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1.
Rev Med Virol ; 31(6): e2221, 2021 11.
Article in English | MEDLINE | ID: covidwho-1575100

ABSTRACT

The current pandemic caused by SARS-CoV-2 virus infection is known as Covid-19 (coronavirus disease 2019). This disease can be asymptomatic or can affect multiple organ systems. Damage induced by the virus is related to dysfunctional activity of the immune system, but the activity of molecules such as C-reactive protein (CRP) as a factor capable of inducing an inflammatory status that may be involved in the severe evolution of the disease, has not been extensively evaluated. A systematic review was performed using the NCBI-PubMed database to find articles related to Covid-19 immunity, inflammatory response, and CRP published from December 2019 to December 2020. High levels of CRP were found in patients with severe evolution of Covid-19 in which several organ systems were affected and in patients who died. CRP activates complement, induces the production of pro-inflammatory cytokines and induces apoptosis which, together with the inflammatory status during the disease, can lead to a severe outcome. Several drugs can decrease the level or block the effect of CRP and might be useful in the treatment of Covid-19. From this review it is reasonable to conclude that CRP is a factor that can contribute to severe evolution of Covid-19 and that the use of drugs able to lower CRP levels or block its activity should be evaluated in randomized controlled clinical trials.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , C-Reactive Protein/antagonists & inhibitors , COVID-19/drug therapy , Complement System Proteins/immunology , Cytokine Release Syndrome/drug therapy , SARS-CoV-2/pathogenicity , ADAM17 Protein/antagonists & inhibitors , ADAM17 Protein/genetics , ADAM17 Protein/immunology , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Biomarkers/blood , C-Reactive Protein/genetics , C-Reactive Protein/immunology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Celecoxib/therapeutic use , Complement System Proteins/genetics , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Cytokines/immunology , Disease Progression , Doxycycline/therapeutic use , Gene Expression Regulation , Humans , Randomized Controlled Trials as Topic , Severity of Illness Index , Survival Analysis
2.
J Med Virol ; 93(12): 6653-6659, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1530185

ABSTRACT

Macrophage activation syndrome (MAS) is one of the main causes of morbidity and mortality in patients with coronavirus disease 2019 (COVID-19). This study aimed to investigate the relationship between the pentraxin 3 (PTX3) gene polymorphisms rs2305619 (281A/G) and rs1840680 (1449A/G) and the development of MAS in patients with COVID-19. The study included a total of 94 patients aged 18-45 who were diagnosed as having COVID-19 between June and December 2020. PTX3 281A/G and 1449A/G polymorphism frequencies were evaluated. PTX3 281A/G allele and genotype frequencies did not deviate from Hardy-Weinberg (HW) equilibrium in the MAS or non-MAS group (χ2 : 0.049, df: 2, p = 0.976, χ2 : 0.430, df: 2, p = 0.806). PTX3 1449A/G allele and genotype frequencies deviated significantly from HW equilibrium in the non-MAS group (χ2 : 6.794, df: 2, p = 0.033) but not in the MAS group (χ2 : 2.256, df: 2, p = 0.324). The AG genotype was significantly more frequent in the non-MAS group, while the AA genotype was significantly more frequent in the MAS group (χ2 : 11.099, df: 2, p= 0.004). Analysis of the PTX3 1449A/G polymorphism showed that individuals with the GG genotype had higher serum PTX3 levels than those with the AA and AG genotypes (p = 0.001 for both). Analysis of the PTX3 1449A/G polymorphism in patients with COVID-19 showed that those with the AG genotype were relatively more protected from MAS compared with individuals with the AA genotype. In addition, lower serum PTX3 levels are observed in patients carrying the A allele.


Subject(s)
C-Reactive Protein/genetics , COVID-19/genetics , Polymorphism, Single Nucleotide/genetics , Serum Amyloid P-Component/genetics , Adolescent , Adult , Alleles , COVID-19/pathology , Disease Progression , Female , Genotype , Humans , Macrophage Activation Syndrome/etiology , Macrophage Activation Syndrome/genetics , Male , Middle Aged , Risk Factors , Severity of Illness Index , Young Adult
3.
J Med Virol ; 93(12): 6653-6659, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1326781

ABSTRACT

Macrophage activation syndrome (MAS) is one of the main causes of morbidity and mortality in patients with coronavirus disease 2019 (COVID-19). This study aimed to investigate the relationship between the pentraxin 3 (PTX3) gene polymorphisms rs2305619 (281A/G) and rs1840680 (1449A/G) and the development of MAS in patients with COVID-19. The study included a total of 94 patients aged 18-45 who were diagnosed as having COVID-19 between June and December 2020. PTX3 281A/G and 1449A/G polymorphism frequencies were evaluated. PTX3 281A/G allele and genotype frequencies did not deviate from Hardy-Weinberg (HW) equilibrium in the MAS or non-MAS group (χ2 : 0.049, df: 2, p = 0.976, χ2 : 0.430, df: 2, p = 0.806). PTX3 1449A/G allele and genotype frequencies deviated significantly from HW equilibrium in the non-MAS group (χ2 : 6.794, df: 2, p = 0.033) but not in the MAS group (χ2 : 2.256, df: 2, p = 0.324). The AG genotype was significantly more frequent in the non-MAS group, while the AA genotype was significantly more frequent in the MAS group (χ2 : 11.099, df: 2, p= 0.004). Analysis of the PTX3 1449A/G polymorphism showed that individuals with the GG genotype had higher serum PTX3 levels than those with the AA and AG genotypes (p = 0.001 for both). Analysis of the PTX3 1449A/G polymorphism in patients with COVID-19 showed that those with the AG genotype were relatively more protected from MAS compared with individuals with the AA genotype. In addition, lower serum PTX3 levels are observed in patients carrying the A allele.


Subject(s)
C-Reactive Protein/genetics , COVID-19/genetics , Polymorphism, Single Nucleotide/genetics , Serum Amyloid P-Component/genetics , Adolescent , Adult , Alleles , COVID-19/pathology , Disease Progression , Female , Genotype , Humans , Macrophage Activation Syndrome/etiology , Macrophage Activation Syndrome/genetics , Male , Middle Aged , Risk Factors , Severity of Illness Index , Young Adult
5.
Nat Immunol ; 22(1): 19-24, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065905

ABSTRACT

Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation1-3. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19)4-7. RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.


Subject(s)
C-Reactive Protein/genetics , COVID-19/genetics , Gene Expression Profiling/methods , Macrophages/metabolism , SARS-CoV-2/isolation & purification , Serum Amyloid P-Component/genetics , A549 Cells , Adult , C-Reactive Protein/metabolism , COVID-19/epidemiology , COVID-19/virology , Cell Line, Tumor , Cells, Cultured , Cohort Studies , Endothelial Cells/metabolism , Epidemics , Female , Humans , Male , Middle Aged , Monocytes/metabolism , Neutrophils/metabolism , Prognosis , SARS-CoV-2/physiology , Serum Amyloid P-Component/metabolism
6.
EBioMedicine ; 64: 103228, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1062316

ABSTRACT

BACKGROUND: Developing insight into the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of critical importance to overcome the global pandemic caused by coronavirus disease 2019 (covid-19). In this study, we have applied Mendelian randomization (MR) to systematically evaluate the effect of 10 cardiometabolic risk factors and genetic liability to lifetime smoking on 97 circulating host proteins postulated to either interact or contribute to the maladaptive host response of SARS-CoV-2. METHODS: We applied the inverse variance weighted (IVW) approach and several robust MR methods in a two-sample setting to systemically estimate the genetically predicted effect of each risk factor in turn on levels of each circulating protein. Multivariable MR was conducted to simultaneously evaluate the effects of multiple risk factors on the same protein. We also applied MR using cis-regulatory variants at the genomic location responsible for encoding these proteins to estimate whether their circulating levels may influence severe SARS-CoV-2. FINDINGS: In total, we identified evidence supporting 105 effects between risk factors and circulating proteins which were robust to multiple testing corrections and sensitivity analyzes. For example, body mass index provided evidence of an effect on 23 circulating proteins with a variety of functions, such as inflammatory markers c-reactive protein (IVW Beta=0.34 per standard deviation change, 95% CI=0.26 to 0.41, P = 2.19 × 10-16) and interleukin-1 receptor antagonist (IVW Beta=0.23, 95% CI=0.17 to 0.30, P = 9.04 × 10-12). Further analyzes using multivariable MR provided evidence that the effect of BMI on lowering immunoglobulin G, an antibody class involved in protection from infection, is substantially mediated by raised triglycerides levels (IVW Beta=-0.18, 95% CI=-0.25 to -0.12, P = 2.32 × 10-08, proportion mediated=44.1%). The strongest evidence that any of the circulating proteins highlighted by our initial analysis influence severe SARS-CoV-2 was identified for soluble glycoprotein 130 (odds ratio=1.81, 95% CI=1.25 to 2.62, P = 0.002), a signal transductor for interleukin-6 type cytokines which are involved in inflammatory response. However, based on current case samples for severe SARS-CoV-2 we were unable to replicate findings in independent samples. INTERPRETATION: Our findings highlight several key proteins which are influenced by established exposures for disease. Future research to determine whether these circulating proteins mediate environmental effects onto risk of SARS-CoV-2 infection or covid-19 progression are warranted to help elucidate therapeutic strategies for severe covid-19 disease. FUNDING: The Medical Research Council, the Wellcome Trust, the British Heart Foundation and UK Research and Innovation.


Subject(s)
COVID-19/blood , Cardiovascular Diseases/blood , SARS-CoV-2/metabolism , Biomarkers/blood , Body Mass Index , C-Reactive Protein/genetics , C-Reactive Protein/metabolism , COVID-19/genetics , Cardiovascular Diseases/genetics , Female , Genome-Wide Association Study , Humans , Interleukin-1/blood , Interleukin-1/genetics , Interleukin-6/blood , Interleukin-6/genetics , Male , SARS-CoV-2/genetics , Severity of Illness Index
7.
Nat Immunol ; 22(1): 19-24, 2021 01.
Article in English | MEDLINE | ID: covidwho-933698

ABSTRACT

Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation1-3. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19)4-7. RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.


Subject(s)
C-Reactive Protein/genetics , COVID-19/genetics , Gene Expression Profiling/methods , Macrophages/metabolism , SARS-CoV-2/isolation & purification , Serum Amyloid P-Component/genetics , A549 Cells , Adult , C-Reactive Protein/metabolism , COVID-19/epidemiology , COVID-19/virology , Cell Line, Tumor , Cells, Cultured , Cohort Studies , Endothelial Cells/metabolism , Epidemics , Female , Humans , Male , Middle Aged , Monocytes/metabolism , Neutrophils/metabolism , Prognosis , SARS-CoV-2/physiology , Serum Amyloid P-Component/metabolism
8.
Front Immunol ; 11: 574593, 2020.
Article in English | MEDLINE | ID: covidwho-846257

ABSTRACT

Familial Mediterranean Fever (FMF) and COVID-19 show a remarkable overlap of clinical symptoms and similar laboratory findings. Both are characterized by fever, abdominal/chest pain, elevation of C-reactive protein, and leukocytosis. In addition, colchicine and IL-1 inhibitors treatments that are effective in controlling inflammation in FMF patients have recently been proposed for off-label use in COVID-19 patients. Thus, FMF may resemble a milder recapitulation of the cytokine storm that is a hallmark of COVID-19 patients progressing to severe disease. We analyzed the sequence of the MEFV-encoded Pyrin protein - whose mutations cause FMF- in mammals, bats and pangolin. Intriguingly, although Pyrin is extremely conserved in species that are considered either a reservoir or intermediate hosts for SARS-CoV-2, some of the most common FMF-causing variants in humans are present as wildtype residues in these species. We propose that in humans, Pyrin may have evolved to fight highly pathogenic infections.


Subject(s)
Betacoronavirus , Colchicine/therapeutic use , Coronavirus Infections , Familial Mediterranean Fever , Mutation , Pandemics , Pneumonia, Viral , Pyrin , Animals , Betacoronavirus/genetics , Betacoronavirus/immunology , C-Reactive Protein/genetics , C-Reactive Protein/immunology , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Familial Mediterranean Fever/drug therapy , Familial Mediterranean Fever/epidemiology , Familial Mediterranean Fever/genetics , Familial Mediterranean Fever/immunology , Humans , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/genetics , Pneumonia, Viral/immunology , Pyrin/genetics , Pyrin/immunology , SARS-CoV-2
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