Introduction
Neutrophils are a type of white blood cell that arise from the bone marrow and circulate in the blood to help fight infections. As part of the innate immune system, neutrophils are first responders to bacteria and other types of foreign cells in the body. When a patient has an absolute neutrophil count (ANC) of less than 1.5 × 109 cells/l they are considered to have neutropenia. Patients are further stratified into mild neutropenia (ANC < 1.5 × 109 cells/l), moderate neutropenia (ANC < 1.0 × 109 cells/l) and severe neutropenia (ANC < 0.5 × 109 cells/l).
When a patient's ANC has been < 1.5 × 109 cells/l on several occasions for more than three consecutive months he or she is considered to have chronic neutropenia and will require a thorough evaluation. There are many causes of chronic neutropenia including acquired and congenital disorders that range from benign to severe or life-threatening. The diagnosis of severe chronic neutropenia is a global term used to describe patients with an ANC < 0.5 × 109 cells/l for at least three months, and possibly a greater risk of infection and predisposition to cancer depending on the underlying cause. In contrast acute neutropenia may be transient in duration. The most common cause of acute neutropenia is viral infection.
Cause
In broad terms, chronic neutropenia is caused by one of the three mechanisms:
| 1. | Decreased production of neutrophils in bone marrow | ||||
| 2. | Increased consumption (e.g. infection, splenic sequestration) | ||||
| 3. | Increased destruction (e.g. immune-mediated processes) | ||||
Although many of the diseases resulting in chronic neutropenia may be benign or short-lasting, it is very important for a physician to determine the cause of chronic neutropenia because patients with disorders of neutrophil production and release from the bone marrow are at a higher risk of infection than patients with neutropenia caused by increased consumption or immune depletion.
When examining patients with severe chronic neutropenia, those with absent bone marrow reserve suffer far more critical consequences. There are four main diseases under the umbrella term of severe chronic neutropenia, each with their own unique significance.
| 1. | Severe congenital neutropenia: A group of inherited disorders resulting in virtually no production of neutrophils, high propensity to severe infections at a very young age and predisposition to acute myelogenous leukemia. This disorder requires treatment and routine surveillance. | ||||
| 2. | Cyclic neutropenia: Defined by a cyclic pattern (usually 21 days) of low-to-absent neutrophil production for 4–6 days accompanied often with fevers, inflamed gums, abdominal pain, and possible infections. The low levels of ANC are associated with peak levels of monocyte count. The reciprocal relationship in the neutrophil and monocyte count can suggest the diagnosis. This disease is also caused by inherited genetic mutations and requires treatment. | ||||
| 3. | Immune-mediated neutropenia: Encompasses a diverse collection of disorders, primarily appearing during early childhood, caused by circulating antibodies attacking and removing neutrophils from the circulation. These patients typically do not require medical intervention due to their strong bone marrow reserve, low-risk of infection and tendency for spontaneous remission of disease. | ||||
| 4. | Chronic idiopathic neutropenia: More common in adulthood, has no identifiable etiology and does not undergo spontaneous remission. However, these patients typically have a normal marrow and lack of significant infections, unless ANC is chronically < 0.5 × 109 cells/l. | ||||
Symptoms and signs
Signs and symptoms of chronic neutropenia vary therefore a patient may go undiagnosed for quite some time. Physicians become concerned for severe neutropenia when a patient has consistently low ANCs and abnormal, frequent infections.
Some signs and symptoms may include:
| • | Absolute neutrophil count of <0.5 × 109 cells/l for three consecutive months. | ||||||||||||||||||||||||||||
| • | Fevers | ||||||||||||||||||||||||||||
| • | Frequent and/or atypical infections
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Tests
Initial evaluation of chronic neutropenia focuses on identifying the cause and significance of the neutropenia. Repeat complete blood count testing can help to confirm a diagnosis; however more specialized testing is usually required to identify the cause.
Preliminary assessment:
| • | General medical history including history of neutropenia, recent infections, recent drug exposure, family history of similar symptoms, etc. | ||||
| • | Physical exam looking for sites/signs of infection or genetic abnormalities: mouth ulcers, dental defects, skin infections, abnormal lung exam, abdominal pain and/or abnormalities in development. | ||||
| • | Full blood count with differential (necessary for determining ANC). If the patient is not acutely ill, he or she may be evaluated for many weeks with blood counts at least three times per week in order to determine a trend. | ||||
Other tests may include:
| • | Bone marrow evaluation | ||||
| • | Genetic testing | ||||
| • | Testing for anti-neutrophil antibodies | ||||
| • | Testing for quantities and qualities of other immune system components such as immunoglobulins and lymphocytes | ||||
Treatment options
The clinical management of chronic neutropenia depends greatly on the severity of neutropenia, adequacy of marrow and predisposition of infection and other diseases. Treatment for clinically severe patients or those with an unfavorable genetic mutation may include:
| • | Granulocyte Colony Stimulating Factors (G-CSF): Can increase the number of neutrophils and reduce the incidence of infection. This is typically used in diseases such as severe congenital neutropenia, cyclic neutropenia and severe idiopathic neutropenia. | ||||
| • | Bone Marrow Transplantation: This treatment modality has been successful in patients who do not respond to G-CSF or are developing AML. | ||||
Outlook
For most patients with neutropenia, clinical manifestations are typically few; however for those with severe chronic neutropenia, treatment with G-CSF is required to prevent repeated infections and definitive cure requires bone marrow transplantation. Employment of new genetic leads is also helping to earlier diagnose and treat these patients.
Additional resources
There are many available resources for patients seeking further information on chronic neutropenia. One website of particular note is the Severe Chronic Neutropenia International Registry (https://depts.washington.edu/registry/). The most recent consensus of pediatric neutropenia, titled ‘Approach to Neutropenia in Childhood’, can be found in the journal Pediatrics in Review, vol. 36, pages 173–187 (April 1, 2013). Information can also be found in the American Society for Hematology's Education Program article ‘How to Approach Neutropenia’ by Laurence A. Boxer, which is available online.