Transcript Neutropenia - UNC School of Medicine

Cat Hathaway
Neutropenia
Definition of neutropenia is ANC <1500
cells/mm3
 African american patients can have ANC
of 1000 cells/mm3 w/o complications
 Severity of neutropenia determines the
risk of infection. Mild is 1000-1500,
Moderate 500-1000, and severe <500
 Neutropenia increases risk of
bacterial/suppurative infections. Not
parasitic or viral infections.
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The neutrophil
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About 60 billion PMNs are produced
DAILY! An equal number are circulating
in the blood, the half life is 6-8 hrs.
 Neutropenia occurs if bone marrow
production lags behind the amount in
circulation, from destruction, ineffective
granulopoeisis, or shifts into tissue
pools/vascular endothelium
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Integral in fighting infection of pyogenic
bacteria, enteric bacteria, and some
fungi
Consequences of Neutropenia
Drug induced granulocytopenia incurs 610% mortality rate
 Cancer patients with neutropenic fever
have 4-30% mortality rate
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 21% patients with cancer and neutropenic
fever will have serious complications
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Patients with ANC <500 will develop
severe infxn within 1-4 weeks, ANC
<1000 is associated with less risk, but
still substantial compared to norms
Congenital neutropenias
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Neutropenias associated with immune defects
Congenital neutropenia due to mutations
 Cyclic neutropenia
 Kostmann Syndrome (Severe Congenital
Neutropenia) – Typically die in early childhood
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Chronic benign neutropenia
Neutropenia w/ phenotypic abnormalities
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Shwachman-diamond-oski syndrome
Cartilage-hair hypoplasia syndrome
Dyskeratosis congenita
Barth Syndrome
Chediak Higashi syndrome
Congential neutropenia
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Benign familial neutropenia
 Don’t mount leukocytosis to infection, but
are able to mount fever and inflammatory
response. Not associated with higher
infection incidence
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Myeloperoxidase deficiency
 Not a real neutropenia, lab error because
some labs identify neutrophils based on
presence of myeloperoxidase
Cyclic neutropenia
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Typically autosomal dominant
Found to be due to germline mutations in
ELA2
 ELA2 encodes neutrophil elastase. Interestingly this
protein in molecular studies seems to be an
oncoprotein
 Kostmann syndrome also assoc with ELA2
mutations and GCSF-r mutations and in 10 yrs 21%
will go on to develop MDS and or AML
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Counts cycle every 21 days with nadirs close
to 0 and peaks near normal
Length of nadir relates to infxs complications
Acquired Neutropenia
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Infections (most common)
 HIV, erhlichia, parasites, parvo B19, EBV, HepB, HCV
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Nutritional deficiency
 B12, copper, folate
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Drugs/chemicals/chemo (1-3.4 cases/million/yr)
 Antithyroid, macrolides, procainamide, sulfonamides
 Clozapine causes agranulocytosis in 1% of patients, but
appears to be genetic not immune
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Immunologic due to BMT or blood tx
Felty Syndrome (RA, splenomegaly, neutropenia)
Splenic sequestration
Complement activation (2/2 ECMO, HD,
cardiopulmonary bypass, etc)
Other differentials
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Leukemia (CLL, CML, ALL, AML, hairy cell)
Lymphoma (Hodgkin, NonHodgkin)
T-LGL – indolent, responds well to
immunosuppression
PNH
Bone marrow failure, MDS
MM
Autoimmune Neutropenia (Primary and
Secondary)
 SLE, RA are assoc with secondary AIN
 Primary AIN typically presents in early childhood
Work up
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CBC with diff
B12, folate
Infectious workup (if fever present)
 Bcx, ucx, cxr, sputum cx
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Bone marrow biopsy
 Esp if anemia/thrombocytopenia also present
 Can evaluate for maturation arrest, fungal
infection, marrow defect, b12/folate deficiency
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Testing for neutrophil antibodies can be
done, but is difficult and false positives and
false negatives are common
Neutrophil Antibody Assays
GIFT (granulocyte immunofluorescent
test) – indirect assay using patient’s
serum and banked normal PMNs
 GAT (granulocyte agglutination test)
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 Normal PMNs incubated with serum from pt
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Tests are difficult secondary to HLA
alloantibodies and immune complexes
 Therefore in routine practice these tests are
not recommended
Medications/Treatment
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Depends on etiology of neutropenia
 Drug related, remove offending agent.
 Viral related, no treatment typically
necessary
Avoid rectal exams/give stool softener
 Neutropenic diet (no fresh fruit/veg)
 If fever present then broad spectrum abx
 For chemo related or cyclic neutropenia
often tx with GCSF agents
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Treatment continued
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Primary AIN
 Typically not associated with severe infections
and often only treated symptomatically for
infections w/ abx
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Secondary AIN
 Often assoc with SLE/RA – can use GCSF but
have to be careful because this can lead to
disease flares and leukocytoclastic vasculitis
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Infections due to neutropenia
 Management of underlying infxn, supportive
abx/treatment
Chemotherapy induced
neutropenia
In patients who have developed prior
episodes of neutropenia, often will
presumptively treat with GCSF as they
are at higher risk for recurrent
neutropenia
 In patients with risk of 20% or more for
neutropenia following treatment primary
prophylaxis with GCSF may be indicated
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Danger on the road
Resources
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Neutropenia: Differential Diagnoses & Workup. Author: John E Godwin, MD, MS, Professor of
Medicine, Chief Division of Hematology/Oncology, Associate Director, Simmons Cooper Cancer
Institute, Southern Illinois University School of Medicine Coauthor(s): Christopher D Braden, DO,
Attending Physician, Department of Hematology and Oncology, St. Francis Cancer Center,
Indianapolis, Indiana. Updated: Oct 16, 2008. Accessed 9/7/09.
Hematology 2004 The American Society of Hematology. Congenital and Acquired Neutropenia
Nancy Berliner, Marshall Horwitz and Thomas P. Loughran Jr.
Clinical Cornerstone Volume 8, Supplement 5, 2006, Pages S5-S11 Neutropenia: Overview and
Current Therapies
Congenital neutropenia Robert L Baehner, MD, Last literature review version 17.2: May
2009 | This topic last updated: March 29, 2009. Accessed 9/9/09
Overview of neutropenia Robert L Baehner, MD, Last literature review version 17.2: May
2009 | This topic last updated: February 19, 2009. Accessed 9/9/09