James A. Hadley

Adult chronic rhinosinusitis: definitions, diagnosis, epidemiology, and pathophysiology.

Abstract Chronic rhinosinusitis Chronic rhinosinusitis (CRS) is a term that has been used to describe a number of entities characterized by chronic symptoms of nasal and sinus inflammation or infection. There has been a lack of consensus regarding definitions and treatments because CRS may be a spectrum of diseases with a range of appropriate treatments. The absence of widely accepted definitions for CRS has resulted in a paucity of research directed at understanding its pathophysiology and has hampered efforts to improve treatment. A Task Force was convened by the Sinus and Allergy Health Partnership to summarize much of the current and important information available regarding the prevalence, economic impact, pathophysiology, common inflammatory mediators, and the role of infectious microbes such as bacteria and fungi in CRS. The goal is to establish a standard and usable definition. Through this thorough review of the literature and the expert input from Task Force members, a definition was developed that serves to create a consistent baseline so that many of the currently debated or unanswered questions may be addressed. The new and more-specific Task Force definition is that “ Chronic rhinosinusitis is a group of disorders characterized by inflammation of the mucosa of the nose and paranasal sinuses of at least 12 weeks duration.” Recommended criteria for making the diagnosis of CRS for both clinical care and research were also outlined.

Rhinosinusitis: Establishing definitions for clinical research and patient care

Background There is a need for more research on all forms of rhinosinusitis. Progress in this area has been hampered by a lack of consensus definitions and the limited number of published clinical trials. Objectives To develop consensus definitions for rhinosinusitis and outline strategies useful in clinical trials. Methods Five national societies, The American Academy of Allergy, Asthma and Immunology; The American Academy of Otolaryngic Allergy; The American Academy of Otolaryngology Head and Neck Surgery; The American College of Allergy, Asthma and Immunology; and the American Rhinologic Society formed an expert panel from multiple disciplines. Over two days, the panel developed definitions for rhinosinusitis and outlined strategies for design of clinical trials. Results Committee members agreed to adopt the term “rhinosinusitis” and reached consensus on definitions and strategies for clinical research on acute presumed bacterial rhinosinusitis, chronic rhinosinusitis without polyposis, chronic rhinosinusitis with polyposis, and classic allergic fungal rhinosinusitis. Symptom and objective criteria, measures for monitoring research progress, and use of symptom scoring tools, quality-of-life instruments, radiologic studies, and rhinoscopic assessment were outlined for each condition. Conclusion The recommendations from this conference should improve accuracy of clinical diagnosis and serve as a starting point for design of rhinosinusitis clinical trials.

Antimicrobial treatment guidelines for acute bacterial rhinosinusitis.

Abstract Treatment guidelines developed by the Sinus and Allergy Health Partnership for acute bacterial rhinosinusitis (ABRS) were originally published in 2000. These guidelines were designed to: (1) educate clinicians and patients (or patients’ families) about the differences between viral and bacterial rhinosinusitis; (2) reduce the use of antibiotics for nonbacterial nasal/sinus disease; (3) provide recommendations for the diagnosis and optimal treatment of ABRS; (4) promote the use of appropriate antibiotic therapy when bacterial infection is likely; and (5) describe the current understanding of pharmacokinetic and pharmacodynamics and how they relate to the effectiveness of antimicrobial therapy. The original guidelines are updated here to include the most recent information on management principles, antimicrobial susceptibility patterns, and therapeutic options. Burden of disease An estimated 20 million cases of ABRS occur annually in the United States. According to National Ambulatory Medical Care Survey (NAMCS) data, sinusitis is the fifth most common diagnosis for which an antibiotic is prescribed. Sinusitis accounted for 9% and 21% of all pediatric and adult antibiotic prescriptions, respectively, written in 2002. The primary diagnosis of sinusitis results in expenditures of approximately

Cutting Edge: Anti-Tumor Necrosis Factor Therapy in Rheumatoid Arthritis Inhibits Memory B Lymphocytes via Effects on Lymphoid Germinal Centers and Follicular Dendritic Cell Networks

3.5 billion per year in the United States. Definition and diagnosis of ABRS ABRS is most often preceded by a viral upper respiratory tract infection (URI). Allergy, trauma, dental infection, or other factors that lead to inflammation of the nose and paranasal sinuses may also predispose individuals to developing ABRS. Patients with a “common cold” (viral URI) usually report some combination of the following symptoms: sneezing, rhinorrhea, nasal congestion, hyposmia/anosmia, facial pressure, postnasal drip, sore throat, cough, ear fullness, fever, and myalgia. A change in the color or the characteristic of the nasal discharge is not a specific sign of a bacterial infection. Bacterial superinfection may occur at any time during the course of a viral URI. The risk that bacterial superinfection has occurred is greater if the illness is still present after 10 days. Because there may be cases that fall out of the “norm” of this typical progression, practicing clinicians need to rely on their clinical judgment when using these guidelines. In general, however, a diagnosis of ABRS may be made in adults or children with symptoms of a viral URI that have not improved after 10 days or worsen after 5 to 7 days. There may be some or all of the following signs and symptoms: nasal drainage, nasal congestion, facial pressure/pain (especially when unilateral and focused in the region of a particular sinus), postnasal drainage, hyposmia/anosmia, fever, cough, fatigue, maxillary dental pain, and ear pressure/fullness. Physical examination provides limited information in the diagnosis of ABRS. While sometimes helpful, plain film radiographs, computed tomography (CT), and magnetic resonance imaging scans are not necessary for cases of ABRS. Microbiology of ABRS The most common bacterial species isolated from the maxillary sinuses of patients with ABRS are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, the latter being more common in children. Other streptococcal species, anaerobic bacteria and Staphylococcus aureus cause a small percentage of cases. Bacterial resistance in ABRS The increasing prevalence of penicillin nonsusceptibility and resistance to other drug classes among S pneumoniae has been a problem in the United States, with 15% being penicillin-intermediate and 25% being penicillin-resistant in recent studies. Resistance to macrolides and trimethoprim/sulfamethoxazole (TMP/SMX) is also common in S pneumoniae. The prevalence of β-lactamase-producing isolates of H influenzae is approximately 30%, while essentially all M catarrhalis isolates produce β-lactamases. Resistance of H influenzae to TMP/SMX is also common. Antimicrobial treatment guidelines for ABRS These guidelines apply to both adults and children. When selecting antibiotic therapy for ABRS, the clinician should consider the severity of the disease, the rate of progression of the disease, and recent antibiotic exposure. The guidelines now divide patients with ABRS into two general categories: (1) those with mild symptoms who have not received antibiotics within the past 4 to 6 weeks, and (2) those with mild disease who have received antibiotics within the past 4 to 6 weeks or those with moderate disease regardless of recent antibiotic exposure. The difference in severity of disease does not imply infection with a resistant pathogen. Rather, this terminology indicates the relative degree of acceptance of possible treatment failure and the likelihood of spontaneous resolution of symptoms—patients with more severe symptoms are less likely to resolve their disease spontaneously. The primary goal of antibiotic therapy is to eradicate bacteria from the site of infection, which, in turn, helps (1) return the sinuses back to health; (2) decrease the duration of symptoms to allow patients to resume daily activities more quickly; (3) prevent severe complications such as meningitis and brain abscess; and (4) decrease the development of chronic disease. Severe or life-threatening infections with or without complications are rare, and are not addressed in these guidelines. Prior antibiotic use is a major risk factor associated with the development of infection with antimicrobial-resistant strains. Because recent antimicrobial exposure increases the risk of carriage of and infection due to resistant organisms, antimicrobial therapy should be based upon the patient’s history of recent antibiotic use. The panel’s guidelines, therefore, stratify patients according to antibiotic exposure in the previous 4 to 6 weeks. Lack of response to therapy at ≥72 hours is an arbitrary time established to define treatment failures. Clinicians should monitor the response to antibiotic therapy, which may include instructing the patient to call the office or clinic if symptoms persist or worsen over the next few days. The predicted bacteriologic and clinical efficacy of antibiotics in adults and children has been determined according to mathematical modeling of ABRS developed by Michael Poole, MD, PhD, based on pathogen distribution, resolution rates without treatment, and in vitro microbiologic activity. Antibiotics can be placed into the following relative rank order of predicted clinical efficacy for adults: 90% to 92% = respiratory fluoroquinolones (gatifloxacin, levofloxacin, moxifloxacin), ceftriaxone, high-dose amoxicillin/clavulanate (4 g/250 mg/day), and amoxicillin/clavulanate (1.75 g/250 mg/day); 83% to 88% = high-dose amoxicillin (4 g/day), amoxicillin (1.5 g/day), cefpodoxime proxetil, cefixime (based on H influenzae and M catarrhalis coverage), cefuroxime axetil, cefdinir, and TMP/SMX; 77% to 81% = doxycycline, clindamycin (based on gram-positive coverage only), azithromycin, clarithromycin and erythromycin, and telithromycin; 65% to 66% = cefaclor and loracarbef. The predicted spontaneous resolution rate in patients with a clinical diagnosis of ABRS is 62%. Antibiotics can be placed into the following relative rank order of predicted clinical efficacy in children with ABRS: 91% to 92% = ceftriaxone, high-dose amoxicillin/clavulanate (90 mg/6.4 mg per kg per day) and amoxicillin/clavulanate (45 mg/6.4 mg per kg per day); 82% to 87% = high-dose amoxicillin (90 mg/kg per day), amoxicillin (45 mg/kg per day), cefpodoxime proxetil, cefixime (based on H influenzae and M catarrhalis coverage only), cefuroxime axetil, cefdinir, and TMP/SMX; and 78% to 80% = clindamycin (based on gram-positive coverage only), cefprozil, azithromycin, clarithromycin, and erythromycin; 67% to 68% = cefaclor and loracarbef. The predicted spontaneous resolution rate in untreated children with a presumed diagnosis of ABRS is 63%. Recommendations for initial therapy for adult patients with mild disease (who have not received antibiotics in the previous 4 to 6 weeks) include the following choices: amoxicillin/clavulanate (1.75 to 4 g/250 mg per day), amoxicillin (1.5 to 4 g/day), cefpodoxime proxetil, cefuroxime axetil, or cefdinir. While TMP/SMX, doxycycline, azithromycin, clarithromycin, erythromycin, or telithromycin may be considered for patients with β-lactam allergies, bacteriologic failure rates of 20% to 25% are possible. Failure to respond to antimicrobial therapy after 72 hours should prompt either a switch to alternate antimicrobial therapy or reevaluation of the patient (see Table 4).When a change in antibiotic therapy is made, the clinician should consider the limitations in coverage of the initial agent. Recommendations for initial therapy for adults with mild disease who have received antibiotics in the previous 4 to 6 weeks or adults with moderate disease include the following choices: respiratory fluoroquinolone (eg, gatifloxacin, levofloxacin, moxifloxacin) or high-dose amoxicillin/clavulanate (4 g/250 mg per day). The widespread use of respiratory fluoroquinolones for patients with milder disease may promote resistance of a wide spectrum of organisms to this class of agents. Ceftriaxone (parenteral, 1 to 2 g/day for 5 days) or combination therapy with adequate gram-positive and negative coverage may also be considered. Examples of appropriate regimens of combination therapy include high-dose amoxicillin or clindamycin plus cefixime, or high-dose amoxicillin or clindamycin plus rifampin. While the clinical effectiveness of ceftriaxone and these combinations for ABRS is unproven; the panel considers these reasonable therapeutic options based on the spectrum of activity of these agents and on data extrapolated from acute otitis media studies. Rifampin should not be used as monotherapy, casually, or for longer than 10 to 14 days

Techniques of intranasal steroid use.

Rheumatoid arthritis (RA) is mediated by a proinflammatory cytokine network with TNF at its apex. Accordingly, drugs that block TNF have demonstrated significant efficacy in the treatment of RA. A great deal of experimental evidence also strongly implicates B cells in the pathogenesis of RA. Yet, it remains unclear whether these two important players and the therapies that target them are mechanistically linked. In this study we demonstrate that RA patients on anti-TNF (etanercept) display a paucity of follicular dendritic cell networks and germinal center (GC) structures accompanied by a reduction in CD38+ GC B cells and peripheral blood memory B cell lymphopenia compared with healthy controls and RA patients on methotrexate. This study provides initial evidence in humans to support the notion that anti-TNF treatment disrupts GC reactions at least in part via effects on follicular dendritic cells.

Rhinosinusitis: Developing guidance for clinical trials

OBJECTIVE: The effectiveness of topical intranasal steroids (INS) sprays for the treatment of allergic and nonallergic rhinitis may be limited by lack of instruction in the optimal spray technique. To determine whether the technique used affects the efficacy and safety of the product, this review of evidence had the goal of identifying and establishing a preferred method of applying INS sprays. STUDY DESIGN: A MEDLINE search of pertinent literature on 7 INS and 1 intranasal antihistamine spray preparations conducted with the use of appropriate search terms, yielded an initial 121 articles, 29 of which were identified as appropriate for review and grading for quality of evidence. RESULTS: The analysis provided no definitive evidence regarding how best to instruct patients to use INS or antihistamine spray devices. CONCLUSIONS: On the basis of a lack of clear evidence regarding instructions to maximize efficacy and safety of these drugs, the panel recommended a 7-step standard technique. (Otolaryngol Head Neck Surg 2004;130:5–24.)

Clinically relevant effect of a new intranasal therapy (MP29-02) in allergic rhinitis assessed by responder analysis.

The Rhinosinusitis Initiative was developed by 5 national societies. The current guidance document is an expansion of the 2004 publication, “Rhinosinusitis: Establishing definitions for clinical research and patient care” and provides templates for clinical trials in antimicrobial, anti-inflammatory, and symptom-relieving therapies for the following: (1) acute presumed bacterial rhinosinusitis, (2) chronic rhinosinusitis (CRS) without nasal polyps, (3) CRS with nasal polyps, and (4) classic allergic fungal rhinosinusitis. In addition to the templates for clinical trials and proposed study designs, the Rhinosinusitis Initiative has developed 6 appendices, which address (1) health outcomes, (2) nasal endoscopy and staging of CRS, (3) radiologic imaging, (4) microbiology, (5) laboratory measures, and (6) biostatistical methods.

RHINOSINUSITIS: Current Concepts in Evaluation and Management

Background: It is unclear what constitutes a clinically meaningful response for allergic rhinitis (AR) outcomes. The objectives of these post hoc analyses were (1) to define a clinically meaningful response using novel efficacy analyses (including a responder analysis), and (2) to compare the efficacy of MP29-02 [a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP)] with commercially available FP, AZE and placebo in seasonal AR (SAR) patients, using these novel analyses. Methods: 610 moderate-to-severe SAR patients (≥12 years old) were randomized into a double-blind, placebo-controlled, 14-day, parallel-group trial. Change from baseline in the reflective total nasal symptom score (rTNSS) over 14 days was the primary outcome. Post hoc endpoints included the sum of nasal and ocular symptoms (rT7SS), efficacy by disease severity and by predominant nasal symptom, and a set of responder analyses. Results: MP29-02 most effectively reduced rT7SS (relative greater improvement: 52% to FP; 56% to AZE) and both nasal and ocular symptoms irrespective of severity. More MP29-02 patients achieved a ≥30, ≥50, ≥60, ≥75 and ≥90% rTNSS reduction, which occurred days faster than with either active comparator; MP29-02 alone was superior to placebo at the ≥60% (or higher) threshold. One in 2 MP29-02 patients achieved a ≥50% rTNSS reduction and 1 in 6 achieved complete/near-to-complete response. Only MP29-02 was consistently superior to placebo for all patients, whatever their predominant symptom. Conclusions: MP29-02 provided faster and more complete symptom control than first-line therapies. It was consistently superior irrespective of severity, response criteria or patient-type, and may be considered the drug of choice for moderate-to-severe AR. These measures define a new standard for assessing relevance in AR.

Long-term, Randomized Safety Study of MP29-02 (a Novel Intranasal Formulation of Azelastine Hydrochloride and Fluticasone Propionate in an Advanced Delivery System) in Subjects With Chronic Rhinitis

Sinusitis is one of the most common health complaints leading to a physician office visit in the United States. Recently standardized terminology with diagnostic parameters are outlined. Following this is a detailed discussion of the basics of relevant history and physical examinations, laboratory and radiology testing, the appropriate selection of pharmacotherapy, and the indications for surgical intervention.

Efficacy and safety of oral telithromycin once daily for 5 days versus moxifloxacin once daily for 10 days in the treatment of acute bacterial rhinosinusitis.

BACKGROUND MP29-02 is a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate (FP) in an advanced delivery system for the treatment of seasonal allergic rhinitis. OBJECTIVE The objective of this study was to evaluate the long-term safety of MP29-02 in subjects with chronic allergic (perennial) or nonallergic (vasomotor) rhinitis. METHODS This was a 1-year, randomized, open-label, active-controlled, parallel-group study in subjects with chronic allergic or nonallergic rhinitis. A total of 612 subjects were randomized in a 2:1 ratio to (1) MP29-02, one spray per nostril twice daily (total daily doses of azelastine hydrochloride and FP were 548 mcg and 200 mcg, respectively); or (2) FP, 2 sprays per nostril once daily (total daily dose 200 mcg). Safety and tolerability assessments were made at months 1, 3, 6, 9, and 12. RESULTS The incidence of treatment-related adverse events was low with both MP29-02 (9.4%) and FP (11.1%), with no evidence of late-occurring adverse events. Nasal examinations showed no evidence of nasal mucosal ulcerations or septal perforations with MP29-02, and the overall incidence of adverse findings was reduced as the study progressed. There were no unusual or unexpected ocular examination findings and no clinically important laboratory findings or clinically important differences between groups in fasting AM serum cortisol levels after 12 months of treatment. CONCLUSIONS MP29-02 was well tolerated. There were no safety findings that would preclude the long-term use of MP29-02 in the treatment of allergic rhinitis.