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Pediatric Autoimmune and Chronic Benign Neutropenia Differential Diagnoses

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

Diagnostic Considerations

Acute transient leukopenia and neutropenia in small infants and young children are extremely common. Regardless of diagnosis, one needs to establish if the neutropenia is transient or chronic. Before suspecting chronic neutropenia, serial blood cell counts are needed. Most transient neutropenia associated with an infection in this age group resolves within 1-2 weeks. In a study of 143 neutropenic hospitalized patients in Greece, median duration of neutropenia was only 3.3 days (range 1-22 d).Two of these children were eventually diagnosed with autoimmune neutropenia.[16]  In a series reported by Lindqvist et al, the mean duration of an absolute neutrophil count of less than 500/μL was longer, 0.5 months with an infectious episode[15]

Differentiating AIN from ethnic neutropenia may be difficult. Inquiring about the ethnicity of the patient and parents is important. As previously mentioned, 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.[10] Ethnic neutropenia does not cause frequent infections. The gene that is responsible for ethnic neutropenia is identified to be DARC (Duffy antigen/chemokine receptor gene).[11, 12] Thus, children with the above ethnic backgrounds, if their red blood cells are Duffy negative, are likely to have ethnic neutropenia.

Autoimmune neutropenia of infancy usually lasts at most 2-3 years before spontaneous resolution. If it persists beyond age 4-5 years with a 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.[17] Thus, the absence of a family member with neutropenia does not exclude the diagnosis of ethnic neutropenia.

In iso (allo)-immune neutropenia of infancy, evaluate maternal serum for neutrophil antibodies, usually anti–HNA-1 or anti–HNA-2. A positive result is consistent with iso (allo)-immune neutropenia. Suspect iso (allo)-immune neutropenia or severe congenital neutropenia if profound neutropenia is present at or shortly after birth.

Antineutrophil antibodies may not be detectable in children with AIN. In their analysis of 240 children with AIN, Bux et al detected granulocyte-specific antibodies during the first investigations in only 74% of patients.[18] In 26% of patients, "Repeated antibody testing with additional samples up to 3 times was necessary for detection of antibodies." Audrain et al found that only 60% of the patients were positive for the anitbodies. Seventy-three percent of these cases were anti–HNA-1 antibodies.[19] They found that younger patients had a higher positivity rate than older children and children with HNA-1 antigen were overrepresented, suggesting this antigen may trigger antibody formation more frequently than other neutrophil antigens.

In a patient with an enlarged spleen, consider hypersplenism in the differential diagnosis. A significantly enlarged spleen suggests this diagnosis.

The following should alert physicians to a diagnosis other than autoimmune neutropenia:

  • Severe illness
  • Life-threatening infections
  • Significant hepatosplenomegaly
  • Neutrophil count fewer than 200 from day 1 of life
  • Purpura
  • Hemorrhagic findings

Aside from the diseases listed in the next subsection, disorders that can mimic the symptoms of autoimmune neutropenia include the following:

  • Iso (allo)-immune neutropenia in neonates
  • Cyclic neutropenia
  • Ethnic neutropenia/leukopenia
  • Hypersplenism
  • Neutropenia due to drugs
  • Neutropenia associated with systemic autoimmune disease
  • Severe congenital neutropenia, autosomal recessive and autosomal dominant
  • Transient leukopenia/neutropenia associated with viral infection
  • Neutropenia associated with congenital immunodeficiency

Go to Neutropenia for complete information on this topic.

Differential Diagnoses

  • **Severe congenital neutropenia, sporadic, autosomal recessive, and autosomal dominant:

  • *Barth syndrome

  • *Cartilage hair hypoplasia

  • *Chediak-Higashi syndrome

  • *Glycogen storage disease type 1b

  • *Griscelli syndrome

  • *Hermansky-Pudlak syndrome

  • *Hyperimmunoglobulin M syndrome

  • *Kostmann syndrome

  • *Schwachman-Diamond syndrome

  • *WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome

  • Cyclic neutropenia

  • Ethnic neutropenia/leukopenia

  • Hypersplenism

  • Iso (allo)-immune neutropenia in neonates

  • May-Hegglin Anomaly

  • Neutropenia associated with congenital immunodeficiency

  • Neutropenia associated with systemic autoimmune disease

  • Neutropenia due to drugs

  • Pediatric HIV Infection

  • Transient leukopenia/neutropenia associated with viral infection

 
 
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].

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  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].

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  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].

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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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