Discussion

The results of our study showed that the administration of corticosteroids in patients admitted
to the general medical ward with AHRF and a diagnosis of COVID-19 pneumonia was associated with a lower
risk of developing the primary outcome composite of ICU transfer, intubation or death. Regarding secondary
outcomes, patients who received corticosteroids were
found to have a lower risk of ICU transfer, intubation, in-hospital death, composite of intubation, or death and
were more likely to be discharged. In the corticosteroid cohort, however, a
lower hazard of mortality did not show statistical significance likely due to a smaller sample
size.
As discussed in the introduction, the findings from earlier studies have indicated the controversial role of
corticosteroids in COVID-19. A preliminary report from the RECOVERY
trial [11] demonstrated a beneficial role of low dose (6 mg) dexamethasone in reducing the
risk of death among patients who required oxygen with or without invasive mechanical ventilation. The study by
Wu et al. demonstrated a beneficial role of methylprednisolone in reducing the risk of death in a subgroup
analysis of 84 patients with ARDS, from an observational
study of 201 patients with COVID-19 [15]. A meta-analysis of randomized clinical trials
Fig 2. Comparison of trend of mean SpO 2/FiO2 ratio since index date with and without corticosteroid.
https://doi.org/10.1371/journal.pone.0238827.g002
PLOS ONE Corticosteroids in non-ICU COVID-19 patients
PLOS ONE | https://doi.org/10.1371/journal.pone.0238827 September 9, 2020 10 / 14
suggested corticosteroid could reduce mortality and need for mechanical ventilation in
patients with severe community-acquired pneumonia, irrespective of bacterial or viral etiology
[16,17]. On the contrary, another meta-analysis showed higher mortality among patients
receiving corticosteroids [18]. However, this meta-analysis included patients with SARS,
MERS, COVID-19, and had high heterogeneity. A subgroup analysis from the same study
reported no significant difference in mortality between two cohorts when included only
COVID-19 patients [18], suggesting corticosteroids may not be harmful in these patients. We
assume studies that showed higher or no difference in mortality with corticosteroid were critically ill with
ARDS, on mechanical ventilation, and they might have passed the point where
adverse outcomes could be modified by corticosteroid.
In COVID-19 pneumonia, lung injury is associated with a direct virus-induced injury.
However, the severity of illness is associated with the virus triggered immune hyper-response
that is characterized by activation of various immune cells and release of numerous pro- and
anti-inflammatory cytokines, including tumor necrosis factor (TNF), Interleukin-6 (IL-6), and
many more. Overwhelming secretion of cytokines leads to severe lung damage manifested as
the destruction of the small airway, alveolar epithelium, and vascular endothelium that progresses to pulmonary
edema and hyaline membrane formation [19,20]. In severe COVID-19
pneumonia, patients’ symptoms worsen and become more hypoxic during the 4–7 days after
onset of symptoms [21]. Hence, it is vital to suppress the cytokine storm before that period.
We, therefore, believe a majority of patients survive and recover if they overcome the period of
the cytokine storm. Corticosteroid is a classical immunosuppressive drug that helps in delaying or halting the
progress of pneumonia and has been effective for the treatment of ARDS
[22,23]. In addition to immunosuppressive properties, corticosteroid possesses anti-inflammatory activity that
reduces systemic inflammation, decreases exudation into the lung tissue, promotes the absorption of
inflammation, and prevents alveolar damage [24]. These effects of
corticosteroid help in relieving hypoxemia earlier, preventing further progression of respiratory insufficiency,
and hence associated with improved primary, secondary outcomes, and SF
ratio in the study.
This study was also unique and different from the RECOVERY trial in the following ways.
Compared with the RECOVERY trial, the average duration of corticosteroids administration
was half, the median equivalent dose of dexamethasone was two times, and various types
(methylprednisolone, dexamethasone, and prednisone) of corticosteroids were used. The present study cohort
only included non-intubated patients admitted to general wards. In the current study, a hazard ratio of a
composite of intubation or mortality was 0.31 (0.15–0.66),
intubation was 0.31 (0.14–0.70), and death was 0.53 (0.22–1.31). In the RECOVERY trial, the
subgroup of patients on oxygen, a hazard ratio of the composite of invasive mechanical ventilation or mortality
was 0.87 (0.79–0.96), and of mortality was 0.82 (0.72–0.94) when they
excluded patients who were receiving invasive mechanical ventilation at randomization. The
difference in the dose and duration of corticosteroid between two studies prompts the possibility of greater
beneficial effect with a higher dose and shorter duration of the corticosteroid on
clinical endpoints. Traditionally corticosteroids are not used early in viral pneumonia due to
concerns of delayed viral clearance. However, delayed treatment may predispose to worsening
and progressive inflammatory response and multiorgan failure. Hence, the authors presume
that careful monitoring of inflammatory markers might help guide the judicious use of corticosteroid. This study
highlights that early administration of moderate-dose of any systemic
corticosteroid (oral or intravenous) for a shorter duration in COVID-19 viral pneumonia may
not be as harmful as initially suspected, and even more beneficial than shown by the RECOVERY trial. The
lower hazard of ICU transfer, intubation, and a higher rate of discharge might
be linked to a better quality of life of the patient if corticosteroids are given during the early
PLOS ONE Corticosteroids in non-ICU COVID-19 patients
PLOS ONE | https://doi.org/10.1371/journal.pone.0238827 September 9, 2020 11 / 14
period of illness. However, data on readmission to hospital or ED visits post-discharge would
be required to confirm this presumptive role.
Limitations
This study has several limitations, given the observational nature of the study. It is a single-center study, and
most of the patients were Hispanic that limits the generalizability of the study.
However, this study could be taken as a role of corticosteroid in the predominantly Hispanic
population. There were missing data for inflammatory markers and potential inaccuracies in
the documentation of variables from the electronic health records; however, as mentioned
above, two authors made sure the accuracy of the collected database. Due to the retrospective
nature of the study, it was not possible to collect data on side effects such as secondary superimposed infection
and hyperglycemia. Hence, one should be vigilant about these adverse
effects while using it. Authors believe that the physicians are familiar with the side effects of
corticosteroid and ways to prevent and treat its complications as it is a long-known drug compared with newer
medications on which we have very limited data. Due to missing data for
inflammatory markers, adjustment with those variables was not possible. Despite the extensive
adjustments, it is still possible that unmeasured confounding prevails. We did not have longitudinal data with
follow-up. A randomized clinical trial is the best approach to determine
whether the benefit can be ascribed to any given therapeutic intervention as the trial design
diminishes the two major hurdles of observational studies, namely unmeasured confounding
and bias. A randomized clinical trial from China has been registered in which patients were
randomly assigned to receive 1 mg/kg methylprednisolone (NCT04273321) or placebo. The
authors tried to minimize confounding by choosing the best possible model in multivariable
regression in this retrospective cohort study.
Conclusions
In our analysis of hospitalized patients in the general ward with COVID-19 pneumonia complicated by acute
hypoxic respiratory failure, early use of moderate dose systemic corticosteroid for the shorter duration was
associated with a significantly lower rate of the primary
outcomes of ICU transfer, intubation, or in-hospital death. Given the observational design, the
study should be interpreted with caution due to potential bias and residual confounders.

A rapid advice guideline for the diagnosis and treatment of 2019 novel
coronavirus (2019-nCoV) infected pneumonia (standard version)
6.3.3 Corticosteroid therapy
The use of corticosteroids for severe ARDS is controversial; therefore, systemic use of glucocorticoids needs to
be cautious. Methylprednisolone can be used as appropriate for patients with rapid disease progression or severe
illness. According to the severity of the disease, 40
to 80 mg of methylprednisolone per day can be considered, and the total daily dose should not exceed 2 mg/kg
(Weak recommendation).
SARS management related researches showed that
timely use of non-invasive continuous positive airway
pressure and corticosteroids is an effective strategy for increased lung shadows and increased dyspnea.
Appropriate
use of glucocorticoids is able to significantly improve the
clinical symptoms of patients with SARS, reduce the degree of disease progression, and accelerate the
absorption
of lung lesions; but it cannot shorten the length of hospital
stay [35, 36]. Be cautious that hormone therapy has some
incidence of adverse reactions [37].

6.3.2 Antibiotic therapy

(1) Principles. Avoid blind or inappropriate use of
antibacterial drugs, especially the combination of
broad-spectrum antibacterial drugs. Enhancement of
bacteriological surveillance should be performed and
promptly given appropriate antibacterial drugs when
it occurs secondary bacterial infection.
(2) According to the clinical manifestations of patients,
if the accompanying bacterial infection cannot be ruled
out, mild patients can take antibacterial drugs against
community-acquired pneumonia, such as amoxicillin,
azithromycin, or fluoroquinolones; empirical antibacterial treatment in severe patients should cover
all possible pathogens, deescalating therapy until the
pathogenic bacteria are clarified.

6.3.4 Other medications

(1) Symptomatic treatment of fever. When the temperature
is higher than 38.5 ℃, ibuprofen can be used for
antipyretic (oral, 0.2 g per time, it can be used every
4–6 h in continuous fever, but no more than 4 times
in 24 h), and the temperature below 38 ℃ is
acceptable. Much lower body temperature is not
conducive to antiviral treatment.
(2) Nutrition support treatment. Inpatients are screened
for nutrition risk based on the NRS2002 score when
they are admitted to the hospital. The recommended
plan for patients with different nutrition risk scores
are as follows:
First, if the total score is < 3 points, it is
recommended to eat protein-rich foods (such as eggs,
fish, lean meat, dairy products) and carbohydratecontaining diets. The supposed ideal energy intake
is 25–30 kcal / (kg∙d) and the protein mass are
1.5 g / (kg∙d).
Second, if the total score is ≥3 points, the patient
should be given nutritional support as early as
possible. It is recommended to increase protein
intake by oral nutrition supplement, 2–3 times/day
(≥ 18 g protein/time). In order to reach the mount
of 18 g protein/time, protein powder can be added
on the basis of standard whole protein preparations.
Enteral nutrition tube should to be placed when the
patient cannot intake supplemental nutrition by
oral routine.
(3) Reduce the incidence of stress ulcers and gastrointestinal
bleeding. Use H2 receptor antagonists or proton pump
inhibitors in patients with gastrointestinal bleeding
risk factors. The risk factors for gastrointestinal
bleeding include mechanical ventilation ≥48 h,
coagulation dysfunction, renal replacement therapy,
liver disease, various complications, and a higher score
of organ failure.
(4) Reduce the secretion of lung glands and improve
the respiratory function. For patients with
dyspnea, cough, wheeze, and respiratory distress
syndrome due to the increased respiratory gland
secretion, it is recommended to use selective
(M1, M3) receptor anticholinergic drugs to reduce
the secretion, relax the smooth muscle in airway,
relieve airway spasm and improve the pulmonary
ventilation.
(5) Reduce the incidence of venous embolism. Evaluate
the risk of venous embolism in patients and use
low-molecular-weight heparin or heparin in highrisk patients without contraindications
The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19

Corticosteroid therapies

Corticosteroids are a class of steroid hormones that have antiinflammatory functions.

Corticosteroids are commonly used to suppress inflammation. During the 2003 SARS epidemic,
corticosteroids were the primary means of immunomodulation. Timely administration of
corticosteroids often leads to early improvements such as reducing fever, relieving radiation
infiltration of the lung, and improving oxygenation.64–66 A retrospective study of 401 patients with
severe SARS revealed that proper administration of glucocorticoids in patients with severe SARS
significantly reduced the mortality rate and shortened the hospital stay. Moreover, secondary
infections and other complications rarely occurred in these glucocorticoid-treated patients.67
However, there are studies showing that administration of corticosteroid therapy during human

SARS-CoV infection led to adverse consequences. Early treatment of SARS patients with
corticosteroids increased plasma viral load in non-ICU patients, resulting in the aggravation of the
disease.64 In treatment of patients with COVID-19, the use of glucocorticoids has again become a
major conundrum for clinicians.68 The timing of administration and the dosage of glucocorticoids
are very important to the outcome of the severely ill patients. A too early administration of
glucocorticoids inhibits the initiation of the body’s immune defense mechanism, thereby increasing
the viral load and ultimately leading to adverse consequences. Therefore, glucocorticoids are mainly
used in critically ill patients suffering inflammatory cytokine storm. Inhibition of excessive
inflammation through timely administration of glucocorticoids in the early stage of inflammatory
cytokine storm effectively prevents the occurrence of ARDS and protects the functions of the
patients’ organs. For patients with progressive deterioration of oxygenation indicators, rapid imaging
progress, and excessive inflammatory response, the use of glucocorticoid in the short term (3–5
days) is appropriate, and the recommended dose is no more than equivalent to methylprednisolone
1–2 mg/kg/day.69 It should be noted that large doses of glucocorticoid may delay the clearance of
coronavirus due to immunosuppression.

IL-6 antagonists

Tocilizumab is an IL-6 antagonist that suppresses the function of the immune system. Currently,
tocilizumab is mainly applied in autoimmune diseases such as rheumatoid arthritis.72 Tocilizumab
itself has a therapeutic effect on the infection-induced cytokine storm.73 Serum IL-6 level is
significantly increased in severely ill patients with COVID-19. Clinical studies from China have shown
that Tocilizumab is effective in treating severely ill patients with extensive bilateral lung lesions, who
have elevated IL-6 levels. The first dose was 4–8 mg/kg. The recommended dosage was 400mg with
0.9% saline diluted to 100 ml. The infusion time was more than 1 h. For patients with poor efficacy of
the first dose, an additional dose can be applied after 12 h (the dose is the same as before), with a
maximum of two cumulative dose.

UPTODATE
Defining disease severity — Mild disease is characterized by fever, malaise, cough, upper respiratory
symptoms, and/or less common features of COVID-19, in the absence of dyspnea. Most of these patients do not
need hospitalization.

If patients develop dyspnea, that raises concern that they have at least moderate severity disease, and these
patients often warrant hospitalization. Patients can have infiltrates on chest imaging and still be considered to
have moderate disease, but the presence of any of the following features indicates severe disease:

●Hypoxia (oxygen saturation ≤94 percent on room air)

●Need for oxygenation or ventilatory support
This definition is consistent with the definition used by the US Food and Drug Administration [144]. Some studies
have used other features in addition to hypoxia to characterize severe disease, such as tachypnea, respiratory
distress, and >50 percent involvement of the lung parenchyma on chest imaging [145].

Nonsevere disease — For most hospitalized patients with nonsevere disease, we suggest supportive care only,
with close monitoring for clinical worsening. If they develop features of severe disease (eg, hypoxia or oxygen
requirement (see 'Defining disease severity' above)), we treat them as described below. (See 'Severe (including
critical) disease' below.)
Some patients with nonsevere disease have laboratory abnormalities that are associated with progression to
severe disease (table 1). We prioritize these patients for clinical trials for treatment of nonsevere disease in
addition to monitoring them closely for progression. A registry of international clinical trials can be found at covid-
trials.org. In the United States, EUAs have been granted for convalescent plasma and for remdesivir for
hospitalized patients with COVID-19, regardless of severity. We do not use convalescent plasma outside clinical
trials for patients with nonsevere disease. However, plasma obtained through the EUA may be a reasonable
option for such patients in locations where access to clinical trials is limited, with the caveat that the benefit
remains uncertain. We also do not routinely use remdesivir for patients with nonsevere disease, as studies
suggest only a modest benefit of uncertain clinical significance in this population, availability may be limited, and
we prioritize it for patients on low-flow oxygen at baseline. (See 'Convalescent plasma and other antibody-based
therapies' above and 'Remdesivir' above.)
We recommend not using dexamethasone in patients with nonsevere disease. 

THE DYNAMIC CHANGES …. RAD

As a solution, Cron
summarized a few approaches focused
on targeting IL-6, IL-1 or JAK/STAT
proteins to suppress the cytokine storm. He
concluded his talk by offering alternative
strategies to reduce hyperinflammation,
such as JAK inhibitors and glucocorticoids.
Specifically, the World Health Organization
initially recommended against the use of
corticosteroids for COVID-19 based on the
experiences of SARS and MERS, but recent
data showed a clear reduction in the need for
ventilation and in mortality in patients with
COVID-19 treated with dexamethasone14.
Steroids are widely available and affordable,
and, with careful dosing and timing, these
agents could become powerful tools in
fighting the cytokine storm triggered by
SARS-CoV-2.

#UPTODATE

COVID-19-SPECIFIC THERAPY

Specific treatments under evaluation

Dexamethasone and other glucocorticoids — We recommend dexamethasone for severely ill patients with
COVID-19 who are on supplemental oxygen or ventilatory support. We use dexamethasone at a dose of 6 mg
daily for 10 days or until discharge, whichever is shorter. If dexamethasone is not available, it is reasonable to
use other glucocorticoids at equivalent doses (eg, total daily doses of hydrocortisone 150
mg, methylprednisolone 32 mg, or prednisone 40 mg), although data supporting use of these alternatives are
more limited than those for dexamethasone. In contrast, we recommend that dexamethasone (or other
glucocorticoids) not be used for either prevention or treatment of mild to moderate COVID-19 (patients not on
oxygen). These recommendations are largely consistent with those of other expert and governmental groups
[4,33-36]. (See 'Severe (including critical) disease' below.)
Patients receiving glucocorticoids should be monitored for adverse effects. In severely ill patients, these include
hyperglycemia and an increased risk of infections (including bacterial, fungal, and Strongyloides infections); the
rates of these infections in patients with COVID-19 are uncertain. Nevertheless, pre-emptive treatment
of Strongyloides prior to glucocorticoid administration is reasonable for patients from endemic areas (ie, tropical
and subtropical regions). This is discussed elsewhere (see "Strongyloidiasis", section on 'Preventive treatment').
Major side effects of glucocorticoids are also discussed in detail elsewhere. (See "Major side effects of systemic
glucocorticoids".)
Data from randomized trials overall support the role of glucocorticoids for severe COVID-19. In a meta-analysis
of seven trials that included 1703 critically ill patients with COVID-19, glucocorticoids reduced 28-day mortality
compared with standard care or placebo (32 versus 40 percent, odds ratio [OR] 0.66, 95% CI 0.53-0.82) and
were not associated with an increased risk of severe adverse events [37]. In another systematic review and
network meta-analysis of randomized trials that evaluated interventions for COVID-19 and were available through
mid-August 2020, glucocorticoids were the only intervention for which there was at least moderate certainty in a
mortality reduction (OR 0.87, 95% CI 0.77-0.98) or risk of mechanical ventilation (OR 0.74, 95% CI 0.58-0.92)
compared with standard care [38].
The majority of the efficacy data on glucocorticoids in these meta-analyses comes from a large, randomized
open-label trial in the United Kingdom in which oral or intravenous dexamethasone reduced 28-day mortality
among hospitalized patients compared with usual care alone [39]. This trial included patients with confirmed or
suspected COVID-19 who had no specific indications or contraindications to dexamethasone; 2104 and 4321
patients were randomly assigned to receive dexamethasone or usual care, respectively, and the proportions of
baseline comorbidities and need for oxygen or ventilatory support were comparable between the two groups.
Reductions in 28-day mortality with dexamethasone in the overall trial population and in prespecified subgroups
were as follows:
●Overall – 17 percent relative reduction (22.9 versus 25.7 percent, rate ratio [RR] 0.83, 95% CI 0.75-0.93).
●Patients on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) at baseline
– 36 percent relative reduction (29.3 versus 41.4 percent, RR 0.64, 95% CI 0.51-0.81). Age-adjusted
analysis suggested a 12.3 percent absolute mortality reduction.
 ●Patients on noninvasive oxygen therapy (including noninvasive ventilation) at baseline – 18 percent
relative reduction (23.3 versus 26.2 percent, RR 0.82, 95% CI 0.72-0.94). Age-adjusted analysis suggested
a 4.1 percent absolute mortality reduction.

In contrast, a benefit was not seen among patients who did not require either oxygen or ventilatory support; there
was a nonstatistically significant trend towards higher mortality (17.8 versus 14 percent, RR 1.19, 95% CI 0.91-
1.55). Results were similar when analysis was restricted to the patients with laboratory-confirmed COVID-19 (89
percent of the total population).

This was a preliminary report, and some uncertainties remain. The baseline mortality rate in this report was
higher than that from some other trials, and the absolute mortality benefit in other settings may not be as high as
in this trial. Adverse effects (including secondary infections) were not reported. Patients on noninvasive oxygen
therapy comprise a heterogeneous group, and additional details are needed to determine if there are subsets of
patients in this group who would most benefit. Thus, overall confidence in the finding of a mortality benefit is low
for patients with COVID-19 who need oxygen supplementation and moderate for those who are on mechanical
ventilation (in part, given the effect size). Additional details from the trial may help increase confidence in the
results.

Data on the efficacy of other glucocorticoids are limited to smaller trials, several of which were stopped early
because of the findings of the trial above [40-42]. Individual trials of hydrocortisone in critically ill patients failed to
demonstrate a clear benefit [40,41]; in a meta-analysis that included three trials evaluating hydrocortisone, there
was a nonstatistically significant trend toward reduced 28-day mortality compared with usual care or placebo (OR
0.69, 95% CI 0.43-1.12) [37]. Trials evaluating methylprednisone have not demonstrated a clear benefit. In a
randomized trial from Brazil that included 393 patients with suspected or confirmed severe COVID-19 (77 percent
of whom were on oxygen or ventilatory support), there was no difference in 28-day mortality rates
with methylprednisolone compared with placebo (37 versus 38 percent) [43]. It is uncertain whether the apparent
difference in results compared with the larger dexamethasone trial is related to the glucocorticoid formulation and
dose, other differences between the trial populations, or issues related to statistical power.
Glucocorticoids may also have a role in the management of refractory shock in critically ill patients with COVID-
19. These issues are discussed elsewhere. (See "COVID-19: Critical care and airway management issues",
section on 'Corticosteroids for COVID-19'.)