Download - Neutropenia in Pediatrics
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
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
