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.

The neutrophil 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

Integral in fighting infection of pyogenic bacteria, enteric bacteria, and some fungi

Consequences of Neutropenia Drug induced granulocytopenia incurs 6-

10% mortality rate Cancer patients with neutropenic fever

have 4-30% mortality rate21% patients with cancer and neutropenic

fever will have serious complications 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 Neutropenias associated with immune defects Congenital neutropenia due to mutations

Cyclic neutropeniaKostmann Syndrome (Severe Congenital

Neutropenia) – Typically die in early childhood Chronic benign neutropenia Neutropenia w/ phenotypic abnormalities

Shwachman-diamond-oski syndromeCartilage-hair hypoplasia syndromeDyskeratosis congenitaBarth SyndromeChediak Higashi syndrome

Congential neutropenia

Benign familial neutropeniaDon’t mount leukocytosis to infection, but

are able to mount fever and inflammatory response. Not associated with higher infection incidence

Myeloperoxidase deficiencyNot a real neutropenia, lab error because

some labs identify neutrophils based on presence of myeloperoxidase

Cyclic neutropenia Typically autosomal dominant Found to be due to germline mutations in

ELA2ELA2 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

Counts cycle every 21 days with nadirs close to 0 and peaks near normal

Length of nadir relates to infxs complications

Acquired Neutropenia Infections (most common)

HIV, erhlichia, parasites, parvo B19, EBV, HepB, HCV Nutritional deficiency

B12, copper, folate Drugs/chemicals/chemo (1-3.4 cases/million/yr)

Antithyroid, macrolides, procainamide, sulfonamidesClozapine causes agranulocytosis in 1% of patients, but

appears to be genetic not immune 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 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 AINPrimary AIN typically presents in early childhood

Work up CBC with diff B12, folate Infectious workup (if fever present)

Bcx, ucx, cxr, sputum cx Bone marrow biopsy

Esp if anemia/thrombocytopenia also presentCan evaluate for maturation arrest, fungal

infection, marrow defect, b12/folate deficiency 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)Normal PMNs incubated with serum from pt

Tests are difficult secondary to HLA alloantibodies and immune complexesTherefore in routine practice these tests are

not recommended

Medications/Treatment 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

Treatment continued Primary AIN

Typically not associated with severe infections and often only treated symptomatically for infections w/ abx

Secondary AINOften assoc with SLE/RA – can use GCSF but

have to be careful because this can lead to disease flares and leukocytoclastic vasculitis

Infections due to neutropeniaManagement 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

Danger on the road

Resources 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