Anti-Inflammatory Agents and Corticosteroids in COVID-19: What’s the Controversy?

Authors: Tyler Siekmann, MD (Emergency Medicine Resident, Carolinas Medical Center, Charlotte, NC) and Kathryn T. Kopec, DO (Emergency Medicine Attending, Medical Toxicologist, Carolinas Medical Center, Charlotte, NC) // Reviewed by: Cynthia Santos, MD (@Cynthia Santos); Alex Koyfman, MD (@EMHighAK); Manny Singh, MD (@MPrizzleER), and Brit Long, MD (@long_brit)

With COVID-19 rapidly spreading, many studies are underway evaluating medical therapies. Our first post evaluated anti-viral agents for treating COVID-19. You can view this post here. This post will evaluate symptomatic therapies, including NSAIDs and corticosteroids, and the controversy surrounding these medications.

 


Anti-Inflammatory Agents: NSAIDs

There has been recent heavy debate on the use of anti-inflammatory drugs in the treatment of SARS-CoV-2 infection. In March 2020, The Lancet published a study by Roth et al. mentioning a theoretical and anecdotal increase in angiotensin converting enzyme 2 (ACE2) receptor expression with ibuprofen use.1 The article did not cite any specific studies substantiating this claim. ACE2 is an enzyme commonly found on type II pneumatocytes that typically degrades angiotensin II, playing a vital role in the renin angiotensin-aldosterone system.2 The ACE2 receptor has been identified as the primary receptor facilitating SARS-CoV-2 (COVID-19) viral infection in the lungs.3

Following the publication of the Roth et al. article, the French Minister of Health Olivier Veran made a public claim that all NSAIDs should be avoided in the treatment of COVID-19 stating, “Anti-inflammatory drugs could be an aggravating factor for the infection”. A World Health Organization (WHO) spokesperson soon after stated the agency was “looking into this to give further guidance” stating “in the meantime we recommend using [acetaminophen], and not using ibuprofen as a self-medication”.  Three days later the BMJ published an article supporting the avoidance of NSAIDs based on anecdotal evidence from Europe including a report of four healthy, young patients that apparently had poor outcomes.4 These reports are unsubstantiated, and any such case series have not been published. The WHO has now retracted their recommendation to avoid NSAIDs citing a lack of evidence. The update states, “We do not currently believe there is any proven scientific evidence linking over-the-counter use of ibuprofen to the aggravation of COVID-19.”5

Concerns regarding NSAID use in COVID-19 stem primarily from ibuprofen’s theoretical up-regulation of ACE2 receptors, the proven primary binding receptor for SARS-CoV-2.3

What evidence exists suggesting such ACE2 up-regulation actually occurs?

On literature review, the only article found claiming up-regulation of ACE2 receptors with ibuprofen use comes from a 2015 China study from Qiao W et al.6 This study showed slight ACE2 up-regulation in diabetic rats after receiving ibuprofen for 8 weeks.6 Semi-quantitative analysis showed ACE2 levels in diabetic rats receiving ibuprofen had about 1.5x ACE2 receptor expression compared to diabetic rats not receiving ibuprofen.6 No human studies have been performed showing similar data, and no studies have been performed in regard to SARS-CoV-2 viral infection.

Interestingly, some conflicting 2006 literature does exist suggesting that the NSAID indomethacin may have potent anti-viral activity against the original SARS-CoV virus. In this study, indomethacin reduced SARS-CoV viral loads both in vitro and in vivo, in some instances reducing viral yield by 99%.7

Currently, the FDA states they are not aware of data associating NSAID use with worsening COVID-19 symptoms, but that “the pharmacological activity of NSAIDs in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.”8


Corticosteroids:

Corticosteroid medications are potent anti-inflammatory agents essential to the treatment of many pro-inflammatory pathologies including interstitial lung disease, ARDS, and systemic vasoplegic shock. Corticosteroid medications were widely used for treatment of prior respiratory viral outbreaks including SARS-CoV-1 and MERS-CoV. In February 2020, The Lancet published a literature review clarifying risks and benefits of corticosteroid treatment in these outbreaks.9 Observational studies in 309 MERS patients demonstrated no mortality benefit and prolonged viral shedding with corticosteroid use.10 Meta-analysis data from SARS-CoV patients demonstrated no mortality benefit and multiple harmful side effects including increased viral shedding after steroid use.11 Based on this information the WHO formally recommends against corticosteroid use for treating COVID-19 pneumonia.12

In severe cases of COVID-19 pneumonia that progresses to ARDS, corticosteroids have been utilized for refractory ARDS. JAMArecently published an observational study of 201 COVID-19 positive ARDS patients treated with methylprednisolone compared to those not receiving corticosteroids. While a small cohort, this study did demonstrate improved survival after methylprednisolone therapy (61.8% vs. 42.0% survival respectively, p=0.003).13 Currently the Society of Critical Care Medicine recommends using corticosteroids for mechanically ventilated patients with ARDS and respiratory failure.14 Further data on this matter will be available after the conclusion of a randomized control trial currently underway in China with results anticipated in May 2020 (NCT04273321).


Bonus: What about ACE inhibitors and/or ARBs?

Due to the mechanism of entry of COVID-19, it has been theorized that ACE inhibitors and ARBs may increase the ACE2 expression in worsen disease severity and infectivity. The American Heart Association, the Heart Failure Society of America, and the American College of Cardiology (ACC) issued a joint statement urging patients with cardiovascular disease diagnosed with COVID-19 to continue taking their ACE inhibitors and ARBs as prescribed.15 The European Society of Cardiology recommends that patients should continue their usual anti-hypertensive therapy “because there is no clinical or scientific evidence to suggest that treatment with ACEI/ARBs should be discontinued because of the COVID-19 infection.”16

Currently, there are no data demonstrating a beneficial or adverse outcome with ACE inhibitors or ARBs in patients with COVID-19.


Key Points:

  • The current literature against NSAID use is theoretical and insufficient to support not using NSAIDs.
  • It is reasonable to use acetaminophen as the first line anti-pyretic for suspected COVID-19 patients as the drug is safe, well understood and widely available; however, there is NO contraindication to using NSAIDs.
  • Providers should continue using corticosteroid medications for clinical indications independent of COVID-19 infection such as asthma exacerbation, COPD exacerbation and refractory septic shock.
  • Avoid routine use of corticosteroid medications in treating COVID-19 pneumonia.
  • Providers may consider use of methylprednisolone or dexamethasone as salvage therapy in COVID-19 patients with refractory ARDS.
  • Currently, there are no data demonstrating a beneficial or adverse outcome with ACE inhibitors or ARBs in patients with COVID-19.

 

References/Further Reading:

  1. Roth M, Fang L, Karakiulakis G. Are patient with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet. 2020; doi:10.1016/S2213-2600(20)30116-8.
  2. Tikellis C, Bernardi S, Burns WC. Angiotensin-Converting Enzyme 2 (ACE2) is a key modulator of the Renin Angiotensin System in health and disease. Int J Pept. 2011. Jan;20(1):62-8.
  3. Guo YR, Cao QD, Hong ZS et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak. Military Medical Research. 2020 Mar 13;7(1):11.
  4. Day M. Covid-19: Ibuprofen should not be used for managing symptoms, says doctors and scientists. BMJ. 2020 Mar 17;368:m1086.
  5. Agence France-Presse. Updated: WHO Now Doesn’t Recommend Avoiding Ibuprofen for COVID-19 Symptoms. AFP. Mar 17 2020. https://www.sciencealert.com/who-recommends-to-avoid-taking-ibuprofen-for-covid-19-symptoms.
  6. Qiao W, Wang C, Chen B et al. Ibuprofen attenuates cardiac fibrosis in Streptozotocin-induced diabetic rats. Cardiology.2015;131(2):97-106.
  7. Amici C, Di Caro A, Ciucci A et al. Indomethacin has a potent antiviral activity against SARS coronavirus. Antivir Ther.2006;11(8):1021-30.
  8. FDA. https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-patients-use-non-steroidal-anti-inflammatory-drugs-nsaids-covid-19
  9. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCov lung injury. Lancet. 2020 Feb 15;395(10223):473-475.
  10. Arabi YM, Mandourah Y, Al-Hameed F et al. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 2018 Mar 15;197(6):757-767.
  11. Stockman LJ, Bellamy R, Garner P et al. SARS: systematic review of treatment effects. PLoS Med. 2006 Sep;3(9):1-7.
  12. World Health Organization. Clinical management of severe acute respiratory infection when COVID-19 disease is suspected. WHO Interim Guidance. 2020 Mar; WHO/2019-nCoV/clinical/2020.4.
  13. Wu C, Chen X, Cai Y et al. Risk factors associated with acute respiratory distress syndrome and death in patients with Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 Mar 13. Doi: 10.1001/jamainternmed.2020.0994.
  14. Alhazzani W, Hylander M, Arabi YM et al. Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19). Pre-publication Critical Care Med. 2020 Mar.
  15. https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19
  16. https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang

 

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