Evaluation of neutropenia

Diseases

Summary

Neutropenia is a low neutrophil count. Neutrophils are essential components of the hematopoietic and immune system, and quantitative or qualitative abnormalities of neutrophils can result in life-threatening infection.

Neutropenia can result from: decreased production, accelerated utilization, increased destruction, or change in location of neutrophils, or any combination of these processes. Causes can be congenital or acquired.

The source of infection in neutropenia is usually endogenous flora of the gut and mucosa (commonly Staphylococcus and gram-negative organisms). Fungal infections occur with increased frequency.

Common sites of infection include mucous membranes (gingivitis, stomatitis, perirectal abscesses), skin (cellulitis), and lungs (pneumonia).[1] [2]

Classification

There is no standard classification system for neutropenia, but the absolute neutrophil count (ANC) is generally used to grade severity. The ANC is calculated as follows:

ANC = white blood cells (microliter) x percent (polymorphonuclear cells + bands)/100

An ANC <1500/microliter is defined as neutropenia and graded as follows:[3]

Mild (1000 to 1500/microliter)
Moderate (500 to 999/microliter)
Severe (200 to 499/microliter)
Very severe (<200/microliter).

As the ANC falls below 1000/microliter, the risk of infection progressively increases. If the ANC falls below 500/microliter, infections may be life-threatening.

An ANC of less than 100/microliter (agranulocytosis) carries a risk of severe, life-threatening infections with susceptibility to opportunistic organism.

However, there are some diseases, such as autoimmune neutropenia, in which a low ANC does not confer an infection risk; infections are rare in these patients despite the ANC often being <500 cells/microliter.

The ANC varies according to age and ethnicity. It is lower in children than in adults. Children <12 months are not considered neutropenic unless the ANC falls below 1000/microliter. After 10 years of age neutrophil values normally exceed 1500/microliter.[4] [5]

Black people, Ethiopians, Yemenite Jews, and some Arab populations display lower average values.[6] [7] [8] [9] The normal range in black people has a lower limit of 1400/microliter.

Common causes

Infections are the most common cause of neutropenia in adults, followed by drug-induced neutropenias.[10] In Europe the incidence of drug-induced neutropenia in the general population is 1.6 to 9.2 cases per million.[11] The incidence within the US is slightly higher, with 2.4 to 15.4 cases per million reported per year.[12] [13]

Acquired bone marrow diseases such as leukemia, lymphoma, and aplastic anemia are relatively common causes of neutropenia in adults, as are nutritional deficiencies (vitamin B12, folate, copper).

Other causes of neutropenia are rare in adults.

The epidemiology of pseudoneutropenia (neutrophil maldistribution) is unknown.

In children, the epidemiology is different. Primary autoimmune neutropenia in infancy is the most common cause of neutropenia in children <2 years old.[14] Neonatal alloimmune (immune response to nonself antigens) neutropenia is also a relatively common cause of neutropenia in infants.

Infections and medications remain common causes in children.

Congenital causes are rarer than acquired causes, and epidemiologic data are limited. The most common and important diseases affecting neutrophil production are severe congenital neutropenia and cyclic neutropenia. Common variable immunodeficiency is the most common immunodeficiency encountered.

Library

Important viral causes of neutropenia to exclude (IV, intravenous; RUQ, right upper quadrant)
Other viral causes of neutropenia in childhood
Other viral causes of neutropenia at any age
Bacterial causes of neutropenia (bpm, beats per minute)
Intracellular pathogens and parasites known to cause neutropenia
Drugs and chemicals associated with neutropenia (ACE, angiotensin-converting enzyme)
Congenital bone marrow failure syndromes (ANC, absolute neutrophil count)
Congenital isolated neutropenias
Congenital immunodeficiency disorders (Ig, immunoglobulin)

Citations

Key Articles

Boxer LA, Newberger PE. A molecular classification of congenital neutropenia syndromes. Pediatr Blood Cancer. 2007 Oct 15;49(5):609-14.[Abstract][Full Text]
Cham B, Bonilla MA, Winkelstein J. Neutropenia associated with primary immunodeficiency syndromes. Semin Hematol. 2002 Apr;39(2):107-12.[Abstract]
Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018 May 10;36(14):1443-53.[Abstract][Full Text]

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