Lung function assessment in children with Long-Covid syndrome.

INTRODUCTION: A significant percentage of patients who survived the Coronavirus Infection Disease 2019 (COVID-19) showed persistent general and respiratory symptoms even months after recovery. This condition, called Post-Acute Sequelae of COVID-19 or Long-Covid syndrome (LCS), has been described also in children with positive history for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Little is known about the pathophysiologic mechanisms underlying this syndrome. The aim of this study was to investigate any difference between children with LCS and asymptomatic peers with previous COVID-19 in terms of lung function and lung ultrasound (LUS) patterns. Secondly, we tested associations between lung function abnormalities and LUS findings with Long-Covid. METHODS: We carried out a prospective, descriptive, observational study including 58 children aged 5-17 years: 28 with LCS compared to 30 asymptomatic children with previous COVID-19. We collected demographic data, history of asthma, allergy or smoke exposure, and acute COVID-19 symptoms. After a median period of 4.5 months (1%-95% range 2-21) since the infection, lung function was assessed by spirometry, body plethysmography, diffusion lung capacity for carbon monoxide (DLCO). Airways inflammation was investigated by fractional exhaled nitric oxide (FeNO). LUS was performed independently by two experienced clinicians. RESULTS: We found that children with LCS were older than controls (mean (SD) 12 (4.1) vs. 9.7 (2.6); p = .04). Children with LCS complained more frequently fatigue (46.4%), cough (17.9%), exercise intolerance (14.3%) and dyspnea (14.3%). Lung function was normal and similar between the two groups. The frequency of LUS abnormalities was similar between the two groups (43.3% children with LCS vs. 56.7% controls; p = .436). Children with LCS showed lower FeNO values (log difference -0.30 (CI 95% -0.50, -0.10)), but no association of LCS with a lower lung function and abnormal LUS findings was found. CONCLUSIONS: LCS seems to be more frequent in older age children. Lung functional and structural abnormalities were not different between children with LCS and asymptomatic subjects with previous COVID-19. In addition, children with LCS showed lower FeNO values than controls, suggesting its potential role as a marker in LCS. However, further and larger studies are needed to confirm our findings.

Longitudinal prospective anthropometric evaluation in Caucasian prepubertal children with lactose intolerance.

Introduction: The health consequences of lactose intolerance remain unclear. We studied the association of lactose intolerance with growth in children. Methods: In this prospective case-control study, we compared Caucasian prepubertal children with lactose intolerance (LI) [n = 30, median age = 7.87 years (3.00-12.75)] to healthy controls [(n = 75, median age = 2.25 years (2.00-7.25)]. A lactose tolerance test was performed for lactose intolerance diagnosis. The gastrointestinal symptom score was administered at baseline and after a lactose-free diet for a median period of 9.0 months [range 5%-95% (6.0-24.0)]. The anthropometric parameters were measured at baseline and follow-up. All the anthropometric data were converted into standard deviation scores (SDS). A linear regression model was used to investigate the association of lactose intolerance with growth parameters. Results: We found no difference in height velocity SDS between the LI and control groups [SDS difference (95% CI): 0.52 (-1.86 to 2.90)]. In addition, we found a significant reduction in the clinical score of the LI group after a lactose-free diet [median (5%-95%): 7.5 (4.0-15.0) and 3 (0.0-8.0); p-value <0.001]. Conclusions: The LI group exhibited no difference in height velocity compared with the control group. Nonetheless, due to the small sample size, the results on the anthropometric profile of the LI group require careful interpretation. More large-scale studies in the pediatric population are required to better understand the association of LI with anthropometric and metabolic profiles.

A 52-week multicenter retrospective real-world study on effectiveness and safety of dupilumab in children with atopic dermatitis aged from 6 to 11 years.

Background: Dupilumab has been shown to be a safe and effective drug for the treatment of atopic dermatitis (AD) in children from 6 months to 11 years in randomized clinical trials. Aim: The aim of this real-life study was to determine the effectiveness in disease control and safety of dupilumab at W52 in moderate-to-severe AD children aged 6-11 years.Methods: All data were collected from 36 Italian dermatological or paediatric referral centres. Dupilumab was administered at label dosage with an induction dose of 300 mg on day 1 (D1), followed by 300 mg on D15 and 300 mg every 4 weeks (Q4W). Treatment effect was determined as overall disease severity, using EASI, P-NRS, S-NRS and c-DLQI at baseline, W16, W24, and W52. Ninety-six AD children diagnosed with moderate-to-severe AD and treated with dupilumab were enrolled.Results: Ninety-one (94.8%) patients completed the 52-week treatment period and were included in the study. A significant improvement in EASI score, P-NRS, S-NRS and c-DLQI was observed from baseline to weeks 16, 24 and 52.Conclusions: Our real-life data seem to confirm dupilumab effectiveness and safety in paediatric patients. Moreover, our experience highlighted that patients achieving clinical improvement at W16 preserved this condition over time.

Long COVID in Children: A Multidisciplinary Review.

Long COVID syndrome has emerged as a long-lasting consequence of acute SARS-CoV-2 infection in adults. In addition, children may be affected by Long COVID, with potential clinical issues in different fields, including problems in school performance and daily activities. Yet, the pathophysiologic bases of Long COVID in children are largely unknown, and it is difficult to predict who will develop the syndrome. In this multidisciplinary clinical review, we summarise the latest scientific data regarding Long COVID and its impact on children. Special attention is given to diagnostic tests, in order to help the physicians to find potential disease markers and quantify impairment. Specifically, we assess the respiratory, upper airways, cardiac, neurologic and motor and psychological aspects. Finally, we also propose a multidisciplinary clinical approach.

Drug-Induced Enterocolitis Syndrome in Children.

Drug-Induced Enterocolitis Syndrome (DIES) is a drug-induced hypersensitivity reaction non-IgE mediated involving the gastrointestinal system that occurs 2 to 4 h after drug administration. Antibiotics, specifically amoxicillin or amoxicillin/clavulanate, represent the most frequent drugs involved. Symptoms include nausea, vomiting, abdominal pain, diarrhea, pallor, lethargy, and dehydration, which can be severe and result in hypovolemic shock. The main laboratory finding is neutrophilic leukocytosis. To the best of our knowledge, 12 cases of DIES (9 children-onset and 3 adult-onset cases) were described in the literature. DIES is a rare clinically well-described allergic disease; however, the pathogenetic mechanism is still unclear. It requires to be recognized early and correctly treated by physicians.

The Role of Nasal Cytology and Serum Atopic Biomarkers in Paediatric Rhinitis.

A Nasal Provocation Test allows the differentiation of allergic and non-allergic rhinitis, but it is difficult and expensive. Therefore, nasal cytology is taking hold as an alternative. We carried out a cross-sectional study, including 29 patients with persistent rhinitis according to ARIA definition and negative skin prick tests. Nasal symptoms were scored from 0 to 5 using a visual analogue scale, and patients underwent blood tests to investigate blood cell count (particularly eosinophilia and basophilia), to analyze serum total and specific IgE and eosinophil cationic protein (ECP), and to perform nasal cytology. We performed a univariate logistical analysis to evaluate the association between total serum IgE, serum eosinophilia, basophils, and ECP and the presence of eosinophils in the nasal mucosa, and a multivariate logistic model in order to weight the single variable on the presence of eosinophils to level of the nasal mucosa. A statistically significant association between serum total IgE levels and the severity of nasal eosinophilic inflammation was found (confidence interval C.I. 1.08-4.65, odds ratio OR 2.24, p value 0.03). For this reason, we imagine a therapeutic trial with nasal steroids and oral antihistamines in patients with suspected LAR and increased total IgE levels, reserving nasal cytology and NPT to non-responders to the first-line therapy.

New Indications of Biological Drugs in Allergic and Immunological Disorders: Beyond Asthma, Urticaria, and Atopic Dermatitis.

Asthma, chronic urticaria, and atopic dermatitis are some of the most numerous allergic diseases affecting children. Recent advances in the understanding of their specific intracellular molecular pathways have led to the approval of monoclonal antibodies targeting definite inflammatory molecules in order to control symptoms and improve quality of life. Less is known about other allergic and immunologic disorders such as rhinosinusitis with nasal polyps, eosinophilic esophagitis, anaphylaxis, and food allergy undergoing allergen immunotherapy. The increasing evidence of the molecular mechanisms underlying their pathogeneses made it possible to find in children new indications for known biological drugs, such as omalizumab and dupilumab, and to develop other ones even more specific. Promising results were recently obtained, although few are currently approved in the pediatric population. In this review, we aim to provide the latest evidence about the role, safety, and efficacy of biologic agents to treat allergic and immunologic diseases in children.

Lung Involvement in Systemic Juvenile Idiopathic Arthritis: A Narrative Review.

Systemic juvenile idiopathic arthritis associated with lung disorders (sJIA-LD) is a subtype of sJIA characterized by the presence of chronic life-threatening pulmonary disorders, such as pulmonary hypertension, interstitial lung disease, pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia, which were exceptionally rare before 2013. Clinically, these children show a striking dissociation between the relatively mild clinical manifestations (tachypnoea, clubbing and chronic cough) and the severity of the pulmonary inflammatory process. Our review describes sJIA-LD as having a reported prevalence of approximately 6.8%, with a mortality rate of between 37% and 68%. It is often associated with an early onset (<2 years of age), macrophage activation syndrome and high interleukin (IL)-18 circulating levels. Other risk factors may be trisomy 21 and a predisposition to adverse reactions to biological drugs. The most popular hypothesis is that the increase in the number of sJIA-LD cases can be attributed to the increased use of IL-1 and IL-6 blockers. Two possible explanations have been proposed, named the "DRESS hypothesis" and the "cytokine plasticity hypothesis". Lung ultrasounds and the intercellular-adhesion-molecule-5 assay seem to be promising tools for the early diagnosis of sJIA-LD, although high resolution computed tomography remains the gold standard. In this review, we also summarize the treatment options for sJIA-LD, focusing on JAK inhibitors.

Total serum IgE levels as predictor of the acquisition of tolerance in children with food allergy: Findings from a pilot study.

Background: The gold standard to diagnose food allergy (FA) is a double-blind, placebo-controlled food challenge (OFC), even if it shows potential risk of severe allergic reactions for the patient and is time-consuming. Therefore, easier, and less invasive methods are needed to diagnose FA and predict the tolerance, changing the clinical practice. Aim: The main aim of this study was to assess whether the total IgE values at the diagnosis of FA were associated with the duration of the tolerance acquisition and thus of the food elimination diet. Methods: We retrospectively analyzed the medical records of 40 patients allergic to milk or egg who performed an OFC for the reintroduction of the causal food at the Pediatric Allergy and Respiratory Unit of the University of Chieti from January 2018 to December 2020. Results: We found a positive association of total serum IgE with the elimination diet duration (ß = 0.152; CI, 95% 0.04-0.27) after adjusting for age, sex, and type of allergy (milk or egg). We also showed a significant correlation (r = 0.41 and p-value = 0.007) between the total IgE values and the duration of the elimination diet and a significant correlation between the casein specific IgE values at diagnosis of FA and the severity of the clinical presentation (r = 0.66; p-value 0.009). Conclusion: Total serum IgE at baseline, along with the downward trend of food-specific IgE levels (to milk or egg), may be useful in the prognostication of natural tolerance acquisition.

Heated Humidified High-Flow Nasal Cannula in Children: State of the Art.

High-flow nasal cannula (HFNC) therapy is a non-invasive ventilatory support that has gained interest over the last ten years as a valid alternative to nasal continuous positive airway pressure (nCPAP) in children with respiratory failure. Its safety, availability, tolerability, and easy management have resulted its increasing usage, even outside intensive care units. Despite its wide use in daily clinical practice, there is still a lack of guidelines to standardize the use of HFNC. The aim of this review is to summarize current knowledge about the mechanisms of action, safety, clinical effects, and tolerance of HFNC in children, and to propose a clinical practices algorithm for children with respiratory failure.

Effect of Invasive Mechanical Ventilation at Birth on Lung Function Later in Childhood.

Background: Despite recent neonatal care improvements, mechanical ventilation still remains a major cause of lung injury and inflammation. There is growing literature on short- and long-term respiratory outcomes in infants born prematurely in the post-surfactant era, but the exclusive role of mechanical ventilation at birth in lung function impairment is still unclear. The aim of this study was to assess the effect of neonatal mechanical ventilation on lung function parameters in children born ≤ 32 weeks of gestational age at 11 years of age. Materials and Methods: In total, 55 ex-preterm children born between January 1, 2006 and December 31, 2007 were enrolled at 11 years of age. Neonatal information was obtained from medical records. Information about family and personal clinical history was collected by questionnaires. At 11 years of age, we measured spirometry parameters, lung volumes, diffusing lung capacity, and fractional exhaled nitric oxide. In addition, an allergy evaluation by skin prick test and eosinophil blood count were performed. A multivariable linear or logistic regression analysis was performed to examine the associations of mechanical ventilation with respiratory outcomes, adjusting for confounders (maternal smoking during pregnancy, gestational age, surfactant replacement therapy, and BMI). Results: No difference in lung function evaluation between ventilated and unventilated children were found. No association was also found between mechanical ventilation with lung function parameters. Conclusion: Mechanical ventilation for a short period at birth in preterm children was not associated with lung function impairment at 11 years of age in our study sample. It remains to define if ventilation may have a short-term effect on lung function, not evident at 11 years of age.

The Role of Breastfeeding on Respiratory Outcomes Later in Childhood.

Background: Breastfeeding is associated with a lower risk of wheezing in early childhood, but its effect later in childhood remains unclear. We investigated the association of breastfeeding and respiratory outcomes in children aged 11 years. Materials and Methods: We performed an observational longitudinal study including 110 prepubertal children. Information about breastfeeding duration, wheezing and asthma was collected by questionnaires. At 11 years of age, we measured spirometry parameters, lung volumes, diffusing lung capacity, and fractional exhaled nitric oxide. We used logistic and linear regression models to examine the associations of breastfeeding duration with the odds of asthma and lung function measures. All multivariable analyses were adjusted for sex, smoking during pregnancy, gestational age at birth, twins, and mode of delivery (confounder model). Results: Breastfeeding duration was associated with FEV1 z-score [ß = 0.04, CI 95% (0.02-0.09)], FEF75 z-score [ß = 0.06, CI 95% (0.03-0.09)] and FEV1/FVC z-score [ß = 0.03, CI 95% (0.00-0.07)], but not with diffusing lung capacity and fractional exhaled nitric oxide. No association of breastfeeding duration with preschool wheezing, ever asthma and current asthma was documented. Conclusion: We showed that children breastfed for longer time presented higher FEV1, FEV1/FVC, and FEF75 z-score values at 11 years of age compared to children breastfed for shorter time, suggesting a protective effect of breastfeeding on airways, and not on lung parenchyma (lung volumes and alveolar capillary membrane) or allergic airway inflammation. The positive effect of breastfeeding duration on lung function lays the foundation to promote breastfeeding more and more as effective preventive measure.

Lifelong Lung Sequelae of Prematurity.

The clinical, functional, and structural pattern of chronic lung disease of prematurity has changed enormously in last years, mirroring a better perinatal management and an increasing lung immaturity with the survival of increasingly premature infants. Respiratory symptoms and lung function impairment related to prematurity seem to improve over time, but premature birth increases the likelihood of lung function impairment in late childhood, predisposing to chronic obstructive pulmonary disease (COPD). It is mandatory to identify those individuals born premature who are at risk for developing long-term lung disease through a better awareness of physicians, the use of standardized CT imaging scores, and a more comprehensive periodic lung function evaluation. The aim of this narrative review was to provide a systematic approach to lifelong respiratory symptoms, lung function impairment, and lung structural anomalies in order to better understand the specific role of prematurity on lung health.

Time-Specific Factors Influencing the Development of Asthma in Children.

Susceptibility to asthma is complex and heterogeneous, as it involves both genetic and environmental insults (pre- and post-birth) acting in a critical window of development in early life. According to the Developmental Origins of Health and Disease, several factors, both harmful and protective, such as nutrition, diseases, drugs, microbiome, and stressors, interact with genotypic variation to change the capacity of the organism to successfully adapt and grow in later life. In this review, we aim to provide the latest evidence about predictive risk and protective factors for developing asthma in different stages of life, from the fetal period to adolescence, in order to develop strategic preventive and therapeutic interventions to predict and improve health later in life. Our study shows that for some risk factors, such as exposure to cigarette smoke, environmental pollutants, and family history of asthma, the evidence in favor of a strong association of those factors with the development of asthma is solid and widely shared. Similarly, the clear benefits of some protective factors were shown, providing new insights into primary prevention. On the contrary, further longitudinal studies are required, as some points in the literature remain controversial and a source of debate.

Use of lung ultrasound in school-aged children with wheezing.

Background: There is limited information available on fast and safe bedside tools that could help clinicians establish whether the pathological process underlying cases of wheezing is due to asthmatic exacerbation, asthmatic bronchitis, or pneumonia. The study's aim was to characterize Lung Ultrasound (LUS) in school-aged children with wheezing and evaluate its use for their follow-up treatment. Materials and methods: We carried out a cross-sectional study involving 68 consecutive outpatients (mean age 9.9 years) with wheezing and suggestive signs of an acute respiratory infection. An expert sonographer, blinded to all subject characteristics, clinical course, and the study pediatrician's diagnosis, performed an LUS after spirometry and before BDT. The severity of acute respiratory symptoms was determined using the Pediatric Respiratory Assessment Measure (PRAM) score. Results: The LUS was positive in 38.2% (26/68) of patients [12 (46.1%) with multiple B-lines, 24 (92.3%) with consolidation, and 22 (84.6%) with pleural abnormalities]. In patients with pneumonia, asthmatic bronchitis, and asthma, the percentages of those patients with a positive LUS were 100%, 57.7%, and 0%, respectively. Of note, patients with a positive LUS were associated with an increased need for hospital admission (30.8% vs. 2.4%, p = 0.001), administration of oxygen therapy (14.6% vs. 0%, p = 0.009), oral corticosteroids (84.6% vs. 19.0%, p < 0.001), and antibiotics (88.5% vs. 11.9%, p < 0.001); and a higher median value of PRAM score (4.0 (2.0-7.0) vs. 2.0 (1.0-5.0); p < 0.001). Conclusions: Our findings would suggest the use of LUS as a safe and cheap tool used by clinicians to define the diagnosis of school-aged children with wheezing of unknown causes.

Effect of tonsillectomy in a child with obesity and obstructive sleep apnea: A case report and review of the literature.

Obstructive sleep apnea (OSA) is an increasingly recognized disorder in children. Adenotonsillectomy is the primary surgical treatment for OSA in children with adenotonsillar hypertrophy (ATH). We present the case of an obese 4-year-old boy hospitalized for severe desaturation during sleep and severe ATH. Nasal steroid therapy proved ineffective with persistent symptoms. Polygraphy documented severe OSA with an apnea-hypopnea index (AHI) equal to 11. Tonsillectomy resulted in prompt symptom improvement and a substantial reduction of the AHI (2.2). In this case, tonsillectomy alone resulted effective in treating OSA, despite obesity. We concluded that the presence of obesity should not postpone/exclude surgical treatment of preschool children for whom ATH is the most important cause of OSA.

A 5-Year-Old Child with a Deep Neck Abscess Complicated by Laryngeal Obstruction.

Deep neck space infections (DNSI) are defined as infections in the potential spaces and fascial planes of the neck. We show the clinical case of a retro and para-pharyngeal abscess in a healthy 5-year-old child complicated by compression and dislocation of the larynx with marked airway caliber reduction and potentially fatal extension up to the mediastinal aditus. DNSI can occur at any age and, due to its rapid progression, requires immediate treatment in children. In healthy children, concurrent abscesses in separate neck spaces are rare. DNSI recurrence should alert the physician to the possibility of a congenital problem, and if imaging fails, laryngoscopy may be the best diagnostic technique.

Immunological Targets of Biologic Drugs in Allergic Skin Diseases in Children.

Atopic dermatitis and urticaria are two invalidating skin disorders that are very common in children. Recent advances in the understanding of their specific intracellular molecular pathways have permitted the development of precise biological molecules, targeting inflammatory mediators and arresting the pathogenetic pathways of skin diseases. Many biologics with promising results have been studied, although few are currently approved in children. In this review, we aim to provide the latest evidence about the use, indications, efficacy and safety of biologic therapies to treat atopic dermatitis and chronic urticaria in children and adolescents.

Emergency Department Visits for allergy related-disorders among children: experience of a single Italian hospital during the first wave of the COVID-19 pandemic.

Introduction: The aim of this study was to compare the number of the Pediatric Emergency Department (PED) visits for young allergic patients with respiratory or cutaneous symptoms during the first wave of the coronavirus disease 19 (COVID-19) pandemic in 2020 with the same period in 2019, evaluating the percentage of positive cases to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We carried out a retrospective analysis using data from young patients who visited the PED with cutaneous or respiratory symptoms in the period from 20th February to 12th May of the years 2020 and 2019. Data on allergy and COVID-19 nasal swab were also collected. We observed eleven (28.2%) PED visits for allergic patients with respiratory or cutaneous symptoms for the period from 20th February to 12th May of the year 2020 and ninety-three (31.8%) PED visits for the same time frame of the year 2019 (p=0.645). Only a two-month-old child out of 39 patients with non-allergic respiratory or cutaneous symptoms resulted positive for SARS-CoV-2. Specifically, we found for all the PED visits: 21 (7.2%) in 2019 vs 2 (5.1%) in 2020 for patients with urticaria/angioedema or atopic dermatitis (p=0.634); 3 (1.0%) in 2019 vs 3 (7.7%) in 2020 for patients with anaphylaxis (p=0.003); 19 (6.5%) in 2019 vs 2 (5.1%) in 2020 for those with asthma (p=0.740); 11(3.8%) in 2019 vs 1(2.6%) in 2020 for those with lower respiratory diseases, excluding asthma (p=0.706); 39(13.4%) in 2019 vs 3 (7.7%) in 2020 for those with upper respiratory diseases (URDs) (p=0.318). We also showed a substantial decrease (~80%) in all PED visits compared with the same time frame in 2019 (absolute number 263 vs 1,211, respectively). Among all the PED visits a significant reduction was mostly found for URDs [155 (12.8%) in 2019 vs 17 (6.5%) in 2020; p=0.045)]. The total number of PED visits for allergic patients with respiratory or cutaneous symptoms dropped precipitously in 2020. It is very tricky to estimate whether it was a protective action of allergy or the fear of contagion or the lockdown or a reduction in air pollution that kept children with allergy from visiting the PED. Further studies are needed to better understand the impact of underlying allergies on COVID-19 susceptibility and disease severity.

Usefulness of Lung Ultrasound in Paediatric Respiratory Diseases.

Respiratory infection diseases are among the major causes of morbidity and mortality in children. Diagnosis is focused on clinical presentation, yet signs and symptoms are not specific and there is a need for new non-radiating diagnostic tools. Among these, lung ultrasound (LUS) has recently been included in point-of-care protocols showing interesting results. In comparison to other imaging techniques, such as chest X-ray and computed tomography, ultrasonography does not use ionizing radiations. Therefore, it is particularly suitable for clinical follow-up of paediatric patients. LUS requires only 5-10 min and allows physicians to make quick decisions about the patient's management. Nowadays, LUS has become an early diagnostic tool to detect pneumonia during the COVID-19 pandemic. In this narrative review, we show the most recent scientific literature about advantages and limits of LUS performance in children. Furthermore, we discuss the major paediatric indications separately, with a paragraph fully dedicated to COVID-19. Finally, we mention potential future perspectives about LUS application in paediatric respiratory diseases.