Assessment of neutropenia

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

Neutropenia can result from: decreased production, accelerated utilisation, 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]Dale DC, Welte K. Neutrophenia and neutrophilia. In: Kaushansky K, Prchal JT, Burns LJ, et al, eds. Williams hematology. 10th ed. New York, NY: McGraw-Hill; 2021 https://hemonc.mhmedical.com/book.aspx?bookID=2962 [2]Lichtman MA. Classification and clinical manifestations of neutrophil disorders. In: Kaushansky K, Prchal JT, Burns LJ, et al, eds. Williams hematology. 10th ed. New York, NY: McGraw-Hill; 2021. https://hemonc.mhmedical.com/book.aspx?bookID=2962

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 (microlitre) x percent (polymorphonuclear cells + bands)/100

An ANC <1500/microlitre or <1.5 x 10⁹/L is defined as neutropenia and graded as follows:[3]Newburger PE, Dale DC. Evaluation and management of patients with isolated neutropenia. Semin Hematol. 2013 Jul;50(3):198-206. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748385 http://www.ncbi.nlm.nih.gov/pubmed/23953336?tool=bestpractice.com

• Mild: 1000 to 1500/microlitre or 1 to 1.5 x 10⁹/L

• Moderate: 500 to 999/microlitre or 0.5 to 0.99 x 10⁹/L

• Severe: 200 to 499/microlitre or 0.2 to 0.49 x 10⁹/L

• Very severe: <200/microlitre or <0.2 x 10⁹/L.

As the ANC falls below 1000/microlitre or 1 x 10⁹/L, the risk of infection progressively increases. If the ANC falls below 500/microlitre or 0.5 x 10⁹/L, infections may be life-threatening.

An ANC of less than 100/microlitre (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/microlitre or <0.5 x 10⁹/L.

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/microlitre or 1 x 10⁹/L. After 10 years of age neutrophil values normally exceed 1500/microlitre or 1.5 x 10⁹/L.[4]Dallman PR. Reference ranges for leukocyte counts in children. In: Nathan DG, Orkin SH, eds. Nathan and Oski's hematology of infancy and childhood. 5th ed. Philadelphia, PA: WB Saunders; 1998.

Black people, Ethiopians, Yemenite Jews, and some Arab populations display lower average values.[5]Hsieh MM, Everhart JE, Byrd-Holt DD, et al. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. Ann Intern Med. 2007 Apr 3;146(7):486-92. http://annals.org/article.aspx?articleid=733880 http://www.ncbi.nlm.nih.gov/pubmed/17404350?tool=bestpractice.com [6]Orfanakis NG, Ostlund RE, Bishop CR, et al. Normal blood leukocyte concentration values. Am J Clin Pathol. 1970 May;53(5):647-51. http://www.ncbi.nlm.nih.gov/pubmed/5444471?tool=bestpractice.com [7]Reed WW, Diehl LF. Leukopenia, neutropenia, and reduced hemoglobin levels in healthy American blacks. Arch Intern Med. 1991 Mar;151(3):501-5. http://www.ncbi.nlm.nih.gov/pubmed/2001132?tool=bestpractice.com [8]Shoenfeld Y, Alkan ML, Asaly A, et al. Benign familial leukopenia and neutropenia in different ethnic groups. Eur J Haematol. 1988 Sep;41(3):273-7. http://www.ncbi.nlm.nih.gov/pubmed/3181399?tool=bestpractice.com The normal range in black people has a lower limit of 1400/microlitre or 1.4 x 10⁹/L.

Common causes

Infections are the most common cause of neutropenia in adults, followed by drug-induced neutropenias.[9]Andres E, Federici L, Weitten T, et al. Recognition and management of drug-induced blood cytopenias: the example of drug-induced acute neutropenia and agranulocytosis. Expert Opin Drug Saf. 2008 Jul;7(4):481-9. http://www.ncbi.nlm.nih.gov/pubmed/18613811?tool=bestpractice.com In Europe the incidence of drug-induced neutropenia in the general population is 1.6 to 9.2 cases per million. The incidence within the US is slightly higher, with 2.4 to 15.4 cases per million reported per year.

Acquired bone marrow diseases such as leukaemia, lymphoma, and aplastic anaemia 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.[10]Berliner N, Horwitz M, Loughran TP Jr. Congenital and acquired neutropenia. Hematology Am Soc Hematol Educ Program. 2004:63-79. http://asheducationbook.hematologylibrary.org/cgi/content/full/2004/1/63 http://www.ncbi.nlm.nih.gov/pubmed/15561677?tool=bestpractice.com Neonatal alloimmune (immune response to non-self 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 epidemiological 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.