With increasing COVID-19 cases to handle, it is crucial to understand the updates around the disease, especially with regard to managing different levels of severity of the infection and the administration of steroids and drugs at the right stage which play a vital role in the overall recovery process of the patient.

For our comprehensive coverage and latest updates on COVID-19 click here.

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Management of COVID-19 cases

Mild illness

They are patients with COVID-19 symptoms who do not have viral pneumonia or hypoxia and who have a respiratory rate of less than 24 breaths per minute. The following steps should be taken-

1. Monitoring (SpO2, NIBP, HR, temperature, etc.)
2. Rehydration
3. Antipyretic
4. Nutritional support
5. There is no substantial evidence for azithromycin/ doxycycline: The national Platform Randomised study of INterventions against COVID-19 in Older People (PRINCIPLE) trial showed that antibiotics azithromycin and doxycycline are not necessarily successful drugs for COVID-19, according to researchers at the University of Oxford in the United Kingdom. It is important to note that the majority of centres/experts have personal experience with these medications and have considered them to be beneficial.
6. Oral Vit C, Vit D, Zinc supplementation etc.
7. HCQs should be avoided

Ivermectin

There is no concrete evidence for use of ivermectin-

1. It has poor antiviral properties at elevated concentrations
2. It is difficult to obtain with clinical current doses in pulmonary endothelium
3. It is only recommended by few state guidelines

The NIH COVID-19 Drug Guidelines Panel says there isn't enough evidence to prescribe ivermectin for COVID-19 treatment. To provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19 results from adequately -powered, well-designed, and well-conducted clinical trials are required.

Rationale: In cell cultures, ivermectin has been shown to suppress SARS-CoV-2 replication. However, pharmacokinetic and pharmacodynamic studies indicate that reaching the plasma concentrations required for the antiviral efficacy found in vitro will necessitate doses up to 100 times higher than those authorised for human usage. Despite the fact that ivermectin tends to concentrate in lung tissue, estimated systemic plasma and lung tissue concentrations are far lower than the half-maximal inhibitory concentration (IC50) of SARS-CoV-2 in vitro, which is 2 M.

Favipiravir

It is a weak antiviral drug of limited efficacy; it may clear the virus, but most people, including those with mild disease, may not need it. If a risk factor for the thrombotic disease exists, a prophylactic dosage of LMWH should be given. Enoxaparin should be given at a rate of 1 mg/kg OD rather than 40 mg OD for all, or Fondaparinux 2.5 mg s/c OD (in high-risk groups).

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Moderate illness

They are patients with pneumonia (clinical/radiology) with no respiratory distress, SpO2 >90%.

1. Consider re-estimating D-dimer on day 4 or earlier, if there is respiratory worsening (if D-dimer is escalating, consider CTPA, 2D echo, lower limbs doppler, or LWMH in empirical clinical doses where imaging is not possible, given there is no contraindication).
2. Use nasal prongs oxygen supplementation for patients with a SpO2 of 90-94 per cent on room air, Enoxaparin 40 mg s/c OD or Fondaparinux 2.5 mg s/c OD injection.
3. Injection co-amoxiclav, 1.2 gm IV TDS +/-, tablet azithromycin 500 mg-1 tab OD (if bacterial infection suspected) can be used.
4. Consider dexamethasone 6 mg IV OD (if oxygen supplementation is required) or Methylprednisolone 40mg to 120 mg /day.
5.  Injection remdesivir 200 mg IV on day 1, followed by 100 mg IV OD (days 2 to 5). Consider remdesivir in patients over the age of 18 who are RT-PCR positive for SARS-CoV-2.
6. According to anticoagulant guidelines, all mild and serious symptomatic COVID-19 patients over the age of 18 who have a clinical presentation of pulse rate >110, RR>24, and SpO2 of 94 per cent, whether hospitalised or at home, should undergo anticoagulant prophylaxis until bleeding complications or reduced platelet counts make it contraindicated.
7. Antivirals are used to treat the virus period in the symptomatic stage, anti-inflammatory steroids are used to treat the immune system in the inflammatory phase, and early anticoagulants are used to prevent thrombophilia in the pulmonary phase.
8. In COVID-19 patients with a low-grade fever, a dry cough, or a sore throat, pneumonia should be suspected in-home care situations to prevent potential emergencies. If pneumonia is suspected based on the history and clinical diagnosis of the condition, or pneumonia is reported by a chest X-ray or CT scan, LMWH should be started on day  5 or on day 1 in the case of high-risk patients.
9. Pneumonia can be confirmed by chest ultrasound, oxygen saturation of 94 per cent or less on room air, or a ratio of arterial oxygen partial pressure to fractional inspired oxygen (PF Ratio) of 300 mm Hg or less within 10 days of symptom onset.

Remdesivir

Remdesivir plays a key role in the first ten days when CT severity score is more than 8 on the CT intensity scale (out of 25). It reduces the duration of complications but has little effect on mortality.

1. The drug can be used in patients with a CT severity score of less than 8, thick consolidation (rather than GGO), high fever without elevated CRP (viremia phase), particularly in the elderly, and co-morbidities even with a normal CT.
2. Hospitalisation is essential for all age ranges to begin remdesivir treatment. Remdesivir is approved by the FDA for the treatment of COVID-19 in paediatric patients weighing 3.5 kg to 40 kg or aged <12 years and weighing 3.5 kg and hospitalised.
3. There is no information available regarding maternity or breastfeeding safety. It is advised to avoid if the patient has hepatic cirrhosis, or if the alanine aminotransferase or aspartate aminotransferase levels are higher than five times the upper limit of average, has established serious renal dysfunction (glomerular filtration rate <30 mL/min per 1.73 m²) or is on continuous renal replacement therapy, haemodialysis, or peritoneal dialysis).
4. Many centres, however, are using remdesivir in compensated cirrhosis patients, renally affected patients, and haemodialysis patients with close supervision and no significant problems.
5. It is better to use it early as the saturation starts to decline earlier than the oxygen requiring stage (especially if the 6-minute walk test is positive), with steroids and heparin along with it, as per your decision and individualised to your patient, and wait for 3-4days for the clinical improvement.
6. If remdesivir is used after the patient desaturates with higher oxygen requirement, it may not help.

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Favipiravir

Tablet favipiravir 1800 mg BD (day 1) followed by 800-1000 mg BD (days 2-14) can be prescribed. Whether or not to take favipiravir at this time is entirely dependent on personal experiences and preferences. Use your own critical thinking. (Think of favipiravir in SARS-CoV 2 RT-PCR confirmed cases of age >18, SpO2 <94 per cent on room air, and symptom onset <12 days.)

Favipiravir seems to have in vitro activity against SARS-CoV-2 and can play a role in COVID-19. However, whether sufficient drug levels can be reached in vivo to suppress SARS-CoV-2 is unknown. This drug has been used in a few clinical studies in people with COVID-19. Oral favipiravir was correlated with a faster time to viral clearance and better chest imaging than lopinavir/ritonavir in a non-randomised, open-label study in China (in both groups, the oral antiviral was given with aerosolised alpha-interferon). However, since the sample was limited and not randomised, concluding that favipiravir is successful in treating COVID-19 was inconceivable.

In patients with COVID-19, a randomised, open-label trial compared favipiravir to umifenovir, an antiviral authorised in Russia and China. On day seven, there was no substantial difference in therapeutic recovery rates between the two groups. Favipiravir tended to have an effect in the subgroup of people who did not have a serious disease, although further research is required. An investigative clinical trial in China randomised 30 COVID-19-positive hospitalised adults into one of three groups: baloxavir marboxil, favipiravir, or placebo. There was no evidence that favipiravir (or baloxivir) had any impact on viral clearance. Favipiravir is currently being used in clinical research for the management of COVID-19.

Warning: Do not use in patients with long QT or PR intervals, second- or third-degree heart block, or arrhythmias, women who are pregnant or breastfeeding, in people with blood ALT/AST levels >5 times the upper limit of average on laboratory findings, H/O alcohol or drug addiction in the previous 5 years.- incomplete

Lopinavir/ritonavir

The IDSA advisory panel advises against using the lopinavir/ritonavir mixture in admitted COVID-19 cases. (Strong recommendation, moderate certainty of evidence)

Steroids precautions 

Steroids should be specifically discouraged in:

• Asymptomatic
• Minimal clinical signs lasting for a week
• CT score below 8 and illness period around 5 to 7 days
• Viral replication stage (high fever with normal CRP and CT)

Steroids should be preferred in all moderate and severe cases; in patients with an SPO2 of less than 94, regardless of the day on which symptoms began. Any of these patients can receive daily doses of 40–120 mg methylprednisolone or 6 mg dexamethasone.

Steroid's role in mild COVID19 disease: Mild cases in the second week of fever, malaise, myalgia, headache, and nausea (all of which are indicative of hyper-inflammation) can be treated with a low dose of methylprednisolone (4–16 mg per day) (or equivalent another steroid for 5 to 7 days). This view argues solely on the basis of expert opinion.

To counteract immune dysregulation, the anti-inflammatory steroid should be started early in the pulmonary process. The optimal time to initiate steroids is after the eighth day of symptoms when the virus has a low propensity for replication and the inflammatory reaction is persistent. It is critical to administer steroids at the appropriate time, with the appropriate medication, at the appropriate dosage, and for the appropriate period.

Methylprednisolone is superior to dexamethasone, and prednisolone is superior to dexamethasone. Methylprednisolone penetrates the lungs and binds to the glucocorticoid receptors more effectively than any other steroid, resulting in the strongest anti-inflammatory effect.

Cytokine storm

Warning for cytokine storm (during the seventh or eighth day of disease) should be ruled out in patients with moderate disease with some important features:

• Unresolved fever
• Hyper ferritinemia
• Cytopenia
• Lung involvement (including ARDS)

Hint for the cytokine storm: If the patient develops breathlessness in the second week (despite previously normal CT), the CRP rises above 50, the CT worsens, or the patient develops a fever in the second week, it indicates an imminent cytokine storm. Daily CRP evaluation and dose correction of steroids are critical in this case.

Treatment of cytokine storms: Methylprednisolone pulse 250 mg to 1000 mg per day for 3 days, Tocilizumab.

Monitoring: Clinical signs/symptoms, SpO2, CRP, D-dimer, serum procalcitonin.

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Severe illness

Evaluate by the signs of pneumonia and any other signs like:

• SpO2 less than 90% on room air
• Respiratory discomfort (use of accessory muscles)
• RR >30/min
• CT imaging indicating fast advancement (>50%) within 24-48 hours

Requirements:

1. Oxygen delivery by nasal cannula, face mask, Venturi mask, or mask with reservoir bag ± NIV*
2. Broad-spectrum empirical antibiotic therapy for any potential superadded infections (↑S.PCT/significant leukocytosis/leucopenia) like:
   1. Inj Dexamethasone 6 mg IV OD (days 1 to 10)
   2. Inj Enoxaparin 40 mg s/c OD or Inj Fondaparinux 2.5 mg s/c OD
   3. Inj Remdesivir 200mg IV day 1, followed by 100 mg IV OD (days 2 to 5) or tab favipiravir 1800 mg BD (day 1) followed by 1000 mg BD (days 2 to 14)
   4. Tocilizumab could be considered
   5. Tocilizumab (400 mg IV over 60 minutes using a dedicated IV line by infusion set) (8 mg/kg body weight; limit up to 800 mg) [Other agents should not be infused into the same line]

If the CRP, D-dimer levels continue to rise after 12 hours, the dose may be repeated after a multidisciplinary team consultation. Itolizumab (made in India) is currently undergoing clinical trials and can be used instead of Tocilizumab if it is not available. It is less expensive.

Tocilizumab can be administered in the following patients:

1. Patients over 18 years old 
2. If SARS-CoV-2 disease is diagnosed using a real-time polymerase chain reaction (PCR)
3. Lung infiltrates are present when the PaO2/FiO2 ratio is between 200 and 300 mmHg
4. The appearance of at least one of the following parameters indicates an exaggerated inflammatory reaction:
   1. Serum CRP greater than or equal to 10 mg/dl
   2. At least one body temperature measurement >38°C in the previous two days
   3. CRP levels are at least twice as high as they were before
   4. With worsening hypoxia despite 24-48 hours of corticosteroids and supportive treatment
   5. D-dimer > 2500 ng/ml or S. ferritin >500 ng/ml

Tocilizumab can only be used under the right circumstances, such as where steroid resistance is increasing or extreme hypoxia is present, and inflammatory pathology is suspected as the cause (level 2C evidence). It is not recommended for all patients.

Note: Before administering Remdesivir and Tocilizumab, the patient's attendants must be given a prescription factsheet and proper informed consent must be obtained.

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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a practising super specialist from New Delhi.