1. Neutropenia in Pediatrics Bradd Hemker MD Pediatric and Adolescent Hematology and Oncology Department of Pediatrics and Human Development Michigan State University

2. Objectives Define neutropenia and risks associated with various levels of neutropenia Review causes of neutropenia in childhood Discuss proper initial evaluation and management of neutropenia Discuss when to refer to pediatric hematologist

3. Definition of Neutropenia Absolute Neutrophil Count (ANC) – ANC = WBC x (% bands + segs) Normal ANC: 1500/mm 3 Neutropenia – Mild: 1000-1500 – Moderate: 500-1000 – Severe: <500 Age matters (slightly)

4. Pediatric Neutropenias History – Recurrent infections – Recurrent oral ulcers

5. Neutropenia Related Infection Risk of serious bacterial or fungal infection when ANC <500 Also depends on bone marrow reserve – Inability to make neutrophils (SCN or chemotherapy) = higher risk – Destruction of neutrophils (auto-immune) = lower risk

6. Causes of Neutropenia Acquired – Infection – Infiltrative bone marrow disease – Immune mediated – Medication Congenital – Severe Congenital – Cyclic neutropenia – Chronic benign neutropenia of childhood – Chronic neutropenia of childhood – Benign Ethnic Neutropenia – Schwachman Diamond syndrome

7. Infection related neutropenia Most common cause of low ANC in pedatrics viral or bacterial – May be immune mediated +/- anti-granulocyte antibodies – Direct bone marrow suppression – Marginalization of neutrophils Treatment: none typically needed – May take 3-4 weeks or longer to resolve!

8. Auto-Immune Neutropenia Often triggered by infection May be part of broader auto-immune disorder Anti-granulocyte antibodies positive Treatment – +/- IVIG, steroids, GCSF – Only if severe infection (ie hospitalized) May take years to resolve!

9. Neonatal Alloimmune Neutropenia Maternal antibodies to paternal antigens on fetal platelets Identical to Rh disease of newborn Typically resolves spontaneously over weeks to few months Diagnosis: testing of parental blood

10. Drug Induced Neutropenia Antibiotics Bactrim Ciprofloxacin Clindamycin Vancomycin Metronidazole Doxycycline Chemotherapy Neuropsychotropics Respiridone Valproic acid Phenytoin Carbamazepine Barbiturates Antihypertensives & Antiarrythmics Analgesics NSAIDS Aspirin Treatment?

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

12. Congenital Neutropenias Schwachmann Diamond Syndrome – Neutropenia, pancreatic insufficiency – Presents in 1 st 10 years of life with steatorrhea, growth failure and infections – Physical anomalies are common (cleft palate, syndactyly, strabismus)

13. Congenital Neutropenia Cyclic Neutropenia – Blood counts cycle every ~21 days ANC most pronounced – Recurrent fevers, bacterial infections when ANC low – Diagnosis Standard = CBC twice weekly x 6 weeks ELA-2 testing – Treatment: GCSF if significant infectious history

14. Congenital Neutropenia Chronic Neutropenia of Childhood – ANC often <500 – Associated with significant infectious history – Diagnosis of exclusion No evidence of cycling counts Normal bone marrow +/- anti-granulocyte antibodies – Treatment: GCSF if significant infections

15. Congenital Neutropenia Chronic Benign Neutropenia of Childhood – ANC often <500 – Not associated with significant infectious history – Diagnosis of exclusion No evidence of cycling counts Normal bone marrow +/- anti-granulocyte antibodies – Treatment: GCSF if significant infections

16. Congenital Neutropenia Syndrome associated neutropenia – Myelokathexis (WHIM syndrome) – Glycogen storage disease type 1 – Mitochondrial disorders – Congenital cobalamin deficiency – X-linked agammaglobulinemia – Chediak-Higashi syndrome – GCSF receptor mutations

17. Benign Ethnic Neutropenia Overall WBC and ANC vary by ethnic group – African Americans tend to run lower compared to causcasians – ANC 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 Neutropenia History, exam – Recurrent infections – Recurrent oral ulcers Labs – CBC w/ differential – Anti-granulocyte antibodies

19. Workup of Neutropenia If suspect post-infectious – Repeat labs in 3-4 weeks – if 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 fever – hospitalization for blood cultures, IV antibiotics Worrisome history – Recurrent fevers, night sweats, weight loss, enlarged lymph nodes, refusal to walk, bone pain Worrisome exam – Lymphadenopathy, organomegaly

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

22. Pediatric Hematology Neutropenia Work-Up Detailed history regarding infections, ulcers, diarrhea, etc. Repeat CBC w/ manual diff – Review peripheral smear – Concern for other cytopenias or other WBC morphologic abnormalities  bone marrow asp/bx Cyclic neutropenia work-up – CBC twice weekly x 6 weeks – ELA2 gene testing Repeat counts every 2-4 weeks—less often if patient stable without ongoing infectious concerns Bone marrow evaluation

23. Treatment of Neutropenia Granulocyte colony stimulating factor (GCSF) – 1-5 mcg/kg SQ Daily Three times per week Weekly... When? – Symptomatic neutropenia (serious infection) – Prevention of neutropenia (if h/o serious infections)

24. Chronic Neutropenia Children need evaluation with any fevers – CBC w/diff – Blood culture – +/- empiric antibiotics (ceftriaxone) If ANC < 500  hospitalize for IV antibiotics until blood cultures negative and ANC improving If ANC > 500  treat like any other child

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

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