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1. Factors driving olfactory loss in patients with chronic rhinosinusitis: a case control study

   https://doi.org/10.1002/alr.22445  

   Schlosser, Rodney J. ; Smith, Timothy L. ; Mace, Jess C. ; Alt, Jeremiah ; Beswick, Daniel M. ; Mattos, Jose L. ; Payne, Spencer ; Ramakrishnan, Vijay R. ; Soler, Zachary M. ( January 2020 , International Forum of Allergy & Rhinology)

   Olfactory dysfunction (OD) in chronic rhinosinusitis (CRS) is common. It is likely that numerous factors such as sex, race, age, allergies, asthma, smoking, and other comorbidities play a role in CRS‐related OD. In order to determine which aspects of OD are due solely to CRS and which are associated with other confounders, control populations are needed to allow appropriate risk assessments.

   Prospective, multi‐institutional enrollment of patients with CRS and control subjects without CRS was performed. Demographic information, comorbidities, and olfactory testing (Sniffin’ Sticks) of threshold (T), discrimination (D), and identification (I) scores (TDI) was collected.

   A total of 224 patients with CRS and 164 control subjects were enrolled. Olfaction was worse in CRS patients compared to controls (mean ± standard deviation (SD) TDI = 22.4 ± 9.5 vs 28.8 ± 7.0, respectively,p< 0.001). Only 27% of CRS patients were normosmic compared to 49% of controls (p< 0.001). When stratifying by nasal polyp (NP) status, CRSwNP patients had significant impairments in TDI, T, D, and I compared to controls with mean differences of 11.2, 3.3, 3.5, and 4.4 points, respectively (allp< 0.001). In contrast, CRSsNP patients only had impaired T when compared to controls with a mean difference of 2.2 points (p< 0.001). Multivariate modeling of TDI scoring showed that OD was driven by polyps, asthma, diabetes, and age. CRSsNP was not independently associated with worse TDI scores.

   OD in CRS patients is multifactorial. Independent drivers appear to be polyp status, asthma, diabetes, and age. OD in patients with CRSsNP is similar to controls with the exception of impaired thresholds.

    

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2. Longitudinal progression of aspirin‐exacerbated respiratory disease: analysis of a national insurance claims database

   https://doi.org/10.1002/alr.22412  

   Roland, Lauren T. ; Wang, Heqiong ; Mehta, C. Christina ; Cahill, Katherine N. ; Laidlaw, Tanya M. ; DelGaudio, John M. ; Wise, Sarah K. ; Levy, Joshua M. ( August 2019 , International Forum of Allergy & Rhinology)

   Aspirin‐exacerbated respiratory disease (AERD) is a recalcitrant inflammatory disorder defined by asthma, nasal polyposis, and sensitivity to cyclooxygenase‐1 inhibitors. The timeline and course of disease progression is unclear.

   The Truven MarketScan Database, a large American health insurance claims repository, was queried to identify patients meeting criteria for AERD from 2009 to 2015. Included patients had associated International Classification of Diseases, 9th edition (ICD‐9) codes consistent with all 3 components of AERD: asthma, nasal polyposis, and drug allergy. Patterns of disease onset and time to progression were analyzed.

   A total of 5628 patients were identified for study inclusion. Of the 3 components of AERD, 3303 patients (59%) were initially diagnosed with asthma, 1408 (25%) were initially diagnosed with nasal polyps, and 917 (16%) were first diagnosed with drug sensitivity. The most common (36%) sequence of diagnoses was asthma, followed by nasal polyps, followed by drug allergy. The median interval between diagnosis of upper or lower airway involvement (ie, nasal polyps and/or asthma) to recognition of drug sensitivity was 259 days (quartiles Q1 to Q3: 92 to 603 days). In patients with both asthma and nasal polyps diagnoses, the risk of developing drug sensitivity during the study time period was 6%.

   Upper and lower airway disease is often initially recognized in patients with AERD, whereas drug sensitivity presents month to years later. This delay may be due to the pathophysiology of AERD and disease progression or due to practice patterns in diagnostic testing and coding. Further work is warranted to identify these patients at early stages in their disease progression.

    

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3. Interleukin 13 (IL‐13) alters hypoxia‐associated genes and upregulates CD73

   https://doi.org/10.1002/alr.22630  

   Khalil, Syed Muaz ; Bernstein, Isaac ; Kulaga, Heather ; Gour, Naina ; Rowan, Nicholas ; Lajoie, Stephane ; Lane, Andrew P. ( July 2020 , International Forum of Allergy & Rhinology)

   Interleukin 13 (IL‐13) is a pleiotropic cytokine that has been shown to be important in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) and other type 2 inflammation–related diseases. Increased IL‐13 expression can elicit several pro‐inflammatory effects, including eosinophilia, and pathology such as increased mucus secretion. Polypogenesis in chronic rhinosinusitis (CRS) can be caused by hypoxia, which can also lead to hyperpermeability of airway epithelium and epithelium‐to‐mesenchymal translation through the upregulation of hypoxia‐associated genes, such as HIF1. Whether T‐helper 2 (Th2) inflammatory cytokines, such as IL‐13, can also induce sinonasal epithelial hypoxia‐associated genes is currently unknown.

   Human air‐liquid interface (ALI) sinonasal epithelial cell cultures treated with recombinant IL‐13 were analyzed by real‐time polymerase chain reaction (PCR) and flow cytometry to determine the effect on epithelial cells.

   Whole tissue from CRSwNP subjects showed increasedHIF1Agene expression. Treatment of fully differentiated human ALI cultures with IL‐13 resulted in a concurrent increase inHIF1AandARNTmessenger RNA (mRNA) expression. However, the level ofEPAS1expression was significantly reduced. IL‐13 also had a dose‐dependent response on the expression of HIF genes and the time course experiment showed peak expression ofHIF1AandARNTat 5 to 7 days poststimulation. Remarkably, CD73 surface expression also peaked at day 5 poststimulation.

   Our data suggests that IL‐13 can induce hypoxia signaling pathway genes leading to surface expression of CD73, which has an anti‐inflammatory effect.

    

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4. Targetable pathogenic mechanisms in nasal polyposis

   https://doi.org/10.1002/alr.22787  

   Schneider, Alexander L. ; Schleimer, Robert P. ; Tan, Bruce K. ( March 2021 , International Forum of Allergy & Rhinology)

   Chronic rhinosinusitis with nasal polyps (CRSwNP) represents a challenging disease entity with significant rates of recurrence following appropriate medical and surgical therapy. Recent approval of targeted biologics in CRSwNP compels deeper understanding of underlying disease pathophysiology. Both of the approved biologics for CRSwNP modulate the type 2 inflammatory pathway, and the majority of drugs in the clinical trials pathway are similarly targeted. However, there remain multiple other pathogenic mechanisms relevant to CRSwNP for which targeted therapeutics already exist in other inflammatory diseases that have not been studied directly. In this article we summarize pathogenic mechanisms of interest in CRSwNP and discuss the results of ongoing clinical studies of targeted therapeutics in CRSwNP and other related human inflammatory diseases.

    

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5. Treatment practices for aspirin‐exacerbated respiratory disease: analysis of a national insurance claims database

   https://doi.org/10.1002/alr.22471  

   Roland, Lauren T. ; Nagy, Celeste ; Wang, Heqiong ; Moore, Renee ; Cahill, Katherine N. ; Laidlaw, Tanya M. ; Wise, Sarah K. ; DelGaudio, John M. ; Kuruvilla, Merin ; Levy, Joshua M. ( November 2019 , International Forum of Allergy & Rhinology)

   Aspirin‐exacerbated respiratory disease (AERD) is the triad of asthma, nasal polyposis, and sensitivity to cyclooxygenase‐1 inhibitors. Treatment options include medical management, surgical intervention, and aspirin desensitization (AsaD).

   AERD patients were identified using the MarketScan Database from 2009 to 2015. Patients were included using International Classification of Diseases, 9th edition (ICD‐9) codes for asthma, nasal polyposis, and drug allergy. Treatments were determined by Current Procedural Terminology (CPT) codes for drug desensitization and endonasal procedures. Geographic trends and timing of interventions between those exposed and not exposed to desensitization were explored.

   A total of 5628 patients met inclusion criteria for AERD, with mean age 46 years, 60% female; 395 (7%) underwent AsaD and 2171 (39%) underwent sinus surgery. Among patients who were desensitized, 229 (58%) underwent surgery, of whom 201 (88%) had surgery prior to AsaD (median [quartile 1, quartile 3]; 61 days [30, 208] prior to desensitization). For patients undergoing surgery following AsaD (n = 46), surgery was performed a median of 302 (163, 758) days after AsaD. Nineteen patients had multiple surgeries post‐AsaD with median time between surgeries being 734 days (312, 1484); 261 patients were not desensitized to aspirin but did undergo multiple surgeries, with the median of the median time between surgeries being 287 days (15, 617), which is shorter than for patients post‐AsaD (p< 0.001).

   A very small percentage of AERD patients undergo AsaD. Patients who had AsaD underwent surgery approximately 2 months prior to AsaD. Patients who underwent AsaD experienced an increased time between surgeries compared to patients who did not undergo AsaD.

    

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