By A/Prof Jane Fitzpatrick, jane.fitzpatrick@unimelb.edu.au

So the twittisphere is alive with experts and casual observers making comments about the use of medications in the wake of the COVID-19 pandemic.

In an unreferenced news article in The BMJ, Michael Day said, “Scientists and senior doctors have backed claims by France’s health minister that people showing symptoms of COVID-19 should use paracetamol (acetaminophen) rather than ibuprofen, a drug they said might exacerbate the condition.”³ This was based on comments from an infectious diseases doctor from France, who noted that 4 young patients had taken NSAIDs and had had severe respiratory problems in association with COVID-19 infection. Whilst it is possible there may be an association it has never been a good epidemiological premise to consider such a small cohort and make sweeping recommendations. So is there any basis for this argument? Should we as sports & exercise medicine physicians be more cautious about prescribing NSAIDs for musculoskeletal conditions in the setting of rising COVID-19 cases?

Paracetamol [Aus/UK]/Acetaminophen [North America] as first line?

The simplest answer to this conundrum, would be to recommend the use of Paracetamol as the first line drug in the treatment of viral infections. But where did this statement come from? In 2009, Bancos et al² studied the effect of Ibuprofen, Indomethacin, aspirin, Naproxen and paracetamol on antibody production in knockout mice. They found that all of these, including paracetamol reduced antibody production in both Immunoglobulin M (IgM) and Immunoglobulin G (IgG). Ibuprofen had a more marked effect than the other NSAIDs or paracetamol. The authors were not however, able to determine whether this was a Cox 1 or 2 related pathway.

If this is correct, we may assume that the effect may be marked in B cell mediated responses such as to bacterial pneumonia. This has been demonstrated in two studies in children– most recently in 203 children who had community acquired bacterial pneumonia. Researchers aimed to determine whether any factors could predict the development of local complications.⁷ Both paracetamol and ibuprofen were found to be predictive for complications, although the odds ratio was more marked for the ibuprofen. Of note, the authors found that immunisation with pneumococcal vaccine markedly reduced the likelihood of complications of pneumonia. These findings were backed up by a recent systematic review¹⁰ in both adults and children with community acquired bacterial pneumonia.

There has been no evidence in published work to date that NSAIDs or paracetamol are associated with adverse outcomes in COVID-19 and both paracetamol and NSAIDs have the potential to reduce the immunological response. What scant evidence there is may suggest Ibuprofen may be the drug to be cautious with.

What do we know about the immunology of COVID-19?

Is that the end of the story?  We are fortunate to have insights into the immunology of the response to COVID-19 from the Doherty Institute in Melbourne, published this week. In their article Thevarajan et al⁹ tested a patient returned from Wuhan with COVID-19 from the development of symptoms for 20 days. This patient did not receive care in ICU, nor did she require other medications. They found “Increased antibody-secreting cells (ASCs), follicular helper T cells (TFH cells), activated CD4+ T cells and CD8+ T cells and immunoglobulin M (IgM) and IgG antibodies that bound the COVID-19 causing coronavirus SARS-CoV-2 were detected in blood before symptomatic recovery.” This strong T cell mediated response was not accompanied by an increase in pro-inflammatory cytokines, which is consistent with the work of Huang et al⁶ who found that  “Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα”.

The issue at hand is avoiding the inflammatory cytokine response that ICU patients are more likely to have. There has been concern that corticosteroids may not be as helpful in the ICU COVID-19 setting. A recent letter in the Lancet by Russell et al⁸ explored the evidence for the use of corticosteroids in COVID-19 and found “the available observational data suggest increased mortality and secondary infection rates in influenza, impaired clearance of SARS-CoV and MERS-CoV, and complications of corticosteroid therapy in survivors.” This advice relates to the use of corticosteroids in ICU and there has not been any suggestion that patients requiring long term corticosteroids should cease their medication particularly given the potential that would have to exacerbate their underlying conditions.

This has led to a rapid search for medication that may help in the management of COVID-19 pneumonia and acute respiratory distress syndrome.

Considering the previous research it is interesting that Amici et al¹ found that Indomethacin (an NSAID) had profound anti-viral effects on SARS-CoV. The effect was due to blocking viral RNA synthesis. Other NSAIDs have not been studied in this way but it is interesting to see the potential for a positive response to Indomethacin. This is really the direction research is heading now, to find anti-viral agents or to find agents that will block the pro-inflammatory cytokines. There has been some promising results using chloroquine, arbidol, remdesivir, and favipiravir and Dong et al⁴ provide insight into the possible mechanisms of action. It does look as though the anti-viral agents may be of value in COVID-19.

What about corticosteroid injections?

Finally, as sport & exercise medicine physicians should we be using corticosteroid injections? Since a patient can be infected with COVID-19 but remain asymptomatic for 10 days we could inject a patient who was already infected without being aware of this. So, if you were to do an injection, how long would it be having a pharmacological effect after you injected it?

There is not much research available in this area. It is plausible that the glucocorticoids injected for musculoskeletal conditions may have an impact on the potential B and T cell responses. It is unlikely this would be profound or prolonged as most patients have only one injection. Corticosteroid injections are performed locally with a view to managing local symptoms but it is important to recognise that the corticosteroid is absorbed from the local site and there is hypothalamic pituitary axis suppression of ACTH and cortisol for up to 4 weeks following the administration of a single injection. Friedly et al⁵ studied this effect in spinal injections and found that methylprednisolone (DepoMedrol) and triamcinolone (Kenacort) injections resulted in pituitary suppresion in 41% of patients at 3 weeks. This effect was not demonstrated with betamethasone (Celestone) or dexamethasone (Decadron) compared to controls. It would be sensible–if there was a need for a corticosteroid injection–to consider the use of betamethasone (Celestone), other management options or to defer the injection until the risk associated with this pandemic is reduced.

Take home messages:

1. Ibuprofen, Indomethacin, aspirin, Naproxen and paracetamol/acetaminophen all reduced antibody production, but Ibuprofen has the greatest effect
2. Both paracetamol and ibuprofen use are predictors for more respiratory problems with bacterial community acquired pneumonia, but nothing is known re COVID-19
3. The use of vaccines e.g. pneumococcal vaccine reduces this risk; the use of the flu vaccine is also likely to reduce the risk of co-morbidity in COVID-19
4. The use of anti-virals and cytokine blocking agents is being investigated for COVID-19 pneumonia
5. If there is an indication for a corticosteroid injection, consider the use of betamethasone (Celestone), consider other management options or defer the injection until the risk associated with this pandemic is reduced.

***

A/Prof Jane Fitzpatrick, University of Melbourne jane.fitzpatrick@unimelb.edu.au

References

1. Amici CDC, A.; Decaro, N.; Buonavoglia, C.; Ciucci, A.; Chiappa, L.;Castillett, C.; Santoro, G. Indomethacin has a potent antiviral activity against SARS coronavirus. Antiviral Therapy. 2006;11:1021–1030.
2. Bancos S, Bernard MP, Topham DJ, Phipps RP. Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells. Cell Immunol. 2009;258(1):18-28.
3. Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. Bmj. 2020.
4. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther. 2020;14(1):58-60.
5. Friedly JL, Comstock BA, Heagerty PJ, et al. Systemic effects of epidural steroid injections for spinal stenosis. Pain. 2018;159(5):876-883.
6. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet. 2020;395(10223):497-506.
7. Krenke K, Krawiec M, Kraj G, Peradzynska J, Krauze A, Kulus M. Risk factors for local complications in children with community-acquired pneumonia. Clin Respir J. 2018;12(1):253-261.
8. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. The Lancet. 2020;395(10223):473-475.
9. Thevarajan I, Nguyen THO, Koutsakos M, et al. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nature Medicine. 2020.
10. Voiriot G, Philippot Q, Elabbadi A, Elbim C, Chalumeau M, Fartoukh M. Risks Related to the Use of Non-Steroidal Anti-Inflammatory Drugs in Community-Acquired Pneumonia in Adult and Pediatric Patients. J Clin Med. 2019;8(6).