current trends, approaches and techniques in ent · dr ben vermaak 8 philosophy, decision-making...

Volume 4 No 1 January 2014Current trends, approaches and techniques in ENT

Current trends, approaches and techniques in ENT

Volume 4 No 1 January 2014

Contents4 A paradigm shift in our

approach to sinusitisDr Ben Vermaak

8 Philosophy, decision-making and outcomes of frontal sinus surgeryDr Yuresh Naidoo

10 Sticky visitors: Biofilms in Chronic RhinosinusitisDr Daniel Cantero and Dr PJ Wormald

13 Local allergic rhinitis -A new phenotype of allergic rhinitisDr Gustav Joyce

If you have any suggestions or topics you would like to see

published or have articles and/or case studies for publishing, please

email us at: [email protected] or

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The views expressed by the authors in this newsletter do not necessarily reflect those of the sponsor, editor or publishers.

Editor: Dr Lance MaronProduction Editors: Ann Lake Publications Ann Lake Helen GonçalvesDesign: Jane Gouveia

Sponsor: Sanofi Enquiries: Ann Lake Publications PO Box 265 Gallo Manor 2052Tel: 011 802 8847Fax: 086 671 9397

Email: [email protected]: www.annlakepublications.co.za

EditorDr Lance Maron

ENTNetcare Parklane Hospital

Johannesburg

3 This newsletter is proudly sponsored by

have been overwhelmed recently by the excess of bad news that has dominated our headlines. Negativity seems to be the order of the day and I have begun to avoid the newspaper. While the articles in this magazine aren’t going to change the world, they are hopefully going to have a significant impact on your daily practices.

With this latest issue of ENT Focus, I hope to bring you a little bit of good news and present some positive developments which may ultimately improve our patients’ quality of life. Sinus pathology has certainly presented us with major challenges in the past and continues to do so today. The battle to eradicate disease is often lost and the surgery has been notorious for its long term failure. Most patients seem to have been told to “learn to live with it”, but it’s time to turn the tide in favour of the physician and the patients.

With new surgical techniques enhanced by modern technology and an advanced understanding of the pathology, pathophysiology and pathogenesis of intractable disease due to relentless research, we are starting to see better results and pleasing patient progress.

This issue covers new developments in the treatment of sinus pathology and offers a glimpse into the latest advances in the understanding of the disease process. I am thrilled to be able to present to you articles by some local and international experts in sinus disease and I thank them most sincerely for their valued input.

Our hope is that they will improve your day-to-day experience in the management of your patients and provide you with better understanding and insight.

I wish you all the best for the new year.

Lance Maron


Dr Ben VermaakENT, Medi House, Wellington Park, Wellington Street, Durbanville, Cape Town

A Paradigm shift in our approach to Sinusitis

octor I have sinus.” How often are we confronted by this history? Try as you may, your patient has come to you with a readymade diagnosis, only to scoff at your attempts at a more in-depth history. Words

have different meaning to different people. The sinus diagnosis made by your patient can mean anything from a headache to a post-nasal drip. The biggest mistake we make is accepting at face value said diagnosis and prescribing yet again an antibiotic.

There are over 30 million documented cases of sinusitis worldwide and this accounts for the most common reason for prescribing antibiotics.1 We have to make a paradigm shift in our thinking.

“Sinusitis is not an entity in itself, but must be considered as an inflammatory disease involving the osteomeatal complex, the nasal cavity, the nasopharynx and the upper and lower respiratory tracts”.2

Josephson, 1994

It is this inflammatory cascade that first and foremost needs our attention when treating sinusitis.

Quality of lifeNumerous studies in the nineties were done to explore the impact of sinusitis on the patient’s quality of life. Symptoms ranging from loss of sleep, tiredness during the day, reduction in concentration, learning ability, reduction in productivity and even increased risk of work accidents were reported.3,4 The seriousness of sinusitis in our patients should not be underestimated.

PhysiologyWhy we have sinuses is a frequent question and the jury is still out. Arguments are made for the sinuses to be humidifiers of the airway, that they lighten the weight of the skull and even that they play a role in our immune response.5 Whatever their function, a sinus cavity needs to ventilate and drain and here the health of the cilia is of utmost importance.

Histologically, sinuses are lined with Pseudostratified Columnar Ciliated Epithelium. They are arranged in columns containing mucus secreting goblet cells and project cilia.6 These cilia are bathed in a sol and gel layer of which the viscosity is partly determined by ion channels.7 Consequently, ensuring balancing ion and water transport becomes important.

Inflammatory mediators not only paralyze the cilia, they also alter the amount and nature of the mucous being formed. Mucous becomes more viscous, the sol phase becomes extremely thin and the gel layer becomes thicker encroaching on the cilia and further aggravating their immobility. Normal secretary draining becomes impaired.8

Mucociliary clearanceSharpey in 1835 was the first to describe ciliary action. The importance of healthy sinus mucosa was, however, only realised when Hilding investigated scar formation and mucuciliary clearance in post-canine sinus surgery. Messerklinger described the sinonasal mucciliary clearance pathway and it was then that the goal of medical and surgical treatment was established;9 restoration of natural sinus physiology, ie, mucociliary clearance.

Volume 4 No 1 January 2014 5

Cilia are complex structures and play a significant role in maintaining a healthy sinus environment clearing pathogens, allergens, debris and toxins. Ciliary dysfunction and the cause thereof should be managed in all sinusitis patients. The inflammatory markers in sinonasal mucusa have been shown to be the most common cause of disruption in normal motility and coordination.8

The common pathophysiological sequelae is ineffective sinonasal mucociliary clearance leading to stasis and subsequent bacterial infection and/or persistent inflammation.

AnatomyBy nature of the sinus draining system, the patency of the osteo meatal complex is of vital importance.11 Any obstruction would lead to reduction in ventilation and drainage, giving rise to recurrent sinus pathology. Assessing this area in your patient with history of recurrent sinusitis becomes paramount. The immediate question then arises, “what can cause such an obstruction?”

Causes of sinus inflammationAllergy Food and inhalants

Anatomical obstruction

Septal deviation, concha Bullosa, scarring of previous surgery

Environmental Inhalation irritants, smoking, day care

Systemic illness Ciliary diskineses, Cystic fibrosis

LPR Laryngo-pharyngeal reflux

Symptom Sinusitis (Bacterial) Allergies Colds (Viral)

Facial pain or pressure Yes Sometimes Sometimes

Duration of illness More than 10-14 days Varies Fewer than 10 days

Nasal discharge Thick, Yellow-green Clear, thin, watery Thick, whitish or thin

Fever Sometimes No Sometimes

Headache Sometimes Sometimes Sometimes

Pain in Upper Teeth Sometimes No No

Bad breath Sometimes No No

Coughing Sometimes Sometimes Yes

Nasal congestion Yes Sometimes Yes

Sneezing No Sometimes Yes


DiagnosisIf we accept the concept of sinusitis primarily being an inflammatory disease, it stands to reason that part of our treatment should be to identify the cause of the inflammation. Bacterial sinusitis is an obvious cause, but not all sinus inflammation is bacterial as can be seen in the table on previous page 5.12 Viral and allergic sinusitis can very easily present with the same symptoms as bacterial.

Prescribing an antibiotic to all patients presenting with sinus symptoms becomes questionable. The EPOS guidelines of when to suspect bacterial infection are well illustrated in the graph on on the right.13

Our tendency to overprescribe antibiotics at the slightest suggestion of inflammatory sinusitis has contributed to the worsening scenario of resistance that has become a worldwide problem. There is a direct relationship between the amount of antibiotic being prescribed and the level of resistance that emerges in a society. The studies of Felmingham et al and Cars et al illustrates this principle quite well.14,15

Our primary objective should be to exclude a bacterial cause for sinusitis. All bacterial sinus infections will cause an inflammatory response in the sinuses, but not all sinus inflammation is bacterial. A patient presenting with a history of recurrent disease should be evaluated for an underlying cause such as undiagnosed allergic rhinitis or obstruction of the osteo meatal complex. In a sense, recurrent sinusitis is a symptom rather than a diagnosis of an underlying problem that has not been diagnosed or has been neglected.

Management

• Intranasal steroidsManagement of the inflammatory process in sinusitis becomes the cornerstone of our treatment. The use of intranasal steroids is strongly advocated. Their mode of action is to make the nasal mucosa an inhospitable site for mast cells. They block the synthesis of both leukotrienes and prostaglandins and prevent influx of neutrophils. The inflammatory cascade is thus altered.

Adapted from Fokkens et al. EP3 OS Guidelines. Rhinol Suppl. 2005;18:1.

0 5 10 15Days

Sym

ptom

s

12Weeks

Colds

Increased symptoms after 5 days

persistent symptoms after 10 days

29

0

20

40

60

80

100

120

France Spain Belgium Italy UK Austria Germany Sweden TheNetherlands

Erythromycin

Penicillin G

Incidence of resistance against AB

Felmingham et al. J Antimicrob Chemother 2002;50(suppl S1):25.

Resi

stan

t iso

late

s (%

tota

l)

28

Outpatient use of AB in Europe

Defined daily dose per

1000 inhabitants per day

40

35

30

25

20

15

10

5

0

Others Macrolides and lincosamides J01FQuinolones J01MTrimethoprim J01EATetracyclines J01ACephalosporins J01DPenicillinase-resistant penicillins J01CFNarrow-spectrum penicillins J01CEBroad-spectrum penicillins J01CA

Cars et al. Lancet. 2001;357:1851.


In studies it has been shown that high dosage, 200ug BD, nasal steroids are superior to Amoxicillin in patients recovery period and symptom score. Symptoms of congestion, rhinorrhoea, sinus headache and facial pain all markedly improved on mono-therapy nasal steroid.16

• Topical nasal decongestantsAs congestion is not only a subjective problem for our patients, it also adds to the obstruction around the osteo-meatal complex. This in turn limits sinus drainage and leads to mucous retention and stasis, making secondary bacterial infection all the more likely. Topical symptomimetic drugs over a short period of time aids in the reduction of nasal congestion and should be used as an adjuvant in any patient being treated for sinusitis.17

• Saline doucheDue to the irritation of the nasal/sinus mucosa, the goblet cells in the pseudostratified columnar ciliated epithelium produce copious amounts of secretions. As has been shown, the sol and gel layer of the epithelial lining is altered with the gel layer encroaching on the cilia with an ever thinning sol layer, thus further impeding the cilia function and secondary stases. Saline douche has been proven to not only clear the excess secretions, but also to aid in the restoring of cilia motility.18

• MucolyticsMucolytic drugs are designed to help loosen and clear the mucus by breaking down the disulfate binding of the nasal/sinus secretions, mucolytics help liquefy the secretions to restore the sol layer of the epithelial cilia.19

• AntibioticsThe routine use of antibiotics in sinusitis should be discouraged. Using antibiotics as monotherapy should be condemned. Evidenced based treatment of sinusitis is advocated. Cultured specimens should be obtained and antibiotic sensitivity evaluated before starting treatment. If empiric treatment with an antibiotic is initiated, guidance for choice of antibiotic should be in keeping with the patient’s community and the latest resistance levels as obtained by the laboratory, keeping

in mind that almost 90 % of all acute sinus infections are caused by Steptoccocus Pneumonia, heamophillus Influenza and Moraxilla Cattarhalis.20

ConclusionSinusitis is a common disease that affects millions of people yearly. It is a disease that affects quality of life and that is often neglected in its diagnosis but more importantly in its treatment. Broadening our thinking of the pathophysiology and understanding the role of inflammation in the presenting symptoms can make our treatment more effective.

The routine use of antibiotics should be discouraged and initial treatment of acute sinusitis should focus on the adjuvant management and treatment protocols.

Bibliography1. Thomas M. File, Jr., MD, MS. Antimicrobial Therapy Guide®2. Josephson JS (ed.) (1994) Sinusitis in. Clinical symposia Vol 46. CIBA, p.463. Simons FE. Allergy Asthma Proc. 1996;17:185-189.4. Marshall PS, Colon EA. Ann Allergy. 1993;71:251-258.5. Neijens HJ (1995) Recurrent sinusitis: the relevance of host defence and its

therapeutic modulation. International journal of Paediatric Otorhinolaryngology 32 (supplement): s32-s35

6. AntunesMB et al. Epithelium, cilia, and mucous: their importance in chronic rhinosinusitis. Immunol Allergy Clin North Am. 2009 Nov;29(4):631-43

7. Van Cauwagenberge P et al. Anatomy and physiology of the nose and the paranasal sinuses. Immunol Allergy clin North Am. 2004 Feb;24(1):1-17

8. Baroody FM. Nasal and Paranasal sinus anatomy and physiology. Clin allergy Immunol 2007; 19:1-21

9. Cohan NA. Sinonasal mucociliary clearance in health and disease. Ann Otol Laryngol Suppl. 2006 Sep;196:20-6

10. Gudis D et al. acquired cilia dysfunction in chronic rhinosinusitis. Am J Rhinol Allergy. 2012 Jan-Feb;26(1):1-6

11. Baraniak JN. Differentiating osteomeatla complex disease and chronic rhinosinusitis from non allergic rhinitis. Clin Allergy Immunol.2007. 19:115-46

12. Rachelefsky GS. National guidelines needed to manage rhinitis and prevent complications. Ann Allergy Asthma Immunol. 1999 Mar;82(3):296-305

13. Wytske Fokkens et. European Position Paper on Rhinosinusitis and Nasal Polyps 2007. al. Rhinology 45; suppl. 20: 1-139

14. Felmingham et al. Incidence in Europe of resistance against AB. J Antimicrob Chemother 2002;50(suppl S1):25.

15. Cars et al. Out patient use of AB in Europe. Lancet. 2001;357:1851. 16. Meltzer et al. NS Monotherapy in Acute Rhino sinusitis J Allergy Clin Immunol.

2005;116:1289 W17. Cochrane Database Syst Rev. 2009;(2):CD001953. Nasal decongestion for the

common cold18. Rabago D, Zgierska A; Saline Nasal Irrigation for Upper Respiratory Conditions;

American Fam Physician; 80(10):1117-1119, 1121-1122; 200919. Baroody FM et al. Mucociliary transport in chronic rhinosinusitis. Clin Allergy

Immunol. 2007;20:103-1920. Rosenfeld RM, Andes D, Bhattacharyya N, Cheung D, Eisenberg S, Ganiats TG, Gelzer

A, Hamilos D, Haydon RC, Hudgins PA, et al: Clinical practice guideline: adult sinusitis. Otolaryngol Head Neck Surg 2007, 137: S1-31.

Summary of treatment guidlinesTreatment ActionIntranasal cortisone• Alone• With Antibiotic

Reduction of inflammation

Oral and topical decongestants

Reduces congestion and improves drainage

Saline lavage Removal of secretions, improves mucosal function

Mucolytics Liquefy phlegm

Antibiotic Control bacterial infection

32

*P≤0.007 vs placebo.†P≤0.040 vs amoxicillin 0.5 g TID.Adapted from Meltzer et al. J Allergy Clin Immunol. 2005;116:1289.

NS Monotherapy in Acute Rhinosinusitis: individual symptom score

Rx (2-15 Days)

-0.8-0.73 -0.71 -0.67

-0.89

-0.77 -0.8 -0.82

-1.08

-0.91-0.81 -0.78

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Cha

nge

in m

ean

AM/P

M s

ympt

oms

Placebo (n=247)Amoxicillin 0.5 g TID (n=249)NS 200 µg BID (n=234)

*†

*†*

Congestion Rhinorrhea Facial painSinus

Headache


Dr Yuresh Naidoo BE (Hons) MBBS FRACSMacquarie and Adelaide UniversityConcord and Auburn Hospitals, Sydney, Australia

Philosophy, decision-making and outcomes of frontal sinus surgery

ndoscopic sinus surgery has been accepted as the treatment of choice for chronic sinusitis refractory to medical treatment. However, surgery of the frontal sinus is perhaps the most technically demanding of all endoscopic sinus surgery. The complex and varied

anatomy, acute nasofrontal angle and proximity to critical structures such as the olfactory fossa, skull base and orbit contribute to the surgical difficulty. These narrow confines, and a penchant for postoperative scarring, make surgical treatment of chronic frontal sinusitis challenging.

Surgical dissection of the frontal recess has in the past been discouraged, even when there is CT scan evidence of mucosal disease in the frontal sinus and frontonasal recess. The concern was that inappropriate mucosal trauma would lead to scarring and obstruction of the frontal sinus ostium, resulting in iatrogenic frontal disease. The risks of such iatrogenic disease are often emphasized in textbooks, even though the incidence of iatrogenic frontal sinus disease is unknown.

For many years, the prevailing paradigm was to treat the osteo-meatal complex and anterior ethmoid sinus (bulla ethmoidalis), with the hope that resolution of disease in this area would improve the mucosa of the frontal sinus and recess.

Many surgeons remain reluctant to operate on the frontal sinus unless there are symptoms of frontal headaches and radiological evidence of opacification of the frontal sinus However, this approach is inconsistent with the way these surgeons approach other sinuses.

Diagnosis of Chronic RhinosinusitisFirstly, let’s review the definition and diagnosis of chronic rhinosinusitis (CRS). CRS with or without nasal polyps in adults is defined as:• inflammation of the nose and the paranasal sinuses

characterised by two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip)

• ± facial pain/pressure• ± reduction or loss of smell for ≥12 weeks

This should be supported by demonstrable disease with either endoscopic signs of:

• nasal polyps, and/or• mucopurulent discharge primarily from middle meatus and/or• oedema/mucosal obstruction primarily in middle meatus

and/or• CT changes: mucosal changes within the ostiomeatal complex

and/or sinuses

Note: facial pain and pressure is NOT a major symptom and is not sinus specific. (In fact, the vast majority of patients that complain of facial pain do not have pain of sinogenic origin.) Yet the prevailing paradigm for the majority of ENT surgeons is not to surgically address the frontal sinus unless the patient has frontal headaches.

Take for example the scan in Figure 1 (left)Most surgeons would recommend ventilating the right maxillary sinus if the patient does not respond appropriately to medical treatment. The decision to offer surgery would not dependent on the patient manifesting symptoms of right malar pain.

Now review Figure 2. This clearly shows a diseased frontal sinus with no other sinuses opacified. In this scenario there is a reluctance to offer surgery UNLESS the patient had symptoms of frontal headache. This is despite the fact that the patient might still suffer from other major symptoms of CRS i.e. nasal obstruction, nasal discharge and hyposmia.

Clearly, this approach to dealing with the sinuses is inconsistent. Furthermore , there is no scientific basis for this approach.

Our philosophy is to treat each sinus without discrimination. If there is objective evidence of disease in a sinus, then it should be addresses surgically if medical therapy is ineffective.

The literature and evolution of endoscopic frontal sinus surgery supports a graduated step-wise approach to tackling disease in the frontal sinus. A wide spectrum of defined endonasal surgical procedures of the frontal sinus has been developed. These are based on the drainage or sinusotomy classification of Draf.

Our philosophy is an all-or-nothing approach to frontal sinus surgery once maximum medical treatment has failed. Limited surgery in the frontal recess places raw surfaces in close proximity to each other, which increases the likelihood of scarring and failure. Draf 2A sinusotomies are performed for primary surgery on the frontal sinus. Failed frontal sinus surgery is treated with a Draf III sinusotomy (otherwise know as endoscopic Modified Lothrop (EMLP) or frontal drillout procedure).

Figure 1. Right maxillary sinusitis

Figure 2. Frontal sinustis with T4 cell. Other sinuses healthy


The excellent results we have achieved justifies this philosophy. Over 85% of patients have long term improvement in their symptoms, with frontal ostium patency rates of over 90%. No patient developed frontal headaches due to the surgery. This was achieved in a cohort of severely diseased sinuses with an average Lund Mackay CT score of over 15. However, there is certainly a group of patients that are still symptomatic after Draf 2A frontal sinusotomies. The risk factors for persistence of symptoms are due to a combination of anatomical, immunological and initial disease load. Patients with polyposis, underlying asthma, narrow frontal sinus ostia and a Lund Mackay score greater than 16 are at an almost 10 times increased risk of failure to control symptoms with a standard Draf 2A frontal sinusotomy. (Figure 3). Fortunately, the majority of these patients do very well with an EMLP.

Inflammatory Load HypothesisSuccessful surgical intervention in diseased sinuses is dependent on total removal of all inflammatory mediators. We call this the “inflammatory load hyptothesis”. There are a number of factors affecting the inflammatory load (Figure 4). Leaving inflammatory mediators behind by not addressing the frontal sinus when it is diseased exposes the patients to persistence of symptoms. When this fails and there is still disease within the frontal sinuses, then the EMLP is employed to achieve this endpoint. The EMLP is more likely to be successful because it facilitates complete removal of inflammatory mediators within the frontal sinus intraoperatively. Standard ESS allows removal of osteitic bone, fungus, eosinophilic mucin, biofilms etc from the maxillary, ethmoid and sphenoid

sinuses. But this is much more difficult in standard Draf 2A frontal sinus surgery due to the narrow frontal ostia which makes instrumentation of all of the frontal sinus nearly impossible.

The EMLP also has important postoperative benefits. The wide opening allows the surgeon to carefully debride the frontal sinus in the immediate postoperative period with causing circumferential trauma with resultant scarring and adhesion formation. It also maximally ventilates the frontal sinus and facilitates long term topical therapy.

SummaryFrontal sinus surgery is the last frontier in endoscopic sinus surgery. It is technically demanding to perform completely and safely. However, it should be treated no differently to other sinuses. A diseased frontal sinus should be treated for optimum symptom improvement. The results of this approach justify this underlying philosophy.

When frontal sinus surgery fails, it is often due to a combination of factors including the underlying immunological status of the patient , disease burden and the presence of very narrow frontal ostia. The narrow opening into the frontal sinus limits intraoperative removal of inflammatory mediators is more likely to narrow and stenose in the postoperative period and limits topical therapy. This group should be counselled regarding the risk of persistence of symptoms and offered the EMLP if standard Draf 2A surgery fails.

TABLE 1. Draf Classification of Endonasal Frontal Sinus Procedures

Type Extent of Surgery Indication

I Anterior ethmoidectomy with drainage of the frontal recess by removal of obstructing disease inferior to the frontal ostium. The frontal ostium itself and any cells protruding into it are not touched.

• History, endoscopy and CT findings suggest chronic frontal sinusitis is due to sinus outflow tract obstruction at the level of the frontal recess

IIA Removal of all ethmoidal cells protruding into the frontal sinus thereby creating an opening between the middle turbinate medially and the lamina papyracea laterally

• Complicated frontal sinusitis or failed Draf I

• Recommended in frontal sinuses with a large anterior–posterior (A–P) diameter (anticipated minimum diameter of frontal neo-ostium 5 mm or more), hypoplastic internal nasal spine (small frontal beak), and a broad ethmoid.

IIB Removal of the frontal sinus floor between the nasal septum mediallyand the lamina papyracea laterally

• Complicated frontal sinusitis in frontal sinuses with a small A–P diameter, hyperplastic internal nasal spine ( ie large frontal beak), or narrow ethmoid

III Bilateral Draf IIB with removal of the upper part of the nasal septum and intersinus septum

• As for Draf IIB • Recommended over type II

sinusotomy for cases with severe polyposis

1728

5062

0

1020

30

4050

6070

CRSwP CRSwP andAsthma

CRSwP,Asthmaand LM >16

CRSwP,Asthma,LM>16 and

FrontalOstium<4mm

Risk of EMLP (%)

RR=1.2

RR=2.4

RR=6.2

RR=9.9

Figure 3. Risk of failing standard Draf 2A frontal sinusotomy and requiring EMLP to control symptoms.

Figure 4. Factors contributing to the overall local inflammatory load


Dr Daniel Cantero and Dr PJ WormaldENT DepartmentUniversity of Adelaide, Australia

Sticky visitors: Biofilms in Chronic Rhinosinusitis

iofilms are complex communities of microrganisms surrounded by an extrapolymeric substance (EPS) that survive adverse environmental conditions being resistant to antibiotics and host defences. Recently, biofilms have been found in the sinus mucosa of

patients suffering from Chronic Rhinosinusitis (CRS) opening a new paradigm to understand the pathophysiology of this prevalent and debilitating condition. In this review, we discuss general concepts related to the biofilm form of life of microorganisms in particular related to CRS, highlighting the current knowledge on the subject and future challenges to prevent and manage biofilm-associated CRS.

IntroductionChronic Rhinosinusitis (CRS) is a common disease affecting around 10% of the population in Western countries. Patients suffering this condition complain of headache, facial pain, nasal obstruction, purulent rhinorrhea and decreased sense of smell. All these symptoms produce a poor quality of life and represent a significant societal burden but despite the clinical and epidemiological relevance of CRS, the pathophysiology of this condition is still unclear.1

The most accepted theory in the pathogenesis of CRS is that extrinsic factors such as bacteria, viruses and fungi can trigger and maintain - in a predisposed host - an unrestrained inflammatory process that is the common factor found in all forms of CRS.

Within the therapeutic options for CRS, antibiotics and steroids are among the most effective alternatives and when these fail, Functional Endoscopic Sinus Surgery (FESS) is the next step to ventilate the Paranasal Cavities (PNC) and remove diseased inflamed tissue such as nasal polyps. The common use of antibiotics and steroids in the treatment of CRS reinforce the fact that bacteria and inflammation are important elements in the pathogenic process of CRS.2

BiofilmsBiofilms are complex communities of microorganisms protected by a slimy extra polymeric substance (EPS) that attach to inert or live surfaces. Biofilms are difficult to eliminate with traditional antibiotic treatments and clinically it is possible to find different types of infections associated with biofilms. For example the vegetations of bacteria located on the heart valves during the course of subacute bacterial endocarditis are today recognized as biofilms. Bacteria from these biofilms can detach and via the blood stream colonize distant sites producing septic emboli in peripheral locations that explain some of the clinical signs of the disease. In hospital environments the infection of catheters, prostheses and in general indwelling medical devices are usually caused by biofilms. An apparent less aggressive example of biofilm is the dental plaque that left it without

control can lead to caries, periodontitis and exfoliation of the teeth.3

Planktonic and biofilm formsBacteria in their free-floating state are called planktonic. Today it is recognised that most of the bacteria found in the environment live as biofilms forms rather than in the planktonic state. However, the initial phase of biofilm formation involves the participation of planktonic cells that create groups to constitute biofilms. At least three important steps during the biofilm cycle are recognized: attachment, growth and dispersal (Figure 1). During the attachment to a biological or nonbiological surface, pioneer planktonic bacteria multiply and express specific factors to facilitate adhesion. The regulation of these factors is controlled through quorum sensing or inter-bacterial signalling after reaching critical numbers of cells. During the second phase of growth or maturation, cell multiplication continues and also the production of the Extra-Cellular Matrix or EPS, a slimy and sticky material that protects the bacteria from phagocytosis and environmental stresses.

Bacterial products but also host components form the EPS; water, DNA, proteins, lipids, polysaccharides, and peptidoglycans are the main components of this peripheral matrix. Inside the biofilms different populations of bacteria co-exist: aerobic, anaerobic, slow growing and dead bacteria interact and share information through quorum sensing. The population of slow growing bacteria - also called persisters - is important because it is not affected by traditional antibiotic treatments and it can re-populate the biofilms when the antibiotics are withdrawn, contributing to recalcitrance and chronicity. After maturation, biofilm fragments can detach

Figure 1. The biofilm cycleBiofilms start when planktonic bacteria attach to biological or nonbiological surfaces. After growth and inter-bacterial communication via quorum sensing a slimy Extra Polymeric Substance (EPS) is formed around the biofilm. When bacteria reach critical populations, the dispersal of biofilm fragments leads to colonization of new niches, starting the biofilm cycle again.


and through dispersion colonize new surfaces re-starting the cycle.4 The whole biofilm cycle from attachment to dispersal can take, according to the species involved, from hours to several days.

Biofilms in CRSThe first description of biofilms in CRS patients was published in 2004.5 Since then, different groups around the globe have focused their efforts to study biofilms on the sinus mucosa and their potential role in the pathogenesis of CRS. Mounting evidence suggests that biofilms are an important etiopathogenic factor in CRS. For this reason, microbiologists have come to consider CRS a Biofilm Associated Infection (BAI).6

One of the difficulties in the clinical assessment of biofilms has been the identification of biofilms in vivo. It is recognized that traditional cultures give low rates of positivity during biofilm infections mainly because biofilms contain different populations of bacteria such as dormant forms that are hard to culture due to the low metabolic and growth rates. In CRS the recovery rate of microorganisms through traditional swabs is highly variable and is also common to have negative cultures. Probably this phenomenon is explained by the presence of biofilms on the mucosal surface.

The electronic microscope has been essential to observe biofilms in the sinus mucosa. Initially using Scanning Electron Microscopy (SEM) but recently it has become clear that the gold standard imaging method to detect biofilms in mucosal samples is Confocal Scanning Laser Microscopy (CSLM) (Figure 2).7 With this technique it was determined that the presence of biofilms in the sinus mucosa of patients undergoing FESS for CRS is around 70%.8

Biofilms in other locations have been found to be usually polymicrobial communities and in CRS was important to study the species within the biofilms. Combining CSLM with a specific staining for species using molecular probes, Fluorescent In Situ Hybridization (FISH) was introduced highlighting the presence of specific bacteria species but also fungi in biofilms. Among the bacteria, S. aureus was one of the most prevalent (Figure 3).

Around half of the CRS samples showed S. aureus as an isolated species forming biofilms or in combination with others species. The presence of S. aureus biofilms was then correlated with severe infection and worse prognosis after surgery.9 In fact, S.

Figure 2. Confocal Scanning Laser Microscopy (CSLM) analysis of sinus tissues using the LIVE/DEAD BacLight bacterial viability kit. This protocol depicts in green live cells and in red dead or damaged cells. The left image shows the normal tissue with predominance of greenstained epithelial cells and absence of biofilm forms. The right image shows bacterial biofilms (thick arrow) in a CRS patient. Groups of live bacteria surrounded by a dark halo probably representing necrotic tissue. Note that satellite formations (planktonic bacteria) shed from the biofilms (thin arrows). CSLM 20X, Zoom=2.

Figure 3. Detection of S. aureus biofilms in the mucosa of a CRS patient (right image) using Fluorescence in situ Hibridization (FISH). Groups of cocci cells are detected using a fluorescent molecular probe for S. aureus (arrows). Biofilms are absent in the control tissue (normal human mucosa, left image). Confocal Scanning Laser Microscope (CSLM) 20X.

Scanning Electron Microscopy (SEM) of S. aureus biofilm grown in vitro over a non-biological surface. Note the coccoid cells and the Extrapolimeric Substance (EPS) around them (by courtesy of Camille Jardeleza, MD). One of the limitations of this image technique in vivo is that biofilms can be confused with dried mucus or can be missed during the fixation process of the sample.


aureus was frequently the culprit of re-infections or exacerbations during the course of CRS particularly during the postoperative period.10

Although highly specific, one of the drawbacks of the FISH technique is that the investigator has to supply the probes of the organisms of interest, probably missing unconsidered species. For this reason, new molecular methods such as Polymerase Chain Reaction (PCR) or DNA sequencing are being developed to detect a broader spectrum - if not all - of the resident microbiome. Recently, using molecular techniques a total of 33 species were identified in CRS and notably S. aureus was the first in the list in terms of relative abundance.11

Other researchers have found that the presence of S. aureus and P. aeruginosa were associated with bad prognosis after surgery, however the presence of other bacteria such as S. epidermidis did not affect the clinical course of the disease. This difference could be explained by the high armamentarium of virulence mechanisms of S. aureus and P. aeruginosa that can produce tissue damage, induce inflammation and at the same time avoid natural defenses and antibiotic treatments.12

Fungi have also been found forming part of biofilms. Previous studies using the sheep model of rhinosinusitis showed that S. aureus facilitates the growth of fungal biofilms.13 Clinically the interrelation between S. aureus and fungi seems to be important in CRS, particularly in eosinophilic cases such as Allergic Fungal Sinusitis.14

Biofilms and inflammation in CRSAlthough incidentally biofilms have been reported in healthy controls in paranasal cavities, evidence suggests that biofilms in the sinuses are present only in pathological cases where there is some degree of mucociliary clearance deficiency such as in CRS. A specific form of CRS with a recognized genetic etiology is cystic fibrosis. These patients produce thick mucus that impairs the mucociliary clearance leading to mucus stagnation and secondary infection of the lungs and paranasal cavities. Biofilms proliferate and are the culprits of acute exacerbations in the lungs (pneumonia) and biofilms probably are also responsible for the chronic damage and inflammation of the airway mucosa. Again the most common bacteria within these biofilms are S. aureus and P. aeruginosa. Many of these patients develop nasal polyps in their PNC as a consequence of the infectious and inflammatory process.15

In the other forms of CRS besides cystic fibrosis, biofilms are also thought to trigger or maintain inflammation in the PNC by other ways than pure infection: S. aureus forming biofilms could secrete toxins such as enterotoxins. Some enterotoxins can act as superantigens producing a nontraditional amplification of the immune response polarizing the adaptive immunity to a Th2 or eosinophilic response.

The association between S. aureus biofilms and the Th2 polarization has been recently confirmed in patients with CRS also suggesting that other biofilm mediators, apart from superantigens, could orchestrate this immune response.16 Considering the high number and diversity of virulence mechanisms from S. aureus such as proteases or toxins, it is logical to think that other factors affect the immune response.

The interrelation between bacteria - or bacterial products - with the mucosa triggering local immune responses is an area of ongoing research that probably will lead to develop more specific treatments to prevent or modulate the inflammatory process and bacterial persistence.17

How to treat biofilms?Dealing with biofilms is difficult because they are intrinsically resistant to traditional antimicrobial treatments and host defences. In the case of indwelling medical devices, the best solution seems to be the prevention of biofilm formation and new materials resistant to bacterial attachment and the use of nanotechnology are strong areas of research in this field. A similar approach is used with antibiotic prophylaxis in endocarditis to prevent biofilm formation in the heart valves of patients at risk of developing this disease. In CRS, unfortunately we still do not have the ideal treatment but the research efforts continue to find an effective solution.

There are a variety of strategies such as to destabilize biofilms targeting the EPS with specific enzymes or directly manipulating the inter-bacterial signals or quorum sensing to favour dispersion. It seems that topical treatments are highly beneficial in biofilm associated CRS: mechanical washings with antibiotic solutions or biocides like Manuka Honey have shown promising results.18,19 In general, anti-biofilm treatments should preserve and restore the delicate mucosa and the mucociliary function without severely altering the local microbiome and avoiding the induction of antimicrobial resistance. A novel approach against S. aureus using a specific bacteriophage is being tested in our laboratory and preliminary data suggest that it is safe and efficacious.

ConclusionCRS is a common disease showing periods of quiescence that alternate with periods of acute exacerbations. Bacterial biofilms particularly S. aureus biofilms play an important role during acute exacerbations and probably on the ongoing inflammatory process observed in CRS patients. Active research is being carried out to strengthen the knowledge of the pathophysiological mechanisms and to develop more targeted treatments to prevent or eradicate biofilms and hopefully modify the clinical course of CRS.

References available on request.

Dealing with biofilms is difficult because

they are intrinsically resistant to traditional

antimicrobial treatments and host

defences


Dr Gustav Joyce MB ChB, MMed (L et O), MSc Sports Medicine, Dip Allergy (SA)Ear, nose and throat surgeonPretoria East Hospital, Pretoria, South Africa

Local allergic rhinitis – a new phenotype of allergic rhinitis

AbstractLocal allergic rhinitis is a new phenotype of rhinitis. The purpose of this review is to discuss the aetiopathophysiology and clinical picture that underlies this form of rhinitis that is typically associated with non-atopic non-allergic rhinitis subjects.

Introductionllergic rhinitis is an IgE-mediated inflammatory response of the nasal mucosa after allergen exposure characterised

by symptoms that include nasal obstruction, rhinorrhoea, itching and sneezing. The diagnosis is based on a thorough history, clinical examination and positive skin-prick testing (SPT) or serum specific IgE (sIgE) antibodies to aero-allergens.

In non-allergic rhinitis (NAR), an allergic cause has been ruled out after negative SPT and the absence of sIgE antibodies to aeroallergens. Many subjects previously diagnosed with NAR, when challenged, developed typical local nasal allergic symptoms, with production of sIgE.1,2 It is hypothesised that allergic T-helper cell type2 (Th2) disease pathways could be present in the nasal mucosa of patients with ‘non-allergic rhinitis’, despite the absence of systemic atopic responses. The term entopy has been proposed to describe this concept of localised allergic responses in the absence of systemic atopy3-5

Local IgE responses in nasal mucosal surfacesHuggins and Borstoff6 in 1975 showed that subjects with clinical histories suggestive of house-dust mite allergy, when challenged nasally with Dermatophagoides pteronyssinus, developed typical nasal symptoms and sIgE in nasal secretions, despite having negative SPT and sIgE (‘local entopy paradigm’). Subsequent studies on patients with idiopathic rhinitis showed that a large proportion of these subjects shared a localised Th2, IgE-mediated cellular immunopathogenesis similar to allergic rhinitis subjects.

Nasal biopsy studies show increased numbers of IgE cells, eosinophils, mast cells and T cells in both idiopathic rhinitis and allergic rhinitis groups when compared to healthy

controls.7-9 Sensi et al.10 proposed that systemic IgE-levels in subjects with allergic rhinitis result from surplus nasal mucosa-produced IgE from B-lymphocytes that enter the systemic circulation.

Diagnosis of local allergic disease in atopic patientsAs sensitised non-atopic patients express the same allergic-type physiological responses to nasal provocation as subjects with allergic rhinitis, the diagnosis is clinical and not difficult to make.

The history includes complaints of intermittent (seasonal) or constant (perennial) nasal itching, sneezing, discharge and blockage of varying degrees. On examination, anterior and posterior rhinoscopy show congested (‘boggy’), blue-grey inferior and middle turbinates with increased vascularity and excessive watery

secretions. In longstanding cases, mucosal disease can be visualised endoscopically in the middle meatus of the nose.

Nasal provocation testing and rhinometry in sensitised non-atopic individuals express identical allergic-type physiological responses to those of allergic rhinitis patients, characterised by nasal itching, sneezing, discharge and blockage with impaired airflow as measured objectively.11,12 Diagnostic measurement of local sIgE and other mediators of tissue inflammation (interleukin-1β (IL-1β), IL-8, tumour necrosis factor (TNF), eosinophil cationic protein (ECP) and tryptase) is reported to be more sensitive than serological detection, provided appropriate sampling methods are followed to avoid false-negative results due to dilutional effects.13

Newer polyurethane foam sampling techniques have been shown to be superior to nasal lavage, as no dilution of inflammatory proteins took place.14 Flow cytometry studies of nasal lavage after allergen challenge in sensitised non-atopic patients showed active involvement of eosinophils and basophils and T- and B-lymphocyte profiling pointed to a localised CD4+ Th2-IgE-mediated cellular immunopathogenesis.1 Immunohistochemical studies by Powe et al15 on patients with idiopathic rhinitis showed increased numbers of mast cells and eosinophils, underscoring the importance of these effector cells in the pathophysiology of non-allergic idiopathic rhinitis.

The term entopy has been proposed to describe

this concept of localised allergic responses in the

absence of systemic atopy


References1. Rondón C, Romero JJ, Lopez S, Antúnez C, et al. Local IgE

production and positive nasal provocation test in patients with persistent nonallergic rhinitis. J Allergy Clin Immunol 2007; 119:899-905.

2. Rondón C, Doña, I, López S, et al. Seasonal idiopathic rhinitis with local inflammatory response and specific IgE in absence of systemic response. Allergy 2008; 63:1352-1358.

3. Powe DG, Bonnin AJ, Jones NS. ‘Entopy’: local allergy paradigm. Clin Exp Allergy 2010;40:987-997.

4. Rondón C, Canto G, Blanca M. Local allergic rhinitis: a new entity, characterization and further studies. Curr Opin Allergy Clin Immunol 2010;10:1-7.

5. Powe DG, Jagger C, Kleinjan A, Carney AS, Jenkins D, Jones NS. ‘Entopy’: localized mucosal allergic disease in the absence of systemic responses for atopy. Clin Exp Allergy 2003;33:1374-1379.

6. Huggins KG, Brostoff J. Local production of specific IgE antibodies in allergic rhinitis patients with negative skin tests. Lancet 1975;2:148-150.

7. Powe DG, Huskisson RS, Carney AS, et al. Mucosal T-cell phenotypes in persistent atopic and nonatopic rhinitis show an association with mast cells. Allergy 2004:59:204-212.

8. Powe DG, Huskisson RS, Carney AS, Jenkins D, Jones NS. Evidence for an inflammatory pathophysiology in idiopathic rhinitis. Clin Exp Allergy 2001;31:864-872.

9. Berger G, Goldberg A, Ophir D. The inferior turbinate mast cell population of patients with perennial allergic and nonallergic rhinitis. Am J Rhinol 1997;11: 63-66.

10. Sensi LG, Piacentini GL, Nobile E, et al. Changes in nasal specific IgE to mites after periods of allergen exposure-avoidance: a comparison with serum levels. Clin Exp Allergy 1994;24:377-382.

11. Carney A, Jones N. Nasal challenge in patients with idiopathic rhinitis: evidence for ‘localised allergy’? Allergologie 1998;11:581.

12. Rondón C, Romero JJ, Lopex S, et al. Positive nasal allergen provocation test and nasal specific-IgE to grass pollen in patients with idiopathic rhinitis. 63rd Annual Meeting of the American Academy of Allergy Asthma and Immunology, San Diego, California, USA, 2007: 1228.

13. Reichelmann H, Deutschle T, Friemel E, Gross H, Bachem M. Biological markers in nasal secretions. Eur Resp J 2003;21:600-605.

14. Lü FX, Esch RE. Novel nasal secretion collection method for the analysis of allergen specific antibodies and inflammatory biomarkers. J Immunol Methods 2010;356:6-17.

15. Powe D, Huskisson R, Carney A, Jenkins D, Jones N. Evidence for an inflammatory pathophysiology in idiopathic rhinitis. Clin Exp Allergy 2001;31:864-872.

16. Rondón C, Doña I, Torres MJ, Campo P, Blanca M. Evolution of patients with nonallergic rhinitis supports conversion to allergic rhinitis. J. Allergy Clin Immunol. 2009;123:1098-1102.

17. Watson N, Bodtke K, Coleman RA, et al. Role of IgE in hyperresponsiveness induced by passive sensitization of human hyperresponsiveness induced by passive sensitizatio airways. Am J Respir Crit Care Med 1997;155:839-844.

Therapeutic management of local allergy in non-atopic patientsLocal treatment of the nose, the target organ, makes common sense. Topical corticosteroids are effective, generally safe and address all of the four main symptoms of allergic rhinitis as well as NAR (congestion, rhinorrhoea, sneezing, post-nasal discharge).16

Antihistamines work in a percentage of NAR patients as they suppress symptoms arising from IgE-dependent as well as IgE-independent mast-cell activation.16 As IgE could be an independent sensitiser of mast cells and basophils, monoclonal anti-IgE antibodies can be of value to address nasal- and resultant bronchial hyperresponsiveness.17

Long-term future prospectsIt is generally accepted that there is a definite relationship between local mucosal IgE-production with expression of allergic disease in atopic subjects. There is, however, no consensus regarding the underlying aetiopathophysiology of local mucosal allergic responses in non-atopic ‘non-allergic’ rhinitis patients and further studies in this regard will have to be done. Rondón et al.16 showed that 24% of patients with NAR underwent de novo sensitisation to aero-allergens as demonstrated by SPT and/or sIgE and concluded that local allergic rhinitis (entopy) may evolve into systemic allergy (atopy).

ConclusionsThe term entopy describes a local mucosal allergic type response in non-atopics and this new entity shares clinical symptoms, nasal production of sIgE and a Th2 nasal inflammatory pattern with classic allergic rhinitis. This entity furthermore supports the idea that localised allergy and atopy can occur independently and that this response could also apply to other mucosal sites, as well as the skin.

Declaration of conflict of interestThe author declares no conflict of interest.

CPD Accreditation

ENTs, Paediatricians and GPs with an interest in ear, nose and throat disorders can acquire CPD points with this newsletter by visiting: www.mycpd.co.za or www.entsociety.co.za and completing an online form of 15 questions. Accreditation is available only for a limited time on the site. Should you have any queries regarding the accreditation, please contact E2 Solutions at: 011 340 9100 or [email protected]

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