Overview of neutropenia in children and adolescents

INTRODUCTION — This topic review will provide an overview of the causes, clinical manifestations, diagnosis, and management of neutropenia when it occurs as an isolated or predominant feature. Neutropenia is also a common manifestation of bone marrow defects associated with reductions in red bloods cells and platelets, such as aplastic anemia, leukemia, myelodysplasia, megaloblastic anemia due to vitamin B12 or folate deficiency, and the administration of chemotherapy. These disorders are reviewed separately.

Laboratory evaluation of neutropenia and neutrophil function, as well as various disorders associated with neutropenia are discussed separately.

●(See "Laboratory evaluation of neutrophil disorders".)

●(See "Congenital neutropenia".)

●(See "Cyclic neutropenia".)

●(See "Immune neutropenia".)

●(See "Infectious causes of neutropenia".)

●(See "Drug-induced neutropenia and agranulocytosis".)

DEFINITIONS AND NORMAL VALUES — The absolute neutrophil count (ANC) is equal to the product of the white blood cell (WBC) count and the fraction of polymorphonuclear cells (PMNs) and band forms noted on the differential analysis:

Neutrophilic metamyelocytes and younger forms are not included in this calculation (calculator 1). An ANC <1500/microL (<1.5 x 10⁹/L) is the generally accepted definition of neutropenia for adults and children over one year of age. (table 1 and table 2).

The normal range for the ANC varies somewhat with age (table 3). The lower limit of normal is 5000/microL (5.0×10⁹/L) for the first week of life, then falls to 1000/microL (1.0×10⁹/L) between two weeks and one year of age [1]. Importantly, the range for ANC may be lower in individuals who inherit certain gene variants, as discussed below. (See 'Normal variants' below.)

Neutropenia is often categorized as mild, moderate or severe, based on the level of ANC. Mild neutropenia corresponds to an ANC between 1000 and 1500/microL, moderate between 500 and 1000/microL, and severe with less than 500/microL. The risk of infection begins to increase at an ANC below 1000/microL (table 2). However, the risk is also dependent on the adequacy of the marrow reserve pool of granulocytes. (See 'Infection propensity' below.)

Leukopenia and granulocytopenia are generally used interchangeably with neutropenia, although they are somewhat different:

●Leukopenia refers to a low total WBC count that may be due to any cause (eg, lymphopenia and/or neutropenia); however, almost all leukopenic patients are neutropenic since the number of neutrophils is so much larger than the number of lymphocytes.

●Granulocytopenia refers to a reduced absolute number of all circulating cells of the granulocyte series (eg, neutrophils, eosinophils, and basophils); however, almost all granulocytopenic patients are neutropenic since the number of neutrophils is so much larger than the number of eosinophils and basophils.

●Agranulocytosis literally means the absence of granulocytes, but the term is often incorrectly used to indicate severe neutropenia (ie, ANC <500/microL).

PROPENSITY TO INFECTION AND SIGNIFICANCE OF NEUTROPENIA — There are two fundamental issues to consider in the neutropenic patient:

●Is the patient at increased risk for infection because of neutropenia?

●Does the presence of neutropenia indicate a serious underlying disorder that is secondarily affecting the neutrophil count?

Since most clinicians' exposure to neutropenia is through experience with malignancy or severe marrow failure syndromes (where neutrophil production is impaired and marrow neutrophil reserve is diminished), it is important to be aware that for most commonly encountered cases of neutropenia, the marrow reserve is not impaired and the propensity to infection may have little relation to the degree of neutropenia.

Infection propensity — Only about 3 percent of the body's neutrophils are circulating in the peripheral blood. The vast majority of neutrophils are in the bone marrow reserve pool and the remainder is in the tissue and marginated pool attached to the lining of blood vessels. Thus, a standard complete blood count (CBC) done on peripheral blood is, in effect, sampling the very smallest compartment of neutrophils and does not accurately reflect the body's capacity to protect against bacterial infection. The most important issue is whether adequate neutrophils get to the site of infection, not how many are sampled in passage from the marrow to the tissue. While one can infer tissue supply of neutrophils from the clinical history and certain physical findings (table 4), there is no good clinical laboratory test available to quantitate tissue neutrophil delivery.

Adequacy of the marrow reserve pool is the most critical determinant of propensity to infection in a neutropenic patient, although having a normal marrow does not guarantee protection against infection, as the condition causing the neutropenia may be associated with infection risk independent of the neutropenia. By "adequate marrow reserve" we mean normal marrow cellularity and normal maturation of the neutrophil series. We would consider low marrow cellularity or myeloid arrest at the myelocyte or metamyelocyte stage to imply decreased reserve. The risk of infection based on ANC is summarized in the table (table 5).

In the neutropenic febrile patient, management decisions must be made without information about the adequacy of the bone marrow reserve. Bone marrow aspiration and biopsy are the only ways to directly evaluate marrow reserve. The table lists clinical signs that infer marrow reserve (table 4). If the bone marrow reserve pool is significantly depleted, there is a rough relationship between the absolute neutrophil count (ANC) and propensity to infection (table 2).

However, and importantly, if the bone marrow reserve pool is completely adequate, there is no relationship between the degree of neutropenia and propensity to infection. If the marrow reserve pool is normal, patients with an ANC of zero may be at no increased risk of serious infection because of the neutropenia. Essentially, patients with normal marrow reserve are able to deliver neutrophils to the site of infection, and those with no marrow reserve are not.

Most clinicians are aware of the extreme danger present in patients with significant fever and very low ANC based on their experiences during training with patients who have received chemotherapy or who have bone marrow failure syndromes. These patients have no bone marrow reserve. Patients with immune mediated neutropenia but normal bone marrow reserve are on the other end of the spectrum and are at no increased risk of infection because of the neutropenia. Note that we are careful to say "no increased risk of infection because of the neutropenia" and not "no increased risk of infection." Neutropenia can be the presenting finding in common variable immunodeficiency, other immunodeficiency states, and collagen vascular diseases, all of which can have adequate marrow reserve yet put the patient at increased risk for infection for reasons other than the neutropenia. (See "Immune neutropenia".)

Various neutropenia syndromes are presented in the table according to marrow reserve (table 5). Some disorders appear in more than one category. For example, post-infectious neutropenia usually has normal marrow reserve, but not always. Classification of neutropenias by marrow reserve status offers a mechanistic link to propensity to infection and has some bearing on treatment. Patients with decreased reserve are likely to benefit from treatment with granulocyte colony-stimulating factor, whereas this agent is not of benefit for patients with normal marrow. The clinical symptoms noted in the table (table 4) can give the clinician some idea of the ability to deliver neutrophils to tissue and thus adequacy of marrow reserve. As examples:

●If a neutropenic patient has a frank abscess or purulent exudate, they can get neutrophils to tissue and likely has a normal marrow.

●The presence of mucosal ulcerations and severe gingivitis suggests inability to deliver neutrophils. However, immune disorders can directly cause similar lesions in the presence of normal reserve neutropenia. (See "Immune neutropenia".)

Significance of neutropenia — Separate from the issue of propensity to infection, neutropenia can be a sign of an underlying systemic disorder (table 6). When neutropenia is discovered during the evaluation of a febrile patient, propensity to infection dominates. However, neutropenia is often discovered on a blood count done for some other reason. The approach to such patients is outlined below.

NORMAL VARIANTS — Some individuals have an absolute neutrophil count (ANC) <1500/microL with no recurrent or severe infections, other cytopenias, or associated illnesses [2]. One cause for this inherited condition is referred to as "Duffy-null associated neutrophil count (DANC)," but other terms have been used. Normal variants in ANC have also been associated with polymorphisms in other genes.

Normal variants in ANC are most often encountered in individuals of African descent, as well as Sephardic Jews, West Indians, Yemenites, Greeks, and Arabs. We favor the designation DANC; while it was previously called constitutional neutropenia or benign ethnic neutropenia, use of the term neutropenia might erroneously imply a pathologic condition [2] or a risk for infection. This normal variant is not associated with recurrent or unusual infections, other cytopenias, physical findings, or other causes of cytopenias (eg, medications, excessive alcohol consumption, liver disease, autoimmune conditions).

Genetic causes of ANC variants include:

●DANC (Duffy null [Fy(a-b-)] phenotype) – DANC is characterized by ANC <1500/microL, but it is clinically insignificant and not associated with increased risk for infections.

DANC is associated with homozygosity for rs2814778, a single nucleotide polymorphism (SNP) of ACKR1 (atypical chemokine receptor [1ACKR1]) [3]. This SNP is the predominant ACKR1 allele in Black individuals [4]. ANC <1500/microL is found in 25 to 50 percent of people of African ancestry in the US, compared with <1 percent of individuals of European or Asian ancestry. The Fy(a-b-) phenotype is protective against malaria and enriched in individuals of sub-Saharan African and Arabic ancestry as an advantageous trait.

●CXCL2/CXCR2 – The rs9131 SNP of the chemokine, CXCL2, has been associated with lower levels of ANC [5]; rare variants of the receptor, CXCR2, are also associated with lower neutrophil counts [6].

●TCIRG1 – Rare variants of TCIRG1 (eg, rs587779413) may be associated with low ANC but a different single nucleotide variant (c.2206C>A, p.Arg736Ser, rs587779413) is associated with severe congenital neutropenia [7]. Homozygous or compound mutations of TCIRG1 may cause osteopetrosis [7,8].

CLASSIFICATION AND ETIOLOGY OF ISOLATED NEUTROPENIA — The causes of isolated neutropenia can be classified by mechanism or by etiologic agent. Neutropenia results from four basic mechanisms: decreased production, ineffective granulopoiesis, shift of circulating polymorphonuclear cells (PMNs) to vascular endothelium or tissue pools, or enhanced peripheral destruction. Confirmation of one of these mechanisms requires leukokinetic studies employing bone marrow cultures, radionuclide tagging of blood PMNs, and other monitoring devices not readily available outside the research laboratory. (See "Approach to the adult with unexplained neutropenia", section on 'Mechanisms'.)

The classification of neutropenia according to marrow reserve status is useful when thinking about mechanism of neutropenia and propensity to infection. However, classification based on whether the neutropenia is acquired or congenital and grouped by known causes or associations provides a practical means to approach the differential diagnosis of these disorders in a clinical setting (table 6). That said, there is great overlap in the disorders listed, which is why we favor a classification based on marrow reserve. There are several named disorders that lead to neutropenia with normal cellularity, late myeloid arrest, and little or no propensity to infection. These likely represent various interactions between subtle genetic differences and environmental factors. Apoptosis of marrow precursors is now recognized as a common mechanism for many acquired and congenital neutropenias.

Acquired neutropenias — There are many acquired causes of neutropenia, with infection, drugs, and immune disorders being the most common. As with all neutropenias, the danger to the patient depends on the marrow status (table 5).

Postinfectious neutropenia — Infectious neutropenias may represent the most common cause of acquired isolated neutropenia. A number of bacterial, viral, parasitic and rickettsial infections are responsible. In most instances, particularly with viral infections, the neutropenia is short-lived and rarely results in bacterial superinfection. Mechanisms include redistribution, sequestration and aggregation, and destruction by circulating antibodies. Hepatitis B virus, Epstein-Barr virus and human immunodeficiency virus can be associated with more severe and protracted neutropenia. (See "Infectious causes of neutropenia".)

Drug-induced neutropenia and agranulocytosis — Drug-induced neutropenia occurs as an adverse idiosyncratic reaction and is the second most common cause of neutropenia. The true incidence of drug-induced neutropenia is not known; the reported incidence of the rare, more severe, agranulocytosis ranges from approximately 1 to 10 cases per million population per year. The usual definition excludes known cytotoxic agents and requires that the drug have been administered within four weeks of the onset of neutropenia. The drugs with the highest risk of inducing severe neutropenia include clozapine, the thionamides (antithyroid drugs), and sulfasalazine (table 7). These drugs appear to cause neutropenia either by immune-mediated destruction of circulating neutrophils by drug-dependent or drug-induced antibodies or by direct toxic effects upon marrow granulocytic precursors. (See "Drug-induced neutropenia and agranulocytosis".)

Nutritional neutropenia — Neutropenia and marrow failure can be seen with severe vitamin B12 deficiency, folate deficiency, and copper deficiency.

●B12 and folate deficiency, as well as inborn errors of B12 metabolism, are well known to be associated with neutropenia and anemia [9]. Dietary deficiency of these vitamins is relatively uncommon in children and adolescents. However, the diagnosis should be thought of in chronically ill children, especially if they have frequent or prolonged hospitalizations or have malabsorption syndromes including short gut. The diagnosis should not be excluded simply because patients are receiving vitamins in parenteral nutrition solutions. The actual requirements for these vitamins are not known in critically ill patients, so it is best to monitor for deficiency. B12 deficiency can also be seen in exclusively breastfed infants of mothers who have B12 deficiency. Diagnosis of B12 deficiency is particularly important because severe developmental delay can occur if severe B12 deficiency is not treated.

B12 and folate deficiency are best diagnosed by measuring their levels in serum. If necessary, the results can be confirmed by testing methylmalonic acid and/or homocysteine, as described separately. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Diagnostic evaluation'.)

●Copper deficiency and subsequent low ceruloplasmin is a well-recognized cause of isolated neutropenia as well as pancytopenia. While not often thought of, it is not uncommon in children with short gut syndromes receiving parenteral nutrition, patients with malabsorption, and post-gastric bypass surgery. It can cause a marrow picture indistinguishable from myelodysplasia. Particularly in young children completely supported via parenteral nutrition, copper is often removed from the intravenous solution and not reintroduced, leading to deficiency [10-13]. Critically ill patients who have prolonged hospitalizations should be screened for these deficiencies if they present with neutropenia, even if they are receiving parenteral nutrition. (See "Overview of dietary trace elements", section on 'Copper'.)

Primary immune disorders — Antineutrophil antibodies mediate neutrophil destruction either by splenic sequestration of opsonized cells or by complement-mediated neutrophil lysis. Immune neutropenia can occur as a myeloid-specific syndrome or in association with other cytopenias. Antineutrophil antibodies are involved in the pathophysiology of the neutropenia caused by some infections, drug exposure, and immune deficiencies. In addition, there are specific primary immune disorders characterized by neutropenia and antineutrophil antibody production.

Assessment of immune neutropenias can be particularly problematic, because the propensity to infection may be more related to the underlying immune disorder than to the neutropenia. Thus, while immune disorders may have antibody-mediated neutropenia, they may also be associated with vasculitis, leading to mucosal ulcers. We have seen the oral symptoms completely resolve with treatment of the underlying vasculitis with no change in the absolute neutrophil count (ANC), proving that the mucositis and the neutropenia are not related. Usually, immune neutropenias have normal marrow reserve (table 5). These disorders are discussed in detail separately and will only be summarized here (see "Immune neutropenia"):

●Isoimmune neonatal neutropenia – Neutropenia can occur in newborn infants secondary to transplacental passage of immunoglobulin G (IgG) antibodies directed against neutrophil-specific antigens inherited from the father. The pathogenesis of this disorder is similar to that of Rh hemolytic disease, except that it can occur with the initial pregnancy [14]. The neutropenia is usually noted in an otherwise healthy infant. Most infants have only mild neutropenia with a mean duration of seven weeks, but moderate to severe neutropenia can also occur.

Transient neutropenia in newborns is due to transplacental passage of antibodies of broad specificity from women with past or present autoimmune neutropenia. The neutropenia is usually mild and disappears after a few weeks [15].

●Neutropenia with adequate bone marrow reserve – Neutropenia with adequate bone marrow reserve usually occurs in infants and children <3 years and is associated with mild or moderate neutropenia; this disorder has also been labeled chronic autoimmune neutropenia, primary autoimmune neutropenia, and chronic benign neutropenia of infants and young children [16-18]. Spontaneous remission (along with disappearance of autoantibodies) within two to three years of onset is common and many children remain free of serious infections with minimal or no medical intervention.

Onset of this disorder after age three is less likely to resolve spontaneously and the neutropenia often heralds development of an underlying immunologic disorder [19]. This later-onset neutropenia shares some features with secondary autoimmune neutropenia, which typically presents in adulthood and is associated with an autoimmune illness, lymphoid malignancy, drug, or viral infection [20,21].

●Chronic idiopathic neutropenia – The term chronic idiopathic neutropenia, also known as benign chronic neutropenia, is used to describe chronic neutropenia for which there is no obvious cause. In contrast to autoimmune neutropenia, which is primarily a disease of infants and young children, chronic idiopathic neutropenia tends to occur in late childhood or adulthood and does not undergo spontaneous remission. Serologic abnormalities and evidence of antibody production have been found in 30 to 40 percent. These patients most often have a benign course despite the degree of neutropenia. The presence of normal marrow reserve may explain the lack of significant infections. (See "Immune neutropenia", section on 'Chronic idiopathic neutropenia'.)

●Pure white cell aplasia – Pure white cell aplasia is a rare disorder characterized by complete disappearance of granulocytopoietic tissue from the bone marrow. It is often associated with thymoma and is due to the presence of antibody mediated GM-CFU inhibitory activity. Such individuals have no marrow reserve and are at risk for infection because of the neutropenia. (See "Immune neutropenia", section on 'Pure white cell aplasia'.)

●Other autoimmune disorders – Other immune disorders that are associated with neutropenia include T-gamma lymphocytosis (large granular lymphocyte syndrome) and Felty syndrome. In the former disorder, there is infiltration of the bone marrow with large granular lymphocytes (LGL), most often due to a clonal expansion of cytotoxic T cells and often associated with rheumatoid arthritis. LGL disease has markedly decreased marrow reserve as well as autoimmune vasculitic components. (See "Large granular lymphocyte leukemia in rheumatoid arthritis" and "Treatment of large granular lymphocyte leukemia".)

●Complement activation – The exposure of blood to artificial membranes, as in dialysis and extracorporeal membrane oxygenation, may result in complement activation in vivo. The complement is typically produced by the classic complement activation pathway and induces neutrophil aggregation and adherence to endothelial surfaces, often in the lung. Neutropenia and cardiopulmonary symptoms typically occur shortly after exposure to the membrane. This complication can be prevented during hemodialysis by using biocompatible membranes. (See "Reactions to the hemodialysis membrane".)

Hypersplenism — Enlargement of the spleen from any etiology can result in neutropenia, due to splenic trapping [22]. The severity of neutropenia is related to the size of the spleen and rarely is sufficient to result in severe infection. Anecdotal information is available indicating the ability of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) to improve absolute neutrophil counts in patients with severe hypersplenism-associated neutropenia [23,24]. However, this treatment is not indicated in this situation and has been associated with splenic enlargement and rupture [25]. (See "Splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)

Bone marrow disorders — A number of diseases affecting the bone marrow are associated with neutropenia (table 6). In most cases, such as aplastic anemia, the leukemias, myelodysplasia, and postchemotherapy, the neutropenia is not an isolated defect, and is associated with varying degrees of anemia and thrombocytopenia. Examination of the peripheral smear and a bone marrow aspirate with biopsy are indicated when more than one cell line is involved.

Congenital neutropenias — Rare primary neutropenias occur and, when associated with severe recurrent infections as in the severe congenital neutropenias, can be treated successfully with hematopoietic growth factors. These syndromes include severe infantile agranulocytosis, myelokathexis, Shwachman-Diamond-Oski syndrome, Chediak-Higashi syndrome, and reticular dysgenesis. The diagnosis is made by examination of the bone marrow, which reveals myeloid hypoplasia. Congenital neutropenia can also be seen with certain inborn errors of metabolism such as glycogen storage disease and with some of the primary immune deficiency states. (See "Congenital neutropenia" and "Shwachman-Diamond syndrome".)

Cyclic neutropenia is characterized by recurrent mouth infections and regular oscillations in the numbers of blood neutrophils, monocytes, eosinophils, lymphocytes and reticulocytes at approximately 21-day intervals. It usually presents in childhood, as a familial syndrome, but there is a subset of patients with onset in adulthood. Treatment is largely supportive, and G-CSF has been effective in preventing infection and reducing symptoms. (See "Cyclic neutropenia".)

Myeloperoxidase deficiency — In many clinical laboratories, neutrophils are identified on the white blood cell differential by virtue of their positivity for myeloperoxidase. Patients with myeloperoxidase deficiency may then be erroneously considered as having severe neutropenia. This subject is discussed separately. (See "Myeloperoxidase deficiency and other enzymatic WBC defects causing immunodeficiency", section on 'Myeloperoxidase deficiency'.)

CLINICAL PRESENTATION — Recurrent infections are the only significant consequence of neutropenia. However, the classic signs of infection may be less evident in patients with neutropenia. This is particularly true in patients with bone marrow hypoplasia who are unable to respond to infection. In this setting, radiographs may not demonstrate pneumonia, or the patient may not exhibit abnormal tenderness with an early ruptured viscus.

The propensity to infection in neutropenic patients has been discussed and is related to the degree of neutropenia (table 2) and the cause of the neutropenia (table 5). Common sites of infection include the oral cavity and mucous membranes, the skin, and, with severe, persistent neutropenia, systemic infections of the lungs and bloodstream may occur. Endogenous bacterial flora are the most common pathogens.

Recurrent ulceration of the mouth or oral mucosa in the presence of significant neutropenia may indicate inadequate neutrophil production. Similarly, gingivitis in the setting of chronic neutropenia may be the only sign that the marrow reserve is decreased. Conversely, the presence of a purulent exudate or draining abscess suggests the patient is able to make neutrophils (table 2 and table 3).

Risk of infection — In a classic study in patients with leukemia published in 1966, which applies to neutropenia with decreased marrow reserve, the relationship between the frequency of infection and both the severity and duration of neutropenia was evaluated during 733 episodes of moderate neutropenia (absolute neutrophil count [ANC] less than 1000/microL) and 125 episodes of severe neutropenia (ANC less than 100/microL) [26]. Identified infections occurred in 80 percent of patients with severe neutropenia within two weeks of onset and in 100 percent at three weeks.

These relationships can be illustrated by the following observations:

●Patients with an ANC <500/microL due to chemotherapy, marrow failure, or marrow exhaustion are at high risk for overwhelming bacterial infection [26-28]. This is particularly true in cancer patients with an ANC <100/microL for more than five days [29]. The source of microbial invasion of the blood is chemotherapy-induced mucositis and breaks in the gastrointestinal lining.

●Efforts have been made to identify febrile neutropenic patients with a lower risk of bacteremia. In one pediatric study of 161 patients experiencing 509 episodes of fever and neutropenia, presentation with chills or hypotension, the requirement for fluid resuscitation, or the diagnosis of leukemia or lymphoma were associated with a higher probability of positive blood cultures [30]. Children without initial signs of sepsis whose fever resolved on antibiotic therapy and whose ANC was ≥100/microL after a 48-hour period in hospital had a low risk of complications.

●The risk is lower in patients with AIDS who may develop neutropenia in whom drug toxicity or autoimmunity may be responsible for the neutropenia. The risk for bacterial infection becomes significant when the ANC is less than 750 to 1000/microL [31,32]. In one series of 2047 HIV-infected patients, the risk for developing a bacterial infection requiring hospitalization occurred at ANCs below 750/microL and increased progressively as the ANC fell below this level (figure 1) [31]. (See "Infectious causes of neutropenia", section on 'HIV'.)

●Children with the benign chronic neutropenia may have an ANC below 200/microL for months or years and remain free of serious infections [33]. Similarly, some adults with immune neutropenia have severe depression of the ANC but never suffer episodes of infection [34]. In both situations, the bone marrow generally shows normal granulocyte maturation up to either the metamyelocyte or band form stage with a paucity of PMNs. This bone marrow picture is referred to as a "maturational arrest."

●Well-appearing children with transient neutropenia, particularly of short duration, are also at low risk for infection. In one study of 119 children, infectious complications occurred in 4 of the 36 patients who had neutropenia for more than 30 days (two with stomatitis, one with cellulitis, and one with pneumonia) but in none with a shorter duration of neutropenia [35].

In addition to differences in bone marrow reserve, several other factors may contribute to the variability in infectious risk. Many patients with chronic forms of neutropenia have normal or increased blood monocyte counts. Monocytes are functioning phagocytes such as the neutrophil and band forms and probably contribute to the lack of correlation between the ANC and infection risk [36,37]. Neutropenia related to underlying immunodeficiency may have normal marrow reserve yet increased risk because of inability to make protective antibodies or mucosal barrier damage secondary to vasculitis.

Another difference is that the delivery of neutrophils to tissues in chronic severe neutropenia appears to be greater than in acute chemotherapy-induced neutropenia of equal degree [29,38]. Furthermore, recovery of neutrophils is evident at tissue sites before the blood [38]. These observations indicate that the ANC does not always accurately reflect neutrophil availability at tissue or organ sites of infection.

Specific pathogens associated with neutropenia — The specific pathogens isolated from infected neutropenic patients are almost exclusively pyogenic or enteric bacteria or certain fungi (eg, Candida species). They are usually endogenous bacteria including Staphylococcus aureus from the skin and Gram-negative organisms from the gastrointestinal and urinary tract. Isolated neutropenia does not increase the susceptibility to viral or parasitic infection. (See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis".)

Common sites of infection include the oral cavity and mucous membranes, the skin, and perirectal and genital areas. With persistent severe neutropenia, systemic infection occurs associated with bacteremia, and infections of the lung and gastrointestinal tract. Patients receiving broad spectrum antibiotics for two weeks or more while neutropenic are more prone to infection with enteric bacteria and/or fungi, while patients with indwelling catheters or other foreign bodies are more likely to become infected with coagulase-negative staphylococci.

One study evaluated the distribution of organisms for 909 episodes of bacteremia and associated outcome among 799 neutropenic febrile cancer patients [29]. Among the bacteremic episodes, 46 percent were due to Gram-positive organisms, 42 percent to Gram-negative organisms, and 12 percent were polymicrobial. Infection at a site other than blood alone was observed in 242 episodes; the sites of involvement included lung (about 40 percent), skin and soft tissue (about 30 percent), urinary tract, sinuses and oropharynx, skeletal, enteric tract, meninges, and endocardium [29]. In general, the initial and ultimate response rates were good when the infection was due to a single type of organism and less favorable when the infection was due to more than one type of microbe.

DIAGNOSTIC APPROACH — The first step in the approach to the patient with neutropenia is confirmation of the diagnosis. Review of a Wright-Giemsa stained peripheral blood smear will confirm the reduced number of neutrophils. In all cases in which the white blood cell differential count has been generated by automatic counters, it should be repeated manually. Pseudoneutropenia can occur if blood is left standing for a prolonged period of time and in the presence of paraproteinemia and certain anticoagulants that can cause cellular clumping.

Because most acquired cases of neutropenia are transient, monitoring of the blood counts for 8 to 12 weeks is often the best approach if there are no other important clinical factors present. An approach for following such patients is shown in the algorithm (algorithm 1). This algorithm works for patients of all ages, including adults. For isolated mild or severe neutropenia in the absence any abnormal clinical findings, obtaining serial blood counts at increasing intervals is the most reasonable approach. We recommend monitoring the sedimentation rate as well. Elevation of the sedimentation rate in the absence of other findings in a neutropenic patient can indicate deep-seated inflammation and may indicate a more serious type of neutropenia. According to this schema, if the patient develops clinical symptoms related to neutropenia or changes in other cell lines in the blood count, a full evaluation should be undertaken.

Infants and young children — The differential diagnosis of neutropenia in infants and young children includes isoimmune neonatal neutropenia, autoimmune neutropenia, severe congenital neutropenia (SCN), Shwachman-Diamond-Oski syndrome, and cyclic neutropenia.

●Transient mild to moderate neutropenia can be caused by a variety of common viral infections during childhood, including respiratory syncytial virus (RSV), influenza A and B, parvovirus, Epstein-Barr virus (EBV), and human herpes virus 6 (HHV6). In most cases, neutropenia occurs during the first few days of the viral illness and persists for three to eight days [1]. (See 'Postinfectious neutropenia' above.)

●Isoimmune neutropenia occurs only in newborns and presents as moderate to severe neutropenia, usually with the first pregnancy. The disorder is due to antineutrophil antibodies transferred from the mother, as discussed separately. (See "Immune neutropenia".)

●Autoimmune neutropenia ("benign neutropenia") is not associated with recurrent severe infections and typically occurs between the ages 5 to 15 months, although the range extends from one month to adulthood. Although unusual, a small number of patients with autoimmune neutropenia present with features characteristic of SCN and the differential diagnosis is ultimately made by bone marrow aspiration and genetic studies. Auto-immune neutropenia is discussed separately. (See "Immune neutropenia".)

●Severe congenital neutropenia (SCN) is very rare and characterized by severe infections in the first month of life, the absence of spontaneous remissions, and maturation arrest of myelopoiesis at the promyelocyte stage, as discussed separately. (See "Congenital neutropenia".)

●Shwachman-Diamond-Oski syndrome is very rare and is characterized by pancreatic insufficiency, metaphyseal dysostosis, neutropenia with or without thrombocytopenia, and/or anemia, as discussed separately. (See "Shwachman-Diamond syndrome".)

●Cyclic neutropenia is very rare and classically occurs as neutropenic periods of three to six days approximately every 21 days. The diagnosis is made by monitoring the absolute neutrophil count (ANC) three times per week for six to eight weeks. (See "Cyclic neutropenia".)

Older children — If anemia, particularly normocytic or macrocytic anemia, or thrombocytopenia is found in the older child with neutropenia, hematologic consultation should be requested immediately and examination of the peripheral smear along with a bone marrow aspiration should be performed unless the cause is clear.

Neutropenia in the absence of recurrent or protracted infection — Most causes of neutropenia are benign, especially if the ANC is above 800/microL. Thus, a period of observation is indicated if the patient is asymptomatic and there are no other significant clinical features, particularly if there is a recent history of viral infection or a medication has been taken that is known to be associated with neutropenia (table 6). Examination of the oral cavity is important, since the presence of gingivitis or tooth abscess suggests the presence of symptomatic neutropenia (algorithm 1).

If the neutropenia resolves, the patient should be followed for one year with complete blood count being obtained whenever fever occurs.

Moderate to severe neutropenia with recurrent infection — Bone marrow aspiration with evaluation of cellularity and morphology should permit identification of late myeloid arrest or myeloid hypoplasia. Late arrest is seen in idiopathic or autoimmune neutropenia, most often associated with antineutrophil antibodies, and in collagen vascular diseases, some drug-induced neutropenias, and chronic infection. Myeloid hypoplasia characterizes toxic drug-induced neutropenias, pure white cell aplasia, T-gamma lymphocytosis (large granular lymphocyte syndrome), severe congenital neutropenia, and myelodysplastic syndrome.

The diagnostic evaluation of isolated neutropenia is listed in the table (table 8). While bone marrow aspiration is often thought of as the first step, we prefer to delay this test unless there is a clear indication to do it immediately. It is only diagnostic in the case of the progranulocyte maturation arrest seen in the rare case of severe congenital neutropenia or marrow infiltration. Most other disorders require other confirmatory testing. Thus, we prefer to do tests for collagen vascular disease and nutritional disorders first, prior to marrow examination.

Patients who have episodic infections should have twice-weekly measurement of the ANC for at least six weeks to confirm the diagnosis of cyclic neutropenia. Patients with cyclic neutropenia have decreased marrow cellularity one week before the nadir of their neutropenia. This is a rare syndrome and usually associated with symptoms every 21 days and should not be considered unless there is good clinical reason or family history. Bone marrow aspiration is not helpful in this disorder; tests for the ELANE gene are positive over 90 percent of the time. (See "Cyclic neutropenia".)

As noted in the table (table 8), the following laboratory studies may be indicated:

●Antinuclear antibodies and complement to screen for collagen vascular disease

●Antineutrophil antibodies are generally not helpful (see "Laboratory evaluation of neutrophil disorders")

●Immunoglobulins and immune evaluation to screen for defects of cellular or humoral immunity (see "Laboratory evaluation of the immune system")

●Screen for HIV infection (see "Screening and diagnostic testing for HIV infection")

●Methylmalonic acid and homocysteine levels to assess vitamin B12 and folate status (see "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency")

●Serum copper and ceruloplasmin levels to assess for copper deficiency

GENERAL ASPECTS OF TREATMENT — The clinical management of neutropenic states depends on the cause and degree of the neutropenia, as well as the presence of associated disease states. Patients with severe neutropenia and little marrow reserve may have sepsis, while patients with hypercellular marrow tend to have chronic infections or no infection. (See "Overview of neutropenic fever syndromes" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications" and "Fever in children with chemotherapy-induced neutropenia" and "Management of children with non-chemotherapy-induced neutropenia and fever", section on 'Risk-based management approach'.)

All patients with chronic neutropenia with decreased marrow reserve should receive regular dental care. Chronic gingivitis and recurrent stomatitis can be major sources of morbidity. If neutropenia and gingivitis are present, some experts offer oral antibacterial rinses with chlorhexidine gluconate; however, it is unpleasant to use routinely, there is only weak evidence of benefit (eg, reduced dental plaque, symptoms of gingivitis, or aerosolization of bacteria), and there are substantial adverse effects (eg, staining of teeth, potential antibacterial resistance, and rare, fatal anaphylactic reactions) [39]. Prophylactic antibiotics are generally not indicated.

Patients with bone marrow hypoplasia and/or severe infections — This group includes patients with chemotherapy-induced neutropenia or bone marrow granulocyte hypoplasia. There are multiple causes of the latter problem, such as aplastic anemia, severe congenital neutropenia, Shwachman-Diamond-Oski syndrome, pure white cell aplasia, large granulocyte lymphocyte syndrome, and drug-induced (toxic-form) agranulocytosis. The general approach involves preventive measures to limit the number and severity of infections and aggressive treatment of infections that occur. Patients should also receive aggressive antibacterial therapy for fever, even in the absence of signs of infection.

Granulocyte colony-stimulating factor (G-CSF) should be given to patients with decreased marrow reserve and an inadequate response to antibiotics. Treatment with G-CSF is indicated in most cases of severe congenital neutropenia, but is typically not needed for patients with Shwachman-Diamond-Oski syndrome.

Antibiotic therapy — The organisms that cause infections in patients with severe neutropenia usually come from the gastrointestinal tract or skin and can result in the rapid onset of overwhelming sepsis. Thus, febrile patients with neutropenia related to marrow suppression should be treated immediately, following culture of body fluids, with broad-spectrum parenteral antibiotics for coverage of both Gram-positive and Gram-negative bacteria [40].

In general, patients with an absolute neutrophil count (ANC) >1000/microL can be managed on an outpatient basis while those with an ANC of <500/microL and marrow aplasia may require inpatient treatment with parenteral antibiotics (table 2). Routine reverse isolation procedures are of no benefit and serve to decrease contact with medical personnel [41,42].

When a patient first presents with high fever and has a very low ANC, one must assume that the patient is high risk and has inadequate marrow reserve. The schema in the algorithm is an accepted approach to such patients (algorithm 2). Specific antibiotic regimens for such patients can be found separately in UpToDate. (See "Overview of neutropenic fever syndromes" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications" and "Fever in children with chemotherapy-induced neutropenia".)

It is now recognized that even in post-chemotherapy patients, outpatient management of fever may be acceptable under certain limited circumstances. If there is any question, the patient should be admitted for observation and treatment.

If the patient is known to be in a low-risk group (table 5), they can be managed as any other patient. Unlike the "low risk" group as defined for oncology patients, these patients may not require any antibiotics at all. "Low risk" febrile oncology patients by definition have decreased marrow reserve and therefore are excluded from our low risk group. Otherwise, the oncology risk classification and treatment approaches are useful for non-oncological neutropenia cases as well [43]. (See "Risk assessment of adults with chemotherapy-induced neutropenia".)

Monitoring of the C-reactive protein level and erythrocyte sedimentation rate (ESR) daily or every other day during acute treatment can be very helpful in these patients, particularly in patients with established severe chronic neutropenia. Often, cultures are negative and treatment is purely empiric. A rapid response can indicate that the appropriate antibiotics have been selected, and poor response or increase in ESR after a response can indicate that a change in antibiotics is necessary.

Antibiotics should be continued for several days after the fever has subsided and the sedimentation rate has normalized. If the ANC has risen above 500/microL on several measures, the antibiotics may be discontinued as long as no source of infection is apparent [40]. If fever persists or there is no clear response to treatment, other therapies should be considered.

●If fever and neutropenia persist beyond seven days in the immunosuppressed patient, antifungal treatment should be considered. This approach has support in post-chemotherapy patients [40]; however, it should not be used in patients with benign forms of neutropenia.

●Granulocyte transfusions have been given, if available, to patients with Gram-negative sepsis who have not shown a clinical response to antibiotics within 24 to 48 hours. Enthusiasm for the use of granulocyte transfusions has waned due in part to difficulties in procurement, to better antibiotics, and to the use of bone marrow growth factors. However, better methods of procurement and their rapid efficacy makes them a useful part of the armamentarium for treating neutropenic patients with sepsis. (See "Granulocyte transfusions".)

Myeloid growth factors — The administration of recombinant granulocyte colony-stimulating factor (G-CSF, filgrastim) can correct the neutropenia and reduce infectious morbidity in infected patients with a variety of causes of severe neutropenia. Included in this group are severe congenital neutropenia, cyclic neutropenia, and AIDS [44-51]. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has also been used successfully in neutropenic patients with AIDS [50] but appears to be less effective than G-CSF in patients with cyclic neutropenia [48].

The potential efficacy of the appropriate use of G-CSF can be illustrated by the following observations:

●A multicenter, phase III trial randomized 123 patients with severe chronic neutropenia and recurrent infection to either immediate treatment with filgrastim (3.45 to 11.5 mcg/kg per day) or a four-month observation period followed by filgrastim treatment [45]. On treatment, 108 patients had a median ANC greater than or equal to 1500/microL and bone marrow aspirates showed increased proportions of maturing neutrophils. Filgrastim therapy was associated with a reduction in the incidence and duration of infection-related events of approximately 50 percent.

●Another multicenter trial randomized 258 HIV-infected patients with a CD4 cell count below 200/microL and an ANC between 750 and 1000/microL to placebo or increasing doses of daily or intermittent filgrastim to maintain an ANC between 2000 and 10,000/microL [49]. The incidence of severe neutropenia or death was much lower in the treated patients (10 versus 34 percent) who also had 31 percent fewer bacterial infections.

However, G-CSF therapy is not indicated for all causes of neutropenia. It is helpful in patients with neutropenia associated with early myeloid arrest and its use should be reserved for patients with demonstrated infectious morbidity related to the neutropenia. The literature is misleading with respect to the use of G-CSF in neutropenias, as there are a number of reports of patients even with benign neutropenia who were given G-CSF and recovered, when in fact they may have recovered spontaneously despite this treatment.

A more complete discussion of the use of G-CSF in patients with chemotherapy-induced neutropenia (eg, use as primary or secondary prophylaxis, neutropenia without fever, neutropenic fever) is presented separately. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".)

Chemotherapy-induced neutropenia — This subject is discussed in depth separately. (See "Overview of neutropenic fever syndromes" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications" and "Fever in children with chemotherapy-induced neutropenia".)

Hematopoietic cell transplantation — Hematopoietic cell transplantation has been used successfully in certain instances of severe neutropenia, such as infantile agranulocytosis [52]. It should be considered if an appropriate donor is available and no therapeutic response is achieved with G-CSF or GM-CSF.

Patients with adequate marrow reserves — Patients with late marrow arrests and a normocellular marrow have an adequate bone marrow supply of neutrophils and usually handle infections reasonably well. Children in whom the diagnosis of chronic benign neutropenia of infancy has been confirmed can be treated as normal children. Less aggressive therapy is also warranted in adults with an adequate bone marrow reserve and a several month history of severe neutropenia without serious infection. However, the subsequent course is not known when these patients are first encountered. As a result, they should initially be treated as other patients with severe forms of neutropenia.

Long-term follow-up of patients with severe combined neutropenia and Shwachman-Diamond-Oski syndrome receiving G-CSF has indicated a 25 to 36 percent cumulative incidence of acute myeloid leukemia or myelodysplasia [53,54]. It is unclear whether G-CSF is a risk factor, since patients with both disorders have developed AML/MDS prior to the use of G-CSF. (See "Congenital neutropenia", section on 'G-CSF receptor mutations'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Neutropenia (The Basics)")

SUMMARY

●Definition – The absolute neutrophil count (ANC) (calculator 1) is equal to the product of the white blood cell (WBC) count and the fraction of polymorphonuclear cells (PMNs) and band forms on the differential analysis:

     ANC = WBC (cells/microL) x percent (PMNs + bands) ÷ 100

●Neutropenia – The normal range for ANC varies somewhat with age (table 3) and among populations. (See 'Definitions and normal values' above.)

Neutropenia is defined by ANC <1500/microL in most populations. However, individuals of African descent, among others, may have ANC <1500/microL without recurrent or severe infections. A common reason for this normal variant is called Duffy-null associated neutrophil count (DANC; formerly called benign ethnic neutropenia or constitutional neutropenia), which is associated with homozygous polymorphism of the Duffy red blood cell antigen. (See 'Normal variants' above.)

●Overview – A peripheral blood WBC count samples the smallest compartment of neutrophils and does not accurately reflect the body's capacity to deliver neutrophils to tissues and protect against bacterial infection. Examination of the bone marrow, which contains most of the body's neutrophils, can determine this most effectively. (See 'Propensity to infection and significance of neutropenia' above.)

●Etiology – Neutropenia can be either acquired or congenital (table 6). Infection, drugs, and immune disorders are the most common acquired causes while congenital causes are rare and confined mostly to infants and children. The danger to the patient depends on the etiology, bone marrow status (table 5), and the ANC (table 2). (See 'Classification and etiology of isolated neutropenia' above and 'Clinical presentation' above.)

●Diagnosis and management – The approach to the subject with isolated neutropenia is shown in the algorithm (algorithm 1). Management depends on the cause of the neutropenia and includes the prevention of infection, regular dental care, antibacterial mouthwashes, aggressive antibacterial therapy for fever, and the judicious use of myeloid growth factors in selected patients with decreased marrow reserve. (See 'Diagnostic approach' above and 'General aspects of treatment' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Laurence A Boxer, MD, and E Richard Stiehm, MD, who contributed as Section Editors to earlier versions of this topic review.