Supplementary Table 2. Current studies investigating COVID-19/ other coronavirus strains and low-dose steroids.

Study Ref	Title	Authors	Country of study	Year	Summary of results
[22]	Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools	Fu, Cheng and Wu	China	2020	This review suggests that: SARS-CoV S protein can downregulate ACE2 Loss of pulmonary ACE2 function has been suggested to be associated with acute lung injury; the reduction in ACE2 function can cause dysfunction of the renin-angiotensin system [23] and enhance inflammation and vascular permeability. ACE2-associated lung injury has been suggested in SARS- CoV infection From reading this article the following article was then discovered…
[24]	Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?	Fang, Karakiulakis and Roth	Greece	2020	The expression of ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs). Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2 ACE2 can be increased by thiazolidinediones and ibuprofen. These data suggest that ACE2 expression is increased in diabetes and treatment with ACE inhibitors and ARBs increases ACE2 expression. Consequently, the increased expression of ACE2 would facilitate infection with COVID-19. The authors therefore hypothesise that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19.
[25]	Drug treatment options for the 2019-new coronavirus (2019- nCoV)	Lu	China	2020	No evidence given for or against using ibuprofen only that ‘anti-inflammatory drugs (such as hormones and other molecules)’ are potential therapeutic options for 2019-nCoV.
[26]	Severe acute respiratory syndrome: clinical and laboratory manifestations.	Lam, Chan, Wong	China	2004	Corticosteroid treatment reduced interleukin 8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and IFN-γ-inducible protein-10 (IP-10) concentrations from 5 - 8 days after treatment in SARS patients. These were all inflammatory markers which were remarkably increased in SARS patients. NB. This study is not specifically looking at SARS-CoV2 only at SARS-CoV.
[27]	Decoding the enigma of antiviral crisis: Does one target molecule regulate all?	Mahmud-Al-Rafat et al	Bangladesh, Germany, Canada, UK and Australia	2019	This review article aimed to look at multiple diseases caused by various viruses including Dengue, Ebola and SARS-CoV. They stated that ribavirin (an antiviral) is the most frequently used drug to combat SARS-CoV, and is administered together with corticosteroids. Although immunosuppressive corticosteroid drugs are commonly used in an attempt to reduce fatality rates, the results of clinical trials are not sufficiently satisfactory to approve as an effective class of therapeutic Glucocorticoid-mediated stimulation of the hypothalamic-pituitaryadrenal axis can also drive lymphocytopenia, or it may promote exaggerated pro-inflammatory responses that eventually cause a worsening of the pathogenic condition. (Please note this is not specific for SARS-CoV-19 and is referring to the 3 viral diseases mentioned).
[28]	The management of coronavirus infections with particular reference to SARS.	Wong SS, Yuen KY		2008	HCoV-OC43 and HCoV-229E initial principal pathogens discovered in 1960’s; acute respiratory diseases of less severity and mortality than SARS-CoV which promoted rapid search for effective antiviral treatments. Immunomodulatory agents (primarily corticosteroids) widely used during SARS to avoid excessive tissue damage by cytokine dysregulation but benefit of use not conclusively demonstrated. Multiple studies demonstrated increased plasma viral load with use of corticosteroids (RCT measured plasma viral load at regular intervals in non-intubated cases found higher concentrations of SARS-CoV RNA in week 2/3 of illness compared to patients who received placebo). 9.9% of patients in Hong Kong cohort study also suffered opportunitistic infections such as aspergillosis and late sequelae (including avascular osteonecrosis) with corticosteroid use.
[29]	Cytokine responses in porcine respiratory coronavirus-infected pigs treated with corticosteroids as a model for severe acute respiratory syndrome.	Zhang X, Alekseev K, Jung K, Vlasova A, Hadya N, Saif LJ	USA	2008	Laboratory study which treated porcine respiratory coronavirus infected pigs with corticosteroid dexamethasone as a model for SARS. Goal to define whether corticosteroid treatment altered immunity and lung inflammatory response at cytokine level and how changes correlated with pig lung lesions. Confirmed infection model applicable and resembled SARS. Treatment with dexamethasone suppressed early local IL-6 levels but increased later on in disease. Suggests may decrease inflammation at early infection stage but not later. Results also suggest that dexamethasone induced reduction of IL-6 might play a role in delayed onset of lung lesions but increases of IL-6 at later infection stage may contribute to severity of lung lesions (mimicking delayed onset of disease severity as seen in SARS patients treated with corticosteroids). Overall findings suggest that 1 or 2 doses of dexamethasone in acute phase of infection may effectively alleviate early pro-inflammatory response, but prolonged DEX administration may play role in enhancing viral replication.
[30]	Indomethacin has a potent antiviral activity against SARS coronavirus.	Amici C, Di Caro A, Ciucci A, Chiappa L, Castilletti C, Martella V, Decaro N, Buonavoglia C, Capobianchi MR, Santoro MG	Italy	2006	Utilised observation that cyclopentenone cyclooxygenase (COX) metabolites are active against several RNA viruses to investigate effect of COX inhibitor indomethacin on coronavirus replication. Indomethacin is common NSAID. Report describes how indomethacin was unexpectedly found to possess potent antiviral activity against canine coronavirus (dramatically inhibit virus replication and protect the host cell from virus-induced damage). Activity also observed in vivo and against human SARS-CoV. Oral administration of concentration 1mg/kg found to be effective.
[31]	A study of pulmonary inflammatory reaction induced by N-protein of SARS-CoV in rat models and effects of glucocorticoids on it	Hao D, He LX, Qu JM, Pan J, Hu BJ, Zhang J, Li ZZ	China (full article only available in Chinese but informative abstract)	2005	Studied pulmonary inflammatory reaction induced by N-protein of SARS-CoV in rat models and effects of glucocorticoids on inflammatory reaction. Mice treated with dexamethasone. N-protein of SARS-CoV shown to have pathogenicity inducing pulmonary inflammatory reaction and acute lung injury which were related to the increase and imbalance of pro-inflammatory and anti-inflammatory cytokines. Glucocorticoids (dexamethasone) demonstrated effectively alleviate pulmonary inflammatory reaction.
[32]	Overview of antiviral and anti-inflammatory treatment for severe acute respiratory syndrome.	Chihrin S, Loutfy MR	Canada	2014	Anti-inflammatory agents heavily utilised during SARS outbreak as it was believed that the development and worsening of the pulmonary disease had inflammatory aetiology and pathogenesis. Immunopathological analysis of 20 SARS patients demonstrated increased Th1 cytokine interferon y and inflammatory cytokines IL-1, IL-6 and IL-12 for > 2 weeks following onset of symptoms. Also observed decrease in viral activity and IgG seroconversion during 2nd week of illness despite general progression of respiratory disease- suggesting respiratory damage is secondary to immune-mediated inflammatory response. Corticosteroids used during SARS outbreak for their ability to module variety of involved cytokines. Numerous papers published outcomes of patients administered corticosteroids (mostly IV hydrocortisone or methylprednisolone) in either early low-dose or pulsed-dose strategies. Most concluded corticosteroids appeared to be effective in reducing immunopathological damage (resulting in improved and rapid resolution of symptoms). Opposition to corticosteroid use centred around use of corticosteroid use in treatment of acute respiratory distress syndrome- concern that corticosteroid treatment may weaken immune response and promote viral rebound. Reports also add evidence to theory. Further opposition includes association with adverse events such as hyperglycaemia, hypokalaemia, hypertension, gastrointestinal haemorrhage and avascular necrosis (AVN).
[33]	High-dose hydrocortisone reduces expression of the pro-inflammatory chemokines CXCL8 and CXCL10 in SARS coronavirus-infected intestinal cells.	Cinatl J Jr, Michaelis M, Morgenstern B, Doerr HW	Germany (needs to be purchased)	2005	Investigated influence of SARS-CoV infection on CXCL8 and CXCL10 in human intestinal epithelial cells. High concentrations of hydrocortisone prevented DNA binding activity of AP-1 and NF-kappabeta and inhibited upregulation of CXCL8 and CXCL10 but did not reduce chemokine expression to basal. Results suggest corticosteroid may be of limited benefit in suppression of chemokine production by SARS-CoV infected cells.
[34]	Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome.	Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan IH, Lit LC, Hui DS, Chan MH, Chung SS, Sung JJ	Hong Kong	2004	Overproduction of TNF-alpha, IL-1, IL-6 and IL-10 hallmark of viral infection. Investigated inflammatory profiles of patients infected with SARS in Hong Kong hospital. Use of corticosteroids significantly reduced IL-8, MCP-1 and IP-10 concentrations from 5-8 days after treatment.
[35]	Description and clinical treatment of an early outbreak of severe acute respiratory syndrome [18] in Guangzhou, PR China.	Zhao Z, Zhang F, Xu M, Huang K, Zhong W, Cai W, Yin Z, Huang S, Deng Z, Wei M, Xiong J, Hawkey PM	China	2003	Patients treated in different methods. 2 groups of 4 received steroids (in form of methyl prednisolone). Early use of high-dose steroids appeared to help recovery from SARS. Early use of high-dose steroids in combination with a quinolone plus azithromycin gave the best outcome with improvement of clinical signs and symptoms, decreased incidence of ARDs and mechanical ventilation as well as mortality. Hypothesised that steroids may help by reducing the damaging effect of the local inflammatory response.