Neutropenia

Neutropenia is "a decrease in the number of neutrophilic leukocytes in the blood." It is a subset of leukopenia and its subset granulocytopenia. The Absolute Neutrophil Count (ANC) is used to define levels of neutropenia; it can be calculated from components of the complete blood count or directly measured by some blood analyzers.

The half-life of a neutrophil is less than one-half of a day.

Diagnosis

Rather by definition, the diagnosis is a laboratory determination, although history and physical may help establish the cause. Since the routine complete blood count allows computation or measurement of neutrophils, neutropenia may come up on routine screening.

Guidelines

There are three general guidelines used to classify the severity of neutropenia based on the absolute neutrophil count (ANC) measured in cells per microliter of blood, and reported as a count:

• Mild neutropenia (1000 < ANC < 1500) — minimal risk of infection
• Moderate neutropenia (500 < ANC < 1000) — moderate risk of infection
• Severe neutropenia (ANC < 500) — severe risk of infection.

In infants aged 2 weeks to 1 year, the lower limit of normal ANC is 1000/µL. There is variation for ethnicity. When they are available, it is desirable to state predictors and ranges in terms of genetic markers rather than the more imprecise race. Subsequent work indicates that the race-related generic abnormality is the "Duffy antigen receptor for chemokine (DARC), which is associated with the ethnic group to which individuals belong. The single-nucleotide polymorphism strongly associated with race is DARC rs2814778."

Neutropenia is more commonly found in women and the elderly. Benign ethnic neutropenia has been observed in Africans, African-Caribbean persons, West Indians Ethiopians, Yemenite Jews and certainArabs.

Grading

A more formal grading system is:

• Grade 1: < 2.0 x 10⁹/L (< 2000/mm³) and > 1.1 x 10⁹/L (> 1500/mm³)
• Grade 2: < 1.5 x 10⁹/L (< 1500/mm³) and > 1.0 x 10⁹/L (> 1000/mm³)
• Grade 3: < 1.0 x 10⁹/L (< 1000/mm³) and > 0.5 x 10⁹/L (> 500/mm³)
• Grade 4: < 0.5 x 10⁹/L (< 500/mm³

Differential diagnosis

There are many causes of neutropenia. Some causes are caused by infections while others are not. Some causes of neutropenia may include Acquired Immune Deficiency Syndrome (AIDS), influenza, typhus, malaria, tuberculosis, dengue, Rickettsial infections, systemic lupus erythematosus, Sjogren’s syndrome, Felty’s syndrome, Kostmann syndrome, enlargement of the spleen, folate deficiencies and sepsis.

Idiopathic and secondary neutropenias

Idiopathic neutropenia

Idiopathic neutropenia includes many types of neutropenia and can happen at any point in life for unknown reasons. It can occur in both adults and children and the effects are variable based on disease severity. As with any classification of "idiopathic" disease, there is an implication that common causes have been ruled out.

Autoimmune neutropenia

Autoimmune neutropenia is found in children between six months and four-years-old that have not been diagnosed with congenital neutropenia. This is the most common cause of neutropenia for children in this age group. Severe bacterial infections are rare. Autoimmune neutropenia may also be found in adults, who are usually between the ages of 20 to 40, and most commonly women. This condition is usually associated with other medical conditions.

Drug-induced neutropenia

Other medical conditions or medicines may cause neutropenia. Cancer patients undergoing chemotherapy could develop neutropenia.

Febrile neutropenia

Clinical practice guidelines define febrile neutropenia as "a single oral temperature of >=38.3°C (101°F) or a temperature of >=38.0°C (100.4°F) for >= 1 h. Neutropenia is defined as a neutrophil count of <500 cells/mm3, or a count of <1000 cells/mm3 with a predicted decrease to <500 cells/mm3"

A clinical prediction rule can estimate the risk of morbidity in the febrile patient with neutropenia. A score of >=21 indicates low risk.

Congenital neutropenia with associated immune defects

• Neutropenia with abnormal immunoglobulins: This disorder is observed in individuals with X-linked agammaglobulinemia, isolated immunoglobulin A (IgA) deficiency, X-linked hyperimmunoglobulin M (XHIGM) syndrome, and dysgammaglobulinemia type I. In XHIGM, which is due to mutations in the CD40 ligand, patients can actually have normal or elevated levels of IgM but markedly decreased serum IgG levels.
• Reticular dysgenesis: Patients demonstrate severe neutropenia, no cell-mediated immunity. agammaglobulinemia, and lymphopenia. Life-threatening infections occur that are refractory to granulocyte colony-stimulating factor (G-CSF).10,11,2 Bone marrow transplantation is the treatment of choice.

Primary inherited neutropenias

Kostmann syndrome, cyclic neutropenia and autoimmune neutropenia are considered rare medical disorders of the blood. Patients may register with the Severe Chronic Neutropenia Registry (SCNIR) founded in 1994 to monitor the clinical course, treatment and disease outcomes of registered patients.

Kostmann syndrome

Kostmann syndrome, also known as congenital neutropenia, is present at birth. It was first described in 1956, in the Swedish Kostmann family. Before the availability of granulocyte colony-stimulating factor, it was largely lethal although some family members survived with antibiotic therapy. The general incidence is 1-2 per million, and mortality in the first year of life remains at 70% without G-CSF, bone marrow transplantation, or peripheral blood stem cell transplantation.

It has been believed inherited disease and therefore, more than one family member can be affected, but sporadic occurrence with only one patient in a family may occur. Genetic counseling can be offered to persons with a family history, although the genetics are not completely clear.

The disease is usually detected after an infant presents with a severe infection, with severe neutropenia and:

• Temperature instability in newborn period
• Fever
• Irritability
• Localized site(s) of infection

Neutrophils typically are in an arrested state of development or maturation arrest in the bone marrow. The neutrophils rarely mature to full stage development leaving the patient incapable of fighting off infection. Diagnosis is usually made during infancy.

Cyclic neutropenia

Cyclic neutropenia also is believed to be inherited. Neutrophil activity runs in cycles, typically 21 days, and range from normal blood counts to low blood counts. It is common for the ANC to drop to less than 200 cells/µl) (0.2 x 109/l). Common symptoms during the low period of the cycle may include mouth ulcers and inflammation. Infections such as otitis media, pneumonia and bacteremia are less likely to be seen.

Prevention

Hematopoietic colony-stimulating factors for primary prevention of febrile neutropenia may not decrease mortality but do decrease infections in patients undergoing cancer chemotherapy or stem cell transplantation according to a systematic review.

Treatment

If neutropenia is secondary to another disease or external chemical, that disorder must be treated. When there is both neutropenia and immunoglobulin deficiency, the infection risk is high, and the treatment is intravenous immunoglobulin (IVIG).

Using G-CSF

Granulocyte colony-stimulating factor can be a potent treatment for severe neutropenia, but it is expensive and not without risk. Granulocyte colony-stimulating factor is indicated in selected settings if the projected chance of febrile neutropenia is at least 20%.