Neutrophils are essential components of the hematopoietic and immune system, and quantitative or qualitative abnormalities of neutrophils can result in life-threatening infection. Neutropenia is a low neutrophil count and results from decreased production, accelerated utilization, increased destruction, or a shift in compartments. A combination of these mechanisms may be present. Causes can be congenital or acquired. The most serious complication of neutropenia is infection, which can be fatal. The source is usually endogenous flora of the gut and mucosa (commonly
Staphylococcus
and gram-negative organisms). Fungal infections occur with increased frequency, but there is no increased risk of viral or parasitic infection. Common sites of infection include mucous membranes (gingivitis, stomatitis, perirectal abscesses), skin (cellulitis), and lungs (pneumonia).
[1]
Dale DC. Neutropenia and neutrophilia. In: Lichtman MA, ed. Williams hematology. 7th ed. New York, NY: McGraw-Hill; 2006.
[2]
Lichtman MA. Classification and clinical manifestations of neutrophil disorders: overview. In: Lichtman MA, ed. Williams hematology. 7th ed. New York, NY: McGraw-Hill; 2006.
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 mild, moderate, severe, or very severe:
[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
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Mild (1000 to 1500/microliter)
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Moderate (500 to 999/microliter)
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Severe (200 to 499/microliter)
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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 200/microliter (agranulocytosis) carries a risk of severe, life-threatening infections with susceptibility to opportunistic organism.
[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
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]
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/microliter.
Common causes
Infections are the most common causes 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 the leukemias, lymphomas, 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.
[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 nonself antigens from members of the same species) 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.