Leukopenia: an overview and more

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Leukopenia is the medical term used to describe a low count of white blood cells (white blood cells). Depending on the severity, leukopenia can increase the risk of infections, sometimes severely. 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 additional tests. In mild cases, the only treatment needed may be to focus on reducing the risk of infection. Treatment options may include the use of growth factors to stimulate white blood cell production, as well as treatments that target the underlying cause of the leukopenia.

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Types of white blood cells

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

Also, some causes of leukopenia can lead to 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 low levels of all types of blood cells, including red blood cells (red blood cells), platelets (platelets), and white blood cells (white blood cells).

All types of blood cells ultimately originate from pluripotent stem cells in the bone marrow. In a process called hematopoiesis , these cells undergo a differentiation process to eventually become all of the specific blood cells found in the bloodstream.

Leukocytes differentiate along two different lines: granulocytes and agranulocytes.

Granulocytes

White blood cells, known as granulocytes, differentiate from progenitor cells along the myeloid cell line and are named after their appearance under the microscope. The resulting white blood cells are the most abundant of the white blood cells in the bone marrow and include:

  • Neutrophils : Neutrophils , which are often considered the most important for low white blood cell counts, are white blood cells that are your main defense against bacteria and other microorganisms. Neutrophils are also called polymorphonuclear cells or PMNs.
  • Basophils – Basophils are much smaller and play a role in protecting the body from bacteria, internal and external parasites (eg, ticks).
  • Eosinophils: better known as a type of white blood cell, often elevated in people with allergies, these cells are important in our body's defense against internal parasites (such as worms).
  • Monocytes : Monocytes develop from monoblasts and are sometimes considered the "garbage trucks" of the immune system. After leaving the bone marrow, they spend only a few days in the bloodstream until they enter the tissues and become macrophages. These cells collect waste using a technique called phagocytosis (essentially eating the waste).

Agranulocytes

Agranulocytes differentiate from a common progenitor cell (lymphoblasts) through a 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 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 another form of defense against microorganisms called humoral immunity. B cells can present antigens (a marker for something abnormal in the body) to T cells in addition to differentiating into antibody-producing plasma cells. Therefore, B cells play an important role in remembering foreign bacteria or other pathogens for the future.
  • Natural Killer Cells : Natural killer cells are different from 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 symptoms associated with infections that can develop, although nonspecific symptoms or fatigue and malaise are often present in severe leukopenia. Warning signs of possible leukopenia include frequent infections, infections that persist, a general feeling of illness and inflammation or sores in or around the mouth. Symptoms of an infection can include:

  • Fever, chills, and / or night sweats.
  • Headache or stiff neck
  • Throat pain
  • Mouth sores or white patches in the mouth.
  • Cough or shortness of breath
  • Pain or burning sensation when urinating.
  • Drainage, redness, or swelling around the skin wound.
  • Abdominal pain and / or diarrhea.

It is important to note that even if there is a severe infection, the signs and symptoms may not be as obvious due to a lack of white blood cells. (White blood cells are responsible for the appearance of signs of inflammation, pus, etc.)

If anemia (low red blood cell count) is also present, symptoms may include:

  • Dizziness or fainting
  • Cardiopalmus
  • Pale skin

If there is also thrombocytopenia, symptoms may include:

  • Bruises
  • Small red spots on the skin that do not go away with pressure (petechiae)
  • Nosebleeds
  • Blood in urine or stool
  • Heavy menstrual periods

Causes

There are many conditions that can cause a low white blood cell count, but the first step is to determine if there is a true decrease in the white blood cell count. And even if that number is small (compared to the laboratory's reference range), whether that number is a concern or not.

Benign ethnic neutropenia (also called physiological leukopenia or constitutional neutropenia) is an inherited disorder in which a person has a low white blood cell count. This lower white blood cell count is a very common cause of overt neutropenia in people of African, Middle Eastern, or West Indian descent. The hallmark of benign ethnic neutropenia is that although white blood cell counts are below normal, these people are not at increased risk of infection .

Knowledge of benign ethnic neutropenia is especially important in cancer treatment, because thresholds for continuing chemotherapy (or withholding) or participating in clinical trials may not account for this diversity in "normal" white blood cell counts.

Pseudoleukopenia is a term that simply means that the white blood cell count appears to be low, but in reality it is not. Pseudoleukopenia can be caused by changes in the laboratory sample after collection (in vitro), for example, the accumulation of cells in response to cold. This phenomenon can also occur early in infection, when white blood cells migrate into tissues (to fight infection) or are temporarily used to fight infection before more can be released from the bone marrow .

Mechanisms

When considering the potential causes of leukopenia, it is helpful to understand the possible mechanisms responsible for the low rates. They may include:

  • Decreased production: conditions such as protein-calorie malnutrition or deficiency of certain vitamins can reduce the availability of basic components for white blood cells so that they are not produced enough. Anything that affects bone marrow function can also cause decreased production.
  • Improved breakdown: Conditions like some autoimmune diseases can produce antibodies against white blood cells, so they break down too quickly.
  • Increased Intake: White blood cells can be "depleted" as they fight infections in the body, especially serious infections (such as sepsis).
  • Sequestration: White blood cells can sequester (accumulate) in the spleen in conditions such as cirrhosis of the liver.

Absolute and relative leukopenia

Considering the number of leukocytes in the general blood test, it is important to note that only a small part of the leukocytes present in the body circulate in the bloodstream. For this reason, the number can sometimes change quite quickly.

Only 2% to 3% of mature leukocytes circulate freely in the blood. About 80% to 90% remain in the bone marrow, where they can be quickly needed. The rest of the leukocytes line the blood vessels, so they cannot circulate freely (and therefore are not detected in a complete blood count). Once in the bloodstream, leukocytes live for an average of two to 16 days .

Several conditions can cause the white blood cells that line the blood vessels to enter the bloodstream ( demargination ), such as shock, intense exercise, or severe stress. This can make it appear normal to have a low white level. Conversely, thinning the blood, such as through a plasma transfusion, can artificially lower the white blood cell count.

General leukopenia

We will start by looking at the possible causes of leukopenia in general, and then we will look at the causes that can lead to the deficiency of one type of blood cell compared to another.

In developed countries, drug-related leukopenia is the most common and can be caused by various mechanisms depending on whether the drug damages the bone marrow or results in autoimmunity that causes cell degradation. Across the world, undernutrition (leading to reduced productivity) is the most common.

Medication and treatment

A wide range of medications can cause leukopenia, and your healthcare provider will likely begin evaluating your leukopenia (in the absence of other symptoms), but will closely examine your medications. Medications can cause leukopenia in a number of ways, including direct suppression of the bone marrow, toxic effects on cells that turn into white blood cells, or by triggering an immune response in which the body attacks its own white blood cells. Some relatively common causes include:

Chemotherapy drugs: 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 the bone marrow in different ways. Although the time varies with medication, the point at which the white blood cell count reaches its lowest point ( nadir ) is approximately 7 to 14 days after the infusion.

Other medications:

  • Anticonvulsants: 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 relievers such as aspirin (very rare) and non-steroidal anti-inflammatory drugs such as ibuprofen.
  • Antiviral medications such as acyclovir.
  • Psychiatric drugs such as clozapine, wellbutrin (bupropion), chlorpromazine, risperidone (rare), and haloperidol (rare)
  • Heart medications such as thiazide diuretics, beta blockers, and spironolactone.
  • Immunosuppressive drugs to prevent graft rejection, treat inflammatory arthritis, such as sirolimus, tacrolimus, mycophenolate mofetil, leflunomide
  • HIV drugs (antiretrovirals)
  • Biological treatments such as TNF inhibitors, proleucine (interleukin-2), and rituxan (rituximab)
  • Medications for multiple sclerosis such as interferon beta-1a and interferon beta-1b.

Idiopathic

Sometimes the cause of leukopenia is not obvious even with a careful laboratory examination. The term idiopathic is used as a general category to describe a condition that occurs for no apparent reason. An example is chronic idiopathic neutropenia.

Infections

Infections, oddly enough, are a relatively common cause of leukopenia. Leukopenia can occur during an acute infection with some infections or mainly in the post-infectious stage with others.

In sepsis , a widespread bacterial infection throughout the body, leukopenia can occur when available white blood cells are "depleted" to fight the infection.

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

  • Viral infections: Epstein-Barr virus (mono), respiratory syncytial virus (RSV), parvovirus, influenza, cytomegalovirus, hepatitis A and B, measles, dengue, HIV (approximately 70% of people with HIV have leukopenia )
  • Rickettsial diseases: Lyme disease, ehrlichiosis, anaplasmosis, typhus, Rocky Mountain spotted fever.
  • Bacterial infections: shigella, salmonella, whooping cough (whooping cough), brucellosis, tuberculosis and atypical strains of mycobacteria, psittacosis.
  • Parasites: malaria

Some of these infections can also cause anemia (low red blood cell count) and thrombocytopenia (low platelet count).

Conditions that affect the bone marrow

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

  • Bone marrow infiltration: Bone marrow infiltration (eg, in acute leukemia and large granular lymphocyte leukemia) can interfere with blood cell formation. Bone marrow metastases can also cause 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 diseases

Several conditions can cause the destruction of white blood cells.

Primary autoimmune conditions include:

  • Primary autoimmune neutropenia
  • Benign chronic neutropenia of childhood

Secondary autoimmune conditions include conditions such as:

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

Some of these conditions can not only cause leukopenia. For example, Felty's syndrome (enlarged spleen plus neutropenia) can also lead to sequestration of white blood cells.

Other autoimmune causes include:

  • Pure leukocyte aplasia.
  • T-gamma lymphocytosis

Environmental impact

Exposure to the environment or lifestyle can lead to leukopenia, including:

  • Exposure to mercury, arsenic, or copper
  • Drinking strong alcohol
  • Exposure to radiation

Vitamin and nutrient deficiency.

Protein and caloric malnutrition is a common cause of leukopenia as a result of inadequate white blood cell production.

Lack of vitamin B12 and folic acid is a relatively common cause, as is iron deficiency anemia.

Inflammatory

Sarcoidosis is a little known inflammatory disease that generally leads to leukopenia.

Hypersplenism

An enlarged spleen can lead to sequestration of white blood cells in the spleen. This can happen with cirrhosis of the liver, certain blood disorders, or Felty's syndrome.

Congenital conditions

Leukopenia or neutropenia is seen in a number of congenital conditions and syndromes, including:

Other reasons

Hemodialysis often causes leukopenia and reactions to blood transfusions.

Causes of low levels of specific types of white blood cells.

Some medical conditions result in a disproportionately low number of a particular type of white blood cell, while other white blood cell counts may be normal. Isolated low levels of some types of white blood cells can also be important in predicting the presence or severity of a disease.

Neutropenia: Low neutrophil counts are often the greatest concern in leukopenia due to the risk of infection. Neutropenia without generalized leukopenia (isolated neutropenia) suggests causes such as autoimmune diseases or vitamin deficiencies (processes that can affect only one type of white blood cell), while conditions associated with the bone marrow usually affect all types of white blood cells.

Eosinopenia: Low levels of eosinophils (eosinophilic leukopenia) are commonly seen during physical or emotional stress (due to the release of stress hormones), Cushing's syndrome, and acute inflammation. Eosinopenia is also an important marker of sepsis .

Basopenia: A low level of basophils (basophilic leukopenia) can occur when:

  • Allergic conditions such as hives, severe allergies, angioedema, and anaphylaxis.
  • With high doses or long-term use of corticosteroids
  • With stress
  • In the acute phase of infection or inflammation.
  • With hyperthyroidism or thyrotoxicosis.

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

  • Corticosteroids
  • Renal insufficiency
  • Radiation
  • Hodgkin's disease
  • Drugs used to prevent graft rejection.
  • Certain viral infections, especially HIV / AIDS with CD4 T cell deficiency.
  • Congenital conditions such as severe combined immunodeficiency

Lymphocyte counts tend to decline with normal aging, although lymphopenia appears to be correlated with the overall risk of death in American adults.

From a prognostic point of view, recent studies show that lymphopenia predicts the severity of the disease and the likelihood that it will enter intensive care or lead to death from COVID-19 .

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

Diagnostics

In some cases, the cause of the leukopenia may be obvious and tests are not required (for example, if the person is receiving chemotherapy). In other cases, making an accurate diagnosis can be challenging.

History and physics

The diagnostic process should begin with a complete history, including all risk factors for the conditions listed above, medications used, travel history, and more. The physical exam should look for any signs of infection (since it may not be present with very low levels of whites, and even the imaging results may not be as obvious as, for example, signs of pneumonia on a chest X-ray) . The lymph nodes (including above the clavicle) and spleen should be carefully checked, and the skin should be checked for bruising.

Blood test

Several laboratory tests can help identify the causes:

  • Complete blood count (CBC) : A laboratory evaluation can begin by evaluating the CBC numbers, including the ratios of white blood cells, red blood cells, and platelets. Red blood cell indices (such as MCV ) can sometimes provide important clues to causes, such as vitamin B12 deficiency. Of course, it is useful to compare the results with any previous CBC.
  • Blood smear: A peripheral blood smear for morphology can be helpful to look for any changes in blood cells, such as toxic granulation in neutrophils, which is sometimes seen in infections. Looking for any signs of immature white blood cells is also very helpful when looking for serious infections or cancers of the blood.
  • Reticulocyte count: If the red blood cell count is also low, the reticulocyte counts can help determine if the blood counts are low due to a lack of production or some other mechanism.

Control ranges

The term leukopenia is commonly used to describe a low total white blood cell count, but this can include reduced 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 in fact, one type of white blood cell may be high.

The normal range of white blood cell counts depends on the time of day. Levels can also change, sometimes significantly, in response to physical or emotional stress.

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

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

Total white blood cell count: The range of the total white blood cell count in adults and children is as follows:

  • Men: 5,000 to 10,000 cells per microliter (μl)
  • Females: 4,500 to 11,000 cells / μL.
  • Children: 5,000 to 10,000 cells per microliter (infancy to adolescence ) .

Absolute Neutrophil Count: The absolute level (total white blood cell count multiplied by the percentage of a specific type of white blood cell) of various types of white blood cell can be a very important laboratory value, especially for neutrophils.

The absolute neutrophil count range is 2500 cells / μL to 6000 cells / μL.

An absolute neutrophil count (ANN) of less than 2500 could be called neutropenia, but this number generally has to drop below 1000 cells / μL before the risk of developing a bacterial infection increases significantly. If the ANC falls below 500 cells / μL, the risk of infection increases dramatically. The term " agranulocytosis " is sometimes used synonymously with ANC less than 500 cells / μL .

In particular, people may have neutropenia despite a normal total white blood cell count (often due to an increase in the absolute lymphocyte count).

Other lab tests

Evidence of cause may include:

  • Vitamin B12 or folate levels
  • Sowing blood
  • Viral cultures
  • Flow cytometry
  • Tests to detect autoimmunity, such as antinuclear antibodies (the antineutrophil antibody test is mainly useful in children)
  • Genetic testing for suspected congenital cause

Bone marrow examination

A bone marrow biopsy may be required to detect an underlying cancer (such as leukemia) or a bone marrow disorder such as aplastic anemia.

Display

Imaging tests are rarely needed to diagnose leukopenia, unless an underlying cancer or bone infection is suspected.

Watch out

The need for treatment for leukopenia depends on the number of white blood cells, especially the absolute number of neutrophils.

Root cause treatment

Often times, treating the underlying cause of leukopenia is more effective, such as replenishing vitamin deficiencies or treating infections. For serious conditions such as aplastic anemia, a bone marrow transplant may be required.

Antibiotics

If the leukopenia is severe (severe absolute neutropenia), such as due to chemotherapy, and there is a fever (or even no fever if the count is very low), antibiotics are sometimes used even if no obvious source of infection is found. This may also be the case for some antiviral or antifungal agents (for example, prophylactic antifungal agents against Aspergillus may be prescribed).

Transfusion

Granulocyte infusions are rarely used and their use is controversial. However, there may be settings where they are recommended, for example for people at very high risk .

Growth factors

Medications (growth factors) can be used to stimulate the production of neutrophils in the bone marrow (prophylactically or as a treatment for low neutrophil counts). The use of growth factors to stimulate the development and maturation of granulocytes has become the standard treatment even for prophylactic purposes in some forms of cancer and has allowed healthcare providers to use higher doses of chemotherapy drugs than in the past.

Available granulocyte colony stimulating factors (G-CSF) and granulocyte and macrophage colony stimulating factors include:

Infection prevention

If a person has a very low white blood cell count, hospitalization may be required. Otherwise, even with the introduction of growth factors, infection prevention is extremely important. This includes:

  • Avoid crowded conditions
  • Visitor restriction in case of hospitalization.
  • Avoid contact with sick people.
  • Compliance with food safety regulations (ban on raw meat or seafood, washing of vegetables, avoidance of soft cheeses, etc.)
  • Be careful with pets (avoid trays, bird cages, do not touch reptiles, etc.)

Get the word of drug information

There are many potential causes of leukopenia, ranging from unpleasant to life-threatening. The main risk is infection, and steps must be taken to reduce this risk and treat existing infections first.

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