CME INDIA Presentation by Admin.

First Published – 18th May 2021; Last Updated – 17th July 2021. PDF link at the end of article.

Basic Framework By:

  • Dr Nishith Kumar, MD, FAPSR, Consultant Department of Pulmonary Medicine, OMC, Ranchi.
  • Dr Chandrakant Tarke, MD, DNB, DM, MNAMS, EDRM, Pulmonologist, Apollo Hospital, Hyderabad.

Edited By:

  • Dr N.K. Singh, MD, FICP, Diabetologist physician, Dhanbad, Editor – cmeindia.in.
  • Dr Akash Kumar Singh, Internist, and Diabetologist, Spandan Multi-Specialty Hospital, Vadodara.

Advisor and Reviewer:

  • Dr Shashank R Joshi, MD, DM, FICP, FACP(USA), FACE(USA), FRCP (Lon, Glsg & Edin) (Padma Shri Awardee 2014). Chair, International Diabetes Federation Southeast Asia, Past Dean, Indian College of Physicians. Member, Covid 19 State Task Force, Maharashtra.

Invitee Reviewer:

  • Dr Banshi Saboo, National President, RSSDI, Ahmedabad.
  • Dr Mangesh Tiwaskar, Consultant Physician & Diabetologist, Mumbai, Hon. General Secretary, API.

Inputs:

  • Dr Murali Mohan B V, Pulmonologist, Narayana Medical Centre, Bengaluru.
  • Dr S K Gupta, MBBS MD(Med), CFM (France), Senior Consultant Physician, Max Hospital, Delhi.
  • Dr Basab Ghosh, MBBS, MDRC (Chennai), Dip Diab (Annamalai), (Prof M Viswanathan Gold Medallist), Senior Diabetologist, Agartala, Tripura.
  • Dr Bijay Patni, Diabetologist physician, Kolkata.
  • Dr Vaibhav Agnihotri, (DCH, DNB (Paediatrics), Fellowship Neonatology (IAP), PGPN, Boston, PCBD USA), Jaipur.
  • Dr Richa Agnihotri, MBBS, DGO, DNB (Obs & Gynae), FGES (lap surgeon), Jaipur.
  • Dr Sanjeev R. Pathak, Diabetologist, Ahmedabad.
  • Dr Urman Dhruv, Consultant Physician, Ahmedabad.
  • Dr Noni G Singha, MD, FICP, Consultant Physician, Dibrugarh, Assam.
  • Special Thanks to Dr Ravi Kirti, HOD, Dept. of Medicine, AIIMS, Patna.
  • Special Thanks to Dr Suresh Kumar, Infectious disease specialist, Apollo Hospital, Chennai
  • Special Thanks to Dr B. B Rewari, MD, FRCP, Former Asso. Prof. of Medicine, Dr RML Hospital, New Delhi. Scientist HIV/AIDS/STI/Hepatitis at WHO SEARO.
  • Dr Prof. Soumitra Ghosh, HOD, Medicine, IPGMER and SSKM Hospital, Kolkata.

Design and Content Management:

  • Mr. Rishav Manaswi, Founder (Dynamic Cognition), MBA (France), 📧 cmeindia.in@gmail.com.

Expert Consensus on COVID-19 Management, July 17, 2021.

Third Wave Blues

  • COVID 19 third wave is inevitable in late 2021, as per factual analytics.
  • More youth and children might be affected.
  • Severe lung Inflammatory disease will be seen.
  • Mortality may be more.
  • More Admission Beds and ICU care will be needed.
  • This updated guideline is in tune to tackle new challenges.


Mild Disease: Home Isolation


Identify

i. Symptomatic patients meeting the case definition for COVID-19

New Alert:

  • Extra-pulmonary symptoms such as vomiting and diarrhoea.
  • Conjunctivitis.
  • Neurological symptoms.
  • Loss of smell/taste.
  • A fairly constant feature is disproportionate fatigue.

ii. No evidence of viral pneumonia or hypoxia/SpO2 > 94 % on Room Air (Many guidelines now consider mild disease if SpO2 >90%).

iii. Respiratory rate < 24/min.

iv. No need of doing CT Scan, do only if strong clinical suspicion, CT of Corads 5, in the absence of a positive RT-PCR (Covid syndrome).

CT Severity Score (On a score of 25 or % lung involvement) < 8/25 < 25%.

v. Must have an identified care giver during this period communicating with a health provider as required.

Manage:

i. Isolation and all COVID appropriate behaviour

ii. Monitoring

  • Check SpO2 three to four times, NIBP, HR, Temperature.
  • The 6MWT will ascertain evidence of hypoxia identified by SpO2 less than 94% or an absolute drop in SpO2 by more than 3% from base line during or at end of the test. Patients over 60 years of age may have a shorter- 3-minute walk test (3MWT) if they are unable to perform a 6-minute test.

iii. What to inform patients?

Monitor following things:
1) Temperature with a clinical thermometer every 3 to 4 hours. Maintain a chart. Temperature more than 100ᵒF for more than 5 days, in spite of tablet Paracetamol, should be informed to the doctor.
2) Look for Pulse rate, if possible, by putting fingers in the wrist below the thumb. Count the numbers for 1 minute. Check for every 3 to 4 hours. Maintain chart. More than 100 per minute for more than 5 days, in spite of Tablet Paracetamol, should be informed to the doctor.
3) Look for Respiratory rate, if possible, by putting palm on abdomen while lying straight. Check for every 3 to 4 hours. Maintain chart. More than 20 per minute for more than 5 days, should be informed to the doctor.
4) Check oxygen saturation by Pulse oximeter, every 5 to 6 hours. Ensure that oximeter fluctuations have stopped before you take the reading. Maintain chart. Less than 94% in the last three readings is an emergency.
5) Six Minute Walking Test (SMWT) is very important and you do it two times daily during regular oxygen saturation measurement. Check oxygen saturation and start walking for six minutes in a normal way, maybe inside the room, now check oxygen saturation again, If the oxygen saturation has dropped below 93% or if there is an absolute drop of more than 3% to 5%, patient is  at risk and may need hospital care.  
Other important advices:

• Patients may perform warm water gargles and take steam inhalation twice a day.
• Sequential change of position every 1- 2 hours; supine, prone, sitting up, right lateral and left lateral.
• Continue taking medicines that you were already on for any pre-existing comorbidity – diabetes, hypertension, asthma, cancer etc. and consult a health care provider.
• Support own mental wellbeing:

i. Do not watch negative news and social media posts excessively.
ii. Meditate and talk with family and friends.
iii. Read books.
iv. Do walking and light exercises within the room.
v. Have proper sleep.

• Nutritional support—high protein diet.

Red flag signs (If developed likely to deteriorate):

  • High-grade fever/ severe cough.
  • Shortness of breath (while walking, talking, sitting), tightness in chest.
  • Feeling of disorientation.
  • Slurred speech/seizures.
  • Unable to wake up or stay awake.
  • respiratory rate ≥ 24/ min.
  • Oxygen saturation < 94% on room air.
  • A low threshold should be kept for patients with high-risk factor/co-morbidities.
  • PF ratio < 300.
  • Focus on 3 Lab tests:
    1. Neutrophil Lymphocyte Ratio >3.2 or RDW above 14.5.
    2. Raised CRP.
    3. Raised D-Dimer.

Note: D-dimer has been shown to increase with age, which can cause a lower specificity (i.e., more false positive tests) in older patients. So, age adjusted D dimer may be useful which can be calculated by: The formula is: Age (years) x 10 ug/L for patients > 50 years of age. Example: Patient age 88 = age adjusted d-dimer of 880 ug/L would be normal for 88 years.

Raised CRP- 5 times of ULN limit, rising CRP from baseline 3 times and D dimer – 2 times above normal limit-Need to act fast.

iv. Treatment

  • Rehydration.
  • Antipyretic (Paracetamol) Take paracetamol tablet 650 mg every 4-6 hours if you have fever – not more than four times in 24 hours. If fever is more than 101 degrees F, do tepid sponging using tap water (not cold water or ice) or take a shower. Mefenamic acid 500mg tablet can be added not subsiding with paracetamol provided renal function is normal.
  • Nutritional support.
  • No role of Azithromycin/ Doxycycline Note: Most of centres/experts use these drugs on personal experiences and have found them useful.
  • Supportive: Anti-tussive SOS /Vitamin C 500 mg OD or 2 weeks /T. Zinc 50 mg BD for 2 weeks Vit D 2000 units once daily or 60000 IU once weekly for 4-8 weeks.
  • Tab Melatonin or Clonazepam if needed to ally anxiety.
  • Say No to HCQS.
  • No solid evidence with Ivermectin – has weak antiviral properties in high concentrations, difficult to achieve with therapeutic current doses in Pulmonary endothelium, still few state guidelines recommend. Tab Ivermectin (200 mcg/kg once a day for 3 to 5 days) may be considered in patients with high-risk features. (Avoid in pregnant/ lactating and very elderly beyond 80 years) Category: Optional.
  • Favipiravir is an antiviral drug with limited value, may clear the virus, but most may not need it especially those with mild disease. May be useful only in first 48 hours to 72 hours hour not later. We do not recommend its use. Category: Optional. Dose – The recommended dosage of favipiravir for adults is 1800 mg orally twice daily on 1st day followed by 800 mg orally twice daily, up to maximum of 14 days. It may cause elevation of liver enzymes and uric acid. Avoid around conception and in Gout.
  • Molinipiravir (800 mg twice a day for 5 day) may be available in near future which also needs early use in first week of viral replication but better data is needed.
  • Steroids MUST NOT be used in patients with only mild disease. Concept of starting steroid on day 1 is detrimental and must be abandoned.
  • Recently Budesonide Inhalation (given via DPI/MDI with Spacer at a dose of 800 mcg BD for 5 to 7 days) to be given if are persistent beyond 5 days of disease onset or even early if in High-Risk Group (PRINCIPLE Trial).

  • Controversies with Early Steroid

It is totally unscientific to start steroids in viral replication phase. It has become a common practice in India that primary care physicians start on Day 1. This harms immensely the patient’s immune system as viral replication is accelerated due to immune suppression. We recommend to completely avoid steroid within 7 days of illness. (Unless indicated for a specific condition).

  • Prophylactic dose of LMWH if risk factor for thrombotic disease – Enoxaparin dose is 1mg/ kg OD not 40mg od for all or Inj Fondaparinux 2.5mg s/c OD. For Home, we prefer- Apixaban 2.5 mg BD Alternatively: Tab Aspirin 75 mg (or clopidogrel 75/ mg) in high-risk groups.
  • Anti-SARS-CoV-2 Monoclonal Antibodies
    • Approved molecules as Emergency use authorization (EUA):
      • Casirivimab,600 mg plus Imdevimab 600 mg: Antibody cocktail- now available in India.
      • Bamlanivimab 700 mg plus etesevimab 1,400 mg: Now not recommended as use of bamlanivimab plus etesevimab has been found to increase in the proportion of the variants of concern (VOC) Gamma (P.1) and Beta (B.1.351). These VOCs have reduced susceptibility to both bamlanivimab and etesevimab.
      • Single monoclonal antibody (sotrovimab). (Casirivimab plus imdevimab and sotrovimab remain active against these variants).

We suggest the use of casirivimab/imdevimab in patients with mild to moderate COVID-19 who are at high risk for progression to severe disease.

Among hospitalized patients with severe COVID-19, we do not recommend this therapy.

But patients who are admitted to the hospital for reasons other than COVID-19, and who have mild-moderate COVID-19, may also receive this therapy. The NIH and CDC suggest that treatment decisions (including use of monoclonal antibody therapy) be made regardless of COVID-19 vaccination status.

This therapy must be initiated in highly selective high-risk patients only as per following table:

FDA’s EUA defines high-risk patients as meeting at least one of the following criteria:   
• Have a body mass index ≥35; 
• Have chronic kidney disease; 
• Have diabetes; 
• Have immunosuppressive disease; 
• Are currently receiving immunosuppressive treatment; 
• Are ≥65 years of age; 
• Are ≥55 years of age AND have cardiovascular disease, OR hypertension OR chronic obstructive pulmonary disease/other chronic respiratory disease; 
• Are 12–17 years of age AND have BMI ≥85th percentile for their age and gender based on CDC growth charts, OR sickle cell disease, OR congenital or acquired heart disease, OR neurodevelopmental disorders, for example, cerebral palsy, OR a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19), OR asthma, reactive airway or other chronic respiratory disease that requires daily medication for control.    

  • When to start: Treatment should be started as soon as possible after the patient receives a positive result on a SARS-CoV-2 antigen test or a nucleic acid amplification test and within 10 days of symptom onset.
  • How to give: The intravenous administration takes about 20 to 30 minutes. For the subcutaneous route, four syringes of 2.5 ml (2 each of Casirivimab & Imdevimab) need to be administered concurrently at four different sites on the abdomen or thigh. Patients should be monitored during the infusion and observed at least one hour after the completion of the infusion and 15-30 minutes after the subcutaneous injection.
  • How supplied: Each pack of Antibody Cocktail (Casirivimab and Imdevimab) contains one vial of Casirivimab and one vial of Imdevimab totaling 2400 mg of the antibody cocktail (one vial of Casirivimab (1200 mg) and one vial of Imdevimab (1200 mg)). Each pack can treat two patients as the dosage per patient is a combined dose of 1200 mg (600 mg of Casirivimab and 600 mg of Imdevimab) administered by intravenous infusion or subcutaneous route. The vials need to be stored at 2°C to 8°C. If opened for the first patients’ dose, a vial can be used for the second patients’ dose within 48 hours if stored at 2°C to 8°C.
  • How much priced: The price for each patient dose [a combined dose of 1200 mg (600 mg of Casirivimab and 600 mg of Imdevimab)] will be INR 59,750 inclusive of all taxes. The maximum retail price for the multi-dose pack (each pack can treat two patients) is INR 119,500 inclusive of all taxes.
  • Alert: Receipt of a COVID-19 vaccine should be deferred for at least 90 days in those who have received anti-SARS-CoV-2 monoclonal antibodies.


Moderate Disease


Identify

i. Respiratory rate > 24 /min.

ii. SpO2 90-94% on room air (Many guidelines now consider SpO2 84-90%).

iii. CT Severity Score (on a score of 25 or % lung involvement) 8-15/25 or 25-50%.

Manage:

i. Admit in ward

ii. Oxygen Support:

  • Target SpO2: 92-96% (88-92% in patients with COPD).
  • Preferred devices for oxygenation: O2 face mask in most as it can deliver around 40 to 60 % oxygen at 6 to 10L/min.
  • Awake proning may be used in those with persistent hypoxia despite use of high flow oxygen (sequential position changes every 1-2 hours).
At a glance - Updated CME INDIA COVID Management Protocol 2021

iii. Laboratory and Clinical Monitoring to Guide Treatment

  • Clinical Monitoring: Work of breathing, Hemodynamic instability, Change in oxygen requirement.
  • Serial CXR, HRCT Chest (if worsening).
  • Lab monitoring:
    • CRP.
    • D-dimer & Ferritin 48-72 hrly.
    • CBC, LFT, KFT 24-48 hrly.
    • IL-6 levels to be done if deteriorating (subject to availability).

(Note: Close monitoring of SpO2 either by themselves or in a hospital/Isolation centre is needed for starting Steroids rather than CRP/D-dimer/NLR monitoring.)

iv. Drugs

A. Antiviral therapy

  • Remdesivir (Most of the guidelines do not recommend it).
  • Dose: Inj Remdesivir 200 mg IV on day 1.
  • Then, 100 mg IV daily for 4 days (can be extended up to 10 days in case of progressive disease).

(Use based on limited available evidence and case to case basis only)

  • Explain – Only reduces days of hospitalization without significant improvement in mortality rates.
  • Start Early – Using this agent after 7 to 10 days of symptom onset has no benefits.
  • Reserve Best reserved for moderate disease (respiratory rate > 24 < 30 and Fever & oxygen saturation below 92) within first 5 to 7 days of symptom onset.
  • SafetyOne should remember that drug is not a safe drug especially in presence of moderate to severe liver or renal disease.
  • Hospitalize – Strictly not to be given at HOME.

B. Convalescent plasma (CP)

  • It may be considered in carefully selected patients but all standard guidelines do not recommend it.

C. Anti-inflammatory or immunomodulatory therapy

  • Inj. Dexamethasone 6 mg IV OD or Oral dexamethasone 6 mg OD for 5-10 days or inj. Methyl Prednisolone 0.5 -1 mg/kg ≈ 60mg OD x 5 -10 Days Stop or taper if significantly better.
  • Dexamethasone 1.5 mg = Methylprednisolone 8mg = Prednisolone 10 mg. So, taking 12 mg Dexamethasone daily is equal to 64 mg methylprednisolone.
  • Good to keep this in mind when prescribing steroids.
  • Anticoagulation: Low dose prophylactic UFH or LMWH (weight based e.g., enoxaparin 0.5mg/kg per day SC). Enoxaparin dose is 1mg/ kg OD not 40 mg OD for all or Inj Fondaparinux 2.5mg s/c OD in High-Risk Group. In ESRD, Unfractionated Heparin – 5000U SC BD.

D. Consider about Antibody Cocktail (Casirivimab and Imdevimab) (Details given above).

E. Stay ALERT for Cytokine Storm (on Day 7/8 of disease)

During Moderate illness keep watch for:

  • Unremitting fever.
  • Cytopenia, Hyper ferritinemia.
  • If the patient in the second week having SOB (even with previous normal CT), rising CRP above 50, CT worsening, fever onset in the second week, etc. points towards impending cytokine storm.
  • Daily CRP monitoring and steroid dose adjustments are crucial here.


Severe Disease


Identify

Any one of:

i. Respiratory rate > 30 /min.

ii. SpO2 < 90% on room air.

(Many guidelines follow <85% now).

Manage:

i. Respiratory support Oxygen delivery by nasal cannula, face mask, Venturi mask, or mask with reservoir bag ± NIV*

At a glance - Updated CME INDIA COVID Management Protocol 2021

ii. Consider broad spectrum empirical antibiotic treatment for possible superadded bacterial pneumonia/infection (↑S.PCT/Significant Leucocytosis/Leukopenia).

iii. Inj Dexamethasone 6mg iv OD or Inj Methylprednisolone 1 to 2mg/kg in 2 divided doses for 5 to 10 In appropriate indication (Clinical worsening, Age<60, no diabetes), Dexamethasone dose could be- 0.2 – 0.4 mg/kg/day (12 – 24 mg /day).

iv. Anticoagulation

  • Unless contraindicated, FULL anticoagulation (on admission to the ICU) with enoxaparin, i.e., 1 mg kg s/c q 12 hourly (dose adjust with Cr Cl < 30mls/min) in those patients with a D-dimer > 3-5 X ULN and those with a rising D-dimer. Heparin is suggested with CrCl < 15 ml/min.
  • In all other ICU patients medium dose anticoagulation; enoxaparin 0.5 mg/kg q 12 hourly.

v. Inj Remdesivir 200mg iv Day 1 Followed by 100mg IV OD (Day2-5)

(Antivirals may be considered if duration of illness < 10-14 days)

vi. Tocilizumab may be considered on a case-to-case basis preferably within 24 to 48 hours of progression to severe disease Tocilizumab (Off-label) may be considered when all of the below criteria are met:

  • Severe disease.
  • Significantly raised inflammatory markers (CRP &/or IL-6) o Not improving despite use of steroids.
  • No active bacterial/ fungal infections.
  • The recommended dose is 4 to 8mg/kg (with a maximum dose of 800 mg at one time) in 100 ml NS over 1 hour (dose can be repeated once after 12 to 24 hours depending on clinical response).
  • IDSA conditionally suggests the use of tocilizumab among hospitalized patients with progressive severe or critical covid-19 and with elevated inflammatory markers. NIH recommends it in combination of dexamethasone if patient is experiencing a rapid respiratory decline with following criteria:
    1. Hospitalized within the last 3 days, admitted to an intensive care unit in the last 24 hours, and require either invasive mechanical ventilation, noninvasive ventilation, or high flow nasal cannula OR
    2. Hospitalized within the last 3 days, not admitted to the intensive care unit, have rapidly increasing oxygen requirements requiring either noninvasive ventilation or high flow nasal cannula, and who have increased markers of systemic inflammation.

If not available

Itolizumab

Very small study-By Biocon company-30 patient study. Dose-1.6 mg/kg in 250 ML NS over 6 hours. (- 25 mg in the first hour and the remaining dose over 5 hours)

If well tolerated and improvement in patient observed, clinician has the discretion to repeat a dose (after 1 week for itolizumab or after 12 hours for tocilizumab only after expert opinion) Informed consent is mandatory.

Bevacizumab and Sarlijumab are other options.

vii. JAK Inhibitors: Among hospitalized adults with severe COVID-19 having elevated inflammatory markers but not on invasive mechanical ventilation, the IDSA panel suggests baricitinib rather than no baricitinib. (Conditional recommendation, Moderate certainty of evidence). Baricitinib appears to demonstrate the most benefit in those with severe COVID-19 on high-flow oxygen/non-invasive ventilation at baseline.

Among hospitalized patients with severe COVID-19 who cannot receive a corticosteroid (which is standard of care) because of a contraindication, the IDSA guideline panel suggests use of baricitinib with remdesivir rather than remdesivir alone (Conditional recommendation, Low certainty of evidence).

Tab Baricitinib 4 mg once daily for 10 days (*Renal modification – 2mg once daily if GFR is between 30 to 60ml/ml/min, avoid if GFR < 30 ml/min) Cost: 4mg tab, 30Rs /tab.

We do recommend it.

viii. Supportive measures

  • Maintain euvolemia.
  • If sepsis/septic shock: manage as per existing protocol and local antibiogram.

ix. Monitoring

  • Serial CXR, HRCT Chest (if worsening)
  • Lab monitoring: CRP, D-dimer & Ferritin 24-48 hrly; CBC, LFT, KFT daily; IL-6 levels to be done if deteriorating (subject to availability)
  • Clue for cytokine storm:
    • Yes. We can predict. If the patient in the second week having SOB (even with previous normal CT), rising CRP above 50, CT worsening, fever onset in the second week, etc. points towards impending cytokine storm. Daily CRP monitoring and steroid dose adjustments are crucial here.

x. Critical Illness recommendations by NIH(UK)

  • Hospitalized and requires oxygen delivery through High-flow Device of NIV. Use one of the following:
    1. Dexamethasone.
    2. Dexamethasone plus Remdesivir.
  • For patients having rapidly increasing oxygen needs and systemic inflammation: Add either Baricitinib or Tocilizumab to one of the two above options.
  • Hospitalized and requires IMV or EMCO.
    1. For most patients -Dexamethasone.
    2. For patients who are within 24 hours of admission-Dexamethasone plus Tocilizumab.

xi. EMCO (Extracorporeal Membrane Oxygenation)

  • At present There are insufficient data to recommend either for or against the use of extracorporeal membrane oxygenation in patients with COVID-19 and refractory hypoxemia.

xii. Lung Transplantation

When to consider lung transplantation for COVID-19 patients?

  1. Candidates should be younger than 65 years of age. Existing experience from ECMO bridge to lung transplantation shows poor outcomes in older patients.
  2. Candidates eligible for transplantation should have only single organ dysfunction.
  3. Sufficient time should be allowed for lung recovery. It is in the best interest of the patient to be able to survive without a transplant given the suboptimal long-term survival rates of lung transplantation (about 60% at 5 years).
  4. There should be radiological evidence of irreversible lung disease, such as severe bullous destruction or evidence of established fibrosis.
  5. The patient should be awake and, in a position, to discuss and consent to his transplantation.
  6. Patients should be able to participate in physical rehabilitation while on the transplantation waiting list.
  7. Patients should fulfil the remaining typical criteria for transplantation. For example, adequate body-mass index and absence of other notable comorbidities, such as severe coronary artery disease etc.
  8. The patient should have a recent negative SARS-CoV-2 PCR test result, or infectivity assays using deep respiratory tract samples showing the absence of viable virus.
  9. The transplantation centre should have substantial experience with cases involving high-risk transplantation.
  10. The centre should have access to a broad donor pool and low waiting-list mortality.

As such, lung transplantation should be considered only in a selected group of patients with COVID-19-related ARDS as the ultimate effect and results of offering this life-saving therapy in this population remain unknown.


Consideration for following drugsColchicine, piroxicam, itolizumab, bevacizumab are also relevant as tocilizumab has scarce availability


  • Piroxicam use: Some physicians have used in those cases where oxygen was needed but beds were not available in moderate cases in dose of 20mg SL dispersible tablet and observed improvement in oxygen saturation. We do not recommend it in absence of any case-controlled study.
  • Colchicine use: Except few studies, most of studies did not found any significant improvement. It is now being used in mild, moderate and severe cases despite any recommendations by standard guidelines. • It is considered if fever persists despite paracetamol• Loading dose: 1.5 mg followed by 0.5 mg of colchicine 60 minutes later if no adverse gastrointestinal effects • Maintenance dosage: 0.5 mg BD until discharge or a maximum of 21 days (reduce to OD if body weight <60 kg) Contraindicated if eGFR<30mL/min/1.73m2. We do not recommend either for or against the use of colchicine for the treatment of non-hospitalized patients. Do not use it in in hospitalized patients.
  • Tofacitinib/baricitinab
    • Two drugs are available, but we recommend to use Baricitinib only as there are no clinical data on the use of tofacitinib to treat COVID-19.
    • For the Initial Viral Replicative Phase of Illness (First 5 days of illness) we recommend AGAINST the use of steroids or any other immunomodulatory medicines during this period.
    • For the Inflammatory Phase of Illness (From Day 6 of onset of symptoms) Immunomodulatory Treatment is recommended for the covid-19 positive patients with any of the following signs of deterioration (after exclusion of alternative causes like secondary infections etc.):
      • SpO2 below 94% at rest on room air.
      • SpO2 falling by > 4% from baseline after 6-minute walk at normal pace.
      • CRP > 30 mg/l; or Doubling of CRP from baseline in second week of illness (if baseline values available).
      • HRCT Severity score >9 score.
    • It has been recommended to start anticoagulation treatment for all patients on JAK inhibitors who have intermediate or high-risk factors for thrombosis. Drug and duration should be decided on Individual basis, based on age, risk factors and D-Dimer levels. (Risk Factors: reduced mobility, active cancer, prior history of DVT, prior h/o anti-phospholipid antibody syndrome, elevated D-dimer levels (>2 times the upper limit of normal).
  • Methylene Blue:
  • As there are only anecdotal reports, it is not indicated.
  • Bevacizumab – (Avastin 400mg single dose vial):
    • It is an anti VEGF recombinant humanized monoclonal antibody
    • It is being tried with severe Covid-19, with respiratory rate ≥30 times/min, oxygen saturation ≤93% with ambient air, or partial arterial oxygen pressure to fraction of inspiration O2 ratio (PaO2/FiO2) >100 mmHg and ≤300 mmHg, and diffuse pneumonia confirmed by chest imaging
    • It is priced between Rs37,500 to Rs39,000
    • Bevacizumab 7.5mg/kg body weight + 0.9% NaCl 100ml, intravenous drip
  • 2-Deoxy-D-Glucose by DRDO
    • A total of 110 patients were part of the Phase-II clinical trials of DRDO’s 2-DG drug. The results showed that in terms of improvement of vital signs of COVID-19 symptomatic patients there was a difference of 2.5 days compared to Standard of Care (SoC). (INDE-GENIUS study)
    • The 2 DG drug, like glucose, spreads through the body, reaches the virus-infected cells and prevents virus growth by stopping viral synthesis and destroys the protein’s energy production. The drug also works on virus infection spread into lungs which help us to decrease patient’s dependability on oxygen.”
    • The anti-COVID drug 2-DG has been developed in powder form and is ingested orally by dissolving it in water.
    • Phase III trial on (40 patients) report led to DCGI approval – 8th May 2021
    • Dose and Regimen: 2-DG: 45 mg/kg body weight AM + 45 mg/kg body weight PM, twice daily for not more than 10 days. Instructions for preparation of one dose (morning or evening) of 2-DG (Dose level – 90 mg/kg body weight/day, administered in two equally divided doses approximately 12 hours apart) DO NOT USE the reconstituted dose solution for further dosing of the patient. Each dose of 2-DG should be prepared using a fresh 5.85 g sachet.
    • At present, we do not recommend for or against its use.
  • Virafin
    • On April 23, 2021, Virafin had received restricted, emergency use approval from the Drug Controller General of India (DCGI).
    • ‘Virafin’ is pegylated interferon alpha-2b. Interferons are signalling proteins that help the body’s immune system defend against viral infections. Pegylated interferon alpha 2b have been  used to help treat Hepatitis C.
    • Its phase 2 trial results were published in the International Journal of Infectious Diseases, in its April 2021 issue.
    • It was conducted with 40 patients who had moderate COVID-19 – 20 of them were assigned to the control arm and 20 to the treatment arm.
    • It was used in RT-PCR confirmed SARS-CoV-2 infection, pneumonia with no signs of severe disease, respiratory rate 15-30 breaths/min, oxygen saturation 90%–94%.
    • Each dose of Virafin costs Rs 9,000 per injection.
    • Due the many flaws in the study, we do not recommend its use at present.
  • Fluvoxamine
    • It is a selective serotonin reuptake inhibitor (SSRI) which is not FDA-approved for the treatment of any infection. There is insufficient evidence either for or against the use of fluvoxamine for the treatment of COVID-19.
  • Drugs not to be used:
    • Baricitinib with tocilizumab.
    • Interferons (alfa or beta) for the treatment of severely or critically ill patients with COVID-19.
    • Kinase inhibitors:
      • Bruton’s tyrosine kinase inhibitors (e.g., acalabrutinib, ibrutinib, zanubrutinib).
      • Janus kinase inhibitors other than baricitinib (e.g., ruxolitinib, tofacitinib).
    • Non-SARS-CoV-2-specific intravenous immunoglobulin (IVIG). But it should not preclude the use of IVIG when it is otherwise indicated for the treatment of complications that arise during the course of COVID-19.
    • Sarilumab for patients who do not require ICU-level care or who are admitted to the ICU for >24 hours but do not require invasive mechanical ventilation, noninvasive ventilation, or high-flow oxygen.
    • The anti-IL-6 monoclonal antibody, siltuximab.


Guideline for tackling Mucormycosis Prevention and treatment


ALERT

  • Rhino-Orbito-Cerebral Mucormycosis (ROCM) being a rapidly progressive disease, even a slight delay in the diagnosis or appropriate management can have devastating implications
  • Outcome can be optimized by early diagnosis prompted by awareness of warning signs and symptoms and high index of clinical suspicion, confirmation of diagnosis by appropriate modalities, and initiation of aggressive medical and surgical treatment by a multidisciplinary team

(Adapted from Mucormycosis Study Group Sir Ganga Ram Hospital, New Delhi and IJO-2021)

Suspected OR confirmed Mucormycosis

Look for

  • Covid history.
  • History of steroid therapy, other medication, hospital stay.
  • Known medical history: DM, renal failure, immunocompromised pt, malignancy,
  • Findings: Facial Swelling, Periorbital Swelling, Severe Headache, Nasal Blockage.
  • Intraoral Pus Discharge, Gingival Abscess, Teeth Mobility.

Do Investigation

  • Blood investigation: CBC, CRP, HbA1c, Renal profile.
  • Radiological: CT PNS or 3D CT Face, MRI Findings- · Early stage: sinusitis · Intermediate stage: Bony erosion in maxilla · Aggressive stage: involvement of orbit and brain.
  • Diagnostic Nasal Endoscopy (DNE) + Otoscopy + Palatal Examination.
  • Deep Nasal Swab for KOH smear & Fungal Culture.
  • Biopsy (in Sterile Saline for Mycology & Formol Saline for Histopathology).
  • [At any point, in very high clinical suspicion – Day 1 till whenever and start liposomal amphotericin B (in very high clinical suspicion) without waiting for the Microbiology Reports].

Treatment

Antifungal medication

  • Inj Amphotericin B (1.0-1.5 mg/kg/day).
  • Inj Liposomal Amphotericin B (5-10 mg/kg/day).
  • For 14 to 21 days.
  • Note: Liposomal Amphotericin is preferred as it has relatively lesser nephrotoxic. The duration of therapy is highly individualised and should encompass the resolution of associated symptoms and findings normalization of radiologic findings, negative cultures from affected site, and resolution of immunosuppression.
  • Tab Posaconazole GR 100 mg (step down or adjutant therapy) First day -300 mg BD Other days- 300 mg OD for 45 days.

Alternate day perform · S. Creatinine · S. Electrolyte To avoid Nephrotoxicity and hypokalaemia.

Regular follow-up (CT PNS every 15 days to 1 month).

Amphotericin B administration protocol.

Pre-hydration

  • 500ml Normal saline 2 hr before infusion Amphotericin B.
  • To reduces the risk of renal toxicity and hypokalaemia: – 500ml Normal Saline + 1 Amp (20mmol) KCL.

Hydration

  • Dilution: 1mg in 10 ml.
  • Always use 5% or 10% dextrose.
  • Avoid Normal saline.
  • 500 mL NS IV given pre-infusion.
  • If fluid overloaded, use 250 mL pre/post or skip post-hydration.
  • If hyperchloremic, may use normosol instead of NS.
  • Protect from light during administration Drugs Recommended Dose Duration Amphotericin B 1.0-1.5 mg/kg/day 14 to 21 days depending on severity.

Surgical

Early stage (only sinus is involved no bony change)

  • Excisional biopsy (deep bone) + sinus lining.
  • FESS (Functional Endoscopic Sinus Surgery).

Confirmed or late stage (bony erosion)

  • Debridement and curettage till healthy bone.
  • Orbital exenteration if indicated after ophthalmologist opinion.
  • FESS.

Test sampling

  • Bacterial or fungal cultural and sensitivity.
  • Histopathological investigation.

New Mantra in COVID cases
1. Baseline HbA1c on Admission.
2. The strict control of blood sugar levels (110-180 mg/dl).
3. Proper management of Diabetic Ketoacidosis (DKA).
4. Rational use of steroids in the high-risk group.
5. Adequate humidification with distilled water used in the humidifiers of the Conventional / Low Flow / High Flow Oxygen delivery systems.
6. Isotonic-Saline Nasal Douche / Spray x 2 Times a day.
7. Maintain the Hygiene of Oxygen Delivery Systems.
8. Complete ENT Evaluation.

New Sutra to Educate patients about the early signs and symptoms of Mucor
1. Nasal Blockage.
2. Blood-tinged nasal discharge.
3. Headache.
4. Pain in the Eye.
5. One sided Facial Pain & Swelling or Numbness.
6. Toothache, Loosening teeth, discomfort during chewing.
7. Swelling of the Eye & Adnexa.
8. Double Vision.

Warning signs and symptoms of Rhino-Orbito-Cerebral Mucormycosis (ROCM)

At a glance - Updated CME INDIA COVID Management Protocol 2021

Prevention of Rhino-Orbito-Cerebral Mucormycosis in the setting of COVID-19(IJO-2021)

At a glance - Updated CME INDIA COVID Management Protocol 2021


Post Discharge


i. Anti-coagulation

  • We do not recommend anticoagulants and antiplatelet therapy for non-hospitalized patients with COVID-19. It should not be initiated for the prevention of venous thromboembolism (VTE) or arterial thrombosis unless the patient has other indications for the therapy.
  • All admitted patients should, if there are no contraindications, receive anticoagulants in a prophylactic dose. Some guidelines do not recommend it but others do. So, aspirin and statin are not recommended for everyone on discharge.
  • The decision on use of anticoagulants needs to take into account the risk of thrombosis and of bleeding on anticoagulants.
  • The National Institutes of Health (NIH) does not recommend routine post discharge VTE prophylaxis for patients with COVID-19.
  • The signal for increased thrombotic risk is sufficient to recommend pharmacologic venous thromboembolism (VTE) prophylaxis in all hospitalized COVID-19 patients as long as there is no contraindication.
  • Extended post-hospital VTE prophylaxis should be considered in patients with COVID-19 (up to 45 days- MAGELLAN, APEX and MARINER studies).
  • It is reasonable to employ individualized risk stratification of thrombotic and bleeding risk, to consider patients with elevated risk of VTE [e.g. Reduced mobility, active cancer, prior DVT, elevated D-dimer (>2 ULN)]. VTE options include Apixaban 2.5 bid, rivaroxaban 10 mg daily or Enoxaparin SQ daily (prevention dose adjusted for weight).
  • When the risk of thrombosis is high, (as assessed by the ISTH SIC score) and a high bleeding risk has been ruled out (using the HAS-BLED score), we would recommend therapeutic anticoagulation.
  • A high HAS-BLED score (≥3) is indicative of the need for regular clinical review and follow-up, but should not be used per se as a reason for stopping oral anticoagulation. All scores are available through online calculators.
  • At hospital discharge, patients must be educated on the signs and symptoms of VTE and advised to seek urgent medical attention should these develop.
  • Postdischarge VTE prophylaxis decisions should be individualized, taking into consideration the patient’s risk factors, including reduced mobility, bleeding risks, and feasibility.
  • Pregnancy Issues: If antithrombotic therapy is prescribed during pregnancy prior to a diagnosis of COVID-19, continue it. If hospitalized for severe COVID-19, prophylactic dose of anticoagulants is recommended. After hospital discharge is not recommended for pregnant patients. Decisions to continue VTE prophylaxis in the pregnant or postpartum patient after discharge needs individualization and consideration of concomitant VTE risk factors. Anticoagulation therapy use during labor should be managed in pregnant patients with COVID-19 in a similar way as in pregnant patients with other conditions that require anticoagulation in pregnancy.
  • Lactation Issues: Unfractionated heparin, low molecular weight heparin, and warfarin do not accumulate in breast milk and do not induce an anticoagulant effect in the newborn. These can be used by breastfeeding individuals with or without COVID-19 who require VTE prophylaxis or treatment.

Note: Use of direct-acting oral anticoagulants during pregnancy is not routinely recommended due to lack of safety data.

ii. Corticosteroid therapy

  • Based on data from the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, NIH guidelines recommend using dexamethasone 6 mg per day for up to 10 days for the treatment of COVID-19 in patients who are mechanically ventilated (level of evidence: AI—strong, based on ≥1 randomized trial) and in patients who require supplemental oxygen but who are not mechanically ventilated (level of evidence: BI—moderate, based on ≥1 randomized trial).
  • It is advised to continue a course of dexamethasone for 10 days even after discharge in recovered COVID-19 patients who required oxygen during hospital admission.
  • NIH guidelines recommend against the use of dexamethasone for COVID-19 cases not requiring supplemental oxygen due to lack of survival benefits and potential harmful effects (AI).

iii. Oxygen therapy

  • Although there is no evidence about the beneficial use of oxygen therapy at home in discharged COVID-19 patients, short-term home oxygen therapy may be considered in hypoxemic patients at rest (oxygen saturation <88% on room air). Risks and benefits should be weighed before discharging patients on home oxygen.

iv. Adjuvant therapies

  • Some vitamins and minerals such as vitamin C, vitamin D, and zinc have been proposed for use in COVID-19 due to their beneficial antioxidant immunomodulatory effect, but NIH recommends against using them due to lack of safety and efficacy.
  • We opine to use these on case to case basis.


Treatment of Post-Covid Symptoms


Investigate it

Not all patients will need all

  • CBC: Anaemia, Lymphopenia.
  • CRP persistent inflammation or super aided infection.
  • LFT, KFT, Blood Sugar.
  • ECG- Bradycardia Cardiac involvement.
  • Ferritin (inflammation and continuing prothrombotic state).
  • D-dimer (thromboembolic disease).
  • Troponin and D-dimer tests may be falsely positive, but a negative result can reduce clinical uncertainty.
  • Troponin (acute coronary syndrome or myocarditis).
  • Chest x-ray for all patients continued respiratory symptoms >12 weeks. –Lung Fibrosis, Residual Pneumonitis, associated Fungal infections.

Issues and Management

Fever

  • After recovery from Covid it is not uncommon to see resurgence of episodes of fever lasting few hours to days, especially after heavy physical activity. Such patients usually don’t land up into serious complications.
  • Rest, paracetamol and short 3-to-5-day course of Non-steroidal anti-inflammatory drugs like Mefenamic acid and Naproxen may be helpful.
  • Some patients may require low dose of Non-steroidal Anti-inflammatory drugs for long duration. However, it may be important to monitor Kidney function in such cases.

Cough

  • Rule out super-infection.
  • Rule out other complications as pleuritis (painful).
  • Graded physical activity in case cough/fever/fatigue/breathlessness is precipitated by walking or talking
  • Medication where indicated:
    • Antihistaminic.
    • Nebulization with Budesonide, Bronchodilators.
    • Proton pump inhibitors (if reflux is suspected).
    • Cough Lozenges.
  • Respiratory Exercises: Helpful in Chronic cough aimed at normalising breathing patterns and increasing the efficiency of the respiratory muscles (including the diaphragm).

Technique

  • The patient should sit in a supported position and breathe in and out slowly, preferably in through the nose and out through the mouth, while relaxing the chest and shoulders and allowing the tummy to rise.
  • They should aim for an inspiration to expiration ratio of 1:2. This technique can be used frequently throughout the day, in 5–10-minute bursts (or longer if helpful). Other breathing techniques—such as diaphragmatic breathing, slow deep breathing, pursed lip breathing, yoga techniques Pranayama are immensely helpful.

Breathlessness

  • Some breathlessness is common after covid-19.  It tends to improve with breathing exercises
  • Treatment remains the same as for cough.
  • But it is important to monitor oxygen by pulse oximeter. Oxygen level of 96% or above and the absence of desaturation on exertional tests like six-minute walk test is reassuring.
  • Oxygen therapy should not be delayed at a level of 92% or below. Amount of supplemental oxygen should be titrated to target a range 94-98%.
  • Survivors of covid-19 ARDS are at risk of long-term impairment of lung function and may require long-term home-based oxygen therapy.

Lung Fibrosis

  • Pirfenidone 200-800 mg BD/TDS is being tried but most of the pulmonologist do not advocate.
  • It appears that majority of post Covid patients recover with time with insignificant/zero lung fibrosis over 3 to 4 months.
  • The key is oxygenation, preventing secondary complications & nursing care.
  • Nintedenib 150mg OD/BD is also being used as anti-fibrotic drugs. It needs to be used with LFT monitoring and only if HRCT shows Fibrosis.
  • We recommend to start these drugs only after consultation of a Pulmonologist. Use of antifibrotic in COVID 19 trials are on going. No evidence in favour or against at present.

Silver Lining

  • Serious interstitial lung disease is rare in patients who are not hypoxic.
  • Lung changes are largely reversible in most of the patients despite high CT severity score.

Multisystem Inflammatory Syndrome in Adults

Diagnosis Clues:

  1. Evidence of acute or recent SARS-CoV-2 infection (documented by a nucleic acid amplification test [NAAT] or antigen or antibody testing) with minimal respiratory symptoms.
  2. With laboratory markers of severe inflammation (e.g., elevated C-reactive protein [CRP], ferritin, D-dimer, cardiac enzymes, liver enzymes, and creatinine).
  3. With various other symptoms, including fever and shock; and signs of cardiovascular, gastrointestinal, dermatologic, and neurologic disease.

Most adults in whom MIS-A has been described have survived.

MIS-A is defined by the following criteria:
• A severe illness requiring hospitalization in an individual aged ≥21 years;
• Current or past infection with SARS-CoV-2;
• Severe dysfunction in one or more extrapulmonary organ systems;
• Laboratory evidence of elevated inflammatory markers (e.g., CRP, ferritin, D-dimer, interleukin [IL]-6);
• Absence of severe respiratory illness; and
• Absence of an alternative unifying diagnosis.

Management:

There are currently no controlled clinical trial data in patients with MIS-A to guide treatment of the syndrome.
Most of the cases have been managed by use of intravenous immunoglobulin, corticosteroids, or anti-IL-6 therapy.

Read the Updated and Detailed: CME INDIA COVID-19 Management Protocol 2021



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