Chapter 49: Lymphocytosis and Lymphocytopenia

Definition

• In adults, the absolute lymphocyte count exceeds 4.0 × 10⁹/L.

• Normal lymphocyte count in childhood is higher than adults (mean ~6.0 × 10⁹/L) (see Chap. 1).

• Table 49–1 lists conditions associated with lymphocytosis.

• Examine blood film to determine if there is abnormal prevalence of:

  — Reactive lymphocytes, associated with infectious mononucleosis (see Chap. 52)

  — Large granular lymphocytes, associated with large granular lymphocyte leukemia (see Chap. 57)

  — Small lymphocytes and smudge cells, associated with chronic lymphocytic leukemia (CLL) (see Chap. 55)

  — Small cleaved lymphocytes, associated with low- or intermediate-grade lymphomas (see Chap. 61)

  — Blasts, associated with acute lymphocytic leukemia (see Chap. 54)

• Several key tests permit discrimination between polyclonal and monoclonal disorders. Flow cytometric immunophenotyping of cell surface markers (CD), serum protein electrophoresis and immunofixation for monoclonal immunoglobulins, studies of T-cell–receptor gene rearrangement, or clonal cytogenetic findings can distinguish monoclonal lymphocytosis (B or T lymphocytic leukemia or lymphoma) from polyclonal (reactive) lymphocytosis.

Primary Clonal Lymphocytosis

• Neoplastic (monoclonal) proliferation of B cells, T cells, or natural killer (NK) cells

• Monoclonal B-cell lymphocytosis (see Chap. 55)

  — There are no associated clinical manifestations.

  — Some patients may develop CLL or another type of progressive lymphoproliferative disease (see Chap. 55).

• Chronic natural killer (NK) cell lymphocytosis (see Chap. 57)

  — CD3–CD16+CD56+ lymphocytes are present.

  — Approximately 60% of cases have no other signs or symptoms.

  — Others may have blood cytopenias, especially neutropenia, neuropathy, and splenomegaly.

• Acute and chronic lymphocytic leukemias and lymphomas with blood involvement (see Chap. 53)

Primary Polyclonal Lymphocytosis

• Persistent polyclonal lymphocytosis of B lymphocytes

  — A high proportion of lymphocytes have bilobed nuclei or have other nuclear abnormalities (Figure 49–1).

  — Lymphocytes are “polyclonal” in their expression of immunoglobulin (Figure 49–1).

  — This is commonly associated only with mild splenomegaly and/or raised serum IgM but can have features that resemble those of patients with monoclonal B-cell malignancies.

  — Most patients have small numbers of B cells with chromosomal abnormalities. These most commonly involve chromosomes 3, 14 (at the immunoglobulin heavy chain locus), and 18 (at the BCL-2 locus).

  — This condition is generally not progressive, although some cases may evolve into a monoclonal lymphoproliferative disease.

Secondary (Reactive) Lymphocytosis

• Lymphocytosis secondary to a physiologic or pathophysiologic response to infection of B lymphocytes, toxins, cytokines, or unknown factors

Infectious Mononucleosis

• This disorder is caused by the Epstein-Barr virus infection (see Chap. 52).

• Lymphocytosis is principally from a polyclonal increase in CD8+ T lymphocytes.

• Characteristic reactive lymphocytes are evident on blood film (see Figure 49–2).

Lymphocytosis Induced by Other Infectious Diseases

• This disease is usually viral (eg, hepatitis A virus).

• It is characterized morphologically by reactive lymphocytes (see Figure 49–2).

Acute Infectious Lymphocytosis

• This childhood disease usually affects individuals aged 2 to 10 years.

• It is characterized by marked lymphocytosis of polyclonal morphologically normal T lymphocytes and NK cells (see Figure 49–2).

• Although an infection of unknown etiology, some cases have been associated with acute infection by coxsackievirus B2, toxoplasmosis, or falciparum malaria.

• The disease is usually asymptomatic, but fever, abdominal pain, or diarrhea may be present for a few days.

• No enlargement of liver or spleen occurs.

• Lymphocytosis is usually 20 to 30 × 10⁹/L but can be as high as 100 × 10⁹/L.

• Lymphocytosis may persist for several weeks after clinical symptoms have subsided.

• Marrow shows variable increase in number of lymphocytes.

• Serum is negative for heterophil antibodies.

Bordetella pertussis Infection

• Lymphocytosis of morphologically normal CD4+ T cells occurs, ranging from 8 to 70 × 10⁹/L.

• Lymphocytosis is caused by failure of lymphocytes to leave the blood because of pertussis toxin, an adenosine diphosphate (ADP)-ribosylase that inhibits chemokine receptor signaling.

• Characteristic clefted nuclei in a proportion of lymphocytes are usually evident.

• Pertussis toxin also may induce T-cell activation by binding to neuraminic acid residues of T-cell–surface glycoproteins.

Large Granular Lymphocytosis

• This type of lymphocytosis can result from increase in NK cells, CD8+ cells or, rarely, CD4+ cells.

• Most common form is result of expansion of CD3-CD16+CD56+ NK cells.

• Termed NK lymphocytosis, NK cell counts range from 4 to 15 × 10⁹/L.

• Expansion of NK cells or T cells may represent an exaggerated response to systematic infections and/or immune deregulation.

• It may be associated with rheumatoid arthritis (< 1.0% of cases).

• See Chap. 57.

Drug-Induced Lymphocytosis

• Dasatinib and ibrutinib are associated with lymphocytosis when used for chronic myelogenous leukemia and CLL, respectively.

Stress Lymphocytosis (Acute)

• Lymphocytosis appears promptly as a consequence of a redistribution of lymphocytes induced by adrenaline.

• Lymphocytosis, often greater than 5 × 10⁹/L, reverts to normal or low levels within hours.

• This condition may be associated with trauma, surgery, acute cardiac failure, septic shock, myocardial infarction, sickle cell crisis, or status epilepticus.

Hypersensitivity Reactions

• Reactions to insect bites may be associated with a large granular lymphocytic lymphocytosis and lymphadenopathy.

Persistent Chronic Polyclonal Lymphocytosis

• Cancer:

  — Solid tumors

  — Thymoma, probably a result of release of thymic hormones by neoplastic thymic epithelium

• Postsplenectomy lymphocytosis.

  — Can persist for prolonged periods after splenectomy (eg, > 50 months)

• Chronic inflammatory diseases:

  — Systemic diseases associated with inflammation (eg, sarcoidosis, Wegener granulomatosis)

• Autoimmune diseases (eg, rheumatoid arthritis):

  — In rheumatoid arthritis patients with Felty syndrome (associated neutropenia), important to rule out T-cell large granular lymphocytic leukemia (see Chap. 57)

• Cigarette smoking:

  — Perhaps a polyclonal increase in CD4+ T cells and in B cells (some binuclear), especially in HLA-DR7-positive women

  — Possible resolution on cessation of smoking

Definition

• Absolute lymphocyte count is less than 1.0 × 10⁹/L.

• Usual cause is a decrease in CD4+ (helper) T cells because this cell type accounts for about half of all blood lymphocytes.

• Table 49–2 lists the conditions associated with lymphocytopenia.

Inherited Causes

• This stem cell abnormality, either quantitative or qualitative, results in ineffective lymphopoiesis (see Chap. 50).

• Other abnormalities, such as the Wiskott-Aldrich syndrome, result in premature destruction of T cells because of cytoskeletal abnormalities (see Chap. 50).

Acquired Lymphocytopenia

Infectious Diseases

• Acquired immunodeficiency syndrome (AIDS); destruction of CD4+ (helper) T cells infected with human immunodeficiency virus-1 or -2 (HIV-1 or HIV-2) (see Chap. 51)

• Other viral diseases such as influenza

• Active tuberculosis; resolution of lymphocytopenia usually 2 weeks after initiating appropriate therapy

Iatrogenic

• Radiotherapy, chemotherapy, or administration of antilymphocyte globulin or alemtuzumab (CAMPATH-1H)

• Treatment of psoriasis with psoralen and ultraviolet A irradiation, which may result in T-lymphocyte lymphopenia

• Glucocorticoid therapy; mechanism unclear, possibly involving redistribution as well as cell destruction

• Major surgery, possibly from redistribution of lymphocytes

• Thoracic duct drainage, because lymphocytes are removed from the body

• Platelet apheresis, because lymphocytes, as well as platelets, are removed from the body, resulting in transient lymphopenia

Systemic Disease Associated with Lymphocytopenia

• Systemic lupus erythematosus that is probably mediated by autoantibodies

• Sarcoidosis, probably a consequence of impaired T-cell proliferation

• Protein-losing enteropathy, in which lymphocytes may be lost from the body

Burns

• Profound T-cell lymphocytopenia caused by redistribution from blood to tissues

Nutritional/Dietary Factors

• Zinc deficiency (Zinc is necessary for normal T-cell development and function.)

• Excess alcohol intake, which may impair lymphocytic proliferation

Idiopathic CD4+ T Lymphocytopenia

• This condition is defined as a CD4+ T-lymphocyte count less than 3 × 10⁸/L on two separate occasions without serologic or virologic evidence of HIV-1 or HIV-2 infection.

• Congenital immunodeficiency diseases, such as common variable immunodeficiency, should be excluded (see Chap. 50).

• Decrease of CD4+ cell counts is generally gradual.

• More than half of reported cases had opportunistic infections indicative of cellular immune deficiency (eg, Pneumocystis jiroveci pneumonia). Such patients are classified as having idiopathic CD4+ T-lymphocytopenia and severe unexplained HIV-seronegative immune suppression. In contrast to patients infected with HIV, these patients generally have stable CD4+ counts over time and reductions in other lymphocyte subgroups, and they may experience complete or partial spontaneous reversal of the CD4+ T lymphocytopenia.