CME INDIA Presentation by Admin.

CME INDIA Guidelines for effectively managing COVID-19. First Published – 6th April 2021; Last Updated – 1st Feb 2022. PDF link available at the end.

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.
• Dr. Akash Kumar Singh, Internist, and Diabetologist, Spandan Multi-Specialty Hospital, Vadodara.

Edited By:

• Dr. N. K. Singh, MD, FICP, Diabetologist physician, Dhanbad, Editor – cmeindia.in.

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.
• Dr. S. K. Gupta, MBBS MD(Med), CFM (France), Senior Consultant Physician, Max Hospital, Delhi.

Inputs:

• Dr. Murali Mohan B V, Pulmonologist, Narayana Medical Centre, Bengaluru.
• Dr. Basab Ghosh, MBBS, MDRC (Chennai), Dip Diab (Annamalai), (Prof M Viswanathan Gold Medalist), Senior Diabetologist, Agartala, Tripura.
• Dr. Bijay Patni, Diabetologist physician, Kolkata.
• Dr. Vaibhav Agnihotri, (DCH, DNB (Pediatrics), 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.
• Dr. Prabhat Agrawal, MD, FRCP (Edinburgh, Glasgow), FICP, FACP, Professor of Medicine, S. N. Medical College, Agra.
• 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.
• Special Thanks to Dr. Prof. Soumitra Ghosh, HOD, Medicine, IPGMER and SSKM Hospital, Kolkata.
• Special thanks to Dr. Rajeev Jayadevan, MD, DNB, MRCP, ABIM (Med), ABIM (Gastro), NY, Vice-Chairman, Kerala – IMA research cell, Member – National IMA Task force on corona epidemic, Cochin.

Design and Content Management:

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

Disclaimer

This is the first-ever guideline by CME INDIA on COVID-19 Management. It has been framed and reviewed by experts. As there are lots of guidelines and not all agree on the same protocol, physicians are advised to apply their own wisdom especially as recommendations keep changing. This guideline is especially meant to tackle the ongoing third wave. It also contains a section on the management of pediatric cases.

Document Flow

(click on the links to see a specific part of the document)

Part 1. (A) What are the Challenges of COVID Management in 2022

Third Wave

Expert Consensus on COVID-19 Management, Feb 1, 2022.

Although Community transmission of Omicron seems unavoidable, practicing ‘COVID APPROPRIATE BEHAVIOUR’ which includes the use of face mask, social distancing, etc. seems to help prevent/delay the transmission.

Third Wave – Omicron

• There is consistent evidence that Omicron has a substantial growth advantage over Delta.
• It is spreading significantly faster than the Delta variant in India.
• Doubling time between 1.5 – 3 days.

• Due to immune evasive properties of the omicron, population susceptible to omicron has remarkably increased.
• Order of susceptibility could be:
  • Unvaccinated >> Double dose vaccinated>> Three dose vaccinated >> Hybrid (Infected + Vaccinated).
• It’s very likely that although omicron may evade the first line of defense (antibodies), however the second line of defense (T cells) are likely to protect against development of severe disease.

• Covid symptoms linked to the new omicron variant stated to be “extremely mild/mild” by the South African experience and Indian experience so far.
• Feeling extremely tired for few days, body ache and headache – these are usual presenting complains.
• 1 to 2 days fever, sore throat and mild cough is being noticed as early Indian experience. It usually settles within 5 days.

Usual Experience of Possible Omicron Cases by Indian Physicians

It is better to follow “Watch List for all Variants (CDC)/ Symptoms may appear 2-14 days after exposure.”

Look for emergency warning signs

The trick of diagnosing Omicron illness is to go for usual tests at present.

This updated guideline is in tune to tackle new challenges.

Quick Look

Mild Disease: Home Isolation

Identify

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

New Alert for considering Delta Variants mainly:

• 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. Do not routinely go in for a CT Scan; a CT scan is indicated only if:

• There is a strong clinical suspicion and the RT PCR is negative.
• Serious comorbidities exist or are suspected such as pneumothorax, or pulmonary mycosis.
• The usual CT Severity Score in mild disease is < 8/25 and < 25% (on a score of 25 or as % lung involvement).

v. Always identify a caregiver who must be the point of contact with the health care provider during the course of the illness.

Table: Day to day working protocol to identify severity

Manage:

(Mild Illness)

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?

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

Treatment of Mild Cases

Do Remember that Omicron Illness, as known till date, is usually MILD. No heroic measures needed. Just treat it symptomatically.

• 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: However, most of centres/experts use these drugs on personal experiences and many 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 (Used during second wave but these medications have no scientific basis to use in Omicron illness. These can be used only if physician suspects deficiency).
• Tab Melatonin or Clonazepam if needed to ally anxiety.
• Say No to HCQS.
• Say no to Ivermectin (Investigational drug) – 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. We strongly recommend NOT TO USE in 2022.
• Note on Anti-viral:
  • As there is persistently high morbidity and mortality attributable to covid-19, we agree that effective antivirals have an obvious appeal.
  • As there is reduced viral load, it would lessen the severity and duration of disease, as well as the risk of transmitting the virus.

• Molnupiravir:

• The Subject Expert Committee (SEC) on COVID-19 of the Central Drugs Standard Control Organisation (CDSCO) on Tuesday 28, Dec 21 recommended granting permission to manufacture and market anti-Covid pill Molnupiravir for restricted emergency use for the treatment of adult patients. Now it is available.
• Molnupiravir is an orally administered form of ribonucleoside that prevents the replication of SARS-CoV-2, which causes Covid-19. It forces SARS-CoV-2 to try to replicate its genetic material. However, as the replication process begins, the pill inserts errors into the genetic code of replicating Virus.
• Mechanism of drug is independent of spike protein mutation so it should work against Omicron. But true results will surface with test of times. Molnupiravir was shown reduce hospitalization or death by 30%. In MoVE-OUT study over which Molnupiravir got EUA has no patients with Omicron. An earlier trial (Move-In) of Molnupiravir in hospital inpatients was discontinued because of lack of efficacy.
• When to start? Molnupiravir should be administered as soon as possible after a diagnosis of COVID-19, and within five days of symptom onset. It is stated to prevent progression of disease leading to hospitalization.
• Whom should it be given? “Treatment of mild-to-moderate COVID-19 in adults with a positive result of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, who are at high risk for progression to severe COVID-19, including hospitalization or death and for whom alternative COVID-19 treatment options authorized by FDA are not accessible or clinically appropriate”- As per Original EUA Authorized Date: 12/23/2021.

• These Points must be remembered:
  • No significant effect of molnupiravir has been found in reducing hospitalization or death in people who had positive nucleocapsid antibody (20% at baseline) suggestive of recent or past SARS-CoV-2 infection. We suggest to avoid its use unless benefit to risk ratio is in favor of molnupiravir.
  • There is no data of molnupiravir effectiveness in vaccinated people having breakthrough infections. In India, more half of population are 2-dose vaccinated and more than two-third had past history of SARS-CoV-2 infection, as per the last serosurvey. This makes Molnupiravir a limited utility medication.
  • As far as safety issues are concerned, short-term use of 5-days is unlikely to have any long-term major concern on individual patient level.
  • Enquire about vaccination status and assess risk vs. benefit of using molnupiravir in fully vaccinated individuals.
  • Enquire about past SARS-CoV-2 infection and assess risk vs. benefit of using.

• Summary of the evidence:
  • Two RCTs reported on treatment of unvaccinated patients with COVID-19 with either 800 mg of molnupiravir or placebo for five days.
  • In one phase 3 trial (MOVe-OUT trial) reported on the outcomes of death, hospitalization and serious adverse events, patients with mild-to-moderate COVID-19 received either molnupiravir or placebo within 5 days after the onset of symptoms.
  • In the phase 2a trial reporting on the outcomes of death and serious adverse events in patients with symptom duration
  • COVID-19-related mortality may be lower in patients receiving molnupiravir rather than placebo (RR: 0.11; 95% CI: 0.01, 0.86; low CoE).
  •  COVID-19-related hospitalizations and the composite of all-cause hospitalization or death may trend towards a reduction among patients receiving molnupiravir rather than no molnupiravir (RR: 0.68; 95% CI: 0.48, 1.00; low CoE and HR: 0.69; 95% CI: 0.48, 1.01; low CoE, respectively).
• Matter of Concern

• We recommend use of Molnupiravir in:

• Dose: Overall, the course has 40 pills. 800 mg (four 200 mg capsules) taken orally every 12 hours for five days, with or without food. Completion of the full five-day treatment course is important to maximize viral clearance and minimize transmission of SARS-CoV-2. Once started the course should be completed.

• The drug is not authorized:

• Contraindications:
  1. Molnupiravir is not recommended for use in patients who are pregnant. Based on findings from animal reproduction studies, molnupiravir may cause fetal harm when administered to pregnant individuals. No human data.
  2. Avoid Pregnancy for 4 days after the last dose
  3. Females of childbearing potential should use a reliable method of contraception correctly and consistently, as applicable, for the duration of treatment and for four days after the last dose of molnupiravir.
  4. Lactational mothers – No details known but based on the potential for adverse reactions in the infant from molnupiravir, breastfeeding is not recommended during treatment with molnupiravir and for 4 days after the final dose. A lactating individual may consider interrupting breastfeeding and may consider pumping and discarding breast milk during treatment and for 4 days after the last dose of molnupiravir.

• Paxlovid:

• Not available now in India, when available prefer Paxlovid over Molnupiravir.
• FDA approved for EUA.
• Paxlovid (combination of nirmatrelvir 150mg and ritonavir 100mg). The treatment disrupts the replication of SARS-CoV-2 in the body by binding to the 3CL-like protease, an enzyme crucial to the virus’ function and reproduction.
• Antiviral with a difference (Reasons to prefer Paxlovid): This novel antiviral pill showed almost 90% efficacy in preventing hospitalizations and deaths in high-risk patients, and recent data from Pfizer suggests the drug retains its effectiveness against the fast-spreading Omicron variant of the coronavirus.
• How is it given –  Paxlovid is administered as three tablets (two tablets of nirmatrelvir and one tablet of ritonavir) taken together orally twice daily for five days, for a total of 30 tablets.  Paxlovid is not authorized for use for longer than five consecutive days.
• Possible side effects of Paxlovid:

• Contraindications:

• Remdesivir in mild cases:
  • Remdesivir – 3 days course approved by CDC. Remdesivir 200 mg IV on Day 1, followed by Remdesivir 100 mg IV daily on Days 2 and 3, initiated as soon as possible and within 7 days of symptom onset in those aged ≥12 years and weighing ≥40 kg.
  • PINETREE trial which showed that 3 consecutive days of IV Remdesivir resulted in an 87% relative reduction in the risk of hospitalization or death compared to placebo.

• Steroids MUST NOT be used in patients with only mild disease. Concept of starting steroid on day 1 is detrimental and must be discouraged.
• Budesonide Inhalation (given via DPI/MDI with Spacer at a dose of 800 mcg BD for 5 to 7 days) may be given if fever and respiratory symptoms are persistent beyond 5 days of disease onset or even early if in High-Risk Group (STOIC and 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 bed ridden patients in Home-isolation, one may consider to use Apixaban 2.5 mg BD Alternatively: Tab Aspirin 75 mg (or clopidogrel 75/ mg) in high-risk groups.
• The decision to anticoagulate or use an anti-platelet agent should be based on a validated risk score such as the IMPROVE DD, and not only on D-dimer which is often confounded by many factors.

• Anti-SARS-CoV-2 Monoclonal Antibodies (Antibody Cocktail)

• Approved molecules as Emergency use authorization (EUA):
  1. Casirivimab, 600 mg plus Imdevimab 600 mg: Antibody cocktail- now available in India.
  2. 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.
  3. Single monoclonal antibody (Sotrovimab). Efficacy for Omicron has been found in studies.

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

• 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, preferably give in 1 hour.
  • The authorized dosage is 600 mg of casirivimab and 600 mg of imdevimab + 100ml NS administered together as a single intravenous infusion over 1 hr.
  • (Add 10 mL of co-formulated casirivimab (5ml) and imdevimab (5ml) into a prefilled 0.9% Sodium Chloride 100ml).
  • 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.

Note: As per revised Home-isolation guidelines, HOME ISOLATION ENDS at 7 days for those COVID PATIENTS who are fully vaccinated and remained asymptomatic (no fever) for last 3 days.

Repeat RT PCR TESTING is also not required

MoH guideline dated 5/1/2022 on home isolation is available at https://www.mohfw.gov.in/pdf/RevisedHomeIsolationGuidelines05012022.pdf

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:

(Moderate Illness)

i. Admit in ward

ii. Oxygen Support:

• Target SpO2: 92+ (88-92% in patients with COPD and Type-2 respiratory failure).
• 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); in fact intermittent awake proning can be recommended in all patients, to allow them to get used to the position.

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.
• Safety – One 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. 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.

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

Severe Disease

Identify

Any one of:

i. Respiratory rate > 30 /min.

ii. SpO2 < 90% on room air.

(Many guidelines follow <85% now).

Manage:

(Severe Illness)

Individuals who have SpO2 <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, a respiratory rate >30 breaths/min, or lung infiltrates >50%.

Treatment options:

Tab Baricitinib 4mg 1 OD up to 14 days/till hospital discharge.

+

Inj Remdesivir 200 mg IV once, then Remdesivir 100 mg IV once daily for 4 days.

+

Inj Dexamethasone 6 mg IV or PO once daily for up to 10 days or until hospital discharge.

VTE prophylaxis

* Baricitinib dose is dependent on eGFR; duration of therapy is up to 14 days or until hospital discharge.

* eGFR ≥60 mL/min/1.73 m2: Baricitinib 4 mg PO once daily.

* eGFR 30 to <60 mL/min/1.73 m2: Baricitinib 2 mg PO once daily.

* eGFR 15 to <30 mL/min/1.73 m2: Baricitinib 1 mg PO once daily.

* eGFR <15 mL/min/1.73 m2: Baricitinib is not recommended.

Critical Disease:

• Needing MV/septic Shock
• MDT
• Consider – Inj Dexamethasone 6mg + iv Tocilizumab

VTE Prophylaxis

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

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 days. 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 (Day 2-5)

(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)
• 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, non-invasive 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 non-invasive 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. 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 drugs – Colchicine, 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 find 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 hospitalized patients.
• Tofacitinib/ baricitinab – If used consider the following:
  • 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, non-invasive ventilation, or high-flow oxygen.
  • The anti-IL-6 monoclonal antibody, siltuximab.

Part 1. (B) What were the Challenges of COVID Management in 2021

2021 strains in India

Current COVID 19 cases were a mixture of various strains. Apart from the previously known strains, a new double mutant strain of the SARS CoV2 virus was detected in India. This was in addition to other UK, South African, and Brazilian variants of the virus already circulating in 18 states of the country.

How variant strain cases differ from first wave:

• The new virus strain having two mutations was highly infectious and had the potential to skip the immunity developed either by natural infection or vaccines.
• That’s why it was not uncommon to see re-infection cases and cases among vaccinated people.
• Newer strains remained not only more transmissible, but also affected the younger population, and lead to more severe illness.

Salient Observations:

Is RT-PCR not relevant always in such cases?

• Ideally, RT-PCR should detect COVID 19 caused by all strains, but still, some newer variants may be missed. According to WHO, some mutations like HV 69/70 have the capability to affect the RT-PCR testing as well and may go undetected in the tests. But the impact of the new mutation on the RT-PCR testing being deployed worldwide is expected to be minimal.
• It is advisable to read the full report of RT-PCR which may still show ORF gene and N gene but the S gene may not be detectable. Some laboratories may interpret these case of S gene drop out as negative.

How to diagnose such cases?

Clinical Features, Serum Markers, and CT scan of the chest should be used for diagnosis where clinical suspicion is high if RT-PCR is negative.

Part 2. Time is the Game Changer

In the entire management of Covid, it is always important to identify the first day of Illness. It is for all management issues. The day of report of RTPCR must not be taken for all decisions.

1. Disease is most transmissible one day prior and 3 to 4 days after the first symptom.

2. For the initial 2-3 days the patient is likely to have high Fever because of high replication of the Virus but at this time innate immunity by Macrophages, Neutrophils, etc. starts mounting defense against the attack of the virus.

3. The beginning of the second week heralds the worsening of symptoms which is mainly immune-mediated inflammatory process and characterized by high-grade fever and increasing oxygen demand, hypoxia, etc. Unchecked hyper inflammation may lead to covid cytokine storm syndrome and multi-organ damage.

So, it is of utmost importance to act swiftly in the first 7 to 10 days by use of anti-inflammatory medications. And most of the current-day medications like corticosteroids, Tocilizumab, convalescent plasma work best when given in time during this phase.

Incubation Period:

• Symptoms may develop 2 days to 2 weeks following exposure to the virus.
• Current estimates of the incubation period are in the region of 4–5 days.
• Clinical Features, Serum Markers and CT scan of Chest may be used for diagnosis where clinical suspicion is high if RT-PCR is negative.
• If RT-PCR is positive after 3 months or becomes positive after two consecutive negatives, consider possible reinfection.
• The six-minute walk test (6MWT) is useful from Day 3-6. If the patient desaturates by 5% on walking, this is indicative of pneumonia and this is considered as an emergency.

Part 3. Initial evaluation of a severe acute respiratory illness (SARI) case

The Moment You get the Patient

Classify COVID Patients Clinically – Table to Access Clinically:

Table to Access Risk Factors for Severe Disease

Table to access need for critical care intervention any one of the following:

Table to pick up Investigations (in admitted patients):

Table showing Lab Findings in Mild/Moderate/Severe cases

Lab Tests are Torchbearer – Pearls in Important Lab Tests Considerations

As per some studies, CRP can be a guide for steroid dose. Higher the CRP, use a higher dose of steroid.⁵ Alert :If CRP rise more than 10 fold.

(Note CRP in some cases can be because of bacterial infection, UTI, line sepsis, etc. In such cases, don’t escalate steroids. Taper steroids and cover with the appropriate antibiotic. Use Procalcitonin, WBC, cultures as a guide.)

IL 6 results are very unreliable due to the following reasons:

1. Lab methods are not standardized. The same sample can give different readings in different labs.

2. Transport delays of the collected blood sample, temperature exposure alters IL 6 values.

3. Use the same lab/assay throughout the follow-up for a patient.

4. Many stable patients can erroneously have IL 6 values in hundreds or thousands too.

D DIMER is an important marker

• D DIMER is also an important marker for treatment decisions after CRP and Procalcitonin.
• All hospitalized patients should receive LMWH (e.g., Enoxaparin 40 mg daily. Start prophylactic dose LMWH (e.g., enoxaparin or equivalent) for all admitted patients.
• Dose is 40 mg for moderate and 1mg/kg/day for severe disease. If D-dimer >1mcg/ml, suspect DVT/PE.
• Start therapeutic anticoagulation (Enoxaparin 60 mg BD) for proven or strongly suspected DVT or PE till excluded on venous doppler/CTPA.
• Monitor d-dimer every 2-3 days. Patients on 60 BD, daily Hb, h/o Melena, etc. should be observed.
• At discharge, consider starting oral anticoagulant (e.g., Apixaban 2.5 mg BD or Rivaroxaban 10 mg OD for 4 weeks high-risk patients (modified IMPROVE-VTE score>4 or score>2 with d-dimer >2 times the upper limit, advanced age, underlying malignancy).

LDH – the increase in LDH is a sign of cell death

• LDH is an enzyme implicated in the conversion of lactate to pyruvate in the cells of most body tissues and increases following tissue breakdown.
• Elevated serum LDH is present in numerous clinical conditions, such as hemolysis, cancer, severe infections and sepsis, liver diseases, hematologic malignancies, and many others.
• Nowadays, there is much evidence suggesting that the serum LDH levels serve as a non-specific indicator of cellular death in many diseases.
• An increase in LDH by 62.5 U/L has an acceptable sensitivity and high specificity for a significantly higher probability of disease progression.
• LDH is a potentially useful follow-up parameter in COVID-19 pneumonia, which might assist in the recognition of disease progression and thus help in risk stratification and early intervention.

Procalcitonin is a mediator of inflammation

• Procalcitonin is the pro-peptide of calcitonin devoid of hormonal activity. Under normal circumstances, it is produced in the C-cells of the thyroid gland.
• In healthy humans, PCT levels are undetectable (< 0.1 ng/mL).
• During severe infection (bacterial, parasitic, and fungal) with systemic manifestations
• PCT levels may rise to over 100 ng/mL, produced mostly by extra-thyroid tissue. PCT is a mediator of inflammation.
• PCT value remains within reference ranges in patients with non-complicated SARS-CoV-2 infection; any substantial increase reflects bacterial co-infection and the development of a severe form of the disease and a more complicated clinical picture.
• PCT in the initial days is to rule out a secondary co-infection and not to assess the severity of covid19 disease.
• PCT values may be influenced by pre-existing comorbid conditions, such as CKD and congestive heart failure, baseline values may be high.

Table – Practical widely available GAME CHANGER clinical/biochemical pearls

Part 4. High Alert

Be vigilant

• Fever > 101º F with drugs or > 103ºF without anti-pyrectics.
• Persistent cough starting after day 3.
• Sudden onset of shortness of breath (or exertional SOB).
• Rapid rise in CRP (>10 mg/L).
• More than 50 % lung involvement on CT (13/25 score).
• Altered sensorium.

Think again

• Clinicians should be aware of the potential for some patients to rapidly deteriorate 1 week after illness onset.
• The median time to Covid-19 associated acute respiratory distress syndrome (CARDS) ranges from 8 to 12 days.
• Lymphopenia, neutrophilia, elevated serum alanine aminotransferase and aspartate aminotransferase levels, elevated lactate dehydrogenase, high CRP, and high ferritin levels may be associated with greater illness severity.

Table – Monitoring of Cases

Part 5. Management of cases

Steroids ALERT

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).

Steroids should be strictly avoided in

1. Asymptomatic.

2. Mild symptoms less than 7 days.

3. CT score less than 8 with disease duration less than 5 to 7 days.

4. Viremia phase (high fever with normal CRP and CT).

Steroids should be used in all moderate and severe cases i.e., all patients with SPO2 less than 94 irrespective of the day of onset of symptoms. All these patients should receive 40 to 120 mg Methylprednisolone/day or dexamethasone 6mg /day.

Role of steroid in mild covid 19 disease: Mild cases second week with fever, malaise, myalgia, headache, fatigue (suggestive of hyper inflammation) can use low dose such as methylprednisolone 4 to 16 mg per day (or equivalent another steroid for 5 to 7 days). This statement is based on expert opinion only.

The anti-inflammatory steroid should be initiated early in the pulmonary phase to counter the immune dysregulation. Ideal time for steroid initiation is after eighth day of symptoms, when virus has very low tendency to replicate and inflammatory response is persistent.

Steroids Consideration: Revisited

• The anti-inflammatory steroid should be initiated early in the pulmonary phase to counter the immune dysregulation. Ideal time for steroid initiation is after eighth day of symptoms, when virus has very low tendency to replicate   and inflammatory response is persistent.
• However, it must be emphasized that corticosteroids should not be used in mild disease, early on in the course of COVID19 illness if not indicated.
• The overall pooled estimate (observational studies and RCTs) has shown significantly reduced mortality in the corticosteroid group¹³.
• For patients who have significant lung involvement defined as resting SpO2 < 94 percent or a 6-minute walk test showing a drop in O2 saturation by 4% or more, patients may be initiated on Inj Methylprednisolone 0.5-1 mg per kg per day preferably in two divided dosages (or equivalent dosages of dexamethasone).
• The patient on corticosteroids can be followed up. If their oxygen requirements, inflammatory markers such as CRP are going up, the dose can be escalated to 2mg per kg per day of Inj Methylprednisolone (or equivalent dosages of inj. dexamethasone) for a brief period till the patient stabilizes (3-5 days) and then we can taper down the dose to 1 mg per day and then to 0.5 mg per day.
• Some centers use pulse therapy with higher dosages of methylprednisolone with doses approaching 500mg- 1gm methylprednisolone per day although this approach is not substantiated with multiple or large multiple trials and RCTs.
• Higher dosages of steroids are used after a meticulous exclusion of bacterial coinfection and tapered off at the earliest.
• At dosages of 0.5-1 mg per kg, methylprednisolone can be used for an extended period of 10 days or more.

Goals of oxygen therapy:

1. Improve oxygenation: target saturation >96% in those without Type 2 respiratory failure and 88-92% in those with hypercapnic respiratory failure
2. Decrease the work of breathing: respiratory rate <35 breaths/min and with no use of accessory muscles of respiration

Part 6. Procedure for awake self-proning

Monitoring

• Continuous O2 monitoring is required. ECG leads to be connected to the posterior chest wall for continuous monitoring.

Before Proning

Prone positioning – the procedure

Time spent proning

• The patient should try proning every 4 hrs. and stay prone as long as tolerated. Proning is often limited by patient discomfort, but they should be encouraged to reach achievable goals, like 1-2 hours (or more if possible).
• The ideal duration is 16 hrs. per 24 hours (e.g., 4 times for 4 hours each session).

When to stop awake proning?

1. A patient can choose to stop awake proning at any time.
2. In case of hemodynamic instability or if impending respiratory failure, it is recommended that the clinician stops proning and considers intubation.

Contraindications of awake self-proning

• Hemodynamic instability (on vasoactive medications): preferable to prone these patients in a monitored environment; if severe/refractory hemodynamic instability, proning is not advised.
• Increased intracranial pressure.
• Increased abdominal pressure.
• Abdominal, Chest, and facial wounds.
• Cervical spine precautions.
• Extreme obesity.
• GCS <8.
• Pregnancy 2nd or 3rd trimester.

Part 7. Patient selection for NIV application

Predictors of NIV success in acute respiratory failure

• Lower acuity of illness (APACHE score).
• Ability to cooperate; better neurologic score (GCS≥10).
• Ability to coordinate breathing with a ventilator.
• Hypercarbia, but not too severe (PaCO2 b/w 45- and 92-mm Hg).
• Acidemia, but not too severe (pH b/w 7.1 and 7.35).
• Improvement in gas exchange, HR & RR within first 2 hours.

Contraindications for NIV application

• Cardiac/Resp arrest or need for immediate intubation.
• Severe encephalopathy (e.g., GCS <10).
• Severe UGI bleeding.
• Hemodynamic instability or unstable cardiac arrhythmia.
• Facial or neurological surgery, trauma, or deformity.
• Upper airway obstruction.
• Inability to cooperate/protect the airway.
• Inability to clear secretions/ High risk for aspiration.
• Untreated pneumothorax.

Part 8. Discharge Policy: Follow state-specific guidelines if any

Please see the following document (dated 09/01/2022):

https://www.mohfw.gov.in/pdf/RevisedDischargePolicyforCOVID19updatedon9thJanuary2022.pdf

Part 9. Pearls in obstetrics and gynecological Covid-19 management

Management of SARS-CoV-2 in Pregnancy¹¹

• Compared to non-pregnant women with COVID-19, pregnant women with COVID-19 have higher rates of intensive care unit (ICU) admission; this may reflect a lower threshold for admission to ICU, rather than more severe disease.
• Pregnant women are not at increased risk of death from COVID-19, according to the largest systematic review.
• Compared to pregnant women without COVID-19, pregnant women with symptomatic COVID-19 requiring hospitalization have overall worse maternal outcomes, including an increased risk of death, although that risk remains very low (the UK maternal mortality rate from COVID-19 is 2.2 per 100 000 maternities).

Risk factors for hospital admission with COVID-19 infection in pregnancy

Risk factors that appear to be associated both with being infected and being admitted to hospital with COVID-19 include:

1. Black, Asian and minority ethnic (BAME) background.
2. Having a BMI of 25 kg/m2 or more.
3. Pre-pregnancy co-morbidity, such as pre-existing diabetes and chronic hypertension.
4. Maternal age 35 years or older.^13,23
5. Living in areas or households of increased socioeconomic deprivation (data not specific to pregnancy).

Effect of COVID-19 on the fetus Key findings

• Symptomatic maternal COVID-19 is associated with an increased likelihood of iatrogenic preterm birth.
• Aside from preterm birth, there is no evidence that COVID-19 infection has an adverse effect on the fetus or on neonatal outcomes.

Key considerations when caring for symptomatic women with suspected or confirmed Covid-19 Consideration:

Setting for birth

If homebirth or birth in a midwifery-led unit is planned, a discussion should be initiated with the woman regarding the potentially increased risk of fetal compromise in active phase of labour if symptomatic with SARS-CoV-2.97

Attending an obstetric unit, where the baby can be monitored using continuous electronic fetal monitoring (CEFM), should be recommended for birth.

Timing for birth: A positive COVID-19 result in an otherwise well woman, when there is also no evidence of fetal compromise, is not an indication to expedite birth.

Induction of labour (IOL) is associated with longer periods of inpatient stay than for spontaneous onset of labour. Review the indication for IOL and consider whether the likely benefits outweigh possible risks. Where possible, review the provision and possibility of outpatient IOL.

Mode of birth: There is currently no evidence to favour one mode of birth over another in women who are SARS-CoV-2 positive, so mode of birth should be discussed with the woman, taking into consideration her preferences and any obstetric indications for intervention. Mode of birth should not be influenced by the presence of COVID-19, unless the woman’s respiratory condition demands urgent intervention for birth.

Respect and consent: Women must still be able to make decisions about the care they receive in line with the principles of informed consent.

Fetal surveillance: Discuss with women the options for fetal surveillance in labour in accordance with existing NICE guidelines. Recommend CEFM for women who are symptomatic of COVID-19. Current infection with SARS-CoV-2 is not a contraindication for application of a fetal scalp electrode or for fetal blood sampling.

Pain relief: There is no evidence that epidural or spinal analgesia or anaesthesia is contraindicated in the presence of coronaviruses. Epidural analgesia should therefore be recommended in labour to women with suspected or confirmed COVID-19 to minimize the need for general anaesthesia.

Intrapartum care: When a woman with confirmed or suspected COVID-19 is admitted to the maternity suite, the following members of the multidisciplinary team should be informed: consultant obstetrician, consultant anaesthetist, midwife-in-charge, consultant neonatologist, neonatal nurse- in-charge, and the infection control team.

Maternal observations and assessment: Should be continued as per standard practice, with the addition of hourly oxygen saturations.

Aim to keep oxygen saturation above 94%, titrating oxygen therapy accordingly. If the woman develops a fever, investigate and treat as per RCOG guidance on sepsis in pregnancy.

Flowchart for Management in Pregnant Women (Adapted from Lancet)¹²

Example of a maternity escalation plan for women with suspected or confirmed Covid-19 (adapted from buy’s and St Thomas’ NHS Foundation Trust)

Part 10. Pearls in pediatric case management

Alert 2022

1. In paediatric practice, there is a proportionate increase in cases – seen along with massive COVID-19 spread in the general population. Most children have no symptoms, some have upper respiratory symptoms, throat irritation. Cough is less prominent.
2. A few young children had febrile seizures, this is expected in a certain number of febrile illnesses at the outset, and is not specifically a feature of COVID-19.
3. As more cases of fever occur, more cases of febrile seizures can be expected. Some of the paediatric COVID-19 admissions are from febrile seizures, as well as from fatigue, some children have fever, headache, body aches and vomiting. A few cases of croup like cough have been described elsewhere.
4. It is possible that adults who are going outdoors are passing the infection on to the children.
5. It’s important to check for rise in pulse rate out of proportion to temperature to rule-out myocarditis.

Community transmission of SARS-CoV-2 is happening in my city. How should I approach a sick child?^8,9

Children with fever, respiratory tract symptoms, loss of taste or smell, or multiple infectious symptoms should undergo testing for covid-19 or be considered to have the disease until proved otherwise.

Clinicians should consider a range of other diagnoses, including other pulmonary infections and systemic illnesses with respiratory manifestations, including non-infectious diagnoses such as diabetic ketoacidosis and watch for labored breathing, dehydration, persistent fever, severe abdominal pain, or altered mental status.

Children with fever and gastrointestinal symptoms (abdominal pain, vomiting, or diarrhea) or any child with other features consistent with Kawasaki disease (e.g., persistent fever plus lymphadenopathy, mucocutaneous changes, conjunctivitis, or swelling of extremities) could have MIS-C.

• MIS-C defined as the Presence of fever for ≥24 hours, Elevated inflammatory markers, Multi-organ dysfunction (≥2 systems: cardiac, dermatological, gastrointestinal, renal, respiratory, hematological, and/or neurological), No plausible alternative diagnosis, Positive viral or serological testing for SARS-CoV-2 or close contact with a person with covid-19 within four weeks of symptom onset.
• MIS-C is typically a progressive illness, and patients who initially had mild symptoms can develop a severe illness with multi-organ dysfunction within a few days of symptom onset, Critical signs should be evaluated for hemodynamic instability, tachycardia, left ventricular dysfunction, and respiratory distress, which could be primary or caused by cardiac dysfunction. Laboratory abnormalities often include lymphopenia, anemia, and thrombocytopenia, in addition to elevations in liver enzymes, creatinine, pro-brain natriuretic protein, troponin, and coagulation studies.
• All patients in whom there is a strong suspicion for MIS-C should have an echocardiogram to evaluate cardiac function and to look for evidence of coronary artery dilatation.
• Children with mild acute covid-19 benefit from usual supportive care measures, including rest, hydration, and antipyretics.
• Dexamethasone was shown to decrease mortality in adults with moderate to severe respiratory distress and may be considered in children with significant respiratory illness, though pediatric data are still forthcoming.
• Similarly, Remdesivir may be prescribed for children with respiratory deterioration (DATA UNDER EVALUATION). Other treatments, such as convalescent plasma or monoclonal antibodies, might be considered in high-risk patients, but these therapeutics require further study in adults and children. Children with MIS-C most commonly are treated with intravenous immunoglobulin and often steroids.
• Primary measures to prevent infection and transmission of SARS-CoV-2 remain important for children and their families and include basic steps such as face masks for children aged 2 years and older, social distancing, and hand hygiene for both children and adults around them. Young children or those with developmental delays may not tolerate or wear masks properly; however, there is value in practicing.
• Given that the risks associated with SARS-CoV-2 are much lower in children than in adults, initial studies and vaccine distribution did not prioritize children. Patients should maintain routine preventive care and vaccination schedules, including seasonal influenza vaccine, as a critical strategy to stay healthy during and beyond the pandemic.

New in 2022

• Overall management in 2022 remains unchanged.
• As of now, use of antivirals or monoclonal antibodies is not recommended for children less than 18 years of age, irrespective of the severity of infection.
• For diagnosing MIS-C, caution should be exercised while interpreting an isolated increase in COVID antibodies.
• The CRP level for diagnosis of MIS-C: >5mg/dL.
• If steroids are used, they should be tapered over 10-14 days, subject to clinical improvement.

Asymptomatic

Mild

Moderate

Severe

Use of steroids and anticoagulants; Post COVID care

Steroids

• Steroids are not indicated and are harmful in asymptomatic and mild cases of COVID-19
• Indicated only in hospitalized severe and critically ill COVID-19 cases
• Steroids should be used at the right time, in right dose and for the right duration
• Indications and recommended dose of corticosteroids – may be used in rapidly progressive moderate and all severe cases o Dexamethasone 0.15 mg/kg, maximum dose 6 mg once a day OR o Methylprednisolone 0.75 mg/kg, maximum dose 30 mg once a day
• Continue for 5-7 days and taper up to 10-14 days, depending on clinical assessment on daily basis
• Avoid steroids in first 3-5 days since onset of symptoms as it prolongs viral shedding.

Anticoagulants

• Not indicated routinely.
• All hospitalized children should be evaluated for risk of developing thrombosis and monitored for development of thrombosis.
• Prophylactic anticoagulant is indicated in following circumstances (the decision to administer prophylactic anticoagulation must be balanced with the child’s bleeding risk):
• strong personal or family history of VTE
• an indwelling central venous line and two or more additional risk factors*
• four or more risk factors*

(*Predisposing risk factors for development of thrombosis – personal history of venous thrombotic events (VTE), family history of first-degree relative with VTE, presence of central venous line, decreased mobility from baseline, burns, active malignancy, estrogen therapy, flare of inflammatory disease, morbid obesity, severe dehydration, recent surgery or trauma)

• Prophylactic dose of low molecular weight heparin (Enoxaparin): 0.5 mg/kg twice daily, till child is discharged from hospital.
• On suspicion of thrombosis, confirm by appropriate investigations and start on low molecular weight heparin in therapeutic doses for period of 12 weeks with monitoring.
• Children already on anticoagulation therapy may continue same unless they develop active bleeding.
• Therapeutic dose of low molecular weight heparin (Enoxaparin): 1 mg/kg twice daily.

Part 11. Summary Pearls 2022

1. Older age, male sex, and comorbidities increase the risk for severe disease.
2. For people hospitalized with Covid-19, 15-30% will go on to develop covid-19 associated acute respiratory distress syndrome (CARDS).
3. When used appropriately, high flow nasal cannula (HFNC) may allow CARDS patients to avoid intubation and does not increase the risk for disease transmission.
4. Steroid/Dexamethasone treatment improves mortality for the treatment of severe and critical covid-19.
5. Remdesivir may have modest benefit in time to recovery in patients with severe disease but shows no statistically significant benefit in mortality or other clinical outcomes.
6. Active symptomatic support remains the key treatment for mildly to moderately ill patients, such as maintaining hydration, nutrition, and controlling fever and cough.
7. Hospitalized for mild to moderate Covid-19 (not hypoxemic) Supportive care:
   • No clear benefit for Remdesivir or Convalescent plasma.
   • Steroids have no demonstrated benefit and may cause harm.
8. Hospitalized for severe covid-19, but not critical (hypoxemic needing low flow supplemental oxygen):
   • Corticosteroids (dexamethasone 6 mg/day × 10 days or until discharge or an equivalent dose of hydrocortisone or methylprednisolone).
   • May consider Remdesivir.
   • May benefit from use of tocilizumab.
9. Hospitalized for covid-19 and critically ill (needing HFNC, NIV, IMV, or ECMO) Supportive care:
   • Corticosteroids (dexamethasone 6 mg/day × 10 days or until discharge or an equivalent dose of hydrocortisone or methylprednisolone).
   • May consider Remdesivir.
   • May benefit from use of tocilizumab.
10. Timely and accurate diagnostic SARS‐CoV‐2 testing is a crucial step in managing the patient.
11. Avoid Fancy anti-virals and HCQS. At present Ivermectin is also not scientifically supported.
12. Low molecular weight heparin, Aspirin, NOACs, (novel oral anticoagulants: dabigatran, rivaroxaban, apixaban, and edoxaban) to be used as it was earlier.
13. Colchicine might help.
14. Tocilizumab: More sepsis-related complications, can be used in selected cases with cytokine storm.
15. Anticoagulants may need to be given for 3 weeks or more (2-4 weeks).
16. People are developing Myocardial infarctions, Stroke, etc. few weeks after Corona infection – the Thromboembolic phenomenon.
17. Oxygen is the superhero.
18. New addition is use of neutralizing antibodies. The ability to standardize the amount of neutralizing activity and the possibility of conferring protection more rapidly than with vaccine-induced immune responses led to emergency use authorization after results of 5 RCTs. Indication: Patients with mild to moderate COVID-19 who are at high risk of progression to severe disease may receive bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab. Local variant susceptibility should be considered in the choice of the most appropriate neutralizing antibody therapy. There are limited data on efficacy in high-risk patients under 18 years of age.
19. Angiotensin-converting enzyme inhibitors, statin therapy, nonsteroidal anti-inflammatory drugs, and oral, inhaled, and intranasal corticosteroids that are prescribed for comorbid conditions should be continued as directed.
20. To be sensible, clinicians must recognize that highly selective, fully effective treatments are uncommon in acute care. Focus on High-Quality Evidence Some clinical research is biased.
21. Even the best research methods, such as randomized trials, can be unreliable. This has been amplified by the rapid pace of research undertaken during the COVID-19.
22. It follows that treatment guidelines, national mandates, and bedside care adapt to new data only when the evidence is rigorous, reproducible, and sufficiently strong.

Part 12. Supplementary materials

1. Six patterns of Covid Xray

2. HRCT in Covid – Indications and importance of HRCT Thorax:

All Covid patients do not need to undergo HRCT Thorax examination.¹⁴

Indications:

• In patients having co-morbidity above the age of 40 and minimal respiratory symptoms (mild disease: RR < 20, SpO2>94), HRCT may be delayed till the end of first week of symptom onset.
• In patients presenting with moderate disease (RR 24-30 and/or SpO2 90-94) or severe disease (RR> 30 and/or SpO2 <90), HRCT may be done at the earliest possible opportunity. If HRCT facilities are not available, X-ray chest must be performed in these cases.
• In patients with high suspicion of Covid (Symptoms, contact, travel, markers), HRCT may be done if 2 consecutive RT PCR tests are negative. However, presence of typical radiological picture is not conclusive of active disease and must be correlated with clinical picture.
• In centers where RT PCR reports are delayed due to scanty resources, HRCT may be used for probable diagnosis as a remote tool.
• Patients coming to the emergency center with atypical signs of COVID 19 should be considered for the possibility of chest CT¹⁵.

(The last three indications must be used very judiciously because most of the viral disease may possibly present with similar radiological picture.)

CT severity Score:

• There are different ways to calculate CT severity score which determines number of lobes of lungs involved and gives a concise picture of pulmonary inflammation. Common score pattern is given out of 25.
• A score of 12/25 should alert the treating physician to possibility of development of Covid Associated Respiratory Distress and should be an indication to start steroids and also for hospitalization and intensive monitoring of oxygen saturation and inflammatory markers.
• A score of 8/25 in a patient having co-morbidity should be a warning symptom for accurate vigilance and more frequent monitoring.

Other usefulness of HRCT Thorax

• CT severity score has been correlated well with severity of disease and also with outcome in Covid patients. However, one should remember that density of ground glass opacities also has equal importance and therefore, radiologist’s opinion should not only mention the distribution of these opacities but also the density.
• HRCT in a Covid patient having sudden onset of breathlessness may point to the need of Pulmonary angiography especially when correlated with ECG, 2 D echo (for RV events) and venous Doppler.

HRCT also points to clinical outcome and possibilities of Covid associated pulmonary fibrosis and help in deciding “Long Covid Symptoms” and need for anti-fibrotic agents.

3. Do’s and Don’ts in the management of Covid infection:

4. Diabetes and Covid-19

During the COVID-19 pandemic, tight control of glucose levels and prevention of diabetes complications might be crucial in patients with diabetes mellitus to keep susceptibility low and to prevent severe courses of COVID-19.

In Type 2 diabetes: For Asymptomatic or mild cases, any diabetic therapy which has kept the glycemia under control should be continued. Monitoring of blood glucose should be more frequent and extra vigilance should be the motto.

Considerations regarding the use of anti-hyperglycemic agents: Evidence suggests that insulin and dipeptidyl peptidase 4 inhibitors can be used safely in patients with diabetes mellitus and COVID-19; metformin and sodium–glucose cotransporter 2 inhibitors might need to be withdrawn in patients at high risk of severe disease.

i. Metformin:

• Metformin, a first line antidiabetic drug in the treatment of type 2 diabetes, has anticipated antiproliferative and immunomodulatory effects but has risks of dehydration and lactic acidosis. Those who have the potential to progress to severe COVID-19 (e.g., who have greater dehydration) should stop taking this drug.
• Most of the patients can continue with metformin as evidence shows that it could be of benefit and inhouse mortality was lower in patients on metformin. 

ii. Dipeptidyl peptidase (DPP)-4 inhibitors:

• They (alogliptin, linagliptin, saxagliptin, sitagliptin, and others) are generally well tolerated and can be continued in these patients.

iii. Sodium-glucose co-transport-2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin):

• These are associated with risks of dehydration and diabetic ketoacidosis, and hence, patients who are prone to infections or have higher chances of severe COVID-19 should stop taking this drug.

iv. Glucagon-like peptide -1 receptor agonists:

• These (dulaglutide, exenatide-extended release, liraglutide, and semaglutide) also have a risk of dehydration, so close monitoring needed.

v. Alpha glucosidase inhibitors:

• Can be continued if gastrointestinal side effects are not a hindrance.

vi. Pioglitazone:

• It has anti-inflammatory and antifibrotic properties but it is known the therapy was associated with weight gain and oedema and more importantly was associated with aggravation of heart failure, which did not support the use of pioglitazone in patients with COVID-19 particularly with moderate disease.
• Though pioglitazone has been shown to decrease the secretion of various proinflammatory cytokines in the monocytes and macrophages and have the potential of blunting the cytokine storm by blocking caspase recruitment domain-containing protein 9 (CARD9) at the center of the immune activation mechanism in macrophages. More clinical trials are needed to optimize the risk-benefit ratio of using pioglitazone in patients with COVID-19.

Choosing Anti-hyperglycemic medications

vii. Insulin:

• Importantly, if any anti-hyperglycemic drugs are discontinued, the alternative treatment of choice is usually insulin. Further, if insulin therapy is already ongoing in a patient, it should be continued and not stopped.
• Insulin is always a preferred modality in any emergent situation irrespective of the degree of renal and hepatic dysfunction and thus it can be used at any stage of COVID-19.
• Subcutaneous (SC) insulin in patients with diabetes and mild to moderate COVID-19, in those taking food orally, is not a challenging issue.
• However, most hospitalized COVID-19 patient with diabetes with poor oral intake or on mechanical ventilator will eventually need intravenous insulin infusion with hourly or 2-hourly monitoring and frequent adjustment of infusion rates.
• This would increase the chance of exposure of health care providers (HCP). To minimize frequent exposure, use of SC short acting insulin analogues can be one approach, however, its role in critically ill patients is not fully known.
• Alternatively, to minimize the exposure, even a single per day SC dose of long-acting basal insulin could be an attractive option
• Models of Insulin pump or continuous subcutaneous insulin infusion (CSII), where insulin rates can be remotely adjusted via a Bluetooth can be useful to minimize exposure of HCP.
• For type 1 diabetes and COVID-19, there is clear need more frequent and close blood glucose monitoring and adjustments of insulin dose based on blood glucose values.
• Overall, the patient and treating physician together should individualize the management of diabetes by assessing and carefully adjusting regular therapy to reach individualized therapeutic goals according to diabetes type, comorbidities, and health status.

Steroid induced hyperglycemia in Covid patients (ward patients):

Methylprednisolone is a short/intermediate acting glucocorticoid of 4–6 h duration, while dexamethasone is a long-acting steroid with steroid induced hyperglycemia lasting for more than 24 h after the last dose, with a minimal fall after an overnight fast.

Recent data suggests that the impact is maximum when steroid is administered acutely, but a spontaneous remission usually happens With a short course of steroids in most of the COVID-19 trials (10-days of dexamethasone in RECOVERY, 3–7 days by other trials with methylprednisolone), it is less likely that steroid induced hyperglycemia or worsening of glycemic control in pre-existing diabetes contributed in any significant way given the fact that in RECOVERY trial both dexamethasone and usual care arm had equal percentage (nearly 25%) of patients with diabetes.

• In combination, high-dose glucocorticoid-therapy-induced impaired glucose metabolism, COVID-19 induced insulin resistance and COVID-19 related impaired insulin production could result in significant hyperglycemia, HHS and DKA in people with and without diabetes, increasing both morbidity and mortality.
• Sulphonylureas are NOT recommended in this context as beta cell function may be impaired and insulin resistance is likely to be severe.
• It is recommended to use larger insulin doses to overcome the greater insulin resistance which may be encountered in many patients treated with high doses of glucocorticoids and should ONLY be used in this context.
• If Diabetic Ketoacidosis and Hyperglycemia Hyperosmolar Syndrome have been ruled out, use a subcutaneous rapid acting insulin analogue for correcting initial hyperglycemia [glucose above 216mg(12mmol/L).]
• For maintaining glycemic control, for people NOT already on an intermediate acting (NPH) or long acting insulin, where glucose has risen above 216mg ( 12.0 mmol/l )due to dexamethasone, start NPH insulin which has an intermediate duration of action 0.3 units/kg/day is conservative, but experience suggests that a dose of 0.5 units/kg/day or more may be required depending on severity of illness, BMI and pre-existing diabetes control as indicated by HbA1c. Give two-thirds of the total daily dose in the morning and the remaining one-third in the early evening. If older (>70 yrs.), frail, or serum creatinine >175 umol/l (eGFR <30 ml/min), use a reduced NPH insulin dose of 0.15 units/kg. There should be a low threshold for dose escalation and referral to the diabetes team. (This is as per NHS -UK guidelines).
• If pre-meal BG value ≥180 mg/dl and/or post-meal BG value ≥250 mg/dl despite being on OAD → start basal-bolus insulin regimen (Ministry of health, India, guideline).
• For people already using once or twice daily long-acting insulin or twice daily NPH including those on basal-bolus regimens, increase the long acting basal or NPH insulin by 20% but this may need rapid escalation by as much as 40% depending on response.
• For people on twice-daily pre-mix insulin, continue mixed insulin and adjust dose. Consider increasing the morning dose by 20% but this may need rapid escalation by as much as 40% each day depending on the response. There should be a low threshold for referral to the diabetes team.
• After glucocorticoid therapy is stopped insulin resistance and requirements usually fall gradually requiring a gradual reduction in insulin requirements, however in COVID-19 patients a faster and a more aggressive reduction in insulin may be necessary. From day one, the total insulin dose may need to be reduced by as much as 50% guided by ‘pre-steroid’ insulin requirements.
• Note: If patient is on high-dose intermediate acting steroid (say prednisolone or methylprednisolone 60 mg) administered as a single dose at 9 am, the peak hyperglycemic effect is expected in the afternoon and evening hours (between 12pm to 8pm). Accordingly, the patient would require a higher dose before lunch. Alternatively, Inj. NPH insulin may be useful since pharmacokinetics of NPH closely mimics the effect of steroid (prednisone/methylprednisolone) on blood glucose level; NPH insulin can be administered at before breakfast or at 9 am in such a scenario.
• Glycemic targets: For most patients on basal-bolus insulin regimen (or for in-patient hyperglycemia management, in general), pre-meal BG level of <140 mg/dl and post-meal BG level of <180 mg/dl can be targeted. In selected individuals, target levels of <120 mg/dl (pre-meal) and <160 mg/dl (post-meal) can be considered, provided these can be achieved without causing undue hypoglycemia. (Ref: Dated 26 th August, 2020 Government of India Ministry of Health & Family Welfare Clinical Guidance on Diabetes Management at COVID-19 Patient Management Facility)

Covid-19 and newly diagnosed Diabetes:

• There is increasing evidence that coronavirus disease 2019 (COVID-19) may lead to new-onset diabetes mellitus (DM). This may occur even in patients without predisposing factors for impaired glucose metabolism.
• Both impaired pancreatic insulin secretion and insulin resistance have been implicated as underlying mechanisms. Importantly, new-onset hyperglycemia is associated with worse prognosis in patients with COVID-19. Indeed, its prognosis may be even more sinister than in patients with pre-existing DM. 
• Controversies remain about whether these cases which are reported are truly newly onset or unmasking of previously undiagnosed diabetes.

Tips:

1. If blood sugar is satisfactory, running treatment should not be interfered much.
2. Dpp4i and Metformin showed beneficial outcomes.
3. If patient is moderate symptomatic and condition is stable, if on SGLT2i alongside other anti-diabetics, we may continue SGLT2i, but if patient’s condition is compromised SGLT2i should be withdrawn with adjustments of other molecules.
4. If patient’s condition is severe to critical, insulin is the best way to manage diabetes.
5. If patient is on steroid, best is to add basal bolus regimen to have better glycemic control, alongside OHAs if continued from before.
6. While the role of admission HbA1c as a marker of COVID‐19 severity is yet to be fully established, HbA1c assists in identifying patients with newly diagnosed diabetes.

5. 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.

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

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

6. 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 do not recommend 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 does not recommend using them due to lack of adequate safety and efficacy data in COVID-19 patients.
• We opine to use these on case-to-case basis.

7. 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 801 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 starting these drugs only after consultation of a Pulmonologist. Use of anti-fibrotic in covid 19 trials are ongoing. 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.

8. 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.

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.

Part 13. CME INDIA Tail Piece

Rapid antigen testing (RAT):

• Results available in an hour or less, tests for SARS-CoV-2
• RAT is most often antibody-based to capture SARS-CoV-2 antigens (typically N protein). They offer the potential to improve access to testing through point-of-care assays.
• In certain scenarios where rapid isolation is desired, it can be used as an initial screening test.
• While the rapid test can get results very quickly, the results may not always be accurate.
• Interpretation:

Positive test: The patient test is positive and the patient actually has the disease.

False-negative test: It means that the test is negative but the patient actually has the disease.

Disadvantages of rapid test: The chances of the false-negative rate can be as high as 50%.

Advantages: The chances of the false positive rate are quite low. So, if a patient tests positive from a rapid test it is more likely that he actually has the disease. In symptomatic patients If RAT is negative, we need to confirm his condition with an RT PCR test

RT-PCR

RT-PCR is considered Gold standard test as of now for the detection of SARSnCOV-2 virus.

This is a real-time Polymerase Chain Reaction (PCR) assay that involves sample purification, nucleic acid amplification, detection of the target sequence in the sample.

• Common gene targets include envelope (E gene), nucleocapsid (N gene), Structural (S gene), RNA-dependent RNA polymerase (RdRP gene) ORF1ab.
• E gene is intended for screening of Sarbecovirus while RdRP gene / N gene / ORF1ab gene / S gene are used for confirmation SARS-CoV-2.
• CT value is inversely proportional to the amount of genetic material present in the sample, although ICMR doesn’t correlate CT values with severity of the disease, it merely indicates amount of viral load.
• Sample – As only nasopharyngeal or oropharyngeal sample has low sensitivity, it is recommended that combination of both advocates high sensitivity.
• Multiple factors can affect the test result like stage of disease, quantity of virus present during sampling, sampling methods, transport, storage, extraction systems, detection kits used etc. There can also be variation in results between two different samples collected. A fresh sample is advised if results don’t correlate clinically.

Timely Prediction is vital

Keep updated for ever changing COVID related recommendations

Read all updates and apply your own wisdom

Part 14. At a Glance – Updated CME INDIA COVID Management Protocol 2022

PDF available for download:

References:

1. Guo, Jun et al. “CURB-65 may serve as a useful prognostic marker in COVID-19 patients within Wuhan, China: a retrospective cohort study.” Epidemiology and infection vol. 148 e241. 1 Oct. 2020, doi:10.1017/S0950268820002368.

2. https://doi.org/10.1002/dmrr.3398 Eugene Merzon , Ilan Green et al.Diabetes Metab Res Rev. 2020;e3398. wileyonlinelibrary.com/journal/dmrr © 2020 John Wiley & Sons Ltd.

3. Sandoval Y, Januzzi JL Jr, Jaffe AS. Cardiac Troponin for the Diagnosis and Risk-Stratification of Myocardial Injury in COVID-19: JACC Review Topic of the Week. J Am Coll Cardiol 2020; Jul 3.

4. Lazzeri C, Bonizzoli M, Peris A. Heart 2020;106:1864. Published Online First 14 October 2020 http://dx.doi.org/10.1136/heartjnl-2020-318310

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9. IAP – COVID guidelines perinatal neonatal Management of COVID 19.

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11. Coronavirus (COVID-19) infection in pregnancy – guidance for healthcare professionals: Version 13 – 19 February 2021 published by the Royal College of Obstetricians and Gynaecologists, Royal College of Midwives and Royal College of Paediatrics and Child Health, with input from the Royal College of Anaesthetists, the Obstetric Anaesthetists’ Association, Public Health England and Public Health Scotland.

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26. ISHLT: The International Society for Heart & Lung Transplantation – Home – www.ishlt.org

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28. EPIC-HR: Study of Oral PF-07321332/Ritonavir Compared With Placebo in Nonhospitalized High Risk Adults With COVID-19 https://clinicaltrials.gov/ct2/show/NCT04960202

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31. Wilhelm, Marek Widera, Katharina Grikscheit, Tuna Toptan, Barbara Schenket al. Reduced Neutralization of SARS-CoV-2 Omicron Variant by Vaccine Sera and Monoclonal AntibodiesAlexander medRxiv 2021.12.07.21267432; doi: https://doi.org/10.1101/2021.12.07.21267432

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34. Heil Emily L., Kottilil Shyam. (2021) The Goldilocks Time for Remdesivir — Is Any Indication Just Right? N Engl J Med DOI: 10.1056/NEJMe2118579.

35. Gottlieb RL, Vaca CE, Paredes R. Early remdesivir to prevent progression to severe covid-19 in outpatients. published on December 22, 2021, at NEJM.org. DOI: 10.1056/NEJMoa2116846

36. Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India Comprehensive Guidelines for Management of COVID-19 in CHILDREN and ADOLESCENTS (below 18 years)Dated 17/01/2022

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