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Purpose: Nijmegen breakage syndrome (NBS) is a DNA repair disorder with a high predisposition to hematologic malignancies. Experimental Design: We describe the natural history of NBS, including cancer incidence, risk of death, and the potential effectiveness of hematopoietic stem cell transplantation (HSCT) in preventing both pathologies: malignancy and immunodeficiency. Results: Among 241 patients with NBS enrolled in the study from 11 countries, 151 (63.0%) patients were diagnosed with cancer. Incidence rates for primary and secondary cancer, tumor characteristics, and risk factors affecting overall survival (OS) were estimated. The cumulative cancer incidence was 40.21% ± 3.5% and 77.78% ± 3.4% at 10 years and 20 years of follow-up, respectively. Most of the tumors n = 95 (62.9%) were non-Hodgkin lymphomas. Overall, 20 (13.2%) secondary malignancies occurred at a median age of 18 (interquartile range, 13.7–21.5) years. The probability of 20-year overall survival (OS) for the whole cohort was 44.6% ± 4.5%. Patients who developed cancer had a shorter 20-year OS than those without malignancy (29.6% vs. 86.2%; P < 10−5). A total of 49 patients with NBS underwent HSCT, including 14 patients transplanted before malignancy. Patients with NBS with diagnosed cancer who received HSCT had higher 20-year OS than those who did not (42.7% vs. 30.3%; P = 0.038, respectively). In the group of patients who underwent preemptive transplantation, only 1 patient developed cancer, which is 6.7 times lower as compared with nontransplanted patients [incidence rate ratio 0.149 (95% confidence interval, 0.138–0.162); P < 0.0001]. Conclusions: There is a beneficial effect of HSCT on the long-term survival of patients with NBS transplanted in their first complete remission of cancer.

Patients with Nijmegen Breakage Syndrome (NBS) suffer from recurrent infections due to humoral and cellular immune deficiency. Despite low number of T lymphocytes and their maturation defect, the clinical manifestations of cell-mediated deficiency are not as severe as in case of patients with other types of combined immune deficiencies and similar T cell lymphopenia. In this study, multicolor flow cytometry was used for evaluation of peripheral T lymphocyte maturation according to the currently known differentiation pathway, in 46 patients with genetically confirmed NBS and 46 sex and age-matched controls. Evaluation of differential expression of CD27, CD31, CD45RA, CD95, and CD197 revealed existence of cell subsets so far not described in NBS patients. Although recent thymic emigrants and naïve T lymphocyte cell populations were significantly lower, the generation of antigen-primed T cells was similar or even greater in NBS patients than in healthy controls. Moreover, the senescent and exhausted T cell populations defined by expression of CD57, KLRG1, and PD1 were more numerous than in healthy people. Although this hypothesis needs further investigations, such properties might be related to an increased susceptibility to malignancy and milder clinical course than expected in view of T cell lymphopenia in patients with NBS.

The aim of this study was to evaluate the serotype-specific pneumococcal status of children and adolescents with inflammatory bowel disease (IBD) who were naïve to pneumococcal vaccination before administering the 13-valent pneumococcal conjugate vaccine (PCV 13). This was an open, prospective study on children and adolescents aged 5–18 years who had IBD and were naïve to pneumococcal vaccination. A single dose of PCV 13 was administered to each patient. The geometric mean concentrations (GMCs) were measured for all 13 serotypes. A total of 122 subjects completed the study. Prevaccination GMCs ranged from 0.55 μg/ml (serotype 4) to 4.26 μg/ml (serotype 19A). Prior to the administration of PCV 13, high GMCs were detected in older children and adolescents who had IBD and were naïve to pneumococcal vaccination.

Nijmegen breakage syndrome (NBS) is a severe chromosomal instability disorder characterized by microcephaly, growth retardation, immune deficiency, and predisposition for malignancy. It is caused by hypomorphic mutations in the NBN gene, which product belongs to the protein complex critical for processing DNA double-strand breaks during mitotic and meiotic recombination. Data on gonadal function in patients with NBS are limited.Growth and sexual development, along with hormonal assays, were evaluated in girls and young women with NBS homozygous for c.657_661del5 mutation.The group comprised 37 girls and young women with NBS (ages, 0.17-24.25 yr), followed between 1993 and 2008. Patients were divided into three age groups: 1) 1-3 yr; 2) 4-9 yr; and 3) 10 yr and older. Growth, puberty, concentrations of gonadotropins and 17-beta-estradiol, bone age, and pelvic ultrasound were assessed.None of the patients presented a typical growth spurt; the adult height ranged between the 3rd and 25th centiles. Median bone age was delayed by 4.05 yr. Pubarche reached stadium P2 in eight patients and P3 in two patients. In all but one girl, thelarche did not exceed Th2, with low 17beta-estradiol levels. Gonadotropin levels showed a biphasic pattern, with median FSH values of 55.0, 10.9, and 81.9 IU/liter, and LH of 3.2, 0.8, and 21.0 IU/liter in consecutive age groups. Ultrasound visualized small ovaries or solid streaks and the hypoplastic uterus.Primary ovarian insufficiency and the associated hypergonadotropic hypogonadism are hallmark manifestations in girls and young women with NBS. Our findings emphasize the need for long-term endocrinological and interdisciplinary supervision of these patients.

Selected viruses and immune parameters were monitored in 57 patients with Nijmegen breakage syndrome as a proposed tool for early detection of changes preceding development of malignancy. The following parameters were analysed: (1) viral infections; (2) monoclonal proteins; and (3) B-cell and T-cell receptor gene rearrangements in peripheral blood lymphocytes. Viral infections were detected in 68.4% of patients with a predominance of EBV (63.2%), followed by HBV (19.2%) and HCV (8.8%). Monoclonal gammopathy detected in 38.6% of cases correlated with the presence of EBV DNA ( p = 0.002) and HCV RNA ( p = 0.04). Clonal Ig and/or TCR gene rearrangements occurred in 73.9% of patients. The presence of at least one of the studied parameters preceded the development of malignancy in 22 patients. Systematic PCR analysis for viral infections and Ig/TCR gene rearrangements, supplemented by detection of monoclonal proteins, is advantageous in monitoring NBS patients before severe complications of the disease, including cancer, appear.

Nijmegen Breakage Syndrome (NBS) is a rare inherited condition, characterized by microcephaly, chromosomal instability, immunodeficiency, and predisposition to malignancy. This retrospective study, characterizing the clinical and immunological status of patients with NBS at time of diagnosis, was designed to assess whether any parameters were useful in disease prognosis, and could help determine patients qualified for hematopoietic stem cell transplantation. The clinical and immunological characteristics of 149 NBS patients registered in the online database of the European Society for Immune Deficiencies were analyzed. Of the 149 NBS patients, 91 (61 %), of median age 14.3 years, remained alive at the time of analysis. These patients were clinically heterogeneous, with variable immune defects, ranging from negligible to severe dysfunction. Humoral deficiencies predisposed NBS patients to recurrent/chronic respiratory tract infections and worsened long-term clinical prognosis. Eighty malignancies, most of lymphoid origin (especially non-Hodgkin’s lymphomas), were diagnosed in 42 % of patients, with malignancy being the leading cause of death in this cohort. Survival probabilities at 5, 10, 20 and 30 years of age were 95, 85, 50 and 35 %, respectively, and were significantly lower in patients with than without malignancies. The extremely high incidence of malignancies, mostly non-Hodgkin’s lymphomas, was the main risk factor affecting survival probability in NBS patients. Because treatment of NBS is very difficult and frequently unsuccessful, the search for an alternative medical intervention such as hematopoietic stem cell transplantation is of great clinical importance.

The IgG subclass distribution of antibody to hepatitis B surface antigen (anti-HBs) was investigated in 19 children with chronic active hepatitis B infection who showed a complete serological seroconversion after interferon-a therapy. Determinations were done 6 and 12 months after treatment. Our results showed no selectivity in anti-HBs synthesis among IgG subclasses. All 4 IgG isotypes were involved in the response, with similar percentage contributions, on average, of IgG1 (35%), IgG3 (27%), and IgG4 (28%), followed by IgG2 (10%). IgG4 became the second most dominant isotype at the end of observation. These results are in contrast to those found after natural seroconversion, in which anti-HBs was highly restricted to neutralizing IgG1 and IgG3, with only a minor contribution from IgG2 and IgG4. It is postulated that analysis of the specific profiles of IgG subclasses may be of value for the estimation of the therapeutic efficacy of recombinant interferon-a used and may be helpful in choosing more-effective treatment. Chronic infection with hepatitis B (HB) virus can occur in children at any age and may lead to chronic hepatitis, liver cirrhosis, or hepatocellular carcinoma during childhood or adulthood [1]. Suppression of viral replication and modulation of the immune responses can prevent disease progression and decrease the severity of liver damage. Thus, the development of an effective therapy against HB virus infection seems to be a high priority. Interferon (IFN)‐a, a molecule that combines antiviral properties with the capacity to modulate the cellular immune response by its effects on the cytokine network [2], was proposed for the treatment of chronic HB »20 years ago [3]. Although its therapeutic use as an antiviral drug has increased significantly in recent years, a complete seroconversion

The IgG subclass profiles of anti-HBs antibodies were investigated in 30 children who had recovered from acute hepatitis B and 40 children vaccinated against hepatitis B virus (HBV) with Engerix B. After natural seroconversion the mean geometric value of anti-HBs titres was ca 41-fold lower than at the peak of response in vaccinees, and specific antibodies were highly restricted to IgG1 subclass followed by IgG3 with only a minor contribution of IgG2 and IgG4. Conversely, in children immunized with recombinant HBsAg, IgG1 and IgG3 dominated after two doses of vaccine and 1 month after the third injection but the response was less selective and more variable. One year after vaccination IgG4 anti-HBs antibodies became the second dominating isotype. Significant statistical differences in the profiles of IgG anti-HBs were observed when the age and maturity of humoral response were considered. While children vaccinated below 5 years of age responded mainly with IgG1 and IgG3 subclasses, older children (> 5 years) showed a high individual variability in the specific profiles with a high contribution of IgG4. We concluded that vaccination at a younger age leads to the production of antibody subclasses which are more effective for virus neutralization.

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive syndrome of chromosomal instability mainly characterized by microcephaly at birth, combined immunodeficiency and predisposition to malignancies. Due to a founder mutation in the underlying NBN gene (c.657_661del5) the disease is encountered most frequently among Slavic populations. The principal clinical manifestations of the syndrome are: microcephaly, present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, and, in females, hypergonadotropic hypogonadism. Combined cellular and humoral immunodeficiency with recurrent sinopulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The NBN gene codes for nibrin which, as part of a DNA repair complex, plays a critical nuclear role wherever double-stranded DNA ends occur, either physiologically or as a result of mutagenic exposure. Laboratory findings include: (1) spontaneous chromosomal breakage in peripheral T lymphocytes with rearrangements preferentially involving chromosomes 7 and 14, (2) sensitivity to ionizing radiation or radiomimetics as demonstrated in vitro by cytogenetic methods or by colony survival assay, (3) radioresistant DNA synthesis, (4) biallelic hypomorphic mutations in the NBN gene, and (5) absence of full-length nibrin protein. Microcephaly and immunodeficiency are common to DNA ligase IV deficiency (LIG4 syndrome) and severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation due to NHEJ1 deficiency (NHEJ1 syndrome). In fact, NBS was most commonly confused with Fanconi anaemia and LIG4 syndrome. Genetic counselling should inform parents of an affected child of the 25% risk for further children to be affected. Prenatal molecular genetic diagnosis is possible if disease-causing mutations in both alleles of the NBN gene are known. No specific therapy is available for NBS, however, hematopoietic stem cell transplantation may be one option for some patients. Prognosis is generally poor due to the extremely high rate of malignancies. Zespół Nijmegen (Nijmegen breakage syndrome; NBS) jest rzadkim schorzeniem z wrodzoną niestabilnością chromosomową dziedziczącym się w sposób autosomalny recesywny, charakteryzującym się przede wszystkim wrodzonym małogłowiem, złożonymi niedoborami odporności i predyspozycją do rozwoju nowotworów. Choroba występuje najczęściej w populacjach słowiańskich, w których uwarunkowana jest mutacją założycielską w genie NBN (c.657_661del5). Do najważniejszych objawów zespołu zalicza się: małogłowie obecne od urodzenia i postępujące z wiekiem, charakterystyczne cechy dysmorfii twarzy, opóźnienie wzrastania, niepełnosprawność intelektualną w stopniu lekkim do umiarkowanego oraz hipogonadyzm hipogonadotropowy u dziewcząt. Na obraz choroby składają się także: niedobór odporności komórkowej i humoralnej, który jest przyczyną nawracających infekcji, znaczna predyspozycja do rozwoju nowotworów złośliwych (zwłaszcza układu chłonnego), a także zwiększona wrażliwość na promieniowanie jonizujące. Wyniki badań laboratoryjnych wykazują: (1) spontaniczną łamliwość chromosomów w limfocytach T krwi obwodowej, z preferencją do rearanżacji chromosomów 7 i 14, (2) nadwrażliwość na promieniowanie jonizujące lub radiomimetyki, co można wykazać metodami in vitro, (3) radiooporność syntezy DNA, (4) hipomorficzne mutacje na obu allelach genu NBN, oraz (5) brak w komórkach pełnej cząsteczki białka, nibryny. Małogłowie i niedobór odporności występują także w zespole niedoboru ligazy IV (LIG4) oraz w zespole niedoboru NHEJ1. Rodzice powinni otrzymać poradę genetyczną ze względu na wysokie ryzyko (25%) powtórzenia się choroby u kolejnego potomstwa. Możliwe jest zaproponowanie molekularnej diagnostyki prenatalnej jeżeli znane są obie mutacje będące przyczyną choroby. Nie ma możliwości zaproponowania specyficznej terapii, ale przeszczep szpiku może być alternatywą dla niektórych pacjentów. Generalnie prognoza nie jest pomyślna z uwagi na wysokie ryzyko rozwoju nowotworu.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, oculocutaneous telangiectasias, chromosomal instability, radiosensitivity, and cancer predisposition. The gene mutated in the patients, ATM, encodes a member of the phosphatidylinositol 3-kinase family proteins. The ATM protein has a key role in the cellular response to DNA damage. Truncating and splice site mutations in ATM have been found in most patients with the classical AT phenotype. Here we report of our extensive ATM mutation screening on 25 AT patients from 19 families of different ethnic origin. Previously unknown mutations were identified in six patients including a new homozygous missense mutation, c.8110T > C (p.Cys2704Arg), in a severely affected patient. Comprehensive clinical data are presented for all patients described here along with data on ATM function generated by analysis of cell lines established from a subset of the patients.

The Nijmegen breakage syndrome (NBS) is a rare inherited condition, characterized by microcephaly, radiation hypersensitivity, chromosomal instability, an increased incidence of (mostly) lymphoid malignancies, and immunodeficiency. NBS is caused by hypomorphic mutations in the NBN gene (8q21). The NBN protein is a subunit of the MRN (Mre11-Rad50-NBN) nuclear protein complex, which associates with double-strand breaks. The immunodeficiency in NBS patients can partly be explained by strongly reduced absolute numbers of B lymphocytes and T lymphocytes. We show that NBS patients have a disturbed precursor B-cell differentiation pattern and significant disturbances in the resolution of recombination activating gene-induced IGH breaks. However, the composition of the junctional regions as well as the gene segment usage of the reduced number of successful immunoglobulin gene rearrangements were highly similar to healthy controls. This indicates that the NBN defect leads to a quantitative defect in V(D)J recombination through loss of juxtaposition of recombination activating gene-induced DNA ends. The resulting reduction in bone marrow B-cell efflux appeared to be partly compensated by significantly increased proliferation of mature B cells. Based on these observations, we conclude that the quantitative defect will affect the B-cell receptor repertoire, thus contributing to the observed immunodeficiency in NBS patients.

EBV loads and abnormalities of humoral responses were monitored in 51 pediatric liver transplant recipients as a proposed non-invasive laboratory tool for early detection of changes preceding severe clinical complications. EBV DNA load, concentrations of IgM, IgG, IgA, and monoclonal proteins were determined in each blood sample. EBV DNA was detected in 70.6% of the children, dysgammaglobulinemia of one or more Ig isotype was present in 41.2% of them. MG detected in 43.1% of patients correlated with the presence of EBV DNA (p = 0.003) and was usually preceded by hypergammaglobulinemia. The median maximum EBV load was significantly higher in EBV DNA+/MG+ patients than in EBV DNA+/MG- patients (p = 0.04), although there was no correlation between current viral load and appearance of MG. Four of 15 EBV DNA-negative patients developed MG, preceded by hypergammaglobulinemia in two. Minimization or cessation of immunosuppression in 42 patients, in whom abnormal biomarkers and/or clinical symptoms raised suspicion of disease progression, permitted complete resolution of abnormalities in all but one patient who developed B-NHL and died. Simultaneous monitoring of protein profiles and EBV DNA load together with thorough physical evaluation of children after LTx is important for early implementation of suitable preemptive therapy.

Objective The objective of this study was to assess the oral cavity status of patients with Nijmegen breakage syndrome (NBS), an inherited genetic disorder that belongs to the group of chromosome instability syndromes and is characterized by microcephaly, a distinct facial appearance, growth retardation, radiation sensitivity, and immunodeficiency. Study design Oral examination was conducted and immunological status assessed in 21 NBS patients (1.7-20.7 years old) and 21 healthy controls (5-21 years old). The differences between the frequency and severity of clinical manifestations and their correlation with immune parameters were analyzed by Student t test, the chi-square test, and Spearman's rank order correlation. Results Lesions of the oral mucosa and gingivitis were diagnosed more frequently in NBS patients than in controls. The mean Gingival Index was significantly higher in NBS subjects (P = 0.00043). Candidiasis was detected in 6 patients (28.6%) and in none of the healthy controls. Immune deficiency (humoral and/or cellular) was detected in 20 of 21 (95.2%) NBS patients. There was a significant association between severity of gingival inflammation and reduced number of B- and/or CD3+/CD4+ T cells combined with IgA+IgG4 deficiency. Conclusion Our study showed that oral manifestations diagnosed in NBS patients were associated with combined deficiencies of the humoral and cellular arms of the immune system. We postulate that periodical examination of the oral cavity is essential for early medical intervention.

Introduction Hereditary angioedema (HAE) is caused by mutations in the C1inh gene, leading to dysfunction of the C1-esterase inhibitor (C1-INH). C1-INH interacts with MASP-1 and MASP-2 proteases, participating in the mannan-binding lectin (MBL) pathway of complement activation. The aim of the study was to investigate the contribution of possible changes in MBL/MASP-2 complex activity and Helicobacter pylori, hepatitis B virus (HBV), and hepatitis C virus (HCV) infections to the severity and frequency of clinical symptoms of HAE. Materials and Methods The study was performed in 65 patients with HAE and 113 healthy persons. The parameters measured were C1-INH, C4, MBL concentration and MBL/MASP-2 complex activity, and serological markers of H. pylori, HBV, and HCV infection. Scores for the frequency and severity of HAE symptoms were determined. Results HAE scores were significantly higher in patients whose C1-INH activity did not exceed 10% than in patients with activity of 10-52% (p=0.016). No significant differences were found in the median levels of MBL concentration and MBL/MASP-2 complex activity between patients and the control group. There was a slight association between contact with H. pylori in patients and HAE symptom score (p=0.052, not significant). Adult patients showed a 2.6-times higher frequency of anti-HBc than the general population. HBV DNA was negative in anti-HBc(+) patients. Conclusions These results suggest that the MBL complement activation pathway itself does not contribute to the frequency of angioedema attacks. Infections with H. pylori and HBV may slightly influence the disease score (not significant).

The aim of our study was to assess: (1) whether seroconversion to IgG anti-HBs, induced by IFN-alpha therapy in children with chronic active hepatitis B, is maintained 4-10 years after treatment; and (2) whether HBV-DNA is present in circulation despite the synthesis of anti-HBs.Serum samples were collected from 38 patients and serological markers of HBV were determined in each of them. HBV-DNA was determined by PCR in anti-HBs positive sera. Serum samples obtained from 19 subjects with a complete spontaneous seroconversion after acute HBV served as controls.Four to 10 years after therapy, anti-HBs were present in ca. 97.4% patients with GMT value of 775 IU/L vs 127 IU/L found in controls. HBsAg was found in 2/38 subjects. In 13 out of 37 patients (35.1%) free and/or bound HBV-DNA was present.This study showed that seroconversion induced by IFN-alpha may not be a sustained phenomenon. HBV-DNA may persist for a long time after therapy despite the anti-HBs synthesis.

Periodontal disease is a complex pathological process involving a wide spectrum of immunological reactions. The aim of the study was to evaluate the influence of surgical periodontal treatments on peripheral blood lymphocyte subpopulations.The study was performed in 40 generally healthy individuals diagnosed with generalized chronic periodontitis and a control group of 36 persons without periodontitis. Peripheral blood lymphocyte subpopulations were examined in both groups. Periodontal treatment was performed, using four different surgical procedures, in the study group. Peripheral blood lymphocyte subpopulations were re-evaluated again after 6 months.Periodontal treatment resulted in a significant improvement of all measured clinical parameters, regardless of the surgical procedure. When evaluated in the study group as a whole, percentages of all but CD8+ T lymphocyte subpopulations were significantly different from the control group at baseline. Values in both groups after treatment were similar. Correlation analysis suggests a connection between the presence of CD25+ cells and selected clinical parameters of periodontal disease (probing depth and clinical attachment loss).Statistically significant differences in the percentages of selected lymphocyte subpopulations in the peripheral blood of patients and healthy controls were found. The results suggest a correlation between selected clinical periodontal parameters and percentage of activated cells expressing the interleukin (IL)-2 receptor. Periodontal treatment resulted in significant improvement in the measured clinical and immunological parameters. It seems that the type of surgical treatment has little effect on the normalization of quantitative disturbances of the examined peripheral blood lymphocytes.

This review deals with the diagnostics of immunoglobulin defects. The development of methods used to detect and quantitate concentrations of immunoglobulins and their subclasses was shortly discussed; following by the role of antibodies in the host defence. Seven out of the ten main immunodeficiencies with the prevalence of antibody defects were then delineated. The diagnostics of humoral immunodeficiencies was illustrated by the example of three boys with hypogammaglobulinemia and three children with common variable immunodeficiency. Percentages of B lymphocytes varied, independent with the very decreased concentrations of immunoglobulin. Concentrations of IgG, IgA, IgM, IgE and IgG subclasses in healthy children of ages from birth to 16 years, were presented in the tables.

In coeliac patients the age of development of symptoms, clinical picture of the disease and complications depend on the dose of ingested gluten. The aim of the study was the evaluation of individual sensitivity to small doses of gluten in the group of 60 patients aged 2.65 to 17.92 (mean age 7.49) treated with gluten-free diet for at least 12 months due to coeliac disease diagnosed according to ESPGAN criteria (food allergy to gluten excluded). Gluten challenge with dose of 10 mg/kg body mass/day was controlled with serological tests (IgAEmA, IgAAGA, and IgGAGA antibodies) carried out every 3 to 6 months. Jejunal biopsy was performed before gluten challenge (normal mucosa), and after positive EmA/AGA antibodies tests to confirm diagnosis (flat mucosa). After 35 months of observation 53.7% of all patients presented of jejunal villious atrophy, and positive IgAEmA. In this group 3.7% presented symptoms after 3 months of gluten challenge, 5.5% after 6 months, 3.7% after 9 months, and 3.7% after 12 months. In some coeliac patients ingestion of small amounts of gluten (10 mg/kg/day) can lead to small intestinal villious atrophy.

Summary During an 8-year period of observation, defects of immune responses were characterized and monitored in 40 of 50 Polish children with Nijmegen breakage syndrome referred to the Children's Memorial Health Institute in Warsaw. The following parameters were determined at diagnosis: (1) concentrations of serum IgM, IgG, IgA; (2) concentrations of IgG subclasses; and (3) lymphocyte subpopulations. In addition, naturally acquired specific antibodies against Streptococcus pneumoniae were determined in 20 patients with a history of recurrent respiratory infections. During follow-up, total serum immunoglobulins and IgG subclasses were monitored systematically in 17 patients who did not receive immunomodulatory therapy. Moreover, anti-HBs antibody response was measured after vaccination of 20 children against HBV. We found that the immune deficiency in NBS is profound, highly variable, with a tendency to progress over time. Systematic monitoring of the humoral response, despite good clinical condition, is essential for early medical intervention.

Common variable immune deficiency (CVID) is a heterogeneous disease associated with ineffective production of antibodies. It is usually diagnosed in adulthood, but a variable proportion of children develop CVID. Early identification of patients with potentially worse prognosis may help to avoid serious complications. The goal of this study was to associate the clinical phenotype of patients with early onset CVID with peripheral B-cell maturation profile. Four color flow cytometry was used to define distribution of peripheral B-cell subsets in 49 children with early-onset CVID. All clinical data were extracted from medical records. A proportion of patients demonstrated diminishing with time total B-lymphocytes pool, beyond physiological age-related changes. Irrespective from duration of the follow-up period the B-cell maturation profile in individual patients remained unchanged. We identified six different aberrant peripheral B cell maturation profiles associated with different clinical characteristics. Patients with an early B-cell maturation block earlier required replacement therapy and were at significantly greater risk of enteropathy, granuloma formation, cytopenia, and lymphoproliferation. B-cell maturation inhibited at the natural effector stage was associated with higher risk of autoimmune manifestations other than autoimmune cytopenia. Prevalence of male patients was observed among patients with B-cell maturation inhibited at naive B-cell stage. In conclusion, the diagnostic process in patients with suspected early-onset CVID shall include routine analysis of peripheral B-cell maturation to provide surrogate markers identifying patients at greater risk of developing certain complications.

BACKGROUND There are only a few studies on immune response to pneumococcal vaccines in patients with inflammatory bowel disease (IBD); all of them assessed polysaccharide vaccines only. The aim of the study was to evaluate the immunogenicity and safety of 13-valent pneumococcal conjugate vaccine (PCV13) in IBD pediatric patients compared with healthy controls. METHODS This was a multicenter, prospective, and controlled study on children and adolescents aged 5 to 18 years with IBD with no history of pneumococcal immunization. The subjects for the study belonged to one of the following groups: patients with IBD on no immunosuppressive therapy (group A), those on tumor necrosis factor agents or immunomodulators (group B), and healthy controls (group C). The study population received 1 intramuscular injection of PCV13. The primary outcome measure was adequate vaccine response defined as postvaccination titer ≥0.35 μg/mL to all 13 serotypes. Geometric mean titers and geometric mean titer rises were measured for all serotypes. The evidence of local and systemic adverse effects for 5 days after the vaccine was registered. RESULTS A total of 178 subjects (122 patients and 56 controls) completed the study course. There was no significant difference in the rate of adequate vaccine response between patients with IBD and controls measured 4 to 8 weeks after vaccination (90.4% versus 96.5%, P = 0.5281). Children in group A had higher geometric mean titer rises than children in group B (P = 0.0369). There were no serious adverse events related to PCV13 during the study. CONCLUSIONS PCV13 is both immunogenic and safe in pediatric patients with IBD.