In COVID-19 any antiviral is more effective when used early in first week of illness.
What should not be used in covid-19 is also discussed in presentation.
2. Clinical Presentation
• Fever, Dyspnea and cough are main complaints.
• According to CDC in US a report of 3,70,000 confirmed patient
Cough 50%,
fever 43%,
malaise 36%,
Dyspnea 29%,
sore throat 20% ,Diarrhoea 19%, Nausea /vomiting 12%,
loss of a smell and taste, abdominal pain and rhinorrhoea less than 10%
• In some other studies loss of smell (anosmia) and dysguesia (change in taste) seen in 40% of
patients.
3. • According to WHO, 80% of COVID-19 infection are mild or asymptomatic,
15% are severe infection requiring oxygen and 5% are critical infections.
4. Complications
• Respiratory Respiratory failure ,Acute respiratory distress syndrome (ARDS)
• Cardiac
• Arrhythmias-Most common arythmia seen is sinus tachycardia .Others are polymorphic
or monomorphic ventricular tachycardia.Bradyarrhythmias like heart block are less
commonly seen.
• Heart failure - In a small retrospective study in seriously ill patients in Wuhan, heart
failure is seen in 49% patient who died and 3% patients who recovered.
• Myocardial injury -Increased cardiac troponin level in 7 to 28% of patients. Myocardial
infarction is also reported. Myocardial injury may be due to stress cardiomyopathy, hypoxic
injury, ischaemic injury( caused by cardiac microvascular damage or epicardial coronary
artery disease) and systemic inflammatory response syndrome (cytokine storm)
6. Complications
• Thromboembolic complications
• Risk of Venous thromboembolism (VTE) increase in 25 to 43% of patients
in ICU often despite prophylactic anticoagulant therapy
• Pulmonary embolism
• Stroke reported in less than 50 years of age of patients without risk factors
• Secondary infections- bacterial and fungal
• Renal AKI
7. Neurological Complications
• In half of hospitalised patients some neurological complaints are present like
headache , dizziness ,myalgia,alteration of consciousness, disorders of the
smell and taste ,weakness, stroke and seizures
• Encephalopathy seen in critically ill patients. MRI brain,EEG and CSF should
be done.
• Stroke in 1-3% of patients. Ischaemic stroke is more common. Haemorrhagic
stroke and CVT can also occur
• Number of cases of Guillain-Barre syndrome are also reported. Rare cases of
Acute disseminated Encephalomyelitis and meningoencephalitis are also
seen.
8. happy hypoxemia
One of the aspects of coronavirus disease 2019 (COVID-19) puzzling
clinicians coping with management of the pneumonia that one of the
disease’s complications is the presentation of patients with extremely low
blood oxygenation, but no sensation of dyspnea .
11. • Even if a patient starts stable, patient can worsen from 7 to 10 days of
illness due to host inflammatory response phase
13. Investigations
• For Covid 19 confirmation
• Real time RTPCR (reverse transcriptase polymerase chain reaction)
test in nasopharyngeal swab,oropharyngeal swab, sputum and
bronchioalveolar lavage.It is gold standard test.
• Rapid detection by antigen test .In May 20 it was issued emergency use
authorisation(EAU) by FDA . Results come in 30 minutes
• Qualitative immunoglobulins ( IgG /IgM ) Antibody test. FDA has issued
emergency use authorisation in September 20.
14. CRP
• CRP(C-reactive protein ) increases in severe inflammation
• According to study results, published in open forum infectious disease, increased
CRP may be a predictive marker in determining, which patients with mild disease
will progress to severe disease. So it is more specific marker to assess disease
progression. It is cheaper,results come early and it should be serially repeated.
• In studies, CRP was found elevated in patients who died of Covid 19. So it could
be promising biomarker for assessing disease lethality
• CRP levels more than 100 mg per litre is significant .Normal is less than 8 mg/L
• Usually increased D dimer is also associated with increased CRP levels.
15. D-dimer and LDH
• D dimer— Predictor of thromboembolic condition
• Increase D dimer is associated with mortality
• Normal D dimer level is less than 500 ng per ML. If more than 1000ng per ML it
is considered significant.
• LDH— is associated with severe Covid disease
• Some studies also shows increase mortality in patients with increased LDH but
larger studies are needed to confirm this findings
• LDH more than 245 units per litre is considered abnormal. Normal is 110 to 210
units per litre
16. Ferritin levels, Procalcitonin levels and IL-6
• Ferritin levels
• Hyperferritinaemia is associated with inflammatory state. It is associated with severity of
disease and disease progression. More than 500 µg per litre is considered abnormal
• Procalcitonin level
• has great specificity in identifying sepsis and can be used in diagnosis of bacterial
infection.It may be associated with severe disease.
• IL-6
• Studies show increased levels of IL-6 seem to be associated with inflammatory
response, respiratory failure, leading to mechanical ventilation and mortality in COVID-
19
17. CBC and LFT
• CBC
• lymphopenia (83%) ii hospitalised Covid patients.It is associated
with increased mortality
• Absolute lymphocyte count less than 800/ microliter
• LFT
• Increase in liver enzymes
18. • Electrolytes, blood sugar, HbA1c, renal function test
• X-ray chest
• HRCT chest American College of radiology does not recommend CT
scan chest for screening or as first line test for diagnosis of COVID-19
because of variabilities of CT scan findings and findings may not be
present in first few days of illness
• ECG
• Echocardiography
22. REMDESEVIR(FDA approved May
20)
• 10 year old anti-viral drug and largest evidence based .
• Found effective against SARS ( severe acute respiratory syndrome ) virus
and MERS(middle east respiratory syndrome) virus but was when tested
against Ebola virus and Marburg virus ,was found ineffective
• Many multinational randomised controlled trials on REMDESEVIR in severe
COVID infection,published in NEJM and LANCET ,all shows same results.
• That is Shorter time to recovery in comparison to placebo( median
11 days as compared to 15 days,patient getting well 3-4 days faster)
but has no impact on mortality)
23. Remdesevir
• I/V use
• Single loading dose 200 mg and maintenance dose 100 mg daily
• 5 days course is as effective as 10 days treatment in hospitalised severe
patients
• According to FDA liver function test should be tested in all patients prior to
starting Remdesevir and daily while receiving Remdesevir.
• Studies in Journal of American medical Association ( JAMA )showed that
in milder cases ,Remdesevir may not be used or may not be needed.
24. FDA (May 20) Remdesevir use was limited to
severe disease
• Severe disease— oxygen saturation less than or equal to 94% in room air
or requiring supplemental oxygen or requiring mechanical ventilation
28. • FDA ( June 20 ) warned for use of HCQS with Remdesevir as HCQS
may decrease anti-viral activity of Remdesevir.
29. FAVIPIRAVIR
• Experimental anti-viral drug not yet FDA or EU approved but available in many
countries including India
• DCGI( disease controller general of India) approved it in June 20
• Work against broad range of influenza viruses
• Oral drug,less price than Remdesevir
• Probably most effective in mild to moderate Covid19 disease
• Use early in symptomatic patients with lot of symptoms of viraemia including
high-grade fever on day one and two,severe myalgia, prostrations
30. FAVIPIRAVIR
• Side effects—Increased transaminases,diarrhoea, decrease WBC count,
hyperuricaemia, increased triglyceride level
• Dose—1800 mg BD on day1 followed by 800 mg BD for 2-14 days
• Disadvantage is high pill burden
31. Convalescent plasma therapy
• FDA granted EUA(Emergency use authorisation) on August 23, 2020 for
use of convalescent plasma in hospitalised patients with COVID-19.After
this Mayo clinic which was coordinating FDA sponsored COVID-19
expanded assess program discontinued enrolment on 28 August 20 .
• Eligible donors with high titres of antibody are selected.
• Transfusion should be done to the patient early within three days of illness
as many patients who were planned for plasma develop their own
antibodies for virus by around 10 days. Slight improvement in mortality was
found in patients who received plasma in Mayo group observational study.
32. Convalescent plasma
• NIH Covid 19 guidelines panel concluded on August 20 that there are
insufficient data to either recommend for or against the use of convalescent
plasma for treatment of COVID-19
• Cochrane review of convalescent plasma use in patients with COVID-19
(July 20 ) expressed uncertainty to the benefits of convalescent plasma in
terms of mortality at hospital discharge, prolonging time to death or improving
clinical symptoms at 7 to 28 days.
• Adverse effects like transfusion transmitted infections example HIV,
hepatitis B,hepatitis C,allergic reactions, anaphylactic reactions, transfusion
related acute lung injury, transfusion associated circulatory overload and
haemolytic reactions.
33. STEROIDS
• In meta analysis of randomised clinical trials in JAMA shows that In critically ill
patients with COVID-19, administration of systemic corticosteroids was associated
with lower 28 days all-cause mortality in comparison to usual care or placebo
• Large study Recovery trial showed that mortality rate was lower among patients
who received dexamethasone in comparison to patient who received a standard
care
• But dexamethasone shows no benefit among patients who don’t need oxygen or
respiratory support
• As we know Steroid is most potent immunosuppressant and suppresses patient’s
own immune system, it is said not to start steroids on day one, start when
inflammatory response is more ( 5th-7th day)
34. • Chinese thoracic Society states that steroids should be used with caution in patients with
hypoxaemia with COVID-19 and dose administration should be less than 0 .5 mg per KG per day
methylprednisolone or equivalent and for a shorter duration that is less than seven days. Short-term use
is safe except temporary hyperglycaemia.
• NIH (national Institute of health, a part of US Department of Health and Human Services ) treatment
guidelines panel
1)Panel recommends using dexamethasone 6 mg per day for up to 10 days or until hospital discharge
in hospitalised patients who are on mechanical ventilation or requiring supplemental oxygen
2)Panel recommends against using dexamethasone for treatment of patients who do not require
supplemental oxygen
3) If dexamethasone is not available panel recommend alternatives such as prednisolone,
methylprednisolone or hydrocortisone
35. Anticoagulants
• Covid 19 patients frequently develop procoagulative state.Mechanism is
poorly understood. It is caused by virus induced endothelial dysfunction,
cytokine storm and compliment cascade activation
• It is common to observe diffuse microvascular thrombi in multiple organs.
Mostly in pulmonary microvessels.
• High D dimer levels are associated with poor prognosis.
36. Anticoagulants
• National Institute of health anti-thrombotic therapy in patients with
COVID-19 May 20
• Measure haematological and coagulation parameters example D dimer,
PT, platelet count, fibrinogen in hospitalised patient
• All hospitalised patients with COVID-19 should receive the Venous
thromboembolism prophylaxis. LMWH preferred
• Hospitalised patients with COVID-19 should not routinely be discharged
on VTE prophylaxis.
37. Immunomodulator TOCILIZUMAB
• It is FDA approved immunosuppressive drug for the treatment of active rheumatoid arthritis
• Currently FDA has not approved TOCILIZUMAB for the treatment of COVID-19
• Interleukin 6 receptor antagonist
• Used in treatment of cytokine storm
• Studies like EMACTA trial (September 20 )show that TOCILIZUMAB decreases the risk of
mechanical ventilation or death in patients of COVID-19 pneumonia
• ROCHE confirmed that Phase 3 COVACTA study(July 20 ) that TOCILIZUMAB fail to
meet the endpoints. Primary endpoint of improving clinical status in covid associated
pneumonia and Secondary endpoint of decreasing mortality
38. • But ROCHE comitted to continue the trial and also to study combination
with antivirals.
• NIH treatment panel also recommend against use of TOCILIZUMAB for
treatment of COVID-19
• There is risk of infections with use of TOCILIZUMAB.
• Side effects are abnormal LFT, neutropenia, upper respiratory tract
infections, nasopharyngitis, headache , increase in BP, increase total
cholesterol, dizziness,rash, gastritis and subcutaneous injection site
reactions
39. Hydroxychloroquine
• It was initially started as treatment of COVID-19 patients
• Studies show that HCQS have no impact on clinical outcome and mortality . Large studies
like SOLIDARITY trial, RECOVERY trial ,NIH(National Institute of health) and NOVARTIS
sponsored HCQS trial closed HCQS limb in study and stopped it as the drug of trial and moved
on with other drugs in trial.
• On July 19 WHO discontinues hydroxychloroquine and Lopinavir/ritonavir treatment arms for
COVID-19 by accepting recommendation from a Solidarity international steering committee
• FDA news release in June 15, 2020 in Coronavirus update says that FDA revokes (cancel)
emergency use authorisation(EAU) for hydroxychloroquine in Covid 19
• So it’s end of road for HCQS in Covid 19
• Not currently recommended for treatment of Covid 19
40. • Side-effects of short duration Use of HCQS side-effects.
• nausea ,vomiting, diarrhoea, constipation, skin rash , QT interval
prolongation, ventricular arrhythmias.
41. • ICMR (Indian Council of medical research) has advised chemoprophylaxis
of hydroxychloroquine in 2 groups
• 1) Asymptomatic healthcare workers involved in treating confirmed or
suspected COVID 19 patients (HCQS 400 mg on day1 followed by 400
mg once weekly for next seven weeks ).
University of Oxford is doing large clinical trial (COPCOV trial) of
hydroxychloroquine to prevent COVID-19 on 40,000 healthcare workers.
• 2) Asymptomatic household contacts of all laboratory confirmed
COVID-19 cases (HCQS 400 mg BD on day one followed by 400 mg
once weekly for next three weeks). Study shows negative result and no
benefit.
42. UPDATE: Solidarity Trial reports interim results
Solidarity is an international clinical trial to help find an effective treatment ,launched
by the World Health Organization and partners. It is one of the largest international
randomized trials for COVID-19 treatments, enrolling almost 12 000 patients in 500
hospital sites in over 30 countries.
Posted on 16 October 2020
The Solidarity Trial published interim results on 15 October 2020. It
found that all 4 treatments evaluated (remdesivir, hydroxychloroquine,
lopinavir/ritonavir and interferon) had little or no effect on overall
mortality, initiation of ventilation and duration of hospital stay in
hospitalized patients.
43. Cytokine storm
• Umbrella term for group of hyperactive immune response triggered by
• Infections
• Complication of autoimmune or autoinflammatory diseases
• Cancer or therapy of cancer
• Most common infections causing it are viral infections like Epstein bar
virus, herpes simplex virus, influenza virus, 2009 H1N1,cytomegalovirus
virus and now this nasty Covid 19
44. Cytokine storm
• Lymphocytes kill viral infected cells and interaction between them leads
to increase in pro-inflammatory cytokines like IL6, IL12, TNF alpha,IL-1
beta
• Result is multiorgan failure
• Most prominent involvement is lung .ARDS.
• Others like kidney (AKI) ,Liver, CNS and heart are also affected
• DIC and thrombocytopenia is also reported
45. Cytokine storm
A hallmark of a cytokine storm is persistent fever and non-specific
constitutional symptoms (weight loss, joint and muscle pain, fatigue,
headache). Progressive widespread systemic inflammation leads to a loss of
vascular tone that is manifested as a drop in blood pressure, vasodilatory
shock, and progressive organ failure. Respiratory failure is the most
prominent .
46. Management of cytokine storm
• Investigations pointing are increase ferritin, CRP, d-dimer ,IL6 and LDH
• Treated by
• Glucocorticoid (immuno suppressants) but side-effect is secondary infections
and worsening of diabetes
• Tocilizumab- IL6 receptor antagonist. NIH treatment panel also recommend
against use of TOCILIZUMAB for treatment of COVID-19
• Anakirna IL1 receptor antagonist. According to NIH treatment guidelines there
is insufficient data for favour or against its use in Covid 19.
47. What Does not work in Covid 19
• ANTIBIOTICS including, doxycycline ,azithromycin except in secondary
sepsis
• According to clinical infectious disease article, In second or third week
of severe hospitalised Covid disease, patients get secondary bacterial
infections But If more and early use of Antibiotics is done there will be
panresistant infections
• HYDROXYCHLOROQUINE (HCQS)
• OSELTAMAVIR (temiflu). is approved for treatment of influenza A and B.
Study in Wuhan reported no positive outcomes in COVID-19.Several trials
are still evaluating it in treating Coronavirus infections
48. What does not work in Covid 19
• IVERMECTIN
• Australian government has issued advice on inappropriate use of ivermectin for COVID-19 and
stated that there is currently no enough evidence to show that Ivermectin is safe or effective to
prevent or treat Covid 19.
• Chaccour et al also raises their concern regarding ivermectin associated neuro toxicity,
particularly in patients with hyper inflammatory state. Finally, evidence suggests that Ivermectin
plasma levels with meaningful activity against COVID-19 would not be achieved without potentially
toxic increase in Ivermectin doses in humans
• NIH COVID-19 treatment guidelines panel recommend against the use of ivermectin for the
treatment of COVID-19
• FDA issued a warning in April 20 that Ivermectin should not be used to treat COVID-19 in humans
49. What does not work in COVID-19
• Side-effects of ivermectin
• Neurotoxicity is main concern.Serious neurological side effects like
• Dizziness, somnolence, vertigo, tremors, Headache, vomiting,
seizures, ataxia, disorientation,Confusional state, Coma
• Other side-effects like fever ,itching, skin rash,joint or muscle pain
tachycardia.
50. What does what does not work in Covid 19
• Lopinavir-Ritonavir was tried in early time but it was negative study.
• NIH also recommend against it in the treatment of COVID-19
51. • NIH COVID-19 treatment guideline panel states “there is insufficient data
to recommend either for or against for use of vitamin C, vitamin D and
Zinc”
52. Medscape commentary
“Has Pandemic 'Infected' Our Approach to Medicine?”
Dr Vinay Prasad MD MPH is a practicing hematologist-oncologist and Associate Professor of Medicine at the
University of California San Francisco.He also studies drugs ,health policy ,clinical trials and better decision
making . Prasad is a noted critic.
Perspective Medscape > Prasad on Medicine
COMMENTARY
Has Pandemic 'Infected' Our Approach to Medicine?
Vinay Prasad, MD, MPH
DISCLOSURES May 20, 2020
“For a sick patient with any other viral illness without a proven treatment, I have never
witnessed doctors giving five, six, or 10 drugs to treat the virus without any proof that it
will help. I have never seen a severely ill patient with influenza, pneumonia, viral
hepatitis, or HIV receiving vitamin C, zinc, hydroxychloroquine, and tocilizumab—all
without any evidence”Description
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