Introduction

Neutrophils are a type of white blood cell that support the immune system in responding to infections. Neutropenia is the medical term for conditions where the number of neutrophils in the blood is lower than normal. In this article, we will discuss the causes, symptoms, treatment and management of neutropenia.¹

Defining neutropenia

Importance of neutrophils in the immune system

Neutrophils, like other white blood cells, are a crucial part of the immune system. They circulate in the bloodstream, migrating to sites of infection or tissue damage. Neutrophils act as the first line of defence, quickly responding to infections and neutralising harmful microorganisms. Their primary role involves ‘phagocytosis’, where they engulf and digest invading microbes. Neutrophils can also release potent chemicals to destroy microorganisms.²

Who’s at risk?

Various factors cause neutropenia, such as medications, infections and cancer. As there are many triggers of neutropenia, the individual risk varies based on the underlying cause. ‘Acute’ neutropenia (severe neutropenia that appears quickly) is more common than chronic (long-term) neutropenia caused by underlying health conditions or syndromes. Neutropenia can occur in individuals of all ages.^1,3

Neutrophil counts

To diagnose neutropenia, doctors will compare the number of neutrophils in the patient's blood to the ‘normal’ count - typically between 1,500 - 8,000 neutrophils per microliter of blood. Using this neutrophil count, the severity of neutropenia is classed into ‘mild’ (1,000 - 1,500), moderate (500 - 1,000) or severe (below 500).

Healthy neutrophil counts can vary by age and ethnic background. Children have a lower normal neutrophil count of 1000 and people of African and certain Middle-Eastern ethnicities may also naturally have lower counts.^1,3

Causes and types of neutropenia

Acquired acute neutropenia

Acute

Certain medications or infections can disrupt the normal ‘life cycle’ of neutrophils. Acute neutropenia typically appears over a few days, making individuals more susceptible to infection in a short time.³ 

Medication-induced neutropenia

Some medications that may cause neutropenia include antipsychotic drugs like clozapine, antibiotics such as trimethoprim, antithyroid medications such as methimazole and propylthiouracil, and some anticonvulsants (seizure medications) like valproic acid.

Chemotherapy drugs are known to affect the bone marrow (where neutrophils are produced), often resulting in neutropenia.⁴ Blood transfusions can also cause neutropenia, as the patient's immune system attempts to fight off ‘foreign’ neutrophils, often also killing its neutrophils.³

Nutritional neutropenia

Deficiencies in protein and certain vitamins, such as vitamin B12, folic acid and copper, can lead to neutropenia. In most cases these deficiencies result in multiple abnormal blood counts rather than just neutropenia. Diagnosis of nutritional neutropenia may involve an examination of the medical history, physical condition and specific vitamin levels.⁵

Cancer

Many cancer patients develop neutropenia as a side effect of chemotherapy. However, certain cancers can directly cause neutropenia - tumours that spread to the bone marrow may disrupt neutrophil production, and blood cancers such as leukaemia can also affect neutrophil counts.⁶

Bacterial and viral infections

Infections will generally cause temporary neutropenia as more neutrophils are used to fight off bacteria or viruses. In the case of serious infections such as sepsis, where microbes enter the bloodstream, the increased demand for neutrophils can potentially deplete their levels. Where neutropenia is severe and appears rapidly, with symptoms of fever, this is known as febrile neutropenia. It is one of the more common serious complications of cancer treatment and can progress to sepsis if not treated quickly.^5,7

Viral infections such as HIV can also impact neutrophil production by directly infecting neutrophils.^8,9

Congenital and chronic neutropenia

The congenital form of neutropenia is present from birth, while chronic neutropenia may develop over time (typically months) and is often associated with autoimmune disease. 

Genetic factors

Genetic factors play a significant role in neutropenia, contributing to conditions such as the ‘Duffy null phenotype’ and cyclic neutropenia.

The Duffy null phenotype is the medical term for the absence of a protein called ‘Duffy’ that can be present on red blood cells, associated with a gene called ‘DARC’. This variation is often found in individuals of African descent and has been linked to a predisposition for neutropenia.³

Cyclic neutropenia is a rare condition often associated with mutations in the ELANE gene,¹⁰ affecting the production and maturation of neutrophils. In cyclic neutropenia, individuals experience periodic drops in neutrophil counts, increasing susceptibility to infections during these phases. During these phases, symptoms such as mouth ulcers and fever can occur. Children are more at risk of severe consequences, such as gangrene or sepsis.³  

Inherited severe congenital and autoimmune neutropenia

There are various inherited conditions associated with neutropenia, often linked to specific genetic mutations, some of which also involve the ‘ELANE’ gene.¹⁰ Though rare, severe congenital syndromes associated with neutropenia include Shwachman-Diamond and Kostmann syndrome, conditions affecting various organs, including the bone marrow.^8,11,12

Autoimmune neutropenia occurs when the immune system mistakenly attacks and destroys its own neutrophils and other cells. Other autoimmune conditions that can cause neutropenia include IBD, rheumatoid arthritis and Sjogren’s syndromes.⁹ 

Idiopathic neutropenia

Neutropenias may initially be described as idiopathic (cause unknown), and only be diagnosed after a period of observation where signs of other neutropenia causes (e.g. infection or cancer) are not seen.¹³ 

Symptoms and diagnosis

Common symptoms of neutropenia

Individuals with neutropenia may experience persistent fatigue, recurring and severe skin or respiratory infections, with delayed healing of wounds. It is important to seek medical attention promptly for these symptoms.¹⁴

Diagnostic tests

Complete Blood Count (CBC)

CBC includes haemoglobin levels and the counts of different blood cells including neutrophils. Low neutrophil counts, coupled with unusual results for other blood components, aid in diagnosing neutropenia.

If non-urgent (e.g. mild neutropenia cases) then the patient may be asked to keep a diary, documenting any symptoms, with regular blood counts being taken over this period.^1,3,5,15

Antibody Tests

If it is suspected that neutropenia might be due to an autoimmune condition or a reaction to a blood transfusion, then an antibody test may be performed. This test looks for the presence of proteins that stick only to neutrophils, telling the immune system to attack them.^1,5

Bone marrow aspiration and biopsy

Bone marrow aspiration and biopsy involve extracting a sample of bone marrow, usually from the rib or hip bone, to assess neutrophil production. Aspiration involves collecting a small amount of bone marrow fluid, whereas biopsy takes some of the bone marrow tissue itself.

Bone marrow tests may be done in the hospital or at a clinic. Medication to relieve pain or anaesthetic will be used. Most patients can return home the same day.^1,3,5,15

Genetic testing

Genetic testing may be used to identify inherited genes contributing to neutropenia. Individuals with a family history of neutropenia or related syndromes may benefit from genetic counselling and testing to identify potential inherited genes.^1,3,5

Complications and risks

Increased susceptibility to infections

Neutropenia significantly increases the risk of infections, which can range from mild to severe. Infections are most likely to occur around the skin, mouth and lungs as these are exposed directly to potential sources of infection. In young children with neutropenia-related infections, signs of oral infection such as ulcers and gingivitis are very common. As the immune system is not functioning properly, the normal symptoms of infection caused by the body’s immune response, such as swelling, redness and pus may not be present.³

Impact on overall health

Untreated neutropenia and recurrent neutropenic infection can impair quality of life and is associated with premature death. Chronic inflammation, reduced ability to fight infections, and potential organ damage underscore the importance of addressing neutropenia comprehensively.^1,9

Treatment options

Medications to stimulate neutrophil production

‘Granulocyte colony-stimulating factor’ (G-CSF) is a medication that plays a key role in managing neutropenia. These drugs enhance the production and release of neutrophils from the bone marrow, supporting the body's infection response.^1,5,16

Antibiotic Therapy

Quickly treating infections with antibiotics is essential in supporting the patient’s impaired immune system to allow recovery, and minimising the risk of more serious infections.^1,5,16

Bone Marrow Transplantation

In some neutropenia cases, such as those involving an underlying genetic condition, bone marrow transplantation may be performed. This involves replacing faulty bone marrow with healthy marrow from a donor, offering a potential cure for the condition.^1,5

Lifestyle and dietary considerations

Precautions to prevent infections

Taking strong hygiene measures is crucial for avoiding infections in individuals with neutropenia. As well as personal hygiene, it is important to avoid areas where there is a high risk of infections being transmitted (e.g. crowded areas or events).¹⁴

Nutritional support for neutropenic individuals

A well-balanced diet that includes immune-boosting nutrients can help support the body’s weakened immune system and promote recovery from infection.⁵

Long-term management strategies

Long-term management involves regular blood counts and closely following prescribed medications. The most important aspects of neutropenia management are preventing infections,  addressing symptoms quickly, and providing supportive care. Close communication between the patient and doctor helps manage the neutrophil counts and work towards a diagnosis.¹³

Living with a chronic condition like neutropenia can also impact mental health. Seeking psychological support and counselling can aid individuals in coping with these challenges.⁵

Summary

Knowledge of the signs and causes of neutropenia can help with early diagnosis and proper management of the underlying cause. By understanding what can contribute to neutropenia and infections, patients can improve their quality of life through good communication with their doctors, discussing any family history of neutropenia, monitoring their symptoms and taking precautions to avoid infection.