**Meet the editors**

Professor Gian Luigi Marseglia was born on April 29th 1955 in Italy. He went to High School in Italy and graduated in classical studies. He finished Medical School in Italy, at the University of Pavia and he then specialized in Pediatrics, Allergy, Respiratory Physiokynesitherapy, and Infectious Diseases. He worked at the University of Lyone (France) and at the University of Brescia (Italy).

Since 1991 he works at the University of Pavia, where he is a full-time Professor of Pediatrics and Head of the Department of Pediatrics and of the Allergy-Immunology Pediatric Unit. Since 2009 he is the chief of the Pediatric Program at the University of Pavia as well. He has published almost 150 articles in international journals, focusing mainly on pediatrics, allergies, respiratory and ORL diseases.

Dr. Davide Paolo Caimmi was born on April 22nd 1982 in Italy. He went to High school in Louisville (KY), United States of America, for a year, but he graduated in Italy, in classical studies. He finished Medical School in Italy, at the University of Pavia and studied for one year at the Free University of Bruxelles (Belgium). He completed his Internship and Residency in Pediatrics,

at the University of Pavia (Italy), where he still works, collaborating at the same time with the Allergy Department of the University of Montpellier (France). His publications mainly concern allergies and pediatric otolaryngoiatric diseases.

Contents

**Preface VII** 

Petr Schalek

**Part 1 Rhinosinusitis, Chronic Rhinosinusitis** 

**and Refractory Chronic Rhinosinusitis 1** 

Chapter 3 **Chronic Rhinosinusitis and Olfactory Dysfunction 39** 

**Part 2 Diagnosis and Treatment of Rhinosinusitis 67** 

**for Chronic Rhinosinusitis 91**  Alan Shikani and Konstantinos Kourelis

Huart Caroline, Franceschi Daniel and Rombaux Philippe

Chapter 1 **Rhinosinusitis - Its Impact on Quality of Life 3** 

Chapter 2 **Microbiology Aspects of Rhinosinusitis 27**  Agnieszka Magryś, Jolanta Paluch-Oleś

and Maria Kozioł-Montewka

Chapter 4 **Refractory Chronic Rhinosinusitis: Etiology & Management 53** 

Mohannad Al-Qudah

Chapter 5 **Imaging Rhinosinusitis 69**  Heidi Beate Eggesbø

Chapter 6 **Topical Membrane Therapy** 

### Contents

#### **Preface XI**


Preface

evaluated.

computed tomography.

surgical training.

pediatric patients.

process.

Rhinitis, rhinosinusitis and respiratory diseases are among those diseases that most often lead a patient to consult a general practitioner. Unfortunately, these diseases are not always easy to manage and cure. Therefore, sometimes it becomes necessary to see a specialist. Among these three entities, rhinosinusitis is probably the one that most often creates confusion over how it should be treated and by what specialist should be

For a long time it has been acknowledged that most of the times the disease has an infectious component, as well as the fact that is more frequent in atopic and allergic patients. Rhinosinusitis is today easily assessed by nasal endoscopy and/or sinusal

The management of such a condition consists of different approaches and it also depends on whether the doctor who treats the patient had a medical rather than a

Ultimately, it has to be recalled that rhinosinusitis is an important and common disease that, among other symptoms, causes pain not only in adults but also in

The clinical presentation of rhinosinusitis is heterogeneous and includes different signs and symptoms: anterior and posterior rhinorrhea, nasal obstruction, fever, halitosis, headache, facial pain, orbital pain, facial edema, edema, more or less marked in the periorbital region, cough. These symptoms, however, vary mostly on the basis of the age of the subject and of the sinuses involved in the inflammatory/infectious

Another aspect of the disease that needs to be taken into account when dealing with a patient presenting with rhinosinusitis is the duration of the symptoms. Considering such a feature, three forms of rhinosinusitis may be described. The acute forms are those that last less than 30 days (distinguished into mild and severe); subacute forms are those whose symptoms persist more than 30 days but less than 3 months; at last, chronic forms are those in which symptoms persist for more than 3 months. In those patients who present with chronic forms of rhinosinusitis, even though most of the

### Preface

Rhinitis, rhinosinusitis and respiratory diseases are among those diseases that most often lead a patient to consult a general practitioner. Unfortunately, these diseases are not always easy to manage and cure. Therefore, sometimes it becomes necessary to see a specialist. Among these three entities, rhinosinusitis is probably the one that most often creates confusion over how it should be treated and by what specialist should be evaluated.

For a long time it has been acknowledged that most of the times the disease has an infectious component, as well as the fact that is more frequent in atopic and allergic patients. Rhinosinusitis is today easily assessed by nasal endoscopy and/or sinusal computed tomography.

The management of such a condition consists of different approaches and it also depends on whether the doctor who treats the patient had a medical rather than a surgical training.

Ultimately, it has to be recalled that rhinosinusitis is an important and common disease that, among other symptoms, causes pain not only in adults but also in pediatric patients.

The clinical presentation of rhinosinusitis is heterogeneous and includes different signs and symptoms: anterior and posterior rhinorrhea, nasal obstruction, fever, halitosis, headache, facial pain, orbital pain, facial edema, edema, more or less marked in the periorbital region, cough. These symptoms, however, vary mostly on the basis of the age of the subject and of the sinuses involved in the inflammatory/infectious process.

Another aspect of the disease that needs to be taken into account when dealing with a patient presenting with rhinosinusitis is the duration of the symptoms. Considering such a feature, three forms of rhinosinusitis may be described. The acute forms are those that last less than 30 days (distinguished into mild and severe); subacute forms are those whose symptoms persist more than 30 days but less than 3 months; at last, chronic forms are those in which symptoms persist for more than 3 months. In those patients who present with chronic forms of rhinosinusitis, even though most of the

#### VIII Preface

times the disease is initially related to an upper respiratory tract infection, clinicians should look for an underlying diseases or an underlying condition possibly predisposing a local or systemic continuous obstruction of the hosts of the sinuses. Similarly, in those patients presenting with a persistent/recurrent rhinosinusitis or with pan-sinusitis, possible local conditions favoring the disease need to be excluded, such as a marked adenoid hypertrophy, anatomical abnormalities of the bones of the nasal cavity, nasal polyps, allergies, cystic fibrosis, immune deficiencies or ciliary dyskinesia.

At last, clinicians should be aware of the rhino-bronchial syndrome and of the need to exclude an association between sinusitis and bronchial hyper-reactivity. Most of the times, this association if discovered when a patient presenting with asthma shows a poor asthma control even after appropriate treatment. These patients show a great benefit after sinusitis treatment. Therefore, whenever such a comorbidity is found, an appropriate nasal treatment should be started.

The present monograph will therefore highlight certain specific topics concerning rhinosinusitis that usually are not clarified in other textbooks. First of all, it has to be clear that patients presenting with rhinosinusitis surely experience a worsening in their quality of life. In the first section of the book one chapter will focus on the microbiological aspects of rhinosinusitis, while two other chapters will explain the peculiar aspects of chronic rhinosinusitis and of recurrent chronic rhinosinusitis. In the second section, a chapter is dedicated to the imaging techniques to visualize the nasal sinuses and the other chapter to a medical topical type of treatment.

Rhinosinusitis is a disease that all clinicians should be aware of. The present book has the peculiarity to focus on certain aspects of the disease that are often neglected elsewhere.

#### **Prof. Gian Luigi Marseglia**

Head of the Department of Pediatrics Head of the Allergy Immunology Pediatric Unit University of Pavia Foundation IRCCS Policlinico San Matteo - Pavia Italy

**Dr. Davide Caimmi**  Department of Pediatrics University of Pavia Foundation IRCCS Policlinico San Matteo - Pavia Italy

VIII Preface

dyskinesia.

appropriate nasal treatment should be started.

times the disease is initially related to an upper respiratory tract infection, clinicians should look for an underlying diseases or an underlying condition possibly predisposing a local or systemic continuous obstruction of the hosts of the sinuses. Similarly, in those patients presenting with a persistent/recurrent rhinosinusitis or with pan-sinusitis, possible local conditions favoring the disease need to be excluded, such as a marked adenoid hypertrophy, anatomical abnormalities of the bones of the nasal cavity, nasal polyps, allergies, cystic fibrosis, immune deficiencies or ciliary

At last, clinicians should be aware of the rhino-bronchial syndrome and of the need to exclude an association between sinusitis and bronchial hyper-reactivity. Most of the times, this association if discovered when a patient presenting with asthma shows a poor asthma control even after appropriate treatment. These patients show a great benefit after sinusitis treatment. Therefore, whenever such a comorbidity is found, an

The present monograph will therefore highlight certain specific topics concerning rhinosinusitis that usually are not clarified in other textbooks. First of all, it has to be clear that patients presenting with rhinosinusitis surely experience a worsening in their quality of life. In the first section of the book one chapter will focus on the microbiological aspects of rhinosinusitis, while two other chapters will explain the peculiar aspects of chronic rhinosinusitis and of recurrent chronic rhinosinusitis. In the second section, a chapter is dedicated to the imaging techniques to visualize the nasal

Rhinosinusitis is a disease that all clinicians should be aware of. The present book has the peculiarity to focus on certain aspects of the disease that are often neglected elsewhere.

**Prof. Gian Luigi Marseglia**

University of Pavia

**Dr. Davide Caimmi**  Department of Pediatrics University of Pavia

Italy

Italy

Head of the Department of Pediatrics

Head of the Allergy Immunology Pediatric Unit

Foundation IRCCS Policlinico San Matteo - Pavia

Foundation IRCCS Policlinico San Matteo - Pavia

sinuses and the other chapter to a medical topical type of treatment.

**Part 1** 

**Rhinosinusitis, Chronic Rhinosinusitis** 

 **and Refractory Chronic Rhinosinusitis** 

## **Part 1**

### **Rhinosinusitis, Chronic Rhinosinusitis and Refractory Chronic Rhinosinusitis**

**1** 

Petr Schalek

*Czech Republic* 

*3rd Medical faculty of Charles University, Prague* 

**Rhinosinusitis - Its Impact on Quality of Life** 

Chronic rhinosinusitis (CRS) is one of the most common chronic diseases, affecting about 15% of the western population. This disease is connected with a significant health care burden having direct annual costs of about 5.8 billion dollars (Anand, 2004). These direct costs do not cover other important expenses to the individual, the community and society, such as lost time from work and / or school and the associated decreased productivity

CRS is an inflammatory process involving the sinonasal mucosa and defined as the presence of two or more symptoms one of which should be either nasal

for more than 12 weeks, together with pathologic endoscopic findings in the middle nasal meatus (Figure 1) and/or CT changes within the ostiomeatal complex and/or sinuses

blockage/obstruction/congestion or nasal discharge (anterior or posterior) with

(Fokkens et al., 2007). Nasal polyposis is considered a subgroup of CRS (Figure 2).

Fig. 1. Endoscopic view of chronic rhinosinusitis- edema and purulent secretion in the

**1. Introduction** 

(Benninger, 2010).

± facial pain (pressure)

middle nasal meatus

± reduced smell

### **Rhinosinusitis - Its Impact on Quality of Life**

### Petr Schalek

*3rd Medical faculty of Charles University, Prague Czech Republic* 

#### **1. Introduction**

Chronic rhinosinusitis (CRS) is one of the most common chronic diseases, affecting about 15% of the western population. This disease is connected with a significant health care burden having direct annual costs of about 5.8 billion dollars (Anand, 2004). These direct costs do not cover other important expenses to the individual, the community and society, such as lost time from work and / or school and the associated decreased productivity (Benninger, 2010).

CRS is an inflammatory process involving the sinonasal mucosa and defined as the presence of two or more symptoms one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior or posterior) with

± facial pain (pressure)

± reduced smell

for more than 12 weeks, together with pathologic endoscopic findings in the middle nasal meatus (Figure 1) and/or CT changes within the ostiomeatal complex and/or sinuses (Fokkens et al., 2007). Nasal polyposis is considered a subgroup of CRS (Figure 2).

Fig. 1. Endoscopic view of chronic rhinosinusitis- edema and purulent secretion in the middle nasal meatus

Rhinosinusitis - Its Impact on Quality of Life 5

The last two decades have been characterized by increasing interest in assessing the quality of life, which is related to the systematic development and validation of QoL questionnaires. Tools used to evaluate the quality of life are either generic health instruments for assessing general conditions or disease-specific questionnaires focused on symptoms of a disease.

Creation of a questionnaire is a relatively complex process involving several steps, each of

The basic criteria which must be met by the questionnaire are: (i) reliability, (ii) validity, (iii)

Confirming that a particular instrument meets those criteria is a process called validation of the questionnaire. Validation studies must be performed on patients who have the same characteristics as the target population and there must be enough patients included in the

Reliability concerns the extent to which the questionnaire is free of random or systematic error. Internal reliability (consistency) reflects the way individual items relate to each other. This property is determined by calculating Cronbach's α (range 0 – 1). If scale has an alpha of at least 0.7 it is considered to be reliable for group level comparisons and a value of 0.9 or more

Test-retest reliability (reproducibility) reflects stability over time with repeated testing. Questionnaires with good reproducibility should give similar results under similar conditions. This property of the questionnaire may be tested using the t- test and a Pearson

The questionnaire can be called valid when it measures what it is supposed to measure.

Construct validity means that the instrument behaves according to an underlying hypothesis, i.e. the measured variables behave in a consistent way relative to theoretical and

Convergent validity reflects the degree of correlation with other instruments of the same

Discriminant validity reflects the ability of the questionnaire to distinguish between disease-

Content validity is appropriateness and redundancy of items and scales of the instrument.

Responsiveness is the sensitivity to change over time, i.e. the ability of the questionnaire to detect a change when it occurs. There are many responsiveness statistics, often it is measured by a standardized response mean- SRM ( > 0.8 - high sensitivity to change).

means it is suitable for assessment at the individual level (Bland & Altman, 1997).

or Spearman correlation coefficient or the intra-class correlation coefficient.

**2. Instruments for quality of life assessment** 

responsiveness and (iv) ease of use or feasibility.

validation study to make it statistically relevant.

Different levels of validity are distinguished.

affected groups of patients and those who are disease free.

**Reliability** 

**Validity** 

concept.

clinical expectations.

**Responsiveness** 

which can significantly affect the final quality of the questionnaire.

Fig. 2. Endoscopic view of nasal polyposis

Quality of life (QoL) is a unique personal experience that reflects not only health status but other factors in a patient's life which can only be described by each individual patient (Piccirillo, 2002). Quality of life may also be defined as the difference between expectations and experience (Calman, 1984). A part of the overall quality of life is health related quality of life (HRQoL), which is influenced by the health of patients and can be changed through treatment. Health related QoL may also be defined as those aspects of an individual's subjective experience that relate both directly and indirectly to health, disease, disability and impairment (Carr et al., 2001). The HRQoL is influenced by the patient's age, culture, expectations and physical and mental capabilities.

It has been shown that CRS has a significant impact on quality of life (Hopkins et al., 2009). Although the symptoms of rhinosinusitis are not life threatening they are associated with a dramatic reduction in QoL (van Oene, et al., 2007). Comparisons with other common chronic diseases revealed significantly lower scores for bodily pain and social functioning in patients with CRS compared to patients with congestive heart failure, angina, chronic obstructive pulmonary disease or back pain (Gliklich & Metson, 1995a).

When disease severity was measured using imaging and the endoscopic grading system, it was found that patients with nasal polyps (NP) appeared to have a more serious medical condition compared to CRS patients without polyps (Bhattacharyya, 2005); however, when measured using QoL instruments, and except for symptoms related to nasal congestion, patients with polyps seem to have a lighter disease burden than those without polyps (Soler & Smith, 2010).

Although there are many diagnostic methods currently available for evaluating sinonasal disease, it can not be said that the results clearly correlate with quality of life, as it is perceived by patients (Lund, 2001).

The way chronic rhinosinusitis affects daily life, from the patient's point of view, is far more important than the results of CT scans or the presence of a small polyp in an ethmoid cell (Schalek et al., 2010).

#### **2. Instruments for quality of life assessment**

The last two decades have been characterized by increasing interest in assessing the quality of life, which is related to the systematic development and validation of QoL questionnaires. Tools used to evaluate the quality of life are either generic health instruments for assessing general conditions or disease-specific questionnaires focused on symptoms of a disease.

Creation of a questionnaire is a relatively complex process involving several steps, each of which can significantly affect the final quality of the questionnaire.

The basic criteria which must be met by the questionnaire are: (i) reliability, (ii) validity, (iii) responsiveness and (iv) ease of use or feasibility.

Confirming that a particular instrument meets those criteria is a process called validation of the questionnaire. Validation studies must be performed on patients who have the same characteristics as the target population and there must be enough patients included in the validation study to make it statistically relevant.

#### **Reliability**

4 Peculiar Aspects of Rhinosinusitis

Quality of life (QoL) is a unique personal experience that reflects not only health status but other factors in a patient's life which can only be described by each individual patient (Piccirillo, 2002). Quality of life may also be defined as the difference between expectations and experience (Calman, 1984). A part of the overall quality of life is health related quality of life (HRQoL), which is influenced by the health of patients and can be changed through treatment. Health related QoL may also be defined as those aspects of an individual's subjective experience that relate both directly and indirectly to health, disease, disability and impairment (Carr et al., 2001). The HRQoL is influenced by the patient's age, culture,

It has been shown that CRS has a significant impact on quality of life (Hopkins et al., 2009). Although the symptoms of rhinosinusitis are not life threatening they are associated with a dramatic reduction in QoL (van Oene, et al., 2007). Comparisons with other common chronic diseases revealed significantly lower scores for bodily pain and social functioning in patients with CRS compared to patients with congestive heart failure, angina, chronic

When disease severity was measured using imaging and the endoscopic grading system, it was found that patients with nasal polyps (NP) appeared to have a more serious medical condition compared to CRS patients without polyps (Bhattacharyya, 2005); however, when measured using QoL instruments, and except for symptoms related to nasal congestion, patients with polyps seem to have a lighter disease burden than those without polyps (Soler

Although there are many diagnostic methods currently available for evaluating sinonasal disease, it can not be said that the results clearly correlate with quality of life, as it is

The way chronic rhinosinusitis affects daily life, from the patient's point of view, is far more important than the results of CT scans or the presence of a small polyp in an ethmoid cell

obstructive pulmonary disease or back pain (Gliklich & Metson, 1995a).

Fig. 2. Endoscopic view of nasal polyposis

expectations and physical and mental capabilities.

& Smith, 2010).

(Schalek et al., 2010).

perceived by patients (Lund, 2001).

Reliability concerns the extent to which the questionnaire is free of random or systematic error.

Internal reliability (consistency) reflects the way individual items relate to each other. This property is determined by calculating Cronbach's α (range 0 – 1). If scale has an alpha of at least 0.7 it is considered to be reliable for group level comparisons and a value of 0.9 or more means it is suitable for assessment at the individual level (Bland & Altman, 1997).

Test-retest reliability (reproducibility) reflects stability over time with repeated testing. Questionnaires with good reproducibility should give similar results under similar conditions. This property of the questionnaire may be tested using the t- test and a Pearson or Spearman correlation coefficient or the intra-class correlation coefficient.

#### **Validity**

The questionnaire can be called valid when it measures what it is supposed to measure. Different levels of validity are distinguished.

Construct validity means that the instrument behaves according to an underlying hypothesis, i.e. the measured variables behave in a consistent way relative to theoretical and clinical expectations.

Convergent validity reflects the degree of correlation with other instruments of the same concept.

Discriminant validity reflects the ability of the questionnaire to distinguish between diseaseaffected groups of patients and those who are disease free.

Content validity is appropriateness and redundancy of items and scales of the instrument.

#### **Responsiveness**

Responsiveness is the sensitivity to change over time, i.e. the ability of the questionnaire to detect a change when it occurs. There are many responsiveness statistics, often it is measured by a standardized response mean- SRM ( > 0.8 - high sensitivity to change).

Rhinosinusitis - Its Impact on Quality of Life 7

**Fairley NSS** 1993 English 12 0-3 yes yes yes yes 5

**SNOT-16** 1999 English 16 0-5 no yes yes yes 5

**RSDI** 1997 English, Turkish 30 0-5 yes yes No data No data 5

**RhinoQoL** 2005 English, French 17 1-5 no yes yes yes 7 **RSI** 2003 English 20 0-5 yes No data yes yes 5 Table 1. Properties of disease-specific QoL questionnaires (MS of CRS-major symptoms of

**Rhinosinusitis Outcome Measure (RSOM-31), Sinonasal Outcome Test-16 (SNOT-16),** 

The RSOM-31 was developed by Piccirillo, in 1995, and contains 31 disease-specific and general items. A condensed version of this questionnaire is the SNOT-20 which has also been validated (Piccirillo et al., 2002). This questionnaire contains 20 questions, which can be divided into five subgroups (nasal symptoms, paranasal symptoms, sleep-related symptoms, and social and emotional impairment). Patients rate individual items on a sixpoint scale (0 - no problem, 5 - most serious problem) and in addition, they can mark which of the five items they consider to be the most important. SNOT-20 is one of the most

Addition questions, regarding nasal obstruction and disorders of smell, were added to SNOT-20 to produce the SNOT-22 (Figure 3). The added questions are very significant because problems with olfaction and nasal obstruction are directly related to the quality of life of patients with CRS and therapeutic interventions are designed to positively influence these two annoying symptoms. The Royal College of Surgeons of England used SNOT-22 in a National Comparative Audit of Surgery for nasal polyposis and chronic rhinosinusitis. Data for this study came from 3128 patients using questionnaire SNOT-22; the questionnaire was found easy to use and provided good discriminant validity (Hopkins et al., 2006). In 2009 the SNOT-22 was validated and recommended for routine clinical practice (Hopkins et

Also a 16-item version of the SNOT questionnaire has been validated. This version proved to have excellent discriminant and construct-related validity, but it does not cover all major

**Sino-nasal outcome test-22 questionnaire** 

Below you will find a list of symptoms and social/emotional consequences of your nasal disorder. We would like to know more about these problems and would appreciate you

**Name: Date:** 

frequently used tools and is particularly popular for its high patient compliance.

1-

**MS of** 

**CRS Reliability Validity** 

Japan 20 0-5 no yes yes yes 7

Danish 22 0-5 yes yes yes yes 7

Norwegian 6 0-100 no yes yes yes 5

5,VAS yes yes yes yes 20

**Responsiveness** 

**Completion (min)** 

**Instrument Developed Language Items Scale** 

English, German,

English, Swedish, Chnese, Czech,

English, Chinese,

CRS symptoms and has not gain general acceptance.

**RSOM-31** 1995 English 31

**SNOT-20** 2002

**SNOT-22** 2003

**CSS** 1995

**SNOT-20 and SNOT-22** 

CRS)

al., 2009).

#### **Feasibility**

Feasibility depends on a patient's understanding and willingness to complete the questionnaire. Complex, time-consuming questionnaires are usually not well received by patients, which will affect the meaningfulness of results. The feasibility can be assessed by pretesting with real patients in order to get feedback.

#### **2.1 General health instruments**

General (generic) health instruments are applicable in different diseases that can be compared regarding their impact on QoL. The following overview includes only a few of the most commonly used questionnaires, which are also frequently used to assess QoL in patients with CRS.

#### **Short form 36 health survey (SF-36)**

This questionnaire is one of the most widely used general QoL instruments. It consists of 36 items forming 8 scales (Ware & Sherbourne, 1992). The scales are: physical function, role physical, bodily pain, general health, vitality, social function, role emotional, and mental health.

#### **Short form 12 health instrument (SF-12)**

This is a shortened version of the SF-36 that contains questions from all eight SF-36 scales. Two summary scales are constructed: (i) physical and (ii) mental summary scores.

#### **Glasgow benefit inventory (GBI)**

This questionnaire was developed in 1996 (Robinson et al., 1996) and is designed to measure outcomes of surgical procedures in the field of otorhinolaryngology. The questionnaire consists of 18 items assessing the quality of life. Patients evaluate each item using the 5 grade scale: extremely positive, positive, no change, negative, extremely negative. GBI overall score the ranges from −100 to +100. Positive values indicate improvement, 0 no change of the state and negative values indicate deterioration of QoL.

#### **2.2 Disease-specific questionnaires**

This type of tool is frequently used to assess QoL in patients with CRS. Compared with general instruments they are able to capture symptoms in greater detail and are more sensitive in detecting changes after therapeutic intervention (Hopkins et al., 2009). The most frequently used validated questionnaires are listed below and their properties are summarized in Table 1.

#### **Nasal symptom questionnaire (also Fairley nasal symptom score)**

This instrument was the first (1993) validated QoL questionnaire for patients with sinonasal disease. The questionnaire consists of 12 items rated on a four-point scale (0-3). A validation study was performed on 411 patients with very good results for reliability and validity (Fairley et al., 1993). This questionnaire is not widely used, possibly due to a paucity of general health correlations.

Feasibility depends on a patient's understanding and willingness to complete the questionnaire. Complex, time-consuming questionnaires are usually not well received by patients, which will affect the meaningfulness of results. The feasibility can be assessed by

General (generic) health instruments are applicable in different diseases that can be compared regarding their impact on QoL. The following overview includes only a few of the most commonly used questionnaires, which are also frequently used to assess QoL in

This questionnaire is one of the most widely used general QoL instruments. It consists of 36 items forming 8 scales (Ware & Sherbourne, 1992). The scales are: physical function, role physical, bodily pain, general health, vitality, social function, role emotional, and mental

This is a shortened version of the SF-36 that contains questions from all eight SF-36 scales.

This questionnaire was developed in 1996 (Robinson et al., 1996) and is designed to measure outcomes of surgical procedures in the field of otorhinolaryngology. The questionnaire consists of 18 items assessing the quality of life. Patients evaluate each item using the 5 grade scale: extremely positive, positive, no change, negative, extremely negative. GBI overall score the ranges from −100 to +100. Positive values indicate improvement, 0 no

This type of tool is frequently used to assess QoL in patients with CRS. Compared with general instruments they are able to capture symptoms in greater detail and are more sensitive in detecting changes after therapeutic intervention (Hopkins et al., 2009). The most frequently used validated questionnaires are listed below and their properties are

This instrument was the first (1993) validated QoL questionnaire for patients with sinonasal disease. The questionnaire consists of 12 items rated on a four-point scale (0-3). A validation study was performed on 411 patients with very good results for reliability and validity (Fairley et al., 1993). This questionnaire is not widely used, possibly due to a paucity of

Two summary scales are constructed: (i) physical and (ii) mental summary scores.

change of the state and negative values indicate deterioration of QoL.

**Nasal symptom questionnaire (also Fairley nasal symptom score)** 

pretesting with real patients in order to get feedback.

**2.1 General health instruments** 

**Short form 36 health survey (SF-36)** 

**Short form 12 health instrument (SF-12)** 

**Glasgow benefit inventory (GBI)** 

**2.2 Disease-specific questionnaires** 

summarized in Table 1.

general health correlations.

patients with CRS.

health.

**Feasibility** 


Table 1. Properties of disease-specific QoL questionnaires (MS of CRS-major symptoms of CRS)

#### **Rhinosinusitis Outcome Measure (RSOM-31), Sinonasal Outcome Test-16 (SNOT-16), SNOT-20 and SNOT-22**

The RSOM-31 was developed by Piccirillo, in 1995, and contains 31 disease-specific and general items. A condensed version of this questionnaire is the SNOT-20 which has also been validated (Piccirillo et al., 2002). This questionnaire contains 20 questions, which can be divided into five subgroups (nasal symptoms, paranasal symptoms, sleep-related symptoms, and social and emotional impairment). Patients rate individual items on a sixpoint scale (0 - no problem, 5 - most serious problem) and in addition, they can mark which of the five items they consider to be the most important. SNOT-20 is one of the most frequently used tools and is particularly popular for its high patient compliance.

Addition questions, regarding nasal obstruction and disorders of smell, were added to SNOT-20 to produce the SNOT-22 (Figure 3). The added questions are very significant because problems with olfaction and nasal obstruction are directly related to the quality of life of patients with CRS and therapeutic interventions are designed to positively influence these two annoying symptoms. The Royal College of Surgeons of England used SNOT-22 in a National Comparative Audit of Surgery for nasal polyposis and chronic rhinosinusitis. Data for this study came from 3128 patients using questionnaire SNOT-22; the questionnaire was found easy to use and provided good discriminant validity (Hopkins et al., 2006). In 2009 the SNOT-22 was validated and recommended for routine clinical practice (Hopkins et al., 2009).

Also a 16-item version of the SNOT questionnaire has been validated. This version proved to have excellent discriminant and construct-related validity, but it does not cover all major CRS symptoms and has not gain general acceptance.

#### **Sino-nasal outcome test-22 questionnaire**

#### **Name: Date:**

Below you will find a list of symptoms and social/emotional consequences of your nasal disorder. We would like to know more about these problems and would appreciate you

Rhinosinusitis - Its Impact on Quality of Life 9

0 weeks 1-2 weeks 3-4 weeks 7-8 weeks

0 weeks 1-2 weeks 3-4 weeks 7-8 weeks

0 weeks 1-2 weeks 3-4 weeks 7-8 weeks

0 weeks 1-2 weeks 3-4 weeks 7-8 weeks

0 weeks 1-2 weeks 3-4 weeks 7-8 weeks

0 weeks 1-2 weeks 3-4 weeks 7-8 weeks

The questionnaire (Figure 5) was developed in 1997 by Benninger and Senior (Benninger & Senior, 1997). RSDI uses three subscales (emotional, physical and functional) to combine measurements of general health status and disease-specific QoL. The questionnaire is characterized by excellent test-retest reliability, good internal consistency, good construct,

c. Nasal congestion or difficulty breathing through the your nose

c. Sinus medications in pill form (such as antihistamines,deconestants)

1. During the past 8 weeks, how many weeks have you had:

2. During the past 8 weeks, how many weeks have you taken

**The rhinosinusitis disability index (RSDI) domains and items** 

3. The pain in my eyes makes it difficult for me to read

8. Food does not taste good because of my change in smell 9. My frequent sniffing is irritating to my friends and family

11. I have difficulty with exertion due to my nasal obstruction

14. Because of my problem I restrict my recreational activities

6. Straining increases or worsens my problem 7. I am inconvenienced by my chronic runny nose

10. Because of my problem I don't sleep well

Because of my problem I feel handicapped

12. My sexual activity is affected by my problem

The pain or pressure in my face makes it difficult for me to concentrate

4. I have difficulty stooping over to lift objects because of face pressure

5. Because of my problem I have difficulty with strenuous yard work and housework

13. Because of my problem I feel restricted in performance of my routine daily activities

a. Sinus headaches, facial pain or pressure

b. Nasal sprays prescribed by your doctor

b. Nasal drainage or postnasal drip

**Chronic Sinusitis Survey-CSS** 

a. Antibiotics

Fig. 4. Chronic Sinusitis Survey-CSS

discriminant and content validity.

**Physical** 

**Functional**

**Rhinosinusitis disability index (RSDI)** 

answering the following question 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.


Fig. 3. The SNOT-22 questionnaire

#### **Chronic sinusitis survey (CSS)**

One of the most frequently used instruments was developed by Gliklich and Metson in 1995 (Gliklich & Metson, 1995b). The CSS consists of two parts, symptom-based and medicationbased (Figure 4). When using the CSS, patients do not assess the severity of symptoms, but their duration, which, together with a limited number of questions can be regarded as a disadvantage (Morley & Sharp, 2006). Furthermore the questionnaire does not include any questions related to olfaction.

#### **Chronic Sinusitis Survey-CSS**

8 Peculiar Aspects of Rhinosinusitis

answering the following question 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

> **Very mild problem**

1. Need to blow nose 0 12345 2. Sneezing 0 12345 3. Runny nose 0 12345 4. Cough 0 12345

6. Thick nasal discharge 0 12345 7. Ear fullness 0 12345 8. Dizziness 0 12345 9. Ear pain 0 12345 10. Facial pain/pressure 0 12345 11. Difficulty falling asleep 0 12345 12. Waking up at night 0 12345 13. Lack of a good night's sleep 0 12345 14. Waking up tired 0 12345 15. Fatigue 0 12345 16. Reduced productivity 0 12345 17. Reduced concentration 0 12345

irritable <sup>0</sup> <sup>1</sup> <sup>2</sup> <sup>3</sup> <sup>4</sup> <sup>5</sup> 19. Sad 0 12345 20. Embarrassed 0 12345 21. Sense of taste/smell 0 12345

nose <sup>0</sup> <sup>1</sup> <sup>2</sup> <sup>3</sup> <sup>4</sup> <sup>5</sup>

One of the most frequently used instruments was developed by Gliklich and Metson in 1995 (Gliklich & Metson, 1995b). The CSS consists of two parts, symptom-based and medicationbased (Figure 4). When using the CSS, patients do not assess the severity of symptoms, but their duration, which, together with a limited number of questions can be regarded as a disadvantage (Morley & Sharp, 2006). Furthermore the questionnaire does not include any

**Mild or slight problem**

0 1 2 3 4 5

**Moderate problem**

**Severe problem**

**Problem as bad as it can be**

they have been over the past two weeks. Thank you for your participation.

**No problem**

**A:** Considering how severe the problem is when you experience it and how frequently it happens, please rate each item below on how 'bad' it is by circling the number that corresponds with how you feel

using this scale

5. Post nasal discharge (dripping at the back of

18. Frustrated/restless/

22. Blockage/congestion of

Fig. 3. The SNOT-22 questionnaire

**Chronic sinusitis survey (CSS)** 

questions related to olfaction.

your nose)


Fig. 4. Chronic Sinusitis Survey-CSS

#### **Rhinosinusitis disability index (RSDI)**

The questionnaire (Figure 5) was developed in 1997 by Benninger and Senior (Benninger & Senior, 1997). RSDI uses three subscales (emotional, physical and functional) to combine measurements of general health status and disease-specific QoL. The questionnaire is characterized by excellent test-retest reliability, good internal consistency, good construct, discriminant and content validity.

#### **The rhinosinusitis disability index (RSDI) domains and items**

#### **Physical**

The pain or pressure in my face makes it difficult for me to concentrate


#### **Functional**

Because of my problem I feel handicapped


Rhinosinusitis - Its Impact on Quality of Life 11

Using statistical constructs, the minimal important difference has been defined as greater than half a standard deviation of the baseline QoL value for the given population. Recently Soler and Smith (Soler & Smith, 2010) summarized minimal important differences for

**Questionnaire Score Range MCID** RSDI total 0-120 ≥10.35 RSDI Physical 0-44 ≥3.80 RSDI Functional 0-36 ≥3.45 RSDI Emotionals 0-40 ≥4.20 CSS total 0-100 ≥9.75 CSS Symptoms 0-100 ≥13.25 CSS Medications 0-100 ≥12.60 SNOT-22 0-110 ≥8.90 Table 2. Minimal important differences (MCID) for disease-specific QoL questionnaires

Another important issue may be how to choose a particular tool for evaluating QoL in patients, regarding assessment of therapeutic effects or comparison of two or more

A review of Chester and Sindwani, from 2007 (Chester & Sindwani, 2007), demonstrates that of the 18 QoL instruments used to evaluate the outcomes of endoscopic sinus surgery (ESS), only 5 were used more than twice: CSS (12 studies), SNOT-20 (11 studies), SF-36 (10 studies),

Gill et al. proposed three recommendations to improve the measurement of quality of life: (i) use of global ratings, ideally one for general QoL and one for disease-specific QoL; (ii) severity and importance of symptoms must be rated; (iii) a possibility for patients to add other annoying symptoms (Gill & Feinstein, 1994). This recommendation takes into account the study of Morley et al, which suggests the SNOT-22 was the best tool for treatment evaluation, especially the after ESS (Morley & Sharp, 2006). This study was published in 2006, before the SNOT-22 had been validated. SNOT-22 fully corresponds to the recommendation of Gill and his co-workers – it includes questions regarding sinonasal symptoms, covers the major symptoms of CRS and also includes questions assessing the overall quality of life. It allows patients to easily assess the severity of symptoms and select the symptoms that are most important from their point of view. In addition, patients have the opportunity to present other troublesome symptoms that are not listed in the

The study of van Oene et al. focused on the issue of quality of disease specific QoL instruments (van Oene, 2007). Only questionnaires that clearly meet the following criteria were included in the study: (i) the questionnaire must be designed for adults with CRS and (ii) must cover all three aspects of HRQL-physical, functional and psychosocial. Parameters of the questionnaire, i.e. construction, description, feasibility, validation study and psychometric properties are all ranked using a points system. Criteria were fulfilled only for

disease specific QoL instruments (Table 2).

(Soler & Smith, 2010)

questionnaire.

therapeutic modalities on QoL.

RSI (4 Studies) and RSDI (3 studies).


#### **Emotional**

Because of my problem I feel stressed in relationships with friends and family


Fig. 5. Rhinosinusitis disability index- RSDI

#### **Rhinosinusitis symptom inventory (RSI)**

One of the more recent questionnaires (Bhattacharyya, 2005) was developed mainly to evaluate improvement of QoL after treatment. The instrument assesses major and minor symptoms of CRS on a six-point scale. Simultaneously, medication use, doctor visits and work absences (directly related to CRS) are recorded.

#### **Rhinosinusitis quality of life survey (RhinoQoL)**

This 17-item questionnaire is based on the CSS and the questioning system of both instruments is identical. The RhinoQoL does not contain questions regarding olfaction disturbances, which is one of major symptoms of CRS. The questionnaire was validated by Atlas on a population of 50 patients (Atlas et al., 2005).

There is also one important question concerning QoL measurement: How is a clinically significant change of health-related QoL defined? Statistically significant improvement does not always mean clinically relevant improvement as perceived by an individual patient. A concept called the minimal important difference helps address this problem. It is defined as the smallest change in QoL that patients perceive as beneficial, in the absence of side effects or excessive cost (Juniper at al., 1994). Prior studies measuring acute pain have shown that the minimal important difference for acute pain is between 0.9 and 1.3 on a 10-point scale. Recent studies reporting scaled symptom scores by Ling and Kountakis (Ling & Kountakis, 2007) and Bhattacharyya (Bhattacharyya, 2005) easily reach this threshold of clinical relevance. For the general health instrument SF-36, 10 to 12.5 points (100-point scale) represents the minimum change believed to be clinically relevant (Wyrwick et al., 2005).

20. Because of my problem I find it difficult to focus my attention away from my

29. My problem places stress on my relationships with members of my family or friends

One of the more recent questionnaires (Bhattacharyya, 2005) was developed mainly to evaluate improvement of QoL after treatment. The instrument assesses major and minor symptoms of CRS on a six-point scale. Simultaneously, medication use, doctor visits and

This 17-item questionnaire is based on the CSS and the questioning system of both instruments is identical. The RhinoQoL does not contain questions regarding olfaction disturbances, which is one of major symptoms of CRS. The questionnaire was validated by

There is also one important question concerning QoL measurement: How is a clinically significant change of health-related QoL defined? Statistically significant improvement does not always mean clinically relevant improvement as perceived by an individual patient. A concept called the minimal important difference helps address this problem. It is defined as the smallest change in QoL that patients perceive as beneficial, in the absence of side effects or excessive cost (Juniper at al., 1994). Prior studies measuring acute pain have shown that the minimal important difference for acute pain is between 0.9 and 1.3 on a 10-point scale. Recent studies reporting scaled symptom scores by Ling and Kountakis (Ling & Kountakis, 2007) and Bhattacharyya (Bhattacharyya, 2005) easily reach this threshold of clinical relevance. For the general health instrument SF-36, 10 to 12.5 points (100-point scale) represents the minimum change believed to be clinically relevant (Wyrwick et al., 2005).

Because of my problem I feel stressed in relationships with friends and family

15. Because of my problem I feel frustrated 16. Because of my problem I feel fatigued 17. Because of my problem I avoid traveling

problem and on other things

21. Because of my problem I feel confused

28. Because of my problem I am depressed

Fig. 5. Rhinosinusitis disability index- RSDI

**Rhinosinusitis symptom inventory (RSI)** 

work absences (directly related to CRS) are recorded. **Rhinosinusitis quality of life survey (RhinoQoL)** 

Atlas on a population of 50 patients (Atlas et al., 2005).

**Emotional**

18. Because of my problem I miss work or social activities 19. My outlook on the world is affected by my problem

22. Because of my problem I have difficulty paying attention 23. Because of my problem I avoid being around people 24. Because of my problem I am frequently angry 25. Because of my problem I do not like to socialize 26. Because of my problem I frequently feel tense 27. Because of my problem I frequently feel irritable

Using statistical constructs, the minimal important difference has been defined as greater than half a standard deviation of the baseline QoL value for the given population. Recently Soler and Smith (Soler & Smith, 2010) summarized minimal important differences for disease specific QoL instruments (Table 2).


Table 2. Minimal important differences (MCID) for disease-specific QoL questionnaires (Soler & Smith, 2010)

Another important issue may be how to choose a particular tool for evaluating QoL in patients, regarding assessment of therapeutic effects or comparison of two or more therapeutic modalities on QoL.

A review of Chester and Sindwani, from 2007 (Chester & Sindwani, 2007), demonstrates that of the 18 QoL instruments used to evaluate the outcomes of endoscopic sinus surgery (ESS), only 5 were used more than twice: CSS (12 studies), SNOT-20 (11 studies), SF-36 (10 studies), RSI (4 Studies) and RSDI (3 studies).

Gill et al. proposed three recommendations to improve the measurement of quality of life: (i) use of global ratings, ideally one for general QoL and one for disease-specific QoL; (ii) severity and importance of symptoms must be rated; (iii) a possibility for patients to add other annoying symptoms (Gill & Feinstein, 1994). This recommendation takes into account the study of Morley et al, which suggests the SNOT-22 was the best tool for treatment evaluation, especially the after ESS (Morley & Sharp, 2006). This study was published in 2006, before the SNOT-22 had been validated. SNOT-22 fully corresponds to the recommendation of Gill and his co-workers – it includes questions regarding sinonasal symptoms, covers the major symptoms of CRS and also includes questions assessing the overall quality of life. It allows patients to easily assess the severity of symptoms and select the symptoms that are most important from their point of view. In addition, patients have the opportunity to present other troublesome symptoms that are not listed in the questionnaire.

The study of van Oene et al. focused on the issue of quality of disease specific QoL instruments (van Oene, 2007). Only questionnaires that clearly meet the following criteria were included in the study: (i) the questionnaire must be designed for adults with CRS and (ii) must cover all three aspects of HRQL-physical, functional and psychosocial. Parameters of the questionnaire, i.e. construction, description, feasibility, validation study and psychometric properties are all ranked using a points system. Criteria were fulfilled only for

Rhinosinusitis - Its Impact on Quality of Life 13

Brandsted and Sindwani demonstrated that 25% of consecutively diagnosed CRS patients were also treated for depression, which is higher than in the general population (10 – 16%) (Brandsted & Sindwani, 2007). In this study the authors also compared the QoL of CRS patients with depression to a control group of CRS patients without depression. The results showed significantly poorer disease-specific and overall QoL scores in depressed CRS

Additionally, Mace reported lower preoperative and postoperative QoL scores in CRS patients with depression compared to non-depressed patients but with comparable

Wasan identified high levels of anxiety and depression in patients who undergo evaluation for CRS using the Rhinosinusitis Symptom Inventory and the Hospital Anxiety and

In conclusion depression is frequently associated with CRS and contributes to lower overall QoL in CRS patients, although it is likely that the diseases are independent (Rudmik &

Sexual activity is another important aspect of QoL. It is not hard to imagine that patients with nasal obstruction, discharge, reduced olfaction, facial pressure and sleep deficits would have an altered sex life compared to healthy controls. The Rhinosinusitis Disability Index (RSDI) is a disease-specific QoL questionnaire which has one question which directly

There are few studies dealing with sexual function in patients with sinonasal disease. Two trials investigating the influence of allergic rhinitis on sexual function, demonstrated lower scores for sexual function in patients suffering from allergic rhinitis compared those without sinonasal disease or with non-allergic rhinitis or anatomical obstruction. Although CRS was not specially evaluated in these studies, the results suggest that CRS may have similar negative effects on sexual function. (Benninger & Benninger, 2009;

Benninger, using the Rhinosinusitis Disability Index, has provided data (on level of evidence IIIb) showing that functional endoscopic surgery for CRS has a positive impact on

Smell disturbance is a common symptom affecting 61 – 83% of patients with CRS. Patient with olfactory impairment often report problems preparing food, decreased appetite, and a decreased sense of self-hygiene. Patients are also not able to detect spoiled foods and safety hazards such as smoke, chemicals, and gas leaks (Litvack et al., 2009). Moreover there are some professions dependent on good olfactory function (chefs, professional tasters, fireman,

plumbers, etc.) and loss of smell in those occupations can be debilitating.

addresses the impact of sinonasal disease on sexual function.

improvements after endoscopic sinus surgery in both groups (Mace et al., 2008).

**3.2 Depression** 

Smith, 2011).

**3.3 Sexual dysfunction** 

Kirmaz et al., 2005).

**3.4 Olfactory dysfunction** 

sexual function (Benninger et al., 2010).

patients (both pre- and postoperatively).

Depression Scale (Wasan et al., 2007).

RSOM-31, SNOT-16, SNOT-20, RSDI and RhinoQoL. The highest scores were achieved by RSOM-31 and SNOT-20. The questionnaire SNOT-22 was not enrolled because it had not yet been validated. CSS and RSDI did not meet the definition of a HRQL questionnaire. The authors point out the importance of the relationship between the characteristics of the questionnaire and the purpose for which it should be used. For example, for use in clinical practice, reliability of the instrument is essential, while for the purposes of clinical research, responsiveness (for longitudinal study) or discriminant validity (for cross-sectional studies) may be critical.

### **3. How the Rhinosinusitis afffects the quality of life**

Symptoms of CRS can be disabling and lead to significant impairment of QoL. The most common reported symptom in CRS is nasal congestion/obstruction (Bhattacharyya, 2003). This symptom is accompanied by nasal discharge (anterior or posterior), reduction or loss of olfaction, facial pain or pressure and headaches, which were reported as the most disabling (Soler et al., 2008). These symptoms can impact all activities (work, leisure and sleep) of CRS patients. It is reasonable to expect that individual CRS symptoms can result in more complex problems such as sleep disturbances, psychological disorders (changes in mood, depression, and anxiety), fatigue, and sexual dysfunction.

#### **3.1 Sleep disturbance and fatigue**

Although sleep impairment has been studied less in CRS compared to allergic rhinitis, it is obvious that CRS is associated with this problem as well (Craig et al., 2008).

Also, a recent study by Benninger demonstrated that patients with CRS have significantly reduced sleep activity scores on the Rhinosinusitis Disability Index (Benninger et al., 2010).

In a population-based, case-control study, patients with nasal polyposis had a 2-fold higher risk of sleep disturbances than controls (Serrano et al., 2005). This is further supported by a study that approached it from the other way around; in a study of general medical outpatients, an increased prevalence of CRS symptoms in patients with unexplained chronic fatigue was observed (Chester, 2003). Thus, sleep impairment is a significant issue for CRS patients and questions regarding quality of the sleep have been incorporated in many disease-specific QoL questionnaires.

Nasal congestion/obstruction is thought to be a major cause of sleep impairment. This bothersome CRS symptom is usually worse at night, which is result of the lower position of the patient's head. Additionally, the overnight decline of serum cortisol levels can contribute to night-time nasal congestion. Nasal obstruction in healthy subjects leads to apneas and hypopneas (Suratt et al., 1986). Other CRS symptoms (e.g. discharge, facial pain and headache) can also reduce sleep quality.

It is also assumed that inflammatory mediators of CRS probably play a direct role in sleep disturbances (Craig et al., 2008).

There is a clear relationship between sleep impairment and daily fatigue. Poorly sleeping patients would be expected to experience fatigue and improved sleep should have a positive influence on fatigue.

#### **3.2 Depression**

12 Peculiar Aspects of Rhinosinusitis

RSOM-31, SNOT-16, SNOT-20, RSDI and RhinoQoL. The highest scores were achieved by RSOM-31 and SNOT-20. The questionnaire SNOT-22 was not enrolled because it had not yet been validated. CSS and RSDI did not meet the definition of a HRQL questionnaire. The authors point out the importance of the relationship between the characteristics of the questionnaire and the purpose for which it should be used. For example, for use in clinical practice, reliability of the instrument is essential, while for the purposes of clinical research, responsiveness (for longitudinal study) or discriminant validity (for cross-sectional studies)

Symptoms of CRS can be disabling and lead to significant impairment of QoL. The most common reported symptom in CRS is nasal congestion/obstruction (Bhattacharyya, 2003). This symptom is accompanied by nasal discharge (anterior or posterior), reduction or loss of olfaction, facial pain or pressure and headaches, which were reported as the most disabling (Soler et al., 2008). These symptoms can impact all activities (work, leisure and sleep) of CRS patients. It is reasonable to expect that individual CRS symptoms can result in more complex problems such as sleep disturbances, psychological disorders (changes in mood,

Although sleep impairment has been studied less in CRS compared to allergic rhinitis, it is

Also, a recent study by Benninger demonstrated that patients with CRS have significantly reduced sleep activity scores on the Rhinosinusitis Disability Index (Benninger et al., 2010). In a population-based, case-control study, patients with nasal polyposis had a 2-fold higher risk of sleep disturbances than controls (Serrano et al., 2005). This is further supported by a study that approached it from the other way around; in a study of general medical outpatients, an increased prevalence of CRS symptoms in patients with unexplained chronic fatigue was observed (Chester, 2003). Thus, sleep impairment is a significant issue for CRS patients and questions regarding quality of the sleep have been incorporated in many

Nasal congestion/obstruction is thought to be a major cause of sleep impairment. This bothersome CRS symptom is usually worse at night, which is result of the lower position of the patient's head. Additionally, the overnight decline of serum cortisol levels can contribute to night-time nasal congestion. Nasal obstruction in healthy subjects leads to apneas and hypopneas (Suratt et al., 1986). Other CRS symptoms (e.g. discharge, facial pain

It is also assumed that inflammatory mediators of CRS probably play a direct role in sleep

There is a clear relationship between sleep impairment and daily fatigue. Poorly sleeping patients would be expected to experience fatigue and improved sleep should have a positive

obvious that CRS is associated with this problem as well (Craig et al., 2008).

**3. How the Rhinosinusitis afffects the quality of life** 

depression, and anxiety), fatigue, and sexual dysfunction.

**3.1 Sleep disturbance and fatigue** 

disease-specific QoL questionnaires.

disturbances (Craig et al., 2008).

influence on fatigue.

and headache) can also reduce sleep quality.

may be critical.

Brandsted and Sindwani demonstrated that 25% of consecutively diagnosed CRS patients were also treated for depression, which is higher than in the general population (10 – 16%) (Brandsted & Sindwani, 2007). In this study the authors also compared the QoL of CRS patients with depression to a control group of CRS patients without depression. The results showed significantly poorer disease-specific and overall QoL scores in depressed CRS patients (both pre- and postoperatively).

Additionally, Mace reported lower preoperative and postoperative QoL scores in CRS patients with depression compared to non-depressed patients but with comparable improvements after endoscopic sinus surgery in both groups (Mace et al., 2008).

Wasan identified high levels of anxiety and depression in patients who undergo evaluation for CRS using the Rhinosinusitis Symptom Inventory and the Hospital Anxiety and Depression Scale (Wasan et al., 2007).

In conclusion depression is frequently associated with CRS and contributes to lower overall QoL in CRS patients, although it is likely that the diseases are independent (Rudmik & Smith, 2011).

#### **3.3 Sexual dysfunction**

Sexual activity is another important aspect of QoL. It is not hard to imagine that patients with nasal obstruction, discharge, reduced olfaction, facial pressure and sleep deficits would have an altered sex life compared to healthy controls. The Rhinosinusitis Disability Index (RSDI) is a disease-specific QoL questionnaire which has one question which directly addresses the impact of sinonasal disease on sexual function.

There are few studies dealing with sexual function in patients with sinonasal disease. Two trials investigating the influence of allergic rhinitis on sexual function, demonstrated lower scores for sexual function in patients suffering from allergic rhinitis compared those without sinonasal disease or with non-allergic rhinitis or anatomical obstruction. Although CRS was not specially evaluated in these studies, the results suggest that CRS may have similar negative effects on sexual function. (Benninger & Benninger, 2009; Kirmaz et al., 2005).

Benninger, using the Rhinosinusitis Disability Index, has provided data (on level of evidence IIIb) showing that functional endoscopic surgery for CRS has a positive impact on sexual function (Benninger et al., 2010).

#### **3.4 Olfactory dysfunction**

Smell disturbance is a common symptom affecting 61 – 83% of patients with CRS. Patient with olfactory impairment often report problems preparing food, decreased appetite, and a decreased sense of self-hygiene. Patients are also not able to detect spoiled foods and safety hazards such as smoke, chemicals, and gas leaks (Litvack et al., 2009). Moreover there are some professions dependent on good olfactory function (chefs, professional tasters, fireman, plumbers, etc.) and loss of smell in those occupations can be debilitating.

Rhinosinusitis - Its Impact on Quality of Life 15

There is a relative lack of documentation regarding improvement of QoL after medical treatment of CRS. Similarly, there are insufficient data regarding comparisons of effects of different medical and surgical treatments on QoL. The lack of well-formed, prospective, randomized, controlled trials, concerning medical treatment can lead to the idea that surgical treatment of CRS has a better effect on QoL than medical treatments (Ragab et al.,

Also the fact that surgical treatment should only be indicated for patients with a more severe course of disease, resistant to medical treatment, makes any comparison of effect of

A study by Lund et al. (Lund et al., 2004) showed no significant difference in the score on a disease-specific questionnaire (Chronic Sinusitis survey-CSS) in patients with CRS without NP, treated for 20 months with intranasal budesonide compared to placebo. In the same study, a significant difference between the two groups was found only in the general health subscale of SF-36 General Health Questionnaire, but no significant difference in the other

Alobid et al. (Alobid et al., 2006) assessed the effect of treatment with oral and intranasal steroids on the quality of life of patients with CRS with nasal polyposis. The patients, after a short-course of oral prednisone, demonstrated a significant improvement in QoL in all domains (compared with base line and the control group) using the general-health QoL instrument SF-36. The improvement was sustained by intranasal steroids after 12, 24 and 48 months. The study was conducted on 60 patients who were compared with a control group

The same group (Alobid et al., 2005) compared, in a randomized trial, medical treatment (53 patients, oral prednisone for two weeks) and surgical treatment (56 patients undergoing ESS) of CRS with nasal polyps. Both groups received intranasal budesonide for 12 months after intervention. At 6 and 12 months, a significant improvement in the QoL, measured

Ragab et al. in a recent prospective, randomized, controlled trial evaluated and compared the effect of medical and surgical treatment of CRS on QoL (Ragab et al., 2010). The study was conducted on ninety CRS patients with and without polyps randomized into medical and surgical groups. The medical group was treated with erythromycin (12 week course), alkaline nasal douches and intranasal steroids. In addition, 3 patients with polyps were prescribed a course of short-term oral steroids. The extent of endoscopic sinus surgery was tailored to the extent of the disease in the surgical group. Following ESS, all patients were prescribed a two-week course of erythromycin and alkaline douches and intranasal steroids as long-term therapy. Quality of life was assessed using the disease specific instrument SNOT-22 and the general health instrument SF-36 before randomization and after 6 and 12 months. A significant improvement in the SNOT score was recorded, without statistically significant difference between medical and surgical group after 6 and 12 month. Also, the SF-36 demonstrated a significant improvement in the QoL in seven out of eight domains. Only physical functioning did not change significantly from the baseline. Furthermore this study does not support the fact that polyps represent a poor prognostic factor for efficacy of treatment, as has been suggested in previous studies (Kennedy, 1992; Sobol et al., 1998).

again using the SF-36, was observed in both the medical and surgical group.

2010).

treatment on QoL more complicated.

subscales were observed.

(18 patients) without treatment.

Although humans and other primates are regarded as primarily "optical animals" with a relatively undeveloped sense of smell, recent studies indicate that humans seem to use olfactory communication, particularly, in interpersonal relationships (Grammer et al., 2005). Perception of substances such as pheromones may modulate changes in interpersonal perception and individual mood, behavior and physiology (Havlicek et al., 2010).

### **4. Effect of rhinosinusitis treatment on quality of life**

The effect of surgical treatment on QoL in patients with CRS has been documented fairly well (Metson & Glicklich, 1998; Salhab et al., 2004; Smith et al., 2005; Ling & Kountakis, 2007).

A review by Smith et al. assessed the effect of surgical treatment of CRS on symptoms and QoL in patients with CRS. Improvement of quality of life or symptoms was demonstrated in all 45 enrolled studies, 11 studies were prospective, and in five, a validated QoL questionnaire was used (Smith. et al., 2005).

Ling and Kountakis (Ling & Kountakis, 2007) showed a greater than 80% improvement in symptoms of CRS from baseline, when measured using a visual analogue scale, 12 months after ESS. These authors also used SNOT-22 scores that showed improvement by as much as 77%, postoperatively.

Improvement of both major and minor symptoms of CRS after ESS was also shown by Bhattacharyya (Bhattacharyya, 2005) using the RSDI (100 patients, average follow-up = 19 months).

Litvack (Litvack et al., 2007) showed that both primary and revision endoscopic surgery equally improved QoL (the RSDI and CSS questionaires were the QoL instruments used in the trial).

A prospective audit conducted on 3128 patients undergoing surgery for CRS also demonstrated a significant improvement of QoL over a 36-month follow-up (SNOT-22) (Hopkins et al., 2006).

Proimos (Proimos et al., 2010) demonstrated improvement of QoL in 86 patients with CRS with nasal polyps and asthma, 12 months after ESS. In this study SNOT-22 was used and additionally, the 5 most important items of SNOT, from the patient's point of view, were evaluated. The results confirmed that ESS satisfied expectations of patients regarding control of most of the important symptoms and a positive influenced on their overall QoL.

In a recent multi-institutional, prospective study, Smith et al. (Smith et al., 2010) demonstrated clinically significant improvement of QoL (CSS and RSDI questionnaires were used in 302 patients, mean ESS follow-up = 17.4 months). Authors of this study also tried to find predictive factors for QoL outcomes after ESS. They used a multivariate logistic regression model to examine predictors of clinically significant improvement of QoL. In this predictive model, after all co-factors were evaluated (e.g. comorbidities, demographic factors, and results of diagnostics tests), surprisingly, only primary or revision surgery was clearly predictive. The authors concluded that clinical phenotype did not provide outcomepredictive information and other factors with possible predictive importance should be investigated.

Although humans and other primates are regarded as primarily "optical animals" with a relatively undeveloped sense of smell, recent studies indicate that humans seem to use olfactory communication, particularly, in interpersonal relationships (Grammer et al., 2005). Perception of substances such as pheromones may modulate changes in interpersonal

The effect of surgical treatment on QoL in patients with CRS has been documented fairly well (Metson & Glicklich, 1998; Salhab et al., 2004; Smith et al., 2005; Ling & Kountakis,

A review by Smith et al. assessed the effect of surgical treatment of CRS on symptoms and QoL in patients with CRS. Improvement of quality of life or symptoms was demonstrated in all 45 enrolled studies, 11 studies were prospective, and in five, a validated QoL

Ling and Kountakis (Ling & Kountakis, 2007) showed a greater than 80% improvement in symptoms of CRS from baseline, when measured using a visual analogue scale, 12 months after ESS. These authors also used SNOT-22 scores that showed improvement by as much as

Improvement of both major and minor symptoms of CRS after ESS was also shown by Bhattacharyya (Bhattacharyya, 2005) using the RSDI (100 patients, average follow-up = 19

Litvack (Litvack et al., 2007) showed that both primary and revision endoscopic surgery equally improved QoL (the RSDI and CSS questionaires were the QoL instruments used in

A prospective audit conducted on 3128 patients undergoing surgery for CRS also demonstrated a significant improvement of QoL over a 36-month follow-up (SNOT-22)

Proimos (Proimos et al., 2010) demonstrated improvement of QoL in 86 patients with CRS with nasal polyps and asthma, 12 months after ESS. In this study SNOT-22 was used and additionally, the 5 most important items of SNOT, from the patient's point of view, were evaluated. The results confirmed that ESS satisfied expectations of patients regarding control of most of the important symptoms and a positive influenced on their overall QoL. In a recent multi-institutional, prospective study, Smith et al. (Smith et al., 2010) demonstrated clinically significant improvement of QoL (CSS and RSDI questionnaires were used in 302 patients, mean ESS follow-up = 17.4 months). Authors of this study also tried to find predictive factors for QoL outcomes after ESS. They used a multivariate logistic regression model to examine predictors of clinically significant improvement of QoL. In this predictive model, after all co-factors were evaluated (e.g. comorbidities, demographic factors, and results of diagnostics tests), surprisingly, only primary or revision surgery was clearly predictive. The authors concluded that clinical phenotype did not provide outcomepredictive information and other factors with possible predictive importance should be

perception and individual mood, behavior and physiology (Havlicek et al., 2010).

**4. Effect of rhinosinusitis treatment on quality of life** 

questionnaire was used (Smith. et al., 2005).

2007).

77%, postoperatively.

(Hopkins et al., 2006).

months).

the trial).

investigated.

There is a relative lack of documentation regarding improvement of QoL after medical treatment of CRS. Similarly, there are insufficient data regarding comparisons of effects of different medical and surgical treatments on QoL. The lack of well-formed, prospective, randomized, controlled trials, concerning medical treatment can lead to the idea that surgical treatment of CRS has a better effect on QoL than medical treatments (Ragab et al., 2010).

Also the fact that surgical treatment should only be indicated for patients with a more severe course of disease, resistant to medical treatment, makes any comparison of effect of treatment on QoL more complicated.

A study by Lund et al. (Lund et al., 2004) showed no significant difference in the score on a disease-specific questionnaire (Chronic Sinusitis survey-CSS) in patients with CRS without NP, treated for 20 months with intranasal budesonide compared to placebo. In the same study, a significant difference between the two groups was found only in the general health subscale of SF-36 General Health Questionnaire, but no significant difference in the other subscales were observed.

Alobid et al. (Alobid et al., 2006) assessed the effect of treatment with oral and intranasal steroids on the quality of life of patients with CRS with nasal polyposis. The patients, after a short-course of oral prednisone, demonstrated a significant improvement in QoL in all domains (compared with base line and the control group) using the general-health QoL instrument SF-36. The improvement was sustained by intranasal steroids after 12, 24 and 48 months. The study was conducted on 60 patients who were compared with a control group (18 patients) without treatment.

The same group (Alobid et al., 2005) compared, in a randomized trial, medical treatment (53 patients, oral prednisone for two weeks) and surgical treatment (56 patients undergoing ESS) of CRS with nasal polyps. Both groups received intranasal budesonide for 12 months after intervention. At 6 and 12 months, a significant improvement in the QoL, measured again using the SF-36, was observed in both the medical and surgical group.

Ragab et al. in a recent prospective, randomized, controlled trial evaluated and compared the effect of medical and surgical treatment of CRS on QoL (Ragab et al., 2010). The study was conducted on ninety CRS patients with and without polyps randomized into medical and surgical groups. The medical group was treated with erythromycin (12 week course), alkaline nasal douches and intranasal steroids. In addition, 3 patients with polyps were prescribed a course of short-term oral steroids. The extent of endoscopic sinus surgery was tailored to the extent of the disease in the surgical group. Following ESS, all patients were prescribed a two-week course of erythromycin and alkaline douches and intranasal steroids as long-term therapy. Quality of life was assessed using the disease specific instrument SNOT-22 and the general health instrument SF-36 before randomization and after 6 and 12 months. A significant improvement in the SNOT score was recorded, without statistically significant difference between medical and surgical group after 6 and 12 month. Also, the SF-36 demonstrated a significant improvement in the QoL in seven out of eight domains. Only physical functioning did not change significantly from the baseline. Furthermore this study does not support the fact that polyps represent a poor prognostic factor for efficacy of treatment, as has been suggested in previous studies (Kennedy, 1992; Sobol et al., 1998).

Rhinosinusitis - Its Impact on Quality of Life 17

Wright et al. showed a slight correlation between endoscopic scores based on the Lund-Kennedy and Sinus Symptom Questionnaire, 1, 3 and 6 months after ESS. However, this study did not show a significant correlation between postoperative endoscopic examination and the CSS (Wright & Agrawal, 2007). Studies evaluating the effect of non-surgical treatment also demonstrated no correlation between RSDI and endoscopic scores (Birch et

A recent study by Mace et al. focused on the correlation between endoscopic scores and HRQOL in patients after ESS. This study evaluated the results of endoscopic scores based on the Lund-Kennedy (score range 0 – 20) and two HRQoL questionnaires, RSDI, and CSS, in 102 patients preoperatively and 12 months after ESS. Changes in endoscopic scores were significantly correlated with improvement in RSDI total scores, physical RSDI subscale scores and functional RSDI subscale scores and CSS symptom scores. On the contrary, no correlation was observed among RSDI emotional subscale scores and CSS medication subscale scores and CSS total scores. When the groups of patients with and without nasal polyps (NP) were assessed separately, patients with CRS + NP (36 patients) demonstrated a significantly stronger correlation. In contrast, the group of patients without NP demonstrated no correlation between improved endoscopic scores and any of the HRQoL instruments. The authors concluded that the reason for the significant increase in quality of life in patients with NP was related to improvement in nasal breathing, olfaction, and relief of the facial pressure. The results of multivariate modeling used in this study revealed that the amount of improvement on the HRQoL can be explained by relatively small improvements on the endoscopic score. For example, with a single point improvement in the endoscopic score, RSDI total scores would be expected to improve by 1.03 units (Mace et

In conclusion the improvement on HRQoL is a complex process that cannot be explained

The studies in this issue are focused primarily on the correlation between eosinophilic inflammation of the paranasal sinus mucosa and other parameters indicative of disease severity (particularly CT scan, endoscopy, examination of olfaction). The presence of eosinophilic inflammation, defines a subgroup of CRS, which is refractory to conservative and surgical treatment and knowledge of the eosinophilic status can provide information regarding the severity of the disease and help in choosing an appropriate treatment strategy. Studies by Kountakis and Baudoin failed to demonstrate a correlation between the eosinophil count and the severity of CRS symptoms (Kountakis et al., 2004; Baudoin et al.,

Soler et al. showed mucosal eosinophilia correlated with disease severity expressed by CT, endoscopy and Smell Identification Test (SIT). In contrast to this finding, they did not demonstrate a correlation between eosinophilia and two disease-specific QoL questionnaires (RSDI, CSS) or with the general QoL instrument, Short Form Health Survey, SF-36. Moreover, the study showed no correlation between QoL and any other cell, stromal and

al., 2001).

al., 2010).

2006).

only by improved endoscopic findings.

epithelial marker of inflammation (Soler et al., 2009).

**5.3 Histopathologic findings** 

In conclusion, the presented data provides evidence that both maximal medical and surgical therapy improve the QoL of CRS patients. CRS should be targeted with maximal medical therapy as the first step and surgery should be reserved for refractory cases.

#### **5. The correlation between quality of life and the results of other measurements in chronic rhinosinusitis**

The relationship between health-related QoL and the results of other examinations of CRS is not entirely clear. Although we might intuitively expect that patients with worse CT and endoscopic findings would have a lower quality of life, results of available studies do not confirm this fact. Also, the influence of CRS symptoms on QoL, relative to treatment, cannot be predicted from endoscopic or CT scores.

The lack of correlation between objective assessment and subjective perception of QoL is not unique to CRS, but can also be seen in such disorders as bronchial asthma, obstructive sleep apnea and low back pain (Soler & Smith 2010).

#### **5.1 Imaging methods**

Bhattacharyya et al. failed to demonstrate a correlation between CT scores and the SNOT-20 (Bhattacharyya et al., 1997) in 221 patients referred for CT scans.

Wabnitz et al. failed to demonstrate a significant correlation between CT scores based on the commonly used Lund-Mackay staging (score range 0-24) and the SNOT-20 QoL questionnaire in 221 patients indicated for CRS surgery; the study also found no correlation between the SNOT-20 and symptom scores (visual analog scale-VAS) (Wabnitz et al., 2005).

In a study by Holbrook et al., they tried to correlate the RSOM-31 questionnaire and the Lund Mackay CT scores. In this study patients were also asked to locate their sinus pain and pressure. The study was not able to demostrate a correlation between QoL scores and CT findings or between CT findings and areas of facial pain (Holbrook et al., 2005).

Hopkins et al. found a small, clinically insignificant association between Lund-Mackay scores and SNOT-22. In the study, CT findings from 1840 patients with CRS were reviewed and the results were consistent with the above mentioned studies. In this study, a small but significant association between CT scores and postoperative improvement on the SNOT-22 was found, which indicates that patients with lower preoperative CT scores benefit more from surgical treatment (Hopkins et al., 2007).

In conclusion CT scans measure a different aspect of CRS than QoL and, of itself, cannot be an indication for surgery. It is necessary for preoperative assessment of the extent of disease and identification of anatomical landmarks, but it should not be used for prediction or localization of CRS symptoms.

#### **5.2 Rhinoendoscopy**

A varying degree of correlation has been shown between improvement of sinonasal symptoms and results from endoscopic examinations after ESS (Giger et al., 2004; Wright & Agrawal, 2007).

In conclusion, the presented data provides evidence that both maximal medical and surgical therapy improve the QoL of CRS patients. CRS should be targeted with maximal medical

The relationship between health-related QoL and the results of other examinations of CRS is not entirely clear. Although we might intuitively expect that patients with worse CT and endoscopic findings would have a lower quality of life, results of available studies do not confirm this fact. Also, the influence of CRS symptoms on QoL, relative to treatment, cannot

The lack of correlation between objective assessment and subjective perception of QoL is not unique to CRS, but can also be seen in such disorders as bronchial asthma, obstructive sleep

Bhattacharyya et al. failed to demonstrate a correlation between CT scores and the SNOT-20

Wabnitz et al. failed to demonstrate a significant correlation between CT scores based on the commonly used Lund-Mackay staging (score range 0-24) and the SNOT-20 QoL questionnaire in 221 patients indicated for CRS surgery; the study also found no correlation between the SNOT-20 and symptom scores (visual analog scale-VAS) (Wabnitz et al., 2005). In a study by Holbrook et al., they tried to correlate the RSOM-31 questionnaire and the Lund Mackay CT scores. In this study patients were also asked to locate their sinus pain and pressure. The study was not able to demostrate a correlation between QoL scores and CT

Hopkins et al. found a small, clinically insignificant association between Lund-Mackay scores and SNOT-22. In the study, CT findings from 1840 patients with CRS were reviewed and the results were consistent with the above mentioned studies. In this study, a small but significant association between CT scores and postoperative improvement on the SNOT-22 was found, which indicates that patients with lower preoperative CT scores benefit more

In conclusion CT scans measure a different aspect of CRS than QoL and, of itself, cannot be an indication for surgery. It is necessary for preoperative assessment of the extent of disease and identification of anatomical landmarks, but it should not be used for prediction or

A varying degree of correlation has been shown between improvement of sinonasal symptoms and results from endoscopic examinations after ESS (Giger et al., 2004; Wright &

findings or between CT findings and areas of facial pain (Holbrook et al., 2005).

therapy as the first step and surgery should be reserved for refractory cases.

**5. The correlation between quality of life and the results of other** 

**measurements in chronic rhinosinusitis** 

be predicted from endoscopic or CT scores.

apnea and low back pain (Soler & Smith 2010).

from surgical treatment (Hopkins et al., 2007).

localization of CRS symptoms.

**5.2 Rhinoendoscopy** 

Agrawal, 2007).

(Bhattacharyya et al., 1997) in 221 patients referred for CT scans.

**5.1 Imaging methods** 

Wright et al. showed a slight correlation between endoscopic scores based on the Lund-Kennedy and Sinus Symptom Questionnaire, 1, 3 and 6 months after ESS. However, this study did not show a significant correlation between postoperative endoscopic examination and the CSS (Wright & Agrawal, 2007). Studies evaluating the effect of non-surgical treatment also demonstrated no correlation between RSDI and endoscopic scores (Birch et al., 2001).

A recent study by Mace et al. focused on the correlation between endoscopic scores and HRQOL in patients after ESS. This study evaluated the results of endoscopic scores based on the Lund-Kennedy (score range 0 – 20) and two HRQoL questionnaires, RSDI, and CSS, in 102 patients preoperatively and 12 months after ESS. Changes in endoscopic scores were significantly correlated with improvement in RSDI total scores, physical RSDI subscale scores and functional RSDI subscale scores and CSS symptom scores. On the contrary, no correlation was observed among RSDI emotional subscale scores and CSS medication subscale scores and CSS total scores. When the groups of patients with and without nasal polyps (NP) were assessed separately, patients with CRS + NP (36 patients) demonstrated a significantly stronger correlation. In contrast, the group of patients without NP demonstrated no correlation between improved endoscopic scores and any of the HRQoL instruments. The authors concluded that the reason for the significant increase in quality of life in patients with NP was related to improvement in nasal breathing, olfaction, and relief of the facial pressure. The results of multivariate modeling used in this study revealed that the amount of improvement on the HRQoL can be explained by relatively small improvements on the endoscopic score. For example, with a single point improvement in the endoscopic score, RSDI total scores would be expected to improve by 1.03 units (Mace et al., 2010).

In conclusion the improvement on HRQoL is a complex process that cannot be explained only by improved endoscopic findings.

#### **5.3 Histopathologic findings**

The studies in this issue are focused primarily on the correlation between eosinophilic inflammation of the paranasal sinus mucosa and other parameters indicative of disease severity (particularly CT scan, endoscopy, examination of olfaction). The presence of eosinophilic inflammation, defines a subgroup of CRS, which is refractory to conservative and surgical treatment and knowledge of the eosinophilic status can provide information regarding the severity of the disease and help in choosing an appropriate treatment strategy.

Studies by Kountakis and Baudoin failed to demonstrate a correlation between the eosinophil count and the severity of CRS symptoms (Kountakis et al., 2004; Baudoin et al., 2006).

Soler et al. showed mucosal eosinophilia correlated with disease severity expressed by CT, endoscopy and Smell Identification Test (SIT). In contrast to this finding, they did not demonstrate a correlation between eosinophilia and two disease-specific QoL questionnaires (RSDI, CSS) or with the general QoL instrument, Short Form Health Survey, SF-36. Moreover, the study showed no correlation between QoL and any other cell, stromal and epithelial marker of inflammation (Soler et al., 2009).

Rhinosinusitis - Its Impact on Quality of Life 19

of the disease. The relationship between QoL measured results and results of other "objective" investigations clearly supports the fact that QoL evaluation measures different

Despite the undeniable benefit of evaluating the quality of life in diagnosis and treatment of CRS, there are some opposition regarding the routine use of this tool in clinical practice.

Completing the most frequently used questionnaire takes less than 10 minutes. When the patient takes the questionnaire for the first time, it is necessary to educate them; therefore, the first measurement may take a little longer. The time devoted to patient instruction will be appreciated during repeated examinations, which are usually less time consuming. Inclusion of QoL measurements in routine practice is also a function of organization; it is time-effective, for example, to ask patients to fill out the questionnaire while they are

Outcomes rated by a clinician may be thought to be more reliable than measures rated by a patient. However, we should realize that grading of the symptoms by a clinician is prone to error. A study comparing the severity of a disease from the patient's viewpoint vs. a doctor's viewpoint, demonstrated that patients evaluate their condition as being more serious (Scadding & Wiliams, 2008); 124 patients with allergic rhinitis participated in the study; however, it can be assumed that similar results would be observed in patients with

We should always keep in mind that it is the symptoms that reduce the quality of life for the patient, and it is the symptoms that motivate the patient to see the doctor; no one else other than the patients, is more competent to comment on how they perceive their symptoms and

As already mentioned the evaluation of quality of life evaluates a different aspect of the disease. Symptoms and QoL are the result of interactions between many factors, of which, measurable biological and physiological variables are only a part (Figure 6) (Wilson & Clearly, 1995). For these same reasons, measurement of QoL cannot serve as a predictor of

It should be emphasized that QoL measurement is only a part of the rhinology examination and cannot substitute for other tests. For instance, a preoperative CT scan is always necessary, as well as imaging in cases of impending complication from sinusitis, which may endanger the patient's life while causing relatively minor subjective complaints. Surgery to improve nasal patency should be always associated with an objective parameter

**The results of QoL measurements do not correlate with outcomes of objective tests** 

**6. Barriers and limitations of the quality of life measurement** 

**Examination of quality of life is too subjective and therefore unreliable** 

aspects of the disease.

Specific objections include:

waiting to be seen.

CRS as well.

treatment outcomes.

how the symptoms impact their life.

**Limitations of QoL measurements** 

(rhinomanometry, inspiratory peak flow) and so on.

**Measurement of QoL takes too much time** 

Another study by Soler et al. focused on the comparison of quality of life in patients with and without eosinophilia after ESS. In accordance with the previous study, no baseline differences were observed for any QoL Instrument (RSDI, CSS, SF-36) between patients with and without eosinophilia. Although both groups showed improved quality of life after surgery, a clear trend towards less improvement in patients with eosinophilia was observed (Soler et al., 2010).

A recent study by Hai (Hai et al., 2010) indicated that patients with biofilm CRS significantly improved their QoL after ESS, however the degree of biofilm reduction did not correlate with QoL.

From the above, the QoL measurement, in the context of histopathological findings, again shows some differences between other parameters, which are often used as indicators of disease severity.

#### **5.4 Olfactory function**

It is generally considered that the loss of smell, a typical CRS symptom, significantly contributes to reduced quality of life (Deems et al., 1991; Temmel et al., 2002; Miwa et al., 2001; Bramerson et al., 2007). From this perspective, the work of Litvack et al., which deals with correlations of olfaction disturbances with other parameters of CRS severity, is interesting. Not surprisingly, endoscopic and CT scores correlated moderately with olfactory scores. In contrast, however, there was no correlation between olfactory function and disease-specific (RSDI, CSS) QoL questionnaires or the general health-related (SF-36) QoL questionnaire (Litvack et al., 2009). In this particular study the reason for these results may be the relatively limited ability of the selected questionnaires to assess olfactory function. Neither the CSS nor the SF-36 contains any questions regarding olfaction, and only one question on the RSDI addresses this issue. A similar deficiency can be found in other CRS-specific validated instruments including the RSOM and SNOT-20.

#### **5.5 Mucociliary transport**

It can be assumed that improved mucociliary transport should positively affect the symptoms of CRS. Boatsman et al. conducted a study that examined the correlation between the results of SNOT-20 and the saccharine test of mucociliary transport. In this study no significant correlation between the parameters was demonstrated. Moreover, no correlation between the individual domain scores and mucociliary clearance time was shown (Boatsman et al. 2006).

Similar research by Naxakis, also failed to demonstrate a correlation between mucociliary velocity, and QoL (SNOT-20) in patients after surgical and conservative treatment of CRS (Naxakis et al., 2009).

Clinicians are used to basing their diagnostic and therapeutic decisions on the results of objective tests, particularly CT and endoscopic findings while letting patient specific symptoms slip into the background. It is important to realize, however, that it is the symptoms that force patients to seek medical care and it is the symptoms of CRS that significantly influence and reduce their quality of life. The above listed data clearly shows that quality of life is a unique, multidimensional tool that can be used to assess the severity

Another study by Soler et al. focused on the comparison of quality of life in patients with and without eosinophilia after ESS. In accordance with the previous study, no baseline differences were observed for any QoL Instrument (RSDI, CSS, SF-36) between patients with and without eosinophilia. Although both groups showed improved quality of life after surgery, a clear trend towards less improvement in patients with eosinophilia was observed

A recent study by Hai (Hai et al., 2010) indicated that patients with biofilm CRS significantly improved their QoL after ESS, however the degree of biofilm reduction did not correlate

From the above, the QoL measurement, in the context of histopathological findings, again shows some differences between other parameters, which are often used as indicators of

It is generally considered that the loss of smell, a typical CRS symptom, significantly contributes to reduced quality of life (Deems et al., 1991; Temmel et al., 2002; Miwa et al., 2001; Bramerson et al., 2007). From this perspective, the work of Litvack et al., which deals with correlations of olfaction disturbances with other parameters of CRS severity, is interesting. Not surprisingly, endoscopic and CT scores correlated moderately with olfactory scores. In contrast, however, there was no correlation between olfactory function and disease-specific (RSDI, CSS) QoL questionnaires or the general health-related (SF-36) QoL questionnaire (Litvack et al., 2009). In this particular study the reason for these results may be the relatively limited ability of the selected questionnaires to assess olfactory function. Neither the CSS nor the SF-36 contains any questions regarding olfaction, and only one question on the RSDI addresses this issue. A similar deficiency can be found in other

It can be assumed that improved mucociliary transport should positively affect the symptoms of CRS. Boatsman et al. conducted a study that examined the correlation between the results of SNOT-20 and the saccharine test of mucociliary transport. In this study no significant correlation between the parameters was demonstrated. Moreover, no correlation between the individual domain scores and mucociliary clearance time was shown

Similar research by Naxakis, also failed to demonstrate a correlation between mucociliary velocity, and QoL (SNOT-20) in patients after surgical and conservative treatment of CRS

Clinicians are used to basing their diagnostic and therapeutic decisions on the results of objective tests, particularly CT and endoscopic findings while letting patient specific symptoms slip into the background. It is important to realize, however, that it is the symptoms that force patients to seek medical care and it is the symptoms of CRS that significantly influence and reduce their quality of life. The above listed data clearly shows that quality of life is a unique, multidimensional tool that can be used to assess the severity

CRS-specific validated instruments including the RSOM and SNOT-20.

(Soler et al., 2010).

disease severity.

**5.4 Olfactory function** 

**5.5 Mucociliary transport** 

(Boatsman et al. 2006).

(Naxakis et al., 2009).

with QoL.

of the disease. The relationship between QoL measured results and results of other "objective" investigations clearly supports the fact that QoL evaluation measures different aspects of the disease.

#### **6. Barriers and limitations of the quality of life measurement**

Despite the undeniable benefit of evaluating the quality of life in diagnosis and treatment of CRS, there are some opposition regarding the routine use of this tool in clinical practice. Specific objections include:

#### **Measurement of QoL takes too much time**

Completing the most frequently used questionnaire takes less than 10 minutes. When the patient takes the questionnaire for the first time, it is necessary to educate them; therefore, the first measurement may take a little longer. The time devoted to patient instruction will be appreciated during repeated examinations, which are usually less time consuming. Inclusion of QoL measurements in routine practice is also a function of organization; it is time-effective, for example, to ask patients to fill out the questionnaire while they are waiting to be seen.

#### **Examination of quality of life is too subjective and therefore unreliable**

Outcomes rated by a clinician may be thought to be more reliable than measures rated by a patient. However, we should realize that grading of the symptoms by a clinician is prone to error. A study comparing the severity of a disease from the patient's viewpoint vs. a doctor's viewpoint, demonstrated that patients evaluate their condition as being more serious (Scadding & Wiliams, 2008); 124 patients with allergic rhinitis participated in the study; however, it can be assumed that similar results would be observed in patients with CRS as well.

We should always keep in mind that it is the symptoms that reduce the quality of life for the patient, and it is the symptoms that motivate the patient to see the doctor; no one else other than the patients, is more competent to comment on how they perceive their symptoms and how the symptoms impact their life.

#### **The results of QoL measurements do not correlate with outcomes of objective tests**

As already mentioned the evaluation of quality of life evaluates a different aspect of the disease. Symptoms and QoL are the result of interactions between many factors, of which, measurable biological and physiological variables are only a part (Figure 6) (Wilson & Clearly, 1995). For these same reasons, measurement of QoL cannot serve as a predictor of treatment outcomes.

#### **Limitations of QoL measurements**

It should be emphasized that QoL measurement is only a part of the rhinology examination and cannot substitute for other tests. For instance, a preoperative CT scan is always necessary, as well as imaging in cases of impending complication from sinusitis, which may endanger the patient's life while causing relatively minor subjective complaints. Surgery to improve nasal patency should be always associated with an objective parameter (rhinomanometry, inspiratory peak flow) and so on.

Rhinosinusitis - Its Impact on Quality of Life 21

CRS is a disease with a high incidence, which significantly affects the quality of life. Quality of life of patients is negatively influenced not only by CRS symptoms (nasal congestion, discharge, facial pain and pressure, headache, anosmia), but it is also accompanied by elevated rates of depression, anxiety, sexual and sleep disturbances and fatigue. The primary interest of

In the last two decades there has been a significant increase in interest in measuring quality of life using specially developed, validated questionnaires. These tools allow the patient to express how CSR affects their daily life. In addition, by measuring the quality of life, we can

Quality of life is the result of interactions among many factors and "measurable" biological and physiological factors are only part of the QoL equation. It is therefore not surprising that the quality of life does not always correlate with results of other tests that we perform

The available data shows that both conservative and surgical treatments lead to

We can conclude by saying that measurement of quality of life should become a routine part of our everyday practice and the results should be considered in context with other indicators of disease severity. Moreover, in some countries, the data obtained by measuring the quality of life of CRS patients may be compulsory for use in evaluating treatment

treatment of rhinologic diseases is to improve the quality of life of patients.

evaluate the effect of treatment or compare different treatment methods.

effectiveness and can thus influence payments to medical care providers.

**7. Conclusion** 

on CRS patients.

**8. Abbreviations** 

improvement in the quality of life.

CRS Chronic Rhinosinusitis CSS Chronic Sinusitis Survey ESS Endoscopic Sinus Surgery GBI Glasgow Benefit Inventory HRQoL Health-related Quality of Life

NP Nasal Polyposis QoL Quality of Life

RhinoQoL Rhinosinusitis Quality of Life Survey RSOM Rhinosinusitis Outcome Measures RSDI Rhinosinusitis Disability Index RSI Rhinosinusitis Symptom Inventory SF-12 Short Form 12 Health Instrument SF-36 Short Form 36 Health Survey SNOT Sinonasal Outcome Test

SRM Standardized Response Mean

Fig. 6. Interactions between factors influencing quality of life (Wilson & Clearly, 1995)

#### **7. Conclusion**

20 Peculiar Aspects of Rhinosinusitis

Fig. 6. Interactions between factors influencing quality of life (Wilson & Clearly, 1995)

CRS is a disease with a high incidence, which significantly affects the quality of life. Quality of life of patients is negatively influenced not only by CRS symptoms (nasal congestion, discharge, facial pain and pressure, headache, anosmia), but it is also accompanied by elevated rates of depression, anxiety, sexual and sleep disturbances and fatigue. The primary interest of treatment of rhinologic diseases is to improve the quality of life of patients.

In the last two decades there has been a significant increase in interest in measuring quality of life using specially developed, validated questionnaires. These tools allow the patient to express how CSR affects their daily life. In addition, by measuring the quality of life, we can evaluate the effect of treatment or compare different treatment methods.

Quality of life is the result of interactions among many factors and "measurable" biological and physiological factors are only part of the QoL equation. It is therefore not surprising that the quality of life does not always correlate with results of other tests that we perform on CRS patients.

The available data shows that both conservative and surgical treatments lead to improvement in the quality of life.

We can conclude by saying that measurement of quality of life should become a routine part of our everyday practice and the results should be considered in context with other indicators of disease severity. Moreover, in some countries, the data obtained by measuring the quality of life of CRS patients may be compulsory for use in evaluating treatment effectiveness and can thus influence payments to medical care providers.

#### **8. Abbreviations**


Rhinosinusitis - Its Impact on Quality of Life 23

Chester, AC. & Sindwani, R. (2007). Symptom outcome in Endoscopic sinus surgery: A systematic review of measurements methods. Laryngoscope, Vol. 117:2239-2243. Craig, TJ., Ferguson, BJ. & Krouse, JH. (2008). Sleep impairment in allergic rhinitis,

Deems, DA, Doty, RL., Settle, G. et al. (1991). Smell and taste disorders. A study of 750

Fokkens, WJ., Lund, VJ., Mullol, J et al. (2007). Position paper on Rhinosinusitis and Nasal

Fairley, JW., Yardley, MPJ. & Durham, LH. (1993). Reliability and validity of a nasal

Gill, TM. & Feinstein, AR. (1994). Acritical appraisal of the quality of life of quality-of-life

Gliklich, RE. & Metson, R. (1995). The health impact of chronic sinusitis in patients seeking otolaryngologic care. *Otolaryngol Head Neck Surg*, Vol. 113:104-109. Gliklich, RE. & Metson, R. (1995). Effect of sinus surgery on quality of life. *Otolaryngol* 

Grammer, K., Fink, B. & Neave, N. (2005). Human pheromones and sexual attraction. *Eur* 

Hai, PV., Lidstone, C. & Wallwork, B. (2010). The effect of endoscopic sinus surgery on

Havlicek, J., Murray, AK., Saxton, TK. et al. (2010). Current issues in the study of

Holbrook, E., Brown, C., Lyden, E. et al. (2005). Lack of significant correlation between

Hopkins, C., Browne, JP., Slack, R. et al. (2006). The national comparative audit of surgery

Hopkins, C., Browne, JP., Slack, R et al. (2007). The Lund-Mackay staging system for

Hopkins, C., Gillett, S., Slack, R., Lund, VJ. &, Browne, JP. (2009). Psychometric validity of

Juniper, EF., Guyatt, GH., Willan, A. et al. (1994). Determining a minimal important

Ling, FT. & Kountakis, SE. (2007). Important clinical symptoms in patients undergoing

22-item sinonasal outcome test. *Clin Otolaryngol,*Vol. 34:447-454.

androstenes in human chemosignaling. *Vitam Horn*, Vol. 83:47-81.

bacterial biofilms in chronic rhinosinusitis. *Otolaryngol Head Neck Surg*, Vol.

rhinosinusitis symptoms and specific region of sinus CT scans. *Am J Rhinol*, Vol.

for nasal polyposis and chronic rhinosinusitis. Clin *Otolaryngol Allied Sci,* Vol.

chronic rhinosinusitis: How is it used and what does it predict? *Otolaryngol Head* 

change in disease-specific Quality of Life Questionnaire. *J Clin Epidemiol*, Vol.

functional endoscopic sinus surgery for chronic rhinosinusitis. *Laryngoscope*, Vol.

*Neck Medicine and Surgery*, Vol. 29:209-217.

*Otolaryngol Head Neck Surg*, Vol. 117:519-528.

Polyps 2007. *Rhinology* Suppl. Vol. 20:1-136.

*Otolaryngol Head Neck Surg*, Vol. 131:534-541.

*J Obstet Gynecol Reprod Med*, Vol. 118:135-142.

*Head Neck Surg*, Vol. 117:12-17.

142:27-32.

19:382-387.

31:390-399.

47:81-87.

117:1090-1093.

*Neck Surg*, Vol 137:555-561.

measurements. *J Am Med Assoc*, Vol. 272:619-626.

rhinosinusitis and nasal polyposis. *American Journal of Otolaryyngology-Head and* 

patients from the University of Pennsylvania Smell and taste center. *Arch*

symptom questionnaire for use as an outcome measure in clinical research and audit of functional endoscopic sinus surgery. *Clin Otolaryngol*, Vol. 18:436-437. Giger, R., Dulguerov, P., Quinodoz, D. et al. (2004). Chronic panrhinosinusitis without

nasal polyps: long-term outcome after functional endoscopic sinus surgery.

#### **9. References**


Alobid, I., Benitez, P., Bernal-Sperkelsen, M. et al. (2005). Nasal polyposis and its impact

Alobid, I., Benitez, P., Pujols, L. et al. (2006). Severe nasal polyposis and its impact on

Anand, VK. (2004). Epidemiology and economic impact of rhinosinusitis. *Ann Otol Rhinol* 

Atlas, SJ., Metson, RB, Singer, DE. et al. (2005). Validity of a new health-related quality of

Baudoin, T., Cupic, H., Geber, G., et al. (2006). Histopathlogic parameters as predictors of

Benninger, MS.& Senior, BA. (1997). The development of Rhinosinusitis Disability Index.

Benninger, MS & Benninger, RM. (2009). The impact of allergic rhinitis on sexual activity,

Benninger, MS, Khalid, AN, Benninger, RM et al. (2010). Surgery for chronic rhinosinusitis may improve sleep and sexual function. *Laryngoscope*, Vol. 120:1696-1700. Bhattacharyya, N., Piccirillo, J. & Wippold, FJ. (1997). Relationship between patient-based

Bhattacharyya, N. (2003). The economic burden and symptom manifestations of chronic

Bhattacharyya, N. (2005). Symptom outcomes after endoscopic sinus surgery for chronic

Birch, DS, Saleh, HA, Wodehouse, T. et al. (2001). Assesing the quality of life for patients

Boatsman, JE., Calhoun, KH. & Ryan, MW. (2006). Relationship between rhinosinusitis

Bramerson, A., Nordin, S. & Bende, M. (2007). Clinical experience with patients wizh

Brandsted, R. & Sindwani, R. (2007). Impact of depression on disease-specific symptoms

Calman, KC. (1984). Quality of life in cancer patients- an hypothesis. *J Med Ethics,* Vol.

Carr, AJ., Gibson, BA. & Robinson, PG. (2001). Is quality of life determined by

Chester, AC. (2003). Symptoms of rhinosinusitis in patients with unexplained chronic fatigue or bodily pain: a pilot study. *Arch Inter Med*, Vol. 163:1832-1836.

rhinosinusitis. *Arch Otolaryngol Head Neck Surg*, Vol. 130:329-334.

Bland, JM. & Altman, DG. (1997). Cronbach's alpha. BMJ, Vol. 314:572.

expectations or experience? *BMJ*, Vol. 322:1240-1243.

rhinosinusitis. *Otolaryngol Head Neck Surg*, Vol. 134:761-766.

*Arch Otolaryngol Head Neck Surg*, Vol.123:1175-1179.

rhinosinusitis. *Am J Rhinol*, Vol. 17:27-32.

sleep and fatigue. *Allergy Asthma Proc*, Vol. 30:358-365.

treatments. *Allergy*, Vol. 60:452-458.

*Laryngol,* Suppl, 193:3-5.

Vol. 123:1189-1192.

Vol. 39:191-196.

127:167-174.

10:124-127.

54.

intranasal steroids tretment. *Rhinology*, Vol. 44:8-13.

on quality of life: comparison between the effects of medical and surgical

quality of life. The effect of short course of oral steroid followed by long-term

life instrument for patients with chronic rhinosinusitis. *Laryngoscope*, Vol. 115:846-

response to endoscopic sinus surgery in nonallergic patients with chronic

descriptions od sinusitis and paranasal sinus CT. *Arch Otolaryngol Head Neck Surg*,

with chronic rhinosinusitis using the "Rhinosinusitis Disability Index". *Rhinology*,

symptoms and mucociliary transport. *Otolaryngol Head Neck Surg*, Vol.134:491-493.

olfactory complaints, and their quality of life. *Acta Oto-Laryngologica* , Vol.

and quality of life in patients with chronic rhinosinusitis. *Am J Rhinol*, Vol. 21:50-

**9. References** 

854.


Rhinosinusitis - Its Impact on Quality of Life 25

Schalek, P, Otruba, L. & Hahn, A. (2010). Quality of life in patients with chronic

Serrano, E., Neukirch, E., Pribil, C. et al. (2005). Nasal polyposis in France: impact on sleep

Smith, TL., Batra, PS., Seiden, AM. et al. (2005). Evidence supporting endoscopic sinus

Smith, TL., Litvack, JR, Hwang, PH. et al. (2010). Determinants of outcomes of sinus

Sobol, SE., Wright, ED. & Frenkiel, S. (1998). One-year outcome analysis of functional endoscopic sinus surgery for chronic sinusitis*. J Otolaryngol*, Vol. 27:252-257. Soler, ZM., Mace, J. & Smith, TL. (2008). Symptom-based presentation of chronic

Soler, ZM., Sauer, DA., Mace, J., et al. (2009). Relationship between clinical measures and

Soler, ZM. & Smith, TL. (2010). Quality of life outcomes after functional endoscopic sinus

Soler, ZM, Sauer, D., Mace, J. et al. (2010). Impact of mucosal eosinophilia and nasal

Suratt, PM, Turner, BL. & Wilhoit, SC. (1986). Effect of intranasal obstruction on breathing

Temmel, AFP., Quint., C., Schickinger-Fischer, B. et al. (2002). Characteristics of olfactory

van Oene, CM., van Reij, EJF., Sprangers, MAG., Fokkens, WJ. (2007). Quality- assessment

Wabnitz, D., Nair, S. & Wormald, PJ. (2005). Correlation between preoperative symptom

Ware, JE. & Sherbourne, CD. (1992). The MOS 36-Item Short Form Health Survey. I. Conceptual framework and item selection. *Med care*, Vol. 30, 473-483. Wasan, A., Fernandez, E., Janison, RN. et al. (2007). Association of anxiety and depression

Wilson, IB. & Clearly PD. (1995). Clinical variables with health-related quality of life.

Wright, ED. & Agrawal, S. (2007). Impact of perioperative systemic steroids on surgical

rhinosinusitis. *Ann Otol Rhinol Laryngol*, Vol. 116:491-497.

*Arch Otorhinolaryngol*. Vol. 267:473-475.

*Am J Rhinol.* Vol. 19:537-543.

*Am J Rhinol*, Vol. 22:297-301.

*Surg*, Vol. 142:55-63.

141:454-461.

*Surg*, Vol. 142:64-71.

*Surg*, Vol. 128:635-641.

JAMA, Vol. 273:59-65.

Suppl. 115:1-28.

and quality of life. *J Laryngol Otol*, Vol. 119:543-549.

surgery. *Otolaryngol Clin N Am*, Vol. 43:605-612.

during the sleep. *Chest*, Vol. 90:324-329.

systematic review. *Allergy*, Vol.62:1359-1370.

rhinosinusitis. *Am J Rhinol*, Vol. 19:91-96.

rhinosinusitis: A validation of the Czech version of SNOT-22 questionnaire. *Eur* 

surgery in the management of adult chronic rhinosinusitis: a systematic review.

surgery: A Multi-Institutional prospective cohort study. *Otolaryngol Head Neck* 

rhinosinusitis and symptom specific outcomes after endoscopic sinus surgery.

histopathologic findings in chronic rhinosinusitis. *Otolaryngol Head Neck Surg*, Vol.

polyposis on quality of life outcommes after sinus surgery. *Otolaryngol Head Neck* 

disorders in relation to major causes of olfactory loss. *Arch Otolaryngol Head Neck* 

of disease-specific quality of life questionnaires for rhinitis and rhinosinusitis: a

scores, quality of life questionnaires and staging with CT in patients chronic

with reported disease severity in patients undergoing evaluation for chronic

outcomes in patients with chronic rhinosinusitis with polyposis: evaluation with a novel perioperative sinus endoscopy (POSE) scoring system. *Laryngoscope*,


Litvack, JR., Grieast, S., James, KE. et al. (2007). Endoscopic and Qualityy-of Life Outcomes After Revision Endoscopic Surgery. *Laryngoscope*, Vol. 117:2233-2238. Litvack., JR., Mace, JC. & Smith, TL. (2009). Olfactory function and disease severity. *Am J* 

Lund, VJ. (2001). Health related quality of life in sinonasal disease. *Rhinology,* Vol 39:182-

Lund, VJ., Black, JH., Szabó, LZ. et al. (2004). Efficacy and tolerability of budesonide aqueous nasal spray ich chronic rhinosinusitis patients. *Rhinology,* Vol. 42:57-62. Kennedy DW. (1992). prognostic factores, outcomes, and staging in etmoid sinus surgery.

Kirmaz, C., Aydemir, O., Bayrak, P. et al. (2005). Sexual dysfunction in patients with allergic rhinoconjuctivitis. *Ann Allergy Asthma Immunol*, Vol. 95:525-529. Kountakis, SE, Arrango, P., Bradley Dewayne, et al. (2004). Molecular and cellular staging for the severity of chronic rhinosinusitis. *Laryngoscope*, Vol. 114:1895-1905. Mace, JC., Michael, YL, Carlson, NC., et al. (2008). Effect of depression on quality of life improvement after endoscopic sinus surgery. *Laryngoscope*, Vol. 118:528-53 Mace, JC., Michael, YL, Carlson, NC., et al. (2010). Correlation between endoscopy score

Metson, R. & Gliklich, RE. (1998). Clinical outcome of endoscopic surgery for frontal

Miwa, T., Furukawa, M., Tsukatani, T et. al. (2001). Impact of olfactory impairment on quality of life and disability. *Arch Otolaryngol Head Neck Surg*, Vol. 127:497-503. Morley, AD. & Sharp, HR. (2006). A review of sinonasal outcome scoring system- which

Naxakis, S., Athanasapoulos, I. & Vlastos I. (2009). Evaluation of nasal mucociliary

Piccirillo, JF., Merrit, MG. & Richards, ML. (2002). Psychometric and clinimetric validity

Proimos, E., Papadakis, CE., Chimona D. et al. (2010). The effect of functional endoscopic

Ragab, SM., Lund, VJ., Scadding, G. et al. (2010). Impact of chronic rhinosinusitis therapy

Robinson, K., Gatehouse, S.& Browning, GG. (1996). Measuring patient benefit from

Rudmik, L. & Smith, TL. (2011). Quality of life in patients with chronic rhinosinusitis. *Curr* 

Salhab, M, Matai, V, & Salam, MA. (2004). The impact of functional endoscopic sinus

Scadding, GK. & Williams, A. (2008) The burden of allergic rhinitis as reported by UK

patients compared with their doctors. *Rhinology,* Vol. 46:99-105.

clearance after medical or surgical treatment of chronic rhinosinusitis. *Eur Arch*

of the 20-item Sino-Nasal Outcome Test (SNOT-20). *Otolaryngol Head Neck* 

sinus surgery on patients with asthma and CRS with nasal polyps. *Rhinology*, Vol.

on quality of life; A prospective randomized controlled trial. *Rhinology*, Vol.

otorhinolaryngological surgery and therapy. *Ann Otol Rhinol Laryngol*, Vol.

sinusitis. *Arch Otolaryngol Head Neck Surg*, Vol. 124:1090-1096.

is best? *Clinical Otolaryngology*, Vol. 31:103-109.

*Otorhinolaryngol*. Vol. 266:1423-1426.

*Allergy Asthma Rep*, Vol. 11:247-252.

surgery on health status. *Rhinology*, Vol. 42:98-102.

*Surg,*Vol. 126:41-47.

48:331-338.

48:305-311.

105:415-422.

and quality of life changes after sinus surgery. *Arch Otolaryngol Head Neck*, Vol.

*Rhinol Allergy*, Vol.23:139-144.

*Laryngoscope*, Suppl 57:1-18.

186.

136:340-346.


**2** 

*Poland* 

**Microbiology Aspects of Rhinosinusitis** 

*Department of Medical Microbiology, Medical University of Lublin,* 

Agnieszka Magryś, Jolanta Paluch-Oleś and Maria Kozioł-Montewka

Rhinosinusitis with its chronic benign course, failure in antibiotic treatment and acute exacerbations, usually require multiple courses of antibiotics or surgical procedures, or both. Nowadays, the pathogenic mechanisms of microbes in rhinosinusitis have gradually been revealed. Many current hypotheses focus on the formation of biofilms, bacterial superantigens, cytokine dysregulation, and abnormalities of cell-mediated immune

"Rhinosinusitis" is a group of disorders characterized by inflammation of the mucosa of the nose and the paranasal sinuses. It is presently accepted that rhinosinusitis is initiated with an inflammatory insult (viral infection of upper respiratory tract, allergic rhinitis, etc.), followed by bacterial or fungal superinfection (Kennedy & Thaler, 1997; van Cauwenberge et al., 2006). Most upper respiratory tract infections are self-limited but progression to acute illness occurs and progression to chronic disease is common. Because specific treatment approaches are crucial for the different types of rhinosinusitis, this review focuses on

Most of the surfaces of the upper respiratory tract (including nasal and oral passages, nasopharynx, oropharynx, and trachea) are colonized by normal flora. The normal flora of human upper respiratory tract is harmless, and usually beneficial for the host. Two main functions are played by these bacteria, that are important in maintaining the healthy state of

1. these organisms compete with pathogenic organisms for potential attachment sites,

The nose is colonized predominantly by staphylococci, with *Staphylococcus aureus* and *Staphylococcus epidermidis* and diphtheroids as the leaders. The most important group of microorganisms native to oropharynx are also the alpha-hemolytic streptococci or viridans streptococci. This group includes *Streptococcus mitis, Streptococcus mutans, Streptococcus milleri,* and *Streptococcus salivarius*. It is believed that these bacteria act as antagonists against

But normal nasopharynx is not only the primary settlement of saprophytic bacteria. It is also the chief carrier of common respiratory pathogens, including *Streptococcus pneumoniae*,

2. they often produce substances (toxins or acids) which are bactericidal.

*Haemophilus influenzae* and *Moraxella catarrhalis* (Baron 1996).

responses (Kilty & Desrosiers, 2008; Zhang et al., 2005, Post et al., 2004).

**1. Introduction** 

the host:

microbiological aspects of rhinosinusitis.

invasion by pathogenic streptococci.

**2. Normal flora of upper respiratory tract** 

Wyrwick, KW, Tierney, WM, Babu, AN. et al. (2005) A comparison of clinically important differences in health-related quality of life fore patients with chronic lung disease, asthma or heart disease. *Health Serv Res*, Vol. 40:577-592.

## **2**

### **Microbiology Aspects of Rhinosinusitis**

Agnieszka Magryś, Jolanta Paluch-Oleś and Maria Kozioł-Montewka *Department of Medical Microbiology, Medical University of Lublin, Poland* 

#### **1. Introduction**

26 Peculiar Aspects of Rhinosinusitis

Wyrwick, KW, Tierney, WM, Babu, AN. et al. (2005) A comparison of clinically important

disease, asthma or heart disease. *Health Serv Res*, Vol. 40:577-592.

differences in health-related quality of life fore patients with chronic lung

Rhinosinusitis with its chronic benign course, failure in antibiotic treatment and acute exacerbations, usually require multiple courses of antibiotics or surgical procedures, or both. Nowadays, the pathogenic mechanisms of microbes in rhinosinusitis have gradually been revealed. Many current hypotheses focus on the formation of biofilms, bacterial superantigens, cytokine dysregulation, and abnormalities of cell-mediated immune responses (Kilty & Desrosiers, 2008; Zhang et al., 2005, Post et al., 2004).

"Rhinosinusitis" is a group of disorders characterized by inflammation of the mucosa of the nose and the paranasal sinuses. It is presently accepted that rhinosinusitis is initiated with an inflammatory insult (viral infection of upper respiratory tract, allergic rhinitis, etc.), followed by bacterial or fungal superinfection (Kennedy & Thaler, 1997; van Cauwenberge et al., 2006). Most upper respiratory tract infections are self-limited but progression to acute illness occurs and progression to chronic disease is common. Because specific treatment approaches are crucial for the different types of rhinosinusitis, this review focuses on microbiological aspects of rhinosinusitis.

#### **2. Normal flora of upper respiratory tract**

Most of the surfaces of the upper respiratory tract (including nasal and oral passages, nasopharynx, oropharynx, and trachea) are colonized by normal flora. The normal flora of human upper respiratory tract is harmless, and usually beneficial for the host. Two main functions are played by these bacteria, that are important in maintaining the healthy state of the host:


The nose is colonized predominantly by staphylococci, with *Staphylococcus aureus* and *Staphylococcus epidermidis* and diphtheroids as the leaders. The most important group of microorganisms native to oropharynx are also the alpha-hemolytic streptococci or viridans streptococci. This group includes *Streptococcus mitis, Streptococcus mutans, Streptococcus milleri,* and *Streptococcus salivarius*. It is believed that these bacteria act as antagonists against invasion by pathogenic streptococci.

But normal nasopharynx is not only the primary settlement of saprophytic bacteria. It is also the chief carrier of common respiratory pathogens, including *Streptococcus pneumoniae*, *Haemophilus influenzae* and *Moraxella catarrhalis* (Baron 1996).

Microbiology Aspects of Rhinosinusitis 29

Allergy is another factor that predispose to rhinosinusitis. Allergy can contribute to rhinosinusitis through either nasal congestion and subsequent ostial obstruction or direct allergic effects on sinus-lining cells. Obstructed sinus ostia, as the results of mucosal swelling and edema, may be more prone to infection **(Fokkens et al., 2007; Thaler & Kennedy, 2008).**  The other factors that predispose to acute rhinosinusitis are nasal polyposis, deviation of the nasal septum and dental procedures. Air pollution, cigarette smoking and overuse of topical decongestants impair ciliary action and predispose to rhinosinusitis as well (Fokkens et al.,

The upper respiratory tract represents a frequent site of infection because it is regularly exposed to direct contact and transmission of environmental pollutants and common

The most common factor associated with rhinosinusitis is upper respiratory infection, which is complicated by bacterial infection. Upper respiratory infections are mainly caused by viruses, leading to symptoms of common cold and inflammation of the paranasal sinuses. Viral rhinosinusitis has seasonal patterns of occurrence based on the virus involved. Rhinovirus is the most common cause of common cold and rhinosinusitis in all age groups, accounting for 30–70% of all respiratory illnesses. Other viruses causing upper respiratory infections are coronaviruses (7–18%), followed by influenza A and B, adenoviruses, parainfluenza viruses, respiratory syncytial viruses (RSV) and enteroviruses, all accounting for minor proportions of common cold cases (Thaler & Kennedy, 2008). Viral upper respiratory tract infection stimulates increases in inflammation and in the local immune response of the nasopharynx and surrounding mucosa. Some viruses, such as influenza virus, produce significant mucosal damage. Others promote the local production of cytokines and other inflammatory mediators, leading to the signs and symptoms of the common cold (Aanan, 2005). Clinically, patients experience a self-limiting illness lasting 3-7

Acute bacterial rhinosinusitis complicates approximately 0.5% of adult and 5% pediatric cases of viral infections. It is usually a secondary infection resulting from ostiomeatal complex obstruction, impaired (delayed or absent) mucociliary clearance and weakened mucociliary integrity caused by an acute viral upper respiratory tract infection (Sande &

Acute bacterial rhinosinusitis is a clinical condition characterized by nasal congestion, purulent rhinorrhea, postnasal dip and facial pain and pressure alone or with associated referred pain of the ears or teeth. The syndromes last for 7-14 days but no more than 4

Several factors may predispose an individual with viral rhinosinusitis to acquire a secondary bacterial infection, including viral virulence, nosopharyngeal colonization and host immunity. The role of bacteria in acute rhinosinusitis is well defined. S*treptococcus pneumoniae* (20%-45%) and non typable strains of *Haemophilus influenzae* (22%-35%)*,* are the most common pathogenic organisms in acute bacterial rhinosinusitis in adults*. Streptococcus* 

**3.3 Microbiology of acute rhinosinusitis: Viral or bacterial?** 

2007).

days.

Gwaltney, 2004).

weeks (Fokkens et al., 2007).

microbes during breathing.

### **3. Acute rhinosinusitis. Epidemiology and predisposing factors**

#### **3.1 Definition**

Sinusitis is inflammation of the sinuses, which are air-filled cavities in the skull. This inflammation leads to blockade of the normal sinus drainage pathways (sinus ostia), which in turn leads to mucus retention, hypoxia, decreased mucociliary clearance, and predisposition to bacterial growth. Acute rhinosinusitis is an inflammatory condition involving the paranasal sinuses, as well as the lining of the paranasal passages, and it lasts up to 4 weeks, after which the symptoms resolve completely. Sinus infection is defined as the invasion and multiplication of microorganisms within a sinus. The etiology can be infectious (bacterial, viral, or fungal) or noninfectious (allergic) triggers (Fokkens et al., 2007; Thaler & Kennedy, 2008).

European Position Statement on Rhinosinusitis and Nasal Polyps defines acute rhinosinusitis as sudden onset of two or more symptoms, one of which should be either nasal blockade/obstruction/congestion or nasal discharge (anterior/posterior nasal dip) with facial pain/pressure or reduction or loss of smell (Fokkens et al., 2007).

#### **3.2 Pathogenic factors of acute rhinosinusitis**

Acute rhinosinusitis occurs when one of the mechanisms essential to sinus clearance breaks down. The ostiomeatal complex is particularly vulnerable to inflammatory changes, swelling and obstruction. Anatomic variations and other factors generally predispose patients to acute bacterial rhinosinusitis by causing inflammation in the ostiomeatal complex. Normal ciliary function, intact mucous membranes and normal mucous production are required for sinus clearance. Many factors can disturb these functional mechanisms predisposing to acute infection (Kennedy & Thaler, 1997; Anon, 2005; Fokkens et al., 2007).

The initial stages of rhinosinusitis comprise inflammatory swelling of the sinus epithelium and mucosa, secretion of proinflammatory factors, including cytokines, accumulation of inflammatory cells, such as eosinophils and lymphocytes, and obstruction of the sinus ostia (Hadley & Siegert, 2004).

Data shows that viral upper respiratory tract infections and pharyngeal colonization with group A streptococci predispose children to acute bacterial rhinosinusitis. The incidence of viral infections in acute rhinosinusitis is unknown, but it is estimated that 0.5-5% of viral infections lead to sinusitis (Brook et al., 2000; Fokkens et al., 2007).

Normal mucociliary flow is a key defense mechanism in the prevention of acute rhinosinusitis. Viral rhinosinusitis results in the loss of ciliated cells and mucociliary flow during the first week of infection. Consequently, the impaired mucociliary function during viral rhinosinusitis increases the risk of bacterial superinfection, which, in turn, results in further disruption of mucociliary flow **(**Fokkens et al., 2007; Sande & Gwaltney 2004). Exposure to bacterial toxins can also reduce ciliary function. Approximately 10% of cases of acute rhinosinusitis result from direct inoculation of the sinus with a large amount of bacteria. Bacterial infection causes inflammation and swelling, which leads to increased mucus production, reduced air flow through the nasal cavity and mucus congestion in the sinuses, enhancing bacterial growth (Hadley & Siegret, 2004).

Sinusitis is inflammation of the sinuses, which are air-filled cavities in the skull. This inflammation leads to blockade of the normal sinus drainage pathways (sinus ostia), which in turn leads to mucus retention, hypoxia, decreased mucociliary clearance, and predisposition to bacterial growth. Acute rhinosinusitis is an inflammatory condition involving the paranasal sinuses, as well as the lining of the paranasal passages, and it lasts up to 4 weeks, after which the symptoms resolve completely. Sinus infection is defined as the invasion and multiplication of microorganisms within a sinus. The etiology can be infectious (bacterial, viral, or fungal) or noninfectious (allergic) triggers (Fokkens et al., 2007;

European Position Statement on Rhinosinusitis and Nasal Polyps defines acute rhinosinusitis as sudden onset of two or more symptoms, one of which should be either nasal blockade/obstruction/congestion or nasal discharge (anterior/posterior nasal dip)

Acute rhinosinusitis occurs when one of the mechanisms essential to sinus clearance breaks down. The ostiomeatal complex is particularly vulnerable to inflammatory changes, swelling and obstruction. Anatomic variations and other factors generally predispose patients to acute bacterial rhinosinusitis by causing inflammation in the ostiomeatal complex. Normal ciliary function, intact mucous membranes and normal mucous production are required for sinus clearance. Many factors can disturb these functional mechanisms predisposing to acute infection (Kennedy & Thaler, 1997; Anon, 2005; Fokkens

The initial stages of rhinosinusitis comprise inflammatory swelling of the sinus epithelium and mucosa, secretion of proinflammatory factors, including cytokines, accumulation of inflammatory cells, such as eosinophils and lymphocytes, and obstruction of the sinus ostia

Data shows that viral upper respiratory tract infections and pharyngeal colonization with group A streptococci predispose children to acute bacterial rhinosinusitis. The incidence of viral infections in acute rhinosinusitis is unknown, but it is estimated that 0.5-5% of viral

Normal mucociliary flow is a key defense mechanism in the prevention of acute rhinosinusitis. Viral rhinosinusitis results in the loss of ciliated cells and mucociliary flow during the first week of infection. Consequently, the impaired mucociliary function during viral rhinosinusitis increases the risk of bacterial superinfection, which, in turn, results in further disruption of mucociliary flow **(**Fokkens et al., 2007; Sande & Gwaltney 2004). Exposure to bacterial toxins can also reduce ciliary function. Approximately 10% of cases of acute rhinosinusitis result from direct inoculation of the sinus with a large amount of bacteria. Bacterial infection causes inflammation and swelling, which leads to increased mucus production, reduced air flow through the nasal cavity and mucus congestion in the

infections lead to sinusitis (Brook et al., 2000; Fokkens et al., 2007).

sinuses, enhancing bacterial growth (Hadley & Siegret, 2004).

**3. Acute rhinosinusitis. Epidemiology and predisposing factors** 

with facial pain/pressure or reduction or loss of smell (Fokkens et al., 2007).

**3.2 Pathogenic factors of acute rhinosinusitis** 

**3.1 Definition** 

et al., 2007).

(Hadley & Siegert, 2004).

Thaler & Kennedy, 2008).

Allergy is another factor that predispose to rhinosinusitis. Allergy can contribute to rhinosinusitis through either nasal congestion and subsequent ostial obstruction or direct allergic effects on sinus-lining cells. Obstructed sinus ostia, as the results of mucosal swelling and edema, may be more prone to infection **(Fokkens et al., 2007; Thaler & Kennedy, 2008).** 

The other factors that predispose to acute rhinosinusitis are nasal polyposis, deviation of the nasal septum and dental procedures. Air pollution, cigarette smoking and overuse of topical decongestants impair ciliary action and predispose to rhinosinusitis as well (Fokkens et al., 2007).

#### **3.3 Microbiology of acute rhinosinusitis: Viral or bacterial?**

The upper respiratory tract represents a frequent site of infection because it is regularly exposed to direct contact and transmission of environmental pollutants and common microbes during breathing.

The most common factor associated with rhinosinusitis is upper respiratory infection, which is complicated by bacterial infection. Upper respiratory infections are mainly caused by viruses, leading to symptoms of common cold and inflammation of the paranasal sinuses. Viral rhinosinusitis has seasonal patterns of occurrence based on the virus involved. Rhinovirus is the most common cause of common cold and rhinosinusitis in all age groups, accounting for 30–70% of all respiratory illnesses. Other viruses causing upper respiratory infections are coronaviruses (7–18%), followed by influenza A and B, adenoviruses, parainfluenza viruses, respiratory syncytial viruses (RSV) and enteroviruses, all accounting for minor proportions of common cold cases (Thaler & Kennedy, 2008). Viral upper respiratory tract infection stimulates increases in inflammation and in the local immune response of the nasopharynx and surrounding mucosa. Some viruses, such as influenza virus, produce significant mucosal damage. Others promote the local production of cytokines and other inflammatory mediators, leading to the signs and symptoms of the common cold (Aanan, 2005). Clinically, patients experience a self-limiting illness lasting 3-7 days.

Acute bacterial rhinosinusitis complicates approximately 0.5% of adult and 5% pediatric cases of viral infections. It is usually a secondary infection resulting from ostiomeatal complex obstruction, impaired (delayed or absent) mucociliary clearance and weakened mucociliary integrity caused by an acute viral upper respiratory tract infection (Sande & Gwaltney, 2004).

Acute bacterial rhinosinusitis is a clinical condition characterized by nasal congestion, purulent rhinorrhea, postnasal dip and facial pain and pressure alone or with associated referred pain of the ears or teeth. The syndromes last for 7-14 days but no more than 4 weeks (Fokkens et al., 2007).

Several factors may predispose an individual with viral rhinosinusitis to acquire a secondary bacterial infection, including viral virulence, nosopharyngeal colonization and host immunity. The role of bacteria in acute rhinosinusitis is well defined. S*treptococcus pneumoniae* (20%-45%) and non typable strains of *Haemophilus influenzae* (22%-35%)*,* are the most common pathogenic organisms in acute bacterial rhinosinusitis in adults*. Streptococcus* 

Microbiology Aspects of Rhinosinusitis 31

findings than those infected with *Haemophilus influenzae*. This fact could result in less severe symptoms and radiographic findings in patients with acute form of the disease (Benninger

*Rhinovirus* 15%-40% 1%

*Adenovirus* ---- 2%

*Influenzae virus* 5% ----

*Parainfluenzae virus* 3% 2%

*Streptococcus pneumoniae* 20%-45% 30%-45%

*Haemophilus influenzae\** 22%-35% 20%-28%

*Moraxella catarrhalis* 0%-8% 20%-28%

*Staphylococcus aureus* 0%-10% 0%-8%

*Streptococcus pyogenes* 0%-7% 3%-9%

Table 1. The commonest pathogens in acute rhinosinusitis. Data are from (Thaler &

Bacterial and viral rhinosinusitis are difficult to differentiate on clinical grounds. On the other hand, bacterial rhinosinusitis must be distinguished from viral infection and treated

**Percentages** 

**Adults Children** 

& Manz, 2010).

**Viruses** 

**Bacteria** 

*\** non typable strains

Kennedy, 2008; Sande & Gwaltney, 2004).

**3.4 Microbiology diagnostics of acute rhinosinusitis** 

**Pathogens** 

*pneumoniae* (30%-45%)*,* non typabl*e Haemophilus influenzae* (20%-28%) and *Morraxella catarrhalis* (20-28%) are reported as predominant in children with acute bacterial rhinosinusitis. Until now *Staphylococcus aureus* has often been considered as a contaminant, but a recent data suggests that *Staphylococcus aureus* is a true pathogen in about 10% of cases of acute bacterial rhinosinusitis in adults (Benninger & Manz 2010; Payne, 2007) (Table 1). This is not surprising, as all these pathogens can be the parts of normal flora in upper respiratory tract.

The growing resistance to antimicrobial agents of all respiratory tract bacterial pathogens has made the management of bacterial rhinosinusitis more difficult.

*Streptococcus pneumoniae* are gram-positive, catalase-negative, facultatively anaerobic cocci that account for up to 45% of acute bacterial rhinosinusitis cases in adults and children. The rise of antimicrobial resistance in *Streptococcus pneumoniae* is a major concern. The most alarming situation is the occurrence of strains with decreased susceptibility to penicillin, that was the drug of choice in pneumococcal infections for many years. Penicillin resistance means the resistance or decreased susceptibility to other β-lactams. This is applied mostly for cephalosporins. Moreover, strains resistant to penicillin are also multi-drug resistant (resistance to macrolids, tetracycline, co-trimoxazole). However, they are still susceptible to increased doses of amoxicillin (Mazur, 2010; Aanan 2005)**.** 

*Haemophilus influenzae* is the second commonest agent of bacterial acute rhinosinusitis responsible for about 25% of rhinosinusitis cases in children. Studies have reported the presence of this bacterium in up to a third of adult rhinosinusitis patients as well. Betalactamase production is the mechanism of antimicrobial resistance for this organism. Of isolates from the paranasal sinus, 32.7% were found to be β-lactamase–positive. Other reports suggest a rate of 44%*.* 

*Moraxella catarrhalis* is mainly isolated from children. Over 75% of all children harbor this bacterium, which causes about 25% of rhinosinusitis cases. The strains of *Moraxella catarrhalis* commonly (more than 90% strains) produce β-lactamases all over the world (Mazur, 2010; Aanan, 2005).

The widespread antibiotic resistance among pathogens that are agents of rhinosinusitis allows for the persistence of infection and the development of chronic rhinosinusitis (CRS) (Thaler & Kennedy, 2008).

Nowadays it is noted that the vaccination of children with heptavalent conjugate pneumococcal vaccine results in significant shift in causative pathogens of acute bacterial rhinosinusitis. While the proportion of *Streptococcus pneumoniae* declined by 11%, the proportion of *Haemophilus influenzae* increased by 6%. A small increase in the isolation of other pathogens (*Moraxella catarrhalis, Staphylococcus auresus* and *Streptococcus pyogenes*) was also noted (Brook et al., 2006). Widespread use of conjugate pneumococcal vaccine has led to decreasing incidence of pneumococcal acute bacterial rhinosinusitis, which may have implications for treatment recommendations for these infections (Benninger, 2008)*.* This pathogen shift may also have an important effect on the severity of acute bacterial rhinosinusitis. It is documented, that patients with acute bactericidal rhinosinusitis infected with *Streptococus pneumoniae* have more significant symptoms and worse radiographic

*pneumoniae* (30%-45%)*,* non typabl*e Haemophilus influenzae* (20%-28%) and *Morraxella catarrhalis* (20-28%) are reported as predominant in children with acute bacterial rhinosinusitis. Until now *Staphylococcus aureus* has often been considered as a contaminant, but a recent data suggests that *Staphylococcus aureus* is a true pathogen in about 10% of cases of acute bacterial rhinosinusitis in adults (Benninger & Manz 2010; Payne, 2007) (Table 1). This is not surprising, as all these pathogens can be the parts of normal flora in upper

The growing resistance to antimicrobial agents of all respiratory tract bacterial pathogens

*Streptococcus pneumoniae* are gram-positive, catalase-negative, facultatively anaerobic cocci that account for up to 45% of acute bacterial rhinosinusitis cases in adults and children. The rise of antimicrobial resistance in *Streptococcus pneumoniae* is a major concern. The most alarming situation is the occurrence of strains with decreased susceptibility to penicillin, that was the drug of choice in pneumococcal infections for many years. Penicillin resistance means the resistance or decreased susceptibility to other β-lactams. This is applied mostly for cephalosporins. Moreover, strains resistant to penicillin are also multi-drug resistant (resistance to macrolids, tetracycline, co-trimoxazole). However, they are still susceptible to

*Haemophilus influenzae* is the second commonest agent of bacterial acute rhinosinusitis responsible for about 25% of rhinosinusitis cases in children. Studies have reported the presence of this bacterium in up to a third of adult rhinosinusitis patients as well. Betalactamase production is the mechanism of antimicrobial resistance for this organism. Of isolates from the paranasal sinus, 32.7% were found to be β-lactamase–positive. Other

*Moraxella catarrhalis* is mainly isolated from children. Over 75% of all children harbor this bacterium, which causes about 25% of rhinosinusitis cases. The strains of *Moraxella catarrhalis* commonly (more than 90% strains) produce β-lactamases all over the world

The widespread antibiotic resistance among pathogens that are agents of rhinosinusitis allows for the persistence of infection and the development of chronic rhinosinusitis (CRS)

Nowadays it is noted that the vaccination of children with heptavalent conjugate pneumococcal vaccine results in significant shift in causative pathogens of acute bacterial rhinosinusitis. While the proportion of *Streptococcus pneumoniae* declined by 11%, the proportion of *Haemophilus influenzae* increased by 6%. A small increase in the isolation of other pathogens (*Moraxella catarrhalis, Staphylococcus auresus* and *Streptococcus pyogenes*) was also noted (Brook et al., 2006). Widespread use of conjugate pneumococcal vaccine has led to decreasing incidence of pneumococcal acute bacterial rhinosinusitis, which may have implications for treatment recommendations for these infections (Benninger, 2008)*.* This pathogen shift may also have an important effect on the severity of acute bacterial rhinosinusitis. It is documented, that patients with acute bactericidal rhinosinusitis infected with *Streptococus pneumoniae* have more significant symptoms and worse radiographic

has made the management of bacterial rhinosinusitis more difficult.

increased doses of amoxicillin (Mazur, 2010; Aanan 2005)**.** 

respiratory tract.

reports suggest a rate of 44%*.* 

(Mazur, 2010; Aanan, 2005).

(Thaler & Kennedy, 2008).

findings than those infected with *Haemophilus influenzae*. This fact could result in less severe symptoms and radiographic findings in patients with acute form of the disease (Benninger & Manz, 2010).


*\** non typable strains

Table 1. The commonest pathogens in acute rhinosinusitis. Data are from (Thaler & Kennedy, 2008; Sande & Gwaltney, 2004).

#### **3.4 Microbiology diagnostics of acute rhinosinusitis**

Bacterial and viral rhinosinusitis are difficult to differentiate on clinical grounds. On the other hand, bacterial rhinosinusitis must be distinguished from viral infection and treated

Microbiology Aspects of Rhinosinusitis 33

CT scans of the paranasal sinuses should be performed only when surgery is being considered. CT scans are indicated in children with complications of acute bacterial sinus infection or those with very persistent or recurrent infections that are not responsive to

Chronic rhinosinusitis can be defined as a group of disorders characterized by inflammation of the mucosal lining of the nasal cavity and para-nasal sinuses lasting for at least 12 weeks. Symptoms are much more subtle then with acute rhinosinusitis. In order to diagnose chronic rhinosinusitis, patients are required to have 2 of the following symptoms for at least 12 consecutive weeks: (1) anterior and /or posterior mucopurulent drainage, (2) nasal obstruction and (3) hyposmia or anosmia but also objective evidence of sino-nasal inflammation on both endoscopy and radiological imaging with computerised tomography. Fever is not typically observed. According to the definitions of the European Position Paper on Rhinosinusitis and Nasal Polyps, chronic rhinosinusitis and nasal polyposis are considered as one disease entity, in which nasal polyposis forms a subgroup of chronic

Chronic rhinosinusitis is mostly diagnosed in association with predisposing conditions such as asthma, allergy, dental disease, cystic fibrosis, polyposis and immunodeficiency

It has been postulated that chronic rhinosinusitis evolves from acute rhinosinusitis, but this has never been definitively proven. Also, the role of bacterial infection in chronic

Chronic rhinosinusitis is now considered a multi-factorial disease involving multiple host and environmental factors. This factors has been broadly categorized into extrinsic or non-host related factors and intrinstic or host related factors. Extrinsic factors that have been implicated as etiologies contributing to the development of CRS include viral, bacterial, and/or fungal colonization and their associated pathogenicity (biofilms, superantigens, osteitis and non-IgE mediated eosinophilic inflammation) as well as exposure to inhaled substances, such as cigarette smoke or allergens. Intrinsic factors found to be associated with chronic rhinosinusitis include anatomic/structural abnormalities, genetic abnormalities, such as cystic fibrosis or primary ciliary dyskinesia and disorders in innate and cell mediated immune system (van Cauwenberg & van

The presence of intracellular *Staphylococcus aureus* in epithelial cells of the nasal mucosa has been suggested to play a significant risk for recurrent episodes of rhinosinusitis due to persistent bacterial clonotypes, which appear refractory to antimicrobial and surgical

rhinosinusitis is less clear than in acute rhinosinusitis (Thaler & Kennedy, 2008).

medical therapy (McAlister et al., 2000; American Academy of Pediatrics, 2001).

**4. Chronic rhinosinusitis** 

rhinosinusitis (Fokkens et al., 2007).

**4.2 Pathogenic factors** 

Hoeche, 2006).

therapy (Plouin-Gaudon et al., 2006).

syndrome (Thaler & Kennedy, 2008; Kennedy & Thaler, 1997).

**4.1 Definition** 

with antibiotics, because serious complications may be associated when bacterial superinfection develops. (Hytönen et al., 2000; Herrmann & Forsen 2004). The reference standard for the diagnosis of acute bacterial rhinosinusitis is sinus puncture with culture and recovery of bacteria in high density (≥ 104 colony forming units/mL) (Hart, 2007). Although sinus aspiration with the possible bacterial culture is the "gold standard" for the diagnosis of acute bacterial rhinosinusitis, it is not recommended in general practice. The reasons are that the procedure is invasive, time-consuming and potentially painful for the patient and can only be performed by a specialist as it requires a local anestethic. However, the results of sinus aspiration correlate with clinical and radiographic findings in patients with acute respiratory symptoms.

The most widely used diagnostic procedures for acute rhinosinusitis are signs and symptoms, supported by radiographic findings. Some experts believe that bacteriological cultures from the posterior parts of nasal cavity and nasopharyngeal aspirates best identify those patients with bacterial superinfection (Anan, 2005).

Because of the difficulty associated with distinguishing viral from bacterial rhinosinusitis, the diagnosis of acute bacterial rhinosinusitis is mostly reserved for patients who experience rhinosinusitis symptoms (eg, sinus pain, tooth pain, nasal congestion) for more than 7 days (Hart, 2007).

#### **3.5 Current recommendations for diagnosing acute rhinosinusitis in children**

Although sinus aspiration is the "gold standard" for the diagnosis of acute bacterial rhinosinusitis, it is not recommended method for routine diagnosis of bacterial sinus infections in children. According to recommendations of American Academy of Pediatrics the diagnosis of acute bacterial rhinusitis is based on clinical criteria in children who present with upper respiratory symptoms that are either persistent or severe (American Academy of Pediatrics, 2001).

*Persistent symptoms* are symptoms of upper respiratory tract infection that last longer than 10 days to 14 days, but less than 30 days. Such symptoms include nasal or postnasal discharge, daytime cough (which may be worse at night), or both.

*Severe symptoms* include a temperature of at least 39ºC and purulent nasal discharge present concurrently for at least 3 to 4 consecutive days in a child who seems ill. In this clinical presentation, the duration of symptoms is not important, and antimicrobial treatment is recommended to be started as soon as possible (American Academy of Pediatrics, 2001).

American Academy of Pediatrics has taken the position that, in children six years and younger who are at the peak age for developing acute bacterial sinusitis, a diagnosis can be made without performing imaging studies. However, controversy exists about the need for radiographs to confirm acute sinusitis in children older than six years with persistent symptoms and for children of any age with severe symptoms (American Academy of Pediatrics, 2001). The American College of Radiology recommends that the diagnosis be made on clinical criteria and that radiographs be used only in patients who do not recover or who worsen during the course of antimicrobial therapy (McAlister et al., 2000).

CT scans of the paranasal sinuses should be performed only when surgery is being considered. CT scans are indicated in children with complications of acute bacterial sinus infection or those with very persistent or recurrent infections that are not responsive to medical therapy (McAlister et al., 2000; American Academy of Pediatrics, 2001).

#### **4. Chronic rhinosinusitis**

#### **4.1 Definition**

32 Peculiar Aspects of Rhinosinusitis

with antibiotics, because serious complications may be associated when bacterial superinfection develops. (Hytönen et al., 2000; Herrmann & Forsen 2004). The reference standard for the diagnosis of acute bacterial rhinosinusitis is sinus puncture with culture and recovery of bacteria in high density (≥ 104 colony forming units/mL) (Hart, 2007). Although sinus aspiration with the possible bacterial culture is the "gold standard" for the diagnosis of acute bacterial rhinosinusitis, it is not recommended in general practice. The reasons are that the procedure is invasive, time-consuming and potentially painful for the patient and can only be performed by a specialist as it requires a local anestethic. However, the results of sinus aspiration correlate with clinical and radiographic findings in patients

The most widely used diagnostic procedures for acute rhinosinusitis are signs and symptoms, supported by radiographic findings. Some experts believe that bacteriological cultures from the posterior parts of nasal cavity and nasopharyngeal aspirates best identify

Because of the difficulty associated with distinguishing viral from bacterial rhinosinusitis, the diagnosis of acute bacterial rhinosinusitis is mostly reserved for patients who experience rhinosinusitis symptoms (eg, sinus pain, tooth pain, nasal congestion) for more than 7 days

Although sinus aspiration is the "gold standard" for the diagnosis of acute bacterial rhinosinusitis, it is not recommended method for routine diagnosis of bacterial sinus infections in children. According to recommendations of American Academy of Pediatrics the diagnosis of acute bacterial rhinusitis is based on clinical criteria in children who present with upper respiratory symptoms that are either persistent or severe (American Academy of

*Persistent symptoms* are symptoms of upper respiratory tract infection that last longer than 10 days to 14 days, but less than 30 days. Such symptoms include nasal or postnasal discharge,

*Severe symptoms* include a temperature of at least 39ºC and purulent nasal discharge present concurrently for at least 3 to 4 consecutive days in a child who seems ill. In this clinical presentation, the duration of symptoms is not important, and antimicrobial treatment is recommended to be started as soon as possible (American Academy of

American Academy of Pediatrics has taken the position that, in children six years and younger who are at the peak age for developing acute bacterial sinusitis, a diagnosis can be made without performing imaging studies. However, controversy exists about the need for radiographs to confirm acute sinusitis in children older than six years with persistent symptoms and for children of any age with severe symptoms (American Academy of Pediatrics, 2001). The American College of Radiology recommends that the diagnosis be made on clinical criteria and that radiographs be used only in patients who do not recover

or who worsen during the course of antimicrobial therapy (McAlister et al., 2000).

**3.5 Current recommendations for diagnosing acute rhinosinusitis in children** 

with acute respiratory symptoms.

(Hart, 2007).

Pediatrics, 2001).

Pediatrics, 2001).

those patients with bacterial superinfection (Anan, 2005).

daytime cough (which may be worse at night), or both.

Chronic rhinosinusitis can be defined as a group of disorders characterized by inflammation of the mucosal lining of the nasal cavity and para-nasal sinuses lasting for at least 12 weeks. Symptoms are much more subtle then with acute rhinosinusitis. In order to diagnose chronic rhinosinusitis, patients are required to have 2 of the following symptoms for at least 12 consecutive weeks: (1) anterior and /or posterior mucopurulent drainage, (2) nasal obstruction and (3) hyposmia or anosmia but also objective evidence of sino-nasal inflammation on both endoscopy and radiological imaging with computerised tomography. Fever is not typically observed. According to the definitions of the European Position Paper on Rhinosinusitis and Nasal Polyps, chronic rhinosinusitis and nasal polyposis are considered as one disease entity, in which nasal polyposis forms a subgroup of chronic rhinosinusitis (Fokkens et al., 2007).

Chronic rhinosinusitis is mostly diagnosed in association with predisposing conditions such as asthma, allergy, dental disease, cystic fibrosis, polyposis and immunodeficiency syndrome (Thaler & Kennedy, 2008; Kennedy & Thaler, 1997).

It has been postulated that chronic rhinosinusitis evolves from acute rhinosinusitis, but this has never been definitively proven. Also, the role of bacterial infection in chronic rhinosinusitis is less clear than in acute rhinosinusitis (Thaler & Kennedy, 2008).

#### **4.2 Pathogenic factors**

Chronic rhinosinusitis is now considered a multi-factorial disease involving multiple host and environmental factors. This factors has been broadly categorized into extrinsic or non-host related factors and intrinstic or host related factors. Extrinsic factors that have been implicated as etiologies contributing to the development of CRS include viral, bacterial, and/or fungal colonization and their associated pathogenicity (biofilms, superantigens, osteitis and non-IgE mediated eosinophilic inflammation) as well as exposure to inhaled substances, such as cigarette smoke or allergens. Intrinsic factors found to be associated with chronic rhinosinusitis include anatomic/structural abnormalities, genetic abnormalities, such as cystic fibrosis or primary ciliary dyskinesia and disorders in innate and cell mediated immune system (van Cauwenberg & van Hoeche, 2006).

The presence of intracellular *Staphylococcus aureus* in epithelial cells of the nasal mucosa has been suggested to play a significant risk for recurrent episodes of rhinosinusitis due to persistent bacterial clonotypes, which appear refractory to antimicrobial and surgical therapy (Plouin-Gaudon et al., 2006).

Microbiology Aspects of Rhinosinusitis 35

activates only 0.01% of all T cells. In the acute setting superantigens may lead to the sudden and massive release of Th1 and Th2 cytokines which accounts for their acute toxicity

Evidence accumulates that S*taphylococcus aureus* colonizes a high percentage of patients with chronic rhinosinusitis with nasal polyposis. *Staphylococcus aureus* can secrete at least 19 different exotoxins capable of functioning as superantigens, triggering massive T-cell activation, and induces an overproduction of immunoglobulin E, as well as a severe

Understanding how superantigens overstimulate the immune system is crucial to set up rational therapeutics for chronic rhinosinusitis. Patients with eosinophilic chronic rhinosinusitis remain the most refractory to medical and surgical intervention (Seiberling,

One possible mechanism for the chronic nature of rhinosinusitis is the involvement of bacterial biofilms. Recent publications estimate that at least 65% of all chronic bacterial

Biofilms are three-dimensional bacterial aggregates embedded together in the slimelike matrix composed of polysaccharides, nucleic acids and proteins (extracellular polymeric substances). Bacteria in biofilm are under different transcriptional regulation and are thus phenotypically different than free living bacteria. The vast majority of bacteria, regardless of species, exist within a biofilm, including those that are important in rhinosinusitis, such as *Haemophilus influenzae*, *Streptococcus pneumoniae* and *Staphylococcus aureus* (Kilty &

The formation of a bacterial biofilm occurs in several concurrent steps. The initiating event is the attachment of individual bacterial cells to a surface by weak reversible physical forces. Differentiation of the biofilm after attachment depends on cell-to-cell signaling, which facilitate the binding of other bacteria to the infected surface. This process initiates phenotypic changes within the bacteria to irreversibly secure the initial

The second stage involves irreversible attachment between specific microbial adhesins and the surface. One important element of this process is polysaccharide intracellular adhesion

Cell aggregation into microcolonies and their division ensure the continued growth of the biofilm into complex structure. When biofilms reach their critical mass, single bacterium or aggregates of bacteria can disperse into the surrounding environment. After detachment bacteria can be redistributed to other areas of the host surface, where further biofilm growth

Owing to its multicellular nature, biofilms provide bacteria with distinct advantages. An adventage that is extremely important clinically is that bacteria in biofilms are very resistant to antibiotics, capable of surviving antibiotic concentrations thousands of time greater than

(PIA), that mediates the cell-cell interactions in some staphylococcal biofilms.

possibly steroid-insensitive eosinophilic inflammation.(Zhang et al., 2005).

infections involve biofilms (Kilty & Desrosiers, 2008; Post et al., 2004).

(Llewelyn et al., 2002; Seiberling, Conley et al., 2005).

Conley et al., 2005).

Desrosiers, 2008).

attachment.

can be initiated (Post et al., 2004).

**4.3.3 Bacterial biofilm** 

#### **4.3 Bacteria and chronic rhinosinusitis**

The microbiology of chronic rhinosinusitis differs when comparing to acute rhinosinusitis. Study shows that in patients with chronic rhinosinusitis, pathogens such as *Staphylococcus aureus*, coagulase negative streptococci and anaerobic Gram-negative bacteria replace the pathogens commonly found in bacterial acute rhinosinusitis. The prevalence of anaerobic species can be explained by physiologic changes in the sinuses including reduced oxygen tension and pH, thereby creating a favorable environment for these organisms (van Cauwenberge et al., 2006; Thaler & Kennedy 2008).

#### **4.3.1 Controversy regarding the role of bacteria in chronic rhinosinusitis**

In contrast with the well-established roles of microbes in the etiology of acute sinusitis with *Streptococcus pneumoniae, Moraxella catarrhalis* and non typable *Haemophilus influenzae* strains as the most common pathogens involved, the exact roles of all of these microbes in the etiology of chronic sinusitis are uncertain. Until now, there have been many controversies concerning the microbial involvement in chronic sinusitis (Kilty & Desrosiers, 2008; Thaler & Kennedy, 2008).

It has been postulated that in many cases of chronic rhinosinusitis bacteria can be present only as non-pathogens. This conclusion arose from the observation, that the sinuses are not sterile as once taught. Also, the fact that poor correlation is observed between clinical findings, microbiology and antibiotic therapy confirmed the limited role of bacteria in chronic rhinosinustis (Post et al., 2004; van Cauwenberge et al., 2006).

Much of the disagreement may be explained by methodology used. Different studies used different sampling methods as well as different methods to detect bacteria and quantify bacterial load (culture vs. PCR). It is thought that these differences may not only affect the culture yield rate but also the type of organism isolated (Kilty & Desrosiers, 2008).

Nowadays, the role of bacteria in chronic rhinosinusitis have gradually been revealed. Several theories raised to explain the patophysiology of this chronic disease. It is currently thought that chronic rhinosinusitis is an immunological inflammatory disease caused simultaneously or singly by several factors, such as: immune conditions, intrinsic upper airway factors, *Staphylococcus aureus* superantigens, and persistent biofilm presence and/or osteitis of the sinus wall (Bezerra et al., 2009)**.** In this paper, the role of bacterial superantigens and biofilm will be overviewed.

#### **4.3.2 Bacterial superantigens**

The superantigen hypothesis of chronic rhinosinusitis suggests that bacterial toxins within the nose stimulate massive oligoclonal expansion of T-cell populations with subsequent eosinophil recruitment and tissue inflammation (Seiberling, Grammer, et al., 2005).

In the pathogenesis of chronic rhinosinusitis with nasal polyposis, this theory have been supported by several studies. Superantigens are microbial derived toxins capable of triggering massive T cell proliferation and activation. They have the ability to activate up to 30% of the T-cell population in contrast to the conventional antigen response, which

The microbiology of chronic rhinosinusitis differs when comparing to acute rhinosinusitis. Study shows that in patients with chronic rhinosinusitis, pathogens such as *Staphylococcus aureus*, coagulase negative streptococci and anaerobic Gram-negative bacteria replace the pathogens commonly found in bacterial acute rhinosinusitis. The prevalence of anaerobic species can be explained by physiologic changes in the sinuses including reduced oxygen tension and pH, thereby creating a favorable environment for these organisms (van

In contrast with the well-established roles of microbes in the etiology of acute sinusitis with *Streptococcus pneumoniae, Moraxella catarrhalis* and non typable *Haemophilus influenzae* strains as the most common pathogens involved, the exact roles of all of these microbes in the etiology of chronic sinusitis are uncertain. Until now, there have been many controversies concerning the microbial involvement in chronic sinusitis (Kilty & Desrosiers, 2008; Thaler

It has been postulated that in many cases of chronic rhinosinusitis bacteria can be present only as non-pathogens. This conclusion arose from the observation, that the sinuses are not sterile as once taught. Also, the fact that poor correlation is observed between clinical findings, microbiology and antibiotic therapy confirmed the limited role of bacteria in

Much of the disagreement may be explained by methodology used. Different studies used different sampling methods as well as different methods to detect bacteria and quantify bacterial load (culture vs. PCR). It is thought that these differences may not only affect the

Nowadays, the role of bacteria in chronic rhinosinusitis have gradually been revealed. Several theories raised to explain the patophysiology of this chronic disease. It is currently thought that chronic rhinosinusitis is an immunological inflammatory disease caused simultaneously or singly by several factors, such as: immune conditions, intrinsic upper airway factors, *Staphylococcus aureus* superantigens, and persistent biofilm presence and/or osteitis of the sinus wall (Bezerra et al., 2009)**.** In this paper, the role of bacterial

The superantigen hypothesis of chronic rhinosinusitis suggests that bacterial toxins within the nose stimulate massive oligoclonal expansion of T-cell populations with subsequent

In the pathogenesis of chronic rhinosinusitis with nasal polyposis, this theory have been supported by several studies. Superantigens are microbial derived toxins capable of triggering massive T cell proliferation and activation. They have the ability to activate up to 30% of the T-cell population in contrast to the conventional antigen response, which

eosinophil recruitment and tissue inflammation (Seiberling, Grammer, et al., 2005).

culture yield rate but also the type of organism isolated (Kilty & Desrosiers, 2008).

**4.3.1 Controversy regarding the role of bacteria in chronic rhinosinusitis** 

chronic rhinosinustis (Post et al., 2004; van Cauwenberge et al., 2006).

**4.3 Bacteria and chronic rhinosinusitis** 

& Kennedy, 2008).

Cauwenberge et al., 2006; Thaler & Kennedy 2008).

superantigens and biofilm will be overviewed.

**4.3.2 Bacterial superantigens** 

activates only 0.01% of all T cells. In the acute setting superantigens may lead to the sudden and massive release of Th1 and Th2 cytokines which accounts for their acute toxicity (Llewelyn et al., 2002; Seiberling, Conley et al., 2005).

Evidence accumulates that S*taphylococcus aureus* colonizes a high percentage of patients with chronic rhinosinusitis with nasal polyposis. *Staphylococcus aureus* can secrete at least 19 different exotoxins capable of functioning as superantigens, triggering massive T-cell activation, and induces an overproduction of immunoglobulin E, as well as a severe possibly steroid-insensitive eosinophilic inflammation.(Zhang et al., 2005).

Understanding how superantigens overstimulate the immune system is crucial to set up rational therapeutics for chronic rhinosinusitis. Patients with eosinophilic chronic rhinosinusitis remain the most refractory to medical and surgical intervention (Seiberling, Conley et al., 2005).

#### **4.3.3 Bacterial biofilm**

One possible mechanism for the chronic nature of rhinosinusitis is the involvement of bacterial biofilms. Recent publications estimate that at least 65% of all chronic bacterial infections involve biofilms (Kilty & Desrosiers, 2008; Post et al., 2004).

Biofilms are three-dimensional bacterial aggregates embedded together in the slimelike matrix composed of polysaccharides, nucleic acids and proteins (extracellular polymeric substances). Bacteria in biofilm are under different transcriptional regulation and are thus phenotypically different than free living bacteria. The vast majority of bacteria, regardless of species, exist within a biofilm, including those that are important in rhinosinusitis, such as *Haemophilus influenzae*, *Streptococcus pneumoniae* and *Staphylococcus aureus* (Kilty & Desrosiers, 2008).

The formation of a bacterial biofilm occurs in several concurrent steps. The initiating event is the attachment of individual bacterial cells to a surface by weak reversible physical forces. Differentiation of the biofilm after attachment depends on cell-to-cell signaling, which facilitate the binding of other bacteria to the infected surface. This process initiates phenotypic changes within the bacteria to irreversibly secure the initial attachment.

The second stage involves irreversible attachment between specific microbial adhesins and the surface. One important element of this process is polysaccharide intracellular adhesion (PIA), that mediates the cell-cell interactions in some staphylococcal biofilms.

Cell aggregation into microcolonies and their division ensure the continued growth of the biofilm into complex structure. When biofilms reach their critical mass, single bacterium or aggregates of bacteria can disperse into the surrounding environment. After detachment bacteria can be redistributed to other areas of the host surface, where further biofilm growth can be initiated (Post et al., 2004).

Owing to its multicellular nature, biofilms provide bacteria with distinct advantages. An adventage that is extremely important clinically is that bacteria in biofilms are very resistant to antibiotics, capable of surviving antibiotic concentrations thousands of time greater than

Microbiology Aspects of Rhinosinusitis 37

Hadley, J.A. & Siegret R. (2004). *Clinician's manual on rhinosinusitis.* Science Press Ltd,

Hart, A.M. (2007). *Diagnosis and management of acute respiratory infections: acute* 

Herrmann, BW & Forsen, JW Jr (2004) *Simultaneous intracranial and orbital complications of* 

Hytönen, M., Atula, T. & Pitkäranta, A. (2000) *Complications of acute sinusitis in children.*

Kennedy, D.W. & Thaler E.R. (1997). Acute vs. chronic sinusitis: etiology, management, and outcomes. Infect. *Dis. Clin. Pract* Vol. 2 Suppl 2, pp. (S 49-S 58) Kilty, S.J., & Desrosiers, M.Y. (2008). The role of bacterial biofilms and the

Llewelyn, M. & Cohen, J. (2002). Superantigens: microbial agents that corrupt immunity.

Mazur, E. (2010). Rational antibiotic therapy of acute upper respiratory tract infections.

McAlister, W.H., Parker, B.R., Kushner, D.C. (2000). *Sinusitis in the pediatric population.* In: ACR Appropriateness Criteria. Reston, VA: American College of Radiology. Payne, S.C, & Benninger, M.S. (2007). *Staphylococcus aureus is a major pathogen in acute bacterial rhinosinusitis: a meta-analysis.* Clin. Infect. Dis. Vol.45, pp. (121–127) Plouin-Gaudon, I., Clement, S., Huggler, E , Chaponnier, C, Francosis, P., Lew, D.,

Post, J.Ch., Stoodley, P., Hall-Stoodley, L. & Ehrlich, G.D. (2004). The role of biofilms in

Ryan, D. (2008). *Management of acute rhinosinusitis in primary care: changing paradigms and the role of intranasal corticosteroids.* Prim. Care Resp. J. Vol. 17, No. 3, pp. (148-155) Sande, M.A. & Gwaltney, J.M. (2004). *Acute community-acquired bacterial sinusitis:* 

Seiberling, K.A, Conley, D.B., Tripathi, A., Grammer, L.C., Shuh L, Haines, G.K.,

Seiberling, K.A., Grammer, L. & Kern, R.C. (2005). *Chronic rhinosinusitis and superantigens.*

Thaler, E.R. & Kennedy D.W. (2008). *Rhinosinusitis: a guide for diagnosis and management.*

van Cauwenberge, P, van Hoecke, H. & Bachert C. (2006) Pathogenesis of chronic

Otolaryngol. Clin. North Am. Vol. 38, No. 6, pp. (1215-1236)

rhinosinusitis. Curr. *Allergy Asthma Rep.* Vol. 6, pp. (487-494)

Springer. ISBN: 978-0-387-73061-5, USA.

*acute rhinosinusitis in children*. Int J Pediatr Otorhinolaryngol Vol. 68, No. 5, pp.

pathophysiology of chronic rhinosinusitis. Curr. Allergy Asthma Rep. Vol. 8,

Schrenzel, J, Vaudaux, P. & Lacroix, J.S. (2006). *Intracellular residency is frequently associated with recurrent Staphylococcus aureus rhinosinusitis.* Rhinology. Vol. 44,

otolaryngologic infections. *Curr. Opin. in Otolaryngol. Head Neck Surg*., Vol. 12,

*continuing challenges and current management.* Clin. Infect. Dis. Vol. 39 Suppl 3, pp.

Schleimer, R.& Kern, R.C. (2005). *Superantigens and chronic rhinosinusitis: detection of staphylococcal exotoxins in nasal polyps*. The Laryngoscope, Vol. 115, pp. (1580-

*rhinosinusitis.* J. Nurs. Pract. Vol.3, No.9, pp. (607-611)

Acta Otolaryngol Suppl 543, pp.(154–157)

Lancet Infect Dis. Vol. 2, No. 3, pp. (156-162)

*Pol. Merk. Lek.* XXIX, Vol. 173, pp. (304-308)

ISBN 1-85873-994-2, Italy

(619–625)

pp.(227-233)

No. 4, pp. (249-254)

pp.(185-190)

(S151-S158)

1585)

free living bacteria (Post et al., 2004). Also, biofilm formation makes the bacteria resistant to host defense mechanisms, because the aggregation of bacteria into biofilm cannot be phagocytized, humoral immune system is not effective against aggregated bacteria as well.

The same properties that make bacteria within biofilm resistant to antibiotics and to the attack of immune system also make it difficult to identify them in laboratory by routine methods. Bacterial biofilms have been found in patients with chronic rhinosinusitis by scanning electron microscopy (SEM), transmission electron microscopy (TEM), confocal scanning laser microscopy, or fluorescent in situ hybridization (FISH) successfully. The use of PCR-based techniques demonstrates a high detection rate of bacterial pathogens in chronic diseases when comparing with conventional culture technique (Kilty & Destrosiers, 2008).

The fact that bacterial existence in the form of biofilm in probably preferred in chronic infections, there is growing evidence for the presence of bacterial biofilms in chronic rhinosinusitis (Kilty & Desrosiers, 2008).

If bacterial biofilms are the cause of certain cases of chronic rhinosinusitis, then the treatment paradigms will have to be changed. Novel nonantimicrobial therapies may have clinical applications to prevent and destabilize biofilms.

#### **5. References**


free living bacteria (Post et al., 2004). Also, biofilm formation makes the bacteria resistant to host defense mechanisms, because the aggregation of bacteria into biofilm cannot be phagocytized, humoral immune system is not effective against aggregated bacteria as well. The same properties that make bacteria within biofilm resistant to antibiotics and to the attack of immune system also make it difficult to identify them in laboratory by routine methods. Bacterial biofilms have been found in patients with chronic rhinosinusitis by scanning electron microscopy (SEM), transmission electron microscopy (TEM), confocal scanning laser microscopy, or fluorescent in situ hybridization (FISH) successfully. The use of PCR-based techniques demonstrates a high detection rate of bacterial pathogens in chronic diseases when comparing with conventional culture technique (Kilty & Destrosiers,

The fact that bacterial existence in the form of biofilm in probably preferred in chronic infections, there is growing evidence for the presence of bacterial biofilms in chronic

If bacterial biofilms are the cause of certain cases of chronic rhinosinusitis, then the treatment paradigms will have to be changed. Novel nonantimicrobial therapies may have

Aanan, J.B. (2005). *Current management of acute bacterial rhinosinusitis and the role of* 

American Academy of Pediatrics: *Clinical Practice Guideline: Management of Sinusitis* (2001).

Baron, S. (1996). *Medical microbiology, 4th edition.* University of Texas Medical Branch at

Benninger, M.S. (2008). *Acute bacterial rhinosinusitis and otitis media: changes in pathogenicity* 

Benninger, M.S. & Manz R. (2010). The impact of vaccination on rhinosinusitis and otitis

Bezerra, T.F.P., Padna, F.G., Gebrim, E.M.M.S., Saldiva, P.H.N. & Voegels, R.L. (2009).

Brook, I., Foote P.A. & Hausfeld J.N. (2006). *Frequency of recovery of pathogens causing acute* 

Fokkens, W.J., Lund, V.J., Mullol, J et al. (2007). *European Position Paper on Nasal Polyps*.

*following widespread use of pneumococcal conjugate vaccine.* Otolaryngol. Head Neck

*Biofilms in chronic rhinosinusitis with nasal polyps.* Braz. J. Otolaryngol. Vol. 75, No.

*maxillary sinusitis in adults before and after introduction of vaccination of children with the 7-valent pneumococcal vaccine. J.* Med. Microbiol. Vol. 55, No. 7, pp. (943-946) Brook, I., Gooch, W.M., Jenkins, S.G., Pichichero, m.E., Reiner, S.A. & Yamauchi T. (2000).

*Medical management of acute bacterial sinusitis recommendations of a clinical advisory committee on pediatric and adult sinusitis.* Ann Otol Rhinol Laryngol Vol.109, pp. (1-

*moxifloxacin*. Clin. Infect. Dis. Vol. 41, pp. (S167-S176)

media. *Curr. Allergy Asthma* Rep. Vol. 10, pp. (411-418)

2008).

**5. References** 

rhinosinusitis (Kilty & Desrosiers, 2008).

clinical applications to prevent and destabilize biofilms.

Pediatrics, Vol. 108, pp. (798-808).

Surg. Vol. 138, No. 3, pp. 274-278

6, pp. (788-793)

20)

Galveston, ISBN – 10: 0-9631172-1-1, USA

Rhinology Vol. 45, Suppl. 20, pp. ( 1-139)


**3** 

*Belgium* 

**Chronic Rhinosinusitis** 

 **and Olfactory Dysfunction** 

Huart Caroline1,2, Franceschi Daniel3 and Rombaux Philippe1,2

*2Institute of Neuroscience, Université Catholique de Louvain, Brussels, 3Department of Otorhinolaryngology, Clinique Sainte-Elisabeth, Brussels,* 

*1Department of Otorhinolaryngology, Cliniques Universitaires Saint-Luc, Brussels,* 

Chronic rhinosinusitis (CRS) is defined, according to the European Position Paper on Rhinosinusitis and Nasal Polyps (Fokkens et al., 2007), as "presence of two or more symptoms one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip) +/- facial pain/pressure +/- reduction or loss of smell for >12 weeks". Olfactory disorder thus appears to be one of the diagnosis criteria for CRS with or without nasal polyposis, underlining the importance of this specific symptom among patients with CRS. Inversely, CRS appears to be the most common cause of olfactory dysfunction in patients presenting to smell evaluating centers and account for 14-30% of the cases (Holbrook and Leopold, 2006; Landis et al., 2004; Mott and Leopold, 1991; Raviv and Kern 2004; Seiden and Duncan, 2001). What underlines the intimate connection between

Several studies have shown that the quality of life is severely impaired in patients suffering from olfactory disorders (Frasnelli and Hummel, 2005; Neuland et al., 2011). It is thus important to detect this symptom and to provide an optimal treatment to patients. Nowadays, we have medical and surgical treatments that may relieve patients but these

Good management and good support to patients highly depend on a good knowledge of this entity. We will thus review important issues about CRS and olfactory dysfunction, beginning with generalities about olfactory dysfunction, to continue with pathophysiology of this entity, assessment of olfactory function in patients, the contribution of imaging and

The incidence of olfactory dysfunction among the population is still a matter of debate. Authors report an incidence of 1-3% of dysfunction among population (Hoffman et al., 1998; Murphy et al., 2002). Nevertheless a recent study by Landis et al. (2004) reported higher values of olfactory dysfunction among population without sinonasal complaints, with a rate

**1. Introduction** 

CRS and olfactory dysfunction.

results are still hazardous.

**2. Olfactory dysfunction** 

finally effects of current treatments on olfactory function.

Zhang, N., Gevaert, P., van Zele, T. Perez-Novo, C., Patou, J., Holtapplers, G., van Cauvenberge, P. & Bachert C. (2005) An update on the impact of Staphylococcus aureus enterotoxins in chronic sinusitis with nasal polyposis. Rhinology. Vol. 43, No.3, pp. (162-168).

### **Chronic Rhinosinusitis and Olfactory Dysfunction**

Huart Caroline1,2, Franceschi Daniel3 and Rombaux Philippe1,2 *1Department of Otorhinolaryngology, Cliniques Universitaires Saint-Luc, Brussels, 2Institute of Neuroscience, Université Catholique de Louvain, Brussels, 3Department of Otorhinolaryngology, Clinique Sainte-Elisabeth, Brussels, Belgium* 

#### **1. Introduction**

38 Peculiar Aspects of Rhinosinusitis

Zhang, N., Gevaert, P., van Zele, T. Perez-Novo, C., Patou, J., Holtapplers, G., van

No.3, pp. (162-168).

Cauvenberge, P. & Bachert C. (2005) An update on the impact of Staphylococcus aureus enterotoxins in chronic sinusitis with nasal polyposis. Rhinology. Vol. 43,

> Chronic rhinosinusitis (CRS) is defined, according to the European Position Paper on Rhinosinusitis and Nasal Polyps (Fokkens et al., 2007), as "presence of two or more symptoms one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip) +/- facial pain/pressure +/- reduction or loss of smell for >12 weeks". Olfactory disorder thus appears to be one of the diagnosis criteria for CRS with or without nasal polyposis, underlining the importance of this specific symptom among patients with CRS. Inversely, CRS appears to be the most common cause of olfactory dysfunction in patients presenting to smell evaluating centers and account for 14-30% of the cases (Holbrook and Leopold, 2006; Landis et al., 2004; Mott and Leopold, 1991; Raviv and Kern 2004; Seiden and Duncan, 2001). What underlines the intimate connection between CRS and olfactory dysfunction.

> Several studies have shown that the quality of life is severely impaired in patients suffering from olfactory disorders (Frasnelli and Hummel, 2005; Neuland et al., 2011). It is thus important to detect this symptom and to provide an optimal treatment to patients. Nowadays, we have medical and surgical treatments that may relieve patients but these results are still hazardous.

> Good management and good support to patients highly depend on a good knowledge of this entity. We will thus review important issues about CRS and olfactory dysfunction, beginning with generalities about olfactory dysfunction, to continue with pathophysiology of this entity, assessment of olfactory function in patients, the contribution of imaging and finally effects of current treatments on olfactory function.

#### **2. Olfactory dysfunction**

The incidence of olfactory dysfunction among the population is still a matter of debate. Authors report an incidence of 1-3% of dysfunction among population (Hoffman et al., 1998; Murphy et al., 2002). Nevertheless a recent study by Landis et al. (2004) reported higher values of olfactory dysfunction among population without sinonasal complaints, with a rate

Chronic Rhinosinusitis and Olfactory Dysfunction 41

It is also mandatory to note that the quality of life of patients suffering from olfactory disorders is severely impaired. Indeed it has been described that patients with olfactory disorders not only complain about daily life problems (cooking, detection of potentially dangerous odors) (Temmel et al., 2002) but also have a higher prevalence of mild to severe depression compared to the general population (Deems et al., 1991). Using questionnaire of olfactory disorder and psychometric tests some authors reported that patients suffering from quantitative olfactory impairment significantly more complaints that patients with normosmia and this was even more important if they had associated parosmia (Frasnelli and Hummel, 2005; Neuland et al., 2011). Finally, since patients reporting an improvement of their olfactory abilities have a better quality of life than patients reporting no improvement (Miwa et al., 2001); it is essential to investigate about the etiology of olfactory dysfunction in instance to provide an optimal treatment to the patients. Particularly in cases of chronic rhinosinusitis, different treatments are available and improve olfactory function.

Traditionally, olfactory dysfunction in CRS is explained by a conductive olfactory loss, caused by swollen or hypertrophic nasal mucosa or nasal polyps, inducing an impaired access of odorants to the olfactory cleft. But clinical studies have failed to prove this hypothesis, as there is only little correlation between nasal resistance and the degree of olfactory dysfunction (Doty and Frye, 1989; Cowart et al., 1992). In addition, results of surgical therapy, although improving the nasal patency, are sometimes uncertain when

 Some studies have shown that the olfactory disturbance might also be explained by inflammatory process in the olfactory cleft (Konstantinidis et al., 2007). Indeed, biopsies of the olfactory neuroepithelium in patients suffering from CRS revealed inflammatory changes in the nasal mucosa and apoptotic pathological changes, including the olfactory receptor neurons and olfactory supporting cells (Hellings and Rombaux, 2009; Naessen, 1971). Also, inflammatory cells release inflammatory mediators, which are known to trigger hypersecretion in respiratory and Bowman's glands (Hellings and Rombaux, 2009; Getchell and Mellert, 1991; Downey et al., 1996). Hypersecretion of Bowman's gland is thought to alter the ion concentrations of olfactory mucus, affecting the olfactory transduction process (Kern et al., 1997; Joshi et al., 1987). In addition, cytokines and mediators, particularly those released by eosinophils, may be toxic to olfactory receptor neurons (Apter et al., 1992; Nakashima et al, 1985), and the degree of inflammation changes in the neuropithelium is

Patients with nasal polyps show a higher incidence of olfactory disturbances and a higher incidence of anosmia than patients with CRS without polyps. This more severe symptomatology may be explained by the conductive olfactory loss induced by polyps but also by degenerative changes associated with recurrent infections, scaring, chronic nasal medication, exotoxins and enhanced secretion of cytokines from Staphylococcus Aureus infection and neurotoxic cytokines released by a huge eosinophilic population (Bernstein et al., 2011; Holcomb et al., 1996; Joshi et al., 1987; Litvack et al., 2008; Vento et al., 2001; Wang

They will be discussed later.

considering the olfactory dysfunction.

related to the severity of olfactory dysfunction (Kern, 2000)

**3. Pathophysiology** 

et al., 2010).

of 4.7% of anosmia and 16% of hyposmia. The most common causes of olfactory disorder are CRS, upper respiratory tract infection and head trauma. It is also mandatory to note that in a significant number of cases the cause of olfactory dysfunction remains unknown, even after investigations. (Table 1)


Table 1. Etiologies of olfactory dysfunction listed in descending order. Rhinosinusitis appears to be the most important cause of olfactory dysfunction in the general population.

In the literature, CRS is described as the most common cause of olfactory dysfunction, accounting for 14-30% of cases (Holbrook and Leopold 2006; Mott and Leopold, 1991; Raviv and Kern 2004; Seiden and Duncan, 2001). Inversely, olfactory impairment is a common symptom affecting 61-83% of patients with CRS (Bhattacharyya, 2003; Litvak et al., 2008; Orlandi and Terrell, 2002; Soler et al., 2008). Nevertheless up to one quarter of patients with CRS are unaware of their decreased olfactory abilities, probably because the olfactory dysfunction in CRS develops slowly and in consequence only a few patients note this disorder (Nordin et al., 1995). Psychophysical tests results show that patients with CRS have quantitative disorders, between hyposmia and anosmia (Holbrook and Leopold 2006; Mott and Leopold, 1991; Raviv and Kern 2004; Seiden and Duncan, 2001; Welge-Luessen, 2009) and may report fluctuating symptoms (Apter et al., 1999). Also it is widely known that patients with CRS with polyps have a higher incidence of smell symptoms and anosmia than patients with CRS without polyps (Hellings and Rombaux, 2009).

Some studies have described that the severity of quantitative disorders is related to the importance of the sinonasal disease (Litvack et al., 2008, 2009a). Indeed, the mean endoscopy score and the mean CT score are significantly higher (more abnormal) in patients with hyposmia and anosmia than in patients with normosmia (Litvack et al., 2009a). Also, the opacification of the olfactory cleft on the CT scan seems to have a negative correlation with the olfactory function (Chang et al., 2009).

Patients with CRS not only report quantitative olfactory dysfunction but also qualitative dysfunction such as parosmia and phantosmia. However, these symptoms seem less frequent when related to sinonasal disease than to other etiologies (i.e. post-infectious, post traumatic) and Reden et al. (2007) reported incidence of parosmia and phantosmia in patients with CRS of 28% and 7%, respectively.

of 4.7% of anosmia and 16% of hyposmia. The most common causes of olfactory disorder are CRS, upper respiratory tract infection and head trauma. It is also mandatory to note that in a significant number of cases the cause of olfactory dysfunction remains unknown, even after

2 Post upper respiratory tract infection

Table 1. Etiologies of olfactory dysfunction listed in descending order. Rhinosinusitis appears to be the most important cause of olfactory dysfunction in the general population. In the literature, CRS is described as the most common cause of olfactory dysfunction, accounting for 14-30% of cases (Holbrook and Leopold 2006; Mott and Leopold, 1991; Raviv and Kern 2004; Seiden and Duncan, 2001). Inversely, olfactory impairment is a common symptom affecting 61-83% of patients with CRS (Bhattacharyya, 2003; Litvak et al., 2008; Orlandi and Terrell, 2002; Soler et al., 2008). Nevertheless up to one quarter of patients with CRS are unaware of their decreased olfactory abilities, probably because the olfactory dysfunction in CRS develops slowly and in consequence only a few patients note this disorder (Nordin et al., 1995). Psychophysical tests results show that patients with CRS have quantitative disorders, between hyposmia and anosmia (Holbrook and Leopold 2006; Mott and Leopold, 1991; Raviv and Kern 2004; Seiden and Duncan, 2001; Welge-Luessen, 2009) and may report fluctuating symptoms (Apter et al., 1999). Also it is widely known that patients with CRS with polyps have a higher incidence of smell symptoms and anosmia

1 Rhinosinusitis

4 Post traumatic

3 Idiopathic

5 Iatrogen 6 Toxic

7 Congenital

8 Miscellaneous

than patients with CRS without polyps (Hellings and Rombaux, 2009).

the olfactory function (Chang et al., 2009).

patients with CRS of 28% and 7%, respectively.

Some studies have described that the severity of quantitative disorders is related to the importance of the sinonasal disease (Litvack et al., 2008, 2009a). Indeed, the mean endoscopy score and the mean CT score are significantly higher (more abnormal) in patients with hyposmia and anosmia than in patients with normosmia (Litvack et al., 2009a). Also, the opacification of the olfactory cleft on the CT scan seems to have a negative correlation with

Patients with CRS not only report quantitative olfactory dysfunction but also qualitative dysfunction such as parosmia and phantosmia. However, these symptoms seem less frequent when related to sinonasal disease than to other etiologies (i.e. post-infectious, post traumatic) and Reden et al. (2007) reported incidence of parosmia and phantosmia in

investigations. (Table 1)

It is also mandatory to note that the quality of life of patients suffering from olfactory disorders is severely impaired. Indeed it has been described that patients with olfactory disorders not only complain about daily life problems (cooking, detection of potentially dangerous odors) (Temmel et al., 2002) but also have a higher prevalence of mild to severe depression compared to the general population (Deems et al., 1991). Using questionnaire of olfactory disorder and psychometric tests some authors reported that patients suffering from quantitative olfactory impairment significantly more complaints that patients with normosmia and this was even more important if they had associated parosmia (Frasnelli and Hummel, 2005; Neuland et al., 2011). Finally, since patients reporting an improvement of their olfactory abilities have a better quality of life than patients reporting no improvement (Miwa et al., 2001); it is essential to investigate about the etiology of olfactory dysfunction in instance to provide an optimal treatment to the patients. Particularly in cases of chronic rhinosinusitis, different treatments are available and improve olfactory function. They will be discussed later.

#### **3. Pathophysiology**

Traditionally, olfactory dysfunction in CRS is explained by a conductive olfactory loss, caused by swollen or hypertrophic nasal mucosa or nasal polyps, inducing an impaired access of odorants to the olfactory cleft. But clinical studies have failed to prove this hypothesis, as there is only little correlation between nasal resistance and the degree of olfactory dysfunction (Doty and Frye, 1989; Cowart et al., 1992). In addition, results of surgical therapy, although improving the nasal patency, are sometimes uncertain when considering the olfactory dysfunction.

 Some studies have shown that the olfactory disturbance might also be explained by inflammatory process in the olfactory cleft (Konstantinidis et al., 2007). Indeed, biopsies of the olfactory neuroepithelium in patients suffering from CRS revealed inflammatory changes in the nasal mucosa and apoptotic pathological changes, including the olfactory receptor neurons and olfactory supporting cells (Hellings and Rombaux, 2009; Naessen, 1971). Also, inflammatory cells release inflammatory mediators, which are known to trigger hypersecretion in respiratory and Bowman's glands (Hellings and Rombaux, 2009; Getchell and Mellert, 1991; Downey et al., 1996). Hypersecretion of Bowman's gland is thought to alter the ion concentrations of olfactory mucus, affecting the olfactory transduction process (Kern et al., 1997; Joshi et al., 1987). In addition, cytokines and mediators, particularly those released by eosinophils, may be toxic to olfactory receptor neurons (Apter et al., 1992; Nakashima et al, 1985), and the degree of inflammation changes in the neuropithelium is related to the severity of olfactory dysfunction (Kern, 2000)

Patients with nasal polyps show a higher incidence of olfactory disturbances and a higher incidence of anosmia than patients with CRS without polyps. This more severe symptomatology may be explained by the conductive olfactory loss induced by polyps but also by degenerative changes associated with recurrent infections, scaring, chronic nasal medication, exotoxins and enhanced secretion of cytokines from Staphylococcus Aureus infection and neurotoxic cytokines released by a huge eosinophilic population (Bernstein et al., 2011; Holcomb et al., 1996; Joshi et al., 1987; Litvack et al., 2008; Vento et al., 2001; Wang et al., 2010).

Chronic Rhinosinusitis and Olfactory Dysfunction 43

abnormal responses with in moderate cases decreased amplitude and an increased latency and in severe cases the absence of olfactory responses (Rombaux et al., 2009). It is interesting to note that while in chronic rhinosinusitis, there is no difference between orthonasal and retronasal score, patients with CRS with polyps have a better retronasal than orthonasal score (Landis et al., 2003). Moreover ortho- and retronasal scores do not have a correlation when patient demonstrate an olfactory dysfunction related to sinonasal disease score proving that ortho- and retronasal scores have a distinct evolution in such cases (Rombaux

The MRI is the imaging modality of choice for the evaluation of the olfactory apparatus since it allows examining the olfactory bulb, olfactory tract and central olfactory projection areas. The assessment of olfactory bulb volume is particularly useful in the evaluation of olfactory disorder associated with CRS. Rombaux et al. (2008) demonstrated that the olfactory bulb volume is correlated with the sinonasal disease score, and patients having a sinonasal disease score > or = 12 significantly have larger olfactory bulb volume than patients with higher score. Smaller olfactory bulb volume is thus associated with a higher degree of sinonasal pathology. On contrast the olfactory function of the patients assessed with psychophysical testing was only slightly decreased or was even normal, emphasizing the idea that the olfactory bulb volume changes are more sensitive to subtle changes in the

Fig. 1. T2-MRI on the coronal place of patient suffering from CRS (A) and control subject (B). Note that the olfactory bulb (white arrow) of the patient seems smaller than the OB of the

CT scan can also be useful in the assessment of patients with olfactory dysfunction associated with CRS. Litvack et al. (2009a) have shown that the severity of quantitative olfactory disorder is associated with the importance of the sinonasal disease and that mean CT score is significantly higher in patients with hyposmia and anosmia than in normosmic patient. It was also demonstrated that the opacification of the olfactory cleft has a negative correlation with the olfactory function in patients with CRS and that it is significantly correlated with the postoperative olfactory results; patients with mild opacification having

et al., 2008).

control subject.

**5. Imaging of the olfactory apparatus in CRS** 

olfactory system than results of psychophysical testing. (Figure1)

#### **4. Assessment of olfactory function**

Assessment of olfactory function should be considered in the clinical evaluation of patients suffering from chronic rhinosinusitis and complaining of olfactory disorders. Not only this evaluation allows detecting and quantifying olfactory disorders but also it is useful to objectively and reproducibly assess the efficacy of a treatment on olfactory function.

Odorants can reach the olfactory cleft both orthonasally (from the nostrils to the olfactory cleft) and retronasally (from the oral cavity to the olfactory cleft).

The most widely used tests for the evaluation evaluation of the orthonasal function are the Sniffin' Sticks test (Hummel et al., 2007; Burghart Medical Technology, Wedel, Germany) and the UPSIT (University of Pennsylvania smell identification test) (Doty et al., 1984). These semi-objective tests have the advantage of being easy to implement and of having been validated in multicenter studies. The Sniffin' Sticks test consists in felt-tip pens that are presented in front of the nose of the patient. It encompasses three different approaches. First the odor threshold (T) assessment; second the odor discrimination (D) and third odor identification (I). To judge the olfactory function, these three results are added together to provide a total TDI score. The UPSIT test 40 items. It encompasses fours "scratch and sniff" booklets that can be self administrated or applied by a third party. Odorants are embedded in microcapsules positioned on brown strips at the bottom of the page of booklets. The stimuli are released by scratching the strip with a pencil and subjects have to choice one of the four proposed descriptors that best corresponds to odor (Doty et al., 1984; Tourbier and Doty, 2007). These two tests are forced choice, what mean that the subject must provide a response even if no odor is perceived.

Retronasal olfactory performances can also be evaluated following a standardized method using a row of 20 items. Powder substances are applied using squeezable plastic vials in the middle of the tongue inside the oral cavity. Each substance is identified by means of a forced-choice procedure between 4 items. (Heilmann et al., 2002)

Nevertheless these tests have the disadvantage to be semi-objective and might be biased by the patient's response.

The objective evaluation of the olfactory function relies on event-related potentials technique. This technique is based on the fact that brief olfactory stimulus elicit transient changes in the ongoing electrographic activity. To evaluate olfactory function a pure odorant substance (i.e. 2-phenylethanol) is delivered in the nose of the patients (Kobal and Hummel, 1988). Since the magnitude of the transient olfactory-induced EEG deflection is much smaller than the magnitude of the background EEG, the event is repeated several times and recorded responses are the added and averaged into a single waveform to increase the signal to noise ratio. The bulk of olfactory chemosensory event-related potentials consist of a negative component (N1) occurring between 320 and 450 ms after stimulus onset, followed by a positive (P2) component occurring between 530-800 ms (Hummel et al., 1992; Hummel et al., 2003; Hummel and Kobal, 1999, 2002; Rombaux et al., 2006).

In cases of chronic rhinosinusitis, both orthonasal and retronasal scores can be decreased, with scoring of both anosmia and hyposmia. Electrophysiological investigations show

Assessment of olfactory function should be considered in the clinical evaluation of patients suffering from chronic rhinosinusitis and complaining of olfactory disorders. Not only this evaluation allows detecting and quantifying olfactory disorders but also it is useful to

Odorants can reach the olfactory cleft both orthonasally (from the nostrils to the olfactory

The most widely used tests for the evaluation evaluation of the orthonasal function are the Sniffin' Sticks test (Hummel et al., 2007; Burghart Medical Technology, Wedel, Germany) and the UPSIT (University of Pennsylvania smell identification test) (Doty et al., 1984). These semi-objective tests have the advantage of being easy to implement and of having been validated in multicenter studies. The Sniffin' Sticks test consists in felt-tip pens that are presented in front of the nose of the patient. It encompasses three different approaches. First the odor threshold (T) assessment; second the odor discrimination (D) and third odor identification (I). To judge the olfactory function, these three results are added together to provide a total TDI score. The UPSIT test 40 items. It encompasses fours "scratch and sniff" booklets that can be self administrated or applied by a third party. Odorants are embedded in microcapsules positioned on brown strips at the bottom of the page of booklets. The stimuli are released by scratching the strip with a pencil and subjects have to choice one of the four proposed descriptors that best corresponds to odor (Doty et al., 1984; Tourbier and Doty, 2007). These two tests are forced choice, what mean that the subject must provide a

Retronasal olfactory performances can also be evaluated following a standardized method using a row of 20 items. Powder substances are applied using squeezable plastic vials in the middle of the tongue inside the oral cavity. Each substance is identified by means of a

Nevertheless these tests have the disadvantage to be semi-objective and might be biased by

The objective evaluation of the olfactory function relies on event-related potentials technique. This technique is based on the fact that brief olfactory stimulus elicit transient changes in the ongoing electrographic activity. To evaluate olfactory function a pure odorant substance (i.e. 2-phenylethanol) is delivered in the nose of the patients (Kobal and Hummel, 1988). Since the magnitude of the transient olfactory-induced EEG deflection is much smaller than the magnitude of the background EEG, the event is repeated several times and recorded responses are the added and averaged into a single waveform to increase the signal to noise ratio. The bulk of olfactory chemosensory event-related potentials consist of a negative component (N1) occurring between 320 and 450 ms after stimulus onset, followed by a positive (P2) component occurring between 530-800 ms (Hummel et al., 1992; Hummel et al., 2003; Hummel and Kobal, 1999, 2002; Rombaux et al.,

In cases of chronic rhinosinusitis, both orthonasal and retronasal scores can be decreased, with scoring of both anosmia and hyposmia. Electrophysiological investigations show

objectively and reproducibly assess the efficacy of a treatment on olfactory function.

cleft) and retronasally (from the oral cavity to the olfactory cleft).

forced-choice procedure between 4 items. (Heilmann et al., 2002)

**4. Assessment of olfactory function** 

response even if no odor is perceived.

the patient's response.

2006).

abnormal responses with in moderate cases decreased amplitude and an increased latency and in severe cases the absence of olfactory responses (Rombaux et al., 2009). It is interesting to note that while in chronic rhinosinusitis, there is no difference between orthonasal and retronasal score, patients with CRS with polyps have a better retronasal than orthonasal score (Landis et al., 2003). Moreover ortho- and retronasal scores do not have a correlation when patient demonstrate an olfactory dysfunction related to sinonasal disease score proving that ortho- and retronasal scores have a distinct evolution in such cases (Rombaux et al., 2008).

#### **5. Imaging of the olfactory apparatus in CRS**

The MRI is the imaging modality of choice for the evaluation of the olfactory apparatus since it allows examining the olfactory bulb, olfactory tract and central olfactory projection areas. The assessment of olfactory bulb volume is particularly useful in the evaluation of olfactory disorder associated with CRS. Rombaux et al. (2008) demonstrated that the olfactory bulb volume is correlated with the sinonasal disease score, and patients having a sinonasal disease score > or = 12 significantly have larger olfactory bulb volume than patients with higher score. Smaller olfactory bulb volume is thus associated with a higher degree of sinonasal pathology. On contrast the olfactory function of the patients assessed with psychophysical testing was only slightly decreased or was even normal, emphasizing the idea that the olfactory bulb volume changes are more sensitive to subtle changes in the olfactory system than results of psychophysical testing. (Figure1)

Fig. 1. T2-MRI on the coronal place of patient suffering from CRS (A) and control subject (B). Note that the olfactory bulb (white arrow) of the patient seems smaller than the OB of the control subject.

CT scan can also be useful in the assessment of patients with olfactory dysfunction associated with CRS. Litvack et al. (2009a) have shown that the severity of quantitative olfactory disorder is associated with the importance of the sinonasal disease and that mean CT score is significantly higher in patients with hyposmia and anosmia than in normosmic patient. It was also demonstrated that the opacification of the olfactory cleft has a negative correlation with the olfactory function in patients with CRS and that it is significantly correlated with the postoperative olfactory results; patients with mild opacification having

Chronic Rhinosinusitis and Olfactory Dysfunction 45

On contrast, studies agree that semi-objective olfactory testing are not correlated with disease-specific or general health-related quality of life instruments (Litvack et al., 2009a;

Only a few clinical studies have been conducted dealing with the improvement of olfactory function as a primary outcome in sinonasal disease treatment. Clinical trials of medical treatment for smell disorders associated with CRS have evaluated the efficacy of nasal and oral corticosteroid treatment, but we found no studies about other treatments that are

Corticosteroids with their potent anti-inflammatory effects are admitted to be the standard treatment for olfactory disorders induced by CRS. Their action mechanism on olfactory function might be explained by an inhibition of the release of proinflammatory mediators (i.e. cytokines, adhesion molecules, mast cells, basophiles, eosinophiles) and a reduction in

Following EPOS recommendations, nasal steroids are recommended as the first line treatment for CRS with or without nasal polyps (Fokkens et al., 2007). Studies have evaluated the efficacy of different topical corticosteroids such as Betamethasone, Flunisolide, Mometasone Furoate, Fluticasone Propionate, Budesonide, Beclomethasone. Studies show that these drugs appear to be highly effective for most of the symptoms associated with CRS, including smell disorder, with a rapid onset of action and a cumulative effect after several days of use. In addition, they have the advantage of being a local therapy with limited side effects. Nevertheless the improvement in olfaction is frequently transient and incomplete (Blomqvist et al., 2003; Golding-Wood et al., 1996; Hellings and Rombaux,

Oral steroids are recommended in the treatment of CRS with nasal polyps as a second line treatment (Fokkens et al, 2007). Several studies have investigated the efficacy of oral steroids in patients with CRS with or without polyps. They have shown that these potent antiinflammatory drugs increase the olfactory function and they appear to be more effective than nasal steroids (Heilmann et al., 2004; Vaidyanathan et al., 2011). Moreover, an initial oral steroid therapy followed by topical steroid therapy seems to be more effective than topical steroid therapy alone (Vaidyanathan et al., 2011). Nevertheless oral steroids have important side effects if they are frequently administrated or if their administration is prolonged. Bonfils et al. (2006) evaluated the risk of oral steroid treatment in patients with CRS with nasal polyps and showed that almost 50% of patients who received more than three short courses of oral steroid treatment had an asymptomatic adrenal insufficiency. Oral corticosteroids should thus be prescribed only if necessary and should be avoided if

Functional endoscopic sinus surgery (FESS) is widely accepted as a treatment for chronic

rhinosinusitis with or without nasal polyps after failure of the medical therapy.

currently used in the treatment of CRS (antileukotrienes, antihistamines,…).

Hox et al., 2010)

possible.

**7. Effects of treatment on olfactory function** 

mucosa swelling (Demoly, 2007; Mygind et al., 2001).

2009; Lildholdt et al., 1995; Mott et al., 1997; Stuck et al., 2003).

**7.2 Surgical therapy and smell dysfunction** 

**7.1 Medical therapy and smell dysfunction** 

better postoperative results than patients with moderate and severe anterior olfactory cleft result (Kim et al., 2011).

Fig. 2. CT-Scan in the coronal plane of a patient suffering from quantitative olfactory disorder. We can note on this picture an opacification of the olfactory cleft (white arrow) whereas there is no obvious rhinosinusitis. This image represents a so-called "olfactory cleft disease".

#### **6. Predictors of olfactory dysfunction in patients with CRS**

As we discuss previously, it is agreed that the severity of olfactory dysfunction is related to the importance of the sinonasal disease (Litvack et al., 2008, 2009a) and that the mean endoscopy and mean CT score are significantly higher in patients with hyposmia and anosmia than in normosmic patients (Litvack et al., 2009a).

But common comorbidities have also been incriminated as severity factors of olfactory loss related to the CRS. Some authors have incriminated age of patients, smoking status, nasal polyposis, asthma, allergic rhinitis, previous endoscopic sinus surgery, septal deviation and inferior turbinate hypertrophy to cause olfactory dysfunction but the results are conflicting (Apter et al., 1999; Damm et al., 2003; Doty and Mishra, 2001; Kimmelman, 1994; Litvack et al., 2008; Simola and Malmberg, 1998). Nevertheless, the majority of authors agree that the age of patients and the presence of nasal polyps are predictors of olfactory dysfunction in CRS (Apter et al., 1999; Doty and Mishra, 2001; Litvack et al., 2008; Simola and Malmberg, 1998). Nasal polyposis is a significant predictor of olfactory dysfunction and it has been showed that there is a negative correlation between the size of the nasal polyps and the olfactory performance. Also, in patients with nasal polyposis, the blood eosinophilia seems to be correlated with subjective smell reduction (Hox et al., 2010).

better postoperative results than patients with moderate and severe anterior olfactory cleft

Fig. 2. CT-Scan in the coronal plane of a patient suffering from quantitative olfactory disorder. We can note on this picture an opacification of the olfactory cleft (white arrow) whereas there is no obvious rhinosinusitis. This image represents a so-called "olfactory cleft

As we discuss previously, it is agreed that the severity of olfactory dysfunction is related to the importance of the sinonasal disease (Litvack et al., 2008, 2009a) and that the mean endoscopy and mean CT score are significantly higher in patients with hyposmia and

But common comorbidities have also been incriminated as severity factors of olfactory loss related to the CRS. Some authors have incriminated age of patients, smoking status, nasal polyposis, asthma, allergic rhinitis, previous endoscopic sinus surgery, septal deviation and inferior turbinate hypertrophy to cause olfactory dysfunction but the results are conflicting (Apter et al., 1999; Damm et al., 2003; Doty and Mishra, 2001; Kimmelman, 1994; Litvack et al., 2008; Simola and Malmberg, 1998). Nevertheless, the majority of authors agree that the age of patients and the presence of nasal polyps are predictors of olfactory dysfunction in CRS (Apter et al., 1999; Doty and Mishra, 2001; Litvack et al., 2008; Simola and Malmberg, 1998). Nasal polyposis is a significant predictor of olfactory dysfunction and it has been showed that there is a negative correlation between the size of the nasal polyps and the olfactory performance. Also, in patients with nasal polyposis, the blood eosinophilia seems

**6. Predictors of olfactory dysfunction in patients with CRS** 

anosmia than in normosmic patients (Litvack et al., 2009a).

to be correlated with subjective smell reduction (Hox et al., 2010).

result (Kim et al., 2011).

disease".

On contrast, studies agree that semi-objective olfactory testing are not correlated with disease-specific or general health-related quality of life instruments (Litvack et al., 2009a; Hox et al., 2010)

#### **7. Effects of treatment on olfactory function**

#### **7.1 Medical therapy and smell dysfunction**

Only a few clinical studies have been conducted dealing with the improvement of olfactory function as a primary outcome in sinonasal disease treatment. Clinical trials of medical treatment for smell disorders associated with CRS have evaluated the efficacy of nasal and oral corticosteroid treatment, but we found no studies about other treatments that are currently used in the treatment of CRS (antileukotrienes, antihistamines,…).

Corticosteroids with their potent anti-inflammatory effects are admitted to be the standard treatment for olfactory disorders induced by CRS. Their action mechanism on olfactory function might be explained by an inhibition of the release of proinflammatory mediators (i.e. cytokines, adhesion molecules, mast cells, basophiles, eosinophiles) and a reduction in mucosa swelling (Demoly, 2007; Mygind et al., 2001).

Following EPOS recommendations, nasal steroids are recommended as the first line treatment for CRS with or without nasal polyps (Fokkens et al., 2007). Studies have evaluated the efficacy of different topical corticosteroids such as Betamethasone, Flunisolide, Mometasone Furoate, Fluticasone Propionate, Budesonide, Beclomethasone. Studies show that these drugs appear to be highly effective for most of the symptoms associated with CRS, including smell disorder, with a rapid onset of action and a cumulative effect after several days of use. In addition, they have the advantage of being a local therapy with limited side effects. Nevertheless the improvement in olfaction is frequently transient and incomplete (Blomqvist et al., 2003; Golding-Wood et al., 1996; Hellings and Rombaux, 2009; Lildholdt et al., 1995; Mott et al., 1997; Stuck et al., 2003).

Oral steroids are recommended in the treatment of CRS with nasal polyps as a second line treatment (Fokkens et al, 2007). Several studies have investigated the efficacy of oral steroids in patients with CRS with or without polyps. They have shown that these potent antiinflammatory drugs increase the olfactory function and they appear to be more effective than nasal steroids (Heilmann et al., 2004; Vaidyanathan et al., 2011). Moreover, an initial oral steroid therapy followed by topical steroid therapy seems to be more effective than topical steroid therapy alone (Vaidyanathan et al., 2011). Nevertheless oral steroids have important side effects if they are frequently administrated or if their administration is prolonged. Bonfils et al. (2006) evaluated the risk of oral steroid treatment in patients with CRS with nasal polyps and showed that almost 50% of patients who received more than three short courses of oral steroid treatment had an asymptomatic adrenal insufficiency. Oral corticosteroids should thus be prescribed only if necessary and should be avoided if possible.

#### **7.2 Surgical therapy and smell dysfunction**

Functional endoscopic sinus surgery (FESS) is widely accepted as a treatment for chronic rhinosinusitis with or without nasal polyps after failure of the medical therapy.

Chronic Rhinosinusitis and Olfactory Dysfunction 47

olfactory dysfunction (Litvack et al., 2009b, Soler et al., 2010). The degree of nasal obstruction, the extent of the rhinosinusitis disease (evaluate by symptom score or CT scan), the coexistence of nasal polyps or allergic rhinitis do not predict the possibility of olfactory improvement after FESS (Bhattacharyya, 2006; Jiang et al., 2009; Wright and Agrawal, 2007). In addition, Jankowski et al. (Jankowski and Bodino, 2003) demonstrated that there was a correlation between the improvement of subjective olfactory function after oral

Jankowski et al. (1997) compared the impact of different surgical approaches on olfactory function. Olfaction was evaluated by a 10-point visual analogue scale. They reported that improvement of olfaction was similar in both functional ethmoidectomy group and radical ethmoidectomy group six months after surgery. Nevertheless olfaction decreased in the functional ethmoidectomy group after six months while it was stable in the radical

CRS is the major cause of olfactory dysfunction among the population. The exact pathophysiology is this entity is still unclear. The olfactory dysfunction in these patients is reversible, as proved by the effect of treatments and MRI studies. Nevertheless, most studies show that the improvement of olfactory function is usually transient and incomplete. Different causes are hypothesized, but this is still a matter of debate. Future studies are

Apter AJ, Gent JF & Frank ME (1999). Fluctuating olfactory sensitivity and distorted odor perception in allergic rhinitis. *Arch Otolaryngol Head Neck Surg,* 125 (9):1005-10 Apter AJ, Mott AE & Cain WS (1992). Olfactory loss and allergic rhinitis. *J Allergy Clin* 

Bernsteins JM, Allen C, Rich G, Dryja D, Bina P, Reiser R, Ballow M & Wilding GE (2011).

Bhattacharyya N (2003). The economic burden and symptom manifestations of chronic

Bhattacharyya N (2006). Radiographic stage fails to predict symptom outcomes after endoscopic sinus surgery for chronic rhinosinusitis. *Laryngoscope,* 116(1):18-22 Blomqvist EH, Lundblad L, Bergstedt H & Stjärne P (2003). Placebo-controlled randomized,

Bonfils P, Malinvaud Y, Soudry Y, Devars du Maine M & Laccourreye O (2009). Surgical

Chang H, Lee HJ, Mo JH, Lee CH & Kim JW (2009). Clinical implication of the olfactory cleft

pathogenesis of nasal polyposis. *Laryngoscope,* 121(3):647-55

treatment of nasal polyposis. *Acta Otolaryngol,* 126(11): 1195-1200

therapy and olfactory function. *B-ENT,* 5 Suppl 13:77-87

Further observations on the role of Staphylococcus Aureus exotoxins and IgE in the

double-blind study evaluating the efficacy of fluticasone propionate nasal spray for the treatment of patients with hyposmia/anosmia. *Acta Otolaryngol,* 123:862-868 Bonfils P, Halimi P & Malinvaud D (2006). Adrenal suppression and osteoporosis after

in patients with chronic rhinosinusitis and olfactory loss. *Arch Otolaryngol Head* 

corticosteroids given preoperatively and olfactory function 1 year after nazalisation.

ethmoidectomy group.

necessary to better understand this entity.

*Immun*, 90:670-680

rhinosinusitis. *Am J Rhinol*, 17:27-32

*Neck Surg,* 135(10):988-92

**8. Conclusion** 

**9. References** 

The only randomized study to attempt comparison between steroid therapy and polypectomy showed significant improvement of subjective and objective olfactory function in both groups, remaining for one year. However these results should be tempered by the fact that the smell evaluation methodology was not described (Lildholdt, 1989)

Several studies have investigated the effect of FESS on olfactory function (for a review see Bonfils et al., 2009). Nevertheless the literature shows that there are major variations in the selection of patients for the surgery and some studies have poor validity because of poorly defined patient groups, lack of clear inclusion or exclusion criteria, poor description of the surgical procedure and poor description of the olfactory evaluation tool.

In this literature, olfactory function was assessed either by subjective patient self-reported olfactory function or by semi-objective olfactory testing (i.e. UPSIT). Considering patients self reported olfactory function, authors agree that FESS lead to a significant improvement of olfactory dysfunction. Park et al. (1998) showed that olfactory disturbance was reported in 72% of patients with CRS with or without polyps or recurrent acute rhinosinusitis preoperatively compared with 38% following FESS. Lund and Mac Kay (1994) also reported that 79% of patients reported improved olfaction after FESS. Klossek et al. (1997) reported a series of patients with nasal polyposis. 100% of patients had anosmia pre-operatively while after surgery 78% of patients recovered the sense of smell. Levine et al. (1990) reported a series of 250 patients with CRS with or without nasal polyps and noted only 16% of patients complaining of smell disturbance before surgery and 3% patients reporting anosmia after a mean follow-up of one year after surgery. Jakobsen and Svendstrup (2000) reported a series of 237 patients with CRS with or without nasal polyps. Anosmia was present in 48% of the patients with nasal polyps before surgery against 21 % after surgery. Only few studies have investigated the effect of FESS on olfactory function by using semi-objective olfactory testing. They have also shown that FESS as a significant positive effect on olfactory function. For examples, Lund and Scading (1994) evaluated olfactory function of patients with CRS using UPSIT and showed significant UPSIT score improvement after surgery. Downey et al. (1996) also used UPSIT to assess the olfactory function of patients with CRS pre- and postoperatively and showed that after surgery, 52% of patients had higher UPSIT score. Min et al. (1995) tested olfactory thresholds to butanol in patients with CRS. Before surgery, 33 % of patients had anosmia and 45% of patients had hyposmia. After surgery these percentages were 16% and 46% respectively. Delank and Stoll (1998) noted a post operative improvement of olfactory function assessed by olfactory thresholds and discrimination in 70% of patients with CRS. Klimek et al. (1997) reported improved odor identification and discrimination score after FESS in patients with CRS with nasal polyps. Hence, FESS seems to significantly improve olfactory function in patients with CRS with or without polyps.

Gudziol et al. (2009) explored the influence of the treatment of CRS on the olfactory function. They measured olfactory bulb volume and olfactory function of patients suffering from CRS before treatment and 3 months after. They showed that the olfactory bulb volume significantly increases after treatment and that the increase of olfactory bulb volume correlated significantly with an increase in odor thresholds.

Some authors have also studied the correlation between the severity of CRS and surgical outcomes on olfaction. It was reported that the improvement after FESS is significantly better in patients with severe olfactory dysfunction whereas it is not in patients with mild olfactory dysfunction (Litvack et al., 2009b, Soler et al., 2010). The degree of nasal obstruction, the extent of the rhinosinusitis disease (evaluate by symptom score or CT scan), the coexistence of nasal polyps or allergic rhinitis do not predict the possibility of olfactory improvement after FESS (Bhattacharyya, 2006; Jiang et al., 2009; Wright and Agrawal, 2007). In addition, Jankowski et al. (Jankowski and Bodino, 2003) demonstrated that there was a correlation between the improvement of subjective olfactory function after oral corticosteroids given preoperatively and olfactory function 1 year after nazalisation.

Jankowski et al. (1997) compared the impact of different surgical approaches on olfactory function. Olfaction was evaluated by a 10-point visual analogue scale. They reported that improvement of olfaction was similar in both functional ethmoidectomy group and radical ethmoidectomy group six months after surgery. Nevertheless olfaction decreased in the functional ethmoidectomy group after six months while it was stable in the radical ethmoidectomy group.

#### **8. Conclusion**

46 Peculiar Aspects of Rhinosinusitis

The only randomized study to attempt comparison between steroid therapy and polypectomy showed significant improvement of subjective and objective olfactory function in both groups, remaining for one year. However these results should be tempered by the

Several studies have investigated the effect of FESS on olfactory function (for a review see Bonfils et al., 2009). Nevertheless the literature shows that there are major variations in the selection of patients for the surgery and some studies have poor validity because of poorly defined patient groups, lack of clear inclusion or exclusion criteria, poor description of the

In this literature, olfactory function was assessed either by subjective patient self-reported olfactory function or by semi-objective olfactory testing (i.e. UPSIT). Considering patients self reported olfactory function, authors agree that FESS lead to a significant improvement of olfactory dysfunction. Park et al. (1998) showed that olfactory disturbance was reported in 72% of patients with CRS with or without polyps or recurrent acute rhinosinusitis preoperatively compared with 38% following FESS. Lund and Mac Kay (1994) also reported that 79% of patients reported improved olfaction after FESS. Klossek et al. (1997) reported a series of patients with nasal polyposis. 100% of patients had anosmia pre-operatively while after surgery 78% of patients recovered the sense of smell. Levine et al. (1990) reported a series of 250 patients with CRS with or without nasal polyps and noted only 16% of patients complaining of smell disturbance before surgery and 3% patients reporting anosmia after a mean follow-up of one year after surgery. Jakobsen and Svendstrup (2000) reported a series of 237 patients with CRS with or without nasal polyps. Anosmia was present in 48% of the patients with nasal polyps before surgery against 21 % after surgery. Only few studies have investigated the effect of FESS on olfactory function by using semi-objective olfactory testing. They have also shown that FESS as a significant positive effect on olfactory function. For examples, Lund and Scading (1994) evaluated olfactory function of patients with CRS using UPSIT and showed significant UPSIT score improvement after surgery. Downey et al. (1996) also used UPSIT to assess the olfactory function of patients with CRS pre- and postoperatively and showed that after surgery, 52% of patients had higher UPSIT score. Min et al. (1995) tested olfactory thresholds to butanol in patients with CRS. Before surgery, 33 % of patients had anosmia and 45% of patients had hyposmia. After surgery these percentages were 16% and 46% respectively. Delank and Stoll (1998) noted a post operative improvement of olfactory function assessed by olfactory thresholds and discrimination in 70% of patients with CRS. Klimek et al. (1997) reported improved odor identification and discrimination score after FESS in patients with CRS with nasal polyps. Hence, FESS seems to significantly improve olfactory function in patients with CRS with or without polyps.

Gudziol et al. (2009) explored the influence of the treatment of CRS on the olfactory function. They measured olfactory bulb volume and olfactory function of patients suffering from CRS before treatment and 3 months after. They showed that the olfactory bulb volume significantly increases after treatment and that the increase of olfactory bulb volume

Some authors have also studied the correlation between the severity of CRS and surgical outcomes on olfaction. It was reported that the improvement after FESS is significantly better in patients with severe olfactory dysfunction whereas it is not in patients with mild

correlated significantly with an increase in odor thresholds.

fact that the smell evaluation methodology was not described (Lildholdt, 1989)

surgical procedure and poor description of the olfactory evaluation tool.

CRS is the major cause of olfactory dysfunction among the population. The exact pathophysiology is this entity is still unclear. The olfactory dysfunction in these patients is reversible, as proved by the effect of treatments and MRI studies. Nevertheless, most studies show that the improvement of olfactory function is usually transient and incomplete. Different causes are hypothesized, but this is still a matter of debate. Future studies are necessary to better understand this entity.

#### **9. References**


Chronic Rhinosinusitis and Olfactory Dysfunction 49

Holcomb JD, Graham S & Calof AL (1996). Neuronal homeostasis in mammalian olfactory

Hox V, Bobic S, Callebaux I, Jorissen M & Hellings PW (2010). Nasal obstruction and smell

Hummel T & Kobal G (1999). Differences in human evokes potentials to trigeminal stimuli

Hummel T & Kobal G (2002). Olfactory event-related potentials. In: *Methods and New frontiers in Neurosciences,* Simon SA editor, pp. 123-148, CRC Press, Boca Raton Hummel T, Futschik T, Frasnelli J & Hüttenbrink KB (2003). Effects of olfactory function,

Hummel T, Kobal G, Gudziol H & Mackay-Sim A (2007). Normative data for the Sniffin

Hummel T, Livermore A, Hummel C & Kobal G (1992). Chemosensory event-related

Jakobsen J & Svendstrup F (2000). Functional endoscopic sinus surgery in chronic sinusitis – a series of 237 consecutively operated patients. *Acta Otolaryngol Suppl,* 543:158-161 Jankowski R & Bodino C (2003). Olfaction in patients with nasal polyposis: effects of

Jankowski R, Pigret D & Decroocq F (1997). Comparison of functional results after

Jiang RS, Su MC, Liang KL, Shiao JY, Hsin CH, Lu FJ & Chen WK (2009). Preoperative

Joshi H, Getchell ML, Zielinski B & Getchell TV (1987). Spectrophotometric determination of cation concentrations in olfactory mucus. *Neurosci Lett,* 82 (3): 321-326 Kern RC, Foster JD& Pitovski DZ (1997). Glucocorticoid (type II) receptors in the olfactory

Kern RC. Chronic sinusitis and anosmia: pathologic changes in the olfactory mucosa.

Kim DW, Kim JY & Jeon SY (2011). The status of the olfactory cleft may predict

Kimmelman CP (1994).The risk of olfaction from nasal surgery. *Laryngoscope,* 104:981-988 Klimek L, Moll B, Amedee RG & Mann WJ (1997). Olfactory function after microscopic endonasal surgery in patients with nasal polyps. *Am J Rhinol,* 11:251-255 Klossek JM, Peloquin L, Friedman WH, Ferrier JC & Fontanel JP (1997). Diffuse nasal

postoperative olfactory function in chronic rhinosinusitis with nasal polyposis. *Am* 

polyposis: post-operative long-term results after endoscopic sinus surgery and

mucosa of the guinea pig: RU 28362. *Chem sens,* 22:313-319

frontal irrigation. *Otolaryngol Head Neck Surg.* 117:355-361

lateralization of chemosensory stimuli. *Toxicol Lett,* 140-141:173-80

impairment in nasal polyp disease: correlation between objective and subjective

change in relation to the interval between repetitive stimulation of the nasal

age, and gender on trigeminally mediated sensations: a study based on the

Sticks including test of odor identification, odor discrimination and odor thresholds: an upgrade based on a group of more than 3000 subjects. *Eur Arch* 

potentials in man; relation to olfactory and painful sensations elicited by nicotine.

systemic steroids and radical ethmoidectomy with middle turbinate resection

ethmoidectomy and nazalisation for diffuse and severe nasal polyposis. *Acta* 

prognostic factors for olfactory change after functional endoscopic sinus surgery.

epithelium: a review*. Am J Rhinol* 10(3):125-134

mucosa. *Eur Arch Otorhinolaryngol,* 256:16-21

*Electroencephalogr Clin Neurophysiol,* 84(2):192-5

(nazalisation). *Rhinology,* 41(4):220-30

parameters*. Rhinology,* 48(4):426-32

*Otorhinol,* 264:237-243

*Otolaryngol.* 117: 601-608

*Am J Rhinol Allergy,* 23(1):64-70

Laryngoscope 2000; 110(7):1071-7

*J Rhinol Allergy,* 25(2):90-4


Cowart B, Flynn-Rodden K, McGeady S &Lowry LD (1992). Hyposmia in allergic rhinitis. *J* 

Damm M, Eckel HE, Jungehulsing M &Hummel T (2003). Olfactory changes at threshold

Deems DA, Doty RL, Settle RG, Moore-Gillon V, Shaman P, Mester AF, Kimmelman CP,

Delank KW & Stoll W (1998). Olfactory function after functional endoscopic sinus surgery

Demoly P (2008). Safety of intranasal corticosteroids in acute rhinosinusitis. *Am J* 

Doty RL & Frye R (1989). Influence of nasal obstruction on smell function. *Otolaryngol Clin* 

Doty RL & Mishra A (2001). Olfaction and its alteration by nasal obstruction, rhinitis and

Doty RL, Shaman P & Dann M (1984). Development of the University of Pennsylvania Smell

Downey LL, Jacobs JB &Leibowitz RA (1996). Anosmia and chronic sinus disease.

Fokkens WJ, Lund VJ, Mullol J et al (2007). European Position Paper on Rhinosinusitis and

Frasnelli J & Hummel T (2005). Olfactory dysfunction and daily life. *Eur Arch* 

Getchell M & Mellert T (1991). Olfactory mucus secretion. In: *Smell and taste in health and* 

Golding-Wood DG, Holmstrom M, Darby Y, Scadding GK & Lund VJ (1996). The treatment of intranasal hyposmia with intranasal steroids. *J Laryngol Otol,* 110:132-135 Gudziol V, Buschhüter D, Abolmaali N, Gerber J, Rombaux P & Hummel T (2009).

Heilmann S, Huettenbrink KB & Hummel T (2004). Local and systemic administration of corticosteroids in the treatment of olfactory loss. *Am J Rhinol*, 18:29-33 Heilmann S, Strehle G, Rosenheim K, Damm M & Hummel T (2002). Clinical assessment of retronasal olfactory function. *Acta Otolaryngol Head Neck Surg,* 128(4):414-8 Hellings PW & Rombaux P (2009). Medical therapy and smell dysfunction. *B-ENT,* 5 Suppl

Hoffman HJ, Ishii EK & MacTurk RH (1998). Age related changes in the prevalence of smell

Holbrook EH & Leopold DA (2006). An updated review of clinical olfaction. *Curr Opin* 

and taste problems among the United States adult population: results of the 1994 Disability Supplement to the National Health Interview Survey (NHIS). *Ann N Y* 

*disease*. Getchell TV, Bartoshuk LM, Doty RL, Snow J, eds, pp.83-95, Raven Press

Increasing olfactory bulb volume due to treatment of chronic rhinosinusitis – a

Identification Test: a standardized microencapsulated test of olfactory function.

and suprathreshold levels following septoplasty with partial inferior turbinectomy.

Brightman VJ & Snow JB (1991). Smell and taste disorders: a study of 750 patients from the University of Pennsylvania Smell and Taste Center. *Arch Otolaryngol Head* 

*Allergy Clin Immunol,* 9:747-751

*Neck Surg,* 117:519-528

*Otolaryngol,* 29(6):403-13

*Physiol Behav,* 32(3):489-502

*North Am*, 22:397-411

*Annals Otol Rhinol Laryngol,* 112:91-97

for chronic rhinoinusitis. *Rhinology,* 36:15-19

rhinosinusitis. *Laryngoscope,* 111:409-423

*Otolaryngol Head Neck Surg,* 115:24-28

editor, ISBN-10:0881677981, New York

longitudinal study. *Brain,* 132 (Pt 11):3096-101

*Otorhinolaryngol,* 262(3):231-235

13:71-5

*Acad Sci,* 855:716-722

*Otolaryngol Head Neck Surg,* 14:23-28

Nasal Polyps 2007. *Rhinology Suppl,* 20:1-139


Chronic Rhinosinusitis and Olfactory Dysfunction 51

Neuland C, Bitter T, Marschner H, Gudziol H & Gutinas-Lichius O (2011). Health-related

Nordin S, Monsch AU & Murphy C (1995). Unawareness of smell loss in normal aging and

Orlandi RR & Terrell JE (2002). Analysis of the adult chronic rhinosinusitis working

Park AH, Lau J, Stankiewicz J & Chow J (1998). The role of functional endoscopic sinus

Raviv JR & Kern KC (2004). Chronic rhinosinusitis and olfactory dysfunction. *Otolaryngol* 

Reden J, Maroldt H, Fritz A, Zahnert T & Hummel T (2007). A study on the prognostic

Rombaux P, Mouraux A, Bertrand B, Guerit JM & Hummel T (2006). Assessment of

Rombaux P, Mouraux A, Collet S, Eloy P & Bertrand B (2009). Usefulness and feasibility of

Rombaux P,Potier H, Bertrand B, Duprez T & Hummel T (2008). Olfactory bulb volume in

Seiden AM & Duncan HJ (2001). The diagnosis of conductive olfactory loss. *Laryngoscope,*

Simola M & Malmberg H (1998). Sense of smell in allergic and non-allergic rhinitis. *Allergy,*

Soler ZM, Mace J & Smith TL (2008). Symptom-based presentation of chronic rhinosinusitis before and after functional endoscopic sinus surgery. *Am J Rhinol,* 22:297-301 Soler ZM, Sauer DA, Mace JC & Smith TL (2010). Ethmoid histopathology does not predict olfactory outcomes after endoscopic sinus surgery. *Am J Rhinol Allergy,* 24(4):281-5 Stuck BA, Blum A, Hagner AE, Hummel T, Klimek L & Hörmann K (2003). Mometasone

Temmel AF, Quint C, Schickinger-Fischer B, Klimek L, Stoller E & Hummel T (2002).

Tourbier IA & Doty RL (2007). Sniff magnitude test: relationship to odor identification, detection and memory tests in a clinic population. *Chem Sens,* 32(6):515-23 Vaidyanathan S, Barnes M, Williamson P, Hopkinson P, Donnan PT & Lipworth B (2011).

furoate nasal spray improves olfactory performances in seasonal allergic rhinitis.

Characteristics of olfactory disorders in relation to major causes of olfactory loss.

Treatment of chronic rhinosinusitis with nasal polyposis with oral steroids followed by topical steroids: and randomized trial. *An Intern Med,* 154(5):293:302 Vento SI, Simola M, Ertama LO & Malmberg CHO (2001). Sense of smell in longstanding

patients with sinonasal disease. *Am J Rhinol,* 22(6):598-601

*Arch Otolaryngol Head Neck Surg,* 128:635-641

nasal polyposis. *Am J Rhinol,* 15:159-163

significance of qualitative olfactory dysfunction. *Eur Arch Otorhinolaryngol,*

olfactory and trigeminal function using chemosensory event-related potentials.

psychophysical and electrophysiological olfactory testing in rhinology clinic.

anosmia or severe hyposmia. *Laryngoscope,* 121(4):867:72

sensitivity. *J Gerontol B Psychol Sci Soc Sci,* 50(4):187-82

surgery in asthmatic patients. *J Otolaryngol,* 27:275-280

definition. *Am J Rhinol*, 16:7-10

*Clin North Am,* 37:1143-1157

*Neurophysiol Clin,* 36(2):53-62

*Rhinology,* 47(1):28-35

264(2):139-44

111:9-14

53:190-194

*Allergy*, 58:1195

and specific olfaction-related quality of life in patients with chronic functional

Alzheimer's disease: discrepancy between self-reported and diagnosed smell


Kobal G & Hummel T (1988). Cerebral chemosensory evoked potentials elicited by chemical

Konstantinidis I, Triaridis S, Printza A, Vital V, Ferekidis E & Constantinidis J (2007).

Landis BN, Giger R, Richchetti A, Leuchter I, Hugentobler M, Hummel T & Lacroix JS

Landis BN, Konnerth CG & Hummel T (2004). A study on the frequency of olfactory

Levine HL (1990). Functional endoscopic sinus surgery: evaluation, surgery and follow-up

Lildholdt T (1989). Surgical versus medical treatment of nasal polyps. *Rhinol Suppl,* 8:31-33 Lildholdt T, Rundcrantz H & Lindqvist N (1995). Efficacy of corticosteroid powder for nasal

Litvack JR, Fong K, Mace J, James KE & Smith TL (2008). Predictors of olfactory dysfunction in patients with chronic rhinosinusitis. *Laryngoscope*, 118(12): 2225-2230 Litvack JR, Mace J & Smith TL (2009b). Does olfactory function improve after endoscopic

Litvack JR, Mace JC & Smith TL (2009a). Olfactory function and disease severity in chronic

Lund VJ & MacKay IS (1994). Outcome assessment of endoscopic sinus surgery. *J R Soc Med,*

Lund VJ & Scadding GK (1994). Objective assessment of sinus surgery in the management of

Min YG, Yun YS, Song BH, Cho YS & Lee KS (1995). Recovery of nasal physiology after

Miwa T, Furukawa M, Tsukatani T, Costanzo RM, DiNardo LJ & Reiter ER (2001). Impact of

Mott AE & Leopold DA (1991). Disorders in taste and smell. *Med Clin North Am,* 75:1321-

Mott AE, Cain WS, Lafreniere D, Leonard G, Gent JF & Frank ME (1997). Topical

Murphy C, Shubert CR, Cruickshanks KJ, Klein BE, Klein R & Nondahl DM (2002). Prevalence of olfactory impairment in older adults. *JAMA,* 288:2307-2312 Mygind N, Nielsen LP, Hoffmann HJ, Shukla A, Blumberga G, Dahl R & Jacobi H (2001)

Naessen R (1971). An inquiry on the morphological characteristics and possible changes

Nakashima T, Kimmelman C & Snow JB (1985). Immunohistopathology of human olfactory

with age in the olfactory regions of man. *Acta Otolaryngol,* 71:49-62

nerve epithelium, nerve and bulb. *Laryngoscope,* 95:391-398

functional endoscopic sinus surgery: olfaction and mucociliary transport. *ORL J* 

olfactory impairment on quality of life and disability. *Arch Otolaryngol Head Neck* 

corticosteroid treatment of anosmia associated with nasal and sinus disease. *Arch* 

Mode of action of intranasal corticosteroids. *J Allergy Clin Immunol,* 108

findings. *ORL J Otorhinolaryngol Relat Spec,* 69(4):226-232

sinus surgery? *Otolaryngol Head Neck Surg,* 140:312-319

chronis rhinosinusitis: an update. *J Laryngol Otol,* 108:749-753

rhinosinusitis. *Am J Rhinol Allergy,* 23(2):139-144

*Otorhinolaryngol Relat Spec,* 57:264-268

*Otolaryngol Head Neck Surg,* 123:367-372

dysfunction. *Laryngoscope,* 114(10):1764-9

of 250 patients. *Laryngoscope,* 100:79-84

*Clin Neurophysiol,* 71:241-50

*Allied Sci,* 20:26-30

*Surg,* 127(5):497-503

(1Suppl):S16-25

87:70-72

1353

stimulation of the human olfactory and respiratory nasal mucosa. *Electroencephalogr* 

Olfactory dysfunction in nasal polyposis: correlation with computed tomography

(2003). Retronasal olfactory function in nasal polyposis. *Laryngoscope,* 113(11):1993-7

polyps: a double-blind, placebo-controlled study of budesonide. *Clin Otolaryngol* 


**4** 

*Jordan* 

**Refractory Chronic Rhinosinusitis:** 

Chronic rhinosinusitis (CRS) is a common disease with significant morbidity and health care cost. Although the medical and surgical treatments for CRS have improved markedly over the past few decades, a subset of patients remains quite resistant to all forms of therapy.

Such patients end up being over-treated and subjected to numerous unsuccessful surgeries some of which can result in serious complications. The optimal treatment for these patients (an entity referred to as refractory or recalcitrant sinusitis) (RCRS) is complex and

The true incidenceof RCRS is unknown. It is estimated that at least 10 % of patients with CRS continue to be symptomatic after appropriate endoscopic sinus surgery (ESS) with long term follow up. This 10% failure rate translates into 30,000 patients yearlyundergoing ESS with poor postoperative outcome.Because these numbers are cumulative over years, approximately450,000 cases in the United States are currently estimatedto have chronic sinusitis that is unresponsive to medical and surgical therapy. Today, these chronic patients

The aims of this chapter are to review the updated possible pathogesis of RCRS and suggest

Thoroughand detailed history is fundamental in evaluating patients to find out whether optimal treatment has been given, and whether there are any personal or technical

Current symptomatology should be determined. Detailed questions regarding nasal symptoms: facial pressure, nasal obstruction, anterior or posterior rhinorrhea,and alteration of sense of smell should be asked. Frequency and duration of symptoms exacerbation as

Routine medical questions should also be included. Specific attention should be paid to thesymptoms of respiratory system, such as cough, wheeze, and shortness of breath.History

form a significant portion of most rhinology practices. (Desrosiers, 2004).

well as different modalities of treatments used should be reviewed.

possible algorithmic management plan for this condition.

**2. History and physical examinations** 

predisposing factors.

**1. Introduction** 

challenging.

 **Etiology & Management** 

*Jordan University of Science & Technology,Irbid,* 

Mohannad Al-Qudah


### **Refractory Chronic Rhinosinusitis: Etiology & Management**

Mohannad Al-Qudah *Jordan University of Science & Technology,Irbid, Jordan* 

#### **1. Introduction**

52 Peculiar Aspects of Rhinosinusitis

Wang JH, Kwon HJ & Jang YJ (2010). Staphylococcus aureus increases cytokine and matrix

Welge-Luessen A (2009). Psychophysical effects of nasal and oral inflammation. *Ann N Y* 

Wright ED & Agrawal S (2007). Impact of perioperative systemic steroids on surgical

Yee KK, Pribitkin EA, Cowart BJ, Vainius AA, Klock CT, Rosen D, Feng P, Mc Lean J, Hahn

rhinosinusitis and nasal polyps. *Am J Rhinol Allergy,* 24(6):422-7

rhinosinusitis. *Am J Rhinol Allergy*, 24(2):110-20

*Acad Sci,* 1170:585-9

Pt 2 Suppl 115): 1-28

metalloproteinase expression in nasal mucosa of patients with chronic

outcomes in patients with chronic rhinosinusitis with polyposis: evaluation with novel perioperative sinus endoscopy (POSE) scoring system. *Laryngoscope,* 117 (11

CG & Rawson NE (2010). Neuropathology of the olfactory mucosa in chronic

Chronic rhinosinusitis (CRS) is a common disease with significant morbidity and health care cost. Although the medical and surgical treatments for CRS have improved markedly over the past few decades, a subset of patients remains quite resistant to all forms of therapy.

Such patients end up being over-treated and subjected to numerous unsuccessful surgeries some of which can result in serious complications. The optimal treatment for these patients (an entity referred to as refractory or recalcitrant sinusitis) (RCRS) is complex and challenging.

The true incidenceof RCRS is unknown. It is estimated that at least 10 % of patients with CRS continue to be symptomatic after appropriate endoscopic sinus surgery (ESS) with long term follow up. This 10% failure rate translates into 30,000 patients yearlyundergoing ESS with poor postoperative outcome.Because these numbers are cumulative over years, approximately450,000 cases in the United States are currently estimatedto have chronic sinusitis that is unresponsive to medical and surgical therapy. Today, these chronic patients form a significant portion of most rhinology practices. (Desrosiers, 2004).

The aims of this chapter are to review the updated possible pathogesis of RCRS and suggest possible algorithmic management plan for this condition.

#### **2. History and physical examinations**

Thoroughand detailed history is fundamental in evaluating patients to find out whether optimal treatment has been given, and whether there are any personal or technical predisposing factors.

Current symptomatology should be determined. Detailed questions regarding nasal symptoms: facial pressure, nasal obstruction, anterior or posterior rhinorrhea,and alteration of sense of smell should be asked. Frequency and duration of symptoms exacerbation as well as different modalities of treatments used should be reviewed.

Routine medical questions should also be included. Specific attention should be paid to thesymptoms of respiratory system, such as cough, wheeze, and shortness of breath.History

Refractory Chronic Rhinosinusitis: Etiology & Management 55

Thin cut CT scan with coronal and sagital reconstruction should be ordered. CT scan can illustrate detail in lateral wall of sinuses where the endoscopic view cannot reach.Extent of sinus involvement, extent of prior surgery, presence of obstruction to sinus drainage, unventilated cells, development of new bone deposition or neo-osteogenesis, and evidence of previous intraoperative complications can be easily visualized. Figure 1 showed the

Although the exact role of bacteria and fungus in the etiology of sinusitis is still controversial, we have reasonable evidences to believe they play significant role in this wide spectrum disease. Bacteria and fungus have been detected in endoscopic guided culture, type of organisms identified in acute sinusitis differs from those reported in chronic and in RCRS. In general, patients with sinusitis report improvement in their symptoms while they are on Antibiotics. Additionally, the prevalence &severity of sinusitis in immuncompromised patients correlate with their immunological status. In fact, Antimicrobial therapy is still the mostcommon form of therapy prescribed by physiciansfor

Various forms of immunodeficiencies predispose to rhinosinusitis, however in RCRS the most important are selective IgA deficiency and systemic subtle humoral immunodeficiencies. These patients are usually diagnosed after being treated with multiple sinus surgeries. Other forms of immunodeficiency, for example, common variable immunodeficiency lymphopenia or neutropenia are more important in the pathogenesis of

Immune dysfunction as a risk factor for RCRS has gained attention in recent years.Chee et al studied the incidence of primary immune deficiency in patients with refractory sinusitis.Among a group of 79 patients with refractory sinusitis 17.9% were noted to have low IgG and 16.7% were noted to have low IgA. Common variable immunodeficiency was found in 9.9% and selective IgA deficiency was diagnosed in 6.2%. Although these numbers are interesting, the authors included some patients who didn't fit with the current definition of RCRS, they defined refractory sinusitis as at least one previous sinussurgery and/or three episodes of objectively documented rhinosinusitis in the previous year ( Cheel et al., 2001). Vanleberghe et al. reported on a series of cases with RCRS whohad undergone immunologic evaluation. Out of 307(261 adults and 46 children) patients tested, 22% had evidence of humoral immunodeficiency.The majority of these were subtle IgG subclass deficits, low level of major immunoglobulins was reported in 7% for IgA and 3.3%.for IgG. Low level of IgM or Common variable immunodeficiency weren't detected

In a recent paper Al-Qudah et al studied the contribution of primary immunodeficiency in 67 patients with RCRS at a large tertiary care medical center. In addition to major immunoglobulin and IgG subclasses blood level, Functional antibody response was assessed by examining the antibody response to the unconjugated pneumococcal

recurrent acute forms of rhinosinusitis and acute invasive fungal sinusitis.

typical CT scan finding in patients with RCRS.

**3. Pathogenesis and treatment 3.1 Immunodeficiency & RCRS** 

the treatment of CRS.

(Vanlerberghe et al., 2006).

of recurrent infections in the skin, urinary tract or digestive tract may indicate immunodeficiency. Additionally, connective tissue disorders, granulomatous diseases and vasculatitis related symptoms need be asked.

Medication should be reviewed and the use of oral immunosuppressive agents determined.

Allergy questionnaires should cover presence of household pets or excess mold in the domestic environment. Work history should be obtained to evaluate occupational causative elements to the disease. Both smoking historyand passive exposure to smoke should be assessed.

Previous nasal surgeries reviewed. Type of surgery, recovery, complications and response should all be documented.

Complete ear, nose, and throat examination is followed. Anterior rhinoscopy should assess nasal patency, nasal mucosa condition, inferior turbinates, and the presence of nasal crusting.

Direct visualization using 0 and 30 degree rigid endoscopy is crucial in this group of patients, to look for any evidenceof active infection or obstruction to sinus ostium. The presence of polyps, pus,synechiae,stenosis, middle turbinate lateralization should also be evaluated.Pathological looking mucosa can be biopsied under local anesthesia as office procedure to rule out systemic diseases or tumors.

Fig. 1. Coronal CT scan for patient with RCRS, thickened mucosa with patent sinus ostium and Osteitis of the left lateral maxillary wall.

If surgery is not technically adequate and evidence of obstruction noticed revision surgery is offered.

Thin cut CT scan with coronal and sagital reconstruction should be ordered. CT scan can illustrate detail in lateral wall of sinuses where the endoscopic view cannot reach.Extent of sinus involvement, extent of prior surgery, presence of obstruction to sinus drainage, unventilated cells, development of new bone deposition or neo-osteogenesis, and evidence of previous intraoperative complications can be easily visualized. Figure 1 showed the typical CT scan finding in patients with RCRS.

#### **3. Pathogenesis and treatment**

#### **3.1 Immunodeficiency & RCRS**

54 Peculiar Aspects of Rhinosinusitis

of recurrent infections in the skin, urinary tract or digestive tract may indicate immunodeficiency. Additionally, connective tissue disorders, granulomatous diseases and

Medication should be reviewed and the use of oral immunosuppressive agents determined. Allergy questionnaires should cover presence of household pets or excess mold in the domestic environment. Work history should be obtained to evaluate occupational causative elements to the disease. Both smoking historyand passive exposure to smoke should be

Previous nasal surgeries reviewed. Type of surgery, recovery, complications and response

Complete ear, nose, and throat examination is followed. Anterior rhinoscopy should assess nasal patency, nasal mucosa condition, inferior turbinates, and the presence of nasal

Direct visualization using 0 and 30 degree rigid endoscopy is crucial in this group of patients, to look for any evidenceof active infection or obstruction to sinus ostium. The presence of polyps, pus,synechiae,stenosis, middle turbinate lateralization should also be evaluated.Pathological looking mucosa can be biopsied under local anesthesia as office

Fig. 1. Coronal CT scan for patient with RCRS, thickened mucosa with patent sinus ostium

If surgery is not technically adequate and evidence of obstruction noticed revision surgery is

vasculatitis related symptoms need be asked.

procedure to rule out systemic diseases or tumors.

and Osteitis of the left lateral maxillary wall.

assessed.

crusting.

offered.

should all be documented.

Although the exact role of bacteria and fungus in the etiology of sinusitis is still controversial, we have reasonable evidences to believe they play significant role in this wide spectrum disease. Bacteria and fungus have been detected in endoscopic guided culture, type of organisms identified in acute sinusitis differs from those reported in chronic and in RCRS. In general, patients with sinusitis report improvement in their symptoms while they are on Antibiotics. Additionally, the prevalence &severity of sinusitis in immuncompromised patients correlate with their immunological status. In fact, Antimicrobial therapy is still the mostcommon form of therapy prescribed by physiciansfor the treatment of CRS.

Various forms of immunodeficiencies predispose to rhinosinusitis, however in RCRS the most important are selective IgA deficiency and systemic subtle humoral immunodeficiencies. These patients are usually diagnosed after being treated with multiple sinus surgeries. Other forms of immunodeficiency, for example, common variable immunodeficiency lymphopenia or neutropenia are more important in the pathogenesis of recurrent acute forms of rhinosinusitis and acute invasive fungal sinusitis.

Immune dysfunction as a risk factor for RCRS has gained attention in recent years.Chee et al studied the incidence of primary immune deficiency in patients with refractory sinusitis.Among a group of 79 patients with refractory sinusitis 17.9% were noted to have low IgG and 16.7% were noted to have low IgA. Common variable immunodeficiency was found in 9.9% and selective IgA deficiency was diagnosed in 6.2%. Although these numbers are interesting, the authors included some patients who didn't fit with the current definition of RCRS, they defined refractory sinusitis as at least one previous sinussurgery and/or three episodes of objectively documented rhinosinusitis in the previous year ( Cheel et al., 2001).

Vanleberghe et al. reported on a series of cases with RCRS whohad undergone immunologic evaluation. Out of 307(261 adults and 46 children) patients tested, 22% had evidence of humoral immunodeficiency.The majority of these were subtle IgG subclass deficits, low level of major immunoglobulins was reported in 7% for IgA and 3.3%.for IgG. Low level of IgM or Common variable immunodeficiency weren't detected (Vanlerberghe et al., 2006).

In a recent paper Al-Qudah et al studied the contribution of primary immunodeficiency in 67 patients with RCRS at a large tertiary care medical center. In addition to major immunoglobulin and IgG subclasses blood level, Functional antibody response was assessed by examining the antibody response to the unconjugated pneumococcal

Refractory Chronic Rhinosinusitis: Etiology & Management 57

In addition to twice daily nasal irrigations and long term nasal steroid all RCRS patients with immunodeficiency need to be on prophylactic oral antibiotics. Our protocol is to use two different antibiotics rotating every two weeks and so any emerging resistant clones will wipe out with the other antibiotic. For many reasons, Bactrim and Doxycycline are our first option: They are old, cheap, safe antibiotics and prescribed twice daily. Additionally these two antibiotics have a potent anti-inflammatory effect. Cephalexin, Amoxcillin and Clarithromycin are alternative options for those patients who are allergic or can't tolerate Bactrim and Doxycycline. The duration of prophylactic antibiotics use is flexible and depends mainly on patient's symptoms duration and clinical response. Antibiotics can be used all through the year or given in symptomatic season. Acute exacerbation is treated according to endoscopic guided culture. Patients who failed to improve on antibiotics can benefit from intravenous or subcutaneous immunoglobulin replacement. The recommended stander dose is 400-600 mg/kg given every four weeks for 1-2 years. (Shearer et al 1996).

Cessation of treatment is schedule during summer months to avoid allergy season and to

Biofilms are a complex organized community of germs that adhere to the mucosal surface and surrounded by a self-produced extensive extracellular polymeric substance called (glycocalyx) which composed primarily of polysaccharides. The glycocalyx is a mixture of bacterial colonies of different phenotypes with various physiochemical properties. It serves as protection for its bacterial inhabitants while also modulating the microenvironment of the colonies through its numerous water channels. Biofilms intermittently release free floating

Biofilm's life cycle and interactions with the environment can be divided into three stages: attachment, growth, and detachment. During the attachment phase,the substratum has to be adequate for the reversible adsorption and ultimately the irreversible attachment of bacteria to the surface. During the growth phase, as thecells divide and colonize the surface, a polysaccharide matrix is formed, and the biofilm begins to display athree-dimensional structure. During this phase water channels are formed. Once biofilms reach maturity, bacteria slough off and embolize to other areaswhere the process may begin again

Bacterial biofilms have two microbiological characteristic: first, they are difficult to detect and culture using routine conventional methods and second, they are 10-1000 time resistant to current antimicrobial therapy when compared with genetically identical planktonic

Quantitative immunoglobulins: IgA, IgE, IgM, IgG and IgG subclasses

Complete blood cell count with differential

Table 1. Immune work up in refractory chronic sinusitis

avoid the high incidence of infections during winter.

bacteria (planktonic ) that can provide a constant nidus of infection.

Allergy Test.

**3.2 Biofilm & RCRS** 

(Sanclement et al.,2005).

bacteria (Kilty & Desrosiers, 2009).

Pneumococcal antibody titers

polysaccharide vaccine. Low IgG was detected in 9%, low IgA in 3%, low IgM in 12% of patients, and IgG subclasses in 19%. Common variable immunodeficiency was diagnosed in one case. 67% of patients failed to produce more than a fourfold increase in postimmunization antibody titer for 7 of 14 serotypes being tested and were considered to have functional antibody deficiency. Interestingly there was no statistically significant difference in the incidence of low level of immunoglobulins between patients with normal antibody response and poor response group. They recommended measurement of serumimmunoglobulin levels in all patients with RCRS; if these are normal, then functional antibody responses should be evaluated (Alqudah et al., 2010).

Functional antibody responses or selective antibody deficiency syndrome is a condition with normal or near normal serum immunoglobulin concentrations but an inadequate production of specific antibodies response to polysaccharide organisms, which are Tindependent type 2 antigens, like Streptococcus pneumonia. Patient with this condition have recurrent respiratory infections such as: sinusitis, bronchitis, and pneumonia.The diagnosis can be reached by taking paired blood sample before and 6-weks after immunization with pneumococcal vaccine.The consensus recommendation is that a normal response in adultsis a fourfold increase in antibody titers to 70% of the14 serotypesunconjugated pneumococcal polysaccharide and a normal response in children is a fourfold increase in antibody titers to 50% of the serotypes tested (Bonilla et al.,2005).

T cell immunodeficiency patients are unlikely to present with Refractory sinusitis symptoms without other apparent clinical presentation. Primary T cell disorders are rare and usually diagnosed during childhood. Secondary T cell deficiency presents with unusual or severe viral, fungal or protozoal infection.

Food allergy is another possible cause of persistent nasal symptoms after proper medical and surgical therapy especially in patient with nasal polyp. Most common ''masked'' food allergens in adults are those foods commonly eaten and include: wheat, dairy, soy, corn, and, eggs (Ferguson et al., 2009).

The condition is usually difficult to recognize by the patients as symptoms may show up hours or even a day after food absorption and the fact that common allergic foods are so prevalent in our diet that many patients eat them nearly every day. An elimination food challenging test is a convenient and inexpensive procedure that can performed by the patient at home. The targeted food is eliminated from the diet for 5 to 7 days and then reintroduced into the diet during this hyperresponsive period of 5 to 10 days following elimination. If the food causes symptoms, then the patient will generally be aware of either nasal or non-nasal symptoms after the food challenge. Those who note symptoms on reintroduction of the food are instructed to eliminate the food from their diet for approximately 3 months, after which time the food may be reintroduced into their diet, although the food should not be eaten on a daily basis (Ozdemir et al., 2009).

Our immune evaluation for patients with RCRS is displayed in Table 1.All patients should have complete blood cell count with differential, measurement of serum IgG, IgA, IgM, IgE and IgG subclasses as well as allergy skin test or radioallergosorbent test. If serum immunoglobulin levels are normal, functional antibody responses should be evaluated by determining specific antibody response to an unconjugated pneumococcal polysaccharide vaccine.

polysaccharide vaccine. Low IgG was detected in 9%, low IgA in 3%, low IgM in 12% of patients, and IgG subclasses in 19%. Common variable immunodeficiency was diagnosed in one case. 67% of patients failed to produce more than a fourfold increase in postimmunization antibody titer for 7 of 14 serotypes being tested and were considered to have functional antibody deficiency. Interestingly there was no statistically significant difference in the incidence of low level of immunoglobulins between patients with normal antibody response and poor response group. They recommended measurement of serumimmunoglobulin levels in all patients with RCRS; if these are normal, then functional

Functional antibody responses or selective antibody deficiency syndrome is a condition with normal or near normal serum immunoglobulin concentrations but an inadequate production of specific antibodies response to polysaccharide organisms, which are Tindependent type 2 antigens, like Streptococcus pneumonia. Patient with this condition have recurrent respiratory infections such as: sinusitis, bronchitis, and pneumonia.The diagnosis can be reached by taking paired blood sample before and 6-weks after immunization with pneumococcal vaccine.The consensus recommendation is that a normal response in adultsis a fourfold increase in antibody titers to 70% of the14 serotypesunconjugated pneumococcal polysaccharide and a normal response in children is a

fourfold increase in antibody titers to 50% of the serotypes tested (Bonilla et al.,2005).

T cell immunodeficiency patients are unlikely to present with Refractory sinusitis symptoms without other apparent clinical presentation. Primary T cell disorders are rare and usually diagnosed during childhood. Secondary T cell deficiency presents with unusual or severe

Food allergy is another possible cause of persistent nasal symptoms after proper medical and surgical therapy especially in patient with nasal polyp. Most common ''masked'' food allergens in adults are those foods commonly eaten and include: wheat, dairy, soy, corn,

The condition is usually difficult to recognize by the patients as symptoms may show up hours or even a day after food absorption and the fact that common allergic foods are so prevalent in our diet that many patients eat them nearly every day. An elimination food challenging test is a convenient and inexpensive procedure that can performed by the patient at home. The targeted food is eliminated from the diet for 5 to 7 days and then reintroduced into the diet during this hyperresponsive period of 5 to 10 days following elimination. If the food causes symptoms, then the patient will generally be aware of either nasal or non-nasal symptoms after the food challenge. Those who note symptoms on reintroduction of the food are instructed to eliminate the food from their diet for approximately 3 months, after which time the food may be reintroduced into their diet,

Our immune evaluation for patients with RCRS is displayed in Table 1.All patients should have complete blood cell count with differential, measurement of serum IgG, IgA, IgM, IgE and IgG subclasses as well as allergy skin test or radioallergosorbent test. If serum immunoglobulin levels are normal, functional antibody responses should be evaluated by determining specific antibody response to an unconjugated pneumococcal polysaccharide

although the food should not be eaten on a daily basis (Ozdemir et al., 2009).

antibody responses should be evaluated (Alqudah et al., 2010).

viral, fungal or protozoal infection.

and, eggs (Ferguson et al., 2009).

vaccine.


Table 1. Immune work up in refractory chronic sinusitis

In addition to twice daily nasal irrigations and long term nasal steroid all RCRS patients with immunodeficiency need to be on prophylactic oral antibiotics. Our protocol is to use two different antibiotics rotating every two weeks and so any emerging resistant clones will wipe out with the other antibiotic. For many reasons, Bactrim and Doxycycline are our first option: They are old, cheap, safe antibiotics and prescribed twice daily. Additionally these two antibiotics have a potent anti-inflammatory effect. Cephalexin, Amoxcillin and Clarithromycin are alternative options for those patients who are allergic or can't tolerate Bactrim and Doxycycline. The duration of prophylactic antibiotics use is flexible and depends mainly on patient's symptoms duration and clinical response. Antibiotics can be used all through the year or given in symptomatic season. Acute exacerbation is treated according to endoscopic guided culture. Patients who failed to improve on antibiotics can benefit from intravenous or subcutaneous immunoglobulin replacement. The recommended stander dose is 400-600 mg/kg given every four weeks for 1-2 years. (Shearer et al 1996).

Cessation of treatment is schedule during summer months to avoid allergy season and to avoid the high incidence of infections during winter.

#### **3.2 Biofilm & RCRS**

Biofilms are a complex organized community of germs that adhere to the mucosal surface and surrounded by a self-produced extensive extracellular polymeric substance called (glycocalyx) which composed primarily of polysaccharides. The glycocalyx is a mixture of bacterial colonies of different phenotypes with various physiochemical properties. It serves as protection for its bacterial inhabitants while also modulating the microenvironment of the colonies through its numerous water channels. Biofilms intermittently release free floating bacteria (planktonic ) that can provide a constant nidus of infection.

Biofilm's life cycle and interactions with the environment can be divided into three stages: attachment, growth, and detachment. During the attachment phase,the substratum has to be adequate for the reversible adsorption and ultimately the irreversible attachment of bacteria to the surface. During the growth phase, as thecells divide and colonize the surface, a polysaccharide matrix is formed, and the biofilm begins to display athree-dimensional structure. During this phase water channels are formed. Once biofilms reach maturity, bacteria slough off and embolize to other areaswhere the process may begin again (Sanclement et al.,2005).

Bacterial biofilms have two microbiological characteristic: first, they are difficult to detect and culture using routine conventional methods and second, they are 10-1000 time resistant to current antimicrobial therapy when compared with genetically identical planktonic bacteria (Kilty & Desrosiers, 2009).

Refractory Chronic Rhinosinusitis: Etiology & Management 59

Pseudomonas biofilms has been shown to be 60-fold greater than the MIC for gentamicin

These date and others encourage rhinologist in the past few years toward treating Biofilms in RCRS with different delivery methods of topical antibiotics at concentration above the MIC level with minimum systemic side effects, taking advantage of the anatomical and physiological changes after ESS where paranasal sinuses become single large cavity

Antibiotics can deliver into nasal cavity by nasal sprays, irrigations, nebulizers or by direct installation using syringe and large gauge needle. Because nasal sprays rely on mucociliary clearance to transport the drug, and this is often impaired in RCRS, as well as their small surface area deposition many believe this method of delivery is suboptimum(Lim et al,

Most of clinical research on topical antibiotics for RCRS is limited with small number of patients, short follow up, different protocols for treatment and inclusions and exclusions criteria, however The conclusion of 2 recent review articles support the use of topical antibiotics in RCRS and recommend the need of larger and better designed randomized

Although CRS begins in the mucosa there are evidences that inflammation can spread and involve underlying bony structures leading to persistent of patients' symptoms following aggressive medical and proper surgical treatment.The mucosa and underlying bone are not

Bolger et al studied the histopathology changes after induce sinus infection in 33 New Zealand white rabbits with Pseudomonas aeruginosa. Histologic analysis of the bone 4, 14, 21, and 28 days after bacterial infection showed stromal changes of bone resorption, reactive osteoblasts, and appositional or intra-membranous new bone formation as early as 4 days after bacterial inoculation. Bacteria were present in the sinus lumen, surface of sinus mucosa, mucosal crypts, mucosal abscesses, and ulcers but not in the bone itself. They conclude that although bacteria were limited to the mucosa, the infection induced histopathological changes at the submucosa and bone level (Bolger et al., 1997). Using the same model and pathogen, Perloff and colleagues confirmed these bony changes to be identical to chronic osteomyelitis, interestingly, in all studied specimens some bony changes were found at the non-infected side . They suggested that inflammation may travel along bone to adjacent sinuses without intervening mucosal disease. Properly inflammatory or infectious agents entered the underlying bone, through Haversian canals, and subsequently activated the remodeling process in sites distant or adjacent to the original inoculation site

In another study, 14 rabbits were induced by Staphylococcus aureus, chronic osteomyelitis

Bony changes had been also reported in studies on patients with CRS.Kennedy et al noted marked activity with features of increased fibrosis, remodeling, and woven bone in ethmoid labyrinth. Ethmoid septations were found to have evidence of marked acceleration in bone

double-blinded placebo-controlled studies (Lim et al, 2008,Richard et al ,2010)

and greater than 1000-fold for ceftazidime and piperacillin(Ceri, 1999)

connected with multiple patent ostiums.

**3.3 Osteitis and neo-osteogenesis in RCRS** 

separated units and they wee communicate with each other.

in the non-infected side was found in (43%) (Khalid et al., 2002).

2008,Richard et al ,2010).

(Perloff et al.,2000).

Antibiotics resistance is most likely related to biofilm slow growth and metabolic rate as well as sharing of multiple resistance genes within the members of the biofilm community. Antibiotic treatment will kill bacteria in the periphery where the cells are metabolically active, but doesn't reach the bacteria in the deeper layers of the biofilm. Thus, the biofilm serves as a bacterial reservoir that sheds planktonic forms causing systemic illness, especially when released intothe circulation. In these circumstances, antibiotic treatment will eliminate the circulating bacteria but not the biofilm, leading to recurring acute exacerbations (Post et al., 2007).

Biofilm infection theory may offer an explanation of the high rate of negative sinus cavities in CRS and why antibiotic treatment is unable to resolve CRS with bacteria that are sensitive to antibiotics.In 2004, Cryer and his colleagues were first to demonstrate the presence of biofilms in the biopsied mucosa from a number of symptomatic CRS patients who had prior appropriate medical and surgical management (Cryer et al.,2004) .One year later Ramadan et al identified biofilms on the mucosa of five patients at the time of ESS.(Ramadan,2006).

Further studies found significant differences in the rate of biofilms formation between control, CRS and refractory sinusitis (Bendouah et al., 2006; Psaltis et al., 2007; Sanclement et al., 2005).

Another support to the biofilm theory is that pathogenic bacteria most commonly implicated in RCRS have been identified in patients with RCRS to exist in the form of a biofilm. In several studies of bacteriology in RCRS performed with conventional culture methods, Staphylococcus aureus, Coagulase negative staphylococci and Pseudomonas aeruginosa have been identified as the most common bacteria to colonize the paranasal sinuses and these same species were the most common bacteria identified in the biofilms of refractory sinusitis patients using different invasive labartory techniques.

The preoperative presence and type of bacteria biofims in sinus mucosa may correlate with continuous postoperative symptoms and mucosal inflammation after ESS. Bendouahet et al took 31 isolates from 19 CRS patients who had undergone ESS a year earlier. 71% of isolates showed biofilm formation. Among the bacteria recovered, Pseudomonas aeruginosa and Staphylococcus aureus biofilm was shown to have a correlation with poor outcome after ESS, whereas Coagulase negative staphylococci biofilm did not (Bendouah et al., 2006). More recently, Psaltis et al retrospectively studied a group of 40 CRS patients who had undergone ESS. Outcome measures revealed that bacterial biofilms were found in 50 percent of the 40 patients and that the poorer post operation symptoms were correlated with the presence of bacterial biofilms. Interestingly biofims formation is independent of many common risk factors,(such as allergy, polyps, samter's triad) cited in the etiology of CRS were not found to be of significant in ( Psaltis et al., 2008).

Staphylococcus aureus, Pseudomonas aeruginosa and Coagulase negative staph. are the most frequent biofilm forming bacteria in RCRS, these bacteria are usually resistant to oral and intravenous antibiotics at minimum inhibitory concentration (MIC). In a study aimed to determine the in vitro activity of moxifloxacin against Staphylococcus aureus in biofilm form with samples recovered from patients with at least 1 year post-ESS, the authors found moxifloxacin at 1000 times the known MIC was statistically significant in reducing the number of viable bacteria (Desrosiers et al., 2007).

In another work, authors studied the MIC of different antibiotics to eradicate Pseudomonas aeruginosa biofilms, they found The minimum biofilm eradication concentration for

Antibiotics resistance is most likely related to biofilm slow growth and metabolic rate as well as sharing of multiple resistance genes within the members of the biofilm community. Antibiotic treatment will kill bacteria in the periphery where the cells are metabolically active, but doesn't reach the bacteria in the deeper layers of the biofilm. Thus, the biofilm serves as a bacterial reservoir that sheds planktonic forms causing systemic illness, especially when released intothe circulation. In these circumstances, antibiotic treatment will eliminate the circulating bacteria but not the biofilm, leading to recurring acute

Biofilm infection theory may offer an explanation of the high rate of negative sinus cavities in CRS and why antibiotic treatment is unable to resolve CRS with bacteria that are sensitive to antibiotics.In 2004, Cryer and his colleagues were first to demonstrate the presence of biofilms in the biopsied mucosa from a number of symptomatic CRS patients who had prior appropriate medical and surgical management (Cryer et al.,2004) .One year later Ramadan et al identified biofilms on the mucosa of five patients at the time of ESS.(Ramadan,2006). Further studies found significant differences in the rate of biofilms formation between control, CRS and refractory sinusitis (Bendouah et al., 2006; Psaltis et al., 2007; Sanclement et al., 2005). Another support to the biofilm theory is that pathogenic bacteria most commonly implicated in RCRS have been identified in patients with RCRS to exist in the form of a biofilm. In several studies of bacteriology in RCRS performed with conventional culture methods, Staphylococcus aureus, Coagulase negative staphylococci and Pseudomonas aeruginosa have been identified as the most common bacteria to colonize the paranasal sinuses and these same species were the most common bacteria identified in the biofilms of

The preoperative presence and type of bacteria biofims in sinus mucosa may correlate with continuous postoperative symptoms and mucosal inflammation after ESS. Bendouahet et al took 31 isolates from 19 CRS patients who had undergone ESS a year earlier. 71% of isolates showed biofilm formation. Among the bacteria recovered, Pseudomonas aeruginosa and Staphylococcus aureus biofilm was shown to have a correlation with poor outcome after ESS, whereas Coagulase negative staphylococci biofilm did not (Bendouah et al., 2006). More recently, Psaltis et al retrospectively studied a group of 40 CRS patients who had undergone ESS. Outcome measures revealed that bacterial biofilms were found in 50 percent of the 40 patients and that the poorer post operation symptoms were correlated with the presence of bacterial biofilms. Interestingly biofims formation is independent of many common risk factors,(such as allergy, polyps, samter's triad) cited in the etiology of CRS

Staphylococcus aureus, Pseudomonas aeruginosa and Coagulase negative staph. are the most frequent biofilm forming bacteria in RCRS, these bacteria are usually resistant to oral and intravenous antibiotics at minimum inhibitory concentration (MIC). In a study aimed to determine the in vitro activity of moxifloxacin against Staphylococcus aureus in biofilm form with samples recovered from patients with at least 1 year post-ESS, the authors found moxifloxacin at 1000 times the known MIC was statistically significant in reducing the

In another work, authors studied the MIC of different antibiotics to eradicate Pseudomonas aeruginosa biofilms, they found The minimum biofilm eradication concentration for

refractory sinusitis patients using different invasive labartory techniques.

were not found to be of significant in ( Psaltis et al., 2008).

number of viable bacteria (Desrosiers et al., 2007).

exacerbations (Post et al., 2007).

Pseudomonas biofilms has been shown to be 60-fold greater than the MIC for gentamicin and greater than 1000-fold for ceftazidime and piperacillin(Ceri, 1999)

These date and others encourage rhinologist in the past few years toward treating Biofilms in RCRS with different delivery methods of topical antibiotics at concentration above the MIC level with minimum systemic side effects, taking advantage of the anatomical and physiological changes after ESS where paranasal sinuses become single large cavity connected with multiple patent ostiums.

Antibiotics can deliver into nasal cavity by nasal sprays, irrigations, nebulizers or by direct installation using syringe and large gauge needle. Because nasal sprays rely on mucociliary clearance to transport the drug, and this is often impaired in RCRS, as well as their small surface area deposition many believe this method of delivery is suboptimum(Lim et al, 2008,Richard et al ,2010).

Most of clinical research on topical antibiotics for RCRS is limited with small number of patients, short follow up, different protocols for treatment and inclusions and exclusions criteria, however The conclusion of 2 recent review articles support the use of topical antibiotics in RCRS and recommend the need of larger and better designed randomized double-blinded placebo-controlled studies (Lim et al, 2008,Richard et al ,2010)

#### **3.3 Osteitis and neo-osteogenesis in RCRS**

Although CRS begins in the mucosa there are evidences that inflammation can spread and involve underlying bony structures leading to persistent of patients' symptoms following aggressive medical and proper surgical treatment.The mucosa and underlying bone are not separated units and they wee communicate with each other.

Bolger et al studied the histopathology changes after induce sinus infection in 33 New Zealand white rabbits with Pseudomonas aeruginosa. Histologic analysis of the bone 4, 14, 21, and 28 days after bacterial infection showed stromal changes of bone resorption, reactive osteoblasts, and appositional or intra-membranous new bone formation as early as 4 days after bacterial inoculation. Bacteria were present in the sinus lumen, surface of sinus mucosa, mucosal crypts, mucosal abscesses, and ulcers but not in the bone itself. They conclude that although bacteria were limited to the mucosa, the infection induced histopathological changes at the submucosa and bone level (Bolger et al., 1997). Using the same model and pathogen, Perloff and colleagues confirmed these bony changes to be identical to chronic osteomyelitis, interestingly, in all studied specimens some bony changes were found at the non-infected side . They suggested that inflammation may travel along bone to adjacent sinuses without intervening mucosal disease. Properly inflammatory or infectious agents entered the underlying bone, through Haversian canals, and subsequently activated the remodeling process in sites distant or adjacent to the original inoculation site (Perloff et al.,2000).

In another study, 14 rabbits were induced by Staphylococcus aureus, chronic osteomyelitis in the non-infected side was found in (43%) (Khalid et al., 2002).

Bony changes had been also reported in studies on patients with CRS.Kennedy et al noted marked activity with features of increased fibrosis, remodeling, and woven bone in ethmoid labyrinth. Ethmoid septations were found to have evidence of marked acceleration in bone

Refractory Chronic Rhinosinusitis: Etiology & Management 61

Fig. 2. Coronal and axial CT for patient with RCRS showed osteitis in the maxillary wall.

physiology with histologic findings including presence of inflammatory cells, fibrosis, and new bone formation. They also reported inflammation in the bone even when the overlying mucosa was intact (Kennedy, 1998).

Giacchiet al. compared bone from ethmoid septa of 20 patients with CRS and control group.Those with CRS typically showed periosteal thickening and resorption or remodeling. They also found a trend toward more advanced histologic bone stage associated with higher CT score indicating that mucosal and bone pathological changes occurred simultaneously (Giacchi et al.,2001).

In a recent study from Netherland , the authors used CT scan to report the incidence of osteitis in 102 CRS patients and in an age- and gender matched control group of 68 non-CRS patients. Forty per cent of the CRS group and none of the control group had evidence of clinically significant osteitis. In the CRS group the severity of osteitis was correlated with Lund–Mackay score (P < 0.001), duration of symptoms (P < 0.01) and previous surgery (P < 0.001). The association between osteitis and number of previous surgery remained strong even after adjusting for the disease duration. There was no association between osteitis and age, gender, smoking, co-existing asthma, allergy or Sumter's triad (Georgalas et al. 2010)

Osteitis and neo-osteogenesis may also affect the success rate after sinus surgery. Kim et al studied the correlation between pre-operative bony changes detected in CT scan and postoperative endoscopic signs of healed sinus cavities in 81 patients. Patients with no radiological signs of bony changes showed better healing mucosa compare to those with bony changes (Kim et al., 2006).

Pathological changes described by human histological studies included: the presence of new bone formation, fibrosis, inflammatory cells, periosteal thickening and a varying degree of increased osteoblastic– osteoclastic activity, as shown by the disruption of organised lamellar bone and formation of immature woven bone, these are best to fit under the terms ostitis and neo-osteogesis. Localized or generalized thickened, irregular, heterogeneous lining of the sinus walls, is the radiological sign observed in CT scan, as illustrated in Figure 2 (Georgalas et al., 2010).

Osteitis and neo-osteogenesisin CRS are probably secondary to inflammatory process rather than direct bacterial invasion. In all animals and human studies, bacteria were not detected in the inflamed bone except in Tovi's study where actinomycosis was found in one patient (Tovi et al., 1992).

Cytokines produced by inflammatory cells such as osteoclast activating factor, interleukins, and tumor necrosis factor as well as prostaglandins such as prostaglandin 2 are known stimulators of bone resorption. These could be important mediators in inflammatory bone resorption and bone loss such as in periodontal disease and arthritis(9). Prostaglandin E is also shown to cause hyperostosis with periosteal osteoblast proliferation, thickened periosteum, and neocortex formation (Kocak et al., 2002; Faye-Petersen et al., 1996).

Mechanical pressure resulting from increased intrasinus pressure caused by inflammation and ostiomeatal unit obstruction may stimulate bone remodeling. This could explain the trend toward more advanced bone stage associated with higher CT stage of mucosal disease observed by Giacchi et al .

physiology with histologic findings including presence of inflammatory cells, fibrosis, and new bone formation. They also reported inflammation in the bone even when the overlying

Giacchiet al. compared bone from ethmoid septa of 20 patients with CRS and control group.Those with CRS typically showed periosteal thickening and resorption or remodeling. They also found a trend toward more advanced histologic bone stage associated with higher CT score indicating that mucosal and bone pathological changes

In a recent study from Netherland , the authors used CT scan to report the incidence of osteitis in 102 CRS patients and in an age- and gender matched control group of 68 non-CRS patients. Forty per cent of the CRS group and none of the control group had evidence of clinically significant osteitis. In the CRS group the severity of osteitis was correlated with Lund–Mackay score (P < 0.001), duration of symptoms (P < 0.01) and previous surgery (P < 0.001). The association between osteitis and number of previous surgery remained strong even after adjusting for the disease duration. There was no association between osteitis and age, gender, smoking, co-existing asthma, allergy or Sumter's triad (Georgalas et al. 2010)

Osteitis and neo-osteogenesis may also affect the success rate after sinus surgery. Kim et al studied the correlation between pre-operative bony changes detected in CT scan and postoperative endoscopic signs of healed sinus cavities in 81 patients. Patients with no radiological signs of bony changes showed better healing mucosa compare to those with

Pathological changes described by human histological studies included: the presence of new bone formation, fibrosis, inflammatory cells, periosteal thickening and a varying degree of increased osteoblastic– osteoclastic activity, as shown by the disruption of organised lamellar bone and formation of immature woven bone, these are best to fit under the terms ostitis and neo-osteogesis. Localized or generalized thickened, irregular, heterogeneous lining of the sinus walls, is the radiological sign observed in CT scan, as illustrated in Figure

Osteitis and neo-osteogenesisin CRS are probably secondary to inflammatory process rather than direct bacterial invasion. In all animals and human studies, bacteria were not detected in the inflamed bone except in Tovi's study where actinomycosis was found in one patient

Cytokines produced by inflammatory cells such as osteoclast activating factor, interleukins, and tumor necrosis factor as well as prostaglandins such as prostaglandin 2 are known stimulators of bone resorption. These could be important mediators in inflammatory bone resorption and bone loss such as in periodontal disease and arthritis(9). Prostaglandin E is also shown to cause hyperostosis with periosteal osteoblast proliferation, thickened

Mechanical pressure resulting from increased intrasinus pressure caused by inflammation and ostiomeatal unit obstruction may stimulate bone remodeling. This could explain the trend toward more advanced bone stage associated with higher CT stage of mucosal disease

periosteum, and neocortex formation (Kocak et al., 2002; Faye-Petersen et al., 1996).

mucosa was intact (Kennedy, 1998).

bony changes (Kim et al., 2006).

2 (Georgalas et al., 2010).

observed by Giacchi et al .

(Tovi et al., 1992).

occurred simultaneously (Giacchi et al.,2001).

Fig. 2. Coronal and axial CT for patient with RCRS showed osteitis in the maxillary wall.

Refractory Chronic Rhinosinusitis: Etiology & Management 63

Gastroesophageal reflux disease (GERD) has been implicated as a contributing factor in many air way disease processes like: dysphonia, benign vocal cord lesions, vocal laryngospasm, subglottic stenosis, asthma, CRS, post nasal drip and idiopathic cough.

Three mechanisms could explain the effect of GERD on sinusitis: direct exposure of the nasopharynx and nose to gastric acid causing mucosal inflammation and impaired mucociliary clearance, the second possible mechanism is a dysfunction of the autonomous nervous system resulting in vagus nerve stimulation, the third possible mechanism relates

DelGaudio was first to document nasopharyngeal reflux (NPR) in RCRS patients, in prospective study using 24 hour pH study with a specially designed probe with sensors located in the nasopharynx, 1 cm above the upper esophageal sphincter, and the distal

He found significant differences in the number of patients with NPR events (pH less than 5) and GERD between patients with RCRS and two control groups, the first consisted of patients who had at least one ESS procedure and had no symptoms of CRS or mucosal inflammation with a minimum of 1 year postoperative follow up. The second control group consisted of subjects with no history of CRS or sinus surgery. Limitation of this paper was that the study and control groups were not matched for age and comorbidities. The study group was older than the control group by approximately 10 years, and also, the study group patientshave more comorbid conditions, especially asthma, comparedwith the control group. This weakness

In prospective study, DiBaise et al treated 11 RCRS patients with proton pump inhibitor, not all patients had frank symptoms of GERD, Individual sinus symptoms (nasal congestion, nasal drainage, sinus pressure, facial headache, malaise) and global satisfaction were modestly improved in 25-89% and 91%, respectively, at 12 week (DiBaise et al.,2002). Flook and Kumar conducted a recent review analysis for the evidence to link acid reflux with chronic sinusitis or any nasal symptoms; their conclusion was that the evidence of a link is poor with no good randomized controlled trials available. The few adult studies that show any link between acid reflux and nasal symptoms are small case-controlled studies with moderate levels of potential bias. There is not enough evidence to consider anti-reflux therapy for adult refractory CRS and there is no evidence that acid reflux is a significant

In our practice, we don't referred asymptomatic patients with RCRS for 24-hour Ph monitoring; however we started all RCRS patients on 20mg omeprazole BID for 3 weeks, if patient reports improvement in nasal symptoms or endoscopic score we recommend to

A group of CRS patients continue to be symptomatic after appropriate medical and surgical therapy. Detailed history, endoscopic examination, laboratory and immunology tests

may question the accuracy of the results and conclusions (DelGaudio, 2005).

**3.5 Gastroesophageal reflux disease** 

to the direct role of Helicobacter pylori.

causal factor in CRS (Flook & Kumar, 2011).

continue on this regimen for 12 weeks.

**4. Conclusions** 

esophagus.

Another possible explanation is bacterial Biofilms may act as a 'depot' for low grade bacterial production and be responsible for the release of soluble bacterial virulence factors that generate local bony changes. The authors of most studies on biofilms and sinusitis didn't specify whether their sinus samples where purely mucosal or with some bony fragments, biofilms have been reported to present in infected bone in orthopedic and dental literature. Indeed, further studies are needed to determine the exact role of biolms in osteitis in RCRS.

Long therapeutic plan required in management of these patients. Complete removal of crust and sequestered bone is essential first step to provide healthy environment for mucosal regeneration. Topical combination of antibiotic and steroid may also help.

#### **3.4 Granulomatous disease and vasculitis in RCRS**

The sinonasal cavity may be the first organ to manifest such a systemic condition. Presenting symptoms and signs may be identical to those of other forms of CRS and thus these patients may have delay diagnosis.

The list of granulomatous diseases that can affect the sinonasal tract is extensive Sarcoidosis, Wegener's granulomatosis, Churg– Strauss syndrome, are the most common. Detailed history, carful systemic examination and local biopsy of any abnormal looking mucosa may be the hint of early identification of these patients.

Sarcoidosis is an inflammatory multisystem disorder of characterized by noncaseating granulomas. Sinonasal cavity is affected in only 0.7% to 6% of cases. Symptoms that may point to sarcoidosis are fatigue, pulmonary symptoms, night sweating, weight loss and fever.Physicalsigns include mucosal hypertrophy, purple mucosa with nodules (granulomas), and lupus pernio. Diagnosis is based on clinical findings, chest radiography, elevated angiotensin-converting enzyme levels, and findings of mucosal biopsy from affected mucosa (Matthew, 2008; Ferguson et al., 2009).

Wegener's granulomatosis is a rare granulomatous vasculitic disorder, affecting primarilymiddle age white people.Sinonasal manifestations are very common and occur in up to 89% of patients.Common symptoms include nasal obstruction, bloody rhinorrhea, epiphora, and crusting. Patients may present with, septal perforation, mucocele, orbital pseudotumor, or saddle-nose deformity. Positive cytoplasmic antineutrophil cytoplasmic antibodies and an elevated erythrocyte sedimentation rate suggest the diagnosis. However, definitive diagnosis depends on histopathologic analysis of affected mucosa.

Churg–Strauss syndrome is a multisystem disorder with necrotizing granulomatous eosinophilic tissue infiltration. Nasal involvement can occur in up to 75% of patients. Nasal polyps and rhinosinusitis are early manifestations of the illness, with subsequent development of eosinophilia and systemic involvement. Diagnosis is based on clinical findings, positive perinuclearantineutrophil cytoplasmic antibodies, and biopsy.

Treatment of nasal granulomatous diseases most commonly includes aggressive sinus debridement to remove crust formation, saline rinses and topical, systemic, intralesional steroids and immunosuppressive medications, surgery is reserved for complicated cases. Early consultation with rheumatology and immunology teams is essential for proper management plan(Ryan 2008, Ferguson and Otto 2009).

#### **3.5 Gastroesophageal reflux disease**

62 Peculiar Aspects of Rhinosinusitis

Another possible explanation is bacterial Biofilms may act as a 'depot' for low grade bacterial production and be responsible for the release of soluble bacterial virulence factors that generate local bony changes. The authors of most studies on biofilms and sinusitis didn't specify whether their sinus samples where purely mucosal or with some bony fragments, biofilms have been reported to present in infected bone in orthopedic and dental literature. Indeed, further studies are needed to determine the exact role of biolms in osteitis

Long therapeutic plan required in management of these patients. Complete removal of crust and sequestered bone is essential first step to provide healthy environment for mucosal

The sinonasal cavity may be the first organ to manifest such a systemic condition. Presenting symptoms and signs may be identical to those of other forms of CRS and thus

The list of granulomatous diseases that can affect the sinonasal tract is extensive Sarcoidosis, Wegener's granulomatosis, Churg– Strauss syndrome, are the most common. Detailed history, carful systemic examination and local biopsy of any abnormal looking mucosa may

Sarcoidosis is an inflammatory multisystem disorder of characterized by noncaseating granulomas. Sinonasal cavity is affected in only 0.7% to 6% of cases. Symptoms that may point to sarcoidosis are fatigue, pulmonary symptoms, night sweating, weight loss and fever.Physicalsigns include mucosal hypertrophy, purple mucosa with nodules (granulomas), and lupus pernio. Diagnosis is based on clinical findings, chest radiography, elevated angiotensin-converting enzyme levels, and findings of mucosal biopsy from

Wegener's granulomatosis is a rare granulomatous vasculitic disorder, affecting primarilymiddle age white people.Sinonasal manifestations are very common and occur in up to 89% of patients.Common symptoms include nasal obstruction, bloody rhinorrhea, epiphora, and crusting. Patients may present with, septal perforation, mucocele, orbital pseudotumor, or saddle-nose deformity. Positive cytoplasmic antineutrophil cytoplasmic antibodies and an elevated erythrocyte sedimentation rate suggest the diagnosis. However,

Churg–Strauss syndrome is a multisystem disorder with necrotizing granulomatous eosinophilic tissue infiltration. Nasal involvement can occur in up to 75% of patients. Nasal polyps and rhinosinusitis are early manifestations of the illness, with subsequent development of eosinophilia and systemic involvement. Diagnosis is based on clinical

Treatment of nasal granulomatous diseases most commonly includes aggressive sinus debridement to remove crust formation, saline rinses and topical, systemic, intralesional steroids and immunosuppressive medications, surgery is reserved for complicated cases. Early consultation with rheumatology and immunology teams is essential for proper

definitive diagnosis depends on histopathologic analysis of affected mucosa.

findings, positive perinuclearantineutrophil cytoplasmic antibodies, and biopsy.

regeneration. Topical combination of antibiotic and steroid may also help.

**3.4 Granulomatous disease and vasculitis in RCRS** 

be the hint of early identification of these patients.

affected mucosa (Matthew, 2008; Ferguson et al., 2009).

management plan(Ryan 2008, Ferguson and Otto 2009).

these patients may have delay diagnosis.

in RCRS.

Gastroesophageal reflux disease (GERD) has been implicated as a contributing factor in many air way disease processes like: dysphonia, benign vocal cord lesions, vocal laryngospasm, subglottic stenosis, asthma, CRS, post nasal drip and idiopathic cough.

Three mechanisms could explain the effect of GERD on sinusitis: direct exposure of the nasopharynx and nose to gastric acid causing mucosal inflammation and impaired mucociliary clearance, the second possible mechanism is a dysfunction of the autonomous nervous system resulting in vagus nerve stimulation, the third possible mechanism relates to the direct role of Helicobacter pylori.

DelGaudio was first to document nasopharyngeal reflux (NPR) in RCRS patients, in prospective study using 24 hour pH study with a specially designed probe with sensors located in the nasopharynx, 1 cm above the upper esophageal sphincter, and the distal esophagus.

He found significant differences in the number of patients with NPR events (pH less than 5) and GERD between patients with RCRS and two control groups, the first consisted of patients who had at least one ESS procedure and had no symptoms of CRS or mucosal inflammation with a minimum of 1 year postoperative follow up. The second control group consisted of subjects with no history of CRS or sinus surgery. Limitation of this paper was that the study and control groups were not matched for age and comorbidities. The study group was older than the control group by approximately 10 years, and also, the study group patientshave more comorbid conditions, especially asthma, comparedwith the control group. This weakness may question the accuracy of the results and conclusions (DelGaudio, 2005).

In prospective study, DiBaise et al treated 11 RCRS patients with proton pump inhibitor, not all patients had frank symptoms of GERD, Individual sinus symptoms (nasal congestion, nasal drainage, sinus pressure, facial headache, malaise) and global satisfaction were modestly improved in 25-89% and 91%, respectively, at 12 week (DiBaise et al.,2002).

Flook and Kumar conducted a recent review analysis for the evidence to link acid reflux with chronic sinusitis or any nasal symptoms; their conclusion was that the evidence of a link is poor with no good randomized controlled trials available. The few adult studies that show any link between acid reflux and nasal symptoms are small case-controlled studies with moderate levels of potential bias. There is not enough evidence to consider anti-reflux therapy for adult refractory CRS and there is no evidence that acid reflux is a significant causal factor in CRS (Flook & Kumar, 2011).

In our practice, we don't referred asymptomatic patients with RCRS for 24-hour Ph monitoring; however we started all RCRS patients on 20mg omeprazole BID for 3 weeks, if patient reports improvement in nasal symptoms or endoscopic score we recommend to continue on this regimen for 12 weeks.

#### **4. Conclusions**

A group of CRS patients continue to be symptomatic after appropriate medical and surgical therapy. Detailed history, endoscopic examination, laboratory and immunology tests

Refractory Chronic Rhinosinusitis: Etiology & Management 65

Giacchi R, Lebowitz R, Yee H, et al.(2001). *Histopathologic evaluation of the ethmoid bone in* 

Georgalas C.,\* Videler W.,†Freling N. &Fokkens W.(2010). *Global Osteitis Scoring Scale and* 

Georgalas C.,\* Videler W.,†Freling N. &Fokkens W.\**Global Osteitis Scoring Scale and chronic rhinosinusitis:a marker of revision surgery. ClinOtolaryngol.* Vol.35, No.6,pp.455-61 Kilty SJ, DesrosiersMY.(2009). *Are Biofilms the Answer in the Pathophysiology and Treatment of Chronic Rhinosinusitis? Immunol Allergy Clin North Am.* Vol.29, No.4,pp.645-56. Khalid AN, Hunt J, Perloff JR, Kennedy DW(2002). *The role of bone in chronic rhinosinusitis*.

Kennedy D, Senior B, Gannon F, et al.(1998). *Histology and histomorphometry of ethmoid bone in* 

Kim HY, Dhong HJ, Lee HJ, Chung YJ, Yim YJ, Oh JW, Chung SK, Kim HJ.(2006).

*rhinosinusitis.* Otolaryngology–Head and Neck Surgery. Vol.135,pp.94-99. Kocak, M; Smith T, MPH†; Smith M(2002). *Bone involvement in CRS, Current Opinion in* 

Matthew W. Ryan(2008). *Diseases associated with chronic rhinosinusitis: what is the significance?, Current Opinion in Otolaryngology & Head and Neck Surgery,*Vol.16,pp.231–236 Ozdemir O, Mete E, Catal F, et al.(2009).*Food intolerances and eosinophilic esophagitis in* 

Post JC, Hiller NL, Nistico L, Stoodley P, Ehrlich GD.(2007).The role of biofilms in

Psaltis AJ, Ha KR, Beule AG, et al.(2007).*Confocal scanning laser microscopy evidence of biofilms in patients with chronic rhinosinusitis.* Laryngoscope. Vol.117, No.7,pp.1302–6. Psaltis AJ, Ha KR, Wormald PJ, et al.(2008).*The effect of bacterial biofilmson post-sinus surgical* 

Perloff J, Gannon F, Bolger W, et al.(2000).*Bone involvement in sinusitis: an apparent pathway of* 

Shearer WT, Buckley RH, Engler RJ, Finn AF Jr, Fleisher TA, Freeman TM, Herrod HG 3rd,

Sanclement JA, Webster P, Thomas J, Ramadan HH.(2005). Bacterial Biofilms in Surgical

Ramadan HH.(2006).*Chronic rhinosinusitis and bacterial biofilms.*CurrOpinOtolaryngol Head

Tovi F, Benharroch D, Gatot A, et al.(1992).Osteoblasticosteitis of the maxillary sinus.

Levinson AI, Lopez M, Rich RR, Rosenfeld SI, Rosenwasser LJ.(1996).Practice parameters for the diagnosis and management of immunodeficiency. The Clinical and Laboratory Immunology Committee of the American Academy of Allergy, Asthma, and Immunology (CLIC-AAAAI)*Ann Allergy Asthma Immunol.*

Specimens of Patients with Chronic Rhinosinusitis *Laryngoscope.* Vol.115,No.4,

otolaryngologic infections: update 2007. *CurrOpinOtolaryngol Head Neck* 

*Hyperostosis may affect prognosis after primary endoscopic sinus surgery for chronic* 

*chronic sinusitis.* Am J Rhinol.Vol.15,pp.193–197.

*chronic rhinosinusitis: a marker of revision surgery.*\*

*chronic rhinosinusitis.* Laryngoscope.Vol.108,pp.502–507.

*Otolaryngology & Head & Neck Surgery.*Vol.10,Issue 1 ,pp 49-52

Laryngoscope.Vol112,No.11,pp.1951-7.

*childhood.* Dig Dis Sci.Vol.54,pp.8–14.

*outcome.* Am J Rhinol.Vol.22,pp.1– 6.

*spread of disease.* Laryngoscope.Vol.110,pp.2095–2099.

*Surg.*Vol.15,No.5,pp.347-51.

Vol.76,No.3,pp.282-94.

Neck Surg.Vol.14,No.3,pp.183-6

Laryngoscope.Vol.102,pp.426–430

pp.578-82.

required to look for any reversible underlying pathology. Further clinical studies and in vitro research are in great needed to support and validate the current management protocol. The current treatment of RCRS is by nasal toilet, debridement, prophylactic antibiotics and immunoglobulin as well as topical medications.

#### **5. References**


required to look for any reversible underlying pathology. Further clinical studies and in vitro research are in great needed to support and validate the current management protocol. The current treatment of RCRS is by nasal toilet, debridement, prophylactic antibiotics and

Alqudah M, Graham SM, BallasZK. *High prevalence of humoral immunodeficiency patients with refractory chronic rhinosinusitis.*Am J Rhinol Allergy. 2010 Nov;24(6):409-12. Bonilla FA, Bernstein IL, Khan DA, Ballas ZK, Chinen J, Frank MM, Kobrynski LJ, Levinson

Bendouah Z, Barbeau J, Hamad WA, et al.(2006). Biofilm formation by Staphylococcus

Bolger W, Leonard D, Dick E, et al.(1997).Gram negative sinusitis: a bacteriologic and

Ceri H, Olson ME, Stremick C, et a (1999)l.: The Calgary Biofilm Device: new technology for

Chee L, Graham SM, Carothers DG, Ballas ZK.(2001). *Immune dysfunction in refractory* 

Cryer J, Schipor I, Perloff JR, Palmer JN.(2004).Evidence of bacterial biofilms in human chronic sinusitis.*ORL J OtorhinolaryngolRelat Spec.* Vol.66,No.3,pp.155-8. DesrosiersM.(2004).*Refractory chronic rhinosinusitis: pathophysiology and management of chronic* 

Desrosiers M, Bendouah Z, Barbeau J(2007): Effectiveness of topical antibiotics on Staphylococcus aureus biofilm in vitro. Am J Rhinol ,Vol 21:149–153. DelGaudioJM(2005). *Direct nasopharyngeal reflux of gastric acid is a contributing factor in refractory chronic rhinosinusitis*. Laryngoscope.Vol.115,No.6,pp.946-57. DiBaise JK, Olusola BF, Huerter JV, Quigley EM(2002).Role of GERD in chronic resistant

Ferguson BJ, Otto BA, Pant H.(2009).*When surgery, antibiotics, and steroids fail to resolve chronic rhinosinusitis.*Immunol Allergy Clin North Am.Vol29,No.4,pp.719-32 Flook EP, Kumar BN.(2011).Is there evidence to link acid reflux with chronic sinusitis or any nasal symptoms? A review of the evidence.*Rhinology.*Vol.49,No.1,pp.11-6. Faye-Petersen O, Johnson W, Carlo W, et al. Prostaglandin E1–induced hyperostosis:

Ferguson BJ, Otto BA, Pant H.(2009).When surgery, antibiotics, and steroids fail to resolve chronic rhinosinusitis. *Immunol Allergy Clin North Am.*Vol,29,No.4,pp.719-32.

*sinusitis in a tertiary care setting.* Laryngoscope, Vol.111,pp.233–235.

Allergy Asthma Immunol. ,Vol.94,No.5 Suppl 1,pp.S1-63

histologic study in rabbits. Am J Rhinol, Vol.11,pp.15–25.

AI, Mazer B, Nelson RP Jr, Orange JS, Routes JM, Shearer WT, Sorensen RU.(2005). *Practice parameter for the diagnosis and management of primary immunodeficiency.*Ann

aureus and Pseudomonas aeruginosa is associated with an unfavorable evolution after surgery for chronic sinusitis and nasal polyposis. Otolaryngol Head Neck

rapid determination of antibiotic susceptibilities of bacterial biofilms. J Clin

*rhinosinusitis persisting after endoscopic sinus surgery.*Curr Allergy Asthma Rep,

sinusitis: a prospective, open label, pilot trial.*Am J Gastroenterol.*Vol.97,No.4,pp.843-

clinicopathologic correlations and possible pathogenic mechanisms. Ped Path Lab

immunoglobulin as well as topical medications.

Surg,Vol.134,No.6,pp.991–6.

Microbiol ,37:1771–1776.

Vol4,No.3,pp.200-7.

Med 1996, Vol.16,pp.489–507.

50.

**5. References** 


**Diagnosis and Treatment of Rhinosinusitis** 

Vanlerberghe L, Joniau S, Jorissen M.(2006).*The prevalence of humoral immunodeficiency in refractory rhinosinusitis: a retrospective analysis.* B-ENT.Vol.2,pp.161–166. **Part 2** 

## *refractory rhinosinusitis: a retrospective analysis.* B-ENT.Vol.2,pp.161–166. **Part 2**

## **Diagnosis and Treatment of Rhinosinusitis**

66 Peculiar Aspects of Rhinosinusitis

Vanlerberghe L, Joniau S, Jorissen M.(2006).*The prevalence of humoral immunodeficiency in* 

**5** 

*Norway* 

**Imaging Rhinosinusitis** 

*Oslo University Hospital, Rikshospitalet* 

Rhinosinusitis is classified as acute, recurrent and chronic. The acute form of rhinosinusitis should be diagnosed on symptoms and clinical findings, and imaging should not be necessary unless inflammatory complications are suspected. In recurrent and chronic rhinosinusitis, imaging is important in making a diagnose and planning the treatment. It is also important to look for inflammatory complications, and to discriminate "simple rhinosinusitis" from fungal infection and neoplasm (Rosenfeld, 2007). Paranasal sinus anatomy and pathology are difficult to interpret correct. Therefore, experienced radiologists

1. Computed tomography (CT) is the "gold standard" in imaging recurrent and chronic rhinosinusitis. CT is perfect for demonstrating the complex bony paranasal sinus anatomy with its variants as well as the localisation and extent of soft the tissue masses. Further, during functional endoscopic sinus surgery (FESS), the coronal or multiplanar CT is used as a bony map. Imaging rhinosinusitis without suspected complications, no

2. Magnetic resonance imaging (MRI) is complementary to CT, when CT has revealed soft tissue masses. In case of advanced unilateral soft tissue masses, MR imaging is

4. Ultrasonography has been used to detect pathology in the maxillary sinuses and anterior nasal fossa, however, the literature is not conclusive of its role in imaging

The radiation dose using CT can be performed with as low mAs (20 mAs) as possible due to the contrast of bone and air, and hence the dose will be almost equal to plain films (Aalokken, 2003; Hagtvedt, 2003). Though MR can demonstrate the anatomy, CT is superior to delineate the bony details, as well as depicting soft tissue masses, in addition the

mandatory to rule out, or further characterise fungal infection and neoplasm. 3. Plain films do not delineate the bony anatomy or soft tissue masses adequately and therefore this examination no longer have a place in imaging rhinosinusitis. The use of

as well as optimal imaging with respect to modality and method is mandatory.

Four imaging modalities have been used for imaging rhinosinusitis.

intravenous contrast medium is needed (Eggesbo, 1999).

plain films should be limited to cases where CT is not available.

**1. Introduction** 

**2. Imaging modalities** 

rhinosinusitis.

surgeons always use CT as a surgical map.

Heidi Beate Eggesbø
