CME INDIA Presentation by Dr H D Sharan, MD, Sr Cardiologist, Ranchi, Ex Chairman, CSI-Jharkhand.

Looking back at 2020

27th of January, Thrissur, Kerala

• On 27th January, a 20yr. old girl reported to the Emergency room of a hospital in Thrissur, Kerala with history of sore throat and cough for the last 24 hrs. She had arrived from Wuhan, China on 23rd January to escape rapidly spreading cases of pneumonia. On 30th January, she tested positive for a new virus that was later named the SARS CoV2.

China failed to inform WHO

• On 31st December, China had informed about these cases of pneumonia of unknown origin for the first time. Unconfirmed reports suggest that Wuhan had seen these cases as early as November but failed to inform the WHO.
• Between 31st December and 3rd January, there were 44 new cases. Most of these patients had history of exposure to a huge sea food market in Wuhan.
• First death from COVID-19 was reported from China in January. India reported its first mortality from COVID-19 on 10th March. He was a 76 yrs. old man from Karnataka.
• WHO declared this outbreak a ” public health emergency of International concern” (PHEIC) IN January and a Pandemic in March, 2020?
• On January 10, China released the genome of the virus causing this atypical pneumonia and severe acute respiratory syndrome.

Virus jumped from Bats

• It was considered to have a Zoonotic origin as the virus jumped from the bats and pangolins to human contacts but it did not take long to decipher a human-to-human spread.
• The other SARS virus seen before this did not spread as rapidly as this. As a result, although the mortality rates were much higher with them, they were restricted within smaller geographical boundaries and did not cause as much economic hardship. There is going to be a large and long-lasting negative effect on world economy.

Cellular response to SARS COV2

• Although details of the cellular responses to this virus are not known, a probable course of events can be postulated based on past studies with SARS-CoV. A cellular biology perspective is useful for framing research questions and explaining the clinical course by focusing on the areas of the respiratory tract that are involved. Based on the cells that are likely infected, COVID-19 can be divided into three phases that correspond to different clinical stages of the disease.

Stage 1: Asymptomatic state (initial 1–2 days of infection)

• The inhaled virus SARS-CoV-2 likely binds to epithelial cells in the nasal cavity and starts replicating. ACE2 is the main receptor for both SARS-CoV2 and SARS-CoV. In vitro data with SARS-CoV indicate that the ciliated cells are primary cells infected in the conducting airways.
• However, this concept might need some revision, since single-cell RNA indicates low level of ACE2 expression in conducting airway cells and no obvious cell type preference. There is local propagation of the virus but a limited innate immune response. At this stage the virus can be detected by nasal swabs. Although the viral burden may be low, these individuals are infectious.
• The RT-PCR value for the viral RNA might be useful to predict the viral load and the subsequent infectivity and clinical course. Perhaps super spreaders could be detected by these studies. For the RT-PCR cycle number to be useful, the sample collection procedure would have to be standardised. Nasal swabs might be more sensitive than throat swabs.

Stage 2: Upper airway and conducting airway response (next few days)

• The virus propagates and migrates down the respiratory tract along the conducting airways, and a more robust innate immune response is triggered.
• Nasal swabs or sputum should yield the virus (SARS-CoV-2) as well as early markers of the innate immune response. At this time, the disease COVID-19 is clinically manifest.
• The level of CXCL10 (or some other innate response cytokine) may be predictive of the subsequent clinical course. Viral infected epithelial cells are a major source of beta and lambda interferons. CXCL10 is an interferon responsive gene that has an excellent signal to noise ratio in the alveolar type II cell response to both SARS-CoV and influenza.
• CXCL10 has also been reported to be useful as disease marker in SARS.
• Determining the host innate immune response might improve predictions on the subsequent course of the disease and need for more aggressive monitoring.
• For about 80% of the infected patients, the disease will be mild and mostly restricted to the upper and conducting airways. These individuals may be monitored at home with conservative symptomatic therapy.

Stage 3: Hypoxia, ground glass infiltrates, and progression to ARDS

• Unfortunately, about 20% of the infected patients will progress to stage 3 disease and will develop pulmonary infiltrates and some of these will develop very severe disease. Initial estimates of the fatality rate are around 2%, but this varies markedly with age.
• The fatality and morbidity rates may be revised once the prevalence of mild and asymptomatic cases is better defined. The virus now reaches the gas exchange units of the lung and infects alveolar type II cells. Both SARS-CoV and influenza preferentially infect type II cells compared to type I cells.
• The infected alveolar units tend to be peripheral and subpleural. SARS-CoV propagates within type II cells, large number of viral particles are released, and the cells undergo apoptosis and die.
• The end result is likely a self-replicating pulmonary toxin as the released viral particles infect type II cells in adjacent units. I suspect areas of the lung will likely lose most of their type II cells, and secondary pathway for epithelial regeneration will be triggered.
• Normally, type II cells are the precursor cells for type I cells. This postulated sequence of events has been shown in the murine model of influenza pneumonia.
• The pathological result of SARS and COVID-19 is diffuse alveolar damage with fibrin rich hyaline membranes and a few multinucleated giant cells. The aberrant wound healing may lead to more severe scarring and fibrosis than other forms of ARDS.
• Recovery will require a vigorous innate and acquired immune response and epithelial regeneration. Administrating epithelial growth factors such as KGF might be detrimental and might increase the viral load by producing more ACE2 expressing cells.
• Elderly individuals are particularly at risk because of their diminished immune response and reduced ability to repair the damaged epithelium. The elderly also has reduced mucociliary clearance, and this may allow the virus to spread to the gas exchange units of the lung more readily.

The Initial phase

• In the initial phase of the Pandemic, the case fatality rate in rich countries with highly advanced medical infrastructure like Italy, France, Spain and then US was very high.
• Unfortunately, this was because the clinicians were not fully aware of the pathogenesis. They were treating these cases as they would treat any other case of ARDS seen with other Corona Virus infections.
• The mechanical ventilation was harming the patients more than helping them. They were also not aware of the hypercoagulable state produced by this infection and therefore failed to take preventive steps in form of prophylactic Heparin.
• An ideal therapy for COVID-19 should consist of an agent that is anti-viral, an agent that takes care of the cytokine storm and an agent that takes care of the hypercoagulable state.

3 main risk factors for life threatening COVID-19 disease are:

1. Male gender
2. Old age
3. Comorbidities

Even among these, severity varies due to pre-existing inflammation or immunity, viral Load and patients’ genetic makeup

Trick of avoiding the initial innate immunity

• This virus has a trick of avoiding the initial innate immunity esp. the early type 1 Interferon response for a significant period of time.
• This highlights the potential for Interferon based therapy for COVID-19.
• It is a very interesting disease as too little immunity is no good but too much immunity is really-really bad. Some people develop antibodies that deactivates their own Interferon. These people find it very hard to fight COVID infection. This happens in 12.4% men and 2.6% women.
• These antibodies were not seen in those with no or mild symptoms. REPLACING INTERFERON IN EARLY PERIOD OF INFECTION COULD HELP TO AVOID SEVERE ILLNESS. Pegihep 100 mcg is available for Rs 14000/- The dose in COVID-19 is not clear yet.

TMPRSS2 (transmembrane protease serine2)

• It is a protein that helps the virus to enter the cells. Its role in prostatic cancer is well established and the anti TMPRSS2 drugs are being tried in the treatment of COVID-19.
• The spikes first get attached to the ACE2 receptors. The TMPRSS2 PROTEIN then chops the spike and helps the virus to merge with the mucus membrane and enter the cells.

Science in Search Mode

• The Solidarity Trial published interim results on 15th October 2020. It found that all 4 treatments evaluated (Remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon) had little or no effect on overall mortality, initiation of ventilation and duration of hospital stay in hospitalized patients.
• Peers who reviewed the results were not very impressed and some of them raised doubts over the methodology.

Dexamethasone

• The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with COVID-19 who are receiving respiratory support. They found no benefit (and the possibility of harm) among patients who did not require oxygen. As of today, Dexamethasone is the only drug with evidence of benefit.
• Clinicians in many countries, especially in Japan and we continue to use Remdesivir. I strongly feel that Remdesivir given early in the disease along with dexamethasone given to right patients at the right time and sub cutaneous low molecular weight Heparin is still the best bet for the COVID-19 19 patients in India.

Why Remdesivir?

• Inside the body, the virus creates copies of itself, followed endlessly by the copies creating copies of themselves. Remdesivir is designed to obstruct replication.
• There has been a global debate over the efficacy of Remdesivir in treating COVID-19 patients. How does the drug act — or is meant to act — against the novel coronavirus SARS-CoV-2?
• Once the virus enters the human cell, it releases its genetic material, which is then copied using the body’s existing mechanism.
• At every stage of infection, various human proteins, virus proteins, and their interactions come into play. At the replication stage, the key viral protein at play is an enzyme called RdRp. It is RdRp that makes the copies, by processing components of the RNA of the virus.
• University of Alberta researchers called it the “engine” of the virus in a paper published this summer, in which they described the action of Remdesivir against this “engine”.
• Again, researchers at the Max Planck Institute of Biophysical Chemistry in Germany described the same enzyme as the “copy machine” of the virus when they imaged the architecture of this “machine” in 3D. In scientific literature, such an enzyme is called a polymerase (the p is RdRp stands for polymerase) or a replicase. In any case, this is the enzyme that is targeted by Remdesivir how exactly does Remdesivir target this enzyme?
• In order to replicate, the copy machine processes raw material from the virus RNA, broken down by another enzyme with that specific function.
• When a patient is given Remdesivir — the inhibitor — it mimics some of this material, and gets incorporated in the replication site. With Remdesivir replacing the material it needs; the virus fails to replicate further. These coronavirus polymerases are sloppy and they get fooled, so the inhibitor gets incorporated many times and the virus can no longer replicate,” University of Alberta microbiologist and immunologist Matthias Götte said in a statement.

How far has this action been established?

• University of Alberta researchers — their study was reported in the Journal of Biological Chemistry — used insect cells to express RdRp complexes of SARS-CoV and SARS-CoV-2.
• They found that an active compound in Remdesivir inhibits the copy machines of both viruses with the same potency and mechanism of action. Previously, the same team had found similar results for Remdesivir action against the coronavirus that causes MERS. The drug itself was designed to act against the Ebola virus, which is not a coronavirus.
• Separately, Chinese researchers have added to the emerging knowledge about the action of remdesivir. Researchers from various institutions under the Chinese Academy of Sciences have imaged the high-resolution structure of the SARS-CoV-2 replicase complex, with Remdesivir bound to it.
• The structure shows where the virus’s RNA template enters the copy machine, where Remdesivir is incorporated, and where the process of replication is terminated. The Chinese researchers too used insect cells.

Ab8 – biomolecule that ‘completely and specifically’ neutralizes the virus

• University of Pittsburgh scientists have isolated a biomolecule that ‘completely and specifically’ neutralizes the virus that causes coronavirus disease.
• Researchers isolated the smallest biological molecule to date that neutralizes the SARS-CoV-2 virus
• The antibody component is 10 times smaller than a full-sized antibody and has been used to create a drug known as Ab8 for use as a therapeutic drug
• Researchers found that Ab8 is ‘highly effective’ in preventing and treating SARS-CoV-2 infection in mice and hamsters.
• It provides hope that there could soon be an effective treatment for patients with COVID-19 or even protection of those who have never had the infection.
• A biomolecule is a chemical compound found in living organisms. These include chemicals that are composed of mainly carbon, hydrogen, oxygen, nitrogen, sulfur and phosphorus. Biomolecules are the building blocks of life and perform important functions in living organisms.

Bradykinins – What is its role?

• Scientists at Oak Ridge National Lab are using IBM summit supercomputer to understand the mysteries of SARS CoV2. The Summit supercomputer at one time was the fastest supercomputer in the world.
• The group is trying to understand the fundamental Biology and molecular evolution of the Virus and how it manifests in human body.
• Their study proposes that COVID-19 is basically a Vascular disease and this aspect is more important than it being merely a Respiratory problem.
• They have found that when the Virus infects a human body, the BRADYKININ activity shows a multifold increase. Bradykinin is a natural vasodilator. They have called this status a Bradykinin Storm akin to the Cytokine Storm.
• This results in increase in vascular permeability and production of Hyaluronic Acid. These Biological Processes ultimately flood the lungs with a gelatin like substance causing difficulty in breathing.
• My question – Is there any role of anti-bradykinin drugs Ecallantide and C1- INH? 

Polyclinal Antibody Cocktail Regeneron – Why was in news?

• It is a synthetically produced B Cell Antibodies against SARS Cov2 virus that causes COVID-19 19 disease. We call it Polyclonal because there are antibodies from B Cells of 2 different lineages in this Cocktail.
• The virus starts mutating as a defence against the antibody which is taken care of by the second antibody.
• Given early in the disease, it is expected to reduce Viral Load and reduce the time to recovery.
• It is given as a single dose of 8mg. It is approved by the FDA for compassionate use.
• Surprising that Dr Trump took this injection instead of IV Sodium Hypochlorite (disinfectant).

Pegylated Interferon – Any role?

• Pegylated Interferon marketed as Pegihep and used for Hepatitis B and C could be tested for COVID-19.
• In cell cultures, SARS CoV2 has been found to be very sensitive to interferon, 99% reduction in viral shedding was seen along with reduction in IL6 response.
• Zydus Cadilla has asked for permission from authorities to start a trial.
• Interestingly, China and Cuba are already using this drug in COVID-19.  Is this the secret weapon they have?

Baritacinib

Baricitinib, sold under the brand name Olumiant among others, is a drug for the treatment of rheumatoid arthritis in adults whose disease was not well controlled using RA medications called tumor necrosis factor (TNF) antagonists.

• It acts as an inhibitor of janus kinase (JAK), blocking the subtypes JAK1 and JAK2. The drug is approved for use in the European Union and the United States.
• On 14 September, efficacy and safety data for Eli Lilly’s Olumiant (baricitinib) in combination with Gilead’s Veklury (Remdesivir) in hospitalised COVID-19 patients from the Phase III Adaptive COVID-19 Treatment Trial (ACTT-2) were announced. The ACTT-2 trial was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and included 1000 patients.
• In the trial, Olumiant and Veklury combination met its primary endpoint of reduction of recovery time compared to Veklury alone. Recovery was defined as patients being well enough for hospital discharge and no longer requiring supplemental oxygen or ongoing medical treatment.
• It is available in India and many doctors are using it.

Drugs on horizon

1. SNG 001 Inhalable Interferon currently being used for SLE. Prevents replication of Virus. Reduces severe disease and mortality by 78 %.
2. Fluvoxamine SSRI anti-depressant. Counters Cytokine storm.

Progression and regression of COVID 19 pandemic in India as on 14/12/2020.

This is just a different way of presenting a data that is available to all.

Progression and regression of COVID in India.

States by No of Daily Cases on 14/12 (more than 1000 cases)

4 states where number of active cases increased in last 24 hrs

For the first time since July, the 5-day average of. new cases came below 30000.

The number of daily cases continued to increase till the 3rd week of September. The fastest million took just 11 days on 16th September. And then, for unknown reasons the cases started declining. It took 29 days for us to reach 10 million on 18/12 from 9 million. There was a fear of second wave after the Bihar elections and the festive season. It did not happen. We have not yet reached a level where the herd immunity can set in. We are generally carefree and undisciplined people with very low levels of masking and physical distancing. Yet, the number of daily cases was less than 25000 for the entire last week. The Positivity Rate is down to less than 3, the R effective is down to 0.89. GOD’S OWN COUNTRY.

Fresh Warning – is it hyped?

• UK is seeing a new mutant of the virus that is 70 percent more transmissible and the authorities there are calling it “out of control.” Several European countries have banned flights to and from UK. Italy has reported finding the same strain in a couple who had returned from UK.
• A similarly contagious strain of the virus has also been seen in South Africa.
• It has mutated to a N501Y variant by changing its spike protein that enables it to cling to and enter the cells more easily.

The Vaccines – Wait is maddening

• No vaccine in history has been so eagerly awaited as the vaccine against SARS CoV2. China, Russia, UK and the USA have already started using the vaccine. For the first time, we have vaccines that are using messenger rNA in place of Live attenuated or killed virus vaccines. Due to the urgency, these vaccines have been granted Emergency Use Authorisation by the FDA.
• What we must remember is that the vaccine will not protect us from getting infected and therefore transmit the disease to others. It will save us from severe disease.

One should strictly observe the current guidelines

Even after getting vaccinated, one should strictly observe the current guidelines for avoiding infection such as:

• Using mask.
• Staying at least six feet away from others.
• Avoiding crowds.
• Washing hands with soap and water for 20 seconds or using hand sanitizer with at least 60% alcohol.
• Following CDC travel guidance.
• Following quarantine guidance after exposure to COIVD-19.
• Following any applicable workplace guidance.

CDC and ACIP recommendations on Vaccine for pregnant ladies and breast-feeding mothers

1. There are limited data.
2. m RNA vaccines are generally safe and the it is wrong to assume that they will alter the genetic pattern of the foetus
3. Pregnant ladies are at increased risk of developing severe disease.
4. Getting vaccination should be a personal choice even for pregnant health workers.

The direction we need to take

• When this pandemic ends, we must plan for the next which could be just around the corner.
• We must have a National Institute of Virology in each state with facilities for extensive research. Virology should be made a super specialty.
• Intensive care beds with Intensivists should be available at district level.
• The process of tracking and tracing contacts should be modernised. Serious efforts and money should go towards reducing pollution.

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