Immunologic biomarkers of noninfectious complications and overall survival in common variable immunodeficiency

Alba Torres-Valle; Jana Neirinck; Susana L. Silva; Sonia de Arriba; Cristina Serrano; Lourdes Cordón; Pedro Pablo Arenas-Caro; Dolores Subirá; Marta Ruiz Mercado; Luis I. González Granado; Catarina Martins; Tomas Kalina; Héctor Balastegui-Martín; Marta Dafne Cabanero-Navalon; Miguel Marcos; Sandra Ines; Teresa Contreras; Carlos Prieto; Lucía Guerrero; M. Carmen García Cañadas; Ana Isabel Cordeiro; Beatriz Albarran; Nicolás González Gómez; Guillermina Hurtado; Abelardo Barez; Ignacio Madruga; Alejandro Martin García-Sancho; José María Bastida; Ignacio Davila; Larraitz Aragon; Pedro Mikel Requejo Olaizola; Mattias Hofmans; Ciel De Vriendt; Elena Blanco; María Jara-Acevedo; Tessa Kerre; Amparo Sempere; Filomeen Haerynck; Álvaro Prada; Ana E. Sousa; Carolien Bonroy; Jacques J.M. van Dongen; Martín Pérez-Andrés; Alberto Orfao

doi:10.1016/j.jaci.2025.10.020

Immunologic biomarkers of noninfectious complications and overall survival in common variable immunodeficiency

Alba Torres-Valle, Jana Neirinck, Susana L. Silva, Sonia de Arriba, Cristina Serrano, Lourdes Cordón, Pedro Pablo Arenas-Caro, Dolores Subirá, Marta Ruiz Mercado, Luis I. González Granado, Catarina Martins, Tomas Kalina, Héctor Balastegui-Martín, Marta Dafne Cabanero-Navalon, Miguel Marcos, Sandra Ines, Teresa Contreras, Carlos Prieto, Lucía Guerrero, M. Carmen García CañadasAna Isabel Cordeiro, Beatriz Albarran, Nicolás González Gómez, Guillermina Hurtado, Abelardo Barez, Ignacio Madruga, Alejandro Martin García-Sancho, José María Bastida, Ignacio Davila, Larraitz Aragon, Pedro Mikel Requejo Olaizola, Mattias Hofmans, Ciel De Vriendt, Elena Blanco, María Jara-Acevedo, Tessa Kerre, Amparo Sempere, Filomeen Haerynck, Álvaro Prada, Ana E. Sousa, Carolien Bonroy, Jacques J.M. van Dongen, Martín Pérez-Andrés, Alberto Orfao

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Abstract

Background: Common variable immunodeficiency (CVID) includes a heterogeneous group of disorders of predominantly antibody deficiencies featuring infectious and noninfectious complications that might lead to severe organ damage and shortened survival. Appropriate clinical management of CVID has been hampered by the lack of robust biomarkers to predict the development of clinical complications and patient outcome. Objective: We investigated the association of individual serologic, cellular, and molecular biomarkers with disease behavior and outcome in CVID. Methods: A multicenter cohort of 209 CVID patients was studied using age-matched reference values from 334 healthy donors to better define TCD4⁺-naive cell defects (late-onset combined immunodeficiency [LOCID]) and classify CVID-associated B-cell/plasma cell (PC) and natural killer (NK) cell defects. Results: Globally, susceptibility to respiratory infections was strongly associated with low serum immunoglobulin (sIg), particularly sIgA, whereas noninfectious complications and disease severity mostly depended on TCD4⁺-naive cell, NK cell, and B-cell/PC defects. LOCID was independently associated with splenomegaly, lymphadenopathy, interstitial lung disease, cytopenia, and lymphoma. Milder B-cell/PC defects (MBC⁺/PC⁺/Ab⁻) protected from noninfectious complications, whereas a marked defect of classical CD27⁺ memory B cells (27MBC⁻) (with decreased NK cell and sIgM) was associated with enteropathy and (with LOCID and sIgA) liver disease. Together, lower sIgG, LOCID, and particularly 27MBC⁻, were strongly associated with shorter survival and early death in CVID. Conversely, CVID-associated pathogenic/risk alleles did not emerge as independent factors associated with disease behavior and outcome. Conclusion: Our results provide a new set of biomarkers closely associated with infectious and noninfectious complications of CVID, which together predict survival and might contribute to guide patient monitoring and clinical management.

Original language	English
Pages (from-to)	454 - 469
Journal	Journal Of Allergy And Clinical Immunology
Volume	157
Issue number	2
DOIs	https://doi.org/10.1016/j.jaci.2025.10.020
Publication status	Published - Feb 2026

Keywords

Common variable immunodeficiency
CVID
disease complications
immunoglobulins
late-onset combined immunodeficiency
memory B cells
NK cells
plasma cells
survival
TCD4-naïve cells

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10.1016/j.jaci.2025.10.020

1-s2.0-S0091674925010796-main (1)Final published version, 1.99 MBLicence: CC BY-NC

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Torres-Valle, A., Neirinck, J., Silva, S. L., de Arriba, S., Serrano, C., Cordón, L., Arenas-Caro, P. P., Subirá, D., Mercado, M. R., González Granado, L. I., Martins, C., Kalina, T., Balastegui-Martín, H., Cabanero-Navalon, M. D., Marcos, M., Ines, S., Contreras, T., Prieto, C., Guerrero, L., ... Orfao, A. (2026). Immunologic biomarkers of noninfectious complications and overall survival in common variable immunodeficiency. Journal Of Allergy And Clinical Immunology, 157(2), 454 - 469. https://doi.org/10.1016/j.jaci.2025.10.020

@article{cebae913d6e34ba9b783fff3b8831dbb,

title = "Immunologic biomarkers of noninfectious complications and overall survival in common variable immunodeficiency",

abstract = "Background: Common variable immunodeficiency (CVID) includes a heterogeneous group of disorders of predominantly antibody deficiencies featuring infectious and noninfectious complications that might lead to severe organ damage and shortened survival. Appropriate clinical management of CVID has been hampered by the lack of robust biomarkers to predict the development of clinical complications and patient outcome. Objective: We investigated the association of individual serologic, cellular, and molecular biomarkers with disease behavior and outcome in CVID. Methods: A multicenter cohort of 209 CVID patients was studied using age-matched reference values from 334 healthy donors to better define TCD4+-naive cell defects (late-onset combined immunodeficiency [LOCID]) and classify CVID-associated B-cell/plasma cell (PC) and natural killer (NK) cell defects. Results: Globally, susceptibility to respiratory infections was strongly associated with low serum immunoglobulin (sIg), particularly sIgA, whereas noninfectious complications and disease severity mostly depended on TCD4+-naive cell, NK cell, and B-cell/PC defects. LOCID was independently associated with splenomegaly, lymphadenopathy, interstitial lung disease, cytopenia, and lymphoma. Milder B-cell/PC defects (MBC+/PC+/Ab−) protected from noninfectious complications, whereas a marked defect of classical CD27+ memory B cells (27MBC−) (with decreased NK cell and sIgM) was associated with enteropathy and (with LOCID and sIgA) liver disease. Together, lower sIgG, LOCID, and particularly 27MBC−, were strongly associated with shorter survival and early death in CVID. Conversely, CVID-associated pathogenic/risk alleles did not emerge as independent factors associated with disease behavior and outcome. Conclusion: Our results provide a new set of biomarkers closely associated with infectious and noninfectious complications of CVID, which together predict survival and might contribute to guide patient monitoring and clinical management.",

keywords = "Common variable immunodeficiency, CVID, disease complications, immunoglobulins, late-onset combined immunodeficiency, memory B cells, NK cells, plasma cells, survival, TCD4-na{\"i}ve cells",

author = "Alba Torres-Valle and Jana Neirinck and Silva, \{Susana L.\} and \{de Arriba\}, Sonia and Cristina Serrano and Lourdes Cord{\'o}n and Arenas-Caro, \{Pedro Pablo\} and Dolores Subir{\'a} and Mercado, \{Marta Ruiz\} and \{Gonz{\'a}lez Granado\}, \{Luis I.\} and Catarina Martins and Tomas Kalina and H{\'e}ctor Balastegui-Mart{\'i}n and Cabanero-Navalon, \{Marta Dafne\} and Miguel Marcos and Sandra Ines and Teresa Contreras and Carlos Prieto and Luc{\'i}a Guerrero and \{Garc{\'i}a Ca{\~n}adas\}, \{M. Carmen\} and Cordeiro, \{Ana Isabel\} and Beatriz Albarran and G{\'o}mez, \{Nicol{\'a}s Gonz{\'a}lez\} and Guillermina Hurtado and Abelardo Barez and Ignacio Madruga and Garc{\'i}a-Sancho, \{Alejandro Martin\} and Bastida, \{Jos{\'e} Mar{\'i}a\} and Ignacio Davila and Larraitz Aragon and \{Requejo Olaizola\}, \{Pedro Mikel\} and Mattias Hofmans and \{De Vriendt\}, Ciel and Elena Blanco and Mar{\'i}a Jara-Acevedo and Tessa Kerre and Amparo Sempere and Filomeen Haerynck and {\'A}lvaro Prada and Sousa, \{Ana E.\} and Carolien Bonroy and \{van Dongen\}, \{Jacques J.M.\} and Mart{\'i}n P{\'e}rez-Andr{\'e}s and Alberto Orfao",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2026",

month = feb,

doi = "10.1016/j.jaci.2025.10.020",

language = "English",

volume = "157",

pages = "454 -- 469",

journal = "Journal Of Allergy And Clinical Immunology",

issn = "0091-6749",

publisher = "MOSBY-ELSEVIER",

number = "2",

}

Torres-Valle, A, Neirinck, J, Silva, SL, de Arriba, S, Serrano, C, Cordón, L, Arenas-Caro, PP, Subirá, D, Mercado, MR, González Granado, LI, Martins, C, Kalina, T, Balastegui-Martín, H, Cabanero-Navalon, MD, Marcos, M, Ines, S, Contreras, T, Prieto, C, Guerrero, L, García Cañadas, MC, Cordeiro, AI, Albarran, B, Gómez, NG, Hurtado, G, Barez, A, Madruga, I, García-Sancho, AM, Bastida, JM, Davila, I, Aragon, L, Requejo Olaizola, PM, Hofmans, M, De Vriendt, C, Blanco, E, Jara-Acevedo, M, Kerre, T, Sempere, A, Haerynck, F, Prada, Á, Sousa, AE, Bonroy, C, van Dongen, JJM, Pérez-Andrés, M & Orfao, A 2026, 'Immunologic biomarkers of noninfectious complications and overall survival in common variable immunodeficiency', Journal Of Allergy And Clinical Immunology, vol. 157, no. 2, pp. 454 - 469. https://doi.org/10.1016/j.jaci.2025.10.020

TY - JOUR

T1 - Immunologic biomarkers of noninfectious complications and overall survival in common variable immunodeficiency

AU - Torres-Valle, Alba

AU - Neirinck, Jana

AU - Silva, Susana L.

AU - de Arriba, Sonia

AU - Serrano, Cristina

AU - Cordón, Lourdes

AU - Arenas-Caro, Pedro Pablo

AU - Subirá, Dolores

AU - Mercado, Marta Ruiz

AU - González Granado, Luis I.

AU - Martins, Catarina

AU - Kalina, Tomas

AU - Balastegui-Martín, Héctor

AU - Cabanero-Navalon, Marta Dafne

AU - Marcos, Miguel

AU - Ines, Sandra

AU - Contreras, Teresa

AU - Prieto, Carlos

AU - Guerrero, Lucía

AU - García Cañadas, M. Carmen

AU - Cordeiro, Ana Isabel

AU - Albarran, Beatriz

AU - Gómez, Nicolás González

AU - Hurtado, Guillermina

AU - Barez, Abelardo

AU - Madruga, Ignacio

AU - García-Sancho, Alejandro Martin

AU - Bastida, José María

AU - Davila, Ignacio

AU - Aragon, Larraitz

AU - Requejo Olaizola, Pedro Mikel

AU - Hofmans, Mattias

AU - De Vriendt, Ciel

AU - Blanco, Elena

AU - Jara-Acevedo, María

AU - Kerre, Tessa

AU - Sempere, Amparo

AU - Haerynck, Filomeen

AU - Prada, Álvaro

AU - Sousa, Ana E.

AU - Bonroy, Carolien

AU - van Dongen, Jacques J.M.

AU - Pérez-Andrés, Martín

AU - Orfao, Alberto

PY - 2026/2

Y1 - 2026/2

N2 - Background: Common variable immunodeficiency (CVID) includes a heterogeneous group of disorders of predominantly antibody deficiencies featuring infectious and noninfectious complications that might lead to severe organ damage and shortened survival. Appropriate clinical management of CVID has been hampered by the lack of robust biomarkers to predict the development of clinical complications and patient outcome. Objective: We investigated the association of individual serologic, cellular, and molecular biomarkers with disease behavior and outcome in CVID. Methods: A multicenter cohort of 209 CVID patients was studied using age-matched reference values from 334 healthy donors to better define TCD4+-naive cell defects (late-onset combined immunodeficiency [LOCID]) and classify CVID-associated B-cell/plasma cell (PC) and natural killer (NK) cell defects. Results: Globally, susceptibility to respiratory infections was strongly associated with low serum immunoglobulin (sIg), particularly sIgA, whereas noninfectious complications and disease severity mostly depended on TCD4+-naive cell, NK cell, and B-cell/PC defects. LOCID was independently associated with splenomegaly, lymphadenopathy, interstitial lung disease, cytopenia, and lymphoma. Milder B-cell/PC defects (MBC+/PC+/Ab−) protected from noninfectious complications, whereas a marked defect of classical CD27+ memory B cells (27MBC−) (with decreased NK cell and sIgM) was associated with enteropathy and (with LOCID and sIgA) liver disease. Together, lower sIgG, LOCID, and particularly 27MBC−, were strongly associated with shorter survival and early death in CVID. Conversely, CVID-associated pathogenic/risk alleles did not emerge as independent factors associated with disease behavior and outcome. Conclusion: Our results provide a new set of biomarkers closely associated with infectious and noninfectious complications of CVID, which together predict survival and might contribute to guide patient monitoring and clinical management.

AB - Background: Common variable immunodeficiency (CVID) includes a heterogeneous group of disorders of predominantly antibody deficiencies featuring infectious and noninfectious complications that might lead to severe organ damage and shortened survival. Appropriate clinical management of CVID has been hampered by the lack of robust biomarkers to predict the development of clinical complications and patient outcome. Objective: We investigated the association of individual serologic, cellular, and molecular biomarkers with disease behavior and outcome in CVID. Methods: A multicenter cohort of 209 CVID patients was studied using age-matched reference values from 334 healthy donors to better define TCD4+-naive cell defects (late-onset combined immunodeficiency [LOCID]) and classify CVID-associated B-cell/plasma cell (PC) and natural killer (NK) cell defects. Results: Globally, susceptibility to respiratory infections was strongly associated with low serum immunoglobulin (sIg), particularly sIgA, whereas noninfectious complications and disease severity mostly depended on TCD4+-naive cell, NK cell, and B-cell/PC defects. LOCID was independently associated with splenomegaly, lymphadenopathy, interstitial lung disease, cytopenia, and lymphoma. Milder B-cell/PC defects (MBC+/PC+/Ab−) protected from noninfectious complications, whereas a marked defect of classical CD27+ memory B cells (27MBC−) (with decreased NK cell and sIgM) was associated with enteropathy and (with LOCID and sIgA) liver disease. Together, lower sIgG, LOCID, and particularly 27MBC−, were strongly associated with shorter survival and early death in CVID. Conversely, CVID-associated pathogenic/risk alleles did not emerge as independent factors associated with disease behavior and outcome. Conclusion: Our results provide a new set of biomarkers closely associated with infectious and noninfectious complications of CVID, which together predict survival and might contribute to guide patient monitoring and clinical management.

KW - Common variable immunodeficiency

KW - CVID

KW - disease complications

KW - immunoglobulins

KW - late-onset combined immunodeficiency

KW - memory B cells

KW - NK cells

KW - plasma cells

KW - survival

KW - TCD4-naïve cells

UR - https://www.scopus.com/pages/publications/105022491291

U2 - 10.1016/j.jaci.2025.10.020

DO - 10.1016/j.jaci.2025.10.020

M3 - Article

C2 - 41176068

AN - SCOPUS:105022491291

SN - 0091-6749

VL - 157

SP - 454

EP - 469

JO - Journal Of Allergy And Clinical Immunology

JF - Journal Of Allergy And Clinical Immunology

IS - 2

ER -

Immunologic biomarkers of noninfectious complications and overall survival in common variable immunodeficiency

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