Addressing global health disparities in the management of RSV infection in infants and children: Strategies for preventing bronchiolitis and post-bronchiolitis recurrent wheezing.

Background: The topic of equitable access to health care and its impact on exacerbating worldwide inequities in child health not only strikes at the heart of our health-care delivery systems but also deeply resonates with our collective social consciences. Nowhere is this better seen on a global scale than in the burden of illness caused by respiratory syncytial virus (RSV) infection, which extracts the most severe morbidity and mortality in infants and children in low- and middle-income countries (LMIC). This report addresses global health disparities that exist in the management of RSV infection in infants and children, and offers strategies for preventing bronchiolitis and postbronchiolitis recurrent wheezing in LMICs. Methods: A systematic literature review was conducted across the PubMed data bases of RSV infection and the socioeconomic impact of bronchiolitis and postbronchiolitis recurrent wheezing in LMICs. Results: The results of the present study address the many issues that deal with the question if prevention of RSV bronchiolitis can mitigate recurrent wheezing episodes and links RSV risks, downstream effects, prevention, malnutrition, and socioeconomic restraints of developing countries with a call for possible global action. Conclusion: The present study stresses the importance of considering the linkage between malnutrition and disease susceptibility because of the known relationships between undernutrition and greater vulnerability to infectious diseases, including RSV infection. These complex interactions between infectious disease and undernutrition also raise issues on the longer-term sequelae of postbronchiolitis recurrent wheezing. This prompts a discussion on whether industrialized countries should prioritize the provision of newly developed monoclonal antibodies and RSV vaccines to LMICs or whether vital nutritional needs should be a first focus. The resolution of these issues will require research and greater international discourse.

Long COVID: A proposed hypothesis-driven model of viral persistence for the pathophysiology of the syndrome.

Background: Long COVID (coronavirus disease 2019) syndrome includes a group of patients who, after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibit lingering mild-to-moderate symptoms and develop medical complications that can have lasting health problems. In this report, we propose a model for the pathophysiology of the long COVID presentation based on increased proinflammatory cytokine production that results from the persistence of the SARS-CoV-2 virus or one of its molecular components. Associated with this hyperproduction of inflammatory cytokines is a heightened activity of nuclear factor κ B (NF-κB) and p38 mitogen-activated protein kinase signaling pathways that regulate cytokine production. Objective: The purpose of the present report was to review the causes of long COVID syndrome and suggest ways that can provide a basis for a better understanding of the clinical symptomatology for the of improved diagnostic and therapeutic procedures for the condition. Methods: Extensive research was conducted in medical literature data bases by applying terms such as "long COVID" associated with "persistence of the SARS-CoV-2 virus" "spike protein' "COVID-19" and "biologic therapies." Results and Conclusions: In this model of the long COVID syndrome, the persistence of SARS-CoV-2 is hypothesized to trigger a dysregulated immune system with subsequent heightened release of proinflammatory cytokines that lead to chronic low-grade inflammation and multiorgan symptomatology. The condition seems to have a genetic basis, which predisposes individuals to have a diminished immunologic capacity to completely clear the virus, with residual parts of the virus persisting. This persistence of virus and resultant hyperproduction of proinflammatory cytokines are proposed to form the basis of the syndrome.

Tiotropium add-on therapy is safe and reduces seasonal worsening in paediatric asthma patients.

There remains an unmet need for effective, well-tolerated therapeutic options in paediatric patients with not fully controlled asthma, for whom safety is of paramount importance.Data were pooled from five randomised, double-blind, placebo-controlled studies evaluating tiotropium 5 or 2.5 µg versus placebo add-on therapy in patients with symptomatic asthma aged 1-17 years. Analysis included adverse events (AEs) and serious AEs (SAEs) reported throughout and for 30 days following treatment.Of 1691 patients treated, 1119 received tiotropium. Reporting of AEs was low and comparable across all groups: tiotropium 5 µg (51%), tiotropium 2.5 µg (51%) and placebo (54%). Reporting of drug-related AEs, those leading to discontinuation and SAEs was also low and balanced between treatment groups, irrespective of age, disease severity or sex. The number of AEs related to asthma symptoms and exacerbations was lower with tiotropium (5 µg) than with placebo, particularly during the seasonal peaks of these AEs.This comprehensive analysis of a large safety database allowed subgroup analyses that are often impractical with individual trials and provides further support for the safety of once-daily tiotropium Respimat add-on therapy in paediatric patients with symptomatic asthma.

Olfactory dysfunction is worse in primary ciliary dyskinesia compared with other causes of chronic sinusitis in children.

Cilia have multiple functions including olfaction. We hypothesised that olfactory function could be impaired in primary ciliary dyskinesia (PCD). Olfaction, nasal nitric oxide (nNO) and sinus CT were assessed in patients with PCD and non-PCD sinus disease, and healthy controls (no CT scan). PCD and non-PCD patients had similar severity of sinus disease. Despite this, defective olfaction was more common in patients with PCD (P<0.0001) and more severe in patients with PCD with major Transmission Electron Microscopy (TEM) abnormalities. Only in classical PCD did olfaction inversely correlate with sinusitis and nNO. We speculate that defective olfaction in PCD is primary in nature.

Correlation between vitamin D serum levels and passive smoking exposure in children with asthma.

OBJECTIVE: To establish the relationship between vitamin D serum levels, pulmonary function, asthma control, and passive smoking exposure in children with asthma. METHODS: We studied the relationship between 25-hydroxy cholecalciferol (25[OH]D) concentrations and baseline spirometry and levels of asthma control, and the effect of parental tobacco smoke exposure in 152 white children (84 boys [55.3%]) with a mean age ± standard deviation of 9.9 ± 2.0 years (range 5-15 years) in a cross-sectional study carried out during the winter and early spring. RESULTS: Only 9.9% of our children had a sufficient serum 25(OH)D level (at least 30-40 ng/mL). A significant positive correlation was found between the force vital capacity % predicted, forced expiratory volume in the first second of expiration % predicted, and serum 25(OH)D level (r = 0.36, p < 0.001 for both). The subjects with controlled asthma had higher serum levels of 25(OH)D than children with partially controlled or noncontrolled asthma, both according to Global Initiative for Asthma parameters and the Test for the control of asthma in childhood (p = 0.011). Children with both nonsmoking parents presented significantly higher serum levels of 25(OH)D than children with both smoking parents (median, 20.5 ng/mL [interquartile range {IQR}, 16.6-24.0 ng/mL] versus median, 14.5 ng/mL [IQR, 11.1-19.1 ng/mL], respectively; p < 0.001), with intermediate values for children exposed to single maternal (median, 20.3 ng/mL [IQR, 13.0-23.2 ng/mL]) or to paternal smoking (median, 17.8 ng/mL [IQR, 14.7-22.1 ng/mL]). CONCLUSION: Our results indicated that hypovitaminosis D was frequent in children with asthma who lived in a Mediterranean country. In these children, lower levels of vitamin D were associated with reduced asthma control and passive smoking exposure.

A randomised controlled trial of tiotropium in adolescents with severe symptomatic asthma.

We present results from the first phase III trial of once-daily tiotropium add-on to inhaled corticosteroids (ICS) plus one or more controller therapies in adolescents with severe symptomatic asthma.In this double-blind, parallel-group trial (NCT01277523), 392 patients aged 12-17 years were randomised to receive once-daily tiotropium 5 µg or 2.5 µg, or placebo, as an add-on to ICS plus other controller therapies over 12 weeks. The primary and key secondary end-points were change from baseline (response) in peak forced expiratory volume in 1 s (FEV1) within 3 h post-dosing (FEV1(0-3h)) and trough FEV1, respectively, after 12 weeks of treatment.Tiotropium 5 µg provided numerical improvements in peak FEV1(0-3h) response, compared with placebo (90 mL; p=0.104), and significant improvements were observed with tiotropium 2.5 µg (111 mL; p=0.046). Numerical improvements in trough FEV1 response and asthma control were observed with both tiotropium doses, compared with placebo. The safety and tolerability of tiotropium were comparable with those of placebo.Once-daily tiotropium Respimat add-on to ICS plus one or more controller therapies in adolescents with severe symptomatic asthma was well tolerated. The primary end-point of efficacy was not met, although positive trends for improvements in lung function and asthma control were observed.

Tiotropium add-on therapy in adolescents with moderate asthma: A 1-year randomized controlled trial.

BACKGROUND: Results from phase III clinical trials in adults and phase II clinical trials in children and adolescents demonstrate that tiotropium is an effective treatment when added to inhaled corticosteroid (ICS) maintenance therapy. OBJECTIVE: We sought to assess the efficacy and safety of once-daily tiotropium Respimat added to ICSs with or without a leukotriene receptor antagonist in a phase III trial in adolescent patients with moderate symptomatic asthma. METHODS: In this 48-week, double-blind, placebo-controlled, parallel-group study, 398 patients aged 12 to 17 years were randomized to receive 5 µg (2 puffs of 2.5 µg) or 2.5 µg (2 puffs of 1.25 µg) of once-daily tiotropium or placebo (2 puffs) administered through the Respimat device every evening, each as add-on treatment to ICS background therapy, with or without a leukotriene receptor antagonist; long-acting ß2-agonist therapy was not permitted during the study. RESULTS: Improvement in peak FEV1 within 3 hours after dosing at 24 weeks (primary end point) was statistically significant with both tiotropium doses compared with placebo: 5 µg of tiotropium, 174 mL (95% CI, 76-272 mL); 2.5 µg of tiotropium, 134 mL (95% CI, 34-234 mL). Significant improvements in trough FEV1 at week 24 (a secondary end point) were observed with the 5-µg dose only. Trends for improvement in asthma control and health-related quality of life over the 48-week treatment period were observed. CONCLUSIONS: Once-daily tiotropium significantly improved lung function and was safe and well tolerated when added to at least ICS maintenance therapy in adolescent patients with moderate symptomatic asthma. Larger responses were observed with the 5-µg tiotropium dose.

Microorganism-induced exacerbations in atopic dermatitis: a possible preventive role for vitamin D?

Atopic dermatitis (AD) is a common skin disease characterized by a complex pathogenesis not completely understood despite numerous studies to date. The clinical patterns result from interactions between genetic disorders determining abnormalities in the epidermis differentiation complex, modification of the cutaneous barrier, and dysfunction of immune responses. Several studies have shown that an alteration of the skin barrier combined with immune dysfunction is important for the onset, maintenance, and risk of exacerbations of the disease. In recent years, new aspects regarding the pathogenesis of the disease, such as the effects of vitamin D (VD) on immunity at the skin level and the role of certain microorganisms (particularly Staphylococcus and Malassezia species) on eczema exacerbations, have been evaluated. This article provides an overview of the evidences supporting the link between VD (deficiency) and microorganisms (skin colonization/sensitization) in AD pathogenesis, based on comprehensive review of the literature. By considering different aspects of disease, it might be possible to improve our understanding, particularly in those patients refractory to conventional treatments. An electronic research strategy was used to search in Medline Pub-Med Library using as research words AD, exacerbation, VD, Staphylococcus aureus (SA), and Malassezia. The results were downloaded and analyzed for systematic review. Few studies actually consider the relationship between VD deficiency (VDD), AD, and SA and Malassezia, but many suggest a correlation between these factors. VDs play a major role against microorganisms in the development of AD and should be considered when treating patients.

Correlation of skin barrier impairment in atopic dermatitis with aeroallergen sensitization.

BACKGROUND: Atopic dermatitis (AD) often predates the development of allergic sensitization in the so-called atopic march. Several studies have pointed out epidermal barrier impairment as a major cause of this evolution. OBJECTIVE: The present study aimed to assess atopic skin integrity by means of transepidermal water loss (TEWL) and Corneometer, and to investigate possible correlations between barrier integrity measurements and the degree of sensitization to aeroallergens (allergy score). METHODS: Sixty-one children (6 months to 17 years old) with AD were clinically evaluated by the Scoring Atopic Dermatitis index. TEWL and Corneometer evaluations were performed on lesion sites as well as on healthy skin. The subjects underwent skin-prick testing, and the severity of allergic sensitization was assessed for each patient by summing all wheal diameters (the allergy score). The same tests were performed in 20 children without AD. RESULTS: In patients with AD, TEWL and Corneometer results were found to be higher and lower, respectively, on eczematous areas in comparison with healthy skin, and differences were significantly correlated to the Scoring Atopic Dermatitis index (p < 0.0001 and p = 0.007, respectively). The TEWL result was significantly higher in nonlesional skin of the patients with AD compared with that of individuals without AD (p = 0.017). Of the patients with AD, 59% were sensitized to inhalant allergens; allergy scores were positively correlated with both AD duration (r = 0.63; p < 0.0001) and nonlesional skin TEWL values (r = 0.46; p = 0.002). No significant correlation was found between allergy scores and skin parameters in subjects without AD. CONCLUSION: Patients with AD are affected by barrier function impairment, even on noneczematous skin. This defect is associated with greater aeroallergen sensitization and may contribute to allergic respiratory symptom development.

The genetic framework of primary ciliary dyskinesia assessed by soft computing analysis.

BACKGROUND: International guidelines disagree on how best to diagnose primary ciliary dyskinesia (PCD), not least because many tests rely on pattern recognition. We hypothesized that quantitative distribution of ciliary ultrastructural and motion abnormalities would detect most frequent PCD-causing groups of genes by soft computing analysis. METHODS: Archived data on transmission electron microscopy and high-speed video analysis from 212 PCD patients were re-examined to quantitate distribution of ultrastructural (10 parameters) and functional ciliary features (4 beat pattern and 2 frequency parameters). The correlation between ultrastructural and motion features was evaluated by blinded clustering analysis of the first two principal components, obtained from ultrastructural variables for each patient. Soft computing was applied to ultrastructure to predict ciliary beat frequency (CBF) and motion patterns by a regression model. Another model classified the patients into the five most frequent PCD-causing gene groups, from their ultrastructure, CBF and beat patterns. RESULTS: The patients were subdivided into six clusters with similar values to homologous ultrastructural phenotype, motion patterns, and CBF, except for clusters 1 and 4, attributable to normal ultrastructure. The regression model confirmed the ability to predict functional ciliary features from ultrastructural parameters. The genetic classification model identified most of the different groups of genes, starting from all quantitative parameters. CONCLUSIONS: Applying soft computing methodologies to PCD diagnostic tests optimizes their value by moving from pattern recognition to quantification. The approach may also be useful to evaluate atypical PCD, and novel genetic abnormalities of unclear disease-producing potential in the future.

Rapid diagnosis of primary ciliary dyskinesia: cell culture and soft computing analysis.

Diagnosis of primary ciliary dyskinesia (PCD) sometimes requires repeated nasal brushing to exclude secondary ciliary alterations. Our aim was to evaluate whether the use of a new method of nasal epithelial cell culture can speed PCD diagnosis in doubtful cases and to identify which are the most informative parameters by means of a multilayer artificial neural network (ANN). A cross-sectional study was performed in patients with suspected PCD. All patients underwent nasal brushing for ciliary motion analysis, ultrastructural assessment and evaluation of ciliary function after ciliogenesis in culture by ANN. 151 subjects were studied. A diagnostic suspension cell culture was obtained in 117 nasal brushings. A diagnosis of PCD was made in 36 subjects (29 of whom were children). In nine out of the 36 patients the diagnosis was made only after a second brushing, because of equivocal results of both tests at first examination. In each of these subjects diagnosis of PCD was confirmed by cell culture results. Cell culture in suspension evaluated by means of ANN allows the separation of PCD from secondary ciliary dyskinesia patients after only 5 days of culture and allows diagnosis to be reached in doubtful cases, thus avoiding the necessity of a second sample.

A bioinformatics approach to identify patients with symptomatic peanut allergy using peptide microarray immunoassay.

BACKGROUND: Peanut allergy is relatively common, typically permanent, and often severe. Double-blind, placebo-controlled food challenge is considered the gold standard for the diagnosis of food allergy-related disorders. However, the complexity and potential of double-blind, placebo-controlled food challenge to cause life-threatening allergic reactions affects its clinical application. A laboratory test that could accurately diagnose symptomatic peanut allergy would greatly facilitate clinical practice. OBJECTIVE: We sought to develop an allergy diagnostic method that could correctly predict symptomatic peanut allergy by using peptide microarray immunoassays and bioinformatic methods. METHODS: Microarray immunoassays were performed by using the sera from 62 patients (31 with symptomatic peanut allergy and 31 who had outgrown their peanut allergy or were sensitized but were clinically tolerant to peanut). Specific IgE and IgG(4) binding to 419 overlapping peptides (15 mers, 3 offset) covering the amino acid sequences of Ara h 1, Ara h 2, and Ara h 3 were measured by using a peptide microarray immunoassay. Bioinformatic methods were applied for data analysis. RESULTS: Individuals with peanut allergy showed significantly greater IgE binding and broader epitope diversity than did peanut-tolerant individuals. No significant difference in IgG(4) binding was found between groups. By using machine learning methods, 4 peptide biomarkers were identified and prediction models that can predict the outcome of double-blind, placebo-controlled food challenges with high accuracy were developed by using a combination of the biomarkers. CONCLUSIONS: In this study, we developed a novel diagnostic approach that can predict peanut allergy with high accuracy by combining the results of a peptide microarray immunoassay and bioinformatic methods. Further studies are needed to validate the efficacy of this assay in clinical practice.

Analysis of urinary parameters as risk factors for nephrolithiasis in children with celiac disease.

PURPOSE: Intestinal malabsorption can cause urinary stone disease via enteric hyperoxaluria. It has been shown that celiac disease, a common malabsorption disorder, is associated with an increased risk of calcium oxalate kidney stones in adults. Since no published data are available in the pediatric population, we analyzed urinary excretion of electrolytes in children with celiac disease to assess the risk of nephrolithiasis. MATERIALS AND METHODS: The study population consisted of 115 children 1 to 16 years old (mean 5 years) with positive serological tests for celiac disease (anti-endomysium and anti-tissue transglutaminase antibodies) referred to us for jejunal biopsy to confirm the diagnosis. Assessment was requested because patients presented with poor growth, anemia, gastrointestinal disorders or a family history of celiac disease. After obtaining informed consent we performed urine tests to measure urinary variables and blood tests to exclude metabolic disorders and evaluate renal function. RESULTS: All patients had a biopsy confirmed diagnosis of celiac disease. Oxaluria was normal in all children studied. However, levels of urinary calcium were decreased in patients with celiac disease and were inversely associated with disease severity (p = 0.0004). CONCLUSIONS: In contrast to adults, increased urinary excretion of oxalate was not detectable in children presenting with celiac disease. Therefore, the risk of nephrolithiasis appears not to be increased compared to healthy children. The observed hypocalciuria probably further decreases the tendency to form kidney stones.

Longitudinal Nitric Oxide Levels and Infections by Ultrastructure and Genotype in Primary Ciliary Dyskinesia.

BACKGROUND: We hypothesized that differences in nasal nitric oxide (nNO) and fractional exhaled nitric oxide (Feno) relate to prognosis in primary ciliary dyskinesia (PCD). RESEARCH QUESTION: What is the relationship between baseline values and longitudinal evolution of nNO and Feno and ultrastructure, genotype, and respiratory infections in PCD? STUDY DESIGN AND METHODS: Prospective, longitudinal, single-center study in adults and children evaluated biannually for up to 10 years. We compared cross-sectional and longitudinal values of nNO and Feno in ultrastructural (inner dynein arm [IDA] and microtubular disorganization [MTD]) and genetic (CCDC39 and CCDC40) groups known to have worse pulmonary function with patients within the ultrastructural and genetic groups with a better prognosis. Linear mixed-effects models were used to evaluate longitudinal associations. RESULTS: One hundred forty-one patients with PCD underwent 1,014 visits. At enrollment, no differences were found in children in nNO or Feno between the IDA and MTD group and the other ultrastructural groups. In adults, nNO (P = .038) and Feno (P = .032) were significantly lower in the IDA and MTD group than in all other combined ultrastructural groups. Feno values were significantly lower in the CCDC39 and CCDC40 group than in the DNAH5 and DNAH11 combined genotype group (P = .033) and in all other genotypes (P = .032). The IDA and MTD group showed a significant decline in nNO with age (P < .01) compared with other ultrastructural groups who showed stable levels. The CCDC39 and CCDC40 group showed the steepest decline in nNO over time (P < .01) compared with all other genotypes. A higher nNO was associated with lower likelihood of any positive bacterial isolate from the lower respiratory tract (P = .008). Changes in Feno over time did not differ between structural groups or genotypes. INTERPRETATION: Lower nNO in patients with PCD with genetic and ultrastructural changes associated with greater lung function decline may be related to worse prognosis, but whether a low nNO is causal needs further study. If lower nNO directly results in a poorer prognosis, strategies augmenting upper airway nitric oxide production may be worth evaluating.

Long-term outcomes of pediatric infections: from traditional infectious diseases to long Covid.

There is limited evidence available on the long-term impact of SARS-CoV-2 infection in children. In this article, the authors analyze the recent evidence on pediatric long Covid and lessons learnt from a pediatric post-Covid unit in Rome, Italy. To gain a better understanding of the concerns raised by parents and physicians in relation to the potential long-term consequences of this novel infection, it is important to recognize that long-term effect of a post-infectious disease is not a new phenomenon.

The authors analyze the recent evidence on pediatric long Covid and lessons learnt from a pediatric post-Covid unit in Rome, Italy. Also, we analyze the long-term effects of other infectious diseases.

Vitamin D serum levels and markers of asthma control in Italian children.

OBJECTIVE: To establish the relationship between vitamin D serum levels, pulmonary function, and asthma control in children. STUDY DESIGN: We studied the relationship between 25-hydroxy cholecalciferol [25(OH)D] concentrations and baseline spirometry and levels of asthma control, assessed according to Global Initiative for Asthma guidelines and the Childhood Asthma Control Test, in 75 children with asthma (age range 5-11 years; 43 males) in a cross-sectional study carried out during the winter and early spring. RESULTS: Only 9.4% of our children had a sufficient serum 25(OH)D (at least 30 to 40 ng/mL). A significant positive correlation was found between forced vital capacity percent predicted and serum 25(OH)D (r = 0.25, P = .040). This was true also for forced expiratory volume in 1 second, even though it was not statistically significant (r = 0.16, P = .157). Subjects with well-controlled asthma had higher serum levels of 25(OH)D than children with partially controlled or non-controlled asthma, with values of (median [Q1; Q3]) 22.2 (16.3; 25.4), 17.8 (11.8; 22.1) and 18.1 (15.0; 18.5), respectively (P = .023). Furthermore, a positive correlation was found between 25(OH)D and the Childhood Asthma Control Test (r = 0.28; P = .011). CONCLUSIONS: Our results indicate that hypovitaminosis D is frequent in children with asthma living in a Mediterranean country. In those children, lower levels of vitamin D are associated with reduced asthma control.

Longitudinal Lung Volume Changes by Ultrastructure and Genotype in Primary Ciliary Dyskinesia.

Rationale: Genotype-phenotype relationships are emerging in primary ciliary dyskinesia (PCD), but little is known about lung volume changes over time. Objectives: To investigate the evolution of static lung volumes with ultrastructural defects, gene mutations, body mass index, and specific infections in PCD. Methods: Prospective, longitudinal, single-center study in children and adults evaluated twice yearly for up to 10 years. Linear mixed-effects models were used to assess associations between ciliary morphology, genetic mutations, and clinical features. Results: A total of 122 patients had 1,096 visits. At enrollment, almost all spirometric and, especially in adults, plethysmographic parameters were significantly worse in absent inner dynein arms (IDAs), central apparatus (CA) defects, and microtubular disorganization (MTD) (IDA/CA/MTD) compared with patients with normal electron microscopy (EM) results. The mean trend increase with time for residual volume (RV) was significantly higher in IDA/CA/MTD group compared with groups with outer dynein arm defect and normal EM results. The mean trend of RV/total lung capacity in the IDA/CA/MTD group was significantly worse than in all other groups. The steepest rise in lung volumes was in CCDC39 and CCDC40, whereas hyperinflation increased less in DNAH5 and DNAH11 groups. RV/total lung capacity showed a significantly steeper rise in patients with Pseudomonas aeruginosa compared with patients with other infections or patients without infection. Conclusions: Patients with IDA/CA/MTD defects or CCDC39 and CCDC40 mutations had the greatest increase in hyperinflation, whereas those with outer dynein arm defect and normal EM results or DNAH11 and DNAH5 mutations had less severe changes. We have robustly confirmed the worse prognosis for some genetic and ultrastructural defects, which association hitherto rested solely on spirometry.