Autoimmune Neutropenia (Granulocytopenia)
In primary AIN (1), neutropenia is the sole haematological abnormality and no associated diseases or factors that might be the cause of neutropenia are present. Primary AIN is not familiar and can be observed in all racial groups. Primary AIN is most often diagnosed in young infants less than 3 years of age and is more frequent than secondary AIN. The annual incidence of AIN in infants has been found in Scotland to be 1:100 000 (2). Diagnosis in infancy is usually made at the age of 5 -15 months but the true onset may be as early as 1 month after birth. AIN is somewhat more prevalent in female than in male patients. Chronic benign neutropenia of infancy is largely the result of autoimmunisation against neutrophils. Clinical findings: Patients with primary AIN often suffer from infections of mild to moderate severity including bacterial infections of the skin and the upper respiratory tract, as well as fever of unknown origin. Recurrent otitis media is typical for AIN in infancy. Severe infections such as sepsis, meningitis and pneumonia are rare. Generally, the older patients with AIN, the less they are affected by infections. Marked splenomegaly is untypical for primary AIN.
In general, during the neutropenic phase, there is an increased number of infections but these are usually not life-threatening and can be treated by routine antibiotic therapy. Spontaneous remission is the rule in infants with primary AIN. However, after the 4th year of age, spontaneous improvement of AIN is unlikely and neutropenia persists. There is no evidence that patients demonstrate an increased susceptibility to diseases, particularly autoimmune diseases or malignancies.
Pathogenesis: The underlying abnormality in patients with primary AIN is poorly understood. Viral infections before onset are not commonly observed. There is increasing evidence that primary AIN in infancy is the result of a combination of genetic predisposition (HNA-1a antigen, some HLA antigens), immaturity of the immune system (T regulatory cells) and contact with microorganisms after birth (bacterial colonisation of the bowels). The occurrence of AIN in only one of monozygotic twins is strong evidence against a strictly hereditary mechanism. Neutropenia is thought to be due to destruction of antibody-coated neutrophils in spleen, liver and already by marrow macrophages. In addition, evidence is growing that some neutrophil-specific autoantibodies interfere with myelopoiesis.
Laboratory and bone marrow findings: In infancy, total leukocyte counts can be normal despite neutropenia. Particularly during infection, the body reacts with monocytosis to compensate for the lack of neutrophils. Myelopoiesis in the bone marrow is usually normal or hypercellular, seldom decreased. Mature neutrophils and band forms are often reduced ("shift to the left") and sometimes absent, giving the marrow the appearance of a developmental arrest at the (meta-) myelocyte stage. However, a maturation arrest in the literal sense does not occur.
Therapy: Treatment has usually been limited to the intermittent use of antibiotics for control of infections. In cases of recurrent infections, preventive administration of antibiotics such as cotrimoxazole is useful. Temporary remission may be achieved by large intravenous doses of immunoglobulin G (IVIgG) or conventional steroid therapy. However, IVIgG can show no improvement and steroids can not only cause side effects but further weaken the immune defense of the patient. Therefore, granulocyte colony-stimulating factor (G-CSF) is now used to increase neutrophil counts (3). G-CSF treatment has been successful in most treated patients with AIN. As infections in AIN usually are not life-threatening and AIN is self-limited in infants, G-CSF or IVIgG should be restricted to severe cases or if surgical intervention is necessary.
Secondary AIN (4): Neutropenia is a common part of many diseases of heterogeneous nature including autoimmune cytopenias (idiopathic thrombocytopenia, autoimmune haemolytic anaemia, Evans syndrome), lymphoproliferative disorders (chronic lymphatic leukaemia, autoimmune lymphoproliferative syndrome) and systemic autoimmune diseases (systemic lupus erythematosus, Sjogren's syndrome). The role of neutrophil autoantibodies in patients with Felty's syndrome is still a matter of debate although there is increasing evidence that in the majority of the cases, neutropenia is not of autoimmune nature. Finally, after stem cell transplantation the formation of neutrophil autoantibodies of the donor versus donor type can cause in post-engraftment neutropenia (5).
Drug-induced immune neutropenia (6) has been reported for a number of drugs including antibiotics (cephalosporins, ß-lactamines), antimalarials (quinine), antithyroid drugs (carbimazole) and analgesics (metamizole).
Neutrophil autoantibody detection: Diagnosis of AIN is made by detection of antineutrophil autoantibodies in the patient's plasma. Direct testing, i.e. determination of surface-bound (granulocyte-associated) immunoglobulin is less predictive. The high number of Fc? receptors on neutrophils results in innate levels of cell-associated immunoglobulins and enhances the nonspecific binding of immune complexes and IgG aggregates by the more or less activated neutrophils from neutropenic patients with or without infections. In addition, patients with severe neutropenia often do not have enough circulating neutrophils for sufficient quantities to be obtained for antibody detection. To detect neutrophil antibodies in patients' sera, a combination of granulocyte agglutination test (GAT) granulocyte immunofluorescence test (GIFT) and a typed granulocyte panel is currently the most effective means of detection. Since neutrophil autoantibodies frequently show specificity for the neutrophil alloantigen HNA-1a, the former NA1, the panel should include test cells from a HNA-1a (NA1) homozygous donor. The level of antineutrophil antibodies in the plasma often begins to wane prior to improvement in the absolute neutrophil count and can give an indication of when recovery will occur.