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Neutropenia

(Agranulocytosis; Granulocytopenia)

By

Mary Territo

, MD, David Geffen School of Medicine at UCLA

Last full review/revision Aug 2021| Content last modified Aug 2021
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Neutropenia is a reduction in the blood neutrophil count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of infection may be muted, but fever is present during most serious infections. Diagnosis is by white blood cell count with differential, and evaluation requires identification of the cause. If fever is present, infection is presumed, and immediate, empiric broad-spectrum antibiotics are necessary, especially if the neutropenia is severe. Treatment with granulocyte colony-stimulating factor is sometimes helpful.

The normal lower limit of the neutrophil count (total white blood cell count × % neutrophils and bands) is 1500/mcL (1.5 × 109/L) in whites and is somewhat lower in blacks (about 1200/mcL [1.2 × 109/L). Neutrophil counts are not as stable as other cell counts and may vary considerably over short periods, depending on many factors such as activity status, anxiety, infections, and drugs. Thus, several measurements may be needed when determining the severity of neutropenia.

Severity of neutropenia relates to the relative risk of infection and is classified as follows:

  • Mild: 1000 to 1500/mcL (1 to 1.5 × 109/L)

  • Moderate: 500 to 1000/mcL (0.5 to 1 × 109/L)

  • Severe: < 500/mcL (< 0.5 × 109/L)

When neutrophil counts fall to < 500/mcL, endogenous microbial flora (eg, in the mouth or gut) can cause infections. If the count falls to < 200/mcL (< 0.2 × 109/L), the inflammatory response may be muted and the usual inflammatory findings of leukocytosis or white blood cells in the urine or at the site of infection may not occur. Acute, severe neutropenia, particularly if another factor (eg, cancer) is present, significantly impairs the immune system and can lead to rapidly fatal infections. The integrity of the skin and mucous membranes, the vascular supply to tissue, and the nutritional status of the patient also influence the risk of infections.

The most frequently occurring infections in patients with profound neutropenia are

Vascular catheters and other puncture sites confer extra risk of skin infections; the most common bacterial causes are coagulase-negative staphylococci and Staphylococcus aureus, but other gram-positive and gram-negative infections also occur. Stomatitis Stomatitis Oral inflammation and ulcers, known as stomatitis, may be mild and localized or severe and widespread. They are invariably painful. (See also Evaluation of the Dental Patient and Gingivitis... read more Stomatitis , gingivitis Gingivitis Gingivitis is a type of periodontal disease characterized by inflammation of the gums (gingivae), causing bleeding with swelling, redness, exudate, a change of normal contours, and, occasionally... read more Gingivitis , perirectal inflammation, colitis, sinusitis Sinusitis Sinusitis is inflammation of the paranasal sinuses due to viral, bacterial, or fungal infections or allergic reactions. Symptoms include nasal obstruction and congestion, purulent rhinorrhea... read more Sinusitis , paronychia Acute Paronychia Paronychia is infection of the periungual tissues. Acute paronychia causes redness, warmth, and pain along the nail margin. Diagnosis is by inspection. Treatment is with antistaphylococcal antibiotics... read more Acute Paronychia , and otitis media Otitis Media (Acute) Acute otitis media is a bacterial or viral infection of the middle ear, usually accompanying an upper respiratory infection. Symptoms include otalgia, often with systemic symptoms (eg, fever... read more Otitis Media (Acute) often occur. Patients with prolonged neutropenia after hematopoietic stem cell transplantation or chemotherapy and patients receiving high doses of corticosteroids are predisposed to fungal infections.

Etiology of Neutropenia

Acute neutropenia (occurring over hours to a few days) can develop as a result of

  • Rapid neutrophil use or destruction

  • Impaired production

Chronic neutropenia (lasting months to years) usually arises as a result of

  • Reduced production

  • Excessive splenic sequestration

Neutropenia also may be classified as

  • Primary due to an intrinsic defect in marrow myeloid cells

  • Secondary due to factors extrinsic to marrow myeloid cells

Table
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Neutropenia caused by intrinsic defects in myeloid cells or their precursors

Neutropenia caused by intrinsic defects in myeloid cells or their precursors is uncommon, but when present, the most common causes include

  • Chronic idiopathic neutropenia

  • Congenital neutropenia

Chronic benign neutropenia is a type of chronic idiopathic neutropenia in which the rest of the immune system appears to remain intact; even with neutrophil counts < 200/mcL (< 0.2 × 109/L), serious infections usually do not occur, probably because neutrophils are sometimes produced in adequate quantities in response to infection. It is more common in women.

Severe congenital neutropenia (SCN, or Kostmann syndrome) is a heterogenous group of rare disorders that are characterized by an arrest in myeloid maturation at the promyelocyte stage in the bone marrow, resulting in an absolute neutrophil count of < 200/mcL and significant infections starting in infancy. SCN can be autosomal dominant or recessive, X-linked, or sporadic. Several genetic abnormalities that cause SCN have been identified, including mutations affecting neutrophil elastase (ELANE/ELA2), HAX1, GFI1, and the G-CSF (granulocyte colony-stimulating factor) receptor (CSF3R). Most patients with SCN will respond to chronic growth factor therapy, but hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers (leukemias, lymphomas, myeloma) and other hematologic disorders... read more may need to be considered for poor responders. SCN patients have an increased risk of developing myelodysplasia Myelodysplastic Syndrome (MDS) The myelodysplastic syndrome (MDS) is group of disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular bone marrow, and a high risk... read more or acute myeloid leukemia Acute Myeloid Leukemia (AML) In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more Acute Myeloid Leukemia (AML) .

Cyclic neutropenia is a rare congenital granulocytopoietic disorder, usually transmitted in an autosomal dominant fashion and usually caused by a mutation in the gene for neutrophil elastase (ELANE/ELA2), resulting in abnormal apoptosis. It is characterized by regular, periodic oscillations in the number of peripheral neutrophils. The mean oscillatory period is 21 ± 3 days. Cycling of other blood cells is also evident in most cases.

Benign ethnic neutropenia occurs in members of some ethnic groups (eg, some people of African, Middle Eastern, and Jewish descent). They normally have lower neutrophil counts but do not have increased risk of infection. In some cases this finding has been linked to the Duffy red blood cell antigen; some experts think neutropenia in these populations is related to protection from malaria Malaria Malaria is infection with Plasmodium species. Symptoms and signs include fever (which may be periodic), chills, rigors, sweating, diarrhea, abdominal pain, respiratory distress, confusion, seizures... read more .

Secondary neutropenia

Secondary neutropenia can result from use of certain drugs, bone marrow infiltration or replacement, certain infections, or immune reactions.

The most common causes include

  • Drugs

  • Infections and immune reactions

  • Marrow infiltrative processes

Drug-induced neutropenia is one of the most common causes of neutropenia. Drugs can decrease neutrophil production through toxic, idiosyncratic, or hypersensitivity mechanisms; or they can increase peripheral neutrophil destruction through immune mechanisms. Only the toxic mechanism (eg, with phenothiazines) causes dose-related neutropenia.

Severe dose-related neutropenia occurs predictably after cytotoxic cancer drugs or radiation therapy due to suppression of bone marrow production.

Idiosyncratic reactions are unpredictable and occur with a wide variety of drugs, including alternative medicine preparations or extracts, and toxins.

Immune-mediated drug-induced neutropenia, thought to arise from drugs that act as haptens to stimulate antibody formation, usually persists for about 1 week after the drug is stopped. It may result from aminopyrine, clozapine, propylthiouracil and other antithyroid drugs, penicillin, or other antibiotics.

Infections can cause neutropenia by impairing neutrophil production or by inducing immune destruction or rapid turnover of neutrophils. Sepsis Sepsis and Septic Shock Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion; acute failure... read more is a particularly serious cause. Neutropenia that occurs with common childhood viral diseases develops during the first 1 to 2 days of illness and may persist for 3 to 8 days. Transient neutropenia may also result from virus- or endotoxemia-induced redistribution of neutrophils from the circulating to the marginal pool. Alcohol may contribute to neutropenia by inhibiting the neutrophilic chemotactic response of the marrow during some infections (eg, pneumococcal pneumonia).

Immune defects can cause neutropenia. Neonatal isoimmune neutropenia can occur with fetal/maternal neutrophil antigen incompatibility associated with transplacental transfer of IgG antibodies against the newborn’s neutrophils (most commonly to HNA-1 antigens). Autoimmune neutropenia can occur at any age and may be operative in many cases of idiopathic chronic neutropenia. Testing for antineutrophil antibodies (immunofluorescence, agglutination, or flow cytometry) is not always available or reliable.

Chronic secondary neutropenia often accompanies HIV infection Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more Human Immunodeficiency Virus (HIV) Infection because of impaired production of neutrophils and accelerated destruction of neutrophils by antibodies. Autoimmune neutropenias may be acute, chronic, or episodic. They may involve antibodies directed against circulating neutrophils or neutrophil precursor cells. They may also involve cytokines (eg, gamma interferon, tumor necrosis factor) that can cause neutrophil apoptosis. Most patients with autoimmune neutropenia have an underlying autoimmune disorder or lymphoproliferative disorder (eg, large granular lymphocyte [LGL syndrome [a clonal disease of large granular lymphocytes], systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more Systemic Lupus Erythematosus (SLE) , Felty syndrome).

Symptoms and Signs of Neutropenia

Neutropenia is asymptomatic until infection develops. Fever is often the only indication of infection. If neutropenia is severe, typical signs of focal inflammation (erythema, swelling, pain, infiltrates) may be muted or absent. Focal symptoms (eg, oral ulcers) may develop but are often subtle. Patients with drug-induced neutropenia due to hypersensitivity may have a fever, rash, and lymphadenopathy as a result of the hypersensitivity.

Some patients with chronic benign neutropenia and neutrophil counts < 200/mcL (< 0.2 × 109/L) do not experience many serious infections. Patients with cyclic neutropenia or severe congenital neutropenia tend to have episodes of oral ulcers, stomatitis, or pharyngitis and lymph node enlargement during severe neutropenia. Pneumonias and septicemia often occur.

Diagnosis of Neutropenia

  • Clinical suspicion (repeated or unusual infections)

  • Confirmatory complete blood count (CBC) with differential

  • Evaluation for infection with cultures and imaging

  • Identification of mechanism and cause of neutropenia

Neutropenia is suspected in patients with frequent, severe, or unusual infections or in patients at risk (eg, those receiving cytotoxic drugs or radiation therapy). Confirmation is by CBC with differential.

Evaluation for infection

The first priority is to determine whether an infection is present. Because infection may be subtle, physical examination systematically assesses the most common primary sites of infection: mucosal surfaces, such as the alimentary tract (gums, pharynx, anus); lungs; abdomen; urinary tract; skin and fingernails; venipuncture sites; and vascular catheters.

If neutropenia is acute or severe, laboratory evaluation must proceed rapidly.

Cultures are the mainstay of evaluation. At least 2 sets of bacterial and fungal blood cultures are obtained from all febrile patients; if an indwelling IV catheter is present, cultures are drawn from the catheter and from a separate peripheral vein. Persistent or chronic drainage material is also cultured for bacteria, fungi, and atypical mycobacteria. Mucosal ulcers are swabbed and cultured for herpes virus and Candida. Skin lesions are aspirated or biopsied for cytology and culture. Samples for urinalysis and urine cultures are obtained from all patients. If diarrhea is present, stool is evaluated for enteric bacterial pathogens and Clostridioides (formerly Clostridium) difficile toxins. Sputum cultures are obtained to evaluate for pulmonary infections.

Imaging studies are helpful. Chest x-rays are done on all patients. A chest CT may also be necessary in immunosuppressed patients. CT of the paranasal sinuses may be helpful if symptoms or signs of sinusitis (eg, positional headache, upper tooth or maxillary pain, facial swelling, nasal discharge) are present. CT scan of the abdomen is usually done if symptoms (eg, pain) or history (eg, recent surgery) suggests an intra-abdominal infection.

Identification of cause

Next, mechanism and cause of neutropenia are determined. The history addresses family history, presence of other disorders, all drugs, other preparations, and possible toxin exposure or ingestion.

If no obvious cause is identified (eg, chemotherapy), the most important test is

  • Bone marrow examination

Further testing, such as flow cytometry and T-cell receptor gene rearrangement for the LGL syndrome, may be needed to determine the cause of neutropenia, depending on the diagnoses suspected. In patients at risk of nutritional deficiencies, levels of copper Acquired Copper Deficiency Copper is a component of many body proteins; almost all of the body’s copper is bound to copper proteins. Copper deficiency may be acquired or inherited. (See also Overview of Mineral Deficiency... read more , folate Folate Deficiency Folate deficiency is common. It may result from inadequate intake, malabsorption, or use of various drugs. Deficiency causes megaloblastic anemia (indistinguishable from that due to vitamin... read more , and vitamin B12 Vitamin B12 Deficiency Dietary vitamin B12 deficiency usually results from inadequate absorption, but deficiency can develop in vegans who do not take vitamin supplements. Deficiency causes megaloblastic anemia, damage... read more are determined. Testing for the presence of antineutrophil antibodies is done if immune neutropenia is suspected. Differentiation between neutropenia caused by certain antibiotics and infection can sometimes be difficult. The white blood cell count just before the start of antibiotic treatment usually reflects the change in blood count due to the infection.

Patients who have had chronic neutropenia since infancy and a history of recurrent fevers and chronic gingivitis should have white cell counts with differential done 3 times/week for 6 weeks, so that periodicity suggestive of cyclic neutropenia can be evaluated. Platelet and reticulocyte counts are done simultaneously. In patients with cyclic neutropenia, eosinophils, reticulocytes, and platelets frequently cycle synchronously with the neutrophils, whereas monocytes and lymphocytes may cycle out of phase.

Molecular genetic testing for ELANE and other genes is appropriate when congenital causes are considered.

Treatment of Neutropenia

  • Treatment of associated conditions (eg, infections, stomatitis)

  • Sometimes antibiotic prophylaxis

  • Myeloid growth factors

  • Discontinuation of suspected etiologic agent (eg, drug)

  • Sometimes corticosteroids

Acute neutropenia

Suspected infections are always treated immediately. If fever or hypotension is present, serious infection is assumed, and empiric, high-dose, broad-spectrum antibiotics are given IV. Regimen selection is based on the most likely infecting organisms, the antimicrobial susceptibility of pathogens at that particular institution, and the regimen’s potential toxicity. Because of the risk of creating resistant organisms, vancomycin is used only if gram-positive organisms resistant to other drugs are suspected.

Indwelling vascular catheters can usually remain in place even if bacteremia is suspected or documented, but removal is considered if infections involve S. aureus, Bacillus, Corynebacterium, or Candida or another fungus or if blood cultures are persistently positive despite appropriate antibiotics. Infections caused by coagulase-negative staphylococci generally resolve with antimicrobial therapy alone. Indwelling Foley catheters can also predispose to infections in neutropenic patients, and change or removal of the catheter should be considered for persistent urinary infections.

If cultures are positive, antibiotic therapy is adjusted to the results of sensitivity tests. If a patient defervesces within 72 hours, antibiotics are continued for at least 7 days and until the patient has no symptoms or signs of infection. When neutropenia is transient (such as that following myelosuppressive chemotherapy), antibiotic therapy is usually continued until the neutrophil count is > 500/mcL (> 0.5 × 109/L); however, stopping antimicrobials can be considered in selected patients with persistent neutropenia, especially those in whom symptoms and signs of inflammation have resolved, if cultures remain negative.

Fever that persists > 72 hours despite antibiotic therapy suggests

  • A nonbacterial cause

  • Infection with a resistant species

  • Superinfection with a 2nd bacterial species

  • Inadequate serum or tissue levels of the antibiotics

  • Localized infection, such as an abscess

Neutropenic patients with persistent fever are reassessed every 2 to 4 days with physical examination, cultures, and chest x-ray. If the patient is well except for the presence of fever, the initial antibiotic regimen can be continued, and drug-induced fever should be considered. If the patient is deteriorating, alteration of the antimicrobial regimen is considered.

Fungal infections Overview of Fungal Infections Fungal infections are often classified as either Opportunistic Primary Opportunistic infections are those that develop mainly in immunocompromised hosts. Primary infections can develop in immunocompetent... read more are the most likely cause of persistent fevers and deterioration. Antifungal therapy is added empirically if unexplained fever persists after 3 to 4 days of broad-spectrum antibiotic therapy. Selection of the specific antifungal drug (eg, fluconazole, caspofungin, voriconazole, posaconazole) depends on the type of risk (eg, duration and severity of neutropenia, past history of fungal infection, persistent fever despite use of narrower spectrum antifungal drug) and should be guided by an infectious disease specialist. If fever persists after 3 weeks of empiric therapy (including 2 weeks of antifungal therapy) and the neutropenia has resolved, then stopping all antimicrobials can be considered and the cause of fever reevaluated.

For afebrile patients with neutropenia, antibiotic prophylaxis can be considered although alterations in the bacterial microbiome may slow bone marrow recovery (1 Treatment reference Neutropenia is a reduction in the blood neutrophil count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of infection may be muted, but fever... read more ). Treatment with fluoroquinolones (levofloxacin, ciprofloxacin) is used in some centers for patients who receive chemotherapy regimens that commonly result in neutrophils ≤ 100/mcL (≤ 0.1 × 109/L) for > 7 days. Prophylaxis is usually started by the treating oncologist. Antibiotics are continued until the neutrophil count increases to > 1500/mcL (> 1.5 × 109/L). Also, antifungal therapy can be given for afebrile neutropenic patients at higher risk of fungal infection (eg, after hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers (leukemias, lymphomas, myeloma) and other hematologic disorders... read more , intensive chemotherapy for acute myeloid leukemia Acute Myeloid Leukemia (AML) In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more Acute Myeloid Leukemia (AML) or a myelodysplastic disorder Myelodysplastic Syndrome (MDS) The myelodysplastic syndrome (MDS) is group of disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular bone marrow, and a high risk... read more , prior fungal infections). Selection of the specific antifungal drug should be guided by an infectious disease specialist. Antibiotic and antifungal prophylaxis is not routinely recommended for afebrile neutropenic patients without risk factors who are anticipated to remain neutropenic for < 7 days on the basis of their specific chemotherapy regimen.

Myeloid growth factors (ie, granulocyte colony-stimulating factor [G-CSF]) are widely used to increase the neutrophil count and to prevent infections in patients with severe neutropenia (eg, after hematopoietic stem cell transplantation and intensive cancer chemotherapy). They are expensive. However, if the risk of febrile neutropenia is 30% (as assessed by neutrophil count < 500 mcL [< 0.5 × 109/L], presence of infection during a previous cycle of chemotherapy, associated comorbid disease, or age > 75), growth factors are indicated. In general, most clinical benefit occurs when the growth factor is administered beginning about 24 hours after completion of chemotherapy. Patients with neutropenia caused by an idiosyncratic drug reaction may also benefit from myeloid growth factors, particularly if a delayed recovery is anticipated. The dose for G-CSF (filgrastim) is 5 to 10 mcg/kg subcutaneously once a day, and the dose for pegylated G-CSF (pegfilgrastim) is 6 mg subcutaneously once per chemotherapy cycle.

Glucocorticoids, anabolic steroids, and vitamins do not stimulate neutrophil production but can affect distribution and destruction. If acute neutropenia is suspected to be drug- or toxin-induced, all potentially etiologic agents are stopped. If neutropenia develops during treatment with a drug known to induce low counts (eg, chloramphenicol), then switching to an alternative antibiotic may be helpful.

Saline or hydrogen peroxide gargles every few hours, liquid oral rinses (containing viscous lidocaine, diphenhydramine, and liquid antacid), anesthetic lozenges (benzocaine 15 mg every 3 or 4 hours), or chlorhexidine mouth rinses (1% solution) twice a day or 3 times a day may relieve the discomfort of stomatitis with oropharyngeal ulcerations. Oral or esophageal candidiasis is treated with nystatin (400,000 to 600,000 units oral rinse 4 times a day; swallowed if esophagitis is present), clotrimazole troche (10 mg slowly dissolved in the mouth 5 times a day), or systemic antifungal drugs (eg, fluconazole). A semisolid or liquid diet may be necessary during acute stomatitis or esophagitis, and topical analgesics (eg,viscous lidocaine) may be needed to minimize discomfort.

Chronic neutropenia

Neutrophil production in congenital neutropenia Neutropenia caused by intrinsic defects in myeloid cells or their precursors Neutropenia is a reduction in the blood neutrophil count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of infection may be muted, but fever... read more , cyclic neutropenia Neutropenia caused by intrinsic defects in myeloid cells or their precursors Neutropenia is a reduction in the blood neutrophil count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of infection may be muted, but fever... read more , and idiopathic neutropenia Neutropenia caused by intrinsic defects in myeloid cells or their precursors Neutropenia is a reduction in the blood neutrophil count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of infection may be muted, but fever... read more can be increased with administration of G-CSF 1 to 10 mcg/kg subcutaneously once a day. Effectiveness can be maintained with daily or intermittent G-CSF for months or years. Long-term G-CSF has also been used in other patients with chronic neutropenia, including those with myelodysplasia, HIV infection, and autoimmune disorders. In general, neutrophil counts increase, although clinical benefits are less clear, especially for patients who do not have severe neutropenia. For patients with autoimmune disorders such as some patients who have the LGL syndrome or who have had an organ transplant, cyclosporine can also be beneficial.

In some patients with accelerated neutrophil destruction caused by autoimmune disorders, corticosteroids (generally, prednisone 0.5 to 1.0 mg/kg orally once a day) can increase blood neutrophils. This increase often can be maintained with alternate-day G-CSF therapy.

Splenectomy has been used in the past to increase the neutrophil count in some patients with splenomegaly and splenic sequestration of neutrophils (eg, Felty syndrome); however, because growth factors and other newer therapies are often effective, splenectomy should be avoided in most patients. Splenectomy can be considered for patients with persistent painful splenomegaly or with severe neutropenia (ie, < 500/mcL [< 0.5 × 109/L]) and serious problems with infections in whom other treatments have failed. Patients should be vaccinated against infections caused by Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae before splenectomy because splenectomy predisposes patients to infection by encapsulated organisms.

Treatment reference

  • 1. Yan H, Baldridge MT, Yang KY: Hematopoiesis and the bacterial microbiome. Blood 132: 559–564, 2018. doi: 10.1182/blood-2018-02-832519

Key Points

  • Neutropenia predisposes to bacterial and fungal infections.

  • The risk of infection is proportional to the severity of neutropenia; patients with neutrophil counts < 500/mcL (< 0.5 × 109/L) are at greatest risk.

  • Because the inflammatory response is limited, clinical findings may be muted, although fever is usually present.

  • Febrile neutropenic patients are treated empirically with broad-spectrum antibiotics pending definitive identification of infection.

  • Antibiotic prophylaxis may be indicated in high-risk patients.

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