What Is Leukopenia?

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Leukopenia is the medical term that is used to describe a low white blood cell (leukocyte) count. Depending on the severity, leukopenia may increase the risk of infections, sometimes to a serious degree. There are many possible causes, including medications, infections, autoimmune conditions, cancer, vitamin deficiencies, and more. The evaluation begins with a complete blood count, but may include a number of further studies. When mild, the only treatment needed may be careful attention to reduce your risk of infections. Treatment options may include the use of growth factors to stimulate the production of white blood cells, as well as therapies that address the underlying cause of the leukopenia.

Types of White Blood Cells

To understand the potential complications and causes of leukopenia, it's very helpful to look at the different types of white blood cells, as certain conditions may affect some white blood cells but not others.

In addition, some causes of leukopenia may result in a low level of red blood cells (anemia) and/or platelets (thrombocytopenia) due to a common production pathway in the bone marrow. Pancytopenia is the medical term used to describe a decreased level of all the types of blood cells, including red blood cells (erythrocytes), platelets (thrombocytes), and white blood cells (leukocytes).

All of the types of blood cells ultimately originate from a pluripotential stem cell in the bone marrow. In a process called hematopoiesis, these cells go through a process of differentiation to eventually become all of the specific blood cells in circulation.

White blood cells differentiate along two different lines—granulocytes and agranulocytes.

Granulocytes

The white blood cells known as granulocytes differentiate from a progenitor cell along the myeloid cell line and are named for their appearance under the microscope. The white blood cells formed are the most numerous of white blood cells in the bone marrow and include:

  • Neutrophils: Often considered most important in relation to a low white blood cell count, neutrophils are white blood cells that are your primary defense against bacteria and other microorganisms. Neutrophils are also referred to as polymorphonuclear cells or PMNs.
  • Basophils: Basophils are much fewer numbers, and play a role in defending the body against bacteria, internal parasites, and external parasites (such as ticks).
  • Eosinophils: Best known as the type of white blood cell often elevated in people with allergies, these cells are important in defending our bodies against internal parasites (such as worms).
  • Monocytes: Monocytes develop from monoblasts and are sometimes thought of as the "garbage trucks" of the immune system. After leaving the bone marrow they spend only a few days in the bloodstream until they migrate into tissues and become macrophages. These cells clean up debris by a method called phagocytosis (essentially eating the debris).

Agranulocytes

Agranulocytes differentiate from a common progenitor cell (lymphoblast) via the lymphoid cell line. These cells differentiate into:

  • T lymphocytes (T cells): T cells work by directly killing bacteria, viruses, and cancer cells in a process called cell-mediated immunity. There are many different types of T cells that all perform different functions, such as cytotoxic T cells, helper T cells, memory T cells, and natural killer T cells. Cytotoxic T cells or CD8+ cells play an important role in removing virus-infected cells from the body.
  • B lymphocytes (B cells): B cells are involved in a different form of defense against microorganisms, referred to as humoral immunity. B cells may present antigens (a marker of something abnormal in the body) to T cells in addition to differentiating into plasma cells that produce antibodies. B cells, in this way, perform an important role in "remembering" a foreign bacteria or other pathogen for the future.
  • Natural killer cells: Natural killer cells are different than natural killer T cells and play an important role in fighting cancer in the body.

Leukopenia Symptoms

The signs and symptoms of leukopenia are primarily the symptoms related to infections that may develop, although with severe leukopenia, nonspecific symptoms or fatigue and feeling ill are often present. Warning signs for potential leukopenia include frequent infections, infections that won't resolve, a general feeling of being ill, and inflammation or ulcers in or around the mouth. Symptoms of infection may include:

  • Fever, chills, and/or night sweats
  • Headache or stiff neck
  • Sore throat
  • Mouth sores or white patches in the mouth
  • Cough or shortness of breath
  • Pain or burning with urination
  • Drainage, redness, or swelling around a skin wound
  • Abdominal pain and/or diarrhea

It's important to note that, even when a serious infection is present, signs and symptoms may not be as apparent due to the lack of white blood cells. (White blood cells are responsible for creating the signs of inflammation, pus, etc.)

If anemia (a low red blood cell count) also occurs, symptoms may include:

  • Lightheadedness or fainting
  • A rapid heart rate
  • Pale skin

If thrombocytopenia s also present, signs may include:

  • Bruising
  • Small red spots on the skin that don't blanch with pressure (petechiae)
  • Nosebleeds
  • Blood in the urine or stool
  • Heavy menstrual periods

Causes

There are many conditions that can result in a low white blood cell count, but the first step is to consider whether a true decrease in the number of white blood cells is present. And even if the number is low (when compared with the lab's reference range), whether the number is of concern or not.

Benign ethnic neutropenia (also called physiologic leukopenia or constitutional neutropenia) is an inherited condition in which a person has a low white blood cell count. These lower white blood cell counts are a very common cause of apparent neutropenia in people of African, Middle Eastern, or West Indian heritage. The hallmark of benign ethnic neutropenia is that even though the white blood cell count is below the normal range, these people do not have an increased risk of infection.

An awareness of benign ethnic neutropenia is particularly important in cancer treatment, as cut-offs for continuing chemotherapy (or holding off) or participating in clinical trials may not consider this diversity in "normal' white blood cell counts.

Pseudoleukopenia is a term that simply means the white blood cell count appears low, but is actually not. Pseudoleukopenia may be caused by changes in the lab specimen after it is drawn (in vitro) such as clumping of cells in response to cold. The phenomenon may also occur at the beginning of an infection as white blood cells migrate into tissues (to fight the infection) or are temporarily used up fighting the infection, before more can be released from the bone marrow.

Mechanisms

In looking at the potential causes of leukopenia, it's helpful to understand the possible mechanisms responsible for the low counts. These can include:

  • Decreased production: Conditions such as protein-calorie malnutrition or some vitamin deficiencies may reduce the availability of "building blocks" for white blood cells so that they are underproduced. Anything that interferes with the bone marrow can also lead to reduced production.
  • Increased breakdown: Conditions such as some autoimmune disorders may produce antibodies against white blood cells so that they are broken down too rapidly.
  • Increased consumption: White blood cells may be "used up" as they fight infections in the body, especially severe infections (eg. sepsis).
  • Sequestration: White blood cells may be sequestered (build up) in the spleen in conditions such as cirrhosis of the liver.

Absolute vs. Relative Leukopenia

When looking at the number of white blood cells on a complete blood count, it's important to note that only a minority of the white blood cells present in the body circulate in the bloodstream. For this reason, the number can sometimes shift quite rapidly.

Only around 2% to 3% of mature leukocytes are circulating freely in the blood. Roughly 80% to 90% remain in the bone marrow, stored in case they might be needed quickly. The remainder of white blood cells line blood vessels so that they do not freely circulate (and thus aren't detected on a CBC). Once in the bloodstream, white blood cells live on average from two to 16 days.

A number of conditions can cause the white blood cells lining the blood vessels to enter the circulation (demargination), such as shock, heavy exercise, or great stress. This may cause a white count that is actually low to appear normal. In contrast, dilution of the blood, such as when a person receives a plasma transfusion, may artificially lower the white blood cell count.

General Leukopenia

We will begin by looking at potential causes of leukopenia in general, and then look at causes that may lead to a deficiency of one type of blood cell over another.

In developed countries, drug induced leukopenia is most common, and can be caused by different mechanisms depending on whether the drug injures bone marrow or results in autoimmunity that causes the breakdown of the cells. Worldwide, malnutrition (leading to decreased production) is most common.

Drug-Induced and Treatment

A wide range of medications may be responsible for leukopenia, and your doctor will likely begin to evaluate your leukopenia (in the absence of other symptoms) but carefully reviewing your medications. Medications can lead to leukopenia in a number of different ways including direct suppression of the bone marrow, by having a toxic effect on the cells that become leukocytes, or by leading to an immune reaction in which the body attacks its own white blood cells. Some relatively common causes include:

Chemotherapy drugs: A low white blood cell count due to chemotherapy (chemotherapy-induced neutropenia) is a very common cause, as well as a serious cause of leukopenia. Different chemotherapy drugs affect bone marrow in different ways. While the timing varies between drugs, the point at which the white blood cell count reaches it's lowest point (the nadir) is roughly 10 to 14 days after an infusion.

Other Medications:

  • Seizure medications: Lamictal (lamotrigine), valproic acid, phenytoin, carbamazepine
  • Antibiotics, especially Septra or Bactrim (trimethoprim/sulfamethoxazole), Minocin (minocycline), penicillin derivatives (such as Amoxicillin), cephalosporins, and Flagyl (metronidazole).
  • Pain medications such as aspirin, and non-steroidal anti-inflammatory drugs such as ibuprofen.
  • Antivirals such as acyclovir
  • Psychiatric medications such as clozapine, Wellbutrin (bupropion), chlorpromazine, risperidone, and haloperidol
  • Heart medications, such as thiazide diuretics, beta-blockers, and spironolactone
  • Immunosuppressive medications to prevent transplant rejection, treat inflammatory arthritis such as sirolimus, tacrolimus, mycophenolate mofetil, leflunomide
  • HIV medications (antiretrovirals)
  • Biologic therapies such as TNF inhibitors, Proleukin (interleukin-2), and Rituxan (rituximab)
  • Multiple sclerosis medications such as interferon beta-1a and interferon beta-1b

Idiopathic

Sometimes a cause of leukopenia is not apparent, even with a thorough laboratory workup. The term idiopathic is used as a catch-all category to describe a condition that occurs for a reason that is not apparent. An example is chronic idiopathic neutropenia.

Infections

Infections are, counterintuitively, a relatively common cause of leukopenia. Leukopenia may occur during the acute infection with some infections or primarily in the postinfectious stage with others.

With sepsis, an overwhelming body-wide bacterial infection, leukopenia may occur as available white blood cells are "used up" fighting the infection.

There are some infections in which leukopenia is quite common, including:

  • Viral infections: Epstein Barr virus (mono), respiratory syncytial virus (RSV), parvovirus, influenza, cytomegalovirus, hepatitis A and B, measles, dengue fever, HIV (roughly 70% of people with HIV will experience leukopenia)
  • Rickettsial diseases: Lyme disease, Ehrlichiosis, anaplasmosis, typhus, Rocky Mountain spotted fever
  • Bacterial infections: Shigella, salmonella, pertussis (whooping cough), brucellosis, tuberculosis and atypical mycobacterial strains, psittacosis
  • Parasites: Malaria

Several of these infections may also cause anemia (a low red blood cell count) and thrombocytopenia (a low platelet count).

Conditions That Affect the Bone Marrow

Anything that interferes with the production of white blood cells in the bone marrow may potentially lead to leukopenia, including:

  • Infiltration of the bone marrow: Infiltration of the bone marrow (such as in acute leukemia and large granular lymphocyte leukemia) can disrupt the process of blood cell formation. Metastases to the bone marrow can similarly lead to leukopenia. Cancers that tend to spread to the bone marrow include breast cancer, prostate cancer, colon cancer, melanoma, and stomach cancer.
  • Bone marrow disorders, including aplastic anemia, myelodysplastic syndromes, multiple myeloma, myelofibrosis

Collagen Vascular Diseases/Autoimmune Conditions

A number of conditions can result in the destruction of white blood cells.

Primary autoimmune conditions include

  • Primary autoimmune neutropenia
  • Chronic benign neutropenia of childhood

Secondary autoimmune conditions include conditions such as:

  • Lupus (very common)
  • Rheumatoid arthritis
  • Sjogren's syndrome
  • Mixed connective tissue disease
  • Polymyalgia rheumatic
  • Crohn's disease

Some of these conditions can lead to leukopenia in more than way. For example, Felty's syndrome (an enlarged spleen plus neutropenia) can lead to the sequestration of white blood cells as well.

Other autoimmune causes include:

  • Pure white cell aplasia
  • T-gamma lymphocytosis

Environmental Exposures

Exposures in the environment or lifestyle practices may lead to leukopenia, including:

  • Mercury, arsenic, or copper exposure
  • Heavy alcohol use
  • Radiation exposure

Vitamin and Nutritional Deficiencies

Protein-calorie malnutrition is a common cause of leukopenia resulting from inadequate production of leukocytes.

Vitamin B12 and folate deficiencies are a relatively common cause, as well as iron deficiency anemia.

Inflammatory

Sarcoidosis is a little-understood inflammatory condition that commonly results in leukopenia.

Hypersplenism

An enlarged spleen can result in the sequestration of leukocytes in the spleen. It may occur with cirrhosis of the liver, some blood disorders, or Felty's syndrome.

Congenital Conditions

Leukopenia or neutropenia are seen with a number of congenital conditions and syndromes, such as:

Other Causes

Hemodialysis often results in leukopenia, as well as transfusion reactions.

Causes of Low Levels Specific Types of White Blood Cells

Some medical conditions lead to a disproportionally low number of one specific type of white blood cells, and other white blood cell counts may be normal. An isolated low level of some types of white blood cells may also be important in predicting the presence of or severity of a disease.

Neutropenia: A low level of neutrophils is often the most concerning of the leukopenia due to the risk of infection. Neutropenia without general leukopenia (isolated neutropenia) suggests causes such as autoimmune diseases or vitamin deficiencies (processes that may affect only the one type of white blood cell) whereas conditions involving the bone marrow usually affect all types of white blood cells.

Eosinopenia: A low level of eosinophils (eosinophilic leukopenia) is commonly seen with physical or emotional stress (due to the release of stress hormones), with Cushing's syndrome, and with acute inflammation. Eosinopenia also appears to be an important marker for sepsis.

Basopenia: A low levels of basophils (basophilic leukopenia) may be seen with:

  • Allergic conditions, such as hives (urticaria), severe allergies, angioedema, and anaphylaxis
  • With high doses or long term use of corticosteroids
  • With stress
  • During the acute phase of infections or inflammation
  • With hyperthyroidism or thyrotoxicosis

Lymphopenia: Lymphopenia without a correspondingly low level of other white blood cells is not very common but can be very important in some cases or provide helpful information. Causes may include:

  • Corticosteroids
  • Kidney failure
  • Radiation
  • Hodgkin's disease
  • Drugs used to prevent transplant rejection
  • Some viral infections, especially HIV/AIDS with a deficiency of CD4 T cells
  • Congenital conditions, such as severe combined immunodeficiency

Lymphocyte counts tend to drop with normal aging, although lymphopenia appears to correlate with the overall risk of death in adults in the U.S.

From a prognostic standpoint, recent research suggests that Lymphopenia predicts the severity of disease, and likelihood that it will progress to the need for intensive care or death with COVID-19.

Monocytopenia: An isolated low level of monocytopenia is most often seen at the beginning of corticosteroid use.

Diagnosis

In some cases, the cause of leukopenia may be obvious and no workup will be needed (for example, if a person is receiving chemotherapy). Other times, making the precise diagnosis can be challenging.

History and Physical

The diagnostic process should begin with a careful history including any risk factors for conditions note above, medications used, a history of travel, and much more. The physical exam should look for any signs of infection (noting that these may not be present with a very low white count, and even imaging findings may not be as obvious, such as signs of pneumonia on a chest X-ray). Lymph nodes (including those above the collar bone), and the spleen should be carefully checked, and the skin examined for any evidence of bruising.

Blood Tests

A number of laboratory tests may help narrow down the causes:

  • Complete blood count (CBC): The laboratory evaluation can begin by evaluating the numbers on the complete blood count, including the proportions of white blood cells, the red blood cell count, and the platelets. Red blood cell indices (such as MCV) can sometimes give important clues as to causes such as vitamin B12 deficiency. Certainly comparing with results with any previous complete blood counts is helpful.
  • Blood smear: A peripheral smear for morphology can be helpful in looking for any changes in the blood cells, such as toxic granulations in neutrophils sometimes seen with infections. Looking for any signs of immature white blood cells is also very helpful when looking for severe infections or blood related cancers.
  • Reticulocyte count: If the red blood cell count is also low, a reticulocyte count can help determine if the blood counts are low due to lack of production, or some other mechanism.

Reference Ranges

The term leukopenia is usually used to describe the total white count being low, but this may involve decreased levels of some types of white blood cells and normal numbers of others. In some cases, the total white blood cell count may be low, but one type of white blood cell may actually be high.

The normal range for white blood cell count varies based on the time of day. The level can also change, sometimes significantly, in response to physical or emotional stress.

Different white blood cells make up different percentages of the total white blood cell count. This includes:

  • Neutrophils (55% to 70%)
  • Band neutrophils (0% to 3%)
  • Lymphocytes (20% to 40%): The percentage of lymphocytes is higher in children between the age of 4 and 18 than it is in adults.
  • Monocytes (2% to 8%)
  • Eosinophils (1% to 4%)
  • Basophils (0.5% to 1%)

Total White Blood Cell Count: The range of total white blood cells in adults in children is as follows:

  • Men: 5,000 to 10,000 cells per microliter (uL)
  • Women: 4,500 to 11,000 cells per uL
  • Children: 5,000 to 10,000 cells per uL (from infancy through adolescence)

Absolute Neutrophil Count: The absolute level (total white blood cell count multiplied by the percentage of a particular type of white cell) of the different types of white blood cells can be a very important lab value, especially with regard to neutrophils.

The range for absolute neutrophil count is between 2,500 cells/uL and 6,000 cells/uL.

An absolute neutrophil count (ANC) less than 2,500 would be called neutropenia, but the number usually needs to fall below 1,000 cells/uL before the risk of developing a bacterial infection increases significantly. If the ANC falls below 500 cells/uL, the risk of infection increases sharply. The term "agranulocytosis" is sometimes used interchangeably with an ANC less than 500 cells/uL.

It's noteworthy that people may have neutropenia despite a normal total white blood cell count (often because the absolute lymphocyte count is elevated).

Other Laboratory Tests

Tests for causes may include:

  • Vitamin B12 or folate levels
  • Blood cultures
  • Viral cultures
  • Flow cytometry
  • Tests to detect autoimmunity such as antinuclear antibodies (anti-neutrophil antibody testing is primarily helpful in children)
  • Genetic testing if a congenital cause is suspected

Bone Marrow Examination

A bone marrow biopsy may be needed in order to look for an underlying cancer (such as leukemia) or bone marrow disorder such as aplastic anemia.

Imaging

Imaging tests are not often needed to diagnose leukopenia, unless an underlying cancer or bone infection is suspected.

Treatment

Whether leukopenia requires treatment depends on the white blood cell count, especially the absolute neutrophil count.

Treatment of the Underlying Cause

Often times, treating the underlying cause of the leukopenia is most effective, such as replacing deficient vitamins or treating infections. With severe conditions such as aplastic anemia, this may require bone marrow transplantation.

Antibiotics

If leukopenia is severe (severe absolute neutropenia) such as due to chemotherapy and a fever is present (or even without a fever if the counts are very low), antibiotics are sometimes used even if an obvious source of infection is not found. This may also be the case with some antivirals or antifungals (for example, preventive antifungals may be given for Aspergillus).

Transfusions

Granulocyte infusions are rarely used and their use is controversial. That said, there may be settings in which they are recommended such as for people who are very high risk.

Growth Factors

Medications (growth factors) may be used to stimulate the production of neutrophils in your bone marrow (preventively or as a treatment for a low neutrophil count). The use of growth factors to stimulate the development and maturation of granulocytes has become standard of care even preventively with some cancers, and has allowed physicians to use chemotherapy drugs at higher doses than in the past.

Granulocyte colony-stimulating factors (G-CSFs) and granulocyte-macrophage colony-stimulating factors that are available include:

Preventing Infections

If a person's white blood cell count is very low, hospital admission may be required. Otherwise, care to prevent infections is crucial even if growth factors are given. This includes:

  • Avoiding crowded conditions
  • Limiting visitors if hospitalized
  • Avoiding contact with anyone who is ill
  • Practicing food safety (no raw meat or seafood, washing vegetables, avoiding soft cheeses, etc.)
  • Practicing caution with pets (avoiding litter boxes, birdcages, not handling reptiles, etc)

A Word From Verywell

There are many potential causes of leukopenia ranging from primarily a nuisance to life-threatening. The primary risk is that of infection, and measures to reduce that risk and treat infections that are present are foremost.

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