Contents
5.1 Epidemiology. . . 133
5.2 Etiology . . . 134
5.3 Symptoms and Clinical Signs . . . 135
5.4 Diagnostic Testing . . . 135
5.5 Treatment . . . 135
5.6 Prognosis . . . 137
5.7 Follow-up . . . 137
Reference . . . 137
Bibliography . . . 137
5.1 Epidemiology
Neutropenia is a condition of inadequate numbers of granulocytes. The absolute neutrophil count (ANC) is calculated by multiplying the white blood cell (WBC) count by the total number of bands plus seg- mented (mature) neutrophils:
ANC = WBC ¥ % neutrophils (bands + segmented forms)
Normal neutrophil counts vary by age and race. New- born infants usually have an elevated ANC for the first few days of life (range 4.5–13.2 ¥ 10
3/mm
3). Cer- tain populations of blacks and Yemenite Jews will have normally lower WBCs and ANC (men 3.36±1.55
¥ 10
3/mm
3; women 3.13±1.47 ¥ 10
3/mm
3) (Baehner and Miller, 1995). Neutropenia is categorized as mild, moderate, or severe, based upon the level of the ANC (Table 5.1). The risk of infection increases as the ANC decreases. Patients with severe neutropenia, especial- ly those with an ANC <200/mm
3, are at significant risk for infection.
Neutropenia
Cara Simon
Table 5.1. Categories of neutropenia
Category of neutropenia ANC (mm3) Risk of infection
None >1,500 None
Mild neutropenia 1,000–500 No significant risk of infection
Moderate neutropenia 500–1,000 Some risk of infection
Severe neutropenia <500 Significant risk of infection
5.2 Etiology
Neutropenia results from four basic mechanisms: de- creased production of granulocytes, ineffective gran- ulopoiesis, a shift of circulating granulocytes to the vascular epithelium or tissue pools, or enhanced pe- ripheral destruction. Confirmation of one of these mechanisms is difficult to obtain outside of the re- search laboratory. Therefore, classification of neu- tropenia is often based on whether the neutropenia is acquired or congenital.
The most common causes of acquired neutropenia are infection, drugs, and immune disorders. Neu- tropenia can result from bacterial (typhoid, paraty- phoid, tuberculosis, brucellosis), viral (HIV, Epstein- Barr virus [EBV], hepatitis A and B, respiratory syn- cytial virus [RSV]), measles, rubella, varicella), and
rickettsial infections. In most cases, neutropenia that results from infection, especially viral infections, is short-lived and rarely results in serious secondary in- fections. Congenital neutropenia is rare and may be associated with severe recurrent infections. Congeni- tal neutropenia has been associated with mutations in the neutrophil elastase gene (Table 5.2).
Drug induced neutropenia is the second most common cause of neutropenia. The drugs at the high- est risk of producing severe neutropenia are clozap- ine, the thionamides, and sulfasalazine (Table 5.3).
Table 5.2. Classification of neutropenias
Infection
Acquired Collagen vascular diseases Complement activation Drug-induced neutropenia Autoimmune
Isoimmune neutropenia Transfusion reaction Chronic benign neutropenia Pure white cell aplasia Hypersplenism Nutritional deficiency Bone marrow disorders
(neutropenia usually not isolated) Congenital Severe infantile agranulocytosis
(Kostmann’s syndrome) Shwachman-Diamond-Oski
syndrome
Myelokathexis/neutropenia with tetraploid leukocytes Cyclic neutropenia Chediak-Higashi syndrome Reticular dysgenesis Dyskeratosis congenita
Table 5.3. Common medications that cause neutropenia
Drug Group Examples Antibiotics Chloramphenicol
Cephalosporins Penicillins Sulfonamides
Trimethoprim-sulfamethoxazole Macrolides
Vancomycin Anticonvulsants Phenytoin
Valproic acid Carbamazepine Ethosuximide Anti-inflammatory Sulfasalazine
agents Nonsteroidal anti-inflammatory drugs
Gold salts Phenylbutazone Cardiovascular Antiarrhythmic agents
agents ACE inhibitors
Propranolol Dipyridamole Digoxin Ticlopidine Psychotropic agents Clozapine
Phenothiazines Tricyclic antidepressants Meprobamate
Antithyroid agents Methimazole (thionamides) Carbimazole
Propylthiouracil
5.3 Symptoms and Clinical Signs
Evaluation of the child with neutropenia should be- gin with a complete history and physical examina- tion. The history should include the child’s family history, drug or toxin exposure, recent illness, age, and ethnicity. Physical examination should pay par- ticular attention to the presence of adenopathy, splenomegaly, evidence of chronic or underlying dis- ease (chronic granulomatous disease [CGD], parox- ysmal nocturnal hemoglobinuria, Fanconi’s anemia, etc.), and stringent evaluation of the skin and mucous membranes for signs and symptoms of infection.
Recurrent infections are the most significant con- sequence of neutropenia. The infections can be seri- ous or minor. The organisms responsible for the in- fection are usually pyogenic or enteric bacteria or certain fungi. The risk of infection is dependent upon the level and duration of neutropenia. Patients who have an ANC <500/mm
3due to chemotherapy, bone marrow failure, or bone marrow exhaustion are at in- creased risk for overwhelming bacterial infection. In contrast, patients who have benign chronic neutrope- nia may have an ANC <200/mm
3for prolonged peri- ods of time but will not experience serious infections such as bacteremia or pneumonia.
Common sites of infection are the mouth, mucous membranes, skin, and perianal and genital areas.
With persistent severe neutropenia, systemic infec- tions can occur in the lungs, blood, and gastrointesti- nal tract. Common infectious organisms include Staphylococcus aureus from the skin and Gram-nega- tive organisms from the gastrointestinal and urinary tracts, such as Escherichia coli and Klebsiella Enter- obacter.
5.4 Diagnostic Testing
Diagnostic testing for neutropenia should start with the evaluation of the full/complete blood count (FBC/
CBC) and examination of the peripheral smear. If the WBC differential has been generated by automatic counters, it should be repeated manually. If the child is asymptomatic and the neutropenia is of less than 6
weeks duration, a WBC count with differential should be done twice a week for 2 weeks to assess for cyclic neutropenia. If the neutropenia occurs after a viral illness or if the child is less than 12 months old, viral serologies should be drawn (i.e., cytomegalovirus [CMV], EBV, parvovirus B-19). A neutrophil antigen should be obtained in newborns (present in isoim- mune neonatal neutropenia).
If the neutropenia persists longer than 8 weeks and the child remains asymptomatic, additional studies should include HIV antibody, quantitative immunoglobulins, C3, C4, CH50, antineutrophil anti- body, ANA, anti-DNA, antiphospholipid panel, and a chest radiograph (to check for thymic shadow). A bone marrow aspiration and biopsy may be neces- sary to identify granulocyte precursors and defects in myeloid maturation. The bone marrow aspiration and biopsy is also helpful to exclude hematologic ma- lignancies (e.g., leukemia), bone marrow infiltration, and fibrosis.
Suggested testing for the child with chronic neu- tropenia that lasts longer than 6 months includes quantitative T and B subsets, diepoxybutane (if the patient has dysmorphic features, to rule out Fanconi’s anemia), B-12 level, folate level, copper level, radi- ographs of the long bones, exocrine pancreatic stud- ies (if the patient has a history of diarrhea, short stature, or failure to thrive), CD55/CD59 (for parox- ysmal nocturnal hemoglobinuria [PNH]), CBCs of family members, and a leukocyte function test to de- termine if patient has CGD (if the patient has a histo- ry of recurrent infections).
5.5 Treatment
Treatment of neutropenia is dependent upon many factors, including whether the neutropenia is acute or chronic, the severity of the neutropenia, and any un- derlying immune defects, illnesses, or malignancies.
Patients with chronic neutropenia should receive reg-
ular dental care at least every 6 months to prevent
chronic gingivitis and recurrent stomatitis. In the
child with neutropenia, measures to prevent infec-
tion, such as good handwashing and protection
against food-borne illness (washing and cooking
foods thoroughly) should be observed. The child with severe neutropenia (<500/mm
3) should have a monthly physical examination with careful attention to skin and mucous membranes and should observe social isolation (avoiding crowds and persons with infection).
Infections that occur in the child with neutropenia should be treated aggressively. Fever higher than 38 °C may be the only presenting sign of infection, and the child with fever and neutropenia should be treated immediately. The child with fever and an ANC
<500/mm
3should be managed as an inpatient.
Following culture of blood and urine, the child with severe neutropenia and fever should receive broad-spectrum parenteral antibiotics for coverage of both Gram-positive and Gram-negative organisms (Table 5.4).
A combination of an aminoglycoside and a beta- lactam antibiotic is good for initial coverage. If the child becomes afebrile, the cultures remain negative, and the clinical course improves, antibiotics may be discontinued after 72 hours. Oral antibiotics are un- necessary if there is not a known source of infection, such as otitis media or pneumonia, and if all cultures remain negative after 72 hours. If fever persists, other therapies, especially antifungal therapies (e.g., fluconazole, flucytosine, or amphotericin B) should be initiated. Patients with fever and an ANC
>1,000/mm
3can generally be managed on an outpa-
tient basis and treated with a beta-lactam antibiotic such as ceftriaxone and an oral cephalosporin such as Cefzil or Ceftin until all cultures are negative after 72 hours. The child who has fever and an ANC between 500/mm
3and 1,000/mm
3may be managed on either an inpatient or outpatient basis, depending upon oth- er presenting signs and symptoms such as cough, chills, shortness of breath, or other signs of infection.
Myeloid growth factors, such as granulocyte- colony stimulating factor (G-CSF), can be used to correct neutropenia in patients with severe neutrope- nia. G-CSF is not indicated for all cases of neutrope- nia and is most effective when the neutropenia is as- sociated with early myeloid arrest. The child with neutropenia and a serious life-threatening infection or sepsis should be started on G-CSF, 5 mcg/kg/day intravenously (IV) or subcutaneously (SQ), until the ANC is >5,000/mm
3on two occasions. If there is no response after 72 hours, the dose of G-CSF can be in- creased to 10 mcg/kg/day IV or SQ.
The child with severe neutropenia (<500/mm
3) with recurrent symptoms or a past history of life- threatening infection should be started on G-CSF.
G-CSF is usually started at a dose of 5 mcg/kg given SQ daily or every other day to maintain an ANC
>1,000/mm
3. Potential side effects of G-CSF include nausea, bone pain, alopecia, diarrhea, low-grade fever, fatigue, anorexia, rash, and headache. Potential complications of G-CSF therapy include the de-
Table 5.4. Gram-positive and Gram-negative organisms and common antibiotic treatment
Bacteria Common organisms Common antibiotics
Gram-positive Staphylocci (coagulase-negative, coagulase-positive) Cefepime
Streptococci (alpha-hemolytic; group D) Oxacillin
Corynebacterium Ticarcillin and clavulanate
Listeria Clindamycin
Clostridium difficile Vancomycin
Cefotaxime Gram-negative Enterobacteriaceae (Escherichia coli, Klebsiella Enterobacter, Citrobacter) Cefotaxime
Pseudomonads (multiresistant) Cefepime
Anaerobes (Bacteroides sp.) Ceftriaxone
Ticarcillin and clavulanate Amikacin
Tobramycin
velopment of a malignancy such as acute myeloid leukemia (AML) and an increased frequency of os- teopenia and osteoporosis. It is unclear whether these are actually complications of G-CSF therapy or are complications of the underlying disease (now evident due to longer life expectancies of children with severe neutropenia). Therefore, the use of G-CSF should be reserved for the child with severe neutropenia who has recurrent symptoms or a past history of life- threatening illness. Patients on long-term therapy with G-CSF should have yearly bone marrow exami- nations, cytogenetic studies, and measurement of bone density.
Bone marrow transplant has been a successful treatment in some children with severe neutropenia (e.g., severe congenital neutropenia). It should be considered in the child who does not respond to G- CSF, if an appropriate HLA-matched donor is avail- able.
5.6 Prognosis
The prognosis of the child with neutropenia depends on several factors, including the severity of the neu- tropenia and any underlying immune defects, illness- es, or malignancies. Prognosis also depends on the incidence, quick recognition, and treatment of life- threatening infections and/or sepsis, and is also af- fected by the potential development of a secondary malignancy due to the use of G-CSF.
5.7 Follow-up
Follow-up of the child with neutropenia is dependent upon many factors, including whether the neutro- penia is acute or chronic, the cause of the neutro- penia, the severity of the neutropenia, and any un- derlying immune defects, illnesses, or malignancies (Table 5.5). The child with chronic benign neutrope- nia of childhood who does not experience severe in- fections related to his neutropenia will require less follow-up than the child with severe neutropenia who requires G-CSF to prevent serious infections.
Reference
Baehner RL, Miller DR (1995) Disorders of granulopoiesis. In:
Blood Diseases of Infancy and Childhood, 7th edn. Mosby- Yearbook, St. Louis, pp. 555–592
Bibliography
Baehner RL (2003) Overview of neutropenia.
www.uptodate.com (06/09/2003) Baehner RL (2003) Cyclic neutropenia.
www.uptodate.com (06/09/2003) Baehner RL (2003) Congenital neutropenia.
www.uptodate.com (06/09/2003)
Boxer LA (2003) Neutrophil abnormalities. Pediatrics in Re- view, 24:52–62
Hastings C (2002) Neutropenia. In: The Children’s Hospital Oakland: Hematology/Oncology Handbook. Mosby, St.
Louis, pp. 101–106
Lanzowsky P (2000). Disorders of the white blood cells. In:
Manual of Pediatric Hematology and Oncology, 3rd edn.
Academic Press, San Diego, pp. 207–232 Table 5.5. Follow-up of acute vs. chronic neutropenia
Type of neutropenia Interval of follow-up Studies required
Acute neutropenia 3–4 weeks FBC/CBC
Chronic neutropenia Monthly Physical examination, FBC/CBC
Yearly Bone marrow (if on G-CSF)
