BACKGROUND:Patients with irritable bowel syndrome (IBS) have an increased risk of developing both airway and allergic diseases. However, the relationship between allergic rhinitis (AR), one of the most common chronic upper airway inflammatory diseases, and IBS remains poorly understood. The aim of this study is to provide a better understanding of airway complications in patients with IBS and to evaluate the presence of potential airborne and dietary antigen cross-reactivity in concomitant IBS and AR. METHODS:A total of 287 participants, 54 healthy volunteers without gastrointestinal complaints and 232 patients with I fulfilling Rome IV criteria, were invited to complete self-administered questionnaires assessing the severity of upper airway symptoms and the prevalence of allergic rhinitis. RESULTS:Overall, patients with IBS had a threefold higher risk of questionnaire-based allergic rhinitis than control subjects (95% CI, 1.49-6.12). Furthermore, patients with IBS + AR showed reduced sleep quality, mood, and personal satisfaction associated with their upper airway complaints, compared to IBS patients without AR. Forty-seven (18/38) percent of IBS + AR patients reported IBS symptoms in response to ingestion of food items with molecular mimicry of the aeroallergen to which the patient is sensitized. CONCLUSION:Our study shows that patients with IBS have an increased frequency of concomitant allergic rhinitis, which contributes to a further reduction in quality of life. We also provide evidence of potential cross-reactive reactions between aeroallergens and dietary antigens in patients with concomitant IBS and AR.

There is growing evidence that neurogenic inflammation contributes to the pathophysiology of upper airway diseases, with nasal hyperreactivity (NHR) being a key symptom. The rare neuroendocrine cells (NECs) in the epithelium have been linked to the pathophysiology of bronchial and intestinal hyperreactivity, however their presence in the nasal mucosa and their potential role in NHR remains unclear. Therefore, we studied the presence of NECs in the nasal epithelium of controls, allergic rhinitis patients and chronic rhinosinusitis with nasal polyps patients, and their link to NHR. The expression of typical NECs markers, CHGA, ASCL1 and CGRP, were evaluated on gene and protein level in human samples using real-time quantitative PCR (RT-qPCR), western blot, immunohistochemistry fluorescence staining, RNA scope assay, flow cytometry and single cell RNA-sequencing. Furthermore, the change in peak nasal inspiratory flow after cold dry air provocation and visual analogue scale scores were used to evaluate NHR or disease severity, respectively. Limited gene expression of the NECs markers CHGA and ASCL1 was measured in patients with upper airway diseases and controls. Gene expression of these markers did not correlate with NHR severity nor disease severity. In vitro, CHGA and ASCL1 expression was also evaluated in primary nasal epithelial cell cultures from patients with upper airway disease and controls using RT-qPCR and western blot. Both on gene and protein level only limited CHGA and ASCL1 expression was found. Additionally, NECs were studied in nasal biopsies of patients with upper airway diseases and controls using immunohistochemistry fluorescence staining, RNA scope and flow cytometry. Unlike in ileum samples, CHGA could not be detected in nasal biopsies of patients with upper airway diseases and control subjects. Lastly, single cell RNA-sequencing of upper airway tissue could not identify a NEC cluster. In summary, in contrast to the bronchi and gut, there is only limited evidence for the presence of NECs in the nasal mucosa, and without correlation with NHR, thereby questioning the relevance of NECs in upper airway pathology.

We present a protocol for the rapid postmortem bedside procurement of selected tissue samples using an endoscopic endonasal surgical technique that we adapted from skull base surgery. We describe steps for the postmortem collection of blood, cerebrospinal fluid, a nasopharyngeal swab, and tissue samples; the clean-up procedure; and the initial processing and storage of the samples. This protocol was validated with tissue samples procured postmortem from COVID-19 patients and can be applied in another emerging infectious disease. For complete details on the use and execution of this protocol, please refer to Khan et al. (2021)1 and Khan et al. (2022).2

BACKGROUND: Nasal hyperreactivity (NHR) is prevalent in all chronic upper airway inflammatory phenotypes, including allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP). Although NHR in patients with non-allergic rhinitis is mediated by neuronal pathways, AR and CRSwNP are mainly characterized by type 2 inflammation. METHODS: Eighteen healthy controls and 45 patients with symptomatic AR/CRSwNP underwent a cold, dry air (CDA) provocation test for objective diagnosis of NHR. Before and after, questionnaires were filled out and nasal secretions and biopsies were collected. Markers for neurogenic inflammation (substance P, calcitonin gene-related peptide, neurokinin A), epithelial activation (IL-33), and histamine were measured in secretions by ELISA; and expression of neuronal markers PGP9.5, TRPV1, and TRPM8 was studied in biopsies by RT-q-PCR. Effects of histamine on TRPV1/A1 were studied with Ca2+-imaging using murine trigeminal neurons. RESULTS: CDA-provocation reduced peak nasal inspiratory flow (PNIF) of patients with subjective NHR but not of non-NHR controls/ patients (p

BackgroundThe skin prick test (SPT) is the gold standard for identifying allergic sensitization in individuals suspected of having an inhalant allergy. Recently, it was demonstrated that SPT using a novel skin prick automated test (SPAT) device showed increased reproducibility and tolerability compared to the conventional SPT, among other benefits.ObjectiveThis study aimed to evaluate prick location bias using the novel SPAT device.MethodsA total of 118 volunteers were enrolled in this study and underwent SPATs with histamine (nine pricks) and glycerol control (one prick) solutions on the volar side of their forearms. Imaging of the skin reactions was performed using the SPAT device, and the physician determined the longest wheal diameter by visually inspecting the images using a web interface. Prick location bias was assessed along the medial vs. lateral and proximal vs. distal axes of the forearm.ResultsIn total, 944 histamine pricks were analyzed. Four medial and four lateral histamine pricks were grouped, and wheal sizes were compared. The longest wheal diameters were not significantly different between the medial and lateral prick locations (p = 0.41). Furthermore, the pricks were grouped by two based on their position on the proximal–distal axis of the forearm. No significant difference was observed among the four groups of analyzed prick locations (p = 0.73).ConclusionThe prick location on the volar side of the forearm did not influence wheal size in SPAT-pricked individuals.

To the Editor, Respiratory allergies affect 30%–40% of individuals worldwide and represent a major health-economic problem.1 Identification of the triggering or causative allergens in symptomatic patients is based on skin prick test or serum-specific IgE analysis in addition to a detailed medical history by the physician.2, 3 Skin prick test (SPT) is the first choice diagnostic instrument according to international guidelines because of reduced cost, faster results, less invasiveness and a better sensitivity-specificity profile compared to extract-based specific IgE analysis.4, 5 However, there is a need for standardized automation of the entire SPT procedure given that SPT exhibits both operator and device-dependent variability.6, 7 A monocentric, prospective diagnostic test accuracy study (ISRCTN14098475) was performed at the University Hospitals of Leuven (UZ Leuven, Belgium) to compare reproducibility, tolerability and safety of a newly developed Skin Prick Automated Test or SPAT (Figure S1A–C) to the Skin Prick Manual Test or SPMT (Figure S1D–F). The full methodology can be found in the Appendix S1. In brief, SPAT was performed on the right arm and SPMT was performed on the left arm. On both arms, pricks were applied with 10 mg/ml histamine (N = 9) and glycerol-saline (N = 1) as respectively positive and negative control (HAL Allergy) in line with previous device validation studies (also Appendix S1). In total, 118 healthy volunteers (49 males – 69 females; mean ± standard deviation age: 40.1 ± 13.3) were enrolled in the study (Figure S2). SPAT showed significantly lower coefficient of variation of the histamine wheal sizes (SPAT median (IQR): 13.6% (10.4%–17.7%)) compared to SPMT (SPMT median: 17.6% (13.6%–22.9%); p < 0.0001; Figure 1). Similar findings were obtained in all but one of the pre-defined age decades (Figure S3). Wheal sizes were significantly larger in SPAT compared to SPMT for both control (p = 0.002) and histamine prick (p < 0.0001; Figure 2A). The wheal size difference between histamine and control wheals was equal between SPAT and SPMT (p = 0.13; Figure 2B). The 97.5% percentile (=4.5 mm) in controls was used to determine the cut-off that defines a positive wheal with SPAT. Sensitivity and specificity profiles of SPAT (respectively 1.00 (0.96–1.00); 0.99 (0.95–1.00)) and SPMT (respectively 0.93 (0.86–0.96); 1.00 (0.96–1.00)) were comparable (Table S1). Subjective scoring of discomfort as assessed by VAS was significantly lower in the SPAT (median (IQR): 2 cm (1–2 cm)) compared to the SPMT (2 cm (1–4 cm)) group (p = 0.0009; Figure S4). No adverse events were reported during the study for either test. Prick failures were analysed on a total number of 1180 pricks (Table S2). Overall, prick failures occurred significantly less frequently during SPAT compared to SPMT (p < 0.0001). The time needed to execute the SPAT pricks per participant (20 s) was markedly less compared to the time needed to execute the SPMT pricks per participant (on average 144 s). The amount of histamine required to carry out the pricks of the entire study with SPAT (4.5 ml) was 2.7 times less compared with SPMT (12.0 ml). Even though the SPAT produces larger histamine wheal sizes, it exhibits lower intra-subject wheal variability compared to SPMT. Larger histamine wheal sizes could be attributed to the combination of vertical pressure and 90° clockwise rotation of the lancet.8 Lower intra-subject test variability represents a major advancement in the field of allergy diagnostics because skin-prick test reproducibility is one of the biggest issues in current clinical practice.9 This study also demonstrated that the ability to discriminate a histamine from a control wheal is as good as with SPMT. In near future, new studies with SPAT in allergic and non-allergic individuals will shed a light on the precision of the device to detect allergy to inhalant allergens. In conclusion, SPAT showed increased reproducibility and tolerability compared to SPMT. SPAT is able to limit the number of prick failures due to human errors during SPMT. The fact that SPAT is time saving and consumes less allergen solution when dropping glasses are used to run the SPT makes it an interesting cost-effective instrument for future allergy diagnostics. We would like to thank Leen Cools and Els Costermans for their coordination of the study on site. We would also like to thank all volunteers who participated in the study. SG, SFS and LVG hold shares of Hippocreates who developed the SPAT device. MJT received consulting fees for statistical advice for the study. SG, DL and SFS are employees of Hippocreates. RS is supported by a FWO senior clinical investigator fellowship (1805518N). SU, WB, MJ, PWH have nothing to disclose. The study was supported by a grant from SmartHub Vlaams Brabant. Appendix S1: Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Can SARS-CoV-2 hitchhike on the olfactory projection and take a direct and short route from the nose into the brain? We reasoned that the neurotropic or neuroinvasive capacity of the virus, if it exists, should be most easily detectable in individuals who died in an acute phase of the infection. Here, we applied a postmortem bedside surgical procedure for the rapid procurement of tissue, blood, and cerebrospinal fluid samples from deceased COVID-19 patients infected with the Delta, Omicron BA.1, or Omicron BA.2 variants. Confocal imaging of sections stained with fluorescence RNAscope and immunohistochemistry afforded the light-microscopic visualization of extracellular SARS-CoV-2 virions in tissues. We failed to find evidence for viral invasion of the parenchyma of the olfactory bulb and the frontal lobe of the brain. Instead, we identified anatomical barriers at vulnerable interfaces, exemplified by perineurial olfactory nerve fibroblasts enwrapping olfactory axon fascicles in the lamina propria of the olfactory mucosa.

Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.

AllergyVolume 76, Issue 12 p. 3806-3809 LETTER TO THE EDITOR Self-reported nasal hyperreactivity is common in all chronic upper airway inflammatory phenotypes and not related to general well-being Wout Backaert, Wout Backaert orcid.org/0000-0001-7942-3345 Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, BelgiumSearch for more papers by this authorBrecht Steelant, Brecht Steelant orcid.org/0000-0002-0358-9362 Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, BelgiumSearch for more papers by this authorMark Jorissen, Mark Jorissen Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium Department of Neurosciences, Experimental Otorhinolaryngology, Rhinology Research, KU Leuven, Leuven, BelgiumSearch for more papers by this authorLukas Van Oudenhove, Lukas Van Oudenhove Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), Laboratory for Brain-Gut Axis Studies (LaBGAS), KU Leuven, Leuven, Belgium Department of Psychological and Brain Sciences, Cognitive and Affective Neuroscience Laboratory (CANlab), Center for Cognitive Neuroscience, Dartmouth College, Hanover, New Hampshire, USASearch for more papers by this authorKarel Talavera, Karel Talavera orcid.org/0000-0002-3124-138X Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, KU Leuven, Leuven, BelgiumSearch for more papers by this authorPeter W. Hellings, Peter W. Hellings orcid.org/0000-0001-6898-688X Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium Department of Otorhinolaryngology, Laboratory of Upper Airways Research, U Ghent, Ghent, Belgium Department of Otorhinolaryngology, Academic Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorLaura Van Gerven, Corresponding Author Laura Van Gerven laura.vangerven@uzleuven.be orcid.org/0000-0002-5325-7956 Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium Department of Neurosciences, Experimental Otorhinolaryngology, Rhinology Research, KU Leuven, Leuven, Belgium Correspondence Laura Van Gerven, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. Email: laura.vangerven@uzleuven.beSearch for more papers by this author Wout Backaert, Wout Backaert orcid.org/0000-0001-7942-3345 Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, BelgiumSearch for more papers by this authorBrecht Steelant, Brecht Steelant orcid.org/0000-0002-0358-9362 Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, BelgiumSearch for more papers by this authorMark Jorissen, Mark Jorissen Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium Department of Neurosciences, Experimental Otorhinolaryngology, Rhinology Research, KU Leuven, Leuven, BelgiumSearch for more papers by this authorLukas Van Oudenhove, Lukas Van Oudenhove Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), Laboratory for Brain-Gut Axis Studies (LaBGAS), KU Leuven, Leuven, Belgium Department of Psychological and Brain Sciences, Cognitive and Affective Neuroscience Laboratory (CANlab), Center for Cognitive Neuroscience, Dartmouth College, Hanover, New Hampshire, USASearch for more papers by this authorKarel Talavera, Karel Talavera orcid.org/0000-0002-3124-138X Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, KU Leuven, Leuven, BelgiumSearch for more papers by this authorPeter W. Hellings, Peter W. Hellings orcid.org/0000-0001-6898-688X Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium Department of Otorhinolaryngology, Laboratory of Upper Airways Research, U Ghent, Ghent, Belgium Department of Otorhinolaryngology, Academic Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorLaura Van Gerven, Corresponding Author Laura Van Gerven laura.vangerven@uzleuven.be orcid.org/0000-0002-5325-7956 Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium Department of Neurosciences, Experimental Otorhinolaryngology, Rhinology Research, KU Leuven, Leuven, Belgium Correspondence Laura Van Gerven, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. Email: laura.vangerven@uzleuven.beSearch for more papers by this author First published: 21 August 2021 https://doi.org/10.1111/all.15060Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Supporting Information Filename Description all15060-sup-0001-FigS1.jpgJPEG image, 791 KB Fig S1 all15060-sup-0002-FigS2.jpgJPEG image, 436.4 KB Fig S2 all15060-sup-0003-Supinfo.docxWord document, 46.6 KB Supplementary Material Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume76, Issue12December 2021Pages 3806-3809 RelatedInformation

A significant proportion (25%-30%) of patients suffering from persistent rhinitis have nasal symptoms without clinical evidence of endonasal infection or systemic signs of sensitization to aeroallergens, a condition often referred to as nonallergic rhinitis.1Hellings P.W. Klimek L. Cingi C. Agache I. Akdis C. Bachert C. et al.Non-allergic rhinitis: position paper of the European Academy of Allergy and Clinical Immunology.Allergy. 2017; 72: 1657-1665Crossref PubMed Scopus (137) Google Scholar Up to 50% of patients with nonallergic rhinitis are classified as having idiopathic rhinitis (IR) after exclusion of occupational, elderly, gustatory, hormonal, and drug-induced rhinitis.1Hellings P.W. Klimek L. Cingi C. Agache I. Akdis C. Bachert C. et al.Non-allergic rhinitis: position paper of the European Academy of Allergy and Clinical Immunology.Allergy. 2017; 72: 1657-1665Crossref PubMed Scopus (137) Google Scholar IR remains a therapeutic challenge because of the inefficacy of intranasal corticosteroids.2Blom H.M. Godthelp T. Fokkens W.J. KleinJan A. Mulder P.G. Rijntjes E. The effect of nasal steroid aqueous spray on nasal complaint scores and cellular infiltrates in the nasal mucosa of patients with nonallergic, noninfectious perennial rhinitis.J Allergy Clin Immunol. 1997; 100: 739-747Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Intranasal administration of capsaicin at a high dose (0.1 mM) is currently the best medical therapeutic option for IR.3Gevorgyan A. Segboer C. Gorissen R. van Drunen C.M. Fokkens W. Capsaicin for non-allergic rhinitis.Cochrane Database Syst Rev. 2015; 7CD010591Google Scholar However, this treatment has limitations because it is uncomfortable for patients owing to the need for prior local anesthesia, time-consuming (5 consecutive applications at 1-hour intervals), and incompletely understood in terms of its working mechanism.4Van Rijswijk J.B. Boeke E.L. Keizer J.M. Mulder P.G.H. Blom H.M. Fokkens W.J. Intranasal capsaicin reduces nasal hyperreactivity in idiopathic rhinitis: a double-blind randomized application regimen study.Allergy. 2003; 58: 754-761Crossref PubMed Scopus (93) Google Scholar Thus, research for better capsaicin treatment formulations and protocols is warranted. To this aim, we conducted a randomized, double-blind, placebo-controlled trial in which we compared the effect of 2 lower-dose capsaicin nasal sprays (0.01 mM and 0.001 mM) that could be self-administered with the current capsaicin treatment (0.1 mM) in suppressing nasal symptoms. Additionally, because of the implication of substance P (SP) in IR,5Baraniuk J.N. Lundgren J.D. Okayama M. Goff J. Mullol J. Merida M. et al.Substance P and neurokinin A in human nasal mucosa.Am J Respir Cell Mol Biol. 1991; 4: 228-236Crossref PubMed Scopus (149) Google Scholar, 6Van Gerven L. Alpizar Y.A. Steelant B. Callebaut I. Kortekaas Krohn I. Wouters M. et al.Enhanced chemosensory sensitivity in patients with idiopathic rhinitis and its reversal by nasal capsaicin treatment.J Allergy Clin Immunol. 2017; 140: 437-446.e2Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 7Van Gerven L. Alpizar Y.A. Wouters M.M. Hox V. Hauben E. Jorissen M. et al.Capsaicin treatment reduces nasal hyperreactivity and transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) overexpression in patients with idiopathic rhinitis.J Allergy Clin Immunol. 2014; 133: 1332-1339.e3Abstract Full Text Full Text PDF PubMed Google Scholar we evaluated how nasal levels of SP are affected by capsaicin treatment to better understand the underlying working mechanism. The study was approved by the medical ethical committee of the University Hospitals of Leuven and registered at ClinicalTrials.gov (NCT02288156). A total of 68 well-characterized patients with IR (see Table E1 in this article’s Online Repository at www.jacionline.org) were randomized to 4 treatment arms (ie, Placebo/Placebo; Placebo/Capsaicin 0.001 mM; Placebo/Capsaicin 0.01 mM; and Capsaicin 0.1 mM/Placebo). Patients received 5 intranasal applications (2 puffs per nostril [0.4 mL per puff]) of either placebo or capsaicin, 0.1 mM, on a single day at 1-hour intervals. After the treatment visit, patients who had received the current capsaicin treatment (capsaicin, 0.1 mM) were sent home with a nasal spray containing placebo for daily use (the Capsaicin 0.1 mM/Placebo arm). Patients who were treated with placebo at the treatment visit received either a nasal spray containing placebo (the Placebo/Placebo arm); capsaicin, 0.001 mM (the Placebo/Capsaicin 0.001 mM); or capsaicin, 0.01 mM (the Placebo/Capsaicin 0.01 mM arm) (Fig 1 and see also Fig E1 in this article’s Online Repository at www.jacionline.org). All patients were asked to stop their treatment after 4 weeks and to score their major and individual nasal symptoms on a visual analogue scale (VAS) at screening, follow-up visit 1 (FU1), follow-up visit 2 (FU2), and follow-up visit 3 (FU3). The therapeutic response evaluation (TRE) was assessed at FU1, FU2, and FU3. SP levels were determined in nasal secretions collected at screening, FU1, and FU2. More details on patient selection and methodology are provided in the Online Repository (at www.jacionline.org). At FU1 and FU2, the VAS score for major symptom was significantly reduced in the Capsaicin 0.1 mM/Placebo and the Placebo/Capsaicin 0.01 mM groups compared with in the Placebo/Placebo group (Fig 2, A). Similarly, the VAS score for nasal obstruction was significantly decreased for both groups at FU2 (Fig 2, B). Nasal symptoms were not altered in the Placebo/Capsaicin 0.001 group versus the Placebo/Placebo group. At FU1, TRE showed an 82% improvement in the Placebo/Capsaicin 0.01 group, which was higher than the TRE of the Capsaicin 0.1/Placebo group (71%) (Fig 2, C). At FU2, a TRE of 73% was still observed for the Placebo/Capsaicin 0.01 group versus for the Placebo/Placebo group (Fig 2, D). At FU3, no significant improvement could be observed in any of the arms (data not shown). Previously, we reported increased SP concentrations in the nasal secretions of patients with IR compared with the nasal secretions of healthy controls.7Van Gerven L. Alpizar Y.A. Wouters M.M. Hox V. Hauben E. Jorissen M. et al.Capsaicin treatment reduces nasal hyperreactivity and transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) overexpression in patients with idiopathic rhinitis.J Allergy Clin Immunol. 2014; 133: 1332-1339.e3Abstract Full Text Full Text PDF PubMed Google Scholar Here, we found that the nasal SP levels of patients in the Placebo/Capsaicin 0.01 and Capsaicin 0.1/Placebo groups were significantly decreased compared with the levels of patients in the Placebo/Placebo group at FU2 (Fig 2, E). No significant difference in nasal SP levels between the Placebo/Capsaicin 0.001 and Placebo/Placebo groups was observed. Interestingly, SP positively correlated with the VAS score for major symptom (r = 0.34; P < .05) (Fig 2, F) and VAS score for nasal obstruction (see Fig E2 in this article’s Online Repository at www.jacionline.org). No correlation between SP and other VAS scores were found at FU1 and FU2 in any of the arms (data not shown). Given that only 70% to 80% of patients with IR will benefit from capsaicin treatment, we studied whether SP could serve as a biomarker to predict therapeutic response. Patients reporting therapeutic improvement at FU1 had a clear reduction in nasal SP levels, which was not observed in patients without therapeutic improvement (Fig 2, G). A decline in nasal SP of more than 7.08 ng/mL had a sensitivity of 72% and specificity of 75% to predict therapeutic continuation/effect (Fig 2, H). Until now, capsaicin has not been routinely used in clinical practice, although symptom reduction is observed in 70% to 80% of patients with IR.3Gevorgyan A. Segboer C. Gorissen R. van Drunen C.M. Fokkens W. Capsaicin for non-allergic rhinitis.Cochrane Database Syst Rev. 2015; 7CD010591Google Scholar,4Van Rijswijk J.B. Boeke E.L. Keizer J.M. Mulder P.G.H. Blom H.M. Fokkens W.J. Intranasal capsaicin reduces nasal hyperreactivity in idiopathic rhinitis: a double-blind randomized application regimen study.Allergy. 2003; 58: 754-761Crossref PubMed Scopus (93) Google Scholar,6Van Gerven L. Alpizar Y.A. Steelant B. Callebaut I. Kortekaas Krohn I. Wouters M. et al.Enhanced chemosensory sensitivity in patients with idiopathic rhinitis and its reversal by nasal capsaicin treatment.J Allergy Clin Immunol. 2017; 140: 437-446.e2Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 7Van Gerven L. Alpizar Y.A. Wouters M.M. Hox V. Hauben E. Jorissen M. et al.Capsaicin treatment reduces nasal hyperreactivity and transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) overexpression in patients with idiopathic rhinitis.J Allergy Clin Immunol. 2014; 133: 1332-1339.e3Abstract Full Text Full Text PDF PubMed Google Scholar, 8Lacroix J.S. Buvelot J.M. Polla B.S. Lundberg J.M. Improvement of symptoms of non-allergic chronic rhinitis by local treatment with capsaicin.Clin Exp Allergy. 1991; 21: 595-600Crossref PubMed Scopus (138) Google Scholar Therefore, the present study was designed to compare novel low-dose capsaicin treatment with the current therapy in improving nasal symptoms and to evaluate the role of SP in the pathology of IR. Daily nasal administration of low-dose capsaicin was well tolerated and similarly reduced nasal symptoms as the current capsaicin treatment at FU1 and FU2, which adds novel information to a recent Cochrane review on the use of capsaicin in the management of nonallergic rhinitis.3Gevorgyan A. Segboer C. Gorissen R. van Drunen C.M. Fokkens W. Capsaicin for non-allergic rhinitis.Cochrane Database Syst Rev. 2015; 7CD010591Google Scholar Furthermore, capsaicin in a concentration of 0.01 mM improved therapeutic response at FU1 and FU2. Interestingly, 23% of patients receiving placebo treatment reported therapeutic improvement, which might be due to daily nasal rinsing. Second, we further explored the role of SP in the pathophysiology of IR. Self-administration of capsaicin in a concentration of 0.01 mM reduced SP levels at FU2. Additionally, we found a positive correlation between SP and nasal obstruction, suggesting that IR symptoms result from abnormally increased SP levels. As SP increases mucus secretion, suppressing SP might represent a novel therapeutic approach, at least in IR.5Baraniuk J.N. Lundgren J.D. Okayama M. Goff J. Mullol J. Merida M. et al.Substance P and neurokinin A in human nasal mucosa.Am J Respir Cell Mol Biol. 1991; 4: 228-236Crossref PubMed Scopus (149) Google Scholar Finally, we investigated whether SP might serve as a biomarker to predict the therapeutic response to capsaicin. A decrease in SP of 7.08 ng/mL at FU1 had a sensitivity of 72% and a specificity of 75% to predict response to therapy. The strength of this study lies in the meticulous patient selection and characterization and the well-executed study design, with 4 groups (including a placebo and a current standard treatment group). In the past, the recruitment of patients with ill-defined nonallergic rhinitis resulted in confusing and contradictory data, such as data on the effect of corticosteroids in nonallergic rhinitis.2Blom H.M. Godthelp T. Fokkens W.J. KleinJan A. Mulder P.G. Rijntjes E. The effect of nasal steroid aqueous spray on nasal complaint scores and cellular infiltrates in the nasal mucosa of patients with nonallergic, noninfectious perennial rhinitis.J Allergy Clin Immunol. 1997; 100: 739-747Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar,9Lundblad L. Sipilä P. Farstad T. Drozdziewicz D. Mometasone furoate nasal spray in the treatment of perennial non-allergic rhinitis: a Nordic, multicenter, randomized, double-blind, placebo-controlled study.Acta Otolaryngol (Stockh). 2001; 121: 505-509Crossref PubMed Scopus (39) Google Scholar The major limitation of our clinical trial, however, is the relatively low number of patients, which resulted from the strict inclusion and exclusion criteria. Furthermore, no objective parameter to evaluate therapeutic response was utilized, and no specific question on adverse effects was being considered, which is warranted for follow-up studies. In conclusion, capsaicin in a concentration of 0.01 mM is equally effective in suppressing nasal symptoms as the current capsaicin treatment and therefore might be a good, novel therapeutic option for patients with IR. The authors would like to thank Steffen Fieuws for providing support for the statistical analyses. We also would like to thank Mrs Emily Dekimpe for helping with the clinical trial. Finally, we thank all the patients for participating in this study. A total of 80 patients with IR were recruited via the outpatient clinic of the Otorhinolaryngology Department of the University Hospitals of Leuven, Belgium, between May 2015 and July 2017. Patients with IR were defined as nonsmoking patients experiencing at least 2 of the following complaints for more than 1 hour a day and for more than 1 year: nasal obstruction, rhinorrhea, sneezing, and itch. These patients had negative skin prick test results, no clinical signs of infection (ie, no discolored secretions), and no anatomic nasal abnormalities responsible for nasal symptoms. To be included, patients had to have IR, be between 18 and 65 years old, have signed the informed consent, and have reported inefficacy of intranasal corticosteroid treatment at the recommended dose (mometasone furoate, 50 μg per spray administered at a rate of 2 sprays twice daily, or fluticasone furoate, 50 μg per spray at a rate of 2 sprays twice daily) for at least 4 weeks. In our experience, patients with local allergic rhinitis do benefit from intranasal corticosteroids because the underlying pathophysiology is mainly IgE-mediated and thus responsive to the classic anti-inflammatory treatment. By including patients with nonallergic rhinitis who are nonresponsive to intranasal corticosteroids, patients with local allergic rhinitis were effectively excluded. The exclusion criteria were a positive skin prick test result for the 18 most frequently inhaled allergens in Belgium (house dust mite; pollen of timothy grass, smooth meadow grass, orchard grass, nettle, plantago, oxeye daisy, mugwort, alder, birch, and hazel; horse; cat; dog; rabbit; and spores of Alternaria, Aspergillus and Cladosporium [HAL Allergy, Leiden, The Netherlands]); pregnancy or lactation; systemic disorders or malignancies; use of medication affecting nasal function; use of local and/or systemic corticosteroids 4 weeks before the study; and history of prolonged use or abuse of decongestant nasal spray such as xylomethazoline. Patients with colored secretions and/or inflammation at the level of the osteomeatal complex were excluded after nasal endoscopy. Nasal medication was prohibited throughout the entire duration of the study. The study was approved by the Medical Ethical Committee on Clinical Investigations of the University Hospitals of Leuven and registered at ClinicalTrials.gov (NCT02288156). The patients with IR were invited for an outpatient visit to the Department of Otorhinolaryngology of the University Hospitals of Leuven on 5 occasions (Figs 1 and E1). This study was performed in a randomized, double-blind, placebo-controlled way. Patients were seen at a screening visit to check inclusion and exclusion criteria. During the treatment visit, patients were randomized to 4 arms in a 1:4 ratio as follows: arm 1, Placebo/Placebo; arm 2, Placebo/Capsaicin 0.001 mM; arm 3, Placebo/Capsaicin 0.01 mM; and arm 4, Capsaicin 0.1 mM/Placebo. In brief, patients received 5 intranasal applications (2 puffs in each nostril, 0.4 mL/puff, per application) of either placebo or capsaicin 0.1 mM on a single day at 1-hour intervals. The nasal mucosa was anesthetized before the first 2 applications by application of a cocaine 5% nasal spray (same volume per spray as already mentioned). To ensure effective local anesthesia, an interval of 15 minutes was maintained between the application of the cocaine and blinded nasal spray. After the treatment visit, patients who had received the current standard treatment with capsaicin, 0.1 mM, were sent home with a nasal spray that contained placebo (Capsaicin 0.1/Placeboarm) for daily use. The other patients who were treated with placebo during the treatment visit, received a nasal spray containing placebo (Placebo/Placebo arm), capsaicin 0.001 mM (Placebo/Capsaicin 0.001 arm), or capsaicin 0.01 mM (Placebo/Capsaicin 0.01 arm) (Fig 1). All patients were asked to stop their treatment after 4 weeks. All patients were invited for a follow-up visit after 4, 12, and 24 weeks. Capsaicin and placebo solutions were prepared at the Center for Clinical Pharmacology at the University Hospitals of Leuven, and the solutions were blinded. The placebo solution contained the same buffer but lacked pelargonic acid vanillylamide. The sample size was calculated to have at least 80% power to detect a significant difference in change in VAS score for major symptom between baseline and week 12 (FU2). Previously, we showed a clear reduction in VAS score for major symptom after capsaicin treatment compared with the score after placebo at week 12.E1Van Gerven L. Alpizar Y.A. Steelant B. Callebaut I. Kortekaas Krohn I. Wouters M. et al.Enhanced chemosensory sensitivity in patients with idiopathic rhinitis and its reversal by nasal capsaicin treatment.J Allergy Clin Immunol. 2017; 140: 437-446.e2Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar,E2Van Gerven L. Alpizar Y.A. Wouters M.M. Hox V. Hauben E. Jorissen M. et al.Capsaicin treatment reduces nasal hyperreactivity and transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) overexpression in patients with idiopathic rhinitis.J Allergy Clin Immunol. 2014; 133: 1332-1339.e3Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Assuming a 50% reduction in VAS score for major symptom at week 12 and α set at 0.0125 (application of Bonferroni correction for the 4 groups) and with an unequal group size (three-fourths of patients received capsaicin and one-fourth received placebo) and a 2-sample t test, 16 patients were needed to detect a ratio of geometric means equal to 2 (ie, with the VAS score for major symptom being 2-fold higher in placebo group). When a dropout rate of 20% was taken into account, 76 patients in total were needed (19 patients per group). All participants were asked to rate the typical nasal symptoms of IR (ie, rhinorrhea, nasal obstruction, itch, and sneezing) on a VAS of 0 to 10 at the screening visit (visit 1) and at FU1 (at week 4), FU2 (at week 12), and FU3 (at week 24). The symptom was considered relevant only if the VAS score was more than 2. The major nasal symptom was selected on the basis of the highest VAS score at screening. At FU1, FU2, and FU3, a TRE was performed. Patients with IR were asked to score the overall improvement in their symptoms compared with baseline (with 0 indicating no reduction of symptoms and 1 indicating reduction of symptoms). At the screening visit, FU1, and FU2, nasal secretions were collected before the Cold Dry Air provocation as described earlier.6Van Gerven L. Alpizar Y.A. Steelant B. Callebaut I. Kortekaas Krohn I. Wouters M. et al.Enhanced chemosensory sensitivity in patients with idiopathic rhinitis and its reversal by nasal capsaicin treatment.J Allergy Clin Immunol. 2017; 140: 437-446.e2Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar For the collection of nasal secretions, a nasal sponge (Ivalon Surgical Products, San Diego, Calif) was weighed and inserted in each nostril for 5 minutes. Afterward, the sponge was removed and weighed again. A volume of saline was added depending on the weight of the collected sponge (1:5 dilution). The sponge was then squeezed and centrifuged at 1500 g and 4°C for 5 minutes. The supernatant was stored at –20°C for further analysis. In nasal secretions, SP was determined with ELISA according to the manufacturer’s guidelines (Cayman Chemicals, Ann Arbor, Mich).Fig E2Correlation between SP and nasal obstruction at FU1. Spearman correlation r = 0.32; P < .05.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table E1Patient characteristics at screeningCharacteristicPlacebo/placeboPlacebo/capsaicin (0.001 mM)Placebo/capsaicin (0.01 mM)Capsaicin (0.1mM)/placeboN18181616Age (y), mean ± SD45 ± 1548 ± 1445 ± 1050 ± 14Sex (male/female)8/109/99/77/9Nasal symptom (%)Nasal obstruction (56%)Rhinorrea (39%)Sneezing (5%)Itch (0%)Nasal obstruction (50%)Rhinorrea (28%)Sneezing (11%)Itch (11%)Nasal obstruction (44%)Rhinorrea (44%)Sneezing (0%)Itch (12%)Nasal obstruction (31%)Rhinorrea (44%)Sneezing (25%)Itch (0%)Allergy (positive SPT result)0%0%0%0%Responders to INCS0%0%0%0%Smokers0%0%0%0%INCS, Intranasal corticosteroid; SPT, skin prick test. Open table in a new tab INCS, Intranasal corticosteroid; SPT, skin prick test.

Despite their high prevalence, the pathophysiology of allergic rhinitis (AR) and chronic rhinosinusitis (CRS) remains unclear. Recently, transient receptor potential (TRP) cation channels emerged as important players in type 2 upper airway inflammatory disorders. In this review, we aim to discuss known and yet to be explored roles of TRP channels in the pathophysiology of AR and CRS with nasal polyps. TRP channels participate in a plethora of cellular functions and are expressed on T cells, mast cells, respiratory epithelial cells, and sensory neurons of the upper airways. In chronic upper airway inflammation, TRP vanilloid 1 is mostly studied in relation to nasal hyperreactivity. Several other TRP channels such as TRP vanilloid 4, TRP ankyrin 1, TRP melastatin channels, and TRP canonical channels also have important functions, rendering them potential targets for therapy. The role of TRP channels in type 2 inflammatory upper airway diseases is steadily being uncovered and increasingly recognized. Modulation of TRP channels may offer therapeutic perspectives.

Brain activation after nasal histamine provocation in house dust mite allergic rhinitis patientsCallebaut I1, Steelant B1, Backaert W1, Peeters R2-3, Sunaert S2-3, Van Oudenhove L4-5*, Hellings PW1*1Allergy and Clinical Immunology Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium2Department of Imaging & Pathology, KU Leuven, Leuven, Belgium3Department of Radiology, University Hospitals Leuven, Leuven, Belgium4Laboratory for Brain-Gut Axis Studies (LaBGAS), Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), University of Leuven, Belgium5Cognitive and Affective Neuroscience Laboratory (CANlab), Center for Cognitive Neuroscience, Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, USA*Joined senior authorshipTo the editor . The nasal mucosa is armed with a complex nervous system of sensory, sympathetic and parasympathetic nerves, allowing swift defensive responses to physical and chemical stimuli. In allergic rhinitis (AR) patients, nasal allergen deposition leads to mast cell activation with release of allergic mediators such as histamine. Apart from its direct effects on the surrounding tissue, histamine also activates sensory nerve endings giving rise to symptoms like sneezing, rhinorrhoea, and/or congestion(1). Activated nasal sensory nerves transmit action potentials to their cell bodies in the trigeminal ganglion and further to the midbrain where secondary synapses lead to the generation of central reflex signals. Despite activation of neural pathways in AR(2), it is not known which particular regions in the brain are activated by different nasal stimuli. Clinical studies using Positron Emission Tomography scans indicate that there is no isolated itch center in the brain but that different cortical centers are involved in the processing of itch(3, 4). Activation of the anterior cingulate cortex (ACC), the supplementary motor area (SMA), and the inferior paretial lobe partly explains the connection between itching and the related reflex of scratching(4). Using functional magnetic resonance imaging (fMRI), the activation of the superior temporal gyrus, insula and nucleus caudate following painful intranasal trigeminal stimulation has been shown(5). When asthmatic patients are challenged with metacholine or allergens, activity in ACC and insula was associated with markers of bronchial inflammation and obstruction(6).To fill the abovementioned knowledge gap, a prospective, single-blind, cross-over study was designed to investigate brain responses to nasal histamine provocation in healthy volunteers and AR patients.Eight house dust mite (HDM) AR patients and 7 non-allergic healthy controls (HC) were recruited at the outpatient clinic for Otorhinolaryngology of University Hospitals Leuven. HDM allergy was confirmed by a skin prick test. Relevant nasal anatomic abnormalities or rhinosinusitis were ruled out by nasal endoscopy. Non-allergic HC showed a negative skin prick test for all the tested allergens, showed no nasal symptoms and had normal nasal endoscopy. Patients of 50 years of age, having used nasal or oral steroid treatment <6weeks prior to the study or nasal or oral antihistamine treatment <4weeks prior to the study were excluded, as well as those with past or ongoing immunotherapy for HDM, asthma, smoking and clinical signs of rhinosinusitis or anatomic nasal deformities. Informed consent was signed by all participants. The study was approved by the local medical ethics committee of the University Hospitals Leuven (B322201215751).All HC and AR patients underwent a nasal provocation by means of a canulla placed under the nose with either nebulized sham solution (saline) or with histamine for 5 minutes while in supine position in the MR scanner on 2 separate days with a minimum of 1 week in between, and in a single-blinded and random order. An aerosol of 10 ml histamine HCl (16 mg/ml) or 10 ml saline was delivered via the canulla by means of air (8 bar) after 10 minutes of baseline scanning in a pharmacological (ph)MRI design. This concentration of histamine was chosen as optimal dose after a pilot study in 3 HCs, 1 birch and grass pollen AR patient and 1 HDM AR patient where the dose of histamine resulted in a reduction of 20% in the Peak Nasal Inspiratory Flow (PNIF). Moreover, patients did not had the urge to sneeze at this concentration, as was the case for the dose of 32 mg/ml.PNIF values were used for measuring nasal flow at baseline and after the nasal provocation at the end of the phMRI scan, as recommended(7). The best value out of three consecutive measurements with a variability of <10% was recorded. Changes in PNIF from baseline to post-provocation were compared between conditons (histamine & saline) as well as between groups (patients & controls) using marginal linear mixed models.phMRI data were preprocessed and analyzed as described previously(8, 9). The effect of interest for the present study was the group (patient versus controls)-by-substance (histamine versus saline)-by-time interaction effect, comparing the time-course of the brain response to histamine vs saline provocation between AR patients and controls. A whole-brain voxel-wise FWE-corrected threshold of p<0.05 was used combined with an extent threshold of k=10 voxels (corresponding to pFWE<0.001 at cluster level).In total, 8 HDM AR patients (5 females and 3 males) and 7 HC (5 females and 2 males) were recruited with a mean age of 22.5 ± 0.72 and 23.8 ± 1.11 years respectively. One female HDM AR and two female HC were excluded due to excessive head movement during MR scanning.After nasal provocation with saline, no significant decrease in PNIF was found compared to baseline in both groups (AR: 135 ± 61.82 l/min vs 137.5 ± 44.88 l/min, p=0.74; HC: 120 ± 36.74 vs 129 ± 31.30, p=0.46). Nasal provocation with histamine induced a significant decrease in PNIF in both HDM AR patients (158.8 ± 71.55 l/min vs 112.5 ± 83.67, p=0.0053) as well as in the HC (134.2 ± 27.64 l/min vs 85.83 ± 40.55, p=0.002).The analysis on PNIF values showed a significant condition-by-time (pre- to post-provocation) interaction effect (F(1,11)=28.8, p=0.0002), driven by a significant decrease in PNIF after histamine (-47.30±8.87, pHolm=0.0004), but not after saline (-5.81±5.96, pHolm=0.35) in the entire sample. No significant group-by-condition-by-time interaction effect was found (F(1,11)=0.09, p=0.78) indicating that the decrease from baseline after histamine compared to saline did not differ between patients and controls, with a significant decrease from baseline after histamine but not saline in both groups (p=0.002 and p=0.015, respectively).Brain regions showing a differential response to histamine versus saline in AR patients versus HCs included bilateral mid-/posterior insula, right anterior insula, bilateral postcentral/superior temporal gyrus/rolandic operculum (including secondary somatosensory cortex), bilateral putamen, left cerebellum (crus 1 & 2), right mid-occipital gyrus, bilateral medial orbital gyrus/gyrus rectus, and right middle/superior frontal gyrus (ventrolateral prefrontal cortex) (Table 1,Figure 1). Most of these differential responses were due to a stronger activation in controls vs AR patients, except for the right anterior insula, right middle occipital gyrus, right middle/superior frontal gyrus, and left cerebellum, where a stronger activation was observed in AR patients.

Purpose of review The diagnosis of occupational rhinitis is a challenge. Underdiagnosis is substantial as the clinical presentation is nonspecific and often no occupational history is taken. Detection of occupational rhinitis can be improved by including screening questions on occupational exposure in the assessment of every patient with adult-onset rhinitis. Recent findings Case reports, case series and epidemiological studies continuously demonstrate new sensitizers and irritants capable of inducing allergic or nonallergic (irritant-induced) occupational rhinitis. Recent reviews have focused on the value of immunological tests with specific IgE, skin prick tests or basophil activation tests in demonstrating sensitization to occupational agents. Nasal provocation tests (NPT) can establish a definite diagnosis of allergic occupational rhinitis. Several NPT guidelines have been published, however, focusing exclusively on standardized high-molecular weight allergens. When performing NPT with nonstandardized agents -- like most occupational sensitizers -- adapted protocols are needed. Summary We provide pragmatic guidance to clinicians taking care of rhinitis patients on how to diagnose occupational rhinitis, based on recent insights from the literature. We focus on the challenges in the diagnostic work-up, on how to identify suspected causes, and on the role of NPT.

Spontaneous and idiopathic CSF leak in the infrasellar, clival region. Problem: Although rarely developing spontaneously, cerebrospinal fluid (CSF) rhinorrhea may have devastating consequences such as meningitis, intracranial hypotension, (meningo)encephalocele formation, or intracranial abscesses. Case Description: A 66-year old man presented with fulminant pneumococcal meningitis. After putting the patient upright, clear CSF was observed leaking through the left nostril and was clinically confirmed. Computed tomography and magnetic resonance imaging showed CSF in the extensively pneumatized left sphenoidal sinus. An endoscopic, endonasal, transsphenoidal exploration revealed an infra- to retrosellar, clival breach and linear dural tear. Inlay plugging with autologous fat and fascia and an overlay covering with a free mucosal flap efficiently closed the defect. Conclusions: Spontaneous CSF leakage without predisposing factors is rare and its exact pathophysiology is incompletely understood, but a consensus exists that a triad of dura disruption, bony defect, and pressure gradient promote these types of CSF leaks.

Organized hematoma of the maxillary sinus: a case report. Problem: Clinical and radiographic diagnosis of organized hematoma remains challenging, and occurrence in the paranasal sinuses is rare. Case report: A 53-year-old patient noted gradual malar swelling and a fibrinous protrusion in the left maxillary buccal sulcus over several weeks. Following multiple episodes of spontaneous intraoral bleeding and epistaxis, an extensive mass was identified in the left maxillary sinus. Computed tomography revealed osteolysis of the lateral, medial, and inferior sinus walls. Expecting malignancy, repeated needle biopsies were performed. However, pathologic examination showed only fibrin and blood with signs of organization, and no atypical cells. In the absence of malignancy, a diagnosis of organized hematoma was postulated. Conclusions: Oral breakthrough is a rare presentation of this difficult diagnosis. This case report raises awareness, aids in clinical characterization, and highlights the most appropriate treatment.