Identification and Clinical Characterization of Children With Benign Ethnic Neutropenia.
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ABSTRACT:
SUBMITTER: Ortiz MV
PROVIDER: S-EPMC5102334 | biostudies-literature | 2016 Apr
REPOSITORIES: biostudies-literature
Publications
Identification and Clinical Characterization of Children With Benign Ethnic Neutropenia.
Ortiz Michael V MV Meier Emily R ER Hsieh Matthew M MM
Journal of pediatric hematology/oncology 20160401 3
Benign ethnic neutropenia (BEN) is an asymptomatic condition reported in adults of African and Middle Eastern descent. The clinical description in children is currently lacking. In our urban outpatient pediatric hematology clinic, the median neutrophil count of children with BEN was lower than previous reports in adults at 893×10 cells/L, but increased with older age. There was an equal male to female ratio and 24% of our BEN children reported ethnicities other than African or Middle Eastern. Ch ...[more]
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Project description:Benign ethnic neutropenia (BEN) is one of the most common causes of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent, affecting many individuals worldwide. Despite its prevalence, many physicians are not familiar with this benign condition, resulting in unnecessary evaluation and testing for neutropenia in otherwise healthy individuals. Clinically, patients with BEN are at no increased risk of infection despite their neutropenia. Implications of this condition are highlighted in those patients receiving therapies that have a known side effect of neutropenia, most commonly chemotherapy agents. Studies have suggested that disparities in survival among those patients receiving chemotherapy between patients of European decent and African decent may be attributed to measured neutropenia in these populations, questioning whether BEN could be an influential factor. This review encompasses all aspects of benign ethnic neutropenia, providing information about this condition and helping to guide clinical decision-making as to when an aggressive work up and referral are indicated and when it is appropriate to monitor. Additionally, we review the role of genetic studies in identifying the genes related to BEN, summarize the theories that offer the most accepted mechanisms behind the condition, and address the importance of pursuing larger studies to assess the implication of BEN in oncology patients as well as patients taking neutropenia-causing medications.
| S-EPMC6702066 | biostudies-literature
Project description:ObjectiveIsolated mild neutropenia is a common clinical problem in some ethnicities including Arabs and Middle Eastern population. The current study aims to authenticate the prevalence of isolated neutropenia in Southern and Southwestern Saudi Arabia, explore the effect of altitude or regional differences and to suggest a new reference range for neutrophil count.MethodsIn this retrospective cross-sectional study, laboratory results of a commercial laboratory were screened over a period of 5 years (2016-2020) in seven different cities of different altitudes in South and southwestern Saudi Arabia. Participants' laboratory investigations were reviewed and excluded for any abnormal complete blood count, renal profile, liver profile, lipid profile, thyroid function test, fasting blood glucose, or HbA1c findings. Descriptive analysis and 95th percentile range were calculated using standard statistical methods.ResultsA total of 91,880 complete blood count results were included in the final analysis. Isolated neutropenia was common laboratory finding, with a prevalence ranging from 11% to 23%. The 2.5th percentile of the neutrophil count was lower than currently utilized 1.5×109/L in all studied seven cities.ConclusionMild to moderate neutropenia is common in Southern and Southwestern Saudi Arabia. Benign ethnic neutropenia (BEN) likely explains this high prevalence. Since BEN has no clinical significance, the reference range for normal neutrophil counts needs to be adjusted to reflect the effect of BEN.
| S-EPMC7894867 | biostudies-literature
Project description:BackgroundBenign ethnic neutropenia (BEN), defined by neutrophil count <1.5 k/μL in the absence of other causes, is an asymptomatic condition more commonly observed in individuals of African ancestry. However, the natural history of this condition has been less well described.MethodsIndividuals with BEN were retrospectively identified by chart review or referral to hematology clinics. They were then invited to enroll in a prospective natural history study. Retrospective and prospective clinical and laboratory data were combined for descriptive analyses.Findings46 participants, younger and older adults from 2 institutions, had BEN. Hypertension was reported in 30%, musculoskeletal disorders in 15%, and upper respiratory infection in 33% of these adults. Their leukopenia resulted from isolated neutropenia, ranging from 1000 and 1500 cells/μL. The severity of infections was mild and the frequency was similar to other healthy individuals in the ambulatory clinic.InterpretationIn this group of BEN participants, their leukopenia was stable over time, and they had low rates of infections or common medical disorders, confirming the benign nature of this condition. The presence of BEN in children, younger adults, and older adults suggest a hereditary pattern for BEN.
| S-EPMC6541485 | biostudies-literature
Project description:BackgroundBenign ethnic neutropenia (BEN) is the most common cause of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent. This phenotype is broadly defined by an absolute neutrophil counts (ANC) below 1.8 × 109 cells/L in the absence of other causes, without an increased risk of infection. BEN has been implicated as a potential source of disparity in patients treated with clozapine, the antipsychotic of choice in treatment-resistant schizophrenia. Our main objective was to examine the current level of BEN recognition in a cohort of patients treated with clozapine and the potential impact of unidentified BEN on the initiation and maintenance of clozapine treatment.MethodsThis was an observational, retrospective analysis of patients registered with clozapine haematological monitoring systems in two large mental health trusts, chosen because they serve an ethnically diverse population. The first objective was to establish certified BEN prevalence in current users of clozapine. The second objective was to explore the stage of treatment at which BEN was identified. The third objective was to evaluate the extent of unrecognised BEN in patients registered on the Central Non-Rechallenge Database (CNRD), a database for patients whose haematological parameters fall below set thresholds when receiving clozapine treatment, meaning they cannot ordinarily be prescribed clozapine again.ResultsThe study population comprised of 2020 patients on the clozapine register. 111 patients were monitored under BEN criteria. BEN was mostly identified after a below threshold haematological result or clozapine rechallenge (68%) compared to at clozapine initiation (32%). Eight of the 18 (42%) black patients registered on the CNRD were classified as BEN after assessment by a haematologist. Of these 8 patients, none would have met CNRD criteria again if monitored with BEN criteria at clozapine initiation.ConclusionsCurrent evidence suggests that BEN remains an uncommonly recognised haematological phenotype. Improved timely identification of BEN will reduce unnecessary interruption or discontinuation of clozapine treatment. Our results suggest consideration should also be given to determining BEN status prior to initiating clozapine. Moreover, adoption of current FDA BEN monitoring criteria in the UK may further reduce clozapine discontinuation due to perceived neutropenia as drug toxicity, particularly in treatment-refractory schizophrenia patients.
| S-EPMC8515765 | biostudies-literature
Project description:Background: Benign ethnic neutropenia (BEN) is a hematologic condition associated with people of African ancestry and specific Middle Eastern ethnic groups. Prior genetic association studies in large population showed that rs2814778 in Duffy Antigen Receptor for Chemokines (DARC) gene, specifically DARC null red cell phenotype, was associated with BEN. However, the mechanism of this red cell phenotype leading to low white cell count remained elusive.Methods: We conducted an extreme phenotype design genome-wide association study (GWAS), analyzed ~16 million single nucleotide polymorphisms (SNP) in 1,178 African-Americans individuals from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study and replicated from 819 African-American participants in the Atherosclerosis Risk in Communities (ARIC) study. Conditional analyses on rs2814778 were performed to identify additional association signals on chromosome 1q22. In a separate cohort of healthy individuals with and without BEN, whole genome gene expression from peripheral blood neutrophils were analyzed for DARC.Results: We confirmed that rs2814778 in DARC was associated with BEN (p = 4.09×10-53). Conditioning on rs2814778 abolished other significant chromosome 1 associations. Inflammatory cytokines (IL-2, 6, and 10) in participants in the Howard University Family Study (HUFS) and Multi-Ethnic Study in Atherosclerosis (MESA) showed similar levels in individuals homozygous for the rs2814778 allele compared to others, indicating cytokine sink hypothesis played a minor role in leukocyte homeostasis. Gene expression in neutrophils of individuals with and without BEN was also similar except for low DARC expression in BEN, suggesting normal function. BEN neutrophils had slightly activated profiles in leukocyte migration and hematopoietic stem cell mobilization pathways (expression fold change <2).Conclusions: These results in humans support the notion of DARC null erythroid progenitors preferentially differentiating to myeloid cells, leading to activated DARC null neutrophils egressing from circulation to the spleen, and causing relative neutropenia. Collectively, these human data sufficiently explained the mechanism DARC null red cell phenotype causing BEN and further provided a biologic basis that BEN is clinically benign.
| S-EPMC5875757 | biostudies-literature
Project description:Benign ethnic neutropenia (BEN) is defined as a neutrophil count of <1.5×109 cells/L in healthy individuals and is more common in populations of certain ethnicities, e.g. African or Middle Eastern ethnicity. Neutrophil values are commonly included in eligibility criteria for research participation, but little is known about the relationship between BEN, HIV acquisition, and the occurrence of adverse events during clinical trials. We investigated these relationships using data from an HIV vaccine efficacy trial of healthy adults from 5 South African sites. We analysed data from the double-blind, placebo-controlled, randomized trial HVTN 503, and its follow-on study HVTN 503-S to assess the prevalence of BEN, its association with HIV infection, and adverse event reporting. These data were then compared with a time- and age-matched, non-pregnant cohort from the National Health and Nutrition Examination Survey (NHANES) conducted between 2007-2008 in the United States (US). The 739 South African participants had a median age of 22.0 years (interquartile range = 20-26) and 56% (n = 412) were male. Amongst the US cohort of 845 participants, the median age was 26 (IQR: 21-30) and the majority (54%, 457/745) were also male. BEN was present at enrolment in 7.0% (n = 52) of South African participants (6% in the placebo group versus 8% in the vaccine group); 81% (n = 42) of those with BEN were male. Pretoria North had the highest prevalence of BEN (11.6%, 5/43), while Cape Town had the lowest (0.7%, 1/152). Participants with BEN had a lower median neutrophil count (1.3 vs. 3.2x109 cells/L; p<0.001) and BMI (20.8 vs. 22.3 kg/m2; p<0.001) when compared to those without BEN. A greater proportion of Black South Africans had neutrophil counts <1.5×109 cells/L compared to US non-Hispanic Whites from the NHANES cohort (7% [52/739] vs. 0.6% [3/540]; p<0.001). BEN did not increase the odds for HIV infection (adjusted odds ratio [aOR]: 1.364, 95% confidence interval [95% CI]: 0.625-2.976; p = 0.4351). However, female gender (aOR: 1.947, 95% CI: 1.265-2.996; p = 0.0025) and cannabis use (aOR: 2.192, 95% CI: 1.126-4.266; p = 0.0209) increased the odds of HIV acquisition. The incidence rates of adverse events were similar between participants in the placebo group with BEN, and those without: 12.1 (95% CI: 7.3-20.1) vs. 16.5 (95% CI: 14.6-18.7; p = 0.06) events per 100 person-years (py) were noted in the infections and infestations system organ class, respectively. The vaccine group had an event incidence rate of 19.7 (95% CI: 13.3-29.2) vs. 14.8 (95% CI: 13.0-16.8; p = 0.07) events per 100py in the group with, and without BEN, respectively. BEN is more prevalent in Black South Africans compared to US Non-Hispanic Whites. Our data do not support excluding populations from HIV vaccine trials because of BEN. BEN was not associated with increased risk for HIV infection or Adverse events on a vaccine trial. Predictors of HIV infection risk were females and cannabis use, underlying the continued importance of prevention programmes in focusing on these populations.
| S-EPMC7822320 | biostudies-literature
Project description:Abstract Background: Benign ethnic neutropenia (BEN) is the occurrence of absolute neutrophil counts (ANC) of less than 1500 cells/mm3 observed in 10% to 30% of African and Middle Eastern ancestry individuals with no increased susceptibility to pyogenic infections. Recent evidence implicates polymorphism in the Duffy Antigen Receptor for Chemokines gene (DARC) in BEN persons of African descent. Until mid-2015 in the United States, the FDA clozapine treatment guidelines for ANC monitoring were based on normative ANC values in European ancestry populations without considerations for BEN. Compared with Caucasians, African Americans are less likely to be initiated on clozapine and their treatment twice as likely to be discontinued for neutropenia. Gathering data indicate no increased agranulocytosis risk in clozapine-treated BEN individuals. Advancing knowledge of BEN pathophysiology could reduce a substantial barrier to clozapine treatment in African-American patients. Methods: We examined ANC data collected on a sample of 136 schizophrenia and 33 healthy control Yoruba participants recruited at the Federal Neuropsychiatric Hospital Yaba, Lagos. Exclusion criteria included medical conditions that could affect white blood cell counts. In the patient group, 100 had been on stable clozapine treatment (>6 months). In a subgroup of participants (n = 69), we assayed the regulatory variant (rs2814778) in the promoter of DARC (DARC -46T > C) implicated in low neutrophil counts in African-ancestry populations. Results: The sample consisted of 88 females and 81 males. Sex was not different between schizophrenia and control groups (P = .3). Age differed between schizophrenia (mean [SD], 40.15 [13.15] years) and controls (mean [SD], 29.12 [5.08] years; P < .001). The sample mean ANC was 2,557/mm3 (range 800 to 6,970); with 31% and 11% showing ANC below 2000 and 1500/mm3, respectively. The mean daily clozapine dose was 224?mg. Clozapine-treated patients had a significantly higher mean ANC (2777/mm3 [0.97]) compared with controls and non-clozapine treated patients (2238/mm3 [0.88]; P < .001). All 69 individuals assayed for rs2814778 were homozygous for the Duffy-null allele (DARC -46T > C). Conclusion: The results are consistent with reported rates of BEN in African populations, supports the safety of clozapine monitoring using lower ANC levels in BEN populations, and demonstrates the common occurrence of the African-derived “null” DARC gene variant in this sample.
| S-EPMC5475632 | biostudies-literature
Project description:CIDR GWAS Benign Neutropenia in African Americans
| PRJNA169015 | ENA
Project description:<p>Benign ethnic neutropenia (BEN) is a clinical condition more commonly observed in African-Americans. It is characterized by a relative reduction in neutrophil count by about 1000 cells per microliter, leading to a decrease in total leukocyte count by similar decrement. Previous reports of this condition showed that there was neither higher frequency nor increased severity of infections in affected individuals. Bone marrow examinations showed normal white cell maturation; and ex vivo culture of marrow cells showed low normal or slightly reduced number of myeloid colonies. Under physiologic stress, the increases in neutrophil and leukocyte counts of BEN individuals are slightly lower, compared to normal African-Americans or Caucasians. These clinical observations suggest that BEN results from a lower 'set point' for cell number in the marrow. Additionally, case reports of familial BEN, the persistence of BEN over many decades in the US, UK, and Africa, and the recent report of Duffy antigen and chemokine receptor (DARC) being associated with neutropenia, all suggest a strong genetic association to neutropenia/leukopenia. Our initial look into microarray analyses in a pilot trial of subjects showed that there were no significant differences in mRNA signals between BEN and normal subjects. Therefore, we are now proposing a larger study, utilizing Illumina Omni Express chips, to look for genetic associations. We have partnered with the Reasons for Geographic and Racial Differences in Stroke study (REGARDS), where nearly half of the cohort are African-Americans. This will be one of the few GWAS being performed in only African-Americans, and will provide valuable genetic information to link with neutropenia and possibly other conditions/diseases.</p> <p>Genotyping was performed by the Johns Hopkins University Center for Inherited Disease Research (CIDR). Quality control of the genotypic and phenotypic data was performed through a collaboration between CIDR and the Genetics Coordinating Center, Department of Biostatistics at the University of Washington, which is funded by a federal contract supported by 14 NIH Institutes (HHSN268200782096C).</p>
| phs000507 | dbGaP
Project description:BackgroundFebrile neutropenia is a common and serious complication during treatment of childhood cancer. Empirical broad-spectrum antibiotics are usually administered until neutrophil cell count recovery. It was the aim of this study to investigate cytokine profiles as potential biomarkers using in-vitro sepsis models to differentiate between distinct clinical courses of febrile neutropenia (FN).MethodsWe conducted an observational study in FN episodes of pediatric oncology patients. Courses of neutropenia were defined as severe in case of proven blood stream infection or clinical evidence of complicated infection. We collected blood samples at various time points from the onset of FN and stimulated ex vivo with lipopolysaccharide (LPS) and Staphylococcus epidermidis (SE) for 24 h. Twenty-seven cytokine levels were measured in the whole blood culture supernatants by a multiplex immunoassay system.ResultsForty-seven FN episodes from 33 children were investigated. IL-8, IL-1β, and MCP-1 expression increased significantly over time. IL-8, MIP-1α, MIP-1β, MCP-1, and TNF-α showed significantly lower concentration in patients with a clinically severe course of the FN.ConclusionsDistinct patterns of cytokine profiles seem to be able to determine infectious FN and to predict the severity of its clinical course. If these data can be verified in a multi-centre setting, this may finally lead to an individualized treatment strategy facilitating antibiotic stewardship in these patients.
| S-EPMC7283414 | biostudies-literature