Patients with refractory chronic rhinosinusitis, by definition, have persistent, poorly controlled symptoms and objective inflammatory findings despite prior medical and surgical therapy. These patients represent a diagnostic and treatment challenge given the complexity of the underlying disease factors and the limitations in available management options. This article presents a practical framework for clinical evaluation and treatment. Germane to discussion are emerging concepts in refractory chronic rhinosinusitis that will likely have important implications in the near future.
Key points
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A multidisciplinary and broad approach is required in the diagnostic evaluation of refractory CRS encompassing patient, environmental, and disease-related factors.
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Treatment of refractory CRSwP requires complete polyp removal and establishment of wide sinus openings to facilitate the postoperative delivery of topical corticosteroids.
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Treatment of refractory nonpolypoid CRS involves surgery to maximize sinus ventilation and drainage, using systemic or topical antibiotics or other adjunctive agents to minimize symptoms.
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A variety of emerging diagnostic and treatment pathways will likely improve management of CRS in the near future.
| AERD | Aspirin-exacerbated respiratory disease |
| CF | Cystic fibrosis |
| CRS | Chronic rhinosinusitis |
| CRSwP | Chronic rhinosinusitis with polyposis |
Introduction
As the understanding of chronic rhinosinusitis (CRS) has evolved from a monomorphic “infection” to a group of distinct inflammatory entities so too has the approach to clinical evaluation and treatment. The need for an individualized approach to diagnosing and managing the possible variables that may have initiated the condition or spurred its persistence is becoming increasingly evident. This is especially true for individuals with refractory CRS. To elucidate the underlying pathophysiologic factors involved in a given patient, a list of several potential host and initiating events may be identified. Additionally, in patients with refractory CRS, the disease course itself may compound the primary infection and contribute to perpetuation of inflammatory injury. Given this dynamic interplay between patient and disease variables, continued investigation and re-diagnosis of the relevant contributing factors is necessary throughout the lifespan of CRS. This article provides a practical approach to diagnostic evaluation and treatment considerations in refractory CRS. Integral to this discussion is an understanding of emerging concepts and future directions.
Introduction
As the understanding of chronic rhinosinusitis (CRS) has evolved from a monomorphic “infection” to a group of distinct inflammatory entities so too has the approach to clinical evaluation and treatment. The need for an individualized approach to diagnosing and managing the possible variables that may have initiated the condition or spurred its persistence is becoming increasingly evident. This is especially true for individuals with refractory CRS. To elucidate the underlying pathophysiologic factors involved in a given patient, a list of several potential host and initiating events may be identified. Additionally, in patients with refractory CRS, the disease course itself may compound the primary infection and contribute to perpetuation of inflammatory injury. Given this dynamic interplay between patient and disease variables, continued investigation and re-diagnosis of the relevant contributing factors is necessary throughout the lifespan of CRS. This article provides a practical approach to diagnostic evaluation and treatment considerations in refractory CRS. Integral to this discussion is an understanding of emerging concepts and future directions.
Diagnostic evaluation of refractory chronic rhinosinusitis
General Principles
The approach to the clinical assessment of a patient with refractory CRS differs from that of routine CRS in several ways. The patient’s prior history including disease course and treatment response is typically extensive. Additionally, the various etiologic issues may have evolved throughout the CRS history resulting in the emergence of CRS-related factors that may not have been initially present. Examples of this include osteitic bony changes and biofilm-producing bacteria. Therefore, a broad and comprehensive approach to diagnosis is imperative.
Patient History
Obtaining a complete medical history of a patient with refractory CRS is often time-consuming and complex. Symptom review encompasses the common sinonasal and related symptoms including nasal congestion, rhinorrhea or postnasal drip, facial pressure or pain, and disturbance in sense of smell or taste. Otologic, pulmonary, and general symptoms (fatigue, malaise, sleep disturbance) may also be present. Severity, duration, change over time, variability, associated modifying factors, and treatment response are assessed. A variety of sinonasal and general quality-of-life measures have been well described and are commonly used in clinical research. Although their role as a diagnostic tool and as an assessment of severity compared with a “normal” population have not been well defined, these tools are sensitive to change in symptom severity in a given individual and therefore have utility to establish a baseline quality-of-life score that can be followed during the course of the disease. The commonly used 22-item Sinonasal Outcome Test addresses multiple domains of sinonasal quality of life including rhinologic symptoms, extranasal rhinologic symptoms, ear/facial symptoms, psychological dysfunction, and sleep dysfunction. The following past medical history should be carefully reviewed including the primary medical record whenever possible in addition to the patient’s narrative report:
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Prior treatment modalities including a list of medications and surgical interventions with dates, durations, compliance, tolerance, and symptom response.
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Prior objective tests including laboratory tests, imaging studies, pathology results, and culture results. For imaging studies, the radiologist report and actual images should be reviewed.
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The medical records of prior treating otolaryngologists and associated medical specialties. Because most patients with refractory CRS have a prior history of sinus surgery, this also includes prior surgical reports.
Clinical Examination
Clinical evaluation of patients with refractory CRS encompasses routine otolaryngologic examination and a detailed endoscopy of the sinonasal cavity. Inspection of the ear, pharynx, and larynx and auscultation of the chest may elucidate extranasal manifestations of CRS given the common occurrence of multisystem dysfunction. Anterior rhinoscopy is performed to examine the position of the nasal septum, inflammatory changes of the inferior turbinate, patency of the nasal airway, and possible inflammatory changes of the nasal mucosa. Nasal endoscopy is performed systematically to examine the nasal cavity; middle meatal structures; sphenoethmoid recess; nasopharynx; and, in postoperative patients, the paranasal sinus cavities. A combination of flexible and rigid endoscopes (straight and angled) is used for a complete examination. Endoscopy allows for visualization of inflammatory changes and outflow tract patency and, when performed on subsequent occasions, fluctuations in disease severity. Debridement, management of postoperative synechia and stenosis, and obtaining mucopurulent secretions for culture are also integral to the care of patients with CRS. Future applications of nasal endoscopy may include attainment of material for additional diagnostic tests (eg, biofilm, microbiome). Finally, multiple reporting measures and grading systems have been described for nasal endoscopy. These measures are largely used in clinical research without a well-defined role in routine patient care. To date, the ability to correlate nasal endoscopy findings to patient symptom scores remains limited, as does the interrater agreement of nasal endoscopy interpretation. A greater degree of nasal endoscopy standardization is necessary.
Imaging
The role of imaging in patients with refractory CRS is multifold and is divided into structural and disease-related findings. Non-contrast computed tomography with fine cuts through the paranasal sinuses with bony windowing is the standard protocol for sinusitis evaluation. Soft tissue windowing can help differentiate various opacification patterns (eg, fungal findings). A systematic approach is used and includes triplanar radiographic evaluation of sinonasal anatomy, presence of anatomic variants, and patency of outflow tracts. In patients with a prior history of sinus surgery, postsurgical changes are also reviewed including patency of surgical sinusotomies, position and integrity of the middle turbinate, and completeness of the surgical changes. Disease assessment includes the extent, pattern, and severity of inflammatory changes, and presence of pathognomonic sinusitis variants (eg, allergic fungal sinusitis, odontogenic infection, osteitis) ( Fig. 1 ). Review of prior studies is useful in determining the evolution of the inflammatory changes. MRI is considered in patients with complex soft tissue pathology and in patients with extension of inflammatory changes beyond the paranasal sinuses (eg, orbit and skull base). Various radiographic grading scores, including the Lund-Mackay scale, are available and are routinely reported in clinical research. Additional assessment of sinus opacification relative to sinus pneumatization may improve the accuracy of radiographic scoring. However, correlation of radiographic severity with patient symptom scores and the utility of these measures for clinical care are limited.
Microbiology
The role of pathogenic bacteria and fungi varies and may include acting as the primary initiating or perpetuating disease factor in certain CRS subtypes. Alternatively, pathogenic organisms may have no significant role, or a limited role, in other CRS phenotypes including various polypoid variants. The interpretation of microbiologic data is based on the broader clinical, radiographic, and if available, pathology findings. In refractory CRS patients with presumed infectious component, cultures of mucopurulent secretions obtained with endoscopic visualization allow for specific assessment of speciation, antibiotic sensitivity, and directed medical therapy. Additionally, identification of specific bacterial pathogens may suggest the presence of biofilm and superantigens. Repeat cultures following treatment and throughout acute flare-ups are also useful given the fluctuations in the paranasal sinus microbiology.
Pathology
The histopathologic findings in most patients with CRS undergoing surgery are reported as nonspecific inflammatory changes. In patients with polypoid CRS, a more specific inflammatory pattern including eosinophilic tissue changes or allergic fungal sinusitis changes may be noted. Quantification of tissue eosinophilia may hold prognostic information, although this has not been fully defined. Other specific CRS variants including osteitis, fungal CRS subtypes, and odontogenic CRS may be discernable on pathology. In these types of cases, direct communication with the pathologist regarding clinical considerations facilitates diagnosis. It is likely that a greater degree of sophistication in histopathologic analysis in the future will convey more specific diagnostic information in patients with CRS.
Host, Environmental, and Disease Cofactors
As reviewed in Table 1 , there is an ever-expanding list of host, environmental, and disease-related factors. Although some of these pathophysiologic factors have a specific clinical phenotypic presentation and associated diagnostic test, several have an incompletely understood impact and several lack a clinically available diagnostic test. In many instances, meaningful feedback regarding the active pathophysiologic factors is attained from assessment of treatment response. It is likely that several cofactors may exist in a patient with CRS, especially refractory disease, including patient, environmental, and disease factors. The decision to pursue an extensive multidisciplinary evaluation and specialized testing for possible cofactors is individualized and may be especially indicated in patients with a suggestive clinical presentation and in patients with refractory disease.
| Disease Factor | Diagnostic Test |
|---|---|
| Patient host factor | |
| Anatomic variants, structural outflow tract obstruction | Nasal endoscopy, computed tomography scan |
| Primary immune deficiency | Total immunoglobulin levels, immunoglobulin subclass levels, specific antibody deficiency ( Streptococcus pneumonia ), complete blood count |
| Primary ciliary dysmotility | Ciliary morphology, ciliary beat frequency testing, genetic testing |
| Cystic fibrosis | Sweat chloride testing, genetic testing |
| Gastroesophageal reflux | Esophagogastroduodenoscopy, dual pH probe, treatment trial with medical therapy |
| Genetic predisposition | Family history, no commercially available test |
| Primary vasculitis/autoimmune disorder | Rheumatology evaluation, serology, tissue biopsies |
| Environmental factors | |
| Allergic rhinitis | Allergy testing (skin prick, radioallergosorbent test), treatment trial with medical therapy, nasal mucous IgE (not commercially available) |
| Toxin exposure | Patient history of occupational exposures, tobacco exposure, illicit drug use, intranasal medication use |
| Microbiologic factors | |
| Pathogenic microbiology | Middle meatus/sphenoethmoid/paranasal sinus cavity culture with endoscopic visualization when off antibiotics Include aerobe, anaerobe, fungus, and acid-fast bacillus testing |
| Biofilm | No commercially available test, more likely with specific bacteria ( Staphylococcus aureus , Pseudomonas aeruginosa ), treatment trial with topical surfactant therapy |
| Superantigen | No commercially available test, more likely with specific bacteria ( S aureus ) |
| Fungal infection subtypes (fungus ball, allergic fungal sinusitis, chronic invasive fungal sinusitis, granulomatous fungal sinusitis) | Patient factors (immune status), radiographic and nasal endoscopy findings, pathology and culture results |
| Specific infection/inflammatory patterns | |
| Odontogenic infection | Typical inflammatory radiographic pattern (unilateral, disproportionate involvement of maxillary sinus), radiographic evidence of odontogenic pathology, dental evaluation |
| Chronic sinusitis with osteitis | Radiographic evidence of osteitis, more common in postoperative patients |
| Aspirin exacerbated respiratory disease (Samter triad) | Severe refractory polypoid CRS, known history of asthma and aspirin (non-steroidal anti-inflammatory) reaction |
| Allergic fungal sinusitis | Characteristic imaging findings, presence of allergic mucin, presence of noninvasive fungal elements, atopy to fungi, polypoid CRS, minor Bent-Kuhn criteria |
| Disruption of the normal sinonasal microbiome | No clinically available test |
Chronic Rhinosinusitis Phenotypes
CRS is increasingly understood as a group of inflammatory disorders each with unique pathophysiologic factors and phenotypes. As the ability to subclassify CRS expands, an individualized approach to diagnosis is becoming increasingly possible. CRS classification is based on several different variables. Summating these variables for a given patient creates a deeper description of the specific CRS subtype. To date, although treatment options remain limited and applied similarly across multiple different phenotypes, more precise treatment pathways will likely be described based on specific disease factors in an algorithmic manner. The different variables used to classify CRS are reviewed in Table 2 .
| Disease Factor | Examples of Variants |
|---|---|
| Time frame |
|
| Microbiology |
|
| Pattern of inflammatory response |
|
| Presence of identifiable initiating event | History of known events (eg, odontogenic infection, initial upper respiratory tract infection event) |
| Presence of identifiable host predisposition | See Table 1 (eg, known immune dysregulation, ciliary dysfunction, obstructive anatomy) |
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