Atopic children are more susceptible to viral respiratory infection at the age of 2-5 years old.

Background: The susceptibility of the atopic population to respiratory infections (RI) has not been fully elucidated. This susceptibility is attributed to the immune dysregulation that characterizes atopic diseases. Although, the exact mechanisms involved are not fully understood, there is evidence that shows that the maturation of innate immunity progresses differently in patients with atopy. Objective: The aim of the study was to evaluate the susceptibility to viral RIs (VRI) based on the number and duration of them in different age groups in subjects with atopy and subjects without atopy. Methods: Seventy-eight subjects (39 healthy and 39 with atopy) were included in the study. All the subjects were evaluated by a specialist and defined as being atopic if they had a clinical history and/or symptoms compatible with any allergic diseases and relevant sensitizations. Epidemiologic data were recorded based on a standardized questionnaire, which included recording habits, conditions, and living environment as well as the history of viral infections during the last year. Results: In our population, children with atopy were found to be more susceptible to viral RIs than children without atopy (p = 0.02), whereas there was no difference in susceptibility between healthy adults and adults with atopy (18-45 years old). More specifically, the atopic age group 2-5 years old showed the higher susceptibility to VRIs. Conclusion: This study provided evidence that children with atopy, especially at ages 2-5 years old, had more numerically and prolonged RIs than did the subjects without atopy. These clinical findings support the hypothesis of distracted maturation of innate immunity in subjects with atopy.

Differential maturation trajectories of innate antiviral immunity in health and atopy.

BACKGROUND: The maturation of innate immune responses in health and atopy is still incompletely understood. METHODS: We aimed to evaluate age-related trajectories of the TLR3 and TLR7/8 pathways from birth to adulthood and whether these differ between healthy and atopic individuals. Peripheral blood mononuclear cells (PBMCs) were isolated from 39 otherwise healthy, atopic and 39 non-atopic subjects, aged 0-45 years. Selected cytokines involved in antiviral responses were measured by Luminex in culture supernatants of poly(I:C)- and R848-stimulated PBMCs. The non-parametric correlation between age and cytokine expression and differences in developmental trajectories between healthy and atopic subjects were estimated. Patterns of cytokine development were identified with principal component analysis. RESULTS: Normal innate immune maturation entails significant and progressive age-related changes in the production of IL-1ß, TNF-α, MIP-1ß, MCP-3, IP-10, IL-10, IL-12p70, and IFN-γ upon TLR3 and/or TLR7/8 stimulation. Individual cytokines made small contributions to the observed variability; chemokines MCP-3 and IP-10 were key contributors. The development of these pathways deviated in atopic subjects with significant differences observed in the trajectories of IL-1ß, MIP-1ß, and IL-10 syntheses. CONCLUSION: TLR3 and TLR7/8 pathways mature during childhood, while atopy is associated with an abnormal maturation pattern. Suboptimal responses in Th1, inflammatory cytokine, and chemokine production may be implicated in poor antiviral immunity in atopics. Moreover, the deficient maturation of IL-10 synthesis may be implicated in the breaking of tolerance, characterizing the onset of atopic disease.

Recurrent Wheeze Exacerbations Following Acute Bronchiolitis-A Machine Learning Approach.

Introduction: Acute bronchiolitis is one of the most common respiratory infections in infancy. Although most infants with bronchiolitis do not get hospitalized, infants with hospitalized bronchiolitis are more likely to develop wheeze exacerbations during the first years of life. The objective of this prospective cohort study was to develop machine learning models to predict incidence and persistence of wheeze exacerbations following the first hospitalized episode of acute bronchiolitis. Methods: One hundred thirty-one otherwise healthy term infants hospitalized with the first episode of bronchiolitis at a tertiary pediatric hospital in Athens, Greece, and 73 age-matched controls were recruited. All patients/controls were followed up for 3 years with 6-monthly telephone reviews. Through principal component analysis (PCA), a cluster model was used to describe main outcomes. Associations between virus type and the clusters and between virus type and other clinical characteristics and demographic data were identified. Through random forest classification, a prediction model with smallest classification error was identified. Primary outcomes included the incidence and the number of caregiver-reported wheeze exacerbations. Results: PCA identified 2 clusters of the outcome measures (Cluster 1 and Cluster 2) that were significantly associated with the number of recurrent wheeze episodes over 3-years of follow-up (Chi-Squared, p < 0.001). Cluster 1 included infants who presented higher number of wheeze exacerbations over follow-up time. Rhinovirus (RV) detection was more common in Cluster 1 and was more strongly associated with clinical severity on admission (p < 0.01). A prediction model based on virus type and clinical severity could predict Cluster 1 with an overall error 0.1145 (sensitivity 75.56% and specificity 91.86%). Conclusion: A prediction model based on virus type and clinical severity of first hospitalized episode of bronchiolitis could predict sensitively the incidence and persistence of wheeze exacerbations during a 3-year follow-up. Virus type (RV) was the strongest predictor.

Preschool wheezing and asthma in children: A systematic review of guidelines and quality appraisal with the AGREE II instrument.

BACKGROUND: Asthma-like symptoms in preschool children, such as wheezing and dyspnea, are common time- and resource-consuming diagnostic and management challenges. Quality of wheezing and asthma recommendations varies. The purpose of this study, carried out by the European Academy of Allergy and Clinical Immunology (EAACI) Task Force for Preschool Wheeze, was to systematically review and assess the quality of guidelines for diagnosis and treatment of preschool wheezing and/or asthma. METHODS: The Cochrane Library, MEDLINE, and EMBASE were searched until June 2018. The methodological rigor, quality, and transparency of relevant guidelines were assessed with the use of the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. RESULTS: We identified 26 guidelines. The quality scores for each domain varied. Of all domains, clarity and presentation had the highest mean score, whereas applicability and stakeholder involvement had the lowest. The scores (median) for individual domains were as follows: score and purpose 86%; stakeholder involvement 49%; rigor of development 54%; clarity of presentation 85%; applicability 51%; and editorial independence 63%. CONCLUSION: Although several guidelines on asthma management in children are available, however, their quality varies. Additionally, there is a considerable gap in reliable recommendations on the management and treatment of non-asthmatic preschool wheeze.

Bronchiolitis needs a revisit: Distinguishing between virus entities and their treatments.

Current data indicate that the "bronchiolitis" diagnosis comprises more than one condition. Clinically, pathophysiologically, and even genetically three main clusters of patients can be identified among children suffering from severe bronchiolitis (or first wheezing episode): (a) respiratory syncytial virus (RSV)-induced bronchiolitis, characterized by young age of the patient, mechanical obstruction of the airways due to mucus and cell debris, and increased risk of recurrent wheezing. For this illness, an effective prophylactic RSV-specific monoclonal antibody is available; (b) rhinovirus-induced wheezing, associated with atopic predisposition of the patient and high risk of subsequent asthma development, which may, however, be reversed with systemic corticosteroids in those with severe illness; and (c) wheeze due to other viruses, characteristically likely to be less frequent and severe. Clinically, it is important to distinguish between these partially overlapping patient groups as they are likely to respond to different treatments. It appears that the first episode of severe bronchiolitis in under 2-year-old children is a critical event and an important opportunity for designing secondary prevention strategies for asthma. As data have shown bronchiolitis cannot simply be diagnosed using a certain cutoff age, but instead, as we suggest, using the viral etiology as the differentiating factor.

Current state and future of pediatric allergology in Europe: A road map.

The history of pediatric allergology (PA) in Europe is relatively youthful, dating back to 1984, when a small group of pediatricians founded the European Working Group on Pediatric Allergy and Immunology-later giving rise to ESPACI (European Society on Pediatric Allergology and Clinical Immunology). In 1990, the first dedicated journal, Pediatric Allergy and Immunology (PAI), was founded. There are striking differences across Europe, and even within European countries, in relation to the training pathways for doctors seeing children with allergic disease(s). In 2016, the EAACIClemens von Pirquet Foundation (CvP) organized and sponsored a workshop with the European Academy of Allergy and Clinical Immunology (EAACI) Pediatric Section. This collaboration focussed on the future of PA and specifically on education, research, and networking/ advocacy. The delegates representing many countries across Europe have endorsed the concept that optimal care of children with allergic diseases is delivered by pediatricians who have received dedicated training in allergy, or allergists who have received dedicated training in pediatrics. In order to meet the needs of children and families with allergic disease(s), the pediatric allergist is highly encouraged to develop several networks. Our challenge is to reinforce a clear strategic approach to scientific excellence to across our member base and to ensure and enhance the relevance of European pediatric research in allergy. With research opportunities in basic, translational, clinical, and epidemiologic trials, more trainees and trained specialists are needed and it is an exciting time to be a pediatric allergologist.

Host natural killer immunity is a key indicator of permissiveness for donor cell engraftment in patients with severe combined immunodeficiency.

BACKGROUND: Severe combined immunodeficiency (SCID) can be cured by using allogeneic hematopoietic stem cell transplantation, and the absence of host immunity often obviates the need for preconditioning. Depending on the underlying genetic defect and when blocks in differentiation occur during lymphocyte ontogeny, infants with SCID have absent or greatly reduced numbers of functional T cells. Natural killer (NK) cell populations are usually absent in the SCID-X1 and Janus kinase 3 forms of SCID and greatly reduced in adenosine deaminase deficiency SCID but often present in other forms of the disorder. OBJECTIVE: To determine if SCID phenotypes indicate host permissiveness to donor cell engraftment. METHODS: A retrospective data analysis considered whether host NK cells influenced donor T-cell engraftment, immune reconstitution, and long-term outcomes in children who had undergone nonconditioned allogeneic stem cell transplantation between 1990 and 2011 in the United Kingdom. Detailed analysis of T- and B-cell immune reconstitution and donor chimerism was compared between the NK(+) (n = 24) and NK(-) (n = 53) forms of SCID. RESULTS: Overall, 77 children underwent transplantation, with survival of 90% in matched sibling donor/matched family donor transplants compared with 60% when alternative donors were used. Infants with NK(-)SCID were more likely to survive than NK(+) recipients (87% vs 62%, P < .01) and had high-level donor T-cell chimerism with superior long-term recovery of CD4 T-cell immunity. Notably, 33% of children with NK(+)SCID required additional transplantation procedures compared with only 8% of children with NK(-)SCID (P < .005). CONCLUSIONS: NK(-)SCID disorders are highly permissive for donor T-cell engraftment without preconditioning, whereas the presence of NK cells is a strong indicator that preparative conditioning is required for engraftment of T-cell precursors capable of supporting robust T-cell reconstitution.

The common cold: potential for future prevention or cure.

The common cold is the most frequent, although generally mild, human disease. Human Rhinoviruses are the prevalent causative agents, but other viruses are also implicated. Being so common, viral colds, have significant implications on public health and quality of life, but may also be life-threatening for vulnerable groups of patients. Specific diagnosis and treatment of the common cold still remain unmet needs. Molecular diagnostic techniques allow specific detection of known pathogens as well as the identification of newly emerging viruses. Although a number of medications or natural treatments have been shown to have some effect, either on the number or on the severity of common colds, no single agent is considerably effective. Virus-specific management remains in most cases a challenging potential as many factors have to be taken into account, including the diversity of the viral genomes, the heterogeneity of affected individuals, as well as the complexity of this long standing host-virus relationship.

Anti-N-methyl-D-aspartate receptor encephalitis presenting with acute psychosis in a preteenage girl: a case report.

INTRODUCTION: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a rare, newly defined autoimmune clinical entity that presents with atypical clinical manifestations. Most patients with anti-N-methyl-D-aspartate receptor encephalitis develop a progressive illness from psychosis into a state of unresponsiveness, with catatonic features often associated with abnormal movements and autonomic instability. This is the first report of anti-N-methyl-D-aspartate receptor encephalitis in a Greek pediatric hospital. CASE PRESENTATION: An 11-year-old Greek girl presented with clinical manifestations of acute psychosis. The differential diagnosis included viral encephalitis. The presence of a tumor usually an ovarian teratoma, a common clinical finding in many patients, was excluded. Early diagnosis and prompt immunotherapy resulted in full recovery up to one year after the initial diagnosis. CONCLUSION: Acute psychosis is a rare psychiatric presentation in children, diagnosed only after possible organic syndromes that mimic acute psychosis are excluded, including anti-N-methyl-D-aspartate receptor receptor encephalitis. Pediatricians, neurologists and psychiatrists should consider this rare clinical syndrome, in order to make an early diagnosis and instigate appropriate treatment to maximize neurological recovery.

Rhinovirus-induced basic fibroblast growth factor release mediates airway remodeling features.

BACKGROUND: Human rhinoviruses, major precipitants of asthma exacerbations, induce lower airway inflammation and mediate angiogenesis. The purpose of this study was to assess the possibility that rhinoviruses may also contribute to the fibrotic component of airway remodeling. METHODS: Levels of basic fibroblast growth factor (bFGF) mRNA and protein were measured following rhinovirus infection of bronchial epithelial cells. The profibrotic effect of epithelial products was assessed by DNA synthesis and matrix metalloproteinase activity assays. Moreover, epithelial cells were exposed to supernatants from cultured peripheral blood mononuclear cells, obtained from healthy donors or atopic asthmatic subjects and subsequently infected by rhinovirus and bFGF release was estimated. bFGF was also measured in respiratory secretions from atopic asthmatic patients before and during rhinovirus-induced asthma exacerbations. RESULTS: Rhinovirus epithelial infection stimulated mRNA expression and release of bFGF, the latter being positively correlated with cell death under conditions promoting rhinovirus-induced cytotoxicity. Supernatants from infected cultures induced lung fibroblast proliferation, which was inhibited by anti-bFGF antibody, and demonstrated increased matrix metalloproteinase activity. Rhinovirus-mediated bFGF release was significantly higher in an in vitro simulation of atopic asthmatic environment and, importantly, during rhinovirus-associated asthma exacerbations. CONCLUSIONS: Rhinovirus infection induces bFGF release by airway epithelium, and stimulates stroma cell proliferation contributing to airway remodeling in asthma. Repeated rhinovirus infections may promote asthma persistence, particularly in the context of atopy; prevention of such infections may influence the natural history of asthma.

The 10th anniversary of the Junior Members and Affiliates of the European Academy of Allergy and Clinical Immunology.

This year is the 10th anniversary of the European Academy of Allergy and Clinical Immunology (EAACI) Junior Members and Affiliates (JMAs). The aim of this review is to highlight the work and activities of EAACI JMAs. To this end, we have summarized all the initiatives taken by JMAs during the last 10 yr. EAACI JMAs are currently a group of over 2380 clinicians and scientists under the age of 35 yr, who support the continuous education of the Academy's younger members. For the past decade, JMAs enjoy a steadily increasing number of benefits such as free online access to the Academy's journals, the possibility to apply for Fellowships and the Mentorship Program, travel grants to attend scientific meetings, and many more. In addition, JMAs have been involved in task forces, cooperation schemes with other scientific bodies, organization of JMA focused sessions during EAACI meetings, and participation in the activities of EAACI communication platforms. EAACI JMA activities represent an ideal example of recruiting, training, and educating young scientists in order for them to thrive as future experts in their field. This model may serve as a prototype for other scientific communities, several of which have already adapted similar policies.

Dendritic cells in viral bronchiolitis.

Dendritic cells (DCs) are major antigen-presenting cells that constitute a link between innate and adaptive immune responses, and are critical in the processes of control and elimination of viral infections. On the other hand, there is a large body of data strongly implicating respiratory viruses in morbidity during infancy through the induction of lower respiratory tract infections, such as bronchiolitis, and later on in childhood and adult life, mainly due to their association with asthma exacerbations. Little is known, however, about the precise role of DCs in human respiratory tract infections. This review focuses on current data, both from in vivo and in vitro studies, that highlight the interplay between DCs and the viral causes of bronchiolitis.