Predictive Findings of Allergic Disease in Fiberoptic Nasolaryngoscopy

The Laryngoscope VC 2014 The American Laryngological, Rhinological and Otological Society, Inc. Predictive Findings of Allergic Disease in Fiberoptic Nasolaryngoscopy Christopher Brook, MD; J. Pieter Noordzij, MD; Kimberly Russell, MD; Avner Aliphas, MD; Michael Platt, MD, MS Objectives/Hypothesis: To determine whether findings on fiberoptic nasolaryngoscopy beyond the nasal cavity can aid in diagnosis of atopy. Study Design: Case control analysis of patients undergoing fiberoptic nasolaryngoscopy and allergy testing at a single academic institution. Methods: Patients who underwent flexible nasolaryngoscopy for either laryngeal or nasal symptoms and allergy testing by in vitro methods were divided into an atopic group and a nonatopic control group based on results of allergy testing. Three board-certified otolaryngologists who were blinded to the atopic status and symptoms viewed 88 patient videos and filled out an 8-item endoscopic rating questionnaire for each. Correlation between rater scores, endoscopic findings, and atopic status was calculated using Randolph s multirater kappa values and Mann-Whitney test. Results: Intrarater reliability was moderate to perfect for all physicians on all questions (kappa 0.545 1.0). Inter-rater reliability was slight to fair (kappa 0.143 0.399) for all questions and the overall impression of atopic disease. Abnormalities of the torus tubarius (P 5.007) and increased nasopharyngeal secretions (P 5.038) were predictive of atopic disease, whereas the presence of an adenoid (P 5.08) and impression of atopic disease (P 5.15) approached significance. All other endoscopic measures were not predictive of atopic status. Conclusions: Fiberoptic nasolaryngeal findings within the nasopharynx rather than the larynx are predictive of a positive atopic status. Key Words: Atopy, nasolaryngoscopy, allergic rhinitis, laryngitis, allergy, pharyngitis, nasopharyngoscopy. Level of Evidence: 3b. Laryngoscope, 125:286 290, 2015 INTRODUCTION Allergic rhinitis is a common chronic condition that affects between 10% and 30% of adults and an even higher proportion of children in industrialized nations, 1 and has significant economic impact, with the direct medical cost of care in the billions of dollars annually in the United States. 2 The gold standard for diagnosis of allergic disease remains clinical with primary use of history and physical exam, and allergy testing used to confirm specific sensitizations. Understanding of physical findings in patients with allergic rhinitis is important in making a correct diagnosis of allergic rhinitis. Allergic disease is not limited to the nasal passages, and the concept of the unified airway suggests that inflammation in one area can affect other areas of the aerodigestive tract as well, including the lower airways. 3 From the Department of Otolaryngology Head and Neck Surgery, Boston University School of Medicine, Boston, Massachusetts, U.S.A. Editor s Note: This Manuscript was accepted for publication July 16, 2014. Presented as a poster at the Triological Society 117th Annual Meeting at COSM, Las Vegas, Nevada, U.S.A., May 15 16, 2014. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to J. Pieter Noordzij, MD, 820 Harrison Avenue, FGH Building, 4th Floor, Boston, MA 02118. E-mail: pietier.noordzij@bmc.org DOI: 10.1002/lary.24880 286 Increasing evidence is mounting that laryngeal and vocal symptoms can be attributable to allergic laryngitis, 4 6 and that introduction of allergens into the larynx can result in vocal fold edema, an increase in laryngeal symptoms, 6 resulting in increases in the subglottic pressure needed to phonate. 7 Laryngeal symptoms that have been attributed to allergic disease are nonspecific and include hoarseness, cough, throat clearing, globus sensation, excessive mucous, and sore throat or throat discomfort. 5 Because of the lack of specificity, recent papers have also discussed the possibility of underdiagnosis of allergy and overdiagnosis of laryngopharyngeal reflux in these patients. 5,8 10 The significance of endoscopic findings beyond the nasal cavity are not completely understood. The purpose of this study was to determine whether abnormalities of the nasopharynx, oropharynx, or larynx correlate with atopic status and can be helpful to aid in the diagnosis of allergic disease. MATERIALS AND METHODS A retrospective case-control study was performed to review fiberoptic nasolaryngoscopy recordings of patients with symptoms of rhinitis and/or laryngitis who were evaluated at a tertiary medical center. Over a 5-year period (2006 2010), all patients who were older than 18 years who had both fiberoptic nasolaryngoscopy and in vitro allergy testing consisting of total immunoglobulin E (IgE) level and in vitro testing to at least 12

Fig. 1. Atopic questionnaire used for each video. antigens were included. Fiberoptic nasolaryngoscopy was edited to start at the posterior nasal cavity/ nasopharynx so that the anterior nasal cavity findings would not bias the reviewers. Patients were excluded from the study if they did not have adequate recordings that demonstrated the nasopharynx, oropharynx, and larynx. Endoscopic findings of patients with a diagnosis of atopy were compared to those with nonatopic status. A diagnosis of atopy was made by clinic symptoms, physical findings, total IgE level >200, and at least one positive specific IgE test (Immuno- Cap, Phadia, Sweden). Negative results were defined as a total IgE of <10, with no positive specific IgE in vitro tests to any allergen antibody. The recordings were randomly assorted into sequential video clips and reviewed by three independent board-certified otolaryngologists who were blinded to the clinical data and results of allergy testing. A 10-question rating system was used to measure the endoscopic findings relating to abnormalities of the nasopharynx, otopharynx, and larynx, as well as an overall impression of positive atopic status (Fig. 1). Repeated endoscopy recordings were used to generate a kappa value for intrarater reliability for each item in the questionnaire and each author. Multirater inter-rater reliability with a Randolph free kappa was calculated. 11 A Mann-Whitney U test was used to compare the average scores in each item between the atopic and the nonatopic group to determine differences between groups. This study was approved by the institutional review board prior to commencing the study. RESULTS Three otolaryngologists reviewed 88 recorded fiberoptic examinations on 77 subjects who met inclusion criteria; demographic information is shown in Table I. Eleven examinations were repeated during the study, six from the atopic group and five from the nonatopic group, to use as a measure of intrarater reliability. An average of 27 inhalant allergens were tested by Immunocap. Thirty-three subjects had a total IgE level >200 and at least one positive test (atopic group), whereas 44 had a total IgE <10 and no positive specific IgE tests (nonatopic group). The reviewers each filled out an eight-topic questionnaire graded on a scale from 1 to 4 on each TABLE I. Demographic Information. Atopic Patients Sex Women 38.4%, Men 61.6% Nonatopic Patients Women 34.7%, Men 65.3% Average age, yr 43.0 44.1 No. of specific IgE positive 8.8 (1 22) 0 Total IgE (range) 585 (204 1,786) 12.5 (3 25) IgE 5 immunoglobulin E. 287

TABLE II. Intrarater and Inter-rater Kappa Scores by Author and Questionnaire Topic. Inferior Turbinate Torus Tubarius Adenoid Pharynx Mucosa Larynx Mucosa Nasopharynx Secretions Larynx Secretions Atopic Diagnosis Intrarater 1 0.773 1.0 1.0 0.659 0.773 0.659 0.545 0.659 Intrarater 2 0.773 1.0 0.773 0.659 0.659 0.886 0.659 0.659 Intrarater 3 0.659 1.0 0.773 0.886 0.773 0.886 0.659 0.545 Inter-rater scores 0.261 0.290 0.328 0.399 0.257 0.190 0.261 0.143 video (1 correlating to no abnormality, 4 correlating to severe abnormalities). A guide to grading of subsites was provided to the reviewers to aid in standardization of interpretation of abnormalities. Intrarater scores were moderate to perfect for all physicians on all repeated questions (kappa 0.545 1.0, Table II). Inter-rater reliability was slight to fair (kappa 0.143 0.399) for all questions and the overall diagnosis of atopic disease (Table II). Comparison of atopic to nonatopic subjects for each question revealed significant differences for abnormalities of the torus tubarius (P 5.007) and increased nasopharyngeal secretions (P 5.038) (Fig. 2). Other measures that did not show a difference included the posterior aspect of the inferior turbinate (P 5.69), adenoid (P 5.081), pharyngeal mucosa (P 5.53), laryngeal mucosa (P 5.63), laryngeal secretions (P 5.28), and overall impression of atopic diagnosis (P 5.15) (Fig. 2). DISCUSSION The diagnosis of allergic diseases remains a clinical challenge that combines patient history, physical findings, and specific allergen testing to determine the atopic status. Identifying abnormalities on physical examination can assist in making an accurate diagnosis. With atopy affecting areas of the upper aerodigestive tract beyond the nose, it is important to understand physical diagnostic abnormalities that are seen on nasolaryngoscopy. This study identified significant findings in the nasopharynx, increased nasopharyngeal secretions (Fig. 3) and abnormalities of the torus tubarius (Fig. 4), which correlate with a positive atopic status and can be used for assisting in diagnosis. The findings in the oropharynx and larynx did not correlate with atopic status and may be nonspecific for inflammation relating to other conditions such as laryngopharyngeal reflux. There is increasing evidence that atopic disease affects other areas in the upper aerodigestive tract. 4 7 Within the concept of the unified airway and shared inflammation of the upper aerodigestive tract, 3 one should expect that abnormalities are seen in the nasal cavity, pharynx, and larynx. Endoscopic findings indicative of allergic disease have been studied independently in areas of the upper airwary. 7,10,12 In the nasal cavity, turbinate edema and coloration have been classically associated with atopic disease, although differing findings have been reported relating to atopic status. 10 A study comparing skin prick testing to endoscopic findings did not correlate this association, 12 and another study demonstrated poor reliability of endoscopy for findings of mucosal inflammation. 13 In pediatric patients, endoscopic nasal findings predictive of allergic rhinitis included inferior turbinate and middle turbinate contact, whereas turbinate color was not predictive of allergic rhinitis, 14,15 and an inverse relationship between adenoid hypertrophy and allergic disease has been demonstrated in the pediatric population. 12,15 Several studies have demonstrated the elevated prevalence of allergic rhinitis in patients with chronic rhinosinusitis. One study out of Korea demonstrated a Fig. 2. Comparison of allergy ratings (scores) between atopic and nonatopic patients stratified by subsite with inter-rater kappa values. Scores ranged from 1 to 4 (1 correlating to no abnormality, 4 correlating to severe abnormalities) and were significantly higher in the atopic patients for ratings of the torus tubarius and nasopharyngeal secretions (P <.05). 288

odds ratio of >13 for the diagnosis of chronic rhinosinusitis in allergic rhinitis patients compared with allergic rhinitis alone. 16 Another study in India demonstrated a prevalence of nearly 40% of sinusitis in patients with allergic rhinitis. 17 Other groups have demonstrated an increased prevalence of allergic rhinitis in pediatric patients with sinusitis. 18 Due to concern for bias based on findings in the nasal cavity, the authors of the current study chose not to include anterior nasal cavity endoscopy in the examinations presented to the reviewers. In the larynx, a correlation between increased endolaryngeal mucous with positive atopic skin prick testing has been reported 10 as well as an increase in endolaryngeal mucous in two patients exposed to transoral allergen stimulation. 7 There has been little published on nasopharyngeal findings in atopic disease other than in regard to the adenoid pad, as mentioned above. 15 One study demonstrated increased interleukin 4 (IL-4), number of eosinophils, and decreased neutrophils in biopsies taken of the torus tubarius in atopic patients. 19 Importantly, endoscopic nasolaryngeal findings have been shown to have poor inter-rater reliability 10,12,20 and poor intrarater reliability. 17 Intrarater reliability was very high for the three reviewers in this study, which is in contrast to previously published findings in nasolaryngoscopy. 20 Interrater reliability was low in the current study, which is consistent with previously published studies that evaluated endoscopy. 10,12,20 The high intrarater findings suggest that standardization in training of interpretation of endoscopic findings could improve inter-rater scores to similar levels, because the authors were able to blindly reproduce their interpretations. This study was limited by a selection bias that exists with a retrospective collection of data. All patients in this study must have had sufficient symptoms or signs on examination to warrant in vitro allergy testing and nasolaryngoscopy. This bias makes it more likely Fig. 3. An atopic patient with increased nasopharyngeal secretions. Fig. 4. An atopic patient with hypertrophy of the mucosa of the torus tubarius. that the nonatopic control group would have abnormal endoscopic findings, and therefore the difference between those patients and the atopic patients might be smaller than one would expect in the general population. Additionally, limitations with in vitro allergy testing may result in some atopic patients falling into the control group, thus making it more difficult to find a difference. Finally, patients were not standardized by symptoms, previous treatments for reflux disease, and symptoms of extraesophageal reflux, which could potentially confound the findings on nasolaryngeal endoscopy. Despite these limitations, significant endoscopic differences were identified that can assist in diagnosis of atopic disease. CONCLUSION Mucosal abnormalities and increased secretions in the nasopharynx on nasolaryngoscopy are suggestive of atopic disease and can be used in assisting in the diagnosis of allergic disease. Similar findings in the oropharynx and larynx did not correlate with positive allergy testing. BIBLIOGRAPHY 1. Steinsvaag SK. Allergic rhinitis: an updated overview. Curr Allergy Asthma Rep 2012;12:99 103. 2. Meltzer EO, Bukstein DA. The economic impact of allergic rhinitis and current guidelines for treatment. Ann Allergy Asthma Immunol 2011; 106(2 suppl):s12 S16. 3. Krouse JH. The unified airway conceptual framework. Otolaryngol Clin North Am 2008;41:257 266. 4. Krouse JH, Altman KW. Rhinogenic laryngitis, cough, and the unified airway. Otolaryngol Clin North Am 2010;43:111 121, ix x. 5. Roth DF, Ferguson BJ. Vocal allergy: recent advances in understanding the role of allergy in dysphonia. Curr Opin Otolaryngol Head Neck Surg 2010;18:176 181. 6. Dworkin JP, Reidy PM, Stachler RJ, Krouse JH. Effects of sequential Dermatophagoides pteronyssinus antigen stimulation on anatomy and physiology of the larynx. Ear Nose Throat J 2009;88:793 799. 7. Roth DF, Verdolini K, Carroll T, Ferguson BJ. Laryngeal allergy, nothing to sniff at: evidence for laryngeal allergy. Presented at: American Academy of Otolaryngologic Allergy 68th Annual Meeting; October 2, 2009; San Diego, CA. 289

8. Randhawa PS, Mansuri S, Rubin JS. Is dysphonia due to allergic laryngitis being misdiagnosed as laryngopharyngeal reflux? Logoped Phoniatr Vocol 2010;35:1 5. 9. Garrett CG, Cohen SM. Otolaryngological perspective on patients with throat symptoms and laryngeal irritation. Curr Gastroenterol Rep 2008; 10:195 199. 10. Eren E, Arslanoglu S, Aktaş A, et al. Factors confusing the diagnosis of laryngopharyngeal reflux: the role of allergic rhinitis and inter-rater variability of laryngeal findings. Eur Arch Otorhinolaryngol 2014;271:743 747. 11. Randolph JJ. Online kappa calculator. 2008. Available at: http://justus.randolph.name/kappa. Accessed September 20, 2013. 12. Eren E, Aktaş A, Arslanoglu S, et al. Diagnosis of allergic rhinitis: interrater reliability and predictive value of nasal endoscopic examination: a prospective observational study [published online ahead of print August 28, 2013]. Clin Otolaryngol. doi: 10.1111/coa.12171. 13. Raithatha R, Anand VK, Mace JC, et al. Interrater agreement of nasal endoscopy for chronic rhinosinusitis. Int Forum Allery Rhinol 2012;2:144 150. 14. Ameli F, Brocchetti F, Tosca MA, Signori A, Ciprandi G. Nasal endoscopy in children with suspected allergic rhinitis. Laryngoscope 2011;121: 2055 2059. 15. Ameli F, Brocchetti F, Tosca MA, Signori A, Ciprandi G. Adenoidal hypertrophy and allergic rhinitis: is there an inverse relationship? Am J Rhinol Allergy 2013;27:e5 e10. 16. Rhee CS, Wee JH, Ahn JC, et al. Prevalence, risk factors and comorbidities of allergic rhinitis in South Korea: The Fifth Korea National Health and Nutrition Examination Survey. Am J Rhinol Allergy 2014; 28:e107 e114. 17. Deb A, Mukherjee S, Saha BK, et al. Profile of patients with allergic rhinitis (AR): a clinic based cross-sectional study from Kolkata, India. J Clin Diagn Res 2014;8:67 70. 18. Sedaghat AR, Phipatanakul W, Cunningham MJ. Prevalence of and associations with allergic rhinitis in children with chronic rhinosinusitis. Int J Pediatr Otorhinolaryngol 2014;78:343 347. 19. Nguyen LH, Manoukian JJ, Sobol SE, et al. Similar allergic inflammation in the middle ear and the upper airway: evidence linking otitis media with effusion to the united airways concept. J Allergy Clin Immunol 2004;114:1110 1115. 20. Branski RC, Bhattacharyya N, Shapiro J. The reliability of the assessment of endoscopic laryngeal findings associated with laryngopharyngeal reflux disease. Laryngoscope 2002;112:1019 1024. 290