CME INDIA Presentation by Dr N K Singh, Admin CME INDIA.
Avoiding premature favorable recommendations for potentially ineffective or harmful interventions has become a cobweb like situation.
In a panic-driven scenario with everchanging concepts, we all are probably overtreating by using untimely and unjustified medications available to us. It is natural to use in hope of getting something better in desperate situations.
One case scenario:
Case is positive on 24/09/20, having nasal congestion, backache and fever since today. No dyspnea, Oxygen saturation normal. All investigation including NL ratio, Inflammatory markers are normal. Should I go for remdesivir? HRCT on 28/9/20.
How Internists react to this…
Dr Ranjeet Ramgarh: In my opinion steroid should be withheld till saturation is Ok. LMWH can be started in prophylactic dose. Antiviral – yes.
Dr B B Rewari, Consultant Physician, New Delhi: Why dexamethasone. Not indicated if not in critical or severe category. It may be harmful in initial stages in mild cases. See WHO 2nd sept. guidance.
Dr Basab Ghosh, Agartala: On 5th day of symptoms, chest is already involved with CORAD 5, is it mild? Should we wait for saturation falls? Or, Dexamethasone should be initiated, keeping Methylprednisolone in hand for the future use?
Dr Kapil Sud, Internist, Aligarh: Should be put on steroids with LMWH. And the rest. Remdesvir at this point is debatable.
Dr Pranab Kanti Datta, Agartala: We are supposed to initiate dexa and scale up to methylpred subsequently?
Dr Awadhesh K Singh, DM Endo., Kolkata: LMWH only in my opinion at the moment. Watch if any fall in O2 – add steroid. Remdesivir can be tried only for mental satisfaction without any expectation.
Dr N K Singh: Uttar Confusion! Please see the minutes of Virtual Meeting of CMAAO NMAs on “CMAAO countries consensus on COVID-19 as on date” 26th September, 2020. (Dr K K Aggarwal, President CMAAO, Dr Alvin Yee-Shing Chan, Hong Kong, Treasurer, CMAAO, Dr Prakash Budhathoki, Nepal, Dr Md. Jamaluddin Chowdhury, Bangladesh, Dr S M Qaisar, Dr Russell D’Souza, UNESCO Chair in Bioethics, Australia, Dr S Sharma, Editor IJCP Group).
“Day 5 is THE crucial day in COVID phase (Lancet. 2020;395(10229):1054-62). In the COVID phase, Day 3 is the day when pneumonia may develop. If steroids and dabigatran are not started by Day 5, the illness may become serious. By Day 5, diagnosis pneumonia must be made to reduce mortality. COVID-19 is in a potential hypercoagulable state. Start patient on anticoagulant such as dabigatran or equivalent drug on Day 1 in high risk persons. It is thrombosis, which may be fatal. If pneumonia develops, treatment is simple but when added with clots it becomes complicated pneumonia. In patients with COVID, MI may occur without blockages due to red clots and not white platelets clots.
- All hospitalized patients should be given LMWH.
- Criteria for starting anticoagulation on day 1: All high-risk patients (HCWs, high CRP, high LDL, prolonged immobilization, diabetes, hypertension, underlying hypercoagulable states or all conditions where we start NOAC or LMWH prophylaxis before surgery.
- Steroids are given when pneumonia is evident.
- Chest X-ray becomes positive on Day 5-7, while CT scan becomes positive on Day 2/3.
- If CRP reduces and then starts rising or if CRP is more than 150, it indicates superadded bacterial infection. CRP doubles every 8 hours. Start with broad spectrum antibiotic and then shift to narrow-spectrum.”
Says, when pneumonia is evident, start steroids. Well, this is not a standard guideline. But, expert opinion. In real world, this is followed by most. As per, guidelines, no use of steroids at present.
I have interacted with many frontlines and they say Remdesivir has good effects.
Dr Basab Ghosh, Agartala: Remdisevir should be initiated if oxygen saturation drops, but before HFNO or mechanical ventilation. Better results of Remdisevir is experienced with Methylprednisolone than Dexamethasone.
Dr A K Virmani, Diabetologist, Jamshedpur: Remdisevir just reduces the hospital stay. No effect on mortality.
Dr Awadhesh K Singh, DM endo, Kolkata: That too minimal or perhaps nothing because that criteria is a very soft endpoint! To me that minuscule benefit has no clinical value!!!
Dr A K Virmani, Jamshedpur: The only things that WORK in COVID:
For Prophylaxis:
- Masking.
- Physical Distancing of > 6 feet.
- Regular Hand Washing Hygiene.
For Treatment:
- Steroids.
- LMWH.
- HFNO.
- Sometimes Remdesivir.
Dr Meena Chhabra, Diabetologist, New Delhi: If CRP is normal, say no to remdesivir.
Dr Basab Ghosh, Agartala: According to Gilead analysis, Remdisevir demonstrated an improvement in clinical recovery and a 62% reduction in the risk of mortality compared to standard of care. The California based company said intravenous remdesivir reduced mortality by 62% compared with standard treatment in the SIMPLE trial of 1132 mainly US patients. Its data showed that 7.6% of COVID-19 patients treated with the drug died compared with 12.5% of control patients. Crucially, however, the study compared treatment and non-treatment groups in different cohorts treated in different conditions. The remdesivir patients were compared with a historical group of more than 800 patients on the “standard of care” of other drugs and oxygen. However, experts have criticized pharmaceutical firm Gilead Sciences after it released data suggesting that its antiviral drug remdesivir can reduce death rates for patients with COVID-19. They say the research is intrinsically flawed and that the claimed benefits are overhyped and inappropriately promoted in press releases.
Dr Noni G Singha, Internist, Debrugarh, Assam: 5/25 CT severity score on 5th day of symptoms. Theoretically, still the phase of Cytokine storm is not over yet. Most important point in this case, we need to see severity markers which should guide for further management. Still, I agree that steroid should be started as patient is still symptomatic and 5th day CT showing changes. LMWH also may be started provided raised d dimer (at least more than 2 times UNL) with normal, PT and platelet count.
Dr Somnath, Internist, Hyderabad: If CRP is normal and saturation more than 95% with room air. Wait and watch for steroid. Can use LMWH and Remedisivir without hesitation.
Dr Ranjan Kumar, MD, Patna: If any active treatment (steroid, LMWH and Remdesivir) to be done it should be done on day 5 or 6.
A webinar on Covid management. 29/9/20(Panellists included Janet Diaz, Clinical Lead, WHO; Peter Horby, PI of the RECOVERY trial and Priscilla Rupali, Head, Infectious Diseases, CMC Vellore. Dr CS Pramesh, Director Tata Memorial Hospital moderated the session). Some take home messages:
HCQ, Favipiravir, Ivermectin, Doxycycline, Azithromycin, Convalescent Plasma – none of them have a proven benefit in Covid positive patients and should not be used outside a clinical trial. A waste of time, money and resources. The CMC Vellore has chosen not to stock Favipiravir in the hospital pharmacy to prevent its irrational prescribing.
Steroids- their misuse in mildly ill febrile patients is an alarming practice. Doctors have started prescribing prednisolone, dexa and methyl prednisolone to patients not on oxygen support. CMC Vellore ID team reported several serious bacterial infections in mildly ill steroid recipients. In particular, the use of oral prednisolone in mild cases should raise alarms, and we must stop its irrational use. We are no better than quacks if we also abuse steroids in a self-limiting viral illness.
CME INDIA Take Home:
- Remdesivir helps in reducing the recovery time from 15 days to 11 days in carefully chosen hypoxic patients but does not reduce their chances of dying.
- Dexamethasone cuts the mortality in hypoxic patients and those on mechanical ventilators but not in mildly sick patients. In fact, steroids up the death rates in such patients.
- Tocilizumab and Itolizumab need to be used very judiciously in our setting – there is a real risk of serious life threatening infections that can kill the patients. So, the urge to use IL-6 blockers must be resisted.
- Plasma- it came, it saw, it went. No proven benefits.
- And as for HCQ, Azithromycin, Ivermectin and favipiravir, the less said the better.
Any Solution? Are these unanswered questions likely to persists forever?
CME INDIA Learning Points:
[1] Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Updated on 25/9/2020. It is followed widely worldwide. Its recommendations are crystal clear, but treating physician is the best judge and he should not follow any guidelines rigorously.
- Non-severe illness – is defined as patient with a SpO2 > 94% not requiring supplemental oxygen
- Severe illness – is defined as patients with SpO2 ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or ECMO.
- Critical illness – is defined as patients on mechanical ventilation and ECMO. Critical illness includes end organ dysfunction as is seen in sepsis/septic shock. In COVID-19, the most commonly reported form of end organ dysfunction is ARDS.
Clinically accessing the severity is essential. Following is AIIMS-suggested:
Mild disease: Upper respiratory tract symptoms (&/or fever) without shortness of breath and hypoxia
Moderate disease: Any of the –
- Respiratory rate>24/min
- SpO2<94% on room air
Severe disease: Any of the –
- Respiratory rate>30/min
- SpO2<90 % on room air
[2] Recommendations:
- Recommendation 1: Among patients with COVID-19, the IDSA guideline panel recommends against hydroxychloroquine. (Strong recommendation, Moderate certainty of evidence).
- Remark: Chloroquine is considered to be class equivalent to hydroxychloroquine.
- Recommendation 2: Among hospitalized patients with COVID-19, the IDSA guideline panel recommends against hydroxychloroquine plus azithromycin. (Strong recommendation, Low certainty of evidence).
- Remark: Chloroquine is considered to be class equivalent to hydroxychloroquine.
- Recommendation 3: Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends the combination of lopinavir/ritonavir only in the context of a clinical trial. (Knowledge gap).
- Recommendation 4: Among hospitalized critically ill patients* with COVID-19, the IDSA guideline panel recommends dexamethasone rather than no dexamethasone. (Strong recommendation, Moderate certainty of evidence).
- Remark: If dexamethasone is unavailable, equivalent total daily doses of alternative glucocorticoids may be used. Dexamethasone 6 mg IV or PO for 10 days (or until discharge) or equivalent glucocorticoid dose may be substituted if dexamethasone unavailable. Equivalent total daily doses of alternative glucocorticoids to dexamethasone 6 mg daily are methylprednisolone 32 mg and prednisone 40 mg.
- *Critical illness is defined as patients on mechanical ventilation and ECMO. Critical illness includes end organ dysfunction as is seen in sepsis/septic shock. In COVID-19, the most commonly reported form of end organ dysfunction is ARDS.
- Recommendation 5: Among hospitalized patients with severe**, but non-critical, COVID-19, the IDSA guideline panel suggests dexamethasone rather than no dexamethasone. (Conditional recommendation, Moderate certainty of evidence).
- Remark: Dexamethasone 6 mg IV or PO for 10 days (or until discharge) or equivalent glucocorticoid dose may be substituted if dexamethasone unavailable. Equivalent total daily doses of alternative glucocorticoids to dexamethasone 6 mg daily are methylprednisolone 32 mg and prednisone 40 mg.
- Recommendation 6: Among hospitalized patients with non-severe*** COVID-19 without hypoxemia requiring supplemental oxygen, the IDSA guideline panel suggests against the use of glucocorticoids. (Conditional recommendation, Low certainty of evidence).
- ***Non-severe illness is defined as patient with a SpO2 > 94% not requiring supplemental oxygen.
- Recommendation 7: Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel suggests against the routine use of tocilizumab. (Conditional recommendation, Low certainty of evidence).
- Recommendation 8: Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends COVID-19 convalescent plasma only in the context of a clinical trial. (Knowledge gap).
- Recommendation 9: In hospitalized patients with severe* COVID-19, the IDSA panel suggests remdesivir over no antiviral treatment. (Conditional recommendation, Moderate certainty of evidence).
- Remark: For consideration in contingency or crisis capacity settings (i.e., limited remdesivir supply): Remdesivir appears to demonstrate the most benefit in those with severe COVID-19 on supplemental oxygen rather than in patients on mechanical ventilation or ECMO.
- Recommendation 10: In patients on supplemental oxygen but not on mechanical ventilation or ECMO, the IDSA panel suggests treatment with five days of remdesivir rather than 10 days of remdesivir. (Conditional recommendation, Low certainty of evidence)
- Remark: In patients on mechanical ventilation or ECMO, the duration of treatment is 10 days.
- Recommendation 11: Among patients with severe COVID-19 on supplemental oxygen but not on mechanical ventilation or ECMO, the IDSA panel suggests treatment with five days of remdesivir rather than 10 days of remdesivir. (Conditional recommendation, low certainty of evidence)
- Remark: In patients on mechanical ventilation or ECMO, the duration of treatment is 10 days.
- Recommendation 12: Among hospitalized patients with severe COVID-19, the IDSA panel suggests against famotidine use for the sole purpose of treating COVID-19 outside of the context of a clinical trial. (Conditional recommendation, very low certainty of evidence).
CME INDIA Tail Piece:
- Development and Evaluation (GRADE) methodology, recommendations are labeled as “strong” or “conditional.”
- The word “recommend” indicates strong recommendations and “suggest” indicates conditional recommendations.
- In situations where promising interventions were judged to have insufficient evidence of benefit to support their use and with potential appreciable harms or costs, the expert panel recommended their use in the context of a clinical trial.
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