Chronic neutropenia

What is chronic neutropenia?

People with chronic neutropenia have a low number of neutrophils, the most common type of white blood cell, in their blood for longer than three months. Neutrophils play an important role in both the innate and adaptive immune systems, helping the body fight off bacterial and fungal infections. The lower a person’s neutrophil count, the greater their risk of infection. Chronic neutropenia is both a rare blood disorder and a rare type of primary immunodeficiency (PI).

There are many ways to categorize neutropenia, including by severity, duration, or cause. However, these categories do not necessarily correlate with each other—for example, not all severe neutropenia is chronic or congenital. If you are diagnosed with neutropenia but do not know exactly what type you have, talk to your doctor about your diagnosis. 

Severity

Based on absolute neutrophil count (ANC), which is part of a complete blood count (CBC) test:

• Mild: 1000-1500 cells (neutrophils) per microliter (µL).
• Moderate: 500-1000 cells/µL.
• Severe: < 500 cells/µL.

Duration

• Acute or transient: temporary, or lasting for less than three months.
• Chronic or persistent: lasting for more than three months.
• Cyclic: varying neutrophil counts with a typical cycle length of 21 days. 

Cause

• Acquired: neutropenia that is caused by infection, medication, or another underlying health condition like systemic autoimmune disease or blood cancer.
• Autoimmune: neutropenia that is the result of the destruction of neutrophils by the immune system; this can be the result of systemic autoimmune diseases like lupus or primary immune regulatory disorders like autoimmune lymphoproliferative disease (ALPS).
• Duffy null phenotype: one of the most common causes of low neutrophil counts in people of African, Middle Eastern, and West Indian descent. Duffy null phenotype is caused by a recessive genetic variant in the ACKR1 gene and people with the phenotype are not at increased risk of infection despite their neutrophil levels.
• Congenital: neutropenia that has a genetic cause.
• Idiopathic: neutropenia where the cause is unknown.

Infants, children, and adults can all be affected by neutropenia. While categories of neutropenia do not necessarily ‘go together,’ there are specific types of neutropenia that medical professionals describe with a combination of the terms above. For example, severe congenital neutropenia describes people who have very low numbers of neutrophils because of a genetic variant. Severe congenital neutropenia is estimated to affect approximately one in 200,000 people.

Idiopathic and autoimmune neutropenia affect women more often than men, with less difference between women and men in congenital forms. Autoimmune neutropenia may occur as a result of a viral infection where autoantibodies to a protein on the surface of neutrophils are generated. This type of neutropenia may persist for several months before spontaneously resolving.

What causes chronic neutropenia?

Chronic congenital neutropenia can be caused by genetic variants that are inherited or by spontaneous genetic variants that aren’t inherited. Genetic variants in the ELANE gene are the most common cause of severe congenital neutropenia and virtually all cases of cyclic neutropenia. Mutations in several other genes, including HAX1, G6PC3, and CXCR4, may also cause chronic neutropenia. 

Chronic neutropenia may also be part of a broader condition like the ones listed below. If you’re unsure, talk to your doctor about how to get the correct diagnosis.

• Barth syndrome.
• Cohen’s syndrome.
• Fanconi anemia.
• Shwachman-Diamond syndrome.
• WHIM syndrome.

What are the symptoms of chronic neutropenia?

Symptoms associated with chronic neutropenia include recurring fevers, mouth sores (ulcers), inflammation of the tissues that surround and support the teeth (periodontitis), and inflammation of the sinuses (sinusitis), throat (pharyngitis), skin (dermatitis), and/or inner ear (otitis). Due to low levels of neutrophils, people with neutropenia may be more likely to get recurring bacterial infections that, in some people, result in life-threatening complications like sepsis. A characteristic feature of chronic neutropenia, especially if it is severe, is a lack or decrease of pus at the site of infections. 

Chronic neutropenia looks very different depending on how low a person’s neutrophil level is in the blood. The risk of infection due to neutropenia correlates with both its severity and duration. 

Those with chronic neutropenia are also at risk of eventually developing bone marrow or blood cancers like myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).

How is chronic neutropenia diagnosed?

Chronic neutropenia can be diagnosed through a complete blood count (CBC) with differential, but a single low neutrophil count is not enough, neutrophil counts must be consistently low for more than three months. In patients with possible cyclic neutropenia, blood counts 2-3 times per week for 4-6 weeks may be necessary. 

While CBC with differential can diagnose chronic neutropenia, CBC with differential cannot determine its cause. Diagnosing the cause of chronic neutropenia starts with a clinical history and hematology evaluation, which may include a bone marrow aspiration. 

Genetic testing is recommended for people with chronic neutropenia. Genetic testing for neutropenia may bring you one step closer to an accurate diagnosis and appropriate clinical management, help you make informed choices about your healthcare, learn the risk for your family members, find resources for your condition, and better understand your options for participating in clinical trial research on investigational therapies. According to a 2024 publication from the International Union of Immunological Societies Expert Committee, variants in 25 different genes can cause chronic neutropenia.

Speak with your doctor or contact a genetic counselor through the patient-initiated testing program about getting a no-cost genetic test from the PATH4WARD program, a partnership between X4 Pharmaceuticals and Invitae.

Here are some questions to ask your doctor to see if you may benefit from genetic testing:

• Have I had a genetic test?
• If I had genetic testing done before, should I have it done again since there are now tests that look at more genes?
• There are free genetic tests available with a doctor’s referral or through a patient-initiated testing program. Do I qualify for one?
• Is there a chance my diagnosis might change depending on the results of a genetic test?
• Would my treatment change if a genetic test finds that I have a specific genetic variant causing chronic neutropenia?
• Are there any clinical trials that I might qualify for based on the results of a genetic test?