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Objectives
After completing this article, readers should be able to:
Describe when a patient has true neutropenia, understanding the variation with age and ethnic background.
Know the relative risk of infection at various values of the absolute neutrophil count.
Discuss the differences between inherited and acquired causes of neutropenia.
List the initial studies to evaluate patients who have neutropenia.
Introduction
The significance of neutropenia is a common query to hematology specialists from primary care physicians. Severe neutropenia is defined as an absolute neutrophil count (ANC) of fewer than 500/mcL (0.5×109/L) and is a common and expected complication of chemotherapy for childhood neoplasms. This article considers those patients who have neutropenia unrelated to chemotherapy toxicity. This type of neutropenia may be noted when a complete blood count (CBC) is performed in a sick newborn, a febrile child, a child taking chronic medication, or as part of a routine evaluation. Severe hereditary conditions such as Kostmann syndrome and certain immunodeficiency syndromes associated with neutropenia are rare, perhaps 1 per 100,000, and are more likely to present in neonates and infants, although acquired conditions such as immune neutropenia and neutropenia related to infection also occur in this age group. A mild-to-moderate decrease in the ANC (percent neutrophils times the total white count) frequently is seen in viral illness or related to medication use as well as in some healthy persons of African ancestry. A number of inherited conditions associated with neutropenia are associated with other congenital anomalies such as dysplastic thumbs in Fanconi anemia, albinism in Chediak-Higashi syndrome, and dwarfism in the cartilage hair or Shwachman-Diamond syndromes.
When to Order a CBC
A CBC is not ordered routinely for well children examined in the pediatrician's office or when children present with common febrile illnesses such as upper respiratory tract infections or otitis media. A CBC is warranted if clinical findings suggest a more severe bacterial infection.Such clinical findings include, but are not limited to, recurrent infections; prolonged or extreme fever (>103°F [39.5°C]); the spreading of localized bacterial infection; infection of the lung, peritoneum, genitourinary tract, or central nervous system; and suspicion of chronic inflammatory disease, immunodeficiency, or malignancy. A CBC also may be warranted if a patient's clinical course is atypical, prolonged, or complicated by signs and symptoms suggesting the development of a secondary bacterial infection.
Normal Values for the ANC and the Definition of Neutropenia
Normal values for the ANC vary by age, particularly during the first weeks after birth. Normal leukocyte counts and ANCs for children from birth to age 21 years are shown in Table 1. The ANC range is shown for each age, as well. The lower limit of normal is 6,000/mcL (6.0×109/L) during the first 24 hours after birth, 5,000/mcL (5.0×109/L) for the first week, 1,500/mcL (1.5×109/L) during the second week, 1,000/mcL (1.0×109/L) between 2 weeks and 1 year of age, 1,500/mcL (1.5×109/L) from ages 1 year through 10 years, and 1,800/mcL (1.8×109/L) thereafter. However, most reports use 1,500/mcL (1.5×109/L) as the lower limit of normal for white adults. Adults and children of African extraction may have ANCs between 1,000 and 1,500/mcL (1.0 and 1.5×109/L), which overlaps the values observed in patients who have “mild neutropenia.” We estimate from the data available that at least 3% to 5% of persons of African ancestry have ANCs below 1,500/mcL (1/5×109/L).
Risk Assessment
For patients older than 1 year of age, mild neutropenia is defined as an ANC of 1,000 to 1,500/mcL (1.0 to 1.5×109/L), moderate neutropenia as an ANC of 500 to 1,000/mcL (0.5 to 1.0×109/L), and severe neutropenia as an ANC of less than 500/mcL (0.5×109/L). Usually, patients are highly susceptible to bacterial infection if the ANC is less than 500/mcL (0.5×109/L), with the risk of infection greatest at the lowest ANCs. Increased infection risk also is related to longer durations of neutropenia and is highest if the neutrophil count remains low without recovery. If neutrophils can be mobilized to respond, infection is less likely to occur, as can be seen in immune neutropenia, a condition in which there is myeloid hyperplasia and heightened neutrophil production. Although serious bacterial infections are observed when the ANC is between 500 and 1,000/mcL (0.5 and 1.0×109/L), they are much less frequent or severe. There is little or no heightened infectious risk if the ANC is greater than 1,000/mcL (1.0×109/L).
Pyogenic Infections Associated With Neutropenia
Moderate-to-severe neutropenia may portend an inadequate neutrophil response to bacterial infection. The clinical signs of neutropenia may include ulcerations of the oral mucosa or gingival inflammation. Otitis media, skin infections that include cellulitis and pustules, adenitis, pneumonia, and bacterial sepsis may occur. The source of the infection may be the child's own skin or bowel flora. Perianal infection and ischiorectal fossa abscesses sometimes are seen. The most common offending organisms are Staphylococcus aureus and the gram-negative bacteria (see section on fever and neutropenia).
Initial Evaluation of the Patient Who Has Neutropenia
The initial evaluation (Table 2) should include a history and physical examination. It is critical to know whether the child has had recurrent bacterial infections, whether there is a family history of neutropenia or infection, and after physical examination, whether there are any associated congenital anomalies that suggest an inherited syndrome. Mouth ulcers may occur in association with neutropenia, and the presence of gingivitis is a good indicator that the patient cannot mobilize adequate neutrophils and, thus, may be susceptible to severe infection. If neutropenia is suspected, it is important to determine if the patient has isolated neutropenia or neutropenia associated with anemia or thrombocytopenia. The clinical implication of deficits of more than one cell type is different from that of an isolated neutropenia. Anemia or thrombocytopenia in conjunction with neutropenia often reflects a more generalized marrow failure syndrome such as aplastic anemia or a marrow infiltrative process such as leukemia. The neutropenia must be confirmed by repeating the CBC to avoid an extensive evaluation due to a laboratory error.
It is reasonable to observe the patient who has a viral illness and mild-to-moderate neutropenia and otherwise appears well. If the neutropenia persists or progresses after 1 to 2 weeks, additional evaluation is necessary. If the neutropenia is recurrent, obtaining blood counts two to three times per week for several weeks can establish any cycles of neutropenia. If additional evaluation is warranted, the presence of antineutrophil antibodies suggests immune neutropenia, and quantifying immunoglobulins, including IgG, IgA, and IgM, and the distribution of lymphocyte subsets may indicate an underlying immunodeficiency syndrome. In addition, screening tests for systemic lupus erythematosus, including an antinuclear antibody titer and anti-double-stranded DNA, can be helpful. If a patient has severe neutropenia, referral to a hematologist is necessary. If severe congenital neutropenia is suspected, assessing for theHAX1 mutation for Kostmann disease and ELA2 mutation for dominant or sporadic severe congenital neutropenia is indicated. A detailed presentation of the potential laboratory evaluation by hematology
Acquired Neutropenia
Infection
When evaluating the child who has neutropenia, the acquired neutropenias are considered first because of their greater frequency (Table4). The most common underlying cause for mild-to-moderate neutropenia is transient marrow suppression due to a variety of viral infections.Neutropenia is seen in patients who have Epstein-Barr virus, respiratory syncytial virus, influenza A and B, hepatitis, and human herpesvirus 6 infections as well as the exanthems (to which most children are immunized), including varicella, rubella, and rubeola. Neutropenia occurs often during the first few days of the viral illness and persists for 3 to 8 days. Severe bacterial infection also may cause neutropenia rather than neutrophilia, which can be transient if the bacterial infection is treated effectively. Other bacterial or rickettsial diseases such as typhoid fever, tuberculosis, and Rocky Mountain spotted fever may cause neutropenia.
Drug-induced
A variety of medications (Table 5), including antibiotics, anticonvulsants, and anti-inflammatory agents, have been associated with neutropenia, a frequent reason for referral to hematology. The dilemma is how to treat the patient who requires the particular medication that is causing a potentially dangerous adverse effect. If the drug-induced neutropenia is idiosyncratic, its severity and persistence may be impossible to predict, and it is difficult to avoid discontinuing the drug. A similar situation exists for drug-induced immune neutropenia. If the drug acts as a hapten, leading to production of an antibody, the ANC should improve within 1 to 2 weeks after cessation of drug administration. On the other hand, if the neutropenia is mild, it may be dose-related, and drug administration could be titrated to permit continued use.
Immune
Neonatal alloimmune neutropenia results from the transfer of fetal cells to the maternal circulation, causing the mother to produce antibody to fetal antigens not present on her own cells in a manner similar to Rh disease. A variety of neutrophil-specific antigens have been identified and are designated HNA-1a (NA1), HNA-1b (NA2), HNA-2a (NB1), HNA-3a (5b), HNA-4a (MART), and HNA-5a (OND). Because the half-life of IgG is approximately 5 to 6 weeks, alloimmune neutropenia usually disappears after age 2 to 3 months. If infections are associated with the neutropenia, granulocyte colony-stimulating factor (G-CSF) may be used to stimulate a heightened neutrophil count.
Passive transfer of maternal antibody also may cause neonatal neutropenia. Pregnant women who have either primary immune neutropenia or immune neutropenia due to a disease such as lupus may transfer IgG antineutrophil antibodies passively to the developing fetus. This type of neonatal neutropenia also is transient.
Primary autoimmune neutropenia of infancy and childhood may be the cause of chronic neutropenia. The diagnosis may be established in most patients with the demonstration of antineutrophil antibodies by leukoagglutination or immunofluorescence. These antibodies may develop as a result of “molecular mimicry,” wherein an epitope on the surface of an infecting virus stimulates production of an antibody that then cross-reacts with a similar antigen on the surface of the neutrophil, leading to neutrophil destruction. Such antibodies often are directed against NA1. Marrow examination reveals myeloid hyperplasia but with few mature neutrophils (pictures of normal bone marrow and marrow in immune neutropenia are available in the online edition of this issue of Pediatrics in Review[http://pedsinreview.aappublications.org/cgi/content/full/29/1/12/DC2]). The neutropenia may be profound, and the child may develop ear, pulmonary, skin, or other infections. Such infections are treated primarily with antibiotics. However, glucocorticoids such as prednisone may suppress the immune destruction of neutrophils, and more recently, G-CSF has been used to heighten neutrophil production to overcome the antibody-induced destruction. The initial dose of prednisone usually is 2 mg/kg per day administered orally in two divided doses, and the initial dose of G-CSF is 5 mcg/kg administered subcutaneously once a day. These therapies usually are administered under the guidance of a pediatric hematologist.
Secondary autoimmune neutropenia more often affects adults and is seen in systemic autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis (Felty syndrome), or systemic sclerosis; in certain infections, such as those due to human immunodeficiency virus, parvovirus B19, or Helicobacter pylori; or in drug-induced neutropenia. Secondary autoimmune neutropenia also has been reported in association with Wilms tumor and Hodgkin disease. Treatment of secondary neutropenias is directed toward the primary disease. Administration of G-CSF may be considered if the neutropenia is severe and protracted.
Chronic Idiopathic
Chronic idiopathic neutropenia likely represents a variety of disorders and is not well characterized. Some of the patients classified as having chronic idiopathic neutropenia actually may have immune neutropenia or familial benign neutropenia. The “idiopathic” diagnosis may be considered when other known causes have been eliminated. The clinical severity appears to be related to the severity of neutropenia, and the marrow findings are not consistent. Ineffective or decreased production of neutrophils may be seen in this condition. Many hematologists watch patients whose conditions appear truly “idiopathic” and whose neutropenia is mild and not associated with an increase in infections, keeping the evaluation to a minimum rather than pursuing a more extensive evaluation that often yields nothing. When therapy is indicated, glucocorticoids and G-CSF have been used.
Sequestration
Splenomegaly and hypersplenism from any cause may result in mild neutropenia (1,000 to 1,500/mcL [1.0 to 1.5×109/L]) due to sequestration. Enlarged spleens may be present in patients who have chronic hemolytic anemias, liver disease, or portal hypertension and in metabolic disorders such as Gaucher disease. These conditions also may result in anemia and thrombocytopenia. Results of the marrow examination are normal or show mild hyperplasia of all elements. Usually, this problem does not require treatment unless the cytopenias are profound or management of the underlying condition requires treatment. In some cases, splenectomy is necessary.
Nutritional Deficiency
Both vitamin B12 and folic acid deficiency may result in ineffective hematopoiesis with megaloblastic erythropoiesis. Patients who develop megaloblastic anemia generally are adults. In addition to megaloblastic anemia, the impairment in DNA processing may result in neutropenia. Neutrophil nuclear maturation is impaired, leading to hypersegmentation of the neutrophil nuclei in the blood as well as ineffective marrow proliferation and maturation. Treatment involves replacement of the deficient factor.
Severe Congenital
evere congenital neutropenia may present as early as infancy with umbilical infection, pyoderma, oral ulcers, pulmonary infections, or perineal infections of the labia or perirectal area. The ANC is less than 500/mcL (0.5×109/L) and often less than 200/mcL (0.2×109/L). Severe congenital neutropenia may be inherited as an autosomal recessive condition (Kostmann syndrome) involving mutations in the HAX1 gene that is involved in signal transduction. It also may be inherited as an autosomal dominant condition, with mutations in the neutrophil elastase gene (ELA2) or, more rarely, in the GFI1 gene that targets ELA2. It has been suggested that such gene mutations result in accelerated apoptosis of myeloid precursors. Examination of the marrow reveals an arrest at the promyelocyte stage of development (a picture of bone marrow in severe congenital neutropenia is available in the online edition of this issue ofPediatrics in Review [www.pedsinreview.org
]). Few or no myelocytes, metamyelocytes, bands, or mature neutrophils are seen, and there may be an associated monocytosis and eosinophilia in the blood. Affected patients have a very high risk of developing a myelodysplastic syndrome or acute myelogenous leukemia, a consequence that has become more evident as patients live longer with treatment using G-CSF. Table 7 describes G-CSF administration.
Cyclic
Cyclic neutropenia is characterized by approximately 21-day cycles of changing neutrophil counts, with neutropenia spanning 3 to 6 days. The nadir of the neutrophil count may be in the severe range. Fever and oral ulcerations usually are seen during the nadir. Patients also may develop gingivitis, pharyngitis, and skin infections. However, by the time the patient comes to medical attention, the neutrophil count may be recovering. Therefore, diagnosing cyclic neutropenia may require obtaining blood counts two to three times per week for 4 to 6 weeks in an effort to observe the periodicity of the cycle.
More serious infections include pneumonia, necrotizing enterocolitis with peritonitis, and Escherichia coli or Clostridium sepsis. Marrow findings reflect the state of neutropenia. Prior to the ANC nadir, the marrow may resemble that associated with severe congenital neutropenia before proceeding to a recovery phase. The periodicity of marrow activity also may be seen in the erythroid series. As in severe congenital neutropenia, mutations occur in the ELA2 gene, but at different locations (Table 6). Also, there does not appear to be an increased risk of myelodysplasia or acute myelogenous leukemia. Prophylactic G-CSF has been recommended to prevent severe symptoms at the nadir of the cycle.
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Detecting and Treating Febrile Neutropenia in Patients With AML - See more at: http://www.ajmc.com/newsroom/detecting-and-treating-febrile-neutropenia-in-patients-with-aml#sthash.duVYZ1Ra.dpuf
Christina Mattina
In a series of interviews with MD Magazine, Yoav Golan, MD, MS, FIDSA, spoke
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