# WikiJournal Preprints/The Effect of Corticosteroids on the Mortality Rate in COVID-19 Patients, v2

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## Article information

Authors: Ghadeer Bustani  , Ahmed Al-Dulaimi  , Bara Al-Hasan  , Muhammad Ali Hameed, Aaqib Farique Azeez
* ↑ bustani@iunajaf.edu.iq

## Background

In December 2019, SARS-CoV-2 was first detected in Wuhan, Hubei Province, China. Research into the virus' origins has supported the notion that SARS-CoV-2 first originated from a wet market in the city, as many of the initial patients of the coronavirus were stall owners, market employees, or regular visitors to the market. Wuhan was the first city in the world to go under lockdown due to the spread of SARS-CoV-2. In February 2020, the World Health Organization (WHO) renamed the "2019 novel coronavirus" to "COVID-19" as the virus was rampantly spreading across the world. On March 11, 2020, the World Health Organization (WHO) officially designated COVID-19 as the fifth pandemic in written history.
COVID-19 is a highly infectious disease that has a reported mortality rate of approximately 3% (May 2020). This percentage is lower than the reported mortality rate of SARS-CoV (10%) and MERS-CoV (35%). Although a lower mortality rate, the COVID-19 pandemic had a larger worldwide impact. SARS-CoV-2 infects the respiratory system and causes additional damage to the alveolis in the lung. This causes hypoxia, resulting in organ failure. Other possible repercussions include heart inflammation (e.g., myocarditis), liver damage, blood clots (could lead to pulmonary embolism), and neurological malfunction (confusion, amnesia, ageusia, etc.). These negative effects can be exacerbated by a cytokine storm, a dangerous overreaction in the body where the immune system releases an excessive amount of cytokines despite the threat no longer being present. For these various health consequences, around 10–20% of hospitalized patients are admitted to the intensive care unit (ICU), 3–10% require intubation and 2–5% succumb to the disease.
Various studies have attempted to find a way to decrease the mortality rate and the severity of COVID-19 symptoms through the use of corticosteroids drugs, as corticosteroids are a useful mechanism in treating inflammation and defects in the immune system.

### Coronavirus

Coronaviruses (derived from the Latin word corona) are a group of zoonotic RNA viruses in the family Coronaviridae of the order Nidovirales that were first isolated in 1937. In 1965, the group of viruses was coined the name "Coronavirus" due to its crown-like appearance observed under a microscope. The species of coronaviruses that have been recorded as of March 2021 are the alpha coronaviruses HCoV-229E and HCoV-NL63; the beta coronaviruses HCoV-OC43 and HCoV-HKU1; SARS-CoV-1; MERS-CoV; and SARS-CoV-2 (Figure 1 to the left represents a model of this virus). Coronaviruses can cause severe respiratory complications in humans. In 2002, a strain of coronavirus, known as severe acute respiratory syndrome (SARS), spread to various parts of Asia in 2002. In 2012, another strain of coronavirus, MERS-CoV, affected the Arabian Peninsula in the Middle East.

### Corticosteroids

Corticosteroids are a type of steroid hormones that are used as treatments for a wide variety of health problems. They are secreted from the adrenal glands of vertebrates and are also artifically made. Corticosteroids are divided into two types: the glucocorticoids and mineralocorticoids. Both of these classes of corticosteroids deal with anti-inflammation and immunosuppressive therapy, but both have specialized roles. The glucocorticoids dial down stress, control metabolism, and control behavior. An example of a glucocotricoid is cortisol (shown in Figure 2). The mineralocorticoids regulate the transportation of sodium and water throughout the body. An example of a mineralocorticoid is aldosterone.
Corticosteroids can be taken in a variety of ways, including IV (injection), tablets, inhalers, rectally, and creams. Which method administered depends on the health condition.

#### Benefits of Corticosteroids

Corticosteroids are indicted for their quick ability to reduce inflammation, control overwhelming immune responses, and maintain homeostasis. They are one of the most prescribed drugs in the world. Corticosteroids are used to treat inflammation, asthma, allergies, hives, hypoglycemia, neurological disorders, skin disorders, and various other conditions. Corticosteroids can be used in the event of an organ transplant. Corticosteroids can be used to replace hormones that are not being produced sufficiently, such as in the case of adrenal insufficiency in Addison's disease.

#### Side Effects of Corticosteroids
### Corticosteroids' Effect on COVID-19 Patients

In cohort studies and case series that used corticosteroids to treat COVID-19 patients, they've yielded conflicting results. Some studies found beneficial effects of corticosteroids while others have found negative effects [5].
In a previous study consisting of a series of six consecutive hospitalized COVID-19 patients with rapidly deteriorating hypoxemia and laboratory indices of COVID-19 associated hyper-inflammatory syndrome (CAHS), all COVID-19 patients made a full recovery following a short course of high-dose corticosteroid (CS) [6].
A previous study suggested that cytokine release syndrome (CRS) could be involved in the pathophysiology of severe or critical COVID-19 cases, frequently resulting in death. Therefore it is essential that the cytokine storm be recognized and suppressed in its early stages in order to save the patient's life [9]. Despite these findings, there isn't sufficient documentation from randomized clinical trials to approve the use of corticosteroids on COVID-19 patients. Although intravenous corticosteroids have been commonly used for patients with severe SARS/MERS pneumonia, their overall efficiency and effectiveness in treating COVID-19 remains argumentative [10]. In an observational study conducted in Wuhu, China from the 24th of January 2020 to the 24th February 2020, the use of corticosteroids in COVID-19 cases were found to have indicated no statistically significant differences in the virologic or clinical outcome between patients who received corticosteroids and those who did not receive corticosteroids [11]. In addition, the use of corticosteroids was not recommended in the treatment of COVID-19 by WHO until 24 June 2020. As a result, many questions regarding the use of corticosteroids in the treatment of COVID-19 patients remain unanswered [12].
However, a study done on June 4, 2020, indicated that severely infected patients of COVID-19 were more likely to require corticosteroids therapy [10].
On June 25, 2020, the National Institutes of Health (NIH) COVID-19 treatment guidelines, based on a preliminary analysis of the data from the Randomised Evaluation of COVID-19 Therapy (RECOVERY), authorized the use of dexamethasone, a corticosteroid, to patients that developed a systemic inflammatory response (potentially leading to lung injury and multi-system organ dysfunction) as a result of COVID-19. For 10 days, the patients were prescribed doses of 6 mg/day. The use of dexamethasone yielded positive consequences in patients with severe COVID-19 (defined as patients who required oxygen therapy) and was observed to have the greatest effect in patients who required mechanical ventilation at the time of enrollment. Simultaneously, no positive effects of dexamethasone were observed in patients who did not require oxygen therapy [5].
In March-July of 2020, a study conducted by Massachusetts General Hospital (MGH) COVID-19 for Treatment Guidance conclusively recommended the use of dexamethasone, both PO (orally) and IV (intravenous) formulations, for patients with mild or moderate COVID-19 infections that eventually progress to oxygen requirement (severe disease). This is because dexamethasone exhibits no mineralocorticoid effects as compared to other steroids. While MGH mentioned that ceasing to inhale steroids may cause or worsen any underlying lung disease, no data has indicated that inhaling corticosteroids worsens COVID-19-related morbidity or mortality [13]. Additionally, a study in India in September-October of 2020 indicated that the use of dexamethasone causes an impressive 35% mortality rate decrease among patients on invasive mechanical ventilation and a 20% mortality rate decrease amongst patients on oxygen therapy (noninvasive ventilation not relevant), but no significant benefit was observed in mild COVID-19 cases [14].
Other steroids that can be used as an alternative for dexamethasone are hydrocortisone (intravenous 50mg every 8hrs), methylprednisolone (intravenous 30mg every day), and prednisone (PO 40mg every day). Unlike the alternatives, dexamethasone exhibits no mineralocorticoid effect. These alternatives would be preferable over dexamethasone in the event of contraindications, such as pregnancy. Dexamethasone is known to have caused negative fetal effects, hypersensitivity, and uncontrolled fungal infection [13].
A document published on July 2, 2020, showed that a daily intake of 20mg IV dexamethasone on days 1-6, followed by a daily intake of 10mg IV dexamethasone, resulted in a decreased duration of mechanical ventilation and overall mortality in comparison to conventional treatment alone [15]. In another study, 2,104 patients were randomly allocated to receive dexamethasone for 28 days. The results of this study are summarized in the table below (table 1) [16].
Table 1: Recovery Trial (dexamethasone) for 28 days :
| | Mortality rate with dexamethasone | Mortality rate with usual care |
| Patients undergoing oxygen therapy | 21.5% | 25% |
| Patients not undergoing oxygen therapy | 17% | 13.2% |
| Patients on mechanical ventilator | 29% | 40.7% |
A study published in April 17, 2020 that made comparisons between the treatment guidelines for COVID-19 in Saudi Arabia, the USA, Europe and Egypt referred to the use of hydrocortisone just in Egypt for critical cases [17]. Prednisone (or methylprednisolone), at a dose of 1 mg/kg equivalent per day, was added to a treatment protocol in a hospital in Reims, France. Significant reductions were observed in hospital mortality in patients with COVID-19 pneumonia who developed ARDS , methylprednisolone appeared to reduce the risk of death. 46% of patients died with the use of methylprednisolone, while those who did not receive methylprednisolone (61.8%) died [15]. Additionally, using single-dose pulse methylprednisolone (40- 500mg methylprednisolone) had no apparent negative impact on virus removal and production of specific IgG while effectively stopping the inflammatory cascade [9]. For septic shock, the effect of corticosteroids in COVID-19 patients may be different than the effects seen in those with acute respiratory distress syndrome (ARDS).
The Surviving Sepsis Campaign and NIH suggest the use of low-dose corticosteroid therapy (e.g., hydrocortisone 200 mg daily as an IV infusion or intermittent doses) over no corticosteroid therapy in adults with COVID-19 and refractory shock [15]. The NIH stated that patients who were taking oral corticosteroids therapy for chronic conditions for an underlying condition prior to COVID-19 infection (e.g., primary or secondary adrenal insufficiency, rheumatologic diseases) should not be discontinued. Inhaled corticosteroids used daily for the management of asthma and chronic obstructive pulmonary disease (COPD) to control airway inflammation should not be discontinued in patients with COVID-19 [15].
In this review, we created a table to summarize using glucocorticoid in the guideline of covid 19 for some countries as indication , dose , rote of administration and the study that dependent in for use (table 2)
In this review, we've created a table to summarize the use of glucocorticoid according to the COVID-19 treatment guidelines in various countries (table 2).
Table 2: Use of Glucocotricoid in Various Countries according to their COVID-19 Treatment Guidelines :
| Guidelines and therapeutic protocols | Glucocorticoids (GC) | Route of Administration | Indications | Dose | Result |
| China [18] | methylprednisolon | intravenous, intraosseous | To patients - - severe and critically ill stage; -with resistance high fever (body temperature >39 °C); - computerized tomography (CT) demonstrated patchy ground-glass attenuation or having >30% area of the lungs involved; -whose CT demonstrated rapid progression (>50% area involved in pulmonary CT images within 48 h); -whose IL-6 is above ≥ 5 ULN. *Appropriate and short-term use of GCs should be considered for patients with severe COVID-19 pneumonia as early as possible. *High dosages of methylprednisolon should be avoided due to the possible adverse complications | *Initial methylprednisolon at a dose of 0.75∼1.5 mg/kg IV once a day (nearly 40 mg once or twice a day) is recommended. *MP at a dose of 40 mg q12 h can be considered for patients with falling body temperature or significantly increased cytokines under routine doses of GCs. *MP at a dose of 40 mg–80 mg q12 h can be used for critical cases. *The dosage of MP should be halved every 3–5 days if: -medical conditions of patients improve; -the body temperature normalizes; -involved lesions on CT are significantly absorbed. *Oral MP once a day is recommended when the IV dose is reduced to 20 mg per day. *The length of GC treatment in not defined; some experts have suggested ceasing GC treatment when patients are near to a full recovery. | Observational/Retrospective |
| National Institutes of Health COVID-19 Treatment Guidelines [5] | dexamethasone | orally intravenously | *patients with COVID-19 who are mechanically ventilated *patients with COVID-19 who require supplemental oxygen, but are not mechanically ventilated *not recommend for patients that do not need oxygen therapy | dexamethasone (at a dose of 6 mg per day for up to 10 days) | At this time, it is not known if other corticosteroids, such as prednisone, methylprednisolone, or hydrocortisone, will have similar benefits as dexamethasone has. The dose equivalencies for dexamethasone 6mg/day are prednisone 40mg/day, methylprednisolone 32 mg/day, and hydrocortisone 160 mg/day. |
| Italian protocols employed by single institutions [18] | methylprednisolon prednisone | intravenous, intraosseous | Patients admitted to intensive care units that are suspected to have developed ARDS. | * methylprednisolon dose 1 mg/kg/day for 5 days; *Afterwards, reduction to 0.5 mg/kg/day for a further 5 days. *In some protocols. prednisone is used as a latest step (for dose reduction) and is administered per OS. | |
| Study promoted by ASUGI (Azienda Sanitaria Universitaria Giuliano Isontina) in Italy [18] | methylprednisolon | intravenous, intraosseous | patients hospitalized in Pneumology/UTIR (Respiratory Intensive Care Unit) | *Day 1: methylprednisolon: 80 mg IV as bolus, followed by 80 mg in IV continuous infusion in 240 mL of physiological saline solution (0.9%) in 24 h. *The following 8 days: give methylprednisolon, 80 mg in IV continuous infusion in 240 mL of physiological saline solution. (0.9%) in 24 h until reach PaO2/FIO2>350 mmHg and/or C-reactive protein 2≤mg/dL. *When PaO2/FIO2>350 mmHg and/or C-reactive protein ≤2 mg/dl (or ≤20 mg/L): oral intake of methylprednisolon 16 mg twice a day (or IV methylprednisolon: 20 mg twice a day) to reduce until withdrawal when C-reactive protein is normal (±20%) and/or PaO2/FIO2>400 or SatHbO2≥95% in air. | Multicentric non-randomized controlled cohort trial, in patients with COVID-19 linked ARDS. |
| Massachusetts General Hospital (MGH) COVID-19 for Treatment Guidance [13] | Dexamethasone Hydrocortisone Methylprednisolone Prednisone | Intravenous oral intravenous intravenous PO | *Patients with moderate to severe COVID19. *Patients requiring oxygen supply. | Dexamethasone at a dose of 6 mg PO/IV for up to 10 days. Hydrocortisone 50mg q8hrs Methylprednisolone 30mg daily Prednisone 40mg qd | |
| US (Yale University) [18] | Methylprednisolone | intravenous | May be considered for use by critical care team for salvage therapy. *GC should be used if clinically indicated as part of the standard of care, such as for an asthma, COPD exacerbation or shock with history of chronic steroid use. *Lack of effectiveness and potential harm shown in literature, specifically inhibition of viral clearance in severe influenza and SARS, though possible benefit with critically ill COVID19 patients. | Methylprednisolone 40 mg q8hr intravenous for three days, then reassess after three days | |
| United Kingdom [18] | Low-dose dexamethasone | intravenous, intraosseous | Hospitalized patients diagnosed with COVID-19 infection | | Randomized controlled trial (RECOVERY) EudraCT number: 2020−001113- 21 |
| WHO [18] | Do not routinely give systemic glucocorticoids for treatment of viral pneumonia outside of clinical trials. A systematic review of observational studies of glucocorticoid administered to patients with SARS reported no survival benefit and possible negative consequences (avascular necrosis, psychosis, diabetes, and delayed viral clearance). WHO has prioritized the evaluation of GCs in clinical trials to assess safety and efficacy. | Do not routinely give systemic glucocorticoids for treatment of viral pneumonia outside of clinical trials. A systematic review of observational studies of glucocorticoid administered to patients with SARS reported no survival benefit and possible negative consequences (avascular necrosis, psychosis, diabetes, and delayed viral clearance). WHO has prioritized the evaluation of GCs in clinical trials to assess safety and efficacy. | Do not routinely give systemic glucocorticoids for treatment of viral pneumonia outside of clinical trials. A systematic review of observational studies of glucocorticoid administered to patients with SARS reported no survival benefit and possible negative consequences (avascular necrosis, psychosis, diabetes, and delayed viral clearance). WHO has prioritized the evaluation of GCs in clinical trials to assess safety and efficacy. | Do not routinely give systemic glucocorticoids for treatment of viral pneumonia outside of clinical trials. A systematic review of observational studies of glucocorticoid administered to patients with SARS reported no survival benefit and possible negative consequences (avascular necrosis, psychosis, diabetes, and delayed viral clearance). WHO has prioritized the evaluation of GCs in clinical trials to assess safety and efficacy. | Do not routinely give systemic glucocorticoids for treatment of viral pneumonia outside of clinical trials. A systematic review of observational studies of glucocorticoid administered to patients with SARS reported no survival benefit and possible negative consequences (avascular necrosis, psychosis, diabetes, and delayed viral clearance). WHO has prioritized the evaluation of GCs in clinical trials to assess safety and efficacy. |
| US IDSA (Infectious Diseases Society of America) [19] | For patients admitted to the hospital with COVID-19 pneumonia, the panel suggests against the use of glucocorticoids. The panel recommends the use of GCs in the context of a clinical trial for patients admitted to the hospital with ARDS due to COVID-19. | For patients admitted to the hospital with COVID-19 pneumonia, the panel suggests against the use of glucocorticoids. The panel recommends the use of GCs in the context of a clinical trial for patients admitted to the hospital with ARDS due to COVID-19. | For patients admitted to the hospital with COVID-19 pneumonia, the panel suggests against the use of glucocorticoids. The panel recommends the use of GCs in the context of a clinical trial for patients admitted to the hospital with ARDS due to COVID-19. | For patients admitted to the hospital with COVID-19 pneumonia, the panel suggests against the use of glucocorticoids. The panel recommends the use of GCs in the context of a clinical trial for patients admitted to the hospital with ARDS due to COVID-19. | For patients admitted to the hospital with COVID-19 pneumonia, the panel suggests against the use of glucocorticoids. The panel recommends the use of GCs in the context of a clinical trial for patients admitted to the hospital with ARDS due to COVID-19. |
Either about inhaled corticosteroids that mentioned in systematic review and clinical perspective that published at April 2020 show in vitro study that inhaled corticosteroid (ciclesonide)have antiviral effect and also have lower immunosuppressive effects . Furthermore, early, not yet peer-reviewed data, suggest ciclesonide blocks SARS-CoV-2 RNA replication in vitro and inhibits SARS-CoV-2 cytopathic activity , which may be of great relevance to reducing the risk of developing of COVID-19 in response to SARS-CoV-2 infection or reducing the severity of the disease[20]. And Pre-treatment of human respiratory epithelial cells in vitro with budesonide, in combination with glycopyrronium and formoterol, has inhibitory actions on coronavirus HCoV-229E replication and cytokine production [20] also the asthmatic patients take inhaled steroid all the time is 22-63% from all asthmatic patients [21]. as in Wuhan china 5% of people are have asthma and just 1% of asthmatic patients hospitalized with covid 19 also in new york the asthma is not on the 10 top of core morbidities even as 10% of new york people asthmatic[22].in other hand in one observational study has shown an increased risk of pneumonia or lower respiratory infection [23].In vitro studies have suggested that corticosteroids may impair antiviral innate immune responses and that inhaled corticosteroids use leads to delayed virus clearance[20] . Many studies mention to some adverse effects of using corticosteroids including hyperglycemia, hypernatremia, and hypokalemia also the WHO does not currently recommend corticosteroids in other viral diseases, like Dengue as the ‘glucocorticoid-mediated stimulation of the hypothalamic- pituitary adrenal axis can also drive lymphocytopenia, or it may promote exaggerated pro-inflammatory responses that eventually cause a worsening of the pathogenic condition[24] Also corticosteroid using may associated with no survival benefit and possible harm (e.g., delayed viral clearance, avascular necrosis, psychosis, diabetes)[15].

## Conclusion

Regard using dexamethasone In patients hospitalized with COVID-19, this reduced mortality and duration of mechanical ventilation among those under mechanical ventilation or oxygen support , but not with patients that need oxygen and regard using methylprednisolone as single-dose (40- 500 mg) that had no apparent negative impact on coronavirus removal and production of specific IgG while effectively stopping the inflammatory cascade. For other glucocorticoids (hydrocortisone,Prednisone) have also been shown to reduce the duration of mechanical ventilation and using as alternative to using dexamethasone or methylprednisolone in equivalent dose decrease overall mortality in patients with established moderate-to-severe patient with ARDS and pneumonia with covid 19 who are under mechanically ventilated and patients Whose are not under mechanically ventilated but need oxygen supply. And about inhaled corticosteroids at this time , there is no evidence as to whether premorbid use or continued administration of it is a factor for adverse or beneficial outcomes in coronavirus ; therefore, corticosteroids should be used with caution in the treatment of COVID-19 .

## Recommendation

Up to last studies we recommending for using dexamethasone or methylprednisolone for patients how need oxygen supply or whose need mechanical ventilation and not for patients that no need oxygen for now. As using it delay the clearance of virus but can using for effective suppression of the cytokine storm for life-saving in severe and critical covid 19 patients. Due to given the paucity of direct evidence and the limitations of indirect evidence we need further multicenter clinical trials to better understand the role of corticosteroids in COVID-19 to verify from benefits and harmful effects . so when using corticosteroids now should be careful from harmful effect. At last I hope all people learn lessons especially in terms of public and global health for any future similar pandemics.

### Limitations

* Covid 19 is new and the updates is continuous with each month so it’s difficult to get information that is reliable
* The limiting in data source for covid 19 as its new disease in the word .
* Many articles are need for credit card and not as free text
* Deficit to get accurate information as it continuous change in each day and I need for newer data

### Funding

Non, self-funded by authors