INTRODUCTION — Lymphocytes are a subset of white blood cells (WBC) that form an integral part of the immune system. They facilitate the body's humoral and cellular immunity against foreign proteins and pathogens. An increase in circulating lymphocytes (lymphocytosis) can be seen following infections such as infectious mononucleosis and pertussis, or in lymphoproliferative disorders such as acute and chronic lymphocytic leukemia. A similar array of disorders can cause a decrease in lymphocyte counts (lymphocytopenia), although immunodeficiency states must also be considered, especially in infants and young children.
The various causes of lymphocytosis and lymphocytopenia in children will be reviewed here. Information on acute lymphoblastic leukemia (ALL), neutrophilia, neutropenia, and lymphocytosis/lymphocytopenia in adults is presented separately.
●Neutrophilia – (See "Approach to the patient with neutrophilia".)
●Neutropenia – (See "Overview of neutropenia in children and adolescents".)
●Adults – (See "Approach to the adult with lymphocytosis or lymphocytopenia".)
DEFINITIONS AND NORMAL VALUES — The absolute lymphocyte count (ALC) is equal to the product of the total white blood cell count (WBC) and the percentage of lymphocytes on the WBC differential:
ALC = WBC (cells/microL) x percent lymphocytes ÷ 100
Lymphocytosis — In individuals older than 12 years, lymphocytosis is defined as an ALC >4000 cells/microL (also expressed as >4000/mm3 or >4.0 x 109/L). Levels of blood lymphocytes are higher in neonates and young children, who may have normal blood absolute lymphocyte counts as high as 8000/microL. While these definitions apply in general, increases in certain subpopulations of lymphocytes can be quite significant even though the normal value for total ALC has not been exceeded.
However, chronic clonal proliferations of lymphocytes are vanishingly rare in children. Lymphocytosis is usually due to infectious causes (table 1) or chronic inflammatory states with relative neutropenia. When the possibility of malignancy is considered in adults, age and ALC are the best predictors of abnormal immunophenotype by flow cytometry. The ALC cutoff values are >4.0 x 109/L for patients over 67 years of age and 6.7 x 109 cells/L for patients between 50 and 67 years of age. Approximately 1.3 percent of individuals over 50 years of age will have an ALC >4.0 x 109, and 59 percent of these will have will have an abnormal immunophenotype [1,2]. Causes of clonal lymphocytosis are discussed in detail separately.
Lymphocytopenia — Lymphocytopenia has been variously defined in older children as an ALC <1500 cells/microL. Infants normally have higher lymphocyte numbers, and lymphocytopenia is usually defined as an ALC <4500 cells/microL in children under eight months of age . (See 'Lymphocytopenia' below.)
Lymphocyte subpopulations — Circulating blood lymphocytes include populations of T cells, B cells, and natural killer (NK) cells. Their normal relative proportions in the blood are:
●T cells (eg, CD3+ cells) – 60 to 80 percent
●B cells (eg, CD20+ cells) – 10 to 20 percent
●NK cells (eg, CD56+ cells) – 5 to 10 percent
The normal relative proportions of T cell subtypes in the blood are:
●Helper/inducer T cells (ie, CD4+ T cells) – 60 to 70 percent
●Suppressor/cytotoxic T cells (ie, CD8+ T cells) – 30 to 40 percent
Clonal versus reactive lymphocytosis — Lymphocytosis can be either a reactive polyclonal proliferation or a clonal expansion.
●Reactive lymphocytosis - This term refers to a polyclonal lymphocytosis in a patient without a history of a hematologic disorder, who has a medical condition likely to be associated with lymphocytosis, and in whom the lymphocyte count normalizes, or is expected to normalize, within less than two months after resolution of this condition. Examples are viral infection and pertussis.
●Clonal lymphocytosis – This term refers to lymphocytosis and an established diagnosis of an acute or chronic lymphoproliferative disorder. Examples are monoclonal B cell lymphocytosis (MBL), chronic lymphocytic leukemia (CLL), and lymphoproliferative disorders of large granular lymphocytes.
While malignant expansions of lymphocytes are clonal, non-malignant clonal expansions of T cells and B cells are now recognized. These disorders can remain stable or can progress to malignancy. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Monoclonal B cell lymphocytosis' and "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'T cell clonopathy of unknown significance'.)
Clonality in the malignant lymphoproliferative disorders is usually determined by the presence of one or more defining abnormalities:
●An abnormal karyotype characteristic of the disease in question, such as the chromosomal translocation t(12;21) seen in many cases of childhood ALL (see "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma").
●A clonal rearrangement of the immunoglobulin genes, as seen in various B cell lymphoma/leukemias (see "General aspects of cytogenetic analysis in hematologic malignancies").
●The presence of a single light chain (eg, either kappa or lambda, but not both) in the circulating lymphoid cells, as seen in B cell CLL (see "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Immunophenotype').
●A clonal rearrangement of the T cell receptor, as seen in various T cell leukemias, such as T cell LGL leukemia (see "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Immunophenotype').
●Malignant NK cell conditions, by definition, will not show clonal rearrangements of immunoglobulin genes or the T cell receptor. However, as in aggressive NK cell leukemia, they may show Epstein-Barr virus (EBV) clonally integrated into cellular DNA  and/or may show clonal chromosomal abnormalities.
EVALUATION OF THE CHILD WITH LYMPHOCYTOSIS — A complete history and physical examination, together with a complete blood count (CBC) and examination of the peripheral blood smear are essential for initial evaluation of the child with lymphocytosis. In particular, one should determine if there is any history of recent infection that could explain the lymphocytosis.
The differential diagnosis will depend on the age of the patient and the symptoms.
●In children, presence of "atypical" or "viral" lymphocytes is quite common. The presence of significant lymphadenopathy or splenomegaly is suggestive of EBV infection, even in the absence of systemic symptoms. EBV serology is indicated in most cases of lymphocytosis in children and young adults.
●The presence of anemia, thrombocytopenia, or neutropenia in conjunction with lymphocytosis is suggestive of a malignant process and warrants immediate referral to a hematologist. If the lymphocytosis is of moderate degree and present on repeated measurements over time, flow cytometry with lymphocyte subset analysis should be done. Hematologic consultation should be obtained.
Blood lymphocyte morphology — Reactive lymphocytosis can be confused with malignant lymphocytosis (ie, the various leukemic states) by an inexperienced observer viewing the Wright-Giemsa-stained blood smear. Certain phenotypic characteristics may suggest a reactive or a malignant cause of the lymphocytosis, which could be confirmed by additional testing.
Reactive lymphocytosis — In general, reactive lymphocytosis is due to the presence in the peripheral blood of one of two types of lymphocytes:
●An absolute increase in mature normal-appearing small lymphocytes, as seen in pertussis and infectious lymphocytosis (picture 1).
●An absolute increase in larger lymphocytes with abundant basophilic cytoplasm and a large irregularly-shaped nucleus containing a rare nucleolus. Infectious mononucleosis during the second and third week of illness results in a marked increase in these larger forms of lymphocytes, so called "atypical", "transformed", or "lymph variants" (picture 2). Similar findings can be seen in the other viral illnesses listed in the table (table 1).
Malignant lymphocytosis — A number of different types of lymphoid cells may appear in the peripheral blood in the various malignant lymphoproliferative disorders. The early phases of B cell, T cell, or NK cell lymphoproliferative malignancies can mimic benign polyclonal or reactive lymphocytosis. Bone marrow, immunophenotyping, gene rearrangement studies, and/or cytogenetic studies are required to differentiate chronic lymphocytic leukemia or, sometimes, T cell leukemia from benign lymphocytosis.
Particularly in infants and very young children, normal peripheral lymphocytes can appear immature and can be mistaken for lymphoblasts by individuals not accustomed to looking at pediatric blood smears. Similarly, bone marrows of young children can contain hematogones (ie, normal maturing B cell precursors) that look immature and can be difficult to distinguish morphologically from lymphocytic leukemia blasts. They can be identified on flow cytometry. Hematogones comprise up to 6.4 percent of peripheral lymphocytes in 60 percent of infants less than one month of age , and can comprise 0.01 to 1.3 percent of WBCs in adults by sensitive flow cytometry methods [6,7].
Usually by the time the child has evidence of significant malignant lymphocytosis, there are other findings in the blood count (eg, anemia, neutropenia, thrombocytopenia) that suggest the diagnosis of leukemia. Complaints of bone pain, especially back or hip pain, which are very uncommon in children, as well as lymphadenopathy or hepatosplenomegaly, are other worrisome findings in the face of lymphocytosis. Malignant disorders of lymphocytes are discussed separately. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Staging and prognosis of chronic lymphocytic leukemia".)
Some lymphoid malignancies may have varying numbers of lymphoid cells in the peripheral blood as part of the disease process. While they may be distinctive enough to suggest the underlying diagnosis, this is a very uncommon presentation in pediatric lymphoid malignancies other than leukemia.
Lymphoblasts in acute lymphoblastic leukemia (ALL) can have varied morphologies where the blasts have essentially no cytoplasm (picture 3), abundant bluish cytoplasm, or deep blue cytoplasm of Burkitt type lymphoblasts (picture 4). (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma", section on 'Morphology' and "Evaluation of the peripheral blood smear", section on 'Worrisome findings'.)
CAUSES OF REACTIVE LYMPHOCYTOSIS — The usual cause of reactive lymphocytosis is one of a variety of viral infections, most frequently observed in children and young adults (table 1).
Infectious mononucleosis — Epstein-Barr virus (EBV) is the major cause of infectious mononucleosis, which is associated with a marked reactive "atypical" lymphocytosis (picture 2). These atypical lymphocytes peak during the second and third week of illness, and persist for as long as two months [8,9]. Oral shedding of virus continues for a median of 174 days and viremia for as long as 90 days in college students . (See "Infectious mononucleosis", section on 'Transmission'.)
Mononucleosis syndrome — A clinical picture resembling infectious mononucleosis (mononucleosis syndrome) may be caused by a number of infectious agents other than EBV. The two most important entities to include in the differential diagnosis of the mononucleosis syndrome are infections with cytomegalovirus (CMV) and the human immunodeficiency virus (HIV-1).
●Cytomegalovirus (CMV), in a substantial minority of cases, causes the infectious mononucleosis syndrome . (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults".)
●During primary infection with HIV-1, patients may present with a mononucleosis syndrome. This presentation of primary HIV infection is occasionally associated with a concomitant CMV infection [12-14]. In primary HIV the peripheral blood lymphocytosis has an immunophenotype pattern of CD3+/CD8+ (ie, suppressor/cytotoxic T cells) . (See "Acute and early HIV infection: Pathogenesis and epidemiology" and "The natural history and clinical features of HIV infection in adults and adolescents".)
Other viral illnesses — Human T-lymphotropic virus type I (HTLV-I) infection has resulted in a self-limited immature T cell lymphocytosis as high as 20,000/microL, evolving into a mature T cell lymphocytosis with a CD4/CD8 ratio of 4.5:1 . Patients with mumps, varicella, influenza, hepatitis, rubella, or measles infections usually have reactive lymphocytosis as a feature of their illness .
Infectious lymphocytosis — A number of viruses including coxsackie virus B2, poliovirus, and other enteroviruses, have been associated with a benign condition called infectious lymphocytosis in children [21-23]. Affected patients have total white blood cell counts ranging from 20,000 to 100,000/microL with 60 to 90 percent small mature T-lymphocytes [21-23]. The illness is often accompanied by mild eosinophilia and subsides over 4 to 10 weeks. The diagnosis is usually made by chance when a blood test is performed. Most patients are asymptomatic, although fever, respiratory signs and symptoms, diarrhea or abdominal pain, and rarely meningoencephalitis or morbilliform rash may occur [21,22].
Pertussis — Acute bacterial infections rarely produce lymphocytosis, except for pertussis (whooping cough), due to infection with Bordetella pertussis. In one study of 11 children, the absolute lymphocyte count ranged from 6500 to 54,800/microL, with a mean of 20,300/microL . Buffy coat smears revealed a significant increase in small lymphocytes with convoluted and cleaved nuclei; mean percentages of circulating WBC were 21 percent B cells and 53 percent T cells (ie, normal percentages by immunophenotype) .This increase in lymphocyte numbers appears to result from a block in the normal extravasation of lymphocytes from the blood into lymph nodes rather than an increase in lymphocyte production.
By contrast, when an identical clinical illness is caused by B. parapertussis, lymphocytosis is not observed. In one study of 114 patients, 38 of whom had B. parapertussis infection and the remainder B. pertussis, the mean leukocyte and lymphocyte counts were significantly lower in the former infection (7600 versus 12,500/microL and 3500 versus 7800/microL, respectively) . Both B. pertussis and B. parapertussis express pertussis toxin; B. pertussis also appears to produce a lymphocytosis-promoting factor toxin .
While the presence of lymphocytosis is not very specific for the diagnosis of pertussis, the absence of lymphocytosis makes pertussis unlikely . (See "Pertussis infection in adolescents and adults: Clinical manifestations and diagnosis" and "Pertussis infection in infants and children: Clinical features and diagnosis".)
Cat scratch disease and other chronic bacterial infections — Bartonella henselae causes cat scratch disease, characterized by solitary lymphadenopathy and systemic signs and symptoms of chronic inflammation. Large atypical lymphocytes may be seen on the blood smear, usually with mild eosinophilia and monocytosis, anemia, or thrombocytopenia . Other systemic chronic infections such as rickettsial infection, tuberculosis, brucellosis, and syphilis often show a similar blood picture. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease".)
Toxoplasmosis — Toxoplasmosis usually produces an asymptomatic infection or lymphadenopathy in immunocompetent patients but may cause disseminated manifestations in immunocompromised hosts. The lymphadenopathy involves multiple lymph node sites and, in one-third of cases, there is associated hepatosplenomegaly. As noted above, the hematologic picture may produce the mononucleosis syndrome (ie, mimic that seen in infectious mononucleosis), with lymphocytosis and large reactive atypical lymphocytes; eosinophilia occurs in 10 to 20 percent of cases [18,28].
Babesiosis — Babesiosis is a tick-borne disease caused by Babesia microti in the United States; it is endemic in Martha's Vineyard, Nantucket, and Long Island. It is also caused by Babesia divergens in Europe. (See "Babesiosis: Microbiology, epidemiology, and pathogenesis".)
As is true for Plasmodium parasites, Babesia infects red blood cells, causing hemolytic anemia; clinical manifestations closely resemble malaria. The organisms can be seen on blood smear (picture 5 and picture 6), which also reveals up to 15 percent atypical lymphocytes [29-31]. However, the total white blood count is not elevated. (See "Babesiosis: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)
Non-infectious causes — Hypersensitivity reactions and stress are the most common etiologies of non-infectious reactive lymphocytosis.
Hypersensitivity reactions — Hypersensitivity reactions are either drug-induced or related to acute serum sickness. Drug-induced hypersensitivity syndromes usually occur two to six weeks after starting the drug, and consist of fever, leukocytosis with eosinophilia, and atypical lymphocytosis. These reactions can progress to multi-organ failure. These reactions can be related to certain HLA types, are associated more commonly with certainly classes of drugs such as anticonvulsants, and can have a mortality of up to 10 percent [32,33]. (See "Drug hypersensitivity: Classification and clinical features".)
Stress-induced lymphocytosis — Transient atypical lymphocytosis with absolute lymphocyte counts ranging from 4000 to 13,000/microL, often followed by neutrophilia, was observed in a group of 73 adults aged 43 to 93 years with cardiac emergencies, trauma, or status epilepticus . Their mortality rate was 50 percent, and the altered blood picture was ascribed either to stress or to administration of epinephrine. In a study of over 45,000 adult inpatients, lymphocytosis by itself, independent of trauma, predicted a threefold increased risk of death within 30 days of admission . The mechanism appears to be redistribution of lymphocytes induced by epinephrine .
The presence of lymphocytosis after trauma appears to be an early recognition sign of the high risk patient . Another emergency department study of 10 adults in sickle cell anemia crisis and 15 others with trauma or serious acute medical conditions and absolute lymphocytosis demonstrated increases in the numbers of CD20+ B cells, as well as T cells of the CD3, CD4, CD8, and CD56 phenotypes . These findings mimicked the effects of parenteral epinephrine administration: a pan-B and pan-T lymphocytosis with marked increase in CD56 (four- to fivefold) and CD8 cells (three- to fourfold), as well as moderate increases in CD20 and CD4 cells (twofold) [38,39].
Postsplenectomy lymphocytosis — Following splenectomy, most patients demonstrate an increase in circulating large granular lymphocytes [40,41]. In one series of 23 patients, most of whom had Hodgkin lymphoma, splenectomy was associated with lymphocytosis in 20; the absolute lymphocyte counts ranged from 4000 to 8700/microL . The lymphocytosis persisted almost unchanged during a median follow-up of 50 months. Some patients have typical large granular lymphocyte morphology with primary expansion of NK cells . In vitro natural killer and antibody dependent cellular cytotoxic activities remain normal .
LYMPHOPROLIFERATIVE DISORDERS — A number of lymphoproliferative disorders are associated with peripheral lymphocytosis. In their early stages, it may be difficult to distinguish them from cases of reactive lymphocytosis. Serial blood counts may be necessary in order to differentiate between these two possibilities. However, the presence of blast forms (ie, lymphoblasts) and/or lymphocyte counts >20,000/microL should prompt immediate referral to a hematologist. Some of these are discussed in this section.
Hereditary polyclonal B cell lymphocytosis — Patients within the same family have presented in infancy with white cell counts in the 30,000 range with 85 percent lymphocytes and splenomegaly due to polyclonal B cells [43,44]. The lymphocytosis persisted throughout childhood and became indistinguishable from chronic lymphocytic leukemia (CLL) by the fourth decade of life. (See "Approach to the adult with lymphocytosis or lymphocytopenia".)
Lymphoproliferative disease of large granular lymphocytes — Lymphoproliferative disease of the large granular lymphocyte is a relatively rare atypical lymphocytosis characterized by the presence in the blood of >2000/microL large lymphocytes with slightly eccentric nuclei and abundant pale-blue cytoplasm containing many azurophilic granules (picture 7) . Phenotypically these cells can be divided into expansions of CD3+/CD8+/CD4- T cells or CD3-/CD56+ NK cells that are usually clonal [46,47]. These patients rarely may present in childhood but usually present in the fourth or fifth decade of life with autoimmune manifestations and neutropenia. While they can have absolute lymphocytosis, they can also have normal total lymphocytes with an increased percent of cytotoxic lymphocytes [48-50]. (See "Treatment of large granular lymphocyte leukemia" and "Natural killer (NK) cell large granular lymphocyte leukemia".)
LYMPHOCYTOPENIA — The causes of lymphocytopenia (ie, an absolute lymphocyte count <1500/microL in older children or adults, <4500/microL in infants) are various and include, among others, infection, iatrogenic causes, systemic disease, and congenital immunodeficiency disorders. A partial list of these causes is presented in the table (table 2).
Lymphocytopenia in hospitalized patients is most frequently reversible. This was shown in a study of 1042 adults with an absolute lymphocyte count <600/microL who were identified over a 102-day period in a single teaching hospital. For the 698 patients who had previous and subsequent blood counts, lymphocytopenia was consistently present in only 6 percent . The most common causes for lymphocytopenia in this report were:
●Bacterial or fungal sepsis – 24 percent
●Postoperative state – 22 percent
●Malignancy – 17 percent
●Use of glucocorticoids – 15 percent
●Cytotoxic chemotherapy and/or radiation therapy – 9 percent
●Trauma or hemorrhage – 8 percent
The main management of isolated persistent lymphocytopenia is observation. If no other cell lines are involved; there are no symptoms; and no history of infections, mouth sores or rheumatological issues, we would follow clinically with serial blood counts. Evaluation for HIV and infections noted in the table (table 2) should be performed. However, in the majority of cases there are likely to be some symptoms that would direct the evaluation. In the absence of any features to guide the diagnostic evaluation, the next step would be to evaluate for immunodeficiency. (See "Primary humoral immunodeficiencies: An overview" and "Combined immunodeficiencies: An overview".)
Reductions in lymphocyte subsets — In addition to a reduction in the total number of circulating lymphocytes, a deficiency of one or more lymphocyte subsets may occur (eg, B cells, T cells, NK cells), and can be characteristic of a number of specific disorders, such as the primary or secondary immunodeficiency states. Patients with immunodeficiency may present with a range of disorders, such as:
●Inflammatory disorders (eg, inflammatory bowel disease, inflammatory arthritis)
●Malignancies (eg, lymphoma)
●Allergic disease (eg, atopic dermatitis, food allergy, allergic rhinosinusitis, asthma)
The approach to patients suspected of having a primary immunodeficiency is described separately. (See "Laboratory evaluation of the immune system", section on 'Initial approach to the patient' and "Laboratory evaluation of the immune system", section on 'Defects in cellular immunity'.)
●Absolute lymphocyte count (ALC) – ALC is calculated as follows:
ALC = white blood cells (WBC) x percent lymphocytes ÷ 100
•Children >12 years – For children >12 years, lymphocytosis is defined as ALC >4000 cells/microL (>4.0 x 109/L).
•Younger children – Levels of circulating lymphocytes are higher in neonates and young children (eg, normal ALC up to 8000/microL).
●Causes of lymphocytosis – Lymphocytosis can be a reactive process or by a clonal disorder (ie, a lymphoproliferative malignancy).
•Reactive – In children, the most common reason for reactive lymphocytosis is an infection, including viral, bacterial, and other agents (table 1). Less commonly, lymphocytosis is associated with a hypersensitivity reaction, autoimmune/rheumatologic illnesses, stress, thyroid disease, and other causes. (See 'Causes of reactive lymphocytosis' above.)
•Malignant – In children, malignant lymphocytosis can be caused by acute lymphoblastic leukemia/lymphoblastic lymphoma, large granular lymphocytosis, and others. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia".)
•Clinical – History and physical examination should evaluate recent infections and note lymphadenopathy and hepatosplenomegaly. (See 'Evaluation of the child with lymphocytosis' above.)
•Complete blood count (CBC) with differential count – Assess abnormalities of erythrocytes, other myeloid cells, and platelets and calculate ALC.
•Blood smear – The blood smear should note the presence of atypical lymphocytes (large lymphocytes with abundant basophilic cytoplasm and a large irregularly-shaped nucleus) (picture 2), lymphoblasts (picture 3), large granular lymphocytes (picture 7), and other findings of lymphocytes or other lineages. (See 'Blood lymphocyte morphology' above.)
●Further evaluation – Additional evaluation should be individualized, based on clinical and laboratory findings.
•Worrisome features – Referral to a pediatric hematologist for a bone marrow aspirate or other specialized testing should be considered for features consistent with a hematologic malignancy. Examples include ALC >20,000/microL, progressive rise of ALC, lymphoblasts, or abnormalities in other blood lineages.
•Others – For children who are clinically stable with none of the features above, we monitor ALC with serial CBCs.
●Lymphocytopenia – There is no consensus, but we define lymphocytopenia as:
•Infants – ALC <4500/microL in children less than 8 months
•Others – ALC <1500 cells/microL
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Laurence A Boxer, MD, now deceased, who contributed to an earlier version of this topic review.
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