Role of SARS-CoV-2-induced cytokine storm in multi-organ failure: Molecular pathways and potential therapeutic options.

Coronavirus disease 2019 (COVID-19) outbreak has become a global public health emergency and has led to devastating results. Mounting evidence proposes that the disease causes severe pulmonary involvement and influences different organs, leading to a critical situation named multi-organ failure. It is yet to be fully clarified how the disease becomes so deadly in some patients. However, it is proven that a condition called "cytokine storm" is involved in the deterioration of COVID-19. Although beneficial, sustained production of cytokines and overabundance of inflammatory mediators causing cytokine storm can lead to collateral vital organ damages. Furthermore, cytokine storm can cause post-COVID-19 syndrome (PCS), an important cause of morbidity after the acute phase of COVID-19. Herein, we aim to explain the possible pathophysiology mechanisms involved in COVID-19-related cytokine storm and its association with multi-organ failure and PCS. We also discuss the latest advances in finding the potential therapeutic targets to control cytokine storm wishing to answer unmet clinical demands for treatment of COVID-19.

Clinical characteristics, multiorgan dysfunction and outcomes of patients with COVID-19: a prospective case series.

BACKGROUND: Characterizing the multiorgan manifestations and outcomes of patients hospitalized with COVID-19 will inform resource requirements to address the long-term burden of this disease. We conducted a descriptive analysis using prospectively collected data to describe the clinical characteristics and spectrum of organ dysfunction, and in-hospital and longer-term clinical outcomes of patients hospitalized with COVID-19 during the first wave of the pandemic at a Canadian centre. METHODS: We conducted a prospective case series involving adult patients (aged ≥ 18 yr) with COVID-19 admitted to 1 of 2 hospitals in London, Ontario, from Mar. 17 to June 18, 2020, during the first wave of the pandemic. We recorded patients' baseline characteristics, physiologic parameters, measures of organ function and therapies administered during hospitalization among patients in the intensive care unit (ICU) and in non-ICU settings, and compared the characteristics of hospital survivors and nonsurvivors. Finally, we recorded follow-up thoracic computed tomography (CT) and echocardiographic findings after hospital discharge. RESULTS: We enrolled 100 consecutive patients (47 women) hospitalized with COVID-19, including 32 patients who received ICU care and 68 who received treatment in non-ICU settings. Respiratory sequelae were common: 23.0% received high-flow oxygen by nasal cannula, 9.0% received noninvasive ventilation, 24.0% received invasive mechanical ventilation and 2.0% received venovenous extracorporeal membrane oxygenation. Overall, 9.0% of patients had cerebrovascular events (3.0% ischemic stroke, 6.0% intracranial hemorrhage), and 6.0% had pulmonary embolism. After discharge, 11 of 19 patients had persistent abnormalities on CT thorax, and 6 of 15 had persistent cardiac dysfunction on echocardiography. INTERPRETATION: This study provides further evidence that COVID-19 is a multisystem disease involving neurologic, cardiac and thrombotic dysfunction, without evidence of hepatic dysfunction. Patients have persistent organ dysfunction after hospital discharge, underscoring the need for research on long-term outcomes of COVID-19 survivors.

Case Report: Severe Rhabdomyolysis and Multiorgan Failure After ChAdOx1 nCoV-19 Vaccination.

Background: Severe skeletal muscle damage has been recently reported in patients with SARS-CoV-2 infection and as a rare vaccination complication. Case summary: On Apr 28, 2021 a 68-year-old man who was previously healthy presented with an extremely severe rhabdomyolysis that occurred nine days following the first dose of SARS-CoV-2 ChAdOx1 nCov-19 vaccination. He had no risk factors, and denied any further assumption of drugs except for fermented red rice, and berberine supplement. The clinical scenario was complicated by a multi organ failure involving bone marrow, liver, lung, and kidney. For the rapid increase of the inflammatory markers, a cytokine storm was suspected and multi-target biologic immunosuppressive therapy was started, consisting of steroids, anakinra, and eculizumab, which was initially successful resulting in close to normal values of creatine phosphokinase after 17 days of treatment. Unfortunately, 48 days after the vaccination an accelerated phase of deterioration, characterized by severe multi-lineage cytopenia, untreatable hypotensive shock, hypoglycemia, and dramatic increase of procalcitonin (PCT), led to patient death. Conclusion: Physicians should be aware that severe and fatal rhabdomyolysis may occur after SARS-CoV2 vaccine administration.

High level of lactate dehydrogenase and ischaemia-reperfusion injury regulate the multiple organ dysfunction in patients with COVID-19.

BACKGROUND: Multiple organ damage has been observed in patients with COVID-19, but the exact pathway is not known. Vital organs of the human body may get affected after replication of SARS-CoV-2, including the lungs, heart, kidneys, liver and brain. It triggers severe inflammation and impairs the function of two or more organ systems. Ischaemia-reperfusion (IR) injury is a phenomenon that can have disastrous effects on the human body. METHODS: In this study, we analysed the laboratory data of 7052 hospitalised patients with COVID-19 including lactate dehydrogenase (LDH). A total of 66.4% patients were men and 33.6% were women, which indicated gender difference as a prominent factor to be considered. RESULTS: Our data showed high levels of inflammation and elevated markers of tissue injury from multiple organs C reactive protein, white blood cell count, alanine transaminase, aspartate aminotransferase and LDH. The number of red blood cells, haemoglobin concentration and haematocrit were lower than normal which indicated a reduction in oxygen supply and anaemia. CONCLUSION: On the basis of these results, we proposed a model linking IR injury to multiple organ damage by SARS-CoV-2. COVID-19 may cause a reduction in oxygen towards an organ, which leads to IR injury.

The role of the ADVanced Organ Support (ADVOS) system in critically ill patients with multiple organ failure.

BACKGROUND: Multi-organ failure characterized by acute kidney injury, liver dysfunction, and respiratory failure is a complex condition associated with high mortality, for which multiple individual support devices may be simultaneously required. This review aims to appraise the current evidence for the ADVanced Organ Support (ADVOS) system, a novel device integrating liver, lung, and kidney support with blood detoxification. METHODS: We performed a literature review of the PubMed database to identify human and animal studies evaluating the ADVOS system. RESULTS: In porcine models of acute liver injury and small clinical studies in humans, ADVOS significantly enhanced the elimination of water-soluble and protein-bound toxins and metabolites, including creatinine, ammonia, blood urea nitrogen, and lactate. Cardiovascular parameters (mean arterial pressure, cerebral perfusion pressure, and cardiac index) and renal function were improved. ADVOS clears carbon dioxide (CO2 ) effectively with rapid correction of pH abnormalities, achieving normalization of CO2 , and bicarbonate levels. In patients with COVID-19 infection, ADVOS enables rapid correction of acid-base disturbance and respiratory acidosis. ADVOS therapy reduces mortality in multi-organ failure and has been shown to be safe with minimal adverse events. CONCLUSIONS: From the small observational studies analyzed, ADVOS demonstrates excellent detoxification of water-soluble and protein-bound substances. In particular, ADVOS permits the correction of metabolic and respiratory acidosis through the fluid-based direct removal of acid and CO2 . ADVOS is associated with significant improvements in hemodynamic and biochemical parameters, a trend toward improved survival in multi-organ failure, and is well-tolerated. Larger randomized trials are now necessary to further validate these encouraging results.

Blocking TNF signaling may save lives in COVID-19 infection.

Global vaccination effort and better understanding of treatment strategies provided a ray of hope for improvement in COVID-19 pandemic, however, in many countries, the disease continues to collect its death toll. The major pathogenic mechanism behind severe cases associated with high mortality is the burst of pro-inflammatory cytokines TNF, IL-6, IFNγ and others, resulting in multiple organ failure. Although the exact contribution of each cytokine is not clear, we provide an evidence that the central mediator of cytokine storm and its devastating consequences may be TNF. This cytokine is known to be involved in activated blood clotting, lung damage, insulin resistance, heart failure, and other conditions. A number of currently available pharmaceutical agents such as monoclonal antibodies and soluble TNF receptors can effectively prevent TNF from binding to its receptor(s). Other drugs are known to block NFkB, the major signal transducer molecule used in TNF signaling, or to block kinases involved in downstream activation cascades. Some of these medicines have already been selected for clinical trials, but more work is needed. A simple, rapid, and inexpensive method of directly monitoring TNF levels may be a valuable tool for a timely selection of COVID-19 patients for anti-TNF therapy.

Interleukin-6 in SARS-CoV-2 induced disease: Interactions and therapeutic applications.

Interleukin-6 (IL-6) is a multi-tasking cytokine that represents high activity in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and cancer. High concentration of this pleiotropic cytokine accounts for hyperinflammation and cytokine storm, and is related to multi-organ failure in patients with SARS-CoV-2 induced disease. IL-6 promotes lymphopenia and increases C-reactive protein (CRP) in such cases. However, blockade of IL-6 is not a full-proof of complete response. Hypoxia, hypoxemia, aberrant angiogenesis and chronic inflammation are inter-related events occurring as a response to the SARS-CoV-2 stimulatory effect on high IL-6 activity. Taking both pro- and anti-inflammatory activities will make complex targeting IL-6 in patient with SARS-CoV-2 induced disease. The aim of this review was to discuss about interactions occurring within the body of patients with SARS-CoV-2 induced disease who are representing high IL-6 levels, and to determine whether IL-6 inhibition therapy is effective for such patients or not. We also address the interactions and targeted therapies in cancer patients who also have SARS-CoV-2 induced disease.

The inflammatory biomarkers profile of hospitalized patients with COVID-19 and its association with patient's outcome: A single centered study.

Several reports highlighted the central role of inflammation in the pathogenesis of corona virus disease-19 (COVID-19) disease. Also, the hyper-inflammatory response that is triggered by severe acute respiratory syndrom-Covid-2 (SARS-CoV-2) infection was believed to play an essential role in disease severity and adverse clinical course. For that reason, the classical inflammatory markers were proposed as a possible indicator for COVID-19 severity. However, an extensive analysis of the predictive value of inflammatory biomarkers in large patients' cohorts is still limited and critically needed. In this study we investigated the predictive value of the classical inflammatory biomarkers in a patient cohort consists of 541 COVID-19 patients admitted to Al Kuwait Hospital, Dubai, UAE. A detailed analysis of the association between the essential inflammatory markers and clinical characteristics as well as clinical outcome of the patients were made. In addition, the correlation between those markers and a wide range of laboratory biomarkers and incidence of acute organs injury were investigated. Our results showed a significant elevation of many inflammatory markers including white cell count (WBC) count, neutrophils count, C-reactive protein (CRP), D-Dimer, ferritin, procalcitonin (PCT), and lactate dehydrogenase (LDH) levels in patients with more severe illness. Also, our results highlighted that higher levels of those markers can predict worse patient outcome including the need of ventilation, intensive care unit (ICU) admission, multiple organs dysfunction as well as death. In addition, Our results showed that the presence of lymphopenia and lower absolute lymphocyte count (ALC) at the time of admission were associated with severe to critical COVID-19 illness (P<0.0001), presence of acute respiratory distress syndrome (ARDS) (P<0.0001) and the need for ventilation and ICU admission., Moreover, our results showed a strong association between lower ALC count and multiple organs dysfunction and patient's death (P<0.0001). In conclusion, our results highlighted the possible use of classical inflammatory biomarkers at time of admission as a potential predictive marker for more severe clinical course in COVID-19 patients that might need more aggressive therapeutic approach including the need of ventilators and ICU admission. The presence of such predictive markers might improve patient's stratification and help in the direction of the available resources to patients in need, which in turn help in improving our response to the disease pandemic.

Coronavirus Disease 2019 as Cause of Viral Sepsis: A Systematic Review and Meta-Analysis.

OBJECTIVE: Coronavirus disease 2019 is a heterogeneous disease most frequently causing respiratory tract infection, which can induce respiratory failure and multiple organ dysfunction syndrome in its severe forms. The prevalence of coronavirus disease 2019-related sepsis is still unclear; we aimed to describe this in a systematic review. DATA SOURCES: MEDLINE (PubMed), Cochrane, and Google Scholar databases were searched based on a prespecified protocol (International Prospective Register for Systematic Reviews: CRD42020202018). STUDY SELECTION: Studies reporting on patients with confirmed coronavirus disease 2019 diagnosed with sepsis according to sepsis-3 or according to the presence of infection-related organ dysfunctions necessitating organ support/replacement were included in the analysis. The primary end point was prevalence of coronavirus disease 2019-related sepsis among adults hospitalized in the ICU and the general ward. Among secondary end points were the need for ICU admission among patients initially hospitalized in the general ward and the prevalence of new onset of organ dysfunction in the ICU. Outcomes were expressed as proportions with respective 95% CI. DATA EXTRACTION: Two reviewers independently screened and reviewed existing literature and assessed study quality with the Newcastle-Ottawa Scale and the Methodological index for nonrandomized studies. DATA SYNTHESIS: Of 3,825 articles, 151 were analyzed, only five of which directly reported sepsis prevalence. Noting the high heterogeneity observed, coronavirus disease 2019-related sepsis prevalence was 77.9% (95% CI, 75.9-79.8; I2 = 91%; 57 studies) in the ICU, and 33.3% (95% CI, 30.3-36.4; I2 = 99%; 86 studies) in the general ward. ICU admission was required for 17.7% (95% CI, 12.9-23.6; I2 = 100%) of ward patients. Acute respiratory distress syndrome was the most common organ dysfunction in the ICU (87.5%; 95% CI, 83.3-90.7; I2 = 98%). CONCLUSIONS: The majority of coronavirus disease 2019 patients hospitalized in the ICU meet Sepsis-3 criteria and present infection-associated organ dysfunction. The medical and scientific community should be aware and systematically report viral sepsis for prognostic and treatment implications.

The clinical characters and prognosis of COVID-19 patients with multiple organ dysfunction.

ABSTRACT: To depict the clinical characters and prognosis of coronavirus disease 2019 patients who developed multiple organ dysfunction syndrome (MODS).A cohort consisted of 526 patients, which including 109 patients complicated MODS, was retrospectively analyzed to examine the clinical characteristics and risk factors of MODS.Among the 526 novel coronavirus-infected pneumonia patients, 109 patients developed multiple organ failure, the incidence rate was 20.7%. Among all 109 patients with MODS, 81.7% were over 60 years old, and 63.3% were male. The most common symptoms were fever (79.8%), dyspnea (73.4%), and fatigue (55.0%). Compared with patients non-MODS patients, there were 70 cases of MODS patients with one or more underlying diseases (64.2% vs 41.0%, P < .001). Respiratory failure (92.7%), circulatory failure (52.0%), and liver function injury (30.9%) were the most common symptoms within the spectrum of MODS. Invasive ventilator, noninvasive ventilator, and high-flow respiratory support treatment for patients in MODS patients were higher than those in the non-MODS group (P < .001). The antiviral therapy and 2 or more antibacterial drug treatments in MODS patients were higher than those in the non-MODS group (P < .001). The median hospital stay of all patients was 16 days (interquartile range [IQR], 9-26), of which 20 days (IQR, 11.5-30.5) in the MODS patients, which was approximately 4 days longer than that of non-MODS patients. In addition, our data suggested that lymphocyte counts <1.0 ∗ 109/L, Troponin T > 0.014 ng/mL and lower oxygenation index were risk factors for MODS. In the early stage of hospital admission, higher inflammatory indexes and lactic acid concentration were associated with increased risk of death.MODS often leads to poor prognosis in coronavirus disease 2019. Our data suggested the importance of early identification of MODS. We recommend close monitoring and timely supportive therapy for patients with high risks, stopping the disease progression before it was too late.

Molecular Mechanisms of Multi-Organ Failure in COVID-19 and Potential of Stem Cell Therapy.

As the number of confirmed cases and deaths occurring from Coronavirus disease 2019 (COVID-19) surges worldwide, health experts are striving hard to fully comprehend the extent of damage caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 primarily manifests itself in the form of severe respiratory distress, it is also known to cause systemic damage to almost all major organs and organ systems within the body. In this review, we discuss the molecular mechanisms leading to multi-organ failure seen in COVID-19 patients. We also examine the potential of stem cell therapy in treating COVID-19 multi-organ failure cases.

[Fatal course of COVID-19 despite IL-6 receptor blockade in cytokine storm : Perimyocarditis and coagulopathy after administration of tocilizumab]. / Fataler COVID-19-Verlauf trotz IL­6­Rezeptor-Blockade im Zytokinsturm : Perimyokarditis und Koagulopathie nach Tocilizumabgabe.

A 59-year-old male patient was admitted to hospital diagnosed with moderate pneumonia associated with COVID-19. Upfront treatment with hydroxychloroquine and azithromycin was started. Due to a clinical deterioration (ARDS, circulatory shock) and greatly increased inflammation markers 6 days after admission, a cytokine storm was suspected and off-label treatment with the IL­6 receptor antagonist tocilizumab was initiated. Subsequently there was a dramatic rise of D­dimers indicating pulmonary intravascular coagulopathy and respiratory insufficiency worsened. After a second dose of tocilizumab was administered severe perimyocarditis with cardiac arrhythmia, hemodynamic instability and ST elevation occurred. Shortly afterwards the patient died due to multiorgan failure. From our experience, exacerbation of COVID-19 following treatment with tocilizumab cannot be ruled out. Randomized controlled studies are necessary to further investigate the efficacy, safety and patient selection criteria for tocilizumab treatment in COVID-19.

The Molecular Mechanism of Multiple Organ Dysfunction and Targeted Intervention of COVID-19 Based on Time-Order Transcriptomic Analysis.

Coronavirus disease 2019 (COVID-19) pandemic is caused by the novel coronavirus that has spread rapidly around the world, leading to high mortality because of multiple organ dysfunction; however, its underlying molecular mechanism is unknown. To determine the molecular mechanism of multiple organ dysfunction, a bioinformatics analysis method based on a time-order gene co-expression network (TO-GCN) was performed. First, gene expression profiles were downloaded from the gene expression omnibus database (GSE161200), and a TO-GCN was constructed using the breadth-first search (BFS) algorithm to infer the pattern of changes in the different organs over time. Second, Gene Ontology enrichment analysis was used to analyze the main biological processes related to COVID-19. The initial gene modules for the immune response of different organs were defined as the research object. The STRING database was used to construct a protein-protein interaction network of immune genes in different organs. The PageRank algorithm was used to identify five hub genes in each organ. Finally, the Comparative Toxicogenomics Database played an important role in exploring the potential compounds that target the hub genes. The results showed that there were two types of biological processes: the body's stress response and cell-mediated immune response involving the lung, trachea, and olfactory bulb (olf) after being infected by COVID-19. However, a unique biological process related to the stress response is the regulation of neuronal signals in the brain. The stress response was heterogeneous among different organs. In the lung, the regulation of DNA morphology, angiogenesis, and mitochondrial-related energy metabolism are specific biological processes related to the stress response. In particular, an effect on tracheal stress response was made by the regulation of protein metabolism and rRNA metabolism-related biological processes, as biological processes. In the olf, the distinctive stress responses consist of neural signal transmission and brain behavior. In addition, myeloid leukocyte activation and myeloid leukocyte-mediated immunity in response to COVID-19 can lead to a cytokine storm. Immune genes such as SRC, RHOA, CD40LG, CSF1, TNFRSF1A, FCER1G, ICAM1, LAT, LCN2, PLAU, CXCL10, ICAM1, CD40, IRF7, and B2M were predicted to be the hub genes in the cytokine storm. Furthermore, we inferred that resveratrol, acetaminophen, dexamethasone, estradiol, statins, curcumin, and other compounds are potential target drugs in the treatment of COVID-19.