An update on the diagnosis and treatment of sinusitis and nasal polyposis

Sinusitis (more properly known as rhinosinusitis due to the regular involvement of the nasal cavity) is a condition with a high and clearly increasing prevalence. According to figures from IMS Health, acute sinusitis was diagnosed 6.3 million times and chronic sinusitis 2.6 million times in a country like Germany over the course of one year (July 2000–June 2001), resulting in 8.5 million and 3.4 million prescriptions, respectively. The number of diagnoses of "nasal polyposis" was approximately 221 000 (according to IMS Health 2001). Even though no reliable epidemiological studies of the incidence of sinusitis exist, these figures do indicate that sinusitis represents a considerable socioeconomic problem. Alongside allergic and viral conditions of the upper airways, sinusitis therefore constitutes one of the most common respiratory tract conditions in humans. Similar data are reported from the USA: in 1997, sinusitis was prevalent in approximately 15% of the population. In the last decade, the frequency of diagnosis in the USA rose by around 18%. The economic significance of sinusitis is huge: for 1992, the total cost, including costs resulting from loss of work, was estimated at over 6 billion dollars for the USA. In the period from 1985 to 1992, the number of antibiotic prescriptions for sinusitis rose from 7.2 million to 13 million (1, 2). Sinusitis is an inflammatory process involving the mucous membranes of one or more sinuses. Generally speaking, the mucous lining of the nose is also involved. Even in the presence of a viral cold, a CT scan will reveal the involvement of the paranasal sinuses in 87% of cases, which is why we speak of rhinosinusitis (3). Bacterial rhinosinusitis (acute sinusitis) is generally preceded by a virus-induced inflammation of the sinuses; approximately 5–10% of childhood upper airway infections develop into acute sinusitis (4). The swelling and "immunological weakness" of the mucous membrane and the blockage of the ostia by the viral infection are today believed to cause bacterial infection of the intrinsically sterile paranasal sinuses by local microorganisms. This gives rise to acute sinusitis, with severe inflammatory infiltration of the mucous membranes and corresponding clinical symptoms. Chronic sinusitis is suspected of being caused by impaired paranasal sinus ventilation and drainage disorders due to a blockage of the ostiomeatal complex in the middle nasal meatus (6); however, the significance of the bacterial infection is doubtful (7). Besides the physical pathological mechanisms, inflammatory changes in the mucous linings of the nose and paranasal sinuses (that may play a considerable part in the pathogenesis of chronic sinusitis) have been increasingly described in the last few years (8). Underlying conditions such as cystic fibrosis, immunodeficiency, ciliary dyskinesia, and others may also play a causal role. The pathogenesis of nasal polyposis is so far largely unknown, although associations exist with other respiratory tract conditions, such as aspirin sensitivity and asthma. More recent studies show that nasal polyps are not an allergic condition, as was often suspected. Rather, nasal polyps are characterized predominantly by inflammation caused by eosinophil granulocytes, whose regulation has been partly explained in the last decade. Very different pathogenic principles (e.g. aspirin sensitivity, cystic fibrosis) underlie the various forms of nasal polyp. In clinical terms, a distinction is made between acute, acute recurrent, and chronic sinusitis (Table 1). Establishing this distinction involves a clinical diagnosis that has to be supplemented by a CT scan only in the case of chronic sinusitis. Chronic sinusitis can be subdivided into forms that are more neutrophilic or eosinophilic, with the eosinophilic form being primarily involved in polyp formation (Table 2). Sinusitis and nasal polyposis can be accompanied by troublesome or agonizing symptoms that markedly impair one's quality of life (9, 10); they even carry serious risks (e.g. orbital or cerebral complications). Furthermore, sinusitis is associated with considerable socioeconomic consequences. Efficient and specific diagnosis and treatment based on the latest findings are therefore desirable, and corresponding evidence-based guidelines are essential. This is particularly true for the surgical and medicinal treatment of the various forms of sinusitis. The guidelines should help to make the most of the limited resources of the health system. "Evidence-based medicine (EBM) is the conscious, express, comprehensible use of the best evidence in decisions about the care of individual patients" (11). While acute sinusitis is understood to be an inflammatory process in which paranasal sinus drainage and ventilation are impaired as a result of a nasal infection, chronic sinusitis is acknowledged to be due to a gradual obstruction caused by increased tissue formation in the ostiomeatal complex. According to the studies conducted so far, blockage of the ostiomeatal complex in the middle nasal meatus leads in turn to impaired ventilation and drainage (12). The significance of physical obstructions caused by morphological/anatomical variations in the paranasal sinus system and nasal septum is a subject of controversy. Although some 40% of patients exhibit these variations, they are observed in equal numbers in healthy people (13, 14). The pathological mechanisms that cause sinusitis to become chronic have hitherto been attributed to mucociliary dysfunction, mucostasis, consecutive hypoxia and the discharge of microbial products (15-19). While Streptoccocus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are among the microorganisms found in 75% of cases of acute sinusitis, Staphylococcus aureus, coagulase-negative Staphylococci, Pseudomonas aeruginosa and anaerobic bacteria, alone or a mixed infection with facultative anaerobic and aerobic pathogens, are the main agents in chronic sinusitis (20-25). However, the significance of bacterial and viral infections in the onset of chronic sinusitis is unclear, because the pathogenicity of these pathogens in chronic sinusitis is largely unknown (26, 27). The prevalence of anaerobic infections ranges in the literature from 80 to 100% (21) and in other studies from 0 to 25% (22, 24). The value of the results of cultures, taken by aspiration or swab from the middle meatus, is limited because of contamination with bacteria from the nasal cavity (25). Generally speaking, results of cultures from specimens taken intraoperatively are considered more valid (28-30). In recent years, not only physical considerations but also the inflammatory mechanisms taking place in the mucous linings of the nose and paranasal sinuses have been ascribed a significant role in the pathophysiological understanding of the condition (8). The fluid obtained by irrigation from the sinuses of people with chronic sinusitis has been found to contain mainly neutrophil granulocytes, but also a few eosinophils, mast cells and basophils (31, 32). High concentrations of histamine, leukotrienes and prostaglandin D2 indicate the involvement of these cells in the chronic inflammation. Studies to identify proinflammatory cytokines in chronic and acute sinusitis have so far demonstrated the role of nonspecific cytokines such as interleukin(IL)-1β, IL-6 and IL-8. Today, little is known about the interaction between the microorganisms and the mucous lining of the paranasal sinuses in terms of neutrophilic chemotaxis induction. In healthy people, more neutrophil granulocytes were found in nasal irrigation fluid (35%) than in the tissue itself (26, 33, 34). The continuous influx of neutrophil granulocytes is attributed to the chemotactic effect of IL-8, which is constitutively synthesized by epithelial cells, glandular cells and leukocytes (31, 35-38). Besides the IL-8-triggered migration of neutrophil granulocytes into inflamed tissue (which clearly plays a role in chronic sinusitis), IL-3 is also believed to be important. IL-3 is synthesized predominantly by activated T-cells (39) and leads to the stimulation, differentiation and activation of macrophages, neutrophils and mast cells, as well as eosinophils. Through the release of various mediators from the above cell populations, IL-3 may contribute to the local immunological response and presumably also to the development of a thickened mucous membrane in the sense of an exaggerated repair mechanism (8, 40). Clinically, the term nasal polyposis comprises all types of nasal polyps, which emerge as blue–gray protuberances in the area of the ethmoid bone, middle meatus nose, and middle turbinate. Larsen (41) and Stammberger (42) identified the mucous membrane of the middle turbinate and middle meatus as the origin, while the inferior turbinate does not tend to form polyps; the reasons for this are unknown. In clinical terms, nasal polyposis, characterized by eosinophil inflammation, is accompanied by acetylsalicylic intolerance in up to 25% of cases. Up to 40% of cases of nasal polyposis are associated with intrinsic asthma. Nasal polyposis associated with corticosteroid-sensitive bronchial asthma and aspirin sensitivity is known as Samter's syndrome. Confirmed associations have also been described between eosinophilic nasal polyposis and Churg–Strauss syndrome, a form of eosinophilic immunovasculitis (43). The predisposing role of an allergy to inhaled allergens in the development of nasal polyposis is questioned because of the low frequency of nasal polyps in allergic patients. Generally speaking, nasal polyps are cited as prevalent in less than 5% of allergic people, while allergy is prevalent in 15% of the general population. A study of 3000 atopic patients found a prevalence of 0.5% for nasal polyps, while the study in 300 nonallergic patients showed a prevalence of 4.5% (43, 44). The example of allergic paranasal sinus mycosis demonstrates that specific IgE and IgG antibodies may be formed jointly and appear to express a locally circumscribed allergic eosinophilic immune response in the paranasal sinuses (45-47). In histological terms, nasal polyps are characterized by edema and/or fibrosis, reduced vascularization, and a reduced number of glands and nerve endings in the presence of often damaged epithelium (41, 48). Histological evaluations of polyps generally make a rough distinction between eosinophilic polyps, which correspond to approximately 65–90% of total cases, and neutrophilic polyps (49). Pathogenically, the increased tissue eosinophilia is explained by increased transendothelial migration and the inhibition of programmed cell death of eosinophils (50, 51). RANTES protein (regulated on activation, T-cell expressed and secreted) is a member of the C–C chemokine family that induces eosinophil chemotaxis, transendothelial migration, the production of reactive oxygen radicals, and the release of eosinophil cationic proteins (ECP) in vitro (52, 53). Besides RANTES, eotaxin plays the main role in the selective migration of eosinophil granulocytes in vivo and in vitro (54, 55). In fact, it has been possible to demonstrate in the context of nasal polyps that RANTES might be responsible for the localization of the cells (56), and eotaxin for the accumulation of eosinophils, especially in IL-5-rich tissue (57). Cytokines such as IL-3, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon(IFN)-γ increase the vitality of eosinophil granulocytes by inhibiting programmed cell death (apoptosis). In-vitro studies of the apoptotic behavior of eosinophils in bilateral nasal polyps show reduced eosinophil apoptosis, which appears to be regulated by the cytokine IL-5. IL-5 is presumably also synthesized and released by eosinophils, setting in motion an autocrine inflammatory mechanism that is responsible for the persistent eosinophilia (50, 51). The extravasation and storage of plasma proteins (albumin) has been identified as a link between eosinophilic inflammation and polyp growth (57). In acetylsalicylic acid intolerance, there is a shift in the arachidonic acid metabolism (cyclooxygenase inhibition) with increased leukotriene production in the presence of a reduced tissue prostaglandin level (58-61). Colonization with enterotoxin-forming Staphylococci, whose products act as super-antigens and cause local polyclonal IgE formation, has recently been described as a possible pathological mechanism in bilateral eosinophilic nasal polyposis with associated asthma and aspirin sensitivity (62). The presence of enterotoxin-specific IgE antibodies in the tissue is accompanied by relatively severe eosinophil inflammation. The significance of these enterotoxins for the clinical severity of the condition needs to be established in more extensive studies. In endemic (in some cases, allergic) paranasal sinus mycosis, the causal importance of fungal infections has been confirmed. The majority of all of the conditions that affect the paranasal sinuses have also recently been attributed to fungal infections, although neither the causal linkage of pathophysiological mechanisms, nor the positive effect of antimycotic treatment, has yet been demonstrated (63, 64). Neutrophil granulocytes are associated with the development of nasal polyps in cystic fibrosis, and in Young's and Kartagener's syndrome. "Neutrophil-dominated polyps" are found in 15–20% of cases by histology. In cystic fibrosis, a genetic defect interferes with the sodium chloride ion pump in the epithelial cells of various organ systems, such as the bronchial mucosa, nasal mucosa and pancreas. The increased secretion of sodium ions and the reduced discharge of chloride ions causes thickening of the nasal secretion as a result of dehydration. The clinical picture of this condition is characterized essentially by recurrent infections with problem microorganisms such as Pseudomonas aeruginosa and Staphylococci. Kartagener's syndrome is a form of ciliary dyskinesia with an estimated incidence of 1 : 20 000. The ciliary immotility affects not only the respiratory epithelium, but also sperm motility. Besides bronchiectasis and nasal polyps, situs inversus is also observed in 50% of cases. Young's syndrome is another condition caused by bronchiectasis, recurrent respiratory infection, and nasal polyposis, whose prevalence is estimated to be higher than that of cystic fibrosis and Kartagener's syndrome. In this condition, ciliary motility is not affected; rather, azoospermia is caused by a change in the ductus epididymidis that is ultimately responsible for 7.4% of cases of male infertility (43). The typical symptoms of acute sinusitis, the episodes of acute recurrent sinusitis or chronic sinusitis, differ quantitatively more than qualitatively, and according to time factors. In acute forms, the condition has a clear onset in time, and the symptoms are nasal obstruction, purulent rhinorrhoea, postnasal secretion, severe headache that typically projects into the paranasal sinuses, and uncharacteristic headache, cough, a general lack of vitality, and depression. In children, vomiting may also be present, particularly in association with coughing episodes. In chronic sinusitis, the symptoms are often less severe, characterized mainly by obstruction and nonspecific headache (65). Although these symptoms are sensitive markers of sinusitis, only fever, facial flushing, and maxillary pain are specific to and therefore evidential of acute sinusitis (66). A purulent secretion from the nose is relatively typical of sinusitis and also has a high incidence (67), but patients with viral rhinitis can also have a purulent secretion, and patients with purulent sinusitis are free from rhinorrhoea when the ostia are blocked. Therefore, purulent secretion has a sensitivity of 72%, but only a specificity of 52% (68). Whereas the above mentioned symptoms are regularly found in acute or recurrent-acute sinusitis, chronic sinusitis is clinically defined above all from the duration of the symptoms. Depending on the author and study group, a symptom duration of 8 weeks (69) to 12 weeks (65) is required for this definition to apply. However, since hardly anyone experiences completely consistent symptoms throughout the 2–3-month period, and since therapeutic interventions bring about symptomatic improvements, it is becoming increasingly common to define chronic sinusitis from the number of episodes per year (more than four, each lasting for 10 days) (5). Besides nasal obstruction and discharge, an important symptom of nasal polyposis is impairment of the sense of smell. In patients with nasal polyps, hyposmia or anosmia were found preoperatively in 76% of patients (70), while only 58% with chronic sinusitis showed an impaired sense of smell (71). The diagnosis of sinusitis is based on the case history, clinical examination, and additional techniques such as imaging, allergy testing, and inflammatory parameters. When taking the history, the typical symptoms of the patient should be recorded during spontaneous conversation and, if necessary, followed by questions on the most important individual symptoms. In a condition such as sinusitis, which follows a complicated time-course, a talk with the doctor can be supplemented—not replaced—by questionnaires. In one study, the symptoms of depression, disturbed sleep, nasal secretion, nasal obstruction, and hyposmia were recognized to be predictive of sinusitis (72, 73). The relative risks of sinusitis for a positive response to the following symptoms are: maxillary pain 2.9; no improvement on antihistamines or decongestants 2.4; purulent secretion according to the patient 2.2; and purulent secretion at rhinoscopy 2.9. These results (68) show that although adequate diagnostic certainty cannot be obtained by taking the history alone, some symptoms are nevertheless indicative. The differential diagnosis of sinusitis also needs to be considered; important conditions are listed in Table 3. During clinical examination, attention should be paid to any swellings and redness as well as any skin changes over the sinuses; patients are relatively frequently found to have halo eyes or discrete eyelid edema. Hypoplasia of the bony middle part of the face also often accompanies chronic sinusitis. An inspection of the facial part of the skull should be followed by anterior rhinoscopy and posterior rhinoscopy. As a sine qua non, endoscopy of both nasal cavities and the nasopharynx with rigid optics is the gold standard in clinical examinations (74, 75). The patient should be given a decongestant nasal spray and a mucous membrane anaesthetic a few minutes beforehand. The examination shows all the structures of the nasal cavity (as well as the ostia of the paranasal sinuses), the structure, color and consistency of the mucous membrane can be assessed differentially, and tumoral masses can be detected at an early stage (76). Currently the best procedure for imaging of the paranasal sinus system has proved to be CT scanning in a coronary and axial plane, or reconstruction (77). With modern generations of equipment, MRI scanning may be used as an alternative in isolated cases in the presence of inflammation (78). In individual cases, as well as for guidance purposes, and in the case of fractures and osteomas, conventional x-rays from occipitomental and occipitofrontal planes are indicated because of the better overall When the it should considered that CT scan findings have to be pathological intraoperatively in up to of cases However, any of pathological findings in the paranasal sinuses should be because these do also in the presence of viral infections (3). A of for the of CT findings have to reveal a with the clinical so at the they have no clinical significance rhinitis be in the diagnostic because of known incidence of up to a procedure is the with of allergens The skin can be supplemented by specific IgE studies are indicated particularly in the presence of a persistent purulent secretion when antibiotic treatment has proved and differentiation are the clinical to be particularly in the presence of acute while in chronic forms eosinophil are often In the presence of suspected the of in is The role of nasal is limited to the particularly in the case of eosinophilic and neutrophilic rhinitis because the is hardly have been for the of nasal mediators standard for eosinophilic proteins can be given ciliary dysfunction, the is used for guidance while may be by Nasal are indicated in cases of suspected and fungal infections it can be that the diagnosis of sinusitis with the case history, is by the of nasal imaging and allergy and may be supplemented by additional techniques (Table The is based on literature The evaluations do not of the of the medicinal products for sinusitis. sinus drainage and ventilation appears to be a therapeutic in both acute and chronic sinusitis. However, nasal decongestants has been only in and hardly at all in sinusitis. A study that used MRI to the decongestant effect was to show only a effect of on the inferior and middle and no effect at all on the mucous membranes of the maxillary and sinuses studies in which decongestants were used with an antibiotic for the treatment of chronic maxillary sinusitis in showed no in therapeutic A treatment study in chronic purulent rhinosinusitis the of and with and the additional local of This an over treatment for both treatment antibiotic treatment no this effect was to the decongestant or to the have been no studies of acute sinusitis. However, antibiotic treatment and/or nasal irrigation have been to be to nasal or decongestant treatment alone or and decongestants nasal obstruction and symptomatic shows that in the middle meatus can be in the however, there is no evidence of in the duration of or in the paranasal sinus symptoms in acute or chronic sinusitis. In the case of or a distinction be made between defined such as or and Although the are often used as antibiotic treatment in sinusitis, there is no evidence that the treatment is have been no studies on sinusitis, in the acute or chronic form of this condition, that evidence of a therapeutic The is different with studies of the and a clinical of acute sinusitis have been with a of These that therapeutic are in acute sinusitis with of a as an to treatment with and decongestant nasal The studies in chronic sinusitis is A mechanism of effect has been for another although there is no of an improvement in the symptoms of the condition according to studies or also positive for other agents in sinusitis, any evidence by Although isolated studies appear to the of no is on the or and chronic sinusitis, as well as nasal polyps, are to be as inflammatory conditions of the paranasal sinuses, which is why treatment of the mucous membrane is a Although the of into the paranasal sinuses is not a therapeutic effect may be explained by the effect in the of the ostiomeatal complex or middle and by the and release of a of cytokines and which are in sinusitis. This is particularly true for IL-8, and IL-6 in acute sinusitis, and IL-3 and in chronic sinusitis the release of leukotrienes and is also Therefore, the neutrophilic inflammatory response with immunological In acute sinusitis, there have been studies of the use of as to an antibiotic (Table reported on a study in to weeks of antibiotic treatment, used for weeks the of the treatment nasal and the total for nasal including headache and facial was in the Similar were made by in from years with acute sinusitis. Besides antibiotic treatment, the patients for only the symptoms of nasal secretion and were reduced in the The and most study was conducted in over patients with acute sinusitis Besides antibiotic treatment, which was in both in the and this was with a nasal spray over a The patients to a of typical sinusitis symptoms and also have a pathological CT treatment, with a total symptom less headache and facial as well as nasal the for secretion and also to be The in symptoms was of the presence of an and the were in both treatment a CT scan at the of treatment showed a in swelling of the mucous particularly in the of the middle meatus and In all of the of was to antibiotic treatment alone, and the typical symptoms of the condition, including nasal blockage and facial Therefore, the additional effect of treatment, as an to an can be as in acute sinusitis. have been studies of the use of in chronic sinusitis (Table An study a of antibiotic with a antibiotic alone in patients with chronic sinusitis, and better with the only of treatment the effect of in patients with chronic sinusitis, at the with a maxillary sinus as well as for The showed a significant improvement in coughing and a significant in nasal symptoms and facial the time, the findings in this were not A recently study in patients with chronic sinusitis a significant improvement in the nasal and quality of life on nasal for 20 weeks In chronic sinusitis, there is a for studies involving imaging The results a treatment effect on the symptoms of chronic sinusitis due to the treatment with in patients have to Nasal polyps associated with in are characterized by a severe inflammatory response by cytokines such as IL-5 and such as eotaxin and