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1.
Int J Mol Sci ; 22(24)2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1572496

ABSTRACT

In humans, over-activation of innate immunity in response to viral or bacterial infections often causes severe illness and death. Furthermore, similar mechanisms related to innate immunity can cause pathogenesis and death in sepsis, massive trauma (including surgery and burns), ischemia/reperfusion, some toxic lesions, and viral infections including COVID-19. Based on the reviewed observations, we suggest that such severe outcomes may be manifestations of a controlled suicidal strategy protecting the entire population from the spread of pathogens and from dangerous pathologies rather than an aberrant hyperstimulation of defense responses. We argue that innate immunity may be involved in the implementation of an altruistic programmed death of an organism aimed at increasing the well-being of the whole community. We discuss possible ways to suppress this atavistic program by interfering with innate immunity and suggest that combating this program should be a major goal of future medicine.


Subject(s)
Altruism , Apoptosis/immunology , Immunity, Innate/immunology , Animals , COVID-19/immunology , Cell Death/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Humans , Inflammasomes/immunology , Inflammation/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Signal Transduction/immunology
2.
Clin Transl Sci ; 14(6): 2146-2151, 2021 11.
Article in English | MEDLINE | ID: covidwho-1526353

ABSTRACT

Tocilizumab is an IL-6 receptor antagonist with the ability to suppress the cytokine storm in critically ill patients infected with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). We evaluated patients treated with tocilizumab for a SARS-CoV-2 infection who were admitted between March 13, 2020, and April 16, 2020. This was a multicenter study with data collected by chart review both retrospectively and concurrently. Parameters evaluated included age, sex, race, use of mechanical ventilation (MV), usage of steroids and vasopressors, inflammatory markers, and comorbidities. Early dosing was defined as a tocilizumab dose administered prior to or within 1 day of intubation. Late dosing was defined as a dose administered > 1 day after intubation. In the absence of MV, the timing of the dose was related to the patient's date of admission only. We evaluated 145 patients. The average age was 58.1 years, 64% were men, 68.3% had comorbidities, and 60% received steroid therapy. Disposition of patients was 48.3% discharged and 29.3% died, of which 43.9% were African American. MV was required in 55.9%, of which 34.5% died. Avoidance of MV (P = 0.002) and increased survival (P < 0.001) was statistically associated with early dosing. Tocilizumab therapy was effective at decreasing mortality and should be instituted early in the management of critically ill patients with coronavirus disease 2019) COVID-19).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , COVID-19/therapy , Cytokine Release Syndrome/therapy , Respiration, Artificial/statistics & numerical data , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , Critical Illness/mortality , Critical Illness/therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Female , Hospital Mortality , Humans , Male , Middle Aged , Retrospective Studies , SARS-CoV-2/immunology , Severity of Illness Index , Time Factors , Time-to-Treatment , Treatment Outcome
3.
Front Immunol ; 12: 735922, 2021.
Article in English | MEDLINE | ID: covidwho-1477823

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. COVID-19 is considered an airway/multi-systemic disease, and demise has been associated with an uncontrolled immune response and a cytokine storm in response to the virus. However, the lung pathology, immune response, and tissue damage associated with COVID-19 demise are poorly described and understood due to safety concerns. Using post-mortem lung tissues from uninfected and COVID-19 deadly cases as well as an unbiased combined analysis of histology, multi-viral and host markers staining, correlative microscopy, confocal, and image analysis, we identified three distinct phenotypes of COVID-19-induced lung damage. First, a COVID-19-induced hemorrhage characterized by minimal immune infiltration and large thrombus; Second, a COVID-19-induced immune infiltration with excessive immune cell infiltration but no hemorrhagic events. The third phenotype correspond to the combination of the two previous ones. We observed the loss of alveolar wall integrity, detachment of lung tissue pieces, fibroblast proliferation, and extensive fibrosis in all three phenotypes. Although lung tissues studied were from lethal COVID-19, a strong immune response was observed in all cases analyzed with significant B cell and poor T cell infiltrations, suggesting an exhausted or compromised immune cellular response in these patients. Overall, our data show that SARS-CoV-2-induced lung damage is highly heterogeneous. These individual differences need to be considered to understand the acute and long-term COVID-19 consequences.


Subject(s)
COVID-19/mortality , COVID-19/pathology , Lung Injury/pathology , Pulmonary Alveoli/pathology , Pulmonary Fibrosis/pathology , Aged , Aged, 80 and over , Autopsy , CD8-Positive T-Lymphocytes/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/pathology , Epithelial Cells/pathology , Female , Hemorrhage/pathology , Humans , Inflammation/pathology , Lung/pathology , Lung Injury/virology , Lymphopenia/pathology , Macrophage Activation/immunology , Macrophages/immunology , Male , Middle Aged , Myocytes, Smooth Muscle/pathology , Neutrophils/immunology , SARS-CoV-2 , Thrombosis/pathology
4.
Medicine (Baltimore) ; 100(29): e26705, 2021 Jul 23.
Article in English | MEDLINE | ID: covidwho-1475905

ABSTRACT

ABSTRACT: Cytokine release syndrome (CRS) or cytokine storm is thought to be the cause of inflammatory lung damage, worsening pneumonia and death in patients with COVID-19. Steroids (Methylprednislone or Dexamethasone) and Tocilizumab (TCZ), an interleukin-6 receptor antagonist, are approved for treatment of CRS in India. The aim of this study was to evaluate the efficacy and safety of combination therapy of TCZ and steroid in COVID-19 associated CRS.This retrospective cohort study was conducted at Noble hospital and Research Centre (NHRC), Pune, India between April 2 and November 2, 2020. All patients administered TCZ and steroids during this period were included. The primary endpoint was incidence of all cause mortality. Secondary outcomes studied were need for mechanical ventilation and incidence of systemic and infectious complications. Baseline and time dependent risk factors significantly associated with death were identified by Relative risk estimation.Out of 2831 admitted patients, 515 (24.3% females) were administered TCZ and steroids. There were 135 deaths (26.2%), while 380 patients (73.8%) had clinical improvement. Mechanical ventilation was required in 242 (47%) patients. Of these, 44.2% (107/242) recovered and were weaned off the ventilator. Thirty seven percent patients were managed in wards and did not need intensive care unit (ICU) admission. Infectious complications like hospital acquired pneumonia, blood stream bacterial and fungal infections were observed in 2.13%, 2.13% and 0.06% patients respectively. Age ≥ 60 years (P = .014), presence of co-morbidities like hypertension (P = .011), IL-6 ≥ 100 pg/ml (P = .002), D-dimer ≥ 1000 ng/ml (P < .0001), CT severity index ≥ 18 (P < .0001) and systemic complications like lung fibrosis (P = .019), cardiac arrhythmia (P < .0001), hypotension (P < .0001) and encephalopathy (P < .0001) were associated with increased risk of death.Combination therapy of TCZ and steroids is likely to be safe and effective in management of COVID-19 associated cytokine release syndrome. Efficacy of this anti-inflammatory combination therapy needs to be validated in randomized controlled trials.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Dexamethasone/therapeutic use , Methylprednisolone/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/complications , COVID-19/mortality , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/mortality , Dexamethasone/administration & dosage , Drug Therapy, Combination , Female , Humans , India , Intensive Care Units/statistics & numerical data , Length of Stay/statistics & numerical data , Male , Methylprednisolone/administration & dosage , Middle Aged , Retrospective Studies , Treatment Outcome
6.
Front Immunol ; 12: 677957, 2021.
Article in English | MEDLINE | ID: covidwho-1337637

ABSTRACT

Patients with inflammatory bowel disease, psoriasis or other rheumatic diseases treated with corticosteroids, immunomodulators and biologics might face additional risk during COVID-19 epidemic due to their immunocompromised status. However, there was still no unanimous opinion on the use of these therapy during COVID-19 epidemic. Current studies suggested that systemic corticosteroids might increase the risk of hospitalization, as well as risks of ventilation, ICU, and death among patients with immune-mediated inflammatory diseases. Anti-TNF agent was associated with lower rate of hospitalization, as well as lower risks of ventilation, ICU, and death. No significant changes in rates of hospitalization, ventilation, ICU and mortality were observed in patients treated with immunomodulators or biologics apart from anti-TNF agents. The underlying mechanism of these results might be related to pathway of antiviral immune response and cytokine storm induced by SARS-COV-2 infection. Decision on the use of corticosteroids, immunomodulators and biologics should be made after weighing the benefits and potential risks based on individual patients.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Biological Products/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Immunosuppressive Agents/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Psoriasis/drug therapy , Rheumatic Diseases/drug therapy , SARS-CoV-2/physiology , Tumor Necrosis Factor Inhibitors/therapeutic use , COVID-19/mortality , Cytokine Release Syndrome/mortality , Hospitalization , Humans , Immunity , Inflammatory Bowel Diseases/mortality , Psoriasis/mortality , Rheumatic Diseases/mortality , Risk , Survival Analysis
7.
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
8.
PLoS One ; 16(6): e0253576, 2021.
Article in English | MEDLINE | ID: covidwho-1282304

ABSTRACT

INTRODUCTION: Statins may reduce a cytokine storm, which has been hypothesized as a possible mechanism of severe COVID-19 pneumonia. The aim of this study was to conduct a systematic review and meta-analysis to report on adverse outcomes among COVID-19 patients by statin usage. METHODS: Literatures were searched from January 2019 to December 2020 to identify studies that reported the association between statin usage and adverse outcomes, including mortality, ICU admissions, and mechanical ventilation. Studies were meta-analyzed for mortality by the subgroups of ICU status and statin usage before and after COVID-19 hospitalization. Studies reporting an odds ratio (OR) and hazard ratio (HR) were analyzed separately. RESULTS: Thirteen cohorts, reporting on 110,078 patients, were included in this meta-analysis. Individuals who used statins before their COVID-19 hospitalization showed a similar risk of mortality, compared to those who did not use statins (HR 0.80, 95% CI: 0.50, 1.28; OR 0.62, 95% CI: 0.38, 1.03). Patients who were administered statins after their COVID-19 diagnosis were at a lower risk of mortality (HR 0.53, 95% CI: 0.46, 0.61; OR 0.57, 95% CI: 0.43, 0.75). The use of statins did not reduce the mortality of COVID-19 patients admitted to the ICU (OR 0.65; 95% CI: 0.26, 1.64). Among non-ICU patients, statin users were at a lower risk of mortality relative to non-statin users (HR 0.53, 95% CI: 0.46, 0.62; OR 0.64, 95% CI: 0.46, 0.88). CONCLUSION: Patients administered statins after COVID-19 diagnosis or non-ICU admitted patients were at lower risk of mortality relative to non-statin users.


Subject(s)
COVID-19/drug therapy , COVID-19/mortality , Cytokine Release Syndrome , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , SARS-CoV-2 , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/mortality , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects
9.
Mol Cells ; 44(6): 384-391, 2021 Jun 30.
Article in English | MEDLINE | ID: covidwho-1259762

ABSTRACT

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.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Host-Pathogen Interactions/immunology , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/immunology , Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , COVID-19/mortality , COVID-19/virology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Dexamethasone/therapeutic use , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate/drug effects , Inflammation , Interferon Type I/genetics , Interferon Type I/immunology , Interleukins/genetics , Interleukins/immunology , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/mortality , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Signal Transduction , Survival Analysis
10.
Viruses ; 13(6)2021 06 03.
Article in English | MEDLINE | ID: covidwho-1259624

ABSTRACT

BACKGROUND: Cytokine storm in COVID-19 is heterogenous. There are at least three subtypes: cytokine release syndrome (CRS), macrophage activation syndrome (MAS), and sepsis. METHODS: A retrospective study comprising 276 patients with SARS-CoV-2 pneumonia. All patients were tested for ferritin, interleukin-6, D-Dimer, fibrinogen, calcitonin, and C-reactive protein. According to the diagnostic criteria, three groups of patients with different subtypes of cytokine storm syndrome were identified: MAS, CRS or sepsis. In the MAS and CRS groups, treatment results were assessed depending on whether or not tocilizumab was used. RESULTS: MAS was diagnosed in 9.1% of the patients examined, CRS in 81.8%, and sepsis in 9.1%. Median serum ferritin in patients with MAS was significantly higher (5894 vs. 984 vs. 957 ng/mL, p < 0.001) than in those with CRS or sepsis. Hypofibrinogenemia and pancytopenia were also observed in MAS patients. In CRS patients, a higher mortality rate was observed among those who received tocilizumab, 21 vs. 10 patients (p = 0.043), RR = 2.1 (95% CI 1.0-4.3). In MAS patients, tocilizumab decreased the mortality, 13 vs. 6 patients (p = 0.013), RR = 0.50 (95% CI 0.25-0.99). CONCLUSIONS: Tocilizumab therapy in patients with COVID-19 and CRS was associated with increased mortality, while in MAS patients, it contributed to reduced mortality.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/classification , Cytokine Release Syndrome/drug therapy , Aged , COVID-19/classification , COVID-19/immunology , COVID-19/mortality , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Female , Ferritins/blood , Humans , Macrophage Activation Syndrome/drug therapy , Macrophage Activation Syndrome/mortality , Macrophage Activation Syndrome/virology , Male , Retrospective Studies , Sepsis/drug therapy , Sepsis/virology , Treatment Outcome
12.
Cytokine ; 144: 155593, 2021 08.
Article in English | MEDLINE | ID: covidwho-1242912

ABSTRACT

An analysis of published data appertaining to the cytokine storms of COVID-19, H1N1 influenza, cytokine release syndrome (CRS), and macrophage activation syndrome (MAS) reveals many common immunological and biochemical abnormalities. These include evidence of a hyperactive coagulation system with elevated D-dimer and ferritin levels, disseminated intravascular coagulopathy (DIC) and microthrombi coupled with an activated and highly permeable vascular endothelium. Common immune abnormalities include progressive hypercytokinemia with elevated levels of TNF-α, interleukin (IL)-6, and IL-1ß, proinflammatory chemokines, activated macrophages and increased levels of nuclear factor kappa beta (NFκB). Inflammasome activation and release of damage associated molecular patterns (DAMPs) is common to COVID-19, H1N1, and MAS but does not appear to be a feature of CRS. Elevated levels of IL-18 are detected in patients with COVID-19 and MAS but have not been reported in patients with H1N1 influenza and CRS. Elevated interferon-γ is common to H1N1, MAS, and CRS but levels of this molecule appear to be depressed in patients with COVID-19. CD4+ T, CD8+ and NK lymphocytes are involved in the pathophysiology of CRS, MAS, and possibly H1N1 but are reduced in number and dysfunctional in COVID-19. Additional elements underpinning the pathophysiology of cytokine storms include Inflammasome activity and DAMPs. Treatment with anakinra may theoretically offer an avenue to positively manipulate the range of biochemical and immune abnormalities reported in COVID-19 and thought to underpin the pathophysiology of cytokine storms beyond those manipulated via the use of, canakinumab, Jak inhibitors or tocilizumab. Thus, despite the relative success of tocilizumab in reducing mortality in COVID-19 patients already on dexamethasone and promising results with Baricitinib, the combination of anakinra in combination with dexamethasone offers the theoretical prospect of further improvements in patient survival. However, there is currently an absence of trial of evidence in favour or contravening this proposition. Accordingly, a large well powered blinded prospective randomised controlled trial (RCT) to test this hypothesis is recommended.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19 , Cytokine Release Syndrome , Influenza A Virus, H1N1 Subtype/immunology , SARS-CoV-2/immunology , COVID-19/drug therapy , COVID-19/immunology , COVID-19/mortality , COVID-19/pathology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/pathology , Disease-Free Survival , Humans , Influenza, Human/drug therapy , Influenza, Human/immunology , Influenza, Human/mortality , Influenza, Human/pathology , Janus Kinases/antagonists & inhibitors , Janus Kinases/metabolism , Lymphocytes/immunology , Lymphocytes/pathology , Survival Rate
13.
Front Immunol ; 12: 592727, 2021.
Article in English | MEDLINE | ID: covidwho-1225860

ABSTRACT

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected over 112M patients and resulted in almost 2.5M deaths worldwide. The major clinical feature of severe COVID-19 patients requiring ventilation is acute respiratory distress syndrome (ARDS) possibly associated with a cytokine storm. Objectives: To elucidate serum levels of TNF-α and soluble TNF-Receptor 1 (sTNFR1) in patients with severe and mild COVID-19 disease as determinants of disease severity. Methods: We determined serum TNF-α and sTNFR1 concentrations in 46 patients with laboratory-confirmed COVID-19 (17 patients with severe disease within the intensive care unit [ICU] and 29 non-severe, non-ICU patients) and 15 healthy controls upon admission using ELISA. Subjects were recruited between March-May 2020 at the Masih Daneshvari Hospital Tehran, Iran. Results: Serum levels of sTNFRI were significantly higher in ICU patients (P<0.0001) and non-ICU patients (P=0.0342) compared with healthy subjects. Serum sTNFR1 were significantly higher in ICU patients than in non-ICU patients (P<0.0001). Serum TNF-α levels were greater in ICU and non-ICU patients than in the healthy subjects group (p<0.0001). The sTNFRI concentration in ICU (r=0.79, p=0.0002) and non-ICU (r=0.42, p=0.02) patients positively correlated with age although serum sTNFRI levels in ICU patients were significantly higher than in older healthy subjects. The sTNFRI concentration in ICU patients negatively correlated with ESR. Conclusions: The study demonstrates higher sTNFRI in ICU patients with severe COVID-19 disease and this be a biomarker of disease severity and mortality. Future studies should examine whether lower levels of systemic sTNFR1 at admission may indicate a better disease outcome.


Subject(s)
COVID-19/blood , COVID-19/mortality , Receptors, Tumor Necrosis Factor, Type I/blood , Tumor Necrosis Factor-alpha/blood , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/pathology , Critical Care , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/mortality , Female , Humans , Intensive Care Units , Interleukin-6/blood , Iran , Male , Middle Aged , Pilot Projects , SARS-CoV-2 , Severity of Illness Index
14.
Front Immunol ; 12: 592727, 2021.
Article in English | MEDLINE | ID: covidwho-1221944

ABSTRACT

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected over 112M patients and resulted in almost 2.5M deaths worldwide. The major clinical feature of severe COVID-19 patients requiring ventilation is acute respiratory distress syndrome (ARDS) possibly associated with a cytokine storm. Objectives: To elucidate serum levels of TNF-α and soluble TNF-Receptor 1 (sTNFR1) in patients with severe and mild COVID-19 disease as determinants of disease severity. Methods: We determined serum TNF-α and sTNFR1 concentrations in 46 patients with laboratory-confirmed COVID-19 (17 patients with severe disease within the intensive care unit [ICU] and 29 non-severe, non-ICU patients) and 15 healthy controls upon admission using ELISA. Subjects were recruited between March-May 2020 at the Masih Daneshvari Hospital Tehran, Iran. Results: Serum levels of sTNFRI were significantly higher in ICU patients (P<0.0001) and non-ICU patients (P=0.0342) compared with healthy subjects. Serum sTNFR1 were significantly higher in ICU patients than in non-ICU patients (P<0.0001). Serum TNF-α levels were greater in ICU and non-ICU patients than in the healthy subjects group (p<0.0001). The sTNFRI concentration in ICU (r=0.79, p=0.0002) and non-ICU (r=0.42, p=0.02) patients positively correlated with age although serum sTNFRI levels in ICU patients were significantly higher than in older healthy subjects. The sTNFRI concentration in ICU patients negatively correlated with ESR. Conclusions: The study demonstrates higher sTNFRI in ICU patients with severe COVID-19 disease and this be a biomarker of disease severity and mortality. Future studies should examine whether lower levels of systemic sTNFR1 at admission may indicate a better disease outcome.


Subject(s)
COVID-19/blood , COVID-19/mortality , Receptors, Tumor Necrosis Factor, Type I/blood , Tumor Necrosis Factor-alpha/blood , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/pathology , Critical Care , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/mortality , Female , Humans , Intensive Care Units , Interleukin-6/blood , Iran , Male , Middle Aged , Pilot Projects , SARS-CoV-2 , Severity of Illness Index
15.
J Med Virol ; 93(3): 1672-1677, 2021 03.
Article in English | MEDLINE | ID: covidwho-1206819

ABSTRACT

While the number of coronavirus disease-2019 (COVID-19) cases is increasing day by day, there is limited information known about the hematological and laboratory findings of the disease. We aimed to investigate whether serum ferritin level predicts mortality is a marker for rapid progression for inpatients. Our study included 56 patients who were died due to COVID-19 as the study group, and 245 patients who were hospitalized and recovered as the control group. The laboratory data of the patients were evaluated from the first blood tests (pre) taken from the first moment of admission to the hospital and the blood tests taken from before the patient's discharge or exitus (post) were evaluated retrospectively. The mean age of the nonsurvivor group was 62.0 ± 15.7 and the mean age of the control group was 54.34 ± 13.03. Age and length of stay are significantly higher in the nonsurvivor group. When comparing the pre- and postvalues of ferritin, according to the two groups separately, there was no significant difference in the control group and a high level of significance was observed in the nonsurvivor group (p < .01). COVID-19 disease caused by severe acute respiratory syndrome coronavirus-2 causes high mortality with widespread inflammation and cytokine storm. Ferritin is a cheap and widespread available marker, ferritin, which can be used for its predictivity of the mortality and hope it would be a useful marker for clinicians for the management of the disease.


Subject(s)
COVID-19/blood , COVID-19/mortality , Cytokine Release Syndrome/mortality , Ferritins/blood , Amides/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/diagnosis , Female , Hospitalization , Humans , Length of Stay , Male , Middle Aged , Prognosis , Pyrazines/therapeutic use , SARS-CoV-2 , Severity of Illness Index
16.
J Med Virol ; 93(2): 831-842, 2021 02.
Article in English | MEDLINE | ID: covidwho-1206798

ABSTRACT

Coronavirus disease 2019 (COVID-19) can lead to a massive cytokine release. The use of the anti-interleukin-6 receptor monoclonal antibody tocilizumab (TCZ) has been proposed in this hyperinflammatory phase, although supporting evidence is limited. We retrospectively analyzed 88 consecutive patients with COVID-19 pneumonia that received at least one dose of intravenous TCZ in our institution between 16 and 27 March 2020. Clinical status from day 0 (first TCZ dose) through day 14 was assessed by a 6-point ordinal scale. The primary outcome was clinical improvement (hospital discharge and/or a decrease of ≥2 points on the 6-point scale) by day 7. Secondary outcomes included clinical improvement by day 14 and dynamics of vital signs and laboratory values. Rates of clinical improvement by days 7 and 14 were 44.3% (39/88) and 73.9% (65/88). Previous or concomitant receipt of subcutaneous interferon-ß (adjusted odds ratio [aOR]: 0.23; 95% confidence interval [CI]: 0.06-0.94; P = .041) and serum lactate dehydrogenase more than 450 U/L at day 0 (aOR: 0.25; 95% CI: 0.06-0.99; P = .048) were negatively associated with clinical improvement by day 7. All-cause mortality was 6.8% (6/88). Body temperature and respiratory and cardiac rates significantly decreased by day 1 compared to day 0. Lymphocyte count and pulse oximetry oxygen saturation/FiO2 ratio increased by days 3 and 5, whereas C-reactive protein levels dropped by day 2. There were no TCZ-attributable adverse events. In this observational single-center study, TCZ appeared to be useful and safe as immunomodulatory therapy for severe COVID-19 pneumonia.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/prevention & control , Immunologic Factors/therapeutic use , SARS-CoV-2/pathogenicity , Administration, Intravenous , Adult , Body Temperature/drug effects , C-Reactive Protein/metabolism , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Female , Heart Rate/drug effects , Humans , Interferon-beta/adverse effects , L-Lactate Dehydrogenase/blood , Male , Middle Aged , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/genetics , Receptors, Interleukin-6/immunology , Respiratory Rate/drug effects , Retrospective Studies , SARS-CoV-2/immunology , Severity of Illness Index , Survival Analysis
17.
Cytokine ; 143: 155543, 2021 07.
Article in English | MEDLINE | ID: covidwho-1188448

ABSTRACT

BACKGROUND: The first case of SARS-CoV-2 in Mexico was reported in February 2020, since then, high rates of mortality due to COVID-19 have been found. Cytokine storm is linked to the severity and decreasing the survival among infected patients by COVID-19. The serum levels of Interleukin 6 (IL-6) have been correlated to mortality in COVID-19 cases and could be used as indicator of mortality in COVID-19 cases. The aim of this study was to determine levels of IL-6 and assess its usefulness as indicator of mortality among COVID-19 patients from Mexico. METHODS: A cohort study among 38 adults (28 men, 10 women) was carried out in the Regional High Specialty Hospital of the Yucatan Peninsula in Merida, Yucatan, Mexico. Demographic and clinical biochemistry data were collected. The serum levels of IL-6 were measured in each patient by specific immunoassays. RESULTS: High frequency of mortality (36.84%) was found in the sample. The average age of individuals that non-survive was significantly higher (59.71 ± 13.83 years) than the survival group (43.29 ± 11.80 years). Serum levels of IL-6 were significantly higher in patients that did not survive. A correlation between IL-6 levels with lymphocyte count, LDH, CRP and procaciltonin was found. The optimal cutoff value of IL-6 was 30.95 pg/mL with high sensitivity and specificity. CONCLUSION: Our findings demonstrate that level of IL-6 is an indicator of mortality among hospitalized COVID-19 patients in Mexico.


Subject(s)
COVID-19/blood , COVID-19/mortality , Cytokine Release Syndrome/blood , Interleukin-6/blood , Adult , Age Factors , Aged , Biomarkers/blood , C-Reactive Protein/analysis , COVID-19/pathology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/pathology , Female , Humans , Immunoassay , Lymphocyte Count , Male , Mexico , Middle Aged , Prognosis , SARS-CoV-2/immunology , Severity of Illness Index , Young Adult
18.
Am J Respir Cell Mol Biol ; 65(1): 13-21, 2021 07.
Article in English | MEDLINE | ID: covidwho-1166652

ABSTRACT

Coronavirus disease (COVID-19), the clinical syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently a global health pandemic with substantial morbidity and mortality. COVID-19 has cast a shadow on nearly every aspect of society, straining health systems and economies across the world. Although it is widely accepted that a close relationship exists between obesity, cardiovascular disease, and metabolic disorders on infection, we are only beginning to understand ways in which the immunological sequelae of obesity functions as a predisposing factor related to poor clinical outcomes in COVID-19. As both the innate and adaptive immune systems are each primed by obesity, the alteration of key pathways results in both an immunosuppressed and hyperinflammatory state. The present review will discuss the cellular and molecular immunology of obesity in the context of its role as a risk factor for severe COVID-19, discuss the role of cytokine storm, and draw parallels to prior viral epidemics such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and 2009 H1N1.


Subject(s)
COVID-19 , Cardiovascular Diseases , Cytokine Release Syndrome , Obesity , SARS-CoV-2 , COVID-19/immunology , COVID-19/metabolism , COVID-19/mortality , Cardiovascular Diseases/immunology , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/mortality , Critical Illness , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Disease-Free Survival , Humans , Obesity/immunology , Obesity/metabolism , Obesity/mortality , Obesity/virology , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Survival Rate
19.
Front Immunol ; 12: 613422, 2021.
Article in English | MEDLINE | ID: covidwho-1121356

ABSTRACT

Hyper-inflammatory responses induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a major cause of disease severity and death. Predictive prognosis biomarkers to guide therapeutics are critically lacking. Several studies have indicated a "cytokine storm" with the release of interleukin-1 (IL-1), IL-6, and IL-8, along with tumor necrosis factor alpha (TNFα) and other inflammatory mediators. Here, we proposed to assess the relationship between IL-6 and outcomes of patients with coronavirus disease 2019 (COVID-19). Our cohort consisted of 46 adult patients with PCR-proven SARS-CoV-2 infection admitted in a COVID-19 ward of the Hospital de Braga (HB) from April 7 to May 7, 2020, whose IL-6 levels were followed over time. We found that IL-6 levels were significantly different between the disease stages. Also, we found a significant negative correlation between IL-6 levels during stages IIb and III, peripheral oxygen saturation (SpO2), and partial pressure of oxygen in arterial blood (PaO2), showing that IL-6 correlates with respiratory failure. Compared to the inflammatory markers available in the clinic routine, we found a positive correlation between IL-6 and C-reactive protein (CRP). However, when we assessed the predictive value of these two markers, IL-6 behaves as a better predictor of disease progression. In a binary logistic regression, IL-6 level was the most significant predictor of the non-survivors group, when compared to age and CRP. Herein, we present IL-6 as a relevant tool for prognostic evaluation, mainly as a predictor of outcome.


Subject(s)
COVID-19 , Cytokine Release Syndrome , Interleukin-6/blood , SARS-CoV-2/metabolism , Adult , Age Factors , Aged , Aged, 80 and over , Biomarkers/blood , C-Reactive Protein/metabolism , COVID-19/blood , COVID-19/mortality , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/mortality , Female , Follow-Up Studies , Humans , Male , Middle Aged , Oxygen/blood
20.
PLoS One ; 15(12): e0244628, 2020.
Article in English | MEDLINE | ID: covidwho-1059971

ABSTRACT

INTRODUCTION: Coronavirus disease 2019 (COVID-19) appeared in China in December 2019 and has spread around the world. High Interleukin-6 (IL-6) levels in COVID-19 patients suggest that a cytokine storm may play a major role in the pathophysiology and are considered as a relevant parameter in predicting most severe course of disease. The aim of this study was to assess repeated IL-6 levels in critically ill COVID-19 patients admitted to our Intensive Care Unit (ICU) and to evaluate their relationship with patient's severity and outcome. METHODS: We conducted a retrospective study on patients admitted to the ICU with a diagnosis of COVID-19 between March 10 (i.e. the date of the first admitted patients) and April 30, 2020. Demographic, clinical and laboratory data were collected at admission. On the day of IL-6 blood concentration measurement, we also collected results of D-Dimers, C-Reactive Protein, white blood cells and lymphocytes count, lactate dehydrogenase (LDH) and ferritin as well as microbiological samples, whenever present. RESULTS: Of a total of 65 patients with COVID-19 admitted to our ICU we included 41 patients with repeated measure of IL-6. There was a significant difference in IL-6 levels between survivors and non-survivors over time (p = 0.001); moreover, non survivors had a significantly higher IL-6 maximal value when compared to survivors (720 [349-2116] vs. 336 [195-646] pg/mL, p = 0.01). The IL-6 maximal value had a significant predictive value of ICU mortality (AUROC 0.73 [95% CI 0.57-0.89]; p = 0.01). CONCLUSIONS: Repeated measurements of IL-6 can help clinicians in identifying critically ill COVID-19 patients with the highest risk of poor prognosis.


Subject(s)
COVID-19/blood , COVID-19/mortality , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/mortality , Interleukin-6/blood , SARS-CoV-2 , Critical Illness , Disease-Free Survival , Female , Humans , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , Survival Rate
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