Multi-Disciplinary Expert Perspective on the Management of Type 2 Inflammation-Driven Severe CRSwNP: A Brief Overview of Pathophysiology and Recent Clinical Insights.

Severe chronic rhinosinusitis with nasal polyposis (CRSwNP) is a disabling airway disease that significantly impacts patients' lives through the severity of symptoms, the need for long-term medical treatment and the high risk of recurrence post-surgery. Biological agents targeting type 2 immune responses underlying the pathogenesis of CRSwNP have shown effectiveness in reducing polyp size and eosinophilic infiltrate, and in decreasing the need for additional sinus surgeries. However, despite recent progress in understanding and treating the disease, type 2 inflammation-driven severe CRSwNP continues to pose challenges to clinical management due to several factors such as persistent inflammation, polyp recurrence, heterogeneity of disease, and comorbidities. This article presents the findings of a scientific discussion involving a panel of ear, nose and throat (ENT) specialists and pulmonologists across Sweden and Finland. The discussion aimed to explore current management practices for type 2 inflammation-driven severe CRSwNP in the Nordic region. The main topics examined encompassed screening and referral, measurements of disease control, treatment goals, and future perspectives. The experts emphasized the importance of a collaborative approach in the management of this challenging patient population. The discussion also revealed a need to broaden treatment options for patients with type 2 inflammation-driven CRSwNP and comorbid conditions with shared type 2 pathophysiology. In light of the supporting evidence, a shift in the disease model from the presence of polyps to that of type 2 inflammation may be warranted. Overall, this discussion provides valuable insights for the scientific community and can potentially guide the future management of CRSwNP.

Eosinophilia, asthma, NERD and the use of oral corticosteroids predict uncontrolled chronic rhinosinusitis with nasal polyps after surgery.

BACKGROUND: Severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) is a challenging condition to treat. The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 (EPOS2020) has the following criteria when considering biological therapy for severe uncontrolled CRSwNP: eosinophilia, need for oral corticosteroids (OCS), symptom score, loss of sense of smell and co-morbid asthma. OBJECTIVE: This study aimed at finding associations of baseline factors with uncontrolled CRSwNP after endoscopic sinus surgery (ESS). METHODS: Electronic health record data of CRSwNP patients (N = 137) undergoing ESS in 2002-17 were used. Endpoints of uncontrolled CRSwNP were revision ESS, purchased OCS and antibiotic courses during follow up. Baseline factors were chosen based on EPOS2020 and the data available: nasal polyp (NP) eosinophilia, peripheral blood eosinophilia, co-existing asthma and/or non-steroidal anti-inflammatory drug exacerbated respiratory disease (NERD), need for OCS during the previous year, previous ESS, endoscopic NP score, and Lund-Mackay score of sinus computed tomography scans. RESULTS: During the follow-up of 10.1 ± 3.1 (mean ± standard deviation) years, 35 (25.5%) individuals underwent revision ESS. The best predictive model was obtained by a sum of baseline (1) blood eosinophilia ≥ 250 cells/≥l and/or NP eosinophilia ≥ 30% (Eos), (2) asthma/NERD, and (3) ≥ 1 OCS/year. It was significantly associated with revision ESS, purchased doctor-prescribed OCS and antibiotic courses during follow-up. CONCLUSIONS: We identified similar predictive variables for uncontrolled CRSwNP that are used in the EPOS2020 indications of biological therapy, thus suggesting that these estimates are usable in clinical practice.

Factors Affecting the Control of Chronic Rhinosinusitis With Nasal Polyps: A Comparison in Patients With or Without NERD.

OBJECTIVES: The aim was to compare the control of chronic rhinosinusitis with nasal polyps (CRSwNP) after endoscopic sinus surgery (ESS), in patients with/without nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NERD).Study Desing: A retrospective hospital-based sample of CRSwNP patients with/without NERD with follow-up. SETTING: Tertiary rhinology centers. METHODS: Electronic patient record data from 116 CRSwNP patients (46 with NERD and 70 without NERD) undergoing ESS during 2001-17 were studied. Mean follow-up time was 9.9 years (range 1.1-15.3). Endpoints reflecting uncontrolled CRSwNP were revision ESS, and need for rescue/advanced therapy (e.g. antibiotics, oral corticosteroids and/or biological therapy) during follow-up. NERD was variable of interest and gender, age, asthma, allergic rhinitis (AR), smoking, Lund-Mackay (LM) score of sinus computed tomography scans previous ESS and baseline total ethmoidectomy were used as covariates. RESULTS: Twenty-one (49.7%) NERD patients and 18 (25.7%) non-NERD patients underwent revision ESS within a mean ± SD of 4.3 ± 2.8 and 3.7 ± 2.6 years, respectively (p = .013, by Logrank test). In Cox´s regression models, NERD, female gender, young age, asthma, AR, previous ESS, and lack of total ethmoidectomy were associated with revision-ESS. In adjusted model, only the total ethmoidectomy predicted revision-free survival. In adjusted logistic regression model, there was an insignificant trend that NERD and LM score were associated with the need for rescue/advanced therapy in the follow-up. CONCLUSIONS: Patients with NERD had higher risk of uncontrolled CRSwNP than patient group without NERD, as measured by revision ESS and/or need for rescue/advanced therapy in the follow-up. In addition, baseline total ethmoidectomy was associated with revision-free survival.

Factors affecting upper airway control of NSAID-exacerbated respiratory disease: A real-world study of 167 patients.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) exacerbated respiratory disease (N-ERD) is a triad with asthma, chronic rhinosinusitis with nasal polyps, and NSAID intolerance. Uncontrolled N-ERD forms a major public health problem due to frequent and difficult-to-treat exacerbations and/or requiring putatively frequent endoscopic sinus surgeries (ESS). Our aim was to study factors affecting control of N-ERD. METHODS: Retrospective patient record data (patient characteristics, prior sinus surgeries, follow-up data in 2020) from 167 N-ERD patients undergoing consultation at three tertiary hospitals from 2001 to 2017 was used. Outcome measurements reflecting uncontrolled N-ERD were revision ESS, corticosteroids/biological therapy, and antibiotic courses during 2016-2020. Associations were analyzed by using nonparametric tests, Cox's proportional hazard, and binary logistic regression models. RESULTS: Nasal polyp eosinophilia increased the risk of revision surgery during the follow-up (adjusted hazard ratio [aHR] 3.21, confidence interval 1.23-8.38). Also baseline oral corticosteroids (OCS; HR, 1.73, 1.04-2.89) and baseline surgery without total ethmoidectomy increased the risk of revision ESS (HR, 2.17, 1.07-4.42) in unadjusted models. In addition, both baseline OCS (adjusted odds ratio [aOR] 2.78, 1.23-6.26) and a history of ≥4 previous ESS (aOR, 2.15, 0.98-4.70) were associated with the use of OCS/biological therapy during the follow-up, but not with high number of antibiotics. CONCLUSIONS: Nasal polyp eosinophilia, baseline OCS, and a history of recurrent ESS predict uncontrolled N-ERD. These factors might be clinically useful in risk-estimation of uncontrolled disease and for organizing follow-ups. Prospective cohort studies with larger sample size are needed to further study the factors affecting the upper airway control of N-ERD.

Baseline Conservative and Surgical Management in the Treatment of NSAID-Exacerbated Respiratory Disease.

Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) is a chronic medical condition that includes asthma, chronic rhinosinusitis with nasal polyposis, and hypersensitivity to aspirin and other NSAIDs. Eosinophilic inflammation in the upper and lower airways is treated with local corticosteroids, repeated antibiotics, oral corticosteroid courses, endoscopic sinus surgery, and in some cases aspirin treatment after desensitization (ATAD). Nevertheless, the disease may be uncontrolled and it has a great impact on quality of life. A better understanding of the pathomechanisms of the disease and the development of medications that target type 2 inflammation mediators may have a crucial role in achieving better disease control in patients with N-ERD.

Association of Picornavirus Infections With Acute Otitis Media in a Prospective Birth Cohort Study.

BACKGROUND: Human rhinoviruses (HRVs), human enteroviruses (HEVs) and human parechoviruses (HPeVs) have been linked to acute otitis media (AOM). We evaluated this association in a prospective birth cohort setting. METHODS: A total of 324 healthy infants were followed up from birth to age 3 years. Nasal swab samples were collected at age 3, 6, 12, 18, 24, and 36 months and screened for HRV and HEV using real-time reverse-transcription quantitative polymerase chain reaction. Stool samples were collected monthly and analyzed for HRV, HEV, and HPeV. AOM episodes diagnosed by physicians were reported by parents in a diary. The association of viruses with AOM was analyzed using generalized estimation equations, and their relative contributions using population-attributable risk percentages. RESULTS: A clear association was found between AOM episodes and simultaneous detection of HEV (adjusted odds ratio for the detection of virus in stools, 2.04; 95% confidence interval, 1.06-3.91) and HRV (1.54; 1.04-2.30). HPeV showed a similar, yet nonsignificant trend (adjusted odds ratio, 1.44; 95% confidence interval, .81-2.56). HRV and HEV showed higher population-attributable risk percentages (25% and 20%) than HPeV (11%). CONCLUSIONS: HEVs and HRVs may contribute to the development of AOM in a relatively large proportion of cases.

Next-Generation Sequencing Combined with Specific PCR Assays To Determine the Bacterial 16S rRNA Gene Profiles of Middle Ear Fluid Collected from Children with Acute Otitis Media.

The aim of the study was to analyze the bacteriome of acute otitis media with a novel modification of next-generation sequencing techniques. Outpatient children with acute otitis media were enrolled in the study, and middle ear fluids were collected during 90 episodes from 79 subjects aged 5 to 42 months (median age, 19 months). The bacteriome profiles of middle ear fluid samples were determined by a nested-PCR amplification of the 16S rRNA gene (V4 region), followed by mass sequencing. The profiling results were compared to the results of specific PCR assays targeting selected prevalent pathogens. Bacteriome profiling using nested amplification of low-volume samples was aided by a bioinformatic subtraction of signal contaminants from the recombinant polymerase, achieving a sensitivity slightly lower than that of specific PCR detection. Streptococcus pneumoniae was detected in 28 (31%) samples, Haemophilus influenzae in 24 (27%), Moraxella catarrhalis in 18 (20%), Staphylococcus spp. in 21 (23%), Turicella otitidis in 5 (5.6%), Alloiococcus otitidis in 3 (3.3%), and other bacteria in 14 (16%) using bacteriome profiling. S. pneumoniae was the dominant pathogen in 14 (16%) samples, H. influenzae in 15 (17%), M. catarrhalis in 5 (5.6%), T. otitidis in 2, and Staphylococcus auricularis in 2. Weaker signals of Prevotella melaninogenica, Veillonella dispar, and Veillonella montpellierensis were noted in several samples. Fourteen samples (16%) were not explainable by bacterial pathogens; novel causative agents were not detected. In conclusion, unbiased bacteriome profiling helped in depicting the true mutual quantitative ratios of ear bacteria, but at present, its complicated protocol impedes its routine clinical use. IMPORTANCE Although S. pneumoniae, H. influenzae, and M. catarrhalis have been long established as the most important pathogens in acute otitis media using culture and specific PCR assays, the knowledge of their mutual quantitative relations and possible roles of other bacteria is incomplete. The advent of unbiased bacteriome 16S rRNA gene profiling has allowed the detection of nearly all bacteria present in the sample, and it helps in depicting their mutual quantitative ratios. Due to the difficulties in performing mass sequencing in low-volume samples, only a few bacteriome-profiling studies of otitis media have been published, all limited to cases of chronic otitis media. Here, we present a study on samples obtained from young children with acute otitis media, successfully using a strategy of nested PCR coupled with mass sequencing, and demonstrate that the method can confer quantitative information hardly obtainable by other methods.

Human enterovirus and rhinovirus infections are associated with otitis media in a prospective birth cohort study.

BACKGROUND: Human enteroviruses (HEVs) and rhinoviruses (HRVs) have been linked to acute otitis media (AOM). OBJECTIVES: The present study evaluates the aforementioned association in a birth cohort setting. STUDY DESIGN: The cohort included 286 healthy infants (191 boys) followed from birth up to the age of 2 years in the Type 1 Diabetes Prediction and Prevention study in Finland. Stool samples were collected monthly and analyzed for the presence of HRV and HEV RNA using RT-PCR. Clinical symptoms were recorded by a questionnaire every 3-6 months. RESULTS: Altogether 610 AOM episodes were reported during the follow-up. 9.8% of the stool samples were positive for HRV and 6.8% for HEV. HRV positivity peaked at the age of 3-6 months declining gradually after this age, whereas HEV positivity peaked later, at the age of 12-24 months. The risk of AOM was increased in children who were HEV positive at least once at the age of 6-12 months (OR 2.2 [95%CI 1.1-4.2], P=0.023) or who were HRV positive at least once at the age of 18-24 months (OR 2.3 [95%CI 1.0-5.2], P=0.042). Having an older sibling, short breast-feeding and maternal smoking during pregnancy were also significantly associated with AOM. CONCLUSIONS: HRV and HEV infections are frequent during the first months of life. The observed trend for increased risk of AOM in HRV and HEV positive children is in line with the results from hospital series suggesting that these viruses may play an independent role in the pathogenesis of AOM.

Moraxella catarrhalis Might Be More Common than Expected in Acute Otitis Media in Young Finnish Children.

According to studies based on bacterial cultures of middle ear fluids, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis have been the most common pathogens in acute otitis media. However, bacterial culture can be affected by reduced viability or suboptimal growth of bacteria. PCR detects bacterial DNA from samples with greater sensitivity than culture. In the present study, we analyzed the middle ear pathogens with both conventional culture and semiquantitative real-time PCR in 90 middle ear fluid samples obtained from children aged 5 to 42 months during acute otitis media episodes. Samples were tested for the presence of S. pneumoniae, H. influenzae, M. catarrhalis, Alloiococcus otitidis, Staphylococcus aureus, and Pseudomonas aeruginosa One or more bacterial pathogens were detected in 42 (47%) samples with culture and in 69 (77%) samples with PCR. According to PCR analysis, M. catarrhalis results were positive in 42 (47%) samples, H. influenzae in 30 (33%), S. pneumoniae in 27 (30%), A. otitidis in 6 (6.7%), S. aureus in 5 (5.6%), and P. aeruginosa in 1 (1.1%). Multibacterial etiology was seen in 34 (38%) samples, and M. catarrhalis was detected in most (85%) of those cases. Fifteen signals for M. catarrhalis were strong, suggesting a highly probable etiological role of the pathogen. In conclusion, even though M. catarrhalis is often a part of mixed flora in acute otitis media, a considerable proportion of cases may be primarily attributable to this pathogen.

Antibiotic resistance in pathogens causing acute otitis media in Finnish children.

INTRODUCTION: Microbiology and susceptibility of middle ear pathogens in children change over time and antibiotic resistance is increasing globally. For the clinicians it is important to be up to date about the resistance situation when considering antibiotic treatment in acute otitis media (AOM). In this study we analysed the resistance profile of AOM pathogens in out-patient children in Finland. METHODS AND MATERIALS: A total of 41 culture positive middle ear fluid (MEF) samples were analysed for bacteria and the presence of antibiotic resistant strains. The samples were obtained from children aged six - 39 months who participated in the otitis media trial during one year period. RESULTS: The most common pathogen was Haemophilus influenzae 17 (40%), followed by Streptococcus pneumoniae in 15 (35%) and Moraxella catarrhalis in 8 (19%). Other pathogens were detected in 3 (7%) of cases. Antibiotic resistance or diminished sensitivity was seen in 63% of the detected bacteria and 28% of pathogens produced beta-lactamase. CONCLUSIONS: Antibiotic resistant bacterial strains causing AOM have increased in Finland. Nevertheless, most of the pathogens (72%) were sensitive to amoxicillin, which is still recommended as the first line antibiotic in the treatment of AOM.

The Experience of Treating Drooling with Repeated Botulinum Toxin Injections.

Botulinum toxin A (BTX-A) injections to the salivary glands are effective in the treatment of drooling, and complications are rare. However, there are only a few previous reports on the long-term use of BTX-A injections. This study retrospectively analyzes our experience of treating drooling with repeated BTX-A injections in patients with neurodegenerative diseases. All patients who received repeated BTX-A injections to the submandibular glands at Tampere University Hospital in 2004-2013 were included in the analysis. Six patients, aged from 6 to 21 years, were included in the study, and a total of 41 bilateral BTX-A injections were administered to their submandibular glands. The average number of injections per patient was 6 (range: 3-11). The average interval between the injections was 9.8 months (range: 4-18), and 95% (39/41) of the injections were performed with good response. The complication rate of the BTX-A injections was 2.4% (1/41), since one of the patients had swallowing problems after an injection. BTX-A injections to the submandibular glands are effective and have a low morbidity rate, and repeated injections can be recommended as long-term treatment of drooling.

Human parechovirus as a minor cause of acute otitis media in children.

Human parechoviruses (HPeVs) cause mild upper respiratory infections, gastrointestinal symptoms, central nervous system infections and some studies have linked them with acute otitis media (AOM). The aim of the present study was to study further the role of HPeV infections in AOM by detecting these viruses directly from middle ear fluid (MEF), respiratory and stool samples collected from children during AOM episodes. A total of 91 MEF samples, 98 nasal swab (NS) samples and 92 stool samples were collected during 100 AOM episodes in a total of 87 children aged between five to 42 months. All specimens were analyzed by real time RT-PCR for the presence of HPeV RNA. HPeV infection was diagnosed in 12 (14%) patients. HPeV RNA was detected in altogether 13 samples, including four MEF samples, three NS samples and six stool samples. One patient was positive in both stool and MEF samples. The results suggest that HPeV may play a role in some AOM cases, but it is not a major cause of AOM in children.

Retrospective analysis of a combined endoscopic and transcutaneous technique for the management of parotid salivary gland stones.

Sialendoscopy is used in the diagnosis and treatment of various symptoms relating to the salivary gland, e.g. chronic swelling or obstruction and inflammation of the salivary duct. Small intraductal stones can be removed with various instruments during sialendoscopy, whereas larger ones can be fragmented with extracorporeal shockwave lithotripsy or laser. However, 5-10% of the patients with parotid stones cannot be treated with these methods. In patients with large impacted stones or stones in a hilus area, a combined endoscopic and transcutaneous technique can be employed. The stone is approached endoscopically, a skin flap is raised over or a small incision is made through the illuminated area, and the stone is removed by an external route with minimal morbidity. This retrospective study analysed the cases of 8 patients treated using the combined technique, 6 of whom became symptom free. Superficial parotidectomy was performed in 1 patient. No complications were observed, and ductal stents were not used. The average diameter of the stones was 7.6 mm (range 7.0-10.2). The combined technique is recommended for the removal of large and impacted intraductal stones in the parotid gland. No major complications have been reported.