Pathogenesis and treatment of cytokine storm in COVID-19

COVID-19 is a viral infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that killed a large number of patients around the world. A hyperinflammatory state resulting in a cytokine storm and adult respiratory distress syndrome seems to be the major cause of the death. Many mechanisms have been suggested in the pathogenesis of COVID-19 associated cytokine storm (COVID-CS). Insufficient viral clearance and persistence of a strong cytokine response despite inadequate antiviral immunity seem to be the main mechanisms underlying the pathogenesis. The diagnosis of COVID-19 is based on relatively constant clinical symptoms, clinical findings, laboratory tests, and imaging techniques, while the diagnosis of COVID-CS is a rather dynamic process, based on evolving or newly emerging findings during the clinical course. Management of COVID-19 consists of using antiviral agents to inhibit SARS-CoV-2 replication and treating potential complications including the cytokine storm together with general supportive measures. COVID-CS may be treated using appropriate immunosuppressive and immunomodulatory drugs that reduce the level of inappropriate systemic inflammation, which has the potential to cause organ damage. Currently corticosteroids, IL-6 blockers, or IL-1 blockers are most widely used for treating COVID-CS.     

Mesenchymal stem/stromal cells as adjuvant therapy in COVID-19-associated acute lung injury and cytokine storm: Importance of cell identification

Theoretically, mesenchymal stem cells (MSCs) are very promising as adjuvant therapy to alleviate coronavirus disease 2019 (COVID-19)-associated acute lung injury and cytokine storm. Several published studies, which used MSCs to alleviate COVID-19-associated acute lung injury and cytokine storm, reported promising results. However, the evidence came from a case report, case series, and clinical trials with a limited number of participants. Therefore, more studies are needed to get robust proof of MSC beneficial effects.     

The cytokine storm in COVID-19: Further advances in our understanding the role of specific chemokines involved

SARS-COV-2 infection represents the greatest pandemic of the world, counting daily increasing number of subjects positive to the virus and, sadly, increasing number of deaths. Current studies reported that the cytokine/chemokine network is crucial in the onset and maintenance of the “cytokine storm”, the event occurring in those patients in whom the progression of COVID-19 will progress, in most cases, to a very severe and potentially threatening disease. Detecting a possible “immune signature” in patients, as assessed by chemokines status in patients with COVID-19, could be helpful for individual risk stratification for developing a more or less severe clinical course of the disease. The present review is specifically aimed at overviewing current evidences provided by in vitro and in vivo studies addressing the issue of which chemokines seems to be involved, at least at present, in COVID-19. Currently available experimental and clinical studies regarding those chemokines more deeply studied in COVID-19, with a specific focus on their role in the cytokine storm and ultimately with their ability to predict the clinical course of the disease, will be taken into account. Moreover, similarities and differences between chemokines and cytokines, which both contribute to the onset of the pro-inflammatory loop characterizing SARS-COV-2 infection, will be briefly discussed. Future studies will rapidly accumulate in the next months and their results will hopefully provide more insights as to the complex physiopathology of COVID-19-related cytokine storm. This will likely make the present review somehow “dated” in a short time, but still the present review provides an overview of the scenario of the current knowledge on this topic.     

AntagomiRs: A novel therapeutic strategy for challenging COVID-19 cytokine storm

Is it possible to develop a reliable, safe treatment for the widespread COVID-19 pandemic shortly? COVID-19 is characterized by a disruptive cytokine storm, quickly and often irreversibly damaging the patient’s lungs, as its main target organ, leading to lung failure and death. Actual experimental therapies are trying to reduce the activation of some specific cytokines, such as IL-6, somewhat reducing the burden for the patient. However, they are often unable to block the whole storm occurring at the cytokine level. In presence of the cytokine storm, especially in severe patients, antagomiRs, already demonstrated to be efficient and secure in cardiovascular disease, could represent a useful alternative to such treatment, customizable upon the disease specificities and applicable to other coronaviruses possibly associated with such clinical manifestations, while a reliable, efficient vaccine is being distributed.     

Of mitochondrion and COVID-19

COVID-19, a pandemic disease caused by a viral infection, is associated with a high mortality rate. Most of the signs and symptoms, e.g. cytokine storm, electrolytes imbalances, thromboembolism, etc., are related to mitochondrial dysfunction. Therefore, targeting mitochondrion will represent a more rational treatment of COVID-19. The current work outlines how COVID-19’s signs and symptoms are related to the mitochondrion. Proper understanding of the underlying causes might enhance the opportunity to treat COVID-19.     

The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system

In 2019–2020 a new coronavirus named SARS-CoV-2 was identified as the causative agent of a several acute respiratory infection named COVID-19, which is causing a worldwide pandemic. There are still many unresolved questions regarding the pathogenesis of this disease and especially the reasons underlying the extremely different clinical course, ranging from asymptomatic forms to severe manifestations, including the Acute Respiratory Distress Syndrome (ARDS). SARS-CoV-2 showed phylogenetic similarities to both SARS-CoV and MERS-CoV viruses, and some of the clinical features are shared between COVID-19 and previously identified beta-coronavirus infections. Available evidence indicate that the so called “cytokine storm” an uncontrolled over-production of soluble markers of inflammation which, in turn, sustain an aberrant systemic inflammatory response, is a major responsible for the occurrence of ARDS. Chemokines are low molecular weight proteins with powerful chemoattractant activity which play a role in the immune cell recruitment during inflammation. This review will be aimed at providing an overview of the current knowledge on the involvement of the chemokine/chemokine-receptor system in the cytokine storm related to SARS-CoV-2 infection. Basic and clinical evidences obtained from previous SARS and MERS epidemics and available data from COVID-19 will be taken into account.     

Fungal Infections in COVID-19 Intensive Care Patients

Opportunistic fungal infections increase morbidity and mortality in COVID-19 patients monitored in intensive care units (ICU). As patients’ hospitalization days in the ICU and intubation period increase, opportunistic infections also increase, which prolongs hospital stay days and elevates costs. The study aimed to describe the profile of fungal infections and identify the risk factors associated with mortality in COVID-19 intensive care patients. The records of 627 patients hospitalized in ICU with the diagnosis of COVID-19 were investigated from electronic health records and hospitalization files. The demographic characteristics (age, gender), the number of ICU hospitalization days and mortality rates, APACHE II scores, accompanying diseases, antibiotic-steroid treatments taken during hospitalization, and microbiological results (blood, urine, tracheal aspirate samples) of the patients were recorded. Opportunistic fungal infection was detected in 32 patients (5.10%) of 627 patients monitored in ICU with a COVID-19 diagnosis. The average APACHE II score of the patients was 28 ± 6. While 25 of the patients (78.12%) died, seven (21.87%) were discharged from the ICU. Candida parapsilosis (43.7%) was the opportunistic fungal agent isolated from most blood samples taken from COVID-19 positive patients. The mortality rate of COVID-19 positive patients with candidemia was 80%. While two out of the three patients (66.6%) for whom fungi were grown from their tracheal aspirate died, one patient (33.3%) was transferred to the ward. Opportunistic fungal infections increase the mortality rate of COVID-19-positive patients. In addition to the risk factors that we cannot change, invasive procedures should be avoided, constant blood sugar regulation should be applied, and unnecessary antibiotics use should be avoided.     

Cytokine storm intervention in the early stages of COVID-19 pneumonia

Clinical intervention in patients with corona virus disease 2019 (COVID-19) has demonstrated a strong upregulation of cytokine production in patients who are critically ill with SARS-CoV2-induced pneumonia. In a retrospective study of 41 patients with COVID-19, most patients with SARS-CoV-2 infection developed mild symptoms, whereas some patients later developed aggravated disease symptoms, and eventually passed away because of multiple organ dysfunction syndrome (MODS), as a consequence of a severe cytokine storm. Guidelines for the diagnosis and treatment of SARS-CoV-2 infected pneumonia were first published January 30^th, 2020; these guidelines recommended for the first time that cytokine monitoring should be applied in severely ill patients to reduce pneumonia related mortality. The cytokine storm observed in COVID-19 illness is also an important component of mortality in other viral diseases, including SARS, MERS and influenza. In view of the severe morbidity and mortality of COVID-19 pneumonia, we review the current understanding of treatment of human coronavirus infections from the perspective of a dysregulated cytokine and immune response.     

Clinical progress in MSC-based therapies for the management of severe COVID-19

Considering the high impact that severe Coronavirus disease 2019 (COVID-19) cases still pose on public health and their complex pharmacological management, the search for new therapeutic alternatives is essential. Mesenchymal stromal cells (MSCs) could be promising candidates as they present important immunomodulatory and anti-inflammatory properties that can combat the acute severe respiratory distress syndrome (ARDS) and the cytokine storm occurring in COVID-19, two processes that are mainly driven by an immunological misbalance. In this review, we provide a comprehensive overview of the intricate inflammatory process derived from the immune dysregulation that occurs in COVID-19, discussing the potential that the cytokines and growth factors that constitute the MSC-derived secretome present to treat the disease. Moreover, we revise the latest clinical progress made in the field, discussing the most important findings of the clinical trials conducted to date, which follow 2 different approaches: MSC-based cell therapy or the administration of the secretome by itself, as a cell-free therapy.     

中西医结合探析COVID-19所致细胞因子风暴

COVID-19大流行已成为一场全球危机, 比以往任何其他传染病都更具破坏性。研究表明, 引起COVID-19的病毒SARS-CoV-2的毒力主要取决于宿主异常免疫反应的触发, 而不是病毒直接诱导的细胞损伤, 尤其是细胞因子风暴的产生。所谓细胞因子风暴, 即机体对外界刺激产生的一种过激免疫反应对自身组织器官所造成的损伤, 大大增加了重症患者的救治难度, 也是目前造成年轻患者死亡的主要原因之一。由于细胞因子风暴产生机制复杂, 因此目前缺乏早期预警指标和特异的有效治疗措施。本文分别从现代医学和传统医学视角解析细胞因子风暴产生机制和治疗策略, 探究二者的局限性以及中西医结合治疗的优势, 为临床实践和深入科研攻关提供线索和思路。

     

Cytokine storm in COVID-19: from viral infection to immune responses,diagnosis and therapy

The COVID-19 outbreak is emerging as a significant public health challenge. Excessive production of proinflammatory cytokines, also known as cytokine storm, is a severe clinical syndrome known to develop as a complication of infectious or inflammatory diseases. Clinical evidence suggests that the occurrence of cytokine storm in severe acute respiratory syndrome secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is closely associated with the rapid deterioration and high mortality of severe cases. In this review, we aim to summarize the mechanism of SARS-CoV-2 infection and the subsequent immunological events related to excessive cytokine production and inflammatory responses associated with ACE2-AngII signaling. An overview of the diagnosis and an update on current therapeutic regimens and vaccinations is also provided.     

微量元素硒在对抗COVID-19中的作用研究进展

自新型冠状病毒肺炎（corona virus disease 2019,COVID-19）疫情爆发以来,严重急性呼吸综合征冠状病毒2（severe acute respiratory syndrome-coronavirus 2, SARS-CoV-2）引起的各类临床表现和后续并发症受到了广泛关注。有研究发现,COVID-19死亡率具有地域差异性,中度或重度缺硒地区感染人群常常具有更高的死亡率,因此硒可能在对抗COVID-19中具有一定的作用。总结了硒缺乏COVID-19患者的临床表现、硒对抗COVID-19的临床效应、以及硒对抗COVID-19的作用机制等方面的研究进展。从目前的研究结果来看,硒在应对感染SARS-CoV-2以及避免过激免疫反应导致的细胞因子风暴过程中具有积极作用,但仍然缺乏临床试验研究证据。     

COVID-19: Pathogenesis,cytokine storm and therapeutic potential of interferons

The outbreak of the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) responsible for coronavirus disease 2019 (COVID-19) has developed into an unprecedented global pandemic. Clinical investigations in patients with COVID-19 has shown a strong upregulation of cytokine and interferon production in SARS-CoV2- induced pneumonia, with an associated cytokine storm syndrome. Thus, the identification of existing approved therapies with proven safety profiles to treat hyperinflammation is a critical unmet need in order to reduce COVI-19 associated mortality. To date, no specific therapeutic drugs or vaccines are available to treat COVID-19 patients. This review evaluates several options that have been proposed to control SARS-CoV2 hyperinflammation and cytokine storm, eincluding antiviral drugs, vaccines, small-molecules, monoclonal antibodies, oligonucleotides, peptides, and interferons (IFNs).     

An Impaired Inflammatory and Innate Immune Response in COVID-19

The recent appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people around the world and caused a global pandemic of coronavirus disease 2019 (COVID-19). It has been suggested that uncontrolled, exaggerated inflammation contributes to the adverse outcomes of COVID-19. In this review, we summarize our current understanding of the innate immune response elicited by SARS-CoV-2 infection and the hyperinflammation that contributes to disease severity and death. We also discuss the immunological determinants behind COVID-19 severity and propose a rationale for the underlying mechanisms.     

Multiple potential targets of opioids in the treatment of acute respiratory distress syndrome from COVID-19

COVID-19 can present with a variety of clinical features, ranging from asymptomatic or mild respiratory symptoms to fulminant acute respiratory distress syndrome (ARDS) depending on the host's immune responses and the extent of the associated pathologies. This implies that several measures need to be taken to limit severely impairing symptoms caused by viral-induced pathology in vital organs. Opioids are most exploited for their analgesic effects but their usage in the palliation of dyspnoea, immunomodulation and lysosomotropism may represent potential usages of opioids in COVID-19. Here, we describe the mechanisms involved in each of these potential usages, highlighting the benefits of using opioids in the treatment of ARDS from SARS-CoV-2 infection.     

间充质干细胞在新型冠状病毒肺炎治疗中的研究现状

新型冠状病毒肺炎(COVID-19)由新型冠状病毒(SARS-CoV-2)导致,可发生严重肺部损伤甚至死亡,目前为止仍在全球范围内广泛蔓延。SARS-CoV-2感染依赖于血管紧张素转换酶2(ACE2)和Ⅱ型跨膜丝氨酸蛋白酶,可导致机体免疫紊乱,促发炎症风暴从而损伤靶器官。COVID-19目前尚无特效药物,间充质干细胞(MSCs)具有组织修复和免疫调节等功能,而且在流感病毒相关性肺炎及其他肺疾病中有一定疗效,因此可能是治疗COVID-19潜在有效药物。目前部分研究也显示出积极的治疗效果,而具体的疗效仍需进一步的临床研究来验证。     

Therapeutic prospects of mesenchymal stem/stromal cells in COVID-19 associated pulmonary diseases: From bench to bedside

The ongoing outbreak of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 has become a sudden public emergency of international concern and seriously threatens millions of people’s life health. Two current studies have indicated a favorable role for mesenchymal stem/stromal cells (MSCs) in clinical remission of COVID-19 associated pulmonary diseases, yet the systematical elaboration of the therapeutics and underlying mechanism is far from satisfaction. In the present review, we summarize the therapeutic potential of MSCs in COVID-19 associated pulmonary diseases such as pneumonia induced acute lung injury, acute respiratory distress syndrome, and pulmonary fibrosis. Furthermore, we review the underlying mechanism of MSCs including direct- and trans-differentiation, autocrine and paracrine anti-inflammatory effects, homing, and neovascularization, as well as constitutive microenvironment. Finally, we discuss the prospects and supervision of MSC-based cytotherapy for COVID-19 management before large-scale application in clinical practice. Collectively, this review supplies overwhelming new references for understanding the landscapes of MSCs in the remission of COVID-19 associated pulmonary diseases.     

Pyroptotic cell death in SARS-CoV-2 infection: revealing its roles during the immunopathogenesis of COVID-19

The rapid dissemination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), remains a global public health emergency. The host immune response to SARS-CoV-2 plays a key role in COVID-19 pathogenesis. SARS-CoV-2 can induce aberrant and excessive immune responses, leading to cytokine storm syndrome, autoimmunity, lymphopenia, neutrophilia and dysfunction of monocytes and macrophages. Pyroptosis, a proinflammatory form of programmed cell death, acts as a host defense mechanism against infections. Pyroptosis deprives the replicative niche of SARS-CoV-2 by inducing the lysis of infected cells and exposing the virus to extracellular immune attack. Notably, SARS-CoV-2 has evolved sophisticated mechanisms to hijack this cell death mode for its own survival, propagation and shedding. SARS-CoV-2-encoded viral products act to modulate various key components in the pyroptosis pathways, including inflammasomes, caspases and gasdermins. SARS-CoV-2-induced pyroptosis contriubtes to the development of COVID-19-associated immunopathologies through leakage of intracellular contents, disruption of immune system homeostasis or exacerbation of inflammation. Therefore, pyroptosis has emerged as an important mechanism involved in COVID-19 immunopathogenesis. However, the entangled links between pyroptosis and SARS-CoV-2 pathogenesis lack systematic clarification. In this review, we briefly summarize the characteristics of SARS-CoV-2 and COVID-19-related immunopathologies. Moreover, we present an overview of the interplay between SARS-CoV-2 infection and pyroptosis and highlight recent research advances in the understanding of the mechanisms responsible for the implication of the pyroptosis pathways in COVID-19 pathogenesis, which will provide informative inspirations and new directions for further investigation and clinical practice. Finally, we discuss the potential value of pyroptosis as a therapeutic target in COVID-19. An in-depth discussion of the underlying mechanisms of COVID-19 pathogenesis will be conducive to the identification of potential therapeutic targets and the exploration of effective treatment measures aimed at conquering SARS-CoV-2-induced COVID-19.     

Opportunistic Candida Infections in Critical COVID-19 Patients

The frequency of opportunistic fungal infections in critically ill patients whose intensive care unit stays are prolonged due to coronavirus disease 2019 (COVID-19) is higher than in the period before COVID-19. We planned this study to improve the management of Candida infections by defining the Candida species, the etiology of infections caused by Candida species, and the antifungal susceptibility of the species. This retrospective study included patients older than 18 hospitalized in the intensive care unit (ICU) with a definitive diagnosis of COVID-19 for seven months (from March 2021 to September 2021). All study data that we recorded in a standard study form were analyzed with TURCOSA (Turcosa Analytics Ltd. Co., Turkey, www.turcosa.com.tr) statistical software. The patients were evaluated in four groups as group 1 (candidemia patients, n = 78), group 2 (candiduria patients, n = 189), group 3 (control patients, n = 57), and group 4 (patients with candidemia in urine cultures taken before Candida was detected in blood culture, n = 42). Candida species were identified using both conventional and VITEK® 2 (BioMérieux, France) methods. The antifungal susceptibility of fungi was determined using the E test method. Of the 5,583 COVID-19 patients followed during the study period, 78 developed candidemia, and 189 developed candiduria. The incidence of candidemia (per 1,000 admissions) was determined to be 1.6. As a result of statistical analysis, we found that Candida albicans was the dominant strain in candidemia and candiduria, and there was no antifungal resistance except for naturally resistant strains. Candida strains grown in blood and urine were the same in 40 of 42 patients. Mortality was 69.2% for group 1, 60.4% for group 2, and 57.8% for group 3. Antifungals were used in 34 (43.5%) patients from group 1, and 95 (50.2%) from group 2. In the candidemia group without antifungal use, mortality was quite high (77.2%). Antifungal use reduced mortality in the group 2 (p < 0.05). Length of ICU stays, comorbidity, broad-spectrum antibiotics, and corticosteroids are independent risk factors for candidemia in critically ill COVID-19 patients. Our study contributes to the knowledge of risk factors for developing COVID-19-related candida infections. The effect of candiduria on the development of candidemia in critically ill COVID-19 patients should be supported by new studies.     

Mesenchymal stem cells as living anti-inflammatory therapy for COVID-19 related acute respiratory distress syndrome

Coronavirus disease 2019(COVID-19), a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2(SARS-Co V2), is growing at an exponential rate worldwide. Manifestations of this disease are heterogeneous; however, advanced cases often exhibit various acute respiratory distress syndrome-like symptoms, systemic inflammatory reactions, coagulopathy, and organ involvements. A common theme in advanced COVID-19 is unrestrained immune activation, classically referred to as a cytokine storm, as well as deficiencies in immune regulatory mechanisms such as T regulatory cells. While mesenchymal stem cells(MSCs) themselves are objects of cytokine regulation, they can secrete cytokines to modulate immune cells by inducing antiinflammatory regulatory Treg cells, macrophages and neutrophils; and by reducing the activation of T and B cells, dendritic and nature killer cells. Consequently, they have therapeutic potential for treating severe cases of COVID-19. Here we discuss the unique ability of MSCs, to act as a living antiinflammatory, which can rebalance the cytokine/immune responses to restore equilibrium. We also discuss current MSC trials and present different concepts for optimization of MSC therapy in patients with COVID-19 acute respiratory distress syndrome.