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1.
J Med Virol ; 93(9): 5515-5522, 2021 09.
Article in English | MEDLINE | ID: covidwho-1363690

ABSTRACT

Complement system hyperactivation has been proposed as a potential driver of adverse outcomes in severe acute respiratory syndrome coronavirus 2 infected patients, given prior research of complement deposits found in tissue and blood samples, as well as evidence of clinical improvement with anticomplement therapy. Its role in augmenting thrombotic microangiopathy mediated organ damage has also been implicated in coronavirus disease 2019 (COVID-19). This study aimed to examine associations between complement parameters and progression to severe COVID-19 illness, as well as correlations with other systems. Blood samples of COVID-19 patients presenting to the emergency department (ED) were analyzed for a wide panel of complement and inflammatory biomarkers. The primary outcome was COVID-19 severity at index ED visit, while the secondary outcome was peak disease severity over the course of illness. Fifty-two COVID-19 patients were enrolled. C3a (p = 0.018), C3a/C3 ratio (p = 0.002), and sC5b-9/C3 ratio (p = 0.021) were significantly elevated in with severe disease at ED presentation. Over the course of illness, C3a (p = 0.028) and C3a/C3 ratio (p = 0.003) were highest in the moderate severity group. In multivariate regression controlled for confounders, complement hyperactivation failed to predict progression to severe disease. C3a, C3a/C3 ratio, and sC5b-9/C3 ratio were correlated positively with numerous inflammatory biomarkers, fibrinogen, and VWF:Ag, and negatively with plasminogen and ADAMTS13 activity. We found evidence of complement hyperactivation in COVID-19, associated with hyperinflammation and thrombotic microangiopathy. Complement inhibition should be further investigated for potential benefit in patients displaying a hyperinflammatory and microangiopathic phenotype.


Subject(s)
ADAMTS13 Protein/blood , COVID-19/blood , Complement C3/analysis , Complement Membrane Attack Complex/analysis , SARS-CoV-2 , Adult , Aged , Biomarkers/blood , Female , Humans , Logistic Models , Male , Middle Aged , Multivariate Analysis , Ohio , Patient Admission , Severity of Illness Index
2.
J Med Virol ; 93(9): 5515-5522, 2021 09.
Article in English | MEDLINE | ID: covidwho-1235670

ABSTRACT

Complement system hyperactivation has been proposed as a potential driver of adverse outcomes in severe acute respiratory syndrome coronavirus 2 infected patients, given prior research of complement deposits found in tissue and blood samples, as well as evidence of clinical improvement with anticomplement therapy. Its role in augmenting thrombotic microangiopathy mediated organ damage has also been implicated in coronavirus disease 2019 (COVID-19). This study aimed to examine associations between complement parameters and progression to severe COVID-19 illness, as well as correlations with other systems. Blood samples of COVID-19 patients presenting to the emergency department (ED) were analyzed for a wide panel of complement and inflammatory biomarkers. The primary outcome was COVID-19 severity at index ED visit, while the secondary outcome was peak disease severity over the course of illness. Fifty-two COVID-19 patients were enrolled. C3a (p = 0.018), C3a/C3 ratio (p = 0.002), and sC5b-9/C3 ratio (p = 0.021) were significantly elevated in with severe disease at ED presentation. Over the course of illness, C3a (p = 0.028) and C3a/C3 ratio (p = 0.003) were highest in the moderate severity group. In multivariate regression controlled for confounders, complement hyperactivation failed to predict progression to severe disease. C3a, C3a/C3 ratio, and sC5b-9/C3 ratio were correlated positively with numerous inflammatory biomarkers, fibrinogen, and VWF:Ag, and negatively with plasminogen and ADAMTS13 activity. We found evidence of complement hyperactivation in COVID-19, associated with hyperinflammation and thrombotic microangiopathy. Complement inhibition should be further investigated for potential benefit in patients displaying a hyperinflammatory and microangiopathic phenotype.


Subject(s)
ADAMTS13 Protein/blood , COVID-19/blood , Complement C3/analysis , Complement Membrane Attack Complex/analysis , SARS-CoV-2 , Adult , Aged , Biomarkers/blood , Female , Humans , Logistic Models , Male , Middle Aged , Multivariate Analysis , Ohio , Patient Admission , Severity of Illness Index
3.
Clin Chem Lab Med ; 59(3): 599-607, 2021 02 23.
Article in English | MEDLINE | ID: covidwho-1067439

ABSTRACT

OBJECTIVES: Severe coronavirus disease 2019 (COVID-19) is associated with a dysregulated immune state. While research has focused on the hyperinflammation, little research has been performed on the compensatory anti-inflammatory response. The aim of this study was to evaluate the anti-inflammatory cytokine response to COVID-19, by assessing interleukin-10 (IL-10) and IL-10/lymphocyte count ratio and their association with outcomes. METHODS: Adult patients presenting to the emergency department (ED) with laboratory-confirmed COVID-19 were recruited. The primary endpoint was maximum COVID-19 severity within 30 days of index ED visit. RESULTS: A total of 52 COVID-19 patients were enrolled. IL-10 and IL-10/lymphocyte count were significantly higher in patients with severe disease (p<0.05), as well as in those who developed severe acute kidney injury (AKI) and new positive bacterial cultures (all p≤0.01). In multivariable analysis, a one-unit increase in IL-10 and IL-10/lymphocyte count were associated with 42% (p=0.031) and 32% (p=0.013) increased odds, respectively, of severe COVID-19. When standardized to a one-unit standard deviations scale, an increase in the IL-10 was a stronger predictor of maximum 30-day severity and severe AKI than increases in IL-6 or IL-8. CONCLUSIONS: The hyperinflammatory response to COVID-19 is accompanied by a simultaneous anti-inflammatory response, which is associated with poor outcomes and may increase the risk of new positive bacterial cultures. IL-10 and IL-10/lymphocyte count at ED presentation were independent predictors of COVID-19 severity. Moreover, elevated IL-10 was more strongly associated with outcomes than pro-inflammatory IL-6 or IL-8. The anti-inflammatory response in COVID-19 requires further investigation to enable more precise immunomodulatory therapy against SARS-CoV-2.


Subject(s)
COVID-19/diagnosis , Interleukin-10/metabolism , Acute Kidney Injury/blood , Acute Kidney Injury/complications , Acute Kidney Injury/diagnosis , Adult , Aged , Bacterial Infections/blood , Bacterial Infections/complications , Bacterial Infections/diagnosis , COVID-19/blood , COVID-19/complications , Cohort Studies , Emergency Service, Hospital , Female , Hospitalization , Humans , Interleukin-10/blood , Lymphocyte Count , Male , Middle Aged , Prognosis
4.
Acta Biomed ; 91(3): e2020008, 2020 09 07.
Article in English | MEDLINE | ID: covidwho-761251

ABSTRACT

BACKGROUND: There is a compelling need to identify clinical and laboratory predictors of unfavorable clinical course and death in patients with coronavirus disease (COVID-19). A trend towards low lymphocyte count and high neutrophil counts in patients with poor outcomes has been reported by earlier studies. We aim to synthesize existing data evaluating the relationship between clinical outcomes and abnormal neutrophil and lymphocyte counts at admission in COVID-19 patients. METHODS: An electronic search was carried out in PubMed, China National Knowledge Infrastructure (CNKI) and Cochrane Central Register of Controlled Trials (CENTRAL) to identify eligible studies reporting frequency data on neutrophilia and lymphopenia at admission in hospitalization in COVID-19 patients. Pooled odds ratios of clinical outcomes for each parameter were calculated using Comprehensive Meta-Analysis. RESULTS: A total of 22 studies (4,969 patients) were included in this meta-analysis. Lymphopenia at admission was found to be significantly associated with increased odd of progression to severe disease (odds ratio [OR], 4.20; 95% confidence interval [95CI%], 3.46-5.09) and death (OR, 3.71; 95%CI, 1.63-8.44). Neutrophilia at admission was also found to be significantly associated with increased odd of progression to severe disease (OR, 7.99; 95%CI, 1.77-36.14) and death (OR, 7.87; 95%CI, 1.75-35.35). Subgroup analysis revealed that COVID-19 patients with severe lymphopenia (<0.5 x10×9/L) had 12-fold increased odds of in-hospital mortality. CONCLUSION: Admission lymphopenia and neutrophilia are associated with poor outcomes in patients with COVID-19. Regular monitoring and early and even more aggressive intervention shall hence be advisable in patients with low lymphocyte and high neutrophil counts. These variables may be useful in risk stratification models.


Subject(s)
Coronavirus Infections/mortality , Leukocyte Disorders/congenital , Lymphopenia/complications , Pandemics , Pneumonia, Viral/mortality , Betacoronavirus , COVID-19 , Coronavirus Infections/complications , Disease Progression , Global Health , Humans , Leukocyte Disorders/complications , Leukocyte Disorders/epidemiology , Lymphopenia/epidemiology , Pneumonia, Viral/complications , Risk Factors , SARS-CoV-2 , Survival Rate/trends
5.
Diagnosis (Berl) ; 7(4): 385-386, 2020 Nov 18.
Article in English | MEDLINE | ID: covidwho-605555

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), shares similarities with the former SARS outbreak, which was caused by SARS-CoV-1. SARS was characterized by severe lung injury due to virus-induced cytopathic effects and dysregulated hyperinflammatory state. COVID-19 has a higher mortality rate in men both inside and outside China. In this opinion paper, we describe how sex-specific immunobiological factors and differences in angiotensin converting enzyme 2 (ACE2) expression may explain the increased severity and mortality of COVID-19 in males. We highlight that immunomodulatory treatment must be tailored to the underlying immunobiology at different stages of disease. Moreover, by investigating sex-based immunobiological differences, we may enhance our understanding of COVID-19 pathophysiology and facilitate improved immunomodulatory strategies.


Subject(s)
Coronavirus Infections/immunology , Coronavirus Infections/mortality , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Angiotensin-Converting Enzyme 2 , Animals , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , CD4 Lymphocyte Count/statistics & numerical data , COVID-19 , Coronavirus Infections/therapy , Coronavirus Infections/virology , Cytokines/metabolism , Female , Humans , Immunomodulation , Interferon-alpha/drug effects , Interferon-alpha/immunology , Lymphopenia/mortality , Male , Membrane Glycoproteins/genetics , Mice , Models, Animal , Pandemics , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , SARS-CoV-2 , Sex Factors , Toll-Like Receptor 7/genetics
7.
Am J Emerg Med ; 38(9): 1722-1726, 2020 09.
Article in English | MEDLINE | ID: covidwho-382112

ABSTRACT

Coronavirus disease 2019 (COVID-19) infection has now reached a pandemic state, affecting more than a million patients worldwide. Predictors of disease outcomes in these patients need to be urgently assessed to decrease morbidity and societal burden. Lactate dehydrogenase (LDH) has been associated with worse outcomes in patients with viral infections. In this pooled analysis of 9 published studies (n = 1532 COVID-19 patients), we evaluated the association between elevated LDH levels measured at earliest time point in hospitalization and disease outcomes in patients with COVID-19. Elevated LDH levels were associated with a ~6-fold increase in odds of developing severe disease and a ~16-fold increase in odds of mortality in patients with COVID-19. Larger studies are needed to confirm these findings.


Subject(s)
Betacoronavirus , Coronavirus Infections/enzymology , L-Lactate Dehydrogenase/blood , Pandemics , Pneumonia, Viral/enzymology , Biomarkers/blood , C-Reactive Protein/metabolism , COVID-19 , Coronavirus Infections/epidemiology , Global Health , Humans , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Severity of Illness Index , Survival Rate/trends
8.
Clin Chim Acta ; 507: 167-173, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-125379

ABSTRACT

Early clinical evidence suggests that severe cases of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are frequently characterized by hyperinflammation, imbalance of renin-angiotensin-aldosterone system, and a particular form of vasculopathy, thrombotic microangiopathy, and intravascular coagulopathy. In this paper, we present an immunothrombosis model of COVID-19. We discuss the underlying pathogenesis and the interaction between multiple systems, resulting in propagation of immunothrombosis, which through investigation in the coming weeks, may lead to both an improved understanding of COVID-19 pathophysiology and identification of innovative and efficient therapeutic targets to reverse the otherwise unfavorable clinical outcome of many of these patients.


Subject(s)
Aldosterone/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Microvessels/immunology , Pneumonia, Viral/immunology , Renin-Angiotensin System/immunology , Thrombophilia/immunology , Thrombosis/immunology , COVID-19 , Coronavirus Infections/physiopathology , Humans , Immunity, Innate/immunology , Inflammation/immunology , Inflammation/physiopathology , Inflammation/virology , Microvessels/physiopathology , Microvessels/virology , Pandemics , Pneumonia, Viral/physiopathology , SARS-CoV-2 , Thrombophilia/physiopathology , Thrombophilia/virology , Thrombosis/physiopathology , Thrombosis/virology
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