Serum Free Light Chains in Common Variable Immunodeficiency Disorders: Role in Differential Diagnosis and Association With Clinical Phenotype

Scarpa, Riccardo; Pulvirenti, Federica; Pecoraro, Antonio; Vultaggio, Alessandra; Marasco, Carolina; Ria, Roberto; Altinier, Sara; Compagno, Nicolò; Firinu, Davide; Plebani, Mario; Carli, Marco De; Matucci, Andrea; Vianello, Fabrizio; Vacca, Angelo; Spadaro, Giuseppe; Quinti, Isabella; Agostini, Carlo; Milito, Cinzia; Cinetto, Francesco

doi:10.3389/fimmu.2020.00319

Cited by 9 publications

(15 citation statements)

References 27 publications

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“…We then compared sFLC patterns (κ − λ + , κ + λ − , κ − λ − , κ + λ + ) with clinical associations in CVID patients. We found that κ − λ − pattern was highly prevalent in CVID patients with enteropathy (66.66%, 4/6 patients, p = 0.01), splenomegaly (50.00%, 7/14 patients, p = 0.2) and bronchiectasis (68.75%, 11/16 patients, p = 0.1), compatible with the association described by other groups (6,7,29).…”

Section: Comparison Of Sflc Values With Clinical Associations In Cvidsupporting

confidence: 87%

“…Scarpa et al analyzed the association of sFLCs patterns (κ − λ + , κ + λ − , κ − λ − , κ + λ + ) and CVID clinical phenotypes. Counterintuitively, infectious and inflammatory phenotypes were more frequently observed in CVID patients with low or absent levels of sFLC (κ − λ − ) (6,7,29). Likewise, we found that enteropathy, splenomegaly and bronchiectasis were more prevalent in the κ − λ − pattern in our cohort, although the non-significance in splenomegaly and bronchiectasis could be due to the small sample size (Supplementary Figure S1).…”

Section: Discussion Sflc As a Diagnostic Tool In Primary Immunodeficimentioning

confidence: 47%

“…Several groups have pioneered a greater understanding on the role of sFLCs in the clinical scenario of PIDs (6)(7)(8)29). While many primary antibody deficiency (PAD) share a common profile of hypogammaglobulinemia, it has not been fully elucidated why only CVID presents a characteristic profile of low or undetectable sFLC (6)(7)(8)29). Unsworth et al described very low sFLCs in 18 out of 20 PID cases, CVID being the commonest diagnosis (16/20), followed by X-linked agammaglobulinemia (XLA, 2/20).…”

Section: Discussion Sflc As a Diagnostic Tool In Primary Immunodeficimentioning

confidence: 99%

“…Given the high clinical variability and immunological heterogeneity in clinical manifestations of common variable immunodeficiency (CVID), several researchers have proposed combinations of clinical and immunological biomarkers in order to refine the diagnosis and to provide more personalized followup and treatment strategies that may improve the prognosis of the individual patient (1)(2)(3)(4). A recently proposed biomarker for CVID diagnosis is the quantification of serum free light chain (sFLC) (5)(6)(7)(8).…”

Section: Background: Immunoglobulin the Master Key Of Many Locksmentioning

confidence: 99%

“…Due to the inherent immunological alterations in a relevant proportion of PID patients, such as polyclonal B cell proliferation, it is particularly challenging to make an early diagnosis of B malignancy in these patients. Interestingly, alterations of sFLC in PID patients (κ/λ ratio), especially in CVID, correlate with clonal processes (6,7,13).…”

Section: Background: Immunoglobulin the Master Key Of Many Locksmentioning

confidence: 99%

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Serum Free Immunoglobulins Light Chains: A Common Feature of Common Variable Immunodeficiency?

et al. 2020

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Serum free light chain (sFLC) is a recently proposed biomarker for CVID diagnosis. Most CVID patients present low or undetectable sFLC up to 10-fold lower compared to other primary antibody deficiencies. Given that κ and λ light chains are normally secreted in excess with respect to immunoglobulins, this finding points to an intrinsic defect of B cell differentiation in CVID. sFLC levels were prospectively evaluated in a cohort of 100 primary immunodeficiency (PID) patients and in 49 patients with secondary immunodeficiency to haematological malignancy (SID). CVID patients had significantly lower κ and/or λ values (mean: κ: 1.39 ± 1.7 mg/L and λ: 1.97 ± 2.24 mg/L) compared to "other PIDs" (κ: 13.97 ± 5.88 mg/L and λ: 12.92 ± 7.4 mg/L, respectively, p < 0.001 both), and SID (κ 20.9 ± 22.8 mg/L and λ 12.8 ± 8.7 mg/L, respectively, p < 0.001 both). The sum of kappa and lambda (sum κ + λ) in CVID patients (7.25 ± 7.90 mg/L) was significantly lower respect to other PIDs (26.44 ± 13.25 mg/L, p < 0.0001), and to SID patients (28.25 ± 26.24 mg/L, p = 0.0002). ROC analysis of the sum κ + λ disclosed an area under the curve (AUC) of 0.894 for CVID diagnosis (SD 0.031; 95% CI: 0.83-0.95, p < 0.0001), with optimal cutoff of 16.7 mg/L, giving the highest combination of sensitivity (92%), specificity (75%) and NPV (98%). The Relative Risk (RR) for patients presenting a sum κ + λ below 16.7 mg/L was 20.35-fold higher (95%, CI: 5.630-75.93) for CVID than below this threshold. A similar behavior of the sFLC in our CVID cohort with respect to previously published studies was observed. We propose a cutoff of sum κ + λ 16.7 with diagnostic application in CVID patients, and discuss potential specific defects converging in low or undetectable sFLC.

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Section: Comparison Of Sflc Values With Clinical Associations In Cvidsupporting

confidence: 87%

Section: Discussion Sflc As a Diagnostic Tool In Primary Immunodeficimentioning

confidence: 47%

Section: Discussion Sflc As a Diagnostic Tool In Primary Immunodeficimentioning

confidence: 99%

Section: Background: Immunoglobulin the Master Key Of Many Locksmentioning

confidence: 99%

Section: Background: Immunoglobulin the Master Key Of Many Locksmentioning

confidence: 99%

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Serum Free Immunoglobulins Light Chains: A Common Feature of Common Variable Immunodeficiency?

et al. 2020

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An Exploratory Approach of Clinically Useful Biomarkers of Cvid by Logistic Regression

Guerra-Galán,

Palacios-Ortega,

Jiménez-Huete

et al. 2024

J Clin Immunol

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Despite advancements in genetic and functional studies, the timely diagnosis of common variable immunodeficiency (CVID) remains a significant challenge. This exploratory study was designed to assess the diagnostic performance of a novel panel of biomarkers for CVID, incorporating the sum of κ+λ light chains, soluble B-cell maturation antigen (sBCMA) levels, switched memory B cells (smB) and the VISUAL score. Comparative analyses utilizing logistic regression were performed against established gold-standard tests, specifically antibody responses. Our research encompassed 88 subjects, comprising 27 CVID, 23 selective IgA deficiency (SIgAD), 20 secondary immunodeficiency (SID) patients and 18 healthy controls. We established the diagnostic accuracy of sBCMA and the sum κ+λ, achieving sensitivity (Se) and specificity (Spe) of 89% and 89%, and 90% and 99%, respectively. Importantly, sBCMA showed strong correlations with all evaluated biomarkers (sum κ+λ, smB cell and VISUAL), whereas the sum κ+λ was uniquely independent from smB cells or VISUAL, suggesting its additional diagnostic value. Through a multivariate tree decision model, specific antibody responses and the sum κ+λ emerged as independent, signature biomarkers for CVID, with the model showcasing an area under the curve (AUC) of 0.946, Se 0.85, and Spe 0.95. This tree-decision model promises to enhance diagnostic efficiency for CVID, underscoring the sum κ+λ as a superior CVID classifier and potential diagnostic criterion within the panel.

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Dissecting Secondary Immunodeficiency: Identification of Primary Immunodeficiency within B-Cell Lymphoproliferative Disorders

Palacios-Ortega,

Guerra-Galán,

Jiménez-Huete

et al. 2024

J Clin Immunol

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Distinguishing between primary (PID) and secondary (SID) immunodeficiencies, particularly in relation to hematological B-cell lymphoproliferative disorders (B-CLPD), poses a major clinical challenge. We aimed to analyze and define the clinical and laboratory variables in SID patients associated with B-CLPD, identifying overlaps with late-onset PIDs, which could potentially improve diagnostic precision and prognostic assessment. We studied 37 clinical/laboratory variables in 151 SID patients with B-CLPD. Patients were classified as “Suspected PID Group” when having recurrent-severe infections prior to the B-CLPD and/or hypogammaglobulinemia according to key ESID criteria for PID. Bivariate association analyses showed significant statistical differences between “Suspected PID”- and “SID”-groups in 10 out of 37 variables analyzed, with “Suspected PID” showing higher frequencies of childhood recurrent-severe infections, family history of B-CLPD, significantly lower serum Free Light Chain (sFLC), immunoglobulin concentrations, lower total leukocyte, and switch-memory B-cell counts at baseline. Rpart machine learning algorithm was performed to potentially create a model to differentiate both groups. The model developed a decision tree with two major variables in order of relevance: sum κ + λ and history of severe-recurrent infections in childhood, with high sensitivity 89.5%, specificity 100%, and accuracy 91.8% for PID prediction. Identifying significant clinical and immunological variables can aid in the difficult task of recognizing late-onset PIDs among SID patients, emphasizing the value of a comprehensive immunological evaluation. The differences between “Suspected PID” and SID groups, highlight the need of early, tailored diagnostic and treatment strategies for personalized patient management and follow up. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-024-01818-2.

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Serum Free Light Chains in Common Variable Immunodeficiency Disorders: Role in Differential Diagnosis and Association With Clinical Phenotype

Cited by 9 publications

References 27 publications

Serum Free Immunoglobulins Light Chains: A Common Feature of Common Variable Immunodeficiency?

Serum Free Immunoglobulins Light Chains: A Common Feature of Common Variable Immunodeficiency?

An Exploratory Approach of Clinically Useful Biomarkers of Cvid by Logistic Regression

Dissecting Secondary Immunodeficiency: Identification of Primary Immunodeficiency within B-Cell Lymphoproliferative Disorders

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