[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.

Can bacterial lysates be useful in prevention of viral respiratory infections in childhood? The results of experimental OM-85 studies.

Respiratory tract infections (RTI) are mainly viral in origin and among the leading cause of childhood morbidity globally. Associated wheezing illness and asthma are still a clear unmet medical need. Despite the continuous progress in understanding the processes involved in their pathogenesis, preventive measures and treatments failed to demonstrate any significant disease-modifying effect. However, in the last decades it was understood that early-life exposure to microbes, may reduce the risk of infectious and allergic disorders, increasing the immune response efficacy. These results suggested that treatment with bacterial lysates (BLs) acting on gut microbiota, could promote a heterologous immunomodulation useful in the prevention of recurrent RTIs and of wheezing inception and persistence. This hypothesis has been supported by clinical and experimental studies showing the reduction of RTI frequency and severity in childhood after oral BL prophylaxis and elucidating the involved mechanisms. OM-85 is the product whose anti-viral effects have been most extensively studied in vitro, animal, and human cell studies and in translational animal infection/disease models. The results of the latter studies, describing the potential immune training-based activities of such BL, leading to the protection against respiratory viruses, will be reported. In response to human rhinovirus, influenza virus, respiratory syncytial virus and severe acute respiratory coronavirus-2, OM-85 was effective in modulating the structure and the functions of a large numbers of airways epithelial and immune cells, when administered both orally and intranasally.

[Beclomethasone dipropionate: efficacy and safety of the administration by nebulization.] / Il beclometasone dipropionato: efficacia e sicurezza della somministrazione mediante nebulizzazione.

The advent of inhaled corticosteroids (ICS) brought a revolution in the management of asthma, representing now the cornerstone in this pathological condition treatment. Indeed, these drugs have clearly shown to possess a high degree of both efficacy and safety. Beclomethasone dipropionate (BDP) is the first molecule tested in the early 1970s. When administered via nebulizers or pressurized metered-dose inhalers (pMDI), BDP was found to be effective in reducing the symptoms frequency and severity in asthmatic patients, even in those previously treated with low-dose oral corticosteroids. The drug was thus produced to be administered by nebulization or via pMDI. Nebulizers are a practical and efficient tool for administering inhaled drugs in patients of all degree of severity and belonging to all ages, but are especially useful for those unable to utilize other inhaler devices correctly. BDP aerosolization, when generated by modern pneumatic nebulizers, can deliver particles with a mass median aerodynamic diameter (MMAD) value of 2.9-3.7 µm. This ability allows the deposition of the drug in small caliber airways, and considerably reduces the amount of drug deposited in the oropharynx, thus improving this molecule pharmacokinetics. This review aims to analyze the factors influencing the efficacy and safety of ICS, evaluating in detail the characteristics of BDP administered by nebulization.

Microbiota profiles in pre-school children with respiratory infections: Modifications induced by the oral bacterial lysate OM-85.

To describe microbiota profiles considering potential influencing factors in pre-school children with recurrent respiratory tract infections (rRTIs) and to evaluate microbiota changes associated with oral bacterial lysate OM-85 treatment, we analyzed gut and nasopharynx (NP) microbiota composition in patients included in the OM-85-pediatric rRTIs (OMPeR) clinical trial (https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-002705-19/IT). Relative percentage abundance was used to describe microbiota profiles in all the available biological specimens, grouped by age, atopy, and rRTIs both at inclusion (T0) and at the end of the study, after treatment with OM-85 or placebo (T1). At T0, Firmicutes and Bacteriodetes were the predominant genera in gut and Proteobacteria, Firmicutes, and Actinobacteria were the predominant genera in NP samples. Gut microbiota relative composition differed with age (<2 vs. ≥2 years) for Firmicutes, Proteobacteria, Actinobacteria (phyla) and Bifidobacterium, Ruminococcus, Lachnospiraceae (genera) (p < 0.05). Moraxella was more enriched in the NP of patients with a history of up to three RTIs. Intra-group changes in relative percentage abundance were described only for patients with gut and NP microbiota analysis available at both T0 and T1 for each study arm. In this preliminary analysis, the gut microbiota seemed more stable over the 6-month study in the OM-85 group, whose mean age was lower, as compared to the placebo group (p = 0.004). In this latter group, the relative abundance of Bacteroides decreased significantly in children ≥2 years. Some longitudinal significant differences in genera relative abundance were also detected in children of ≥2 years for NP Actinobacteria, Haemophilus, and Corynebacterium in the placebo group only. Due to the small number of patients in the different sub-populations, we could not identify significant differences in the clinical outcome and therefore no associations with microbiota changes were searched. The use of bacterial lysates might play a role in microbiota rearrangement, but further data and advanced analysis are needed to prove this in less heterogeneous populations with higher numbers of samples considering the multiple influencing factors such as delivery method, age, environment, diet, antibiotic use, and type of infections to ultimately show any associations with prevention of rRTIs.

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.

Can Resveratrol-Inhaled Formulations Be Considered Potential Adjunct Treatments for COVID-19?

The pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has led to an extraordinary threat to the global healthcare system. This infection disease, named COVID-19, is characterized by a wide clinical spectrum, ranging from asymptomatic or mild upper respiratory tract illness to severe viral pneumonia with fulminant cytokine storm, which leads to respiratory failure. To improve patient outcomes, both the inhibition of viral replication and of the unwarranted excessive inflammatory response are crucial. Since no specific antiviral drug has been proven effective for the treatment of patients and the only upcoming promising agents are monoclonal antibodies, inexpensive, safe, and widely available treatments are urgently needed. A potential anti-inflammatory molecule to be evaluated, which possesses antiviral activities in several experimental models, is the polyphenol resveratrol. This compound has been shown to inhibit SARS-CoV-2 replication in human primary bronchial epithelial cell cultures and to downregulate several pathogenetic mechanisms involved in COVID-19 severity. The use of resveratrol in clinical practice is limited by the low bioavailability following oral administration, due to the pharmacokinetic and metabolic characteristics of the molecule. Therefore, topical administration through inhaled formulations could allow us to achieve sufficiently high concentrations of the compound in the airways, the entry route of SARS-CoV-2.

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.

Dysbiosis in Pediatrics Is Associated with Respiratory Infections: Is There a Place for Bacterial-Derived Products?

Respiratory tract infections (RTIs) are common in childhood because of the physiologic immaturity of the immune system, a microbial community under development in addition to other genetic, physiological, environmental and social factors. RTIs tend to recur and severe lower viral RTIs in early childhood are not uncommon and are associated with increased risk of respiratory disorders later in life, including recurrent wheezing and asthma. Therefore, a better understanding of the main players and mechanisms involved in respiratory morbidity is necessary for a prompt and improved care as well as for primary prevention. The inter-talks between human immune components and microbiota as well as their main functions have been recently unraveled; nevertheless, more is still to be discovered or understood in the above medical conditions. The aim of this review paper is to provide the most up-to-date overview on dysbiosis in pre-school children and its association with RTIs and their complications. The potential role of non-harmful bacterial-derived products, according to the old hygiene hypothesis and the most recent trained-innate immunity concept, will be discussed together with the need of proof-of-concept studies and larger clinical trials with immunological and microbiological endpoints.

Distinct Antiviral Properties of Two Different Bacterial Lysates.

Oral bacterial lysates (OBLs) can reduce the frequency and severity of recurrent respiratory tract infections in children from viral and bacterial origins. OBL-induced early innate immune reaction was already shown, but the specific features of different OBLs have never been studied and compared. A study was conducted to assess in vitro the protective effects on rhinovirus- (RV-) infected human bronchial epithelial cells (BECs) of two slightly different OBLs: OM-85 and Pulmonarom. Furthermore, since immune cells represent the key arm for antiviral defence, the capacity of these OBLs to induce selected cytokine production in mouse bone marrow-derived DCs (BMDCs) was also evaluated. Although different OBLs may share some mechanisms to protect host cells from virus infection, some product-specific antimicrobial activities were observed on RV-infected human BECs and mouse BMDCs. These results are consistent with a product-specific response possibly triggered by different pathogen-associated molecular patterns (PAMPs) contained in OBLs.

Upregulation of neuropeptides and obstructive airway disorder in infancy: A review with focus on post-RSV wheezing and NEHI.

Obstructive airway disorders, common in infancy and early childhood, include some entities that are recognized to have neuro immune mediators as their underlying pathogenetic mechanisms. The best characterized example amongst post-viral wheezing phenotypes is the disorder that follows respiratory syncytial virus (RSV) infection and leads to intermittent, long-term wheezing. The underlying mechanisms of the airway reactivity related to RSV infection have been extensively studies and are associated with dysregulation of the nonadrenergic-noncholinergic (NANC) system, via upregulation of neurotransmitters, typically Substance P. Neuroendocrine hyperplasia of infancy (NEHI), while a less common entity, is a disorder characterized by more severe and long-term obstructive airway disease. NEHI is pathophysiologically characterized by abundance of neuroendocrine cells in the airways containing the neuroimmune mediator bombesin, the release of which is presumed to be the driver of the persistent small airway obstruction and functional air-trapping. Here we review the NANC and neuroendocrine cells, the neurotransmitter systems and their studied roles in pulmonary diseases with a focus on their role in lung development, and subsequent various pediatric lung diseases. We focus on the juxtaposition of the separate neuroimmune mechanisms underlying the pathogenesis of post-RSV recurrent wheezing and NEHI's persistent small airway obstruction. We finally propose a unifying concept of neuropeptides in obstructive disorders that may encompass these two entities and possibly others.

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.

Viral infections and wheezing-asthma inception in childhood: is there a role for immunomodulation by oral bacterial lysates?

Severe and recurrent infections of the respiratory tract in early childhood constitute major risk factors for the development of bronchial hyper-responsiveness and obstructive respiratory diseases in later life. In the first years of life, the vast majority of respiratory tract infections (RTI) leading to wheezing and asthma are of a viral origin and severity and recurrence are the consequence of a greater exposure to infectious agents in a period when the immune system is still relatively immature. Therefore, boosting the efficiency of the host immune response against viral infections seems to be a rational preventative approach. In the last decades it has been demonstrated that living in farm environments, i.e. early-life exposure to microbes, may reduce the risk of allergic and infectious disorders, increasing the immune response efficacy. These findings have suggested that treatment with bacterial lysates could promote a nonspecific immunomodulation useful in the prevention of recurrent RTIs and of wheezing inception and persistence. Experimental and clinical studies showing the reduction of RTI frequency and severity in childhood and elucidating the involved mechanisms can support this hypothesis.

Immunoactive preparations and regulatory responses in the respiratory tract: potential for clinical application in chronic inflammatory airway diseases.

Introduction: The prevalence of chronic inflammatory airway diseases is rising. Their treatment with corticosteroids increases infection risk, while overuse of antimicrobial agents may increase morbidity and antimicrobial resistance. Nonspecific immunomodulatory compounds alter immune responses to both infectious and atopic challenges. These compounds may offer an alternative approach for symptom reduction and prophylaxis against both infections and exacerbations in chronic inflammatory airway disease.Areas covered: We assessed the available data on the efficacy of nonspecific immunomodulators including bacterial lysates, synthetic compounds, and vaccines in chronic rhinosinusitis (CRS); allergic and non-allergic rhinitis; chronic obstructive pulmonary disease (COPD), and asthma. A search of PubMed was carried out using the 'Clinical Trials' filter for each condition and immunomodulatory product detailed below, where available, data from meta-analyses were reported.Expert opinion: Pre-clinical data has revealed a coherent mechanistic path of action for oral immunomodulators on the respiratory immune system, principally via the gut-lung immune axis. In patients with asthma, allergic rhinitis, CRS, and COPD immunomodulatory therapy reduces symptoms, exacerbations, hospitalizations, and drug consumption. However, data are heterogeneous, and study quality remains limited. A lack of high-quality recent trials remains the major unmet research need in the field.

Viral strategies predisposing to respiratory bacterial superinfections.

Acute respiratory infections are amongst the leading causes of childhood morbidity and mortality globally. Viruses are the predominant cause of such infections, but mixed etiologies with bacteria has for decades raised the question of the interplay between them in causality and determination of the outcome of such infections. In this review, we examine recent microbiological, biochemical, and immunological advances that contribute to elucidating the mechanisms by which infections by specific viruses enable bacterial infections in the airway, and exacerbate them. We analyze specific domains in which viruses play such facilitating role including enhancement of bacterial adhesion by unmasking cryptic receptors and upregulation of adhesion proteins, disruption of tight junction integrity favoring paracellular transmigration of bacteria and loss of epithelial barrier integrity, increased availability of nutrient, such as mucins and iron, alteration of innate and adaptive immune responses, and disabling defense against bacteria, and lastly, changes in airway microbiome that render the lung more vulnerable to pathogens. Separate exhaustive analysis of each domain focuses on individuals with cystic fibrosis (CF), in whom viruses may play a key role in paving the way for the primary injury that leads to permanence of bacterial pathogens, viruses may then serve as triggers for "CF exacerbations"; these constituting the signature and ultimately the outcome determinants of these patients.

Impact of the 2014 American Academy of Pediatrics recommendation and of the resulting limited financial coverage by the Italian Medicines Agency for palivizumab prophylaxis on the RSV-associated hospitalizations in preterm infants during the 2016-2017 epidemic season: a systematic review of seven Italian reports.

BACKGROUND: The only pharmacologic prophylaxis against respiratory syncytial virus (RSV) infection in preterm infants is the humanized monoclonal antibody palivizumab. After the 2014 modification of the American Academy of Pediatrics (AAP) recommendations, the Italian Medicines Agency (AIFA) limited the financial coverage for palivizumab prescriptions to otherwise healthy preterm infants with < 29 weeks of gestational age (wGA) aged < 12 months at the beginning of the 2016-2017 RSV season. However, due to the effect on disease severity and hospitalizations following this limitation, shown by several Italian clinical studies, in November 2017 AIFA reinstated the financial coverage for these infants. In this systematic review, we critically summarize the data that show the importance of palivizumab prophylaxis. METHODS: Data from six Italian pediatric institutes and the Italian Network of Pediatric Intensive Care Units (TIPNet) were retrieved from the literature and considered. The epidemiologic information for infants 29-36 wGA, aged < 12 months and admitted for viral-induced acute lower respiratory tract infection were retrospectively reviewed. RSV-associated hospitalizations were compared between the season with running limitation, i.e. 2016-2017, versus 2 seasons before (2014-2015 and 2015-2016) and one season after (2017-2018) the AIFA limitation. RESULTS: During the 2016-2017 RSV epidemic season, when the AIFA limited the financial coverage of palivizumab prophylaxis based on the 2014 AAP recommendation, the study reports on a higher incidences of RSV bronchiolitis and greater respiratory function impairment. During this season, we also found an increase in hospitalizations and admissions to the Pediatric Intensive Care Units and longer hospital stays, incurring higher healthcare costs. During the 2016-2017 epidemic season, an overall increase in the number of RSV bronchiolitis cases was also observed in infants born full term, suggesting that the decreased prophylaxis in preterm infants may have caused a wider infection diffusion in groups of infants not considered to be at risk. CONCLUSIONS: The Italian results support the use of palivizumab prophylaxis for otherwise healthy preterm (29-36 wGA) infants aged < 6 months at the beginning of the RSV season.

Airway microenvironment alterations and pathogen growth in cystic fibrosis.

Cystic Fibrosis Transmembrane Regulator (CFTR) dysfunction is associated with epithelial cell vulnerability and with dysregulation of the local inflammatory responses resulting in excessive airway neutrophilic inflammation and pathogen growth. In combination with impaired mucociliary clearance, and dysregulation of defense function, bacterial infection follows with eventual airway damage and remodeling. Because of these inherent vulnerabilities, viral infections are also more severe and prolonged and appear to render the airway even more prone to bacterial infection. Airway acidity, deficient nitric oxide production and increased iron concentrations, further enhance the airway milieu's susceptibility to infection. Novel diagnostic techniques of the airway microbiome elucidate the coexistence of an array of non-virulent taxa beyond the recognized virulent organisms, predominantly Pseudomonas aeruginosa. The complex interplay between these two bacterial populations, including upregulation of virulence genes and utilization of mucin as a nutrient source, modulates the action of pathogens, modifies the CF airway milieu and contributes to the processes leading to airway derangement. The review provides an update on recent advances of the complex mechanisms that render the CF airway vulnerable to inflammation, infection and ultimately structural damage, the key pathogenetic elements of CF. The recent contributions on CF pathogenesis will hopefully help in identifying new prophylactic measures and therapeutic targets for this highly destructive disorder.