Approach to the adult with lymphocytosis or lymphocytopenia

INTRODUCTION — Lymphocytosis refers to an increase of peripheral blood lymphocytes, which for adults corresponds to >4000 lymphocytes/microL in most clinical laboratories.

Lymphocytopenia refers to a decrease of peripheral blood lymphocytes, which generally corresponds to <1000 lymphocytes/microL in adults.

This topic discusses the causes and our approach to clinical evaluation of lymphocytosis and lymphocytopenia in adults. The evaluation and causes of leukocytosis and lymphocytopenia in children are discussed separately. (See "Approach to the child with lymphocytosis or lymphocytopenia".)

DEFINITIONS AND NORMAL VALUES — The normal range (ie, two standard deviations above and below the mean) for the white blood cell (WBC) count in adults is 4400 to 11,000 cells/microL in most clinical laboratories. Lymphocytes generally constitute 8 to 33 percent of WBCs in peripheral blood.

●Absolute lymphocyte count – The absolute lymphocyte count (ALC) is used to quantitate lymphocytes in peripheral blood (rather than the percentage of lymphocytes in the WBC differential count).

ALC is calculated as follows:

ALC (cells/microL) = WBC (cells/microL) x percent lymphocytes ÷ 100

Normal values for ALC generally correspond to 1000 to 4000 lymphocytes/microL, but may vary in different laboratories.

●Lymphocytosis corresponds to ALC >4000 cells/microL for adults.

●Lymphocytopenia corresponds to ALC <1000 cells/microL for adults.

●Lymphocyte subsets – Normal proportions of T lymphocytes, B lymphocytes, and natural killer (NK) cells in the peripheral blood are:

•T cells (CD3+) – 60 to 80 percent

•B cells (CD20+) – 10 to 20 percent

•NK cells (CD56+) – 5 to 10 percent

●T lymphocyte subtypes – Normal proportions of T cell subtypes in peripheral blood are:

•Helper/inducer T cells (CD4+) – 60 to 70 percent

•Suppressor/cytotoxic T cells (CD8+) – 30 to 40 percent

Normal values for WBC and lymphocyte counts in children vary by age and are discussed separately. (See "Approach to the child with lymphocytosis or lymphocytopenia".)

MECHANISMS — Lymphocyte differentiation and maturation are life-long processes that take place in the bone marrow and secondary lymphoid organs (eg, lymph nodes, spleen, thymus). Details of lymphocyte development are discussed separately. (See "Normal B and T lymphocyte development".)

Lymphocytosis may be caused by increased production, redistribution (from bone marrow and/or secondary lymphoid organs), and/or decreased cell death (eg, from impaired apoptosis in some lymphoproliferative disorders). Various causes of lymphocytosis differ in the contribution from each of these mechanisms.

Increased lymphocyte production may be due to a malignant process or in response to an infectious or inflammatory stimulus. Malignant lymphocytosis involves expansion of a clone of related cells, whereas reactive processes generally reflect polyclonal expansion of lymphocytes. Reactive processes may lead to expansion of one or more subsets of lymphocytes (ie, T cells, B cells, and/or NK cells).

CAUSES OF LYMPHOCYTOSIS

Infectious causes — Specific infectious causes of reactive lymphocytosis vary depending on demographic characteristics of the population. As examples, the incidence of certain infections varies based on geography, and infectious mononucleosis is more common in young adults.

●Infectious mononucleosis (IM) is a viral infection characterized by fever, tonsillar pharyngitis, and lymphadenopathy. Lymphocytosis is the most common hematologic manifestation of IM, and lymphocytes may constitute more than half of circulating leukocytes. The peripheral blood smear usually contains reactive "atypical" lymphocytes (picture 1) that peak during the second and third week of illness and may persist for up to two months [1]. (See 'Peripheral blood smear' below.)

IM is most often caused by infection with Epstein-Barr virus (EBV). IM may also be associated with other hematologic findings, including hemolytic anemia and thrombocytopenia. (See "Infectious mononucleosis", section on 'Hematologic abnormalities'.)

Other infectious agents can cause a nearly indistinguishable IM syndrome including cytomegalovirus (CMV), human immunodeficiency virus (HIV), other viruses, and toxoplasmosis. (See "Infectious mononucleosis", section on 'EBV-negative mononucleosis'.)

●Other viral illnesses that can be associated with lymphocytosis include:

•HIV

•HTLV-I (human T-lymphotropic virus type I)

•CMV

•Mumps

•Rubella

•Measles

•Influenza

•Hepatitis

•Adenovirus

•Coxsackie virus

•Poliovirus

●Pertussis – Pertussis (whooping cough) is a respiratory infection caused by Bordetella pertussis infection. Unlike most other acute bacterial infections, pertussis commonly causes lymphocytosis. The lymphocytes in pertussis often have a characteristic appearance with a convoluted and/or cleaved nucleus (picture 2). Clinical manifestations and diagnosis of pertussis are described separately. (See "Pertussis infection in adolescents and adults: Clinical manifestations and diagnosis".)

Lymphocytosis appears to be specific to B. pertussis infection, since it is not seen with a clinically identical illness caused by B. parapertussis. As an example, in one study of 114 patients the mean absolute lymphocyte count (ALC) was significantly lower in those infected with B. parapertussis than in those with B. pertussis (3500 versus 7800/microL, respectively) [2]. Because both B. pertussis and B. parapertussis express pertussis toxin, some other effect of B. pertussis must account for the lymphocytosis.

The lymphocytosis in pertussis is polyclonal with a normal T:B lymphocyte ratio and appears to be due to a block in extravasation of lymphocytes from the blood into lymph nodes, rather than an increase in lymphocyte production [3].

●Cat scratch disease – Cat scratch disease is an infection with Bartonella henselae that manifests as lymphadenopathy and can be associated with neurologic, ocular, and other organ involvement. The lymphocytosis usually includes large atypical lymphocytes and may be accompanied by mild eosinophilia, monocytosis, anemia, and/or thrombocytopenia [4]. Details of the clinical presentation and diagnosis of cat scratch disease are discussed separately. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease".)

●Other infectious causes – Infections such as tuberculosis, brucellosis, syphilis, babesiosis, and rickettsial infections may present a similar hematologic picture.

Non-infectious causes

Drug hypersensitivity reactions — Drug reaction with eosinophilia and systemic symptoms (DRESS) is an allergic/hypersensitivity reaction to a medication. DRESS usually occurs two to six weeks after starting the offending drug. Lymphocytosis (eg, in the range of 10,000/microL) with atypical lymphocytes and eosinophilia is seen in 30 to 70 percent of cases of DRESS [5]. Additional details are presented separately (table 1). (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)" and "Drug hypersensitivity: Classification and clinical features".)

Stress — Lymphocytosis can be associated with severe medical stress, including trauma, cardiac emergencies, or status epilepticus. A study of 73 adults (age 43 to 93 years) with such conditions reported ALCs from 4000 to 13,000/microL that was often followed by neutrophilia [6]. Lymphocytosis in this setting has been associated with mortality rates of 25 to 50 percent [6,7].

Persistent polyclonal B cell lymphocytosis — A syndrome of persistent polyclonal B cell lymphocytosis (PPBL) has been described in young to middle-aged women who smoke cigarettes. The syndrome includes polyclonal B cell expansion, a polyclonal increase in serum IgM, and may be accompanied by splenomegaly and/or lymphadenopathy [8-12]. The median ALC is 5500 cells/microL (range 2000 to 21,000 cells/microL) with characteristic binucleate lymphocytes (picture 3).

Despite the presence of cytogenetic anomalies in most patients (eg, isochromosome 3q, BCL2/immunoglobulin gene rearrangements), the clinical course typically remains stable for years. As an example, a study of more than 100 patients reported 89 percent four-year event-free survival [13,14].

The pathogenesis of PPBL is not known. Potential mechanisms include a defect in the CD40 activation pathway, expansion of functional IgD+ CD27+ memory B cells, or undefined genetic defects [15-19].

Asplenia — Moderate levels of polyclonal lymphocytosis are common after splenectomy. Most patients with post-splenectomy lymphocytosis have large granular lymphocytes on the peripheral smear and expansion of NK cells [20,21]. In one series, 20 of 23 patients who underwent splenectomy (most for Hodgkin lymphoma) had lymphocyte counts from 4000 to 8700/microL; lymphocytosis persisted almost unchanged with median follow-up of more than four years [20].

Thymoma — Thymoma is a thymic malignancy that typically affects middle-aged adults and may be associated with paraneoplastic autoimmune syndromes (eg, myasthenia gravis, pure red cell aplasia). Thymoma is occasionally associated with polyclonal T cell lymphocytosis that can range from 6900 to 24,000/microL and resolves following successful treatment of the tumor [22-25]. The cause of the lymphocytosis is unclear, but the circulating lymphocytes appear normal by morphology, immunophenotyping, and T cell receptor gene rearrangement studies [23]. Further description of clinical aspects of thymoma is provided separately. (See "Clinical presentation and management of thymoma and thymic carcinoma".)

Clonal processes — Causes of clonal lymphocytosis exist on a spectrum and range from premalignant disorders (that may later evolve to overt malignancies) to a variety of lymphomas and leukemias.

Monoclonal B lymphocytosis — Monoclonal B cell lymphocytosis (MBL) refers to a monoclonal population of B lymphocytes <5000 cells/microL in peripheral blood (ie, below the threshold for diagnosis of chronic lymphocytic leukemia [CLL]), without associated clinical findings of an autoimmune condition, infectious disease, or lymphoproliferative disorder (eg, no lymphadenopathy, hepatosplenomegaly, cytopenias, fever, weight loss, or sweats). B cell clonality may be detected in some individuals with <4000 lymphocytes/microL (ie, the threshold for defining lymphocytosis).

Most patients with MBL have an immunophenotype that is indistinguishable from CLL, while other cases have an atypical or non-CLL-like immunophenotype. Epidemiology, diagnosis, classification, prognosis, and management of MBL are discussed separately. (See "Monoclonal B cell lymphocytosis".)

Congenital B cell lymphocytosis — Congenital B cell lymphocytosis is a rare familial syndrome in which infants present with splenomegaly and polyclonal expansion of B cells that progresses to CLL by the fourth decade of life [26].

Affected patients have mutations of CARD11, which encodes a protein (caspase recruitment domain-containing protein 11) required for nuclear factor-kappa B activation of B and T lymphocytes. CARD11 deficiency syndrome is described separately. (See "Primary humoral immunodeficiencies: An overview", section on 'Isotype, light chain, or functional deficiencies with generally normal numbers of B cells'.)

Large granular lymphocyte leukemia — Large granular lymphocyte (LGL) leukemia is characterized by infiltration of peripheral blood and bone marrow by clonal LGLs, splenomegaly, and cytopenias (usually neutropenia). Patients typically present in the fourth or fifth decade of life with autoimmune manifestations and neutropenia. The blood smear characteristically reveals large lymphocytes with slightly eccentric nuclei, abundant pale-blue cytoplasm, and azurophilic granules (picture 4) at levels >2000 cells/microL; some patients have a normal ALC with an increased percentage of cytotoxic (CD8+) lymphocytes [27-29].

Details of the clinical presentation and diagnosis of LGL leukemia are discussed separately. (See "Natural killer (NK) cell large granular lymphocyte leukemia".)

Chronic lymphocytic leukemia — Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative neoplasm characterized by progressive accumulation in peripheral blood and bone marrow of lymphocytes that may be accompanied by lymphadenopathy, splenomegaly, and/or constitutional symptoms. CLL is defined by the presence of ≥5000 lymphocytes/microL. The leukemic cells are typically small and mature-appearing with a dense nucleus, partially clumped chromatin, no discernible nucleoli, and a thin border of clear or slightly basophilic cytoplasm. Some of the lymphocytes may be larger with a notched nucleus, lacy-appearing chromatin, and prominent visible nucleoli (so-called prolymphocytes). The smear typically contains characteristic "smudge" cells that appear to have been damaged when smeared on a glass slide (picture 5).

Clinical manifestations, pathologic features, and diagnosis of CLL are discussed in detail separately. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Non-Hodgkin lymphoma — Most categories of non-Hodgkin lymphoma (NHL) can be associated with lymphocytosis, but certain subtypes are more likely:

●Sézary syndrome, which is defined by the presence of circulating malignant T lymphocytes; details of clinical manifestations and diagnosis are presented separately. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)

●Mantle cell lymphoma (MCL) has the highest prevalence of lymphocytosis among B cell lymphomas; about one half of patients with MCL have lymphocytosis. Additional details are presented separately. (See "Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis".)

●Follicular lymphoma and splenic marginal zone lymphoma are often associated with lymphocytosis. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma" and "Splenic marginal zone lymphoma".)

●Subtypes of NHL less commonly associated with lymphocytosis include diffuse large B cell lymphoma, Burkitt lymphoma, and T cell lymphoma other than Sézary syndrome. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma" and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified".)

The morphologic appearance and immunophenotype of circulating lymphocytes depends on the subtype of underlying NHL.

Acute lymphoblastic leukemia — Acute lymphoblastic leukemia (ALL) may be derived from T, B, or NK cells, and can present at any age. Lymphoblasts vary from small cells with scant cytoplasm, condensed nuclear chromatin, and indistinct nucleoli to larger cells with moderate amounts of cytoplasm, dispersed chromatin, and multiple nucleoli; a few azurophilic cytoplasmic granules may be present. Typical presenting symptoms are nonspecific and may include symptoms of cytopenias, fever, bone pain, lymphadenopathy, organomegaly, and/or mediastinal mass. The immunophenotype varies depending on the lineage of the leukemic cells (eg, B versus T lineage).

Details of the clinical presentation and diagnosis of B cell ALL and T cell leukemia/lymphoma in adults are discussed separately (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

EVALUATION

Urgency of evaluation — The urgency of evaluation of lymphocytosis is guided by the patient's clinical condition, the degree and rate of rise of lymphocytosis (if known), and worrisome findings (eg, leukemic blasts) on the blood smear.

As examples:

●Lymphocytosis accompanied by hemodynamic instability, respiratory compromise, or other clinical emergency requires immediate hospitalization and urgent evaluation.

●Asymptomatic lymphocytosis without worrisome findings on blood smear or blood chemistries may be evaluated as an outpatient. (See 'Peripheral blood smear' below.)

No specific level of lymphocytosis constitutes a medical emergency. The response to marked lymphocytosis is influenced by whether a diagnosis has previously been established.

As examples:

●If the cause of lymphocytosis is not known, an absolute lymphocyte count (ALC) >50,000 cells/microL may require prompt evaluation and hematology consultation to make an initial assessment about the urgency of further testing. (See "Approach to the patient with neutrophilia", section on 'Leukemoid reaction/hyperleukocytosis'.)

●Conversely, an asymptomatic, clinically stable patient with documented chronic lymphocytic leukemia (CLL) does not require urgent hematologic consultation based on elevated ALC alone; a patient with documented CLL may remain asymptomatic and clinically stable irrespective of the degree of lymphocytosis.

Initial evaluation — Lymphocytosis may be encountered in the course of evaluating other clinical findings or as an incidental abnormality on a complete blood count (CBC) and differential.

Initial evaluation of lymphocytosis includes CBC, history and physical examination, and review of the blood smear.

The initial evaluation of lymphocytosis cannot determine clonality or the subtype of lymphocytes (ie, B versus T versus NK cells); such conclusions require flow cytometry or other specialized tests, as described below. (See 'Distinguishing clonal versus polyclonal processes' below.)

Complete blood count (CBC) — The abnormal CBC and differential count should be repeated to exclude laboratory error:

●Repeat CBC should be performed immediately if the patient is clinically unstable, worrisome findings are reported (eg, leukemic blasts), or ALC is markedly elevated (eg, >30,000 cells/microL) without a known diagnosis.

●The CBC can be repeated with less urgency (eg, within one to two weeks) if the patient is clinically stable, the lymphocytosis is modest, and no worrisome findings are reported on blood smear.

When available, prior CBCs (both normal and abnormal) can provide important information about the duration and trajectory of lymphocytosis.

ALCs can rise to 20,000 to 30,000 cells/microL in reactive lymphocytoses (eg, infection or inflammation). The higher the ALC is above these values, the lower is the likelihood of a reactive disorder. That is, the likelihood of a malignant disorder increases with ALC >30,000/microL and/or characteristic findings on the blood smear (eg, lymphoblasts, smudge cells). (See 'Peripheral blood smear' below.)

In general, reactive lymphocytosis can be expected to persist while the underlying inflammatory/infectious process is active. Lymphocytosis caused by an acute condition (eg, infection) should resolve within one to two months; a longer duration of lymphocytosis might raise concerns regarding an underlying malignant process.

Lymphocytosis may be the sole abnormality in the CBC and blood smear, or it may be accompanied by other blood abnormalities, including:

●Increased eosinophils or basophils accompanying lymphocytosis may be due to:

•Allergic conditions or medications (see 'Drug hypersensitivity reactions' above)

•Infections (see 'Infectious causes' above)

•Inflammatory conditions (see 'Non-infectious causes' above)

●Increased neutrophils and/or monocytes accompanying lymphocytosis may be due to:

•Infections (see 'Infectious causes' above)

•Inflammatory conditions (see 'Non-infectious causes' above)

•Medications (see 'Drug hypersensitivity reactions' above)

•Severe medical stress or other conditions (eg, asplenia) (see 'Non-infectious causes' above)

●Anemia – Anemia associated with lymphocytosis can have varied causes. Examples include:

•Hemolytic anemia or pure red cell aplasia associated with CLL or large granular lymphocyte leukemia (see "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Cytopenias' and "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Clinical features')

•Anemia of chronic disease associated with chronic inflammatory conditions or infections (see "Anemia of chronic disease/anemia of inflammation")

•Bone marrow infiltration by various leukemias and infections

Clinical evaluation of anemia is discussed in greater detail separately (see "Diagnostic approach to anemia in adults")  

History and physical examination — The history should seek evidence of disorders that might account for lymphocytosis. (See 'Causes of lymphocytosis' above.)

Important aspects of the history include evidence of:

●Active or prior infection or inflammatory processes (eg, trauma, seizure, arthritis, rash). (See 'Causes of lymphocytosis' above.)

●Previously diagnosed hematologic malignancy (eg, lymphoma, leukemia) or related symptoms and/or signs (eg, unexplained lymphadenopathy, fevers, sweats, weight loss). (See 'Clonal processes' above.)

●Surgical or functional asplenia. (See 'Asplenia' above.)

●Medications, including the association between the onset of lymphocytosis (if known) and onset of drugs associated with drug reaction with eosinophilia and systemic symptoms (DRESS) (table 1). (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

●Cigarette smoking. (See 'Persistent polyclonal B cell lymphocytosis' above.)

●Family history of lymphoid neoplasms or lymphocytosis. (See 'Monoclonal B lymphocytosis' above.)

Physical examination should seek evidence of infection, inflammation, or malignancy, such as fever, lymphadenopathy, hepatosplenomegaly, joint redness, abdominal pain, and lung findings.

The presence of lymphadenopathy and/or splenomegaly does not indicate whether the lymphocytosis is malignant versus reactive (ie, infectious or non-infectious) because those clinical findings can be associated with either category of disease.

Peripheral blood smear — The peripheral blood smear should be reviewed to assess lymphocyte morphology and detect other hematologic findings.

Examples of lymphocyte findings on the blood smear include:

●Normal-appearing small lymphocytes may be seen with certain infections (eg, pertussis), CLL, monoclonal B cell lymphocytosis, and other disorders.

●Atypical lymphocytes (ie, large lymphocytes with abundant basophilic cytoplasm and a large, irregularly shaped nucleus that may exhibit nucleoli) (picture 1) are often seen in infectious mononucleosis and other viral illnesses (table 2).

●Binucleate lymphocytes are characteristic of persistent polyclonal B cell lymphocytosis (PPBL). (See 'Persistent polyclonal B cell lymphocytosis' above.)

●Normal maturing B lymphocyte precursors (so-called "hematogones") can be mistaken for lymphoblasts and represent 0.01 to 1.3 percent of leukocytes in adults, as detected by sensitive flow cytometry methods [30-32].

●Distinctive lymphoid forms may be seen in certain malignant disorders, including:

•"Smudge" lymphocytes (picture 6) are characteristic (but not diagnostic) of CLL. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Peripheral smear'.)

•Villous projections (picture 7) may be seen with splenic marginal zone lymphoma. (See "Splenic marginal zone lymphoma", section on 'Morphology'.)

•"Hair-like" projections (picture 8) are seen in hairy cell leukemia. (See "Clinical features and diagnosis of hairy cell leukemia", section on 'Morphology'.)

•Small lymphocytes with cleaved nuclei (picture 9) may be seen with follicular lymphoma and mantle cell lymphoma. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Blood and bone marrow'.)

•Lymphocytes with "cerebriform" nuclei (ie, Sézary cells) (picture 10) are seen in Sézary syndrome/mycosis fungoides. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Circulating Sézary cells'.)

•Lymphocytes with azurophilic granules (picture 4) may be seen in large granular lymphocyte leukemia. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Peripheral blood'.)

•Lymphoblasts can vary from cells with little cytoplasm (picture 11) to abundant bluish cytoplasm or deep blue cytoplasm (picture 12) in acute lymphoblastic leukemia (ALL). (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma".)

Other laboratory tests — Other laboratory tests may be included in the initial evaluation to help distinguish malignant disorders from reactive causes of lymphocytosis and/or identify associated clinical findings or complications include:

●Kidney and liver function tests may identify associated medical conditions or complications (eg, acute kidney injury due to tumor lysis syndrome associated with ALL).

●Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated in inflammation and infection, and may be helpful in evaluating the cause of lymphocytosis; as an example, elevated ESR and/or CRP in an asymptomatic patient may suggest an underlying inflammatory condition.

ASSESSMENT OF CLONALITY

Distinguishing clonal versus polyclonal processes — Distinguishing clonal from polyclonal processes is often an important step in determining the cause of lymphocytosis. Clonality cannot be determined by the initial evaluation (ie, history, physical examination, complete blood count [CBC], and blood smear).

For most patients, flow cytometry is the preferred initial technique to define clonality, as described below. (See 'Selection of specialized tests' below.)

While all malignant lymphocytosis is clonal, not all clonal expansions are malignant; some infectious or inflammatory causes of lymphocytosis may be associated with oligoclonal expansion of lymphocytes (eg, two to five distinct low-abundance clones).

Conversely, premalignant disorders (eg, monoclonal B lymphocytosis) or early stages of some leukemias may exhibit only low levels of clonal lymphocytes among a larger population of normal polyclonal lymphocytes; in such cases, the diagnosis may only be revealed with follow up (eg, clinical observation, serial CBCs, and/or repeat flow cytometry or molecular testing).

Which patients require flow cytometry? — Flow cytometry should not be performed in all patients with lymphocytosis.

A decision to perform flow cytometry and the urgency of testing are informed by the patient's clinical status, the level of lymphocytosis and its trajectory (if known), worrisome findings on blood smear, and clinician and/or patient concern.

Flow cytometry should be performed promptly when there is:

●Suspicion for acute leukemia (eg, lymphoblasts on blood smear) (see 'Peripheral blood smear' above)

●Absolute lymphocyte count (ALC) >30,000 cells/microL without a known diagnosis

In less urgent settings, our approach is to repeat the CBC and differential in one to two weeks. We perform flow cytometry of peripheral blood to assess clonality and immunophenotype for the following findings:

●ALC >5000 cells/microL, unless lymphocytosis can be accounted for by evidence of a recent viral infection, offending drug, or asplenia

●Unexplained ALC >4000 cells/microL for >1 month

●Rising ALC

●Lymphocyte morphology suggestive of malignancy (eg, lymphoblasts, smudge cells, hairy cells) (see 'Peripheral blood smear' above)

●Cytopenias

●Hepatosplenomegaly

●Lymphadenopathy

Selection of specialized tests — Selection of specialized tests is informed by the nature of the clinical questions, the urgency of testing, and the specimens that are available.

In general, flow cytometry of peripheral blood is the preferred initial test for determining clonality in the patient with lymphocytosis. Compared with other specialized techniques (eg, chromosome analysis, molecular/genetic testing), flow cytometry provides more rapid and cost-effective results, and it can also define lymphocyte lineage. (See 'Definitions and normal values' above.)

In some cases, flow cytometry of peripheral blood may not be necessary in a patient with lymphocytosis. If clonality was already defined by other techniques (eg, immunohistochemistry of a lymph node, molecular testing of a bone marrow specimen), flow cytometry of peripheral blood generally does not need to be performed.

Specialized tests for clonality

Flow cytometry — Flow cytometry can define clonality and determine the lineage and immunophenotype of lymphocytes.

Our approach to deciding when and for whom to perform flow cytometry for evaluation of lymphocytosis is described above. (See 'Which patients require flow cytometry?' above.)

Use of flow cytometry for characterizing lymphocytes is described separately. (See "Flow cytometry for the diagnosis of inborn errors of immunity", section on 'Technical aspects' and "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma", section on 'Flow cytometry'.)

Molecular/Genetic testing — Molecular techniques that can detect clonal populations of lymphocytes include polymerase chain reaction (PCR) and DNA sequencing.

These techniques can demonstrate the presence of a dominant clone of cells based on rearrangements of either immunoglobulin genes (in B lymphocyte) or T cell receptor genes (in T cells). NK cells are not amenable to such testing, but clonal integration of Epstein-Barr virus (EBV) may be detected in some cases [33]. (See "Natural killer (NK) cell large granular lymphocyte leukemia", section on 'Laboratory findings'.)

Additional aspects of PCR and DNA sequencing are provided separately. (See "Polymerase chain reaction (PCR)" and "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Chromosome analysis — Chromosome analysis by conventional karyotype or fluorescence in situ hybridization can identify acquired and inherited causes of lymphocytosis, especially in certain lymphoid leukemias and lymphomas.

●FISH – Fluorescence in situ hybridization (FISH) on peripheral blood, bone marrow, or lymph nodes can help to define the category of malignant lymphocytosis.

FISH is particularly important in diagnosing clonal disorders that are not definitively identified based on morphology and immunophenotype. One important example is the t(11;14) probe for CCND1/IgH, which is positive in mantle cell lymphoma (MCL) and negative in other lymphoid malignancies. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Fluorescence in situ hybridization'.)

●Karyotype – An abnormal karyotype is seen in some cases of adult ALL, CLL, MCL, and other hematologic malignancies. Additional description is provided separately. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma" and "General aspects of cytogenetic analysis in hematologic malignancies".)

LYMPHOCYTOPENIA — Lymphocytopenia refers to an absolute lymphocyte count (ALC) below a lower threshold, which differs by age. (See 'Definitions and normal values' above.)

Causes and evaluation — Lymphocytopenia may be caused by many conditions (table 3). Examples include viral infections, such as human immunodeficiency virus (HIV), influenza, coronaviruses (eg, SARS, SARS-CoV-2), hepatitis, measles; bacterial, mycobacterial, fungal, and parasitic infections; protein-energy undernutrition; systemic diseases; congenital immunodeficiency disorders, such as common variable immunodeficiency; and chemotherapy or immunosuppressive therapy, including glucocorticoids.

The history and physical examination should seek evidence of recent viral or other infections, document medications and possible nutritional deficiencies, and underlying systemic disorders. The severity and duration of lymphocytopenia should be documented, if possible. When the underlying diagnosis is not obvious from the initial evaluation and review of medications, we assess HIV status and measure lymphocyte subpopulations (eg, CD4 count) and immunoglobulin levels. Additional testing for suspected primary immunodeficiency is described separately. (See "Laboratory evaluation of the immune system".)

Examples of common findings and typical presentations are illustrated by the following:

●In a study of 1042 hospitalized adults with an ALC <600/microL in a teaching hospital, the most common causes for lymphocytopenia were as follows [34]:

•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

For the 698 patients in this study who had previous and subsequent blood counts, lymphocytopenia was persistently present in only 6 percent.

●Patients with immunodeficiency due to primary or secondary immunodeficiency syndromes may present with a range of disorders, such as:

•Recurrent infections

•Autoimmune disorders

•Inflammatory disorders (eg, inflammatory bowel disease, inflammatory arthritis)

•Malignancies (eg, lymphoma)

•Allergic disease (eg, atopic dermatitis, food allergy, allergic rhinosinusitis, asthma)

Prospective cohort studies from Denmark that included more than 100,000 individuals reported an association between lymphocytopenia and mortality (1.6-fold); associations with cancer, cardiovascular disease, and infections were also identified [35,36]. Because of the nature of these studies, the causes of lymphocytopenia could not be ascertained.

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. (See "Primary humoral immunodeficiencies: An overview" and "Combined immunodeficiencies: An overview" and "Severe combined immunodeficiency (SCID): An overview".)

Management (lymphocytopenia) — Management of lymphocytopenia depends on the underlying condition responsible and may include therapy related to associated cytopenias and/or other immune defects.

If the patient has an immunodeficiency syndrome associated with hypogammaglobulinemia, immunoglobulin replacement therapy may be administered. (See "Immune globulin therapy in inborn errors of immunity".)

Hematopoietic cell transplantation (HCT) can be considered for patients with congenital immunodeficiencies and has curative potential in these patients. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

In contrast, we generally do not intervene for patients with asymptomatic lymphocytopenia without an associated illness.

SUMMARY

●Definition – Lymphocytosis in adults is defined as an absolute lymphocyte count (ALC) >4000 lymphocytes/microL.

●Causes of lymphocytosis – A broad range of conditions can cause lymphocytosis (see 'Causes of lymphocytosis' above):

•Reactive/polyclonal – Infectious or non-infectious causes (table 2).  

•Clonal/malignant – Lymphoid malignancies and certain premalignant causes (eg, monoclonal B lymphocytosis).

●Initial evaluation

•Clinical – History and examination should evaluate recent infections, constitutional symptoms (fevers, sweats, weight loss), lymphadenopathy, hepatosplenomegaly, medications, smoking, and comorbid illnesses.

•Laboratory – Complete blood count (CBC) with differential count and review of blood smear should be performed.

●Urgency – Patients who are clinically unstable or have lymphoblasts on the blood smear should be evaluated promptly. For others, we generally repeat the CBC in two to four weeks.

●Further evaluation – The clinical setting and trajectory of ALC guide further evaluation:

•Resolved/improved lymphocytosis – No further evaluation is needed for lymphocytosis that improves/resolves with observation. Examples include infectious mononucleosis, pertussis, other infections, and medications (table 2). (See 'Infectious causes' above.)  

•Persistent/increasing lymphocytosis – For patients with persistent lymphocytosis, further evaluation is individualized. A decision to perform a diagnostic test (eg, flow cytometry, bone marrow [BM] examination) is guided by the level and trajectory of lymphocytosis, the clinical setting, and associated clinical findings.

Examples of clinical scenarios include:

-Suspected chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) – CLL/SLL should be suspected for patients with persistent lymphocytosis, lymphadenopathy, organomegaly, and smudge cells on blood smear (picture 5). Flow cytometry reveals co-expression of B cell markers and CD5 by the malignant lymphocytes.

Further evaluation, diagnosis, and staging for CLL/SLL are described separately. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

-Suspected acute leukemia – Acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) should be suspected in patients with a rapidly rising ALC, unexplained cytopenias, progressive lymphadenopathy or organomegaly, and/or a mediastinal mass.

Flow cytometry and BM examination should be performed urgently to evaluate an acute leukemia. Details of the evaluation and diagnosis of ALL/LBL are described separately. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".) and

-Large granular lymphocyte (LGL) disorders – LGLs on the blood smear, especially if associated with cytopenias and/or rheumatologic disorders, suggests a potential LGL disorder; flow cytometry is used to confirm the immunophenotype. Evaluation and diagnosis of LGL disorders are described separately. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia".)

-Isolated lymphocytosis/no other findings – For persistent lymphocytosis without lymphadenopathy or splenomegaly and no lymphoblasts on blood smear, we perform flow cytometry for clonality, immunophenotype, and quantitation of lymphocyte subsets. Possible diagnoses include early-stage CLL, monoclonal B cell lymphocytosis (MBL), and LGL leukemia. (See "Monoclonal B cell lymphocytosis".)

●Lymphocytopenia – Lymphocytopenia may be caused by drugs (eg, chemotherapy, immunosuppressive therapy), infections (eg, HIV), protein-energy undernutrition, systemic disease, congenital immunodeficiency disorders (eg, Wiskott-Aldrich syndrome, severe-combined immunodeficiency disorder), and other causes (table 3). (See 'Lymphocytopenia' above.)

ACKNOWLEDGMENT — UpToDate acknowledges Nancy Berliner, MD who contributed to earlier versions of this topic review.

The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.