5^th June, 2021, Saturday, 9.30am-10.30am

Key points from the discussion

#1. JAK Inhibitor in moderate to severe Covid 19

Dr Rohit Aggarwal, Medical Director, Arthritis and Autoimmunity Center, Professor of Medicine, University of Pittsburgh

• In patients with severe COvid-19, the cytokine storm can cause significant lung damage; it can also damage other organs including the brain, kidneys and blood vessels via endothelial disruption and angiogenesis.
• The plasma levels of the proinflammatory cytokine IL-6 are raised; it is a prognostic indicator of mortality. It acts mainly through JAK/STAT pathway, which can be blocked by JAK inhibitors.
• All JAK inhibitors block different types of JAK receptors JAK, 1, 2,3 and Tyk 2. Different JAK inhibitors block different types of cytokines; the advantage of using JAK inhibitors are that they block multiple cytokines.
• Baricitinib is a JAK inhibitor. It has a dual mode of action. By inhibiting numb-associated kinases (NAKs) and thereby viral endocytosis, it reduces viral infectivity. It exerts anti-inflammatory action via blockade of JAK1/2. IL-6 and IFN are the cytokines where baricitinib is really believed to work.
• Baricitinib is an oral drug, so easy to administer; 4 mg once daily x 7-14 days or until discharge. Recommended for use only in hospitalized covid patients requiring oxygen and high CAP.
• In an observational study from Italy, baricitinib arm vs non-baricitinib arm. Patients also got HCQ, lopinavir/ritonavir, antibiotics, steroids and LMWH. Death or invasive mechanical ventilation was almost 17% in baricitinib group. It was almost double in the comparator group. Baricitinib was also independently associated as a protective variable with the primary outcome of death/ventilation in multivariate cox regression analysis. Very importantly, the favorable effect of baricitinib was seen early and was persisted until the end of follow-up. In this study, there were some cases of liver enzyme elevation, but they did not require discontinuation of drug. Other side effects were lymphocytopenia, infectious complications. There were no signs of coagulopathy or thrombosis; but most patients were anticoagulated with LMWH.
• Baricitinib + remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patient with Covid-19, especially among those receiving high flow oxygen or noninvasive ventilation (NEJM, March 2021).
• Results from the Phase 3 COV-BARRIER study of baricitinib 4 mg once daily + standard of care vs versus placebo + SoC show that it did not meet the primary endpoint (patients progressing to the first occurrence of non-invasive ventilation including high flow oxygen or invasive mechanical ventilation including extracorporeal membrane oxygenation (ECMO) or death by Day 28). A significant reduction in death from any cause by 38% was noted.
• The US FDA has issued an EUA to permit the emergency use of baricitinib, in combination with remdesivir, for treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in hospitalized adults and pediatric patients 2 years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or ECMO.
• Immune profiling with vaccine is very different from that with native infection.
• Covid vaccine can generate aberrant immune responses leading to autoimmunity, especially in patients who are more predisposed, but they are rare. Post-vaccine lupus-like syndrome has been reported.
• Tocilizumab vis a vis baricitinib: Tocilizumab is a specific IFN inhibitor, it inhibits IL-6, while baricitinib inhibits multiple cytokines; therefore using baricitinib might be better if one is not sure that the inflammation is IL-6 driven. But, it has to be decided on case to case. Tocilizumab is to be given in hospital-setting as is baricitinib.
• We do not know yet if the vaccine-induced complications are reversible or permanent. We are still learning in the short-term. 
• Repeat a negative antibody test after a vaccine/infection. Immune suppression drugs reduce vaccine response.

#2. Country Updates

• India Update: the second wave is receding. At the peak, there were more than 4 lakh cases; the number has declined to less 1.2 lakhs. Vaccination is ongoing on a large scale and more than 17 crore people have been vaccinated. There are chances of reinfection with the delta variant (B.1.617.2) even after full vaccination. The infectivity is higher, but duration of infection has reduced (≤1 week); also, mortality has not increased. Children are also getting infected; the Federation of Obstetricians and Gynaecologists Society of India (FOGSI) is now recommending vaccination for pregnant women.
• Bangladesh Update: cases are high in areas bordering India; the delta variant is predominant strain now.
• About 1800-2000 new cases per day and 30-40 deaths per day now; 
• Hong Kong Update: There had been zero cases since more than a month; but yesterday, there has been a confirmed case of a 17-year-old student who did not travel anywhere or had a history of close contact with any confirmed cases. This is a case of unknown origin, which is alarming. Another cause of worry is the case of a medical student, who developed intracerebral hemorrhage after the vaccination. The government will now provide one day off after the vaccination for civil servants.
• Pakistan Update: The third wave has reached its peak; the positivity rate has come down from 24% to 2%.  Earlier the UK variant was the major strain, but now three cases of variant from India have been detected, which is worrying.
• Malaysia Update: The country is in the fourth phase of the infection. Cases are increasing; there are around 7000-8000 cases per day, deaths per day are now 90-100 per day. There is a total lockdown during which only 20% of the workforce will work. The government is trying to rope in the private sector for to help them with the vaccination. The vaccination process is very slow. Doctors have died from the infection even after full vaccination.
• South Africa Update: The country is in the midst of the third wave; numbers are rising. It’s the flu season in South Africa; it’s difficult to differentiate between Covid and mild flu and colds. South Africa did not use AstraZeneca vaccine as it was shown to be not effective against the South Africa variant, which is causing the bulk of cases in the country. Hence, J&J and Pfizer vaccines are now used. Pfizer vaccine has been started only recently. The gap between first second doses has been expanded from 21 to 42 days.
• Nepal Update: There is a second wave in the country; about 8000 to 10,000 new infections occur per day and around 150-200 deaths per day; deaths have reduced to around 100 per day. All healthcare workers have been vaccinated; the general population is hesitant to take the vaccine. There is scarcity of oxygen, beds and ICUs etc. the country is in a strict lockdown. Death rate is very high in patients on ventilators with a recovery rate of less than one percent.
• Australia Update: About 4-5 cases of the delta variant, in a family who had travelled to NSW, have been detected. This is worrying and authorities are trying to trace the source of infection. The lockdown may get extended on account of these cases. Vaccination is slow.
• Singapore Update: The serial interval is very short, about 2-3 days indicating high transmissibility. There were seven cases yesterday. Of these, one is an unlinked case. Four million of the total population of 5.5 million has been vaccinated. About 2.2 have received the first dose; the rest have received both doses. Children are now being vaccinated.

Participants

Member NMAs

Dr Yeh Woei Chong, Singapore Medical Association, Chair CMAAO

Dr Ravi Naidu, Malaysian Medical Association, Immediate Past President CMAAO

Prof Ashraf Nizami, First Vice President CMAAO, President PMA Lahore

Dr Alvin Yee-Shing Chan, Hong Kong Medical Association, Treasurer, CMAAO

Dr Marthanda Pillai, India, Member World Medical Council

Dr Salma Kundi, President, Pakistan Medical Association

Dr Angelique Coetzee, President South African Medical Association

Dr Marie Uzawa Urabe, Japan Medical Association

Dr Md Jamaluddin Chowdhury, Bangladesh Medical Association

Dr Akhtar Hussain, South African Medical Association

Dr Mukti Shrestha, Nepal Medical Association

Invitees

Dr Russell D’Souza, Australia UNESCO Chair in Bioethics

Dr Brahm Vasudev, USA

Dr Monica Vasudev, USA

Dr Rohit Aggarwal, USA

Dr Sumit Soni

Dr Rishabh Popli

Dr S Sharma, Editor IJCP Group

Dr Meenakshi Soni Barnwal, HCFI

Moderator

Mr Saurabh Aggarwal