Lymphocytosis

What is Lymphocytosis?

Lymphocytosis refers to a condition where there is an increase in the count of a particular kind of white blood cell known as lymphocytes. In adults, if there are more than 4000 lymphocytes per microliter of blood, this is called lymphocytosis. This medical condition is quite common and is seen as an abnormality related to blood condition. To determine the lymphocyte count, medical professionals calculate the total count of white blood cells and then look at the percentage of lymphocytes in the blood.

This increment could be in different types of lymphocytes like T cells, B cells, or NK cells, and it highly depends on the specific cause of the increase. Generally, lymphocytes make up around 20 to 40% of all white blood cells. Relative lymphocytosis is referred to when there is an increase of more than 40% of white blood cells, but the absolute count of white cells is normal.

In this explanation, we discuss the most common causes of lymphocytosis in adults. We’ll also cover a general strategy towards its diagnosis and treatment, focusing on the causes that are most frequently encountered.

What Causes Lymphocytosis?

Telling the difference between an immune response and a harmful growth of white blood cells can be difficult and will often depend on things like age and other individual factors. Here are some of the most common reasons why you might see an increase in white blood cells in your system:

One of the things that can cause a white blood cell increase is infections:

• Viral infections can make your body produce more white blood cells to fight off the infection. This can be seen in illnesses like:
  • Mononucleosis, which is caused by the Epstein-Barr Virus and is often accompanied by fever, swollen glands, sore throat, swelling of the spleen, and other symptoms.
  • Cytomegalovirus, which can cause a disease that has similar symptoms as mononucleosis.
  • HIV: Although long-term HIV infection decreases white blood cells and a specific type of white blood cells (CD4+), early HIV infection can cause symptoms similar to mononucleosis, and also increase the number of white blood cells.
• Other viruses such as influenza, hepatitis, mumps, measles, rubella, and more can also cause an increase in white blood cells.
• Bacterial infections: While most bacterial infections cause an increase in a different kind of white blood cells called neutrophils, there are some exceptions like Bartonella Henselae, which is responsible for cat scratch disease, and Bordetella Pertussis, which causes pertussis or whooping cough.
• Parasites: Toxoplasma Gondii, which typically affects people with weakened immune systems can also increase white blood cells.

Certain disorders can cause an increase in white blood cells, including chronic lymphocytic leukemia (a common type of blood cancer in the USA), non-Hodgkin lymphoma (a type of cancer that originates from cells in the immune system), and acute lymphoblastic lymphoma (a type of cancer that starts from young white blood cells).

Certain medications and drug reactions can also cause an increase in white blood cells. Persistent increased white blood cells might also indicate a rare genetic disorder, especially if it is present from birth and often leading to leukemia by adulthood. Stress and physical conditions, like the removal of the spleen, could also increase the amount of white blood cells.

Please note that having a high white blood cell count is often a sign of an infection or other immune response, and it is important to investigate the underlying cause to provide appropriate treatment.

Risk Factors and Frequency for Lymphocytosis

Lymphocytosis, or an increased number of lymphocytes in the blood, varies based on age and the various causes. Here are a few reasons behind it:

• EBV infection: This is a common condition worldwide and affects all age groups. About 90% of adults will catch it at some point. It usually affects young adults aged 15 to 24 but can occur later too. This condition seems to affect Caucasians more than African Americans.
• Pertussis and Cat Scratch Disease: Pertussis mainly affects children under ten years of age, but can also occur in adults and can be more severe in older people. On the other hand, Cat Scratch Disease is more common in children and young adults. In the United States, it’s more common in the southeastern region with a rate as high as 6.4 cases per 100,000 people.
• CLL: Also known as Chronic Lymphocytic Leukemia, CLL is the most common type of leukemia in adults in the U.S. It’s especially prevalent in older adults with the median age of diagnosis being 70. It’s more common in men and the white population.
• NHL: Also, called Non-Hodgkin’s Lymphoma, it’s present in 20 to 80% of cases of lymphocytosis.
• MBL: Monoclonal B-cell Lymphocytosis impacts 5 to 9% of people over age 60. MBL affects men more than women.
• DRESS: This is a severe allergic reaction to a drug. Lymphocytosis is present in 30 to 70% of DRESS cases.

Signs and Symptoms of Lymphocytosis

Taking a person’s medical history and performing a physical examination is a critical step in diagnosing an illness. This process may reveal the cause of the health issue and may also indicate the urgency of further examinations. Some important factors to consider during this evaluation are:

• The circumstances when the person sought medical help, such as after experiencing seizures or a heart problem
• Whether the person or their family has a history of lymphoproliferative disorders, diseases where the body produces too many lymphocytes
• Whether the person has been experiencing symptoms like fever, weight loss, or night sweats, which might indicate a clonal process or a disease involving the cells
• The age of the person because some diseases, like Chronic Lymphocytic Leukemia, usually affect older people, while others, similar to Acute Infectious Mononucleosis, are more common in young adults
• Whether the person had any previous surgery, such as the removal of the spleen which can lead to increased production of lymphocytes
• An examination of what medications a person is currently taking

Additional aspects of the person’s history might also be important, such as their sexual history, particularly if a suspected illness like HIV could have been transmitted sexually. The physical examination should be interpreted in the context of a person’s symptoms and situation, since signs such as rash, swollen lymph nodes, or an enlarged spleen could signify various types of disorders.

Testing for Lymphocytosis

If you have a higher number of lymphocytes (white blood cells that help your body fight off illnesses and diseases) than normal, your doctor might want to carry out detailed checks to find out why. This condition is known as lymphocytosis. Two important starting points for the investigation are a detailed health and lifestyle questionnaire and a physical examination.

Your doctor will likely perform a complete blood count (CBC). This is a blood test that counts all the different types of cells in your blood. This test can confirm lymphocytosis and can also show if there are changes to other blood cells too. For example, if you also have low levels of hemoglobin or platelets (other types of cells present in your blood), this could suggest a certain type of disorder such as chronic lymphocytic leukemia (CLL) or lymphoma. The CBC can also reveal the severity of the lymphocytosis and if there are irregular or young cells (blasts) in the blood. The presence of these could help decide the urgency for further checks.

Your doctor may also take a more detailed look at your blood under a microscope (called a peripheral blood smear or PBS). This can identify specific features of your lymphocytes which might suggest certain conditions. For example:

• Small, mature-looking lymphocytes and ‘smudge cells’ could indicate CLL (a type of blood and bone marrow cancer) or MBL (a condition where there are more lymphocytes than normal in the blood).
• Atypical large lymphocytes could indicate certain viral infections, such as EBV, CMV or early HIV.
• Lymphocytes with unusual shapes could be associated with diseases like pertussis (whooping cough) or follicular lymphoma (a slow-growing type of non-Hodgkin lymphoma cancer).
• Some types of lymphocyte might suggest specific forms of leukemia.

In some cases, further testing might be needed. For example, a test called flow cytometry might be used which can identify if there are too many identical (monoclonal) cells. But this is an expensive test, and only used in certain circumstances such as:

• The presence of lymphoblasts (a type of white blood cell) under the microscope, suggesting acute lymphoblastic leukemia (ALL) and warranting further investigation.
• Presence of other abnormal lymphocyte seen on the microscopic examination.
• A significantly high lymphocyte count.
• Persistent unexplained lymphocytosis for more than a month.
• Abnormalities in other cell lines including anemia and thrombocytopenia.
• Presence of lymphadenopathy (swollen lymph nodes) and/or hepatosplenomegaly (an enlarged liver and spleen) and the doctor has ruled out non-cancerous causes.

Further genetic tests like Fluorescence in situ hybridization (FISH), karyotype, and mutation analysis can help diagnose and risk stratification of blood cancers such as CLL and lymphomas. FISH test detects changes in genes or chromosomes that could indicate the presence of certain types of lymphomas.

Treatment Options for Lymphocytosis

If you’re diagnosed with lymphocytosis, which means you have a higher than normal amount of white blood cells called lymphocytes, how it’s managed will depend on its cause. It can be a response to something simple like stress, and won’t require treatment. But sometimes it’s due to a serious cause like cancer, and then treatment may be necessary.

If the lymphocytosis is caused by an infection like mononucleosis, management is typically supportive. Taking over-the-counter pain relievers can help ease symptoms, and patients are advised to avoid contact sports to prevent possible spleen damage, which is often enlarged due to the infection. The use of steroid medication to relieve symptoms is not broadly agreed upon due to a lack of strong supporting evidence.

For other infectious causes of lymphocytosis, treatment typically involves taking care of the infection at hand. For example, antibiotics are generally prescribed within the first three weeks of symptoms for adults who have pertussis, also known as whooping cough. Similarly, antibiotics can be used to treat infections caused by the bacteria Bartonella Henselae, infections related to Tuberculosis (MTB), HIV, or toxoplasmosis.

For chronic lymphocytic leukemia (CLL), a type of blood and bone marrow cancer that causes lymphocytosis, recent treatment advances have shifted towards targeted therapies such as certain inhibitors. The first step in managing CLL is determining which patients need treatment. This can be based on a variety of factors including symptoms, the size of lymph nodes and spleen, and the loss of normal blood cells. The second step is risk stratification and looking out for certain mutation markers as they can impact the effect of standard chemotherapy treatments. In some instances, targeted therapy might be a better option.

Research has shown that combining targeted therapies like ibrutinib (a type of BTK inhibitor) and rituximab – especially within younger patients (less than 70 years old) who have been diagnosed with CLL without a particular type of mutation – has significantly prolonged the life expectancy of the patients without disease getting worse, as well as the overall survival rate.

Management of non-Hodgkin lymphoma (NHL), another type of cancer that causes lymphocytosis, depends on the specific type of NHL. While an aggressive type called ‘double-hit’ DLBCL may require immediate treatment, a type known as low-grade FL may just be monitored for signs of growth or changes. Traditional chemotherapy medications are often used as a first-line of treatment, but there are newer targeted therapies available that are showing promise in improving patient outcomes. For MCL type of NHL, intense chemotherapy and sometimes stem cell transplantation are used.

For patients with MBL, or monoclonal B-cell lymphocytosis, which is a condition where a person has too many of a certain type of white blood cell but doesn’t have symptoms of CLL, typical management includes monitoring of the patient’s blood cell levels. Only patients with symptoms or worsening blood tests need further testing like imaging or bone marrow biopsies.

For DRESS syndrome, a reaction to a medication that causes extensive rash and affects internal organs, it’s important to stop taking the medication that caused the reaction. Supportive measures usually work for this condition. Corticosteroids may be needed depending on the extent of skin and internal organ involvement.

What else can Lymphocytosis be?

The possible causes of high lymphocyte count, also known as lymphocytosis, are numerous. The conditions that a doctor needs to rule out when diagnosing Lymphocytosis are: – Chronic lymphocytic leukemia (CLL) or lymphoma – Certain viral infections, such as EBV, CMV, or early HIV – Pertussis (whooping cough) or follicular lymphoma – Specific forms of leukemia – Acute lymphoblastic leukemia (ALL) – Non-cancerous causes of lymphadenopathy (swollen lymph nodes) and hepatosplenomegaly (enlarged liver and spleen)

What to expect with Lymphocytosis

The future health condition of a person with lymphocytosis largely depends on the root cause. Let’s explain a few specific cases:

• Acute mononucleosis: While most people recover from the initial bout of mononucleosis, some might feel tired for a long period. Also, the presence of Epstein-Barr virus (EBV) in the body’s B cells can lead to the formation of EBV-related blood cell disorders. Examples of these are disorders that occur after transplantation, Hodgkin lymphoma (HL), and Non-Hodgkin lymphoma, particularly in persons with weakened immune systems.
• Other infections: Pertussis, also known as whooping cough, in adults may lead to prolonged symptoms, lasting for more than two weeks. In the past, people in the advanced stages of HIV had a low life expectancy, anywhere from 12 to 18 months. Nowadays, the outlook depends on various factors, including how well antiretroviral therapies are working. There are also different models used to predict life expectancy in HIV patients, for instance, the Veterans Aging Cohort Study index.
• CLL: The outlook for Chronic Lymphocytic Leukemia (CLL) is mostly determined by how risky the case is and whether a patient has high-risk features or not. High-risk factors include certain genetic mutations and high levels of certain proteins and molecules, like ZAP-70, CD38, and Beta-2 microglobulin.
• NHL: The prognosis for Non-Hodgkin Lymphoma (NHL) depends on the subtype. Some subtypes, such as Follicular Lymphoma (FL), Marginal Zone Lymphoma (MZL), and Hodgkin Lymphoma (HL) are incurable but develop slowly and gradually. Conversely, Diffuse Large B-Cell Lymphoma (DLBCL) and T-cell lymphomas are aggressive but typically respond well to treatment.
• DRESS: For this severe skin reaction to certain medications, death rates range between 5 to 10 percent. However, most patients recover after stopping the problematic drug.

Possible Complications When Diagnosed with Lymphocytosis

The complications that come with lymphocytosis depend on the main cause, with leukemia being the most prevalent disease at the root of it.

• Hyperleukocytosis: This term refers to a white cell count surpassing 100000 cells/microliter. It’s more common in people who have been diagnosed with acute myeloid leukemia but can also be seen in individuals with acute lymphoblastic leukemia or CML. Hyperleukocytosis can lead to leukostasis (a symptom is vision loss), stroke, and even heart attack. Starting immediate treatment to lower the white-cell count, like taking hydroxyurea or doing leukapheresis, is necessary to alleviate symptoms.
• Infectious mononucleosis: People with infectious mononucleosis could experience rupture of the spleen and chronic tiredness as short-term complications. Long-term problems might include B-cell malignancies stemming from EBV infection, such as PTLD, HL, and NHL. These are typically seen in people with weakened immune systems.
• CLL (Chronic Lymphocytic Leukemia): CLL patients rarely experience leukostasis. Autoimmune processes can be a complication with CLL, including autoimmune hemolytic anemia and immune thrombocytopenia. Also, common is hypogammaglobulinemia, with or without recurrent infections. CLL patients are also at a higher risk for secondary cancers, both solid and blood-related ones.
• DRESS: In patients with DRESS, different organs can be affected, including the liver, lungs, and kidneys. Moreover, these patients have a higher chance of developing autoimmune diseases and future unexpected reactions to medications, regardless of whether the substances are structurally related or not.

Preventing Lymphocytosis

Lymphocytosis is a term that refers to having a high number of lymphocytes, a type of white blood cell, in your body. This condition often points to an underlying health problem. Doctors gauge this by looking if there are more than 4000 lymphocytes per micro-liter of blood. Highlighting this is a crucial first stage.

Knowing the level of urgency for referring the patient to a blood specialist (hematologist) is also important. Therefore, a thorough patient history, physical check-up, and blood count analysis give the initial indication towards the root cause of lymphocytosis.

For patients who don’t have worrying symptoms and their history points to a trigger for lymphocytosis, they can be comforted and observed regularly. Patients diagnosed with infectious mononucleosis, which is usually caused by the Epstein-Barr virus, should avoid playing contact sports during their illness’s peak stage. It’s also worth noting that tiredness might linger after other symptoms have disappeared.

However, if a patient has troubling symptoms like serious weight loss, lack of appetite, excessive nighttime sweats, or an unusual physical check-up result (like swelling in the lymph nodes or an enlarged liver or spleen), this should prompt an immediate referral to a hematologist for further evaluation. Patients who are suspected or confirmed to have leukemia, which is a type of cancer of the blood or bone marrow, should be quickly referred to specialty hospitals with expertise in leukemia treatment.