Sinusitis is inflammation of the membrane that lines the facial sinuses. Sinusitis is most often due to infection, usually spread from the nose. The maxillary and ethmoidal sinuses are most commonly affected. Sinusitis may cause pressure, headache, facial pain, and a feeling of fullness in the affected area; there may also be fever, a stuffy nose, and loss of the sense of smell. A common complication is the formation of pus, causing pain and nasal discharge.
Synonyms are: Acute rhinosinusitis, Acute sinusitis, Chronic rhinosinusitis, Chronic sinusitis, Recurrent acute rhinosinusitis, Rhinosinusitis, and Subacute rhinosinusitis
Treatment of sinusitis is usually by steam inhalations and a decongestant, but in some cases antibiotics may be necessary. If sinusitis persists despite treatment, surgical drainage of the affected sinuses may be performed.
Note: In 1996, the Task Force on Rhinosinusitis, which included representatives from the American Academy of Otolaryngology- Head and Neck Surgery, the American Academy of Otolaryngic Allergy, and the American Rhinologic Society, recommended the term rhinosinusitis replace the more commonly used term sinusitis.
Sinusitis (or rhinosinusitis) in detail - technical
As noted above, in 1996, the Task Force on Rhinosinusitis, recommended the term rhinosinusitis replace the more commonly used term sinusitis.
Rhinitis is the term used to define inflammation of the nasal cavity. Likewise, sinusitis is the term for inflammation of the paranasal sinuses. Inflammation of the nasal cavity usually precedes and accompanies inflammation of the paranasal sinuses. For this reason, the term rhinosinusitis is preferred (Lanza and Kennedy 1997).
The 2009 Summary Health Statistics for U.S. Adults National Health Interview Survey notes that over 29.3 million adults in the United States reported physician diagnosed rhinosinusitis. This represents 12.6% of the US population. Of those reporting rhinosinusitis, the diagnosis is nearly twice as common in women (18.8 million) versus men (10.6 million). Rhinosinusitis occurs at approximately rates in age groups 18–44 years (11.3 million) and 45–64 years (12.8 million). Far fewer cases are reported over 65 years (5.1 million).
With regard to race and ethnicity, people reporting rhinosinusitis were overwhelmingly white (24.4 million, 83.3%). Blacks or African-Americans comprised 3.5 million (11.9%), and other races comprised the remaining 4.8% (Pleis et al. 2009). It is estimated that 30–40% of patients with strong symptomatology of chronic rhinosinusitis (CRS) have no objective evidence of rhinosinusitis on computerized tomography (CT) of the sinuses or sinonasal endoscopy. Therefore, research definitions of rhinosinusitis require objective documentation of rhinosinusitis by nasal endoscopy or CT (Stankiewicz and Chow 2002; Bhattacharrya 2006; Bhattacharrya and Lee 2010).
Although many classifications of rhinosinusitis exist, most categorizations are based on duration of symptoms. As initially proposed by the 1996 Task Force on Rhinosinusitis, based on expert opinion and subsequently endorsed by the 2007 American Academy of Otolaryngology Clinical Practice Guidelines for Acute Sinusitis, acute rhinosinusitis (ARS) is defined as symptoms present for 4 weeks or less. CRS is defined as presence of symptoms for at least 12 weeks. The intervening period of symptoms greater than 4 weeks but less than 12 weeks is defined as subacute rhinosinusitis. Finally, recurrent acute rhinosinusitis is defined as four or more episodes of acute rhinosinusitis within a 12-month period, with complete resolution of symptoms between episodes (Lanza and Kennedy 1997; Rosenfeld et al. 2007a).
Common symptoms of rhinosinusitis include nasal obstruction or nasal congestion, mucoid or purulent nasal discharge, decreased sense of smell, facial pain or pressure, and postnasal drainage. Fever, cough, fatigue, headache, halitosis, dental pain, sore throat, ear pain, and aural fullness may also accompany rhinosinusitis. Of these, the symptoms of nasal obstruction, purulent nasal discharge, and facial pressure or pain are referred to as cardinal symptoms. This is based upon the increased sensitivity and specificity of these three symptoms for acute bacterial sinusitis, especially when present for at least 7–10 days (Rosenfeld et al. 2007a; Pearlman and Conley 2008).
In rare cases, ARS or CRS may progress beyond the paranasal sinus cavities to involve the orbit, intracranial structures, or facial soft tissues. Symptoms of potential orbital complication of rhinosinusitis include orbital pain, blurred or decreased vision, double vision, or visual field deficits, while physical findings include swelling or erythema of the eyelids, proptosis, impaired vision, or ocular mobility. Symptoms and signs of potential intracranial complications include severe headache, photophobia or phonophobia, altered level of consciousness or altered mental status, seizures, or unilateral neurologic complaints. Facial swelling or erythema may indicate soft tissue spread from rhinosinusitis. Finally, severe maxillary dental pain with associated gingival swelling may represent involvement of maxillary rhinosinusitis with a tooth root, although it is more common for the etiology of bacterial maxillary sinusitis associated with upper tooth pain to be odontogenic in origin (Table 1).
The remainder of a patient’s history may provide important information about predisposition or contributors to rhinosinusitis. Chronic medical conditions associated with rhinosinusitis, though not causal, include allergic rhinitis, asthma or other pulmonary conditions, and systemic inflammatory conditions such as sarcoidosis or Wegener’s granulomatosis. In addition, medical conditions or medications that suppress the immune system may predispose to rhinosinusitis, such as hematologic malignancies, bone marrow or solid organ transplants, chemotherapy, or other immunosuppressive medications for inflammatory conditions like rheumatoid arthritis.
Prior nasal or facial trauma, especially with placement of implants, prior nasal or sinus surgery, or prior nasal intubation or instrumentation may be risk factors for persistent or recurrent rhinosinusitis. Aspirin intolerance associated with nasal polyposis, and frequently, asthma is termed aspirin exacerbated respiratory disease and is occasionally referred to eponymously as Samter’s triad or aspirin hypersensitivity syndrome. The relationship of cigarette smoking or exposure to tobacco smoke to rhinosinusitis is controversial, although exposure to cigarette smoke does delay mucociliary clearance.
While a strong history of acute symptoms is useful in diagnosing ARS, it does not specifically differentiate between a cold and acute bacterial rhinosinusitis (ABRS) (Fig. 1). For CRS, a strong history of sinus symptoms is only successful in correct identification of presence of inflammation in the sinuses, independent of role of bacteria in 60–70% of cases. Therefore, nasal endoscopy and anterior rhinoscopy are critical in the objective verification of rhinosinusitis, with the added advantage of permitting endoscopically obtained cultures of purulent material (to be discussed subsequently). Prior to topical nasal decongestion, anterior rhinoscopy may reveal edema of the nasal mucosa, inferior turbinate enlargement, anterior septal deviations, generalized mucosal irritation, or even frank purulence.
The application of topical nasal decongestants and anesthetics usually allow a comfortable examination of the posterior nasal cavity, nasopharynx, middle meatus, and sphenoethmoid recess with nasal endoscopy. On nasal endoscopy, particular attention may be paid to evidence of nasal polyposis, mucosal edema, hyperemia, purulent drainage, or more posterior septal deviations and spurs. Endoscopically guided culture of purulent drainage from the middle meatus or sinus ostia may guide future antibiotic therapy. Endoscopically guided culture is sensitive and accurate for diagnosing acute bacterial rhinosinusitis (Benninger et al. 2006). In patients who have undergone prior sinus surgery, flexible endoscopy frequently permits evaluation of the floor of the maxillary sinuses for evidence of mucosal edema or purulence as well as a more thorough evaluation of other sinus cavities.
Oropharyngeal evaluation may reveal thick, colored, or clear postnasal drainage or signs of erythema around the gums and tooth roots or carious dentition. Crowding of the oropharynx may lead one to suspect possible obstructive sleep apnea, a common comorbidity in patients with nasal blockage. Tenderness to percussion over the maxillary or frontal areas is a nonspecific sign for rhinosinusitis and frequently presents in patients with fibromyalgia without objective evidence of rhinosinusitis. Ophthalmologic evaluation should note presence of impaired acuity, mobility, proptosis, erythema, or swelling. Ocular abnormalities may be present acutely, as in impending orbital infectious complications or an insidious finding from silent sinus syndrome (enophthalmos from an atelectatic maxillary sinusitis) or a mucocele of the frontal or ethmoid sinuses.
In patients with suspected pulmonary complications or associations, such as asthma, auscultation of the lungs should be included in the physical examination. A suspicion of intracranial complication of rhinosinusitis should prompt a thorough neurological examination.
In most cases, ARS will be treated by a primary care or urgent care provider. The vast majority of ARS in adults are viral, with concomitant pathogenic nasopharyngeal, bacterial presence in around 25% of cases. Regardless of viral or bacterial cause, the natural history of ARS in most cases is one of spontaneous resolution, although antibiotic therapy does speed resolution of symptoms in patients with a nasopharyngeal bacterial association (Puhakka et al. 1998; Kaiser et al. 2001; Lacroix et al. 2002). In 2009, Wald and colleagues demonstrated superiority of amoxicillin clavulanate over placebo in time to resolution of sinusitis symptoms; however, it is telling that over 1,000 children with URI symptoms were screened in order to enroll 56 children symptomatic enough to qualify for the trial. So antibiotics are effective, but only in highly screened or culture-positive patients (Wald et al. 2009).
In the event that the patient is seen by an otolaryngologist or other provider with training in nasal endoscopy, endoscopically guided culture of purulent secretions in the middle meatus have 80.9% sensitivity, 90.5% specificity, and 87.0% overall accuracy for diagnosis of bacterial pathogens in acute bacterial rhinosinusitis (Benninger et al. 2006). Even a nasopharyngeal swab in adults predicts the correct bacteria on maxillary sinus tap in ARS in 98% of patients. Although, even when the tap was negative, 50% of patients still had nasopharyngeal pathogens (Savolainen et al. 1987).
Imaging studies are not recommended initially in the setting of uncomplicated ARS. If a complication of ARS or extrasinus extension is suspected or if an alternative diagnosis is being considered, such as sinonasal neoplasm, sinus computed tomography (CT) is the usual imaging study of choice. In rare situations, in which the diagnosis of ARS is in question, a negative sinus CT can be valuable in reassuring the clinician and patient that sinusitis is not present. Since a sinus CT is positive for mucosal thickening in up to 80% of patients with a cold, it is not helpful in distinguishing bacterial from viral illness acutely.
In cases of CRS, altered bacterial flora is common (Niederfuhr et al. 2009). Endoscopically guided sinonasal culture may be helpful in choosing antibiotic therapy in the setting of CRS, although the exact role of bacteria in the pathogenesis of CRS continues to be debated. In general, coagulasenegative staphylococcus, diptheroids, strep viridians, and alpha hemolytic strep are discounted as pathogens. The role Staphylococcus aureus and Pseudomonas aeruginosa play in CRS is more controversial, and usually moderate to heavy growth on culture is required as a prerequisite for directing either systemic or topical antimicrobial therapy. Acute pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, and Moraxella catarrhalis frequently represent acute exacerbations of CRS. Cultures resulted in changes in therapy in almost 50% of patients with CRS and acute exacerbations of CRS (Cincik and Ferguson 2006).
Either skin testing (prick or intradermal methods) or in vitro assessment of specific IgE is useful in the complete evaluation of patients with CRS associated with allergic symptoms, nasal polyposis, or suspicion of allergic fungal rhinosinusitis (AFRS). Although all patients with CRS do not require allergy testing or immunotherapy, allergies cause symptoms often mistaken for CRS and should be treated when present in the sufficiently symptomatic patient with or without CRS. Up to 15% of patients with strong histories of exposure-induced allergic rhinitis symptoms may have negative in vitro tests or skin testing yet positive nasal provocation. Conversely, patients can have positive allergy testing and seemingly no symptoms on exposure to that particular antigen. Therefore, allergy testing results are useful as a guide but are not the definitive answer regarding presence or absence of allergies (Van Cauwenberge 2002). Food allergy is associated with CRS with nasal polyps in several small studies, while the role of inhalant allergy and nasal polyps is much less clear (Fokkens et al. 2007).
Plain radiographs or x-rays have been used in the past for the diagnosis of rhinosinusitis. The typical sinus x-ray series consists of a lateral view, a posterioranterior or Caldwell view, and occipitomental or Waters’ view. Plain-film sinus x-rays are easy to obtain, have a low radiation dose (1.4 cGy for each film), are inexpensive, and have relatively high sensitivity (67%) and specificity (87%) for diagnosing maxillary sinusitis. However, the sensitivity of plain x-rays for diagnosing ethmoid, sphenoid, and frontal sinusitis is much lower (Batra 2004; Konen et al. 2000). At this time, plain x-rays of the sinuses are not recommended for routine diagnosis of acute or chronic rhinosinusitis.
Although routine imaging of uncomplicated ARS is typically not indicated, sinus CT is the imaging modality of choice, obtained in patients who are still symptomatic despite directed medical therapy and in whom sinus surgery is being considered. A sinus CT is only a picture in time, and assessment of chronic symptoms by CT should be obtained at baseline and not during an acute flair such as a cold. Other indications for sinus CT are the puzzling patient, who is not responding to medical therapy, and the patient with an impending complication. Sinus CT is also superior to panorex or plain dental films in identifying dental pathology such as a periapical abscess which may be driving the maxillary sinusitis. In the recent past, standard sinus CT scans were obtained in the coronal plane with 3-mm slice thickness. Most facilities have now transitioned to CT image acquisition in the axial plane at 0.5– 1.0 mm slice thickness with triplanar reconstructions formatted from the axial data set. Obtaining images in this manner is also necessary when the CT data set is planned for use in image guidance systems during sinus surgery.
First, the bony anatomy of the paranasal sinuses is best assessed on CT scan. This includes size and configuration of each of the sinus cavities, presence of any paranasal sinus variant cells that may contribute to sinus ostia narrowing, and any bony erosion or discontinuities of the sinus walls. Evaluation of soft tissue densities on sinus CT scan includes air-fluid levels within the sinus cavities, paranasal sinus mucosal thickening, presence of polyps or soft tissue masses, and assessment of the heterogeneity of paranasal sinus secretions. In addition, any extrasinus extension of paranasal sinus pathology may also be preliminarily assessed on sinus CT scan. If extrasinus extension of paranasal sinus disease is suspected, obtaining the sinus CT scan with iodinated contrast is often helpful for improved diagnosis (Lanza and Kennedy 1997; Rosenfeld et al. 2007a; Batra 2004).
The Lund-Mackay system is commonly used to classify the extent of sinus disease on CT scan with respect to the sinus involved and the degree of opacification of each sinus (Lund and Mackay 1993). The Lund-Mackay CT grading system or the Zinreich method is useful in clinical practice and in the rhinology research setting. This system allows standardization of the radiologic extent of paranasal sinus disease for improved communication among care providers. CT scan is more costly and delivers an increased dose of radiation (5–6 cGy) compared to plain x-ray. If dental pathology is of primary concern, a cone beamdental CT may provide exquisite bony detail of dentition and abnormalities missed on panorex, with a radiation dosage significantly less than that of a sinus CT, although a bit more than a panorex.
Magnetic resonance imaging
Magnetic resonance imaging (MRI) is not routinely performed for uncomplicated ARS or CRS. However, the superb soft tissue differentiation of gadolinium-enhanced MRI scanning may be extremely useful for evaluation of intracranial or orbital extension of paranasal sinus disease. Intracranial or intraorbital abscesses, phlegmon, or mucoceles extending from the sinus cavities will be well characterized on MRI scan. MRI is recommended for complete evaluation of neoplasms and suspected encephaloceles and meningoencephaloceles (Table 2).
The differential diagnosis is guided primarily by time course. Most patients with less than 4 weeks of symptoms have a cold. Without a culture, this is virtually indistinguishable from an acute bacterial infection. Discolored drainage can occur in both entities. In both conditions, the natural history is usually one of spontaneous resolution within 4 weeks.
For patients with chronic symptoms, the diagnosis of presence of sinus inflammation remains in question until confirmed by imaging or endoscopy since so many conditions cause symptoms mistaken for CRS. Conditions that mimic CRS and are often contributors to CRS include allergic and non allergic rhinitis, anatomic nasal obstruction, headache (including migraine), facial pain syndromes, maxillary dental infection and pathology, obstructive sleep apnea, laryngopharyngeal reflux, and rarely, sinonasal tumors. A detailed and directed history and physical examination will frequently provide clues to the correct diagnosis, augmented by imaging studies in refractory patients.
Typical allergic symptoms include itchy or watery eyes, nasal congestion, nonpurulent rhinorrhea, sneezing, itchy throat, wheezing, coughing, or other asthma symptoms. Patients with perennial symptoms manifested with unchanging nasal congestion or postnasal drainage may be much less aware of possibility of allergies as cause. Testing for perennial allergens such as mold or dust mite hypersensitivity can occasionally be quite helpful in directing pharmacotherapy, environmental controls, or immunotherapy in these patients. Allergic rhinitis alone does not routinely have persistent purulent nasal drainage, significant facial pain or pressure, headache, or dental pain. Both allergy testing and sinus CT may be useful in such patients. Allergy testing is helpful for confirming diagnosis and directing avoidance and immunotherapy, and sinus CT, for excluding sinusitis in the refractory allergic rhinitis patient.
Symptoms of nonallergic rhinitis also include rhinorrhea and nasal irritation. However, the ocular, throat, skin, and pulmonary symptoms associated with allergic rhinitis are not typically seen in nonallergic rhinitis. Nonallergic rhinitis may be associated with triggers such as eating, weather changes, hormonal changes, pregnancy, and certain medications. As with allergic rhinitis, nonallergic rhinitis is not typically associated with purulent rhinorrhea or significant headache or facial pain. Some subset of nonallergic rhinitis may be due to allergies without systemic IgE presence. Presence of nasal eosinophilia in the absence of allergies is termed nonallergic rhinitis with eosinophilia (NARES) and is usually remarkably responsive to topical steroid management. NARES probably represents the nasal form of the continuum of eosinophilic mucin rhinosinusitis without fungus (EMRS) (Ferguson 2000). The role of allergy in nonfungal EMRS is unclear and may represent mechanisms discussed below, such as superantigen immunomodulation.
Anatomic nasal obstruction
Causes for anatomic nasal airway obstruction not associated with sinusitis or nasal polyps include nasal septal deviation and inferior turbinate hypertrophy, although large middle turbinate concha bullosa may cause similar symptoms. Thorough physical examination and nasal endoscopy is usually sufficient to diagnose anatomic nasal obstruction. Nasal congestion and nasal airway obstruction are the primary complaints. Symptoms may be unilateral or bilateral. Again, purulent rhinorrhea, significant headache, and localizing facial pain or pressure are typically absent.
Headache and facial pain
“Sinus headache” and “sinus pain” are extremely common complaints seen in the otolaryngology clinic and are more commonly seen in patients without evidence of rhinosinusitis than in patients with rhinosinusitis. While the differential diagnosis of facial pain and headache does include rhinosinusitis, more common causes include migraine or tension headache, morning frontal headache caused by obstructive sleep apnea, temporomandibular joint disease, and dental pathology, among others. In the setting of headache or facial pain without true rhinosinusitis, purulent rhinorrhea will typically be absent. However, nasal congestion may be present, particularly recumbently in the patient with OSA. Frequency, duration, character, and location of the pain are important elements of the history and will often be helpful in determining the etiology of the pain. In addition to appropriate rhinologic examination, careful oral cavity and neurologic examination should be performed as well. Finally, imaging studies should be strongly considered if the history and physical examination do not solidify the diagnosis or the patient fails to respond to directed therapy. Any severe new onset headache accompanied by systemic signs such as nausea and disequilibrium should have prompt neurological consultation or MRI.
Symptoms of sinonasal tumors often include nasal obstruction, occasional mucoid drainage, facial pressure, and intermittent epistaxis. These symptoms do have some overlap with rhinosinusitis. However, sinonasal tumors will routinely cause unilateral symptoms, as opposed to bilateral symptoms commonly seen with rhinosinusitis. Any cranial nerve dysfunction or severe pain should alert the physician to the possibility of neoplasm. On physical examination and nasal endoscopy, a unilateral mass is often seen. Biopsy of the mass will reveal the true pathology. Of note, imaging studies, such as CT and MRI scans, are recommended prior to consideration of biopsy so that the extent and origin of the mass can be determined. In addition, meningoencephalocele should be ruled out by imaging as this can also present with unilateral nasal mass and should not be biopsied. Finally, due to the propensity for hemorrhage, practitioners will often elect to perform biopsy of sinonasal masses in the operating room.
The pathophysiology of ARS is largely infectious, with viral infection accounting for the greatest proportion of ARS. Implicated viral pathogens include rhinovirus, adenovirus, and influenza and parainfluenza viruses, with rhinovirus being the most commonly isolated pathogen in studies of community-acquired ARS (Meltzer et al. 2004; Gwaltney 1996). As an example of viral pathophysiology in ARS, the sequence of rhinovirus infection has been described. Rhinovirus particles enter the nose on a contaminated solid substance or via airborne particles. Mucus transports the virus to the adenoid region, where it attaches to the receptor intercellular adhesion molecule 1 (ICAM-1).
Within hours, viral replication and inflammatory reaction is seen, leading to common symptoms of viral ARS such as rhinorrhea, nasal obstruction, and sore throat (Meltzer et al. 2004). Nose blowing has been demonstrated to increase intranasal pressure and likely contributes to the transmission of viral particles to the paranasal sinuses during viral ARS (Gwaltney et al. 2000). During acute viral rhinosinusitis, changes of mucosal thickening and fluid have been identified on sinus CT scan within all of the paranasal sinus cavities, including the maxillary sinus (87%), ethmoid sinus (67%), sphenoid sinus (39%), and frontal sinus (32%) (Gwaltney et al. 1994). Based upon this information, viral ARS, or the common cold, can be truly considered rhinosinusitis due to the involvement of the paranasal sinus cavities and the nasal cavity. The clinical course of the symptoms of the common cold is shown in Fig. 1.
Bacterial infection occurs in 2% or less of ARS cases, based on survey data from the 1960s. Up to 25–30% of adults have pathogenic bacteria present in their nasopharynx during a cold and are significantly more symptomatic than patients without bacterial presence (Puhakka et al. 1998). However, up to 21% of all the antibiotics prescribed for adults are for acute bacterial rhinosinusitis (Meltzer et al. 2004; Anon et al. 2004; Rosenfeld et al. 2007b; Sharp et al. 2007). Various mechanisms may contribute to bacterial infection in ARS. Mucosal edema can obstruct the drainage of sinus ostia. In addition, mucociliary function and mucus clearance is inhibited in the setting of inflammation (Dykewicz and Hamilos 2009).
In the absence of infection, the paranasal sinuses are thought to be sterile. However, many bacteria colonize the nasal cavity and nasopharynx. This normal flora includes coagulase-negative staphylococci, Staphylococcus aureus, Corynebacterium species, Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae (Gwaltney 1996; Meltzer et al. 2004). S. pneumoniae is the most common bacterial isolate in both adults and children with bacterial ARS. H. influenzae is also common in adults and children, and the possibility of b-lactamase-producing organisms should be kept in mind. Other isolates in bacterial ARS include M. catarrhalis, Streptococcus species, S. aureus, and anaerobes.
In contrast to the largely infectious etiology of ARS, many of the recent concepts of the pathophysiology of CRS are based in chronic inflammation. Inflammation is a series of processes that occur on a cellular and molecular level with the goal of reacting to foreign agents and repairing tissue damage. In ARS and CRS without nasal polyposis, neutrophilic inflammatory infiltrates predominate, whereas eosinophilic inflammatory infiltrates tend to predominate in CRS with nasal polyposis (Meltzer et al. 2004). The potential underlying causes of inflammation in CRS are numerous, and this condition is often multifactorial. Noninflammatory contributors to CRS also include autonomic dysfunction, deficiencies of mucociliary clearance, and systemic conditions such as reflux of gastric acid (Meltzer et al. 2004). Below, highlighted are some of the more commonly implicated pathophysiologic factors in CRS. This list, however, is by no means exhaustive. Ongoing research into CRS pathophysiology will continue to expand our knowledge of this process.
Bacterial infection versus colonization
While many previously considered CRS to represent persistent bacterial infection unresponsive to medical therapy, the precise role of bacteria in CRS is currently disputed. In bacterial culture studies of CRS, some of the most frequently isolated organisms are coagulase negative staphylococci, S. aureus, and viridans streptococci. Gram-negative enteric rods are also commonly isolated, including Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, and Escherichia coli. In addition, anaerobic bacteria have also been identified in cultures from CRS patients. There is notable heterogeneity among CRS culture studies. For example, isolation of anaerobic bacteria in CRS ranges from 0% to 100% in various studies, with numbers in between. Possible reasons for such discordance in bacterial culture results include culturing techniques, failure to quantify bacterial isolates, evaluation of coincident inflammatory response, use of antibiotics at the time of and/or prior to culture, and presence of nasal polyps. The role of bacteria in CRS remains unclear. Bacteria, when present in CRS, may contribute to the chronic inflammation as causal organisms or may be simply be mucosal colonizers (Meltzer et al. 2004).
Biofilms are associated with bacterial organisms, fungal organisms, or both and consist of colonies of microorganisms surrounded by a glycocalyx. Biofilms form on solid surfaces, which may be biologic or nonbiologic. In the biofilm state, organisms have a reduced metabolic rate, are less susceptible to antimicrobials and host inflammatory defenses, and are more difficult to isolate on culture. Periodically, organisms will leave the biofilm state in a mobile, or planktonic, state. In the planktonic state, the organisms are more susceptible to antimicrobial therapy. Biofilms have been identified on specimens taken from CRS patients at the time of surgery (Sanclement et al. 2005). Some recent studies have indicated that the presence of bacterial biofilms at the time of surgery was significantly associated with persistent postoperative inflammation after sinus surgery (Hochstim et al. 2010). Although current knowledge of biofilms in CRS is expanding, further research is necessary before the role of biofilms in the pathophysiology of CRS is fully elucidated.
CRS cases are often associated with thickened paranasal sinus bone. This bony thickening, frequently referred to as “osteitis” or “osteoneogenesis,” may be seen surrounding the paranasal sinus cavities, along the skull base and lamina papyracea, and involving the ethmoid partitions. Bony changes may be identified on CT scan in the bone-window algorithm or noted during surgery for CRS. Bone remodeling has also been verified pathologically in patients undergoing surgery for CRS (Kennedy et al. 1998; Lee et al. 2006). A recent prospective study which was undertaken to develop a global osteitis scoring scale found that among CRS patients, severity of osteitis was correlated with prior sinus surgery, Lund-Mackay score, and symptom duration (Georgalas et al. 2010). Bacterial organisms are not identified within pathologic bony specimens obtained during endoscopic sinus surgery; the precise role of bone in the development or perpetuation of the CRS inflammatory state has not been fully determined (Meltzer et al. 2004).
The production of exotoxins or enterotoxins by bacterial or fungal organisms has been documented in CRS. Enterotoxins cross-link antigen presenting cell MHC II molecules with the T-lymphocyte receptor variable beta region, thus directly activating T lymphocytes without classical antigen presentation. This process allows activation of significantly more T lymphocytes versus classical pathways (Meltzer et al. 2004). An example of the role of superantigens in CRS is demonstrated by examining S. aureus superantigens in nasal polyposis. In patients with IgE to S. aureus enterotoxin, total polyp IgE is correlated with elevated IL-5 and eosinophil cationic protein. Patients with aspirin-sensitive nasal polyposis have increased IL-5, eosinophil cationic protein, total IgE, and S. aureus enterotoxin specific-IgE versus aspirin-tolerant nasal polyp samples and controls. Further, lymphoid organizations with B cells, T cells, plasma cells, and IgE to S. aureus enterotoxins have been demonstrated in nasal polyp tissue specimens (Gevaert et al. 2005; Perez-Novo et al. 2004; Bachert et al. 2001). These observations indicate that bacterial and/or fungal enterotoxins acting as superantigens likely play a role in disease modification in some types of CRS, especially in the setting of nasal polyposis.
Sensitivity to environmental allergens has a clear association with symptoms of rhinitis. However, the relationship of environmental allergy with rhinosinusitis is less clear. Perennial allergic rhinitis is associated with ARS, and seasonal allergic rhinitis is a risk factor for ARS orbital complications in children (Berrettini et al. 1999; Holtzmann et al. 2001). In nonpolypoid CRS, eosinophilic inflammation and Th2 cytokine profiles are more commonly seen in allergic patients, whereas neutrophilic inflammation and mixed Th1/Th2 cytokine profiles are seen in those without allergy (Demoly et al. 1997; Ghaffar et al. 1998). When undertaking treatment of environmental allergy concomitant with nonpolypoid CRS, it is typically advocated that allergy treatment be targeted toward allergy symptoms. Controlling allergy symptoms will likely help in the overall care and quality of life of the patient with CRS and allergy.
In the setting of CRS with nasal polyposis, systemic environmental allergy is found in 55.5% of patients (Settipane and Chafee 1977). Similar to CRS without polyps, allergy treatment aimed to control allergy symptoms should be of benefit in the care of patients with allergic polypoid CRS. It should be noted that in some cases of nasal polyposis with weak or negative systemic allergy testing, elevated levels of antigenspecific IgE have been detected in nasal polyp homogenates (Suh et al. 2002; Sheahan et al. 2010). Some suggest that local tissue production of antigenspecific IgE plays a significant role in nasal polyp pathophysiology and local symptomatology. Local IgE production may account for a certain proportion of patients previously thought to be nonallergic at the systemic level.
The role of fungi in the pathophysiology of CRS has been one of the most debated issues in the last decade. In 1999, Ponikau et al. reported that 96% of CRS patients had positive fungal cultures, with a mean of 2.7 organisms per patient (Ponikau et al. 1999). However, 100% of control patients also had positive fungal organisms on culture and a mean of 2.3 organisms per patient. These results indicate that fungal colonization of the sinonasal cavities is common in the presence and absence of CRS. Fungi are ubiquitous and fungal spores have the ability to proliferate in sinonasal mucus. This sinonasal fungal colonization may result in saprophytic growth visible on intranasal crusts or fungus balls present in obstructed sinus cavities (Meltzer et al. 2004). Saprophytic fungal growth and fungus balls are both treated by removal and debridement.
One special case of fungal involvement in CRS is allergic fungal rhinosinusitis (AFRS), which consists of a noninvasive, noninfectious, intense inflammatory sinonasal process. The most rigid diagnosis of AFRS requires histological evidence of noninvasive fungi in eosinophilic mucin, along with demonstration of atopy to cultured fungus. Associated clinical findings which usually accompany AFRS were outlined in 1994 by Bent and Kuhn and include type I IgE-mediated hypersensitivity, nasal polyposis, characteristic CT scan findings, eosinophilic mucin without fungal invasion, and positive fungal stain (Bent and Kuhn 1994). Positive systemic allergy testing is commonly demonstrated to both fungal and nonfungal antigens. Specific immunotherapy has been advocated as part of the treatment paradigm for AFRS, with improvement in symptoms, sinus mucosal stage, and reduction in the use of steroid medications (Folker et al. 1998).
Characteristic CT scan findings of AFRS include asymmetric paranasal sinus involvement, heterogeneous paranasal sinus signal intensity, and bony expansion or erosion of the paranasal sinus walls (Meltzer et al. 2004). On pathologic examination, allergic mucin, or eosinophilic mucin, is defined by eosinophilia, fungal hyphae, and Charcot-Leyden crystals. Along a theoretical continuum that includes AFRS, other entities have been described. Eosinophilic fungal rhinosinusitis has been proposed to describe the situation in which the presence of fungi leads to eosinophilic inflammation in sinonasal tissues, but IgE-mediated allergy is absent (Ponikau et al. 1999). Alternatively, Ferguson has described EMRS as a systemic dysregulation of immunological controls (Ferguson 2000). Patients with EMRS do not demonstrate fungal elements on pathology, but there is a higher association with asthma, aspirin sensitivity, and IgG1 deficiency.
Another fungal rhinosinusitis entity that deserves special mention is invasive fungal rhinosinusitis (IFRS). In contrast to saprophytic fungal growth, fungus balls, and AFRS, IFRS is truly a fungal infection with fungal invasion into sinonasal tissues. Most commonly reported in the fulminant form, acute IFRS occurs in patients with significant immunodeficiency or diabetic ketoacidosis. In acute fulminant cases of IFRS, work-up includes immediate CT and/or MRI imaging, otolaryngology consultation, and frozen section biopsy of sinonasal mucosa. Aspergillus species, Mucor species, and Rhizopus species are common fungal organisms identified in acute IFRS. Acute fulminant IFRS confirmed by biopsy or while highly suspected cases should be treated with urgent surgical debridement, systemic antifungal therapy, and correction of the underlying immunodeficiency or diabetic ketoacidosis, if possible. Mortality from acute fulminant IFRS has historically been high. In contrast to acute IFRS, patients with more mild immunodeficiencies may present with chronic or subacute IFRS. In cases of chronic IFRS, pathology reveals invasive fungal organisms. Treatment of chronic IFRS also consists of surgical debridement, systemic antifungal therapy, and correction of any underlying immunodeficiency (Meltzer et al. 2004).
Systemic diseases and conditions
Various systemic conditions may contribute to CRS or be found in association with CRS. A few examples are provided here. First, aspirin exacerbated respiratory disease (AERD) includes the triad of rhinosinusitis, nasal polyposis, and asthma which develops in adults (Farenholtz 2003). In individuals with AERD, aspirin and other nonsteroidal anti-inflammatory medications cause severe reactivity of the upper and lower airway, including bronchospasm and angioedema. AERD may be diagnosed by aspirin challenge, but this must be done by a trained provider with appropriate resuscitative equipment. In most cases, patient history and physical findings provide adequate information to make the diagnosis of AERD.
Systemic disorders affecting ciliary function and mucociliary clearance also contribute to the development of CRS. For example, primary ciliary dyskinesia is an autosomal recessive genetic disorder that affects the structure and function of respiratory cilia. Impaired ciliary motility in primary ciliary dyskinesia results in mucus stasis, CRS, and bronchiectasis. Cystic fibrosis is also an autosomal recessive genetic disorder that is caused by a mutation in the gene for the cystic fibrosis transmembrane conductance regulator. Abnormalities in chloride ion secretion in cystic fibrosis result in thick, tenacious respiratory mucus and impaired mucus clearance. Patients with cystic fibrosis also develop CRS, bronchiectasis, and recurrent pneumonia and have a shortened lifespan.
Humoral immunodeficiency in CRS patients with recurrent or persistent infection is common. In a 2006 study of 307 refractory CRS patients, the overall incidence of humoral immunodeficiency was 21.8%, with IgG3 deficiency representing the most common immunologic defect. IgA deficiency, IgG2 deficiency, and combined deficits were also seen (Vanlerberghe et al. 2006).
Extraesophageal reflux of gastric acid has been associated with refractory CRS. pH probe studies have detected gastric acid at the level of the nasopharynx in refractory CRS patients at a significantly higher rate than in controls (DelGaudio 2005). Wellperformed controlled studies of gastroesophageal reflux treatment on CRS outcomes have not been performed, however. In a double-blind, randomized, controlled trial of individuals with normal sinus CT and negative allergy testing, significant improvement in the complaint of postnasal drainage was seen at 8 and 16 weeks in patients treated with a proton pump inhibitor compared to placebo, and improvement was not predicted by measures of esophageal reflux or dysmotility (Vaezi et al. 2010). Thus, it seems reasonable that the symptom of postnasal drainage attributed to “sinusitis” by many patients may actually be from gastroesophageal reflux independent of sinus disease.
In this section, various theories and contributors to the pathophysiology of CRS have been discussed. As CRS is often multifactorial, many of these things may be at play simultaneously in a single patient. As knowledge of CRS continues to grow, many of these theories will be refined over time.
The treatment of rhinosinusitis frequently involves multiple different therapeutic modalities. To date, there are no medications approved for the treatment of CRS with the exception of nasal steroid sprays for CRS with nasal polyps. Therefore, all recommendations for treatment are “off label.” Even though antibiotics are approved for the treatment of ABRS, no antibiotics have been approved for this since 2006, when the FDA began to require placebo-controlled or superiority trials to obtain approval for this indication. Although surgery may be indicated in specific instances of ARS and CRS, this entry will focus on medical management strategies for rhinosinusitis.
Topical nasal saline
Some research has been performed to evaluate nasal saline irrigations in patients with ARS, and studies do suggest that normal and hypertonic saline irrigations improve mucociliary clearance in ABRS. Further, hypertonic saline irrigations improve symptoms, medication use, and quality of life in ABRS (Desrosiers et al. 2011). It is not clear whether isotonic or hypertonic saline is superior, as studies are mixed. In reality, efficacy probably varies with the patient. It is clear from randomized controlled trials that hypertonic saline nebulizations to lungs of cystic fibrosis (CF) patients are superior to isotonic, and it may well be that hypertonic nasal rinsing is superior for this subset of patients with CF or for those with thick viscous mucus.
With facial pain, pressure, or headache being frequent complaints of acute viral or bacterial rhinosinusitis, oral analgesics are recommended as one of the primary symptomatic therapies. Most often, acetaminophen or nonsteroidal anti-inflammatory medications are chosen for ARS. These are also helpful for their antipyretic effects (Rosenfeld et al. 2007a).
In the setting of viral ARS, decongestants may reestablish the patency of sinus ostia. Although both systemic and topical decongestants are used for this purpose, topical nasal decongestants are more powerful on the intranasal tissues and typically provide more symptom control. Use of topical decongestants should be limited to 72 h due to their propensity to cause rebound congestion and rhinitis medicamentosa. Oral decongestants also show benefit for rhinosinusitis symptom control, especially nasal congestion. Those choosing oral decongestants should ensure there are no medical contraindications to their use. The use of oral decongestants in CRS has not been adequately evaluated in controlled studies (Rosenfeld et al. 2007a; Desrosiers et al. 2011).
In viral rhinosinusitis, only minimal evidence supports the use of topical intranasal corticosteroids (INCS), and systemic steroid therapy is not supported by current evidence. Combined with antibiotic therapy for ABRS, INCS have been show to improve cough, nasal discharge, and overall symptom score and shorten recovery time. INCS are therefore recommended in association with antibiotic therapy in the setting of ABRS. In CRS with polyposis, INCS have been shown to decrease polyp grade and improve symptoms. Studies of INCS in nonpolypoid CRS are less clear. While decreased nasal congestion, improved nasal discharge, and improved sense of smell have been demonstrated in nonpolypoid CRS with the use of INCS in one study, this is not consistent in other studies. Given the significant inflammatory component in all types of CRS, INCS are recommended. Systemic corticosteroid use is also supported in short courses in polypoid CRS and around the time of endoscopic sinus surgery (Rosenfeld et al. 2007a; Desrosiers et al. 2011; Fokkens et al. 2007).
Guaifenesin is used as an expectorant with the purpose of loosening mucus and phlegm. A randomized controlled trial of guaifenesin in otherwise healthy subjects failed to show benefit for ARS. A controlled clinical trial evaluated guaifenesin in CRS in patients with human immunodeficiency viral infection before effective antiretrovirals were available. This did show improvement in mucociliary transport. However, studies in healthy patients have not been performed. Although mucolytics may theoretically provide some symptomatic benefit in the treatment of rhinosinusitis, their use is not supported by current available evidence (Rosenfeld et al. 2007a; Desrosiers et al. 2011).
The first-generation, sedating antihistamines possess anticholinergic properties which can dry secretions, and such antihistamines have been used for symptomatic relief of viral rhinosinusitis, without concomitant level 1 evidence. No clinical trials support the use of antihistamines in nonatopic ARS or CRS. In fact, the drying effects of antihistamines may actually worsen the symptoms of rhinosinusitis. Patients with a history of environmental allergies may benefit from the use of antihistamines to control allergy symptoms that may be coincident with rhinosinusitis, however (Rosenfeld et al. 2007a; Desrosiers et al. 2011).
Leukotriene modifiers and leukotriene receptor antagonists
Small studies have shown symptomatic benefit with leukotriene modifiers and leukotriene receptor antagonists in nasal polyp patients, especially in the setting of asthma. In addition, nasal polyp recurrence has been decreased in aspirin-sensitive patients treated with montelukast. Despite these findings, currently there is no recommendation for the use of leukotriene modifiers and leukotriene receptor antagonists in CRS, however, as larger, randomized controlled trials are still necessary before firm conclusions can be drawn (Desrosiers et al. 2011).
As stated previously, most cases of ARS are caused by viral infection. Only an extremely small proportion of ARS cases (0.5–2.0%) progress to acute bacterial rhinosinusitis (ABRS) (Gwaltney 1996). Viral rhinosinusitis is self-limited and may be treated with supportive care and symptom control; no antibiotic therapy is necessary. For this reason, it is important for the physician to appropriately differentiate viral rhinosinusitis from bacterial rhinosinusitis in the acute setting. In the first 1–4 days of ARS, this differentiation is nearly impossible. However, as the illness continues, certain clues may be helpful. First, an illness lasting less than 10 days without worsening should be considered viral. ABRS is more likely when the illness lasts beyond 10 days or worsens after initial improvement (double worsening). In addition, the three cardinal symptoms of purulent nasal drainage, nasal obstruction, and facial pain or pressure have a higher correlation with ABRS (Rosenfeld et al. 2007a).
In cases of ABRS based upon 10-day duration or double worsening, or when extrasinus complications of ABRS are identified, antibiotic therapy is indicated. It is important to adhere to these guidelines to avoid overprescribing antibiotics for rhinosinusitis, development of side effects or complications from antibiotic therapy, and perpetuation of antibiotic resistance (Pearlman and Conley 2008). Otolaryngologists have the advantage of being able to perform endoscopic culture which can aid in selection of culture-directed antibiotics or the decision to not use antibiotics.
In one ENT clinic, for example, the practice is to to obtain cultures if possible and, if the patient is quite ill, to initiate antibiotics; however, if the symptoms are not so severe, then the specialist will wait an additional 48 h for results of the culture. If the patient has improved significantly in the interim, then even with a positive culture, antibiotics are not prescribed. If the patient’s symptoms persist, then the narrowest spectrum antibiotic appropriate to cultured pathogen is chosen. If the culture is negative, then steroids or a macrolide antibiotic or both are considered for a short trial.
In the absence of culture data, amoxicillin is recommended as first-line therapy for ABRS as it is safe, moderately efficacious, inexpensive, and has a narrow microbiologic spectrum. Alternatives for penicillin- allergic patients include trimethoprimsulfamethoxazole and macrolides. Additional antibiotic options should also be considered when local antibiotic resistance patterns indicate a high incidence of amoxicillin- resistant S. pneumoniae or b-lactamase-producing M. catarrhalis and H. influenzae.
Other factors that may influence antibiotic choice in ABRS include the use of an antibiotic in the preceding 4–6 weeks and having a child in daycare. In these cases, amoxicillinclavulanate, fluoroquinolones, or high-dose amoxicillin may be considered (Rosenfeld et al. 2007a; Pearlman and Conley 2008; Desrosiers et al. 2011).
Most randomized trials have administered antibiotics for ABRS for 10 days. In order to improve compliance, the shortest effective antibiotic course with the easiest dosing schedule should be chosen. Typically, treatment courses of 5–10 days are recommended; extremely short antibiotic courses should be avoided. Patients should be advised of potential adverse events and side effects from antibiotics, as well as the importance of medication compliance. If symptom improvement does not occur within 72 h of initiating antibiotic therapy, consideration should be given to another antibiotic alternative (Rosenfeld et al. 2007a; Desrosiers et al. 2011).
Initial treatment for uncomplicated CRS without polyps typically consists of oral or topical nasal steroid therapy in conjunction with oral antibiotics. However, there is no evidence to support antibiotic use in CRS. In reality, if purulence is present, then the appropriateness of antibiotic therapy is probably higher. In addition, a culture may be obtained. In patients with polypoid CRS, treatment is primarily based on oral and topical corticosteroids, with antibiotics added when infectious symptoms or purulence is present. C
RS antibiotic selection is typically of broader spectrum, although there is no evidence for this nor is there evidence that a longer duration of therapy is efficacious, despite widespread practice of 4 weeks of a broad-spectrum antibiotic before surgery is contemplated. Recommended empiric antibiotics for CRS include amoxicillin clavulanate or fluoroquinolones. If purulent material is visible on nasal endoscopy, culture should be obtained to guide antibiotic therapy.
As with any antibiotics therapy, patients should be advised of potential side effects, adverse reactions, and the need for strict compliance with prescribed medications (Desrosiers et al. 2011). Refractory purulent sinusitis can be due to dental infection, even if the dentist finds no evidence of dental pathology. A sinus CT showing a periapical abscess is helpful in diagnosing such cases. Symptoms usually do not resolve in cases of odontogenic rhinosinusitis until the involved tooth is treated.
No well-designed, large, randomized, placebocontrolled studies of antibiotic therapy in CRS have been reported; however, the senior author is aware of one such study utilizing nebulized tobramycin in patients with prior sinus surgery and purulence which failed to show superiority over placebo and was not published. Therefore, evidence is limited, and current recommendations are based upon extrapolation from lower quality studies (Desrosiers et al. 2011).
In conclusion, many otolaryngology specialists treat every patient as a therapeutic experiment. Patients with purulence are cultured and culture-directed oral antibiotics are commonly used. In refractory CRS with purulence, topical irrigations appropriate to cultured pathogens are used. For Gram-negative bacteria, antibiotic irrigations are usually gentamicin 80 mg/ml with 20 ml douched per side. For S. aureus, mupirocin ointment is solubilized at a dose of 5 g in 45 ml of saline. In nonpurulent cases of patients with CRS symptoms, the following medications are utilized, but individually, as an experiment.
The patient is instructed to try each medication individually. If no improvement in symptoms is noted, after a few days, they are instructed to stop the medication and try the next medication listed. If any medication is somewhat helpful, they can continue that medication and add the next medication on their list to the trial. Thus, each patient’s therapy is individualized and symptom relief directs continuation or cessation of the medication.
The medications commonly utilized in this “rational patient experiment” include the following: antihistamine nasal sprays, nasal steroid sprays, saline douching prior to application of sprays, adequate hydration, montelukast, culture-directed topical or oral antibiotics in patients with purulence, control of acid reflux disease, and mucolytics. Additional medications utilized in refractory patients, such as omaluzumab and zileuton, are beyond the scope of this discussion on therapy of the usual patient with ARS and CRS.
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