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1202 Part IX: Lymphocytes and Plasma Cells Chapter 79: Lymphocytosis and Lymphocytopenia 1203

leukocyte antigen (HLA)-DR7 positive. In addition, there are shared Acute Infection Lymphocytosis
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cases among identical twins and in families. 37,38 Moreover, evaluation Acute infection lymphocytosis is a disorder that occurs in children usu-
of first-degree relatives of individuals with this type of lymphocytosis ally between the ages of 2 and 10 years. It is characterized by an increase
may identify new patients who have all the criteria for its diagnosis or in blood lymphocytes, often to 20 to 30 × 10 /L and occasionally as
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have slight increases in serum IgM, suggesting a possible hereditary or high as 100 × 10 /L, which might be mistaken for acute leukemia. The
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genetic contribution to the pathogenesis. 39 lymphocytes may vary in size but are otherwise similar to normal blood
Patients can have features resembling those of patients with various lymphocytes (Fig. 79–2). Patients usually are asymptomatic but may
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monoclonal B-cell malignancies. Patients may have mild splenomegaly. have fever, abdominal pain, or diarrhea. Lymph node enlargement and
Histologic examination of marrow and secondary lymphoid tissues splenomegaly do not occur, and the patient’s serum usually is negative
from patients with progressive splenomegaly can reveal features resem- for heterophile antibodies found in patients with infectious mononu-
bling marginal zone B-cell lymphoma (Chap. 101). In possibly another cleosis caused by EBV. In this regard, the disease resembles infectious
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manifestation of this syndrome, first identified in Japan as hairy B-cell mononucleosis caused by viruses other than EBV, such as cytomegalo-
lymphoproliferative disorder, the patients can present with anemia, virus (CMV; Chap. 82). 58–60 Clinical symptoms last for a few days, but
thrombocytopenia, and splenomegaly and have an excess of polyclonal the lymphocytosis may persist for several weeks. Eosinophilia may be
B lymphocytes that appear similar in morphology and immune pheno- present. Examination of marrow from a few patients has shown min-
type to the neoplastic B cells in hairy cell leukemia (Chap. 93). 42,43 imal increases in lymphocytes, but marked infiltration with lympho-
Although the lymphocytosis generally is not progressive, most cytes also has been observed. In some cases, the lymphocytosis has been
patients have small numbers of blood B cells with chromosomal abnor- found in association with acute infection by coxsackievirus B2. 61
malities. These abnormalities can include an additional isochromosome
+i(3q) and premature chromosome condensation, and/or the t(14;18) Bordetella pertussis
translocation involving the BCL-2 and immunoglobulin heavy-chain loci A marked increase in the number of lymphocytes occurs in patients
that typically is found in the neoplastic B cells of patients with follicular infected with the Gram-negative bacterium Bordetella pertussis. Abso-
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lymphoma (Chap. 99). 44–47 In another study of 43 patients, two-thirds of lute lymphocyte counts range from 8 to 70 × 10 /L, with a mean of
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patients had lymphocytes with independent chromosomal abnormalities, approximately 30 × 10 /L, involving all lymphocyte subsets. A nota-
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such as del(6q), +der, +8, or other polyploidy karyotypic abnormalities. 48,49 ble proportion of lymphocytes have cleaved nuclei, characteristic of the
In any one patient, these chromosomal abnormalities are restricted to B cells in cases of pertussis (see Chap. 73, Fig. 73–1C).
lymphocytes independent of their expression of immunoglobulin or light Lymphocytosis primarily results from failure of lymphocytes
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chains. For cases associated with smoking, these cytogenetic abnormal- to leave the blood because of pertussis toxin, which is released by the
ities apparently persist after the discontinuation of tobacco use. 36,51 The bacteria. Pertussis toxin is an adenosine diphosphate ribosylase that
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finding of such chromosome abnormalities is consistent with the notion modifies G proteins in mammalian lymphocytes. This inhibits the
that this disorder represents a preneoplastic state. Extensive proliferation capacity of lymphocytes to traffic from blood into lymphoid tissues,
of CD27+ IgM+IgD+ cells have been noted as well, which may explain the primarily through inhibition of chemokine receptors. Pertussis toxin
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finding of splenomegaly. Occasional reports of clonal immunoglobulin also may stimulate egress of maturing T cells from the thymus and may
gene rearrangements in this disorder suggest that polyclonal expansion in bind to neuraminic acid residues of T-cell surface glycoproteins to induce
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some cases may be followed by the emergence of one predominant clone. T-cell activation. 65,66 Despite high levels of vaccination, recent epidemics
Moreover, a small proportion of patients ultimately develop monoclonal have been noted primarily as a result of waning immunity in adults who
B-cell lymphoma or B-cell leukemia. 40,52,53 subsequently serve as a source of infection to household infants. 67
Large Granular Lymphocytosis
SECONDARY (REACTIVE) LYMPHOCYTOSIS Large granular lymphocytosis can result from expansions of NK cells,
Secondary lymphocytosis defines conditions associated with an increase CD8+ T cells, or, more rarely, CD4+ T cells. 68,69 In the most common form,
in the absolute number of lymphocytes secondary to a physiologic or the lymphocytosis is secondary to CD3–CD16+CD56+ NK cells and is
pathophysiologic response to infection, toxins, cytokines, or unknown termed NK lymphocytosis, in which NK cell counts typically approximate
factors. 4 × 10 /L, but can sometimes exceed 15 × 10 /L. The blood lympho-
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cytes of patients with T-cell large granular lymphocytosis should be eval-
Infectious Mononucleosis uated for clonal rearrangements in the T-cell receptor genes (Chap. 76),
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The most common reactive lymphocytosis is infectious mononucleo- which would be indicative of T-cell large granular lymphocytic leukemia
sis (see Table 79–1). In cases of mononucleosis secondary to infection (LGLL); LGLL is a heterogeneous disorder characterized by an increase
with Epstein-Barr virus (EBV), the atypical lymphocytes commonly in the number of blood large granular lymphocytes between 2 and 20 ×
consist of polyclonal populations of CD8+ T cells, γ/δ T cells, and 10 /L for more than 6 months without a clearly identified cause (see Chap.
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CD16+CD56+ NK cells that are stimulated in response to EBV- infected 94, Fig. 94–1). Currently NK cell lymphoproliferative disorder is consid-
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B cells (see Chap. 82, Fig. 82–1). A study prospectively evaluated ered as a provisional entity, distinct from T-LGLL and NK-LGLL in the
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university students to determine the incidence, risk factors, and viro- 2008 WHO (World Health Organization) classification. A retrospective
logic and immune correlates of disease severity. During a median of review compared clinical and pathologic features between patients with
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3 years of observation of EBV antibody-negative students, 66 subjects T-LGLL and chronic NK lymphocytosis. They noted that median age,
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experienced primary infection. Of these, 77 percent had infectious association with autoimmune diseases and hematologic malignancies
mononucleosis, 12 percent had atypical symptoms, and 11 percent were were similar between the two groups. However, neutropenia and associa-
asymptomatic. Although viremia was transient, median oral shedding tion with rheumatoid arthritis was less prevalent in NK cell lymphoprolif-
was 175 days. Increases were observed in numbers of NK cells and erative disorder than in T-LGLL.
CD8+ T cells but not in numbers of CD4+ T cells during acute infec- Large granular lymphocytosis has been observed in 20 percent of
tion. Severity of illness correlated with both blood EBV load (P = 0.015) allogeneic stem cell transplant recipients for a variety of malignancies
and CD8+ lymphocytosis (P = 0.0003). with a median onset of 312 days from transplant. CMV-seropositive
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