Molecular and Cellular Staging for the Severity of Chronic Rhinosinusitis

APPENDICES

Stilianos E. Kountakis, MD, PhD

Department of Otolaryngology-Head and Neck Surgery

Medical College of Georgia, Augusta, GA

Pablo Arango, M.D., New York, NY

Dewayne Bradley, MD2, Dept. of Otolaryngology, University of Virginia, Charlottesville,

Zane K. Wade, M.D., Dept. of Pathology, Medical College of Georgia, Augusta, GA

Larry Borish, M.D.4, Division of Allergy, University of Virginia, Charlottesville, VA

Correspondence: Stilianos E. Kountakis, MD, PhD, Professor of Otolaryngology-Head and Neck Surgery, Medical College of Georgia, 1120 Fifteenth St., Augusta, GA 30912.

Phone: 706-721-6100

Fax: 706-721-0112

Email: [email protected] 2

I: HISTORY AND REVIEW OF PREVIOUS WORK

Nasal Endoscopy

Physicians have attempted to devise methods to examine various body cavities since the time of Hippocrates and this eventually led to the development of endoscopes and minimally invasive surgical techniques. The problems these pioneer physicians and instrument designers had to overcome were two-fold. The first obstacle was with obtaining adequate illumination and the second was achieving miniaturization of the instruments, the problems being interrelated.

Illumination during the early times was sunlight-directed using reflective mirrors.

Artificial light was incorporated using candles, oil or chemical mixtures. The problem with these methods was with the instability of the light rays and the necessity for bulky instruments directing the light making examination difficult. Later on, heated platinum wires produced satisfactory light but they generated large amounts of heat requiring cooling with water. Once light bulbs were invented, the way for better instruments was cleared, and the construction of miniature light bulbs allowed the development of smaller endoscopes. One of the first papers in the English literature that described the use of endoscopes to examine the nasopharynx, was written by Fidenberg (A1) in 1909. Dennis and Mullen (A2) described the value of endoscopy in the diagnosis of chronic maxillary sinus disease in 1922. Contemporary use of nasal endoscopes became possible when Karl

Storz Hopkins invented the Hopkins rigid endoscope in the early 1950’s. The improved optics, small diameter size and the reliability of the instrument revolutionized the examination and diagnosis of sinonasal problems. The most comprehensive report on the history of endoscopy is by Reuter (A3) who published a detailed illustrated 660-page 3 book on the subject. Professor Stammberger (A4) has also included a complete account of the development of nasal endoscopes in his book “Functional Endoscopic Sinus

Surgery”.

Functional Endoscopic Sinus Surgery

Early physicians designed ingenious ways to remove large nasal polyps from the nasal cavity. Hippocrates removed large nasal polyps by using a string, which was looped around the nasal polyp (A5). The string was then passed posteriorly through the nose to the nasopharynx and then withdrawn out through the mouth to remove the polyp (Figure

A7). Smaller polyps were removed in a similar fashion by using a cloth ball dragged posteriorly through the nasal cavity (Figure A8). During the subsequent centuries, sinonasal surgery was limited by the level of anesthesia patients that could be provided to the patients. The discovery of cocaine in the late 1800’s allowed more aggressive but not necessarily appropriate, nor successful surgery. The Caldwell-Luc procedure (A6) allowed for the creation of an antrostomy in the inferior meatus, a technique that it is still used today, even though many find its use controversial in the management of chronic maxillary rhinosinusitis since it bypasses the natural ostium of the maxillary sinus. Lynch

(A7) in 1921 reported a 100% cure rate with his open approach to the fronto-ethmoid cavities, results that have never been duplicated. The proximity of the ethmoid sinuses to the intracranial cavity and the orbits led to serious surgical complications as sinus surgery became more popular. By 1929 Mosher (A8) made his famous remark “any surgery in the (ethmoid) region… has proven one of the easiest ways to kill a patient”. 4

Mucociliary studies and further understanding of sinonasal disease led to the development of conservative techniques. Messerklinger (A9), published the first detailed description of the anatomy of the lateral nasal wall and advocated surgical techniques designed to preserve sinus mucosa. This conservative approach was adopted by other rhinologists in Europe (A10-12). The first investigator, however, to emphasize mucosal preservation is Kennedy, who popularized endoscopic sinus surgery techniques in the

United States. In his landmark papers in 1985, Kennedy (A13-14) used the term

“functional” endoscopic sinus surgery to emphasize the objective of the technique to direct surgery to the ostiomeatal complex while preserving sinus mucosa.

CT, Endoscopy, Patient Symptoms and Outcomes

The advent of improved instrumentation has led to more precise endoscopic surgical techniques for the management of chronic rhinosinusitis (CRS) once medical therapy fails. Naturally, rhinologists began to report surgical techniques and outcomes, and multiple studies appeared in the literature (A15-26). The need for a standard definition of the disease and consistent outcomes reporting became rapidly apparent.

Lanza and Kennedy4 established the current definition for rhinosinusitis in adults. This definition is now supported by the American Academy of Otolaryngology – Head and

Neck Surgery and by most rhinologists. A limitation of this definition, as discussed in the

Main Text, is that it is based only on the chronology of symptoms and does not reflect the nature of the underlying pathology that gives rise to these symptoms.

Until the middle 1980’s, polytomography was the best way to evaluate sinus anatomy and disease. Once CT use emerged in the United States it became obvious that 5

CT of sinuses was much superior to polytomography (A27-29). Soon afterwards, CT sinus anatomy, anatomic variants, and extent of radiologic evidence of rhinosinusitis were evaluated in relationship to surgical findings and treatment outcomes (A30-34).

Radiologic staging systems were then developed as part of an attempt to standardize reporting and provide guidelines for the evaluation of rhinosinusitis (A35-36). Because of its simplicity, the CT-based radiologic system as reported by Lund and Mackay26 has become very popular and is the most commonly used CT staging system in the evaluation of rhinosinusitis. However, the problem with radiologic systems is that they reflect the degree of sinus mucosal changes but they do not incorporate the underlying pathology that caused these changes. As reported in the Main Text, Kennedy9 found that the extent of disease seen on CT of the sinuses correlated with the likelihood for surgical success.

Other studies24, however, have not supported such a relationship. Metson et al. (A37) compared 5 different sinus CT staging systems9,26 (A38-40) evaluating intrarater variability. They reported that the CT system described by Lund-MacKay26 was comprehensive and sensitive and the system by Gliklich and Metson (A40) had good rater agreement. More recently, Stewart et al.7,28 reported that both CT staging systems correlated with the degree of symptomatic improvement but CT scan findings did not correlate with patient symptoms.

Nasal endoscopy provides the best method to closely examine the middle meatus and as such, it is recommended in the evaluation of sinusitis (A1,A14). The procedure in one study contributed additional information in 68% of the patients that had radiologic evidence of rhinosinusitis on CT of the sinuses (A41). In the same study, the authors showed that 9% of the symptomatic patients with negative CT of the sinuses had 6 abnormal findings on endoscopic examination explaining their symptoms. Nasal endoscopy and CT scan of the sinuses are complimentary in the evaluation of rhinosinusitis. Casiano (A42) also correlated nasal endoscopy findings with CT findings in 240 patients. The sensitivity and specificity of nasal endoscopy were 75% and 84% , respectively. Stankiewicz and Chow (A43) evaluated the place of endoscopy in the diagnosis of CRS. Overall, endoscopic findings correlated with CT findings but 26% of patients with negative endoscopy had positive CT results. This number is similar to the number of patients that have positive CT findings for rhinosinusitis but are asymptomatic.25 In their study, Stankiewicz and Chow (A43) showed that when purulence, mucosal congestion and polyps were present, nasal endoscopy correlated well with CT findings. Normal endoscopy also correlated well with negative CT findings in

71% of the patients. They concluded that endoscopy in an important tool in the evaluation of CRS.

The definition of CRS is based on patient symptoms and the length of time the patients have those symptoms.4 Even though objective techniques have been developed and continue to be explored, the main outcome measures also concentrate on patient symptoms after treatment, including overall quality of life issues. Multiple outcome instruments have been developed and were validated (A44-53). The Sino-nasal outcome instrument (SNOT-20) is a simple, easy-to-complete questionnaire and is a short version of the rhinosinusitis outcome measure that contains 31 items (RSOM-31)16. Because of its simplicity and its repeatability, the SNOT-20 questionnaire was chosen for this study.

Having both objective (CT and endoscopy) and subjective (symptom and quality of life instruments) systems available for the evaluation of CRS, the next natural step was 7 to evaluate the correlation of the objective measures with subjective patient symptom and quality of life issues. Investigators have been unable to show any good correlation7, and the current report is no exception. The problem may be that the importance of each subjective patient-measured item or symptom and the weight it should have in these subjective outcome instruments are unknown. Continued collection and analysis of data may one day help produce an importance factor for each item measured and therefore the development of an outcome instrument that incorporates conversion factors to produce a total “corrected” score.

Asthma, molecular and histologic markers

One of the key factors leading to the development of CRS is mucosal inflammation. Patients with CRS may have acute exacerbations of infectious etiology but there is no conclusive evidence that bacterial infection is the main factor contributing to mucosal inflammation in CRS. Infectious processes may contribute to the initiation of cascade of events that eventually lead to CRS but the exact association of these infectious processes with CRS, once it develops, is unclear. Histologically, mucosal biopsies from patients with CRS show an abundance of inflammatory cells, fibroblasts and goblet cells

(A54). If an infectious component is present, microscopic sinus mucosal examination reveals the presence of neutrophils, since these cells are the hallmark of infection. One patient had neutrophils present on pathologic examination and was excluded from our analysis. When the eosinophils present are activated, there is increased production of a cascade of inflammatory mediators and cytokines (A55). The inflammatory cascade becomes self-propagating through mediators such as interleukin-5 that recruit additional 8 inflammatory cells with increased production of potent inflammatory mediators such as cysteinyl leukotrienes (A56). The molecules are formed via the 5-lipoxygenase pathway of arachidonic acid metabolism (A57) and can cause increased mucous production and bronchoconstriction in the lower airways (A58-60). In one of the recent studies, the number of inflammatory cells producing these compounds such as eosinophils had a direct relationship with the degree of mucosal thickening on CT of the sinuses.32

The association of sinusitis and asthma is documented in the early (A61-63) and recent literature (A64-68). It is also documented that successful management of CRS improves the severity of asthma symptoms and leads to decreased use of asthma medications (A69-73). A recent study by Goldstein MF (A74) failed to support the hypothesis that first-time sinus surgery in patients with refractory CRS and asthma leads to asthma symptom improvement and reduction of asthma medication usage. However, the majority of the studies in the literature support this hypothesis. Asthma symptom improvement rates were not evaluated in this report. Evidence supporting the relationship between CRS and asthma was shown at the cellular and molecular level.32 Eosinophils, leukotrienes and various cytokines were found in sinus and lower airway epithelium in patients who have both asthma and CRS (A75). Marney (A76) listed 5 different possible mechanisms for the relationship between rhinosinusitis and asthma: aspiration of secretions which may contribute to the infection and inflammation of the lower airways, vagal-mediated nasal-pulmonary reflex with bronchoconstriction, nasal obstruction with resultant mouth-breathing causing drying and irritation of the lower airways, loss of bronchodilatation mediated by bacterial toxin produced in the sinuses though partial B- blockade, and lastly systemic release of inflammatory mediators by diseased sinus 9 mucosa that reach the respiratory epithelium of the lower airways. The last mechanism is the one favored in the literature. The first clinical study to explore the association between aspirin-sensitive asthma and nasal polyposis was authored by Samter (A77) in

1968 (Samter’s triad). Studies in the patients show that sinus surgery improves asthma symptoms for relatively long periods of time (A78). In addition, Stevenson et al. (A79) documented significant improvement of sinusitis and asthma severity after aspirin desensitization treatment in these patients. The small number of patients with aspirin- sensitive asthma in this report did not allow derivation of any useful conclusions.

II. SUPPLEMENTARY RESULTS

The specific demographics of the 52 patients studied are listed in Table AI. There was a slight higher incidence of CRS in females than males in this study. All patients completed the Sino-Nasal Outcome Test (SNOT-20) preoperatively and 1 year after surgery. The SNOT-20 is a short version of the rhinosinusitis outcome measure that contains 31 items (RSOM-31). Table AII lists all items evaluated in the SNOT-20 survey.

All patients were evaluated with rigid nasal endoscopy preoperatively and 1 year after surgery. A total endoscopy score was calculated for each patient as explained in Table

AIII. All patients underwent a CT of the sinuses and the CT was graded according to

Lund and Mackay.17 The total CT score was calculated as explained in Table AIV.

The frequency of polyps in patients with asthma vs. patients without asthma and in patients with allergies vs. non-allergic patients is listed in Figure A1. Asthma was more frequently diagnosed in patients with polyps than without polyps. Conversely, the incidence of polyps was similar between the allergic and non-allergic patient groups. 10

Average preoperative and postoperative SNOT-20 scores are listed in Figure A2.

The average symptom improvement after surgery was 70%. Four of 52 patients did not improve, with 2 of those patients actually having slightly worse symptom scores (Figure

A3). All 4 of these patients had eosinophilic nasal polyposis and required revision surgery. With medical management, the 4 patients that required revision sinus surgery were polyp-free 4 to 6 months after revision. Their endoscopic exam, however, continued to show mucosal edema and polypoid degeneration. Preoperative and postoperative

SNOT-20 scores were analyzed for correlation with sinus CT and nasal endoscopy findings. Regression analysis did not reveal any correlation with these parameters

(Figures A3, A4).

Eosinophils play an important role in the inflammatory cascade seen in the sinus mucosa of patients with CRS and in the epithelium of the lower airways in patients with asthma. It this study, the number of peripheral eosinophils correlated well with preoperative sinus CT scores (Main Text, r=0.78, p<0.05, Figure 7). There was some correlation with nasal endoscopy scores (r=0.40, p<0.05, Figure A6) as expected, since peripheral eosinophilia correlated with sinus mucosal eosinophilia and the presence of eosinophils contributes to the escalation of sinus mucosal inflammation. This inflammation results in mucosal edema and in some patients it contributes to the formation of nasal polyps. The presence of edema and polyps then contributes to a higher endoscopy score. However, the correlation between peripheral eosinophilia and nasal endoscopy scores was not as significant as the correlation between peripheral eosinophilia and sinus CT findings. The sinus CT is a more sensitive barometer of sinus 11 mucosal inflammation than nasal endoscopy since it can precisely measure mucosal thickening. Peripheral eosinophilia did not correlate with SNOT-20 scores (Figure A6).

Sinus tissue was stained for EG2 to determine the degree of activated eosinophils.

When the number of eosinophils was less than 5 cells/High Power Field (HPF), none of the specimen stained for EG2 (EG2- or Group 1: non-eosinophilic group), while 78% of the tissue with more than 5 eosinophils/HPF was EG2+ (Group 2 or eosinophilic group).

The mean endoscopy and CT scores for these 2 patient groups are shown in

Figure A8. Patients with sinus mucosa eosinophilia (EG2+, Group 2) had higher scores than patients without sinus tissue eosinophilia (EG2-, Group 1). In addition, sinus tissue leukotriene C4 levels (picogram/gram tissue) were similar between the two groups

(Figure A9).

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Figure legends.

Figure A1: Frequency of Polyps in Patients with Asthma vs. No Asthma and in Patients with Allergies vs. No Allergies.

Table AI: Patient Demographics

N 52 Males 21 Females 31 Average Age 44 (18-80) Patients with Polyps 36 Patients w/o Polyps 16 25

Table AII: SINO-NASAL OUTCOME TEST (20 Items)

Below you will find a list of symptoms and social/emotional consequences of your rhinosinusitis. We would like to know more about these problems and would appreciate your answering the following questions to the best of your ability. There are no right or wrong answers, and only you can provide us with this information. Please rate your problems as they have been over the past two weeks. Thank you for your participation. N M M S

1. Considering how severe the problem is when you e o i o v l

d d p experience it and how frequently it happens, please e e r r o e o r a r

rate each item below on how “bad” it is by circling the b P

t s l e r e l

number that corresponds with how you feel using this P g b r h l o e

scale. t b

m P l e r o m b l e m

1. Need to blow nose 0 1 2 3 2. Sneezing 0 1 2 3 3. Runny Nose 0 1 2 3 4. Cough 0 1 2 3 5. Post-nasal discharge 0 1 2 3 6. Thick nasal discharge 0 1 2 3 7. Ear fullness 0 1 2 3 8. Dizziness 0 1 2 3 9. Ear pain 0 1 2 3 10. Facial pain/pressure 0 1 2 3 11. Difficulty falling asleep 0 1 2 3 12. Wake up at night 0 1 2 3 13. Lack of a good night’s sleep 0 1 2 3 14. Wake up tired 0 1 2 3 15. Fatigue 0 1 2 3 16. Reduced productivity 0 1 2 3 17. Reduced concentration 0 1 2 3 18. Frustrated/restless/irritable 0 1 2 3 19. Sad 0 1 2 3 20. Embarrassed 0 1 2 3 26

Table AIII: Endoscopy Score

Left Right Polyp Edema Discharge Scarring, right Crusting, left Total Points

For polyps: 0=absence of polyps, 1=polyps in middle meatus only, 2=polyps beyond middle meatus. For edema, scaring, and crusting: 0=absent, 1=mild, 2=severe. For discharge: 0=no discharge, 1=clear, thin discharge, 2=thick purulent discharge 27

Table AIV: CT score according to Lund and Mackay17

Left Right Maxillary Sinus Anterior Ethmoids Posterior Ethmoids Sphenoid Sinus Frontal Sinus Ostiomeatal Complex Total

For maxillary sinus, anterior and posterior ethmoids, sphenoid sinus, frontal sinus: 0=no abnormalities, 1=partial opacification, 2=total opacification. For ostiomeatal complex: 0=not occluded, 2=occluded. 28

Figure Legends

Figure A1. Frequency of polyps in patients with asthma vs. no asthma and in patients with allergies vs. no allergires.

Figure A2. Average preoperative and postoperative SNOT-20 Scores (p<0.0001).

Figure A3: Preoperative and postoperative SNOT-20 scores in patients requiring revision sinus surgery.

Figure A4. Correlation between preoperative CT and SNOT-20 scores.

Figure A5. Correlation between preoperative endoscopy scores and preoperative SNOT-

20 scores.

Figure A6. Correlation between endoscopy score and peripheral eosinophil count.

Figure A7. Correlation between SNOT-20 scores and peripheral eosinophil count.

Figure A8. Mean preoperative CT and endoscopy scores in patients with and without sinus mucosal eosinophilia.

Figure A9. Leukotriene C4 levels in patients with polyps, asthma and mucosal eosinophilia compared to patients without these conditions. 29

Figure A1

Frequency of Polyps in Patients with Asthma vs. No Asthma and in Patients with Allergies vs. No Allergies

t Polyp

n 30 e

i Nonpolyp t

a 25 P

b 15 m

u 10 N

0 Asthma No Asthma Allergy No allergy Patient Group 30

Figure A2

Mean SNOT-20 Scores for All Patients

18 16 14 e r

o 12 c S 10 0 2 - 8 T O

N 6 S 4 2 0 Preop Postop 31

Figure A3

Preop and Postop SNOT-20 Scores in Patients Requiring Revision Sinus Surgery Preop SNOT-20 Score 50 Postop SNOT-20 45 Score 40 e r

o 35 c

2 25 - T 20 O

N 15 S 10 5 0 Patient 1 Patient 2 Patient 3 Patient 4 32

Figure A4

Preoperative CT Scores vs. Preoperative SNOT-20 Scores

50 45 40 e r 35 o c

2 25 - T 20 O N

S 15 10 5 0 0 5 10 15 20 25 30 CT Score 33

Figure A5

Preoperative Endoscopy Scores vs. Preoperative SNOT-20 Scores

50 45 40 e

r 35 o

c 30 S

0 25 2 -

T 20 O

N 15 S 10 5 0 0 5 10 15 Endoscopy Score 34

Figure A6

Endoscopy Score v. Peripheral Eosinophil Count (r=0.40, p<0.05)

1000 900 800 t n

u 700 o C

600 l i h

p 500 o n

i 400 s o

E 300 200 100 0 0 2 4 6 8 10 12 14 Endoscopy score 35

Figure A7

Preoperative SNOT-20 Scores vs. Peripheral Eosinophil Count

50 45 40 e

r 35 o c

o 25 t p 20 m y

S 15 10 5 0 0 200 400 600 800 1000 Eosinophil Number 36

Figure A8

CT and Endoscopy Scores v. Mucosal Eosinophilia

20 18 Group 1 (EG2-) 16 Group 2 (EG2+) 14 e r

o 12 c S 10 n a

e 8 M 6 4 2 0 CT Score Endoscopy Score 37

Figure A9

LTC4 Levels in Patients with Polyps, Asthma and Mucosal Eosinophilia

60 ) e u

s 50 s i t

m 40 a r g /

g 30 p (

C 20 T L 10

0 Polyps No Polyps Asthma No Group 1 Group 2 Asthma (EG2-) (EG2+) Patient Group