Supplementary Table 4. Current studies investigating COVID-19/ other coronavirus strains and IL-6. (continued).

Study Ref	Title	Authors	Country of study	Year	Summary of results
[38]	Diagnostic Utility of Clinical Laboratory Data Determinations for Patients with the Severe COVID-19.	Gao Y; Li T; Han M; Li X; Wu D; Xu Y; Zhu Y; Liu Y; Wang X; Wang L.	China	2020	They investigated forty‐three adult patients with COVID‐19. The patients were classified into mild group (28 patients) and severe group (15 patients). Comparison of the haematological parameters between the mild and severe groups showed significant differences in IL‐6, D‐Dimer, GLU, TT, FIB and CRP (p <0.05). Infection-related biomarkers appeared to differ between the two groups (IL-6).However, the proportion of IL-6 above normal was [36.10(23.00,59.20) pg/mL]in the severe group, which was significantly higher than that in the mild group [10.60(5.13,24.18) pg/mL]. The AUC of IL-6 which was used to predict the severity of COVID-19 was 0.795 (P<0.0001), which could better predict whetherrCOVID-19 was complicated by severe pneumonia. The optimum critical point of IL-6 in the group was 24.3 pg/ml, which was the upper limit of no severe pneumonia. IL‐6 and D‐Dimer were closely related to the occurrence of severe COVID‐19 in the adult patients, and their combined detection had the highest specificity and sensitivity for early prediction of the severity of COVID‐19 patients.
[39]	Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by COVID-19: anti-inflammatory strategies.	Conti, P; Ronconi, G; Caraffa, A; Gallenga, C; Ross, R; Frydas, I; Kritas, S.	Italy	2020	When COVID-19 infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1b and IL-6. The binding of COVID-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-1b which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1b which is a mediator of lung inflammation, fever and fibrosis. Proinflammatory cytokines levels are correlated with COVID-19 replication and disease. Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections.
[40]	Inhibitory effects of glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells	Yamaya M; Nishimura H; Deng X; Sugawara M; Watanabe O; Nomura K; Shimotai Y; Momma H; Ichinose M; Kawase T.	Netherlands	2020	Primary human nasal (HNE) and tracheal (HTE) epithelial cell cultures were infected with HCoV-229E coronavirus. Pretreatment of HNE and HTE cells with glycopyrronium or formoterol decreased viral RNA levels and/or titers, the expression of the HCoV-229E receptor CD13, the number and fluorescence intensity of acidic endosomes where HCoV-229E RNA enters the cytoplasm, and the infection-induced production of cytokines, including IL-6, IL-8, and IFN-beta. IL-6 and IL-8 are related to airway inflammation in COPD and bronchial asthma exacerbation induced by viral infection. The decreased production of IL-6 and IL-8 in cells pretreated with glycopyrronium, formoterol, and budesonide, as well as the increased inhibitory effects of GFB observed in the present study, may be associated with the inhibitory effects of these drugs on COPD and bronchial asthma exacerbation.
[41]	Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia	Chen, L; Liu, H G; Liu, W; Liu, J; Liu, K; Shang, J; Deng, Y; Wei, S.	China	2020	29 patients with 2019-ncov admitted to the isolation ward of Tongji hospital ( mild (15 cases), severe (9 cases) and critical (5 cases). The expression levels of inflammatory cytokines and other markers in the serum of each group were detected. There were statistically significant differences in the expression levels of interleukin-2 receptor (IL-2R) and IL-6 in the serum of the three groups (p < 0.05), among which the critical group was higher than the severe group and the severe group was higher than the mild group. However, there were no statistically significant differences in serum levels of tumor necrosis factor-alpha (TNF-alpha), IL-1, IL-8, IL-10, hs-CRP, lymphocyte count and LDH among the three groups (P>0.05).
[26]	Severe acute respiratory syndrome: clinical and laboratory manifestations.	Lam, Christopher W K; Chan, Michael H M; Wong, Chun K.	Australia	2004	They have investigated daily changes in plasma inflammatory cytokines and chemokines in 20 adult SARS patients [19 men and 1 woman, mean (SD) age 33 (12) years, range 21–58] for 19 consecutive days upon hospital admission (from ≤ 2 days after disease onset). The cytokine profile showed marked elevation of T-helper lymphocyte type 1 (Th1) cytokine IFN-γ, inflammatory cytokines IL-1β, IL-6 and IL-12 for at least two weeks after disease onset, but there was no significant increase in inflammatory cytokine TNF-α, anti-inflammatory cytokine IL-10, Th1 cytokine IL-2, and T-helper lymphocyte type 2 (Th2) cytokine IL-4. We have also performed serial studies of plasma cytokine and chemokine profiles of 8 children with SARS (5 boys and 3 girls, age 0.3 – 6.2 years) and found that these patients had a much milder cytokine and chemokine storm, rendering the use of corticosteroids more controversial if not unjustified.
[42]	Clinical Progression and Cytokine Profiles of Middle East Respiratory Syndrome Coronavirus Infection.	Kim ES; Choe PG; Park WB; Oh HS; Kim EJ; Nam EY; Na SH; Kim M; Song KH; Bang JH; Park SW; Kim HB; Kim NJ; Oh MD.	Korea (South)	2016	17 patients with laboratory-confirmed MERS-CoV during the 2015 outbreak in Korea were studied. The severe group had higher neutrophil counts during week 1 than the mild group (4,500 versus 2,200/muL, P = 0.026). In the second week of illness, the severe group had higher serum levels of IL-6 (54 versus 4 pg/ml, p = 0.006) and CXCL-10 (2,642 versus 382 pg/ml, p < 0.001).
[27]	Decoding the enigma of antiviral crisis: Does one target molecule regulate all?. [Review]	Mahmud-Al-Rafat A; Majumder A; Taufiqur Rahman KM; Mahedi Hasan AM; Didarul Islam KM; Taylor-Robinson AW; Billah MM	England	2019	IL-6 Interleukin acts as a mediator between pro- and anti-inflammatory reactivity by initiating trans- and classical-signalling, which might relate to the cytokine storm that is triggered by excessive pro-inflammatory responses to Ebola, SARS-CoV and dengue infections in humans. Future antivirals should thus aim to target the mechanism that regulates switching between IL-6 trans- and classical-signaling The tumour necrosis factor-α converting enzyme ADAM-17 could be the master molecule involved in regulating IL-6 class switching and through this in controlling pro- and anti-inflammatory responses to viral antigenic stimuli. ADAM-17 should be considered as a potential target molecule for novel antiviral drug discovery that would regulate host reactivity to infection and thereby limit or prevent fatal outcomes.
[43]	Extraordinary GU-rich single-strand RNA identified from SARS coronavirus contributes an excessive innate immune response.	Li Y; Chen M; Cao H; Zhu Y; Zheng J; Zhou H.	France	2013	They identified a set of SARS-CoV specific GU-rich ssRNA fragments with a high-density distribution in the genome. In vitro experiments, the result showed the representative SARS-CoV ssRNAs had powerful immunostimulatory activities to induce considerable level of pro-inflammatory cytokine TNF-a, IL-6 and IL-12 release via the TLR7 and TLR8, almost 2-fold higher than the strong stimulatory ssRNA40 that was found previously from other virus. Moreover, SARS-CoV ssRNA was able to cause acute lung injury in mice with a high mortality rate in vivo experiment. It suggests that SARS-CoV specific GU-rich ssRNA plays a very important role in the cytokine storm associated with a dysregulation of the innate immunity and could open a new therapeutic strategy.
[44]	Regulation of the p38 mitogen-activated protein kinase and dual-specificity phosphatase 1 feedback loop modulates the induction of interleukin 6 and 8 in cells infected with coronavirus infectious bronchitis virus.	Liao Y; Wang X; Huang M; Tam JP; Liu DX	US	2011	Characterised cellular mechanisms exploited by coronavirus infectious bronchitis virus (IBV) to regulate the induction of two pro-inflammatory cytokines, interleukin (IL)-6 and IL-8, at the transcriptional level. IBV modulates the infection by inducing the expression of dual-specificity phosphatase 1 (DUSP1), a negative regulator of the p38 MAPK, in order to limit the production of an excessive amount of IL-6 and IL-8 in the infected cells. DUSP1 and p38 MAPK are possible therapeutic targets for IBV.
[45]	A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo.	Day CW; Baric R; Cai SX; Frieman M; Kumaki Y; Morrey JD; Smee DF; Barnard DL.	US	2009	A new strain of SARS-CoV (strain v2163) was characterised and it was highly lethal in 5- to 6-week-old BALB/c mice. It had nine mutations affecting 10 amino acid residues. Strain v2163 increased IL-1alpha, IL-6, MIP-1alpha, MCP-1, and RANTES in mice, and high IL-6 expression correlated with mortality.
[46]	Neutralising antibody against severe acute respiratory syndrome -coronavirus spike is highly effective for the protection of mice in the murine SARS model.	Ishii K; Hasegawa H; Nagata N; Ami Y; Fukushi S; Taguchi F; Tsunetsugu-Yokota Y	Australia	2009	The efficacy of three SARS vaccine candidates was tested in a murine SARS model utilising low-virulence Pp and SARS-CoV coinfection. Vaccinated mice were protected from severe respiratory disease. A high level of IL-6 and on days 2 and 3 after SARS-CoV infection was closely linked to the virus replication and disease severity, suggesting the importance of these cytokines in the lung pathogenicity of SARS-CoV infection.
[47]	Severe acute respiratory syndrome (18) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells.	Yoshikawa T; Hill T; Li K; Peters CJ; Tseng CT.	US	2009	In highly polarised human lung epithelial Calu-3 cells modelled the cellular bases of the host antiviral innate immunity within the lungs. Role of IL-6 as a key SARS-CoV-induced epithelial cytokine capable of inhibiting the T-cell-priming ability of Denditric cells leading to an exacerbated inflammatory cascades and severe tissue damage in SARS patients.
[48]	Nucleocapsid protein of SARS-CoV activates interleukin-6 expression through cellular transcription factor NF-kappaB.	Zhang X; Wu K; Wang D; Yue X; Song D; Zhu Y; Wu J.	US	2007	High levels of IL6 High levels of interleukin-6 (IL-6) in the acute stage associated with lung lesions were found in SARS patients. The viral nucleocapsid SARS-CoV N protein activate IL-6 expression in the lung cells.
[49]	Cytokine regulation in SARS coronavirus infection compared to other respiratory virus infections.	Okabayashi T; Kariwa H; Yokota S; Iki S; Indoh T; Yokosawa N; Takashima I; Tsutsumi H; Fujii N.	US	2006	They compared the cytokine profile in Caco2 cells after infection of SARS coronavirus (SARS-CoV) with other respiratory viruses including respiratory syncytial virus (RSV), influenza A virus (FluAV), and human parainfluenza virus type 2 (hPIV2). Interferon (IFN) system (production and response) was not suppressed by SARS-CoV infection SARS-CoV and RSV induced high levels of IL-6 and RANTES compared with FluAV and hPIV2. Induction level of suppressor of cytokine signaling-3 (SOCS3) by SARS-CoV was significantly lower than that by RSV in spite of the significant production of IL-6. Collectively, overinduction of inflammatory cytokine and dysregulation of cytokine signaling may contribute to the immunopathology associated with “severe” inflammation in SARS.
[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	2005	The pulmonary inflammatory reaction in rat models were induced by intratracheal instillation of N-protein of SARS-CoV and glucocorticoids were administrated to one of the groups. The N-protein of SARS-CoV presented pathogenicity and could induce pulmonary inflammatory reaction and acute lung injury, which were related to the increase and imbalance of pro-inflammatory and anti-inflammatory cytokines. Glucocorticoids could effectively alleviate the pulmonary inflammatory reaction induced by N-protein of SARS-CoV.
[50]	Clinical manifestations and inflammatory cytokine responses in patients with severe acute respiratory syndrome.	Sheng WH; Chiang BL; Chang SC; Ho HN; Wang JT; Chen YC; Hsiao CH; Hseuh PR; Chie WC; Yang PC.	Singapore	2005	Fourteen hospitalised patients with a diagnosis of SARS-associated coronavirus infection. There were no significant differences in peak levels of IL-6, IL-8 and TNF-alpha between patients with and without acute respiratory distress syndrome. CRP and TNF-alpha are associated with worse outcomes and might be used as prognostic markers of SARS.
[51]	Severe acute respiratory syndrome and the innate immune responses: modulation of effector cell function without productive infection.	Tseng CT; Perrone LA; Zhu H; Makino S; Peters CJ.	US	2005	SARS-CoV does not productively infect human macrophages or Dentritic cells, it appears to exert differential effects on Mphi and DC maturation and functions, which might contribute to SARS pathogenesis. It modulates a massive release of IL-6 and IL-12. However, the endocytic capacity (e.g., Ag capture) of Mphi was significantly compromised upon exposure to infectious SARS-CoV.
[52]	An interferon-gamma-related cytokine storm in SARS patients.	Huang KJ; Su IJ; Theron M; Wu YC; Lai SK; Liu CC; Lei HY.	US	2005	Fourteen cytokines or chemokines were analysed on 88 RT-PCR-confirmed severe acute respiratory syndrome [18] patients. IFN-gamma, IL-18, TGF-beta, IL-6, IP-10, MCP-1, MIG, and IL-8, but not of TNF-alpha, IL-2, IL-4, IL-10, IL-13, or TNFRI, were highly elevated in the acute phase sera of Taiwan SARS patients. IL-18, IP-10, MIG, and MCP-1 were significantly higher in the death group than in the survival group An interferon-gamma-related cytokine storm was induced post SARS coronavirus infection, and this cytokine storm might be involved in the immunopathological damage in SARS patients.
[53]	Temporal relationship of viral load, ribavirin, interleukin (IL)-6, IL-8, and clinical progression in patients with severe acute respiratory syndrome.	Wang WK; Chen SY; Liu IJ; Kao CL; Chen HL; Chiang BL; Wang JT; Sheng WH; Hsueh PR; Yang CF; Yang PC; Chang SC;	US	2004	8 patients with acute respiratory syndrome [18], were included to study the link between viral load, ribavirin, proinflammatory cytokines, and clinical progression. ribavirin was not effective in reducing the SARS coronavirus load in 3 of 8 probable cases studied elevated levels of interleukin (IL)-6 and IL-8 subsequent to the peak viral load were found in 8 and 6 cases, respectively.
[54]	Analysis of serum cytokines in patients with severe acute respiratory syndrome.	Zhang Y; Li J; Zhan Y; Wu L; Yu X; Zhang W; Ye L; Xu S; Sun R; Wang Y; Lou J.	US	2004	Serum from 110 individuals (healthy donors, patients with SARS, patients with severe SARS, and patients with SARS in convalescence) was collected and cytokine profile was studied. The IL-6 concentration was increased in SARS patients and was significantly elevated in severe SARS patients, but the IL-6 concentrations were similar in convalescent patients and control subjects, suggesting that there was a positive relationship between the serum IL-6 concentration and SARS severity. The concentrations of IL-8 and TGF-beta were decreased in SARS patients and significantly reduced in severe SARS patients, but they were comparable in convalescent SARS patients and control subjects, suggesting that there was a negative relationship between the IL-8 and TGF-beta concentrations and SARS severity. The concentrations of IL-1 and TNF-alpha were not significantly different in different groups.
[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.	England	2004	Changes in plasma T helper (Th) cell cytokines, inflammatory cytokines and chemokines in 20 patients diagnosed with SARS were assessed. Th1 cytokine interferon (IFN)-gamma, inflammatory cytokines interleukin (IL)-1, IL-6 and IL-12 was elevated for at least 2 weeks after disease onset, but there was no significant elevation of inflammatory cytokine tumour necrosis factor (TNF)-alpha, anti-inflammatory cytokine IL-10, Th1 cytokine IL-2 and Th2 cytokine IL-4. The chemokine profile demonstrated significant elevation of neutrophil chemokine IL-8, monocyte chemoattractant protein-1 (MCP-1), and Th1 chemokine IFN-gamma-inducible protein-10 (IP-10). Corticosteroid reduced significantly IL-8, MCP-1 and IP-10 concentrations from 5 to 8 days after treatment (all p < 0.001).
[55]	Dynamic changes and the meanings of blood cytokines in severe acute respiratory syndrome	Wang and Pang	China	2003	(Abstract only) This study observed changed in various serum IL levels in patients with SARS. The authors stated that the mean concentration of serum IL-6 in SARS patients did not differ from the control group in 3-7-day group and 8-14-day group, but became significantly higher in over 14-day group as compared to the control group, 3-7-day group and 8-14-day group (p < 0.01). The results of the study led the authors to conclude that the immune state of SARS was abnormal. However, as only the abstract was available it is hard to draw upon any more conclusions from this study in relation in IL-6 specifically.
[56]	Inflammatory Cytokine Profile in Children With Severe Acute Respiratory Syndrome	Ng et al	Hong Kong	2004	The authors of this study set out to study the inflammatory cytokine profile in children with SARS. They found that the plasma concentrations key proinflammatory cytokines, including IL-6 were not substantially increased in any of the patients throughout the course of illness. From this the authors stated that the cytokine results cast doubt on the liberal use of corticosteroids in paediatric SARS patients, as the host immunologic response did not seem to be as severe as initially anticipated.