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MD Consult: Books: Goldman: Cecil Medicine: Chapter 173 – LEUKOPENIA AND LEUKOCYTOSIS

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 173 – LEUKOPENIA AND LEUKOCYTOSIS

Grover C. Bagby Jr.

The normal peripheral white blood cell count ranges from 5.0 to 10.0 × 109/L, and a low total white blood cell count (<4.5 × 109/L) is known as leukopenia. When leukopenia is discovered, a most important first step is to determine which type of white blood cell is at low levels. Circulating leukocytes consist of heterogeneous cell types (neutrophils, monocytes, basophils, eosinophils, B lymphocytes, T lymphocytes, and natural killer cells), each of which serves a unique purpose and represents a different fractional component of the total body leukocyte population. Therefore, patients may be either severely neutropenic or lymphocytopenic despite having total white blood cell counts that fall within the normal range. Consequently, in a number of clinical settings (e.g., patients with an acute infection or those with recurrent infections), differential white blood cell counts are important to obtain even in the absence of leukopenia.

   NEUTROPENIA

Definition

The clinical consequences of prolonged phagocyte dysfunction can be life-threatening. Fortunately, acquired and inherited phagocyte dysfunction syndromes are rare. However, a reduction in the number of circulating phagocytes is more common in clinical practice, the most life-threatening instances of which result from bone marrow failure. Neutropenia is said to exist when a patient’s peripheral neutrophil count is less than 2.0 × 109/L. Because the normal range in Yemenite Jews and black individuals is somewhat lower, neutropenia in these populations is defined as counts less than 1.5 × 109/L. The role of the neutrophil in phagocytic defense of the host is generally met if the neutrophil count is higher than 1.0 × 109/L. If the neutrophil count drops further, particularly below 0.5 × 109/L, the threat of recurrent, severe, life-threatening, and difficult-to-treat infections increases enormously.

Pathobiology

Categorizing the causes of neutropenia requires an understanding of normal neutrophil kinetics. Neutrophils arise from a pool of marrow precursor cells through serial divisions and synchronous maturation steps ( Fig. 173-1 ). The rate of neutrophil production is high: more than 1011 cells per day. In the bone marrow, neutrophil precursors that retain replicative potential (myeloblasts, promyelocytes, and myelocytes) constitute the mitotic pool. Late differentiation–stage cells (metamyelocytes, bands, and segmented neutrophils) do not replicate and therefore form a nonmitotic precursor pool. A retained pool of fully developed neutrophils forms a neutrophil storage pool within the bone marrow. These cells are held in reserve, ready for rapid release into circulating blood when environmental conditions call for their release.

FIGURE 173-1  Production and distribution of neutrophils involve three compartments: marrow, peripheral blood, and the extravascular space. Unlike red blood cells, phagocytes are destined to function primarily in the extravascular space. The critical issue for clinicians to consider is whether delivery of phagocytes to this extracellular space is adequate. Stem cells, committed progenitor cells, and morphologically recognizable bone marrow precursor cells proliferate and mature; they differentiate under the influence of a variety of humoral regulatory factors that govern the production of neutrophils (granulocyte colony-stimulating factor), monocytes (macrophage colony-stimulating factor), and eosinophils (interleukin-5). These replicative responses occur in the mitotic pool (MiP). Once more differentiated cells reach the intermediate maturation stage known as the metamyelocyte, they stop replicating but continue differentiating into bands and segmented neutrophils. These cells, though capable of leaving the marrow when needed (e.g., in the setting of an acute bacterial infection), spend up to 5 days in the marrow in the storage pool (SP). The neutrophils then enter the blood stream. Half of these circulating cells adhere to endothelial cells and compose the marginated pool (MaP). The nonmarginated cells make up the circulating pool (CP). After their very brief sojourn in peripheral blood, the neutrophils invade the extravascular compartments of most organs, where they are used as defenders or garbage disposal devices (a process that involves both destruction of the offending organism and self-destruction), or they die within 1 to 2 days. EP = extravascular pool.

Released after a few days’ sojourn in bone marrow, neutrophils move through the blood in one of two pools. Half the cells circulate freely for a few hours; this circulating pool contains all the neutrophils sampled in the white blood cell count. The other half (the marginated pool) literally rolls along endothelial surfaces, held loosely in place by the shear forces of blood flow and by the interaction of families of adhesion molecules on the neutrophil surface with ligand molecules on the endothelial cell surface. These cells are not counted as part of the white blood cell count but can be recruited to circulate instantaneously by various stimuli (e.g., epinephrine). Ultimately, virtually all neutrophils leave the circulation in a matter of 6 to 12 hours and move into the extravascular space to look for organisms and debris to destroy. However, because the circulating pool is measured and the marginated pool is not, the true intravascular neutrophil number, consisting of the circulating and the marginated pools, is ordinarily twice that measured by the neutrophil count. By taking these kinetic considerations into account, a simple pathophysiologic classification of neutropenia can be derived from the three-compartment model: (1) the marrow compartment, (2) the peripheral blood compartment, (3) the extravascular compartment, or (4) combinations of these three ( Fig. 173-2 ).

FIGURE 173-2  Causes of neutropenia arranged according to the compartment with which the pathophysiologically relevant mechanism is linked. One should begin the diagnostic approach to a neutropenic patient by seeking to identify the pathophysiologically relevant compartment. Management of a neutropenic patient whose neutrophil production is reduced is entirely different from that of a neutropenic patient whose production is normal and in whom the rate of delivery to the extravascular compartment is normal or appropriately increased in the context of acute infec-tions. AIDS = acquired immunodeficiency syndrome.

Abnormalities in the Marrow Compartment

Bone marrow defects (failure to produce and release neutrophils at a normal rate) account for the majority of neutropenia in clinical practice. Failure of the marrow compartment can occur as a result of direct injury to either hematopoietic progenitors and stem cells or cells in the hematopoietic microenvironment. With both types of injury, the marrow usually contains fewer than normal numbers of hematopoietic cells, or maturation defects of hematopoietic cells result in normal or increased numbers of morphologically abnormal hematopoietic cells. In either case, neutropenia of this type frequently occurs along with abnormalities in the number of platelets and red blood cells.

Marrow injury can occur as a consequence of a variety of diseases, but drug-induced injury is most common ( Table 173-1 ). Antineoplastic, certain antiviral, and some immunosuppressive agents are generally designed to inflict injury on a nonmyeloid cell population (e.g., neoplastic cells); myelosuppressive toxicity is the rule but is generally predictable because its intensity varies directly with the dose. Drugs that are not usually myelosuppressive and that are well tolerated in the majority of patients can sometimes induce either marrow injury or peripheral neutrophil destruction. These idiosyncratic drug-induced reactions can result from direct drug-mediated cytotoxicity or from an immune mechanism in which (1) neutrophils are destroyed in extramedullary sites as a result of antineutrophil antibodies (e.g., the penicillins) or (2) the marrow compartment is injured (e.g., procainamide, chloramphenicol, dapsone, tocainide).


TABLE 173-1   — 
DRUGS THAT CAUSE NEUTROPENIA

   Antiarrhythmics

   Tocainide, procainamide, propranolol, quinidine
   Antibiotics

   Chloramphenicol, penicillins, sulfonamides, para-aminosalicylic acid, rifampin, vancomycin, isoniazid, nitrofurantoin, ganciclovir
   Antimalarials

   Dapsone, quinine, pyrimethamine
   Anticonvulsants

   Phenytoin, mephenytoin, trimethadione, ethosuximide, carbamazepine
   Hypoglycemic agents

   Tolbutamide, chlorpropamide
   Antihistamines

   Cimetidine, brompheniramine, tripelennamine
   Antihypertensives

   Methyldopa, captopril
   Anti-inflammatory agents

   Aminopyrine, phenylbutazone, gold salts, ibuprofen, indomethacin
   Antithyroid agents

   Propylthiouracil, methimazole, thiouracil
   Diuretics

   Acetazolamide, hydrochlorothiazide, chlorthalidone
   Phenothiazines

   Chlorpromazine, promazine, prochlorperazine
   Immunosuppressive agents

   Antimetabolites
   Cytotoxic agents

   Alkylating agents, antimetabolites, anthracyclines, vinca alkaloids, cisplatin, hydroxyurea, dactinomycin
   Other agents

   Recombinant interferons, allopurinol, ethanol, levamisole, penicillamine, zidovudine, streptokinase, carbamazepine, clozapine

Radiation ( Chapter 18 ) may result in acute self-limited bone marrow injury and chronic marrow failure. Chronic radiation-induced injury can also result in the later development of myelodysplasia and nonlymphocytic leukemia, both of which may be accompanied by neutropenia. In addition, benzene toxicity can result in acute or chronic neutropenia and, like radiation-induced marrow failure, is associated with a high risk for acute nonlymphocytic leukemia.

Immune-mediated bone marrow failure can be mediated by autoantibodies or, more often, by T lymphocytes that inhibit the growth of bone marrow precursor cells. Apart from those with acquired aplastic anemia (often immunologically mediated; see Chapter 171 ), most patients with immune-mediated leukopenia have concurrent rheumatic or autoimmune diseases, which are especially likely if the neutropenia is “isolated” (i.e., the only severe hematologic defect in patients who otherwise have normal red blood cell and platelet counts). Infection of the marrow per se is unusual and most often does not result in neutropenia; some exceptions include mycobacterial infections (especially those caused by Mycobacterium tuberculosis and Mycobacterium kansasii; see Chapters 345 and 346 ) and certain viral infections.

Bone marrow invasion by abnormal cells can result in neutropenia. Carcinoma of the lung ( Chapter 201 ), breast ( Chapter 208 ), prostate ( Chapter 211 ), and stomach ( Chapter 202 ), as well as malignant hematopoietic disorders, can occupy enough of the medullary space to cause global marrow failure. Similarly, in certain myeloproliferative diseases and leukemias, bone marrow fibroblasts can proliferate significantly in the marrow (myelofibrosis) and may contribute to bone marrow failure (see Fig. 173-2 ). This type of global marrow dysfunction nearly always results in both neutropenia and anemia, but platelet counts can be variable, particularly in syndromes associated with myelofibrosis.

Maturation arrest can result in functional bone marrow failure even though the bone marrow is full of granulocyte precursors. In the bone marrows of patients with folate or vitamin B12 deficiency, for example, numerous morphologically abnormal granulocyte precursors fail to mature normally and therefore suffer a high rate of intramedullary death because of the effects of the vitamin deficiency state on nuclear replication ( Chapter 170 ). The marrow is hypercellular but is packed with peculiar cells exhibiting dys-synchronous nuclear and cytoplasmic maturation (e.g., undifferentiated nuclei and differentiated cytoplasm [the hallmark of megaloblastic change]). Hematopoietic activity in the primitive cell population is intensely active, but the proliferative activity is ineffective in delivering terminally differentiated cells into the blood stream—a process known as ineffective hematopoiesis. Certain congenital neutropenias also represent maturation abnormalities, as do the acute nonlymphocytic leukemias, myelodysplastic syndromes, and paroxysmal nocturnal hemoglobinuria.

Abnormalities in the Peripheral Blood Compartment

Perturbations of the peripheral blood compartment result from shifts from the marginated to the circulating pool and vice versa (see Figs. 173-1 and 173-2 [1] [2]). In one syndrome, pseudoneutropenia, neutrophil production and utilization are normal, but the size of the marginated pool is increased and the circulating pool is decreased. Because these marginated cells, while hidden from the blood cell counting machine, maintain their capacity to migrate to sites of infection, patients with pseudoneutropenia are not at increased risk for infection unless an abnormality in neutrophil function coexists. Acquired pseudoneutropenia often occurs as an acute or subacute response to systemic infection; it is generally associated with acute changes in other compartments ( Fig. 173-3 ) and resolves when the infection is appropriately treated or spontaneously abates. Finally, a truly artifactual type of pseudoneutropenia can be seen as a result of clumping of neutrophils induced by ethylenediaminetetraacetic acid (EDTA; the anticoagulant in the complete blood count tube), which can be eliminated by adding kanamycin to the sample.

FIGURE 173-3  Pathophysiologic mechanisms of neutropenia. The size of a given compartment is represented by the size of the corresponding cylindrical pool. The relative number of cells leaving one compartment and headed for the next (highly variable from case to case) is represented by the size of the arrow between those compartments. Flow between compartments is unidirectional. CP = circulating pool; EP = extravascular pool; MaP = marginated pool; MiP = mitotic pool; SP = storage pool. Notice that in every case the circulating neutrophil pool is small but the size of the other pools is variable. In marrow injury, there is a global decline in the size of all pools. A maturation abnormality (e.g., deficiency of folic acid or vitamin B12), however, is characterized by an increase in the number of precursor cells that do not mature, which results in an absolute decrease in mature neutrophils in the marrow, blood, and tissues. Pseudoneutropenia is characterized by movement of circulating neutrophils to the marginated pool, but because delivery of cells to the extravascular space is usually normal, such patients are not at increased risk for infections. In patients who have acute infections, the demand for neutrophils in the infected extravascular site can result in a transient loss of storage pool neutrophils before the hypercellular (but as yet immature) mitotic compartments can renew the storage pool. This kind of neutropenia is very transient and occurs most often in cases of overwhelming infection, although certain organisms (e.g., Salmonella typhosa) seem to induce this type of response more than others do. Excessive destruction of neutrophils can also result in neutropenia, but this is not particularly common, except in cases of human immunodeficiency virus infection.

Demands of the Vascular Compartment

Neutrophils and their precursors respond to a number of environmental cues in a highly regulated fashion. The most frequent of these cues evolve in response to infection. These responses are governed by a variety of hematopoietic growth factors, adhesion molecules, and interleukins, including two granulopoietic factors, granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), and an important chemokine, interleukin-8 (IL-8). These factors, along with IL-1 and tumor necrosis factor-α, cytokines that induce the synthesis and release of granulopoietic factors and adhesion molecules on both neutrophils and endothelial cells, account for (1) a prompt increase in the rate of production of neutrophils in the mitotic compartment, a response mediated by a complex network of cellular and humoral regulatory interactions; (2) early release of neutrophils from the marrow storage pool to the peripheral blood pool; (3) an increase in the rate of neutrophil egress from the peripheral blood pool to the invaded tissue or tissues; and (4) increased phagocytic and bactericidal activity of the neutrophils. Rarely, increased demand for neutrophils in the extravascular compartment can lead to transient neutropenia, especially in patients with severe acute infections (see Fig. 173-3 ). In such cases, the immediate demand for neutrophils in the zone of infection calls forth such a substantial release response that the marrow storage pool is used up before it can be restored by increased proliferative activity of the granulocyte progenitor cells. This kind of neutropenia is not uncommon in cases of Salmonella typhoid fever ( Chapter 329 ), in which leukopenia is common in the acute phase. In such cases, the infected tissue serves as a sink for neutrophils for a brief period (sometimes up to 5 to 6 days). Ultimately, even under these conditions the neutrophil count generally rises well above normal within a few days because the bone marrow is highly effective in responding to infectious events, so the demand for neutrophils almost never exceeds the capacity of the mitotic pool to supply them if the bone marrow is completely normal. In contrast, neutrophil consumption in patients with autoimmune neutropenia and hypersplenism can, indeed, outstrip the capacity of the bone marrow to keep up with the losses.

Clinical Manifestations

Neutropenia can occur as a manifestation of a wide variety of systemic diseases (see Fig. 173-2 ), the manifestations of which may dominate the clinical picture. Many neutropenic patients remain asymptomatic, most often those whose neutrophil count exceeds 1.0 × 109/L or those whose neutropenia is acute or of brief duration. When symptoms do occur, they generally result from recurrent, often severe bacterial infections because of the pivotal importance of the neutrophil in defense of the host against microorganisms ( Chapter 175 ).

This risk for bacterial infection increases slightly as the peripheral neutrophil count falls below 1.0 × 109/L, but it is substantially increased at levels below 0.5 × 109/L. The degree to which monocytosis compensates for neutropenia may modify the risk. Some patients with severe congenital neutropenia have such substantial compensatory monocytosis that their clinical course is very mild. Because of the capacity of the extra monocytes to “cover” for neutrophil deficiencies, such rare patients have few bacterial infections. The lungs, genitourinary system, gut, oropharynx, and skin are the most frequent sources of infection in neutropenic patients. The infecting organisms are the “usual suspects” for the given anatomic site, with the caveat that for patients who have recurrent infections and require prolonged and recurrent antibacterial therapy, unusual (often hospital-acquired) organisms can colonize and subsequently cause infection. Consequently, the antibiotic history of infected neutropenic patients is important to obtain.

One must look carefully for infections in neutropenic patients because the usual signs and symptoms of infection are often diminished or absent as a result of the reduction in cells that mediate much of the inflammatory responses to infection. Thus, neutropenic patients with severe bilateral bacterial pneumonia may initially be seen with minimal infiltrates demonstrable on chest imaging (sometimes no infiltrates can be seen at all until after about 3 or 4 days of full-blown symptoms) and can have benign-looking, nonpurulent sputum, patients with pyelonephritis may not exhibit much pyuria, patients with bacterial pharyngitis may not have purulence in their oropharynx, and patients with severe bacterial infection of the skin may have only mild erythroderma rather than furunculosis. In a neutropenic patient, infections that in an otherwise normal individual might have been well localized quickly become disseminated. Therefore, not only does an infected neutropenic patient represent a diagnostic problem, but in addition, because any given infection is more likely to be widespread at the time of diagnosis, these patients are often gravely ill at the time that they are initially seen by their caregivers.

Diagnosis

The diagnostic evaluation of neutropenia is influenced by its severity and the clinical setting in which it occurs. The assessment of patients with neutrophil counts of less than 0.5 to 1.0 × 109/L must proceed briskly. A patient with fever, sepsis, or both in whom neutropenia is discovered for the first time presents a particularly difficult problem. In such patients, it is impossible to determine immediately whether the neutropenia antedated the sepsis, a situation with both prognostic and therapeutic implications, or whether the neutropenia is merely a short-lived response to the infection itself (see Fig. 173-3 ). Examination of the peripheral blood smear and differential white blood cell count can be helpful in such cases. An increase in the fraction of circulating band neutrophil forms to levels above 20% suggests that marrow granulopoietic activity is responding appropriately ( Fig. 173-4 ). Although the clinical context is more important to consider than this single data point, colloquially known as “bandemia,” it is nonetheless a data point more compatible with the notion that the bone marrow of the patient is in the midst of recovering from injury or that the neutropenia is derived from a transient shift to the marginated pool or to the extravascular compartment.

FIGURE 173-4  The nuclear lobes in a segmented form are separated by fine filaments absent in the band. Band neutrophils are “younger” forms than segmented neutrophils. In time, bands residing in the bone marrow undergo segmentation. Normally, band neutrophils account for less than 4% of the total circulating neutrophils. Band percentages greater than 6 to 7% suggest that the storage pool is releasing granulocytes early under the influence of increased levels of granulopoietic factors and that neutrophils are being consumed in the periphery. Alternatively, if neutropenia is the result of bone marrow failure, the bone marrow may be in the midst of an early recovery.

The diagnostic evaluation of neutropenia must first address the question of severity and then whether the patient has fever, sepsis, or both. A patient with sepsis and severe neutropenia should be treated promptly with intravenous antibiotics after obtaining blood for appropriate cultures but without waiting for the results of those cultures. Once these important initial questions are answered, the remainder of the diagnostic evaluation can proceed ( Fig. 173-5 ): (1) identifying any potential drugs and toxins to which the patient might have been exposed (see Table 173-1 ); (2) determining, if possible, the chronicity of the neutropenia (e.g., seeking evidence about whether the patient ever had a normal white blood cell count and when); (3) ascertaining whether there have been recurrent infections; (4) identifying any underlying systemic disease that might be causative; and (5) examining the blood counts and blood and bone marrow morphology (marrow examination is virtually always warranted unless a diagnosis is clear from simple blood tests, e.g., serum folate, homocysteine, methylmalonate, or vitamin B12 levels) to determine the most likely pathophysiologic explanation. In some cases, specialized bone marrow studies (e.g., progenitor cell colony assays before and after removing T lymphocytes from the sample) are warranted even with a clear diagnosis. Felty’s syndrome, for example, a well-recognized syndrome of neutropenia in patients with rheumatoid arthritis ( Chapter 285 ), is caused by one of two pathophysiologic mechanisms. One is mediated by antineutrophil antibodies, the other by T lymphocyte–mediated bone marrow failure. Each mechanism has a distinctly different therapeutic implication.

FIGURE 173-5  Practical algorithm for the evaluation of patients with neutropenia. The fundamental diagnostic principle is that for patients with severe neutropenia or for those with bicytopenia or pancytopenia, bone marrow examination will probably be necessary unless the following diagnoses are made: (1) a nutritional (folate or vitamin B12) deficiency or (2) drug- or toxin-induced neutropenia in a patient whose neutropenia resolves after discontinuation of the offending agent. AIDS = acquired immunodeficiency syndrome; MCV = mean corpuscular volume; RBC = red blood cell.

After the severity of the neutropenia is quantified, careful examination of the peripheral blood counts and blood smear is in order (see Fig. 173-5 ). Patients with selective neutropenia are approached differently from those with additional deficiencies of platelets and red blood cells, although drugs or toxins may be involved in either category. Potentially offending drugs should obviously be discontinued if such a maneuver is possible based on the nature of the disease for which the agent was prescribed and the availability of alternative drugs. Patients with selective neutropenia but with no drug or toxin exposure, no history of recurrent sepsis, and no underlying chronic inflammatory or autoimmune disease may have stable and benign neutropenia; this category includes some cases of familial and congenital neutropenia and pseudoneutropenia. Any patient with selective neutropenia and a history of sepsis and all patients with known toxin exposure should undergo bone marrow examination to assess (1) the cellularity of each compartment (storage and mitotic pools), (2) the distribution of differentiation stages found in each pool, and (3) whether any morphologic abnormality (e.g., acute leukemia or myelodysplasia) exists in the hematopoietic cells.

In patients with pancytopenia or bicytopenia, bone marrow aspiration plus biopsy is absolutely required. The only exception to this rule would be patients with unambiguous evidence of vitamin B12 or folate deficiency ( Chapter 170 ).

Inherited Neutropenia Syndromes

Cyclic Neutropenia

Cyclic neutropenia is characterized by 14- to 21-day periodic oscillations of the neutrophil count, with regularly occurring 3- to 5-day periods of severe neutropenia. The disease is associated with mutations located near the junction of exons 4 and 5 of the ELA2 gene; these mutations lead to apoptosis and ineffective neutrophil production. The cause of the periodicity is unknown. During the severely neutropenic periods, patients may experience oral ulcers, pharyngitis, and lymphadenopathy. Up to 10% of patients die as a result of pneumonia, cellulitis, or peritonitis. Bone marrow biopsy reveals hyperplasia or arrest of cell division at the myelocyte stage. To establish this diagnosis, complete blood counts with differential white blood cell counts should be performed twice weekly for 6 weeks.

Severe Congenital Neutropenia

Severe congenital neutropenia, also called Kostmann’s syndrome, is, like cyclic neutropenia, associated with ELA2 mutations that result in apoptosis of neutrophil precursor cells. This disease is accompanied by infections, including omphalitis, stomatitis, and respiratory infections. Bacterial cultures often reveal Staphylococcus aureus and Escherichia coli as the infecting agents. Patients typically have monocytosis and eosinophilia. The risk for acute myelogenous leukemia is high in patients with this disease.

Other Rare Neutropenia Syndromes

Myelokathexis, which is an autosomal dominant disorder caused by truncating mutations of the chemokine receptor CXCR4, is associated with hypersegmentation of neutrophils in the marrow and peripheral blood. In light of the characteristic bone marrow hypercellularity, apoptosis of well-differentiated neutrophil precursors in the marrow is thought to result because abnormalities in the proper release of neutrophils from marrow lead to severe neutropenia and recurrent infections.

The Shwachman-Diamond syndrome is an autosomal recessive disease caused by mutations of a gene (SDBS) that encodes a protein involved in ribosome biosynthesis. The disease is associated with neutropenia, pancreatic insufficiency, short stature, and skeletal abnormalities. Like all of the inherited neutropenia syndromes just mentioned, bone marrow myeloid precursor cells are apoptotic. Similar to severe congenital neutropenia, the disease is associated with a high risk for acute leukemia.

Treatment

Treatments Specifically Designed to Increase the Neutrophil Count

Immunosuppressive therapy (e.g., glucocorticoids, antithymocyte globulin, cyclosporine) very commonly elicits favorable responses in patients with marrow failure mediated by cytotoxic T lymphocytes or antineutrophil antibodies. Splenectomy is rarely helpful in the management of neutropenic patients, even those with Felty’s syndrome; it is now reserved for patients with unambiguous hypersplenism in whom bone marrow function is normal.

Recombinant Human Granulopoietic Factors

GM-CSF and G-CSF (either native G-CSF or the pegylated long-acting form) can increase the neutrophil count in selected neutropenic patients. As a general rule, patients with drug-induced neutropenia (e.g., after cancer chemotherapy) recover more rapidly if they receive either GM-CSF or G-CSF. These agents are indicated in the settings of (1) bone marrow transplantation; (2) management of patients with inherited neutropenic syndromes, including cyclic neutropenia; (3) induction of stem cell mobilization from marrow to peripheral blood in preparation for transplantation; and (4) combined therapy with erythropoietin for selected patients with myelodysplastic syndromes. Additional potential roles of these agents in clinical practice are unclear. Large clinical studies indicate that G-CSF hastens neutrophil recovery in patients receiving cytotoxic therapy but does not reduce the rate of hospitalization for febrile episodes, prolong survival, reduce culture-positive infections, or reduce the cost of supportive care, whether given preemptively or to treat neutropenic fever.[1] In addition, there is no evidence that these recombinant growth factors reduce mortality in non-neutropenic patients with nosocomial pneumonia in the intensive care unit.[2] In view of their attendant costs, routine use of G-CSF or GM-CSF to prevent infection in neutropenic cancer patients cannot be encouraged outside the setting of well-designed controlled clinical trials. For nontransplant patients not participating in such studies, it seems most rational to use these granulopoietic factors in patients undergoing cytotoxic chemotherapy only if the dose intensity of the chemotherapeutic agents has a demonstrated impact on overall survival (e.g., Hodgkin’s disease, germ cell neoplasms) and one of following three criteria apply: (1) serious, potentially life-threatening complications of neutropenia (e.g., documented bacterial infection) have developed in the patient in previous rounds of therapy; (2) the prior probability for prolonged myelosuppression is high (e.g., patients seropositive for human immunodeficiency virus type 1); or (3) the patient’s persistent neutropenia interferes with scheduled doses of chemotherapy.

Bone Marrow Transplantation

In patients with severe aplastic anemia, the role of bone marrow transplantation is well established ( Chapters 171 and 184 ). Other marrow failure states (e.g., myelodysplastic syndromes and inherited neutropenia) may also respond. Before transplantation is seriously considered, the duration and severity of the neutropenia must be assessed; marrow failure must be established as the primary cause. If the patient has an identical twin, transplantation might be attempted with fewer constraints, but allogeneic transplantation should always be reserved for individuals with severe and symptomatic neutropenia caused by marrow failure.

Antibiotics for Prophylaxis and Treatment of Neutropenic Patients

Each patient with neutropenia should be taught the function of neutrophils, the consequences of neutrophil deficiency, and the importance of communicating with the physician the moment that signs and symptoms of infection occur. In patients with neutropenia induced by cytotoxic chemotherapy for the treatment of malignant disease, prophylaxis with fluoroquinolone antibiotics decreases the incidence and severity of infections and reduces mortality.[3] When neutropenia is caused by chemotherapy in patients with acute myelogenous leukemia or the myelodysplastic syndrome, antifungal prophylaxis with posaconazole improves survival.[4] For all other neutropenic patients, the indications for antibiotic use are based on the individualized clinical context. If a neutropenic patient is afebrile and there is no sign of sepsis, diagnostic evaluation of the neutropenia should take place in the outpatient setting to avoid unnecessary exposure to nosocomial organisms. Patients with severe neutropenia and fever, however, should generally be hospitalized ( Chapter 303 ). Cultures of urine, blood, and other relevant sites should be obtained, but broad-spectrum antibiotics should be given without waiting for the results of these cultures. One of three responses will be seen:

   1.    A causative organism will be identified, in which case the spectrum of antimicrobial agents can be promptly and appropriately narrowed.
   2.    A candidate organism will not be found, but the patient still improves with empirical therapy. In this situation a full course of broad-spectrum antibiotics should be given. Moreover, after a full course of parenteral antibiotics, some of which may be given on an outpatient basis, another 7 to 14 days of oral antibiotics should be considered, especially in patients with invasive infections associated with necrosis, slow responses to initial antibiotic therapy, or recurrent infections in the same anatomic site.
   3.    No organism is found, and the clinical picture has not changed for the better after 3 days of empirical treatment. This unsettling situation occurs with some regularity in practice, and the approach depends on the seriousness of the infection. For a patient who has localized disease and is not critically ill, it is sometimes helpful for empirical therapy to be discontinued and for repeat cultures to be obtained. If the patient is critically ill, however, antibiotics should be discontinued only if other antibiotics are substituted. Among the antibiotics to consider under these circumstances are antiviral and antifungal agents. Antifungal agents should be added to the therapeutic regimen for patients with acute leukemia, diabetes, dysphagia or esophagitis, endophthalmitis, or defective cell-mediated immunity (including those receiving immunosuppressive therapy) and for those who have received prolonged treatment with broad-spectrum antibacterial agents in the recent past.

   DEFICIENCIES OF OTHER CIRCULATING PHAGOCYTES

Monocytopenia, eosinopenia, and basophilopenia are seen in most of the bone marrow failure states associated with neutropenia. Although transient monocytopenia can result from hemodialysis, stable isolated monocytopenia is very unusual. In view of the heterogeneous and critical roles played by the monocyte-macrophage in normal physiology, complete failure of monocyte production for a period of more than 9 to 10 months (the estimated lifespan of tissue macrophages) is probably incompatible with life.

Eosinopenia and basophilopenia are more common than monocytopenia in clinical practice and most often represent redistributional mechanisms resulting from stress, including acute infections, widespread neoplasms, and severe injury (e.g., burns). A variety of humoral factors, including glucocorticoids, prostaglandins, and epinephrine, are released in such settings and are known to induce eosinopenia. In fact, because of the reliable reduction of peripheral eosinophils during infectious events, if a patient with bacterial infection does not have eosinopenia, one should consider that adrenocortical insufficiency or a primary myeloproliferative syndrome may coexist.

   LYMPHOCYTOPENIA

Lymphocyte production and traffic are difficult to assess because (1) both T and B lymphocytes replicate in heterogeneous anatomic sites, including the lymph nodes, spleen, tonsils, and bone marrow, and (2) lymphocytes are capable of leaving and then later re-entering a given compartment. Given these variables, it is surprising that lymphocyte counts in peripheral blood are so tightly regulated; normal counts range from 2 to 4 × 109/L, with approximately 20% being B lymphocytes and 70% being T lymphocytes. Lymphocytopenia is defined as a peripheral blood lymphocyte count below 1.5 × 109/L, but severe lymphocytopenia is considered to be less than 0.7 × 109/L.

Pathobiology

Lymphocytopenia can result from (1) abnormalities in lymphocyte production, (2) abnormalities in lymphocyte traffic, and (3) lymphocyte loss and destruction ( Table 173-2 ).


TABLE 173-2   — 
CAUSES OF LYMPHOCYTOPENIA

   ABNORMALITIES IN LYMPHOCYTE PRODUCTION
   Protein-calorie malnutrition
   Radiation
   Immunosuppressive therapeutic agents

   Glucocorticosteroids
   Cyclosporine
   Congenital immunodeficiency states

   Wiskott-Aldrich syndrome
   Nezelof’s syndrome
   Adenosine deaminase deficiency
   Viral infections
   Hodgkin’s disease
   Multiple myeloma
   Widespread granulomatous infection (mycobacterial, fungal)
   Cytotoxic chemotherapy
   Direct dose-related effects (e.g., fludarabine)
   Long-term effects (e.g., cyclophosphamide)
   Idiosyncratic drug reactions (e.g., quinine)
   ALTERATIONS IN LYMPHOCYTE TRAFFIC
   Acute bacterial/fungal infection
   Surgery
   Trauma
   Hemorrhage
   Glucocorticosteroid therapy
   Viral infection
   Widespread granulomatous infection
   Hodgkin’s disease
   LYMPHOCYTE DESTRUCTION OR LOSS
   Viral infection (e.g., human immunodeficiency virus, severe acute respiratory syndrome [SARS])
   Antibody-mediated lymphocyte destruction (e.g., systemic lupus erythematosus)
   Protein-losing enteropathy
   Chronic right ventricular failure
   Thoracic duct drainage or rupture
   Extracorporeal circulation
   Graft-versus-host disease
Reduced Production of Lymphocytes

The most common cause of reduced lymphocyte production in the world is protein-calorie malnutrition. Immune paresis resulting from malnutrition ( Chapter 234 ) contributes to the high incidence of infection in malnourished populations. Radiation ( Chapter 18 ) and immunosuppressive agents ( Chapter 33 ), including alkylating agents and antithymocyte globulin, can induce lymphocytopenia by injuring the progenitor pool and inhibiting the replication of more well differentiated cells. T-cell deficiencies have been found in some long-term survivors of intensive chemotherapy for childhood cancer. A variety of congenital lymphocytopenic immunodeficiency states exist, some of which result in selective deficiencies of B lymphocytes, some of T cells, and some of combined deficiencies of both T and B cells. The mechanisms by which production and maturation of B and T lymphocytes are impaired in these patients are heterogeneous; many remain ill defined, although in some cases, inactivating mutations of receptors for lymphopoietic factors are the cause. Even in the absence of lymphocytopenia, immunodeficiency states can clearly exist because of abnormal lymphocyte function or selective deficiency of a component of the circulating lymphocyte population.

Certain viruses are capable of inducing lymphocytopenia; some of these agents infect lymphoid cells and cause their destruction. Such viruses include measles, polio, varicella-zoster, and human immunodeficiency virus. Human immunodeficiency virus does not frequently cause lymphocytopenia, but it infects the helper (CD4+) subset of T lymphocytes and destroys them, a process that results in a marked decline in the absolute numbers of helper T cells in the peripheral circulation ( Chapter 416 ). Patients with untreated Hodgkin’s disease occasionally have lymphocytopenia, especially during the late stages of the disease or in instances associated with the least favorable histologic subtypes ( Chapter 197 ).

Alterations in Lymphocytic Traffic

Traffic redistribution is common and most frequently represents transient responses to a variety of stressful events, including bacterial infections, surgery, trauma, and hemorrhage. These responses are probably mediated by high levels of endogenous glucocorticoids that induce rapid declines in circulating levels of B and T lymphocytes. In hospitalized patients with lymphocytopenia, glucocorticosteroid therapy ( Chapter 33 ) is the third most common cause, after acute bacterial or fungal infections and surgery. The lymphocytopenic response to this type of steroid results from a self-limited shift of lymphocytes away from the peripheral blood compartment. Lymphocyte values generally return to normal within 24 to 48 hours. For this reason, the transient declines induced by endogenous steroid production are not associated with functional immunologic deficiency. Certain viruses can also bind to lymphocyte populations and cause their departure from the blood compartment into other sites. Given the rapid onset of disease in patients with severe acute respiratory syndrome (SARS; Chapter 97 ), this mechanism may also account for the prevalence of lymphocytopenia in such patients.

More persistent lymphocytopenia has been described in patients with widespread granulomatous disease, a phenomenon that is probably multifactorial and derived from both inhibition of production and alterations in traffic. Patients with these disorders are often difficult to treat. In daily practice, establishing a cause-and-effect relationship between the infection and lymphocytopenia can be difficult when one considers that the reverse might just as easily be true; consider, for example, the frequency of mycobacterial infection in patients with the acquired immunodeficiency syndrome.

Increased Destruction of Lymphocytes

Viral infections or antilymphocyte antibodies, especially in patients with underlying autoimmune or rheumatic diseases, increase lymphocyte destruction. Loss of viable lymphocytes can also occur as a result of structural defects in sites of high-density lymphocyte traffic (e.g., via thoracic duct fistulas). In such patients, both T cells and B cells decline in the peripheral blood. Loss of lymphocytes from intestinal lymphatics can occur in cases of protein-losing enteropathy, severe heart failure, or primary diseases of the gut or intestinal lymphatics (see Table 173-2 ).

Clinical Manifestations

There are no specific clinical manifestations of lymphocytopenia per se. Whether the patient exhibits signs of immunologic deficiency depends on the pathophysiology of the disorder, the duration of the disease, the type of lymphocytes affected, the intactness of nodal tissues, and the degree to which cellular or humoral immunity is functionally perturbed.

Diagnosis

Unless the clinical setting is clearly one in which transient lymphocytopenia is likely, the approach to diagnosis should involve comprehensive assessment of the integrity of the immune apparatus. Specifically, the subsets of lymphocytes remaining in the circulating blood should be quantified, including B cells, helper-inducer T cells (CD4+), and cytotoxic-suppressor T cells (CD8+). In addition, quantitative immunoglobulin levels in serum should be measured and a series of skin tests should be performed to detect deficiencies of cell-mediated immunity.

Treatment

Because lymphocytopenia ordinarily represents a response to an underlying disease, primary attention must be paid to establishing the nature of that disease and instituting therapy for it. Patients whose lymphocytopenia is accompanied by hypogammaglobulinemia may benefit significantly from the administration of intravenous immunoglobulin, which often reduces the incidence of infectious events. Treatment of severe deficiencies of cell-mediated immunity remains experimental. Responses have been described with transplantation of allogeneic bone marrow, fetal liver, or thymic epithelial cells. Treatment with IL-7 can hasten immune recovery in nonhuman primates rendered neutropenic by radiation and antithymocyte globulin, so IL-7 and other lymphopoietic factors may have future roles that parallel the role of granulopoietic factors.

   LEUKOCYTOSIS AND LEUKEMOID REACTIONS

Circulating leukocytes consist of neutrophils, monocytes, eosinophils, basophils, and lymphocytes (T cells, B cells, and natural killer cells). Any one or all of these cell types can increase to abnormal levels in peripheral blood in response to various stimuli. Each type of leukocyte is produced in the bone marrow (and in the case of lymphocytes, in lymph nodes, the spleen, and the thymus as well) in response to specific growth factors and, in the case of some lymphocytes, in response to antigenic stimuli. The term leukocytosis is used to describe a total leukocyte count above 11.0 × 109/L; it is a common and diagnostically important finding in clinical practice. Once leukocytosis is discovered, it is essential to examine the differential white blood cell count so that one can determine which white blood cell types are increased. The terms neutrophilia (neutrophilic leukocytosis), monocytosis, lymphocytosis, eosinophilia, and basophilia suggest specific sets of diagnostic considerations.

Leukocytosis is a common finding in acutely ill patients. When the leukocyte count exceeds 25 to 30 × 109/L, the condition is sometimes termed a leukemoid reaction. Leukemoid reactions generally reflect the response of healthy bone marrow to cytokines released by auxiliary cells (lymphocytes, macrophages, and stromal cells) exposed to infection or trauma. Leukemoid reactions are not synonymous with leukoerythroblastosis, which indicates the presence of immature white blood cells and nucleated red blood cells in the peripheral blood, irrespective of the total leukocyte count. Leukoerythroblastosis is less common than leukemoid reactions but frequently, especially in adult patients, reflects serious marrow dysfunction ( Table 173-3 ). Consequently, the finding of leukoerythroblastosis represents a clear indication to perform bone marrow aspiration and biopsy, unless the clinical setting is specifically an acute severe hemolytic anemia, sepsis in a patient with hyposplenism, or acute massive trauma with multiple fractures.


TABLE 173-3   — 
CAUSES OF LEUKOERYTHROBLASTOSIS

NORMAL BONE MARROW

   Severe acute hemolytic anemia
   Acute infection in hyposplenic patients
ABNORMAL BONE MARROW

   Marrow infiltration
   Metastatic malignancy (e.g., carcinoma of the lung, breast, prostate, or stomach)
   Hematologic malignancies

   Acute leukemia
   Multiple myeloma
   Chronic myeloproliferative diseases (e.g., myeloid metaplasia or chronic myelogenous leukemia)
   Lymphoma
   Granulomatous diseases

   Mycobacterial infection
   Fungal diseases
OTHER DISORDERS

   Osteopetrosis
   Gaucher’s disease
   Amyloidosis
   Paget’s disease of bone
   Severe tissue hypoxia
   Multiple fractures
   Neutrophilia

Pathobiology

The number of neutrophil precursors in the marrow mitotic pool ( Fig. 173-6 ) is largely influenced by the hematopoietic growth factors, the most neutrophil lineage specific of which is the granulopoietic factor G-CSF. G-CSF not only functions to stimulate the growth and differentiation of granulocyte progenitor cells but also functionally activates neutrophils by enhancing their capacity to kill ingested organisms. The same holds true for macrophage colony-stimulating factor (M-CSF, which activates mononuclear phagocytes) and IL-5 (the growth factor that activates eosinophils).

FIGURE 173-6  Pathophysiologic mechanisms of neutrophilia. A, In this figure, the size of a given compartment is represented by the relative size of the cylinder-shaped “pool.” The absolute number of cells leaving one pool for the next is represented by the size of the arrows between the pools. CP = circulating granulocyte pool; EP = extravascular pool; MaP = marginated pool; MiP = mitotic pool of neutrophil precursor cells; SP = neutrophil storage pool. Notice that the circulating neutrophil pool is large (necessarily true for patients with neutrophilic leukocytosis) but the size of the other pools is variable. B, A variety of stresses, such as infection, can result in the release of storage pool granulocytes, probably mediated through the actions of glucocorticosteroids or the granulopoietic factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. C, The circulating granulocyte pool can also increase in size because of a shift of neutrophils from the marginated to the circulating pool. The demargination response can be regularly elicited by the administration of epinephrine. This is a response that also occurs in infections, but not generally without other dynamic alterations in other pools. D, In most bacterial infections and other inflammatory processes, the demand for neutrophils in the infected extravascular site results in the simultaneous release of storage pool neutrophils and demargination. E, Later in the inflammatory response, after the hematopoietic growth factors released in response to the inflammatory stimulus have induced a few days of proliferation in the mitotic pool, the content of neutrophils in all pools increases and delivery to the tissues is maximized.

The marrow storage pool can provide the periphery with neutrophils for about 5 days in the steady state, even if it received no input from the mitotic pool. Neutrophils are released from the storage pool into the circulating pool in response to a variety of physiologic stresses, including endogenous glucocorticoids (see Fig. 173-6B ). Neutrophilia can result from a shift of neutrophils from the marginated to the circulating pool, termed demargination (see Fig. 173-6C ). This response is rapid and can be induced by injections of epinephrine and glucocorticosteroids. In patients with acute inflammatory illnesses, storage pool release and demargination usually occur together (see Fig. 173-6D ).

Neutrophilic leukocytosis is the most common type of leukocytosis in clinical practice. It evolves in response to the release of factors that govern the production and traffic of this cell type, including G-CSF, and factors that augment the mitotic activity of G-CSF, including IL-3, Steel factor, and GM-CSF. These and additional less well defined granulopoietic factors are produced by a network of auxiliary cells in the bone marrow, including mononuclear phagocytes, microvascular endothelial cells, fibroblasts, and lymphocytes. These growth factor–producing cells respond to acute inflammatory events by augmenting production of the critically important colony-stimulating factors. The colony-stimulating factors stimulate replication of granulopoietic progenitor cells, which leads to expansion of the neutrophil storage pool and subsequent neutrophilia (see Fig. 173-6E ). In response to the infection and the induced cytokines and adhesion molecules, the transit time of neutrophils in the mitotic and postmitotic pools in the bone marrow is shorter than in the uninfected state, and immature neutrophils (bands and metamyelocytes) are released from the storage pool. This new high level of production persists until the inflammatory process resolves.

Diagnosis

Neutrophilia (neutrophil counts >7.5 × 109/L), a common finding in clinical practice, usually reflects the inflammatory response to acute or subacute infections ( Fig. 173-7 ; Table 173-4 ), so it should trigger a diagnostic search for its cause. Such searches generally involve a careful history and physical examination and just a few inexpensive laboratory tests (the nature of which depends on the findings on physical examination) because in most cases the cause will become apparent and usually proves to be an active infectious process.

FIGURE 173-7  Evaluation of patients with neutrophilic leukocytosis. bcr/abl = translocation of the c-abl gene from chromosome 9 to the bcr gene on chromosome 22q; CML = chronic myelogenous leukemia; LAP = leukocyte alkaline phosphatase; Ph1 = Philadelphia chromosome.


TABLE 173-4   — 
COMMON CAUSES OF NEUTROPHILIC LEUKOCYTOSIS

INFECTIONS
Bacteria
Viruses
Fungi
Parasites
Rickettsia
RHEUMATIC AND AUTOIMMUNE DISORDERS
Rheumatoid arthritis
Vasculitis
Autoimmune hemolytic anemia
Inflammatory bowel disease
Gout
NEOPLASTIC DISORDERS
Pancreatic, gastric, bronchogenic, breast, and renal cell carcinoma
Melanoma
Any cancer metastatic to bone marrow
Lymphoma, especially Hodgkin’s disease
Chronic myeloproliferative disorders (chronic myelogenous leukemia, agnogenic myeloid metaplasia, essential thrombocytosis, polycythemia vera)
Myelodysplastic disorders and acute leukemia
CHEMICALS
Mercury poisoning
Venoms (reptiles, insects, jellyfish)
Ethylene glycol
Histamine
TRAUMA
Thermal injury
Hypothermia
Crush injury
Electrical injury
ENDOCRINE AND METABOLIC DISORDERS
Ketoacidosis
Lactic acidosis
Thyrotoxicosis
HEMATOLOGIC DISORDERS (NON-NEOPLASTIC)
Acute hemolytic anemias and transfusion reactions
Post-splenectomy status
Recovery from marrow failure
OTHER DISORDERS
Tissue necrosis
Pregnancy
Eclampsia
Exfoliative dermatitis
Hypoxia
DRUGS
Corticosteroids
Lithium
Epinephrine
Granulocyte colony-stimulating factor
Granulocyte-macrophage colony-stimulating factor

When neutrophilia occurs in the absence of evidence of acute inflammation or illness, three explanations should be considered: (1) chemical effects, including agents such as glucocorticoids, lithium chloride, and epinephrine; (2) malignant tumors, in which cancer cells may inappropriately express certain of the genes encoding granulopoietic factors (e.g., G-CSF or IL-5); and (3) chronic myeloproliferative disorders, including chronic myelogenous leukemia (CML), agnogenic myeloid metaplasia, essential thrombocytosis, and polycythemia vera.

Neutrophil morphology can lead to early diagnosis. Toxic granulation of neutrophils ( Fig. 161-29 ), Döhle bodies ( Fig. 161-30 ), and vacuoles in the neutrophil cytoplasm suggest that overt or subclinical inflammation, toxin exposure, trauma, or neoplasia exists. Because glucocorticoids induce prompt eosinopenia and basophilopenia, these cells are almost universally absent in the blood of an acutely injured or infected patient. Thus, the presence of eosinophils should indicate that (1) the acutely ill patient may have concomitant adrenocortical insufficiency ( Chapter 245 ), (2) the neutrophilia derives from the inappropriate production of GM-CSF or IL-5 (e.g., by malignant cells), or (3) the neutrophilia is one manifestation of a hematopoietic neoplasm (a chronic myeloproliferative disorder, myelodysplastic syndrome, lymphoma, or acute nonlymphocytic leukemia associated with eosinophilia).

The diagnostic approach to patients with neutrophilia (see Fig. 173-7 ) leads quickly to the performance of bone marrow aspiration and biopsy for patients with leukoerythroblastosis. In patients without leukoerythroblastosis, neutrophilic leukocytosis usually results from acute toxic, inflammatory, or traumatic stress, and it is generally best to observe the course of neutrophilia to determine its degree of linkage with the underlying disease. If the underlying disease resolves and the neutrophilia does not, other, less common explanations must be pursued.

Leukocyte alkaline phosphatase (LAP) is an enzyme found in neutrophils. When neutrophilia represents a reaction to an acute illness, LAP levels usually increase substantially. In patients with CML ( Chapter 195 ), however, the LAP score is markedly decreased. A low LAP level in a patient with neutrophilia should therefore lead to a diagnostic evaluation designed to exclude CML ( Table 173-5 ).


TABLE 173-5   — 
DISTINCTIONS BETWEEN NEUTROPHILIC LEUKEMOID REACTIONS AND CHRONIC MYELOGENOUS LEUKEMIA

Finding/Result Leukemoid Reaction CML
Presence of fever or other manifestations of acute or subacute inflammation Usual[*] Infrequent[]
Splenomegaly Rare Frequent
Natural course of neutrophilia Resolution linked with abatement of the underlying disease Progressive slow increase over time
Peripheral blood basophilia Rare[] Common
LAP score High Low[§]
Philadelphia chromosome bcr/abl translocation Absent Frequent (> 85%)
  Absent Frequent (> 90%)

* Exceptions include patients with leukemoid reactions associated with certain cancers.
Infections can also develop in patients with CML. The time to evaluate this possibility is when the inflammatory process resolves and the neutrophilia does not.
Patients with acute allergic reactions and patients with parasitic diseases are exceptions to this rule.
§ LAP scores can be normal in some CML patients, particularly after splenectomy. CML = chronic myelogenous leukemia; LAP = leukocyte alkaline phosphatase.

Neutrophilic Leukemoid Reactions

Neutrophilic leukemoid reactions generally occur in patients who are obviously systemically ill. When the neutrophil count exceeds 80 × 109/L or when the mildness of the systemic illness seems discordant with the extremely high level of neutrophils in peripheral blood, the diagnosis most often considered is CML or chronic myelomonocytic leukemia. A number of additional features distinguish leukemoid reactions from CML and chronic myelomonocytic leukemia (see Table 173-5 ). The diagnostic tests for CML are those designed to identify the classic balanced chromosomal rearrangement (a chromosome 9;22 translocation) either morphologically (cytogenetic analysis) or by molecular methods (identification of bcr/abl DNA, mRNA, or protein).

Monocytosis

Monocytosis is defined as absolute peripheral blood monocyte counts greater than 0.80 × 109/L in children and greater than 0.50 × 109/L in adults. Monocytes present processed antigens to lymphocytes, mediate cellular cytotoxicity, release procoagulants, participate in bone remodeling and wound repair, dispose of damaged cells, and regulate immune and hematopoietic responses by producing IL-1, tumor necrosis factor-α, G-CSF, IL-6, and certain interferons. The most specific growth/survival factor for mononuclear phagocytes is M-CSF (see Fig. 173-7 ) produced by stromal cells, including endothelial cells and fibroblasts. M-CSF–knockout mice have monocytopenia and macrophage deficiency, but GM-CSF–knockout mice do not. The cytokine IL-13 also induces monocytosis.

The mononuclear phagocyte is more sluggish than the neutrophil in moving toward and killing bacteria but is as effective, if not more so, in killing intracellular parasites such as fungi, yeast, and viruses. In addition, the mononuclear phagocyte participates in all types of granulomatous inflammation. Accordingly, monocytosis is often seen in patients with tuberculosis, syphilis, fungal infections, ulcerative and granulomatous colitis, and sarcoidosis ( Table 173-6 ). Mild monocytosis is common in patients with Hodgkin’s disease and a variety of cancers. High levels of monocytes in blood are most often seen in patients with hematopoietic malignancies, including acute and chronic myelomonocytic leukemia, acute monocytic leukemia, and the juvenile type of CML.


TABLE 173-6   — 
CAUSES OF MONOCYTOSIS

INFECTIONS
Tuberculosis
Brucellosis
Endocarditis
Typhoid and paratyphoid
Syphilis
Fungal
Recovery from acute infections
Protozoal
Viral (e.g., varicella, dengue)
NEOPLASTIC DISEASES
Hodgkin’s disease
Carcinoma (many varieties)
Acute and chronic myelomonocytic leukemia
Juvenile chronic myelomonocytic leukemia
Acute monocytic leukemia
Myelodysplasia
Myeloma and Waldenström’s macroglobulinemia
Chronic lymphocytic leukemia (rare)
GASTROINTESTINAL DISORDERS
Ulcerative colitis
Granulomatous colitis
Cirrhosis
Sarcoidosis
Drug reactions
Recovery from marrow suppression
Congenital neutropenia
Eosinophilia

Eosinophilic leukocytosis (eosinophilia) exists when the eosinophil count in peripheral blood exceeds 0.4 × 109/L ( Chapter 176 ). Eosinophils are produced by progenitor cells in the marrow, largely under the influence of IL-5, a protein that also stimulates the growth and differentiation of B lymphocytes. Eosinophils not only function as phagocytes but also play an extraordinarily important role in modulating the potentially toxic effects of mast cell degranulation in hypersensitivity reactions.

Lymphocytosis

Lymphocytosis ( Table 173-7 ) is defined as a lymphocyte count in excess of 5.0 × 109/L. Atypical lymphocytosis is present when atypical lymphocytes account for more than 20% of the total peripheral blood lymphocyte population. A number of humoral factors induce the growth of T lymphocytes (IL-2, IL-3, IL-7, IL-15), natural killer cells (IL-2, IL-12, IL-1), and B lymphocytes (IL-10, IL-6, IL-5, IL-4, IL-7, IL-13, IL-14, IL-15).


TABLE 173-7   — 
CAUSES OF LYMPHOCYTOSIS

HIGH (>15 × 109/L)
Infectious mononucleosis
Pertussis
Acute infectious lymphocytosis
Chronic lymphocytic leukemia and variants thereof
Acute lymphocytic leukemia
MODERATE (< 15 × 109/L)
Many viral infections
Infectious mononucleosis
Measles
Varicella
Hepatitis
Coxsackievirus
Adenovirus
Mumps
Cytomegalovirus
Human immunodeficiency virus type 1 (acute lymphadenopathy)
Other infectious diseases
Toxoplasmosis
Brucellosis
Tuberculosis
Typhoid fever
Syphilis (secondary)
Neoplastic disorders
Carcinoma
Hodgkin’s disease
Acute lymphocytic leukemia (early)
Chronic lymphocytic leukemia
Thymoma
Sjögren’s syndrome
Graves’ diseases
Drug reactions (e.g., tetracycline)
Diagnosis

Mild to moderate lymphocytosis (lymphocyte counts <12 × 109/L) is most commonly caused by viral infections, including infectious mononucleosis and viral hepatitis. Careful examination of peripheral blood lymphocyte morphology can help distinguish between these two disorders. In cases of infectious mononucleosis, many of the lymphocytes are large, with abundant cytoplasm and a “ballerina skirt”–like cytoplasmic border; these are the characteristic “atypical” lymphocytes that exceed 20% of the total lymphocyte population during the course of this disease ( Fig. 173-8 ). Interestingly, whereas the B lymphocyte is the target of the causative Epstein-Barr virus, the majority of cells in the peripheral blood of patients with this disease are T lymphocytes. This proliferation of T lymphocytes in response to Epstein-Barr virus infection of B cells plays a role in eradicating the infected B-cell population. This response is a critical one in view of the oncogenic potential of this virus.

FIGURE 173-8  Infectious mononucleosis. A peripheral smear shows pleomorphic, atypical (or “reactive”) lymphocytes.

Acute bacterial infections rarely cause lymphocytosis. One exception is pertussis (seen almost exclusively in children), in which profound lymphocytosis (up to 60 × 109/L) is sometimes seen. It has been known for 30 years that specific soluble factors derived from the causative organism Bordetella pertussis induce lymphocytosis in experimental animals. Perhaps with the exception of patients with early chronic lymphocytic leukemia, most patients with lymphocytosis and especially those with substantial lymphocytosis (>12 to 15 × 109/L) have overt signs of an underlying illness involving anatomic sites other than the lymphohematopoietic system. The diagnostic approach depends simply on establishing a tissue diagnosis to exclude malignant disease in patients who do not have clear-cut evidence of one of the more benign disorders. Bone marrow aspiration and biopsy are required when lymphocytosis coexists with leukoerythroblastosis, peripheral lymphocytes are immature (lymphoblasts), and the lymphocytosis is persistent in a patient who has no evidence of acute or subacute infection.

Immunophenotyping by flow cytometric analysis (“lymphocyte markers”) should be performed with monoclonal antibodies to definitive integral membrane proteins. Not only will such studies provide evidence for or against dominance of one lymphocyte type and differentiation stage, but analysis of immunoglobulin light chain types can also determine whether B lymphocytes in the circulation are all members of a single (and therefore probable neoplastic) clone.

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