Neutropenia

Editor-in-Chief: Aric Hall, M.D. Beth Israel Deaconess Medical Center, Boston, MA[mailto:achall@bidmc.harvard.edu]; C. Michael Gibson, M.S., M.D.

Overview
Neutropenia (or neutropaenia, adjective neutrop(a)enic) is a hematological disorder characterized by an abnormally low number of neutrophil granulocytes (a type of white blood cell). Neutrophils usually make up 50-70% of circulating white blood cells and serve as the primary defense against infections by destroying bacteria in the blood. Hence, patients with neutropenia are more susceptible to bacterial infections and without prompt medical attention, the condition may become life-threatening. Neutropenia can be acute or chronic depending on the duration of the illness. A patient has chronic neutropenia if the condition lasts for greater than 3 months. It is sometimes used interchangeably with the term leukopenia. However, neutropenia is more properly considered a subset of leukopenia as a whole.

Classification
There are 3 general guidelines used to classify the severity of neutropenia based on the absolute neutrophil count (ANC) measured in cells per microliter of blood: NOTE: These are ranges for Caucasians. Neutropenia in black individuals is defined as ANC < 1200. This is a not well known fact that results in overdiagnosis of neutropenia in black population.
 * Mild neutropenia (1000 < ANC < 1500) &mdash; minimal risk of infection
 * Moderate neutropenia (500 < ANC < 1000) &mdash; moderate risk of infection
 * Severe neutropenia (ANC < 500) &mdash; severe risk of infection.

Types
Severe chronic neutropenia may be present at birth (congenital neutropenia) or may occur at any stage in life (acquired neutropenia). There are several types of severe chronic neutropenia:

Severe congenital neutropenia &mdash; a rare inherited form of the disease usually detected soon after birth. It affects children mainly and may result in premature loss of teeth and peremptory gum infections. The most severe form of chronic congenital neutropenia is known as Kostmann’s syndrome. It is genetically heterogeneous. Most commonly, it arises as a result of new, autosomal dominant mutations in the gene, ELA2, encoding the neutrophil granule protease, neutrophil elastase, NE. The gene responsible for many cases of autosomal recessively inherited severe congenital neutropenia is HAX1. The mechanism for congenital neutropenia is not well-understood. There is evidence that mutations in neutrophil elastase, or in other genes associated with syndromic forms of neutropenia, disrupt its intracellular trafficking. Apoptosis may be a final effector for neutropenia, but the original studies from Dale and Aprikian supporting this pathway were retracted.

Cyclic neutropenia &mdash; tends to occur every three weeks and lasting three to six days at a time due to changing rates of cell production by the bone marrow. It is often present among several members of the same family. Cyclic neutropenia is also the result of autosomal dominantly inherited mutations in ELA2, the gene encoding neutrophil elastase.

Idiopathic neutropenia &mdash; a rare form of neutropenia which develops in children and adults usually in response to an illness. It is diagnosed when the disorder cannot be attributed to any other diseases and often causes life-threatening infections.

Myelokathexis &mdash; a rare form of inherited autosomal dominant disease associated with severe neutropenia. Some but not all patients have Warts, Hypogammaglobulinemia, and recurrent Infections. Therefore myelokathexis is also known as the W.H.I.M. syndrome. In spite of severe neutropenia (low number of neutrophils) in peripheral blood of myelokathexis patients, their bone marrow is hypercellular and it is packed with mature neutrophils indicating an impaired mobilization of hematopoietic cells in this disorder. Truncating mutations in the human cytokine receptor CXCR4 gene were identified in most of the families afflicted by myelokathexis. The molecular mechanism is not yet defined. Recent reports demonstrate that CXCR4 mutations appear to result in an increased sensitivity of bone marrow hematopoietic cells to its ligand, a stromal-derived growth factor SDF-1 that provides proliferative and survival signals.

Autoimmune neutropenia &mdash; most common in infants and young children where the body identifies the neutrophils as enemies and makes antibody to destroy them. This form usually lessens in severity within two years of diagnosis.

Drug-induced neutropenia &mdash; Many drugs can cause agranulocytosis (complete absence of white cells) and neutropenia. Many anti-neoplastic drugs cause agranulocytosis and neutropenia by bone marrow suppression. Neutropenia and agranulocytosis can also result from antibody or complement-mediated damage to the stem cells. Some drugs may cause increased peripheral destruction of white cells. About 75% of all cases of agranulocytosis in the United States are related to medication. Clozapine, procainamide, anti-thyroid drugs (e.g. methimazole, and sulfasalazine are at the top of the list of drugs causing this problem, but many others (such as antiepileptics) have been implicated.

Differential diagnosis of causes of neutropenia
Causes can be divided into the following groups:
 * Decreased production in the bone marrow:
 * Hereditary disorders (e.g. congenital neutropenia, Cyclic neutropenia)
 * Cancer
 * Drugs
 * Radiation
 * Vitamin B12 or folate deficiency.
 * Increased destruction:
 * Aplastic anemia
 * Autoimmune neutropenia.
 * Chemotherapy
 * Marginalisation and sequestration:
 * Hemodialysis

There is usually a mild neutropenia in viral infections.

Signs and symptoms
Neutropenia can go undetected, but is generally discovered when a patient has developed severe infections or sepsis. Some common infections can take an unexpected course in neutropenic patients; formation of pus, for example, can be notably absent, as this requires circulating neutrophil granulocytes.

Some common symptoms of neutropenia include:
 * Fever
 * Frequent infections due to lessened ability to fight bacterial infections
 * Mouth ulcers
 * Diarrhea
 * Burning sensation when urinating
 * Unusual redness, pain, or swelling around a wound
 * Sore throat
 * Shortness of breath
 * Shaking chills

Diagnosis
Low neutrophil counts are detected on a full blood count. A peripheral blood smear is often useful to evaluate for abnormal morphology of the visible cells, which may help suggest the diagnosis. Evaluation for metabolic abnormalities, genetic causes neutropenia, and/or other underlying metabolic or toxic causes will often follow. When the etiology is uncertain, or serious causes such as malignancy and marrow replacement are suspected, bone marrow biopsy is often necessary.

Therapy
There is no ideal therapy for neutropenia, but recombinant G-CSF (granulocyte-colony stimulating factor) can be effective in chemotherapy patients, in patients with congenital forms of neutropenia including severe congenital neutropenia, autosomal recessive Kostmann's syndrome, cyclic neutropenia, myelokathexis, and some other causes...