Neutropenia in Pediatrics BraddHemker MD Pediatric and Adolescent Hematology and Oncology Department of Pediatrics and Human Development Michigan State University
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
Definition of Neutropenia • Absolute Neutrophil Count (ANC) • ANC = WBC x (% bands + segs) • Normal ANC: 1500/mm3 • Neutropenia • Mild: 1000-1500 • Moderate: 500-1000 • Severe: <500 • Age matters (slightly)
Pediatric Neutropenias • History • Recurrent infections • Recurrent oral ulcers
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
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
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!
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!
Neonatal AlloimmuneNeutropenia • 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
Drug Induced Neutropenia Antibiotics Bactrim Ciprofloxacin Clindamycin Vancomycin Metronidazole Doxycycline Antihypertensives & Antiarrythmics Neuropsychotropics Respiridone Valproic acid Phenytoin Carbamazepine Barbiturates Analgesics NSAIDS Aspirin Chemotherapy Treatment?
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
Congenital Neutropenias • Schwachmann Diamond Syndrome • Neutropenia, pancreatic insufficiency • Presents in 1st 10 years of life with steatorrhea, growth failure and infections • Physical anomalies are common (cleft palate, syndactyly, strabismus)
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
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
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
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
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!
Workup of Neutropenia • History, exam • Recurrent infections • Recurrent oral ulcers • Labs • CBC w/ differential • Anti-granulocyte antibodies
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
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
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 . . .
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
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)
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
References • Donadieu et al. Congenital neutropenia: diagnosis, molecular bases and patient management. OrphanetJ 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 • WalkovichK, 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 NonchemotherapyDrugs. Ann Intern Med. 2007;146:657-665