Coronavirus 2019 (COVID-19) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are interchangeable referred to the novel fast-spreading pandemic viral infections that belong to the coronavirus family that was identified in Wuhan, China in 209. MVICU SARS-CoV-2 infected patients has a significant mortality that most likely related to cytokine storm associated severe ARDS [1-2]. In severe ARDS, the alveolar architecture with parenchymal lung tissues are diffusely distorted. An exaggerated pro-inflammatory hyperfiltration elicits an hyperinflammatory status called cytokine storm which is the primary culprit for MVICU affected COVID-19 patients’ mortality. Cytokine storm with other interrelated mortality associated storms, particularly hyperoxidative associated radical storm and hypercoagulability associated thrombosis storm, are responsible for the exponential progression in COVID-19 infection status which is necessitating for invasive mechanical ventilation [3-4].

Pathophysiologically, ARDS is primarily emerging from imbalancing between pro-inflammatory/anti-inflammatory mediators and this dysregulated hyperactive diffuse-severe systemic inflammation associated cytokine storm results in mechanical ventilation dependent acute hypoxemic respiratory failure with high mortality (40–60%). As previously mentioned, cytokine storm is commonly accompanied with other subsequential storms, radical and thrombotic storms, which collectively are responsible for exaggerated complications in MVICU-SARS-CoV-2 infected patients [5-11]. While MVICU severe ARDS affected COVID-19 patients are primarily managed on critical care units, there is no specific highly cost-effective drug, rather than corticosteroidal agents, can mitigate the cytokine storm and consequently the sequential complications accompanied with this storm. The clinical effectiveness of corticosteroidal drugs, most commonly Dexamethasone and Methylprednisolone, is extrapolated from continuously emerging data regarding corticosteroidal positive clinical impacts in management mechanically intubated SARS-CoV-2 infected patients. Practically, Dexamethasone 6 mg PO or IV and Methylprednisolone 20 mg IV Q 12 hours are now considered as part of 1^st line therapeutics protocol in early management of severe ARDS affected COVID-19 patients [12-13].

Although there has been continuously emerging data which signify the corticosteroidal dual anti-inflammatory/anti-fibrotic effects and their powerful rebalancing efficacy in distorted hyper-inflammatory/anti-inflammatory imbalances, the clinical efficacy of corticosteroidal therapeutics in COVID-19 related complications remains controversial [14-17]. In this study, we evaluated those corticosteroidal emerging pieces of evidence in our institutional admitted MVICU patients and additionally, we elucidated whether the higher dose regimens (HD) of corticosteroidal drugs had superior positive clinical impacts over the standard dose regimens (SD). Initially, we postulated that higher dose regimens of Dexamethasone [DEX HD Cohort, 6 mg Q 12 hrs] and Methylprednisolone [MET HD Cohort, 40 mg Q 12 hrs] could have significantly superior clinical advantages compared with standard-dose regimens of Dexamethasone [DEX SD Cohort, 6 mg Q 24 hrs] and Methylprednisolone [MET SD Cohort, 20 mg Q 12 hrs].

This study was retrospectively conducted on admitted MVICU ARDS affected COVID-19 patients at Queen Alia Military Hospital isolation department, Royal Medical Services, Amman, Jordan. The study was reviewed and approved by our Institutional Review Board at Royal Medical Services under reference number of 54_12/2021. All demographical, co-morbidities, biochemical, clinical, radiological andpharmacological data were retrospectively collected from our electronic medical record system (Hakeem) over 19 months between Mar 2020 and Sep 2021. Severe ARDS affected SARS-CoV-2 infected patients who aged above 18 years and who stay at least 3 days on ICU. Both of confirmed and suspected affected critically ill COVID-19 patients were included in our study. SARS-CoV-2 infected patients whose PCR test were negative but had clinical, radiological andbiochemical signs of COVID-19 infection were considered as suspected. Also, patients who had more than 20% of missing data were excluded from our study. A signed consent form was waived owing to the study’s retrospective design. In our study, severe ARDS affected COVID-19 patients were numerically translated into persistent average Pa02/FiO2<200 with radiologically evidences of pulmonary architecture distortions.

Comparative variables were compared across four MVICU severe ARDS affected SARS-CoV-2 infected patients allocated cohorts [DEX SD Cohort (6 mg IV Q 24 hours), MET SD Cohort (20 mg IV Q 12 hours), DEX HD Cohort (6 mg IV Q 12 hours) and MET HD Cohort (40 mg IV Q 12 hours)]. Comparative studied variables were firstly evaluated for normality of distribution by using Kolmogorov-Smirnov Test. One-Way ANOVA Test was conducted to analyze the continuous variables and to express their results as Mean ± SD. In other side, non-parametric categorical/ordinal variables were analyzed by Chi Square Test and the analysis outcomes were presented as Number (Percentages). The primary outcomes of our study were to compare the major clinical impacts of length of stay days (ICU and overall hospital) and 28-day overall ICU mortality rates across the two investigated corticosteroidal dose regimens (SD vs HD and among the two tested corticosteroidal drugs (DEX vs MET). Statistical analyses were performed using IBM SPSS ver. 25 (IBM Corp., Armonk, NY, USA) and p-values ≤0.05 were considered statistically significant.

From three hundred and seventy-four (N = 374) adult and elderly admitted MVICU severe affected ARDS SARS-CoV-2 infected patients in our isolation department at Queen Alia Military Hospital, Royal Medical Services, Amman, Jordan between March 2020 and Sep 2021, two hundred and forty-three (N = 243) were finally included in this study with sixty (N = 60), fifty (N = 50), twelve (N = 12), twenty-four (N = 24) andthirteen (N = 13) cases were excluded from the study due to either not developing moderate-severe ARDS (persistent Pa02: FiO2<200 and radiologically confirmed), not receiving Dexamethasone or Methylprednisolone as the steroid of choice, not receiving steroidal agents at all andmissing data exceeding 20%, respectively. One hundred and twenty-one (N = 121, 49.8%) of the eligible affected COVID-19 patients have received the standard doses of Dexamethasone (N = 61, 25.1%) and Methylprednisolone (N = 60, 24.7%) which are equivalent to 6 mg IV once daily and 20 mg IV twice daily, respectively. In contrast, one hundred and twenty-two (N = 122, 50.2%) of the eligible whole tested cohort were received the higher doses of Dexamethasone (N = 63, 25.9%) and Methylprednisolone (N = 59, 24.3%) which are equivalent to 6 mg IV twice daily and 40 mg IV twice daily, respectively.

The average age of our whole study cohort was 59.80 ±10.74 years andthe DEX Cohorts [DEX SD Cohort and DEX HD Cohort] were insignificantly older than the MET Cohorts [MET SD Cohort and MET HD Cohort] with Mean±SD of 61.55±12.18 years and 60.65 ±9.45 years versus 56.78±8.65 years and 59.8±11.76 years, respectively, p>0.05). Significantly, males were distributed in the study in M: F ratio of approximately 2.42: 1 [162 (66.67%) versus 67 (27.57%), respectively, p<0.05] in which 53 (86.89%), 35 (58.33%), 37 (58.73%) and37 (62.71%) of the admitted MVICU severe affected ARDS SARS-CoV-2 infected men were allocated into Group I [DEX SD Cohort], Group II [MET SD Cohort], Group III [DEX HD Cohort] andGroup IV [MET HD Cohort] compared to 8 (13.11%), 25 (41.67%), 26 (41.27%) and22 (37.29%) of the admitted MVICU severe affected ARDS SARS-CoV-2 infected women, respectively.

The primary outcome of this study (An overall 28-day ICU mortality) was detected in one hundred and thirty-six (N = 136) of the admitted MVICU severe affected ARDS SARS-CoV-2 infected patients with an overall incidence of 55.97% during an average of 13.40±4.79 days and 19.67±6.81 days of the ICU and hospital stay days, respectively, in which it was significantly lowest in the DEX HD Cohort [27 (42.86%)] followed by MET HD Cohort [33 (55.93%)], MET SD Cohort [37 (61.67%)] andlastly by DEX SD Cohort [39 (63.93%)]. Also in our study, we further subdivided the overall 28-day ICU mortality into two phases, The Early Phase (≤14 days) and the Late Phase (>14 days), for which the incidence of mortality of our eligible admitted MVICU severe affected ARDS SARS-CoV-2 infected patients was significantly lower in the Early Phase compared to the Late Phase [60 (24.69%) vs 76 (31.28%), respectively, p<0.05].

Hemodynamically, the Shock Index (SI) is significantly lower in the MET Cohorts [MET HD Cohort and MET SD Cohort] compared with DEX Cohorts [DEX HD Cohort and DEX SD Cohort] with Mean ± SD of (1.12±0.03 bpm/mmHg and 1.22±0.04 bpm/mmHg) vs (1.29±0.17 bpm/mmHg and 1.31±0.23 bpm/mmHg) even though there was a statistically insignificant difference regarding Norepinephrine (NE) rate across the aforementioned cohorts (9.01±1.67 mcg/min and 9.94±1.89 mcg/min) vs (9.27±1.68 mcg/min and 9.55±2.49 mcg/min), respectively. Biochemically, the diagnostic and prognostic biochemical indicators of C-Reactive Protein (CRP), Ferritin (FER), Lactate Dehydrogenase (LDH) andD-Dimer had significantly distributed values in order that matched the overall 28-day ICU mortality in which the DEX HD Cohort had the lowest significant values and the DEX SD Cohort had the highest significant values [88.38±34.38 mg/dL, 465.8±154.1 ng/mL, 234.6±34.2 IU/ml and0.58±0.21 mg/L, respectively, p<0.05] vs [156.55±51.88 mg/dL, 1009.9±465.9 ng/mL, 414.2±67.1 IU/L and0.87±0.33 mg/l, respectively, p<0.05]. Also, the derivative diagnostic and prognostic ratios of CRP: ALB and FER: ALB were significantly ordered in the same aforementioned manner, DEX HD Cohort [31.92±19.06 and 176.3±76.6] < MET HD Cohort [53.76±27.09 and 293.2±107.6] <MET SD Cohort [58.71±24.91 and 346.1±112.9] <DEX SD Cohort [61.47±21.11 and 396.3±175.9], respectively, p<0.05.

Table 1:   Comparatively Studied Variables between Group I (DEX SD Cohort), Group II (MET SD Cohort), Group III (DEX HD Cohort), and Group IV (MET HD Cohort) among Admitted Critically Ill SARS-CoV-2 Infected Patients at Queen Alia Military Hospital, Jordan between Mar 2020 and Sep 2021

The parametric comparative variables are presented as Mean ± SD and are analyzed by using ANOVA Test. While the non-parametric comparative variables are presented as either Number (Percentage) by using Chi Square Test, Group I (DEX SD Cohort): Mechanically ventilated critically ill severe ARDS affected SARS-CoV-2 infected patients whose cytokine storm was primarily managed by the Standard Dose (SD) of Dexamethasone (DEX) which is equivalent to 6 mg IV once daily, Group II (MET SD Cohort): Mechanically ventilated critically ill severe ARDS affected SARS-CoV-2 infected patients whose cytokine storm was primarily managed by the Standard Dose (SD) of Methylprednisolone (MET) which is equivalent to 20 mg IV twice daily, Group III (DEX HD Cohort): Mechanically ventilated critically ill severe ARDS affected SARS-CoV-2 infected patients whose cytokine storm was primarily managed by the higher dose (HD) of Dexamethasone (DEX) which is equivalent to 6 mg IV twice daily, Group IV (MET SD Cohort Mechanically ventilated critically ill severe ARDS affected SARS-CoV-2 infected patients whose cytokine storm was primarily managed by the Standard Dose (HD) of Methylprednisolone (MET) which is equivalent to 40 mg IV twice daily. FiO2: Fraction of Inspired oxygen, PaO2: Partial Pressure of Oxygen, PaCO2: Partial Pressure of Carbon Dioxide. PD: Protein density, ARDS: Acute respiratory distress syndrome, GCS: Glasgow coma scale, T_avg: The average of core body temperature, T_var: The variation of core body temperature, LOS: Length of stay day(s), SD: Standard Dose, HD: Higher Dose, DEX: Dexamethasone, MET: Methylprednisolone, Cs: Corticosteroid

Table 2: Comparatively studied variables between Group I (DEX SD Cohort), Group II (MET SD Cohort), Group III (DEX HD Cohort) and Group IV (MET HD Cohort) among admitted critically ill SARS-CoV-2 infected patients at Queen Alia Military Hospital, Jordan between Mar 2020 and Sep 2021

The parametric comparative variables are presented as Mean ± SD and are analyzed by using ANOVA Test. While the non-parametric comparative variables are presented as either Number (Percentage) by using Chi Square Test, Group I (DEX SD Cohort): Mechanically ventilated critically ill severe ARDS affected SARS-CoV-2 infected patients whose cytokine storm was primarily managed by the Standard Dose (SD) of Dexamethasone (DEX) which is equivalent to 6 mg IV once daily, Group II (MET SD Cohort): Mechanically ventilated critically ill severe ARDS affected SARS-CoV-2 infected patients whose cytokine storm was primarily managed by the Standard Dose (SD) of Methylprednisolone (MET) which is equivalent to 20 mg IV twice daily, Group III (DEX HD Cohort): Mechanically ventilated critically ill severe ARDS affected SARS-CoV-2 infected patients whose cytokine storm was primarily managed by the Higher Dose (HD) of Dexamethasone (DEX) which is equivalent to 6 mg IV twice daily, Group IV (MET SD Cohort Mechanically ventilated critically ill severe ARDS affected SARS-CoV-2 infected patients whose cytokine storm was primarily managed by the standard dose (HD) of Methylprednisolone (MET) which is equivalent to 40 mg IV twice daily, Years: Years, CRP: C-Reactive Protein, CRP: ALB: C-reactive protein to Albumin Ratio, ALB: Albumin Level, ARDS: Acute Respiratory Distress Syndrome, H.ALB: Human Albumin 20%, N: Number of study’s hospitalized patients, LDH: Lactate Dehydrogenase, SI: Shock Index, FER: Ferritin level, SD: Standard Dose, HD: Higher Dose, DEX: Dexamethasone, MET: Methylprednisolone, CrCl: Creatinine Clearance, UO: Urine Output

Though there were insignificant differences across the four tested Cohorts I-IV regarding average core body temperature (T_avg), [37.91±3.31°C, 37.34±2.66°C, 37.51±0.45°C and37.40±1.53°C, respectively, p>0.05], the daily core body temperature variation was significantly lowest in Group III [4.9%±0.7%] followed by Group IV [5.6%±2.5%], Group II [6.7%±2.4%] and lastly Group I [9.5%±2.1%]. Across our tested Group I-IV, there were insignificant differences regarding the Glasgow Coma Scale (GSC), Child-Pugh Score, anthropometric Body Weight (BW), estimated Creatinine Clearance (CrCl) and the analgosedative of morphine infusion rate with an overall Median (Range) or Mean ± SD of [12 (12-13), 6 (6-8), 73.91±10.33 kg, 72.8±23.5 mL/min and 2.46±1.74 mg/hr, respectively, p>0.05]. The Mechanically ventilated critically ill SARS-CoV-2 infected patients’ comparative variables and analyzed outcome data between DEX SD Cohort [Group I], MET SD Cohort [Group II], DEX HD Cohort [Group III] andMET HD Cohort [Group IV] are fully summarized in Tables 1 and 2.

An observational- retrospective study was conducted in the COVID-19 isolation critical care unit at Queen Alia Military Hospital, Jordan between March 2020 and Sep 2021. Our study included four proposed corticosteroidal dose regimens which were distributed evenly across four admitted MVICU severe affected ARDS SARS-CoV-2 infected cohorts [DEX SD Cohort (6 mg IV once daily), MET SD Cohort (20 mg IV twice daily), DEX HD Cohort (6 mg IV twice daily) and MET HD Cohort (40 mg IV twice daily)]. In this emerging debatable issue during the corresponding outbreaks of COVID-19, therapeutic immuno-suppressive/immuno-modulator drugs were initially proposed based on many strong knowledgeable-based rationales and theories [18-19]. Systemic administration of Dexamethasone or Methylprednisolone, the most two commonly used systemic corticosteroids, has been proposed as a cytokine storm controller and an alternative salvage treatment tool to early mitigate the SARS-CoV-2-associated mortality in these mechanically ventilated critically ill patients [20-22]. Since the global outbreak of COVID-19 diseases, corticosteroids had been extensively used in advanced COVID-19 infectious cases management, specifically the ARDS affected mechanically ventilated critically ill patients with evidence of cytokine storm associated pulmonary V-Q mismatching [23-24]. To the best of our knowledge, at least in our middle-east regions, the uniqueness of this study is primarily involved in the direct comparison of two investigated corticosteroidal drugs (Dexamethasone vs Methylprednisolone) among two proposed dose regimens (SD vs HD) in severe ARDS affected mechanically ventilated critically ill SARS-CoV-2 infected patients regarding major clinical outcomes of admission days (ICU and overall hospital) and mortality (early, late and 28-day overall mortality).

The rationales for the immuno-suppressive role of corticosteroids in the management of COVID-19 diseases eliciting immuno-mediated Acute Lung Injury (ALI) are primarily based on postmortem histopathology observations [25-27]. In addition to the reported postmortem case series and afterward retrospectively or prospectively, non-randomized andobservational studies, the significant positive impacts that were investigated in the UK randomized, controlled andopen-label studies, positioned corticosteroidal therapeutics as the most and first evidence-based highly cost-effective therapeutic modality that most likely benefit severe SARS-CoV-2 infected patients with an expected positive clinical outcomes, including but not excluded to, improving Ventilation Free Days (VFDs), reducing ICU and overall hospital LOS, lowering the probability of immuno-mediated associated Multi-Organs Failure (MOF), facilitating the post-ICU recovery phase, minimizing the burden of COVID-19 associated complications, lowering the risk of early, late andoverall mortality [28-30].

Despite the aforementioned positive outcomes expected from using corticosteroidal agents (Cs) in severe COVID-19 cases, there is still uncertainty about whether a Higher Dose regimen (HD) of Dexamethasone or Methylprednisolone could provide a greater benefit, especially in the severe ARDS affected mechanically ventilated critically ill COVID-19 patients. Villar et al. clinical trial, 277 moderate-severe ARDS affected hospitalized affected COVID-19 patients intervened with either low dose (<10 mg/day) of Dexamethasone IV [equivalent to the DEX SD that was used in our study], moderate dose (<20 mg/day) of Dexamethasone IV [equivalent to the DEX HD that was used in our study], or standard care without corticosteroidal management. The aforementioned study revealed that a low-moderate dose of Dexamethasone IV for an average course time of 10 days had sizable significant positive outcomes regarding VFDs and overall ICU mortality rate. [31-32] Similarly, Our study demonstrated a mortality benefits in the tested MVICU severe ARDS affected SARS-CoV-2 infected patients for the two investigated Cs (Dexamethasone and Methylprednisolone) at the two investigated dose strengths (Standard dose and higher dose) over an insignificant average Cs course time of 9.33±2.87 days for which it was significantly lowest in the DEX HD Cohort [27 (42.86%)] followed by MET HD Cohort [33 (55.93%)], MET SD Cohort [37 (61.67%)] and lastly by DEX SD Cohort [39 (63.93%)]. However, results for the Cs role in COVID-19 diseases are inconclusive in most studies due to fact that the Cs may also delay the clearance of SARS-CoV-2 viruses and even be harmful to the treated patients if they are early used among hospitalized SARS.CoV-2 infected patients [33-34].

Although there were insignificant differences across the Group I-IV in analgosedative requirements of Morphine and the vasopressor requirements of Norepinephrine [2.37±1.68 mg/hr and 9.55±2.49 mcg/min vs 2.26±1.85 mg/hr and 9.94±1.89 mcg/min vs 2.60±1.71 mg/hr and 9.27±1.68 mcg/min vs 2.69±1.74 mg/hr and 9.01±1.67 mcg/min, retrospectively, p>0.05], the septic shock (SI) which were significantly lower in HD Group I vs SD Group II [12.12±2.91 mcg/min vs 14.23±3.00 mcg/min, respectively, p<0.05], the Shock Index (SI), a bedside hemodynamic stability assessment indicator that numerically defines as Heart Rate (HR) over Systolic Blood Pressure (SBP) with a normal range of 0.5 to 0.7 in healthy adults, is significantly lowest in the MET Cohorts [MET HD Cohort (1.12±0.03 bpm/mmHg) and MET SD Cohort (1.22±0.04 bpm/mmHg)] compared with DEX Cohorts [DEX HD Cohort (1.29±0.17 bpm/mmHg) and DEX SD Cohort (1.31±0.23 bpm/mmHg)], respectively, p<0.05. The significantly lower SI in MET Cohorts compared with DEX Cohorts is most likely due to higher mineralocorticoid activity for Methylprednisolone (1/2 Cortisol at equivalent dose) compared with Dexamethasone (No mineralocorticoid activity) [35].

Generally, the COVID-19 associated complications and mortality result from complex and interrelated pathology mechanistics of uncontrolled dysfunctional hyperimmunity reactions, hyperinflammatory associated cytokine storm, exaggerated positive acute phase reactants of C-Reactive Protein (CRP) and Ferritin (FER) levels, hyper-oxidative stress associated radical storm andhypercoagulopathy associated thrombotic storm [36]. Many studies investigated the validities, utilities, performances, sensitivities, specificities, accuracies, positive and negative predictive values andthe youden’s indices for numerous proposed biochemical indicators as an early diagnosticator or prognosticator or both for COVID-19 diseases. The most commonly used prognosticators in SARS-CoV-2 infected critically ill patients either mechanically ventilated or non-intubated, including but not excluded to, CRP, FER, ratios of CRP and FER to albumin levels (CRP: ALB and FER: ALB, respectively), D-Dimer andLactate Dehydrogenase (LDH) [37]. In this study, we demonstrated a significantly lower Mean ± SD of CRP, FER, LDH, D-Dimer, CRP: ALB andFER: ALB prognosticators in HD Cohorts compared with SD Cohorts as thoroughly described in the result section.

In conclusion, higher dose regimens of either Dexamethasone (12 mg/day) or Methylprednisolone (80 mg/day) in severe affected ARDS mechanically ventilated critically ill SARS-CoV-2 infected patients have a significantly higher positive clinical impact, including but not excluded to, admission days and mortalities compared with lower dose regimens of either Dexamethasone (6 mg/day) or Methylprednisolone (40 mg/day). Individually, Methylprednisolone 40 mg/day has superior positive clinical impacts over Dexamethasone 6 mg/day at the lower Cs level while at the higher Cs level, Dexamethasone 12 mg/day has superior positive clinical impacts over Methylprednisolone 80 mg/day. The retrospective, observational and single center design of our study may limit the value of its conclusions. Despite these limitations, our conclusions may have an added value to the current excessively evolving controversial pieces of evidence regarding the clear role of higher versus lower dose regimens of various Cs in severe ARDS-affected COVID-19 management, especially in the mechanically ventilated critically ill cohorts.

1. Centers for Disease Control and Prevention. “2019 Novel Coronavirus, Wuhan, China. Information for Healthcare Professionals.” CDC, https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html. Accessed 14 Feb. 2020.

2. World Health Organization (WHO). “Novel Coronavirus – China.” WHO, www.who.int/csr/don/12-january-2020-novel-coronavirus-china/en/. Accessed 9 July 2020.

3. Carsana, L. et al. “Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: A two-centre descriptive study.” The Lancet Infectious Diseases, vol. 20, 2020, pp. 1135–1140. https://doi.org/10.1016/S1473-3099(20)30434-5.

4. Ackermann, M. et al. “Pulmonary vascular endothelialitis, thrombosis andangiogenesis in COVID-19.” New England Journal of Medicine, vol. 383, 2020, pp. 120–128. https://doi.org/10.1056/NEJMoa2015432.

5. Matthay, M.A. et al. “Acute respiratory distress syndrome.” Nature Reviews Disease Primers, vol. 5, 2019. https://doi.org/10.1038/s41572-019-0069-0.

6. Wu, Z. and J.M. McGoogan. “Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention.” JAMA, vol. 323, no. 13, 2020, pp. 1239–1242. https://doi.org/10.1001/jama.2020.2648.

7. Guan, W.J. et al. “Clinical characteristics of coronavirus disease 2019 in China.” New England Journal of Medicine, vol. 382, 2020, pp. 1708–1720. https://doi.org/10.1056/NEJMoa2002032.

8. Ferrando, C. et al. “Clinical features, ventilatory management andoutcome of ARDS caused by COVID-19 are similar to other causes of ARDS.” Intensive Care Medicine, vol. 46, 2020, pp. 2200–2211. https://doi.org/10.1007/s00134-020-06192-2.

9. Nadeem, A. et al. “ICU outcomes of COVID-19 critically ill patients: An international comparative study.” Anaesthesia Critical Care and Pain Medicine, vol. 39, 2020, pp. 487–489. https://doi.org/10.1016/j.accpm.2020.07.005.

10. Meduri, G.U. et al. “Activation and regulation of systemic inflammation in ARDS: Rationale for prolonged glucocorticoid therapy.” Chest, vol. 136, 2009, pp. 1631–1643. https://doi.org/10.1378/chest.08-2408.

11.  Wu, C. et al. “Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.” JAMA Internal Medicine, vol. 180, 2020, pp. 1–11. https://doi.org/10.1001/jamainternmed.2020.0994.

12. Bouadma, L. et al. “Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists.” Intensive Care Medicine, vol. 46, 2020, pp. 579–82.

13.  Vardhana, S.A. and J.D. Wolchok. “The many faces of the anti-COVID immune response.” Journal of Experimental Medicine, vol. 217, 2020, e20200678. https://doi.org/10.1084/jem.20200678.

14. Fu, Y. et al. “Understanding SARS-CoV-2-mediated inflammatory responses: From mechanisms to potential therapeutic tools.” Virologica Sinica, vol. 35, 2020, pp. 266–71. https://doi.org/10.1007/s12250-020-00207-4.

15. Rhen, T. andJ.A. Cidlowski. “Anti-inflammatory action of glucocorticoids-new mechanisms for old drugs.” New England Journal of Medicine, vol. 353, 2005, pp. 1711–23.

16. Annane, D. et al. “Guidelines for the diagnosis and management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in critically ill patients (part 1): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017.” Critical Care Medicine, vol. 45, 2017, pp. 2078–88.

17. Mehta, P. et al. “COVID-19: consider cytokine storm syndromes and immunosuppression.” The Lancet, vol. 395, 2020, pp. 1033–34. https://doi.org/10.1016/S0140-6736(20)30628-0.

18. Zhang, W. et al. “The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The perspectives of clinical immunologists from China.” Clinical Immunology, vol. 214, 2020, 108393. https://doi.org/10.1016/j.clim.2020.108393.

19. Tobaiqy, M. et al. “Therapeutic management of patients with COVID-19: A systematic review.” Infection Prevention in Practice, vol. 2, 2020, 100061. https://doi.org/10.1016/j.infpip.2020.100061.

20. Dorward, D.A. et al. “Tissue-specific tolerance in fatal COVID-19.” medRxiv, 2020. https://doi.org/10.1101/2020.07.02.20145003.

21.  Ye, Q. et al. “The pathogenesis and treatment of the ‘cytokine storm’ in COVID-19.” Journal of Infection, vol. 80, 2020, pp. 607–13. https://doi.org/10.1016/j.jinf.2020.03.037.

22. Randomised Evaluation of COVID-19 Therapy (RECOVERY). Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19. 2020. https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19. Accessed 12 July 2020.

23. Sterne, J.A.C. et al. “Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: A meta-analysis.” JAMA, vol. 324, 2020, pp. 1–13. https://doi.org/10.1001/jama.2020.17023.

24. Tomazini, B.M. et al. “Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial.” JAMA, vol. 324, 2020, pp. 1–11. https://doi.org/10.1001/jama.2020.17021.

25. Yang, Z. et al. “The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis.” Journal of Infection, vol. 81, 2020, e13–e20. https://doi.org/10.1016/j.jinf.2020.03.062.

26. Dequin, P.F. et al. “Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: A randomized clinical trial.” JAMA, vol. 324, 2020, pp. 1–9. https://doi.org/10.1001/jama.2020.16761.

27. Angus, D.C. et al. “Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain randomized clinical trial.” JAMA, vol. 324, 2020, pp. 1317–29. https://doi.org/10.1001/jama.2020.17022.

28. Villar, J. and A.S. Slutsky. “Golden anniversary of the acute respiratory distress syndrome: Still much work to do!” Current Opinion in Critical Care, vol. 23, 2017, pp. 4–9.

29. Arabi, Y.M. et al. “Corticosteroid therapy for critically ill patients with the Middle East respiratory syndrome.” American Journal of Respiratory and Critical Care Medicine, vol. 197, 2018, pp. 757–67. https://doi.org/10.1164/rccm.201706-1172OC.

30. Kolilekas, L. et al. “Can steroids reverse the severe COVID-19 induced ‘cytokine storm’?” Journal of Medical Virology, 2020. https://doi.org/10.1002/jmv.26165.

31. Fadel, R. et al. “Early short course corticosteroids in hospitalized patients with COVID-19.” Clinical Infectious Diseases, 2020, ciaa601. https://doi.org/10.1093/cid/ciaa601.

32. Stewart, P.M. and N.P. Krone. “The Adrenal Cortex.” In: Williams Textbook of Endocrinology. Melmed, S. et al. (Eds.), Saunders Elsevier, 2011.

33. Petrilli, C.M. et al. “Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: Prospective cohort study.” BMJ, vol. 369, 2020, m1966. https://doi.org/10.1136/bmj.m1966.

34. Liu, T. et al. “The role of interleukin-6 in monitoring severe case of coronavirus disease 2019.” EMBO Molecular Medicine, vol. 12, 2020, e12421. https://doi.org/10.15252/emmm.202012421.

35. Ishida, I. et al. “Serum albumin levels correlate with inflammation rather than nutrition supply in burns patients: A retrospective study.” Journal of Medical Investigation, vol. 61, no. 3–4, 2014, pp. 361–68.

36. Zha, Q. et al. “Study on early laboratory warning of severe COVID-19.” Laboratory Medicine, vol. 35, 2020, pp. 557–60. https://doi.org/10.3969/j.issn.1673-8640.2020.06.009.

37. Song, H. et al. “Predictive value of multiple inflammatory indexes on the prognosis of patients with coronavirus disease 2019.” Practical Journal of Cardiac Cerebral Pneumal and Vascular Disease, vol. 28, 2020, pp. 13–16. https://doi.org/10.3969/j.issn.1008-5971.2020.06.003.