Top

Published in:

Open Access 01-12-2021 | Neutropenia | Research

Benign ethnic neutropenia: an analysis of prevalence, timing and identification accuracy in two large inner-city NHS hospitals

Authors: Ebenezer Oloyede, Olubanke Dzahini, Nigel Barnes, Aleksandar Mijovic, Shreyans Gandhi, Sara Stuart-Smith, Theo de Witte, David Taylor, Eromona Whiskey

Published in: BMC Psychiatry | Issue 1/2021

Abstract

Background

Benign 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.

Methods

This 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.

Results

The 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.

Conclusions

Current 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.

Available only for authorised users

Manu P, Sarvaiya N, Rogozea LM, Kane JM, Correll CU. Benign ethnic neutropenia and clozapine use: a systematic review of the evidence and treatment recommendations. J Clin Psychiatry. 2016;77(7):e909–16. https://doi.org/10.4088/JCP.15r10085.CrossRefPubMed

Whiskey E, Olofinjana O, Taylor D. The importance of the recognition of benign ethnic neutropenia in black patients during treatment with clozapine: case reports and database study. J Psychopharmacol. 2011;25(6):842–5. https://doi.org/10.1177/0269881110364267.CrossRefPubMed

Legge SE, Pardiñas AF, Helthuis M, et al. A genome-wide association study in individuals of African ancestry reveals the importance of the Duffy-null genotype in the assessment of clozapine-related neutropenia. Mol Psychiatry. 2019;24(3):328–37. https://doi.org/10.1038/s41380-018-0335-7.CrossRefPubMed

Kyle RA, Linman JW. Chronic idiopathic neutropenia: a newly recognized entity? N Engl J Med. 1968;279(19):1015–9. https://doi.org/10.1056/NEJM196811072791902.CrossRefPubMed

Dancey JT, Brubaker LH. Neutrophil marrow in chronic benign idiopathic neutropenia. Am J Med. 1980;68(2):251–4. https://doi.org/10.1016/0002-9343(80)90362-9.CrossRefPubMed

Cutting HO, Lang JE. Familial benign chronic neutropenia. Ann Intern Med. 1964;61(5_Part_1):876–87.CrossRef

Mant MJ, Gordon PA, Akabutu JJ. Bone marrow granulocyte reserve in chronic benign idiopathic neutropenia. Clin Lab Haematol. 1987;9(3):281–8. https://doi.org/10.1111/j.1365-2257.1987.tb00092.x.CrossRefPubMed

Pathak S, Chandra AB, Huang Y, Xu Y. Etiology of Incidental Asymptomatic Neutropenia and Prevalence of Benign Ethnic Neutropenia in Patients of Chinese Ethnicity: American Society of Hematology. Blood. 2009;114(22): 4515.

Oloyede E, Dzahini O, Whiskey E, Taylor D. Clozapine and Norclozapine plasma levels in patients switched between different liquid formulations. Ther Drug Monit. 2020;42(3):491–6. https://doi.org/10.1097/FTD.0000000000000711.CrossRefPubMed

10.

Munro J, O'Sullivan D, Andrews C, Arana A, Mortimer A, Kerwin R. Active monitoring of 12760 clozapine recipients in the UK and Ireland. Br J Psychiatry. 1999;175(6):576–80. https://doi.org/10.1192/bjp.175.6.576.CrossRefPubMed

11.

Farooq S, Choudry A, Cohen D, Naeem F, Ayub M. Barriers to using clozapine in treatment-resistant schizophrenia: systematic review. BJPsych bulletin. 2019;43(1):8–16. https://doi.org/10.1192/bjb.2018.67.CrossRefPubMedPubMedCentral

12.

Kelly DL, Kreyenbuhl J, Dixon L, Love RC, Medoff D, Conley RR. Clozapine underutilization and discontinuation in African Americans due to leucopenia. Schizophr Bull. 2007;33(5):1221–4. https://doi.org/10.1093/schbul/sbl068.CrossRefPubMed

13.

Rajagopal S. Clozapine, agranulocytosis, and benign ethnic neutropenia. Postgrad Med J. 2005;81:545-546.

14.

Meyer J, Stahl S. The clozapine handbook: Stahl’s handbooks. Cambridge: Cambridge University Press; 2019.

15.

Myles N, Myles H, Xia S, Large M, Bird R, Galletly C, et al. A meta-analysis of controlled studies comparing the association between clozapine and other antipsychotic medications and the development of neutropenia. Aus N Z J Psychiatry. 2019;53(5):403–12. https://doi.org/10.1177/0004867419833166.

16.

Myles N, Myles H, Xia S, Large M, Kisely S, Galletly C, et al. Meta-analysis examining the epidemiology of clozapine-associated neutropenia. Acta Psychiatr Scand. 2018;138(2):101–9. https://doi.org/10.1111/acps.12898.

17.

Gurrera RJ. A commentary on improving clozapine accessibility and reducing treatment cost. Psychiatry Res. 2021;296:113644. https://doi.org/10.1016/j.psychres.2020.113644.CrossRefPubMed

18.

Whiskey E, Dzahini O, Ramsay R, O’Flynn D, Mijovic A, Gaughran F, et al. Need to bleed? Clozapine haematological monitoring approaches a time for change. Int Clin Psychopharmacol. 2019;34(5):264–8. https://doi.org/10.1097/YIC.0000000000000258.

19.

Oloyede E, Casetta C, Dzahini O, et al. There Is Life After the UK Clozapine Central Non-Rechallenge Database. Schizophr Bull. 2021. https://doi.org/10.1093/schbul/sbab006.

20.

Mylan. Clozaril 25mg tablets. Accessed 14 Jul 2020. https://www.medicines.org.uk/emc/product/4411/smpc

21.

Limited BP. Denzapine 50mg/ml Oral Suspension. Accessed 17 Jul 2020. https://www.medicines.org.uk/emc/product/6121/smpc

22.

BV LD. Zaponex 100 mg Tablets. Accessed 17 Jul 2020. https://www.medicines.org.uk/emc/product/7715/smpc

23.

Merz LE, Achebe M. When Non-Whiteness Becomes a Condition. Blood. 2021;137(1):13-5. https://doi.org/10.1182/blood.2020008600.

24.

Das-Munshi J, Bhugra D, Crawford MJ. Ethnic minority inequalities in access to treatments for schizophrenia and schizoaffective disorders: findings from a nationally representative cross-sectional study. BMC Med. 2018;16(1):55. https://doi.org/10.1186/s12916-018-1035-5.CrossRefPubMedPubMedCentral

25.

Ali F, Alsayegh F, Sharma P, Waheedi M, Bayoud T, Alrefai F. White blood cell subpopulation changes and prevalence of neutropenia among Arab diabetic patients attending Dasman Diabetes Institute in Kuwait. PLoS One. 2018;13(3):e0193920. https://doi.org/10.1371/journal.pone.0193920.CrossRefPubMedPubMedCentral

26.

Kelly DL, Freudenreich O, Sayer MA, Love RC. Addressing barriers to clozapine underutilization: a national effort. Am Psychiatric Assoc. 2018;69(2):224–7.

27.

Casetta C, Gaughran F, Oloyede E, Onwumere J, Pritchard M, Shergill SS, et al. Real-world effectiveness of admissions to a tertiary treatment-resistant psychosis service: 2-year mirror-image study. BJPsych Open. 2020;6(5):e82. https://doi.org/10.1192/bjo.2020.51.

28.

Whiskey E, Barnard A, Oloyede E, Dzahini O, Taylor D, Shergill SS. An evaluation of the variation and underuse of clozapine in the United Kingdom. Acta Psychiatr Scand, 2021. https://doi.org/10.1111/acps.13280.

29.

Freudenreich O, Henderson DC, Sanders KM, Goff DC. Training in a clozapine clinic for psychiatry residents: a plea and suggestions for implementation. Acad Psychiatry. 2013;37(1):27–30. https://doi.org/10.1176/appi.ap.11090159.CrossRefPubMed

30.

Cohen D. Prescribers fear as a major side-effect of clozapine. Acta Psychiatr Scand. 2014;130(2):154–5. https://doi.org/10.1111/acps.12294.CrossRefPubMed

31.

Lin CH, Chan HY, Hsu CC, Chen FC. Temporal trends in clozapine use at time of discharge among people with schizophrenia at two public psychiatric hospitals in Taiwan, 2006–2017. Sci Rep. 2020;10(1):17984. https://doi.org/10.1038/s41598-020-75022-8.CrossRefPubMedPubMedCentral

32.

Frater JL. How I investigate neutropenia. Int J Lab Hematol. 2020;42(S1):121–32. https://doi.org/10.1111/ijlh.13210.CrossRefPubMed

33.

Lima CSP, Paula EV, Takahashi T, Saad STO, Lorand-Metze I, Costa FF. Causes of incidental neutropenia in adulthood. Ann Hematol. 2006;85(10):705–9. https://doi.org/10.1007/s00277-006-0150-0.CrossRefPubMed

34.

Denic S, Showqi S, Klein C, Takala M, Nagelkerke N, Agarwal MM. Prevalence, phenotype and inheritance of benign neutropenia in Arabs. BMC Hematol. 2009;9(1):3. https://doi.org/10.1186/1471-2326-9-3.CrossRef

35.

Black LL, Greenidge LL, Ehmann T, Ganesan S, Honer WG. A centralized system for monitoring clozapine use in British Columbia. Psychiatric Serv (Washington, DC). 1996;47(1):81–3.CrossRef

36.

Grassi B, Ferrari R, Epifani M, Dragoni C, Cohen S, Scarone S. Clozapine lacks previous clinical efficacy when restarted after a period of discontinuation: a case series. European Neuropsychopharmacology. 1999;9(6):479-481.

37.

Denic S, Nicholls MG. A call for screening for benign neutropenia in Arab populations. Saudi Med J. 2011;32(738):9.

38.

Hershman D, Weinberg M, Rosner Z, Alexis K, Tiersten A, Grann VR, et al. Ethnic neutropenia and treatment delay in African American women undergoing chemotherapy for early-stage breast cancer. J Natl Cancer Inst. 2003;95(20):1545–8. https://doi.org/10.1093/jnci/djg073.

39.

Grann VR, Bowman N, Joseph C, Wei Y, Horwitz MS, Jacobson JS, et al. Neutropenia in 6 ethnic groups from the Caribbean and the US. Cancer. 2008;113(4):854–60. https://doi.org/10.1002/cncr.23614.

40.

Newman LA, Kaljee LM. Health disparities and triple-negative breast cancer in African American women: a review. JAMA Surg. 2017;152(5):485–93. https://doi.org/10.1001/jamasurg.2017.0005.CrossRefPubMed

41.

Denic S, Nicholls MG. A call for screening for benign neutropenia in Arab populations. Saudi Med J. 2011;32(7):738–9.PubMed

42.

Curry B, Palmer E, Mounce C, Smith G, Shah V. Assessing prescribing practices of clozapine before and after the implementation of an updated risk evaluation and mitigation strategy. Mental Health Clin. 2018;8(2):63–7. https://doi.org/10.9740/mhc.2018.03.063.CrossRef

43.

Tirupati S, Nagesh O, Gulati S. Benign ethnic neutropenia and clozapine treatment protocol in Australia. Aust N Z J Psychiatry. 2020;54(2):210–1. https://doi.org/10.1177/0004867419883024.CrossRefPubMed

44.

Ortiz MV, Meier ER, Hsieh MM. Identification and clinical characterization of children with benign ethnic neutropenia. J Pediatr Hematol Oncol. 2016;38(3):e140–3. https://doi.org/10.1097/MPH.0000000000000528.CrossRefPubMedPubMedCentral

45.

Reich D, Nalls MA, Kao WH, et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet. 2009;5(1):e1000360. https://doi.org/10.1371/journal.pgen.1000360.CrossRefPubMedPubMedCentral

46.

Charles BA, Hsieh MM, Adeyemo AA, Shriner D, Ramos E, Chin K, et al. Analyses of genome wide association data, cytokines, and gene expression in African-Americans with benign ethnic neutropenia. PLoS One. 2018;13(3):e0194400. https://doi.org/10.1371/journal.pone.0194400.

47.

Teteh DK, Dawkins-Moultin L, Hooker S, Hernandez W, Bonilla C, Galloway D, et al. Genetic ancestry, skin color and social attainment: the four cities study. PLoS One. 2020;15(8):e0237041. https://doi.org/10.1371/journal.pone.0237041.

48.

Hsieh MM, Everhart JE, Byrd-Holt DD, Tisdale JF, Rodgers GP. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. Ann Intern Med. 2007;146(7):486–92. https://doi.org/10.7326/0003-4819-146-7-200704030-00004.CrossRefPubMed

49.

Barreto MESF, Lipay ME, Santos LD, et al. Duffy phenotyping and FY*B-67T/C genotyping as screening test for benign constitutional neutropenia. Hematol Transfus Cell Ther. 2020. https://doi.org/10.1016/j.htct.2020.08.015.

50.

Papadaki HA, Eliopoulos AG, Kosteas T, Gemetzi C, Damianaki A, Koutala H, et al. Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells. Blood. 2003;101(7):2591–600. https://doi.org/10.1182/blood-2002-09-2898.

51.

Addas-Carvalho M, de Paula EV, Lima CS, Saad ST. Polymorphisms of interleukin-1 gene complex, IL6 and tumour necrosis factor genes in chronic idiopathic neutropenia of adults. Ann Hematol. 2005;84(11):709–14. https://doi.org/10.1007/s00277-005-1066-9.CrossRefPubMed

52.

Mpofu R, Otwombe K, Mlisana K, Nchabeleng M, Allen M, Kublin J, et al. Benign ethnic neutropenia in a south African population, and its association with HIV acquisition and adverse event reporting in an HIV vaccine clinical trial. PLoS One. 2021;16(1):e0241708. https://doi.org/10.1371/journal.pone.0241708.

53.

Mantzaris I, Msaouel P, Lam AP, Friedman EW, Yu Y, Verma A. Ethnicity specific cutoffs for neutropenia are predictive of overall survival in a large elderly cohort: an analysis of 26,652 individuals. Blood. 2014;124(21):4944. https://doi.org/10.1182/blood.V124.21.4944.4944.CrossRef

54.

Coates S, Wang D, Pierscionek T, Fernandes S, Djumanov D, Lorch U, et al. Time-and race-specific Haematological reference intervals for healthy volunteer trials: a retrospective analysis of pooled data from multiple phase I trials. Front Pharmacol. 2020;11:314. https://doi.org/10.3389/fphar.2020.00314.

55.

Lim E, Miyamura J, Chen JJ. Racial/ethnic-specific reference intervals for common laboratory tests: a comparison among Asians, blacks, Hispanics, and white. Hawai'i J Med Public Health. 2015;74(9):302–10.

Title: Benign ethnic neutropenia: an analysis of prevalence, timing and identification accuracy in two large inner-city NHS hospitals
Authors: Ebenezer Oloyede
Olubanke Dzahini
Nigel Barnes
Aleksandar Mijovic
Shreyans Gandhi
Sara Stuart-Smith
Theo de Witte
David Taylor
Eromona Whiskey
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Neutropenia
Clozapine
Published in: BMC Psychiatry / Issue 1/2021
Electronic ISSN: 1471-244X
DOI: https://doi.org/10.1186/s12888-021-03514-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Benign ethnic neutropenia: an analysis of prevalence, timing and identification accuracy in two large inner-city NHS hospitals

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Mental health condition of physicians working frontline with COVID-19 patients in Bangladesh

How best to provide help to bereaved adolescents: a Delphi consensus study

Attention-deficit/hyperactivity disorder with developmental coordination disorder: 24-year follow-up of a population-based sample

Efficacy and safety of fixed doses of intranasal Esketamine as an add-on therapy to Oral antidepressants in Japanese patients with treatment-resistant depression: a phase 2b randomized clinical study

Anhedonia difference between major depressive disorder and bipolar disorder II

Predictors of the one-year-change in depressiveness in informal caregivers of community-dwelling people with dementia