Introduction

The word “lymphocytosis” means there is a sudden increase in the number of lymphocytes in the blood, usually after an infection. These cells are one of the forms of WBC (white blood cell), which can be divided into 3 cells: T-cells, B-cells and Natural killer cells, that help strengthen immunity by fighting against different diseases.¹

Other than the common typical causes, which are infections, autoimmune diseases, tumours and certain cancers, multiple other factors may lead to lymphocytosis, but drug-induced lymphocytosis is a cause that is often overlooked.

Here, we will look at the medications that play a role in developing this condition and explain why it is important to identify it. Knowing this stops wrong medical evaluation or diagnosis and ensures people living with this condition get the right quality care and health services.

Overview of lymphocytosis

Normal range of lymphocytes

Generally,20% to 40% of white blood cells are lymphocytes. The total lymphocyte count in blood is between 1000 and 4800 per μL (microliter) in adults, and in children, the levels are between 3000 and 9500 per μL (microliter).

Mechanisms behind Drug-Induced Lymphocytosis

The following are a few different mechanisms behind drug-induced lymphocytosis.

• Immune activation: Some drugs activate the immune response of the body, which causes an increase in the production of lymphocytes as part of the body’s defence response
• Allergic reactions: When the body thinks of a drug as a threat, and the immune system reacts by increasing lymphocyte levels, it is known as a hypersensitivity reaction
• Shifting from tissues to bloodstream: Some medications can cause lymphocytes that normally reside in tissues to move or distribute into the bloodstream, temporarily increasing their levels in blood tests
• Boosting bone marrow activity: A few drugs promote overall white blood cell production in the bone marrow, which includes a rise in lymphocytes²

Signs & symptoms of lymphocytosis

Having an increased number of lymphocytes on its own doesn’t necessarily make you feel ill or show obvious signs and symptoms. But the health problem or certain medications can show clear signs.

For example, if your body is responding to an infection or disease, such as tuberculosis, hepatitis, or pertussis, by mounting a defence, your neck glands or lymph nodes might swell. How you feel depends on what’s causing the lymphocyte rise – some people feel absolutely okay, while others may not because of experiencing illness or discomfort. Often, people don’t know their lymphocyte count is high until a blood test for something else finds it.^3,4

Drugs commonly associated with lymphocytosis 

Tyrosine Kinase Inhibitors (TKIs)

Example: Dasatinib

Mechanism: TKIs (tyrosine kinase inhibitors) are usually dispensed for chronic myeloid leukaemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL). One of its interesting immune-related effects is the expansion of cytotoxic CD8+ T cells and natural killer (NK) cells, which causes the development of large granular lymphocytosis (LGL).⁵ 

Burton’s Tyrosine Kinase Inhibitors (BTKIs)

Example: Ibrutinib

Mechanism: It is an oral BTK inhibitor mostly used for the treatment of chronic lymphocytic leukaemia (CLL). One of the distinguishing features that is seen in early treatment is lymphocytosis, which is initially concerning but is now recognised as part of the drug’s therapeutic effect. It works by irreversibly binding to Burton’s Tyrosine Kinase Inhibitor (BTKI), which is a key enzyme in the B-cell receptor (BCR), and blocks it by disrupting the signals that keep malignant B-cells anchored in lymphoid tissues, which results in the movement of these cells into the bloodstream, causing a temporary spike in lymphocyte counts. It shows effective drug action and may persist beyond one year in patients, but remains charmless, without affecting overall treatment success.^6,7

Anticonvulsants

Example: Lamotrigine

Mechanism: In some cases, Anticonvulsants can cause a severe immune reaction known as DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms). This reaction involves abnormal activation of T-lymphocytes, leading to atypical lymphocytosis. The immune system mistakenly identifies the drug as harmful or a threat to the body, causing T-cells to multiply rapidly and move into the bloodstream.⁶

Antibiotics & antimicrobial

Example: Vancomycin, Sulfa drugs also known as sulphonamides

Mechanism: In some cases, both of these antibioticdrugs can also cause DRESS syndrome, as discussed in the above heading of Anticonvulsant drugs.^2,8

How is drug-induced lymphocytosis diagnosed?

History and physical examination

• A detailed medication and symptoms history is essential to identify recent drug administration
• Besides this, a physical exam may show signs and symptoms of a drug reaction, such as skin rashes or red spots, fever and lymph node enlargement²

Lab tests

• A complete blood count (CBC) test is used to confirm lymphocytosis by assessing the actual lymphocyte count in the blood sample
• Also, looking at a blood smear test results helps in distinguishing between reactive lymphocytes (usually from infections or drug adverse or side effects) and odd or cancerous cells that may point to a blood illness or blood cancer²

Lymphocytosis transformation Test (LTT)

It checks if T-cells grow or send out signals when reacting to a drug or medications, which helps spot immune reactions, but results don’t always match with signs and symptoms.⁹

How is it done?

• Blood with heparin gets T cells out while avoiding too many macrophages that ruin the test
• Test Setup: Cells are grown in petri dishes in the lab with either special serum or the patient’s own plasma, as results can change or vary⁹

Clinical management of drug-induced lymphocytosis.

• Stop the suspected drug: Discontinue the medication immediately, causing an immune response or hypersensitivity reaction
• Monitor lymphocyte count: Regularly check lymphocyte levels in the blood to track recovery through techniques, like flow cytometry or Coulter Counter¹⁰
• Symptomatic treatment or support: Treat symptoms if present (e.g., rash, fever) with antihistamines, corticosteroids, or supportive care
• Alternative medications: Pick a different, safer drug that doesn’t induce lymphocytosis if treatment is still needed to continue

Latest research and ongoing studies on drug-induced lymphocytosis

As there is a considerable amount of research on new drugs, which are mainly for cancer, either malignant or benign and autoimmune problems or different diseases are introduced, experts and researchers are finding more links between these medications and blood-related diseases like lymphocytosis.^5,6,7,8

Recent studies are actively monitoring and evaluating which new medications are most likely to cause these changes and have a big impact on patients' bodies. There's increasing attention on the safety of drugs, which is also called pharmacovigilance, which means keeping track of medication usage and reporting side effects or adverse effects caused by medications. By finding and understanding new trends or patterns, we can keep people safe and act quickly when a drug is linked to odd blood levels and causes abnormality in blood cells. 

FAQs

Is drug-induced lymphocytosis life-threatening?

In most cases, it's not life-threatening and can be reversed after stopping certain medications. However, it must be monitored to rule out the risks and benefits of taking medicines, like in managing serious conditions, e.g, leukaemia or viral infections.

How is drug-induced lymphocytosis different from viral or cancer-related lymphocytosis?

• Viral: Lymphocytes may be reactive & infection signs are present like fever or sore throat, but it is temporary and returns to normal after the infection clears
• Cancer (e.g. CLL): It happens when normal lymphocytes in your bone marrow mutate, turn into cancerous cells and start multiplying uncontrollably. It involves malignant cells and needs targeted cancer therapy 
• Drug-induced: It can be reversed after stopping certain medications & there are no malignant cells

Should I stop taking my medicines if I get lymphocytosis?

No, you should not stop any medicines without a doctor's say so. It could cause bigger health problems.

Summary 

Lymphocytosis refers to an increase in the number of lymphocytes in the blood, usually after an infection. Drug-induced lymphocytosis occurs when a person has too many lymphocytes in their white blood cells due to certain medications. People or health care providers frequently neglect and think it’s an infection or blood cancer.

Drugs like cancer medications, e.g., Tyrosine Kinase Inhibitors (TKIs) like dasatinib, Bruton’s Tyrosine Kinase Inhibitors (BTKIs) like Ibrutinib; anti-seizure drugs like lamotrigine; and antibiotics, like vancomycin and Sulfonamide drugs. It can be induced by alterations in lymphocytes in the blood, due to allergic-like reactions, or the immune system of the individual being alerted, or shifts of lymphocytes into the blood.

The majority of people going through lymphocytosis are treatable with a thorough and precise medication history, observing blood cell count, symptoms, dependent treatment, and medication changes when necessary. Awareness among medical professionals and the general public can stop misdiagnosis and unnecessary testing and strengthen the overall healthcare system.