Thomas F. Michniacki, Kelly J. Walkovich
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 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
Table 157.3
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.
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
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 |
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.
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.
Poor nutrition can contribute to neutropenia. Ineffective myelopoiesis may result in neutropenia caused by acquired dietary copper, vitamin B12 , 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.
Immune-mediated neutropenia is usually associated with the presence of circulating antineutrophil antibodies, which may mediate neutrophil destruction by complement-mediated lysis or splenic phagocytosis of opsonized neutrophils, or by accelerated apoptosis of mature neutrophils or myeloid precursors.
Alloimmune neonatal neutropenia occurs after transplacental transfer of maternal alloantibodies directed against antigens on the infant's neutrophils, analogous to Rh-hemolytic disease. Prenatal sensitization induces maternal IgG antibodies to neutrophil antigens on fetal cells. The neutropenia is often severe and infants may present within the 1st 2 wk of life with skin or umbilical infections, fever, and pneumonia caused by the usual microbes that cause neonatal disease. By 7 wk of age, the neutrophil count usually returns to normal, reflecting the decay of maternal antibodies in the infant's circulation. Treatment consists of supportive care and appropriate antibiotics for clinical infections, plus granulocyte colony-stimulating factor (G-CSF) for severe infections without neutrophil recovery.
Mothers with autoimmune disease may give birth to infants who develop transient neutropenia, known as neonatal passive autoimmune neutropenia . The duration of the neutropenia depends on the time required for the infant to clear the maternally transferred circulating IgG antibody. It persists in most cases for a few weeks to a few months. Neonates almost always remain asymptomatic.
Autoimmune neutropenia (AIN) of infancy is a benign condition with an annual incidence of approximately 1 per 100,000 among children between infancy and 10 yr of age. Patients usually have severe neutropenia on presentation, with ANC <500/µL, but the total WBC count is generally within normal limits. Monocytosis or eosinophilia may occur but does not impact the low rate of infection. The median age of presentation is 8-11 mo, with a range of 2-54 mo. The diagnosis is often evident when a blood count incidentally reveals neutropenia in a child with a minor infection or when a routine complete blood count is obtained at the 12 mo well-child visit. Occasionally, children may present with more severe infections, including abscesses, pneumonia, or sepsis. The diagnosis may be supported by the presence of antineutrophil antibodies in serum; however, the test has frequent false-negative and false-positive results, so the absence of detectable antineutrophil antibodies does not exclude the diagnosis, and a positive result does not exclude other conditions. Therefore the diagnosis is best made clinically based on a benign course and, if obtained, a normal or hyperplastic myeloid maturation in the bone marrow. There is considerable overlap between AIN of infancy and “chronic benign neutropenia.”
Treatment is not generally necessary because the disease is only rarely associated with severe infection and usually remits spontaneously. Low-dose G-CSF may be useful for severe infections, to promote wound healing following surgery, or to avert emergency room visits or hospitalizations for febrile illnesses. Longitudinal studies of infants with AIN demonstrate median duration of disease ranging from 7-30 mo. Affected children generally have no evidence or risk of other autoimmune diseases.
AIN in older children can occur as an isolated process, as a manifestation of other autoimmune diseases, or as a secondary complication of infection, drugs, or malignancy. In primary AIN, low circulating neutrophil counts are the only hematologic finding, and associated diseases or other factors that cause neutropenia are absent. Secondary AIN associated with immune dysregulation or other factors is more often identified in older children and is less likely to remit spontaneously. AIN is distinguished from other forms of neutropenia by the demonstration of antineutrophil antibodies (with caveats previously discussed) and myeloid hyperplasia on bone marrow examination. The most common antineutrophil antibody targets are human neutrophil antigens 1a, 1b, and 2.
Treatment of AIN relies on management of any underlying disorders. In addition, judicious use of appropriate antibiotics for bacterial infections and regular dental hygiene are generally beneficial, as is family and primary care provider education. Infections tend to be less frequent in AIN than with the corresponding degree of neutropenia from other causes, probably because tissue delivery of neutrophils is greater than that in conditions resulting from impaired production. Prophylactic antibiotics may be helpful for the management of recurrent minor infections. For patients with serious or recurrent infections, G-CSF is generally effective at raising the ANC and preventing infection. Very low doses (<1-2 µg/kg/day) are usually effective, and administration of standard doses can lead to severe bone pain from marrow expansion.
Various acquired bone marrow disorders lead to neutropenia, usually accompanied by anemia and thrombocytopenia. Hematologic malignancies, including leukemia, lymphoma, and metastatic solid tumors, suppress myelopoiesis by infiltrating the bone marrow with tumor cells. Neutropenia may also accompany aplastic anemia, myelodysplastic disorders, or preleukemic syndromes, which are characterized by multiple cytopenias and often macrocytosis. Treatment requires management of the underlying disease.
Splenic enlargement resulting from intrinsic splenic disease (storage disease), portal hypertension, or systemic causes of splenic hyperplasia (inflammation or neoplasia) can lead to neutropenia. Most often the neutropenia is mild to moderate and is accompanied by corresponding degrees of thrombocytopenia and anemia. The reduced neutrophil survival corresponds to the size of the spleen, and the extent of the neutropenia is inversely proportional to bone marrow compensatory mechanisms. Usually the neutropenia can be corrected by successfully treating the underlying disease. In select cases, splenectomy may be necessary to restore the neutrophil count to normal, but results in increased risk of infections by encapsulated bacterial organisms. Patients undergoing splenectomy should receive appropriate preoperative immunizations and may benefit from antibiotic prophylaxis after splenectomy to help mitigate the risk of sepsis. Splenectomy should be avoided in patients with common variable immunodeficiency (CVID), autoimmune lymphoproliferative disease, and other immunodeficiency syndromes because of the higher risk of sepsis.
Intrinsic disorders of proliferation or maturation of myeloid precursor cells are rare. Table 157.6 presents a classification based on genetics and molecular mechanisms; select disorders are discussed next.
Table 157.6
Intrinsic Disorders of Myeloid Precursor Cells
| SYNDROME | INHERITANCE (GENE) | CLINICAL FEATURES (INCLUDING STATIC NEUTROPENIA UNLESS OTHERWISE NOTED) |
|---|---|---|
| PRIMARY DISORDERS OF MYELOPOIESIS | ||
| Cyclic neutropenia | AD (ELANE) | Periodic oscillation (21-day cycles) in ANC |
| Severe congenital neutropenia | AD (primarily ELANE, also GFI and others) | Risk of MDS/AML |
| AR (G6PC3, HAX1) (HAX1 = Kostmann syndrome) | G6PC3: cardiac and urogenital anomalies, venous angioectasias; HAX1: neurologic abnormalities, risk of MDS/AML | |
| XL (WAS) | Neutropenic variant of Wiskott-Aldrich syndrome | |
| DISORDERS OF MOLECULAR PROCESSING | ||
| Shwachman-Diamond syndrome | Ribosomal defect: AR (SBDS, DNAJC21, EFL1, SRP54) | Pancreatic insufficiency, metaphyseal dysostosis, bone marrow failure, MDS/AML |
| Dyskeratosis congenita | Telomerase defects: XL (DKC1), AD (TERC), AR (TERT) | Nail dystrophy, leukoplakia, abnormal and carious teeth, lacey reticulated hyperpigmentation of the skin, bone marrow failure |
| DISORDERS OF VESICULAR TRAFFICKING | ||
| Chédiak-Higashi syndrome | AR (LYST) | Partial albinism, giant granules in myeloid cells, platelet storage pool defect, impaired NK cell function, HLH |
| Griscelli syndrome, type II | AR (RAB27a) | Partial albinism, impaired NK cell function, neurologic impairment, HLH |
| Cohen syndrome | AR (COH1) | Partial albinism, pigmentary retinopathy, developmental delay, facial dysmorphism |
| Hermansky-Pudlak syndrome, type II | AR (AP3B1) | Cyclic neutropenia, partial albinism, HLH |
| p14 deficiency | Probable AR (MAPBPIP) | Partial albinism, decreased B and T cells |
| VPS45 defects | AR (VPS45) | Neutrophil dysfunction, bone marrow fibrosis, nephromegaly |
| DISORDERS OF METABOLISM | ||
| Glycogen storage disease, type 1b | AR (G6PT1) | Hepatic enlargement, growth retardation, impaired neutrophil motility |
| Methylmalonic/propionic acidemias |
AR Mutase or cobalamin transporters/propionyl coenzyme A carboxylase |
Ketoacidosis, metabolic stroke, depressed consciousness |
| Barth syndrome | XL (TAZ1) | Episodic neutropenia, dilated cardiomyopathy, methylglutaconic aciduria |
| Pearson syndrome | Mitochondrial (DNA deletions) | Episodic neutropenia, pancytopenia; defects in exocrine pancreas, liver, and kidneys |
| NEUTROPENIA IN DISORDERS OF IMMUNE FUNCTION | ||
| Common variable immunodeficiency | Familial, sporadic (TNFRSF13B) | Hypogammaglobulinemia, other immune system defects |
| IgA deficiency | Unknown (Unknown or TNFRSF13B ) | Decreased IgA |
| Severe combined immunodeficiency | AR, XL (multiple loci) | Absent humoral and cellular immune function |
| Hyper-IgM syndrome | XL (HIGM1) | Absent IgG, elevated IgM, autoimmune cytopenias |
| WHIM syndrome | AD (CXCR4) | Warts, hypogammaglobulinemia, infections, myelokathexis |
| Cartilage-hair hypoplasia | AR (RMRP) | Lymphopenia, short-limbed dwarfism, metaphyseal chondrodysplasia, fine sparse hair |
| Schimke immunoosseous dysplasia | Probable AR (SMARCAL1) | Lymphopenia, pancytopenia, spondyloepiphyseal dysplasia, growth retardation, renal failure |
| X-linked agammaglobulinemia | Bruton tyrosine kinase (Btk) | Agammaglobulinemia, neutropenia in ~25% |
AD, Autosomal dominant; AML, acute myelogenous leukemia; ANC, absolute neutrophil count; AR, autosomal recessive; HLH, hemophagocytic lymphohistiocytosis; MDS, myelodysplastic syndrome; XL, X-linked.
Cyclic neutropenia is an autosomal dominant congenital granulopoietic disorder occurring with an estimated incidence of 0.5-1 cases per 1 million population. The disorder is characterized by regular, periodic oscillations, with the ANC ranging from normal to <200/µL, mirrored by reciprocal cycling of monocytes. Cyclic neutropenia is sometimes termed cyclic hematopoiesis because of the secondary cycling of other blood cells, such as platelets and reticulocytes. The mean oscillatory period of the cycle is 21 days (±4 days). During the neutropenic nadir, many patients develop malaise, fever, oral and genital ulcers, gingivitis, periodontitis, or pharyngitis, and occasionally lymph node enlargement. More serious infections occasionally occur, including pneumonia, mastoiditis, and intestinal perforation with peritonitis leading to life-threatening clostridial sepsis. Before the availability of G-CSF, approximately 10% of patients developed fatal clostridial or gram-negative infections. Cyclic neutropenia arises from a regulatory abnormality involving early hematopoietic precursor cells and is almost invariably associated with mutations in the neutrophil elastase gene, ELANE , that lead to accelerated apoptosis as a result of abnormal protein folding. Many patients experience abatement of symptoms with age. The cycles tend to become less noticeable in older patients, and the hematologic picture often begins to resemble that of chronic idiopathic neutropenia.
Cyclic neutropenia is diagnosed by obtaining blood counts 3 times/wk for 6-8 wk. The requirement for repeated blood counts is necessary because some of the elastase mutations overlap with those in patients who have severe congenital neutropenia . Demonstrating oscillation or a lack thereof in the blood counts helps to identify the patients' risk for progression to myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) , a risk that is only associated with severe congenital neutropenia. The diagnosis can be confirmed with genetic studies demonstrating a mutation in ELANE . Affected patients with neutrophil nadirs <200/µL are treated with G-CSF, and their cycle of profound neutropenia changes from a 21-day period with at least 3-5 days of profound neutropenia to 9-11 days with 1 day of less profound neutropenia. The dose needed to maintain nadirs >500/µL is usually 2-4 µg/kg/day administered daily or every other day.
Severe congenital neutropenia (SCN) is a rare, genetically heterogeneous, congenital granulopoietic disorder with an estimated incidence of 1-2 cases per 1 million population. The disorder is characterized by an arrest in myeloid maturation at the promyelocyte stage in the bone marrow, resulting in ANCs consistently <200/µL and may occur sporadically, with autosomal dominant or recessive inheritance. The dominant form is caused most often by mutations in ELANE , which accounts for 60–80% of SCN cases, whereas recessive forms arise from mutations in HAX1 (the form also known as Kostmann disease ) or G6PC3 (encoding a myeloid-specific isoform of glucose-6-phosphatase). HAX1 mutations may be associated with neurologic deficits, and G6PC3 with heart defects, urogenital abnormalities, and venous angiectasia. In addition to severe neutropenia, peripheral blood counts generally show monocytosis and many also exhibit eosinophilia; chronic inflammation may lead to secondary anemia and thrombocytosis. Patients who have SCN experience frequent episodes of fever, skin infections (including omphalitis), oral ulcers, gingivitis, pneumonia, and perirectal abscesses, typically appearing in the 1st few mo of life. Infections often disseminate to the blood, meninges, and peritoneum and are usually caused by S. aureus , Escherichia coli, and Pseudomonas species. Without filgrastim therapy, most patients die of infectious complications within the first 1-2 yr of life despite prophylactic antibiotics.
More than 95% of SCN patients respond to filgrastim treatment with an increase in the ANC and a decrease in infections. Doses required to achieve an ANC >1000/uL vary greatly. A starting dose of filgrastim at 5 µg/kg/day is recommended; the dose should be gradually increased, if necessary, as high as 100 µg/kg/day to attain an ANC of 1,000-2,000/µL. The 5% of patients who do not respond to filgrastim or who require high doses (>8 µg/kg/day) should be considered for hematopoietic stem cell transplantation (HSCT). Besides infections, patients with SCN are at risk for developing MDS associated with monosomy 7 and AML. For this reason, regular monitoring with blood counts and yearly bone marrow surveillance, including karyotyping and fluorescence in situ hybridization, should be performed on all SCN patients. Although clonal cytogenetic abnormalities may spontaneously remit, their appearance should be considered a strong indication for HSCT, which is much more likely to be successful before progression to MDS/AML.
Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder classically characterized by neutropenia, pancreatic insufficiency, and short stature with skeletal abnormalities. SDS is most commonly caused by proapoptotic mutations of the SBDS gene, which encodes a protein that plays a role in ribosome biogenesis and RNA processing. The initial symptoms are usually steatorrhea and failure to thrive because of malabsorption, which usually develops by 4 mo of age, although the gastrointestinal symptoms may be subtle in some patients and go unrecognized. Patients have also been reported to have respiratory problems with frequent otitis media, pneumonia, and eczema. Virtually all patients with SDS have neutropenia, with the ANC periodically <1000/µL. Some children have defects in chemotaxis or in the number or function of B, T, and natural killer (NK) cells that may contribute to the increased susceptibility to pyogenic infection. The diagnosis of SDS is based on clinical phenotype; approximately 90% of patients have mutations identified in SBDS with additional mutations now recently discovered in DNAJC21, EFL1, and SRP54 . SDS may progress to bone marrow hypoplasia or MDS/AML; cytogenetic abnormalities, particularly isochromosome i(7q) and del(20q), often precede conversion to MDS, so bone marrow monitoring is warranted. Treatment includes pancreatic enzyme replacement, plus G-CSF in patients with severe neutropenia.
Dyskeratosis congenita , a disorder of telomerase activity, most often presents as bone marrow failure rather than isolated neutropenia. The classic phenotype also includes nail dystrophy, leukoplakia, malformed teeth, and reticulated hyperpigmentation of the skin, although many patients, particularly young ones, do not exhibit these clinical features.
This group of rare primary immunodeficiency syndromes (see Table 157.6 ) derives from autosomal recessive defects in the biogenesis or trafficking of lysosomes and related endosomal organelles. As a result, the syndromes share phenotypic characteristics, including defects in melanosomes contributing to partial albinism, abnormal platelet function, and immunologic defects involving not only neutrophil number, but also the function of neutrophils, B lymphocytes, NK cells, and cytotoxic T lymphocytes. The syndromes share a high risk of hemophagocytic lymphohistiocytosis (HLH) as a result of defects in T and NK cells.
Chédiak-Higashi syndrome , best known for the characteristic giant cytoplasmic granules in neutrophils, monocytes, and lymphocytes, is a disorder of subcellular vesicular dysfunction caused by mutations in the LYST gene, with resultant giant granules in all granule-bearing cells. Patients have increased susceptibility to infections, mild bleeding diathesis, progressive peripheral neuropathy, and predisposition to life-threatening HLH. The only curative treatment is HSCT, but transplant does not treat all aspects of the disorder.
Griscelli syndrome type II also features neutropenia, partial albinism, and a high risk of HLH, but peripheral blood granulocytes do not show giant granules. Patients often have hypogammaglobulinemia. The disorder is caused by mutations in RAB27a , which encodes a small guanosine triphosphatase that regulates granule secretory pathways. The only curative treatment is HSCT.
Recurrent infections with neutropenia are a distinctive feature of glycogen storage disease (GSD) type Ib . As in classic von Gierke disease (GSDIa), glycogen storage in GSDIb causes massive hepatomegaly and severe growth retardation. Mutations in glucose-6-phosphate transporter 1, G6PT1 , inhibit glucose transport in GSDIb, resulting in both defective neutrophil motility and increased apoptosis associated with neutropenia and recurrent bacterial infections. Treatment with G-CSF can correct the neutropenia but does not correct the underlying functional neutrophil defects.
Congenital immunologic disorders that have severe neutropenia as a clinical feature include X-linked agammaglobulinemia (XLA), CVID, the severe combined immunodeficiencies, autoimmune lymphoproliferative syndrome, hyperimmunoglobulin M syndrome, WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome, GATA2 haploinsufficiency, and a number of even rarer immunodeficiency disorders (see Table 157.6 ).
Chronic benign neutropenia of childhood represents a common group of disorders characterized by mild to moderate neutropenia that does not lead to an increased risk of pyogenic infections. Spontaneous remissions are often reported, although these may represent misdiagnosis of AIN of infancy, in which remissions often occur during childhood. Chronic benign neutropenia may be sporadic or inherited in either dominant or recessive form. Because of the relatively low risk of serious infection, patients usually do not require any therapy.
Idiopathic chronic neutropenia is characterized by the onset of neutropenia after 2 yr of age, with no identifiable etiology. Patients with an ANC persistently <500/µL may have recurrent pyogenic infections involving the skin, mucous membranes, lungs, and lymph nodes. Bone marrow examination reveals variable patterns of myeloid formation with arrest generally occurring between the myelocyte and band forms. The diagnosis overlaps with chronic benign and AINs.
The management of acquired transient neutropenia associated with malignancies, myelosuppressive chemotherapy, or immunosuppressive chemotherapy differs from that of congenital or chronic forms of neutropenia. In the former situation, infections sometimes are heralded only by fever, and sepsis is a major cause of death. Early recognition and treatment of infections may be lifesaving (see Chapter 205 ). Therapy of severe chronic neutropenia is dictated by the clinical manifestations. Patients with benign neutropenia and no evidence of repeated bacterial infections or chronic gingivitis require no specific therapy. Superficial infections in children with mild to moderate neutropenia may be treated with appropriate oral antibiotics. In patients who have invasive or life-threatening infections, broad-spectrum intravenous antibiotics should be started promptly.
Subcutaneously administered G-CSF can provide effective treatment of severe chronic neutropenia, including SCN, cyclic neutropenia, and chronic symptomatic idiopathic neutropenias. Treatment leads to dramatic increases in neutrophil counts, resulting in marked attenuation of infection and inflammation. Doses range from 2-5 µg/kg/day for cyclic, idiopathic, and autoimmune neutropenias, to 5-100 µg/kg/day for SCN. The long-term effects of G-CSF therapy include a propensity for the development of moderate splenomegaly, thrombocytopenia, and rarely vasculitis; only patients with SCN are at risk for MDS/AML.
Patients with SCN or SDS who develop MDS or AML respond only to HSCT; chemotherapy is ineffective. HSCT is also the treatment of choice for aplastic anemia or familial HLH.
The definition of lymphopenia , as with neutropenia, is age dependent and can have acquired or inherited causes. The absolute lymphocyte count (ALC) is determined by multiplying the total WBC count by the percentage of total lymphocytes. For children <12 mo old, lymphopenia is defined as an ALC <3,000 cells/µL. For older children and adults, an ALC <1,000 cells/µL is considered lymphopenia. In isolation, mild to moderate lymphopenia is generally a benign condition often detected only in the evaluation of other illnesses. However, severe lymphopenia can result in serious, life-threatening illness. Lymphocyte subpopulations can be measured by flow cytometry, which uses the pattern of lymphocyte antigen expression to quantitate and classify T, B, and NK cells.
Acute lymphopenia is most often a result of infection and/or is iatrogenic from lymphocyte-toxic medications and treatments (Table 157.7 ). Microbial causes include viruses (e.g., respiratory syncytial virus, cytomegalovirus, influenza, measles, hepatitis), bacterial infections (e.g., tuberculosis, typhoid fever, histoplasmosis, brucellosis), and malaria. The mechanisms behind infection-associated lymphopenia are not fully elucidated but probably include lymphocyte redistribution and accelerated apoptosis. Corticosteroids are a common cause of medication-induced lymphopenia, as are lymphocyte-specific immunosuppressive agents (e.g., antilymphocyte globulin, alemtuzumab, rituximab), chemotherapy drugs, and radiation. In most cases, infectious and iatrogenic causes of acute lymphopenia are reversible, although full lymphocyte recovery from chemotherapy and lymphocyte-specific immunosuppressive agents may take several months to years. Prolonged lymphopenia (Table 157.7 ) may be caused by recurrent infection; persistent infections, mostly notably HIV; malnutrition; mechanical loss of lymphocytes through protein-losing enteropathy or thoracic duct leaks; or systemic diseases such as lupus erythematosus, rheumatoid arthritis, sarcoidosis, renal failure, lymphoma, and aplastic anemia.
Table 157.7
| ACQUIRED | |
| Infectious diseases | AIDS, hepatitis, influenza, sepsis, tuberculosis, typhoid |
| Iatrogenic | Corticosteroids, cytotoxic chemotherapy, high-dose PUVA, immunosuppressive therapy, radiation, thoracic duct drainage |
| Systemic diseases | Hodgkin disease, lupus erythematosus, myasthenia gravis, protein-losing enteropathy, renal failure, sarcoidosis |
| Other | Aplastic anemia, dietary deficiencies, thermal injury |
| INHERITED | |
| Aplasia of lymphopoietic stem cells | Cartilage-hair hypoplasia, ataxia-telangiectasia, SCID, thymoma, Wiskott-Aldrich syndrome |
PUVA, Psoralen and ultraviolet A irradiation; SCID, severe combined immunodeficiency.
Primary immunodeficiencies and bone marrow failure syndromes are the main cause of inherited lymphopenia in children (see Table 157.7 ). Primary immunodeficiency may result in a severe quantitative defect, as in XLA and severe combined immunodeficiency (SCID), or a qualitative or progressive defect, as in Wiskott-Aldrich syndrome and CVID. XLA is characterized by a near-absence of mature B cells because of a mutation in BTK that results in a dysfunctional tyrosine kinase. SCIDs are a genetically heterogeneous group of disorders characterized by abnormalities of thymopoiesis and T-cell maturation. Newborn screening for severe T-cell deficiency, by analysis of T-cell receptor excision circles from dried blood spot Guthrie cards, aids in the rapid identification and treatment of infants with SCID and other T-cell disorders. Quantitative defects in lymphocytes can also be appreciated in select forms of inherited bone marrow failure such as reticular dysgenesis, SCN secondary to GFI1 mutation, and dyskeratosis congenita.