Alarmins and innate lymphoid cells 2 activation: A common pathogenetic link connecting respiratory syncytial virus bronchiolitis and later wheezing/asthma?

Severe respiratory syncytial virus (RSV) infection in infancy is associated with increased risk of recurrent wheezing in childhood. Both acute and long-term alterations in airway functions are thought to be related to inefficient antiviral immune response. The airway epithelium, the first target of RSV, normally acts as an immunological barrier able to elicit an effective immune reaction but may also be programmed to directly promote a Th2 response, independently from Th2 lymphocyte involvement. Recognition of RSV transcripts and viral replication intermediates by bronchial epithelial cells brings about release of TSLP, IL-33, HMGB1, and IL-25, dubbed "alarmins." These epithelial cell-derived proteins are particularly effective in stimulating innate lymphoid cells 2 (ILC2) to release IL-4, IL-5, and IL-13. ILC2, reflect the innate counterparts of Th2 cells and, when activate, are potent promoters of airway inflammation and hyperresponsiveness in RSV bronchiolitis and childhood wheezing/asthma. Long-term epithelial progenitors or persistent epigenetic modifications of the airway epithelium following RSV infection may play a pathogenetic role in the short- and long-term increased susceptibility to obstructive lung diseases in response to RSV in the young. Additionally, ILC2 function may be further regulated by RSV-induced changes in gut microbiota community composition that can be associated with disease severity in infants. A better understanding of the alarmin-ILC interactions in childhood might provide insights into the mechanisms characterizing these immune-mediated diseases and indicate new targets for prevention and therapeutic interventions.

Is secondary tracheomalacia associated with airway inflammation and infection?

BACKGROUND: Recurrent lower respiratory tract infections are among the most prevalent symptoms in secondary tracheomalacia due to mediastinal vascular anomalies (MVAs). It is not known whether this condition could result in persistent lower respiratory tract inflammation and subclinical infection. METHODS: A retrospective study was performed on records of children with tracheomalacia due to MVAs and recurrent respiratory infections who underwent computed tomography scan, bronchoscopy, and bronchoalveolar lavage (BAL) as part of their clinical evaluation. RESULTS: Thirty-one children were included in the study: 21 with aberrant innominate artery, four with right aortic arch, one with double aortic arch, and five with aberrant innominate artery associated with right aortic arch. Cytological evaluation of bronchoalveolar lavage fluid showed increased neutrophil percentages and normal lymphocyte and eosinophil proportions. Microorganism growth was detected in 13 BAL samples, with a bacterial load ≥104 colony-forming units/mL in eight (25.8%) of them. Most isolates were positive for Haemophilus influenzae. Bronchiectasis was detected in four children, all with BAL culture positive for H. influenzae. Four patients underwent MVA surgical correction and 27 conservative management, i.e., respiratory physiotherapy in all and high-dose amoxicillin/clavulanic acid (40 mg/kg/day) for 2-4 weeks in those with significant bacterial growth. There was an excellent outcome in most of them. CONCLUSIONS: Neutrophilic alveolitis is detectable in secondary tracheomalacia but is associated with a clinically significant bacterial load only in a quarter of the patients. Caution should be used regarding inappropriate antibiotic prescriptions to avoid the emergence of resistance, whilst airway clearance maneuvers and infection preventive measures should be promoted.

Respiratory syncytial virus and airway microbiota - A complex interplay and its reflection on morbidity.

The immunopathology of respiratory syncytial virus (RSV) infection varies considerably, severe disease occurring only in a minority of the affected children. The variability of the clinical presentation is in part explained by viral and environmental factors but, in infants and young children, disease severity is certainly linked to the physiologic immaturity of the innate and adaptive immune system. There is evidence that the maturation of the host immune response is positively influenced by the composition of the nasopharyngeal microbiome that, promoting an efficient reaction, can counteract the predisposition to develop viral respiratory infections and lower the risk of disease severity. However, interaction between the nasopharyngeal microbiota and respiratory viruses can be bidirectional since microbial dysbiosis may also represent a reflection of the disease-induced alterations of the local milieu. Moreover, viruses like RSV can also increase the virulence of potential pathogens in nasopharynx, a main reservoir of bacteria, and therefore promote their spread to the lower airways causing superinfection. Moreover, if negative changes in microbial community composition in early life may constitute a heightened risk toward severe RSV respiratory infection, on the contrary specific groups of microorganisms seem to be associated with protection. A better understanding into the potential negative and positive role of the different nasopharyngeal bacterial species on RSV infection may improve primary prevention and possibly care of this highly contagious disorder.

Differences and similarities between SARS-CoV and SARS-CoV-2: spike receptor-binding domain recognition and host cell infection with support of cellular serine proteases.

Novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) became pandemic by the end of March 2020. In contrast to the 2002-2003 SARS-CoV outbreak, which had a higher pathogenicity and lead to higher mortality rates, SARSCoV-2 infection appears to be much more contagious. Moreover, many SARS-CoV-2 infected patients are reported to develop low-titer neutralizing antibody and usually suffer prolonged illness, suggesting a more effective SARS-CoV-2 immune surveillance evasion than SARS-CoV. This paper summarizes the current state of art about the differences and similarities between the pathogenesis of the two coronaviruses, focusing on receptor binding domain, host cell entry and protease activation. Such differences may provide insight into possible intervention strategies to fight the pandemic.

Respiratory syncytial virus-Host interaction in the pathogenesis of bronchiolitis and its impact on respiratory morbidity in later life.

Respiratory syncytial virus (RSV) is the most common agent of severe airway disease in infants and young children. Large epidemiologic studies have demonstrated a clear relationship between RSV infection and subsequent recurrent wheezing and asthma into childhood, thought to be predominantly related to long-term changes in neuroimmune control of airway tone rather than to allergic sensitization. These changes appear to be governed by the severity of the first RSV infection in infancy which in term depends on viral characteristics and load, but perhaps as importantly, on the genetic susceptibility and on the constitutional characteristic of the host. A variety of viral and host factors and their interplay modify the efficiency of the response to infection, including viral replication and the magnitude of structural and functional damage to the respiratory structures, and ultimately the extent, severity, and duration of subsequent wheezing.

Gradually worsening dyspnea and dry cough in an elderly patient.

Primary tracheal chondrosarcomas are an extremely rare condition that affect adult of all ages, 24% being more that 70 years old.  The progression may be slow, with symptoms that may continue up to 72 months before diagnosis is made. The clinical manifestations, that include a combination of nonproductive cough, wheezing, and dyspnea without hemoptysis often leads to misdiagnosis of asthma or chronic obstructive pulmonary disease. We report a case of an 87-year-old male, a Medical Doctor, with such a history, in whom a diagnosis of a tracheal chondrosarcoma was finally performed, 12 months after the first manifestation of the disease.

Recurrence of right lower lobe pneumonia 3 years after the first episode in an otherwise healthy 13-year-old girl.

Recurrent pneumonia is one of the most frequent reasons for referral to paediatric chest physicians. The diagnostic work-up is dependent on whether infection repeatedly occurs in the same lung lobe, or affects multiple lobes and/or different areas in different episodes. A 13-year-old girl was admitted with a second episode of right lower lobe pneumonia. The chest x-ray demonstrated an inhomogeneous opacity, without a clearly recognizable segmental distribution. A contrast-enhanced CT scan, was therefore performed that showed a polycyclic consolidation with blood supply from a systemic artery, originated from the thoracic aorta. A diagnosis of superinfection of an intralobar sequestration was made. The patient was treated with systemic antibiotics and, four weeks later, a segmental resection of the lesion was performed. The histological evaluation of the surgical specimen confirmed the diagnosis.

Post-infectious persistent cough: pathogenesis and therapeutic options.

Post-infectious cough is a common symptom associated with common colds and/or upper respiratory tract infection. This cough is expected to last for only for few days and resolve spontaneously, whilst when persists for longer than three weeks is defined "persistent" and is associated tickling or an irritating sensation in the throat which often leads to paroxysms of coughing. Persistent post-infectious cough can cause morbidity since it may interfere with usual living. Despite the recent advances in understanding the mechanisms that regulate cough, in physiological and pathological conditions, current therapeutic options for post-infectious cough are little or only moderately effective.

Long-Term Extracorporeal Membrane Oxygenation as Bridging Strategies to Lung Transplantation in Rapidly Devastating Isolated Langerhans Cell Histiocytosis.

Isolated pulmonary involvement in pediatric Langerhans cell histiocytosis (LCH) is extremely rare. While the multisystem-LCH course varies from spontaneous remission to rapid deterioration with lethal outcome, single system involvement is generally associated with favorable prognosis. A child with isolated pulmonary LCH had an extremely rapid progression leading to respiratory failure, despite treatment with prednisone and vinblastine. Since lung hyperinflation and cystic degeneration contraindicated conventional mechanical ventilation, extracorporeal membrane oxygenation (ECMO) was chosen for 50 days as a bridge to lung transplantation. The mechanisms involved in disease progression and the usefulness of long-term ECMO are discussed.

Infantile respiratory syncytial virus and human rhinovirus infections: respective role in inception and persistence of wheezing.

There is evidence that respiratory viruses play a key role in the development and exacerbation of obstructive respiratory diseases in children. This review attempts to juxtapose the separate profiles and prototypes of pathogenetic mechanisms represented by the two most common amongst such viruses: respiratory syncytial virus (RSV) and human rhinovirus (HRV). RSV represents the most common agent of severe airway disease in infants and young children, and is predominant in winter months. Large epidemiological studies have revealed an unequivocal relationship between RSV infection and subsequent wheezing into childhood, thought to be related to long-term changes in neuroimmune control of the airways rather than allergic sensitisation. HRV is a highly diverse group of viruses that affect subjects of all ages, is ubiquitous and occurs year-round. In contrast to RSV, infections with HRV cause minimal cytotoxicity but induce a rapid production of cytokines and chemokines with amplification of the inflammatory response. The susceptibility to HRV-induced bronchiolitis and subsequent wheezing appears to be linked to individual predisposition since it is often associated with a family or personal history of asthma/atopy. Thus, RSV probably serves as an "inducer" rather than a "trigger". Conversely, HRVs seem to serve as a "trigger" rather than an "inducer" in predisposed individuals.

[The topical treatment of allergic and vasomotor rhinitis: the role of beclomethasone dipropionate]. / Il trattamento topico delle riniti allergiche e vasomotorie: il ruolo del beclometasone dipropionato.

Allergic rhinitis is the most frequent allergic disorder, as its prevalence is more than 20% in the general population. Non-allergic rhinitis has similar symptoms, but pathogenic mechanisms are non-IgE-mediated. Anyway, both diseases share a common inflammatory pathway, thus anti-inflammatory drugs represent the optimal therapeutical option. Beclomethasone dipropionate (BDP) is a corticosteroid that is long time available both as intranasal spray and aerosol solution. The present review aims at analysing the most relevant and recent studies concerning the BDP use in allergic and non-allergic rhinitis. The research was performed using Medline and Scopus database, key words were: allergic and non-allergic rhinitis, beclomethasone (last access 31st July 2014). BDP is a corticosteroid with proved efficacy in the treatment of rhinitis, both as spray and aerosol. Safety issue has been satisfactory explored, thus BDP is usually safe and well tolerated.

[Recent updates on the antibacterial clofoctol.] / Recenti aggiornamenti sull'antibatterico clofoctolo.

Due to the worry growing increase in bacterial antibiotic resistance and the scanty availability of new antibiotics, it is highly recommended to use not recently synthesized, but still active molecules. Clofoctol is a synthetic chemotherapeutic agent with a different mechanism of action, as compared with the other antibacterial molecules currently available. By reducing intracellular ATP, clofoctol inhibits the synthesis of bacterial cytoplasmic membrane peptidoglycans, inducing the arrest of cell wall synthesis, thus characterizing the molecule as a "membrane-acting agent". More recently, however, it has been shown that clofoctol is also able to induce apoptosis by inhibiting the translation of intracellular proteins. An important property of clofoctol is the rapidity of the antimicrobial effect, which allows the complete eradication of the pathogen and makes the development of resistance unlikely. Administered rectally, the drug rapidly accumulates in the tissues. Most of the clinical studies conducted on clofoctol concern the treatment of respiratory diseases in children. The drug appears to be more active in upper rather than in lower respiratory tract infections. Tolerability was reported to be good, with a low incidence of side effects.

Cytokines induce tight junction disassembly in airway cells via an EGFR-dependent MAPK/ERK1/2-pathway.

Epithelial barrier permeability is altered in inflammatory respiratory disorders by a variety of noxious agents through modifications of the epithelial cell structure that possibly involve tight junction (TJ) organization. To evaluate in vitro whether pro-inflammatory cytokines involved in the pathogenesis of respiratory disorders could alter TJ organization and epithelial barrier integrity, and to characterize the signal transduction pathway involved Calu-3 airway epithelial cells were exposed to TNF-a, IL-4 and IFN-g to assess changes in: (a) TJ assembly, that is, occludin and zonula occludens (ZO)-1 expression and localization, evaluated by confocal microscopy; (b) apoptotic activity, quantified using terminal transferase deoxyuridine triphosphate nick-end labeling staining; (c) epithelial barrier integrity, detected as transmembrane electrical resistance and expressed as G(T) values; (d) epidermal growth factor receptor (EGFR)-dependent mitogenactivated protein (MAP) kinase (MAPK)/extracellular signal-regulated kinases (ERK)1/2 phosphorylation, assessed by western blotting. Exposure to cytokines for 48 h induced a noticeable downregulation of the TJ transmembrane proteins. The degree ZO-1 and occludin colocalization was 62±2% in control cultures and significantly decreased in the presence of TNF-a (47±3%), IL-4 (43±1%) and INF-g (35±3%). Although no apoptosis induction was detected following exposure to cytokines, changes in the epithelial barrier integrity were observed, with a significant enhancement in paracellular conductance. G(T) values were, respectively, 1.030±0.0, 1.300±0.04, 1.260±0.020 and 2.220±0.015 (mS/cm²)1000 in control cultures and in those exposed to TNF-a, IFN-g and IL-4. The involvement of EGFR-dependent MAPK/ERK1/2 signaling pathway in cytokine-induced damage was demonstrated by a significant increase in threonine/tyrosine phosphorylation of ERK1/2, already detectable after 5 min incubation. All these cytokine-induced changes were markedly prevented when Calu-3 cells were cultured in the presence of an EGFR inhibitor (AG1478, 1 µM) or a MAP kinase inhibitor (U0126, 25 µM). In conclusion, cytokine-induced epithelial injury includes TJ disassembly and epithelial barrier permeability alteration and involves the EGFR-dependent MAPK/ERK1/2 signaling pathway.

Breathlessness perception assessed by visual analogue scale and lung function in children with asthma: a real-life study.

BACKGROUND: In children with asthma, discrepancies between objective indicators of airway obstruction and symptom perception are often observed. Although visual analogue scale (VAS) has been proposed as a useful tool for assessing accurate symptom perception, previous studies conducted in children with asthma included only small cohorts. A study was therefore designed to investigate the usefulness of VAS in establishing a reliable relationship between breathlessness perception and lung function in a large cohort of children with clinical diagnosis of asthma. METHODS: A total of 703 children [470 boys and 233 girls, median age 10.29 (8.33-12.58) yr] with asthma were included in this cross-sectional, real-life study. Perception of breathlessness was assessed by using VAS, and lung volumes and expiratory flows were measured by spirometry. RESULTS: Most children had intermittent or mild persistent asthma (93.3%), and only 46 children had a significant bronchial obstruction defined by FEV(1) values <80% of predicted. Globally, VAS was significantly, even though weakly, related to lung function. Analyzing children with bronchial obstruction, a moderate relationship between both FEV(1) (r = 0.47) and FEF(25-75) (r = 0.42) and VAS was detected. A VAS value of 6 was found to be a reliable cutoff for discriminating children with bronchial obstruction (AUC 0.83 at ROC curve; OR 9.4). CONCLUSION: The present study demonstrates that VAS might be considered a useful tool to assess symptom perception, mainly in children with airflow limitation.

The IgE repertoire in children and adolescents resolved at component level: a cross-sectional study.

BACKGROUND: It is well known that allergy evolves at clinical level from the birth to adulthood, and this has been clearly demonstrated also at a level of sensitization. However, little information is available on the evolution of the IgE repertoire directed to single allergenic components. In this cross-sectional, observational study, the evolution of the IgE repertoire was analysed at component level. METHODS: Serum samples from 901 allergic patients, stratified in 6 groups according to age, were analysed by ImmunoCAP ISAC, a microarray chip that allows to identify the presence of specific IgE towards 103 different allergen components. Total IgE were also evaluated. RESULTS: The behaviour of total IgE according to age strictly paralleled that of the sum of specific IgE directed to molecular components. As expected, food-related components (in particular those of milk and egg) were the most frequently recognized in the earliest ages, whereas specific IgE to plant allergens appeared invariably later. Nonetheless, IgE specific to mite components was the most represented in all age classes. Of note, specific IgE against cross-reacting allergens was virtually absent in the first years and tended to appear only after the age of 6. CONCLUSION: Despite this was not a study performed on a cohort of patients followed up from birth to adolescence, the molecular patterns of allergen recognition resulted modified according to age. These findings may support, at molecular level, the clinical features of the allergic march.

Pharmacological modulation of the bradykinin-induced differentiation of human lung fibroblasts: effects of budesonide and formoterol.

OBJECTIVE: Bradykinin (BK) induces differentiation of lung fibroblasts into myofibroblasts, which play an important role in extracellular matrix remodeling in the airways of asthmatic patients. It is unclear whether this process is affected by antiasthma therapies. Here, we evaluated whether a glucocorticoid, budesonide (BUD), and a long-acting ß2-agonist, formoterol (FM), either alone or in combination, modified BK-induced lung fibroblast differentiation, and affected the BK-activated intracellular signaling pathways. METHODS: Human fetal lung fibroblasts were incubated with BUD (0.001-0.1 µM) and/or FM (0.0001-0.1 µM) before exposure to BK (0.1 or 1 µM). Fibroblast differentiation into α-smooth-muscle-actin-positive (α-SMA⁺) myofibroblasts, BK2 receptor (B2R) expression, extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation (p-ERK1/2), intracellular Ca²âº concentration ([Ca²âº]i), and p65 nuclear factor kappa B translocation were evaluated. RESULTS: BUD (0.1 µM) and FM (0.1 µM), either alone or in combination, completely inhibited BK-induced α-SMA protein expression and decreased the numbers of α-SMA⁺ fibroblasts, with a clear reduction in α-SMA stress fibers organization. BUD also completely inhibited the increase of B2R, whereas FM with or without BUD had no effect. BK-induced increases of [Ca²âº]i and p-ERK1/2 were significantly reduced to similar levels by BUD and FM, either alone or in combination, whereas p65 translocation was completely inhibited by all treatments. CONCLUSION: Both BUD and FM, either alone or in combination, effectively inhibited the BK-induced differentiation of fibroblasts into α-SMA⁺ myofibroblasts and the intracellular signaling pathways involved in fibroblast activation. These results suggest that BUD and FM combination therapy has potential to inhibit fibroblast-dependent matrix remodeling in the airways of asthmatic patients.

Intraoperative bronchoscopy for bronchial carcinoid parenchymal-sparing resection: a pediatric case report.

Bronchial carcinoid tumors are the most common primary pulmonary neoplasm in the pediatric population. The widely accepted treatment for carcinoid tumors is surgical, specifically aiming at being as much as conservative on lung parenchyma, while the entire tumor is resected. A brief case is described, highlighting the importance and advantages of a surgical and endoscopic combined approach.