Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Background

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

Methods

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

Results

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.

Conclusion

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AC:

Autoimmune cytopenia

AIHA:

Autoimmune hemolytic anemia

AIN:

Autoimmune neutropenia

CVID:

Common variable immuno-deficiency

ENT:

Ears, nose, and throat

GAT:

Granulocyte aggregation test

GIFT:

Granulocyte immunofluorescence test

HNA:

Human neutrophil antigen

ITP:

Idiopathic thrombocytopenic purpura

LOCID:

Late-onset combined immunodeficiency

LP:

Lymphoproliferation

MAIGA:

Monoclonal antibody immobilization of granulocyte antigen

OS:

Overall survival

References

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Castigli E, Geha R. Molecular basis of common variable immunodeficiency. J Allergy Clin Immunol. 2006;117:740–6.

    Article  CAS  PubMed  Google Scholar 

  4. Kopecký O, Lukesová S. Genetic defects in common variable immunodeficiency. Int J Immunogenet. 2007;34:225–9.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  10. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  14. Garrison EBG. Haplotype-based variant detection from short-read sequencing. Q-BioGN. 2012:1207–3907.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  26. Lopes-da-Silva S, Rizzo LV. Autoimmunity in common variable immunodeficiency. J Clin Immunol. 2008;28:46–55.

    Article  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Notarangelo LD, Kim M-S, Walter JE, Lee YN. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol. 2016;16:234–46.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  45. von Bülow GU, van Deursen JM, Bram RJ. Regulation of the T-independent humoral response by TACI. Immunity. 2001;14:573–82.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

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.

Author information

Authors and Affiliations

  1. Department of Clinical Immunology and Internal Medicine, Strasbourg University Hospital, National Reference Center for Autoimmune Diseases, Strasbourg, France

    Aurélien Guffroy, Vincent Gies, Thierry Martin, Vincent Poindron, Pauline Soulas-Sprauel & Anne-Sophie Korganow

  2. CNRS UPR 3572 Immunopathology and Therapeutic Chemistry/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France

    Aurélien Guffroy, Vincent Gies, Thierry Martin, Pauline Soulas-Sprauel & Anne-Sophie Korganow

  3. Department of Internal Medicine B, Strasbourg University Hospital, Strasbourg, France

    Rachel Mourot-Cottet

  4. Department of Clinical Immunology, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris (APHP), Paris, France

    Laurence Gérard, Claire Fieschi & Eric Oksenhendler

  5. EA3518, Université Paris Diderot Paris 7, Paris, France

    Laurence Gérard, Claire Fieschi & Eric Oksenhendler

  6. INSERM UMR 1163 Human Lympho Hematopopoiesis Laboratory, Paris Descartes Sorbonne Paris Cite University, Imagine Institute, Paris, France

    Chantal Lagresle & Isabelle André-Schmutz

  7. INSERM UMR 1163 Bioinformatic Platform, Paris Descartes Sorbonne Paris Cite University, Imagine Institute, Paris, France

    Aurore Pouliet

  8. INSERM UMR 1163 Genomic Platform, Paris Descartes Sorbonne Paris Cite University, Imagine Institute, Paris, France

    Patrick Nitschké

  9. INSERM UMR 1163 Translational Genetic Platform, Paris Descartes Sorbonne Paris Cite University, Imagine Institute, Paris, France

    Sylvain Hanein

  10. Department of Internal Medicine, Caen University Hospital, Caen, France

    Boris Bienvenu

  11. Department of Internal Medicine, Cabinet de Médecine Interne et Maladies Infectieuses, Pôle Santé République, Clermont-Ferrand, France

    Valérie Chanet

  12. Department of Pediatric Hematology and Oncology, Hôpital d’enfants Armand-Trousseau, Paris University Hospital, Paris, France

    Jean Donadieu

  13. Department of Hematology, Angers University Hospital, Angers, France

    Martine Gardembas

  14. Department of Clinical Immunology, European Hospital Georges Pompidou, Paris University Hospital, Paris, France

    Marina Karmochkine

  15. Department of Internal Medicine, Lyon University Hospital, Pierre-Bénite, France

    Raphaele Nove-Josserand

  16. INSERM UMR 1163 Immunogenetics of pediatric autoimmune diseases laboratory, Paris Descartes Sorbonne Paris Cite University, Imagine Institute, Paris, France

    Fréderic Rieux-Laucat

Authors
  1. Aurélien Guffroy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rachel Mourot-Cottet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laurence Gérard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vincent Gies
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chantal Lagresle
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aurore Pouliet
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Patrick Nitschké
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sylvain Hanein
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Boris Bienvenu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Valérie Chanet
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jean Donadieu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Martine Gardembas
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Marina Karmochkine
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Raphaele Nove-Josserand
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Thierry Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Vincent Poindron
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Pauline Soulas-Sprauel
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Fréderic Rieux-Laucat
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Claire Fieschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Eric Oksenhendler
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Isabelle André-Schmutz
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Anne-Sophie Korganow
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

the DEFI study group

Contributions

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.

Corresponding author

Correspondence to Anne-Sophie Korganow.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Additional information

Aurélien Guffroy and Rachel Mourot-Cottet contribute equally to the work.

Electronic supplementary material

ESM 1

(DOCX 194 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guffroy, A., Mourot-Cottet, R., Gérard, L. et al. Neutropenia in Patients with Common Variable Immunodeficiency: a Rare Event Associated with Severe Outcome. J Clin Immunol 37, 715–726 (2017). https://doi.org/10.1007/s10875-017-0434-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-017-0434-2

Keywords

Search

Navigation