The Journal of Otolaryngoiogy, Volume 34, Supplement 1, June 2005

Infectious Adult Rhinosinusitis: Etiology, Diagnosis, and Management Principles

Erin D. Wright, MDCM, MEd, FRCSC, and Saul Frenkiel, MDCM, FRCSC

Abstract

Rhinosinusitis represents a complicated and multifaceted group of diseases that is generally classified into the categories of acute and chronic. Although many instances of acute rhinosinusitis lasting longer than 7 days are thought to be of bacterial origin, most are thought to be inflammatory rather than infectious. The contribution of infectious organisms to the pathogenesis of chronic rhinosinusitis is an area of controversy and active investigation. Examples of these areas of investigation include biofilms, osteitis, and bacterial superantigens. This review discusses the role of infectious organisms in both acute and chronic sinusitis, with special focus on the etiology and diagnosis of these conditions, and includes a discussion of principles of their management.
Sommairc!

Bien qu'habituellement classee en aigue ou chronique, la rhinosinusite represente plutot un spectre de maladies diverses et complexes. On croit souvent que les rhinosinusites qui persistent pour plus de 7 jours sont d'origine bacterienne. Il semblerait que la plupart des rhinosinusites chroniques soient en fait plutot inflammatoires que bacteriennes. La contribution des agents infectieux dans la pathogenese de la rhinosinusite chronique est un sujet tres controverse et tres etudie. Dans ce champ d'etude, on retrouve les recherches sur les biofilms, l'osteite et les superantigenes bacteriens. Cet article a pour but de discuter le role des agents infectieux dans la sinusite aigue et chronique. Une attention plus speciale sera portee a I'etiologie, au diagnostic et aux principes de traitement de ces conditions. Key words: acute rhinosinusitis, chronic rhinosinusitis, rhinosinusitis

hinosinusitis represents a complicated and multifaceted group of diseases, with an infectious etiology representing only one of its distinct entities. In the broadest sense, these infections may be classified into acute (ARS) and chronic (CRS) forms, with infecting organisms playing a different role in each. The predisposing factors and clinical presentations are also different for each type. It is therefore extremely important to properly diagnose each entity and assess the underlying factors to institute the appropriate therapeutic measures. This article focusses on infectious adult rhinosinusitis, including the role that organisms play in both its acute and chronic forms. We assume that the reader will have a fairly sophisticated understanding of sinonasal anatomy and physiology, as well as experience in treating patients with rhinosinusitis.

Statement of Scope and Definitions

Terminology

Erin D. Wright: Department of Otolaryngoiogy, University of Western Ontario, London, ON; Saul Frenkiel: Department of Otolaryngoiogy, McGill University, Montreal, QC. Address reprint requests to: Dr. Erin Wright, London Rhinosinology Centre, St Joseph's Health Care London, 900 Richmond Street, 3rd Floor, London, ON N6A 5B3.

Use of the term "rhinosinusitis" has been almost universally accepted in recent years and is reflective of several observations.^'^ First, sinusitis is often preceded by rhinitis and is rarely seen to occur without concomitant rhinitis. Second, the mucous membranes of the nose and paranasal sinuses are contiguous and histologically similar. Finally, patients suffering from viral infections of the upper respiratory tract (ie, the common cold) have been demonstrated to have involvement of the paranasal sinuses based on computed tomographic (CT) findings. Thus, to be intellectually consistent, "rhinosinusitis" seems to be the most appropriate term for this disease. The definition of rhinosinusitis used for this article is that put forth by the Rhinosinusitis Task Force: "...the condition manifested by an inflammatory response involving the following: the mucous membranes of the nasal cavity and paranasal sinuses, fluids within these cavities, and/or underlying bone."^ These authors also state that the fluids within these cavities are dynamic and are related to dynamic pathologic changes in the bone and soft tissues of the nose and paranasal sinuses.

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For the purposes of this discussion, "infection" is defined as the invasion or multiplication of microorganisms in tissue, which is assumed to include the paranasal sinuses and their contents. This is distinguished from colonization, which implies the mere presence of organisms without invasion or overgrowth. In addition, the term "inflammation" is used and is defined as a series of cellular and molecular responses designed to eliminate foreign agents and promote repair of damaged tissues.^
Classification

Sinusitis has traditionally been classified from a temporal perspective to include acute, subacute, and chronic sinusitis. These definitions are clearly stated in the sections that follow that deal specifically with ARS and CRS. However, recent evolution in our thinking regarding rhinosinusitis has permitted articulation of consensus definitions and clinical trial guidelines.-^ This refinement in classification is based on a consensus of a large group of experts in the field of rhinosinusitis. These conclusions were based on the clinical presentation of disease and on basic science and pathophysiologic evidence and thus can be considered to be partially evidence based. Because of the rather stringent criteria used and the need for consensus, this classification scheme (Table 1) is, of necessity, not exhaustive, and several clinical entities remain that could be added as further subclassifications. It is likely that further research will lead to these entities being added to the current classification scheme. Such possible entities would almost certainly include acetylsalicylic acid-sensitive patients. Additionally, the presence and degree of eosinophilia may one day be distinguishing factors for different types of CRS. As stated above, we acknowledge that rhinosinusitis is of multifactorial pathophysiology, the underlying core of which involves inflammatory processes. We examine the roles of infectious organisms in ARS and CRS. Acute Rhinosinusitis
Etioiogy

ARS is temporally defined as rhinosinusitis lasting up to 4 weeks and is most commonly thought to be infectious in nature. Most readers are aware of evidence that acute viral infection of the upper respiratory tract can result in associated inflammatory changes that will affect the paranasal sinuses, with the maxillary and ethmoid sinuses being most commonly involved.^ In

the first 7 to 14 days in which symptoms of upper respiratory infection and sinusitis are present, viruses are thought to be the predominant etiologie factor. During the initial phase of a viral upper respiratory infection, it is assumed that virions and associated inflammatory mediators enter the sinus cavities or air cells, where they produce further inflammation associated with increased mucus production, which is often more viscous than normal. Viruses most commonly associated with the common cold include human rhinovirus (50%), coronavirus, influenza virus, parainfluenza, and adenovirus, as well as respiratory syncytial virus. When symptoms persist for longer than 7 to 14 days, then bacteria are assumed to be the predominant cause or perpetuating factor, and infection with bacteria can be said to be present. It has been estimated that this complication of viral rhinosinusitis with progression to a secondary bacterial infection occurs only 0.5 to 2% of the time.'' A commonly used definition for the presence of bacterial infection is at least 1000 colony-forming units per millilitre, with the most common offending agents being Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.^ The mechanism for the development of acute bacterial rhinosinusitis has not been definitively ascertained; however, some evidence does exist to shed some light on this process. To begin, certain viruses, such as adenovirus and influenza virus, have been demonstrated to cause significant damage to the nasal epithelium.^ There is evidence that such damage can impair mucosal defenses and permit invasion of bacteria into the paranasal sinus mucosa.^ Epithelial damage by viruses can also disrupt the mucociliary clearance mechanism either by altering or up-regulating mucus production or by directly damaging the cilia. Either of these events could reasonably be expected to impair clearance of bacteria and permit local overgrowth. Additionally, and perhaps most importantly, inflammation associated with viral rhinosinusitis results in edema of the sinonasal mucosa, which can result in obstruction of sinus drainage. This obstruction is thought to be fundamental to the development of sinusitis and likely plays a significant role in acute bacterial rhinosinusitis. This hypothesis is supported by evidence from a rabbit model demonstrating that introduction of pathogenic bacteria into unobstructed sinuses failed to produce sinusitis.'^
Diagnosis

Table 1 Consensus Classification of Rhinosinusitis Acute (presumed bacterial) rhinosinusitis Chronic rhinosinusitis without nasal polyposis Chronic rhinosinusitis with nasal polyposis Classic allergic fungal rhinosinusitis Adapted from Meltzer EO et al.^

In recent years, many attempts have been made to characterize the cardinal symptoms and signs that could facilitate the clinical diagnosis of acute bacterial rhinosinusitis. A reasonable starting point for this discussion would be the American Academy of Otolaryngology-Head and Neck Surgery task force criteria, which were broken down into major and minor symptoms and are presented in Table 2.^ It has been sug-

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gested that two major criteria or one major criterion and two minor criteria are sufficient to make the diagnosis. However, to underline the difficulty in using symptoms alone to predict the presence of acute bacterial rhinosinusitis, we can look to a recent study that used a multivariate model including coloured nasal discharge, facial pain, and radiologically determined maxillary sinus changes. In this study, the model demonstrated only 69% sensitivity and 64% specificity.^ In an effort to improve clinical accuracy in diagnosing ARS, additional clinical criteria have been proposed. The most useful of these is to simply elicit the appropriate clinical history of an upper respiratory infection that has failed to resolve within 10 days or that significantly worsens after 5 to 7 days.' Combined with the criteria outlined previously, this is likely to increase diagnostic accuracy. This temporal relationship to the presence of bacterial infection is supported by consensus articles that unequivocally state that a diagnosis of bacterial sinusitis should be entertained only after the patient's symptoms have been present for at least 7 days.'"''' Finally, another study found three symptoms or signs that were significant independent predictors of ARS based on likelihood ratios.'^ These included maxillary toothache, purulent nasal secretions, and a poor response to decongestants, and the presence of more than one of these criteria increased the likelihood further. In terms of investigations to make the diagnosis of ARS, the gold standard remains antral puncture with culture of infected secretions.'^ This invasive procedure is clearly not indicated in routine situations of ARS in the ambulatory or primary care setting. However, a more detailed physical examination in a decongested nose using fibre-optic endoscopy permits clear visualization of the middle meatus, and direct culture of purulence noted in this region may correlate with culture from maxillary sinus aspirates.''*

Diagnostic imaging can sometimes be a useful adjunct to the clinical impression; however, it is not routinely necessary. Plain sinus radiographs can be helpful in diagnosing ARS when air-fluid levels are present or when the maxillary sinus is opacified'^; however, they are plagued with only moderate sensitivity and specificity compared with antral puncture.'^ Computed tomography is necessary only for the investigation of more complex cases. Given its extreme sensitivity, it would seem to be a useful modality; however, its low specificity for ARS (a high incidence of abnormality in the setting of any upper respiratory inflammation) and its expense make it less useful or practical.
Management Principles

Table 2 Symptoms Associated with the Diagnosis of Rhinosinusitis Major symptoms Purulent anterior nasal discharge Purulent poserior nasal discharge Nasal obstruction Facial congestion Facial pain/pressure Hyposmia/anosmia Fever (acute) Minor symptoms Headache Otalgia/aural fullness Halitosis Dental pain Cough Fever Fatigue

Therapy for ARS is typically thought of in two categories: antimicrobial therapy and adjunctive measures. The decision as to which of these to use is best determined by the clinical condition of the patient and the history of the patient's disease. Several guidelines have been published in recent years addressing this issue of therapy. In view of the previously discussed challenges in diagnosing ARS and the general need to treat the patient without a specific culture and sensitivity, we base our choices for therapy on historical studies and on resistance data from our regional data. Historical data have shown that approximately 70% of acute bacterial rhinosinusitis is associated with two organisms, namely S. pneumoniae and H. influenzae; thus, antimicrobial therapy must account for these organisms. Other organisms to consider covering include M. catarrhalis, Staphylococcus aureus, Streptococcus pyogenes, and anaerobic organisms. A significant concern with regard to the choice of an antimicrobial therapy is the prevalence of resistant organisms. Across the country, the incidence of penicillin-resistant S. pneumoniae is approximately 15% and has remained relatively stable for the last few years."'''^ Of some concern, however, is that penicillinresistant S. pneumoniae often exhibits multidrug resistance across other antimicrobial classes, including fluoroquinolones. Resistance to H. influenzae is less of a concern, although recent estimates have placed the rate of p-lactamase production (ie, resistance to aminopenicillins) at approximately 40%.'^ A discussion of the most effective or appropriate treatment for ARS should logically be preceded by an examination of the need to treat at all. Several factors must be considered in this debate. First, we must be sure as to the diagnosis; more specifically, does the patient have a bacterial infection? If we are able to make the assumption that a patient has a bacterial infection, which we have seen can be challenging, we must then consider whether treating with antimicrobial therapy makes a difference. Although an extensive dis-

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cussion of this issue is beyond the scope of this article, a brief summary of the existing data is worthwhile. Several articles have been published that have demonstrated the effectiveness of antimicrobial therapy versus placebo.^""^^ On the other side of the argument, several placebo-controlled trials have failed to demonstrate a significant benefit for the use of antibiotics to treat ARS.^"*"^^ In summary, although the evidence is somewhat conflicting and there are some methodologic concerns with some of these articles, it is generally recommended in published guidelines to treat accurately diagnosed ARS with antimicrobial therapy.'-^^ When contemplating the choice of antimicrobial agent to treat a given patient's ARS, several published guidelines can be considered. These guidelines address not only the hierarchy of classes of antibiotics but also the duration of therapy. We first examine the most recently published Canadian guidelines for the treatment of acute bacterial sinusitis in adults (Table 3).'^ These guidelines recommend first-line antibiotic therapy for sinusitis symptoms lasting longer than 7 days. The recommended duration of therapy for this initial treatment is 10 days. The argument in favour of first-line therapy in the current age of antibiotic resistance is that the symptoms of most patients will still resolve when treated with these agents.^'^ The Canadian guidelines recommend a reassessment of the response to therapy at 72 to 96 hours after initiation. A failure to respond by this time should lead one to either reconsider the diagnosis or switch to a second-line antibiotic. Patients who are at risk of frontal or sphenoid sinusitis based on their clinical presentation, as well as those who have received antibiotics in the previous 3 months, should also be considered for second-line therapy from the outset. Finally, patients who have an allergy to P-lactam antibiotics will have to be treated with second-line therapy. The most recent US guidelines for the treatment of ARS make an interesting distinction between two patient groups (Table 4).' The first group comprises those who have mild disease and have not received antibiotic ther-

apy in the preceding 4 to 6 weeks. The second group includes those patients who have mild disease who have received antimicrobial therapy in the preceding 4 to 6 weeks, as well as those who have moderate disease severity. These authors state that the main reason to treat with antimicrobial therapy is to improve patient health and reduce exposure to unreasonable or unnecessary morbidity. As with the Canadian guidelines, they recommend reassessment of response to therapy at around 72 hours following initiation of therapy, and the duration of treatment ranges from 10 to 14 days. In terms of the choice of antimicrobial agent, the US guidelines differ slightly in that they do not classify as firstand second-line agents but rather determine therapy based on the previously discussed disease severity. Although not addressed in the most recent US guidelines, the importance of adjunctive measures in the treatment of ARS is well covered in the Canadian guidelines and merits a brief discussion. A commonly used adjunct to antibiotics is an intranasal corticosteroid spray. There is some evidence that the addition of an intranasal steroid to antibiotics in the treatment of ARS improved symptom relief and hastened resolution of the episode.^' Conversely, there are also articles that report only modest improvement with these medications.-^' The authors of the Canadian guidelines also felt that topical intranasal steroids increase the time to recurrence in individuals with a history of recurrent disease. There is no evidence to date to support the use of systemic or topical decongestants, although they have obvious theoretical advantages in the setting of ostial obstruction. Likewise, the use of saline irrigations offers theoretical advantages and is often recommended; however, there is no definite evidence that it is effective. Chronic Rhinosinusitis
Etiology

CRS, as outlined previously, is an exceedingly complex group of disease entities that grows more complex the

Table 3 Canadian Antibiotic Guidelines for Acute Bacterial Rhinosinusitis First-line antibiotics Second-line antibiotics Amoxicillin Macrolides Clarithromycin Oral p-lactams Amoxicillin-clavulanate Cephalosporins Cefixime Cefprozil Cefuroxime Fluoroquinolones Gatifloxacin Levofloxacin Moxifloxacin 500 mg tid 500 mg bid 500 mg tid or 875 mg bid 400 mg od 250-500 mg bid 250-500 mg bid 400 mg od 500 mg od 400 mg od

Adapted from Desrosiers M et al.''

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Table 4 US Guidelines for Antibiotic Therapy for Adults with Acute Bacterial Rhinosinusitis (modified) Mild disease with no recent antibiotic use Amoxicillin-clavulanate Amoxicillin Cefuroxime P-Lactam allergic Trimethoprim-sulfamethoxazole Clarithromycin Telithromycin Mild disease with recent antibiotic therapy or moderate disease Gatifloxacin/levofloxacin/moxifloxacin Amoxicillin-clavulanate Ceftriaxone (i-Lactam allergic Gatilloxacin/levofloxacin/moxifloxacin Clindamycin and rifampin Modified from Anon JB et al.'

Infectious CRS

more that we learn about it. It is becoming apparent that much of CRS is inflammatory in origin and that infection, as defined in this article, plays a role in only a small subset. Nonetheless, there are several instances in which infection may play a significant role, such as in CRS associated with chronic purulence, osteitis, biofilms., and bacterial superantigens. These instances are discussed further here; however, it is worth emphasizing that there is little evidence at this time to support the use of antibiotics in the treatment of most forms of chronic sinus disease and that failure to recognize this will result in their continued use and may contribute to further increasing antibiotic resistance.
Acute Exacerbations

The qualifying statements made above notwithstanding, there are undoubtedly instances in which chronic bacterial infection is an integral part of a patient's chronic inflammatory sinus disease. Whether this entity simply represents chronically infected sinus cavities or repeatedly damaged mucosal linings that have lost their normal state of sterility^" may be moot because it does appear to be a definable entity with well-documented microbiology. Significant differences identified in studies of the microbiology of CRS (compared with ARS) include the relative increase in isolation of coagulasenegative staphylococci, S. aureus, and gram-negative rods, as well as anaerobic organisms.^^"^-' Unfortunately, compared with the well-documented microbiology, the treatment of CRS (purulent) is not easily based on solid evidence. There is little debate that endoscopically guided cultures can be helpful in identifying offending organisms in CRS,^'' and using this information to direct antimicrobial therapy is a commonly accepted practice. The most recent guidelines addressing the issue of therapy selection and duration still recommend 4 to 6 weeks of uninterrupted therapy for CRS.^^ These same authors also report the frequent use of anaerobic coverage (eg, clindamycin) as part of this regimen. In patients who have failed more traditional medical regimens, potentially including CRS associated with chronic purulence, selective irrigation of the sinuses with a solution containing antibiotics and corticosteroids has shown promising potential.^*
Other Roles for Bacteria

A specific entity discussed first is that of acute infectious exacerbation of CRS that is of an underlying inflammatory origin. Such exacerbation can occur in the patient who has undergone surgery and the patient who has never had sinus surgery. The underlying etiology may be obstructive, as in ARS; however, other causes, such as damaged mucociliary function, colonization with a resistant organism, immune deficiencies, and several others that are discussed below, should also be considered. These acute on chronic situations can be managed similarly to ARS; however, important differences should be taken into consideration. The first is the need to address the underlying disease; the second is the need to cover the often different bacterial origin (increased role for S. aureus and gram negatives) and the higher likelihood of bacterial resistance. Acute or chronic exacerbations are likely best managed with an accurate diagnosis, including culture documentation of infection and the guidance of antimicrobial therapy. This practice will help avoid unnecessary use of antibiotics, reduce the selection of resistance, and increase the likelihood of treatment success.

In recent years, several other potential roles for bacteria in the etiology of CRS have been identified. These include bacterial superantigens in patients with CRS with nasal polyposis, biofilms as a source of ongoing inflammation, and osteitis in the paranasal sinuses as a perpetuating factor in chronic mucosal inflammation.
Biofilms

As described elsewhere,^ biofilms are communicating organizations of microorganisms surrounded by a glycocalyx (glycoprotein and lipopolysaccharide) that frequently form on altered or damaged biologic surfaces, such as the paranasal sinus mucosa. Such biofilms have been demonstrated to form in the middle ear,^^ a surface not unlike that of the sinonasal mucosa. Of etiologic significance in the setting of CRS is that organisms living within a biofilm are relatively impervious to host defenses and antimicrobial agents. Despite definitive evidence to demonstrate their role in CRS, the potential role for biofilms in CRS may explain the improvement and subsequent relapse in certain patients receiving antimicrobial therapy despite seemingly negative cultures and imaging. One can therefore understand why some have recommended mechanical

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debridement as the only manner in which to resolve a biofilm and why some patients otherwise refractory to other treatment respond to surgery and irrigation. Biofilms may also explain the success of recently described minimally invasive irrigation techniques for the treatment of CRS.^^ Although some might argue that biofilms are not strictly within the definition of infection used for this article, they do represent pathologic persistence of microorganisms within the contents of the paranasal sinuses that contribute to disease and are thus Included. Finally, more work in this area is clearly indicated and will undoubtedly be forthcoming in the not too distant future.
Osteitis

in nasal polyps.''-^ Furthermore, these IgE levels correlated with eosinophilic infiltration. In view of the above-described pathophysiology of the inflammation in this situation, antimicrobial therapy would not be of value because the role of microorganisms significantly preceded the manifestation of chronic disease. This form of CRS would then be managed by treating the resulting inflammation, just as in the majority of cases of CRS. Conclusion In front-line clinical practice, physicians must constantly be vigilant of the ever-changing gamut of organisms and underlying factors that contribute to the development of rhinosinusitis. There is a need for professional groups and surveillance organizations to monitor resistance patterns and the efficacy of treatments. However, it is most important for the front-line physician to accurately diagnose sinusitis and differentiate the acute and chronic forms. Each of these entities has its own distinctive clinical features, which dictate appropriate principles of management. References
Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Otolaryngol Head Neck Surg 1997;117(3 Pt 2):Sl-7. 2. Meltzer EO, Hamilos DL, Hadley JA, et al. Rhinosinusitis: establishing definitions for clinical research and patient care. Otolaryngol Head Neck Surg 2004;131 Suppl 6:Sl-62. 3. Gwaltney JM Jr, Phillips CD, Miller RD, Riker DK. Computed tomographic study of the common cold. N Engl J Med 1994;330(l):25-30. 4. Gwaltney JM Jr, Wiesinger BA, Patrie JT. Acute communityacquired bacterial sinusitis: the value of antimicrobial treatment and the natural history. Clin Infect Dis 2004;38(2): 227-33. 5. Winther B, Gwaltney JM Jr, Mygind N, Hendley JO. Viralinduced rhinitis. Am J Rhinol 1998;12(l):17-20. 6. Karlsson G, Holmberg K. Does allergic rhinitis predispose to sinusitis? Acta Otolaryngol Suppl 1994;515:26-8; discussion 29. 7. Johansson P, Kumlien J, Soderlund K, Hultman E. Experimental acute sinusitis in rabbits. Energy metabolism in sinus mucosa and secretion. Acta Otolaryngol 1988;106(5-6):460-7. 8. Lacroix JS, Ricchetti A, Lew D, et al. Symptoms and clinical and radiological signs predicting the presence of pathogenic bacteria in acute rhinosinusitis. Acta Otolaryngol 2002; 122(2):192-6. 9. Anon JB, Jacobs MR, Poole MD, et al. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2004;130(l Suppl):1^5. 10. Snow V, Mottur-Pilson C, Hickner JM. Principles of appropriate antibiotic use for acute sinusitis in adults. Ann Intern Med 2001;134(6):495-7. 1.

Perhaps more germane to the discussion of the role of infections in CRS is that of osteitis. Evidence of osteitis indicated by bony thickening and increased density is frequently seen in areas of chronic inflammation on CT scans and has been postulated to play a significant role in ongoing CRS.^* Evidence to further support this etiology is the increased bone remodelling activity seen in patients with CRS compared with controls.^^ There is even some evidence that osteitic inflammation may spread through haversian canals.''" In this same study, experimentally induced chronic maxillary sinusitis was demonstrated to induce osteitis and associated changes in bone metabolism. Over time, osteitic changes have been demonstrated to become fibrotic and essentially permanent and may again explain the relative resistance of certain forms of CRS, even with what would seem to be maximal medical therapy. Again, from a therapeutic perspective, surgical intervention in the form of removal of diseased bony partitions may explain the improvement following endoscopic sinus surgery of otherwise recalcitrant disease.
Bacterial Superantigens

Another novel theory was recently proposed wherein a previous bacterial infection can precipitate immunologic responses that result in chronic inflammatory rhinosinusitis. The theory is that exotoxins produced by certain bacteria and fungi are capable of activating a large population of T cells compared with traditional antigens that activate a specific and small subset of T cells. A superantigen produced by S. aureus has been postulated to play a role in some cases of nasal polyposis (CRS with nasal polyposis). The mechanism for bacterial superantigen stimulation of eosinophilic or T helper type 2 inflammation (as opposed to the neutrophilie infiltrate seen in bacterial sinusitis) is explained by the production of bacteriaspecific immunoglobulin E (IgE) in response to superantigen stimulation.''^ Other authors have uncovered corroborating evidence for this theory in the form of detection of specific IgE to staphyloeoeeal enterotoxins

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11. Hickner JM, Bartlett JG, Besser RE, et al. Principles of appropriate antibiotic use for acute rhinosinusitis in adults: background. Ann Emerg Med 2001;37(6):703-10. 12. Williams JW Jr, Simel DL. Does this patient have sinusitis? Diagnosing acute sinusitis by history and physical examination. JAMA 1993;270(10):1242-6. 13. Evans FO Jr, Sydnor JB, Moore WE, et al. Sinusitis of the maxillary antrum. N Engl J Med 1975;293(15):735-9. 14. Benninger MS, Appelbaum PC, Denneny JC, et al. Maxillary sinus puncture and culture in the diagnosis of acute rhinosinusitis: the case for pursuing alternative culture methods. Otolaryngol Head Neck Surg 2002;127(l):7-12. 15. Desrosiers M, Erenkiel S, Hamid QA, et al. Acute bacterial sinusitis in adults: management in the primary care setting. J Otolaryngol 2002;31 Suppl 2:2S2-14. 16. Axelsson A, Grebelius N, Chidekel N, Jensen C. The correlation between the radiological examination and the irrigation findings in maxillary sinusitis. Acta Otolaryngol 1970; 69(4):302-6. 17. Zhanel GG, Karlowsky JA, Palatnick L, et al. Prevalence of antin'iicrobial resistance in respiratory tract isolates of Streptococcus pneumoniae: results of a Canadian national surveillance study. The Canadian Respiratory Infection Study Group. Antimicrob Agents Chemother 1999;43(10):2504-9. 18. NETyVORK Canadian Bacterial Surveillance Network. BS. Penicillin resistant S. PneumoniaeCanada Isolates 1993-2003. In; April 2004. 19. Chen DK, McGeer A, de Azavedo JC, Low DE. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. Canadian Bacterial Surveillance Network. N Engl J Med 1999;341(4):233-9. 20. Axelsison A, Chidekel N, Grebelius N, Jensen C. Treatment of acute maxillary sinusitis. A comparison of four different methods. Acta Otolaryngol 1970;70(l):71-6. 21. Wald ER, Chiponis D, Ledesma-Medina J. Comparative effectiveness of amoxicillin and amojcicillin-clavulanate potassium in acute paranasal sinus infections in children: a double-blind, placebo-controlled trial. Pediatrics 1986;77(6):795-800. 22. Lindbaek M, Hjortdahl P, Johnsen UL. Randomised, double blind, placebo controlled trial of penicillin V and amoxycillin in treatment of acute sinus infections in adults. BMJ 1996;313(7053):325-9. 23. Hansen JG, Schmidt H, Grinsted P. Randomised, double blind, placebo controlled trial of penicillin V in the treatment of acute maxillary sinusitis in adults in general practice. Scand J Prim Health Care 2000;18(l):44-7. 24. Stalman W, van Essen GA, van der Graaf Y, de Melker RA. The end of antibiotic treatment in adults with acute sinusitis-like complaints in general practice? A placebo-controlled double-blind randomized doxycycline trial. Br J Gen Pract 1997;47(425):794-9. 25. Garbutt JM, Goldstein M, Gellman E, et al. A randomized, placebo-controlled trial of antimicrobial treatment for children with clinically diagnosed acute sinusitis. Pediatrics 2001;107(4):619-25.

26. van Buchem FL, Knottnerus JA, Schrijnemaekers VJ, Peeters MF. Primary-care-based randomised placebo-controlled trial of antibiotic treatment in acute maxillary sinusitis. Lancet 1997;349(9053):683-7. 27. Piccirillo JF, Mager DE, Frisse ME, Brophy RH, Goggin A. Impact of first-line vs second-line antibiotics for the treatment of acute uncomplicated sinusitis. JAMA 2001;286(15): 1849-56. 28. Meltzer EO, Charous BL, Busse WW, et al. Added relief in the treatment of acute recurrent sinusitis with adjunctive mometasone furoate nasal spray. The Nasonex Sinusitis Group. J Allergy Clin Immunol 2000;106(4):630-7. 29. Meltzer EO, Orgel HA, Backhaus JW, et al. Intranasal flunisolide spray as an adjunct to oral antibiotic therapy for sinusitis. J Allergy Clin Immunol 1993;92(6):812-23. 30. Van Cauwenberge PB, Ingels KJ, Bachert C, Wang DY. Microbiology of chronic sinusitis. Acta Otorhinolaryngol Belg 1997;51(4):239^6. 31. Finegold SM, Flynn MJ, Rose FV, et al. Bacteriologic findings associated with chronic bacterial maxillary sinusitis in adults. Clin Infect Dis 2002;35{4):428-33. 32. Jiang RS, Lin JF, Hsu CY. Correlation between bacteriology of the middle meatus and ethmoid sinus in chronic sinusitis. J Laryngol Otol 2002;116(6):443-6. 33. Biel MA, Brown CA, Levinson RM, et al. Evaluation of the microbiology of chronic maxillary sinusitis. Ann Otol Rhinol Laryngol 1998;107(ll Pt l):942-5. 34. Nadel DM, Lanza DC, Kennedy DW. Endoscopically guided cultures in chronic sinusitis. Am J Rhinol 1998;12(4): 233-41. 35. Benninger MS, Anon J, Mabry RL. The medical management of rhinosinusitis. Otolaryngol Head Neck Surg 1997; 117(3 Pt2):S41-9. 36. Lavigne F, Tulic MK, Gagnon J, Hamid Q. Selective irrigation of the sinuses in the management of chronic rhinosinusitis refractory to medical therapy: a promising start. J Otolaryngol 2004;33(l):10-6. 37. Post JC. Direct evidence of bacterial biofilms in otitis media. Laryngoscope 2001;lll(12):2083-94. 38. Khalid AN, Hunt J, Perloff JR, Kennedy DW. The role of bone in chronic rhinosinusitis. Laryngoscope 2002;112(ll): 1951-7. 39. Kennedy DW, Senior BA, Gannon FH, et al. Histology and histomorphometry of ethmoid bone in chronic rhinosinusitis. Laryngoscope 1998;108(4 Pt l):502-7. 40. Perloff JR, Gannon FH, Bolger WE, et al. Bone involvement in sinusitis: an apparent pathway for the spread of disease. Laryngoscope 2000;110(12):2095-9. 41. Calenoff E, McMahan JT, Herzon GD, et al. Bacterial allergy in nasal polyposis. A new method for quantifying specific IgE. Arch Otolaryngol Head Neck Surg 1993;119{8): 830-6. 42. Bachert C, Gevaert P, Holtappels G, et al. Total and specific IgE in nasal polyps is related to local eosinophilic inflammation. J Allergy Clin Immunol 2001;107(4):607-14.