With a global tally of more than 500 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections to date, there are growing concerns about the post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Recent studies suggest that exaggerated immune responses are key determinants of the severity and outcomes of the initial SARS-CoV-2 infection as well as subsequent PASC. The complexity of the innate and adaptive immune responses in the acute and post-acute period requires in-depth mechanistic analyses to identify specific molecular signals as well as specific immune cell populations which promote PASC pathogenesis. In this review, we examine the current literature on mechanisms of immune dysregulation in severe COVID-19 and the limited emerging data on the immunopathology of PASC. While the acute and post-acute phases may share some parallel mechanisms of immunopathology, it is likely that PASC immunopathology is quite distinct and heterogeneous, thus requiring large-scale longitudinal analyses in patients with and without PASC after an acute SARS-CoV-2 infection. By outlining the knowledge gaps in the immunopathology of PASC, we hope to provide avenues for novel research directions that will ultimately lead to precision therapies which restore healthy immune function in PASC patients. 

Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC)

Eosinophils are bone marrow-derived granulocytes that, under homeostatic conditions, account for as much as 1-3% of peripheral blood leukocytes. During inflammation, eosinophils can rapidly expand and infiltrate inflamed tissues, guided by cytokines and alarmins (such as IL-33), adhesion molecules and chemokines. Eosinophils play a prominent role in allergic asthma and parasitic infections. Nonetheless, they participate in the immune response against respiratory viruses such as respiratory syncytial virus and influenza. Notably, respiratory viruses are associated with asthma exacerbation. Eosinophils release several molecules endowed with antiviral activity, including cationic proteins, RNases and reactive oxygen and nitrogen species. On the other hand, eosinophils release several cytokines involved in homeostasis maintenance and Th2-related inflammation. In the context of SARS-CoV-2 infection, emerging evidence indicates that eosinophils can represent possible blood-based biomarkers for diagnosis, prognosis, and severity prediction of disease. In particular, eosinopenia seems to be an indicator of severity among patients with COVID-19, whereas an increased eosinophil count is associated with a better prognosis, including a lower incidence of complications and mortality. In the present review, we provide an overview of the role and plasticity of eosinophils focusing on various respiratory viral infections and in the context of viral and allergic disease comorbidities. We will discuss the potential utility of eosinophils as prognostic/predictive immune biomarkers in emerging respiratory viral diseases, particularly COVID-19. Finally, we will revisit some of the relevant methods and tools that have contributed to the advances in the dissection of various eosinophil subsets in different pathological settings for future biomarker definition.

/pdf/eosinophils-as-potential-biomarkers-in-respiratory-viral-3d7nc0nc.pdf

Eosinophils as potential biomarkers in respiratory viral infections

Rapid discrimination between viral and bacterial infections in a Point-of-Care setting will improve clinical outcome. Expression of CD64 on neutrophils (neuCD64) increases during bacterial infections, whereas expression of CD169 on classical monocytes(cmCD169) increases during viral infections. The diagnostic value of automated Point-of-Care neuCD64 and cmCD169 analysis was assessed for detecting bacterial and viral infections at the Emergency Department (ED). Additionally, their value as input for machine learning models was studied. A prospective observational cohort study in patients suspected of infection was performed at a ED. A fully automated Point-of-Care flow cytometer measured neuCD64, cmCD169 and additional leukocyte surface markers. Flow cytometry data was gated using the FlowSOM algorithm. Bacterial and viral infections were assessed in standardized clinical care. The sole and combined diagnostic value of the markers was investigated. Clustering based on unsupervised machine learning identified unique patient clusters. Eighty-six patients were included. Thirty-five had a bacterial infection, 30 a viral infection and 21 had no infection. NeuCD64 was increased in bacterial infections (p < 0.001), with an Area Under the Receiver Operating Characteristics (AUROC) of 0.73. CmCD169 was higher in virally infected patients (p < 0.001; AUROC 0.79). Multivariate analyses incorporating additional markers increased the AUROC for bacterial and viral infections to 0.86 and 0.93, respectively. The additional clustering identified four distinctive patient clusters based on infection type and outcome. Automated neuCD64 and cmCD169 determination can discriminate between bacterial and viral infections. These markers can be determined within 30 minutes, allowing fast infection diagnostics in the acute clinical setting.

Point-of-Care neutrophil and monocyte surface markers differentiate bacterial from viral infections at the emergency department within 30 minutes.

Neutrophils are important players in COVID-19, contributing to tissue damage by release of inflammatory mediators, including reactive oxygen species (ROS) and neutrophil elastase. Longitudinal studies on the effects of COVID-19 on neutrophil phenotype and function are scarce. Here, we longitudinally investigated the phenotype and degranulation of neutrophils in COVID-19 patients (28 non-hospitalized and 35 hospitalized patients) compared to 17 healthy donors (HDs). We assessed phenotype, degranulation, CXCL8 (IL-8) release and ROS generation within 8 days, at one or six month(s) after COVID-19 diagnosis. For degranulation and ROS production, we stimulated neutrophils, either with single-stranded RNA (ssRNA) and tumor necrosis factor (TNF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) and N-Formylmethionyl-leucyl-phenylalanine (fMLP). During active COVID-19, neutrophils from hospitalized patients were more immature than from HDs and were impaired in degranulation and ROS generation, while neutrophils from non-hospitalized patients only demonstrated reduced CD66b+ granule release and ROS production. Baseline CD63 expression, indicative of primary granule release, and CXCL8 production by neutrophils from hospitalized patients were elevated for up to six months. These findings show that patients hospitalized due to COVID-19, but not non-hospitalized patients, demonstrated an aberrant neutrophil phenotype, degranulation, CXCL8 release and ROS generation that partially persists up to six months after infection. This article is protected by copyright. All rights reserved.

Aberrant neutrophil degranulation in hospitalized patients with COVID-19 partially remains for six months.

Abstract Objectives: The number of geriatric hip fracture patients is high and expected to rise in the coming years, and many are frail and at risk for adverse outcomes. Early identification of high-risk patients is crucial to balance treatment and optimize outcome, but remains challenging. Previous research in patients with multitrauma suggested that neutrophil phenotype analysis could aid in early identification of high-risk patients. This pilot study investigated the feasibility and clinical value of neutrophil phenotype analysis in geriatric patients with a hip fracture. Methods: A prospective study was conducted in a regional teaching hospital in the Netherlands. At the emergency department, blood samples were collected from geriatric patients with a hip fracture and analyzed using automated flow cytometry. Flow cytometry data were processed using an automated clustering algorithm. Neutrophil activation data were compared with a healthy control cohort. Neutrophil phenotype categories were assessed based on two-dimensional visual assessment of CD16/CD62L expression. Results: Blood samples from 45 geriatric patients with a hip fracture were included. Neutrophils showed an increased activation profile and decreased responsiveness to formyl peptides when compared to healthy controls. The neutrophil phenotype of all patients was categorized. The incidence of severe adverse outcome was significantly different between the different categories (P = 0.0331). Moreover, patients with neutrophil phenotype category 0 developed no severe adverse outcomes. Conclusions: Using point-of-care fully automated flow cytometry to analyze the neutrophil compartment in geriatric hip fracture patients is feasible and holds clinical value in determining patients at risk for adverse outcome. This study is a first step toward immuno-based precision medicine for identifying geriatric hip fracture patients that are deemed fit for surgery.

Identification of neutrophil phenotype categories in geriatric hip fracture patients aids in personalized medicine

Introduction Neutrophil and eosinophil activation and its relation to disease severity has been understudied in primary care patients with COVID-19. In this study, we investigated whether the neutrophil and eosinophil compartment were affected in primary care patients with COVID-19. Methods COVID-19 patients, aged ≥ 40 years with cardiovascular comorbidity presenting to the general practitioner with substantial symptoms, partaking in the COVIDSat@Home study between January and April 2021, were included. Blood was drawn during and 3 to 6 months after active COVID-19 disease and analyzed by automated flow cytometry, before and after stimulation with a formyl-peptide (fNLF). Mature neutrophil and eosinophil markers at both time points were compared to healthy controls. A questionnaire was conducted on disease symptoms during and 3 to 6 months after COVID-19 disease. Results The blood of 18 COVID-19 patients and 34 healthy controls was analyzed. During active COVID-19 disease, neutrophils showed reduced CD10 (p = 0.0360), increased CD11b (p = 0.0002) and decreased CD62L expression (p < 0.0001) compared to healthy controls. During active COVID-19 disease, fNLF stimulated neutrophils showed decreased CD10 levels (p < 0.0001). Three to six months after COVID-19 disease, unstimulated neutrophils showed lowered CD62L expression (p = 0.0003) and stimulated neutrophils had decreased CD10 expression (p = 0.0483) compared to healthy controls. Both (un)stimulated CD10 levels increased 3 to 6 months after active disease (p = 0.0120 and p < 0.0001, respectively) compared to during active disease. Eosinophil blood counts were reduced during active COVID-19 disease and increased 3 to 6 months after infection (p < 0.0001). During active COVID-19, eosinophils showed increased unstimulated CD11b (p = 0.0139) and decreased (un)stimulated CD62L expression (p = 0.0036 and p = 0.0156, respectively) compared to healthy controls. Three to six months after COVID-19 disease, (un)stimulated eosinophil CD62L expression was decreased (p = 0.0148 and p = 0.0063, respectively) and the percentage of CD11bbright cells was increased (p = 0.0083 and p = 0.0307, respectively) compared to healthy controls. Conclusion Automated flow cytometry analysis reveals specific mature neutrophil and eosinophil activation patterns in primary care patients with COVID-19 disease, during and 3 to 6 months after active disease. This suggests that the neutrophil and eosinophil compartment are long-term affected by COVID-19 in primary care patients. This indicates that these compartments may be involved in the pathogenesis of long COVID.

/pdf/neutrophil-and-eosinophil-responses-remain-abnormal-for-2n38f79l.pdf

Neutrophil and Eosinophil Responses Remain Abnormal for Several Months in Primary Care Patients With COVID-19 Disease

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Neutrophil and Eosinophil Responses Remain Abnormal for Several Months in Primary Care Patients With COVID-19 Disease