[Biologics in severe childhood asthma]. / Les biothérapies en 2023 dans l'asthme sévère de l'enfant.

INTRODUCTION: Severe asthma in children remains relatively rare. It is no longer considered as a single disease but rather as a syndrome corresponding to different phenotypes and distinct pathophysiological pathways. Various biomarkers can contribute to phenotyping, essentially specific IgE test results, blood eosinophil counts, the exhaled fraction of NO (FeNO) assay, as well as deep lung biomarkers from induced sputum, bronchoalveolar lavage or bronchial biopsy. STATE OF KNOWLEDGE: In children, the biologics currently approved for severe asthma are omalizumab, mepolizumab and dupilumab from the age of 6, and tezepelumab from the age of 12. PERSPECTIVES: Benralizumab and tezepelumab offer promising perspectives and a pediatric extension could be of interest in future treatment of severe pediatric asthma. CONCLUSIONS: Based on physiopathological mechanisms, biologics represent a new and promising approach in the treatment of asthma. That said, the long-term efficacy and impact of these treatments on the natural history of the disease require further investigation. It is of paramount importance to take into account the specificities of pediatric asthma and, more particularly, to conduct clinical trials in younger patients.

[Allergic immunotherapy in children and adolescents]. / Immunothérapie allergénique chez l'enfant et l'adolescent.

Specific allergic immunotherapy requires repeated administration of allergens in order to induce clinical and immunological tolerance. This is the only therapy with an aetiological aim that modifies the course of the disease by ensuring remission after the interruption of the procedure. The prevention of new sensitizations by immunotherapy is still under discussion. In this review we will consider the main immunological mechanisms and indications for immunotherapy in children and adolescents.

MASK 2017: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma multimorbidity using real-world-evidence.

mHealth, such as apps running on consumer smart devices is becoming increasingly popular and has the potential to profoundly affect healthcare and health outcomes. However, it may be disruptive and results achieved are not always reaching the goals. Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline using the best evidence-based approach to care pathways suited to real-life using mobile technology in allergic rhinitis (AR) and asthma multimorbidity. Patients largely use over-the-counter medications dispensed in pharmacies. Shared decision making centered around the patient and based on self-management should be the norm. Mobile Airways Sentinel networK (MASK), the Phase 3 ARIA initiative, is based on the freely available MASK app (the Allergy Diary, Android and iOS platforms). MASK is available in 16 languages and deployed in 23 countries. The present paper provides an overview of the methods used in MASK and the key results obtained to date. These include a novel phenotypic characterization of the patients, confirmation of the impact of allergic rhinitis on work productivity and treatment patterns in real life. Most patients appear to self-medicate, are often non-adherent and do not follow guidelines. Moreover, the Allergy Diary is able to distinguish between AR medications. The potential usefulness of MASK will be further explored by POLLAR (Impact of Air Pollution on Asthma and Rhinitis), a new Horizon 2020 project using the Allergy Diary.

New insights into the phenotypes of atopic dermatitis linked with allergies and asthma in children: An overview.

Atopic dermatitis (AD) is a complex disease with multiple causes and complex mechanistic pathways according to age of onset, severity of the illness, ethnic modifiers, response to therapy and triggers. A group of difficult-to-manage patients characterized by early-onset AD and severe lifelong disease associated with allergic asthma and/or food allergy (FA) has been identified. In this study, we focus on these severe phenotypes, analysing their links with other atopic comorbidities, and taking into account the results from recent cohort studies and meta-analyses. The main hypothesis that is currently proposed to explain the onset of allergic diseases is an epithelial barrier defect. Thus, the atopic march could correspond to an epithelial dysfunction, self-sustained by a secondary allergenic sensitization, explaining the transition from AD to allergic asthma. Furthermore, AD severity seems to be a risk factor for associated FA. Results from population-based, birth and patient cohorts show that early-onset and severe AD, male gender, parental history of asthma, and early and multiple sensitizations are risk factors leading to the atopic march and the development of asthma. The importance of environmental factors should be recognized in these high-risk children and prevention programs adapted accordingly. Effective targeted therapies to restore both barrier function and to control inflammation are necessary; early emollient therapy is an important approach to prevent AD in high-risk children. Clinicians should also keep in mind the specific risk of atopic comorbidities in case of filaggrin loss-of-function mutations and the rare phenotypes of orphan syndromes due to heritable mutations in skin barrier components.

Food allergy phenotypes: The key to personalized therapy.

Food allergies (FAs) are of increasing public health concern and are characterized by a large spectrum of diseases. Their diversity is well known for immunologic pathways (IgE, non-IgE-mediated FAs) and natural history. Many other factors and patient characteristics are involved including type of food, exposure route, allergic comorbidities, gender, racial and ethnic backgrounds, cofactors and health conditions. Food allergen components and sensitization profiles are also involved in FA phenotypes. A new approach to chronic disorders based on the identification of phenotypes through extensive knowledge of all the complex components is also applicable to FAs and could lead towards integrative care management. Diagnostic biomarkers for FAs are emerging which also contribute to better care modalities. The aim of this article was to highlight current knowledge regarding the phenotypic diversity of FA. This review will focus on IgE-mediated FAs and how identifying phenotypes may help to better understand the pathophysiological complexity, improve diagnosis and lead to personalized treatment strategies.

Clinical phenotypes in asthma during childhood.

Asthma is a heterogeneous disease characterized by numerous phenotypes relating to age of onset, triggers, comorbidities, severity (assessed by multiple exacerbations, lung function pattern) and finally the inflammatory cells involved in the pathophysiologic pathway. These phenotypes can vary over time in relation to changes in the principal triggers involved in the aetiology of the disease. Nevertheless, in a patient with multiple allergies and early-onset disease (defined as multiple sensitizations and allergic comorbidities), the prognosis of asthma is poor with a high risk of persistence and severity of the disease during childhood. Future research will focus on classifying phenotypes into groups based on pathophysiologic mechanisms (endotypes) and the biomarkers attached to these endotypes, which could predict prognosis and lead to targeted therapy. Currently, these biomarkers are related to inflammatory cells associated with the asthma endotype, essentially eosinophils and neutrophils (and related cytokines) attached to Th-2 and non Th-1 pathways, respectively. The most severe asthma (refractory asthma) is linked to neutrophil-derived inflammation (frequently associated with female sex, obesity and possibly disorganized airway microbiota) encountered in very young children or teenagers. Severe asthma is also linked to or a marked eosinophil inflammatory process (frequently associated with multiple atopy and, more rarely, with non-atopic hypereosinophilic asthma in children) and frequently encountered in teenagers. Severe phenotypes of asthma could also play a role in the origin of chronic obstructive pulmonary disease in adult life.

What lessons can be learned about asthma phenotypes in children from cohort studies?

'Phenotyping' asthma by multivariate analyses and more recently by unsupervised analysis has been performed in children cohorts. We describe the key findings that have emerged from these cohorts. It would appear that there are three wheeze phenotypes in children of preschool age: the mild episodic viral wheeze phenotype; the multitrigger atopic wheeze; and, less often encountered, the severe non-atopic wheeze. Early onset of allergy in asthma (more prevalent in boys) is associated with poor prognosis unlike the severe non-atopic wheeze phenotype which has a female predominance. The prognosis of the severe non-atopic wheeze depends on time of onset (early or late) of allergic expression. At school age, the risk of severe asthmatic exacerbations is associated with eosinophil predominant inflammation frequently related to allergic asthma, whereas neutrophil inflammation is associated with moderate-to-severe asthma with poorer lung function. Nevertheless, allergic asthma is also a heterogeneous disease with a severe allergic phenotype strongly associated with atopic dermatitis and very high eosinophil-driven inflammatory markers. Further studies are required to find non-invasive biological markers in very young children to better define wheezing phenotypes associated with an elevated risk of developing severe asthma with a view to personalizing treatment.

Aquatic pollution may favor the success of the invasive species A. franciscana.

The genus Artemia consists of several bisexual and parthenogenetic sibling species. One of them, A. franciscana, originally restricted to the New World, becomes invasive when introduced into ecosystems out of its natural range of distribution. Invasiveness is anthropically favored by the use of cryptobiotic eggs in the aquaculture and pet trade. The mechanisms of out-competition of the autochthonous Artemia by the invader are still poorly understood. Ecological fitness may play a pivotal role, but other underlying biotic and abiotic factors may contribute. Since the presence of toxicants in hypersaline aquatic ecosystems has been documented, our aim here is to study the potential role of an organophosphate pesticide, chlorpyrifos, in a congeneric mechanism of competition between the bisexual A. franciscana (AF), and one of the Old World parthenogenetic siblings, A. parthenogenetica (PD). For this purpose we carried out life table experiments with both species, under different concentrations of the toxicant (0.1, 1 and 5µg/l), and analyzed the cholinesterase inhibition at different developmental stages. The results evidence that both, AF and PD, showed an elevated tolerance to high ranges of chlorpyrifos, but AF survived better and its fecundity was less affected by the exposure to the pesticide than that of PD. The higher fecundity of AF is a selective advantage in colonization processes leading to its establishment as NIS. Besides, under the potential selective pressure of abiotic factors, such as the presence of toxicants, its higher resistance in terms of survival and biological fitness also indicates out-competitive advantages.

Geographic variation of life-history traits in the sand lizard, Lacerta agilis: testing Darwin's fecundity-advantage hypothesis.

The fecundity-advantage hypothesis (FAH) explains larger female size relative to male size as a correlated response to fecundity selection. We explored FAH by investigating geographic variation in female reproductive output and its relation to sexual size dimorphism (SSD) in Lacerta agilis, an oviparous lizard occupying a major part of temperate Eurasia. We analysed how sex-specific body size and SSD are associated with two putative indicators of fecundity selection intensity (clutch size and the slope of the clutch size-female size relationship) and with two climatic variables throughout the species range and across two widespread evolutionary lineages. Variation within the lineages provides no support for FAH. In contrast, the divergence between the lineages is in line with FAH: the lineage with consistently female-biased SSD (L. a. agilis) exhibits higher clutch size and steeper fecundity slope than the lineage with an inconsistent and variable SSD (L. a. exigua). L. a. agilis shows lower offspring size (egg mass, hatchling mass) and higher clutch mass relative to female mass than L. a. exigua, that is both possible ways to enhance offspring number are exerted. As the SSD difference is due to male size (smaller males in L. a. agilis), fecundity selection favouring larger females, together with viability selection for smaller size in both sexes, would explain the female-biased SSD and reproductive characteristics of L. a. agilis. The pattern of intraspecific life-history divergence in L. agilis is strikingly similar to that between oviparous and viviparous populations of a related species Zootoca vivipara. Evolutionary implications of this parallelism are discussed.

Casein-specific IL-4- and IL-13-secreting T cells: a tool to implement diagnosis of cow's milk allergy.

BACKGROUND: Cow's milk allergy (CMA) is a frequent food allergy in young children. The oral food challenge is the gold standard for diagnosis, and there is currently no reliable biological test. Our aim was to evaluate the diagnostic potential of a functional assay quantifying allergen-specific Th2 cells in CMA children. METHODS: A total of 29 children aged 2.8-10.5 years underwent a double-blind, placebo-controlled food challenge (DBPCFC) to cow's milk. Blood was collected before performing the DBPCFC, and peripheral mononuclear cells were cultured in an 18-h ELISpot assay with casein, α-lactalbumin, or ß-lactoglobulin. Numbers of antigen-specific IL-4- and IL-13-secreting lymphocytes and serum-specific IgE, IgG4, and total IgE levels were assessed. Receiver operating characteristic (ROC) curves were generated. RESULTS: A total of 17 (59%) children reacted to cow's milk and were therefore considered as allergic to cow's milk (CMA). The mean number of casein-specific IL-4- and IL-13-secreting T cells was higher in CMA than in non-CMA children (P = 0.009, 0.004, respectively). Moreover, it was inversely correlated with the cumulative dose of cow's milk tolerated (P = 0.003, 0.0009, respectively). ROC curve of combined IL-4 and IL-13 analysis showed an area under the curve of 0.98 (95% CI 0.90-1.06). For a cutoff of 10 IL-4- and 12 IL-13-secreting T cells, sensitivity and negative predictive value were 100%. CONCLUSIONS: Enumeration of casein-specific IL-4- and IL-13-secreting T cells appears a promising tool to improve diagnosis and, if confirmed in larger studies, could permit less frequent use of the oral food challenge.

[Characteristics of admissions to pediatric emergency departments for exacerbations of asthma. Assessment and prospects for improving prehospital care]. / Caractéristiques des consultations pour exacerbation d'asthme aux urgences pédiatriques. Évaluation et perspectives pour une amélioration de la gestion pré-hospitalière.

INTRODUCTION: The frequency of emergency department visits for asthma is a major public health problem in pediatrics. The aim of this study is to establish the characteristics of children visiting pediatric emergency departments for acute asthma and to assess their therapeutic management prior to admission. METHODS: A prospective clinical study performed during 3 months at the pediatric emergency department of the university teaching hospital of Clermont-Ferrand, of children aged 1 to 16 years admitted to the department with a clinical diagnosis of asthma exacerbation. RESULTS: One hundred and forty-three patients were included in the study. Asthma crises were moderate to severe in 69.2% of cases (n=99). Initial therapeutic management prior to the admission to the emergency department was appropriate in 17.5% of cases (n=25). Most of the known asthmatic patients had not been followed up by a pediatric pulmonologist (n=56). A crisis protocol had been set up in 16.5% of cases (n=20). Exacerbations were more severe among younger patients (P=0.002) and economically disadvantaged children (P=0.025). CONCLUSIONS: This study uncovers poor knowledge of the disease among asthmatic children and their families, and an insufficient awareness among health practitioners of current recommendations for the treatment of asthmatic children. Admissions to the emergency department for asthma could be partly avoided by improving diagnosis and therapeutic education.

Functional rare males in diploid parthenogenetic Artemia.

Functional males that are produced occasionally in some asexual taxa - called 'rare males' - raise considerable evolutionary interest, as they might be involved in the origin of new parthenogenetic lineages. Diploid parthenogenetic Artemia produce rare males, which may retain the ability to mate with females of related sexual lineages. Here, we (i) describe the frequency of male progeny in populations of diploid parthenogenetic Artemia, (ii) characterize rare males morphologically, (iii) assess their reproductive role, using cross-mating experiments with sexual females of related species from Central Asia and characterize the F1 hybrid offspring viability and (iv) confirm genetically both the identity and functionality of rare males using DNA barcoding and microsatellite loci. Our result suggests that these males may have an evolutionary role through genetic exchange with related sexual species and that diploid parthenogenetic Artemia is a good model system to investigate the evolutionary transitions between sexual species and parthenogenetic strains.

[Complications of bacterial rhino-sinusitis in children: a case report and a review of the literature]. / Complications des sinusites bactériennes du grand enfant. A propos d'un cas et revue de la littérature.

Acute sinusitis in children is a controversial issue in terms of its diagnostic criteria, classification and therapeutic management. A therapeutic delay can lead to complications if the cause is bacterial. Guidelines have been set, but they are not consensual in pediatrics. Complications of acute bacterial sinusitis are uncommon in children, but they can be extremely severe and cause high morbidity and mortality. Because of their rarity, they often are not identified early, exposing the patient to an unfavorable outcome. We report on a case of acute bacterial pan-sinusitis complicated with thrombophlebitis of the cavernous sinuses and meningitis in a 9-year-old child, in spite of early and adapted antibiotic therapy. The bacterial agent was Staphylococcus aureus, which had no resistance or toxin profile. The progression was favorable under intravenous antibiotic therapy and after bilateral sphenoidectomy. This case raises the question of the best therapy for acute bacterial sinusitis in pediatrics and the management of complications.

Characterization of polymorphic microsatellite markers in the brine shrimp Artemia (Branchiopoda, Anostraca).

The brine shrimp Artemia is a complex genus containing sexual species and parthenogenetic lineages. Artemia franciscana is native to America and its cysts (diapausing eggs) are used worldwide as a food source in aquaculture. As a consequence, this anostracan has become an invasive species in many hypersaline aquatic ecosystems of other continents. Parthenogenetic Artemia lineages occur only in the Old World. Ten and five microsatellite markers were developed to characterize two populations for A. franciscana and two populations for diploid parthenogenetic Artemia, respectively. For A. franciscana the number of alleles ranged from 11 to 58 per locus, while for parthenogens the number of alleles ranged from three to 10. The levels of heterozygosity in A. franciscana and in parthenogens ranged from 0.115 to 0.976 and from 0.000 to 0.971, respectively. These microsatellite loci showed a high population assignment power, which will be useful for future studies of population genetics and invasive processes in Artemia.

Noninfectious dermatological diseases associated with chronic exposure to mine tailings in a Peruvian district.

BACKGROUND: Mine tailings are metallic wastes which are deposited in the environment due to mining activity. Long-term exposure to these metals is harmful to human health. OBJECTIVE: To determine if chronic exposure to mine tailings constitutes a risk factor for the development of dermatological diseases in the district of San Mateo de Huanchor (Lima, Peru). METHODS: An observational case-control study was carried out in the communities of Mayoc, Daza and Tamboraque (exposed to mine tailings, case group) located in the district of San Mateo de Huanchor, and also in the communities of Choccna and Caruya (not exposed to mine tailings, control group) located in the same district. Out of 230 adults, 121 were exposed and 109 were not exposed to mine tailings and out of 135 children, 71 were exposed and 64 were not exposed to mine tailings. RESULTS: In the adult group, 71% of the exposed cases had some noninfectious dermatological disease while in the nonexposed group the frequency was 34% [P < 0.001; odds ratio (OR) 5.40; 95% confidence interval (CI) 3.02-9.68]. A statistically significant difference between groups was found for arsenical dermatitis, nonpruritic papulovesicular eruption, atopic dermatitis, contact dermatitis, seborrhoeic dermatitis and xerosis. In the paediatric population, 71 exposed and 64 nonexposed children were evaluated. Sixty-nine per cent of the exposed group had some noninfectious dermatological disease vs. 30% in the nonexposed group (P < 0.001; OR 6.00; 95% CI 2.71-13.31). A statistically significant difference between groups was found for xerosis and atopic dermatitis. CONCLUSION: Chronic exposure to mine tailings represents a risk factor for development of noninfectious dermatological diseases in both adults and children.

Acute toxicity of dichlorvos to Aphanius iberus (Cuvier & Valenciennes, 1846) and its anti-cholinesterase effects on this species.

This study evaluates the toxic effects of the organophosphate pesticide (OP) dichlorvos to the endangered Iberian toothcarp (Aphanius iberus). To this end, the lethal toxicity of dichlorvos based on 96h-LC50 bioassays was determined in saline water (50g/L), and in vivo effects of dichlorvos on cholinesterase (ChE) activity were investigated in adult female and male specimens. The 96h-LC50 value determined by probit analysis was 3.17mg/L (95% confidence limits: 1.34-3.97). The characterisation of the ChE using different substrates and specific inhibitors was also carried out in head and muscle tissues. Acetylthiocholine was the substrate preferred by both head and muscle ChE in males and females. Eserine sulphate and BW284C51 significantly inhibited both head and muscle enzyme activity at low concentrations (muM range), and iso-OMPA had no significant effect. These results indicate that in the head and muscle the predominant ChE form is acetylcholinesterase (AChE) for both sexes. The kinetic parameters for ChE activity (Km and Vmax) were similar in both sexes. The 96h-LC50 value obtained for adult specimens of Iberian toothcarp was 3.17mg/L. ChE activity in head and body tissues of both sexes was significantly inhibited in all concentrations tested (0.5, 1, 2 and 4mg/L) after "in vivo" dichlorvos exposure. However, Iberian toothcarp was able to tolerate high concentrations of dichlorvos, and resist high levels of brain and muscle ChE inhibition without mortality. Both ChE inhibition and recovery followed a similar time-course pattern in response to sub-lethal exposure to dichlorvos (1mg/L), and the enzyme activity did not return to control levels after 96h in clean water. The results of this study show that ChE activity is a good biomarker of exposure to OP in the Iberian toothcarp adults.