Neutropenia in Pediatrics

Bradd Hemker MDPediatric and Adolescent Hematology and OncologyDepartment 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 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

Drug Induced Neutropenia Antibiotics

BactrimCiprofloxacinClindamycinVancomycin

MetronidazoleDoxycycline

Chemotherapy

NeuropsychotropicsRespiridoneValproic acid

PhenytoinCarbamazepine

Barbiturates

Antihypertensives & Antiarrythmics

AnalgesicsNSAIDSAspirin

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

Questions?

Bradd.Hemker@hc.msu.edu

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Review. 2013;34;173• Horwitz et al. Neutrophil elastase in cyclic and severe congenital neutropenia.

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Hematology Education Book. 2004, 1:63-79• Andersohn et al. Systematic Review: Agranulocytosis Induced by

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