Management of antibiotic allergy in children: a practical approach.

BACKGROUND: About 10% of children are declared as allergic to antibiotics, with beta(ß)-lactams being the most common perpetrators. However, few of these are confirmed by allergy tests. This characteristic of being allergic follows a child well into adulthood, leading to alternative, usually more expensive broad-spectrum antibiotics, contributing to antibiotic resistance and increasing healthcare expenses. OBJECTIVE: This review presents a practical approach to managing pediatric patients with antibiotic hypersensitivity reactions. MATERIAL AND METHODS: We updated the guidelines on antibiotic allergy in children by conducting systematic literature research using the best available evidence from PubMed search by entering the keywords "antibiotic allergy" and "children." The search output yielded 5165 citations. RESULTS: Management of antibiotic allergy depends on the culprit antibiotic, and it includes confirmation of the diagnosis and finding a safe alternative to the culprit antibiotic. In particular patients with a history indicative of penicillin allergy can be treated with cephalosporins as an alternative to penicillin, especially with third-generation cephalosporins, except for those with similar R1 side chains. In patients with a history of immediate-type reactions to cephalosporins who require treatment with cephalosporins or penicillin, skin tests with cephalosporin or penicillin with different side chains should be performed. If allergy to macrolides is suspected, challenge tests are currently the only reliable diagnostic tool. The best strategy for managing patients with sulfonamide hypersensitivity is an alternative antibiotic. The skin prick tests and intradermal tests are not recommended for diagnosis of quinolone allergy, as they can activate dermal mast cells leading to false-positive results. Quinolone challenge test is the most appropriate test for diagnosing quinolone hypersensitivity. CONCLUSION: Although adverse drug reactions to antibiotics are frequently documented, immunologically mediated hypersensitivity is unusual. In the event of an reaction, an appropriate diagnostic workup is required to identify the drug's causal role. It is critical to avoid "labeling" a child as allergic without first conducting a proper diagnostic workup.

Association of IL-10 gene promoter polymorphisms with food allergy susceptibility and serum IL-10 level in a pediatric Caucasian population.

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.

Interleukin 10: the critical role of a pleiotropic cytokine in food allergy.

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.

Validation study of the pediatric allergic rhinitis quality of life questionnaire.

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 the 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.

Screening for coeliac disease in preschool Greek children: the feasibility study of a community-based project.

AIM: Evaluation of the prevalence of coeliac disease (CD) in Greek paediatric population. METHODS: The project consists of two parts: (i) a pilot study of preschool children aged 2-6 years to test the feasibility and diagnostic accuracy of community-based screening and (ii) a CD prevalence study, by random clustered sampling and proportionate stratification of various geographical areas in Greece. Trained nonmedical staff performed a rapid immunochromatographic test to detect IgA antibodies to tTG-IgA and IgA deficiency. Toddlers with positive results were referred to a paediatric gastroenterologist for further assessment with serum anti-tTG IgA and EMA-IgA. Children with positive serum anti-tTG and anti-EMA underwent upper gastrointestinal tract endoscopy and small bowel biopsy and were subsequently in gluten-free diet. RESULTS: In this project participated 1136 toddlers, who were tested at school. The prevalence of positive rapid anti-tTG screening was 1:154, of IgA deficiency 1:120 and of biopsy-proven CD 1:154. The prevalence of CD from this pilot study served as expected prevalence value for sample size calculation for the main prevalence study. CONCLUSION: This protocol using rapid immunochromatographic test for the detection of both IgA deficiency and CD is easy to be performed by nonmedical staff in a community setting, enabling the accurate identification of new CD cases among asymptomatic population.

Barriers to and requirements for a successful transition in inflammatory bowel disease from pediatric to adult care in Greece.

Background: The incidence of pediatric-onset inflammatory bowel disease (IBD) is rising, while the relapsing and often severe nature of IBD, and its impact on emotional and pubertal development and social maturation underline the need for a successful transition from pediatric to adult care. Methods: A web-based survey was distributed via the Hellenic Group for the Study of IBD, the Hellenic Society of Gastroenterology Department of North Greece, and the Hellenic Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Results: The questionnaire was answered by 98 individuals (78 adult and 20 pediatric gastroenterologists, out of 357 and 30, respectively). The response rate was 25.3%. A higher response rate was found among pediatric (66.6%) vs. adult gastroenterologists 21.8% (P<0.001). Pediatric gastroenterologists believed that the appropriate age for transition was either 16-17 or 17-18 years, whereas 59% of the adult gastroenterologists chose the age group of 16-17 years. Both adult and pediatric gastroenterologists stated that the most significant initiators for a successful transition process were cognitive maturity and patients' ability to manage their disease independently. The lack of communication and collaboration between pediatric and adult gastroenterologists was the main barrier to the transition process, as identified by adult gastroenterologists (27.7%). In contrast, 43.5% of pediatric gastroenterologists suggested that differences in the follow up of patients with IBD between pediatric and adult clinics were the main restrictions. Conclusion: These results highlight the need for a transitional education program for pediatric IBD patients, and the importance of improving collaboration among adult and pediatric gastroenterologists.

COVID-19 mRNA Vaccination Mimicking Heart Attack in a Healthy 56-Year-Old Physician.

We report our experience regarding a 56-year-old physician who developed severe symptoms mimicking a heart attack a few days after receiving the second dose of the new mRNA vaccine of Pfizer-BioNTech for COVID-19 protection. The patient is a healthy individual with no comorbidities and a normal clinical and laboratory profile. Five days after receiving the second dose on his left shoulder, he manifested sudden, severe pain on the whole left arm which lasted for about one hour, gradually intensifying and migrating to the chest and presenting as severe angina or heart attack. All work-up, however, was negative, with no evidence of ischemic heart attack or myocarditis. Severe acute symptoms lasted for about 20 h and completely resolved after 36 h. Although myocarditis as a potential side effect of the vaccine with associated heart pain has been identified, chest pain mimicking heart attack with otherwise normal workup has not been reported. Physicians must consider this likely rare and self-resolving symptom in order to increase awareness and prevent themselves and their patients from increased anxiety and unnecessary laboratory investigations.

Drug allergy evaluation in children with suspected mild antibiotic allergy.

Background: Adverse antibiotic reactions caused by an immunological mechanism are known as allergic reactions. The percentage of reported antibiotic allergies is likely to differ from the one validated after a drug provocation test (DPT) with the culprit antibiotic. This study aimed to compare the percentage of children who were thought to be allergic to a certain antibiotic with those who have a true allergy, as confirmed by DPTs. We also validated Skin Prick Tests (SPTs) and Intradermal Tests (IDTs) by assessing their sensitivity and specificity, in diagnosing antibiotic allergies using DPT as the gold standard. Furthermore, we investigated epidemiological risk factors such as personal and family history of atopic disease and eosinophilia. Methods: Children with a history of possible allergic reaction to an antibiotic underwent a diagnostic procedure that included: (1) Eosinophil blood count, (2) SPTs, (3) IDTs and (4) DPTs. The parameters were compared with Pearson's Chi-Square and Fisher's Exact Test. Several risk factors that were found significant in univariate analysis, such as personal and family history of atopic disease, and positive SPTs and IDTs were examined with multiple logistic regression analysis to see if they were related to a higher risk for a positive DPT. Results: Semi-synthetic penicillin was the most common group of antibiotics thought to cause allergic reactions in this study. Overall, 123 children with a personal history of an adverse reaction to a certain antibiotic, were evaluated. In 87.8% of the cases, the symptoms had occurred several hours after administration of the culprit antibiotic. Both SPTs and IDTs had low sensitivity but high specificity. Moreover, they had a high positive predictive value (PPV). In contrast, eosinophilia was not recognized as a risk factor. Seventeen patients (13.8%) had a true antibiotic allergy, as confirmed by a positive DPT. A positive IDT was a strong predictor of a positive DPT, along with a positive personal and family history of atopy. Conclusion: SPTs and IDTs are very reliable in confirming antibiotic allergy when found positive. A negative result of a SPT highly predicts a negative DPT. A positive IDT and a positive personal and family history of atopy were recognized as significant risk factors for antibiotic allergy.

Covid-19: Face Mask Protection in the Pediatric Setting.

We report our experience regarding a pediatric patient-case who had a covid-19 infection, which was initially considered a common viral infection and was managed accordingly for the first 36 hours while being hospitalized. Wearing a simple surgical face mask was the only protective measure which our personnel has adopted. All staff members were tested for covid-19 infection with swab specimens from the nasopharynx and pharynx and were found to be negative in 7-10 days after coming into contact with the patient. Thirty-one days after contact with the covid-19 patient, no one of the staff members had respiratory symptoms, and therefore, they all returned to work. This case shows the importance of face-mask wearing to prevent the transmission various of respiratory infections, including that caused by the novel SARS-CoV-2 microorganism.

De novo HBV Hepatitis in a Child with Liver Transplantation.

Background: Omental torsion (OT) presents as a rare, infrequent pathology with often non-specific symptoms. This condition occurs when the greater omentum is twisted around its axis, producing perfusion defects and vascular impairment of the organ. This case report describes an overweight 26-year-old Caucasian man presenting with acute abdomen in previous appendectomy, whose definitive surgical diagnosis was omental torsion. Omental torsion is a rare pathology regarding the causes of acute abdomen associated with a challenging diagnosis. Case report: We report about a female toddler with liver transplantation due to extrahepatic biliary atresia, who was detected to have positive HBsAg, 27 months after transplantation. Before liver transplantation, routine serologic assessments were negative for HBV infection, the child was vaccinated with three doses of HBV vaccine and developed seroprotective Abs titers. Organ donor was the father, who was negative for HBV infection had negative anti-HBc and had seroprotective titers of anti HBs. A PCR assay in our patient revealed the presence of serum HBV DNA with an increased viral load. The patient started antiviral treatment with Entecavir and had serological response within three months, showing elimination of serum HBV DNA and HBsAg values. Serological investigation of all family members and information from the transplantation unit did not reveal the infection source. Conclusion:de novo Hepatitis B in liver recipients is a rare phenomenon. In donor positive anti-HBc cases, it appears as reactivation of HBV infection. There are very few published cases in which recipients developed de novo HBV hepatitis, despite seronegative HBcAb donors. Caregivers should always be alert for de novo hepatitis B in liver transplanted children as loss of immunity could be an unexpected phenomenon, despite pre-transplant negative serology of the donor and recipient as so as despite seroprotective Abs titers after immunisation of the recipient.

Tacrolimus Immunosuppression Causes Drug-Induced Hypersensitivity Reactions in Liver-Transplant Patients: A 3-Case Report.

BACKGROUND: Drug-induced hypersensitivity reactions attributed to the immunosuppressive agent tacrolimus after an organ transplant are rare in the literature. We present 3 cases of male adult patients grafted with a cadaveric liver who developed delayed hypersensitivity reactions to tacrolimus in the form of the prolonged-release capsules (Advagraf). Furthermore, the appropriate drug concentration solutions used for allergy testing are proposed. METHODS: All patients received a liver transplant (LT) because of cirrhosis of various etiologies. They were immunosuppressed with tacrolimus once daily. Several months after they had been placed on an immunosuppressive regimen with tacrolimus in the form of prolonged-release capsules (Advagraf), the patients presented with delayed hypersensitivity reactions and torturous pruritic rash that affected the whole body and was unresponsive to treatment with oral ursodeoxycholic acid, cholestyramine, or levocetirizine. Allergy testing that was performed by skin prick testing was negative. Nevertheless, intradermal testing yielded positive results in all 3 patients. Management was by interruption of the culprit agent, which was followed by symptom resolution. The immunosuppressive treatment was continued with alternative drugs. RESULTS: Appropriate nonirritating drug concentration solutions of the drug used for intradermal testing were highly sensitive and confirmed the clinical diagnosis of tacrolimus allergy in all the affected patients. CONCLUSION: Immunosuppressive treatment with tacrolimus in the form of prolonged-release capsules may cause a drug hypersensitivity reaction. A suspicion of allergy warrants a referral for allergy testing. Pruritic rash refractory to treatment in liver transplanted patients should be evaluated by an allergist for possible drug allergy when bile stasis and graft disease have been excluded. Intradermal testing has proven a highly sensitive method for confirming a drug allergy diagnosis, whereas skin prick testing did not.

Diet Quality: A Neglected Parameter in Children With Food Allergies. A Cross-Sectional Study.

Background-Objective: With recent evidence suggesting that growth is no longer considered a major issue in children with food allergies (FA) on elimination diet, priority has shifted to diet quality to establish healthy eating patterns and prevent non-communicable diseases. The Diet Quality Index - International (DQI-I) could be useful for assessing the overall diet quality of FA-children. This study aimed to evaluate the impact of elimination diet on DQI-I in children with FA and the accuracy of DQI-I in reflecting nutrient intake. Materials-methods: In a prospective, cross-sectional, cohort study of FA-children (2-14 years), nutritional intake was evaluated using a 7-day food frequency questionnaire, 24-h dietary recall, and the DQI-I. Results: Of the 76 children recruited, 44.7% had multiple allergies. Mean overall DQI-I score was 52 points, with only 28% of participants having good overall DQI-I (≥60 points). DQI-I moderation and balance were the most affected domains. Participants with multiple allergies had higher DQI-I moderation and balance and lower vitamin D and Ca intake. Compared to toddlers, schoolchildren had higher DQI-I variety and lower moderation and received higher vitamin B2, vitamin B12, Ca, P, and Zn. The number of allergies, age, and milk avoidance were independently associated with adjusted DQI-I moderation and balance, energy, and certain micronutrient intake. Higher percentages of participants with good DQI-I received adequate amounts of Mn and vitamins A, B6, C, and folate than those with poor DQI-I. Conclusions: In children with FA on elimination diet, the DQI-I accurately captured the deflection of diet quality related to the development of chronic, non-communicable diseases through its moderation and balance components. This is DQI-I's main purpose as a healthy diet indicator and as such it would be a useful tool responding to the needs of the contemporary shifting of priorities in FA-children's diet from quantity to quality. Nevertheless, it does not accurately reflect the intake of certain micronutrients potentially compromised by elimination diets. Therefore, regular nutritional assessment utilizing both the DQI-I and tools assessing individual nutrient intakes along with professional nutrition counseling should be integral parts of the individualized management of children with FA to ensure adequate nutrient intake and establish healthy dietary patterns.

Inflammatory Bowel Disease in Children and Adolescents - a Retrospective Study of 13 Years of Records Investigating Potential Prognostic Factors.

Purpose: To assess the landscape of management of pediatric inflammatory bowel disease (IBD) patients in Greece and investigate possible prognostic factors for the disease outcome. Method: The medical records of all IBD patients who visited the gastroenterology divisions of two university pediatric clinics as in- or outpatients over 13 years were examined. Results: Twenty-seven females and 25 males were included in the study. Ulcerative colitis (UC) was diagnosed in 46% of cases, Crohn's Disease (CD) in 33% and unclassified IBD (IBD-U) remained the diagnosis in 21%. The CRP level was elevated in 68% of cases at diagnosis, whereas only 27.4% of patients had ESR levels and platelet counts within the age-adjusted normal range. No parameter derived from patient history, physical examination or laboratory and imaging was found to influence the time to diagnosis. Abdominal pain and lack of diarrhea at the time of diagnosis were significantly associated with the need for biologic therapy during the disease course in CD. Consistent with the "step-up" approach the treating physicians practiced, an increased number of relapses correlated with the addition of biologics in the treatment of both CD and UC patients (P=.03 and P=.002, respectively). Conclusion: It is the first time that clinical data regarding IBD pediatric patients in Greece were reviewed. Some clinical and imaging factors were associated with more aggressive disease, an increased need for biological treatment and frequent hospitalizations for IBD flares. Moreover, it was observed that the clinical features of IBD in Greek children were similar to those in other countries.

Hepatobiliary scan in Alagille syndrome; arteriohepatic dysplasia.

Arteriohepatic dysplasia or congenital paucity of interlobular bile ducts - Alagille Syndrome, is a well defined syndrome characterized by five major features, including chronic cholestasis, posterior embryotoxon, butterfly-like vertebral arch defects, peripheral pulmonary artery hypoplasia or stenosis and facial dysmorphy. The disease is very rare. Only three cases have been reported in Greece and none with renal involvement. Hepatobiliary scan was a fundamental tool in the patients diagnosis and therefore we present the following case.

Thiamine Deficiency in a Child with Short Bowel Syndrome and Review.

Thiamine (vitamin B1) is a water-soluble vitamin that is not endogenously synthesized in humans. It is absorbed by the small intestine, where it is activated. Its active form acts as a coenzyme in many energy pathways. We report a rare case of thiamine deficiency in a 3.5-year old boy with short bowel syndrome secondary to extensive bowel resection due to necrotizing enterocolitis during his neonatal age. The patient was parenteral nutrition-dependent since birth and had suffered from recurrent central catheter-related bloodstream infections. He developed confusion with disorientation and unsteady gait as well as profound strabismus due to bilateral paresis of the abductor muscle. Based on these and a very low thiamine level he was diagnosed and treated for Wernicke encephalopathy due to incomplete thiamine acquisition despite adequate administration. He fully recovered after thiamine administration. After 1999 eight more cases have been reported in the PubMed mostly of iatrogenic origin.

Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome Associated With a Novel Mutation of FOXP3 Gene.

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.

Trichohepatoenteric syndrome: A rare mutation in SKIV2L gene in the first Balkan reported case.

Trichohepatoenteric syndrome or syndromic diarrhea is a rare and severe Mendelian autosomal recessive syndrome characterized by intractable diarrhea, facial and hair abnormalities, liver dysfunction, immunodeficiency and failure to thrive. It has been associated with mutations in TTC37 and SKIV2L genes, which encode proteins of the SKI complex that contributes to the cytosolic degradation of the messenger RNA by the cell's exosome. We report a case of a male infant who suffered from typical symptoms and signs of trichohepatoenteric syndrome without immunodeficiency. The patient's genetic testing showed a very rare mutation in SKIV2L gene's 25 exons (p.Glu1038 fs*7 (c.3112_3140del)). Even though our patient was provided with total parenteral nutrition from birth, the child's death in the third year of age highlights the severity of the disease and the poor prognosis of this particular type of genetic predisposition.

A Synbiotic Infant Formula with High Magnesium Content Improves Constipation and Quality of Life.

PURPOSE: To evaluate the efficacy of synbiotic formula with partial whey hydrolysate and high magnesium content in infants presenting with functional constipation. METHODS: Sixty-five infants with functional constipation were included. Forty infants were treated during one month with parental reassurance and the intervention formula and were compared to a control group of 25 infants treated with parental reassurance only. Parents completed a quality of life (QoL) questionnaire at baseline and during the last week of the study. RESULTS: At inclusion, stool characteristics and QoL were similar in both groups. The control group was slightly older than the intervention group (7.5±3.9 vs. 6.2±3.6 weeks). At onset, stool composition was "hard and tight" (Bristol stool scale 1 and 2) in all infants. After one month, stool composition remained unchanged in the control group except in two infants that developed "creamy" stools (Bristol stool scale type 3 and 4). In the intervention group, stools remained "hard and tight" in 27.5%, and became "creamy" in 47.5%, "loose" (Bristol stool scale type 5) in 22.5% and "watery" (Bristol stool type 6 and 7) in 2.5%. The benefit of the intervention formula was estimated to be "very important" in 70%. The median scores for QoL improved significantly in the intervention group for all parameters and for one in the control group. CONCLUSION: The intervention formula significantly improved functional constipation resulting in a better QoL of the parents and infants.