CME INDIA Presentation by Dr. Basab Ghosh, Senior Diabetologist, Agartala, Tripura.
“Early” and “timely” are very important in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) infected COVID-19 management for both diagnosis as well as in treatment. Screening should be at the “earliest”. On the first day of the symptom virus is maximum replicable and contagious; the best “time” for screening is within the 5th day of symptoms.
If we give attention to the clinical course of the disease, then it is easier to understand the course of management of COVID-19.
1. Incubation period: It is the period between the exposure and the display of symptoms and on average is 4 to 7 days; however can go up to 14 days and this is also the “pre-symptomatic” period. “Pre-symptomatic” or “asymptomatic” positive case is a person who is infected with the virus, but does not develop symptoms; both pre-symptomatic and asymptomatic persons are highly contagious and carries mostly 80% of the total cases. During this stage there is no need for any investigations and active treatment. Basically they should be screened early and isolated properly to avoid spread of the virus.
2. Symptomatic period: After incubation period, once symptoms develop can last for7 to 8 days and known as “symptomatic” period. Once infected, the virus is replicable throughout this phase and is at its peak replication when symptoms start appearing. The duration of incubation period and symptomatic phase are on an average 10 to 12 days. According to symptoms, clinical sighs and oxygen demand clinically there are mild, moderate and severe stages of the disease. Mild stage does not require any investigations and active treatment; only symptomatic treatment for fever, body ache, cough, etc. are enough. Daily monitoring of two to three hourly temperature, counting of respiratory rates per minute twice in a day, three to four times measurement of oxygen saturation by regular pulse oxymeter including two times Six Minute Walking Test, daily measurement of breath holding time, are very important tool for assessment of home quarantine or institutional quarantine cases in CovidCare Centers (CCC).Moderate stage is the stage of hypoxia with oxygen saturation 90% to 93%either detected during monitoring or elicited by SMWT. All cases should be admitted either in Dedicated Covid Health Centers (DCHC) or in Dedicated Covid Hospitals (DCH) as per severity of state of oxygen requirement. Timely initiation of oxygen therapy is the cornerstone of the management which is grossly disturbed by “late reporting” to hospital and is the major concern to increase mortality in any set up! In this stage of hypoxia antiviral treatment modules like reserved drug Remdisevir, Plasma (not recommended now and scientist suspect its use is responsible for awkward viral mutations), Monoclonal antibodies (best use in first 3 days of symptoms), DRDO experimentation 2-DG, if planned, should be administered in the viral replicable stage and earliest is the best outcome! However hypoxia is the basic clinical cut off to initiate any active treatment based on RECOVERY trial and we must remember the virus is non-replicable and non-culturable after 9th day of infection, so steroid should be planned after viral replicable stage; always better to avoid at least in the first week. In the viral stage steroid induces several multiplication of viral replication, ultimately leading to cytokine storm!
3. Pulmonary phase: Next is pulmonary phase of lung injury. First 4 to 5 days is early pulmonary phase of immune dysregulation due to inflammatory reactions to viral debris and is monitored by laboratory measurements of complete blood count, inflammatory markers and radio imaging by chest x-ray and HRCT. NLR in blood count more than 3.2 is indicative of initiation of effective antibiotics to avoid secondary bacterial infection. Subsequently severity progress to late pulmonary phase as marked by cytokine storm and over activation of Mast cells! “Cytokine storm” and “Mast-cell Activation Syndrome” may appear after 14 days of infection and ultimately contributes to increase mortality in COVID-19. Lung is grossly involved; oxygen saturation drops in 90 to 93% in moderate symptomatic cases and less than 90% in severe cases. As mentioned earlier, timely initiation of oxygen therapy is the cornerstone of the management which is grossly disturbed by “late reporting” to hospital and is the major concern to increase mortality in any set up! ‘Right steroid’ Dexamethasone (or equivalent) in ‘right time’ of hypoxia in ‘right dose’ of 6mg daily in moderate cases and 6mg twice daily in severe case for short course of 5 to 10 days is established in RECOVERY trial. COVID-19 is a thrombo-embolic disease. In early pulmonary phase there is thrombophilia, and severe COVID-19 is associated with features of disseminated intravascular coagulation (DIC) and hypercoagulable states which can manifest as venous thromboembolism (VTE) and / or micro thrombosis. Prophylactic anticoagulation in all hospitalized cases such as Low Molecular Weight Heparin 40mg subcutaneously daily (0.5mg per kg body weight) is a recommended dictum by Ministry of Health and Family Welfare, Govt of India. Off-label drug Tocilizumab has been approved in India to use only in severe and critically ill patients.
Management of hyperglycemia:
Proper diagnosis of new onset diabetes due to COVID-19 and control of blood sugars during the disease are very vital in both morbidity and mortality outcomes in this pandemic as experienced in both first and second wave of COVID-19. SARS-Cov-2 can spread and inflict injury to insulin producing B-cell via ACE 2 receptor present in those cells of pancreas; that probably causing new onset diabetes and dysglycaemia in COVID-19. Mild to moderate cases can be controlled with oral agents; it is advisable not to change the treatment module until unsuitable for acute covid situation. In moderate to severe diabetic COVID-19 cases or in uncontrolled glycaemia in steroid treated covid cases, insulin is the only safe choice. Basal bolus insulin regimen with three doses of prandial regular insulin and one or two doses of NPH insulin for those who have regular diet pattern is ideal. For irregular diet cases and critical cases intravenous insulin infusion with regular insulin is preferred.
There are more than 100 COVID-19 vaccines in trial in different countries and 8 vaccines are already approved by WHO for inclusion on the Emergency Use List (EUL) till 1st June 2021. Those are Pfizer BNT162b2, Moderna mRNA-1273, Johnson & Johnson Ad26.COV2.S, two versions of AstraZeneca AZD1222, Sinopharma SARS-COV-2, the Serum Institute of India Covishield and China’s SinovacSARS-COV-2. Covaxin produced by Bharat Biotech in Hyderabad, India is not yet on the WHOs EUL, nor does it have similar permission from the European Medicines Agency (EMA). According to WHOs most recent guidelines, released on 18th May 2021, Bharat Biotech has submitted “expression of interest” to be accredited, but that “additional information” is needed; however WHO expressed there will be a pre-submission meeting very recently in June 2021! Bharat Biotech has not yet applied for regulatory approval from the EMA, however Covaxin is permitted for usage in Iran, Mauritius, Zimbabwe, the Philippines, Nepal, Guyana, Mexico, and Paraguay, in addition to India. Pakistan produced Chinese CanSinoBio Ad5-nCoV vaccine, USA based Novavax NVX-CoV2373 and Russian Sputnik V are also waiting for WHO`s final nod.
India is using Covishield and Covaxin for world’s largest vaccination program launched on 16th January 2021. While Sputnik V has been approved to be imported from Russia by Dr Reddy’s, but is yet to be widely available in India. People has to be vaccinated, as and when time comes, as per government schedules which are based on proper scientific evidence. In the Coronavirus Vaccine-induced Antibody Titre (COVAT) study there is no difference in seropositivity or median titre amongst people who took 2nd dose at 4-6 weeks vs 8-12 weeks, in fact with this decision of delaying in Covishield 2nd dose from initial 4-6 weeks to present 12-16 weeks maximum people will be covered by 1st dose. There is no contraindication for vaccination including lactating mothers, except approval in age below 18 and pregnant women are awaited by the ongoing safety trials till 1st June 2021! In fact non vaccinated people of any age group are at maximum risk as experienced in the 2nd wave of COVID-19. Vaccine will not prevent from new infection, but produce good immunogenicity against SARS-COV-2 infection. In fact COVAT study, conducted amongst 525 Health Care Workers, showed both Covishield and Covaxin produce 79.3% seropositivity after 21 days of the 1st dose and further confirmed 95% seropositivity of humoral antibody response 21 days after both the doses and those 5% who had break through infection after vaccination none required hospitalization, oxygen supplementation or mechanical ventilation, in fact it was limited to mild to moderate infections. This study further showed anti-spike antibody production in Covishield vs Covaxin is 98.1% vs 80%. Of course study addressed better spike protein humoral immunity of Covishield vs Covaxin but not mentioned about neutrilizing antibody or cellular T cell immunity to come to any final conclusion of better immunogenicity! In fact break through infection risk was lower in Covaxin vs Covishield (2.2% vs 5.5%).
Multi organ injury in COVID-19 is a real concern in both acute COVID-19 and post-covid. ACE 2 receptors are the binding site in the host cells for SARS-COV-2 and distribution of ACE2 in the lung, heart, kidney, liver, brain, intestine and both alpha and beta cells of the pancreas make them vulnerable to SARS-COV-2 in acute as well as post-covid and that is the main alarm for the doctors across the globe. So, prevention of viral entry is the ideal life style approach in this pandemic even if whole country is vaccinated! Preventive life style “SMS” is the best “social vaccine” available in this pandemic – Social distance of six feet, Mask covering mouth and nose and Sanitizing hands frequently.
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