Haematological manifestations of COVID-19: From cytopenia to coagulopathy.

Emerging data from the management of patients with coronavirus disease 2019 (COVID-19) suggests multi-systemic involvement, including the hemopoietic system. The haematological manifestations of COVID-19 include blood count anomalies notably lymphopenia and neutrophilia which are of prognostic significance. Hyperferritinemia and elevated lactate dehydrogenase have also been associated with increased mortality. Furthermore, there is considerable evidence of a distinct coagulopathy associated with COVID-19 characterised by elevated D-dimers and an increased risk of thrombotic events. This comprehensive review summarises the latest evidence from published studies and discusses the implications of the various haematological manifestations of COVID-19 with a view to guiding clinical management and risk stratification in this rapidly evolving pandemic.

Neutrophilia and mortality in women with uterine carcinosarcoma.

OBJECTIVE: The objective of this study was to investigate the relationship between pre-treatment absolute neutrophil count and clinical outcomes in patients with uterine carcinosarcoma. METHODS: In an Institutional Review Board approved, retrospective cohort study of 103 patients with uterine carcinosarcoma, the pre-treatment absolute neutrophil count data were obtained from the medical records, along with clinical, pathologic, treatment, and outcome data. Kaplan-Meier survival estimates were calculated and compared by the log rank test. Univariable and multivariable Cox proportional hazard regression models were used to examine the relationship of pre-treatment absolute neutrophil count with progression-free survival and overall survival. RESULTS: Uterine carcinosarcoma patients in the highest quartile of pre-treatment absolute neutrophil count had significantly reduced progression-free survival (p<0.001, log rank test), and overall survival (p<0.001, log rank test), compared with patients in the lower absolute neutrophil count quartiles. On multivariable analysis, high absolute neutrophil count was an independent poor prognostic factor for disease recurrence, HR 2.97 (95% CI 1.35 to 6.53, p=0.007) for highest versus lowest quartile absolute neutrophil count, and for mortality, HR 4.43 (95% CI 1.64 to 12.00, p= 0.003). CONCLUSIONS: High pre-treatment absolute neutrophil count is an independent poor prognostic factor in patients with uterine carcinosarcoma and may be useful as a potential biomarker in clinical trials. The mechanistic relationship of neutrophilia and uterine carcinosarcoma progression merits further investigation.

ALS blood expression profiling identifies new biomarkers, patient subgroups, and evidence for neutrophilia and hypoxia.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a debilitating disease with few treatment options. Progress towards new therapies requires validated disease biomarkers, but there is no consensus on which fluid-based measures are most informative. METHODS: This study analyzed microarray data derived from blood samples of patients with ALS (n = 396), ALS mimic diseases (n = 75), and healthy controls (n = 645). Goals were to provide in-depth analysis of differentially expressed genes (DEGs), characterize patient-to-patient heterogeneity, and identify candidate biomarkers. RESULTS: We identified 752 ALS-increased and 764 ALS-decreased DEGs (FDR < 0.10 with > 10% expression change). Gene expression shifts in ALS blood broadly resembled acute high altitude stress responses. ALS-increased DEGs had high exosome expression, were neutrophil-specific, associated with translation, and overlapped significantly with genes near ALS susceptibility loci (e.g., IFRD1, TBK1, CREB5). ALS-decreased DEGs, in contrast, had low exosome expression, were erythroid lineage-specific, and associated with anemia and blood disorders. Genes encoding neurofilament proteins (NEFH, NEFL) had poor diagnostic accuracy (50-53%). However, support vector machines distinguished ALS patients from ALS mimics and controls with 87% accuracy (sensitivity: 86%, specificity: 87%). Expression profiles were heterogeneous among patients and we identified two subgroups: (i) patients with higher expression of IL6R and myeloid lineage-specific genes and (ii) patients with higher expression of IL23A and lymphoid-specific genes. The gene encoding copper chaperone for superoxide dismutase (CCS) was most strongly associated with survival (HR = 0.77; P = 1.84e-05) and other survival-associated genes were linked to mitochondrial respiration. We identify a 61 gene signature that significantly improves survival prediction when added to Cox proportional hazard models with baseline clinical data (i.e., age at onset, site of onset and sex). Predicted median survival differed 2-fold between patients with favorable and risk-associated gene expression signatures. CONCLUSIONS: Peripheral blood analysis informs our understanding of ALS disease mechanisms and genetic association signals. Our findings are consistent with low-grade neutrophilia and hypoxia as ALS phenotypes, with heterogeneity among patients partly driven by differences in myeloid and lymphoid cell abundance. Biomarkers identified in this study require further validation but may provide new tools for research and clinical practice.

Decreased soluble RAGE in neutrophilic asthma is correlated with disease severity and RAGE G82S variants.

The advanced glycosylation end product-specific receptor (RAGE) has been demonstrated to be an important mediator of asthma pathogenesis. The soluble isoform of RAGE (sRAGE) acts as a 'decoy' to sequester RAGE ligands, and thus prevents their binding to the receptor. A number of reports have linked deficiency of sRAGE to the severity and outcomes of various human diseases, and association with RAGE G82S variants. However, whether sRAGE levels are increased or decreased in asthmatic patients is unclear. The aim of the present study was to determine plasma sRAGE levels in different asthma phenotypes and associations of plasma sRAGE levels with RAGE G82S variants. A total of 85 neutrophilic and 109 non­neutrophilic newly diagnosed asthmatic patients, and 118 healthy controls, were recruited. Plasma sRAGE levels were measured by ELISA analysis. RAGE G82S genotypes were detected using the Sanger sequencing method. Plasma sRAGE levels were decreased in neutrophilic asthmatics (443.67±208.9 pg/ml) and increased in non­neutrophilic asthmatics (677.63±300.75 pg/ml) compared with healthy controls (550.02±300.83 pg/ml) (P<0.001). Plasma sRAGE levels were positively correlated with FEV1% predicted (FEV1% Pre) (rp=0.258; P=0.023) in neutrophilic asthmatics. The frequency of G82S genotypes was significantly different between neutrophilic and non­neutrophilic asthmatics (P=0.009). Neutrophilic asthmatics with genotypes A/G or A/A (389.83±150.37 and 264.59±161.74 pg/ml, respectively) had significantly decreased sRAGE levels compared with the G/G genotype (498.64±235.37 pg/ml) (P=0.022). Those with the A/G and A/A genotype (60.14±22.36%) displayed a trend toward lower FEV1% Pre compared with those with the G/G genotype (64.51±27.37%). No significant difference in sRAGE levels or an association with FEV1% Pre was observed between the different genotypes in non­neutrophilic asthmatics. In conclusion, the results of the present study indicated that plasma sRAGE levels are altered in different asthma inflammatory phenotypes. Plasma sRAGE may be a biomarker of asthma severity and may be associated with G82S gene variants in neutrophilic asthmatics.

The Significance of Pretreatment Thrombocytosis and Its Association With Neutrophilia in Patients With Surgically Treated Endometrial Cancer.

OBJECTIVE: The aim of this study was to investigate the prognostic significance of a pretreatment thrombocytosis and its association with neutrophilia in patients with surgically treated endometrial cancer. METHODS: The baseline characteristics and outcome data of 508 patients with surgically treated endometrial cancer between January 2000 and December 2010 were collected and retrospectively reviewed. The patients were separated into 4 groups according to their platelet counts and the neutrophil counts, and the progression-free and overall survival rates of the 4 groups were compared. A Cox proportional hazards regression model was used to explore the independent prognostic factors. RESULTS: Pretreatment thrombocytosis was found to be associated with advanced stage (P = 0.0186), nonendometrioid histology (P = 0.0139), a deeper myometrial invasion (P = 0.0103), lymphovascular space involvement (P = 0.0404), cervical involvement (P = 0.004), positive peritoneal cytology (P = 0.0198), lymph node metastasis (P = 0.0301), and more frequent treatment failure (P = 0.0006). Multivariate analysis demonstrated that an older age (hazard ratio [HR], 2.54; 95% confidence interval [CI], 1.46-4.51; P = 0.0009), advanced clinical stage (HR, 5.27; 95% CI, 2.94-9.86; P < 0.0001), lymphovascular space involvement (HR, 3.37; 95% CI, 1.74-7.07; P = 0.0002), and pretreatment thrombocytosis (HR, 4.99; 95% CI, 2.47-9.39; P < 0.0001) were significant predictors of survival. When examined according to clinical stage, pretreatment thrombocytosis was prognostically significant only in patients with stage III-IV disease. The neutrophil count in patients who display thrombocytosis was significantly greater than that observed in patients without thrombocytosis (median, 6702 vs 4406/µL; P < 0.0001). Moreover, patients who displayed both thrombocytosis and neutrophilia had significantly shorter survival than that in those with either thrombocytosis or neutrophilia alone. CONCLUSIONS: Presence of thrombocytosis at the time of the initial diagnosis is an independent predictor of shorter survival in patients with advanced-stage (stages III-IV) endometrial cancer. Moreover, pretreatment thrombocytosis and concurrent neutrophilia are an independent predictor of shorter survival regardless of clinical stage.

Leukocytosis and neutrophilia predicts outcome in anal cancer.

OBJECTIVE: Leukocytosis and neutrophilia could be the tip of the iceberg in the inflammatory tumor microenvironment. We aimed to validate their prognostic significance in a cohort of patients treated with definitive chemoradiation for anal squamous cell carcinoma (SCC). MATERIALS & METHODS: Clinical records from all consecutive patients treated in a single institution between 2006 and 2016 with curative-intent radiotherapy were retrospectively analyzed. Leukocytosis and neutrophilia, defined as leukocyte or neutrophil count over 10,000 and 7500/mm3, respectively, were studied in terms of overall survival (OS), progression (PFS), locoregional (LFS) and distant (DFS)-free survival. RESULTS: We identified 103 non-metastatic HIV-negative patients, with concurrent chemotherapy use in 78%. Twelve and 8% displayed baseline leukocytosis and neutrophilia, respectively. Estimated 3-year OS and PFS were 88% and 67%, respectively. In univariate analysis, both leukocytosis and neutrophilia were strongly associated with inferior OS, PFS, LFS and DFS (p<0.01). In multivariate analysis, leukocytosis and neutrophilia remained strongly associated with patient outcome (p<0.01), independently from tumor T and N-stage. Anemia was an independent predictor of worse OS and PFS, while chemoradiation overall treatment time below 50days improved PFS. CONCLUSION: Leukocytosis and neutrophilia are strong prognostic factors for OS, PFS, LFS and DFS in anal cancer treated with chemoradiation. These biomarkers could help identify patients with higher risk of tumor relapse that require treatment intensification.

Eosinopenia as a Predictive Factor of the Short-Term Risk of Mortality and Infection after Acute Cerebral Infarction.

BACKGROUND: Eosinopenia has been shown to be a prognostic factor in bacteremia, chronic obstructive pulmonary disease, and myocardial infarction, but studies focusing on cerebral infarction are lacking. METHODS: We conducted a retrospective study of 405 patients admitted to the Asahi General Hospital from June 2011 to September 2014 with a diagnosis of cerebral infarction within 24 hours after symptom onset. Differences in mortality, mortality associated with infection, and the prevalence of infection within 2 months of hospital admission were assessed between patients with and without eosinopenia at presentation. RESULTS: Patients with eosinopenia had a significantly higher mortality rate (hazard ratio (HR) 2.54, 95% confidence interval (CI) 1.17-5.21, P = .01), mortality associated with infection (HR 28.7, 95% CI 4.9-542.2, P <.0001), and an increased prevalence of infection (HR 1.83, 95% CI 1.12-2.89, P = .01) than patients without eosinopenia. Patients with neutrophilia and eosinopenia showed a significantly higher mortality rate than patients without neutrophilia (HR 3.15, 95% CI 1.40-6.92, P = .007), whereas patients with neutrophilia without eosinopenia showed no significant difference in mortality compared with patients without neutrophilia (HR 1.57, 95% CI .56-3.93, P = .37). Eosinopenia was a significant risk factor in 2-month mortality rate in multivariate analyses (HR 2.34, 95% CI 1.05-4.95, P = .04). CONCLUSIONS: Eosinopenia is a novel predictive factor for complications after acute cerebral infarction. Stroke patients with eosinopenia should be monitored carefully for infection.

Acute bacterial infection negatively impacts cancer specific survival of colorectal cancer patients.

AIM: To assess the impact of bacterial infections on cancer-specific survival in patients with colorectal cancer. METHODS: This was a retrospective cohort study of colorectal cancer patients treated at the A.C. Camargo Cancer Center between January 2006 and April 2010. The presence of bacterial infection during cancer treatment, or up to one year after, was confirmed by laboratory tests or by the physician. Infections of the urinary, respiratory or digestive tracts, bloodstream, skin or surgical site were defined by testing within a single laboratory. Criteria for exclusion from the study were: chronically immunosuppressed patients; transplant patients (due to chronic immunosuppression); human immunodeficiency virus carriers; chronic use of corticosteroids or other immunosuppressive drugs; patients with autoimmune disease or primary immunodeficiency; known viral or parasitic infections. Patients with infections that did not require hospitalization were not included in the study because of the difficulty of collecting and tracking data related to infectious processes. In addition, patients hospitalized for pulmonary thromboembolism, stroke, acute myocardial infarction, uncontrolled diabetes, malignant hypercalcemia or other serious non-infectious complications not directly related to infection were also excluded. Survival curves were plotted using the Kaplan-Meier method, and log-rank tests (univariate analysis) and a Cox test assuming a proportional hazards model (multivariate analysis) were performed to examine associations between clinical history and characteristics of infection with cancer-specific survival. RESULTS: One-hundred and six patients with colorectal cancer were divided into two groups based on the presence or absence of bacterial infection. Patient ages ranged from 23 to 91 years, with a median of 55 years. The majority of patients were male (57/106, 53.77%) with stage III colorectal cancer (45/106, 44.11%). A total of 86 bacteriologic events were recorded. Results indicate that the presence and number of infections during or after the end of treatment were associated with poorer-cancer specific survivals (P = 0.02). Elevated neutrophil counts were also associated with poorer cancer-specific survival (P = 0.02). Analysis of patient age revealed that patients > 65 years of age had a poorer cancer-specific survival (P = 0.04). A multivariate analysis demonstrated that infection was an independent predictor of poor survival (HR = 2.62, 95%CI: 1.26-5.45; P = 0.01) along with advanced clinical staging (HR = 2.63, 95%CI: 1.08-6.39; P = 0.03). CONCLUSION: Infection and high neutrophil counts are associated with a poorer cancer-specific survival in colorectal cancer patients.

Functional characterization of natural killer cells in type I leukocyte adhesion deficiency.

In this study, we analyzed IL-2-activated polyclonal natural killer (NK) cells derived from 2 patients affected by leukocyte adhesion deficiency type I (LAD1), an immunodeficiency characterized by mutations of the gene coding for CD18, the beta subunit shared by major leukocyte integrins. We show that LAD1 NK cells express normal levels of various triggering NK receptors (and coreceptors) and that mAb-mediated engagement of these receptors results in the enhancement of both NK cytolytic activity and cytokine production. Moreover, these activating NK receptors were capable of recognizing their specific ligands on target cells. Thus, LAD1 NK cells, similarly to normal NK cells, were capable of killing most human tumor cells analyzed and produced high amounts of IFN-gamma when cocultured in presence of target cells. Murine target cells represented a common exception, as they were poorly susceptible to LAD1 NK cells. Finally, LAD1 NK cells could efficiently kill or induce maturation of monocyte-derived immature dendritic cells (DCs). Altogether our present study indicates that in LAD1 patients, 3 important functions of NK cells (eg, cytotoxicity, IFN-gamma production, and DC editing) are only marginally affected and provides new insight on the cooperation between activating receptors and LFA-1 in the induction of NK cell activation and function.

Hyperviscosity as a complication in a variety of disorders.

For a considerable time, hyperviscosity syndrome has been widely recognized as a serious manifestation of polycythemia and plasma cell dyscrasia. In this article a number of conditions will be considered in which the association with hyperviscosity has been more recently recognized and is less widely known. These conditions are hyperleukocytosis, retinoic acid therapy, and connective tissue disease such as rheumatoid arthritis. The essential problems in the first two are the hugely elevated white cell count (WCC) and the mechanical properties of the leukocytes, in other words, their relatively poor deformability and their adhesiveness for the endothelium. In the last, the essential problem is hugely elevated plasma viscosity due to immunocomplexes. They lead to increased flow resistance, especially in the microvessels, abnormal flow, and significant clinical symptoms. The details of the causes of the hyperviscosity, the symptoms that result, and the forms of treatment are discussed.

Peripheral blood lymphopenia and neutrophilia in children with severe respiratory syncytial virus disease.

It is not known why respiratory syncytial virus (RSV) is associated with prolonged sequelae in many children. Measles virus (also a paramyxovirus), acute stress in sepsis, and cardiac bypass all cause lymphopenia. Using a retrospective analysis of records of children in Bristol with RSV infections over 5 years, we found that children with RSV had lower lymphocyte counts than unstressed, stable children prior to cardiac surgery. Children who required intensive care had the lowest lymphocyte counts. Neutrophil counts were raised in RSV-infected children. These data may offer an insight into pathological mechanisms, and suggest new research avenues.