CME INDIA Presentation by Dr N K Singh, Admin.

Pyrexia in COVID-19 is not an easy to tackle problem in many cases. Remember it is not only thermal dysregulation, it is cytokine fever. Many cases are reported who get fever post discharge for 2 to 3 weeks. How to deal such cases? Why is it happening?

The Way Ahead

You need a drug which reduces fever and CRP

• In post-COVID-19 patients, when an anti-inflammatory is required, you need a drug which reduces fever and CRP. It should be steroid-sparing.

Long COVID-19 is a persistent cytokine disease.

• We may get usually 2 patterns of fever:
  • 1st group having fever persisting into the second week of illness,
  • 2nd while the second group displaying a saddleback pattern of fever, similar to that previously observed in dengue.
• Cases with prolonged fever are defined as patients with fever lasting >7 days. Cases with saddleback fever are defined as patients with recurrence of fever lasting <24 hours, after effervescence, beyond day 7 of illness. 
• The significance of these 2 patterns of fever with regards to the development of complications is unknown.
• A dysregulated immune response in COVID-19 has been postulated to lead a deleterious cytokine storm.

Principles of managing Fever

• During the viral replication phase, we should not choose drugs that help the virus to replicate.
• Divide COVID-19 illness into two phases:
  1. Viral (RT PCR) illness.
  2. Inflammatory (cytokine – CRP) illness.
• In the first phase of the infection, we have to see the presentation, what the virus is doing to the body and in the second phase, what the body does to the virus.

Pearls of Wisdom

• Once cytokines are released, the virus has no role to play. Responses of Th1, Th2 and Th17 cells decide the future action. If more of the good cytokines are released, the phenomenon is short-lived.
• CRP starts rising within 4-6 hours; it peaks at 36-48 hours and comes down to normal within 17 hours.
• Therefore, CRP should become normal by Day 4. If does not return to baseline, this means shifting from viral phase to cytokine wave.
• By the 10th day, CRP should be less than 10.
• If more than 10, then the body is under cytokine control → recurrent inflammation → symptoms and cytokine crisis.

Use CRP as your Torch bearer

• From 9-90 days, there can be two types of illnesses: CRP normal or CRP more than 2.
• If CRP is less than 2, there is residual damage, which is autonomic dysfunction.
• If CRP is more than 2, this is persistent cytokine state, where an anti-inflammatory drug is needed (HCQ, mefenamic acid, steroid, colchicine). If there is fever, then mefenamic acid is the drug.

What to do when CRP is persistently high, there are four options:

1. Mefenamic acid.
2. Indomethacin.
3. Naproxen.
4. Nimesulide.

Paracetamol

• It increases IL-1β, reduces TNF- α; it does not reduce cytokine fever.
• Paracetamol reduces fever but not CRP.
• Paracetamol (PCM) does not inhibit the synthesis of prostaglandins in the periphery; it does not possess any anti-inflammatory action.

Mefenamic

• It acts on IL-1β, -6 and -18, TNF-α and NLRP3. Is drug of choice for COVID-19 inflammation (including inflammation induced fever).
• Mefenamic acid is a potent inhibitor of cyclooxygenase. It has a central as well as peripheral analgesic action.
• Mefenamic acid reduces both fever and CRP.
• Of these, first is mefenamic acid, which can be given for 3 months; nimesulide is approved only for two weeks, then come indomethacin and naproxen.
• Mefenamic acid can be used safely right from the first week of infection where there is a tendency to choose steroids to bring down the fever, which can be detrimental.
• It gives the effect of antiviral, anti-inflammatory and antipyretic. The inhibitory effect of mefenamic acid against RNA viruses has been estimated as 90% at a concentration of 30 μM.
• Mefenamic acid can be started from Day 1 itself; it will help bring down the fever and also reduce inflammation.
• The virus requires serine protease to enter the cells. Serine protease inhibitors are required in such cases.
• Mefenamic acid is a serine protease inhibitor and this way it can work also as an antiviral.
• Since it is also an anti-pyretic, its main role may be of bringing down the fever but its action as an anti-viral, as a supportive medicine can very useful.

Diclofenac

• It is anti-inflammatory.
• it is not a very good antipyretic.

Ibuprofen and ketoprofen

• These have been shown to upregulate ACE2 receptors thereby increasing the viremic load.
• IL-6 reduction with ibuprofen is not as evident as seen with other drugs. Ibuprofen is not contraindicated.
• The current recommendation is that those patients who are on ibuprofen should continue with it.

CME INDIA Learning Points

• Clinical use of mefenamic acid has generally declined in an era where other NSAID use has flourished.
• While having modes of action and general toxicities similar to other NSAIDs, mefenamic acid, as a member of the fenamates.
• It possesses some unique in vitro effects that have the potential to distinguish this agent from others. 
• Its use as anti-pyretic in COVID-19 is not popular in India, but its profile looks better.
• In patients with prolonged fever, close monitoring for deterioration should be instituted, while patients with saddleback fever who remain well and do not require supplemental oxygenation are unlikely to require close monitoring in the hospital.
• Interestingly, there are also higher plasma levels of IL-1RA in patients with prolonged fever compared with control patients. Despite being an anti-inflammatory cytokine that acts as a modulator for the IL-1 pathway. IL-1RA has been found to be also associated with increased viral load, lung injury, and severe clinical outcomes
• IL-1RA is naturally secreted by human hosts to limit the activity of IL-1 during hyperinflammation.
• The elevation of circulating IL-1RA may reflect overactive IL-1 activation, which has been reported to associated with severe outcomes in COVID-19.

CME INDIA Tail Piece

• Which drug to choose should be left on the treating doctor. Now the personal experience of the doctor is all that matters.
• While remdesivir may not reduce mortality, it does reduce severity of infection. In severe cases, the viral load definitely comes down. It has been given emergency use authorization in India.

Source:

1. Based on Minutes of Virtual Meeting of CMAAO NMAs on “CMAAO Update & Covid-19 and anti-inflammatory drugs on 27th October, 2020, Saturday
2. Use of Mefenamic Acid as a Supportive Treatment of COVID-19: A Repurposing Drug Article in International Journal of Science and Research (IJSR) · June 2020 DOI: 10.21275/SR20530150407
3. Open Forum Infectious Diseases, Volume 7, Issue 9, September 2020, ofaa375, https://doi.org/10.1093/ofid/ofaa375.

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