Leukopenia (low white blood cell count) has many possible causes and can increase the risk of infection. Reviewed by a board-certified physician. 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
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.
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.
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:
Agranulocytes differentiate from a common progenitor cell (lymphoblast) via the lymphoid cell line. These cells differentiate into:
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:
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:
If thrombocytopenia s also present, signs may include:
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.
In looking at the potential causes of leukopenia, it's helpful to understand the possible mechanisms responsible for the low counts. These can include:
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.
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.
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 its lowest point (the nadir) is roughly 7 to 14 days after an infusion.
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 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:
Several of these infections may also cause anemia (a low red blood cell count) and thrombocytopenia (a low platelet count).
Anything that interferes with the production of white blood cells in the bone marrow may potentially lead to leukopenia, including:
A number of conditions can result in the destruction of white blood cells.
Primary autoimmune conditions include
Secondary autoimmune conditions include conditions such as:
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:
Exposures in the environment or lifestyle practices may lead to leukopenia, including:
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.
Sarcoidosis is a little-understood inflammatory condition that commonly results in leukopenia.
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.
Leukopenia or neutropenia are seen with a number of congenital conditions and syndromes, such as:
Hemodialysis often results in leukopenia, as well as transfusion reactions.
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:
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:
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.
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.
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.
A number of laboratory tests may help narrow down the causes:
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:
Total White Blood Cell Count: The range of total white blood cells in adults in children is as follows:
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).
Tests for causes may include:
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 tests are not often needed to diagnose leukopenia, unless an underlying cancer or bone infection is suspected.
Whether leukopenia requires treatment depends on the white blood cell count, especially the absolute neutrophil count.
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.
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).
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.
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:
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:
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.