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Background: Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited., Objectives: This study sought to describe NRH prevalence, associated features, and impact in patients with XLA., Methods: Medical records of all patients with XLA referred to the National Institutes of Health between October 1994 and June 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher exact test and Mann-Whitney test were used for statistical comparisons., Results: Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent ≥1 liver biopsy of whom 6 (29% of the National Institutes of Health XLA cohort) were NRH+. The median age at NRH diagnosis was 20 years (range, 17-31). Among patients who had liver biopsies, alkaline phosphatase levels were only increased in patients who were NRH+ (P = .04). Persistently low platelet count (<100,000 per μL for >6 months), mildly to highly elevated hepatic venous pressure gradient and either hepatomegaly and/or splenomegaly were present in all patients who were NRH+. In opposition, persistently low platelet counts were not seen in patients who were NRH-, and hepatosplenomegaly was observed in only 1 patient who was NRH-. Hepatic venous pressure gradient was normal in the only patient tested who was NRH-. All-cause mortality was higher among patients who were NRH+ (5 of 6, 83%) than in the rest of the cohort (1 of 15, 7% among patients who were NRH- and who were classified as unknown; P = .002)., Conclusions: NRH is an underreported, frequent, and severe complication in XLA, which is associated with increased morbidity and mortality., (Published by Elsevier Inc.)

Background: Rituximab is a B-cell depleting agent used in B-cell malignancies and autoimmune diseases. A subset of adult patients may develop prolonged and symptomatic hypogammaglobulinemia following rituximab treatment. However, this phenomenon has not been well delineated in the pediatric population., Objectives: This study sought to determine the prevalence, risk factors, and clinical significance of hypogammaglobulinemia following rituximab therapy in children., Methods: This was a multicenter, retrospective cohort study that extracted clinical and immunological data from pediatric patients who received rituximab., Results: The cohort comprised 207 patients (median age, 12.0 years). Compared to baseline values, there was a significant increase in hypogammaglobulinemia post-rituximab therapy, with an increase in prevalence of hypo-IgG (28.7%-42.6%; P = .009), hypo-IgA (11.1%-20.4%; P = .02), and hypo-IgM (20.0%-62.0%; P < .0001). Additionally, low IgG levels at any time post-rituximab therapy were associated with a higher risk of serious infections (34.4% vs 18.9%; odds ratio, 2.3; 95% CI, 1.1-4.8; P = .03). Persistent IgG hypogammaglobulinemia was observed in 27 of 101 evaluable patients (26.7%). Significant risk factors for persistent IgG hypogammaglobulinemia included low IgG and IgA levels pre-rituximab therapy. Nine patients (4.3%) within the study were subsequently diagnosed with a primary immunodeficiency, 7 of which received rituximab for autoimmune cytopenias., Conclusions: Hypogammaglobulinemia post-rituximab treatment is frequently diagnosed within the pediatric population. Low IgG levels are associated with a significant increase in serious infections, and underlying primary immunodeficiencies are relatively common in children receiving rituximab, thus highlighting the importance of immunologic monitoring both before and after rituximab therapy., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Hypogammaglobulinemia has been reported after cardiac surgery and may be associated with adverse outcomes. We sought to define baseline immunoglobulin (Ig) concentration in neonates and infants with congenital heart disease, determine their course after cardiopulmonary bypass (CPB), and determine if post-CPB hypogammaglobulinemia was associated with increased morbidity., Methods: This was a single-center, retrospective analysis of infants who underwent cardiac surgery with CPB between June 2010 and December 2011. The Ig concentration was obtained from banked plasma of 47 patients from a prior study (pre-CPB, immediately post-CPB, and 24 and 48 hours post-CPB). In addition, any Ig levels drawn for clinical purposes after CPB were included. Ig levels were excluded if drawn after chylothorax diagnosis or intravenous IgG administration., Results: The median age was 7 days. Preoperative Ig concentration was similar to that described in healthy children. IgG level decreased to less than 50% of preoperative concentration by 24-hour post-CPB and failed to recover by 7 days. Of 47 patients, 25 (53%) had low IgG (<248 mg/dL) after CPB. Despite no difference in demographics or risk factors between patients with low and normal IgG, low IgG patients had more positive fluid balance at 24 hours and increased proinflammatory plasma cytokine levels, duration of mechanical ventilation, and cardiac intensive care unit length of stay. In addition, low IgG patients had an increased incidence of postoperative infections (40% vs 14%; P = .056)., Conclusions: Hypogammaglobulinemia occurs in half of infants after CPB. Its association with fluid overload and increased inflammatory cytokines suggests it may result from capillary leak. Postoperative hypogammaglobulinemia is associated with increased morbidity, including more secondary infections., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Adenosine deaminase (ADA)-severe combined immunodeficiency (SCID) is an SCID caused by a defect in the enzyme adenosine deaminase. It is usually fatal in infancy because of severe recurrent infections. When diagnosis is made, permanent damage caused by infections or by metabolites is often present. Gene therapy, bone marrow transplantation, or enzyme therapy might be effective if performed early. ADA-SCID complies with all the criteria for inclusion in a newborn screening program. However, screening methods are still expensive or provide a non-negligible number of indeterminate results., Objective: The aim of the present study was to develop a simple, reliable, and inexpensive method for diagnosis of ADA-SCID by using dried blood spot (DBS) samples taken at birth. Cost per test was calculated, including the cost for reagents, equipment, and operators., Methods: DBS samples from 4 patients with genetically confirmed ADA-SCID and 12,020 DBS samples from healthy newborns were examined. Adenosine and 2'-deoxyadenosine were tested by using tandem mass spectrometry (PCT EP2010/070517)., Results: The mean levels of adenosine and 2'-deoxyadenosine were 7.8 ± 3.1 and 8.5 ± 6.0 μmol/L, respectively, in affected children; adenosine was found at 0.23 ± 0.09 μmol/L, whereas 2'-deoxyadenosine was never detected in healthy control subjects (adenosine: P < 10(-6) [95% confidence limit, 7.59-7.78] and 2'-deoxyadenosine: P < 10(-6) [95% confidence limit, 8.65-8.82] for control subjects vs patients with ADA-SCID). No indeterminate or false-positive results were found. Cost per test was €0.01 ($0.013). A pilot population-based newborn screening for ADA-SCID has started in Tuscany, Italy., Conclusion: Tandem mass spectrometry can be used for diagnosis of one of the most frequent form of SCID at a negligible cost., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: The maturation of normal B lymphocytes proceeds through a growth phase and a differentiation phase. These two phases appear to be under the influence of mediators released by immune cells, B-cell growth factor(s), which induce proliferation of B cells; and B-cell differentiation factor(s), which induce B-cell differentiation., Methods: We analyzed the ability of peripheral blood mononuclear cells from patients with hypogammaglobulinemia to produce B-cell growth factor and B-cell differentiation factor activity in comparison with normal peripheral blood mononuclear cells., Results: Of 27 patients tested, 26 had normal production of B-cell growth factor activity. A quantitative but not absolute defect in B-cell growth factor production was demonstrable in one boy with hypogammaglobulinemia. Interleukin-2 and interleukin-4 levels, as determined antigenically in these supernatants, had a similar distribution pattern from patients' or from control peripheral blood mononuclear cells; that is, undetectable levels of interleukin-2 were produced by cells from 4 of 16 patients tested and from 4 of 13 control subjects, and undetectable levels of interleukin-4 produced by cells from 6 of 16 patients and 4 of 13 control subjects. B-cell differentiation factor activity was absent in only one child tested but present in all other patients. Two patients had quantitatively low secretion of B-cell differentiation factor, but all others were within normal range. The two patients with quantitatively depressed B-cell differentiation factor activity had normal levels of B-cell growth factor activity, interleukin-2, and interleukin-4 produced from their cells., Conclusion: Peripheral blood mononuclear cells from the majority of patients with hypogammaglobulinemia appear to have the capacity to produce B-cell growth factors and B-cell differentiation factor activity in vitro.

Retinoic acid (RA) has been demonstrated to drive both phenotypic and functional in vitro differentiation of B cell hybridomas from patients with common variable immunodeficiency (CVI) who manifest an "intrinsic" defect in terminal B cell differentiation (J Exp Med 1988;168: 55-71). Therefore, we conducted an open trial to determine the effects of oral 13-cis RA (0.5 mg/kg/day; 12 weeks receiving and 12 weeks without drug) on in vivo B cell differentiation in subjects with CVI. At various times before, during, and after drug administration, patients' B cells were tested for changes in cell-surface phenotype and in vitro immunoglobulin production in response to recombinant cytokines. Before 13-cis RA, all patients had decreased Leu-8 coexpression on CD20+ cells. Seven of eight subjects demonstrated "normalization" of this phenotype after 8 to 16 weeks of 13-cis RA administration. Patients whose B cells demonstrated more than normal CD20 display also had a fall toward normal in this parameter. These effects persisted for 6 to 12 weeks after drug was stopped. It appears that 13-cis RA drives B cells of patients with CVI to express a more differentiated cell-surface phenotype and may promote functional differentiation in some patients.

Interleukin-6 (IL-6/B cell stimulatory factor 2) has been found to drive activated human B-lymphocytes through the final stages of differentiation to become immunoglobulin-producing cells. Most patients with common variable immunodeficiency (CVI) have B-lymphocytes that fail to differentiate into high-rate immunoglobulin-secreting cells in vivo and in vitro. In view of (1) the known effects of IL-6 to promote B-lymphocyte terminal differentiation and (2) the defect in differentiation in B-lymphocytes of patients with CVI, we believed that it was important to analyze the role of this cytokine in patients with CVI. Using an IL-6-dependent murine hybridoma cell line in a bioassay, serum IL-6 levels were determined in 17 patients with CVI and in eight normal control subjects. Thirteen of the 17 patients with CVI exhibited serum IL-6 levels that were twofold to 18-fold higher than the range (mean, +2 SD) of normal control subjects. Spontaneous IL-6 production by peripheral blood mononuclear cells (PBMC) of patients with CVI was significantly higher than that from normal control subjects, whereas lipopolysaccharide maximally stimulated IL-6 production by PBMCs of patients with CVI or PBMCs of normal control subjects was equivalent. A substance inhibitory of IL-6 bioactivity was found in equivalent amounts in sera of both patients and normal control subjects. Sera from patients with CVI with high IL-6 bioactivity were found to have saturated this IL-6 inhibitory substance, thus resulting in large amounts of free IL-6 in the sera. These studies suggest that the failure of B cells from patients with CVI to terminally differentiate into high-rate immunoglobulin-secreting cells cannot be attributed to a decrease in the serum levels of IL-6 and that the increased circulating IL-6 levels in patients with CVI result from hyperproduction rather than decreased use of IL-6. The persistently elevated levels of IL-6 observed in some patients with CVI may secondarily result in the induction of the neoplastic and autoimmune phenomena associated with this disease.