Vassiliki Papaevangelou’s research while affiliated with National and Kapodistrian University of Athens and other places

According to parental reports, about 10% of children are believed to be allergic to at least one antibiotic, leading to the prescription of second line medications. This incurs higher costs, results in less effective treatments, and contributes to global concern of antibiotic resistance. De-labeling programs could mitigate these problems. The primary objectives of this study were to assess the proportion of children that tolerate the suspected antibiotic well through allergy testing and, secondly, to examine which information in their medical history correlates with a positive test result. Children with a history of antibiotic allergy were categorized into high- and low-risk groups for immediate allergic reaction. The latter underwent oral provocation testing (OPT), while the high-risk group underwent the test only after negative skin tests (STs). In total, 76.8% of children tolerated the tested antibiotic well. Among children with positive OPT, two (8.0%) had to receive adrenaline for symptom resolution. Children who had exhibited suspected symptoms within one hour after antibiotic administration, and those with a history of asthma or food allergy, had an increased risk of positive allergic testing (p < 0.05). In conclusion, the adoption of a standardized protocol for an antibiotic allergy de-labeling program is essential for every allergy department.

The development of early-onset cow’s milk protein allergy and atopic dermatitis during the first months of life is multifactorial, including both genetic and nutritional aspects. This study aims to assess the impact of different feeding patterns on the incidence of cow’s milk protein allergy, atopic dermatitis, and growth among infants with a family history of allergy. A total of 551 high-risk infants were randomly recruited from 3 European countries in three feeding regimens: exclusive breastfeeding, partially hydrolyzed formula, or standard formula with intact protein either exclusively or supplementary to breastfeeding. During the first 6 months of intervention, amongst infants with a family history of atopic dermatitis, 6.5% of partially hydrolyzed formula-fed infants and 22.7% of exclusively breastfed infants (p = 0.007) presented with atopic dermatitis respectively. Growth as assessed by weight increase did not differ between the aforementioned groups. Although cow’s milk protein allergy was not related to the different milk feeding regimens in the whole cohort, when adjusting for high breast milk intake, the respective incident was significantly lower in the infants consuming partially hydrolyzed formula (p < 0.001). This data indicates that a specific partially hydrolyzed formula could serve as a more appropriate complement to breast milk compared to a standard intact protein formula in high-risk infants, to reduce the incidence of atopic dermatitis.

Background: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2-11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75-1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58-1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91-1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70-1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11-0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50-0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38-0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45-0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health.

Background SARS-CoV-2 infection has been associated with adverse maternal and neonatal outcomes, yet uptake of SARS-CoV-2 vaccines during pregnancy and lactation has been slow. As a result, millions of pregnant and lactating women and their infants remain susceptible to the virus. Methods We measured Spike-specific immunoglobulin G (anti-S IgG) and A (anti-S IgA) in serum and breastmilk (BM) samples from 3 prospective mother-infant cohorts recruited in two academic medical centers. The primary aim was to determine the impact of maternal SARS-CoV-2 immunization vs infection and their timing on systemic and mucosal immunity. Results The study included 28 mothers infected with SARS-CoV-2 in late pregnancy (INF), 11 uninfected mothers who received 2 doses of the BNT162b2 vaccine in the latter half of pregnancy (VAX-P) and 12 uninfected mothers who received 2 doses of BNT162b2 during lactation (VAX-L). VAX dyads had significantly higher serum anti-S IgG compared to INF dyads (p < .0001), while INF mothers had higher BM: serum anti-S IgA ratios compared to VAX mothers (p = .0001). Median IgG placental transfer ratios were significantly higher in VAX-P compared to INF mothers (p < 0.0001). There was a significant positive correlation between maternal and neonatal serum anti-S IgG after vaccination (r = 0.68, p = 0.013), but not infection. Conclusions BNT161b2 vaccination in late pregnancy or lactation enhances systemic immunity through serum anti-S Ig, while SARS-CoV-2 infection induces mucosal over systemic immunity more efficiently through BM Ig production. Next generation vaccines boosting mucosal immunity could provide additional protection to the mother-infant dyad. Future studies should focus on identifying the optimal timing of primary and/or booster maternal vaccination for maximal benefit.

Background The role of partially hydrolyzed formulas (pHF) as part of nutritional interventions to prevent the development of allergic manifestations (AM) is questioned, and efficacy of each specific pHF should be substantiated. Objective To investigate the risk-reduction effect of a whey-based pHF on the development of cow's milk protein allergy (CMPA) and atopic dermatitis (AD) in infants at high-risk for allergy within the first 6 months of life. Materials and Methods In a multicenter double-blinded randomized controlled setting, healthy non-exclusively breastfed full-term infants, received either a specific whey-based pHF or a standard cow's milk-based formula (SF) and were clinically assessed for AM at 2, 4, and 6 months of age, supported by the objective scoring tools SCORAD and CoMiSS. CMPA was confirmed by open food challenge. Intention-to-Treat (ITT) and Per-Protocol (PP) analyses were performed. Results Of 331 randomized subjects (ITT analysis set), 160 received the pHF and 171 the SF. Six (3.8%) infants in the pHF and 12 (7%) in the SF group developed CMPA ( p = 0.186). AD incidence was significantly lower in those receiving pHF as compared to SF (10.6% vs. 18.7%, p = 0.024) with a relative risk (RR, 95% CI) of 0.54 (0.32, 0.92), in particular when adjusting for family history of AD [6.5% vs. 27.3%, RR 0.24 (0.07, 0.78), p = 0.018] representing a risk reduction of 76%. The PP analysis showed similar results. Conclusion This specific whey-based pHF reduced the risk of AD development, particularly in those with a family history of AD, and tended to reduce the development of CMPA in non-exclusively breastfed infants at high-risk for allergy. The A.R.T. study suggests that this particular pHF may contribute to measures aimed at prevention of allergic manifestations. However, further studies are needed to confirm this risk-reduction effect.

In childhood, a multitude of causes leads to pulmonary alveolar proteinosis (PAP), an excessive surfactant accumulation in the alveolar space limiting gas exchange. Autoantibodies against GM-CSF causing autoimmune PAP, the principle etiology in adults, are rare. In this first series on autoimmune PAP we detail the presentation and management issues of four children. Whereas three children presented insidiously with progressive dyspnea, one was acutely sick with suspected pneumonia. During management, one patient was hospitalised with COVID-19, non-invasively ventilated, and recovered. All treatment modalities known from adults including whole lung lavages, augmentation of GM-CSF by inhaled GM-CSF, removal of neutralising antibody by plasmapheresis and interruption of antibody production by Rituximab were considered, however not all options were available at all sites. Inhaled GM-CSF appeared a non-invasive and comfortable therapeutic approach. The management with best benefit to harm ratio in autoimmune PAP is unknown and specialised physicians must select the least invasive and most effective treatment. To collect this cohort in a rare condition became feasible as patients were submitted to an appropriate registry. To accelerate authorisation of novel treatments for autoimmune PAP competent authorities should grant an inclusion of adolescents into trials in adults.

Noonan syndrome (NS) is an autosomal dominant disorder characterized by clinical and genetic heterogeneity. It belongs to a wider group of pathologies, Rasopathies, due to the implication of mutations in more than 10 genes encoding components of the Ras/MAPK signalling pathway. Recording the genetic alterations across populations helps assessing specific features to specific genes which is essential for better disease’s prognosis and monitoring. Herein, we report the clinical and molecular data of a Greek cohort comprising of 86 patients. Patients identified as NS or NS-like syndrome from a single tertiary Centre in Athens, Greece. The analysis was performed using Sanger and Next-Generation-Sequencing, comprising 14 different genes. Heterozygous variants were revealed in 11/14 genes: PTPN11 (32.5%), RIT1 (8.1%), SOS1 (4.7%), A2ML1 (4.7%), SPRED1 (3.5%), BRAF (1.2%), CBL (1.2%), KRAS (1.2%), MAP2K1 (1.2%); RAF1 (1.2%); SHOC2 (1.2%), corresponding to 59.5% of positivity in our population. The genotype-phenotype analysis showed statistically significant differences regarding craniofacial dysmorphisms (p=0.0015), pulmonary valve stenosis (PS) (p<0.001) and neurological features (p<0.001) between patients harboring a mutation in any of the tested genes and mutation-free patients. Patients with at least one mutation had 7.36 times greater odds to develop PS compared to mutation-negative patients [OR=7.36, 95%; CI= (2.69,20.18)]. Conclusion: Craniofacial dysmorphism, neurological defects and PS prevail among mutation positive compared to mutation negative NS and NS-like patients. The significant prevalence of the Ras/MAPK mutations (28%), other than PTPN11, in Greek patients, highlights the necessity of a wider spectrum of molecular diagnosis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy is associated with a higher risk for severe morbidity and mortality when compared with infection in non-pregnant women of childbearing age. An increasing number of countries recommend immunization against SARS-CoV-2 in pregnant women. Recent studies provide preliminary and supportive evidence on safety, immunogenicity and effectiveness of coronavirus disease 2019 (COVID-19) vaccines in pregnant women; however, important knowledge gaps remain which warrant further studies. This collaborative consensus paper provides a review of the current literature on COVID-19 vaccines in pregnant women, identifies knowledge gaps and outlines priorities for future research to optimize protection against SARS-CoV-2 in the pregnant women and their infants.