CME INDIA Presentation by Prof. Dr. S. Arulrhaj, MD, PhD, FRCP(G), FRCP(L), MBA, National President, API, Head Acute Medicine, Sundaram Arulrhaj Hospitals & Research Foundation, Tuticorin.

Mask is the Vaccine.

Hand wash is the medicine.

Distancing is immunity.

Early Detection and Effective Treatment are Key.

Biography of SARS-CoV-2

Family Name:Corona viridae
Misnomers:Manmade China-Virus
Date of Birth:November or December 2019
Place of Birth:Wuhan, Hubei Province
China, Locality:Huanan Seafood Wholesale Market            
Birth Day in India:30th Jan 2020
Profession:Corona virus Disease 19, COVID-19
Current Address:Type-II Pneumocytes, Lung
Bar Code to Residence:ACE2
Roaming Address:Rogue Virus, Globe trotter
Gen Bank Number:MN908947 (NCBI)

Define it

Acute Manageable Immunogenic Thrombogenic Inflammatory Viral Notifiable Disease.

Catch It

  • Incubation period: 1-27 days
  • Recovery time: 3 weeks to 6 weeks
  • Frequently reported signs and symptoms of patients include:
  • Fever, usually low grade (77%–98%)
  • cough (46%–82%) Dry throat, Dry cough
  • myalgia or fatigue (11%–52%)
  • Loss of smell – Nose Corona
  • Loss of taste – jaggery taste – Throat Corona
  • shortness of breath (3%-31%) – Lung Corona
  • Happy hypoxia (spo2)
  • Low hand grip strength
  • 6-minute walk test – plan 3-6 – 5% desaturation
  • Any symptom with close contact.
  • Any 1: symptom: taste, smell loss (partial or total), left red eye.
  • Any 2: Fever, Throat irritation, SOB, Loose Motion.
  • Any 3: Headache, Nausea, Vomiting, Rash, Pain Below Knees, Cystitis, Anorexia, Altered sensorium.

Confirm It

  1. Travel history to endemic areas.
  2. CBC.
  3. Chest X-Ray (cheaper & easier with 60% sensitivity).
  4. PCR (30%-70% sensitivity).
  5. Chest CT Scan (95% sensitivity, low specificity).
  6. IgM/IgG antibody test for COVID-19.

COVID Nectars Identified

In Severe COVID-19

  • Decrease lymphocyte count-Lymphopenia
  • Decrease albumin
  • Decrease haemoglobin levels
  • Increase C-reactive protein (CRP)
  • Increase Erythrocyte Sedimentation Rate Increase Lactate Dehydrogenase (LDH)
  • Increase D-dimer
  • Increase Ferritin
  • Increase Neutrophil count
  • Increase in NLR
  • Increase Alanine Aminotransferase Increase Aspartate Aminotransferase
  • Increase Cardiac biomarkers
  • Increase Procalcitonin

Investigate It

  • CBC, Neutrophil Lymphocyte Ratio 3:1 significant, >7 is severe.
  • D-Dimer – more than 1.5-mcg/ml,>10 is severe
  • S. Ferritin > than 400 nanogram /ml, severe > 1500
  • CRP >2.5 mg/dl, severe >100
  • Serum Procalcition – < 0.5 nanogram / ml
  • LDH >220 IU/I, > 500 severe
  • Serum IL6 levels: >8PCG/ml

Test it

1. RTPCR –  gold standard, expensive, 6 hrs.

  • Cycles threshold(Ct) number: 17-24 – high viral load.
  • Cycles threshold(Ct) number: 24-31 – moderate.
  • Cycles threshold(Ct) number: > 31 –  low viral load.

2. CBNAAT –  gene expert

  • screening and confirmation
  • result 2 hrs.
  • ICMR –  ICU & SARI

3. TRUENAT

  • Detects genes
  • result in 1 hr.
  • ICMR –  screening

4. Rapid antigen

  • containment zones
  • economic
  • sensitivity moderate, specificity – high

5. Antibody test

  • IgM: 3rd day – 22nd day
  • IgG: 7th day – long period

COVID Nectars Identified

Serology

CXR

6 patterns of COVID on chest X-Ray


Pattern 1 – Reverse Batwing
Pattern 2 – Multifocal lower lobe predominant consolidation
Pattern 3 – Peribronchial rounded consolidations
Pattern 4 Multifocal bilateral consolidations
Pattern 5 – Ball pattern or round pneumonia
Pattern 6 – Bilateral symmetrical diffuse lung involvement

COVID Nectars Identified - X-Rays

HRCT

All go in favour of Corona

  • Peripheral lesions
  • Ground Glass Haziness
  • Consolidation patches
  • Reverse Halosign
  • Vaculation sign
  • Air Bronchograms
  • Prominent Pulmonary Vessels
  • Crazy Pavement Patterns on CT-SCAN

RTPCR Negative CT Positive, what to do?

Virus enters through nose and throat.  Will stay there 4 – 7 days in nose / throat.

  • later descend to lung
  • RTPCR taken for the swab from nose and throat
  • hence RTPCR positive only in early days.  When virus has moved in lungs, RTPCR is negative. BAL will help.
  • Hence CT helps:

CORAD – COVID radiologist finding:

  • CORADS 2-3: suspicious
  • CORADS 4-5: confirmatory

Hence RTPCR may be negative

COVID Nectars Identified - CT for Covid-19 diagnosis

rtPCR, what you need to know?

Frequently asked questions:


1. What is the full form of RT PCR?

Ans: Reverse Transcription Polymerase Chain Reaction

2. Why test is only 67% specific & not 100%? What are the pitfalls?

Ans
: Problem can be at 4 levels:

  • very low viral load at the time of sample collection
  • faulty sample collection
  • improper transport of the sample &
  • faulty laboratory technique.

So, test must be repeated in high clinical suspicion.

3. Is there any false positive result?

Ans: No false positives- positive is certainly positive. It can be false negative. (Repeat the Test- if high clinical suspicion).

4. How many types of antigen are present in COVID- 19 virus?

Ans: COVID-19 virus has 6(six) antigens – E, S, N, ORF 1a, ORF 1 b &, RDRP.

5. Which antigen is common to all corona viruses?

Ans: E antigen is common to all CORONAVIRUSES. If E is negative – No Corona. Other 5 are specific to COVID-19.

6. Do all countries test same antigens?

Ans: Testing of antigen differ from one country to another. In Singapore, chip machines check for N, ORF and S antigens at the airports.

7. Certified as Non-Infectious?

Ans: The patient demonstrates the presence of IgG antibodies with or without presence of antigens, the patient is asymptomatic after 10 days without doing antigen test, the patient is positive for 2 weeks, his ESR and CRP are normal.

Classification of COVID Patients Clinically

  1. Asymptomatic – RTPCR positive, no symptoms, X-ray – normal
  2. Mild – URI symptoms, Fatigue, fever, GI, CT Corad 1-2
  3. Moderate – Pneumonia, no hyposaturation, CT Positive Corad 2-3
  4. Severe – pneumonia with hypsaturation (SpO2 <92%) CT Positive Corad 4-5
  5. Critical – ARDS, shock, encephalopathy, HF, Coagulation dysfunction, AKI

Manage it Simply

OXYGEN – SUPER HERO

  • Oxygen Therapy
  • HFNO/ NIV/ Invasive
  • Antibiotics
  • Steroids
  • Antivirals
  • Heparin
  • Monoclonal Antibodies
  • Plasma Therapy
  • ECMO
  • Lung Transplant

Antibiotics in COVID

  • Antibiotics act on Bacteria
    • Bacteriostatic
    • Bacteriocidal
  • Antibiotics are not viricidal.
  • Can be used to treat secondary infections
  • They are for Off label use.

Why we are using in COVID?

Because of their:

  • Non-Bactericidal Properties
  • VIRISTATIC Properties

Effect on Virus

  • Entry inhibition
  • Inhibition of uncoating of virus
  • Replication
  • Post translational modification

Effect on Host

DOXYCYCLINE, Why?

  • Doxycycline showed its effect in
    • Antiviral – Dengue
    • Anti-Typhus
    • Anti-Parasite – Malaria
  • Doxycycline inhibited the post-infection replication in addition to reducing the virus’s ability to enter the cultured cells.
  • Tetracyclines may act through their well-known anti-inflammatory capabilities including downregulation of the nuclear factor–k B pathway as well as a decrease in levels of inflammatory cytokines such as tumor necrosis factor-a, interleukin (IL)-1b, and IL-6 independent of its antibiotic mechanism.
  • Two other studies showed that chemically modified tetracyclines can induce apoptosis of mast cells and activation of protein kinase C, thus decreasing levels of circulating inflammatory agents.

Ref: Doxycycline as a potential partner of COVID-19 therapies

Author links open overlay panel AlexandreE.MalekBrunoP.GranwehrDimitriosP.Kontoyiannis

HYDROXYQUINOLINE: Still Live, may be on backbench

  • The effect of hydroxychloroquine and chloroquine on viral replication goes beyond cytokine inhibition.
  • These medications are weak bases that can affect acid vesicles and inhibit several enzymes. This characteristic allows them to inhibit the viral entry to the cell when the endocytosis is pH dependent.
  • It also inhibits glycosyl-transferases, viral post-translational modifications and replication of some viral families.
  • The antiretroviral effect has been considered to be caused by the inhibition of viral glycosylation, a major antiviral mechanism of these drugs.

Prophylactic & Therapeutics

  • Recovery Trial September 2020

Ref: https://pmj.bmj.com/content/early/2020/05/28/postgradmedj-2020-137785

IVERMECTIN Emerged as SHAKTIMAN?

  • Inhibition of importin α/β1 mediated transport of viral proteins in and out of the nucleus

Bangladesh Study –  observational study:

  • No: 60 positive cases treated with
  • Ivermectin Single dose and Doxycycline 200 mg day 1 & 100 mg BD X 7
  • 19 cases Negative and symptom free 

ICMR Started Ivermectin Schedule September 2020

API study is on

Monash University-led collaborative study 

Prophylactic & Therapeutics

Ref: Gupta D, Sahoo AK, Singh A. Ivermectin: potential candidate for the treatment of COVID 19 [published online ahead of print, 2020 Jun 28]. Braz J Infect Dis. 2020; S1413-8670(20)30081-7. doi: 10.1016/j.bjid.2020.06.002

How you start?

  • Protocol Based OXYGEN THERAPY.
  •  Document hypoxia by noninvasive or invasive methods.
  •  Start 2 therapy assessing SPO2 and deciding low flow system or high flow system.
  •  O2 therapy to be initiated if SPO2 less than 95%.
  •  Target SPO2 more than 94%.
  •  Titrate up or down based on monitoring spo2 and clinical assessment of hypoxia.
  •  For patients with normal rate and depth of breathing, each liter per minute of nasal O2 therapy increase the FIO2 by 4%.

COVID Nectars Identified - Oxygen Therapy

COVID Nectars Identified - HFOT Device

COVID Nectars Identified - Ventilatory Support

Nocturnal oxygen therapy as an option for early COVID-19; Know it…

Highlights:

  • Oxygen supplementation may disrupt virus replication.
  • Oxygen therapy can improve the antiviral immune response.
  • An oxygen-rich environment may down-regulate ACE2 expression.
  • Nocturnal oxygen therapy may delay the progression of COVID-19.HTS

Ref. International Journal of Infectious Diseases Volume 98, September 2020, Pages 176-179 By Chongxing Shena et al.

Mantra in COVID:

  • Once diagnosed or suspect, on Day I, do baseline minimum, Quantitative CRP, CBC, Blood sugar, ESR, 6MWT, (Ferritin, D Dimer, IL6, tnf Alpha, RDW, LDH, Fibrinogen levels may add in deciding the clinical severity).
  • On Day I, consider starting azithromycein: ivermectin: vitamin Lmelatonin, favipiravir, famotidine
  • In health care workers or high-risk individuals with base line CRP>1MG/L start blood thinner Dabigatran 110 mg BID or Rivaroxaban 10mg OD or Abeiximab 2.5 mg BID or Enoxaparin SC (if hospitalized). Aspirin may not be helpful in big viral load.
  • If high risk with comorbid condition, start low dose Steroids on Day 3(if there is an evidence of pneumonia as evident by fever>101 F, CRP>10MG/L, cough starting on day 3 or fall in SPO2 saturation by 4% or CT proven)
  • Do 6MWT AND CRP daily on days 1-5.
  • Treat fever with mefemic acid if not contraindicated (indomethacin/naproxen are other options). (Pareek Rp. Use of mefenamic acid as a supportive treatment or COVID-19: a repurposing drug. International Journal of science and Research(IJSR).2020:9(6):69
  • Do not miss MI or CVA as the first presentation. (SiddamreddyS,et.al.Corona virus disease 20 (COVID-19)presenting as acute ST elevation myocardial infarction. Cureus.2020;12(4):e7782 Avula A,et.al.COVID-19 presenting as stroke. Brain Behav Immam 2020; 87:115-9).
  • Do not miss COVID cystitis (pus cells with culture negative and no bacteria)
  • High CRP can cause sudden reduction of LDL; be on the alert
  • Consider high dose statins for low grade inflammation (CRP 1-3 mg% and high LDL>80 mg%
  • On day 0, if CRP is 1-3 mg/L and LDL is high, there is high risk of acute thrombosis.
  • Most antenatal cases (50%)will be asymptomatic. (Allotey J,et.al.(Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ.2020 sep 1; 370: m3320. doi:10.1136/bmj.m3320).
  • Consider preoperative RTPCR in elective surgeries along with pooled RTCPR of family. (somashekhar SP, et.al.ASI’S Consenus Guidelines: ABCs of what Do and what not during COVID-19 Pandemic. Indian J surg, 2020 Jan 9:1-11).
  • Isolation, quarantine and monitoring: you should isolate, quarantine and all family members and close contacts should monitor themselves.

Never Forget:

  1. We can reduce mortality if we monitor each case properly from day 6 to 12. PCR after 4 days.
  2. Start antivirals early and judiciously. Favipiravir is comparatively less effective than remdesmivir. Mild cases start favipiravir. Moderate to severe start remdesivir. If pt not improving clinically on favipiravir shift pt to remdesivir early.
  3. Don’t use Dexa with remdedivir. Use methylprednosolone inj with remdesivir.
  4. ABG is important in milder and severe cases. Prolonged high FiO2 is harmful, so manage Fi02 to maintain P02 around 60.
  5. When pt is on HFNO with flow more than 35lit per min, take precautions while giving DC shock in ICU. chances/ cases of fire are seen.
  6. Changing positions while ventilator helps to improve oxygenation.
  7.  Patients with positive 6 min walk test should not go to washroom. He should use bed pan. Mortality is high in washroom while straining in hypoxic cases.
  8. Risk of mortality is high in relatives where any one has died due to COVID infection. (Genetic reason) so other positive relatives should be closely monitored.
  9. To reduce chances of pulmonary fibrosis, cases. with CT score, more than 15 should undergo repeat scan and should be on warfarin, oral steroids, and antifibrotic drugs like perfinidine etc. for minimum 6 wks. Then tapering of steroid.
  10. If COVID Pt develops AKI with good urine output but high creatinine and urea. All COVID cases needs adequate hydration.
  11. COVID patient can’t spread active virus after day 12 to 14.
  12. All home quarantine cases use surgical masks at home also. Use of hot flush or use of sodiumhypochliride for toilets is important to avoid spread at home. Virus spreads through fecal matter also.
  13. Now many paediatric cases are coming with bad COVID infection and mortality.
  14. No role of antivirals after day 14 of disease.
  15. Role of steroid from day 4/5 to day 18 to 20. (Judiciously used.)

What with Comorbidities?

  • Age > 60
  • Diabetes
  • HTN
  • CAD
  • CKD
  • Smoker
  • Alcoholic CLD
  • Cancer
  • Immunocompromised

Watch for complications:

A. Immediate:

  • Sepsis & Septic shock
  • ARDS 7 Refractory Hypoxemia
  • Happy Hypoxia
  • ACS, HF, Myocarditis, Dysrhythmias HTN & Thrombo Embolism
  • Diabetes; New onset & aggravation DKA
  • GI, AKI, CNS & Skin
  • The virus is present in skin. The Lancet has published a case report where RT PCR was negative, but the skin biopsy samples from rash, were positive for the virus.

B. Delayed:

  • Pulmonary Fibrosis, Stroke, & ACS
  • Reinfection

Wait for 2021

COVID Nectars Identified - Vaccine Status

HOPE is there

COVID Nectars Identified - There is Hope

COVID Nectars Identified - Recent Observations


CME INDIA LEARNING POINTS

  1. Swab negative, CT positive, high inflammatory markers- runs sick in ICU – Outcome bad
  2. Past CAD and autoimmune disorder on proper treatment has good outcome.
  3. Pt on aspirin, clopidogrel have mild disease –  come out well.
  4. No emergency to correct hypoxia in high inflammatory markers. Patient tolerate hypoxia well.
  5. Chronic hypoxia in COVID does not cause more problem as we expect.
  6. Oxygen, statins, anticoagulant do good.
  7. COVID aggravates and cause hyperglycaemia. Glycemic control must be adequate with insulin.
  8. HTN control with ACEi and CCB is good
  9. DM stiffly controlled wit Insulin – Short & long acting
  10. Lung involvement and ischemic CVA is common. Use anticoagulant – They come out well.
  11. At discharge recommend aspirin 75mg Atrovastatin to be continued for 3 months.
  12. Radiological resolution takes 3 months.
  13. Reinfection is usually mild & numbers low, Reported in USA, Hong Kong & India
  14. Fit for Procedures & surgery: Asymptomatic, PCR Negative, IgG positive, Markers normal, ECHO & PFT normal. CT will take time.

RED FLAGS:

  • Fever > 101º F with drugs or > 103ºF without anti-pyretics
  • 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


CME INDIA TAIL PIECE

Decision Simplified:

  • Corona is not a lung disease, a systemic Thrombo hyper inflammation Vasculitis Disease
  • The Virus is non – replicating after Day 9. (Muge Cevik, et al. SARS – CoV-2, SARS- CoV-1 and MERS-CoV viral load dynamics, duration of viral shedding and infectiousness: a living systematic review and meta- analysis, MedRxiv, Posted July29, 2020)
  • Fever > 101º F, CRP > 10 mg/L, Rapid rise of CRP, Cough on Day 3 or fall of SPO2 on six-minutes walk test by 54% are suggestive of pneumonia.
  • Day 5 is the THE day in critical phase (Fei Z,et.al.Lancet,2020;395 (10229):1054-62).
  • Day 90 is THE day after which the word COVID ends (CDC Duration of isolation for adults with COVID-19. Updated sept.10,2020. Available at https://www.cdc.gov/coronavncov/bcp/duration-islation.btml
  • Loss of Smell is THE symptom equal to RTPCR test (Hacbner A,et.al.ORL J Otorbinolaryngol Relat Spec.2020:82(4)175-80.
  • 15 minutes THE time to get the infection (CDC Contact tracing for COVID -19. Available at: https://www.cde.gov/coronavirus/2019-ncov/plop/contact-tracing /contact –tracing-plan.
  • Clinical Features, Serum Markers and CT scan of Chest are much better diagnostic tools than depending on PCR test
  • RT PCR may remain positive up to 90 days, but Ct value should increase. (up-to-date)
  • If RTPCR is positive after 3 months or becomes positive after two consecutive negatives, consider possible reinfection. (Gupta V, et al. Asymptomatic reinfection in two healthcare workers from India with genetically distinct SARS- CoV-2. Clin Infect Dis. 2020 Sep 23; ciaall 1451)
  • Antibody test can be done once a month to check for exposure.
  • RTPCR Ct is THE test for diagnosis (Tang YW,et.al.J Clin Microbial.2020;58(6)
  • CRP is THE lab test for assessment of seriousness (Knight SR,et.al.BMJ.2020 Sep 9;370:m 3339)
  • The six-minute walk test (6MWT) is now mandatory from Day 3-6. If the patient desaturates by 5% on walking, this is indicative of pneumonia with thrombosis and this is considered as an emergency.
  • Toilets are recognized as a COVID chamber – Contact time from 30/10 minutes to 15/5 minutes in closed areas.
  • Home Isolation is THE modality of Treatment (maria N,et.al.Int J   Surg,2020;77:206-16)
  • 12 years is THE age when the mortality starts (Gotzinger,et.al.Lancet child Adolese Health 2020;4(9):653-61).
  • Remdesvir for all COVID 19 admitted pts irrespective of severity.
  • Treatment is Anti coagulants and immune suppressants
  • Steroids (high dose) for all hypoxic pts and shows mortality benefit.
  • LMWH for pts with high D DIMER values.
  • Tolicizumab more sepsis related complications, not much benefit.
  • Starting treatment early even with Ivermectin and Doxycycline, followed by LMWH and dexamethasone at right time can reduce need of Remdesiver and Tocilizumab
  • Anticoagulants may need to be given for 3weeks or more.
  • Zinc is THE mineral (Wessels I, et.al. Front Immaunol, 2020;11;:1712); D is THE vita Z.et.al.PLoS One.2020;15(9):e0239799)
  • People are developing Myocardial infarctions, Stroke, etc. few weeks after Corona infection – Thromboembolic phenomenon
  • Oxygen is the superhero.
  • Consider zero power eye glass for protection. (Maragakis LL. Eye protection and the risk of coronavirus disease 2019: does wearing eye protection mitigate risk in public, non- health care settings? JAMA Ophthalmol.2020 Sep 16 ) Glass provide partial barrier
  • In OPD areas, consider screening for loss of taste and smell/ fever /SpO2 hand grip before entry
  • Masking is THE prevention (Esposito S,et.al Enr Respir J.2020;55 (6):2001260).
  • All HCPs (Care takers) while on duty (clinical and non- clinical areas) should wear N95/FF2P/Surgical, three- Layered Mask (correct and consistent use.) Transmission risk is < 0.5% with N95 mask. Y Qian, ei al. Performance of N95 respirators: filtration efficiency for airborne microbial and inert particles. Am Ind Hyg Assoc J.1998:59(2):128-32
  • In India HCWs (care takers) in practice may consider ICMR recommendation and take HCQ 400mg per week, If not contraindicated. (Revised advisory on the use of Hydroxychloroquine (HCQ) as prophylaxis for SARS-CoV-2 infection, ICMR, 22/05/2020) I May change from country/state to country / state or as per WHO)
  • In India if HCQ is contraindicated or by choice, may consider Ivermectin 12 mg once a week (UP protocol 1,7,30, days and then once a month).
  • Vaccine will be ready by January 2021.


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