CHAPTER 158
White Blood Cell Disorders
White blood cells (leukocytes) are an important part of the body’s defense against infectious organisms and foreign substances. To defend the body adequately, a sufficient number of white blood cells must receive a message that an infectious organism or foreign substance has invaded the body, get to where they are needed, and then kill and digest the harmful organism or substance (see page 1099 and art on page 1100).
Like all blood cells, white blood cells are produced in the bone marrow. They develop from stem (precursor) cells that mature over time into one of the five major types of white blood cells—neutrophils, lymphocytes, monocytes, eosinophils, and basophils.
Normally, people produce about 100 billion white blood cells a day. The number of white blood cells in a given volume of blood is expressed as cells per microliter of blood. The total white blood cell count normally ranges between 4,000 and 11,000 cells per microliter. The proportion of each of the five major types of white blood cells and the total number of cells of each type can also be determined in a given volume of blood.
Too few or too many white blood cells indicates a disorder. Leukopenia, a decrease in the number of white blood cells to fewer than 4,000 cells per microliter of blood, makes people more susceptible to infections. Leukocytosis, an increase in the number of white blood cells to more than 11,000 cells per microliter of blood, may result from the normal response of the body to help fight an infection. However, an increase in the number of white blood cells can also result when the regulation of white blood cell development is disrupted and immature or abnormal cells are released into the blood.
Some white blood cell disorders involve only one of the five types of white blood cells. Other disorders may involve a few types together or all five types. Disorders of neutrophils and disorders of lymphocytes are the most common. Disorders that involve monocytes and eosinophils are less common, and disorders involving basophils are rare.
Neutropenia
Neutropenia is an abnormally low number of neutrophils in the blood.
Neutropenia significantly increases the risk of life-threatening infection.
Neutropenia is often caused by cancer chemotherapy or radiation therapy.
Doctors suspect neutropenia in people who have frequent or unusual infections.
A blood sample is used to make the diagnosis of neutropenia, and a sample of bone marrow is needed if the cause is not obvious.
Treatment depends on the cause and severity of the disorder.
Neutrophils serve as the major defense of the body against acute bacterial and certain fungal infections. Neutrophils usually constitute about 45 to 75% of all white blood cells in the bloodstream. When the neutrophil count falls below 1,000 cells per microliter of blood, the risk of infection increases somewhat; when it falls below 500 cells per microliter, the risk of infection increases greatly. Without the key defense provided by neutrophils, people have problems controlling infections and are at risk of dying from an infection.
Causes
Neutropenia can develop if neutrophils are used up or destroyed in the bloodstream faster than the bone marrow can make new ones. With some bacterial infections, some allergic disorders, and some drug treatments, neutrophils are destroyed faster than they are produced. People with an autoimmune disease can make antibodies that destroy neutrophils and result in neutropenia. People with an enlarged spleen (see page 1072) may have a low neutrophil count because the enlarged spleen traps and destroys neutrophils.
Neutropenia can also develop if the production of neutrophils in the bone marrow is reduced, as can occur in some people with cancer, viral infections such as influenza, bacterial infections such as tuberculosis, myelofibrosis, or deficiencies of vitamin B12 or folate (folic acid). People who have received radiation therapy that involves the bone marrow may also develop neutropenia. Many drugs, including phenytoin, chloramphenicol, sulfa drugs, and many drugs used in cancer treatment (chemotherapy), as well as certain toxins (benzene and insecticides) can also impair the bone marrow’s ability to produce neutrophils.
Did You Know…
Because neutropenia has no symptoms, doctors often do not suspect the disorder unless people have frequent or unusual infections.
Production of neutrophils in the bone marrow is also affected by a severe disorder called aplastic anemia (in which the bone marrow may shut down production of all blood cells—see box on page 1036). Certain rare hereditary diseases also cause the number of neutrophils to decrease.
Symptoms and Diagnosis
Neutropenia can develop suddenly over a few hours or days (acute neutropenia), or it can develop gradually and last for months or years (chronic neutropenia). Because neutropenia itself has no specific symptoms, it is usually diagnosed when an infection occurs. In acute neutropenia, people can develop fever and painful sores (ulcers) around the mouth and anus. Bacterial pneumonia and other severe infections can follow. In chronic neutropenia, the course may be less severe if the number of neutrophils is not extremely low, and the course can occasionally be intermittent (cyclic neutropenia).
When people have frequent or unusual infections, doctors suspect neutropenia and order a complete blood cell count to make the diagnosis. A low neutrophil count indicates neutropenia. In many cases, the neutropenia is expected and the cause is known, as in people receiving chemotherapy or radiation therapy. When the cause is not known, it must be determined.
Doctors usually take a sample of bone marrow through a needle (see page 1025). The bone marrow sample is examined under a microscope to determine whether it looks normal, has a normal number of neutrophil stem cells, and shows normal development of neutrophils. By determining whether the number of stem cells is decreased and whether these cells are maturing normally, doctors may be able to determine whether the problem lies in faulty production of the cells or whether too many cells are being used or destroyed in the bloodstream. Sometimes, the bone marrow examination indicates that other diseases, such as leukemia or other cancers, or infections, such as tuberculosis, are affecting the bone marrow.
Treatment
The treatment of neutropenia depends on its cause and severity. Drugs that may cause neutropenia are stopped whenever possible, and exposures to suspected toxins are avoided. Sometimes the bone marrow recovers by itself without treatment. The neutropenia accompanying viral infections (such as influenza) may be transient and resolve after the infection has cleared. People who have mild neutropenia generally have no symptoms and may not need treatment.
People who have severe neutropenia can rapidly succumb to infection because their bodies lack the means to fight invading organisms. When these people develop infections, they are generally hospitalized and immediately given strong antibiotics, even before the cause and exact location of the infection are identified. Fever, the symptom that usually indicates infection in people who have neutropenia, is an important sign that immediate medical attention is needed.
Growth factors called colony-stimulating factors, which stimulate the production of white blood cells, are sometimes helpful. Corticosteroids may help if the neutropenia is caused by an autoimmune reaction. Antithymocyte globulin or other types of therapy that suppress the activity of the immune system may be used when a disorder such as aplastic anemia is present. Removing an enlarged spleen may cure the neutropenia resulting from hypersplenism.
When neutropenia is caused by another disorder (such as tuberculosis or leukemia or other cancers), treatment of the underlying disorder may resolve the neutropenia. Bone marrow (or stem cell) transplantation is not used to treat neutropenia per se, but it may be recommended to treat certain serious causes of neutropenia, such as aplastic anemia or leukemia.
Neutrophilic Leukocytosis
Neutrophilic leukocytosis is an abnormally high number of neutrophils in the blood.
Neutrophils help the body fight infections and heal injuries. Neutrophils may increase in response to a number of conditions or disorders. In many instances, the increased number of neutrophils is a necessary reaction by the body, as it tries to heal or ward off an invading microorganism or foreign substance. Infections by bacteria, viruses, fungi, and parasites may all increase the number of neutrophils in the blood. The number may rise in people who have an injury, such as a hip fracture or burn. Inflammatory disorders, including autoimmune disorders such as rheumatoid arthritis, can cause an increase in the number and activity of neutrophils. Some drugs, such as corticosteroids, also lead to an increased number of neutrophils in the blood. Myelocytic leukemias can lead to an increased number of immature or mature neutrophils in the blood.
Doctors may do blood tests, including a complete blood count, if people have symptoms, such as prolonged fever, weight loss, or fatigue. If doctors discover an increased number of neutrophils, a blood sample is viewed under a microscope to determine if immature neutrophils (myeloblasts) are leaving the bone marrow and entering the bloodstream. Immature neutrophils in the bloodstream may indicate the presence of a disorder in the bone marrow, such as leukemia. When immature neutrophils are found in the bloodstream, doctors usually take a sample of bone marrow (bone marrow biopsy—see page 1025).
An increased number of mature neutrophils in the blood is not usually a problem in itself. Therefore, doctors focus on treating the condition or disorder that caused the number of neutrophils to increase.
Lymphocytopenia
Lymphocytopenia is an abnormally low number of lymphocytes in the blood.
Many disorders can decrease the number of lymphocytes in the blood, but AIDS and malnutrition are the most common.
People may have no symptoms, or they may have fever and other symptoms of an infection.
A blood sample is used to make the diagnosis of lymphocytopenia, but a sample of bone marrow or lymph node may be needed to determine the cause.
Doctors treat the cause of lymphocytopenia.
Some people are given gamma globulin, and some benefit from stem cell transplantation.
Lymphocytes usually constitute 20 to 40% of all white blood cells in the bloodstream. The lymphocyte count is normally above 1,500 cells per microliter of blood in adults and above 3,000 cells per microliter of blood in children. A reduction in the number of lymphocytes may not cause a significant decrease in the total number of white blood cells.
Various disorders and conditions, including infection with human immunodeficiency virus (HIV)—the virus that causes AIDS, can decrease the number of lymphocytes in the blood. Also, the number of lymphocytes can decrease briefly during starvation, times of severe stress, and during use of corticosteroids (such as prednisone), chemotherapy for cancer, and radiation therapy. Severe reduction in lymphocytes can occur in certain hereditary disorders (the hereditary immunodeficiency disorders—see page 1104).
There are three types of lymphocytes: B lymphocytes, T lymphocytes, and natural killer cells, all of which have important functions in the immune system. Too
Some Causes of Lymphocytopenia
AIDS
Cancer (leukemias, lymphomas, Hodgkin lymphoma)
Chronic infections (such as miliary tuberculosis)
Hereditary disorders (certain agammaglobulinemias, DiGeorge anomaly, Wiskott-Aldrich syndrome, severe combined immunodeficiency syndrome, and ataxia-telangiectasia)
Rheumatoid arthritis
Some viral infections
Systemic lupus erythematosus (lupus)
few B lymphocytes can lead to a decrease in the number of plasma cells and reduced antibody production. People who have too few T lymphocytes or too few natural killer cells have problems controlling certain infections, especially viral, fungal, and parasitic infections. Severe lymphocyte deficiencies can result in uncontrolled infections that can be fatal.
Symptoms and Diagnosis
Mild lymphocytopenia may cause no symptoms and is usually detected by chance when a complete blood cell count is done for other reasons. Drastically reduced numbers of lymphocytes lead to infections with bacteria, viruses, fungi, and parasites.
When the numbers of lymphocytes are drastically reduced, doctors usually take a sample of bone marrow to examine under a microscope (bone marrow biopsy). The number of specific types of lymphocytes (T lymphocytes, B lymphocytes, and natural killer cells) can also be determined in the blood. A decrease in certain types of lymphocytes may help doctors diagnose some diseases, such as AIDS or certain hereditary immunodeficiency disorders.
Treatment
Treatment depends mainly on the cause. Lymphocytopenia caused by a drug usually begins to resolve within days after a person stops taking the drug. If the lymphocytopenia is the result of AIDS, combination therapy with at least three antiviral agents of different classes can increase the number of T lymphocytes and improve survival.
Did You Know…
AIDS and undernutrition are the most common causes of lymphocytopenia.
Gamma globulin (a substance rich in antibodies) may be given to help prevent infections in people with too few B lymphocytes (who therefore have a deficiency of antibody production). People with a hereditary immunodeficiency may benefit from bone marrow (stem cell) transplantation. If an infection develops, a specific antibiotic, antifungal, antiviral, or antiparasitic drug directed against the infective organism is given.
Lymphocytic Leukocytosis
Lymphocytic leukocytosis is an abnormally high number of lymphocytes in the blood.
The number of lymphocytes can increase in response to infections, especially by viruses. Some bacterial infections, such as tuberculosis, may also increase the number. Certain types of cancer, such as lymphomas and acute or chronic lymphocytic leukemia, may produce an increase in the number of lymphocytes, in part by releasing immature lymphocytes (lymphoblasts) or the lymphoma cells into the bloodstream. Graves’ disease and Crohn’s disease may also result in an increase in the number of lymphocytes in the bloodstream.
When the number of lymphocytes increases, symptoms may result from the infection or other disease that has caused the number of lymphocytes to increase, rather than from the increase in lymphocytes per se. When an infection is suspected, doctors may do blood tests. When doctors discover an increased number of lymphocytes, a blood sample is examined under a microscope to determine if the lymphocytes in the bloodstream appear activated (as occurs in response to viral infections) or if they appear immature or abnormal (as occurs in certain leukemias or lymphomas).
Treatment for lymphocytic leukocytosis depends on the cause.
Monocyte Disorders
Monocytes help other white blood cells remove dead or damaged tissues, destroy cancer cells, and regulate immunity against foreign substances. Monocytes are produced in the bone marrow and then enter the bloodstream, where they account for about 1 to 10% of the circulating leukocytes (200 to 600 monocytes per microliter of blood). After a few hours in the bloodstream, they migrate to tissues (such as spleen, liver, lung, and bone marrow tissue), where they mature into macrophages, the main scavenger cells of the immune system. Genetic abnormalities that affect the function of monocytes and macrophages and cause buildup of debris within the cells result in the lipid storage diseases (such as Gaucher’s disease—see page 1839—and Niemann-Pick disease—see page 1840).
An increased number of monocytes in the blood (monocytosis) occurs in response to chronic infections, in autoimmune disorders, in blood disorders, and in cancers. A proliferation of macrophages in tissues can occur in response to infections, sarcoidosis (see page 511), and Langerhans’ cell histiocytosis (granulomatosis—see page 509).
A low number of monocytes in the blood (monocytopenia) can occur in response to the release of toxins into the blood by certain types of bacteria (endotoxemia), as well as in people receiving chemotherapy or corticosteroids.
Eosinophilic Disorders
Eosinophils usually account for less than 7% of the circulating leukocytes (100 to 500 eosinophils per microliter of blood). These cells have a role in the protective immunity against certain parasites but also contribute to the inflammation that occurs in allergic disorders.
An increased number of eosinophils in the blood (eosinophilia) usually indicates the response of the body to abnormal cells, parasites, or substances that cause an allergic reaction (allergens).
A low number of eosinophils in the blood (eosinopenia) can occur with Cushing’s syndrome, stress reactions, and treatment with corticosteroids but does not usually cause problems because other parts of the immune system compensate adequately.
Idiopathic hypereosinophilic syndrome is a disorder in which the number of eosinophils increases to more than 1,500 cells per microliter of blood for more than 6 months without an obvious cause.
People of any age can develop idiopathic hypereosinophilic syndrome, but it is more common in men older than 50. The increased number of eosinophils can damage the heart, lungs, liver, skin, and nervous system. For example, the heart can become inflamed in a condition called Löffler’s endocarditis, leading to formation of blood clots, heart failure, heart attacks, or malfunctioning heart valves.
Symptoms may include weight loss, fevers, night sweats, fatigue, cough, chest pain, swelling, stomachache, rashes, pain, weakness, confusion, and coma. Additional symptoms of this syndrome depend on which organs are damaged. The syndrome is suspected when repeated blood tests reveal that the number of eosinophils is persistently increased in people who have these symptoms. The diagnosis is confirmed when doctors determine that the eosinophilia is not caused by a parasitic infection, an allergic reaction, or another diagnosable disorder.
Without treatment, generally more than 80% of the people who have this syndrome die within 2 years, but with treatment, more than 80% survive. Heart damage is the principal cause of death. Some people need no treatment other than close observation for 3 to 6 months, but most need drug treatment with prednisone or hydroxyurea. Some people with idiopathic hypereosinophilic syndrome have an acquired abnormality of a gene that regulates cell growth. This type of hypereosinophilia can respond to treatment with imatinib, a drug used to treat cancer. If these drugs fail, various other drugs may be used, and they can be combined with a procedure to remove eosinophils from the blood (leukapheresis).
Basophilic Disorders
Basophils account for less than 3% of the circulating leukocytes (0 to 300 basophils per microliter of blood). These cells have some role in immune surveillance and wound repair. Basophils can release histamine and other mediators and play a role in the initiation of allergic reactions. A decrease in the number of basophils (basopenia) can occur as a response to thyrotoxicosis, acute hypersensitivity reactions, and infections. An increase in the number of basophils (basophilia) can occur in people with hypothyroidism. In the myeloproliferative disorders (for example, polycythemia vera and myelofibrosis), a marked increase in the number of basophils can occur.