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1204 Part IX: Lymphocytes and Plasma Cells Chapter 79: Lymphocytosis and Lymphocytopenia 1205

of lymphocytes from nodal compartments. Although this resolves Because approximately 80 percent of normal adult blood lymphocytes
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within 8 months in most patients, a small minority has sustained lym- are T lymphocytes and nearly two-thirds of blood T lymphocytes are
phocytosis lasting more than a year. Biologic characterization of the CD4+ (helper) T lymphocytes, most patients with lymphocytopenia
lymphocytosis has shown that the persistent CLL cells do not prolifer- have reductions in the absolute numbers of T lymphocytes, particularly
ate and do not represent clonal evolution. The prolonged lymphocytosis CD4+ T lymphocytes. The average absolute number of T lymphocytes
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likely represents a persistent quiescent clone and is not associated with in normal adult blood is 1.9 × 10 /L, ranging from 1.0 to 2.3 × 10 /L. The
a risk of relapse. 90 average absolute number of CD4+ T lymphocytes is 1.1 × 10 /L, ranging
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from 7.2 to 14 × 10 /L. The average absolute number of cells of the other
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Stress Lymphocytosis major T-cell subgroup, CD8+ T lymphocytes, is 6.5 × 10 /L, ranging
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Transient stress lymphocytosis has been identified as a common cause of from 3.8 to 9.7 × 10 /L.
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lymphocytosis in patients admitted to a hospital. Both trauma and non- Table 79–3 summarizes the conditions associated with lympho-
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traumatic stress have been associated with lymphocytosis. 92,93 Trauma, cytopenia. The mechanism of lymphocytopenia is not established for
surgery, acute cardiac failure, septic shock, myocardial infarction, sickle many of these disorders, and several possible mechanisms exist. Further
cell crisis, or status epilepticus may be associated with an elevated lym- discussion of lymphocytes and of the diseases associated with lympho-
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phocyte count, often greater than 5 × 10 /L, which may revert to normal cytopenia are presented in the cited reports (see Table 79–3).
or below-normal levels within hours. 94,95 The increased lymphocyte count The relative incidence of each of these conditions varies, depend-
appears promptly after the event and appears secondary to lymphocyte ing upon the patient population. In one New Zealand survey of patients
redistribution affecting all major lymphocyte subsets. A transient lym- who had significant lymphocytopenia (<0.6 × 10 /L), the patients fell
92
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phocytosis can be induced by the redistribution of leukocyte subsets after into several categories with some overlap. In order of decreasing fre-
both physical and psychological stress. 96,97 Characteristically, two phases quency, the factors associated with lymphocytopenia were bacterial or
are recognized after catecholamine administration: a quick (<30 minutes) fungal sepsis (250 patients), major surgery (228 patients), definite (153
mobilization of lymphocytes, followed by an increase in granulocyte patients) or suspected (53 patients) glucocorticoid therapy, malignancy
numbers with decreasing lymphocyte numbers. 98,99 (180 patients), cytotoxic therapy and/or radiotherapy (90 patients),
recent trauma or hemorrhage (86 patients), renal allograft (38 patients),
Hypersensitivity Reactions marrow allograft (35 patients), “viral infections” other than HIV (26
Delayed hypersensitivity reactions to insect bites, especially mosquitos, patients), or infection with HIV (13 patients). Only one patient was sus-
may be associated with a large granular lymphocytic lymphocytosis and pected of having idiopathic CD4+ T lymphocytopenia.
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adenopathy. These delayed hypersensitivity reactions can be associ-
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ated with EBV-NK lymphocytosis. Idiosyncratic drug reactions also INHERITED CAUSES
may be associated with subacute lymphocytosis, typically developing 2
to 8 weeks after initiating administration of the responsible drug. 102–107 Patients with inherited immunodeficiency diseases may have associ-
An infectious mononucleosis-like syndrome can be induced in some ated lymphocytopenia (see Table 79–3 and see Chap. 80, Table 80–2).
patients by salazosulfapyridine or sulfasalazine (see Fig. 79–2). 108 Inherited immunodeficiency disorders may have a quantitative or qual-
itative stem cell abnormality, resulting in ineffective lymphopoiesis (see
Persistent Lymphocytosis references cited in Table 79–3). Moreover, mutations in the genes that
Patients may have subacute or chronic lymphocytosis, termed persis- are critical for T-cell development can result in severe combined immu-
tent lymphocytosis, in association with a variety of clinical conditions nodeficiency and lymphocytopenia as a consequence of the inability
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(see Table 79–1). to generate mature T cells (Chap. 76). Other immune deficiencies,
Patients with lymphocytosis may have underlying neoplastic dis- such as the Wiskott-Aldrich syndrome, have associated lymphopenia
ease. Most notably, patients with malignant thymoma may have a poly- because of premature destruction of T cells secondary to a defect in the
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clonal T-cell lymphocytosis thought to be secondary to the aberrant lymphocyte cytoskeleton. Studies have reported that certain ethnic
release of thymic hormones by the neoplastic thymic epithelium. 109–111 groups have lower CD4+ T-cell counts in the absence of other identified
A reactive lymphocytosis or plasmacytosis may be detected in patients factors, for example, Ethiopians and Chukotka natives. 121,122
with acute myeloid leukemia or systemic mastocytosis. 112–114 Patients
with solid tumors also may develop lymphocytosis following cancer ACQUIRED LYMPHOCYTOPENIA
chemotherapy. Acquired lymphocytopenia defines syndromes associated with depletion
Patients may develop polyclonal lymphocytosis following of blood lymphocytes that are not secondary to inherited disease.
splenectomy. 76,115,116 An absolute lymphocyte count ranging from 4.0 to
8.7 × 10 /L often is noted 4 to 242 (median: 70) months after splenectomy Infectious Diseases
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and can persist for prolonged periods (e.g., longer than 50 months). The most common infectious disease associated with lymphopenia is
AIDS caused by HIV (Chap. 81). The lymphocytopenia results in part
Chronic Infections A reactive lymphocytosis commonly is associated
with many viral and certain bacterial infections, which, if protracted, from destruction and/or clearance of CD4+ T cells infected with HIV-1
123,124
can result in subacute or chronic lymphocytosis (see Table 79–1). 117 or HIV-2.
Other viral and bacterial diseases may be associated with lympho-
LYMPHOCYTOPENIA cytopenia (see Table 79–3). Patients presenting with active tuberculo-
sis often have lymphocytopenia, even if they are HIV negative and this
DEFINITION usually resolves 2 weeks after initiating appropriate antimicrobial ther-
125–127
Patients with severe acute respiratory syndrome resulting from
apy.
Chapter 2 presents the methods for determining the absolute lym- infection with coronavirus typically have lymphocytopenia that resolves
phocyte count and the normal range for such counts. Lymphocytope- following recovery. 128,129 Several other common viral diseases, such as
nia is defined as a total lymphocyte count less than 1.0 × 10 /L, but measles, typically are associated with transient lymphocytopenia during
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some consider the lower limit of normal to be 1.5 × 10 /L (1500/μL). the acute phases of infection, which in turn is thought to contribute to
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