**Imaging Rhinosinusitis**

Heidi Beate Eggesbø *Oslo University Hospital, Rikshospitalet Norway* 

#### **1. Introduction**

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 as well as optimal imaging with respect to modality and method is mandatory.

#### **2. Imaging modalities**

Four imaging modalities have been used for imaging rhinosinusitis.


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 surgeons always use CT as a surgical map.

Imaging Rhinosinusitis 71

and pterygoid processes may occur. The sphenoid sinuses have close relation to the cranial nerves, 3rd, 4th, 5thI, 5thII and 6th, and the carotid artery passing in the cavernous sinus and the optic nerve. When sphenoethmoid cells or pneumatisation of the anterior clinoid process are seen, the optic nerves are frequently inside the sinus and should not be mistaken for a soft

(a) (b) Fig. 2. (a) Coronal CT through the sphenoid bone shows four cells, where the superior cells are posterior ethmoid (sphenoethmoid) cells (arrows) that have continued into the sphenoid bone superior to the true sphenoid sinuses. (b) Sagittal CT demonstrates a sphenoethmoid cell (arrow) superior to the true sphenoid cell. Also notice the optic nerves (asterisks) running

The ethmoid sinuses are developed by birth as fluid filled evaginations, and air-filled during the first year. Adult ethmoid sinuses consist of 3-18 sinuses (termed cells) on each side. The anterior and posterior ethmoid sinuses are divided by the posterior wall (Stammberger, 1995) of the largest and most constant ethmoid cell termed the ethmoid bulla (Latin word

In a healthy person with no mucosal disease, the ethmoid cells may expand to the

The most common pneumatisation variants from the anterior ethmoid cells are concha bullosa (pneumatisation of the middle turbinate), pneumatisation below the orbital floor and adjacent to the maxillary ostium, termed infraorbital cells or Haller cells (after the Swiss biologist Albrecht von Haller in 1743 (1708-1777) (Caversaccio, 2011), and agger nasi cells (pneumatisation of the most the anterior part of the maxillary bone). The importance of these pneumatisation variants is their close relation to the mucociliary drainage routes. E.g. a large infraorbital cell may obstruct the drainage from the maxillary sinus causing and infundibular inflammatory pattern, a large agger nasi cell may obstruct the drainage from the frontal sinus causing frontal sinusitis, and a large concha bullosa or large ethmoid bulla may obstruct the middle meatus and hence involve the ipsilateral frontal, anterior ethmoid and maxillary sinuses referred to as an OMC inflammatory pattern. A large ethmoid bulla may also obstruct the mucociliary clearance from the ipsilateral frontal, anterior ethmoid

surrounding bone and form extra cells referred to as pneumatisation variants.

through the sphenoethmoid (Onodi) cells in fig (a).

tissue mass or polyp.

for bubble).

and maxillary sinuses.

The only patient preparation needed prior to CT and MR examination is nose blowing. Nasal spray with decongestants prior to examination is not needed. In order to delineate bony anatomy most properly, the patient should be in the prone position at CT in order let fluid drain away from the sinus openings, also referred to as the ostiomeatal complex (OMC) (Babbel, 1991). In acute recurrent rhinosinusitis imaging could favourable be postponed for some weeks for better delineation of the bony details when the soft tissue masses are less pronounced.

Fig. 1. CT is the primary modality in sinonasal imaging. (a) Coronal CT through the anterior paranasal sinuses with the maxillary, anterior ethmoid including bilateral concha bullosa (arrows) and the frontal sinuses. (b) Axial CT through sphenoid, maxillary and ethmoid sinuses with bilateral concha bullosa (arrows).

#### **3. Paranasal sinus development, anatomical and pneumatisation variants**

It is mandatory for a correct imaging report that the radiologist is familiar with the development of the paranasal sinuses and recognises the bony variants and their influence on the mucociliary drainage routes.

The paranasal sinuses develop from fetal life till the nearly adult size by the age of 12 years.

The maxillary sinuses are present as evaginations from the nasal cavities at birth and show a biphasic growth with a rapid growth from birth till the age of six years. Then a second accelerated growth from the age of seven years takes place. Chronic rhinosinusitis in childhood may abort this acceleration of sinus development and cause maxillary sinus hypoplasia. On coronal imaging, maxillary sinus hypoplasia is easily recognised as the maxillary sinus floor above the nasal floor together with an oval shaped orbit and low ethmoid roof (Eggesbo, 2001b). The surgeon must be aware of this variant, because the uncinate process that is a bony landmark during surgery, is lateral displaced and the orbit can easily be exposed during surgery as well as a low ethmoid roof may expose the brain.

The sphenoid sinuses also develop from birth. At the age of six years the presphenoid is pneumatised and by the age of twelve years also the sphenoid bone below the sella turcica, termed the basisphenoid, is pneumatised. Finally, pneumatisation of the anterior clinoid

The only patient preparation needed prior to CT and MR examination is nose blowing. Nasal spray with decongestants prior to examination is not needed. In order to delineate bony anatomy most properly, the patient should be in the prone position at CT in order let fluid drain away from the sinus openings, also referred to as the ostiomeatal complex (OMC) (Babbel, 1991). In acute recurrent rhinosinusitis imaging could favourable be postponed for some weeks for better delineation of the bony details when the soft tissue

(a) (b)

Fig. 1. CT is the primary modality in sinonasal imaging. (a) Coronal CT through the anterior paranasal sinuses with the maxillary, anterior ethmoid including bilateral concha bullosa (arrows) and the frontal sinuses. (b) Axial CT through sphenoid, maxillary and ethmoid

**3. Paranasal sinus development, anatomical and pneumatisation variants** 

It is mandatory for a correct imaging report that the radiologist is familiar with the development of the paranasal sinuses and recognises the bony variants and their influence

The paranasal sinuses develop from fetal life till the nearly adult size by the age of 12 years. The maxillary sinuses are present as evaginations from the nasal cavities at birth and show a biphasic growth with a rapid growth from birth till the age of six years. Then a second accelerated growth from the age of seven years takes place. Chronic rhinosinusitis in childhood may abort this acceleration of sinus development and cause maxillary sinus hypoplasia. On coronal imaging, maxillary sinus hypoplasia is easily recognised as the maxillary sinus floor above the nasal floor together with an oval shaped orbit and low ethmoid roof (Eggesbo, 2001b). The surgeon must be aware of this variant, because the uncinate process that is a bony landmark during surgery, is lateral displaced and the orbit can easily be exposed during surgery as well as a low ethmoid roof may expose the brain. The sphenoid sinuses also develop from birth. At the age of six years the presphenoid is pneumatised and by the age of twelve years also the sphenoid bone below the sella turcica, termed the basisphenoid, is pneumatised. Finally, pneumatisation of the anterior clinoid

masses are less pronounced.

sinuses with bilateral concha bullosa (arrows).

on the mucociliary drainage routes.

and pterygoid processes may occur. The sphenoid sinuses have close relation to the cranial nerves, 3rd, 4th, 5thI, 5thII and 6th, and the carotid artery passing in the cavernous sinus and the optic nerve. When sphenoethmoid cells or pneumatisation of the anterior clinoid process are seen, the optic nerves are frequently inside the sinus and should not be mistaken for a soft tissue mass or polyp.

Fig. 2. (a) Coronal CT through the sphenoid bone shows four cells, where the superior cells are posterior ethmoid (sphenoethmoid) cells (arrows) that have continued into the sphenoid bone superior to the true sphenoid sinuses. (b) Sagittal CT demonstrates a sphenoethmoid cell (arrow) superior to the true sphenoid cell. Also notice the optic nerves (asterisks) running through the sphenoethmoid (Onodi) cells in fig (a).

The ethmoid sinuses are developed by birth as fluid filled evaginations, and air-filled during the first year. Adult ethmoid sinuses consist of 3-18 sinuses (termed cells) on each side. The anterior and posterior ethmoid sinuses are divided by the posterior wall (Stammberger, 1995) of the largest and most constant ethmoid cell termed the ethmoid bulla (Latin word for bubble).

In a healthy person with no mucosal disease, the ethmoid cells may expand to the surrounding bone and form extra cells referred to as pneumatisation variants.

The most common pneumatisation variants from the anterior ethmoid cells are concha bullosa (pneumatisation of the middle turbinate), pneumatisation below the orbital floor and adjacent to the maxillary ostium, termed infraorbital cells or Haller cells (after the Swiss biologist Albrecht von Haller in 1743 (1708-1777) (Caversaccio, 2011), and agger nasi cells (pneumatisation of the most the anterior part of the maxillary bone). The importance of these pneumatisation variants is their close relation to the mucociliary drainage routes. E.g. a large infraorbital cell may obstruct the drainage from the maxillary sinus causing and infundibular inflammatory pattern, a large agger nasi cell may obstruct the drainage from the frontal sinus causing frontal sinusitis, and a large concha bullosa or large ethmoid bulla may obstruct the middle meatus and hence involve the ipsilateral frontal, anterior ethmoid and maxillary sinuses referred to as an OMC inflammatory pattern. A large ethmoid bulla may also obstruct the mucociliary clearance from the ipsilateral frontal, anterior ethmoid and maxillary sinuses.

Imaging Rhinosinusitis 73

Swelling of the mucosal lining or polyps at the level of the sinus openings cause obstruction of the drainage routes and cause rhinosinusitis. One of the issues of imaging is to evaluate the patency of the mucociliary drainage routes and report on mucosal swellings and

In reporting paranasal sinus imaging the radiologist must be aware of normal physiological changes in order not to "over report" the normal findings as inflammatory changes. E.g. the nasal cycle first described by Kayser in 1889. The nasal cycle is a cyclical swelling of the ipsilateral turbinates and nasal mucosa. Unilateral enlarged turbinates are therefore a normal imaging finding (Zinreich, 1988). Also the ethmoid mucosal linings are influenced by the nasal cycle, hence mucosal thickening of 2 mm is commonly seen due to the nasal cycle and must not be reported as abnormal. Concerning the frontal and sphenoid sinuses the mucosal linings should not be visualised at CT, while maxillary sinus mucosal thickening up to 4 mm is often seen in healthy individuals and considered as a normal

The nasal cycle, paranasal mucosa and mucous/serous production are regulated by the autonomic nerve system and neuropeptides from the primary sensory neurons. The complex system is still not completely understood, however it is known that the parasympathetic

(a) (b)

symptoms of a acute sinusitis, no action to this finding is needed. Notice also opacified right

Primary sensory neurons releasing neurotransmittors can also cause increased mucosal swelling and fluid production. Finally, drugs that have a vasoactive effect can increase the thickness of mucosal lining and increase the serous fluid production (Cingi, 2011). Fluid filled sinuses can therefore be an incidental finding, especially in bedridden patients, and must be interpreted with care (Naclerio, 2010; Sarin, 2006). Air-fluid level is frequently seen in healthy patients and is not equivalent to rhinosinusitis. Only if the patient has symptoms of

Fig. 4. (a) Axial CT shows incidental finding of an air-fluid level (arrows) in the right maxillary sinus in a patient undergoing cerebral CT. There is no sclerotic bone thickening and hence no indication for follow-up. (b) Axial CT shows incidental total opacification of the right maxillary sinus (asterisk) without sclerotic bone thickening. Unless clinical

concha bullosa (arrow) and normal fluid filled lacrimal ducts (arrowheads)

system and sympathetic ß-receptors stimulate secretion (Naclerio, 2010; Sarin, 2006).

anatomical variants that may contribute to obstruction of these drainage routes.

finding (Rak, 1991). With age, the nasal cycles become less prominent.

The most common pneumatisation variants from the posterior ethmoid cells are posterior ethmoid cells that continue posteriorly into the sphenoid bone either laterally or superiorly to the sphenoid sinus, termed sphenoethmoid or Onodi cells. (after the Hungarian rhinolaryngologist Adolf Onodi in 1903 (1857-1919)).

The frontal sinuses are the last sinuses to develop and termed frontal sinuses first when the ethmoid recesses (sinuses) pass the superior orbital rims. This usually occurs by the age of six years. Aplasia and hypoplasia of the frontal sinuses is common, with aplasia seen in 5% of the population. A frontal sinus can be regarded as pneumatisation variant since its occurrence depends on the pneumatisation potential of the ethmoid sinuses.

By the simultaneous introduction of CT imaging and endoscopic surgery in the 1980's the pneumatisation variants were viewed as a main cause for rhinosinusitis. This is no longer the theory. Pneumatisation variants are a result of healthy sinuses that has greater pneumatisation potential than diseased sinuses. However, when pneumatisation variants are present, only a slight mucosal swelling can cause obstruction of the mucosal drainage route and cause rhinosinusitis. Therefore, removing the bony walls of pneumatisation variants, is an usual procedure when FESS is required.

#### **4. Mucociliary clearance and normal mucosal variants**

The paranasal sinuses are covered by a ciliated epithelium that beats with a frequency up to 1000 cycles a minute. The epithelium produce mucous that entraps particles and microorganisms and the ciliated cells clean up by turning the mucus blanket over every 10- 30 minutes. The paranasal sinuses also contribute to humidify the inhaled air. Therefore, the mucous and fluid production of the paranasal sinuses can be as high as one to two liters every day. Each sinus has its own specific drainage route before passing through the ostium into the superior or medial meatus then passing to the choana. The anterior ethmoid, frontal and maxillary sinuses drain into the middle meatus and the posterior ethmoid and sphenoid sinuses drain into the superior meatus.

Fig. 3. Coronal CT demonstrating the mucociliary drainage route for (a) the maxillary sinus with it's final route through the ethmoid infundibulum (red arrow) and (b) the frontal sinus with it's final route through the frontal recess (red dotted arrow).

The most common pneumatisation variants from the posterior ethmoid cells are posterior ethmoid cells that continue posteriorly into the sphenoid bone either laterally or superiorly to the sphenoid sinus, termed sphenoethmoid or Onodi cells. (after the Hungarian

The frontal sinuses are the last sinuses to develop and termed frontal sinuses first when the ethmoid recesses (sinuses) pass the superior orbital rims. This usually occurs by the age of six years. Aplasia and hypoplasia of the frontal sinuses is common, with aplasia seen in 5% of the population. A frontal sinus can be regarded as pneumatisation variant since its

By the simultaneous introduction of CT imaging and endoscopic surgery in the 1980's the pneumatisation variants were viewed as a main cause for rhinosinusitis. This is no longer the theory. Pneumatisation variants are a result of healthy sinuses that has greater pneumatisation potential than diseased sinuses. However, when pneumatisation variants are present, only a slight mucosal swelling can cause obstruction of the mucosal drainage route and cause rhinosinusitis. Therefore, removing the bony walls of pneumatisation

The paranasal sinuses are covered by a ciliated epithelium that beats with a frequency up to 1000 cycles a minute. The epithelium produce mucous that entraps particles and microorganisms and the ciliated cells clean up by turning the mucus blanket over every 10- 30 minutes. The paranasal sinuses also contribute to humidify the inhaled air. Therefore, the mucous and fluid production of the paranasal sinuses can be as high as one to two liters every day. Each sinus has its own specific drainage route before passing through the ostium into the superior or medial meatus then passing to the choana. The anterior ethmoid, frontal and maxillary sinuses drain into the middle meatus and the posterior ethmoid and sphenoid

(a) (b) Fig. 3. Coronal CT demonstrating the mucociliary drainage route for (a) the maxillary sinus with it's final route through the ethmoid infundibulum (red arrow) and (b) the frontal sinus

with it's final route through the frontal recess (red dotted arrow).

occurrence depends on the pneumatisation potential of the ethmoid sinuses.

rhinolaryngologist Adolf Onodi in 1903 (1857-1919)).

variants, is an usual procedure when FESS is required.

sinuses drain into the superior meatus.

**4. Mucociliary clearance and normal mucosal variants** 

Swelling of the mucosal lining or polyps at the level of the sinus openings cause obstruction of the drainage routes and cause rhinosinusitis. One of the issues of imaging is to evaluate the patency of the mucociliary drainage routes and report on mucosal swellings and anatomical variants that may contribute to obstruction of these drainage routes.

In reporting paranasal sinus imaging the radiologist must be aware of normal physiological changes in order not to "over report" the normal findings as inflammatory changes. E.g. the nasal cycle first described by Kayser in 1889. The nasal cycle is a cyclical swelling of the ipsilateral turbinates and nasal mucosa. Unilateral enlarged turbinates are therefore a normal imaging finding (Zinreich, 1988). Also the ethmoid mucosal linings are influenced by the nasal cycle, hence mucosal thickening of 2 mm is commonly seen due to the nasal cycle and must not be reported as abnormal. Concerning the frontal and sphenoid sinuses the mucosal linings should not be visualised at CT, while maxillary sinus mucosal thickening up to 4 mm is often seen in healthy individuals and considered as a normal finding (Rak, 1991). With age, the nasal cycles become less prominent.

The nasal cycle, paranasal mucosa and mucous/serous production are regulated by the autonomic nerve system and neuropeptides from the primary sensory neurons. The complex system is still not completely understood, however it is known that the parasympathetic system and sympathetic ß-receptors stimulate secretion (Naclerio, 2010; Sarin, 2006).

(a) (b)

Fig. 4. (a) Axial CT shows incidental finding of an air-fluid level (arrows) in the right maxillary sinus in a patient undergoing cerebral CT. There is no sclerotic bone thickening and hence no indication for follow-up. (b) Axial CT shows incidental total opacification of the right maxillary sinus (asterisk) without sclerotic bone thickening. Unless clinical symptoms of a acute sinusitis, no action to this finding is needed. Notice also opacified right concha bullosa (arrow) and normal fluid filled lacrimal ducts (arrowheads)

Primary sensory neurons releasing neurotransmittors can also cause increased mucosal swelling and fluid production. Finally, drugs that have a vasoactive effect can increase the thickness of mucosal lining and increase the serous fluid production (Cingi, 2011). Fluid filled sinuses can therefore be an incidental finding, especially in bedridden patients, and must be interpreted with care (Naclerio, 2010; Sarin, 2006). Air-fluid level is frequently seen in healthy patients and is not equivalent to rhinosinusitis. Only if the patient has symptoms of

Imaging Rhinosinusitis 75

(a) (b) Fig. 6. (a) Coronal CT shows infundibular inflammatory pattern with bilateral opacification of the maxillary sinuses due to obstruction of mucociliary drainage at the level of the ethmoid infundibulum (arrows). (b) Coronal CT shows unilateral left sided infundibular inflammatory pattern, and sporadic mucosal thickening in the right maxillary sinus floor. 2. The second pattern is caused by obstruction of the middle meatus, which is the final mucociliary drainage route of the ipsilateral maxillary, anterior ethmoid, and frontal sinuses. This pattern is referred to as the ostiomeatal (derived from ostium and meatus)

The frontal sinus drains either via the frontal recess directly to the middle meatus or through the anterio-superiorly aspect of the ethmoid infundibulum. Isolated frontal sinusitis

(a) (b) Fig. 7. Coronal CT shows OMC inflammatory pattern with ipsilateral opacification of the (a)

complex (OMC) inflammatory pattern.

is regarded as a variant of OMC inflammatory pattern.

maxillary (1), anterior ethmoid (2) and (b) frontal sinuses (3).

rhinosinusitis and the fluid contains air-bubbles, the findings can be interpreted as acute rhinosinusitis. The surrounding bone is a clue to diagnose chronic rhinosinusitis. If normal thickness of the surrounding bone a chronic infection can be ruled out.

#### **5. Solitary polyps and retention cysts**

Solitary polyps and retention cysts are common incidental findings in the paranasal sinuses and usually have no clinical implication. The maxillary sinus is the most common origin, especially from the floor of the sinus. Polyps are due to accumulation of fluid in the mucosa as are serous retention cysts, while mucous retention cysts are due to obstruction of a seromucinous gland. Polyps and retention cysts are seen as smooth, outwardly convex soft tissue masses at CT and MR imaging and cannot be differentiated. The MR signal depends on the water and protein content, and when the water content dominates, solitary polyps and retention cysts have homogeneous, high T2- and low T1-signal. If no underlying bony destruction is present at CT, the term retention cyst should be used and no follow-up imaging should be necessary.

Fig. 5. (a) Coronal CT shows a smooth, outwardly convex soft tissue mass (asterisk) originating from the maxillary floor. No underlying bone destruction or periondontic abscess are seen and the mass should be interpreted as a retention cyst. (b) Coronal CT in another patient shows retention cyst in each maxillary sinus and slight mucosal thickening/retention cyst in the right nasal cavity.

#### **6. Inflammatory patterns**

Five inflammatory patterns at CT have been described in chronic rhinosinusitis (Sonkens, 1991). These patterns are: 1. Infundibular, 2. Ostiomeatal complex (OMC), 3). Sphenoethmoid recess (SER), 4. Polyposis, and 5. Sporadic. The first three inflammatory patterns are caused by obstruction of mucociliary drainage routes.

1. The first pattern is caused by obstruction at the level of the ethmoid infundibulum, which is the drainage route of the maxillary sinus, and hence called infundibular inflammatory pattern. In this pattern only the ipsilateral maxillary sinus is involved.

rhinosinusitis and the fluid contains air-bubbles, the findings can be interpreted as acute rhinosinusitis. The surrounding bone is a clue to diagnose chronic rhinosinusitis. If normal

Solitary polyps and retention cysts are common incidental findings in the paranasal sinuses and usually have no clinical implication. The maxillary sinus is the most common origin, especially from the floor of the sinus. Polyps are due to accumulation of fluid in the mucosa as are serous retention cysts, while mucous retention cysts are due to obstruction of a seromucinous gland. Polyps and retention cysts are seen as smooth, outwardly convex soft tissue masses at CT and MR imaging and cannot be differentiated. The MR signal depends on the water and protein content, and when the water content dominates, solitary polyps and retention cysts have homogeneous, high T2- and low T1-signal. If no underlying bony destruction is present at CT, the term retention cyst should be used and no follow-up

(a) (b)

originating from the maxillary floor. No underlying bone destruction or periondontic abscess are seen and the mass should be interpreted as a retention cyst. (b) Coronal CT in another patient shows retention cyst in each maxillary sinus and slight mucosal thickening/retention

Five inflammatory patterns at CT have been described in chronic rhinosinusitis (Sonkens, 1991). These patterns are: 1. Infundibular, 2. Ostiomeatal complex (OMC), 3). Sphenoethmoid recess (SER), 4. Polyposis, and 5. Sporadic. The first three inflammatory

1. The first pattern is caused by obstruction at the level of the ethmoid infundibulum, which is the drainage route of the maxillary sinus, and hence called infundibular inflammatory pattern. In this pattern only the ipsilateral maxillary sinus is involved.

Fig. 5. (a) Coronal CT shows a smooth, outwardly convex soft tissue mass (asterisk)

patterns are caused by obstruction of mucociliary drainage routes.

thickness of the surrounding bone a chronic infection can be ruled out.

**5. Solitary polyps and retention cysts** 

imaging should be necessary.

cyst in the right nasal cavity.

**6. Inflammatory patterns** 

Fig. 6. (a) Coronal CT shows infundibular inflammatory pattern with bilateral opacification of the maxillary sinuses due to obstruction of mucociliary drainage at the level of the ethmoid infundibulum (arrows). (b) Coronal CT shows unilateral left sided infundibular inflammatory pattern, and sporadic mucosal thickening in the right maxillary sinus floor.

2. The second pattern is caused by obstruction of the middle meatus, which is the final mucociliary drainage route of the ipsilateral maxillary, anterior ethmoid, and frontal sinuses. This pattern is referred to as the ostiomeatal (derived from ostium and meatus) complex (OMC) inflammatory pattern.

The frontal sinus drains either via the frontal recess directly to the middle meatus or through the anterio-superiorly aspect of the ethmoid infundibulum. Isolated frontal sinusitis is regarded as a variant of OMC inflammatory pattern.

Fig. 7. Coronal CT shows OMC inflammatory pattern with ipsilateral opacification of the (a) maxillary (1), anterior ethmoid (2) and (b) frontal sinuses (3).

Imaging Rhinosinusitis 77

5. The last and fifth pattern, includes all opacities that do not fit into the four previous patterns, e.g. solitary polyps, retentions cysts, mucosal thickening, and postoperative

It is important to recognise these inflammatory patterns in order to plan whether the patient will benefit from FESS, and if so the region and extent of the FESS procedure. E.g. In the infundibular pattern an uncinectomy or medial antrostomy alone will open the natural maxillary sinus ostium, while in the OMC pattern more extensive surgery including both

Fig. 10. (a) Coronal CT shows a retention cysts and sparse mucosal thickening classified as a

In chronic rhinosinusitis, several systems for grading and monitoring have been proposed and evaluated. The Lund-Mackay system from 1997 (Lund, 1997) has been easy to use, however, all staging systems have shown limited clinical application (Zinreich, 2004).

Many conditions may mimic the inflammatory patterns described and differential diagnoses

An antrochoanal polyp that occupies the maxillary sinus can be misinterpreted as an infundibular inflammatory pattern. The clue to the diagnosis is a small air-filled space superior in the sinus and soft tissue masses in the choana and with a polyp seen in the oropharynx.

Periodontal infection may cause inflammation to the ipsilateral maxillary sinus as well as the ipsilateral anterior ethmoid and frontal sinuses, and hence mimic an OMC inflammatory pattern. It is mandatory that the technicians include the maxillary alveolar ridge in the scanning, in order to rule out, or demonstrate an odontogenic origin. In case of dental filling

artefacts, axial volume scanning will limit the dental artefacts to the axial plan.

mucosal thickening etc. and therefore is referred to as the sporadic pattern.

medial antrostomy and anterior ethmoidectomy may be needed.

sporadic inflammatory pattern.

must always be considered.

**7. Grading and monitoring chronic rhinosinusitis** 

**8. Conditions mimicking rhinosinusitis** 

3. The third pattern is caused by obstruction of the sphenoethmoid recess (SER), which is the drainage route of both the sphenoid and ipsilateral posterior ethmoid sinuses. An obstruction can proceed to rhinosinusitis only of the sphenoid sinus or also the ipsilateral posterior ethmoid sinus.

Fig. 8. (a) Axial CT shows total opacification of the left sphenoid sinus with slightly thickening of the surrounding bone. Note that the left SER (arrow) contains air. This indicates that the obstruction can be at the level of the sphenoid ostium or the opacification can be due to a polyp originating from inside the sphenoid sinus. (b) Axial CT shows sclerotic bone surrounding the total opacified right sphenoid sinus (arrow), indicating a longstanding infection.

4. The fourth pattern is bilateral sinonasal polyposis and is characterised by enlargement of the ethmoid infundibulum as well as bulging and remodelling of the ethmoid sinus cells. In addition, the nasal cavities are filled with polyps, recognised by it's downward convexity contour.

Fig. 9. (a) Coronal CT of polyposis inflammatory pattern. Note the typical broadening of the ethmoid infundibulum bilateral (arrows). (b) Another patient where coronal CT also shows the involvement of the frontal sinuses.

3. The third pattern is caused by obstruction of the sphenoethmoid recess (SER), which is the drainage route of both the sphenoid and ipsilateral posterior ethmoid sinuses. An obstruction can proceed to rhinosinusitis only of the sphenoid sinus or also the

(a) (b)

4. The fourth pattern is bilateral sinonasal polyposis and is characterised by enlargement of the ethmoid infundibulum as well as bulging and remodelling of the ethmoid sinus cells. In addition, the nasal cavities are filled with polyps, recognised by it's downward

(a) (b) Fig. 9. (a) Coronal CT of polyposis inflammatory pattern. Note the typical broadening of the ethmoid infundibulum bilateral (arrows). (b) Another patient where coronal CT also shows

Fig. 8. (a) Axial CT shows total opacification of the left sphenoid sinus with slightly thickening of the surrounding bone. Note that the left SER (arrow) contains air. This indicates that the obstruction can be at the level of the sphenoid ostium or the opacification can be due to a polyp originating from inside the sphenoid sinus. (b) Axial CT shows sclerotic bone surrounding the total opacified right sphenoid sinus (arrow), indicating a

ipsilateral posterior ethmoid sinus.

longstanding infection.

convexity contour.

the involvement of the frontal sinuses.

5. The last and fifth pattern, includes all opacities that do not fit into the four previous patterns, e.g. solitary polyps, retentions cysts, mucosal thickening, and postoperative mucosal thickening etc. and therefore is referred to as the sporadic pattern.

It is important to recognise these inflammatory patterns in order to plan whether the patient will benefit from FESS, and if so the region and extent of the FESS procedure. E.g. In the infundibular pattern an uncinectomy or medial antrostomy alone will open the natural maxillary sinus ostium, while in the OMC pattern more extensive surgery including both medial antrostomy and anterior ethmoidectomy may be needed.

Fig. 10. (a) Coronal CT shows a retention cysts and sparse mucosal thickening classified as a sporadic inflammatory pattern.

#### **7. Grading and monitoring chronic rhinosinusitis**

In chronic rhinosinusitis, several systems for grading and monitoring have been proposed and evaluated. The Lund-Mackay system from 1997 (Lund, 1997) has been easy to use, however, all staging systems have shown limited clinical application (Zinreich, 2004).

#### **8. Conditions mimicking rhinosinusitis**

Many conditions may mimic the inflammatory patterns described and differential diagnoses must always be considered.

An antrochoanal polyp that occupies the maxillary sinus can be misinterpreted as an infundibular inflammatory pattern. The clue to the diagnosis is a small air-filled space superior in the sinus and soft tissue masses in the choana and with a polyp seen in the oropharynx.

Periodontal infection may cause inflammation to the ipsilateral maxillary sinus as well as the ipsilateral anterior ethmoid and frontal sinuses, and hence mimic an OMC inflammatory pattern. It is mandatory that the technicians include the maxillary alveolar ridge in the scanning, in order to rule out, or demonstrate an odontogenic origin. In case of dental filling artefacts, axial volume scanning will limit the dental artefacts to the axial plan.

Imaging Rhinosinusitis 79

Several systemic diseases may show or present with sinonasal symptoms that may mimic or be equal to the patterns of inflammatory rhinosinusitis. The systemic diseases that may

Fungal rhinosinusitis can imitate all five inflammatory patterns and must be considered in all patients with chronic rhinosinusitis. The characteristics of fungal rhinosinusitis are

Tumours are rare in the paranasal sinuses and contributing to only 1% of all malignant tumours. Therefore, malignant tumours are commonly interpreted as rhinosinusitis. All solitary nasal polyps should be considered for histopathologic examination. Destruction of

Sclerotic bone at CT is the most frequent response and complication to recurrent and chronic rhinosinusitis. Opacified sinus together with sclerotic surrounding bone should always alert the radiologist for the need of complementary MR imaging or follow-up CT. The thickness and morphology of the surrounding bone is an important clue to differentiate chronic from

(a) (b)

Fig. 13. Axial CT showing total opacification of the maxillary (a) and the frontal (b) sinuses accompanied with sclerotic bone thickening (arrows) indicating a chronic infection.

commonly referred to as a Pott's puffy tumour.

Osteomyelitis is a rare complication to rhinosinusitis. Infection of the bone marrow of diploetic frontal bone due to frontal sinusitis may present with a subperiosteal abscess,

present with sinonasal manifestations are listed later in this chapter.

adjacent bone at CT is one clue to suspect a malignant tumour.

acute rhinosinusitis or parasympathetic dominance in a bedridden patient.

described later in this chapter.

**9. Inflammatory complications** 

Fig. 11. Sagittal CT shows polypoid mucosal thickening in the maxillary sinus due to en underlying odontogen infection (arrows).

Rhinolithiasis is a rare and an under-diagnosed finding that is caused by mineralisation of an endogenous or exogenous foreign material (Yaşar, 2009). The patients usually present with a foul-smelling nasal discharge. When dental amalgam is the cause, the ethmoid infundibulum or the middle meatus may be obstructed and cause rhinosinusitis that mimic the infundibular or OMC patterns. Also an ectopic molar tooth free inside the maxillary sinus can give the same imaging appearance.

Fig. 12. (a) Coronal CT shows advanced opacification of the left ethmoid and maxillary sinuses as in OMC inflammatory pattern. However, the inflammatory changes are due to an elongated calcification (arrow) located in the middle meatus. (b) A few months later, the patient delivered an ectopic molar tooth.

Fig. 11. Sagittal CT shows polypoid mucosal thickening in the maxillary sinus due to en

Rhinolithiasis is a rare and an under-diagnosed finding that is caused by mineralisation of an endogenous or exogenous foreign material (Yaşar, 2009). The patients usually present with a foul-smelling nasal discharge. When dental amalgam is the cause, the ethmoid infundibulum or the middle meatus may be obstructed and cause rhinosinusitis that mimic the infundibular or OMC patterns. Also an ectopic molar tooth free inside the maxillary

(a) (b)

Fig. 12. (a) Coronal CT shows advanced opacification of the left ethmoid and maxillary sinuses as in OMC inflammatory pattern. However, the inflammatory changes are due to an elongated calcification (arrow) located in the middle meatus. (b) A few months later, the

underlying odontogen infection (arrows).

sinus can give the same imaging appearance.

patient delivered an ectopic molar tooth.

Several systemic diseases may show or present with sinonasal symptoms that may mimic or be equal to the patterns of inflammatory rhinosinusitis. The systemic diseases that may present with sinonasal manifestations are listed later in this chapter.

Fungal rhinosinusitis can imitate all five inflammatory patterns and must be considered in all patients with chronic rhinosinusitis. The characteristics of fungal rhinosinusitis are described later in this chapter.

Tumours are rare in the paranasal sinuses and contributing to only 1% of all malignant tumours. Therefore, malignant tumours are commonly interpreted as rhinosinusitis. All solitary nasal polyps should be considered for histopathologic examination. Destruction of adjacent bone at CT is one clue to suspect a malignant tumour.

#### **9. Inflammatory complications**

Sclerotic bone at CT is the most frequent response and complication to recurrent and chronic rhinosinusitis. Opacified sinus together with sclerotic surrounding bone should always alert the radiologist for the need of complementary MR imaging or follow-up CT. The thickness and morphology of the surrounding bone is an important clue to differentiate chronic from acute rhinosinusitis or parasympathetic dominance in a bedridden patient.

Fig. 13. Axial CT showing total opacification of the maxillary (a) and the frontal (b) sinuses accompanied with sclerotic bone thickening (arrows) indicating a chronic infection.

Osteomyelitis is a rare complication to rhinosinusitis. Infection of the bone marrow of diploetic frontal bone due to frontal sinusitis may present with a subperiosteal abscess, commonly referred to as a Pott's puffy tumour.

Imaging Rhinosinusitis 81

Inflammatory spread to the orbits is more common than intracranial spread. I case of orbital abscess, the ethmoid sinuses usually is the origin of infection because the thin lamina papyracea and the ethmoid valveless veins easily allow spread of infection. Inflammatory processes in the sphenoid, maxillary and frontal sinuses, in descending order, are less likely

Only 3% of cerebral abscesses are due to rhinosinusitis, with the frontal and sphenoid sinuses as the most common origin of infection, followed by the ethmoid and maxillary

(a) (b)

Fig. 16. Coronal (a) and axial (b) CT show bilateral opacification of the ethmoid sinuses. On the right side there is exophthalmos due to spread of infection (arrows) from the right

Obstruction of a sinus ostium can proceed to formation of a mucocele, which is made up of mucous and desquamated epithelium. Over time, expanding of a mucocele will remodel the adjacent bone and sometimes also cause extension into neighbouring sinuses, orbit or cranium. Mucocele is most often seen in the frontal sinus, followed by the ethmoid and maxillary sinuses, while rare in the sphenoid sinus. When a mucocele is super-infected it is

to cause orbital infection.

sinuses.

ethmoid sinus.

termed a pyocele.

**10. Mucocele vs. pyocele** 

Fig. 14. (a) Sagittal CT shows total opacification of the frontal sinus with erosion of the anterior wall (arrows) due to an eroding frontal sinus abscess, referred to as Pott's puffy tumour. (b) Axial CT in the same patient

Silent sinus syndrome, also more correctly referred to as chronic maxillary atelectasis, is a relatively newly described entity. The CT imaging features are almost pathognomonic with collapse of the sinus walls due to longstanding negative pressure, sclerotic thickening of the surrounding bone, and oval shaped orbit giving rise to the clinical finding of enophthalmos. (Soparkar, 1994). In this condition, the maxillary sinus volume is small, but should not be misinterpreted as maxillary sinus hypoplasia in where the molar eminence will not be pneumatised. Enophthalmos without the typical CT findings should not be misdiagnosed as silent sinusitis (Burroughs, 2003).

Fig. 15. Coronol CT in a patient with silent sinusitis syndrome due to bilateral, longstanding maxillary rhinosinusitis. The maxillary sinus volumes are reduced due to the inward retraction of the sinus walls (arrows). Note also the enlarged, oval shaped orbits.

(a) (b) Fig. 14. (a) Sagittal CT shows total opacification of the frontal sinus with erosion of the anterior wall (arrows) due to an eroding frontal sinus abscess, referred to as Pott's puffy tumour. (b)

Silent sinus syndrome, also more correctly referred to as chronic maxillary atelectasis, is a relatively newly described entity. The CT imaging features are almost pathognomonic with collapse of the sinus walls due to longstanding negative pressure, sclerotic thickening of the surrounding bone, and oval shaped orbit giving rise to the clinical finding of enophthalmos. (Soparkar, 1994). In this condition, the maxillary sinus volume is small, but should not be misinterpreted as maxillary sinus hypoplasia in where the molar eminence will not be pneumatised. Enophthalmos without the typical CT findings should not be misdiagnosed as

Fig. 15. Coronol CT in a patient with silent sinusitis syndrome due to bilateral, longstanding maxillary rhinosinusitis. The maxillary sinus volumes are reduced due to the inward retraction of the sinus walls (arrows). Note also the enlarged, oval shaped orbits.

Axial CT in the same patient

silent sinusitis (Burroughs, 2003).

Inflammatory spread to the orbits is more common than intracranial spread. I case of orbital abscess, the ethmoid sinuses usually is the origin of infection because the thin lamina papyracea and the ethmoid valveless veins easily allow spread of infection. Inflammatory processes in the sphenoid, maxillary and frontal sinuses, in descending order, are less likely to cause orbital infection.

Only 3% of cerebral abscesses are due to rhinosinusitis, with the frontal and sphenoid sinuses as the most common origin of infection, followed by the ethmoid and maxillary sinuses.

Fig. 16. Coronal (a) and axial (b) CT show bilateral opacification of the ethmoid sinuses. On the right side there is exophthalmos due to spread of infection (arrows) from the right ethmoid sinus.

#### **10. Mucocele vs. pyocele**

Obstruction of a sinus ostium can proceed to formation of a mucocele, which is made up of mucous and desquamated epithelium. Over time, expanding of a mucocele will remodel the adjacent bone and sometimes also cause extension into neighbouring sinuses, orbit or cranium. Mucocele is most often seen in the frontal sinus, followed by the ethmoid and maxillary sinuses, while rare in the sphenoid sinus. When a mucocele is super-infected it is termed a pyocele.

Imaging Rhinosinusitis 83

Sinonasal manifestations and chronic rhinosinusitis are described for many systemic diseases ( Som, 2011), and may often also be the initial presentation of the systemic

Cystic fibrosis is an autosomal recessive disease and almost only present in the Caucasian population. Though lung infections and malabsorption are the main clinical manifestations that usually are referred, all patients have sinonasal disease with mucosal thickening of all sinuses. In addition 40% present with additional polyposis. In CF children with mouth breathing and nocturnal snoring, a common finding is bilateral maxillary sinus pyocele. At CT imaging, they have characteristic medial bulging of the lateral nasal walls that totally can obstruct the nasal cavities. In these cases, a complementary MR examination will show peripheral mucosal thickening with high T2 signal and centrally signal void or very low signal equivalent to pus. The corresponding T1 signal is high or intermediate and will distinguish pus from an air-filled sinus lumen. The MR examination is mandatory in selecting patients that will benefit from surgery and to guide the surgeons to the pus-filled areas in the maxillary and ethmoid sinuses

(a) (b)

(c) (d)

**12. Sinonasal manifestations in patients with systemic disease** 

disease.

**Cystic fibrosis** 

(Eggesbo, 2001a).

Fig. 17. Pus-filled maxillary sinuses and a fluid-rich polyp in the left nasal cavity. (a) Coronal MR with STIR sequence shows bilateral hyperintense maxillary sinus lining (small arrows). and centrally signal void equal to pus (asterisks). In addition there is a hyperintense mass filling the left nasal cavity equal to a polyp (large arrows). (b) The complementary coronal MR with T1 sequence shows low signal in the mucosal lining and intermediate to high signal centrally, while the fluid-rich polyp has low signal.

At CT a mucocele and pyocele cannot be differentiated, though a pyocele tend to have higher density than the surrounding mucosa. Using MR however, the oedematous mucosal lining shows high T2 signal, surrounding a signal void or low signal centrally equally to the pus-filled lumen. The corresponding T1 signal is high or intermediate (Eggesbo, 2001a).

#### **11. Atrophic rhinosinusitis**

In atrophic rhinosinusitis the respiratory epithelium covering the nasal and paranasal surface is replaced by non-ciliated epithelium The primary form presents with a foulsmelling nasal discharge due to Klebsiella ozenae and widened nasal passages with a paradoxical feeling of nasal congestion. It is most common in young adults from developing countries as Southern Saudi Arabia, China, Africa, India, Mediterranean and Philippines

The secondary form is the most frequent and associated to previous nasal injury, surgery or inflammation (deShazo, 2011).

Atrophic rhinitis has become a more common form of chronic rhinosinusitis. However, due to lack of clinical criteria the condition is under-diagnosed (Ly, 2009). It has been suggested that the secondary form is a nal common pathway following injury of the nasal mucosa Only a few papers describe the CT findings in atrophic rhinitis. These are nasal and paranasal mucosal thickening, small inferior and middle turbinates with atrophic mucosa and partial or total bony erosion. In addition small maxillary sinuses are described. This finding may be equal to "silent sinus syndrome" where chronic obstruction cause negative maxillary sinus pressure and with time the sinus walls collapse including the orbital floor, hence the patient may present with bilateral enophthalmos.

(a) (b) Fig. 17. Pus-filled maxillary sinuses and a fluid-rich polyp in the left nasal cavity. (a) Coronal MR with STIR sequence shows bilateral hyperintense maxillary sinus lining (small arrows). and centrally signal void equal to pus (asterisks). In addition there is a hyperintense mass filling the left nasal cavity equal to a polyp (large arrows). (b) The complementary coronal MR with T1 sequence shows low signal in the mucosal lining and

At CT a mucocele and pyocele cannot be differentiated, though a pyocele tend to have higher density than the surrounding mucosa. Using MR however, the oedematous mucosal lining shows high T2 signal, surrounding a signal void or low signal centrally equally to the pus-filled lumen. The corresponding T1 signal is high or intermediate (Eggesbo, 2001a).

In atrophic rhinosinusitis the respiratory epithelium covering the nasal and paranasal surface is replaced by non-ciliated epithelium The primary form presents with a foulsmelling nasal discharge due to Klebsiella ozenae and widened nasal passages with a paradoxical feeling of nasal congestion. It is most common in young adults from developing countries as Southern Saudi Arabia, China, Africa, India, Mediterranean and

The secondary form is the most frequent and associated to previous nasal injury, surgery or

Atrophic rhinitis has become a more common form of chronic rhinosinusitis. However, due to lack of clinical criteria the condition is under-diagnosed (Ly, 2009). It has been suggested that the secondary form is a nal common pathway following injury of the nasal mucosa Only a few papers describe the CT findings in atrophic rhinitis. These are nasal and paranasal mucosal thickening, small inferior and middle turbinates with atrophic mucosa and partial or total bony erosion. In addition small maxillary sinuses are described. This finding may be equal to "silent sinus syndrome" where chronic obstruction cause negative maxillary sinus pressure and with time the sinus walls collapse including the orbital floor,

intermediate to high signal centrally, while the fluid-rich polyp has low signal.

**11. Atrophic rhinosinusitis** 

inflammation (deShazo, 2011).

hence the patient may present with bilateral enophthalmos.

Philippines

#### **12. Sinonasal manifestations in patients with systemic disease**

Sinonasal manifestations and chronic rhinosinusitis are described for many systemic diseases ( Som, 2011), and may often also be the initial presentation of the systemic disease.

#### **Cystic fibrosis**

Cystic fibrosis is an autosomal recessive disease and almost only present in the Caucasian population. Though lung infections and malabsorption are the main clinical manifestations that usually are referred, all patients have sinonasal disease with mucosal thickening of all sinuses. In addition 40% present with additional polyposis. In CF children with mouth breathing and nocturnal snoring, a common finding is bilateral maxillary sinus pyocele. At CT imaging, they have characteristic medial bulging of the lateral nasal walls that totally can obstruct the nasal cavities. In these cases, a complementary MR examination will show peripheral mucosal thickening with high T2 signal and centrally signal void or very low signal equivalent to pus. The corresponding T1 signal is high or intermediate and will distinguish pus from an air-filled sinus lumen. The MR examination is mandatory in selecting patients that will benefit from surgery and to guide the surgeons to the pus-filled areas in the maxillary and ethmoid sinuses (Eggesbo, 2001a).

Imaging Rhinosinusitis 85

Nijmegen's Breakage syndrome have microcephaly and variable rhinosinusitis and hypersensitivity to gamma radiation and hence, MR should be performed instead of CT, if

Aspirin triad syndrome in where the patients are hypersensitive to aspirin. The symptoms

Autonomic nerve dysfunction is common in adult with cyclic vomiting disorder with sympathetic abnormalities dominating, while parasympathetic nerve function appears to be

Yellow nail syndrome is characterised of thickened yellow nail, primary lymphoedema due to lymphatic hypoplasia, chronic cough, pleural effusions, bronchiectasis, and a propensity

"Periodic fever, aphtous stomatitis, pharyngitis and cervical adenitis" syndrome (PFAPA), probably on a genetic basis. This autoinflammatory entity also includes chronic rhinosinusitis.

Ataxia-Telangiectasia syndrome is an autosomal recessive disease or sporadic occurring

Weskit Aldrich syndrome is an X-linked recessive disorder where the patients from early

Sarcoidosis may present with nodules (non-caseating granulomas) in the septum and along the neurovascular bundles and chronic rhinosinusitis though rare, are reported as the initial

Wegener's granulomatosis (WG) is a necrotising granulomatous vasculitis involving the lungs and kidneys. However, the nasal cavity and sinuses are frequently involved and also may be the initial presentation with destruction of the nasal septum and lateral nasal walls accompanied by mucosal inflammation and sclerotic thickening of the paranasal bones. The

Patients with asthma and allergy commonly show polypoid mucosal thickening of all paranasal sinuses. Due to mucosal thickening also at the level of the mucociliary drainage routes, exacerbation of disease are commonly followed by extensive rhinosinusitis of both

life have eczema, bloody diarrhea and recurrent infections including rhinosinusitis.

findings at imaging may mimic postoperative findings and chronic rhinosinusitis.

to develop malignancies. Chronic rhinosinusitis is seen in almost all patients.

with in immunsystem deficit leading to recurrent or chronic rhinosinusitis.

**Nijmegen's Breakage syndrome** 

are asthma and chronic rhinosinusitis with polyposis.

imaging is required.

**Aspirin triad syndrome** 

**Cyclic vomiting disorder** 

intact (Venkatesan, 2010). **Yellow nail syndrome** 

**PFAPA syndrome** 

**Ataxia-Telangiectasia syndrome** 

findings in this systemic disease.

**Wegener's granulomatosis** 

**Asthma and allergy** 

**Weskit Aldrich syndrome** 

**Sarcoidosis** 

Fig. 18. Two-year-old boy with cystic fibrosis (CF). (a) Coronal CT with bone algorithm shows bilateral, homogeneous, ethmomaxillary soft tissue masses (asterisks). (b) Coronal CT with soft tissue algorithm can differentiate the mucosal lining (arrows) from the sticky mucous centrally. (c) Axial CT demonstrates the advanced medial bulging of the lateral nasal walls (arrows). (d) Coronal CT demonstrates sphenoid sinus hypoplasia seen in all CF patients. (e) Coronal MR with STIR sequence differentiates the mucosal lining from the pus-filled maxillary sinus lumen centrally. (f) The corresponding coronal MR T1 sequence is mandatory in order to discriminate the signal void lumen at STIR sequence from airfilled lumen.

#### **Primary ciliary dyskinesia**

Primary ciliary dyskinesia (immotile cilia syndrome) is an autosomal recessive disease with an incidence of 1/16000. The sinonasal manifestations are almost the same as in cystic fibrosis with opacification of all sinuses.

#### **Young's syndrome**

Young's syndrome manifest with obstructive azoospermie, pulmonary infections and chronic rhinosinusitis. This condition may also present with panopacification of the sinuses.

#### **Sertoly-cell-only syndrome**

Sertoly-cell-only syndrome with absence of spermatogones, bronchiectasis and chronic rhinosinusitis.

#### **Hyperimmunoglobulinemia E syndrome**

Hyperimmunoglobulinemia E syndrome is an autosomal recessive disease with dermatitis, skin infections, otitis media, pneumonia, impaired neutrophile chemotaxis, and high serum IgE and chronic rhinosinusitis is an usual finding.

#### **Churg-Strauss syndrome**

Churg-Strauss syndrome is a rare multisystemic disease, primarily in adults and with initial symptoms of asthma and allergic rhinosinusitis that cannot be differentiated from chronic rhinosinusitis.

(e) (f) Fig. 18. Two-year-old boy with cystic fibrosis (CF). (a) Coronal CT with bone algorithm shows bilateral, homogeneous, ethmomaxillary soft tissue masses (asterisks). (b) Coronal CT with soft tissue algorithm can differentiate the mucosal lining (arrows) from the sticky mucous centrally. (c) Axial CT demonstrates the advanced medial bulging of the lateral nasal walls (arrows). (d) Coronal CT demonstrates sphenoid sinus hypoplasia seen in all CF patients. (e) Coronal MR with STIR sequence differentiates the mucosal lining from the pus-filled maxillary sinus lumen centrally. (f) The corresponding coronal MR T1 sequence is mandatory in order to discriminate the signal void lumen at STIR sequence from air-

Primary ciliary dyskinesia (immotile cilia syndrome) is an autosomal recessive disease with an incidence of 1/16000. The sinonasal manifestations are almost the same as in cystic

Young's syndrome manifest with obstructive azoospermie, pulmonary infections and chronic rhinosinusitis. This condition may also present with panopacification of the

Sertoly-cell-only syndrome with absence of spermatogones, bronchiectasis and chronic

Hyperimmunoglobulinemia E syndrome is an autosomal recessive disease with dermatitis, skin infections, otitis media, pneumonia, impaired neutrophile chemotaxis, and high serum

Churg-Strauss syndrome is a rare multisystemic disease, primarily in adults and with initial symptoms of asthma and allergic rhinosinusitis that cannot be differentiated from chronic

filled lumen.

**Primary ciliary dyskinesia** 

**Sertoly-cell-only syndrome** 

**Churg-Strauss syndrome** 

**Young's syndrome** 

sinuses.

rhinosinusitis.

rhinosinusitis.

fibrosis with opacification of all sinuses.

**Hyperimmunoglobulinemia E syndrome** 

IgE and chronic rhinosinusitis is an usual finding.

#### **Nijmegen's Breakage syndrome**

Nijmegen's Breakage syndrome have microcephaly and variable rhinosinusitis and hypersensitivity to gamma radiation and hence, MR should be performed instead of CT, if imaging is required.

#### **Aspirin triad syndrome**

Aspirin triad syndrome in where the patients are hypersensitive to aspirin. The symptoms are asthma and chronic rhinosinusitis with polyposis.

#### **Cyclic vomiting disorder**

Autonomic nerve dysfunction is common in adult with cyclic vomiting disorder with sympathetic abnormalities dominating, while parasympathetic nerve function appears to be intact (Venkatesan, 2010).

#### **Yellow nail syndrome**

Yellow nail syndrome is characterised of thickened yellow nail, primary lymphoedema due to lymphatic hypoplasia, chronic cough, pleural effusions, bronchiectasis, and a propensity to develop malignancies. Chronic rhinosinusitis is seen in almost all patients.

#### **PFAPA syndrome**

"Periodic fever, aphtous stomatitis, pharyngitis and cervical adenitis" syndrome (PFAPA), probably on a genetic basis. This autoinflammatory entity also includes chronic rhinosinusitis.

#### **Ataxia-Telangiectasia syndrome**

Ataxia-Telangiectasia syndrome is an autosomal recessive disease or sporadic occurring with in immunsystem deficit leading to recurrent or chronic rhinosinusitis.

#### **Weskit Aldrich syndrome**

Weskit Aldrich syndrome is an X-linked recessive disorder where the patients from early life have eczema, bloody diarrhea and recurrent infections including rhinosinusitis.

#### **Sarcoidosis**

Sarcoidosis may present with nodules (non-caseating granulomas) in the septum and along the neurovascular bundles and chronic rhinosinusitis though rare, are reported as the initial findings in this systemic disease.

#### **Wegener's granulomatosis**

Wegener's granulomatosis (WG) is a necrotising granulomatous vasculitis involving the lungs and kidneys. However, the nasal cavity and sinuses are frequently involved and also may be the initial presentation with destruction of the nasal septum and lateral nasal walls accompanied by mucosal inflammation and sclerotic thickening of the paranasal bones. The findings at imaging may mimic postoperative findings and chronic rhinosinusitis.

#### **Asthma and allergy**

Patients with asthma and allergy commonly show polypoid mucosal thickening of all paranasal sinuses. Due to mucosal thickening also at the level of the mucociliary drainage routes, exacerbation of disease are commonly followed by extensive rhinosinusitis of both

Imaging Rhinosinusitis 87

the fungal hyphae. In response to the fungal hyphae the mucosal lining shows advanced

(a) (b) Fig. 20. (a) Coronal CT shows total opacification of ipsilateral maxillary and ethmoid sinuses as well as the nasal cavity. The high density of the opacifications (asterisks) are a typical finding in allergic fungal sinusitis. (b) Coronal MR with STIR sequence shows signal void

(a) (b) Fig. 21. (a) Axial CT with bone algorithm shows total opacification of the right sphenoid sinus. The surrounding sclerotic bone thickening is equivalent to chronic rhinosinusitis (arrows). (b) Axial CT, with soft tissue algorithm reveals hyperdense calcifications (arrows) highly suspicious of a fungal infection. This was an incidental finding in a patient referred to

cerebral CT, and missed initially.

(asterisks) corresponding to the high density at CT. Courtesy A. ElBeltagi, Kuwait.

thickening with high T2 signal surrounding the fungus ball.

OMC and SER inflammatory patterns. These patients also are more likely to have the sinonasal polyposis inflammatory pattern.

#### **Gastrointestinal disease**

In Crohn's disease and ulcerative colitis sinonasal mucosal thickening is a frequent finding, However, the literature is sparse about the sinonasal manifestations.

#### **HIV seropositive patients**

HIV seropositive patients rarely have rhinosinusitis as a part of the manifestations.

#### **Cocaine nose**

Cocaine nose presents with a hole in the nasal septum. In advanced cases both cartilaginous and bony septum can be eroded with destruction proceeding to the surrounding bones. The imaging findings are similar to Wegener's granulomatosis but the latter usually shows more irregular sclerotic paranasal sinus bones.

Fig. 19. (a) Coronal and (b) axial CT shows a hole in the anterior nasal septum (arrows) in a patient abusing cocaine.

#### **13. Fungal rhinosinusitis**

Fungal sinusitis is classified as non-invasive and invasive. The two non-invasive forms are limited within the paranasal sinuses and consist of fungus ball (mycetoma) and allergic fungal sinusitis (AFS). In the invasive forms the fungal hyphae are found in the mucosal lining of the sinuses, in the bone and in the perisinus soft tissue. The three invasive forms are acute, chronic and granulomatous.

A fungus ball presents with foul-smelling nasal discharge. A typical CT finding is advanced unilateral sinus opacification with centrally scattered microcalcifications that are the clue to the correct diagnosis. At MR imaging the fungus ball has low T2 signal due to the microcalcifications, but also due to the paramagnetic properties of iron and manganese in

OMC and SER inflammatory patterns. These patients also are more likely to have the

In Crohn's disease and ulcerative colitis sinonasal mucosal thickening is a frequent finding,

Cocaine nose presents with a hole in the nasal septum. In advanced cases both cartilaginous and bony septum can be eroded with destruction proceeding to the surrounding bones. The imaging findings are similar to Wegener's granulomatosis but the latter usually shows more

(a) (b) Fig. 19. (a) Coronal and (b) axial CT shows a hole in the anterior nasal septum (arrows) in a

Fungal sinusitis is classified as non-invasive and invasive. The two non-invasive forms are limited within the paranasal sinuses and consist of fungus ball (mycetoma) and allergic fungal sinusitis (AFS). In the invasive forms the fungal hyphae are found in the mucosal lining of the sinuses, in the bone and in the perisinus soft tissue. The three invasive forms

A fungus ball presents with foul-smelling nasal discharge. A typical CT finding is advanced unilateral sinus opacification with centrally scattered microcalcifications that are the clue to the correct diagnosis. At MR imaging the fungus ball has low T2 signal due to the microcalcifications, but also due to the paramagnetic properties of iron and manganese in

HIV seropositive patients rarely have rhinosinusitis as a part of the manifestations.

However, the literature is sparse about the sinonasal manifestations.

sinonasal polyposis inflammatory pattern.

irregular sclerotic paranasal sinus bones.

**Gastrointestinal disease** 

**HIV seropositive patients** 

patient abusing cocaine.

**13. Fungal rhinosinusitis** 

are acute, chronic and granulomatous.

**Cocaine nose** 

the fungal hyphae. In response to the fungal hyphae the mucosal lining shows advanced thickening with high T2 signal surrounding the fungus ball.

Fig. 20. (a) Coronal CT shows total opacification of ipsilateral maxillary and ethmoid sinuses as well as the nasal cavity. The high density of the opacifications (asterisks) are a typical finding in allergic fungal sinusitis. (b) Coronal MR with STIR sequence shows signal void (asterisks) corresponding to the high density at CT. Courtesy A. ElBeltagi, Kuwait.

Fig. 21. (a) Axial CT with bone algorithm shows total opacification of the right sphenoid sinus. The surrounding sclerotic bone thickening is equivalent to chronic rhinosinusitis (arrows). (b) Axial CT, with soft tissue algorithm reveals hyperdense calcifications (arrows) highly suspicious of a fungal infection. This was an incidental finding in a patient referred to cerebral CT, and missed initially.

Imaging Rhinosinusitis 89

Every patients referred to imaging may be a candidate for FESS, hence the report should start with developmental, pneumatisation and anatomical variants that may influence on the endoscopic procedure. The next step is to describe the localisation and extent of opacifications and to decide if it fits into one or more of the five inflammatory patterns described. Then most important when the patient has opacifications is to decide whether this is a "simple rhinosinusitis", then if there are complications to the rhinosinusitis, and last to rule out conditions mimicking inflammatory patterns, fungal infection, or tumour. In case of systemic disease, paranasal sinus affection can be sparse or mimic inflammatory disease, hence it is mandatory that the referring clinician includes sufficient information for the

Aalokken, T.M. *et al.* (2003). Conventional sinus radiography compared with CT in the

Babbel, R. *et al.* (1991). Optimization of techniques in screening CT of the sinuses. *AJNR Am J* 

Burroughs, J.R. *et al.* (2003). Misdiagnosis of silent sinus syndrome. *Ophthal Plast Reconstr* 

deShazo, R.D. &S.P. Stringer. (2011). Atrophic rhinosinusitis: progress toward explanation of

Eggesbo, H.B. *et al.* (2001a). Complementary role of MR imaging of ethmomaxillary sinus disease depicted at CT in cystic fibrosis. *Acta Radiol*. 42, 2, pp 144-50. Eggesbo, H.B. *et al.* (1999). CT and MR imaging of the paranasal sinuses in cystic fibrosis.

Eggesbo, H.B. *et al.* (2001b). CT characterization of developmental variations of the

Hagtvedt, T. *et al.* (2003). A new low-dose CT examination compared with standard-dose CT

Lund, V.J. &D.W. Kennedy. (1997). Staging for rhinosinusitis. *Otolaryngol Head Neck Surg*.

Ly, T.H. *et al.* (2009). Diagnostic criteria for atrophic rhinosinusitis. *The American journal of* 

M Som, P. &H. D Curtin. (2011). Head and Neck Imaging - 2 Volume Set: Expert Consult-

Naclerio, R.M. *et al.* (2010). Pathophysiology of nasal congestion. *Int J Gen Med*. 3, pp 47-57. Rak, K.M. *et al.* (1991). Paranasal sinuses on MR images of the brain: significance of mucosal

thickening. *AJR. American journal of roentgenology*. 156, 2, pp 381-4.

paranasal sinuses in cystic fibrosis. *Acta Radiol*. 42, 5, pp 482-93.

in the diagnosis of acute sinusitis. *Eur Radiol*. 13, 5, pp 976-80.

an unsolved medical mystery. *Current opinion in allergy and clinical immunology*. 11,

Correlation with microbiological and histopathological results. *Acta Radiol*. 40, 2, pp

Caversaccio, M. *et al.* (2011). Historical review of Haller's cells. *Ann Anat*. 193, 3, pp 185-90. Cingi, C. *et al.* (2011). Nasal obstruction as a drug side effect. *Ther Adv Respir Dis*. 5, 3, pp

diagnosis of acute sinusitis. *Dentomaxillofac Radiol*. 32, 1, pp 60-2.

**15. The radiological report** 

radiologist.

**16. References** 

175-82.

1, pp 1-7.

154-62.

*Neuroradiol*. 12, 5, pp 849-54.

*Surg*. 19, 6, pp 449-54.

117, 3 Pt 2, pp S35-40.

*medicine*. 122, 8, pp 747-53.

Online and Print. pp 3080.

Fig. 22. (a) Axial CT with bone algorithm shows right maxillary sinus with advanced mucosal thickening (arrows) surrounded by sclerotic bone. (b) Axial CT with soft tissue algorithm reveals preantral and postantral soft tissue masses (arrows) due to invasive sinusitis. Notice also the septal thickening referred to as an eschar (asterisk).

Allergic fungal sinusitis is most common in warm and humid areas. The CT findings usually are extensive to all paranasal sinuses, but can also be limited to one sinus. The clue to the diagnosis is hyperdense central fillings surrounded by less dense mucosal thickening. The hyperdense central fillings is due to thick inpissated allergic mucin. At MR, the allergic mucin shows signal void at T2 and high or intermediate signal at T1.

In invasive fungal sinusitis, the acute and chronic form can be differentiated by its presentation. The chronic form can simulate chronic rhinosinusitis, while the acute form presents with rapidly progressive symptoms, while the granulomatous form is rarely seen. The clue to diagnosis of invasive fungal sinusitis is to look for obliteration of the fatty or soft tissue planes outside the sinuses. In invasive fungal sinusitis of the maxillary sinus one should look for preantral and retroantral soft tissue masses. In addition, a nasal septal ulcer may be seen, referred to as an eschar

In case of invasive fungal sinusitis from the sphenoid sinus the orbital apex and cranial nerves may be affected and the patient present with visual disturbances referred to as orbital apex syndrome.

#### **14. Sinonasal tumour**

Tumours in the sinonasal cavities can be extremely difficult to discriminate from rhinosinusitis in the early stage. In case of advanced unilateral opacification, bone destruction or bone remodelling, a malign neoplasm must be ruled out with complementary MR imaging. A malignant tumour may present as a single "inflammatory" polyp and therefore all polyps should be considered histopathologic evaluation.

(a) (b)

Allergic fungal sinusitis is most common in warm and humid areas. The CT findings usually are extensive to all paranasal sinuses, but can also be limited to one sinus. The clue to the diagnosis is hyperdense central fillings surrounded by less dense mucosal thickening. The hyperdense central fillings is due to thick inpissated allergic mucin. At MR, the allergic

In invasive fungal sinusitis, the acute and chronic form can be differentiated by its presentation. The chronic form can simulate chronic rhinosinusitis, while the acute form presents with rapidly progressive symptoms, while the granulomatous form is rarely seen. The clue to diagnosis of invasive fungal sinusitis is to look for obliteration of the fatty or soft tissue planes outside the sinuses. In invasive fungal sinusitis of the maxillary sinus one should look for preantral and retroantral soft tissue masses. In addition, a nasal septal ulcer

In case of invasive fungal sinusitis from the sphenoid sinus the orbital apex and cranial nerves may be affected and the patient present with visual disturbances referred to as

Tumours in the sinonasal cavities can be extremely difficult to discriminate from rhinosinusitis in the early stage. In case of advanced unilateral opacification, bone destruction or bone remodelling, a malign neoplasm must be ruled out with complementary MR imaging. A malignant tumour may present as a single "inflammatory" polyp and

Fig. 22. (a) Axial CT with bone algorithm shows right maxillary sinus with advanced mucosal thickening (arrows) surrounded by sclerotic bone. (b) Axial CT with soft tissue algorithm reveals preantral and postantral soft tissue masses (arrows) due to invasive

sinusitis. Notice also the septal thickening referred to as an eschar (asterisk).

mucin shows signal void at T2 and high or intermediate signal at T1.

therefore all polyps should be considered histopathologic evaluation.

may be seen, referred to as an eschar

orbital apex syndrome.

**14. Sinonasal tumour** 

#### **15. The radiological report**

Every patients referred to imaging may be a candidate for FESS, hence the report should start with developmental, pneumatisation and anatomical variants that may influence on the endoscopic procedure. The next step is to describe the localisation and extent of opacifications and to decide if it fits into one or more of the five inflammatory patterns described. Then most important when the patient has opacifications is to decide whether this is a "simple rhinosinusitis", then if there are complications to the rhinosinusitis, and last to rule out conditions mimicking inflammatory patterns, fungal infection, or tumour. In case of systemic disease, paranasal sinus affection can be sparse or mimic inflammatory disease, hence it is mandatory that the referring clinician includes sufficient information for the radiologist.

#### **16. References**


**1. Introduction** 

**6** 

*Baltimore, United States* 

**Topical Membrane Therapy** 

**for Chronic Rhinosinusitis** 

Alan Shikani and Konstantinos Kourelis *Union Memorial Hospital, Department of Rhinology* 

Chronic Rhinosinusitis (CRS) constitutes a longstanding disease process and a significant health hazard. Its pathophysiology may entail inherent epithelial irregularities, infectious insults, antigenic fermentations, and anatomic abnormalities, acting separately or in cooperation. Hence, various state-of-the-art treatment modalities have evolved, focusing on the surgical restoration of sinus homeostasis: endoscopic approach and visualization, fine surgical tools, power-instrumentation, precise imaging, combination of intranasal and external accesses, and navigation techniques. Despite the impressive technological advances in operative interventions, the medical aspects of CRS have not been investigated to the same extent, and the relevant remedies have changed very little over the years. Topical therapy in CRS is a relatively novel methodology, which relies on the local pharmacological management of sinus inflammatory status, and aims to supplement the existing treatment options. Topically applied medications have been used successfully for decades in dermatology, ophthalmology and urology. This chapter reviews the philosophy of topical therapy for CRS, its applications and effectiveness, as well as our institution's experience and findings regarding a complete

CRS is one of the commonest chronic diseases, affecting 14.2% of the United States population (Lethbridge-Cejku et al., 2004). It places a substantial cost burden on the health care system and is responsible for a considerable portion of sick leaves and decreased productivity(Gliklich and Metson, 1998). The modern opinion points towards a multifactorial etiology which includes fungi, bacterial superantigens, allergy, aspirin sensitivity, exposure to environmental irritants, and lately, bacterial biofilms (Chiu et al., 2008). Moreover, conditions impairing the mucociliary function, such as primary ciliary dyskinesia and cystic fibrosis(Armengot et al., 1994) have also been implicated. The resulting chronic inflammation of the sinus mucosa leads to defense reactions and alterations, i.e. edema, high mucus secretion, cilia loss, and

Surgery to remove the diseased mucosa and open the sinus ostia in order to restore the physiological mucociliary clearance, in combination with systemic antibiotics, has been the

local treatment protocol utilized for the management of refractory CRS.

particularly, polyp formation (Meltzer et al., 2004).

**2. Refractoriness of CRS and the rationale for topical therapy** 


### **Topical Membrane Therapy for Chronic Rhinosinusitis**

Alan Shikani and Konstantinos Kourelis *Union Memorial Hospital, Department of Rhinology Baltimore, United States* 

#### **1. Introduction**

90 Peculiar Aspects of Rhinosinusitis

Rosenfeld, R.M. *et al.* (2007). Clinical practice guideline: adult sinusitis. *Otolaryngol Head* 

Sarin, S. *et al.* (2006). The role of the nervous system in rhinitis. *Journal of Allergy and Clinical* 

Sonkens, J.W. *et al.* (1991). The impact of screening sinus CT on the planning of functional endoscopic sinus surgery. *Otolaryngol Head Neck Surg*. 105, 6, pp 802-13. Soparkar, C.N. *et al.* (1994). The silent sinus syndrome. A cause of spontaneous

Stammberger, H.R. &D.W. Kennedy. (1995). Paranasal sinuses:anatomic terminology and

Venkatesan, T. *et al.* (2010). Autonomic nerve function in adults with cyclic vomiting syndrome: a prospective study. *Neurogastroenterol Motil*. 22, 12, pp 1303-7, e339. Yaşar, H. *et al.* (2009). Rhinolithiasis: a retrospective study and review of the literature. *Ear* 

Zinreich, S.J. (2004). Imaging for staging of rhinosinusitis. *Ann Otol Rhinol Laryngol Suppl*.

Zinreich, S.J. *et al.* (1988). MR imaging of normal nasal cycle: comparison with sinus

nomenclature. The Anatomic Terminology Group. *Ann Otol Rhinol Laryngol Suppl*.

*Neck Surg*. 137, 3 Suppl, pp S1-31.

*Immunology*. 118, 5, pp 999-1014.

*Nose Throat J*. 88, 7, pp E24.

167, pp 7-16.

193, pp 19-23.

enophthalmos. *Ophthalmology*. 101, 4, pp 772-8.

pathology. *J Comput Assist Tomogr*. 12, 6, pp 1014-9.

Chronic Rhinosinusitis (CRS) constitutes a longstanding disease process and a significant health hazard. Its pathophysiology may entail inherent epithelial irregularities, infectious insults, antigenic fermentations, and anatomic abnormalities, acting separately or in cooperation. Hence, various state-of-the-art treatment modalities have evolved, focusing on the surgical restoration of sinus homeostasis: endoscopic approach and visualization, fine surgical tools, power-instrumentation, precise imaging, combination of intranasal and external accesses, and navigation techniques. Despite the impressive technological advances in operative interventions, the medical aspects of CRS have not been investigated to the same extent, and the relevant remedies have changed very little over the years. Topical therapy in CRS is a relatively novel methodology, which relies on the local pharmacological management of sinus inflammatory status, and aims to supplement the existing treatment options. Topically applied medications have been used successfully for decades in dermatology, ophthalmology and urology. This chapter reviews the philosophy of topical therapy for CRS, its applications and effectiveness, as well as our institution's experience and findings regarding a complete local treatment protocol utilized for the management of refractory CRS.

#### **2. Refractoriness of CRS and the rationale for topical therapy**

CRS is one of the commonest chronic diseases, affecting 14.2% of the United States population (Lethbridge-Cejku et al., 2004). It places a substantial cost burden on the health care system and is responsible for a considerable portion of sick leaves and decreased productivity(Gliklich and Metson, 1998). The modern opinion points towards a multifactorial etiology which includes fungi, bacterial superantigens, allergy, aspirin sensitivity, exposure to environmental irritants, and lately, bacterial biofilms (Chiu et al., 2008). Moreover, conditions impairing the mucociliary function, such as primary ciliary dyskinesia and cystic fibrosis(Armengot et al., 1994) have also been implicated. The resulting chronic inflammation of the sinus mucosa leads to defense reactions and alterations, i.e. edema, high mucus secretion, cilia loss, and particularly, polyp formation (Meltzer et al., 2004).

Surgery to remove the diseased mucosa and open the sinus ostia in order to restore the physiological mucociliary clearance, in combination with systemic antibiotics, has been the

Topical Membrane Therapy for Chronic Rhinosinusitis 93

and the entire anterior wall of the sphenoid sinus may be removed. Regardless of the technique used for drug administration, the penetration in unoperated sinuses does not exceed 3% of the total volume placed intranasally(Hyo et al., 1989). On the other hand, radical surgical dissection allows contact of the drug with up to 96% of total sinus internal surface(Miller et al., 2004). Exactly how much improvement is provided by sinus surgery is difficult to assess though, as the various operative techniques are different in terms of intervention, and range broadly from minimally invasive (e.g. balloon sinuplasty) to extremely aggressive (e.g. modified endoscopic Lothrop procedure). Apart from the apparent gain in the total sinus surface contacted directly by the topical agents, clinical studies document as well that steroid sprays, when used by patients who had sinus surgery, produce more significant improvement of symptoms, endoscopical and histopathological findings, than in CRS sufferers having not being treated surgically(Lavigne et al., 2002).

Fig. 1. In the unoperated patient (Left), the lateral nasal wall is an anatomical barrier to the delivery of topical medications, whereas the post-surgery paranasal cavities (Right) are

Individual anatomical details, further modify the pharmacological penetration into the paranasal cavities. Inferior turbinate hypertrophy limits the intranasal flow, whereas in case of uncorrected nasal septal deviation, accumulation of the local agent immediately anterior to the spur is noted. Moreover, the variations taking place during the nasal cycle influence the temporal pattern of drug dissemination. Altogether, a patent nasal passageway, not narrowed by all of the above anatomical factors, permits 90% penetration rate of the locally

A much debatable issue related to the delivery of local treatment is the patient's optimal positioning during irrigations or nebulizations. The traditional "Mecca" position with the head brought forward is becoming now less popular than placing the head backward. Lateral positions have also been proposed as more appropriate for delivery to the frontal

A third consideration regarding the distribution of locally applied drugs is the configuration of sinuses in relation to gravity. Whereas the roof of the ethmoid and the frontal recess are dependent areas, so that the pharmacological deposits drain rapidly downwards, the

accessible through wide windows.

applied agents(Unno et al., 1983).

sinus(Karagama et al., 2001).

mainstay of treatment for the past decades(Gosepath and Mann, 2005). The long-term success rate of endoscopic sinus surgery is reported as high as 76%. In the remaining patients, either no improvement is noted, or the CRS recurs soon after treatment. Interestingly, in the majority of failures, the post-operative sinus anatomy demonstrates ostium patency and wide-open ethmoid cavities, abundantly ventilated(Levine, 1990). Specifically, Kennedy has reported that 15% of patients who undergo endoscopic surgery, show mild to no clinical improvement, despite the "optimal" surgical outcome(Kennedy, 1992). These difficult-to-treat patients sometimes demonstrate inflammatory or idiosyncratic features, such as eosinophilia, history of asthma, allergic fungal sinusitis, nasal polyps, and aspirin sensitivity(Zadeh et al., 2002). The common denominator of the above conditions, is an intrinsic pro-inflammatory state of the sinus mucosa which predisposes to clinicopathological exacerbations, in the absence of substantial external irritation.

In addition to the aberrations of the end-organ, that is, the sinus epithelium, an unusual issue of resistance of ordinary bacteria to potent antimicrobials has emerged. This notable finding has been associated with the concept of biofilms, which cover the surface epithelium of paranasal cavities. The common bacterial species H. influenzae, S. pneumoniae, and S. aureus have been identified in biofilms, and their capacity to produce this organic matrix correlates with the refractoriness of CRS. Microorganisms colonizing the biofilms are much less vulnerable to systemic antibiotics which reach the standard tissue Minimally Inhibitory Concentration (MIC). Both the physical and chemical protection imposed by the organic layer on the microbial colonies, call for higher local concentrations of the antibacterial agents (Bendouah et al., 2006).

The principle of the local therapy is prolonged delivery of a highly concentrated drastic substance, whether pharmacological or not, to the sinus cavities, so as to exert its maximal effect on the desired anatomical site, without significant systemic toxicity. Oftentimes, the existing antibiotics and anti-inflammatory medications produce a temporary relief from CRS, combined with mild to moderate side effects, depending on the comorbidities of the patient.

#### **3. Parameters affecting the efficacy of local treatment**

#### **3.1 Macro-anatomy**

By definition, topical therapy should address thoroughly the target-organ, and reach all the subregions of the diseased paranasal cavities. Several patient- or drug-related factors influence the macro-delivery of medications, but the role of sinus surgery simply cannot be overstated enough.

The paranasal sinuses, have limited communication with the nasal cavity proper, and this is even more evident in the disease state, when the edema and mucociliary impairment further restrict the access to the inflamed regions. This situation changes dramatically after a successful endoscopic surgery. Even if, because of the aforementioned idiosyncratic factors, the CRS persists, creation of wide, readily-accessible surgical cavities is critical for the efficient local application of the therapeutic agents (Fig. 1). The frontal and sphenoid sinuses practically cannot be reached by intranasal administration, while a minimal diameter of 4mm is required for a slightly accessible maxillary ostium(Harvey and Schlosser, 2009). During an endoscopic procedure, the maxillary entrance can be opened as widely as 2.5cm,

mainstay of treatment for the past decades(Gosepath and Mann, 2005). The long-term success rate of endoscopic sinus surgery is reported as high as 76%. In the remaining patients, either no improvement is noted, or the CRS recurs soon after treatment. Interestingly, in the majority of failures, the post-operative sinus anatomy demonstrates ostium patency and wide-open ethmoid cavities, abundantly ventilated(Levine, 1990). Specifically, Kennedy has reported that 15% of patients who undergo endoscopic surgery, show mild to no clinical improvement, despite the "optimal" surgical outcome(Kennedy, 1992). These difficult-to-treat patients sometimes demonstrate inflammatory or idiosyncratic features, such as eosinophilia, history of asthma, allergic fungal sinusitis, nasal polyps, and aspirin sensitivity(Zadeh et al., 2002). The common denominator of the above conditions, is an intrinsic pro-inflammatory state of the sinus mucosa which predisposes to

clinicopathological exacerbations, in the absence of substantial external irritation.

(Bendouah et al., 2006).

**3.1 Macro-anatomy** 

overstated enough.

patient.

In addition to the aberrations of the end-organ, that is, the sinus epithelium, an unusual issue of resistance of ordinary bacteria to potent antimicrobials has emerged. This notable finding has been associated with the concept of biofilms, which cover the surface epithelium of paranasal cavities. The common bacterial species H. influenzae, S. pneumoniae, and S. aureus have been identified in biofilms, and their capacity to produce this organic matrix correlates with the refractoriness of CRS. Microorganisms colonizing the biofilms are much less vulnerable to systemic antibiotics which reach the standard tissue Minimally Inhibitory Concentration (MIC). Both the physical and chemical protection imposed by the organic layer on the microbial colonies, call for higher local concentrations of the antibacterial agents

The principle of the local therapy is prolonged delivery of a highly concentrated drastic substance, whether pharmacological or not, to the sinus cavities, so as to exert its maximal effect on the desired anatomical site, without significant systemic toxicity. Oftentimes, the existing antibiotics and anti-inflammatory medications produce a temporary relief from CRS, combined with mild to moderate side effects, depending on the comorbidities of the

By definition, topical therapy should address thoroughly the target-organ, and reach all the subregions of the diseased paranasal cavities. Several patient- or drug-related factors influence the macro-delivery of medications, but the role of sinus surgery simply cannot be

The paranasal sinuses, have limited communication with the nasal cavity proper, and this is even more evident in the disease state, when the edema and mucociliary impairment further restrict the access to the inflamed regions. This situation changes dramatically after a successful endoscopic surgery. Even if, because of the aforementioned idiosyncratic factors, the CRS persists, creation of wide, readily-accessible surgical cavities is critical for the efficient local application of the therapeutic agents (Fig. 1). The frontal and sphenoid sinuses practically cannot be reached by intranasal administration, while a minimal diameter of 4mm is required for a slightly accessible maxillary ostium(Harvey and Schlosser, 2009). During an endoscopic procedure, the maxillary entrance can be opened as widely as 2.5cm,

**3. Parameters affecting the efficacy of local treatment** 

and the entire anterior wall of the sphenoid sinus may be removed. Regardless of the technique used for drug administration, the penetration in unoperated sinuses does not exceed 3% of the total volume placed intranasally(Hyo et al., 1989). On the other hand, radical surgical dissection allows contact of the drug with up to 96% of total sinus internal surface(Miller et al., 2004). Exactly how much improvement is provided by sinus surgery is difficult to assess though, as the various operative techniques are different in terms of intervention, and range broadly from minimally invasive (e.g. balloon sinuplasty) to extremely aggressive (e.g. modified endoscopic Lothrop procedure). Apart from the apparent gain in the total sinus surface contacted directly by the topical agents, clinical studies document as well that steroid sprays, when used by patients who had sinus surgery, produce more significant improvement of symptoms, endoscopical and histopathological findings, than in CRS sufferers having not being treated surgically(Lavigne et al., 2002).

Fig. 1. In the unoperated patient (Left), the lateral nasal wall is an anatomical barrier to the delivery of topical medications, whereas the post-surgery paranasal cavities (Right) are accessible through wide windows.

Individual anatomical details, further modify the pharmacological penetration into the paranasal cavities. Inferior turbinate hypertrophy limits the intranasal flow, whereas in case of uncorrected nasal septal deviation, accumulation of the local agent immediately anterior to the spur is noted. Moreover, the variations taking place during the nasal cycle influence the temporal pattern of drug dissemination. Altogether, a patent nasal passageway, not narrowed by all of the above anatomical factors, permits 90% penetration rate of the locally applied agents(Unno et al., 1983).

A much debatable issue related to the delivery of local treatment is the patient's optimal positioning during irrigations or nebulizations. The traditional "Mecca" position with the head brought forward is becoming now less popular than placing the head backward. Lateral positions have also been proposed as more appropriate for delivery to the frontal sinus(Karagama et al., 2001).

A third consideration regarding the distribution of locally applied drugs is the configuration of sinuses in relation to gravity. Whereas the roof of the ethmoid and the frontal recess are dependent areas, so that the pharmacological deposits drain rapidly downwards, the

Topical Membrane Therapy for Chronic Rhinosinusitis 95

Fluid irrigations remain a traditional, simple, and well-tested technique for conveying treatment formulas directly to the sinonasal surface epithelium. It is well-established that commercial nasal sprays, do not penetrate the frontal and sphenoid sinuses. On the contrary, a high volume of liquid solution (over 100mL) ensures access into these unapproachable sinuses. In post-operative cases, irrigations with a bulb syringe are superior to every other delivery methods, in terms of access to anatomical subsites. Yet, up to 30mL of solution pour out immediately from the nasal cavities, so that a considerable irrigation volume is wasted(Miller et al., 2004). Given a specific volume of solution, the pressure of irrigations can be modified by the device used. Low-pressure lavage using commercial pots, seem to be suitable for unoperated sinuses, whereas high-pressure douches delivered by squeeze-bottles are proper in case of surgically created open cavities(Harvey and Schlosser,

Nasal sprays have been classically used to provide local application of drugs in rhinosinusitis. Among the various devices developed over the years (spray bottles, aqueous pumps, dry powder atomizers), aqueous spray pumps are most accepted. Such pumps contain a medication-containing solution, which is released in the form of droplets. Smaller, lighter droplets demonstrate a broad distribution across the mucosal surface, as they travel a longer distance from the nostril. The viscosity of the solution is an additional factor, as thicker liquids project in a narrower cone and do not reach the peripheral intranasal regions(Kundoor and Dalby, 2010). Despite the refinements of spraying pumps, the droplets barely penetrate the sinuses in unoperated patients, and their effect is essentially restricted to the nasal cavities only. The maximal concentration of the sprayed agent is detected in the anterior nasal cavity, due to the obstructive mass of the inferior turbinate. Half of the dose does not approach the ostiomeatal complex, an anatomical structure central to the

Nebulized medications are a novel topical approach to rhinosinusitis, and have been used for the past decade in clinical practice in Europe. In Japan, they were adopted in 1950, and in the United States, nebulizers and nebulized medications are covered by most medical insurances(Vaughan and Carvalho, 2002). Nebulization devices provide an aerosolized mist which is created by a mechanical pulse. The latter is produced either by a high-pressure jet, or a vibrating mesh. The earliest devices emitted an aerosolized stream of particles larger than 10μm, and the penetration of medications into the sinuses was limited as most of the particles are filtered by macro- or micro-anatomical barriers. Innovative technologies are now capable of generating airflow consisting of particles with a diameter less than 3μm, and accumulation on sinus mucosa is much more extensive. The main advantage of nebulizers, in comparison with the traditional spray pumps, is the deposition of pharmacological agents in the posterior nasal cavity. Moreover, sprayed formulations are undetected in the sinus cavities of patients who have not had surgery, whereas 8% of intranasally placed aerosols

The advantage of topical therapy is the accumulation of very high concentrations of medications directly at the target site. Equivalent doses would not be possible to be administered systemically, due to unacceptable toxicity. Nonetheless, the systemic absorption of locally applied drugs should be always kept in mind, so that potential side-

2009).

pathogenesis of CRS(Merkus et al., 2006).

remain in the sinuses(Moller et al., 2010).

**4. Systemic absorption** 

maxillary antrum with its highly-situated ostium retains most of its contents, until they are cleared by the mucociliary mechanism.

#### **3.2 Micro-anatomy**

Even when the local agent enters the sinuses in sufficient quantities, its efficacy is not guaranteed, as it needs to reach its pharmacological target, and stay in contact for an adequate amount of time. This becomes particularly important in the sinonasal cavities, where the microenvironment is structured specifically to eliminate foreign particles, including medications, using several clearance mechanisms.

All sinus surfaces are covered by a mucus layer with the purpose to entrap foreign particles and filter the inhaled air. The production rate of the mucus fluctuates greatly, depending on the inflammatory status of the epithelium. Understandably, CRS is a condition predisposing to mucosal irritability and subsequent hypersecretion of thick mucus(Harvey and Schlosser, 2009). The thickness of the viscous gel phase of the mucus layer, which overlaps the respiratory cell cilia, varies from 7 μm in healthy mucosa, to 200 μm in high-grade inflammatory states(Tarran et al., 2001). Mechanical removal of the viscous mucus blanket, by high-volume sinus rinses results in more potent effect of locally administrated steroids(Daviskas and Anderson, 2006).

The mucus contents are as important as its physical dimensions and texture. Besides water, organic salts, enzymes, and immunoglobulins, the mucins constitute the basic ingredient of this supra-epithelial blanket. These are glycoproteins responsible for the viscous consistency of the mucus. In detail, mucins form fibers which bind to each other via cross-linking attachments, to make up a web that serves as the skeletal component of the threedimensional layer. The mucin tangle contributes to the support of air particles, but also presents a network of hydrophobic sites, that act as receptors for macromolecules with similar physicochemical properties. Hydrophobic molecules are retained in the mucus and exert a prolonged pharmacologic effect(Ugwoke et al., 2005). On the basis of this finding, conjugation of topical medications with mucoadhesive gels, aiming to achieve sustained drug release, has been proposed(Nakamura et al., 1999).

In contrast with all the other Head and Neck sites, the sinonasal cavities are covered by respiratory-type epithelium, instead of the standard squamous-cell epithelial layer. Material that is captured in the mucus is gradually propelled outside the sinus cavities and carried to the nasopharynx, by means of constant ciliary beating. An intact mucociliary mechanism can clear the entire maxillary sinus of foreign particles in less than twenty minutes(Harvey and Schlosser, 2009). In CRS though, the chronic infection impairs the ciliary function, in favor of the prolonged residence of topically delivered medications. On the other hand, it is suggested that the active transfer of medications to the choanae might actually enhance their distribution to remote mucosal subsites(Goh and Goode, 2000).

#### **3.3 Major delivery techniques**

In the history of rhinosinusitis topical therapy, several methods for the delivery of the drastic agent have been utilized: Fluid irrigation, spray pumps, drops/powder/gel instillation, nebulization, and regional injection, aim to provide optimal spatiotemporal conditions of contact between the medication and its target.

maxillary antrum with its highly-situated ostium retains most of its contents, until they are

Even when the local agent enters the sinuses in sufficient quantities, its efficacy is not guaranteed, as it needs to reach its pharmacological target, and stay in contact for an adequate amount of time. This becomes particularly important in the sinonasal cavities, where the microenvironment is structured specifically to eliminate foreign particles,

All sinus surfaces are covered by a mucus layer with the purpose to entrap foreign particles and filter the inhaled air. The production rate of the mucus fluctuates greatly, depending on the inflammatory status of the epithelium. Understandably, CRS is a condition predisposing to mucosal irritability and subsequent hypersecretion of thick mucus(Harvey and Schlosser, 2009). The thickness of the viscous gel phase of the mucus layer, which overlaps the respiratory cell cilia, varies from 7 μm in healthy mucosa, to 200 μm in high-grade inflammatory states(Tarran et al., 2001). Mechanical removal of the viscous mucus blanket, by high-volume sinus rinses results in more potent effect of locally administrated

The mucus contents are as important as its physical dimensions and texture. Besides water, organic salts, enzymes, and immunoglobulins, the mucins constitute the basic ingredient of this supra-epithelial blanket. These are glycoproteins responsible for the viscous consistency of the mucus. In detail, mucins form fibers which bind to each other via cross-linking attachments, to make up a web that serves as the skeletal component of the threedimensional layer. The mucin tangle contributes to the support of air particles, but also presents a network of hydrophobic sites, that act as receptors for macromolecules with similar physicochemical properties. Hydrophobic molecules are retained in the mucus and exert a prolonged pharmacologic effect(Ugwoke et al., 2005). On the basis of this finding, conjugation of topical medications with mucoadhesive gels, aiming to achieve sustained

In contrast with all the other Head and Neck sites, the sinonasal cavities are covered by respiratory-type epithelium, instead of the standard squamous-cell epithelial layer. Material that is captured in the mucus is gradually propelled outside the sinus cavities and carried to the nasopharynx, by means of constant ciliary beating. An intact mucociliary mechanism can clear the entire maxillary sinus of foreign particles in less than twenty minutes(Harvey and Schlosser, 2009). In CRS though, the chronic infection impairs the ciliary function, in favor of the prolonged residence of topically delivered medications. On the other hand, it is suggested that the active transfer of medications to the choanae might actually enhance their

In the history of rhinosinusitis topical therapy, several methods for the delivery of the drastic agent have been utilized: Fluid irrigation, spray pumps, drops/powder/gel instillation, nebulization, and regional injection, aim to provide optimal spatiotemporal

cleared by the mucociliary mechanism.

steroids(Daviskas and Anderson, 2006).

including medications, using several clearance mechanisms.

drug release, has been proposed(Nakamura et al., 1999).

distribution to remote mucosal subsites(Goh and Goode, 2000).

conditions of contact between the medication and its target.

**3.3 Major delivery techniques** 

**3.2 Micro-anatomy** 

Fluid irrigations remain a traditional, simple, and well-tested technique for conveying treatment formulas directly to the sinonasal surface epithelium. It is well-established that commercial nasal sprays, do not penetrate the frontal and sphenoid sinuses. On the contrary, a high volume of liquid solution (over 100mL) ensures access into these unapproachable sinuses. In post-operative cases, irrigations with a bulb syringe are superior to every other delivery methods, in terms of access to anatomical subsites. Yet, up to 30mL of solution pour out immediately from the nasal cavities, so that a considerable irrigation volume is wasted(Miller et al., 2004). Given a specific volume of solution, the pressure of irrigations can be modified by the device used. Low-pressure lavage using commercial pots, seem to be suitable for unoperated sinuses, whereas high-pressure douches delivered by squeeze-bottles are proper in case of surgically created open cavities(Harvey and Schlosser, 2009).

Nasal sprays have been classically used to provide local application of drugs in rhinosinusitis. Among the various devices developed over the years (spray bottles, aqueous pumps, dry powder atomizers), aqueous spray pumps are most accepted. Such pumps contain a medication-containing solution, which is released in the form of droplets. Smaller, lighter droplets demonstrate a broad distribution across the mucosal surface, as they travel a longer distance from the nostril. The viscosity of the solution is an additional factor, as thicker liquids project in a narrower cone and do not reach the peripheral intranasal regions(Kundoor and Dalby, 2010). Despite the refinements of spraying pumps, the droplets barely penetrate the sinuses in unoperated patients, and their effect is essentially restricted to the nasal cavities only. The maximal concentration of the sprayed agent is detected in the anterior nasal cavity, due to the obstructive mass of the inferior turbinate. Half of the dose does not approach the ostiomeatal complex, an anatomical structure central to the pathogenesis of CRS(Merkus et al., 2006).

Nebulized medications are a novel topical approach to rhinosinusitis, and have been used for the past decade in clinical practice in Europe. In Japan, they were adopted in 1950, and in the United States, nebulizers and nebulized medications are covered by most medical insurances(Vaughan and Carvalho, 2002). Nebulization devices provide an aerosolized mist which is created by a mechanical pulse. The latter is produced either by a high-pressure jet, or a vibrating mesh. The earliest devices emitted an aerosolized stream of particles larger than 10μm, and the penetration of medications into the sinuses was limited as most of the particles are filtered by macro- or micro-anatomical barriers. Innovative technologies are now capable of generating airflow consisting of particles with a diameter less than 3μm, and accumulation on sinus mucosa is much more extensive. The main advantage of nebulizers, in comparison with the traditional spray pumps, is the deposition of pharmacological agents in the posterior nasal cavity. Moreover, sprayed formulations are undetected in the sinus cavities of patients who have not had surgery, whereas 8% of intranasally placed aerosols remain in the sinuses(Moller et al., 2010).

#### **4. Systemic absorption**

The advantage of topical therapy is the accumulation of very high concentrations of medications directly at the target site. Equivalent doses would not be possible to be administered systemically, due to unacceptable toxicity. Nonetheless, the systemic absorption of locally applied drugs should be always kept in mind, so that potential side-

Topical Membrane Therapy for Chronic Rhinosinusitis 97

rhinitis, a major component of the CRS pathogenesis. Its main drawback however, is the

Apart from their chemical composition and salt concentration, a second characteristic of saline douches, unique in topical therapy, is the high volume of solution used in each irrigation. The importance of volume and pressure parameters has already been described. Altogether, the benefit from saline irrigations to the management of CRS includes the mechanical removal of infectious/irritating/allergenic material, decrease of mucosal edema, improvement of the mucociliary function, and thinning of mucus secretions. Usually, saline rinses are prescribed in combination with other means of topical therapy, and there is evidence that they enhance the bio-supply of the primary medications(Papsin and

Intranasal steroids have been initially the mainstay of topical therapy for allergic rhinitis. Due to their potent anti-inflammatory action, especially the deceleration of late-phase response, they diminish the manifestations of nasal allergy (congestion, rhinorrhea, pruritus). Their anti-decongestant properties in allergic rhinitis had been appreciated, and local steroids were subsequently introduced to the treatment of acute bacterial sinusitis, as adjuncts to systemic antibiotics. Interestingly, the infectious edema of acute sinusitis requires higher doses of steroids than those administered in allergic rhinitis(Moller et al., 2010). In CRS, local steroids were at first prescribed cautiously, and only in case of exacerbations, which resemble the pathophysiology of acute rhinosinusitis. It was the beneficial effect of steroids on nasal polyposis and hyperplastic sinusitis, that indicated their prolonged use in CRS. When steroids are administered orally, they have a clearly superior effect on nasal polyps ("medical polypectomy"), than any form of topical treatment(Palmer and Kennedy, 2003). Naturally, the advantage of steroid sprays is their capacity for longterm use with minimal side-effects. Perhaps the effective way to get the most out of corticosteroid therapy, is a combination of "induction" systemic administration to reduce the severe edema, along with a "maintenance" schedule of intranasal spaying, to control the

Local steroids are administered in several forms, in order to achieve greater efficacy. Intranasal placement of fluticasone drops has demonstrated a distinct benefit in patients with hyperplastic CRS, precluding the need for endoscopic surgery in half of the cases. The authors suggest that nasal drops are more successful than sprays, as they reach easier the middle meatus(Aukema et al., 2005). A modification of drops administration involves direct instillation in the office, utilizing a soft catheter, under endoscopic vision. This method accomplishes focused application in difficult-to-approach regions, such as the frontal recess(Palmer and Kennedy, 2003). A more invasive technique, combining the efficacy of systemic treatment with the low side-effect pharmacological profile of local drops, utilizes injection of steroids into the polyp mass. Although this procedure has been performed enthusiastically in the 1950s, reports of visual loss emphasized the need for cautiousness(Mabry, 1981). Embolization or spasm of the central retinal artery, have been hypothesized as the mechanism of blindness. Placing the injection into the center of the

continuous, low-grade inflammation of CRS(Wahl and Otsuji, 2003).

discomfort often reported by the patients.

McTavish, 2003).

**5.2 Corticosteroids** 

effects are avoided. The nasal mucosa incorporates a rich capillary network, and certain substances applied onto the broad epithelial cover of the sinus cavities may reach high concentrations in plasma. The significance of drug absorption by the nasal mucosa is evident from the strong interest in the design of intranasally administered systemic treatments for miscellaneous diseases, e.g. diabetes (insulin), migraine (propranolol, sumatriptan), smoking cessation (nicotine), osteoporosis (calcitonin), and acromegaly (octreotide)(Ranade, 2001).

Orally administered medications undergo first-pass hepatic metabolism, and therefore a portion of the dose does not reach the systemic circulation. This is not the case in topical sinus medications, which are absorbed directly by the surface respiratory epithelium, and thus by-pass liver metabolism. However, the epithelial target cells of the nasal mucosa, contain an array of drastic enzymes, which also metabolize the pharmacological deposits. The levels of Cytochrome P-450, which participates in hepatic metabolism, are extremely high in the nasal mucosa, too. Phase II enzymes, like glutathione-transferase, which transfer micromolecular groups to the metabolized medications, are also prevalent. The nasal mucosa is deficient in proteases, though. Consequently, proteins are not lysed topically, and their absorption rate is substantial(Chien and Chang, 1987).

#### **5. Agents used in topical therapy**

#### **5.1 Saline**

Prior to the local application of therapeutic antimicrobial or anti-inflammatory agents, mechanical cleansing of the sinuses with saline irrigations has been one of the oldest and most widely used methods for the management of CRS. Mucopurulent secretions filling up the infected cavities are a frequent finding in CRS exacerbations. Furthermore, during the post-operative period following endoscopic sinus surgery for chronic rhinosinusitis, a collection of old blood, crusts, necrotic debris, or allergic fungal mucin, is accumulating periodically and regular meticulous cleansing is as important as the surgical procedure itself(Palmer and Kennedy, 2003). Office debridement, with the help of curved suctions is the optimal way to maintain sinus health. However, it is impractical and uncomfortable for the patients to visit the rhinologist too often for debridements as the only means of removing the "toxic" material. Our own policy is performing this debridement on a weekly basis, until the sinus cavities are clean. Frequent, as needed saline irrigations may be performed easily at home and are the simplest and least expensive form of topical therapy.

The appropriate saline concentration for the sinus lavage is controversial. Iso-, hypo-, and hyper-tonic salive, as well as Ringer's Lactate solution, have all been tested for their efficacy and side effects. Isotonic saline is the basic irrigation solution, as it provides only mechanical cleansing, without creating an osmotic gradient between the sinonasal cavities and the surface epithelial cells. It is suggested though that the isotonic concentration also modifies the rheological properties of the mucus, making the secretions less viscous. On the other hand, hypertonic solutions have been introduced subsequently into CRS management, as they decrease mucosal edema by creating an efflux of water from the intercellular space. Not only that, but it is documented that hypertonic irrigations improve the mucociliary function, in comparison to isotonic saline. High salt concentration in the sinus cavities is postulated to promote intracellular calcium release, which sets off the biochemical cascade resulting to cilia movement(Daviskas et al., 1996). Hypertonic sinus lavage also has an effect on allergic rhinitis, a major component of the CRS pathogenesis. Its main drawback however, is the discomfort often reported by the patients.

Apart from their chemical composition and salt concentration, a second characteristic of saline douches, unique in topical therapy, is the high volume of solution used in each irrigation. The importance of volume and pressure parameters has already been described.

Altogether, the benefit from saline irrigations to the management of CRS includes the mechanical removal of infectious/irritating/allergenic material, decrease of mucosal edema, improvement of the mucociliary function, and thinning of mucus secretions. Usually, saline rinses are prescribed in combination with other means of topical therapy, and there is evidence that they enhance the bio-supply of the primary medications(Papsin and McTavish, 2003).

#### **5.2 Corticosteroids**

96 Peculiar Aspects of Rhinosinusitis

effects are avoided. The nasal mucosa incorporates a rich capillary network, and certain substances applied onto the broad epithelial cover of the sinus cavities may reach high concentrations in plasma. The significance of drug absorption by the nasal mucosa is evident from the strong interest in the design of intranasally administered systemic treatments for miscellaneous diseases, e.g. diabetes (insulin), migraine (propranolol, sumatriptan), smoking cessation (nicotine), osteoporosis (calcitonin), and acromegaly

Orally administered medications undergo first-pass hepatic metabolism, and therefore a portion of the dose does not reach the systemic circulation. This is not the case in topical sinus medications, which are absorbed directly by the surface respiratory epithelium, and thus by-pass liver metabolism. However, the epithelial target cells of the nasal mucosa, contain an array of drastic enzymes, which also metabolize the pharmacological deposits. The levels of Cytochrome P-450, which participates in hepatic metabolism, are extremely high in the nasal mucosa, too. Phase II enzymes, like glutathione-transferase, which transfer micromolecular groups to the metabolized medications, are also prevalent. The nasal mucosa is deficient in proteases, though. Consequently, proteins are not lysed topically, and

Prior to the local application of therapeutic antimicrobial or anti-inflammatory agents, mechanical cleansing of the sinuses with saline irrigations has been one of the oldest and most widely used methods for the management of CRS. Mucopurulent secretions filling up the infected cavities are a frequent finding in CRS exacerbations. Furthermore, during the post-operative period following endoscopic sinus surgery for chronic rhinosinusitis, a collection of old blood, crusts, necrotic debris, or allergic fungal mucin, is accumulating periodically and regular meticulous cleansing is as important as the surgical procedure itself(Palmer and Kennedy, 2003). Office debridement, with the help of curved suctions is the optimal way to maintain sinus health. However, it is impractical and uncomfortable for the patients to visit the rhinologist too often for debridements as the only means of removing the "toxic" material. Our own policy is performing this debridement on a weekly basis, until the sinus cavities are clean. Frequent, as needed saline irrigations may be performed easily at home and are the simplest and least expensive form of topical therapy. The appropriate saline concentration for the sinus lavage is controversial. Iso-, hypo-, and hyper-tonic salive, as well as Ringer's Lactate solution, have all been tested for their efficacy and side effects. Isotonic saline is the basic irrigation solution, as it provides only mechanical cleansing, without creating an osmotic gradient between the sinonasal cavities and the surface epithelial cells. It is suggested though that the isotonic concentration also modifies the rheological properties of the mucus, making the secretions less viscous. On the other hand, hypertonic solutions have been introduced subsequently into CRS management, as they decrease mucosal edema by creating an efflux of water from the intercellular space. Not only that, but it is documented that hypertonic irrigations improve the mucociliary function, in comparison to isotonic saline. High salt concentration in the sinus cavities is postulated to promote intracellular calcium release, which sets off the biochemical cascade resulting to cilia movement(Daviskas et al., 1996). Hypertonic sinus lavage also has an effect on allergic

their absorption rate is substantial(Chien and Chang, 1987).

**5. Agents used in topical therapy** 

**5.1 Saline** 

(octreotide)(Ranade, 2001).

Intranasal steroids have been initially the mainstay of topical therapy for allergic rhinitis. Due to their potent anti-inflammatory action, especially the deceleration of late-phase response, they diminish the manifestations of nasal allergy (congestion, rhinorrhea, pruritus). Their anti-decongestant properties in allergic rhinitis had been appreciated, and local steroids were subsequently introduced to the treatment of acute bacterial sinusitis, as adjuncts to systemic antibiotics. Interestingly, the infectious edema of acute sinusitis requires higher doses of steroids than those administered in allergic rhinitis(Moller et al., 2010). In CRS, local steroids were at first prescribed cautiously, and only in case of exacerbations, which resemble the pathophysiology of acute rhinosinusitis. It was the beneficial effect of steroids on nasal polyposis and hyperplastic sinusitis, that indicated their prolonged use in CRS. When steroids are administered orally, they have a clearly superior effect on nasal polyps ("medical polypectomy"), than any form of topical treatment(Palmer and Kennedy, 2003). Naturally, the advantage of steroid sprays is their capacity for longterm use with minimal side-effects. Perhaps the effective way to get the most out of corticosteroid therapy, is a combination of "induction" systemic administration to reduce the severe edema, along with a "maintenance" schedule of intranasal spaying, to control the continuous, low-grade inflammation of CRS(Wahl and Otsuji, 2003).

Local steroids are administered in several forms, in order to achieve greater efficacy. Intranasal placement of fluticasone drops has demonstrated a distinct benefit in patients with hyperplastic CRS, precluding the need for endoscopic surgery in half of the cases. The authors suggest that nasal drops are more successful than sprays, as they reach easier the middle meatus(Aukema et al., 2005). A modification of drops administration involves direct instillation in the office, utilizing a soft catheter, under endoscopic vision. This method accomplishes focused application in difficult-to-approach regions, such as the frontal recess(Palmer and Kennedy, 2003). A more invasive technique, combining the efficacy of systemic treatment with the low side-effect pharmacological profile of local drops, utilizes injection of steroids into the polyp mass. Although this procedure has been performed enthusiastically in the 1950s, reports of visual loss emphasized the need for cautiousness(Mabry, 1981). Embolization or spasm of the central retinal artery, have been hypothesized as the mechanism of blindness. Placing the injection into the center of the

Topical Membrane Therapy for Chronic Rhinosinusitis 99

propels the mucosal coating out of the cavities in less than twenty minutes. Thus, antibiotics such as penicillins, cephalosporins, or macrolides, which are first-choice systemic treatment options for sinusitis, cannot be considered ideal for topical therapy, due to their rapid clearance(Palmer and Kennedy, 2003). An additional factor influencing the selection of topical agents is their differential metabolic processing locally and systemically. Drugs which are deactivated promptly in plasma, but remain intact in the sinus secretions, are both effective and safe. Mupirocin belongs to this class, and is currently the only FDA-approved medication for intranasal use(Uren et al., 2008). With regard to non-bacterial causes of CRS, fungi are considered a prominent etiologic factor, in up to 90% of cases in several studies(Ponikau et al., 1999). Therefore, antimycotic agents, like amphotericin B and itraconazole, are promising local agents, since their chronic systemic administration

A few delivery methods have been tried for local antimicrobial therapy. Spraying of solutions with the use of atomizers, which is an efficient technique in the case of nasal steroids, has produced the poorest results. Small mucosal surface of initial application, along with the slow mucocliliary clearance which commonly accompanies CRS, possibly result in a limited area of drug deposition(Sykes et al., 1986). In contrast, sinus lavage with antibacterial solutions is more popular, and seems to be more effective as well. Frequent bottle irrigations with 300ml of ceftazidime, an antibiotic not available in oral form, are successful in eradicating Pseudomonas from patients with recalcitrant sinusitis(Leonard and Bolger, 1999). However, their efficacy may not be dependent solely on the proper delivery of the antibiotic, but also on the effects of the lavage itself, that is, the mechanical cleansing, dilution of mucus, and decrease of mucosal edema(Lim et al., 2008). A more advanced irrigation technique, employing endoscopic catheterization of the middle meatus, has achieved the resolution of CRS in the morbid context of cystic fibrosis. Yet, this modification of sinus rinsing requires frequent office visits, and interferes with patient compliance(Moss and King, 1995). Nebulization of antibiotics has emerged as both an effective and convenient delivery method. When the size of aerosolized particles is optimized to less than 5μm, this form of topical antimicrobial therapy is superior even to IV mode of administration. Similar to the case of antibiotic irrigations, an additional, non anti-infectious, beneficial mechanism of the aerosolized stream was postulated. Possibly, nebulization into the sinonasal cavities

promotes anti-inflammatory and anti-edematous effects(Lim et al., 2008).

The findings from studies investigating the efficacy of topical antimicrobial therapy, are quite encouraging. Up to 88% of patients experience significant improvement, good quality of life, and few local side effects (rhinitis), after four weeks of treatment(Vaughan and Carvalho, 2002). This symptomatic relief is concurrent with reversal of the endoscopic findings. Refractory infections by resistant strains of Staphylococcus aureus in particular, respond dramatically to irrigations with mupirocin solution(Uren et al., 2008). On the other hand, topical application of antifungal agents did not produce a distinct therapeutic result in the management of CRS(Weschta et al., 2004). This finding is not in agreement with the hypothesis that fungal infection accounts for the majority of chronic sinusitis. Since fungi are ubiquitous in the environment and the sinus cavities, they seem impossible to be eradicated simply by local administration of antimycotic drugs. In the case of CRS induced by fungi, the pathogenesis entails an immune host reaction against fungal antigens, and as a result,

produces serious adverse effects.

polyp lessens the risk of intra-arterial administration. Possibly, intra-polyp steroid injections do not have a role in the routine treatment of common CRS, but their efficacy could be useful in recalcitrant cases, not responding to oral or instilled corticosteroids(Antunes and Becker, 2010).

The chronic topical therapy with steroids has raised concerns of absorption into the circulation, and their well-known systemic effects: growth inhibition due to hypothalamic suppression, loss of bone density, hypertension, diabetes, and psychosis(Demoly, 2008). From each sprayed dose, 30% of the medication stays within the sinonasal cavities, and undergoes metabolism on the nasal mucosa, whereas the remaining 70% follows the oral route and is subject to hepatic metabolism. Altogether, the absorption into the circulation depends largely on the steroid compound, and ranges from 49%(flunisolide) to less than 0.1%(mometasone). A multitude of clinical studies has investigated the safety profile of intranasal steroids and no significant systemic side-effect was reported, either in adult or pediatric patients. Specifically for the latter, one-year duration of administration did not impede growth(Schenkel et al., 2000). Local adverse effects (dry rhinitis, epistaxis), sometimes causing considerable discomfort, have been documented, though(Giger et al., 2003). Interestingly, even in the case of intranasal injection, there is no clinical or biochemical evidence of adrenal suppression, although raised plasma concentration of the steroid has been noted(Mabry, 1981).

#### **5.3 Antimicrobials**

Unquestionably, microorganisms have a fundamental role in the pathogenesis of CRS, either by maintaining prolonged infectious processes, or by generating toxic allergic reactions. Antibiotics have been persistently used for acute and chronic rhinosinusitis, in oral or intravenous form. The rationale for topical administration derives from the concept of biofilm, which is clearly an "epi-mucosal" phenomenon(Lim et al., 2008). Among the various advantages that the microenvironment of biofilms provides to microorganisms is its poor penetration by systemically administrated antimicrobial agents(Stewart and Costerton, 2001). Moreover, the bacterial species found in biofilms, are no different from those commonly identified with conventional cultures in CRS (Al-Mutairi and Kilty, 2011). Interestingly, the minimal antibiotic concentration for the eradication of microorganisms residing in biofilms, can be as high as 1000 times their Minimal Inhibition Concentration (MIC) in the cultures from the same bacteria(Ceri et al., 1999). Therefore, chronic sinus infections refractory to culture-directed oral antibiotics was considered an indication for an alternative approach, which could overcome resistance by delivering high concentrations of medications in direct contact with the colonized epithelial coating.

The choice of antibiotic should be based on endoscopically-guided culturing of sinus secretions, keeping in mind the multi-pathogen etiology of CRS. When it comes to selection among drugs to which microbes demonstrate equal sensitivity, antibiotics that kill bacteria once they reach a critical concentration (concentration-dependent), like quinolones or aminoglycosides, may exert a more potent bactericidal effect, in comparison with timedependent antibacterial medications. The latter, although effective in lower levels, require prolonged action at the target site. As already mentioned, the constant beating of the cilia

polyp lessens the risk of intra-arterial administration. Possibly, intra-polyp steroid injections do not have a role in the routine treatment of common CRS, but their efficacy could be useful in recalcitrant cases, not responding to oral or instilled corticosteroids(Antunes and

The chronic topical therapy with steroids has raised concerns of absorption into the circulation, and their well-known systemic effects: growth inhibition due to hypothalamic suppression, loss of bone density, hypertension, diabetes, and psychosis(Demoly, 2008). From each sprayed dose, 30% of the medication stays within the sinonasal cavities, and undergoes metabolism on the nasal mucosa, whereas the remaining 70% follows the oral route and is subject to hepatic metabolism. Altogether, the absorption into the circulation depends largely on the steroid compound, and ranges from 49%(flunisolide) to less than 0.1%(mometasone). A multitude of clinical studies has investigated the safety profile of intranasal steroids and no significant systemic side-effect was reported, either in adult or pediatric patients. Specifically for the latter, one-year duration of administration did not impede growth(Schenkel et al., 2000). Local adverse effects (dry rhinitis, epistaxis), sometimes causing considerable discomfort, have been documented, though(Giger et al., 2003). Interestingly, even in the case of intranasal injection, there is no clinical or biochemical evidence of adrenal suppression, although raised plasma concentration of the steroid has

Unquestionably, microorganisms have a fundamental role in the pathogenesis of CRS, either by maintaining prolonged infectious processes, or by generating toxic allergic reactions. Antibiotics have been persistently used for acute and chronic rhinosinusitis, in oral or intravenous form. The rationale for topical administration derives from the concept of biofilm, which is clearly an "epi-mucosal" phenomenon(Lim et al., 2008). Among the various advantages that the microenvironment of biofilms provides to microorganisms is its poor penetration by systemically administrated antimicrobial agents(Stewart and Costerton, 2001). Moreover, the bacterial species found in biofilms, are no different from those commonly identified with conventional cultures in CRS (Al-Mutairi and Kilty, 2011). Interestingly, the minimal antibiotic concentration for the eradication of microorganisms residing in biofilms, can be as high as 1000 times their Minimal Inhibition Concentration (MIC) in the cultures from the same bacteria(Ceri et al., 1999). Therefore, chronic sinus infections refractory to culture-directed oral antibiotics was considered an indication for an alternative approach, which could overcome resistance by delivering high concentrations of

The choice of antibiotic should be based on endoscopically-guided culturing of sinus secretions, keeping in mind the multi-pathogen etiology of CRS. When it comes to selection among drugs to which microbes demonstrate equal sensitivity, antibiotics that kill bacteria once they reach a critical concentration (concentration-dependent), like quinolones or aminoglycosides, may exert a more potent bactericidal effect, in comparison with timedependent antibacterial medications. The latter, although effective in lower levels, require prolonged action at the target site. As already mentioned, the constant beating of the cilia

medications in direct contact with the colonized epithelial coating.

Becker, 2010).

been noted(Mabry, 1981).

**5.3 Antimicrobials** 

propels the mucosal coating out of the cavities in less than twenty minutes. Thus, antibiotics such as penicillins, cephalosporins, or macrolides, which are first-choice systemic treatment options for sinusitis, cannot be considered ideal for topical therapy, due to their rapid clearance(Palmer and Kennedy, 2003). An additional factor influencing the selection of topical agents is their differential metabolic processing locally and systemically. Drugs which are deactivated promptly in plasma, but remain intact in the sinus secretions, are both effective and safe. Mupirocin belongs to this class, and is currently the only FDA-approved medication for intranasal use(Uren et al., 2008). With regard to non-bacterial causes of CRS, fungi are considered a prominent etiologic factor, in up to 90% of cases in several studies(Ponikau et al., 1999). Therefore, antimycotic agents, like amphotericin B and itraconazole, are promising local agents, since their chronic systemic administration produces serious adverse effects.

A few delivery methods have been tried for local antimicrobial therapy. Spraying of solutions with the use of atomizers, which is an efficient technique in the case of nasal steroids, has produced the poorest results. Small mucosal surface of initial application, along with the slow mucocliliary clearance which commonly accompanies CRS, possibly result in a limited area of drug deposition(Sykes et al., 1986). In contrast, sinus lavage with antibacterial solutions is more popular, and seems to be more effective as well. Frequent bottle irrigations with 300ml of ceftazidime, an antibiotic not available in oral form, are successful in eradicating Pseudomonas from patients with recalcitrant sinusitis(Leonard and Bolger, 1999). However, their efficacy may not be dependent solely on the proper delivery of the antibiotic, but also on the effects of the lavage itself, that is, the mechanical cleansing, dilution of mucus, and decrease of mucosal edema(Lim et al., 2008). A more advanced irrigation technique, employing endoscopic catheterization of the middle meatus, has achieved the resolution of CRS in the morbid context of cystic fibrosis. Yet, this modification of sinus rinsing requires frequent office visits, and interferes with patient compliance(Moss and King, 1995). Nebulization of antibiotics has emerged as both an effective and convenient delivery method. When the size of aerosolized particles is optimized to less than 5μm, this form of topical antimicrobial therapy is superior even to IV mode of administration. Similar to the case of antibiotic irrigations, an additional, non anti-infectious, beneficial mechanism of the aerosolized stream was postulated. Possibly, nebulization into the sinonasal cavities promotes anti-inflammatory and anti-edematous effects(Lim et al., 2008).

The findings from studies investigating the efficacy of topical antimicrobial therapy, are quite encouraging. Up to 88% of patients experience significant improvement, good quality of life, and few local side effects (rhinitis), after four weeks of treatment(Vaughan and Carvalho, 2002). This symptomatic relief is concurrent with reversal of the endoscopic findings. Refractory infections by resistant strains of Staphylococcus aureus in particular, respond dramatically to irrigations with mupirocin solution(Uren et al., 2008). On the other hand, topical application of antifungal agents did not produce a distinct therapeutic result in the management of CRS(Weschta et al., 2004). This finding is not in agreement with the hypothesis that fungal infection accounts for the majority of chronic sinusitis. Since fungi are ubiquitous in the environment and the sinus cavities, they seem impossible to be eradicated simply by local administration of antimycotic drugs. In the case of CRS induced by fungi, the pathogenesis entails an immune host reaction against fungal antigens, and as a result,

Topical Membrane Therapy for Chronic Rhinosinusitis 101

additive effect could be accomplished by concurrent use of the two medications(Yoo et al., 1997). Although vasoactive decongestants reverse fast and effectively the mucosal edema, their local complications (rebound congestion, dry rhinitis, epistaxis) preclude their chronic

Antihistamines do not treat rhinosinusitis per se, but they alleviate the mucosal inflammation of allergic rhinitis. Although allergic rhinitis reasonably seems a predisposing factor for CRS, a direct etiologic relationship has not been demonstrated. Nonetheless, the incidence of CRS is higher in patients with allergic rhinitis or atopy. Furthermore, chronic sinusitis in the setting of allergic rhinitis is more resistant either to medical or surgical treatment, than the CRS variant of the non-allergic population(Krouse, 2000). Therefore, antihistamines could be incorporated into the management plan of selected CRS cases. Systemic antihistamines have been traditionally used in allergic rhinitis, with certain central nervous side-effects, such as sedation, poor attention, and impaired school or work

Aiming to achieve maximum therapeutic action, as well as a lower rate of adverse effects, intranasally sprayed antihistamines are now included in the treatment armamentarium. Topical agents (azelastine, olopatadine) have shown indeed superior efficacy and safer profile than oral antihistamines. Moreover, they have the fastest onset of action (15 minutes for azelastine), among all the drugs administered for rhinitis, whether systemically or topically(Horak and Zieglmayer, 2009). Olopatadine, is well tolerated in children without causing somnolence, or compromising school performance(Berger et al., 2009). Interestingly, azelastine, besides blocking H1-receptors, exerts a few anti-inflammatory effects, e.g. mastcell stabilization, inhibition of Tumor Necrosis Factor-alpha, and reduction of proinflammatory cytokines. Thus, it is effective in both allergic and non-allergic rhinitis(Horak

As already mentioned, chronic rhinosinusitis is persistent and symptomatic even after optimal medical or surgical management, in 5-25% of cases. In spite of widely open sinus cavities that are ventilated and drain readily to the nasal cavity, the mucosa is still inflamed and edematous, often with gross polyposis. We suspect that this variant of CRS is a medical disease, and the element of surgical obstruction is not the key pathogenetic factor. The sinus mucosa itself may be inherently predisposed to sustained inflammation, and in that case, it should be the target of pharmacological interventions. Even when these patients receive maximal standard medical treatment, sinus inflammation responds poorly or temporarily,

Consequently, patients undergo multiple surgical procedures, essentially for polyp debulking only, receive high doses of systemic steroids or potent antibiotics, and follow long courses of immunotherapy or desensitization therapy to address the allergic

use(Eccles et al., 2008).

**5.6 Antihistamines** 

performance.

and Zieglmayer, 2009).

and relapses are very common.

**6. Our experience in topical CRS therapy** 

**6.1 The rhinotopic protocol: Why we do it** 

inflammatory modifiers might be more appropriate than any anti-infectious remedy(Lim et al., 2008).

#### **5.4 Mucoactive agents**

As stated previously, biofilms may alter significantly the pathophysiology of CRS and protect the pathogens from systemic or local treatments, thus perpetuating the infection. Not only that, but it is suggested that this bioorganic coating acts as a reservoir of bacteria, and releases microorganisms in the conventional "planktonik" form, into the sinus cavity(Al-Mutairi and Kilty, 2011). Obviously, novel approaches to refractory sinusitis cases, focus on the elimination of this enigmatic entity. Being a distinct structure, analogous to a foreign body, biofilm is an ideal target for topical therapy, as the regional vasculature might not deliver sufficient amounts of systemic medications to the interface between the epithelium and the colonized structure.

Surfactants are ampthipathic compounds, that is, they possess both hydrophilic and lipophilic properties. Consequently, they are soluble both to water and organic substances. The well-known pulmonary surfactant decreases the adhesiveness of sputum to the lung respiratory epithelium, and facilitates the removal of mucus from the lung parenchyma. It is hypothesized that in a similar fashion, intranasally administered surfactants interfere with the adherence of the biofilm layer to the underlying sinus epithelium(Suh et al., 2010). This would result in biofilm peeling off the sinus walls, and the transition of recalcitrant CRS to a less complicated form, amenable to treatment. This scenario has been clinically tested in patients irrigating with baby shampoo, an inexpensive, nontoxic mixture of various surfactants. Almost half of the patients reported a marked improvement in their "mucusrelated" symptoms, i.e. thick nasal discharge and post-nasal drip(Chiu et al., 2008). Secondary effects of surfactants have also been postulated, such as destabilization of bacterial membranes with leaking of electrolytes.

A promising local agent, due to its safety profile and low cost, is honey. In vitro testing documented eradication of Staphylococcus aureus and Pseudomonas aeruginosa in biofilm colonies, after treatment with several types of honey. Notably, honey was effective even against Methicillin Resistant Staphylococcus Aureus (MRSA), which is considered a plague of our time(Alandejani et al., 2009). The exact antimicrobial and mucoactive properties of honey are yet to be discovered.

#### **5.5 Decongestants**

Intranasal decongestants are the most frequently local agents used by sinusitis patients (16%) in the United States, more often even than local steroids. Perhaps the high prevalence of use can be explained by their availability over the counter, as well as the rapid, almost immediate, relief they provide from nasal congestion. Physicians usually prescribe a shortterm course of decongestant sprays only in cases of severe, acute exacerbations of CRS(Sharp et al., 2007). Local decongestants are sympathomimetic agonists, which stimulate alpha-adrenergic receptors on the smooth-muscle fibers of the vessels beneath the nasal respiratory epithelium. As a result, brisk, potent vasoconstriction ensues. Interestingly, local sympathomimetics and steroids produce decongestion via different mechanisms, so that an additive effect could be accomplished by concurrent use of the two medications(Yoo et al., 1997). Although vasoactive decongestants reverse fast and effectively the mucosal edema, their local complications (rebound congestion, dry rhinitis, epistaxis) preclude their chronic use(Eccles et al., 2008).

#### **5.6 Antihistamines**

100 Peculiar Aspects of Rhinosinusitis

inflammatory modifiers might be more appropriate than any anti-infectious remedy(Lim et

As stated previously, biofilms may alter significantly the pathophysiology of CRS and protect the pathogens from systemic or local treatments, thus perpetuating the infection. Not only that, but it is suggested that this bioorganic coating acts as a reservoir of bacteria, and releases microorganisms in the conventional "planktonik" form, into the sinus cavity(Al-Mutairi and Kilty, 2011). Obviously, novel approaches to refractory sinusitis cases, focus on the elimination of this enigmatic entity. Being a distinct structure, analogous to a foreign body, biofilm is an ideal target for topical therapy, as the regional vasculature might not deliver sufficient amounts of systemic medications to the interface between the

Surfactants are ampthipathic compounds, that is, they possess both hydrophilic and lipophilic properties. Consequently, they are soluble both to water and organic substances. The well-known pulmonary surfactant decreases the adhesiveness of sputum to the lung respiratory epithelium, and facilitates the removal of mucus from the lung parenchyma. It is hypothesized that in a similar fashion, intranasally administered surfactants interfere with the adherence of the biofilm layer to the underlying sinus epithelium(Suh et al., 2010). This would result in biofilm peeling off the sinus walls, and the transition of recalcitrant CRS to a less complicated form, amenable to treatment. This scenario has been clinically tested in patients irrigating with baby shampoo, an inexpensive, nontoxic mixture of various surfactants. Almost half of the patients reported a marked improvement in their "mucusrelated" symptoms, i.e. thick nasal discharge and post-nasal drip(Chiu et al., 2008). Secondary effects of surfactants have also been postulated, such as destabilization of

A promising local agent, due to its safety profile and low cost, is honey. In vitro testing documented eradication of Staphylococcus aureus and Pseudomonas aeruginosa in biofilm colonies, after treatment with several types of honey. Notably, honey was effective even against Methicillin Resistant Staphylococcus Aureus (MRSA), which is considered a plague of our time(Alandejani et al., 2009). The exact antimicrobial and mucoactive properties of

Intranasal decongestants are the most frequently local agents used by sinusitis patients (16%) in the United States, more often even than local steroids. Perhaps the high prevalence of use can be explained by their availability over the counter, as well as the rapid, almost immediate, relief they provide from nasal congestion. Physicians usually prescribe a shortterm course of decongestant sprays only in cases of severe, acute exacerbations of CRS(Sharp et al., 2007). Local decongestants are sympathomimetic agonists, which stimulate alpha-adrenergic receptors on the smooth-muscle fibers of the vessels beneath the nasal respiratory epithelium. As a result, brisk, potent vasoconstriction ensues. Interestingly, local sympathomimetics and steroids produce decongestion via different mechanisms, so that an

al., 2008).

**5.4 Mucoactive agents** 

epithelium and the colonized structure.

bacterial membranes with leaking of electrolytes.

honey are yet to be discovered.

**5.5 Decongestants** 

Antihistamines do not treat rhinosinusitis per se, but they alleviate the mucosal inflammation of allergic rhinitis. Although allergic rhinitis reasonably seems a predisposing factor for CRS, a direct etiologic relationship has not been demonstrated. Nonetheless, the incidence of CRS is higher in patients with allergic rhinitis or atopy. Furthermore, chronic sinusitis in the setting of allergic rhinitis is more resistant either to medical or surgical treatment, than the CRS variant of the non-allergic population(Krouse, 2000). Therefore, antihistamines could be incorporated into the management plan of selected CRS cases. Systemic antihistamines have been traditionally used in allergic rhinitis, with certain central nervous side-effects, such as sedation, poor attention, and impaired school or work performance.

Aiming to achieve maximum therapeutic action, as well as a lower rate of adverse effects, intranasally sprayed antihistamines are now included in the treatment armamentarium. Topical agents (azelastine, olopatadine) have shown indeed superior efficacy and safer profile than oral antihistamines. Moreover, they have the fastest onset of action (15 minutes for azelastine), among all the drugs administered for rhinitis, whether systemically or topically(Horak and Zieglmayer, 2009). Olopatadine, is well tolerated in children without causing somnolence, or compromising school performance(Berger et al., 2009). Interestingly, azelastine, besides blocking H1-receptors, exerts a few anti-inflammatory effects, e.g. mastcell stabilization, inhibition of Tumor Necrosis Factor-alpha, and reduction of proinflammatory cytokines. Thus, it is effective in both allergic and non-allergic rhinitis(Horak and Zieglmayer, 2009).

#### **6. Our experience in topical CRS therapy**

#### **6.1 The rhinotopic protocol: Why we do it**

As already mentioned, chronic rhinosinusitis is persistent and symptomatic even after optimal medical or surgical management, in 5-25% of cases. In spite of widely open sinus cavities that are ventilated and drain readily to the nasal cavity, the mucosa is still inflamed and edematous, often with gross polyposis. We suspect that this variant of CRS is a medical disease, and the element of surgical obstruction is not the key pathogenetic factor. The sinus mucosa itself may be inherently predisposed to sustained inflammation, and in that case, it should be the target of pharmacological interventions. Even when these patients receive maximal standard medical treatment, sinus inflammation responds poorly or temporarily, and relapses are very common.

Consequently, patients undergo multiple surgical procedures, essentially for polyp debulking only, receive high doses of systemic steroids or potent antibiotics, and follow long courses of immunotherapy or desensitization therapy to address the allergic

Topical Membrane Therapy for Chronic Rhinosinusitis 103

diseased mucosa is excised for histopathological assessment, as well as identification and

The patients follow a 6-week regimen at home, consisting of saline irrigations twice a day, followed by intranasal aerosolization (Fig. 2) of mometasone and an antibiotic chosen based on the pre-treatment naso-endoscopic guided swab culture. These drugs are FDA approved and already being used clinically both in pill form and liquid (injectable) formulations for

Mometasone is among the most potent intranasally used steroids, in terms of its affinity with the glucocorticoid receptor(Derendorf and Meltzer, 2008). The culture-directed antibiotic is selected among several concentration-dependent agents, with minimal systemic absorption: levofloxacin, tobramycin, mupirocin, and vancomycin. The steroid/antibiotic aerosolized mixture is self-administered using a vibrating mesh nebulizer, which creates an aerosol mist by a rapidly vibrating mesh with hundreds of 4 to 8 μm holes, and allows a fast

In addition, endoscopic nasal toilet, with careful removal of biofilm and crusts from the sinuses, will be performed weekly by the treating rhinologist after the application of numbing spray in the nasal cavity. Following nasal toilet, topical mometasone and culturedirected antibiotic preparations are instilled inside the sinus cavities using a curved suction tip (Fig. 2). The drugs are introduced into the sinuses in a gel form (Fig. 3), which is prepared by a pharmacy, specifically for the needs of the rhinotopic protocol. Three mL of gel are instilled in each side, and distributed evenly in the maxillary sinus cavity, along the opened sphenoid and ethmoid cells, and towards the frontal recess. This drug-containing hydrophilic gel contains the non-ionic ether hydroxyethyl cellulose, which is a mucoadhesive agent. Upon its placement into the paranasal sinuses, it forms a mucoadherent film, resistant to erosion, which remains in contact with the respiratory epithelium. The prolonged attachment of the polymer matrix to the diseased mucosa, facilitates effective drug release onto the pharmacological target, and negates the mucociliary clearance of therapeutic agents(Ugwoke et al., 2005). Patients are advised to refrain from sinus rinsing or drug nebulization for the next 24 hours subsequently to gel

Fig. 2. The NasoNeb™ nebulizer (Left) is used for drug aerosolization in the rhinotopic protocol, and the hydroxyethyl cellulose gel (Right) is instilled through a curved suction tip.

and uniform delivery of small aerosolized medication particles to the sinus walls.

quantification of the supra-epithelial biofilm layer.

the treatment of infections.

placement.

component of rhinosinusitis. Chronic or recurrent severe symptoms, impose a considerable cost burden due to multiple ineffective treatment attempts, but also impair dreadfully the quality of life. The frustration that patients naturally experience, introduces the "psychosinus" component to the natural history of refractory CRS. Typically, patients are fatigued, depressed and express their hopelessness. They confront the rhinologist with their feelings of disappointment and questions about new promising therapies, whereas they soon become non-compliant with the physician's instructions. The emotional distress of CRS sufferers is more debilitating than that of more severe, life-threatening chronic illnesses, such as congestive heart failure and chronic obstructive pulmonary disease(Gliklich and Metson, 1995).

The rhinotopic protocol is a comprehensive form of topical therapy for CRS unresponsive to standard regimens. It focuses on sinus membrane therapy, and aims to provide long-term alleviation of symptoms, with minimal discomfort and adverse effects.

#### **6.2 The rhinotopic protocol: How we do it**

The rhinotopic protocol originated in our rhinology practice, in a teaching community hospital. Moreover, patients follow a thorough treatment regimen at home(Shikani et al., 2010).

#### **6.2.1 Patients**

Inclusion criteria:


Exclusion criteria:


#### **6.2.2 Protocol design**

The rhinotopic protocol is a strictly local form of CRS therapy, and does not involve administration of any systemic medications at any point. Two weeks prior to the beginning of treatment, a swab aerobic & anaerobic culture is taken endoscopically from the middle meatus to determine the dominant microorganism(s). Under local anesthesia, a piece of

component of rhinosinusitis. Chronic or recurrent severe symptoms, impose a considerable cost burden due to multiple ineffective treatment attempts, but also impair dreadfully the quality of life. The frustration that patients naturally experience, introduces the "psychosinus" component to the natural history of refractory CRS. Typically, patients are fatigued, depressed and express their hopelessness. They confront the rhinologist with their feelings of disappointment and questions about new promising therapies, whereas they soon become non-compliant with the physician's instructions. The emotional distress of CRS sufferers is more debilitating than that of more severe, life-threatening chronic illnesses, such as congestive heart failure and chronic obstructive pulmonary disease(Gliklich and

The rhinotopic protocol is a comprehensive form of topical therapy for CRS unresponsive to standard regimens. It focuses on sinus membrane therapy, and aims to provide long-term

The rhinotopic protocol originated in our rhinology practice, in a teaching community hospital. Moreover, patients follow a thorough treatment regimen at home(Shikani et al.,

5. Trial of at least 2 courses of oral antimicrobial treatment without significant

6. Prolonged use of standard local treatments (saline irrigations, intranasal steroid sprays,

The rhinotopic protocol is a strictly local form of CRS therapy, and does not involve administration of any systemic medications at any point. Two weeks prior to the beginning of treatment, a swab aerobic & anaerobic culture is taken endoscopically from the middle meatus to determine the dominant microorganism(s). Under local anesthesia, a piece of

3. Endoscopic and radiologic evidence of sinus mucosal thickening or polyps.

4. Endoscopic and radiologic evidence of patent sinus ostia.

alleviation of symptoms, with minimal discomfort and adverse effects.

**6.2 The rhinotopic protocol: How we do it** 

1. Previous endoscopic sinus surgery. 2. Recurrent or chronic sinusitis symptoms.

intranasal decongestants)

5. Patient currently taking oral corticosteroids. 6. Patient currently taking oral antibiotics.

1. Minor (<18 years of age). 2. Patient above 80 years of age. 3. Pregnant and breastfeeding women. 4. Allergy to specific antibiotics.

Metson, 1995).

2010).

**6.2.1 Patients**  Inclusion criteria:

improvement.

**6.2.2 Protocol design** 

Exclusion criteria:

diseased mucosa is excised for histopathological assessment, as well as identification and quantification of the supra-epithelial biofilm layer.

The patients follow a 6-week regimen at home, consisting of saline irrigations twice a day, followed by intranasal aerosolization (Fig. 2) of mometasone and an antibiotic chosen based on the pre-treatment naso-endoscopic guided swab culture. These drugs are FDA approved and already being used clinically both in pill form and liquid (injectable) formulations for the treatment of infections.

Mometasone is among the most potent intranasally used steroids, in terms of its affinity with the glucocorticoid receptor(Derendorf and Meltzer, 2008). The culture-directed antibiotic is selected among several concentration-dependent agents, with minimal systemic absorption: levofloxacin, tobramycin, mupirocin, and vancomycin. The steroid/antibiotic aerosolized mixture is self-administered using a vibrating mesh nebulizer, which creates an aerosol mist by a rapidly vibrating mesh with hundreds of 4 to 8 μm holes, and allows a fast and uniform delivery of small aerosolized medication particles to the sinus walls.

In addition, endoscopic nasal toilet, with careful removal of biofilm and crusts from the sinuses, will be performed weekly by the treating rhinologist after the application of numbing spray in the nasal cavity. Following nasal toilet, topical mometasone and culturedirected antibiotic preparations are instilled inside the sinus cavities using a curved suction tip (Fig. 2). The drugs are introduced into the sinuses in a gel form (Fig. 3), which is prepared by a pharmacy, specifically for the needs of the rhinotopic protocol. Three mL of gel are instilled in each side, and distributed evenly in the maxillary sinus cavity, along the opened sphenoid and ethmoid cells, and towards the frontal recess. This drug-containing hydrophilic gel contains the non-ionic ether hydroxyethyl cellulose, which is a mucoadhesive agent. Upon its placement into the paranasal sinuses, it forms a mucoadherent film, resistant to erosion, which remains in contact with the respiratory epithelium. The prolonged attachment of the polymer matrix to the diseased mucosa, facilitates effective drug release onto the pharmacological target, and negates the mucociliary clearance of therapeutic agents(Ugwoke et al., 2005). Patients are advised to refrain from sinus rinsing or drug nebulization for the next 24 hours subsequently to gel placement.

Fig. 2. The NasoNeb™ nebulizer (Left) is used for drug aerosolization in the rhinotopic protocol, and the hydroxyethyl cellulose gel (Right) is instilled through a curved suction tip.

Topical Membrane Therapy for Chronic Rhinosinusitis 105

The response to treatment is assessed by pre- and post-therapeutic evaluation of four

Nasal blockage or congestion 0-10 Headache 0-10 Facial Pain 0-10 Hyposmia 0-10 Nasal discharge or post-nasal drip 0-10 Sneezing 0-10 *Total Symptom Score 0-60* 

Table 1. Lund-Kennedy symptom scale: The patient is interviewed with regard to the severity of his symptoms over the past week, and provides a score of 0 (absent symptom) to

**Endoscopic feature Score** 

Edema 0-2 0-2 Polyps 0-2 0-2 Discharge 0-2 0-2 Crusting 0-2 0-2 Adhesions 0-2 0-2 *Total Endoscopic Score 0-20* 

 Histopathological diagnosis and grading of the mucosal inflammation. In detail, characteristics of chronic inflammation (epithelial necrosis, sub-mucosal edema, polypoid degeneration, lymphocyte infiltration) are identified on Hematoxylin & Eosin

Biofilm quantification. A piece of the mucosa specimen is subjected to a colony forming

In order to assess the efficacy of the rhinotopic protocol, we conducted a prospective study with the participation of 20 patients. All subjects suffered from refractory CRS, and fulfilled the inclusion criteria for receiving the rhinotopic therapy. This study tested the hypothesis that direct intra-sinus administration of antibiotics and steroids in a gel & aerosol media, in

units - assay, which provides an estimate of the biofilm's bacterial burden.

Table 2. Lund-Kennedy endoscopic appearance scale: The rhinologist assesses five endoscopic parameters on each side, providing a score of 0, 1, or 2, as follows: Edema, adhesions, and discharge: 0-absent, 1-mild, 2-severe. Polyps: 0-absent, 1-polyps only in middle meatus, 2-polyps extending beyond middle meatus. Discharge: 0-clear, 1-thin

**R L** 

**Symptom Score** 

**6.2.4 Patient monitoring** 

clinicopathological parameters:

10 (maximum possible symptom).

secretions, 2-thick, purulent secretions.

tissue sections.

**6.2.5 Rhinotopic study** 

Swab culture from the middle meatus.

LK symptom (Table 1) and endoscopic scores (Table 2).

Fig. 3. The steroid & antibiotic releasing gel is introduced into the left maxillary and ethmoid cavities with a curved suction.

The duration of the protocol is six weeks, and one month later, the swab culture and the biopsy of the mucosa are repeated, to document the effect of treatment on the bacteriology, pathology, and biofilm formation.

On each patient encounter after treatment beginning (weekly debridement visits, one and two months post treatment), the clinical response to the protocol is monitored (Fig. 4). The evaluation outcome is quantified using the Lund-Kennedy (LK) symptoms score and the endoscopic appearance score(Lund and Kennedy, 1997).

Fig. 4. Graphic of the protocol time-plan (numbers represent days).

#### **6.2.3 Risks**

The most serious possible side effects of the topical treatment protocol may include:


#### **6.2.4 Patient monitoring**

104 Peculiar Aspects of Rhinosinusitis

Fig. 3. The steroid & antibiotic releasing gel is introduced into the left maxillary and ethmoid

The duration of the protocol is six weeks, and one month later, the swab culture and the biopsy of the mucosa are repeated, to document the effect of treatment on the bacteriology,

On each patient encounter after treatment beginning (weekly debridement visits, one and two months post treatment), the clinical response to the protocol is monitored (Fig. 4). The evaluation outcome is quantified using the Lund-Kennedy (LK) symptoms score and the

cavities with a curved suction.

pathology, and biofilm formation.

**6.2.3 Risks** 

(<0.1%).

endoscopic appearance score(Lund and Kennedy, 1997).

Fig. 4. Graphic of the protocol time-plan (numbers represent days).

Early and/or late recurrence of sinus symptoms.

and another medication will be chosen.

The most serious possible side effects of the topical treatment protocol may include:

 Allergic reaction to the antibiotic. If the patient has ever had any unusual or allergic reaction to any of the medications that are to be instilled, then these will be avoided,

 Subjects will be inconvenienced only by the need to undergo pre- and post-treatment biopsies of sinus mucosa. Bleeding, pain and infection may occur as a result of biopsies. Since there is minimal systemic absorption, we do not expect any immunosuppressive effect of the corticosteroids or any adrenal suppression effect. As mentioned previously, mometasone is the intranasally used steroid with the lowest systemic absorption rate The response to treatment is assessed by pre- and post-therapeutic evaluation of four clinicopathological parameters:

LK symptom (Table 1) and endoscopic scores (Table 2).


Table 1. Lund-Kennedy symptom scale: The patient is interviewed with regard to the severity of his symptoms over the past week, and provides a score of 0 (absent symptom) to 10 (maximum possible symptom).


Table 2. Lund-Kennedy endoscopic appearance scale: The rhinologist assesses five endoscopic parameters on each side, providing a score of 0, 1, or 2, as follows: Edema, adhesions, and discharge: 0-absent, 1-mild, 2-severe. Polyps: 0-absent, 1-polyps only in middle meatus, 2-polyps extending beyond middle meatus. Discharge: 0-clear, 1-thin secretions, 2-thick, purulent secretions.


#### **6.2.5 Rhinotopic study**

In order to assess the efficacy of the rhinotopic protocol, we conducted a prospective study with the participation of 20 patients. All subjects suffered from refractory CRS, and fulfilled the inclusion criteria for receiving the rhinotopic therapy. This study tested the hypothesis that direct intra-sinus administration of antibiotics and steroids in a gel & aerosol media, in

Topical Membrane Therapy for Chronic Rhinosinusitis 107

None of the patients reported any systemic or local adverse reactions. Careful endoscopy during the follow-up visits, did not reveal severe irritation, crusting, or signs of recent

Refractory chronic sinusitis is a multifactorial disease, and its chronicity relies on constant debris accumulation, unremitting inflammation, and insidious infection. The optimal management needs to be multifactorial as well, and address all three components concurrently. The rhinotopic protocol is a comprehensive, strictly topical, approach to this difficult-to-treat entity. It is not applied routinely to any CRS case, but it is rather indicated for selected patients, who had previously received high-quality surgical and medical treatment, but continue to experience prolonged symptoms of moderate to severe intensity. Mechanical cleansing by means of frequent high-pressure saline irrigations and weekly office debridements, although simple, ensures the efficacy of the pharmacological interventions. Crusts, mucopurulent secretions, and exudates, are toxic to the underlying epithelium, and perpetuate the inflammation. Meticulous removal of debris is the sine qua non of every topical therapy, in the same way it is essential for the normal healing process

The anti-inflammatory effect of the treatment is achieved by the sustained action of mometasone, one of the most potent commercially available steroids. The steroid is applied locally via a combination of two advanced delivery techniques, i.e., nebulization of small aerosolized particles, and endoscopically-guided instillation of a mucoadhesive gel. Remarkable edema reduction, and down-regulation of the eosinophilic infiltration, are among the proven consequences of systemic steroid use. Even though, this clinical improvement may not be very long-lasting. According to our data, resolution of inflammation-related symptoms, such as congestion, nasal discharge, and facial tenderness,

Antimicrobial agents are administered simultaneously with the steroids, via the same two delivery methods. The role of infection in chronic sinusitis is unclear, and it is common belief that CRS exacerbations are pathophysiologically analogous to acute sinusitis, and should be treated as such. Typically, culture-directed systemic antibiotics may temporarily suppress the infection, but recurrence caused by the same pathogen is frequently noted(Lim et al., 2008). The sustained, highly concentrated application of antimicrobial agents directly onto the diseased membrane, according to the rhinotopic protocol, aims to eradicate the etiologic microorganism from the sinus mucosa. It is suggested that a key factor for the successful elimination of infection is overcoming the resistance of bacteria within the biofilm shelter. The antibiotic-releasing mucoadherent gel is specifically attached to this surfaceorganized community, and places a dense concentration of bactericidal agents at the infection site. Our findings show an impressive decline in the population of viable bacteria residing in biofilms, as assayed by Colony Forming Units cultures, following the rhinotopic therapy. This suggests that one of the mechanisms responsible for the protocol's efficacy is the disruption of biofilms. A contributing factor to the biofilm extirpation, may be the highpressure hydrotherapy performed by the patient alternately with the antibiotic administration. Saline irrigations possibly wash out panktonik bacteria before they become

is still documented one month after the topical protocol's completion.

fixed to sinus walls and recolonize the organic matrix(Suh et al., 2010).

epistaxis.

**6.2.6 The rhinotopic protocol: How it works** 

post-sinus surgery(Palmer and Kennedy, 2003).

addition to frequent sinus cleansing, restores the health of the mucosa, prevents adhesion formation, reduces polyp recurrence, and eradicates sinus pathogens that are otherwise resistant to other types of treatment. We did not use a control group, because every candidate for rhinotopic therapy had been unsuccessfully treated in the past with a standard regimen of oral antibiotics, so that all controls by definition represent treatment failures.

The study population included 12 women (60%) and 8 men (40%), with age range from 13 to 76 years (mean age: 48 years). Four patients (20%) were tested positive in allergy workup (allergen-specific IgE measurement) upon enrolment, and received immunotherapy. Two patients (10%) presented with the Samter's triad of symptoms, and leukotriene inhibitors were prescribed. The most commonly cultured aerobic bacteria were Staphylococcus aureus (8 cases, 40%), and Pseudomonas aeruginosa (6 patients, 30%). Anaerobe growth was not documented. The culture-directed antibiotics that were used in the study included tobramycin in 14 cases (70%), vancomycin and levofloxacin.

Outcome measures of the sudy were the differences between pre- and post-treatment LK symptom/endoscopic scores, swab culture results, histological gravity of chronic inflammation, as well as the bacterial density of the supra-epithelial biofilm. There was a statistically significant improvement between the mean pre- and post-treatment LK symptom and endoscopic appearance scores (student's t-test, P<0.001). All six LK symptoms were individually improved as well. The post-treatment culture results showed no growth in 65% of the cases, normal respiratory flora in 25%, and infection by the original pathogenic organism in 10%. Comparison of histopathological findings in the pre- and post-treatment specimens, revealed a substantial reversal of almost all indices of chronic inflammation (Fig. 5). With regard to the bacterial density of biofilm, the mean number of CFUs/ml has decreased by 98.7%, one month after the completion of the rhinotopic protocol. This sharp drop clearly indicates the elimination of viable microorganisms within the biofilm matrix.

Fig. 5. Histopathological microphotographs of sinus mucosa in CRS. Left: Before the rhinotopic protocol, epithelial attenuation, disruption of epithelia layer, and marked eosinophilic inflammation are evident. Right: Post-treatment, epithelial integrity increases and inflammation resolves.

addition to frequent sinus cleansing, restores the health of the mucosa, prevents adhesion formation, reduces polyp recurrence, and eradicates sinus pathogens that are otherwise resistant to other types of treatment. We did not use a control group, because every candidate for rhinotopic therapy had been unsuccessfully treated in the past with a standard regimen of oral antibiotics, so that all controls by definition represent treatment failures.

The study population included 12 women (60%) and 8 men (40%), with age range from 13 to 76 years (mean age: 48 years). Four patients (20%) were tested positive in allergy workup (allergen-specific IgE measurement) upon enrolment, and received immunotherapy. Two patients (10%) presented with the Samter's triad of symptoms, and leukotriene inhibitors were prescribed. The most commonly cultured aerobic bacteria were Staphylococcus aureus (8 cases, 40%), and Pseudomonas aeruginosa (6 patients, 30%). Anaerobe growth was not documented. The culture-directed antibiotics that were used in the study included

Outcome measures of the sudy were the differences between pre- and post-treatment LK symptom/endoscopic scores, swab culture results, histological gravity of chronic inflammation, as well as the bacterial density of the supra-epithelial biofilm. There was a statistically significant improvement between the mean pre- and post-treatment LK symptom and endoscopic appearance scores (student's t-test, P<0.001). All six LK symptoms were individually improved as well. The post-treatment culture results showed no growth in 65% of the cases, normal respiratory flora in 25%, and infection by the original pathogenic organism in 10%. Comparison of histopathological findings in the pre- and post-treatment specimens, revealed a substantial reversal of almost all indices of chronic inflammation (Fig. 5). With regard to the bacterial density of biofilm, the mean number of CFUs/ml has decreased by 98.7%, one month after the completion of the rhinotopic protocol. This sharp drop clearly indicates the elimination of viable microorganisms within the biofilm matrix.

Fig. 5. Histopathological microphotographs of sinus mucosa in CRS. Left: Before the rhinotopic protocol, epithelial attenuation, disruption of epithelia layer, and marked eosinophilic inflammation are evident. Right: Post-treatment, epithelial integrity increases

and inflammation resolves.

tobramycin in 14 cases (70%), vancomycin and levofloxacin.

None of the patients reported any systemic or local adverse reactions. Careful endoscopy during the follow-up visits, did not reveal severe irritation, crusting, or signs of recent epistaxis.

#### **6.2.6 The rhinotopic protocol: How it works**

Refractory chronic sinusitis is a multifactorial disease, and its chronicity relies on constant debris accumulation, unremitting inflammation, and insidious infection. The optimal management needs to be multifactorial as well, and address all three components concurrently. The rhinotopic protocol is a comprehensive, strictly topical, approach to this difficult-to-treat entity. It is not applied routinely to any CRS case, but it is rather indicated for selected patients, who had previously received high-quality surgical and medical treatment, but continue to experience prolonged symptoms of moderate to severe intensity.

Mechanical cleansing by means of frequent high-pressure saline irrigations and weekly office debridements, although simple, ensures the efficacy of the pharmacological interventions. Crusts, mucopurulent secretions, and exudates, are toxic to the underlying epithelium, and perpetuate the inflammation. Meticulous removal of debris is the sine qua non of every topical therapy, in the same way it is essential for the normal healing process post-sinus surgery(Palmer and Kennedy, 2003).

The anti-inflammatory effect of the treatment is achieved by the sustained action of mometasone, one of the most potent commercially available steroids. The steroid is applied locally via a combination of two advanced delivery techniques, i.e., nebulization of small aerosolized particles, and endoscopically-guided instillation of a mucoadhesive gel. Remarkable edema reduction, and down-regulation of the eosinophilic infiltration, are among the proven consequences of systemic steroid use. Even though, this clinical improvement may not be very long-lasting. According to our data, resolution of inflammation-related symptoms, such as congestion, nasal discharge, and facial tenderness, is still documented one month after the topical protocol's completion.

Antimicrobial agents are administered simultaneously with the steroids, via the same two delivery methods. The role of infection in chronic sinusitis is unclear, and it is common belief that CRS exacerbations are pathophysiologically analogous to acute sinusitis, and should be treated as such. Typically, culture-directed systemic antibiotics may temporarily suppress the infection, but recurrence caused by the same pathogen is frequently noted(Lim et al., 2008). The sustained, highly concentrated application of antimicrobial agents directly onto the diseased membrane, according to the rhinotopic protocol, aims to eradicate the etiologic microorganism from the sinus mucosa. It is suggested that a key factor for the successful elimination of infection is overcoming the resistance of bacteria within the biofilm shelter. The antibiotic-releasing mucoadherent gel is specifically attached to this surfaceorganized community, and places a dense concentration of bactericidal agents at the infection site. Our findings show an impressive decline in the population of viable bacteria residing in biofilms, as assayed by Colony Forming Units cultures, following the rhinotopic therapy. This suggests that one of the mechanisms responsible for the protocol's efficacy is the disruption of biofilms. A contributing factor to the biofilm extirpation, may be the highpressure hydrotherapy performed by the patient alternately with the antibiotic administration. Saline irrigations possibly wash out panktonik bacteria before they become fixed to sinus walls and recolonize the organic matrix(Suh et al., 2010).

Topical Membrane Therapy for Chronic Rhinosinusitis 109

Chiu AG*, et al.* (2008). Baby shampoo nasal irrigations for the symptomatic post-

Daviskas E*, et al.* (1996). Inhalation of hypertonic saline aerosol enhances mucociliary

Daviskas E & Anderson SD. (2006). Hyperosmolar agents and clearance of mucus in the diseased airway. *J Aerosol Med,* Vol. 19, No. 1, pp. 100-109, ISSN 0894-2684 Demoly P. (2008). Safety of intranasal corticosteroids in acute rhinosinusitis. *Am J* 

Derendorf H & Meltzer EO. (2008). Molecular and clinical pharmacology of intranasal

Eccles R, Eriksson M, Garreffa S, & Chen SC. (2008). The nasal decongestant effect of

Giger R*, et al.* (2003). Comparison of once- versus twice-daily use of beclomethasone

Gliklich RE & Metson R. (1995). The health impact of chronic sinusitis in patients seeking

Gliklich RE & Metson R. (1998). Economic implications of chronic sinusitis. *Otolaryngol* 

Goh YH & Goode RL. (2000). Current status of topical nasal antimicrobial agents.

Gosepath J & Mann WJ. (2005). Current concepts in therapy of chronic rhinosinusitis and

Harvey RJ & Schlosser RJ. (2009). Local drug delivery. *Otolaryngol Clin North Am,* Vol. 42,

Horak F & Zieglmayer UP. (2009). Azelastine nasal spray for the treatment of allergic and

Hyo N, Takano H, & Hyo Y. (1989). Particle deposition efficiency of therapeutic aerosols

Karagama YG, Lancaster JL, Karkanevatos A, & O'Sullivan G. (2001). Delivery of nasal

Kennedy DW. (1992). Prognostic factors, outcomes and staging in ethmoid sinus surgery. *Laryngoscope,* Vol. 102, No. 12 Pt 2 Suppl 57, pp. 1-18, ISSN 0023-852X Krouse JH. (2000). Computed tomography stage, allergy testing, and quality of life in

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*Otolaryngol,* Vol. 29, No. 6, pp. 403-413, ISSN 1532-818X

37, ISSN 1050-6586

732, ISSN 0903-1936

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1050-6586

ISSN 0937-4477

ISSN 0194-5998

ISSN 0301-1569

1744-8409

ISSN 0194-5998

No. 5, pp. 829-845, ix, ISSN 1557-8259

No. 4, pp. 226-229, ISSN 0300-0729

functional endoscopic sinus surgery patient. *Am J Rhinol,* Vol. 22, No. 1, pp. 34-

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corticosteroids: clinical and therapeutic implications. *Allergy,* Vol. 63, No. 10, pp.

xylometazoline in the common cold. *Am J Rhinol,* Vol. 22, No. 5, pp. 491-496, ISSN

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#### **7. Conclusion**

Chronic rhinosinusitis is evidently a unique disease process, and far more complex than what we commonly describe as an "infection". CRS refractory to standard treatment is not an exception to the rule, but rather an increasingly occurring phenomenon. In such a chronic illness, the side-effects of systemic medications underlie the necessity of topical therapy. The latter, as this chapter has showed, is not merely restricted to placement of a drug locally, but has been developed with the help of technology into a dynamic approach, tailored to the disease's pathophysiology. Advances in endoscopy and particularly in sinus surgery, have made the paranasal cavities accessible to application of a variety of pharmacological agents.

Our proposal is an integrated topical protocol, for the restoration of the sinus mucosa homeostasis. Preliminary results are promising, and the ultimate goal of this approach is to establish a long-term effect after treatment completion, rather than transient symptom relief. Longer follow-up of patients, and modifications of the protocol guided by ongoing findings, would be the next step.

#### **8. References**


Chronic rhinosinusitis is evidently a unique disease process, and far more complex than what we commonly describe as an "infection". CRS refractory to standard treatment is not an exception to the rule, but rather an increasingly occurring phenomenon. In such a chronic illness, the side-effects of systemic medications underlie the necessity of topical therapy. The latter, as this chapter has showed, is not merely restricted to placement of a drug locally, but has been developed with the help of technology into a dynamic approach, tailored to the disease's pathophysiology. Advances in endoscopy and particularly in sinus surgery, have made the paranasal cavities accessible to application of a variety of pharmacological agents. Our proposal is an integrated topical protocol, for the restoration of the sinus mucosa homeostasis. Preliminary results are promising, and the ultimate goal of this approach is to establish a long-term effect after treatment completion, rather than transient symptom relief. Longer follow-up of patients, and modifications of the protocol guided by ongoing findings,

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### *Edited by Gian Luigi Marseglia and Davide Paolo Caimmi*

Rhinosinusitis has both a great practical interest and a broad significance due to the scientific complexity of the pathogenetic problems related to the disease, not yet completely resolved, and their implications for clinical treatment. This book highlights certain specific topics that usually are not clarified in other resources. The first chapter is devoted to the impoverished quality of life experienced by patients suffering from rhinosinusitis. The second chapter focuses on the microbiological aspects of rhinosinusitis, while the two subsequent chapters explain the peculiar aspects of chronic rhinosinusitis and of recurrent chronic rhinosinusitis. The first chapter of the second section of the book is dedicated to the imaging techniques used to visualize the nasal sinuses and the other to a medical topical type of treatment.

Peculiar Aspects of Rhinosinusitis

Peculiar Aspects of

Rhinosinusitis

*Edited by Gian Luigi Marseglia* 

*and Davide Paolo Caimmi*

Photo by Dr\_Microbe / iStock