With input from Dr Monica Vasudev

1125: Minutes of Virtual Meeting of CMAAO NMAs on “CMAAO Update & COVID-19 and anti-inflammatory drugs”

27^th October, 2020, Saturday, 9.30am-10.30am

Participants: Member NMAs: Dr KK Aggarwal, President CMAAO; Dr Yeh Woei Chong, Singapore Chair CMAAO; Dr Alvin Yee-Shing Chan, Hong Kong, Treasurer, CMAAO; Dr Ravi Naidu, Malaysia; Dr Marie Uzawa Urabe, Japan; Dr Christine Tinio, Philippines; Dr SM Qaisar Sajjad, Secretary General, Pakistan Medical Association; Dr Md Jamaluddin Chowdhury, Bangladesh; Dr Lochan Karki, Nepal

Invitees: Dr Russell D’Souza, UNESCO Chair in Bioethics, Australia; Dr Suneela Garg; Dr Anita Kant; Dr RP Pareek; Dr Ketan Mehta; Dr Major Prachi Garg; Ms Pooja Banerjee, Editor IJCP Group; Dr S Sharma, Editor IJCP Group

Key points from the discussion 

• E protein is common to all coronaviruses, but spike protein is different among different coronaviruses.
• When the virus enters the body, various cytokines, TNF, interferon (IFN)-alpha take care of the virus. If IFN does not act, the virus is tackled by natural killer cells. If IFN-1 is not formed, then cytokine crisis results.
• Proinflammatory mediators in viral infection: IFN, TFN, ILs, chemokines.
• Inflammatory mediators in viral infection: PGs, thromboxanes, leukotrienes.
• If lifestyle is proinflammatory, a virus will make it inflammatory.
• When IFN-1 is not formed, then macrophages produce NLRP3 → IL-18 and IL-1β. IL-1β induces production of ferritin, causes tissue damage.
• Th1 cells produce IL-6 → fibrinogen and CRP; TNF-α and IL-8 produce inflammation, via PLA2 and increased neutrophil migration, respectively.
• Treatment approaches: Either block TNF or interleukin, increase interferon or act at the level of colony stimulating factors.
• Various treatment strategies: Targeting viral RdRp, modulation of immune defense, supplements and neutraceuticals, vaccines, antivirals, gene therapy, blocking virus entry in the cell, targeting cellular signaling pathways.
• Potentially harmful effects of NSAIDs in COVID patients include adverse effects in GIT, heart and kidneys; exacerbation of asthma; increased incidence of hypercoagulation; increased secretion of some inflammatory cytokines contributing to cytokine storm; reduction of host immune response against the virus and increased formation of neutrophil extracellular traps (NETs).
• Potentially beneficial effects of NSAIDs in COVID patients: Reduce the risk of developing severe COVID-19; reduce entry and replication of virus; inhibit migration and activation of neutrophils and macrophages; inhibit activation of NLRP3 inflammasome and production of inflammatory cytokines and repress inflammatory Th1/Th17 cells.
• Fever in COVID-19 is not only thermal dysregulation, it is cytokine fever.
• Azithromycin (decreases viral entry in cells), HCQ (prevents virus binding to ACE2 receptor), doxycycline (prevents viral entry and replication) and ivermectin (inhibits viral replication) do not act on NLRP3.
• Ivermectin does not act on IL-1β, -6 and -18, TNF-α or NLRP3.
• Paracetamol increases IL-1β, reduces TNF- α; it does not reduce cytokine fever.
• Mefenamic acts on IL-1β, -6 and -18, TNF-α and NLRP3. It is drug of choice for COVID-19 inflammation (including inflammation induced fever).
• Paracetamol reduces fever but not CRP; mefenamic acid reduces both fever and CRP.
• When CRP is persistently high, there are four options: Mefenamic acid, indomethacin, naproxen, nimesulide. Of these, first is mefenamic acid, which can be given for 3 months; nimesulide is approved only for two weeks, then come indomethacin and naproxen.
• Diclofenac is anti-inflammatory; it is not a very good antipyretic.
• In post-COVID patients, when an anti-inflammatory is required, we need a drug which reduces fever and CRP and is steroid-sparing.
• In the first phase of the infection, we have to see the presentation, what the virus is doing to the body and in the second phase, what the body does to the virus.
• During the viral replication phase, we should not choose drugs that help the virus to replicate. Mefenamic acid can be used safely right from the first week of infection where there is a tendency to choose steroids to bring down the fever, which can be detrimental. It gives the effect of antiviral, anti-inflammatory and antipyretic.
• COVID-19 illness can be divided into two: Viral (RT PCR) illness and inflammatory (cytokine - CRP) illness. Once cytokines are released, the virus has no role to play. Responses of Th1, Th2 and Th17 cells decide the future action. If more of the good cytokines are released, the phenomenon is short-lived.
• CRP starts rising within 4-6 hours; it peaks at 36-48 hours and comes down to normal within 17 hours. Therefore, CRP should become normal by Day 4. If it does not return to baseline, this means shifting from viral phase to cytokine wave. By the 10^thday, CRP should be less than 10. If more than 10, then the body is under cytokine control → recurrent inflammation → symptoms and cytokine crisis.
• Long COVID is a persistent cytokine disease.
• From 9-90 days, there can be two types of illnesses: CRP normal or CRP more than 2.
• If CRP is less than 2, there is residual damage, which is autonomic dysfunction. If CRP is more than 2, this is persistent cytokine state, where an anti-inflammatory drug is needed (HCQ, mefenamic acid, steroid, colchicine). If there is fever, then mefenamic acid is the drug.
• There are very few patients now in Japan and only limited numbers of hospitals are seeing patients.
• In Australia, the number of patients is coming down. Mefenamic acid has been used as also dexamethasone.
• In Malaysia, all COVID patients are treated at designated government hospitals only.
• There is a strong recommendation now that all tertiary hospitals should have post-COVID clinics. Guidelines should be standardized and adopted by these clinics.
• Ibuprofen and ketoprofen have been shown to upregulate ACE2 receptors, thereby increasing the viremic load. IL-6 reduction with ibuprofen is not as evident as seen with other drugs. Ibuprofen is not contraindicated. The current recommendation is that those patients who are on ibuprofen should continue with it.
• Mefenamic acid can be started from Day 1 itself; it will help bring down the fever and also reduce inflammation. The virus requires serine protease to enter the cells. Serine protease inhibitors are required in such cases. Mefenamic acid is a serine protease inhibitor and this way it can work also as an antiviral.
• Ivermectin has antiviral properties, but it does not reduce inflammation. So, it has to be combined with an anti-inflammatory drug.
• Choose drugs which act at different levels.
• Which drug to choose should be left on the treating doctor; it is the personal experience of the doctor, which decides what works best for the patient.
• While remdesivir may not reduce mortality, it does reduce severity of infection. In severe cases, the viral load definitely comes down. It has been given emergency use authorization in India.
• The presence of CMAAO countries in the forthcoming WMA meeting was raised.
• Post-vaccination deaths have been reported in South Korea, although the government has said that these deaths are unrelated to the flu vaccination. This did create some panic among doctors in Hong Kong that if something happens after vaccination, is it defendable?

Dr KK Aggarwal

President CMAAO, HCFI and Past National President IMA