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 WBC count with differential, but 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-macrophage colony-stimulating factor or granulocyte colony-stimulating factor is sometimes helpful.

Neutrophils (granulocytes) are the body’s main defense against bacterial and fungal infections. When neutropenia is present, the inflammatory response to such infections is ineffective. Normal lower limit of the neutrophil count (total WBC × % neutrophils and bands) is 1500/μL in whites and is somewhat lower in blacks (about 1200/μL).

Severity of neutropenia relates to the relative risk of infection:

Mild (1000 to 1500/μL)

Moderate (500 to 1000/μL)

Severe (< 500/μL)

When neutrophil counts fall to < 500/μL, endogenous microbial flora (eg, in the mouth or gut) can cause infections. If the count falls to < 200/μL, inflammatory response may be muted and the usual inflammatory findings of leukocytosis or WBCs in the urine or at the site of infection will not occur. Acute, severe neutropenia, particularly if another factor (eg, cancer) is present, also 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.
Clinical Calculator

The most frequently occurring infections in patients with profound neutropenia are


Liver abscesses




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, gingivitis, perirectal inflammation, colitis, sinusitis, paronychia, and otitis media often occur. Patients with prolonged neutropenia after bone marrow transplantation or chemotherapy and patients receiving high doses of corticosteroids are predisposed to fungal infections.


Acute neutropenia (occurring over hours to a few days) can develop from rapid neutrophil use or destruction or from impaired production. Chronic neutropenia (lasting months to years) usually arises from reduced production or excessive splenic sequestration.

Neutropenia also may be classified as due to an intrinsic defect in marrow myeloid cells or as secondary (due to factors extrinsic to marrow myeloid cells—see Table 1: Neutropenia and Lymphocytopenia: Classification of Neutropenias).
Table 1

Classification of Neutropenias


Neutropenia due to intrinsic defects in myeloid cells or their precursors
Aplastic anemia

Chronic idiopathic neutropenia, including benign neutropenia

Cyclic neutropenia


Neutropenia associated with dysgammaglobulinemia

Paroxysmal nocturnal hemoglobinuria

Severe congenital neutropenia (Kostmann syndrome)

Syndrome-associated neutropenias (eg, cartilage-hair hypoplasia syndrome, dyskeratosis congenita, glycogen storage disease type IB, Shwachman-Diamond syndrome)

Secondary neutropenias

Autoimmune neutropenia, including chronic secondary neutropenia in AIDS

Bone marrow replacement by cancer, myelofibrosis (eg, due to granuloma), or Gaucher cells

Cytotoxic chemotherapy or radiation therapy

Drug-induced neutropenia

Folate or vitamin B12 deficiency



Tγ lymphoproliferative disease

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

Chronic idiopathic neutropenia

Congenital neutropenia

Cyclic neutropenia is a rare congenital granulocytopoietic disorder, usually transmitted in an autosomal dominant fashion. It is characterized by regular, periodic oscillations in the number of peripheral neutrophils. The mean oscillatory period is 21 ± 3 days.

Severe congenital neutropenia (Kostmann syndrome) is a rare disorder that occurs sporadically in the US and is characterized by an arrest in myeloid maturation at the promyelocyte stage in the bone marrow, resulting in an absolute neutrophil count of < 200/μL.

Chronic idiopathic neutropenia is a group of uncommon, poorly understood disorders involving stem cells committed to the myeloid series; RBC and platelet precursors are unaffected. The spleen is not enlarged.

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/μL, serious infections usually do not occur, probably because neutrophils are sometimes produced in adequate quantities in response to infection.

Neutropenia can also result from bone marrow failure due to rare syndromes (eg, cartilage-hair hypoplasia syndrome, Chédiak-Higashi syndrome, dyskeratosis congenita, glycogen storage disease type IB, Shwachman-Diamond syndrome). Neutropenia is also a prominent feature of myelodysplasia (see Leukemias: Diagnosis), where it may be accompanied by megaloblastoid features in the bone marrow, and of aplastic anemia (see Anemias Caused by Deficient Erythropoiesis: Aplastic Anemia) and can occur in dysgammaglobulinemia and paroxysmal nocturnal hemoglobinemia.

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



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 by increased peripheral neutrophil destruction through immune mechanisms. Only the toxic mechanism (eg, with phenothiazines) produces dose-related neutropenia. Idiosyncratic reactions are unpredictable and occur with a wide variety of drugs, including alternative medicine preparations or extracts, and toxins. Hypersensitivity reactions are rare and occasionally involve anticonvulsants (eg, phenytoin

, phenobarbital

). These reactions may
last for only a few days or for months or years. Often, hepatitis, nephritis, pneumonitis, or aplastic anemia accompanies hypersensitivity-induced neutropenia. Immune-mediated drug-induced neutropenia, thought to arise from drugs that act as haptens to stimulate antibody formation, usually persists for about 1 wk after the drug is stopped. It may result from aminopyrine, propylthiouracil

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

Neutropenia due to ineffective bone marrow production can occur in megaloblastic anemias caused by vitamin B12 or folate deficiency. Usually, macrocytic anemia and sometimes mild thrombocytopenia develop simultaneously.

Bone marrow infiltration by leukemia, myeloma, lymphoma, or metastatic solid tumors (eg, breast, prostate) can impair neutrophil production. Tumor-induced myelofibrosis may further exacerbate neutropenia. Myelofibrosis can also occur from granulomatous infections, Gaucher disease, and radiation therapy. Hypersplenism of any cause can lead to moderate neutropenia, thrombocytopenia, and anemia.

Infections can cause neutropenia by impairing neutrophil production or by inducing immune destruction or rapid use of neutrophils. Sepsis 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 response of the marrow during some infections (eg, pneumococcal pneumonia).

Chronic secondary neutropenia often accompanies 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. Most patients with autoimmune neutropenia have an underlying autoimmune disorder or lymphoproliferative disorder (eg, SLE, Felty syndrome).

Symptoms and Signs

Neutropenia is asymptomatic until infection develops. Fever is often the only indication of infection. Focal symptoms may develop but are often subtle. Patients with drug-induced neutropenia due to hypersensitivity may have a fever, rash, and lymphadenopathy from the hypersensitivity.

Some patients with chronic benign neutropenia and neutrophil counts 500/μL; 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 h despite antibiotic therapy suggests a nonbacterial cause, infection with a resistant species, a superinfection with a 2nd bacterial species, inadequate serum or tissue levels of the antibiotics, or 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. If the patient is deteriorating, alteration of the antimicrobial regimen is considered.

Fungal infections are the most likely cause of persistent fevers and deterioration. Antifungal therapy (eg, with an azole, echinocandin, or polyene drug) is added empirically if unexplained fever persists after 4 days of broad-spectrum antibiotic therapy. If fever persists after 3 wk of empiric therapy (including 2 wk of antifungal therapy) and the neutropenia has resolved, then stopping all antimicrobials can be considered and the cause of fever reevaluated.

Antibiotic prophylaxis in afebrile neutropenic patients remains controversial. Trimethoprim/sulfamethoxazole

(TMP/SMX) prevents Pneumocystis jirovecii pneumonia in neutropenic and
nonneutropenic patients with associated impaired cell-mediated immunity. Also, TMP/SMX may prevent bacterial infections in patients expected to be profoundly neutropenic for > 1 wk. The disadvantages of TMP/SMX prophylaxis include adverse effects, potential myelosuppression, and development of resistant bacteria and oral candidiasis. Antifungal prophylaxis is not routinely recommended for neutropenic patients, but patients at high risk of developing fungal infections (eg, after bone marrow transplantation and after receiving high doses of corticosteroids) may benefit.

Myeloid growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF] and 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 bone marrow transplantation and intensive cancer chemotherapy). They are expensive. However, if the risk of febrile neutropenia is ≥ 30% (as assessed by neutrophil count 75), growth factors are indicated. In general, most clinical benefit occurs when the growth factor is administered beginning about 24 h 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 is 5 μg/kg sc once/day; for GM-CSF, 250 μg/m2 sc once/day.

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, anesthetic lozenges (benzocaine

mg q 3 or 4 h), or chlorhexidine mouth rinses (1% solution) bid or tid 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 qid; 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, cyclic, and idiopathic neutropenia can be increased with administration of G-CSF 1 to 10 μg/kg sc once/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, 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 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 po once/day) increase blood
neutrophils. This increase often can be maintained with alternate-day G-CSF therapy.

Splenectomy increases the neutrophil count in some patients with splenomegaly and splenic sequestration of neutrophils (eg, Felty’s syndrome, hairy cell leukemia). However, splenectomy should be reserved for patients with severe neutropenia (ie, < 500/μL) 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 and after splenectomy because splenectomy predisposes patients to infection by encapsulated organisms.

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/μL are at greatest risk.

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

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

Antibiotic prophylaxis in afebrile neutropenic patients is controversial.

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