal being scored and the players rejoicing as they stood adequately apart from one another. However Augsburg’s head coach Heiko Herrlich had been penalised for leaving his hotel to buy toothpaste from a local supermarket, he was denied permission to attend the first ever football game his team was playing (in the Bundesliga) in Covid-19 times. It was to be his first game as head coach. Herrlich will be permitted to rejoin his team affairs after he tests negative twice for the virus. Toothpaste can become radioactive in a post Covid-19 world.

Tennis could carry on. So could badminton, table tennis, gymnastics, the long jump and high jump. Even pole vaulting and the throws. So also archery and shooting. But sports entailing proximity are more or less out. The knowledgables will turn to the magical vaccine. The solution they will say is quite simple. Get vaccinated and do your sport, represent your school, club or country. The catch that most people do not seem to understand is that making an effective vaccine is easier said than done. HIV has been around for more then 30 years, it has killed more than 30 million people, but even today we do not have a vaccine against it. The situation is the same with hepatitis C, no vaccine yet after decades. There is no vaccine against malaria or TB. Both have been around for hundreds of years. As I write there are not more 2-3 development trials testing a vaccine against TB, which kills more than 3000 people in one day. Note that Covid-19 has not resulted in 3000 deaths in 5 months in India. TB kills more than a million or 10 lakhs in a year. We have however more than a 100 trials scrambling to develop a Covid-10 vaccine. The vaccine against common flu has never been fully effective. The efficacy ranges form 20 to 60% only. The flu virus keeps mutating. Also despite the flu vaccine being around, more than 60,000 people died from it 2017-18 in the US alone. So getting a vaccine will not be a panacea.

Right now the company that is leading the charge to make the Covid-19 vaccine is a US based company called Moderna. Interestingly Moderna has never manufactured a vaccine ever before. Also it is trying a method that has not been employed previously. It hopes to inject a person with a messenger RNA that will coax the cell in ones body to make components of the SARS-CoV-2 . The messenger RNA is supposed to nudge or order a human cell to either make the spike or the nuceleocaspid component of the corona virus, but not the entire virus. By making only bits of the virus the vaccine will never get lethal, but elicit the immune system to kick in antibodies against SARS-CoV-2. The idea is dazzling on the drawing board but we however have to wait for it to work. A vaccine not only must be effective but be without serious hazards. Usually it takes years to develop a vaccine, as mentioned earlier many dangerous diseases are yet to prevented by an effective vaccine. It is being bandied about that the vaccine will be present as early as September. This is impossible. A vaccine has to first tested in animals and then in human volunteers. One has to wait to see if major side effects like paralysis, epilepsy or cancer may present as side effects. The list of ill effects is long and need not be mentioned here. But they have to watched out for.

Conjuring a vaccine in 6 months makes for sexy reading, but would entail too many corners getting cut. Maybe for all you know a vaccine is already there. We are merely going through the motions of developing one. This is too far fetched. Suffice to reiterate that an effective vaccine takes time to make, and once it is rolling it still may not be effective in the entire population. A direct intervention against this virus makes greater sense.

 

 

What does the sportsperson do even with a vaccine in her? The American College of Cardiology has hurriedly made guidelines about how an athlete can get back to competitive sports after bout of Covid-19. The society seems oblivious of the fact most contact sports shall be impossible anyway in the future. The guidelines imagine a world that has gone back to what it was till the November of 2019. The guidelines rely entirely on the protocol subsequent to spell of myocarditis, published in 2015. But makes absolutely no mention of issues related to masks or social distancing. The advisory albeit essential seems to miss the point that sports will be the first casualty of the new world.

The guidelines emphasise that the physician will have to first decide who has and who has not been infected with SARS-CoV-02. The problem is that almost 50% of infected people do not have symptoms. This means to know whether an athlete has been infected in the past a serological test for presence of antibodies will have to be done. I do not need to remind you that of the symptomatic people almost 80% have mild symptoms. Around 15% get sick enough to need hospitalisation while 5-6% need ICU treatment. How do we go about with people known to be infected? They will have to wait for 3-6 months before resuming serious raining. The waiting period is not decided as yet. After 3 -6 months each athlete will need a thorough cardiac evaluation. Covid-19 affects the heart in almost 20-25% in a variety of ways. There can be myocarditis, pericarditis, ischemia, myocardial infarction type 1 and 2, arrhythmias and even heart failure. SARS-CoV-2 can directly attack heart muscle or indirectly by producing an inflammatory state. Blood vessels (endothelium) can be damage or blood become more coagulable. All this happens in the acute phase. When the athlete wishes to resume competitive or leisure activity it has to be ensured the heart has healed.

 

 

The ECG is a must and this must ideally not show any residual ischemic changes. An echocardiogram will be needed to ensure the heart muscles have recovered, the left ventricle ejection fraction has a normal ejection fraction. All cardiac biomarkers and inflammatory markers should have returned to normal. Troponins should be normal and also the brain natriuretic peptides (NT-pro-BNP). CRP, ferritin and D-dimer shouts also have fallen to normal levels. Holter monitoring will need to be done to rule out high grade ventricular premature beats or ectopy.

Obviously in the presence of ongoing myocarditis sports cannot be recommended. These rules are applicable for all types of viral myocarditis, not necessarily for Covid-19 alone. Cardiac MRI or endocardial biopsy could be reserved for specific cases. Cardiac MRI in the acute phase picks up more water in heart muscle and later the presence of gadolinium suggestive of myocarditis, active or healed. I do not know of any data on cardiac MRI in Covid-19 as of now.

I used to love to run as a boy, in fact I still do. Most if not all young people cannot do without some sport or the other. I don’t know for how long you can deny them a good game of cricket or foot ball. Will millions of young people have to wait for a vaccine before they can play or watch a game? The current men’s world record is 9.58 seconds, set by Jamaica’s Usain Bolt in 2009, who gets to break this ? The Indian cricket team will have to be tested both for the virus and antibodies. The BCCI, I am sure, must be working on this. It could buy the best antibody tests available in the world to pick up previous infection. The BCCI has the muscle if not the vaccine. Welcome to the manifestly abnormal post Covid-19 world.

How do children get to play games in a post Covid-19 world? How far away do slip fielders in cricket position themselves from one another? How do you get to play soccer or run a 100 m race ? These questions demand answers now. How and when does a patient resume running after a Covid-19 attack?

 

A Game Plan for the Resumption of Sport and Exercise After Coronavirus Disease 2019 (COVID-19) Infection.JAMA Cardiology Published online May 13, 2020.

 

AHA/ACC Scientific Statement Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 3: Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy and Other Cardiomyopathies, and Myocarditis A Scientific Statement From the American Heart Association and American College of Cardiology (Circulation. 2015;132:e273-e280. DOI: 10.1161/CIR.0000000000000239.)

 

 

 

 

Drugs used in treatment of hypertension, heart failure or diabetes do not increase risk of higher rate of infection, severity of dies or death in patients with Covid-19. Covid -19 disease is caused when SARS-CoV-2 ( a beta coronavirus) enters your body via receptors called ACE 2 (angiotensin converting enzyme 2). At the beginning of the pandemic it was theorised that popular and effective classes of medicines often used to treat hypertension ,heart failure or diabetes , would be detrimental because they increase the ACE-2 receptor. The logic was single , a lot of hypertensives and patients with heart failure were falling down dead with Covid-19, so the usage of these drugs may explain increased mortality. The drugs are named angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB).

 

Examples of the ACEI group of medicines are ramipril, lisinopril, trandalopril, captopril…….so they can also be called the “prils.”. The angiotensin recep[tor blockers are losartan, telimisartan, valsartan……..also termed the “sartans.”. Randomised rials done over decades have confirmed efficacy and safety of these medicines in treatment of hypertension and heart failure. SARS-CoV-2 , the coronavirus, penetrates human cell by using the spikes attached to its surface on to the ACE2 receptors present in abundance in the lungs, heart, intestines , and kidney. It was no surprise that Whatsapp messages were spreading like wildfire regarding these medicines.

 

“Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?” This was the title of this scientific letter written to The Lancet on March 11, 2020 (Published OnlineMarch 11, 2020 https://doi.org/10.1016/ S2213-2600(20)30116-8). The authors of the letter went on “ suggest that patients with cardiac diseases, hypertension, or diabetes, who are treated with ACE2- increasing drugs, are at higher risk for severe COVID-19 infection and, therefore, should be monitored for ACE2-modulating medications, such as ACE inhibitors or ARBs’. A conundrum was treated for clinicians , because millions of patents were at stake. Do we continue with an ACEI or ARB or not was the burning question clinicians were asking amongst themselves ?

 

 

The picture is clearer now with 3 good, albeit, observational papers recently published. A large study included 8910 patients in 11 countries across 3 continents. All patients had been hospitalised. By applying statistics (multivariate logistic-regression analysis) they found out that age >65 years, coronary artery disease, heart failure, history of arrhythmia, chronic obstructive lung disease and current smoking were associated with raised risk of death. Females had a lesser risk. Importantly, both ACEI and ARB were not associated with increased risk.

 

An Italian study from the region of Lombardy similarly showed no increased risk with ACEI or ARB’s in confirmed cases of 6272 Covid-19 patients when compared with more than 30,000 controls having similar sex, age and place of residence. Once again logistic-regression multivariate analysis failed to show increased incidence of Coivid-19. Also there was no increased risk associated with these drugs in severely affected patients or in patients who died.

 

 

The third study analysed data from health records of 12, 594 patients; of these almost 6000 patients were founds to be infected. More than 1000 had severe infection, defined as admission to intensive care, ventilation or death. The researchers did not find association for any of the analysed drugs for a positive test to severe illness.

 

All 3 studies negate the theory that ACEI or ARB is associated with risk of SARS-CoV-2 infection , severity of illness or risk of death. There was a hint in one studies that there was in fact a lower risk of in hospital death with use if ACEI or statins, but this cannot be taken for granted as this was an observational trial. Every professional scientific society has advised ACEI or ARB should not be stopped due to concern of increased susceptibility or severity of Covid-19 infection.There is also no increased risk with other classes of medicines such as beta-blockers, thiazide diuretics and calcium channel blockers. Hence despite the theory that ACEI’s or ARBS’s could increase levels of the ACE2 proteins that happen to be the entry point for SARS-CoV-2 into human cell, there is no increased risk of Covid-19 infection or death by it.

 

 

A recent letter in the Lancet describes experimental evidence that ACEI actually down regulates the ACE2 receptors in lung tissue. “It is possible that long-term ACEI use downregulates lung ACE2 expression by reducing substrate (ie, angiotensin II) availability, which might also explain why no effect of ARBs was seen. In theory, ACE2 down regulation might reduce the risk of SARS-CoV-2 infection because of reduced virus receptor availability.” But animal studies that reduced ACE2 can increase acute lung injury. The clinical significance of effect of ACEI on the ACE 2 receptor however remains unclear.

The message is simple , do NOT stop your blood pressure pill, lock down or no lock down.

The RT-PCR test is considered the gold standard for detection of SARS-CoV-2. But this was not based on an actual virus specimen or virus isolate ; the test was developed from the genome put up on the internet. The authors of the published paper concede this in their own paper.

 

 

 

Euro Surveill. 2020 Jan 23; 25(3): 2000045. doi: 10.2807/1560-7917.ES.2020.25.3.2000045

N Engl J Med 2020; 382:970-971 DOI: 10.1056/NEJMc2001468

 

SARS-CoV-2 definitely produces antibodies; testing for antibodies is sorely and urgently needed in India, especially in health workers. The ratio of new cases is significantly less than in other countries .

 

 

https://youtu.be/2LLbKTiA0iU

 

It is time the Indian public was told the facts about Covid-19. Lets begin by learning that the fatality or mortality rate in India is very low; so please do not fear the virus. Please examine the evidence and apply some common sense.