AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

AIN is either primary or secondary. In primary AIN, neutropenia is the only abnormality. In secondary AIN, other primary pathologies occur, including systemic autoimmune disease, infections, and malignancy. In infants, secondary AIN is extremely rare. The most common type of chronic neutropenia in children is chronic benign neutropenia of childhood.

Infections associated with primary AIN are usually limited and mild. Infections include skin problems, stomatitis, gingivitis, upper respiratory tract infections, and otitis media. 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 agranulocytosis (Kostmann disease), children with aplastic anemia, or children with neutropenia receiving chemotherapy. The reasons may be related to the fact that individuals with AIN 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 AIN, and autoimmune hemolytic anemia or immune thrombocytopenia often occur later or at the same time. Antiphospholipid antibody syndrome is common, and, ultimately, systemic lupus or a lupuslike illness predominates. Therefore, in this age group, a rigorous search for evidence of other autoimmune phenomenon should be made.

Pathophysiology

AIN 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 AIN 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 the neutrophil specific antigens antineutralizing antibody (NA)₁ and anti-NA₂ (most commonly against NA₁ but also against other neutrophil antibodies.) 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 alpha (TNF-a), and interleukin (IL)-1 beta 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 AIN.

Mortality/Morbidity

Infections associated with primary AIN usually are limited and mild.

Race

The incidence does not vary among different ethnic populations.

Sex

AIN 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.
• 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.
• Although febrile illnesses appear to be more common in children with AIN than in healthy children, AIN usually does not affect the child's growth and development, although some exceptions occur.
• Suspect iso (allo)-immune neutropenia if neutropenia is present at or shortly after birth.

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 AIN:
• • 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 ITP.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Iso (allo)-immune neutropenia in neonates
Cyclic neutropenia
Ethnic neutropenia/leukopenia
Hypersplenism
Neutropenia due to drugs
Neutropenia associated with systemic autoimmune disease
Transient neutropenia associated with viral infection

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC count
• • A CBC count demonstrates a WBC count that is either decreased or within the reference range and a neutrophil count less than 1000/µ L (absolute neutropenia).
  • Performing sequential CBC counts with differential to document chronicity is important because most neutropenia in infants resolves with recovery from an acute infection. In individuals with AIN, the absolute neutrophil count (ANC) often remains less than 500.
  • Monocytosis and eosinophilia may occur, although significant eosinophilia is rare, unlike in severe congenital neutropenia. In individuals with primary autoimmune neutropenia (AIN), hemoglobin and platelet counts are normal. In patients with secondary AIN, associated anemia, an increased reticulocyte count due to hemolysis, and thrombocytopenia may be present.
  • Antinuclear antibodies (ANA) may be positive in patients with secondary AIN, although only rarely in infants. Direct antiglobulin test (DAT; direct Coombs test) findings may be positive in individuals with secondary AIN; perform this study when evidence of hemolysis or thrombocytopenia (Evan syndrome) is present.
• Tests for neutrophil antibodies
• • Documentation of neutrophil antibodies is not always necessary for patients with a benign course of AIN. Age of onset, benign clinical course, and bone marrow findings are sufficient to make a diagnosis of chronic benign neutropenia of childhood or primary AIN. However, from the point of prognostication, documenting the presence of antibodies is reassuring.
  • Clinical severity and frequency of infections, rather than severity of neutropenia, should dictate the extent of laboratory workup, since finding a periodic drop in the neutrophil count to zero is not uncommon.
  • Results may not be positive. Lalezali and colleagues demonstrated antibodies in 119 of 121 infants and children with chronic neutropenia, whereas Jonsson and Buchanan demonstrated a positive result in only 13 of 28 patients studied.^{2, 3} Bruin et al demonstrated that in patients with primary AIN, antibodies were exclusively directed against the NA alloantigens, whereas in patients with secondary AIN, antibodies had pan-FC gamma RIIIb specificity.⁶ These authors also noted that, in some patients, antibodies detected at the onset were not detectable on retesting before the patients recovered. This implies that antibody test findings may not be always positive, depending on the timing. Also, sensitivity for antibody detection varies depending on the test. Indirect granulocyte immunofluorescence test (GIFT) is more sensitive than monoclonal antibody-specific immobilization of granulocyte antigens (MAIGA).
  • In iso (allo)-immune neutropenia of infancy, evaluate maternal serum for neutrophil antibodies, usually anti-NA₁ or anti-NA₂. A positive result is consistent with iso (allo)-immune neutropenia. In their analysis of 240 children with AIN, Bux et al detected granulocyte-specific antibodies during the first investigations in only 74% of patients.⁷ In 26% of patients, "Repeated antibody testing with additional samples up to 3 times was necessary for detection of antibodies."
• Bone marrow examination
• • Bone marrow examination is often necessary to exclude other diagnoses.
  • Bone marrow may be hypercellular or normocellular with myeloid hyperplasia.
  • Bone marrow can be totally normal, including physiologic lymphoid hyperplasia.
  • In clinically severe instances of AIN, "maturation arrest" may be observed because a paucity of mature neutrophils is present, but bands and metamyelocytes may be increased.
• Serum immunoglobulin quantitation: Serum immunoglobulin quantitation helps to exclude neutropenia associated with hypogammaglobulinemia.

Imaging Studies

• Generally, no imaging studies are indicated.

Histologic Findings

The bone marrow usually demonstrates normal-to-hypercellular marrow with scanty or absent mature neutrophils, sometimes with a preponderance of myelocytes, metamyelocytes, and bands. Megakaryocytes and normoblasts are normal. Often, an increased number of mature lymphocytes consistent with the patient's age are present. Bone marrow findings alone are not diagnostic.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Focus treatment on intercurrent infections. In patients with frequent infections, prophylactic antibiotics with trimethoprim and sulfamethoxazole may help.

• Good dental hygiene is important to prevent gingivitis, stomatitis, and other mucous membrane infections of the mouth.
• G-CSF has been demonstrated to raise the neutrophil count and may be useful for treatment of persistent infections. Intravenous gammaglobulin may be used for the same purpose. Reserve these medications for infections that do not respond to conventional antibiotics.

Surgical Care

An invasive procedure, such as splenectomy, is not warranted because virtually all patients spontaneously recover from chronic neutropenia.

Consultations

Hematologic consultation is recommended to exclude other possibilities and to obtain assistance in the interpretation of neutrophil antibody studies. Once the diagnosis is firmly established, primary care physicians can monitor patients.

Diet

No specific diet is recommended.

Activity

No restrictions in daily activities are required.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Colony-stimulating factors

These agents are used for recurrent or refractory infections unresponsive to conventional therapy. They act as a hematopoietic growth factor that stimulates the development of granulocytes. They are used to treat or prevent neutropenia when receiving myelosuppressive cancer chemotherapy and to reduce the period of neutropenia associated with bone marrow transplantation. These agents are also used to mobilize autologous peripheral blood progenitor cells for bone marrow transplantation and in the management of chronic neutropenia.

Drug Category: Immunoglobulins

These agents are used for infections unresponsive to conventional measures. Immunoglobulins are used for passive immunization, thus conferring immediate protection against some infectious diseases.

Drug Category: Antibiotics

These agents are used for prevention of frequent infections.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Direct treatment to intercurrent infections.
• If patient is free from significant infection, treatment is unnecessary other than consideration of prophylactic oral antibiotic administration based on low neutrophil count alone.

Deterrence/Prevention

Prevent frequent infections because autoimmune neutropenia (AIN) cannot be prevented.

Prognosis

Prognosis is excellent; virtually all patients recover by age 5 years.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Thoroughly discussing the natural history is important to prevent undue anxiety created by low neutrophil counts.
• Because the child with autoimmune neutropenia (AIN) usually has infections before seeking medical advice, mentioning the natural history validates the parents' and/or caregivers' experience and, in turn, increases their confidence in the physician's diagnosis and treatment.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Zuelzer WW, Bajoghli M. Chronic granulocytopenia in childhood. Blood. 1964;23:359-374.
2. Lalezari P, Khorshidi M, Petrosova M. Autoimmune neutropenia of infancy. J Pediatr. Nov 1986;109(5):764-9. [Medline].
3. 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].
4. 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].
5. Lyall EG, Lucas GF, Eden OB. Autoimmune neutropenia of infancy. J Clin Pathol. May 1992;45(5):431-4. [Medline].
6. Bruin MC, von dem Borne AE, Tamminga RY, et al. Neutrophil antibody specificity in different types of childhood autoimmune neutropenia. Blood. Sep 1 1999;94(5):1797-802. [Medline].
7. Bux J, Behrens G, Jaeger G, Welte K. Diagnosis and clinical course of autoimmune neutropenia in infancy: analysis of 240 cases. Blood. Jan 1 1998;91(1):181-6. [Medline]. [Full Text].
8. 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].
9. 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].
10. 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].
11. 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].
12. Dinauer MC. The phagocyte system and disorders of granulopoiesis and granulocyte function. In: Nathan DG, Orki SH, eds. Hematology of Infancy and Childhood. 5^th ed. 1998:915-7.
13. 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].
14. 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].
15. 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].

Article Last Updated: Sep 26, 2007