Pediatric Autoimmune and Chronic Benign Neutropenia 

The most common type of chronic neutropenia in pediatric patients is chronic benign neutropenia of childhood, ie, neutropenia lasting over 6 months. Chronic benign neutropenia can be regarded as a synonym for autoimmune neutropenia in children.

The definition of neutropenia in infants is different from that in adults. In infants aged 2 weeks to 1 year, the lower limit of the normal neutrophil count is 1000/µL. After the first year of life, the lower limit is 1500/µL, as in adults.

The mean age at diagnosis of autoimmune neutropenia 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.

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Primary and secondary autoimmune neutropenia

Autoimmune neutropenia is either primary or secondary. In primary autoimmune neutropenia, neutropenia is the only abnormality. Infections associated with the primary form are usually limited and mild.

In secondary autoimmune neutropenia, other primary pathologies occur, including systemic autoimmune disease, infections, and malignancy. Autoimmune neutropenia that occurs in the older pediatric age group and adolescents must be regarded as a totally distinct entity separate from chronic benign neutropenia. The clinical course of the secondary autoimmune neutropenia is not benign. In infants, secondary autoimmune neutropenia is extremely rare.

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, Sjögren syndrome, and/or a lupuslike illness predominate. Therefore, in this age group, a rigorous search for evidence of other autoimmune phenomena should be made.

Lalezari and colleagues demonstrated neutrophil antibodies in 119 of 121 infants and children with chronic neutropenia, thereby establishing the autoimmune nature of the disease.^[1] In the study, all patients had at one time an absolute neutrophil count of less than 500/µL.

Primary autoimmune neutropenia is similar to immune thrombocytopenic purpura (ITP) of young children, 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. A similar age group is affected, and recovery is expected in both. Some studies have shown 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 gamma RIIIb (or CD 16b) and human neutrophil antigen 1 (HNA1), 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 these, most common antibodies are directed against HNA-1, which consists of NA-1, NA-2, and SH. They are not anti–human leukocyte antigen (HLA) antibodies. Demonstration of anti-HLA antibodies as the cause of chronic benign neutropenia is very rare.

Bruin et al demonstrated that in patients with primary autoimmune neutropenia, antibodies were exclusively directed against the NA alloantigens, whereas in patients with secondary autoimmune neutropenia, antibodies had pan-FC gamma RIIIb specificity.^[2]

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 the 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.^[3] This may indicate that the bone marrow in these patients have enough maturation pool cells to dampen a trigger to increase G-CSF output.

In this study, 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.

The incidence of autoimmune neutropenia does not vary among different ethnic populations.

A Scottish study estimated that in the Scottish population, the incidence of autoimmune neutropenia is 1 in 100,000 children per year.^[4] This may have been an underestimate, however, because laboratory tests are not usually performed in most cases of autoimmune neutropenia.

Autoimmune neutropenia has a slight preponderance in girls in one study,^[1] but not in others.^[5] The mean age at diagnosis of autoimmune neutropenia is 8-12 months, with a range of 3-30 months.

A high frequency of benign neutropenia is widely recognized in African Americans, Yemenite and Falasha Jews, Black Beduin, blacks of South African extraction, West Indians, Arab Jordanians, and various tribal groups inhabiting the United Arab Emirates.^[6]

Morbidity

Infections associated with primary autoimmune neutropenia, which, as previously mentioned, are usually limited and mild, include just fever, otitis media, upper respiratory tract infection, pneumonia, skin infection, stomatitis, and gingivitis. 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 who are receiving chemotherapy.

The reasons for this difference between primary autoimmune and severe congenital neutropenia may be related to the fact that individuals with autoimmune neutropenia have an adequate bone marrow neutrophil reserve and can therefore 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.

Although febrile illnesses appear to be more common in children with autoimmune neutropenia than they are in healthy children, autoimmune neutropenia usually does not affect the child's growth and development, although some exceptions occur. (See History.)

The prognosis for autoimmune neutropenia of infancy is excellent. The condition usually lasts only 2-3 years before spontaneous resolution, and virtually all patients recover by age 5 years.

Thoroughly discussing the natural history of autoimmune neutropenia with the patient’s parents and/or caregivers is important, since this can prevent undue anxiety created by low neutrophil counts.

In addition, because medical advice is usually sought after infections have occurred in a child with autoimmune neutropenia, discussing the condition’s natural history validates the experience of the parents and/or caregivers and, in turn, increases their confidence in the physician's diagnosis and treatment.

It is important for patients to maintain good dental hygiene in order to prevent gingivitis, stomatitis, and other mucous membrane infections of the mouth.