key: cord-0078966-u3bmojht
authors: Kocks, Janwillem; Kerkhof, Marjan; Scherpenisse, Jan; van de Maat, Aimée; van Geer-Postmus, Iris; le Rütte, Thomas; Schaart, Jan; Gans, Reinold O. B.; Kerstjens, Huib A.M.
title: A potential harmful effect of dexamethasone in non-severe COVID-19: results from the COPPER-pilot study
date: 2022-05-12
journal: ERJ Open Res
DOI: 10.1183/23120541.00129-2022
sha: 61a00356d6b64b24eee50a6e62a3b17befdc41d9
doc_id: 78966
cord_uid: u3bmojht

The coronavirus disease 2019 (COVID-19) pandemic poses major challenges to healthcare professionals. General practitioners (GPs) are at the frontline and may play an important role in preventing progression to severe disease, and in countering shortage of hospital beds. However, guideline-based treatment options for COVID-19 are still limited for general practitioners [1].

In short, patients consulting their GP were enrolled when testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), having a peripheral oxygen saturation (S pO 2 ) ⩾92% at rest and providing written informed consent.

In due course, patients who showed an absolute drop in S pO 2 of ⩾4% or S pO 2 to <92% after a 1-min sit-to-stand test [9] were randomised 1:1 to home-based disease monitoring with or without dexamethasone treatment. S pO 2 and disease course were monitored three times per day, captured electronically, and remotely monitored up to 28 days after enrolment.

Although we aimed to enrol 50 patients in the pilot, recruitment was stopped after 2 months (16 February to 20 April 2021) following the advice of the Data and Safety Monitoring Board due to low recruitment rates (seven patients were randomised) coupled with a relatively low incidence rate of COVID-19 in the Netherlands at that time due to seasonal variation and quickly rising vaccination numbers. Four patients were randomised to dexamethasone 6 mg prescribed for 10 days, of whom three developed severe disease within 3 days after inclusion, defined as requiring oxygen supplementation at S pO 2 <90%. Two of these patients were hospitalised (after 24 h and 3 days) and were censored for follow-up after discharge (table 1) . The third patient started oxygen supplementation at home after 3 days and felt unrecovered at the end of 28 days of follow-up. The fourth patient reported recovery once on day 25, despite continuing mild shortness of breath and tightness in the chest but felt unrecovered at the end of follow-up (day 28). This patient had fluctuating S pO 2 levels going down to 89% twice in the first week.

Three patients were randomised to home-based monitoring under usual care. One of these control patients did not start monitoring and was lost to follow-up after randomisation. Both control patients who started monitoring did not develop severe COVID-19 and reported recovery in the second week of follow-up (table 1) .

Time to recovery for the randomised groups was significantly longer in the dexamethasone group than in the control group ( p-value=0.03, log-rank test), assuming that hospitalised patients were not recovered before discharge date and were right-censored after discharge.

In summary, in this pilot-RCT we have encountered a relatively unfavourable disease course in patients who had non-severe COVID-19 and dexamethasone prescribed in the out-of-hospital setting. Clearly, due to low numbers, a pure chance effect cannot be excluded.

Multiple randomised trials found that systemic corticosteroid use improves clinical outcomes and reduces mortality in hospitalised patients with severe COVID-19 who require supplemental oxygen [10] . In participants who were hospitalised but who did not require oxygen therapy at admission, the RECOVERY-trial found no survival benefit of corticosteroids (rate ratio for 28-day mortality: 1.19; 95% confidence interval: 0.91-1.55).

A systematic review of corticosteroids for noncritically ill patients with COVID-19, suggested a potential harmful effect in mild or moderate cases [8] . Two of the three identified observational studies that used propensity score matching found that corticosteroids were associated with longer hospitalisation and viral shedding [8] . One study also reported that more patients in the corticosteroids group (N=55) developed severe disease (12.7% versus 1.8%), p=0.03) than in the non-corticosteroids group (N=55) [7] . A more recently published controlled observational study also found systemic corticosteroids to be associated with a higher risk of developing severe COVID-19 (hazard ratio (HR): 1.81 (1.47-2.21)) and a longer hospitalisation. It also reported a higher all-cause mortality rate (HR 2.92 (1.39-6.15)) in non-severe patients who used corticosteroids (29.8% of 1726) [11] .

An Italian study that assessed the degree of acute respiratory distress syndrome (ARDS) by measuring the ratio of arterial oxygen partial pressure to fractional inspired oxygen in 511 COVID-19 patients at admission reported a detrimental effect of corticosteroids treatment on 28-day mortality in patients with mild or no ARDS [12] .

COVID-19 treatment guidelines currently recommend against the use of systemic corticosteroids in non-hospitalised patients with COVID-19 without another indication [13] . However, in the Netherlands, the impression exists that many patients do receive oral corticosteroids in outpatient settings with or without oxygen therapy. We suggest caution when prescribing corticosteroids in clinical practice, and would call upon other researchers to assess and report the effects of the use of systemic corticosteroids in non-severe COVID-19 in any study, observational or more controlled studies. As far as research goes, based on our ClinicalTrials.gov entry, we have been contacted by several clinicians across the globe considering conducting a study similar to our COPPER-RCT, indicating interest in our research question. In light of our small sample size results, we cannot discourage the conduct of larger well-designed studies for this question, but a very strict safety protocol with careful monitoring of patients seems warranted.

2 RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with COVID-19

Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial

Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial

Efficacy of inhaled ciclesonide for outpatient treatment of adolescents and adults with symptomatic COVID-19: a randomized clinical trial

Inhaled and intranasal ciclesonide for the treatment of COVID-19 in adult outpatients: CONTAIN phase II randomised controlled trial

Efficacy evaluation of early, low-dose, short-term corticosteroids in adults hospitalized with non-severe COVID-19 pneumonia: a retrospective cohort study

A systematic review of corticosteroid treatment for noncritically ill patients with COVID-19

The 1-minute sit-to-stand test to detect exercise-induced oxygen desaturation in patients with interstitial lung disease

Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis

Effectiveness of systemic corticosteroids therapy for nonsevere patients with COVID-19: a multicenter, retrospective, longitudinal cohort study

Benefits of steroid therapy in COVID-19 patients with different PaO 2 /FiO 2 ratio at admission

COVID-19) Treatment Guidelines. Bethesda, National Institutes of Health. Date last accessed: 21