scholarly journals Impairment of Neutrophil Functions and Homeostasis in COVID-19 Patients: Association With Disease Severity

2021 ◽  
Author(s):  
Chloé Loyer ◽  
Arnaud Lapostolle ◽  
Tomas Urbina ◽  
Alexandre Elabbadi ◽  
Jean-Rémi Lavillegrand ◽  
...  
Keyword(s):  
Disease Severity ◽  
Oxidative Burst ◽  
Vascular Inflammation ◽  
Severe Disease ◽  
Fatal Outcome ◽  
Endothelial Activation ◽  
Endothelial Damage ◽  
Community Acquired Pneumonia ◽  
Blood Neutrophils ◽  
Severe Community Acquired Pneumonia

Abstract Background Emerging data based on analyses of peripheral and pulmonary immune responses to SARS-CoV-2 increasingly suggest that a dysregulated immune response underpins the development of severe disease in COVID-19 patients. Neutrophils are key components of early innate immunity that, if not tightly regulated, contribute to uncontrolled systemic inflammation. We sought to decipher the role of neutrophil phenotypes, functions, and homeostasis in COVID-19 disease severity and outcome. Methods This longitudinal study compares study compares peripheral whole-blood neutrophils from 90 COVID-19 ICU patients with those of 22 SARS-CoV-2 – patients hospitalized for severe community-acquired pneumonia (CAP) and 38 healthy controls. We also assessed correlations between these phenotypic and functional indicators and markers of endothelial damage as well as disease severity. Results At ICU admission, the circulating neutrophils of the COVID-19 patients showed continuous basal hyperactivation not seen in CAP patients, associated with higher circulating levels of soluble E- and P-selectin, which reflect platelet and endothelial activation. Furthermore, COVID-19 patients had expanded aged-angiogenic and reverse transmigrated neutrophil subsets — both involved in endothelial dysfunction and vascular inflammation. Simultaneously, COVID-19 patients had significantly lower levels of neutrophil oxidative burst in response to bacterial formyl peptide, an abnormality that was greater in superinfected than non-superinfected COVID-19 patients. Moreover, patients dying of COVID-19 had significantly higher expansion of aged-angiogenic neutrophil subset and greater impairment of oxidative burst response than survivors. Conclusions These data suggest that neutrophil exhaustion may play a central role in the pathogenesis of severe COVID-19 and identify angiogenic neutrophils as a potentially harmful subset involved in fatal outcome.

scholarly journals Proadrenomedullin Predicts Severe Disease in Children with Suspected Community-Acquired Pneumonia

2020 ◽  
Author(s):  
Todd A Florin ◽  
Lilliam Ambroggio ◽  
Cole Brokamp ◽  
Yin Zhang ◽  
Eric S Nylen ◽  
...  
Keyword(s):  
Disease Severity ◽  
Odds Ratio ◽  
Severe Disease ◽  
Antibiotic Use ◽  
Supplemental Oxygen ◽  
Community Acquired Pneumonia ◽  
C Reactive Protein ◽  
Chest Drainage ◽  
Reactive Protein ◽  
Complicated Pneumonia

Abstract Background Proadrenomedullin (proADM), a vasodilatory peptide with antimicrobial and anti-inflammatory properties, predicts severe outcomes in adults with community-acquired pneumonia (CAP) to a greater degree than C-reactive protein and procalcitonin. We evaluated the ability of proADM to predict disease severity across a range of clinical outcomes in children with suspected CAP. Methods We performed a prospective cohort study of children 3 months to 18 years with CAP in the emergency department (ED). Disease severity was defined as: mild (discharged home), mild-moderate (hospitalized but not moderate-severe or severe), moderate-severe (e.g., hospitalized with supplemental oxygen, broadening of antibiotics, complicated pneumonia), and severe (e.g., vasoactive infusions, chest drainage, severe sepsis). Outcomes were examined using proportional odds logistic regression within the cohort with suspected CAP and in a subset with radiographic CAP. Results Among 369 children, median proADM increased with disease severity [mild: median 0.53 nmol/L (IQR:0.43, 0.73), mild-moderate: 0.56 nmol/L (IQR:0.45, 0.71), moderate-severe: 0.61 nmol/L (IQR:0.47, 0.77), severe: 0.70 nmol/L (IQR:0.55, 1.04) (p=.002)]. ProADM was significantly associated with increased odds of developing severe outcomes (suspected CAP odds ratio (OR) 1.68 [95% CI, 1.2, 2.36], radiographic CAP OR 2.11 [95% CI, 1.36, 3.38]) adjusted for age, fever duration, antibiotic use, and pathogen. ProADM had an area under the ROC curve (AUC) of 0.64 (95%CI, 0.56,0.72) in those with suspected CAP and AUC 0.77 (95% CI, 0.68,0.87) in radiographic CAP. Conclusions ProADM was associated with severe disease and discriminated moderately well children who developed severe disease from those who did not, particularly in radiographic CAP.

scholarly journals TNFA and IL10 Polymorphisms and IL-6 and IL-10 Levels Influence Disease Severity in Influenza A(H1N1)pdm09 Virus Infected Patients

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1914
Author(s):  
Kalichamy Alagarasu ◽  
Himanshu Kaushal ◽  
Pooja Shinde ◽  
Mahadeo Kakade ◽  
Urmila Chaudhary ◽  
...  
Keyword(s):  
Disease Severity ◽  
Influenza A ◽  
Severe Disease ◽  
Fatal Outcome ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Mild Disease ◽  
Pdm09 Virus ◽  
Potential Biomarker ◽  
Influenza A H1n1

Cytokines are key modulators of immune response, and dysregulated production of proinflammatory and anti-inflammatory cytokines contributes to the pathogenesis of influenza A(H1N1)pdm09 virus infection. Cytokine production is impacted by single nucleotide polymorphisms (SNPs) in the genes coding for them. In the present study, SNPs in the IL6, TNFA, IFNG, IL17A, IL10, and TGFB were investigated for their association with disease severity and fatality in influenza A(H1N1)pdm09-affected patients with mild disease (n = 293) and severe disease (n = 86). Among those with severe disease, 41 patients had fatal outcomes. In a subset of the patients, levels of IL-2, IL-4, IL-6, IL-10, TNF, IFN-γ, and IL-17 were assayed in the plasma for their association with severe disease. The frequency of TNFA rs1800629 G/A allele was significantly higher in severe cases and survived severe cases group compared to that of those with mild infection (OR with 95% for mild vs. severe cases 2.95 (1.52–5.73); mild vs. survived severe cases 4.02 (1.84–8.82)). IL10 rs1800896-rs1800872 G-C haplotype was significantly lower (OR with 95% 0.34 (0.12–0.95)), while IL10 rs1800896-rs1800872 G-A haplotype was significantly higher (OR with 95% 12.11 (2.23–76.96)) in fatal cases group compared to that of the mild group. IL-6 and IL-10 levels were significantly higher in fatal cases compared to that of survived severe cases. IL-6 levels had greater discriminatory power than IL-10 to predict progression to fatal outcome in influenza A(H1N1)pdm09 virus-infected patients. To conclude, the present study reports the association of TNFA and IL10 SNPs with severe disease in Influenza A(H1N1)pdm09 virus-infected subjects. Furthermore, IL-6 levels can be a potential biomarker for predicting fatal outcomes in Influenza A(H1N1)pdm09 virus infected subjects.

scholarly journals Endothelial glycocalyx degradation and disease severity in Plasmodium vivax and Plasmodium knowlesi malaria

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bridget E. Barber ◽  
Matthew J. Grigg ◽  
Kim A. Piera ◽  
Youwei Chen ◽  
Timothy William ◽  
...  
Keyword(s):  
Falciparum Malaria ◽  
Disease Severity ◽  
Vivax Malaria ◽  
Severe Disease ◽  
Kidney Injury ◽  
Endothelial Activation ◽  
Endothelial Glycocalyx ◽  
Healthy Controls ◽  
Angiopoietin 2 ◽  
Urinary Glycosaminoglycans

AbstractDegradation of the endothelial glycocalyx is associated with mortality in adult falciparum malaria. However, its role in the pathogenesis of non-falciparum malaria is unknown. In Malaysian patients with knowlesi (n = 200) and vivax (n = 61) malaria, and in healthy controls (n = 50), we measured glycocalyx breakdown products plasma syndecan-1 and urinary glycosaminoglycans, and evaluated correlations with biomarkers of disease severity. Urinary glycosaminoglycans were increased in patients with knowlesi and vivax malaria compared to healthy controls, and in knowlesi malaria were highest in those with severe disease. In knowlesi malaria, plasma syndecan-1 was also highest in those with severe disease, and correlated with markers of endothelial activation (angiopoietin-2, osteoprotegerin, ICAM-1), asymmetric dimethylarginine (ADMA) and impaired microvascular reactivity. Syndecan-1 also correlated with endothelial activation (ICAM-1, angiopoietin-2) and ADMA in vivax malaria. In knowlesi malaria increased syndecan-1 was associated with acute kidney injury, after controlling for age and parasitemia. In knowlesi malaria, the difference in median syndecan-1 between severe and non-severe disease was more marked in females than males. Endothelial glycocalyx degradation is increased in knowlesi and vivax malaria, and associated with disease severity and acute kidney injury in knowlesi malaria. Agents that inhibit glycocalyx breakdown may represent adjunctive therapeutics for severe non-falciparum malaria.

scholarly journals Development and Internal Validation of a Prediction Model to Risk Stratify Children With Suspected Community-Acquired Pneumonia

2020 ◽  
Author(s):  
Todd A Florin ◽  
Lilliam Ambroggio ◽  
Douglas Lorenz ◽  
Andrea Kachelmeyer ◽  
Richard M Ruddy ◽  
...  
Keyword(s):  
Prediction Model ◽  
Disease Severity ◽  
Clinical Judgment ◽  
Severe Disease ◽  
Pediatric Emergency ◽  
Community Acquired Pneumonia ◽  
Positive Pressure ◽  
Internal Validation ◽  
Final Model ◽  
Moderate Disease

Abstract Background Although community-acquired pneumonia (CAP) is one of the most common infections in children, no tools exist to risk stratify children with suspected CAP. We developed and validated a prediction model to risk stratify and inform hospitalization decisions in children with suspected CAP. Methods We performed a prospective cohort study of children aged 3 months to 18 years with suspected CAP in a pediatric emergency department. Primary outcome was disease severity, defined as mild (discharge home or hospitalization for <24 hours with no oxygen or intravenous [IV] fluids), moderate (hospitalization <24 hours with oxygen or IV fluids, or hospitalization >24 hours), or severe (intensive care unit stay for >24 hours, septic shock, vasoactive agents, positive-pressure ventilation, chest drainage, extracorporeal membrane oxygenation, or death). Ordinal logistic regression and bootstrapped backwards selection were used to derive and internally validate our model. Results Of 1128 children, 371 (32.9%) developed moderate disease and 48 (4.3%) severe disease. Severity models demonstrated excellent discrimination (optimism-corrected c-indices of 0.81) and outstanding calibration. Severity predictors in the final model included respiratory rate, systolic blood pressure, oxygenation, retractions, capillary refill, atelectasis or pneumonia on chest radiograph, and pleural effusion. Conclusions We derived and internally validated a score that accurately predicts disease severity in children with suspected CAP. Once externally validated, this score has potential to facilitate management decisions by providing individualized risk estimates that can be used in conjunction with clinical judgment to improve the care of children with suspected CAP.

scholarly journals Simultaneous Depression of Immunological Synapse and Endothelial Injury is Associated with Organ Dysfunction in Community-Acquired Pneumonia

2019 ◽  
Vol 8 (9) ◽  
pp. 1404 ◽  
Author(s):  
Menéndez ◽  
Méndez ◽  
Almansa ◽  
Ortega ◽  
Alonso ◽  
...  
Keyword(s):  
Organ Failure ◽  
Organ Dysfunction ◽  
Immunological Synapse ◽  
Cd40 Ligand ◽  
Endothelial Damage ◽  
Community Acquired Pneumonia ◽  
Histocompatibility Complex ◽  
Polymerase Chain ◽  
Severe Community Acquired Pneumonia ◽  
Digital Polymerase Chain Reaction

Rationale: A depressed expression of antigen presentation is, along with endothelial dysfunction, a recognized signature of severe community-acquired pneumonia (CAP). We aimed to evaluate the expression of a number of genes involved in the immunological synapse in non-critically ill CAP patients with or without organ dysfunction and to profile endothelial biomarkers such as proendothelin-1 (proET1) and proadrenomedullin (proADM). Methods: A nested study in a prospective cohort in CAP patients was performed. Expression levels of major histocompatibility complex class II DR alpha (HLA-DRA), CD40 ligand (CD40LG), CD3E, CD28, and inducible T-cell costimulator (ICOS) were quantified by using droplet digital polymerase chain reaction and endothelial biomarkers by immunofluorescence. Results: Ninety-four patients were included, 44.7% of whom had organ failure in one or more organs. A significant decrease in the expression of the five genes with increased levels of proadrenomedullin (proADM) and proendothelin-1 (proET1) was found in CAP with organ failure. The depressed expression of HLA-DRA (odds ratio (OR), 2.94), CD40LG (OR, 3.90), and CD28 (OR, 3.48) was independently associated with organ failure after adjustment for age, Charlson score, and severity. Conclusions. CAP with organ failure showed depressed expression of immunological synapse genes with increased levels of biomarkers denoting endothelial damage. Simultaneous profiling of immunological and endothelial signatures could help in the early identification of organ failure in CAP and in the implementation of personalized treatment.

scholarly journals Changing epidemiology of melioidosis? A case of acute pulmonary melioidosis with fatal outcome imported from Brazil

2005 ◽  
Vol 133 (5) ◽  
pp. 871-875 ◽  
Author(s):  
H. AARDEMA ◽  
E. M. LUIJNENBURG ◽  
E. F. SALM ◽  
H. A. BIJLMER ◽  
C. E. VISSER ◽  
...  
Keyword(s):  
Fatal Outcome ◽  
Severe Pneumonia ◽  
Human Case ◽  
Community Acquired Pneumonia ◽  
Tropical Regions ◽  
Therapeutic Consequences ◽  
Mycoplasma Pneumonia ◽  
Sporadic Cases ◽  
Severe Community Acquired Pneumonia ◽  
Possible Cause

Melioidosis is an infectious disease caused by Burkholderia pseudomallei. It is endemic in South East Asia and tropical regions of Northern Australia. Sporadic cases have been described elsewhere. In this article we present a case of acute pulmonary melioidosis with fatal outcome imported from Brazil. The most common pathogen causing severe community-acquired pneumonia in Brazil is Streptococcus pneumoniae. Other possible pathogens include Legionella spp., Mycoplasma pneumonia, Gram-negative rods and viruses. There are few reports of melioidosis in the Americas. This article represents the second known human case of melioidosis from Brazil. Recognition of melioidosis as a possible cause of severe pneumonia, even if a patient has not been travelling in a highly endemic area, is important because of the therapeutic consequences. The epidemiology of melioidosis will be reviewed.

scholarly journals Early and High SARS-CoV-2 Neutralizing Antibodies Are Associated with Severity in COVID-19 Patients from India

2021 ◽  
Author(s):  
Shubham Shrivastava ◽  
Sonali Palkar ◽  
Jignesh Shah ◽  
Prajakta Rane ◽  
Sanjay Lalwani ◽  
...  
Keyword(s):  
Disease Severity ◽  
Neutralizing Antibodies ◽  
Wide Spectrum ◽  
Severe Disease ◽  
Fatal Outcome ◽  
Asymptomatic Infection ◽  
Live Virus ◽  
Immune Correlates ◽  
Asymptomatic Individuals ◽  
Time Of Presentation

Patients with SARS-CoV-2 infection have a wide spectrum of clinical presentations, from asymptomatic infection, to mild illness, to severe disease with recovery or fatal outcome. Immune correlates of protection are not yet clear. To understand the association between presence and titers of neutralizing antibodies (NAb) with recovery, we screened 82 COVID-19 patients classified in mild (n = 56) and severe (n = 26) disease groups on different days post onset of disease and 27 viral RNA–positive asymptomatic contacts examined within 1 week of the identification of index cases. Of 26 patients with severe disease, six died and 20 recovered. Anti-SARS-CoV-2 NAb levels in plasma and serum were measured using a plaque reduction neutralization test with live virus. The proportion of asymptomatic and symptomatic infections was 1:7.8 in males and 1:1 in females, with males predominating the severe disease group (21/26, 80.7%). At the time of presentation, NAb positivity and titers were comparable among groups with asymptomatic and mild infections. Notably, patients with severe disease exhibited higher NAb seropositivity and titers (25 of 26, 96.2%; 866 ± 188) than those in the mild category (39 of 56, 69.6%; 199 ± 50, P < 0.0001) and asymptomatic individuals (21 of 27, 77.8%; 124 ± 28, P = 0.0002). Within first 2 weeks of onset, NAb titers were significantly higher among patients with severe disease than those with mild presentation. Our data suggest that irrespective of fatal outcome, progression to disease severity was associated with induction of early and high levels of NAb. In our patient series, clinical disease, severity and fatality were predominantly seen in males. The role of NAbs in immunopathogenesis or protection needs to be defined.

scholarly journals Increased prevalence and clinical impact of hypocalcaemia in severe COVID-19 distinguishes it from other forms of infective pneumonia

2021 ◽  
Author(s):  
Meera Mehta ◽  
Hakim Ghani ◽  
Felix Chua ◽  
Adrian Draper ◽  
Sam Calmonson ◽  
...  
Keyword(s):  
Disease Severity ◽  
Serum Calcium ◽  
Respiratory Infections ◽  
Severe Disease ◽  
Community Acquired Pneumonia ◽  
Host Cells ◽  
World Health ◽  
Level Of Care ◽  
Increased Risk ◽  
Health Organization

Background: Hypocalcaemia has been reported in the context of acute COVID-19, where it has been associated with an increased risk of hospitalisation and disease severity. Calcium is an important intracellular messenger that controls diverse cellular processes. Two other clinically important coronaviruses, SARS-CoV-1 and Middle East respiratory syndrome (MERS)-CoV, can use calcium ions to enter and replicate within host cells. Calcium may therefore be important in the pathophysiology of COVID-19 infection. We sought to investigate whether calcium derangement was a specific feature of COVID-19 that distinguishes it from other infective pneumonias, and its association with disease severity. Methods: We conducted a single centre retrospective study of albumin-corrected serum calcium on adult patients with COVID-19 who presented between March 1st and May 16th 2020. The primary outcome was maximal level of care based on the World Health Organization Clinical Progression Scale for COVID-19. Cases with community acquired pneumonia (CAP) and viral pneumonia (VP) were identified through a clinical database over three intervals (January to February 2018, January to February 2019 and September to December 2019). Results: We analysed data from 506 patients with COVID-19, 95 patients with CAP and 152 patients with VP. Hypocalcaemia (serum calcium <2.2mmol/L) was a specific and common clinical finding in patients with COVID-19 that was not present in other respiratory infections. Calcium levels were significantly lower in those with severe disease. Ordinal regression of risk estimates for categorised care levels showed that baseline hypocalcaemia was incrementally associated with odds ratio of 2.33 for higher level of care, superior to other variables that have previously been shown to predict worse COVID-19 outcome. Serial calcium levels showed improvement by day 7-9 of admission, only in in survivors of COVID-19. Conclusion: Hypocalcaemia may independently predict not only more severe but more progressive disease and warrants detailed prognostic investigation. The fact that decreased serum calcium is observed at the time of clinical presentation in COVID-19, but not other infective pneumonias, suggests that its early derangement is pathophysiological and may influence the deleterious evolution of this disease. If calcium is ultimately shown to be critical to the entry and replication of SARS-CoV-2 in host cells, unravelling how this mechanism could be therapeutically targeted deserves more intensive examination. Trial registration HRA: 20/HRA/2344.

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