Prevention and treatment of upper respiratory diseases in the pandemic COVID-19 era.

In the pandemic coronavirus disease 2019 (COVID-19) era, the need to use preventive-curative treatments is compelling. A series of non-pharmacological compounds, including oligo-elements, vitamins, nutraceuticals, and bacteriotherapy, might affect the risk of COVID-19, both reinforcing the immune system and improving the inflammation resolution during respiratory infections. Non-pharmacological remedies are very popular and usually have no relevant side effects. Bacterial and natural products may potentiate the immune system against respiratory viruses. Moreover, these compounds also exert antiinflammatory and antioxidant activity. Consequently, these non-chemical remedies could be prescribed to build up the immune defence and adequately treat the upper respiratory infection. In this way, natural compounds could be used to manage people in the pandemic COVID-19 era.

Lactoferrin: a potential candidate to fight respiratory infections in the pandemic COVID-19 era.

Respiratory infections are a significant burden at any age, but especially in childhood and aging. The COVID-19 pandemic has worsened the issue since there is no specific treatment and vaccine is not available. Moreover, respiratory symptoms cause social stigma in subjects suffering from an infection of any kind. As new drugs require a very long time to be marketed, a natural compound's interest is growing. In this regard, lactoferrin is a multifunctional protein present in secretions, mainly in breast milk. Lactoferrin has marked antimicrobial activity, including antibacterial, antiviral, antiparasitic, and antifungal. Moreover, lactoferrin strongly affects immune response and cellular control activity. Therefore, this natural component could provide a promising effect in preventing respiratory infections and potentially also for COVID-19.

Can Pseudomonas aeruginosa growth be modulated by natural compounds?

Pseudomonas aeruginosa is an opportunistic human pathogen that frequently induces antibiotic resistance, as it mainly tends to form biofilms. Iron chelation may be an intriguing strategy to contrast bacterial growth. Lactoferrin is a natural compound able to chelate iron. A new multi-component medical device also contains lactoferrin. This study analyzed this compound investigating the in vitro capacity to inhibit Pseudomonas aeruginosa growth. In conclusion, this study demonstrated that a multicomponent medical device (Saflovir), also containing lactoferrin, could inhibit the in vitro growth of P. aeruginosa. This activity could be positively used in the prevention of respiratory nasal infections.

Laryngopharyngeal reflux management in clinical practice.

Laryngopharyngeal reflux (LPR) is an inflammatory reaction of the mucosa of the pharynx, larynx, and other associated upper respiratory organs, caused by a reflux of stomach contents outside the esophagus. LPR is considered a relatively new clinical entity with a vast number of clinical manifestations that are sometimes treated empirically and without a correct diagnosis. Alginate is a reasonable therapeutic option as a first-line or add-on option. A survey included 35 Italian otorhinolaryngologists. The survey considered ten practical queries. LPR is a common disease in clinical practice. History and fiber-optic endoscopy constitute the main diagnostic tools. Alginates represent a frequent medication to treat LPR both as first-line and add-on. The mean effectiveness rate is 44% for first-line choice and 76% for the add-on. In conclusion, the current survey provided exciting information about the management of LPR in clinical practice.

The efficacy and tolerability of Streptococcus salivarius 24SMB and Streptococcus oralis 89a administered as nasal spray in the treatment of recurrent upper respiratory tract infections in children.

OBJECTIVE: Nasal administration of Streptococcus salivarius 24SMB and Streptococcus oralis 89a has been proposed to reduce the risk of new episodes of adenoiditis, tonsillitis and acute rhinosinusitis in children. PATIENTS AND METHODS: We enrolled 202 children with a recent diagnosis of recurrent upper respiratory tract infection. All the patients were treated twice daily for 7 days each month for 3 consecutive months with a nasal spray whose active agents were two specific bacterial strains: Streptococcus salivarius 24SMB and Streptococcus oralis 89a. Evaluation was performed at the end of treatment and at follow-up at 3, 6, and 12 months. RESULTS: Patients who completed the entire 90-day course of bacteriotherapy and the follow-up period showed a 64.3% reduction in their episodes of upper respiratory tract infections compared to the number of episodes recorded in the previous year. Treatment decreased the reported incidence of infection events by 52.4% in the first 3 months, 31.2% at 6-month follow-up, and 20.8% after 12 months. Enrolled patients tolerated the product well, and there were no dropouts. CONCLUSIONS: Prophylactic bacteriotherapy by administration of Streptococcus salivarius 24SMB and Streptococcus oralis 89a in children with a history of recurrent upper respiratory tract infection could reduce the number of episodes of otolaryngologic infections. Bacteriotherapy can be even more clinically important due to increasing difficulty in finding new effective antibiotic compounds. New alternative therapeutic approaches must be found with, in comparison to antibiotics, greater specificity and safety with respect to patients' native beneficial flora; lack of drug interactions; the ability to leverage complementary systemic modes of action; and drastically reduced risk of developing resistance within the patient population and the environment.

An overview on upper respiratory tract infections and bacteriotherapy as innovative therapeutic strategy.

OBJECTIVE: The aim of this review is to describe the most common recurring and chronic upper respiratory tract infections (URTI) in children and discuss the role of bacterial interference and bacteriotherapy in their prevention and treatment. MATERIALS AND METHODS: A literature review has been performed on the following topics: acute otitis media, adenoiditis, tonsillitis, rhinosinusitis, microbiotics and the role of bacterial interference, and bacteriotherapy in the prevention and treatment of URTI. RESULTS: Research studies into the characteristics of the microbiological flora and its role in the pathogenesis of URTI have focused on a single pathogen, on resistance to and ineffectiveness of antibiotic therapies, or on the persistence of bacterial biofilm. Recent evidence supports a central role of the existing microbial ecosystem in the pathogenesis of respiratory disease. In light of this, new therapeutic approaches include the implantation and persistence within the normal microflora of relatively innocuous "effector" bacteria that can competitively exclude or prevent the outgrowth of potentially disease-causing bacteria. Recently, a retrospective and observational study demonstrated that S. salivarius 24SMB and S. oralis 89a nasal spray could be effective in the prevention of recurrent otitis media in a real-life setting. Other studies have focused on the role of bacteriotherapy in children with beneficial effects in the prevention of URTI. CONCLUSIONS: The results of previous studies on the role of bacteriotherapy in paediatric URTI suggest that the use of bacterial interference phenomena through bacteriotherapy is a feasible, safe approach and deserves proper consideration as a promising therapeutic strategy against URTI.

Bromelain's penetration into the blood and sinonasal mucosa in patients with chronic rhinosinusitis.

SUMMARY: The aim of this research is to investigate penetration of Bromelain into sinonasal mucosa in patients with chronic rhinosinusitis (CRS) versus a control group. Bromelain is derived from pineapple (Ananas comosus) and has various pharmacological effects. 40 patients (20 patients and 20 controls) were enrolled in the study. Bromelain 500 mg tablet twice daily was administered for 30 days. We scored bromelain presence in turbinate and ethmoid mucosas and in the serum of both the groups. Bromelain has an excellent distribution from blood to rhinosinusal mucosa. Its diffusion ability may allow the use of bromelain as an anti-inflammatory agent in paranasal sinus pathologies.

Glycyrrhetinic acid suppressed hmgb1 release by up-regulation of Sirt6 in nasal inflammation.

To extend our understanding of previous studies on the pathogenesis and mechanism of high mobility group box 1 (HMGB1) in chronic rhinosinusitis with nasal polyps (CRSwNP), here we show that Sirtuin 6 (Sirt6), one of the Sirtuin family members which are widely studied in aging, DNA repair, metabolism, inflammation and cancer, was expressed in normal nasal mucosa using immunohistochemical staining and Western blot assay. Sirt6 expression levels were decreased in CRSwNP tissue. Sirt6 expression levels were modulated by small interfering RNA transfection in human nasal epithelial cells (HNE). We found that depletion of Sirt6 suppressed the number of human nasal epithelial cell cilia, and dramatically induced HMGB1 translocation from nucleus to cytoplasm in the HNE cells. Glycyrrhizic acid (GA) and glycyrrhetinic acid (GTA) are specific chemical compounds that may be isolated from the licorice plant. GTA has been shown to have anti-inflammatory and anti-allergic activity: it binds selectively to HMGB1 protein released extra-cellularly and inhibits its cytokine activities through a scavenger mechanism on the protein accumulation. In an in vitro study we used the 18-ß-stereoisomer of GTA to enhance Sirt6 expression levels, inhibiting through this mechanism the translocation of HMGB1 protein from nucleus and reversing its extracellular accumulation stimulated by lipopolysaccharides. These findings reveal a previously unknown role for nasal mucosa steady-state conditions in the control of Sirt6 activity, and provide evidence for a relationship between HMGB1 and Sirt6 in CRSwNP, and promising benefits of glycyrrhetinic acid for CRSwNP patients.

A comparative study on oxidative stress role in nasal breathing impairment and obstructive sleep apnoea syndrome.

Obstructive sleep apnoea syndrome (OSAS) is a sleep disorder that leads to metabolic abnormalities and increased cardiovascular risk. This study aimed to define the expression and clinical significance of biomarkers involved in oxidative stress in patients with OSAS. A prospective study was designed to compare outcomes of oxidative stress laboratory tests in three groups of subjects. The study involved the recruitment of three groups of subjects, 10 patients with obstructive sleep apnoea syndrome with AHI > 30; 10 patients suffering from snoring at night with AHI < 15; 10 patients with nasal respiratory impairment with AHI < 5. Patients were subjected to skin prick tests for common aero-allergens, nasal endoscopy, active anterior rhinomanometry, fibrolaryngoscopy and polysomnography; and extra-routine diagnostic tests and procedures; analysis of oxidative and antioxidant (plasma thiol groups) biomarkers in blood and urine samples. No statistical differences in age, sex distribution or body mass index were present between the three groups (p > 0.05). There were significant differences in AHI among the three groups of patients (p < 0.05). No statistical significance was found in the Analysis of Variance (ANOVA) test (p > 0.05) between the levels of biomarkers of oxidative stress in the three populations studied. The results of our study show that the nose can play a role in the pathogenesis of OSAS through the production of biomarkers of oxidative stress.

Phytoneering: a new way of therapy for rhinosinusitis.

A growing amount of scientific evidence suggests that herbal medicine may be helpful as an adjuvant treatment in rhinosinusitis. Herein, we systematically review and determine the role, efficacy and safety of phytotherapy in the treatment of acute and chronic rhinosinusitis and establish the qualities of herbal drugs as demonstrated by in vitro and in vivo experiments. Eligible studies published in English or German from January 1990 until June 2014 were identified via electronic database searches. Keywords were: sinusitis, phytotherapy, phytomedicine and herbal drugs. Additional studies were obtained through the references of selected articles. Twenty-two articles met inclusion criteria. Overall, the publications indicated that herbal medicines can have mucolytic, antiviral, antimicrobial, anti-inflammatory and secretolytic effects in experimental animals. Phytotherapy has also been found to be efficacious in reducing the symptoms of acute and chronic rhinosinusitis in children and the adult population in vivo, demonstrating a high level of tolerability and safety. Herbal products developed using phytoneering techniques have shown improvements in performance compared with previous formulations. The current literature suggests that phytotherapy is an effective and safe form of ancillary treatment for rhinosinusitis. In particular, herbal drugs made with the technique of phytoneering have proven effective in acute rhinosinusitis.

Efficacy and safety of a medical device in reducing nasal obstruction in allergic children.

AIM: Despite the availability of a number of pharmacological options, relief of allergic rhinitis (AR) symptoms, especially nasal obstruction, is often limited and local and systemic adverse reactions are not infrequent. The main aim of the present pilot study was to provide subjective and objective evidence of the clinical efficacy in reducing symptoms and safety of a medical device-Grip stop DMG (lactoferrin, carboximetil ß-glucan, D-panthenol, dipotassiumglycyrrhizinate) in children affected by allergic rhinitis. METHODS: A prospective study with a pre- and post-design has been performed consecutively enrolling 50 pediatric both genders patients affected by persistent AR. Patients received 2 puffs into each nostril twice a day over the course of 4 weeks. The severity of AR symptoms was assessed subjectively as measured by a 0 to 5 Visual Analog Scale, and objectively through active anterior rhinomanometry (AAR) and by means of the evaluation of mucociliary transport time (MCTt). Differences in symptoms scores measured before and after the treatment were compared using Paired-Sample Wilcoxon Signed Rank Test. Proportion of participants with adverse effects attributed to the treatment was computed. The relationship between the subjective score and the AAR and MCT measurements was also assessed. RESULTS: All considered symptoms, including nasal congestion, significantly improved after treatment (P<0.001), while only 1 patient suffered from moderate adverse effects. CONCLUSION: Results confirm efficacy and safety of this device used in the pediatric population. As previously reported in the scientific literature, also in our study, patient's perception of nasal symptoms corresponded with objective testing.

LPS may enhance expression and release of HMGB1 in human nasal epithelial cells in vitro.

Chronic rhinosinusitis with nasal polyps is a common disease with still unclear pathophysiologic mechanisms. The airway epithelial barrier has been shown to be involved in different chronic disorders, including rhinitis, nasal polyposis and asthma. High mobility group box 1 (HMGB1), a primarily nuclear protein, is involved in the induction of airway inflammation in patients with chronic rhinosinusitis, allergy, asthma and COPD. Pathogen-derived lipopolysaccharide is widely used as a trigger for inflammation. However, the molecular dialogue between LPS and HMGB1 in the delayed inflammatory processes remains to be explored, and the regulation of HMGB1 release through LPS from epithelial cells has not been extensively studied in patients with chronic rhinosinusitis and nasal polyps. The objective of the present study was to investigate the relocation of HMGB1 in LPS-induced human nasal epithelial cells in vitro. We obtained epithelial cells of nasal polyps from 10 patients requiring surgery for sinusitis at the ENT Department of the Chinese PLA General Hospital. The primary cultured human nasal epithelial (HNE) cells were stimulated with LPS. The expression and translocation of HMGB1 in intracellular and culture supernatants were determined using Western blot and immunofluorescence assay. HMGB1 protein was released in a time-dependent fashion in culture supernatants: in fact, expression of HMGB1 protein in HNE cells showed no significant changes at 0-24 h after exposure to 100 µg/ml LPS, but increased significantly at 48 and 72 hr. Immunofluorescence analysis revealed the transfer of HMGB1 from nuclei to cytoplasm in response to LPS exposure after 24 hr. These data reveal a hitherto unrecognized association between HMGB1 and LPS in human nasal epithelial cells. LPS can affect HMGB1 translocation and release, suggesting the involvement of HMGB1, through inflammatory mediators, in chronic rhinosinusitis with nasal polyps.

Are HMGB1 protein expression and secretion markers of upper airways inflammatory diseases?

Taking into account the mechanisms at the origin of the airways inflammatory pathologies, our attention has been recently addressed to the study of HMGB1, a protein belonging to the group of alarmins. Alarmins are those molecules which in homeostatic conditions carry out specific metabolic and/or structural functions; furthermore, after a direct trauma or an infection, these molecules are released in the extracellular milieu becoming there activators of the innate immunity and powerful inflammatory factors. In a previous research we found in patients affected with chronic rhinosinusitis with/without nasal polyposis (CRSwNP) an increased expression of this protein in the nucleus of nasal mucosa epithelial cells. HMGB1 was overexpressed also as focal subepithelial infiltration and in the inflammatory cells of patients in comparison with controls. These results suggested a possible pathogenetic role of HMGB1 in CRSwNP. The aim of the present study was to investigate if the expression and localization (nuclear, cytoplasmic and extracellular) of the HMGB1 protein-cytokine is somehow related to the severity and complexity of the histological and clinical picture. We noticed values which have around statistical significance between nuclear HMGB1 and eosinophils infiltrate (p=0.0607) and between nuclear HMGB1 and inflammatory infiltrate (P=0.0524). Even more significant was the correlation between extra-cellular HMGB1 expression and the presence of allergic-hyper reactive conditions such as asthma, allergic rhinitis, NSADs intolerance, antibiotic allergy. HMGB1 was significantly more expressed in the nucleus (p=0.0499) and in the intercellular space (p=0.0380) in allergic patients than in non-allergic subjects and as extra-cellular infiltrate in patients with NSADs intolerance (p=0.0022). These results confirm the role of HMGB1 in the pathogenesis of chronic rhinosinusitis with/without nasal polyposis; besides the higher extra-cellular expression in patients with a more severe clinical and inflammatory picture and the presence of associated co-morbidities suggests to seek for new compounds: these compounds, decreasing the extra-cellular release of this alarmin through a scavenger mechanism, could keep under control the inflammatory process without interfering with the nuclear transcriptional messengers.

The role of High Mobility Group Box 1 chromosomal protein in the pathogenesis of chronic sinusitis and nasal polyposis.

Chronic rhinosinusitis with nasal polyposis is considered to be a multifactorial disease where different stimuli (mechanical, viral, bacterial, fungal infection, immunological disorders or dysreactivity, environmental pollution), acting on the mucosa of nasal cavities and paranasal sinuses, lead to epithelial damage and mucosal inflammation. Inflammatory cell infiltration (predominantly eosinophils, but also neutrophils, mast cells, macrophages and lymphocytes), cytokine release and sub-epithelial oedema are the histological pictures that are associated, from the clinical point of view, with nasal congestion, secretion and/or post-nasal drip and facial pain/headache. Recently, the importance of the HMG B-1 protein in the pathogenesis of several inflammatory diseases has been demonstrated. This protein is released from necrotic/damaged cells or immune-activated cells, and by acting on specific membrane receptors causes the release of pro-inflammatory mediators, endothelial activation and the survival of inflammatory cells. The objective of the present study was: i) to determine whether HMG B1 is augmented in chronic rhinosinusitis with nasal polyps; ii) if its expression is associated with eosinophils, TNF-α, IL 5 and IL 8 cytokines typically present in chronic inflammation of the nose and paranasal sinuses; iii) to investigate a hypothetical role of this protein in the pathogenesis of nasal polyposis. Nasal polyps tissue from 21 patients affected by CRSwNP and nasal mucosa from 8 controls was collected at the ENT Department of the Chinese PLA General Hospital and underwent immunohistological staining for detection of HMG B1 protein and IL -5, IL -8 and TNF-α inflammatory cytokines. The degree of HMG B1 protein expression was evaluated by dividing the stained sections in 4 portions: 1) nucleus of epithelial cells, 2) cytoplasm of epithelial cells, 3) focal extracellular infiltration, 4) inflammatory cells. HMG B1 was more expressed in the nucleus of epithelial cells of patients compared with controls. In contrast, epithelial cytoplasm HMG B1 staining was significant lower in patients. Sub-epithelial focal infiltration of HMG B1 protein expression was lower in controls, whereas the expression of HMG B1 in the inflammatory cells in patients was significantly increased in comparison with controls. These data, together with the correlation we found between HMG B1 protein expression in different portions and the number of eosinophils infiltrating cells, or IL -5, IL -8 and TNF-α positive cells in patients, suggest that HMG B1 may play a crucial role in the pathogenesis of chronic rhinosinusitis with nasal polyps.

Correlation between female sex and allergy was significant in patients presenting with dysphonia.

Aim of the present study was to investigate the prevalence of allergy in patients affected by both organic and/or functional vocal fold disorders. The secondary aim was to assess the correlation between sex and allergy in dysphonic patients. A retrospective chart review was performed on dysphonic patients. A total of 76 patients underwent fiberoptic endoscopy to assess the objective picture. Logistic regression analyses have been conducted to assess the association between sex and the outcome variables. The laryngoscopic examination revealed the presence of poor glottic closure in 32.9%, hyperkinesias in 11.8%, redness in 11.84%, polyps in 5.3%, oedema in 3.95%, vocal fold hypertrophy in 5.3%, nodules in 42.1%, cordectomy in 2.6%. Allergic rhinitis was present in 56.6%, milk intolerance in 13.2%, asthma in 9.2%, atopic dermatitis in 3.9%, drugs intolerance in 11.8%. A total of 76.32% patients presenting with dysphonia were allergic. A statistically significant association was found between female sex and presence of allergy. In conclusion, allergy testing should be performed routinely on female professional voice users. Mild respiratory disorders must be taken into serious consideration in female professional voice users, who may primarily complain of vocal dysfunction rather than upper and lower respiratory diseases.

Rhino-Bronchial Syndrome. The SIO-AIMAR (Italian Society of Otorhinolaryngology, Head Neck Surgery-Interdisciplinary Scientific Association for the Study of the Respiratory Diseases) survey.

In spite of the amount of literature demonstrating the relationship between upper and lower airways, both from the anatomical, and pathophysiological point of view, little is known about the epidemiology, diagnosis and treatment of the Rhino-Bronchial Syndrome (RBS). After the publication, in 2003, of a Consensus Report defining the Rhino-Bronchial Syndrome, an interdisciplinary group of experts made up from the Italian ENT Society (SIO) and the Interdisciplinary Scientific Association for the Study of Respiratory Diseases (AIMAR) met again in 2005 in order to study a protocol which would have, as the main tasks, the analysis of RBS signs and symptoms and standardization of the diagnostic approach. A secondary endpoint was to characterize the most effective therapeutic options and to correct the great dyshomogeneity in the therapeutic approaches. With this aim, 9 ENT and Pneumology Centres were selected, based on the ability to multidisciplinary cooperation, availability of useful instrumentation and homogeneous distribution over the entire National territory. Overall, 159 patients were enrolled according to clinical history (major and minor symptoms of upper and lower airways) and inclusion/exclusion criteria. All underwent a two level diagnostic approach. In 116 patients, the diagnosis was confirmed on the basis of I level (rhinopharyngeal endoscopy and basal spirometry, respectively, for upper and lower airways) examination. Allergic and infectious diseases were significantly more frequent (37.9% vs 20.9% and 73.3% vs 46.55, respectively) in patients with a confirmed diagnosis for Rhino-Bronchial Syndrome. Nasal obstruction (93%), rhinorrhoea (75%), cough (96%) and dyspnoea (69%) were the more frequent symptoms. The presence of meatal secretions or polyps were the clinical findings significantly differing at endoscopy in the two groups. After 3 months of treatment, according to "good clinical practice" (inhaled steroids, antibiotics, nasal lavages), 96% of the patients recovered. On the basis of these results, a diagnostic flow-chart is proposed according to which the persistence of some symptoms (cough, dyspnoea, rhinorrhoea and nasal obstruction) should lead the patient to a multidisciplinary and multi-level diagnostic approach by an otorhinolaryngology and a pneumology specialist working together for a definitive diagnosis. The recovery rate of about 94% of patients after 3 months of treatment, stresses the importance of a correct diagnosis.