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Leukopenia
Leukopenia refers to an abnormally low number of white blood cells (WBCs) in the circulating blood secondary to a paucity of lymphocytes, granulocytes, or both. Because there are marked developmental changes in normal values for WBC counts during childhood (see Chapter 748 ), normal ranges must be considered in the context of age. For newborns, the mean WBC count at birth is high, followed by a rapid fall beginning at 12 hr through the 1st wk of life. Thereafter, values are stable until 1 yr of age, after which a slow, steady decline in the WBC count continues throughout childhood until adult values are reached during adolescence. Evaluation of patients with leukopenia begins with a thorough history, physical examination, and at least 1 confirmatory complete blood count with differential. Further evaluation then depends on whether the leukopenia represents a decreased number of neutrophils, lymphocytes, or both cell populations ( Table 157.1 ). Treatment depends on the etiology and clinical manifestations of the leukopenia.
Table 157.1
Diagnostic Approach for Patients With Leukopenia
| EVALUATION | ASSOCIATED CLINICAL DIAGNOSES |
|---|---|
| INITIAL EVALUATION | |
|
|
|
Congenital syndromes (severe congenital neutropenia, cyclic neutropenia, Shwachman-Diamond, Wiskott-Aldrich, Fanconi anemia, dyskeratosis congenita, glycogen storage disease type Ib, disorders of vesicular transport, GATA2 haploinsufficiency, and primary immunodeficiencies) |
|
|
|
Hypersplenism |
|
Drug-associated neutropenia |
|
Neutropenia, aplastic anemia, autoimmune cytopenias |
| IF ANC <1,000/µL | |
| Evaluation of Acute-Onset Neutropenia | |
|
Transient myelosuppression (e.g., viral) |
|
Active or chronic infection with viruses (e.g., EBV, CMV), bacteria, mycobacteria, rickettsia |
|
Drug-associated neutropenia |
|
Autoimmune neutropenia |
|
Neutropenia associated with disorders of immune function |
| IF ANC <500/µL ON 3 SEPARATE TESTS | |
|
Severe congenital neutropenia, cyclic neutropenia, Shwachman-Diamond syndrome, myelokathexis; chronic benign or idiopathic neutropenia; reticular dysgenesis |
|
Chronic benign or idiopathic neutropenia, some autoimmune neutropenias |
|
Cyclic neutropenia |
|
Shwachman-Diamond syndrome |
|
Shwachman-Diamond syndrome, cartilage-hair hypoplasia, Fanconi anemia |
| IF ALC <1000/µL | |
|
Transient leukopenia (e.g., viral) |
| IF ALC <1000/µL ON 3 SEPARATE TESTS | |
|
HIV-1 infection, AIDS |
|
Congenital or acquired disorders of immune function |
| IF THERE IS PANCYTOPENIA | |
|
Bone marrow replacement by malignancy, fibrosis, granulomata, storage cells; aplastic anemia |
|
Myelodysplasia, leukemia |
|
Vitamin deficiencies |
ALC, Absolute lymphocyte count; ANC, absolute neutrophil count; CBC, complete blood count; CMV, cytomegalovirus; EBV, Epstein-Barr virus.
Neutropenia
Neutropenia is defined as a decrease in the absolute number of circulating segmented neutrophils and bands in the peripheral blood. The absolute neutrophil count (ANC) is determined by multiplying the total WBC count by the percentage of segmented neutrophils plus bands. Normal neutrophil counts must be stratified for age and race. Neutrophils predominate at birth but rapidly decrease in the 1st few days of life. During infancy, neutrophils constitute 20–30% of circulating leukocyte populations. Near-equal numbers of neutrophils and lymphocytes are found in the peripheral circulation at 5 yr of age, and the characteristic 70% predominance of neutrophils that occurs in adulthood is usually attained during puberty. For white children >12 mo old, the lower limit of normal for the ANC is 1,500/µL; for black children >12 mo old, the lower limit of normal is 1,200/µL. The relatively lower limit of normal in blacks likely reflects the prevalence of the Duffy negative (Fy−/−) blood group, which is enriched in populations in the malarial belt of Africa and is associated with ANCs 200-600/µL less than those who are Duffy positive.
Neutropenia may be characterized as mild (ANC 1,000-1,500/µL), moderate (ANC 500-1,000/µL), or severe (ANC <500/µL). ANC <200 is also termed agranulocytosis . This stratification aids in predicting the risk of pyogenic infection in patients who have neutropenia resulting from disorders of bone marrow production, because only patients with severe neutropenia have a significantly increased susceptibility to life-threatening infections. Neutropenia associated with monocytopenia, lymphocytopenia, or hypogammaglobulinemia increases the risk for infection compared to isolated neutropenia. Patients with neutropenia caused by increased destruction (e.g., autoimmune) may tolerate very low ANCs without increased frequency of infection, because of their often robust ability to generate additional neutrophils from their functioning marrow when needed.
Acute neutropenia evolves over a few days and is often a result of rapid neutrophil use and compromised neutrophil production. Chronic neutropenia by definition lasts longer than 3 mo and arises from reduced production, increased destruction, or excessive splenic sequestration of neutrophils. The etiology of neutropenia can be classified as either an acquired disorder or extrinsic insult ( Table 157.2 ) or more rarely an inherited, intrinsic defect ( Table 157.3 ).
Table 157.2
Causes of Neutropenia Extrinsic to Marrow Myeloid Cells
| CAUSE | ETIOLOGIC FACTORS/AGENTS | ASSOCIATED FINDINGS |
|---|---|---|
| Infection | Viruses, bacteria, protozoa, rickettsia, fungi | Clinical features and laboratory findings of the infectious agent |
| Drug induced | Phenothiazines, sulfonamides, anticonvulsants, penicillins, aminopyrine | Usually none; occasional hypersensitivity reaction (fever, lymphadenopathy, rash, hepatitis, nephritis, pneumonitis, aplastic anemia) or antineutrophil antibody |
| Immune neutropenia | Alloimmune, autoimmune | Myeloid hyperplasia with left shift in bone marrow (may appear to be “arrest” at metamyelocyte or band stage) |
| Reticuloendothelial sequestration | Hypersplenism | Anemia, thrombocytopenia |
| Bone marrow replacement | Myelofibrosis, malignancy (leukemia, lymphoma, metastatic solid tumor, etc.) | Anemia, thrombocytopenia, marrow fibrosis, malignant cells in bone marrow sites of extramedullary hematopoesis |
| Cancer chemotherapy or radiation therapy | Suppression of myeloid cell production | Anemia, thrombocytopenia, bone marrow hypoplasia |
Table 157.3
Acquired Disorders of Myeloid Cells
| CAUSE | ETIOLOGIC FACTORS/AGENTS | ASSOCIATED FINDINGS |
|---|---|---|
| Aplastic anemia | Stem cell destruction and depletion | Pancytopenia |
| Vitamin B 12 , copper, or folate deficiency | Malnutrition; congenital deficiency of B 12 absorption, transport, and storage; vitamin avoidance | Megaloblastic anemia, hypersegmented neutrophils |
| Acute leukemia, chronic myelogenous leukemia | Bone marrow replacement with malignant cells | Pancytopenia, leukocytosis |
| Myelodysplasia | Dysplastic maturation of stem cells | Bone marrow hypoplasia with megaloblastoid red cell precursors, thrombocytopenia |
| Prematurity with birthweight <2 kg | Impaired regulation of myeloid proliferation and reduced size of postmitotic pool | Maternal preeclampsia |
| Chronic idiopathic neutropenia | Impaired myeloid proliferation and/or maturation | None |
| Paroxysmal nocturnal hemoglobinuria | Acquired stem cell defect secondary to mutation of PIGA gene | Pancytopenia, thrombosis (hepatic vein thrombosis) |
Clinical Manifestations of Neutropenia
Individuals with neutrophil counts <500/µL are at substantial risk for developing infections, primarily from their endogenous flora as well as from nosocomial organisms. However, some patients with isolated chronic neutropenia may not experience many serious infections, probably because the remainder of the immune system remains intact or because neutrophil delivery to tissues is preserved, as in autoimmune neutropenias. In contrast, children whose neutropenia is secondary to acquired disorders of production, as occurs with cytotoxic therapy, immunosuppressive drugs, or radiation therapy, are likely to develop serious bacterial infections because many arms of the immune system are markedly compromised and the ability of the marrow to robustly generate new phagocytes is impaired. Neutropenia associated with additional monocytopenia or lymphocytopenia is more highly associated with serious infection than neutropenia alone. The integrity of skin and mucous membranes, the vascular supply to tissues, and nutritional status also influence the risk of infection.
The most common clinical presentation of profound neutropenia includes fever, aphthous stomatitis, and gingivitis. Infections frequently associated with neutropenia include cellulitis, furunculosis, perirectal inflammation, colitis, sinusitis, warts, and otitis media, as well as more serious infections such as pneumonia, deep tissue abscess, and sepsis. The most common pathogens causing infections in neutropenic patients are Staphylococcus aureus and gram-negative bacteria. Isolated neutropenia does not heighten a patient's susceptibility to parasitic or viral infections or to bacterial meningitis but does increase the risk of fungal pathogens causing disease. The usual signs and symptoms of local infection and inflammation (e.g., exudate, fluctuance, regional lymphadenopathy) may be diminished in the absence of neutrophils because of the inability to form pus, but patients with agranulocytosis still experience fever and feel pain at sites of inflammation.
Laboratory Findings
Isolated absolute neutropenia has a limited number of causes (see Tables 157.2 to 157.5 ). The duration and severity of the neutropenia greatly influence the extent of laboratory evaluation. Patients with chronic neutropenia since infancy and a history of recurrent fevers and chronic gingivitis should have WBC counts and differential counts determined 3 times/wk for 6-8 wk to evaluate for periodicity suggestive of cyclic neutropenia . Bone marrow aspiration and biopsy should be performed on select patients to assess cellularity and myeloid maturation. Additional marrow studies, such as cytogenetic analysis and special stains for detecting leukemia and other malignant disorders, should be obtained for patients with suspected intrinsic defects in the myeloid progenitors and for patients with suspected malignancy. Selection of further laboratory tests is determined by the duration and severity of the neutropenia and the associated findings on physical examination (see Table 157.1 ).
Table 157.4
Infections Associated With Neutropenia
| Viral | Cytomegalovirus, dengue, Epstein-Barr virus, hepatitis viruses, HIV, influenza, measles, parvovirus B19, rubella, varicella, HHV-6 |
| Bacterial | Brucella, paratyphoid, pertussis, tuberculosis (disseminated), tularemia, Shigella, typhoid; any form of sepsis |
| Fungal | Histoplasmosis (disseminated) |
| Protozoan | Malaria, leishmaniasis (kala-azar) |
| Rickettsial | Anaplasma (formerly Ehrlichia ) phagocytophilum, psittacosis, Rocky Mountain spotted fever, typhus, rickettsialpox |
Table 157.5
Forms of Drug-Induced Neutropenia
| IMMUNOLOGIC | TOXIC | HYPERSENSITIVITY | |
|---|---|---|---|
| Paradigm drugs | Aminopyrine, propylthiouracil, penicillins | Phenothiazines, clozapine | Phenytoin, phenobarbital |
| Time to onset | Days to weeks | Weeks to months | Weeks to months |
| Clinical appearance | Acute, often explosive symptoms | Often asymptomatic or insidious onset | May be associated with fever, rash, nephritis, pneumonitis, or aplastic anemia |
| Rechallenge | Prompt recurrence with small test dose | Latent period; high doses required | Latent period; high doses required |
| Laboratory findings | Antineutrophil antibody may be positive; bone marrow myeloid hyperplasia | Bone marrow myeloid hypoplasia | Bone marrow myeloid hypoplasia |
Acquired Neutropenia
Infection-Related Neutropenia
Transient neutropenia often accompanies or follows viral infections and is the most frequent cause of neutropenia in childhood ( Table 157.4 ). Viruses causing acute neutropenia include influenzas A and B, adenovirus, respiratory syncytial virus, enteroviruses, human herpesvirus 6, measles, rubella, and varicella. Parvovirus B19 and hepatitis A or B may also cause neutropenia, but are more often associated with pure red cell aplasia or multiple cytopenias, respectively. Viral-associated acute neutropenia often occurs during the 1st 24-48 hr of illness and usually persists for 3-8 days, which generally corresponds to the period of viremia. The neutropenia is related to virus-induced redistribution of neutrophils from the circulating to the marginating pool. In addition, neutrophil sequestration may occur after virus-induced tissue damage or splenomegaly.
Significant neutropenia also may be associated with severe bacterial, protozoal, rickettsial, or fungal infections (see Table 157.4 ). Bacterial sepsis is a particularly serious cause of neutropenia, especially among younger infants and children. Premature neonates are especially prone to exhausting their marrow reserve and rapidly succumbing to bacterial sepsis.
Chronic neutropenia often accompanies infection with Epstein-Barr virus, cytomegalovirus, or HIV and certain immunodeficiencies such as X-linked agammaglobulinemia, hyper IgM syndrome and HIV. The neutropenia associated with AIDS probably arises from a combination of viral bone marrow suppression, antibody-mediated destruction of neutrophils, and effects of antiretroviral or other drugs.
Drug-Induced Neutropenia
Drugs constitute a common cause of neutropenia ( Table 157.5 ). The incidence of drug-induced neutropenia increases dramatically with age; only 10% of cases occur among children and young adults. The majority of cases occur among adults >65 yr, likely reflecting the more frequent use of multiple medications in that age-group. Almost any drug can cause neutropenia. The most common offending drug classes are antimicrobial agents, antithyroid drugs, antipsychotics, antipyretics, and antirheumatics. Drug-induced neutropenia has several underlying mechanisms—immune-mediated, toxic, idiosyncratic, hypersensitivity, idiopathic—that are distinct from the severe neutropenia that predictably occurs after administration of antineoplastic drugs or radiotherapy.
Drug-induced neutropenia from immune mechanisms usually develops abruptly, is accompanied by fever, and lasts for about 1 wk after the discontinuation of the drug. The process likely arises from effects of drugs such as propylthiouracil or penicillin that act as haptens to stimulate antibody formation, or drugs such as quinine that induce immune complex formation. Other drugs, including the antipsychotic drugs such as the phenothiazines, can cause neutropenia when given in toxic amounts, but some individuals, such as those with preexisting neutropenia, may be susceptible to levels at the high end of the usual therapeutic range. Late-onset neutropenia can occur after rituximab therapy. Idiosyncratic reactions, for example to chloramphenicol, are unpredictable with regard to dose or duration of use. Hypersensitivity reactions are rare and may involve arene oxide metabolites of aromatic anticonvulsants. Fever, rash, lymphadenopathy, hepatitis, nephritis, pneumonitis, and aplastic anemia are often associated with hypersensitivity-induced neutropenia. Acute hypersensitivity reactions such as those caused by phenytoin or phenobarbital may last for only a few days if the offending drug is discontinued. Chronic hypersensitivity may last for months to years.
Once neutropenia occurs, the most effective therapeutic measure is withdrawal of nonessential drugs, particularly drugs most commonly associated with neutropenia. Usually the neutropenia will resolve soon after withdrawal of the offending drug. If the neutropenia fails to improve with drug withdrawal and the patient is symptomatic with infection or stomatitis, subcutaneous administration of recombinant human granulocyte colony-stimulating factor (filgrastim, 5 µg/kg/day) should be considered. Drug-induced neutropenia may be asymptomatic and noted only as an incidental finding or because of regular monitoring of WBC counts during drug therapy. For patients who are asymptomatic, continuation of the suspected offending drug depends on the relative risks of neutropenia vs discontinuation of a possibly essential drug. If the drug is continued, blood counts should be monitored for possible progression to agranulocytosis.
Neutropenia usually and predictably follows the use of anticancer drugs or radiation therapy, especially radiation directed at the pelvis or vertebrae, secondary to cytotoxic effects on rapidly replicating myeloid precursors. A decline in the WBC count typically occurs 7-10 days after administration of the anticancer drug and may persist for 1-2 wk. The neutropenia accompanying malignancy or following cancer chemotherapy is frequently associated with compromised cellular immunity and barrier compromise secondary to central venous lines and mucositis, thereby predisposing patients to a much greater risk of infection (see Chapter 205 ) than found in disorders associated with isolated neutropenia. Patients with chemotherapy/radiation-related neutropenia and fever must be treated aggressively with broad-spectrum antibiotics.
Nutrition-Related Neutropenia
Poor nutrition can contribute to neutropenia. Ineffective myelopoiesis may result in neutropenia caused by acquired dietary copper, vitamin B 12 , or folic acid deficiency. In addition, megaloblastic pancytopenia also can result from extended use of antibiotics such as trimethoprim/sulfamethoxazole that inhibit folic acid metabolism and from the use of phenytoin, which may impair folate absorption in the small intestine, or from surgical resection of the small intestine. Neutropenia also occurs with starvation and marasmus in infants, with anorexia nervosa, and occasionally among patients receiving prolonged parenteral nutrition without vitamin supplementation.
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