Figure 1. Subgroups of patients with rhinosinusitis symptoms and bacterial infection
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The Agency for Health Care Policy and Research (AHCPR), through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHCPR and conduct additional analyses when appropriate prior to developing their reports and assessments.
To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHCPR encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the nation. The reports undergo peer review prior to their release.
AHCPR expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.
We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Health Care Policy and Research, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.
| John M. Eisenberg, M.D. | Douglas B. Kamerow, M.D. |
| Administrator | Director, Center for Practice and Technology Assessment |
| Agency for Health Care Policy and Research | Agency for Health Care Policy and Research |
| The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Health Care Policy and Research or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service. |
We thank our colleagues, Helena Varonen, Marjukka Mäkelä, Seppo Savolainen, and Esa Läärä, from Finland, and Jörgen Hilden from Denmark, for generously providing us with a copy of their manuscript on a meta-analysis of the diagnostic tests for acute sinusitis. We would like to give special thanks to Dr. Varonen for her assistance in extracting the necessary data from a Finnish language article.
We thank the technical experts representing the partner organizations for their most valuable contributions. They provided critical insights on this topic, reviewed an earlier draft of this report, and provided prompt assistance when requested. We also thank our patient representatives for taking time out to provide important insights from the patient's perspective in the clinical management of this condition.
We are very grateful to the British Medical Journal for permission to use in the evidence report substantial portions of the material, including text, tables, and figures, from a meta-analysis authored by several EPC members.
This report summarizes the published evidence on the diagnosis and treatment of community-acquired acute bacterial rhinosinusitis in children and adults. The performance of diagnostic tests and the efficacy of antibiotics and ancillary treatments were assessed.
Human studies of sinusitis were identified from MEDLINE (1966 to May 1998), technical experts, and bibliographies.
Acute bacterial rhinosinusitis was defined as bacterial infection of the paranasal sinuses and symptoms lasting up to 4 weeks. Only diagnostic studies that compared two or more tests were used. Only randomized controlled trials were used to assess treatment efficacy. Studies that met methodologic quality criteria were used in meta-analyses.
Data for meta-analyses were extracted in duplicate. Summary receiver operating characteristics curves were created from the meta-analyses of diagnostic tests. The random-effects model was used to estimate antibiotic efficacy. Decision and cost-effectiveness analyses were conducted to evaluate clinical management strategies.
Compared with sinus puncture, the reference standard for diagnosing acute bacterial rhinosinusitis, sinus radiography has moderate sensitivity (76 percent) and specificity (79 percent). Sinus ultrasonography has similar test characteristics, but the results are more variable and the procedure is not commonly used in the United States. Limited evidence suggests that diagnoses based on clinical criteria may be as accurate as those using sinus radiography. In a meta-analysis of six placebo controlled trials, antibiotics reduced the incidence of clinical failures by one-half (risk ratio [RR], 0.54; 95 percent confidence interval [CI], 0.37 to 0.79), although about two-thirds of the patients improved by 14 days without antibiotics. The risk of clinical failure did not differ significantly between amoxicillin (14 trials, RR, 0.85; 95 percent CI, 0.62 to 1.17) or folate inhibitors (e.g., trimethoprim/sulfamethoxazole) (nine trials, RR, 1.01; 95 percent CI, 0.52 to 1.97) and newer, more expensive antibiotics. No serious complications from lack of treatment were reported.
Some of the 10 trials assessing nonantibiotic, ancillary treatments reported statistically significant results. However, these trials included different treatments, often in conjunction with antibiotics, so further analyses were limited.
To minimize symptom duration, initial symptomatic treatment is the most cost-effective strategy up to a prevalence of 25 percent, the use of clinical criteria to guide treatment is most cost-effective for a prevalence between 25 percent and 83 percent, and empirical antibiotic treatment with amoxicillin or a folate inhibitor is cost effective only above the prevalence of 83 percent. Sinus radiography-guided treatment, as an initial management strategy for uncomplicated patients, is not cost effective at any prevalence.
The quality of the diagnostic and treatment trials reviewed was suboptimal. However, the results were generally consistent, sensitivity analyses showed the results to be robust, and the conclusions are consistent with the majority of expert opinions.
In primary care, where the prevalence of bacterial infection in patients presenting with symptoms suggesting acute rhinosinusitis is low to moderate, initial symptomatic treatment or the use of clinical criteria to guide treatment is the most cost effective approach for patients with uncomplicated infections. If antibiotics are given, amoxicillin or a folate inhibitor should be considered initially, as should the severity of the symptoms.
Future studies should use more rigorous diagnostic standards and clinical outcome measures. The optimal duration of antibiotic treatment, the role of patient preferences in clinical decisionmaking, and the issue of emerging antibiotic resistance also need to be addressed.
This document is in the public domain and may be used and reprinted without permission.
Suggested citation:
Lau J, Zucker D, Engels EA, Balk E, et al. Diagnosis and treatment of acute bacterial rhinosinusitis. Evidence Report/Technology Assessment No. 9 (Contract 290-97-0019 to the New England Medical Center). Rockville, MD: Agency for Health Care Policy and Research. March 1999.
Acute rhinosinusitis, viral or otherwise, is one of the most common infections in the United States. Millions of cases occur each year, affecting all age groups and all segments of the population. Although only a small percentage of these cases come to the attention of a physician, this high prevalence translates into high costs for individual health, work time lost, and medical expenditures. In 1992, in the United States, $200 million was spent on prescription cold medications for rhinosinusitis and more than $2 billion for over-the-counter medications.
In the majority of cases, inflammation of the paranasal sinuses (sinusitis) is accompanied by inflammation of the nasal passages (rhinitis); thus, the clinical condition often referred to as "sinusitis" is, in fact, rhinosinusitis: inflammation of the sinuses with concomitant inflammation of the nasal passages. In clinical practice, the focus is on patients in whom this rhinosinusitis results in clinical symptoms. Conditions that cause or predispose individuals to rhinosinusitis include infectious agents (bacteria, viruses, and fungi), allergic conditions (allergic rhinitis), anatomic abnormalities, systemic diseases (endocrine, metabolic, genetic), trauma, and noxious chemicals. The prevalence of rhinosinusitis resulting from each cause is unknown, although certain causes, such as viral infection, are more common. In some cases, the cause may be multifactorial (e.g., viral infection with bacterial superinfection).
Despite the common nature of rhinosinusitis, its management is controversial. Therapies are usually directed to alleviating or reducing symptoms, eradicating the underlying cause, or both. A major question is whether antibiotics should be used, and if so, which one? Because the premise of treatment with antibiotics is that bacterial infection will be eliminated, patients with bacterial rhinosinusitis need to be identified. In addition, other disease and patient characteristics, such as age and duration and pattern of illness, may help in distinguishing patient subgroups for more specific types of treatment (e.g., antibiotics to eradicate specific bacterial species). Because bacterial infection of the sinuses is potentially serious, the use of antimicrobials to prevent these complications is of interest. However, concern is increasing about the overuse or abuse of antibiotics, both for the individual, in terms of potential side effects and financial costs, as well as for society, in terms of cost and the development of antibiotic-resistant bacteria.
In this report, we summarize the evidence for the diagnosis and treatment of uncomplicated, community-acquired, acute bacterial rhinosinusitis in children and adults. We present evidence regarding the prevalence of this illness in both general primary care and subspecialty clinic settings. We analyzed the data from clinical studies that compared the performance of various diagnostic tests (including clinical examination criteria) for identifying patients with acute bacterial rhinosinusitis. We assessed randomized controlled trials that compared the treatment effects of antibiotics with those of placebo and the effects of inexpensive antibiotics, such as amoxicillin and folate inhibitors (e.g., trimethoprim/sulfamethoxazole), with those of newer, more expensive antibiotics (e.g., cephalosporins). We also collected evidence on ancillary therapies, such as decongestants, steroids, and sinus irrigation. Finally, we combined the evidence in a decision analysis and a cost-effectiveness analysis to compare clinical strategies in managing patients with acute bacterial rhinosinusitis to help translate the evidence into practice. Although sinusitis can include acute, recurrent, and chronic forms, this report focuses on the Agency for Health Care Policy and Research (AHCPR)-designated topic of acute sinusitis and more specifically, on community-acquired, acute bacterial rhinosinusitis.
The Evidence-based Practice Center (EPC) staff, along with a panel of technical experts, including representatives from four professional organizations (the American Academy of Family Physicians, American Academy of Otolaryngology-Head and Neck Surgery, American Academy of Pediatrics, and American College of Physicians), formulated the following questions to be addressed in this evidence report for acute sinusitis in children and adults.
1. What is the prevalence of bacterial infection in patients presenting with acute rhinosinusitis in primary care and specialty settings?
2. What is the diagnostic value of clinical features and imaging technologies for identifying acute rhinosinusitis and acute bacterial rhinosinusitis?
3. Given a (clinical) diagnosis of acute bacterial rhinosinusitis, are antibiotics effective in resolving symptoms and in preventing complications or recurrence?
4a. In treating acute bacterial rhinosinusitis, what is the efficacy of antibiotics compared with that of placebo, and among the various antibiotics, what is their comparative efficacy?
4b. What evidence do these comparative studies provide regarding side effects?
5a. Are there data to support the use of other types of treatments for acute rhinosinusitis and acute bacterial rhinosinusitis, specifically: decongestants, steroids, antihistamines, and drainage and irrigation?
5b. What is the efficacy of antibiotics compared with that of other types of treatment?
5c. What evidence do any comparative studies provide regarding side effects of these treatments?
We systematically reviewed the literature for evidence addressing these questions. Prospective studies that compared two or more diagnostic tests were used to assess diagnostic test performance, and randomized controlled trials were used to assess treatment efficacy. We searched for English-language articles indexed in the MEDLINE database between 1966 to May 1998 using several sensitive search strategies for human studies on sinusitis. The titles, MeSH headings, and abstracts of the retrieved citations were manually screened to identify articles for retrieval. Technical experts were consulted, and bibliographies of retrieved primary studies, review articles, and published and unpublished meta-analyses on the diagnosis or treatment of acute rhinosinusitis were examined for additional references. A separate MEDLINE search for potentially useful foreign-language articles was also conducted to assess the magnitude of the bias caused by excluding foreign-language articles from the primary search strategy. Several studies published in other languages were included in our analyses.
Data from primary clinical studies that met inclusion criteria were extracted to develop evidence tables pertaining to the specified questions. A summary receiver operating characteristic (SROC) curve was constructed from a meta-analysis to assess the performance of clinical criteria and various imaging technologies commonly used to diagnose acute bacterial rhinosinusitis. Meta-analyses were also performed to pool the clinical outcomes of patients treated with and without antibiotics and to compare different individual and classes of antibiotics. Several subgroup analyses were performed to identify factors that may be related to treatment variations.
A decision analysis was performed from the patient's perspective to evaluate several diagnostic tests and treatment strategies for managing a patient presenting with the symptoms of acute bacterial rhinosinusitis. We also performed a cost-effectiveness analysis from the payer's perspective to estimate the cost-effectiveness of several common treatment strategies. We used both a single-time-point decision tree and a Markov process to model the clinical decisions, possible events, and clinical outcomes. The models used estimates from the evidence report's meta-analyses, primary studies, review articles, expert opinions, and consensus.
The overall methodologic quality and reporting of both diagnostic and treatment studies on this topic are poor. Few studies were conducted in North America. So few studies met strict diagnostic criteria (sinus puncture with bacterial culture) that we had to relax the criteria to have enough studies for meta-analyses (we accepted the investigators' diagnoses). Still, only 14 of 48 diagnostic test comparison studies and only 30 of the 74 randomized controlled trials on antibiotics met the revised criteria. For studies of children, only one diagnostic test study and two antibiotic treatment studies met the revised criteria for their respective meta-analysis. Although there is a pathophysiologic basis for differentially treating children and adults, the lack of evidence for children precluded making distinctions in diagnosis and treatment in these populations beyond inspection of the individual studies. Data on prevalence were obtained from the studies reviewed, although estimates from additional observational studies are also described.
1. What is the prevalence of bacterial infection in patients presenting with acute rhinosinusitis in primary care and specialty settings?
Prevalence data for acute bacterial rhinosinusitis in the general population are sparse. The 1994 National Health Interview Survey report on chronic sinusitis estimated 35 million cases.
The prevalence of acute sinusitis appears to be increasing, according to data from the National Ambulatory Medical Care Survey (from 0.2 percent of diagnoses at office visits in 1990 to 0.4 percent of diagnoses at office visits in 1995).
Up to 38 percent of patients with symptoms of sinusitis in adult general medicine clinics may have acute bacterial rhinosinusitis. In otolaryngology practices, the prevalence was higher (50 to 80 percent). Between 6 and 18 percent of the children in the primary care setting presenting with upper respiratory infections may have acute bacterial sinusitis.
2. What is the diagnostic value of clinical features and imaging technologies for identifying acute rhinosinusitis and acute bacterial rhinosinusitis?
Bacterial rhinosinusitis has been diagnosed from clinical criteria, sinus puncture with culture of the aspirate, sinus radiography, ultrasonography, and computed tomography.
Although sinus puncture with culture is the diagnostic reference standard, it is rarely used because it is invasive and costly; it is not a practical routine procedure.
A meta-analysis of six studies shows that sinus radiography has moderate sensitivity (76 percent) and specificity (79 percent) compared with the sensitivity and specificity of sinus puncture in the diagnosis of acute bacterial rhinosinusitis.
Studies comparing sinus ultrasonography with puncture or sinus radiography were inconclusive in determining how well ultrasonography identifies patients with acute bacterial rhinosinusitis. The results of ultrasonography varied substantially, possibly because of differences in patient populations, ultrasonography techniques, or medical personnel involved in diagnostic testing.
Limited evidence suggests that clinical criteria (i.e., the presence of three or four of the following symptoms: purulent rhinorrhea with unilateral predominance, local pain with unilateral predominance, bilateral purulent rhinorrhea, and the presence of pus in the nasal cavity) may have a diagnostic accuracy similar to that of sinus radiography.
We found no studies comparing magnetic resonance imaging or endoscopy. The one randomized trial comparing computed tomography with sinus radiography was inadequately reported.
3. Given a (clinical) diagnosis of acute bacterial rhinosinusitis, are antibiotics effective in resolving symptoms and in preventing complications or a recurrence?
More patients were cured, and cured earlier, when treated with antibiotics rather than placebo.
About two-thirds of the patients receiving placebos recovered without antibiotics.
Serious complications of rhinosinusitis, such as meningitis, brain abscess, and periorbital cellulitis, are rare, and none was reported in the clinical trials we examined.
Most clinical trials have only short-term followup and report no data on relapse.
4a. In treating acute bacterial rhinosinusitis, what is the efficacy of antibiotics compared with that of placebo, and among the various antibiotics, what is their comparative efficacy?
Antibiotics are significantly more effective than placebo for treating acute bacterial rhinosinusitis, reducing the clinical failure rate by one-half (risk ratio [RR], 0.54; 95 percent confidence interval [CI], 0.37 to 0.79). Patients are cured more quickly and more often when treated with antibiotics compared with no treatment.
Amoxicillin or folate inhibitors were as efficacious as the newer and more expensive antibiotics. The current evidence does not justify the use of the newer antibiotics for treating uncomplicated, community-acquired acute bacterial rhinosinusitis.
4b. What evidence do these comparative studies provide regarding side effects?
About 4 percent of the patients in the amoxicillin arms of the clinical trials withdrew as a result of side effects, but this percent did not differ statistically from that in patients treated with other antibiotics. The data for folate inhibitors are more limited but similar.
5a. Are there data to support the use of other types of treatments for acute rhinosinusitis and acute bacterial rhinosinusitis, specifically: decongestants, steroids, antihistamines, and drainage and irrigation?
Ten randomized controlled trials evaluated ancillary treatment for rhinosinusitis. Meta-analysis was not possible because of the differences in treatments, diagnostic criteria, and outcomes measures among the studies, and because the concurrent and inconsistent use of antibiotics in many studies confounded statements about the efficacy of treatments.
5b. What is the efficacy of antibiotics compared with that of other types of treatment?
Many studies of antibiotic treatment also included ancillary therapies. However, these therapies were seldom standardized, which prevented an analysis of their benefits.
5c. What evidence do any comparative studies provide regarding side effects of these treatments?
Data from randomized controlled trials are insufficient to answer this question.
We conducted a cost-effectiveness analysis to compare four treatment strategies: (1) a sinus radiography-directed strategy, (2) the use of clinical criteria to guide treatment, (3) initial symptomatic (ancillary) treatment, and (4) routine empirical use of antibiotics, with either amoxicillin or a folate inhibitor. The result is essentially a "toss-up" in terms of symptom days for empirical, radiography-guided, and clinical-criteria-guided treatments. Symptomatic treatment alone provided fewer symptom-free days at all but the very lowest prevalence of acute bacterial rhinosinusitis. In terms of cost, the use of clinical criteria to guide treatment and initial symptomatic treatment is a toss-up at any prevalence. Empirical treatment is more costly at all but the highest range of prevalence. Radiography is considerably more costly at any prevalence. Initial symptomatic treatment is the most cost effective strategy, at prevalence of up to 25 percent, the use of clinical criteria to guide treatment is most cost effective for a prevalence between 25 and 83 percent, and empirical antibiotic treatment with amoxicillin or a folate inhibitor is cost effective only at prevalence greater than 83 percent. Sinus radiography is never a cost-effective strategy at any prevalence. The prevalence thresholds for various strategies are moderately sensitive to the severity of sinus symptoms as reflected in the utilities for computing quality-of-life adjustments.
At the prevalence of acute bacterial rhinosinusitis likely to be encountered in most primary care settings, a strategy of either initial symptomatic treatment or the use of clinical criteria to guide treatment is an effective and cost-effective approach for patients with uncomplicated cases. Given our finding that most patients' symptoms resolve without antibiotic treatment and that serious complications are rare, watchful waiting (before giving antibiotics) for 7 to 10 days after onset of "sinus" symptoms is a reasonable strategy. If antibiotics are to be given, amoxicillin or a folate inhibitor should be the initial choice. The severity of the patient's symptoms affected the utilities used in the decision models and thus may also need to be considered in the management decision.
Many patients with acute rhinosinusitis are not seen by health care providers. The prevalence of this condition needs to be known to help distinguish those people requiring treatment with antibiotics from those not requiring antibiotics or further evaluation.
Because of the developmental anatomical differences in children and adults, diagnostic and treatment studies should be conducted on pediatric populations.
Future studies should also be dedicated to studies of patients with comorbidities (e.g., allergies, asthma, and human immunodeficiency [HIV] infection) that may influence the development, progression, and response to treatment of acute bacterial rhinosinusitis.
Involvement of other sinuses other than maxillary sinuses needs to be studied.
The diagnostic reference standard of sinus puncture with culture of aspirate is infeasible in routine practice, and most trials based diagnosis on other criteria. Alternative less invasive reference standard methods for diagnosing acute rhinosinusitis are needed.
Future studies of clinical criteria (including risk scores), ultrasonography, and endoscopy with middle meatal sampling, ideally comparing them with sinus puncture in a variety of research and clinical settings, are needed to establish their diagnostic utility.
The designs of future studies need to be improved. In particular, definitions of the populations to be treated, the test methods, and the criteria for diagnosis need to be more precise and investigators need to be masked.
The role of antibiotic resistance in individual clinical decisionmaking needs to be clarified. More data are needed on patients with resistant organisms and their responses to therapies and on the association between laboratory and clinical resistance.
Outcome measures need to be reassessed. In particular, assessing outcomes at different time points may better represent the differential effect of therapies. In addition to a better understanding of the connection between treatment and time to resolution of symptoms, increased knowledge regarding treatments and relapse rates or the potential development of recurrent sinusitis is also needed.
In addition to better understanding of the connection between treatment and time to resolution of symptoms, there is a need for increased knowledge regarding treatments and relapse rates or the potential development of recurrent sinusitis.
Standardization and focused evaluations of ancillary treatments are needed.
The influences of several factors on patient-assigned utilities (patient-physician interactions, availability of "time for sickness," and variability of severity of episodes) need to be better understood when evidence is applied to clinical practice.
This report summarizes the scientific evidence for diagnosing and treating community-acquired, acute bacterial rhinosinusitis in children and adults. This topic was selected by the Agency for Health Care Policy and Research (AHCPR) in response to requests from both the American Academy of Otolaryngology and the American Academy of Pediatrics. It is an aid for clinical practice and, therefore, has been developed with a practical clinical focus. This report provides summaries of evidence for use by different groups, including primary care practitioners, specialists, researchers, policy decisionmakers, and insurers and other third-party payers. Recognizing the different interests and approaches of these groups, we focus the analyses on the diagnosis and treatment of acute bacterial rhinosinusitis in the primary care, clinical practice setting. We assessed the diagnostic performance of clinical criteria and other commonly used tests for identifying patients with acute bacterial rhinosinusitis and summarized evidence to assess the efficacy of common treatments for the defined patient subgroup(s). We also provide a decision analysis as a model for using the evidence in clinical decisionmaking and a cost-effectiveness analysis to guide policy decisionmaking.
The term "sinusitis" technically refers to inflammation of the mucosa of the paranasal sinuses. Many factors underlie the development of sinusitis, including various environmental and host factors. The complexity of sinusitis and the many factors involved in its development have precluded the development of a single, standardized definition and classification system for this condition (Lanza and Kennedy, 1997). In part, the definition depends on the questions being addressed. For clinical practice -- and for this evidence report -- interest in the definition of acute sinusitis is based on the premise that identifying patients with community-acquired acute bacterial rhinosinusitis will allow for specific beneficial interventions.
"Sinusitis" is often loosely used to denote a broad group of clinical syndromes with different causes and presentations. Estimates of disease prevalence vary, in part from differences in definitions of the disease and in part from differences in the populations in which the prevalence is assessed Sinusitis, as broadly defined and estimated through insurance reimbursement claims and population statistics (e.g., National Ambulatory Medical Care Survey [NAMCS]), is one of the most common health complaints in the United States (Kennedy, 1990). Gwaltney (1996), using estimates of the average number of acute respiratory illnesses per year (six to eight for children; two to three for adults) and data suggesting that 90 percent of patients with colds have sinusitis (viral or otherwise), estimated that there are over a billion cases of sinusitis annually.
| Survey year | 1990 | 1991 | 1992 | 1993 | 1994 | 1995 |
|---|---|---|---|---|---|---|
| Number of total visits | 704,604 | 669,689 | 762,045 | 717,191 | 681,457 | 697,082 |
| Number of acute sinusitis diagnoses 2 | 1,387 | 766 | 2,546 | 1,533 | 2,671 | 2,897 |
| Percent of acute sinusitis diagnoses | 0.2 | 0.1 | 0.3 | 0.2 | 0.4 | 0.4 |
Data are expressed in thousands/year.
ICD-9-CM-461
Although population studies agree that sinusitis is common, they use broad and different definitions of the condition that include several pathophysiologic conditions. Estimating the prevalence of various sinusitis subgroups (e.g., acute bacterial rhinosinusitis) requires the use of more specific diagnostic criteria in research studies. Even if the same definition is used, however, selection biases can lead to differing estimates for the general population, for patients in specific clinical settings, and for patients enrolled in studies where other initial selection criteria are applied. The relationship between the prevalence estimates obtained from population-based prevalence data (e.g., from insurance claims and survey data) and those from various subgroups of rhinosinusitis defined by clinical or diagnostic criteria from research studies remains unclear.
The high prevalence of sinusitis translates into high costs for individual health, work time lost, and medical expenditures. McCaig and Hughes (1995) analyzed the 1985, 1989, and 1992 NAMCS data and found an increasing trend of office visits for sinusitis. They reported sinusitis (ICD-9-CM-461 and -473, including both acute and chronic sinusitis) as the fifth most common diagnosis for antibiotic prescriptions, representing 7 percent, 9 percent, and 12 percent of all recorded prescriptions in 1985, 1989, and 1992, respectively. The use of more expensive, broad-spectrum drugs (e.g., cephalosporins) increased, and the use of less expensive, narrow-spectrum antibiotics (e.g., the penicillins) decreased during this period. These trends have important ramifications in terms of health care costs, as well as the development of resistance to antimicrobials.
In 1992, in the United States, approximately $200 million was spent on prescription cold medications for sinusitis, a $50 million increase over 1989 (Gwaltney, Jones, and Kennedy, 1995). In addition, the U.S. population spends more than $2 billion annually on over-the-counter medications for nasal and sinus disorders (Williams, Aguilar, Makela, et al., 1997). Increasing rates of antibiotic resistance have led to a recognition of the need for more prudent use of antibiotics and to limiting their use to the treatment of bacterial infections (Levy, 1998). The costs of antibiotic use need to be balanced against the limitations of diagnostic certainty and risks of nontreatment. The high prevalence of sinusitis and its associated costs highlight the need for optimizing effective therapy.
The paranasal sinuses consist of four pairs of air-filled cavities in the skull (the frontal, maxillary, ethmoid, and sphenoid sinuses), which are lined by mucosa and connect to the nasal passages (Gwaltney, 1996; MacLeod, 1991). Normal mucous secretions contain antibodies, help collect soluble pollutants, and, together with ciliary action, work to clear particulate matter, including bacteria, from the sinuses (Gwaltney, Jones, and Kennedy, 1995). Maintaining the mucociliary flow and an intact local mucosal surface are key host defenses against infection and for maintaining sinus health (Gwaltney, 1996; Gwaltney, Jones, and Kennedy, 1995). It is widely believed that the paranasal sinuses are normally sterile, although there have been conflicting reports (Bjorkwall, 1950; Brook, 1981; Gwaltney, Scheld, Sande, et al., 1992).
In addition to inflammation of the paranasal sinuses, most cases of sinusitis are accompanied by inflammation of the nasal passages (Gwaltney, Phillips, Miller, et al., 1994; Lund and Kennedy, 1995). As such, the clinical condition often referred to as "sinusitis" is, in fact, rhinosinusitis: inflammation of the sinuses with concomitant inflammation of the nasal passages. In some circumstances, inflammation may also include portions of the surrounding bone (Lanza and Kennedy, 1997). For the purposes of this report, this grouping of conditions will be referred to as rhinosinusitis.
| Headache | Fever |
| Facial pain and pressure (worse with bending forward) | Halitosis |
| Nasal congestion | Maxillary toothache |
| Thick colored anterior nasal discharge or posterior nasal drainage | Cough |
| Olfactory disturbance | Irritability (for children) |
Clinical diagnosis aims to identify cases that have a similar pathophysiologic cause and presentation and that therefore would presumably benefit from similar treatment. Factors affecting inflammation of the sinuses include infectious agents, allergic conditions, anatomic abnormalities, systemic diseases (endocrine, metabolic, genetic), trauma, and noxious chemicals (Gwaltney, 1996; Gwaltney, Jones, and Kennedy, 1995; Lanza and Kennedy, 1997). In some cases, these factors cause inflammation of the mucosal linings directly (e.g., allergic, infectious); in others, host conditions predispose the mucosal linings to inflammation, infection, or both (e.g., anatomic abnormalities, neoplasms, ciliary function abnormalities). Although infectious agents can be the primary cause of sinus inflammation, they also may represent a secondary infection. In these cases, the initial inflammation predisposes the sinuses to infection, as for example, when bacterial rhinosinusitis follows viral rhinosinusitis (Berg, Carenfelt, Rystedt, et al., 1986; Gable, Jones, Floor, et al., 1994).
| Inflammatory (multiple causes): decongestants, steroids |
| Allergic: antihistamines, steroids |
| Bacterial: antibiotic |
| Viral: treat symptoms (inflammation) |
| Structural: (surgical) removal |
Microbiologic classification of infectious causes of rhinosinusitis includes bacteria, viruses, and fungi. Data on the prevalence of cases resulting from each of these microbiologic agents are lacking. However, viruses, as the leading cause of upper respiratory infections, are among the most common (Wald, 1996). Approximately 0.5 percent to 2 percent of adult and up to 10 percent of pediatric cases of viral rhinosinusitis develop into bacterial infections (Berg, Carenfelt, Rystedt, et al., 1986; Dingle, Badger, and Jordan, 1964; Gable, Jones, Floor, et al., 1994; Gwaltney, 1996).
The rationale for identifying patients with increased likelihood of infectious rhinosinusitis stems from the potential use of anti-infective agents. Antibiotics are widely available and are effective at eliminating specific bacteria. The ability to identify cases of bacterial rhinosinusitis (either as a primary or secondary infection) would thus identify potential candidates for antibacterial therapies (Figure 1
). Adequate levels of antibiotics can eradicate bacteria
from maxillary sinus fluid aspirates (Eneroth and Lundberg, 1976; Hamory, Sande, Sydnor, et al., 1979).
In this report, we focus on acute bacterial rhinosinusitis because antibiotics are widely available and should be used only for bacterial infection. Bacterial infection of the sinuses can result in chronic sinusitis, as well as in other serious complications (e.g., meningitis, brain abscess). Antibiotics can be used to prevent these developments. At the same time, concerns have increased about the inappropriate use of antibiotics, both for the individual and society. For the individual, the concerns are for potential side effects and out-of-pocket expenses. For society, the concerns are for overall costs and the development of antibiotic resistance leading to loss of the therapeutic efficacy of antibiotics (Levy, 1998).
Bacterial rhinosinusitis can refer to several physiologic conditions, all of which include the presence of bacteria concomitant with sinus inflammation. The inflammation may be a direct response to bacterial infection or to nonbacterial causes that provide a setting for a secondary bacterial infection. Given, however, that in all instances bacterial rhinosinusitis entails bacterial infection, a microbiologic definition remains the current accepted diagnostic reference standard: more than 104 colony-forming unit (CFU)/ml in sinus aspirate (Turner, Cail, Hendley, et al., 1992; Winther and Gwaltney, 1990). Lower colony concentrations could potentially represent early infection. However, studies of maxillary sinus aspirates generally yield titers above 105 CFU/ml (Winther and Gwaltney, 1990), and the cutoff choice of 104 CFU/ml of sinus aspirate (rather than complete absence of bacteria) may in part compensate for the potential contamination of the sinus aspirate during collection (Wald, 1991). Whether the sinuses are sterile under normal circumstances or whether they are routinely colonized with anaerobic and aerobic bacteria is still debated (Bjorkwall, 1950; Brook, 1981; Gwaltney, Scheld, Sande, et al., 1992).
Several studies have reported bacterial species profiles isolated from maxillary sinus aspirates and have looked at changes in the predominant species over time (Berg, Carenfelt, and Kronvall, 1988; Bjorkwall, 1950; Gwaltney, Scheld, Sande, et al., 1992; Jousimies-Somer, Savolainen, and Ylikoski, 1988; Suzuki, Nishiyama, Sugiyama, et al., 1996; Urdal and Berdal, 1949). Whereas -hemolytic streptococci and Streptococcus pneumoniae were the most frequent isolates in studies circa 1950 (Bjorkwall, 1950; Urdal and Berdal, 1949), studies in the 1970s and 1980s noted that S. pneumoniae and Hemophilus influenzae predominate (Berg, Carenfelt, and Kronvall, 1988; Gwaltney, Sydnor, and Sande, 1981; Jousimies-Somer, Savolainen, and Ylikoski, 1988; Van Cauwenberge, Verschraegen, and Van Renterghem, 1976). Followup studies in the 1990s reported that these two organisms remained the major species in adults, whereas Moraxella catarrhalis was an additional, high-prevalence species isolated from children (Benninger, Anon, and Mabry, 1997; Gwaltney, Scheld, Sande, et al., 1992; Suzuki, Nishiyama, Sugiyama, et al., 1996; Wald, Reilly, Casselbrant, et al., 1984). Other species were also cultured in many of these studies (including -hemolytic streptococci, Staphylococcus aureus, and anaerobes), but their prevalence was much lower in cases of acute bacterial rhinosinusitis (Benninger, Anon, and Mabry, 1997; Berg, Carenfelt, and Kronvall, 1988; Brook, 1996; Gwaltney, Sydnor, and Sande, 1981; Gwaltney, Scheld, Sande, et al., 1992; Jousimies-Somer, Savolainen, and Ylikoski, 1988; Wald, 1991).
Even though direct microbiologic evaluation of sinus aspirates has been the diagnostic reference standard, the puncture technique has been largely limited to sampling the maxillary sinuses. One study reported good agreement between the bacterial species obtained from the frontal sinus trephination and those obtained from the same patients' maxillary sinus (Antila, Suonpaa, and Lehtonen, 1997). However, the prevalence of bacterial species in sinuses other than the maxillary sinuses and the potential clinical significance of different patterns of the sinuses affected require further study.
Although sinus puncture and culture is the diagnostic standard for bacterial rhinosinusitis, its routine use in primary care practices is not feasible. As such, the practical identification of patients with acute bacterial rhinosinusitis remains a clinical diagnosis that relies on alternate diagnostic methods. Less invasive methods for direct sampling and microbiologic testing (i.e., nasopharyngeal swabs and middle meatal sampling by endoscopy) have been compared with sinus puncture aspirates, but the degree of agreement was weak (Axelsson and Brorson, 1972; Evans, Sydnor, Moore, et al., 1975; Gwaltney, Sydnor, and Sande, 1981; Williams, Holleman, Samsa, et al., 1995). However, modifications in the techniques for middle meatal sampling by endoscopy may improve their accuracy (Druce, 1992; Ferguson and Mabry, 1997; Klossek, Dubreuil, Richet, et al., 1996).
In patients with bacterial rhinosinusitis, further distinct subgroups may be defined that differ in pathophysiology and whose identification and distinction could further direct specific therapy. Subgrouping criteria have included patterns of disease presentation (e.g., temporal patterns) and patient characteristics (e.g., age, comorbidities).
The use of temporal patterns as distinguishing markers has resulted from clinical experience in the response of patients to therapies and, as such, to presumed and observed differences in the likely causes and nature of the symptoms. In the clinical setting, temporal patterns can be used to define subgroups with increased likelihood of similar conditions, but these temporal distinctions lack clearly defined boundaries (Lanza and Kennedy, 1997).
The distinctions between acute rhinosinusitis, chronic rhinosinusitis, and recurrent acute rhinosinusitis are based on temporal differences in presentation and on presenting features. Acute and chronic rhinosinusitis also differ in histopathologic and bacteriologic characteristics. The most common distinction between these conditions has been made on their temporal patterns, and although somewhat arbitrary, consensus has been reached about defining these three distinct but related clinical conditions on the basis of duration of symptoms and defining clinical factors (Lanza and Kennedy, 1997).
Acute rhinosinusitis has been defined as having a sudden onset, with symptoms lasting less than 4 weeks (Lanza and Kennedy, 1997). Many cases of rhinosinusitis accompany viral infections of the upper respiratory tract. Because most common cold symptoms last 5 to 7 days and mimic those of bacterial rhinosinusitis, a minimal duration of symptoms (7 to 10 days) is generally recommended before a diagnosis of bacterial infection is made. Recurrent acute infections are defined by the presence of four or more episodes per year, each lasting more than 7 days, and by the absence of intervening signs or symptoms that would suggest an ongoing or chronic rhinosinusitis. Rhinosinusitis becomes chronic when the symptoms last longer than 12 weeks and the diagnosis is confirmed by clinical or radiographic criteria (Lanza and Kennedy, 1997). Occasional acute worsening of symptoms in individuals with chronic rhinosinusitis may suggest an acute exacerbation of the chronic condition. With treatment of the acute symptoms, these individuals return to the baseline chronic rhinosinusitis condition. Because individuals with acute rhinosinusitis have symptoms for less than 4 weeks and those with chronic rhinosinusitis have symptoms for more than 12 weeks, those who have symptoms lasting between 4 and 12 weeks are considered to have a subacute infection. Some of these cases will resolve within 12 weeks, and others will progress to chronic rhinosinusitis (Lanza and Kennedy, 1997).
Chronic rhinosinusitis is histopathologically distinct from acute rhinosinusitis. In acute rhinosinusitis, neutrophils predominate and hemorrhage, ulcerations, necrosis, and exudate are present (Coltran, Kumar, and Robbins, 1995; Lanza and Kennedy, 1997). In chronic rhinosinusitis, a proliferative process is evident and is accompanied by lymphocytes, plasma cells, and eosinophils. Fibrosis of the lamina propria is also present, and fungi and bacteria may be seen (Lanza and Kennedy, 1997). These two temporally different stages of rhinosinusitis also differ bacteriologically. S. pneumoniae and H. influenzae are the predominant organisms in acute rhinosinusitis, whereas Staphylococcus species (especially S. aureus), gram-negative bacteria (e.g., Enterobacteriaceae), and fungi also may be seen in chronic rhinosinusitis (Benninger, Anon, and Mabry, 1997).
In this report, we focus on acute bacterial rhinosinusitis because it is the largest subgroup and because timely, appropriate treatment may shorten the illness and prevent progression and complications.
Patient characteristics provide another criteria for subgrouping. In particular, studies have looked at the similarities and differences between children and adults. The age of a patient with acute bacterial rhinosinusitis helps predict, to some extent, the agents most likely to be causing the sinus infection. Two major risk factors for the development of acute bacterial rhinosinusitis are acute, viral, upper respiratory infections and allergic inflammation. In children, acute community-acquired viral upper respiratory infections probably underlie 80 percent of the cases of acute bacterial rhinosinusitis, and allergic rhinitis is the cause of most of the remaining cases.
The peak age group for acute bacterial rhinosinusitis is between 3 and 6 years. This range corresponds to the peak age for incidence of community-acquired upper respiratory infections. Children in this age group experience an average of six to eight respiratory infections per year (Gwaltney, 1997). An estimated 0.5 to 10 percent of viral upper respiratory infections are complicated by acute bacterial rhinosinusitis (Berg, Carenfelt, Rystedt, et al., 1986; Dingle, Badger, and Jordan, 1964). Children with "severe" symptoms (marked fever, purulent discharge, periorbital swelling) or "persistent" symptoms (nasal discharge, daytime cough worsening at night, symptoms lasting longer than 10 days and not improving by 30 days) had high rates of abnormal radiographic findings (80 to 88 percent) and positive sinus puncture cultures (70 to 75 percent of those with symptoms and a positive radiograph) (Wald, Chiponis, and Ledesma-Medina, 1986; Wald, Reilly, Casselbrant, et al., 1984). Using these criteria of protracted respiratory symptoms (nasal discharge or cough, or both, lasting more than 10 days without evidence of improvement) plus abnormal radiographs (occipitomental radiographs showing mucosal swelling, diffuse opacification, or an air-fluid level) as a common marker of acute bacterial rhinosinusitis in an office practice setting, Ueda and Yoto (1996) found that 6.7 percent of patients with upper respiratory symptoms have maxillary rhinosinusitis. Using only the clinical criteria of "severe" or "persistent" symptoms as defined by Wald, Reilly, and Casselbrant, et al. (1984), Aitkin and Taylor (1998) in a study of children in a U.S. primary care clinic estimated the prevalence of rhinosinusitis in the winter months to be 9.3 percent of all presenting clinic patients and 17.3 percent of patients who presented for treatment of a cold or cough. In a study of children cared for in a variety of day care settings, 6 to 13 percent had upper respiratory infections that lasted more than 15 days (Wald, Guerra, and Byers, 1991). Thus, symptoms lasting more than 10 days without improvement may serve as a marker for acute bacterial rhinosinusitis. Although similar, the differences in estimates for different populations could result from the differences in diagnostic criteria (clinical vs. clinical examination and radiographic findings). Seasonal variation also may affect prevalence (Gable, Jones, Floor, et al., 1994).
Approximately 15 to 20 percent of the U.S. population has atopic disease (Spector, 1997). In children, atopic disease may be manifest as dermatitis, reactive airway disease, or allergic rhinitis. The local symptoms of allergic rhinitis may include nasal discharge, nasal obstruction, pruritis, and anosmia (Meltzer, 1997; Wright, Holberg, Martinez, et al., 1994). In children with mucositis caused by viral infection or allergy, the sinus ostia will be partially or completely obstructed (mechanically or functionally). The obstruction of the sinus ostia fosters the development of a negative pressure within the sinus cavity. In turn, the negative pressure facilitates the entry of selected normal nasopharyngeal flora into the paranasal sinus cavities, causing acute bacterial rhinosinusitis (Parsons and Wald, 1996). The microbiologic agents that subsequently infect the paranasal sinuses of children include S. pneumoniae, nontypable H.influenzae, and M. catarrhalis.
Whereas the same conditions -- community-acquired viral upper respiratory infections and allergic rhinitis -- predispose adults to acute bacterial rhinosinusitis, the incidence is considerably lower. Adults usually experience two to three upper respiratory infections annually (Gwaltney, 1997). The cause of acute bacterial rhinosinusitis in adults is mostly S. pneumoniae and H.influenzae; M. catarrhalis is an unusual cause of acute bacterial rhinosinusitis in adults (Winther and Gwaltney, 1990).
In light of these similarities and differences, we collected and analyzed evidence for both the pediatric and adult populations.
Additional characteristics may affect a patient's likelihood of developing acute bacterial rhinosinusitis. A strong connection between acute bacterial rhinosinusitis and allergic rhinitis has been suggested, but in light of conflicting research results, the nature and extent of this connection remain unclear (Benninger, 1992; International Rhinosinusitis Advisory Board, 1997). An association of acute bacterial rhinosinusitis with asthma also has been suggested, although this may relate to the presence of allergic rhinitis (Benninger, 1992; Kaliner, Osguthorpe, Fireman, et al., 1997; Spector, 1997).
Ciliary function is important in maintaining sinus health (Gwaltney, 1996; Gwaltney, Jones, and Kennedy, 1995). Genetic disorders with mucociliary dysfunction (cystic fibrosis and Kartagener's syndrome) are associated with chronic sinusitis (Kaliner, Osguthorpe, Fireman, et al., 1997). Cigarette smoking may present an additional risk for developing rhinosinusitis. Smoking reduces the mucociliary clearance of nasal mucosa, and the extent of reduction depends on the amount and extent of smoking (Mahakit and Pumhirun, 1995). Currently, no direct evidence links smoking to acute rhinosinusitis. However, a better understanding of the relationship, if any, between smoking and acute sinusitis is needed.
The above distinctions hold in all settings, but the prevalence of acute bacterial rhinosinusitis in different clinical settings and in various patient subgroups may vary. Patients seen in related specialties (i.e., otolaryngology and infectious disease) often have been referred by primary care physicians. Therefore, patients seen in these specialty settings may have a different spectrum of rhinosinusitis than those in general medical clinics. Recognition of these setting differences is important in evaluating research results. As with study inclusion criteria, study settings may influence the underlying disease rate (prevalence) and may markedly influence study outcomes (Schmid, Lau, McIntosh, et al., 1998).
In clinical practice, it is necessary to identify, with reasonable certainty, patients with acute bacterial rhinosinusitis. Current tests and criteria include specific physical examination findings, sinus imaging studies (including plain-film radiography, computed tomography, and ultrasonography), and the diagnostic reference standard of bacterial isolation from a sinus puncture. The combination of tests and criteria with the highest sensitivity will identify the greatest number of patients with true acute bacterial rhinosinusitis. The most specific combination will help to identify patients without acute bacterial rhinosinusitis among those who present with upper respiratory symptoms. One goal of this report is to present the evidence for the accuracy of specific clinical and test criteria for optimal diagnosis. Appropriate application of these tests in clinical practice should help to identify those patients with a high likelihood of having acute bacterial rhinosinusitis for antibacterial therapies (Figure 2
).This report focuses on acute bacterial rhinosinusitis, given the question of the effectiveness of antibiotics for treatment. Although antibiotic use was the a priori basis for focusing on this subgroup, we also explored evidence for other therapies for this diagnosis (Figure 3
).As noted above, the predominant organisms isolated from cases of maxillary sinusitis include S. pneumonia, H. influenzae, and, in children, M. catarrhalis. Absent direct sampling and antibiotic-sensitivity testing, first-line antibiotic choices reflect data demonstrating effectiveness in eradicating the most likely pathogens, while also taking into account patient factors (e.g., drug-allergy history, use of other drugs that may interact), medication factors (e.g., formulation, dosing schedule) and accessibility factors (e.g., availability, cost) (Gwaltney, Jones, and Kennedy, 1995). Although studies have not reported recent significant shifts in the species and their prevalence in maxillary sinus aspirates, they have reported significant changes in the susceptibility of these organisms to various antibiotics (Gwaltney, 1996; Jorgensen, Doern, Mahar, et al., 1990; Neu, 1992).
Penicillin has long been used against S. pneumoniae, and the use of the aminopenicillins (e.g., ampicillin, amoxicillin) broadened that activity to include many gram-negative organisms, including H. influenzae and M. catarrhalis (Chambers and Neu, 1995a; Green and Wald, 1996). However, the increasing prevalence of antibiotic resistance factors has changed and is continuing to change the susceptibility profiles of many of these species' isolates. Since the first reports of penicillin-resistant S. pneumoniae isolates in the United States in the 1970s, the prevalence of resistant strains has been increasing (Friedland and McCraken, 1994; Nelson, Mason, and Kaplan, 1994). At the same time, increasing levels of -lactamase-producing H. influenzae and M. catarrhalis (from 8 to 65 percent and up to 98 percent, respectively) are raising concerns about the choice of antibiotics for first-line treatment of acute bacterial rhinosinusitis (Green and Wald, 1996; Jorgensen, Doern, Mahar, et al., 1990; Rodriguez, Schwartz, and Thorne, 1995). Other classes of antibiotics can provide varying levels of antimicrobial activity in penicillin-resistant S. pneumoniae (e.g., clindamycin, macrolides) and in -lactamase-producing H. influenzae and M. catarrhalis strains (e.g., folate inhibitors, second-generation cephalosporins) (Friedland and McCracken, 1994; Green and Wald, 1996; Jorgensen, Doern, Mahar, et al., 1990). In addition, combinations of antibiotics with -lactamase inhibitors (e.g., clavulanate, sulbactam) provide broader spectrum activity against -lactamase-producing strains (Chambers and Neu, 1995). The finding of antibiotic-resistant strains is complicated by frequent concomitant multidrug resistance and by wide geographic variation in the prevalence of antibiotic resistance for the various bacterial species (Friedland and McCraken, 1994; Green and Wald, 1996; Jorgenson, Doern, Mahar, et al., 1990; Levy, 1993; Mason, Kaplan, Lamberth, et al., 1992). More information is needed to understand the relationships between in vitro antibiotic-susceptibility determinations and clinical responses and to understand fully the factors affecting the rise in antibiotic-resistant pathogens (Baquero, 1996; Klugman, 1996; Nelson, Mason, and Kaplan, 1994).
The increased prevalence of resistant bacterial strains has been associated with antibiotic use (Levy, Fitzgerald, and Macone, 1976), and the prevalence of resistant strains has been shown to decline when the use of the specific antibiotic is stopped (Seppala, Klaukka, Vuopio-Varkila, et al., 1997). Although the development of antibiotic resistance is a national and global concern, increased awareness of the problem and its ramifications for local clinical practice is focusing on the need for surveillance data to aid practitioners in choosing antibiotics and in heightening awareness of the need for limiting antibiotic use appropriately (Bradley, Kaplan, Klugman, et al., 1995; Green and Wald, 1996; Levy, 1993; Werk and Bauchner, 1998).
Several classes of medications are commonly used in the treatment of rhinosinusitis (of varying causes) to restore the normal sinus environment and function (Benninger, Anon, and Mabry, 1997; International Rhinosinusitis Advisory Board, 1997). Some of the common treatments are aimed at restoring mucociliary function by increasing mucosal moisture (e.g., saline solution sprays or irrigation) and reducing the viscosity of nasal secretions (e.g., mucolytic agents). Additionally, treatments may be directed to resolving airway blockages through reducing mucosal inflammation by vasoconstriction (e.g., decongestants) or through the effect of inflammation pathways (e.g., antihistamines, steroids). As with other medical conditions, alternative medical therapies are also being explored for treating rhinosinusitis (Davies, Lewith, Goddard, et al., 1998; Linde, Clausius, Ramirez, et al., 1997; Sezik and Yesilada, 1995; Wiesenauer, Gaus, Bohnacker, et al., 1989). These treatments are aimed at rhinosinusitis of varying causes, but we explored the evidence for their efficacy in the treatment of acute bacterial rhinosinusitis.
The eventual outcomes of acute rhinosinusitis, including acute bacterial rhinosinusitis, are generally excellent even without specific treatment. Short-term, placebo-controlled studies show improvement or resolution of symptoms without antibiotic treatment in approximately two-thirds of patients between 8 and 12 days after presentation to the physician. Even in the preantibiotic era, serious complications (meningitis, brain abscess, and osteomyelitis) were rare. Efficacy estimates for the treatment of acute bacterial rhinosinusitis depend on the outcomes measured and may include relief of symptoms and reduced incidence of serious complications, rates of relapse and reinfection, progression to chronic rhinosinusitis, and adverse side effects of the treatments.
For the large majority of patients with acute bacterial rhinosinusitis, the main effects of the illness are troublesome symptoms that may keep them out of work or school and occasionally may lead to hospitalization. Most studies of the efficacy of treatments for rhinosinusitis have evaluated the outcomes in terms of the extent of persisting symptoms at the end of treatment (typically about 10 days after the onset of treatment). Some have evaluated symptom relief at more than one interval, and a few have tracked the incidence of recurrence (relapse or reinfection) in the weeks after treatment. All of these approaches yield data in the form of percentage response (cured, improved, or failure of treatment) at one or sometimes at two or three time points. Given that rhinosinusitis usually resolves spontaneously within weeks, inferring efficacy from one or two time points ("snapshots") is insufficient to quantify the benefits of treatment. It would be better to follow the rate of resolution of symptoms (e.g., with a Kaplan-Meier plot) so that the benefits, if any, of a treatment could be expressed as a reduction in symptom-days.
Complications of acute bacterial rhinosinusitis are rare. The main serious complications of bacterial rhinosinusitis are local extensions of the infection (osteitis of the sinus bones, intracranial cavity infection, and orbital cellulitis) and metastatic spread to the central nervous system (meningitis, brain abscess, and infection of the intracranial venous sinuses, including the cavernous sinus). These complications are exceedingly rare, and reliable data for their frequency as a result of acute rhinosinusitis are not available. An estimated 1 in 10,000 general hospital admissions is for brain abscess, and in different geographic locations, there is wide variation in the estimated percentage of hospitalizations (0.5 percent in China and 15 to 25 percent in Northern Europe) that are secondary to rhinosinusitis (Wispelwey and Scheld, 1995). In 1995, the number of U.S. hospital discharges for brain abscesses (ICD-9 code 324.0) was 5,000 (National Center for Health Statistics, 1990-1995). Using the highest estimated percentage of brain abscess secondary to rhinosinusitis (25 percent), about 1,250 cases were likely from among 118,255,000 discharges recorded for that year (approximately 1 out of 95,000 admissions).
It is well known among medical practitioners that even when patients with allergic rhinosinusitis are excluded, some patients have frequent recurrences of presumed acute bacterial rhinosinusitis. Among these patients, it is difficult to distinguish a relapse of acute bacterial rhinosinusitis (from incomplete treatment) from multiple isolated episodes of acute bacterial rhinosinusitis (reinfection). There are no standardized criteria to assess "full recovery." The current definition of recurrent acute bacterial rhinosinusitis, based on total number of recurrences (fewer than four per year) and symptom-free intervals (at least 8 weeks), is arbitrary and not related to pathophysiologic features (International Rhinosinusitis Advisory Board, 1997). The effect of antibiotic or other treatment for a given episode of rhinosinusitis on the subsequent recurrences is unknown. Although the evidence is largely circumstantial, factors relating to structural interference of sinus passage have been postulated as risk factors in the development of chronic rhinosinusitis (see below). The relationship of these factors to the development of recurrent rhinosinusitis is unclear (International Rhinosinusitis Advisory Board, 1997).
A small proportion of patients with acute rhinosinusitis, especially those with multiple episodes of acute rhinosinusitis, experience chronic rhinosinusitis. Although strong evidence is lacking, several risk factors have been implicated in the development of chronic rhinosinusitis. These risk factors include abnormalities in the normal flow of mucus and air through the sinus and nasal passages as a result of obstruction (ostial obstruction, allergic reaction, direct injury) or functional (ciliary abnormalities, abnormalities in mucus secretion) conditions, or as a result of increased susceptibility to infection (immunodeficiency, or secondary to aforementioned sinus or nasal blockage). The development of chronic rhinosinusitis remains poorly understood.
The side effects of treatment range from the risks of the diagnostic procedure to the potential side effects of various therapies. The reference standard for diagnosis of acute bacterial rhinosinusitis has been the sinus puncture. The complication rates of a sinus puncture depend on the skill of the operator. In skilled hands, epistaxis as a minor complication is common and, for the most part, unimportant. Serious complications are rare and include damage to the orbit with possible blindness. There are no good estimates of the rate of this complication.
Major side effects from antibiotics are uncommon. Minor rashes and gastrointestinal complaints (e.g., nausea and diarrhea) are most common and usually respond to withdrawing the antibiotic. Rarely, blood dyscrasias, hepatitis, or renal impairment may occur. With some agents, such as macrolides, quinolones, and tetracyclines, drug interactions with other medications may be a problem. A few agents may be photosensitizing (e.g., sulfonamides and doxycycline). There is no evidence of an interaction between the treatment of a particular infection and the incidence of side effects. As such, there is no reason to suspect that the nature and incidence of side effects from antibiotics in the treatment of rhinosinusitis would differ from the profiles of those drugs for the treatment of other infections if the dosage and duration of treatment are similar.
Similarly, for other treatments (decongestants, steroids, and so on), other than reports of drug interactions (e.g., terfenidine and erythromycin), we found no data that support differential side-effect profiles of these medications in the treatment of acute bacterial rhinosinusitis as compared with the treatment of nonbacterial rhinosinusitis or infections at other anatomic locations.
Given our current understanding of the causes and pathophysiology of acute bacterial rhinosinusitis and the premise that appropriate antibiotic use should be reserved for the treatment of bacterial infections, we summarize in this report the evidence relating to the diagnosis and treatment of acute bacterial rhinosinusitis. We performed meta-analyses to summarize evidence on several diagnostic modalities that have been used for this condition. We also performed meta-analyses to summarize the evidence on the effects of antibiotic treatments, and we sought evidence for the use of symptomatic (ancillary) treatments. We performed decision and cost-effectiveness analyses using the meta-analysis results to provide guidance on the use of the evidence.
This evidence report is based on a systematic review of the literature (Mulrow and Cook, 1998), as well as several supplemental analyses to summarize the evidence. Meetings and teleconferences with technical expert representatives from four partner organizations (the American Academy of Family Physicians, American Academy of Otolaryngology-Head and Neck Surgery, American Academy of Pediatrics, and American College of Physicians) and several EPC internal technical experts (the technical expert advisory group) were held to formulate the five key questions addressed in this evidence report. A comprehensive search of the medical literature was conducted to identify the evidence available to address these questions. Two supplemental analyses were conducted to provide answers to the key questions. The first analysis is a meta-analysis of studies of diagnostic test comparisons. The second analysis is a meta-analysis of randomized controlled trials of antibiotic treatment.
After the formulation of the five key questions, the group felt that decision and cost-effectiveness analyses would be useful to guide the use of the evidence. Thus, a third supplemental analysis was conducted. It consists of decision and cost-effectiveness analyses using results of the meta-analyses to provide insights into translating the evidence into practice.
Detailed information about the studies used in the meta-analyses was abstracted, and the results are presented as evidence tables. Two patients who had presumed acute bacterial rhinosinusitis were interviewed to assess their experiences and preferences in the management of this condition. Their comments were integrated into this evidence report and helped to frame the decision and cost-effectiveness analyses.
The EPC staff and the technical experts arrived at consensus on five key questions following discussions and broad intermeeting solicitation of comments from the group members. In addition to the evidence model of diagnosing patients with acute bacterial rhinosinusitis discussed in Chapter 1, Figure 4
depicts the causal pathway for treatment of acute bacterial
rhinosinusitis.
1. What is the prevalence of acute bacterial infection in patients presenting with acute rhinosinusitis in primary care and specialty settings?
Although sinus puncture with microbiologic testing of the aspirate is the most widely accepted reference standard for diagnosing bacterial rhinosinusitis, it is not routinely performed in most clinical settings. Knowledge of the prevalence of bacterial rhinosinusitis is therefore important for the clinician to assess the likelihood of bacterial infection and guide therapeutic decisions for patients with rhinosinusitis. We agreed that the distinction of bacterial rhinosinusitis as compared with other forms of rhinosinusitis is important, since antibiotics are used in current clinical practice for the treatment of bacterial infections and timely therapy is presumed to be beneficial. Understanding that patients with acute rhinosinusitis seen in primary care clinics may differ from those seen in specialty clinics, the advisory group was interested in gathering any available prevalence data for populations evaluated in each of these clinical settings.
2. What is the diagnostic value of clinical features/imaging modalities for identifying acute rhinosinusitis and acute bacterial rhinosinusitis?
Accurate diagnosis is important for effective care in the clinical setting. In addition to evidence regarding overall prevalence of bacterial rhinosinusitis in different clinical practice settings, the advisory group agreed that it was necessary to review the evidence regarding various clinical features and tests that can help the practitioner diagnose acute bacterial rhinosinusitis with better accuracy. Although a main objective is to accurately identify patients with bacterial rhinosinusitis, the group recognized that this diagnosis might entail a multistep process -- first identifying acute rhinosinusitis and then assessing the probability of bacterial infection.
3. Given a (clinical) diagnosis of acute bacterial rhinosinusitis, are antibiotics effective in resolving symptoms, and in preventing complications or recurrence?
As previously noted, current clinical practice attempts to distinguish rhinosinusitis with concurrent bacterial infection (bacterial rhinosinusitis) from other cases of rhinosinusitis, since antibiotic treatment is used to treat bacterial infections. This report summarizes the available evidence regarding the effectiveness of antibiotic therapy for patients who are diagnosed clinically to have acute bacterial rhinosinusitis. The evidence regarding efficacy includes several outcomes, which the advisory group agreed were clinically important, namely: resolution of symptoms, prevention of complications, and prevention of recurrence.
4a. In treatment of acute bacterial rhinosinusitis, what is the efficacy of antibiotics compared with that of placebo, and among the various antibiotics, what is their comparative efficacy?
4b. What evidence do these comparative studies provide regarding side effects?
Although the previous question addresses the effectiveness of antibiotic therapy for various outcomes, this question concerns comparative studies of specific antibiotics compared with placebo and compared with other available antibiotics. Comparison with placebo provides evidence regarding efficacy of antimicrobial treatment in general, whereas the comparisons between different antibiotics provide relative efficacy between therapeutic regimens.
The advisory group recognized that although efficacy assessments may look at the benefits of treatment using the outcomes noted in question 3, clinical decisions to use any of the treatments will also require understanding of the risks of side effects. Therefore, we examined available data on comparative risks for the various available antibiotic regimens.
5a. Are there data to support the use of other types of treatments for acute rhinosinusitis and acute bacterial rhinosinusitis, specifically: decongestants, steroids, antihistamines, drainage, sinus irrigation, others?
5b. What is the efficacy of antibiotics compared with other types of treatment?
5c. What evidence do comparative studies provide regarding side effects?
Patients with acute bacterial rhinosinusitis have acute rhinosinusitis with concomitant bacterial infection. In addition to antibiotics, symptomatic (ancillary) treatments also may be used. This report presents the available evidence for the use of these ancillary treatments (both conventional and nonconventional) in the treatment of acute bacterial rhinosinusitis. Evidence for comparative efficacy of antibiotics and other treatments is examined, as well as evidence on the efficacy of combination treatments. As for the antibiotics, clinical use of the available therapeutic options requires assessment of both risk and benefit. Therefore the advisory group agreed on the importance of summarizing the evidence available regarding side effects of these other treatments and of combination treatment regimens.
I - PRIMARY MEDLINE SEARCH STRATEGY
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II - SECONDARY LITERATURE SEARCH
Second MEDLINE search
strategy
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We also searched Excerpta Medica and recent Abstracts for the Interscience Conference on Antimicrobial Agents and Chemotherapy (American Society for Microbiology, 1993-1997) and inspected references of all trials, review articles, and special issues for additional studies.
Additional articles were identified by consultations with technical experts and colleagues and review of bibliographies of retrieved primary clinical studies, review articles, and published and unpublished meta-analyses. A manuscript on the meta-analysis of diagnostic tests was provided to us by a research group in Finland (Varonen, Mäkelä, Savolainen, et al., unpublished). One group in the Netherlands published a meta-analysis on diagnostic tests (de Bock, Houwing-Duistermaat, Springer, et al., 1994) and a meta-analysis on antibiotic treatment (de Bock, Dekker, Stolk, et al., 1997); these articles were reviewed for additional references. A meta-analysis on antibiotic treatment for acute bacterial rhinosinusitis published in the British Medical Journal by EPC members also provided additional references (deFerranti, Ioannidis, Lau, et al., 1998).
A separate MEDLINE search for potentially useful foreign language articles was conducted to assess the magnitude of bias in excluding non-English literature. Several non-English language studies already identified by other published meta-analyses were included in our report. These studies are more likely to be useful as other groups have already critically appraised them.
Because the unequivocal diagnosis of acute bacterial rhinosinusitis requires a bacteriologic evaluation (routinely obtained by maxillary sinus puncture), the true prevalence of acute bacterial rhinosinusitis is difficult to obtain reliably. There are no epidemiologic studies that used sinus puncture to estimate the prevalence of this condition in a given population. In this evidence report, the prevalence of sinusitis is estimated from diagnostic test studies and from treatment studies that used sinus puncture as the reference standard. In addition, we review data from several observational studies.
Studies identified in the literature search described in the Search Strategy and Study Selection sections were included if they presented data prospectively comparing the performance of two or more tests in the diagnosis of acute bacterial rhinosinusitis. These diagnostic tests included clinical criteria (studies had to evaluate a composite measure such as overall clinical impression or a decision aid such as a risk score), radiographs, ultrasonography, or sinus puncture/aspiration. Although studies evaluating computed tomography or magnetic resonance imaging would be eligible, no comparative studies of these tests meeting inclusion criteria were identified (there were several studies of chronic sinusitis). Studies were excluded if diagnostic tests were evaluated on individuals not presenting with symptoms of acute bacterial rhinosinusitis. However, the definition of acute bacterial rhinosinusitis varied among studies; for example, two studies evaluated some subjects with prolonged symptoms (Berg and Carenfelt, 1988; Williams, Simel, Roberts, et al., 1992), whereas others did not provide a definition of sinusitis. To avoid the problem of verification bias (Irwig, Tostetson, Gatsonis, et al., 1994), studies were excluded if some subjects did not undergo all tests being compared.
The comparison matrix is used to help assess whether a relevant clinical question is addressable by determining whether a sufficient number of potentially useful studies is available to conduct a meta-analysis. In consultation with the technical experts, three meta-analyses of antibiotic trials were identified. The meta-analyses are based on an article published by several EPC members in the British Medical Journal (deFerranti, Ioannidis, Lau, et al., 1998). This meta-analysis was updated and provided the basis for the supplemental analyses of antibiotic treatment in this evidence report. Parts of this published article are used in this evidence report with permission from the journal.
Trials were eligible for inclusion in a meta-analysis if three criteria were met: (1) the trial compared amoxicillin or a folate inhibitor agent (e.g., trimethoprim/sulfamethoxazole) to another agent, generally one with a broad spectrum of activity including cephalosporins, penicillins with β-lactamase inhibitors, tetracyclines, quinolones, and macrolides; (2) patients were assigned randomly; and (3) the trial evaluated acute sinusitis or an acute exacerbation of chronic sinusitis ("acute-on-chronic"). Both adult and pediatric studies qualified. Trials of subacute or chronic sinusitis (greater than 4 weeks mean symptom duration) were excluded. Although dosage or duration comparison studies would provide useful information, a quick scan of the matrix revealed few such studies, and a meta-analysis was not possible. Placebo-controlled studies were examined to assess the effect of antibiotics on the natural history of acute bacterial rhinosinusitis.
Because the focus of this evidence report is on uncomplicated, community-acquired, acute bacterial rhinosinusitis, we excluded studies with immunocompromised patients such as patients with malignancy receiving chemotherapy, human immunodeficiency virus (HIV) infection, cystic fibrosis, asthma, Kartagener's syndrome, IgA and IgG deficiencies, and trauma or surgery-related sinus infections. Even though HIV infection and asthma are part of the exclusion criteria, we screened the MEDLINE search results for randomized controlled trials specific for these populations with the intention of performing separate subgroup analyses. We found none.
Since we found only 10 randomized controlled trials of ancillary treatments, a comparison matrix is not useful. Because of the heterogeneous mix of treatments, diagnostic definitions, and protocols, a meaningful meta-analysis was not possible for ancillary treatments. The data from these studies were abstracted and summarized in the evidence tables.
Data from qualifying studies were extracted in duplicate. Discrepancies were resolved in a conference or by a third reviewer. Our data abstraction forms (Attachment A) were developed to minimize subjective interpretation of reported data. Besides a few easily recognizable misinterpretations by one or the other extractor, there was no important disagreement between the two independent reviewers, and final consensus was reached on all items. The biggest data extraction problem was in the interpretation of ambiguous data (e.g., where data reported in different parts of the study appear to disagree where needed data must be derived indirectly). In these instances, the project staff worked together with the technical experts to come up with the most likely answer.
For each included study, we extracted test data cross-classifying individuals as having or not having bacterial rhinosinusitis. To calculate sensitivity and specificity in a comparison of two diagnostic tests, it is necessary first to decide which test is the "test of interest" and which is the "reference test." For included studies, comparisons of diagnostic tests were derived in a manner consistent with a "hierarchy" of accuracy: most accurate was sinus puncture, followed by radiography, ultrasonography, and then clinical criteria. Therefore, for example, estimates of sensitivity and specificity of ultrasound were derived with respect to radiography (and not vice versa). Many studies reported data only for "sinuses" and not for "patients"; these sensitivity and specificity data were used in the analyses.
When studies presented test performance data for more than one threshold or cut-point for tests of interest, we extracted data for each cut-point separately. For instance, for the clinical examination compared with radiography, data for overall clinical impressions of intermediate probability and high probability were included separately.
The following data were also extracted from each study: country where the study was performed and publication year of the study; age of study participants and duration of their symptoms; location of the study (hospital, office practice, or emergency department); and type of physicians who evaluate patients (primary care physicians or otolaryngologists). We also noted whether each diagnostic test was evaluated in a manner blinded to the results of the other evaluated tests.
Outcomes of interest were clinical "cure," "improvement," and "failure" as assessed within 48 hours of the end of treatment. Although we would have been interested in analyzing other outcome measures such as rates of improvement in the treatment and control arms and relapses, most studies do not report them. Cures and failures were recorded as defined by the individual study; "cure" generally meant resolution of all signs and symptoms, and "failure" generally signified no change or worsening of signs and symptoms. Data on radiographic "cure," "improvement," or "failure" and bacteriologic "cure" or "failure" were also extracted as defined by each study. The main analyses used clinical outcomes as the endpoint most relevant to clinicians because primary care practitioners do not routinely obtain sinus films for uncomplicated acute bacterial rhinosinusitis and almost never perform cultures of sinus aspirates. Furthermore, there is only limited evidence suggesting a correlation between radiographic or bacteriologic failure and clinical outcomes. Separate analyses assessed bacteriologic failures, radiographic failures, and patient withdrawals due to adverse drug effects.
In addition to clinical outcomes, data were also extracted on study design characteristics such as blinding, disease definition, publication year, and age group. These factors provided the basis for sensitivity analyses.
The reliability of the conclusions from a meta-analysis depends on the methodologic quality and reporting of the studies used (internal validity issues). Although it is important to perform critical appraisal of the literature prior to quantitative synthesis of the data, there is no consensus on how the results of such "quality" assessments should be used (Ioannidis and Lau, 1998). Two approaches generally taken are sensitivity analyses of specific factors that possibly relate to systematic bias of result and the use of a composite quality score. Both of these approaches were used in the meta-analysis of treatment trials.
Evidence Tables 3 through 8 list the items frequently considered in various quality assessments of diagnostic test studies. These items include specification and diagnostic criteria of the reference standard and the test and blinding of the interpreter of a test to the clinical information and the results of the other test. There were too few studies in each of the categories of the diagnostic test comparisons to allow a meaningful sensitivity analysis. Therefore, these items are included for descriptive purposes only. To avoid the problem of verification bias (Irwig, Tostetson, Gatsonis, et al., 1994), studies were excluded if some subjects did not undergo all tests being compared.
In each trial, the following characteristics pertaining to the quality of study design, conduct, and reporting were assessed by two investigators with subsequent consensus: blinded vs. unblinded design, specification of criteria for the diagnosis of sinusitis, detailed reporting as to the use of decongestants, and robustness of the assessment of clinical outcomes and completeness of the information on outcomes (losses to followup). The diagnosis of sinusitis was categorized as "firm" if a trial performed sinus aspirations and culture or radiographic evaluations (assessing the presence of air-fluid levels, mucosal thickening greater than 6 mm, or opacification of sinuses). Any other diagnostic criteria, including clinical judgment or nasal swabs, were categorized as "subjective." Outcome criteria were judged to be well-specified when a study scaled symptoms or signs as assessed by patients and/or physicians in a way that could be replicated. Trials, which specified criteria to some extent, noted the signs or symptoms used to evaluate cure, improvement, or failure but were not specific about how these data were evaluated. Trials with unclear criteria made no mention of how clinical outcomes were determined.
In addition to this subject-specific assessment of quality components, we also used a previously developed, validated scale of assessing the methodologic quality of the trials on a scale of 0 to 5 with a value of 5 being the perfect score of a specific study (Jadad, Moore, Carroll, et al., 1996). This scale focuses on randomization, double-blinding, and description of withdrawals and has been widely implemented.
We further explored quality issues by conducting subgroup analyses by dichotomizing studies into two groups using factors thought to be associated with higher quality. Cumulative meta-analyses ordered by methodologic quality of the studies were used to explore possible treatment effect trends as studies with lower quality scores were added to studies with higher quality scores.
We followed the general principles of conducting a meta-analysis of diagnostic test studies described several years ago in the Annals of Internal Medicine (Irwig, Tosteston, Gatsonis, et al., 1994). For each combination of the test of interest and the reference test, a summary receiver operator characteristic (SROC) curve was constructed based on the method described by Moses, Shapiro, and Littenberg (1993). Multiple data points from studies that provided data at different cut-points were used to derive these curves; because these observations were not independent, confidence intervals around SROC curves could not readily be calculated. SROC curves were derived for data points weighted by the inverse of the variance. When studies provided estimates of specificity over a wide range (approximating the total possible range from 0 to 1), the area under the SROC curve was calculated by extrapolation. In addition to the SROC method, random-effects weighted average was used to calculate the average sensitivity and specificity for each comparison. Although pooling these values separately as we did tends to underestimate the true test sensitivity and specificity, they are nonetheless useful estimates of the average test performance. We assessed the appropriateness of this method by noting the distance of the estimates from the SROC curve. Statistical analyses using the SROC curve method was performed using "Meta-Test" version 0.6, a computer program developed by the EPC director (Dr. Lau).
In addition to the SROC curve method, we explored a method described by de Bock, Dekker, Stolk, et al. (1997) for combining studies to estimate the sensitivity and specificity of diagnostic tests either when there is no reference standard or when a reference standard is not available for all comparisons. We applied this method to the diagnostic studies for acute rhinosinusitis.
Estimates are obtained by maximizing the likelihood through the Expectation Maximization (EM) algorithm (Dempster, Laird, and Rubin, 1977). Through an iterative procedure, the method estimates the true sensitivity and specificity of each test without assuming that any of the tests is a reference standard. First, starting values are assigned for the sensitivity and specificity of each test and for prevalence of the disease associated with each study. Second, based on these parameter values, the number of diseased and not diseased are estimated for each study. This is called the E-step, for estimation. Third, the maximum likelihood estimates are computed using the estimates from the E-step. This is called the M-step, for maximization. The estimates from the M-step are then used in the E-step, and the process iterates until convergence. The process should be repeated with different starting values to make sure the initial choice of parameters does not affect the final estimates.
The validity of the method relies on two key assumptions. One assumption is that an individual's results on two tests are independent, conditioned on whether the person has the disease. The other assumption is that the sensitivity and specificity of each test do not vary from study to study. Both of these assumptions are violated by the data available in the literature. Most studies did not blind the interpreter of the reference test to the results of the test of interest, so conditional independence is unlikely. Another way conditional independence can be violated is if the disease is not dichotomous, and different tests pick up the disease at different severity levels, as pointed out by the authors of this method. In our meta-analysis of diagnostic tests, the SROC curve analysis is evidence that the sensitivity and specificity for a given modality vary. Indeed, there are several criteria for defining a positive sinus radiograph with sensitivity estimates varying from 0.41 to 0.90.
We abandoned this method because of the violations of its assumptions and based our conclusions on the SROC curve method.
First, treatment outcomes from studies that had placebo arms were pooled to determine the effect of treatment with any antimicrobial on the natural history of acute bacterial rhinosinusitis. Second, two main comparisons between antibiotic groups were made: newer and/or expensive antibiotics including cephalosporins, macrolides, quinolones, tetracyclines, and penicillins with a β-lactamase inhibitor vs. amoxicillin, and newer and/or expensive antibiotics (as above) vs. folate inhibitors.
The general method of quantitative synthesis was followed (Laird and Mosteller, 1990; Lau, Ioannidis, and Schmid, 1997). Pooling of risk ratios, risk differences, and control group event rates were performed using both the Mantel-Haenszel fixed effects model (Mantel and Haenszel, 1959) and the DerSimonian and Laird random effects model (Fleiss, 1993; Ioannidis, Cappelleri, Lau, et al., 1995). The random effects model takes into account the variability of the true treatment effect between studies and provides a wider confidence interval (compared with the fixed effect model) when heterogeneity is present. Heterogeneity between studies was assessed with a chi-square statistic. This test is not very sensitive; therefore, heterogeneity was considered statistically significant if p<0.10 (Lau, Ioannidis, and Schmid, 1997). Weighted rates are also reported; rates were weighted by the inverse of their variance with random effects.
For the main outcome of clinical failure, we performed sensitivity analyses excluding: (1) pediatric studies; (2) studies in which amoxicillin or folate inhibitors were compared against tetracyclines which have been available almost as long, but continue to be more expensive; (3) studies in which patients with resistant organisms had been excluded; (4) studies in which diagnosis of sinusitis was not made on firm criteria; (5) studies with unclear assessment of outcomes; (6) studies that were not double-blind; (7) studies published before 1993; and (8) studies with a "Jadad" quality score of lower than 3. In each case, heterogeneity between excluded and remaining studies was assessed by the chi-square test and deemed significant for p<0.1. Statistical analyses of pooling treatment effects from randomized controlled trials were performed using "Meta-Analyst" version 0.991, another computer program developed by the EPC director (Dr. Lau).
Decision and cost/effectiveness analyses were performed to aid the translation of evidence into practice. Standard methods of decision analysis and cost-effectiveness analysis were followed (Drummond, Brandt, Luce, et al., 1993; Kassirer, Moskowitz, Lau, et al., 1987). We developed two decision models incorporating alternative clinical strategies, uncertain events, and various clinical outcomes. For each of the two models, a decision analysis was performed from the patient's perspective, and a cost-effectiveness analysis was performed from the payer's perspective. The first model used a single time-point decision tree and compared eight different clinical strategies. The second model used a Markov process (Beck and Pauker, 1983) to model varying rates of clinical cure over the course of 2 weeks. For the single time-point model, an arbitrary utility scale with values varying between 0 and 1 was used to assign quality to various clinical outcomes. For the Markov model, a quality-adjusted symptom-day was used.
Data on diagnostic test performance and antibiotic efficacy used in the decision analysis were obtained from the meta-analyses performed for this evidence report. Additional required data were obtained from literature review, technical expert estimates, and modeling of published data. Costs, rather than charges, were used wherever possible in the cost-effectiveness analyses. Quality-of-life adjustments, when possible, were estimates derived from the patients interviewed for this evidence report. Since the decision/cost-effectiveness analysis uses a short-term time horizon of only 2 weeks, discounting of the cost or utility was not considered.
The decision and cost-effectiveness analyses are described in detail in the supplemental analysis section. The decision models and analyses were performed using DMAKER 7.0, a computer program developed by Dr. Stephen Pauker, of the New England Medical Center EPC's decision/cost-effectiveness analysis core.
EPC staff recruited two patients from a primary care setting with recent episodes of presumed acute bacterial rhinosinusitis to provide input into the decision analysis models and in the formulation of future research questions. A meeting was held to inform the patients of the evidence report process and to obtain feedback from the patients regarding: (1) their personal experience with this illness, (2) their responses to potential diagnostic and treatment modalities, and (3) their evaluations of the value of tests and treatment options. The questions formulated by the technical experts and preliminary results from the evidence report were presented to the patients for their responses and to identify issues or topics about which they would like to see future research.
The primary MEDLINE search strategy yielded 4,070 English language titles. Additional search strategies along with secondary sources and subsequent MEDLINE updates yielded an additional 38 articles, bringing the total number of records to 4,108.
Screening of the abstracts and articles identified about 330 articles potentially useful to address the five questions formulated by the advisory group, and these were retrieved for review. Detailed examination of these articles identified 49 prospective comparisons of diagnostic tests or clinical criteria and 83 randomized controlled treatment trials. Of the antibiotic treatment trials, 72 articles reported 74 comparisons that met the basic inclusion criteria as outlined for the evidence report. Detailed data abstraction was performed on studies that met inclusion criteria for meta-analyses: 14 comparisons of diagnostic studies and 30 randomized controlled trials. In addition, even though not used in a meta-analysis, data were extracted from the 10 randomized ancillary treatment trials. The results of the detailed data extraction are presented in the evidence tables.
We performed a MEDLINE search to assess the potential bias of excluding non-English articles in the primary search strategy. Over 3,200 foreign language titles were retrieved using the text word, "sinusitis" and "human" and "not English" between 1966 and February 1998. The number of non-English articles represents 43 percent of the total number of MEDLINE indexed articles using the search strategy of "sinusitis" and "human."
| MEDLINE | MED93 | MED90 | MED85 | MED80 | MED75 | MED66 | ||
|---|---|---|---|---|---|---|---|---|
| 1995-98 | 1993-94 | 1990-92 | 1985-89 | 1980-84 | 1975-79 | 1966-74 | Subtotal | |
| All sinusitis and human | 1,194 | 687 | 975 | 1,284 | 953 | 810 | 1,525 | 7,428 |
| English only | 942 | 514 | 654 | 771 | 551 | 339 | 435 | 4,206 |
| non-English | 252 | 173 | 321 | 513 | 402 | 471 | 1,090 | 3,222 |
| Percentage non-English | 21% | 25% | 33% | 40% | 42% | 58% | 71% | 43% |
| Russian | 48 | 21 | 68 | 120 | 69 | 148 | 276 | 750 |
| German | 54 | 30 | 53 | 120 | 124 | 130 | 235 | 746 |
| French | 31 | 33 | 61 | 65 | 59 | 55 | 146 | 450 |
| Japanese | 37 | 24 | 53 | 76 | 40 | 28 | 171 | 429 |
| Spanish | 36 | 25 | 24 | 32 | 12 | 6 | 25 | 160 |
| Italian | 12 | 6 | 18 | 16 | 18 | 14 | 70 | 154 |
| Polish | 6 | 10 | 8 | 12 | 23 | 21 | 41 | 121 |
| Rumanian | 1 | 0 | 1 | 13 | 13 | 24 | 37 | 89 |
| Dutch | 3 | 3 | 5 | 15 | 13 | 6 | 9 | 54 |
| Czech | 1 | 0 | 1 | 6 | 12 | 11 | 15 | 46 |
| Chinese | 13 | 4 | 8 | 9 | 2 | 0 | 2 | 38 |
| Portuguese | 0 | 3 | 1 | 0 | 2 | 2 | 17 | 25 |
| Danish | 2 | 2 | 5 | 6 | 1 | 2 | 6 | 24 |
| Serbo-Croatian | 1 | 1 | 6 | 7 | 3 | 8 | 6 | 32 |
| Hungarian | 0 | 0 | 0 | 0 | 1 | 4 | 16 | 21 |
| Norwegian | 1 | 5 | 1 | 1 | 0 | 2 | 7 | 17 |
| Swedish | 2 | 4 | 2 | 2 | 3 | 1 | 3 | 17 |
| Finnish | 0 | 0 | 3 | 3 | 1 | 2 | 4 | 13 |
| Slovak | 1 | 0 | 0 | 6 | 1 | 1 | 2 | 11 |
| Hebrew | 1 | 2 | 1 | 0 | 4 | 1 | 0 | 9 |
| Bulgarian | 1 | 0 | 0 | 0 | 0 | 5 | 0 | 6 |
| Turkish | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 3 |
| Ukraine | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 2 |
| Korean | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 2 |
| Afrikaans | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
| Multilingual | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 |
| Thai | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| MEDLINE file | Medline | MED93 | MED90 | MED85 | MED80 | MED75 | MED66 | |
|---|---|---|---|---|---|---|---|---|
| 1995-98 | 1993-94 | 1990-92 | 1985-89 | 1980-84 | 1975-79 | 1966-74 | Subtotal | |
| All sinusitis and human | 1,194 | 687 | 975 | 1,284 | 953 | 810 | 1,525 | 7,428 |
| English only | 942 | 514 | 654 | 771 | 551 | 339 | 435 | 4,206 |
| non-English | 252 | 173 | 321 | 513 | 402 | 471 | 1,090 | 3,222 |
| Percentage non-English | 21% | 25% | 33% | 40% | 42% | 58% | 71% | 43% |
| Treatment comparisons | ||||||||
| Screened in by title | 2 | 3 | 3 | 4 | 3 | 1 | 16 | |
| Language | Ger, Fre | Rus, Fre, Spa | Dut, Fre, Fre | Spa, Ita, Ger(2) | Ger(2), Spa | Rus | ||
| ? Suitable | 0 | 0 | 1 (Fre) | 1 (Ger) | 2 (Ger, Spa) | 0 | ||
| Rejected by abstract, MH | 1 (Ger) | 1 (Rus) | 0 | 0 | 0 | 1 | ||
| Meets criteria for M-A | 0 | |||||||
| Diagnostic studies | ||||||||
| Screened in by title | 1 | 2 | 1 | 1 | 1 | 2 | 8 | |
| Language | Ita | Rus, Jpn | Ita | Ger | Dut | Ger (2) | ||
| ? Suitable | 0 | 1 (Jpn) | 1 (Ita) | 0 | 1 (Dut) | 2 (Ger) | ||
| Rejected by abstract, MH | 1 (Ita) | 1 (Rus) | 0 | 1 (Ger) | 0 | |||
| Meets criteria for M-A | 0 | 0 |
Evidence Tables 1-24 provide information about the characteristics and results of the studies supporting conclusions in the evidence report and in the meta-analyses. In addition to the diagnostic criteria, several important study characteristics are described here.
The research reference standard for verification of bacterial infection of the sinuses relies on microbiologic culture of sinus aspirates. Of the studies reviewed for inclusion in this evidence report, 7 of 14 studies of diagnostic test comparisons, 5 of 30 antibiotic treatment trials, and none of the 10 ancillary treatment trials used this technique for evaluation. The procedure requires technical expertise and is invasive, which may account in part for its low rate of utilization, particularly in treatment evaluations (Laine, Maättä, Varonen, et al., 1998; van Buchem, Peeters, Beaumont, et al., 1995). Anatomy of the sinus cavities limits current sinus puncture sampling to aspirates of the maxillary sinuses, and as such, use of this reference standard in research leads to direct conclusions regarding maxillary sinus infections and not infections of other sinuses (Gwaltney, Scheld, Sande, et al., 1992). Data comparing microbial flora from infected maxillaryand frontal sinuses in individual patients correlated well but are very limited (Antila, Suonpaa, and Lehtonen, 1997).
One of the criteria for paper inclusion was study of patients with acute bacterial rhinosinusitis defined as symptoms of 4 weeks duration or less. Review of the literature revealed that many of the papers only specified "acute" without providing specific time periods. This was true for studies of the diagnostic tests (Evidence Tables 3-6) as well as studies of both antibiotic (Evidence Tables 15-17) and ancillary (Evidence Tables 22-24) treatments. In some instances, the duration of symptoms was reported as a mean value. In these cases, studies reporting mean estimates of 4 weeks or less were included. The lack of clearer definition of the populations used in these research studies raises questions regarding the validity of directly comparing the results of different studies and applying these results to specific patient populations.
Most studies of diagnostic tests focused on adult populations. In many studies, patients under 18 years of age were also included (usually teenagers), but the reported results did not distinguish these distinct age groups. Two studies comparing radiography with puncture did include patients as young as 7 and 10 years old (McNeill, 1962, and Revonta, 1980, respectively) but did not separately report the pediatric population findings. One study from Sweden (Jannert, Andreasson, Helin, et al., 1982) compared clinical examination and radiography in a solely pediatric population. Other pediatric population studies (Wald, Chiponis, and Ledesma-Medina, 1986; Wald, Reilly, Casselbrant, et al., 1984) reported on the results of diagnostic studies in their patients but did not perform all tests on all patients, precluding use of these data for diagnostic test comparisons.
Most studies on antibiotic treatment of rhinosinusitis used adult populations. Two studies focused specifically on pediatric populations (Wald, Chiponis, and Ledesma-Medina, 1986; Wald, Reilly, Casselbrant, et al., 1984). Although adult medicine in the United States usually includes patients over 18, many of the trials also included some younger patients, from as young as 10 years old (Wallace, Marsh, and Talbot, 1985), within their study populations. In these studies, however, reported results did not distinguish between the adult and pediatric patients.
Among studies of ancillary treatments, two studies focused specifically on pediatric populations, each testing different ancillary medications (Barlan, Erkan, Bakir et al., 1997; McCormick, John, Swischuk, et al., 1996). Most of the other ancillary treatment trials included some pediatric patients (most over 9 years of age) but did not separately analyze the outcomes for these patients as compared with the adults.
Evidence for the key questions addressed in this evidence report are derived from two supplemental analyses: Meta-analyses of Diagnostic Tests (Attachment B) and Meta-analyses of Antibiotic Treatments (Attachment C). Details of these analyses can be found in those attachments. The main results are summarized here.
1. What is the prevalence of acute bacterial infection in patients presenting with acute rhinosinusitis in primary care and specialty settings?
Prevalence is defined as the proportion of subjects in a population with a defined condition at a given time. Therefore, it is clear that determinations of the prevalence of acute bacterial rhinosinusitis will be affected by definition of the condition, criteria used for diagnosis, and the population chosen for study. Lack of consensus in the definition and criteria for diagnosis of acute bacterial rhinosinusitis has led to difficulty in determining the prevalence of this condition. For this evidence report, criteria used to identify studies on acute bacterial rhinosinusitis included enrollment of patients with sinus symptoms lasting less than 4 weeks. In addition, a sinus puncture aspirate positive for bacterial infection was defined as the reference standard for diagnosis. Although sinus puncture techniques are limited to evaluation of maxillary sinus aspirates, evaluation of the studies using this diagnostic reference standard permits comparisons of prevalence estimates using a standardized method for diagnosis in patients with acute disease. We therefore reviewed these data for prevalence determinations.
The wide variation in prevalence estimates among these studies, all of which used the diagnostic reference standard, highlights the difficulty in assessing prevalence and comparing estimates from different studies. Although some of the variation may result from differences in sinus puncture technique, aspirate processing, and bacteriologic evaluation, other factors (e.g., patient characteristics, geographic location, seasonal variation) which can affect disease development and population selection may play a role (Axelsson and Brorson, 1972).
As noted above, primary care vs. referral/specialty clinics would be expected to draw different populations. Add to that the potential selection bias due to research protocols, such as the use of sinus puncture. In addition to the aforementioned limitation of sinus puncture to maxillary sinus evaluation, studies have raised concerns that patients' fears and researchers' ethical concerns may be potential sources of selection bias. Laine, Maättä, Varonen, et al. (1998) reported increasing difficulty recruiting patients because of the use of sinus puncture in their protocol. Citing ethical concerns, van Buchem, Peeters, Beaumont, et al. (1995) reported a change in protocol for later patient enrollees such that sinus puncture was performed only in patients with radiographic findings suggestive of rhinosinusitis. Sinus puncture may be the most valid reference standard for diagnosing patients, but the pain, need for referral, and cost attendant to puncture preclude its routine use in primary care settings and have prompted use of alternative tests for diagnosis. Using four-view sinus radiography as the diagnostic criterion, Williams, Simel, Roberts, et al. (1992) reported that 38 percent of the 247 patients seen in an outpatient veterans hospital setting presenting with symptoms suggestive of rhinosinusitis had evidence of sinus infection. In this study, not only were the criteria for diagnosis different, but the population was preselected. The patients enrolled in this study were reported to be approximately 1 percent of all the patients presenting to the participating clinics during the study period.
Similar preselection was reported in the study by Aitkin and Taylor (1998), which used clinical criteria to determine the prevalence of acute bacterial rhinosinusitis in a pediatric outpatient clinic. In their study, the overall prevalence was estimated at 9.3 percent, although in patients presenting with cold/cough symptoms, the prevalence was 17.3 percent. Clearly, prescreening (to varying extents) can significantly affect prevalence estimates.
Good evidence on the prevalence of acute bacterial rhinosinusitis in the general population and in general primary care practices is lacking. As studies evaluate the prevalence in larger populations, the methods for diagnosis are less well defined. Gwaltney (1996) estimated the prevalence of acute bacterial rhinosinusitis based on estimates of viral infections and estimates of the frequency of bacterial infections presumed to complicate the common cold. Again, however, this latter estimate is from studies (Berg, Carenfelt, Rystedt, et al., 1986; Dingle, Badge, and Jordan, 1964) in which sinus aspirate cultures were not performed.
In contrast to extrapolating from smaller studies to the entire population, alternative approaches to directly ascertain community prevalence include surveying individuals' rhinosinusitis (e.g., National Health Interview Survey) or using reimbursement claims data (e.g., National Ambulatory Medical Care Survey, National Hospital Discharge Survey). These approaches have several limitations. For example, the National Health Interview Survey does not specifically assess acute bacterial rhinosinusitis, and hospital discharge data (National Hospital Discharge Survey) clearly represent a selected population not typical for the majority of cases of acute bacterial rhinosinusitis. In addition, both the National Ambulatory Medical Care Survey and the National Hospital Discharge Survey, although based on clinically assessed cases, are financial reimbursement estimates and as such do not focus directly on the clinical aspects of the condition.
Although additional examples and prevalence estimates can be presented, depending on one's specific goal in determining the disease prevalence, different studies may provide the "best currently available" estimate. It is evident from the confusion, however, that increased information regarding the comparability of diagnostic tests is needed. In addition, it is critical that studies report in detail the methods used in the selection of patients to permit better clarification of the changing universe of patients being evaluated and to allow for validation and use of the data.
2. What is the diagnostic value of clinical features/imaging modalities for identifying acute rhinosinusitis and acute bacterial rhinosinusitis?
Sinus aspiration and culture make up the reference standard for the diagnosis of bacterial rhinosinusitis. In addition to needle aspiration, alternative sampling procedures for microbiologic culture have included nasal swabs and endoscopic sampling. Clinical criteria may include elements of the patient's history and physical findings such as facial pain, nasal discharge, olfactory disturbance, or fever. Sometimes, several clinical criteria are combined to obtain a clinical risk score. Imaging modalities have included sinus radiography (using two to four radiographs all including the occipitomental [Water's] view), computed tomography, magnetic resonance imaging, ultrasound scanning (A-mode), and transillumination. Imaging studies assess mucosal wall thickness, sinus fluid, and sinus opacity.
Attachment B presents a detailed description of the meta-analysis of diagnostic tests and the results. The key results are reproduced here. We found only one study comparing computed tomography with sinus radiograph (Burke, Guertler, and Timmons, 1994). This study of 29 patients reported that sinus computed tomography is more sensitive than sinus radiography in diagnosing sinusitis. This study did not use sinus puncture as the reference standard, and the comparison was based on a subset of patients with a clinical diagnosis of sinusitis.
Six studies compared sinus radiographs with sinus puncture (Kuusela, Kurri, and Sirola, 1982; Laine, Maättä, Varonen, et al., 1998; McNeill, 1962; Revonta, 1980; Savolainen, Pietola, Kiukaanniemi, et al., 1997; van Buchem, Peeters, Beaumont, et al., 1995). Each of the studies used a series of three or four radiographs; all included the occipitomental (Water's) view. Because three studies provided more than one comparison of test performance, 10 values of sensitivity and specificity were available for analysis.
Each of the comparisons is plotted as an ellipse. The size
of the ellipse is proportional to study size. 95% confidence
intervals (CI) are shown. The "X" represents the estimate and the
rectange represents the 95% CI of the random effects average. The
curve line is the SROC curve.
displays these 10 values
of sensitivity and specificity and the SROC curve derived from them. The 10
data points appear to be well described by the curve. Shown as dark gray
ellipses are the five observations of sensitivity and specificity using the
criterion "sinus fluid or opacity" to define positive radiographs. Shown as
light gray ellipses are the three observations based on the criterion "sinus
fluid or opacity or mucous membrane thickening" to define positive
radiographs. The remaining two estimates are shown as white ellipses: One of
these studies used the criterion "opacification of sinus," and the explicit
criteria defining a positive radiograph were not available for one estimate.
Adding "mucous membrane thickening" as one of the criteria for a positive radiograph increased the sensitivity of radiographs and decreased their specificity. The random effects estimates for sensitivity and specificity, using "fluid or opacity" as the definition of a positive radiograph, were 0.73 (95 percent confidence interval [CI], 0.60-0.83) and 0.80 (0.71-0.87), respectively. With the definition of positive radiograph "sinus fluid or opacity or mucous membrane thickening," the estimates for sensitivity and specificity were 0.90 (0.68-0.97) and 0.61 (0.20-0.91), respectively. These random-effects estimates and confidence intervals are displayed as "X's " and rectangles in Figure 6
. With
positive radiographs restricted to "opacification of sinus," specificity
increased only slightly to 0.85 (0.76-0.91), but sensitivity decreased
dramatically to 0.41 (0.33-0.49). The area under the weighted SROC curve was
0.83.A single study compared clinical criteria with sinus puncture (Berg and Carenfelt, 1988). This study reported data on clinicians' overall impression and also provided a risk score derived from the number of findings present from the following four-item list: purulent rhinorrhea with unilateral predominance, local pain with unilateral predominance, bilateral purulent rhinorrhea, and presence of pus in the nasal cavity.
Figure 7
plots the five values of
sensitivity and specificity derived from this report. The four-item risk
score (shown with dark gray ellipses) appears to have better discrimination
than the overall clinical impression (white ellipse); the SROC curve, fit
only to the risk score thresholds, has an area-under-the-curve of 0.91.
Unfortunately, characteristics of this study throw into question its internal validity. First, the reference test, sinus puncture and aspiration, is poorly described because it is not clear whether radiography was used in conjunction with aspiration in identifying those with sinusitis. Second, it is unclear how to use both "purulent rhinorrhea with unilateral predominance" and "bilateral purulent rhinorrhea" as independent risk-score predictors of sinusitis.
Three studies evaluated clinical examination in comparison to sinus radiographs. One study compared an otolaryngologist's overall clinical impression with sinus radiography (Axelsson and Runze, 1976). The study by Jannert, Andreasson, Helin, et al. (1982) evaluated a clinical risk score for children in which individuals could have 0 to 3 of the following findings: purulent nasal secretions on examination, history of upper respiratory infection during the 2 weeks prior to presenting symptoms, and sinus pain or tenderness. The study by Williams, Simel, Roberts, et al. (1992) evaluated a clinical risk score for adults in which individuals could have 0 to 5 of the following findings: maxillary toothache, abnormal transillumination, poor response to decongestants, purulent secretions on examination, and colored nasal discharge by history. The Williams, et al., (1992) study also included data for overall clinical impressions of "intermediate" or "high" probability of bacterial rhinosinusitis. There were therefore 11 values of sensitivity and specificity available for analysis.
Figure 8
displays these 11 values
of sensitivity and specificity and the SROC curve. The data points are well
described by the SROC curve. The risk score results, shown as gray ellipses,
appear to have similar discrimination to the overall impressions of
clinicians, shown as white ellipses. The area under the weighted SROC curve
was 0.74.Five reports provided data comparing ultrasound of the sinuses with sinus aspiration (Kuusela, Kurri, and Sirola, 1982; Laine, Maättä, Varonen, et al., 1998; Revonta, 1992; Savolainen, Pietola, Kiukaanniemi, et al., 1997; van Buchem, Peeters, Beaumont, et al., 1995). Reports provided data on more than one set of patients or for more than one diagnostic cut-point, so there were 10 values of sensitivity and specificity available for analysis (Figure 9
). Of note, these points do not appear well described by
the SROC curve, implying that variability in test performance is present.
Ultrasound performance appeared to be poorest in the study by Laine, Maättä, Varonen, et al.
(1998) (shown as a white ellipse in Figure 9); this was the only study in which untrained primary
care physicians performed and interpreted the ultrasounds.
Three reports provided data for five comparisons of ultrasound to sinus radiograph (Figure 10
) (Berg and Carenfelt, 1985; Jensen and von Sydow, 1987; Rohr, Spector, Siegel, et al.,
1986). It is difficult to interpret these comparisons because the
five data points fall close together in the SROC plot, and it is unclear how
well the SROC curve describes them or how the SROC curve can be
extrapolated.A single study compared findings on clinical examination with ultrasound (van Duijn, Brouwer, and Lamberts, 1992). Although this study provided data on sensitivity and specificity of individual clinical symptoms and signs, it provided no data for an overall clinical impression or risk score. However, summarizing data from this study, a published meta-analysis reported a sensitivity of 0.36 (95 percent CI, interval 0.29-0.43) and specificity of 0.90 (0.85-0.93) for clinical examination compared with ultrasound (de Bock, Houwing-Duistermaat, Springer, et al., 1994).
3. Given a (clinical) diagnosis of acute bacterial rhinosinusitis, are antibiotics effective in resolving symptoms and in preventing complications or recurrence?
The evidence to answer this question and question 4 is based on a meta-analysis of randomized controlled trials of antibiotic treatment for acute bacterial rhinosinusitis recently published by EPC members (de Ferranti, Ioannidis, Lau, et al., 1998). Attachment C presents a detailed description of the meta-analysis of antibiotic treatment trials and the results. The key results are reproduced here.
Six studies compared any antibiotics against placebo (Axelsson, Chidekel, Greblius, et al., 1970; Ganaça and Trabulsi, 1973; Lindbaek, Hjortdahl, and Johnson, 1996a; Stalman, van Essen, van der Graaf, et al., 1997; van Buchem, Knottnerus, Schrijnemackers, et al., 1997; Wald, Chiponis, and Ledesma-Medina, 1986) (Evidence Table 13 and Figure 11
). Antibiotics were
significantly more effective than placebo, reducing treatment failures by
almost one-half. However, symptoms improved or were cured in 69 percent of
patients without any antibiotic treatment at all (95 percent CI, 57 to 79
percent). Although the observed heterogeneity did not reach statistical
significance, there was a suggestion that one trial (Stalman, van Essen, van der Graaf, et al., 1997)
that included patients simply on the basis of sinusitis-like symptoms
without further diagnostic documentation had the highest cure or improvement
rates in the placebo group (85 percent at 10 days) and showed absolutely no
benefit from antibiotics, whereas trials with more tightly defined patient
populations and lower spontaneous improvement rates showed a more clear
benefit from antibiotics.
4a. In treatment of acute bacterial rhinosinusitis, what is the efficacy of antibiotics compared with that of placebo, and among the various antibiotics, what is their comparative efficacy?
Fourteen trials compared newer antibiotics, most of which have an expanded spectrum of activity, to amoxicillin (Evidence Table 14 and Figure 12
). First, the agents of our comparative arms were heterogeneous. By
and large, they are all substantially more expensive than amoxicillin or
folate inhibitors. However, their antibacterial profile is not identical.
Some of the newer agents have a very broad spectrum that should readily
encompass β-lactamase producing strains of H. influenzae
and M. catarrhalis (e.g., amoxicillin-clavulanic acid,
cefuroxime axetil, and cefixime). Others, such as the macrolides
(azithromycin, clarithromycin, and roxithromycin) are not exceptional in
this respect. The pooled failure rate in patients treated with amoxicillin
was low (11 percent; 95 percent CI, 8-14), and the further decrease in
clinical failures with broad-spectrum antibiotics was not clinically
important. Treating 100 patients with amoxicillin would lead to only 0.85
more failures (95 percent CI, 3.1 more to 1.4 fewer failures).
Similar results were obtained through analysis of the failure data of newer antibiotic vs. folate inhibitors (Evidence Table 15 and Figure 13
); treatment failures occurred at an essentially identical rate
with other antibiotics as with folate inhibitors. However, data on folate
inhibitors were limited and of poor quality. An analysis with respect to
cures gave comparable results with risk ratios close to one, both for any
other antibiotic vs. amoxicillin and any other antibiotic vs. folate
inhibitors. The risk differences of clinical cure using amoxicillin or
folate inhibitors compared with other antibiotics were not clinically
important (3.2 percent [95 percent CI, -1.5 to 7.8 percent], and 1.2 percent
[95 percent CI, -10 to 12.4 percent], respectively). The results were
comparable when a trial comparing penicillin with azithromycin was added to
the amoxicillin comparisons: risk ratio for clinical cures is 1.05 [95
percent CI, 0.99 to 1.11], and risk ratio for clinical failures is 0.82 [95
percent CI, 0.62 to 1.11].
There was no statistically significant heterogeneity of treatment effects in the amoxicillin comparisons; however, there was some evidence of heterogeneity between the studies that compared folate inhibitors with other antibiotics (p=0.09 for clinical cures; p=0.18 for clinical failures), possibly because trimethoprim-sulfamethoxazole seemed less effective than pivampicillin/pivmecillinam in one study (Osman and Menday, 1983).
A number of sensitivity analyses showed that the results were similar when the selection of studies was restricted according to various criteria (see Attachment B). In all sensitivity analyses, there was an estimated 11 to 20 percent risk reduction in clinical failures with other antibiotics over amoxicillin, which was not statistically significant, possibly because of the small numbers of patients. Still, this reduction was clinically negligible (less than 1 failure averted per 100 patients). Sensitivity analyses were less informative for folate inhibitors because the data were sparse.
Radiographic and bacteriologic data were not available for many trials (Evidence Tables 14 and 15). Rates of radiographic failures within 48 hours of the end of treatment were not significantly different between patients treated with other antibiotics and patients treated with amoxicillin, penicillin, or folate inhibitors. Likewise, rates of bacteriologic failure were not significantly different between patients treated with newer antibiotics and those treated with amoxicillin or folate inhibitors, although the majority of samples were obtained using nasal swabs, and the data therefore are not reliable.
4b. What evidence do these comparative studies provide regarding side effects?
The common side effects of amoxicillin and folate inhibitors are well known: skin rash, diarrhea, and gastrointestinal disturbances. There is no evidence suggesting that the side effects of these antibiotics are different for patients with acute bacterial rhinosinusitis.
There was no significant difference between regimens in the rate of withdrawal from treatment, either between other antibiotics and amoxicillin or between other antibiotics and folate inhibitors. In some instances, rash or gastrointestinal side effects led to discontinuation of the medications, whereas in other cases they were reported as minor adverse events (Evidence Tables 19 and 20). The reported adverse reactions numbered under 20 percent in the majority of trials. However, in a few studies, the percentages were higher (up to 50 percent in one study, Lindbaek, Hjortdahl, Johnsen, 1996a), mostly reported as gastrointestinal related. With some agents (e.g., macrolides, quinolones, tetracyclines), drug interactions may be a problem. Adverse reactions from interactions generally were not specifically identified, perhaps in part because most studies did not standardize the use of ancillary medications.
5a. Are there data to support the use of other types of treatments for acute rhinosinusitis and acute bacterial sinusitis, specifically: decongestants, steroids, antihistamines, drainage, flushing, others?
5b. What is the efficacy of antibiotics compared with that of other types of treatment?
None of the randomized trials of ancillary treatments compared antibiotic to nonantibiotic therapy. In most studies, patients were treated with 7 to 21 days of antibiotics in conjunction with the assessed ancillary treatments. One study did not give antibiotics to all patients (Lewison, 1970) but reported that antibiotics were given to patients in either trial arm when bacterial infection was "obvious."
5c. What evidence do any comparative studies provide regarding side effects?
To complete the decision analysis, we derived utilities from information provided by the two patients on our technical expert advisory group. These patients had a history of presumed acute bacterial rhinosinusitis. They were briefed on the purpose of the evidence report, informed about the study questions, and provided a status report on the work.
Both patients had had several episodes of presumed acute bacterial rhinosinusitis in the past several years. Both had been treated with antibiotics on several occasions but also had received ancillary therapies. Both reported that their episodes of rhinosinusitis appeared to be related to other conditions, such as environmental or seasonal allergies or upper respiratory illness. From their descriptions, it was clear that the severity of the episodes differed greatly, even for the same patient. Both reported initially using over-the-counter medications and self-treatment prior to coming to the physician's office. They both noted the presence of fever as a factor likely to bring them to a physician's office.
When asked about their sources for information, they reported using magazines, the Internet, and information from their physicians on various visits. Interest in obtaining information regarding medical conditions was mentioned as a factor increasing use of the Internet for medical information. One patient was interested in reading the final evidence report, and the other declined.
When the various diagnostic tests were discussed, both declined to undergo extensive testing (particularly invasive testing: puncture or endoscopy), although they reported that this would be affected by the severity of their symptoms and other pressures affecting their thresholds for symptom tolerance (e.g., need to care for a child, need to be at work, and so on). As these factors increased, so did both patients' interest in more definitive diagnosis and treatment at the initial physician visit.
In discussions of treatment options, the trust in their treating physician came out as an important factor in acceptance of a "watchful waiting" approach (e.g., treatment with ancillary medication, not antibiotics). Both, however, noted a preference for followup that did not entail a return office visit (e.g., obtaining a prescription for later or calling the physician back). Both patients were aware of (and in some cases experienced with) the potential individual adverse effects of antibiotic treatment (allergic reaction, vaginitis, interference with birth control). Although both expressed a concern regarding the development of antibiotic resistance, they expressed the initial need for "self-preservation" with regard to obtaining antibiotics for their individual episodes.
In discussing the utility of accurate diagnosis and treatment, both stressed that episodes varied and as such the value placed on these processes would vary by episode. In addition, it was noted that the utility was relative to other experiences with other episodes of rhinosinusitis or other illnesses. When sinusitis was viewed in light of experience with another illness such as pneumonia, the "severity evaluation" was recalibrated and as such the utility of the processes of diagnosis and treatment also changed.
Supplemental decision and cost-effectiveness analyses were performed to guide the use of the evidence in this report (Attachment D). A detailed description of the model and data used can be found in that section. Key results are summarized here.
A cost-effectiveness analysis was performed comparing the strategies of using sinus radiography to guide treatment -- using a set of clinical criteria to guide treatment, initial symptomatic treatment, and empirical antibiotic treatment with amoxicillin or a folate inhibitor.
The result is essentially a "toss-up" in terms of symptom days for empirical, clinical criteria-guided, and radiography-guided treatments. Symptomatic treatment alone provided fewer symptom-free days overall but the very lowest prevalence of acute bacterial rhinosinusitis. In terms of cost, a choice between clinical criteria and initial symptomatic treatment is a toss-up throughout the range of prevalence. Empirical treatment is more costly at all but the highest range of prevalence. Radiography is considerably more costly at any prevalence. Initial symptomatic treatment is the most cost-effective strategy to minimize symptom days at a prevalence of up to 25 percent, use of clinical criteria to guide treatment is most cost effective between a prevalence of 25 and 83 percent, and empirical antibiotic treatment with amoxicillin or a folate inhibitor is cost effective only at a prevalence greater than 83 percent. Performing sinus radiography is never a cost-effective strategy at any prevalence.
The prevalence thresholds for various strategies are moderately sensitive to the severity of sinus symptoms as reflected in quality-of-life adjustments. With mild symptoms, the range of prevalence in which clinical criteria-guided treatment is most cost effective is 49 to 97 percent. With severe symptoms, however, clinical criteria are most cost effective at a prevalence range from 31 to 90 percent.
At the base case prevalence estimate of 50 percent, empirical, clinical criteria-guided, and radiography-guided treatment all yield approximately 6.4 symptom-free days over a 14-day course. Symptomatic treatment yields only 5.0 symptom-free days. Symptomatic and clinical criteria-guided treatments both yield costs of $25; empirical treatment is somewhat more costly at $37; and radiography-guided treatment is much more costly at $132. Clinical criteria-guided treatment is most cost effective at $4.03 per symptom-free day, with a marginal cost-effectiveness of $0.21 over symptomatic treatment, which has a cost-effectiveness of $5.01 per symptom-free day. Empirical treatment is slightly less cost effective at $5.64 but has a marginal cost-effectiveness of $42.36 compared with that of clinical criteria-guided treatment. Radiography-guided treatment is much less cost effective at $20.52 per symptom-free day and can be eliminated by strict dominance.
With mild symptoms, all strategies yielded very similar effectiveness, at 12.0 to 12.2 quality-adjusted days. Thus, the marginal cost-effectiveness of clinical criteria-guided treatment was greater than above, at $1.52 per quality-adjusted day. The marginal cost-effectiveness of empirical treatment over clinical criteria-guided treatment rose substantially to $378 per quality-adjusted day.
Sensitivity analysis showed that lowered efficacy of amoxicillin or folate inhibitor, resulting from increased antibiotic resistance, had a substantial effect on cost-effectiveness. With poorer antibiotic efficacy, symptomatic treatment was most cost effective at all levels of symptom severity and at all prevalences. Only if the goal of treatment is to minimize duration of any symptoms was clinical criteria-guided treatment most cost effective at a prevalence above 86 percent.
If newer, more expensive antibiotics are used or are necessary because of antibiotic resistance, then symptomatic treatment is most cost effective. It is never cost effective to treat initially with expensive antibiotics prior to a period of watchful waiting.
At the prevalence of acute bacterial rhinosinusitis likely to be encountered in most primary care settings, either strategy of initial symptomatic treatment or the use of clinical criteria to guide treatment is an effective and cost-effective approach for uncomplicated patients. Given our finding that most patients' symptoms resolve without antibiotic treatment and that serious complications are rare, watchful waiting (7 to 10 days after onset of "sinus" symptoms) is a reasonable strategy. If antibiotics are to be given, amoxicillin or a folate inhibitor should be the initial choice. The severity of the patient's symptoms should also be taken into consideration in the management decision.
In this chapter, we provide discussions and conclusions on the five key questions addressed in this evidence report. In addition, in translating the evidence into practice, we discuss the implications and limitations of patient responses to issues regarding the diagnosis and treatment of acute bacterial rhinosinusitis and conclude by highlighting the results of the decision and cost-effectiveness analyses, along with their key "take-home" messages.
1. What is the prevalence of acute bacterial infection in patients presenting with acute rhinosinusitis in primary care and specialty settings?
As seen from the evidence, the range of estimates of the prevalence of acute bacterial rhinosinusitis is wide. Several factors appear to contribute to this variation, in particular, the patient populations selected for study and the criteria used to identify cases of acute bacterial rhinosinusitis. Even when the diagnostic reference of maxillary sinus puncture is used, several potential confounding factors, including patient age, geographic and socioeconomic conditions, seasonal variation, sampling technique, sample processing, and bacteriologic evaluation could have an effect on prevalence determinations (Axelsson and Brorson, 1972). Among the studies we reviewed in detail -- all of which used the reference standard of maxillary sinus aspiration for diagnosis -- the prevalence estimates differed greatly.
Much of the variation also may result from the initial screening of the populations for study, which may change the denominator for the prevalence estimates. For example, in a study of children in a primary care practice, the overall prevalence was estimated at 9.3 percent, although in patients presenting with cold and cough symptoms, the prevalence was 17.3 percent (Aitkin and Taylor, 1998). Two studies of adults documented efforts to evaluate relatively unselected patients (Savolainen, Pietola, Kiukaanniemi, et al., 1997; van Buchem, Peeters, Beaumont, et al., 1995) and reported a prevalence of 50 percent and 83 percent, respectively. The latter study was carried out in a specialty clinic. Many of the patients in this study may have been referred by their primary care physicians, which may have added an additional population selection bias.
These findings demonstrate the need for clear description of the populations enrolled in clinical trials because prescreening (to varying extents) can substantially change estimates of prevalence. These changes, in turn, can affect the predictive values of various diagnostic tests and, as noted in the decision and cost-effective analyses, may affect clinical decisionmaking.
The prevalence of acute bacterial rhinosinusitis in actual primary care settings could be lower than that observed in clinic-based studies. Good evidence on the prevalence of acute bacterial rhinosinusitis in the general population and in general primary care practices is lacking. Studies to assess community prevalence (e.g., the National Hospital Discharge Survey and the National Ambulatory Medical Survey) rely on much less rigorous criteria for diagnosis. These inconsistencies and the expected variations (for example, in general practice vs. referral or specialty clinics) require more detailed descriptions of inclusion criteria, populations studied, and diagnostic methods. Although sinus puncture is used as the "gold standard" diagnostic procedure for research, its limitations preclude its widespread use, and patient and researcher acceptance also may limit its use in research settings. As reviewed in this report, knowing how well other tests perform in comparison to sinus puncture is critical to enable studies in more widespread clinical settings. As seen from variations in the evidence, the selection of patients for these comparative studies also may influence test evaluations, emphasizing the need for detailed reporting of study protocols and populations.
2. What is the diagnostic value of clinical features/imaging modalities for identifying acute rhinosinusitis and acute bacterial rhinosinusitis?
Sinus radiography offers fair-to-good discrimination between patients who have puncture-documented acute bacterial rhinosinusitis and those who do not. Interobserver agreement is good for four-view sinus radiographs, particularly in the diagnosis of maxillary sinusitis (Williams, Roberts, Distell, et al., 1992). Using the summary estimates of sensitivity and specificity based on the radiographic criterion of "fluid or opacity," for a prevalence of 50 percent, a positive sinus radiogram increases the posttest probability of acute bacterial rhinosinusitis to 78 percent, whereas a negative radiogram decreases it to 25 percent.
Studies included in this report also evaluated the radiographic criterion "sinus fluid or opacity or mucous membrane thickening." However, these data leave the specificity of radiographs based on this criterion imprecisely estimated (95 percent confidence interval [CI], 0.20 to 0.91). Therefore, likelihood ratios and posttest probabilities based on this threshold also are relatively imprecise, and it remains difficult to know how to interpret radiographically documented mucous membrane thickening.
) (Littenberg and Moses, 1993). This added variability perhaps
may arise through differences in patient populations, ultrasonography techniques, or
medical personnel involved in diagnostic testing, and it calls into question the
reliability of ultrasound. As documented by the poor performance of ultrasound in
the study by Laine, Maättä, Varonen, et al.
(1998), careful training and experience with ultrasonography may be
necessary before clinicians can accurately interpret test results. Before
ultrasonography can be accepted as a useful and reliable diagnostic tool, further
studies, ideally comparing it with sinus puncture in a variety of research and
clinical settings, are necessary.
Five studies looked at clinical examination criteria as a diagnostic tool in identifying patients with acute bacterial rhinosinusitis, comparing it with sinus puncture (Berg and Carenfelt, 1988), radiography (Axelsson and Runze, 1976; Jannert, Andreasson, Helin, et al., 1982; Williams, Simel, Roberts, et al., 1992), or ultrasound (van Duijn, Brouwer, and Lamberts, 1992). The clinical examination, composed of items from the patient's history and physical examination, provides a rapid, readily available, and reasonably inexpensive approach to the diagnosis of acute bacterial rhinosinusitis. Unfortunately, assessment of the ability of clinical criteria to diagnose acute bacterial rhinosinusitis is limited by methodologic problems with two studies, namely, inadequate description of the reference test (Berg and Carenfelt, 1988), and inadequate description of the clinical criteria (Berg and Carenfelt, 1988; van Duijn, Brouwer, and Lamberts, 1992).
, area under SROC curve, 0.74). In turn, this ability might imply that some
components of the clinical examination may be useful for determining which patients
would benefit most from radiography as part of the diagnostic evaluation. An
approach in which clinical findings dictate which patients receive sinus radiography
may have important cost implications and deserves further evaluation.
An important type of clinical examination tool is the risk score. With a risk score, a clinician determines the presence or absence of each of a series of patient symptoms and signs; the probability of acute bacterial rhinosinusitis increases with each additional finding, and the clinician can use this information to help decide whether acute bacterial rhinosinusitis is present. Three studies presented data on how well different risk scores, consisting of three to five separate clinical symptoms and signs, identify acute bacterial rhinosinusitis. One of these studies suggested that a risk score performs better than a physician's overall clinical impression (Berg and Carenfelt, 1988). On the other hand, two studies (one of which evaluated diagnosis of bacterial rhinosinusitis in children) suggested equivalent discrimination between a clinician's overall impression and a risk score (Jannert, Andreasson, Helin, et al., 1982; Williams, Simel, Roberts, et al., 1992). Because a risk score may be simple to apply and because it may depend less on clinical experience and acumen than does a clinician's overall impression, further work is needed to develop risk scores that can assist clinicians by adding to or performing better than their overall impressions. Ideally, new risk scores would be carefully described, easily reproducible, and prospectively validated against a reference test.
Two limitations to conclusions about diagnostic test performance should be noted. First, some studies of diagnostic tests were of poor quality. In the studies included in this report, the most common of these problems were inadequately described study populations, poorly described test methods and criteria for a positive test (for both reference tests and tests under evaluation), and lack of blinding of investigators to results of one test when they were performing and interpreting another test. The information from Evidence Tables 3 to 8 highlights the need in future work for more careful attention to study design and reporting. Second, because data on test performance were extracted from each study for all available thresholds, the observations used to calculate the SROC curve were not independent. This lack of independence, in turn, precludes calculation of confidence intervals for the SROC curve. However, few studies were available for each comparison of diagnostic tests, and including several observations from each study had the important advantage of allowing for a relatively comprehensive evaluation of tests over a range of possible thresholds.
3. Given a (clinical) diagnosis of acute bacterial rhinosinusitis, are antibiotics effective in resolving symptoms and in preventing complications or recurrence?
About two-thirds of patients with acute bacterial rhinosinusitis improve or are cured without antibiotics. In patient populations defined by clinical symptoms alone, without a firm radiographic or bacteriologic diagnosis, this rate may even be higher. Treatment with any antibiotic, regardless of type, reduces the rate of clinical failures by about one-half. For the large number of patients with uncomplicated acute bacterial rhinosinusitis, a course of inexpensive antibiotics is probably adequate first-line treatment if antibiotics are to be given.
A concern in interpreting the results of this meta-analysis is the comparability of patients included in these trials with current patient populations, particularly in terms of the rates of antimicrobial resistance in sinusitis pathogens. Some of the included studies were conducted before the widespread emergence of resistance in common causes of acute bacterial rhinosinusitis, such as H. influenzae, M. catarrhalis, and most recently, S. pneumoniae. Yet we found no evidence of a difference in results between recent and older studies or between studies that included or excluded patients with organisms resistant to their allocated antibiotic. It is possible that the clinical resolution of acute bacterial rhinosinusitis may not be strongly influenced by the resistance profile of the pathogen, whatever the antibiotic, although data gathered from sinus puncture were not sufficient to permit an analysis of clinical outcomes in patients infected with resistant organisms in the studies included in our meta-analysis. To further investigate this question, we performed a MEDLINE search of the past 5 years looking for clinical outcomes of acute bacterial rhinosinusitis patients infected with resistant pathogens isolated from sinus puncture. We were unable to find any other relevant data. Such data should be collected in future studies.
Complications of bacterial rhinosinusitis can be serious and include brain abscess, orbital cellulitis, subdural empyema, and meningitis. We found no specific mention of such complications in more than 2,700 patients in the 28 analyzed trials. Large referral hospitals covering populations over wide geographic areas have reported only a handful of such complications over periods of 10 or more years (Johnson, Markle, Wiedermann, et al., 1988; Skelton, Maixner, and Isaacs, 1992). To our knowledge, there are no data showing that in clinical practice the use of more expensive, broad-spectrum antibiotics in uncomplicated cases would abort the development of these rare complications. It would be useful to collect such data in large-scale field studies because serious complications are important to prevent. However, avoiding delays in instituting therapy, obtaining adequate blood levels of antibiotics, and draining pus are certainly more important in aborting complications than the initial choice of antibiotic. The results of our meta-analysis should not be extrapolated beyond uncomplicated community-acquired acute bacteria rhinosinusitis. Serious cases and patients with predisposing factors should get aggressive treatment. On the other hand, evidence suggests that extensive use of antibiotics is associated with widespread development of resistant microorganisms in the community (Arason, Kristinsson, Sigurdsson, et al., 1996; Nissinen, Gronroos, Huovinen, et al., 1995; Seppala, Klaukka, Lehtonen, et al., 1995). This association would reduce the utility of new antibiotics in serious infections when they are most needed. Such potential misuse of these agents for the uncomplicated presentations of a common and benign syndrome may pose an ethical issue.
4a. In treatment of acute bacterial rhinosinusitis, what is the efficacy of antibiotics compared with that of placebo, and among the various antibiotics, what is their comparative efficacy?
and 13 suggests that there is no consistent
superiority of any of the drug classes over the inexpensive reference agents. It is
important to recognize, too, that many of the trials included in our analysis were
carried out before the reports of rapidly rising levels of antibiotic-resistant
organisms being isolated from community-acquired infections. As such, the
significance with regard to treatment efficacy in the face of laboratory-diagnosed
antibiotic resistance is unclear. This issue needs further and expedient
investigation.
The trials in this meta-analysis did not include fluoroquinolones because we found no trial comparing these agents with an inexpensive reference drug, with the exception of one that addressed a variety of upper respiratory infections (Falser, Mittermayer, and Weuta, 1988). On the other end of the range of antimicrobial agents, the main analysis did not include penicillin VK, which is a favored choice in some practices, particularly in Scandinavia. Nevertheless, a sensitivity analysis including a large study involving penicillin VK gave similar results. The data with penicillin VK (Haye, Lingaas, Hoivik, et al., 1996) are more limited than the evidence available for amoxicillin. Amoxicillin is more active against susceptible strains of H. influenzae than is penicillin VK, and in a direct comparison of the two antibiotics, amoxicillin performed marginally better (Lindbaek, Hjortdahl, and Johnsen, 1996a). The cost of both antibiotics is approximately the same. Amoxicillin is theoretically preferable on the grounds of its antimicrobial spectrum of activity, but more clinical evidence is needed.
Most studies included in this meta-analysis were of small size. The total evidence was more substantial and of better quality for amoxicillin than for folate inhibitors. There were trends suggesting that newer antibiotics may offer some advantage over amoxicillin, and formal statistical significance might have been reached if more data were available. However, the chance of this advantage being large enough to be clinically important is small. One would need to treat 118 patients with newer, more expensive antibiotics instead of amoxicillin to prevent one case of clinical failure. Even if newer agents would avert 1 clinical failure per 32 patients treated with amoxicillin or 1 clinical failure per 16 patients treated with a folate inhibitor (the most extreme scenarios for the 95 percent confidence intervals obtained from the meta-analyses), this result is unlikely to be meaningful enough to justify their use as first-line therapy.
These results also should be viewed in the context of possible bias. Publication bias (Ioannidis, 1998) is unavoidable in this domain, where mostly small studies of modest quality are conducted, and there may be some unpublished studies on acute bacterial rhinosinusitis. However, in contrast to the usual situation for most meta-analyses, in which publication bias would lead to spuriously positive pooled results, the effect of publication bias in our meta-analysis would be to show that amoxicillin and trimethoprim-sulfamethoxazole are not better than newer agents. The same might have been true for bias related to poor methodologic quality, which as empirical evidence suggests, tends to favor new, experimental treatments (Schulz, Chalmers, Hayes, et al., 1995). That this bias is not shown even with the available data only strengthens the hypothesis that these inexpensive agents are probably adequate in the treatment of acute bacterial rhinosinusitis. We performed sensitivity analyses and found that, when only good quality trials with a Jadad score of at least 3 were considered, the estimates for all major endpoints of treatment effect were similar for all the main comparisons. For example, the risk ratio (RR) for clinical failures was 0.53 (95 percent CI, 0.34 to 0.84) for antibiotics vs. placebo, 0.86 (95 percent CI, 0.58 to 1.28) for other antibiotics vs. amoxicillin, and 1.01 (95 percent CI, 0.52 to 1.97) for other antibiotics vs. folate inhibitors.
In this meta-analysis, both groups of reference medications were generally as effective as other antibiotics. We found only two direct comparisons of the efficacy of folate inhibitors with amoxicillin that had adequate data, but with a total of 113 patients, the data were too few to reliably compare the agents, as indicated by the very wide confidence intervals of the pooled estimate for these two comparisons (folate inhibitors treatment failure RR, 0.5; 95 percent CI, 0.08 to 3.01) (Hamory, Sande, Sydnor, et al., 1979; Nyffenegger, Riebenfeld, Macciocchi, 1991). Trimethoprim-sulfamethoxazole has a broader spectrum than amoxicillin, covering amoxicillin-resistant H. influenzae and M. catarrhalis, and its use should largely satisfy those who would like to take antimicrobial resistance into account in prescribing treatment for acute community-acquired bacterial rhinosinusitis in the absence of extensive, conclusive data.
4b. What evidence do these comparative studies provide regarding side effects?
Major side effects from antibiotics are uncommon. Minor rashes and gastrointestinal complaints (e.g., nausea and diarrhea) are most common and were the most commonly reported side effects listed in the trials. Although not statistically evaluated in this report, the nature and incidence of side effects from antibiotics in the treatment of rhinosinusitis did not appear to differ from reported profiles of the various antibiotics for the treatment of infections at other sites at similar treatment dosage and duration.
5a. Are there data to support the use of other types of treatments for acute rhinosinusitis and acute bacterial rhinosinusitis, specifically: decongestants, steroids, antihistamines, drainage, sinus irrigation, others?
5b. What is the efficacy of antibiotics compared with that of other types of treatment?
5c. What evidence do any comparative studies provide regarding side effects?
Studies of ancillary treatments for acute bacterial rhinosinusitis are limited. All but one study tested ancillary treatments in the presence of antibiotic therapies. Although many of the antibiotic effectiveness studies also reported patient use of ancillary medications, this use was often not systematic and not the focus of the trials. No randomized trials assessing nondrug interventions for acute bacterial rhinosinusitis were found. None of the studies directly compared antibiotic treatment with nonantibiotic interventions. Several studies reported side effects in patients participating in these trials of ancillary therapies, but the major effects were attributed to the antibiotics also used in the trials and not to the ancillary treatments. Cost data suggest that patients are using large amounts of nonantibiotic treatments to address the symptoms of rhinosinusitis, but the evidence is not available to assess the potential benefits of the various treatments, either qualitatively or quantitatively.
This report summarizes the extensive literature relating to the five questions formulated by the advisory group members. As noted in the introduction in Chapter 1, we expect that many groups will benefit from the data in this report for a variety of uses. Among the users are those in day-to-day clinical practice.
Our interview with two patients, although clearly a very limited number, was revealing of a number of key points that emphasize the variation among patients and the importance of clinical judgment in the application of evidence in practice. The patients were not that interested in extensive diagnostic testing, particularly not in invasive tests. Willingness to undergo a diagnostic procedure such as an x-ray might increase if symptoms are severe and where a reduction in diagnostic uncertainty would improve treatment. Severity of symptoms, other life pressures that affected patients' ability to allow themselves time for resolution of symptoms (e.g., the need to care for a child, work demands), and trust in their physician all were factors affecting responses to treatment options. Patients have societal concerns regarding antibiotic resistance and, in particular, noted the relatively high exposure of children to antibiotics today as compared with the previous generation. However, they stressed the need for individual well-being and individually tailored treatment. It was clear that utility estimates for evaluation of diagnostic and treatment procedures would vary both between individuals and between episodes for a given individual.
The decision and cost-effectiveness analyses highlight the complexity of decisionmaking with regard to both diagnosis and treatment of acute bacterial rhinosinusitis. By providing a framework for putting together the evidence for practical application, the analyses also help to identify gaps in the scientific evidence, as well as areas in which the presence of heterogeneity (e.g., patient populations, disease severity) dictates individualized evaluation in decisionmaking.
In a manner somewhat analogous to the relationship between controlled research that estimates efficacy and real-life estimates of effectiveness, the decision analysis assesses decisions for optimal outcomes, and the cost-effectiveness analysis incorporates additional "real-world" factors (utility and monetary cost) into the decisionmaking process. The two models developed in this report were designed to assess different outcomes. The first model (multiple strategies) provides a greater focus on the comparisons between various diagnostic and treatment choices using a fixed-time-point outcome (14 days). Based on the results of this model, the second (symptom duration) model uses the most effective strategies and focuses on duration of symptoms, rather than on single-time-point estimates.
From these models, it is clear that disease prevalence affects the determination of the most effective strategies. In both models, symptomatic treatment is as effective or better than other strategies at very low disease prevalence. At high disease prevalence, empirical treatment is most effective in both models.
Sinus puncture, as the research reference standard, is the most accurate procedure for distinguishing patients with acute bacterial rhinosinusitis from those without. As such, it maximizes cure, minimizes disease complications, and completely avoids inappropriate treatment. The effectiveness of the other diagnostic strategies does not differ greatly between strategies across the range of prevalence. At all prevalence values, they are nearly as effective as the most effective strategy (sinus puncture or empirical treatment).
The cost-effectiveness analyses incorporate both monetary costs and patient utility estimates. Given the very high cost of many of the diagnostic strategies, all except the use of clinical criteria to guide treatment are not cost effective when assessed in light of empirical treatment with inexpensive antibiotics. When these and other cost estimates are incorporated into the models, the results for both outcomes are similar: Symptomatic treatment is most cost effective at low disease prevalence (up to 41 percent in the multiple-strategies model, and 25 percent in the symptom-duration model), empirical treatment is most cost effective at higher prevalence (greater than 95 percent in the multiple-strategies model, and 83 percent in the symptom-duration model), and at the intermediate prevalence levels, the use of clinical criteria to guide treatment is most cost effective. In both models, the cost-effectiveness of symptomatic treatment and clinical criteria are so close as to be a toss-up below a prevalence of about 50 percent. Likewise, it is a toss-up between clinical criteria and empirical treatment at prevalences greater than 75 or 80 percent.
These conclusions, however, are limited by the paucity of data on test performance of various sets of clinical criteria. Our models relied on a single, flawed set of clinical criteria, which had good test performance. If the test performance of a given practitioner is lower, the prevalence range in which clinical criteria-guided treatment is most cost-efficient can narrow substantially.
The results highlight the effect that factors altering the disease prevalence (e.g., treatment setting, seasonal effects) may have on clinical decisionmaking. Heterogeneity of the patient populations with regard to disease prevalence, as well as a patient's quality-of-life issues, must be recognized as critical issues, both in research studies and in clinical practice.
For clinical practice, these results also can be viewed with an eye toward the individual patient by looking at the risk profiles (a probability distribution of outcomes). Using selected prevalence estimates in the low (25 percent), medium (50 percent) and high (75 percent) ranges, the cure rates for all strategies are similar using clinical criteria and other diagnostic strategies. As expected, cure rates for symptomatic treatment decline as the prevalence of acute bacterial rhinosinusitis increases. Similarly, cure rates for empirical antibiotics increase with increasing prevalence.
However, using various strategies at different prevalence rates, the numbers of patients receiving antibiotics, both appropriately and inappropriately, differ. Inappropriate antibiotic treatment of patients without acute bacterial rhinosinusitis is approximately two to four times greater with empirical treatment as compared with the clinical criteria-directed strategy. Although lower levels of inappropriate antibiotic use are also seen with the other diagnostic procedures as a result of estimates of poor specificity, the percentage of patients given antibiotics inappropriately in response to false-positive diagnostic tests is relatively high. This conclusion, however, is limited by the very limited amount of data on diagnostic test performance.
The effect of prevalence also reemphasizes the need for better data regarding the actual prevalence of acute bacterial rhinosinusitis in various populations to translate the research results into clinical practice.
Inappropriate antibiotic use in clinical practice is of increasing concern owing to the potential for development of antibiotic resistance. This use can markedly affect the cost and effectiveness of treatments for both society and individuals. Increased resistance could result in reduced cure rates and increased need for different and presumably more expensive antibiotics. Because there is no model to quantify the development and impact of antibiotic resistance on the treatment of an individual, the decision models do not directly address this issue. However, using sensitivity analyses for the rate of cure (which decreases with increasing resistance) and the use of more expensive antibiotics (which would be needed to replace amoxicillin or folate inhibitors), we found that the cost-effectiveness of antibiotic treatment was below that of symptomatic treatment at essentially all levels of disease prevalence.
Although the above discussion presents a quantitative framework for using the evidence report data, several qualitative, clinical "take-home" messages may also be derived from the summary and analyses of the data:
For patients in whom clinical examination suggests acute bacterial rhinosinusitis, treatment with antibiotics results in higher cure rates.
In patients with suspected acute bacterial rhinosinusitis, many patients' symptoms will resolve without antibiotic therapy. However, treatment with antibiotics will shorten the time course of symptoms and increase the 2-week cure rate.
In choosing a specific antibiotic for treating patients with uncomplicated community-acquired acute bacterial rhinosinusitis and without drug allergies, the less expensive antibiotics (amoxicillin or folate inhibitors) are as effective as the newer, more expensive broad-spectrum antibiotics and are considerably more cost effective.
It is important to know the extent of antibiotic resistance in sinusitis-related bacterial strains in the community when antibiotic treatment choices are made.
The prevalence of acute bacterial rhinosinusitis in a clinical population affects the cost-effectiveness of diagnostic and treatment strategies.
Patient factors (e.g., trust in the physician, availability of time for sickness, variability of severity of episodes) are additional influences that need to be taken into consideration when translating evidence into clinical practice.
This evidence report highlights the need to improve the quality of studies in both diagnosing acute bacterial rhinosinusitis and evaluating outpatient treatment options. Assessment and comparison of the available evidence emphasize the need for increased rigor in future research study design and implementation. Several specific areas for future research are identified by the qualitative and quantitative gaps in the evidence found for this report. In addition, the uncertainties encountered in the decision analysis models suggest areas of needed research for the translation of evidence into clinical decisions.
For studies of both diagnosis and treatment, there is a need for improvements regarding several general study design issues. First, the characteristics of patients enrolled in studies need to be clearly defined. This is critical to insure internal validity and allow for study comparisons and data analyses. It is also critical when clinicians attempt to apply the study results to clinical practice. Study protocols, however, should rigorously identify patients with acute bacterial rhinosinusitis using direct bacteriologic evaluation (e.g., antral puncture and aspiration) or standardized radiographic imaging as entry criteria. Particularly for treatment studies, the need for increased distinction of the patient populations in evaluations underscores the need to study patients with chronic and subacute rhinosinusitis separately from patients with acute rhinosinusitis.
In addition to improved definition of patient populations, there is a need for improved description of study populations, test methods, and criteria for test-positive determinations. Both description and implementation of patient randomization and the blinding of investigators are required. Because of the subjective nature of the relevant endpoints, double-blinding is exceptionally important in evaluating treatments for acute bacterial rhinosinusitis.
Future work evaluating diagnostic tests for acute bacterial rhinosinusitis may follow several lines of investigation. Current and future diagnostic modalities need to be rigorously evaluated and compared with a reference standard. To date, there are no published comparisons of either computed tomography or magnetic resonance imaging with other diagnostic modalities, such as sinus puncture or radiography for acute bacterial rhinosinusitis. The clear cross-sectional images provided by these technologies may offer improved discrimination between patients with rhinosinusitis and those without. Studies comparing ultrasound or transillumination with sinus puncture need to evaluate the extent of operator training on the results.
In addition, newer culturing techniques such as middle meatal cultures have not been rigorously compared with sinus puncture (Gold and Tami, 1997). Importantly, given the limitation of sinus puncture (that it is limited to sampling the maxillary sinuses, requires referral to a specialist or specific training for the general practitioner, and is not readily acceptable to patients), there is a great need for better noninvasive methods for diagnosing acute bacterial rhinosinusitis (Hansen, Schmidt, Rosborg, et al., 1995; Lindbaek, Hjortdahl, and Johnsen, 1996b). Further research into techniques, such as middle meatal sampling, may provide alternative methods for more readily applicable, direct bacteriologic evaluations. These may also help in studies to better understand the clinical correlation of abnormalities of the nonmaxillary sinuses.
Since the most cost-effective diagnostic method appears to be the use of clinical criteria to guide treatment, identifying clinical criteria with improved diagnostic accuracy, perhaps through the development of risk scores or other clinical decision aids, may prove particularly fruitful. In addition to using clinical criteria to a make diagnosis and guide treatment, clinical criteria may be used to single out patients for additional (and more expensive) diagnostic tests.
Along with comparisons of antibiotic classes, further study into the optimal duration of treatment should be addressed. The analyses in this report could not address this issue, since most studies used treatments of 10 to 14 days in duration. A recent well-designed trial of short-term (3 days) vs. traditional (10 days) treatment of sinusitis shows it is possible to conduct high-quality studies in this domain (Williams, Holleman, Samsa, et al., 1995).
In the future, comparative studies will need to consider antibiotic resistance as a factor in choosing drugs for comparison. Future studies should not exclude patients infected with resistant bacteria but should specifically study populations with a high prevalence of resistant organisms. If a trial is focusing on bacterial resistance to chosen antibiotics, bacteriology should be done using antral puncture and aspiration or alternative procedures for microbiologic evaluation. Data are needed regarding patients with resistant organisms, specifically, information of extent of resistance and effects on patients' responses to treatment. Correlation between laboratory minimal inhibitory concentration values and clinical response will be needed to guide future antibiotic treatment choices. Additionally, there is a need for surveillance programs to provide information regarding local, national, and global patterns of antibiotic resistance to aid treatment decisionmaking.
More studies are needed to look at optimal ancillary treatment regimens for acute bacterial rhinosinusitis, since evidence for the effectiveness of widely used therapies is lacking. In addition, in studies of antibiotic treatments, any use of over-the-counter medications should be clearly regulated and standardized to allow rigorous evaluation of the incremental benefit of antibiotics.
For all studies of treatment, clinical outcomes should be defined explicitly, using detailed physician and/or patient scoring. As seen with the decision models, a patient's preference can alter the assessments of a strategy's effectiveness. Limited studies suggest that one of the major effects of antibiotic treatment is shortening the length of symptoms, and as such, assessments of outcomes at different time points may better represent the differential effect of an antibiotic as compared with placebo. In addition to a need for better understanding of the connection between treatment and time to resolution of symptoms, there is a need for more information on treatments and relapse rates or the potential development of recurrent bacterial rhinosinusitis. More widespread population studies are needed to obtain data on complication rates. Large-scale studies are needed because the events are rare.
Rigorous, narrowly defined studies need to be balanced with studies for direct clinical application. Not only are clinical studies with better defined patient populations needed, but studies of patients in the community setting also are needed to assess their similarities and differences compared with the research populations. As evidenced in the decision analyses, for both diagnosis and treatment of acute bacterial sinusitis, the most effective and cost-effective strategies can be influenced by disease prevalence. Prevalence of acute bacterial rhinosinusitis varied widely in different studies in this report. Some of the differences may be due to practice setting, seasonal variation, or geographic variation. Some may result from preselection of patients for studies. Future studies should also be dedicated to specific patient populations such as patients with comorbidities (e.g., allergies, asthma, and HIV infection) that may influence the development, progression, and response to treatment of acute bacterial rhinosinusitis.
More primary care research and population studies are needed to better understand the factors affecting prevalence and to enable widespread application of the research results. Much of the current population data are based on insurance claims whose correlation to the presence of microbiologically defined acute bacterial rhinosinusitis is unknown. Research to assess and optimize the correlation between claims data and rigorous diagnosis is needed.
Many patients with acute bacterial rhinosinusitis do not see their providers, and many are never treated. Study of these patients as compared with those seeking treatment may help to better distinguish those requiring treatment from others. Additional studies in the primary care setting also may help to increase understanding about the influences of patient factors (patient-physician interactions, availability of time for sickness, variability of severity of episodes) on the process of applying evidence into clinical practice.
ABRS: acute bacterial rhinosinusitis
AHCPR: Agency for Health Care Policy and Research
CFU: colony-forming unit
CI: confidence interval
CNS: central nervous system
CT: computerized tomography
EM: Expectation maximization
ENT: ear, nose, and throat specialist
EPC: Evidence-based Practice Center
FN: false negative
GI: gastrointestinal
GP: general practice
Gtt: drops
HIV: human immunodeficiency virus
HMO: health management organization
Hx: history
ICD-9-CM: International Classification of Disease, 9th edition, clinically modified
MRI: magnetic resonance imaging
NAMCS: National Ambulatory Medical Care Survey
NEMC: New England Medical Center
NRSA: National Research Service Award
pts: patients
q-adj day: quality-adjusted day
QAO: quality-adjusted outcome
QID: 4 times per day
QOD: every other day
RR: risk ratio
Rx: antibiotic prescription
SE: antibiotic side effect
Sens: sensitivity
SMZ: sulfamethoxazole
Spec: specificity
SROC: summary receiver operating characteristic
Sx-free day: symptom-free day
TID: 3 times per day
TMP: trimethoprim
TN: true negative
TP: true positive
Tx: treatment
1/Var.: 1/Variance; provides the relative weight of the study
VAS: Visual Analog Scale
Acute rhinosinusitis - : rhinosinusitis symptoms of less than 4 weeks duration.
Cost-effectiveness analysis - : a comparison of alternative strategies using the ratio of costs overthe effects, frequently based on a decision-analysis model.
Cumulative meta-analysis - : a meta-analysis method of ordering studies according to the values of a study covariate to detect statistical trends. For example, a cumulative meta-analysis ordered by decreasing study quality scores may be used to assess the impact of adding successively lower quality score studies to higher quality score studies.
Decision analysis - : a quantitative method that uses an explicit model to integrate evidence, beliefs, and value of outcomes to compare alternatives to assist decisionmaking.
Efficacy - : measure of the treatment effect under controlled conditions, as in a randomized controlled trial.
Folate inhibitors - : a class of antibiotic. An example is trimethoprim/sulfamethoxazole (BactrimTM, SeptraTM).
Meta-analysis - : a quantitative method for combining effects across several similar studies using any of several established analytic models and statistical methods for data synthesis.
Prevalence - : the proportion of subjects in a population with a defined condition at a given time.
Rhinosinusitis - : inflammation, with or without infection, of the nose and the paranasal sinuses.
Risk ratio (relative risk) - : the ratio of the proportion of exposed or at-risk people who develop a condition to the proportion of nonexposed or not-at-risk people who develop the condition.
SROC (summary receiver operating characteristic) curve - : a statistical method to combine the results of multiple studies assessing the diagnostic performance of a test. It involves tradeoffs between sensitivity and specificity of a test.
Sensitivity - : the proportion of positive tests among all patients known to have the condition.
Sensitivity analysis - : additional analyses performed to test the robustness of the results by varying assumptions and estimates used in the baseline analysis.
Sinusitis - : inflammation of the paranasal sinus mucosa. It may occur in the maxillary, ethmoidal, sphenoidal, or frontal sinus. It may be allergic or infectious in origin.
Specificity - : the proportion of negative tests among all patients known not to have the condition.
Subgroup data
available: Yes No
If YES, list subgroups:
Outcome
Measure:
Comments on Outcomes:
Sinus puncture with culture is the acknowledged diagnostic reference standard for diagnosing acute bacterial rhinosinusitis. However, sinus puncture is invasive, and few patients are willing to undergo this procedure. Also, it is costly and impractical in the primary care setting. The aim of this meta-analysis is to assess the accuracy of other noninvasive procedures such as sinus radiography and ultrasonography, as well as the use of clinical criteria to guide treatment. Additional details of the methodology are described in relevant methods sections in Chapter 2.
Fourteen studies were included, five of which provided comparisons of more than two tests; these studies are described in Evidence Tables 1-8. Twelve studies were conducted in Europe, including all of those utilizing sinus puncture as a reference test. Only two studies were conducted in the United States (Rohr, Spector, Siegel, et al., 1986; Williams, Simel, Roberts, et al., 1992).
Among 12 studies that described the age range of subjects, eight studies examined only adolescents and/or adults, and four studies included children or examined only children. Six studies provided a description of symptoms that had to be present for subjects to be included in the study (typically nasal symptoms or headache); the remainder of studies included patients as study subjects when they or their physicians suspected sinusitis. Only four studies limited how long subjects could have symptoms before evaluation: two studies limited duration of symptoms to 30 days, and two studies limited duration of symptoms to 90 days.
Five studies used the patient as the unit of analysis for comparing diagnostic tests (Berg and Carenfelt, 1985, 1988; Jannert, Andreasson, Helin, et al., 1982; van Duijn, Brouwer, and Lamberts, 1992; Williams, Simel, Roberts, et al., 1992). In the remaining nine studies, the unit of analysis was the sinus.
Four studies that used sinus puncture as a reference test provided estimates of the prevalence of sinusitis in the populations. Two studies that included subjects from an office practice provided prevalence estimates of 49 percent and 51 percent (Laine, Maättä, Varonen, et al., 1998;van Buchem, Peeters, Beaumont, et al., 1995). A study that included only subjects from an otolaryngology clinic found a higher prevalence of 83 percent (Savolainen, Pietola, Kiukaanniemi, et al., 1997). A Finnish study observed a prevalence of 53 percent (Kuusela, Kurri, and Sirola, 1982).
Only four studies stated that interpretation of both the reference test and test of interest occurred under blinded conditions (Jensen and von Sydow, 1987; Rohr, Spector, Siegel et al., 1986; van Buchem, Peeters, Beaumont, et al., 1995; Williams, Simel, Roberts, et al., 1992). Four other studies described blinded interpretation of the test of interest, but investigators interpreting the reference test were not blinded to the results of the test of interest (Berg and Carenfelt, 1988; Laine, Maättä, Varonen, et al., 1998; Revonta, 1980; Savolainen, Pietola, Kiukaanniemi, et al., 1997). In the study by Laine, Maättä, Varonen, et al. (1998), interpretation of sinus aspiration results occurred with knowledge of results of radiography but not ultrasound.
Six studies compared sinus radiographs with sinus puncture (Kuusela, Kurri, and Sirola, 1982; Laine, Maättä, Varonen, et al., 1998; McNeill, 1962; Revonta, 1980; Savolainen, Pietola, Kiukaanniemi, et al., 1997; van Buchem, Peeters, Beaumont, et al., 1995). The studies used a series of three or four radiographs, all including the occipitomental (Water's) view. Because three studies provided more than one comparison of test performance, there were 10 values of sensitivity and specificity available for analysis.
| No. | Study | TP/FN | TP/FN | Sens | 95% CI | Spec | 95% CI | 1/Var. |
|---|---|---|---|---|---|---|---|---|
| 1 | van Buchem | 10/6 | 4/42 | 0.63 | 0.36-0.84 | 0.91 | 0.78-0.97 | 2.0987 |
| 2 | Laine | 14/9 | 1/48 | 0.61 | 0.39-0.79 | 0.98 | 0.88-1.00 | 1.4186 |
| 3 | Savolainen-a | 174/13 | 18/29 | 0.93 | 0.88-0.96 | 0.62 | 0.46-0.75 | 6.0478 |
| 4 | McNeill-a | 113/35 | 23/71 | 0.76 | 0.69-0.83 | 0.76 | 0.65-0.84 | 10.7593 |
| 5 | Kuusela | 68/14 | 21/53 | 0.83 | 0.73-0.90 | 0.72 | 0.60-0.81 | 6.8033 |
| 6 | Revonta-a | 56/23 | 7/84 | 0.71 | 0.59-0.80 | 0.92 | 0.84-0.97 | 5.0447 |
| 7 | Revonta-b | 28/7 | 5/20 | 0.80 | 0.63-0.91 | 0.80 | 0.59-0.92 | 2.5847 |
| 8 | Savolainen-b | 99/88 | 11/36 | 0.53 | 0.46-0.60 | 0.77 | 0.62-0.87 | 7.4595 |
| 9 | McNeill-b | 143/5 | 74/20 | 0.97 | 0.92-0.99 | 0.21 | 0.14-0.31 | 4.2304 |
| 10 | McNeill-c | 60/88 | 14/80 | 0.41 | 0.33-0.49 | 0.85 | 0.76-0.91 | 9.2877 |
| Total (Range) | 1053 | 661 | 0.41-0.97 | 0.21-0.98 | ||||
Random effects average (95% CI) 0.76 0.62-0.86 0.79 0.63-0.89
Area under extrapolated SROC curve (weighted analysis) 0.8261
Abbreviations: TP = true positive; BR = false negative; TN = true negative; BR = false negative; Sens = sensitivity; Spec = specificity; CI = confidence interval; 1/Var. = 1/Variance; provides the relative weight of the study.
(Chapter 3) displays
the 10 pairs of sensitivity and specificity and the SROC curve derived
from the studies. The 10 data points appear to be well described by the
curve. The random effects estimates are displayed in Figure 8 (Chapter 3). The area under the weighted
(extrapolated) SROC curve was 0.83.
(Chapter 3) as dark gray ellipses
are the five observations of sensitivity and specificity using the
criterion "sinus fluid or opacity" to define positive radiographs. Shown
as light gray ellipses are the three observations based on the criterion
"sinus fluid or opacity or mucous membrane thickening" to define
positive radiographs. The remaining two estimates are shown as white
ellipses: one of these used the criterion "opacification of sinus," and
the explicit criterion defining a positive radiograph was not available
for one estimate.
Adding "mucous membrane thickening" as one of the criteria for a positive radiograph increased the sensitivity of radiographs and decreased their specificity. The random effects estimates for sensitivity and specificity, using "fluid or opacity" as the definition of a positive radiograph, were 0.76 (95 percent CI, 0.62-0.86) and 0.79 (95 percent CI, 0.63-0.89), respectively. With the definition of positive radiograph "sinus fluid or opacity or mucous membrane thickening," the estimates for sensitivity and specificity were 0.90 (95 percent CI, 0.68-0.97) and 0.61 (95 percent CI, 0.20-0.91), respectively. With positive radiographs restricted to "opacification of sinus," specificity increased only slightly to 0.85 (95 percent CI, 0.76-0.91), but sensitivity decreased dramatically to 0.41 (95 percent CI, 0.33-0.49).
A single study compared clinical examination with sinus puncture (Berg and Carenfelt, 1988). This study provided data for clinicians' overall impressions and also for a risk score derived from the number of findings present from the following four-item list: purulent rhinorrhea with unilateral predominance, local pain with unilateral predominance, bilateral purulent rhinorrhea, and presence of pus in the nasal cavity.
| Clinical Criteria vs. Sinus Aspiration/Puncture | ||||||||
|---|---|---|---|---|---|---|---|---|
| Study Characteristics and Pooled Results | ||||||||
| No. | Study | TP/FN | FP/TN | Sens | 95% CI | Spec | 95% CI | 1/Var. |
| 1 | Berg A | 55/13 | 10/77 | 0.81 | 0.69-0.89 | 0.89 | 0.79-0.94 | 5.1145 |
| 2 | Berg B | 52/16 | 27/60 | 0.76 | 0.64-0.86 | 0.69 | 0.58-0.78 | 7.6022 |
| 3 | Berg C | 65/3 | 20/67 | 0.96 | 0.87-0.99 | 0.77 | 0.67-0.85 | 3.0112 |
| 4 | Berg D | 16/52 | 3/84 | 0.24 | 0.14-0.36 | 0.97 | 0.90-0.99 | 2.9103 |
| 5 | Berg E | 67/1 | 44/43 | 0.99 | 0.91-1.00 | 0.49 | 0.39-0.60 | 1.7614 |
| Total (Range) | 340 | 435 | 0.24-0.99 | 0.49-0.97 | ||||
Random effects average (95% CI) 0.83 0.52-0.96 0.80.62-0.90
Area under extrapolated SROC curve (weighted analysis) 0.8766
Abbreviations: TP = true positive; FN = false negative; TN = true negative; FN = false negative; Sens = sensitivity; Spec = specificity; CI = confidence interval; 1/Var. = 1/Variance; provides the relative weight of the study.
(Chapter 3) plots the five values
of sensitivity and specificity derived from this report. The four-item
risk score (shown with dark gray ellipses) appears to have better
discrimination than the overall clinical impression (white ellipse); the
SROC curve, fit only to the risk score thresholds, has an area under the
weighted (extrapolated) SROC curve of 0.91.
Unfortunately, the characteristics of this study throw into question its internal validity. First, the reference test, sinus puncture and aspiration, is poorly described in the report because it is not clear whether radiography was used in conjunction with aspiration in identifying those with sinusitis. Second, it is unclear how to use both "purulent rhinorrhea with unilateral predominance" and "bilateral purulent rhinorrhea" as independent risk score predictors of sinusitis.
Three studies evaluated clinical examination in comparison with sinus radiographs. The Axelsson and Runze (1976) study compared an otolaryngologist's overall clinical impression with sinus radiography. The study by Jannert, Andreasson, Helin, et al. (1982) evaluated a clinical risk score for children in which individuals could have 0-3 of the following findings: purulent nasal secretions on examination, history of upper respiratory infection during the 2 weeks prior to presenting symptoms, and sinus pain or tenderness. The study by Williams, Simel, Roberts, et al. (1992) evaluated a clinical risk score for adults in which individuals could have 0-5 of the following findings: maxillary toothache, abnormal transillumination, poor response to decongestants, purulent secretions on examination, and colored nasal discharge by history. The Williams study also included data for overall clinical impressions of intermediate" or "high" probability of sinusitis. Therefore, there were 11 values of sensitivity and specificity available for analysis.
| No. | Study | TP/FN | FP/TN | Sens | 95% CI | Spec | 95% CI | 1/Var. |
|---|---|---|---|---|---|---|---|---|
| 1 | Axelsson | 49/76 | 56/129 | 0.39 | 0.31- 0.48 | 0.70 | 0.62-0.76 | 17.0580 |
| 2 | Williams A | 48/47 | 22/130 | 0.51 | 0.40-0.61 | 0.86 | 0.79-0.91 | 10.7384 |
| 3 | Jannert A | 75/22 | 27/51 | 0.77 | 0.68-0.85 | 0.65 | 0.54-0.76 | 8.8598 |
| 4 | Jannert B | 21/76 | 6/72 | 0.22 | 0.14-0.31 | 0.92 | 0.83-0.97 | 4.5954 |
| 5 | Williams B | 38/57 | 15/137 | 0.40 | 0.30-0.51 | 0.90 | 0.84-0.94 | 8.8075 |
| 6 | Williams C | 72/23 | 55/97 | 0.76 | 0.66-0.84 | 0.64 | 0.56-0.71 | 11.8773 |
| 7 | Williams D | 16/79 | 4/148 | 0.17 | 0.10-0.26 | 0.97 | 0.93-0.99 | 3.5696 |
| 8 | Williams E | 76/19 | 64/88 | 0.80 | 0.70-0.87 | 0.58 | 0.50-0.66 | 11.0564 |
| 9 | Williams F | 91/4 | 118/34 | 0.96 | 0.89-0.99 | 0.22 | 0.16-0.30 | 3.9951 |
| 10 | Williams G | 2/93 | 0/152 | 0.02 | 0.00-0.08 | 1.00 | 0.98-1.00 | 0.7349 |
| 11 | Jannert C | 96/2 | 61/16 | 0.98 | 0.92-1.00 | 0.21 | 0.13-0.32 | 2.3636 |
| Total (Range) | 1082 | 1482 | 0.02-0.98 | 0.21-1.00 | ||||
Random effects average 0.57 0.37-0.74 0.76 0.60-0.87
Area under extrapolated SROC curve (weighted analysis) 0.7371
Abbreviations: TP = true positive; FN = false negative; TN = true negative; FN = false negative; Sens = sensitivity; Spec = specificity; CI = confidence interval; 1/Var. = 1/Variance; provides the relative weight of the study.
(Chapter 3) display these 11 values of sensitivity and
specificity and the SROC curve. The data points are well-described by
the SROC curve. The risk scores, shown as gray ellipses, appear to have
similar discrimination to the overall impressions of clinicians, shown
as white ellipses. The area under the (extrapolated) weighted SROC curve
was 0.74.
| No. | Study | TP/FN | TP/FN | Sens | 95% CI | Spec | 95% CI | 1/Var. |
|---|---|---|---|---|---|---|---|---|
| 1 | van Buchem 1 | 7/6 | 2/33 | 0.54 | 0.26-0.79 | 0.94 | 0.80-0.99 | 1.5116 |
| 2 | Laine | 14/9 | 23/26 | 0.61 | 0.39-0.79 | 0.53 | 0.38-0.67 | 3.9336 |
| 3 | Savolainen | 180/7 | 33/14 | 0.96 | 0.92-0.98 | 0.30 | 0.18-0.45 | 4.3602 |
| 4 | Kuusela | 60/22 | 27/47 | 0.73 | 0.62-0.82 | 0.64 | 0.51-0.74 | 8.4808 |
| 5 | van Buchem 2 | 44/1 | 31/35 | 0.98 | 0.87-1.00 | 0.53 | 0.40-0.65 | 1.6842 |
| 6 | Revonta 1 | 69/10 | 8/83 | 0.87 | 0.78-0.93 | 0.91 | 0.83-0.96 | 4.331 |
| 7 | Revonta 4 | 98/9 | 18/75 | 0.92 | 0.84-0.96 | 0.81 | 0.71-0.88 | 5.6298 |
| 8 | Revonta 3 | 33/2 | 7/18 | 0.94 | 0.80-0.99 | 0.72 | 0.51-0.87 | 1.7926 |
| 9 | Savolainen B | 152/35 | 13/34 | 0.81 | 0.75-0.86 | 0.72 | 0.57-0.84 | 7.3193 |
| 10 | Kuusela B | 58/24 | 27/47 | 0.71 | 0.60-0.80 | 0.64 | 0.51-0.74 | 8.699 |
| Total (Range) | 840 | 601 | 0.54-0.98 | 0.30-0.94 | ||||
Random effects average (95% CI) 0.84 0.75-0.90 0.69 0.57-0.79
Area under extrapolated SROC curve (weighted analysis) 0.8273
Abbreviations: TP = true positive; FN = false negative; TN = true negative; FN = false negative; Sens = sensitivity; Spec = specificity; CI = confidence interval; 1/Var. = 1/Variance; provides the relative weight of the study.
[Chapter 3]). Of note, these points do not appear
well-described by the SROC curve, implying that variability in test
performance is present. Ultrasound performance appeared to be poorest in
the study by Laine and colleagues (shown as a white ellipse in Figure 9) (Laine, Maättä, Varonen, et al., 1998); this was
the only study in which untrained primary care physicians performed and
interpreted the ultrasounds.
[Chapter 3]). It is difficult to interpret these comparisons
because the five data points fall close together in the SROC plot, and
it is unclear how well the SROC curve describes them or how the SROC
curve can be extrapolated.A single study compared findings on clinical examination with ultrasound (van Duijn, Brouwer, and Lamberts, 1992). Although this study provided data on sensitivity and specificity of individual clinical symptoms and signs, it provided no data for an overall clinical impression or risk score. However, summarizing data from this study, a published meta-analysis reported a sensitivity of 0.36 (95 percent CI, 0.29-0.43) and specificity of 0.90 (95 percent CI, 0.85-0.93) for clinical examination compared with ultrasound (de Bock, Houwing-Duistermaat, Springer, et al., 1994).
Meta-analyses were conducted to quantify the treatment effect of antibiotics compared with placebo and also the effects of amoxicillin or folate inhibitors compared with newer and more expensive antibiotics. This analysis is based on a meta-analysis (de Ferranti, Ioannidis, Lau et al., 1998) published in the British Medical Journal. The analysis was coauthored by Dr. Lau, (EPC director) and Dr. Barza (EPC technical expert) and was supported in part by an earlier AHCPR grant to Dr. Lau (R01 HS07782). Portions of this publication are used in this evidence report with permission from the British Medical Journal. The published meta-analysis was updated in this evidence report with one study not indexed in MEDLINE (Fiscella and Chow, 1991). Several additional sensitivity analyses were performed. The methodologies of the meta-analysis are described in Chapter 2 of this report.
Eleven of the 28 trials were double-blind, six were single-blind (five investigator-blind), and 10 were unmasked. Thirteen of 28 trials used "firm" methods for diagnosing acute bacterial rhinosinusitis. The other 15 trials qualified patients as having acute bacterial rhinosinusitis on clinical grounds. Eight trials specifically required patients to use nasal decongestants, 3 trials allowed but did not require the use of decongestants, and the other 17 did not specify a protocol about the use of over-the-counter medications. The criteria for clinical outcomes were well-specified in 9 of the 28 trials, specified to some extent in 12 trials, and unclear in 7 trials. Bacteriologic evaluation was done using antral puncture only in three trials (Karma, Pukander, Penttila, et al., 1991; Matthews and Suprax/Amoxicillin Clinical Study Team, 1997; Wald,Reilly, Casselbrant, et al., 1984), and antral puncture or nasal swab was done in two trials (Felstead and Daniel, 1991; Mattucci, Levin, and Habib, 1986) included in the amoxicillin analysis. Two folate inhibitor trials and one amoxicillin trial seemingly only cultured nasal discharge, a method that is unreliable.
Some additional methodologic issues were noted. Casiano (1991) excluded all patients infected with resistant organisms from the analysis; the exclusions were not distributed evenly (azithromycin arm n=2; amoxicillin arm n=11). Karma, Pukander, Penttila, et al. (1991) and probably Matthews and Suprax/Amoxicillin Clinical Study Team (1997) also excluded patients with resistant organisms. A fourth trial (Edelstein, Avner, Chow, et al., 1993) changed the treatment to amoxicillin-clavulanate in all patients with resistant organisms but analyzed such patients according to intention-to-treat when they were in the amoxicillin arm, whereas it excluded such patients from the analysis when they were in the cefixime arm. Preferably, all patients should have been analyzed similarly. We performed sensitivity analyses excluding these four trials. Finally, three trials (Matthews and Suprax/Amoxicillin Clinical Study Team, 1997; Rimmer and Suprax/Amoxicillin Clinical Study Team, 1997; von Sydow, Savolainen, and Soderqvist, 1995) used several different approaches for defining the population to be analyzed including "per protocol," "evaluated patients" or "evaluative patients," and a "modified intention-to-treat" analysis (used for the meta-analysis).
| No. | Study | Year | Experiment | Control | Risk Ratio | 95% CI | Percent Wt | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Obs | Tot | Obs | Tot | Low | High | |||||
| 1 | Axelsson | 1970 | 12 | 74 | 9 | 32 | 0.58 | 0.27 | 1.23 | 13.36 |
| 2 | Ganança | 1973 | 4 | 30 | 10 | 20 | 0.27 | 0.1 | 0.73 | 7.5 |
| 3 | Wald | 1986 | 12 | 58 | 14 | 35 | 0.52 | 0.27 | 0.99 | 18.36 |
| 4 | Lindbaek | 1996a | 12 | 86 | 19 | 44 | 0.32 | 0.17 | 0.6 | 19.69 |
| 5 | van Buchem | 1997 | 18 | 105 | 23 | 101 | 0.75 | 0.43 | 1.31 | 25.13 |
| 6 | Stalman | 1997 | 13 | 85 | 14 | 91 | 0.99 | 0.5 | 1.99 | 15.93 |
| Total patients | 761 | 71 | 438 | 89 | 323 | 0.54 | 0.37 | 0.79 | ||
z = 3.1846; 2P = 0.0014 Overall heterogeneity: Q = 8.82; Tau = 0.0938
Abbreviations: Obs = Observed cases; Tot = total cases; Q = Q statistic; z = z score; 2P = two-sided test
| Antibiotic vs. Placebo | Studies | Patients | Risk Ratio | 95 % CI | Outcomes with Placebo [95% CI] |
|---|---|---|---|---|---|
| Clinical cures | 6 | 761 | 1.33 | 1.02-1.74 | 34 % [21-51] cured clinically |
| Clinical failures | 6 | 761 | 0.54 | 0.37-0.79 | 31 % [21-43] had clinical failure |
Reprinted with permission from the British Medical Journal.
[Chapter
3]). Antibiotics were significantly more effective than placebo,
reducing treatment failures by almost one-half. However, symptoms improved
or were eliminated in 69 percent of patients without any antibiotic
treatment (95 percent CI, 57-79) (Table
12). Although the observed heterogeneity did not
reach statistical significance, one trial (Stalman, van Essen, van der Graaf, et al., 1997)
that included patients simply on the basis of sinusitis-like symptoms
without further diagnostic documentation had the highest cure or improvement
rates in the placebo group (85 percent at 10 days) and showed absolutely no
benefit from antibiotics, whereas trials with more tightly defined patient
populations and lower spontaneous improvement rates showed a more clear
benefit from antibiotics.
Radiographic and bacteriologic data were not available for many trials. Rates of radiographic failures within 48 hours of treatment completion were not significantly different between patients treated with other antibiotics and patients treated with amoxicillin or penicillin or folate inhibitors. Likewise, rates of bacteriologic failure were not significantly different between patients treated with newer antibiotics and those treated with amoxicillin or folate inhibitors, although the majority of samples were obtained using nasal swabs, and the data are therefore not reliable. There was no significant difference between regimens in the rate of withdrawal from treatment, either between other antibiotics and amoxicillin or between other antibiotics and folate inhibitors.
| No. | Study | Year | Experiment | Control | Risk Ratio | 95% CI | Percent Wt | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Obs | Tot | Obs | Tot | Low | High | |||||
| 1 | Wald | 1984 | 3 | 23 | 4 | 27 | 0.88 | 0.22 | 3.53 | 5.25 |
| 2 | Wald | 1986 | 7 | 28 | 5 | 30 | 1.50 | 0.54 | 4.18 | 9.64 |
| 3 | Matucci | 1986 | 0 | 25 | 1 | 22 | 0.29 | 0.01 | 6.89 | 1.02 |
| 4 | Edelstein | 1993 | 3 | 53 | 2 | 49 | 1.39 | 0.24 | 7.95 | 3.32 |
| 5 | Felstead | 1991 | 3 | 123 | 2 | 121 | 1.48 | 0.25 | 8.68 | 3.23 |
| 6 | Casiano | 1991 | 0 | 23 | 0 | 15 | 0.67 | 0.01 | 31.92 | 0.67 |
| 7 | Huck | 1993 | 4 | 28 | 4 | 28 | 1.00 | 0.28 | 3.61 | 6.15 |
| 8 | Karma | 1991 | 1 | 32 | 3 | 35 | 0.36 | 0.04 | 3.33 | 2.07 |
| 9 | Fiscella | 1991 | 2 | 16 | 3 | 15 | 0.63 | 0.12 | 3.24 | 3.74 |
| 10 | Brodie | 1989 | 6 | 65 | 9 | 71 | 0.73 | 0.27 | 1.93 | 10.63 |
| 11 | Calhoun | 1993 | 5 | 55 | 7 | 61 | 0.79 | 0.27 | 2.35 | 8.56 |
| 12 | von Sydow | 1996 | 9 | 130 | 15 | 128 | 0.59 | 0.27 | 1.3 | 16.26 |
| 13 | Matthews | 1997 | 6 | 37 | 4 | 34 | 1.38 | 0.43 | 4.47 | 7.32 |
| 14 | Rimmer | 1997 | 13 | 148 | 18 | 162 | 0.79 | 0.40 | 1.56 | 22.08 |
| Total patients | 1,584 | 62 | 786 | 77 | 798 | 0.85 | 0.62 | 1.17 | ||
z = 1.0191; 2P = 0.31; Overall heterogeneity: Q = 4.68; Tau = 0.0000
Abbreviations: Obs = Observed cases; Tot = total cases; Q = Q statistic; z = z score; 2P = two-sided test
[Chapter 3]). The pooled failure rate in patients
treated with amoxicillin was low (11 percent; 95 percent CI, 8-14), and the
further decrease in clinical failures with broad-spectrum antibiotics was
not clinically important. Treating 100 patients with amoxicillin would lead
to only 0.85 more failures (95 percent CI, 3.1 more to 1.4 fewer failures).
| No. | Study | Year | Experiment | Control | Risk Ratio | 95% CI | Percent Wt | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Obs | Tot | Obs | Tot | Low | High | |||||
| 1 | Osman | 1983 | 5 | 42 | 13 | 34 | 0.31 | 0.12 | 0.79 | 31.16 |
| 2 | Otte | 1983 | 2 | 17 | 1 | 14 | 1.65 | 0.17 | 16.33 | 5.08 |
| 3 | Wallace | 1985 | 5 | 30 | 5 | 38 | 1.27 | 0.40 | 3.97 | 20.48 |
| 4 | Salmi | 1986 | 0 | 6 | 0 | 8 | 1.29 | 0.03 | 57.1 | 1.86 |
| 5 | Manzini | 1993 | 11 | 38 | 5 | 35 | 2.03 | 0.78 | 5.25 | 29.53 |
| 6 | Bockmeyer | 1994 | 1 | 21 | 0 | 24 | 3.41 | 0.15 | 79.47 | 2.7 |
| 7 | Arndt | 1994 | 1 | 26 | 1 | 28 | 1.08 | 0.07 | 16.35 | 3.61 |
| 8 | Rahlfs | 1996 | 0 | 13 | 1 | 9 | 0.24 | 0.01 | 5.26 | 2.79 |
| 9 | Rahlfs | 1996 | 1 | 13 | 0 | 14 | 3.21 | 0.14 | 72.55 | 2.75 |
| Total patients | 410 | 26 | 206 | 26 | 204 | 1.01 | 0.52 | 1.97 | ||
z = 0.0320; 2P = 0.97; Overall heterogeneity: Q = 10.48; Tau = 0.2252
Abbreviations: Obs = Observed cases; Tot = total cases; Q = Q statistic; z = z score; 2P = two-sided test
| Others vs. Amoxicillin | Studies | Number of Patients | Risk Ratio (95 % CI) 1 | Outcomes with Amoxicillin % [95 % CI] |
|---|---|---|---|---|
| Others vs. Folate Inhibitors | Studies | Number of Patients | Risk Ratio (95 % CI) 1 | Outcomes with Folate Inhibitors % [95 % CI] |
| Clinical failures | 14 | 1,584 | 0.85 (0.62-1.17) | 11 [8-14] had clinical failure |
| Clinical cures | 11 | 1,172 | 1.04 (0.98-1.11) | 72 [64-80] were clinically cured |
| Radiographic failures | 4 | 270 | 0.89 (0.35-2.26) | 17 [9-31] had radiologic failure |
| Bacteriologic failures | 7 | 435 | 0.68 (0.41-1.14) | 10 [5-9] had bacteriologic failure |
| Treatment withdrawals | 12 | 1,505 | 1.01 (0.56-1.81) | 4 [3-6] withdrew from treatment |
| Clinical failures | 9 | 410 | 1.01 (0.52-1.97) | 11 [6-22] had clinical failures |
| Clinical cures | 7 | 361 | 1.01 (0.88-1.17) | 73 [58-84] were clinically cured |
| Radiographic | 3 | 132 | 1.46 (0.79-2.71) | 20 [7-44] had radiologic failure |
| Bacteriologic failures | 3 | 122 | 1.70 (0.90-3.21) | 19 [9-37] had bacteriologic failure |
| Treatment withdrawals | 5 | 219 | 0.47 (0.10-2.20) | 6 [3-3] withdrew from treatment |
For each outcome, a risk ratio above 1 signifies that it is more likely to have this outcome with an expensive, typically broad-spectrum antibiotic than with a reference agent (amoxicillin, penicillin, or folate inhibitor)
Updated and reprinted with permission from the British Medical Journal.
[Chapter 3]); treatment failures occurred at an
essentially identical rate with other antibiotics as with folate inhibitors.
However, data on folate inhibitors were limited and of poor quality. An
analysis with respect to cures gave comparable results with risk ratios
close to 1, both for any other antibiotic vs. amoxicillin or folate
inhibitors (Table 15).
The risk differences of clinical cure using amoxicillin or folate inhibitors compared with those of other antibiotics were not clinically important (3.2 percent [95 percent CI, 1.5-7.8 percent], and 1.2 percent [95 percent CI, 10-12.4 percent], respectively). The results were comparable when a trial comparing penicillin with azithromycin was added to the amoxicillin comparisons: risk ratio for clinical cures is 1.05 (95 percent CI, 0.99-1.11); risk ratio for clinical failures is 0.82 (95 percent CI, 0.62-1.11).
There was no heterogeneity of treatment effects in the amoxicillin comparisons; however, there was some evidence of heterogeneity between the studies that compared folate inhibitors with other antibiotics (p=0.09 for clinical cures; p=0.18 for clinical failures), possibly because trimethoprim-sulfamethoxazole seemed less effective than pivampicillin/pivmecillinam in one study (Osman and Menday, 1983).
| Other Antibiotics vs. Amoxicillin | Other Antibiotics vs. Folate Inhibitors | |||
|---|---|---|---|---|
| Subgroups | Trials (patients) | Risk Ratio (95% CI) | Trials (patients) | Risk Ratio (95% CI) |
| Pediatric trials | 2 (108) | 1.24 (0.54-2.84) | No studies | Not applicable |
| Adult trials | 12 (1,476) | 0.79 (0.56-1.12) | 9 (410) | 1.01 (0.52-1.97) |
| Comparisons with tetracyclines | 1 (47) | 3.39 (0.15-79.2) | 5 (148) | 1.17 (0.32-4.23) |
| All other comparisons | 13 (1,537) | 0.86 (0.62-1.18) | 4 (262) | 1.03 (0.35-3.00) |
| Trials excluding resistant pathogens | 3 (176) | 1.00 (0.37-2.72) | 1 (45) | 3.41 (0.15-79.5) |
| Trials including all pathogens | 11 (1,408) | 0.85 (0.60-1.17) | 8 (365) | 0.96 (0.48-1.95) |
| Trials with subjective diagnosis of sinusitis | 4 (543) | 0.89 (0.46-1.71) | 8 (379) | 0.99 (0.47-2.08) |
| Trials with firm diagnosis of sinusitis | 10 (1,041) | 0.88 (0.60-1.28) | 1 (31) | 1.65 (0.17-16.3) |
| Trials with unclear assessment of outcomes | 3 (468) | 0.88 (0.50-1.55) | 4 (131) | 1.18 (0.44-3.13) |
| Trials with specified outcomes assessment | 11 (1,116) | 0.85 (0.57-1.26) | 5 (279) | 1.05 (0.35-3.10) |
| Unblinded/single-blind trials | 8 (821) | 0.89 (0.53-1.50) | 7 (365) | 0.99 (0.44-2.23) |
| Double-blind trials | 6 (763) | 0.85 (0.55-1.25) | 2 (45) | 1.54 (0.22-11.0) |
| Trials published 1983-91 | 8 (671) | 0.89 (0.52-1.51) | 4 (189) | 0.71 (0.28-1.81) |
| Trials published 1993-98 | 6 (913) | 0.82 (0.55-1.23) | 5 (221) | 1.77 (0.79-3.96) |
| Jadad quality score <3 | 7 (570) | 0.83 (0.49-1.40) | 7 (365) | 0.99 (0.44-2.23) |
| Jadad quality score >3 | 7 (1,014) | 0.86 (0.58-1.28) | 2 (45) | 1.54 (0.22-11.0) |
The estimates of the most reliable subgroup for each sensitivity analysis are shown in the lower line of each set of sensitivity analyses. Risk ratios less than 1 mean that other antibiotics are better than the reference agents (amoxicillin or folate inhibitors). There was no significant heterogeneity between subgroups for any of the sensitivity analyses (p>0.1).
Updated and reprinted with permission from the British Medical Journal.
, 15, and
16. No apparent trend of bias
by studies with a low Jadad score (poor quality) was identified.As reported in the meta-analyses of antibiotic treatments for uncomplicated, community-acquired acute bacterial rhinosinusitis, antibiotics provide better clinical outcomes than does symptomatic treatment alone. However, given the uncertainty of bacterial infection in patients with suggestive symptoms, the need to weigh the benefits of treatment against the cost and side effects, and the high cost of many available diagnostic modalities, the management of these patients has been controversial.
We performed decision and cost-effectiveness analyses to estimate the effectiveness and cost-effectiveness of various diagnostic and treatment options that a clinician may take in managing a patient who presents with possible acute bacterial rhinosinusitis. The decision analyses are designed from the patients' perspective in that the outcome utilities used relate to the individual patient's quality of life or length of illness. The cost-effectiveness analyses include both the individual patient's perspective and the payer's perspective. The costs are those that the payer, such as a health management organization (HMO) bears in managing the disease. Thus, indirect costs, such as lost days of work, are not included.
Although the number of antibiotic prescriptions written to treat patients are estimated for the various strategies, no estimates could be made as to the direct effect on increasing bacterial antibiotic resistance that each strategy implies. Even though this is an important area of concern, no data are available on antibiotic use causing resistance in rhinosinusitis.
In addition, the question of recurrence of disease after treatment is important. However, few clinical trials report recurrence data. As extrapolation of the models would weaken the conclusions, the models addressed only the clinical management over a 2-week time horizon.
The models include results from meta-analyses conducted in this report, from individual studies, and from expert opinions and consensus. As the preponderance of studies included both pediatric and adult populations and did not report the data separately for the two populations, we designed the models and estimated variable values for the combined population of pediatric and adult patients.
We performed two separate analyses. The first compares multiple diagnostic and treatment strategies and uses single time-point estimates of cure. The second focuses on four commonly used strategies and models the development of daily events.
In our first analysis, the multiple-strategies comparison model, we sought to compare all the currently available diagnostic and treatment strategies for acute bacterial rhinosinusitis management. The treatment strategies include symptomatic treatment alone and empiric antibiotic treatment. The diagnostic test strategies use various tests to determine treatment choice. These tests include sinus radiography, ultrasonography, computerized tomography (CT), magnetic resonance imaging (MRI), and the use of a specific set of clinical criteria to diagnose acute bacterial rhinosinusitis. These strategies are also compared with the generally accepted reference standard, sinus puncture and culture. Although sinus puncture is generally impractical and may be ill-advised, it is the only diagnostic method that accurately documents the presence of inflammation and bacteria in the maxillary sinuses.
The majority of studies available reported three possible patient outcomes (cure, improvement without cure, and no improvement) and gave only single time-point estimates (of generally 10 to 14 days) for cure and improvement proportions. Our first model corresponds to the majority of reported data by using these three outcomes, along with serious complications resulting from infection and the single time-point estimate of outcome proportions.
As this first model uses a single time point for clinical outcomes, it fails to consider the possibility that the primary difference in treatment choice is in the duration of symptoms rather than differences in outcome at a predefined time point. We therefore designed a second model, the symptom-duration model, using a Markov process (described below), that used daily cure rates to estimate the number of symptom-free days for each strategy. We focused on the commonly employed strategies of empiric treatment with antibiotics, deferment of antibiotic treatment, and determination of treatment option either by use of a set of clinical criteria or by use of sinus radiography.
We limited the antibiotics studied in our primary analyses to amoxicillin and folate-inhibitors (e.g., trimethoprim-sulfamethoxazole) as our meta-analyses showed that they are equally efficacious as the more costly antibiotics available. However, we also examined the effect on cost of using newer, more expensive antibiotics.
DecisionMaker 7.0TM(Sonnenberg, Pauker, Kassirer, 1990) was used to construct our decision models and MathSoft S-Plus 4.5TM (1997) was used to perform statistical calculations.
The methods and results of the first, multiple-strategies comparisons, model will be presented first, followed by the methods and results of the second, symptom-duration, model.
The assumptions used in the model are listed below .
Patients are seen by health care providers with symptoms suggestive of uncomplicated community-acquired acute bacterial rhinosinusitis.
The patient's illness meets criteria for our meta-analyses: they have symptoms for more than 5 days and less than 4 weeks not due to a recurrence of rhinosinusitis. Patients, who are immunocompromised; have a malignancy, cystic fibrosis, or trauma; or had sinus-related surgery are not included.
A certain percentage of the patients in the model have acute bacterial rhinosinusitis, as determined by the underlying prevalence of the disease; the remainder have a disease process other than bacterial infection such as viral infection or environmental allergies that is not responsive to antibiotic treatment.
Patients have no known allergy to amoxicillin (penicillins) or folate inhibitors (sulfa drugs).
Patients are given symptomatic treatment only, are given amoxicillin empiricly, or have diagnostic testing done to select the appropriate treatment.
All patients use over-the-counter and/or prescription symptomatic treatments such as decongestants.
All the placebo trials allowed use of symptomatic treatment. Thus, the meta-analysis estimate of cure rates on placebo is equivalent to that of symptomatic treatment.
Amoxicillin is equally efficacious and has a similar aggregate side effect profile (categorized as major and minor) as folate inhibitors and other antibiotics used for acute bacterial rhinosinusitis.
The test performances (sensitivity and specificity) for each test used to diagnose acute bacterial rhinosinusitis may be different.
Patients receiving a sinus puncture have a risk of developing complications due to the procedure independent of whether they have acute bacterial rhinosinusitis. These complications include hemorrhage, orbital trauma, and facial cellulitis.
Patients receiving amoxicillin assume a given risk of major and minor side effects. A major side effect, such as pruritic or urticarial rash, necessitates changing antibiotics. A minor side effect, such as minor gastrointestinal upset or vaginitis, does not necessitate changing antibiotics.
Patients who develop a major side effect to amoxicillin are given a folate inhibitor as a replacement antibiotic.
Patients who are switched to a folate inhibitor because of a side effect to amoxicillin do not develop an additional side effect to the replacement antibiotic. Their cure and improvement rates are determined by the relevant rates for folate inhibitors.
Patients do not develop a side effect to any adjuvant medications they may take for their rhinosinusitis symptoms (such as decongestants).
The majority of antibiotic trials reported cure rates at 10 to 14 days. Thus, outcomes are determined at 2 weeks from the decision point (time of initial office visit). This does not imply that antibiotic-treated patients are given a full 14 days of antibiotic treatment.
Patients with acute bacterial rhinosinusitis may develop a complication due to the infection. These complications include facial osteomyelitis, facial cellulitis, orbital cellulitis and abscesses, subdural empyema, brain abscess, cavernous sinus thrombosis, and meningitis.
Patients who do not develop an infection complication may be fully cured, improve incompletely, or have no improvement.
The symptom resolution rate of all patients who do not have acute bacterial rhinosinusitis is the same and is independent of treatment.
Quality of life over the 2-week period described by the model is affected by the occurrence of unfavorable events and outcomes, including the occurrence of a complication related to sinus puncture, a major or minor side effect, a complication related to disease, and cure, improvement, or no improvement.
Each event or outcome affects the patient's quality of life.
Costs of treatment, diagnostic tests, complications, side effects, and necessary followup are those incurred by the payer.
Costs do not include indirect costs such as loss of income or additional costs of child care.
Note: CT - computerized tomography; MRI - magnetic
resonance imaging
and 18 is the decision tree that
depicts the comparison of the eight management strategies modeled in our
analysis. The multiple-strategies comparison model decision tree models
management strategies, the risk of complication due to sinus puncture,
prevalence of rhinosinusitis, test performance, risk of treatment side
effect, risk of disease complication, and probability of cure or
improvement.
by the branches off the square decision node to
the far left of the diagram. Two of the strategies include no specific
diagnostic workup: symptomatic treatment alone without antibiotics and
empiric treatment with amoxicillin. The remaining six strategies include
the use of diagnostic tests to determine treatment choice. Diagnostic
tests include the application of a specific set of clinical criteria,
sinus radiography,sinus ultrasonography, sinus CT, sinus MRI, and sinus
puncture and culture.
For each strategy there are given probabilities of certain events occurring. These are represented by the circles, or chance nodes, at each subsequent branching. If a given strategy is applied to a cohort of 100 patients, the number of patients who move into each branch at a chance node is determined by the probability of an event occurring at that chance node. For example, if the probability of event A occurring is 15 percent, then 15 patients will move to the branch representing "event A," and the remaining 85 will move to the branch representing "not event A." The 15 patients in the event A branch may incur a cost related to event A and may have their quality of life affected by the occurrence of event A. If there is an "event B" chance node, these 15 patients will again divide into groups depending on the probability of event B occurring. It should be noted that the probability of event B occurring may be determined by whether event A occurred.
.
.
). The test outcome, in turn, is determined by the
sensitivity (measuring the proportion of patients with disease who have
a positive test) and specificity (measuring the proportion of patients
without disease who have a negative test) of the given test. Thus, in
the model, the sensitivity chance node (which comes off the "acute
bacterial rhinosinusitis" branch of the diagnostic tests) separates the
true positive tests from the false negative tests. Likewise, the
specificity chance node (coming off the "no acute bacterial
rhinosinusitis" branch of the diagnostic tests) separates the false
positive tests from the true negative tests. All patients with positive
test results are treated with amoxicillin. All those with negative test
results are not given amoxicillin.
by the
chance node off the treatment arm, all patients who are treated may
develop a major or minor side effect to the amoxicillin. If a patient
develops a major side effect, the antibiotic is changed to a folate
inhibitor. If the patient develops a minor side effect or no side
effect, the antibiotic is not changed. Patients who develop a major or
minor side effect incur monetary costs due to the side effect, and their
quality of life is affected by the side effect. Patients who are not
treated with amoxicillin do not develop a side effect to the drug.
. All patients with acute bacterial
rhinosinusitis have a risk of developing a disease complication. The
level of this risk is determined by whether they are being treated with
antibiotics. A cost and adjustment to quality of life are incurred by
the occurrence of a disease complication. Patients without acute
bacterial rhinosinusitis have no risk of developing a disease
complication.
.
They may be cured, improve, or not improve. The likelihood of a given
patient moving into one of the final outcomes is determined by whether
he or she has acute bacterial rhinosinusitis, and if so, by whether that
patient is being treated with amoxicillin, a folate inhibitor, or no
antibiotic. Again, each outcome is associated with a final cost and
quality-of-life adjustment.
| Variable | Base Case Value | Sensitivity Analysis (range) | Reference | ||
|---|---|---|---|---|---|
| Probabilities | |||||
| Bacterial
rhinosinusitis (prevalence) | 50% | 0-100% | Kuusela, 1982; Laine, 1998; van Buchem, 1995 | ||
| Complication due to sinus puncture | 1% | 0-5% | Expert opinion | ||
| Major antibiotic side effect | 5% | 0-20% | Bigby, 1986; Saxon, 1987; Lin, 1992; Caldwell, 1974 | ||
| Minor antibiotic side effect | 4% | 0-20% | Expert opinion | ||
| Cure rate | |||||
| Low | High | ||||
| No antibiotic (symptomatic treatment) | |||||
| Cure | 34% | 21% | 51% | Treatment meta-analysis | |
| Improvement | 35% | 36% | 28% | Treatment meta-analysis | |
| No improvement | 31% | 43% | 21% | Treatment meta-analysis | |
| Complication | 0.01% | - | - | See text | |
| With amoxicillin | |||||
| Cure | 72% | 64% | 80% | Treatment meta-analysis | |
| Improvement | 17% | 22% | 12% | Treatment meta-analysis | |
| No improvement | 11% | 14% | 8% | Treatment meta-analysis | |
| Complication | 0% | - | - | Assumption | |
| With folate inhibitor | |||||
| Cure | 73% | 58% | 84% | Treatment meta-analysis | |
| Improvement | 16% | 20% | 10% | Treatment meta-analysis | |
| No improvement | 11% | 22% | 6% | Treatment meta-analysis | |
| Complication | 0% | - | - | Assumption | |
| If symptoms not due to acute bacterial rhinosinusitis | |||||
| Cure | 67% | 35% | 90% | Expert opinion | |
| Improvement | 17% | 14% | 5% | Expert opinion | |
| No improvement | 16% | 49% | 5% | Expert opinion | |
| Complication | 0% | - | - | Definition | |
| Diagnostic test performance | Bias against test | Bias toward test | |||
| Applied clinical criteria | Berg, 1988, Expert opinion | ||||
| Sensitivity | 0.81 | 0.70 | 1.00 | ||
| Specificity | 0.89 | 0.70 | 1.00 | ||
| Sinus radiography | Diagnostic meta-analysis | ||||
| Sensitivity | 0.90 | 0.68 | 1.00 | ||
| Specificity | 0.61 | 0.20 | 1.00 | ||
| Sinus ultrasonography | Diagnostic meta-analysis; Laine, 1998 | ||||
| Sensitivity | 0.84 | 0.61 | 1.00 | ||
| Specificity | 0.69 | 0.53 | 1.00 | ||
| Sinus CT | Expert opinion | ||||
| Sensitivity | 0.90 | 0.80 | 1.00 | ||
| Specificity | 0.60 | 0.50 | 1.00 | ||
| Sinus MRI | Expert opinion | ||||
| Sensitivity | 0.95 | 0.90 | 1.00 | ||
| Specificity | 0.60 | 0.50 | 1.00 | ||
| Sinus puncture and culture | Reference standard assumed perfect | ||||
| Sensitivity | 1.00 | - | - | ||
| Specificity | 1.00 | - | - | ||
| Cost | Low | High | |||
| Treatment | |||||
| Amoxicillin | $15 | - | $100 | Cardinale, 1997 | |
| Folate inhibitor | $15 | plus estimated | |||
| Symptomatic therapy 1 | $0 | pharmacy cost | |||
| Diagnostic tool | |||||
| Applied clinical criteria | $0 | ||||
| Sinus radiography | $103 | Maximum | |||
| Sinus CT scan | $300 | allowable fees, | |||
| Sinus ultrasonography | $150 | Nov. 1996 | |||
| Sinus MRI | $463 | " | |||
| Sinus puncture and culture | $293 | " | |||
| Adverse events | |||||
| Sinus puncture complication | $2,500 2 | See notes | |||
| Major side effect | $50 3 | - | - | " | |
| Minor side effect | $10 4 | - | - | " | |
| Disease Outcome | |||||
| Cure | $0 | - | - | ||
| Improvement | $35 5 | - | - | " | |
| No improvement | |||||
| Symptomatic treatment | $70 6 | - | $155 7 | " | |
| Empirical treatment | $155 7 | - | $258 8 | " | |
| Negative diagnostic test | $70 6 | - | $155 7 | " | |
| Positive diagnostic test | $155 7 | - | - | " | |
| Sinusitis complication | $10,000 | - | - | " | |
| (e.g., hospitalization, intravenous antibiotics, surgery, etc.) | |||||
| Quality-of-life adjustments | |||||
| The adjustment terms are multiplied together for the final utility.The larger the value, the better the quality of life (or the healthier). | |||||
| Sinus puncture complication | 0.6 | Expert opinion | |||
| Major side effect | 0.7 | " | |||
| Minor side effect | 0.9 | " | |||
| Cure | 1.0 | " | |||
| Improvement | 0.8 | " | |||
| No improvement | 0.5 | " | |||
| Sinusitis complication | 0.1 | " | |||
It is assumed that all patients will receive symptomatic treatment; thus,there is no additional cost to symptomatic treatment.
Average of bleed, introduced infection, orbital damage, possible hospitalization, surgery and intravenous antibiotics
50 percent return office visit, treatment of side effect symptoms and change antibiotics to folate inhibitor
Treatment of side effect symptoms
50 percent return office visits and additional symptomatic therapy
Return office visit and amoxicillin or folate inhibitor
Return office visit and new, expensive antibiotic
Return office visit, sinus radiograph and new, expensive antibiotic
As discussed in meta-analysis of diagnostic test studies, most of the estimates of prevalence of acute bacterial rhinosinusitis in patients seen by providers with sinus symptoms are in the range of 50 percent (Kuusela, Kurri, and Sirola, 1982; Laine, Maättä, Varonen, et al., 1998;van Buchem, Peeters, Beaumont, et al., 1995). We therefore use this prevalence for our baseline estimates. The estimates are tested across the full range of prevalence (0-100 percent).
No data are available as to the complication rate of sinus puncture. We therefore used consensus opinion of our technical experts to arrive at an estimate of a 1 percent complication rate.
For the clinical criteria strategy we used the approach taken in the one trial that compared clinical signs and symptoms with sinus puncture (Berg and Carenfelt, 1988 ). As described in meta-analysis of diagnostic test studies (clinical examination compared with sinus puncture), Berg's paper provides data from which we were able to derive the sensitivity and specificity for four-item risk scores calculated by the presence of: (1) purulent rhinorrhea with unilateral predominance, (2) local pain with unilateral predominance, (3) bilateral purulent rhinorrhea, and (4) pus in the nasal cavity.
We used a "Berg score" of three or more (three or four of the signs or symptoms are present) which allowed for a moderately high sensitivity and high specificity. For comparison, we used the test performance estimates derived from a study that compared the physician's "overall clinical impression" with sinus radiography (Axelsson and Runze, 1976), which had poorer test performance.
As discussed in meta-analysis of diagnostic test studies, data exist for estimates of sinus radiography sensitivity and specificity for various methods of reading the films. All the methods include a series of three or four views including the occipitomental (Water's) view. However, the definition of a positive radiograph can include "opacification of sinus" only, "sinus fluid or opacity," or "sinus fluid or opacity or mucous membrane thickening." For the baseline decision analysis, we chose the definition of a positive radiograph that yielded the highest sensitivity while allowing for a moderate specificity, namely, "sinus fluid or opacity or mucous membrane thickening." We also performed sensitivity analysis using the lower bounds of the 95 percent confidence interval limits of the random effects pooled results.
We used the random effects pooled estimates of test performance for sinus ultrasonography from our meta-analysis of diagnostic test studies. Most of the available data are from studies in which ultrasonograms were performed by otolaryngologists. The results of the ultrasonography study with the poorest test performance (Laine, Maättä, Varonen, et al., 1998) were used in the sensitivity analysis.
No trials are available that compare either sinus CT or MRI to sinus puncture. Thus, no data are available from the literature of these tests' sensitivity or specificity. We therefore used consensus opinion of our technical experts to arrive at estimates of CT and MRI test performances. The consensus was that CT and MRI have high sensitivity but lower specificity. Lower test performances were also tested in the sensitivity analysis.
Sinus puncture includes endoscopic evaluation of the maxillary sinuses, sampling of any fluid present, and bacteriologic culture and sensitivity of the aspirated fluid. This strategy in conjunction with clinical history and examination is the most reliable method of diagnosing acute bacterial rhinosinusitis. However, because of its invasive nature, it is not routinely used. We included it in our model to provide an assumed perfect reference standard for comparison. Thus, the sensitivity and specificity of sinus puncture and culture are set at 100 percent.
Reviews of the literature of penicillin allergy generally quote an incidence of reactions or side effects at between 1 and 10 percent (Lin, 1992). The three studies found that discussed allergic reactions to amoxicillin (or ampicillin) (Bigby, Jick, Jick, et al., 1986; Caldwell and Cluff, 1974; Saxon, Beall, Rohr, et al., 1987) all report a rate of cutaneous or more severe drug reactions of approximately 5 percent in hospitalized patients. We used an estimate of 5 percent for severe drug allergies requiring change of antibiotic and tested the estimate in a wide range of 0 to 20 percent.
No data were found estimating the rate of minor side effects, which do not require a change in antibiotic. By consensus expert opinion, we estimated the rate of minor side effect to be somewhat lower than that of major side effect, or 4 percent. This estimate was also tested across a wide range of 0 to 20 percent.
No explicit evidence exists about the rate of complications of community-acquired, acute bacterial rhinosinusitis. However, using Gwaltney's (1996) estimate of approximately 1 billion cases annually of viral rhinosinusitis and a middle estimate that 1 percent of these cases are complicated by acute bacterial infection (Berg, Carenfelt, Rystedt, et al., 1986; Dingle, Badger, and Jordan, 1964), we can estimate 10 million cases of acute bacterial rhinosinusitis annually. The 1994 National Hospital Discharge Survey reported approximately 5,000 or fewer cases of intracranial abcesses. We estimated that approximately 20 percent of these cases were a result of bacterial rhinosinusitis (Bradley and Shaw, 1983; Small and Dale,1984). Extrapolating from these data, we used an estimate of major complication rate due to acute bacterial rhinosinusitis of 1/10,000 cases. To further bias our model toward treatment with antibiotics (specifically to avoid complications), we used this estimate for the complication rate only in patients not receiving antibiotics. We assumed that patients treated with antibiotics are fully protected against complications (their complication rate is 0). Patients who do not in fact have acute bacterial rhinosinusitis cannot develop a complication due to the disease.
Cure and improvement rate estimates were derived from the antibiotic treatment meta-analyses. We derived cure rate estimates for treatment with amoxicillin and folate inhibitors from the meta-analyses of the relevant trials. Cure rate estimates for symptomatic treatment were derived from the meta-analysis of the placebo arms of relevant trials. The cure rates for antibiotic and symptomatic treatments were varied across the 95 percent confidence intervals of the meta-analyses estimates.
We used consensus estimates of 67 percent cure and 17 percent improvement for patients who are seen with symptoms of rhinosinusitis but do not, in fact, have acute bacterial rhinosinusitis.
In our interviews with patients, we were told that the effect on quality of life of rhinosinusitis symptoms is likely to vary significantly both between patients and in the same patient between episodes of acute bacterial rhinosinusitis. Some episodes are accompanied by more severe symptoms than others thus resulting in lower quality of life. As our baseline estimates of quality adjustments for improvement and no improvement were set for relatively more severe symptoms (which bias the results toward empiric antibiotic treatment), we also tested a scenario where symptoms of disease are relatively mild (milder than antibiotic side-effect symptoms) that would bias the findings away from empiric antibiotic treatment.
Costs of diagnostic tests were derived from maximum allowable reimbursements from a managed care company as of November 1996, including radiologists' fees. Applying clinical criteria as a decision tool for treatment has no additional cost. The cost of a sinus puncture includes the reimbursement cost of obtaining a culture and antimicrobial sensitivities of the fluid sample.
The cost of a major antibiotic side effect includes the reimbursement cost of an additional office visit, the cost of therapy to treat the side effect, and the cost of switching antibiotics. The cost of a minor antibiotic side effect includes the cost of therapy to treat the side effect.
The cost of sinus puncture complication and disease complication includes the total costs of hospitalization including surgery, intravenous antibiotics, and so on. The actual figure used is from consensus expert opinion.
Through consensus expert opinion, we estimated that only 50 percent of patients who improve return for an office visit; the rest either continue symptomatic treatment on their own or speak to their provider without an office visit. The cost of improvement, thus, includes 50 percent of the cost of a return office visit and the cost of additional over-the-counter symptomatic therapy. It is assumed that these patients will not require an additional course of antibiotics.
In addition, we tested the model under the assumption that the first antibiotic given to the patient was a newer, more expensive choice than amoxicillin. However, under this scenario we used the symptom resolution and side effect proportions of amoxicillin.
| Prevalence of acute bacterial rhinosinusitis = 50% | |||||
|---|---|---|---|---|---|
| Cost per patient | Outcome utility | Cost-Effectiveness | Marginal cost-Effectiveness | ||
| Symptomatic treatment | $30.53 | 0.830 | $36.78 | ||
| Clinical criteria guided treatment | $31.38 | 0.878 | $35.76 | $17.89/QAO | |
| Empirical antibiotic treatment | $45.52 | 0.882 | $51.64 | $3,667/QAO | |
| Radiography guided treatmen | $138.79 | 0.880 | $157.61 | **** | |
| Ultrasonography guided treatment | $184.57 | 0.878 | $210.29 | **** | |
| CT guided treatmen | $335.96 | 0.881 | $381.53 | **** | |
| Sinus Puncture guided treatmen | $347.38 | 0.890 | $390.38 | $35,865/QAO | |
| MRI guided treatment | $498.90 | 0.884 | $564.67 | **** |
CT = computed axial tomography, MRI = magnetic resonance imaging; QAO = quality-adjusted outcome QAO = quality adjusted outcome
As expected, the greater the performance of a given diagnostic test, the greater the quality-adjusted outcome utility. Thus, the order of most effective diagnostic tests (from highest to lowest) at our base prevalence rate of 50 percent was sinus puncture, MRI, CT, radiography, ultrasonography, and clinical criteria. At acute bacterial rhinosinusitis prevalence of 50 percent, empiric treatment with antibiotics was as effective as treatment guided by most of the diagnostic methods. Symptomatic treatment alone of all patients was least effective, as none of the 50 percent of patients with acute bacterial rhinosinusitis was cured as effectively as the patients would have been had they been given antibiotics.
It should be noted, as discussed below, the relative effectiveness of the strategies varies depending on the cohort's prevalence of acute bacterial rhinosinusitis. In addition, all the outcome utilities (as measures of effectiveness) lie within a narrow range of values that is equivalent to being somewhat better than having improved but not been fully cured (utility = 0.8).
As all the diagnostic procedures are fairly costly, the total cost per patient for each of the diagnostic procedure strategies was significantly more expensive than for the other strategies. The costs per patient were in direct relation to the cost of the diagnostic procedure performed.
The cost per healthy outcome of all the other diagnostic tests was much greater in direct relation to the cost of the diagnostic test.
Note: CT - computerized tomography; MRI -
magnetic resonance imaging
. The marginal cost-effectiveness of one
strategy over another is the additional cost of the first
strategy that achieves an additional quality-adjusted outcome of
1 over the second strategy [(Cost Strategy A - Cost Strategy B)
/ (Effectiveness Strategy A - Effectiveness Strategy B)]. In
Figure 19, the more
cost-effective strategies will be toward the upper left corner
of the figure, having greater outcome utility and lower costs.
The marginal cost-effectiveness between any two strategies is
the inverse of the slope connecting the two points representing
the strategies in the graph above. Only additional costs per
additional utility are considered; thus the first strategy being
considered must be to the upper right of the second, with
greater cost and greater utility. Strategies that are more
costly and less effective are "eliminated by strict dominance."
| Prevalence =25% | Outcome (% patients) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Cost per patient | Cure | Improvement | No improvement | Complication | % Pts receiving Rx | # of Rx per true case | % of all Pts incorrectly | ||
| given Rx | not given Rx | ||||||||
| Empirical Tx | $47.46 | 68% | 17% | 15% | 0% | 100% | 4.0 | 75% | 0% |
| Symptomatic Tx | $23.84 | 59% | 21% | 20% | 0.03% | 0% | 0.0 | 0% | 75% |
| Clinical exam | $26.04 | 66% | 18% | 16% | 0.005% | 46% | 1.8 | 8% | 5% |
| Radiography | $135.76 | 67% | 17% | 15% | 0.003% | 52% | 2.1 | 29% | 3% |
| Ultrasonography | $180.86 | 67% | 18% | 15% | 0.004% | 44% | 1.8 | 23% | 4% |
| CT | $333.00 | 67% | 17% | 15% | 0.003% | 53% | 2.1 | 30% | 3% |
| MRI | $495.97 | 68% | 17% | 15% | 0.001% | 54% | 2.2 | 30% | 1% |
| Sinus puncture | $341.27 | 68% | 17% | 15% | 0% | 25% | 1.0 | 0% | 0% |
| Prevalence =50% | Outcome (% patients) | ||||||||
| Cost per patient | Cure | Improvement | No improvement | Complication | % Pts receiving Rx | # of Rx per true case | % of all Pts incorrectly | ||
| given Rx | not given Rx | ||||||||
| Empirical Tx | $45.52 | 69% | 17% | 13% | 0% | 100% | 2.0 | 50% | 0% |
| Symptomatic Tx | $30.53 | 50% | 26% | 23% | 0.05% | 0% | 0.0 | 0% | 50% |
| Clinical exam | $31.38 | 66% | 19% | 15% | 0.01% | 60% | 1.2 | 5% | 10% |
| Radiography | $138.79 | 68% | 18% | 14% | 0.005% | 65% | 1.3 | 20% | 5% |
| Ultrasonography | $184.57 | 67% | 18% | 15% | 0.008% | 58% | 1.2 | 16% | 8% |
| CT | $335.96 | 68% | 18% | 14% | 0.005% | 65% | 1.3 | 20% | 5% |
| MRI | $498.90 | 69% | 17% | 14% | 0.003% | 68% | 1.4 | 20% | 3% |
| Sinus puncture | $347.39 | 69% | 17% | 13% | 0% | 50% | 1.0 | 0% | 0% |
| Empirical Tx | $43.55 | 71% | 17% | 12% | 0% | 100% | 1.3 | 25% | 0% |
| Symptomatic Tx | $37.30 | 42% | 30% | 27% | 0.08% | 0% | 0.0 | 0% | 25% |
| Clinical exam | $36.79 | 65% | 20% | 15% | 0.01% | 75% | 1.0 | 3% | 4% |
| Radiography | $141.86 | 68% | 18% | 14% | 0.008% | 77% | 1.0 | 10% | 8% |
| Ultrasonography | $188.29 | 66% | 19% | 15% | 0.01% | 71% | 0.9 | 8% | 12% |
| CT | $338.94 | 69% | 17% | 15% | 0.008% | 78% | 1.0 | 10% | 8% |
| MRI | $501.86 | 69% | 18% | 13% | 0.04% | 81% | 1.1 | 10% | 4% |
| Sinus puncture | $353.59 | 71% | 17% | 12% | 0% | 75% | 1.0 | 0% | 0% |
ABRS = acute bacterial rhinosinusitis, Pts = patients, Tx = treatment, Rx = antibiotic prescription Note: Outcome percentages may not add to 100% due to rounding error.
Symptomatic treatment alone (withholding antibiotics for all patients) is inferior to all other strategies at all prevalences shown in terms of cure rate, complication rate, and, by definition, percentage of patients with disease who are left untreated. All other strategies have very similar cure and complication rates, and all others but the idealized sinus puncture-guided treatment have similar numbers of prescriptions written per true case of acute bacterial rhinosinusitis and similar numbers of unnecessary prescriptions written for patients without acute bacterial rhinosinusitis.
Cure and complication rates for cohorts of patients with different underlying prevalences of acute bacterial rhinosinusitis will differ; for example, those cohorts with a high prevalence of acute bacterial rhinosinusitis will respond much more effectively to antibiotic treatment than those with a low prevalence. To fully evaluate the relative costs, effectiveness, and cost-effectiveness of the various strategies, we performed sensitivity analyses of the prevalence wherein we adjusted the acute bacterial rhinosinusitis prevalence from 0 to 100 percent and determined estimates at various levels.
Note: CT - computerized tomography; MRI - magnetic
resonance imaging; TX - treatment
Note: CT - computerized tomography; MRI - magnetic
resonance imaging; TX - treatment
Figure 22. Expanding the scale of Figure 21 to highlight strategies of
interest
Note: TX - treatment
Note: TX - treatment
, 21, 22, and 23.
. As it correctly diagnoses
acute bacterial rhinosinusitis all the time, sinus puncture and
culture avoids unnecessary treatment and maximizes appropriate
treatment; it, thus, is always most effective. The effectiveness
of the diagnostic test-guided treatment strategies are directly
related to the test performance (sensitivity and specificity) of
each test. As the test performances modeled are generally fairly
high, the effectiveness of the tests is relatively high and
stable across the range of prevalence.
Because of the increasing failure rate with symptomatic treatment, its effectiveness falls rapidly with increasing acute bacterial rhinosinusitis prevalence. The effectiveness of empiric antibiotic therapy rises with increasing prevalence, as the proportion of patients benefitting from antibiotic treatment rises. At low prevalence, the value of the empiric antibiotic therapy is low, but the rate of unnecessary side effects is high compared with that of the other strategies. As prevalence increases, the value of empiric treatment rises until it is equal to that of sinus puncture-guided treatment at 100 percent prevalence where all patients are being treated by both strategies.
(average cost per treatment), the costs for strategies involving
diagnostic procedures (those lines above $100/treatment) do not
vary considerably with acute bacterial rhinosinusitis
prevalence. This is a result of the high costs of these
procedures relative to the costs of further workup and treatment
of the few patients who do not improve with empiric treatment.
, an expanded
version of Figure 21,
reveals that the relative costs of empiric treatment,
symptomatic treatment, and treatment guided by a set of clinical
criteria differ depending on the underlying prevalence of acute
bacterial rhinosinusitis in the cohort of patients. Symptomatic
treatment and clinical criteria-guided treatment are very close
to each other in cost across the full range of prevalence.
Symptomatic treatment is marginally less costly at a prevalence
lower than 66 percent; clinical criteria-guided treatment is
less costly at a higher prevalence. The cost of empiric
treatment is relatively flat across prevalence. Only at very
high prevalence (>99 percent) is empiric treatment less
costly than clinical criteria.
shows the
relative cost-effectiveness for the four least costly strategies
(symptomatic, clinical criteria-guided, empiric, and
radiography-guided treatment). As in the graph of cost across
prevalence (Figure 22),
symptomatic treatment and clinical criteria-guided treatment are
similar across the range of prevalence. Clinical criteria-guided
treatment is the most cost-effective strategy when prevalence of
acute bacterial rhinosinusitis is between 41 and 95 percent.
Below a prevalence of 41 percent, symptomatic treatment is most cost effective; and at a prevalence greater than 95 percent, empiric treatment is most cost effective. At a low prevalence, most patients' symptoms will respond spontaneously; thus, antibiotic treatment can be deferred and still achieve good average outcome and minimal cost of followup for patients whose symptoms fail to resolve. At very high prevalence, the cost of not treating those patients with acute rhinosinusitis who have negative clinical criteria is greater than the cost of treating everyone, and the outcome is poorer. Therefore, empiric treatment is most cost effective at very high prevalence.
| Value | Effectiveness | Cost per patient | Cost-effectiveness | |
|---|---|---|---|---|
| Clinical criteria | ||||
| Low sensitivity | 0.70 | 0.870 | $34.57 | $39.76/QAO |
| Low specificity | 0.70 | |||
| Base sensitivity | 0.81 | 0.878 | $31.38 | $35.76/QAO |
| Base specificity | 0.89 | |||
| Perfect sensitivity | 1.00 | 0.890 | $29.39 | $33.03/QAO |
| Perfect specificity | 1.00 | |||
| Radiography | ||||
| Low sensitivity | 0.68 | 0.864 | $145.66 | $168.58/QAO |
| Low specificity | 0.20 | |||
| Base sensitivity | 0.90 | 0.880 | $138.79 | $157.61/QAO |
| Base specificity | 0.61 | |||
| Perfect sensitivity | 1.00 | 0.890 | $132.39 | $148.77/QAO |
| Perfect specificity | 1.00 | |||
| Ultrasonography | ||||
| Low sensitivity | 0.61 | 0.863 | $187.42 | $217.27/QAO |
| Low specificity | 0.53 | |||
| Base sensitivity | 0.84 | 0.878 | $184.57 | $210.29/QAO |
| Base specificity | 0.69 | |||
| Perfect sensitivity | 1.00 | 0.890 | $179.39 | $201.59/QAO |
| Perfect specificity | 1.00 | |||
| CT | ||||
| Low sensitivity | 0.80 | 0.874 | $337.68 | $386.48/QAO |
| Low specificity | 0.50 | |||
| Base sensitivity | 0.90 | 0.881 | $335.96 | $381.53/QAO |
| Base specificity | 0.60 | |||
| Perfect sensitivity | 1.00 | 0.890 | $329.39 | $370.15/QAO |
| Perfect specificity | 1.00 | |||
| MRI | ||||
| Low sensitivity | 0.90 | 0.880 | $500.57 | $569.02/QAO |
| Low specificity | 0.50 | |||
| Base sensitivity | 0.95 | 0.884 | $498.90 | $564.67/QAO |
| Base specificity | 0.60 | |||
| Perfect sensitivity | 1.00 | 0.890 | $492.39 | $553.32/QAO |
| Perfect specificity | 1.00 | |||
CT = computed axial tomography; MRI = magnetic resonance imaging; QAO = quality-adjusted outcom
For all the diagnostic tests, the effectiveness and total cost of the strategies are fairly stable across the range of test performances tested. The cost-effectiveness of the diagnostic tests with an up-front cost of the test (e.g., radiography) are also fairly stable and at no test performance level approach the cost-effectiveness of the strategies without up-front test costs (symptomatic, empiric, and clinical criteria). The cost-effectiveness of clinical criteria, however, does vary in a range across that of symptomatic treatment.
We, therefore, tested a two-way sensitivity analysis of clinical criteria test performance and rhinosinusitis prevalence to compare the cost-effectiveness of the three low-cost strategies. If clinical criteria had perfect test performance, and thus were perfectly discriminatory between acute bacterial rhinosinusitis and other disease, then clearly this would be the most cost-effective strategy across the range of prevalence. If, however, the test performance of clinical criteria was worse than our base case assumption (with a sensitivity and specificity of 0.70), then the range in which clinical criteria are more cost-effective narrows from 41 to 95 percent (base case) to 66 to 80 percent.
The assumptions used in the model are listed below.
Patients are seen by health care providers with symptoms suggestive of uncomplicated possible acute community-acquired bacterial rhinosinusitis.
The patient's illness meets criteria for our meta-analyses: They have symptoms for more than 5 days and less than 4 weeks and not as a result of a recurrence of rhinosinusitis. Patients who are immunocompromised, have a malignancy, cystic fibrosis, or trauma, or have had sinus-related surgery are not included.
A proportion of the patients in the model have true acute bacterial rhinosinusitis represented by the prevalence of the disease. The remaining patients have a disease process other than acute bacterial rhinosinusitis such as viral infection or environmental allergies that is not responsive to antibiotic treatment.
Patients have no known allergy to amoxicillin (penicillins) or folate inhibitors.
Patients are given symptomatic treatment only, are given amoxicillin empirically, have a set of clinical criteria applied to determine treatment choice, or have a sinus radiograph done to determine treatment choice
All patients use over-the-counter and/or prescription treatment for symptoms such as decongestants.
All the placebo trials allowed use of symptomatic treatment. Thus, the estimates of cure rate on placebo are equivalent to symptomatic treatment
Amoxicillin is equally efficacious and has a similar aggregate side effect profile (categorized as major and minor) as folate inhibitors and other antibiotics used for acute bacterial rhinosinusitis.
Clinical criteria and sinus radiography have a sensitivity and specificity for diagnosing acute bacterial rhinosinusitis obtained from our meta-analyses of diagnostic test studies.
The daily risk of antibiotic side effects remains constant for the 14-day course of treatment.
Side-effect symptoms last for 2 days only and can occur only once during the 14-day course. Patients who are switched to an alternative antibiotic because of a major side effect do not develop an additional side effect to the replacement antibiotic.
Side effects minor enough not to necessitate discontinuation of amoxicillin are not included.
Patients do not develop side effects to any adjuvant medications they may take for their rhinosinusitis symptoms (such as decongestants).
Patients with acute bacterial rhinosinusitis may develop a complication due to the infection. These complications include facial osteomyelitis, facial cellulitis, orbital cellulitis and abscesses, subdural empyema, brain abscess, cavernous sinus thrombosis, and meningitis.
On any given day during the 14-day course, patients who are sick may be fully cured or may remain sick. The intermediate state of "improvement" used in the first model is not included. The proportion of patients cured on any given day varies according to data estimated in the literature and from our models.
Once resolved, a patient's symptoms do not relapse during the 14-day course.
The cure rate of all patients who do not have acute bacterial rhinosinusitis is the same and is independent of antibiotic treatment.
The model estimates number of symptom-free days (free of symptoms due to rhinosinusitis or to side effects) and quality-adjusted days (adjusted for severity of rhinosinusitis symptoms) over a 14-day course.
Measures of effectiveness (symptom-free days or quality-adjusted days) are from the individual patient's perspective.
Costs are determined by the costs of antibiotic treatment, sinus radiography, treatment of side effects, and followup determined by the final outcome (cured or sick) on day 14 that are incurred by the payer.
Costs do not include indirect costs such as loss of income or additional costs of child care.
Note: w/ - with; SE - antibiotic side effect
and Figure 25 show the
symptom-duration model. The model depicts the comparison of four
management strategies: withholding antibiotics and treating symptoms of
rhinosinusitis only, empiric treatment of all patients with amoxicillin,
use of a set of clinical criteria to determine choice of treatment
option, and immediate sinus radiograph to determine choice of treatment
option. The symptom-duration model uses a Markov decision tree and
models the management strategies, prevalence of rhinosinusitis, sinus
radiography test performance, risk of disease complication, risk of
treatment side effect, and probability of cure.
Patients with symptoms suggestive of acute bacterial rhinosinusitis are managed by one of the four strategies shown in the left-hand column. The prevalence of acute bacterial rhinosinusitis is modeled in the next column to the right, followed by the test performance for clinical criteria and sinus radiography-guided treatment in the third column. Patients with a positive test result receive antibiotic treatment, whereas those with a negative test result receive symptomatic treatment only. The likelihood of treatment is thus determined by the sensitivity and specificity of the tests.
).The Markov process is a recursive process where patients' health states change during each cycle of the process. Each cycle can represent a given length of time (in our model, a day) and the cycles can be repeated for a set number of times (in our model, for 14 days) or until no further changes in health state occur.
In our model, potential initial states of health for any given day are shown by the ovals in the top row. A cohort of patients enters the model on the first day in the initial state of health (in our model, sick without antibiotic side-effect symptoms). In each cycle of the model, a probability exists of transition from one health state to another (for example, from sick without side-effect symptoms to sick with side-effect symptoms or to cure without side-effect symptoms). The possible health states at the end of each cycle are represented in the bottom row. In our model, the initial and final health states for each cycle are the same. The possible transitions that can be made from initial to final health state in each cycle are represented by the arrows. The proportion of patients moving from a given initial health state to a final health state in each cycle is determined by the probabilities of various events occurring during the cycle (in our model, the probability of cure and of side effect). These probabilities of transitions in health state can vary from cycle to cycle.
,
are: sick without side-effect symptoms, sick on the first day of
side-effect symptoms, sick on the second day of side-effect
symptoms, sick after having had side-effect symptoms, cured without
side-effect symptoms, cured on the first day of side-effect
symptoms, cured on the second day of side-effect symptoms, and cured
after having had side-effect symptoms. The multiple health states
involving side-effect symptoms exist to account for the assumptions
that side effects last 2 days and can occur only once per course.
Transition possibilities are limited by the model assumptions. The entire cohort of patients start in the "sick, no side effect" state. During the first cycle, they have a probability of remaining sick without antibiotic side effect, remaining sick and starting the first day of side-effect symptoms, being cured with no side effect, and being cured but starting the first day of side-effect symptoms.
In subsequent cycles, the following possibilities can occur:
Sick patients may be cured.
Patients who currently have had no side effects may enter the first day of side effects.
Patients currently in the first day of side effects must enter the second day of side effects (though those who are sick may simultaneously be cured).
Patients currently in the second day of side effects must enter the sick or cured "post-side-effect" state (in which they no longer have side-effect symptoms).
Patients currently in a post-side-effect state (sick or cured) remain in a post-side-effect state (sick patients may simultaneously be cured).
Cured patients remain in a cured health state.
| Variable | Base Case Value | Sensitivity Analysis (range) | Reference | |||||
|---|---|---|---|---|---|---|---|---|
| Probabilities | ||||||||
| Sinusitis (prevalence) | 50% | 0-100% | Kuusela, 1982; Laine, 1998; van Buchem, 1995 | |||||
| Antibiotic side effect | Bigby, 1986; Saxon, 1987; | |||||||
| (over whole course) | 5% | 0-20% | Lin, 1992; Caldwell, 1974 | |||||
| (per day) | 0.35% | 0-1.3% | Expert opinion | |||||
| Complication | ||||||||
| (with amoxicillin) | 0% | - | Assumption | |||||
| (without amoxicillin) | 0.01% | - | See text | |||||
| Cure of acute bacterial
rhinosinusitis on amoxicillin at: | ||||||||
| Weibull | ||||||||
| Base | Slow cure | Fast cure | Linear | Exponential | Reference | |||
| Day 3 | 2% | 1% | 3% | 17% | 26% | Lindbaek, 1996 | ||
| Day 7 | 24% | 14% | 32% | 41% | 51% | |||
| Day 10 | 54% | 35% | 66% | 64% | 64% | |||
| Day 14 | 87% | 68% | 95% | 76% | 76% | |||
| Cure of acute bacterial
rhinosinusitis on symptomatic treatment at: | ||||||||
| Weibull | ||||||||
| Base | Slow cure | Fast cure | Linear | Exponential | Reference | |||
| Day 3 | 0% | 0% | 1% | 9% | 15% | Lindbaek,1996 | ||
| Day 7 | 5% | 1% | 9% | 22% | 31% | |||
| Day 10 | 15% | 4% | 25% | 31% | 42% | |||
| Day 14 | 41% | 25% | 55% | 43% | 53% | |||
| Cure of symptoms if no acute
bacterial rhinosinusitis at: | ||||||||
| Weibull | ||||||||
| Base | Slow cure | Fast cure | Linear | Exponential | Reference | |||
| Day 3 | 35% | 17% | 66% | 18% | 32% | Expert | ||
| Day 7 | 61% | 32% | 81% | 42% | 60% | opinion | ||
| Day 10 | 74% | 40% | 86% | 60% | 63% | |||
| Day 14 | 84% | 51% | 90% | 84% | 84% | |||
| Cost | ||||||||
| Variable | Base Case Value | Sensitivity analysis (range) | Reference | |||||
| Low | High | |||||||
| Treatment | ||||||||
| Amoxicillin | $15 | - | $100 | Red Book, 1997 | ||||
| Symptomatic therapy 1 | $0 | plus estimated | ||||||
| pharmacy cost | ||||||||
| Diagnostic tool | ||||||||
| Sinus radiography | $103 | Maximum | ||||||
| allowable fees, | ||||||||
| Adverse events | ||||||||
| Side effect, per day | $25 2 | $65 3 | See notes | |||||
| Disease complication | $10,000 | Expert opinion | ||||||
| Disease outcome (at end of 14-day course) | ||||||||
| Cure | $0 | |||||||
| Sick Strategy: | ||||||||
| Symptomatic treatment | $70 4 | - | $155 5 | See notes | ||||
| Empirical amoxicillin | $155 5 | - | $258 6 | See notes | ||||
| Sinus radiography | (negative reading→no treatment) | |||||||
| or Clinical exam | $70 4 | - | $155 5 | See notes | ||||
| Sinus radiography | (positive reading→treatment) | |||||||
| or Clinical exam | $155 5 | - | - | See notes | ||||
| Variable | Base Case Value | Reference | ||||||
| Utilities | ||||||||
| Symptom free days | ||||||||
| Disease complication | 0 | Definition | ||||||
| Cure without side effect symptoms (Symptom-free day) | 1.0 | |||||||
| Cure with side effect symptoms | 0 | " | ||||||
| Sick without side effect symptoms | 0 | " | ||||||
| Sick with side effect symptoms | 0 | " | ||||||
| Quality adjusted days | ||||||||
| Disease complication | 0 | Expert opinion | ||||||
| Cure without side effect symptoms (Symptom-free day) | 1.0 | 0.7 | " | " | ||||
| Cure with side effect symptoms | 0.7 | " | " | |||||
| Sick without side effect symptoms Mild rhinosinusitis symptoms | 0.75 | 0.525 | " | " | ||||
| Sick with side effect symptoms Mild rhinosinusitis symptoms | 0.525 | " | " | |||||
| Sick without side effect symptoms Moderate rhinosinusitis symptoms | 0.50 | " | " | |||||
| Sick with side effect symptoms Moderate rhinosinusitis symptoms | 0.35 | 0.35 | " | " | ||||
| Sick without side effect symptoms Severe rhinosinusitis symptoms | 0.25 | " | " | |||||
| Sick with side effect symptoms Severe rhinosinusitis symptoms | 0.175 | 0.175 | " | " | ||||
It is assumed that all patients will receive symptomatic treatment; thus, there is no additional cost to symptomatic treatment.
50 percent return office visit, treatment of side effect symptoms and change antibiotics to folate inhibitor
50 percent return office visit, treatment of side effect symptoms and change antibiotics to new, expensive antibiotic
Return office visit and amoxicillin or folate inhibitor
Return office visit and new, expensive antibiotic
Return office visit, sinus radiograph and new, expensive antibiotic
As for the multiple-strategies comparison model, we used a prevalence of 50 percent. We varied the prevalence from 0 to 100 percent in the sensitivity analysis.
We used the same estimates for radiography test performance that were used in the multiple-strategies comparison model. These assumed that a sinus radiograph is read as positive for acute bacterial rhinosinusitis if there is "sinus fluid or opacity of mucous membrane thickening." For the sensitivity analysis, we used the lower bounds of the 95 percent confidence interval limits of the random effects pooled results and the idealized situation of perfect sensitivity and specificity.
We used the same estimates for test performance of applying a set of clinical criteria to diagnose acute rhinosinusitis that was used in the multiple-strategies comparison model. These used a "Berg score" of three or more as described above (Berg and Carenfelt, 1988). For sensitivity analysis, we used an estimate of lower test performance from expert opinion.
As in the first model, we assumed a high disease complication rate of 1/10,000 for patients not treated with antibiotic. To further bias the model toward treatment to prevent complications, we assumed a disease complication rate of 0 for patients treated.
As in the first model, we used an estimate of 5 percent for drug allergies for the entire 14-day course. As we assumed that the risk of side effects was constant during the whole course of treatment, the daily risk of side effect was 0.35 percent. In the sensitivity analysis, the risk of side effect was varied from 0 to 20 percent (or a daily risk of 0 to 1.3 percent).
Note: For comparison, point estimates and 95
percent confidence intervals are shown at day 12 for
treatment meta-analysis estimates of cure at day 10-14.
with their
respective fitted Weibull curves. For comparison, the point
estimates and 95 percent confidence intervals for the proportion of
patients cured from our meta-analyses of amoxicillin and placebo are
included.
To test the stability of the conclusions under varying assumptions, sensitivity analyses of the daily cure rates were performed using Weibull curves fit to the upper and lower 95 percent confidence intervals of the Lindbaek Kaplan-Meier survival curves.
In addition, we ran the model with different assumptions as to the form of the cure-rate curve. We tested a linear function, y = 1-m·d (where m is the slope of the line). From each trial with an amoxicillin or placebo arm, we fit a line to the proportion cured on the final day reported. The slope, m, is the weighted average (by trial size) of the slopes of the fitted lines.
We also tested an exponential curve,y = e -µ·d (where µ describes the slope of the curve). Again, µ is a weighted average of the µ values from fitting an exponential curve to the final day data point from each of the studies.
| Weibull | Linear | Exponential | ||
|---|---|---|---|---|
| λ | α | m | µ | |
| Acute bacterial rhinosinusitis | ||||
| Placebo | ||||
| Lindbaek, 1996 | 5.618X10-5 | 3.467 | 0.0227 | 0.0376 |
| Lower 95% CI | 1.133X10-7 | 5.587 | - | - |
| Upper 95% CI | 2.933X10-4 | 2.993 | - | - |
| Amoxicillin | ||||
| Lindbaek, 1996 | 1.064X10-3 | 2.848 | 0.0579 | 0.1132 |
| Lower 95% CI | 5.746X10-4 | 2.880 | - | - |
| Upper 95% CI | 1.250X10-3 | 2.939 | - | - |
| Non-acute bacterial rhinosinusitis | ||||
| Base Estimate | 0.1160 | 1.111 | 0.0600 | 0.1309 |
CI = confidence interval
In the baseline symptom-duration model, all days with symptoms (whether due to rhinosinusitis or to antibiotic side effect) and disease complication were treated equivalently. Each day that a patient was in the cured state without side-effect symptoms has a value of one (1); those who were either sick or had side-effect symptoms on that day had a value of zero (0). Patients who developed a disease complication were assigned a value of zero (0) for the whole 2 weeks. Thus the assumption was made that the quality of life on all days with rhinosinusitis symptoms prior to cure was equally as undesirable as a day with disease complication, rhinosinusitis symptoms, and antibiotic side-effect symptoms or side-effect symptoms alone.
Mild symptoms reduce quality of life (to a value of 0.75) to a lesser degree than do symptoms of a major antibiotic side effect (0.7).
Moderate symptoms reduce quality of life to the same degree as having no improvement in the multiple-strategies comparison model (to a value of 0.5).
Severe symptoms reduce quality of life to a greater degree (to a value of 0.25) but to a lesser degree than disease complication.
The quality adjustment for side-effect symptoms is that of major side effects (0.7).
The quality adjustment for disease complication is set at zero (0) to maximally bias the conclusions toward treatment to avoid disease complications.
At the conclusion of each cycle, the percentage of patients in each health state is multiplied by the outcome utility associated with that state and the values are summed across the various health states (e.g., 50% X 0.5 [for Sick No Side Effect] + 5% X 0.5 X 0.7 [for Sick with Side Effect] + 45% X 1 X 0.7 [for Cured No Side Effect] + 0% X 1 X 0.7 [for Cured with Side Effect] = 0.5825). In the model, this number represents the average quality of life of patients on a given day. In the symptom-free-day scenario, it represents the proportion of patients on a given day who are symptom-free. The daily proportions are then summed together across all days. This final outcome utility represents the number of quality-adjusted healthy days or the average number of symptom-free days during the 14 days that the given strategy implies. When symptom-free days are calculated, the average number of days to symptom-free state is simply 14 minus the number of symptom-free days.
The costs of amoxicillin treatment, symptomatic treatment, and sinus radiograph are the same as described in the multiple-strategies comparison model.
The total cost of an antibiotic side effect is the sum of the costs of treatment for the side effect and of switching to a folate-inhibitor. As the side-effect symptoms are assumed to last for 2 days, the daily cost is one-half the total cost.
The cost of disease complication includes the total costs of hospitalization including surgery, intravenous antibiotics, and so on. The actual figure used is from consensus expert opinion.
| Prevalence of acute bacterial rhinosinusitis = 50% | Cost per patient | Symptom-free days 1 | Cost per symptom-free day 1 | Marginal cost-effectiveness |
|---|---|---|---|---|
| Symptomatic treatment | $25.11 | 5.02 | $5.01 | |
| Clinical criteria guided treatment | $25.38 | 6.30 | $4.03 | $0.21/Sx-free day |
| Empirical antibiotic treatment | $37.10 | 6.58 | $5.64 | $42.36/Sx-free day |
| Radiography guided treatment | $132.02 | 6.44 | $20.52 | Dominated |
over 14 days
Sx-free day = symptom-free day
| Mild symptoms of rhinosinusitis | (utility of "sick" = 0.75) | |||
|---|---|---|---|---|
| Prevalence of acute
bacterial rhinosinusitis = 50% | ||||
| Cost per patient | Quality-adjusted days1 | Cost per symptom-free day1 | Marginal cost-effectiveness | |
| Symptomatic treatment | $25.11 | 12.02 | $2.09 | |
| Clinical criteria guided treatment | $25.38 | 12.20 | $2.08 | $1.52/Sx-free day |
| Empirical antibiotic treatment | $37.10 | 12.23 | $3.03 | $378.03/Sx-free day |
| Radiography guided treatment | $132.02 | 12.21 | $11.26 | **** |
| Symptom duration model,quality-adjusted symptom-days | ||||
| Moderate symptoms of rhinosinusitis | (utility of "sick" = 0.5) | |||
| Prevalence of acute
bacterial rhinosinusitis = 50% | ||||
| Cost per patient | Quality-adjusted days1 | Cost per symptom-free day1 | Marginal cost-effectiveness | |
| Symptomatic treatment | $25.11 | 9.68 | $2.59 | |
| Clinical criteria guided treatment | $25.38 | 10.23 | $2.48 | $0.49/Sx-free day |
| Empirical antibiotic treatment | $37.10 | 10.35 | $3.58 | $98.07/Sx-free day |
| Radiography guided treatment | $132.02 | 10.29 | $12.83 | **** |
| Symptom duration model,quality-adjusted symptom-days | ||||
| Severe symptoms of rhinosinusitis | (utility of "sick" = 0.25) | |||
| Prevalence of acute
bacterial rhinosinusitis = 50% | ||||
| Cost per patient | Quality-adjusted days1 | Cost per symptom-free day1 | Marginal cost-effectiveness | |
| Symptomatic treatment | $25.11 | 7.35 | $3.42 | |
| Clinical criteria guided treatment | $25.38 | 8.27 | $3.07 | $0.29/Sx-free day |
| Empirical antibiotic treatment | $37.10 | 8.48 | $4.37 | $56.34/Sx-free day |
| Radiography guided treatment | $132.02 | 8.37 | $15.77 | **** |
1 over 14 days
Q-adj day = quality-adjusted day
Whether symptom-free days or quality-adjusted days with mild, moderate, or severe symptoms are estimated, the effectiveness of empiric antibiotic treatment, clinical criteria-guided treatment, and radiography-guided treatment were very similar. These strategies outperform symptomatic treatment because of the latter's high rate of failure to cure. However, in the scenario of mild rhinosinusitis symptoms (where rhinosinusitis symptoms are milder than symptoms of antibiotic side effect) all strategies yield similar estimates of effectiveness.
At a 50 percent acute bacterial rhinosinusitis prevalence, the cost per patient seen was least for those given symptomatic treatment alone. Because of the cost of amoxicillin for all patients, empiric treatment was somewhat more costly. The cost of clinical criteria-guided treatment was only slightly higher than symptomatic treatment. It was less costly than empiric treatment because the cost of "excess" amoxicillin given to all patients without acute bacterial rhinosinusitis was greater than the cost of the few patients with acute bacterial rhinosinusitis left untreated because of inaccurate clinical criteria. Because of its high cost compared with amoxicillin, sinus radiography-guided treatment is by far the costliest strategy. (Note that the cost per patient is independent of the outcome utility or the severity of disease symptoms.)
At the given prevalence of 50 percent, clinical criteria-guided treatment is the most cost-effective strategy in all the given scenarios. This strategy incurs no additional up-front cost, yields fewer treatment failures and disease complications than symptomatic treatment alone, yet avoids the additional cost and lessened effectiveness due to additional antibiotic side effects in patients who do not have acute bacterial rhinosinusitis. However, as the severity of a patient's rhinosinusitis symptoms lessen, the cost-effectiveness of symptomatic treatment alone improves, such that with mild and moderate disease symptoms the cost-effectiveness of symptomatic treatment and clinical criteria-guided treatment are very similar.
Note: Effectiveness measured in symptom-free
days.
and
Table 23. The marginal
cost-effectiveness for the other scenarios is shown in
Table 24.
Although for each scenario symptomatic treatment is the least costly, it is also the least effective. As the cost of clinical criteria-guided treatment is only slightly greater than symptomatic treatment and is more effective, the marginal cost-effectiveness (the additional cost required of the second strategy compared with the first to achieve an additional unit of effectiveness) is small. Empiric antibiotic use, on the other hand, achieves greater effectiveness but at a much greater cost.
As radiography-guided treatment is both less effective than symptomatic treatment and more costly, it is eliminated by strict dominance.
The more severe the rhinosinusitis symptoms, the smaller the marginal cost-effectiveness of both clinical criteria-guided treatment and empiric treatment.
Note: Tx = treatment
Note: Tx - treatment
to 30.
.
for mild,
moderate, and severe rhinosinusitis symptoms. The milder the
symptoms, the closer the relative effectiveness is and the
greater the absolute value of the quality-adjusted symptom days.
Note: Tx - treatment
,
the cost per patient of radiography-guided treatment rises with
increased prevalence, as the proportion of patients being
treated (and thus having side effects), and also not being cured
and having disease complications rises. At no prevalence is
sinus radiography-guided treatment less costly than the other
strategies.
The cost of empiric treatment rises only minimally with increasing prevalence as the cost of treatment and side effects are stable and only the proportions of uncured patients and disease complications rise; however, these proportions remain relatively low as all patients are being treated.
The cost of symptomatic treatment rises rapidly with increasing acute bacterial rhinosinusitis prevalence. This is because of the increasing percentage of patients with acute bacterial rhinosinusitis who are not being cured and thus require a return office visit and the patients who are developing disease complications (at a higher rate than if they were treated). The cost of clinical criteria-guided and radiography-guided treatment rises rapidly with increasing prevalence, since at higher prevalence, there is increased use of amoxicillin which includes increased side effects and an increased overall rate of disease complication and treatment failures.
At acute bacterial rhinosinusitis prevalence below 24 percent, symptomatic treatment per patient is least costly. Clinical criteria-guided treatment is least costly from 24 to 91 percent. Thereafter, empiric treatment is least costly. However, the costs of symptomatic and clinical criteria-guided treatment are very similar at lower prevalence, as are the costs of empiric treatment and clinical criteria-guided treatment at high prevalence.
. For each strategy, as the prevalence of acute
bacterial rhinosinusitis rises, the cost increases (as a result
of the increased persistence of symptoms requiring followup, the
increased rate of disease complications, and the increased use
of antibiotics in the test-guided strategies) and the
effectiveness decreases (as a result of the longer duration of
symptoms and the likelihood of disease complications with acute
bacterial rhinosinusitis than without). Thus the value of the
cost-effectiveness rises for each strategy with increased
prevalence. (Note that the lower the value, in dollars per
symptom-free or quality-adjusted day, the more cost effective
the strategy.)
In the symptom-free-day scenario, the cost-effectiveness of symptomatic treatment and clinical criteria-guided treatment are similar across the range of prevalence. Symptomatic treatment is more cost effective (fewer dollars per symptom-free day) below a prevalence of 25 percent. Clinical criteria-guided treatment is the most cost effective at a prevalence between 25 and 83 percent. Empiric treatment is most cost effective at prevalence above 83 percent.
| Symptomatic treatment | Clinical criteria | Empirical criteria | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Base case scenarios | |||||||||
| Mild symptoms | <49% | 49% | - | 97% | >97% | ||||
| Moderate symptoms | <39% | 39% | - | 94% | >94% | ||||
| Severe symptoms | <31% | 31% | - | 90% | >90% | ||||
| Symptom-free days | < 25% | 25% | - | 83% | >83% | ||||
| Low clinical criteria Test performance | |||||||||
| Mild symptoms | <73% | 73% | - | 93% | >93% | ||||
| Moderate symptoms | <62% | 62% | - | 88% | >88% | ||||
| Severe symptoms | <51% | 51% | - | 81% | >81% | ||||
| Symptom-free days | <42% | 42% | - | 73% | >73% | ||||
| Faster cure with amoxicillin Slower cure without amoxicillin | |||||||||
| Mild symptoms | <11% | 11% | - | 81% | >81% | ||||
| Moderate symptoms | <11% | 11% | - | 79% | >79% | ||||
| Severe symptoms | <10% | 10% | - | 76% | >76% | ||||
| Symptom-free days | <9% | 9% | - | 71% | >71% | ||||
| Slower cure with amoxicillin Faster cure without amoxicillin | |||||||||
| Mild symptoms | 0% | - | 100% | - | |||||
| Moderate symptoms | 0% | - | 100% | - | |||||
| Severe symptoms | 0% | - | 100% | - | |||||
| Symptom-free days | 0% | - | 100% | - | |||||
| Slower cure with amoxicillin Base Case rate of cure without amoxicillin | |||||||||
| Mild symptoms | 0% | - | 100% | - | |||||
| Moderate symptoms | 0% | - | 100% | - | |||||
| Severe symptoms | 0% | - | 100% | - | |||||
| Symptom-free days | < 86% | 86% | - | 95% | > 95% | ||||
| Risk of antibiotic side effect = 0% | |||||||||
| Mild symptoms | < 36% | 36% | - | 95% | > 95% | ||||
| Moderate symptoms | < 30% | 30% | - | 92% | > 92% | ||||
| Severe symptoms | < 26% | 26% | - | 88% | > 88% | ||||
| Symptom-free days | < 21% | 21% | - | 81% | > 81% | ||||
| Risk of antibiotic side effect = 20 % | |||||||||
| Mild symptoms | 0% | - | 100% | - | - | - | - | ||
| Moderate symptoms | < 71% | 71% | - | 98% | > 98% | ||||
| Severe symptoms | < 49% | 49% | - | 93% | > 93% | ||||
| Symptom-free days | < 37% | 37% | - | 87% | > 87% | ||||
| Initial use of new, expensive antibiotic | |||||||||
| Mild symptoms | 0% | - | 100% | - | - | ||||
| Moderate symptoms | 0% | - | 100% | - | - | ||||
| Severe symptoms | 0% | - | 100% | - | - | ||||
| Symptom-free days | 0% | - | 100% | - | - | ||||
Lowering the test performance (sensitivity and specificity) of the clinical criteria test shrank the range of prevalence in which using clinical criteria to discriminate between those who should be treated symptomatically and those who should be given amoxicillin.
We used the extremes of the 95 percent confidence intervals for the Kaplan-Meier curves of cure rate with and without amoxicillin from the Lindbaek, Hjortdahl, and Johnsen (1996a) study. In one scenario, we assumed amoxicillin is maximally more effective than placebo (or symptomatic treatment) by using the high cure rate estimate for amoxicillin and the low cure rate estimate for placebo. This scenario implies that empiric treatment is most cost effective at lower prevalence than the base case scenario at high prevalence and that symptomatic treatment is most cost effective only at very low prevalence.
The opposite assumption, that the cure rate with amoxicillin is more similar to that of placebo resulted in the conclusion that symptomatic treatment, although not always most effective, is most cost effective across the full range of prevalence, no matter the severity of disease.
To reproduce the effect of antibiotic resistance, we lowered the cure rate with amoxicillin and left that of placebo at its base level. Again, symptomatic treatment was most cost effective across prevalence for disease severity-adjusted outcome. This is because of the lessened effectiveness of the antibiotic. Only if the goal of treatment is the minimization of any symptom is clinical criteria-guided treatment or empiric antibiotic treatment cost effective at very high prevalence.
If the risk of antibiotic side effects is nil (as opposed to 5 percent in the base case scenario), then use of antibiotics becomes more cost effective as costs (of treating side effects) are lower and effectiveness is higher (as outcome utility is not decreased for any patients because of side effects). The range of prevalence in which both clinical criteria-guided treatment and empiric treatment are most cost effective shift downward somewhat.
If the risk of antibiotic side effect is very high (at 20 percent), then symptomatic treatment is always most cost effective in mild disease (where the symptoms of rhinosinusitis are less severe than those of side effect would be). The range of prevalence in which both clinical criteria-guided treatment and empiric treatment are most cost effective shift upward and, as in all scenarios, the more severe the symptoms (in comparison to the quality of life of having a side effect), the more cost-effective the use of antibiotics becomes.
Because of the high cost of treatment, symptomatic treatment for mild and moderate disease is most cost effective across the range of prevalence. Even for rhinosinusitis with severe symptoms, the cost-effectiveness of symptomatic treatment is greatest until very high prevalence. Empiric treatment with amoxicillin ranges in cost-effectiveness from approximately $2 to $5 per quality-adjusted day (across the full range of prevalence and in all base case scenarios). Our hypothetical expensive antibiotic meanwhile ranges in cost-effectiveness from $4 to $20 per quality-adjusted day.
The model was also tested using linear and exponential functions instead of the Weibull function to describe the change in daily cure rate (as described above). Although there were small quantitative differences in the costs, effectiveness, and cost-effectiveness thresholds, qualitatively the results were the same (data not shown). The Weibull function more closely describes the biology of infectious diseases (Kalbfleisch and Prentice, 1980) and more closely fits the Kaplan-Meier curves from Lindbaek's trial (1996a) than do linear or exponential functions. Therefore, we believe that the results from the Markov model using the Weibull function are more robust, and that the results from models using the other curves can be disregarded.
EPC/Project Director: Joseph Lau, MD
Project Manager: Deirdre Devine, M.Lit
Assistant Project Director: Deborah Zucker, MD, PhD
Statistician: Norma Terrin, PhD
Research Associate: Priscilla Chew, MPH
Technical Editor: Thomas A. Lang, MA
Research Assistant: David Liu, BA
AHCPR NRSA Research Fellows: Eric A. Engels, MD, MPH; Ethan Balk, MD
Michael Barza, MD
Infectious Diseases, New England Medical Center (NEMC)
Michael S. Benninger, MD
Otolaryngology, Henry Ford Hospital
American Academy of Otolaryngology-Head and Neck Surgery
Larry Culpepper, MD
Family Medicine, Boston Medical Center
American Academy of Family Physicians
Aidan Long, MD
Allergy, NEMC
Anne Meneghetti, MD
Blue Cross and Blue Shield of Massachusetts
Rosalie Phillips, MPH
Tufts Managed Care Institute
Eli Rebeiz, MD
Otolaryngology, NEMC
Carol Sakala, PhD, MSPH
Educational Development Center, Inc.
Ellen R. Wald, MD
Pediatric Infectious Diseases, University of Pittsburgh
American Academy of Pediatrics
John W. Williams, Jr., MD,MHS
Internal Medicine, South Texas Veterans Health Care System
American College of Physicians
John B. Wong, MD
Decision/Cost-effectiveness Analysis, NEMC
Gladys Luna
Lucy T. Porro
American Academy of Family Physicians
American Academy of Otolaryngology-Head and Neck Surgery
American Academy of Pediatrics
American College of Physicians
Ethan Balk, MD
NRSA Research Fellow
Division of Clinical Care Research
New England Medical Center
Michael Barza, MD
Professor of Medicine
Chairman, Division of Infectious Diseases and Geographical Medicine
Tufts University School of Medicine
Michael S. Benninger, MD
Immediate Past Chair, Board of Governors
Board of Directors
American Academy of Otolaryngology-Head and Neck Surgery
President, American Rhinologic Society
Chairman, Department of Otolaryngology-Head & Neck Surgery
Henry Ford Hospital
Priscilla Chew, MPH
Research Associate
New England Medical Center EPC
Larry Culpepper, MD
Professor and Chairman
Department of Family Medicine
Boston University Medical Center
Deirdre DeVine, M.Lit
Project Manager, New England Medical Center EPC
Administrator, New England Cochrane Center
Division of Clinical Care Research
New England Medical Center
Eric Engels, MD, MPH
NRSA Research Fellow
Division of Clinical Care Research
New England Medical Center
Carla T. Herrerias, BS, MPH
Program Manager
Division of Quality Care
American Academy of Pediatrics
Susan Elaine Sedory Holzer, MA
Director of Outcomes Research
American Academy of Otolaryngology-Head and Neck Surgery Foundation
One Prince Street
Alexandria, VA 22314
Joseph Lau, MD
Director, New England Medical Center EPC
Director, New England Cochrane Center
Associate Professor of Medicine
Tufts University School of Medicine
Aidan Long, MD
Assistant Professor of Medicine
Tufts University School of Medicine
David Liu, BA
Research Assistant
New England Medical Center EPC
Gladys Luna
Waltham, MA
Anne Meneghetti, MD
Assistant Professor of Medicine
Tufts University School of Medicine
Adjunct Instructor of Medicine
Boston University School of Medicine
Director of Medical Policy
Blue Cross and Blue Shield of Massachusetts
Rosalie Phillips, MPH
Executive Director
Tufts Managed Care Institute
Lucy Porro
South Boston, MA
Eli Rebeiz, MD
Associate Professor of Otolaryngology
Director, Head and Neck Cancer Surgery
Department of Otolaryngology
Tufts University School of Medicine
Carol Sakala, PhD, MSPH
Senior Scientist
Center for Applied Ethics and Professional Practice
Norma Terrin, PhD
Statistician, New England Medical Center EPC
Associate Professor of Medicine
Tufts University School of Medicine
Ellen R. Wald, MD
Professor of Pediatric and Otolaryngology
Interim Chairperson, Department of Pediatrics
Chief, Division of Allergy, Immunology and Infectious Diseases
University of Pittsburgh School of Medicine
Children's Hospital of Pittsburgh
John W. Williams, Jr., MD, MHS
Associate Professor of Medicine
South Texas Veterans Health Care System
University of Texas Health Science Center - San Antonio
John B. Wong, MD
Associate Professor of Medicine
Tufts University School of Medicine
Chief, Division of Clinical Decision Making, Medical Informatics, and Telemedicine
New England Medical Center
Deborah Zucker, MD, PhD
Assistant Professor of Medicine
Tufts University School of Medicine
The evidence report partner organizations nominated individuals to participate in the peer review of the evidence report. Additional individuals with appropriate methodologic and clinical expertise were identified by the EPC. Two reviewers chose to remain anonymous. Review of the evidence report by these individuals does not represent endorsement of the report. We are grateful to the peer reviewers for generously offering their time and participation.
Hanan Bell, PhD
Co-director, AAFP-University of Washington
Clinical Policy Program
Alfred Berg, MD, MPH
Professor and Associate Chair
Department of Family Medicine
University of Washington
Charles Driscoll, MD
Chair, Commission on Clinical Policy and Research
American Academy of Family Physicians
Douglas Long, MD
West Endfield, ME
William Phillips, MD, MPH
Clinical Professor
Department of Family Medicine
University of Washington School of Medicine
Jack Anon, MD
Associate Clinical Professor
University of Pittsburgh College of Medicine
Department of Otolaryngology
Chairman, Rhinology and Paranasal Sinus Committee
American Academy of Otolaryngology-Head and Neck Surgery
James Hadley, MD
Clinical Associate Professor of Surgery (Otolaryngology)
University of Rochester Medical Center
Donald Leopold, MD
Director of Rhinology
Otolaryngology-Head and Neck Surgery
Johns Hopkins Outpatient Center
Robert Naclerio, MD
Professor and Chief
Sinus Disease/Pediatric Otolaryngology
University of Chicago, Pritzker School of Medicine
William Clayton Bordley, MD, MPH
Assistant Professor of Pediatric and Emergency Medicine
University of North Carolina, Chapel Hill
Michael Marcy, MD
Clinical Professor of Pediatrics
University of California, Los Angeles
Anne-Marie Audet, MD, MSc, SM
Associate Director for Quality Improvement
MassPRO
Preston Winters, MD
White Plains, NY
Rowena Dolor, MD
Director, Primary Care Research Consortium
Duke Clinical Research Institute
Thomas Hines, MD
Acting Chief, Division of Family Medicine
Tufts University School of Medicine
Jack Lasche, Jr., MD
Chief of Pediatrics
Harvard Vanguard Medical Associates
Pamela McInnes, DDS, MSc(Dent)
Chief, Respiratory Diseases Branch
National Institute of Allergy and Infectious Diseases
Jay Piccirillo, MD
Assistant Professor of Otolaryngology, Medicine, and Occupational Therapy
Director, Clinical Outcomes Research
Washington University School of Medicine
David Samson
Associate Director
Technology Evaluation Center
Evidence-based Practice Center
Blue Cross Blue Shield Association
Helena Varonen, MD
Stakes, National Research and Development Center for Welfare and Health
Helsinki, Finland
David Witsell, MD
Assistant Professor
Division of Otolaryngology-Head and Neck Surgery
Duke University Medical Center
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