CME INDIA Presentation by Dr Basab Ghosh, Internist, Agartala.

COVID-19 is a clinical diagnosis and RT-PCR is to confirm the diagnosis. RT-PCR is positive in 80% cases, rest 20% can be clinically identified to isolate and treat. In COVID-19 treatment ‘timing’ is very important for all treatment options.

As anti-inflammatory drug steroid is lifesaving for COVID-19, but right time, right drug, right dose and right period of time is important.

Clinical assessment for treatment initiation is vital now, as a huge number of COVID-19 cases are now getting home treatment in home quarantine and our guidance should be on that directive to give better coverage to the sufferings.

In home quarantine, hardly laboratory tests or radiological support is possible in most of the Indian states in present pandemic situation. Rather main available tools in home quarantine treatment are clinical thermometer, self-monitored blood pressure instrument, pulseoxymeter, etc.!

Identification of day one of symptoms is vital in clinical guidance of treatment initiation in COVID-19.

If we see the infective course of the highly contagious SARS COV2 virus: 

1. Incubation period: It is 3 to 5 days and mostly unidentified.

2. Symptomatic period: After incubation period 7 to 8 days of symptomatic period appears. Once infected, the virus is replicable till the symptomatic phase and the virus is at its peak replicable stage when symptoms start appearing. The incubation period and symptomatic phase are over by 10 to 12 days.

The symptoms are fever, malaise, headache, sore throat, dry cough, diarrhoea, etc. Clinically in mild symptomatic cases the patient can present with fever, dry cough, malaise with increased pulse rate of up to 100 per minute and normal respiratory of 12 to 20 per minute and stable oxygen saturation of >96% as measured in Pulseoxymeter. In moderate symptomatic cases, fever may rise, pulse rate may be >110 per minute, respiratory rate > or = 24 per minute and oxygen saturation <94% in room air.

The virus is replicable and culturable till 9th day of infection or from the day of first symptoms and from 10th day onwards it is non-replicable and non-culturable. But viral remnants are present up to three weeks and in few cases seen up to three months as reported in literature.

3. Pulmonary phase: After incubation period and symptomatic phase, next is pulmonary phase and first 4 to 5 days is early pulmonary phase and next is late pulmonary phase which may appear after 14 days of infection and may last for few weeks as described by experts.

Pulmonary phase or respiratory phase is the phase of inflammatory response due to the presence of viral debris. After symptomatic phase, virus is non-replicable and non-culturable, if viral load is more there will be huge viral debris and those will cause severe inflammation in the host cells. Early pulmonary phase is phase of thrombophilia for 3 to 4 days; thrombophilia is a condition in which there’s an imbalance in naturally occurring blood-clotting proteins, or clotting factors. This can put the patient at risk of developing blood clots. Next there is macrophage over activation syndrome and cytokine storm. Overall there is immune dysregulation in pulmonary phase.

COVID steroid response
Fig: The course of COVID-19 and General Approach to treatment. (Collected from, EVMS Critical care COVID-19 management protocol dt. 28th September, 2020).

Time for Antiviral treatment: It has to be given in symptomatic phase when virus is replicable; first eight days of the symptoms are ideal for any antiviral treatment including Remdisevir. Remdisevir is indicated in moderate symptomatic cases as mentioned earlier based on reduced oxygen saturation but patient should not be on high flow oxygen / NIV / mechanical ventilation. Even Convelacent Plasma and Interferon alpha are to be given in the first 10 days of symptoms when the virus is replicable. Any treatment module targeting the viral antigen including antivirals has to be initiated in the viral replicable period in both mild or moderate symptomatic cases.

Time for Steroid treatment: 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 is very low replicable and inflammatory response is about to settle down. If steroid is started in the early viral replicable phase i.e. early phase of symptoms then there is a chance that the virus will replicate more.

In pulmonary phase steroid has to be given and start early with the standard dose, then after 24 hours, dose can be increased seeing the clinical and biochemical response and this is the ideal approach as suggested by many experts. There is profound inflammation in pulmonary phase, so anti-inflammatory steroid has huge role to counter the process.

Methylprednisolone is better than Dexamethasone and Dexamethasone is better than Prednisolone. Methylprednisolone penetrates much better into the lungs and binds much better into the glucocorticoid receptors among all steroids, so it gives best anti-inflammatory response. So, for steroid treatment right time, right drug, right dose and right duration is very important.

Pneumonia may develop much before than pulmonary phase on day 3 of symptomatic phase in clinically mild symptomatic presentation. In X-Ray chest, pneumonia is indicated on day 5 to 7, but in CT scan chest it is visible on day 2 to 3. To reduce morbidity and mortality diagnosis of pneumonia should be completed by day 5. Treatment module should be antibiotics to prevent super added bacterial infections, anticoagulant to prevent thrombophilia in pulmonary phase preferably by parenteral LMWH and steroid to counter the inflammatory storm preferably Methylprednisolone or Dexamethasone and all should be initiated by day 5. By the time steroid is initiated actually it is minimum 8th day of symptoms, so increased reliability is not a serious issue at that point. For high risk group like HCWs, diabetes, hypertension, prolonged immobilization, underlying hypercoagulable states, already on LMWH prophylaxis, high LDL, high CRP, etc. anticoagulant should be given on day 1, but steroid initiation is as per the clinician’s decision on day 1 as virus may replicate more because of steroid at the initial days of symptomatic phase. So the dictum for steroid treatment in COVID-19 should be start treatment early when the patient develops pulmonary sign.

Time for Anticoagulant Treatment: Severe COVID-19 disease is associated with features of disseminated intravascular coagulation (DIC) and hypercoagulable states which can manifest as venous thromboembolism (VTE) and / or microthrombosis. Microvascular thrombosis is hypothesized to be involved in hypoxemic respiratory failure in some patients with COVID-19. Autopsy studies show large vessel and microvascular thrombosis, pulmonary hemorrhage and high prevalence of Venous Thrombo Embolism (VTE). In early pulmonary phase there is thrombophilia, which is established after symptomatic phase due to inflammatory response to the presence of viral debris.

So, as per anticoagulant guidelines, all moderate and severe symptomatic COVID-19 patients age > or = 18 yrs. with clinical presentation of pulse rate >110, RR > 24, SpO2 <94%, either hospitalised or in home treatment should receive anticoagulant prophylaxis until contraindicated with bleeding disorders or low platelet counts.

Even with low grade fever with dry cough or sore throat in COVID-19 patients, pneumonia should be suspected in home treatment cases to avoid future emergencies. If clinically pneumonia is suspected by the history and clinical presentation of the disease or pneumonia is confirmed by X-Ray chest or CT scan chest, then LMWH should be initiated on day 5 or in case of high risk group on day 1, as discussed above.

In conclusion we can say, treat the viral period in symptomatic phase with antiviral, treat the immune system in inflammatory phase with anti-inflammatory steroid and use early anticoagulant to avoid thrombophilia in pulmonary phase.

Reference list:
3. EVMS critical care COVID-19 management protocol dt. 28th Sept, 2020.
4. Interim clinical guidance for management of COVID-19 (version 1.5), AIIMS, New Delhi dt. 8th September 2020
5. Investigation and treatment protocol for COVID-19 by Apollo Hospitals, Version 28 (updated 26th August, 2020).

CME INDIA Tail Piece

1. Incubation Period:

  • Symptoms may develop 2 days to 2 weeks following exposure to the virus.
  • A pooled analysis of 181 confirmed cases of COVID-19 outside Wuhan, China, found the mean incubation period to be 5.1 days and that 97.5% of individuals who developed symptoms did so within 11.5 days of infection. For COVID-19.
  • Current estimates of the incubation period are in the region of 4–5 days.

2. Alert

  • Clinicians should be aware of the potential for some patients to rapidly deteriorate 1 week after illness onset.
  • The median time to acute respiratory distress syndrome (ARDS) 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.

3. Choice of Steroid as per CDC

  • Whether use of prednisone, methylprednisolone or hydrocortisone for the treatment of COVID-19 provides the same benefit as dexamethasone is unclear.
  • The total daily dose equivalencies for these drugs to dexamethasone 6 mg (oral or intravenous [IV]) are:
    • Prednisone 40 mg
    • Methylprednisolone 32 mg
    • Hydrocortisone 160 mg
  • Half-life, duration of action, and frequency of administration vary among corticosteroids.
    • Long-acting corticosteroid: dexamethasone; half-life: 36 to 72 hours, administer once daily.
    • Intermediate-acting corticosteroids: prednisone and methylprednisolone; half-life: 12 to 36 hours, administer once daily or in two divided doses daily.
    • Short-acting corticosteroid: hydrocortisone; half-life: 8 to 12 hours, administer in two to four divided doses daily.

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