How Does the Corrected Exhalyzer Software Change the Predictive Value of LCI in Pulmonary Exacerbations in Children with Cystic Fibrosis?

Aim: Recently, the most commonly used for multiple breath washout device, the Exhalyzer D, has been shown to overestimate lung clearance index (LCI) results due to a software error. Our study aimed to compare the predictive values of LCI in the CF pulmonary exacerbations (PE) calculated with the updated (3.3.1) and the previous (3.2.1) version of the Spiroware software. Materials and Methods: The measurements were performed during 259 visits in CF pediatric patients. We used 39ΔPE pairs (PE preceded by stable visit) and 138ΔS pairs (stable visit preceded by stable visit) to compare the LCI changes during PE. The areas under the receiver operating curves (AUCROC) and odds ratios were calculated based on the differences between ΔPEs and ΔSs. The exacerbation risk was estimated using a logistic regression model with generalized estimating equations (GEE). Results: There were statistically significant differences in LCI 2.5% median values measured using the two versions of the software in the stable condition but not during PE. The AUCROC for changes between the two consecutive visits for LCI did not change significantly using the updated Spiroware software. Conclusions: Despite the lower median values, using the recalculated LCI values does not influence the diagnostic accuracy of this parameter in CF PE.

Infections and immune dysregulation in ataxia-telangiectasia children with hyper-IgM and non-hyper-IgM phenotypes: A single-center experience.

Ataxia-telangiectasia (A-T) is a severe syndromic neurodegenerative inborn error of immunity characterized by DNA reparation defect, chromosomal instability, and hypersensitivity to ionizing radiation, thereby predisposing affected individuals to malignant transformation. While the leading disease symptomatology is associated with progressively debilitating cerebellar ataxia accompanied by central and peripheral nervous system dysfunctions, A-T is a multisystemic disorder manifesting with the heterogeneity of phenotypic features. These include airway and interstitial lung disease, chronic liver disease, endocrine abnormalities, and cutaneous and deep-organ granulomatosis. The impaired thymic T cell production, defective B cell development and antibody production, as well as bone marrow failure, contribute to a combined immunodeficiency predisposing to infectious complications, immune dysregulation, and organ-specific immunopathology, with the A-T hyper-IgM (HIGM) phenotype determining the more severe disease course. This study aimed to clarify the immunodeficiency and associated immune dysregulation as well as organ-specific immunopathology in children with A-T. We also sought to determine whether the hyper-IgM and non-hyper-IgM phenotypes play a discriminatory role and have prognostic significance in anticipating the clinical course and outcome of the disease. We retrospectively reviewed the medical records of twelve A-T patients, aged from two to eighteen years. The patients' infectious history, organ-specific symptomatology, and immunological workup including serum alpha-fetoprotein, immunoglobulin isotypes, IgG subclasses, and lymphocyte compartments were examined. For further comparative analysis, all the subjects were divided into two groups, HIGM A-T and non-HIGM A-T. The clinical evaluation of the study group showed that recurrent respiratory tract infections due to viral and bacterial pathogens and a chronic obstructive airway disease along with impaired humoral immunity, in particular complete IgA deficiency, were noted in all the A-T patients, with both HIGM and non-HIGM phenotypes. The most important features with the discriminatory role between groups, were autoimmune disorders, observable four times more frequently in HIGM than in non-HIGM A-T. Two patients with the HIGM A-T phenotype were deceased due to liver failure and chronic Epstein-Barr virus (EBV) infection. It may therefore be assumed that the HIGM form of A-T is associated with more profound T cell dysfunction, defective immunoglobulin class switching, chronic EBV expansion, and poorer prognosis.

The CXCR5 T follicular helper cell compartment in children with antibody deficiencies—in search of a prognostic marker of childhood hypogammaglobulinemia

Background Novel immunodiagnostic markers are required in order to discriminate between mild hypogammaglobulinemia and severe humoral primary immune deficiencies in children. The efficacy of an antibody response to infections and vaccines is underpinned by T follicular helper (Tfh) cells, activating an immunoglobulin class switch recombination, somatic hypermutations, and affinity maturation. Objective To determine the formation of the Tfh cells in antibody deficient children and to define their importance as prognostic markers helpful in defining the severity of hypogammaglobulinemia. Methods We retrospectively reviewed medical records of 200 children aged from 2 months to 10 years, in whom hypogammaglobulinemia was assessed, from January to December 2019. In all the children studied, a flow cytometric analysis of the Tfh cell compartment was performed. Results In young infants aged from 2 to 9 months, the mean relative frequency of the Tfh population was lower than in the control population. Concomitantly, the relative values of Tfh cells, corresponding with the 95th percentile, were below the reference values in all age groups. Conclusions A deficiency of Tfh cells in young infants mirrors the immaturity of the humoral immune response, whereas in older children Tfh cells are proposed as a prognostic marker facilitating to distinguish between mild hypogammaglobulinemia and the developing common variable immunodeficiency (AU)

The CXCR5 T follicular helper cell compartment in children with antibody deficiencies-in search of a prognostic marker of childhood hypogammaglobulinemia.

BACKGROUND: Novel immunodiagnostic markers are required in order to discriminate between mild hypogammaglobulinemia and severe humoral primary immune deficiencies in children. The efficacy of an antibody response to infections and vaccines is underpinned by T follicular helper (Tfh) cells, activating an immunoglobulin class switch recombination, somatic hypermutations, and affinity maturation. OBJECTIVE: To determine the formation of the Tfh cells in antibody deficient children and to define their importance as prognostic markers helpful in defining the severity of hypogammaglobulinemia. METHODS: We retrospectively reviewed medical records of 200 children aged from 2 months to 10 years, in whom hypogammaglobulinemia was assessed, from January to December 2019. In all the children studied, a flow cytometric analysis of the Tfh cell compartment was performed. RESULTS: In young infants aged from 2 to 9 months, the mean relative frequency of the Tfh population was lower than in the control population. Concomitantly, the relative values of Tfh cells, corresponding with the 95th percentile, were below the reference values in all age groups. CONCLUSIONS: A deficiency of Tfh cells in young infants mirrors the immaturity of the humoral immune response, whereas in older children Tfh cells are proposed as a prognostic marker facilitating to distinguish between mild hypogammaglobulinemia and the developing common variable immunodeficiency.

Cutaneous and systemic granulomatosis in ataxia-telangiectasia: a clinico-pathological study.

INTRODUCTION: The development of granulomas is a well-recognized manifestation of immunodeficiency in ataxia-telangiectasia (A-T), resulting from lymphocyte developmental abnormalities, impaired immunosurveillance, and inappropriate innate immune response-driven inflammation. AIM: To better understand pathological and immunological phenomena involved in development of cutaneous and visceral granulomatosis observable in patients with ataxia-telangiectasia. MATERIAL AND METHODS: We retrospectively reviewed medical records of eight A-T children, aged from 2 to 13 years, with regard to clinical, immunological and histopathological features of cutaneous and visceral granulomatosis. RESULTS: In four out of eight A-T patients studied, cutaneous granulomas clinically presented as skin nodules and ulcerated erythematous plaques disseminated on the face, and on trauma-prone areas of upper and lower extremities. Visceral granulomatosis had a severe clinical course and involved the lungs, the spleen, the liver and the larynx. Histologically, cutaneous and laryngeal granulomas showed extensive cellular infiltrations containing T lymphocytes with predominating CD8+ phenotype and with CD68+ histiocytes. The immunological profile with the hyper-IgM phenotype, markedly reduced numbers of B and naive CD4+ and CD8+ T cells with predominating IgM-only memory B cells and skewed repertoire of a T cell receptor was observable in patients with skin and visceral granulomatosis. CONCLUSIONS: In the setting of combined immunodeficiency in A-T, cutaneous and systemic granulomatosis reflects a granulomatous reaction pattern, as a result of inappropriate immune regulation.

The B-cell compartment in antibody-deficient infants and young children - developing common variable immunodeficiency or transient immune maturation?

BACKGROUND: Hypogammaglobulinemia in early childhood is a common feature characterized by distinct intrinsic and extrinsic factors leading to disturbed peripheral blood lymphocyte homeostasis. Detailed flow cytometric immunophenotyping of the peripheral blood B cell compartment is an informative tool for delineating disturbed generation of B cell subpopulations crucial for the diagnosis of hypogammaglobulinemia in young children. METHODS: We analyzed by flow cytometry the proportions and absolute values of total, naïve, memory - non-switched and switched, transitional and immature B lymph cells as well as plasmablasts in the peripheral blood of 50 hypogammaglobulinemic children aged from 3 to 50 months. RESULTS: Beyond physiological, age-related changes within the B cell pool, a proportion of children manifested defective differentiation into switched memory and accumulation of CD21lo immature B cells. CONCLUSIONS: Dynamic shifts within B cell subpopulations of the immature immune system being most prominent during the first two years of life contribute to the age-related developmental abnormalities of the B cell compartment. Therefore, a reliable diagnosis of common variable immunodeficiency (CVID) in young hypogammaglobulinemic children cannot yet be established despite their clinical and immunological phenotypes sharing common features with this primary immunodeficiency.