Neutropenia

What is Neutropenia?

Neutrophils are a type of white blood cells that are commonly found in our bloodstream. They are an important part of our immune system because they eat up and destroy any harmful microorganisms such as bacteria and fungi that enter our body. This process involves moving through the blood vessels, a process known as transendothelial migration. If neutrophils can’t perform this role properly, it results in a weakened immune system that’s prone to repeated infections.

Problems with the neutrophils can be either quantitative (not enough neutrophils) or qualitative (the neutrophils not functioning well). The number of neutrophils in your blood should ideally be greater than 1.5 x 109/L. If it’s less, it’s called neutropenia, which can be mild, moderate, severe, or very severe (agranulocytosis).

Here’s how the neutropenia levels are classified based on the count of neutrophils in your blood:

• Mild: 1.0 to 1.5 x 109/L
• Moderate: 0.5 to 1.0 x 109/L
• Severe: less than 0.5 x 109/L
• Agranulocytosis (very severe): less than 0.2 x 109/L with absence of neutrophils in bone marrow

There are many reasons for neutropenia. It can be due to a problem in the bone marrow (where blood cells are made), a genetic condition, or it might occur in cycles. Other possible reasons include cancer affecting the bone marrow, autoimmune diseases, drugs used in chemotherapy, certain infections, and even some antibiotics. Neutropenia can be due to multiple reasons and is not uncommon in patients undergoing chemotherapy and on strong antibiotics.

Primary neutropenia is when there is a decrease in production due to issues in the bone marrow. This could be due to benign conditions, cyclical neutropenia, or certain inherited conditions. Acquired neutropenia, on the other hand, can be due to drugs, leukemia, certain illnesses, or infections. There are also rare inherited forms of neutropenia, which can range in severity. Some of the most serious forms of neutropenia include conditions like leukocyte adhesion deficiency syndromes, Chediak-Higashi syndrome, Shwachman-Diamond syndrome, and chronic granulomatous disease.

What Causes Neutropenia?

Neutrophils, a type of white blood cell, are the body’s primary defense against bacteria and certain fungal infections. When the number of neutrophils dips below a certain level, the body becomes more susceptible to recurring infections. In some cases, the body might increase the production of another type of white blood cell, monocytes, to compensate.

Neutropenia, a condition characterized by low neutrophil levels, can be either short-term (less than 3 months) or long-term (more than 3-6 months). How this condition is assessed also involves looking at how much the bone marrow (where blood cells are made) is responding. Only a small percentage of neutrophils are circulating in the body, the rest are stored in the bone marrow and are released when there’s an infection or other trigger. So even if the neutrophil count is low in the blood, if the bone marrow has enough reserves, the risk of infection can be lower.

There are two main types of Neutropenia:

1. In cases where bone marrow reserves are low, this could be due to factors within the body like certain genetic mutations or an acquired condition like myelodysplastic syndrome. Factors outside the body, like certain physical diseases (like leukemia) that affect the bone marrow, or external limiting factors like infections, radiation, drug misuse, alcoholism or deficiencies in certain essential nutrients like folate, vitamin B12 and copper can also contribute to neutropenia.

2. If bone marrow reserves are normal, the neutrophils might be getting destroyed, trapped, used up or being transported wrongly and thus, not functioning properly.

Certain genetic conditions can cause neutropenia by affecting how neutrophils function. Defective neutrophil function could mean they’re not able to move to sites of inflammation, stick to cells, swallow up bacteria, produce compounds to kill pathogens, or create bags of enzymes to digest these pathogens.

Various drugs, like chemotherapy agents, can cause neutropenia either by suppressing bone marrow production of neutrophils or triggering an autoimmune response that destroys them. Even some commonly used medications are known to cause neutropenia, and an antipsychotic drug Clozapine, although very effective, is underused due to its side-effect of causing severe neutropenia.

The body’s own immune system can also destroy neutrophils, leading to a condition called autoimmune neutropenia. However, the level of neutropenia does not always correlate with the level of antibodies that are causing the destruction. Infants can get autoimmune neutropenia due to antibodies against neutrophils, but this condition usually resolves on its own within 2 to 3 years. Adult women between 25 and 40, especially those with symptoms of diseases like lupus and Sjögren syndrome, more commonly have autoimmune neutropenias.

In certain other health conditions and infections, neutrophils can be destroyed. And sometimes, neutropenia can be idiopathic, meaning we simply do not know why it occurred. Almost half the people with neutropenia could fall into this category. There is ongoing research to understand more about this type of neutropenia.

Risk Factors and Frequency for Neutropenia

Research has discovered that in the United States, a condition known as neutropenia is found amongst different racial groups. It is seen in 0.38% of Mexican-Americans, 0.79% of Whites, and 4.5% of Black participants. Another study found that there’s a 17% chance of getting a fever caused by neutropenia during the course of chemotherapy treatment for solid tumors. In Europe, chronic neutropenia is found in between 0.12% and 1.4% of people. Men are more likely to have neutropenia that’s passed down through families, while autoimmune neutropenia, where the body’s immune system attacks the neutrophils, is more common in women.

• In the United States, 0.38% of Mexican-Americans, 0.79% of Whites, and 4.5% of Black participants have neutropenia.
• There is a 17% risk of febrile neutropenia during chemotherapy treatment for solid tumors.
• In Europe, chronic neutropenia ranges from 0.12% to 1.4% in the population.
• Men are more affected by inherited neutropenia than women.
• Autoimmune neutropenia is more common in women than men.

Signs and Symptoms of Neutropenia

Neutropenia is a condition where you have a low count of neutrophils, a type of white blood cell that helps fight off infections. Individuals with neutropenia often have a history of recurrent infections, including infections from rare bacteria and fungi, opportunistic infections, and frequently need antibiotics and antifungal medications. Fever combined with neutropenia is also common, particularly in patients undergoing chemotherapy.

In cases where neutropenia is caused by an autoimmune disorder, patients may show signs such as an enlarged liver or spleen (hepatosplenomegaly), symptoms of thyroid or connective tissue disease such as arthralgias, skin rashes, and Raynaud phenomena. If the underlying cause is malignancy, patients may experience symptoms like fatigue, weariness, bone pain, night sweating, or weight loss. Among patients with specific syndromes, physical characteristics may vary: Warts for WHIM syndrome, eczema with Wiskott-Aldrich syndrome, and albinism in Chediak-Higashi syndrome. Patients with Schwachman-Diamond syndrome often present with malabsorption as infants.

• Issues of normal digestion and absorption
• Delayed separation of the umbilical cord (seen in alloimmune neutropenia)
• Fever
• Meningitis, Septicemia, Bacteremia (body-wide infections)
• Skin infections
• Tiredness
• Gum disease
• Purulent conjunctivitis
• Recurrent tonsillitis
• Sore throat
• Mouth ulcers
• Middle ear infection
• Coarse facial features
• Mucocutaneous candidiasis
• Cough, Lung abscesses, Pneumatoceles (air-filled bubbles in the lungs)
• Sinus and lung infections
• Bronchiectasis, Deep abscesses (wider airways filled with mucus)
• Granulomas (inflammation) with certain organisms
• Bone infection
• Joint infection
• Abdominal lining infection
• Splenomegaly (Enlarged spleen)
• Diarrhea
• Urinary Sepsis (serious infection that can affect the kidneys)
• Vasculitis (inflammation of blood vessels)
• Poor wound healing

Testing for Neutropenia

To understand if a patient has neutropenia, which is a condition characterized by a low number of a certain type of white blood cells called neutrophils, different types of tests can be performed, focusing mainly on the immune system.

One of the tests measures levels of immunoglobulins, which are proteins produced by immune cells to fight against bacteria and viruses. Among immunoglobulins, doctors usually checks IgG, IgM, IgA, and IgE. If the levels of IgG and IgM are high, this could indicate that the neutropenia might be due to an autoimmune condition, especially if there are other signs of systemic illness.

Another part of the immune system that can be evaluated are B lymphocytes or B cells. These can be measured using markers called CD19 and CD20. B cells play a crucial role in our body’s response to infections. Certain conditions, like WHIM syndrome, can cause a decrease in B cells.

A test can also be done to see how well phagocytes, a type of white blood cell, are working. One method involves using a chemical called nitroblue tetrazolium. It changes color in response to the interactions of phagocytes with harmful bacteria, helping doctors see the phagocytes in action. This test is particularly helpful in conditions like chronic granulomatous disease where usual color change does not occur.

Testing for autoantibodies, which are immune proteins that mistakenly target and react with a person’s own tissues or organs, is often done in neutropenia. Their presence could suggest an autoimmune disease. Thyroid disease and autoimmune neutropenia are more common in patients having these types of antibodies. For newborns with neutropenia, a test to detect antibodies from the mother that target the baby’s neutrophils may be carried out.

The complement system, part of immune system that enhances the body’s ability to fight microbes, can also be checked. Here doctors may measure C3 and C4, two important proteins that help carry out immune responses. There is also a specific test that measures total complement activity (CH50) which gives a broad view on the activation of complement system.

Just like any other conditions, bacteria or viruses can be possible causes of neutropenia. For this reason, sample cultures from blood, urine, stool, sputum, and cerebrospinal fluid can be taken.

When neutropenia is suspected, the doctor might also check other lab indicators such as complete blood cell count, blood chemistry, and tumor markers like CEA, CA 19-9, CA-125, and PSA. Assessing nutritional deficiencies and infectious causes, especially HIV and Hepatitis B/C, are also important.

Apart from blood tests, a blood smear can reveal if neutropenia is a false result or not and it might show other abnormalities. In specific cases, bone marrow biopsy could be performed to differentiate between certain causes of neutropenia. It can show the proportion and health of different cells in the bone marrow.

To confirm certain inherited disorders, genetic testing such as fluorescent in situ hybridization (FISH) and nucleic acid testing may also be performed.

For possible infections, an x-ray of the chest or a CT scan of the abdomen might be done. Ultrasonography can be used to see if the liver and spleen are enlarged, which could be a clue for certain causes of neutropenia.

Treatment Options for Neutropenia

Neutropenia, a condition characterized by a low level of a type of white blood cell called neutrophils, can be treated with granulocyte-colony stimulating factor (G-CSF). G-CSF helps stimulate your body’s production of neutrophils, improving your immunity. This is particularly effective when the issue lies in their production process. However, the goal is not to increase the neutrophils to their maximum but to raise them to a level that’s generally considered safe, typically more than 1000 cells per microliter of blood.

If neutropenia arises due to an autoimmune condition, the start of G-CSF treatment usually depends on whether the patient is experiencing infections or inflammation of the mouth (stomatitis). Lower doses are often used in such cases to conserve bone marrow reserves. To manage autoimmune neutropenia, some adults may require drugs that suppress the immune system, such as glucocorticoids, cyclosporine, cyclophosphamide, or methotrexate. However, the use of these options should be patient-specific as there’s a potential risk of relapse.

In patients whose neutrophil function is diminished, such as in chronic granulomatous disease, preventive use of antibiotics and antifungal medications is common to fend off infections. Interferon-gamma was previously used to enhance the activity of neutrophils, but its popularity waned due to possible side effects such as fever, muscle pain, and general discomfort.

In some severe cases of neutropenia that don’t respond to G-CSF treatment, a hematopoietic stem cell transplant (HSCT) may be considered. This would also apply to cases that have progressed into a malignancy related to myeloid cells (blood cells made in the bone marrow) or those that recurrently experience severe infections. After the transplant, extra care should be taken to prevent any infections as these patients are especially vulnerable.

Furthermore, a newer class of medication, CXCR4 antagonists, are being studied for the treatment of genetic disorders that affect the movement of neutrophils. These medications have been useful in treating certain conditions like WHIM syndrome, which causes an abnormal retention of neutrophils in the bone marrow. Clinical trials are also ongoing for gene therapy as a potential treatment method for some types of neutropenia.

What else can Neutropenia be?

Neutropenia is a condition where a person has a low count of a type of white blood cell called neutrophils. This can be differentiated from another group of conditions called antibody deficiency disorders, where certain proteins called immunoglobulins that help to fight off infections, are at lower levels than normal or completely missing. The main symptom of these conditions is that the person gets frequent infections from bacteria and fungi, some of which are usually not harmful to a person with a healthy immune system.

Even though someone with neutropenia might have a good acquired immune response, their neutrophils may not be functioning properly or may be in low numbers. Sometimes, other conditions like C3 Deficiency, a condition where a crucial part of the immune system called the complement system is defective, can also lead to frequent bacterial infections and neutropenia. However, testing the quantity and the functionality of the components of the complement system can help to identify or dismiss such conditions.

What to expect with Neutropenia

The outlook for neutropenia, a condition that involves a low number of a type of white blood cells called neutrophils, depends on its cause and the organs it affects.

When neutropenia is a result of chemotherapy or certain drugs, it usually gets better after the body’s natural factors for growth are supplied or when the therapy is stopped. Conditions like cyclic neutropenia (neutropenia that follows a pattern), Duffy antigen null neutropenia (a specific type of neutropenia), and drug-related neutropenia often have a good outlook and aren’t typically deadly.

However, it’s worth noting that a good number of neutropenic patients can get serious infections, and many of them might need to be hospitalized repeatedly. If not treated, neutropenia may put one at a high risk of death due to opportunistic infections, which refer to infections that occur more frequently and are more severe because of a weakened immune system.

Possible Complications When Diagnosed with Neutropenia

People with neutropenia, a condition that causes low levels of a type of white blood cell, often face recurring and severe bacterial, viral, or fungal infections. These individuals also run a higher risk of developing myelodysplastic syndrome or acute myeloid leukemia, particularly if they have inherited neutropenia due to certain gene mutations such as ELANE, HAX1, WAS, GATA2, G6PC3, and SBDS. This can be a significant cause of death among neutropenia patients. Regular health checks, like complete blood counts every 3 to 4 months and yearly bone marrow biopsies, are vital to detect any worrisome developments.

Neutropenia patients commonly experience osteoporosis and osteopenia, conditions that lead to weakened bones, although the exact cause is undetermined. Fortunately, serious bone fractures aren’t typical, but patients should still be regularly monitored. G-CSF, a medication often used to treat severe combined neutropenia, can lead to bone pain, thereby impacting a patient’s willingness to continue the treatment. Second-generation antihistamines, like loratadine, could be used to provide relief from this discomfort.

Potential Complications and Side Effects:

• Recurring and serious bacterial, viral, or fungal infections
• Increased risk of developing myelodysplastic syndrome or acute myeloid leukemia, particularly in patients with inherited neutropenia
• Death, in severe cases
• Development of osteoporosis and osteopenia (weakened bones)
• The possibility of bone fractures
• Bone pain caused by the drug G-CSF

Preventing Neutropenia

Patients who have a health condition that causes a low level of neutrophils, or white blood cells, in the body (a state known as neutropenia) should be well-informed about methods to control infection. This includes washing their hands thoroughly and regularly, and wearing masks when necessary. It’s critical that they keep their vaccines up to date, and pay particular attention to keeping their mouths clean and healthy. Genetic counselling and early testing before a baby is born should be considered for those patients who either have a family history or have been diagnosed with a condition where the body does not produce enough neutrophils from birth (congenital neutropenia). Moreover, family members of the patients could also undergo tests for health disorders and to see if they can donate stem cells for transplantation treatment.