Journal of Clinical Immunology

, Volume 37, Issue 7, pp 715–726 | Cite as

Neutropenia in Patients with Common Variable Immunodeficiency: a Rare Event Associated with Severe Outcome

  • Aurélien Guffroy
  • Rachel Mourot-Cottet
  • Laurence Gérard
  • Vincent Gies
  • Chantal Lagresle
  • Aurore Pouliet
  • Patrick Nitschké
  • Sylvain Hanein
  • Boris Bienvenu
  • Valérie Chanet
  • Jean Donadieu
  • Martine Gardembas
  • Marina Karmochkine
  • Raphaele Nove-Josserand
  • Thierry Martin
  • Vincent Poindron
  • Pauline Soulas-Sprauel
  • Fréderic Rieux-Laucat
  • Claire Fieschi
  • Eric Oksenhendler
  • Isabelle André-Schmutz
  • Anne-Sophie KorganowEmail author
  • the DEFI study group
Original Article



Common variable immunodeficiency (CVID) is characterized by infections and hypogammaglobulinemia. Neutropenia is rare during CVID.


The French DEFI study enrolled patients with primary hypogammaglobulinemia. Patients with CVID and neutropenia were retrospectively analyzed.


Among 473 patients with CVID, 16 patients displayed neutropenia (lowest count [0–1400]*106/L). Sex ratio (M/F) was 10/6. Five patients died during the follow-up (11 years) with an increased percentage of deaths compared to the whole DEFI group (31.3 vs 3.4%, P < 0.05). Neutropenia was diagnosed for 10 patients before 22 years old. The most frequent symptoms, except infections, were autoimmune cytopenia, i.e., thrombopenia or anemia (11/16). Ten patients were affected with lymphoproliferative diseases. Two patients were in the infection only group and the others belonged to one or several other CVID groups. The median level of IgG was 2.6 g/L [0.35–4.4]. Most patients presented increased numbers of CD21low CD38low B cell, as already described in CVID autoimmune cytopenia group. Neutropenia was considered autoimmune in 11 cases. NGS for 52 genes of interest was performed on 8 patients. No deleterious mutations were found in LRBA, CTLA4, and PIK3. More than one potentially damaging variant in other genes associated with CVID were present in most patients arguing for a multigene process.


Neutropenia is generally associated with another cytopenia and presumably of autoimmune origin during CVID. In the DEFI study, neutropenia is coupled with more severe clinical outcomes. It appears as an “alarm bell” considering patients’ presentation and the high rate of deaths. Whole exome sequencing diagnosis should improve management.


Neutropenia Autoimmune cytopenia Common variable immunodeficiency (CVID) Next genome sequencing 



Autoimmune cytopenia


Autoimmune hemolytic anemia


Autoimmune neutropenia


Common variable immuno-deficiency


Ears, nose, and throat


Granulocyte aggregation test


Granulocyte immunofluorescence test


Human neutrophil antigen


Idiopathic thrombocytopenic purpura


Late-onset combined immunodeficiency




Monoclonal antibody immobilization of granulocyte antigen


Overall survival


Authorsʼ Contribution

A.G., R.M-C., L.G., C.F, E.O., A.S.K designed the research.

A.G., R.M-C, L.G., B.B., V.C., J.D., M.G., M.K., R.N-J., T.M, V.P, P.S-S, C.F, E.O, and A.S.K performed the research.

A.G, R.M-C., V.G, C.L, A.P, F.R-L, I.A-S, and A.S.K. analyzed the data.

A.G., R.M-C., V.G., I.A-S, and A.S.K. wrote the paper.

All the authors read and approve the final manuscript.


APJC (appel à projet jeune chercheur) DICEP GIRCI Grand Est 2016.

RARENET co-financed by the ERDF of the EU in the framework of the INTERREG V Upper Rhine program.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

10875_2017_434_MOESM1_ESM.docx (195 kb)
ESM 1 (DOCX 194 kb)


  1. 1.
    Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, et al. International consensus document (ICON): common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4:38–59.CrossRefPubMedGoogle Scholar
  2. 2.
    Picard C, Al-Herz W, Bousfiha A, Casanova J-L, Chatila T, Conley ME, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for primary immunodeficiency 2015. J Clin Immunol. 2015;35:696–726.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Castigli E, Geha R. Molecular basis of common variable immunodeficiency. J Allergy Clin Immunol. 2006;117:740–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Kopecký O, Lukesová S. Genetic defects in common variable immunodeficiency. Int J Immunogenet. 2007;34:225–9.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Orange JS, Glessner JT, Resnick E, Sullivan KE, Lucas M, Ferry B, et al. Genome-wide association identifies diverse causes of common variable immunodeficiency. J Allergy Clin Immunol. 2011;127:1360–1367e6.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bogaert DJA, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet. 2016;53:575–90.CrossRefPubMedGoogle Scholar
  7. 7.
    Grimbacher B, Warnatz K, Yong PFK, Korganow A-S, Peter H-H. The crossroads of autoimmunity and immunodeficiency: lessons from polygenic traits and monogenic defects. J Allergy Clin Immunol. 2016;137:3–17.CrossRefPubMedGoogle Scholar
  8. 8.
    Boileau J, Mouillot G, Gérard L, Carmagnat M, Rabian C, Oksenhendler E, et al. Autoimmunity in common variable immunodeficiency: correlation with lymphocyte phenotype in the French DEFI study. J Autoimmun. 2011;36:25–32.CrossRefPubMedGoogle Scholar
  9. 9.
    Chapel H, Lucas M, Patel S, Lee M, Cunningham-Rundles C, Resnick E, et al. Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts. J Allergy Clin Immunol. 2012;130:1197–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48.CrossRefPubMedGoogle Scholar
  11. 11.
    Chapel H, Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. Br J Haematol. 2009;145:709–27.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119:1650–7.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wehr C, Gennery AR, Lindemans C, Schulz A, Hoenig M, Marks R, et al. Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency. J Allergy Clin Immunol. 2015;135:988–997.e6.CrossRefPubMedGoogle Scholar
  14. 14.
    Garrison EBG. Haplotype-based variant detection from short-read sequencing. Q-BioGN. 2012:1207–3907.Google Scholar
  15. 15.
    Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008;111:77–85.CrossRefPubMedGoogle Scholar
  16. 16.
    Rakhmanov M, Gutenberger S, Keller B, Schlesier M, Peter H-H, Warnatz K. CD21low B cells in common variable immunodeficiency do not show defects in receptor editing, but resemble tissue-like memory B cells. Blood. 2010;116:3682–3.CrossRefPubMedGoogle Scholar
  17. 17.
    for the DEFI Study Group, Mouillot G, Carmagnat M, Gérard L, Garnier J-L, Fieschi C, et al. B-cell and T-cell phenotypes in CVID patients correlate with the clinical phenotype of the disease. J Clin Immunol. 2010;30:746–55.CrossRefGoogle Scholar
  18. 18.
    Bertinchamp R, Gérard L, Boutboul D, Malphettes M, Fieschi C, Oksenhendler E, et al. Exclusion of patients with a severe T-cell defect improves the definition of common variable immunodeficiency. J Allergy Clin Immunol Pract. 2016;4:1147–57.CrossRefPubMedGoogle Scholar
  19. 19.
    Malphettes M, Gérard L, Carmagnat M, Mouillot G, Vince N, Boutboul D, et al. Late-onset combined immune deficiency: a subset of common variable immunodeficiency with severe T cell defect. Clin Infect Dis. 2009;49:1329–38.CrossRefPubMedGoogle Scholar
  20. 20.
    Oksenhendler E, Gérard L, Fieschi C, Malphettes M, Mouillot G, Jaussaud R, et al. Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis. 2008;46:1547–54.CrossRefPubMedGoogle Scholar
  21. 21.
    Romberg N, Virdee M, Chamberlain N, Oe T, Schickel J-N, Perkins T, et al. TNF receptor superfamily member 13b (TNFRSF13B) hemizygosity reveals transmembrane activator and CAML interactor haploinsufficiency at later stages of B-cell development. J Allergy Clin Immunol. 2015;136:1315–25.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Castigli E, Wilson S, Garibyan L, Rachid R, Bonilla F, Schneider L, et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet. 2007;39:430–1.CrossRefPubMedGoogle Scholar
  23. 23.
    Kutukculer N, Gulez N, Karaca NE, Aksu G, Berdeli A. Three different classifications, B lymphocyte subpopulations, TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF13 (APRIL) gene mutations, CTLA-4 and ICOS gene polymorphisms in Turkish patients with common variable immunodeficiency. J Clin Immunol. 2012;32:1165–79.CrossRefPubMedGoogle Scholar
  24. 24.
    Aricò M, Boggio E, Cetica V, Melensi M, Orilieri E, Clemente N, et al. Variations of the UNC13D Gene in Patients with Autoimmune Lymphoproliferative Syndrome. Wallace GR, editor. PLoS ONE. 2013;8:e68045.Google Scholar
  25. 25.
    Morbach H, Schickel J-N, Cunningham-Rundles C, Conley ME, Reisli I, Franco JL, et al. CD19 controls toll-like receptor 9 responses in human B cells. J Allergy Clin Immunol. 2016;137:889–898.e6.CrossRefPubMedGoogle Scholar
  26. 26.
    Lopes-da-Silva S, Rizzo LV. Autoimmunity in common variable immunodeficiency. J Clin Immunol. 2008;28:46–55.CrossRefGoogle Scholar
  27. 27.
    Quinti I, Soresina A, Spadaro G, Martino S, Donnanno S, Agostini C, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol. 2007;27:308–16.CrossRefPubMedGoogle Scholar
  28. 28.
    Kuijpers TW, de Haas M, de Groot CJ, von dem Borne AE, Weening RS. The use of rhG-CSF in chronic autoimmune neutropenia: reversal of autoimmune phenomena, a case history. Br J Haematol. 1996;94:464–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Lemos S, Jacob CMA, Pastorino AC, Castro APBM, Fomin ABF, Carneiro-Sampaio MMS. Neutropenia in antibody-deficient patients under IVIG replacement therapy. Pediatr. Allergy Immunol. Off. Publ. Eur. Soc. Pediatr. Allerg Immunol. 2009;20:97–101.CrossRefGoogle Scholar
  30. 30.
    Warnatz K, Bossaller L, Salzer U, Skrabl-Baumgartner A, Schwinger W, Burg MV d, et al. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood. 2006;107:3045–52.CrossRefPubMedGoogle Scholar
  31. 31.
    Hart M, Page E, Ford T, Greathead L, Wilson R, Loebinger M, et al. Increases in CD21low B cells are significantly associated with levels of circulating TNF family chemokines BAFF and APRIL in CVID patients. Immunology. 2010;131:96.Google Scholar
  32. 32.
    Wehr C, Eibel H, Masilamani M, Illges H, Schlesier M, Peter H-H, et al. A new CD21low B cell population in the peripheral blood of patients with SLE. Clin Immunol. 2004;113:161–71.CrossRefPubMedGoogle Scholar
  33. 33.
    Isnardi I, Ng Y-S, Menard L, Meyers G, Saadoun D, Srdanovic I, et al. Complement receptor 2/CD21- human naive B cells contain mostly autoreactive unresponsive clones. Blood. 2010;115:5026–36.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Warnatz K, Wehr C, Dräger R, Schmidt S, Eibel H, Schlesier M, et al. Expansion of CD19hiCD21lo/neg B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia. Immunobiology. 2002;206:502–13.CrossRefPubMedGoogle Scholar
  35. 35.
    Unger S, Seidl M, van Schouwenburg P, Rakhmanov M, Bulashevska A, Frede N, et al. The TH1 phenotype of follicular helper T cells indicates an IFN-γ-associated immune dysregulation in patients with CD21low common variable immunodeficiency. J Allergy Clin Immunol 2017.Google Scholar
  36. 36.
    Maffucci P, Filion CA, Boisson B, Itan Y, Shang L, Casanova J-L, et al. Genetic diagnosis using whole exome sequencing in common variable immunodeficiency. Front Immunol. 2016;7:220.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Berkovitch M, Dolinski G, Tauber T, Aladjem M, Kaplinsky C. Neutropenia as a complication of intravenous immunoglobulin (IVIG) therapy in children with immune thrombocytopenic purpura: common and non-alarming. Int J Immunopharmacol. 1999;21:411–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Niebanck AE, Kwiatkowski JL, Raffini LJ. Neutropenia following IVIG therapy in pediatric patients with immune-mediated thrombocytopenia. J Pediatr Hematol Oncol. 2005;27:145–7.CrossRefPubMedGoogle Scholar
  39. 39.
    Dungarwalla M, Marsh JCW, Tooze JA, Lucas G, Ouwehand W, Pettengell R, et al. Lack of clinical efficacy of rituximab in the treatment of autoimmune neutropenia and pure red cell aplasia: implications for their pathophysiology. Ann Hematol. 2007;86:191–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Weng W-K, Negrin RS, Lavori P, Horning SJ. Immunoglobulin G fc receptor FcγRIIIa 158 V/F polymorphism correlates with rituximab-induced neutropenia after autologous transplantation in patients with non-Hodgkin’s lymphoma. J Clin Oncol. 2010;28:279–84.CrossRefPubMedGoogle Scholar
  41. 41.
    Bride KL, Vincent T, Smith-Whitley K, Lambert MP, Bleesing JJ, Seif AE, et al. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2016;127:17–28.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Zheng P, Chang X, Lu Q, Liu Y. Cytopenia and autoimmune diseases: a vicious cycle fueled by mTOR dysregulation in hematopoietic stem cells. J Autoimmun. 2013;41:182–7.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Notarangelo LD, Kim M-S, Walter JE, Lee YN. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol. 2016;16:234–46.CrossRefPubMedGoogle Scholar
  44. 44.
    Martinez-Gallo M, Radigan L, Almejún MB, Martínez-Pomar N, Matamoros N, Cunningham-Rundles C. TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. J Allergy Clin Immunol. 2013;131:468–76.CrossRefPubMedGoogle Scholar
  45. 45.
    von Bülow GU, van Deursen JM, Bram RJ. Regulation of the T-independent humoral response by TACI. Immunity. 2001;14:573–82.CrossRefGoogle Scholar
  46. 46.
    Seshasayee D, Valdez P, Yan M, Dixit VM, Tumas D, Grewal IS. Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as an inhibitory BLyS receptor. Immunity. 2003;18:279–88.CrossRefPubMedGoogle Scholar
  47. 47.
    Salzer U, Chapel HM, Webster ADB, Pan-Hammarström Q, Schmitt-Graeff A, Schlesier M, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005;37:820–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Aurélien Guffroy
    • 1
    • 2
  • Rachel Mourot-Cottet
    • 3
  • Laurence Gérard
    • 4
    • 5
  • Vincent Gies
    • 1
    • 2
  • Chantal Lagresle
    • 6
  • Aurore Pouliet
    • 7
  • Patrick Nitschké
    • 8
  • Sylvain Hanein
    • 9
  • Boris Bienvenu
    • 10
  • Valérie Chanet
    • 11
  • Jean Donadieu
    • 12
  • Martine Gardembas
    • 13
  • Marina Karmochkine
    • 14
  • Raphaele Nove-Josserand
    • 15
  • Thierry Martin
    • 1
    • 2
  • Vincent Poindron
    • 1
  • Pauline Soulas-Sprauel
    • 1
    • 2
  • Fréderic Rieux-Laucat
    • 16
  • Claire Fieschi
    • 4
    • 5
  • Eric Oksenhendler
    • 4
    • 5
  • Isabelle André-Schmutz
    • 6
  • Anne-Sophie Korganow
    • 1
    • 2
    Email author
  • the DEFI study group
  1. 1.Department of Clinical Immunology and Internal MedicineStrasbourg University Hospital, National Reference Center for Autoimmune DiseasesStrasbourgFrance
  2. 2.CNRS UPR 3572 Immunopathology and Therapeutic Chemistry/Laboratory of Excellence MedalisInstitute of Molecular and Cellular Biology (IBMC)StrasbourgFrance
  3. 3.Department of Internal Medicine BStrasbourg University HospitalStrasbourgFrance
  4. 4.Department of Clinical Immunology, Saint-Louis HospitalAssistance Publique Hôpitaux de Paris (APHP)ParisFrance
  5. 5.EA3518Université Paris Diderot Paris 7ParisFrance
  6. 6.INSERM UMR 1163 Human Lympho Hematopopoiesis LaboratoryParis Descartes Sorbonne Paris Cite University, Imagine InstituteParisFrance
  7. 7.INSERM UMR 1163 Bioinformatic PlatformParis Descartes Sorbonne Paris Cite University, Imagine InstituteParisFrance
  8. 8.INSERM UMR 1163 Genomic PlatformParis Descartes Sorbonne Paris Cite University, Imagine InstituteParisFrance
  9. 9.INSERM UMR 1163 Translational Genetic PlatformParis Descartes Sorbonne Paris Cite University, Imagine InstituteParisFrance
  10. 10.Department of Internal MedicineCaen University HospitalCaenFrance
  11. 11.Department of Internal MedicineCabinet de Médecine Interne et Maladies Infectieuses, Pôle Santé RépubliqueClermont-FerrandFrance
  12. 12.Department of Pediatric Hematology and Oncology, Hôpital d’enfants Armand-TrousseauParis University HospitalParisFrance
  13. 13.Department of HematologyAngers University HospitalAngersFrance
  14. 14.Department of Clinical Immunology, European Hospital Georges PompidouParis University HospitalParisFrance
  15. 15.Department of Internal MedicineLyon University HospitalPierre-BéniteFrance
  16. 16.INSERM UMR 1163 Immunogenetics of pediatric autoimmune diseases laboratoryParis Descartes Sorbonne Paris Cite University, Imagine InstituteParisFrance

Personalised recommendations