Introduction
Neutrophils are produced from hematopoietic cells. Before these hematopoietic cells mature into fully functional neutrophils and enter the blood stream, they migrate through three cellular compartments, namely, the mitotic compartment, post-mitotic compartment and the storage compartment. Neutropenia is a condition characterized by decrease in the neutrophil count. Neutrophils are essential for fighting infections in the body. Common causes of neutropenia are chemotherapy, autoimmune disorders, drug reactions and genetic reasons. Absolute blood neutrophil count (ANC) in mild neutropenia is between 1.0 and 1.5 109/L. In severe neutropenia, the ANC is less than 0.5 109/L. Neutropenia can either be inherited or acquired. (Boxer & Dale, 2002).
Epidemiology
Acquired neutropenia is more common compared to cyclic or congenital neutropenia. Caucasians are more susceptible to neutropenia when compared to people of African descent. Acute neutropenia is rarely lethal and in fact normalizes very quickly on its own. Chromic neutropenia may last for weeks or months together. (Boxer, 2012).
Causes of neutropenia
Neutropenia can develop due to destruction of the cells, increased margination, faulty cell production process or loss of blood cells into space within the body (sequestration). 40% of the patients undergoing radiation therapy are affected by neutropenia. Drug-induced neutropenia is the most common cause of temporary neutropenia. Viruses such as influenza virus, hepatitis A, hepatitis B, Epstein-Barr virus, HIV, parvovirus, etc. can cause infections leading to neutropenia. Bacterial infections such as tuberculosis, salmonellosis, brucellosis, etc. are also popular causes of neutropenia. Collagen vascular diseases show characteristic neutropenia. Deficiency of vitamin B12 and folate causes neutropenia, anemia and thrombocytopenia. Leukemia, myelodysplasia and other forms of cancer may suppress neutrophil formation leading to neutropenia. (Munshi & Montgomery, 2000).
Symptoms
Patients suffering from neutropenia might be experience recurrent infections, night sweats, weight loss, rheumatologic problems, fever, gingivitis, abscess, mucositis, adenopathy, hepatosplenomegaly, myelodysplasia or megaloblastosis. (Munshi & Montgomery, 2000).
Diagnosis
Blood smear and peripheral blood count is done to evaluate the ANC for that particular age. Repeat counts are recommended to eliminate the possibility of transient neutropenia. A manual differential count must be done, which can give specific diagnoses such as myeloblast leading to leukemia, nucleated red blood cells, hypersegemented neutrophils (suggesting vitamin B12 and folate deficiency). Increased spleen size with associated neutropenia symptoms might be due to hypersplenism. Recent drug exposure must be evaluated for drug-induced neutropenia. Bone marrow aspiration in recommended for some cases. Antineutrophil antibodies are detected using granulocyte agglutination test (GAT) and granulocyte immune-fluorescence test (GIFT). Tests for systemic lupus erythematosus, vitamin B12 and folate levels are also recommended for evaluation (Boxer, 2012).
Types of neutropenia
Acquired. Neutropenia is usually acquired through drug interaction or as a cause of other treatments such as chemotherapy. Types of acquired neutropenia are discussed below.
Immune neutropenia. When the body produces antibody against neutrophils (Antineutrophil antibodies) due to faulty immune recognition, it results in immune neutropenia. Such antineutrophil antibodies can be detected using granulocyte agglutination test (GAT) and granulocyte immune-fluorescence test (GIFT). In GAT, there is a visible agglutinating of neutrophils. In GIFT, the neutrophil bound antibodies are detected by fluorescence labelled IgGs. Some of the frequently encountered antineutrophil antibodies are HNA-1a-1c and HNA-2a-5a. (Berliner, Horwitz & Loughran, 2004)
Alloimmune neonatal neutropenia. Alloimmune neonatal neutropenia (AINN) occurs due to maternal IgG sensitization to paternal neutrophil antigens. This IgG can pass through the placenta and cause temporary neutropenia in newborns. However, the condition usually passes away by 11 weeks after birth. (Berliner, Horwitz & Loughran, 2004)
Primary autoimmune neutropenia. Primary autoimmune neutropenia (AIN) is seen in children under the age of 3 years. This condition is treated with antibiotics. Treatment with G-CSF is reserved for chronic cases. Primary AIN is directed towards HNA-1 and HNA-2. Primary AIN rarely occurs in adults. Primary AIN is usually diagnosed using GIFT. However, 3% of the cases may require GAT for positive detection (Berliner, Horwitz & Loughran, 2004).
Secondary autoimmune neutropenia. Secondary AIN is predominantly seen in adults in association with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Felty’s syndrome (FS) occurs in patients with RA and leads to neutropenia. Patients with FS have high morbidity. SLE-associated neutropenia is not lethal and has very little impact on how the disease progresses. Secondary AIN in children is very rare. It usually occurs as part of lymphoproliferative syndrome. (Berliner, Horwitz & Loughran, 2004)
Drug-induced neutropenia. Drug-induced neutropenia is a rare side effect. However, it is deemed fatal due to increased infection and complication. Nearly 10% of the patients with drug-induced neutropenia, die. Sulfonamides, sulfasalazine, dipyrone, thiouracil, methimazole, carbamizole, cephalosporin, penicillin, chloramphenicol and valproic acid are common causes of drug-induced neutropenia. Some patients can show drug-induced neutropenia with Clozapine due to hereditary reasons. (Berliner, Horwitz & Loughran, 2004). Mortality is typically seen in patients over 60 years of age who have increased risk of renal failure and bacteremia. The mechanism of drug-induced neutropenia is poorly understood. However, it is thought that there is decreased myeloid production in the bone marrow due to prolonged exposure. (Boxer, 2012).
Cell mediated neutropenia. Cell mediated neutropenia is also known as chronic idiopathic neutropenia. It is characterized by absence of any antineutrophil antibodies and is usually benign. The patient might show anemia and thrombocytopenia. The bone marrow shows hypoplasia and an increase in interstitial T-lymphocytes. Patients with large granular lymphocyte (LGL) leukemia present neutropenia as a result of impaired neutrophil production in the bone marrow aided by faulty cell-mediated mechanisms. (Boxer, 2012)
Hereditary.
Cyclic neutropenia. Cyclic neutropenia is an autosomal dominant disorder that is caused by a mutated gene for neutrophil elastase (ELA-2). This mutation is seen in 80% of the patients diagnosed with cyclic neutropenia. The ANC oscillates between 1.0 and 1.5 109/L every 21 days and hence the name cyclic neutropenia. The actual existence of neutropenia is only for 3 to 6 days. During the neutropenia days, the patient may experience painful mouth ulcers, fever, ulceration of mucus membrane, malaise, etc. Death due to bacterial sepsis is common in cyclic neutropenia. Bacteremia is usually caused by Clostridium species in such cases. (Boxer & Dale, 2002). Children suffering from cyclic neutropenia can develop gangrene and septic shock. Diagnosis of cyclic neutropenia is established through serial differential white count 3 times a week for 6 weeks. (Boxer & Newburger, 2007)
Severe congenital neutropenia (SCN) and Kostmann disease. Kostmann described SCN as an autosomal recessive disorder. However, recent research shows that SCN could be autosomal dominant or even X-linked. ANC is significantly below 200/μl accompanied by severe infections in neonates. One of the main causes of SCN is myeloid maturation arrest as premyelocyte-myelocyte stage. This arrest in maturation is unique to SCN and thus helps differentiating it from other forms of neutropenia. Patients affected by SCN suffer from oral ulcers, abscesses, pneumonia, septicemia and gingivitis. (Boxer & Newburger, 2007)
Treatment
Drug-induced neutropenia goes away on its own once the drug is removed from the system. The same is applicable for neutropenia due to viral infection. If the neutropenia is due to chemotherapy, it may be treated using granulocyte colony–stimulating factor (G-CSF) or granulocyte-macrophage colony–stimulating factor (GM-CSF). In case of severe neutropenia due to chemotherapy, it is recommended that the patient be treated with cytokine therapy. In very severe cases, allogenic marrow transplant maybe considered. (Munshi & Montgomery, 2000).
Conclusion
Neutropenia maybe a result of defective genes (cyclic neutropenia and SCN), defective cell mediated mechanisms, drug-related, malnourishment (lack of vitamin B12 and folate) or diagnosed as a secondary symptom of an underlying malignant or benign disease, such as cancer. The mechanism of neutropenia is not properly understood. However, it is clear that neutrophil deficiency occurs due to suppressed production, self-destruction and sequestration. The best diagnostic method is serial counts done 3 times a week for at least 6 weeks along with bone marrows aspirate analysis. Molecular mechanisms of genes and associated myeloid functioning have helped understanding neutropenia disorders.
References
Berliner, N., Horwitz, M., & Loughran, T. P. (2004). Congenital and acquired neutropenia. ASH Education Program Book, 2004(1), 63-79.
Boxer, L. A. (2012). How to approach neutropenia. ASH Education Program Book, 2012(1), 174-182.
Boxer, L., & Dale, D. C. (2002, April). Neutropenia: causes and consequences. In Seminars
in hematology (Vol. 39, No. 2, pp. 75-81). WB Saunders.
Boxer, L. A., & Newburger, P. E. (2007). A molecular classification of congenital neutropenia syndromes. Pediatric blood & cancer, 49(5), 609-614.
Munshi, H. G., & Montgomery, R. B. (2000). Evidence-Based Case Review: Severe neutropenia: a diagnostic approach. Western Journal of Medicine, 172(4), 248.
