New opportunities with biologic treatments in pediatric allergic and respiratory diseases.

In the last 20 years, the introduction of monoclonal antibodies has dramatically changed allergic diseases. At present, several monoclonal antibodies are approved for treating asthma, atopic dermatitis, chronic spontaneous urticaria, and chronic sinusitis with nasal polyps in children. Biologics have also changed the management of these diseases in the pediatric population, tending toward personalized medicine based on the type-2 inflammatory pattern.

Severe asthma: When to resort to biological agents.

Asthmatic children usually reach good control of symptoms with a low-medium dose of inhaled corticosteroids (ICS), but approximately 5% has severe asthma. In this group of patients, when the diagnosis of severe asthma is confirmed, biologic agents have to be considered when there is no control of the symptoms despite conventional treatment with controllers according to guidelines. At present, the only biologic agent available in clinical practice for severe asthma treatment in children (6-18 years) is omalizumab. Mepolizumab has been recently approved by EMA for pediatric use. Reslizumab is a monoclonal antibody anti-IL-5 that has been approved for severe eosinophilic asthma treatment only in patients >12 years. Because of their action on specific molecular targets of the asthma pathophysiology, biologic agents are very promising therapeutic options for severe asthmatic patients based on individual endotypes.

Anti-IL-5 in pediatric allergic diseases.

Interleukin (IL)-5 is a potent mediator of the inflammatory cascade in the allergic response. Its predominant role in atopic reactions makes this cytokine an ideal target for blocking the eosinophilic inflammatory hyper-responsiveness to allergens. The management of allergic diseases in childhood-such as severe asthma, atopic dermatitis, and eosinophilic esophagitis-is a challenge. In particular, there are concerns regarding the use of high-dose corticosteroids. Over the last few years, biologics targeting IL-5 or IL-5 receptor-that are mepolizumab, reslizumab, and benralizumab-represent a new, promising, and more personalized therapeutic option.

Canned tuna tolerance in children with IgE-mediated fish allergy: an allergological and nutritional view.

Scientific research, diagnostic tools and clinical experience have shown that children suffering from IgE-mediated fish allergy do not need to follow a strict exclusion diet. In fact, they could tolerate some species of fish, which could be reintroduced in the diet by verifying their tolerance with an oral food challenge in a clinical setting. Consequently, it is possible to look a new insight on diagnosis and management of IgE-mediated fish allergy in children, considering the use of canned tuna in clinical settings. Authors performed a literature search through the Cochrane Library and Medline/PubMed databases. All quantitative and qualitative pediatric studies involving diagnosis and management of IgE-mediated fish allergy and the use of canned tuna in clinical settings were considered. Articles related to allergological and nutritional features of fish, and especially canned tuna, were selected. This research was conducted on May 2020. Canned tuna shows peculiar allergological and nutritional characteristics. Relating to allergy, canning process, characterized by cooking the fish under pressure for a time equal to about 7 hours, can lead a conformational change in parvalbumin, making it less allergenic. In terms of nutrition, canned tuna contains B, D and A vitamins and, above all, omega-3 fatty acids and shows a favourable and significantly sustainable nutritional profile. Lower allergenicity, adequate nutritional value and its rich availability in markets at reasonable costs, could make the use of canned tuna as a solution with an excellent risk/benefit ratio in the field of IgE-mediated fish allergy.

Feasibility of structured light plethysmography for the evaluation of lung function in preschool children with asthma.

BACKGROUND: Structured light plethysmography (SLP) is a new noninvasive technology to capture the movement of the thoracic and abdominal wall, and to assess some parameters indicative for lung function. OBJECTIVE: The purpose of the study was to evaluate the feasibility of SLP in children with asthma. METHODS: A total of 52 patients were enrolled: 25 with asthma exacerbation (group 1), 13 with well-controlled asthma (group 2), and 14 healthy controls (group 3). Every patient underwent SLP evaluation and a lung function test. RESULTS: SLP evaluations showed that the ratio of inspiratory flow at 50% of tidal volume (Vt) to expiratory flow at 50% of Vt, in which Vt is taken to be the exhaled chest wall movement, and flow is taken to be the time derivative of the chest wall movement (IE50) value increased in group 1 compared with groups 2 and 3, with statistical significance (p = 0.018); the data were consistent with the spirometry parameter. A correlation between the IE50 and forced expiratory volume in the first second of expiration was highlighted (r = -0.35, p = 0.019). CONCLUSION: SLP assessed airway obstruction, and its use in clinical practice could be applied in preschool children in future studies.

Antioxidant supplementation and exhaled nitric oxide in children with asthma.

BACKGROUND: The effect of allergen avoidance on airway inflammation is similar to that observed with treatment with inhaled steroids, whereas inhaled steroids have no effect on oxidative stress-induced inflammation. OBJECTIVE: The aim of this study was to retrospectively evaluate the potential effect of an antioxidant dietary supplement on exhaled nitric oxide over a month in pediatric patients on stable antiasthma treatment. METHODS: Forty-seven children with moderate-to-severe asthma were retrospectively evaluated. All the patients were sensitive to Dermatophagoides pteronyssinus and Dermatophagoides farinae, and they were receiving the minimum inhaled corticosteroid dosage required to maintain adequate control. Within a few weeks of admission at Misurina Hospital in the Alps, the regular treatment was gradually reduced, then some children who were receiving a daily dose of inhaled corticosteroids, ≤200 mcg of fluticasone propionate, were prescribed a nutraceutical dietary supplement for at least 4 weeks. Lung function and fractional exhaled nitric oxide (FeNO) measurements were recorded at the beginning and after 1 month of the dietary supplementation. RESULTS: Baseline lung function and FeNO values did not differ between the two groups of patients. After 4 weeks of nutraceutical supplementation, FeNO values decreased, from 19.00 ppb (interquartile range, 14-31 ppb) to 11.00 ppb (interquartile range, 6-23 ppb) (p = 0.03). No significant reduction was observed in the group that did not receive the supplementation, and no significant difference between groups was observed, both at baseline and after 4 weeks of nutraceutical supplementation. CONCLUSION: Supplementation with a nutraceutical of antioxidants and anti-inflammatory compounds, such as curcumin, resveratrol, soy phospholipids, zinc, selenium, and vitamin D, may be associated with reduced airway inflammation, as documented by a fall in FeNO.

Effect of montelukast on markers of airway remodeling in children with asthma.

BACKGROUND: Asthma is a pathology characterized by chronic inflammation and remodeling of the airways. OBJECTIVES: To evaluate the effect of montelukast treatment on markers of airway inflammation and remodeling in children with mild asthma and to evaluate if the administration of montelukast to children with mild asthma could inhibit the release of matrix metallopeptidase 9, matrix metallopeptidase 12, tissue inhibitor of metalloproteinase 1, transforming growth factor beta 1, C-peptide terminal procollagen type (PICP), and eosinophils count, which are markers of inflammation and remodeling in induced sputum. METHODS: Thirty children with mild asthma were recruited. They were randomized into two groups: group A received montelukast and as needed beta-2-agonist for 8 weeks (T0-T1), whereas group B received placebo and as needed beta-2-agonist for 8 weeks. After 2 weeks of washout (T1-T2), they were reallocated for treatment according a crossover design (T2-T3). Tests for lung function, oral exhaled nitric oxide, and hypertonic saline solution-induced sputum level were performed at T0-T1-T2-T3. RESULTS: In the placebo group, the PICP mean (standard deviation [SD]) value at baseline was 2279.42 ± 2530.77 pg/mL and 1916.00 ± 2178.75 pg/mL after treatment. Patients treated with montelukast, in contrast, showed a baseline mean (SD) value of 2439.29 ± 2834.51 pg/mL and 1406.72 ± 1508.65 pg/mL after treatment. The difference between the mean pre- and posttreatment decrease of PICP in the two groups was statistically significant (delta -690.21 pg/mL [95% confidence interval, -1220.83 to -159.5844 pg/mL]; p = 0.011). The mean (SD) percentage of the eosinophil count in the placebo group was 3.11 ± 4.03% at baseline and 4.86 ± 5.83% after treatment. Patients treated with montelukast, in contrast, showed a percentage mean (SD) value at baseline of 4.51 ± 5.48% and, after treatment, of 3.06 ± 3.29%. The difference between the mean pre- and posttreatment decrease of the percentage eosinophil count in the two groups was statistically significant (delta -2.76% [95% confidence interval, -4.65 to -0.87%]; p = 0.004). CONCLUSION: This study investigated in vivo effects of montelukast on remodeling markers. The reduction of PICP levels and eosinophil count supported the hypothesis that montelukast can modulate collagen deposition in airways and reduce eosinophilic airway inflammation. Clinical Trials database clinicaltrials.gov (NCT00875082).

25-hydroxyvitamin D serum level in children of different ethnicity living in Italy.

UNLABELLED: Several factors including ethnicity are known to influence 25(OH)D levels. The purpose of our study was to assess 25(OH)D levels among 1374 pediatric subjects of different ethnicity and to determine the prevalence of vitamin D deficiency and insufficiency among different ethnic groups. The prevalence of 25(OH)D ≤ 20 ng/ml was 44.2, 65.2, 69.2, 54.0, and 44.8 % among Caucasians, Africans, North Africans, Indians, and others, respectively (P < 0.001). The median of 25(OH)D was 21.0 ng/ml (IQR = 14.0-29.6 ng/ml) for the cohort. Season of blood sampling, age, ethnicity, gestational age, birth weight, and z-score BMI were associated with 25(OH)D levels. Caucasians had higher median 25(OH)D levels than sub-Saharan Africans (P < 0.001), North Africans (P < 0.001), and Indians (P < 0.001). There were no significant differences in the median 25(OH)D levels between ethnic groups among infants, whereas for children older than 1 year we found significant differences in 25(OH)D levels in the different ethnic groups, compared to Caucasians. CONCLUSION: Ethnicity was correlated with 25(OH)D levels among children older than 1 year. We found a high prevalence of vitamin D deficiency and insufficiency after the first year of life, and this was more remarkable in non-Caucasian children.

The Evolution of Scientific Knowledge in Childhood Asthma over Time: A Surprising History.

Asthma is a disease that has been described since the times of Hammurabi. However, it is only since the 1960s that effective therapeutic strategies have been available. Pathogenic mechanisms underlying the disease have been deeply studied, contributing to creating a "patient-specific asthma" definition. Biological drugs have been approved over the last twenty years, improving disease management in patients with severe asthma via a "precision medicine-driven approach". This article aims to describe the evolution of scientific knowledge in childhood asthma, focusing on the most recent biological therapies and their indications for patients with severe asthma.

Association between individual sensor behavior of an electronic nose and airways inflammation in children with asthma: a pilot study at alpine altitude climate.

BACKGROUND: Markers of airway inflammation can be helpful in the management of childhood asthma. Residential activities, such as intensive asthma camps at alpine altitude climate (AAC), can help reduce bronchial inflammation in patients who fail to achieve optimal control of the disease. Analysis of volatile organic compounds (VOCs) can be obtained using electronic devices such as e-Noses. We aimed to identify alterations in urinary e-Nose sensors among children with asthma participating in an intensive camp at AAC and to investigate associations between urinary e-Nose analysis and airway inflammation. METHODS: We analyzed data collected in children with asthma recruited between July and September 2020. All children were born and resided at altitudes below 600 m asl. Urinary VOCs (measured using the Cyranose 320® VOC analyzer), Fractional exhaled Nitric Oxide (FeNO) and spirometry were evaluated upon children's arrival at the Istituto Pio XII, Misurina (BL), Italy, at 1756 m asl (T0), and after 7 (T1) and 15 days (T2) of stay. RESULTS: Twenty-two patients (68.2% males; median age: 14.5 years) were enrolled. From T0 to T1 and T2, the negative trend for FeNO was significant (p < .001). Significant associations were observed between e-Nose sensors S7 (p = .002), S12 (p = .013), S16 (p = .027), S17 (p = .017), S22 (p = .029), S29 (p = .021), S31 (p = .009) and ΔFeNO at T0-T1. ΔFeNO at T0-T2 was significantly associated with S17 (p = .015), S19 (p = .004), S21 (p = .020), S24 (p = .012), S25 (p = .018), S26 (p = .008), S27 (p = .002), S29 (p = .007), S30 (p = .013). CONCLUSIONS: We showed that a decrease in FeNO levels after a short sojourn at AAC is associated with behaviors of individual urinary e-Nose sensors in children with asthma.

Diagnosis and Management of Allergic Rhinitis in Asthmatic Children.

Allergic rhinitis (AR) is a common upper airways inflammatory condition especially in paediatric population; its burden potentially impacts on quality of life, quality of sleep and daily performance, which can be difficult to perceive but not less relevant in the middle-long term. The present review aims to provide an updated overview on AR epidemiology, diagnosis and with a special focus on its connections with bronchial asthma. In fact, when considering asthmatic pediatric population, AR is probably the most important risk factor for asthma onset and the most impactful extra-bronchial determinant of asthma control. Under this perspective, allergen immunotherapy (AIT) should always be considered in the light of a precision medicine approach. In fact, AIT does represent a unique opportunity to specifically interfere with AR immunological background, improve both AR and bronchial asthma control and prevent allergic disease evolution. Verifying the patient's eligibility to that option should be considered as a priority for every physician managing children suffering from AR, especially when associated with bronchial asthma.

Mental Health and Cognitive Development in Symptomatic Children and Adolescents Scoring High on Habitual Snoring: Role of Obesity and Allergy.

BACKGROUND: Obstructive sleep apnea can have a negative impact on children's and adolescents' neurocognitive abilities and hinder their academic and adaptive progress in academic, social, and/or behavioral dimensions. In this retrospective cross-sectional study, we investigated the influence of body weight conditions and allergy status on long-term mental health, cognitive development, and quality of life in children and adolescents who snored. METHODS: The study sample included 47 subjects (age range 4.1 to 15.3 years) who exhibited high levels of snoring and underwent home-based polysomnography between 2015 and 2019. Follow-up assessments (3 years on average between baseline and follow-up) entailed phone interviews with the subject's parents/caregivers who completed three validated questionnaires investigating sleep, quality of life, and parental ratings. RESULTS: We found a correlation between age at diagnosis and being retrospectively overweight and high levels of snoring. In addition to a higher risk of developing emotional symptoms (8.2% increase in retrospective overweight status for each unit increase in the emotional score at follow-up) and oppositional behavior (9% increase in retrospective overweight status for each unit of oppositional T points at follow-up), we also noted reduced long-term social symptoms (11% decrease in retrospective overweight status for each unit increase in the social score at follow-up) and cognitive symptoms (10.6% decrease in retrospective overweight status for each unit increase in the cognitive score at follow-up), as well as a 6.1% increase in retrospective allergy status for each unit increase in academic performance at follow-up. CONCLUSIONS: Snoring can have negative impacts on mental health and cognitive development in the long term. Early detection and intervention for neuropsychological disorders is important in children and adolescents who score high on snoring. In the long term, the effects of snoring on neuropsychological disorders may vary based on previous body weight and allergy status.

Predictive Power of Oxygen Desaturation Index (ODI) and Apnea-Hypopnea Index (AHI) in Detecting Long-Term Neurocognitive and Psychosocial Outcomes of Sleep-Disordered Breathing in Children: A Questionnaire-Based Study.

Pediatric obstructive sleep apnea can negatively affect children's neurocognitive function and development, hindering academic and adaptive goals. Questionnaires are suitable for assessing neuropsychological symptoms in children with sleep-disordered breathing. The study aimed to evaluate the effectiveness of using the Oxygen Desaturation Index compared to the Obstructive Apnea-Hypopnea Index in predicting long-term consequences of sleep-disordered breathing in children. We conducted a retrospective analysis of respiratory polysomnography recordings from preschool and school-age children (mean age: 5.8 ± 2.8 years) and followed them up after an average of 3.1 ± 0.8 years from the home-based polysomnography. We administered three validated questionnaires to the parents/caregivers of the children by phone. Our results showed that children with an Oxygen Desaturation Index (ODI) greater than one event per hour exhibited symptoms in four domains (physical, school-related, Quality of Life [QoL], and attention deficit hyperactivity disorder [ADHD]) at follow-up, compared to only two symptoms (physical and school-related) found in children with an Obstructive Apnea-Hypopnea Index greater than one event per hour at the time of diagnosis. Our study also found a significant correlation between the minimum SpO2 (%) recorded at diagnosis and several outcomes, including Pediatric Sleep Questionnaire (PSQ) scores, physical, social, and school-related outcomes, and ADHD index at follow-up. These results suggest that the Oxygen Desaturation Index could serve as a valuable predictor of long-term symptoms in children with sleep-disordered breathing, which could inform treatment decisions. Additionally, measuring minimum SpO2 levels may help assess the risk of developing long-term symptoms and monitor treatment outcomes.

Lung abscess as a complication of Lemierre Syndrome in adolescents: a single center case reports and review of the literature.

BACKGROUND: Fusobacterium necrophorum is an anaerobic, gram-negative, non-motile, filamentous, non-spore forming bacillus found in the oral cavity, gastrointestinal tract, and female genital tract, responsible of a rare disease named Lemierre Syndrome, characterized by septic thrombophlebitis of the internal jugular vein, which mainly affects previously healthy adolescents and young adults; some risk factors are reported, as smoking or primary viral or bacterial infection leading to the disruption of mucosa. The syndrome originates commonly from an upper respiratory infection such as pharyngotonsillitis, acute otitis media, cervical lymphadenitis, sinusitis, or odontogenic abscess, and may result in multiorgan metastasis, more frequently leading to pulmonary complications, especially lung abscesses. CASE PRESENTATION: We describe two cases of adolescents with atypical Lemierre Syndrome evaluated in a tertiary care center, one with a confirmed infection by Fusobacterium necrophorum and one with a presumptive diagnosis based on clinical features, who developed lung abscesses needing a prolonged antibiotic course and hospitalization. Of interest, both were user of electronic cigarette, configuring a possible new risk factor. The proper diagnosis of Lemierre Syndrome is often difficult to establish, so a high degree of suspicion is needed, especially in the case of lung abscesses in otherwise healthy adolescents. CONCLUSION: The current study will contribute to providing insight into Lemierre Syndrome clinical presentation and management in adolescents, promoting awareness for a rare but potentially fatal disease. Moreover, it suggests a possible relationship between Lemierre syndrome and the use of electronic cigarette, that should be investigated by future studies.

Severe pediatric asthma therapy: Dupilumab.

Severe asthma is a rare disease affecting <5% of children with asthma. This group of patients account for about 50% of the costs of healthcare for children with asthma. Nowadays, several biological agents are available for pediatric severe asthma. One of these is dupilumab, a monoclonal antibody against the Interleukin (IL)-4 receptor α-subunit that acts as an antagonist against both IL-4 and IL-13. Dupilumab binds the subunit of the IL-4 receptor, at the level of the subunit shared by the IL-13 receptor, blocking the inflammatory cascade of these two cytokines and the progression of the Th2-inflammatory pathway. The efficacy and safety of dupilumab have been investigated in recently published randomized controlled trials including pediatric patients with asthma. Currently, its use in asthma is approved in adults, adolescents, and children with severe asthma with type 2 inflammation, that are not controlled in spite of high-dose inhaled corticosteroids plus another maintenance drug. Studies are warranted for the evaluation of long-term treatment with dupilumab, including steroid sparing effect and discontinuation of treatment. Further research should also be planned in order to investigate dupilumab potential ability to interfere with the natural history of atopy since early childhood.

Vitamin D and Healthcare Service Utilization in Children: Insights from a Machine Learning Approach.

Vitamin D deficiency and insufficiency is a global health issue: an association has been demonstrated between vitamin D deficiency and a myriad of acute and chronic illnesses. Data regarding vitamin D status among children hospitalized with non-critical illnesses are scanty. We aimed to: (1) identify profiles of children hospitalized due to non-critical illnesses, using vitamin D levels as the driving outcome; (2) assess the association between patient profiles and length of stay. The study included 854 patients (1−17 years old) who underwent blood tests for detecting vitamin D levels. A regression tree was used to stratify patients. The relationship between vitamin D levels and length of stay was explored using Poisson regression. The regression tree identified three subgroups. Group A (16%): African, North African, Hispanic, and Indian patients. Group B (62%): Caucasian and Asian patients hospitalized for respiratory, metabolic, ill-defined, infective, and genitourinary diseases. Group C (22%): Caucasian and Asian patients hospitalized for digestive, nervous, and musculoskeletal diseases, blood and skin diseases, and injuries. Mean serum vitamin D level (ng/mL) was 13.7 (SD = 9.4) in Group A, 20.5 (10.0) in Group B, and 26.2 (12.6) in Group C. Group B was associated with the highest BMI z-score (p < 0.001) and the highest frequency of preterm births (p = 0.041). Mean length of stay was longer in Group A than in the other groups (p < 0.001) and decreased significantly by 9.8% (p = 0.024) in Group A and by 5% (p = 0.029) in Group B per 10 ng/mL increase in vitamin D level. We identified three subgroups of hospitalized children, defined according to ethnicity and discharge diagnosis, and characterized by increasing vitamin D levels. Vitamin D levels were associated with length of hospitalization.

Airways flat angioma misdiagnosed as difficult asthma in an adolescent.

A 15 years-old boy came to our attention with a diagnosis of poorly controlled asthma. This case required thorough investigations: CT scan imaging revealed a flat angioma extending from the carina to the left main bronchus. Rigid bronchoscopy confirmed the presence of an angioma showing widespread mucosal diffusion involving most of the posterior tracheal wall and main bronchi, on the left side. We present this case report and these images to readers seeking for other experiences in the diagnosis of wide superficial bronchial angioma in pediatric age.

Isoprostane-8 in the exhaled breath condensate: Could it represent a noninvasive strategic tool for primary ciliary dyskinesia diagnosis and management?

BACKGROUND AND OBJECTIVES: Exhaled breath condensate (EBC) represents a potential diagnostic tool for Primary Ciliary Diskinesia (PCD). An increased oxidative stress is present in the airways of children affected and many neutrophil chemoattractants and markers of oxidative stress can be involved. The aim of the study is to evaluate leukotriene B4 (LTB-4), interleukin 8 (IL-8), 8-isoprostane (8-IP) concentration in PCD subjects, investigating their potential role as non-invasive markers of inflammation for the diagnosis and management of PCD. METHODS: Cross-sectional study. 43 patients were enrolled in the study and divided in two groups: PCD (27) and healthy subjects (16). Physical examination, lung function test, nFeNO measurement and EBC collection were performed in all subjects. RESULTS: PCD subjects showed an EBC 8-IP concentration significantly higher than the control group (median value: 11.9 pg/ml; IQR, 5.5-24.0 vs. median, 6.7 pg/ml; IQR, 2.5-11.3, p-value of Wilcoxon rank-sum test 0.0436). LTB4 EBC concentration did not differ between the two group (median, 4.3 pg/ml; IQR, 3.0-8.8 vs. 7.5 pg/ml; IQR, 3.0-9.5; P=0.4901). No significant correlation was found between FEV1 and EBC 8-IP (r=-0.10, P=0.6314) or LTB4 concentration (r=0.03, P=0.8888) in PCD subjects. No significant correlation was found between nFeNO and EBC 8-IP (r=-0.31, P=0.1385) or LTB4 (r=0.04, P=0.8565) in PCD subjects. CONCLUSIONS: EBC 8-IP levels are significantly increased in PCD subjects, highlighting the role of oxidative stress in airway inflammation. It could have a potential role as a non-invasive marker of inflammation for the diagnosis and management of PCD, although a therapeutic application of this evidence seems far.