Peripheral Neutrophil Counts Research Articles

Clinical characteristics of SARS-CoV-2 Omicron pneumonia in immunocompromised and immunocompetent patients: A retrospective cohort study

ObjectivePrevious studies evaluating the differences in COVID-19 mortality rates between immunocompromised patients and other patient groups have shown conflicting findings. This research aimed to compare the mortality rates of immunocompromised and immunocompetent patients during the Omicron-dominant period of the SARS-CoV-2 pandemic, and to identify factors associated with prognosis. MethodsWe conducted a retrospective analysis of 1085 adult patients (aged ≥18 years) admitted with COVID-19 pneumonia to the China-Japan Friendship Hospital between December 1, 2022, and January 31, 2023. We assessed the prevalence of comorbidities, incidence of co-infections and nosocomial infections, and 30-day mortality. ResultsAmong the 1085 patients, 254 were immunocompromised, and 831 were immunocompetent. Immunocompromised patients had higher rates of non-invasive ventilation use (30.3 % vs. 21.1 %), invasive ventilation (12.2 % vs. 5.3 %), and 30-day mortality (19.7 % vs. 13.7 %) compared to immunocompetent patients. However, overall mortality rates did not significantly differ based on immunocompromised status. Cox regression analysis identified that elevated troponin T (≥0.15 ng/mL), respiratory failure, high lactate dehydrogenase (≥272.5 U/L), elevated D-dimer (≥1.295 mg/L), increased C-reactive protein (≥90 mg/L), elevated interleukin-6 (>11.67 ng/L), high peripheral blood neutrophil count (>9.84 × 10⁹/L), and immunocompromised status were independent predictors of poor COVID-19 prognosis. In the immunocompetent group, current smoking and a history of interstitial lung disease were related to a worse prognosis. ConclusionsCOVID-19 pneumonia due to the Omicron variant may lead to worse outcomes in immunocompromised patients. In immunocompetent patients, careful monitoring is essential for those with respiratory failure, smoking history, or interstitial lung disease to prevent adverse outcomes.

Generalized pustular psoriasis patient with a heterozygous hypomorphic MPO variant refractory to intravenous spesolimab

AbstractGeneralized pustular psoriasis (GPP) is a recurrent and sometimes life‐threatening sterile pustular disease. Because interleukin (IL)‐36 is the central cytokine in disease formation, spesolimab, which interferes with IL‐36 receptor signaling, is highly effective. Here, we report a patient with GPP with a heterozygous hypomorphic MPO variant refractory to intravenous spesolimab. Although spesolimab showed excellent clinical efficacy in resolving pre‐existing pustules and erythema, it did not suppress the emergence of new pustules and erythema, which did not decrease the peripheral blood neutrophil count, therefore bimekizumab, an anti‐IL‐17A/IL‐17F antibody, was administered after the second spesolimab infusion, which resolved the pustules and erythema. We discuss the possible reasons for the resistance mechanism to spesolimab.

Systemic immune-inflammation index values are associated with non-melanoma skin cancers: evidence from the National Health and Nutrition Examination Survey 2010-2018.

The systemic immune-inflammation index (SII), based on peripheral lymphocyte, neutrophil, and platelet counts, has recently been investigated as a prognostic marker in several tumors. However, the SII has rarely been reported in skin cancers. In this study, we aimed to assess the association between SII values and the risk of occurrence of skin cancers. This cross-sectional study was based on National Health and Nutrition Examination Survey data from 2010 to 2018 and involved 32,012 participants. The SII was calculated as the platelet count × neutrophil count/lymphocyte count. A weighted multivariate logistic analysis was conducted to examine the relationship between SII values and the occurrence of skin cancers. In addition, a subgroup analysis and a sensitivity analysis were conducted to identify underlying moderators and the stability of the relationship, respectively. Compared with participants in the lowest quartile of SII values, the odds ratios for non-melanoma skin cancer were 1.650 (95% CI: 1.158-2.352) for participants in the quartile with the highest SII values after multivariate adjustments. In subgroup analyses, we found significant interactions between log-transformed SII values and age (p < 0.001 for interaction), race (p < 0.001 for interaction), education level (p < 0.001 for interaction), marital status (p < 0.001 for interaction), and annual household incomes (p < 0.001 for interaction) in the association with non-melanoma skin cancer. Our findings suggest a positive association between high SII values and skin cancers in the U.S. population. Age, levels of education, marital status, and annual household incomes affect the positive association between high SII values and non-melanoma skin cancers.

Novel neutrophil biology insights underlying atypical chemokine receptor-1/Duffy antigen receptor of chemokines-associated neutropenia.

Atypical chemokine receptor-1 (ACKR1)/Duffy antigen receptor of chemokines (DARC)-associated neutropenia (ADAN; OMIM 611862), previously named benign ethnic neutropenia, and present in two-thirds of individuals identifying as Black in the USA, is associated with mild to moderate decreases in peripheral neutrophil counts that nevertheless do not lead to increased infections. Consequently, recent initiatives have sought to establish normal neutrophil count reference ranges for ADAN, considering it a normal variant rather than a clinical disorder requiring medical intervention. A limited number of studies elucidating the mechanism of neutropenia in ADAN has suggested that neutrophils may redistribute from peripheral blood to the tissues including the spleen: this might explain why ADAN is not associated with increased risks of infection since the total number of neutrophils in the body remains normal. In this review, we critically examine the research underlying the molecular basis of ADAN. Insights into the biology of neutrophils and their trafficking may inform the clinical interpretation of neutropenia in ADAN. The bulk of research suggests that ADAN does not lead to a diminished host defense as do other forms of neutropenia. However, ADAN may lead to increased proinflammatory signaling, with possible implications for senescence of the immune system and predisposition to autoimmunity and cancer.

Predictive value of peripheral neutrophil count on admission for young patients with acute coronary syndrome

ObjectiveThe present study aimed to explore the relationship between neutrophil count on admission and major adverse cardiovascular and cerebrovascular events (MACCE) and left ventricular ejection fraction (LVEF) during hospitalization in young ACS patients, which have rarely been investigated in previous studies. MethodsThis study included 400 young ACS patients (<45 years old) who underwent coronary angiography. According to the median neutrophil count at admission, the patients were divided into two groups. The relationship between neutrophil count and MACCE and LVEF during hospitalization was analyzed by regression analysis. The receiver operating characteristic (ROC) curve and the Youden index was used to determine the optimal cut-off value of neutrophil count. ResultsNeutrophil count at admission was an independent risk factor of in-hospital MACCE (OR: 1.33, 95 % CI: 1.13–1.56, P<0.001) and LVEF <50 % (OR: 1.28, 95 % CI: 1.12–1.47, P<0.001) in young ACS patients.The cutoff value of neutrophil count for predicting the occurrence of in-hospital MACCE was 6.935 × 10^9/L with a sensitivity of 92.1 %, specificity of 59.4 %, and AUC is 0.820 (95 % CI: 0.7587–0.8804, P<0.001), and for identifying the LVEF <50 % was 8.660 × 10^9/L with a sensitivity of 69.8 %, specificity of 76.8 %, and AUC is 0.775 (95 % CI: 0.6997–0.8505, P<0.001). ConclusionThe neutrophil count upon admission is an independent predictor of in-hospital MACCE and LVEF in young ACS patients, giving important information for predicting the poor prognosis of young ACS patients.

Absence of Neutropenia in Patients With Early Exon Nonsense Mutations in ELANE : Clinical Evidence to Support Gene Therapy Approaches for Severe Congenital Neutropenia.

Severe congenital neutropenia is an inherited bone marrow failure disorder characterized by profoundly low neutrophil counts and promyelocytic maturation arrest in bone marrow. Severe congenital neutropenia is most often caused by heterozygous ELANE mutations. In vitro and mouse xenograft studies using CRISPR/Cas9 have shown that introduction of frameshift/nonsense mutations in mutant ELANE may restore neutrophil counts, providing a model for gene therapy. Here, we present 2 children with inherited nonsense mutations in ELANE analogous to those proposed for gene therapy. Their normal peripheral blood neutrophil counts provide support for this approach through human "experiments of nature."

The development of a prediction model based on random survival forest for the prognosis of non- Hodgkin lymphoma: A prospective cohort study in China

Background and objectiveThe pathological staging of non-Hodgkin lymphoma (NHL) is complex, the clinical manifestations are varied, and the prognosis differ considerably. To provide a useful reference for early detection and effective treatment of NHL, we developed a random survival forest (RSF) prognostic model based on machine learning (ML) algorithms using prospective cohort data collected from Chongqing Cancer Hospital from Jan 1, 2017 to Dec 31, 2019 (n = 1449) to compare with the traditional cornerstone method Cox proportional hazards (CPH) model and evaluate the predictability of the model. MethodsPatients were randomly split into a training cohort (TC) and validation cohort (VC) based on 65/35 ratio. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to extracted the important features. And the RSF was modeled to explore the prognostic factors impacting the overall survival (OS) of patients with NHLs in the TC and validated in the VC. The C-index, the Integrated Brier Score (IBS), Kaplan-Meir method, the receiver operating characteristic (ROC) curve, and the area under the ROC curve (AUC) were selected to measure performances and discriminations of the models. In addition, individual survival probability predicted for NHL patients. ResultsAccording to the features extracted by LASSO model and univariable Cox model, 16 variables were selected to develop the RSF model with log-rank splitting rule, which were age, ethnicity, medical insurance, Ann Arbor stage, pathology, targeted-therapy, chemo-therapy, peripheral blood neutrophil count to lymphocyte count ratio (NLR), peripheral blood platelet count to lymphocyte count ratio (PLR), serum lactate dehydrogenase (LDH), CD4/CD8, platelet (PLT), absolute neutrophil count (ANC), lymphocyte (LYM), B-symptoms, and (CPR) were important prognostic factors. Compared to the CPH model (C-index = 0.748, IBS = 0.166), the RSF model (C-index = 0.786, IBS = 0.165) is outperformed in predictability and accuracy. The AUC of the RSF model to estimate the 1-, 3-, and 5-year OS in TC were 0.847, 0.847, and 0.809, respectively; while those in the CPH were 0.816, 0.803, and 0.750, respectively. ConclusionsTo provide practical implications for the implementation of individualized therapy, the study constructed a high-performed RSF model and reveal that it outperformed the traditional model CPH. And the RSF model ranked the risk variables. In addition, we stratified the risk of NHL patients and estimated individual survival probability based on the RSF model.

High peripheral neutrophil and monocyte count distinguishes renal cell carcinoma from renal angiomyolipoma and predicts poor prognosis of renal cell carcinoma

BackgroundThe presence of peripheral inflammatory cells has been linked to the prognosis of cancer. This study aims to investigate the distinct roles of absolute neutrophil count (ANC) and absolute monocyte count (AMC) in differentiating renal cell carcinoma (RCC) from renal angiomyolipoma (RAML), as well as their prognostic significance in RCC. MethodsWe conducted a comprehensive analysis of peripheral immune cell data, clinicopathological data, and tumor characteristics in patients diagnosed with RCC or RAML from January 2015 to December 2021. Receiver operating characteristic (ROC) curves, as well as univariate and multivariate analyses, were employed to assess the diagnostic utility of AMC and ANC in differentiating between RCC and RAML. Kaplan-Meier curve analysis was used to study the survival of RCC patients with different AMC and ANC. The prognostic value of AMC and ANC in RCC was investigated using COX univariate and multivariate analysis. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used for bioinformatic correlation analysis. ResultsA total of 1120 eligible patients were included in the study. The mean preoperative AMC and ANC in patients with RCC were found to be significantly higher compared to those in patients with RAML (P = 0.001 and P < 0.001, respectively). High preoperative AMC and ANC significantly correlated with smoking history, tumor length, gross hematuria, and high T Stage, N stage, and pathological grade. In multivariate analyses, an ANC> 3.205 *10^9/L was identified to be independently associated with the presence of RCC (HR = 1.618, P = 0.008). High AMC and ANC were significantly associated with reduced OS and PFS (P < 0.05), and ANC may be an independent prognostic factor. Public database analysis showed that signature genes of tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) were highly expressed in ccRCC. ConclusionsElevated preoperative ANC and AMC can distinguish RCC from RAML and predict poor prognosis in patients with RCC. Furthermore, the signature genes of TAMs and TANs exhibit high expression levels in clear cell RCC.

#1265 Circulating neutrophils in diabetic kidney disease—the relationship with long-term cardiovascular outcomes

Abstract Background and Aims Neutrophils play important roles in the pathogenesis of cardiovascular inflammation and affects cardiovascular disease (CVD) outcomes. The relationship of circulating neutrophil counts with cardiovascular disease (CVD) and all-cause mortality in patients with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD) remains unclear. Method We retrieved data from 44,494 participants in the National Health and Nutrition Examination Surveys (NHANES) from 2005 to 2020, and investigated the associations between circulating neutrophil counts, kidney functions and CVD mortality in T2DM and DKD patients. Clinical predictive models and risk scores for long-term mortality were constructed. Results Among the cohort of 44,332 patients (18% with T2DM and 82% without T2DM), a total of 2,220 patients were diagnosed with diabetic kidney disease (DKD) and 775 of them experienced mortality (31.5% related to CVD) during a follow-up of 6.18 (range: 5.94-6.42) years. The weighted mean of peripheral neutrophil count level (×109 /L) in DKD participants was 4.98. DKD patients in the highest quintile of neutrophil count exhibited a positive correlation with urine albumin-creatinine ratio (uACR) and a negative association with estimated glomerular filtration rate (eGFR), when compared to those in the lowest quintile. In the multivariate logistic regression analysis with RCS, circulating neutrophil counts showed a U-shaped association with CVD mortality. Neutrophil counts of 3.68 × 109 /L and 3.69 × 109 /L were associated with the lowest risk of CVD mortality and all-cause mortality respectively in DKD patients. Clinical predictive models showed good diagnostic performance for 5- and 10-year CVD mortality-free survival (all ROC AUC values &amp;gt;0.75). Conclusion In this study, higher peripheral neutrophil count was associated with an increased risk of cardiovascular mortality in DKD individuals. Our clinical predictive models may help identify at-risk patients for more aggressive CVD risk factors control.

Abstract 2704: cGAS-STING drives myeloid inflammation in chromosomally unstable esophageal cancer

Abstract Esophageal adenocarcinoma (EAC) is an aggressive disease characterized by chromosomal instability (CIN), whereby cells continuously acquire chromosomal abnormalities that promote therapeutic resistance, immune evasion and metastasis. CIN in cancers also fuels the misplacement of genomic DNA in the form of structural abnormalities of the nucleus, such as micronuclei (MN), that lead to chronic activation of the cytosolic DNA sensing cGAS-STING pathway. However, how chronic cGAS-STING pathway activation is tolerated and shapes the tumor landscape of CINhigh EAC cancers is poorly understood. Using publicly available RNA-seq and genome sequencing data of EAC tumours and esophageal cancer cell lines as well as a panel of EAC cell lines, we demonstrate that the core cGAS-STING pathway machinery is rarely inactivated in EAC despite high levels of baseline CIN and aneuploidy. Through transcriptomic profiling of an isogenic EAC precursor cell line model of variable CIN and cGASKO/WT EAC cell lines we show that both chronic and transient CIN-driven cGAS-STING activation converge on the expression of CXCR1/2 ligands and other pro-inflammatory cytokines and chemokines rather than typical anti-tumor type I interferon signalling in EAC cells. Indeed, a novel transcriptional signature of cGAS+ micronuclear burden-correlated genes correlates with orthogonal measures of CIN in EAC tumours and esophagogastric cancer cell lines and is associated with an enrichment in myeloid-derived cells as well as poor prognosis. Correspondingly, using multiplexed immunofluorescence (IF) we find that a high preponderance of cGAS+MN and STING expression in human EAC samples is associated with decreased tumor purity, increased myeloid cell and macrophage infiltration, and increased peripheral blood neutrophil counts, indicative of tumor-promoting myeloid inflammation. Ongoing multiplexed IF and single-nuclei RNAseq analysis of cGAS+MNhigh and cGAS+MNlow EAC tumors will further help characterise the components that comprise the CIN EAC tumor microenvironment (TME) and the CIN- and cGAS-STING-dependent cell-cell interactions that govern it. Taken together, our findings provide an explanation for the observed maintenance of cGAS and STING in EAC and identify disruption of cGAS-STING-dependent myeloid cell inflammation and recruitment as a potential therapeutic target for CINhigh EAC. Citation Format: Bruno Beernaert, Erkin Erdal, Rose Clark, Tong Liu, Ester M. Hammond, Eileen E. Parkes. cGAS-STING drives myeloid inflammation in chromosomally unstable esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2704.

Propionyl-l-carnitine mitigates ischemia-reperfusion injury in rat epigastric island flaps

BackgroundIschemia-reperfusion injury presents a substantial concern in various medical scenarios, notably in reconstructive surgery involving tissue flaps. Despite reports on the protective benefits of Propionyl-l-carnitine against ischemia-reperfusion injury, a thorough assessment of its efficacy in epigastric island flap models is currently lacking. MethodsSixteen male Sprague-Dawley rats underwent epigastric island flap surgery and were divided into two groups: a Propionyl-l-carnitine group that received intraperitoneal Propionyl-l-carnitine prior to ischemia induction and a sham group that received saline treatment. A comprehensive evaluation was performed including macroscopic, biochemical and histological assessments encompassing measurements of flap survival areas, lipid peroxidation (malondialdehyde), glutathione, myeloperoxidase, nitric oxide and peripheral neutrophil counts. ResultsThe Propionyl-l-carnitine group demonstrated significantly increased flap survival areas when compared to the sham group. Administration of Propionyl-l-carnitine led to reduced malondialdehyde levels and elevated glutathione levels indicating a reduction in oxidative stress. Furthermore, the Propionyl-l-carnitine group exhibited lower myeloperoxidase levels, higher nitric oxide levels and reduced peripheral neutrophil counts, suggesting a decrease in the inflammatory response. Histopathological analysis revealed decreased levels of inflammation, necrosis, polymorphonuclear leukocyte infiltration and edema in the Propionyl-l-carnitine group. Additionally, vascularity was enhanced in the Propionyl-l-carnitine group. ConclusionThis study provides compelling evidence that Propionyl-l-carnitine administration effectively mitigates the deleterious effects of ischemia-reperfusion injury in epigastric island flaps. This is substantiated by the improved flap survival, diminished oxidative stress and inflammation, as well as the enhanced vascularity observed. Propionyl-l-carnitine emerges as a promising therapeutic intervention to enhance tissue flap survival in reconstructive surgery, warranting further exploration through larger-scale investigations.

Expression of Siglec-9 in peripheral blood neutrophils was increased and associated with disease severity in patients with AECOPD

BackgroundThe pathogenesis and treatment strategies for chronic obstructive pulmonary disease (COPD) require further exploration. Abnormal neutrophil inflammation and the overexpression of neutrophil extracellular traps (NETs) are closely associated with acute exacerbations of COPD (AECOPD). Siglec-9, a specific receptor expressed on neutrophils that inhibits their function, prompted us to investigate its relationship with NETs found in induced sputum and the severity of the disease. MethodsWe collected clinical data from patients with AECOPD and assessed the expression of Siglec-9 in peripheral blood neutrophils and the presence of NETs in induced sputum. We then observed the correlation between Siglec-9, the inflammatory response, and the severity of AECOPD. ResultsWe observed an increase in the expression of Siglec-9 in the peripheral blood neutrophils of patients with AECOPD. Concurrently, these patients exhibited more severe clinical symptoms, higher systemic inflammation levels, and a reduced quality of life compared to those with induced sputum NET expression. Further subgroup analysis of AECOPD patients with high Siglec-9 expression revealed worsened quality of life and more severe inflammation, particularly in indicators such as the BODE index, CRP, peripheral blood neutrophil count, IL-6, IL-8, TNF-α expression, and others. Furthermore, we noted a significant increase in NET-specific expression in the sputum of patients with high Siglec-9 expression levels. In comparison to patients with low Siglec-9 expression, those with high expression experienced more systemic inflammatory reactions and a lower quality of life. Correlation analysis of the aforementioned indicators revealed that the expression ratio of Siglec-9 in the peripheral blood of patients correlated with lung function, quality of life, and NETs in the induced sputum of patients with AECOPD. ConclusionThe increased expression of Siglec-9 in peripheral blood neutrophils of AECOPD patients leads to elevated NET expression in induced sputum, exacerbating the systemic inflammatory response and worsening lung function and quality of life in these patients.

Should we consider Systemic Inflammatory Response Index (SIRI) as a new diagnostic marker for rectal cancer?

The Systemic Inflammatory Response Index (SIRI), which depends on peripheral neutrophil, monocyte, and lymphocyte count, was found to be an effective prognostic indicator for various malignancies. In this study, we aimed to investigate the diagnostic value and the prognostic impact of SIRI on rectal cancer patients. The medical records of patients underwent sphincter-sparing rectal cancer surgery at general surgery between 2017 and 2022 were examined retrospectively. Patient demographics, operation types, neoadjuvant chemo/radiotherapies, pathological results, and complications were recorded. A total number of 99 patients who operated with diagnoses other than cancer were conducted as a control group. SIRI was calculated from preoperative peripheral blood samples' neutrophil, lymphocyte, and monocyte count. The optimal cut-off value for SIRI was found to be 1.38. The clinicopathological outcomes and Overall Survival (OS) were analyzed under two groups according to the SIRI values lower or higher than 1.38. The number of eligible patients was 104. The median age of the entire cohort was 62 (31-89). The median follow-up time was 33 (1-62) months. The median SIRI value in the study group was significantly higher compared with the control group. The study group was examined under two groups: SIRI 1.38 and SIRI > 1.38. The male gender was significantly more frequent in the high SIRI group. The remaining patient demographics and operation types were similar between the groups. The pathological outcomes were similar between the two groups. Overall Survival rate was better in the low SIRI group than those higher. The higher group had significantly higher complication rates than the lower SIRI group (p: 0.004). SIRI may be a valuable diagnostic marker in rectal cancer patients. Higher SIRI levels were also associated with poorer prognosis and increased complication rates. Still, further prospective studies with a larger number of patients are needed.

Impact of different genetic mutations on granulocyte development and G-CSF responsiveness in congenital neutropenia

AbstractCongenital neutropenia (CN) is a genetic disorder characterized by persistent or intermittent low peripheral neutrophil counts, thus increasing susceptibility to bacterial and fungal infections. Various forms of CN, caused by distinct genetic mutations, exhibit differential responses to granulocyte colony–stimulating factor (G-CSF) therapy, with the underlying mechanisms not fully understood. This study presents an in-depth comparative analysis of clinical and immunological features in 5 CN patient groups (severe congenital neutropenia [SCN]1, SCN3, cyclic neutropenia [CyN], warts, hypogammaglobulinaemia, infections and myelokathexis [WHIM], and Shwachman-Bodian-Diamond Syndrome [SBDS]) associated with mutations in ELANE, HAX1, CXCR4, and SBDS genes. Our analysis led to the identification of 11 novel mutations in ELANE and 1 each in HAX1, CXCR4, and G6PC3 genes. Investigating bone marrow (BM) granulopoiesis and blood absolute neutrophil count after G-CSF treatment, we found that SCN1 and SCN3 presented with severe early-stage disruption between the promyelocyte and myelocyte, leading to a poor response to G-CSF. In contrast, CyN, affected at the late polymorphonuclear stage of neutrophil development, showed a strong G-CSF response. WHIM, displaying normal neutrophil development, responded robustly to G-CSF, whereas SBDS, with moderate disruption from the early myeloblast stage, exhibited a moderate response. Notably, SCN1 uniquely impeded neutrophil development, whereas SCN3, CyN, WHIM, and SBDS also affected eosinophils and basophils. In addition, SCN1, SCN3, and CyN presented with elevated serum immunoglobulins, increased BM plasma cells, and higher A Proliferation-Inducing Ligand levels. Our study reveals a strong correlation between the stage and severity of granulocyte development disruption and the efficacy of G-CSF therapy.

Breastfeeding and Neonatal Age Influence Neutrophil-Driven Ontogeny of Blood Cell Populations in the First Week of Human Life.

The first few days of life are characterized by rapid external and internal changes that require substantial immune system adaptations. Despite growing evidence of the impact of this period on lifelong immune health, this period remains largely uncharted. To identify factors that may impact the trajectory of immune development, we conducted stringently standardized, high-throughput phenotyping of peripheral white blood cell (WBC) populations from 796 newborns across two distinct cohorts (The Gambia, West Africa; Papua New Guinea, Melanesia) in the framework of a Human Immunology Project Consortium (HIPC) study. Samples were collected twice from each newborn during the first week of life, first at Day of Life 0 (at birth) and then subsequently at Day of Life 1, 3, or 7 depending on the randomization group the newborn belongs to. The subsequent analysis was conducted at an unprecedented level of detail using flow cytometry and an unbiased automated gating algorithm. The results showed that WBC composition in peripheral blood changes along patterns highly conserved across populations and environments. Changes across days of life were most pronounced in the innate myeloid compartment. Breastfeeding, and at a smaller scale neonatal vaccination, were associated with changes in peripheral blood neutrophil and monocyte cell counts. Our results suggest a common trajectory of immune development in newborns and possible association with timing of breastfeeding initiation, which may contribute to immune-mediated protection from infection in early life. These data begin to outline a specific window of opportunity for interventions that could deliberately direct WBC composition, and with that, immune trajectory and thus ontogeny in early life. This trial is registered with NCT03246230.

Multivariate prognostic index and triplet regimen efficacy predictive index in locally advanced and metastatic gastric cancer: pooled analysis from three clinical trials using individual patient data.

To construct an effective prognostic index to predict overall survival (OS) and triplet regimen efficacy for advanced gastric cancer (AGC) patients treated with platinum-based and fluorouracil-based chemotherapy. Between 2011 and 2021, 679 patients from two randomized phase III trials and one phase II trial were enrolled. We collected 11 baseline clinicopathological and 14 hematological parameters to establish a prognostic index. Univariate and multivariate Cox analyses were used to screen prognostic factors, and a prognostic index nomogram was conducted. Seven prognostic factors were identified: primary tumor site in the non-proximal gastric area, signet-ring cell carcinoma (SRCC)/mucinous carcinoma, peritoneal metastasis, neutrophil count higher than the upper limit of normal value (ULN), lymphocyte count lower than the lower limit of normal value, lactate dehydrogenase level higher than the ULN, and alkaline phosphatase level higher than the ULN as significant for prognosis. A prognostic nomogram named the Fudan advanced gastric cancer prognostic risk score (FARS) index was constructed, and patients in the high-risk group had significantly shorter OS than those in the low-risk group (median OS, 15.5 versus 8.0 months, p < 0.001). The areas under the curve of the FARS index for 1-, 2-, and 3-year OS were 0.70, 0.72, and 0.77, respectively. A validation and external cohort verified the prognostic value of the FARS index. Moreover, three triplet regimen efficacy parameters were identified: SRCC/mucinous adenocarcinoma, primary tumor location in the non-proximal gastric area, and peripheral neutrophil count higher than the ULN; a TRIS index was subsequently conducted. In patients with any two of the three parameters, the triplet regimen showed significantly longer OS than the doublet regimen (p = 0.018). The constructed FARS index to predict the OS of AGC patients and the TRIS index to screen out the dominant population for triplet regimens can be used to aid clinical decision-making and individual risk stratification.

Systemic immune-inflammation index is associated with ulcerative plaque in patients with acute ischemic stroke: A single center exploratory study.

This study explored the correlation between inflammatory markers and ulcerative plaques based on carotid doppler ultrasound (CDU) in individuals with acute ischemic stroke (AIS). A total of 202 cases diagnosed with AIS associated with atherosclerotic plaque (AP) in the carotid artery were enrolled in this research. Collecting clinical baseline data, laboratory data (such as the complete blood count) and imaging data (CDU and Brain magnetic resonance imaging [MRI]). Then the correlation between Systemic immune-inflammation index (SII, SII = P N/L, where P, N, and L were the peripheral blood platelet, neutrophil and lymphocyte counts, respectively), the shape and position of AP, the degree of carotid artery stenosis, and the presence of ulcerative plaques. Cutoff values were determined accordingly. SII and high sensitivity CRP (hs-CRP) were independent risk factors for the presence of vulnerable carotid plaques. SII, type A plaque, plaque above carotid bifurcation, and severe carotid stenosis were independent risk factors for the presence of ulcerative plaque. The AUC value, the sensitivity, specificity, the best cutoff value of SII in predicting the presence of ulcerative plaque was 0.895, 93.3%, 89.2%, and 537.4 (109 /L), respectively. SII at admission was found to be independently associated with the presence of AIS with vulnerable plaque, especially ulcerative plaques. Moreover, plaque ulceration was more likely to form when the area of higher plaque thickness was located in the upstream arterial wall of maximum plaque thickness (WTmax), plaque was above the carotid bifurcation and severe carotid stenosis.

Neutrophil-to-Lymphocyte Ratio in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Background: This study aimed to clarify the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). Methods: Eighty-six patients diagnosed with AE-IPF were included in this single-center retrospective study. The NLR was calculated by dividing the peripheral neutrophil count by the peripheral lymphocyte count. The cut-off values of the NLR for predicting 90-day survival were determined using receiver operating characteristic curve analysis. Oxygenation deterioration on days 4 and 8 relative to that on day 1 was clinically defined. The prognostic value of NLR was evaluated using Cox proportional hazard regression analysis. Results: The cut-off value of day-1, day-4, and day-8 NLRs for predicting 90-day survival was 12.13, 14.90, and 10.56, respectively. A higher day-1 NLR was a significant predictor of a poor prognosis in univariate and multivariate analyses. Survival was significantly better in patients without oxygenation deterioration on days 4 and 8 than in those with deterioration. Day-4 and day-8 NLR could predict 90-day survival in patients without oxygenation deterioration. Conclusions: Day-1 NLR was a useful predictor of 90-day survival in AE-IPF. Further, monitoring day-4 and day-8 NLRs and evaluating oxygenation deterioration may be useful for managing AE-IPF.

Nifedipine-induced agranulocytosis: A rare case report and literature review

Rationale: Drug-induced agranulocytosis (DIAG) is a fatal idiosyncratic reaction characterized by a peripheral neutrophil count &lt;0.5 × 109/L. Almost all classes of medications have been implicated with DIAG. However, agranulocytosis induced by antihypertensive drugs is rare worldwide. To the best of our knowledge, this is the first case of nifedipine-associated agranulocytosis with a positive rechallenge. Patient concerns: An 82-year-old man was admitted to our hospital due to uncontrolled fasting blood sugar. He had a history of hypertension and underwent treatment with nifedipine 6 years prior to admission. Blood tests showed white blood cell count of 2.30 × 109/L with a neutrophil count of 0.49 × 109/L. Diagnosis: Other malignancies that contributed to agranulocytosis were excluded, and the patient was diagnosed with DIAG. Interventions and outcomes: At first, gliclazide, rather than nifedipine, was considered as the culprit for DIAG and it was discontinued. Neutrophil count improved upon hematopoietic growth factors and traditional Chinese medicine. During the follow-up, the neutrophil count decreased again, and nifedipine was thought to be the offending agent for agranulocytosis. The neutrophil count increased to 0.91 × 109/L 2 months after nifedipine discontinuation. However, the patient was re-exposed to nifedipine and the neutrophil count decreased to 0.70 × 109/L. Lessons: Nifedipine-induced agranulocytosis is a rare but serious adverse drug reaction. For any patients with clinical suspicion or diagnosis of DIAG, a full drug history should be chronologically and completely taken in order to identify the suspected agents. Sometimes diagnosis of DIAG is challenging since some patients may be entirely asymptomatic. Management of DIAG starts with immediate discontinuation of the implicated drug. Empirical broad-spectrum antibiotics and hematopoietic growth factors may improve patient outcomes and reduce recovery time.

Iron Restricted Erythropoiesis Under Hepcidin Mimetic Treatment (PN23114) Improved Disease Parameters in a Mouse Model for Sickle Cell Disease

Sickle Cell Disease (SCD) is an inherited hemolytic disorder that results from a single point mutation in the hemoglobin-beta (HBB) gene that encodes for the beta-globin subunit of hemoglobin, causing the production of abnormal hemoglobin S (HbS). HbS polymerizes under low oxygen conditions, causing sickling effects on red blood cells (RBCs). Sickling of RBCs initiates vaso-occlusion, downstream inflammatory responses, and hemolysis (Zhang D, et al., Blood. 2016;127:801-9). Previous studies have shown that polymerization under low oxygen conditions is extremely sensitive to HbS concentrations within the RBCs (Hofrichter J, et al, Proc Natl Acad Sci USA. 1974;71:4864-8; Sunshine HR, et al. Nature. 1978;275:238-40). Controlling iron delivery for erythropoiesis provides a mechanism to potentially down-modulate the HbS concentration, thereby reducing the potential for HbS polymerization and sickling of RBCs (Parrow NL, et al., Blood. 2021;137:1553-5). The potent hepcidin mimetic peptide PN23114 targets the iron exporter membrane protein ferroportin to trigger its degradation, thus preventing iron export from cells. We hypothesize that the resulting pharmacodynamic effect of limiting iron availability for erythropoiesis should reduce HbS concentrations within the RBCs that may prevent sickling and hemolysis. Townes mice (genetically altered to contain the human SCD HbSS homozygous mutation) are a well-established experimental model for human SCD (Li-Chen W, et al., Blood. 2006;108:1183-8). They exhibit severe hemolysis as indicated by elevated bilirubin and lactate dehydrogenase (LDH) levels, and a shortened RBC half-life compared to wild type (WT) mice. These mice also develop vaso-occlusive events and elevated inflammatory responses (for example, increases in peripheral blood white blood cell [WBC] and neutrophil counts). To test whether iron restriction mediated by a hepcidin mimetic may alter outcomes in this model, PN23114 was administered subcutaneously to Townes HbSS mice. Mice were treated over 4-weeks (3 times weekly) with vehicle or PN23114 at 1 or 2.5 mg/kg (vehicle treated WT mice served as controls). At the end of 4 weeks, total bilirubin was elevated in the HbSS-vehicle group compared to WT-vehicle (Figure 1A). Total bilirubin was dose-dependently reduced by PN23114 treatment compared to the HbSS-vehicle group (Figure 1A). LDH was also elevated in the HbSS-vehicle group and was dose-dependently reduced with PN23114 treatment (557±105 units/L in WT-vehicle, 809±145 units/L in HbSS-vehicle, 611±341 units/L in HbSS-PN23114-1mg/kg and 372±71 units/L in HbSS-PN23114-2.5mg/kg groups). Peripheral blood WBC counts were dose-dependently reduced by PN23114 treatment compared to HbSS-vehicle (Figure 1B), with concomitant decreases in peripheral blood neutrophil counts. Reduction in hemoglobin values was observed with PN23114 treatment in HbSS (5.9±0.9 g/dL in HbSS-1mg/kg group and 4.4±0.4 g/dL in HbSS-2.5 mg/kg group) compared to the HbSS-vehicle group (7.1±0.3 g/dL). These results suggest that pharmacologic iron restriction with PN23114, a hepcidin mimetic peptide, led to a reduction in hemolysis and inflammatory markers in a SCD model. Therefore, a hepcidin mimetic therapeutic could potentially be a novel approach to prevent hemolysis, inflammation and downstream clinical complications associated with human SCD.