Transcript Neutropenia in Pediatrics

Neutropenia in Pediatrics
Bradd Hemker 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
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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
Antihypertensives &
Antiarrythmics
Bactrim
Ciprofloxacin
Clindamycin
Vancomycin
Metronidazole
Doxycycline
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
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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?
[email protected]
References
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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