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1.
Surg Infect (Larchmt) ; 22(9): 948-954, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1522102

ABSTRACT

Background: In trauma, direct pulmonary injury and innate immune response activation primes the lungs for acute respiratory distress syndrome (ARDS). The inflammasome-dependent release of interleukin-18 (IL-18) was recently identified as a key mediator in ARDS pathogenesis, leading us to hypothesize that plasma IL-18 is a diagnostic predictor of ARDS in severe blunt trauma. Patients and Methods: Secondary analysis of the Inflammation and Host Response to Injury database was performed on plasma cytokines collected within 12 hours of severe blunt trauma. Trauma-related cytokines, including IL-18, were compared between patients with and without ARDS and were evaluated for association with ARDS using regression analysis. Threshold cytokine concentrations predictive of ARDS were determined using receiver-operating curve (ROC) analysis. Results: Cytokine analysis of patients without ARDS patients (n = 61) compared with patients with ARDS (n = 19) demonstrated elevated plasma IL-18 concentration in ARDS and IL-18 remained correlated with ARDS on logistic regression after confounder adjustment (p = 0.008). Additionally, ROC analysis revealed IL-18 as a strong ARDS predictor (area under the curve [AUC] = 0.83), with a threshold IL-18 value of 170 pg/mL (Youden index, 0.3). Unlike in patients without ARDS, elevated IL-18 persisted in patients with ARDS during the acute injury phase (p ≤ 0.02). Other trauma-related cytokines did not correlate with ARDS. Conclusions: In severe blunt trauma, IL-18 is a robust predictor of ARDS and remains elevated throughout the acute injury phase. These findings support the use of IL-18 as a key ARDS biomarker, promoting early identification of trauma patients at greater risk of developing ARDS. Timely recognition of ARDS and implementation of advantageous supportive care practices may reduce trauma-related ARDS morbidity and costs.


Subject(s)
Respiratory Distress Syndrome , Wounds, Nonpenetrating , Humans , Interleukin-18 , Logistic Models , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Risk Assessment , Wounds, Nonpenetrating/complications , Wounds, Nonpenetrating/diagnosis
2.
Front Immunol ; 12: 709759, 2021.
Article in English | MEDLINE | ID: covidwho-1450807

ABSTRACT

The clinical features of SARS-CoV-2 infection range from asymptomatic to severe disease with life-threatening complications. Understanding the persistence of immune responses in asymptomatic individuals merit special attention because of their importance in controlling the spread of the infections. We here studied the antibody and T cell responses, and a wide range of inflammation markers, in 56 SARS-CoV-2 antibody-positive individuals, identified by a population screen after the first wave of SARS-CoV-2 infection. These, mostly asymptomatic individuals, were reanalyzed 7-8 months after their infection together with 115 age-matched seronegative controls. We found that 7-8 months after the infection their antibodies to SARS-CoV-2 Nucleocapsid (N) protein declined whereas we found no decrease in the antibodies to Spike receptor-binding domain (S-RBD) when compared to the findings at seropositivity identification. In contrast to antibodies to N protein, the antibodies to S-RBD correlated with the viral neutralization capacity and with CD4+ T cell responses as measured by antigen-specific upregulation of CD137 and CD69 markers. Unexpectedly we found the asymptomatic antibody-positive individuals to have increased serum levels of S100A12, TGF-alpha, IL18, and OSM, the markers of activated macrophages-monocytes, suggesting long-term persistent inflammatory effect associated with the viral infection in asymptomatic individuals. Our results support the evidence for the long-term persistence of the inflammation process and the need for post-infection clinical monitoring of SARS-CoV-2 infected asymptomatic individuals.


Subject(s)
Antibodies, Viral/blood , Asymptomatic Infections , CD4-Positive T-Lymphocytes/immunology , COVID-19/pathology , Inflammation Mediators/blood , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , CD4 Lymphocyte Count , Coronavirus Nucleocapsid Proteins/immunology , Humans , Inflammation/immunology , Interleukin-18/blood , Macrophages/immunology , Monocytes/immunology , Oncostatin M/blood , Phosphoproteins/immunology , Protein Domains/immunology , S100A12 Protein/blood , Spike Glycoprotein, Coronavirus/immunology , Transforming Growth Factor alpha/blood
3.
Arthritis Rheumatol ; 73(10): 1791-1799, 2021 10.
Article in English | MEDLINE | ID: covidwho-1391545

ABSTRACT

OBJECTIVE: Infection with the novel coronavirus SARS-CoV-2 triggers severe illness with high mortality in a subgroup of patients. Such a critical course of COVID-19 is thought to be associated with the development of cytokine storm, a condition seen in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH). However, specific data demonstrating a clear association of cytokine storm with severe COVID-19 are still lacking. The aim of this study was to directly address whether immune activation in COVID-19 does indeed mimic the conditions found in these classic cytokine storm syndromes. METHODS: Levels of 22 biomarkers were quantified in serum samples from patients with COVID-19 (n = 30 patients, n = 83 longitudinal samples in total), patients with secondary HLH/MAS (n = 50), and healthy controls (n = 9). Measurements were performed using bead array assays and single-marker enzyme-linked immunosorbent assay. Serum biomarker levels were assessed for correlations with disease outcome. RESULTS: In patients with secondary HLH/MAS, we observed pronounced activation of the interleukin-18 (IL-18)-interferon-γ axis, increased serum levels of IL-1 receptor antagonist, intercellular adhesion molecule 1, and IL-8, and strongly reduced levels of soluble Fas ligand in the course of SARS-CoV-2 infection. These observations appeared to discriminate immune dysregulation in critical COVID-19 from the well-recognized characteristics of other cytokine storm syndromes. CONCLUSION: Serum biomarker profiles clearly separate COVID-19 from MAS or secondary HLH in terms of distinguishing the severe systemic hyperinflammation that occurs following SARS-CoV-2 infection. These findings could be useful in determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID-19.


Subject(s)
COVID-19/diagnosis , Cytokine Release Syndrome/etiology , Interleukin-18/blood , Interleukin-8/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Macrophage Activation Syndrome/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/blood , COVID-19/complications , Cytokine Release Syndrome/blood , Diagnosis, Differential , Female , Humans , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/complications , Macrophage Activation Syndrome/blood , Macrophage Activation Syndrome/complications , Male , Middle Aged , Young Adult
4.
Proc Natl Acad Sci U S A ; 118(37)2021 09 14.
Article in English | MEDLINE | ID: covidwho-1373495

ABSTRACT

The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlating with poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19-linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.


Subject(s)
COVID-19/etiology , T-Lymphocytes, Regulatory/physiology , Adult , Aged , CD4-Positive T-Lymphocytes/virology , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Profiling , Gene Expression Regulation , Humans , Inflammation/metabolism , Inflammation/virology , Interleukin-18/genetics , Interleukin-18/metabolism , Interleukin-2 Receptor alpha Subunit/genetics , Interleukin-2 Receptor alpha Subunit/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Lymphocytes, Tumor-Infiltrating/physiology , Male , Middle Aged , Severity of Illness Index , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/virology , Transcription Factors/genetics , Transcription Factors/metabolism
5.
Front Immunol ; 12: 719544, 2021.
Article in English | MEDLINE | ID: covidwho-1348491

ABSTRACT

Background: Hyperinflammation with dysregulated production of galectins and cytokines may develop in COVID-19 or adult-onset Still's disease (AOSD). Given the similar clinical features in both diseases, it is necessary to identify biomarkers that can differentiate COVID-19 from AOSD. However, the related data remain scarce currently. Methods: In this cross-sectional study, plasma levels of galectin-3, galectin-9, and soluble TIM-3 (sTIM-3) were determined by ELISA in 55 COVID-19 patients (31 non-severe and 24 severe), 23 active AOSD patients, and 31 healthy controls (HC). The seropositivity for SARS-CoV-2 was examined using an immunochromatographic assay, and cytokine profiles were determined with the MULTIPLEX platform. Results: Significantly higher levels of galectin-3, galectin-9, IL-1ß, IL-1Ra, IL-10, IFN-α2, IL-6, IL-18, and TNF-α were observed in severe COVID-19 and active AOSD patients compared with HC (all p<0.001). AOSD, but not COVID-19, showed significantly higher IFN-γ and IL-17A compared with HC (both p<0.01). Moreover, active AOSD patients had 68-fold higher IL-18 levels and 5-fold higher ferritin levels than severe COVID-19 patients (both p<0.001). IL-18 levels at the cut-off value 190.5pg/mL had the highest discriminative power for active AOSD and severe COVID-19, with AUC 0.948, sensitivity 91.3%, specificity 95.8%, and accuracy of 91.5% (p<0.005). Multivariate regression analysis revealed IL-18 as a significant predictor of active AOSD (p<0.05). Conclusion: Active AOSD patients share features of hyperinflammation and cytokine storm with severe COVID-19 patients but possess a distinct cytokine profile, including elevated IL-18, IL-6, IFN-γ, and IL-17A. IL-18 is a potential discriminator between AOSD and COVID-19 and may significantly predict active AOSD.


Subject(s)
COVID-19 , Interleukin-18 , SARS-CoV-2 , Still's Disease, Adult-Onset , Adult , Biomarkers/blood , COVID-19/blood , COVID-19/immunology , Cross-Sectional Studies , Female , Humans , Interleukin-18/blood , Interleukin-18/immunology , Male , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Still's Disease, Adult-Onset/blood , Still's Disease, Adult-Onset/immunology
6.
J Biol Chem ; 296: 100630, 2021.
Article in English | MEDLINE | ID: covidwho-1333548

ABSTRACT

Unchecked inflammation can result in severe diseases with high mortality, such as macrophage activation syndrome (MAS). MAS and associated cytokine storms have been observed in COVID-19 patients exhibiting systemic hyperinflammation. Interleukin-18 (IL-18), a proinflammatory cytokine belonging to the IL-1 family, is elevated in both MAS and COVID-19 patients, and its level is known to correlate with the severity of COVID-19 symptoms. IL-18 binds its specific receptor IL-1 receptor 5 (IL-1R5, also known as IL-18 receptor alpha chain), leading to the recruitment of the coreceptor, IL-1 receptor 7 (IL-1R7, also known as IL-18 receptor beta chain). This heterotrimeric complex then initiates downstream signaling, resulting in systemic and local inflammation. Here, we developed a novel humanized monoclonal anti-IL-1R7 antibody to specifically block the activity of IL-18 and its inflammatory signaling. We characterized the function of this antibody in human cell lines, in freshly obtained peripheral blood mononuclear cells (PBMCs) and in human whole blood cultures. We found that the anti-IL-1R7 antibody significantly suppressed IL-18-mediated NFκB activation, reduced IL-18-stimulated IFNγ and IL-6 production in human cell lines, and reduced IL-18-induced IFNγ, IL-6, and TNFα production in PBMCs. Moreover, the anti-IL-1R7 antibody significantly inhibited LPS- and Candida albicans-induced IFNγ production in PBMCs, as well as LPS-induced IFNγ production in whole blood cultures. Our data suggest that blocking IL-1R7 could represent a potential therapeutic strategy to specifically modulate IL-18 signaling and may warrant further investigation into its clinical potential for treating IL-18-mediated diseases, including MAS and COVID-19.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/pharmacology , Immunologic Factors/pharmacology , Interleukin-18/genetics , Receptors, Interleukin-18/genetics , Anti-Inflammatory Agents/metabolism , Antibodies, Monoclonal/biosynthesis , Antibodies, Neutralizing/biosynthesis , COVID-19/drug therapy , Candida albicans/growth & development , Candida albicans/pathogenicity , Gene Expression Regulation , HEK293 Cells , Humans , Immunologic Factors/biosynthesis , Inflammation , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-18/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/microbiology , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Macrophage Activation Syndrome/drug therapy , NF-kappa B/genetics , NF-kappa B/immunology , Primary Cell Culture , Receptors, Interleukin-18/antagonists & inhibitors , Receptors, Interleukin-18/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
7.
Int J Mol Sci ; 22(11)2021 May 24.
Article in English | MEDLINE | ID: covidwho-1273453

ABSTRACT

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway.


Subject(s)
Acute Lung Injury/drug therapy , Amides/pharmacology , Cytokines/metabolism , Ethanolamines/pharmacology , MAP Kinase Signaling System/drug effects , Palmitic Acids/pharmacology , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Amides/therapeutic use , Animals , Ethanolamines/therapeutic use , Immunohistochemistry , Inflammation/metabolism , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Lipopolysaccharides/administration & dosage , Lipopolysaccharides/toxicity , Macrophages/drug effects , Macrophages/immunology , Male , Mast Cells/drug effects , Mast Cells/pathology , Mice , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , NF-KappaB Inhibitor alpha/metabolism , NF-kappa B/metabolism , Neutrophils/drug effects , Neutrophils/immunology , Palmitic Acids/therapeutic use , Peroxidase/metabolism , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
8.
J Med Virol ; 93(4): 2090-2098, 2021 04.
Article in English | MEDLINE | ID: covidwho-1227749

ABSTRACT

BACKGROUND: Many laboratory parameters have been associated with morbidity and mortality in SARS-CoV-2 (COVID-19), which emerged in an animal market in Wuhan, China in December 2019 and has infected over 20 million people. This study investigated the relationship between serum interleukin (IL)-18, IL-1 receptor antagonist (IL-1Ra), and alpha defensin levels and the clinical course and prognosis of COVID-19. MATERIALS AND METHODS: This study included 100 patients who were admitted to the chest diseases department and intensive care unit of our hospital and diagnosed with COVID-19 by real-time polymerase chain reaction (PCR) of nasopharyngeal swab samples between March 24 and May 31, 2020. The control group consisted of 50 nonsymptomatic health workers with negative real-time PCR results in routine COVID-19 screening in our hospital. RESULTS: Serum alpha defensin, IL-1Ra, and IL-18 levels were significantly higher in patients who developed macrophage activation syndrome (MAS) and acute respiratory distress syndrome (ARDS) compared to patients who did not (p < .001 for all). Alpha defensin, IL-1Ra, and IL-18 levels were significantly higher in COVID-19 patients with and without MAS or ARDS when compared to the control group (p < .001 for all). When the 9 patients who died were compared with the 91 surviving patients, IL-1Ra and IL-18 levels were found to be significantly higher in the nonsurvivors (p < .001). CONCLUSION: Our findings of correlations between alpha defensin and levels of IL-1Ra and IL-18, which were previously shown to be useful in COVID-19 treatment and follow-up, indicates that it may also be promising in treatment.


Subject(s)
COVID-19/immunology , Interleukin 1 Receptor Antagonist Protein/blood , Interleukin-18/blood , Macrophage Activation Syndrome/virology , Respiratory Distress Syndrome/virology , alpha-Defensins/blood , Adult , Aged , Aged, 80 and over , COVID-19/epidemiology , Female , Humans , Male , Middle Aged , Prognosis , Turkey
9.
Int Immunopharmacol ; 97: 107684, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1188658

ABSTRACT

A cell-surface heparan proteoglycan called Syndecan-1 (SDC-1) has multiple roles in healthy and pathogenic conditions, including respiratory viral infection. In this study, we explore the dynamic alternation in the levels of SDC-1 in cases with COVID-19. A total of 120 cases definitely diagnosed with COVID-19 were admitted to the Firoozgar Hospital, Tehran, Iran, from December 1, 2020, to January 29, 2021, and included in our study. Also, 58 healthy subjects (HS) were chosen as the control group. Patients were classified into two groups: 1) ICU patients and (63 cases) 2) non-ICU patients (57 cases). The dynamic changes of serum SCD-1, CRP, IL-6, IL-10, IL-18, and Vit D levels a well as the disease activity were investigated in three-time points (T1-T3). Our results indicated that the COVID-19 patients had significantly increased SCD-1, CRP, IL-6, IL-10, and IL-18 levels than in HS, while the Vit D levels in COVID-19 patients were significantly lower than HS. Further analysis demonstrated that the SCD-1, CRP, IL-6, IL-10, and IL-18 levels in ICU patients were significantly higher than in non-ICU patients. Tracking dynamic changes in the above markers indicated that on the day of admission, the SCD-1, CRP, IL-6, IL-10, and IL-18 levels were gradually increased on day 5 (T2) and then gradually decreased on day 10 (T3). ROC curve analysis suggests that markers mentioned above, SDC-1, IL-6, and IL-18 are valuable indicators in evaluating the activity of COVID-19. All in all, it seems that the serum SDC-1 levels alone or combined with other markers might be a good candidate for disease activity monitoring.


Subject(s)
COVID-19/diagnosis , Syndecan-1/blood , Adult , Aged , Biomarkers/blood , COVID-19/mortality , Critical Care , Cross-Sectional Studies , Female , Healthy Volunteers , Humans , Interleukin-10/blood , Interleukin-18/blood , Interleukin-6/blood , Male , Middle Aged , ROC Curve , Receptors, Immunologic/blood , Severity of Illness Index , Time Factors , Vitamin D/blood
10.
Science ; 371(6528): 521-526, 2021 01 29.
Article in English | MEDLINE | ID: covidwho-1093836

ABSTRACT

Mucosal-associated invariant T (MAIT) cells are innate sensors of viruses and can augment early immune responses and contribute to protection. We hypothesized that MAIT cells may have inherent adjuvant activity in vaccine platforms that use replication-incompetent adenovirus vectors. In mice and humans, ChAdOx1 (chimpanzee adenovirus Ox1) immunization robustly activated MAIT cells. Activation required plasmacytoid dendritic cell (pDC)-derived interferon (IFN)-α and monocyte-derived interleukin-18. IFN-α-induced, monocyte-derived tumor necrosis factor was also identified as a key secondary signal. All three cytokines were required in vitro and in vivo. Activation of MAIT cells positively correlated with vaccine-induced T cell responses in human volunteers and MAIT cell-deficient mice displayed impaired CD8+ T cell responses to multiple vaccine-encoded antigens. Thus, MAIT cells contribute to the immunogenicity of adenovirus vectors, with implications for vaccine design.


Subject(s)
Adenoviridae/immunology , Immunogenicity, Vaccine , Mucosal-Associated Invariant T Cells/immunology , Viral Vaccines/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Genetic Vectors/immunology , Humans , Interferon-alpha/metabolism , Interleukin-18/metabolism , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Tumor Necrosis Factor-alpha/metabolism
11.
Elife ; 102021 01 14.
Article in English | MEDLINE | ID: covidwho-1063493

ABSTRACT

Although the range of immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is variable, cytokine storm is observed in a subset of symptomatic individuals. To further understand the disease pathogenesis and, consequently, to develop an additional tool for clinicians to evaluate patients for presumptive intervention, we sought to compare plasma cytokine levels between a range of donor and patient samples grouped by a COVID-19 Severity Score (CSS) based on the need for hospitalization and oxygen requirement. Here we utilize a mutual information algorithm that classifies the information gain for CSS prediction provided by cytokine expression levels and clinical variables. Using this methodology, we found that a small number of clinical and cytokine expression variables are predictive of presenting COVID-19 disease severity, raising questions about the mechanism by which COVID-19 creates severe illness. The variables that were the most predictive of CSS included clinical variables such as age and abnormal chest x-ray as well as cytokines such as macrophage colony-stimulating factor, interferon-inducible protein 10, and interleukin-1 receptor antagonist. Our results suggest that SARS-CoV-2 infection causes a plethora of changes in cytokine profiles and that particularly in severely ill patients, these changes are consistent with the presence of macrophage activation syndrome and could furthermore be used as a biomarker to predict disease severity.


Subject(s)
Algorithms , COVID-19/diagnosis , COVID-19/immunology , Cytokines/blood , Adult , Age Factors , Aged , Aged, 80 and over , Chemokine CXCL10/blood , Humans , Interleukin 1 Receptor Antagonist Protein/blood , Interleukin-18/blood , Lung/diagnostic imaging , Macrophage Colony-Stimulating Factor/blood , Middle Aged , Severity of Illness Index
12.
Nat Immunol ; 22(3): 322-335, 2021 03.
Article in English | MEDLINE | ID: covidwho-1060966

ABSTRACT

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.


Subject(s)
COVID-19/immunology , Interferon-alpha/immunology , Interleukin-18/immunology , Macrophages/immunology , Monocytes/immunology , Mucosal-Associated Invariant T Cells/immunology , Adult , Aged , Aged, 80 and over , Animals , Bronchoalveolar Lavage , Case-Control Studies , Chlorocebus aethiops , Cohort Studies , Female , France , Humans , Immunophenotyping , Interleukin-10/immunology , Interleukin-15/immunology , Interleukin-1beta/immunology , Interleukin-6/immunology , Interleukin-8/immunology , Male , Middle Aged , RNA-Seq , SARS-CoV-2 , Severity of Illness Index , Single-Cell Analysis , Vero Cells , Young Adult
13.
Elife ; 102021 01 14.
Article in English | MEDLINE | ID: covidwho-1028863

ABSTRACT

Although the range of immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is variable, cytokine storm is observed in a subset of symptomatic individuals. To further understand the disease pathogenesis and, consequently, to develop an additional tool for clinicians to evaluate patients for presumptive intervention, we sought to compare plasma cytokine levels between a range of donor and patient samples grouped by a COVID-19 Severity Score (CSS) based on the need for hospitalization and oxygen requirement. Here we utilize a mutual information algorithm that classifies the information gain for CSS prediction provided by cytokine expression levels and clinical variables. Using this methodology, we found that a small number of clinical and cytokine expression variables are predictive of presenting COVID-19 disease severity, raising questions about the mechanism by which COVID-19 creates severe illness. The variables that were the most predictive of CSS included clinical variables such as age and abnormal chest x-ray as well as cytokines such as macrophage colony-stimulating factor, interferon-inducible protein 10, and interleukin-1 receptor antagonist. Our results suggest that SARS-CoV-2 infection causes a plethora of changes in cytokine profiles and that particularly in severely ill patients, these changes are consistent with the presence of macrophage activation syndrome and could furthermore be used as a biomarker to predict disease severity.


Subject(s)
Algorithms , COVID-19/diagnosis , COVID-19/immunology , Cytokines/blood , Adult , Age Factors , Aged , Aged, 80 and over , Chemokine CXCL10/blood , Humans , Interleukin 1 Receptor Antagonist Protein/blood , Interleukin-18/blood , Lung/diagnostic imaging , Macrophage Colony-Stimulating Factor/blood , Middle Aged , Severity of Illness Index
14.
Cytokine ; 137: 155302, 2021 01.
Article in English | MEDLINE | ID: covidwho-1023524

ABSTRACT

BACKGROUND: The effectual immune response is crucial to defeat viral infections. However, exuberant immune response with features of macrophage activation syndrome (MAS) lead detrimental consequences in COVID-19 patients. Interleukin (IL)-18 is one of the leading cytokines in MAS which has not been studied in COVID-19. OBJECTIVE: To investigate the association of IL-18 with the other inflammatory markers and disease severity in COVID-19 for predicting disease prognosis. METHODS: Patients with COVID-19 who had confirmed diagnosis with SARS-CoV-2 nucleic acid RT-PCR were enrolled into the study. Data on demographic and clinical characteristics, and laboratory values of CRP, ferritin, d-dimer and procalcitonin were measured on admission. Patients were followed up prospectively with a standardized approach until hospital discharge or death. Individuals were classified as asymptomatic, mild and severe pneumonia according to their clinical, laboratory and radiological characteristics. Worse outcome was defined as requirement of intensive care unit (ICU) admission or death. Blood samples were collected at enrollment and serum levels of IL-6 and IL-18 were determined by ELISA. Association between IL-18 and other inflammatory markers and prognosis were analyzed. RESULTS: There were 58 COVID-19 patients (50% male) with a median age of 43 (min 22-max 81) years. Twenty age and sex matched healthy subjects were served as control group. The study population was divided into three groups according to disease severity: asymptomatic (n = 20), mild pneumonia group (n = 27) and a severe group (n = 11). During follow up nine (15.5%) patients required ICU admission and three of them were died eventually. Serum IL-18 were correlated with other inflammatory markers and biochemical markers of organ injury; creatinine, liver enzymes and troponin. Serum IL-18 levels were remarkably higher in COVID-19 patients compared to healthy subjects with being highest in severe pneumonia group (p < 0.001). IL-18 serum concentrations were almost four-fold higher in patients with worse outcome compared to good outcome (p < 0.001). Serum IL-18 above the cut off value of 576 pg/mL on admission was associated with 11.7 fold increased risk of ICU admission. CONCLUSIONS: The serum concentrations of IL-18 correlate with other inflammatory markers and reflect disease severity. Results of the present study shed light on role of IL-18 on COVID-19 pathogenesis and might provide an evidence for the clinical trials on IL-18 antagonists for the treatment of severe COVID-19 patients.


Subject(s)
COVID-19/blood , COVID-19/diagnosis , Interleukin-18/blood , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/mortality , COVID-19/physiopathology , Female , Humans , Inflammation/blood , Interleukin-6/blood , Male , Middle Aged , Prognosis , Severity of Illness Index
15.
Cytokine ; 137: 155302, 2021 01.
Article in English | MEDLINE | ID: covidwho-802811

ABSTRACT

BACKGROUND: The effectual immune response is crucial to defeat viral infections. However, exuberant immune response with features of macrophage activation syndrome (MAS) lead detrimental consequences in COVID-19 patients. Interleukin (IL)-18 is one of the leading cytokines in MAS which has not been studied in COVID-19. OBJECTIVE: To investigate the association of IL-18 with the other inflammatory markers and disease severity in COVID-19 for predicting disease prognosis. METHODS: Patients with COVID-19 who had confirmed diagnosis with SARS-CoV-2 nucleic acid RT-PCR were enrolled into the study. Data on demographic and clinical characteristics, and laboratory values of CRP, ferritin, d-dimer and procalcitonin were measured on admission. Patients were followed up prospectively with a standardized approach until hospital discharge or death. Individuals were classified as asymptomatic, mild and severe pneumonia according to their clinical, laboratory and radiological characteristics. Worse outcome was defined as requirement of intensive care unit (ICU) admission or death. Blood samples were collected at enrollment and serum levels of IL-6 and IL-18 were determined by ELISA. Association between IL-18 and other inflammatory markers and prognosis were analyzed. RESULTS: There were 58 COVID-19 patients (50% male) with a median age of 43 (min 22-max 81) years. Twenty age and sex matched healthy subjects were served as control group. The study population was divided into three groups according to disease severity: asymptomatic (n = 20), mild pneumonia group (n = 27) and a severe group (n = 11). During follow up nine (15.5%) patients required ICU admission and three of them were died eventually. Serum IL-18 were correlated with other inflammatory markers and biochemical markers of organ injury; creatinine, liver enzymes and troponin. Serum IL-18 levels were remarkably higher in COVID-19 patients compared to healthy subjects with being highest in severe pneumonia group (p < 0.001). IL-18 serum concentrations were almost four-fold higher in patients with worse outcome compared to good outcome (p < 0.001). Serum IL-18 above the cut off value of 576 pg/mL on admission was associated with 11.7 fold increased risk of ICU admission. CONCLUSIONS: The serum concentrations of IL-18 correlate with other inflammatory markers and reflect disease severity. Results of the present study shed light on role of IL-18 on COVID-19 pathogenesis and might provide an evidence for the clinical trials on IL-18 antagonists for the treatment of severe COVID-19 patients.


Subject(s)
COVID-19/blood , COVID-19/diagnosis , Interleukin-18/blood , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/mortality , COVID-19/physiopathology , Female , Humans , Inflammation/blood , Interleukin-6/blood , Male , Middle Aged , Prognosis , Severity of Illness Index
16.
J Intern Med ; 289(4): 523-531, 2021 04.
Article in English | MEDLINE | ID: covidwho-796040

ABSTRACT

BACKGROUND: A high proportion of COVID-19 patients have cardiac involvement, even those without known cardiac disease. Downregulation of angiotensin converting enzyme 2 (ACE2), a receptor for SARS-CoV-2 and the renin-angiotensin system, as well as inflammatory mechanisms have been suggested to play a role. ACE2 is abundant in the gut and associated with gut microbiota composition. We hypothesized that gut leakage of microbial products, and subsequent inflammasome activation could contribute to cardiac involvement in COVID-19 patients. METHODS: Plasma levels of a gut leakage marker (LPS-binding protein, LBP), a marker of enterocyte damage (intestinal fatty acid binding protein, IFABP), a gut homing marker (CCL25, ligand for chemokine receptor CCR9) and markers of inflammasome activation (IL-1ß, IL-18 and their regulatory proteins) were measured at three time points (day 1, 3-5 and 7-10) in 39 hospitalized COVID-19 patients and related to cardiac involvement. RESULTS: Compared to controls, COVID-19 patients had elevated plasma levels of LBP and CCL25 but not IFABP, suggesting impaired gut barrier function and accentuated gut homing of T cells without excessive enterocyte damage. Levels of LBP were twice as high at baseline in patients with elevated cardiac markers compared with those without and remained elevated during hospitalization. Also, markers of inflammasome activation were moderately elevated in patients with cardiac involvement. LBP was associated with higher NT-pro-BNP levels, whereas IL-18, IL-18BP and IL-1Ra were associated with higher troponin levels. CONCLUSION: Patients with cardiac involvement had elevated markers of gut leakage and inflammasome activation, suggestive of a potential gut-heart axis in COVID-19.


Subject(s)
COVID-19 , Chemokines, CC/metabolism , Gastrointestinal Microbiome/immunology , Heart Diseases , Inflammasomes/metabolism , Intestinal Mucosa , SARS-CoV-2 , Acute-Phase Proteins/metabolism , COVID-19/complications , COVID-19/immunology , Carrier Proteins/metabolism , Correlation of Data , Heart Diseases/immunology , Heart Diseases/virology , Humans , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Intestinal Mucosa/physiopathology , Membrane Glycoproteins/metabolism , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Troponin/blood
17.
Cell ; 183(4): 982-995.e14, 2020 11 12.
Article in English | MEDLINE | ID: covidwho-756809

ABSTRACT

Initially, children were thought to be spared from disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a month into the epidemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. Herein, we report on the immune profiles of nine MIS-C cases. All MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with intact neutralization capability. Cytokine profiling identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1), and mucosal immune dysregulation (IL-17A, CCL20, and CCL28). Immunophenotyping of peripheral blood revealed reductions of non-classical monocytes, and subsets of NK and T lymphocytes, suggesting extravasation to affected tissues. Finally, profiling the autoantigen reactivity of MIS-C plasma revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal, and immune-cell antigens. All patients were treated with anti-IL-6R antibody and/or IVIG, which led to rapid disease resolution.


Subject(s)
Inflammation/pathology , Systemic Inflammatory Response Syndrome/pathology , Adolescent , Antibodies, Viral/blood , Autoantibodies/blood , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , COVID-19 , Chemokine CCL3/metabolism , Child , Child, Preschool , Coronavirus Infections/complications , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Humans , Immunity, Humoral , Infant , Infant, Newborn , Inflammation/metabolism , Interleukin-17/metabolism , Interleukin-18/metabolism , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Male , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Young Adult
18.
J Cell Physiol ; 236(3): 1638-1657, 2021 03.
Article in English | MEDLINE | ID: covidwho-720323

ABSTRACT

Interleukin (IL)-18 is a pro-inflammatory cytokine belonging to the IL-1 family, first identified for its interferon-γ-inducing properties. IL-18 regulates both T helper (Th) 1 and Th2 responses. It acts synergistically with IL-12 in the Th1 paradigm, whereas with IL-2 and without IL-12 it can induce Th2 cytokine production from cluster of differentation (CD)4+ T cells, natural killer (NK cells, NKT cells, as well as from Th1 cells. IL-18 also plays a role in the hemophagocytic lymphohistiocytosis, a life-threatening condition characterized by a cytokine storm that can be secondary to infections. IL-18-mediated inflammation was largely studied in animal models of bacterial, viral, parasitic, and fungal infections. These studies highlight the contribution of either IL-18 overproduction by the host or overresponsiveness of the host to IL-18 causing an exaggerated inflammatory burden and leading to tissue injury. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19). The damage in the later phase of the disease appears to be driven by a cytokine storm, including interleukin IL-1 family members and secondary cytokines like IL-6. IL-18 may participate in this hyperinflammation, as it was previously found to be able to cause injury in the lung tissue of infected animals. IL-18 blockade has become an appealing therapeutic target and has been tested in some IL-18-mediated rheumatic diseases and infantile-onset macrophage activation syndrome. Given its role in regulating the immune response to infections, IL-18 blockade might represent a therapeutic option for COVID-19, although further studies are warranted to investigate more in detail the exact role of IL-18 in SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , Interleukin-18/immunology , Animals , Humans , Inflammation/immunology , Inflammation/virology , Interleukin-18/antagonists & inhibitors , SARS-CoV-2/immunology
19.
JCI Insight ; 5(17)2020 09 03.
Article in English | MEDLINE | ID: covidwho-676865

ABSTRACT

BACKGROUNDElevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare with those observed in critically ill patients with acute respiratory distress syndrome (ARDS) or sepsis due to other causes.METHODSWe used a Luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTSFifteen hospitalized COVID-19 patients, 9 of whom were critically ill, were compared with critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONLevels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDINGFunding was received from NHLBI K23 HL125663 (AJR); The Bill and Melinda Gates Foundation OPP1113682 (AJR and CAB); Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687 NIH/NIAID U19AI057229-16; Stanford Maternal Child Health Research Institute; and Chan Zuckerberg Biohub (CAB).


Subject(s)
Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Cytokines/immunology , Pneumonia, Viral/immunology , Respiratory Distress Syndrome/immunology , Sepsis/immunology , Adult , Aged , COVID-19 , Case-Control Studies , Coronavirus Infections/blood , Cytokine Release Syndrome/blood , Cytokines/blood , Female , Humans , Interleukin 1 Receptor Antagonist Protein/blood , Interleukin 1 Receptor Antagonist Protein/immunology , Interleukin-18/blood , Interleukin-18/immunology , Interleukin-1beta/blood , Interleukin-1beta/immunology , Interleukin-6/blood , Interleukin-6/immunology , Interleukin-8/blood , Interleukin-8/immunology , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Respiratory Distress Syndrome/blood , Sepsis/blood , Severity of Illness Index , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/immunology
20.
JAMA Cardiol ; 5(11): 1281-1285, 2020 11 01.
Article in English | MEDLINE | ID: covidwho-676377

ABSTRACT

Importance: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be documented in various tissues, but the frequency of cardiac involvement as well as possible consequences are unknown. Objective: To evaluate the presence of SARS-CoV-2 in the myocardial tissue from autopsy cases and to document a possible cardiac response to that infection. Design, Setting, and Participants: This cohort study used data from consecutive autopsy cases from Germany between April 8 and April 18, 2020. All patients had tested positive for SARS-CoV-2 in pharyngeal swab tests. Exposures: Patients who died of coronavirus disease 2019. Main Outcomes and Measures: Incidence of SARS-CoV-2 positivity in cardiac tissue as well as CD3+, CD45+, and CD68+ cells in the myocardium and gene expression of tumor necrosis growth factor α, interferon γ, chemokine ligand 5, as well as interleukin-6, -8, and -18. Results: Cardiac tissue from 39 consecutive autopsy cases were included. The median (interquartile range) age of patients was 85 (78-89) years, and 23 (59.0%) were women. SARS-CoV-2 could be documented in 24 of 39 patients (61.5%). Viral load above 1000 copies per µg RNA could be documented in 16 of 39 patients (41.0%). A cytokine response panel consisting of 6 proinflammatory genes was increased in those 16 patients compared with 15 patients without any SARS-CoV-2 in the heart. Comparison of 15 patients without cardiac infection with 16 patients with more than 1000 copies revealed no inflammatory cell infiltrates or differences in leukocyte numbers per high power field. Conclusions and Relevance: In this analysis of autopsy cases, viral presence within the myocardium could be documented. While a response to this infection could be reported in cases with higher virus load vs no virus infection, this was not associated with an influx of inflammatory cells. Future investigations should focus on evaluating the long-term consequences of this cardiac involvement.


Subject(s)
Autopsy/methods , COVID-19/complications , Cardiovascular Infections/etiology , SARS-CoV-2/genetics , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/virology , Cardiovascular Infections/metabolism , Cardiovascular Infections/virology , Chemokines/metabolism , Cohort Studies , Female , Germany/epidemiology , Humans , Incidence , Interferon-gamma/metabolism , Interleukin-18/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Male , Myocarditis/etiology , Myocarditis/metabolism , Myocarditis/virology , Myocardium/immunology , Myocardium/metabolism , Pandemics , Peptide Fragments/metabolism , SARS-CoV-2/isolation & purification , Tumor Necrosis Factor-alpha/metabolism , Viral Load/statistics & numerical data
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