COVID-19 Cytokine Storm Research Articles

Hypocoagulable Coagulation Profile and Endogenous Heparinoids Are Associated with Invasive Ventilation and Mortality in COVID-19

Background & Aims: A procoagulant state with pulmonary micro-thrombosis has been described in COVID-19, which contributes to pathophysiology of respiratory failure along with diffuse alveolar damage. Cytokine storm and systemic inflammation in COVID-19 generates endogenous heparinoids from the endothelium which leads to secondary organ failures. We prospectively studied the dynamic association of the coagulation abnormalities with respiratory failure and mortality in patients with COVID-19.Methods: We did a prospective observational study in adults aged between 18-80 years with COVID 19 pneumonia requiring intensive care (ICU) admissions in a tertiary care hospital in North India. All patients received standard medical therapy based on best available evidence. Patients were categorized based on the oxygen support therapy into low flow, high flow and invasive ventilation groups. In patients considered to be at risk of thromboembolic or bleeding phenomena, paired coagulation tests were performed at days 1 and 3 with, Sonoclot ® (glass beaded and heparinase-treated). All patients were consecutively followed for inflammatory markers, ventilator requirements and survival. Activated clotting time (ACT) 75 units were used as the cut-off for hypercoagulable state. The heparin like effect (HLE) was considered by a correction of ≥ 40 s in hACT (heparinized treated ACT). The trial is registered with ClinicalTrials.gov (NCT04668404).Results: A total of 2324 patients with COVID-19 were screened from August 2020 to November 2020. Two hundred and fifteen patients requiring ICU admission were assessed and 74 patients with a median age of 54(42-67) years were enrolled. A procoagulant profile was seen in 45.5%, 32.4% and 20.7% in low-flow, high-flow, and invasive ventilation. Paired Sonoclot ® assays in 33 patients demonstrated HLE in 17 (51.5%) and 20 (62.5%) at days 1 and 3 respectively. In multivariate analysis, the presence of HLE (HR 1.02; CI 1.08-1.6; p 131 s, clot rate 96.7 mg/l at admission predicted mortality.Conclusions: HLE contributes to hypocoagulable effect, need for invasive ventilation and mortality in patients with COVID-19.Trial Registration: The trial is registered with ClinicalTrials.gov (NCT04668404).Funding Statement: NoneDeclaration of Interests: NoneEthics Approval Statement: Ethical clearance was obtained from the Institutional Review Board (PGI/IEC/2020/000997 dated 24 August 2020)

A research update: Significance of cytokine storm and diaphragm in COVID-19

Emerging research on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) shows that it is spreading to multiple organs in addition to the respiratory system. Though the SARS-CoV2 enters the human body by binding to ACE2 receptors on pulmonary alveolar cells, recent studies indicate that it is spreading to the central nervous system, cardiac and skeletal muscles leading to various pathological conditions in these organs. In particular, the effects of SARS-CoV-2 on triggering the cytokine storm and its consequential effects on skeletal muscles has generated a lot of discussion. The effects of this virus on muscular function especially in susceptible elderly populations is still being explored. However, its effects on diaphragm, a respiratory muscle which plays an important role in determining lung capacity are not completely explored. Currently, as new evidence on using lung ultrasounds to confirm COVID-19 diagnosis is gaining traction, it is necessary to explore the role of diaphragm in treating COVID-19 patients. This article will review the effects of cytokine storm triggered by the SARS-CoV-2 and its resultant effects on skeletal muscle with a specific focus on the diaphragm in order to identify knowledge gaps in effectively treating COVID-19 patients, especially those who are on a mechanical ventilator.

The host immune responses to SARS-CoV-2 and therapeutic strategies in the treatment of COVID-19 cytokine storm

<abstract> <p>The ravaging pandemic caused by SAR-CoV-2, a member of β-coronaviruses, marks the end of the year 2019. Despite being identified and classified at the earliest stage, the virus records worldwide soaring transmissibility, morbidity, and mortality. Global data have shown the infection with SARS-CoV-2 to be severe among at least 15% of the infected; the aged and those with premorbid conditions like cancer, cardiovascular, and respiratory diseases. The highest prevalence and mortality are seen in the Americas, with African countries least affected. Severe respiratory distress and multiorgan failure are the usual findings in severe cases. A hyperinflammatory, fulminant, hypercytokinemia that is often further complicated by hypercoagulopathy and multiorgan failure has been reported extensively among severely infected patients. Scientists describe hyper-activated immune response mediated by macrophages secreting copious amounts of interleukin (IL)-6 forming the epicenter of cytokine storm (CS), thereby perpetuating signaling cascade through JAK/Kinase pathway that yields a hypercytokinemia. Researchers globally are exploring JAK/kinase inhibitors, immunomodulatory (immunosuppressive) therapy, cytokines, and cytokine receptor blockers for CS management. In which interestingly some of these agents possess antiviral activity. Here, we reviewed published studies with their respective outcome. However, a lot needs to be done to address the CS of COVID-19 to avert its fatal outcome.</p> </abstract>

Emerging nanomaterials applied for tackling the COVID-19 cytokine storm.

During the global outbreak of coronavirus disease 2019 (COVID-19), a hyperinflammatory state called the cytokine storm was recognized as a major contributor to multiple organ failure and mortality. However, to date, the diagnosis and treatment of the cytokine storm remain major challenges for the clinical prognosis of COVID-19. In this review, we outline various nanomaterial-based strategies for preventing the COVID-19 cytokine storm. We highlight the contribution of nanomaterials to directly inhibit cytokine release. We then discuss how nanomaterials can be used to deliver anti-inflammatory drugs to calm the cytokine storm. Nanomaterials also play crucial roles in diagnostics. Nanomaterial-based biosensors with improved sensitivity and specificity can be used to detect cytokines. In summary, emerging nanomaterials offer platforms and tools for the detection and treatment of the COVID-19 cytokine storm and future pandemic.

A digital protein microarray for COVID-19 cytokine storm monitoring.

Despite widespread concern regarding cytokine storms leading to severe morbidity in COVID-19, rapid cytokine assays are not routinely available for monitoring critically ill patients. We report the clinical application of a digital protein microarray platform for rapid multiplex quantification of cytokines from critically ill COVID-19 patients admitted to the intensive care unit (ICU) at the University of Michigan Hospital. The platform comprises two low-cost modules: (i) a semi-automated fluidic dispensing/mixing module that can be operated inside a biosafety cabinet to minimize the exposure of the technician to the virus infection and (ii) a 12-12-15 inch compact fluorescence optical scanner for the potential near-bedside readout. The platform enabled daily cytokine analysis in clinical practice with high sensitivity (<0.4 pg mL-1), inter-assay repeatability (∼10% CV), and rapid operation providing feedback on the progress of therapy within 4 hours. This test allowed us to perform serial monitoring of two critically ill patients with respiratory failure and to support immunomodulatory therapy using the selective cytopheretic device (SCD). We also observed clear interleukin-6 (IL-6) elevations after receiving tocilizumab (IL-6 inhibitor) while significant cytokine profile variability exists across all critically ill COVID-19 patients and to discover a weak correlation between IL-6 to clinical biomarkers, such as ferritin and C-reactive protein (CRP). Our data revealed large subject-to-subject variability in patients' response to COVID-19, reaffirming the need for a personalized strategy guided by rapid cytokine assays.

Are losartan and imatinib effective against SARS-CoV2 pathogenesis? A pathophysiologic-based in silico study.

Proposing a theory about the pathophysiology of cytokine storm in COVID19, we were to find the potential drugs to treat this disease and to find any effect of these drugs on the virus infectivity through an in silico study. COVID-19-induced ARDS is linked to a cytokine storm phenomenon not explainable solely by the virus infectivity. Knowing that ACE2, the hydrolyzing enzyme of AngII and SARS-CoV2 receptor, downregulates when the virus enters the host cells, we hypothesize that hyperacute AngII upregulation is the eliciting factor of this ARDS. We were to validate this theory through reviewing previous studies to figure out the role of overzealous activation of AT1R in ARDS. According to this theory losartan may attenuate ARDS in this disease. Imatinib, has previously been elucidated to be promising in modulating lung inflammatory reactions and virus infectivity in SARS and MERS. We did an in silico study to uncover any probable other unconsidered inhibitory effects of losartan and imatinib against SARS-CoV2 pathogenesis. Reviewing the literature, we could find that over-activation of AT1R could explain precisely the mechanism of cytokine storm in COVID19. Our in silico study revealed that losartan and imatinib could probably: (1) decline SARS-CoV2 affinity to ACE2. (2) inhibit the main protease and furin, (3) disturb papain-like protease and p38MAPK functions. Our reviewing on renin-angiotensin system showed that overzealous activation of AT1R by hyper-acute excess of AngII due to acute downregulation of ACE2 by SARS-CoV2 explains precisely the mechanism of cytokine storm in COVID-19. Besides, based on our in silico study we concluded that losartan and imatinib are promising in COVID19.Electronic supplementary materialThe online version of this article (10.1007/s40203-020-00058-7) contains supplementary material, which is available to authorized users.

Potential Therapeutic Role of Purinergic Receptors in Cardiovascular Disease Mediated by SARS-CoV-2.

Novel coronavirus disease 2019 (COVID-19) causes pulmonary and cardiovascular disorders and has become a worldwide emergency. Myocardial injury can be caused by direct or indirect damage, particularly mediated by a cytokine storm, a disordered immune response that can cause myocarditis, abnormal coagulation, arrhythmia, acute coronary syndrome, and myocardial infarction. The present review focuses on the mechanisms of this viral infection, cardiac biomarkers, consequences, and the possible therapeutic role of purinergic and adenosinergic signalling systems. In particular, we focus on the interaction of the extracellular nucleotide adenosine triphosphate (ATP) with its receptors P2X1, P2X4, P2X7, P2Y1, and P2Y2 and of adenosine (Ado) with A2A and A3 receptors, as well as their roles in host immune responses. We suggest that receptors of purinergic signalling could be ideal candidates for pharmacological targeting to protect against myocardial injury caused by a cytokine storm in COVID-19, in order to reduce systemic inflammatory damage to cells and tissues, preventing the progression of the disease by modulating the immune response and improving patient quality of life.

Consideration of immunomodulatory actions of morphine in COVID-19 - Short report.

Cytokine storm in COVID-19 is linked to disease severity and mortality. 40% of patients with severe COVID-19 require mechanical ventilation. Analgesia and sedation are used for treatment of pain, facilitation of mechanical ventilation, or management of acute agitation. Herein, we present the immunomodulating actions of morphine that may either improve or worsen the clinical course of COVID-19 once cytokine storm develops. A literature search was performed to find articles on potential immunomodulatory effects of morphine. Taken together, the results of in vitro and in vivo models in non-COVID-19 conditions suggest that morphine could have a beneficial effect by mitigating the cytokine storm in the early stages of severe COVID-19. In contrast, it could be potentially harmful in late stages of severe COVID-19, especially in the presence of septic shock.

A Review of Cytokine Storm in COVID-19

A Review of Cytokine Storm in COVID-19

Mendelian randomization analysis identified genes pleiotropically associated with the risk and prognosis of COVID-19

ObjectivesCOVID-19 has caused a large global pandemic. Patients with COVID-19 exhibited considerable variation in disease behavior. Pervious genome-wide association studies have identified potential genetic variants involved in the risk and prognosis of COVID-19, but the underlying biological interpretation remains largely unclear.MethodsWe applied the summary data-based Mendelian randomization (SMR) method to identify genes that were pleiotropically associated with the risk and various outcomes of COVID-19, including severe respiratory confirmed COVID-19 and hospitalized COVID-19.ResultsIn blood, we identified 2 probes, ILMN_1765146 and ILMN_1791057 tagging IFNAR2, that showed pleiotropic association with hospitalized COVID-19 (β [SE]=0.42 [0.09], P = 4.75 × 10−06 and β [SE]=-0.48 [0.11], P = 6.76 × 10−06, respectively). Although no other probes were significant after correction for multiple testing in both blood and lung, multiple genes as tagged by the top 5 probes were involved in inflammation or antiviral immunity, and several other tagged genes, such as PON2 and HPS5, were involved in blood coagulation.ConclusionsWe identified IFNAR2 and other potential genes that could be involved in the susceptibility or prognosis of COVID-19. These findings provide important leads to a better understanding of the mechanisms of cytokine storm and venous thromboembolism in COVID-19 and potential therapeutic targets for the effective treatment of COVID-19.

Adaptation of the hypothalamo-pituitary-thyroid and hypothalamo-pituitary-adrenal systems to a new infectious disease - COVID-19 in the development of COVID-19 pneumonia and/or cytokine storm

The “new disease” COVID-19, which causes acute respiratory distress syndrome, by the time of writing this article had already affected 5 million 400 thousand people on Earth and claimed the lives of at least 400 thousand people in more than 200 countries. The disease can be either asymptomatic or occur with the development of severe viral pneumonia, complicated by acute respiratory syndrome and sepsis, myocarditis and renal failure. Although the likelihood of a more severe course is noted in individuals with diabetes, and these patients are mainly drawn to the attention of endocrinologists in the pandemic, the actual endocrine manifestations of COVID-19 are not yet considered in detail. There are few data on coronavirus damage to the pituitary, hypothalamus, thyroid gland and adrenal glands, their structural and functional disorders in case of COVID-19 infection, due to the lack of convincing results of preclinical and clinical studies. The literature review presented in this article does not claim to be a full-fledged systematic review, not only for the reason that to date, only 51 works have been found at the time of writing in the databases for the keywords «thyroid and COVID-19» and «adrenal and COVID-19», after excluding duplicates, but also because these messages themselves contain little information and are mainly based on analogies with previously existing viral infections and their role in the development of hypothalamus-pituitary axis pathology-adrenal glands and hypothalamus-pituitary-thyroid.

Missteps in Pursuit of the Cytokine Storm in COVID-19: Reliability of Clinical Laboratory Data in the Midst of a Pandemic

Disease caused by novel coronavirus SARS-CoV-2 (COVID-19) has resulted in significant morbidity and mortality worldwide. One mechanism of severe disease is thought to be a cytokine storm in a subset of patients, where a hyper-inflammatory state characterized by elevated levels of circulating cytokines and chemokines is thought to portend a poor prognosis. We report on our experience in clinical laboratory assessment of cytokine levels in patients hospitalized with COVID-19. We demonstrate alarming discrepancies in levels of cytokines reported by different vendors. Our findings provide a basis for the ongoing debates surrounding the relevance of cytokine storm in COVID-19. Moreover, they prompt caution when comparing cytokine levels in patients with COVID-19 and other disease entities due to potential variations in assay platforms and temporality. Our results underscore an urgent need for standardizing such tests that guide prognostication and therapeutic intervention.

Can chloroquine/hydroxychloroquine prove efficient in cancer cachexia? A hypothesis in the era of COVID-19

Cancer cachexia (CC) is a progressive loss of muscle mass (with or without a decrease of adipose tissue). Gradual deterioration of the patient's fitness is resistant to nutritional intervention. The biochemical foundation of observed catabolism, detrimental protein, and energy balance is complex. However, the generalized inflammatory response plays a vital role. It is a kind of cytokine storm, which involves increased activity of TNF-α, IL-1, IL-6, and INF-γ. Pharmacological treatment of cachexia consists mainly of progestagens and glucocorticosteroids. Still, the assessment of new options limiting the harmful impact of cachexia could be beneficial. Chloroquine (CQ) and hydroxychloroquine (HCQ) are old antimalarial agents endowed with immunomodulatory properties. Being potent autophagy inhibitors, they could lead to a form of intracellular starvation in both cytokine-releasing cells and cancer cells, thus limiting the harmful impact of CC. CQ and HCQ are also efficient in particular connective tissue disorders. They have gained special attention since the World Health Organization announced the coronavirus disease 2019 (COVID-19) pandemic. According to initial reports, people with a severe inflammatory reaction showed significant benefits. Possibly they could not be attributed to the antiviral activity alone. It is worth noting that the cytokine storm in COVID-19, connective tissue disorders, and cancer cachexia share some similarities. Therefore, we hypothesize that low doses of CQ/HCQ may prove efficient in cancer cachexia.

An anti-CD6 monoclonal antibody (itolizumab) reduces circulating IL-6 in severe COVID-19 elderly patients

BackgroundSince the COVID-19 outbreak an unprecedented challenge for healthcare systems around the world has been placed. In Cuba, the first case of COVID-19 was reported on March 11. Elderly with multiple comorbidities have been the most risky population. Although most patients present a mild to moderate disease, some have developed severe symptoms. One of the possible mechanisms underlying rapid disease progression is a cytokine storm, in which interleukin (IL) -6 seems to be a major mediator. Itolizumab is a humanized recombinant anti-CD6 monoclonal antibody (MAb), with the ability of reducing serum interferon gamma (INF-γ), tumour necrosis factor alpha (TNFα) and IL-6. Based on these previous results in patients with psoriasis and rheumatoid arthritis, an expanded access clinical trial was approved by the Cuban regulatory agency for COVID-19 critically, severely and moderately ill patients.ResultsWe show here a short kinetic of IL-6 serum concentration in the first 24 COVID-19 patients treated with itolizumab. Most of patients were elderly with multiple comorbidities. We found that with one itolizumab dose, the circulating IL-6 decreased in critically and severely ill patients, whereas in moderately ill patients the values didn’t rise as compared to their low baseline levels.ConclusionThese findings suggest that itolizumab could be an attractive therapeutic option to decrease the negative outcome of the cytokine storm in COVID-19 patients.Trial registrationCECMED IIC RD-EC 179, RPCEC00000311. Registered 4 May 2020 - Retrospectively registered, http://rpcec.sld.cu/ensayos/RPCEC00000311-Sp or http://rpcec.sld.cu/trials/RPCEC00000311-En

COVID-19 Cytokine Storm Complications in Asthmatic Patients

The pandemic of coronavirus disease 2019 has inflicted millions of people in the world and caused severe complications in immunocompromised individuals. Some evidences suggest that severe COVID-19 complications are associated with the cytokine storm syndrome, contributing to the high mortality rate of the disease. Asthma is a complicated disease of the respiratory system. COVID-19 symptoms can be worse in asthmatic patients than others. Corticosteroids with anti-inflammatory functions which are used in asthmatic patients may have adverse outcomes in coronavirus infection and are not recommended for the treatment of COVID-19. Furthermore, asthmatic patients (using inhalation corticosteroids) have a suppressed immune system in the lung, which increases their susceptibility to COVID-19 infection.

42-Year-Old Patient With Severe COVID-19 Pneumonia and Cytokine Storm: Hurdles During Management

A middle aged man presented with fever for 14 days, dry cough for 10 days and shortness of breath for 6 days. He tested positive for RT-PCR for COVID-19 on 5th day of illness. Patient was maintaining home isolation until he developed shortness of breath. After hospitalization patient was treated with standard dose of Remdesivir, dexamethasone and antibiotics. But his oxygen demand was increasing day by day. Inflammatory markers including serum ferritin, CRP level was also increasing. Patient was having a cytokine storm. At this point of treatment anti IL6 Tocilizumab was being considered. But patient’s wellbeing was improved and tocilizumab was not given. Our patient gradually recovered from severe COVID-19 pneumonia and cytokine storm without tocilizumab.&#x0D; J MEDICINE JUL 2020; 21 (2) : 119-122

Cytokine Storm in COVID-19 in Diabetic Patients: A Review

COVID-19, a global pandemic has created a worldwide disaster since its first outbreak in December 2019 in Wuhan, China. Studies based in China have reported that people with diabetes and infected with COVID-19 showed higher hospital admission rates, serious pneumonia development, and higher mortality rates. SARS-CoV-2 can increase the metabolism of glucose by fueling immune cell overproduction - a phenomenon known as a 'cytokine storm'. Glucose metabolism is said to contribute to diverse COVID-19 outcomes. In this study, we are overviewing the linkage among SARS-CoV-2, diabetes, and cytokine storm for a better understanding of aggravating health conditions in diabetic patients due to this SARS-CoV-2 virus. In conclusion, this review will contribute to understanding complications that is rising among diabetic patients due to SARS-CoV-2 induced cytokine storm.&#x0D; Bangladesh Journal of Infectious Diseases, October 2020;7(suppl_2):S46-S49

A Multicenter Questionnaire-based Study to Know the Awareness and Medical Treatment Plan of Physicians Involved in the Management of COVID-19 Patients.

IntroductionThe pandemic coronavirus disease 2019 (COVID-19) is on the rise in our country and there is no specific treatment modality available presently. The treatment of the disease largely remains symptomatic but repurposed drugs used to treat other disease conditions are being used to treat moderate to severe form of the disease. As the clinical trials for these drugs are ongoing, we conducted this survey to know the physicians’ medical treatment plan for COVID-19 patients.Materials and methodsIt was a web-based questionnaire study. Institutional ethical committee clearance was taken before the commencement of the study. There were a total of 17 questions, the first 6 being about the demographics, place of work, and whether the clinician was involved in the care of COVID-19 patients. Subsequent 11 questions were to assess physician's awareness and plan of the medical management of the COVID-19 patients.ResultsThe majority of the clinicians were aware of the various treatment modalities available for the treatment of COVID-19. Regarding the plan for use of hydroxychloroquine (HCQ), 55% of the total respondents intended to use the drug in combination with azithromycin, even as 62% agreed that there was no clear evidence yet. About 90% of all clinicians, from junior residents to consultants, were monitoring electrocardiogram (ECG) during HCQ therapy; however, there were 10% of physicians who were not practicing ECG monitoring. About 68% of clinicians were aware of the various therapeutic options being tested, like convalescent plasma, lopinavir–ritonavir, and 64% knew about remdesivir. There was divergence regarding the use of steroids in a cytokine storm among the physicians, with only 39% of consultants planning to use steroids whereas about 50% of junior residents and 79% of junior consultants were planning to use the drug.ConclusionThe majority of the clinicians involved in the management of COVID-19 were aware of the various drug modalities available for treatment. However, more emphasis on the adverse effects and possible drug interactions is required. There is disaccord regarding the use of steroids in cytokine storm in COVID-19 and further guidelines and educational programs should address these issues.Clinical significanceClinicians have to be made more aware of the possible adverse effects and drug interactions of the medications used for the treatment of COVID-19. The treatment of the serious, cytokine storm syndrome and the role of steroids must be elucidated as soon as it is feasible.How to cite this articleMaddani SS, Chaudhuri S, Deepa HC, Amara V. A Multicenter Questionnaire-based Study to Know the Awareness and Medical Treatment Plan of Physicians Involved in the Management of COVID-19 Patients. Indian J Crit Care Med 2020;24(10):919–925.

Comparative Survival Analysis of Immunomodulatory Therapy for Coronavirus Disease 2019 Cytokine Storm

BackgroundCytokine storm is a marker of coronavirus disease 2019 (COVID-19) illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes.Research QuestionDo immunomodulatory therapies improve survival in patients with COVID-19 cytokine storm (CCS)?Study Design and MethodsWe conducted a retrospective analysis of electronic health records across the Northwell Health system. COVID-19 patients hospitalized between March 1, 2020, and April 24, 2020, were included. CCS was defined by inflammatory markers: ferritin, > 700 ng/mL; C-reactive protein (CRP), > 30 mg/dL; or lactate dehydrogenase (LDH), > 300 U/L. Patients were subdivided into six groups: no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-IL-6 antibody (tocilizumab), or anti-IL-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality.ResultsFive thousand seven hundred seventy-six patients met the inclusion criteria. The most common comorbidities were hypertension (44%-59%), diabetes (32%-46%), and cardiovascular disease (5%-14%). Patients most frequently met criteria with high LDH (76.2%) alone or in combination, followed by ferritin (63.2%) and CRP (8.4%). More than 80% of patients showed an elevated D-dimer. Patients treated with corticosteroids and tocilizumab combination showed lower mortality compared with patients receiving standard-of-care (SoC) treatment (hazard ratio [HR], 0.44; 95% CI, 0.35-0.55; P < .0001) and with patients treated with corticosteroids alone (HR, 0.66; 95% CI, 0.53-0.83; P = .004) or in combination with anakinra (HR, 0.64; 95% CI, 0.50-0.81; P = .003). Corticosteroids when administered alone (HR, 0.66; 95% CI, 0.57-0.76; P < .0001) or in combination with tocilizumab (HR, 0.43; 95% CI, 0.35-0.55; P < .0001) or anakinra (HR, 0.68; 95% CI, 0.57-0.81; P < .0001) improved hospital survival compared with SoC treatment.InterpretationThe combination of corticosteroids with tocilizumab showed superior survival outcome when compared with SoC treatment as well as treatment with corticosteroids alone or in combination with anakinra. Furthermore, corticosteroid use either alone or in combination with tocilizumab or anakinra was associated with reduced hospital mortality for patients with CCS compared with patients receiving SoC treatment.

Pharmacological validation of targets regulating CD14 during macrophage differentiation.

The signalling receptor for LPS, CD14, is a key marker of, and facilitator for, pro-inflammatory macrophage function. Pro-inflammatory macrophage differentiation remains a process facilitating a broad array of disease pathologies, and has recently emerged as a potential target against cytokine storm in COVID19. Here, we perform a whole-genome CRISPR screen to identify essential nodes regulating CD14 expression in myeloid cells, using the differentiation of THP-1 cells as a starting point. This strategy uncovers many known pathways required for CD14 expression and regulating macrophage differentiation while additionally providing a list of novel targets either promoting or limiting this process. To speed translation of these results, we have then taken the approach of independently validating hits from the screen using well-curated small molecules. In this manner, we identify pharmacologically tractable hits that can either increase CD14 expression on non-differentiated monocytes or prevent CD14 upregulation during macrophage differentiation. An inhibitor for one of these targets, MAP2K3, translates through to studies on primary human monocytes, where it prevents upregulation of CD14 following M-CSF induced differentiation, and pro-inflammatory cytokine production in response to LPS. Therefore, this screening cascade has rapidly identified pharmacologically tractable nodes regulating a critical disease-relevant process.