Lymphocytosis – Causes, Symptoms, Diagnosis, Treatment

Lymphocytosis defined by an increase in absolute lymphocyte count (ALC) to more than 4000 lymphocytes/microL in adult patients, is a common hematologic abnormality. ALC calculates as the total white blood cell count (WBC) multiplied by the percentage of lymphocytes in the peripheral blood. Different lymphocyte subsets (T cells, B cells, or NK cells) may be increased depending on the particular etiology. Lymphocytes represent around 20 to 40% of WBC. The definition of relative lymphocytosis is an increase in WBC of more than 40% in the presence of a normal absolute white cell count. In this review, we present the most common causes in adult patients, in addition to a general approach to diagnosis and management of frequently encountered etiologies.

Lymphocytosis is an increase in the number or proportion of lymphocytes in the blood. Absolute lymphocytosis is the condition where there is an increase in the lymphocyte count beyond the normal range while relative lymphocytosis refers to the condition where the proportion of lymphocytes relative to white blood cell count is above the normal range. In adults, absolute lymphocytosis is present when the lymphocyte count is greater than 4000 per microliter (4.0 x 10⁹/L), in older children greater than 7000 per microliter and in infants greater than 9000 per microliter.^[rx] Lymphocytes normally represent 20% to 40% of circulating white blood cells. When the percentage of lymphocytes exceeds 40%, it is recognized as relative lymphocytosis.

The epidemiology of lymphocytosis varies by age and particular etiologies. Below is some demographic data for the most common causes.

• EBV: EBV infection is widespread worldwide among all age groups, and around 90% of adults will eventually become seropositive. IM though traditionally peaks in young adults at age 15 to 24 years, but can happen later in life.[rx] Symptomatic clinical infection is much more common in the Caucasians compared to African Americans.[rx]
• Pertussis and cat-scratch disease: pertussis predominantly affects children less than ten years of age, but could occur in adults where it might portend a more severe course in the elderly.[rx] Cat-scratch disease is also more common among children and young adults. Within the US, it is more common in the southeastern region, where the incidence might be as high as 6.4 cases per 100000 people.
• CLL: CLL is the most common leukemia in adult patients in the US, especially in older adults with a median age of diagnosis of 70 years. It is more common in men (male to female ratio of around 1.5 to 1) and more common among the White population.
• NHL: The frequency of peripheral blood lymphocytosis varies by the type of lymphoma and ranges from 20 to 80%.[rx]
• MBL: The prevalence of MBL is very high compared to CLL and reaches 5 to 9% in the population over 60 years of age. MBL is also more common in males than in females.[rx]
• Drug reaction with eosinophilia and systemic symptoms (DRESS): Lymphocytosis in DRESS can occur in around 30 to 70% of cases.

Infectious:

Diagnosis of Lymphocytosis

History and Physical

History and physical (H&P) is an essential part of the evaluation as it might reveal the underlying etiology, or may help to point out the need for an expedited evaluation. Some of the critical points in H&P include:

• The clinical setting is crucial as it occurs in patients presenting to the emergency department following seizures, trauma, or cardiac events.
• The patient has a personal or family history of a lymphoproliferative disorder.
• The patient has a history of B-symptoms (fever, weight loss, and night sweats) that could point out a clonal process.
• Demographics: age is an important feature, as some cases occur in specific populations (e.g., CLL is mainly a disease of the elderly), while others are more common in certain groups (for example, AIM is common in young adults).
• Surgical history: Splenectomy is associated with lymphocytosis.
• Medications review.
• History for methods of transmissions if certain viral infections are suspected (e.g., sexual history in HIV).
• The physical exam findings should be interpreted in the clinical context as rash, lymphadenopathy, or splenomegaly can occur in different malignant or reactive disorders.

Evaluation

The evaluation of lymphocytosis begins with a detailed history and physical examination. The complete blood count (CBC) and review of the peripheral blood smear (PBS) are essential to start an appropriate workup.

1. CBC: CBC review will help to confirm the presence of absolute lymphocytosis and to delineate abnormalities in other blood components such as hemoglobin and platelets. Anemia and thrombocytopenia might indicate a clonal disorder such as CLL or lymphoma. Also, the magnitude of the rise and the presence of abnormal or immature forms of cells (e.g., blasts) will help dictate the urgency of evaluation.

2. PBS: examples of distinct lymphocyte forms that may be identifiable on PBS include:

   • Small mature looking lymphocytes and “smudge cells” in CLL and MBL
   • Atypical large lymphocytes are visible in EBV and other viral infections such as CMV or early HIV
   • Lymphocytes that are cleaved angulated, or have indented nuclei can be associated with pertussis or malignancies such as follicular lymphoma.
   • “Hairy cells” with regular cytoplasmic projections are seen in hairy cell leukemia
   • Sezary Cells have cribriform nuclei with compact chromatin
   • “Villous” lymphocytes are seen in MZL
   • Large lymphocytes with multiple azurophilic granules are present in T-LGL
   • Lymphoblasts in ALL

3. Additional testing: 

   1. Flow Cytometry: Peripheral blood flow cytometry is essential to determine the proliferation of monoclonal cells. It is a costly test and should not be ordered routinely on all patients with lymphocytosis.

      1. Certain features on peripheral blood smear or on review of CBC which prompt a physician to order flow cytometry include:

         • The presence of lymphoblasts on the peripheral blood smear, suggesting ALL- This should also prompt a referral to a tertiary care center to obtain further workup.
         • The presence of other abnormal lymphocyte morphology on PBS as detailed above
         • ALC more than 30000 cells/microL
         • Persistent unexplained lymphocytosis for more than one month
         • Abnormalities in other cell lines including anemia and thrombocytopenia
         • Presence of lymphadenopathy and/or hepatosplenomegaly in the right clinical context where reactive causes have been ruled out

Treatment of Lymphocytosis

The management of lymphocytosis depends on the underlying etiology. While some causes reflect only a reactive or physiologic process that does not need any intervention (e.g., stress or asplenia), others indicate a malignant or clonal process that might require intervention.

• Acute infectious mononucleosis: The management is typically supportive, with analgesics and/or non-steroidal anti-inflammatory drugs (NSAIDs). As the majority of patients have splenomegaly, they should be instructed to avoid contact sports during the early acute stage to avoid splenic rupture. The use of corticosteroids is controversial, and the current body of literature does not provide enough evidence to support its use for symptomatic relief.[rx]
• Other infectious causes: The management of the underlying etiology directs the treatment. For example; The management of pertussis differs from infants to adolescents and adults. Antibiotics (e.g., azithromycin or clarithromycin) are generally indicated in adult patients when presenting within three weeks of the cough onset. Likewise, appropriate antimicrobials are an option for Bartonella Henselae, MTB, HIV, or toxoplasmosis.
• CLL: The management of CLL has moved towards the use of targeted therapies such as BTK inhibitors (Ibrutinib), BCL-2 inhibitor (Venetoclax), and PI3K inhibitors (Idelalisib). In general, the first step in CLL management is by appropriate selection of patients needing therapy. These are patients with progressive cytopenias, constitutional symptoms, progressive or symptomatic lymphadenopathy, and hepatosplenomegaly. The second important step in CLL management relies on risk stratification and predictive factors. Particularly, the presence of 17p del or TP53 mutation predicts for lack of response from standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine plus rituximab (BR). These patients are better suited for the use of BTK inhibitors (Ibrutinib) or Venetoclax in combination with the humanized anti-CD20 monoclonal antibody obinutuzumab. The phase III ECOG-E1912 has proved the superiority of the combination of Ibrutinib and rituximab (IbRx) over the FCR regimen in younger patients (age less than 70 years) diagnosed with CLL without del17 mutation. The progression-free survival (89.4% in the IbRx arm vs. 72.9% in the FCR arm at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001)and overall survival (98.8% in the IbRx arm vs. 91.5% in FCR arm at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001) were significantly prolonged in patients diagnosed with CLL, even in those with IGHV mutation.[rx]
• NHL: The management of NHL management depends on the histology. For instance, where a patient diagnosed with ‘double-hit’ DLBCL may require prompt initiation of treatment, a patient diagnosed with low-grade FL can be monitored clinically for signs of growth or transformation. The treatment options for NHL have increased with the advent of targeted agents. The typical medications, namely, rituximab, doxorubicin, cyclophosphamide, vincristine, and steroids (either prednisone or dexamethasone) are still in use as first-line treatment in various permutations and combinations. However, newer drugs like brentuximab vedotin (anti-CD-30 and drug conjugate), lenalidomide, obinutuzumab, etc. are being tested and approved in both first-line and second-line setting to improve patient outcomes. The treatment of MCL requires more intense chemotherapy, with a possibility of performing autologous stem cell transplantation in consolidation. Purine analogs (cladribine and pentostatin) are standard treatments for HCL. Methotrexate is usually the initial drug for T-LGL patients requiring therapy.
• MBL: All patients diagnosed with MBL can receive clinical monitoring. Typically, they follow up with their hematologist twice a year for the first two years for high count CLL-like MBL and atypical MBL, which can extend longer for stable patients. Only symptomatic patients or those whose blood tests show a worsening lymphocytosis warrant further imaging and bone marrow aspirate and biopsy.
• DRESS: The first step in managing patients with DRESS is to withdraw the offending drug. Supportive measures usually suffice. Topical or systemic corticosteroids may be needed depending on the extent of involvement of the skin and/or other organs.

Prognosis

The prognosis of a patient with lymphocytosis depends on the underlying etiology. Examples of specific disease prognosis are as follows:

• Acute IM: Most patients recover from the acute episode of mononucleosis, although some continue to have fatigue for a prolonged period.[rx] However, EBV infected latent B cells may lead to the development of EBV-related lymphoproliferative disorders, including post-transplant lymphoproliferative disorder (PTLD), Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma in immunocompromised individuals.[rx]
• Other infections: Pertussis in adults may cause prolonged symptoms (greater than two weeks).[rx] Prior to antiretroviral therapy, advanced HIV infection median overall survival was dismal, ranging from 12 to 18 months. Prognosis depends on many factors, including the ability to successfully implement antiretroviral therapies, and there are several indices used to estimate survival in HIV infections (e.g., Veterans Aging Cohort Study index).
• CLL: CLL prognosis is highly dependant on risk stratification and whether a patient presents with high-risk features or not. These latter include a high-risk karyotype (del 17p and del 11q), unmutated IGHV status, high ZAP-70, CD38, and Beta-2 microglobulin levels.
• NHL: The prognosis depends on the type of histology. Histologies like FL, MZL, and HL are incurable but have a prolonged indolent course. On the other hand, DLBCL and T-cell lymphomas are aggressive but responsive to therapy.
• DRESS: mortality rates from DRESS are reported to be around 5 to 10%.[rx] However, most patients will recover following offending drug withdrawal.

Complications

The complications from lymphocytosis coincide with the underlying etiology where leukemia is the most common underlying disease.

• Hyperleukocytosis: Defined as a white cell count above 100000 cells/microL. It is more commonly seen in patients diagnosed with acute myeloid leukemia but can appear in patients presenting with acute lymphoblastic leukemia as well as CML. Hyperleukocytosis can lead to leukostasis and consequent symptoms like vision loss, stroke, myocardial infarction, etc. Prompt initiation of white-cell lowering treatment (either hydroxyurea or leukapheresis) is required to relieve the symptoms.[rx]
• Infectious mononucleosis: splenic rupture and chronic fatigue are short term complications that may happen in patients with infectious mononucleosis. B-cell malignancies are potential long term sequelae of EBV infection, including PTLD, HL, and NHL, which usually occur in the immunocompromised patients.[rx]
• CLL: Leukostasis is uncommon in CLL. Autoimmune processes may complicate CLL, including autoimmune hemolytic anemia and immune thrombocytopenia. Hypogammaglobulinemia, with or without recurrent infections, is also common. CLL patients are also at a higher risk of developing secondary malignancies, including solid and hematologic ones.[rx]
• DRESS: DRESS patients may have different organ involvement, including liver, lung, and kidneys. Further, these patients are reported to have a higher subsequent incidence of autoimmune diseases as well as future drug reactions to potentially structurally unrelated medications.

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