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Rhinosinusitis (RS) affects approximately 1 in 7 adults in the United States, and its effect on quality of life, productivity, and finances is substantial. During the past 10 years, several expert panels from authoritative bodies have published evidence-based guidelines for the diagnosis and management of RS and its subtypes, including acute viral RS, acute bacterial RS, chronic RS (CRS) without nasal polyposis, CRS with nasal polyposis, and allergic fungal RS. This review examines and compares the recommendations of the Rhinosinusitis Initiative, the Joint Task Force on Practice Parameters, the Clinical Practice Guideline: Adult Sinusitis, the European Position Paper on Rhinosinusitis and Nasal Polyps 2007, and the British Society for Allergy and Clinical Immunology. Points of consensus and divergent opinions expressed in these guidelines regarding classification, diagnosis, and management of adults with acute RS (ARS) and CRS and their various subtypes are highlighted for the practicing clinician. Key points of agreement regarding therapy in the guidelines for ARS include the efficacy of symptomatic treatment, such as intranasal corticosteroids, and the importance of reducing the unnecessary use of antibiotics in ARS; however, guidelines do not agree precisely regarding when antibiotics should be considered as a reasonable treatment strategy. Although the guidelines diverge markedly on the management of CRS, the diagnostic utility of nasal airway examination is acknowledged by all. Important and relevant data from MEDLINE-indexed articles published since the most recent guidelines were issued are also considered, and needs for future research are discussed.
ABRS = acute bacterial RS; AFRS = allergic fungal RS; AR = allergic rhinitis; ARS = acute RS; AVRS = acute viral RS; BSACI = British Society for Allergy and Clinical Immunology; CPG:AS = Clinical Practice Guideline: Adult Sinusitis; CRS = chronic RS; CT = computed tomography; EP3OS = European Position Paper on Rhinosinusitis and Nasal Polyps 2007; FDA = US Food and Drug Administration; JTFPP = Joint Task Force on Practice Parameters; NP = nasal polyposis; RI = Rhinosinusitis Initiative; RS = rhinosinusitis; VAS = visual analog scale
Rhinosinusitis (RS) poses a major health problem, substantially affecting quality of life, productivity, and finances. According to a recent analysis of US National Health Interview Survey data, RS affects approximately 1 in 7 adults.1 The number of workdays missed annually because of RS was similar to that reported for acute asthma (5.67 days vs 5.79 days, respectively), and patients with RS were more likely to spend greater than $500 per year on health care than were people with chronic bronchitis, ulcer disease, asthma, and hay fever (all, P<.001).2 Other data suggest that chronic RS (CRS) affects certain general health domains (social functioning, bodily pain) more than angina, chronic heart failure, chronic obstructive pulmonary disease, or chronic back pain.3
Although a common illness, RS presents a number of diagnostic and management challenges to the practicing clinician. Rhinosinusitis is the broad umbrella term covering multiple disease entities, including acute RS (ARS), CRS, and nasal polyposis (NP).4 However, RS has numerous subtypes and distinct etiologies, wide variations in severity and clinical presentation, and overlapping symptomatology and/or pathology with other medical conditions. Simple and accurate office-based testing methods for its detection are lacking.
During the past decade, a number of expert panels have put forth evidence-based guidelines for the diagnosis and management of RS, including its subtypes.4-7 Table 1 lists the organizations contributing to each of the projects: the European Position Paper on Rhinosinusitis and Nasal Polyps 2007 (EP3OS),4 the Rhinosinusitis Initiative (RI),5,9 the Joint Task Force on Practice Parameters (JTFPP),6 and the Clinical Practice Guideline: Adult Sinusitis (CPG:AS).7 Another, comparatively brief, guideline has been released by the British Society for Allergy and Clinical Immunology (BSACI)8; its recommendations frequently correspond with those of the EP3OS. These guidelines draw from the evidence base of the published literature and reflect as well the viewpoints of many leading experts in the fields of allergy, immunology, and otolaryngology. Intended to benefit the practicing clinician, this review compares the recommendations made for the diagnosis and management of RS in these 5 guidelines and evaluates the sometimes limited and contradictory evidence that underpins them and the variable quality of the studies that produced that evidence. Significant, relevant data published in MEDLINE-indexed articles since the most recent guidelines were issued are
also reviewed. Key recommendations for diagnosis and treatment are indicated throughout the article in italics. As it is beyond the scope of this review to address the entire contents of these guidelines, the reader is encouraged to refer to the original documents.
Of the 5 guidelines and expert panel documents, 4 (EP3OS, RI, CPG:AS, and BSACI)4,5,7,8 have adopted the term rhinosinusitis in place of sinusitis, the exception being the JTFPP.6 The term rhinosinusitis may be more appropriate given that the nasal middle turbinate extends directly into the ethmoid sinuses, and effects on the middle turbinate may be seen in the anterior ethmoid sinuses as well. Clinically, sinus inflammation (ie, sinusitis) rarely occurs without concomitant inflammation of the contiguous nasal mucosa.7 Regardless, the expert panels that adopted rhinosinusitis acknowledged that the terms rhinosinusitis and sinusitis should be used interchangeably, especially because the term rhinosinusitis has only come into common use during the past decade.
Of the various subclassifications of RS, the simplest differentiation is based on duration of symptoms. Acute RS is defined by 3 of the guidelines (RI, JTFPP, and CPG:AS) as symptom duration of 4 weeks or less.5-7 The EP3OS4 and BSACI8 guidelines qualify ARS as lasting less than 12 weeks, with complete resolution of symptoms. The CPG:AS includes a category of subacute RS, defined as symptom duration between 4 and 12 weeks,7 whereas the JTFPP6 definition specifies 4 to 8 weeks. Recurrent ARS is classified by the CPG:AS guidelines as 4 or more episodes of ARS within 1 year, without persistent symptoms between episodes.7 The JTFPP defines recurrent RS as 3 or more episodes per year.6
All 5 guidelines recognize that an assessment of symptom severity is important to define the magnitude of disease and assist with treatment selection. For clinical purposes, the EP3OS and BSACI guidelines categorize disease severity on the basis of a 10-cm visual analog scale (VAS) that has been statistically validated for use in patients with RS. Patients responding to the question “How troublesome are your symptoms of rhinosinusitis?” provide a rating, with the scale ranging from 0 (“not troublesome”) to 10 (“worst thinkable troublesome”). Scores are categorized as follows, between 0 and 3, mild disease; greater than 3 to 7, moderate disease; and greater than 7 to 10, severe disease.4 Scores greater than 5 have been correlated with quality of life detriments.10
The expert guidelines demonstrate close agreement in their identification of the hallmark signs or symptoms of ARS; however, specific algorithms differ somewhat, as detailed in Table 2.4-7 Three major signs or symptoms are consistently cited across all the guidelines as being primary diagnostic indicators for ARS: nasal congestion, obstruction, or blockage; anterior and/or posterior purulent rhinorrhea (EP3OS4 and BSACI8 do not specify “purulent”); and facial pain or pressure. The RI guidelines5 state that a diagnosis of ARS is probable if 2 or more of these major symptoms are present (the 3 already cited, as well as hyposmia-anosmia and fever), or 1 major symptom along with 2 or more minor symptoms (listed in Table 2). The JTFPP guidelines6 include these 4 symptoms along with headache and cough as being indicative of ARS. The CPG:AS guidelines7 require evidence of purulent nasal discharge for an ARS diagnosis, which must be accompanied by nasal obstruction, facial pain or pressure, or both. The EP3OS guidelines4 require the presence of 2 or more major symptoms, 1 of which must be either nasal discharge or nasal blockage, congestion, or obstruction; other symptoms can include facial pain or pressure or reduction or loss of smell. The BSACI guidelines8 have these requirements plus characteristic signs on either endoscopy or computed tomography (CT). It should be noted that fever is cited as a possible diagnostic indicator only in the RI guidelines.5
Acute RS is most commonly viral in origin (eg, the common cold). The incidence of acute viral RS (AVRS) is extremely high, estimated to occur from 2 to 5 times per year in an average adult.4 Secondary bacterial infection is thought to complicate only a very small percentage of cases (0.5%-2.0%).4 One of the primary challenges in managing ARS is the proper identification of cases with bacterial etiology.
Although the general presentation of AVRS and acute bacterial RS (ABRS) can be extremely similar, a particular emphasis on the duration, pattern, and/or severity of symptoms can help differentiate bacterial from viral illness. As illustrated in Figure 1,7,10,11 AVRS symptoms typically peak within 2 to 3 days of onset, decline gradually thereafter, and disappear within 10 to 14 days. Thus, cases that deviate from this pattern are likely not viral. This remains one of the simplest and most reliable means of evaluating ARS etiology. Persistent symptoms between days 5 to 10 are the most difficult to assess, because they can represent either lingering evidence of viral disease or the beginning of bacterial infection.7 Four of the guidelines (all except the BSACI guidelines8) agree that symptoms persisting for 10 days or more and/or showing a pattern of initial improvement followed by worsening are likely bacterial in origin (Table 2). Of the 5 guidelines,5-9 4 (RI, JTFPP, CPG:AS, and BSACI) suggest that unusually severe symptoms (eg, high fever, unilateral facial/tooth pain, orbital cellulitis, intracranial expansion), particularly during the first several days of disease, are also suggestive of ABRS. The JTFPP6 and CPG:AS7 guidelines indicate that neither nasal mucus color nor the presence of fever is useful in differentiating bacterial from viral disease.
The CPG:AS document highlights 3 cardinal symptoms with the highest relative specificity and sensitivity for ARS in general: purulent nasal drainage in the presence of nasal obstruction and/or facial pain, pressure, or fullness is the cornerstone of diagnosis.7 Nasal purulence alone cannot distinguish between viral and bacterial infection, but a diagnosis of ABRS is unlikely in its absence, even when other cardinal symptoms are evident. In other words, specificity for ABRS increases when nasal obstruction or facial pain occurs in combination with nasal purulence. Isolated symptoms of nasal obstruction or facial pain could have a broad differential diagnosis, but when coupled with purulent nasal discharge, they become much more specific for ABRS, particularly when they persist longer than 10 days.7
Acute RS can generally be diagnosed adequately on the basis of clinical findings alone, without the use of special imaging techniques or other assessments. However, the consensus guidelines recognize particular situations in which special assessments may have a role. According to all the guidelines, plain radiography is neither useful nor cost-effective. Computed tomography is not recommended as part of the routine work-up but is mentioned by some guidelines (EP3OS and CPG:AS) as a preferred imaging option for cases characterized by severe disease, immunocompromised state, or suspected complications.4,7 The RI guidelines recommend CT before surgery and for evaluation of cases with recurrent ARS. The JTFPP asserts that radiographic assessment is generally unnecessary, but imaging studies (CT, not plain radiography) can be useful in certain situations to support the diagnosis or establish the degree of mucosal involvement.6 The BSACI guidelines recommend the use of CT but do not consider it a “primary investigation.”8
Nasal Endoscopy. Compared with anterior nasal examination, nasal endoscopy provides a better means of examining the middle meatus region and sphenoethmoidal recesses for the presence of purulence associated with ARS.12 However, it is not available to most primary care physicians. Aside from the BSACI, the guidelines are in agreement that nasal endoscopy is not essential for the diagnosis of ARS.8 The RI document states that nasal endoscopy might be indicated for evaluating cases refractory to empirical treatment, patients with unilateral disease without septal deviation, and patients with severe, disabling symptoms.9 The JTFPP guidelines suggest considering nasal endoscopy during the initial work-up or in cases of treatment failure.6
Nasal Culture. Nasal culture is not generally recommended for the routine work-up of uncomplicated ARS (JTFPP, CPG:AS, BSACI)6-8; however, the EP3OS guidelines4 consider it an option in the event of treatment failure or complications. The RI guidelines5 affirm that properly obtained endoscopic cultures can be useful to identify causative organisms in certain forms of RS.
Sinus Puncture. Although rarely indicated for routine patient care, sinus puncture is the methodology considered the criterion standard for confirming bacterial pathogens within the maxillary sinuses (EP3OS, JTFPP, CPG:AS, RI).4,6,7,9,13 As such, sinus puncture has most applicability in the clinical trial setting. However, the JTFPP mentions certain clinical situations that may warrant sinus puncture to obtain diagnostic cultures; for example, it may be useful in acute episodes that are refractory to treatment or for rapid and accurate identification of the causative organism in immunosuppressed patients.5 Sinus puncture is typically performed by inserting a large-bore needle into the maxillary sinus through the inferior meatus or canine fossa.9,14,15
The fundamental issue in determining appropriate treatment is identifying which ARS cases warrant antibiotics. Survey data confirm a remarkable overuse of antibiotics for ARS that is most likely viral rather than bacterial. Only an estimated 0.5% to 2.0% of ARS episodes have a bacterial etiology. In addition, the recent consensus documents discussed herein have reconsidered the appropriateness of antibiotic use for mild cases of presumed ABRS. Clinical studies have confirmed that roughly 60% of presumed ABRS cases resolve spontaneously without antibiotics. Despite this compelling evidence indicating that antibiotics are overused, recent data from the United States and United Kingdom indicate that antibiotics are prescribed in 81% to 92% of ARS cases.16,17 Unnecessary prescribing of antibiotics adds to treatment costs, puts patients at risk of adverse events, and adds to the growing problem of antimicrobial resistance.
Evidence-based treatment recommendations from EP3OS, JTFPP, and CPG:AS are summarized in Table 3, along with their strength and level of evidence.4,6,7 The graded evidence-based recommendations from BSACI simply note that the use of topical corticosteroids or an antihistamine together with antibiotics is associated with more rapid symptom resolution, and this is given a grade of A; elsewhere it is noted that antibiotics should be reserved for severe symptoms, such as maxillary pain, swelling, and fever.8 Although the BSACI grading system is undefined, it appears similar to that used by the EP3OS guidelines (Table 3). The key features for evaluating antibiotic appropriateness should be symptom severity and duration. These 4 guidelines (all except BSACI) recommend antibiotics for any patient presenting with severe illness, and EP3OS, JTFPP, and CPG:AS recommend antibiotics for those who do not show improvement beyond given time points or for those whose symptoms worsen (see Table 3 for specific criteria). The EP3OS guidelines recommend no treatment other than symptomatic relief for at least the first 5 days because this is the “window” of time when AVRS is still the most likely diagnosis. If symptoms persist or increase beyond 5 days, moderate cases should first be prescribed intranasal corticosteroids, with antibiotics added if no improvement occurs after 14 days; severe cases qualify for initial combination therapy with intranasal corticosteroids plus antibiotics.4 The CPG:AS cautions that mucus color should not dictate antibiotic use because color relates to the presence of neutrophils, not bacteria.7 Clearly, the intent of these key recommendations is to reduce the use of antibiotics for cases of AVRS and mild ABRS.
“Watchful waiting” and symptomatic relief are generally recommended initially for cases not meeting the criteria for antibiotic intervention. The 4 guidelines with evidence-based ARS treatment recommendations (EP3OS, JTFPP, CPG:AS, and BSACI) recognize the usefulness of intranasal corticosteroids, which is supported by strong evidence from multiple randomized controlled trials.4,6-8 However, it should be noted that intranasal corticosteroids are not approved by the US Food and Drug Administration (FDA) for treatment of ABRS.
The EP3OS guidelines suggest that oral corticosteroids may be useful for pain relief in severe disease.4 The use of topical or oral decongestants is acknowledged, but the EP3OS, JTFPP, and CPG:AS guidelines conclude that sufficient data are lacking to fully evaluate the usefulness of these agents in ARS. Data on antihistamine use in ARS are also scarce; the JTFPP does not recommend their use,6 whereas the CPG:AS, EP3OS, and BSACI guidelines recognize their potential value in allergic patients.4,7,8 The CPG:AS also recommends nasal saline irrigation.7
Despite a good deal of overlap between ARS and CRS with regard to individual symptoms, CRS is much more heterogeneous. The greater complexity of CRS is exemplified by a lack of agreement among leading authorities as to the categorization of the disease. Of the 5 consensus guidelines, the RI group has proposed the most detailed subclassification scheme to date (Figure 2).5 In this scheme, the most important differentiating features are the presence or absence of the following: (1) NP, (2) eosinophilic or other inflammatory features, and (3) fungal hyphae in sinus mucus. Determination of inflammatory characteristics of the nasal mucosa requires evaluation of sinus tissue and/or sinus mucus. If such evaluations are not feasible in a clinical setting, the minimal recommended classification should at least differentiate between CRS with vs without NP. The proposed RI classification also takes into account other underlying or predisposing factors, such as mucus recirculation, humoral immune deficiency, abnormal mucociliary function, and allergic rhinitis (AR).5 The role of fungal involvement in CRS continues to be a focus of research and debate. Fungal allergy and the presence of fungal hyphae in eosinophil-laden mucus (known as allergic mucin) are key features identifying a small subset of cases of allergic fungal RS (AFRS). However, many more patients with CRS show immune hyperresponsiveness to fungi such as Alternaria species, as evidenced by increased cytokine expression independent of IgE levels, indicating that nonallergic mechanisms also play a role.77
In contrast to ARS, CRS generally cannot be diagnosed on the basis of symptoms alone. In fact, the guidelines display a general similarity in outlining diagnostic parameters for CRS that combine symptom assessments with objective findings of some type. Objective evidence of chronic sinus disease helps to distinguish CRS from other possible causes of CRS-type symptoms, including neoplasm or other sources of headache or dental pain.
Prolonged duration of RS symptoms (more than 8-12 weeks) is the primary reason to evaluate a patient for CRS.7 In this regard, it is important to distinguish CRS from recurrent ARS, the latter of which is typified by 2 to 4 isolated episodes of ARS per year, with complete resolution of symptoms between episodes. Such episodes should be treated like any other ARS event but also warrant further work-up to investigate potential underlying causes for the recurrence (eg, AR, cystic fibrosis, immunologic deficiency, ciliary dyskinesia, anatomic abnormalities).7
In general, individual symptoms of CRS are similar to those seen in ARS (anterior or posterior mucopurulent drainage; nasal obstruction; facial pain, pressure, or fullness) but may be milder or less dramatic and variable in presentation (Table 4).4-7 Rare cases of CRS may display a single symptom.5 A decreased sense of smell is identified by 4 guidelines (EP3OS, RI, CPF:AS, and BSACI)4,5,7,8 as an important CRS symptom but by only 2 guidelines as a symptom diagnostic of ARS.4,8 The EP3OS guidelines suggest additional minor symptoms of CRS, including ear pain or pressure, halitosis, dental pain, cough, fever, and fatigue.4 The EP3OS guidelines recommend evaluating the magnitude of symptom severity (mild, moderate, or severe), as discussed earlier for ARS, for purposes of treatment decisions.4
The RI, CPG:AS, and EP3OS guidelines are in relatively good agreement with regard to diagnostic symptom criteria. The RI guidelines5 stipulate the persistence for 12 or more weeks of at least 2 of 4 possible symptoms: (1) nasal congestion; (2) anterior or posterior mucopurulent drainage; (3) facial pain, pressure, or fullness; and (4) a decreased sense of smell. Facial pain, pressure, or fullness is relatively more common in CRS without NP, whereas a decreased sense of smell is more common in CRS with NP. The CPG:AS stipulates that, when present for 12 or more weeks, any 2 of the same 4 symptoms are diagnostic for CRS in general.7 The EP3OS and BSACI criteria are essentially the same as the CPG:AS, except that 1 of the hallmark symptoms must be either nasal discharge or nasal blockage and obstruction.4,8
In 4 guidelines, the importance of diagnostic testing is a key difference between CRS and ARS (Table 4).4-7 Some form of nasal airway examination is recommended by 4 of the guidelines (EP3OS, RI, CPG:AS, and BSACI) to establish a CRS diagnosis. Supportive findings include purulent mucus or edema in the middle meatus or ethmoid region; the presence or absence of NP can be established with examination.4,5,7,8 The JTFPP suggests that nasal endoscopy be considered in patients with CRS or ARS.6 The EP3OS, RI, CPG:AS, and BSACI guidelines preferentially support nasal endoscopy over anterior rhinoscopy, although anterior rhinoscopy is cited as a basic, preliminary evaluation tool.4,5,7 Nasal endoscopy allows better illumination and visualization of the posterior nasal cavity, nasopharynx, and sinus drainage pathways in the middle and superior meatus; it also allows delineation of nasal septal deviation, NP, and secretions in posterior regions. A 2010 study by Bhattacharyya and Lee78 found that addition of nasal endoscopy to symptom assessment substantially increased diagnostic accuracy in confirming the presence of CRS using sinus CT as the criterion standard. Nasal endoscopy can also facilitate the procurement of endoscopic cultures that are useful in guiding antibiotic selection in appropriate cases.5
All 5 guidelines acknowledge that CT has particular value in evaluating suspected CRS; however, it fails to achieve the status of a routine, first-line recommendation (Table 4). The RI guidelines state that CT is not essential to a diagnosis of CRS but should be strongly considered.5 The CPG:AS document requires objective documentation of inflammation, which can be achieved either by nasal endoscopy or CT.7 The EP3OS guidelines actually recommend against CT for primary care work-up of RS and characterize it as an optional work-up for ear, nose, and throat specialists.4
The JTFPP guidelines assert that imaging techniques (CT or magnetic resonance imaging) may be useful in confirming a diagnosis in patients with vague symptoms or if symptoms persist despite optimal medical treatment.6 A sinus CT may also be useful to identify structural abnormalities in the sinuses, bony erosion, or extrasinus involvement.7 Certain “benign” conditions can also cause extrasinus involvement, such as bony erosion and/or mucocele formation, which are found in some cases of AFRS. Such findings may require further evaluation by magnetic resonance imaging (EP3OS and CPG:AS).4,7 Magnetic resonance imaging, which provides an excellent display of the mucosa rather than of the bony anatomy, may be particularly useful in distinguishing bacterial or viral inflammation from fungal concretions (RI).5
Plain radiography has no benefit in the work-up of suspected CRS. When radiographic imaging is desired, the consensus documents are consistent in their recommendation of CT as a preferred technique.
Allergy and Immunology Evaluation. The JTFPP document recommends that patients with recurrent RS or CRS be evaluated for underlying allergy.6 Allergy testing is cited as an optional work-up in the CPG:AS guidelines in cases of CRS or recurrent ARS, with skin testing being the preferred method.7 The EP3OS guidelines recommend questioning patients with regard to allergies and doing further testing in patients with a history of allergy.4 The RI provides in-depth review of the association between allergic disease and RS but makes no formal recommendation regarding when such testing should be implemented.5
As many as 60% of patients with CRS have substantial allergic sensitivities, primarily to perennial allergens, such as house dust mites, cockroaches, pet dander, and fungi.79 Presumably, management of concomitant AR might be expected to decrease the frequency of RS through a reduction in nasal mucosal swelling and inflammation adjacent to the sinus outflow tract. Unfortunately, despite the epidemiological data, evidence-based data to support this assumption are somewhat sparse, leading the CPG:AS guidelines to conclude that allergy testing could not be “strongly recommended” but should be considered optional.7 The BSACI guidelines recommend skin prick testing in all cases of RS; however, it is noted that results should be interpreted in light of clinical history.8 In our experience, it is not uncommon for patients with CRS to be referred for an allergy evaluation only after having undergone a surgical procedure without benefit. Because many of these patients have perennial allergies, they could have had a better response to medical management of CRS had their allergies been identified in advance of sinus surgery. A suggested approach would be to evaluate any patient with CRS whose symptoms are not easily controlled by saline irrigations and intranasal medications for underlying allergies. This approach is especially recommended for patients who are being considered for sinus surgery.
The EP3OS, JTFPP, and CPG:AS guidelines recommend immunologic testing in patients with CRS or recurrent ARS in whom aggressive management has failed or who demonstrate recurrent or persistent purulent infections.4,6,7 An analysis of 79 radiographically confirmed cases of recurrent or refractory RS uncovered a diagnosis of common variable immunodeficiency in 10% of patients and selective IgA deficiency in 6%. Low titers of IgG, IgA, and IgM were noted in 18%, 17%, and 5% of cases, respectively.80 Sinus symptoms are also highly prevalent among patients infected with the human immunodeficiency virus.81,82 Laboratory work-up might include quantitative immunoglobulin assays (IgG, IgA, IgM), specific antibody responses to tetanus toxoid and pneumococcal vaccines (both before and after immunization), and assessments of T-cell number and function.6,7
Special Testing for AFRS. Only the RI and BSACI guidelines outline diagnostic criteria specific to AFRS. For the RI, these include the presence of at least 1 CRS symptom, the presence of endoscopy-documented allergic mucin and inflammation, skin or blood tests positive for fungus-specific IgE, and no histologic evidence of invasive fungal disease.5 For the BSACI, these include the presence of CRS with NP; specific antifungal IgE; CT heterogeneity, expansion, or erosion; eosinophilic mucin without fungal invasion; and fungi in sinus contents.8
The lack of an overall consensus or a succinct algorithm for the treatment of CRS is due in large part to the paucity of controlled studies for this indication. The design and interpretation of CRS clinical trials have been hindered by the inherent heterogeneity of the disease, a lack of uniform definitions for the various subtypes, an incomplete understanding of the underlying pathologies, and a lack of useful and standardized clinical and laboratory end points to measure response to therapy.83 In 2006, for the first time, the FDA included CRS (without specifying subtypes) in its guidelines for RS studies84 and began to recognize the validity of some CRS studies. Regardless, it may take time to acquire a sufficient body of reliable clinical data for this indication. Although an FDA-approved treatment for NP (mometasone furoate nasal spray) is currently available, no treatments have been approved by the FDA for CRS.
The EP3OS guidelines put forth treatment recommendations for CRS, categorized into 3 major subtypes (a scheme also adopted in large part by the BSACI guidelines8): CRS without NP, CRS with NP, and AFRS. Recommendations are stratified according to disease severity, using a VAS scale of 0 (none) to 10 (most severe). Table 5 summarizes these recommendations along with the less detailed guidance provided by the JTFPP and CPG:AS; levels of evidence and strength of recommendation given by the various guidelines are indicated. Other therapeutic modalities were also graded by the EP3OS guidelines (including antifungal agents, bacterial lysates, mucolytics, and short-term antibiotics), but these were not judged by the EP3OS authors to have clinical relevance and thus are not presented in Table 5.
CRS Without NP. Management of CRS without NP is divided into 2 categories. For mild symptoms (VAS score, 0-3), recommended initial management consists of intranasal corticosteroids along with nasal saline lavage. If the condition does not improve after 3 months, culture should be performed and long-term macrolide therapy instituted; CT may be useful at this stage. Lack of response to this strategy after another 3 months should prompt further CT evaluation and consideration of sinus surgery. In cases that do respond, ongoing follow-up is recommended, along with continued intranasal corticosteroid use and nasal saline lavage, with or without long-term macrolide therapy.4 For moderate or severe symptoms (VAS score, >3-10), initial management should include intranasal corticosteroids, nasal saline lavage, culture, and long-term macrolide therapy. If no response is seen after 3 months, further CT evaluation and surgical work-up are warranted. The EP3OS guidelines do not discuss how the results from sinus cultures might affect treatment.
The level of evidence assigned to some therapies by the EP30S guidelines is open to debate. For instance, the recommendation for long-term macrolide therapy is based on a study by Ragab et al,101 which was graded as level Ib evidence (based on at least 1 randomized controlled trial). In this trial, patients randomly assigned to medical treatment with erythromycin, alkaline nasal irrigation, and intranasal corticosteroids were found to have symptom scores and endoscopic findings at 6 and 12 months that were not significantly different from scores seen in patients who underwent surgery.101 However, no sham surgery was performed on the medically treated patients, making it impossible to rule out a placebo effect. Patients who underwent surgery also received medical therapy with erythromycin, intranasal corticosteroids, and alkaline nasal irrigation, and medical therapy late in the study could be tailored to each patient's symptoms, making it difficult to identify a true control group and thus to assess the value of any 1 therapy. These features are atypical for most randomized clinical trials. The study by Wallwork et al,102 also cited as Ib evidence, was a randomized, placebo-controlled investigation of 150 mg of roxithromycin vs placebo. In this study, patients in the roxithromycin group showed a statistically significant change from baseline in the Sino-Nasal Outcome Test 20 (SNOT20) score at 12 weeks not seen in the placebo group. In a similar “change from baseline” analysis, the roxithromycin group also showed an improvement in saccharine transit time and nasal endoscopy not seen in the placebo group. However, the statistical analysis in this study was unconventional in that it evaluated the results of each study arm at study end against respective values at baseline rather than a more conventional comparison of the change from baseline in each arm using an analysis of covariance model. Given this limitation, the efficacy of roxithromycin cannot be confirmed by the results of this study.
Studies cited by the EP3OS guidelines as evidence of the efficacy of nasal lavage for CRS with NP also merit a closer look. Bachmann et al90 randomly assigned 40 patients to nasal irrigation with isotonic Ems salt solution or isotonic sodium chloride solution. Significant improvements from baseline in subjective and objective measurement were seen, but no significant difference was found between groups. No true control group was studied; as the authors noted, it is not possible to find a true placebo because any watery solution would remove secretions and crusts in the nose and produce therapeutic effect. Despite these drawbacks, this study is cited in the EP3OS guidelines as level Ib evidence. Similarly, the studies by Shoseyov et al92 and Friedman et al94 are cited as level Ib evidence. Although both are randomized, double-blind studies, they compare 2 different solutions for nasal irrigation, with no true control. Additionally, the trial by Pinto et al,93 cited as level Ib, was randomized and controlled but examined normal or buffered hypertonic saline sprays (not irrigation) vs no treatment and found no beneficial effect for either active treatment. However, the randomized controlled studies by Rabago et al67 (N=62) and Taccariello et al91 (N=76) cited by the EP3OS guidelines showed significant benefit for nasal lavage vs control.
The evidence base supporting the order and duration of therapies recommended by EP3OS is also unclear. For example, an initial 3-month course of intranasal corticosteroids is recommended for mild symptoms of CRS. The recommendation of intranasal corticosteroids for CRS is cited as level Ib evidence, but the studies cited ranged in duration from 11 days to 20 weeks.85-89 The utility of the therapy may be supported by level Ib evidence, but no evidence is given for the 3-month duration.
The BSACI recommendations8 differ from the EP3OS guidelines4 on the following points: the recommendation for surgery only for treatment failures and the grade A recommendation for long-term antibiotics were both based solely on the study by Ragab et al,101 and addition of antihistamines for allergic patients is given a grade A recommendation. Additionally, surgery is recommended for AFRS.
CRS With NP. The EP3OS guidelines for managing CRS with NP are generally similar to CRS without NP, with the notable exception that antibiotics are not recommended.4
For symptoms of mild severity (VAS score, 0-3), treatment with an intranasal corticosteroid is recommended; if improvement is noted after 3 months, treatment should be continued with follow-up every 6 months. If no improvement is seen within 3 months, a short course of oral corticosteroids for 1 month is recommended. If that too is unsuccessful, CT is recommended, and the patient should be evaluated as a potential surgical candidate.
In cases of symptoms of moderate severity (VAS score, >3-7), topical corticosteroid drops are recommended initially for 3 months, with continued use and follow-up every 6 months thereafter if effective. If no improvement is seen after the initial 3 months, a short course of oral corticosteroids may be added for 1 month. If this strategy fails, CT is recommended, and the patient should be evaluated as a potential surgical candidate. If improvement is noted after the 1-month oral corticosteroid course, the patient can be switched back to topical corticosteroid drops.
Severe cases of CRS with NP (VAS score, >7-10) should initially be managed using a short course (1 month) of oral corticosteroids in combination with topical corticosteroids. If improvement occurs on this regimen alone, the patient may be switched to topical corticosteroids alone. Patients who do not initially show improvement should be evaluated via CT and considered for surgical intervention. After polypectomy, maintenance treatment with intranasal corticosteroids is generally recommended.
Again, the evidence on which EP3OS bases its recommendations for order and duration of therapies merits examination. For example, therapy with oral corticosteroids for CRS with polyps is cited as level Ib evidence on the basis of studies by Benitez et al122 and Hissaria et al.123 Both are randomized controlled trials that found significant benefit for oral corticosteroids vs placebo, as seen in objective measures of polyp size and subjective assessment of symptoms; however, both involved 14-day courses of corticosteroids, so it is unclear what evidence contributed to the recommendation of a 1-month course. Further, it is unclear what evidence supports the choice of corticosteroid drops vs sprays at any given point; the evidence level is cited as Ib for topical corticosteroids, and the trials provided as evidence include evaluations of both drops and spray formulations.
In addition to largely adopting the EP3OS recommendations, the BSACI guidelines recommend corticosteroid drops specifically for NP, citing 2 randomized controlled trials that the EP3OS guidelines also cited in recommending “topical” corticosteroids.4,8,111,114 The addition of oral antihistamines for allergic patients with CRS is given a grade A recommendation, and the use of antileukotrienes is given a grade C recommendation but considered clinically relevant.
AFRS. The EP3OS guidelines4 do not present a detailed treatment algorithm for AFRS. Surgery is indicated as a first-line treatment, along with topical or systemic antifungal drugs.
The JTFPP and CPG:AS guidelines propose very general management strategies for CRS, with no categorization of subtypes by CRS with vs without NP or AFRS. The RI document does not provide specific treatment recommendations.
The JTFPP guidelines6 indicate that the role of antibiotics in CRS is controversial but that antibiotics may be required for acute exacerbations of CRS. Intranasal corticosteroids are suggested as being modestly beneficial in CRS as an adjunct to antibiotic therapy in cases of recurrent ARS or CRS. The JTFPP guidelines state that antihistamines may have a role in the treatment of CRS when AR is also present because AR and CRS cause overlapping symptoms and AR may predispose patients to the development of CRS. (See “Allergy and Immunology Evaluation” for supportive evidence of a relationship between AR and CRS.) The guidelines acknowledge that topical and oral decongestants are often used in both ARS and CRS, although there are insufficient studies to determine their value for these indications. The guidelines also conclude that the role of antifungal agents in CRS has not been established.
The CPG:AS guidelines7 offer no specific treatment recommendations for CRS but rather try to minimize symptoms and prevent exacerbations by focusing on preventive measures, such as saline nasal irrigation, concomitant management of underlying conditions (eg, gastroesophageal reflux disease), and good hand hygiene to prevent AVRS. A recommendation is made to evaluate patients with CRS for the presence of contributory factors or other disease states that might complicate disease management (eg, AR, cystic fibrosis, immunodeficiency, ciliary dyskinesia, or anatomic variations).
Many issues remain to be addressed in the field of RS management, particularly CRS. An encouraging upsurge in the number of CRS-oriented investigational studies has occurred since publication of the most recent RS guidelines. Promising areas of investigation in CRS include studies of the role of bacterial biofilms, immune hyperresponsiveness to colonizing fungi, and defects in innate immunity in the initiation or persistence of CRS.
Many recent studies have been conducted in patients with CRS.165 Among the interventions being evaluated are topical antibiotic and antifungal agents, maxillary sinus irrigation or nasal spray, oral corticosteroids, a recombinant DNA–derived humanized IgG1κ monoclonal antibody (omalizumab), a novel leukotriene receptor antagonist (pranlukast), and the use of probiotics.165 However, lack of a clear consensus on the definition of subgroups within the CRS patient population, demonstrated by the varying definitions proposed by these guidelines, continues to hinder study design and limit the conclusions that can be drawn. The RI document9 presents recommendations to address these issues, including detailed guidance on study designs specific for subtypes of CRS and specific forms of treatment (eg, antimicrobial vs anti-inflammatory). These recommendations can be used in designing future trials, with the goal of evaluating appropriate interventions for the various etiologies and pathologies that can produce CRS. In addition to the efforts of the RI, the FDA published a 2006 guidance document on clinical trials of nonantibiotic agents for CRS.84 It is hoped that progress toward clinical trials will follow from this work because pharmaceutical and biotechnical companies have pointed to the lack of consensus on definitions and study designs for CRS as a major stumbling block to drug development. Although progress has been slow, expert panels have shown great motivation to advance this field, and there has been an uptick in funding from the National Institutes of Health for basic CRS investigations.165
Current consensus and evidence-based guidelines are in agreement with regard to the diagnosis and treatment of ARS. The efficacy of intranasal corticosteroids has been well established by clinical trial data, and all 4 guidelines with evidence-based treatment recommendations (EP3OS, JTFPP, CPG:AS, and BSACI) advise their use in ARS; these 4 guidelines also recommend antibiotics for patients presenting with severe ARS symptoms. An issue of great concern in ARS, in which most cases by far are viral and self-limiting, remains the continued high rate at which clinicians overprescribe antibiotics, a point on which the guidelines agree. However, although all the guidelines recognize symptom severity as a factor for determining when to use antibiotics, the means recommended for determining severity vary, from VAS in the EP3OS, BSACI, and RI guidelines to various possible scales in the CPG:AS guidelines to specific symptoms (eg, fever, purulent nasal discharge, facial pain or tenderness, and periorbital swelling) in the JTFPP guidelines. Thus, clinicians are presented with discordant guidance and must rely on clinical experience and judgment.
In contrast, consensus and evidence-based guidelines regarding CRS are much less congruent, possibly because of the greater complexity and heterogeneity of this condition and the paucity of clinical trials in this area. No overall consensus has been reached regarding treatment of CRS. The recommendations made by the EP3OS guidelines (and subsequently by the BSACI guidelines) for pharmacological treatment of CRS help fill a void in the literature but are sometimes lacking in rigorous evidence (eg, in their consideration of long-term use of macrolides). Few clinical trials have been conducted comparing the treatment of CRS without NP, CRS with NP, and AFRS as separate entities, although there has been a strong push to promote such trials.9 The guidelines also vary in their consideration of surgery, and one (CPG:AS) makes no recommendation what-soever regarding surgery. Many questions remain regarding optimal patient selection and surgical strategies. Nevertheless, the publication of 5 consensus documents within the past 6 years is a very good sign, and substantial progress has been made toward consensus disease definitions and basic investigations in CRS. The detailed CRS subgroup classification scheme and diagnostic methods proposed by the RI may be particularly useful in this regard. The lack of category I evidence for therapeutic modalities for CRS and the lack of understanding of CRS pathophysiology are continuing issues. Future clinical research should establish appropriate diagnostic testing strategies to identify pathogenic factors (eg, allergic, infectious, fungal) and ascertain which treatments are most effective for each. As a practical matter, we consider allergy testing (as recommended by the JTFPP, EP3OS, and BSACI guidelines) to be valuable for patients with long-standing or recurrent symptoms, especially when these symptoms are uncontrolled by topical saline and intranasal corticosteroids. Such testing is likely to play a part in forthcoming treatment strategies that are more closely directed to the underlying cause of CRS. It is hoped that the next generation of consensus guidelines will have a much greater knowledge base on which to draw to refine recommendations for practicing clinicians, with the ultimate goal of improving patient health outcomes.
We thank Karl Torbey, MD, and Rob Coover, MPH, of AdelphiEden Health Communications for editorial assistance. This assistance was funded by Schering Corp, now Merck & Co.
An earlier version of this article appeared Online First.