CME INDIA Presentation – Compiled by Dr N K Singh (Admin CME INDIA) and Dr Basab Ghosh, Internist, Agartala, Tripura.

“As of now there is limited evidence of post-COVID sequalae and further research is required and is being actively pursued. A holistic approach is required for follow up care and well-being of all post COVID recovering patients”

– Ministry of Health & Family Welfare Directorate General of Health Services (EMR Division), 13th September 2020.

Manta Revisited:

“Better outcome is observed if first week initiation of treatment is done early and timely, without lingering to second week.”

Dr Somnath, Hyderabad, says about his one case: As per report and history, I strongly believe in benefit of doubt. Initial CT might not give typical picture. In this case 12 days CT showed CORAD5.

And see such news on 12/09/20:

Panic Scenario all over. The news headlines say that People are getting Reinfection. But Scenario may not be like this.

Timing is very important in COVID-19 active management in both asymptomatic and symptomatic cases. Now even for post covid management, Government of India, Ministry of Health and Family Welfare, in their updated 13th September 2020 “Post Covid Management Protocol” instructed to look for early warning signs like:

• High grade fever, breathlessness,
• Spo2 <95%, unexplained chest pain,
• New onset confusion,
• Focal weakness.

Some experts suggested even sudden onset painless loss of vision as post covid consequences due to blocked Retinal artery by micro thrombus.

Like any other critical care “timing” is very important in COVID-19 management in both asymptomatic and symptomatic cases. Identification of the day one of infection is not easy to identify in all stages of communicable diseases. However, in COVID-19, day one of symptoms identification is very helpful in further management in both asymptomatic and mild symptomatic or in symptomatic cases.

For most of the cases, second week is eventful, like asymptomatic cases develop wide variety of mild symptoms and signs like fatigue, body ache, cough, sore throat, difficulty in breathing, etc; mild symptomatic cases develop more prominent symptoms, symptomatic cases worsen very fast! More over fever is a constant bothering at second week as expressed by several experts. Older people and people with many serious medical conditions are the most likely to experience lingering COVID-19 symptoms. The most common signs and symptoms that linger over time include: Fatigue, Cough, Shortness of breath, Headache, Joint pain.

In COVID-19, which is behaving as viral thrombo-embolic pulmonary and cardiac disease, so far non-controversial are only three therapies.

1. Early initiation of Oxygen without delay, if respiratory rate is >24 or SpO2 <94% (for home quarantine patients SpO2 <95%).
2. Alongside timely steroid initiation.
3. Timely anti-coagulant treatment initiation, if not contraindicated with known cases of active bleeding or a low platelet count of <25×10 to the power 9 / L.

See this WhatsApp post circulated as KEM Mumbai recommendation:

At present steroids are recommended for people who become hypoxic. “Start early steroid irrespective of hypoxia, if CRP and other inflammatory markers are elevated”. Oral prednisolone 20mg or Tab Dexa 4mg /day for 5 to 7 days will do the job if there are mild symptoms. Steroids will definitely make patient feel better. Steroids also prevent long term lung fibrosis. There is a controversy regarding when to start anticoagulant. Better to start it early if CT changes are seen, as the changes in CT are actually microvascular thrombi. After 5 days, if disease course is stable, you can switch to oral anticoagulant Tab Rivaroxaban 10mg OD for 4 weeks.

So a great temptation is going all over India and many parts of world to start steroids so early. We have no matched studies to recommend it scientifically. But in these desperate times, primary care physicians are applying their own wisdom.

“Early” and “Timely” are very important as all experts highlighted in COVID-19 management.

All guidelines levelled antiviral Remdesivir, immuno modulator Tocilizumab and Plasma therapy as experimental therapies for COVID-19. However, Apollo in their 26th August, 2020 updated version 28 of treatment protocol of COVID-19, considered Remdesivir in their treatment modules in moderate and severe stages, provided the patient if not on high flow oxygen/NIV/ mechanical ventilation. According to them efficacy expected to be greatest if started early in illness, so “timing” is very important for Remdesivir outcomes.

However, Tocilizumab and Convalescent Plasma Therapy (CPT) are still in their experimental drug list. Apollo protocol considered experimental therapy Tocilizumab, if condition is very very critical or worsening, or severe Macrophage Activation Syndrome (MAS) indicated with very high IL-6 levels (>1000pg/L) despite all steroids, anticoagulants, antivirals.

Regarding Convalescent Plasma Therapy (CPT):

If all treatment options tried then comes experimental therapies. They considered CPT in severe category patients (oxygen saturation <90% in room air) presenting within 3 days of diagnosis or <7 days from onset of symptoms. So far better outcome of Convalescent Plasma Therapy (CPT) is experienced by experts when it is given in less than 7 days duration COVID-19 cases who became severe very fast with oxygen saturation <90% in room air. “The ICMR study does not say there are no benefits of plasma therapy, it says CPT may not be effective for a patient on a ventilator. It should be noted that scientists and medical experts across the world are cautious about promoting the use of CPT and call it an experimental treatment which may help in aiding recovery. The World Health Organization has maintained that there is not enough evidence that plasma therapy works in treating those battling the novel coronavirus.”

What is important to understand about reinfection?

• The emergence of adaptive immunity in response (SARS-CoV-2), occurs within the first 7 to 10 days of infection.
• Understanding the key features and evolution of B-cell– and T-cell–mediated adaptive immunity to SARS-CoV-2 is essential in forecasting coronavirus disease 2019 (COVID-19) outcomes Ascertaining long-term B-cell and T-cell immunological memory against SARS-CoV-2 is also critical to understanding durable protection.
• A robust memory B-cell and plasmablast expansion is detected early in infection with secretion of serum IgM and IgA antibodies by day 5 to 7 and IgG by day 7 to 10 from the onset of symptoms
• Believe on T Cells- Simultaneously, SARS-CoV-2 activates T cells in the first week of infection, and virus-specific memory CD4+ cells and CD8+ T cells reportedly peak within 2 weeks but remain detectable at lower levels for 100 or more days of observation.
• Grifoni et al and others have identified SARS-CoV-2–specific memory CD4+ T cells in up to 100% and CD8+ T cells in approximately 70% of patients recovering from COVID-19.
• There occurs a decline in IgG neutralizing antibodies to SARS-CoV-2 in convalescence, raising apprehension of susceptibility to reinfection.
• It is often not appreciated that after this reduction, serological memory is then maintained by the smaller number of long-lived plasma cells that reside in the bone marrow and constitutively secrete antibody in the absence of antigen.
• The antibody recall response comes from this pool of memory B cells that are also long-lived. In fact, rare circulating memory cells have been shown to produce highly potent neutralizing antibodies when serum neutralizing titers are low.
• Thus, an early decline of neutralizing antibody levels should not be of concern.
• The key is at what levels the antibody titers stabilize after natural infection or vaccination. This represents the generation of long-lived plasma cells to protect against subsequent infection.

• Individuals with mild or asymptomatic disease are reported to exhibit robust memory T-cell responses months after COVID-19 infection.
• However, it is unknown whether memory T cells in the absence of detectable circulating antibodies protect against SARS-CoV-2

CME INDIA Tail Piece:

• We are in a troubled time having very pathetic POST COVID symptoms, new HRCT findings, Increased D Dimer levels and many others.
• We do not know, whether early steroids and anti-coagulation might cut short such post COVID complications.
• We need a very vigilant approach to start steroids and anticoagulation at earliest time
• Re-infection, at present is rarely a problem. In most of cases immunity is gained and it is our best hope to curtail panic in society.

Article is based on very recent papers:

• Grifoni A, Weiskopf D, Ramirez SI, et al. Targets of T cell responses to SARS-CoV-2 coronavirus in Humans with COVID-19 disease and unexposed individuals. Cell. 2020;181(7):1489-1501.e15. doi:10. 1016/j.cell.2020.05.015
• COVID-19 and the Path to Immunity. David S. Stephens, MD et al. Published Online: September 11, 2020. doi:10.1001/jama.2020.16656

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