Autoimmune cytopenias in children: When to think of primary immunodeficiency?


Mohamed Hbibi
Mounira El Alaoui El Hanafi
Zakaria Kasmi
Hind Ouair
Sarra Benmiloud
Fatima Ailal
Moustapha Hida
Ahmed Aziz Bousfiha


Autoimmune cytopenias are defined by autoantibodies' immune destruction of one or more blood elements. Most often it is autoimmune hemolytic anemia or immune thrombocytopenia or both that define Evans syndrome. It may be secondary to infection or to underlying pathology such as systemic autoimmune disease or primary immunodeficiency, especially when it becomes chronic over several years.

Primary Immunodeficiencies or inborn errors of immunity (IEI) are no longer defined solely by infections: autoimmunity is part of the clinical features of several of these diseases. It is dominated by autoimmune cytopenias, in particular, immune thrombocytopenia (ITP) and autoimmune hemolytic anaemia (AIHA).

The challenges for the clinician are the situations where autoimmune cytopenias are chronic, recurrent and/or refractory to the various long-term therapeutic options. Most of these therapies are similar in action and generally consist of non-mediated immune suppression or modulation. In these situations, primary Immunodeficiencies must be diagnosed as soon as possible to allow the initiation of a targeted treatment and to avoid several ineffective therapeutic lines.


IEI , Autoimmunity, Thrombocytopenia, Purpura, Leukopenia, Human, Evans Syndrome



  1. - Taylor O K, Jenny M D. Primary and Secondary Immune Cytopenias: Evaluation and Treatment Approach in Children. Hematol Oncol Clin North Am 2019 Jun;33:489-506.
  2. - Suarez F, Ghez D, Delarue R, Hermine O. Cytopénies auto-immunes périphériques.Réanimation 2005;14:587-93.
  3. - Notarangelo LD. Primary immunodeficiencies (PIDs) presenting with cytopenias.Hematol Am Soc Hematol Educ Progr 2009;1:139–43.
  4. - Teachey DT, Lambert MP. Diagnosis and management of autoimmune cytopenias in childhood. Pediatr Clin North Am 2013;60:1489–511
  5. - Al Ghaithi I, Wright NA, Breakey VR, Cox K, Warias A, Wong T, et al... Combined Autoimmune Cytopenias Presenting in Childhood. Pediatr Blood Cancer 2016; 63:292–8.
  6. - Singh G, Bansal D, Wright NAM. Immune thrombocytopenia in children: consensus and controversies. Indian J Pediatr 2020;87:150–7.
  7. - Despotovic JM, Grimes AB.Pediatric ITP: is it different from adult ITP? Hematology Am Soc Hematol Educ Program 2018; 2018:405–411.
  8. -Sfaihi L, Kassar O, Medhaffar O, Kamoun T, Hadiji S, Aloulou H et al. Primary immune thrombocytopenia in childhood: a regional study in the south of Tunisia. Tunis Med. 2014 Mar;92(3):219-23.
  9. - Singh A, Uzun G, Bakchoul T. Primary immune thrombocytopenia: novel insights into pathophysiology and disease management. J Clin Med 2021;10:789.
  10. - Audia S, Lorcerie B, Godeau B, Bonnotte B. Physiopathologie du purpura thrombopénique immunologique. La Revue de médecine interne 32 (2011) 350–357
  11. - Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011;117:4190–4207.
  12. - S. Mazigh M S, Ouederni M, Bouyahia O, Gharsallah L, Boukthir S, Samoud G A. Thrombocytopenic idiopathic purpura: predictive factors for chronic disease. Tunis Med . 2009 Jan;87(1):72-5.
  13. - Kühne T. Diagnosis and management of immune thrombocytopenia in childhood. Hamostaseologie 2017;37:36–44
  14. - Weli M, Ben Hlima A, Belhadj R, Maalej B, Elleuch A, Mekki N et al (2020) Diagnosis and management of autoimmune hemolytic anemia in children. Transfus Clin Biol;27:61–64
  15. - Bass GF, Tuscano ET, Tuscano JM. Diagnosis and classification of autoimmune hemolytic anemia. Autoimmun Rev 2014;13:560–564
  16. - Voulgaridou, A.; Kalfa, T.A.Autoimmune Hemolytic Anemia in the Pediatric Setting.J. Clin. Med 2021;10:216.
  17. - Kalfa TA. Warm antibody autoimmune hemolytic anemia. Hematology Am Soc Hematol Educ Program 2016; 2016:690–697
  18. - Donadieu J, Fenneteau O. Constitutional and acquired neutropenia. EMC-Hématologie 2 (2005) 158–186
  19. - Bousfiha A, Moundir A, Tangye SG, Picard C, Jeddane L, Al-Herz W, et al. The 2022 update of IUIS phenotypical classification for human inborn errors of immunity. J Clin Immunol 2022;42:08–20.
  20. - Alain Fischer, Johan Provot, Jean-Philippe Jais, Alexandre Alcais, Nizar Mahlaoui, Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. CEREDIH. J Allergy Clin Immunol 2017 Nov;140:1388-1393.
  21. - Jolan E Walter, Irmel A Ayala, and Diana Milojevic. Autoimmunity as a continuum in primary immunodeficiency. Curr Opin Pediatr 2019 Dec;31:851-862
  22. - Shanmuganathan Chandrakasan , Sharat Chandra, Blachy J Davila Saldana, Troy R Torgerson, David Buchbinder. Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case-based review. Pediatr Blood Cancer 2019 May;66
  23. - Gholamreza Azizi, Alireza Ghanavatinejad, Hassan Abolhassani, Reza Yazdani, Nima Rezaei, Abbas Mirshafiey et al. Autoimmunity in primary T-cell immunodeficiencies. Expert Rev Clin Immunol 2016 Sep;12:989-1006
  24. - Markus G. Seide. Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment. Blood 2014 Oct 9;124:2337-44
  25. - Jolan E Walter, Jocelyn R Farmer, Zsofia Foldvari, Troy R Torgerson, Megan A Cooper. Mechanism-Based Strategies for the Management of Autoimmunity and Immune Dysregulation in Primary Immunodeficiencies. J Allergy Clin Immunol Pract Nov-Dec 2016;4:1089-1100.
  26. - Frédéric Rieux-Laucat. Le syndrome lymphoprolifératif avec auto-immunité : Un défaut hérité ou acquis d’apoptose lymphocytaire. MEDECINE/SCIENCES 2006 ; 22 : 645-9
  27. - Daniel R. Matson, MD, PhD; David T. Yang, MD. Autoimmune Lymphoproliferative Syndrome: An Overview. Arch Pathol Lab Med—Vol 144, February 2020
  28. - Oliveira JB, Bleesing JJ, Dianzani U, et al... Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood 2010;116
  29. - Hadjadj J, Aladjidi N, Fernandes H, Leverger G, Magérus-Chatinet A, Mazerolles F, et al.. Pediatric Evans Syndrome Is Associated With a High Frequency of Potentially Damaging Variants in Immune Genes. Blood 2019;134:9–21.
  30. - Besnard C. Pediatric-onset Evans syndrome: heterogeneous presentation and high frequency of monogenic disorders including LRBA and CTLA4 mutations. Clin Immunol 2018;188:52–57.
  31. - Miano M, Guardo D, Grossi A, et al.. Underlying inborn errors of immunity in patients with Evans syndrome and multilineage cytopenias. a single centre analysis. Front Immunol 2022;13
  32. - Ibrahim Al Ghaithi, Nicola A M Wright, Vicky R Breakey , Kelly Cox, Ashley Warias , Tiffany Wong, et al. Combined Autoimmune Cytopenias Presenting in Childhood. Pediatr Blood Cancer 2016 Feb;63:292-8
  33. - Cortesi M, Soresina A, Dotta L, et al.. Pathogenesis of autoimmune cytopenias in inborn errors of immunity revealing novel therapeutic targets. Front Immunol 2022;13:1–10