Receiving a blood test result that shows an extremely high white blood cell count can be a profoundly frightening moment. The first thought that often jumps to the minds of patients, families, and even doctors is leukemia. However, it is crucial to understand that there is another condition, known as a leukemoid reaction, that can perfectly mimic the laboratory findings of leukemia but is, in fact, a benign (non-cancerous) and temporary response to a severe underlying medical issue. It is a “great imitator” of blood cancer. A correct diagnosis is absolutely essential, because while the blood count may look alarming, a leukemoid reaction is not a disease in itself and will resolve completely once the underlying problem is treated.

A leukemoid reaction is defined as a very high white blood cell (WBC) count in the blood (typically above 50,000 cells per microliter) that is not caused by a primary bone marrow cancer like leukemia. It is a dramatic but appropriate reaction of a healthy bone marrow to a significant physiological stress, such as a severe infection, inflammation, or certain types of tumors.

To understand this critical distinction, it is helpful to use an analogy. Think of your bone marrow as a national military academy and your bloodstream as the country it protects.

• Leukemia is like a coup d’état within the academy itself. The training process has broken down. The academy begins to churn out massive numbers of defective, undisciplined, and immature cadets (cancerous blast cells). These faulty cells don’t know how to do their job, and they flood the country, causing chaos and preventing the real soldiers from functioning. The problem is with the academy.
• A Leukemoid Reaction is completely different. In this case, the military academy is perfectly healthy and functional. However, the country is facing a massive external invasion (like a severe bacterial infection). In response, the central command sends an emergency, “all-hands-on-deck” signal to the academy.
• The academy goes into overdrive, graduating every senior and near-senior cadet it can (mature and nearly mature neutrophils) and sending them out to fight the real threat. The number of “soldiers” on the streets is astronomically high, which looks alarming, but they are all well-trained, functional soldiers responding appropriately, if excessively to a real crisis. The problem is not the academy; the problem is the invasion it is fighting.

This is the key difference: leukemia is a malignant disease of the bone marrow, while a leukemoid reaction is a benign response from a healthy bone marrow.

In my experience, many clinicians initially confuse a leukemoid reaction with leukemia due to the dramatic white blood cell (WBC) elevation. It takes careful evaluation to distinguish the two.

The direct cause of a leukemoid reaction is the release of a massive number of white blood cells, primarily mature neutrophils, from the bone marrow into the bloodstream. This is triggered by high levels of inflammatory signals and growth factors in the body.

The underlying cause is always severe physiological stress. The most common conditions that can trigger this dramatic response include:

• Severe Infections: This is the most frequent cause. The body mounts an overwhelming response to fight off a life-threatening infection. Classic examples include:
  • Clostridioides difficile (C. diff) colitis, a severe colon infection.
  • Sepsis, a body-wide infection that has entered the bloodstream.
  • Tuberculosis (TB), particularly when it is widespread (miliary TB).
  • Other severe bacterial infections like whooping cough.
• Certain Cancers (as a Paraneoplastic Syndrome): Some solid tumors, such as certain types of lung cancer or kidney cancer, can produce and release their own growth factors that directly stimulate the bone marrow to overproduce white blood cells.
• Severe Inflammation or Tissue Injury: Conditions like major burns or massive trauma can cause a significant inflammatory response that triggers the bone marrow.
• Use of Certain Medications: The administration of high doses of corticosteroids or specific bone marrow-stimulating drugs called colony-stimulating factors (CSFs), like G-CSF, will predictably cause a leukemoid reaction.
• Severe Hemorrhage: A massive bleed can also trigger the bone marrow to release a large number of cells.

In my experience, patients typically develop leukemoid reactions as part of the body’s intense response to acute physiological stress often during sepsis, tissue necrosis, or hypoxia.

A person develops a leukemoid reaction as a secondary response to one of the severe underlying medical conditions listed above. It is not contagious, and it is not an inherited condition. It is a sign that the body is under extreme stress and that the bone marrow is mounting a powerful, defensive response. The risk factors for a leukemoid reaction are the risk factors for developing a severe infection or one of the other triggering conditions.

Clinically, I’ve encountered it most in hospitalized patients with untreated infections, metastatic cancers, or following major trauma or surgery.

This is a crucial point: There are no signs or symptoms of the leukemoid reaction itself. It is a laboratory finding discovered on a blood test.

The signs and symptoms a patient experiences are entirely due to the underlying condition that is causing the reaction. For example:

• If the cause is sepsis, the patient will have a high fever, a rapid heart rate, low blood pressure, and will appear very ill.
• If the cause is C. difficile infection, the patient will have severe, watery diarrhea, abdominal pain, and fever.
• If the cause is an underlying cancer, the patient may have symptoms like unexplained weight loss, chronic cough, or fatigue.

The leukemoid reaction is simply a clue that doctors use to understand the severity of the underlying illness.

Patients may not have symptoms directly from the high WBC count, but I usually focus on identifying underlying causes, fever, abdominal pain, respiratory distress, or bleeding.

When a blood test reveals a white blood cell count over 50,000, it is a critical finding that requires an immediate and thorough investigation by a hematologist. The entire goal of the diagnostic process is to definitively answer one question: Is this a benign leukemoid reaction or is it a life-threatening leukemia?

The Critical Distinction: Leukemoid Reaction vs. Chronic Myeloid Leukemia (CML)
The condition that a leukemoid reaction most closely mimics is a type of blood cancer called Chronic Myeloid Leukemia (CML). A hematologist will use a series of specific tests to tell them apart.

1. Peripheral Blood Smear: The first step after the initial CBC result is for a pathologist to carefully examine a smear of the blood under a microscope.
   • In a leukemoid reaction, the neutrophils are mature and often show “toxic changes” (like toxic granulation and Döhle bodies), which are signs that they are actively fighting a severe infection. Immature “blast” cells are typically absent.
   • In CML, the smear shows the entire spectrum of cell development, from very immature blast cells to mature neutrophils, all present at the same time. The number of other white blood cells, like basophils, is also often elevated.
2. Leukocyte Alkaline Phosphatase (LAP) Score: This is a classic biochemical test that can be very helpful. LAP is an enzyme found within mature, functional neutrophils.
   • In a leukemoid reaction, the mature neutrophils are healthy and working hard, so the LAP score is high.
   • In CML, the neutrophils are cancerous and dysfunctional, so the LAP score is characteristically low.
3. Genetic Testing for CML: This is the definitive test to rule out CML. A blood or bone marrow sample is tested for the specific genetic hallmark of CML, which is a translocation between chromosomes 9 and 22, known as the Philadelphia chromosome. This creates a unique fusion gene called BCR-ABL.
   • The presence of the BCR-ABL gene confirms a diagnosis of CML.
   • The absence of the BCR-ABL gene rules out CML and provides strong evidence that the high white blood cell count is a leukemoid reaction.
4. Bone Marrow Biopsy: A bone marrow biopsy may be performed. In a leukemoid reaction, the marrow will be hypercellular but will show orderly maturation and no evidence of a primary cancer.

In my experience, bone marrow biopsy is rarely needed unless there’s uncertainty or suspicion of hematologic malignancy, monitoring WBC trends in response to treatment is key.

The leukemoid reaction itself is a benign process and is never treated. The extremely high white blood cell count is a symptom, not the disease. Attempting to lower the white blood cell count would be like silencing a fire alarm while the building is still on fire.

The treatment is focused entirely on diagnosing and aggressively treating the underlying cause that triggered the reaction.

• If the cause is a severe bacterial infection, the patient will be treated with powerful intravenous antibiotics.
• If the cause is a C. difficile infection, specific antibiotics targeted at that bacteria will be given.
• If the cause is an underlying solid tumor, treatment will be for cancer.
• If the cause is medication, the offending drug will be stopped.

As the underlying condition is successfully treated and resolves, the stimulus for the bone marrow’s extreme response will disappear. The white blood cell count will then gradually return to the normal range on its own.

I focus treatment on the underlying cause whether infection, inflammation, or hemorrhage because the leukocytosis itself is not harmful and often resolves as the trigger is addressed.

A leukemoid reaction is a dramatic but benign overproduction of white blood cells that serves as a powerful signal that the body is fighting a severe underlying stress, most commonly a major infection. While the initial blood test results can be terrifying because they mimic the appearance of leukemia, it is essential to know that this is a completely different entity. It is the sign of a healthy, albeit over-reactive, bone marrow, not a cancerous one. A definitive diagnosis can be made with specific laboratory and genetic tests that can clearly distinguish it from leukemia. Clinically, I’ve found that differentiating it from leukemia through detailed workup helps avoid unnecessary panic and ensures that urgent underlying conditions get the attention they need.

1. The Merck Manual Professional Version. (2022). Leukemoid Reaction. Retrieved from https://www.merckmanuals.com/professional/hematology-and-oncology/leukemias/leukemoid-reaction
2. National Institutes of Health, National Cancer Institute (NCI). (n.d.). NCI Dictionary of Cancer Terms – Leukemoid Reaction. Retrieved from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/leukemoid-reaction