Severe spontaneous epistaxis: retrospective study in a tertiary ENT centre.

PURPOSE: To investigate the clinical profile and outcomes of different treatment strategies in patients hospitalized for spontaneous severe epistaxis. METHODS: This is a retrospective descriptive study of a case series of patients hospitalized for epistaxis in the University Hospital of Ghent between 2005 and 2012. RESULTS: 124 patients with, respectively, 132 episodes were included. 64% were male. The mean age was 65 years. 73% had comorbidities of which arterial hypertension was the most common. 61% were taking one or more antithrombotics and in 25.7% a recent change in the medication schedule took place. 47% of the episodes necessitated a vascular intervention. The most performed surgery was endoscopic sphenopalatine artery ligation. The 1-year success rate of conservative treatment was 47% and of vascular intervention 81%. No significant difference between the recurrence rates and need for vascular intervention of the different comorbidities and medications was detected using Pearson chi-squared and Fisher's exact testing. The overall 5-year survival rate was 83.6%. CONCLUSIONS: The typical pattern of a patient presenting with severe epistaxis was a patient in the sixth decade, male, suffering from comorbidities and taking one or more antithrombotic agents. Based on the above-mentioned success rates of the different treatment options, we think all centres treating epistaxis should apply a well-defined protocol to guide the decision when to proceed with surgery. Furthermore, prospective research needs to precisely investigate the role played by comorbidities and their treatment in the occurrence of epistaxis and to test the effectiveness of proposed algorithms.

Longitudinal changes in hearing threshold levels for noise-exposed military personnel.

PURPOSE: Military personnel are exposed to variable and sometimes very high noise in their professional environment. The aim of this study is to evaluate through a longitudinal study if our hearing conservation program has to be adapted to consider specific interventions for subgroups of our military population still subject to a higher risk of hearing loss. METHODS: We conducted a retrospective longitudinal study in 2015-2016 to describe the evolution of hearing threshold levels of military personnel as measured during periodic audiometric screening over a period of 6 years (2009-2014) after the implementation of our hearing conservation program. A linear mixed model explored the relationship of pure-tone average (PTA) on 3, 4 and 6 KHz with probability of noise exposure, gender, age at baseline, time since baseline, hearing loss at baseline and ear. RESULTS: For 18,672 military individuals, our results show a small but statistically significant increase of 0.08 dB per year in PTA on 3, 4 and 6 KHz over the 6-year period that is consistently decelerating as a function of time. An additional annual increase of hearing thresholds due to higher age and moderate and high probability of exposure to noise was also found. CONCLUSIONS: No major adaptation of our hearing conservation program is required but efforts should be strengthened to better evaluate and counsel older individuals and subjects exposed to noise regarding avoidance of noise and correct use of personal hearing protection.

Remodeling and Repair in Rhinosinusitis.

Remodeling refers to the development of specific but potentially irreversible structural changes in tissue. Caucasian eosinophilic chronic rhinosinusitis (CRS) with polyps associated or not with cystic fibrosis was discriminated by edema from CRS without nasal polyps, characterized by extensive fibrotic fields. However, changes in epithelial and extracellular matrix structures are common findings in all types of chronic inflammatory diseases of upper airways, but rarely specific and highly variable in extend. Recent studies have shown that remodeling in CRS appears to occur in parallel, rather than purely subsequent to inflammation. Furthermore, some preferential remodeling associations can be recognized. Tremendous efforts have been put in research on coagulation factors, cytokines, growth factors, and proteases supporting all phases of upper airway remodeling. The current exploration of other CRS sub-groups and of the particular link with concomitant asthma aims to optimize the classification of CRS and its staging modes and to develop novel therapies.

[Why, when and how to monitor new oral anticoagulants]. / Pourquoi, quand et comment doser les nouveaux anticoagulants oraux?

Several direct oral anticoagulants (DOACs) are now widely used in the prevention and treatment of thromboembolic events. Unlike vitamin K antagonists, DOACs exhibit predictable pharmacokinetics and pharmacodynamics. DOACs are to be administered at fixed doses without routine coagulation monitoring. However, in some patient populations or specific clinical circumstances, measurement of drug exposure may be useful, such as in suspected overdose, in patients with a haemorrhagic or thromboembolic event during treatment with an anticoagulant, in those with acute renal failure, or in patients who require urgent surgery. This article provides practical guidance on laboratory testing of DOACs in routine practice and summarizes the influence of DOACs on commonly used coagulation assays.

Tinnitus, anxiety and automatic processing of affective information: an explorative study.

Anxiety is found to play an important role in the severity complaint of tinnitus patients. However, when investigating anxiety in tinnitus patients, most studies make use of verbal reports of affect (e.g., self-report questionnaires and/or interviews). These methods reflect conscious appraisals of anxiety, but do not map underlying processing mechanisms. Nonetheless, such mechanisms, like the automatic processing of affective information, are important as they modulate emotional experience and emotion-related behaviour. Research showed that highly anxious people process threatening information (e.g., fearful and angry faces) faster than non-anxious people. Therefore, this study investigates whether tinnitus patients process affective stimuli (happy, sad, fearful, and angry faces) in the same way as highly anxious people do. Our sample consisted out of 67 consecutive tinnitus patients. Relationships between tinnitus severity, pitch, loudness, hearing loss, and the automatic processing of affective information were explored. Results indicate that especially in severely distressed tinnitus patients, the severity complaint is highly related to the automatic processing of fearful (r = 0.37, p < 0.05), angry (r = 0.44, p < 0.00) and happy (r = -0.44, p < 0.00) faces, and these relationships became even stronger after controlling for hearing loss. Furthermore, in contrast with findings on the relation between audiological characteristics (pitch and loudness) and conscious report of anxiety, we did find that the audiological characteristic, loudness, tends to be in some degree related to the automatic processing of fearful faces (r = 0.25, p = 0.08). We conclude that tinnitus is an anxiety-related problem on an automatic processing level.

Different types of tissue composition in inflammatory or reparative upper airway disorders.

BACKGROUND: Composition changes of extracellular matrix (ECM) can lead to functional disorders of the upper airways (UA). The aim of this study was to systematically measure both the association patterns and the correlation degree between tissue composition parameters in UA inflammatory diseases. METHODOLOGY: Nasal samples were obtained from patients with chronic rhinosinusitis with (CRS+NP), without nasal polyps (CRS), with post-operative adhesions (S) and normal nasal mucosa (NM). A reproducible semi-quantitative method, which takes epithelial and lamina propria damages into account was applied for haematoxylin and eosin, alpha-smooth muscle actin, reticulin, elastin, laminin and collagen type IV stainings. RESULTS: The most severe cases of epithelial shedding have been found in a significant higher amount in CRS+NP when compared with NM. The most severe cases of inflammatory reaction were mainly found in CRS+NP. CRS+NP had significantly more severe cases of oedema than NM. Excluding elastin, networks in other ECM proteins were found modified in fibrotic fields but to a lesser extend in oedematous regions in all conditions. CONCLUSION: Although non specific, oedema in the lamina propria is a key-feature of CRS+NP, while fibrosis, massively present in CRS and S, affects profoundly the distribution of ECM proteins in these areas.

Tinnitus severity and its association with cognitive and somatic anxiety: a critical study.

Tinnitus has been defined as a phantom auditory perception. Research indicates the necessity to make a distinction between the physical symptom and the subjective severity of the tinnitus symptom, since especially the latter seems to vary among patients. The relationship between tinnitus severity and psychological variables has been well established. Anxiety is considered to be an important variable for understanding the differences in the subjective tinnitus severity. Although many studies confirm the relationship between anxiety and tinnitus severity, most studies do not take the possibility of shared method variance and content overlap between questionnaires into account. Furthermore, anxiety is a broad concept and contains both a cognitive and somatic dimension. Research including both dimensions of anxiety in tinnitus population is rare. According to us two conditions must be fulfilled before theorization on the relation is useful: (1) the presence of clinically relevant cognitive and/or somatic anxiety, (2) evidence of a substantial or "real" relationship. In our sample, almost 60% reported more than average cognitive anxiety and 40.8% reported clinical relevant somatic anxiety. After controlling for content overlap between the questionnaires used, the relation between tinnitus severity and cognitive and somatic anxiety remains significant. Two hypothetical models concerning this relationship that deserve future research attention are described.

Immunohistological study of wound healing after submucosal radiofrequency tissue ablation of inferior nasal turbinate in a sheep model.

BACKGROUND: Data on the molecular processes involved in nasal mucosa wound healing after radiofrequency tissue ablation (RTA) of the inferior nasal turbinate (INT) are missing. This study was designed to examine tissue expression of fibronectin, collagen III, CD68, and matrix metalloproteinase (MMP) 9 in the INT (ventral) after RTA in sheep. METHODS: An experimental randomized controlled study was performed. Seventeen INTs (ventral) of nine sheep were used. RTA was applied in 12 INTs. Turbinate samples were studied 1, 3, and 8 weeks postoperatively (4 samples/time point) and in five control INTs (without surgery). Besides hematoxylin and eosin staining, immunostaining was done for MMP-9, collagen III, fibronectin, and CD68. A quantitative grading ranging between 0 (no immunoreactivity at all) and 100% (profuse immunoreactivity) was performed by a blinded senior pathologist. Comparisons between groups were performed using Mann-Whitney U test and Kruskal-Wallis one-way ANOVA. Spearman's rho correlation coefficients were calculated between histological and/or immunohistological variables. RESULTS: At week 8, fibronectin (p = 0.025), collagen III (p = 0.004), and MMP-9 (p < 0.001) immunoreactivity was significantly higher than controls, while immunoreactivity for CD68 was higher, although not significantly (p = 0.114) compared with controls. Strong correlations have been found between mucosal vascularization and interstitial space volume (r = 0.776), interstitial space volume and epithelial cell necrosis (r = 0.730), and CD68 immunostaining and epithelial cell necrosis (r = 0.784). CONCLUSION: Given their high tissue concentrations after RTA application, fibronectin, collagen III, CD68, and MMP-9 deserve further study as candidate modulators of the INT wound-healing process.

Tinnitus severity and the relation to depressive symptoms: a critical study.

OBJECTIVE: In this study, the authors investigated whether tinnitus severity is a problem related to depression. If so, the following 2 conditions should be fulfilled: first, there should be evidence for the presence of moderate to severe depressive symptomatology in a substantial group of tinnitus patients; second, there should be evidence of a substantial relationship between depressive symptoms and tinnitus severity. STUDY DESIGN: Cross-sectional. SETTING: Ear, Nose, and Throat (ENT) Department of the Ghent University Hospital. SUBJECTS AND METHODS: In total, 136 consecutive help-seeking tinnitus patients were seen by a psychologist, an audiologist, and an ENT specialist. All patients filled in the Beck Depression Inventory II (BDI-II) and the Tinnitus Handicap Inventory (THI) and underwent psychoacoustic measurement. RESULTS: Mean scores indicate the presence of no or minimal depressive symptoms. There was a positive correlation (P < .01) between the BDI-II and the THI. No correlations were found between psychoacoustic measures and the self-report questionnaires. Linear regression analysis was performed to examine the predictive role of the 3 components of depression (cognitive, somatic, and affective) in tinnitus severity. Results show that only the somatic depression subscale of the BDI-II significantly predicted tinnitus severity, which can be explained because of content overlap between the BDI-II and the THI. CONCLUSION: Tinnitus does not appear to be a problem related to depression. The authors did not find a substantial group of tinnitus patients with moderate to severe depressive symptoms. The relation between depressive symptoms and tinnitus severity seems to be an artifact of content overlap between the BDI-II and the THI.

Actual concepts in rhinosinusitis: a review of clinical presentations, inflammatory pathways, cytokine profiles, remodeling, and management.

Rhinosinusitis (RS) is a heterogeneous group of diseases. It is a significant and increasing health problem that affects about 15% of the population in Western countries. It has a substantial impact on patients' health-related quality of life and daily functioning and represents a huge financial burden to society and the health care system as a result of the direct and indirect costs. In addition, RS is not well-understood, and little is known about the etiology and pathophysiology. In the past decade, many papers have been published that have changed our understanding of RS. RS is commonly classified into acute and chronic RS based on symptom duration. In acute RS, an inflammatory reaction initiated by a viral infection characterizes most uncomplicated, mild to moderate cases. Therefore, the first line of treatment for these cases are intranasal steroids and not antibiotics. In severe and complicated cases, antibiotics combined with topical steroids remain the treatment of choice. On the other hand, chronic RS is actually subdivided into two distinct entities (chronic rhinosinusitis with and without polyps), as growing evidence indicates that these entities have specific inflammatory pathways and cytokine profiles. The authors review recent data regarding the clinical presentations, cytokine profiles, tissue remodeling, and modalities of treatment for each form of RS.

Ultrasound submucosal inferior nasal turbinate reduction technique: histological study of wound healing in a sheep model.

AIM OF THE STUDY: To describe histological changes after application of an ultrasound tissue reduction (UTR) technique in a newly introduced sheep model to study inferior nasal turbinate mucosal wound healing. MATERIALS AND METHODS: An experimental study in a sheep model. Stromal fibrosis, submucosal interstitial space volume (ISV), mucosal epithelial cell necrosis, mucosal inflammation and blood vessels' engorgement in inferior turbinate samples were assessed after application of UTR using hematoxylin/eosin staining in 12 turbinate samples after different time points. Histological grading was performed using a 4-point scale RESULTS: After one week, extensive development of fibrosis (p = 0.006) and significant reduced stromal ISV (p < 0.001) compared to controls were observed. The degree of fibrosis and the stromal ISV remained constant during the 8-week period. The extensive epithelial cell necrosis observed at week 1, diminished later, so that at 8 weeks no significant difference with controls in the necrosis extent was noted. Significant reduction of engorgement of blood vessels in the submucosal layer was noted after 8 weeks (p = 0.008, compared with baseline). Mucosal inflammation, while pronounced at week 1 (p = 0.005, compared with baseline), was normalized at week 8. CONCLUSION: Due to the rapid induction of extensive fibrosis, to the limited inflammation reaction, to the moderate degree of epithelial necrosis, to the reduction of subepithelial ISV and the persistence of these features till week 8 at least, UTR emerges as an effective minimally invasive technique for inferior nasal turbinate volume reduction.

Continuous versus on-demand pharmacotherapy of allergic rhinitis: evidence and practice.

This review aims to compare continuous with on-demand pharmacotherapy of allergic rhinitis by focusing on pharmacodynamic, pharmacokinetic, safety, effectiveness, cost and cost-effectiveness considerations. A working party of experts reviewed and discussed the literature and guidelines, and conducted a qualitative analysis of the Summary of Product Characteristics of specific medicines. With respect to medicines, the working party limited itself to antihistamines, nasal corticosteroids and leukotriene antagonists. Based on a review of the evidence from a multidisciplinary perspective, this article makes pharmacotherapeutic recommendations that are easy, functional and applicable to daily practice in primary care. The pharmacotherapeutic evidence for continuous versus on-demand treatment of allergic rhinitis was limited. Clearly, for corticosteroids, their mechanism of action in allergic rhinitis of reducing allergic inflammation requires continuous therapy at least for the duration of symptoms. For H(1)-antihistamines, some trials suggest that continuous treatment is preferable but more studies are needed to confirm this conclusion. For both H(1)-antihistamines and nasal corticosteroids safety data indicate that continuous treatment may be given without fears of adverse consequences, although a distinction can be made between the first and the second generation antihistamines. With regard to the cost and cost-effectiveness implications of continuous therapy versus on-demand therapy, more studies are necessary before definitive conclusions may be made.

Drug metabolism and pharmacokinetics.

In this article, aspects of absorption, distribution, metabolism, and excretion have been described bearing in mind the pathogenesis of allergic diseases and their possible therapeutic opportunities. The importance of the routes of administration of the different therapeutic groups has been emphasized. The classical aspects of drug metabolism and disposition related to oral administration have been reviewed, but special emphasis has been given to intranasal, cutaneous, transdermal, and ocular administration as well as to the absorption and the subsequent bioavailability of drugs. Drug-metabolizing enzymes and transporters present in extrahepatic tissues, such as nasal mucosa and the respiratory tract, have been particularly discussed. As marketed antiallergic drugs include both racemates and enantiomers, aspects of stereoselective absorption, distribution, metabolism, and excretion have been discussed. Finally, a new and promising methodology, microdosing, has been presented, although it has not yet been applied to drugs used in the treatment of allergic diseases.

Therapeutic management of allergic diseases.

Allergic diseases are characterized by the activation of inflammatory cells and by a massive release of mediators. The aim of this chapter was to describe succinctly the modes of action, indications, and side effects of the major antiallergic and antiasthmatic drugs. When considering the ideal pharmacokinetic characteristics of a drug, a poorly metabolized drug may confer a lower variability in plasma concentrations and metabolism-based drug interactions, although poorly metabolized drugs may be prone to transporter-based disposition and interactions. The ideal pharmacological properties of a drug include high binding affinity, high selectivity, and appropriate association and dissociation rates. Finally, from a patient perspective, the frequency and route of administration are important considerations for ease of use.

Physiologically based pharmacokinetics (PBPK).

Allometric scaling is widely used to predict human pharmacokinetic parameters from preclinical species, and many different approaches have been proposed over the years to improve its predictive performance. Nevertheless, prediction errors are commonly observed in the practical application of simple allometry, for example, in cases where the hepatic metabolic clearance is mainly determined by enzyme activities, which do not scale allometrically across species. Therefore, if good correlation was noted for some drugs, poor correlation was observed for others, highlighting the need for other conceptual approaches. Physiologically based pharmacokinetic (PBPK) models are now a well-established approach to conduct extrapolations across species and to generate simulations of pharmacokinetic profiles under various physiological conditions. While conventional pharmacokinetic models are defined by drug-related data themselves, PBPK models have richer information content and integrate information from various sources, including drug-dependent, physiological, and biological parameters as they vary in between species, subjects, or with age and disease state. Therefore, the biological and mechanistic bases of PBPK models allow the extrapolation of the kinetic behavior of drugs with regard to dose, route, and species. In addition, by providing a link between tissue concentrations and toxicological or pharmacological effects, PBPK modeling represents a framework for mechanistic pharmacokinetic-pharmacodynamic models.

Pharmacokinetics in special populations.

Pharmacokinetics are typically dependent on a variety of physiological variables (e.g., age, ethnicity, or pregnancy) or pathological conditions (e.g., renal and hepatic insufficiency, cardiac dysfunction, obesity, etc.). The influence of some of these conditions has not always been thoroughly assessed in the clinical studies of antiallergic drugs. However, the knowledge of the physiological grounds of the pharmacokinetics can provide some insight for predicting the potential alterations and guiding the initial prescription strategies. It is important to recognize that both pharmacokinetic and pharmacodynamic differences between populations should be considered. The available information on drugs used for the therapy of allergic diseases is reviewed in this chapter.

Population pharmacokinetic and pharmacodynamic analysis in allergic diseases.

In this chapter, we introduce the concepts and methodologies of population analysis as applied to analyzing pharmacokinetic and pharmacodynamic data. One of the key determining characteristics of the population approach is that through it, one seeks not only to characterize deterministic trends in the data, but also to identify and estimate the magnitudes of the important sources of variability within the data. The first section of this chapter provides an introduction to the primary concepts of, and motivation for, population modeling by way of a hypothetical case study. Then, the various methodologies that have been employed throughout the history of population analysis are described in further detail. Of these, the most commonly employed today is nonlinear mixed-effects (NLME) modeling. Finally, notable examples of the application of population PK and PK/PD modeling to treatments for allergies and asthma are discussed. Population PK models have frequently been used to extrapolate exposures to special populations, such as pediatrics, as well as to optimize treatment regimens and trial designs for these populations. Population PK/PD models have most frequently been applied to analyzing and interpreting data from wheal and flare trials, but are also becoming increasingly important in the analysis of PD data from monoclonal antibodies.

Drug interactions.

Drugs for allergy are often taken in combination with other drugs, either to treat allergy or other conditions. In common with many pharmaceuticals, most such drugs are subject to metabolism by P450 enzymes and to transmembrane transport. This gives rise to considerable potential for drug-drug interactions, to which must be added consideration of drug-diet interactions. The potential for metabolism-based drug interactions is increasingly being taken into account during drug development, using a variety of in silico and in vitro approaches. Prediction of transporter-based interactions is not as advanced. The clinical importance of a drug interaction will depend upon a number of factors, and it is important to address concerns quantitatively, taking into account the therapeutic index of the compound.