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Pediatric Autoimmune and Chronic Benign Neutropenia Workup

  • Author: Susumu Inoue, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
 
Updated: Oct 09, 2015
 

Approach Considerations

Neutropenia is usually discovered during the workup of a febrile illness. However, leukopenia and neutropenia are often discovered incidentally, as a result of a routine CBC or a CBC performed for an unrelated reason.

The clinical severity and frequency of infections, rather than the severity of neutropenia, should dictate the extent of laboratory workup, since finding a periodic drop in the neutrophil count to zero is not uncommon in chronic benign neutropenia.[1]  Lindqvist et al published an algorithm for the workup of children with neutropenia that may be practical and helpful.[15]

Go to Neutropenia for complete information on this topic.

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CBC

A CBC demonstrates a white blood cell (WBC) count that is either decreased or within the reference range and a neutrophil count of less than 1000/µL (absolute neutropenia).

Performing sequential CBCs with differential to document chronicity is important, because most neutropenia in infants resolves with recovery from an acute infection. In individuals with autoimmune neutropenia, the absolute neutrophil count often remains less than 500 (see the Absolute Neutrophil Count calculator).

Monocytosis and eosinophilia may occur, although significant eosinophilia is rare, unlike in severe congenital neutropenia. In individuals with primary autoimmune neutropenia, hemoglobin and platelet counts are normal. In patients with secondary autoimmune neutropenia, associated anemia, an increased reticulocyte count due to hemolysis, and thrombocytopenia may be present.

Antinuclear antibodies may be positive in patients with secondary autoimmune neutropenia, although only rarely in infants. Direct antiglobulin test (DAT) or direct Coombs test results may be positive in individuals with secondary autoimmune neutropenia; perform this study when evidence of hemolysis or thrombocytopenia (Evan syndrome) is present.

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Tests for Neutrophil Antibodies

Documentation of neutrophil antibodies is not always necessary for patients with a benign course of autoimmune neutropenia. In addition, an absence of demonstrable antineutrophil antibodies does not exclude the diagnosis. The age of onset (most commonly 3-15 mo), a benign clinical course, and normal bone marrow findings are sufficient to make a diagnosis of chronic benign neutropenia of childhood or primary autoimmune neutropenia. However, from the point of prognostication, documenting the presence of antibodies is reassuring.

In addition, research has indicated that, in some patients, antibodies detected at the onset are not detectable on retesting before the patient has recovered.[19] Thus, antibody test findings may not always be positive, depending on the timing. Also, sensitivity for antibody detection varies depending on the test. The indirect granulocyte immunofluorescence test (GIFT) is more sensitive than monoclonal antibody-specific immobilization of granulocyte antigens (MAIGA). It appears that panantibodies to FcγRIIIb are positive during the early period of neutropenia, but it disappears earlier than HNA1 antibodies.[20]

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Bone Marrow Examination

Bone marrow examination is often necessary to exclude other diagnoses, although bone marrow findings alone are not diagnostic.

The bone marrow may be hypercellular or normocellular with myeloid hyperplasia. However, it can be completely normal, including physiologic lymphoid hyperplasia.

In clinically severe instances of autoimmune neutropenia, "maturation arrest" may be observed, in that there is a paucity or absence of mature neutrophils. However, a preponderance of myelocytes, metamyelocytes, and bands may be present. In rare instances, intramedullary phagocytosis of granulocytes may be observed.[5]

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Serum Immunoglobulin Quantitation

Serum immunoglobulin quantitation helps to exclude neutropenia associated with hypogammaglobulinemia or hyper-IgM syndrome.

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Histologic Findings

In most instances, bone marrow findings are normal. Maturation arrest at promyelocyte or myelocyte stage typically seen in severe congenital neutropenia is absent.

Often, an increased number of mature lymphocytes consistent with the patient's age are present.

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Contributor Information and Disclosures
Author

Susumu Inoue, MD Professor of Pediatrics and Human Development, Michigan State University College of Human Medicine; Clinical Professor of Pediatrics, Wayne State University School of Medicine; Director of Pediatric Hematology/Oncology, Associate Director of Pediatric Education, Department of Pediatrics, Hurley Medical Center

Susumu Inoue, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Gary D Crouch, MD Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Uniformed Services University of the Health Sciences

Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA Executive Vice President, Chief Medical and Academic Officer, Renown Heath

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

Gary R Jones, MD Associate Medical Director, Clinical Development, Berlex Laboratories

Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research

Disclosure: Nothing to disclose.

References
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  2. Lalezari P, Khorshidi M, Petrosova M. Autoimmune neutropenia of infancy. J Pediatr. 1986 Nov. 109(5):764-9. [Medline].

  3. Nakamura K, Miki M, Mizoguchi Y, Karakawa S, Sato T, Kobayashi M. Deficiency of regulatory T cells in children with autoimmune neutropenia. Br J Haematol. 2009 Jun. 145(5):642-7. [Medline].

  4. Bruin MC, von dem Borne AE, Tamminga RY, Kleijer M, Buddelmeijer L, de Haas M. Neutrophil antibody specificity in different types of childhood autoimmune neutropenia. Blood. 1999 Sep 1. 94(5):1797-802. [Medline].

  5. Urban C, Lackner H, Sovinz P, Beham-Schmid C. Intramedullary aggregation and phagocytosis of neutrophils in chronic benign neutropenia of childhood. Br J Haematol. 2008 Aug. 142(4):504. [Medline].

  6. Perdikogianni Ch, Dimitriou H, Stiakaki E, Markaki EA, Kalmanti M. Adhesion molecules, endogenous granulocyte colony-stimulating factor levels and replating capacity of progenitors in autoimmune neutropenia of childhood. Acta Paediatr. 2003 Nov. 92(11):1277-83. [Medline].

  7. Kobayashi M, Ueda K, Kojima S, Nishihira H, Ishiguro A, Shimbo T. Serum granulocyte colony-stimulating factor levels in patients with chronic neutropenia of childhood: modulation of G-CSF levels by myeloid precursor cell mass. Br J Haematol. 1999 May. 105(2):486-90. [Medline].

  8. Lyall EG, Lucas GF, Eden OB. Autoimmune neutropenia of infancy. J Clin Pathol. 1992 May. 45(5):431-4. [Medline]. [Full Text].

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  10. Denic S, Showqi S, Klein C, Takala M, Nagelkerke N, Agarwal MM. Prevalence, phenotype and inheritance of benign neutropenia in Arabs. BMC Blood Disord. 2009 Mar 27. 9:3. [Medline]. [Full Text].

  11. Grann VR, Ziv E, Joseph CK, Neugut AI, Wei Y, Jacobson JS. Duffy (Fy), DARC, and neutropenia among women from the United States, Europe and the Caribbean. Br J Haematol. 2008 Oct. 143(2):288-93. [Medline].

  12. Sella R, Flomenblit L, Goldstein I, Kaplinsky C. Detection of anti-neutrophil antibodies in autoimmune neutropenia of infancy: a multicenter study. Isr Med Assoc J. 2010 Feb. 12(2):91-6. [Medline].

  13. Shete M, Thompson JW, Naidu SI, Stocks RM, Wang WC. Olaryngologic manifestations in children with chronic neutropenia. Int J Pediatr Otorhinolaryngol. 2012 Mar. 76(3):392-5. [Medline].

  14. Fioredda F, Calvillo M, Burlando O, et al. Infectious complications in children with severe congenital, autoimmune or idiopathic neutropenia: a retrospective study from the Italian Neutropenia Registry. Pediatr Infect Dis J. 2013 Apr. 32 (4):410-2. [Medline].

  15. Lindqvist H, Carlsson G, Moell J, Winiarski J, Sundin M. Neutropenia in childhood: a 5-year experience at a tertiary center. Eur J Pediatr. 2015 Jun. 174 (6):801-7. [Medline].

  16. Vlacha V, Feketea G. The clinical significance of non-malignant neutropenia in hospitalized children. Ann Hematol. 2007 Dec. 86(12):865-70. [Medline].

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  20. Bruin M, Dassen A, Pajkrt D, Buddelmeyer L, Kuijpers T, de Haas M. Primary autoimmune neutropenia in children: a study of neutrophil antibodies and clinical course. Vox Sang. 2005 Jan. 88(1):52-9. [Medline].

 
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A case of secondary autoimmune neutropenia. 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.
 
 
 
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