Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + LYMPHOCYTOSIS Download Section PDF Listen +++ +++ 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. ++Table Graphic Jump LocationTABLE 49–1CAUSES OF LYMPHOCYTOSISView Table||Download (.pdf) TABLE 49–1 CAUSES OF LYMPHOCYTOSIS Primary lymphocytosis Lymphocytic malignancies Acute lymphocytic leukemia (Chap. 54) Chronic lymphocytic leukemia and related disorders (Chap. 55) Prolymphocytic leukemia (Chap. 54) Hairy cell leukemia (Chap. 56) Adult T-cell leukemia (Chaps. 54 and 66) Leukemic phase of B-cell lymphomas (Chaps. 60, 61) Large granular lymphocytic leukemia (Chaps. 57, 66) Natural killer (NK) cell leukemia (Chap. 66) CD8+ T-cell large granular lymphocytic leukemia (Chap. 66) CD4+ T-cell large granular lymphocytic leukemia (Chap. 66) γ/δ T-cell large granular lymphocytic leukemia (Chap. 66) Monoclonal B-cell lymphocytosis (Chap. 55) Persistent polyclonal B cell lymphocytosis Reactive lymphocytosis Mononucleosis syndromes (Chap. 52) Epstein-Barr virus Cytomegalovirus Human immunodeficiency virus Herpes simplex virus type II Rubella virus Toxoplasma gondii Adenovirus Infectious hepatitis virus Dengue fever virus Human herpes virus type 6 (HHV-6) Human herpes virus type 8 (HHV-8) Varicella zoster virus Bordetella pertussis NK cell lymphocytosis (see Chap. 57) Stress lymphocytosis (acute) Cardiovascular collapse Acute cardiac failure Myocardial infarction Staphylococcal toxic shock syndrome Drug-induced Major surgery Sickle cell crisis Status epilepticus Trauma Hypersensitivity reactions Insect bite Drugs Persistent lymphocytosis (subacute or chronic) Cancer Cigarette smoking Hyposplenism Chronic infection Leishmaniasis Leprosy Strongyloidiasis Thymoma Source: Williams Hematology, 9th ed, Table 79–1. +++ 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. ++ FIGURE 49–1 Persistent polyclonal lymphocytosis of B lymphocytes. Blood film. A–C. Examples of the nuclear abnormality of lymphocytes in this disorder. The lymphocyte nucleus may be bilobed or segmented although not fully bilobed. Some are monolobed. D. Light-chain analysis. Immunoenzymatic method. Cytocentrifuge cell preparation. Anti-kappa immunoglobulin light chain tagged with peroxidase and anti-lambda light chain tagged with alkaline phosphatase. Note polyclonal reactivity of lymphocytes; some cells with surface kappa light chains (brownish) and some with surface lambda light chains (reddish). Molecular studies did not show immunoglobulin gene rearrangement. (Used with permission from Dr. Xavier Troussard, Laboratoire d’Hématologie CHU Côte de Nacre, Caen, France. Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ 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). ++ FIGURE 49–2 Blood films. A. Acute infectious lymphocytosis. The lymphocytosis in this disorder of childhood is composed of normal-appearing lymphocytes, which may vary somewhat in size as shown in the blood of this case. Note typical small lymphocyte with dense chromatin pattern and scant rim of cytoplasm and somewhat two larger lymphocytes with less dense chromatin pattern. B, C. Reactive lymphocytes. Large lymphocytes with an increased proportion of cytoplasm with basophilic cytoplasmic edges, often engaging neighboring red cells. Nucleoli may occasionally be evident. This variation in lymphocyte appearance can occur in a variety of disorders that provoke an immunologic response, including viral illnesses. They are indistinguishable in appearance by light microscopy from the reactive lymphocytes seen in infectious mononucleosis, viral hepatitis, or other conditions such as Dengue fever. D–F. Plasmacytoid lymphocytes. In this type of reactive lymphocytosis, the lymphocytes are large and have deep blue-colored cytoplasm, approaching the coloration of plasma cell cytoplasm, but they retain the nuclear appearance, cell shape, and cell size of a medium-size lymphocyte, and they do not develop a prominent paranuclear clear zone or markedly eccentric nuclear position as do most plasma cells. They may be seen in a variety of situations, including infections, drug hypersensitivity, and serum sickness-type reactions. (Reproduced with permission from Lichtman’s Atlas of Hematology, www.accessmedicine.com.) Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ 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 + LYMPHOCYTOPENIA Download Section PDF Listen +++ +++ 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. ++Table Graphic Jump LocationTABLE 49–2CAUSES OF LYMPHOCYTOPENIAView Table||Download (.pdf) TABLE 49–2 CAUSES OF LYMPHOCYTOPENIA Inherited causes Congenital immunodeficiency diseases (Chap. 50) Severe combined immunodeficiency disease Aplasia of lymphopoietic progenitor cells Adenosine deaminase deficiency Absence of histocompatibility antigens Absence of CD4+ helper cells Thymic alymphoplasia with aleukocytosis (reticular dysgenesis) Mutations in genes required for T-cell development Common variable immune deficiency Ataxia-telangiectasia Wiskott-Aldrich syndrome Immunodeficiency with short-limbed dwarfism (cartilage-hair hypoplasia) Immunodeficiency with thymoma Purine nucleoside phosphorylase deficiency Immunodeficiency with veno-occlusive disease of the liver Lymphopenia resulting from genetic polymorphism Acquired causes Aplastic anemia (Chap. 3) Infectious diseases Viral diseases Acquired immunodeficiency syndrome (Chap. 51) Severe acute respiratory syndrome West Nile encephalitis Hepatitis Influenza Herpes simplex virus Herpes virus type 6 (HHV-6) Herpes virus type 8 (HHV-8) Measles virus Other Bacterial diseases Tuberculosis Typhoid fever Pneumonia Rickettsiosis Ehrlichiosis Sepsis Parasitic diseases: acute phase of malaria infection Iatrogenic Immunosuppressive agents Antilymphocyte globulin therapy Alemtuzumab (CAMPATH 1-H) Glucocorticoids High-dose psoralen plus ultraviolet A treatment Stevens-Johnson syndrome Chemotherapy Platelet or stem cell apheresis procedures Radiation Major surgery Extracorporeal bypass circulation Renal or marrow transplant Thoracic duct drainage Hemodialysis Apheresis for donor lymphocyte infusion Systemic disease associated Autoimmune diseases Arthritis Systemic lupus erythematosus Sjögren syndrome Myasthenia gravis Systemic vasculitis Behçet-like syndrome Dermatomyositis Wegener granulomatosis Hodgkin lymphoma (Chap. 59) Carcinoma Idiopathic myelofibrosis Protein-losing enteropathy Heart failure Sarcoidosis Thermal injury Severe acute pancreatitis Strenuous exercise Silicosis Celiac disease Nutritional and dietary Ethanol abuse Zinc deficiency Idiopathic: idiopathic CD4+ T lymphocytopenia Source: Williams Hematology, 9th ed, Table 79–3. +++ 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. ++ For a more detailed discussion, see Sumithira Vasu and Michael A. Caligiuri: Lymphocytosis and Lymphocytopenia, Chap. 79 in Williams Hematology, 9th ed.