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Preterm birth has been associated with increased risk for developing hypertension and other chronic diseases during childhood and adulthood. The aim of the current prospective case-control study was to investigate the associations of preterm birth with ambulatory blood pressure (BP) levels and arterial stiffness during childhood and adolescence.The study population included 52 children and adolescents born preterm and 26 healthy children born full term with similar age. The participants underwent ambulatory BP monitoring (ABPM) and assessment of carotid-femoral pulse wave velocity (PWV).Preterm children presented higher night SBP z score values compared to controls, but did not differ in other ABPM parameters, office peripheral and central SBPs. Nocturnal hypertension was found in 78% (7/9) of ex-preterm children with ambulatory BP hypertension. Preterm birth was an independent predictor of PWV z score adjusted for heart rate. Estimated marginal means for PWV z score adjusted for age, sex, presence of kidney disease at birth, office BPs, night BPs, central SBP, and BMI z scores were significantly higher in preterm individuals compared to controls (0.703, 95% confidence interval [CI] 0.431-0.975 versus -0.19, 95% CI -0.574-0.536, respectively, P = 0.027). Preterm children who were overweight presented the highest values of night SBP and PWV z score.Preterm birth is associated with higher nocturnal BP and increased arterial stiffness in childhood and adolescence. Increased awareness for detection of hypertension and prevention of obesity in childhood could prevent future adverse cardiovascular outcomes in preterm individuals.

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

A term neonate presented with persistent severe thrombocytopenia, elevated liver enzymes, conjugated hyperbilirubinemia, hepatosplenomegaly, and mild hypotonia.A thorough workup for infections, congenital thrombocytopenias, and neonatal malignancies was negative. Because of increased anti-SARS-CoV-2 IgG antibodies after maternal Covid-19, multisystem inflammatory syndrome of neonates was considered and intravenous immunoglobulin was administered. The clinical condition of the neonate deteriorated and due to laboratory evidence of hyperinflammation, hemophagocytic lymphohistiocytosis was suspected, and treatment with etoposide and dexamethasone was initiated with temporary stabilization. Gaucher disease type 2 was eventually diagnosed.Gaucher disease can rarely present in neonates as hemophagocytic lymphohistiocytosis.

BACKGROUND AND AIMS This cross-sectional study investigates the association between adipokine profile, serum interleukin-6 (IL-6) levels and protein-energy wasting (PEW) in children with chronic kidney disease (CKD). METHOD Serum adiponectin, leptin, resistin and IL-6 were measured in 53 patients, with a median age of 12.9 years, presenting CKD stage 3–5. Body composition indices, lean tissue (LTI) and fat tissue index (FTI), were measured by bioimpedance analysis spectroscopy. PEW was defined as the presence of muscle wasting [LTI adjusted to height and age (LTI HA) Z-score RESULTS PEW was present in 8 (15.1%) patients. At least 1,2,3 and 4 PEW criteria were present in 25 (47.2%), 16 (30.2%), 9 (17%), 3 (5.6%) patients respectively. Among the PEW criteria, muscle wasting was present in 18 (34%), poor growth in 14 (30.2%), reduced appetite in 8 (15%) and low serum albumin in 13 (24.5%) patients respectively. PEW was more frequent in CKD stage 5 (P = .010). Adiponectin and resistin levels were higher in CKD stage 5 (P CONCLUSION In advanced paediatric CKD, adiponectin and resistin are probably involved in muscle wasting and systemic inflammation process respectively. Serum leptin reflects adiposity status. Apart from serum inflammatory cytokines, serum adiponectin may be a useful biomarker of PEW in children with CKD.

Despite advances in research, the pathophysiology of food allergy has not yet been fully elucidated. IL-10 has both a pro- and anti-inflammatory effect on the development of food allergy and in order to understand its different immune-modulatory effects the factors that influence the inflammatory microenvironment need to be taken into account. Specific single nucleotide polymorphisms of the IL-10 gene seem to confer an increased risk of developing food allergy, but to date there is a substantial lack of genome- wide association studies regarding the genetic and epigenetic underpinnings of the disease. Special interest has been drawn to the development of allergen-specific regulatory CD4+CD25+ T-cells secreting IL-10 in the immunotherapy of allergic diseases. In addition, a distinct population of human tolerogenic dendritic cells (DC), DC-10 seems to hold great potential and could potentially serve as a therapeutic tool to improve the management of food allergy.

A Knowledge, Attitudes and Practices (KAP) study was conducted at the end of May 2021 engaging 1456 healthcare workers (HCWs) from 20 hospitals throughout Greece. Acceptance of vaccination against coronavirus disease 2019 (COVID-19) was estimated at 77.7%, with lower vaccine acceptance identified in nurses compared to physicians. Fears related to vaccine safety, lack of information and general knowledge about vaccinations, influenza vaccine acceptance, education level and years of practice were among the factors independently associated with vaccine acceptance. A strong association was identified between vaccination of HCWs in each health region and the population coverage, indicating that HCWs may be role models for the general population. Information campaigns should continue despite decisions taken regarding mandatory vaccinations.

Objective: This single center cross-sectional study aims to investigate the association between secondary hyperparathyroidism and body composition in pediatric patients with moderate (stage 3) and advanced (stage 4–5) chronic kidney disease (CKD).Methods: 61 patients (median age: 13.4 years) were included. Body composition indices, including lean tissue index (LTI) and fat tissue index (FTI), were measured using multi-frequency bio-impedance spectroscopy. Muscle wasting was defined as LTI adjusted to height-age (HA) z-score < −1.65 SD and high adiposity as FTI z-score > 1.65 SD. Serum mineral metabolism parameters, including serum intact parathormone (iPTH), calcium, phosphorus and 25-hydroxyvitamin D, as well as serum leptin were measured in each patient. In advanced CKD patients, the mean values of serum mineral laboratory parameters of the 6 months prior to body composition assessment were recorded, and alfacalcidol index, defined as weekly alfacalcidol dose (mcg/week) per pg/ml of iPTH × 1,000, was calculated.Results: In moderate CKD (31 patients), high iPTH (>90 ng/ml) was observed in 10 (32.3%) patients and was associated with higher FTI z-score (p = 0.022). Moreover, serum iPTH was negatively correlated to LTI HA z-score (rs = −0.486, p = 0.006), and positively correlated to serum leptin levels (rs = 0.369, p = 0.041). The positive correlation between FTI z-score and iPTH (rs = 0.393, p = 0.039) lost significance after adjustment for serum leptin. iPTH was positively associated with high adiposity (12 patients, 38.7%) after adjustment for the other mineral metabolism parameters (OR 1.023, 95% CI 1.002–1.045, p = 0.028). In advanced CKD (30 patients), no significant correlation was observed between iPTH and body composition indices and serum leptin levels. Eleven (36.7%) patients with muscle wasting presented lower alfacalcidol index (p = 0.017). Alfacalcidol index ≤ 24 was strongly associated with muscle wasting after adjustment for CKD stage and other mineral metabolism parameters (OR 7.226, 95% CI 1.150–45.384, p = 0.035).Conclusion: Secondary hyperparathyroidism is associated with high adiposity in moderate but not in advanced CKD, with leptin acting as a potential contributive factor. In advanced CKD, targeting higher alfacalcidol weekly dose per each unit of serum PTH seems beneficial for preventing muscle wasting.

Congenital anomalies of the urinary tract, and particularly of obstructive nephropathy such as ureteropelvic junction obstruction (UPJO) in infants, can later lead to chronic kidney disease and hypertension. Fundamental questions regarding underlying mechanisms remain unanswered. The aim of the present study was to quantitate the systemic amino acids metabolome in 21 UPJO infants requiring surgery (Group A) and 21 UPJO infants under conservative treatment (Group B). Nineteen healthy age-matched infants served as controls (Group C). Serum amino acids involved in several pathways and representative metabolites, including the L-arginine-derived nitric oxide (NO) metabolites nitrite and nitrate and the lipid peroxidation biomarker malondialdehyde (MDA) were measured by gas chromatography–mass spectrometry (GC–MS) methods using their stable-isotope labeled analogs as internal standards after derivatization to their methyl esters N-pentafluoropropionic amides (amino acids) and to their pentafluorobenzyl derivatives (nitrite, nitrate, MDA). The concentrations of the majority of the biomarkers were found to be lower in Group A compared to Group B. Statistical analysis revealed clear differentiation between the examined study groups. Univariate statistical analysis highlighted serum homoarginine (q = 0.006), asymmetric dimethylarginine (q = 0.05) and malondialdehyde (q = 0.022) as potential biomarkers for UPJO infants requiring surgery. Group A also differed from Group B with respect to the diameter of the preoperative anterior–posterior renal pelvis (AP) as well as regarding the number and extent of inverse correlations between AP and the serum concentrations of the biomarkers. In Group A, but not in Group B, the AP diameter strongly correlated with hydroxy-proline (r = −0.746, p = 0.0002) and MDA (r = −0.754, p = 0.002). Our results indicate a diminished amino acids metabolome in the serum of UPJO infants requiring surgery comparing to a conservative group.

Familial Mediterranean Fever (FMF) is a genetic disorder of the innate immunity characterized by chronic inflammatory state. The diagnosis is mainly based on clinical criteria and supported by genotyping, especially in atypical phenotypes. The primary objective was to depict the Familial Mediterranean Fever (FMF) genotype of Greek patients and investigate the contribution of Next Generation Sequencing (NGS) beyond the contemporary techniques [(Polymerase Chain Reaction (PCR)/hybridization and Non-Isotopic RNase Cleavage Assay (NIRCA). The secondary objective was to unravel any associations between the mutated genes with the disease course and response to treatment. In this single center, retrospective study 31 patients with clinical diagnosis with FMF, but non-conclusive genetic analysis with PCR/hybridization and NIRCA, underwent NGS genotyping. PCR/NIRCA detected ≥ 1 mutation in 25/31 patients, most frequently M694V (29%), while NGS in 26/31 (83.9%), most frequently R202Q (61.3%). NGS genetically confirmed the clinical diagnosis (heterozygosity to compound or complex genotype) in 19 (61.3%) patients of our cohort. R202Q was significantly more prevalent by NGS than by contemporary techniques (61.3 vs 12.9%, p = 0.0002) and was associated with FMF. Rare mutations were detected by NGS in 19.2% patients. NGS clarifies the genetic profile of patients with atypical phenotypes and supports therapeutic management decisions. NGS unveiled the frequent involvement of R202Q in the pathogenesis of our FMF patients.

BACKGROUND Interleukin 10 has been shown to play a critical role in the regulation of the immune responses in allergic diseases. AIM To investigate if genetic polymorphisms in the promoter region of the IL-10 gene are associated with food allergy (FA) susceptibility in Caucasian pediatric patients with concomitant allergic diseases and IL-10 levels. METHODS The single nucleotide polymorphisms (SNPs) at -1082A > G (rs1800896), -819 T > C (rs1800871), and -592A > C (rs1800872) of 62 pediatric patients with IgE-mediated FA were analyzed and correlated with clinical parameters, serum IgE and IL-10 levels. The results were compared with those of 92 healthy controls without FA, personal and/or family history of atopy. RESULTS Analysis and comparison of genotype distributions, allele frequencies, and haplotypes showed that none of the genotypes confers an increased risk of FA. The genotype -1082 AA in FA patients was associated with moderate to severe symptoms of FA, the development of atopic asthma, and higher levels of IL-10. In a linear regression study, we confirmed that the genotype -1082 AA acts as an independent factor for the higher levels of IL-10. A positive association was also observed between -819T/C and -592 A/C SNPs and later onset of FA. CONCLUSION Polymorphisms in the promoter region of the IL-10 gene are not associated with FA susceptibility in our cohort. In FA patients, -1082 A/G SNPs seem to influence the production of IL-10, the severity of FA symptoms, and the development of atopic asthma in this population.

Background: The growing phenomenon of vaccine hesitancy and the severe economic crisis may have affected compliance with the National Immunization Program (NIP) in Greece over the last years. We investigated compliance with the NIP among children attending nurseries in the urban area of Thessaloniki. Methods: A cross-sectional study was conducted, including nursery attendees born between 01/01/2014-01/10/2015 in each of the municipalities of Thessaloniki urban area. Public and private nurseries were randomly selected. Immunization data were anonymously collected from the child’s health booklet. Both coverage and timeliness of immunization were recorded for all recommended vaccines according to the NIP. Results: In total, 432 children with a mean age of 2.9 years were studied, of which 245 (57 %) were attending private nurseries. Full coverage was >90 % for most of the recommended vaccines except for pneumococcal (81 %), meningococcal serogroup C (68.3 % and 82 % for 2011 and 2015 schedule, respectively), hepatitis A (38.9 %) and rotavirus (25.9%) vaccine. Delay rates for one or more doses ranged between 21-90.3 % for all vaccines; time of median delay ranged between 3.8-6.7 months. Lower coverage and higher delay rates were observed for Roma children. Conclusions: While high coverage appears to be sustained for most of the recommended vaccines, delay of scheduled shots may compromise age-appropriate protection. Suboptimal immunization against pneumococcal, meningococcal serogroup C, hepatitis A, and rotavirus infections may increase morbidity in this age group and needs to be addressed. HIPPOKRATIA 2019, 23(4): 147-153.

Ureteropelvic junction obstruction (UPJO) constitutes the predominant cause of obstructive nephropathy in both neonates and infants. Fundamental questions regarding UPJO's mechanism, assessment, and treatment still remain unanswered. The aim of the present study was to elucidate potential differences through serum metabolic profiling of surgical cases of infants with UPJO compared to both nonsurgical cases and healthy age-matched controls. Early diagnosis of renal dysfunction in this cohort based on highlighted biomarkers was the ultimate goal. Thus, serum samples were collected from 20 patients preoperatively, 19 patients with mild stenosis treated conservatively, and 17 healthy controls. All samples were subjected to targeted metabolomics analysis by hydrophilic interaction liquid chromatography coupled to mass spectrometry (HILIC LC-MS/MS). Both univariate and multivariate statistical analyses were performed. Principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) score plots showed that the studied groups differed significantly, with a panel of metabolites, including creatinine, tryptophan, choline, and aspartate, distinguishing patients who required surgery from those followed by systematical monitoring as well as from healthy controls, showing high performance as indicators of UPJO disease.

Background: Complement dysregulation has been documented in the molecular pathophysiology of COVID-19 and recently implicated in the relevant pediatric patient inflammatory responses. Aims: Based on our previous data in adults, we hypothesized that signatures of complement genetic variants would also be detectable in pediatric patients exhibiting COVID-19 signs and symptoms. Methods: We prospectively studied consecutive pediatric patients from our COVID-19 Units (November 2020-March 2021). COVID-19 was confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR). Patient data were recorded by treating physicians that followed patients up to discharge. DNA was obtained from peripheral blood samples. Probes were designed using the Design studio (Illumina). Amplicons cover exons of complement-associated genes (C3, C5, CFB, CFD, CFH, CFHR1, CFI, CD46, CD55, MBL2, MASP1, MASP2, COLEC11, FCN1, FCN3 as well as ADAMTS13 and ΤHBD) spanning 15 bases into introns. We used 10ng of initial DNA material. Libraries were quantified using Qubit and sequenced on a MiniSeq System in a 2x150 bp run. Analysis was performed using the TruSeq Amplicon application (BaseSpace). Alignment was based on the banded Smith-Waterman algorithm in the targeted regions (specified in a manifest file). We performed variant calling with the Illumina-developed Somatic Variant Caller in germline mode and variant allele frequency higher than 20%. Both Ensembl and Refseq were used for annotation of the output files. A preliminary analysis (A) for the identification of variants of clinical significance was based on annotated ClinVar data, while a further and more selective analysis (B) was performed to identify missense complement coding variants that may biochemically contribute to the deregulation of innate responses during infection. This analysis was mainly based on the dbSNP and UniProt databases and available literature. Results: We studied 80 children and adolescents, 8 of whom developed inflammatory syndromes (MIS-C group). Among them, 41 were hospitalized and eventually all survived. In our preliminary analysis, patients exhibited heterogeneous variant profiles including pathogenic, benign, likely benign, and variants of unknown significance (median number of variants: 97, range: 61-103). We found a variant of ADAMTS13 (rs2301612, missense) in 39 patients. We also detected two missense risk factor variants, previously detected in complement-related diseases: rs2230199 in C3 (33 patients); and rs800292 in CFH (36 patients). Among them, 40 patients had a combination of these characterized variants. This combination was significantly associated with the presence of dyspnea (p=0.031) and cough (p=0.042). Furthermore, 27 patients had a pathogenic variant in MBL2 (rs1800450), and 7 a pathogenic deletion in FCN3 that have been previously associated with inflammatory syndromes.The results of our further analysis are summarized in Figure. We identified common variants, some well represented by relatively high frequencies (>70%) (rs11098044 in CFI, rs1061170 in CFH and rs12711521 in MASP2) and others less abundant, but varying considerably between the hospitalized group, the non-admitted group and the MIS-C individuals (rs2230199 in C3, rs1065489 in CFH, rs12614 and rs641153 in CFB, rs1800450 in MBL2, rs2273346 and rs72550870 in MASP2, rs72549154 in MASP3 and rs7567833 in COLEC11, all highlighted in Figure in red).). Structurally, the majority of these common variants of interest encode charge reversal mutations. These may influence protein-protein interactions in complex formations that are important for complement activation and/or regulation. Conclusion: In pediatric COVID-19 we have detected a novel set of complement missense coding variants some of which have been implicated earlier in inflammatory syndromes and endothelial stress responses. Certain combinations of mutations of alternative and/or lectin pathway components may increase the threshold dynamics of complement consumption and therefore alter COVID-19 phenotypes. Figure 1 Figure 1. Disclosures Gavriilaki: Alexion, Omeros, Sanofi Corporation: Consultancy; Gilead Corporation: Honoraria; Pfizer Corporation: Research Funding. Anagnostopoulos: Abbvie: Other: clinical trials; Sanofi: Other: clinical trials ; Ocopeptides: Other: clinical trials ; GSK: Other: clinical trials; Incyte: Other: clinical trials ; Takeda: Other: clinical trials ; Amgen: Other: clinical trials ; Janssen: Other: clinical trials; novartis: Other: clinical trials; Celgene: Other: clinical trials; Roche: Other: clinical trials; Astellas: Other: clinical trials .

Background and objectives: Monoallelic (heterozygous) or biallelic (homozygous or compound heterozygous) TACI mutations have been reported as the most common genetic defects in patients with common variable immunodeficiency (CVID), which is the most common clinically significant primary immunodeficiency in humans. The aim of our study was to evaluate the prevalence and any correlations of TACI defects in Greek patients with primary antibody deficiencies. Materials and Methods: 117 patients (male/female: 53/64) with CVID (110) and a combined IgA and IgG subclass deficiency (7) with a CVID-like clinical phenotype were enrolled in the study. Genomic DNA was extracted from peripheral blood and the molecular analysis of the TACI gene was performed by PCR (Polymerase Chain Reaction) and sequencing of all 5 exons, including exon–intron boundaries. Results: Seventeen patients (14.5%) displayed TACI defects, four (23.5%) carried combined heterozygous mutations and 13 (76.5%) carried single heterozygous mutations. The most frequently detected mutation was C104R (58.8%), followed by I87N (23.5%) and A181E (11.8%), while R20C, C62Y, P151L, K188M and E236X mutations were present in only one patient each. Patients with TACI defects were more frequently male (p = 0.011) and displayed a benign lymphoproliferation (splenomegaly and lymph node enlargement, p = 0.047 and p = 0.002, respectively), had a history of tonsillectomy (p = 0.015) and adenoidectomy (p = 0.031) and more frequently exhibited autoimmune cytopenias (p = 0.046). Conclusions: Considering that accumulating evidence suggests several CVID patients have a complex rather than a monogenic inheritance, our data further support the notion that TACI mutations, particularly as monoallelic defects, should be primarily considered as susceptibility co-factors and/or modifiers of primary antibody deficiencies.

Summary The discovery of serum biomarkers specific for paediatric lupus nephritis (pLN) will facilitate the non-invasive diagnosis, follow-up and more appropriate use of treatment. The aim of this study was to explore the role of serum high-mobility group box 1 (HMGB1) protein, antibodies against nucleosomes (anti-NCS), complement factor C1q (anti-C1q) and glomerular basement membrane (anti-GBM) in pLN. Serum samples of 42 patients with paediatric systemic lupus erythematosus (pSLE) (22 with pLN and 20 without renal involvement), 15 patients with other autoimmune nephritis (AN) and 26 healthy controls (HCs) were examined using enzyme-linked immunosorbent assay (ELISA). The activity of both pSLE and pLN was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) tool. The levels of all four biomarkers were significantly higher in pLN compared to AN and to HCs. The anti-NCS, anti-GBM and HMGB1 serum levels were significantly higher in pLN than in pSLE without renal involvement. The anti-C1q and the HMGB1 serum levels were correlated positively with pSLE activity. The HMGB1 serum levels were also correlated positively with pLN activity. These findings suggest that serum anti-NCS, anti-GBM and HMGB1 may serve as biomarkers specific for the presence of nephritis in pSLE. HMGB1 emerged as a useful biomarker for the assessment of pLN and pSLE activity, whereas anti-C1q only of pSLE activity.

Background Atopic dermatitis (AD) is an inflammatory disease of the skin, which is characterised by a chronic relapsing course. Aim The aim of the study was to assign the prevalence of clinically active food allergies among a group of children between 3 months and 7 years of age, with AD. Methods Eighty-eight children with AD were screened for specific IgE antibodies to food proteins. All patients with AD and specific IgE antibodies to food proteins were subjected to Oral Food Challenges (OFCs) with the relevant foods. Results Food-sensitised patients with moderate levels of sIgE had clinically active food allergy to milk (39.28%) and egg (42.34%) on the basis of positive OFCs. High IgE and eosinophilia had a prevalence of almost 80% and 25%, regardless of concomitant food sensitisation and disease severity. Conclusions In this study, clinically active food allergies were recognised in 26.13% of children with AD. Nevertheless, no association was confirmed between food sensitisation and AD severity. High IgE and peripheral eosinophilia have not been found more prevalent among children with severe AD nor among children with food sensitisation. Infants and younger children with AD should be screened for an underlying food allergy, regardless of disease severity.

AimsThe causes and diagnosis of ‘double-negative’ (CD3+CD4−CD8−) T-cell lymphocytosis are not well studied. We aimed to define the causes of double-negative T-cell lymphocytosis in children and adults, and to identify simple clinical and laboratory features that would help to differentiate between the underlying conditions.MethodsWe collected clinical and laboratory data on 10 children and 30 adults with significantly increased peripheral-blood double-negative T-cells (>10% of total lymphocytes). We identified conditions associated with double-negative T-lymphocytosis with flow cytometry, peripheral-blood morphology and T-cell receptor-gene rearrangement studies. Patients were assigned to diagnostic categories on the basis of these test results.Results and conclusionsThe causes of double-negative T-cell lymphocytosis in children were autoimmune lymphoproliferative syndrome (ALPS) and reactive γ/δ Τ-lymphocytosis. T-cell large granular lymphocyte (T-LGL) leukaemia, reactive γ/δ T-lymphocytosis and hepatosplenic T-cell lymphoma (HSTL) were the the most common disorders underlying double-negative T-cell lymphocytosis in adults. Less common causes included hypereosinophilic syndrome, peripheral T-cell lymphoma, ALPS and monoclonal, double-negative T-lymphocytosis of uncertain significance. CD5/CD7/Vδ2 expression and absolute double-negative lymphocyte count (9/L) were useful discriminators for distinguishing patients with reactive γ/δ T-lymphocytosis from those with γ/δ lymphoproliferative disorders. Differentiating between γ/δ T-LGL and HSTL can be difficult. Expression of CD57 and cellular morphology (pale cytoplasm with distinct granules) would support a diagnosis of γ/δ T-LGL.

The immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare, x-linked, recessive disorder characterized by dysfunction of the T regulatory (Treg) lymphocytes leading to autoimmune diseases. Herein we report a male patient with IPEX syndrome who presented with severe diarrhea, eczema, and malabsorption leading to failure to thrive and necessitating total parenteral nutrition, as well as with liver dysfunction. Laboratory investigation showed elevated liver enzymes that declined following treatment with glucocorticosteroids and immunosuppressive drugs, marked eosinophilia, increased total IgE, and decreased Treg cells. DNA analysis revealed that the patient himself was hemizygous and his mother heterozygous for the exon 10, c.1015C>T (p.Pro339Ser) mutation of the FOXP3 gene, which has not been previously reported. The current case indicates that mutations resulting in substitution of a certain amino-acid (i.e., proline 339) by different amino-acids are manifested with different IPEX phenotypes.

The ideal management of ureteropelvic junction obstruction (UPJO) remains debatable. This prospective case-control study aimed to investigate if urinary levels of Neutrophil Gelatinase-Associated Lipocalin (NGAL) and serum levels of cystatin C could distinguish surgical from non-surgical cases of UPJO and if they could detect earlier impairment of renal function. Biomarkers were measured in the following age-matched groups: (a) 22 infants with surgical UPJO, at initial diagnosis and 12 months postoperatively (groups A1 and A2, respectively); (b) 19 infants with non-surgical UPJO (group B); and (c) 17 controls (group C). Based on serum cystatin C levels, estimated glomerular filtration rate (eGFR) was calculated. Urinary NGAL (uNGAL) was significantly higher in group A1 vs. group A2 (p = 0.02) and in group A1 vs. group C (p = 0.03), whereas there was no statistically significant difference between groups A2 and C (p = 0.77). Likewise, cystatin C levels were significantly higher in group A1 vs. group A2 and in group A1 vs. group C (p = 0.004 and p = 0.02, respectively), but no statistically significant difference between groups A2 and C (p = 0.82). uNGAL and serum cystatin C did not differ between groups B and A, nor did they differ between groups B and C. Cystatin C levels and eGFR of group A1 were significantly higher than those of group A2 and group C (p = 0.0001 and p = 0.02, respectively). It seems that NGAL and cystatin C are able to distinguish patients who were treated surgically from healthy controls, and their levels appear to improve significantly following surgery.

Measles outbreaks have surfaced in Europe during the last decades. Infants &lt, 12 months of age were the most severely affected pediatric population. The aim of this study was to investigate the duration of maternally derived measles antibodies in infants aged 1 to 12 months in relation to maternal humoral immune status and other parameters. In a prospective, cross-sectional cohort study, 124 mother/infant pairs and 63 additional infants were recruited from October 2015 through December 2019. Infants were hospitalized in a university pediatric department of a general hospital. Demographic and epidemiological data were recorded and blood samples were collected from mothers and their infants. Commercially available enzyme-linked immunosorbent assay (ELISA) was used for measuring measles antibodies. Fifty nine percent of mothers had vaccine-induced and 15% infection-acquired measles immunity. Eighty-eight percent and 94% of infants were unprotected by 5 and 10 months of age, respectively. Maternal antibody levels and infant age were significant independent predictors of infants’ antibody levels whereas the method of maternal immunity acquisition, age, and origin [Greek/non-Greek] were not. Our findings suggest that about 90% of infants are susceptible to measles beyond the age of 4 months. To our knowledge, these are the first data from Greece reported under the current community composition and epidemiological conditions.

To assess longitudinally the course and outcome of juvenile idiopathic arthritis (JIA) in patients diagnosed and followed-up exclusively in the biologic era; also, to define possible predictors of the disease progression and need for early implementation of biologicals. Prospective and retrospective, monocentric cohort study of 120 JIA patients, diagnosed between 2001 and 2010, and followed-up for ≥ 4 years (median 8.04). Disease activity, cumulative articular/extra-articular damage and quality of life were evaluated by the assessment tools Juvenile Arthritis Disease Activity Score (JADAS71), Juvenile Arthritis Damage Index (JADI) and Childhood Health Assessment Questionnaire (CHAQ), respectively. Moreover, potential predictors of the disease progression and their relation to biologic therapy were investigated. High JADAS71 score (> 9) at diagnosis was indicative of progression to polyarticular course and the need for early introduction of biologic treatment. Other independent predictors of progression to polyarthritis, were: involvement of upper limb, hip and ankle within 6 months following JIA diagnosis and percentage of cumulative time with active disease > 35% within the first year. At the end of the study, both the median JADAS71 score and the Disability Index were significantly lower than the initial (p

Current knowledge on the human pathophysiology of fungal infections highlights the crucial role of genetic pitfalls in specific immunity pathways that determine, together with other risk factors, the predisposition to and clinical outcome of fungal disease. In several studies, associations between gene polymorphisms and genetic errors have been implicated in an immunodeficiency phenotype and an increased incidence of opportunistic fungal diseases. The major challenge is to fully understand the complex interactions between genetic variations and multiple factors, and their relative contributions to the final clinical fungal disease phenotype. The aim of this review is to present updated knowledge on immunity genetics and susceptibility to medically relevant fungal diseases, such as those caused by Candida, Aspergillus, and certain other more rare fungi.

Patients with common variable immunodeficiency (CVID) develop autoimmune hematologic manifestations. We report a 14-year-old boy with Evans syndrome, who presented at the age of 11.5 years with autoimmune hemolysis and was successfully managed with corticosteroids. Initially, the serum immunoglobulins were within the low-normal range for age, but two years after presentation he definitely fulfilled the diagnostic criteria for CVID, despite a negative history for serious infections. DNA sequencing by PCR of the TNFSRF13B gene that encodes the TACI receptor disclosed the heterozygous mutation C104R that is found in approximately 10–15% of patients with CVID. Common variable immunodeficiency should be considered in the differential diagnosis of autoimmune hematologic manifestations, since its timely diagnosis may considerably affect clinical management and patient outcome.

Sialic acid acetylesterase (SIAE) deficiency was suggested to lower the levels of ligands for sialic acid-binding immunoglobulin-like receptors, decreasing the threshold for B-cell activation. In humans, studies of rare heterozygous loss-of-function mutations in SIAE gene in common autoimmune diseases, including juvenile idiopathic arthritis (JIA), yielded inconsistent results. Considering the distinct pathogenesis of the two main subtypes of JIA, autoinflammatory systemic (sJIA) and autoimmune oligo/polyarticular (aJIA), and a predisposition to autoimmunity displayed by patients and families with primary antibody deficiencies (PADs), the aim of our study was to analyze whether SIAE rare variants are associated with both the phenotype of JIA and the autoimmunity risk in families with PADs. A cohort of 69 patients with JIA, 117 healthy children, 54 patients, and family members with PADs were enrolled in the study. Three novel SIAE variants (p.Q343P, p.Y495X, and c.1320+33T>C) were found only in patients with aJIA but interestingly also in their healthy relatives without autoimmunity, while none of PAD patients or their relatives carried SIAE defects. Our results show that SIAE rare variants are not causative of autoimmunity as single defects.

Background We aimed to investigate whether the presence of mannose binding lectin (MBL2), ficolin 2 (FCN2) polymorphisms or the combined deficiency significantly influence the risk and subsequently the frequency of chemotherapy-induced bacterial infections in children with B acute lymphoblastic leukemia (B-ALL). Procedure MBL2 polymorphisms for exon 1 and FCN2 polymorphisms for promoter regions −986, −602, −557, −64, −4 and exon 8 regions +6,359, +6,424 were determined in children with B-ALL. FCN2 haplotype was determined by gene sequencing. Number and duration of FN episodes as well as number of bacterial infections were recorded during induction chemotherapy. Results Forty-four children with B-ALL (median age 4.3 years, 65.9% males) suffered from 142 FN episodes and 92 bacterial infections (40.2% Gram positive and 59.8% Gram negative). MBL2 low-risk genotype was found in 59.1%, medium-risk in 31.8% and high-risk in 9%. FCN2 low-risk haplotypes were detected in 38.2%, medium-risk in 44.1% and high-risk in 17.6%. MBL2 genotype and FCN2 haplotype were not associated with increased frequency of FN episodes. MBL2 medium/high-risk genotype and FCN2 medium/high-risk haplotype were associated with prolonged duration of FN (P = 0.007 and P = 0.001, respectively) and increased number of bacterial infections (P = 0.001 and P = 0.002, respectively). The combined MBL2/FCN2 medium/high-risk genotype was associated with an increased number of bacterial infections (P = 0.001). Conclusions MBL2 and FCN2 single or combined deficiencies are associated with increased duration of FN episodes as well as increased number of bacterial infections in children with B-ALL suggesting a prognostic role of these genes. Pediatr Blood Cancer 2014;61:1017–1022. © 2014 Wiley Periodicals, Inc.

The current European Society for Immunodeficiencies (ESID) registry was established 10 years ago in 2004, when the system was moved from a paper-based to an online system. The purpose of the registry is to collect data on European patients with primary immunodeficiencies (PIDs) and their treatment, with the aim of building an easily accessible database for use by physicians and researchers. During the 10 years for which the current registry has been operational, the number of patients registered has grown substantially; after 4 years, more than 7000 patients were registered and, as of 25 June, 19 355 patients are registered in Europe as having a PID. Longitudinal data (20 or more data sets, documented every 6 months) is now available for some of the patients in the registry. Children younger than age 15 years represent two-thirds of this cohort. More than half the patients (57%) have an antibody disorder, and this is also the group with the greatest number of adult patients. Of the 19 355 registered, treatment data are available on approximately 14 000, of whom 6476 receive immunoglobulin (Ig) treatment; 4239 patients are receiving intravenous immunoglobulin (IVIg) treatment and approximately 2181 receive subcutaneous immunoglobulin (SCIg). One of the interesting comparisons arising from the registry data is the difference in minimum prevalence of PIDs between countries. In France, for example, 6·058 cases are documented per 100 000 inhabitants; much higher than in Switzerland (4·157 per 100 000) or Germany (2·105 per 100 000). This is most probably because France has a very efficient documenting system, whereby designated documenters, financed by local grants in France, visit centres to enter patients' data into the registry. Thus, the more efficient the documenting system, the higher the quality of data collected. Physicians and researchers can apply for access to the registry data by writing to ESID with details of their specific project, or with a proposal to collect new and different data on patients with specific diseases. Despite the large number of patients in the registry and the large amount of data collected, only 23 papers have been published, which is an average of more than two per year over 10 years. However, considering that more than 200 physicians and researchers have access to the database, this still means that the registry is one of the most under-used data sets of its kind in Europe. In a recent registry publication we analysed the subset of common variable immunodeficiency (CVID) subjects 1. There are more than 4000 CVID subjects in the registry, but because not all have complete data sets, the cohort described in this paper included 2212 subjects. As CVID has a variable clinical presentation, we investigated the frequencies of different disease phenotypes in the cohort 1. The most common clinical features were pneumonia (32%) and autoimmunity (29%). Other features included splenomegaly (26%), bronchiectasis (23%) and granulomatous disease (10%), and a further 10% had enteropathy. Surprisingly, 5% of patients had solid tumours and 4% had meningitis/encephalitis [conditions associated more usually with X-linked agammaglobulinaemia (XLA)]. Less frequent clinical features were lymphoma, found in 3% of the patients, splenectomy in 2% and lobectomy in 1%. With regard to how efficiently patients are being diagnosed, CVID has been described as having a bi-modal age of manifestation, with a peak in diagnoses between the ages of 5 and 10 years, a trough around the age of 20, and then another peak between 30 and 40 years. However, when patients are asked about the onset of their symptoms the reported age is lower, with most patients experiencing recurrent infections in childhood, and fewer than half manifesting after age 20 (Fig. 1). In some countries, the delay between onset of symptoms and CVID diagnosis is greater than others, the average being 4·1 years, ranging from 1·8 years in Poland to 7 years in France 1. Figure 1 (a) Age at onset of symptoms in the total cohort (n = 1914), among female patients (n = 985) and among male patients (n = 929). (b) Age at diagnosis in the total cohort (n = 2134), among ... We showed that adult CVID cases were diagnosed more promptly than paediatric cases (aged

WOS: 000398771800023, PubMed ID: 27697500, Background: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. Objectives: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. Methods: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. Results: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 +/- 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. Conclusion: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates., Jeffrey Modell Foundation; National Institutes of Health Office of Rare Diseases, National Center for Advancing Translational Sciences and National, Institute of Allergy and Infectious Disease [U54 AI 082973, R13AI094943], Supported by a grant from Jeffrey Modell Foundation (to M.d.l.M.). The Primary Immune Deficiency Treatment Consortium (PIDTC) is supported by the National Institutes of Health Office of Rare Diseases, National Center for Advancing Translational Sciences and National, Institute of Allergy and Infectious Disease grants U54 AI 082973 and R13AI094943.

Background: The Paediatric Allergic Rhinitis Quality of Life Questionnaire (Ped-AR-QoL) is the first tool developed for the assessment of health-related quality of life (QoL) in Greek children with allergic rhinitis (AR). Objective: The aim of the current study was to validate the child and parent forms of the Ped-AR-QoL in children aged 6-14 years-old who suffered from AR and were followed in a pediatric allergy clinic. Methods: The Ped-AR-QoL, which was completed by 112 children and their parents, was correlated to the generic QoL questionnaire (Disabkids), which is already valid in Greece for children with chronic disorders, as well as with expert opinions on the severity of disease. Results : The Ped-AR-QoL child and parent forms had very good internal consistency (α values of 0.797 and 0.872, respectively), while there was a moderate positive correlation of the disease-specific questionnaire with most of the subscales of the generic questionnaire. There has been a statistically significant association between the Ped-AR-QoL and the expert perception of disease severity. Conclusions: The Ped-AR-QoL had very good reliability and convergent validity when compared with the generic Disabkids QoL. The significance of association between the disease-specific questionnaire and the expert opinion is an important finding validating the questionnaire. The Ped-AR-QoL may become a helpful tool which can be used in everyday clinical practice by clinicians and it may also be used for assessing therapeutic interventions in clinical trials. DOI 10.12932/ AP0651 .34.2. 2016

Our aim was to evaluate bone status in boys with haemophilia using dual energy X-ray absorptiometry (DXA) and quantitative ultraSonography (QUS), and in addition, to compare these two methods with the use of biochemical markers of bone turnover. Twenty-six boys with a mean decimal age of 12.08 ± 4.44 years were included in the study which included a DXA scan at lumbar spine and radial, as well as tibial QUS. Serum levels of soluble receptor activator of nuclear factor κB ligand (sRANK-L), osteoprotegerin (OPG) and osteocalcin (OC) were measured and joint evaluation was performed using the Hemophilia Joint Health Score (HJHS). With regard to the study results, only 2 of 26 patients (7.7%) had bone mineral density (BMD) Z-scores < -2, and 4 patients (15.4%) had BMD Z-scores between -1 and -2. Only one patient had radial and other two had tibial QUS Z-scores < -2. No agreement was recorded between QUS and DXA in identifying patients at risk for osteoporosis (k = 0.275, P = 0.063). Haemophiliacs had significantly higher serum levels of sRANK-L (21.04 ± 4.78 vs. 18.58 ± 2.28 ng mL(-1), P = 0.038) and of OC (5.35 ± 2.29 vs. 3.09 ± 0.61 ng mL(-1), P = 0.002) and significantly decreased levels of OPG (15.78 ± 2.53 vs. 23.79 ± 4.39 pg mL(-1), P < 0.001) compared with controls. QUS Z-scores at tibia significantly correlated with HJH Scores (r = -0.450, P = 0.040), whereas lumbar BMD Z-scores significantly correlated with body mass index Z-scores (r = 0.500, P = 0.009). More studies are warranted to identify the most accurate densitometric method for assessing bone status in haemophiliacs.