Paeds · haematology-oncology-and-transfusion

Neutropenia and neutrophil disorders

Also known as Neutropenia · Low neutrophil count · Severe congenital neutropenia · Cyclic neutropenia · Autoimmune neutropenia of infancy · Benign ethnic neutropenia

Fellowship guide to neutropenia and the neutrophil disorders in children. Covers the absolute neutrophil count thresholds that define and grade neutropenia from mild to severe, the neutrophil kinetic model that localises the mechanism to marrow production failure, peripheral destruction, splenic sequestration or marrow retention, and the full differential from common transient post-viral and chemotherapy causes through autoimmune neutropenia of infancy and alloimmune neonatal neutropenia to the inherited syndromes including ELANE severe congenital neutropenia, cyclic neutropenia, Shwachman-Diamond with SBDS, GATA2 deficiency, WHIM with CXCR4, Chediak-Higashi with LYST and Barth syndrome with TAZ. Details the workup of the incidental low count, anti-neutrophil antibody testing, bone marrow and gene panel, the first-hour management of febrile severe neutropenia with empiric anti-pseudomonal beta-lactam, the lifelong granulocyte colony-stimulating factor of severe congenital neutropenia with annual marrow surveillance for myelodysplastic syndrome and acute myeloid leukaemia, the curative role of haematopoietic stem cell transplant, and the reassuring prognosis of benign ethnic neutropenia and autoimmune neutropenia of infancy.

high14 referencesUpdated 16 July 202627 min readVerification in progress

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Red flags

A febrile child with a neutrophil count under 0.5 times ten to the ninth per litre, defined as a single temperature of 38.5 degrees Celsius or higher or 38.0 degrees or higher over one hour, is presumed bacteraemic and must receive empiric intravenous anti-pseudomonal beta-lactam within the first hour after blood culturesNeutropenia with pancytopenia, blasts or dysplasia on the film points to marrow failure or infiltration such as acute leukaemia or aplastic anaemia and needs urgent bone marrow rather than outpatient monitoringA single low neutrophil count must be repeated on a fresh sample before any workup, because ethylenediaminetetraacetic-acid clumping and post-viral dips are common and spuriousBenign ethnic neutropenia of African, Middle Eastern or Yemenite Jewish ancestry is a normal Duffy-null variant with a normal marginated pool and normal function, and must not be over-investigated or labelled dangerousSevere congenital neutropenia carries a cumulative risk of myelodysplastic syndrome and acute myeloid leukaemia of roughly twenty per cent over ten years on granulocyte colony-stimulating factor, so annual marrow surveillance with cytogenetics is mandatoryA neonate with omphalitis, delayed cord separation, skin pustulosis or unexplained sepsis may have alloimmune or maternal autoimmune neutropenia, so anti-neutrophil antibodies and human neutrophil antigen typing of mother and baby are part of the neonatal sepsis workup

Life stages

neonateinfanttoddlerpreschoolschool-ageadolescent

Care settings

preventive-medical-homeoutpatientwarded-acutenicupicurural-remotetelehealth

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Defines neutropenia as an absolute neutrophil count under 1.5 times ten to the ninth per litre and grades it as mild, moderate and severeLists the common acquired causes including post-viral, drug and chemotherapy, autoimmune and nutritional causesRecognises febrile severe neutropenia as an emergency requiring prompt empiric antibioticsExplains neutrophil kinetics and localises the mechanism of neutropenia to production failure, peripheral destruction, sequestration or retentionDistinguishes severe congenital neutropenia, cyclic neutropenia, Shwachman-Diamond, GATA2 deficiency, WHIM and Chediak-Higashi by their genes and phenotypeApplies the Severe Chronic Neutropenia International Registry evidence for granulocyte colony-stimulating factor and marrow surveillance for myelodysplastic syndrome and acute myeloid leukaemiaThe workup of the child with isolated neutropenia and the timing of anti-neutrophil antibody testing and bone marrowRecognition and first-hour management of the febrile severely neutropenic childCounselling the family of a child with benign ethnic neutropenia or autoimmune neutropenia of infancy on the benign courseBedside assessment of a child with recurrent infections and a low neutrophil count, including the syndrome cluesCommunication of the diagnosis of autoimmune neutropenia of infancy and the safety-net to the familyCoordination of the multidisciplinary care of a child with a congenital neutropenia syndrome and the transplant decisionLevel 1: Recognises the common benign causes of neutropenia in childhood and the febrile-neutropenia emergencyLevel 2: Applies the neutrophil kinetic model, the severity grading and the targeted investigationsLevel 3: Manages the chronic congenital neutropenia syndromes with granulocyte colony-stimulating factor, prophylaxis, surveillance and transplant referralAbsolute neutrophil count definition and severity gradingNeutrophil kinetics and the mechanism-based classification of neutropeniaGenes and phenotypes of the congenital neutropenia syndromes and the benign variantsHistory and examination of a child with recurrent infections and a low neutrophil countCommunication of a benign diagnosis such as autoimmune neutropenia of infancy or benign ethnic neutropeniaAssessment and immediate management of a febrile neutropenic childCalculation of the absolute neutrophil count and interpretation of severity bandsDiagnosis and management of severe congenital neutropenia and cyclic neutropenia with granulocyte colony-stimulating factorRecognition of the congenital neutropenia syndromes and the role of haematopoietic stem cell transplantTargeted investigation of chronic neutropenia including bone marrow and a gene panelLongitudinal care and surveillance of the child with severe congenital neutropeniaDiagnosis and management of childhood neutropenia in the Canadian paediatric populationRecognition of benign ethnic neutropenia and avoidance of over-investigationManagement of the congenital neutropenia syndromes with granulocyte colony-stimulating factor and transplant referral

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Target exams

RACP General PaediatricsRACP DWERACP DCEMRCPCH TheoryMRCPCH ClinicalABP General PediatricsRCPSC Pediatrics

Red flags

Life stages

neonateinfanttoddlerpreschoolschool-ageadolescent

Care settings

preventive-medical-homeoutpatientwarded-acutenicupicurural-remotetelehealth

Clinical exam formats

written-only

Board mappings

Overview & Definition

A worried parent brings in a healthy-looking three-year-old for a repeat blood count. The first count, taken during a viral cold a week ago, showed a neutrophil count of 0.8 times ten to the ninth per litre. Today the count is normal. This is the commonest face of paediatric neutropenia: a brief, benign, post-viral dip that resolves on its own. The skill is to recognise that face confidently, and at the same time to know the small minority in whom a low neutrophil count is the first clue to a congenital marrow failure syndrome, a leukaemia, or an immune process. [1]

Neutropenia means an absolute neutrophil count below the age- and population-appropriate lower limit. For practical purposes in older children and adults that lower limit is 1.5 times ten to the ninth per litre. The absolute neutrophil count is not printed by accident; it is calculated from the full blood count as the white cell count multiplied by the percentage of segmented neutrophils plus bands, all divided by one hundred. Severity is graded in three bands, and the band matters, because infection risk climbs sharply only in the severe band. Mild neutropenia is 1.0 to 1.5, moderate is 0.5 to 1.0, and severe is under 0.5 times ten to the ninth per litre. [1]

Neutrophils are the front-line defence against pyogenic bacteria and fungi. They turn over rapidly, surviving only hours in the circulation, so the count is a sensitive read-out of the balance between marrow production and peripheral use. When that balance breaks, the child becomes vulnerable to the very organisms that live on the skin, in the gut and in the mouth, and the first sign can be a single spike of fever that demands same-hour antibiotics. The fellowship candidate must hold three things at once: the thresholds that grade severity, the kinetic model that localises the mechanism, and the gene list that names the congenital syndromes. [1]

One-sentence answer for the exam

Neutropenia in a child is an absolute neutrophil count under 1.5 times ten to the ninth per litre, graded as mild 1.0 to 1.5, moderate 0.5 to 1.0, and severe under 0.5, and the first move is always to repeat the count on a fresh sample and examine the film, because most childhood neutropenia is a benign transient post-viral or drug-related dip. The dangerous scenario is febrile severe neutropenia, defined as a temperature of 38.5 degrees Celsius or higher with a count under 0.5, which needs blood cultures and empiric intravenous anti-pseudomonal beta-lactam within the first hour. The chronic congenital syndromes (severe congenital neutropenia and cyclic neutropenia from ELANE, Shwachman-Diamond from SBDS, GATA2 deficiency, WHIM from CXCR4, Chediak-Higashi from LYST) are managed with lifelong granulocyte colony-stimulating factor, antimicrobial prophylaxis, annual marrow surveillance for myelodysplastic syndrome and acute myeloid leukaemia, and haematopoietic stem cell transplant for transformation or marrow failure; autoimmune neutropenia of infancy and benign ethnic neutropenia are benign and need only reassurance.

[1][2]

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References14Show ledger

[1]Newburger PE, Dale DC Evaluation and management of patients with isolated neutropenia. Semin Hematol, 2013.PMID 23953336
[2]Welte K, Zeidler C, Dale DC Severe congenital neutropenia. Semin Hematol, 2006.PMID 16822461
[3]Dale DC, Cottle TE, Fier CJ, Bolyard AA, Bonilla MA, Boxer LA, et al Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol, 2003.PMID 12555210
[4]Rosenberg PS, Alter BP, Bolyard AA, Bonilla MA, Boxer LA, Cham B, et al The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood, 2006.PMID 16497969
[5]Makaryan V, Zeidler C, Bolyard AA, Skokowa J, Boxer L, Dale DC, et al The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol, 2015.PMID 25427142
[6]Horwitz MS, Corey SJ, Grimes HL, et al. ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematol Oncol Clin North Am, 2013.PMID 23351986
[7]Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, Rommens JM Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet, 2003.PMID 12496757
[8]Dror Y, Donadieu J, Koglmeier J, Dodge J, Toiviainen-Salo S, Makitie O, et al Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N Y Acad Sci, 2011.PMID 22191555
[9]Maheshwari A Neutropenia in the newborn. Curr Opin Hematol, 2014.PMID 24322487
[10]Lakhotia R, Aggarwal A, Link ME, et al. Natural history of benign ethnic neutropenia in individuals of African ancestry. Blood Cells Mol Dis, 2019.PMID 30909074
[11]Reich D, Nalls MA, Kao WH, Akylbekova EL, Tandon A, Patterson N, 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.PMID 19180233
[12]Kaplan J, De Domenico I, Ward DM Chediak-Higashi syndrome. Curr Opin Hematol, 2008.PMID 18043242
[13]Hsu AP, Sampaio EP, Khan J, Calvo KR, Lemieux ME, Patel SY, et al Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood, 2011.PMID 21670465
[14]Gulino AV, Moratto D, Sozzani S, Cavadini P, Otero K, Tassone L, et al Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome. Blood, 2004.PMID 15026312

Neutropenia and neutrophil disorders

Also known as Neutropenia · Low neutrophil count · Severe congenital neutropenia · Cyclic neutropenia · Autoimmune neutropenia of infancy · Benign ethnic neutropenia

high14 referencesUpdated 16 July 202627 min readVerification in progress

Practise this topic

Overview & Definition

Paediatrics Fellowship Pro

You have read the opening of this topic. The complete unit — every section and its primary-source references — is part of the Paediatrics Fellowship fellowship atlas.

References14Show ledger

[1]Newburger PE, Dale DC Evaluation and management of patients with isolated neutropenia. Semin Hematol, 2013.PMID 23953336
[2]Welte K, Zeidler C, Dale DC Severe congenital neutropenia. Semin Hematol, 2006.PMID 16822461
[3]Dale DC, Cottle TE, Fier CJ, Bolyard AA, Bonilla MA, Boxer LA, et al Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol, 2003.PMID 12555210
[4]Rosenberg PS, Alter BP, Bolyard AA, Bonilla MA, Boxer LA, Cham B, et al The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood, 2006.PMID 16497969
[5]Makaryan V, Zeidler C, Bolyard AA, Skokowa J, Boxer L, Dale DC, et al The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol, 2015.PMID 25427142
[6]Horwitz MS, Corey SJ, Grimes HL, et al. ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematol Oncol Clin North Am, 2013.PMID 23351986
[7]Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, Rommens JM Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet, 2003.PMID 12496757
[8]Dror Y, Donadieu J, Koglmeier J, Dodge J, Toiviainen-Salo S, Makitie O, et al Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N Y Acad Sci, 2011.PMID 22191555
[9]Maheshwari A Neutropenia in the newborn. Curr Opin Hematol, 2014.PMID 24322487
[10]Lakhotia R, Aggarwal A, Link ME, et al. Natural history of benign ethnic neutropenia in individuals of African ancestry. Blood Cells Mol Dis, 2019.PMID 30909074
[11]Reich D, Nalls MA, Kao WH, Akylbekova EL, Tandon A, Patterson N, 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.PMID 19180233
[12]Kaplan J, De Domenico I, Ward DM Chediak-Higashi syndrome. Curr Opin Hematol, 2008.PMID 18043242
[13]Hsu AP, Sampaio EP, Khan J, Calvo KR, Lemieux ME, Patel SY, et al Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood, 2011.PMID 21670465
[14]Gulino AV, Moratto D, Sozzani S, Cavadini P, Otero K, Tassone L, et al Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome. Blood, 2004.PMID 15026312