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1.
J Med Virol ; 93(12): 6641-6652, 2021 12.
Article in English | MEDLINE | ID: covidwho-1544314

ABSTRACT

Acute kidney injury (AKI) may develop in patients with coronavirus disease 2019 (COVID-19) and is associated with in-hospital death. We investigated the incidence of AKI in 223 hospitalized COVID-19 patients and analyzed the influence factors of AKI. The incidence of cytokine storm syndrome and its correlation with other clinicopathologic variables were also investigated. We retrospectively enrolled adult patients with virologically confirmed COVID-19 who were hospitalized at three hospitals in Wuhan and Guizhou, China between February 13, 2020, and April 8, 2020. We included 124 patients with moderate COVID-19 and 99 with severe COVID-19. AKI was present in 35 (15.7%) patients. The incidence of AKI was 30.3% for severe COVID-19 and 4.0% for moderate COVID-19 (p < 0.001). Furthermore, cytokine storm was found in 30 (13.5%) patients and only found in the severe group. Kidney injury at admission (odds ratio [OR]: 3.132, 95% confidence interval [CI]: 1.150-8.527; p = 0.025), cytokine storm (OR: 4.234, 95% CI: 1.361-13.171; p = 0.013), and acute respiratory distress syndrome (ARDS) (OR: 7.684, 95% CI: 2.622-22.523; p < 0.001) were influence factors of AKI. Seventeen (48.6%) patients who received invasive mechanical ventilation developed AKI, of whom 64.7% (11/17) died. Up to 86.7% of AKI patients with cytokine storms may develop a secondary bacterial infection. The leukocyte counts were significantly higher in AKI patients with cytokine storm than in those without (13.0 × 109/L, interquartile range [IQR] 11.3 vs. 8.3 × 109/L, IQR 7.5, p = 0.005). Approximately 1/6 patients with COVID-19 eventually develop AKI. Kidney injury at admission, cytokine storm and ARDS are influence factors of AKI. Cytokine storm and secondary bacterial infections may be responsible for AKI development in COVID-19 patients.


Subject(s)
Acute Kidney Injury/etiology , Bacterial Infections/etiology , COVID-19/complications , Cytokine Release Syndrome/complications , Adult , Aged , China , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Respiration, Artificial/adverse effects , Respiration, Artificial/statistics & numerical data , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/etiology , Retrospective Studies , Risk Factors
2.
Front Immunol ; 12: 730088, 2021.
Article in English | MEDLINE | ID: covidwho-1394763

ABSTRACT

In December 2019, a new viral disease emerged and quickly spread all around the world. In March 2020, the COVID-19 outbreak was classified as a global pandemic and by June 2021, the number of infected people grew to over 170 million. Along with the patients' mild-to-severe respiratory symptoms, reports on probable central nervous system (CNS) effects appeared shortly, raising concerns about the possible long-term detrimental effects on human cognition. It remains unresolved whether the neurological symptoms are caused directly by the SARS-CoV-2 infiltration in the brain, indirectly by secondary immune effects of a cytokine storm and antibody overproduction, or as a consequence of systemic hypoxia-mediated microglia activation. In severe COVID-19 cases with impaired lung capacity, hypoxia is an anticipated subsidiary event that can cause progressive and irreversible damage to neurons. To resolve this problem, intensive research is currently ongoing, which seeks to evaluate the SARS-CoV-2 virus' neuroinvasive potential and the examination of the antibody and autoantibody generation upon infection, as well as the effects of prolonged systemic hypoxia on the CNS. In this review, we summarize the current research on the possible interplay of the SARS-CoV-2 effects on the lung, especially on alveolar macrophages and direct and indirect effects on the brain, with special emphasis on microglia, as a possible culprit of neurological manifestation during COVID-19.


Subject(s)
COVID-19/complications , Central Nervous System Infections/complications , Central Nervous System Infections/virology , Lung/virology , SARS-CoV-2/pathogenicity , COVID-19/immunology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Humans , Lung/immunology , Microglia/immunology , Microglia/pathology , Microglia/virology , Nervous System Diseases/virology , SARS-CoV-2/immunology
3.
BMC Infect Dis ; 21(1): 398, 2021 Apr 29.
Article in English | MEDLINE | ID: covidwho-1327867

ABSTRACT

BACKGROUND: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory event and a fatal complication of viral infections. Whether sHLH may also be observed in patients with a cytokine storm induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still uncertain. We aimed to determine the incidence of sHLH in severe COVID-19 patients and evaluate the underlying risk factors. METHOD: Four hundred fifteen severe COVID-19 adult patients were retrospectively assessed for hemophagocytosis score (HScore). A subset of 7 patients were unable to be conclusively scored due to insufficient patient data. RESULTS: In 408 patients, 41 (10.04%) had an HScore ≥169 and were characterized as "suspected sHLH positive". Compared with patients below a HScore threshold of 98, the suspected sHLH positive group had higher D-dimer, total bilirubin, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine, triglycerides, ferritin, interleukin-6, C-reactive protein, procalcitonin, lactate dehydrogenase, creatine kinase isoenzyme, troponin, Sequential Organ Failure Assessment (SOFA) score, while leukocyte, hemoglobin, platelets, lymphocyte, fibrinogen, pre-albumin, albumin levels were significantly lower (all P < 0.05). Multivariable logistic regression revealed that high ferritin (>1922.58 ng/mL), low platelets (<101 × 109/L) and high triglycerides (>2.28 mmol/L) were independent risk factors for suspected sHLH in COVID-19 patients. Importantly, COVID-19 patients that were suspected sHLH positive had significantly more multi-organ failure. Additionally, a high HScore (>98) was an independent predictor for mortality in COVID-19. CONCLUSIONS: HScore should be measured as a prognostic biomarker in COVID-19 patients. In particular, it is important that HScore is assessed in patients with high ferritin, triglycerides and low platelets to improve the detection of suspected sHLH.


Subject(s)
COVID-19/complications , Lymphohistiocytosis, Hemophagocytic/etiology , Adult , Aged , Aspartate Aminotransferases/blood , COVID-19/epidemiology , COVID-19/therapy , China/epidemiology , Comorbidity , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/virology , Female , Ferritins/blood , Humans , Incidence , Lymphocyte Count , Lymphohistiocytosis, Hemophagocytic/epidemiology , Lymphohistiocytosis, Hemophagocytic/mortality , Male , Middle Aged , Mortality , Retrospective Studies , Risk Factors
4.
J Med Virol ; 93(12): 6641-6652, 2021 12.
Article in English | MEDLINE | ID: covidwho-1326777

ABSTRACT

Acute kidney injury (AKI) may develop in patients with coronavirus disease 2019 (COVID-19) and is associated with in-hospital death. We investigated the incidence of AKI in 223 hospitalized COVID-19 patients and analyzed the influence factors of AKI. The incidence of cytokine storm syndrome and its correlation with other clinicopathologic variables were also investigated. We retrospectively enrolled adult patients with virologically confirmed COVID-19 who were hospitalized at three hospitals in Wuhan and Guizhou, China between February 13, 2020, and April 8, 2020. We included 124 patients with moderate COVID-19 and 99 with severe COVID-19. AKI was present in 35 (15.7%) patients. The incidence of AKI was 30.3% for severe COVID-19 and 4.0% for moderate COVID-19 (p < 0.001). Furthermore, cytokine storm was found in 30 (13.5%) patients and only found in the severe group. Kidney injury at admission (odds ratio [OR]: 3.132, 95% confidence interval [CI]: 1.150-8.527; p = 0.025), cytokine storm (OR: 4.234, 95% CI: 1.361-13.171; p = 0.013), and acute respiratory distress syndrome (ARDS) (OR: 7.684, 95% CI: 2.622-22.523; p < 0.001) were influence factors of AKI. Seventeen (48.6%) patients who received invasive mechanical ventilation developed AKI, of whom 64.7% (11/17) died. Up to 86.7% of AKI patients with cytokine storms may develop a secondary bacterial infection. The leukocyte counts were significantly higher in AKI patients with cytokine storm than in those without (13.0 × 109/L, interquartile range [IQR] 11.3 vs. 8.3 × 109/L, IQR 7.5, p = 0.005). Approximately 1/6 patients with COVID-19 eventually develop AKI. Kidney injury at admission, cytokine storm and ARDS are influence factors of AKI. Cytokine storm and secondary bacterial infections may be responsible for AKI development in COVID-19 patients.


Subject(s)
Acute Kidney Injury/etiology , Bacterial Infections/etiology , COVID-19/complications , Cytokine Release Syndrome/complications , Adult , Aged , China , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Respiration, Artificial/adverse effects , Respiration, Artificial/statistics & numerical data , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/etiology , Retrospective Studies , Risk Factors
5.
Int J Mol Sci ; 22(14)2021 Jul 15.
Article in English | MEDLINE | ID: covidwho-1314667

ABSTRACT

The COVID-19 pandemic examines not only the state of actual health care but also the state of fundamental medicine in various countries. Pro-inflammatory processes extend far beyond the classical concepts of inflammation. They manifest themselves in a variety of ways, beginning with extreme physiology, then allostasis at low-grade inflammation, and finally the shockogenic phenomenon of "inflammatory systemic microcirculation". The pathogenetic core of critical situations, including COVID-19, is this phenomenon. Microcirculatory abnormalities, on the other hand, lie at the heart of a specific type of general pathological process known as systemic inflammation (SI). Systemic inflammatory response, cytokine release, cytokine storm, and thrombo-inflammatory syndrome are all terms that refer to different aspects of SI. As a result, the metabolic syndrome model does not adequately reflect the pathophysiology of persistent low-grade systemic inflammation (ChSLGI). Diseases associated with ChSLGI, on the other hand, are risk factors for a severe COVID-19 course. The review examines the role of hypoxia, metabolic dysfunction, scavenger receptors, and pattern-recognition receptors, as well as the processes of the hemophagocytic syndrome, in the systemic alteration and development of SI in COVID-19.


Subject(s)
COVID-19/pathology , Cytokine Release Syndrome/complications , Inflammation/complications , Lymphohistiocytosis, Hemophagocytic/complications , SARS-CoV-2/isolation & purification , COVID-19/immunology , COVID-19/therapy , COVID-19/virology , Humans
6.
Islets ; 13(3-4): 66-79, 2021 07 04.
Article in English | MEDLINE | ID: covidwho-1310869

ABSTRACT

The link between COVID-19 infection and diabetes has been explored in several studies since the start of the pandemic, with associations between comorbid diabetes and poorer prognosis in patients infected with the virus and reports of diabetic ketoacidosis occurring with COVID-19 infection. As such, significant interest has been generated surrounding mechanisms by which the virus may exert effects on the pancreatic ß cells. In this review, we consider possible routes by which SARS-CoV-2 may impact ß cells. Specifically, we outline data that either support or argue against the idea of direct infection and injury of ß cells by SARS-CoV-2. We also discuss ß cell damage due to a "bystander" effect in which infection with the virus leads to damage to surrounding tissues that are essential for ß cell survival and function, such as the pancreatic microvasculature and exocrine tissue. Studies elucidating the provocation of a cytokine storm following COVID-19 infection and potential impacts of systemic inflammation and increases in insulin resistance on ß cells are also reviewed. Finally, we summarize the existing clinical data surrounding diabetes incidence since the start of the COVID-19 pandemic.


Subject(s)
Insulin-Secreting Cells/physiology , SARS-CoV-2/physiology , Bystander Effect/physiology , COVID-19/complications , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/physiopathology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Diabetes Mellitus/immunology , Diabetes Mellitus/metabolism , Diabetes Mellitus/virology , Humans , Inflammation/complications , Inflammation/metabolism , Inflammation/virology , Insulin Resistance/physiology , Insulin-Secreting Cells/virology , Pandemics , SARS-CoV-2/pathogenicity
7.
Molecules ; 25(19)2020 Sep 24.
Article in English | MEDLINE | ID: covidwho-1302391

ABSTRACT

There is a vast practice of using antimalarial drugs, RAS inhibitors, serine protease inhibitors, inhibitors of the RNA-dependent RNA polymerase of the virus and immunosuppressants for the treatment of the severe form of COVID-19, which often occurs in patients with chronic diseases and older persons. Currently, the clinical efficacy of these drugs for COVID-19 has not been proven yet. Side effects of antimalarial drugs can worsen the condition of patients and increase the likelihood of death. Peptides, given their physiological mechanism of action, have virtually no side effects. Many of them are geroprotectors and can be used in patients with chronic diseases. Peptides may be able to prevent the development of the pathological process during COVID-19 by inhibiting SARS-CoV-2 virus proteins, thereby having immuno- and bronchoprotective effects on lung cells, and normalizing the state of the hemostasis system. Immunomodulators (RKDVY, EW, KE, AEDG), possessing a physiological mechanism of action at low concentrations, appear to be the most promising group among the peptides. They normalize the cytokines' synthesis and have an anti-inflammatory effect, thereby preventing the development of disseminated intravascular coagulation, acute respiratory distress syndrome and multiple organ failure.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Immunologic Factors/therapeutic use , Peptides/therapeutic use , Pneumonia, Viral/drug therapy , Respiratory System Agents/therapeutic use , Acute Disease , Anti-Inflammatory Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Betacoronavirus/drug effects , Betacoronavirus/growth & development , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Disseminated Intravascular Coagulation/complications , Disseminated Intravascular Coagulation/diagnosis , Disseminated Intravascular Coagulation/drug therapy , Disseminated Intravascular Coagulation/virology , Host-Pathogen Interactions/drug effects , Humans , Immunologic Factors/chemical synthesis , Lung/blood supply , Lung/drug effects , Lung/pathology , Lung/virology , Pandemics , Peptides/chemical synthesis , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Respiratory Insufficiency/complications , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/prevention & control , Respiratory Insufficiency/virology , Respiratory System Agents/chemical synthesis , SARS-CoV-2 , Structure-Activity Relationship
8.
Nat Commun ; 12(1): 4117, 2021 07 05.
Article in English | MEDLINE | ID: covidwho-1297301

ABSTRACT

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.


Subject(s)
COVID-19/complications , COVID-19/immunology , Cytokine Release Syndrome/complications , Monocytes/pathology , Neutrophil Activation , Aged , Antigen-Presenting Cells/immunology , COVID-19/blood , COVID-19/virology , Case-Control Studies , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Cytokines/blood , Extracellular Traps/metabolism , Female , Histocompatibility Antigens Class II/metabolism , Humans , Immunophenotyping , Male , Middle Aged , SARS-CoV-2/physiology , Severity of Illness Index
9.
Acta Neuropsychiatr ; 33(4): 165-177, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1297283

ABSTRACT

Neuropsychiatric sequalae to coronavirus disease 2019 (COVID-19) infection are beginning to emerge, like previous Spanish influenza and severe acute respiratory syndrome episodes. Streptococcal infection in paediatric patients causing obsessive compulsive disorder (PANDAS) is another recent example of an infection-based psychiatric disorder. Inflammation associated with neuropsychiatric disorders has been previously reported but there is no standard clinical management approach established. Part of the reason is that it is unclear what factors determine the specific neuronal vulnerability and the efficacy of anti-inflammatory treatment in neuroinflammation. The emerging COVID-19 data suggested that in the acute stage, widespread neuronal damage appears to be the result of abnormal and overactive immune responses and cytokine storm is associated with poor prognosis. It is still too early to know if there are long-term-specific neuronal or brain regional damages associated with COVID-19, resulting in distinct neuropsychiatric disorders. In several major psychiatric disorders where neuroinflammation is present, patients with abnormal inflammatory markers may also experience less than favourable response or treatment resistance when standard treatment is used alone. Evidence regarding the benefits of co-administered anti-inflammatory agents such as COX-2 inhibitor is encouraging in selected patients though may not benefit others. Disease-modifying therapies are increasingly being applied to neuropsychiatric diseases characterised by abnormal or hyperreactive immune responses. Adjunct anti-inflammatory treatment may benefit selected patients and is definitely an important component of clinical management in the presence of neuroinflammation.


Subject(s)
Autoimmune Diseases/psychology , COVID-19/psychology , Obsessive-Compulsive Disorder/psychology , Streptococcal Infections/psychology , Anti-Inflammatory Agents/therapeutic use , Autoimmune Diseases/epidemiology , Autoimmune Diseases/immunology , COVID-19/complications , COVID-19/diagnosis , COVID-19/epidemiology , Cyclooxygenase 2 Inhibitors/therapeutic use , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Female , Humans , Inflammation/complications , Inflammation/immunology , Inflammation/psychology , Obsessive-Compulsive Disorder/epidemiology , Obsessive-Compulsive Disorder/etiology , Obsessive-Compulsive Disorder/immunology , SARS-CoV-2/genetics , Streptococcal Infections/complications , Streptococcal Infections/epidemiology , Streptococcal Infections/immunology
10.
Int J Mol Sci ; 22(10)2021 May 16.
Article in English | MEDLINE | ID: covidwho-1234743

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is still an ongoing global health crisis. Immediately after the inhalation of SARS-CoV-2 viral particles, alveolar type II epithelial cells harbor and initiate local innate immunity. These particles can infect circulating macrophages, which then present the coronavirus antigens to T cells. Subsequently, the activation and differentiation of various types of T cells, as well as uncontrollable cytokine release (also known as cytokine storms), result in tissue destruction and amplification of the immune response. Vitamin D enhances the innate immunity required for combating COVID-19 by activating toll-like receptor 2. It also enhances antimicrobial peptide synthesis, such as through the promotion of the expression and secretion of cathelicidin and ß-defensin; promotes autophagy through autophagosome formation; and increases the synthesis of lysosomal degradation enzymes within macrophages. Regarding adaptive immunity, vitamin D enhances CD4+ T cells, suppresses T helper 17 cells, and promotes the production of virus-specific antibodies by activating T cell-dependent B cells. Moreover, vitamin D attenuates the release of pro-inflammatory cytokines by CD4+ T cells through nuclear factor κB signaling, thereby inhibiting the development of a cytokine storm. SARS-CoV-2 enters cells after its spike proteins are bound to angiotensin-converting enzyme 2 (ACE2) receptors. Vitamin D increases the bioavailability and expression of ACE2, which may be responsible for trapping and inactivating the virus. Activation of the renin-angiotensin-aldosterone system (RAS) is responsible for tissue destruction, inflammation, and organ failure related to SARS-CoV-2. Vitamin D inhibits renin expression and serves as a negative RAS regulator. In conclusion, vitamin D defends the body against SARS-CoV-2 through a novel complex mechanism that operates through interactions between the activation of both innate and adaptive immunity, ACE2 expression, and inhibition of the RAS system. Multiple observation studies have shown that serum concentrations of 25 hydroxyvitamin D are inversely correlated with the incidence or severity of COVID-19. The evidence gathered thus far, generally meets Hill's causality criteria in a biological system, although experimental verification is not sufficient. We speculated that adequate vitamin D supplementation may be essential for mitigating the progression and severity of COVID-19. Future studies are warranted to determine the dosage and effectiveness of vitamin D supplementation among different populations of individuals with COVID-19.


Subject(s)
Adaptive Immunity , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , Immunity, Innate , SARS-CoV-2/immunology , Vitamin D/metabolism , Vitamin D/pharmacology , COVID-19/mortality , COVID-19/physiopathology , COVID-19/virology , Cytokine Release Syndrome/complications , Cytokines/metabolism , Humans , Receptors, Virus/metabolism , Renin-Angiotensin System/physiology
11.
Front Immunol ; 12: 668507, 2021.
Article in English | MEDLINE | ID: covidwho-1226979

ABSTRACT

SARS-COV-2 virus is responsible for the ongoing devastating pandemic. Since the early phase of the pandemic, the "cytokine-storm" appeared a peculiar aspect of SARS-COV-2 infection which, at least in the severe cases, is responsible for respiratory treat damage and subsequent multi-organ failure. The efforts made in the last few months elucidated that the cytokine-storm results from a complex network involving cytokines/chemokines/infiltrating-immune-cells which orchestrate the aberrant immune response in COVID-19. Clinical and experimental studies aimed at depicting a potential "immune signature" of SARS-COV-2, identified three main "actors," namely the cytokine IL-6, the chemokine CXCL10 and the infiltrating immune cell type macrophages. Although other cytokines, chemokines and infiltrating immune cells are deeply involved and their role should not be neglected, based on currently available data, IL-6, CXCL10, and infiltrating macrophages could be considered prototype factors representing each component of the immune system. It rapidly became clear that a strong and continuous interplay among the three components of the immune response is mandatory in order to produce a severe clinical course of the disease. Indeed, while IL-6, CXCL10 and macrophages alone would not be able to fully drive the onset and maintenance of the cytokine-storm, the establishment of a IL-6/CXCL10/macrophages axis is crucial in driving the sequence of events characterizing this condition. The present review is specifically aimed at overviewing current evidences provided by both in vitro and in vivo studies addressing the issue of the interplay among IL-6, CXCL10 and macrophages in the onset and progression of cytokine storm. SARS-COV-2 infection and the "cytokine storm."


Subject(s)
COVID-19/immunology , Chemokine CXCL10/immunology , Cytokine Release Syndrome/immunology , Interleukin-6/immunology , Macrophages/immunology , COVID-19/complications , COVID-19/virology , Chemokines/immunology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/virology , Cytokines/immunology , Humans , Respiratory System/immunology , Respiratory System/virology , SARS-CoV-2/immunology , SARS-CoV-2/physiology
12.
Oxid Med Cell Longev ; 2021: 6648199, 2021.
Article in English | MEDLINE | ID: covidwho-1211620

ABSTRACT

Introduction: Mortality among critically ill COVID-19 patients remains relatively high despite different potential therapeutic modalities being introduced recently. The treatment of critically ill patients is a challenging task, without identified credible predictors of mortality. Methods: We performed an analysis of 160 consecutive patients with confirmed COVID-19 infection admitted to the Respiratory Intensive Care Unit between June 23, 2020, and October 2, 2020, in University Hospital Center Bezanijska kosa, Belgrade, Serbia. Patients on invasive, noninvasive ventilation and high flow oxygen therapy with moderate to severe ARDS, according to the Berlin definition of ARDS, were selected for the study. Demographic data, past medical history, laboratory values, and CT severity score were analyzed to identify predictors of mortality. Univariate and multivariate logistic regression models were used to assess potential predictors of mortality in critically ill COVID-19 patients. Results: The mean patient age was 65.6 years (range, 29-92 years), predominantly men, 68.8%. 107 (66.9%) patients were on invasive mechanical ventilation, 31 (19.3%) on noninvasive, and 22 (13.8%) on high flow oxygen therapy machine. The median total number of ICU days was 10 (25th to 75th percentile: 6-18), while the median total number of hospital stay was 18 (25th to 75th percentile: 12-28). The mortality rate was 60% (96/160). Univariate logistic regression analysis confirmed the significance of age, CRP, and lymphocytes at admission to hospital, serum albumin, D-dimer, and IL-6 at admission to ICU, and CT score. Serum albumin, D-dimer, and IL-6 at admission to ICU were independently associated with mortality in the final multivariate analysis. Conclusion: In the present study of 160 consecutive critically ill COVID-19 patients with moderate to severe ARDS, IL-6, serum albumin, and D-dimer at admission to ICU, accompanied by chest CT severity score, were marked as independent predictors of mortality.


Subject(s)
Blood Coagulation Disorders/complications , COVID-19/complications , COVID-19/mortality , Cytokine Release Syndrome/complications , Oxygen Inhalation Therapy/methods , Respiratory Distress Syndrome/complications , SARS-CoV-2/genetics , Adult , Aged , Aged, 80 and over , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/virology , COVID-19/epidemiology , COVID-19/therapy , Critical Care , Critical Illness , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/virology , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Intensive Care Units , Interleukin-6/blood , Length of Stay , Male , Middle Aged , Real-Time Polymerase Chain Reaction , Respiration, Artificial , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/virology , Serbia/epidemiology , Serum Albumin, Human/analysis , Severity of Illness Index , Treatment Outcome
13.
J Int Med Res ; 49(3): 3000605211002695, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1145418

ABSTRACT

Over the past several decades, studies have demonstrated the existence of bi-directional relationships between periodontal disease and systemic conditions. Periodontitis is a polymicrobial and multifactorial disease involving both host and environmental factors. Tissue destruction is primarily associated with hyperresponsiveness of the host resulting in release of inflammatory mediators. Pro-inflammatory cytokines play a major role in bacterial stimulation and tissue destruction. In addition, these cytokines are thought to underlie the associations between periodontitis and systemic conditions. Current research suggests that increased release of cytokines from host cells, referred to as the cytokine storm, is associated with disease progression in patients with coronavirus disease 2019 (COVID-19). An intersection between periodontitis and pulmonary disease is biologically plausible. Hence, we reviewed the evidence linking COVID-19, cytokines, and periodontal disease. Plaque control is essential to prevent exchange of bacteria between the mouth and the lungs, reducing the risk of lung disease. Understanding these associations may help identify individuals at high risk and deliver appropriate care at early stages.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Dental Plaque/immunology , Host-Pathogen Interactions/immunology , Periodontitis/immunology , SARS-CoV-2/pathogenicity , Stress, Psychological/immunology , COVID-19/complications , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Dental Plaque/complications , Dental Plaque/genetics , Dental Plaque/virology , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Lung/immunology , Lung/pathology , Lung/virology , Pathogen-Associated Molecular Pattern Molecules/immunology , Pathogen-Associated Molecular Pattern Molecules/metabolism , Periodontitis/complications , Periodontitis/genetics , Periodontitis/virology , SARS-CoV-2/immunology , Signal Transduction , Stress, Psychological/complications , Stress, Psychological/genetics , Stress, Psychological/virology , Tooth/immunology , Tooth/pathology , Tooth/virology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
14.
Cell Stress Chaperones ; 26(3): 515-525, 2021 05.
Article in English | MEDLINE | ID: covidwho-1101014

ABSTRACT

Hyperinflammation distinguishes COVID-19 patients who develop a slight disease or none, from those progressing to severe and critical conditions. CIGB-258 is a therapeutic option for the latter group of patients. This drug is an altered peptide ligand (APL) derived from the cellular stress protein 60 (HSP60). In preclinical models, this peptide developed anti-inflammatory effects and increased regulatory T cell (Treg) activity. Results from a phase I clinical trial with rheumatoid arthritis (RA) patients indicated that CIGB-258 was safe and reduced inflammation. The aim of this study was to examine specific biomarkers associated with hyperinflammation, some cytokines linked to the cytokine storm granzyme B and perforin in a cohort of COVID-19 patients treated with this peptide. All critically ill patients were under invasive mechanical ventilation and received the intravenous administration of 1 or 2 mg of CIGB-258 every 12 h. Seriously ill patients were treated with oxygen therapy receiving 1 mg of CIGB-258 every 12 h and all patients recovered from their severe condition. Biomarker levels associated with hyperinflammation, such as interleukin (IL)-6, IL-10, tumor necrosis factor (TNF-α), granzyme B, and perforin, significantly decreased during treatment. Furthermore, we studied the ability of CIGB-258 to induce Tregs in COVID-19 patients and found that Tregs were induced in all patients studied. Altogether, these results support the therapeutic potential of CIGB-258 for diseases associated with hyperinflammation. Clinical trial registry: RPCEC00000313.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Chaperonin 60/therapeutic use , Cytokine Release Syndrome/drug therapy , Adult , Aged , Aged, 80 and over , Anti-Inflammatory Agents/chemistry , COVID-19/blood , COVID-19/complications , Chaperonin 60/chemistry , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/complications , Female , Humans , Inflammation/blood , Inflammation/complications , Inflammation/drug therapy , Interleukin-10/blood , Interleukin-6/blood , Male , Middle Aged , SARS-CoV-2/drug effects , T-Lymphocytes, Regulatory/drug effects , Tumor Necrosis Factor-alpha/blood , Young Adult
15.
Protein Pept Lett ; 28(8): 945-952, 2021.
Article in English | MEDLINE | ID: covidwho-1097235

ABSTRACT

Given that conventional therapies are ineffective for COVID-19, obtained exosomes from stem cells have been proposed as a sustainable and effective treatment. Exosomes are subsets with lengths between 30 and 100 nanometers, and they can be secreted by different cells. Exosomes are containing different types of miRNAs, mRNAs, and different proteins. The role of immune system modulation of exosomes of mesenchymal stem cells has been studied and confirmed in more than one study. Exosome miRNAs detect and reduce cytokines that cause cytokine storms such as IL-7, IL-2, IL-6, etc. These miRNAs include miR-21, miR-24, miR-124, miR-145, etc. The risks associated with treatment with exosomes from different cells are relatively small compared to other treatments because transplanted cells do not stimulate the host immune system and also has reduced infection transmission. Due to the ineffectiveness of existing drugs in reducing inflammation and preventing cytokine storms, the use of immune-boosting systems may be suggested as another way to control cytokine storm.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/therapy , Exosomes/metabolism , Mesenchymal Stem Cells/cytology , Cytokine Release Syndrome/pathology , Humans , MicroRNAs/genetics
16.
Life Sci ; 272: 119245, 2021 May 01.
Article in English | MEDLINE | ID: covidwho-1087130

ABSTRACT

In the past 20 years, infections caused by coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 have posed a threat to public health since they may cause severe acute respiratory syndrome (SARS) in humans. The Complement System is activated during viral infection, being a central protagonist of innate and acquired immunity. Here, we report some interactions between these three coronaviruses and the Complement System, highlighting the central role of C3 with the severity of these infections. Although it can be protective, its role during coronavirus infections seems to be contradictory. For example, during SARS-CoV-2 infection, Complement System can control the viral infection in asymptomatic or mild cases; however, it can also intensify local and systemic damage in some of severe COVID-19 patients, due to its potent proinflammatory effect. In this last condition, the activation of the Complement System also amplifies the cytokine storm and the pathogenicity of coronavirus infection. Experimental treatment with Complement inhibitors has been an enthusiastic field of intense investigation in search of a promising additional therapy in severe COVID-19 patients.


Subject(s)
COVID-19/immunology , Complement System Proteins/immunology , SARS-CoV-2/immunology , Animals , COVID-19/complications , COVID-19/drug therapy , COVID-19/pathology , Complement Activation/drug effects , Complement C3/immunology , Complement Inactivating Agents/pharmacology , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Humans , Inflammation/complications , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Middle East Respiratory Syndrome Coronavirus/immunology , SARS Virus/immunology , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/pathology
17.
PLoS One ; 16(1): e0245924, 2021.
Article in English | MEDLINE | ID: covidwho-1042604

ABSTRACT

SARS-CoV-2 is a single stranded RNA (ssRNA) virus and contains GU-rich sequences distributed abundantly in the genome. In COVID-19, the infection and immune hyperactivation causes accumulation of inflammatory immune cells, blood clots, and protein aggregates in lung fluid, increased lung alveolar wall thickness, and upregulation of serum cytokine levels. A serum protein called serum amyloid P (SAP) has a calming effect on the innate immune system and shows efficacy as a therapeutic for fibrosis in animal models and clinical trials. Here we show that aspiration of the GU-rich ssRNA oligonucleotide ORN06 into mouse lungs induces all of the above COVID-19-like symptoms. Men tend to have more severe COVID-19 symptoms than women, and in the aspirated ORN06 model, male mice tended to have more severe symptoms than female mice. Intraperitoneal injections of SAP starting from day 1 post ORN06 aspiration attenuated the ORN06-induced increase in the number of inflammatory cells and formation of clot-like aggregates in the mouse lung fluid, reduced ORN06-increased alveolar wall thickness and accumulation of exudates in the alveolar airspace, and attenuated an ORN06-induced upregulation of the inflammatory cytokines IL-1ß, IL-6, IL-12p70, IL-23, and IL-27 in serum. SAP also reduced D-dimer levels in the lung fluid. In human peripheral blood mononuclear cells, SAP attenuated ORN06-induced extracellular accumulation of IL-6. Together, these results suggest that aspiration of ORN06 is a simple model for both COVID-19 as well as cytokine storm in general, and that SAP is a potential therapeutic for diseases with COVID-19-like symptoms and/or a cytokine storm.


Subject(s)
COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Pneumonia/drug therapy , Serum Amyloid P-Component/therapeutic use , Animals , COVID-19/complications , COVID-19/pathology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/pathology , Disease Models, Animal , Female , Humans , Lung/drug effects , Lung/pathology , Male , Mice , Mice, Inbred C57BL , Pneumonia/complications , Pneumonia/pathology , Serum Amyloid P-Component/administration & dosage
18.
Future Med Chem ; 13(6): 587-592, 2021 03.
Article in English | MEDLINE | ID: covidwho-1038712

ABSTRACT

Understanding the potential association between the poly (ADP-ribose) polymerase member 14 (PARP14) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may aid in understanding the host immunopathological response to the virus. PARP14 has an emerging role in viral infections, and this article considers its potential mechanisms for action in either a pro- or anti-viral manner. It is evident that more experimental work is required; however, PARP14 appears vital in controlling the interferon response to the SARS-CoV-2 infection and has potential roles in balancing the proinflammatory cytokines of the cytokine storm. Furthermore, the SARS-CoV-2 macrodomain can prevent the PARP14-mediated antiviral response, suggesting a more complex relationship between PARP14 activity and SARS-CoV-2 infections.


Subject(s)
COVID-19/immunology , Poly(ADP-ribose) Polymerases/immunology , SARS-CoV-2/immunology , COVID-19/complications , COVID-19/pathology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Humans , Immunity , Inflammation/complications , Inflammation/immunology , Inflammation/pathology , Interferons/immunology
19.
Nature ; 590(7844): 29-31, 2021 02.
Article in English | MEDLINE | ID: covidwho-1038200
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