•White blood cells (leukocytes) are an important part of the body’s defense against infectious organisms and foreign substances (the immune system).
•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.
•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 in a given volume of blood can also be determined through laboratory tests.
•Too few or too many white blood cells indicates a disorder.
Symptoms
•Symptoms of WBC disorders vary based on the type of illness, though some people do not have any symptoms. Symptoms are predominantly related to infection and include:
•frequent or recurrent infections
•infections with unusual bacteria, viruses, or fungus
•fever
•mouth ulcers
•skin abscesses (commonly called boils)
•pneumonia
Causes
•WBC disorders can be due to over or underproduction of cells, a problem with the function of the cells, or difficulty with a particular type of WBC. Too many of one type of WBC is indicated by the suffix -philia, while too few is called -penia.
•White blood cell disorders can be caused by viral infections, autoimmune disorders, cancer, certain medications, or severe infections, though some people can be born with congenital white blood cell disorders.
Common white blood cell disorders include:
•Leukocytosis is an increased number of white blood cells. The most common causes are infection, medications like prednisone, or leukemia.
•Autoimmune neutropenia occurs when the body produces antibodies that attack and destroy neutrophils.
•Severe congenital neutropenia is secondary to a genetic mutation. People with severe congenital neutropenia have recurrent bacterial infections.
•Cyclic neutropenia is also due to a genetic mutation, similar to severe congenital neutropenia. However, the neutropenia does not occur every day but in cycles of about 21 days.
•Leukemia is a cancer of the cells that produce white blood cells in the bone marrow.
•Chronic granulomatous disease is a disorder where multiple types of WBCs (neutrophils,eosinophil,basophil ) are unable to function properly. It is an inherited condition and results in multiple infections, particularly pneumonia and abscesses.
•Leukocyte adhesion deficiency is a disorder where the white blood cells are unable move to areas of infection.
•The normal number of WBC for adults ranges from 4 to 11 billion cells per liter, while counts for newborns to age 2 is higher range, from around 9 to 30 billion cells per liter.
•African Americans have lower baseline WBC counts than Caucasians.
Neutropenia
•Neutropenia is an abnormally low number of neutrophils (a type of white blood cell) in the blood.
•Neutropenia, if severe, significantly increases the risk of life-threatening infection.
•Neutropenia is often a side effect of the treatment of cancer with 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 may be needed if the cause is not apparent.
•Treatment depends on the cause and severity of the disorder and can include drugs to stimulate the body’s production of neutrophils.
•Antibiotics are given if the person has neutropenia and fever or other signs of infection.
•Neutrophils are a type of white blood cell that serve as the body’s major defense against acute bacterial and certain fungal infections.
•Neutrophils usually constitute about 45 to 75% of all white blood cells in the bloodstream. Without the key defense provided by neutrophils, people have problems controlling infections and are at risk of dying from an infection.
•Neutropenia may resolve quickly when the infection resolves or the exposure stops.
•Chronic neutropenia may last for months or years.
Severity of neutropenia
•The typical lower limit of the neutrophil count is about 1500 cells per microliter of blood. As the count goes below this level, the risk of infection increases. Neutropenia severity is classified as:
•Mild (1000 to 1500)
•Moderate (500 to 1000)
•Severe (below 500) When the neutrophil count falls below 500 cells per microliter (severe neutropenia), the risk of infection increases greatly. People may even develop infections by the bacteria that normally live harmlessly in the mouth and intestines.
Causes of neutropenia
•Neutropenia has many causes, but they fall into two main categories:
•Neutrophils are used up or destroyed faster than the bone marrow can produce new ones
•The production of neutrophils in the bone marrow is reduced
•Rapid use or destruction of neutrophils
•Many disorders cause neutrophils to be used up or destroyed. These disorders include certain bacterial infections, some allergic disorders, and some drug treatments (such as drugs used to treat hyperthyroidism). People with an autoimmune disorder can make antibodies that destroy neutrophils and result in neutropenia. People with an enlarged spleen may have a low neutrophil count because the enlarged spleen traps and destroys neutrophils.
•Reduced production of neutrophils
•Production of neutrophils in the bone marrow can be reduced by 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, 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.
•Production of neutrophils in the bone marrow is also affected by a disorder called aplastic anemia (in which the bone marrow may shut down production of all blood cells).
•Certain rare hereditary disorders also cause a decrease in the number of neutrophils. In cyclic neutropenia, the number of neutrophils rises and falls regularly over a period of weeks.
•In chronic benign neutropenia, neutrophil counts are low but infections are rare, probably because people produce adequate numbers in response to infection.
•Severe congenital neutropenia is a group of disorders that prevent neutrophils from becoming mature, and people develop serious infections starting in infancy.
Symptoms of neutropenia
•Neutropenia can develop suddenly over a few hours or days in response to certain infections or exposures gradually.
•Neutropenia itself has no specific symptoms, so it is usually diagnosed when an infection occurs. People may develop fever and painful sores (ulcers) around the mouth and anus. Bacterial pneumonia and other severe infections can occur.
•In chronic neutropenia, people may not have many symptoms if the number of neutrophils is not extremely low.
•When neutropenia is caused by drugs, people may have a fever, rash, and swollen lymph nodes.
•In cyclic neutropenia, people can have symptoms that come and go as their white blood cell count rises and falls over time.
Diagnosis of neutropenia
•Complete blood count
•Bone marrow examination
•When people have frequent or unusual infections or if people are taking drugs known to cause neutropenia, doctors order a blood test (complete blood 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.
•And whether the cause is known or not, doctors usually also search for a hidden infection that may have been caused by the neutropenia.
Determination of cause
•Doctors ask about drug or toxic exposures and look for infections or other disorders that can cause the neutropenia. They frequently take a sample of bone marrow through a needle.
•The bone marrow sample is examined under a microscope to determine whether it looks normal, has a normal number of neutrophil stem (precursor) 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 blood. Sometimes, the bone marrow examination indicates whether other diseases, such as leukemia or other cancers, or infections, such as tuberculosis, are affecting the bone marrow.
Evaluation for infection
•Because people with neutropenia might not have all the typical symptoms and examination findings of an infection, doctors ask people detailed questions about their symptoms and examine them from head to toe.
•Tests are done for any concerning findings, for example, if the person has abdominal discomfort, computed tomography (CT) of the abdomen may be done.
•Even if there are no specific findings, doctors typically also do urinalysis and urine culture, blood cultures, and a chest x-ray. When doctors do a culture, they take a sample of the material being tested (in this case, urine or blood) and send it to the laboratory to grow bacteria or other organisms that may be present.
Treatment of neutropenia
•Antibiotics Drugs to stimulate production of neutrophils.
•The most important thing is to treat any infection that is found. In people with severe neutropenia, infections can rapidly become serious or fatal.
•Even if doctors cannot diagnose a specific infection, people who have neutropenia and fever are presumed to have an infection. Such people are given antibiotics effective against common infectious organisms.
•The treatment of neutropenia itself 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 die as a result of infection because their bodies lack the means to fight invading organisms.
•When these people develop infections, they are usually 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 by the bone marrow, are sometimes helpful and are given as a injection (under the skin or into a vein).
•Corticosteroids may help if the neutropenia is caused by an autoimmune disorder.
•Antithymocyte globulin or other types of therapy that suppress the activity of the immune system may be given by vein when a disorder such as aplastic anemia is present.
•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.
Severe Congenital Neutropenia
•Severe congenital neutropenia describes this condition perfectly. It is a congenital (meaning you are born with it) condition with severe neutropenia (defined as neutrophil count < 500 cells per microliter, often < 200). One specific form is called Knostman Syndrome. It is a rare condition affecting 2 -3 people for every one million people.
Symptoms of congenital neutropenia
•Symptoms generally start shortly after birth. Neutrophils are a type of white blood cell that fights bacterial infections.
•The severely low neutrophil count increases your risk of bacterial infections. Fever is also a common symptom, but this is due to the infection not the neutropenia. Birth defects are generally not seen.
•Otitis media (ear infections)
•Cellulitis (skin infection)
•Oral ulcers
•Gingivitis (gum inflammation)
Diagnosed of severe congenital neutropenia
•complete blood count (CBC). Severe neutropenia (< 500 cells/microliter) should be the only blood cell affected. The red blood cells and platelets should be normal.
•Usually the monocytes (another type of white blood cell will be elevated). If more than one type of blood cell is affected, other diagnoses (like Schwachman Diamond Syndrome) should be considered.
•The next step is a bone marrow biopsy. This test involves removing a small piece of bone from your hip to assess the bone marrow, the area where white blood cells are made.
•In severe congenital neutropenia, the cells are made normally initially but then at some point they die before being released into circulation.
Treatments of severe congenital neutropenia
•Granulocyte Colony Stimulating Factor (G-CSF or filgrastim): G-SCF is given as subcutaneous (under the skin) injections daily. This medication stimulates bone marrow production and maturation of neutrophils. The goal is to bring the neutrophil count to normal consistently to prevent infections.
•Bone marrow transplantation: Bone marrow transplantation can be curative. This is usually considered for people with poor response to G-CSF. If receiving a bone marrow transplant from a sibling, it is important to make sure they do not have a milder form of severe congenital neutropenia.
•Antibiotics: If you have severe congenital neutropenia and develop a fever, you should seek immediate medical attention. Fever may be the only symptom of a serious infection.
•Blood work should be sent to identify a possible cause of infection. During this time, you will be placed on IV (through the vein) antibiotics in case you have an infection.
Cyclic Neutropenia
•Cyclic neutropenia is an inherited condition where the neutrophil count (white blood cell that fights bacterial infections) becomes severely low (usually less than 500 cells/mL) on a cycle of approximately every 21 days.
•It usually presents in the first year of life. The cycles decrease with age, and it can disappear in some adult patients.
•When the neutrophil count is normal, there are no symptoms. Symptoms generally lag behind the neutropenia (low neutrophil count) meaning the neutrophil count has already been extremely low for a couple of days prior to the development of symptoms.
•Opposed to other congenital forms of neutropenia (severe congenital neutropenia, Schwachman Diamond Syndrome, etc.), birth defects are not seen.
•Symptoms include:
•Aphthous ulcers (ulcers in the mouth)
•Throat inflammation (pharyngitis)
•Gum inflammation (gingivitis)
•Skin infections
•Fever
•Cyclic neutropenia is a congenital meaning the person is born with the condition.
•It is passed down in families in an autosomal dominant fashion meaning only one parent has to be affected to pass it on to their children.
•Not all family members may be affected similarly and some may, but some may not have any symptoms.
Diagnosis
•Cyclic neutropenia can be challenging to diagnose as the severe neutropenia only lasts 3 to 6 days during each cycle. In between these cycles, the neutrophil counts are normal.
•Recurrent oral infections and fever every 21 to 28 days should raise suspicion for cyclic neutropenia.
•In order to catch the cycle of severe neutropenia, complete blood counts (CBC) are performed 2 to 3 times per week for 6 to 8 weeks.
•In addition to the severe neutropenia, there can be a decrease in the immature red blood cells (reticulocytopenia) and/or platelets (thrombocytopenia).
•The monocyte count (another type of white blood cell) often increases during the time of severe neutropenia.
•If cyclic neutropenia is suspected based on serial blood counts, genetic testing should be sent to look for mutations in the ELANE gene (on chromosome 19). 90 – 100% of patients with cyclic neutropenia have an ELANE mutation.
•Mutations in the ELANE gene have been associated with cyclic neutropenia and severe congenital neutropenia.
•Given the clinical presentation and confirmatory genetic testing, bone marrow biopsy is not required but is often performed during the work-up of neutropenia.
Treatments of cyclic neutropenia
•Although cyclic neutropenia is considered a benign condition, deaths secondary to serious infections have occurred. Treatment is geared towards preventing and/or treating infections.
•Granulocyte Colony-Stimulating Factor (G-CSF, also called filgrastim): G-CSF stimulates the bone marrow to produce more neutrophils. It is used to prevent the neutrophil count from dropping below 500 cells/mL.
•G-CSF has been shown to decrease the severity of the neutropenia and decrease the number of infections. G-CSF is administered subcutaneously (just beneath the skin) every 1 – 2 days.
•Some patients may be able to discontinue G-CSF as an adult because sometimes the neutropenia gets milder with age.
•Preventative dental care: Because many of the infections occur in the mouth, it is important to maintain good oral hygiene. Antibacterial mouthwashes may be recommended.
•Evaluation for fever: Because patients with cyclic neutropenia can develop severe bacterial infections, it is important that episodes of fever be evaluated carefully. Sometimes, the episodes will require hospitalization with intravenous (IV) antibiotics until serious infection can be ruled out.