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Lymphcytosis

Relative lymphocytosis

Lymphocytes are small, mononuclear cells that migrate to areas of inflammation in both early and late stages of the process. They play an important role in immunologic reactions.

Normal lymphocyte count is in the rage between 16-45% of white blood cells (WBCs). Increased lymphocytes (lymphocytosis) in adults is defined as an absolute lymphocyte count greater than 4,000/mm3.

It is necessary to distinguish between absolute and relative lymphocytosis. Absolute lymphocytosis may be defined as an increase in blood lymphocytes above 4,000/mm3. Relative lymphocytosis occurs when there is an increased percentage of circulating lymphocytes, but the absolute number does not exceed 4,000/mm3. Relative, rather than absolute, leukocytosis occurs in a number of clinical situations, such as infancy, viral infections, connective tissue diseases, thyrotoxicosis and Addison's disease. Splenomegaly causes relative lymphocytosis as a result of splenic sequestration of granulocytes.

An example of relative lymphocytosis occurs in patients with neutropenia, when the decreased granulocyte count produces leukopenia and most remaining cells are lymphocytes. The absolute number of lymphocytes, however, remains normal.

 

Absolute lymphocytosis

Lymphocytes are small, mononuclear cells that migrate to areas of inflammation in both early and late stages of the process. They play an important role in immunologic reactions.

Normal lymphocyte count is in the rage between 16-45% of white blood cells (WBCs). Increased lymphocytes (lymphocytosis) in adults is defined as an absolute lymphocyte count greater than 4,000/mm3.

Lymphocytosis can be either primary or secondary. The reactive, or secondary, lymphocytoses are conditions that involve absolute increases in lymphocytes caused by physiologic or pathophysiologic responses to infection (especially viral), inflammation, toxins, cytokines, or unknown agents.

Lymphocytosis is also associated with stress and consequent release of epinephrine, such as that seen in patients who have had cardiovascular collapse, septic shock, sickle cell crisis, status epilepticus, trauma, major surgery, drug reactions, or hypersensitivity. Persistent lymphocytosis may be seen in patients with autoimmune disorders, sarcoidosis, hyposplenism, or cancer and in those who are long-term cigarette smokers.

Primary lymphocytosis, often called lymphoproliferative disease, include the leukemias, the lymphomas, and monoclonal B cell lymphocytosis.

Primary bone marrow disorders should be suspected in patients who present with extremely elevated white blood cell counts or concurrent abnormalities in red blood cell or platelet counts. Weight loss, bleeding or bruising, liver, spleen or lymph node enlargement, and immunosuppression also increase suspicion for a marrow disorder.[1]

The most common bone marrow disorders can be grouped into acute leukemias, chronic leukemias and myeloproliferative disorders. Patients with an acute leukemia are more likely to be ill at presentation, whereas those with a chronic leukemia are often diagnosed incidentally because of abnormal blood cell counts. White blood cell counts above 100,000 per mm3 (100 X 109 per L) represent a medical emergency because of the risk of brain infarction and hemorrhage.

References:
==========
Abramson N, Melton B. Leukocytosis: Basics of Clinical Assessment. Am Fam Physician 2000;62:2053-60.

 

The most common causes of reactive lymphocytosis are viral infections: Epstein-Barr virus, cytomegalovirus, herpes simplex virus, varicella-zoster virus, rubella, human T cell lymphotropic virus type I (HTLV-I), HIV, adenovirus, or one of the hepatitis viruses is frequently responsible for the disease. Other pathogens that produce lymphocytosis are Toxoplasma gondii and, in children, Bordetella pertussis (which causes the lymphocyte count to rise to as high as 70,000/mm3).

B cells control the antigen-antibody response are said to have “memory”. They are also the source of serum immunoglobulins. T cells are responsible for cellular immune response  and include CD4+ T-helper cells, killer cells, cytotoxic cells, and CD8+ T-suppressor cells.

All lymphocytes are manufactured in the bone marrow. B lymphocytes mature in the bone marrow, and T lymphocytes mature in the thymus gland.
Plasma cells are similar in appearance to lymphocytes. They have abundant blue cytoplasm and an eccentric, round nucleus. Plasma cells are not normally present in blood.
 

Pathophysiology: Most circulating lymphocytes are T cells, which traffic continuously between the blood, the tissues, and the lymph nodes until they become activated by exposure to specific antigen on antigen-presenting cells.

Normal lymphocyte count is in the rage between 16-45% of white blood cells (WBCs).

Increased lymphocytes (lymphocytosis) in adults is defined as an absolute lymphocyte count greater than 4,000/mm3. In children with the disease, lymphocyte counts are higher than in adults and may be as high as 20,000/mm3 in the first year of life. The blood film of any patient with lymphocytosis should be carefully examined to determine the morphology and diversity of the lymphocytes (e.g., reactive lymphocytes, large granular lymphocytes, blasts, or smudge cells). 

Lymphocytosis can be either primary or secondary. Primary lymphocytosis, often called lymphoproliferative disease, is caused by dysregulation in the production of lymphocytes. The primary lymphocytoses include the leukemias (e.g., chronic lymphocytic leukemia, acute lymphocytic leukemia, hairy-cell leukemia, or large granular lymphocyte leukemia), the lymphomas, and monoclonal B cell lymphocytosis [see Table 7].

The reactive, or secondary, lymphocytoses are conditions that involve absolute increases in lymphocytes caused by physiologic or pathophysiologic responses to infection, inflammation, toxins, cytokines, or unknown agents. The most common causes of reactive lymphocytosis are viral infections: Epstein-Barr virus, cytomegalovirus, herpes simplex virus, varicella-zoster virus, rubella, human T cell lymphotropic virus type I (HTLV-I), HIV, adenovirus, or one of the hepatitis viruses is frequently responsible for the disease. Other pathogens that produce lymphocytosis are Toxoplasma gondii and, in children, Bordetella pertussis (which causes the lymphocyte count to rise to as high as 70,000/mm3). Lymphocytosis is also associated with stress and consequent release of epinephrine, such as that seen in patients who have had cardiovascular collapse, septic shock, sickle cell crisis, status epilepticus, trauma, major surgery, drug reactions, or hypersensitivity. Persistent lymphocytosis may be seen in patients with autoimmune disorders, sarcoidosis, hyposplenism, or cancer and in those who are long-term cigarette smokers.

It is necessary to distinguish between absolute and relative lymphocytosis. Absolute lymphocytosis may be defined as an increase in blood lymphocytes above 4.0 ´ 109 per liter. Relative lymphocytosis occurs when there is an increased percentage of circulating lymphocytes, but the absolute number does not exceed 4.0 ´ 109 per liter. An example of relative lymphocytosis occurs in patients with neutropenia, when the decreased granulocyte count produces leukopenia and most remaining cells are lymphocytes. The absolute number of lymphocytes, however, remains normal. Conditions that may be associated with elevated peripheral lymphocyte counts are listed in Box 80-1.
Moderate increases in reactive lymphocytes are seen as a characteristic response to viruses and other infections, especially in children. Increases also occur in a wide variety of other situations, including primary and secondary immune responses, hypersensitivity reactions, and autoimmune disorders.

The differential diagnosis of marked lymphocytosis composed solely of normal small lymphocytes is limited in scope. In the adult the major consideration is chronic lymphocytic leukemia. This diagnosis may best be confirmed by demonstrating the monoclonal B-cell nature of the proliferation and coexpression of the CD5 antigen by appropriate lymphocyte surface marker studies. In childhood and adolescence the chief considerations are pertussis and acute infectious lymphocytosis.



occurs in infectious diseases (infectious mononucleosis, tuberculosis, viral pneumonia, infectious hepatitis, cholera, rubella, brucellosis, systemic syphilis, toxoplasmosis, pertussis); and some neoplastic conditions (lymphocytic leukemia, malignant lymphoma).

 


 

TABLE 4
Etiology of Lymphocytosis

Absolute lymphocytosis
Acute infections: cytomegalovirus infection, Epstein-Barr virus infection, pertussis, hepatitis, toxoplasmosis
Chronic infections: tuberculosis, brucellosis
Lymphoid malignancies: chronic lymphocytic leukemia
Relative lymphocytosis
Normal in children less than 2 years of age
Acute phase of several viral illnesses
Connective tissue diseases
Thyrotoxicosis
Addison's disease
Splenomegaly with splenic sequestration
TABLE 5
Clinical Factors Increasing Suspicion of an Underlying Bone Marrow Disorder

Leukocytosis: white blood cell count greater than 30,000 per mm3 (30 X 109 per L)*
Concurrent anemia or thrombocytopenia
Organ enlargement: liver, spleen or lymph nodes
Life-threatening infection or immunosuppression
Bleeding, bruising or petechiae
Lethargy or significant weight loss

*--If the white blood cell count is greater than 100,000 per mm3 (100 X 109 per L), a hematology consultation should be promptly obtained.


 

 

Table 7 - Causes of Lymphocytosis
Lymphoproliferative disorders (primary lymphocytosis)
Leukemia
Acute lymphocytic leukemia
Chronic lymphocytic leukemia
Hairy-cell leukemia
Large granular lymphocyte leukemia
Lymphoma
Monoclonal B cell lymphocytosis
Reactive (secondary) lymphocytosis
Viral infection (mostly like with EBV, CMV, HIV, HSV, VZV, rubella, adenovirus, or hepatitis virus)
Toxoplasmosis
Pertussis
Stress
Acute
Cardiovascular collapse
Septic shock
Sickle cell crisis
Status epilepticus
Trauma
Surgery
Drugs
Hypersensitivity
Chronic
Autoimmune disorders
Cancer
Hyposplenism
Sarcoidosis
Cigarette smoking
CMV---cytomegalovirus EBV---Epstein-Barr virus HSV---herpes simplex virus VZV---varicella-zoster virus
 

 


 

LYMPHOCYTE COUNTS.


 

Lymphopenia


Lymphocytes are small, mononuclear cells without specific granules. These agranulocytes are motile cells that migrate to areas of inflammation in both early and late stages of the process. These cells are the source of serum immunoglobulins and of cellular immune response and play an important role in immunologic reactions. All lymphocytes are manufactured in the bone marrow. B lymphocytes mature in the bone marrow, and T lymphocytes mature in the thymus gland. B cells control the antigen-antibody response that is specific to the offending antigen and is said to have “memory.” The T cells, the master immune cells, include CD4+ T-helper cells, killer cells, cytotoxic cells, and CD8+ T-suppressor cells (see Chapter 8 for further tests of T cells).
Plasma cells are similar in appearance to lymphocytes. They have abundant blue cytoplasm and an eccentric, round nucleus. Plasma cells are not normally present in blood.

Most circulating lymphocytes are T cells, which traffic continuously between the blood, the tissues, and the lymph nodes until they become activated by exposure to specific antigen on antigen-presenting cells.

Normal Lymphocyte Count: 16-45% of white blood cells (WBCs).

Decreased Lymphocytes: Lymphopenia. CLINICAL OCCURRENCE: Idiopathic idiopathic lymphopenia; Infectious acute infections (viral, HIV), chronic HIV; Metabolic/Toxic drugs (corticosteroids, irradiation therapy, cancer chemotherapy); Neoplastic carcinoma, lymphoma.
 

Section 5 / Chapter VII - Nonmalignant Disorders of Leukocytes
Table 8 - Causes of Lymphocytopenia
Inherited
Congenital immunodeficiency diseases
Severe combined immunodeficiency
Adenosine deaminase deficiency
Purine-nucleoside phosphorylase deficiency
Reticular dysgenesis
Ataxia-telangiectasia
Wiskott-Aldrich syndrome
Cartilage-hair hypoplasia
Idiopathic CD4+ T lymphocytopenia
Acquired
Infection
Viral (e.g., with HIV, a hepatitis virus, influenza virus, or respiratory syncytial virus)
Bacterial (e.g., typhoid fever, pneumonia, sepsis, or tuberculosis)
Aplastic anemia
Autoimmune diseases
Hodgkin disease
Sarcoidosis
Renal failure
Protein-losing enteropathies
Chylous ascites
Zinc deficiency
Chronic alcohol ingestion
Immunosuppressive agents (e.g., antihymocyte globulin, corticosteroids, chemotherapeutic agents, and radiation)

 

Lymphocytopenia is defined as a total lymphocyte count less than 1,000/mm3. Because in adults 80% of lymphocytes are T cells, most cases of lymphocytopenia are caused by a reduction in the T cell count. The mechanisms of lymphocytopenia are often unknown, and the causes are usually differentiated as inherited or acquired.

Inherited lymphocytopenias are usually caused by congenital immunodeficiency diseases. These diseases include severe combined immunodeficiency (e.g., adenosine deaminase deficiency, purine-nucleoside phosphorylase deficiency, and reticular dysgenesis), ataxia-telangiectasia, Wiskott-Aldrich syndrome, and cartilage-hair hypoplasia [see Table 8]. In addition, some persons have idiopathic CD4+ T cell lymphocytopenia.

Acquired lymphocytopenia can be seen in patients with viral infections, such as HIV infection, hepatitis, influenza, and respiratory syncytial virus infection; in patients with certain bacterial infections, such as typhoid fever, pneumonia, sepsis, and tuberculosis; and in patients with aplastic anemia, autoimmune diseases, Hodgkin disease, sarcoidosis, renal failure, protein-losing enteropathies, and chylous ascites. Zinc deficiency and long-term alcohol ingestion are also associated with lymphocytopenia. Finally, immunosuppressive agents, such as antithymocyte globulin, corticosteroids, chemotherapeutic agents, and radiation, also produce lymphocytopenia.
 

 

TABLE 135-4. CAUSES OF LYMPHOCYTOPENIA
Inherited Causes Acquired Causes
Aplasia of lymphopoietic stem cells
Severe combined immunodeficiency associated with defect in interleukin-2 receptor γ-chain, deficiency of ADA or PNP or unknown
Ataxia-telangiectasia
Wiskott-Aldrich syndrome
Immunodeficiency with thymoma
Cartilage-hair hypoplasia
Idiopathic CD4+ T lymphocytopenia
Infectious diseases, including AIDS, hepatitis, influenza, TB, typhoid fever, sepsis
Iatrogenic after administration of immunosuppressive therapy, glucocorticoids, high-dose psoralen and ultraviolet A irradiation therapy, cytotoxic chemotherapy, radiation, thoracic duct drainage
Systemic disease associated with autoimmune diseases; eg, SLE, myasthenia gravis, Hodgkin's disease, protein-losing enteropathy, renal failure, sarcoidosis, thermal injury, aplastic anemia
Dietary deficiency associated with ethanol abuse, zinc deficiency
ADA = adenosine deaminase; PNP = purine nucleoside phosphorylase.
Adapted from Boxer LA: "Approach to the patient with leukopenia," in Textbook of Internal Medicine, ed. 3, edited by WN Kelley. Philadelphia, Lippincott-Raven Publishers, 1997, pp. 1299 -1305.