(PDF) Sinusitis: Bench to bedside

CLINICAL IMMUNOLOGY VOLUME 99 Sinusitis: Bench to Bedside Current Findings, Future Directions Michael A. Kaliner, MD, a J. Jack Anon, MD, d John Georgitis, Robert Naclerio, MD,g and David Washington, D.C., Charleston, Pittsburgh and Philadelphia, Pa. Sinusitis, an inflammatory disease of the sinus, of the most commonly reported diseases in the United States, affecting an estimated 14% of the population. The prevalence of sinusitis is rising. Between 1990 and 1992, persons with sinusitis reported approximately 73 million restricted activity days--an increase from the 50 million restricted activity days reported between 1986 and 1988. Because critical questions remain unan- swered about its cause, pathophysiology, and optimal treatment, sinusitis continues to generate health care costs and affects the quality of large segment of the U.S. population. To identify cal directions for research on sinus disease, the American Academy of Allergy, Asthma and Immunology and the American Academy of Otolaryngology-Head and Neck Surgery Foundation, Inc., convened a meeting in January 1996 in collaboration with the National Institutes of Allergy and Infectious Disease. ment summarizes the proceedings of that meeting and presents what is intended to be the background for future investigation of the many unanswered related to sinusitis. (J Allergy Clin Immunol $829-48.) Key words: Sinusitis, allergy, otolaryngology, sinus surgery, public health-sinusitis From the aInstitutefor Asthma and Allergy at Center, bMedical University of South Carolina, Pittsburgh Children's Hospital, auniversity of Medicine, eBowman Gray School of Medicine, fAmerican Academy of Allergy, Asthma and Immunology, gUniversity of Chicago, and hUniversityof Pennsylvania. *See page $848 for a list of others who contributed and review of this supplement. Reprint requests: Michael A. Kaliner, MD, AAAAI, 611 East Wells Street, Milwaukee, WI 53202. Copyright © 1997 by the Mosby-Year Book, Inc. 0091-6749/97/$5.00 + 0 1/0/82059 S830 K a l i n e r et al. causes sinusitis is frequently associated with inflam- marion of the nasal passages, the term rhinosinusitis might more precisely define this disease state. Several considerations support this contention. Rhinitis typi- cally precedes sinusitis, and sinusitis without rhinitis is rare. The mucosa of the nasal and sinus tissues are contiguous, and the symptoms of nasal obstruction and nasal discharge are prominent in sinusitis. In cer- tain clinical situations, either rhinitis (i.e., allergic rhinitis) or sinusitis (e.g., acute frontal sinusitis) may occur alone, but many cases feature some involve- ment of the contiguous secondary site. A study by Gwaltney et al. 1 used CT to document radiographic changes in the sinuses of otherwise healthy patients with an uncomplicated presumed viral upper respira- tory infection ("common cold") of brief duration. The study found radiographic evidence of sinusitis in 95% of subjects, supporting the use of the term rhi- nosinusitis. 1 Thus rhinosinusitis may be a more appropriate term than either rhinitis or sinusitis alone. Sinusitis is often classified chronologically as an acute, recurrent acute, subacute, or chronic (persistent) disease process. At this time acute sinusitis is defined as the symptom complex accompanying inflammation of the sinuses present for less than 8 weeks in adults and less than 12 weeks in children. The clinical pre- sentation of acute bacterial sinusitis often follows a viral upper respiratory infection (URI), and persis- tence of the URI for more than 7 to 10 days usually indicates the development of sinusitis. A subset of patients---often those with a history of previous sinus infecrions--have a more abrupt onset of sinus-related symptoms with or without an associated URI. With appropriate therapy, the signs and symptoms of acute sinusitis usually resolve completely. Subacute sinusitis is the manifestation of persistent minimal to moderate signs and symptoms of sinus inflammation, sometimes lasting for long periods of time. Chronic sinusitis is frequently defined as signs and symptoms of inflammation of the sinuses persisting more than 8 to 12 weeks. A recent conference 2 defined chronic sinusitis as persistent inflammation documented with imaging techniques at least 4 weeks after initiating appropriate medical therapy in the absence of an intervening acute episode. In contrast to acute sinusitis, the role of bacterial infection in suba- cute and chronic sinusitis is less certain. PUBLIC HEALTH IMPACT A number of national data sets shed light on the great expense and increasing health care burden that sinusitis places on the U.S. population. For example, J ALLERGY CLIN IMMUNOL VOLUME 99, NUMBER 6, PART 3 TABLE I. Costs of sinusitis People with sinusitis Sinus surgeries, 1994 Restricted activity days per year, 1986-88 Restricted activity days per year, 1990-92 1993 U.S. hospital discharges, acute sinusitis* 1993 U.S. hospital discharges, chronic sinusitis* 1991 physician office visits for sinusitis 1985 antibiotic prescriptions for sinusitis 1992 antibiotic prescriptions for sinusitis 1992 direct medical costs of sinusitis *Does not include admissionsfor inpatient or tDoes not include cost of surgery. tis as one of the most expensive disorders experienced by the U.S. population. Sinusitis and quality of life A precise definition of health-related quality of life (HRQL) remains elusive, but HRQL generally refers to how patients feel and are able to function in their day- to-day lives as a result of their illness. Improvements in survey methodology increasingly provide valid and reliable tools to obtain this information. 7 Two types of instruments, a generic health assess- ment and a disease-specific assessment, are generally combined to effectively measure HRQL. The generic or general health assessment provides a global view of the patient's well-being, but generic HRQL mea- sures may not be sensitive enough to detect small but clinically important changes that occur as the result of intervention. 8,9 Disease-specific instruments focus on impairments important to patients with a given condi- tion. In general, they provide more sensitivity than generic instruments, as has been demonstrated in chronic sinusitis. 10 By combining the generic and dis- ease-specific health assessments, one can avoid the disadvantage of each and portray a more complete pictm'e of illness. One of the most widely tested and currently used instruments for general health assessment is the SF- 36 (Medical Outcomes Study, Short-form, 36-item Health Survey). ~° This instrument, which is used to measure HRQL in select populations, has shown that patients with chronic sinusitis (compared with age- adjusted normative data) experienced significant decrements in domains such as physical role func- tioning, bodily pain, general health, vitality, and social functioning. Chronic sinusitis elicited HRQL measures similar to other severe chronic illnesses studied with the SF-36, including chronic obstructive pulmonary disease, congestive heart failure, and angi- na pectoris. $832 K a l i n e r et al. ine the prevalence of these normal structures in both healthy and diseased patient populations. Concha bul- losas may be found in 20% of normal subjects but are more frequent in patients with chronic or recurrent sinusitis. The anatomic development of the paranasal sinus- es may be divided into prenatal development and the postnatal aeration of the sinuses that results in the "mature" anatomy. We know little about the role of potential cellular growth factors in the development of the ethmoid air cells within the fetal frontal recess, suprabullar recess, and ethmoid infundibnlum. Data on these growth factors would help us better under- stand situations such as the various permutations of drainage of the frontal sinus into the frontal recess and subsequently into the ethmoid infundibulum. Epithelial function and host response Alterations in epithelial function may play an important role in the pathogenesis of sinusitis. Not only is epithelial hyperplasia a common feature of chronic sinusitis, but altered production of epithelial cell products could play a role in 9ellu!~ .inflamma- tion. Epithelial cells are capable of producing a range of cytokines, such as IL-8, IL-6, IL-11, RANTES, MCP-1, and granulocyte-macr0phage colony-stimu- lating factor (GM-CSF). Altered production of such cytokines could affect the recruitment, survival, and activation state of inflammatory leukocytes. Moreover, altered production of nitric oxide by the epithelium could be important in changing the antibacterial protection of the sinuses. Infection of epithelial cells with common respirato- ry viruses such as rhinoviruses, respiratory syncytial virus, and influenza can induce the production of sev- ern cytokines. 15-17 Studies with rhinovirus show that this response does not depend on any overt cytotoxic actions of the virus. Production of IL-8 could recruit neutrophils and some types of T-lymphocytes into the sinus mucosa, whereas RANTES is chemotactic for eosinophils. Eosinophil survival in the sinus mucosa would be supported by increased production of GM- CSF, which also primes these cells for enhanced responses to activating stimuli. Once activated, eosinophil products can alter epithelial ion transport processes and induce ciliostasis. On the basis of these observations, it is attractive to hypothesize that inflammation influenced by changes in epithelial function could in some manner facilitate bacterial colonization. This process could be influ- enced by production of nitric oxide, which is generat- ed in large quantities by the nasal epithelium. Several bacterial products can also affect both epithelial func- tion and cytokine production and could further extend the cycle of inflammation. Eventually this inflamma- J ALLERGY CLIN IMMUNOL VOLUME 99, NUMBER 6, PART 3 polyps, combined with eosinophilia, mimic the late phase of allergic inflammation in the nasal mucosa. 3° Recent work shows the presence of CD4 + lympho- cytes, mainly in polyps, in the mucosa of patients with recurrent sinusitis. 31,32 However, studies of polyps from nonallergic subjects have shown that the number of CD3 + T lymphocytes and the number of IL-4 or IL-5 mRNA + cells are not increased. 28,29 Because eosinophilia is a prominent feature of both allergic and nonallergic nasal polyposis, these data suggest that a nonallergic mechanism exists for eosinophilia in chronic sinusitis. It is important to investigate the inflammatory mechanisms that drive chronic sinusitis. Better meth- ods are needed to dissect the pathologic process of chronic inflammation to understand the critical cellu- lar elements, cytokines, and mediators involved. This task can be approached by direct examinations of pathologic specimens. In addition, specific cellular mechanisms, cytokines, or mediators can be exam- ined in response to pharmacologic intervention aimed at abrogating selected elements in the inflammatory cascade. Immunopathologic studies should carefully control for confounding effects of medication use. Consideration should be given to performing micro- biologic studies in conjunction with these investiga- tions, because superimposed infection is potentially critical to the appearance of the inflammatory process. There are limitations to the information that can be derived from studies of chronically inflamed tissues. However, potential inciting agents such as viral or other microbial pathogens can be examined. In addi- tion, the need exists to develop models of disease pathogenesis (or recurrence) that incorporate an ini- tial attempt to revert the sinus mucosa toward nor- reality. Various strategies could be used, including surgery, treatment with antibiotics, elimination of allergic factors, treatment with topical or systemic cort!costeroids, other pharmacologic approaches, or a combination of these strategies. The sinus mucosa is then more suitable to study in response to various types of exogenous stimuli. Research is needed to identify factors that initiate or perpetuate chronic sinusitis, including the charac- teristic eosinophilic inflammatory infiltrate. These factors include bacterial, viral, or fungal organisms or microbial products. Genetic factors Although chronic sinus disease has been observed in multiple family members, the roles of genetic fac- tors in sinusitis remain unclear. Two well-defined genetic disorders, cystic fibrosis (CF) and primary cilia dyskinesia (Kartagener's syndrome), are associ- $834 K a l i n e r et al. ly exhaled air: It appears that only small amounts of NO are released from the nasal mucosa. Therefore, a rough estimation of sinus NO production and the pas- sage of this gas into the nasal cavity may be per- formed noninvasively by analyzing NO levels in nasally derived air. In children with chronic sinus dis- ease resulting from primary ciliary dyskinesia or CF, nasal NO levels are markedly reduced compared with those of age-matched healthy controls. It has been suggested that this simple test could prove useful in the early diagnosis of these chronic airway disor- ders. 36 We do not know whether the low nasal NO levels in patients with CF or primary ciliary dyskine- sia reftect a genuine reduction in mucosal NO pro- duction or a reduced passage of NO from the sinuses to the nasal cavity. Inhaled high-dose exogenous NO has been used to treat pulmonary hypertension7 This vasodilator gas selectively dilates vessels that supply well-ventilated areas of the lung, resulting in increased arterial oxy- genation and reduced pulmonary artery pressure. Interestingly, NO derived from the sinus bathes the lower airways and the lungs during normal respira- tion. Results of a recent study indicate that inhalation of endogenous NO may also have biologic effects in the lungs. 38 In patients who are intubated and who are deprived of endogenous NO inhalation, arterial oxy- genation increases acutely if nasal air containing NO is aspirated from the patient's nose and added to the inspiratory flow of the ventilator. These findings indi- cate that sinus NO may act as an airborne or "aero- crine" messenger, produced in the upper airways and transported by the airstream to a distal site of action in the lungs. Neural physiology Trigeminal sensory, parasympathetic, and sympa- thetic neurons innervate the sinus mucosae. Little information is available about the functions of each type of neuron in normal sinus physiology and sinusi- tis pathophysiology. However, functions can be pos- tulated on the basis of our understanding of the con- tiguous nasal mucosa, tracheobronchial mucosa, skin, and other structures. 39-41 Nociceptive (pain-carrying) sensory neurons are relevant to sinusitis because they convey the sensa- tions of acute pain, headache, congestion, and full- ness that are cardinal symptoms of both acute and chronic sinusitis. Nociceptive neurons are thin, non- myelinated C fibers that innervate respiratory epithe- lium, blood vessels, and possibly those glands that may be present. Nociceptive neurons are thought to be polymodal and sensitive to thermomechanical and chemical stimuli. 42 Endogenous mediators that stim- J ALLERGY CLIN IMMUNOL VOLUME 99, NUMBER 6, PART3 neurotransmitters in cholinergic neurons may include vasoactive intestinal peptide and possibly NO. The presence of parasympathetic reflexes in human paranasal sinuses has not been well investigated. 46 Axon response-parasympathetic reflex responses may be anticipated to promote the production of sinus mucus secretions .46 The sources of secretions are dic- tated by the histologic findings. Goblet cells are the major source of exocytosed mucins in maxillary sinuses. It is believed that epithelial cells generate NO, endothelin, IL-6, and IL-8; levels increase under inflammatory conditions. When compared with the nasal turbinates, sinuses have a relative paucity of submucosal glands with their serous and mucous cells. Levels of the serous cell products lysozyme and lactoferfin are increased in the nasal secretions of recurrent sinusitis subjects, 49 although changes in sinus aspirates have not been studied. Sympathetic neurons that innervate blood vessels contain norepinephrine plus neuropeptide Y (NPY), 39 both of which are potent vasoconstrictors. Norepi- nephrine has a rapid onset and short duration of activ- ity, whereas NPY has a slow onset but 10ng-lasting effect. Despite the extensive use of c~-adrenergic ago- nists in sinusitis, their efficacy and sites of action are still unclear. Sympathetic neurotransmitters may also function to limit neurogenic inflammation by binding to oc2-adrenergic and/or NPY inhibitory autoreceptors that inactivate nociceptive and parasympathetic neu- rons 42 Although these postulated roles of nociceptive, parasympathetic, and sympathetic neurons in sinus pathophysiology and mucus production are tantaliz- ing, the lack of basic information about sinus ogy permits only educated guesses about the roles of neurogenic inflammation and these potent neurotrans- mitters in sinusitis. ENVIRONMENTAL FACTORS No convincing evidence exists to support the role of environmental pollutants andtoxicants in causing or prolonging sinusitis. However, whereas most stud- ies on this subject have focused on the potential car- cinogenic effects of toxicants on the upper aerodiges- tive tract, a scant few have addressed their potential for causing subacute and chronic inflammatory disor- ders of the nasal passages. For example, ozone is known to cause increased respiratory symptoms by compromising the host defense mechanism and by disrupting cellular membranes through its powerful oxidizing properties. In some cases an inhaled toxi- cant (such as CO 2, NO2, and SO2) is selectively absorbed by the nasal mucosa, giving rise to a con- centrated effect of irritation and/or inflammation. S836 K a l i n e r et al. These cells produce a number of molecules, including TNF-'~, IL-4, IL-5, IL-6, IL-8, and colony-stimulat- ing factors such as GM-CSE These polypeptides attract inflammatory cells, particularly eosinophils and basophils from the microcirculation, and prolong their survival. In turn these inflammatory cells can produce cytokines such as IL-3, TNF-c~, and GM- CSF in an autocrine up-regulated fashion; these cytokines then recruit more inflammatory cells. The factors that lead to the initial insult in the lateral wall of the nose are not known but could be bacteria, virus- es, allergens, or pollutants. The regulation of these events in the nasal polyp is minimally understood and requires more study. CF is commonly associated with nasal polyps, but nasal polyps occur most frequently in chronic sinusi- tis and occur universally in association with aspirin sensitivity. Inflammation in the polyp can cause de- differentiation of the polyp epithelium, possibly lead- ing to defective migration of the CFTR protein into the cell membrane. 52 This phenomenon could alter sodium absorption and chloride secretion, which might lead to water retention--the pathophysiologic hallmarks of nasal polyposis. In non-CF nasal polyps a defect in the apical sodium channel also exists, which is characterized by an increase in sodium absorption. This increased sodium absorption can be abrogated by amiloride, which might represent a new direction in the treatment of recurrent nasal polyposis. Thus it is possible that polyps form because of inflammatory changes that result in abnormal elec- trolyte fluxes in the nasal epithelium. Asthma and sinusitis Sinusitis frequently complicates asthma, and med- ical and/or surgical therapy for underlying sinusitis can improve asthma. In addition, in some patients with chronic cough who are thought to have asthma, the cough is probably the result of sinusitis (sec- ondary to the associated postnasal drip). When the sinusitis is treated, the cough is eliminated or signifi- cantly diminished. Although an association exists between sinusitis and asthma in children, little objec- tive data exist to prove that sinusitis causes or wors- ens asthma. Research is needed to evaluate the relationship between sinusitis and asthma. Sinusitis appears to be common in children with respiratory allergy, as first demonstrated by Rachelefsky et al,53 who observed that of 70 children with allergic rhinitis, 37 (53%) had abnormal sinus x-rays and 15 (21%) had one or more opacified maxillary sinuses. In a summary of experi- ence with sinusitis and its relationship to asthma, Adinoff and Cummings 54 noted that active sinus J ALLERGY CLtN IMMUNOL VOLUME 99, NUMBER 6, PART 3 not known but several possibilities have been sug- gested, including damage from the eosinophil, a cell found in both sites, inflammation from mediators produced by the sinus mucosa, and vagal neural reflexes. It is also possible that disease involving one contagious tissue (the nasal/sinus mucosa) might involve the other airway mucosa. A recent hypothesis suggests that a pharyngobronchial reflex triggered by seeding of the inflammatory process into the pharynx results in extrathoracic airway hyperresponsiveness. Rhinitis and sinusitis Clinicians commonly associate nasal inflammation and sinus inflammation, often assuming that rhinitis antedates much of sinus disease and that treatment of rhinitis can prevent or improve sinus disease. Actually, the evidence for causality and even an asso- ciation between rhinitis and sinusitis is not always straightforward. Reinforcing the possibility of association, Ra- chelefsky et al. 53 and Shapiro 5s have described an increased incidence of sinusitis defined by history, physical examination, and imaging criteria in children referred to the allergist-immunologist for evaluation of rhinitis. In addition, skin testing proved that a large proportion of children in both groups were atopic, supporting a connection between allergic rhinitis and sinus disease. Among a group of children with recal- citrant sinusitis who were evaluated for allergy and immunodeficiency, approximately 50% were atopic, again supporting the connection between allergic rhinitis mad sinusitis. 59 In a sample of patients under- going surgery for chronic sinus disease, only the group with extensive disease exhibited an association between chronic sinusitis and allergy. 6° A large-scale evaluation of a primary care patient population would help determine whether a relation- ship truly exists between chronic rhinitis--specifical- ly allergic rhinitis--and sinus disease. However, in designing such a trial, agreeing upon a definition of sinusitis for use in screening a large number of patients will pose a major challenge. In a recent study of 200 consecutive patients evaluated for chronic sinusitis in an al!ergist's office, allergic rhinitis was found in 56%, vasomotor rhinitis in 23%, and nasal septal deviation in 23%. 61 The question of whether continuity exists between the nasal and sinus mucosa with regard to inflamma- tory processes, including cellular infiltration and cytokine profiles, has not yet been resolved. Lavage and biopsy studies that sample the nasal and sinus mucosae will help improve our understanding of the role of the nose in the scheme of sinus disease. $838 K a l i n e r et al. baseline status when they were scheduled for imme- diate sinus surgery. It seems likely that these bacteri- al infections have a role in the disease, but it is not clear whether they participate in the basic process ini- tiating the chronic sinus disease. The second category of bacterial infection includes persistent S. aureus or Pseudomonas aeruginosa cul- tures. These bacteria are usually seen in patients who have undergone sinus surgery and continue to experi- ence symptoms of chronic sinus disease despite CT and rhinoscopic evidence of satisfactory surgical removal of anatom{c obstruction. These infections are associated with persistent crusting and/or impaction of thick and sometimes "concretized" secretions in widely patent sinus cavities. In these patients, pro- longed treatment with appropriate antibiotics m a y suppress the infection and lead to improvement, although permanent cure is not common. These two observations suggest that S. aureus and P. aeruginosa do, in fact, cause disease in this setting. The third category of bacterial infections include cultures yielding Staphylococcus epidermidis, other coagulase negative staphylococci, corynebacterium species, and anaerobic bacteria. These bacteria have been recovered from surgical specimens and, when quantified, are usually present in low titers. 66-71 In this setting the role of these bacteria in causing dis- ease is less clear and their role as pathogens is sus- pect. To better understand and manage patients with viral and bacterial sinusitis, a number of important questions need to be addressed. These questions include knowing more about how viruses cause sinus disease, what risk factors lead to secondary bacterial infection, and what new approaches to treatment will prove useful in these conditions. We have many important questions about the role of bacteria in chronic sinus disease. Do bacteria have an underlying role in the cause of chronic sinus disease? Are they involved in the bony changes sometimes seen in chronic sinusitis? If so, what species are involved, and what are the pathogenic mechanisms? Some patients are recurrently infected with specific types of bacteria and apparently cannot or do not mount an effective immunologic response. Also, if bacteria are not the primary cause of chronic sinus disease, do they have a role in its perpetuation or severity? Allergic fungal sinusitis Allergic fungal sinusitis (AFS) is the fungal sinus affliction about which we know the least. It is caused by a variety of fungi, and we do not know the mech- anisms that initiate or perpetuate the disease. It has been suggested that its pathogenesis i s similar to J ALLERGYCLINIMMUNOL VOLUME99, NUMBER6, PART3 resistance, as well as beta lactamase-producing strains of H. influenzae and M. catarrhalis. Table II lists the minimal inhibitory capacity (MIC90s) against intermediate-resistant pneumococci of antimicrobial agents that have commonly been used to treat acute community-acquired bacterial sinusitis, v° Only agents with MIC90s of <4 against intermediate-resis- tant pneumococci are likely to be effective against these organisms because of the blood levels that can be achieved. A number of antimicrobial agents previ- ously useful in treating acute sinusitis now have MIC90s of >8 against intermediate-resistance pneu- mococci, which limits their usefulness for treating acute sinusitis. In chronic sinusitis, bacteria are less consistently obtained from the sinuses and the complexity of the flora increases, with a shift toward multiple organ- isms, gram-negative organisms, S. aureus, and more antimicrobial resistance. In these patients antibiotic therapy should usually be based on culture and sensi- tivity results. In patients who have continued disease after sinus surgery, chronic S. aureus and P. aerugi- nosa infections are a special problem. Often examination of these patients shows osteitis as evi- - dence of bone involvement as part of the disease process. The continuing rise in antimicrobial resistance complicates the antibiotic selection process and increases the failure rate of empiric treatments. Strains of intermediate and high-level drug-resistant pneumococci are now widespread in many but not all areas of the United States and are increasing in prevalence. Physicians treating acute community- acquired bacterial sinusitis need timely information on the resistant patterns of pathogens in their area, especially S. pneumoniae. Unless the rate of resis- tance is known to be low, caution should be used in selecting antimicrobials to which S. pneumoniae strains have developed increased resistance. In addi- tion, clinical follow-up becomes more important, and timely culture and sensitivity testing is increasingly desirable, especially if persistent infection may be causing significant symptoms or if the patient is being considered for surgical treatment options. The use of antimicrobials with suboptimal activity also has the potential for hastening the emergence of resistant bacteria. Several factors affect the optimal duration of ther- apy for sinusitis. Ten to 14 days of antimicrobial ther- apy has repeatedly been shown to eradicate or markedly reduce bacteria in the sinus cavity in patients with acute sinusitis and is the generally accepted duration of treatment. 71 In patients with per- sistent or chronic sinus disease, there is little pub- S840 Kaliner et al. TABLE III. Bacteriology of acute and subacute sinusitis in children Sireptococcus pneumoniae 30% Moraxella catarrhalis 20% Haemophilus influenzae 20% Streptococcus pyogenes 4% penicillin-resistant pneumococci, the preferred antimicrobials include amoxicillin/clavulanic acid, cefuroxime axetil, and cefpodoxime proxetil. Available data regarding the microbiology of chronic sinusitis in children are limited and confusing because of the variable definitions of chronic sinusi- tis, the failure to obtain specimens aseptically, the lack of quantitative results, and concurrent use of other antibiotics. 73 In patients with acute exacerba- tions of chronic sinusitis (intermittent episodes char- acterized by purulent nasal discharge), the usual microorganisms associated with acute sinusitis S. pneumoniae, M. catarrhalis, and H. influenzae) causative 74-75 and treatment should include the same antimicrobials shown in Table IV. In patients with chronic persistent sinusitis (nasal congestion, puru- lent rhinorrhea or cough, alone or in combination for more than 8 weeks), the role of specific bacterial agents is less clear and, accordingly, the need for antibiotic treatment is controversial. 76-77 Corticosteroids Like many of the treatments of sinusitis currently being used, the use of corticosteroids remains contro- versial. The properties of corticosteroids that make them potentially useful include their ability to reduce mucosal swelling and thereby facilitate drainage of the sinuses, the reduction in tissue eosinophilia accompanying corticosteroid administration, and the proven efficacy of corticosteroids in shrinking nasal polyps. Moreover, topical corticosteroids have been proved effective and are widely accepted in treating allergic and nonallergic rhinitis. Thus many clinicians believe that corticosteroids are essential in the treat- ment of all forms of sinusitis; however, only scant controlled studies support this conjecture. The few relevant studies of the use of cortico- steroids in the treatment of sinusitis can be summa- rized briefly. One study compared groups treated with either topical dexamethasone alone or dexamethasone combined with topical neomycin and patients treated with placebo. The patients in the dexamethasone groups improved significantly compared with the patients who received a placebo. 78 A second study showed equivalent results when resolution of abnor- J ALLERGY CLIN IMMUNOL VOLUME 99, NUMBER 6, PART 3 chronic sinusitis. Decongestants are vasoconstrictor agents that reduce the thickness of the nasal mucosa. They act on c~-adrenoreceptors or are involved in the release, re-uptake, or degradation of noradrena- line. Most of the blood in nasal mucosa is contained in sinusoids, which functionally serve as capacitance vessels. Thus vasoconstrictors represent the optimal drug class to decongest the nose by constricting capacitance vessels, a-1 Receptors respond to cate- cholamines with vasoconstriction. Current sympath- omimetics are primarily oral medications; oc-2 recep- tors respond to imidazoline derivatives, and current preparations are primarily topical. No controlled stud- ies document the beneficial effects of topical or sys- temic vasoconstrictors in sinusitis. Adjunctive therapy Clinicians generally (but not universally) agree that in principle the adjunctive use of systemic mucolytic agents or physical mucoevacuant measures should benefit patients with chronic sinusitis. 8° However, very little or no data are available to support such treatment. Most pharmacologic mucolytic agents are used pri- mari!y for treatment of the lower respiratory tract. Because sinusitis and lower respiratory tract infec- tions both produce thick secretions, the utility of mucolytic agents has been extended to sinusitis. Most systemically administered mucolytics are derived from herbs or have a bitter or pungent taste. 81 Large quantities produce nausea, but in subemetic doses they may produce vagal stimulation, which in turn stimulates the bronchial mucus glands. Guaifenesin is now the mucolytic most commonly used in treating sinusitis. A single study of its effec- tiveness has been published. 82 In a double-blind study, Wawrose 82 administered 2400 mg daily of guaifenesin or placebo to 23 HIV-positive patients with chronic rhinosinusitis and found that the treatment group reported statistically significant improvement in nasal congestion and thick secretions compared with control subjects. Physical mncoevacuant measures range from the simple use of patient-made saline solution snuffed from the cupped hand or administered via a bulb syringe, to pulsed irrigation of the nasal postoperative sinus cavities administered with use of a Water-Pik device and a nasal adapter. The modali- ties of steam, heated mist (including delivery intranasally under pressure) and dry, hot air have been studied in patients with allergic rhinitis and the com- mon cold. However, none of this work has been extended to sinusitis. $842 Kaliner et al. TABLE V. Absolute indications for surgery for rhinosinusitis Sinusitis is causing a brain abscess or meningitis, a subperi- osteal/orbital abscess, cavernous sinus thrombosis, another contiguous infection, or an impending complica- tion (e.g., pott's tumor) Sinus mucocele or pyocele Fungal sinusitis (all varieties) Nasal polyps (massive, i.e., causing obstruction of most or all of the nasal lumens) Neoplasm or suspected neoplasm (causing sinus obstruc- tion) ly performed after a careful history and physical examination. Advantages to each of the endoscopic modalities exist. The technique of nasal endoscopy is well described. 86 Properly performed nasal endoscopy need not be painful for the patient. Endoscopic sampling of nasal/sinus pathology should be studied to determine the underlying cause and optimal treatment regimens. Although endoscopically obtained cultures are thought to be valuable in the management of recalci- trant chronic bacterial sinusitis, their precise the treatment of sinusitis requires further analy- sis. 87,88 Mucin can be sent for histopathologic analy- sis to assist in the diagnosis of allergic fungal sinus disease. Mucosal biopsy specimens may be used to rule out ciliary dyskinesia, to assess causes of granulomatous disease, and to determine the nature of polyps sus- pected of being inverted papilloma or other neo- plasms. The future of nasal endoscopy lies in the introduc- tion of thinner (1.7 ram) nasal endoscopes and contact nasal endoscopy. Contact nasal endoscopy with a rigid endoscope offers an in situ examination of the pathology in the nasal cavity. This may offer an opportunity to evaluate the response of the pathology to the medical treatment. SURGERY Because widely accepted definitions for the types of sinusitis and a clear definition of appropriate med- ical therapy are lacking, it is challenging to identify those types of inflammatory sinus diseases and the proper time in their temporal development for surgi- cal intervention. The "absolute indications" for surgery for rhinosinusitis are easily defined (Table V), but the "relative indications" for which most surgery is (appropriately) performed are much more difficult. Chronic rhinosinusitis (arbitrarily defined as 12 or more weeks of disease) is the most common "relative J ALLERGY CLIN IMMUNOL VOLUME 99, NUMBER 6, PART 3 surgery is directed to the middle meatus and the infundibulum. The posterior sinuses, composed of the posterior ethmoids and sphenoid, may present with a more complex set of complaints and change the pro- gression to surgery. For example, sphenoid sinusitis may present with a higher prevalence of orbital prob- lems, such as optic neuritis and visual loss. The frontal sinus may also provide its own set of medical and surgical challenges. A patient with forehead pain or edema may need an immediate trial of oral and/or intravenous antibiotics, with surgical intervention if symptoms do not resolve. The reason for this aggres- siveness in frontal sinusitis is to avoid intracranial infection or bony infection such as osteomyelitis. General considerations The goals of surgery are to provide adequate sinus drainage and thereby reduce inflammation, to change the nasal anatomy to fit Proetz's principles, and to provide access to the sinuses for appropriate biopsies, irrigation, and cultures. Surgery may also be used to aerate the sinuses, to remove foreign bodies and polyps, and to prevent or reduce the morbidity of orbital, bony, and intracranial c0mplications. The classic indication for surgery for rhinosinusitis is failed medical treatment. The essential questionsin medical treatment are: Which type of sinusitis is being treated, and what is the optimal medical thera- py? Chronic rhinosinusitis is frequently a multifacto- rial problem and may include different predisposing factors such as anatomic, infectious, immunologic, allergic, ciliary, or mucus-related factors. Medical treatment of rhinosinusitis must be modified to fit a combination of causes in each individual patient, pro- viding a wide range of medical therapies. The indications for surgery for rhinosinusitis may vary on the basis of the type of surgery considered. The classic approach in the 1990s is to perform transnasal sinusectomies. However, this approach poses several questions related to the extent of manip- ulation, the nature of mucosal removal, the size of the ostia produced, and the selection of the sinuses and sides operated on. For the frontal sinus, many sur- geons may face dilemmas as they select intranasal and extranasal procedures. Ancillary procedures such as adenoidectomy, septoplasty, and turbinectomies may also be selected. Septoplasties may be performed to improve the airflow through the nose. to provide access to the posterior sinuses, and to allow for ready manipulation of the nose and sinuses with the endo- scopes, both intraoperatively and for postoperative care. The turbinates may be partially removed or moved to allow improved access to the sinuses or to reduce mucosal hypertrophy. S844 K a [ i n e r et al. ing cause such as CF, immunodeficiency, marked allergy, or mucociliary dysfunction. Outcomes Good short to intermediate follow-up data are now available on the subjective results of surgery for rhino- sinusitis. With use of functional endoscopic sinus surgery, overall symptomatic improvement usually has been reported in the range of 80% to 97.5% of patients. However, intermediate results of objective changes in the postoperative patient are less satisfac- tory, and several studies have demonstrated a poor cor- relation between subjective and objective evaluations. Kennedy89 studied a limited number of patients with both subjective and careful objective evaluation. Patients were recruited both prospectively and retro- spectively. To evaluate for bias in the patients recruit- ed into the study retrospectively, questionnaires were also mailed to a similar postoperative patient group who did not return for follow-up during the study period. The extent of preoperative disease was staged radiographically and patients were questioned to eval- uate for the major diseases associated with rhinosi- nusitis and with regard to smoking and allergies. All patients were also treated medically. Mean follow up was 18 months. Subjective improvement occurred in 97.5% of patients, with a greater than 50% improve- ment in symptom score in between 80% and 90% of patients (depending on disease stage). No significant difference" was found in subjective results between different radiographic stages of disease. Of 42 patients with asthma, 86% reported improvement. However, objective endoscopic resolution of disease was highly dependent on radiographic disease extent. Whereas totally normal mucosa was seen in 85% of patients with stage 1 disease, totally normal mucosa was seen in only 25% of patients with stage This data is particularly interesting when combined with the HRQL sinusitis data mentioned earlier. At this time longer term prospective studies are required to evaluate the natural history of chronic rhi- nosinusitis and its response to surgical intervention and prolonged medical therapy. The respective roles of subjective and objective evaluation need to be fur- ther evaluated. However, it is clear that symptomatic improvement does not correlate well with resolution of disease. Therefore, if a study is being performed for evaluation of a staging system or if the aim of the study is to evaluate for resolution of disease, it is paramount to perform evaluation. As a first step toward internationally accepted stag- ing criteria for sinus disease, a group met in Princeton in 1991 and decided to begin to grade sinus disease on the basis of CT. They agreed to follow the Lurid- J ALLERGY CLIN IMMUNOL VOLUME 99, NUMBER 6, PART 3 define the extent of our knowledge that the envelope can be extended. It is evident that we need to study all aspects o f sinusitis, from who gets this disease and why to how to properly diagnose and treat it. This workshop vided an unprecedented opportunity for epidemiolo- gists, pediatricians, internists, surgeons, gists/immunologists to discuss sinusitis and high- , lighted for us the dearth o f answers currently avail- able and the deficiencies in our knowledge that we face when we treat these patients. B r o a d l y stated, the following areas important directions for research: 1) Define the clinical, radiographic, and state and describe the epidemiologic characteris- tics of sinusitis, facilitating studies of natural his- tory and assessment of therapeutic outcomes. 2) Investigate alterations in sinus epithelial function and biology as potential causes or contributi factors in sinusitis. 3) Detemaine the role of infectious agents, includ- ing viruses, bacteria, and fungi, in the cause of chronic sinusitis. 4) Investigate host response to pathogens, mental toxicants, irritants, and allergens in terms of sinus mucosal pathophysiologic, neuronal, and immune responses and identify genetic fac- tors in the development of sinusitis. 5)Investigate the cellular and mediator-induced mechanisms of chronic inflammation in sinusitis and nasal polyp formation. 6)Understand the epidemiologic, pathophysiolog- ic, and therapeutic implications of the relation- ships between sinusitis and asthma, sinusitis rhinitis, and sinusitis and aspirin sensitivity. 7) Define the role of antibiotics and other medical therapies (including topical and systemic corti- costeroids, decongestants, and mucoevacuants) in acute, chronic, and recurrent sinusitis. 8) Define the indications, preoperative and postop- erative staging criteria and clinical, pathologic, microbiologic, and radiographic responses to sinus surgery in selected patients with chronic sinusitis by various age groups. This list by no means exhausts available research needs; this workshop, sponsored collaboratively b y the A m e r i c a n A c a d e m y o f Allergy, A s t h m a and I m m u n o l o g y and the A m e r i c a n A c a d e m y of O t o l a r y n g o l o g y - H e a d and N many other questions for future study. The authors hope that this workshop is an important first step toward heightening awareness of sinusitis and setting priorities for the direction of future research. $846 K a l i n e r et al. sion molecule-1 expression in human endothelial cells. J Immunol 1995;154:799-803. 19. Wellicorne SM, Thornhill MH, Pitzalis antibody that detects a novel antigen are induced by tumor necrosis factor, ride. J Immunol 144(7):2558-65. 20. Groves RW, Ross E, Barker JN, Ross JS, Camp RD, MacDonald DM. Effect of in vivo interleuldn-1 on adhesion molecule expression in normal human skin. 1992;98:384-7. 21. Groves RW, Allen MH, Ross EL, Barker JM, MacDonald DM. Tumor necrosis factor alpha is pro-inflammatory in normal human skin and modulates cutaneous adhesion molecule expression. Br J Dermatol 1995;132:345-52. 22. Hantilos DL, Leung DYM, Wood R, et al. Evidence for dis- tinct cytokine expression in allergic ic sinusitis. J Allergy Clin Immunol 1995;96:537-44. 23. Denburg JA, Gauldie J, Dolovich J, Ohtoshi M. Structural cell-derived cytokines Int Arch Allergy Appl lmmunol 1991;94:127-32. 24. Marini M, Vittori E, Hollemborg J, Mattoli the potent inflammatory cytokines, granulocyte-macrophage colony-stimulating factor and interleukin-6 in bronchial epithelial ceils of patients Clin Immunol 1992;89:1001-9. 25. Dolovich J, Ohtoshi T, Jordana M, Gauldie J, Denburg J. Nasal polyps: local inductive microenvironment genesis of the inflammation. In: Mygind N, Pipkorn U, Pipkorn D, editors. Copenhagen: Munksgaard; 1990. p. 233- 41. 26. Finotto S, Ohno I, Marshall JS, et al. eosinophils in upper airway inflammation Immtmol 1994;153:2278-89. 27. Slavin RG. Sinusitis in adults and its tis, asthma, and nasal polyps. J Allergy Clin Immunol 1988;82(5 Pt 2):950-6. 28. Hamilos DL, Leung DYM, Wood R, et al. Chronic hyerplastic sinusitis: association of tissue eosinophilia with mRNA expression of granulocyte-macrophage colony-stimulating factor and interleukin-3. J Allergy Clin 1):39-48. 29. Hamilos DL, Leung DYM, Wood R, et al. Evidence for dis- tinct cytokine expression in allergic ic sinusitis. J Allergy Clin Immunol 1995;96:537-44. 30. Durham SR, Ying S, Varney VA, et al. Cytokine messenger RNA expression for IL-3, IL-4, granulocyte/macrophage-colony-stimtdating factor in the nasal mucosa after local allergen provocation: tissue eosinophilia. J Immunol 1992;148:2390-4. 31. Igarashi Y, Goldfich MS, Kaliner MA, Irani AMM, Schwartz LB, White MV. Quantification of inflammatory cells in the nasal mucosa of allergic rhinitis and Clin Immunol 1995;95:716-25. 32. Moss RB, Scott TA, Goldrich M, et al. HIV-] seropositive patients with sinusitis. press. 33. Lundberg JO, Farkas-Szallasi T, Weitzberg oxide in human paranasal sinuses. Nat Med 1995;1:370-3. 34. Jaln B, Rubenstein I, Robbins RA, Leishe KL, Sisson JH. Modulation of airway epithelial cell nitric oxide. Biochem Biophys Res Commun 1993;191:83-8. 35. Lundberg JO, Weitzberg E, Nordvall SL, Kuylensticrna R, Lundberg JM, Alving K. Primarily nasal origin of exhaled nitric oxide and absence in Kartagener's J 1994;7:1501-4. J ALLERGY CLIN IMMUNOL VOLUME 99, NUMBER 6, PART 3 56. Rachelefsky GS, Katz RM, Siegel SC. Chronic sinus disease with associated reactive airway disease 1984;73:526-9. 57. Zimmerman B, Stringer D, Feanny S, et al. Prevalence of abnormalities found by sinus x-rays in of relation to severity of asthma. J Allergy Clin Immunol 1987;80(3 Pt 1):268-73. 58. Shapiro GG. Role of allergy in sinusitis. 1985;4(6 Suppl):S55-9. 59. Shapiro GG, Virant FS, Furukawa CT, Pierson WE, Bierman CW. Immunologic defects in children with Pediatrics 1991;87:311-6. 60. Newman LJ, Platts-Mills TA, Phillips CD, Hazen KC, Gross CW. Chronic sinusitis: Relationship of computed tomograph- ic findings to allergy, asthma and eosinophilia. JAMA 1994;271:363-7. 61. McNally PA, White MV, Kaliner MA. Sinusitis in an ailer- gist's office: analysis of 200 consecutive cases. Allergy Asthma Proc. In press. 62. Hamory BH, Sande MA, SydnorA Jr, Seale DL, Gwaltney JM Jr. Etiology and antimicrobial therapy of acute maxillary sinusitis. J Infect Dis 1979;139:197-202. 63. Dingle JH, Badger GF, Jordan WS Jr. Illness in the home: a study of 25,000 illnesses in a group of Cleveland families. Cleveland: The Press of Western Reserve University; 1964. p. 347. 64. Berg O, Carenfelt C, Rystedt G, Anggard A. Occurrence of asymptomatic sinusitis in common cold and other acute ENT- infections. Rhinology 1986;24:223-5. 65. Evans FO Jr, Sydnor JB, Moore WE, et al. Sinusitis of the maxillary antrum. N Engl J Med 1975;293:735-9. - . . . . 66. Orobello PW Jr, Park RI, Belcher LJ, et al. Microbioiogy o f chronic sinusitis in children. Arch Otolaryngol Head Neck Snrg 1991;117:980-3. 67. Karma P, Jokipii L, Sipila E Luotunen J, in chronic maxillary sinusitis. Arch Otolaryngol 1979; 105:386-90. 68. Muntz HR, Lusk RR Bacteriology of the ethmoid bullae in children with chronic sinusitis. Arch Otolaryngol Head Neck Surg 1991;117:179-81. 69. Gwaltney JM Jr. State-of-the-art: acute community- acquired sinusitis. Clin Infect Dis 1996;23:1209-23. 70. Doern GV, Brueggemann A, Holley HP Jr, Ranch AM. Antimicrobial resistance of Streptococcus pnenmoniae recov- ered from outpatients in the United States during the winter months of 1994 to 1995: results of a 3-center lance study. Antimicrob Agents Chemother 1996;40:1208-13. 71. Gwaltney JM Jr, Scheld WM, Sande MA, Sydnor A. The microbial etiology and antimicrobial therapy of adults with acute community-acqnired sinusitis: a fifteen-year A list S848 K a l i n e r et al. CONTRIBUTORS The following persons contributed to the writing and review of this supplement: Vijay Anand, MD President, American Rhinologic Society James N. Baraniuk, MD Georgetown University Joel Bernstein, MD Amherst Otolaryngology Center Gary Cutting, MD Johns Hopkins University David Edelstein, MD Manhattan Eye, Ear and Throat Hospital Peter Gergen, MD National Institutes of Health Richard E. Gliklich, MD Harvard Medical School/Massachusetts Eye and Ear Infirmary J. Gwaltney, MD University of Virginia James Hadley, MD President American Academy of Otolaryngic Allergy Daniel L. Hamilos, MD Washington University School of Medicine Richard G. Holt, MD Editor in Chief Otolaryngology-Head and Neck Surgery Elizabeth Juniper, MCSP, MSc McMaster University Fred A. Kuhn, MD Georgia Ear Institute Donald Lanza, MD University of Pennsylvania Jon Lundberg, MD Karolinska Institute, Sweden Richard Mabry, MD University of Texas-Southwestern SUPPLEMENT TO THE JOURNAL OF ALLERGY AND NUMBER 6, PART 3 David Osguthorpe, MD, b Philip Fireman, MD, c MD, e Mary L. Davis, M A , f Kennedy, M D h* S.C., Winston-Salem, N.C., Milwaukee, Wis., Chicago, Ill., and is one Abbreviations used AFS: Allergic fungal sinusitis CF: Cystic fibrosis CFTR: Cystic fibrosis transmembrane conductance regulator CT: Computed tomography GM-CSF: Granulocyte-macrophage colony- stimulating factor significant HRQL: Health-related quality of life life of a NO: Nitric oxide criti- NPY: Neuropeptide Y SP: Substance P TNF: Tumor necrosis factor URI: Upper respiratory infection This docu- questions The paranasal sinuses are air-filled spaces w i t h i n 1997;99: the bones of the head. In healthy adults the air and bone are separated by a ciliated epithelium containing goblet cells, nerves, blood and lymphatic vessels, and glandular rich connective tissue. The biologic func- tions of the sinuses remain unknown. It has been Washington Hospital hypothesized that sinuses exist to provide vocal reso- cUniversity of nance and sound protection and to decrease the of Pittsburgh School weight of the skull; other roles include olfaction, humidification, arid regulation o f intranasal pressure and mucus. to the writing DEFINITION A N D CLASSIFICATION OF ACUTE A N D CHRONIC SINUSITIS Sinusitis requires a more precise definition and classification. Because the inflammatory process that $829 J ALLERGY CLIN ]MMUNOL JUNE 1997 sinusitis was the most frequently reported chronic dis- ease in the 1993 National Health Interview Survey, a yearly interview survey of the noninstitutionalized U.S. civilian population. Nearly 15% of all respon- dents of the 1993 survey reported having sinusitis that lasted at least 3 months. 3 Sinusitis rates are relatively high in the Midwest and South compared with the Northeast and Western regions of the United States. No apparent association exists between sinusitis and family income or urban residence. Between 1982 and 1993 the prevalence of sinusitis increased dramatically (Table I). Between 1990 and 1992 approximately 73 million restricted activity days per year were reported by persons who had sinusitis. This figure represents a 50% increase from the approximately 50 million restricted activity days per year reported between 1986 and 1988. 4 The 1993 National Hospital Discharge Survey, a yearly survey of hospital discharges for non-Federal U.S. hospitals, documented 16,000 discharges for acute sinusitis (ICD-9 code 461) and 29,000 dis- charges for chronic sinusitis (ICD-9 code 473). 2 These data indicate that women are hospitalized more often than men for both acute and chronic sinusitis. The 1991 National Ambulatory Care Survey, a periodic national physician survey of patient visits to private physicians' offices, reported approximately 11.6 million visits for chronic sinusitis. The data con- firm that more women than men visited physicians' offices for sinusitis. Persons between 25 and 64 years of age and children less than 15 years of age utilized the most services. Sinusitis was the fifth leading cause for antibiotic prescriptions during ambulatory care visits between 1985 and 1992. 6 In 1992, 13 million antibiotic prescriptions were prescribed for acute and chronic sinusitis--more than a twofold increase from 5.8 million prescriptions in 1985. 6 In 1992, direct medical costs of sinusitis reached almost $2.4 billion, a conservative estimate. Direct costs include hospitalizations for acute and chronic sinusitis, visits to both private physicians' offices and hospital outpatient units for chronic sinusitis, and pre- scriptions for antimicrobial treatment for acute and chronic sinusitis. These costs do not include the expense of managing a coexistent illness such as allergic rhinitis or nasal polyps or the expense of surgery and its related costs. In addition, no data have been aggregated to indicate the billions of dollars of indirect costs resulting from sinusitis or the costs for several expensive and important treatments, such as ambulatory endoscopic surgery and diagnostic CT imaging. Thus the total cost of sinusitis is certain to be much larger than $2.4 billion, establishing sinusi- K a l i n e r e t al. $831 14.7% of population 1 170,000 to 200,00082 50 million 2 73 million 2 16,0003 29,0003 11.6 million 4 5.8 million 5 13 million 5 $2.4 billion 6t outpatient sinus surgery. A disease-specific HRQL measure for sinusitis. increases our ability to monitor patient outcomes before and after intervention. The Chronic Sinusitis Survey, an instrument designed to monitor patient outcomes after surgical and medical interventions, has been demonstrated to be valid, reliable, and sen- sitive to clinically important changes. 11-13 To address other aspects of sinusitis-related quality of life, it may be necessary to develop additional disease-specific measures, t4 However, HRQL instruments can and should endure rigorous assessment for reliability and validity, the benchmarks of comparison when choos- ing an instrument for a clinical study. Unlike patients with hearing or vision loss, patients with sinusitis suffer in ways that are more difficult to measure but are nonetheless critical to their function- ing and well-being. To improve our understanding of the ways sinusitis and its treatments affect quality of life, quality of life measures should be a vital part of clinical studies with patients who have sinusitis. PHYSIOLOGY OF THE SINUS Developmental anatomy From the late 1800s through the mid 1900s, researchers detailed the anatomic terminology of the sinuses. Although revived interest in this area has ele- vated our awareness of the importance of the anatomy of the paranasal sinuses, inconsistent anatomic termi- nology is used. Establishing standard terminology would help clarify communication about this disease. The only "normal" anatomic picture of the paranasal sinuses exists on an artist's canvas. "Abnormal structures," such as a concha bullosa or an ethmomaxiliary cell (infraorbital ethmoid cell or Hailer cell), may or may not lead to a pathologic con- dition. The structure of a person's paranasal sinuses is as unique as a set of fingerprints. Even from side to side in the same person, anatomic features may vary markedly. CT studies have been performed to exam- J ALLERGYCLIN [MMUNOL JUNE 1997 tory cycle could become self-perpetuating and lead to long-term epithelial thickening and goblet cell hyper- plasia. To test these hypotheses, however, it is impor- tant to perform detailed studies of the sinus mucosa by analyzing washings and biopsies and by studying cultural epithelium. Chronic sinusitis: Associations with eosinophilic inflammation Chronic sinusitis represents an ongoing inflamma- tory process for which inciting agents have been dif- ficult to identify or prove. Chronic sinusitis with or without nasal polyposis is characterized by inflamma- tory thickening and polypoid changes in the sinus mucosa.18-20 The histologic hallmark is marked tissue eosinophilia. 18"21 The majority of the eosinophils express the activation marker EG2, a phenotype asso- ciated with degranulation and other signs of activa- tion, such as cytokine and mediator production. Nasal polyp biopsies probed for various cytokine mRNA by in situ hybridization revealed a marked increase in inflammatory cells expressing mRNA for GM-CSF, IL-3, and tumor necrosis factor-~ (TNF-~). 21-23 These cytokines are known to promote eosinophil accumulation through the up-regulation of endothelial cell adhesion molecules, including vascular cell adhe- sion molecule-l, and to cause eosinophil activation and prolonged survival (GM-CSF, IL-3). Activated eosinophils in nasal polyps produce GM-CSF and TNF-a mRNA, and eosinophils per se account to some extent for the presence of these cytokines in nasal polyp tissues. However, the driving force for eosinophil accumulation in chronic sinusitis remains unknown. Various cellular elements such as constitutive cells (epithelial cells, fibroblasts, and mast cells) and monocytes produce cytokines within nasal polyps. 24- 9_6Epithelial and fihroblast explants produce abundant quantities of GM-CSF, IL-6, and IL-8. 23, 24 These studies suggest that the epithelium and constitutive cells contribute significantly to chronic eosinophilic inflammation, possibly producing a vicious cycle in which eosinophil infiltration is triggered by abnor- malities within the epithelium and perpetuated further by the damaging effects of eosinophil-derived pro- teins and mediators on the epithelium. A role for T lymphocytes and TH2 cytokines in the development of chronic sinusitis/nasal polyposis has not been clearly defined. Most studies have indicated that approximately 40% of patients with chronic hyperplastic sinusitis with nasal polyposis have asso- ciated allergiesY -29 Nasal polyps from these patients show increased numbers of CD4 + T lymphocytes and increased numbers of inflammatory cells positive for IL-4 and IL-5 mRNA. 27,29 The features of these Kaliner et al. $833 ated with persistent sinus disease. Cloning of the gene responsible for CF has provided new insights into electrolyte transport in respiratory epithelia. The CF transmembrane conductance regulator (CFTR) func- tions as a cyclic adenosine monophosphate-activated chloride channel and as a regulator of two separate channels: one that conducts chloride and one that con- ducts sodium. Mutations in the CFTR gene can affect one or both functions. In patients with a classic form of CF, both functions are disrupted. Interestingly, some genetic defects cause subtle alterations in CFTR function. The result- ing phenotype in patients carrying these "mild" muta- tions is attenuated; only one or two features of the dis- ease are observed. Indeed, persons who have chronic sinus disease and elevated sweat chloride concentra- tions but no other symptoms of CF have been report- ed to carry mutations in each CFTR gene. Together these observations suggest that defects in CFTR and/or one of the proteins that interact with CFTR may account for a fraction of patients with persistent sinus disease. Genetic tools are available to analyze the entire CFTR gene in select groups of patients. Screening of patients with sinus disease recalcitrant to medical and surgical therapy may provide insights into the frequency of this association. Furore studies could involve other genes that encode components of apical membrane electrolyte transport in sinus epithe- lia. Collecting DNA from families with multiple mem- bers affected by the disease would be most helpful in this type of study, because genetic linkage studies might be used to assess the likelihood that a candidate gene is responsible for disease. If a sufficient number of family samples are obtained, a more extensive search of the human genome could be undertaken for genes involved in sinusitis. This approach, called positional cloning, might identify a gene that encodes a novel protein or a protein previously not known to cause sinus pathology. However, all of these genetic studies will require universally accepted diagnostic criteria for chronic sinusitis. The role of nitrous oxide Recently it was shown that nitric oxide (NO) is produced in large quantities in healthy human paranasal sinus epithelium. Concentrations of this gas in the sinuses can rise close to the highest permissible environmental pollution levels. 33 A role of NO in sinus host defense has been suggested because of its well-known bacteriostatic and antiviral properties. Furthermore, NO may up-regulate ciliary activi- ty.34,35 Sinus NO enters the nasal cavity via the ostia and contributes largely to the levels of NO found in nasal- J ALLERGY CLIN ]MMUNOL JUNE 1997 ulate nociceptive neurons during tissue ischemia, inflammation, and atopy include H +, K ÷, free radicals, bradykinin (B2 receptor), and histamine (HI recep- tor). Other inhaled irritant factors such as SO 2, O 3, and cigarette smoke can stimulate nasal and tracheo- bronchial neurons, but it is unclear if these can acti- vate sinus nociceprive neurons given the low rate of air exchange in normal sinuses. Capsaicin, the hot, spicy essence of chili peppers, has been an excellent tool for studying the functions of nociceptive neu- rons. Topical capsaicin causes the release of sub- stance P (SP) and other neuropeptides that in turn activate a variety of nasal responses, individual glan- dular secretion, and increased vascular permeability. Activation of epithelial nociceptive endings is thought to generate an action potential that is con- ducted throughout the entire neuron to the trigeminal association areas of the brain stem and cervical spine. Depolarization extends to all the "dendritic" branches of the neuron in the epithelium and other innervated structures and leads to release of neuropeptide trans- mitters from neurosecretory swellings ("varicosities") in these locations. The neuropeptides may include SP, neurokinin A, calcitonin gene-related peptide, gastrin- releasing peptide, and possibly other peptides. 39-41 This efferent mechanism of afferent nerves is termed the axon response and leads to "neurogenic inflam- marion." Evidence suggests that axon responses cause increased ciliary activity in rabbit maxillary sinus, rat tracheal goblet cell exocytosis, a small increase in superficial blood flow in porcine nasal mucosa, and grannlocyte exudation in human nasal mucosa. 43-46 The effects of individual peptides in the sinuses have not been fully evaluated but can be postulated on the basis of analogies from nasal mucosa and other sites. 39-41 SP may induce epithelial cell ciliary activi- ty, goblet cell exocytosis, postcapillary endothelial cell contraction that permits plasma extravasarion, cytokine generation, 47 and, as shown in human skin, 48 induction of endothelial cell adhesion markers such as E-selectin and vascular cell adhesion mole- cule that promote eosinophil and neutrophil dia- pedesis. Allodynia, the increase in pain responses to innocuous stimuli, 42 may be the result of inflamma- tion-induced dysregulatory effects on nociceptive mad other nerve populations and their central intemeurons that could lead to the exquisite tenderness of acute sinusitis or the unrelenting pain or sense of conges- tion or fullness of chronic noninfectious sinusitis. Sensory nerve activation recruits parasympathetic reflexes in the nasal and tracheobronchial mucosae. 39 Cholinergic reflexes are thought to contribute to cil- iary motion and goblet cell exocytosis, but evidence for epithelial cholinergic neurons is lacking. Other K a l i n e r et al. $ 8 3 5 This cellular damage can initiate a series of cascading events in the inflammatory process, such as the release of inflammatory mediators, causing vascular extravasation of inflammatory cells and tissue edema. Such events lead to nasal mucosal swelling, decreased air flow, and the possibility of ostiomeatal complex obstruction. Certain occupations may expose workers to more occupational hazards than others. These occupations include woodworking and carpentry; dye, paint, and solvent manufacturing; leather tanningl oil and gas distilleries; chemical plants; and hazardous waste dis- posal units. Host susceptibility may influence the inflammatory reaction to toxicant exposure, perhaps on a genetic basis. Interaction with or sensitization by a preexisting nasal condition such as allergic or vaso- motor rhinitis may also potentiate the inflammatory reaction by an environmental toxicant. A "susceptibil- ity/exposure index" would relate the factor of host susceptibility to the level and duration of exposure, an important epidemiologic evaluation. This type of potentiation is illustrated in studies of IgE responses induced by inhalation of diesel fuel particulates. 5° To determine the areas of risk, who is at risk, and how risk might be reduced, it is important that sinusi- tis surveillance programs based on sound epidemio- logic principles be implemented by health profession- als who deal with disorders of the respiratory tract. If research determines that sinusitis is a common com- plication of occupational and household exposures to nasal mucosal toxicants, health professionals must develop preventive measures to decrease risk and pro- vide medical oversight. physiol- ASSOCIATED CONDITIONS Nasal polyps and sinusitis Nasal polyps represent the ultimate manifestation of chronic inflammation. Nasal polyps most com- monly arise from the lateral wall of the nose, although the anterior ethmoids and other sinuses may also be the primary site of origin. This inflammatory entity differs distinctly from the normal nasal mucosa and is characterized histologically by (1) cystically dilated. inspissated mucous glands that are completely differ- ent than the seromucinous glands of the inferior or middle turbinates; (2) a large influx of inflammatory cells, with the eosinophil predominant; and (3) dedif- ferenfiation of the epithelium, including basal cell hyperplasia, goblet cell hyperplasia, and squamous metaplasia. The microenvironmental theory of lateral nasal air- way inflammation suggests that an extensive network of cytokines released by the resident structural cells (epithelial cells and fibroblasts) is up-regulated. 51 J ALLERGY CUN IMMUNOL JUNE 1997 intervention improved asthma, and they noted a trend (though not significant) toward better results of pul- monary function testing and reduced methacholine reactivity in the actively treated patients compared with the patients treated with placebo. Businco et al.55 evaluated 80 children between the ages of 4 and 14 years who had asthma. Sinus x-ray films revealed abnormal findings in 55 of the 80 chil- dren; however, "abnormal" was defined as a 2 mm thickening of one or more maxillary sinus(es). The children were treated with either inhaled nasal corti- costeroid with an antihistamine/decongestant or ampi- cillin plus an antihistamine/decongestant. Patients were evaluated 30 days following treatment. After both interventions the decreased severity of asthma and the findings of the sinus x-ray films improved sig- nificantly. However, the study did not include placebo or control groups. In 1984 Rachelefsky et al. 56 studied a nonrandom- ized group of 48 children with a mean age of 8.2 years who had moderate to severe asthma and almost daily wheezing for at least 7 months. With pharmacologic or surgical intervention for ~assoeiated sinusitis, 80% were able to discontinue their asthma medicine, 80% had normal findings on x-ray films, and the majority of patients had normalized pulmonary function and could stop taking their asthma medications. Continued follow-up in these patients revealed that their asthma recurred when sinusitis subsequently developed. Another study examined gradations of asthma and abnormal sinus x-ray findings of 138 children with conditions ranging from cough-variant asthma to severe asthma. 57 The percentage with abnormal sinus x-ray findings ranged narrowly between 27% and 36%. No predictive difference in radiologic abnor- mality existed with regard to the severity of the asth- ma. The authors concluded that the sinus abnormality was not related to the asthma; however, they did not treat the sinusitis to see if they could eliminate the symptoms of asthma and improve the disease process. Past studies that attempted to evaluate the associa- tion of asthma and sinusitis in pediatric patients have not been well designed in terms of randomization and placebo/control and did not account for the variabili- ty of childhood asthma. Therefore a carefully designed, prospective, randomized, placebo-con- trolled study would help answer these clinical ques- tions. Appropriate surgical intervention for medically resistant sinusitis has also been shown to benefit patients with coexistent asthma. This is also true both for bilateral intranasal sphenoethmoidectomy and functional endoscopic sinus surgery in children and adults. The mechanism for sinusitis-induced asthma is K a l i n e r et al. $ 8 3 7 ROLE OF INFECTIOUS AGENTS IN ACUTE SINUSITIS Recent work has shown that radiologic evidence of sinusitis is frequently found in patients who have a viral-associated common cold. 1 Thus colds, are in reality a viral rhinosinusitis, which makes viral-asso- ciated sinusitis among the most frequent acute infec- tion in humans. It is not known if virus invasion of the sinus cavity is necessary to produce these changes, but viruses (rhinovirus, influenza virus, and parain- fluenza virus) have been recovered from up to 15% of sinus aspirates in patients with suspected acute com- munity-acquired sinusitis. 62 Viral sinusitis and infundibulitis may be important predisposing factors for the development of sinusitis in an estimated 0.5% to 2.5% of adult patients with upper respiratory infec- tions in whom secondary acute bacterial sinusitis develops. 63,64 It is estimated that 10% of colds in chil- dren lead to sinusitis. The cause of acute community-acquired bacterial sinusitis has been well defined by sinus puncture studies that date back to the 1950s. Several important principles in the study of infectious disease, including bacterial titers, correlation with gram stain, and asso- ciation with tissue or fluid leukocytosis, suggest a causal relationship between a positive bacterial cul- ture and sinusitis. Streptococcus pneumoniae and Hemophilus influenzae, the most important path- ogens, cause more than haft of the cases in adults. Other streptococcal species, Moraxella catarrhalis, Staphylococcus aureus, and mixtures of anaerobic bacteria also each cause a small proportion of cases. While the incidence of the various bacterial species has not changed, their antimicrobial sensitivities have changed, creating important problems for antimicro- bial therapy. Although the roles of viruses and bacteria in the cause of acute infectious sinus disease are well estab- lished, the role of microbial infection in chronic sinus disease is less well defined. Few studies have per- formed sinus aspirations and quantitative bacterial culture in patients with chronic sinus disease. Currently it is difficult to quantify the role of bacteri- al infection in sinusitis. On the basis of available results, it is possible to recognize three categories of bacterial infection that may have different degrees of importance in chronic sinus disease. The first category includes sinus aspirale cultures from which S. pneumoniae, H. influenzae, and other well-established bacterial causes of acute sinusitis are recovered in titers of _>104 CFU/ml. 65 These results were obtained from patients with chronic sinus dis- ease, some of whom experienced acute sinus symp- toms and others from whom a culture was obtained at J ALLERGY CLIN IMMUNOL JUNE 1997 allergic bronchopulmonary aspergillosis. Various serum markers, including total and fungal-specific IgE, and serum and mucin eosinophilic cationic pro- tein have been investigated to predict disease recur- rence with no conclusive correlation. Monthly endo- scopic mucosal staging has also been suggested to monitor disease progress. Left untreated, AFS is asso- ciated with bone reabsorption and remodeling and may markedly distort the face. Possible progressive epithelial damage resulting from eosinophil influx associated with the presence of fungi and apparent allergic responses may initiate a self-perpetuating, cyclical inflammatory/immunologic response only temporarily suppressed by oral steroids. Current treat- ment requires both corticosteroids and surgery, usual- ly functional endoscopic sinus surgery, although we still do not know the optimal treatment program. The treatment for AFS involves a combination of surgical approaches and aeration of the sinus with use of antiinflammatory therapies including oral and top- ical corticosteroids. Prednisone at 0.2 mg/kg per day may suppress the inflammation and sometimes restores the mucosa to normal. If the steroid dose is too low or is stopped too soon, the disease may recur even up to 22 to 34 months after surgery and up to 6 months after discontinuation of corticosteroids. The disease often progresses into the development of a polypoid sinus mucosa (with thick eosinophil-laden mucin with a peanut butter consistency.) The role of immunotherapy in the treatment of this disorder has yet to be determined. We need more studies to define the clinical settings that lead to AFS, how we can rec- ognize the disease more readily, and how to treat the disease most effectively. Recent work suggests that antifungal agents such as itraconazole may be helpful in allergic bronchopulmonary aspergillosis. Controlled studies need to be performed to evaluate the role of antifungal therapy in patients with AFS. PHARMACOTHERAPY Antimicrobial therapy for sinusitis in adults Antimicrobial therapy has been shown to reduce or eliminate bacteria in the maxillary sinus and to improve symptoms in acute community-acquired bac- terial sinusitis. 69 However, because most cases of acute community-acquired sinusitis have a viral com- ponent that also affects the clinical course 1 and because acute sinusitis is usually a self-limited dis- ease, defining the relative efficacy of various agents and regimens may be difficult. For patients with acute bacterial sinusitis for whom organisms have been rather consistently identified, the antimicrobial selectedshould be effective against strains of S. pneumoniae with intermediate penicillin Kaliner et al. $839 TABLE II. MIC90s of 216 p e n i c i l l i n - i n t e r m e d i a t e strains of S. pneumoniae to a n t i m i c r o b i a l agents c o m m o n l y used to treat acute c o m m u n i t y - acquired sinusitis Antimicrobial agent MIC90 Amoxicillin* 1 Amoxicillin-clavulanate 1 CefpodoximC 2 Cefuroxime 4 Cefprozil ? 8 TMP/SMX 8 Clarithromycin~ 8 Azithromycin ~ 8 Cefixime 16 Cefaclor 64 Loracarbef 64 *Not effectiveagainst [3-1actamase-producingH. influenzae and M. eatarrhalis. tNot evaluatedin pre- and post-treatmentsinus aspirateculture studies. SEffectivenessagainstH. influenzae not evaluatedin pre- and post-treatmentsinus aspirate culture studies. Data from Wald ER. J Pediatr 1995;127:339-47. sinus CT lisliedinf0rmation on which t0 base duration Of trdat- ment. Longer and repeated courses of antimicrobial therapy are usually given to these patients, but clini- cal response is often unsatisfactory. Work is urgently needed on the pathogenesis of chronic sinus disease and on the role of infectious agents in initiating or complicating the process to allow more rational use of antimicrobial treatment. Antibiotic therapy for sinusitis in children For children with sinusitis, antibiotic selection requires knowledge of likely infectious pathogens. Table III profiles the bacteriology of acute and suba- cute sinusitis in children. Previous studies have established the efficacy of antibiotic therapy for children with acute and suba- cute sinusitis. Children treated with antibiotics recov- er more quickly and more often than do children treat- ed with placebo, v2 With these pathogens in mind, the choices for antibiotic therapy are shown in Table IV. Amoxicillin is often recommended as first-line therapy because it is usually effective and it is inex- pensive and safe. Safety continues to be important, especially when treating children with uncomplicated infections who have not recently been treated with antibiotics. Table IV includes alternative antibiotic selections for children who do not respond or who worsen while receiving amoxicillin. Most of these antibiotics have been studied both in children and adults for either otitis media or sinusitis. For patients living in a geographic area with a high prevalence of J ALLERGY CLIN IMMUNOL JUNE 1997 TABLE IV. Antibiotics for treatment of sinusitis in children • Amoxicillin • AmoxiciUin/clavulanic acid* • Erythromycin/sulfisoxazole • Sulfamethoxazole/trimethoprim • Cefaclor • Cefuroxime axetil* • Cefprozil • Cefpodoxime proxetil* • Loracarbef • Clarithromycin • Azithromycin • Clindamycin t *These antibiotics are preferred when (1) the patient lives in a geographic area in which there is a high prevalence of ~-lacta- mase-producing bacteria or a high prevalence of penicillin-resis- tant pneumococci, (2) the infection is severe, or (3) the infection fails to improve while the patient is receiving amoxicillin. tClindamycin is preferred when the patient is known to be infect- ed with penicillin-resistant Streptococcuspneumoniae. (i.e., are real radiographs in groups treated with antibiotics were compared with subjects treated with topical beclomethasone. 55 In a third study, adding topical flu- nisolide to antibiotic treatments improved global evaluations and possibly reduced exacerbations. 79 However, none of these studies unequivocally proves efficacy or justifies general advocacy of topical corti- costeroids in sinusitis. To determine the outcomes of the medical management of sinusitis, large studies should compare antibiotic and topical corticosteroid treatment for patients with either chronic or recurrent symptoms. Prospective studies of the use of corticosteroids are needed to answer the following questions: In acute sinusitis, do topical corticosteroids play a role in effective management? In recurrent sinusitis, do topi- cal corticosteroids reduce recurrence rates? In chron- ic sinusitis, do corticosteroids induce symptomatic relief? What is the precise role of topical corticos- teroids in the management of nasal polyps? In patients with either recurrent or chronic sinusitis, should topical nasal corticosteroids be used prophy- lactically, and if so, for how long? What is the role of systemic corticosteroids in the management of acute, chronic, or recurrent sinusitis? What are the side effects or topical steroids? What are the roles of topi- cal or systemic steroids in the treatment of nasal polyps? Decongestants and mucoevacuants Topical and systemic decongestant therapies have been recommended to adjunctively treat acute and K a l i n e r et al. $ 8 4 1 RADIOGRAPHIC IMAGING Even though imaging is increasingly used to evalu- ate patients with rhinosinusitis, the major role and benefit of this practice remains unclear. Two imaging modalities are used--plain films and CT scanning. Both modalities were compared by Lusk et al. .3 in a pediatric population; plain films were shown to be inaccurate in 75% of cases. Several investigators used plain films and measured the thickness of the inflam- matory mucosa within the major sinuses to define sinusitis. 84 It remains unclear how the presence and extent of inflammatory disease shown on x-ray stud- ies correlates with the patients' clinical presentation and course. Only after this correlation is clearly understood can we use imaging to examine patients with sinusitis and determine how they should be man- aged and what therapy should be used. Clinical, endo- scopic, transillumination, and other noninvasive, non- radiographic diagnostic imaging could and should be used to provide the information sought from x-ray imaging. Such noninvasive practices could signifi- cantly reduce costs and help patients avoid x-ray exposure. CT is the radiographic modality of choice to exam- ine the nasal cavity and paranasal sinuses. The coro- nal plane best simulates the endoscopic view, and <3 mm scans provide the most accurate representation of the regional anatomy. Because CT is primarily per- formed to provide anatomic information, it should be. performed when the patient's mucosal inflammation is under optimal control, s5 Inflammatory mucosa obscures the fine bony detail, resulting in a more lim- ited evaluation. Thus optimal information is achieved when the CT study is performed 4 to 6 weeks after the initiation of medical therapy. In postoperative patients and patients with chronic recurrent sinusitis, bony thickening is increasingly detected by CT. Many patients can correlate their symptoms (pain) with the location of thisprocess. Unfortunately, the reason for bony thickening is not understood, and the following questions remain unan- swered. What is this process? Is this an osteitis? How does this process influence the patient's symptoms, and can it be treated? Surgeries continue to be aimed at adjacent mucosal inflammatory disease without addressing the bony process. cavity and ENDOSCOPY Nasal endoscopy has greatly improved our ability to diagnose nasal and sinus disease and assess the response to medical and surgical therapy. Patients with recalcitrant complaints referable to the nose or paranasal sinus are particularly good candidates for this procedure. Flexible or rigid endoscopy is typical- J ALLERGYCLINIMMUNOL JUNE 1997 TABLE Vl. Important considerations for surgery for rhinosinusitis Anatomic factor(s)that impede sinus drainage (e.g., substan- tial septal deviation, concha bullosa, paradoxically curved middle turbinate) Abnormalities in the mucociliary clearance (Kartagener's syndrome) Deficiency (e.g, HIV) or suppression (e.g, status post trans- plantation) of immune system Insulin-dependent diabetes mellitus Cystic fibrosis Sinobronchial syndrome asthma Aspirin sensitivity triad Sarcoidosis/aut0immune/connective tissue disorder Nasal polyps Allergic rhinitis: poorly controlled by avoidance, pharma- cotherapy, or immunotherapy Failure of prior surgical therapy Failure of adenoidectomy (children) Failure of sinus irrigations (children and adults) Presence of, or suspicion of, resistant organisms Grade 4 or 5 anesthesia risk classification,or other relative contraindication to elective local/general anesthesia Major coagulopathy role in indication" for surgery for rhinosinusitis. In general, a thorough trial of medical therapy should be per- formed before surgical intervention in patients with chronic rhinosinusitis. Such medical therapy may include antibiotics, mucolytics, decongestants, steroids, and/or immunotherapy. However, a wide variety of factors (Table VI) will modify the timing of surgical therapy as well as the type and extent of sur- gical intervention. In the majority of patients who have chronic rhi- nosinusitis refractory to an adequate trial of medical therapy, surgery decreases symptoms and improves the quality of life. However, outcomes studies are needed to ascertain the type and appropriate length of medical therapy before surgical intervention. An out- comes study on the management of sinusitis must control for the factors that modify the responses to therapy, including (1) anatomic abnormalities, (2) patient age, and (3) the sinus(es) involved. To better define the appropriate time for surgical intervention, we must develop standardized reporting of the results of surgical intervention specific to the disease addressed, the modifying factors, and the time of fol- low-up. As stated earlier, all sinuses are not the same. Classic rhinosinusitis involves the maxillary sinus and the anterior ethmoid sinuses with the common symptoms of facial pain, rhinorrhea, postnasal drip, anosmia, and dental pain. In this circumstance, K a l i n e r et al. S 8 4 3 Age is an important variable in considering surgery. Although most authors readily classify prospective sinus surgery patients as children and adults, some attention should be made to more anatomic or physiologic issues that vary on the basis of growth and development of the nose, dentition, midface, orbits, forehead, and sinuses. In adults, changes occur with senescence that may alter the symptomatic innervation and modify the mucosal removal and postoperative care. Revision surgery for residual or recurrent disease demands special attention. Noses and sinuses that have been previously manipulated may present unique diagnostic and surgical challenges. First, sig- nificant areas of scarring and bony regrowth that are not normally seen may be present. Second, a higher predominance of gram-negative and anaerobic organ- isms may be present. Indications for surgery in these patients may depend on a different natural history of the disease or a series of missed diagnoses and surgi- cal problems. Pediatric considerations Because -of the. lack. of=firm scientific ..evidence identifying the appropriate role Of prolonged medical therapy, i n sinusitis, indications for surgery of the paranasal, sinuses in children are broadly described. Particular considerations in Children are a lack of knowledge regarding the natural history of rhinosi- nusitis, anatomic features that require special tech- niques for surgery, and concerns regarding the poten- tial effects of both surgery and chronic infection on paranasal growth. In general, surgery in children should be performed very conservatively and selec- tively. Sinus surgery in children entails special considera- tions that do not apply to adults. Sinus surgery is more difficult in children; the smaller, more delicate anatomic features of children require special skill and instrumentation to avoid damaging the mucosa and to promote normal healing. Unlike in adults, the turbinates in children need to be preserved. Growth change has been discussed previously. The role of adenoidectomy and sinus irrigation needs review and may be recommended before sinus surgery. Scarring and synechia require further study, and no studies of pediatric rhinosinusitis have provided objective data. Current information indicates that scarring can occur rapidly, and second-look or third-look procedures can be necessary postoperatively to allow proper healing. In addition, recurrent infections still occur in young children, and although most children improve, few are cured. Several studies show a higher incidence of surgeries performed in patients who have an underly- J ALLERGYCLIN IMMUNOL JUNE 1997 Mackay system in which each sinus (anterior ethmoid maxillary posterior ethmoid sphenoid and frontal sinus) is given a numeric score on the basis of the extent of CT opacification (0 = no opacification; 1 = partial opacification; 2 = total opacification). The osteomeatal complex is given a score of either 0 or 2 depending on whether it is involved. To appropriately evaluate disease resolution, para- meters for objective evaluation need to be developed, raising the question of whether endoscopic evaluation is sufficient or whether all patients should undergo postoperative CT. Kennedy s9 chose to use endoscopy but considered the sinus to be normal only if endoscopy demonstrated that each sinus was com- pletely normal (i.e., no mucosal thickening, dis- charge, adhesions, inflammation, or polyposis). With the advent of endoscopic evaluation it is clear that patients can be followed up after surgical inter- vention and that in many cases persistent disease can be treated either medically or by local debridement before it becomes symptomatic. However, the long- term cost-effectiveness of managing sinus disease in this fashion and the long-term effects of this type of management on patients' overall health clearly need to be studied. Similarly, with the advent of endo- scopes and the ability to perform endoscopic follow- up, it is clearly possible to avoid a situation in which the patient returns after prior surgery with massive nasal polyposis and nasal obstruction requiring exten- sive revision surgery. Image-guided surgery is in its infancy. It is now commonly used in neurosurgery and, if used in endo- scopic surgery, could assist in guiding the surgery and help decrease these complications. As this equipment becomes more available, image-guided surgery will need to be evaluated and the advantages determined. 4 disease. CONCLUSIONS AND RECOMMENDATIONS FOR RESEARCH Sinusitis is an exceptionally important disease viewed from any perspective. Medical interest and analysis of various treatments for this disease has only recently begun to develop; until recently, surgery involved techniques developed 100 years ago. Surgical procedures have undergone a radical change in the past decade. Because of the limited time frame for the determination of the long-term results of func- tional endoscopic surgery, the efficacy of this proce- dure beyond the first year after surgery is poorly defined as yet. Even the discussion of sinusitis in the classic texts of medicine or allergy are scant and inad- equate. Thus the importance of this disease far out- weighs the current scientific basis for its diagnosis and treatment, and it is only with conferences that Kaliner et aL $845 With a disease that costs society billions of dollars each year and affects a significant portion of the pop- ulation, it is appropriate to begin the push for more funding, more research, and more answers. pro- REFERENCES and aller- 1. Gwaltney JM Jr, Phillis CD, Miller RD, Riker DK. Computed tornographic study of the common cold. N Engl J Med 1994;330:25-30. 2. Kennedy DW. International conference on sinus disease: ter- minology, staging, therapy. Ann Otol Rhinol Laryngol 1995;104(10). constitute 3. 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Laryngoscope 1992;102(12). o f contributors appears on page $848 J ALLERGYCLIN IMMUNOL JUNE 1997 Marshall Plaut, MD National Institute of Allergy and Infectious Diseases Michael Poole, MD University of Florida David Proud, PhD Johns Hopkins Asthma & Allergy Center Gary Rachelefsky, MD President American Academy of Allergy, Asthma and Immunology David L. Rosenstreich, MD Albert Einstein College of Medicine Gail Shapiro, MD Northwest Asthma & Allergy Center Raymond G. Slavin, MD St. Louis University School of Medicine James A. Stankiewicz, MD Loyola University Ellen Wald, MD University of Pittsburgh Children's Hospital S. James Zinreich, MD The Johns Hopkins Medical Institution Michael Maves, MD, MBA Executive Vice President American Academy of Otolaryngology-Head and Neck Surgery Foundation, Inc. James Hansen-Flaschen, MD American Thoracic Society Frank Vira_nt, MD American Academy of Pediatrics Neil Ward, MD President American Academy of Otolaryngology-Head and Neck Surgery Foundation, Inc. Betty Wray, MD President American College ofAllergy,Asthma & Immunology