Management of the adult with non-chemotherapy-induced neutropenia

INTRODUCTION — The management of adults with neutropenia can be challenging because the number of neutrophils circulating in the peripheral blood (reflected in the absolute neutrophil count [ANC]) is not always predictive of the individual's ability to respond to infection. This topic will discuss the management of the adult patient with non-chemotherapy-induced neutropenia (ie, neutropenia that is not the result of chemotherapy or hematopoietic cell transplant [HCT]).

The diagnostic evaluation of adults with non-chemotherapy-induced neutropenia is presented separately. (See "Approach to the adult with unexplained neutropenia".)

The management of children with neutropenia is also discussed separately.

●(See "Management of children with non-chemotherapy-induced neutropenia and fever".)

●(See "Fever in children with chemotherapy-induced neutropenia".)

●(See "Congenital neutropenia".)

●(See "Cyclic neutropenia".)

●(See "Overview of neutropenia in children and adolescents".)

Fever in a patient with neutropenia due to chemotherapy, HCT, or bone marrow suppression from any cause is a medical emergency because such patients are at risk of sepsis and death from overwhelming infection. The management of chemotherapy-induced neutropenia and chemotherapy-induced neutropenia with fever are presented separately.

●(See "Risk assessment of adults with chemotherapy-induced neutropenia".)

●(See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults".)

●(See "Evaluation of children with non-chemotherapy-induced neutropenia and fever".)

●(See "Overview of neutropenic fever syndromes".)

DEFINITION OF NEUTROPENIA — The definition of neutropenia varies from institution to institution. Neutropenia is usually defined (and defined herein) as an absolute neutrophil count (ANC) <1500 cells/microL (<1.5 x 10⁹/L) in an adult. The ANC is equal to the product of the white blood cell (WBC) count and the percentage of neutrophils from the WBC differential (calculator 1). (See "Approach to the adult with unexplained neutropenia", section on 'Definitions and normal values'.)

INFECTIOUS RISK STRATIFICATION

Overview of risk stratification — The most important factor in managing a patient with neutropenia is determining the patient's risk of developing an infection and ability to respond to a severe infection. While most clinicians are familiar with the uniformly high risk of infection in those with chemotherapy-induced neutropenia, the risk of infection in those with non-chemotherapy-induced neutropenia can be quite variable, ranging from no increased risk to severe, life-threatening risk. Details of the evaluation of adults with unexplained neutropenia are presented separately. (See "Approach to the adult with unexplained neutropenia".)

The main determinant of the infectious risk in patients with non-chemotherapy-induced neutropenia is the adequacy of the bone marrow neutrophil reserve (ie, the ability of the bone marrow to produce neutrophils) (table 1). As a general rule, patients with an adequate bone marrow reserve may have chronic, non-life-threatening infections or no infections, while those with inadequate bone marrow reserve are at high risk of severe infection and sepsis. (See 'Bone marrow evaluation' below.)

The ability of the bone marrow to produce adequate neutrophils can be assessed directly by bone marrow examination, or indirectly from clinical findings that suggest adequate delivery of neutrophils to the tissues. (See 'Bone marrow evaluation' below and 'Clinical features' below.)

However, a patient may develop an infection before the adequacy of the bone marrow reserve is known. If a patient first presents with fever (ie, a single oral temperature >38.3°C [101°F] or >38.0°C [100.4°F] sustained for >1 hour) and neutropenia of unknown cause, one must assume that the patient has inadequate marrow reserve and is at high risk. (See 'Patients with inadequate bone marrow reserve' below.)

Another factor that can increase infectious risk is the presence of disease states such as vasculitis and defective cellular immunity, which sometimes accompany neutropenia. The severity of these conditions can increase infectious risk independently of the bone marrow ability to produce neutrophils or the severity of the neutropenia. (See "The adaptive cellular immune response: T cells and cytokines" and "The adaptive humoral immune response".)

Bone marrow evaluation — The gold standard for determining the adequacy of the bone marrow ability to produce neutrophils is examination of a bone marrow aspirate and biopsy specimen. Bone marrow examination is commonly performed in the course of the initial evaluation for patients with congenital neutropenias or pancytopenia.

Bone marrow neutrophil production is considered to be adequate if the cellularity and maturation of the neutrophil series is normal or increased. In contrast, reduced bone marrow cellularity or myeloid arrest at the myelocyte or metamyelocyte stage implies decreased bone marrow reserve. (See "Evaluation of bone marrow aspirate smears", section on 'Estimation of cellularity and myeloid to erythroid ratio' and "Regulation of myelopoiesis", section on 'Neutrophil production and maturation'.)

Bone marrow sampling may not be necessary (or indicated) for those with mild or transient neutropenia, lack of infections, or infections associated with signs of adequate neutrophil delivery. In particular, in patients with longstanding mild neutropenia suggestive of Duffy-negative associated neutrophil count (DANC; formerly called benign ethnic neutropenia [BEN]), bone marrow examination is uniformly uninformative and need not be performed. The diagnosis of DANC can be confirmed by determining Duffy-negative phenotype in the blood bank [1].

Clinical features — For patients who have not had a bone marrow evaluation or in whom the bone marrow findings are equivocal, the following clinical features may be useful in predicting the bone marrow reserve and/or the presence of an active infection (table 2):

●Purulent material or abscess formation suggests adequate bone marrow reserve and tissue delivery of neutrophils.

●Markedly increased dental caries and/or ulcerations of the oral mucosa and severe gingivitis suggest an inability to deliver neutrophils. However, some lymphocyte and vascular disorders can cause similar lesions.

●Splenomegaly may be a sign of a chronic inflammatory state or an underlying hematologic disorder, both of which may impair an otherwise appropriate response to infection. (See "Splenomegaly and other splenic disorders in adults" and "Clinical manifestations and diagnosis of Felty syndrome".)

●Elevations of the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) suggest an ongoing inflammatory process, which may be a sign of other immune deficits or inadequate neutrophil production. However, elevated ESR or CRP should be interpreted with caution, as many co-morbid illnesses in adults (eg, diabetes, cardiovascular disease) can be associated with increases in these inflammatory markers. (See "Acute phase reactants", section on 'Clinical use'.)

●Increased (or normal) absolute monocyte counts are seen in many patients with chronic forms of neutropenia. Monocytes are functioning phagocytes, but their motile response is sluggish and their presence may not suggest a decreased risk of infection [2-4].

●Lymphocytopenia (decreased absolute lymphocyte count) suggests an underlying immunodeficiency state, which can increase infectious risk independently of the neutropenia. Lymphocytopenia can occur in those with congenital or acquired immunodeficiencies, sepsis, malignancy, and in the postoperative period. (See "Laboratory evaluation of the immune system" and "Approach to the child with lymphocytosis or lymphocytopenia", section on 'Lymphocytopenia'.)

Counseling regarding infectious risk — For all patients with neutropenia, it is important to inform the patient and caregiver(s) about whether their risk of infection is high or low, and when they should seek medical attention. Although it is not our goal to unduly worry those with asymptomatic neutropenia, it can be reassuring if these individuals and their caregiver(s) are aware of the warning signs of a more serious condition.

While it is important to reduce infectious risk, it is also important to reassure patients that they do not need to sterilize their environment, and to help them find good sources of information about risk reduction [5]. We also reassure patients with isolated chronic asymptomatic neutropenia that they are not at increased risk of developing leukemia.

PATIENTS WITH INADEQUATE BONE MARROW RESERVE

Overview of infectious risk — Individuals with inadequate bone marrow production of neutrophils (eg, drug-induced neutropenia/agranulocytosis) are at increased infectious risk, the degree of which correlates with the absolute neutrophil count (ANC). An ANC <500 cells/microL (500 x 10⁹ cells/L) in a patient with diminished bone marrow capacity carries a significant risk of infection, whereas an ANC >1500 cells/microL carries a risk similar to the general population (table 3). (See 'Infectious risk stratification' above.)

The high risk of infection in a patient with an ANC <100 cells/microL was demonstrated in a classic study of patients with leukemia published in 1966 [6]. This study evaluated the relationship between the frequency, severity, and duration of neutropenia during 125 episodes of severe neutropenia and 733 episodes of moderate neutropenia. Infections occurred in 80 percent of patients with severe neutropenia (ANC <100/microL) within two weeks of onset and in 100 percent at three weeks. However, it should be noted that patients in this study had leukemia and therefore had many reasons to have intercurrent infection related to the effects of chemotherapy on mucosal surfaces, indwelling intravenous catheters, and the other aspects of their disease and its treatment.

Patients with chronic idiopathic neutropenia may have a very benign course and tolerate an ANC <100 cells/microL without experiencing infectious episodes, but others may experience gingivitis and painful mouth ulcers requiring treatment with G-CSF.

In most cases, individuals with post-infectious neutropenia and neutropenia due to nutrient deficiencies will experience a rapid resolution of neutropenia once the infection resolves or the nutritional deficiency is corrected, and these individuals can be presumed to handle infections adequately once the neutrophil count begins to improve.

Preventing infection

Overview of infection prevention — The major means of preventing infection in those with inadequate bone marrow neutrophil reserve include reducing exposures and raising the neutrophil count with myeloid growth factors.

We also suggest the following in all patients:

●Emphasize dental hygiene and regular dental care to prevent oral infections and bacteremia from an oral source. Antibiotic mouthwashes, such as chlorhexidine gluconate (0.12% oral rinse), can be used by individuals with gingivitis to reduce the severity of this condition.

●Promote hand hygiene, which is especially important during influenza season, travel, and encounters with medical personnel. (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Hand hygiene'.)

●Regularly update age-appropriate immunizations and annual influenza vaccines. Inactivated vaccines are appropriate for those with coexisting immunodeficiencies. (See "Standard immunizations for nonpregnant adults" and "Immunizations for travel".)

We do not use any special dietary practices in individuals with neutropenia. Prophylactic antibiotics are also generally not of value in those with inadequate bone marrow reserve of neutrophils who do not have an active infection. Exceptions include antibiotics to prevent travelers' diarrhea and appropriate peri-procedural antibiotics.

If a patient requires treatment for severe or recurrent infections, we treat with G-CSF to maintain an adequate neutrophil count. Although there are no strict criteria by which we decide when to initiate this therapy, we treat most patients with an ANC <500 who have recurrent aphthous ulcers, have had a single life-threatening unprovoked infection, or have had two or more serious infections over the course of a year. Patients who develop severe G-CSF-related side effects can have a trial off therapy to determine whether they need chronic cytokine support.

Prophylactic antibiotics have not been demonstrated to be of value in the setting of non-chemotherapy-induced neutropenia with frequent infections. The use of prophylactic antibiotics in individuals with chemotherapy-induced neutropenia is discussed separately. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications" and "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults".)  

Myeloid growth factors to reduce infectious risk — Myeloid growth factors, including granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been used successfully in some neutropenic patients as a means of preventing infections. G-CSF should not be given based on the severity of the neutropenia, but rather based on the presence of recurrent infections. As previously noted, many patients with chronic idiopathic neutropenia are asymptomatic despite an ANC <100 cells/microL, and do not require G-CSF. Use of G-CSF in those patients can be associated with severe side effects (eg, bone pain, nausea, vomiting, splenomegaly), supporting the practice of avoiding G-CSF administration that is not dictated by clinical presentation. In patients with recurrent infections, low doses of G-CSF (eg, 1 to 3 mcg/kg/day) may be used and may be well tolerated.

We use G-CSF to improve neutrophil production in patients with the following conditions when there is a strong history of infections:

●Congenital neutropenias (see "Congenital neutropenia", section on 'Treatment')

●Human immunodeficiency virus (HIV) infection

●Aplastic anemia

●Chronic idiopathic neutropenia with recurrent infections (see "Immune neutropenia", section on 'Chronic idiopathic neutropenia')

When using G-CSF, we use short-acting preparations, rather than long-acting pegylated G-CSF, because of increased side effects with the latter in this patient population. (See "Introduction to recombinant hematopoietic growth factors".)

The potential efficacy of G-CSF in preventing infections in patients with inadequate bone marrow reserve 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 G-CSF (3.45 to 11.5 mcg/kg per day) or a four-month observation period followed by G-CSF treatment [7]. Patients treated with G-CSF had a median ANC ≥1500 cells/microL, and bone marrow aspirates showed increased proportions of maturing neutrophils. G-CSF therapy was associated with a reduction in secondary endpoints, including the incidence and duration of infection-related events and antibiotic use.

●Another multicenter trial randomized 258 HIV-infected patients with a CD4 cell count <200/microL and an ANC between 750 and 1000 cells/microL to placebo or increasing doses of daily or intermittent G-CSF to maintain an ANC between 2000 and 10,000/microL [8]. The incidences of the composite primary endpoint (severe neutropenia or death) was lower in the G-CSF-treated patients (10 versus 34 percent), and the risk of severe bacterial infection was lower with G-CSF (relative risk 0.46; 95% CI 0.26–0.79).

The benefits of myeloid growth factors in preventing severe or life-threatening infection must be balanced against the concerns of unnecessary toxicities and resource utilization in those who would have recovered without myeloid growth factor treatment.

Patients may express concerns that G-CSF administration could increase the risk of developing acute myeloid leukemia (AML), as occurs in some patients with congenital neutropenia. Such risk is not seen in patients with other forms of neutropenia, and adult patients may need to be reassured that they are not at risk for developing AML if they receive G-CSF. (See "Congenital neutropenia", section on 'G-CSF receptor mutations'.)

The use of myeloid growth factors in patients with chemotherapy-induced neutropenia is discussed 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".)

Hematopoietic cell transplantation — Allogeneic hematopoietic cell transplantation (HCT) has the potential to reduce the infectious risk from severe neutropenia with inadequate bone marrow reserve. HCT can also correct other hematologic deficiencies when present (table 4). Because the risks associated with allogeneic HCT are high (eg, graft-versus-host disease, graft failure), this approach is generally reserved for children with congenital neutropenias who have frequent infections or other risks from their underlying condition and for whom the response to myeloid growth factors is insufficient.

Discussion of the role of HCT for some of the neutropenic conditions is presented in more detail separately:

●Congenital neutropenias – (See "Congenital neutropenia", section on 'Treatment'.)

●Primary immunodeficiency syndromes associated with neutropenia – (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity" and "Chediak-Higashi syndrome", section on 'Treatment'.)

Treatment of infection

Overview of treatment — Patients with inadequate bone marrow neutrophil reserve may not exhibit typical signs of infection (eg, pus, abdominal pain, infiltrate on chest radiography) due to lack of circulating neutrophils. Thus, fever (ie, a single oral temperature >38.3°C [101°F] or >38.0°C [100.4°F] sustained for >1 hour) should always be presumed to be due to infection regardless of the presence of these other findings. Treatment with empiric broad-spectrum antibiotics, including coverage for gram negative organisms (including Pseudomonas species) should be initiated rapidly. (See "Overview of neutropenic fever syndromes", section on 'Timing of antibiotics'.)

Although antibiotics should not be delayed while obtaining cultures, blood and urine cultures should be obtained prior to starting antibiotics, if possible, along with cultures of other body fluids if appropriate (eg, sputum in a patient with productive cough). This evaluation is discussed in detail separately (table 5). (See "Diagnostic approach to the adult cancer patient with neutropenic fever".)

The need for hospitalization depends upon the degree of neutropenia and the severity of infection (table 3). In general, patients with an ANC >1000 cells/microL can be managed on an outpatient basis, while those with an ANC of <500 cells/microL and bone marrow aplasia require inpatient treatment with parenteral antibiotics. Patients with an ANC between 500 and 1000 cells/microL can occasionally be managed on an outpatient basis. We have a low threshold for hospital admission if the patient does not respond to outpatient therapy. Routine reverse isolation procedures are of no benefit and serve to decrease contact with medical personnel [9,10].

The management of infection in adults with chemotherapy-induced neutropenia is discussed separately. (See "Overview of neutropenic fever syndromes" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

Specific pathogens and sites of infection — The range of potential infectious organisms and sites of infection is broad. Consideration of likely pathogens and sites of infection may help guide management.

●Pathogens – The pathogens isolated from infected neutropenic patients are almost exclusively pyogenic or enteric bacteria or certain fungi (eg, Candida species). The bacteria are usually endogenous organisms from the skin (eg, Staphylococcus aureus) and gram-negative organisms from the gastrointestinal or urinary tracts (eg, Pseudomonas species). Isolated neutropenia does not increase the susceptibility to viral or parasitic infection. (See "Overview of neutropenic fever syndromes", section on 'Epidemiology' and "Candidemia in adults: Epidemiology, microbiology, and pathogenesis".)

●Sites of infection – Common sites of infection include the oral cavity and mucous membranes, the skin, and perirectal and genital areas. With persistent severe neutropenia, systemic infection can be 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.

These findings were illustrated in a study that evaluated the distribution of organisms for 909 episodes of bacteremia and associated outcomes among 799 neutropenic febrile cancer patients [11]. 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 [11]. 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.

Antimicrobials — Patients with fever should receive broad-spectrum antibacterial therapy to cover gram-positive and gram-negative organisms, and the antibiotic coverage should remain broad until the organism(s) are identified. Often, cultures are negative and treatment is purely empiric. The use of intravenous antibiotics is usually appropriate unless the neutropenia is mild or expected to resolve rapidly. This practice is similar to that used in individuals with chemotherapy-induced neutropenia. (See "Overview of neutropenic fever syndromes" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

Addition of antifungal and/or antiviral therapy is appropriate in those with positive cultures for fungal or viral organisms and in those with persistent fever after several days of appropriate antibacterial therapy. However, it should be noted that the risk of fungal or viral infection in these patients is much lower than the risk of bacterial infection, unless they have concomitant defects in acquired immunity, as is seen in congenital immunodeficiency. (See "Primary humoral immunodeficiencies: An overview" and "Severe combined immunodeficiency (SCID): An overview".)

Myeloid growth factors to treat infection — Recombinant myeloid growth factors, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF), can correct neutropenia and reduce infectious morbidity in infected patients with a variety of causes of neutropenia. (See "Congenital neutropenia", section on 'Treatment' and "Cyclic neutropenia", section on 'G-CSF' and "Drug-induced neutropenia and agranulocytosis", section on 'Granulocyte colony-stimulating factor'.)  

We typically use chronic G-CSF for patients with demonstrated recurrent infections or oral ulcers related to the neutropenia. Acute administration of G-CSF is indicated in any patients with acute infection in the setting of the following conditions [7,8,12-18]:

●Severe congenital neutropenia

●Cyclic neutropenia

●Neutropenia associated with early myeloid arrest

●Acquired immune deficiency syndrome (AIDS)

●Acquired bone marrow defects with severe neutropenia (ie, ANC <500 cells/microL)

●Chronic idiopathic neutropenia with severe neutropenia

●Drug-induced neutropenia/agranulocytosis with severe neutropenia

The use of myeloid growth factors to treat infections in those with chemotherapy-induced neutropenia is discussed 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", section on 'Neutropenic fever'.)

Granulocyte transfusions — Granulocyte transfusions have been given to patients with gram-negative sepsis who have not shown a clinical response to antibiotics within 24 to 48 hours. Granulocytes must be procured from an appropriate donor whose neutrophil count has been raised with a myeloid growth factor, transfused within a day of collection, and repeated on a daily basis until the patient improves. At institutions where this is possible, granulocyte transfusions are a useful adjunct to therapy in some patients (eg, those with sepsis). Additional issues regarding the administration of granulocyte transfusions and their efficacy are discussed separately. (See "Granulocyte transfusions".)

Monitoring response to treatment — Because the presenting symptoms of infection in patients with neutropenia may be subtle due to lack of neutrophils, the response may also be less obvious. Thus, it is important to monitor temperature and constitutional symptoms to determine whether infections in patients with neutropenia are being adequately treated.

Antibiotics should be continued for several days after the fever has subsided. If the ANC has risen above 500 cells/microL, the antibiotics may be discontinued as long as no source of infection is apparent [19]. The duration of therapy for patients with clinically or microbiologically documented infections depends on the clinical syndrome and pathogen. (See "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications", section on 'Duration' and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Duration'.)

If fever persists or there is no clear response to treatment, a thorough search for a source of occult infection should be made. Repeat cultures of blood and other cultures or diagnostic tests should be performed on the basis of symptoms and signs. As an example, diarrhea should be evaluated with a Clostridioides difficile toxin assay. Persistent or recurrent fever should also prompt evaluation for the use of other therapies (eg, antifungal agents). (See 'Antimicrobials' above.)

PATIENTS WITH ADEQUATE BONE MARROW RESERVE

Monitoring asymptomatic individuals — Patients with an adequate bone marrow reserve of neutrophils (eg, those with normocellular bone marrow or late myeloid arrests, those with a history of adequate response to infection, or those with signs of adequate neutrophil delivery such as pus) usually handle infections reasonably well and do not require extensive monitoring for infection. Patients in this category include those with Duffy-negative associated neutrophil count (DANC), autoimmune neutropenia, drug-induced mild to moderate neutropenia that is dose-related and stable, splenic sequestration of neutrophils, and chronic idiopathic neutropenia without frequent infections. We monitor patients more frequently around the time of their initial diagnosis if we are unsure about whether a more severe deficiency may be evolving. (See 'Infectious risk stratification' above.)

Most patients who are not experiencing frequent infections can have their complete blood count (CBC) with differential monitored on a periodic basis as an outpatient. The frequency of visits can be decreased as it becomes clear that the neutropenia is not evolving to a more severe condition, and as greater time without infections elapses. This is described in more detail separately. (See "Approach to the adult with unexplained neutropenia", section on 'Monitoring'.)

If testing for nutritional disorders and collagen/vascular disorders was not done at the time of the initial evaluation, this should be performed. (See "Approach to the adult with unexplained neutropenia", section on 'Other initial laboratory testing'.)

For those at increased risk of infection due to an associated immunodeficiency or other non-neutropenia-associated risk, testing of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be done to evaluate for evidence of an infectious or inflammatory process. If these values were abnormal on the previous visit and suggestive of an infection or inflammation, they should be repeated to document resolution of an infection or to prompt further search for the infectious site and organism. It should be noted, however, that both of these findings are non-specific, and other co-morbidities (eg, diabetes, cardiovascular disease) can cause an elevated ESR or CRP.

If a previously asymptomatic patient develops new symptoms or physical findings (eg, neurologic findings, splenomegaly, new abnormalities on the CBC), a re-evaluation of the cause of neutropenia is appropriate. (See "Approach to the adult with unexplained neutropenia", section on 'Initial evaluation'.)

Treatment of infection — The treatment of infection in those known to have adequate bone marrow neutrophil reserve can be similar to the general population, as long as other aspects of immune function, such as cell-mediated immunity, are known to be adequate. (See 'Infectious risk stratification' above.)

An exception is the treatment of infection in adult patients who have chronic idiopathic neutropenia with severe neutropenia (eg, ANC <500 cells/microL). Although these individuals do not require routine myeloid growth factor support, we administer G-CSF in the setting of acute infection to increase the ANC to >500 to 1000 cells/microL. Often, the cause of infection is readily identified (eg, appendicitis, diverticulitis, cholecystitis).

SUMMARY AND RECOMMENDATIONS

●Patients with non-chemotherapy-induced neutropenia have variable risk of infection, ranging from life-threatening sepsis to chronic or no infections (table 1). Determinants of the infectious risk include the bone marrow neutrophil reserve, the severity of the neutropenia in those with inadequate bone marrow neutrophil production (table 3), and the presence of associated immunodeficiencies. (See 'Overview of risk stratification' above.)

●The gold standard for determining the bone marrow neutrophil reserve is examination of a bone marrow aspirate and biopsy. For those in whom bone marrow evaluation is not done (or not indicated), clinical features (eg, presence of pus, splenomegaly, erythrocyte sedimentation rate, C-reactive protein, and monocyte count) may be helpful in predicting the bone marrow reserve (table 2). (See 'Bone marrow evaluation' above and 'Clinical features' above.)

●Monitoring and infection prevention measures should take into account the patient's infectious risk.

•All patients should be counseled regarding their infectious risk and indications for seeking medical attention, as well as general strategies to reduce infectious exposures. (See 'Counseling regarding infectious risk' above and 'Preventing infection' above.)

•Those with inadequate bone marrow reserve should be monitored closely and may benefit from the use of myeloid growth factors (eg, granulocyte colony-stimulating factor [G-CSF]), depending on the underlying cause of the neutropenia and infectious history. Prophylactic antibiotics are generally of no value. (See 'Overview of infectious risk' above and 'Preventing infection' above.)

•Those with adequate bone marrow reserve can be monitored at gradually increasing intervals if there are no signs of worsening hematological findings or infection. (See 'Monitoring asymptomatic individuals' above.)

●Individuals with inadequate bone marrow neutrophil reserve are at risk of severe infections and sepsis. Fever should always be presumed to be due to infection, because these individuals may not present with typical signs of infection (eg, they may lack pus, abdominal pain, infiltrate on chest radiography) due to lack of circulating neutrophils. (See 'Treatment of infection' above.)

•Cultures should always be obtained as quickly as possible, but should not delay administration of antibiotics. (See 'Overview of treatment' above.)

•Broad-spectrum antibacterial therapy should be used to cover gram-positive and gram-negative organisms. (See 'Specific pathogens and sites of infection' above and 'Antimicrobials' above.)

•Myeloid growth factors and/or granulocyte transfusions may be appropriate in those with severe neutropenia and demonstrated infectious morbidity from the neutropenia. (See 'Myeloid growth factors to treat infection' above and 'Granulocyte transfusions' above.)

●For those known to have an adequate bone marrow reserve of neutrophils, the treatment of infection is similar to the general population. An exception is patients with severe chronic idiopathic neutropenia (eg, ANC <500 cells/microL); we administer G-CSF to these patients in the setting of acute infection. (See 'Treatment of infection' above.)

●Management of children with neutropenia is discussed separately. (See "Management of children with non-chemotherapy-induced neutropenia and fever" and "Fever in children with chemotherapy-induced neutropenia" and "Overview of neutropenia in children and adolescents".)

●Fever in a patient with who is neutropenic due to chemotherapy or hematopoietic cell transplantation is a medical emergency. This issue is discussed separately. (See "Overview of neutropenic fever syndromes" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges the late Laurence A Boxer, MD, for his previous role as a section editor for this topic.