eMedicine Specialties > Pediatrics: General Medicine > Hematology
Autoimmune and Chronic Benign Neutropenia
Updated: Oct 13, 2009
Introduction
Background
Chronic benign neutropenia (ie, neutropenia lasting >6 mo, as opposed to acute) can be regarded as a synonym of autoimmune neutropenia (AIN) in children.
Most infants and children with the identical clinical characteristics of chronic benign neutropenia, originally described by Zuelzer and Bajoghli, subsequently appeared to have antineutrophil antibodies.1 Lalezari and colleagues demonstrated neutrophil antibodies in 119 of 121 infants and children with chronic neutropenia, thereby establishing the autoimmune nature of the disease.2 In the study by Lalezari et al, all patients had an absolute neutrophil count of less than 500/µL at one time.
The definition of neutropenia in infants is different from that in adults. In infants aged 2 weeks to 1 year, the lower limit of normal neutrophil count is 1000/µL. After the first year of life, the lower limit is 1500/µL, as in adults.
Autoimmune neutropenia is either primary or secondary. In primary autoimmune neutropenia, neutropenia is the only abnormality. In secondary autoimmune neutropenia, other primary pathologies occur, including systemic autoimmune disease, infections, and malignancy. In infants, secondary autoimmune neutropenia is extremely rare. The most common type of chronic neutropenia in children is chronic benign neutropenia of childhood.
Infections associated with primary autoimmune neutropenia are usually limited and mild. Infections include skin problems, stomatitis, gingivitis, upper respiratory tract infections, and otitis media.
This patient presented with recurrent otitis and areas of cellulitis in the diaper area. Pseudomonas aeruginosa and Staphylococcus aureus were isolated from the skin lesions. Autoimmune hemolytic anemia and autoimmune neutropenia were confirmed based on the presence of autoantibodies. The patient has a mutation on exon 15, A504T, which changed an asparagine residue to a valine residue.
According to Jonsson and Buchanan, 6 of 23 girls had an abscess or cellulitis of the labia majora.3 Sepsis and pneumonia are rare. This is in contrast to severe life-threatening infections (quite often systemic) experienced by infants with severe congenital neutropenia (Kostmann disease and other types), children with aplastic anemia, or children with neutropenia receiving chemotherapy. The reasons may be related to the fact that individuals with autoimmune neutropenia have an adequate bone marrow neutrophil reserve and, thus, can mount some level of neutrophil response to an infection, even though these neutrophils are rapidly destroyed; this is in contrast to patients with poor or no bone marrow reserve.
Older children, adolescents, and young adults predominantly develop secondary autoimmune neutropenia, and autoimmune hemolytic anemia or immune thrombocytopenia often occur later or at the same time. Antiphospholipid antibody syndrome is common, and, ultimately, systemic lupus, Felty syndrome, and/or a lupuslike illness predominates. Therefore, in this age group, a rigorous search for evidence of other autoimmune phenomenon should be made.
Pathophysiology
Autoimmune neutropenia is similar to immune thrombocytopenic purpura (ITP), a more common cytopenia in children. ITP is believed to be triggered by a viral infection and, in some individuals, by immunization. Whether autoimmune neutropenia is commonly triggered by similar etiologies is not known. The age group is affected in a similar fashion, and recovery is expected in both. Some studies showed an association with parvovirus B19 infection.
When identified in chronic benign neutropenia, antibodies most commonly include immunoglobulin G (IgG) antibodies against neutrophil glycosylated isoforms of Fc γ IIIb (or CD 16b), which are linked to the plasma membrane via a glycosylphosphatidylinositol anchor. The human neutrophil antigen (HNA) system consists of HNA-1 through HNA-5. Of which, most common antibodies are directed against HNA-1, which consists of NA1, NA2, and SH. They are not anti–human leukocyte antigen (HLA) antibodies. Bone marrow examination typically demonstrates increased cellularity of myeloid elements (myeloid hyperplasia) with an absent or decreased number of mature neutrophils.
In some cases, mature forms of neutrophils are seen. This suggests that, in most cases, neutropenia is due to increased consumption of neutrophils in the peripheral circulation and in the tissues that result from phagocytosis of the antibody-coated neutrophils.
In a study by Perdikogianni et al, circulating granulocyte colony-stimulating factor (G-CSF) levels (serum or plasma) were found to be normal, even during the neutropenic period, except when patients had infections.4 This may indicate that the bone marrow in these patients have enough maturation pool cells to dampen a trigger to increase G-CSF output. Serum levels of intercellular adhesion molecule 1 (ICAM-1), tumor necrosis factor α (TNF-α), and interleukin (IL)-1 β levels were inversely correlated with the neutrophil count, suggesting a low degree of inflammatory process, which activates endothelial cells without obvious clinical infection. In 65% of patients who were studied, serum G-CSF levels were within the reference range.
Frequency
International
The estimated incidence in the Scottish population is approximately 1 in 100,000 children per year.5 This may be an underestimate, because laboratory tests are not usually performed in most cases of autoimmune neutropenia.
Mortality/Morbidity
Infections associated with primary autoimmune neutropenia are usually limited and mild.
Race
The incidence does not vary among different ethnic populations.
Sex
Autoimmune neutropenia has a slight preponderance in girls.2
Age
The mean age at diagnosis is 8-12 months, with a range of 3-30 months. Spontaneous recovery occurs by age 5 years, and the mean duration of neutropenia is approximately 20 months.
Clinical
History
- Most children with autoimmune neutropenia (AIN) receive initial medical attention because of a febrile illness during the last 6 months of infancy, including the following
- Acute otitis media
- Gastroenteritis
- Tonsillitis
- Skin infection
- Neutropenia is usually discovered during the workup of the febrile illness.
- However, incidental discovery of leukopenia and neutropenia in a routine CBC count or a CBC count performed for an unrelated reason is also a common history that results in the diagnosis of autoimmune neutropenia.
- No family history of neutropenia or leukopenia is reported, and, if performed earlier in the child's life, a CBC count is usually within the reference range.
- Suspect iso (allo)-immune neutropenia, or severe congenital neutropenia, if profound neutropenia is present at or shortly after birth.
- Although febrile illnesses appear to be more common in children with autoimmune neutropenia than in healthy children, autoimmune neutropenia usually does not affect the child's growth and development, although some exceptions occur.
- Differentiating autoimmune neutropenia from ethnic neutropenia may be difficult. Inquiring about the ethnicity of the patient and parents is important. A high frequency of benign neutropenia is widely recognized in African Americans, Yemenite and Falashah Jews, Black Beduin, blacks of South African extraction, West Indians, Arab Jordanians, and various tribal groups inhabiting the United Arab Emeritas.6
- Autoimmune neutropenia of infancy usually lasts only 2-3 years before spontaneously resolving. If it persists beyond age 4-5 years with benign course, and if the child is of one of the ethnicities listed above, one may suspect ethnic neutropenia. A family history of neutropenia may be helpful in this differentiation. However, neutrophil counts increase with age even in individuals with ethnic neutropenia.7 Thus, absence of a family member with neutropenia does not exclude the diagnosis of ethnic neutropenia.
Physical
- Physical examination may reveal signs of a local infection, including mouth ulcer; gingivitis; frequent upper respiratory infections; impetigo; otitis media; and, rarely, cellulitis, abscesses, or sepsis.
- Many children may simply present with fever without any focal infection.
- Patients generally do not exhibit growth failure or chronic illness.
- The following should alert physicians to a diagnosis other than autoimmune neutropenia:
- Severe illness
- Life-threatening infections
- Significant hepatosplenomegaly
- Purpura
- Hemorrhagic findings
- In individual with an enlarged spleen, consider hypersplenism in the differential diagnosis. A significantly enlarged spleen indicates a different diagnosis.
Causes
- The initial trigger may be a viral illness (including human parvovirus B19 infection) analogous to immune thrombocytopenic purpura (ITP).
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References
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Lalezari P, Khorshidi M, Petrosova M. Autoimmune neutropenia of infancy. J Pediatr. Nov 1986;109(5):764-9. [Medline].
Jonsson OG, Buchanan GR. Chronic neutropenia during childhood. A 13-year experience in a single institution. Am J Dis Child. Feb 1991;145(2):232-5. [Medline].
Perdikogianni Ch, Dimitriou H, Stiakaki E, et al. Adhesion molecules, endogenous granulocyte colony-stimulating factor levels and replating capacity of progenitors in autoimmune neutropenia of childhood. Acta Paediatr. Nov 2003;92(11):1277-83. [Medline].
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Bruin M, Dassen A, Pajkrt D, et al. Primary autoimmune neutropenia in children: a study of neutrophil antibodies and clinical course. Vox Sang. Jan 2005;88(1):52-9. [Medline].
Bussel J, Lalezari P, Hilgartner M, et al. Reversal of neutropenia with intravenous gammaglobulin in autoimmune neutropenia of infancy. Blood. Aug 1983;62(2):398-400. [Medline].
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Coppo P, Clauvel JP, Bengoufa D, et al. Autoimmune cytopenias associated with autoantibodies to nuclear envelope polypeptides. Am J Hematol. Nov 2004;77(3):241-9. [Medline].
Corbacioglu S, Bux J, Konig A, et al. Serum granulocyte colony-stimulating factor levels are not increased in patients with autoimmune neutropenia of infancy. J Pediatr. Jul 2000;137(1):96-9. [Medline].
Dinauer MC. The phagocyte system and disorders of granulopoiesis and granulocyte function. In: Nathan DG, Orki SH, eds. Hematology of Infancy and Childhood. 5th ed. 1998:915-7.
Komiyama A, Ishiguro A, Kubo T, et al. Increases in neutrophil counts by purified human urinary colony- stimulating factor in chronic neutropenia of childhood. Blood. Jan 1988;71(1):41-5. [Medline].
Lalezari P, Jiang AF, Yegen L, Santorineou M. Chronic autoimmune neutropenia due to anti-NA2 antibody. N Engl J Med. Oct 9 1975;293(15):744-7. [Medline].
Taniuchi S, Masuda M, Hasui M, et al. Differential diagnosis and clinical course of autoimmune neutropenia in infancy: comparison with congenital neutropenia. Acta Paediatr. 2002;91:1179-82. [Medline].
Further Reading
Keywords
autoimmune benign neutropenia, chronic benign neutropenia, autoimmune neutropenia, AIN, autoimmune granulocytopenia, autoimmune neutropenia of infancy, antineutrophil antibodies, primary AIN, primary autoimmune neutropenia, secondary AIN, secondary autoimmune neutropenia, immune thrombocytopenic purpura, ITP, stomatitis, gingivitis, upper respiratory tract infections, otitis media, autoimmune hemolytic anemia, immune thrombocytopenia, antiphospholipid antibody syndrome, systemic lupus, parvovirus B19 infection, gastroenteritis, tonsillitis
