Evaluation of treatment and long-term management of anaphylaxis in pediatric departments of Greece: a 2-year nationwide survey.

BACKGROUND: Anaphylaxis proportions of incidence are increasing globally. However, limited data are available regarding anaphylaxis in the pediatric population of Greece. PURPOSE: The aim of the study was to evaluate management of anaphylaxis in Greek pediatric departments. METHODS: We performed a questionnaire-based study of children aged less than 16 years presenting with anaphylaxis in 10 national pediatric hospitals over a period of 2 years. Management of anaphylaxis was assessed prior to and after an informative intervention. RESULTS: In all, 127 cases of anaphylaxis were identified. Epinephrine was administered in almost half of all cases (51.2%), predominantly through intramuscular route (88.5%), while the majority of anaphylaxis patients were treated with antihistamines (92.9%) and corticosteroids (70.1%). Epinephrine was more likely administered by physicians if the elicitor was a drug (P < 0.003). Regarding long-term management, an epinephrine auto-injector was prescribed in 66.9% of patients. Follow-up information was available for most of the patients (92.9%), the majority of whom (76.3%) were referred to an allergist. More than half of these patients (63.6%) had a documented allergy follow-up, which identified a causative allergen in 53.3% of cases. No statistically significant differences were recorded prior to and after the intervention regarding management of anaphylaxis. CONCLUSIONS: This nationwide study highlighted the necessity of further improvement in terms of anaphylaxis treatment and secondary prevention measures. This presupposes appropriate education and training of healthcare professionals, thus contributing to proper and comprehensive care of the pediatric population.

Role of FGF21 and Leptin for the Diagnosis of Metabolic Health in Children with and without Obesity.

Obesity and unfavorable metabolic profiles increase the risk for cardiovascular complications in adults. Although it is important to distinguish different metabolic health states at an early stage, there are limited data on the related value of biomarkers in childhood. We aimed to identify biomarkers for the detection of different metabolic health states in children with and without obesity. The serum levels of metabolic regulators (fibroblast growth factor 21 [FGF21], leptin, adiponectin and insulin-like growth factor binding protein 1) and vascular indices (flow-mediated dilation [FMD] and carotid intima-media thickness) were assessed in 78 children. Differences between the metabolically healthy and unhealthy state within children with normal weight (MHN vs. MUN), and within children with overweight/obesity (MHO vs. MUO) were investigated; the discriminatory power of the biomarkers was studied. Both MUN and MUO groups expressed altered lipid and glucose homeostasis compared to their healthy counterparts. The metabolic unhealthy state in children with normal weight was linked to higher FGF21 levels which had good discriminatory ability (area under the curve [AUC]: 0.71, 95% CI: 0.54-0.88; p = 0.044). In overweight/obese children, leptin was increased in the metabolically unhealthy subgroup (AUC: 0.81, 95% CI: 0.68-0.95; p = 0.01). There was a decrease in FMD indicating worse endothelial function in overweight/obese children versus those with normal weight. Distinct states of metabolic health exist in both children with normal weight and overweight/obese children. FGF21 and leptin may help to identify the metabolic unhealthy state in children with normal weight and in overweight/obese children, respectively, early in life.

Association of fibroblast growth factor 21 with metabolic syndrome and endothelial function in children: a prospective cross-sectional study on novel biomarkers.

PURPOSE: Metabolic and cardiovascular disease prevention starting in childhood is critical for reducing morbidity later in life. In the present study, the association of novel biomarkers with metabolic syndrome (MS) and vascular function/structure indices of early atherosclerosis in children was investigated. METHODS: This was a prospective study of 78 children (8-16 years of age) grouped based on the presence or absence of MS. The serum biomarkers investigated included fibroblast growth factor 21 (FGF21), leptin, adiponectin, and insulinlike growth factor binding protein-1 (IGFBP1). Endothelial function and carotid atherosclerosis were assessed based on brachial artery flow-mediated dilation (FMD) and carotid intima-media thickness, respectively. RESULTS: Children with MS (n=12) had higher levels of FGF21 (median [interquartile range]: 128 [76-189] pg/mL vs. 60 [20-98] pg/mL, P=0.003) and leptin (18.1 [11-34.8] pg/mL vs. 7.5 [1.9-16.5] ng/mL, P=0.003), and lower levels of IGFBP1 (1.5 [1.2-2.1] ng/mL vs. 2.3 [1.5-6] ng/mL, P=0.028) compared with children without MS. FMD inversely correlated with FGF21 (Spearman rho= -0.24, P=0.035) and leptin (rho= -0.24, P=0.002) in all children. The best cutoff value of FGF21 levels for MS diagnosis was above 121.3 pg/mL (sensitivity/specificity, 58/86%). Only FGF21 was significantly associated with the presence of MS after adjustment for body mass index, age, and sex (odds ratio per 10 pg/mL increase: 1.10 [95% confidence interval, 1.01-1.22]; P=0.043). CONCLUSION: Increased FGF21 levels were associated with the presence of MS and worse endothelial function in children. Larger studies are needed to evaluate the potential value of FGF21 as a biomarker that could predict future metabolic/cardiovascular disease at an early stage.

A refugee child with multiple patterned ecchymoses: a diagnostic dilemma between nonaccidental injury and primary hemostatic defect.

A 4-year-old girl from Syria presented to the hospital with multiple bruises on her body. Bruises were observed in protected areas in a shape of fingerprints and objects, while no other bruises occurred during hospitalization. The parents also reported a history of bleeding diathesis from infancy. Both the initial laboratory evaluation and the secondary tests done for possible thrombocytopenia and coagulation factors deficiencies were normal. Thus, the nonaccidental injury protocol of the Hospital was activated, and the possibility of abuse was not quite evident. Investigation for platelet disorders followed. Platelet aggregation test and flow cytometry were indicative of Glanzmann's thrombasthenia. It is of great importance in these cases, that the doctor eliminates any possibility of physical abuse and examines the patient for common and rare primary hemostatic defects, although both can co-exist.

A Novel εγδß-Thalassemia Deletion Associated with Severe Anemia at Birth and a ß-Thalassemia Intermedia Phenotype Later in Life in Three Generations of a Greek Family.

We describe a novel deletion causing heterozygous εγδß-thalassemia (εγδß-thal) across three generations of a Greek family. The Greek deletion is about 72 kb in length, spanning from the hypersensitive site 4 (HS4) in the locus control region (LCR) to the 3' end of the ß-globin gene, thus encompassing the entire ß-globin gene cluster. The deletion caused severe but transient neonatal anemia and a non transfusion-dependent chronic hemolytic anemia state later in life, resembling mild ß-thalassemia intermedia (ß-TI) rather than ß-thalassemia (ß-thal) trait, as had been previously reported. Apart from the presentation of clinical and laboratory characteristics, the challenges involving clinical management are also discussed.

Cyanosis Due to Methemoglobinemia as the Presenting Sign of Glucose-6-Phosphate Dehydrogenase Deficiency in a Child: Diagnostic and Clinical Implications.

A previously healthy 3-year-old boy presented with pallor, jaundice, cyanosis, and a 24-hour history of vomiting and anorexia following fava bean ingestion. Clinical examination and laboratory findings were consistent with severe nonimmune hemolytic anemia with methemoglobinemia. Given the patient's history, a previously unrecognized glucose-6-phosphate dehydrogenase deficiency was suspected and diagnosed. The aim of this article is to delineate the possible coexistence of methemoglobinemia and glucose-6-phosphate dehydrogenase deficiency in children presented with acute hemolysis and discuss its management while reviewing the existing literature.

Elevated 1-hour post-load plasma glucose identifies obese youth with abnormal glucose metabolism and an unfavourable inflammatory profile.

CONTEXT: Adults with plasma glucose levels at one hour (1h-GL) ≥8.6 mmol/L during an oral glucose tolerance test (OGTT) are at increased risk for type 2 diabetes mellitus and present an unfavourable cardiometabolic and inflammatory profile, but relevant data on children are scarce. OBJECTIVE: To investigate if elevated 1h-GL during OGTT in obese children and adolescents is associated with insulin resistance and specific pro-inflammatory biomarkers. RESEARCH DESIGN AND METHODS: The study group comprised 88 obese children who attended the Outpatient Pediatric Clinic of our Hospital between January and December 2016. Children were divided into two groups according to 1h-GL during an OGTT: group 1 (n = 57) consisted of those with 1h-GL <8.6 mmol/L and group 2 (n = 31) of those with 1h-GL ≥8.6 mmol/L. Arterial blood pressure, body mass index (BMI) and waist circumference (WC) z-scores were measured in all participants. Specific insulin resistance (IR) indices, that is HOMA-IR, Matsuda index and Cederholm insulin sensitivity index (ISI) were calculated. Further, pro-inflammatory biomarkers that have been correlated with obesity complications, namely adiponectin, leptin, visfatin and interleukin (IL)-6 together with lipid levels were measured in all participants. Logistic regression analysis was used. RESULTS: Children in group 2 had higher insulin (15.5 ± 6.4 vs 10.9 ± 4.8 µU/mL), HOMA-IR (3.41 ± 1.4 vs 2.34 ± 1.05) and lower Matsuda index [4.7 (3.1) vs 18.4 (17) median plus IQR] and Cederholm ISI (38 ± 6 vs 56 ± 11), than children in group 1 (all P < 0.001). They also had higher visfatin (15.4 ± 5.2 vs 10.1 ± 7 ng/mL), and IL-6 [12.5 (6.7) vs 4.8 (4.4) pg/mL], and lower adiponectin (5.9 ± 3.4 vs 11.8 ± 4.7 µg/mL) than children in group 1 (all P < 0.001). Logistic regression showed that these differences between the two groups were independent of age, sex, Tanner stage, BMI and WC z-scores. CONCLUSIONS: In obese children, 1h-GL ≥8.6 mmol/L during an OGTT is correlated with worsened IR, and an unfavourable metabolic and inflammatory profile. Thus, 1h-GL could be used as an additional marker to identify obese children and adolescents at increased risk of developing obesity complications.

Does idiopathic hypercalciuria affect bone metabolism during childhood? A prospective case-control study.

BACKGROUND: A limited number of studies have evaluated biochemical bone metabolism markers in children with idiopathic hypercalciuria, which in adults has been linked with osteopenia. Our aim was to investigate in children with idiopathic hypercalciuria biochemical markers of bone formation and resorption and the osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kB ligand (sRANKL) system which is involved in the osteoclastogenesis process. METHODS: A prospective study was conducted on 50 children with idiopathic hypercalciuria and 50 healthy age-, sex-, and Tanner stage-matched control subjects. Following the diagnosis, patients were requested to follow a 3-month dietary recommendation for idiopathic hypercalciuria. In patients, at diagnosis and at 3 months of follow-up, and in controls, bone-related hormones and serum/urine biochemical parameters were studied. The bone formation markers (total ALP and osteocalcin) and the bone resorption markers (ß-Crosslaps) and the OPG and sRANKL levels were determined. RESULTS: No differences were found in the bone formation markers or OPG and sRANKL between the children with idiopathic hypercalciuria and controls. The ß-Crosslaps and the ß-Crosslaps/osteocalcin ratio were higher in the patients at diagnosis than in controls (p = 0.019 and p = 0.029, respectively), with a trend to decrease after the 3-month dietary intervention. The initially increased 24-h urinary Ca in the patients decreased after the 3-month dietary intervention (p = 0.002). CONCLUSIONS: Children with idiopathic hypercalciuria had biochemical markers compatible with normal bone formation but increased bone resorption. After a 3-month dietary intervention, the trend observed towards decrease in the serum ß-Crosslaps may reflect a beneficial response.

Rare Association of Hb D-Los Angeles (HBB: c.364G>C) with Hb H Disease: Diagnosis and Clinical Implications.

Hb D-Los Angeles (or Hb D-Punjab) (HBB: c.364G > C) is found worldwide and is derived from a point mutation in the ß-globin gene prevalent in the Punjab region of Northwestern India. Heterozygous or homozygous inheritance does not cause significant medical problems, whereas association with other hemoglobinopathies, especially ß-thalassemia (ß-thal) and sickle cell disease, changes the phenotype. Coinheritance of Hb D-Los Angeles with Hb H disease (α-/- -) has never been reported before. The presence of this rare combination in a family of Greek origin is herein described, and the challenges involving clinical management are discussed.

Repetitive reddish discoloration of urine in a female adolescent following short-distance walking on a smooth road: Questions.

A previously healthy 15-year-old girl was evaluated following five episodes of reddish urine discoloration after walking for approximately 30 min on a smooth roadway. In each episode, the discoloration lasted for four to five urinations and followed by normal urine dipstick tests. No other exercise-produced urine discoloration and no other symptoms were reported. Laboratory evaluation during the episodes revealed a reddish urine sample with 3+ hemoglobin/myoglobin and absence of hematuria. Full blood count, serum creatinine, liver function tests, and electrolyte levels were all within normal limits. Myoglobulinuria was excluded, since muscle enzymes were within normal limits. Blood smear analysis showed mild anisopoikilocytosis with stomatocytes and ovalocytes, leading to extended evaluation for erythrocyte disorders. This case is interesting in that the hemoglobinuria occurred after mild walking and was accompanied by erythrocyte morphological changes. This quiz discusses the differential diagnosis of hemoglobinuria with particular reference to the conditions of appearance (after walking) and emphasizes the importance of step-by-step investigations to reach a definitive diagnosis.

Severe Thrombocytopenic Purpura in a Child with Brucellosis: Case Presentation and Review of the Literature.

Brucellosis is still endemic and a significant public health problem in many Mediterranean countries, including Greece. It is a multisystemic disease with a broad spectrum of clinical manifestations including hematological disorders, such as anemia, pancytopenia, leucopenia, and thrombocytopenia. Thrombocytopenia is usually moderate and attributed to bone marrow suppression or hypersplenism. Rarely, autoimmune stimulation can cause severe thrombocytopenia with clinically significant hemorrhagic manifestations. We present the case of a girl with severe thrombocytopenic purpura as one of the presenting symptoms of Brucella melitensis infection. Treatment with intravenous immunoglobulin and the appropriate antimicrobial agents promptly resolved the thrombocyte counts. A review of similar published cases is also presented.

Prognostic Factors for Immune Thrombocytopenia Outcome in Greek Children: A Retrospective Single-Centered Analysis.

Immune thrombocytopenia (ITP) in children has a varied course and according to duration is distinguished as newly diagnosed (<3 months), persistent (3-12), and chronic (>12) types. Several studies have evaluated the prognostic factors for the progression of the disease, but similar works have yet to be performed in Greece. We aimed to identify prognostic markers for the three forms of the disease in 57 Greek children during a 13-year period. Information regarding age, gender, preceding infection, bleeding type, duration of symptoms and platelets at diagnosis, treatment, disease course, and immunological markers was recorded. 39 children had newly diagnosed, 4 persistent, and 14 chronic disease. Chronic ITP children were more likely to be of age > 10 years (p = 0.015) and have gradual initiation of the disease (p = 0.001), platelets > 10 × 109/L (p = 0.01), and impaired immunological markers (p < 0.003) compared to newly diagnosed/persistent groups. Recent history of infection was found mainly in the newly diagnosed/persistent group (p = 0.013). None of the children exhibited severe spontaneous bleeding. Conclusion. Even though ITP in children usually has a self-limited course, with rare serious bleeding complications, the chronic form of the disease is characterized by different predictive parameters, which can be used in clinical practice.

Atypical manifestations of Epstein-Barr virus in children: a diagnostic challenge / Manifestações atípicas do vírus de Epstein-Barr em crianças: um desafio diagnóstico

Abstract Objective: Clarify the frequency and the pathophysiological mechanisms of the rare manifestations of Epstein–Barr virus infection. Sources: Original research studies published in English between 1985 and 2015 were selected through a computer-assisted literature search (PubMed and Scopus). Computer searches used combinations of key words relating to "EBV infections" and "atypical manifestation. Summary of the findings: "Epstein–Barr virus is a herpes virus responsible for a lifelong latent infection in almost every adult. The primary infection concerns mostly children and presents with the clinical syndrome of infectious mononucleosis. However, Epstein–Barr virus infection may exhibit numerous rare, atypical and threatening manifestations. It may cause secondary infections and various complications of the respiratory, cardiovascular, genitourinary, gastrointestinal, and nervous systems. Epstein–Barr virus also plays a significant role in pathogenesis of autoimmune diseases, allergies, and neoplasms, with Burkitt lymphoma as the main representative of the latter. The mechanisms of these manifestations are still unresolved. Therefore, the main suggestions are direct viral invasion and chronic immune response due to the reactivation of the latent state of the virus, or even various DNA mutations. Conclusions: Physicians should be cautious about uncommon presentations of the viral infection and consider EBV as a causative agent when they encounter similar clinical pictures.

Resumo Objetivo: Esclarecimento da frequência e dos mecanismos patofisiológicos das manifestações raras da infecção por vírus de Epstein-Barr. Fontes: Estudos de pesquisas originais publicados em inglês entre 1985 e 2015 foram selecionados por meio de uma busca na literatura assistida por computador (Pubmed e Scopus). As buscas no computador usaram combinações de palavras-chave relacionadas a "infecções por VEB" e "manifestação atípica". Resumo dos achados: O vírus de Epstein-Barr é um herpesvírus responsável por uma infecção latente vitalícia em quase todo adulto. A infecção primária ocorre principalmente em crianças e se apresenta como síndrome clínica da mononucleose infecciosa. Contudo, a infecção por vírus de Epstein-Barr pode apresentar diversas manifestações raras, atípicas e de alto risco. Ela pode causar infecções secundárias e diversas complicações dos sistemas respiratório, cardiovascular, geniturinário, gastrointestinal e nervoso. O vírus de Epstein-Barr também desempenha um papel significativo na patogênese de doenças, alergias e neoplasias autoimunes. O linfoma de Burkitt é o principal representante das últimas. Os mecanismos dessas manifestações ainda não foram resolvidos. Portanto, as principais sugestões são invasão viral direta e resposta imune crônica devido à reativação do estado latente do vírus ou mesmo a diversas mutações do DNA. Conclusões: Os médicos devem tomar cuidado sobre apresentações incomuns de infecção viral e considerar o VEB um agente causador quando encontrarem situações clínicas semelhantes.

Atypical manifestations of Epstein-Barr virus in children: a diagnostic challenge.

OBJECTIVE: Clarify the frequency and the pathophysiological mechanisms of the rare manifestations of Epstein-Barr virus infection. SOURCES: Original research studies published in English between 1985 and 2015 were selected through a computer-assisted literature search (PubMed and Scopus). Computer searches used combinations of key words relating to "EBV infections" and "atypical manifestation." SUMMARY OF THE FINDINGS: Epstein-Barr virus is a herpes virus responsible for a lifelong latent infection in almost every adult. The primary infection concerns mostly children and presents with the clinical syndrome of infectious mononucleosis. However, Epstein-Barr virus infection may exhibit numerous rare, atypical and threatening manifestations. It may cause secondary infections and various complications of the respiratory, cardiovascular, genitourinary, gastrointestinal, and nervous systems. Epstein-Barr virus also plays a significant role in pathogenesis of autoimmune diseases, allergies, and neoplasms, with Burkitt lymphoma as the main representative of the latter. The mechanisms of these manifestations are still unresolved. Therefore, the main suggestions are direct viral invasion and chronic immune response due to the reactivation of the latent state of the virus, or even various DNA mutations. CONCLUSIONS: Physicians should be cautious about uncommon presentations of the viral infection and consider EBV as a causative agent when they encounter similar clinical pictures.

aHUS associated with C3 gene mutation: a case with numerous relapses and favorable 20-year outcome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is frequently associated with gene mutations in complement-regulatory proteins and activators. Different complement C3 gene mutations have been associated with different outcomes in aHUS. CASE-DIAGNOSIS/TREATMENT: We report the case of a 21-year-old male with a C3 heterozygous gene mutation (p.Ile1157Thr) who developed aHUS at the age of 10 months and had six relapses, the last at the age of 14.5 years. Each relapse was characterized by an apparent predominance of hematological manifestations with milder renal involvement and was followed by complete recovery, with creatinine values and hematological parameters usually recovering after the 3rd to 6th day of hospitalization. The patient was treated with plasma infusion, apart from the initial and the last episode, when dialysis was needed. Twenty years after the onset, he retains normal renal function, with no proteinuria or hypertension. One similar case of highly recurrent aHUS carrying the same C3 mutation as our patient with recovery of renal function has been previously reported. CONCLUSIONS: We further support that aHUS associated with the p.Ile1157Thr C3 mutation may be highly recurrent, but with recovered renal function. The prevalent p.Ile1157Thr C3 gene mutation has variable disease manifestations and both severe and milder renal phenotypes have been found.