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.
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Autoimmune hemolytic anemia
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
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.
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.
Castigli E, Geha R. Molecular basis of common variable immunodeficiency. J Allergy Clin Immunol. 2006;117:740–6.
Kopecký O, Lukesová S. Genetic defects in common variable immunodeficiency. Int J Immunogenet. 2007;34:225–9.
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.
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.
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.
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.
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.
Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48.
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.
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.
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.
Garrison EBG. Haplotype-based variant detection from short-read sequencing. Q-BioGN. 2012:1207–3907.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Lopes-da-Silva S, Rizzo LV. Autoimmunity in common variable immunodeficiency. J Clin Immunol. 2008;28:46–55.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Notarangelo LD, Kim M-S, Walter JE, Lee YN. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol. 2016;16:234–46.
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.
von Bülow GU, van Deursen JM, Bram RJ. Regulation of the T-independent humoral response by TACI. Immunity. 2001;14:573–82.
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.
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.
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.
Conflict of Interest
The authors declare that they have no conflicts of interest.
Aurélien Guffroy and Rachel Mourot-Cottet contribute equally to the work.
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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
- Autoimmune cytopenia
- Common variable immunodeficiency (CVID)
- Next genome sequencing