Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1000/μL in infants and less than 1500/μL in older children. Autoimmune neutropenia (AIN) is a disease characterized by chronic reduction of the absolute neutrophil count below the threshold for age, because of the presence of antibodies against human neutrophil antigens. According to the current knowledge and classification, autoimmune neutropenia is designated as primary or secondary.
Primary autoimmune neutropenia (PAIN) occurs in early infancy, usually before the age of 3 years. It shows a mild/moderate phenotype, and almost always spontaneously resolves over time, with 90% of cases recovering within 24 to 36 months of onset. Conversely, secondary autoimmune neutropenia is usually associated with autoimmune diseases (i.e., rheumatoid arthritis, Felty syndrome, systemic lupus erythematosus, scleroderma), or malignancies (i.e., large granular lymphocytic leukemia, chronic lymphocytic leukemia), viral infections, and drugs may appear after hematopoietic stem cell transplantation (HSCT). This is mostly seen in adults.
The most significant symptom associated with AIN is fever, as this may indicate a serious infection. The clinical manifestations vary from being completely asymptomatic to severe forms of infections complicated by overwhelming sepsis (a condition with microorganisms in the blood). Other symptoms such as cough, vomiting, diarrhea, and rash may also be present.
Signs and symptoms of autoimmune neutropenia include infections associated with primary autoimmune neutropenia, which are usually limited and mild, including fever, otitis media, upper respiratory tract infection, common cold, viral gastroenteritis (acute infection/inflammation of stomach and intestine), skin infection, stomatitis (inflammation of the mucous membrane of the mouth), and gingivitis (inflammation of the gums), very rarely, cellulitis (inflammation of the connective tissue below the skin), abscesses (collection of pus in any part of the body), urinary tract infection (UTI), or sepsis.
Some patients are asymptomatic, whereas a complete blood count (CBC) performed for an unrelated reason, such as a routine CBC, may reveal neutropenia. Sometimes the condition is usually discovered during the workup of a febrile illness. Diagnosis is based on the patient’s medical clinical history, physical examination, laboratory investigations mainly antineutrophil antibodies test, followed by bone marrow examination and serum immunoglobulin quantitation.
Many children present with fever without any focal infection or they may physically be entirely normal. Physical examination in patients may reveal signs of local infection, including mouth ulcer, gingivitis, upper respiratory tract infections, impetigo, otitis media, pneumonia, and, very rarely, cellulitis, abscesses, or sepsis. The various laboratory investigations which are necessary include complete blood count, antinuclear antibody test, bone marrow examination, and serum immunoassays.
The PAINs are usually benign or self-limiting. Most cases require no specific therapy. If the patient is free from significant infection, treatment is unnecessary. Spontaneous recovery after 6-24 months is typical. Severe infectious complications are overall less frequent in AIN. Consequently, AIN children should have a normal lifestyle. In case of fever, the parents are recommended to consult primary care physicians/general practitioners to make early use of antibiotics. Antibiotics are normally sufficient to deal with infections. But since severe infections are very rare and the wide use of antibiotics may trigger microbial resistance, routine antibiotic prophylaxis is not always preferred. The utility of medium-term to long-term antibiotic prophylaxis must be assessed on a case-by-case basis.
In patients with severe infections or in those who require surgical intervention, remission can be achieved by treatment with corticosteroids, intravenous gamma globulin (IgG), and growth factors, particularly granulocyte colony-stimulating factor (G-CSF). Corticosteroids, usual prednisolone, have been used in small case series in the past, that appear to have limited effect on immune-mediated neutropenias. Intravenous gamma globulin (IgG) is used or reserved for infections that do not respond to conventional antibiotics. However, such treatments are not always active (50% of cases) and, importantly, the effect is short lasting (1–2 weeks).
For primary forms of AIN, G-CSF is currently the first-line therapy to achieve remission of neutropenia. The goal is to keep the neutrophil count above 1000/µl, which can usually be done by giving G-CSF intravenously or subcutaneously at a dose of 5–10 µg/kg per day for 3 days, after which further doses can be given, depending on the response. Granulocyte-colony stimulating factor (G-CSF) at an initial dose of 1–2µg/kg/day should be used only in the presence of serious infections and/or in the case of surgery. Severe or unresponsive secondary AIN may be treated with G-CSF to increase neutrophil counts and reduce the risk for infection. G–CSF is also used for recurrent or refractory infections that are unresponsive to conventional therapy.
Finally, although AIN usually does not require strong medical intervention, enrolling patients in a monitoring program is very important and beneficial until the disease is finally resolved.