Like Drinking from a Firehose

Trying to keep up with the evolution of steroids during COVID-19 isn’t easy.

Since our world has been turned upside down by the COVID-19 pandemic, many of us have spent countless hours trying to process the massive amounts of data being published worldwide in attempt to stay ahead of the surge. One quick search in PubMed for “COVID-19” shows just how much has been accomplished since December, with more than 50,000 papers published. It’s quite impressive and keeping up with the literature may be likened to drinking out of a firehose.

No matter how much you read, there’s always something else to consider, and many aspects are anything but straightforward due to unknowns. When evaluating corticosteroid use since the start of the pandemic, just one of the many moving parts of COVID-19 treatment, recommendations have changed significantly.

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Why consider steroids?

While we are still learning about COVID-19 and potential treatment modalities, much of our initial management has been extrapolated from that of other disease states and viral infections.

COVID-19 has been associated with a pro-inflammatory “cytokine storm” that can result in acute respiratory distress syndrome (ARDS), respiratory failure, and death in those with severe disease.[¹] Steroid use in patients with moderate to severe non-COVID-19 ARDS is debated, but has been shown in some studies to have a mortality benefit and reduced ventilator-free days when initiated early.[^2,3]This was further supported by the most recent and largest DEXA-ARDS Trial published earlier this year.[⁴]

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Conversely, corticosteroid use in similar coronavirus infections, such as Severe Acute Respiratory Syndrome (SARS) and Middle Eastern Respiratory Syndrome (MERS), has been controversial. Most evidence stems from small, observational studies, some of which showed mortality benefit and decreased length of stay.[^5,6] Others identified increased viral load,[⁷] inflammation that persisted despite viral clearance,[^8-10] and associated adverse events including diabetes, psychosis and avascular necrosis.[^11-13]

Based on these data, several organizations developed treatment guidelines supporting corticosteroid use only in those patients with ARDS while on mechanical ventilation and refractory shock.[^14-16] Additionally, the Chinese Thoracic Society recommended low dose corticosteroids for no more than seven days, but this was based primarily on anecdotal evidence and firsthand experience with treating COVID-19 patients.

Trial by fire with steroids in COVID-19

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Since the original corticosteroid guideline statements were published, we’ve had the benefit of treating more COVID-19 patients to evaluate steroid use. Until last month, we had many small studies describing incidental corticosteroid use in COVID-19 patients, but only a few trials that sought to evaluate outcomes. The majority of these are retrospective, observational, or open-label studies.

Two retrospective studies were unable to identify a benefit using corticosteroids, with one suggesting potential harm.[^17,18 ] The remaining studies all suggested benefit to using corticosteroids concomitantly with standard of care. A multicenter, pre-post quasi-experimental study out of Detroit evaluated the addition of methylprednisolone versus standard of care for a duration of three to seven days depending on severity of illness.

The composite endpoint of escalation to the ICU, progressive respiratory failure requiring mechanical ventilation, or in-hospital all-cause mortality occurred at a statistically significantly lower rate in the corticosteroid treatment arm.[¹⁹]

Additionally, the GLUCOCOVID-19 Trial found that methylprednisolone plus standard of care was associated with a reduced risk of the composite endpoint of death, ICU admission, or requirement of non-invasive ventilation versus standard of care alone.[²⁰] In other studies, steroids were also associated with faster time to defervescence, oxygen saturation normalization, CT improvement and intubation avoidance.[^21,22]

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The RECOVERY Trial Preliminary Report, the largest randomized, controlled, open-label trial evaluating corticosteroid use in COVID-19, was published in late June.[²³] Trial investigators randomly assigned 6,425 patients to receive either usual care plus oral or intravenous dexamethasone 6 mg daily for up to 10 days versus usual care alone. The primary outcome of 28-day mortality was met, with 22.9% in the dexamethasone treatment arm versus 25.7% in the usual care arm (NNT 36).

A pre-specified analysis of the primary endpoint evaluated respiratory status, which revealed that the mortality benefit was driven primarily by those patients who required mechanical ventilation (NNT 9), as well as those who required oxygen without mechanical ventilation (NNT 35). However, those patients who received dexamethasone without any oxygen supplementation appeared to do worse.

Just when almost every guideline statement was updated to recommend dexamethasone use based on the RECOVERY Trial, several additional randomized controlled trials and a meta-analysis were published in the Sept. 1 issue of JAMA. The prospective meta-analysis conducted by the WHO REACT Working Group included RECOVERY and six other randomized, controlled trials that were conducted in 12 countries: DEXA-COVID-19 19, CoDex, CAPE COVID-19, COVID-19 STEROID, REMAP-CAP and Steroids-SARI.[²⁴]

A total of 1,703 patients were included. The primary outcome was all-cause mortality at 28-days when comparing steroids versus standard of care, with a secondary outcome evaluating serious adverse events. Steroid dosing regimens were evaluated and characterized as low and high dose dexamethasone, low dose hydrocortisone and high dose methylprednisolone.

In short, 32.8% patients who received corticosteroids versus 41.5% of those who received only standard of care died at 28 days (NNT 12).  Serious adverse events occurred in 18% of patients who received corticosteroids versus 23% in those who did not (NNH 20). Regarding time of initiation, the evidence indicates that there may be more benefit with starting steroids after seven days rather than earlier in the clinical course. The ideal corticosteroid dose and treatment duration could not be elucidated by this study, but overall, it appears that high dose corticosteroids are not necessarily more effective than low dose.

The best steroid for the job

While we are still identifying the most appropriate corticosteroid for COVID-19 treatment, consideration of individual steroid properties may help identify an ideal agent. Each steroid is slightly different than the next, with varying glucocorticoid and mineralocorticoid properties, as well as potency. Just as a refresher, mineralocorticoid receptor stimulation leads to sodium retention, which can affect fluid status and potentially lead to volume overload. Glucocorticoid receptor stimulation regulates several things, including immune cell activation.[²⁵]

In the case of COVID-19, we are relying on glucocorticoid properties, and theoretically would prefer to avoid mineralocorticoid properties due to potential volume overload in sick ARDS patients. As dexamethasone is a potent, pure glucocorticoid agent with a long half-life (36 to 54 hours) allowing for single daily dosing and auto-tapering, it seems that it may be an ideal corticosteroid to consider for this indication. These properties should also be weighed with common adverse events, including but not limited to agitation, psychosis, hyperglycemia, adrenal suppression and immune suppression that may lead to infection.[²⁵]

The day after the RECOVERY Trial was published, dexamethasone went on national backorder due to a demand surge. As such, we had to make do with other equivalent steroids to achieve similar effects. Some equivalents that were commonly used are methylprednisolone 32 mg, prednisone 40 mg and hydrocortisone 160 mg daily in divided doses based on half-life.

Many EM providers are familiar with using methylprednisolone 125 mg in their patients for various respiratory ailments, so the recommended steroid dose for Covid may seem small in comparison. However, the majority of evidence for treating COPD exacerbations and other chronic lung diseases recommends lower doses, such as prednisone 40 mg daily (equivalent steroid doses: methylprednisolone 32 mg, dexamethasone 6 mg).26,27 While the RECOVERY Trial utilized dexamethasone 6 mg daily, two other trials included in the WHOs meta-analysis used higher initial doses of 20 mg. Both studies were stopped early due to equipoise once the RECOVERY Trial was published. Considering the benefit of using dexamethasone 6 mg and balancing that with common steroid adverse events, it makes sense to use lower doses until evidence suggests otherwise. However, providers should consider patients individually and if certain situations justify higher steroid doses.

The Bottom Line

One thing is for certain: This a lot of information to process in a really short time frame. Not to mention, until very recently some of it has been contradictory.

Currently, most organizations recommend steroid administration, particularly dexamethasone 6 mg PO/IV daily for up to 10 days, in patients with COVID-19 who require supplemental oxygen; however, it is not recommended in those patients who do not.[^26,27] The WHO also released a statement on Sept. 2 recommending “systemic corticosteroids” for severe and critical COVID-19 patients, but suggested they should not be used in non-critical patients due to lack of benefit and potential harm.[¹⁵] No specific corticosteroid or dose were recommended, but examples given were dexamethasone 6 mg PO/IV once daily or hydrocortisone 50 mg IV every eight hours, an equivalent dose to dexamethasone, for seven to 10 days.

Another consideration is the oxygen saturation on room air necessary to initiate steroids. Each guideline defines “Severe COVID-19” slightly differently, but oxygen saturations they deem acceptable to consider steroid administration range between 90-94% on room air or lower. The RECOVERY trial utilized a SpO₂ of <92%. When considering acceptable oxygen saturations and steroid use, providers should continue to assess their patients individually and consider the whole clinical picture.

Several organizations have still not had time to react to the newest literature published in the last few days, so it will be interesting to see how current guidance documents change based on these data. A quick search on clinicaltrials.gov also shows several dozen studies in the pipeline that plan to evaluate various steroids and delivery mechanisms, including inhaled and intranasal corticosteroids, for COVID-19 patients. Until newer data present themselves, we’ll continue to face off against the firehose.

References

1. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-513. doi:10.1016/S0140-6736(20)30211-7
2. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354(16):1671-1684. doi:10.1056/NEJMoa051693
3. Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007;131(4):954-963. doi:10.1378/chest.06-2100
4. Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-276. doi:10.1016/S2213-2600(19)30417-5.
5. So LK, Lau AC, Yam LY, et al. Development of a standard treatment protocol for severe acute respiratory syndrome. Lancet. 2003;361(9369):1615-1617. doi:10.1016/s0140-6736(03)13265-5
6. Cheng VC, Tang BS, Wu AK, Chu CM, Yuen KY. Medical treatment of viral pneumonia including SARS in immunocompetent adult. J Infect. 2004;49(4):262-273. doi:10.1016/j.jinf.2004.07.010
7. Lee N, Allen Chan KC, Hui DS, et al. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. J Clin Virol. 2004;31(4):304-309. doi:10.1016/j.jcv.2004.07.006
8. Peiris JS, Chu CM, Cheng VC, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003;361(9371):1767-1772. doi:10.1016/s0140-6736(03)13412-5.
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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;197(6):757-767. doi:10.1164/rccm.201706-1172OC.
11. Lee DT, Wing YK, Leung HC, et al. Factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study. Clin Infect Dis. 2004;39(8):1247-1249. doi:10.1086/424016
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16. Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19). Crit Care Med. 2020;48(6):e440-e469. doi:10.1097/CCM.0000000000004363
17. Wu J, Huang J, Zhu G, Liu Y et al. Systemic corticosteroids show no benefit in severe and critical COVID-19 patients in Wuhan, China: a retrospective cohort study, medRxiv preprint doi: https://doi.org/10.1101/2020.05.11.20097709
18. Lu X, Chen T, Wang Y, Wang J, et al. Adjuvant corticosteroid therapy for critically ill patients with COVID-19, medRxiv preprint doi: https://doi.org/10. 1101/2020.04.07.20056390[not certified by peer review]. (not certified by peer review)
19. Fadel R, Morrison AR, Vahia A, et al. Early Short Course Corticosteroids in Hospitalized Patients with COVID-19 [published online ahead of print, 2020 May 19]. Clin Infect Dis. 2020;ciaa601. doi:10.1093/cid/ciaa601
20. Corral L, Bahamonde A, delas Revillas FA, et al. GLUCOCOVID-19: A controlled trial of methylprednisolone in adults hospitalized with COVID-19 pneumonia. MedRxiv preprint doi: https://doi.org/10.1101/2020.06.17.20133579
21. Wang Y, Jiang W, He Q, Liu B, Dong N, et al. Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China, medRxiv preprint doi: https://doi.org/10.1101/2020.03.06.20032342
22. Chorobozcek T, Lacoste M, Wackenheim C, Challan Belval T, et al., Beneficial effect of corticosteroids in severe COVID-19 pneumonia: a propensity score matching analysis. medRxiv preprint doi: https://doi.org/10.1101/2020.05.08. 20094755 (not certified by peer review).
23. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with COVID-19 – Preliminary Report [published online ahead of print, 2020 Jul 17]. N Engl J Med. 2020;NEJMoa2021436. doi:10.1056/NEJMoa2021436
24. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis [published online ahead of print, 2020 Sep 2]. JAMA. 2020;10.1001/jama.2020.17023. doi:10.1001/jama.2020.17023
25. Ericson-Neilsen W, Kaye AD. Steroids: pharmacology, complications, and practice delivery issues. Ochsner J. 2014;14(2):203-207.
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27. Infectious Diseases Society of America (2020). Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. (https://www.idsociety.org/practice-guideline/COVID-19-guideline-treatment-and-management/#toc-5, accessed 3 Sep 2020).