Rhinosinusal Inflammation and High Mobility Group Box 1 Protein: A New Target for Therapy.

BACKGROUND/AIMS: High mobility group box 1 (HMGB1) is a protein belonging to the class of damage-associated molecular pattern molecules, which activates innate immunity and powerful inflammatory factors. The aim of this review is to show the importance of HMGB1 in the pathogenesis of nasal inflammatory diseases and to suggest that inhibition of HMGB1 may be an innovative therapeutic target. METHODS: We used immunohistochemistry to study whether HMGB1 increases in chronic rhinosinusitis with nasal polyps and whether its expression is associated with eosinophils and inflammatory cytokines. Using primary cultures of human nasal epithelial cells, we localised lipopolysaccharide-induced active translocation and release of HMGB1 by immunofluorescence assay and Western blot. RESULTS: Patients with severe symptoms have the highest HMGB1 serum levels. Glycyrrhetic acid inhibits the chemotactic and mitogenic function of HMGB1, binding to the hydrophobic residues that delimit the pockets in box A and B. CONCLUSIONS: Chronic inflammatory diseases of the nose and paranasal sinuses are increasingly prevalent and are a financial burden for society. HMGB1 has been shown to play a role in several inflammatory diseases of otolaryngological interest. The inhibition of HMGB1 may be an innovative therapeutic target for patients with chronic upper airway inflammatory diseases having nasal obstruction as a major symptom.

A prospective open-label study to assess the efficacy and safety of a herbal medicinal product (Sinupret) in patients with acute rhinosinusitis.

AIMS: We present a multicenter, prospective, open-label study to assess the efficacy and safety of a phytomedicine. The aim of the research was to evaluate the efficacy and safety of 14 days of treatment with Sinupret for acute rhinosinusitis. Sinupret is a herbal preparation used to restore and maintain the physiological function of the membranes in the sinus cavity. METHODS: Sixty patients with acute rhinosinusitis based on the EPOS guidelines were enrolled in the study. Thirty patients were treated with Sinupret Forte, while 30 patients were treated with intranasal fluticasone furoate. The criteria for the evaluation of efficacy were the major symptom scores according to the investigator and the Health-Related Quality of Life score. The criteria used to evaluate safety were the number of patients with adverse events, the patients' vital signs, and laboratory safety. RESULTS: All patients considered showed significant improvements in symptoms. Among the patients treated with Sinupret, none had an adverse event, while 3 patients treated with fluticasone furoate had minor adverse events. The patients' vital signs and laboratory values were normal. CONCLUSIONS: The results of this study suggest that this phytomedicinal preparation has a significant level of efficacy in acute rhinosinusitis and that treatment is safe.

PLUNC proteins positivity in patients with chronic rhinosinusitis: a case-control study.

INTRODUCTION: Innate immunity is the first protection against microorganisms. Nowadays, there is a growing interest in innate immune molecule known as palate, lung, nasal epithelial clone (PLUNC). PLUNC is a specific product of the airways, of approximately 25 kDa, encoded by adjacent genes found within a 300 kb region of chromosome 20; these proteins must be detected predominantly in the upper respiratory tract. MATERIALS AND METHODS: We performed a case-control study to investigate the presence of this protein in nasal tissue of patients affected by chronic rhinosinusitis. 59 patients were enrolled (44 cases, 15 controls). We have examined the correlation between the presence of pathology and the PLUNC proteins positivity. RESULTS: 100% of controls have a +++ rated PLUNC proteins positivity, while cases have a lower percentage of positivity. We used χ (2) statistical test to analyze the results of the study and there is a difference statistically significant between cases and controls in PLUNC proteins positivity. CONCLUSIONS: These observations suggest that, in response to agents or chemical factors, nasal mucosal epithelium will react and produce PLUNC proteins. So PLUNC proteins have a protective function on upper airways mucosa, as we can see by evaluating the high positivity in control group.

Activity of coenzyme Q 10 (Q-Ter multicomposite) on recovery time in noise-induced hearing loss.

A potential consequence of exposure to noise is a temporary reduction in auditory sensitivity known as temporary threshold shift (TTS), which mainly depends on the intensity and duration of exposure to the noise. Recovery time is related to the amount of initial hearing loss, and the most recovery takes place during the first 15 min following exposure. This study evaluated the efficacy in otoprotection against noise-induced hearing loss of an orally administrated food supplement containing coenzyme Q 10 -Ter. This water-soluble formulation of coenzyme Q 10 shows better bioavailability than the native form and has been found to have a protective effect on outer hair cells after exposure to noise in animal models. Thirty volunteers were enrolled, and the right ear of each subject was exposed to a narrow-band noise centered at 3 kHz for 10 min at the intensity of 90 dB HL. In the 30 subjects enrolled, TTS was evaluated after 2, 15, and 30 min and the recovery time was recorded in each subject. The longest recovery time was 45 min. Among the 18 subjects who underwent a second test after treatment with Q-Ter, the mean recovery time was 31.43 min. The results of the present study show that 30 days' treatment with Q-Ter can aid faster recovery after exposure to noise (P < 0.0001). The reduction in the recovery time following treatment can be explained by Q-Ter-mediated improvement of the outer hair cells' response to oxidative stress.

Local allergic rhinitis: considerations.

The term "local allergic rhinitis" has gained popularity as a clinical entity in recent years. Despite the apparent contradiction in the definitions of "nasal" and "local," we offer insights based on our extensive experience in the field. Local allergic rhinitis has been recognized and treated for many years, so it is not a new discovery. The nasal provocation test, which was introduced in the 1980s, was critical in identifying allergic rhinitis cases with suggestive symptoms but negative allergy tests. Our reflections aim to contribute to a precise terminological decision that is consistent with various points of view.

Rhinosinusitis: clinical-based phenotyping.

Rhinosinusitis (RS) is a common disease and is currently classified into two main types: acute RS (ARS) and chronic RS (CRS), which in turn includes CRS with or without nasal polyps. Different guidelines consider this classification. However, in clinical practice, other phenotypes exist. The current article would propose new clinical-based phenotyping of RS, including the following clinical phenotypes: simple catarrhal RS, Acute RS, acute bacterial RS, severe (complicated) acute RS, chronic RS, and recurrent chronic RS. Treatment strategy should be tailored considering the clinical phenotype and could include phytomedicines, intranasal non-pharmacological remedies, and local bacteriotherapy. In conclusion, RS requires thorough diagnostic work-up, and the therapeutic approach should be mainly based on appropriate management.

Nasal foreign bodies: the experience of the Buenos Aires pediatric otolaryngology clinic.

OBJECTIVE: The aim of the present paper is to present nasal foreign cases observed at the Children's Hospital Gutierrez in Buenos Aires, Argentina, over a 4-year period and to compare the main findings with data from other case series. METHODS: A prospective study was undertaken on children having inhaled/aspired a foreign body (FB), with regard to age and sex distribution, FB type, dimensions and consistency, FB location, clinical presentation, removal and occurrence of complications. RESULTS: A total of 1559 cases of foreign body inhalation were observed. The mean age of the children was 3.48 years (SD 1.60). Injuries frequently occurred during recreational activities: in 1154 cases (74.1%) the child was playing, while in 52 cases the accident occurred during a party. In 1417 cases (90.9%) adults were present. Children frequently (1123 cases) insert small objects with a rigid consistency in their noses, like pearls or little metal objects. In the majority of cases nasal FB injuries are due to insertion of inorganic objects (72.7%). CONCLUSION: Injuries are frequently due to the incorrect manipulation of objects not conceived for children use, including pins, nails, screws and floats. Batteries and magnets deserve particular mention because they require immediate treatment, as they can cause septal necrosis and perforation within hours. Unfortunately, an adult being present does not seem to be sufficient to prevent injuries, and parents are frequently unaware of the danger. The dissemination of information regarding safe behaviors could be fundamental in preventing injuries and need to be promoted by family pediatricians and health practitioners.

Foreign bodies in the ears in children: the experience of the Buenos Aires pediatric ORL clinic.

Even if foreign body (FB) insertion in the external auditory canal (EAC) is not an uncommon event, the literature based on large series is scarce. In the present study, ear FB cases observed at the Children's Hospital Gutierrez in Buenos Aires over five years of otorhinolaryngology (ORL) activity are presented, and the main findings are compared with data coming from other well-known published case series. Three hundred ninety-two injury cases were observed. Eighty percent of them occurred while the child was playing; in 328 cases (83.7%), adults were present. The retrieved FB included food items and objects usually available at home, such as pins, while fragments of toys were found in only 2 cases. These findings testify to the efficacy of regulations imposing manufacturing quality standards on toys; on the other hand, parents seem to be unaware of the risk imposed by FB insertion, since injuries usually happen under adult supervision while children are manipulating objects not adapted for their age.

HMGB1-antagonism exerted by glycyrrhizin could be fruitful against COVID-19.

The COVID-19 pandemic era is causing a relevant issue for the health. There is no specific drug able to antagonize the SARS-CoV-2 infection. As a consequence, there is growing interest about potential molecules able to contrast infection. In this regard, HMGB, an alarmin, may play a relevant role in pathogenic mechanisms induced by SARS-CoV-2.  As HMGB1 is antagonized by glycyrrhizin, this substance could be potentially useful as ancillary treatment in COVID-19.

A randomized, double-blind, placebo- -controlled study to investigate the use of bacteriophages in patients with chronic rhinosinusitis with nasal polyps.

Background A randomized, double-blind placebo-controlled study investigated the use of bacteriophages in the treatment of chronic rhinosinusitis with nasal polyps. Materials and Methods 40 adult patients with сhronic rhinosinusitis with nasal polyps were examined. All patients underwent functional endoscopic sinus surgery. After the surgery, 20 patients got the intranasal gel with a bacteriophages mixture (Otofag, Micromir, Russia) twice a day for ten weeks, and 20 patients got a placebo. Results On the 10th day, IL-1ß secretion diminished (63 mg/ml versus 440 mg/ml in control). There was a decrease in the total number of microorganisms and Enterobacteriaceae (5.7 x 106 CFU/ml versus 1.2 x 109 CFU/ml in control), and the absence of Streptococci (versus 2.1 x 109 CFU/ml in control) on the 30th day of the treatment in the group with the bacteriophages. On the 10th day, a decrease in the activity of secretory IL-1ß and IL-8 strongly and very strongly correlated with a total number of microorganisms (r = 0.7; r = 0.9 respectively), as well as secretory IL-8 with Enterobacteriaceae (r = 0.72) and Staphylococci (r = 0.65) in the active group treated with the bacteriophages. On the 30th day, the decrease in serum IL-1ß significantly correlated with the total number of microorganisms (r = 0.80) and enterobacteria (r = 0.90) in the active group. Conclusions The administration of bacteriophages restored the balance of microorganisms in the nasal cavity and decreased the inflammatory response in chronic rhinosinusitis with nasal polyps. These changes, such as an inflammation dampening, could theoretically reduce the recurrent growth of polyp tissue in the future.

HMGB1 in nasal inflammatory diseases: a reappraisal 30 years after its discovery.

INTRODUCTION: High mobility group protein box 1 (HMGB1) is a protein belonging to the alarmin family. HMGB1 has a relevant role in starting the inflammatory cascade by means of receptors, such as RAGE and TLR. HMGB1 supports transcription of many genes in interactions with many transcription factors, including NF-kB. The axis HMGB1-RAGE-NF-kB has, therefore, a pivotal role in the inflammatory cascade. HMGB1 controls the production of several pro-inflammatory cytokines and the proliferation and activation of many inflammatory cells. AREAS COVERED: The present report concerns the role of HMGB1 in nasal inflammatory disorders, including allergic and non-allergic rhinitis, and chronic rhinosinusitis with nasal polyps. HMGB1 modulation has been the aim of several studies. The literature search included recent papers that covered this topic. EXPERT OPINION: As HMGB1 has a pivotal role in inflammatory events, its modulation could be attractive for designing new therapeutic strategies. In this regard, glycyrrhetic acid (GA), the active component of Glycyrrhiza glabra, can efficiently block HMGB1. Promising reports seem to suggest that GA could exert favorable anti-inflammatory activity in patients with nasal inflammatory disorders.

The impact of allergic rhinitis in clinical practice: an Italian Survey.

Allergic rhinitis (AR) is a very common disorder. The current Survey was conducted on a sample of about 5,000 adult subjects in 5 Italian cities. A questionnaire, containing 15 questions, was administered on the road. AR affects about 20% of the general population. The most common diagnostic test was the skin prick test, but only 12% of patients performed an allergy test to confirm the diagnosis. About 50% of patients did not take any medicine. Even about 40% of treatments were suggested by friends or pharmacists. In conclusion, the current Survey demonstrated that AR is a common disorder in Italy, the diagnostic work-up is still incorrect, and the therapeutic approach does not adhere to the guidelines. Therefore, there is a need to implement adequate information on this topic in Italy.

Chronic rhinosinusitis with nasal polyposis: the role of personalized and integrated medicine.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a frequent disorder. From a clinical and an immunopathological point of view, different phenotypes and endotypes have been identified. The frequent comorbidity with asthma allowed to pave the way to the use of biological agents for the treatment of CRSwNP. Biological agents are targeted to antagonize IgE, interleukin (IL) 4, IL-5, and IL-13 at present. However, a correct and appropriate workup is mandatory, mainly concerning the exact definition of the specific pheno-endotype. The preliminary outcomes are promising, even though there is a need for well-established indications, criteria of responsiveness, duration, and safety. On the other hand, this personalized medicine could be fruitfully integrated with gold-standard medications, such as intranasal corticosteroids. As CRSwNP is a chronic disorder, treatment should be long-lasting, so complementary anti-inflammatory treatments could be opportunely integrated and/or alternated to steroids.

A comparison between mometasone furoate nasal spray and intranasal glycyrrhetic acid in patients with allergic rhinitis: a preliminary study in clinical practice.

Allergic rhinitis (AR) is caused by an IgE-mediated inflammatory reaction consequent to the exposure to the causal allergen. Glycyrrhetic acid (GlyAc) is a natural compound extracted from the liquorice that exerts anti-inflammatory activity. This real-life study compared intranasal GlyAc, present in a medical device containing also glycerol and mannitol, with mometasone furoate nasal spray (MFNS) in 50 adult outpatients with AR. Both treatments lasted 2 months. Endoscopic signs, perception of symptom severity, assessed by VAS, and nasal function measured by rhinomanometry were evaluated at baseline (T0), after one (T1) and two (T2) months. The intergroup analysis showed that at T1 there was no significant difference between groups about the use of decongestants and antihistamines, turbinate hypertrophy and pale mucosa, perception of olfaction and snoring. At T2 there was no significant difference between groups about use of relievers, all endoscopic signs, and perception of nasal discomfort, nasal obstruction, olfaction, and snoring. The intragroup analysis showed that in MFNS group there was a significant change during the entire period of treatment for all parameters except watery rhinorrhea (sign) and ocular discomfort; in GlyAc group there was a significant change during the entire period of treatment for all parameters. In conclusion, this preliminary study, conducted in clinical practice, evidenced that intranasal CysAC plus mannitol was able to significantly improve nasal endoscopic signs, perception of symptoms, and nasal function in patients with AR. Therefore, GlyAc could be a reasonable therapeutic option to control allergic inflammation.

Medical education and attitudes about acute otitis media guidelines: a survey of Italian pediatricians and otolaryngologists.

BACKGROUND: Medical education and guidelines have been advocated as major means of improving the management of otitis media. Limited data are available concerning medical education in acute otitis media (AOM), and the association between medical education and attitudes about AOM guidelines has never been explored. OBJECTIVES: To assess the prevalence of medical education concerning AOM, of a positive attitude toward AOM guidelines and of appropriate diagnostic methods in a large sample of Italian pediatricians (PEDs) and otolaryngologist (ENTs) and to look for possible associations between them. SUBJECTS AND METHODS: This cross-sectional survey was based on the responses of 2012 physicians (1160 PEDs and 852 ENTs) to a mailed anonymous questionnaire. RESULTS: Very few (9%) of the responders had received any AOM medical education during medical school, but the number increased during residency (38%) and peaked in the postresidency period (53%) with slight differences between PEDs and ENTs. Forty percent reported a positive attitude toward AOM guidelines, with PEDs having a better attitude than ENTs (46% vs. 32%, P < 0.001). An appropriate diagnostic method for AOM was reported by only 21% of the physicians (PEDs 11% vs. ENTs 35%, P < 0.001). AOM medical education during postresidency and reporting the use of appropriate diagnostic methods were significantly associated with a positive attitude about AOM guidelines. CONCLUSIONS: Specific educational programs concerning AOM should be implemented and rigorously evaluated, before physicians become fully trained PEDs and ENTs, and maintained during postresidency. Evidence-based guidelines should be further incorporated into everyday practice of both PEDs and ENTs.

Preventive nasal bacteriotherapy for the treatment of upper respiratory tract infections and sleep disordered breathing in children.

OBJECTIVES: The purpose of this prospective study was to assess the effectiveness and safety of Streptococcus salivarius 24SMBc administered as a nasal spray in children affected by recurring infections of the upper airways, adenotonsillar hypertrophy, and sleep disordered breathing (SDB). METHODS: Prospective study on 42 children with SDB. Anamnestic and general examination data were collected using the 'Sleep Clinical Record' (SCR) questionnaire during the first inspection and after three months of treatment with Streptococcus salivarius 24SMBc nasal spray. Quantitative variables were statistically compared. RESULTS: After three months, the enrolled patients showed lower SCR scores than during the first inspection (6.0 vs 7.5 p < 0.000), with a significant reduction of nasal obstruction (p = 0.001) and oral breathing (p = 0.04), and a positive Brouillette Score (p = 0.001). The children and parents did not declare any adverse reactions during the three months of treatment. CONCLUSIONS: This series confirms the effectiveness and safety of Streptococcus salivarius 24SMBc treatment in children affected by recurring upper respiratory tract infections, adenotonsillar hypertrophy, and sleep disordered breathing.

HMGB1 in the Pathogenesis of Nasal Inflammatory Diseases and its Inhibition as New Therapeutic Approach: A Review from the Literature.

Introduction This study is a systematic review on recent developments about the importance of HMGB1 protein in the pathogenesis of rhino-sinusal inflammatory diseases. We also report data on the use of 18-ß-glycyrrhetic acid (GA), which has been shown able to inhibit the pro-inflammatory activities of HMGB1, in young patients affected by allergic rhinitis and complaining of nasal obstruction as main symptom. Objectives The objective of this study was to review the literature to demonstrate the importance of HMGB1 in the pathogenesis of nasal inflammatory disorders and understand whether the inhibition of this protein may be an efficacious and innovative therapeutic strategy for patients with rhino-sinusal inflammation. Data Synthesis Authors searched for pertinent articles indexed in PubMed, Scopus, and other health journals between 2004 and 2015. In total, the authors gathered 258 articles: 219 articles through Pubmed and 39 articles from other search engines. The search terms used were as follows: HMGB1 AND "respiratory epithelium," "airway inflammation," "rhinitis," "allergic rhinitis," "rhinosinusitis," "nasal polyposis," "glycyrrhetic acid," "children." Conclusions Patients with severe symptoms have the highest serum levels and the highest extracellular expression of HMGB1. GA inhibits HMGB1 chemotactic and mitogenic function by a scavenger mechanism on extracellular HMGB1 accumulation stimulated by lipopolysaccharides in vitro. Treatment of allergic rhinitis with GA is not associated with local or systemic side effects in children and adults.

Radon-enriched hot spring water therapy for upper and lower respiratory tract inflammation.

Background Radon-222-enriched hot spring therapy, which is characterized by a safe level of radioactivity, is used for the treatment of rheumatic disorders, and its efficacy has already been studied in several clinical trials. Radon-water inhalation therapy for the treatment of upper and lower airway inflammatory diseases is used in many hot springs centers. However, its application has not been reviewed to date. Methods We systematically searched the PubMed and Scopus databases for clinical trials published in the last 20 years in which objective parameters of upper and lower airway function had been tested before and after radon-enriched inhalation treatment. Results Four prospective studies were found: 1 asthma trial, 1 placebo-controlled chronic rhinosinusitis trial, 1 upper respiratory tract inflammation with nasal obstruction trial, and 1 case-control allergic rhinitis trial. Patients were treated with nasal inhalations of radon-enriched water for 12 to 28 days and were assessed at baseline and after therapy. After 2 weeks of treatment, nasal resistance decreased, flow increased, mucociliary clearance was enhanced, ciliated-to-muciparous cell ratio increased, and %FEV1 increased in asthmatic patients. Conclusion Radon-enriched inhalation therapy improves objective indicators of nasal function in allergic rhinitis and chronic rhinosinusitis, and causes relief of pulmonary obstruction in asthma.