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Neutropenia

(Agranulocytosis; Granulocytopenia)

by Mary Territo, MD

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 may 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.

The most frequently occurring infections in patients with profound neutropenia are

  • Cellulitis

  • Liver abscesses

  • Furunculosis

  • Pneumonia

  • Septicemia

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 hematopoietic stem cell transplantation or chemotherapy and patients receiving high doses of corticosteroids are predisposed to fungal infections.

Etiology

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: Classification of Neutropenias).

Classification of Neutropenias

Classification

Etiology

Neutropenia due to intrinsic defects in myeloid cells or their precursors

Aplastic anemia

Chronic idiopathic neutropenia, including benign neutropenia

Cyclic neutropenia

Myelodysplasia

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

Alcoholism

Autoimmune neutropenia, including chronic secondary neutropenia in AIDS

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

Cytotoxic chemotherapy or radiation therapy

Drug-induced neutropenia

Folate or vitamin B 12 deficiency

Hypersplenism

Infection

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 and usually caused by a mutation in the gene for neutrophil elastase, 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.

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. Several genetic abnormalities that cause increased neutrophil apoptosis have been identified.

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 Myelodysplastic Syndrome : Diagnosis), where it may be accompanied by megaloblastoid features in the bone marrow, and of aplastic anemia (see 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

  • Drugs

  • Infections

  • 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 B 12 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. 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, SLE, Felty syndrome).


Symptoms and Signs

Neutropenia is asymptomatic until infection develops. Fever is often the only indication of infection. 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 from the hypersensitivity.

Some patients with chronic benign neutropenia and neutrophil counts < 200/μL 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 chronic neutropenia. Pneumonias and septicemia often occur.

Diagnosis

  • Clinical suspicion (repeated or unusual infections)

  • Confirmatory 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, 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 fungi and atypical mycobacteria. Mucosal ulcers are swabbed and cultured for herpes simplex virus. 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 Clostridium difficile toxins.

Imaging studies are helpful. Chest x-rays are done on all 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 all drugs, other preparations, and possible toxin exposure or ingestion. Physical examination addresses the presence of splenomegaly and signs of other underlying disorder (eg, arthritis, lymphadenopathy).

The most important test is

  • Bone marrow examination

Bone marrow examination determines whether neutropenia is due to decreased marrow production or is secondary to increased destruction or use of the cells (determined by normal or increased production of the cells). Bone marrow may also indicate the specific cause of the neutropenia (eg, aplastic anemia, myelofibrosis, leukemia). Additional marrow studies (eg, cytogenetic analysis; special stains and flow cytometry for detecting leukemia, other malignant disorders, and infections) are obtained.

Further testing for the cause of neutropenia may be necessary, depending on the diagnoses suspected. In patients at risk of deficiency, levels of folate and vitamin B 12 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 WBC 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 have WBC counts with differential done 3 times/wk for 6 wk, so that periodicity suggestive of cyclic neutropenia can be evaluated. Platelet and reticulocyte counts are done simultaneously. Eosinophils, reticulocytes, and platelets frequently cycle synchronously with the neutrophils, whereas monocytes and lymphocytes may cycle out of phase.


Treatment

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

  • Sometimes antibiotic prophylaxis

  • Myeloid growth factors

  • Discontinuation of suspected etiologic agent (eg, drug)

  • Sometimes corticosteroids

  • Rarely splenectomy

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 or Bacillus, Corynebacterium, or Candida sp 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 these 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 h, 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/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 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 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.

For afebrile patients with neutropenia, antibiotic prophylaxis with fluoroquinolones (levofloxacin, ciprofloxacin) is given to those treated with any one of many chemotherapy regimens that commonly result in neutrophils ≤ 100/µL for > 7 days. Prophylaxis is usually started by the treating oncologist. Antibiotics are continued until the neutrophil count increases to > 1500/µL. Also, antifungal therapy is given for afebrile neutropenic patients at higher risk of fungal infection (eg, after hematopoietic stem cell transplantation, intensive chemotherapy for acute myelogenous leukemia or a myelodysplastic disorder, 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 (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 μL, 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 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 (filgrastim) is 5 to 10 mcg/kg sc once/day, and the dose for pegylated G-CSF (pegfilgrastim) is 6 mg sc 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, anesthetic lozenges (benzocaine 15 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 mcg/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 syndrome). 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 influenzaebefore 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 is indicated in high-risk patients.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • No US brand name
  • DILANTIN
  • NYSTOP
  • NEUPOGEN
  • MYCELEX
  • ANBESOL
  • VANCOCIN
  • VFEND
  • IQUIX, LEVAQUIN, QUIXIN
  • NEULASTA
  • DIFLUCAN
  • CILOXAN, CIPRO
  • XYLOCAINE
  • CANCIDAS
  • NOXAFIL
  • NEORAL, SANDIMMUNE
  • RAYOS

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