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Published on: September 7, 2022
Age-matched reference values for B-lymphocyte subpopulations and CVID classifications in children
E J H Schatorjé1, E F A Gemen, G J A Driessen
1Department of Pediatrics, Jeroen Bosch Hospital, `s-Hertogenbosch, the Netherlands.
Insights
Accurate reference values for pediatric B-lymphocyte subpopulations are crucial for diagnosing common variable immunodeficiency disorders (CVID). This study establishes reliable pediatric reference ranges using tolerance intervals, highlighting age as a key factor in TACI expression.
Area of Science:
- Immunology
- Pediatrics
- Hematology
Background:
- Standard reference ranges for B-lymphocyte subpopulations are often based on small sample sizes, leading to inaccuracies.
- Common Variable Immunodeficiency Disorders (CVID) classification in children is challenging due to the developing immune system and adult-derived criteria.
- Age-matched reference values are essential for accurate interpretation of pediatric immune cell data.
Purpose of the Study:
- To establish accurate, age-matched reference values for B-lymphocyte subpopulations in healthy children.
- To compare these new reference values with existing EUROclass cut-off values for CVID classification in pediatric patients.
- To investigate the influence of age on TACI expression in B-lymphocytes.
Main Methods:
- Utilized tolerance intervals, a statistical method suitable for smaller sample sizes, to determine reference values.
- Analyzed B-lymphocyte subpopulations in healthy children.
- Compared determined reference values with EUROclass classification cut-offs for CVID.
Main Results:
- Age was identified as the primary determinant of TACI expression on B-lymphocytes, independent of switched memory B-lymphocyte counts.
- Established more accurate, age-specific reference ranges for pediatric B-lymphocyte subpopulations.
- Demonstrated significant developmental changes in the B-lymphocyte compartment during childhood.
Conclusions:
- Established pediatric-specific reference values for B-lymphocyte subpopulations using robust statistical methods.
- Adult-derived CVID classifications may not be suitable for pediatric patients due to significant immune system maturation.
- Age-specific reference values are critical for accurate diagnosis and prognosis of CVID in children.
Abstract:
Age-matched reference values are generally presented with 5th and 95th percentiles as 'normal' reference range. However, they are mostly determined in relatively small groups, which renders this presentation inaccurate. We determined reference values for B-lymphocyte subpopulations in healthy children with the statistical method of tolerance intervals that deals far better with the relatively small numbers tested, and compared these to the cut-off values used in the currently used EUROclass classification for common variable immunodeficiency disorders (CVID) in children. CVID is a heterogeneous group of primary immunodeficiency diseases characterized by low serum immunoglobulin levels and inadequate response to vaccination. Disease-modifying heterozygous amino acid substitutions in TACI are found in around ±10% of CVID patients. Interestingly, we found that age is the primary determinant of TACI-expression on B-lymphocytes, independent of switched memory B-lymphocyte numbers. Immunophenotyping of B-lymphocyte subpopulations is increasingly used to classify patients with CVID into subgroups with different clinical prognosis according to the composition of their B-lymphocyte compartment. These classifications were mainly developed with data obtained in adults. Because of the maturing paediatric immune system, they may not be equally applicable in children: our and other age-matched reference values show great changes in the composition of the B-lymphocyte compartment during development. Although the greatest changes in B-lymphocyte subpopulations occur below the age of 2 years, when the diagnosis of CVID cannot yet be made, it is likely that a classification developed in adults cannot be used to classify the prognosis of children.
