Neutropenia in Pediatrics - PowerPoint Presentation

1. Neutropenia in PediatricsBradd Hemker MDPediatric and Adolescent Hematology and OncologyDepartment of Pediatrics and Human DevelopmentMichigan State University

2. ObjectivesDefine neutropenia and risks associated with various levels of neutropeniaReview causes of neutropenia in childhoodDiscuss proper initial evaluation and management of neutropeniaDiscuss when to refer to pediatric hematologist

3. Definition of NeutropeniaAbsolute Neutrophil Count (ANC)ANC = WBC x (% bands + segs)Normal ANC: 1500/mm3 NeutropeniaMild: 1000-1500Moderate: 500-1000Severe: <500Age matters (slightly)

4. Pediatric NeutropeniasHistoryRecurrent infectionsRecurrent oral ulcers

5. Neutropenia Related InfectionRisk of serious bacterial or fungal infection when ANC <500Also depends on bone marrow reserveInability to make neutrophils (SCN or chemotherapy) = higher riskDestruction of neutrophils (auto-immune) = lower risk

6. Causes of NeutropeniaAcquiredInfectionInfiltrative bone marrow diseaseImmune mediatedMedicationCongenitalSevere Congenital Cyclic neutropeniaChronic benign neutropenia of childhoodChronic neutropenia of childhoodBenign Ethnic NeutropeniaSchwachman Diamond syndrome

7. Infection related neutropeniaMost common cause of low ANC in pedatricsviral or bacterialMay be immune mediated+/- anti-granulocyte antibodiesDirect bone marrow suppressionMarginalization of neutrophilsTreatment: none typically neededMay take 3-4 weeks or longer to resolve!

8. Auto-Immune NeutropeniaOften triggered by infectionMay be part of broader auto-immune disorderAnti-granulocyte antibodies positiveTreatment+/- IVIG, steroids, GCSFOnly if severe infection (ie hospitalized)May take years to resolve!

9. Neonatal Alloimmune NeutropeniaMaternal antibodies to paternal antigens on fetal plateletsIdentical to Rh disease of newbornTypically resolves spontaneously over weeks to few monthsDiagnosis: testing of parental blood

10. Drug Induced Neutropenia AntibioticsBactrimCiprofloxacinClindamycinVancomycinMetronidazoleDoxycyclineChemotherapyNeuropsychotropicsRespiridoneValproic acidPhenytoinCarbamazepineBarbituratesAntihypertensives & AntiarrythmicsAnalgesicsNSAIDSAspirin Treatment?

11. Congenital NeutropeniasSevere Congenital Neutropenia (Kostmann Syndrome)Incidence ~1/1,000,000Severe infections early in life—pneumonia, abscesses, etc Inability to make neutrophils  ANC very lowTypically diagnosed in infancyElastase 2 mutation (ELA-2)Treatment: GCSF

12. Congenital NeutropeniasSchwachmann Diamond SyndromeNeutropenia, pancreatic insufficiencyPresents in 1st 10 years of life with steatorrhea, growth failure and infectionsPhysical anomalies are common (cleft palate, syndactyly, strabismus)

13. Congenital NeutropeniaCyclic NeutropeniaBlood counts cycle every ~21 days ANC most pronouncedRecurrent fevers, bacterial infections when ANC lowDiagnosisStandard = CBC twice weekly x 6 weeksELA-2 testingTreatment: GCSF if significant infectious history

14. Congenital NeutropeniaChronic Neutropenia of ChildhoodANC often <500Associated with significant infectious historyDiagnosis of exclusionNo evidence of cycling countsNormal bone marrow+/- anti-granulocyte antibodiesTreatment: GCSF if significant infections

15. Congenital NeutropeniaChronic Benign Neutropenia of ChildhoodANC often <500Not associated with significant infectious historyDiagnosis of exclusionNo evidence of cycling countsNormal bone marrow+/- anti-granulocyte antibodiesTreatment: GCSF if significant infections

16. Congenital NeutropeniaSyndrome associated neutropeniaMyelokathexis (WHIM syndrome)Glycogen storage disease type 1Mitochondrial disordersCongenital cobalamin deficiencyX-linked agammaglobulinemiaChediak-Higashi syndromeGCSF receptor mutations

17. Benign Ethnic NeutropeniaOverall WBC and ANC vary by ethnic groupAfrican Americans tend to run lower compared to causcasiansANC of 1100 may not be abnormal for some patients! Slightly low ANC without any signficant infectious history may not require any further work up!

18. Workup of NeutropeniaHistory, examRecurrent infectionsRecurrent oral ulcersLabsCBC w/ differentialAnti-granulocyte antibodies

19. Workup of NeutropeniaIf suspect post-infectiousRepeat labs in 3-4 weeksif ANC remains low but improved and patient is clinically well—repeat in another 3-4 weeks.If no change over this time  consider referral to hematologist

20. When to worry . . . ANC <500 with feverhospitalization for blood cultures, IV antibioticsWorrisome history Recurrent fevers, night sweats, weight loss, enlarged lymph nodes, refusal to walk, bone painWorrisome examLymphadenopathy, organomegaly

21. When to Refer Persistently low ANC (< 1000) regardless of infectious historyMildly low ANC with significant infectious historyWorrisome history or exam findings that are not improving as viral symptoms do . . .

22. Pediatric Hematology Neutropenia Work-UpDetailed history regarding infections, ulcers, diarrhea, etc. Repeat CBC w/ manual diffReview peripheral smearConcern for other cytopenias or other WBC morphologic abnormalities  bone marrow asp/bxCyclic neutropenia work-upCBC twice weekly x 6 weeksELA2 gene testingRepeat counts every 2-4 weeks—less often if patient stable without ongoing infectious concernsBone marrow evaluation

23. Treatment of NeutropeniaGranulocyte colony stimulating factor (GCSF)1-5 mcg/kg SQ DailyThree times per weekWeekly . . . When? Symptomatic neutropenia (serious infection)Prevention of neutropenia (if h/o serious infections)

24. Chronic NeutropeniaChildren need evaluation with any feversCBC w/diffBlood culture+/- empiric antibiotics (ceftriaxone)If ANC < 500  hospitalize for IV antibiotics until blood cultures negative and ANC improvingIf ANC > 500  treat like any other child

25. Questions? Bradd.Hemker@hc.msu.edu

26. ReferencesDonadieu et al. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis. 2011;6:26James RM, Kinsey SE. The investigation and management of chronic neutropenia in children. Arch Dis Child. Oct 2006; 91(10): 852-858Walkovich K, Boxer LA. How to approach Neutropenia in Childhood. Pediatrics in Review. 2013;34;173Horwitz et al. Neutrophil elastase in cyclic and severe congenital neutropenia. Blood 2007, 109(5):1817-1824Dale et al. Cyclic Neutropenia. Seminars in Hematology. 2002,39(2):89-94Berliner et al. Congenital and Acquired Neutropenia. American Society of Hematology Education Book. 2004, 1:63-79Andersohn et al. Systematic Review: Agranulocytosis Induced by Nonchemotherapy Drugs. Ann Intern Med. 2007;146:657-665