Airway epithelial development and function: A key player in asthma pathogenesis?

Though asthma is a common and relatively easy to diagnose disease, attempts at primary or secondary prevention, and cure, have been disappointing. The widespread use of inhaled steroids has dramatically improved asthma control but has offered nothing in terms of altering long-term outcomes or reversing airway remodeling and impairment in lung function. The inability to cure asthma is unsurprising given our limited understanding of the factors that contribute to disease initiation and persistence. New data have focused on the airway epithelium as a potentially key factor orchestrating the different stages of asthma. In this review we summarize for the clinician the current evidence on the central role of the airway epithelium in asthma pathogenesis and the factors that may alter epithelial integrity and functionality.

COVID-19 in Children with Asthma.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects both children and adults but epidemiological and clinical data demonstrate that children are less likely to have a severe disease course or die. Furthermore, asthmatic children show less severe disease manifestations when infected with SARS-CoV-2 comparing to adults. This review focuses on SARS-CoV-2 and childhood asthma interaction and aims at summarizing the current knowledge of the potential mechanisms that ameliorate disease symptomatology in asthmatic children.

Childhood chronic cough made easy: a simplified approach for the primary care setting.

Cough is a defense mechanism, but when it becomes persistent and troublesome, it must be carefully assessed. Chronic cough, that is, cough persisting for more than 4 weeks, has a proven negative impact on a child's quality of life; it interferes with daily activities, sleep, and schooling and may involve frequent health care visits and long-lasting treatments. Currently, there is a plethora of algorithms in the literature aiming to assist in the assessment of chronic cough in children; however, referring to complex flowcharts may be impractical for the usually busy primary care physician. Herein, we provide a simplified tool for the assessment of children with chronic cough in the primary care setting, presenting a basic approach to the most common causes along with hints to avoid common pitfalls in everyday practice. Finally, the most common clinical scenarios are analyzed, aiming to assist primary care physicians in providing the appropriate care to these patients.

Time-dependent gene-environment interactions are essential drivers of asthma initiation and persistence.

Asthma is a clinical syndrome caused by heterogeneous underlying mechanisms with some of them having a strong genetic component. It is known that up to 82% of atopic asthma has a genetic background with the rest being influenced by environmental factors that cause epigenetic modification(s) of gene expression. The interaction between the gene(s) and the environment has long been regarded as the most likely explanation of asthma initiation and persistence. Lately, much attention has been given to the time frame the interaction occurs since the host response (immune or biological) to environmental triggers, differs at different developmental ages. The integration of the time variant into asthma pathogenesis is appearing to be equally important as the gene(s)-environment interaction. It seems that, all three factors should be present to trigger the asthma initiation and persistence cascade. Herein, we introduce the importance of the time variant in asthma pathogenesis and emphasize the long-term clinical significance of the time-dependent gene-environment interactions in childhood.

Well-Established and Traditional Use of Vegetal Extracts as an Approach to the "Deep Roots" of Cough.

Cough is a common presenting symptom for patients in a primary care setting and significantly impacts a patient's quality of life. Cough involves a complex reflex arc beginning with the stimulation of sensory nerves that function as cough receptors that stimulate the cough center in the brain. This "cough center" functions to receive these impulses and produce a cough by activating efferent nervous pathways to the diaphragm and laryngeal, thoracic, and abdominal musculature. Drugs that suppress the neural activity of cough are non-specific as those treatments are not directed toward pathogenic causes such as inflammation and oxidative stress. Moreover, they block a reflex called the watchdog of the lung and have a defense mechanism. Acute respiratory infections of the upper and lower airways most commonly cause acute cough. In contrast, the most common causes of chronic cough are upper airway cough syndrome, asthma, and gastroesophageal reflux disease, all associated with an inflammatory reaction at the level of the cough receptors. The use of natural compounds or herbal drugs such as carob syrup, dry blackcurrant extract, dry extract of caraway fruit, dry extract of ginger rhizome, dry extract of marshmallow root, and dry extract of ivy leaves, to name a few, not only have anti-inflammatory and antioxidant activity, but also act as antimicrobials, bronchial muscle relaxants, and increase gastric motility and empty. For these reasons, these natural substances are widely used to control cough at its deep roots (i.e., contrasting its causes and not inhibiting the arch reflex). With this approach, the lung watchdog is not put to sleep, as with peripheral or central inhibition of the cough reflex, and by contrasting the causes, we may control cough that viruses use at self-advantage to increase transmission.

Pathogenesis of nontypeable Haemophilus influenzae infections in chronic suppurative lung disease.

The respiratory tract antimicrobial defense system is a multilayered defense mechanism that relies upon mucociliary clearance and components of both the innate and adaptive immune systems to protect the lungs from inhaled or aspirated microorganisms. One of these potential pathogens, nontypeable Haemophilus influenzae (NTHi), adopts several, multifaceted redundant strategies to successfully colonize the lower airways and establish a persistent infection. NTHi can impair mucociliary clearance, express multiple multifunctional adhesins for various cell types within the respiratory tract and evade host defenses by surviving within and between cells, forming biofilms, increasing antigenic drift, secreting proteases and antioxidants, and by host-pathogen cross-talk, impair macrophage and neutrophil function. NTHi is recognized as an important pathogen in several chronic lower respiratory disorders, such as protracted bacterial bronchitis, bronchiectasis, cystic fibrosis, and primary ciliary dyskinesia. The persistence of NTHi in human airways, including its capacity to form biofilms, results in chronic infection and inflammation, which can ultimately injure airway wall structures. The complex nature of the molecular pathogenetic mechanisms employed by NTHi is incompletely understood but improved understanding of its pathobiology will be important for developing effective therapies and vaccines, especially given the marked genetic heterogeneity of NTHi and its possession of phase-variable genes. Currently, no vaccine candidates are ready for large phase III clinical trials.

Enigma variations: The multi-faceted problems of pre-school wheeze.

Numerous publications on wheezing disorders in children younger than 6 years have appeared in the medical literature over the last decades with the aim of shedding light on the mechanistic pathways (endotypes) and treatment. Nevertheless, there is yet no consensus as to the appropriate way to manage preschool wheeze mainly because of the lack of a clear definition of "preschool asthma" and the paucity of scientific evidence concerning its underlying endotypes. A symptom-based approach is inadequate since the human airway can respond to external stimuli with a limited range of symptoms and signs, including cough and wheeze, and these manifestations represent the final expression of many clinical entities with potentially different pathophysiologies requiring different individualized treatments. Hence, new studies challenge the symptom-based approach and promote the importance of managing the wheezy child based on the "airway phenotype." This will enable the clinician to identify not only the child with a serious underlying pathology (e.g., a structural airway disorder or immunodeficiency) who is in need of prompt and specific treatment but also increase the specificity of treatment for the child with symptoms suggestive of an "asthma" syndrome. In the latter case, focus should be given to the identification of treatable traits. This review summarizes the current understanding in management of preschool wheezing and highlights the unmet need for further research.

Vaping in Asthmatic Adolescents: Time to Deal with the Elephant in the Room.

Adolescence is a period characterized by developmental, psychological, and psychosocial alterations, with a major impact on youths' attitudes and perceptions. Adolescents with asthma may not comply with treatment and may develop risky behaviors, including smoking, vaping, and other substance use, leading to unanticipated exacerbations and consequences. Vaping has become extremely popular in this age group, and studies have suggested that it has potential adverse effects on asthmatic airways. More well-designed studies are needed to confirm the initial worrying data, and action must be taken by both medical officers and health authorities to deal with the elephant in the room and curb the vaping pandemic. The aim of this paper is to provide a review of the current knowledge regarding the effect of vaping on adolescents with asthma and to propose actions to restrain this fast-growing trend.

History Taking as a Diagnostic Tool in Children With Chronic Cough.

Chronic cough is a common symptom of many underlying respiratory and non-respiratory disorders and may be associated with less serious causes, such as gastroesophageal reflux and nasal diseases. Chronic cough in children differs from that in adults with respect to its etiologies and management since it can indicate a symptom of an underlying disease in children. Guidelines for managing chronic cough in children are based on recording the history, followed by physical examination, chest radiography, and spirometry. Thus, taking accurate respiratory history for coughing helps delineate the pathophysiological basis of the cause of chronic cough. Detailed history taking enhances the evaluation and treatment, and facilitates a tailored diagnostic identification of likely diagnoses. While studies have described evidence-based red flags in children with chronic cough, the value of skilled physicians regarding history taking has received less attention for the best patient care. In the present article, we outline the major questions comprising a detailed history taking for chronic cough in children.

Calprotectin: An Ignored Biomarker of Neutrophilia in Pediatric Respiratory Diseases.

Calprotectin (CP) is a non-covalent heterodimer formed by the subunits S100A8 (A8) and S100A9 (A9). When neutrophils become activated, undergo disruption, or die, this abundant cytosolic neutrophil protein is released. By fervently chelating trace metal ions that are essential for bacterial development, CP plays an important role in human innate immunity. It also serves as an alarmin by controlling the inflammatory response after it is released. Extracellular concentrations of CP increase in response to infection and inflammation, and are used as a biomarker of neutrophil activation in a variety of inflammatory diseases. Although it has been almost 40 years since CP was discovered, its use in daily pediatric practice is still limited. Current evidence suggests that CP could be used as a biomarker in a variety of pediatric respiratory diseases, and could become a valuable key factor in promoting diagnostic and therapeutic capacity. The aim of this study is to re-introduce CP to the medical community and to emphasize its potential role with the hope of integrating it as a useful adjunct, in the practice of pediatric respiratory medicine.

Action and Reaction of Pre-Primary and Primary School-Age Children to Restrictions during COVID-19 Pandemic in Greece.

The fast-spreading coronavirus disease 2019 (COVID-19) pandemic forced countries to apply restrictive measures to counteract it. School closure was quickly adopted by health authorities. We aimed to investigate the compliance of children aged 4 to 12 years with the COVID-19 lockdown restrictions and evaluate the impact of school closure on the children's educational, social, economic, and psychological outcomes. An online survey was distributed through a social networking platform to parents of pre-primary and primary school-age children. The study period was defined as from 27 November 2020 to 3 December 2020, two weeks after the school closure due to the general lockdown in Greece. This study showed that the school units were well-informed and complied with the protection measures against COVID-19. The pupils quickly adopted the protection measures, even those whose parents suggested masks were less effective. The quarantine-forced school closure highly impacted primary school children's physical activity, quality of sleep, psychological status, eating habits, academic performance, and household income. Web use showed an increase, with the children over-spending extracurricular time in web activities. Our study highlights the need for long term monitoring of these aforementioned indices, and the development of COVID-19 mitigation measures that carefully incorporate effectiveness and societal impact.

Lung Function Variability in Children and Adolescents With and Without Asthma (LUV Study): Protocol for a Prospective, Nonrandomized, Clinical Trial.

BACKGROUND: Variability analysis of peak expiratory flow (PEF) and forced expiratory volume at 1 second (FEV1) has been used in research to predict exacerbations in adults with asthma. However, there is a paucity of data regarding PEF and FEV1 variability in healthy children and adolescents and those with asthma. OBJECTIVE: The objective of this study is the assessment of PEF and FEV1 variability in (1) healthy children and adolescents, to define the normal daily fluctuation of PEF and FEV1 and the parameters that may influence it, and (2) children and adolescents with asthma, to explore the differences from healthy subjects and reveal any specific variability changes prior to exacerbation. METHODS: The study will include 100 healthy children and adolescents aged 6-18 years (assessment of normal PEF and FEV1 variability) and 100 children and adolescents of the same age with diagnosed asthma (assessment of PEF and FEV1 variability in subjects with asthma). PEF and FEV1 measurements will be performed using an ultraportable spirometer (Spirobank Smart; MIR Medical International Research) capable of smartphone connection. Measurements will be performed twice a day between 7 AM and 9 AM and between 7 PM and 9 PM and will be dispatched via email to a central database for a period of 3 months. PEF and FEV1 variability will be assessed by detrended fluctuation and sample entropy analysis, aiming to define the normal pattern (healthy controls) and to detect and quantify any deviations among individuals with asthma. The anticipated duration of the study is 24 months. RESULTS: The study is funded by the "C. Caratheodory" Programme of the University of Patras, Greece (PN 47014/24.9.2018). It was approved by the Ethics Committee (decision 218/19-03-2019) and the Scientific Board (decision 329/02-04-2019) of the University Hospital of Patras, Greece. Patient recruitment started in January 2020, and as of June 2020, 100 healthy children have been enrolled (74 of them have completed the measurements). The anticipated duration of the study is 24 months. The first part of the study (assessment of lung function variability in healthy children and adolescents) will be completed in August 2020, and the results will be available for publication by October 2020. CONCLUSIONS: Healthy children and adolescents may present normal short- and long-term fluctuations in lung function; the pattern of this variability may be influenced by age, sex, and environmental conditions. Significant lung function variability may also be present in children and adolescents with asthma, but the patterns may differ from those observed in healthy children and adolescents. Such data would improve our understanding regarding the chronobiology of asthma and permit the development of integrated tools for assessing the level of control and risk of future exacerbations. TRIAL REGISTRATION: ClinicalTrials.gov NCT04163146; https://clinicaltrials.gov/ct2/show/NCT04163146. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/20350.